O CO2Me CO2Me CO2Me O OH IBD–KOH MeOH H2O PhI O CO2Me R a R = H b R = Me 1 PhI CO2Me O 5 2 3 4 2–4 a R = H; b R = Me HCl (a) (b) O CO2Me O CO2Me O CO2Me IBD–KOH MeOH IBD–KOH MeOH OMe OMe 6 7 8 OH OMe OMe R R R OMe O CO2Me 6 OTs 10 HTIB CH2Cl2 O CO2Me 9 2a HTIB CH2Cl2 (a) (b) OTs CO2Me O– 2a –OMe IBD–KOH MeOH CO2Me O I Ph OMe 11 –OMe O OMe CO2Me 12 –OMe 3a PhI(OMe)2 32 J. CHEM. RESEARCH (S), 1998 J. Chem. Research (S), 1998, 32–33† Functionalization of Fused Cyclopentane Derivatives using Hypervalent Iodine Reagents† Robert M.Moriarty,* Neena Rani, Eric J. May, Liang Guo and Om Prakash*‡ Department of Chemistry, University of Illinois at Chicago, 845 West Taylor St., Chicago, IL 60607, USA Fused cyclopentane derivatives, viz. methyl 2-oxobicyclo[3.1.0]hexane-1-carboxylate (2a), methyl 6-methyl- 2-oxobicyclo[3.1.0]hexane-1-carboxylate (2b) and methyl 3-oxotricyclo[3.3.0.02,8]octane-2-carboxylate (6), have been functionalized by using the hypervalent iodine reagents iodobenzene diacetate (IBD) and [hydroxy(tosyloxy)iodo]benzene (HTIB).Considerable attention has been devoted to the development of methods for the synthesis and functionalization of fused cyclopentane derivatives because of the presence of this ring system in a large number of biologically active natural products.1,2 As part of our programme on the synthetic utility of hypervalent iodine reagents, we have earlier reported a useful approach for intramolecular cyclopropanation.3,4 This methodology, involving copper(I)-catalysed decomposition of iodonium ylides, has led to the synthesis of various bicyclic and tricyclic compounds containing a cyclopentane ring.In this paper we describe the application of hypervalent iodine reagents to the functionalization of fused bi- and tricyclopentane derivatives, viz. methyl 2-oxobicyclo[3.1.0]hexane- 1-carboxylate (2a), methyl 6-methyl-2-oxobicyclo[3.1.0]hexane- 1-carboxylate (2b) and methyl 3-oxotricyclo[3.3.0.02,8]- octane-2-carboxylate (6).The cyclic oxo esters 2a, 2b and 6, synthesized by copper( I)-catalysed intramolecular cyclization of the respective iodonium ylides 1a, 1b and 5,3 were first subjected to oxidation with iodobenzene diacetate (IBD) in methanolic potassium hydroxide. This system (IBD–KOH/MeOH) is employed to introduce a hydroxy group at the a-position of an enolizable ketone via a-hydroxy dimethyl acetal formation. 5 In the present study, oxidation of bicyclic ketones 2a and 2b with IBD (1 mol equivalent) in KOH–MeOH afforded the normal a-hydroxy dimethyl acetals 3a and 3b, but no indication of the formation of such a product was observed in the oxidation of the tricyclic ketone 6 (Scheme 1a).Instead, this reaction led to the formation of the a,a-dimethoxy ketone 8 in about 35% yield (Scheme 1b). The formation of product 8 occurs via the intermediate 7. As expected, treatment of 6 with 2 mol equivalents of IBD gave 8 in optimum yield (77%).Keeping in mind that methyl 3-hydroxy-2-oxobicyclo- [3.1.0]hexane-1-carboxylate (4a) could be used as a ring A synthon in vitamin D synthesis,6 it was considered worthwhile to hydrolyse the acetals 3a and 3b to 4a and 4b respectively. Thus, 3a and 3b were treated with dilute hydrochloric acid to obtain the corresponding a-hydroxyketones (4a and 4b). We then turned our attention to effecting a-tosyloxylation of the ketones 2a and 6 with [hydroxy(tosyloxy)iodo]benzene (HTIB, Koser’s reagent).The method of Koser et al.7,8 successfully transformed these ketones into the corresponding a-tosyloxy ketones 9 and 10 (Scheme 2a and b). The observed difference in the reactivity pattern of the bicyclic and tricyclic ketones towards IBD–KOH/MeOH may be rationalized on the basis of steric factors involved in the mechanistic pathway. The first step in the iodine(III)- mediated a-hydroxy dimethyl acetal formation is the creation of an electrophilic centre a to the carbonyl group by addition of the hypervalent iodine species PhI(OMe)2 [generated from IBD–KOH/MeOH] to give an IIII intermediate (e.g., 11 from 2a).The fate of this intermediate is controlled both by the reaction conditions as well as its chemical structure. In the presence of KOH–MeOH, formation of an a-hydroxy dimethyl acetal occurs by nucleophilic attack of methoxide ion in two steps: initial attack of µOMe at the carbonyl group gives epoxide 12, which subsequently undergoes ring opening by the second attack of µOMe to yield the product (3a starting from 2a; Scheme 3).The tricyclic ketone 6 does not follow the normal pathway, presumably because of the steric hindrance associated with *To receive any correspondence. †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). ‡On leave of absence from Kurukshetra University, India.Scheme 1 Scheme 2 Scheme 3OMe CO2Me 13 O CO2Me 14 OH OMe OMe J. CHEM. RESEARCH (S), 1998 33 the epoxide 13 which is prerequisite for the formation of the desired a-hydroxy dimethyl acetal 14.5 In this case the IIII intermediate (analogous to 11) undergoes nucleophilic substitution by methoxide ion followed by further oxidation of the resultant a-methoxy ketone 7 to yield the a,a-dimethoxy ketone 8. The formation of the a-toxyloxy ketones 9 and 10 occurs according to the general pathway for a-tosyloxylation of ketones.7,8 Finally, noteworthy features of this study are: (i) several new a-functionalized ketones containing bicyclo[3.1.0]hexane and tricyclo[3.3.0.02,8]octane systems are easily accessible; (ii) reaction conditions employed for these a-functionalizations do not affect the cyclopropane system of the ketones 2a, 2b or 6; (iii) it is demonstrated that hypervalent oxidative a-hydroxylation of ketones using IBD–KOH/MeOH is applicable to the [3.1.0]bicyclic ketones 2a and 2b, but that the ketone 6, which contains the tricyclo[3.3.0.02.8]octane system, leads to an a,a-dimethoxylated ketone; and (iv) the HTIB-induced method works successfully to introduce a tosyloxy group at the a-position for both bicyclic and tricyclic ketones.Experimental Mps and bps are uncorrected. Silica gel (230–400 mesh) was used for column chromatography. The cyclic ketones 2a, 2b and 6 were prepared according to our previous method involving copper(I)-catalysed decomposition of the corresponding iodonium ylides 1a, 1b and 5, which in turn were prepared from the reaction of appropriate b-oxo esters with IBD– KOH/MeOH.3 Conversion of Methyl 2-Oxobicyclo[3.1.0]hexane-1-carboxylate (2a) into Methyl 3-Hydroxy-2-oxobicyclo[3.1.0]hexane-1-carboxylate (4a).·Step 1.Methyl 3-hydroxy-2,2-dimethoxybicyclo[3.1.0]hexane- 1-carboxylate (3a). To a stirred solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (40 ml) at 0 °C was added a solution of the ketone 2a (1.54 g, 10 mmol) in methanol (10 ml) over 10 min.The solution was stirred for another 10 min and then iodobenzene diacetate (3.54 g, 11 mmol) was added in three portions over 10 min. The resulting homogenous mixture was stirred for 2 h at 0 °C and then for 2 h at room temperature, concentrated in vacuo, diluted with water (40 ml) and extracted with dichloromethane (3Å50 ml).The combined organic extracts were dried (MgSO4) and concentrated in vacuo to remove solvent and iodobenzene. The crude hydroxy dimethyl acetal 3a (1.60 g), obtained as an oil [vmax/cmµ1 (neat) 3505, 1725; dH (400 MHz, CDCl3) 1.35 (m, 1 H), 1.48 (t, J 5.5 Hz, 1 H), 1.76 (d, J 14 Hz, 1 H), 2.07 (m, 1 H), 2.24 (m, 1 H), 3.29 (s, 3 H), 3.59 (s, 3 H), 3.62 (s, 3 H), 4.01 (d, J 7.0 Hz, 1 H). dC (100 MHz, CDCl3) 16.87, 26.88, 31.84, 34.454, 59.26, 51.39, 53.04, 73.43, 108.21, 171.10; m/z (CI) 217 (M+1, 1.4%), 199 (3), 185 (51), 1543 (100)], was used as such for the next step.Step 2. Methyl 3-hydroxy-2-oxobicyclo[3.1.0]hexane-1-carboxylate (4a). To a solution of the crude dimethyl acetal 3a (1.5 g) in methanol (10 ml) was added 2 M HCl (10 ml) and the homogeneous mixture was allowed to stir at room temperature for 3 h. Methanol was removed in vacuo and the aqueous mixture was extracted with dichloromethane (4Å25 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo and the resulting residual mass was purified by flash column chromatography on silica gel eluting with hexanes–diethyl ether (1:1 v/v) to give 0.5 g (42%) of 4a as an oil, v,max/cmµ1 (neat) 3463, 1757, 1722; dH (300 MHz, CDCl3) 0.84 (d, J 5.5 Hz, 1 H), 1.69–1.74 (m, 1 H), 2.16–2.22 (m, 1 H), 2.40 (d, J 18 Hz, 1 H), 2.78 (d, J 2.7 Hz, 1 H), 2.83–2.91 (m, 1 H), 3.76 (s, 3 H), 5.01 (s, 1 H); dC (75.43 MHz, CDCl3) 17.87, 21.28, 30.90, 38.38, 52.37, 75.02, 172.70, 211.82; m/z (CI) 171 (M+1, 31%), 153 (100), 139 (22) (Found: C, 55.86; H, 5.99.C8H10O4 requires C, 56.47; H, 5.88%). Conversion of 2b into 4b was also effected according to the above method. 3b: oil; yield 51%; vmax/cmµ1 (neat) 3521, 1732; dH (300 MHz, CDCl3) 1.03 (d, J 6.3 Hz, 3 H), 1.33–1.48 (m, 2 H), 1.64 (t, 1 H), 2.32–2.43 (m, 1 H), 2.62 (br d, 1 H), 3.27 (s, 3 H), 3.53 (s, 3 H), 3.67 (s, 3 H), 4.10 (m, 1 H); dC (75.43 MHz, CDCl3) 13.37, 25.35, 28.20, 29.59, 33.69, 42.46, 49.99, 51.57, 51.77, 76.98, 107.60; m/z (CI) 231 (M+1, 11%), 213 (23), 199 (30), 185 (74), 167 (90), 153 (100), 135 (45) (Found: C, 58.13; H, 7.50.C11H18O5 requires C, 57.39; H, 7.83%). 4b: oil; vmax/cmµ1 (neat) 1754, 1723; dH (300 MHz, CDCl3) 1.18–1.23 (m, 1 H), 1.31 (d, J 6.0 Hz, 3 H), 2.05 (t, J 5.4 Hz, 1 H), 2.42 (d, J 18 Hz, 1 H), 2.76–2.88 (m, 2 H), 3.79 (s, 3 H, 4.83 (s, 1 H); dC (75.43 MHz, CDCl3) 11.45, 26.59, 27.14, 35.67, 38.65, 52.16, 75.80, 171.46, 212.16; m/z (CI) (M+1, 54%), 167 (100), 153 (58), 135 (26) (Found: C, 58.48; H, 6.74.C9H12O4 requries C, 58.70; H, 6.52%). Methyl 4,4-Dimethoxy-3-oxotricyclo[3.3.0.02,8]octane-2-carboxylate (8).·A solution of the ketone 6 (1.8 g, 10 mmol) in methanol (5 ml) was treated with KOH (3.36 g, 60 mmol) in methanol (50 ml) followed by IBD (6.44 g, 20 mmol) according to the procedure described for the conversion of 2 into 3. The crude product was purified by flash column chromatography on silica gel, eluting with hexanes–diethyl ether (1:1) to give 1.74 g (77%) of 8 as an oil, vmax/ cmµ1 (neat) 1733, 1717; dH (300 MHz, CDCl3) 1.80–2.04 (m, 3 H), 2.18–2.34 (m, 2 H), 2.74–2.79 (m, 1 H), 2.85–2.92 (m, 1 H), 3.44 (s, 3 H), 3.57 (s, 3 H), 3.68 (s, 3 H); dC 22.93, 31.36, 33.03, 39.93, 40.29, 49.47, 50.40, 51.99, 52.82, 100.39, 169.20, 211.94; m/z (CI) 241 (M+1, 15%), 223 (30), 209 (100) (Found: C, 59.61; H, 6.62; C12H16O5 requires C, 60.00; H, 6.67%).Procedure for the a-Tosyloxylation of 2 and 6.·To a stirred solution of the ketone (10 mmol) in dichloromethane (30 ml) was added [hydroxy(tosyloxy)iodo]benzene (7.84 g, 20 mmol) and the mixture was refluxed overnight.The solvent was removed in vacuo and the residue was chromatographed on silica gel to give the a-tosyloxy ketone as a colourless crystalline solid which was recrystallized from the appropriate solvent. Methyl 2-oxo-3-tosyloxybicyclo[ 3.1.0]hexane-1-carboxylate (9), yield 65%, had mp 118–119 °C; vmax/cmµ1 (KBr) 1765, 1720, 1372, 1177; dH (400 MHz, CDCl3) 1.62 (t, J 5.4 Hz, 1 H), 2.08 (dd, J1 2.6 Hz, J2 15.1 Hz, 1 H), 2.13 (m, 1 H), 2.40 (s, 3 H), 2.50 (m, 1 H), 2.61 (m, 1 H), 3.67 (s, 3 H), 4.65 (dd, J1 2.6 Hz, J2 9.7 Hz, 1 H), 7.33 (d, J 8.1 Hz, 2 H), 7.75 (d, J 8.1 Hz, 2 H); dC (100 MHz, CDCl3) 21.66, 23.67, 29.45, 29.56, 36.79, 52.53, 78.08, 128.08, 129.92, 132.85, 145.33, 167.80, 197.37; m/z (CI) 325 (M+1, 100%), 293 (39), 169 (17), 155 (49), 153 (94) (Found: C, 55.48; H, 4.95; S, 9.87.C15H16O6S requires C, 55.56; H, 4.94; S, 9.88). Methyl 3-oxo-4-tosyloxybicyclo[3.1.0.02,8]octane-2-carboxylate (10), yield 75%, had mp 158–160 °C; vmax/cmµ1 (KBr) 1738, 1711, 1368, 1179; dH (400 MHz, CDCl3) 1.85 (m, 1 H), 2.10–2.20 (m, 3 H), 2.38 (m, 1 H), 2.49 (s, 3 H), 2.68 (d, 1 H), 2.98 (dd, J1 4.3 Hz, J2 7.7 Hz, 1 H), 3.75 (s, 3 H), 5.08 (t, J 5.0 Hz, 1 H), 7.38 (d, J 8.3 Hz, 2 H), 7.80 (d, J 8.3 Hz, 2 H); dC (100 MHz, CDCl3) 15.47, 21.66; 24.04, 37.47, 38.93, 44.26, 45.66, 52.49, 73.91, 127.80, 130.14, 133.33, 145.44, 166.63, 200.53; m/z (CI) 351 (M+1, 79%), 319 (8), 179 (100) (Found: C, 57.89; H, 5.16; S, 8.84.C17H18O6S requires C, 58.29; H, 5.14; S, 9.14). We are thankful to the National Science Foundation for the financial support of this work (Grant No. CHE- 95230157). Received, 28th February 1997; Accepted, 18th September 1997 Paper E/7/01440F References 1 L. A. Paquette, Top. Curr. Chem., 1979. 40, 41. 2 O. Sticher, in New Natural Products and Plant Drugs with Pharmacological, Biological or Therapeutical Activity, ed. H. Wagner and P. Wolff, Springer, Berlin and New York, 1977, p. 137. 3 R. M. Moriarty, O. Prakash, R. K. Vaid and L. Zhao, J. Am. Chem. Soc., 1989, 111, 6443. 4 R. M. Moriarty, J. Kim and L. Guo, Tetrahedron Lett., 1993, 34, 4129. 5 For review articles see: R. M. Moriarty and O. Prakash, Acc. Chem. Res., 1986, 19, 244; O. Prakash, N. Saini, M. P. Tanwar and R. M. Moriarty, Contemp. Org. Synth., 1995, 2, 121. 6 H. Nemoto, X.-M. Wu, H. Kurobe, M. Ihara and K. Fukumoto, Tetrahedron Lett., 1983, 24, 4257; H. Nemoto, X.-M. Wu, H. Kurobe, M. Ihara, K. Fukumoto and T. Kameleni, Tetrahedron Lett., 1984, 25, 3095. 7 G. F. Koser, A. G. Relenyi, A. N. Kalos, L. Rebrovic and R. H. Wettach, J. Org. Chem., 1982, 47., 2487. 8 For a review, see R. Moriarty, R. K. Vaid and G. F. Koser, Synlett, 1990, 365.