Synthesis of -statine

Greenberg, W.A., Varvak, A., Hanson, S.R. el ai (2005) Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proceedings of the National Academy of Sciences of the United States of America, 101, 5788-5793. 

Scheme 11. Aldolase-catalyzed synthesis of statin drugs via the megagenonuc approach...

Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proc Natl Acad Sci USA 101 5788-5793... 

J. V. N. Vara Prasad and D. H. Rich, Addition of allylic metals to ot-amino aldehydes. Application to the synthesis of statine, ketomethylene and hydroxyethylene dipeptide isosteres. Tetrahedron Lett. 37 1803 (1990). 

The aldol reaction between a chiral a-amino aldehyde 16 and an acetate derived enolate 17 creates a new stereogenic center and two possible diastereomers. Several different methods for the synthesis of statine derivatives following an aldol reaction have been reported most of them lead to a mixture of the (35,45)- and (3/ ,45)-diastereomers 18 (Scheme 3), which have to be separated by laborious chromatographic methods.[17 211 Two distinct approaches for stereochemical control have been used substrate control and reagent control. 

Intramolecular radical addition to vinylsilane moiety has been used for the synthesis of statine 148 (equation 124)216 and the pyrrolizidine skeleton217. Tandem [2+1] radical cyclization of bromides 149 with BusSnH is extremely sensitive to the nature of the substituent on the diene moiety. Bicyclo[3.1.0] skeleton 150 is obtained in the presence of the silyl substituent (equation 125). When the silyl substituent in 149 is replaced by a t-butyl group, the six-membered ring product 151 is obtained exclusively218. 

Fig. 17 Ketoreductase-catalyzed chemoenzymatic synthesis of statin side chains...

Konno, H. Toshiro, E. Hinoda, N. An epoxide ring-opening reaction via a hyperva-lent silicate intermediate synthesis of statine. Synthesis 2003, 2161-2164. 

Scheme 106 Stereospecific synthesis of Statine from IPCF.

Much less is known about aldol additions to chiral aldehydes that have heteroatoms other than oxygen at the a-stereocenter. In connection with a synthesis of statine analogs, a-amino aldehyde (176) was allowed to react with ethyl lithioacetate to obtain (177) and (178) in a ratio of 60 40 (equation 114). 

Scheme 10-61 A tether-directed radical cyclization provided the key step in the formal synthesis of statine 189 by Hiemstra, Speckamp, and co-workers.

Two different approaches to ( —)-statine (831), an unusual amino acid component of pepstatine, both employ 793c as their starting point. In the first synthesis (Scheme 120) [183], reduction of 793c with sodium borohydride produces a mixture of two isomeric 5-hydroxy-pyrrolidinones, from which the pure cis product 824 crystallizes in 85% yield. Conversion of bisacetate 825 to thioether 826 followed by removal of the acetate and silylation of the resulting alcohol affords 827. Radical cyclization of 827 produces a 3 2 mixture of isomers 828. Desilylation and debenzylation gives 829 as a single diastereomer. The Boc-protected intermediate 830 intersects with a known synthesis of ( —)-statine (831). 

A much shorter synthesis of ( —)-statine (831) relies on the regiospecific addition of methallylmagnesium chloride to the C-2 carbonyl of 793c as a way of introducing the... 

As seen for the synthesis of statine, highly substituted hydroxy amino acids may be peptidase inhibitors. Several analogs have been prepared with the goal of preparing new peptidase inhibitors. Some of these amino acid syntheses are collected into this section. 

P-Hydroxy-amino acids (Figure 10.7) are multifunctional compoimds with valuable interest as intermediates for the synthesis of statine derivatives (106) [166-168], protease inhibitors [169], antivirals [170, 171], peptide mimetics [172], idulonic acid mimetics, for example, 3R,5R-dihydroxy-L-homoproline (111) [173], immimosup-pressive lipid mycestericin d (112) [174], 3,4-dihydroxyprolines (113) [175], (2S,3R)-2-amino-3-hydroxybutyrolactone, precursor of monobactam antibiotics [176], or L-ffereo-3-[4-(me ylthio)phenylserine] precursor of thiamphenicol (114), florfenicol (115) [177], sialyl Lewis x mimetics (117) [178], p-hydroxyomithine (109), a relevant building block for the p-lactamase inhibitor, clavulanic acid, and the antibiotic and anticancer acivicin [179], surveyed in previous reviews [41,57]. 

SCHEME 28.19. DERA-catalyzed chiral and sequential syntheses of intermediate compounds 41 and 44 in the synthesis of statins. 

Andrushko N, Andrushko V, Tararov V, Korostylev A, Konig G, Bomer A. Highly stereoselective hydrogenations-as key-steps in the total synthesis of statins. Chirality 2010 22 (5) 534-541. 

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