Synthesis compactin

Decalin unit 121, an intermediate in the total synthesis of compactin, has been prepared by intramolecular cycloaddition reaction [117] of trienone-carboxylic acid 122 carried out under either thermal conditions or microwave irradiation. The desired cxo-adduct 123 was the major stereoisomer (Equation 2.34). Similar results were observed in the cycloadditions of the corresponding esters. 

The synthesis of the decalin unit of compactin (59), a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which acts as an effective hypocholesterolemic agent, was planned to incorporate an intramolecular Diels-Alder reaction (Scheme 9.15) [57]. 

Intramolecular [4 + 2]-cycloadditions of vinylallenes have been utilized in the synthesis of complex molecules including natural products such as compactin. Heating the vinylallene 208 at 140 °C gave hexahydronaphthalene 209. The crude mixture was immediately reduced with LiB(sBu)3H because of the instability of /3,y-unsatu-rated ketones [175]. 

A well-designed synthesis of the bottom portion of (+)-compactin (44) was reported by Keck and Kachensky using a vinylallene as the diene in an intramolecular Diels-Alder reaction (Scheme 19.10) [12]. This was done at a time when there was very little literature precedent on the use of vinylallenes as dienes. Based on examination of molecular models, it was reasoned that the transition state for the... 

Still, occasionally the other fuctional groups react as well, for example in 38 under basic conditions the propargylic alcohol isomerizes to the a,/3-unsaturated ketone [73] (Scheme 1.15), whereas in a closely related substrate from the synthesis of a subunit of compactin an allylic alcohol remains unchanged [74],... 

MacMillan reported a short and effective synthesis of spiculisporic acid which elegantly exemplified his Mukaiyama-Michael addition of silyloxyfurans to a,P-unsatu-rated aldehydes [88], Robichaud and Tremblay augmented this in a formal synthesis of compactin [224], Within this report it was shown that low enantioselectivities were obtained in the conjugate addition to aCTolein. Use of p-silyl acrolein 177 circumvented this and gave butenohde 178 in 95% yield and 82% ee. Conversion of adduct 178 to the decaUn (179) in eight steps resulted in a formal synthesis (Scheme 71). 

Scheme 71 Iminium ion catalysed Mukaiyama-Michael reaction in the synthesis of compactin...

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... 

Enzymatic DKRs have also been applied in domino one-pot processes [97]. The combination of a lipase-catalyzed resolution with an intramolecular Diels-Alder reaction led to interesting building blocks for the synthesis of natural products such as compactin [98,99] or forskolin [100-102], A ruthenium catalyst is employed for the racemization of the slow reacting enantiomer of the starting material. The DKR with lipase B from C. antarctica delivered high enantiomeric excesses which could mainly be contained through the Diels-Alder reaction (Fig. 12). 

Robichaud J, Tremblay F (2006) Formal enantioselective synthesis of (+)-compactin. Org Lett 8 597-600... 

Another target, that at first seems to be unfavorable since it is principally common for all organisms, is the enzyme HMG-CoA-reduc-tase which is the regulatory enzyme in terpenoid biosynthesis. Results from trials with naturally produced inhibitors for that enzyme, such as Compactine and Mevinoline, indicate that these compounds are able to lower the cholesterol content in mammals, but not markedly depress sterol synthesis in fungi U3). 

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. 

Heathcock, C. H. Davis, B. R. Hadley, C. R. Synthesis and biological evaluation of a mono-cyclic, fully functional analogue of compactin. /. Med. Chem. 1989, 32, 197-202. 

A review cataloging intramolecular Diels-Alder reactions as key steps in the total synthesis of natural products has been published.78 A key step in the total synthesis (g) of (+)-dihydrocompactin (66) is the intramolecular ionic Diels-Alder reaction of the trienone (63) to yield the (+)-compactin core compound (65) via the intermediate cyclic vinyloxocarbenium ion (64) (Scheme 17).79 The intramolecular Diels-Alder reaction of the Asp-Thr tethered compound (67) produced the cycloadduct (68) with high regio- and stereo-selectivity (Scheme 18).80 Mixed quantum and molec- (g) ular mechanics (QM/MM) combined with Monte Carlo simulations and free-energy perturbation (FEP) calculations have been used to show that macrophomate synthase... 

Reduction of 30 with the mild reducing agent Zn/HOAc at 0°C gives the oxime 31 that can be hydrolysed directly to the ketone 32 without isolation.8 This ketone was used in a synthesis of compactin.9... 

Octahydronapthalene synthesis.1 An intramolecular version of this annelation using a Michael addition to a vinyl sulfone provides the octahydronapthalene unit (1) of compactin (2), a mevinic acid of interest as an inhibitor of cholesterol synthesis. 

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