Enantiospecific synthesis

The elegant, enantiospecific synthesis of biotin (1) by Hoffmann-La Roche1 is based on a strategy that takes advantage of the powerful intramolecular nitrone-olefin cycloaddition reaction. Our analysis begins with model studies in which the straightforward conversion of L-cysteine (2) into aldehyde 3 (see Scheme 1) constitutes... 

The carbanions of 1-alkenyl sulphoxides 400 also react with carbonyl compounds to give the corresponding condensation products384 (equation 237). Solladie and Moine have used this type of reaction in their enantiospecific synthesis of the chroman ring of a-tocopherol 401. Addition of the lithio reagent 402 to the aldehyde 403 affords the allylic alcohol 404 in 75% yield as a sole diastereoisomer481 (equation 238). 

Keywords enantiospecific synthesis, intramolecular Diels-Alder approaches... 

Carless HAJ (1992) The use of cyclohexa-3,5-diene-l,2-diols in enantiospecific synthesis. Tetrahedron Asymmetry 3 795-826. 

In Entry 11 the dienophile is an a-methylene lactam. As noted for this class of dienophiles, the stereoselectivity results from preferred exo addition (see p. 471). The reaction in Entry 12 was used in an enantiospecific synthesis of estrone. The dienophile was used in enantiomerically pure form and the dioxolane ring imparts a high facial selectivity to the dienophile. The reaction occurs through an endo TS. 

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

Entry 10 was used in conjunction with dihydroxylation in the enantiospecific synthesis of polyols. Entry 11 illustrates the use of SnCl2 with a protected polypropionate. Entries 12 and 13 result in the formation of lactones, after MgBr2-catalyzed additions to heterocyclic aldehyde having ester substituents. The stereochemistry of both of these reactions is consistent with approach to a chelate involving the aldehyde oxygen and oxazoline oxygen. 

Section B shows some Hofmann rearrangements. Entry 9, using basic conditions with bromine, provided an inexpensive route to an intermediate for a commercial synthesis of an herbicide. Entry 10, which uses the Pb(OAc)4 conditions (see p. 949), was utilized in an enantiospecific synthesis of the naturally occurring analagesic (-)-epibatidine. Entry 11 uses phenyliodonium diacetate as the reagent. The product is the result of cyclization of the intermediate isocyanate and was used in an enantioselective synthesis of the antianxiety drug (tf)-fluoxetine. 

An enantiospecific synthesis of longifolene was done starting with camphor, a natural product available in enantiomerically pure form (Scheme 13.31) The tricyclic ring was formed in Step C by an intramolecular Mukaiyama reaction. The dimethyl Multistep Syntheses substituents were formed in Step E-l by hydrogenolysis of the cyclopropane ring. 

Another enantiospecific synthesis of longifolene shown in Scheme 13.32 used an intramolecular Diels-Alder reaction as a key step. An alcohol intermediate was resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the dihydropyrone ring was introduced by 7-addition of the ester enolate of methyl 3-methylbutenoate, followed by cyclization. 

A simple modification of the foregoing route to (+)-A-mcthylmayscninc allowed the enantiospecific synthesis of (-)-A-mcthylmayscninc. 

Osmylation of C—C double bonds adjacent to the (diene)Fe(CO)3 functionality has been reported (Scheme 57)205. This methodology has been used in the enantiospecific synthesis of 5,6- and 11,12-diHETEs. 

The optical activity of biologically-active chemicals is important to their activity and toxicology. Pure enantiomers, or optical isomers, of pharmaceuticals and agrochemicals can in many cases be made by enantiospecific synthesis. An alternative method is to use a less complicated synthesis followed by chromatographic resolution of the racemic mixture into its enantiomers. 

Swainsonine is a trihydroxylated bicyclic indolizidine alkaloid with four chiral centres, whose relative stereochemistry was determined by X-ray crystallographic analysis and the absolute configuration was deduced on the basis of biosynthetic and asymmetric induction studies, and then confirmed by an enantiospecific synthesis from D-mannose [2a]. 

D. Hendry, L. Hough, and A. C. Richardson, Enantiospecific synthesis of I-deoxy-castanospermine, (6S,7R,8R,8aR)-trihydroxyindolizidine, from D-glucose, Tetrahedron Lett., 28 (1987) 4597-4600. 

I. Izquierdo-Cubero, M. T. P. Lopez-Espinosa, M. D. Suarez-Ortega, and A. C. Richardson, Enantiospecific synthesis of 1-deoxythiomannojirimycin from a deriviative of D-glucose, Carbohydr. Res., 242 (1993) 109-118. 

Prous, J. Castaner, J. Drugs Future 1991, 16, 804, and references cited therein this source also describes enantiospecific synthesis for this drug. 

An enantiospecific synthesis of the potent anti-Alzheimer s agent (-t-)-ferruginine 1 and two enantiospecific syntheses of the potent anti-Alzheimer s agent anatoxin-a 2 were submitted essentially simultaneously earlier this year. In each case, the starting material used was the inexpensive pyroglutamic acid 3, and in each case the synthesis depended on Ru-catalyzed alkyne-alkene metathesis. 

Scheme 9. Convergent, enantiospecific synthesis of atorvastatin calcium (1).

Corey, E. J. Ohtani, M. Enantiospecific Synthesis of a Rigid C2 Symmetric, Chiral Guanidine by a New and Direct Method, Tetrahedron Lett. 1989, 30, 5227-5230. 

P. Boquel, C. Loustau Cazalet, Y. Chapleur, S. Samreth, and F. Bellamy, An expeditious enantiospecific synthesis of a precursor of the lactonic portion of mevinic acids, Tetrahedron Lett. 33 1997 (1992). 

L. Pettersson, T. Frejd, and G. Magnusson, An enantiospecific synthesis of a taxol A-ring building unit, Tetrahedron Lett. 28 2753 (1987). 

The stereochemistry of the dipeptide isosteres has been determined by X-ray crystallography/87 93 by chemical conversion/66 by circular dichroism/93 94 and by enantiospecific synthesis. 43 ... 

Recently, much effort has been directed to the synthesis of analogs of the biologically active form of vitamin D3, la,25-dihydroxyvitamin D3 [la,25(OH)2D3] as an important new field in medicinal chemistry [50], As a new and efficient route to this class of compounds, the symmetry -assisted enantiospecific synthesis of the A-ring of the vitamin D-hybrid analogs, 19-nor-22-oxa-la,25(OH)2D3 was reported (Scheme 8C.20) [51]. It should be noted that any gem-dialkyl substituents is not necessary to attain a high level of enantioselectivity. 

Scheme 8C.20. Symmetry -assisted enantiospecific synthesis of A-ring of Vitamin D analogues based on asymmetric ene cyclization.

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