Compactin lactone synthesis

In the synthesis of the compactin lactone precursor 76, an aldol—> 1,3-diol conversion was included in the usual sequence, and the required aldehyde function... 

The PLE-catalyzed asymmetric hydrolysis of /neso-l,3-cts-3,5-cij-l,3-diacetoxy-5-benzyloxycyclohexane afforded (lS,35,5/f)-l-acetoxy-5-benzyloxycyclohexan-3-ol, which could be used as chiral building block for the synthesis of the compactin lactone moiety and quinic acid (eq 4). ... 

The synthesis of the (+ )-compactin lactone 30, an important component of the statins, illustrates the power of the dihydroxylation methodology when coupled with regioselective sulfite ring opening (Scheme 3.28) [339]. 

The arrangement of functional groups as well as the erythro configuration of the latent diol makes carbonate 517 an excellent candidate as a compactin lactone synthon (99) and it has in fact been used in the synthesis of both compactin (97) and mevinolin (98) (Scheme 75) [112]. 

In model studies related to the synthesis of compactin (97) and mevinolin (98), the upper-half lactone moiety was constructed from 550 starting with an oxirane ring-opening reaction by vinyl Grignard reagent (Scheme 81) [136]. lodocarbonation of 560 followed by hydrolysis and ketalization affords isomerically pure acetonide 562, the compactin lactone synthon. 

A relatively concise synthesis of a compactin lactone (99) derivative makes use of 590 as the source of chirality (Scheme 93) [142]. Addition of ethyl acetate enolate to 590 produces a 1 1 mixture of aldols 633 in 58% yield. After silylation of the hydroxyl group, cleavage of the acetonide furnishes lactone 635 as a crystalline solid. Tosylation of the primary alcohol and separation of the isomers furnishes 636 (47% yield) and 637 (44% yield). The desired isomer 636 is a suitably protected and functionalized version of compactin lactone . 

Danishefsky, S. J. Simoneau, B. Total synthesis of ML-236A and compactin by combining the lactonic (silyl) enolate rearrangement and aldehyde-diene cyclocondensation technologies./. Am. Chem. Soc. 1989, 111, 2599-2604. 

An excellent application of the Narasaka reduction is a diastereoselective synthesis by Merck scientists of 7, a structurally novel analog of the natural product compactin (8)7, which is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase8 (Scheme 4.1e). The key step in the construction of the P-hydroxy-8-lactone moiety in 7 is the highly diastereoselective reduction of the P-hydroxy ketone 9 using a triethyl borane/sodium borohydride system. The yyn-diol 10 was obtained in high yield and with a remarkably high level of diastereoselectivity. 

However, excellent simple (exo endo = 95 5) and induced diastereoselectivity (94 6) was obtained by Jurczak [88] by applying the bornane sulfone amide derivative of glyoxylic acid 2-23 in the presence of a catalytic amount of a europium salt. Reaction of 2-23 with 1-methoxy-1,3-butadiene 2-24 gave predominantly 2-25 a which was transformed into the lactone 2-26 aiming towards the synthesis of compactin (Fig. 2-7)[89]. 

In DERA reactions, where acetaldehyde is the donor, products are also themselves aldehydes. In certain cases a second aldol reaction will proceed until a product has been formed that can cyclize to a stable hemiacetal.71 For example, when a-substituted aldehydes were used, containing functionality that could not cyclize to a hemiacetal after the first aldol reaction, these products reacted with a second molecule of acetaldehyde to form 2,4-dideoxyhexoses, which then cyclized to a hemiacetal, preventing further reaction. Oxidation of these materials to the corresponding lactone, provided a rapid entry to the mevinic acids and compactins (Scheme 5.43). Similar sequential aldol reactions have been studied, where two enzyme systems have been employed72 (Scheme 5.44). The synthesis of 5-deoxy ketoses with three substitutents in the axial position was accomplished by the application of DERA and RAMA in one-pot (Scheme 5.44). The long reaction time required for the formation of these thermodynamically less stable products, results in some breakdown of the normally observed stereoselectivity of the DERA and FDP aldolases. In a two-pot procedure, DERA and NeuAc aldolase have... 

Few synthetically useful examples of the oxidation of ethers by oxygen or ozone have been publish-ed.7 96 Q0 In 1978, Ourisson and coworkers reported that ozonization of the natural product cedrane oxide (43) on silica gel at -78 °C led to the formation of the corresponding lactone (44) in 30% yield (equation 32).A small amount of the tertiary alcohol (45) was also produced. Later, in the course of a chiral total synthesis of compactin, Hirama examined the ozonolysis of the alkene (46 equation 33). ° Under carefully controlled conditions, selective ozonolysis of the double bond could be achieved in 88% yield. However, when excess ozone was employed, significant amounts of the benzoate (47) were obtained, even at -78 C. In subsequent studies, benzyl ethers of primary and secondary alcohols,and carbohydrates were oxidized to the corresponding benzoates in excellent yields. Surprisingly, no further synthetic rqrplications of this reaction have been reported. 

Hetero Diels-Alder Reaction. The hetero-Diels-Alder reaction involving glyoxylate as the dienophile provides an efficient access to the asymmetric synthesis of monosaccharides. The hetero Diels-Alder reaction with methoxydienes proceeds smoothly with catalysis by BINOL-TiCl2 to give the cis product in high enantiomeric excess (eq 14). The dibromide affords a higher cis selectivity, however, with a lower enantioselectivity, particularly in the trans adduct. The product thus obtained can be readily converted to the lactone portion of HMG-CoA inhibitors such as mevinolin or compactin. ... 

N,P P, P] Danishefsky and Simoneau utilized the sequential Michael-aldol reaction for the synthesis of compactin and ML-236A (51.1 and 51.2 in Scheme 51) (101). In this context, the HgI2-promoted addition of the rerf-butyldimethylsilyl ketene acetal derived from ethyl acetate to cyclohex-enone 51.3 followed by reaction with crotonaldehyde and acidic work-up produces 35-42% of lactone 51.4 as one stereoisomer. As enone 51.3 is available in optically pure form from quinic acid (102), the naturally occurring enantiomer of compactin can be obtained. 

A synthesis of the lactone part (56) of the coenzyme A reductase inhibitor compactin has been reported, starting from compound (57) derived from triacetyl-D-glucal. The chiral intermediate (58), derived also from triacetyl-D-glucal, has been converted to the corresponding lactone and Incorporated ( via C-6 substitution) in a synthesis of the compactin relative (+)-dihydromevinolin. ... 

Several synthesis of the Prelog-Djerassi lactone elevate the compound almost to the position of cis-jasmone in terms of its popularity as a synthetic target. Full details of the Danishefsky route to ( )-quadrone have appeared as well as a report of a concurrent synthesis. A new method for the preparation of 5-lactones involving the reaction of a y,5-unsaturated aldehyde with NaOH followed by oxidation has been applied to the synthesis of ( )-pentaleno-lactone. The first total synthesis of (+)-compactin has been reported. ... 

Hiyama et al. have reported an enantioselective synthesis of p-hydroxy 5-lactones as simplified analogs of compactin and mevinolin [47] (Scheme 10). The p,5-diketo ester 54 derived from Taber s chiral alcohol 57 was subjected to a stereoselective reduction with sodium borohydride in the presence of Et2BOMe to afford a syn diol, which upon saponification and then heating in dry toluene led to the chiral lactone 56. 

The easy detection of the end of the a-aminoxylation reaction catalyzed by (S)-prolrne (21) has allowed the in situ transformation of compounds 97 into interesting chiral functionalized compounds through the use of tandem one-potprocesses [118]. This synthetic strategy has been applied to the formal synthesis of HRV 3C-protease inhibitor (lR,2S)-thysanone [119], the synthesis of the atorvastatin side chain (a building block present in the statin family that acted as cholesterol regulator) [120], and the synthesis of the lactone moiety of compactin and mevinoUn [121]. 

One of the pervasive problems in asymmetric synthesis has been the development of stereoselective acetate ester aldol reactions. Although a number of chiral auxiliaries perform superbly well in diastereoselective propionate aldol additions, these have, with rare exceptions, been unsuccessful in the corresponding additions of unsubstituted acetate-derived enolates [19, 63, 64). Braun s disclosure of a stereoselective acetate aldol addition reaction with 103 was an important milestone in the development of the field (Scheme 4.11) [63, 65]. The diol auxiliary can easily be prepared from mandelic acid esterification of the secondary alcohol is obsei ved, without interference from the tertiary counterpart. Its use has been showcased in a number of syntheses [53]. The high yield and diastereoselectivity generally obtained with 103 were highlighted by investigators at Merck in the construction of the chiral lactone fragment that is common in a number of HMG-CoA reductase inhibitors, such as compactin (105) [66]. 

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