Palladium-catalyzed enantioselective addition of two distinct nucleophiles across alkenes capable of quinone methide formation

Article abstract of DOI:10.1021/ja909030c

(Chemical Equation Presented) A sequential intramolecular-intermolecular enantioselective alkene difunctionalization reaction has been developed which is thought to proceed through Pd-catalyzed quinone methide formation. The synthesis of new chiral heterocyclic compounds with adjacent chiral centers is achieved in enantiomeric ratios up to 99:1 and diastereomeric ratios up to 10:1.

Full text of DOI:10.1021/ja909030c

Published on Web 11/10/2009
Palladium-Catalyzed Enantioselective Addition of Two Distinct Nucleophiles
across Alkenes Capable of Quinone Methide Formation
Katrina H. Jensen, Tejas P. Pathak, Yang Zhang, and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112
Received October 22, 2009; E-mail: sigman@chem.utah.edu
Scheme 1. Avoiding ꢀ-Hydride Elimination To Develop
The formation of two carbon-heteroatom bonds across an alkene
is a process which rapidly increases molecular complexity. The
osmium-catalyzed Sharpless dihydroxylation1 is the epitome of
enantioselective alkene difunctionalization, though recent research
has included other metal catalysts and expanded to the formation
of functional groups other than 1,2-diols.2 Currently, significant
focus has been on palladium catalysis, likely due to the efficiency
with which palladium activates olefins for nucleophilic attack.3
However, to achieve the second bond construction, ꢀ-hydride
elimination from a Pd-alkyl intermediate A, which leads to a
Wacker-type monofunctionalized alkene product 1,4 must be
prevented (Scheme 1). The alkene dialkoxylation reaction developed
in our laboratory is believed to accomplish this through the
formation of a quinone methide intermediate, which allows for
attack by a second equivalent of alcohol.5 Based on this mechanistic
proposal, we envisioned an alkene difunctionalization reaction
where a sequential intramolecular-intermolecular process would
allow for the selective formation of two distinct carbon-heteroatom
bonds by employing substrates which contain a nucleophile tethered
to the alkene (Scheme 1). We hypothesized initial intramolecular
nucleopalladation to form heterocyclic intermediate B. Subsequent
formation of a quinone methide intermediate C allows for attack
by an exogenous nucleophile to form the product and release Pd0,
which is reoxidized using molecular oxygen. Herein we report a
highly enantioselective addition of two distinct nucleophiles across
alkenes capable of quinone methide formation to access oxygen-
based heterocycles with contiguous chiral centers.
Pd-Catalyzed Alkene Difunctionalization Reactions
Table 1. Optimization of Reaction Conditions
In exploring the possibility of sequential intraintermolecular alkene
functionalization reactions, we examined 2 as a substrate6 with
methanol as the exogenous nucleophile. Under the standard conditions
for enantioselective intermolecular alkene dialkoxylation,5b using (S)-
iPrQuinox as the chiral ligand, a low yield of the desired product was
observed with promising enantioselectivity, but low diastereoselectivity
(Table 1, entry 1).7 Addition of a catalytic amount of base and removal
of molecular sieves led to modest improvements in product yield (entry
2). Reflecting on our intermolecular asymmetric dialkoxylation reac-
tion, where copper improved yield and chemoselectivity but was
removed to achieve high enantioselectivity, we revisited the use of
copper as an additive to improve the reaction.5b We hypothesized that
the reason for decreased enantioselectivity with increased copper
loading was that Cu sequesters the chiral ligand from Pd via ligand
substitution, resulting in an achiral palladium catalyst. Thus we added
20 mol % CuCl2 along with enough chiral ligand to coordinate both
metals (32 mol %). A significant improvement in yield was observed
without a detrimental effect on the enantiomeric ratio (entry 3). Based
on the accelerated rate of the reaction, we were able to decrease the
metal and ligand loadings (entry 4). To find conditions that would
allow for the use of nucleophiles other than methanol, other solvents
were evaluated. We were encouraged to find that both THF and toluene
led to increased enantioselectivity, albeit with a decrease in rate and
product yield (entries 5 and 6). A 1:1 mixture of THF/toluene was
also found to be a viable solvent system (entry 7). Improvements in
rate and yield were observed when using CuCl instead of CuCl2,
potentially due to a decrease in the [Cl-] or a change in oxidation
potential (entry 9).8
With these optimized conditions, the scope of the alkene
difunctionalization reaction was evaluated. In addition to methanol,
n-butanol can be used as an exogenous nucleophile (Table 2, 3b)
where the use of toluene as solvent was found to give slightly
improved yields.9 Alcohols containing a functional group are also
well tolerated, including 3-butenol, 2-methoxyethanol, and 2-chlo-
9
17074 J. AM. CHEM. SOC. 2009, 131, 17074–17075
10.1021/ja909030c  2009 American Chemical Society

C O M M U N I C A T I O N S
lectivity.12 This complexity generating reaction sets four contiguous
stereocenters and allows access to novel functionalized chroman
derivatives, an important pharmacophore.13
Table 2. Evaluation of Scope
In conclusion, we have developed a highly enantioselective Pd-
catalyzed alkene difunctionalization reaction involving the addition
of two distinct nucleophiles, a process which allows for the
formation of complex chiral molecules from relatively simple
starting materials. Future work will focus on expansion of the scope
to include other types of nucleophiles and Diels-Alder partners,
improvement of reaction conditions to reduce the required amount
of the second nucleophile, and development of a deeper understand-
ing of the mechanistic details of the reaction.
Acknowledgment. This work was supported by the National
Institutes of Health (NIGMS RO1 GM3540). Crystal structure
analysis was performed by Atta Arif. We thank Gary Keck and
Ryan Looper for insightful discussions.
Supporting Information Available: Experimental procedures and
full spectroscopic data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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