Scheme 1. Sites of inhibition of cholesterol biosynthesis by Mevacor and zaragozic acid A.

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Scheme 2. The osmium tetroxide mediated dihydroxylation reaction.

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Scheme 4. Upjohn's catalytic di hydroxylation process with OsO4 and 4-methylmorpholine N-oxide (NMO).

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Scheme

5.

The first enantioselective dihydroxylation reactions (developed by Sharpless).

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Figure

1 . Selected bidentate ligands used in the stoichiometric asymmetric dihydroxylation (AD).

(a) Yamada, T.; Narasaka, K. Chem. Lett. 1986, 1 3 1 ; (b) Tokles, M.; Snyder, T. K. Tetrahedron Lett. 1986, 2 7, 395 1 ; (c) Oishi, T. ; Hirama, M. J. Org. Chem. 1989, 54, 5834; (d) Nakajima, M.; Tomioka, K.; Iitaka, Y. ; Koga, K. Tetrahedron 1993, 49, 1 0793; (e) Corey, E . J . ; Jardine, P. D.; Virgil, S.; Yuen, P.-W. ; Connell, R. D. J. Am. Chem. Soc. 1989, 1 1 1 , 9243 ; (f) Hanessian, S.; Meffre, P. ; Girard, M.; Beaudoin, S . ; Sanceau, J.-Y.; Bennani, Y. L. J. Org. Chem. 1993,

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Scheme 6. The first catalytic asymmetric dihydroxylation (developed by Sharpless).

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Figure 2. Structures of phthalazine, pyrimidine, and indoline ligands used in the Sharpless AD

and composition of AD-mixtures.

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Scheme

7.

Mechanistic alternatives: [2+2] vs. [3+2] cycloaddition of OsO4 and an olefin .

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Scheme

9. Synthesis of zaragozic acid A from key intermediate.

(a) Nicolaou, K. C . ; Yue, E. W. ; Naniwa, Y. ; D e Riccardis, F. ; Nadin, A.; Leresche, J. E.; La Greca, S.; Yang, Z. ibid. 1994, 33, 2 1 84; (b) Nicolaou, K. C.; Yue, E. W.; La Greca, S . ; Nadin, A. ; Yang. Z.; Leresche, J. E. ; Tsuri, T.; Naniwa, Y. ; De Riccardis, F. Chem. Eur. I. , 1995, 1 ,

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Synthesis of Key Intermediate Aldehyde

Scheme 10a.

Synthesis of aldehyde Intermediate

(a) Zhang, H. X . ; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1 857.(b) Shevchuk, M. I.; Tolochko, A. F. ; Dombrovskii, A. V.

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Scheme 10c.

Synthesis of aldehyde Intermediate

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Scheme 11.

Synthesis of bicyclic core

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(a). Still, W. C . ; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. (b) Katsuki, T. ; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974; (c) Gao, Y. ; Hanson, R. M . ; Klunder, J . M . ; Ko, S. Y.; Masamune, H.; Sharpless, K. B .ibid. 1987, 1 09, 5765 .(d) For example: Roush, W. R.; Adam, M. A.; Peseckis, S. M. Tetrahedron Lett. 1983, 24, 1 377. (e) Pfaltz, A.; Mattenberger, A. Angew. Chem. Suppl. 1982, 1 6 1 . (f) Nakatsuka, M.; Ragan, J. A.; Sammakia, T. ; Smith, D. B . ; Uehling, D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583. (g) Mancuso, A. J.; Huang, S.-L. ; Swem, D. J. Org. Chem. 1978, 43, 2480. (h) Bhide, R. S.; Levinson, B. S . ; Sharma, R. B . ; Ghosh, S . ; Salomon, R. G. Tetrahedron Lett. 1986, 27, 67 1 . (i) Evans, D. A.; Ennis, M. D . ; Mathre, D. J. J. Am. Chem. Soc. 1982, 1 04, 1 737. (j) Oppolzer, W. ; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 5603. (k) Enders, D. In Asymmetric Synthesis, Morri son, J. D., Ed.,

.

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Scheme 13.

Synthesis

of

C-6 acyl side chain

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Scheme 14.

Coupling of bicyclic core and alkyl side chain

(a) Newton, R. F. ; Reynolds, D . P. ; Finch, M. A. W. ; Kelly, D. R.; Roberts, S . M . Tetrahedron Lett. 1979, 20, 398 1 ; (b) Newton, R. F.; Reynolds, D. P. ; Webb, C. F. ; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1981, 2055; (c) Ogawa, Y.; Nunomoto, M . ; Shibasaki, M. J.

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Figure

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