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

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

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.

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. In consideration of these speculations in mind, we made no effort to find a all these results, we recommend the use of free alcohols be- method to prepare diastereomer 3a after the failure of the cause of their higher reactivity compared to TBS-ethers. Mitsunobu inversion of 3a under the standard conditions. We envisaged the synthesis of 26, 28, and 32 using the above reaction. These compounds are intermediates for the C H C5H11 7b 7a 7c H 5 11 synthesis of protectin D1, maresin 1, resolvin E1, and – H TMS CC H 7d H leukotriene B . Addition of lithium acetylide 8 to aldehyde SiMe3 (1) 4 8 OH O O 21 followed by oxidation with PCC gave ketone 22 in 80% Li TMS yield (Scheme 6). Subsequently, the asymmetric transfer 4a 13 17 (TS for 3a and 8) hydrogenation produced (S)-5b with 96% ee as deter- mined by chiral HPLC analysis. The four-step conversion de- C5H11 C5H11 veloped for racemic 5b was applied to (S)-5b to afford (S)- 8 H H H 10b in 47% overall yield, which was similar to the yield for H SiMe (2) 3 OTBS 5b (44.1%). Silylation of (S)-10b with TBSCl followed by re- O O TBS Li TMS gioselective desilylation of the resulting bis-TBS ether with 13 PPTS in MeOH and subsequent oxidation of alcohol 23 gave 18 (TS for 7a and 8) aldehyde 24 in a good yield. Finally, aldehyde 24 was subjected to the Wittig reaction with the ylide derived from n- H H H Pr phosphonium salt 25 and NaHMDS (NaN(TMS)2). Since 8 C5H11 C5H11 H the elimination of the TBS-oxy group was expected, HMPA SiMe3 (3) OH 14 O O was added according to the previous results, and the pro- Li TMS tectin D1 intermediate 267b was produced in 94% yield. Sim- ent-4a 19 (TS for diastereomer of 3a) ilarly, the Wittig reaction of 24 with 27/NaHMDS afforded 28, which is the synthetic fragment of maresin 1.7a The syn- 7c 7d thesis of 32, the intermediate of RvE1 and LTB4, com- OLi menced with the addition of acetylide 8 to aldehyde 29, fol- 8 H lowed by oxidation and subsequent asymmetric reduction H C5H11 SiMe3 H to afford alcohol (S)-5d, which was subjected to the key O transfonrmation to afford (S)-10d in 62% yield via (S)-3d. 20 (S)-5d TBS protection/deprotection produced alcohol 30 Scheme 5 Plausible transition states uneventfully. Finally, a two-step oxidation followed by es-

terification of the resulting acid with CH2N2 gave 32 in a In conclusion of the above study, cis-epoxy alcohols 3a– good yield. The 1H NMR and 13C NMR spectra of 26, 28, and d were good substrates for the Hudrlik–Peterson reaction 32 confirmed the high chemical and stereoisomeric purity with TMS-acetylide 8 to produce cis-enynyl alcohols 10a–d and were consistent with the spectra reported previously.7 after the TMS desilylation with K2CO3 in MeOH. The reac- In conclusion, the Hudrlik–Peterson reaction of four cis- tion of 3a with lithium acetylides 11 and 12 afforded 4e and TMS-epoxy alcohols 3a–d possessing different alkyl sub- 4f in good yields. TBS-ether 7a was also a substrate for the stituents with TMS-acetylide 8 and anions 11 and 12 de- reaction, but lower reactivity was observed for the reac- rived from 1-heptyne and phenylacetylene completed in 1 h to afford cis-enynyl alcohols in good yields.15 The TBS

Syn lett S. Saito et al. Letter

Synthesis of 26 b O OTBS OH OTBS 1) H2, P-2 Ni, EDA a OTBS 1) 8 (S,S)-Ru (5 mol%) 2) m-CPBA, NaHCO3 OHC TMS 2) PCC i-PrOH, rt, 3 h TMS 3) 8 (4 equiv), HMPA (8 equiv), THF 21 22 (S)-5b 80% 98% 4) K2CO3, MeOH 96% ee 47%

OH OTBS OTBS OTBS – + OTBS Br Ph3P (25) CHO 1) TBSCl, imid. OH (COCl)2, DMSO NaHMDS

2) PPTS (1 equiv) then Et3N THF/HMPA (10:1) H H H H MeOH, rt, 12 h 88% –78 °C to rt, 1 h (S)-10b 70% 23 24 94% 26

Synthesis of 28 OTBS NaHMDS (1.5 equiv) THF/HMPA (10:1) – + 24 + I Ph3P 27 (2 equiv) –78 °C to rt, 1 h H 94% 28

Synthesis of 32 b OH OTBS 1) 8 OH OTBS 1) H2, P-2 Ni, EDA OTBS 2) PCC 2) m-CPBA, NaHCO3 OHC 3) (S,S)-Rua (5 mol %) TMS 3) 8 (4 equiv), HMPA (8 equiv), THF

29 i-PrOH, rt, 3 h (S)-5d, 95% ee 4) K2CO3, MeOH H 68% 62% (S)-10d

OTBS OH OTBS OTBS 1) NaClO2, 2-methyl-2-butene CHO CO2Me 1) TBSCl, imid. (COCl)2, DMSO t-BuOH/pH 6.8 buffer

2) PPTS (1 equiv) then Et3N 2) CH2N2 MeOH, rt, 12 h H H 85% H 91% 74% 30 31 32 Scheme 6 Synthesis of intermediates 26, 28, and 32. a (S,S)-Ru: Ru[(S,S)-TsDPEN](p-cymene). b Ethylenediamine. ether 7a was a substrate for the reaction with 8, although References and Notes the reactions with anions 11 and 12 required more time (2– 5 h). The reaction was applied to cis-TMS-epoxy alcohols in (1) Hudrlik, P. F.; Peterson, D.; Rona, R. J. J. Org. Chem. 1975, 40, 2263. optically active forms, and the resulting enynyl alcohols (2) (a) Kitano, T.; Matsumoto, T.; Sato, F. J. Chem. Soc., Chem. were transformed to the synthetic intermediates of protec- Commun. 1986, 1323. (b) Alexakis, A.; Jachiet, D. Tetrahedron tin D1, maresin 1, resolvin E1, and leukotriene B4. Further- 1989, 45, 381. (c) Soderquist, J. A.; Santiago, B. Tetrahedron Lett. more, the method would give compounds for the study of 1989, 30, 5693. structure and activity relationship. (3) Zhang, Y.; Miller, J. A.; Negishi, E. J . Org. Chem. 1989, 54, 2043. (4) Nanba, Y.; Morita, M.; Kobayashi, Y. Synlett 2018, 29, 1791. (5) (a) Kitano, Y.; Matsumoto, T.; Sato, F. J. Chem. Soc., Chem. Funding Information Commun. 1986, 1323. (b) Kitano, Y.; Matsumoto, T.; Sato, F. Tet- rahedron 1988, 44, 4073. This work was supported by JSPS KAKENHI (Grant Number (6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. JP15H05904).Japan Society for the Promotion o fScience KAKENHI (JP15H05904) (7) (a) Ogawa, N.; Tojo, T.; Kobayashi, Y. Tetrahedron Lett. 2014, 55, 2738. (b) Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2011, 52, 3001. (c) Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2009, 50, Supporting Information 6079. (d) Kobayashi, Y.; Shimazaki, T.; Taguchi, H.; Sato, F. J. Org. Chem. 1990, 55, 5324. Supporting information for this article is available online at (8) Okamoto, S.; Shimazaki, T.; Kobayashi, Y.; Sate, F. Tetrahedron https://doi.org/10.1055/s-0037-1611809. Supporting InformationSupporting Information Lett. 1987, 28, 2033.

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(9) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46. was stirred at 0 °C for 1 h and diluted with saturated NH4Cl (10) Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem. Commun. 1973, solution to afford a mixture of 4a, 9a, and 10a (total 93 mg). A

553. mixture of the products and K2CO3 (95 mg, 0.687 mmol) in (11) Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron Lett. MeOH (1.6 mL) was stirred at rt for 1 h and diluted with satu-

1979, 4733. rated NH4Cl solution. The mixture was extracted EtOAc three (12) The 1H NMR analysis suggested the trans-olefin formed for- times and purified by chromatography on silica gel (hex-

mally by dehydration of 3a and the cis-olefin derived by the ane/EtOAc, 4:1) to afford 10a (59 mg, 83% from 3a): liquid; Rf = 1 oxy-Hudrlik–Peterson reaction with p-NO2C6H4CO2H. 0.50 (hexane/EtOAc, 4:1). H NMR (400 MHz, CDCl3):  = 0.87 (t, (13) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. J = 7.2 Hz, 3 H), 1.22–1.67 (m, 8 H), 2.21 (br s, 1 H), 3.12 (dd, J = Soc. 1997, 119, 8738. 2.2 Hz, 0.8 Hz, 1 H), 4.61–4.68 (m, 1 H), 5.50 (ddd, J = 11.2 Hz, (14) Suganuma, Y.; Saito, S.; Kobayashi, Y. Synlett 2019, 30, 338. 2.2 Hz, 0.8 Hz, 1 H), 5.96 (ddd, J = 11.2 Hz, 8.4 Hz, 0.8 Hz, 1 H). 13 (15) To an ice-cold solution of trimethylsilylacetylene (0.29 mL, 2.10 C–APT NMR (100 MHz, CDCl3):  = 14.1 (+), 22.6 (–), 24.8 (–), mmol) in THF (0.8 mL) was added n-BuLi (1.57 M in hexane, 31.7 (–), 36.5 (–), 70.0 (+), 79.6 (–), 82.7 (–), 108.8 (+), 147.6 (+). + + 1.20 mL, 1.88 mmol) dropwise. After 30 min of stirring at 0 °C, HRMS (EI ): m/z calcd for C10H16O [M ]: 152.1201; found: HMPA (0.64 mL, 3.68 mmol) and a solution of epoxy alcohol 3a 152.1206. (101 mg, 0.467 mmol) in THF (0.7 mL) were added. The solution