Friday, January 30, 2009

The Hydrolytic Kinetic Resolution – Jacobsen’s Catalyst

An Introduction

Enantiomerically pure epoxides are extremely valuable
chemical compounds due to controllable but high reactivity of
epoxides coupled with the vast array of reactions they can
undergo with retention of stereochemical integrity. One can
envision a number of direct routes to asymmetric epoxides
(Figure 1). Asymmetric carbene addition has never achieved
broad applicability due to both the instability of the carbenes,
low yields and low enantioselectivities. The most common
methods for epoxide formation is controlled addition of
activated oxygen to an alkene. For some olefins, this process
can be made enantioselective, an achievement for which K.
Barry Sharpless was awarded 1/2 of the Nobel prize in 2001.
The Sharpless asymmetric epoxidation is restricted to internal
olefins with pendent functionality such as an alcohol which
helps direct the reaction. In 1990, Jacobsen, fresh of a postdoc with Sharpless and at the beginning of his
independent career at UIUC, introduced a system which obviated the use of a directing group, but the
enantioselctivies were not phenomenal and yields were not spectacular. Furthermore, terminal olefins were still
difficult. Simultaneously and independently, Katsuki (a Sharpless postdoc from ten years prior) revealed a
closely related system which suffered the same drawbacks.
In the mid 1990’s, having moved to Harvard, Jacobsen
was exploring the use of a variety of metal catalysts all based
around a chiral “salen” ligand scaffold (Figure 2). The first
breakthrough came with the desymmetrization of meso
epoxides with Me3SiN3 catalyzed by a complex where M =
CrCl (Figure 3). While it is generally easily controlled on the
laboratory scale, the potentially explosive nature of Me3SiN3
makes it a poor choice for industrial processes. Furthermore, the resolution of terminal epoxides remained
elusive. Thus the search of a better both a better catalyst and a better nucleophile continued. The hydrolytic
kinetic resolution (Figure 3) was discovered due to a fortunate accident. Jacobsen had been working with a
reduced for of a chromium-salen complex. Surprisingly, 1,2-epoxyhexane (Figure 3, R = n-Bu) proved to be an
extraordinarily good substrate. Furthermore, the
solid residue isolated from the end of reactions
with that substrate worked extraordinarily well to
resolve others! Careful investigation led to the
discovery that acetic acid, left from the industrial
synthesis of epoxyhexane, had served to catalyze
the air-oxidation of the metal, increasing the activity of the catalyst. At long last, enantiomerically pure terminal
epoxides were readily available through a simple two step process – epoxidation of a terminal olefin and
selective hydrolysis of one enantiomer of the resulting epoxide. This was an event dramatic enough to warrant
publication in Science, an extreme rarity for a synthetic methodology.
Jacobsen has proceeded to exploit this ligand framework, and some variations on it, to enantioselectively
catalyze a broad range of reactions including an array of nucleophilic epoxide opening reactions,
hydrocyanation of aldehydes and imines, conjugate addition of HCN, aldol variations and Diels-Alder
variations, to name a few. In fact, the ligand shown in Figure 2 has become known simply as “Jacobsen’s
ligand”. The technologies developed in Jacobsen’s lab have been commercialized by Rhodia ChiRex, a joint
venture between Jacobsen and global chemical giant Rhodia. The catalysts have been used in many
pharmaceutical syntheses and, it sometimes seems, by nearly every synthetic organic chemist alive. Other
researchers too numerous to name have also used these ligands and catalysts in developing other reactions too
numerous to count. Truly it is a phenomenal impact for an accidental discovery barely a decade old.



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