Total synthesis of both (+)-compactin and (+)-mevinolin. A general strategy based on the use of a special titanium reagent for dicarbonyl coupling

Abstract

A strategy is described for stereocontrolled synthesis of hypocholesterolemic compounds, (+)-compactin and (+)-mevinolin, by an approach (Scheme 11) based on 6, 7, 4-pentenal (9a), and (R)-3-methyl-4-pentenal (9b). The Evans asymmetric Diels-Alder technique was used (Scheme 111) to prepare 13, which was converted into the cis ester 17. Chain extension, iodolactonization, and elimination of HI then gave optically pure 6. The homochiral epoxide 24, made (Scheme IV) from (.!$)-malic acid, was converted into 25 and then, by iodocarbonation, hydrolysis, and ketalization, into the iodo ketal 7. Evans asymmetric alkylation was used (Scheme V) to prepare 9b. Ozonolysis, ketalization, and reduction (LiAIH,) of 28 gave 31, which was transformed by Swern oxidation, Wittig methylenation, and acid hydrolysis into 9b. An optically pure intermediate (8), common to both syntheses, was assembled (Scheme VI) by alkylation of 6 with 7, reduction to a mixture of lactols, allylic oxidation, and decarbonylation. Aldol condensation (Scheme VII) of 8 with 4-pentena1, triethylsilylation, and ozonolysis gave the enone aldehydes 39, epimeric at C-1 . A modified McMurry reaction requiring an excess of a reagent prepared from C8K and Tic& (2:l molar ratio) in DME, produced the ethers 40, which were converted into (+)-compactin by appropriate modification of the oxygen functionality. The strategy is general and was applied with minor modifications (Scheme VIII) to the synthesis of (+)-mevinolin. Introduction3

Chiral Syn-1,3-diol Derivatives via a One-Pot Diastereoselective Carboxylation/ Bromocyclization of Homoallylic Alcohols

“…As depicted in Scheme 3 , chiral homoallylic alcohol 1a was subjected to t BuOCl and NaBr in DMF at −40°C under a continuously bubbling CO 2 system to give, after crystallization, pure bromocarbonate product 2a in 76% yield, >99% ee, and >19:1 dr without column chromatography isolation. Compound 2a was then converted to acetate 7 in two steps via acetonidation ( Clive et al., 1990 , Radl et al., 2002 , Beck et al., 1995 ) followed by an S N 2 reaction with a total yield of 74%. Subsequent hydrolysis of the acetate proceeded smoothly to give Kaneka alcohol 8 in 93% yield ( Fan et al., 2011 , Sun et al., 2007 ), which could be transformed to the final rosuvastatin 9 via known procedures ( Wess et al., 1990 ).…”

Organocatalytic Enantioselective Formal Conjugate Addition of a Hydroxymoyl Anion to α,β‐Unsaturated Aldehydes

“…At this point we could also assign the absolute configuration of the b-stereocenter generated at the initial conjugate addition reaction by chemical correlation. 3 , for the R isomer) [16] allowed us to assign a R configuration for the a stereocenter to the formyl moiety in compound 7 a and this configuration was extended to all compounds 4, 5, 6, and 7 prepared previously, in which the stereocenter had been already installed in the initial conjugate addition reaction between aldehydes 2 a-2 o and N-nitromethylphthalimide 1 by using catalyst 3. Moreover, this configuration is also in agreement with the configuration of conjugate addition products obtained in other Michael-type reactions catalyzed by 3.…”

Recent advances in the chemistry of parainfluenza‐1 (Sendai) virus inhibitors

“…82,83 However, total or semi-synthetic chemical routes have been considered. 84,85 As an example, the preparation of lovastatin (56) and analogue compounds has been reported 86 via a regioselective enzymatic esterification of the commercially available diol (57) with the (S)-( þ )-2-methylbutyric acid (58) (Scheme 12).…”