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J. Chem. Soc. Perkin Trans. 1 1997 577 Palladium-catalysed enantiodivergent synthesis of cis- and trans-4-aminocyclohex-2-enols Roberto G. P. Gatti Anna L. E. Larsson and Jan-E. Bäckvall * Department of Organic Chemistry University of Uppsala Box 531 S-751 21 Uppsala Sweden Enantiomerically pure cis- and trans-4-aminocyclohex-2-enols are prepared from cyclohexa-1,3-diene via (2)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a using palladium(0) chemistry. Benzylamine and diethylamine are tested in the Pd0-catalysed allylic amination reactions. Since acetate is too slow as a leaving group and gave considerable amounts of side products a number of leaving groups have been investigated. Of these phosphinate and 2,4-dichlorobenzoate are excellent leaving groups and result in efficient and highly stereoselective reactions; chloride as allylic leaving group also gives good results.By variation of the leaving group and proper choice of the protecting group it is possible to synthesise all four stereoisomers of 4-aminocyclohex-2-enol in good yield and high enantiomeric excess. Introduction 4-Aminocyclohex-2-enols are important structural elements in a number of biologically active compounds such as conduramines 1 and derivatives.2 In connection with a project dealing with new substances for treatment of bronchitis complications there was a need for a general synthesis of optically pure 4- aminocyclohex-2-enols. We recently reported a method for an enantiodivergent synthesis of 4-substituted 2-cycloalkenols from cycloalka-1,3- dienes with a combination of palladium and enzyme chemistry (Scheme 1).3 The method allows for preparation of both enantiomers with high selectivity.In the present paper we have used enantiomerically pure (2)- cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a as a key intermediate for further stereocontrolled palladium(0)-catalysed functionalisation and report on the enantiocontrolled synthesis of all four stereoisomers of 4-aminocyclohex-2-enol (Scheme 2). An interesting observation is that phosphinates are excellent leaving groups in the Pd0-catalysed allylic substitution with primary and secondary amines. Scheme 1 Results and discussion (A) Racemates The objective was to synthesise cis- and trans-4-aminocyclohex- 2-enols in optically pure form starting from (2)-2a.4 Diethylamine and benzylamine (BnNH2) were employed as representative amines in the palladium(0)-catalysed allylic aminations.First the allylic amination was performed to produce a racemic mixture of the amino alcohols (Scheme 3). Thus cis-4- diethylaminocyclohex-2-enol 6a and cis-4-benzylaminocyclohex- 2-enol 6b were prepared starting from cis-1-acetoxy-4- chlorocyclohex-2-ene 8.5 The racemic trans stereoisomers were synthesised from (±)- 2a.6 Substitution of the OH by chloride with PPh3 and Nchlorosuccinimide (NCS)7 in THF afforded trans-1-acetoxy-4- chlorocyclohex-2-ene 9. Pd0-catalysed allylic amination of chloroacetate 9 with diethylamine or benzylamine gave after hydrolysis trans-4-diethylaminocyclohex-2-enol 7a or trans-4- benzylaminocyclohex-2-enol 7b respectively. Amino alcohols 6 and 7 were used to set up a method for determination of the ee.However with 9 as the allylic substrate a moderate regioselectivity was observed. Using conditions A in Scheme 3 and diethylamine as the nucleophile about 20% of the g-substitution product (of trans stereochemistry) was obtained. Usually Scheme 2 578 J. Chem. Soc. Perkin Trans. 1 1997 attack at the 4-position relative to the acetate is strongly favoured in analogous 1,4-disubstituted alk-2-enes.5 However due to steric interaction between the acetate and the L2Pdgroup in p-allyl intermediate I (Fig. 1) palladium is forced away from the acetate which weakens the palladium–carbon bond in the 2-position.8 This will increase the relative rate of attack at the 2-position in I. When R is tert-butyl II the relative amount of attack in the 2-position increased to 50–60% in the corresponding reaction (vide infra).The reaction conditions were further investigated by variation of the solvent amount of catalyst and ligand and by addition of salt (LiCl). The system with Pd(dba)2 and PPh3 in THF with an addition of 25 mol% LiCl decreased the amount of g-product of I from 20 to 13% with Et2NH and from 12 to 5% with BnNH2. (B) cis Enantiomers It has been shown that acetate can be used as a leaving group in Pd0-catalysed allylic amination with both primary and secondary amines.9 However when (±)-2a was treated with benzylamine in the presence of Pd(dba)2 PPh3 and Et3N in THF the conversion was low. In an attempt to improve the reaction different catalysts ligands and solvents were tried together with variation of the concentration and temperature. The best results were obtained with acetonitrile as the solvent at a reaction temperature of 40 8C.However the yield of the desired product 6 was still unsatisfactory with considerable amounts of g-product as well as inversion and elimination products.† Therefore better leaving groups were called for. To increase the reactivity in the Pd0-catalysed nucleophilic displacement the hydroxy group in 2a was transformed into a reactive leaving group. It has been reported in the literature that ethyl and methyl carbonate can be used as a leaving group in Pd0- Scheme 3 Reagents and conditions A 5% Pd(dba)2 15% PPh3 1.2–3 equiv. NHR1R2 3 equiv. Et3N in THF RT N2 or Ar atm 10a (77%) 10b (81%); B K2CO3 in MeOH–H2O at RT 6a (95%) 6b (98%) 7a (96%) 7b (98%); C NCS PPh3 THF RT (97%); D reagents as for A but longer reaction times and 25% LiCl added to the reaction mixture 11a (71%) 11b (76%) Fig.1 Weaker bond in the 2-position because of steric interactions which increase the relative amount of g-substitution product † Loss of regio- and stereo-selectivity has previously been observed in Pd-catalysed reaction of allylic acetates with amines.9b,g catalysed allylic amination 10 but carbonate 12 gave the nondesired carbamate 13 on reaction with benzylamine [eqn. (1)].‡ The same results for similar substrates have been reported earlier in our laboratory 11 and elsewhere.12 The use of trifluoroacetate 14 in the corresponding reaction gave 2a and Nbenzyltrifluoroacetamide presumably because of faster nitrogen attack at the carbonyl carbon rather than formation of the p-allyl complex. Attempts to use a diethylphosphate ester 9d,e as the leaving group failed since 15 was very sensitive and hydrolysed quickly after preparation.We next tried diphenylphosphinic and benzoate esters. Diphenylphosphinic ester 16 was prepared from enantiomerically pure (2)-2a (89%) according to Liebeskind et al.13 and 2,4- dichlorobenzoate ester 17 was prepared (80% yield) by esterifi- cation of (2)-2a following the method of Hassner.14 Both 16 and 17 were excellent substrates in the Pd0-catalysed allylic amination with diethylamine and benzylamine and afforded the amino acetates (1S,4R)-10a and (1S,4R)-10b which upon hydrolysis yielded the amino alcohols (1S,4R)-6a and (1S,4R)- 6b respectively (Scheme 4). In each case the allylic amination was highly stereoselective and the enantiomeric excess (ee) of the amino alcohols was �98% in both cases.For (1S,4R)-6a 2% of the trans isomer was observed. An explanation could be isomerisation of the p-allyl intermediate by nucleophilic attack by free Pd0 on the allyl ligand.15 To form a carbon–nitrogen bond at the other allylic carbon in (2)-2a it was necessary to protect the hydroxy group and then selectively hydrolyse the acetate before attachment of a leaving group (Scheme 5). The hydroxy acetate (2)-2a was transformed into the alcohol 18a with tetrahydropyran (THP) protection 16 and subsequent hydrolysis of the acetoxy group. The alcohol 18a was transformed into its 2,4-dichlorobenzoate ester 19 (vide supra) which on Pd0-catalysed amination and subsequent removal of the THP group afforded (1R,4S)-6a and (1R,4S)-6b. Scheme 4 Reagents and conditions A 5% Pd(dba)2 15% PPh3 1.2–3 equiv.NHR1R2 3 equiv. Et3N in THF at RT N2 or Ar atm 16 to 10a (82%) 16 to 10b (79%) 17 to 10a (73%) 17 to 10b (70%); B K2CO3 in MeOH–H2O at Ryields as for step B shown in Scheme 3 ‡ The reaction proceeds via a (p-allyl)palladium intermediate.11 J. Chem. Soc. Perkin Trans. 1 1997 579 (C) trans Enantiomers Reaction of the enantiomerically pure hydroxy acetate (2)-2a with NCS and PPh3 in THF afforded optically active (1S,4S)-9 with high stereospecificity (cf. racemic reaction Scheme 3). Subsequent Pd0-catalysed allylic amination employing Et2NH and BnNH2 followed by hydrolysis gave (1S,4S)-7a and (1S,4S)-7b respectively [eqn. (2)]. The yields were the same as for the racemates (Scheme 3) and the ee was in each case � 98%. When preparing the other trans enantiomer the group at the other stereogenic carbon had to be substituted.Some difficulties were encountered when solving this problem. Substitution of the hydroxy group in 18a by chloride with inversion using LiCl methanesulfonyl chloride (MsCl) 2,4,6-trimethylpyridine in DMF and subsequent Pd0-catalysed allylic amination of the allylic chloride 20a should in analogy to the preparation of (1S,4S)-7 from (1S,4S)-9 give (1R,4R)-7 after removal of the protecting group. Unfortunately and to a much greater extent than what had been seen for 9 the predominant product was the g-substitution product (vide supra). Using pivalate § as protecting group instead of THP led to the same discouraging result (Scheme 6). For example with the pivalate 20b the amount of g-substitution product was 50–60% with diethylamine.This result supports the explanation suggested in Fig. 1 for the increased relative amount of g-isomer. The use of tert-butyldimethylsilyl (TBDMS)¶ led to decomposition of the silyl ether bond in the amination. Another way to reach the other trans enantiomer (1R,4R)-7 would be by a Mitsunobu reaction 18 of 6. However reaction of 6b under Mitsunobu conditions failed even when the amine was protected with tertbutoxycarbonyl (TBOC).|| To solve the problem of obtaining the trans-(1R,4R)- enantiomer of the amino alcohol we prepared (1R,4R)-9 as Scheme 5 Reagents and conditions A i DHP PPTS in CH2Cl2 at RT (98%); ii 20% K2CO3 in MeOH–H2O at RT (86%); B 2,4- dichlorobenzoic acid DCC DMAP in CH2Cl2 at RT (87%); C i 5% Pd(dba)2 15% PPh3 1.2–3 equiv.NHR1R2 3 equiv. Et3N in THF at RT N2 or Ar atm; ii p-TsOH MeOH RT 6a 55% yield in two steps 6b 65% yield in two steps § Prepared by selective hydrolysis of the acetate (Na2CO3 MeOH RT)17 in (±)-cis-1-acetoxy-4-pivaloyloxycyclohex-2-ene. The latter was obtained from esterification of (±)-2a. ¶ For an experimental procedure see preparation of 20c in the Experimental section. || The protection was done by mixing the aminoacetate with (BOC)2O Et3N and catalytic amounts DMAP in methylene dichloride. Before the Mitsunobu reaction the acetate was hydrolysed. described in Scheme 7. Silylation of (2)-2a with TBDMS-Cl gave cis-(1S,4R)-1-acetoxy-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene 21c. This compound was converted into (1R,4R)-9 in the following way hydrolysis of the acetate in 21c and stereospecific substitution of the hydroxy group by chloride with inversion of configuration using MsCl LiCl and Et3N in methylene dichloride gave trans-(1R,4R)-1-chloro-4-(tert-butyldimethylsilyloxy) cyclohex-2-ene 20c.Deprotection of TBDMS with tetrabutylammonium fluoride (TBAF) followed by quenching with acetic anhydride gave (1R,4R)-9 (83%). Transformation of (1R,4R)-9 into (1R,4R)-7a and (1R,4R)-7b was done as shown in eqn. (2) and the ee obtained was �98%.19 Conclusion All four stereoisomers of biologically interesting 4-aminocyclohex- 2-enols have been prepared in enantiomerically pure form by palladium(0)-catalysed reactions from the same starting material (2)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a. Experimental 1H and 13C NMR spectra were recorded for CDCl3 solutions at 300 or 400 and 75.4 or 100.6 MHz respectively.19F NMR spectra were recorded for CDCl3 solutions at 376.3 MHz. Chemical shifts are reported in ppm with CDCl3 as internal standard (7.26 for 1H and 77.00 ppm for 13C) and coupling constants (J) are given in Hz. Assignment of 13C was done with HETCOR and COSY experiments. Mass spectra were recorded on a Scheme 6 Scheme 7 Reagents and conditions A TBDMS-Cl imidazole CH2Cl2 0 8C to RT (99%); B i 20% KOH in MeOH at RT (98%); ii MsCl LiCl Et3N in CH2Cl2 220 8C to RT (91%); C i TBAF in THF at RT; ii Ac2O (83%); D i 5% Pd(dba)2 15% PPh3 25% LiCl 1.2–3 equiv. NHR1R2 0–3 equiv. Et3N in THF at RT; ii K2CO3 in MeOH–H2O at RT yields as in Scheme 3 580 J. Chem. Soc. Perkin Trans. 1 1997 Finnigan MAT INCOS 50 or a Hewlett Packard 5971 series instrument at 70 eV.Where indicated mass spectra were recorded with pneumatically assisted electrospray mass spectrometry (ES-MS) on a Micromass VG Platform apparatus using direct inlet of a solution in acetonitrile or with an LCcolumn (Kromasil 100 × 4.6 mm acetonitrile–water gradient with 5 mM formic acid). Optical rotations recorded in units of 1021 deg cm2 g21 measured at 25.0 8C on a Perkin–Elmer 241 polarimeter and concentrations are expressed as g 100 ml21 in spectroscopically pure ethanol or methylene dichloride. Elemental analyses were performed by Analytische Laboratorien Engelskirchen Germany. Bis(dibenzylideneacetone)- palladium(0) [Pd(dba)2] was prepared according to a literature procedure.20 THF was distilled under nitrogen from sodium benzophenone ketyl.Pyridine and methylene dichloride were distilled under nitrogen from calcium hydride. Benzylamine diethylamine and triethylamine were distilled from KOH and stored over KOH under nitrogen until used. Thin-layer chromatography (TLC) was run on Merck pre-coated silica gel 60-F254 plates. All reactions were carried out in oven-dried glassware and the Pd0-catalysed reactions also under an argon or nitrogen atmosphere unless otherwise stated. Progress of reaction was followed by TLC until judged complete for all reactions. For flash chromatography Merck Kieselgel 60 (230–400 mesh) was used. Enantiomeric excess (ee) was checked with 1H and 19F NMR in CDCl3 by Mosher esterification 21 for the diethylaminocyclohex-2-enols and by salt formation with optically pure (S)-mandelic acid,22 for the 4-benzylaminocyclohex- 2-enols.General procedure for the Pd0-catalysed aminations exemplified by the synthesis of (±)-cis-1-acetoxy-4-benzylaminocyclohex-2- ene 10b To a solution that had been stirred at room temperature (RT) for 20 min containing Pd(dba)2 (172 mg 0.29 mmol) PPh3 (225 mg 0.86 mmol) BnNH2 (737 mg 6.87 mmol) and Et3N (1.74 g 17.18 mmol) in THF (30 ml) was added the cis-chloro acetate 8 (1.00 g 5.73 mmol) in THF (10 ml). The reaction mixture was stirred at RT for 8 h and then evaporated. The residue was dissolved in diethyl ether (20 ml) and extracted with 1 M aq. HCl (3 × 50 ml). The aqueous phase was charged with fresh ether (80 ml) and the pH was adjusted to >10 with K2CO3 and KOH followed by two more extractions with ether (50 ml). The combined ether extracts were dried (K2CO3) and concentrated.The crude product was purified on silica (ethyl acetate– pentane gradient) to give 10b (1.14 g 81%). The silica was first conditioned with 2% Et3N in pentane (Found for the HCl-salt C 63.9; H 7.05. Calc. for C15H20ClNO2 C 63.9; H 7.15%); dH(400 MHz; CDCl3) 1.3–1.5 (1 H br s NH) 1.58–1.71 (1 H m CH2) 1.73–1.84 (1 H m CH2) 1.84–1.93 (2 H m CH2) 2.04 (3 H s COCH3) 3.14–3.21 (1 H m CHNHBn) 3.85 3.88 (2 H AB-system JAB 13.1 PhCH2) 5.13–5.25 (1 H m CHOAc) 5.79 (1 H ddd J 10.0 3.5 and 1.7 olefinic) 6.00 (1 H dd J 10.1 and 2.7 olefinic) and 7.21–7.37 (5 H m Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.3 (COCH3) 25.3 (CH2CHOAc) 26.1 (CH2CHN) 51.0 (CH2Ph) 52.3 (CHN) 67.2 (CHOAc) 126.3 (CH Ph) 126.9 (olefinic CHCHOAc) 128.1 (CH Ph) 128.4 (CH Ph) 135.4 (olefinic CHCHN) 140.3 (C Ph) and 170.7 (C]] O).(A) Synthesis of the cis-4-aminocyclohex-2-enols (±)-cis-1-Acetoxy-4-diethylaminocyclohex-2-ene 10a. The synthesis was carried out according to the general procedure above. Amounts used were allylic substrate 8 (300 mg 1.718 mmol) Pd(d (51 mg 0.086 mmol) PPh3 (68 mg 0.258 mmol) Et2NH (151 mg 2.06 mmol) Et3N (521 mg 5.15 mmol) and THF (10 ml); reaction time 16 h; yield 280 mg 77%; dH(300 MHz; CDCl3) 1.04 (6 H app t J 7.2 CH3) 1.41–1.61 (2 H m CH2) 1.81–1.91 (1 H m CH2) 2.04 (3 H s COCH3) 2.11– 2.20 (1 H m CH2) 2.34–2.61 (4 H m NCH2) 3.40–3.53 (1 H m CHNEt2) 5.26–5.38 (1 H m CHOAc) 5.64–5.73 (1 H m olefinic) and 5.67–5.85 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.4 (NCH2CH3) 21.3 (CH3CO2) 22.3 (CH2CHN) 28.3 (CH2CHOAc) 44.1 (NCH2) 56.4 (CHN) 70.2 (CHOAc) 129.2 (olefinic CHCHN) 134.8 (olefinic CHCHOAc) and 170.8 (C]] O).cis-(1S,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1S,4R)-10a. The synthesis was carried out according to the general procedure. Amounts used were allylic substrate 16 (616 mg 1.718 mmol) Pd(dba)2 (51 mg 0.086 mmol) PPh3 (68 mg 0.258 mmol) Et2NH (151 mg 2.06 mmol) Et3N (521 mg 5.15 mmol) and THF (20 ml); reaction time 2 h; yield 298 mg 82%. Allylic substrate 17 (485 mg 1.473 mmol) Pd(dba)2 (44 mg 0.074 mmol) PPh3 (58 mg 0.221 mmol) Et2NH (183 mg 2.50 mmol) Et3N (447 mg 4.42 mmol) and THF (20 ml); reaction time 6 h; yield 228 mg 73%. Spectral data are in accordance with the racemate. (±)-cis-4-Diethylaminocyclohex-2-enol 6a. The amino acetate 10a (250 mg 1.19 mmol) was dissolved in a stirred solution of K2CO3 (9 mg 0.06 mmol) in MeOH–H2O (4 1; 10 ml) at RT.After 5 h the mixture was evaporated diluted with diethyl ether (100 ml) washed with water (10 ml) and brine (10 ml) dried (K2CO3) and evaporated. Purification of the residue on silica (gradient of diethyl ether–pentane 60 40 to ethyl acetate– MeOH 90 10) gave the title compound 6a (191 mg 95%) (Found for the HCl-salt C 58.3; H 9.7. Calc. for C10H20ClNO C 58.4; H 9.8%); dH(300 MHz; CDCl3) 1.04 (6 H app t CH3) 1.56–1.71 (3 H m 6-H and 5-H) 1.79–1.89 (1 H m 5-H) 1.96–2.14 (1 H br s OH) 2.38–2.65 (4 H m CH2) 3.26–3.33 (1 H m 1-H) 4.07–4.12 (1 H m 4-H) and 5.79–5.91 (2 H m 5-H and 6-H); dC(75.4 MHz; CDCl3 8 peaks) 14.2 (CH3) 17.9 (CH2) 30.2 (CH2) 44.2 (NCH2) 56.7 (CHNEt2) 63.4 (CHOAc) 130.2 (CH olefinic) 135.4 (CH olefinic); nmax/cm21 3346 (OH br) 2967 2937 2871 1386 and 1066.(2)-cis-(1S,4R)-4-Diethylaminocyclohex-2-enol (2)-(1S,4R)- 6a. Starting from (1S,4R)-10a and applying the same conditions as for the preparation of (±)-6a yielded (2)-6a. Spectral data are in accordance with (±)-6a; [a]D 25 270 (c 1.91 in EtOH); ee �98%. (+)-cis-(1R,4S)-4-Diethylaminocyclohex-2-enol (+)-(1R,4S)- 6a. See general procedure according to 10b. Allylic substrate 19 (802 mg 2.16 mmol) Pd(dba)2 (64 mg 0.108 mmol) PPh3 (85 mg 0.324 mmol) Et2NH (174 mg 2.38 mmol) Et3N (656 mg 6.48 mmol) and THF (25 ml) for 15 h yielded cis-(1R,4S)-4- diethylamino-1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (373 mg 68%). The THP group in the latter product (299 mg 1.18 mmol) was removed with toluene-p-sulfonic acid (190 mg 1.00 mmol) in MeOH (5 ml) at RT.After 12 h the mixture was evaporated and treated with diethyl ether (100 ml) and 1 M NaOH (10 ml). After extraction the organic phase was washed with water (10 ml) and brine (10 ml) dried (MgSO4) and evaporated. Purification of the residue on silica (gradient of diethyl ether–pentane 60 40 to ethyl acetate–MeOH 90 10) gave the title compound (+)-(1R,4S)-6a (161 mg 81%; totally 55% in two steps). Same spectral data as for (±)-6a; [a]D 25 +66 (c 1.70 in EtOH); ee �98%. (±)-cis-1-Acetoxy-4-benzylaminocyclohex-2-ene 10b. This compound is described above under the general procedure. cis-(1S,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4R)- 10b. See general procedure for (±)-10b. Pd(PPh3)4 (87 mg 0.075 mmol) was used instead of Pd(dba)2 for the allylic substrate 16 (539 mg 1.504 mmol); amounts of reactants used were PPh3 (20 mg 0.076 mmol) BnNH2 (161 mg 1.503 mmol) Et3N (340 mg 3.36 mmol) and THF (17 ml); reaction time 2 h; yield 292 mg 79%.For the allylic substrate 17 (311 mg 0.95 mmol) the following amounts were used Pd(dba)2 (28 mg 0.047 mmol) PPh3 (38 mg 0.142 mmol) BnNH2 (311 mg 2.83 mmol) and THF (17 ml); reaction time 2 h; yield 163 mg 70%. Spectral data were in accordance with those of racemic 10b. (±)-cis-4-Benzylaminocyclohex-2-enol 6b. Prepared from amino acetate 10b using the same hydrolysis conditions as for J. Chem. Soc. Perkin Trans. 1 1997 581 the preparation of 6a in 98% yield; dH(400 MHz; CDCl3) 1.56– 1.88 (6 H m 2 × CH2 OH NH) 3.09–3.21 (1 H m CHNHBn) 3.83 3.87 (2 H AB-system JAB 13.0 PhCH2NH) 4.09– 4.18 (1 H m CHOH) 5.81–5.89 (2 H m olefinic) and 7.22– 7.34 (5 H m Ph); dC(100.6 MHz; CDCl3 11 peaks) 24.9 (CH2) 29.1 (CH2) 51.1 (CH2Ph) 52.3 (CHN) 64.7 (CHOH) 127.0 (CH Ph) 128.1 (CH Ph) 128.4 (CH Ph) 130.7 (CH olefinic) 133.1 (CH olefinic) and 140.3 (C Ph).(2)-cis-(1S,4R)-4-Benzylaminocyclohex-2-enol (2)-(1S,4R)- 6b. This compound was prepared as above for 6b but starting with (1S,4R)-10b. Spectral data are as for (±)-6b; [a]D 25 24.3 (c 0.845 in EtOH); ee �98%. (+)-cis-(1R,4S)-4-Benzylaminocyclohex-2-enol (+)-(1R,4S)- 6b. See general procedure for 10b. Allylic substrate 19 (557 mg 1.50 mmol) Pd(dba)2 (45 mg 0.075 mmol) PPh3 (50 mg 0.188 mmol) BnNH2 (160 mg 1.50 mmol) Et3N (340 mg 3.36 mmol) in THF (12 ml) for 20 h gave cis-(1R,4S)-4-benzylamino- 1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (426 mg 94%).The THP group was removed according to the preparation of (+)-(1R,4S)-6a in 69% yield (65% in two steps); spectral data as for (±)-6b; [a]D 25 +4.2 (c 1.79 in EtOH); ee �98%. (B) Synthesis of the trans-4-aminocyclohex-2-enols (±)-trans-1-Acetoxy-4-diethylaminocyclohex-2-ene 11a. The general procedure described for 10b was used but 25 mol% of LiCl was added to the reaction mixture together with the catalyst phosphine and amine. Allylic substrate 9 (131 mg 0.750 mmol) Pd(dba)2 (22 mg 0.037 mmol) PPh3 (40 mg 0.153 mmol) LiCl (8 mg 0.189 mmol) HNEt2 (165 mg 2.26 mmol) in THF (7.5 ml) for 20 h yielded 11a (113 mg 71%); dH(300 MHz; CDCl3) 1.04 (6 H app t J 7.2 CH3) 1.41–1.61 (2 H m CH2) 1.81–1.91 (1 H m CH2) 2.04 (3 H s COCH3) 2.11–2.20 (1 H m CH2) 2.34–2.61 (4 H m NCH2) 3.40–3.53 (1 H m CHNEt2) 5.26–5.38 (1 H m CHOAc) 5.64–5.73 (1 H m olefinic) and 5.76–5.85 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.2 (NCH2CH3) 21.2 (CH3CO2) 22.3 (CH2CHN) 28.2 (CH2CHOAc) 44.1 (NCH2) 56.4 (CHN) 70.1 (CHOAc) 129.2 (olefinic CHCHN) 134.8 (olefinic CHCHOAc) and 170.8 (C]] O); m/z (LC prior to ES-MS) 212 ([M + H]+ 82%) 139 (66%) 79 (7%) 61 (13%) and 60 (100%).Spectroscopic data for the corresponding g-product to 11a. (±)-trans-4-Acetoxy-3-diethylaminocyclohexene; dH(400 MHz; CDCl3) 1.01 (6 H app t J 7.1 CH3) 1.56–1.75 (2 H m CH2) 1.86–1.96 (1 H m CH2) 2.04 (3 H s COCH3) 2.07–2.20 (1 H m CH2) 2.53 (4 H app q NCH2) 3.36–3.43 (1 H m CHNEt2) 5.00 (1 H ddd J 11.1 7.7 3.6 CHOAc) 5.53–5.60 (1 H m olefinic) and 5.74–5.82 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.5 21.5 24.0 27.6 44.4 60.4 70.9 127.7 128.9 and 170.6.trans-(1S,4S)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1S,4S)-11a. The same procedure was used as for racemic 11a but starting from (2)-9. Spectral data are in accordance with the racemate. trans-(1R,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1R,4R)-11a. The same procedure was used as for racemic 11a but starting from (+)-9. Spectral data are in accordance with the racemate. (±)-trans-4-Diethylaminocyclohex-2-enol 7a. This substance was prepared from amino acetate 11a using the same hydrolysis conditions as for 6a in 96% yield; dH(300 MHz; CDCl3) 1.01 (6 H app t CH3) 1.32–1.53 (2 H m 6-H) 1.76–1.89 (1 H m 5-H) 2.06–2.18 (1 H m 5-H) 2.31–2.59 (4 H m NCH2) 2.60– 2.80 (1 H br s OH) 3.37–3.47 (1 H m 1-H) 4.16–4.28 (1 H m 4-H) and 5.63–5.79 (2 H m 5-H and 6-H); dC(100.6 MHz; CDCl3 8 peaks) 14.1 (CH3) 22.4 (CH2) 32.5 (CH2) 44.1 (NCH2) 56.6 (CHNEt2) 67.3 (CHOAc) 132.4 (CH olefinic) 133.6 (CH olefinic); m/z (LC prioMS) 170 ([M + H]+ 100%); nmax/cm21 3331 (OH br) 2968 2935 2864 1451 1384 and 1065.(2)-trans-(1S,4S)-4-Diethylaminocyclohex-2-enol (2)- (1S,4S)-7a. Preparation as for (±)-7a but with (1S,4S)-11a as the substrate. Same spectral data as for (±)-7a; [a]D 25 2102 (c 1.165 in EtOH); ee �98%. (+)-trans-(1R,4R)-4-Diethylaminocyclohex-2-enol (+)- (1R,4R)-7a. Preparation as for (±)-7a but with (1R,4R)-11a as the substrate. Same spectral data as for (±)-7a; [a]D 25 +98 (c 0.600 in EtOH). (±)-trans-1-Acetoxy-4-benzylaminocyclohex-2-ene 11b. The general procedure described for 10b was used but 25 mol% of LiCl was added to the reaction mixture together with the catalyst phosphine and amine.Amounts used were trans-chloro acetate 9 (720 mg 4.13 mmol) Pd(dba)2 (124 mg 0.21 mmol) PPh3 (162 mg 0.62 mmol) LiCl (44 mg 1.03 mmol) BnNH2 (531 mg 4.95 mmol) and Et3N (1.25 g 12.37 mmol) in THF (36 ml). The reaction mixture was stirred at RT for 20 h to give on work-up the amino acetate 11b (770 mg 76%); dH(400 MHz; CDCl3) 1.45–1.64 (2 H m CH2) 1.99–2.19 (2 H m CH2) 2.04 (3 H s COCH3) 2.58 (1 H br s NH) 3.27–3.33 (1 H m CHNHBn) 3.83 3.86 (2 H AB-system JAB 13.2 PhCH2NH) 5.28–5.34 (1 H m CHOAc) 5.72 (1 H dddd J 10.4 3.2 2.0 1.2 olefinic CHCHOAc) 5.93 (1 H dddd J 10.4 2.8 1.6 1.2 olefinic CHCHN) and 7.20–7.45 (5 H m Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.2 (COCH3) 26.9 (CH2CHOAc) 27.3 (CH2CHN) 50.6 (CH2Ph) 52.2 (CHN) 69.1 (CHOAc) 127.0 (CH Ph) 127.9 (olefinic CHCHOAc) 128.1 (CH Ph) 128.4 (CH Ph) 133.8 (olefinic CHCHN) 139.8 (C Ph) and 170.6 (C]] O); m/z (LC prior to ES-MS) 246 ([M + H]+ 100%) 139 (54%) 108 (3%) 79 (5%) and 61 (6%).Spectroscopic data for the corresponding g-product to 11b (±)-trans-4-acetoxy-3-benzylaminocyclohexene; dH(400 MHz; CDCl3) 1.65–2.05 (3 H br s and two m overlapping CH2 NH) 2.10–2.19 (2 H m CH2) 3.25–3.33 (1 H m CHNH) 3.83 3.88 (2 H AB-system JAB 13.3 PhCH2NH) 4.99 (1 H ddd J 8.9 6.3 and 3.1 CHOAc) 5.62–5.69 (1 H m olefinic) 5.76–5.84 (1 H m olefinic) and 7.18–7.38 (5 H m aromatic); dC(100.6 MHz; CDCl3 13 peaks) 21.4 23.2 25.2 50.5 56.5 72.6 126.9 127.1 128.1 128.3 128.8 140.6 and 170.8. trans-(1S,4S)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4S)-11b. The same procedure was used as for racemic 11b but starting from (2)-9.Spectral data are in accordance with the racemate. trans-(1R,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1R,4R)-11b. The same procedure was used as for racemic 11b but starting from (+)-9. Spectral data are in accordance with the racemate. (±)-trans-4-Benzylaminocyclohex-2-enol 7b. The title compound was prepared from amino acetate 11b using the same hydrolysis conditions as for 6a in 98% yield; dH(400 MHz; CDCl3) 1.36–1.51 (2 H m CH2) 1.57–1.68 (2 H br s NH and OH) 2.03–2.15 (2 H m CH2) 3.24–3.28 (1 H m CHNH) 3.82 3.85 (2 H AB-system JAB 13.0 PhCH2NH) 4.23–4.26 (1 H m CHOH) 5.75–5.83 (2 H m olefinic) and 7.22–7.34 (5 H m Ph); dC(100.6 MHz; CDCl3 11 peaks) 27.9 (CH2) 31.2 (CH2) 50.8 (CH2Ph) 52.7 (CHN) 66.8 (CHOH) 127.1 (CH Ph) 128.2 (CH Ph) 128.5 (CH Ph) 132.0 (CH olefinic) 132.1 (CH olefinic) and 140.1 (C Ph).(2)-trans-(1S,4S)-4-Benzylaminocyclohex-2-enol (2)- (1S,4S)-7b. Preparation as for (±)-7b but with (1S,4S)-11b as the substrate. Same spectral data as for (±)-7b; [a]D 25 2122 (c 1.773 in EtOH); ee �98%. (+)-trans-(1R,4R)-4-Benzylaminocyclohex-2-enol (+)- (1R,4R)-7b. Preparation as for (±)-7b but with (1R,4R)-11b as the substrate. Same spectral data as for (±)-7b; [a]D 25 +120 (c 1.394 in EtOH); ee �98%. (C) Synthesis of the allylic substrates (±)-cis-4-Acetoxycyclohex-2-enol (±)-2a. 1,4-Diacetoxycyclohex- 2-ene 6 (17.39 g 87.72 mmol) and K2CO3 (606 mg 4.39 mmol) were dissolved in methanol–water (4 1; 150 ml) and the 582 J. Chem. Soc. Perkin Trans. 1 1997 solution stirred at RT for 40 min.It was then neutralised with 1 M aq. HCl and the methanol was removed in vacuo. The aqueous phase was saturated with NaCl and extracted with EtOAc and the extract was dried (MgSO4) and concentrated. The residue was separated on silica (gradient EtOAc–pentane) to give 2a (8.118 g 59%). The spectral data were consistent with those previously reported.4 (2)-cis-(1R,4S)-4-Acetoxycyclohex-2-enol (2)-(1R,4S)-2a. Preparation according to ref. 4. cis-1-Acetoxy-4-chlorocyclohex-2-ene 8. The preparation was carried out as in ref. 5 and the spectral data were in accord with those reported therein. (±)-trans-1-Acetoxy-4-chlorocyclohex-2-ene 9. To N-chlorosuccinimide (806 mg 6.04 mmol) in THF (7 ml) under nitrogen was added a solution of PPh3 (1.575 g 6.01 mmol) in THF (7 ml). A slightly exothermic reaction ensued.After the reaction mixture had cooled to room temperature the alcohol 2a (632 mg 4.047 mmol) dissolved in THF (6 ml) was added to it; the mixture was then stirred at room temperature for 15 h. The solvent was removed and the residue was dissolved in a small amount of CH2Cl2 and purified on silica (diethyl ether–pentane 5 95) to give the title compound 9 (684 mg 97%). About 4% of the corresponding SN29-product was formed in the reaction. Spectral data for 9 were in accord with those reported in ref. 5. (2)-trans-(1S,4S)-1-Acetoxy-4-chlorocyclohex-2-ene (2)- (1S,4S)-9. This compound was prepared in the same way as for the racemic compound 9 starting from (2)-2a. [a]D 25 2395 (c 1.01 in EtOH); 2.5% of the SN29-product contaminated the product. (+)-trans-(1R,4R)-1-Acetoxy-4-chlorocyclohex-2-ene (+)- (1R,4R)-9.To a solution of compound 20c (594 mg 2.406 mmol) in THF (15 ml) was added tetrabutylammonium fluoride (TBAF) (1 M soln. in THF 2.53 ml 2.53 mmol) at room temperature. After 3 h acetic anhydride (2.3 ml 24.4 mmol) was added to the reaction mixture which was then stirred for an additional 12 h. It was then evaporated and the residue was separated on silica (gradient ether–pentane 5 95–15 85) to give the title compound (+)-9 (347 mg 83%). Spectral data were in accord with those reported in ref. 5; [a]D 25 +415 (c 0.89 in EtOH). cis-(1R,4S)-4-Acetoxycyclohex-2-enyl diphenylphosphinate (1R,4S)-16. The title compound was synthesized from the alcohol (2)-2a (1.00 g 6.32 mmol) according to procedure A reported in ref. 14 (reaction time 30 h) except that in the aqueous work-up the organic extract was washed with saturated copper sulfate (3×) water (1×) and brine (1×) before being dried (MgSO4).After evaporation of the extract the crude product was filtered through basic alumina eluting with diethyl ether. Removal of the ether afforded a colourless oil of the title compound 16 (2.02 g 89%) which was sufficiently pure for the next step; dH(400 MHz; CDCl3) 1.80–1.94 (3 H m CH2) 2.01– 2.06 (1 H m CH2) 2.06 (3 H s COCH3) 4.84–4.91 [1 H m CHOP(O)Ph2] 5.15–5.20 (1 H m CHOAc) 5.83–5.96 (2 H m olefinic) 7.44 (4 H o-Ph) 7.51 (2 H m p-Ph) 7.82 (4 H tdd 2JHP 12.6 JHH 8.2 1.4 o-Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.1 (CH3CO2) 24.6 (CH2CHOAc) 26.9 (d 3JCP 3.8 CH2CHOP) 67.0 (CHOAc) 69.0 (d 2JCP 6.0 CHOP) 128.4 (d 3JCP 12.2 aromatic CH) 129.9 (olefinic CHCHOAc) 131.5 (d 2JCP 17.5 aromatic CH) 131.5 (d 3JCP 3.0 olefinic CHCHOP) 131.87 (d 1JCP 136.6 aromatic C) 131.92 (d 4JCP 137.3 aromatic C) 132.1 (d 4JCP 1.5 aromatic CH) and 170.2 (C]] O); m/z (NH4CO2 added prior to ES-MS) 379 ([M + Na]+ 5%) 374 ([M + NH4]+ 4%) 357 ([M + H]+ 50%) 297 (3%) 219 (11%) 139 (100%) and 79 (6%).cis-(1R,4S)-4-Acetoxycyclohex-2-enyl 2,4-dichlorobenzoate (1R,4S)-17. A solution of cis-4-acetoxycyclohex-2-enol (2)-2a (953 mg 6.10 mmol) 2,4-dichlorobenzoic acid (1.72 g 9.00 mmol) dicyclohexylcarbodiimide (DCC) (1.86 g 9.01 mmol) and p-dimethylaminopyridine (DMAP) (16 mg 0.13 mmol) in methylene dichloride (50 ml) was stirred at RT for 3 h. Diethyl ether (50 ml) was added to the reaction mixture which was then washed with cold 5% aq.HCl (2 × 25 ml) and saturated aqueous NaHCO3 (3 × 25 ml) dried (MgSO4) and concentrated. The crude product was filtered through basic alumina and purified ona using MPLC (EtOAc–CH2Cl2 1 1 gradient in pentane) to give the title compound 17 (1.61 g 80%); dH(300 MHz; CDCl3) 1.90–2.06 (4 H m 2 × CH2) 2.07 (3 H s COCH3) 5.23–5.33 (1 H m CHOAc) 5.39–5.51 [1 H m CHOC(O)Ar] 5.94–6.05 (2 H m olefinic) 7.29 (1 H dd J 8.4 and 2.0 ArH) 7.47 (1 H d J 2.0 ArH) and 7.79 (1 H d J 8.4 ArH); dC(100.6 MHz; CDCl3 15 peaks) 21.1 (CH3CO2) 24.8 (CH2) 25.0 (CH2) 67.4 (CHOAc) 68.6 [CHOC(O)Ar] 126.9 (aromatic CHCHCCl) 128.4 (aromatic C) 129.3 [olefinic CHCHOC(O)Ar] 130.9 (aromatic CClCHCCl) 131.2 (olefinic CHCHOAc) 132.4 (aromatic CCHCH) 134.8 (aromatic C) 138.2 (aromatic C) 164.2 (C]] O) and 170.4 (C]] O); m/z 273 (0.6%) 271 (5%) 269 (7%) 177 (12%) 175 (65%) 173 (100%) 149 (2%) 147 (8%) 145 (12%) 139 (12%) 96 (43%) and 79 (26%); [a]D 25 +56 (c 1.16 in EtOH).(+)-cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enol (+)-(1S,4R)-18a. To (2)-2a (535 mg 3.38 mmol) dissolved in methylene dichloride (30 ml) was added dihydropyran (DHP) (425 mg 5.05 mmol) and pyridinium toluene-p-sulfonate (PPTS) (85 mg 0.338 mmol). The solution was stirred at RT for 4 h after which it was diluted with diethyl ether (100 ml) washed with brine–water (1 1; 20 ml) and concentrated. The resulting crude product was dissolved in methanol (5 ml) and treated with K2CO3 (23 mg 0.17 mmol) in water (1 ml). After being stirred at RT for 5 h the reaction mixture was diluted with water (10 ml) and then concentrated by evaporation of most of the methanol.The aqueous phase was extracted with diethyl ether (3 × 50 ml) and the combined organic fractions were then washed with brine (20 ml) dried (MgSO4) and concentrated. Purification of the residue on silica (diethyl ether–pentane 60 40) gave the title compound 18a (650 mg 98%) (Found C 65.9; H 8.8. Calc. for C11H18O3 C 66.6; H 9.15%); dH(400 MHz; CDCl3) 1.48–1.94 (10 H m 5- H 6-H 8-H 9-H and 10-H) 3.45–3.54 (1 H m 11-H) 3.86– 3.97 (1 H m 11-H) 4.08–4.18 (2 H m 4-H and 7-H) 4.72– 4.78 (1 H m 1-H) and 5.88–5.91 (2 H m 2-H and 3-H); dC(100.6 MHz; CDCl3) 19.5 (C-9) 24.3 and 26.2 (C-5) 25.3 and 25.4 (C-10) 28.1 and 28.5 (C-6) 30.9 and 31.0 (C-8) 62.4 and 62.5 (C-11) 65.1 and 65.2 (C-1) 68.9 and 70.0 (C-4) 96.8 and 97.8 (C-7) 130.1 and 131.3 (olefinic) 132.5 and 132.6 (olefinic); m/z (M+ >0.5%) 97 (51%) 85 (90%) 79 (63%) 67 (64%) 57 (65%) and 55 (100%); nmax/cm21 3404 (OH br) 2942 2869 1133 1074 1032 and 1000; [a]D 25 +38.1 (c 0.91 in CH2Cl2).cis-4-Pivaloyloxycyclohex-2-enol 18b. To a solution of the hydroxyacetate 2a (1.00 g 6.402 mmol) Et3N (3.24 g 32.01 mmol) and DMAP (22 mg 0.180 mmol) in THF (25 ml) was added pivaloyl chloride (1.58 ml 12.81 mmol). The reaction mixture was stirred at 50 8C for 24 h after which the solvent was removed and ether (60 ml) was added to the residue. The solution was washed with 1 M hydrochloric acid (× 3) sat’d aqueous NaHCO3 and brine dried (MgSO4) and concentrated. Separation of the residue on silica (diethyl ether–pentane 3 97 then 5 95) yielded cis-4-acetoxy-1- pivaloyloxycyclohex-2-ene (1.485 g 95%); dH(400 MHz; CDCl3) 1.19 (9 H s But) 1.77–1.96 (4 H m CH2) 2.07 (3 H s COCH3) 5.15–5.24 (2 H m CHOAc CHOPiv) and 5.81– 5.91 (2 H m olefinic); dC(100.6 MHz; CDCl3 11 peaks) 21.3 24.8 24.9 27.1 38.7 66.9 67.4 130.0 130.5 170.5 178.0.Selective hydrolysis of the acetate (1.112 g 4.627 mmol) was performed with a 10% solution of Na2CO3?10 H2O (133 mg 0.465 mmol) in MeOH–H2O (4 1 23 ml) at RT for 9 h. After removal of the methanol from the mixture it was extracted with ether and the extract dried (Na2SO4) and concentrated to give the title compound 18b (839 mg 92%); dH(400 MHz; J. Chem. Soc. Perkin Trans. 1 1997 583 CDCl3) 1.18 (9 H s But) 1.62–1.98 (5 H m CH2 OH) 4.14– 4.26 (1 H m CHOH) 5.10–5.24 (1 H m CHOPiv) 5.73–5.84 (1 H m olefinic) and 5.90–6.00 (1 H m olefinic); dC(100.6 MHz; CDCl3 9 peaks) 24.9 (C-5) 27.1 (C-9) 28.1 (C-6) 38.7 (C-8) 65.3 (C-1) 66.9 (C-4) 128.0 (C-3) 134.5 (C-2) and 178.1 (C-7); m/z 180 (2%) 113 (3%) 97 (23%) 96 (67%) 95 (14%) 85 (21%) 79 (21%) and 57 (100%).cis-(1S,4R)-4-(tert-Butyldimethylsilyloxy)cyclohex-2-enol (1S,4R)-18c. To a stirred solution of 21c (3.256 g 12.039 mmol) was added KOH (135 mg 2.408 mmol) in methanol (40 ml). The reaction mixture was stirred at RT for 4 h after which the solvent was removed and the residue was treated with water (30 ml) and diethyl ether (60 ml); the layers were separated and the pH of the aqueous layer was adjusted to 7 with 1 M hydrochloric acid; it was then further extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the product (2.698 g 98%) which was pure enough for the next step; dH(400 MHz; CDCl3) 0.073 (3 H s SiCH3) 0.076 (3 H s SiCH3) 0.89 [9 H s SiC(CH3)3] 1.60–1.90 (5 H m 2 × CH2 OH) 4.06–4.18 (2 H two overlapping m CHOH CHOSi) 5.75 (1 H dd J 10.2 and 2.4 olefinic) and 5.79 (1 H dd J 10.2 and 3.1 olefinic); dC(100.6 MHz; CDCl3 10 peaks) 24.7 (C-7) 24.6 (C-79) 18.1 (C-8) 25.8 (C-9) 28.2 (C-5) 28.4 (C-6) 64.8 (C-1) 66.3 (C-4) 130.7 (C-2) and 133.9 (C-3); [a]D 25 +34 (c 1.58 in EtOH).cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enyl 2,4- dichlorobenzoate (1S,4R)-19. A solution of DCC (1.297 g 6.285 mmol) and DMAP (13 mg 0.105 mmol) in methylene dichloride (10 ml) was added to a stirred solution of 18a (1.246 g 6.285 mmol) and 2,4-dichlorobenzoic acid (1.200 g 6.285 mmol) in methylene dichloride (25 ml) at RT.The solution was stirred at RT for 10 h after which it was diluted with diethyl ether (300 ml). The organic phase was washed with 5% aqueous acetic acid (50 ml) water (20 ml) and brine (20 ml) dried (MgSO4) and concentrated. Purification of the residue on silica (diethyl ether–pentane 60 40) gave the title compound 19 (2.20 g 87%); dH(400 MHz; CDCl3) 1.43–2.07 (10 H m 5-H 6-H 8-H 9-H and 10-H) 3.47–3.54 (1 H m 11-H) 3.86–3.94 (1 H m 11-H) 4.15–4.27 (1 H two overlapping m 4-H) 4.73–4.78 (1 H m 7-H) 5.39–5.45 (1 H m 1-H) 5.89–5.95 (1 H m 3-H) and 6.01–6.09 (1 H m 2-H); dC(100.6 MHz; CDCl3) 19.5 and 19.6 (CH2) 24.4 and 26.3 (CH2) 25.2 and 25.4 (CH2) 25.5 and 26.1 (CH2) 30.9 and 31.0 (CH2) 62.5 and 62.6 (CH2) 68.7 and 68.8 [allyl-CHOC(O)Ar] 69.3 and 70.4 (allyl-CHOTHP) 97.0 and 98.1 (THP-OCHO) 126.9 (aromatic CH) 127.0 and 127.1 [olefinic CHCHOC(O)Ar] 128.5 (aromatic C) 130.9 (aromatic CH) 132.5 (aromatic CH) 133.8 and 134.9 (olefinic CHCHOTHP) 135.8 (aromatic C) 138.1 (aromatic C) and 164.2 (C]] O); m/z 273 (19%) 271 (29%) 194 (6%) 192 (61%) 190 (81%) 177 (12%) 175 (68%) 173 (100%) 147 (12%) and 145 (28%).trans-1-Chloro-4-(tetrahydropyran-2-yloxy)cyclohex-2-ene 20a. A solution of 18a (100 mg 0.504 mmol) LiCl (46 mg 1.08 mmol) and 2,4,6-trimethylpyridine (504 ml 3.78 mmol) in DMF (750 ml) was cooled to 0 8C and treated with MsCl (58 ml 0.83 mmol) followed after 20 min by diethyl ether (40 ml). The solution was washed with water (5 ml) and brine (5 ml) dried (MgSO4) and concentrated. The residue was purified on silica (diethyl ether–pentane 40 60) to give the title compound 20a (98 mg 90%).Since the product is extremely unstable it should be prepared directly before further use; dH(400 MHz; CDCl3) 1.40–2.40 (10 H m 5-H 6-H 8-H 9-H 10-H) 3.43–3.58 (1 H m 11-H) 3.83–3.98 (1 H m 11-H) 4.16–4.30 (1 H m 4-H) 4.54–4.65 (1 H m 7-H) 4.66–4.80 (1 H m 1-H) and 5.82–6.03 (2 H m olefinic); dC(100.6 MHz; CDCl3) 19.7 25.4 25.4 25.5 27.5 29.3 29.7 29.8 31.1 31.1 54.6 54.6 62.6 62.7 68.3 69.0 97.3 98.1 130.4 130.6 131.1 and 131.7. trans-1-Chloro-4-pivaloyloxycyclohex-2-ene 20b. Triphenylphosphine (836 mg 3.19 mmol) dissolved in THF (3 ml) was added to a solution of N-chlorosuccinimide (426 mg 3.19 mmol) in THF (5 ml) to give slightly exothermic phosphonium salt formation. After cooling of the reaction mixture to RT (20 min) 18b (416 mg 2.098 mmol) in THF (3 ml) was added to it; it was then stored at RT for 24 h.After this the solvent was evaporated from the mixture and pentane was added to the residue. The precipitated triphenylphosphine oxide and succinimide were filtered off and the pentane was removed in vacuo to give a residue which was purified on silica (EtOAc–pentane 1 99). This afforded 20b (305 mg 67%) (8% of the reaction product was derived from the SN29 substitution mechanism); dH(400 MHz; CDCl3) 1.17 (9 H s But) 1.68–1.78 (1 H m CH2) 1.94–2.04 (1 H m CH2) 2.12–2.32 (2 H m CH2) 4.57– 4.64 (1 H m CHCl) 5.20–5.28 (1 H m CHOPiv) 5.82–5.89 (1 H m olefinic) and 5.98–6.04 (1 H m olefinic); dC(100.6 MHz; CDCl3 9 peaks) 24.8 (CH2) 27.1 (CH3) 28.7 (CH2) 38.7 (C) 53.6 (CHCl) 65.7 (CHOPiv) 128.3 (olefinic CH) 132.3 (olefinic CH) and 177.8 (C]] O).trans-(1R,4R)-1-Chloro-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene (1R,4R)-20c. To compound 18c (1.503 g 6.58 mmol) was added LiCl (558 mg 13.16 mmol) and Et3N (2.75 ml 19.74 mmol) in CH2Cl2 (25 ml). The solution was cooled to 220 8C and MsCl (610 ml 7.881 mmol) was added to it via a syringe. The mixture was brought to RT over 3 h after which it was stirred for a further 17 h. It was then diluted with water– NaHCO3 (sat’d) (1 1; 30 ml) and the phases were separated. The aqueous phase was extracted with diethyl ether (3 × 70 ml). The combined organic phases were washed with brine (20 ml) dried (MgSO4) and passed through a silica column packed with Et3N–diethyl ether–pentane (4 2 94). Elution with diethyl ether–pentane (2 98 then 5 95) gave the title compound 20c (1.484 g 91%); dH(400 MHz; CDCl3) 0.08 (6 H s SiCH3 × 2) 0.89 [9 H s SiC(CH3)3] 1.60–1.67 (1 H m CH2) 1.84–1.93 (1 H m CH2) 2.02–2.11 (1 H m CH2) 2.29–2.37 (1 H m CH2) 4.23–4.27 (1 H m CHOSi) 4.56–4.60 (1 H m CHCl) 5.77 (1 H dd J 10.4 and 3.1 olefinic) and 5.82 (1 H dd J 10.4 and 3.2 olefinic); dC(100.6 MHz; CDCl3 10 peaks) 24.7 (C-7) 24.6 (C-79) 18.2 (C-8) 25.8 (C-9) 29.7 (C-6) 29.9 (C-5) 54.9 (C-1) 64.9 (C-4) 129.5 (C-2) and 133.5 (C-3); m/z 248 (1%) 246 (2%) 191 (24%) 189 (64%) 93 (18%) 77 (15%) and 75 (100%); [a]D 25 +259 (c 1.75 in EtOH).cis-(1S,4R)-1-Acetoxy-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene (1S,4R)-21c. A solution of TBDMS-Cl (2.665 g 17.68 mmol) in methylene dichloride (40 ml) was cooled to 0 8C and imidazole (6.74 g 99.0 mmol) was added to it.After 5 min (2)- 2a (2.209 g 14.14 mmol) dissolved in methylene dichloride (30 ml) was added to the mixture which was then stirred at 0 8C for ca. 30 min and then at RT for 20 h. After being quenched with water (10 ml) the reaction mixture was extracted with methylene dichloride (3 × 50 ml). The combined organic fractions were washed with brine (20 ml) dried (Na2SO4) concentrated and subjected to chromatography (diethyl ether–pentane 5 95) to give the title compound 21c (3.79 g 99%); dH(400 MHz; CDCl3) 0.078 (3 H s SiCH3) 0.082 (3 H s SiCH3) 0.90 [9 H s SiC(CH3)3] 1.65–1.95 (4 H m 2 × CH2) 2.04 (3 H s COCH3) 4.15–4.19 (1 H m CHOSi) 5.13–5.17 (1 H m CHOAc) 5.71–5.75 (1 H m olefinic) and 5.85–5.88 (1 H m olefinic); dC(100.6 MHz; CDCl3) 24.7 (SiCH3) 24.6 (SiCH3) 18.1 (SiC) 21.2 (COCH3) 25.3 (CH2CHOAc) 25.8 [SiC(CH3)3] 28.4 (CH2CHOSi) 66.3 (CHOSi) 67.0 (CHOAc) 126.2 (olefinic CHCHOAc) 136.3 (olefinic CHCHOSi) and 170.6 (C]] O); m/ z 210 (2%) 117 (100%) 79 (12%) and 75 (33%); [a]D 25 240 (c 1.63 in EtOH).Acknowledgements Financial support from the Swedish Natural Science Research Council The Research Council of the Board of Technical Development and the Swedish Research Council for Engineering Sciences is gratefully acknowledged. 584 J. Chem. Soc. Perkin Trans. 1 1997 References 1 (a) C. R. Johnson P. A. Plé and J. P. Adams J. Chem. Soc. Chem. Commun. 1991 1006; (b) T. Hudlicky and H. F. Olivo Tetrahedron Lett. 1991 32 6077; (c) L. Dumortier P. Liu S. Dobbelaere J. van der Eycken and M. Vandewalle Synlett 1992 243; (d ) C. R. Johnson P. A.Plé L. Su L. M. J. Heeg and J. P. Adams Synlett 1992 388. 2 (a) S. Knapp A. B. J. Naughton and T. G. Murali Dhar Tetrahedron Lett. 1992 33 1025; (b) K. Ramesh M. S. Wolfe Y. Lee D. Vander Velde and R. T. Borchardt J. Org. Chem. 1992 57 5861; (c) N. Dyatkina B. Costisella F. Theil and M. von Janta-Lipinski Tetrahedron Lett. 1994 35 1961; (d ) N. Dyatkina F. Theil and M. von Janta-Lipinski Tetrahedron 1995 51 761. 3 J. E. Bäckvall R. Gatti and H. E. Schink Synthesis 1993 343. 4 Alcohol (2)-2a was prepared according to R. J. Kazlauskas A. N. E. Weissfloch A. T. Rappaport and L. A. Cuccia J. Org. Chem. 1991 56 2656. 5 Compound 8 was prepared according to J. E. Bäckvall J. E. Nyström and R. E. Nordberg J. Am. Chem. Soc. 1985 107 3676. 6 Racemic (±)-2a was prepared by selective hydrolysis (5% K2CO3 in MeOH–H2O) of cis-1,4-diacetoxycyclohex-2-ene which was prepared from cyclohexadiene according to J.E. Bäckvall S. E. Byström and S. E. Nordberg J. Org. Chem. 1984 49 4619. 7 (a) W. Oppolzer J.-M. Gaudin and T. N. Birkinshaw Tetrahedron Lett. 1988 29 4705; (b) A. K. Bose and B. Lal Tetrahedron Lett. 1973 3937. 8 (a) A. Pfaltz Acc. Chem. Res. 1993 26 339; (b) N. W. Murral and A. J. Welch J. Organomet. Chem. 1986 301 109; (c) A. Pfaltz in Stereoselective Synthesis E. Ottow K. Schöllkopf and B.-G. Schulz eds. Springer-Verlag Berlin Heidelberg 1993 pp. 15–36. 9 (a) B. M. Trost and J. P. Genêt J. Am. Chem. Soc. 1976 98 8516; (b) B. M. Trost and E. Keinan J. Am. Chem. Soc. 1978 100 7779; (c) J. E. Bäckvall R. E. Nordberg J. E. Nyström T. Högberg and B. Ulff J. Org. Chem. 1981 46 3479; (d ) Y.Tanigawa K. Nishimura A. Kawasaki and S.-I. Murahashi Tetrahedron Lett. 1982 23 5549; (e) S. E. Byström R. Aslanian and J. E. Bäckvall Tetrahedron Lett. 1985 26 1749; (f ) J.-P. Genêt M. Balabane J. E. Bäckvall and J. E. Nyström Tetrahedron Lett. 1983 24 2745; (g) R. E. Nordberg and J. E. Bäckvall J. Organomet. Chem. 1985 285 C24. 10 (a) T. Hayashi K. Kishi A. Yamamoto and Y. Ito Tetrahedron Lett. 1990 31 1743; (b) R. Tanikaga T. X. Jun and A. Kaji J. Chem. Soc. Perkin Trans. 1 1990 1185; (c) J.-P. Genêt S. Thorimbert and A. M. Touzin Tetrahedron Lett. 1993 34 1159; (d ) P. von Matt O. Loiseleur G. Koch A. Pfaltz C. Lefeber T. Feucht and G. Helmchen Tetrahedron Asymmetry 1994 5 573. 11 J. E. Bäckvall K. L. Granberg and A. Heumman Isr. J. Chem. 1991 31 17. 12 R. Tanikaga J.Takeuchi M. Takyu and A. Kaji J. Chem. Soc. Chem. Commun. 1987 386. 13 L. Liebeskind and J. S. McCallum Synthesis 1993 819. 14 A. Hassner and V. Alexanian Tetrahedron Lett. 1978 35 5713. 15 (a) K. L. Granberg and J. E. Bäckvall J. Am. Chem. Soc. 1992 114 6858; (b) T. Takahashi Y. Jinbo K. Kitamura and J. Tsuji Tetrahedron Lett. 1984 25 5921; (c) P. B. Mackenzie J. Whelan and B. Bosnich J. Am. Chem. Soc. 1985 107 2046; (d ) T. Hayashi A. Yamamoto and T. Hagihara J. Org. Chem. 1986 51 723. 16 M. Miyashita A. Yoshikoshi and P. A. Grieco J. Org. Chem. 1977 42 3772. 17 J. E. Bäckvall K. L. Granberg and R. B. Hopkins Acta Chem. Scand. 1990 44 492. 18 O. Mitsunobu Synthesis 1981 1. 19 For a recent approach to Pd0-catalysed desymmetrisation of cycloalk-2-ene-1,4-diol derivatives leading to enantiopure 1,4- aminoalcohol derivatives see B.M. Trost and S. R. Pulley J. Am. Chem. Soc. 1995 117 10 143. 20 T. Ukai H. Kawazura Y. Ishii J. J. Bonnet and J. A. Ibers Organomet. Chem. 1974 65 253. 21 (a) J. A. Dale D. L. Dull and H. S. Mosher J. Org. Chem. 1969 34 2543; (b) J. A. Dale and H. S. Mosher J. Am. Chem. Soc. 1973 95 512. 22 J. K. Whitesell and D. Reynolds J. Org. Chem. 1983 48 3548. Paper 6/00779A Received 1st February 1996 Accepted 7th October 1996 J. Chem. Soc. Perkin Trans. 1 1997 577 Palladium-catalysed enantiodivergent synthesis of cis- and trans-4-aminocyclohex-2-enols Roberto G. P. Gatti Anna L. E. Larsson and Jan-E. Bäckvall * Department of Organic Chemistry University of Uppsala Box 531 S-751 21 Uppsala Sweden Enantiomerically pure cis- and trans-4-aminocyclohex-2-enols are prepared from cyclohexa-1,3-diene via (2)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a using palladium(0) chemistry.Benzylamine and diethylamine are tested in the Pd0-catalysed allylic amination reactions. Since acetate is too slow as a leaving group and gave considerable amounts of side products a number of leaving groups have been investigated. Of these phosphinate and 2,4-dichlorobenzoate are excellent leaving groups and result in efficient and highly stereoselective reactions; chloride as allylic leaving group also gives good results. By variation of the leaving group and proper choice of the protecting group it is possible to synthesise all four stereoisomers of 4-aminocyclohex-2-enol in good yield and high enantiomeric excess. Introduction 4-Aminocyclohex-2-enols are important structural elements in a number of biologically active compounds such as conduramines 1 and derivatives.2 In connection with a project dealing with new substances for treatment of bronchitis complications there was a need for a general synthesis of optically pure 4- aminocyclohex-2-enols.We recently reported a method for an enantiodivergent synthesis of 4-substituted 2-cycloalkenols from cycloalka-1,3- dienes with a combination of palladium and enzyme chemistry (Scheme 1).3 The method allows for preparation of both enantiomers with high selectivity. In the present paper we have used enantiomerically pure (2)- cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a as a key intermediate for further stereocontrolled palladium(0)-catalysed functionalisation and report on the enantiocontrolled synthesis of all four stereoisomers of 4-aminocyclohex-2-enol (Scheme 2).An interesting observation is that phosphinates are excellent leaving groups in the Pd0-catalysed allylic substitution with primary and secondary amines. Scheme 1 Results and discussion (A) Racemates The objective was to synthesise cis- and trans-4-aminocyclohex- 2-enols in optically pure form starting from (2)-2a.4 Diethylamine and benzylamine (BnNH2) were employed as representative amines in the palladium(0)-catalysed allylic aminations. First the allylic amination was performed to produce a racemic mixture of the amino alcohols (Scheme 3). Thus cis-4- diethylaminocyclohex-2-enol 6a and cis-4-benzylaminocyclohex- 2-enol 6b were prepared starting from cis-1-acetoxy-4- chlorocyclohex-2-ene 8.5 The racemic trans stereoisomers were synthesised from (±)- 2a.6 Substitution of the OH by chloride with PPh3 and Nchlorosuccinimide (NCS)7 in THF afforded trans-1-acetoxy-4- chlorocyclohex-2-ene 9.Pd0-catalysed allylic amination of chloroacetate 9 with diethylamine or benzylamine gave after hydrolysis trans-4-diethylaminocyclohex-2-enol 7a or trans-4- benzylaminocyclohex-2-enol 7b respectively. Amino alcohols 6 and 7 were used to set up a method for determination of the ee. However with 9 as the allylic substrate a moderate regioselectivity was observed. Using conditions A in Scheme 3 and diethylamine as the nucleophile about 20% of the g-substitution product (of trans stereochemistry) was obtained. Usually Scheme 2 578 J. Chem. Soc. Perkin Trans. 1 1997 attack at the 4-position relative to the acetate is strongly favoured in analogous 1,4-disubstituted alk-2-enes.5 However due to steric interaction between the acetate and the L2Pdgroup in p-allyl intermediate I (Fig.1) palladium is forced away from the acetate which weakens the palladium–carbon bond in the 2-position.8 This will increase the relative rate of attack at the 2-position in I. When R is tert-butyl II the relative amount of attack in the 2-position increased to 50–60% in the corresponding reaction (vide infra). The reaction conditions were further investigated by variation of the solvent amount of catalyst and ligand and by addition of salt (LiCl). The system with Pd(dba)2 and PPh3 in THF with an addition of 25 mol% LiCl decreased the amount of g-product of I from 20 to 13% with Et2NH and from 12 to 5% with BnNH2.(B) cis Enantiomers It has been shown that acetate can be used as a leaving group in Pd0-catalysed allylic amination with both primary and secondary amines.9 However when (±)-2a was treated with benzylamine in the presence of Pd(dba)2 PPh3 and Et3N in THF the conversion was low. In an attempt to improve the reaction different catalysts ligands and solvents were tried together with variation of the concentration and temperature. The best results were obtained with acetonitrile as the solvent at a reaction temperature of 40 8C. However the yield of the desired product 6 was still unsatisfactory with considerable amounts of g-product as well as inversion and elimination products.† Therefore better leaving groups were called for. To increase the reactivity in the Pd0-catalysed nucleophilic displacement the hydroxy group in 2a was transformed into a reactive leaving group.It has been reported in the literature that ethyl and methyl carbonate can be used as a leaving group in Pd0- Scheme 3 Reagents and conditions A 5% Pd(dba)2 15% PPh3 1.2–3 equiv. NHR1R2 3 equiv. Et3N in THF RT N2 or Ar atm 10a (77%) 10b (81%); B K2CO3 in MeOH–H2O at RT 6a (95%) 6b (98%) 7a (96%) 7b (98%); C NCS PPh3 THF RT (97%); D reagents as for A but longer reaction times and 25% LiCl added to the reaction mixture 11a (71%) 11b (76%) Fig. 1 Weaker bond in the 2-position because of steric interactions which increase the relative amount of g-substitution product † Loss of regio- and stereo-selectivity has previously been observed in Pd-catalysed reaction of allylic acetates with amines.9b,g catalysed allylic amination 10 but carbonate 12 gave the nondesired carbamate 13 on reaction with benzylamine [eqn.(1)].‡ The same results for similar substrates have been reported earlier in our laboratory 11 and elsewhere.12 The use of trifluoroacetate 14 in the corresponding reaction gave 2a and Nbenzyltrifluoroacetamide presumably because of faster nitrogen attack at the carbonyl carbon rather than formation of the p-allyl complex. Attempts to use a diethylphosphate ester 9d,e as the leaving group failed since 15 was very sensitive and hydrolysed quickly after preparation. We next tried diphenylphosphinic and benzoate esters. Diphenylphosphinic ester 16 was prepared from enantiomerically pure (2)-2a (89%) according to Liebeskind et al.13 and 2,4- dichlorobenzoate ester 17 was prepared (80% yield) by esterifi- cation of (2)-2a following the method of Hassner.14 Both 16 and 17 were excellent substrates in the Pd0-catalysed allylic amination with diethylamine and benzylamine and afforded the amino acetates (1S,4R)-10a and (1S,4R)-10b which upon hydrolysis yielded the amino alcohols (1S,4R)-6a and (1S,4R)- 6b respectively (Scheme 4).In each case the allylic amination was highly stereoselective and the enantiomeric excess (ee) of the amino alcohols was �98% in both cases. For (1S,4R)-6a 2% of the trans isomer was observed. An explanation could be isomerisation of the p-allyl intermediate by nucleophilic attack by free Pd0 on the allyl ligand.15 To form a carbon–nitrogen bond at the other allylic carbon in (2)-2a it was necessary to protect the hydroxy group and then selectively hydrolyse the acetate before attachment of a leaving group (Scheme 5).The hydroxy acetate (2)-2a was transformed into the alcohol 18a with tetrahydropyran (THP) protection 16 and subsequent hydrolysis of the acetoxy group. The alcohol 18a was transformed into its 2,4-dichlorobenzoate ester 19 (vide supra) which on Pd0-catalysed amination and subsequent removal of the THP group afforded (1R,4S)-6a and (1R,4S)-6b. Scheme 4 Reagents and conditions A 5% Pd(dba)2 15% PPh3 1.2–3 equiv. NHR1R2 3 equiv. Et3N in THF at RT N2 or Ar atm 16 to 10a (82%) 16 to 10b (79%) 17 to 10a (73%) 17 to 10b (70%); B K2CO3 in MeOH–H2O at RT yields as for step B shown in Scheme 3 ‡ The reaction proceeds via a (p-allyl)palladium intermediate.11 J.Chem. Soc. Perkin Trans. 1 1997 579 (C) trans Enantiomers Reaction of the enantiomerically pure hydroxy acetate (2)-2a with NCS and PPh3 in THF afforded optically active (1S,4S)-9 with high stereospecificity (cf. racemic reaction Scheme 3). Subsequent Pd0-catalysed allylic amination employing Et2NH and BnNH2 followed by hrolysis gave (1S,4S)-7a and (1S,4S)-7b respectively [eqn. (2)]. The yields were the same as for the racemates (Scheme 3) and the ee was in each case � 98%. When preparing the other trans enantiomer the group at the other stereogenic carbon had to be substituted. Some difficulties were encountered when solving this problem. Substitution of the hydroxy group in 18a by chloride with inversion using LiCl methanesulfonyl chloride (MsCl) 2,4,6-trimethylpyridine in DMF and subsequent Pd0-catalysed allylic amination of the allylic chloride 20a should in analogy to the preparation of (1S,4S)-7 from (1S,4S)-9 give (1R,4R)-7 after removal of the protecting group.Unfortunately and to a much greater extent than what had been seen for 9 the predominant product was the g-substitution product (vide supra). Using pivalate § as protecting group instead of THP led to the same discouraging result (Scheme 6). For example with the pivalate 20b the amount of g-substitution product was 50–60% with diethylamine. This result supports the explanation suggested in Fig. 1 for the increased relative amount of g-isomer. The use of tert-butyldimethylsilyl (TBDMS)¶ led to decomposition of the silyl ether bond in the amination. Another way to reach the other trans enantiomer (1R,4R)-7 would be by a Mitsunobu reaction 18 of 6.However reaction of 6b under Mitsunobu conditions failed even when the amine was protected with tertbutoxycarbonyl (TBOC).|| To solve the problem of obtaining the trans-(1R,4R)- enantiomer of the amino alcohol we prepared (1R,4R)-9 as Scheme 5 Reagents and conditions A i DHP PPTS in CH2Cl2 at RT (98%); ii 20% K2CO3 in MeOH–H2O at RT (86%); B 2,4- dichlorobenzoic acid DCC DMAP in CH2Cl2 at RT (87%); C i 5% Pd(dba)2 15% PPh3 1.2–3 equiv. NHR1R2 3 equiv. Et3N in THF at RT N2 or Ar atm; ii p-TsOH MeOH RT 6a 55% yield in two steps 6b 65% yield in two steps § Prepared by selective hydrolysis of the acetate (Na2CO3 MeOH RT)17 in (±)-cis-1-acetoxy-4-pivaloyloxycyclohex-2-ene. The latter was obtained from esterification of (±)-2a.¶ For an experimental procedure see preparation of 20c in the Experimental section. || The protection was done by mixing the aminoacetate with (BOC)2O Et3N and catalytic amounts DMAP in methylene dichloride. Before the Mitsunobu reaction the acetate was hydrolysed. described in Scheme 7. Silylation of (2)-2a with TBDMS-Cl gave cis-(1S,4R)-1-acetoxy-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene 21c. This compound was converted into (1R,4R)-9 in the following way hydrolysis of the acetate in 21c and stereospecific substitution of the hydroxy group by chloride with inversion of configuration using MsCl LiCl and Et3N in methylene dichloride gave trans-(1R,4R)-1-chloro-4-(tert-butyldimethylsilyloxy) cyclohex-2-ene 20c. Deprotection of TBDMS with tetrabutylammonium fluoride (TBAF) followed by quenching with acetic anhydride gave (1R,4R)-9 (83%).Transformation of (1R,4R)-9 into (1R,4R)-7a and (1R,4R)-7b was done as shown in eqn. (2) and the ee obtained was �98%.19 Conclusion All four stereoisomers of biologically interesting 4-aminocyclohex- 2-enols have been prepared in enantiomerically pure form by palladium(0)-catalysed reactions from the same starting material (2)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a. Experimental 1H and 13C NMR spectra were recorded for CDCl3 solutions at 300 or 400 and 75.4 or 100.6 MHz respectively. 19F NMR spectra were recorded for CDCl3 solutions at 376.3 MHz. Chemical shifts are reported in ppm with CDCl3 as internal standard (7.26 for 1H and 77.00 ppm for 13C) and coupling constants (J) are given in Hz. Assignment of 13C was done with HETCOR and COSY experiments.Mass spectra were recorded on a Scheme 6 Scheme 7 Reagents and conditions A TBDMS-Cl imidazole CH2Cl2 0 8C to RT (99%); B i 20% KOH in MeOH at RT (98%); ii MsCl LiCl Et3N in CH2Cl2 220 8C to RT (91%); C i TBAF in THF at RT; ii Ac2O (83%); D i 5% Pd(dba)2 15% PPh3 25% LiCl 1.2–3 equiv. NHR1R2 0–3 equiv. Et3N in THF at RT; ii K2CO3 in MeOH–H2O at RT yields as in Scheme 3 580 J. Chem. Soc. Perkin Trans. 1 1997 Finnigan MAT INCOS 50 or a Hewlett Packard 5971 series instrument at 70 eV. Where indicated mass spectra were recorded with pneumatically assisted electrospray mass spectrometry (ES-MS) on a Micromass VG Platform apparatus using direct inlet of a solution in acetonitrile or with an LCcolumn (Kromasil 100 × 4.6 mm acetonitrile–water gradient with 5 mM formic acid).Optical rotations recorded in units of 1021 deg cm2 g21 measured at 25.0 8C on a Perkin–Elmer 241 polarimeter and concentrations are expressed as g 100 ml21 in spectroscopically pure ethanol or methylene dichloride. Elemental analyses were performed by Analytische Laboratorien Engelskirchen Germany. Bis(dibenzylideneacetone)- palladium(0) [Pd(dba)2] was prepared according to a literature procedure.20 THF was distilled under nitrogen from sodium benzophenone ketyl. Pyridine and methylene dichloride were distilled under nitrogen from calcium hydride. Benzylamine diethylamine and triethylamine were distilled from KOH and stored over KOH under nitrogen until used. Thin-layer chromatography (TLC) was run on Merck pre-coated silica gel 60-F254 plates. All reactions were carried out in oven-dried glassware and the Pd0-catalysed reactions also under an argon or nitrogen atmosphere unless otherwise stated.Progress of reaction was followed by TLC until judged complete for all reactions. For flash chromatography Merck Kieselgel 60 (230–400 mesh) was used. Enantiomeric excess (ee) was checked with 1H and 19F NMR in CDCl3 by Mosher esterification 21 for the diethylaminocyclohex-2-enols and by salt formation with optically pure (S)-mandelic acid,22 for the 4-benzylaminocyclohex- 2-enols. General procedure for the Pd0-catalysed aminations exemplified by the synthesis of (±)-cis-1-acetoxy-4-benzylaminocyclohex-2- ene 10b To a solution that had been stirred at room temperature (RT) for 20 min containing Pd(dba)2 (172 mg 0.29 mmol) PPh3 (225 mg 0.86 mmol) BnNH2 (737 mg 6.87 mmol) and Et3N (1.74 g 17.18 mmol) in THF (30 ml) was added the cis-chloro acetate 8 (1.00 g 5.73 mmol) in THF (10 ml).The reaction mixture was stirred at RT for 8 h and then evaporated. The residue was dissolved in diethyl ether (20 ml) and extracted with 1 M aq. HCl (3 × 50 ml). The aqueous phase was charged with fresh ether (80 ml) and the pH was adjusted to >10 with K2CO3 and KOH followed by two more extractions with ether (50 ml). The combined ether extracts were dried (K2CO3) and concentrated. The crude product was purified on silica (ethyl acetate– pentane gradient) to give 10b (1.14 g 81%). The silica was first conditioned with 2% Et3N in pentane (Found for the HCl-salt C 63.9; H 7.05. Calc. for C15H20ClNO2 C 63.9; H 7.15%); dH(400 MHz; CDCl3) 1.3–1.5 (1 H br s NH) 1.58–1.71 (1 H m CH2) 1.73–1.84 (1 H m CH2) 1.84–1.93 (2 H m CH2) 2.04 (3 H s COCH3) 3.14–3.21 (1 H m CHNHBn) 3.85 3.88 (2 H AB-system JAB 13.1 PhCH2) 5.13–5.25 (1 H m CHOAc) 5.79 (1 H ddd J 10.0 3.5 and 1.7 olefinic) 6.00 (1 H dd J 10.1 and 2.7 olefinic) and 7.21–7.37 (5 H m Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.3 (COCH3) 25.3 (CH2CHOAc) 26.1 (CH2CHN) 51.0 (CH2Ph) 52.3 (CHN) 67.2 (CHOAc) 126.3 (CH Ph) 126.9 (olefinic CHCHOAc) 128.1 (CH Ph) 128.4 (CH Ph) 135.4 (olefinic CHCHN) 140.3 (C Ph) and 170.7 (C]] O).(A) Synthesis of the cis-4-aminocyclohex-2-enols (±)-cis-1-Acetoxy-4-diethylaminocyclohex-2-ene 10a. The synthesis was carried out according to the general procedure above. Amounts used were allylic substrate 8 (300 mg 1.718 mmol) Pd(dba)2 (51 mg 0.086 mmol) PPh3 (68 mg 0.258 mmol) Et2NH (151 mg 2.06 mmol) Et3N (521 mg 5.15 mmol) and THF (10 ml); reaction time 16 h; yield 280 mg 77%; dH(300 MHz; CDCl3) 1.04 (6 H app t J 7.2 CH3) 1.41–1.61 (2 H m CH2) 1.81–1.91 (1 H m CH2) 2.04 (3 H s COCH3) 2.11– 2.20 (1 H m CH2) 2.34–2.61 (4 H m NCH2) 3.40–3.53 (1 H m CHNEt2) 5.26–5.38 (1 H m CHOAc) 5.64–5.73 (1 H m olefinic) and 5.67– (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.4 (NCH2CH3) 21.3 (CH3CO2) 22.3 (CH2CHN) 28.3 (CH2CHOAc) 44.1 (NCH2) 56.4 (CHN) 70.2 (CHOAc) 129.2 (olefinic CHCHN) 134.8 (olefinic CHCHOAc) and 170.8 (C]] O).cis-(1S,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1S,4R)-10a. The synthesis was carried out according to the general procedure. Amounts used were allylic substrate 16 (616 mg 1.718 mmol) Pd(dba)2 (51 mg 0.086 mmol) PPh3 (68 mg 0.258 mmol) Et2NH (151 mg 2.06 mmol) Et3N (521 mg 5.15 mmol) and THF (20 ml); reaction time 2 h; yield 298 mg 82%.Allylic substrate 17 (485 mg 1.473 mmol) Pd(dba)2 (44 mg 0.074 mmol) PPh3 (58 mg 0.221 mmol) Et2NH (183 mg 2.50 mmol) Et3N (447 mg 4.42 mmol) and THF (20 ml); reaction time 6 h; yield 228 mg 73%. Spectral data are in accordance with the racemate. (±)-cis-4-Diethylaminocyclohex-2-enol 6a. The amino acetate 10a (250 mg 1.19 mmol) was dissolved in a stirred solution of K2CO3 (9 mg 0.06 mmol) in MeOH–H2O (4 1; 10 ml) at RT. After 5 h the mixture was evaporated diluted with diethyl ether (100 ml) washed with water (10 ml) and brine (10 ml) dried (K2CO3) and evaporated. Purification of the residue on silica (gradient of diethyl ether–pentane 60 40 to ethyl acetate– MeOH 90 10) gave the title compound 6a (191 mg 95%) (Found for the HCl-salt C 58.3; H 9.7.Calc. for C10H20ClNO C 58.4; H 9.8%); dH(300 MHz; CDCl3) 1.04 (6 H app t CH3) 1.56–1.71 (3 H m 6-H and 5-H) 1.79–1.89 (1 H m 5-H) 1.96–2.14 (1 H br s OH) 2.38–2.65 (4 H m CH2) 3.26–3.33 (1 H m 1-H) 4.07–4.12 (1 H m 4-H) and 5.79–5.91 (2 H m 5-H and 6-H); dC(75.4 MHz; CDCl3 8 peaks) 14.2 (CH3) 17.9 (CH2) 30.2 (CH2) 44.2 (NCH2) 56.7 (CHNEt2) 63.4 (CHOAc) 130.2 (CH olefinic) 135.4 (CH olefinic); nmax/cm21 3346 (OH br) 2967 2937 2871 1386 and 1066. (2)-cis-(1S,4R)-4-Diethylaminocyclohex-2-enol (2)-(1S,4R)- 6a. Starting from (1S,4R)-10a and applying the same conditions as for the preparation of (±)-6a yielded (2)-6a. Spectral data are in accordance with (±)-6a; [a]D 25 270 (c 1.91 in EtOH); ee �98%.(+)-cis-(1R,4S)-4-Diethylaminocyclohex-2-enol (+)-(1R,4S)- 6a. See general procedure according to 10b. Allylic substrate 19 (802 mg 2.16 mmol) Pd(dba)2 (64 mg 0.108 mmol) PPh3 (85 mg 0.324 mmol) Et2NH (174 mg 2.38 mmol) Et3N (656 mg 6.48 mmol) and THF (25 ml) for 15 h yielded cis-(1R,4S)-4- diethylamino-1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (373 mg 68%). The THP group in the latter product (299 mg 1.18 mmol) was removed with toluene-p-sulfonic acid (190 mg 1.00 mmol) in MeOH (5 ml) at RT. After 12 h the mixture was evaporated and treated with diethyl ether (100 ml) and 1 M NaOH (10 ml). After extraction the organic phase was washed with water (10 ml) and brine (10 ml) dried (MgSO4) and evaporated. Purification of the residue on silica (gradient of diethyl ether–pentane 60 40 to ethyl acetate–MeOH 90 10) gave the title compound (+)-(1R,4S)-6a (161 mg 81%; totally 55% in two steps).Same spectral data as for (±)-6a; [a]D 25 +66 (c 1.70 in EtOH); ee �98%. (±)-cis-1-Acetoxy-4-benzylaminocyclohex-2-ene 10b. This compound is described above under the general procedure. cis-(1S,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4R)- 10b. See general procedure for (±)-10b. Pd(PPh3)4 (87 mg 0.075 mmol) was used instead of Pd(dba)2 for the allylic substrate 16 (539 mg 1.504 mmol); amounts of reactants used were PPh3 (20 mg 0.076 mmol) BnNH2 (161 mg 1.503 mmol) Et3N (340 mg 3.36 mmol) and THF (17 ml); reaction time 2 h; yield 292 mg 79%. For the allylic substrate 17 (311 mg 0.95 mmol) the following amounts were used Pd(dba)2 (28 mg 0.047 mmol) PPh3 (38 mg 0.142 mmol) BnNH2 (311 mg 2.83 mmol) and THF (17 ml); reaction time 2 h; yield 163 mg 70%.Spectral data were in accordance with those of racemic 10b. (±)-cis-4-Benzylaminocyclohex-2-enol 6b. Prepared from amino acetate 10b using the same hydrolysis conditions as for J. Chem. Soc. Perkin Trans. 1 1997 581 the preparation of 6a in 98% yield; dH(400 MHz; CDCl3) 1.56– 1.88 (6 H m 2 × CH2 OH NH) 3.09–3.21 (1 H m CHNHBn) 3.83 3.87 (2 H AB-system JAB 13.0 PhCH2NH) 4.09– 4.18 (1 H m CHOH) 5.81–5.89 (2 H m olefinic) and 7.22– 7.34 (5 H m Ph); dC(100.6 MHz; CDCl3 11 peaks) 24.9 (CH2) 29.1 (CH2) 51.1 (CH2Ph) 52.3 (CHN) 64.7 (CHOH) 127.0 (CH Ph) 128.1 (CH Ph) 128.4 (CH Ph) 130.7 (CH olefinic) 133.1 (CH olefinic) and 140.3 (C Ph). (2)-cis-(1S,4R)-4-Benzylaminocyclohex-2-enol (2)-(1S,4R)- 6b.This compound was prepared as above for 6b but starting with (1S,4R)-10b. Spectral data are as for (±)-6b; [a]D 25 24.3 (c 0.845 in EtOH); ee �98%. (+)-cis-(1R,4S)-4-Benzylaminocyclohex-2-enol (+)-(1R,4S)- 6b. See general procedure for 10b. Allylic substrate 19 (557 mg 1.50 mmol) Pd(dba)2 (45 mg 0.075 mmol) PPh3 (50 mg 0.188 mmol) BnNH2 (160 mg 1.50 mmol) Et3N (340 mg 3.36 mmol) in THF (12 ml) for 20 h gave cis-(1R,4S)-4-benzylamino- 1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (426 mg 94%). The THP group was removed according to the preparation of (+)-(1R,4S)-6a in 69% yield (65% in two steps); spectral data as for (±)-6b; [a]D 25 +4.2 (c 1.79 in EtOH); ee �98%. (B) Synthesis of the trans-4-aminocyclohex-2-enols (±)-trans-1-Acetoxy-4-diethylaminocyclohex-2-ene 11a. The general procedure described for 10b was used but 25 mol% of LiCl was added to the reaction mixture together with the catalyst phosphine and amine.Allylic substrate 9 (131 mg 0.750 mmol) Pd(dba)2 (22 mg 0.037 mmol) PPh3 (40 mg 0.153 mmol) LiCl (8 mg 0.189 mmol) HNEt2 (165 mg 2.26 mmol) in THF (7.5 ml) for 20 h yielded 11a (113 mg 71%); dH(300 MHz; CDCl3) 1.04 (6 H app t J 7.2 CH3) 1.41–1.61 (2 H m CH2) 1.81–1.91 (1 H m CH2) 2.04 (3 H s COCH3) 2.11–2.20 (1 H m CH2) 2.34–2.61 (4 H m NCH2) 3.40–3.53 (1 H m CHNEt2) 5.26–5.38 (1 H m CHOAc) 5.64–5.73 (1 H m olefinic) and 5.76–5.85 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.2 (NCH2CH3) 21.2 (CH3CO2) 22.3 (CH2CHN) 28.2 (CH2CHOAc) 44.1 (NCH2) 56.4 (CHN) 70.1 (CHOAc) 129.2 (olefinic CHCHN) 134.8 (olefinic CHCHOAc) and 170.8 (C]] O); m/z (LC prior to ES-MS) 212 ([M + H]+ 82%) 139 (66%) 79 (7%) 61 (13%) and 60 (100%).Spectroscopic data for the corresponding g-product to 11a. (±)-trans-4-Acetoxy-3-diethylaminocyclohexene; dH(400 MHz; CDCl3) 1.01 (6 H app t J 7.1 CH3) 1.56–1.75 (2 H m CH2) 1.86–1.96 (1 H m CH2) 2.04 (3 H s COCH3) 2.07–2.20 (1 H m CH2) 2.53 (4 H app q NCH2) 3.36–3.43 (1 H m CHNEt2) 5.00 (1 H ddd J 11.1 7.7 3.6 CHOAc) 5.53–5.60 (1 H m olefinic) and 5.74–5.82 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.5 21.5 24.0 27.6 44.4 60.4 70.9 127.7 128.9 and 170.6. trans-(1S,4S)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1S,4S)-11a. The same procedure was used as for racemic 11a but starting from (2)-9. Spectral data are in accordance with the racemate. trans-(1R,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1R,4R)-11a.The same procedure was used as for racemic 11a but starting from (+)-9. Spectral data are in accordance with the racemate. (±)-trans-4-Diethylaminocyclohex-2-enol 7a. This substance was prepared from amino acetate 11a using the same hydrolysis conditions as for 6a in 96% yield; dH(300 MHz; CDCl3) 1.01 (6 H app t CH3) 1.32–1.53 (2 H m 6-H) 1.76–1.89 (1 H m 5-H) 2.06–2.18 (1 H m 5-H) 2.31–2.59 (4 H m NCH2) 2.60– 2.80 (1 H br s OH) 3.37–3.47 (1 H m 1-H) 4.16–4.28 (1 H m 4-H) and 5.63–5.79 (2 H m 5-H and 6-H); dC(100.6 MHz; CDCl3 8 peaks) 14.1 (CH3) 22.4 (CH2) 32.5 (CH2) 44.1 (NCH2) 56.6 (CHNEt2) 67.3 (CHOAc) 132.4 (CH olefinic) 133.6 (CH olefinic); m/z (LC prior to ES-MS) 170 ([M + H]+ 100%); nmax/cm21 3331 (OH br) 2968 2935 2864 1451 1384 and 1065. (2)-trans-(1S,4S)-4-Diethylaminocyclohex-2-enol (2)- (1S,4S)-7a.Preparation as for (±)-7a but with (1S,4S)-11a as the substrate. Same spectral data as for (±)-7a; [a]D 25 2102 (c 1.165 in EtOH); ee �98%. (+)-trans-(1R,4R)-4-Diethylaminocyclohex-2-enol (+)- (1R,4R)-7a. Preparation as for (±)-7a but with (1R,4R)-11a as the subse spectral data as for (±)-7a; [a]D 25 +98 (c 0.600 in EtOH). (±)-trans-1-Acetoxy-4-benzylaminocyclohex-2-ene 11b. The general procedure described for 10b was used but 25 mol% of LiCl was added to the reaction mixture together with the catalyst phosphine and amine. Amounts used were trans-chloro acetate 9 (720 mg 4.13 mmol) Pd(dba)2 (124 mg 0.21 mmol) PPh3 (162 mg 0.62 mmol) LiCl (44 mg 1.03 mmol) BnNH2 (531 mg 4.95 mmol) and Et3N (1.25 g 12.37 mmol) in THF (36 ml). The reaction mixture was stirred at RT for 20 h to give on work-up the amino acetate 11b (770 mg 76%); dH(400 MHz; CDCl3) 1.45–1.64 (2 H m CH2) 1.99–2.19 (2 H m CH2) 2.04 (3 H s COCH3) 2.58 (1 H br s NH) 3.27–3.33 (1 H m CHNHBn) 3.83 3.86 (2 H AB-system JAB 13.2 PhCH2NH) 5.28–5.34 (1 H m CHOAc) 5.72 (1 H dddd J 10.4 3.2 2.0 1.2 olefinic CHCHOAc) 5.93 (1 H dddd J 10.4 2.8 1.6 1.2 olefinic CHCHN) and 7.20–7.45 (5 H m Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.2 (COCH3) 26.9 (CH2CHOAc) 27.3 (CH2CHN) 50.6 (CH2Ph) 52.2 (CHN) 69.1 (CHOAc) 127.0 (CH Ph) 127.9 (olefinic CHCHOAc) 128.1 (CH Ph) 128.4 (CH Ph) 133.8 (olefinic CHCHN) 139.8 (C Ph) and 170.6 (C]] O); m/z (LC prior to ES-MS) 246 ([M + H]+ 100%) 139 (54%) 108 (3%) 79 (5%) and 61 (6%).Spectroscopic data for the corresponding g-product to 11b (±)-trans-4-acetoxy-3-benzylaminocyclohexene; dH(400 MHz; CDCl3) 1.65–2.05 (3 H br s and two m overlapping CH2 NH) 2.10–2.19 (2 H m CH2) 3.25–3.33 (1 H m CHNH) 3.83 3.88 (2 H AB-system JAB 13.3 PhCH2NH) 4.99 (1 H ddd J 8.9 6.3 and 3.1 CHOAc) 5.62–5.69 (1 H m olefinic) 5.76–5.84 (1 H m olefinic) and 7.18–7.38 (5 H m aromatic); dC(100.6 MHz; CDCl3 13 peaks) 21.4 23.2 25.2 50.5 56.5 72.6 126.9 127.1 128.1 128.3 128.8 140.6 and 170.8.trans-(1S,4S)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4S)-11b. The same procedure was used as for racemic 11b but starting from (2)-9. Spectral data are in accordance with the racemate. trans-(1R,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1R,4R)-11b. The same procedure was used as for racemic 11b but starting from (+)-9. Spectral data are in accordance with the racemate.(±)-trans-4-Benzylaminocyclohex-2-enol 7b. The title compound was prepared from amino acetate 11b using the same hydrolysis conditions as for 6a in 98% yield; dH(400 MHz; CDCl3) 1.36–1.51 (2 H m CH2) 1.57–1.68 (2 H br s NH and OH) 2.03–2.15 (2 H m CH2) 3.24–3.28 (1 H m CHNH) 3.82 3.85 (2 H AB-system JAB 13.0 PhCH2NH) 4.23–4.26 (1 H m CHOH) 5.75–5.83 (2 H m olefinic) and 7.22–7.34 (5 H m Ph); dC(100.6 MHz; CDCl3 11 peaks) 27.9 (CH2) 31.2 (CH2) 50.8 (CH2Ph) 52.7 (CHN) 66.8 (CHOH) 127.1 (CH Ph) 128.2 (CH Ph) 128.5 (CH Ph) 132.0 (CH olefinic) 132.1 (CH olefinic) and 140.1 (C Ph). (2)-trans-(1S,4S)-4-Benzylaminocyclohex-2-enol (2)- (1S,4S)-7b. Preparation as for (±)-7b but with (1S,4S)-11b as the substrate. Same spectral data as for (±)-7b; [a]D 25 2122 (c 1.773 in EtOH); ee �98%.(+)-trans-(1R,4R)-4-Benzylaminocyclohex-2-enol (+)- (1R,4R)-7b. Preparation as for (±)-7b but with (1R,4R)-11b as the substrate. Same spectral data as for (±)-7b; [a]D 25 +120 (c 1.394 in EtOH); ee �98%. (C) Synthesis of the allylic substrates (±)-cis-4-Acetoxycyclohex-2-enol (±)-2a. 1,4-Diacetoxycyclohex- 2-ene 6 (17.39 g 87.72 mmol) and K2CO3 (606 mg 4.39 mmol) were dissolved in methanol–water (4 1; 150 ml) and the 582 J. Chem. Soc. Perkin Trans. 1 1997 solution stirred at RT for 40 min. It was then neutralised with 1 M aq. HCl and the methanol was removed in vacuo. The aqueous phase was saturated with NaCl and extracted with EtOAc and the extract was dried (MgSO4) and concentrated. The residue was separated on silica (gradient EtOAc–pentane) to give 2a (8.118 g 59%). The spectral data were consistent with those previously reported.4 (2)-cis-(1R,4S)-4-Acetoxycyclohex-2-enol (2)-(1R,4S)-2a.Preparation according to ref. 4. cis-1-Acetoxy-4-chlorocyclohex-2-ene 8. The preparation was carried out as in ref. 5 and the spectral data were in accord with those reported therein. (±)-trans-1-Acetoxy-4-chlorocyclohex-2-ene 9. To N-chlorosuccinimide (806 mg 6.04 mmol) in THF (7 ml) under nitrogen was added a solution of PPh3 (1.575 g 6.01 mmol) in THF (7 ml). A slightly exothermic reaction ensued. After the reaction mixture had cooled to room temperature the alcohol 2a (632 mg 4.047 mmol) dissolved in THF (6 ml) was added to it; the mixture was then stirred at room temperature for 15 h. The solvent was removed and the residue was dissolved in a small amount of CH2Cl2 and purified on silica (diethyl ether–pentane 5 95) to give the title compound 9 (684 mg 97%).About 4% of the corresponding SN29-product was formed in the reaction. Spectral data for 9 were in accord with those reported in ref. 5. (2)-trans-(1S,4S)-1-Acetoxy-4-chlorocyclohex-2-ene (2)- (1S,4S)-9. This compound was prepared in the same way as for the racemic compound 9 starting from (2)-2a. [a]D 25 2395 (c 1.01 in EtOH); 2.5% of the SN29-product contaminated the product. (+)-trans-(1R,4R)-1-Acetoxy-4-chlorocyclohex-2-ene (+)- (1R,4R)-9. To a solution of compound 20c (594 mg 2.406 mmol) in THF (15 ml) was added tetrabutylammonium fluoride (TBAF) (1 M soln. in THF 2.53 ml 2.53 mmol) at room temperature. After 3 h acetic anhydride (2.3 ml 24.4 mmol) was added to the reaction mixture which was then stirred for an additional 12 h.It was then evaporated and the residue was separated on silica (gradient ether–pentane 5 95–15 85) to give the title compound (+)-9 (347 mg 83%). Spectral data were in accord with those reported in ref. 5; [a]D 25 +415 (c 0.89 in EtOH). cis-(1R,4S)-4-Acetoxycyclohex-2-enyl diphenylphosphinate (1R,4S)-16. The title compound was synthesized from the alcohol (2)-2a (1.00 g 6.32 mmol) according to procedure A reported in ref. 14 (reaction time 30 h) except that in the aqueous work-up the organic extract was washed with saturated copper sulfate (3×) water (1×) and brine (1×) before being dried (MgSO4). After evaporation of the extract the crude product was filtered through basic alumina eluting with diethyl ether. Removal of the ether afforded a colourless oil of the title compound 16 (2.02 g 89%) which was sufficiently pure for the next step; dH(400 MHz; CDCl3) 1.80–1.94 (3 H m CH2) 2.01– 2.06 (1 H m CH2) 2.06 (3 H s COCH3) 4.84–4.91 [1 H m CHOP(O)Ph2] 5.15–5.20 (1 H m CHOAc) 5.83–5.96 (2 H m olefinic) 7.44 (4 H o-Ph) 7.51 (2 H m p-Ph) 7.82 (4 H tdd 2JHP 12.6 JHH 8.2 1.4 o-Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.1 (CH3CO2) 24.6 (CH2CHOAc) 26.9 (d 3JCP 3.8 CH2CHOP) 67.0 (CHOAc) 69.0 (d 2JCP 6.0 CHOP) 128.4 (d 3JCP 12.2 aromatic CH) 129.9 (olefinic CHCHOAc) 131.5 (d 2JCP 17.5 aromatic CH) 131.5 (d 3JCP 3.0 olefinic CHCHOP) 131.87 (d 1JCP 136.6 aromatic C) 131.92 (d 4JCP 137.3 aromatic C) 132.1 (d 4JCP 1.5 aromatic CH) and 170.2 (C]] O); m/z (NH4CO2 added prior to ES-MS) 379 ([M + Na]+ 5%) 374 ([M + NH4]+ 4%) 357 ([M + H]+ 50%) 297 (3%) 219 (11%) 139 (100%) and 79 (6%).cis-(1R,4S)-4-Acetoxycyclohex-2-enyl 2,4-dichlorobenzoate (1R,4S)-17. A solution of cis-4-acetoxycyclohex-2-enol (2)-2a (953 mg 6.10 mmol) 2,4-dichlorobenzoic acid (1.72 g 9.00 mmol) dicyclohexylcarbodiimide (DCC) (1.86 g 9.01 mmol) and p-dimethylaminopyridine (DMAP) (16 mg 0.13 mmol) in methylene dichloride (50 ml) was stirred at RT for 3 h. Diethyl ether (50 ml) was added to the reaction mixture which was then washed with cold 5% aq. HCl (2 × 25 ml) and saturated aqueous NaHCO3 (3 × 25 ml) dried (MgSO4) and concentrated. The crude product was filtered through basic alumina and purified on silica using MPLC (EtOAc–CH2Cl2 1 1 gradient in pentane) to give the title compound 17 (1.61 g 80%); dH(300 MHz; CDCl3) 1.90–2.06 (4 H m 2 × CH2) 2.07 (3 H s COCH3) 5.23–5.33 (1 H m CHOAc) 5.39–5.51 [1 H m CHOC(O)Ar] 5.94–6.05 (2 H m olefinic) 7.29 (1 H dd J 8.4 and 2.0 ArH) 7.47 (1 H d J 2.0 ArH) and 7.79 (1 H d J 8.4 ArH); dC(100.6 MHz; CDCl3 15 peaks) 21.1 (CH3CO2) 24.8 (CH2) 25.0 (CH2) 67.4 (CHOA8.6 [CHOC(O)Ar] 126.9 (aromatic CHCHCCl) 128.4 (aromatic C) 129.3 [olefinic CHCHOC(O)Ar] 130.9 (aromatic CClCHCCl) 131.2 (olefinic CHCHOAc) 132.4 (aromatic CCHCH) 134.8 (aromatic C) 138.2 (aromatic C) 164.2 (C]] O) and 170.4 (C]] O); m/z 273 (0.6%) 271 (5%) 269 (7%) 177 (12%) 175 (65%) 173 (100%) 149 (2%) 147 (8%) 145 (12%) 139 (12%) 96 (43%) and 79 (26%); [a]D 25 +56 (c 1.16 in EtOH).(+)-cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enol (+)-(1S,4R)-18a. To (2)-2a (535 mg 3.38 mmol) dissolved in methylene dichloride (30 ml) was added dihydropyran (DHP) (425 mg 5.05 mmol) and pyridinium toluene-p-sulfonate (PPTS) (85 mg 0.338 mmol).The solution was stirred at RT for 4 h after which it was diluted with diethyl ether (100 ml) washed with brine–water (1 1; 20 ml) and concentrated. The resulting crude product was dissolved in methanol (5 ml) and treated with K2CO3 (23 mg 0.17 mmol) in water (1 ml). After being stirred at RT for 5 h the reaction mixture was diluted with water (10 ml) and then concentrated by evaporation of most of the methanol. The aqueous phase was extracted with diethyl ether (3 × 50 ml) and the combined organic fractions were then washed with brine (20 ml) dried (MgSO4) and concentrated. Purification of the residue on silica (diethyl ether–pentane 60 40) gave the title compound 18a (650 mg 98%) (Found C 65.9; H 8.8.Calc. for C11H18O3 C 66.6; H 9.15%); dH(400 MHz; CDCl3) 1.48–1.94 (10 H m 5- H 6-H 8-H 9-H and 10-H) 3.45–3.54 (1 H m 11-H) 3.86– 3.97 (1 H m 11-H) 4.08–4.18 (2 H m 4-H and 7-H) 4.72– 4.78 (1 H m 1-H) and 5.88–5.91 (2 H m 2-H and 3-H); dC(100.6 MHz; CDCl3) 19.5 (C-9) 24.3 and 26.2 (C-5) 25.3 and 25.4 (C-10) 28.1 and 28.5 (C-6) 30.9 and 31.0 (C-8) 62.4 and 62.5 (C-11) 65.1 and 65.2 (C-1) 68.9 and 70.0 (C-4) 96.8 and 97.8 (C-7) 130.1 and 131.3 (olefinic) 132.5 and 132.6 (olefinic); m/z (M+ >0.5%) 97 (51%) 85 (90%) 79 (63%) 67 (64%) 57 (65%) and 55 (100%); nmax/cm21 3404 (OH br) 2942 2869 1133 1074 1032 and 1000; [a]D 25 +38.1 (c 0.91 in CH2Cl2). cis-4-Pivaloyloxycyclohex-2-enol 18b. To a solution of the hydroxyacetate 2a (1.00 g 6.402 mmol) Et3N (3.24 g 32.01 mmol) and DMAP (22 mg 0.180 mmol) in THF (25 ml) was added pivaloyl chloride (1.58 ml 12.81 mmol).The reaction mixture was stirred at 50 8C for 24 h after which the solvent was removed and ether (60 ml) was added to the residue. The solution was washed with 1 M hydrochloric acid (× 3) sat’d aqueous NaHCO3 and brine dried (MgSO4) and concentrated. Separation of the residue on silica (diethyl ether–pentane 3 97 then 5 95) yielded cis-4-acetoxy-1- pivaloyloxycyclohex-2-ene (1.485 g 95%); dH(400 MHz; CDCl3) 1.19 (9 H s But) 1.77–1.96 (4 H m CH2) 2.07 (3 H s COCH3) 5.15–5.24 (2 H m CHOAc CHOPiv) and 5.81– 5.91 (2 H m olefinic); dC(100.6 MHz; CDCl3 11 peaks) 21.3 24.8 24.9 27.1 38.7 66.9 67.4 130.0 130.5 170.5 178.0. Selective hydrolysis of the acetate (1.112 g 4.627 mmol) was performed with a 10% solution of Na2CO3?10 H2O (133 mg 0.465 mmol) in MeOH–H2O (4 1 23 ml) at RT for 9 h.After removal of the methanol from the mixture it was extracted with ether and the extract dried (Na2SO4) and concentrated to give the title compound 18b (839 mg 92%); dH(400 MHz; J. Chem. Soc. Perkin Trans. 1 1997 583 CDCl3) 1.18 (9 H s But) 1.62–1.98 (5 H m CH2 OH) 4.14– 4.26 (1 H m CHOH) 5.10–5.24 (1 H m CHOPiv) 5.73–5.84 (1 H m olefinic) and 5.90–6.00 (1 H m olefinic); dC(100.6 MHz; CDCl3 9 peaks) 24.9 (C-5) 27.1 (C-9) 28.1 (C-6) 38.7 (C-8) 65.3 (C-1) 66.9 (C-4) 128.0 (C-3) 134.5 (C-2) and 178.1 (C-7); m/z 180 (2%) 113 (3%) 97 (23%) 96 (67%) 95 (14%) 85 (21%) 79 (21%) and 57 (100%). cis-(1S,4R)-4-(tert-Butyldimethylsilyloxy)cyclohex-2-enol (1S,4R)-18c.To a stirred solution of 21c (3.256 g 12.039 mmol) was added KOH (135 mg 2.408 mmol) in methanol (40 ml). The reaction mixture was stirred at RT for 4 h after which the solvent was removed and the residue was treated with water (30 ml) and diethyl ether (60 ml); the layers were separated and the pH of the aqueous layer was adjusted to 7 with 1 M hydrochloric acid; it was then further extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the product (2.698 g 98%) which was pure enough for the next step; dH(400 MHz; CDCl3) 0.073 (3 H s SiCH3) 0.076 (3 H s SiCH3) 0.89 [9 H s SiC(CH3)3] 1.60–1.90 (5 H m 2 × CH2 OH) 4.06–4.18 (2 H two overlapping m CHOH CHOSi) 5.75 (1 H dd J 10.2 and 2.4 olefinic) and 5.79 (1 H dd J 10.2 and 3.1 olefinic); dC(100.6 MHz; CDCl3 10 peaks) 24.7 (C-7) 24.6 (C-79) 18.1 (C-8) 25.8 (C-9) 28.2 (C-5) 28.4 (C-6) 64.8 (C-1) 66.3 (C-4) 130.7 (C-2) and 133.9 (C-3); [a]D 25 +34 (c 1.58 in EtOH).cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enyl 2,4- dichlorobenzoate (1S,4R)-19. A solution of DCC (1.297 g 6.285 mmol) and DMAP (13 mg 0.105 mmol) in methylene dichloride (10 ml) was added to a stirred solution of 18a (1.246 g 6.285 mmol) and 2,4-dichlorobenzoic acid (1.200 g 6.285 mmol) in methylene dichloride (25 ml) at RT. The solution was stirred at RT for 10 h after which it was diluted with diethyl ether (300 ml). The organic phase was washed with 5% aqueous acetic acid (50 ml) water (20 ml) and brine (20 ml) dried (MgSO4) and concentrated. Purification of the residue on silica (diethyl ether–pentane 60 40) gave the title compound 19 (2.20 g 87%); dH(400 MHz; CDCl3) 1.43–2.07 (10 H m 5-H 6-H 8-H 9-H and 10-H) 3.47–3.54 (1 H m 11-H) 3.86–3.94 (1 H m 11-H) 4.15–4.27 (1 H two overlapping m 4-H) 4.73–4.78 (1 H m 7-H) 5.39–5.45 (1 H m 1-H) 5.89–5.95 (1 H m 3-H) and 6.01–6.09 (1 H m 2-H); dC(100.6 MHz; CDCl3) 19.5 and 19.6 (CH2) 24.4 and 26.3 (CH2) 25.2 and 25.4 (CH2) 25.5 and 26.1 (CH2) 30.9 and 31.0 (CH2) 62.5 and 62.6 (CH2) 68.7 and 68.8 [allyl-CHOC(O)Ar] 69.3 and 70.4 (allyl-CHOTHP) 97.0 and 98.1 (THP-OCHO) 126.9 (aromatic CH) 127.0 and 127.1 [olefinic CHCHOC(O)Ar] 128.5 (aromatic C) 130.9 (aromatic CH) 132.5 (aromatic CH) 133.8 and 134.9 (olefinic CHCHOTHP) 135.8 (aromatic C) 138.1 (aromatic C) and 164.2 (C]] O); m/z 273 (19%) 271 (29%) 194 (6%) 192 (61%) 190 (81%) 177 (12%) 175 (68%) 173 (100%) 147 (12%) and 145 (28%).trans-1-Chloro-4-(tetrahydropyran-2-yloxy)cyclohex-2-ene 20a. A solution of 18a (100 mg 0.504 mmol) LiCl (46 mg 1.08 mmol) and 2,4,6-trimethylpyridine (504 ml 3.78 mmol) in DMF (750 ml) was cooled to 0 8C and treated with MsCl (58 ml 0.83 mmol) followed after 20 min by diethyl ether (40 ml). The solution was washed with water (5 ml) and brine (5 ml) dried (MgSO4) and concentrated. The residue was purified on silica (diethyl ether–pentane 40 60) to give the title compound 20a (98 mg 90%). Since the product is extremely unstable it should be prepared directly before further use; dH(400 MHz; CDCl3) 1.40–2.40 (10 H m 5-H 6-H 8-H 9-H 10-H) 3.43–3.58 (1 H m 11-H) 3.83–3.98 (1 H m 11-H) 4.16–4.30 (1 H m 4-H) 4.54–4.65 (1 H m 7-H) 4.66–4.80 (1 H m 1-H) and 5.82–6.03 (2 H m olefinic); dC(100.6 MHz; CDCl3) 19.7 25.4 25.4 25.5 27.5 29.3 29.7 29.8 31.1 31.1 54.6 54.6 62.6 62.7 68.3 69.0 97.3 98.1 130.4 130.6 131.1 and 131.7.trans-1-Chloro-4-pivaloyloxycyclohex-2-ene 20b. Triphenylphosphine (836 mg 3.19 mmol) dissolved in THF (3 ml) was added to a solution of N-chlorosuccinimide (426 mg 3.19 mmol) in THF (5 ml) to give slightly exothermic phosphonium salt formation. After cooling of the reaction mixture to RT (20 min) 18b (416 mg 2.098 mmol) in THF (3 ml) was added to it; it was then stored at RT for 24 h. After this the solvent was evaporated from the mixture and pentane was added to the residue. The precipitated triphenylphosphine oxide and succinimide were filtered off and the pentane was removed in vacuo to give a residue which was purified on silica (EtOAc–pentane 1 99).This afforded 20b (305 mg 67%) (8% of the reaction product was derived from the SN29 substitution mechanism); dH(400 MHz; CDCl3) 1.17 (9 H s But) 1.68–1.78 (1 H m CH2) 1.94–2.04 (1 H m CH2) 2.12–2.32 (2 H m CH2) 4.57– 4.64 (1 H m CHCl) 5.20–5.28 (1 H m CHOPiv) 5.82–5.89 (1 H m olefinic) and 5.98–6.04 (1 H m olefinic); dC(100.6 MHz; CDCl3 9 peaks) 24.8 (CH2) 27.1 (CH3) 28.7 (CH2) 38.7 (C) 53.6 (CHCl) 65.7 (CHOPiv) 128.3 (olefinic CH) 132.3 (olefinic CH) and 177.8 (C]] O). trans-(1R,4R)-1-Chloro-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene (1R,4R)-20c. To compound 18c (1.503 g 6.58 mmol) was added LiCl (558 mg 13.16 mmol) and Et3N (2.75 ml 19.74 mmol) in CH2Cl2 (25 ml). The solution was cooled to 220 8C and MsCl (610 ml 7.881 mmol) was added to it via a syringe.The mixture was brought to RT over 3 h after which it was stirred for a further 17 h. It was then diluted with water– NaHCO3 (sat’d) (1 1; 30 ml) and the phases were separated. The aqueous phase was extracted with diethyl ether (3 × 70 ml). The combined organic phases were washed with brine (20 ml) dried (MgSO4) and passed through a silica column packed with Et3N–diethyl ether–pentane (4 2 94). Elution with diethyl ether–pentane (2 98 then 5 95) gave the title compound 20c (1.484 g 91%); dH(400 MHz; CDCl3) 0.08 (6 H s SiCH3 × 2) 0.89 [9 H s SiC(CH3)3] 1.60–1.67 (1 H m CH2) 1.84–1.93 (1 H m CH2) 2.02–2.11 (1 H m CH2) 2.29–2.37 (1 H m CH2) 4.23–4.27 (1 H m CHOSi) 4.56–4.60 (1 H m CHCl) 5.77 (1 H dd J 10.4 and 3.1 olefinic) and 5.82 (1 H dd J 10.4 and 3.2 olefinic); dC(100.6 MHz; CDCl3 10 peaks) 24.7 (C-7) 24.6 (C-79) 18.2 (C-8) 25.8 (C-9) 29.7 (C-6) 29.9 (C-5) 54.9 (C-1) 64.9 (C-4) 129.5 (C-2) and 133.5 (C-3); m/z 248 (1%) 246 (2%) 191 (24%) 189 (64%) 93 (18%) 77 (15%) and 75 (100%); [a]D 25 +259 (c 1.75 in EtOH).cis-(1S,4R)-1-Acetoxy-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene (1S,4R)-21c. A solution of TBDMS-Cl (2.665 g 17.68 mmol) in methylene dichloride (40 ml) was cooled to 0 8C and imidazole (6.74 g 99.0 mmol) was added to it. After 5 min (2)- 2a (2.209 g 14.14 mmol) dissolved in methylene dichloride (30 ml) was added to the mixture which was then stirred at 0 8C for ca. 30 min and then at RT for 20 h. After being quenched with water (10 ml) the reaction mixture was extracted with methylene dichloride (3 × 50 ml).The combined organic fractions were washed with brine (20 ml) dried (Na2SO4) concentrated and subjected to chromatography (diethyl ether–pentane 5 95) to give the title compound 21c (3.79 g 99%); dH(400 MHz; CDCl3) 0.078 (3 H s SiCH3) 0.082 (3 H s SiCH3) 0.90 [9 H s SiC(CH3)3] 1.65–1.95 (4 H m 2 × CH2) 2.04 (3 H s COCH3) 4.15–4.19 (1 H m CHOSi) 5.13–5.17 (1 H m CHOAc) 5.71–5.75 (1 H m olefinic) and 5.85–5.88 (1 H m olefinic); dC(100.6 MHz; CDCl3) 24.7 (SiCH3) 24.6 (SiCH3) 18.1 (SiC) 21.2 (COCH3) 25.3 (CH2CHOAc) 25.8 [SiC(CH3)3] 28.4 (CH2CHOSi) 66.3 (CHOSi) 67.0 (CHOAc) 126.2 (olefinic CHCHOAc) 136.3 (olefinic CHCHOSi) and 170.6 (C]] O); m/ z 210 (2%) 117 (100%) 79 (12%) and 75 (33%); [a]D 25 240 (c 1.63 in EtOH). Acknowledgements Financial support from the Swedish Natural Science Research Council The Research Council of the Board of Technical Development and the Swedish Research Council for Engineering Sciences is gratefully acknowledged.584 J. Chem. Soc. Perkin Trans. 1 1997 References 1 (a) C. R. Johnson P. A. Plé and J. P. Adams J. Chem. Soc. Chem. Commun. 1991 1006; (b) T. Hudlicky and H. F. Olivo Tetrahedron Lett. 1991 32 6077; (c) L. Dumortier P. Liu S. Dobbelaere J. van der Eycken and M. Vandewalle Synlett 1992 243; (d ) C. R. Johnson P. A. Plé L. Su L. M. J. Heeg and J. P. Adams Synlett 1992 388. 2 (a) S. Knapp A. B. J. Naughton and T. G. Murali Dhar Tetrahedron Lett. 1992 33 1025; (b) K. Ramesh M. S. Wolfe Y. Lee D. Vander Velde and R. T. Borchardt J. Org. Chem. 1992 57 5861; (c) N. Dyatkina B. Costisella F. Theil and M. von Janta-Lipinski Tetrahedron Lett.1994 35 1961; (d ) N. Dyatkina F. Theil and M. von Janta-Lipinski Tetrahedron 1995 51 761. 3 J. E. Bäckvall R. Gatti and H. E. Schink Synthesis 1993 343. 4 Alcohol (2)-2a was prepared according to R. J. Kazlauskas A. N. E. Weissfloch A. T. Rappaport and L. A. Cuccia J. Org. Chem. 1991 56 2656. 5 Compound 8 was prepared according to J. E. Bäckvall J. E. Nyström and R. E. Nordberg J. Am. Chem. Soc. 1985 107 3676. 6 Racemic (±)-2a was prepared by selective hydrolysis (5% K2CO3 in MeOH–H2O) of cis-1,4-diacetoxycyclohex-2-ene which was prepared from cyclohexadiene according to J. E. Bäckvall S. E. Byström and S. E. Nordberg J. Org. Chem. 1984 49 4619. 7 (a) W. Oppolzer J.-M. Gaudin and T. N. Birkinshaw Tetrahedron Lett. 1988 29 4705; (b) A. K. Bose and B. Lal Tetrahedron Lett.1973 3937. 8 (a) A. Pfaltz Acc. Chem. Res. 1993 26 339; (b) N. W. Murral and A. J. Welch J. Organomet. Chem. 1986 301 109; (c) A. Pfaltz in Stereoselective Synthesis E. Ottow K. Schöllkopf and B.-G. Schulz eds. Springer-Verlag Berlin Heidelberg 1993 pp. 15–36. 9 (a) B. M. Trost and J. P. Genêt J. Am. Chem. Soc. 1976 98 8516; (b) B. M. Trost and E. Keinan J. Am. Chem. Soc. 1978 100 7779; (c) J. E. Bäckvall R. E. Nordberg J. E. Nyström T. Högberg and B. Ulff J. Org. Chem. 1981 46 3479; (d ) Y. Tanigawa K. Nishimura A. Kawasaki and S.-I. Murahashi Tetrahedron Lett. 1982 23 5549; (e) S. E. Byström R. Aslanian and J. E. Bäckvall Tetrahedron Lett. 1985 26 1749; (f ) J.-P. Genêt M. Balabane J. E. Bäckvall and J. E. Nyström Tetrahedron Lett. 1983 24 2745; (g) R. E. Nordberg and J.E. Bäckvall J. Organomet. Chem. 1985 285 C24. 10 (a) T. Hayashi K. Kishi A. Yamamoto and Y. Ito Tetrahedron Lett. 1990 31 1743; (b) R. Tanikaga T. X. Jun and A. Kaji J. Chem. Soc. Perkin Trans. 1 1990 1185; (c) J.-P. Genêt S. Thorimbert and A. M. Touzin Tetrahedron Lett. 1993 34 1159; (d ) P. von Matt O. Loiseleur G. Koch A. Pfaltz C. Lefeber T. Feucht and G. Helmchen Tetrahedron Asymmetry 1994 5 573. 11 J. E. Bäckvall K. L. Granberg and A. Heumman Isr. J. Chem. 1991 31 17. 12 R. Tanikaga J. Takeuchi M. Takyu and A. Kaji J. Chem. Soc. Chem. Commun. 1987 386. 13 L. Liebeskind and J. S. McCallum Synthesis 1993 819. 14 A. Hassner and V. Alexanian Tetrahedron Lett. 1978 35 5713. 15 (a) K. L. Granberg and J. E. Bäckvall J. Am. Chem. Soc. 1992 114 6858; (b) T. Takahashi Y. Jinbo K.Kitamura and J. Tsuji Tetrahedron Lett. 1984 25 5921; (c) P. B. Mackenzie J. Whelan and B. Bosnich J. Am. Chem. Soc. 1985 107 2046; (d ) T. Hayashi A. Yamamoto and T. Hagihara J. Org. Chem. 1986 51 723. 16 M. Miyashita A. Yoshikoshi and P. A. Grieco J. Org. Chem. 1977 42 3772. 17 J. E. Bäckvall K. L. Granberg and R. B. Hopkins Acta Chem. Scand. 1990 44 492. 18 O. Mitsunobu Synthesis 1981 1. 19 For a recent approach to Pd0-catalysed desymmetrisation of cycloalk-2-ene-1,4-diol derivatives leading to enantiopure 1,4- aminoalcohol derivatives see B. M. Trost and S. R. Pulley J. Am. Chem. Soc. 1995 117 10 143. 20 T. Ukai H. Kawazura Y. Ishii J. J. Bonnet and J. A. Ibers Organomet. Chem. 1974 65 253. 21 (a) J. A. Dale D. L. Dull and H. S. Mosher J. Org. Chem. 1969 34 2543; (b) J. A. Dale and H.S. Mosher J. Am. Chem. Soc. 1973 95 512. 22 J. K. Whitesell and D. Reynolds J. Org. Chem. 1983 48 3548. Paper 6/00779A Received 1st February 1996 Accepted 7th October 1996 J. Chem. Soc. Perkin Trans. 1 1997 577 Palladium-catalysed enantiodivergent synthesis of cis- and trans-4-aminocyclohex-2-enols Roberto G. P. Gatti Anna L. E. Larsson and Jan-E. Bäckvall * Department of Organic Chemistry University of Uppsala Box 531 S-751 21 Uppsala Sweden Enantiomerically pure cis- and trans-4-aminocyclohex-2-enols are prepared from cyclohexa-1,3-diene via (2)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a using palladium(0) chemistry. Benzylamine and diethylamine are tested in the Pd0-catalysed allylic amination reactions. Since acetate is too slow as a leaving group and gave considerable amounts of side products a number of leaving groups have been investigated.Of these phosphinate and 2,4-dichlorobenzoate are excellent leaving groups and result in efficient and highly stereoselective reactions; chloride as allylic leaving group also gives good results. By variation of the leaving group and proper choice of the protecting group it is possible to synthesise all four stereoisomers of 4-aminocyclohex-2-enol in good yield and high enantiomeric excess. Introduction 4-Aminocyclohex-2-enols are important structural elements in a number of biologically active compounds such as conduramines 1 and derivatives.2 In connection with a project dealing with new substances for treatment of bronchitis complications there was a need for a general synthesis of optically pure 4- aminocyclohex-2-enols.We recently reported a method for an enantiodivergent synthesis of 4-substituted 2-cycloalkenols from cycloalka-1,3- dienes with a combination of palladium and enzyme chemistry (Scheme 1).3 The method allows for preparation of both enantiomers with high selectivity. In the present paper we have used enantiomerically pure (2)- cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a as a key intermediate for further stereocontrolled palladium(0)-catalysed functionalisation and report on the enantiocontrolled synthesis of all four stereoisomers of 4-aminocyclohex-2-enol (Scheme 2). An interesting observation is that phosphinates are excellent leaving groups in the Pd0-catalysed allylic substitution with primary and secondary amines. Scheme 1 Results and discussion (A) Racemates The objective was to synthesise cis- and trans-4-aminocyclohex- 2-enols in optically pure form starting from (2)-2a.4 Diethylamine and benzylamine (BnNH2) were employed as representative amines in the palladium(0)-catalysed allylic aminations.First the allylic amination was performed to produce a racemic mixture of the amino alcohols (Scheme 3). Thus cis-4- diethylaminocyclohex-2-enol 6a and cis-4-benzylaminocyclohex- 2-enol 6b were prepared starting from cis-1-acetoxy-4- chlorocyclohex-2-ene 8.5 The racemic trans stereoisomers were synthesised from (±)- 2a.6 Substitution of the OH by chloride with PPh3 and Nchlorosuccinimide (NCS)7 in THF afforded trans-1-acetoxy-4- chlorocyclohex-2-ene 9. Pd0-catalysed allylic amination of chloroacetate 9 with diethylamine or benzylamine gave after hydrolysis trans-4-diethylaminocyclohex-2-enol 7a or trans-4- benzylaminocyclohex-2-enol 7b respectively.Amino alcohols 6 and 7 were used to set up a method for determination of the ee. However with 9 as the allylic substrate a moderate regioselectivity was observed. Using conditions A in Scheme 3 and diethylamine as the nucleophile about 20% of the g-substitution product (of trans stereochemistry) was obtained. Usually Scheme 2 578 J. Chem. Soc. Perkin Trans. 1 1997 attack at the 4-position relative to the acetate is strongly favoured in analogous 1,4-disubstituted alk-2-enes.5 However due to steric interaction between the acetate and the L2Pdgroup in p-allyl intermediate I (Fig. 1) palladium is forced away from the acetate which weakens the palladium–carbon bond in the 2-position.8 This will increase the relative rate of attack at the 2-position in I.When R is tert-butyl II the relative amount of attack in the 2-position increased to 50–60% in the corresponding reaction (vide infra). The reaction conditions were further investigated by variation of the solvent amount of catalyst and ligand and by addition of salt (LiCl). The system with Pd(dba)2 and PPh3 in THF with an addition of 25 mol% LiCl decreased the amount of g-product of I from 20 to 13% with Et2NH and from 12 to 5% with BnNH2. (B) cis Enantiomers It has been shown that acetate can be used as a leaving group in Pd0-catalysed allylic amination with both primary and secondary amines.9 However when (±)-2a was treated with benzylamine in the presence of Pd(dba)2 PPh3 and Et3N in THF the conversion was low.In an attempt to improve the reaction different catalysts ligands and solvents were tried together with variation of the concentration and temperature. The best results were obtained with acetonitrile as the solvent at a reaction temperature of 40 8C. However the yield of the desired product 6 was still unsatisfactory with considerable amounts of g-product as well as inversion and elimination products.† Therefore better leaving groups were called for. To increase the reactivity in the Pd0-catalysed nucleophilic displacement the hydroxy group in 2a was transformed into a reactive leaving group. It has been reported in the literature that ethyl and methyl carbonate can be used as a leaving group in Pd0- Scheme 3 Reagents and conditions A 5% Pd(dba)2 15% PPh3 1.2–3 equiv.NHR1R2 3 equiv. Et3N in THF RT N2 or Ar atm 10a (77%) 10b (81%); B K2CO3 in MeOH–H2O at RT 6a (95%) 6b (98%) 7a (96%) 7b (98%); C NCS PPh3 THF RT (97%); D reagents as for A but longer reaction times and 25% LiCl added to the reaction mixture 11a (71%) 11b (76%) Fig. 1 Weaker bond in the 2-position because of steric interactions which increase the relative amount of g-substitution product † Loss of regio- and stereo-selectivity has previously been observed in Pd-catalysed reaction of allylic acetates with amines.9b,g catalysed allylic amination 10 but carbonate 12 gave the nondesired carbamate 13 on reaction with benzylamine [eqn. (1)].‡ The same results for similar substrates have been reported earlier in our laboratory 11 and elsewhere.12 The use of trifluoroacetate 14 in the corresponding reaction gave 2a and Nbenzyltrifluoroacetamide presumably because of faster nitrogen attack at the carbonyl carbon rather than formation of the p-allyl complex.Attempts to use a diethylphosphate ester 9d,e as the leaving group failed since 15 was very sensitive and hydrolysed quickly after preparation. We next tried diphenylphosphinic and benzoate esters. Diphenylphosphinic ester 16 was prepared from enantiomerically pure (2)-2a (89%) according to Liebeskind et al.13 and 2,4- dichlorobenzoate ester 17 was prepared (80% yield) by esterifi- cation of (2)-2a following the method of Hassner.14 Both 16 and 17 were excellent substrates in the Pd0-catalysed allylic amination with diethylamine and benzylamine and afforded the amino acetates (1S,4R)-10a and (1S,4R)-10b which upon hydrolysis yielded the amino alcohols (1S,4R)-6a and (1S,4R)- 6b respectively (Scheme 4).In each case the allylic amination was highly stereoselective and the enantiomeric excess (ee) of the amino alcohols was �98% in both cases. For (1S,4R)-6a 2% of the trans isomer was observed. An explanation could be isomerisation of the p-allyl intermediate by nucleophilic attack by free Pd0 on the allyl ligand.15 To form a carbon–nitrogen bond at the other allylic carbon in (2)-2a it was necessary to protect the hydroxy group and then selectively hydrolyse the acetate before attachment of a leaving group (Scheme 5). The hydroxy acetate (2)-2a was transformed into the alcohol 18a with tetrahydropyran (THP) protection 16 and subsequent hydrolysis of the acetoxy group. The alcohol 18a was transformed into its 2,4-dichlorobenzoate ester 19 (vide supra) which on Pd0-catalysed amination and subsequent removal of the THP group afforded (1R,4S)-6a and (1R,4S)-6b.Scheme 4 Reagents and conditions A 5% Pd(dba)2 15% PPh3 1.2–3 equiv. NHR1R2 3 equiv. Et3N in THF at RT N2 or Ar atm 16 to 10a (82%) 16 to 10b (79%) 17 to 10a (73%) 17 to 10b (70%); B K2CO3 in MeOH–H2O at RT yields as for step B shown in Scheme 3 ‡ The reaction proceeds via a (p-allyl)palladium intermediate.11 J. Chem. Soc. Perkin Trans. 1 1997 579 (C) trans Enantiomers Reaction of the enantiomerically pure hydroxy acetate (2)-2a with NCS and PPh3 in THF afforded optically active (1S,4S)-9 with high stereospecificity (cf. racemic reaction Scheme 3). Subsequent Pd0-catalysed allylic amination employing Et2NH and BnNH2 followed by hydrolysis gave (1S,4S)-7a and (1S,4S)-7b respectively [eqn.(2)]. The yields were the same as for the racemates (Scheme 3) and the ee was in each case � 98%. When preparing the other trans enantiomer the group at the other stereogenic carbon had to be substituted. Some difficulties were encountered when solving this problem. Substitution of the hydroxy group in 18a by chloride with inversion using LiCl methanesulfonyl chloride (MsCl) 2-trimethylpyridine in DMF and subsequent Pd0-catalysed allylic amination of the allylic chloride 20a should in analogy to the preparation of (1S,4S)-7 from (1S,4S)-9 give (1R,4R)-7 after removal of the protecting group. Unfortunately and to a much greater extent than what had been seen for 9 the predominant product was the g-substitution product (vide supra).Using pivalate § as protecting group instead of THP led to the same discouraging result (Scheme 6). For example with the pivalate 20b the amount of g-substitution product was 50–60% with diethylamine. This result supports the explanation suggested in Fig. 1 for the increased relative amount of g-isomer. The use of tert-butyldimethylsilyl (TBDMS)¶ led to decomposition of the silyl ether bond in the amination. Another way to reach the other trans enantiomer (1R,4R)-7 would be by a Mitsunobu reaction 18 of 6. However reaction of 6b under Mitsunobu conditions failed even when the amine was protected with tertbutoxycarbonyl (TBOC).|| To solve the problem of obtaining the trans-(1R,4R)- enantiomer of the amino alcohol we prepared (1R,4R)-9 as Scheme 5 Reagents and conditions A i DHP PPTS in CH2Cl2 at RT (98%); ii 20% K2CO3 in MeOH–H2O at RT (86%); B 2,4- dichlorobenzoic acid DCC DMAP in CH2Cl2 at RT (87%); C i 5% Pd(dba)2 15% PPh3 1.2–3 equiv.NHR1R2 3 equiv. Et3N in THF at RT N2 or Ar atm; ii p-TsOH MeOH RT 6a 55% yield in two steps 6b 65% yield in two steps § Prepared by selective hydrolysis of the acetate (Na2CO3 MeOH RT)17 in (±)-cis-1-acetoxy-4-pivaloyloxycyclohex-2-ene. The latter was obtained from esterification of (±)-2a. ¶ For an experimental procedure see preparation of 20c in the Experimental section. || The protection was done by mixing the aminoacetate with (BOC)2O Et3N and catalytic amounts DMAP in methylene dichloride. Before the Mitsunobu reaction the acetate was hydrolysed. described in Scheme 7. Silylation of (2)-2a with TBDMS-Cl gave cis-(1S,4R)-1-acetoxy-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene 21c.This compound was converted into (1R,4R)-9 in the following way hydrolysis of the acetate in 21c and stereospecific substitution of the hydroxy group by chloride with inversion of configuration using MsCl LiCl and Et3N in methylene dichloride gave trans-(1R,4R)-1-chloro-4-(tert-butyldimethylsilyloxy) cyclohex-2-ene 20c. Deprotection of TBDMS with tetrabutylammonium fluoride (TBAF) followed by quenching with acetic anhydride gave (1R,4R)-9 (83%). Transformation of (1R,4R)-9 into (1R,4R)-7a and (1R,4R)-7b was done as shown in eqn. (2) and the ee obtained was �98%.19 Conclusion All four stereoisomers of biologically interesting 4-aminocyclohex- 2-enols have been prepared in enantiomerically pure form by palladium(0)-catalysed reactions from the same starting material (2)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a.Experimental 1H and 13C NMR spectra were recorded for CDCl3 solutions at 300 or 400 and 75.4 or 100.6 MHz respectively. 19F NMR spectra were recorded for CDCl3 solutions at 376.3 MHz. Chemical shifts are reported in ppm with CDCl3 as internal standard (7.26 for 1H and 77.00 ppm for 13C) and coupling constants (J) are given in Hz. Assignment of 13C was done with HETCOR and COSY experiments. Mass spectra were recorded on a Scheme 6 Scheme 7 Reagents and conditions A TBDMS-Cl imidazole CH2Cl2 0 8C to RT (99%); B i 20% KOH in MeOH at RT (98%); ii MsCl LiCl Et3N in CH2Cl2 220 8C to RT (91%); C i TBAF in THF at RT; ii Ac2O (83%); D i 5% Pd(dba)2 15% PPh3 25% LiCl 1.2–3 equiv.NHR1R2 0–3 equiv. Et3N in THF at RT; ii K2CO3 in MeOH–H2O at RT yields as in Scheme 3 580 J. Chem. Soc. Perkin Trans. 1 1997 Finnigan MAT INCOS 50 or a Hewlett Packard 5971 series instrument at 70 eV. Where indicated mass spectra were recorded with pneumatically assisted electrospray mass spectrometry (ES-MS) on a Micromass VG Platform apparatus using direct inlet of a solution in acetonitrile or with an LCcolumn (Kromasil 100 × 4.6 mm acetonitrile–water gradient with 5 mM formic acid). Optical rotations recorded in units of 1021 deg cm2 g21 measured at 25.0 8C on a Perkin–Elmer 241 polarimeter and concentrations are expressed as g 100 ml21 in spectroscopically pure ethanol or methylene dichloride. Elemental analyses were performed by Analytische Laboratorien Engelskirchen Germany.Bis(dibenzylideneacetone)- palladium(0) [Pd(dba)2] was prepared according to a literature procedure.20 THF was distilled under nitrogen from sodium benzophenone ketyl. Pyridine and methylene dichloride were distilled under nitrogen from calcium hydride. Benzylamine diethylamine and triethylamine were distilled from KOH and stored over KOH under nitrogen until used. Thin-layer chromatography (TLC) was run on Merck pre-coated silica gel 60-F254 plates. All reactions were carried out in oven-dried glassware and the Pd0-catalysed reactions also under an argon or nitrogen atmosphere unless otherwise stated. Progress of reaction was followed by TLC until judged complete for all reactions. For flash chromatography Merck Kieselgel 60 (230–400 mesh) was used. Enantiomeric excess (ee) was checked with 1H and 19F NMR in CDCl3 by Mosher esterification 21 for the diethylaminocyclohex-2-enols and by salt formation with optically pure (S)-mandelic acid,22 for the 4-benzylaminocyclohex- 2-enols.General procedure for the Pd0-catalysed aminations exemplified by the synthesis of (±)-cis-1-acetoxy-4-benzylaminocyclohex-2- ene 10b To a solution that had been stirred at room temperature (RT) for 20 min containing Pd(dba)2 (172 mg 0.29 mmol) PPh3 (225 mg 0.86 mmol) BnNH2 (737 mg 6.87 mmol) and Et3N (1.74 g 17.18 mmol) in THF (30 ml) was added the cis-chloro acetate 8 (1.00 g 5.73 mmol) in THF (10 ml). The reaction mixture was stirred at RT for 8 h and then evaporated. The residue was dissolved in diethyl ether (20 ml) and extracted with 1 M aq. HCl (3 × 50 ml).The aqueous phase was charged with fresh ether (80 ml) and the pH was adjusted to >10 with K2CO3 and KOH followed by two more extractions with ether (50 ml). The combined ether extracts were dried (K2CO3) and concentrated. The crude product was purified on silica (ethyl acetate– pentane gradient) to give 10b (1.14 g 81%). The silica was first conditioned with 2% Et3N in pentane (Found for the HCl-salt C 63.9; H 7.05. Calc. for C15H20ClNO2 C 63.9; H 7.15%); dH(400 MHz; CDCl3) 1.3–1.5 (1 H br s NH) 1.58–1.71 (1 H m CH2) 1.73–1.84 (1 H m CH2) 1.84–1.93 (2 H m CH2) 2.04 (3 H s COCH3) 3.14–3.21 (1 H m CHNHBn) 3.85 3.88 (2 H AB-system JAB 13.1 PhCH2) 5.13–5.25 (1 H m CHOAc) 5.79 (1 H ddd J 10.0 3.5 and 1.7 olefinic) 6.00 (1 H dd J 10.1 and 2.7 olefinic) and 7.21–7.37 (5 H m Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.3 (COCH3) 25.3 (CH2CHOAc) 26.1 (CH2CHN) 51.0 (CH2Ph) 52.3 (CHN) 67.2 (CHOAc) 126.3 (CH Ph) 126.9 (olefinic CHCHOAc) 128.1 (CH Ph) 128.4 (CH Ph) 135.4 (olefinic CHCHN) 140.3 (C Ph) and 170.7 (C]] O).(A) Synthesis of the cis-4-aminocyclohex-2-enols (±)-cis-1-Acetoxy-4-diethylaminocyclohex-2-ene 10a. The synthesis was carried out according to the general procedure above. Amounts used were allylic substrate 8 (300 mg 1.718 mmol) Pd(dba)2 (51 mg 0.086 mmol) PPh3 (68 mg 0.258 mmol) Et2NH (151 mg 2.06 mmol) Et3N (521 mg 5.15 mmol) and THF (10 ml); reaction time 16 h; yield 280 mg 77%; dH(300 MHz; CDCl3) 1.04 (6 H app t J 7.2 CH3) 1.41–1.61 (2 H m CH2) 1.81–1.91 (1 H m CH2) 2.04 (3 H s COCH3) 2.11– 2.20 (1 H m CH2) 2.34–2.61 (4 H m NCH2) 3.40–3.53 (1 H m CHNEt2) 5.26–5.38 (1 H m CHOAc) 5.64–5.73 (1 H m olefinic) and 5.67–5.85 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.4 (NCH2CH3) 21.3 (CH3CO2) 22.3 (CH2CHN) 28.3 (CH2CHOAc) 44.1 (NCH2) 56.4 (CHN) 70.2 (CHOAc) 129.2 (olefinic CHCHN) 134.8 (olefinic CHCHOAc) and 170.8 (C]] O).cis-(1S,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1S,4R)-10a. The synthesis was carried out according to the general procedure. Amounts used were allylic substrate 16 (616 mg 1.718 mmol) Pd(dba)2 (51 mg 0.086 mmol) PPh3 (68 mg 258 mmol) Et2NH (151 mg 2.06 mmol) Et3N (521 mg 5.15 mmol) and THF (20 ml); reaction time 2 h; yield 298 mg 82%. Allylic substrate 17 (485 mg 1.473 mmol) Pd(dba)2 (44 mg 0.074 mmol) PPh3 (58 mg 0.221 mmol) Et2NH (183 mg 2.50 mmol) Et3N (447 mg 4.42 mmol) and THF (20 ml); reaction time 6 h; yield 228 mg 73%.Spectral data are in accordance with the racemate. (±)-cis-4-Diethylaminocyclohex-2-enol 6a. The amino acetate 10a (250 mg 1.19 mmol) was dissolved in a stirred solution of K2CO3 (9 mg 0.06 mmol) in MeOH–H2O (4 1; 10 ml) at RT. After 5 h the mixture was evaporated diluted with diethyl ether (100 ml) washed with water (10 ml) and brine (10 ml) dried (K2CO3) and evaporated. Purification of the residue on silica (gradient of diethyl ether–pentane 60 40 to ethyl acetate– MeOH 90 10) gave the title compound 6a (191 mg 95%) (Found for the HCl-salt C 58.3; H 9.7. Calc. for C10H20ClNO C 58.4; H 9.8%); dH(300 MHz; CDCl3) 1.04 (6 H app t CH3) 1.56–1.71 (3 H m 6-H and 5-H) 1.79–1.89 (1 H m 5-H) 1.96–2.14 (1 H br s OH) 2.38–2.65 (4 H m CH2) 3.26–3.33 (1 H m 1-H) 4.07–4.12 (1 H m 4-H) and 5.79–5.91 (2 H m 5-H and 6-H); dC(75.4 MHz; CDCl3 8 peaks) 14.2 (CH3) 17.9 (CH2) 30.2 (CH2) 44.2 (NCH2) 56.7 (CHNEt2) 63.4 (CHOAc) 130.2 (CH olefinic) 135.4 (CH olefinic); nmax/cm21 3346 (OH br) 2967 2937 2871 1386 and 1066.(2)-cis-(1S,4R)-4-Diethylaminocyclohex-2-enol (2)-(1S,4R)- 6a. Starting from (1S,4R)-10a and applying the same conditions as for the preparation of (±)-6a yielded (2)-6a. Spectral data are in accordance with (±)-6a; [a]D 25 270 (c 1.91 in EtOH); ee �98%. (+)-cis-(1R,4S)-4-Diethylaminocyclohex-2-enol (+)-(1R,4S)- 6a. See general procedure according to 10b. Allylic substrate 19 (802 mg 2.16 mmol) Pd(dba)2 (64 mg 0.108 mmol) PPh3 (85 mg 0.324 mmol) Et2NH (174 mg 2.38 mmol) Et3N (656 mg 6.48 mmol) and THF (25 ml) for 15 h yielded cis-(1R,4S)-4- diethylamino-1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (373 mg 68%).The THP group in the latter product (299 mg 1.18 mmol) was removed with toluene-p-sulfonic acid (190 mg 1.00 mmol) in MeOH (5 ml) at RT. After 12 h the mixture was evaporated and treated with diethyl ether (100 ml) and 1 M NaOH (10 ml). After extraction the organic phase was washed with water (10 ml) and brine (10 ml) dried (MgSO4) and evaporated. Purification of the residue on silica (gradient of diethyl ether–pentane 60 40 to ethyl acetate–MeOH 90 10) gave the title compound (+)-(1R,4S)-6a (161 mg 81%; totally 55% in two steps). Same spectral data as for (±)-6a; [a]D 25 +66 (c 1.70 in EtOH); ee �98%. (±)-cis-1-Acetoxy-4-benzylaminocyclohex-2-ene 10b. This compound is described above under the general procedure.cis-(1S,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4R)- 10b. See general procedure for (±)-10b. Pd(PPh3)4 (87 mg 0.075 mmol) was used instead of Pd(dba)2 for the allylic substrate 16 (539 mg 1.504 mmol); amounts of reactants used were PPh3 (20 mg 0.076 mmol) BnNH2 (161 mg 1.503 mmol) Et3N (340 mg 3.36 mmol) and THF (17 ml); reaction time 2 h; yield 292 mg 79%. For the allylic substrate 17 (311 mg 0.95 mmol) the following amounts were used Pd(dba)2 (28 mg 0.047 mmol) PPh3 (38 mg 0.142 mmol) BnNH2 (311 mg 2.83 mmol) and THF (17 ml); reaction time 2 h; yield 163 mg 70%. Spectral data were in accordance with those of racemic 10b. (±)-cis-4-Benzylaminocyclohex-2-enol 6b. Prepared from amino acetate 10b using the same hydrolysis conditions as for J. Chem. Soc. Perkin Trans.1 1997 581 the preparation of 6a in 98% yield; dH(400 MHz; CDCl3) 1.56– 1.88 (6 H m 2 × CH2 OH NH) 3.09–3.21 (1 H m CHNHBn) 3.83 3.87 (2 H AB-system JAB 13.0 PhCH2NH) 4.09– 4.18 (1 H m CHOH) 5.81–5.89 (2 H m olefinic) and 7.22– 7.34 (5 H m Ph); dC(100.6 MHz; CDCl3 11 peaks) 24.9 (CH2) 29.1 (CH2) 51.1 (CH2Ph) 52.3 (CHN) 64.7 (CHOH) 127.0 (CH Ph) 128.1 (CH Ph) 128.4 (CH Ph) 130.7 (CH olefinic) 133.1 (CH olefinic) and 140.3 (C Ph). (2)-cis-(1S,4R)-4-Benzylaminocyclohex-2-enol (2)-(1S,4R)- 6b. This compound was prepared as above for 6b but starting with (1S,4R)-10b. Spectral data are as for (±)-6b; [a]D 25 24.3 (c 0.845 in EtOH); ee �98%. (+)-cis-(1R,4S)-4-Benzylaminocyclohex-2-enol (+)-(1R,4S)- 6b. See general procedure for 10b. Allylic substrate 19 (557 mg 1.50 mmol) Pd(dba)2 (45 mg 0.075 mmol) PPh3 (50 mg 0.188 mmol) BnNH2 (160 mg 1.50 mmol) Et3N (340 mg 3.36 mmol) in THF (12 ml) for 20 h gave cis-(1R,4S)-4-benzylamino- 1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (426 mg 94%).The THP group was removed according to the preparation of (+)-(1R,4S)-6a in 69% yield (65% in two steps); spectral data as for (±)-6b; [a]D 25 +4.2 (c 1.79 in EtOH); ee �98%. (B) Synthesis of the trans-4-aminocyclohex-2-enols (±)-trans-1-Acetoxy-4-diethylaminocyclohex-2-ene 11a. The general procedure described for 10b was used but 25 mol% of LiCl was added to the reaction mixture together with the catalyst phosphine and amine. Allylic substrate 9 (131 mg 0.750 mmol) Pd(dba)2 (22 mg 0.037 mmol) PPh3 (40 mg 0.153 mmol) LiCl (8 mg 0.189 mmol) HNEt2 (165 mg 2.26 mmol) in THF (7.5 ml) for 20 h yielded 11a (113 mg 71%); dH(300 MHz; CDCl3) 1.04 (6 H app t J 7.2 CH3) 1.41–1.61 (2 H m CH2) 1.81–1.91 (1 H m CH2) 2.04 (3 H s COCH3) 2.11–2.20 (1 H m CH2) 2.34–2.61 (4 H m NCH2) 3.40–3.53 (1 H m CHNEt2) 5.26–5.38 (1 H m CHOAc) 5.64–5.73 (1 H m olefinic) and 5.76–5.85 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.2 (NCH2CH3) 21.2 (CH3CO2) 22.3 (CH2CHN) 28.2 (CH2CHOAc) 44.1 (NCH2) 56.4 (CHN) 70.1 (CHOAc) 129.2 (olefinic CHCHN) 134.8 (olefinic CHCHOAc) and 170.8 (C]] O); m/z (LC prior to ES-MS) 212 ([M + H]+ 82%) 139 (66%) 79 (7%) 61 (13%) and 60 (100%).Spectroscopic data for the corresponding g-product to 11a. (±)-trans-4-Acetoxy-3-diethylaminocyclohexene; dH(400 MHz; CDCl3) 1.01 (6 H app t J 7.1 CH3) 1.56–1.75 (2 H m CH2) 1.86–1.96 (1 H m CH2) 2.04 (3 H s COCH3) 2.07–2.20 (1 H m CH2) 2.53 (4 H app q NCH2) 3.36–3.43 (1 H m CHNEt2) 5.00 (1 H ddd J 11.1 7.7 3.6 CHOAc) 5.53–5.60 (1 H m olefinic) and 5.74–5.82 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.5 21.5 24.0 27.6 44.4 60.4 70.9 127.7 128.9 and 170.6.trans-(1S,4S)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1S,4S)-11a. The same procedure was used as for racemic 11a but starting from (2)-9. Spectral data are in accordance with the racemate. trans-(1R,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1R,4R)-11a. The same procedure was used as for racemic 11a but starting from (+)-9. Spectral data are in accordance with the racemate. (±)-trans-4-Diethylaminocyclohex-2-enol 7a. This substance was prepared from amino acetate 11a using the same hydrolysis conditions as for 6a in 96% yield; dH(300 MHz; CDCl3) 1.01 (6 H app t CH3) 1.32–1.53 (2 H m 6-H) 1.76–1.89 (1 H m 5-H) 2.06–2.18 (1 H m 5-H) 2.31–2.59 (4 H m NCH2) 2.60– 2.80 (1 H br s OH) 3.37–3.47 (1 H m 1-H) 4.16–4.28 (1 H m 4-H) and 5.63–5.79 (2 H m 5-H and 6-H); dC(100.6 MHz; CDCl3 8 peaks) 14.1 (CH3) 22.4 (CH2) 32.5 (CH2) 44.1 (NCH2) 56.6 (CHNEt2) 67.3 (CHOAc) 132.4 (CH olefinic) 133.6 (CH olefinic); m/z (LC prior to ES-MS) 170 ([M + H]+ 100%); nmax/cm21 3331 (OH br) 2968 2935 2864 1451 1384 and 1065.(2)-trans-(1S,4S)-4-Diethylaminocyclohex-2-enol (2)- (1S,4S)-7a. Preparation as for (±)-7a but with (1S,4S)-11a as the substrate. Same spectral data as for (±)-7a; [a]D 25 2102 (c 1.165 in EtOH); ee �98%. (+)-trans-(1R,4R)-4-Diethylaminocyclohex-2-enol (+)- (1R,4R)-7a. Preparation as for (±)-7a but with (1R,4R)-11a as the substrate.Same spectral data as for (±)-7a; [a]D 25 +98 (c 0.600 in EtOH). (±)-trans-1-Acetoxy-4-benzylaminocyclohex-2-ene 11b. The general procedure described for 10b was used but 25 mol% of LiCl was added to the reaction mixture together with the catalyst phosphine and amine. Amounts used were trans-chloro acetate 9 (720 mg 4.13 mmol) Pd(dba)2 (124 mg 0.21 mmol) PPh3 (162 mg 0.62 mmol) LiCl (44 mg 1.03 mmol) BnNH2 (531 mg 4.nd Et3N (1.25 g 12.37 mmol) in THF (36 ml). The reaction mixture was stirred at RT for 20 h to give on work-up the amino acetate 11b (770 mg 76%); dH(400 MHz; CDCl3) 1.45–1.64 (2 H m CH2) 1.99–2.19 (2 H m CH2) 2.04 (3 H s COCH3) 2.58 (1 H br s NH) 3.27–3.33 (1 H m CHNHBn) 3.83 3.86 (2 H AB-system JAB 13.2 PhCH2NH) 5.28–5.34 (1 H m CHOAc) 5.72 (1 H dddd J 10.4 3.2 2.0 1.2 olefinic CHCHOAc) 5.93 (1 H dddd J 10.4 2.8 1.6 1.2 olefinic CHCHN) and 7.20–7.45 (5 H m Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.2 (COCH3) 26.9 (CH2CHOAc) 27.3 (CH2CHN) 50.6 (CH2Ph) 52.2 (CHN) 69.1 (CHOAc) 127.0 (CH Ph) 127.9 (olefinic CHCHOAc) 128.1 (CH Ph) 128.4 (CH Ph) 133.8 (olefinic CHCHN) 139.8 (C Ph) and 170.6 (C]] O); m/z (LC prior to ES-MS) 246 ([M + H]+ 100%) 139 (54%) 108 (3%) 79 (5%) and 61 (6%).Spectroscopic data for the corresponding g-product to 11b (±)-trans-4-acetoxy-3-benzylaminocyclohexene; dH(400 MHz; CDCl3) 1.65–2.05 (3 H br s and two m overlapping CH2 NH) 2.10–2.19 (2 H m CH2) 3.25–3.33 (1 H m CHNH) 3.83 3.88 (2 H AB-system JAB 13.3 PhCH2NH) 4.99 (1 H ddd J 8.9 6.3 and 3.1 CHOAc) 5.62–5.69 (1 H m olefinic) 5.76–5.84 (1 H m olefinic) and 7.18–7.38 (5 H m aromatic); dC(100.6 MHz; CDCl3 13 peaks) 21.4 23.2 25.2 50.5 56.5 72.6 126.9 127.1 128.1 128.3 128.8 140.6 and 170.8.trans-(1S,4S)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4S)-11b. The same procedure was used as for racemic 11b but starting from (2)-9. Spectral data are in accordance with the racemate. trans-(1R,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1R,4R)-11b. The same procedure was used as for racemic 11b but starting from (+)-9. Spectral data are in accordance with the racemate. (±)-trans-4-Benzylaminocyclohex-2-enol 7b. The title compound was prepared from amino acetate 11b using the same hydrolysis conditions as for 6a in 98% yield; dH(400 MHz; CDCl3) 1.36–1.51 (2 H m CH2) 1.57–1.68 (2 H br s NH and OH) 2.03–2.15 (2 H m CH2) 3.24–3.28 (1 H m CHNH) 3.82 3.85 (2 H AB-system JAB 13.0 PhCH2NH) 4.23–4.26 (1 H m CHOH) 5.75–5.83 (2 H m olefinic) and 7.22–7.34 (5 H m Ph); dC(100.6 MHz; CDCl3 11 peaks) 27.9 (CH2) 31.2 (CH2) 50.8 (CH2Ph) 52.7 (CHN) 66.8 (CHOH) 127.1 (CH Ph) 128.2 (CH Ph) 128.5 (CH Ph) 132.0 (CH olefinic) 132.1 (CH olefinic) and 140.1 (C Ph).(2)-trans-(1S,4S)-4-Benzylaminocyclohex-2-enol (2)- (1S,4S)-7b. Preparation as for (±)-7b but with (1S,4S)-11b as the substrate. Same spectral data as for (±)-7b; [a]D 25 2122 (c 1.773 in EtOH); ee �98%. (+)-trans-(1R,4R)-4-Benzylaminocyclohex-2-enol (+)- (1R,4R)-7b. Preparation as for (±)-7b but with (1R,4R)-11b as the substrate. Same spectral data as for (±)-7b; [a]D 25 +120 (c 1.394 in EtOH); ee �98%. (C) Synthesis of the allylic substrates (±)-cis-4-Acetoxycyclohex-2-enol (±)-2a. 1,4-Diacetoxycyclohex- 2-ene 6 (17.39 g 87.72 mmol) and K2CO3 (606 mg 4.39 mmol) were dissolved in methanol–water (4 1; 150 ml) and the 582 J.Chem. Soc. Perkin Trans. 1 1997 solution stirred at RT for 40 min. It was then neutralised with 1 M aq. HCl and the methanol was removed in vacuo. The aqueous phase was saturated with NaCl and extracted with EtOAc and the extract was dried (MgSO4) and concentrated. The residue was separated on silica (gradient EtOAc–pentane) to give 2a (8.118 g 59%). The spectral data were consistent with those previously reported.4 (2)-cis-(1R,4S)-4-Acetoxycyclohex-2-enol (2)-(1R,4S)-2a. Preparation according to ref. 4. cis-1-Acetoxy-4-chlorocyclohex-2-ene 8. The preparation was carried out as in ref. 5 and the spectral data were in accord with those reported therein.(±)-trans-1-Acetoxy-4-chlorocyclohex-2-ene 9. To N-chlorosuccinimide (806 mg 6.04 mmol) in THF (7 ml) under nitrogen was added a solution of PPh3 (1.575 g 6.01 mmol) in THF (7 ml). A slightly exothermic reaction ensued. After the reaction mixture had cooled to room temperature the alcohol 2a (632 mg 4.047 mmol) dissolved in THF (6 ml) was added to it; the mixture was then stirred at room temperature for 15 h. The solvent was removed and the residue was dissolved in a small amount of CH2Cl2 and purified on silica (diethyl ether–pentane 5 95) to give the title compound 9 (684 mg 97%). About 4% of the corresponding SN29-product was formed in the reaction. Spectral data for 9 were in accord with those reported in ref. 5. (2)-trans-(1S,4S)-1-Acetoxy-4-chlorocyclohex-2-ene (2)- (1S,4S)-9.This compound was prepared in the same way as for the racemic compound 9 starting from (2)-2a. [a]D 25 2395 (c 1.01 in EtOH); 2.5% of the SN29-product contaminated the product. (+)-trans-(1R,4R)-1-Acetoxy-4-chlorocyclohex-2-ene (+)- (1R,4R)-9. To a solution of compound 20c (594 mg 2.406 mmol) in THF (15 ml) was added tetrabutylammonium fluoride (TBAF) (1 M soln. in THF 2.53 ml 2.53 mmol) at room temperature. After 3 h acetic anhydride (2.3 ml 24.4 mmol) was added to the reaction mixture which was then stirred for an additional 12 h. It was then evaporated and the residue was separated on silica (gradient ether–pentane 5 95–15 85) to give the title compound (+)-9 (347 mg 83%). Spectral data were in accord with those reported in ref. 5; [a]D 25 +415 (c 0.89 in EtOH). cis-(1R,4S)-4-Acetoxycyclohex-2-enyl diphenylphosphinate (1R,4S)-16.The title compound was synthesized from the alcohol (2)-2a (1.00 g 6.32 mmol) according to procedure A reported in ref. 14 (reaction time 30 h) except that in the aqueous work-up the organic extract was washed with saturated copper sulfate (3×) water (1×) and brine (1×) before being dried (MgSO4). After evaporation of the extract the crude product was filtered through basic alumina eluting with diethyl ether. Removal of the ether afforded a colourless oil of the title compound 16 (2.02 g 89%) which was sufficiently pure for the next step; dH(400 MHz; CDCl3) 1.80–1.94 (3 H m CH2) 2.01– 2.06 (1 H m CH2) 2.06 (3 H s COCH3) 4.84–4.91 [1 H m CHOP(O)Ph2] 5.15–5.20 (1 H m CHOAc) 5.83–5.96 (2 H m olefinic) 7.44 (4 H o-Ph) 7.51 (2 H m p-Ph) 7.82 (4 H tdd 2JHP 12.6 JHH 8.2 1.4 o-Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.1 (CH3CO2) 24.6 (CH2CHOAc) 26.9 (d 3JCP 3.8 CH2CHOP) 67.0 (CHOAc) 69.0 (d 2JCP 6.0 CHOP) 128.4 (d 3JCP 12.2 aromatic CH) 129.9 (olefinic CHCHOAc) 131.5 (d 2JCP 17.5 aromatic CH) 131.5 (d 3JCP 3.0 olefinic CHCHOP) 131.87 (d 1JCP 136.6 aromatic C) 131.92 (d 4JCP 137.3 aromatic C) 132.1 (d 4JCP 1.5 aromatic CH) and 170.2 (C]] O); m/z (NH4CO2 added prior to ES-MS) 379 ([M + Na]+ 5%) 374 ([M + NH4]+ 4%) 357 ([M + H]+ 50%) 297 (3%) 219 (11%) 139 (100%) and 79 (6%).cis-(1R,4S)-4-Acetoxycyclohex-2-enyl 2,4-dichlorobenzoate (1R,4S)-17. A solution of cis-4-acetoxycyclohex-2-enol (2)-2a (953 mg 6.10 mmol) 2,4-dichlorobenzoic acid (1.72 g 9.00 mmol) dicyclohexylcarbodiimide (DCC) (1.86 g 9.01 mmol) and p-dimethylaminopyridine (DMAP) (16 mg 0.13 mmol) in methylene dichloride (50 ml) was stirred at RT for 3 h.Diethyl ether (50 ml) was added to the reaction mixture which was then washed with cold 5% aq. HCl (2 × 25 ml) and saturated aqueous NaHCO3 (3 × 25 ml) dried (MgSO4) and concentrated. The crude product was filtered through basic alumina and purified on silica using MPLC (EtOAc–CH2Cl2 1 1 gradient in pentane) to give the title compound 17 (1.61 g 80%); dH(300 MHz; CDCl3) 1.90–2.06 (4 H m 2 × CH2) 2.07 (3 H s COCH3) 5.23–5.33 (1 H m CHOAc) 5.39–5.51 [1 H m CHOC(O)Ar] 5.94–6.05 (2 H m olefinic) 7.29 (1 H dd J 8.4 and 2.0 ArH) 7.47 (1 H d J 2.0 ArH) and 7.79 (1 H d J 8.4 ArH); dC(100.6 MHz; CDCl3 15 peaks) 21.1 (CH3CO2) 24.8 (CH2) 25.0 (CH2) 67.4 (CHOAc) 68.6 [CHOC(O)Ar] 126.9 (aromatic CHCHCCl) 128.4 (aromatic C) 129.3 [olefinic CHCHOC(O)Ar] 130.9 (aromatic CClCHCCl) 131.2 (olefinic CHCHOAc) 132.4 (aromatic CCHCH) 134.8 (aromatic C) 138.2 (aromatic C) 164.2 (C]] O) and 170.4 (C]] O); m/z 273 (0.6%) 271 (5%) 269 (7%) 177 (12%) 175 (65%) 173 (100%) 149 (2%) 147 (8%) 145 (12%) 139 (12%) 96 (43%) and 79 (26%); [a]D 25 +56 (c 1.16 in EtOH).(+)-cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cycloheenol (+)-(1S,4R)-18a. To (2)-2a (535 mg 3.38 mmol) dissolved in methylene dichloride (30 ml) was added dihydropyran (DHP) (425 mg 5.05 mmol) and pyridinium toluene-p-sulfonate (PPTS) (85 mg 0.338 mmol). The solution was stirred at RT for 4 h after which it was diluted with diethyl ether (100 ml) washed with brine–water (1 1; 20 ml) and concentrated. The resulting crude product was dissolved in methanol (5 ml) and treated with K2CO3 (23 mg 0.17 mmol) in water (1 ml).After being stirred at RT for 5 h the reaction mixture was diluted with water (10 ml) and then concentrated by evaporation of most of the methanol. The aqueous phase was extracted with diethyl ether (3 × 50 ml) and the combined organic fractions were then washed with brine (20 ml) dried (MgSO4) and concentrated. Purification of the residue on silica (diethyl ether–pentane 60 40) gave the title compound 18a (650 mg 98%) (Found C 65.9; H 8.8. Calc. for C11H18O3 C 66.6; H 9.15%); dH(400 MHz; CDCl3) 1.48–1.94 (10 H m 5- H 6-H 8-H 9-H and 10-H) 3.45–3.54 (1 H m 11-H) 3.86– 3.97 (1 H m 11-H) 4.08–4.18 (2 H m 4-H and 7-H) 4.72– 4.78 (1 H m 1-H) and 5.88–5.91 (2 H m 2-H and 3-H); dC(100.6 MHz; CDCl3) 19.5 (C-9) 24.3 and 26.2 (C-5) 25.3 and 25.4 (C-10) 28.1 and 28.5 (C-6) 30.9 and 31.0 (C-8) 62.4 and 62.5 (C-11) 65.1 and 65.2 (C-1) 68.9 and 70.0 (C-4) 96.8 and 97.8 (C-7) 130.1 and 131.3 (olefinic) 132.5 and 132.6 (olefinic); m/z (M+ >0.5%) 97 (51%) 85 (90%) 79 (63%) 67 (64%) 57 (65%) and 55 (100%); nmax/cm21 3404 (OH br) 2942 2869 1133 1074 1032 and 1000; [a]D 25 +38.1 (c 0.91 in CH2Cl2).cis-4-Pivaloyloxycyclohex-2-enol 18b. To a solution of the hydroxyacetate 2a (1.00 g 6.402 mmol) Et3N (3.24 g 32.01 mmol) and DMAP (22 mg 0.180 mmol) in THF (25 ml) was added pivaloyl chloride (1.58 ml 12.81 mmol). The reaction mixture was stirred at 50 8C for 24 h after which the solvent was removed and ether (60 ml) was added to the residue. The solution was washed with 1 M hydrochloric acid (× 3) sat’d aqueous NaHCO3 and brine dried (MgSO4) and concentrated.Separation of the residue on silica (diethyl ether–pentane 3 97 then 5 95) yielded cis-4-acetoxy-1- pivaloyloxycyclohex-2-ene (1.485 g 95%); dH(400 MHz; CDCl3) 1.19 (9 H s But) 1.77–1.96 (4 H m CH2) 2.07 (3 H s COCH3) 5.15–5.24 (2 H m CHOAc CHOPiv) and 5.81– 5.91 (2 H m olefinic); dC(100.6 MHz; CDCl3 11 peaks) 21.3 24.8 24.9 27.1 38.7 66.9 67.4 130.0 130.5 170.5 178.0. Selective hydrolysis of the acetate (1.112 g 4.627 mmol) was performed with a 10% solution of Na2CO3?10 H2O (133 mg 0.465 mmol) in MeOH–H2O (4 1 23 ml) at RT for 9 h. After removal of the methanol from the mixture it was extracted with ether and the extract dried (Na2SO4) and concentrated to give the title compound 18b (839 mg 92%); dH(400 MHz; J.Chem. Soc. Perkin Trans. 1 1997 583 CDCl3) 1.18 (9 H s But) 1.62–1.98 (5 H m CH2 OH) 4.14– 4.26 (1 H m CHOH) 5.10–5.24 (1 H m CHOPiv) 5.73–5.84 (1 H m olefinic) and 5.90–6.00 (1 H m olefinic); dC(100.6 MHz; CDCl3 9 peaks) 24.9 (C-5) 27.1 (C-9) 28.1 (C-6) 38.7 (C-8) 65.3 (C-1) 66.9 (C-4) 128.0 (C-3) 134.5 (C-2) and 178.1 (C-7); m/z 180 (2%) 113 (3%) 97 (23%) 96 (67%) 95 (14%) 85 (21%) 79 (21%) and 57 (100%). cis-(1S,4R)-4-(tert-Butyldimethylsilyloxy)cyclohex-2-enol (1S,4R)-18c. To a stirred solution of 21c (3.256 g 12.039 mmol) was added KOH (135 mg 2.408 mmol) in methanol (40 ml). The reaction mixture was stirred at RT for 4 h after which the solvent was removed and the residue was treated with water (30 ml) and diethyl ether (60 ml); the layers were separated and the pH of the aqueous layer was adjusted to 7 with 1 M hydrochloric acid; it was then further extracted with ether.The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the product (2.698 g 98%) which was pure enough for the next step; dH(400 MHz; CDCl3) 0.073 (3 H s SiCH3) 0.076 (3 H s SiCH3) 0.89 [9 H s SiC(CH3)3] 1.60–1.90 (5 H m 2 × CH2 OH) 4.06–4.18 (2 H two overlapping m CHOH CHOSi) 5.75 (1 H dd J 10.2 and 2.4 olefinic) and 5.79 (1 H dd J 10.2 and 3.1 olefinic); dC(100.6 MHz; CDCl3 10 peaks) 24.7 (C-7) 24.6 (C-79) 18.1 (C-8) 25.8 (C-9) 28.2 (C-5) 28.4 (C-6) 64.8 (C-1) 66.3 (C-4) 130.7 (C-2) and 133.9 (C-3); [a]D 25 +34 (c 1.58 in EtOH). cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enyl 2,4- dichlorobenzoate (1S,4R)-19. A solution of DCC (1.297 g 6.285 mmol) and DMAP (13 mg 0.105 mmol) in methylene dichloride (10 ml) was added to a stirred solution of 18a (1.246 g 6.285 mmol) and 2,4-dichlorobenzoic acid (1.200 g 6.285 mmol) in methylene dichloride (25 ml) at RT.The solution was stirred at RT for 10 h after which it was diluted with diethyl ether (300 ml). The organic phase was washed with 5% aqueous acetic acid (50 ml) water (20 ml) and brine (20 ml) dried (MgSO4) and concentrated. Purification of the residue on silica (diethyl ether–pentane 60 40) gave the title compound 19 (2.20 g 87%); dH(400 MHz; CDCl3) 1.43–2.07 (10 H m 5-H 6-H 8-H 9-H and 10-H) 3.47–3.54 (1 H m 11-H) 3.86–3.94 (1 H m 11-H) 4.15–4.27 (1 H two overlapping m 4-H) 4.73–4.78 (1 H m 7-H) 5.39–5.45 (1 H m 1-H) 5.89–5.95 (1 H m 3-H) and 6.01–6.09 (1 H m 2-H); dC(100.6 MHz; CDCl3) 19.5 and 19.6 (CH2) 24.4 and 26.3 (CH2) 25.2 and 25.4 (CH2) 25.5 and 26.1 (CH2) 30.9 and 31.0 (CH2) 62.5 and 62.6 (CH2) 68.7 and 68.8 [allyl-CHOC(O)Ar] 69.3 and 70.4 (allyl-CHOTHP) 97.0 and 98.1 (THP-OCHO) 126.9 (aromatic CH) 127.0 and 127.1 [olefinic CHCHOC(O)Ar] 128.5 (aromatic C) 130.9 (aromatic CH) 132.5 (aromatic CH) 133.8 and 134.9 (olefinic CHCHOTHP) 135.8 (aromatic C) 138.1 (aromatic C) and 164.2 (C]] O); m/z 273 (19%) 271 (29%) 194 (6%) 192 (61%) 190 (81%) 177 (12%) 175 (68%) 173 (100%) 147 (12%) and 145 (28%).trans-1-Chloro-4-(tetrahydropyran-2-yloxy)cyclohex-2-ene 20a. A solution of 18a (100 mg 0.504 mmol) LiCl (46 mg 1.08 mmol) and 2,4,6-trimethylpyridine (504 ml 3.78 mmol) in DMF (750 ml) was cooled to 0 8C and treated with MsCl (58 ml 0.83 mmol) followed after 20 min by diethyl ether (40 ml).The solution was washed with water (5 ml) and brine (5 ml) dried (MgSO4) and concentrated. The residue was purified on silica (diethyl ether–pentane 40 60) to give the title compound 20a (98 mg 90%). Since the product is extremely unstable it should be prepared directly before further use; dH(400 MHz; CDCl3) 1.40–2.40 (10 H m 5-H 6-H 8-H 9-H 10-H) 3.43–3.58 (1 H m 11-H) 3.83–3.98 (1 H m 11-H) 4.16–4.30 (1 H m 4-H) 4.54–4.65 (1 H m 7-H) 4.66–4.80 (1 H m 1-H) and 5.82–6.03 (2 H m olefinic); dC(100.6 MHz; CDCl3) 19.7 25.4 25.4 25.5 27.5 29.3 29.7 29.8 31.1 31.1 54.6 54.6 62.6 62.7 68.3 69.0 97.3 98.1 130.4 130.6 131.1 and 131.7. trans-1-Chloro-4-pivaloyloxycyclohex-2-ene 20b. Triphenylphosphine (836 mg 3.19 mmol) dissolved in THF (3 ml) was added to a solution of N-chlorosuccinimide (426 mg 3.19 mmol) in THF (5 ml) to give slightly exothermic phosphonium salt formation.After cooling of the reaction mixture to RT (20 min) 18b (416 mg 2.098 mmol) in THF (3 ml) was added to it; it was then stored at RT for 24 h. After this the solvent was evaporated from the mixture and pentane was added to the residue. The precipitated triphenylphosphine oxide and succinimide were filtered off and the pentane was removed in vacuo to give a residue which was purified on silica (EtOAc–pentane 1 99). This afforded 20b (305 mg 67%) (8% of the reaction product was derived from the SN29 substitution mechanism); dH(400 MHz; CDCl3) 1.17 (9 H s But) 1.68–1.78 (1 H m CH2) 1.94–2.04 (1 H m CH2) 2.12–2.32 (2 H m CH2) 4.57– 4.64 (1 H m CHCl) 5.20–5.28 (1 H m CHOPiv) 5.82–5.89 (1 H m olefinic) and 5.98–6.04 (1 H m olefinic); dC(100.6 MHz; CDCl3 9 peaks) 24.8 (CH2) 27.1 (CH3) 28.7 (CH2) 38.7 (C) 53.6 (CHCl) 65.7 (CHOPiv) 128.3 (olefinic CH) 132.3 (olefinic CH) and 177.8 (C]] O).trans-(1R,4R)-1-Chloro-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene (1R,4R)-20c. To compound 18c (1.503 g 6.58 mmol) was added LiCl (558 mg 13.16 mmol) and Et3N (2.75 ml 19.74 mmol) in CH2Cl2 (25 ml). The solution was cooled to 220 8C and MsCl (610 ml 7.881 mmol) was added to it via a syringe. The mixture was brought to RT over 3 h after which it was stirred for a further 17 h. It was then diluted with water– NaHCO3 (sat’d) (1 1; 30 ml) and the phases were separated. The aqueous phase was extracted with diethyl ether (3 × 70 ml). The combined organic phases were washed with brine (20 ml) dried (MgSO4) and passed through a silica column packed with Et3N–diethyl ether–pentane (4 2 94).Elution with diethyl ether–pentane (2 98 then 5 95) gave the title compound 20c (1.484 g 91%); dH(400 MHz; CDCl3) 0.08 (6 H s SiCH3 × 2) 0.89 [9 H s SiC(CH3)3] 1.60–1.67 (1 H m CH2) 1.84–1.93 (1 H m CH2) 2.02–2.11 (1 H m CH2) 2.29–2.37 (1 H m CH2) 4.23–4.27 (1 H m CHOSi) 4.56–4.60 (1 H m CHCl) 5.77 (1 H dd J 10.4 and 3.1 olefinic) and 5.82 (1 H dd J 10.4 and 3.2 olefinic); dC(100.6 MHz; CDCl3 10 peaks) 24.7 (C-7) 24.6 (C-79) 18.2 (C-8) 25.8 (C-9) 29.7 (C-6) 29.9 (C-5) 54.9 (C-1) 64.9 (C-4) 129.5 (C-2) and 133.5 (C-3); m/z 248 (1%) 246 (2%) 191 (24%) 189 (64%) 93 (18%) 77 (15%) and 75 (100%); [a]D 25 +259 (c 1.75 in EtOH). cis-(1S,4R)-1-Acetoxy-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene (1S,4R)-21c.A solution of TBDMS-Cl (2.665 g 17.68 mmol) in methylene dichloride (40 ml) was cooled to 0 8C and imidazole (6.74 g 99.0 mmol) was added to it. After 5 min (2)- 2a (2.209 g 14.14 mmol) dissolved in methylene dichloride (30 ml) was added to the mixture which was then stirred at 0 8C for ca. 30 min and then at RT for 20 h. After being quenched with water (10 ml) the reaction mixture was extracted with methylene dichloride (3 × 50 ml). The combined organic fractions were washed with brine (20 ml) dried (Na2SO4) concentrated and subjected to chromatography (diethyl ether–pentane 5 95) to give the title compound 21c (3.79 g 99%); dH(400 MHz; CDCl3) 0.078 (3 H s SiCH3) 0.082 (3 H s SiCH3) 0.90 [9 H s SiC(CH3)3] 1.65–1.95 (4 H m 2 × CH2) 2.04 (3 H s COCH3) 4.15–4.19 (1 H m CHOSi) 5.13–5.17 (1 H m CHOAc) 5.71–5.75 (1 H m olefinic) and 5.85–5.88 (1 H m olefinic); dC(100.6 MHz; CDCl3) 24.7 (SiCH3) 24.6 (SiCH3) 18.1 (SiC) 21.2 (COCH3) 25.3 (CH2CHOAc) 25.8 [SiC(CH3)3] 28.4 (CH2CHOSi) 66.3 (CHOSi) 67.0 (CHOAc) 126.2 (olefinic CHCHOAc) 136.3 (olefinic CHCHOSi) and 170.6 (C]] O); m/ z 210 (2%) 117 (100%) 79 (12%) and 75 (33%); [a]D 25 240 (c 1.63 in EtOH).Acknowledgements Financial support from the Swedish Natural Science Research Council The Research Council of the Board of Technical Development and the Swedish Research Council for Engineering Sciences is gratefully acknowledged. 584 J. Chem. Soc. 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Nordberg J. Am. Chem. Soc. 1985 107 3676. 6 Racemic (±)-2a was prepared by selective hydrolysis (5% K2CO3 in MeOH–H2O) of cis-1,4-diacetoxycyclohex-2-ene which was prepared from cyclohexadiene according to J. E. Bäckvall S. E. Byström and S. E. Nordberg J. Org. Chem. 1984 49 4619. 7 (a) W. Oppolzer J.-M. Gaudin and T. N. Birkinshaw Tetrahedron Lett. 1988 29 4705; (b) A. K. Bose and B. Lal Tetrahedron Lett. 1973 3937. 8 (a) A. Pfaltz Acc. Chem. Res. 1993 26 339; (b) N. W. Murral and A. J. Welch J. Organomet. Chem. 1986 301 109; (c) A. Pfaltz in Stereoselective Synthesis E. Ottow K. Schöllkopf and B.-G. Schulz eds. Springer-Verlag Berlin Heidelberg 1993 pp. 15–36. 9 (a) B. M. Trost and J.P. Genêt J. Am. Chem. Soc. 1976 98 8516; (b) B. M. Trost and E. Keinan J. Am. Chem. Soc. 1978 100 7779; (c) J. E. Bäckvall R. E. Nordberg J. E. Nyström T. Högberg and B. Ulff J. Org. Chem. 1981 46 3479; (d ) Y. Tanigawa K. Nishimura A. Kawasaki and S.-I. Murahashi Tetrahedron Lett. 1982 23 5549; (e) S. E. Byström R. Aslanian and J. E. Bäckvall Tetrahedron Lett. 1985 26 1749; (f ) J.-P. Genêt M. Balabane J. E. Bäckvall and J. E. Nyström Tetrahedron Lett. 1983 24 2745; (g) R. E. Nordberg and J. E. Bäckvall J. Organomet. Chem. 1985 285 C24. 10 (a) T. Hayashi K. Kishi A. Yamamoto and Y. Ito Tetrahedron Lett. 1990 31 1743; (b) R. Tanikaga T. X. Jun and A. Kaji J. Chem. Soc. Perkin Trans. 1 1990 1185; (c) J.-P. Genêt S. Thorimbert and A. M. Touzin Tetrahedron Lett. 1993 34 1159; (d ) P.von Matt O. Loiseleur G. Koch A. Pfaltz C. Lefeber T. Feucht and G. Helmchen Tetrahedron Asymmetry 1994 5 573. 11 J. E. Bäckvall K. L. Granberg and A. Heumman Isr. J. Chem. 1991 31 17. 12 R. Tanikaga J. Takeuchi M. Takyu and A. Kaji J. Chem. Soc. Chem. Commun. 1987 386. 13 L. Liebeskind and J. S. McCallum Synthesis 1993 819. 14 A. Hassner and V. Alexanian Tetrahedron Lett. 1978 35 5713. 15 (a) K. L. Granberg and J. E. Bäckvall J. Am. Chem. Soc. 1992 114 6858; (b) T. Takahashi Y. Jinbo K. Kitamura and J. Tsuji Tetrahedron Lett. 1984 25 5921; (c) P. B. Mackenzie J. Whelan and B. Bosnich J. Am. Chem. Soc. 1985 107 2046; (d ) T. Hayashi A. Yamamoto and T. Hagihara J. Org. Chem. 1986 51 723. 16 M. Miyashita A. Yoshikoshi and P. A. Grieco J. Org. Chem. 1977 42 3772. 17 J. E. Bäckvall K.L. Granberg and R. B. Hopkins Acta Chem. Scand. 1990 44 492. 18 O. Mitsunobu Synthesis 1981 1. 19 For a recent approach to Pd0-catalysed desymmetrisation of cycloalk-2-ene-1,4-diol derivatives leading to enantiopure 1,4- aminoalcohol derivatives see B. M. Trost and S. R. Pulley J. Am. Chem. Soc. 1995 117 10 143. 20 T. Ukai H. Kawazura Y. Ishii J. J. Bonnet and J. A. Ibers Organomet. Chem. 1974 65 253. 21 (a) J. A. Dale D. L. Dull and H. S. Mosher J. Org. Chem. 1969 34 2543; (b) J. A. Dale and H. S. Mosher J. Am. Chem. Soc. 1973 95 512. 22 J. K. Whitesell and D. Reynolds J. Org. Chem. 1983 48 3548. Paper 6/00779A Received 1st February 1996 Accepted 7th October 1996 J. Chem. Soc. Perkin Trans. 1 1997 577 Palladium-catalysed enantiodivergent synthesis of cis- and trans-4-aminocyclohex-2-enols Roberto G.P. Gatti Anna L. E. Larsson and Jan-E. Bäckvall * Department of Organic Chemistry University of Uppsala Box 531 S-751 21 Uppsala Sweden Enantiomerically pure cis- and trans-4-aminocyclohex-2-enols are prepared from cyclohexa-1,3-diene via (2)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a using palladium(0) chemistry. Benzylamine and diethylamine are tested in the Pd0-catalysed allylic amination reactions. Since acetate is too slow as a leaving group and gave considerable amounts of side products a number of leaving groups have been investigated. Of these phosphinate and 2,4-dichlorobenzoate are excellent leaving groups and result in efficient and highly stereoselective reactions; chloride as allylic leaving group also gives good results. By variation of the leaving group and proper choice of the protecting group it is possible to synthesise all four stereoisomers of 4-aminocyclohex-2-enol in good yield and high enantiomeric excess.Introduction 4-Aminocyclohex-2-enols are important structural elements in a number of biologically active compounds such as conduramines 1 and derivatives.2 In connection with a project dealing with new substances for treatment of bronchitis complications there was a need for a general synthesis of optically pure 4- aminocyclohex-2-enols. We recently reported a method for an enantiodivergent synthesis of 4-substituted 2-cycloalkenols from cycloalka-1,3- dienes with a combination of palladium and enzyme chemistry (Scheme 1).3 The method allows for preparation of both enantiomers with high selectivity.In the present paper we have used enantiomerically pure (2)- cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a as a key intermediate for further stereocontrolled palladium(0)-catalysed functionalisation and report on the enantiocontrolled synthesis of all four stereoisomers of 4-aminocyclohex-2-enol (Scheme 2). An interesting observation is that phosphinates are excellent leaving groups in the Pd0-catalysed allylic substitution with primary and secondary amines. Scheme 1 Results and discussion (A) Racemates The objective was to synthesise cis- and trans-4-aminocyclohex- 2-enols in optically pure form starting from (2)-2a.4 Diethylamine and benzylamine (BnNH2) were employed as representative amines in the palladium(0)-catalysed allylic aminations. First the allylic amination was performed to produce a racemic mixture of the amino alcohols (Scheme 3).Thus cis-4- diethylaminocyclohex-2-enol 6a and cis-4-benzylaminocyclohex- 2-enol 6b were prepared starting from cis-1-acetoxy-4- chlorocyclohex-2-ene 8.5 The racemic trans stereoisomers were synthesised from (±)- 2a.6 Substitution of the OH by chloride with PPh3 and Nchlorosuccinimide (NCS)7 in THF afforded trans-1-acetoxy-4- chlorocyclohex-2-ene 9. Pd0-catalysed allylic amination of chloroacetate 9 with diethylamine or benzylamine gave after hydrolysis trans-4-diethylaminocyclohex-2-enol 7a or trans-4- benzylaminocyclohex-2-enol 7b respectively. Amino alcohols 6 and 7 were used to set up a method for determination of the ee. However with 9 as the allylic substrate a moderate regioselectivity was observed. Using conditions A in Scheme 3 and diethylamine as the nucleophile about 20% of the g-substitution product (of trans stereochemistry) was obtained.Usually Scheme 2 578 J. Chem. Soc. Perkin Trans. 1 1997 attack at the 4-position relative to the acetate is strongly favoured in analogous 1,4-disubstituted alk-2-enes.5 However due to steric interaction between the acetate and the L2Pdgroup in p-allyl intermediate I (Fig. 1) palladium is forced away from the acetate which weakens the palladium–carbon bond in the 2-position.8 This will increase the relative rate of attack at the 2-position in I. When R is tert-butyl II the relative amount of attack in the 2-position increased to 50–60% in the corresponding reaction (vide infra). The reaction conditions were further investigated by variation of the solvent amount of catalyst and ligand and by addition of salt (LiCl).The system with Pd(dba)2 and PPh3 in THF with an addition of 25 mol% LiCl decreased the amount of g-product of I from 20 to 13% with Et2NH and from 12 to 5% with BnNH2. (B) cis Enantiomers It has been shown that acetate can be used as a leaving group in Pd0-catalysed allylic amination with both primary and secondary amines.9 However when (±)-2a was treated with benzylamine in the presence of Pd(dba)2 PPh3 and Et3N in THF the conversion was low. In an attempt to improve the reaction different catalysts ligands and solvents were tried together with variation of the concentration and temperature. The best results were obtained with acetonitrile as the solvent at a reaction temperature of 40 8C. However the yield of the desired product 6 was still unsatisfactory with considerable amounts of g-product as well as inversion and elimination products.† Therefore better leaving groups were called for.To increase the reactivity in the Pd0-catalysed nucleophilic displacement the hydroxy group in 2a was transformed into a reactive leaving group. It has been reported in the literature that ethyl and methyl carbonate can be used as a leaving group in Pd0- Scheme 3 Reagents and conditions A 5% Pd(dba)2 15% PPh3 1.2–3 equiv. NHR1R2 3 equiv. Et3N in THF RT N2 or Ar atm 10a (77%) 10b (81%); B K2CO3 in MeOH–H2O at RT 6a (95%) 6b (98%) 7a (96%) 7b (98%); C NCS PPh3 THF RT (97%); D reagents as for A but longer reaction times and 25% LiCl added to the reaction mixture 11a (71%) 11b (76%) Fig. 1 Weaker bond in the 2-position because of steric interactions which increase the relative amount of g-substitution product † Loss of regio- and stereo-selectivity has previously been observed in Pd-catalysed reaction of allylic acetates with amines.9b,g catalysed allylic amination 10 but carbonate 12 gave the nondesired carbamate 13 on reaction with benzylamine [eqn.(1)].‡ The same results for similar substrates have been reported earlier in our laboratory 11 and elsewhere.12 The use of trifluoroacetate 14 in the corresponding reaction gave 2a and Nbenzyltrifluoroacetamide presumably because of faster nitrogen attack at the carbonyl carbon rather than formation of the p-allyl complex. Attempts to use a diethylphosphate ester 9d,e as the leaving group failed since 15 was very sensitive and hydrolysed quickly after preparation.We next tried diphenylphosphinic and benzoate esters. Diphenylphosphinic ester 16 was prepared from enantiomerically pure (2)-2a (89%) according to Liebeskind et al.13 and 2,4- dichlorobenzoate ester 17 was prepared (80% yield) by esterifi- cation of (2)-2a following the method of Hassner.14 Both 16 and 17 were excellent substrates in the Pd0-catalysed allylic amination with diethylamine and benzylamine and afforded the amino acetates (1S,4R)-10a and (1S,4R)-10b which upon hydrolysis yielded the amino alcohols (1S,4R)-6a and (1S,4R)- 6b respectively (Scheme 4). In each case the allylic amination was highly stereoselective and the enantiomeric excess (ee) of the amino alcohols was �98% in both cases. For (1S,4R)-6a 2% of the trans isomer was observed.An explanation could be isomerisation of the p-allyl intermediate by nucleophilic attack by free Pd0 on the allyl ligand.15 To form a carbon–nitrogen bond at the other allylic carbon in (2)-2a it was necessary to protect the hydroxy group and then selectively hydrolyse the acetate before attachment of a leaving group (Scheme 5). The hydroxy acetate (2)-2a was transformed into the alcohol 18a with tetrahydropyran (THP) protection 16 and subsequent hydrolysis of the acetoxy group. The alcohol 18a was transformed into its 2,4-dichlorobenzoate ester 19 (vide supra) which on Pd0-catalysed amination and subsequent removal of the THP group afforded (1R,4S)-6a and (1R,4S)-6b. Scheme 4 Reagents and conditions A 5% Pd(dba)2 15% PPh3 1.2–3 equiv. NHR1R2 3 equiv. Et3N in THF at RT N2 or Ar atm 16 to 10a (82%) 16 to 10b (79%) 17 to 10a (73%) 17 to 10b (70%); B K2CO3 in MeOH–H2O at RT yields as for step B shown in Scheme 3 ‡ The reaction proceeds via a (p-allyl)palladium intermediate.11 J.Chem. Soc. Perkin Trans. 1 1997 579 (C) trans Enantiomers Reaction of the enantiomerically pure hydroxy acetate (2)-2a with NCS and PPh3 in THF afforded optically active (1S,4S)-9 with high stereospecificity (cf. racemic reaction Scheme 3). Subsequent Pd0-catalysed allylic amination employing Et2NH and BnNH2 followed by hydrolysis gave (1S,4S)-7a and (1S,4S)-7b respectively [eqn. (2)]. The yields were the same as for the racemates (Scheme 3) and the ee was in each case � 98%. When preparing the other trans enantiomer the group at the other stereogenic carbon had to be substituted.Some difficulties were encountered when solving this problem. Substitution of the hydroxy group in 18a by chloride with inversion using LiCl methanesulfonyl chloride (MsCl) 2,4,6-trimethylpyridine in DMF and subsequent Pd0-catalysed allylic amination of the allylic chloride 20a should in analogy to the preparation of (1S,4S)-7 from (1S,4S)-9 give (1R,4R)-7 after removal of the protecting group. Unfortunately and to a much greater extent than what had been seen for 9 the predominant product was the g-substitution product (vide supra). Using pivalate § as protecting group instead of THP led to the same diraging result (Scheme 6). For example with the pivalate 20b the amount of g-substitution product was 50–60% with diethylamine. This result supports the explanation suggested in Fig.1 for the increased relative amount of g-isomer. The use of tert-butyldimethylsilyl (TBDMS)¶ led to decomposition of the silyl ether bond in the amination. Another way to reach the other trans enantiomer (1R,4R)-7 would be by a Mitsunobu reaction 18 of 6. However reaction of 6b under Mitsunobu conditions failed even when the amine was protected with tertbutoxycarbonyl (TBOC).|| To solve the problem of obtaining the trans-(1R,4R)- enantiomer of the amino alcohol we prepared (1R,4R)-9 as Scheme 5 Reagents and conditions A i DHP PPTS in CH2Cl2 at RT (98%); ii 20% K2CO3 in MeOH–H2O at RT (86%); B 2,4- dichlorobenzoic acid DCC DMAP in CH2Cl2 at RT (87%); C i 5% Pd(dba)2 15% PPh3 1.2–3 equiv. NHR1R2 3 equiv. Et3N in THF at RT N2 or Ar atm; ii p-TsOH MeOH RT 6a 55% yield in two steps 6b 65% yield in two steps § Prepared by selective hydrolysis of the acetate (Na2CO3 MeOH RT)17 in (±)-cis-1-acetoxy-4-pivaloyloxycyclohex-2-ene.The latter was obtained from esterification of (±)-2a. ¶ For an experimental procedure see preparation of 20c in the Experimental section. || The protection was done by mixing the aminoacetate with (BOC)2O Et3N and catalytic amounts DMAP in methylene dichloride. Before the Mitsunobu reaction the acetate was hydrolysed. described in Scheme 7. Silylation of (2)-2a with TBDMS-Cl gave cis-(1S,4R)-1-acetoxy-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene 21c. This compound was converted into (1R,4R)-9 in the following way hydrolysis of the acetate in 21c and stereospecific substitution of the hydroxy group by chloride with inversion of configuration using MsCl LiCl and Et3N in methylene dichloride gave trans-(1R,4R)-1-chloro-4-(tert-butyldimethylsilyloxy) cyclohex-2-ene 20c.Deprotection of TBDMS with tetrabutylammonium fluoride (TBAF) followed by quenching with acetic anhydride gave (1R,4R)-9 (83%). Transformation of (1R,4R)-9 into (1R,4R)-7a and (1R,4R)-7b was done as shown in eqn. (2) and the ee obtained was �98%.19 Conclusion All four stereoisomers of biologically interesting 4-aminocyclohex- 2-enols have been prepared in enantiomerically pure form by palladium(0)-catalysed reactions from the same starting material (2)-cis-(1R,4S)-4-acetoxycyclohex-2-enol (2)-2a. Experimental 1H and 13C NMR spectra were recorded for CDCl3 solutions at 300 or 400 and 75.4 or 100.6 MHz respectively. 19F NMR spectra were recorded for CDCl3 solutions at 376.3 MHz.Chemical shifts are reported in ppm with CDCl3 as internal standard (7.26 for 1H and 77.00 ppm for 13C) and coupling constants (J) are given in Hz. Assignment of 13C was done with HETCOR and COSY experiments. Mass spectra were recorded on a Scheme 6 Scheme 7 Reagents and conditions A TBDMS-Cl imidazole CH2Cl2 0 8C to RT (99%); B i 20% KOH in MeOH at RT (98%); ii MsCl LiCl Et3N in CH2Cl2 220 8C to RT (91%); C i TBAF in THF at RT; ii Ac2O (83%); D i 5% Pd(dba)2 15% PPh3 25% LiCl 1.2–3 equiv. NHR1R2 0–3 equiv. Et3N in THF at RT; ii K2CO3 in MeOH–H2O at RT yields as in Scheme 3 580 J. Chem. Soc. Perkin Trans. 1 1997 Finnigan MAT INCOS 50 or a Hewlett Packard 5971 series instrument at 70 eV. Where indicated mass spectra were recorded with pneumatically assisted electrospray mass spectrometry (ES-MS) on a Micromass VG Platform apparatus using direct inlet of a solution in acetonitrile or with an LCcolumn (Kromasil 100 × 4.6 mm acetonitrile–water gradient with 5 mM formic acid).Optical rotations recorded in units of 1021 deg cm2 g21 measured at 25.0 8C on a Perkin–Elmer 241 polarimeter and concentrations are expressed as g 100 ml21 in spectroscopically pure ethanol or methylene dichloride. Elemental analyses were performed by Analytische Laboratorien Engelskirchen Germany. Bis(dibenzylideneacetone)- palladium(0) [Pd(dba)2] was prepared according to a literature procedure.20 THF was distilled under nitrogen from sodium benzophenone ketyl. Pyridine and methylene dichloride were distilled under nitrogen from calcium hydride. Benzylamine diethylamine and triethylamine were distilled from KOH and stored over KOH under nitrogen until used.Thin-layer chromatography (TLC) was run on Merck pre-coated silica gel 60-F254 plates. All reactions were carried out in oven-dried glassware and the Pd0-catalysed reactions also under an argon or nitrogen atmosphere unless otherwise stated. Progress of reaction was followed by TLC until judged complete for all reactions. For flash chromatography Merck Kieselgel 60 (230–400 mesh) was used. Enantiomeric excess (ee) was checked with 1H and 19F NMR in CDCl3 by Mosher esterification 21 for the diethylaminocyclohex-2-enols and by salt formation with optically pure (S)-mandelic acid,22 for the 4-benzylaminocyclohex- 2-enols. General procedure for the Pd0-catalysed aminations exemplified by the synthesis of (±)-cis-1-acetoxy-4-benzylaminocyclohex-2- ene 10b To a solution that had been stirred at room temperature (RT) for 20 min containing Pd(dba)2 (172 mg 0.29 mmol) PPh3 (225 mg 0.86 mmol) BnNH2 (737 mg 6.87 mmol) and Et3N (1.74 g 17.18 mmol) in THF (30 ml) was added the cis-chloro acetate 8 (1.00 g 5.73 mmol) in THF (10 ml).The reaction mixture was stirred at RT for 8 h and then evaporated. The residue was dissolved in diethyl ether (20 ml) and extracted with 1 M aq. HCl (3 × 50 ml). The aqueous phase was charged with fresh ether (80 ml) and the pH was adjusted to >10 with K2CO3 and KOH followed by two more extractions with ether (50 ml). The combined ether extracts were dried (K2CO3) and concentrated. The crude product was purified on silica (ethyl acetate– pentane gradient) to give 10b (1.14 g 81%).The silica was first conditioned with 2% Et3N in pentane (Found for the HCl-salt C 63.9; H 7.05. Calc. for C15H20ClNO2 C 63.9; H 7.15%); dH(400 MHz; CDCl3) 1.3–1.5 (1 H br s NH) 1.58–1.71 (1 H m CH2) 1.73–1.84 (1 H m CH2) 1.84–1.93 (2 H m CH2) 2.04 (3 H s COCH3) 3.14–3.21 (1 H m CHNHBn) 3.85 3.88 (2 H AB-system JAB 13.1 PhCH2) 5.13–5.25 (1 H m CHOAc) 5.79 (1 H ddd J 10.0 3.5 and 1.7 olefinic) 6.00 (1 H dd J 10.1 and 2.7 olefinic) and 7.21–7.37 (5 H m Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.3 (COCH3) 25.3 (CH2CHOAc) 26.1 (CH2CHN) 51.0 (CH2Ph) 52.3 (CHN) 67.2 (CHOAc) 126.3 (CH Ph) 126.9 (olefinic CHCHOAc) 128.1 (CH Ph) 128.4 (CH Ph) 135.4 (olefinic CHCHN) 140.3 (C Ph) and 170.7 (C]] O). (A) Synthesis of the cis-4-aminocyclohex-2-enols (±)-cis-1-Acetoxy-4-diethylaminocyclohex-2-ene 10a.The synthesis was carried out according to the general procedure above. Amounts used were allylic substrate 8 (300 mg 1.718 mmol) Pd(dba)2 (51 mg 0.086 mmol) PPh3 (68 mg 0.258 mmol) Et2NH (151 mg 2.06 mmol) Et3N (521 mg 5.15 mmol) and THF (10 ml); reaction time 16 h; yield 280 mg 77%; dH(300 MHz; CDCl3) 1.04 (6 H app t J 7.2 CH3) 1.41–1.61 (2 H m CH2) 1.81–1.91 (1 H m CH2) 2.04 (3 H s COCH3) 2.11– 2.20 (1 H m CH2) 2.34–2.61 (4 H m NCH2) 3.40–3.53 (1 H m CHNEt2) 5.26–5.38 (1 H m CHOAc) 5.64–5.73 (1 H m olefinic) and 5.67–5.85 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.4 (NCH2CH3) 21.3 (CH3CO2) 22.3 (CH2CHN) 28.3 (CH2CHOAc) 44.1 (NCH2) 56.4 (CHN) 70.2 (CHOAc) 129.2 (olefinic CHCHN) 134.8 (olefinic CHCHOAc) and 170.8 (C]] O). cis-(1S,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1S,4R)-10a.The synthesis was carried out according to the general procedure. Amounts used were allylic substrate 16 (616 mg 1.718 mmol) Pd(dba)2 (51 mg 0.086 mmol) PPh3 (68 mg 0.258 mmol) Et2NH (151 mg 2.06 mmol) Et3N (521 mg 5.15 mmol) and THF (20 ml); reaction time 2 h; yield 298 mg 82%. Allylic substrate 17 (485 mg 1.473 mmol) Pd(dba)2 (44 mg 0.074 mmol) PPh3 (58 mg 0.221 mmol) Et2NH (183 mg 2.50 mmol) Et3N (447 mg 4.42 mmol) and THF (20 ml); reaction time 6 h; yield 228 mg 73%. Spectral data are in accordance with the racemate. (±)-cis-4-Diethylaminocyclohex-2-enol 6a. The amino acetate 10a (250 mg 19 mmol) was dissolved in a stirred solution of K2CO3 (9 mg 0.06 mmol) in MeOH–H2O (4 1; 10 ml) at RT. After 5 h the mixture was evaporated diluted with diethyl ether (100 ml) washed with water (10 ml) and brine (10 ml) dried (K2CO3) and evaporated.Purification of the residue on silica (gradient of diethyl ether–pentane 60 40 to ethyl acetate– MeOH 90 10) gave the title compound 6a (191 mg 95%) (Found for the HCl-salt C 58.3; H 9.7. Calc. for C10H20ClNO C 58.4; H 9.8%); dH(300 MHz; CDCl3) 1.04 (6 H app t CH3) 1.56–1.71 (3 H m 6-H and 5-H) 1.79–1.89 (1 H m 5-H) 1.96–2.14 (1 H br s OH) 2.38–2.65 (4 H m CH2) 3.26–3.33 (1 H m 1-H) 4.07–4.12 (1 H m 4-H) and 5.79–5.91 (2 H m 5-H and 6-H); dC(75.4 MHz; CDCl3 8 peaks) 14.2 (CH3) 17.9 (CH2) 30.2 (CH2) 44.2 (NCH2) 56.7 (CHNEt2) 63.4 (CHOAc) 130.2 (CH olefinic) 135.4 (CH olefinic); nmax/cm21 3346 (OH br) 2967 2937 2871 1386 and 1066. (2)-cis-(1S,4R)-4-Diethylaminocyclohex-2-enol (2)-(1S,4R)- 6a.Starting from (1S,4R)-10a and applying the same conditions as for the preparation of (±)-6a yielded (2)-6a. Spectral data are in accordance with (±)-6a; [a]D 25 270 (c 1.91 in EtOH); ee �98%. (+)-cis-(1R,4S)-4-Diethylaminocyclohex-2-enol (+)-(1R,4S)- 6a. See general procedure according to 10b. Allylic substrate 19 (802 mg 2.16 mmol) Pd(dba)2 (64 mg 0.108 mmol) PPh3 (85 mg 0.324 mmol) Et2NH (174 mg 2.38 mmol) Et3N (656 mg 6.48 mmol) and THF (25 ml) for 15 h yielded cis-(1R,4S)-4- diethylamino-1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (373 mg 68%). The THP group in the latter product (299 mg 1.18 mmol) was removed with toluene-p-sulfonic acid (190 mg 1.00 mmol) in MeOH (5 ml) at RT. After 12 h the mixture was evaporated and treated with diethyl ether (100 ml) and 1 M NaOH (10 ml).After extraction the organic phase was washed with water (10 ml) and brine (10 ml) dried (MgSO4) and evaporated. Purification of the residue on silica (gradient of diethyl ether–pentane 60 40 to ethyl acetate–MeOH 90 10) gave the title compound (+)-(1R,4S)-6a (161 mg 81%; totally 55% in two steps). Same spectral data as for (±)-6a; [a]D 25 +66 (c 1.70 in EtOH); ee �98%. (±)-cis-1-Acetoxy-4-benzylaminocyclohex-2-ene 10b. This compound is described above under the general procedure. cis-(1S,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4R)- 10b. See general procedure for (±)-10b. Pd(PPh3)4 (87 mg 0.075 mmol) was used instead of Pd(dba)2 for the allylic substrate 16 (539 mg 1.504 mmol); amounts of reactants used were PPh3 (20 mg 0.076 mmol) BnNH2 (161 mg 1.503 mmol) Et3N (340 mg 3.36 mmol) and THF (17 ml); reaction time 2 h; yield 292 mg 79%.For the allylic substrate 17 (311 mg 0.95 mmol) the following amounts were used Pd(dba)2 (28 mg 0.047 mmol) PPh3 (38 mg 0.142 mmol) BnNH2 (311 mg 2.83 mmol) and THF (17 ml); reaction time 2 h; yield 163 mg 70%. Spectral data were in accordance with those of racemic 10b. (±)-cis-4-Benzylaminocyclohex-2-enol 6b. Prepared from amino acetate 10b using the same hydrolysis conditions as for J. Chem. Soc. Perkin Trans. 1 1997 581 the preparation of 6a in 98% yield; dH(400 MHz; CDCl3) 1.56– 1.88 (6 H m 2 × CH2 OH NH) 3.09–3.21 (1 H m CHNHBn) 3.83 3.87 (2 H AB-system JAB 13.0 PhCH2NH) 4.09– 4.18 (1 H m CHOH) 5.81–5.89 (2 H m olefinic) and 7.22– 7.34 (5 H m Ph); dC(100.6 MHz; CDCl3 11 peaks) 24.9 (CH2) 29.1 (CH2) 51.1 (CH2Ph) 52.3 (CHN) 64.7 (CHOH) 127.0 (CH Ph) 128.1 (CH Ph) 128.4 (CH Ph) 130.7 (CH olefinic) 133.1 (CH olefinic) and 140.3 (C Ph).(2)-cis-(1S,4R)-4-Benzylaminocyclohex-2-enol (2)-(1S,4R)- 6b. This compound was prepared as above for 6b but starting with (1S,4R)-10b. Spectral data are as for (±)-6b; [a]D 25 24.3 (c 0.845 in EtOH); ee �98%. (+)-cis-(1R,4S)-4-Benzylaminocyclohex-2-enol (+)-(1R,4S)- 6b. See general procedure for 10b. Allylic substrate 19 (557 mg 1.50 mmol) Pd(dba)2 (45 mg 0.075 mmol) PPh3 (50 mg 0.188 mmol) BnNH2 (160 mg 1.50 mmol) Et3N (340 mg 3.36 mmol) in THF (12 ml) for 20 h gave cis-(1R,4S)-4-benzylamino- 1-(tetrahydropyran-2-yloxy)cyclohex-2-ene (426 mg 94%). The THP group was removed according to the preparation of (+)-(1R,4S)-6a in 69% yield (65% in two steps); spectral data as for (±)-6b; [a]D 25 +4.2 (c 1.79 in EtOH); ee �98%.(B) Synthesis of the trans-4-aminocyclohex-2-enols (±)-trans-1-Acetoxy-4-diethylaminocyclohex-2-ene 11a. The general procedure described for 10b was used but 25 mol% of LiCl was added to the reaction mixture together with the catalyst phosphine and amine. Allylic substrate 9 (131 mg 0.750 mmol) Pd(dba)2 (22 mg 0.037 mmol) PPh3 (40 mg 0.153 mmol) LiCl (8 mg 0.189 mmol) HNEt2 (165 mg 2.26 mmol) in THF (7.5 ml) for 20 h yielded 11a (113 mg 71%); dH(300 MHz; CDCl3) 1.04 (6 H app t J 7.2 CH3) 1.41–1.61 (2 H m CH2) 1.81–1.91 (1 H m CH2) 2.04 (3 H s COCH3) 2.11–2.20 (1 H m CH2) 2.34–2.61 (4 H m NCH2) 3.40–3.53 (1 H m CHNEt2) 5.26–5.38 (1 H m CHOAc) 5.64–5.73 (1 H m olefinic) and 5.76–5.85 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.2 (NCH2CH3) 21.2 (CH3CO2) 22.3 (CH2CHN) 28.2 (CH2CHOAc) 44.1 (NCH2) 56.4 (CHN) 70.1 (CHOAc) 129.2 (olefinic CHCHN) 134.8 (olefinic CHCHOAc) and 170.8 (C]] O); m/z (LC prior to ES-MS) 212 ([M + H]+ 82%) 139 (66%) 79 (7%) 61 (13%) and 60 (100%).Spectroscopic data for the corresponding g-product to 11a. (±)-trans-4-Acetoxy-3-diethylaminocyclohexene; dH(400 MHz; CDCl3) 1.01 (6 H app t J 7.1 CH3) 1.56–1.75 (2 H m CH2) 1.86–1.96 (1 H m CH2) 2.04 (3 H s COCH3) 2.07–2.20 (1 H m CH2) 2.53 (4 H app q NCH2) 3.36–3.43 (1 H m CHNEt2) 5.00 (1 H ddd J 11.1 7.7 3.6 CHOAc) 5.53–5.60 (1 H m olefinic) and 5.74–5.82 (1 H m olefinic); dC(100.6 MHz; CDCl3 10 peaks) 14.5 21.5 24.0 27.6 44.4 60.4 70.9 127.7 128.9 and 170.6. trans-(1S,4S)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1S,4S)-11a.The same procedure was used as for racemic 11a but starting from (2)-9. Spectral data are in accordance with the racemate. trans-(1R,4R)-1-Acetoxy-4-diethylaminocyclohex-2-ene (1R,4R)-11a. The same procedure was used as for racemic 11a but starting from (+)-9. Spectral data are in accordance with the racemate. (±)-trans-4-Diethylaminocyclohex-2-enol 7a. This substance was prepared from amino acetate 11a using the same hydrolysis conditions as for 6a in 96% yield; dH(300 MHz; CDCl3) 1.01 (6 H app t CH3) 1.32–1.53 (2 H m 6-H) 1.76–1.89 (1 H m 5-H) 2.06–2.18 (1 H m 5-H) 2.31–2.59 (4 H m NCH2) 2.60– 2.80 (1 H br s OH) 3.37–3.47 (1 H m 1-H) 4.16–4.28 (1 H m 4-H) and 5.63–5.79 (2 H m 5-H and 6-H); dC(100.6 MHz; CDCl3 8 peaks) 14.1 (CH3) 22.4 (CH2) 32.5 (CH2) 44.1 (NCH2) 56.6 (CHNEt2) 67.3 (CHOAc) 132.4 (CH olefinic) 133.6 (CH olefinic); m/z (LC prior to ES-MS) 170 ([M + H]+ 100%); nmax/cm21 3331 (OH br) 2968 2935 2864 1451 1384 and 1065.(2)-trans-(1S,4S)-4-Diethylaminocyclohex-2-enol (2)- (1S,4S)-7a. Preparation as for (±)-7a but with (1S,4S)-11a as the substrate. Same spectral data as for (±)-7a; [a]D 25 2102 (c 1.165 in EtOH); ee �98%. (+)-trans-(1R,4R)-4-Diethylaminocyclohex-2-enol (+)- (1R,4R)-7a. Preparation as for (±)-7a but with (1R,4R)-11a as the substrate. Same spectral data as for (±)-7a; [a]D 25 +98 (c 0.600 in EtOH). (±)-trans-1-Acetoxy-4-benzylaminocyclohex-2-ene 11b. The general procedure described for 10b was used but 25 mol% of LiCl was added to the reaction mixture together with the catalyst phosphine and amine. Amounts used were trans-chloro acetate 9 (720 mg 4.13 mmol) Pd(dba)2 (124 mg 0.21 mmol) PPh3 (162 mg 0.62 mmol) LiCl (44 mg 1.03 mmol) BnNH2 (531 mg 4.95 mmol) and Et3N (1.25 g 12.37 mmol) in THF (36 ml).The reaction mixture was stirred at RT for 20 h to give on work-up the amino acetate 11b (770 mg 76%); dH(400 MHz; CDCl3) 1.45–1.64 (2 H m CH2) 1.99–2.19 (2 H m CH2) 2.04 (3 H s COCH3) 2.58 (1 H br s NH) 3.27–3.33 (1 H m CHNHBn) 3.83 3.86 (2 H AB-system JAB 13.2 PhCH2NH) 5.28–5.34 (1 H m CHOAc) 5.72 (1 H dddd J 10.4 3.2 2.0 1.2 olefinic CHCHOAc) 5.93 (1 H dddd 1.6 1.2 olefinic CHCHN) and 7.20–7.45 (5 H m Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.2 (COCH3) 26.9 (CH2CHOAc) 27.3 (CH2CHN) 50.6 (CH2Ph) 52.2 (CHN) 69.1 (CHOAc) 127.0 (CH Ph) 127.9 (olefinic CHCHOAc) 128.1 (CH Ph) 128.4 (CH Ph) 133.8 (olefinic CHCHN) 139.8 (C Ph) and 170.6 (C]] O); m/z (LC prior to ES-MS) 246 ([M + H]+ 100%) 139 (54%) 108 (3%) 79 (5%) and 61 (6%).Spectroscopic data for the corresponding g-product to 11b (±)-trans-4-acetoxy-3-benzylaminocyclohexene; dH(400 MHz; CDCl3) 1.65–2.05 (3 H br s and two m overlapping CH2 NH) 2.10–2.19 (2 H m CH2) 3.25–3.33 (1 H m CHNH) 3.83 3.88 (2 H AB-system JAB 13.3 PhCH2NH) 4.99 (1 H ddd J 8.9 6.3 and 3.1 CHOAc) 5.62–5.69 (1 H m olefinic) 5.76–5.84 (1 H m olefinic) and 7.18–7.38 (5 H m aromatic); dC(100.6 MHz; CDCl3 13 peaks) 21.4 23.2 25.2 50.5 56.5 72.6 126.9 127.1 128.1 128.3 128.8 140.6 and 170.8. trans-(1S,4S)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1S,4S)-11b. The same procedure was used as for racemic 11b but starting from (2)-9. Spectral data are in accordance with the racemate.trans-(1R,4R)-1-Acetoxy-4-benzylaminocyclohex-2-ene (1R,4R)-11b. The same procedure was used as for racemic 11b but starting from (+)-9. Spectral data are in accordance with the racemate. (±)-trans-4-Benzylaminocyclohex-2-enol 7b. The title compound was prepared from amino acetate 11b using the same hydrolysis conditions as for 6a in 98% yield; dH(400 MHz; CDCl3) 1.36–1.51 (2 H m CH2) 1.57–1.68 (2 H br s NH and OH) 2.03–2.15 (2 H m CH2) 3.24–3.28 (1 H m CHNH) 3.82 3.85 (2 H AB-system JAB 13.0 PhCH2NH) 4.23–4.26 (1 H m CHOH) 5.75–5.83 (2 H m olefinic) and 7.22–7.34 (5 H m Ph); dC(100.6 MHz; CDCl3 11 peaks) 27.9 (CH2) 31.2 (CH2) 50.8 (CH2Ph) 52.7 (CHN) 66.8 (CHOH) 127.1 (CH Ph) 128.2 (CH Ph) 128.5 (CH Ph) 132.0 (CH olefinic) 132.1 (CH olefinic) and 140.1 (C Ph). (2)-trans-(1S,4S)-4-Benzylaminocyclohex-2-enol (2)- (1S,4S)-7b.Preparation as for (±)-7b but with (1S,4S)-11b as the substrate. Same spectral data as for (±)-7b; [a]D 25 2122 (c 1.773 in EtOH); ee �98%. (+)-trans-(1R,4R)-4-Benzylaminocyclohex-2-enol (+)- (1R,4R)-7b. Preparation as for (±)-7b but with (1R,4R)-11b as the substrate. Same spectral data as for (±)-7b; [a]D 25 +120 (c 1.394 in EtOH); ee �98%. (C) Synthesis of the allylic substrates (±)-cis-4-Acetoxycyclohex-2-enol (±)-2a. 1,4-Diacetoxycyclohex- 2-ene 6 (17.39 g 87.72 mmol) and K2CO3 (606 mg 4.39 mmol) were dissolved in methanol–water (4 1; 150 ml) and the 582 J. Chem. Soc. Perkin Trans. 1 1997 solution stirred at RT for 40 min. It was then neutralised with 1 M aq. HCl and the methanol was removed in vacuo. The aqueous phase was saturated with NaCl and extracted with EtOAc and the extract was dried (MgSO4) and concentrated.The residue was separated on silica (gradient EtOAc–pentane) to give 2a (8.118 g 59%). The spectral data were consistent with those previously reported.4 (2)-cis-(1R,4S)-4-Acetoxycyclohex-2-enol (2)-(1R,4S)-2a. Preparation according to ref. 4. cis-1-Acetoxy-4-chlorocyclohex-2-ene 8. The preparation was carried out as in ref. 5 and the spectral data were in accord with those reported therein. (±)-trans-1-Acetoxy-4-chlorocyclohex-2-ene 9. To N-chlorosuccinimide (806 mg 6.04 mmol) in THF (7 ml) under nitrogen was added a solution of PPh3 (1.575 g 6.01 mmol) in THF (7 ml). A slightly exothermic reaction ensued. After the reaction mixture had cooled to room temperature the alcohol 2a (632 mg 4.047 mmol) dissolved in THF (6 ml) was added to it; the mixture was then stirred at room temperature for 15 h.The solvent was removed and the residue was dissolved in a small amount of CH2Cl2 and purified on silica (diethyl ether–pentane 5 95) to give the title compound 9 (684 mg 97%). About 4% of the corresponding SN29-product was formed in the reaction. Spectral data for 9 were in accord with those reported in ref. 5. (2)-trans-(1S,4S)-1-Acetoxy-4-chlorocyclohex-2-ene (2)- (1S,4S)-9. This compound was prepared in the same way as for the racemic compound 9 starting from (2)-2a. [a]D 25 2395 (c 1.01 in EtOH); 2.5% of the SN29-product contaminated the product. (+)-trans-(1R,4R)-1-Acetoxy-4-chlorocyclohex-2-ene (+)- (1R,4R)-9. To a solution of compound 20c (594 mg 2.406 mmol) in THF (15 ml) was added tetrabutylammonium fluoride (TBAF) (1 M soln.in THF 2.53 ml 2.53 mmol) at room temperature. After 3 h acetic anhydride (2.3 ml 24.4 mmol) was added to the reaction mixture which was then stirred for an additional 12 h. It was then evaporated and the residue was separated on silica (gradient ether–pentane 5 95–15 85) to give the title compound (+)-9 (347 mg 83%). Spectral data were in accord with those reported in ref. 5; [a]D 25 +415 (c 0.89 in EtOH). cis-(1R,4S)-4-Acetoxycyclohex-2-enyl diphenylphosphinate (1R,4S)-16. The title compound was synthesized from the alcohol (2)-2a (1.00 g 6.32 mmol) according to procedure A reported in ref. 14 (reaction time 30 h) except that in the aqueous work-up the organic extract was washed with saturated copper sulfate (3×) water (1×) and brine (1×) before being dried (MgSO4).After evaporation of the extract the crude product was filtered through basic alumina eluting with diethyl ether. Removal of the ether afforded a colourless oil of the title compound 16 (2.02 g 89%) which was sufficiently pure for the next step; dH(400 MHz; CDCl3) 1.80–1.94 (3 H m CH2) 2.01– 2.06 (1 H m CH2) 2.06 (3 H s COCH3) 4.84–4.91 [1 H m CHOP(O)Ph2] 5.15–5.20 (1 H m CHOAc) 5.83–5.96 (2 H m olefinic) 7.44 (4 H o-Ph) 7.51 (2 H m p-Ph) 7.82 (4 H tdd 2JHP 12.6 JHH 8.2 1.4 o-Ph); dC(100.6 MHz; CDCl3 13 peaks) 21.1 (CH3CO2) 24.6 (CH2CHOAc) 26.9 (d 3JCP 3.8 CH2CHOP) 67.0 (CHOAc) 69.0 (d 2JCP 6.0 CHOP) 128.4 (d 3JCP 12.2 aromatic CH) 129.9 (olefinic CHCHOAc) 131.5 (d 2JCP 17.5 aromatic CH) 131.5 (d 3JCP 3.0 olefinic CHCHOP) 131.87 (d 1JCP 136.6 aromatic C) 131.92 (d 4JCP 137.3 aromatic C) 132.1 (d 4JCP 1.5 aromatic CH) and 170.2 (C]] O); m/z (NH4CO2 added prior to ES-MS) 379 ([M + Na]+ 5%) 374 ([M + NH4]+ 4%) 357 ([M + H]+ 50%) 297 (3%) 219 (11%) 139 (100%) and 79 (6%).cis-(1R,4S)-4-Acetoxycyclohex-2-enyl 2,4-dichlorobenzoate (1R,4S)-17. A solution of cis-4-acetoxycyclohex-2-enol (2)-2a (953 mg 6.10 mmol) 2,4-dichlorobenzoic acid (1.72 g 9.00 mmol) dicyclohexylcarbodiimide (DCC) (1.86 g 9.01 mmol) and p-dimethylaminopyridine (DMAP) (16 mg 0.13 mmol) in methylene dichloride (50 ml) was stirred at RT for 3 h. Diethyl ether (50 ml) was added to the reaction mixture which was then washed with cold 5% aq. HCl (2 × 25 ml) and saturated aqueous NaHCO3 (3 × 25 ml) dried (MgSO4) and concentrated. The crude product was filtered through basic alumina and purified on silica using MPLC (EtOAc–CH2Cl2 1 1 gradient in pentane) to give the title compound 17 (1.61 g 80%); dH(300 MHz; CDCl3) 1.90–2.06 (4 H m 2 × CH2) 2.07 (3 H s COCH3) 5.23–5.33 (1 H m CHOAc) 5.39–5.51 [1 H m CHOC(O)Ar] 5.94–6.05 (2 H m olefinic) 7.29 (1 H dd J 8.4 and 2.0 ArH) 7.47 (1 H d J 2.0 ArH) and 7.79 (1 H d J 8.4 ArH); dC(100.6 MHz; CDCl3 15 peaks) 21.1 (CH3CO2) 24.8 (CH2) 25.0 (CH2) 67.4 (CHOAc) 68.6 [CHOC(O)Ar] 126.9 (aromatic CHCHCCl) 128.4 (aromatic C) 129.3 [olefinic CHCHOC(O)Ar] 130.9 (aromatic CClCHCCl) 131.2 (olefinic CHCHOAc) 132.4 (aromatic CCHCH) 134.8 (aromatic C) 138.2 (aromatic C) 164.2 (C]] O) and 170.4 (C]] O); m/z 273 (0.6%) 271 (5%) 269 (7%) 177 (12%) 175 (65%) 173 (100%) 149 (2%) 147 (8%) 145 (12%) 139 (12%) 96 (43%) and 79 (26%); [a]D 25 +56 (c 1.16 in EtOH).(+)-cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enol (+)-(1S,4R)-18a. To (2)-2a (535 mg 3.38 mmol) dissolved in methylene dichloride (30 ml) was added dihydropyran (DHP) (425 mg 5.05 mmol) and pyridinium toluene-p-sulfonate (PPTS) (85 mg 0.338 mmol). The solution was stirred at RT for 4 h after which it was diluted with diethyl ether (100 ml) washed with brine–water (1 1; 20 ml) and concentrated. The resulting crude product was dissolved in methanol (5 ml) and treated withO3 (23 mg 0.17 mmol) in water (1 ml). After being stirred at RT for 5 h the reaction mixture was diluted with water (10 ml) and then concentrated by evaporation of most of the methanol. The aqueous phase was extracted with diethyl ether (3 × 50 ml) and the combined organic fractions were then washed with brine (20 ml) dried (MgSO4) and concentrated.Purification of the residue on silica (diethyl ether–pentane 60 40) gave the title compound 18a (650 mg 98%) (Found C 65.9; H 8.8. Calc. for C11H18O3 C 66.6; H 9.15%); dH(400 MHz; CDCl3) 1.48–1.94 (10 H m 5- H 6-H 8-H 9-H and 10-H) 3.45–3.54 (1 H m 11-H) 3.86– 3.97 (1 H m 11-H) 4.08–4.18 (2 H m 4-H and 7-H) 4.72– 4.78 (1 H m 1-H) and 5.88–5.91 (2 H m 2-H and 3-H); dC(100.6 MHz; CDCl3) 19.5 (C-9) 24.3 and 26.2 (C-5) 25.3 and 25.4 (C-10) 28.1 and 28.5 (C-6) 30.9 and 31.0 (C-8) 62.4 and 62.5 (C-11) 65.1 and 65.2 (C-1) 68.9 and 70.0 (C-4) 96.8 and 97.8 (C-7) 130.1 and 131.3 (olefinic) 132.5 and 132.6 (olefinic); m/z (M+ >0.5%) 97 (51%) 85 (90%) 79 (63%) 67 (64%) 57 (65%) and 55 (100%); nmax/cm21 3404 (OH br) 2942 2869 1133 1074 1032 and 1000; [a]D 25 +38.1 (c 0.91 in CH2Cl2).cis-4-Pivaloyloxycyclohex-2-enol 18b. To a solution of the hydroxyacetate 2a (1.00 g 6.402 mmol) Et3N (3.24 g 32.01 mmol) and DMAP (22 mg 0.180 mmol) in THF (25 ml) was added pivaloyl chloride (1.58 ml 12.81 mmol). The reaction mixture was stirred at 50 8C for 24 h after which the solvent was removed and ether (60 ml) was added to the residue. The solution was washed with 1 M hydrochloric acid (× 3) sat’d aqueous NaHCO3 and brine dried (MgSO4) and concentrated. Separation of the residue on silica (diethyl ether–pentane 3 97 then 5 95) yielded cis-4-acetoxy-1- pivaloyloxycyclohex-2-ene (1.485 g 95%); dH(400 MHz; CDCl3) 1.19 (9 H s But) 1.77–1.96 (4 H m CH2) 2.07 (3 H s COCH3) 5.15–5.24 (2 H m CHOAc CHOPiv) and 5.81– 5.91 (2 H m olefinic); dC(100.6 MHz; CDCl3 11 peaks) 21.3 24.8 24.9 27.1 38.7 66.9 67.4 130.0 130.5 170.5 178.0.Selective hydrolysis of the acetate (1.112 g 4.627 mmol) was performed with a 10% solution of Na2CO3?10 H2O (133 mg 0.465 mmol) in MeOH–H2O (4 1 23 ml) at RT for 9 h. After removal of the methanol from the mixture it was extracted with ether and the extract dried (Na2SO4) and concentrated to give the title compound 18b (839 mg 92%); dH(400 MHz; J. Chem. Soc. Perkin Trans. 1 1997 583 CDCl3) 1.18 (9 H s But) 1.62–1.98 (5 H m CH2 OH) 4.14– 4.26 (1 H m CHOH) 5.10–5.24 (1 H m CHOPiv) 5.73–5.84 (1 H m olefinic) and 5.90–6.00 (1 H m olefinic); dC(100.6 MHz; CDCl3 9 peaks) 24.9 (C-5) 27.1 (C-9) 28.1 (C-6) 38.7 (C-8) 65.3 (C-1) 66.9 (C-4) 128.0 (C-3) 134.5 (C-2) and 178.1 (C-7); m/z 180 (2%) 113 (3%) 97 (23%) 96 (67%) 95 (14%) 85 (21%) 79 (21%) and 57 (100%).cis-(1S,4R)-4-(tert-Butyldimethylsilyloxy)cyclohex-2-enol (1S,4R)-18c. To a stirred solution of 21c (3.256 g 12.039 mmol) was added KOH (135 mg 2.408 mmol) in methanol (40 ml). The reaction mixture was stirred at RT for 4 h after which the solvent was removed and the residue was treated with water (30 ml) and diethyl ether (60 ml); the layers were separated and the pH of the aqueous layer was adjusted to 7 with 1 M hydrochloric acid; it was then further extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the product (2.698 g 98%) which was pure enough for the next step; dH(400 MHz; CDCl3) 0.073 (3 H s SiCH3) 0.076 (3 H s SiCH3) 0.89 [9 H s SiC(CH3)3] 1.60–1.90 (5 H m 2 × CH2 OH) 4.06–4.18 (2 H two overlapping m CHOH CHOSi) 5.75 (1 H dd J 10.2 and 2.4 olefinic) and 5.79 (1 H dd J 10.2 and 3.1 olefinic); dC(100.6 MHz; CDCl3 10 peaks) 24.7 (C-7) 24.6 (C-79) 18.1 (C-8) 25.8 (C-9) 28.2 (C-5) 28.4 (C-6) 64.8 (C-1) 66.3 (C-4) 130.7 (C-2) and 133.9 (C-3); [a]D 25 +34 (c 1.58 in EtOH).cis-(1S,4R)-4-(Tetrahydropyran-2-yloxy)cyclohex-2-enyl 2,4- dichlorobenzoate (1S,4R)-19. A solution of DCC (1.297 g 6.285 mmol) and DMAP (13 mg 0.105 mmol) in methylene dichloride (10 ml) was added to a stirred solution of 18a (1.246 g 6.285 mmol) and 2,4-dichlorobenzoic acid (1.200 g 6.285 mmol) in methylene dichloride (25 ml) at RT. The solution was stirred at RT for 10 h after which it was diluted with diethyl ether (300 ml).The organic phase was washed with 5% aqueous acetic acid (50 ml) water (20 ml) and brine (20 ml) dried (MgSO4) and concentrated. Purification of the residue on silica (diethyl ether–pentane 60 40) gave the title compound 19 (2.20 g 87%); dH(400 MHz; CDCl3) 1.43–2.07 (10 H m 5-H 6-H 8-H 9-H and 10-H) 3.47–3.54 (1 H m 11-H) 3.86–3.94 (1 H m 11-H) 4.15–4.27 (1 H two overlapping m 4-H) 4.73–4.78 (1 H m 7-H) 5.39–5.45 (1 H m 1-H) 5.89–5.95 (1 H m 3-H) and 6.01–6.09 (1 H m 2-H); dC(100.6 MHz; CDCl3) 19.5 and 19.6 (CH2) 24.4 and 26.3 (CH2) 25.2 and 25.4 (CH2) 25.5 and 26.1 (CH2) 30.9 and 31.0 (CH2) 62.5 and 62.6 (CH2) 68.7 and 68.8 [allyl-CHOC(O)Ar] 69.3 and 70.4 (allyl-CHOTHP) 97.0 and 98.1 (THP-OCHO) 126.9 (aromatic CH) 127.0 and 127.1 [olefinic CHCHOC(O)Ar] 128.5 (aromatic C) 130.9 (aromatic CH) 132.5 (aromatic CH) 133.8 and 134.9 (olefinic CHCHOTHP) 135.8 (aromatic C) 138.1 (aromatic C) and 164.2 (C]] O); m/z 273 (19%) 271 (29%) 194 (6%) 192 (61%) 190 (81%) 177 (12%) 175 (68%) 173 (100%) 147 (12%) and 145 (28%).trans-1-Chloro-4-(tetrahydropyran-2-yloxy)cyclohex-2-ene 20a. A solution of 18a (100 mg 0.504 mmol) LiCl (46 mg 1.08 mmol) and 2,4,6-trimethylpyridine (504 ml 3.78 mmol) in DMF (750 ml) was cooled to 0 8C and treated with MsCl (58 ml 0.83 mmol) followed after 20 min by diethyl ether (40 ml). The solution was washed with water (5 ml) and brine (5 ml) dried (MgSO4) and concentrated. The residue was purified on silica (diethyl ether–pentane 40 60) to give the title compound 20a (98 mg 90%). Since the product is extremely unstable it should be prepared directly before further use; dH(400 MHz; CDCl3) 1.40–2.40 (10 H m 5-H 6-H 8-H 9-H 10-H) 3.43–3.58 (1 H m 11-H) 3.83–3.98 (1 H m 11-H) 4.16–4.30 (1 H m 4-H) 4.54–4.65 (1 H m 7-H) 4.66–4.80 (1 H m 1-H) and 5.82–6.03 (2 H m olefinic); dC(100.6 MHz; CDCl3) 19.7 25.4 25.4 25.5 27.5 29.3 29.7 29.8 31.1 31.1 54.6 54.6 62.6 62.7 68.3 69.0 97.3 98.1 130.4 130.6 131.1 and 131.7.trans-1-Chloro-4-pivaloyloxycyclohex-2-ene 20b. Triphenylphosphine (836 mg 3.19 mmol) dissolved in THF (3 ml) was added to a solution of N-chlorosuccinimide (426 mg 3.19 mmol) in THF (5 ml) to give slightly exothermic phosphonium salt formation. After cooling of the reaction mixture to RT (20 min) 18b (416 mg 2.098 mmol) in THF (3 ml) was added to it; it was then stored at RT for 24 h. After this the solvent was evaporated from the mixture and pentane was added to the residue.The precipitated triphenylphosphine oxide and succinimide were filtered off and the pentane was removed in vacuo to give a residue which was purified on silica (EtOAc–pentane 1 99). This afforded 20b (305 mg 67%) (8% of the reaction product was derived from the SN29 substitution mechanism); dH(400 MHz; CDCl3) 1.17 (9 H s But) 1.68–1.78 (1 H m CH2) 1.94–2.04 (1 H m CH2) 2.12–2.32 (2 H m CH2) 4.57– 4.64 (1 H m CHCl) 5.20–5.28 (1 H m CHOPiv) 5.82–5.89 (1 H m olefinic) and 5.98–6.04 (1 H m olefinic); dC(100.6 MHz; CDCl3 9 peaks) 24.8 (CH2) 27.1 (CH3) 28.7 (CH2) 38.7 (C) 53.6 (CHCl) 65.7 (CHOPiv) 128.3 (olefinic CH) 132.3 (olefinic CH) and 177.8 (C]] O). trans-(1R,4R)-1-Chloro-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene (1R,4R)-20c.To compound 18c (1.503 g 6.58 mmol) was added LiCl (558 mg 13.16 mmol) and Et3N (2.75 ml 19.74 mmol) in CH2Cl2 (25 ml). The solution was cooled to 220 8C and MsCl (610 ml 7.881 mmol) was added to it via a syringe. The mixture was brought to RT over 3 h after which it was stirred for a further 17 h. It was then diluted with water– NaHCO3 (sat’d) (1 1; 30 ml) and the phases were separated. The aqueous phase was extracted with diethyl ether (3 × 70 ml). The combined organic phases were washed with brine (20 ml) dried (MgSO4) and passed through a silica column packed with Et3N–diethyl ether–pentane (4 2 94). Elution with diethyl ether–pentane (2 98 then 5 95) gave the title compound 20c (1.484 g 91%); dH(400 MHz; CDCl3) 0.08 (6 H s SiCH3 × 2) 0.89 [9 H s SiC(CH3)3] 1.60–1.67 (1 H m CH2) 1.84–1.93 (1 H m CH2) 2.02–2.11 (1 H m CH2) 2.29–2.37 (1 H m CH2) 4.23–4.27 (1 H m CHOSi) 4.56–4.60 (1 H m CHCl) 5.77 (1 H dd J 10.4 and 3.1 olefinic) and 5.82 (1 H dd J 10.4 and 3.2 olefinic); dC(100.6 MHz; CDCl3 10 peaks) 24.7 (C-7) 24.6 (C-79) 18.2 (C-8) 25.8 (C-9) 29.7 (C-6) 29.9 (C-5) 54.9 (C-1) 64.9 (C-4) 129.5 (C-2) and 133.5 (C-3); m/z 248 (1%) 246 (2%) 191 (24%) 189 (64%) 93 (18%) 77 (15%) and 75 (100%); [a]D 25 +259 (c 1.75 in EtOH).cis-(1S,4R)-1-Acetoxy-4-(tert-butyldimethylsilyloxy)cyclohex- 2-ene (1S,4R)-21c. A solution of TBDMS-Cl (2.665 g 17.68 mmol) in methylene dichloride (40 ml) was cooled to 0 8C and imidazole (6.74 g 99.0 mmol) was added to it. After 5 min (2)- 2a (2.209 g 14.14 mmol) dissolved in methylene dichloride (30 ml) was added to the mixture which was then stirred at 0 8C for ca.30 min and then at RT for 20 h. After being quenched with water (10 ml) the reaction mixture was extracted with methylene dichloride (3 × 50 ml). The combined organic fractions were washed with brine (20 ml) dried (Na2SO4) concentrated and subjected to chromatography (diethyl ether–pentane 5 95) to give the title compound 21c (3.79 g 99%); dH(400 MHz; CDCl3) 0.078 (3 H s SiCH3) 0.082 (3 H s SiCH3) 0.90 [9 H s SiC(CH3)3] 1.65–1.95 (4 H m 2 × CH2) 2.04 (3 H s COCH3) 4.15–4.19 (1 H m CHOSi) 5.13–5.17 (1 H m CHOAc) 5.71–5.75 (1 H m olefinic) and 5.85–5.88 (1 H m olefinic); dC(100.6 MHz; CDCl3) 24.7 (SiCH3) 24.6 (SiCH3) 18.1 (SiC) 21.2 (COCH3) 25.3 (CH2CHOAc) 25.8 [SiC(CH3)3] 28.4 (CH2CHOSi) 66.3 (CHOSi) 67.0 (CHOAc) 126.2 (olefinic CHCHOAc) 136.3 (olefinic CHCHOSi) and 170.6 (C]] O); m/ z 210 (2%) 117 (100%) 79 (12%) and 75 (33%); [a]D 25 240 (c 1.63 in EtOH).Acknowledgements Financial support from the Swedish Natural Science Research Council The Research Council of the Board of Technical Development and the Swedish Research Council for Engineering Sciences is gratefully acknowledged. 584 J. Chem. Soc. 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Paper 6/00779A Received 1st February 1996 Accepted 7th October 1996

ISSN:1472-7781    

DOI:10.1039/a600779a

出版商:RSC    

年代:1997

数据来源: RSC