Molybdenum-catalyzed asymmetric allylation of 3-alkyloxindoles: Application to the formal total synthesis of (-)-physostigmine

Article abstract of DOI:10.1021/ja060560j

The first example of Mo-catalyzed asymmetric allylation for the generation of quaternary stereocenters at a prochiral nucleophile is reported. A variety of 3-alkyl oxindoles can be alkylated with high yields and enantioselectivity. This method provides expedited access to (-)-physostigmine and its analogues. Copyright

Full text of DOI:10.1021/ja060560j

Published on Web 03/18/2006
Molybdenum-Catalyzed Asymmetric Allylation of 3-Alkyloxindoles:
Application to the Formal Total Synthesis of (-)-Physostigmine
Barry M. Trost* and Yong Zhang
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received January 24, 2006; E-mail: bmtrost@stanford.edu
Table 1. Selected Optimization Studies for Oxindole 4a
The 3,3′-dialkyl oxindoles are ubiquitous in nature and have been
shown to be valuable building blocks for alkaloid synthesis.1
However, only a few methods exist for the direct asymmetric
synthesis of such a structural motif due to the difficulty of
constructing all-carbon quaternary stereocenters.2 Recently, our
group has demonstrated the palladium-catalyzed asymmetric allylic
alkylation (AAA reaction) of prochiral nucleophiles to be an
effective strategy for the generation of quaternary stereocenters,
giving excellent yields and enantioselectivities for â-ketoesters,3a
ketones,3b-c and 3-aryl oxindoles.3d However, when the Pd-catalyzed
AAA reaction was applied to 3-alkyl oxindoles, only modest
enantioselectivity was obtained despite numerous optimizations.
Therefore, we turned our attention to the molybdenum-catalyzed
AAA reaction, which has been demonstrated to proceed with
excellent regio-, enantio, and diastereoselecivities when unsym-
metrical allyl carbonates were used as electrophiles.4 The mecha-
nism of the Mo-catalyzed AAA reaction involves nucleophiles
precoordinating to the metal followed by reductive elimination and
hence is distinctively different from that of the palladium process,
which proceeds via direct attack of the nucleophiles on the π-allyl
from the face opposite palladium.5 The intimate interaction between
the nucleophiles and the chiral metal catalyst in the molybdenum
system led us to postulate the possibility of reacting prochiral
nucleophiles with symmetrical allyl carbonate to generate quaternary
stereocenters. Herein, we report the first examples of molybdenum-
catalyzed enantioselective allylation of any prochiral nucleophiles
(eq 1) and the application of this method to the formal synthesis of
(-)-physostigmine and its analogues.6
entry
base
temperature
ee (%)b
yield (%)c
1
2
3
4
5
6
7
8
9
KHMDS
NaHMDS
LiHMDS
67 °C
67 °C
67 °C
67 °C
rt
rt
rt
rt
38
60
75-78
71
80
81
-
80-82
82
73
-
-
75-92
-
s-BuLi
LiHMDS
45(94)d
95
LiHMDS/LiOtBu
LiHMDS (2 equiv)
LiOtBu (2 equiv)
LiOtBu (2 equiv)
LiOtBu (2 equiv)
trace
95-98
95
4 °C
-10 °C
10
90
a Reaction performed with Mo(C7H8)(CO)3 (10% mol), ligand 2 (15%
mol), and oxindoles/allyl tert-butyl carbonate/base (1/1.2/1) at 0.1 M in
THF. b Determined by chiral HPLC. c Isolated yields of allylated oxindoles.
d Based on recovered starting material.
Figure 1. Model for enantiodiscrimination.
After establishing the optimized conditions, the scope and
limitation of the reaction was examined (Table 2). In nearly all
cases, excellent yields and good-to-excellent enantioselectivity were
obtained. Substitution on the oxindole ring does not affect the
reaction (entry 1). A large variety of functionalities at the three
positions of the oxindoles are tolerated. Increasing the size of the
3-alkyl group increased the ee (entries 2, 4, and 8, entries 14 and
16). However, increasing the size of the N-protecting group was
detrimental to the enantioselectivity (entries 2-3, 4-7, 8-9, and
14-16). This is not unexpected as the oxindole enolate is likely
coordinated to the bulky molybdenum catalyst during the reaction
and would try to minimize steric interactions by steering the large
substituent away from the catalyst. The alkylation reaction is also
highly chemoselective. No R-alkylation of a nitrile (entries 10 and
11) or N-alkylation of a Boc-protected aniline (entry 12) was
observed despite the fact that 2 equiv of base was used.
Optimization of the ligand, solvent, and base revealed that the
countercation of the base had the largest effect on the enantiose-
lectivity of the reaction (Table 1). Bases with lithium as counter-
cation provided the highest enantioselectivity (entries 3-9).
Addition of 1 equiv of LiOtBu and 1 equiv of LiHMDS (entry 6),
or simply 2 equiv of LiOtBu (entry 7), afforded the best conversion.7
Running the reaction at room temperature or 4 °C gave comparable
enantioselectivity and yields; lowering the termperature further
lowers the ee. Thus, the use of Mo(C7H8)(CO)3 (10% mol), ligand
2 (15% mol), and LiOtBu (2 equiv) in THF at room temperature
became our standard conditions for the synthesis of allylated 3-alkyl
oxindoles.
9
4590
J. AM. CHEM. SOC. 2006, 128, 4590-4591
10.1021/ja060560j CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Mo-catalyzed AAA for 3-Alkyl Oxindoles
powerful inhibitor of acetyl cholinesterase (eqs 2-3).
The oxindole 4 is readily available in two steps from 4-methoxy-
N-methylaniline and chloroacetone.8 Oxidation of allylated oxin-
doles (S)-5 (OsO4, NMO, then NaIO4) provided the aldehyde (S)-
24 in 92% yield. Two recrystalizations from isopropyl alcohol-
cyclohexane furnished enantiopure (S)-24 in 66% overall yield from
oxindole 5. Reductive cyclization of (S)-24 using conditions
optimized by Overman affored (-)-esermethole, which has been
transformed to (-)-physostigmine1b and (-)-phenserine9 in two
steps. Thus, our work constitutes a formal total synthesis of (-)-
physostigmine and (-)-phenserine, a clinically more promising
candidate, in seven total steps from commercially available starting
materials.
In summary, we have developed the first enantioselective Mo-
catalyzed AAA reaction for the generation of quaternary stereo-
centers at a prochiral nucleophile, in this case the 3-position of
3-alkyl oxindoles. The reaction is successful with a variety of alkyl
substitutions, and its utility can be seen in the synthesis of (-)-
physostigmine.
Acknowledgment. We thank the National Science Foundation
and National Institute of Health (NIH-13598), for their generous
support of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of California, San
Francisco, supported by the NIH Division of Research Resources
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org
References
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The absolute stereochemistry of 5 was established by oxidation
of the allyl group to its corresponding aldehyde (eq 2) and
comparison of its optical rotation with the known enantiomer.1b
The stereochemistry of the remaining examples are then assumed
by analogy. The selectivity is in agreement with the transition state
depicted in Figure 1. The facial approach in A is favored because
it lessens the steric congestion between the ligand and the enolate
of the oxindole as the C-terminus of the enolate moves toward the
π-allyl. In the alternative approach in B, the steric interaction
becomes more severe as the bulk of the oxindole is pushed toward
the ligand during the bond formation. One or more lithium cations
are likely also present to help organize and rigidify the chiral pocket
and hence enhance the enantioselectivity of the reaction.
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(7) We have previously observed that excess amount of base enhanced both
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The utility of the Mo-catalyzed AAA of 3-alkyl oxindoles is
demonstrated by a formal total synthesis of (-)-physostigmine, a
JA060560J
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