Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.

Formal total synthesis of (+)-trehazolin. Application of an asymmetric aldol-olefin metathesis approach to the synthesis of functionalized cyclopentenes.

An asymmetric synthesis of the aminocyclopentitol pseudosugar of trehazolin has been completed. The synthesis hinges on an asymmetric aldol-ring closing metathesis strategy to construct the five-membered ring with control of both the relative and absolute stereochemistry.

An aldol approach to the synthesis of the EF fragment of spongistatin 1.

A synthesis of the C29-C51 fragment of spongistatin 1, containing the E and F rings, has been completed. The approach relies on four diastereoselective aldol additions and an asymmetric glycolate alkylation to establish eight of the eleven stereogenic centers. The intact chlorodiene side chain was appended by a Lewis acid catalyzed addition of an allylstannane to an epoxy enol ether.

An efficient, general asymmetric synthesis of carbocyclic nucleosides: application of an asymmetric aldol/ring-closing metathesis strategy.

A general and efficient synthesis of carbocyclic and hexenopyranosyl nucleosides has been developed. The strategy combines three key transformations: an asymmetric aldol addition to establish the relative and absolute configuration of the pseudosugar, a ring-closing metathesis to construct the pseudosugar ring, and a Trost-type palladium(0)-mediated substitution to assemble the pseudosugar and the aromatic base. Carbovir, abacavir, and their 2'-methyl derivatives as well as hexenopyranosyl nucleoside analogues have been prepared by this sequence.

Diastereoselective alkylations of oxazolidinone glycolates: a useful extension of the Evans asymmetric alkylation.

[reaction: see text] The diastereoselective alkylation of glycolate oxazolidinones has been demonstrated as a method for the enantioselective preparation of alpha-alkoxy carboxylic acid derivatives and selectively protected 1,2-diols. Various protecting groups on the glycolate hydroxyl and multiple substitution patterns on allylic iodides are tolerated in the alkylation. Yields for the alkylations are typically 70-85% with diastereoselectivities of >98:2.

Synthesis of crossed [2 + 2] photocycloadducts: a novel approach to the synthesis of bridged bicyclic alkenes.

[reaction: see text] A solution to the synthesis of "crossed" intramolecular [2 + 2] photocycloadducts has been achieved. Through the use of a temporary heteroatom linker, the equivalent of a crossed photocycloadduct can be accessed at the expensive of the normal "straight" adduct. Selectivity as high as 94:6 for the "crossed" adduct has been observed.

Synthesis of the C1-C13 fragment of leucascandrolide A.

[reaction: see text] The synthesis of the C1-C13 fragment 3 of leucascandrolide A has been completed utilizing a stereoselective and regioselective reductive cleavage of a highly functionalized spiroketal to incorporate the cis-2,6-disubstituted tetrahydropyan. The spiroketal was constructed by addition of a lithiated pyrone 5 to aldehyde 6.

Solid-phase synthesis of carbocyclic nucleosides.

[formula: see text] An efficient solid-phase synthesis of carbocyclic nucleosides has been developed. The key step is the palladium-catalyzed coupling of a purine derivative to a resin-bound allylic benzoate. The resulting products may be further functionalized on the solid phase. Acidic cleavage affords carbocyclic nucleosides, a class of compounds with demonstrated biological activity and substantial current interest.

Synthesis of the C16-C28 spiroketal subunit of spongistatin 1 (altohyrtin A): the pyrone approach.

The synthesis of the CD spiroketal fragment of spongistatin 1 (altohyrtin A) has been accomplished utilizing the addition of a metalated pyrone to an aldehyde and subsequent acid-catalyzed spirocyclization. A stereoselective hydrogenation and subsequent conformational inversion establish the C19 stereocenter and the axial-equatorial spiroketal center.

Titanium enolates of thiazolidinethione chiral auxiliaries: versatile tools for asymmetric aldol additions.

[formula: see text] Asymmetric aldol additions using chlorotitanium enolates of thiazolidinethione propionates proceed with high diastereoselectivity for the "Evans" or "non-Evans" syn product depending on the nature and amount of the base used. With (-)-sparteine as the base, selectivities of 97:3 to > 99:1 were obtained for the Evans syn products with 2 equivalents of base and for the non-Evans syn when 1 equiv of base was employed. The thiazolidinethione auxiliaries are easily removed, and the aldol adducts can be readily transformed to various functional groups. Even direct reduction to the aldehyde with diisobutylaluminum hydride is possible.

Total synthesis of (+)-laurencin: an asymmetric alkylation-ring-closing metathesis approach to medium ring ethers.

[formula: see text] The enantioselective total synthesis of (+)-laurencin 1 is achieved in 18 steps from (S)-(+)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone. The key steps in this synthesis are an asymmetric glycolate alkylation leading to acyl oxazolidinone 2 and a subsequent ring-closing olefin metathesis to construct the oxocene core of 1. The approach to medium ring ethers utilized in this synthesis provides a general and efficient route to the cyclic core of other marine natural products.