Total synthesis of (±)-dihydrokawain-5-ol. Regioselective monoprotection of vicinal syn-diols derived from the iodocyclofunctionalization of α-allenic alcohols

Journal of Organic Chemistry

Volumn 61, Issue 26, 1996, Pages 9103-9110

  Friesen, Richard W ^a   Vanderwal, Christopher ^a  

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

DIHYDROKAWAIN 5 OL; PYRAN DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CHIRALITY; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS; STEREOCHEMISTRY;

EID: 0030459567     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo961653u     Document Type: Article

References (54)

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22. (a) Ogilvie, K. K.; Hakimelahi, G. H.; Proba, Z. A.; McGee, D. P. C. Tetrahedron Lett. 1982, 23, 1997.
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31. 10
32. 2; TBAF) from the TBDMS diol 23a. Diols 10b and 10c were prepared directly from the diols 7b and 7c, respectively. Diols 10d and 10e were prepared via the acetonide derivatives of diols 7d and 7e, respectively. See the Experimental Section for details.
33. 1H NMR spectra of the crude reaction mixtures, their volatility and/or instability precluded their isolation.
34. Anti diol 15 was prepared from 8b via an unoptimized three-step sequence involving (1) Mitsunobu inversion, (2) hydrolysis, and (3) deprotection. See Experimental Section for details.
35. The regioselective reductive cleavage of benzylidene acetals and other related systems has also been explained by a mechanism in which C-O bond cleavage takes place at the site of metal complexation. See, for example: (a) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97. (b) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593. (c) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans 1 1984, 2371. (d) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron Lett. 1987, 28, 6613. (e) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987, 2033.
36. The regioselective reductive cleavage of benzylidene acetals and other related systems has also been explained by a mechanism in which C-O bond cleavage takes place at the site of metal complexation. See, for example: (a) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97. (b) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593. (c) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans 1 1984, 2371. (d) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron Lett. 1987, 28, 6613. (e) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987, 2033.
37. The regioselective reductive cleavage of benzylidene acetals and other related systems has also been explained by a mechanism in which C-O bond cleavage takes place at the site of metal complexation. See, for example: (a) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97. (b) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593. (c) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans 1 1984, 2371. (d) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron Lett. 1987, 28, 6613. (e) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987, 2033.
38. The regioselective reductive cleavage of benzylidene acetals and other related systems has also been explained by a mechanism in which C-O bond cleavage takes place at the site of metal complexation. See, for example: (a) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97. (b) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593. (c) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans 1 1984, 2371. (d) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron Lett. 1987, 28, 6613. (e) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987, 2033.
39. The regioselective reductive cleavage of benzylidene acetals and other related systems has also been explained by a mechanism in which C-O bond cleavage takes place at the site of metal complexation. See, for example: (a) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97. (b) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593. (c) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans 1 1984, 2371. (d) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron Lett. 1987, 28, 6613. (e) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987, 2033.
40. 21a
41. One possibility is that the regiochemical outcome is a reflection of the relative stabilites of the intermediates 21 and 22. The intermediate 22 would be expected to be destabilized relative to 21 due to the requirement for forming an oxomium ion with the already electron deficient allylic (or propargylic) oxygen. As a result, reduction of 21 may be more facile than that of 22. In addition, the predominant formation of the acetals 13d and 14d (R = t-Bu) in the reduction of the orthoesters derived from diols 7d and 10d could be explained by complexation of DIBAL-H to the OMe oxygen atom of the orthoester 18 rather than the oxygen atoms of the five-membered ring as in 19 or 20. This alternative pathway would be favored in these latter examples since the increased steric bulk of the tert-butyl group would make complexation to the oxygen atoms of the five-membered ring in orthoester 18 less facile than when R is a statically less demanding substituent.
42. (a) Jeong, K.-S.; Sjö, P.; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 3833.
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44. (a) Jones, S. S.; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 1979, 2763.
45. (b) Mulzer, J.; Scheöllhorn, B. Angew. Chem., Int. Ed. Engl. 1990, 29, 431.
46. The base-mediated addition of alcohols (ROH) to α,β-acetylenic esters usually provides the Z-isomer as the predominant reaction product under kinetically controlled conditions. (a) Winterfeldt, E.; Preuss, H. Chem. Ber. 1966, 99, 450. (b) Winterfeldt, E.; Preuss, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 423. Therefore, it is somewhat surprising that such high conversions of δ-hydroxy-α,β-acetylenic esters to 4-alkoxy-α,β-unsaturated lactones under base catalysis (eq 7) have been reported unless there is a mechanistic pathway available for the isomerization of the preferentially formed Z-isomer (such as (Z)-29) to the E-isomer which is required for lactonization. Obviously, in our case the base-catalyzed Z to E isomerization is not observed. Therefore, one must conclude that the oxygen substituent at C5 is in some way inhibiting this transformation since no other reported examples include an alkoxy group at the C5 position.
47. The base-mediated addition of alcohols (ROH) to α,β-acetylenic esters usually provides the Z-isomer as the predominant reaction product under kinetically controlled conditions. (a) Winterfeldt, E.; Preuss, H. Chem. Ber. 1966, 99, 450. (b) Winterfeldt, E.; Preuss, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 423. Therefore, it is somewhat surprising that such high conversions of δ-hydroxy-α,β-acetylenic esters to 4-alkoxy-α,β-unsaturated lactones under base catalysis (eq 7) have been reported unless there is a mechanistic pathway available for the isomerization of the preferentially formed Z-isomer (such as (Z)-29) to the E-isomer which is required for lactonization. Obviously, in our case the base-catalyzed Z to E isomerization is not observed. Therefore, one must conclude that the oxygen substituent at C5 is in some way inhibiting this transformation since no other reported examples include an alkoxy group at the C5 position.
48. 3, THF, or MeOH. All of these conditions were inferior to those described, resulting either in little isomerization or much more extensive decomposition of the labile functionality (methyl vinyl ether and MOM ether) in the starting material and/or product. Obviously, there is a fine line between the acidic reaction conditions that lead to decomposition and those that result in isomerization.
49. These calculations were carried out using the recently published Merck Molecular Force Field. We would like to thank Dr. Christopher Bayly for assistance in carrying out these calculations. (a) Halgren, T. J. Comput. Chem. 1996, 17, 490. (b) Halgren, T. J. Comput. Chem. 1996, 17, 520. (c) Halgren, T. J. Comput. Chem. 1996, 17, 553. (d) Halgren, T.; Nachbar, R. B. J. Comput. Chem. 1996, 17, 587. (e) Halgren, T. J. Comput. Chem. 1996, 17, 616.
50. These calculations were carried out using the recently published Merck Molecular Force Field. We would like to thank Dr. Christopher Bayly for assistance in carrying out these calculations. (a) Halgren, T. J. Comput. Chem. 1996, 17, 490. (b) Halgren, T. J. Comput. Chem. 1996, 17, 520. (c) Halgren, T. J. Comput. Chem. 1996, 17, 553. (d) Halgren, T.; Nachbar, R. B. J. Comput. Chem. 1996, 17, 587. (e) Halgren, T. J. Comput. Chem. 1996, 17, 616.
51. These calculations were carried out using the recently published Merck Molecular Force Field. We would like to thank Dr. Christopher Bayly for assistance in carrying out these calculations. (a) Halgren, T. J. Comput. Chem. 1996, 17, 490. (b) Halgren, T. J. Comput. Chem. 1996, 17, 520. (c) Halgren, T. J. Comput. Chem. 1996, 17, 553. (d) Halgren, T.; Nachbar, R. B. J. Comput. Chem. 1996, 17, 587. (e) Halgren, T. J. Comput. Chem. 1996, 17, 616.
52. These calculations were carried out using the recently published Merck Molecular Force Field. We would like to thank Dr. Christopher Bayly for assistance in carrying out these calculations. (a) Halgren, T. J. Comput. Chem. 1996, 17, 490. (b) Halgren, T. J. Comput. Chem. 1996, 17, 520. (c) Halgren, T. J. Comput. Chem. 1996, 17, 553. (d) Halgren, T.; Nachbar, R. B. J. Comput. Chem. 1996, 17, 587. (e) Halgren, T. J. Comput. Chem. 1996, 17, 616.
53. These calculations were carried out using the recently published Merck Molecular Force Field. We would like to thank Dr. Christopher Bayly for assistance in carrying out these calculations. (a) Halgren, T. J. Comput. Chem. 1996, 17, 490. (b) Halgren, T. J. Comput. Chem. 1996, 17, 520. (c) Halgren, T. J. Comput. Chem. 1996, 17, 553. (d) Halgren, T.; Nachbar, R. B. J. Comput. Chem. 1996, 17, 587. (e) Halgren, T. J. Comput. Chem. 1996, 17, 616.
54. 30