Asymmetric Synthesis of (-)-Tetrahydrolipstatin from a β-Hydroxy-δ-oxo Sulfoxide

Abstract

An asymmetric synthesis of (-)-tetrahydrolipstatin is ­described. A palladium-catalyzed regioselective oxidation of an alkene to a ketone, highly diastereoselective reduction of a β-­hydroxy ketone, selective oxidation of a diol, and modular synthesis are the key features of the synthesis.

Key words

asymmetric synthesis - sulfoxide - palladium - tetra­hydrolipstatin - Frater-Seebach alkylation

References and Notes

• 1a Weibel EK. Hadvary P. Hochuli E. Kupfer E. Lengsfeld H. J. Antibiot.  1987,  40:  1081 
• 1b Hochuli E. Kupfer E. Maurer R. Meister W. Mercadal Y. Schmidt K. J. Antibiot.  1987,  40:  1086 
• 2a Hadvary P. Sidler W. Meister W. Vetter W. Wolfer H. J. Biol. Chem.  1991,  266:  2021 
• 2b Hadvary P. Lengsfeld H. Wolfer H. Biochem. J.  1988,  256:  357 
• 2c Borgstrom B. Biochim. Biophys. Acta  1988,  96:  308 
• 3a Barbier P. Schneider F. Widmer U. Helv. Chim. Acta  1987,  70:  1412 
• 3b Barbier P. Schneider F. Widmer U. Helv. Chim. Acta  1987,  70:  196 
• 3c Barbier P. Schneider F. J. Org. Chem.  1988,  53:  1218 
• 3d Hanessian S. Tehim A. Chen P. J. Org. Chem.  1993,  58:  7768 
• 3e Dirat O. Kouklovsky C. Langlois Y. Org. Lett.  1999,  1:  753 
• 3f Ghosh AK. Liu C. Chem. Commun.  1999,  1743 
• 3g Paterson I. Doughty VA. Tetrahedron Lett.  1999,  40:  393 
• 3h Wedler C. Costisella B. Schick H. J. Org. Chem.  1999,  64:  5301 
• 3i Parsons PJ. Cowell JK. Synlett  2000,  107 
• 3j Ghosh AK. Fidanze S. Org. Lett.  2000,  2:  2405 
• 3k Bodkin JA. Humphries EJ. McLeod MD. Aust. J. Chem.  2003,  56:  795 
• 3l Bodkin JA. Humphries EJ. McLeod MD. Tetrahedron Lett.  2003,  44:  2869 
• 3m Thadani AN. Batey RA. Tetrahedron Lett.  2003,  44:  8051 
• 3n Polkowska J. Lukaszewicz E. Kiegiel J. Jurczak J. Tetrahedron Lett.  2004,  45:  3873 
• 3o Yadav JS. Vishweshwar Rao K. Sridhar Reddy M. Prasad AR. Tetrahedron Lett.  2006,  47:  4393 
• 3p Yadav JS. Vishweshwar Rao K. Prasad AR. Synthesis  2006,  3888 
• 3q Yadav JS. Sridhar Reddy M. Prasad AR. Tetrahedron Lett.  2006,  47:  4995 
• 3r Kumaraswamy G. Markondaiah B. Tetrahedron Lett.  2008,  49:  327 
• 4 Raghavan S. Sreekanth T. Tetrahedron Lett.  2008,  49:  1169 
• 5 Drago C. Caggiano L. Jackson RFW. Angew. Chem. Int. Ed.  2005,  44:  7221 
• 7 Solladie G. Frechou C. Hutt J. Demailly G. Bull. Soc. Chim. Fr.  1987,  827 
• 8a Solladie G. Demailly G. Greck C. Tetrahedron Lett.  1985,  26:  435 
• 8b Solladie G. Frechou C. Demailly G. Greck C. J. Org. Chem.  1986,  51:  1912 
• 8c Carreno MC. Garcia Ruano JL. Martin AM. Pedregal C. Rodriguez JH. Rubio A. Sanchez J. Solladie G. J. Org. Chem.  1990,  55:  2120 
• 9 Raghavan S. Krishnaiah V. Rathore K. Tetrahedron Lett.  2008,  49:  4999 
• 11 Chen K. Harttmann G. Prasad K. Repic O. Shapiro HJ. Tetrahedron Lett.  1987,  28:  155 
• 12a Raghavan S. Mustafa S. Tetrahedron  2008,  64:  10055 
• 12b Ishibashi H. Komatsu H. Ikeda M. J. Chem. Res., Synop.  1987,  296 
• 13 Oikawa Y. Yoshioka T. Yonemitsu O. Tetrahedron Lett.  1982,  23:  889 
• 14 Cink RD. Forsyth CJ. J. Org. Chem.  1995,  60:  8122 
• 15 De Mico A. Margarita R. Parlanti L. Vescovi A. Piancatelli G. J. Org. Chem.  1997,  62:  6974 
• 16 Bal BS. Childers WE. Pinnick HW. Tetrahedron  1981,  37:  2091 
• 17a Frater G. Helv. Chim. Acta  1979,  62:  2828 
• 17b Seebach D. Wasmuth D. Helv. Chim. Acta  1980,  63:  197 
• 18a Colucci WJ. Tung RD. Petri JA. Rich DH. J. Org. Chem.  1990,  55:  2895 
• 18b Tung RD. Rich DH. J. Am. Chem. Soc.  1985,  107:  4342 
• 19 Wu Y. Sun Y.-P. J. Org. Chem.  2006,  71:  5748 

6

The unsaturated ester 6 was prepared by a three-step sequence. Selective protection of 1,3-propane diol as its
p-methoxybenzyl ether followed by Swern oxidation and Wittig olefination afforded 6 in 40% overall yield.

10

Synthesis of Compound 8
A suspension of PdCl₂ (352 mg, 1.98 mmol) and CuCl (1.96 g, 19.8 mmol) in a mixture of DMF and H₂O (1:1, 20 mL) was stirred under an O₂ atmosphere for 1 h. A solution of allyl alcohol 4 (7.13 g, 19.8 mmol) in DMF and H₂O (1:1, 10 mL) was added to the above, and the reaction mixture was stirred at 50 ˚C for 4 h. The reaction mixture was extracted with Et₂O (3 × 75 mL), washed successively with H₂O (2 × 20 mL), brine (20 mL), and dried over anhyd Na₂SO₄. Evaporation of the solvent in vacuo afforded the crude product which was purified by column chromatography using 60% EtOAc-hexane as the eluent to furnish β-hydroxy ketone 8 (5.21 g, 13.9 mmol) in 70% yield as a viscous oil. TLC: R _f = 0.15 (70% EtOAc-hexane); [α]_D +84.9 (c 0.35, CHCl₃). IR (neat): 3138, 2925, 2657, 1630, 1384, 1245, 1088, 1029, 754 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.67-7.59 (m, 2 H), 7.56-7.48 (m, 3 H), 7.16 (d, J = 8.8 Hz, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 4.52 (quin, J = 5.9 Hz, 1 H), 4.39 (s, 2 H), 3.78 (s, 3 H), 3.66 (t, J = 5.9 Hz, 2 H), 2.98-2.73 (m, 4 H), 2.66 (t, J = 5.9 Hz, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 208.62, 159.34, 143.63, 131.33, 129.93, 129.43, 129.35, 123.99, 113.87, 72.91, 64.73, 61.99, 55.28, 49.02, 43.67. ESI-MS: 399 [M + Na]⁺. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₀H₂₄O₅NaS: 399.1242; found: 399.1240.
Synthesis of Compound 9
To a solution of β-hydroxy ketone 8 (5.21 g, 13.9 mmol) in THF (110 mL) cooled at -78 ˚C was added diethylmethoxy-borane (1 M in THF, 15.4 mL, 15.4 mmol) followed by MeOH (28 mL), and stirred for 30 min. Then solid NaBH₄ (577 mg, 15.3 mmol) was added in three portions and the mixture stirred for 2 h at the same temperature. The reaction was quenched using a mixture of pH 7 phosphate buffer (20 mL), MeOH (30 mL), and 30% (w/v) H₂O₂ soln (10 mL). This mixture was allowed to warm to r.t. and stirred at r.t. for further 18 h. The organic solvent was evaporated in vacuo, and the aqueous layer was extracted with Et₂O (3 × 75 mL). The combined organic layers were washed with brine (20 mL) and dried over anhyd Na₂SO_4. Evaporation of the solvent in vacuo yielded the crude product, which was purified by column chromatography using 65% EtOAc-hexane as the eluent to afford the syn 1,3-diol 9 (3.82 g, 10.1 mmol) in 73% yield as a viscous oil. TLC: R _f = 0.2 (70% EtOAc-hexane); [α]_D +56 (c 2.25, CHCl₃). IR (neat): 3386, 2923, 2856, 2362, 1611, 1512, 1441, 1303, 1246, 1175, 1088, 1030, 820, 753, 691, 503 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.67-7.62 (m, 2 H), 7.55-7.46 (m, 3 H), 7.18 (d, J = 8.3 Hz, 2 H), 6.82 (d, J = 8.3 Hz, 2 H), 4.41 (s, 2 H), 4.36-4.24 (m, 1 H), 3.78 (s, 3 H), 3.69-3.53 (m, 3 H), 3.03 (dd, J = 7.6, 12.8 Hz, 1 H), 2.80 (dd, J = 4.5, 12.8 Hz, 1 H), 1.86-1.62 (m, 4 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 159.37, 143.86, 131.21, 129.84, 129.36, 124.08, 113.93, 77.01, 73.05, 71.54, 68.43, 63.42, 55.28, 42.71, 29.68. ESI-MS: 401 [M + Na]⁺. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₀H₂₆O₅NaS: 401.1398; found: 401.1405.
Synthesis of Compound 12
To a suspension of NaH (60% in Nujol, 310 mg, 7.7 mmol) in anhyd THF (10 mL), cooled at 0 ˚C, was added a solution of diol 11 (810 mg, 3.1 mmol) in THF (20 mL) dropwise. The mixture was gradually allowed to warm to r.t. and further stirred for 1 h at the same temperature. It was then recooled at 0 ˚C and N-Ts-Imd (686 mg, 3.1 mmol) was added in three equal potions over a period of 20 min. The mixture was warmed to r.t. and stirred for 40 min, then CuCN (55 mg, 0.61 mmol) was added. After stirring for an additional 5 min, the mixture was cooled at -10 ˚C, and a freshly prepared solution of decylmagnesium bromide (0.7 M in Et₂O, 13.3 mL, 9.31 mmol) was added via syringe. The reaction mixture was kept at the same temperature for 2 h and then allowed to warm to 0 ˚C gradually over a period of 1 h. The reaction was quenched by the addition of aq sat. NH₄Cl solution (10 mL) and diluted with Et₂O (65 mL). The separated organic phase was washed with H₂O (2 × 25 mL) and brine (25 mL). The aqueous layers were re-extracted with Et₂O (2 × 25 mL), and the combined organic layers were dried over anhyd Na₂SO₄. Evaporation of the solvent in vacuo furnished the crude residue which was purified by column chromatography using 10% EtOAc-hexane as the eluent to afford triol 12 (846 mg, 2.1 mmol) in 70% yield as a viscous oil. TLC: R _f = 0.5 (20% EtOAc-hexane); [α]_D
-14.9 (c 1.1, CHCl₃). IR (neat): 3447, 2922, 2853, 1634, 1459, 558 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.31 (d, J = 9.1 Hz, 2 H), 6.82 (d, J = 9.1 Hz, 2 H), 5.45 (s, 1 H), 4.22 (dd, J = 4.5, 12.1 Hz, 1 H), 4.13-4.02 (m, 1 H), 3.92 (dt, J = 2.3, 12.1 Hz, 1 H), 3.86-3.80 (m, 1 H), 3.78 (s, 3 H), 1.92-1.23 (m, 24 H), 0.88 (distorted t, J = 6.8 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.83, 130.67, 127.15, 113.57, 101.07, 78.10, 71.36, 66.98, 55.32, 42.77, 37.66, 31.56, 29.72, 29.69, 29.42, 25.51, 22.76, 14.22. ESI-MS: 393 [M + H]⁺. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₄H₄₀O₄Na: 415.2824; found: 415.2804.