The enantioselective Tsuji allylation

Article abstract of DOI:10.1021/ja044812x

The first catalytic enantioselective examples of the Tsuji allylation using enol carbonates and enol silanes are described. The products possess a quaternary stereogenic center and are useful building blocks for synthetic chemistry. Copyright

Full text of DOI:10.1021/ja044812x

Published on Web 10/28/2004
The Enantioselective Tsuji Allylation
Douglas C. Behenna and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received August 27, 2004; E-mail: stoltz@caltech.edu
Table 1. Ligand Screen
Palladium-catalyzed enantioselective allylation chemistry has
played a critical role in the evolution of asymmetric catalysis as a
field.1 Developments in the area of asymmetric C-C bond
formation by these methods over the past two decades by Trost,
Helmchen, Pfaltz, and others have been focused primarily on the
direct allylation of malonates by prochiral electrophiles.1 In general,
reactions involving prochiral nucleophiles are rare; however,
examples using activated dicarbonyl compounds2 and carbonyl
compounds that can only form a single enolate under the base-
mediated reaction conditions (e.g., tetralones) have recently been
reported.3 Due to these constraints, there are no enantioenriched
examples of even the simplest 2-methyl-2-allyl cyclohexanone (i.e.,
2) in the literature. In the course of a total synthesis investigation,
we became interested in such R-quaternary cycloalkanones and
initiated an effort to prepare them in a catalytic asymmetric fashion.4
Moreover, the potential broad utility of such chiral building blocks
warranted investigation. Herein, we present the first examples of
the asymmetric Tsuji allyl enol carbonate5 and silyl enol ether
allylations,6 which provide unprecedented access to these important
cyclohexanones in a highly enantioenriched form.
Of the numerous examples of palladium-catalyzed allylic alkyl-
ations, we became interested in the decarboxylative alkylation of
allyl enol carbonates to the corresponding R-allylcyclohexanone
derivatives described by Tsuji (i.e., 1 f 2, ligand ) PPh3).5 Despite
the power of this reaction to build quaternary carbon centers under
essentially neutral conditions, it has seen limited use in the 20 years
since its discovery.4,7 Our analysis revealed the Tsuji allylation to
be an ideal reaction for the synthesis of asymmetric R-quaternary
cycloalkanones because the selective formation of the enol carbonate
moiety provides position control of the enolate and, thereby, the
product.5b,8 Therefore, we initiated an effort to promote the asym-
metric Tsuji allylation of enol carbonate 1 under palladium catalysis.
We examined the transformation of enol carbonate 1 to allyl
ketone 2 using a variety of chiral ligands (12.5 mol %) and
Pd2(dba)3 (5 mol %) in THF at 25 °C.9 As shown in Table 1,
palladium catalysts derived from C2-symmetric (bis)phosphines (i.e.,
3-6) and mixed P/O ligands (e.g., 7) displayed good reactivity
but produced ketone 2 in low to modest enantiopurity (entries 1-5).
Interestingly, mixed P/N-type ligands were more effective at
inducing asymmetry (entries 6-10).10 In particular, the phosphino-
oxazolines (PHOX) 9-1211 induced high degrees of enantioselec-
tivity and reactivity in the allylation (entries 7-10). In the ideal
case, the use of the (S)-t-Bu-PHOX ligand 12 provided cyclohex-
anone (S)-212 in 96% yield and 88% ee (entry 10). As a final
refinement, reactions could be performed reliably using 6.25 mol
% ligand 12 and 2.5 mol % Pd2(dba)3 (Table 2).
a GC yield relative to an internal standard (tridecane). b Enantiomeric
excess measured by chiral GC (ref 14). c (R)-2 produced as the major product
(ref 12).
be substituted (entries 9 and 10) and unsaturated (entries 11-13)
in various ways. Gratifyingly, the allylation can be applied to seven-
and eight-membered rings (entries 14 and 15) in addition to
cyclohexanones.13 We have also demonstrated that 2 can be obtained
in near enantiopurity (96% ee) after a single crystallization of the
corresponding semicarbazone (entry 2).14 Importantly, all of the
products displayed in Table 2 possess a catalytically generated
asymmetric quaternary carbon center and, with the exception of
the tetralone examples (entries 12 and 13), were previously un-
known as enantioenriched entities, despite their apparent simplicity.
Having successfully prepared a range of R-quaternary cyclo-
alkanones in high enantiomeric purity via the corresponding enol
carbonates, we investigated the possibility of using simple enol
ethers as the nucleophilic component (Table 3).6 To our delight, a
range of tetrasubstituted trimethylsilyl enol ethers underwent smooth
R-allylation using commercially available diallyl carbonates as elec-
trophiles. Again, we observed high yields and enantioselectivities
for the production of an array of R-quaternary cycloalkanones using
the Pd2(dba)3/12-derived catalyst and a substoichiometric amount
of Bu4NPh3SiF2 (TBAT) to serve as an initiator. The allylation of
silyl enol ethers complements the enol carbonate chemistry as the
preparation of the former is often more convenient.14
We applied these optimized conditions to the allyl enol carbon-
ates of a variety of substituted cyclic ketones (Table 2). The
asymmetric allylic alkylation tolerates a range of substitution at
the 2-position of the cyclohexenyl portion of the enol carbonate
(entries 1-7). Additionally, a 2-methallylated product can be
generated from the corresponding 2′-methyl allyl carbonate (entry
8). Furthermore, the ring portion of the cyclic enol carbonate can
To display the utility of these R-quaternary cyclic ketones, we
carried out a number of straightforward synthetic transformations
on the parent 2-allyl-2-methyl cyclohexanone (Scheme 1). Namely,
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J. AM. CHEM. SOC. 2004, 126, 15044-15045
10.1021/ja044812x CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Tsuji Enol Carbonate Allylationa
Scheme 1 a
a From ref 14.
in high enantiopurity and excellent chemical yield. Investigation
of this chemistry in other settings is currently being explored.
Acknowledgment. The authors are grateful to the Fannie and
John Hertz Foundation (predoctoral fellowship to D.C.B.), Caltech,
the A. P. Sloan Foundation, and Research Corporation for financial
support, and E. Kwei for experimental assistance.
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: New York, 2000; pp 593-649. (b) Pfaltz, A.;
Lautens, M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 2, pp
833-884. (c) Helmchen, G. J. Organomet. Chem. 1999, 576, 203-214.
(d) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1-14. (e) Trost, B. M.;
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C.; Chen, I.; Schroeder, G. M. J. Am. Chem. Soc. 2004, 126, 4480-4481.
(4) For recent reviews on the catalytic enantioselective generation of
quaternary stereocenters, see: (a) Douglas, C. J.; Overman, L. E. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5363-5367. (b) Christoffers, J.; Mann,
A. Angew. Chem., Int. Ed. 2001, 40, 4591-4597. (c) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388-401.
(5) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140-145. (b) Tsuji, J.;
Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793-1796. (c) Tsuji,
J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J. Org.
Chem. 1985, 50, 1523-1529.
a Reactions were performed using 1.0 mmol of substrate in THF (0.033
M in substrate) at 25 °C, with Pd2(dba)3 (2.5 mol %) and 12 (6.25 mol %),
unless stated otherwise. b Isolated yields. c Measured by chiral GC or HPLC
(ref 14). d Performed on a 5.1 mmol scale. e In parentheses, is the % ee
after one recrystallization of the corresponding semicarbazone (ref 14).
f Reaction performed at 12 °C (GC yield). g Performed with 5 mol %
Pd2(dba)3 and 12.5 mol % 12. h Isolated yield after conversion to the corre-
sponding diketone via Wacker oxidation (ref 14). i Performed at 10 °C.
Table 3. Enantioselective Tsuji Enol Silane Allylationa
(6) Tsuji, J.; Minami, I.; Shimizu, I. Chem. Lett. 1983, 12, 1325-1326.
(7) For examples of Tsuji enol carbonate allylations in synthesis, see: (a)
Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755-767. (b) Nicolaou,
K. C.; Vassilikogiannakis, G.; Ma¨gerlein, W.; Kranich, R. Angew. Chem.,
Int. Ed. 2001, 40, 2482-2486. (c) Herrinton, P. M.; Klotz, K. L.; Hartley,
W. M. J. Org. Chem. 1993, 58, 678-682.
(8) Such enolate position control has not been achieved using direct in situ
protocols.1-3 Interestingly, the almost-exclusive existence of direct allyl-
ations contrasts developments in the area of asymmetric aldol chemistry,
where enolate preactivation is usually required and, until recently, direct
reactions were the exception.
(9) In addition to THF, a range of solvents, including dioxane,5,6 PhH, PhCH3,
Et2O, tert-butyl methyl ether, diisopropyl ether, and EtOAc could be used
in the tranformation with little change in reactivity and selectivity.
(10) For a recent review of chiral mixed P/N ligands for asymmetric catalysis,
see: Guiry, P. J.; Saunders, C. P. AdV. Synth. Catal. 2004, 346, 497-
537.
a Reactions were performed using 1.0 mmol of substrate in THF (0.033
M in substrate) at 25 °C, with Pd2(dba)3 (2.5 mol %), 12 (6.25 mol %),
diallyl carbonate (1.05 equiv), and TBAT (35 mol %), unless stated
otherwise. b Isolated yields. c Measured by chiral GC or HPLC (ref 14).
d Reaction performed with dimethallyl carbonate (1.05 equiv).
(11) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345. (b)
Williams, J. M. J. Synlett 1996, 705-710 and references therein.
(12) The absolute configuration of (S)-2 has been established by X-ray analysis
of the derived crystalline (isopinocampheylamine) semicarbazone.14 The
absolute stereochemistry of the product in Table 2, entry 12, is known.3
The absolute configuration shown for all other compounds is by analogy
to these examples.
(13) Application of this methodology to cyclopentanone derivatives has, to
date, resulted in modest enantioselectivities.
(14) See Supporting Information for details.
ketone (S)-2 (98% ee) was converted to products 13-16 by standard
methods.14 These representative transformations illustrate the
potential versatility and importance of allyl cycloalkanones as chiral
building blocks in synthesis.
In summary, we have developed the first catalytic enantioselec-
tive Tsuji allylations of simple alkanone derivatives. These mild,
operationally straightforward, and stereoselective reactions produce
chiral cycloalkanones with quaternary stereocenters at the R-position
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