An organocatalytic asymmetric nazarov cyclization

Article abstract of DOI:10.1021/ja103028r

An organocatalytic asymmetric Nazarov cyclization of diketoesters that proceeds by means of a dual activation mechanism has been developed. Screening of a number of catalysts led to a new thiourea that incorporates a primary amino group. The method gives rise to cyclic products with two adjacent quaternary asymmetric carbon atoms, one of which is an all-carbon stereocenter, with complete or nearly complete diastereoselectivity and in high or very high enantiomeric excess. A brief and very convenient synthesis of the acyclic diketoester starting materials through nucleophilic addition to a ketene is also described.

Full text of DOI:10.1021/ja103028r

Published on Web 05/27/2010
An Organocatalytic Asymmetric Nazarov Cyclization
Ashok K. Basak,† Naoyuki Shimada,† William F. Bow,† David A. Vicic,† and Marcus A. Tius*,†,‡
Department of Chemistry, 2545 The Mall, UniVersity of Hawaii, Honolulu, Hawaii 96822, and The Cancer
Research Center of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii 96813
Received April 16, 2010; E-mail: tius@hawaii.edu
In earlier work, we described cyclizations of R-ketoenones under
a variety of mild reaction conditions. For example, ketoenone 1
can be converted to R-hydroxycyclopentenone 2 in 71% yield by
exposure to silica gel and triethylamine in the absence of solvent
at room temperature (eq 1).1 Alternatively, treatment of 1 with
Figure 1. Organocatalysts.
lithium tetramethylpiperidide or with Yb(OTf)3 and pyrrolidine
Scheme 1. Synthesis of Diketoesters and Cyclization
leads to 2 in 71 or 63% yield, respectively.2 There are earlier
examples of diketone cyclizations that lead to R-hydroxycyclopen-
tenones that may proceed through a similar mechanism. For
example, in 1975 Weinreb and Auerbach, inspired by an observation
published in 1965 by Muxfeldt and co-workers,3 described the
cyclization of diketone 3 to 4 under the influence of Mg(OMe)2
during their synthesis of cephalotaxine (eq 2).4,5 Both Muxfeldt
reaction was slow (7.5 d) and a catalytic cycle was not established,
presumably because of the exceptional stability of a covalent
and Weinreb described the cyclization as an intramolecular Michael
intermediate.
reaction of a chelated magnesium enolate. Moreover, both groups
Our strategy for overcoming this problem was the use of weaker
noted that the cyclization did not proceed in the absence of Lewis
noncovalent catalysts in combination with diketoesters, as shown
acidic metal species. Although we cannot rule out the intramolecular
in eq 4. During the course of our studies, we accumulated evidence
Michael addition, we have described our reactions as Nazarov
cyclizations6 for two reasons. First, the intramolecular Michael
addition is a forbidden 5-endo-trig process,7 and second, many of
our cyclizations are favored by enolate substitution, whereas steric
encumbrance of the nucleophile would be expected to inhibit a
Michael reaction.
A longstanding goal in our group has been to develop a useful
asymmetric organocatalytic Nazarov cyclization of R-ketoenones.8,9
Many Nazarov cyclizations require strongly acidic conditions, but
that more highly enolic diketones underwent cyclization with greater
facility. Moreover, enolic diketoesters are attractive substrates
the mild conditions for the cyclizations of 1 gave us reason to
because either the E or Z enol isomer can be formed selectively,11
believe that an organocatalytic process could be developed. Our
sparing us the labor of controlling the geometry of a tetrasubstituted
iminium ion-mediated Nazarov cyclization of R-ketoenones pro-
alkene. These substrates also have the potential to generate two
adjacent stereogenic carbon atoms diastereoselectively, one of which
is an all-carbon stereocenter. Our catalytic system was designed to
ceeded via exposure of 1 to a stoichiometric amount of diamine
triflate 5, giving (S)-2 in 60% yield and 97/3 er (eq 3).10 The
induce complementary polarization at the two terminal carbon
atoms,12 as indicated in 8 (eq 4); consequently, a bifunctional
organocatalyst combining Bronsted acidic and Lewis basic groups
was developed (see Figure 1).
It remained for us to develop the general and convenient
diketoester synthesis that is summarized in Scheme 1. Lithiated
cyanohydrin silyl ether13 14 was added to ketene 15, leading to
ketoester 16 in 65% yield. Exposure of 16 to CsF led to 17 in 88%
† University of Hawaii.
‡ Cancer Research Center of Hawaii.
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8266 J. AM. CHEM. SOC. 2010, 132, 8266–8267
10.1021/ja103028r  2010 American Chemical Society

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
of charge via the Internet at http://pubs.acs.org.
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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