Asymmetric reactions induced by phase-tagged phosphoric acid organocatalysts and copper hydride-catalyzed reductions of unsaturatedthioesters

Abstract

Two syntheses of non-cross-linked polystyrene-supported TADDOL-based

phosphoric acid organocatalyst have been developed. The optimal polymer-supported

catalyst 2.29d exhibited comparable catalytic activity to its small molecule

counterpart in asymmetric Mannich-type reactions, and the syntheses of several chiral

β-amino esters were demonstrated using 2.29d as catalyst. However, when this

TADDOL-based phosphoric acid was immobilized on a polystyrene cross-linked with

1,4-bis(4-vinylphenoxy)butane, ie. JandaJelTM, the catalytic activity diminished in the

first recycling and reuse of the catalyst.

Building on the success of the immobilization of chiral phosphoric acid, a more

robust phase-tagged BINOL-based phosphoric acid organocatalyst was developed.

By taking advantage of a tetraarylphosphonium salt as a solubility-controlling group,

a widely-used BINOL-based phosphoric acid, TRIP (3.1), was introduced onto a

tetraphenylphosphonium salt to produce a phosphonium salt-tagged phosphoric acid

catalyst 3.3e. After systematic optimizations of reaction conditions, it was found that

the catalyst 3.3e with PF6

as counteranion exhibited the best performance in terms of

enantioselectivity. Catalyst 3.3e was proved to be highly effective in asymmetric

Friedel-Crafts reaction of indoles because it was shown to be recyclable and reusable

after six cycles without loss of catalytic activity.

Based on our previous studies on the reduction of unsaturated thioesters catalyzed

by (BDP)CuH, further investigation of ligand effects revealed that in addition to BDP,

dppf was also an effective ligand for the simple reduction of 5.8. In the

stoichiometric reduction of unsaturated thioester 5.8, dppe and dppf were both

efficient ligands for copper hydride that could convert 5.8 to aldehyde 5.18 in the

presence of TMSCl, without the formation of the undesired enol ester 5.17, which was

a major product when stoichiometric amounts of Stryker’s reagent was employed.

When 5.30 bearing both a saturated and unsaturated thioester was reduced under these

conditions, only the enethioate functional group underwent reaction to yield the

mono-reduced product 5.31 while the saturated thioester functional group remained

inert.

The desymmetrizing reductive aldol reactions of symmetrical keto-enethioates

6.19, 6.22, 6.24 and 6.26 catalyzed by in situ generated chiral copper hydride were

investigated. After a screening of the reaction conditions, TaniaPhos L8 was found to

be the most effective chiral ligand to achieve high ee and yields. Under the optimum

reaction condition (5 mol% Cu(OAc)-H2O and L8 with 2.0 eq. PhSiH3), a range of

keto-enethioates smoothly underwent desymmetrizing reductive aldol cyclizations,

offering bicyclic or polycyclic β-hydroxythioesters (6.28a-6.32a, 6.37a-6.47a) in 35-

84% yield and 30-97% ee with high diastereoselectivity. The addition of 5 mol% of

bipyridine as additive resulted in an accelerated reaction rate in all of the reductions of

keto-enethioates. The crystal structure of the L8-copper bromide complex allowed

the rationalization of the major enantiomer (eg. 6.48a), in which all of the substituents

are cis, to be a result of a reductively generated (Z)-thioester enolate reacting through

a Zimmerman-Traxler transition state.

This stereochemical outcome is in contrast to the reduction of the analogous

oxoesters, which yield trans β-hydroxyesters, (eg. 6.54b), as the major products.

Several proposals to explain the divergent stereochemistry, including the

predominance of a Zimmerman-Traxler transition state of (E)-enolates or subsequent

retroaldol rearrangements, were discussed. The retroaldol rearrangement has been

observed in the conversion of 6.48a to 6.57c, in which there was retention of the

configuration at C5 and a perfect conservation of enantiomeric purity.