Chiral Dihydroxyacetone Equivalents in Synthesis: Rapid Assembly of Styryl 1,2-Polyols as an Entry to the Styryllactone Family of Natural Products

 

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Abstract

A rapid entry to the polyol framework of the styryllactone family of natural products is reported. The key steps are two highly diastereoselective boron-mediated aldol reactions of a chiral dihydroxyacetone equivalent followed by a 1,3-anti or 1,3-syn-selective reduction. In addition, Evans-Tishchenko reduction of the cyclic aldol products effected an equilibration to the 1,2-syn aldol product before 1,3-anti selective reduction.

References

• 1a Ulven T. Carlsen PHJ. Eur. J. Org. Chem.  2001,  3367 
  Google Scholar
• 1b Majewski M. Nowak P. J. Org. Chem.  2000,  65:  5152 
  Google Scholar
• 1c Doyle MP. Tedrow JS. Dyatkin AB. Spaans CJ. Ene DG. J. Org. Chem.  1999,  64:  8907 
  Google Scholar
• 1d Enders D. Hundertmark T. Eur. J. Org. Chem.  1999,  751 
  Google Scholar
• 1e Enders D. Prokopenko OF. Liebigs. Ann.Chem.  1995,  1185 
  Google Scholar
• 1f Enders D. Whitehouse DL. Runsink J. Chem.-Eur. J.  1995,  1:  382 
  Google Scholar
• 1g Enders D. Jegelka U. Tetrahedron Lett.  1993,  34:  2453 
  Google Scholar
• 1h Enders D. Jegelka U. Dücker B. Angew. Chem., Int. Ed. Engl.  1993,  32:  423 
  Google Scholar
• 1i Enders D. Jegelka U. Synlett  1992,  999 
  Google Scholar
• 1j Hirama M. Noda T. Itô S. J. Org. Chem.  1988,  53:  708 
  Google Scholar
• 2 Enders D. Ince SJ. Synthesis  2002,  619 
  Article in Thieme ConnectGoogle Scholar
• 3 For a review of structure and activity see: Blázquez MA. Bermejo A. Zafra-Polo MC. Cortes D. Phytochem. Anal.  1999,  10:  161 
  CrossrefGoogle Scholar
• For selected total syntheses see:
• 4a Bermejo A. Tormo JR. Cabedo N. Estornell E. Figadère B. Cortes D. J. Med. Chem.  1998,  41:  5158 
  CrossrefGoogle Scholar
• 4b Bermejo A. Blázquez MA. Serrano A. Zafra-Polo MC. Cortes D. J. Nat. Prod.  1997,  60:  1338 
  CrossrefGoogle Scholar
• 4c Bruns R. Wernicke A. Koll P. Tetrahedron  1999,  55:  9793 
  CrossrefGoogle Scholar
• 4d Chen W.-P. Roberts SM. J. Chem. Soc., Perkin Trans. 1  1999,  103 
  CrossrefGoogle Scholar
• 4e Dixon DJ. Ley SV. Tate EW. J. Chem. Soc., Perkin Trans. 1  1998,  3125 
  CrossrefGoogle Scholar
• 4f Friesen RW. Bissada S. Can. J. Chem.  1998,  76:  94 
  CrossrefGoogle Scholar
• 4g Gracza T. Szolcsanyi P. Molecules  2000,  5:  1386 
  CrossrefGoogle Scholar
• 4h Harris JM. O’Doherty GA. Tetrahedron  2001,  57:  5161 
  CrossrefGoogle Scholar
• 4i Mereyala HB. Gadikota RR. Indian J. Chem., Sect. B.  2000,  39:  166 
  CrossrefGoogle Scholar
• 4j Mukai C. Hirai S. Hanaoka M. J. Org. Chem.  1997,  62:  6619 
  CrossrefGoogle Scholar
• 4k Paddon-Jones GC. Hungerford NL. Hayes P. Kitching W. Org. Lett.  1999,  1:  1905 
  CrossrefGoogle Scholar
• 4l Shing TKM. Tsui H.-C. Zhou Z.-H. J. Org. Chem.  1995,  60:  3121 
  CrossrefGoogle Scholar
• 4m Su YL. Yang CS. Teng SJ. Zhao G. Ding Y. Tetrahedron  2001,  57:  2147 
  CrossrefGoogle Scholar
• 4n Surivet J.-P. Vatèle J.-M. Tetrahedron  1999,  55:  13011 
  CrossrefGoogle Scholar
• 4o Tsubuki M. Kanai K. Nagase H. Honda T. Tetrahedron  1999,  55:  2493 
  CrossrefGoogle Scholar
• 4p Yang M. Li HM. Zhao G. Yu QS. Ding Y. Chin. J. Chem.  2000,  18:  225 
  CrossrefGoogle Scholar
• 4q Yang ZC. Zhou WS. Heterocycles  1997,  45:  367 
  CrossrefGoogle Scholar
• 4r Ye JH. Bhatt RK. Falck JR. Tetrahedron Lett.  1993,  34:  8007 
  CrossrefGoogle Scholar
• 4s Yi XH. Meng Y. Hua XG. Li CJ. J. Org. Chem.  1998,  63:  7472 
  CrossrefGoogle Scholar
• For analogue synthesis see:
• 5a Bermejo A. Léonce S. Cabedo N. Andreu I. Caignard DH. Atassi G. Cortes D. J. Nat. Prod.  1999,  62:  1106 
  CrossrefGoogle Scholar
• 5b Li HM. Yang M. Zhou G. Yu QS. Ding Y. Chin. J. Chem.  2000,  18:  388 
  CrossrefGoogle Scholar
• 5c Mereyala HB. Gadikota RR. Joe M. Arora SK. Dastidar SG. Agarwal S. Biorg. Med. Chem. Lett.  1999,  7:  2095 
  CrossrefGoogle Scholar
• 5d Peris E. Estornell E. Cabedo N. Cortes D. Bermejo A. Phytochemistry  2000,  54:  311 
  CrossrefGoogle Scholar
• 5e Shing TKM. Tai VWF. J. Org. Chem.  1999,  64:  2140 
  CrossrefGoogle Scholar
• 6a For isolation see: Fang X.-P. Anderson JE. Qiu X.-X. Kozlowski JF. Chang C.-J. McLaughlin JL. Tetrahedron  1993,  49:  1563 
  CrossrefGoogle Scholar
• 6b For semisynthesis and structure revision see: Mukai C. Yamashita H. Hirai S. Hanaoka M. McLaughlin JL. Chem. Pharm. Bull.  1999,  47:  131 
  CrossrefGoogle Scholar
• 7 Evans DA. Hoveyda AH. J. Am. Chem. Soc.  1990,  112:  6447 
  CrossrefGoogle Scholar
• 9 Enders D. Prokopenko OF. Raabe G. Runsink J. Synthesis  1996,  1095 
  Article in Thieme ConnectGoogle Scholar
• 11 Lu L. Chang H.-Y. Fang J.-M. J. Org. Chem.  1999,  64:  843 
  CrossrefPubMedGoogle Scholar
• 16 Paterson I. Perkins MV. Tetrahedron  1996,  52:  1811 
  CrossrefGoogle Scholar
• 19 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 
  CrossrefGoogle Scholar
• 20 Hundertmark T. Dissertation   RWTH; Aachen: 2000. 
  Google Scholar
• 21 Vicario JL. Badía D. Domínguez E. Rodríguez M. Carrillo L. J. Org. Chem.  2000,  65:  3734 
  Google Scholar
• 22 For a review of use in directed reductions see: Oishi T. Nakata T. Acc. Chem. Res.  1984,  17:  338 
  CrossrefGoogle Scholar
• 23 Evans D. Hoveyda AH. J. Org. Chem.  1990,  55:  5190 
  CrossrefGoogle Scholar
• For several theoretical models of substituted 1,3-dioxan-5-ones see:
• 24a Artau A. Ho Y. Kenttämaa H. Squires RR. J. Am. Chem. Soc.  1999,  121:  7130 
  Google Scholar
• 24b Wu Y. Houk KN. J. Am. Chem. Soc.  1993,  115:  10993 
  Google Scholar
• 25 For a related examination of substituted 1,3-dioxanes see: Cieplak P. Howard AE. Powers JP. Rychnovsky SD. Kollman PA. J. Org. Chem.  1996,  61:  3662 
  Google Scholar
• 26 For reductions of 4-mono- and 4,6-bis-alkylated 1,3-dioxan-5-ones see: Enders D. Kownatka D. Hundertmark T. Prokopenko OF. Runsink J. Synthesis  1997,  649 ; and references 1a-e and 1g
  Article in Thieme ConnectGoogle Scholar
• 29 Prepared from the hydroboration of freshly distilled cyclohexene with monochloroborane dimethyl sulfide complex (Aldrich). For a procedure see: Cowden CJ. Paterson I. In Organic Reactions   Vol. 51:  Paquette LA. Wiley; New York: 1997.  p.1 
  Google Scholar

All new compounds gave consistent analytical data including correct elemental analysis and/or HRMS.

CCDC 179448 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

In contrast, the reaction of α-silyl ketone 1 with SmI₂ and PhCHO, according to the conditions described for cyclohexanone in ref. [11] , was very sluggish and poorly diastereoselective.

NMR analysis of ketone 4 confirms it to be in a twist-boat conformation. In this respect a discussion of the reduction selectivity is complicated, as true axial or equatorial attack is no longer applicable in a twist-boat system. Pseudoaxial attack seems possible for both the syn- and anti-aldol products, the latter case may be disfavoured due to the proximity of the electron rich aryl ring and the coordinating Sm species.

A range of protic and Lewis acidic hydrolyses, transketalisations and thioketalisation were unsuccessful giving starting material or inseparable mixtures of TBS/acetal deprotection. It is possible that the C-5 alcohol is acting as a general acid.

(S,S)-10: See ref. [9]

Prepared in two steps from propane-1,3-diol (silylation, Dess-Martin oxidation). Purified by chromatography on silica gel before use.

Analytical HPLC (chiral stationary phase) showed that the ee of 1 was carried through to the reduction products with no depreciation. 1 was prepared in up to 96% ee as judged by GC (chiral stationary phase).

In this case the much smaller ligands on boron may make chelate formation much easier. The observed colour change of the reaction, from red to yellow, is consistent with H₂ transfer to the Rh(I) catalyst. On closer examination of a model there would appear to be more steric crowding on the lower face of the chelated complex, consistent with the observed outcome.

Preparation of 1,3-syn diol 14 (over 2 steps from ketone 11):
To a stirred solution of Cy₂BCl [29] (2.0 mL, 9.0 mmol, 1.5 equiv) in anhyd Et₂O (50 mL) at -78 ºC, under an Ar atmosphere, was sequentially added freshly distilled Et₃N (1.42 mL, 10.2 mmol, 1.7 equiv) and a solution of ketone 11 (2.35 g, 6.0 mmol, 1.0 equiv, de = 73%) in anhyd Et₂O (20 mL) dropwise via syringe. Stirring was continued at -78 ºC for a further 20 min before warming to 0 ºC for 1 h. The resulting bright yellow suspension was recooled to -78 ºC and a solution of freshly prepared 3-(tert-butyl-diphenyl-silanyloxy)-propionaldehyde (3.45 g, 11.0 mmol, 1.8 equiv) in anhyd Et₂O (10 mL) was added dropwise via syringe. Stirring was continued at -78 ºC for a further 90 min before the flask was sealed and allowed to stand in a freezer (-24 ºC) for 10 h. The reaction was quenched with phosphate buffer (pH 7, 120 mL) and extracted. The aq layer was extracted with Et₂O and the combined organic portions were concentrated in vacuo. The oily residue was resuspended in phosphate buffer (pH 7, 36 mL) and MeOH (36 mL) and cooled to 0 ºC. Aq H₂O₂ solution (30%, 18 mL) was added dropwise and the mixture stirred vigorously for a further 1 h. The mixture was poured into phosphate buffer (pH 7, 120 mL) and extracted with CH₂Cl₂ (4 × 100 mL). The combined organic portions were washed with H₂O (50 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to give a colourless oil. Purification by chromatography on silica gel (gradient elution: 19:1 → 8:1 pentane:Et₂O) gave the title compound 13 (4.94 g, de = 74%) heavily contaminated with aldehyde. An analytical sample (de = 74%) was afforded by further chromatography; [α]²⁵ _D +58.9 (c 1.0 in CHCl₃); IR (thin film): 3543, 3071, 3050, 3032, 2942, 2891, 2866, 1739, 1472, 1464, 1428, 1383, 1219, 1169, 1112, 1068, 1030 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 0.96-1.08 (m, 30 H, CH TIPS, CH₃ TIPS and TBDPS), 1.33 (s, 3 H, CH₃ acetal), 1.41 (s, 3 H, CH₃ acetal), 1.66-1.74 (m, 1 H, CH _aH_b), 1.75-1.82 (m, 1 H, CH_a H _b), 3.15 (d, 1 H, J = 3.3 Hz, (CHOH), 3.72 (dd, 1 H, J = 5.9, 1.0 Hz, H-4), 3.74-3.88 (m, 1 H, CH₂OTBDPS), 4.06-4.12 (m, 1 H, CHOH), 4.46 (dd, J = 2.8, 1.0 Hz, 1 H, H-6), 5.28 (d, J = 2.8 Hz, 1 H, (CH(OTIPS)), 7.20-7.67 (m, 15 H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ = 12.5 (SiCH(CH₃)₂), 18.1, 18.2 (SiCH(CH₃)₂), 19.4 (SiC(CH₃)₃), 24.0, 24.3 (CH₃ acetal), 27.1 (SiC(CH₃)₃), 34.6 (CH₂), 61.6 (CH₂OTBDPS), 68.6 (CHOH), 74.4 (CH(OTIPS)), 76.1 (C-4); 80.0 (C-6), 101.5 (acetal C), 127.7, 127.8, 127.9, 128.0, 129.9, 130.0, (Ar-C), 133.7, 133.8 (Ar-C, ipso), 135.8 (Ar-C), 140.2 (Ar-C, ipso), 209.5 (C=O); MS (CI): m/z (%)= 350(4), 349(16), 313(56), 263(100), 235(62), 175(13); HRMS (EI): m/z calcd for C₁₉H₂₉O₄Si [M⁺ - C₂₂H₃₁O₂Si]: 349.1835. Found: 349.1835. Anal. Calcd for C₄₀H₆₀O₆Si (705.08): C, 69.84; H, 8.85. Found: C, 69.29; H, 8.60.
To a stirred suspension of NaBH₄ (2.70 g, 70 mmol, 2.0 equiv) in anhyd Et₂O (210 mL) under an Ar atmosphere, at r.t., was added a solution of ZnCl₂ in Et₂O (Aldrich, 1.0 M, 35 mL, 35 mmol, 1.0 equiv) via syringe. The resulting white suspension was stirred for a further 2 d before allowing the precipitate to settle. The resulting clear supernatant solution of Zn(BH₄)₂ in Et₂O (ca. 0.14 M) was cooled to -78 ºC.
To a stirred solution of the crude ketone 13 (4.21 g, ca 5.97 mmol, 1.0 equiv) at -78 ºC, under an Ar atmosphere, was added the chilled supernatant solution of Zn(BH₄)₂ in Et₂O (ca 240 mL, ca 34 mmol, 5.6 equiv), via double-ended needle over 45 min. The reaction mixture was warmed very slowly to r.t. The reaction mixture was quenched after 24 h with H₂O until effervescence ceased (ca 5 mL) and stirred vigorously for 1 h. The resulting white suspension was filtered through Celite^® and the filter-cake washed thoroughly with Et₂O (400 mL). The combined filtrates were washed with sat. aq NaHCO₃ solution and the aq portion back-extracted with Et₂O (200 mL). The combined organic portions were dried (Na₂SO₄), filtered and concentrated in vacuo to give a cloudy colourless oil. Purification by chromatography on silica gel (gradient elution: 6:1 → 1:1 pentane:Et₂O gave the title compound 14 (3.67 g, 87%, 52% ds, 74% de for reduction). On smaller scales a reduction de of 85% could be achieved; IR (thin film): 3472, 3071, 3050, 3031, 2943, 2892, 2866, 1471, 1463, 1428, 1380, 1224, 1198, 1172, 1112, 1069, 1029 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 0.95-1.10 (m, 30 H, CH TIPS, CH₃ TIPS and TBDPS), 1.21 (s, 3 H, CH₃ acetal), 1.39 (s, 3 H, CH₃ acetal), 1.70-1.81 (m, 2 H, CH₂), 3.14 (d, 1 H, J = 2.5 Hz, CHOH), 3.59 (ap t, 1 H, J = 5.5 Hz, H-4), 3.70 (dd, J = 4.7, 3.0 Hz, 1 H, H-6), 3.78-3.90 (m, 2 H, CH₂OTBDPS), 3.92-3.97 (m, 1 H, CHOH), 4.09-4.13 (m, 1 H, H-5), 4.45 (d, 1 H, J = 3.6 Hz, 5-OH), 5.16 (d, 1 H, J = 4.7 Hz, CH(OTIPS)), 7.24-7.46 (m, 10 H, Ar-H), 7.63-7.67 (m, 5 H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ = 12.7 (SiCH(CH₃)₂), 18.2 (× 2) (SiCH(CH₃)₂, 19.4 (SiC(CH₃)₃), 24.1, 25.5 (CH₃ acetal), 27.2 (SiC(CH₃)₃), 34.5 (CH₂), 63.2 (CH₂OTBDPS), 69.7 (C-5), 72.4 (CHOH), 73.8 (C-6), 77.7 (CH(OTIPS)), 78.6 (C-4), 101.3 (acetal C), 127.1, 127.9 (× 2), 128.3 (× 2), 130.0 (Ar-C), 133.2, 133.3 (Ar-C, ipso), 135.7, 135.8 (Ar-C)], 141.3 (Ar-C, ipso); MS (CI): m/z (%) = 709(9) [MH⁺ + 1], 534(54), 476(41), 458(29), 235(10), 175(100), 163(15); HRMS (EI): m/z calcd for C₃₈H₅₅O₆Si₂ [M⁺ - C₃H₇]: 663.3537. Found: 663.3534.