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. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/174528 |
| Date | January 2011 |
| Creators | Ou, Jun, 欧军 |
| Contributors | Chiu, P |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47849708 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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