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This is the published version of a paper presented at Organikerdagarna, Kalmar, Sweden.
Citation for the original published paper:
Olofsson, B., Aggarwal, V. (2006)
Enantioselective alfa-Arylation of Ketones: Application to the Synthesis of (–)-Epibatidine.
In: Organikerdagarna, Kalmar, Sweden (pp. Le21, P47-).
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Enantioselective α-Arylation of Ketones:
Application to the Synthesis of (–)-Epibatidine
B. Olofssona and V. K. Aggarwalb
a
Organic Chemistry, Stockholm University, 106 91 Stockholm, SWEDEN. [email protected]
b
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK.
The enantioselective introduction of electrophiles α to carbonyl compounds occupies a central
position in asymmetric synthesis. Although asymmetric α−alkylations have been well
developed, high enantioselectivity in α-arylation of ketones has only been achieved in a limited
number of cases.
We have developed a direct arylation reaction of cyclohexanones, employing diaryl
iodonium(III) salts as electrophiles. The reaction was made enantioselective by the use of a
chiral base, resulting in 2,4-substituted cyclohexanones in high yields and with high
enantiomeric excesses and diastereoselectivities (Scheme 1).
1) 2 equiv
·HCl,
Ph
N
H
4 equiv BuLi, THF, -118 °C
O
O
Ph
Ph
2) Ph 2I+OTf-, DMF, -45 °C
up to
80% yield,
>20:1dr,
> 90% ee
R
R
Scheme 1. Asymmetric coupling with Simpkins’ base.
This methodology was applied in a short, enantioselective synthesis of (–)-Epibatidine, an
alkaloid recently isolated from the Ecuadorian poison frog Epipedobates tricolor. The
synthesis was accomplished in 6 steps and 31% overall yield, thus providing the shortest and
most efficient asymmetric route to this important compound to date (Scheme 2).
O
1) 2 equiv
Cl
N
H
Ph
Ph
·HCl,
O
N
4 equiv BuLi, THF, -118 °C
N
I+ Cl-
2)
N(Boc)2
Cl
H
N
2
, DMF, -45 °C
Cl
41%, dr >20:1, 94% ee
N(Boc)2
(-)-Epibatidine
Scheme 2. Synthesis (–)-Epibatidine.
V. K. Aggarwal and B. Olofsson, Angew. Chem. Int. Ed. 2005, 44, 5516-5519.