10784
J. Am. Chem. Soc. 2001, 123, 10784-10785
Table 1. Ligand Effect on Catalytic Enantioselective Reissert-Type
Reaction
Enantioselective Construction of Quaternary
Stereocenter through a Reissert-Type Reaction
Catalyzed by an Electronically Tuned Bifunctional
Catalyst: Efficient Synthesis of Various Biologically
Significant Compounds
entry
catalyst
time (h)
yield (%)b
ee (%)c
Ken Funabashi, Hassen Ratni, Motomu Kanai, and
Masakatsu Shibasaki*
1
2
3
4
5d
6
7
3 (X ) H)
4 (X ) F)
5 (X ) Cl)
6 (X ) Br)
6 (X ) Br)
7 (X ) I)
48
48
48
48
48
60
60
72
74
88
91
93
85
68
56
71
81
84
88
81
48
Graduate School of Pharmaceutical Sciences, The UniVersity
of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
ReceiVed August 25, 2001
8 (X ) CF3)
Catalytic enantioselective construction of chiral quaternary
stereocenters is a formidable challenge.1 For this type of reaction
to proceed successfully, catalysts must differentiate between the
subtle sterical differences of substituents on a pro-chiral carbon
that lacks the remarkably small hydrogen. In addition, catalysts
must activate substrates more strongly than in cases of chiral
tertiary stereocenter construction, due to higher steric repulsion
during bond-formation. Chiral quaternary centers are quite often
essential for the activity of biologically active natural products
and pharmaceuticals. Therefore, development of enantioselective
catalysts that can promote chiral fully substituted carbon formation
is extremely important. In this communication, we describe the
first example of a catalytic enantioselective Reissert-type reaction
in which chiral quaternary stereocenters can be constructed. This
new reaction was successfully applied to an efficient catalytic
enantioselective synthesis of several biologically significant
compounds (10-12), such as the potent anticonvulsant MK801
(dizocilpine, 10).2
a Y (counterion of aluminum) ) Cl. b Isolated yield. c Determined
by HPLC analysis. d Vinyl chloroformate (1.2 equiv) was used instead
of phenyl chloroformate.
The bifunctional catalyst was then electronically tuned to further
improve its efficiency. The Lewis acidity and/or Lewis basicity
were increased by substitution on the naphthyl or phenyl groups.
Although the catalyst containing a more electron-rich di-p-
methoxyphenylphosphine oxide gave poorer results (29% yield
and 40% ee), the strategy to increase the Lewis acidity by
introducing an electron-withdrawing group at the 6,6′-positions
of the BINOL (X) was successful. Thus, as shown in Table 1,
entries 2-4 and 6, catalysts derived from the 6,6′-dihalogen
substituted BINOL had improved activity and enantioselectivity.6
Among them, the 6,6′-dibromo-substituted catalyst 6 (Y ) Cl)
had the best results and the product was obtained in 91% yield
with 84% ee (entry 4). Use of vinyl chloroformate improved yield
(93%) and ee (88%) (entry 5).
These initial promising results led us to apply this reaction to
a catalytic enantioselective synthesis of a pharmaceutically
important agent, MK801 (10).7 MK801 is a very potent noncom-
petitive antagonist of the N-methyl-D-aspartate (NMDA) subclass
of receptors for the excitatory amino acid L-glutamate in brain
tissue, and might therefore be clinically useful as an anticonvulsant
and neuroprotective drug. The (5S,10R)-(+) isomer is seven times
more potent than the (5R,10S)-(-) isomer; however, there are
no reports of an enantioselective synthesis.8 We expected that
Reissert compound 2h would be directly converted to the 10,11-
dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine core structure of
MK801 by regioselective radical cyclization.
Thus, we attempted a Reissert-type reaction of 1-o-bromophe-
nylisoquinoline (1h) at -40 °C in the presence of 9 mol % of 6
(Y ) Cl), and product 2h was obtained in 53% yield with 73%
ee (Table 2, entry 1). To improve the yield and enantioselectivity,
we further increased the Lewis acidity of the catalyst by tuning
the counterion (Y) of the aluminum.9 As shown in Table 2, when
an aluminum triflate (Y ) OTf) was used as the Lewis acid,
product 2h was obtained in higher yield (63%) with 98% ee (entry
3). These improvements were not attributed to the formation of
We developed the first catalytic enantioselective Reissert-type
reaction with quinolines using a bifunctional catalyst (such as 3,
Y ) Cl), giving products containing chiral trisubstituted carbons.3
The quaternary stereocenter-constructing reaction did not proceed,
however, when the optimized reaction conditions (9 mol % of
catalyst, 1.1 equiv of 2-furoyl chloride as an acylating reagent,
and 2 equiv of TMSCN) were applied to 2-methylquinoline as a
substrate. On the other hand, the more reactive substrate,
1-methylisoquinoline (1a), gave the corresponding Reissert
product in 60% yield with 38% ee at -40 °C for 48 h.4
Preliminary screening of acylating reagents revealed that chlo-
roformates produced better chemical yields and enantioselectivity
than acid chlorides.5 Thus, PhOCOCl gave the corresponding
product from 1a in 72% yield with 56% ee at -60 °C (Table 1,
entry 1).
(5) Benzyl chloroformate and methyl chloroformate gave the corresponding
Reissert products at -40 °C in 57% yield with 52% ee and 64% yield with
48% ee, respectively.
(6) There was a good correlation between ee values and Hammet constants
for para substitutions: F (0.06), Cl (0.22), Br (0.23), I (0.18), CF3 (0.53) (Pine,
S. H.; Hendrickson, J. B.; Cram, D. J.; Hammond, G. S. Organic Chemistry,
4th ed.; McGraw-Hill: New York, 1980).
(7) For a review on target-oriented catalytic enantioselective reactions,
see: Hoveyda, A. H. In Stimulating Concepts in Chemistry; Vo¨gtle, F.,
Stoddart, J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, Germany, 2000;
p 145.
(8) Enantiomerically pure 10 was obtained by resolution. For racemic
synthesis of 10, see: (a) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1999,
64, 6515-6517. (b) Christy, M. E.; Anderson, P. S.; Britcher, S. F.; Colton,
C. D.; Evans, B. E.; Remy, D. C.; Engelhardt, E. L. J. Org. Chem. 1979, 44,
3117. (c) Evans, B. E.; Anderson, P. S.; Christy, M. E.; Colton, C. D.; Remy,
D. C.; Rittle, K. E.; Engelhardt, E. L. J. Org. Chem. 1979, 44, 3127.
(1) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(2) Thompson, W. J.; Anderson, P. S.; Britcher, S. F.; Lyle, T. A.; Thies,
J. E.; Magill, C. A.; Varga, S. L.; Schwering, J. E.; Lyle, P. A.; Christy, M.
E.; Evans, B. E.; Colton, D.; Holloway, M. K.; Springer, J. P.; Hirshfield, J.
M.; Ball, R. G.; Amato, J. S.; Larsen, R. D.; Wong, E. H. F.; Kemp, J. A.;
Tricklebank, M. D.; Singh, L.; Oles, R.; Priestly, T.; Marshall, G. R.; Knight,
A. R.; Middlemiss, D. N.; Woodruff, G. N.; Iversen, L. L. J. Med. Chem.
1990, 33, 789-808.
(3) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 6801-6808.
(4) For racemic Reissert-type reaction with 1-substituted isoquinolines,
see: Berg, M. A.; Gibson, H. W. J. Org. Chem. 1992, 57, 748-750.
10.1021/ja016935c CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001