Camphor A Chiral Starting Material in Natural Product Synthesis T. Money Department of Chemistry University of British Columbia Vancouver Canada V6T 1Y6 1 Introduction 2 C( 10)-Functionalization of Camphor and its Derivatives 3 C(9)-Functionalization of Camphor and its Derivatives 4 C(8)-Functionalization of Camphor and its Derivatives 5 C( 10)-Functionalization of C(9)- and C(8)-Substituted Camphor Derivatives 6 C(5)-Functionalization of Camphor and its Derivatives 6.1 Chemical Methods 6.2 Biological Methods 7 C(3)-Functionalization of Camphor and its Derivatives 7.1 C(3)-Hydrogen Exchange 7.2 C(3)-Monobromination 7.3 C( 3)-Met h ylat ion 7.4 Enol Derivatives of Camphor and their Reactions 8 Ring-cleavage Reactions of Camphor and its Derivatives 8.1 Cleavage of the C(l)-C(2) Bond 8.2 Cleavage of the C(2)-C(3) Bond 8.3 Cleavage of the C(ltC(7) Bond 9 Rearrangement of Camphor and its Derivatives 10 The Use of Derivatives of Camphor in Natural Product Synthesis 11 References 'No substance known to us suffers rearrangement of its parts and undergoes a complete change of type more readily than doescamphor.. .'[H. E. Armstrong and T. M. Lowry J.Chem. SOC.,1902 81 14411 1 Introduction Interest in the chemistry of camphor and its has been continuous throughout the history of natural product chemistry. This interest is largely associated with the fact that (+)-or (-)-camphor is readily available and undergoes a wide variety of transformations which often involve fascinating rearrangement processes.Much of this chemistry has had a considerable impact on theoretical and mechanistic organic chemistry and various compounds that are derived from camphor have been used as key intermediates in organic synthesis. H@ 3 H 4 X (5) X = H (6)X = Br The versatility and importance of camphor as a chiral starting material in the enantiospecific synthesis of natural products is primarily due to the availability of methods for the direct or indirect introduction of functionality at C-3 C-5 C-8 C-9 and C-10 (see Figure 1). Inaddition cleavage of the C(1)- C(2) and C(2)-C(3) bonds in camphor and its derivatives can be accomplished by a variety of methods to provide useful synthetic intermediates.A description of the methods that have been used to functionalize camphor and the use of these derivatives in the synthesis of natural products is provided in this review. 2 C(10)-Functionalization of Camphor and its Derivatives Regiospecific and stereospecific functionalization of camphor at C-10 (which in early literature is described as a-or p-substitution)'-' can be accomplished by sulphonating (+)-camphor (1)697 or (+)-3-endo-bromocamphor (2)899 with sulphuric acid and acetate anhydride. The mechanism' of C( I 0)-sulphonation probably involves Wagner-Meerwein rearrangement of protonated camphor followed by sulphona- tion and regeneration of the camphor framework (cf. Scheme 1). In contrast the direct stereospecific C( 10)-bromination of camphor has not been reported and 10-bromocamphor (8) is normally prepared by thermolysis of camphor-1 0-sulphonyl bromide (7)' 3,14 or less efficiently by brominative rearrange- ment of camphene (9)15 or 1-hydroxycamphene (1 1)16 (Scheme 2).If the mechanism'* that is illustrated in Scheme 1 is operating during C(10)-sulphonation it is conceivable that interception of the intermediate (3) with electrophilic bromine 27 34 5 Figure 1 The numbering system that is used for the camphor molecule in this review @SO3H u (4) Reagents i H2S04 Ac,O; ii SO3 scheme 1 NATURAL PRODUCT REPORTS 1985 Reagents i KOH MeOH; ii PBr,; iii heat in xylene; iv MeCONHBr H30+; v Cr03 H+; vi Br2 HOAc; vii Br2 H2S04-Ac20; viii Zn HOAc Scheme 2 Table 1 Derivatives of camphor that have been synthesized and for which the structure is 25 R References CH2S03H 1-3 6-11 CH2S02Cl 18 19 CH2S02Br 13 14 C(Cl)=S==o CH2S02Me 21 25 32 34 20 CH2SH 11 20 CH2CI 11 13 CH2Br 11 13-17 CH2I 11 CHZOAC 1 22 CHzOH CH ,OCOPh 1 2 23 CH=CH2 24 CH=CHPh 14 CH*D CDZH CD3 C02H (ketopinic acid) 1-3 10 25-28 20 21 30 31 33 CH2S02H 11 Br 27 33 CHO 1 C H 2 COZH 1 29 CH2S02N MePh 19 could lead to the direct formation of 10-bromocamphor.As a result of this speculation 3,3-dibromocamphor (1 2)* was treated with bromine (3 moles) in acetic anhydride-sulphuric acid (2:1) followed by selective debromination (by zinc and acetic acid) and a low yield (-10%) of 10-bromocamphor (8) was obtained.I7 It is probable that further work on this approach could lead to a viable synthesis of this compound.Camphor-10-sulphonic acid is the synthetic precursor of a great variety of C(10)-derivatives of camphor and these are listed in Table 1. 3 C(9)-Functionalization of Camphor and its Derivatives Regiospecific sulphonation of (+)-camphor (1) at C-97 is a well-known reaction which can be accomplished by using The useof camphor or 3-endo-bromocamphor under these conditions resulted in C(3)-bromination and a minor amount of C(10)-bromination. t In the literature this is often described as the n position. The term was used originally36b to describe chlore or bromo-camphor that was produced by thermal decomposition ('pyrogenic formation') of the corresponding camphorsulphonyl halide (subsequently named camphor-n-sulphonyl bromide or chloride).SO3H I Jo3" Iii so3w I Br Br (2) (14) Reagents i ClS03H or HZS04-S03;ii Br2 HOAc; iii Zn NH3 Scheme 3 chlorosulphonic acid or fuming sulphuric acid as However the product of these reactions is a mixture of (+)-and (-)-camphor-9-sulphonic acid [(13a) and (13b)] and this diminishes their synthetic potential. Fortunately this problem can be solved in a simple fashion by using (+)-3-endo- bromocamphor (2) [which is obtained by treating (+)-camphor with bromine in acetic acid4'] in the sulphonation reac-ti~n.~'-~O The product 3-endo-bromocamphor-9-sulphonic acid (14) is debrominated to provide (+)-camphor-9-sulphonic acid (1 3a) with the same absolute configuration as the original (+)-camphor (1) (Scheme 3).Probable mechanisms' 2*42-43 for the production of partially racemic camphor-9-sulphonic acid (1 3a 13b) from (+)-camphor (1) and of (+)-3-endo-bromocam-phor-9-sulphonic acid (14) from (+)-3-endo-bromocamphor (2) are shown in Scheme 4. In essence these mechanisms involve Wagner-Meerwein rearrangement of camphor followed by a NATURAL PRODUCT REPORTS. 1985 -T. MONEY 255 x (1) X 3; H I x \Y v (13a) X = H Y = SO3H 18) 17) (21) (14) X=Br,Y =SO3H (19a) X=H,Y = Br I2,6 -ti 1 (20) X=Y=Br I Y (13b) X = H,Y = S03H (25) X = Br Y = SO3H (19b) X = H Y = Br (26) X=Y=Br [W M = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl .shift; 2,6-H = 2,b-hydride shift] Scheme 4 Nametkin shift of the exo-methyl group to produce an intermediate (16) which can follow two pathways [(A) and (B)].In the shorter pathway (A) sulphonation of (16) followed by reversal of the rearrangement processes that are outlined above provides (+)-camphor-9-sulphonic acid (13a) having the same absolute configuration as that of the original camphor. Alternatively intermediate (1 7) can undergo Wag- ner-Meerwein rearrangement 2,6-hydride shift and Wagner- Meerwein rearrangement [pathway (B)] to provide the enantio- meric intermediate (23) and hence (-)-camphor-9-sulphonic acid (13b). Evidence for this mechanistic scheme was obtained when [8-14C]camphor (1; A = 14C) was used in the sulphonation reaction.43 The results that were obtained were consistent with the mechanism that is outlined in Scheme 4 i.e.the methyl groups C-8 and C-10 were interchanged while the methyl group C-9 was transformed into the methylenesul- phony1 group. When (+)-3-endo-bromocamphor (2) is used as substrate the operation of the alternative pathways (A) and (B) that are shown in Scheme 4 would involve structurally different intermediates and result in the formation of (+)-3-endo-bromocamphor-9-sulphonic acid (14) (which is the actual product of the reaction) and 6-endo-bromocamphor-9-sul-phonic acid (25) with a configuration that is enantiomeric to that of the original camphor. The absence of the latter compound in the reaction product indicates that only the shorter pathway (A) is operating when 3-endo-bromocamphor is used in the sulphonation reaction.Appropriate modification of the conditions for C(9)-sulphonation has led to pro~edures~~,~~,~~ for the stereospecific bromination of camphor at C-9.$ Thus treatment of (+)-camphor (1) with bromine and chlorosulphonic acid provides a mixture of (+)-9-bromocamphor (19a) and (-)-9-bromocam- phor (19b) while similar treatment of (+)-3-endo-bromocam-phor (2) provides (+)-3-endo,9-dibromocamphor (20) and a small amount of (+)-3-endo,9,9-tribromocamphor(27)47-48 (Scheme 5). Selective removal (by zinc and acetic acid or by zinc and hydrobromic acid) of the bromine substituent at C-3 converts (+)-3-endo,9-dibromocamphor (20) into optically pure (+)-9-bromocamphor (19a).The mechani~m~~,~'.~~ of C(9)-bromination of (+)-camphor (1) and of (+)-3-endo-bromocamphor (2) is similar to that which has been pro- posed' 2,42.43 for the corresponding sulphonation processes (see Scheme 4) with the distinguishing feature being the reaction of the intermediates (16; X = H) and (16; X = Br) with bromine rather than with sulphur trioxide (or its equivalent). Although the formation of (-)-6-endo,9-dibromocamphor(26) from (+)-3-endo-bromocamphor (2) by the operation of path (B) in Scheme 4 is not observed in the bromination process the acid- catalysed (H2S04 or C1SO3H) rearrangement of (+)-3-endo,9-dibromocamphor (20) to ( -)-6-endo,9-dibromocamphor(26) 1Early literature reports'12 describing n-substituted camphor derivatives can give the impression that these compounds have their substituents in the C(8) position.More recent reports36te.43.45b.45c have clearly established that the n-substituted camphor derivatives that were obtained by the well-known sulphonation and bromination processes that are described in this Section have their functional groups (S03Hand Br) at C-9. The structure that was assigned to x-substituted compounds in the early literature'.2 should therefore be regarded with caution. As far as we are aware the only method that is available for the direct functionalization of the methyl group C-8 was developed recently by Money and ~o-workers.~~.~~ (cf. p. 257). NATURAL PRODUCT REPORTS 1985 er Bt R Br Br (2) (10) (27) Reagents i Bt2 CIS0,H; ii Brz HOAc; iii Zn HBr or Zn HOAc Scheme 5 (28a) Ccf.(17) in Scheme k] Br Br ABr (27) (28d) j Scheme 6 has been rep~rted.~~*~~*~~ (cf. p. 275). It has recently been shown 224b that this rearrangement can also be accomplished in -55% yield when 3-endo,9-dibromocamphor is heated in chlorosulphonic acid for 1 hour at 50 "C. As shown in Scheme 4 this transformation presumably involves the reversal of path (A) followed by the sequence of rearrangements that is embodied in path (B) (cf. also p. 275 and Scheme 31 Confirmation for the mechanism of bromination at C-9 that is shown in Scheme 4 has been obtained by using 8-deuteriocamphor (1; A = 2H) (see Scheme 4) and 3-endo- bromo-8-deuteriocamphor (2; A = 2H) in the bromination reaction.49 The former compound provided (+)-9-bromocam-phor (19a) and (-)-9-bromocamphor (19b) in which deuterium atoms were located at C-8 and at C-10 respectively while (2; A = 2H) provided (+)-3-endo,9-dibromocamphor (20) with deuterium located only at C-8.(+)-3-endo,9,9-Tribromocam-phor (27) is probably formed by further bromination of the intermediate (28b) (Scheme 6) followed by reversion to the camphor framework. 9-Bromocamphor (19) and 3-endo,9-dibromocamphor (20) can also be prepared in high yield by thermal decomposition of camphor-9-sulphonyl bromide and 3- endo-bromocamphor-9-sulphonyl bromide [cf. (14)], respec ti vely . 9 6*43 9 9 According to the mechanistic proposals that are shown in Scheme 4 the presence of an endo-bromo-substituent at C-3 in camphor ensures that C(9)-sulp hona tion and C(9)- bromination provides 3,9-disubstituted derivatives with retention of confi- guration.However it seems reasonable to suggest that other endo-substituents at C-3 would produce a similar result [the assumptions being (a) that the reactivity of the camphor derivative is not drastically reduced by the substituent and (b) that the 3-end0 configuration is stable under the reaction conditions for example 3-endo-bromocamphor is much more readily brominated than camphor and is also much more stable than its 3-exo-isomer]; consistent with this proposal is the observation that bromination (by Br2 and C1SO3H for 48 hours) of 3-endo-methylcamphor (33) (Scheme 4) provides (+)-9-bromo-3-endo-methylcamphor(34) in 50% yield.5 3-endo-Methylcamphor (33) is prepared by methylation (by LiNPrj and MeI at 0 "C) of camphor (see p.266 and Scheme 23) followed by equilibration (by NaOMe and MeOH) of the mixture (4 :1) of 3-exo- and 3-endo-methyl isomers [(32) and (33)] that is obtained. The final mixture contains -90% of 3-endo-methylcamphor which is readily isolated by crystallization. A minor isomeric product in the bromination of (33) is (+)-9-bromo-6-endo-meth ylisofenc hone (3 5a),5 and the formation of this compound from 3-endo-methylcamphor (33) or by rearrangement of 9-bromo-3-endo-methylcamphor (34) can be rationalized by the sequence of transformations that is shown in Scheme 7 [cf.path (B) in Scheme 41.Thus intermediate (3Oc) [derived from (33) or from (34)] could undergo 2,bhydride shift and subsequent rearrangement to produce (35a) (Scheme 7). An alternative Wagner-Meerwein rearrangement of intermediate (30c) [cf. (24) Scheme 41 could provide 9-bromo-6-endo- methylcamphor (31) but no evidence was found for the formation of this product. It is interesting to note that 9-bromo- 3-endo-methylcamphor (34) partially rearranges to 9-bromo-6- endo-methylisofenchone (35a) when treated with chloro-sulphonic acid for 8 hours.51 NATURAL PRODUCT REPORTS 1985 -T. MONEY 257 V (341 (35a) R = H (35b) R = Br + [2,3-Me](em) Br Br (294 ( 29 b) (29~1) (30d1 [cf. (17) in Scheme 41 [cf.(iB) in Scheme L] 4*p+@H,&*B& Br Br Br (30d (30b) (30~) (31) [cf.(ZL)in Scheme&] [WM = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl shift; 2,6-H = 2,Ghydride shift] Reagents i LiNPrj THF at 0 "C; ii MeI at 0 "C; iii HCl HOAc heat; iv Br2 CIS03H for 48 hours; v ClS03H for 8 hours Scheme 7 A selection of C(9)-substituted camphor derivatives is listed Table 2 Derivatives of camphor that have been synthesized in Table 2.4 C(8)-Functionalization of Camphor and its and for which the structure is & Derivatives Camphor derivatives in which functional groups are attached to C-846.47.62.64,65 have become much more accessible since stereospecific conversion of 3,3-dibromo- R the rep~rted~~.~~ References camphor (12) into 8-bromocamphor (37)69a that is shown in CHZSO3H 1-4 12 35-40 43 Scheme 8.[However the original authors have been unable to CH2Br 41 44,45 35 36 43 repeat the yield that is quoted in ref. 46 and consistently find CH 2S02Br 21 that 8-bromocamphor (37) can be obtained from 3,3-dibromo- CH 2S02C1 21 camphor (1 2) in -40% overall yield.]$ Previous twelve-step C(CI)=S=o CH~OAC 41a 43 456 53-56 synthetic ro~tes~~,~~ (cf Scheme 9) from camphor to optically CH2OH 1 2 41a 43 45b 53 54 active 8-bromocamphor were based on transformations that C02H (trans-isoketopinic acid) 1 2 21 41a 43 456 53 54 had been reported by various research gro~ps.~~*~~~-~~ 54 55 57 58 Routes CH2I 67 or from CHzCN 45b 55 58 59 to racemic 8-bromocamphor from cy~lopentadiene~~* 8,9,10-trinorcamphoP have also been described (Scheme 10).CHzCOzH 59 An attempted synthesis of 8-bromocamphor by ring-opening of CH2CH2OH 59 has been shown to provide a bicyclo- CH2CH3 3P,8-~yclocamphof'~b 59 [3.3.0]octane derivative.68 CHzOCOPh 60 CH2CH2CH=CMe2 54 It has been s~ggested~~,~~ that the direct C(8)-bromination CH2SH 21 55 process occurs by a mechanism (Scheme 11) which is similar to CH2CH2C02Me 58 that involved in the C(9)-bromination of 3-endo-bromocam- CH2D 19 21 41a 61-63 phor (2) (cf Scheme 4). The crucial difference between the two CHO 1 2 mechanisms is the postulated occurrence of 2,3-endo-methyl CD3 31 41a shifts in the C(8)-bromination reaction and of 2,3-exo-methyl CH2F 55 shifts in the C(9)-bromination reacti~n.~~~~~?~~ CH2N3 Results that are 55 55 consistent with the C(8)-bromination mechanism that is CH2OCOCFj CH20COCMe 55 8 A dibromeketone (62yL6~69band a tetrabromo-ketone (66yL'~~~~ have been CH~SBU' 55 identified as additional products in this reaction; their formation can be CH~SO~BU' 55 explained by the mechanism that is shown in Scheme 12.NATURAL PRODUCT REPORTS 1985 b Br& (19a) X (1) X = H (2) X = Br iv-vii 1;; Br Br I I ... Br (37) (36) liV v vi HO a5 xi;; or xiv (39) . & &-m (43) R = Ts (45) X = Br vii -0 I441 R = COPh (46) X = I 7 Reagents i Br, HOAc; ii Br, CIS0,H; iii Zn HOAc or Zn HBr; iv KOAc HOAc; v KOH EtOH; vi CrO, MnO, H,SO,; vii NaBH,; viii CF,CO,H H2S04; ix LiAlH,; x TsC1 pyridine; xi Reagents i Br,; ii Br, ClS0,H; iii Zn HOAc; iv Mg THF; v PhCOCl pyridine; xii CrO, H2S04 or Cr03 pyridine; xiii PBr, Me3COK Me,COD; vi Me,COK Me,COH; vii Me3COK quinoline PhBr; xiv NaI HMPA or NaI DMSO Me,COH at 250 "C in a sealed tube Scheme 8 Scheme 9 ... 0A:yNi (48) J eOlH (47) (50) (51) CH3 Jvi U (5b) Reagents i Ph,CNa Me]; ii 180 "C; iii KOH EtOH H,O; iv H, Pd/C; v Ph,CNa CO,; vi MeMgBr; vii 85% H2S04; viii LiAlH,; ix CrO, HISO, Me,CO; x PBr, quinoline PhBr; xi TsCl pyridine; xii CrO, pyridine; xiii NaI DMSO Scheme 10 NATURAL PRODUCT REPORTS. 1985 -T. MONEY outlined in Scheme 11 have been obtained by using 3,3- A selection of optically active C(8)-substituted camphor dibromo-8- and -9-deuteriocamphor as substrate^.^^ 8-Bromo-derivatives which have been synthesized from camphor is camphor (37) that was derived from these deuterium-labelled listed in Table 3.precursors had deuterium located at C-8 and C-9 respectively [cf. (60a) and (60b) in Scheme 111. Reductive cyclization of 8-bromocamphor (37) provides 5 C( 10)-Functionalization of C(9)- and C(8)- camphor-y-homoenol (38) (see Scheme 8) in high yield Substituted Camphor Derivatives (-90%).70 This compound can be reconverted into the The reaction of 3-endo,9-dichlorocamphor(67) with fuming camphor system (Scheme 8) and is potentially useful as a sulphuric acid or with bromine in chlorosulphonic acid has precursor of other C(8)-derivatives of camphor. The corre- been reported75 to yield the corresponding 3,9,10-trisubstituted sponding anion (40) has been invoked to explain the exchange camphor derivatives (68) and (69).The synthetic potential of of the protons at C-8 of camphor in strong base.15 8,lO- and 9,lO-disubstituted camphor derivatives in the CWMI C 2,3 -Me 1 Br Br (561 ( 57) (55a) A ='H (55b) A = 'H CWMI L2,3-Mc 3 -Br r Br (59) (58) (60al (60b) [ WM = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl shift] Scheme 11 \Br [2,3-B~] .& [WM] Br + (exo) 4 Br Br Br Br Br (64) (65) (66) [ W M = Wagner-Meerwein rearrangement; 2,3-Br = 2,3-bromine shift] %heme 12 NATURAL PRODUCT REPORTS 1985 Br Br Br I I I Br (70) (71) i ii,iv ( c f. Scheme 8) 8r (72) Br (73) Reagents i Br2; ii Br2 ClS03H for 4 hours; iii Br, CIS03H for 5 days; iv Zn HOAc for 30 minutes at 5 "C; v Br, HOAc Scheme 13 Table 3 Derivatives of camphor that have been synthesized and for which the structure is 23 R References CH2Br 46 54 62 CH2I 54 66 CHZOH CD2OH 1 2 62 71 CHZD CHD2 CD3 31 62 65 CHZOCOPh CD2OCOPh 62 71 CH~OAC 62 71 CHZCN 64,224a CHZCECH 64 CH,C=CCMe,OH 64 CH2COCH=CMe 64 CH2CH2CH=CMe2 (campherenone) 54 224a CH2CH=CHCHMel 64 CH 2C02H 71 CHzCHO 64 C02H (cis-isoketopinic acid) 1 2 43 456 72 CHO 1 2 71 CH(OH)CH2CH=CMe2 71 CH(CN)CH2CH=CMe 73 224a CH (C N )COCH=C Me 73 CH=CH 71 COMe 71 CH 2CH zC02 H 74 CI CI 61 CI (67) (68) X = SO3H (69) X = Br synthesis of terpenoids and steroids has stimulated recent investigation^'^ which have shown that treatment of (+)-3-endo,9-dibromocamphor (20) with bromine in chlorosulphonic acid for 5 days provides (+)-3-endo,9,10-tribromocamphor (70).Selective monodebromination of (70) with zinc and acetic acid produces (+)-9,lO-dibromocamphor (71)51*76 in 50% overall yield (see Scheme 13) although the published76 yield (-60%) for the conversion of 3-endo,9,10-tribromocamphor into 9,lO-dibromocamphor has been increased to 90% by conducting the selective debromination (using Zn HOAc and Et,O) at 0-5°C for 30 minutes. Using identical procedures (+)-3-endo,8-dibromocamphor (72) [derived from (+)-8-bromocamphor (37) by treatment with bromine in acetic acid] can be converted into (+)-8,lO-dibromocamphor (74).52-76 Bromination of (+)-3-endo,9-dibromocamphor(20) and of (+)-3-endo,8-dibromocarnphor(72) at C-10 presumably occurs by a mechanism (Scheme 14) which is similar to that which has been proposed to explain C(10)-sulphonation of camphor (cf.Scheme 1). Thus we can assume that Wagner-Meerwein rearrangement of (20) or (72) provides an intermediate camphene derivative (75a b; X or Y = Br) which can react with bromine and subsequently revert to the camphor framework. It is interesting to note that related investigations have shown that 3-end0 1 0-dibromocamphor and 10-benzoyl- oxy-3-endo-bromocamphor are not readily brominated when treated with bromine in chlorosulphonic acid.77 In these cases the substituent at C-10 may inhibit the formation of carbonium ion intermediates similar to (75a b; X = Y = H)(see Scheme 14) and hence C(9)-bromination does not occur to any significant extent.q Dibromofenchones (76a) and (76b) as shown in Scheme 15 are produced in -10% yield during the C(10)-bromination of 3-endo,9-di bromocamp hor (20) and 3-endo,8-di bromocamphor (72) respectively.It seems reasonable to assume that these fenchone derivatives are produced by a mechanism (double Wagner-Meerwein rearrangement) which is identical to that which has been proposed for the acid-catalysed interconversion of camphor and fenchone (cf. Scheme 35). Recent studies have shown that treatment of 9-bromo-3- endo-methylcamphor (34) with bromine in chlorosulphonic acid does not provide 3-endo-methyl-9 lO-dibromocamph~r.~ Instead acid-catalysed rearrangement as described previously (see p.256 and Scheme 7) provides 9-bromo-6-endo-methyliso-fenchone (35a),52 which undergoes bromination to furnish an additional product syn-7,9dibromo-6-endo-methylisofen-chone (35b) as shown in Scheme 15. The structure of the latter compound although based on excellent n.m.r. evidence has yet to be confirmed by X-ray analysis. Other 8,lO- and 9,lO-disubstituted camphor derivatives (77)-(80) have been synthesized from (71) and (74) as shown in 7 C(10)-Brominationof 8-bromocamphor and of 9-bromocamphor can also be accomplished but these reactions are less efficient and much slower than C(10)- bromination of the corresponding 3-bromoderivatives (20) and (72).'8 NATURAL PRODUCT REPORTS 1985 -T.MONEY 26 1 XY U ti@ Br (2) X tYtH (20) X =H,Y = Br (72) X -Br,Y =H X Y -"Q&Br Br (70) X = H Y = Br (73) X = Br,Y = H Reagents i ClSO,H; ii Br2 Scheme 14 XY X OH Br Br (20) X = H,Y = Br (ma) X = H,Y = Br (72) X = Br,Y= H (76b) X = Br,Y = H Br '& '& (cf. Scheme 7) Br2,CISOjH teBr, + I Br (34) (35a) (35b) Scheme 15 $02Me - 0&Br I-III. ... O&CN ,, o&WMe V vi ,vii 1 Br CN I er Me (79) Reagents:i (CH,OH), H+; ii NaCN DMSO; iii HOAc H20; iv MeOH HCl; v LiNPt2 at 0 "C;vi MeI at 0 "C for 30 minutes; vii HCl HOAc Scbeme 16 Scheme 16 and these compounds are currently being evaluated as intermediates in steroid ~ynthesis.'~ 6 C(5)-Functionalization of Camphor and its Derivatives Direct functionalization of (+)-camphor (l) (-)-bornyl acetate (81) and (+)-isobornyl acetate (82) at C-5 an be accomplished in variable yield by using various chemical or biological techniques.6.1 Chemical Methods Oxidation of (-)-bornyl acetate (81) with CrO and or with CrO, HOAc and Ac2081-86 provides a mixture of 5-oxobornyl acetate (83) [24-40% yield] 6-oxobornyl acetate (84) [5-15% yield] and other minor products86 (Scheme 17). Remote oxidation (i.e. oxidation at a position that is remote from the activating functionality) of (+)-isobornyl acetate (82) with CrO, HOAc and Ac20 provides a mixture of (4 :1) of 5-oxoisobornyl acetate (87) and its 6-0x0-isomer (88) in 55% yield87-90 (Scheme 17).The one-step transformation of (+)-isobornyl acetate (82) into ( -)-5-oxoisobornyl acetate (87) is the most efficient way to prepare this compound and has been NATURAL PRODUCT REPORTS 1985 Remote oxidation of (+)-camphor (1) with CrO and Ac20 provides a low yield (6%) of a mixture containing approximate- ly equal amounts of bornane-2,Sdione (89) and the 2,6-isomer (90)91 (Scheme 17). Although the yield in this oxidation is synthetically useless the process provides authentic samples of bornanediones which assist86 in the identification of the products that are obtained in the remote oxidation of (-)-bornyl acetate (81) and (+)-isobornyl acetate (82).Other indirect routes to C(5)-substituted derivatives of camphor [e.g. (93)-(95)] involve ring-cleavage of 3,5-cyclo- camphanone (91),21*83,92-97 which can readily be prepared from 3-diazocamphor (92) or 3,3-dibromocamphor (12) (cf Scheme 18). 6.2 Biological Methods Administration of (+)-camphor (1) to dogs 98 and to rabbits99 results in the formation of 5-endo-hydroxycamphor (96) and variable amounts of 3-endo-hydroxy- 8-hydroxy- and 9-hydroxy-camphor [(97)-(99); see Scheme 191. Bacterial degra- dation of camphor by strains of Pseudomonasputida100-106 has been shown to involve sequential formation of 5-exo-hydroxy- camphor (100) and the products (89) (96) and (101)-(106) used in various synthetic st~dies~~*~~*~~~~~ (see Table 9).that are formed by enzymic oxidation reduction and 'Baeyer- (83) '&:Ac -t AcO &:Ac &ic+ 1 (84) H (86) + o&:Ac &F0:. (81) (82) (87) (88) (891 " (90) Reagents i CrO, HOAc Ac20; ii CrO, HOAc Scheme 17 (95) (93) (94) Reagents i EtzZn benzene; ii Ag+ THFor Cu; iii HBr; iv AgOAc HOAc; v aluminium amalgam D20 Scheme 18 NATURAL PRODUCT REPORTS 1985 -T. MONEY Villiger’ ring-cleavage of the C( 1)-C(2) and C(4)-C(5) bonds (Scheme 19). Microbiological hydroxylation of (->bornyl acetate (81) by cultures of Helminthosporium satioum (syn. Bipolaris sorokin- iana) provides a mixture of (-)-5-exo-hydroxyborneol (107) (-)-5-endo-hydroxyborneol (1OS) (->6-exo-hydroxyborneol (109) and (-)-3-exo-hydroxyborneol (1 10)lo7 (Scheme 20).The overall yield of diols is -50% and the relative proportion of2,5-,2,6- and 2,3-isomers is 5 :2 :1. When (+>bornyl acetate (1 11) is used as substrate the regiospecificity of hydroxylation increases considerably and the only major products i.e. (+>5-exo-hydroxyborneol (1 12) and its 5-endo-isomer (1 13) are produced in 3545% yield (Scheme 20). Microbiological hydroxylation of (->bornyl acetate (81) by cultures of Fusarium culmorum provides 5-exo-hydroxybornyl acetate (115) as the only major product in 12% yield.lo7 An (96) OH OH (97) + + +o + L& odRl@ R2 R’ H02C C02ti (89) R’ R2=0 (101) R’ = R2= H (1 05) (106) (96) R’ = H R~=OH (102) R’ = OH R2=H (100) R1 = OH R2= H (103) R’= H,R2= OH (104) R’ R2=0 Organism i dog; ii rabbit; iii Pseudomonas putida Scheme 19 OAc OH + Ho&H OH + & (81) R~ (107) R’=OH,R~=H (109) (110) H OH (108) R’= H R2=OH J.‘; H 1115) (113) R’= H R’= OH Organism ; i Helminthosporium sativum ;ii Fusarium culmorum scheme 20 264 almost identical result was obtained when (+)-bornyl acetate (1 11) was used as the substratell (Scheme 20).The ability of cultures of I;.culmorum to hydroxylate bornyl acetate exclusive- ly at C-5 while leaving the acetate group at C-2 intact could be of value in synthetic studies. It has been suggestedlo7 that the remarkable similarity between the regiospecificity of chemical and microbiological functionalization of bornyl acetate and isobornyl acetate is probably due to the greater accessibility of C-5 to interaction with chemical reagents and enzymic systems.7 C(3)-Functionalization of Camphor and its Derivatives Position 3 in camphor (1) displays a degree of reactivity that would normally be expected for active methylene groups and a large number of C(3)-substituted camphor derivatives have been reported1-5 (cf. Tables 4 and 5). However the stereoselec- tivity of many C(3)-monosubstitution reactions has not been clearly established; in the few examples (hydrogen exchange bromination methylation) where this information is available the observed stereoselectivity has not been adequately explained. 7.1 C(3)-Hydrogen Exchange Various investigationslog have established that base-catalysed hydrogen-deuterium exchange in (+)-camphor (1) (see 11 Preliminary studies indicate that I;.culmorum also converts isobornyl acetate into the 5-hydroxy-derivative.108 Table 4 C(3)-Substituted camphor derivatives of structure R& R References D 109 110 NO2 1-3~ NH2 NHR Or NR2 1 3a 144 OH or OAc 1-3~ 98 99 145 146 OSiMe 136 OSiMe2Bu1 126 OOSiMe 136 SO3 H 1 2 SOC,H,Me 145 SiMe 130a c1 1-3~ Br 1-5 41 113-115 I 1-3~ N3 1 CN 1-3~ Me 1 2 117-119 147 Et 1 2 144 R'CH2 R2CH PhCH2 or PhCHR 1 2 COMe or COPh 1 2 COBu' 148 CH2COMe 1 2 CH2CO2R 1 2 C(OH)Me2 131 CH 2N Me2 1 2 135 144 CH2CH2NMe2 144 COR (R = alkyl) 1 CS2H 1 C02Me C02Et C02H 1-3 COCO2Et 1 CH2CH2CMe (exo and endo) 229g COCF3 237 NATURAL PRODUCT REPORTS 1985 Scheme 21) and in other rigid bicyclic ketones (121)-(126) involves exclusive removal of the 3-exo-hydrogen and exo- protonation of the intermediate enolate ion (cf.Scheme 21). In addition debromination of 3-endo-bromocamphor (2) also involves exclusive exo-protonation of the intermediate enolate system' lo (cf. Scheme 21). Although explanations that are based on stericlll and torsional11z effects have been proposed to account for the exo-selectivity of enolization and enolate (enol) protonation of bicyclo[2.2.l]heptan-2-onederivatives a c'onsiderable amount of experimental effort has provided resultslogb-f which are not consistent with these explanations. 7.2 C(3)-Monobromination Treatment of (+)-camphor (1) with bromine in acetic acid,41 ethanol -3 or provides 3-endo-bromocamphor (2) as the major product (-92%) (Scheme 22).This is also the most stable derivative since treatment with a base (NaOMe or KOBu') does not change the relative proportions of C(3)- epimers ([endo]:[exo] = 92 :8).** Bromination of camphor (1) with pyridinium bromide perbromidett or of camphor enol ** This ratio was estimated from values of optical rotation. A value of 55 :45 calculated from n.m.r. data has also been reported." Treatment of 3-edo-bromocamphor with NaOMe in MeOH for 24 hours under reflux has yielded a mixture (92 :8) whose composition was determined from the 400MHz n.m.r. spectrum. tt In contrast kinetic C(3>bromination of 8,9,1@trinorcamphor (1 24) (Scheme 22) with this reagent produces a mixture (95 :5) of 3-exo-bromo-8,9,10-trinorcamphor (1 33) and 3-endo-bromo-8,9,10-trinorcamphor(134) which on treatment with base (KOBu') is converted into an equimolar mixture.116 .Table 5 C(3)-Substituted camphor derivatives of structure R References D&D 45 149 N2 1-3~ 96 150 152 0 1-3 41~ 153 F&F 150 Br & F 1-3 46 47 95 155 NNH2 1 2 NOH 1-3~ 157 CHOH 1-3~ CHOMe 1 61a CHCl 1 CHSH 1 CHR CHPh or CH2 1-3 CHCOMe 1 CHC02Me 1 154 CH[CH2],C02Me(n = 1 or 2) 1 CHCH~BU' 229g C( Ph)C02 H 1 C02Me & CH2C02Me 1 CPh2 151 CH2 154 Me & Me 1 2 147 Me & Br 115 CH & CD 119 Me & OH 1 61 CHO & CHZCH--CHz 154 CHO & CH2CH2CH3 154 alkyl & OH 1 Ph & OH 1 PhCH2 & OH 1 OH & CH2N02 1 -OCH2CH2+ 61 156 OEt & OEt 1 -CH 2CH 2-238 NATURAL PRODUCT REPORTS 1985 -T.MONEY D (118) D (119) Br (120) Reagents i D20 DO-; ii BuLi; iii CD,CO,D; iv EtOD EtO-; v HzO HO-; vi HOAc; vii Zn DOAc; viii Zn HOAc Scheme 21 o& i wiii + ii iv or v T\ Vi Me3si0& -fi + Br & i or iii Me Me C( 32) + (3313 Br (129) Me (130) Me (34) Br (131) Me (132) (124) Reagents:i Br2 HOAc; ii NaOMe MeOH; iii C5H,NHBr3 HOAc; iv KOBu' HOBu'; v HCl HOAc heat; vi Br2 dioxane-pyridine Scheme 22 trimethylsilyl ether (128) with bromine in dioxane-pyridine leads to approximately equal amounts of 3-exo-bromocamphor (1 27) and 3-endo-bromocamphor (2).Subsequent equilibra- tion of this mixture with base (NaOMe in MeOH) provides the thermodynamic mixture ([endo]:[exo] = 92 :8). In contrast bromination of 3-exo-methylcamphor (32) and its epimer (33) with bromine in acetic acid or with pyridinium bromide perbromide in acetic acid occurs with endo stereoselectivity and the product is a mixture (-4:1) of 3-endo-bromo-3-exo-methylcamphor(1 29) and its epimer (1 30). A similar result is obtained when 9-bromo-3-endo-methyl- camphor (34) is brominated with these reagents.l15 7.3 C(3)-Methylation The literature' -3 indicates that C(3)-monomethylation of camphor is readily accomplished but the stereochemistry of the methyl group that is introduced has not been clearly established.1-3 I 7 * Recent investigations however have shown that sequential treatment of (+)-camphor (1) in THF with lithium di-isopropylamide (1 mole equivalent) and with methyl iodide (excess) at 0 "C provides a product (-75% yield) which was shown by n.m.r. (400 MHz) and capillary g.1.c. to be a mixture ( -4 :1) of 3-exo-methylcamphor (32) and 3-endo- vii,vi,ix Br I NATURAL PRODUCT REPORTS 1985 methylcamphor (33)' (Scheme 23). Subsequent treatment of this mixture with NaOMe in MeOH or with HCl and HOAc provides a mixture ( -9 :1) in which the major component is 3- endo-methylcamphor (33). Similarly protonation of 3-methyl- camphor enolate results in the formation of 3-endo-methyl-camphor (33) and a small amount of the 3-exo-methyl epimer (32) ([endo]:[exo] i= 9 :l).51 C(3)-Methylation of (+)-9-bromocamphor (19a) and of (+)-9,lO-dibromocamphor (71) can be accomplished similarly in yields of 80% and SO% respective1y.ll9 In each case n.m.r.(400 MHz) evidence established that the ratio of exo-methyl to endo-methyl epimers was 1.8 :1 (Scheme 23). Subsequent equilibration with acid (HCl and HOAc) provided the corresponding 3-endo-methyl derivatives [(34) and (79)] in -90% yield. In contrast to the results described above C(3)- methylation of the 3-methylcamphors displays endo stereo- selectivity. For example addition of excess CD31 to 3-methylcamphor enolate yields a product whose lH and *H n.m.r. spectra indicate that it is a mixture (3.4 1) of 3-exo-methyl-3-endo-trideuteriomethylcamphor(1 37) and its C(3)- epimer (1 38).Other investigators have reported that 8,9,10-trinorcamphor (124)120 and the 5,6-didehydro-ketones (140a) and (140b)12' undergo kinetic exo-methylation while the related 5,6-didehy- vi ( cf. Scheme 7 1 Br Br I vii-lX 1 0ABr i,;i V+ Me aBr (71) H (136) Me (79) Reagents i LiNPr,' THF-HMPA (20 :1) at 0 "C; ii MeI at 0 "C; iii CD31 at 0 "C; iv NaOMe MeOH heat; v HCI HOAc heat; vi Br, C1SO3H,for 4 hours; vii Br2 HOAc; viii Br2 C1S03H for 6 days; ix Zn HOAc Scheme 23 NATURAL PRODUCT REPORTS 1985 -T. MONEY dro-ketones (142a-e) 121.122 having a syn methyl group at C- 7 undergo exclusive endo-methylation (Scheme 24). In addi- tion it has been reported that 5-oxobornyl methyl ether (143) can be converted exclusively into the corresponding 6-0x0-ally1 derivative.' 23 [Recent investigation^^^^ have shown that kinetic methylation of 5,6-didehydrocamphor also occurs with almost complete endo stereoselectivity.] 7.4 Enol Derivatives of Camphor and their Reactions Consistent with current trends in synthetic methodology camphor has been converted into various enol derivatives (Schemes 25-27).These include the end trimethylsilyl ether (128),l249125 the enol t-butyldimethylsilyl ether (144),l26 the enol triethylsilyl ether (147),' 27 the enol triethylgermyl. ether (148),'*' the enol acetate (146),128 and the enol triflate (145)129 ( t24) (139) H (140a) R = CH3 (14la) H (140b) R = CH2CH20CH2Ph (141 b) (142a) R = CH,OThp (l42b) R CH2CHZCH2OThp (142~)R = CH20CHzPh H&Me0 0 (l42d) R = CHMeOThp Me0 '0 (142e) R =CH3 (143) (Thp = tetrahydropyran -2-yl ) Scheme 24 (145) %"e3si0& (128) +R3si0& Bu'MezSiO (148) Aco& -v;,vii (1461 Reagents i LiNPri DME Tf2NPh (Tf = CF,SO,); ii LiNPri Me,SiCl DME; iii TfOSiMe, benzene; iv MeLi THF Tf2NPh; v LiNPri THF ButMe2SiC1; vi BuLi THF; vii Ac20 at -50°C; viii Br2 HOAc; ix Zn Et20 Me,SiCl; x Hg(SiEt,),; xi Hg(GeEt3)2 Scheme 25 (Scheme 25).In addition the dilithio-dianion (149) and the corresponding disilylated enol ether (150) have been pre- paredI3O from 3-endo-bromocamphor (2) (Scheme 26) and converted respectively into 3-benzylidenecamphor (1 51)130a and a mixture of 3-exo-and 3-endo-trimethylsilylcamphor (152).l 30b The diethylaluminium enolate (1 53)' 31 has recently NATURAL PRODUCT REPORTS 1985 been proposed as an intermediate in the conversion of 3-endo-bromocamphor (2) into the aldol product (1 54) (Scheme 26).A recent reportI3* indicates that the morpholine enamine (156) the pyrrolidine enamine (1 57) and the piperidine enamine (1 58) of camphor can be prepared by treating camphor nitrimine (1 55) with the appropriate cyclic amine (Scheme 27). v;; (153) HO (154) Reagents i LiN(SiMe,),; ii Bu'Li; iii Me,SiCl; iv MeOH; v PhCHO; vi Et,AlCl Zn CuBr THF; vii Me,CO Scheme 26 (155) (157) (158) Reagents i morpholine benzene 5A molecular sieves; ii pyrrolidine benzene 5A molecular sieves; iii piperidine MeCN 5A molecular sieves; iv PhSCH,NMe, HCl EtOH Scheme 27 NATURAL PRODUCT REPORTS 1985 -T.MONEY Ro&-(128) R = SiMe3 ... (144) R = SiMeZBu' fi(Cexol:Cendo3=56:bt) (1611 R =SiMeJBut (162) R = SiMe3 (1141 (1 64) + Reagents i Br2 dioxane pyridine; ii Me,N=CH I- CH2C12;iii .03,CH,CI, MeOH; iv lo2,CCI,; v BH,; vi H,O, HO- Scheme 28 The morpholine enamine (1 56) has also been used to prepare the 3-(phenylthiomethy1)amphor (1 59). 33 Bromination of camphor enol trimethylsilyl ether (128) provides a mixture (1 :1) of 3-endo-bromocamphor (2) and 3- exo-bromocamphor (127) in 90% yield' 34 and similarly alkylation with Eschenmoser's salt yields the Mannich base (160) as a mixture of epimers135 (Scheme 28).Ozonization of the t-butyldimethylsilyl enol ether (144)' 26 or of the enol trimethylsilyl enol ether (128)' 36 does not result in ring- cleavage and the product has been identified as a mixture of 3-exo-and 3-endo-t-butyldimethylsilyloxycamphor(1 61) or the i;; corresponding trimethylsilyloxy-compounds(162) ([endo] :[em] = 56 :a).In contrast the reaction of the enol trimethylsilyl ether (I 28) with singlet oxygen (lo2) provides a mixture (6 :94) of 3-exo- and 3-endo-trimethylsilylperoxycamphor(163)' 36 (Scheme 28). Hydroboration-oxidation of the enol trimethylsilyl ether (128) has been reportedI3' to provide a mixture (-1 :2) of " (167) (166a) R = Me isomerictrans-camphane-2,3-diols(1 14) and (164) (Scheme 28).(166b) R = Et Since it was assumed that hydroboration occurred preferential- Reagents P,S,, diglyme; ii HC(OMe), MeOH HCI H2S; iii, ly on the eQdo face of the enolate system the major product of Me,SO NaH RI (R = Me or Et); iv 03,pyridine-dichloromethane the trans-diol mixture was assigned the 2-exo-3-endo-diol structure (164). However the known stereoselectivity of Scheme 29 reactions involving camphor enolate and camphor enol derivatives coupled with other chemical and n.m.r. evidence has led to the proposal138 that the major product in the above hydroboration-xidation reaction is the known 2-endo-3-exo- diol (1 14) (cf. Scheme 20). Ozonization of the alkenyl sulphides (1 66a) and (1 66b) 39 which were each derived from thiocamphor (165),14* also results in retention of the camphane framework and produces the camphorquinone (1 67) (Scheme 29).Recent reports have described the conversion of camphor hydrazone (1 68) cam-phor tosylhydrazone (1 69) and camphor trisylhydrazone (1 70) into the alkenyl iodide (l7l),l4' the alkenylsilane (172),142 and the alkenyl bromide (1 73),143 respectively (Scheme 30). 8 Ring-cleavage Reactions of Camphor and its Derivatives 8.1 Cleavage of the C(l)-C(2) Bond Cleavage of the C(ltC(2) bond in camphor and in various derivatives has been accomplished by the variety of methods illustrated in Table 6. It is worth noting that Baeyer-Villiger- type cleavage of the C(l)-C(2) bond in camphor also occurs microbiologically (cf. p. 262). NATURAL PRODUCT REPORTS 1985 MeC6H,NHN ..... 11 111 (170) "' (173) Reagents i 12 Bu'N=C(NMe,) or 12 HN=C(NMe2)2; ii BuLi TMEDA; iii Me,SiCl; ivy BusLi THF; v BuI; vi BrCH2CH2Br Scheme 30 Table 6 Cleavage of the C(l)-C(2) bond in camphor and its derivatives Reaction'5MQCO~H,N~OACOf Phs103H References 158 -163 (1) ( 174) (1 75) 164 (1 76) (177) 165 (179a) (179b) McCOCl or TsCI CgHgN or H2SO4 166-170 or hV (1801 Ii CN -,N-OH TsCl C5H5N7 V 58 CN (183) NATURAL PRODUCT REPORTS 1985 -T. MONEY 271 Table 6 Cleavage of the C(l)-C(2) bond in camphor and its derivatives Reaction References 222 (184) 171 -175 CHO (179b) 02N-N zb hJ 171 (186) CN H02C (187a),( 187b) KOH EtOH heat or NaOEt ,EtOH,hcat 178,239 o@Br x ROzC (8) X = H (189a) X = H R = H or Et (188) X = Br (189b) X = Br,R = H or Et NaOMc MeOH 179.232 or KOH,THF H20 ’ y?3 x3 OX f l B rOr KOH DMSO H20 u (701 X = 8r ROzC I (71) X = H (190a) X = Br,R = Me Y = Br (190b) X = H R = Me Y = Br (190~)X = R = H Y I Br (190d) X = R = H Y = OH NATURAL PRODUCT REPORTS 1985 Table 6 Cleavage of the C(l)-C(2) bond in camphor and its derivatives (continued) Reaction References Br 179 R 221 1 I (192a) R = H \CHO (192b) R = CN (193a) R = H (193b) R = CN Table 7 Cleavage of the C(2tC(3) bond in camphor and its derivatives Reaction References HNO3 1 -3~) 1230 180 or HN03,Hg2SO& KOH ButOH 181 CCI 4 CI HC 162 163 182 R HOzC (198) (196) R = CN (1971 R =COz H ~ 1 -3183 ~ NATURAL PRODUCT REPORTS 1985 -T.MONEY Table 7 Cleavage of the C(2)-C(3) bond in camphor and its derivatives Reaction References 0. Ad HO-N w lr2,l8L 185 186 HO-N w (ii) 187 188 189 Br Br 190 8.2 Cleavage of the C(2)-C(3) Bond A summary of the methods that are available for cleavage of the Table 8 Cleavage of the c(1)-c(7) bond in camphor and its C(2)-C(3) bond in camphor and its derivatives is given in Table derivatives 7. Reaction References 8.3 Cleavage of the C(l)-C(7) Bond 191 Cleavage of the C(ltC(7) bond in 9-bromocamphor can be No-K Et2O accomplished in high yield (96%) by using sodium-potassium 61a,191 alloy.lgl Other less efficient processes for cleavage of the C(lt C(7) bond610p192 are also shown in Table 8.(19a) (209) 9 Rearrangement of Camphor and its Deriv-atives wm I Rearrangements*-5*58 93-203 of camphor under acid condi- KOBU~,OMSO ~ "'"m 2 192 tions form the mechanistic basis for those reactions in which camphor is brominated or sulphonated at C-8 C-9 and C-10 (CJ pp. 253-262). In addition (+)-camphor (1) can be racemized in concentrated sulphuric acid ; the mechanism42 (210) that has been proposed (Scheme 31) involving a combination (211) of Wagner-Meerwein rearrangements 2,3-exo-methyl shifts NATURAL PRODUCT REPORTS 1985 &H+- CWMI +C2,3-MeIL CWMI (ex01 ~ Y (212b) Y (213b) (215) X =Y =H (211b) (216) X=Br,Y = H (26) X=Y= Br ( A = 14c or 0 = 2~) [WM = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl shift; 2,6-H = 2,6-hydride shift] Scheme 31 + (refs.198,199) (217a) (21%) oc0ccI3 ( refs.1970,200) (218) Oh-L& ... & (ref. 19%) (219) ' C02Et (ref. 203) C02Et (220) (2 210) Reagents i Tf20 (Tf = CF3S03);ii (Cl3CC0),O; iii PC15 PC13; iv N,CHCO,Et BF3-Et20; v Zn HOAc Scheme 32 NATURAL PRODUCT REPORTS 1985 -T. MONEY and 2,6-hydride shifts is supported by 14C-labelling evi-recently been shown224bthat this rearrangement can be A similar mechanism can be proposed for the accomplished in -55% yield by heating a solution of (+)-3-den~e.~~ conversion of (+)-3-endo,9-dibromocamphor (20) in concen-endo,9-dibromocamphor (20) in chlorosulphonic acid for 1 hour trated sulphuric acid into ( -)-6-endo,9-dibromocamphor at 50"C.An analogous rearrangement (Scheme 31) of (+)-3-(Scheme 31) (cf. p. 256 and Scheme 4). It has endo-bromocamphor (2) to ( -)-6-endo-bromocamphor (216) (26)30~42750 HF SbFg OZb (+I -Camphor (1) v+ "O? I ;i' I (-1 -Camphor ( 215) It O-eL (224) \ (223) Scheme 33 (229) (225) (209) ( cf. Scheme 331 J O&eHO&' Scheme 34 has also been shown to wcur in chlorosulphonic The mechanism (Scheme 3 1) of this transformation is supported by the observation that (+)-3-endo-bromo-lO-deuteriocamphor rearranges in chlorosulphonic acid to (-)-6-endo-bromo-8-deuteriocamphor.During the initial stages of the racemization of camphor (Scheme 3 l) it is assumed that Wagner-Meerwein rearrange- ment produces a protonated 1-hydroxycamphene (21 2a) which undergoes a 2,3-exo-methyl shift to provide a protonated 4- hydroxycamphene intermediate (21 3a). Other investigations have established that camphor can be converted into stable 1- substituted and 4-substituted camphene derivatives197-200~203 (Scheme 32). Camphor also undergoes racemization and rearrangement in the presence of HF-SbFS to provide a mixture of a cyclohexenone derivative (223) and a bicyclo- [2.2.2]octanone derivative (224)lg3 (Scheme 33). Related to this + 1-camphor (1) C 2,6 -hydride shift 3 1 0 Coxidation 1 NATURAL PRODUCT REPORTS 1985 result is the observation that thermolysis of dihydrocarvone (209) produces (+)-camphor (l) toluene and m-xylene2O4 (Scheme 34).It has been suggested that the aromatic products in this reaction are formed from a bi~yclo[2.2.2]octanone intermediate (222) by retro-Diels-Alder reactions. 204 The remarkable oxidative rearrangement of (+)-camphor (1) or (+)-fenchone (23 1) to 3,4-dimethylacetophenone(233) has been studied in detail by the use of 14C-labelled substrates. 94-1 96 Camphor and fenchone are interconverted under these reaction conditions (conc. H2S04) and two complex mechanisms which occur to different extents [Mecha- nism A (90%) is shown in Scheme 35; Mechanism B (10%) is shown in Scheme 361 have been proposed to account for the labelling pattern in 3,4-dimethylacetophenone.195*Ig6 Photolysis of camphor benzenesulphonylhydrazone(234) in methanolic sodium methoxide results in rearrangement to ,& HO I a C76'1.3 / I I T (232) ( 233) (0 ,'kc1 Scheme 35 NATURAL PRODUCT REPORTS 1985 -T. MONEY C2,3-hydride shift 3 1 \ 1 Cox idat ionI (232) 9 (235a) 02 (240) (241) (242) Reagents i hv NaOMe MeOH; ii N,H4,benzene Scheme 37 278 NATURAL PRODUCT REPORTS 1985 (167) 0& (167) 0FF II CO H (249) 0 (248) Reagents i PhMgBr; ii H2S04 Scheme 39 heat SO3H SO3' & -4? I (251a) (251b) [WM = Wagner-Meerwein rearrangement; 2,3-Me = 2,3-methyl shift; 2,6-H = 2,6-hydride shift] Scheme 40 NATURAL PRODUCT REPORTS 1985 -T.MONEY camphene (236),P-pinene (238),and the derivatives (237)and (239)2020*b (cf. Scheme 37). A similar reaction carried out on the cyclic sulphonylhydrazone (241)[which was derived from (+)-camphor-1 0-sulphonyl chloride (240)]-,provides higher yields (-80%) of camphene and P-pinene202' (Scheme 37). Camphorquinone (1 67) undergoes interesting rearrange- ments when treated with strong acid.3a For example in concentrated sulphuric acid the major product is 2,2,3-trimethyl-4-oxocyclohexanecarboxy~c while acid (244)205-209 in fuming sulphuric acid a mixture of this acid (244) and isocamphorquinone(245)is produced205* 209 (Scheme 38). The structure of isocamphorquinone (245)was finally established by careful degradative studies21° and by its synthesis,21 and a which accounts for the formation of these products from a common intermediate (243) is shown in Scheme 38.Related investigations2 have shown that the alcohol (246)(derived from camphorquinone) rearranges to the bicyclic lactone (249)when treated with concentrated sulphuric acid at 0°C (Scheme 39). The unsaturated carboxylic acid (248) which has been proposed212 as an intermediate in this transformation is presumably formed by rearrangement processes (Scheme 39)similar to these described above for the conversion of camphorquinone into the acid (244). Thermal rearrangement of 10-isobornyl sultone (250) which can be derived from (+)-camphor-10-sulphonic acid (S) results in formation of (f)-em-camphene sultone (251 a 251b),2 and the mechanism that has been suggested for this transformation (Scheme 40) is supported indirectly by labelling studies.2 3b Table 9 Natural products and intermediates for natural products that have been synthesized from camphor derivatives From C(10)-derivatives of camphor (4-tizanoic acid 177b (-) -2-epi-Zizanoic acid177u From C(9)-derivatives of camphor HO-(+) -Isoepi~ampherenol~~ (+)-a-Santalene (X = H)2'582'6 (+)-a-Santalo( (x= OH)217-220 (+I -€pi-p-santa~ene~~*~~~ steroid steroid intermediotez2l vitamin 6,+nter med iates Vitamin B12int ermed iate 222 (X = H or CNIz2' From C(9),C( 10)-derivatives of camphor (-1 -Oest rone '79,232 ent-Pseudoguaianolide intermediates 223a [(+I -0estrone from (-)-camphor] steroid intermediate 234 [enantiomers from (-1-camphor I I A California Red Scale pheromone 233 280 NATURAL PRODUCT REPORTS 1985 Table 9 Natural products and intermediates for natural products that have been synthesized from camphor derivatives (continued) From C(8)-derivatives of camphor JzyqcJ OH (-1 -~ampbrenot~~ Y Y (+I-Copacamphor54 Longicamphor intermediates 64g223be224a Vitamin B, intermediate185 From C(5)-derivatives of camphor OH ( +I -Nojigiku alcohol 88 carot en0 id inter med iat e From C(3)-derivatives of camphor or from camphoric acid etc.Vitamin B12intermediates carotenoid intermediatezz5- 227 t erpenoid intermediates 123 f erpenoid intermediates '23 NATURAL PRODUCT REPORTS 1985 -T.MONEY 28 1 10 The Use of Derivatives of Camphor in Natu- products is illustrated by the examples in Table 9. In addition ral Product Synthesis derivatives of (+)-and of (-)-camphor have also been used as chiral auxiliaries in the enantiospecific synthesis of natural The versatility of camphor derivatives in the synthesis of prod~cts.~~*-~~ * Some representative syntheses using a variety natural products and of synthetic intermediates for natural of camphor derivatives are outlined in Schemes 41-51. v,v i I 'Cl (-1 -Khusimone (-1-2-epi-fizanoic acid (R1= H R2= C02H) (+) -2izanoic acid ( R1= C02H,F$= H1 Reagents i KOH heat; ii K2C03 MeI; iii 0,; iv H+ benzene; v H,C==C(OEt), hv;vi H30+; vii butan-2-one ethylene acetal; viii NaOH MeOH; ix NaH; x MeMgBr; xi CH,N,; xii SOCl, pyridine; xiii LiAlH,; xiv POCl, pyridine; xv N,CHCO,Et BF3; xvi NaOH; xvii Me,SOCH,; xviii BF3.Et,0; xix Cr03 Me,CO H+ Scheme 41"' iv 4 (+I -a-Santalem f Reagents i N2H4; ii HgO heat; iii Mg Me2C=CHC02C6H2Me3; iv NaI DMSO; v [Me,C=CHCH,NiBr], DMF Scheme 42 282 NATURAL PRODUCT REPORTS 1985 /vi,vii $ -Yi (+) -a-Santalol Reagents i N,H,; ii HgO heat; iii LiCH2CrCSiMe3; iv AgN03 EtOH; v KCN H,O; vi BuLi; vii CH,O; viii Bu\AlH; ix I,; x MsCl; xi LiBr Et,O; xii NaBH, DMSO; xiii Ni(CO), NaOMe MeOH; xiv LiAlH Scheme 43 H (+I -Epicamphereno ne (+I -lsoepi campherenol (+I-€pi-P-santalene Reagents i NaI HMPA; ii (CH20H), H+; iii [Me,C=CHCH,NiBr], DMF; iv Me,CO HCl; v LiAl(OMe),H THF vi TsCl pyridine Scheme qqS4 CN I CN CN Iviii,ix 5-a x-xii k ~ &A 0 I steroid intermediate Reagents i KI DMF at 110"C; ii NaCH(CO,Me), DMF; iii NH,OH.HCl; iv TsCl pyridine; v CF,C02H CH,Cl,; vi CF3C02H (CF,CO),O; vii KOBu' THF; viii H2C=CHCOMe NEt, MeOH THF; ix Me2C(CH20H), TsOH; x K A1,0,; xi HOAc H,O; xii NaOMe MeOH Scheme 4Sa NATURAL PRODUCT REPORTS 1985 -T.MONEY I i i,v iii,iv I ICNI vi-viii iv -(-) -Campherenone (-1 -eSantalene (+) -Isocampherenol (-1 -Campherenot Reagents i NaI HMPA; ii (CH,OH), H+; iii [Me,C=CHCH,NiBr], DMF; iv Me,CO HCI; v NaCN HMPA; vi LiNPr', THF; vii Me,C=CHCH,Br THF; viii K HMPA Bu'OH; ix LiAIH(OMe), THF; x TsCl pyridine; xi Na propanol Scheme 4654,224a I (-1-Campherenone I (+I-Copacamphor (+I-Ylangocamphor v,v i v,viI I v I (-1 -Copacamphene (-) -Sat ivene Reagents i CIC,H,C03H benzene; ii ButOK Bu'OH; iii SOCI, pyridine; iv H2 Pt; v LiAlH,; vi MeSO,CI pyridine Scheme 4754 284 NATURAL PRODUCT REPORTS 1985 \ii Ace yJ$(4&& OH iv,v oti iii 0 0 1 vi,vii Ho& viii,ix 'OsimzBut I Nojigiku alcohol Reagents i CrO, Ac,O HOAc; ii SeO,; iii Zn HOAc; iv (CH,SH), BF3.Et20; v Raney nickel; vi ButMe2SiC1 imidazole; vii KOH EtOH; viii MsCl pyridine; ix Bu4N+ F-Scheme W8 i-iii (cf.Scheme 13) Br (2) H02C v-vii HO f----o~ viii-xi xii ~ 0 IH H \NMe x iii & xiv 0 ~ __+ H xv,xvi 0 Me0 \ Me0 IH lxvii $.0 00.. xviii,xix (-1 -Oest rone Reagents i Br, C1SO3H for 1 hour; ii Br, C1SO3H for 5 days; iii Zn HOAc Et20 at 0 "C; iv KOH DMSO H20 for 24 hours; v MeLi THF; vi Me3SiC1; vii 1M-HCl; viii pyridinium dichromate CH2C12 at 20 "C for 24 hours; ix 2M-NaOH MeOH at 0 "C for 5 minutes; x MsCl Et,N DMAP; xi DBU; xii (Me2N),CHOBut heat; xiii rn-MeOC,H,CH2MgC1 Et,O; xiv Li NH, Et,O; xv 03,CH2Clz; xvi Me,S; xvii HCl HOAc; xviii H, Pd; xix BBr, CHZCl2 Scheme 49' 79,232 NATURAL PRODUCT REPORTS 1985 -T. MONEY 285 i-iii iv tviii +Me02cw RO v,x,xi RO J (ref.235) (ref. 236) ( R = SiMepBut) J done A California Red Scale Pheromone Reagents i Br, CIS03H for 1 hour; ii Br, ClS03H 5 days; iii Zn HOAc Et,O at 0°C; iv KOH DMSO H20; v LiAlH, THF; vi Bu1Me2SiC1 4dimethylaminopyridine CH2C12 ;vii O, MeOH ;viii Me,S; ix NaOMe MeOH; x pyridinium dichromate CH2C12 ;xi H2C= PPh, THF; xii Bu,N+ F- THF; xiii H,C=C(Me)MgBr THF Scheme i-iii i iv-vi 1 viii,ix 1 (-1 -9-Santalene Reagents i L-Selectride@; ii NaH Bu1CH2Br; iii H30+;iv BrCH2COBr AgCN; v PPh,; vi MeCOCl NEt, CH,Cl,; vii cyclopentadiene TiCl,(OPr), at -20 "C; viii NaBH, Ni(OAc), H,; ix LiNPr, Me2C=CHCH2CH21; x LiAlH,; xi pyridinium chlorochromate CH2C12; xii NtH4 KOH Scheme 51229d 11 References 1 ‘Elsevier’s Encyclopaedia of Organic Chemistry’ Vol.12A ed. E. Josephy and F. Radt Elsevier Amsterdam 1948. 2 J. L. Simonsen and L. N. Owen ‘The Terpenes’ Vol.11 2nd edn.,Cambridge University Press 1949. 3 (a)A. Pelter and S. H. 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