C O M M U N I C A T I O N S
transmitted to the developing C-C bond that is remote from the
stereogenic carbon atoms of the catalyst. Since asymmetric induc-
tion in 18 requires the imposition of helicity in 17, it is plausible
that coordination with the catalyst results in torsion of the C3-C4
bond. The other elements of novelty in this work are the synthesis
of the starting materials and the discovery of an unusual organo-
catalytic process that generates two adjacent stereogenic carbon
atoms, one of which is an all-carbon stereocenter.18 The acyclic
substrates will likely prove to be versatile starting materials for
several other variants of the Nazarov cyclization. We will explore
these and also address the problem of product inhibition.
Acknowledgment. Generous support by the National Institutes
of Health (GM57873) is acknowledged.
Supporting Information Available: Detailed experimental and
spectroscopic data and reproductions of 1H and 13C NMR data for
18-30 and the intermediates leading to them; X-ray data for the (-)-
camphanic acid derivative of 19 (CIF). This material is available free
Figure 2. Examples of the organocatalytic cyclization.
yield. The ketene was formed conventionally by treating the
malonate monoacid chloride with Hu¨nig’s base in ether at -78
°C.14 The commercial availability of several chiral thiourea catalysts
allowed us to provide a proof of principle quickly.15,16 Exposure
of 17 to 20 mol % thiourea 9 led to the desired product 18 in 68/
32 er. However, catalyst 10, which lacks a basic amino group, was
completely ineffective and did not lead to cyclization of 17.
Addition of 0.2 equiv of Hu¨nig’s base to the reaction mixture of
17 and 10 induced catalytic activity and led to 18 in 70/30 er. In
all cases, the relative stereochemistry indicated a conrotatory process
that had taken place from the E enol of 17. The absolute
stereochemistry was assigned on the basis of X-ray crystallographic
analysis. These data provide strong support for the dual activation
mechanism that is implicit in 8 (eq 4) and are consistent with the
observations of both Muxfeldt and Weinreb mentioned above that
also suggest dual activation.
A fairly extensive screening of bifunctional catalysts led to our
choice of 11. A few trends revealed themselves during this work.
For example, catalyst 12 bearing a tertiary amino group led to 18
in only 56/44 er, whereas 13 bearing a secondary amine led to
product in 74/26 er. The optimal catalyst 11 led to 18 in 90.5/9.5
er (67%, 14 d). Since the cyclization of 17 to 18 could be induced
by base alone, the cooperative mechanism may be suppressed with
more hindered amines.
A number of examples of the cyclization of diketoesters under
the optimized conditions (20 mol % 11, 0.1 M in toluene, 23 °C)
are summarized in Figure 2. Reaction yields were generally good
(58-95%), and er’s were good to excellent (90/10 to 98.5/1.5).
The reactions were slow, requiring between 4 and 21 days for
completion. This may reflect product inhibition, since the product
is likely to engage the catalyst in a similar way as the enol form of
the acyclic starting material. Support for this hypothesis was
provided by 7 (Ar ) R1 ) R2 ) Ph, R3 ) Et; 87%, 75/25 er, 2
days), which precipitated from the reaction mixture and was formed
in the fastest reaction of the ones examined. In only four examples
(7, 21, 25, 29) were we able to detect the diastereomeric cyclo-
pentenone product derived from the Z enol (∼5% yield). In the
absence of a C6 aryl group, cyclization was extremely slow. The
cyclization requires an aryl group at C6 but tolerates alkyl or phenyl
groups at C2.17
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If the mechanistic hypothesis implicit in eq 4 is valid, it raises
the interesting question of how stereochemical information is
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