Lipase-catalyzed Transesterification of Methyl 2-Substituted 3-Hydroxy-4-pentenoates and its Synthetic Application to the Taxol Side Chain

Abstract

Syn-and anti-methyl 2-substituted 3-hydroxy-4-pentenoates were efficiently resolved in lipase-catalyzed transesterification. This protocol was successfully applied to the synthesis of the taxol side chain.

Key words

syn- and anti-methyl 2-substituted 3-hydroxy-4-pentenoates - lipase-catalyzed kinetic resolution - 1,2-amino alcohols - the taxol side chain

References

• 1 Gargano JM. Lees WJ. Tetrahedron Lett.  2001,  42:  5845 
• 2a Sakaitani M. Ohfune Y. Tetrahedron Lett.  1987,  28:  3987 
• 2b Sakaitani M. Ohfune Y. J. Am. Chem. Soc.  1990,  112:  1150 
• 2c Alemany C. Bach J. Farràs J. Garcia J. Org. Lett.  1999,  1:  1831 ; and references therein
• 3 Jost S. Gimbert Y. Green AE. Fotiadu F. J. Org. Chem.  1997,  62:  6672 ; and references therein
• 4 For a review on 1,2-amino alcohols as chiral auxiliaries in asymmetric synthesis: Ager DJ. Prakash I. Schaad DR. Chem. Rev.  1996,  96:  835 
• 5a Sibi MP. Lu J. Edwards J. J. Org. Chem.  1997,  62:  5864 
• 5b Ghosh AK. Hussain KA. Fidanze S. J. Org. Chem.  1997,  62:  6080 
• 5c Pais GCG. Maier ME. J. Org. Chem.  1999,  64:  4551 
• For syn-aldol reactions:
• 6a Evans DA. Taber TR. Tetrahedron Lett.  1980,  21:  4675 
• 6b Evans DA. Bartroli J. Shih TL. J. Am. Chem. Soc.  1981,  103:  2127 
• 6c For anti-aldol reactions: Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am. Chem. Soc.  2002,  124:  392 
• 6d Also see: Evans DA. Downey CW. Shaw JT. Tedrow JS. Org. Lett.  2002,  4:  1127 
• 7 For a review: Carrea G. Riva S. Angew. Chem. Int. Ed.  2000,  39:  2226 
• 8 Panunzio M. Camerini R. Mazzoni A. Donati D. Marchioro C. Pachera R. Tetrahedron: Asymmetry  1997,  8:  15 
• 9 Vrielynck S. Vandewalle M. Tetrahedron Lett.  1995,  36:  9023 
• 10 Wünsche K. Schwaneberg U. Bornscheuer UT. Meyer HH. Tetrahedron: Asymmetry  1996,  7:  2017 
• 11 Kaga H. Hirosawa K. Takahashi T. Goto K. Chirality  1998,  10:  693 
• Lipase-catalyzed enantioselective hydrolysis of 2-methy-3-acetoxy esters has been reported, see:
• 12a Akita H. Matsuura H. Oishi T. Tetrahedron Lett.  1986,  27:  5241 
• 12b Akita H. Chen CY. Nagumo S. Tetrahedron: Asymmetry  1994,  5:  1207 
• Lipase-catalyzed enantioselective acylation of 1-alkene-3-ols has been well examined, see:
• 14a Ito T. Akasaki E. Kudo K. Shirakami S. Chem. Lett.  2001,  262 
• 14b Ito T. Kudo K. Tanaka N. Sakabe K. Takagi Y. Kihara H. Tetrahedron Lett.  2000,  41:  4591 
• 16

  The enantiomeric purity of alcohols 3 and 6 were determined by Chiralcel OD-H (hexane-2-propanol, 230 nm or 254 nm). Acetates 2 and 5 were also analyzed by Chiralcel OD-H (hexane/2-propanol, 230 nm or 254 nm) after having been converted to the corresponding alcohols via methanolysis (K₂CO₃/MeOH, r.t., 1 h). Some of them were transformed into known 1,2-amino alcohols to confirm their absolute configuration. For instance, acetates 2b (96% ee), 3b (90% ee after resubjection to the lipase-catalyzed transesteri-fication), 5b (>99% ee), and 6b (99% ee) were converted to N-protected amino alcohols in 58%, 67%, 61%, and 56% overall yields, respectively via sequential alkaline hydrol-ysis (2 M NaOH/MeOH, r.t., 2 h), Curtius rearrangement (DPPA/Et₃N/toluene, r.t., 4 h and 80 °C, 1 h), N-protection [(Boc)₂O/Et₃N/cat. DMAP/THF, r.t., 2 h], and ring opening (0.4 equiv. of Cs₂CO₃/MeOH, r.t., 11 h), [25] the results being summarized below (Scheme [5] ). The optical rotation values were compared with those of reported in the literatures. See:

• 16a Leanna MR. DeMattei JA. Li W. Nichols PJ. Rasmussen M. Morton HE. Org. Lett.  2000,  2:  3627 
• 16b DeMattei JA. Leanna MR. Li W. Nichols PJ. Rasmussen MW. Morton HE. J. Org. Chem.  2001,  66:  3330 
• 17a Chen C.-S. Fujimoto Y. Girdaukas G. Sih CJ. J. Am. Chem. Soc.  1982,  104:  7294 
• 17b Chen C.-S. Wu S.-H. Girdaukas G. Sih CJ. J. Am. Chem. Soc.  1987,  109:  2812 
• 18a Pearce GT. Gore WE. Silverstein RM. Peacock JW. Cuthbert RA. Lanier GN. Simeone JB. J. Chem. Ecol.  1975,  1:  115 
• 18b Mori K. In The Total Synthesis of Natural Products   Vol. 9:  ApSimon J. Wiley; New York: 1992.  p.101 
• 19 Groves JT. Ma KW. J. Am. Chem. Soc.  1977,  99:  4076 
• 20 Sayo N. Azuma K. Mikami K. Nakai T. Tetrahedron Lett.  1984,  25:  565 
• 21a The attempted alkaline hydrolysis of the corresponding methyl ester of 10 failed entirely due to the intensive retro-aldol reaction. Thus we adopted the allyl ester 10 cleanly convertible to the free carboxylic acid by the palladium-catalyzed hydrogenolysis under a neutral condition. The compound 10 was prepared according to the Mulzer’s protocol: Mulzer J. Segner J. Brüntrup G. Tetrahedron Lett.  1977,  4651 
• 21b

  A solution of phenylacetic acid (13.6 g, 100 mmol) in THF (40 mL) was added dropwise to a stirred solution of LDA (210 mmol) in THF-hexane (140 mL/135 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 45 min and at r.t. for 2 h. The solvent was removed under reduced pressure and the residual viscous material was dried in vacuo at 70 °C for 2 h to give pale yellow solids. The lithium enolate thus obtained was dispersed in THF (100 mL) and acrolein (8.02 mL, 120 mmol) was added dropwise at 0 °C. After being stirred at r.t. for 48 h, the solvent was evaporated and ice-cold 3 N HCl (120 mL) was added to the residue. Extraction with CHCl₃ gave 2-phenyl-3-hydroxy-4-pentenoic acid (anti/syn = ca. 10:1) as a viscous oil (17.4 g) which without purification was esterified with allyl alcohol (14.9 mL, 220 mmol) in methanol-free CH₂Cl₂ (150 mL) in the presence of concd H₂SO₄ (2 mL) at r.t. for 48 h to give a diastereomeric mixture of allyl esters. The anti-ester 10 was isolated in 60% overall yield (Scheme [6] ) by medium-pressure column chromatography (SiO₂, toluene-EtOAc = 10:1˜5:1).

• 22 For a review: Tsuji J. Mandai T. Synthesis  1996,  1 
• 23 Lee DG. Chen T. In Comprehensive Organic Synthesis   Vol. 7:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  Chap. 3.8. p.541 
• 24 Wang Z.-M. Kolb HC. Sharpless KB. J. Org. Chem.  1994,  59:  5104 
• 25 Ishizuka T. Kunieda T. Tetrahedron Lett.  1987,  28:  4185 

13

For instance, compounds 1b and 4b were prepared as follows. A solution of methyl 4-methylvalerate (7.48 g, 57.5 mmol) in THF (20 mL) was added dropwise to a solution of LDA (60.3 mmol) in hexane (38.7 mL)/THF (50 mL) at
-78 °C and the mixture was stirred for 1 h. Then, acrolein (4.61 mL, 68.9 mmol) was added and the mixture was stirred at -78 °C for 2 min. After usual workup, the oil obtained was purified by medium-pressure column chromatography (Yamazen, Ultra Pack^TM,  50 × 300 mm, hexane/ethyl acetate = 6:1˜4:1 as eluent) to afford the less polar syn-racemate 1b (5.03 g, 27.0 mmol, 47% yield) and the more polar anti-racemate 4b (4.70 g, 25.2 mmol, 44% yield). Each compound can easily be discriminated by the chemical shifts of methine protons at 2- and 3-positions in ¹H NMR spectra (CDCl₃, 500 MHz) : δ 2.62-2.68 (m, 1 H, CHCOO) and 4.28-4.33 (m, 1 H, CHOH) for 1b, and δ 2.58-2.63 (m, 1 H, CHCOO) and 4.14-4.20 (m, 1 H, CHOH) for 4b. The chemical shifts of the methine protons at 2- and 3-positions of 1 are generally observed in the down field compared with those of 4. Additionally, syn-racemates 1 are generally less polar than anti-racemates 4 on TLC analysis (hexane/ethyl acetate = 5:1˜3:1).

15

The quantity of the lipase was not optimized. The lipase collected was washed with ether, dried in air for 5 min and stored below 5 °C. The lipase retains full activity and can be reused at least three times.