A Rational Approach to Catalytic Enantioselective Enolate Alkylation Using a Structurally Rigidified and Defined Chiral Quaternary Ammonium Salt under Phase Transfer Conditions

Full text of DOI:10.1021/ja973174y

12414
J. Am. Chem. Soc. 1997, 119, 12414-12415
A Rational Approach to Catalytic Enantioselective
Enolate Alkylation Using a Structurally Rigidified
and Defined Chiral Quaternary Ammonium Salt
under Phase Transfer Conditions
E. J. Corey,* Feng Xu, and Mark C. Noe
Department of Chemistry and Chemical Biology
HarVard UniVersity
Cambridge, Massachusetts, 02138
Figure 1. ORTEP structure of O(9)-allyl-N-(9-anthracenylmethyl)-
cinchonidinium bromide (1) (left).
ReceiVed September 10, 1997
Ion-pair-mediated reactions under phase transfer conditions
(
phase transfer catalysis, PTC) have been increasingly useful
1
in organic synthesis since their introduction. However, there
have been no successful applications to catalytic asymmetric
synthesis,1 except for a few involving the use of cinchona-
alkaloid-derived quaternary ammonium salts. The most out-
standing of these is the methylation of 6,7-dichloro-5-methoxy-
d
2
-phenyl-1-indanone using N-(p-trifluoromethyl)benzylcin-
choninium bromide sodium hydroxide complex under PTC to
form (S)-R-methylated indanone in 92% enantiomeric excess
2
(
ee). Noteworthy, but more modest enantioselectivities have
been reported for the alkylation of tert-butyl glycinate-
benzophenone Schiff base (range of 5:1-2.5:1) using the
3
N-benzylcinchoninium ion-sodium hydroxide PTC system.
The reasons for the enantioselective bias in these cases have
been unclear. In this paper, we present the initial results of a
research program aimed at the determination of the mechanistic
and geometrical factors responsible for enantioselectivity in PTC
and the rational design of highly effective new phase transfer
catalysts based on the cinchona alkaloid system. We have
focused on the development of catalytic asymmetric alkylation
at carbon because this is one of the most urgently needed
synthetic methods.
Figure 2. ORTEP structure of O(9)-allyl-N-(9-anthracenylmethyl)-
cinchonidinium p-nitrophenoxide (2).
to a quaternary ammonium structure of well-defined geometry
+
Our approach may be summarized simply. If the bridgehead
nitrogen of a cinchona alkaloid quaternary salt is taken to be at
the center of a tetrahedron, the phase transfer catalyst should
be structured so as to provide steric screening which prevents
close approach of the counterion to three of the faces of this
tetrahedron, while the fourth face should be sufficiently open
in which a second tetrahedral face about N is blocked by the
9-anthracenyl subunit, whose spatial position is fixed for steric
4
f
reasons. Further, it was apparent that a third tetrahedral face
+
about N could be effectively screened simply by the attachment
of an allyl or benzyl group to the secondary hydroxyl group;
indeed, such ethers had already been studied in PTC reactions.3b
O(9)-Allyl-N-(9-anthracenylmethyl)cinchonidinium bromide
+
to allow close contact between the substrate counterion and N .
There should also be a nearby binding surface for attractive
van der Waals interaction. Quaternary ammonium salts of
cinchona alkaloids are ideal because one of the tetrahedron faces
about the charged bridged nitrogen is totally blocked by the
(
1) was prepared in two steps from cinchonidine and subjected
to single-crystal X-ray diffraction analysis which revealed the
structure shown in Figure 1. As expected, the substituents
about the N -CH2 anth bond were staggered with the 9-anth
carbon (C(21) in Figure 1) antiperiplanar to C(11), and the Br
counterion was positioned in close contact with N(1) at the open
tetrahedral face (backside to C(16)) with a Br-N(1) distance
of 4.06 Å. Essentially the same structural arrangement was
determined for the chloride corresponding to 1 by X-ray
diffraction. Crystals of O(9)-allyl-N-(9-anthracenylmethyl)-
cinchonidinium p-nitrophenoxide (2) were also prepared and
subjected to X-ray crystallographic analysis, which revealed the
6
4f
+
4
ring system itself. In addition, recent studies have elucidated
-
the fundamental reasons for enantioselectivity in the bis-
cinchona-alkaloid-catalyzed dihydroxylation of olefins by OsO4.
Especially relevant was the finding that the attachment of the
9-anthracenylmethyl (anth) group to a bridgehead nitrogen leads
(
1) Makosza, M.; Ludwikow, M. Rocz. Chem. 1965, 39, 1223. (b)
Makosza, M.; Serafinowa, B. Rocz. Chem. 1965, 39, 1401, 1595, 1647,
799, 1805. (c) Makosza, M. Pure Appl. Chem. 1975, 43, 439. (d) Dehmlow,
1
E. V.; Dehmlow, S. S. Phase Transfer Catalysis, 3rd ed.; VCH: Weinheim,
7
analogous structure shown in Figure 2. In this case the negative
oxygen of the aryloxide counterion is also in close contact (3.46
1
993.
(
2) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
1
984, 106, 446. (b) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.;
Schoenewaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745.
(5) Quaternary bromide 1 was prepared in 94% yield by the following
sequence: (1) reaction of cinchonidine with 9-(chloromethyl)anthracene
in toluene at reflux for 2 h and (2) O-allylation of the resulting quaternary
salt with allyl bromide in a CH2Cl2-50% aqueous KOH mixture at 23 °C
for 4 h to form 1, mp 194-196 °C, [R] D -320 (c 0.45, CHCl3).
(6) (a) Crystal structure data for 1: C39H48BrN2O2, orthorhombic,
P212121, a ) 12.0138(3) Å, b ) 14.8225(2) Å; c ) 20.0482(4) Å; R ) â
) γ ) 90°, Z ) 4, R1(I > 2σI) ) 0.0668. (b) Detailed X-ray crystallographic
data are available from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, U.K.
(7) Salt 2 was prepared by reaction of 1 with potassium p-nitrophenoxide
in CH3OH and recrystallized from CH2Cl2-hexane (vapor diffusion). Crystal
structure data for 2‚2CH2Cl2: C45H45Cl4N3O4, orthorhombic, P212121, a
) 9.2400(6) Å, b ) 18.987(1) Å; c ) 23.257(2) Å; R ) â ) γ ) 90°, Z
) 4, R1(I > 2σI) ) 0.0540.
(3) (a) O’Donnell, M. J.; Benett, W. D.; Wu, S. J. Am. Chem. Soc. 1989,
1
11, 2353. (b) O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994,
0, 4507. (c) Lipkowitz, K. B.; Cavanaugh, M. W.; Baker, B.; O’Donnell,
5
23
M. J. J. Org. Chem. 1991, 56, 5181. (d) O’Donnell, M. J. et al. U.S. Patent
5
,554, 753, September 10, 1996. (e) O’Donnell, M. J.; Esikova, I. A.; Mi.
A.; Shullenberger, D. F.; Wu, S. In Phase-Transfer Catalysis; Halpern, M.
E., Ed.; ACS Symposium Series 659; American Chemical Society:
Washington, DC, 1997; Chapter 10.
(
4) (a) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038.
(
b) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115, 12579. (c) Corey,
E. J.; Noe, M. C.; Sarshar, S. Tetrahedron Lett. 1994, 35, 2861. (d) Corey,
E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319. (e) Corey, E. J.; Noe,
M. C.; Sarshar, S. J. Am. Chem. Soc. 1993, 115, 3828. (f) Corey, E. J.;
Noe, M. C.; Ting, A. Tetrahedron Lett. 1996, 37, 1735.
S0002-7863(97)03174-0 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 50, 1997 12415
Table 1. Enantioselective Catalytic Phase Transfer Alkylation
Figure 3. Stereopair representation of the preferred three-dimensional
arrangement of the ion pair from 1 and the enolate 3. Alkylation of the
enolate occurs by attack of the electrophile at si (front) face of the
enolate for steric reasons, leading to the enantiomeric products shown
in Table 1.
proceed via a highly organized transition state.8 This process
9
is very practical (especially for nonnatural amino acids) since
the chiral PTC catalyst is efficently extracted from aqueous
1
0
solution for reuse.
Taking into account all of the above results, including the
X-ray crystal data for 1 and 2, the transition-state assembly
shown in Figure 3 follows as most likely (the electrophile has
been omitted for clarity). We regard these exothermic alkyla-
tions as proceeding via an early transition state with the major
reaction channel being through the most stable geometry of the
tight ion pair of cation 1 and enolate 3, as shown in Figure 3,
and with approach of the electrophile to the si (front) face of
the ion-paired enolate. The reasons why the three-dimensional
arrangement of the ion pair shown in Figure 3 is favored include
the following: (1) the fixed orientation of the bulky N-9-
anthracenylmethyl substituent in 1 provides steric screening and
also rigidifies the cation so that there is a minimum entropic
cost in forming the intimate, highly structured ion pair shown
in Figure 3; (2) as indicated in the Introduction, direction-
specific ion pairing occurs so as to bring into proximity the
enolate oxygen with the sterically least encumbered face of the
+
bridgehead N ; and (3) complementary surfaces of the gege-
nions are brought together for maximum van der Waals
attraction. Extensive search for alternative ion-pairing geom-
etries, with the same arrangement of O and N as shown in
Figure 3, that would lead to the enantiomeric (R) alkylation
products has revealed no structures with van der Waals contacts
comparable to those shown in Figure 3.
We believe that the ideas expressed herein provide a useful
new paradigm for enantioselective catalysis using ordered
contact ion pairing. They are easily testable and provide clear
guidance for the design of still more effective catalysts.
Å) with that same tetrahedral face of N(1) (backside to C(16)).
These X-ray structures provide experimental evidence that the
tetrahedral face of N in these salts which is least subject to
-
+
+
steric shielding is the one that contacts the counteranion; this
face is backside to the unsubstituted two-carbon (CH2-CH2)
bridge of the quinuclidinium subunit of 1. If enolate ions pair
selectively and intimately with the cation 1 in the same way as
p-nitrophenoxide, this preferred arrangement coupled with the
expected rigidity of the cation and the effects of van der Waals
contacts could lead to enantioselective alkylation by a carbon
electrophile. This prediction has been confirmed in gratifying
fashion by the results which are summarized below.
Acknowledgment. This paper is dedicated to the memory of
Wolfgang von Oppolzer. We are grateful to the National Institutes of
Health and the National Science Foundation for financial support and
to Dr. Florian K u¨ hnle for the X-ray crystallographic data.
We chose for initial investigations the alkylation of the enolate
derived from tert-butyl glycinate-benzophenone Schiff base (3)
since this substrate had been thoroughly studied in the pioneering
Supporting Information Available: Experimental procedures,
spectroscopic data for synthetic intermediates, and detailed X-ray
crystallographic data for 1 and 2 (25 pages). See any current masthead
page for ordering and Internet access information.
3
research of O’Donnell et al., which demonstrated an enanti-
oselectivity base line of 5:1 to 2.5:1. We used solid cesium
hydroxide monohydrate as the basic phase in order to minimize
the possibility of water in the organic phase (CH2Cl2) and to
JA973174Y
(8) Somewhat lower enantioselectivities (average 20:1) were observed
using 50% aqueous KOH at -20 °C instead of the CsOH‚H2O system as
in Table 1. Also, lower enantioselectivities resulted when the methyl or
ethyl ester of the glycine-benzophenone Schiff base was used as the
substrate for alkylation.
allow the use of lower temperatures (-60 to -78 °C) than are
possible with 50% aqueous KOH or NaOH.2
,3
Table 1
summarizes the results obtained for the alkylation of 3 with a
wide variety of carbon halides (RBr or RI) using 10 mol % of
catalyst 1 and CsOH‚H2O as base in CH2Cl2 at -60 to -78
(
9) The amino acid derivatives produced from entries 10 and 11 in Table
1
are valuable building blocks for the synthesis of the potent antitumor
agent ecteinascidin 743, see: Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am.
Chem. Soc. 1996, 118, 9202.
°
C. Extremely high enantioselectivities, as high as 400:1 and
(10) Extensions of this research to highly enantioselective Michael
averaging 65:1, were observed for the products (4), an indication
that catalyst 1 is indeed very effective and that these reactions
addition and ring-forming double-alkylation reactions will be described in
a separate publication.