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The Hudrlik–Peterson Reaction of Secondary Cis-TMS-Epoxy Alcohols and Its Application to the Synthesis of the Fatty Acid Intermediates

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The Hudrlik–Peterson Reaction of Secondary Cis-TMS-Epoxy Alcohols and Its Application to the Synthesis of the Fatty Acid Intermediates SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2019, 30, 1085–1089 letter 1085 en Syn lett S. Saito et al. Letter The Hudrlik–Peterson Reaction of Secondary cis-TMS-Epoxy Alcohols and its Application to the Synthesis of the Fatty Acid Intermediates Shun Saito OH OTBS OH OTBS OH OTBS Yutaro Nanba TMS C C Li K2CO3 Masao Morita O MeOH THF, HMPA Yuichi Kobayashi* TMS Hudrlik–Peterson TMS H Department of Bioengineering, Tokyo Institute of Technology, OTBS OTBS Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan via Wittig [email protected] ; H Protectin D1 H Maresin 1 intermediate intermediate Received: 15.02.2019 acetylenes.8,9 Consequently, the different accesses to 4 by Accepted after revision: 04.04.2019 the previous and present methods would complement each Published online: 16.04.2019 DOI: 10.1055/s-0037-1611809; Art ID: st-2019-u0094-l other in organic synthesis. Herein, we report the results of this investigation and its application to the synthesis of the Abstract As an extension of the study on the Hudrlik–Peterson reac- intermediates. tion of trans-TMS-epoxy alcohols with lithium acetylides, four cis-TMS- epoxy alcohols possessing different alkyl substituents were subjected to Previous work the reaction with TMS-acetylide. The reaction completed in 1 h at 0 °C to OH OH afford cis-enynyl alcohols in good yields. The results indicated that cis- R2 CC– Li+ 1 (1) TMS-epoxy alcohols had higher reactivity than the trans-isomers. An- TMS R1 R O ions derived from 1-heptyne and phenylacetylene participated in the R2 reaction as well. The reaction was applied to optically active cis-TMS-ep- 1 2 oxy alcohols, and the resulting enynyl alcohols were transformed to the synthetic intermediates of protectin D1, maresin 1, resolvin E1, and leu- Present work OH kotriene B4. OH 2 – + 1 1 R CC Li R R (2) Key words epoxy alcohol, trimethylsilyl, acetylene, enyne, protectin O D1, maresin 1, resolvin E1 TMS R2 3 4 The epoxide ring opening of a TMS-epoxide followed by Scheme 1 Hudrlik–Peterson reaction of epoxy alcohols the elimination of the TMS-oxy group is a process known as the Hudrlik–Peterson reaction.1,2 Although the reaction with alkynyl anions has been limited to sterically less con- Preparation of cis-epoxy alcohols 3a–d and the TBS gested TMS epoxides,3 we were able to extend the reaction ether of 3a is summarized in Scheme 2. The propargylic al- to secondary trans-TMS-epoxy alcohols 1 in THF/HMPA to cohols 5a–d were synthesized by addition of lithium TMS- afford trans-enynyl alcohols 2 (Scheme 1, eq. 1).4 The reac- acetylides to the corresponding aldehydes and reduced ste- tion was combined with the asymmetric epoxidation/kinet- reoselectively by using P-2 nickel10 as a catalyst under hy- ic resolution of racemic trans-TMS-epoxy alcohol5 to devel- drogen to afford 6a–d with 94–97% stereoselectivity, which op a synthesis of 18R-HEPE. As an extension, we conceived was stereoselectively converted into syn-epoxides 3a–d the Hudrlik–Peterson reaction of cis-TMS-epoxy alcohols 3. with m-CPBA in CH2Cl2 at room temperature (rt) in good The products 4 possessing the TMS group as R2 would be yields. The epoxides were purified by column chromatogra- desilylated to enynyl alcohols without the TMS group, phy on silica gel, and small quantities of the stereoisomers which have been used as synthetic intermediates of metab- were removed. The stereochemistry of the epoxides was as- olites of fatty acids via the Suzuki–Miyaura coupling6 with signed as depicted based on the literature results.11 Alcohol trans-iodo olefins.7 Previously, 4 have been synthesized 3a was converted into TBS-ether 7a, which was a substrate from trans-TMS-allylic alcohols by bromination, desilyla- of the present reaction as well. An attempted Mitsunobu in- tion of the resulting bromine adducts with TBAF, and the version of 3a afforded compounds other than the expected Sonogashira coupling of cis-bromoallylic alcohols with stereoisomer.12 Epoxidation of the TBS ether of 6a gave 7a © Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 1085–1089 1086 Syn lett S. Saito et al. Letter OH Peterson reaction. Production of 4b–d, TMS ethers, and the OH H2, TMS-desilylated enynes was confirmed by TLC, and the P-2 Ni, EDAb R m-CPBA, NaHCO R 3 products were treated with K2CO3 in MeOH to give 10b–d in TMS MeOH, rt TMS CH2Cl2, rt good yields (Scheme 3, eq. 2). The reaction of 3a with lithi- 5a–d 75–87%6a–d 61–84% um acetylides 11 and 12 also afforded 4e and 4f, respective- ly (eq. 3). OH OTBS TBS-ether 7a derived from 3a underwent the Hudrlik– R TBSOTf, 2,6-lutidine R O O Peterson reaction with acetylide 8 in THF/HMPA to afford a TMS CH2Cl2, –50 °C TMS mixture of 13 and 14 in 84:16 ratio, and the subsequent re- 3a–d 87% for 3a 7a action of the mixture with K2CO3 afforded 14 in 67% yield from 7a (Scheme 4, eq. 1). The reaction of 7a with anion 11 Scheme 2 Preparation of racemic substrates 3a–da and 7a. a R: a, proceeded as well, but slowly, and completed in 5 h, giving C H ; b, (CH ) OTBS; c, (CH ) OTBS; d (CH ) OTBS. b Ethylenediamine. 5 11 2 2 2 3 2 4 15 in 59% yield (Scheme 4, eq. 2). The reaction with acetylide 12 was also slow but produced 16 in 83% yield. Unfortunately, a ratio of 16 and the trans-isomer was 88:12 and the stereoisomer in an 81:19 ratio. Consequently, 3a–d by 1H NMR spectroscopy. and 7a were substrates of the present investigation. A plausible transition state (TS) 17 for the reaction of 3a The procedure established for trans-epoxy alcohols4 and 8 is depicted in Scheme 5 (eq. 1), in which the oxygen was applied to 3a with lithium TMS-acetylide 8 (4 equiv) atom in the epoxide group is necessarily coordinated to the with HMPA (8 equiv) in THF at 0 °C (Scheme 3, eq. 1). The lithium cation to assist the Hudrlik reaction. Since the con- reaction completed in 1 h, which was less time than for the formation of 3a is fixed with C5H11 in a distal position from trans-epoxy isomer of 3a, and produced a mixture of 4a, TMS, the conformation is ready to move to the TS with little the TMS-ether of 4a (i.e., 9a) and 10a in an 89:8:3 ratio in conformational change, and hence, the TS energy is lower an 87% combined yield. Then, the mixture was exposed to than that for the trans epoxy alcohols. Similarly, the confor- K2CO3 in MeOH to afford cis-enynyl alcohol 10a in 83% yield mation of TBS ether 7a is fixed for the chelation to the lithi- from 3a. The use of less equivalents of 8 (2 equiv) produced um cation (Scheme 5, eq. 2). In contrast, steric congestion 10a in a 67% yield. The reaction did not proceed without between TMS and C5H11 groups in the diastereomer of 3a HMPA. apparently disfavors TS 19 for the reaction to proceed Epoxy alcohols 3b–d with different methylene lengths (Scheme 5, eq. 3), and thus the TS energy for 19 would be and the TBS-oxy group were subjected to the Hudrlik– high, whereas 20 in the equilibrium was thought to be less OH OTMS OH OH C H C H C H HMPA (2x equiv) 5 11 5 11 5 11 x yield 4a/9a/10a C5H11 (1) O + TMS Li + + TMS 8 (x equiv) THF, 0 °C, 1 h 4 87% 89:8:3 TMS TMS 2 79% 63:27:10 3a 4a 9a 10a K2CO3 (1.5 equiv) 4a + 9a + 10a 10a X = 4, 83% from 3a MeOH, rt, 1 h X = 2, 67% from 3a OH OH OH 8 (4 equiv) (CH ) OTBS K2CO3 (1.5 equiv) (CH ) OTBS (CH2)nOTBS 2 n 2 n (2) O + othersa TMS HMPA (8 equiv) MeOH, rt, 30 min 10b, n = 2, 78% 3b, n = 2 THF, 0 °C, 1 h TMS H 10c, n = 3, 90% 3c, n = 3 4b–d (major products) 10d, n = 4, 85% 3d, n = 4 OH HMPA (8 equiv) C5H11 (3) 3a + R Li THF, 0 °C, 1 h 11, R = C H 5 11 R 12, R = Ph 4e, R = C5H11, 87% (each 4 equiv) 4f, R = Ph, 85% Scheme 3 The Hudrlik–Peterson reaction of cis-epoxy alcohols with lithium acetylides. a TMS ethers of 4b–d and 10b–d. © Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 1085–1089 1087 Syn lett S. Saito et al. Letter OTBS OTBS OTBS 8 (2 equiv) C5H11 C5H11 K CO (1 equiv) C5H11 2 3 (1) O + 14 TMS HMPA (4 equiv) MeOH, rt, 2 h 67% (two steps) THF, 0 °C, 1 h TMS H 7a 13 14 13/14 = 84:16 OTBS HMPA (4 equiv) 11, R = C H C5H11 (2) 7a + 5 11 12, R = Ph THF, 0 °C, 15, R = C5H11, 59% (each 2 equiv) 5 h for 11, 2 h for 12 R 16,a R = Ph, 83% Scheme 4 The Hudrlik–Peterson reaction of the TBS ether with lithium acetylides. a Mixture of 16 and the trans-isomer (ratio 88:12). reactive because of the absence of chelation by Li. With tions with lithium acetylides 11 and 12.
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