Asymmetric Synthesis of the Polyol Portion of the Polyene Macrolide Antibiotic RK-397

Abstract

A highly convergent and asymmetric synthesis of a fully functionalized polyol portion of the new polyene macrolide antibiotic RK-397 has been achieved taking advantage of a novel polyol synthesis.

RK-397 - polyene macrolide antibiotics - total synthesis - aldol reaction - Cope rearrangement

References

1 Kobinata K. Koshino H. Kudo T. Isono K. Osada H. J. Antibiot.  1993,  46:  1616 

2 Koshino H. Kobinata K. Isono K. Osada H. J. Antibiot.  1993,  46:  1619 

3 Suenaga T. Nakamura H. Koshino H. Kobinata K. Osada H. Nakata T. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu  1997,  39:  607 

4 Omura S. Macrolide Antibiotics: Chemistry, Biology, Practice   Academic Press; New York: 1984. 

Reviews:

5a Oishi T. Nakata T. Synthesis  1990,  635 

5b Rychnovsky SD. Chem. Rev.  1995,  95:  2021 

5c Schneider C. Angew. Chem. Int. Ed.  1998,  37:  1375 ; Angew. Chem. 1998 , 110, 1445

5d For selected examples see: Poss CS. Rychnovsky SD. Schreiber SL. J. Am. Chem. Soc.  1993,  115:  3360 

5e Rychnovsky SD. Hoye RC. J. Am. Chem. Soc.  1994,  116:  1753 

5f Mori Y. Asai M. Okumura A. Furukawa H. Tetrahedron  1995,  51:  5299 

5g Weigand S. Brückner R. Liebigs Ann. Recl.  1997,  1657 

5h Rychnovsky SD. Khire UR. Yang G. J. Am. Chem. Soc.  1997,  119:  2058 

5i Smith AB. Boldi AM. J. Am. Chem. Soc.  1997,  119:  6925 

5j Krüger J. Carreira EM. Tetrahedron Lett.  1998,  39:  7013 

5k Dreher SD. Leighton JL. J. Am. Chem. Soc.  2001,  123:  341 

5l Paterson I. Collet LA. Tetrahedron Lett.  2001,  42:  1187 

6 Review: Schneider C. Synlett  2001,  1079 ; and references cited therein

7a Schneider C. Rehfeuter M. Tetrahedron Lett.  1998,  39:  9 

7b Schneider C. Rehfeuter M. Chem.-Eur. J.  1999,  5:  2850 

8 Paterson I. Gibson KR. Oballa RM. Tetrahedron Lett.  1996,  37:  8585 

9 Evans DA. Coleman PJ. Cote B. J. Org. Chem.  1997,  62:  788 

10

Experimental Procedure: An amount of 149 mg (0.39 mmol) of methyl ketone 7 was dissolved in 4 mL diethyl ether and cooled to -78 °C. For enolization 0.59 mL (0.59 mmol) of a 1 M solution of dibutylboron triflate in dichloromethane were added and subsequently 92 µL (0.66 mmol) triethyl-amine and the resulting solution was stirred for 30 min at -78 °C and for 30 min at 0 °C. Then the solution was cooled to -100 °C and 122 mg (0.27 mmmol) of aldehyde 8, dissolved in 1 mL diethyl ether, were added with a syringe. Stirring was continued for 3 h at -100 °C and 3 h at -78 °C after which the reaction was quenched with pH 7 buffer. After separation of the phases the aq phase was repeatedly extracted with diethyl ether, the combined organic extracts were dried over MgSO₄, filtered and evaporated in vacuo. Purification of the crude mixture through flash chromatography with diethyl ether/pentane (1:2) as eluent yielded 145 mg (65%) of the desired aldol product 9 as a colourless oil (84:16 mixture of stereo-isomers) along with 34 mg (27%) of unreacted aldehyde 8 and 44 mg (30%) of methyl ketone 7 both of which were used again in the aldol reaction. [α]_D ²⁰ +19.7 (c 0.58, CHCl₃); IR(film): ν = 3471 (OH), 2992, 2949, 2857 (CH), 1741 (C=O), 1712 (C=O) cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 0.05 (s, 6 H, SiMe₂), 0.90 (s, 9 H, t-Bu), 1.07-1.33 (m, 2 H), 1.36, 1.40, 1.41 [3 s, 12 H, 2 × C(CH₃)₂], 1.50-1.97 (m, 10 H), 2.37 (dd, J = 15.5, 6.0 Hz, 1 H, 2-H), 2.43-2.65 (m, 4 H) 2.73 (dd, J = 15.5, 7.0 Hz, 1 H, 2-H), 3.68 (s, 3 H, OMe), 3.65-4.29 (m, 9 H), 4.45, 4.48, 4.55, 4.56 (4 × d, J = 11.5 Hz, 4 H, 2 × OBn), 7.25-7.36 (m, 10 H, 2 × Ph); ¹³C NMR (75 MHz, CDCl₃): δ = -5.35, 18.30, 19.81, 19.84, 25.94, 30.11, 30.26, 36.86, 37.41, 39.45, 40.20, 40.47, 41.18, 42.39, 49.29, 50.81, 51.60, 58.77, 65.28, 65.48, 65.76, 65.87, 66.49, 70.36, 72.44, 71.93, 74.63, 98.36, 98.81, 127.70, 127.80, 128.00, 128.10, 128.40, 138.10, 138.30, 171.30, 209.40; MS (200 eV, DCI/NH₃):
m/z (%) = 847(100) [M + NH₄ ⁺]; calcd for C₄₆H₇₂O₁₁Si (829.15): C, 66.63; H, 8.75. Found: C, 66.82; H, 8.50.

11 Evans DA. Duffy JL. Dart MJ. Tetrahedron Lett.  1994,  35:  8537 

12 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 

13 For an account on the stereochemical analysis of 1,3-diol acetonides by ¹³C NMR see: Rychnovsky SD. Rogers BN. Richardson TI. Acc. Chem. Res.  1998,  31:  9 

14a

Direct acetonide formation on diol 10 furnished a triacetonide with two syn- and one anti-stereochemical relationships. When the reduction of aldol product 9 was performed in a syn-selective manner with NaBH₄ and Et₂BOMe according to Narasaka [14b] with subsequent debenzylation and tetraacetonide formation the major stereoisomer contained two syn- and two anti-stereo-chemical relationships in agreement with the assigned configurations.

14b Narasaka K. Pai F.-C. Tetrahedron  1984,  40:  2233 

15a Wieland H. Chem. Ber.  1912,  45:  484 

15b Barbier P. Locquin R. C. R. Chim.  1913,  156:  1443 

16 Burgess EM. Penton HR. Taylor EA. J. Org. Chem.   1973.  38:  p.26 

17

Spectroscopic Data of 2: [α]_D ²⁰ 0 (c 0.2, CHCl₃); IR(film): ν = 2990, 2938, 2857 (CH), 1745 (C=O) cm^-1; ¹H NMR (500 MHz, C₆D₆): δ = 0.06, 0.08 (2 × s, 6 H, SiMe₂), 0.98 (s, 9 H, t-Bu), 1.10-1.60 (m, 14 H), 1.32, 1.37, 1.47, 1.49, 1.50, 1.54, 1.55 [7 s, 24 H, 8 × C(CH₃)₂], 1.67 (s, 3 H, OAc), 1.73-1.82 (m, 1 H), 2.06 (quint, J = 7.0 Hz, 1 H), 3.68 (dt, J = 10.0, 5.0 Hz, 1 H, CH₂OTBS), 3.82 (ddd, J = 10.0, 8.5, 5.0 Hz, 1 H, CH₂OTBS), 3.83-3.89 (m, 1 H), 3.96-4.34 (m, 9 H); ¹³C NMR (150 MHz, C₆D₆): δ = -5.38, 18.49, 19.82, 19.92, 19.97, 20.42, 24.86, 26.13, 30.39, 30.63, 30.67, 37.60, 37.80, 39.46, 40.16, 42.80, 43.08, 43.59, 59.20, 62.55, 62.69, 64.86, 65.34, 65.60, 65.71, 65.76, 67.38, 67.70, 98.54, 98.59, 98.80, 100.50, 170.10; MS (200 eV, EI): m/z (%) = 715(34) [M⁺ - CH₃], 414(4), 380(5), 337(10), 256(18), 149(21), 57(100) [C₄H₉]; HRMS calcd for C₃₈H₇₀O₁₁Si: for [M⁺ - CH₃] 715.4453. Found: 715.4531.