A Novel Strategy for the Convergent Synthesis of 1,3,5,…-Polyols: Enone Formation, Asymmetric Dihydroxylation, Reductive Cleavage, Hydride Addition

Abstract

Asymmetric dihydroxylation of α,β-unsaturated ketones provided α,β-dihydroxyketones with up to 100% ee. The C^α-O bond of these intermediates or their bis-TMS ethers, acetonides, phenylborates or orthoformiates was cleaved with SmI₂, affording β-hydroxyketones. The latter can be reduced to furnish syn- or anti-configured 1,3-diols of any desired configuration.

defunctionalization - 1,3-diol - Horner-Wadsworth-Emmons olefination - β-hydroxy ketones - samarium iodide - α,β-unsaturated ketones

References

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9

Compounds αS,βR-10a-g, αR,βS-10a-g, 11a-g, αR,βS-12c, 13, 15, 17, 18, syn-21, and anti-21 provided correct ¹H NMR spectra and combustion analyses. Compounds αS,βR-12a-g except c were too volatile for combustion analysis and intermediates 14, 16, and 19 deemed not worth it; these compounds were characterized by ¹H NMR and low-resolution mass spectra only.

10

(3 S ,4 R )-3,4-Dihydroxy-2-octanone (α S ,β R -10a).
At 0 °C, trans-3-octen-2-one (1.20 g, 1.38 mL, 9.51 mmol) was added to a stirred mixture of K₂OsO₂(OH)₄ (35.0 mg, 0.095 mmol, 1.0 mol%), (DHQD)₂PHAL (370.0 mg, 0.475 mmol, 5.0 mol%), NaHCO₃ (2.40 g, 28.5 mmol, 3.0 equiv), K₂CO₃ (3.95 g, 28.5 mmol, 3.0 equiv), MeSO₂NH₂ (903 mg, 9.51 mmol, 1 equiv), and K₃Fe(CN)₆ (9.39 g, 28.5 mmol, 3.0 equiv) in t-BuOH (25 mL) and H₂O (25 mL). After stirring for 60 h sat. aq Na₂SO₃ (120 mL) was added. The mixture was warmed to r.t. and extracted with EtOAc (3 × 70 mL). The combined organic extracts were washed with brine (60 mL) and dried over MgSO₄. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel [11] (column filling 5 cm × 20 cm, cyclohexane-EtOAc 1:2, 60 mL fractions) provided the title compound (fractions 5-8, 1.39 g, 89%) as a colorless oil. The ee was ³99% according to chiral GC {CP-Chirasil-Dex CB 25 m × 0.25 mm catalog number CP7502; from 60 °C/10 min at 5 °C/min to 170 °C/20 min; 80 kPa, t _R (major enantiomer) = 26.46 min; no compound eluted around t _R = 25.71 min [which was the independently measured value of t _R (minor enantiomer)]}. ¹H NMR (500 MHz, TMS internal standard in CDCl₃): δ = 0.93 (t, J _8,7 = 7.1 Hz, 8-H₃), 1.34-1.42 (m, 7-H₂, 6-H¹), 1.44-1.50 (m, 6-H²), 1.66 (m_c, presumably interpretable as ddd, J _5,4 = J _{5,6-H ( 1)} = J _{5,6-H ( 2)} = 6.9 Hz, 5-H₂), superimposed partly by 1.73 (br s, 4-OH), 2.28 (s, 1-H₃), 3.70 (br s, 3-OH), 3.95 (td, J _4,5 = 6.9 Hz, J _4,3 = 1.4 Hz, 4-H), 4.08 (d, J _3,4 = 1.5 Hz, 3-H). [α]_D ²⁰ +94.6 (c 0.45, CHCl₃). IR (CDCl₃): 3575, 3465, 2960, 2935, 2875, 2860, 1715, 1465, 1460, 1385, 1360, 1235, 1130, 1090, 935, 910, 885 cm^-1. Anal. Calcd for C₈H₁₆O₃ (160.2): C, 59.97; H, 10.07. Found: C, 59.68; H, 10.09.

11 Still WC. Kahn M. Mitra A. J. Org. Chem.  1978,  43:  2923 

Enantioselective AD of achiral α,β-unsaturated ketones:

12a Becker H. Soler MA. Sharpless KB. Tetrahedron  1995,  51:  1345 

12b Takikawa H. Shimbo K.-i. Mori K. Liebigs Ann./Recl.  1997,  821 

12c Yokoyama Y. Mori K. Liebigs Ann./Recl.  1997,  849 

12d List B. Shabat D. Barbas CF. Lerner RA. Chem.-Eur. J.  1998,  4:  881 

12e Giner J.-L. Tetrahedron Lett.  1998,  39:  2479 

12f Shabat D. List B. Lerner RA. Barbas CF. Tetrahedron Lett.  1999,  40:  1437 

12g Toshima H. Aramaki H. Ichihara A. Tetrahedron Lett.  1999,  40:  3587 

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12k Cox RJ. de Andres-Gomez A. Godfrey CRA. Org. Biomol. Chem.  2003,  1:  3173 

12l Kumar DN. Rao BV. Tetrahedron Lett.  2004,  45:  2227 

Diastereoselective AD of γ-chiral α,β-unsaturated ketones:

13a Carreira EJ. DuBois J. J. Am. Chem. Soc.  1995,  117:  8106 

13b Cid MB. Pattenden G. Synlett  1998,  540 

13c Ishiyama H. Takemura T. Tsuda M. Kobayashi J.-i. J. Chem. Soc., Perkin Trans. 1  1999,  1163 

13d Ohi K. Nishiyama S. Synlett  1999,  573 

13e Lee D.-H. Rho M.-D. Tetrahedron Lett.  2000,  41:  2573 

14 Diastereoselective AD of δ- and β′-chiral α,β-unsaturated ketones: Nicolaou KC. Li Y. Sugita K. Monenschein H. Guntupalli P. Mitchell HJ. Fylaktakidou KC. Vourloulis D. Giannakakou P. O’Brate A. J. Am. Chem. Soc.  2003,  125:  15443 

Diastereoselective AD of β′-chiral α,β-unsaturated ketones:

15a Schuppan J. Ziemer B. Koert U. Tetrahedron Lett.  2000,  41:  621 

15b Trost BM. Harrington PE. J. Am. Chem. Soc.  2004,  126:  5028 

15c Trost BM. Wrobelski ST. Chisholm JD. Harrington PE. Jung M. J. Am. Chem. Soc.  2005,  127:  13589 

16 Review: Kagan HB. Tetrahedron  2003,  59:  10351 

17

Confer ref. 18a for a different rationalization.

18a Molander GH. Hahn G. J. Org. Chem.  1986,  51:  1135 

18b Similarly an O^α-SiMe₂ t-Bu bond was cleaved off a ketone by: Abad A. Agulló C. Arnó M. Cuñat AC. García MT. Zaragozá RJ. J. Org. Chem.  1996,  61:  5916 

19a Mori Y. Yaegashi K. Furukawa H. J. Am. Chem. Soc.  1997,  119:  4557 

19b Mori Y. Yaegashi K. Furukawa H. J. Org. Chem.  1998,  63:  6200 

19c Voight EA. Seradj H. Roethle P. Burke SD. Org. Lett.  2004,  6:  4045 

20 In lactones, oxygen-containing α-substituents including OH groups can be removed by SmI₂ in THF-HMPA, too: Hanessian S. Girard C. Chiara JL. Tetrahedron Lett.  1992,  33:  573 

21 Holton RA. Somoza C. Chai K.-B. Tetrahedron Lett.  1994,  35:  1665 

22a Py S. Khuong-Huu F. Tetrahedron Lett.  1995,  36:  1661 

22b Georg GI. Cheruvallath ZS. Vander Velde DG. Himes RH. Tetrahedron Lett.  1995,  36:  1783 

22c Georg GI. Harriman GCB. Datta A. Ali S. Cheruvallath ZS. Vander Velde DG. Himes RH. J. Org. Chem.  1998,  63:  8926 

23 Molander GH. Hahn G. J. Org. Chem.  1986,  51:  2596 

24 White DJ. Nolen EG. Miller CH. J. Org. Chem.  1986,  51:  1150 

25a Smith AB. Dunlap NK. Sulikowski GA. Tetrahedron Lett.  1988,  29:  439 

25b Kim D. Min J. Ahn SK. Lee HW. Choi NS. Moon SK. Chem. Pharm. Bull.  2004,  52:  447 

26 Hosaka M. Hayakawa H. Miyashita M. J. Chem. Soc., Perkin Trans. 1  2000,  4227 

27 Rho H.-S. Synth. Commun.  1997,  27:  3887 

28a

(4 R )-4-Hydroxy-2-octanone ( 11a).
At -78 °C a solution of SmI₂ (0.1 M in THF, 42 mL, 4.2 mmol, 2.1 equiv) was added dropwise to a stirred solution of acetonide αS,βR-12a (0.40 g, 2.0 mmol) in THF (12 mL) and MeOH (6 mL). After 15 min the reaction mixture was gradually warmed to r.t. (within 30 min) and aq HCl (1 M, 4.2 mL) was added. After evaporating volatile material in vacuo the residue was diluted with H₂O (10 mL) and extracted with t-BuOMe (3 × 15 mL). The combined organic extracts were washed with sat. aq NaHCO₃ (10 mL) and brine (8 mL) and dried over MgSO₄. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel [11] (column filling 1.5 cm × 15 cm, cyclohexane-EtOAc 4:1, 4 mL fractions) afforded the title compound (fractions 20-39, 0.186 g, 65%) as a colorless oil. ¹H NMR (400 MHz, MHz, TMS internal standard in CDCl₃): δ = 0.91 (t, J _8,7 = 7.1 Hz, 8-H₃), 1.29-1.54 (m, 5-H₂, 6-H₂, 7-H₂), 2.18 (s, 1-H₃), AB signal (δ_A = 2.53, δ_B = 2.62, J _AB = 17.7 Hz, A part in addition split by J _A,4 = 9.0 Hz, B part in addition split by J _B,4 = 2.9 Hz, 3-H₂), 2.94 (br s, 4-OH), 4.03 (m_c, 4-H). [α]_D ²⁰ -31.50 (c 0.20, CHCl₃). IR (CDCl₃): δ = 3565, 2960, 2935, 2875, 2860, 1705, 1470, 1460, 1415, 1385, 1365, 1315, 1275, 1165, 1060 cm^-1. Anal. Calcd for C₈H₁₆O₂ (144.2): C, 66.63; H, 11.18. Found: C, 66.74; H, 10.97.

28b Enantiomer S-11a was prepared by an organocatalytic aldol addition (86% ee, 12% yield). See: Tang Z. Jiang F. Yu L.-T. Cui X. Gong L.-Z. Mi A.-Q. Jiang Y.-Z. Wu Y.-D. J. Am. Chem. Soc.  2003,  125:  5262 

Borinylated β-hydroxyketone and NaBH₄:

29a Narasaka K. Pai F.-C. Chem. Lett.  1980,  1415 

29b Narasaka K. Pai F.-C. Tetrahedron  1984,  40:  2233 

29c Chen K.-M. Hardtmann GE. Prasad K. Repic O. Shapiro MJ. Tetrahedron Lett.  1987,  28:  155 

29d Chen K.-M. Gunderson KG. Hardtmann GE. Prasad K. Repic O. Shapiro MJ. Chem. Lett.  1987,  1923 

30 BCl₃-complexed β-hydroxyketone and tetraalkylammonium boronate: Sarko CS. Collibee SE. Knorr AR. DiMare M. J. Org. Chem.  1996,  61:  868 

31 Reduction with DIBAL-H: Kiyooka S. Kuroda H. Shimasaki Y. Tetrahedron Lett.  1986,  27:  3009 

32 Reduction with catecholborane: Evans DA. Hoveyda AH. J. Org. Chem.  1990,  55:  5190 

33a Reduction with Zn(BH₄)₂: Kashihara H. Suemune H. Fujimoto K. Sakai K. Chem. Pharm. Bull.  1989,  37:  2610 ; in Et₂O

33b Dakin LA. Panek JS. Org. Lett.  2003,  5:  3995 ; in CH₂Cl₂

Reduction with tetraalkylammonium triacetoxyboro-hydride:

34a Evans DA. Chapman KT. Tetrahedron Lett.  1986,  27:  5939 

34b Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 

34c See also with sodium triacetoxyborohydride: Roeyeke Y. Keller M. Kluge H. Grabley S. Hammann P. Tetrahedron  1991,  47:  3335 

Intramolecular hydrosilylation:

35a Anwar S. Davis AP. J. Chem. Soc., Chem. Commun.  1986,  831 

35b Anwar S. Davis AP. Tetrahedron  1988,  44:  3761 

36a Reduction with SmI₂ and an aldehyde: Evans DA. Hoveyda AH. J. Am. Chem. Soc.  1990,  112:  6447 

Related Tishchenko reductions:

36b Schneider C. Klapa K. Hansch M. Synlett  2005,  91  and literature cited therein

37 LiClO₄-complexed β-hydroxyketone and amine-complexed BH₃: Narayana C. Reddy MR. Hair M. Kabalka GW. Tetrahedron Lett.  1997,  38:  7705 

38a Reduction with SmI₂: Keck GE. Wager CA. Sell T. Wager TT. J. Org. Chem.  1999,  64:  2172 

38b The diastereoselectivity of this reduction is sensitive to solvent variation: Chopade PR. Davis TA. Prasad E. Flowers RA. Org. Lett.  2004,  6:  2685 

39 LiI-complexed β-hydroxyketone and LiAlH(Ot-Bu)₃: Ball M. Baron A. Bradshaw B. Omori H. MacCormick S. Thomas EJ. Tetrahedron Lett.  2004,  45:  8737 

40

Methyl (6 R )-7-[(4 R )-2,2-Dimethyl-1,3-dioxolan-4-yl]-6-hydroxy-4-oxoheptanoate ( 24).
A suspension of 1,2-diiodoethane (2.062 g, 7.316 mmol, 3.0 equiv) and Sm powder 40 mesh (1.155 g, 7.316 mmol, 3.15 equiv) in THF (70 mL) was stirred at r.t. for 2 h. A deep-blue solution of SmI₂ was obtained. At -78 °C acetonide 25 (805 mg, 2.44 mmol) in THF-MeOH 2:1 (30 mL) was added within 10 min. After another 10 min, the mixture was warmed to r.t. and the reaction quenched 20 min later by the addition of aq HCl (1 M, 7.4 mL). The aqueous phase was separated and extracted with t-BuOMe (3 × 25 mL). The combined organic phases were washed successively with sat. aq NaHCO₃ (15 mL) and brine (12 mL) and dried over MgSO₄. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel [11] (column filling 3 cm × 20 cm, eluent = cyclohexane-EtOAc, 40:60) provided the title compound (fractions 8-24, 601 mg, 90%). ¹H NMR (500 MHz, CDCl₃): δ = 1.36 and 1.41 [2 × s, 2′-(CH₃)₂], AB signal (δ_A = 1.69, δ_B = 1.73, J _AB = 13.1 Hz, in addition split by J _{7-H ( A),6} = 7.3 Hz,* J _{7-H ( A),4 ′} = 4.1 Hz,*
J _{7-H ( B),4 ′} = 8.3 Hz,** J _{7-H ( B),6} = 4.9 Hz,** 7-H₂), presumably extreme AB signal where the 8 off-center signals are too small to be identified (so that J _AB cannot be extracted) so that the best description is: 2.61 (dd, J _{3-H ( 1),2-H ( 1)} = 6.6 Hz, J _{3-H ( 1),2-H ( 2)} = 3.8 Hz), 2.62 (dd, J _{3-H ( 2),2-H ( 2)} = 6.6 Hz,***
J _{3-H ( 2),2-H ( 1)} = 2.7 Hz,*** 3-H₂), 2.68 and 2.76 (2 × m_c, 2-H₂, 5-H₂), 3.26 (d, J _OH,6 = 3.5 Hz, 6-OH), 3.57 (dd, J _gem = J _{5 ′ -H ( 1),4 ′} = 7.8 Hz, 5′-H¹), 3.68 (s, 1-OCH₃), 4.09 (dd, J _gem = 7.9 Hz, J _{5 ′ -H ( 2), 4 ′} = 6.1 Hz, 5′-H²), 4.25-4.33 (m, 6-H, 4′-H); *, **, *** coupling constants exchangeable. ¹³C NMR [75 MHz, CDCl₃; APT spectrum, peak orientation ‘up’ (‘+’) for CH₃ and CH and ‘down’ (‘-’) for CH₂ and C_quat]: δ = ‘+’ 25.67 and ‘+’ 26.91 [2′-(CH₃)₂], ‘-’ 27.55 (C-2), ‘-’ 37.80 (C-3), ‘-’ 39.94 (C-7), ‘-’ 49.66 (C-5), ‘+’ 51.88 (1-OCH₃), ‘+’ 65.46 (C-6), ‘-’ 69.64 (C-5’), ‘+’ 73.37 (C-4’), ‘-’ 108.75 (C-2’), ‘-’ 173.21 (C-1), ‘-’ 209.34 (C-4). [α]_D ²⁰
-22.6 (c 1.92, CHCl₃). IR (film): 3490, 3015, 2985, 2945, 1735, 1715, 1435, 1415, 1370, 1215, 1165, 1060, 990, 870, 855 cm^-1. Anal. Calcd for C₁₃H₂₂O₆ (274.3): C, 56.92; H, 8.08. Found: C, 57.12; H, 7.99.