Enantioselective synthesis of D-threo-methylphenidate [8]

Full text of DOI:10.1021/ja991466o

J. Am. Chem. Soc. 1999, 121, 6511-6512
6511
Scheme 1
Enantioselective Synthesis of
D-threo-Methylphenidate
Jeffrey M. Axten, Robert Ivy, Lori Krim, and
Jeffrey D. Winkler*
Department of Chemistry
The UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
Table 1
ReceiVed May 4, 1999
Methylphenidate (Ritalin) is the most commonly prescribed
psychotropic medication for children in the United States.1 It is
currently marketed as a racemate, although the D-threo isomer is
ca. 13 times more active than its mirror image.2 Various strategies
for the preparation of the more active isomer of methylphenidate
have been examined, including resolution3 and synthesis from
scalemic precursors.4 We report herein that the rhodium-mediated
C-H insertion reaction of methyl phenyldiazoacetate 1 with
N-Boc-piperidine 2 (R ) N-Boc) leads to a remarkably efficient
and highly stereoselective process for the formation of the
bioactive isomer of methylphenidate 3 (Scheme 1).5,6
The pioneering work of Doyle has established that scalemic
ligands on rhodium can lead to high levels of enantioselectivity
in the C-H insertion reaction.5,7 While the intramolecular C-H
insertion pathway in our recently disclosed diastereoselective
synthesis of methylphenidate8 was not sensitive to metal catalysis,9
we are delighted to report that the intermolecular C-H insertion
reaction proceeds in the presence of the Doyle catalyst Rh2(5R-
10
MEPY)4 with exceedingly high levels of stereochemical con-
trol.11 Reaction of methyl phenyldiazoacetate 112 with N-Boc-
piperidine 213 (R ) N-Boc) in the presence of 1 mol % of
Rh2(5R-MEPY)4 leads to the selective formation of D-threo-
methylphenidate in 94% de and 69% ee.14 Two recrystallizations
of the crude product from ethanol/diethyl ether gave D-threo-
methylphenidate in 95% de and >95% ee.
a The initially observed 69% ee was increased to >95% by two
(1) Volkow, N.; Ding, Y.; Fowler, J.; Wang, O.; Logan, J.; Gatley, J.;
Dewey, S.; Ashby, C.; Libermann, J.; Hitzemann, R.; Wolf, A. Arch. Gen.
Psychiatry 1995, 52, 456.
(2) Schweri, M.; Skolnick, P.; Rafferty, M.; Rice, K.; Janowsky, A.; Paul,
S. J. Neurochem. 1985, 45, 1062.
recrystallizations from 1:1 v/v diethyl ether/ethanol.
The effect of varying both the catalyst employed and the
protecting group on the piperidine nitrogen on the stereochemical
outcome of the C-H insertion reaction was next examined, and
our results are summarized in Table 1. Both the Rh2(IBAZ)4 515
and the Rh2(MPPIM)4 616 catalysts led to attenuated diastereo-
and enantioselectivities. Similarly, the McKervey proline sul-
fonamide catalyst 717 gave only modest diastereoselectivity and
enantioselectivity. Finally, the Jacobsen catalyst 8, which has
recently been reported to effect highly enantioselective Si-H
insertion,18 led to only modest stereoselection in this reaction.
The stereoselective formation of the D-threo stereoisomer of
methylphenidate 3 with Rh2(5R-MEPY)4 4 can be rationalized
as shown in Figure 1. The carbene can coordinate to the rhodium
(3) (a) Prashad, M.; Har, D.; Ropic, O.; Blacklock, T. J.; Giannousis, P.
Tetrahedron: Asymmetry 1998, 9, 2133. (b) Faulconbridge, S.; Zavareh, H.;
Evans, G.; Langston, M. PCT Int. Appl. Chem. Abstr. 1998, 129, 67705. (c)
Langston, M.; Zavareh, H. PCT Int. Appl. Chem. Abstr. 1997, 127, 205477.
(d) Zavareh, H. PCT Int. Appl. Chem. Abstr. 1997, 127, 278144.
(4) (a) Thai, D. L.; Sapko, M. T.; Reiter, C. T.; Bierer, D. E.; Perel, J. M.
J. Med. Chem. 1998, 41, 591. (b) Prashad, M.; Kim, H.; Lu, Y.; Har, D.;
Repic, O.; Blacklock, T. J. Giannousis, P. J. Org. Chem. 1999, 64, 1750.
(5) For excellent recent reviews of asymmetric reactions of diazo com-
pounds, see: (a) Calter, M. Curr. Org. Chem. 1997, 1, 37. (b) Doyle, M.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds; John Wiley & Sons: New York; 1998; Chapter 3.
(6) Presented in part at the 217th National Meeting of the American
Chemical Society, Anaheim, CA, March 22, 1999; ORGN 142.
(7) Doyle, M. P.; van Oeveren, A.; Westrum, L.; Protopopova, M.; Clayton,
T. J. Am. Chem. Soc. 1991, 113, 8982.
(8) Axten, J. M.; Krim, L.; Kung, H. F.; Winkler, J. D. J. Org. Chem.
1998, 63, 9628.
(14) Professor Huw Davies (State University of New York, Buffalo) has
observed that the use of the rhodium prolinate catalyst described in ref 11 in
this reaction leads to the formation of methylphenidate with attenuated
diastereoselectivity. We thank him for sharing his results with us prior to
publication.
(15) Doyle, M. P.; Zhou, Q.-L.; Simonsen, S. H.; Lynch, V. Synlett 1996,
697.
(9) For examples of rhodium-mediated intramolecular C-H insertion
reactions, see: (a) Watanabe, N.; Anada, M.; Hashimoto, S.; Ikegami, S. Synlett
1994, 1031. (b) Doyle, M. P.; Kalinin, A. Synlett 1995, 1075. (c) Sawamura,
M.; Sasaki, H.; Nakata, T.; Ito, Y. Bull. Chem. Soc. Jpn. 1993, 66, 5. (d)
Yakura, T.; Yamada, S.; Azuma, M.; Ueki, A.; Ikeda, M. Synthesis 1998,
973. (e) Hashimoto, S.; Watanabe, N.; Kawano, K.; Ikegami, S. Synth.
Commun. 1994, 24, 3277. (f) Ye, T.; McKervey, M.; Brandes, B.; Doyle, M.
P. Tetrahedron Lett. 1994, 35, 7269.
(16) Doyle, M. P.; Austin, R.; Bailey, A.; Dwyer, M.; Dyatlain, A.; Kalinan,
A.; Kwai, M.; Liras, S.; Oalmann, C.; Pieters, R.; Protopopova, M.; Raab,
C.; Roos, G.; Zhou, Q.; Martin S. J. Am. Chem. Soc. 1995, 117, 5763.
(17) (a) Kennedy, M.; McKervey, M.; Maguire, A.; Roos, G. J. Chem.
Soc., Chem. Commun. 1990, 361. (b) McKervey, M.; Ye, T. J. Chem. Soc.,
Chem. Commun. 1992, 823. (c) Doyle, M. P.; McKervey, M. A. J. Chem.
Soc., Chem. Commun. 1997, 983.
(10) Doyle, M. P.; Winchester, W. R.; Hoorn, J.; Lynch, V.; Simonsen,
S.; Ghosh, R. J. Am. Chem. Soc. 1993, 115, 9968.
(11) For a recent example of rhodium mediated intermolecular C-H
insertion, see: Davies, H.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(12) Moritani, I.; Hosokawa, T.; Obata, N. J. Org. Chem. 1969, 34, 670.
(13) Dieter, R. K.; Li, S. J. Org. Chem. 1997, 62, 7726.
(18) Dakin, L.; Schaus, S.; Jacobsen, E.; Panek, J. Tetrahedron Lett. 1998,
39, 8947.
10.1021/ja991466o CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/24/1999

6512 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
Communications to the Editor
the carbomethoxy group on the indicated pyrrolidinone ring as
shown in C and D, respectively. Support for this model for the
reaction of 1 and 2 is obtained by decreasing the size of R, the
nitrogen protecting group (see Table 1, R ) Cbz or Alloc), which
leads to an attenuation of the stereoselectivity of the insertion
reaction. It is interesting to note that reaction of N-Boc-
diethylamine with methyl phenyldiazoacetate 1 in the presence
of Rh2(5R-MEPY)4 4 occurs in a stereorandom manner, indicating
that the more highly ordered six-membered ring substrate is
critical to the stereoselectivity of the reaction.
These results establish a highly stereoselective and efficient
pathway for the synthesis of methylphenidate in scalemic form.
Further studies on the generality of both the enantioselectivities
and diastereoselectivities that have distinguished this work are
currently in progress, and our results will be reported in due
course.
Acknowledgment. The assistance of Mr. Daniel Macks in the
preparation of this manuscript is gratefully acknowledged. We thank
SmithKline Beecham, the American Chemical Society (Division of
Organic Chemistry Graduate Fellowship to J.M.A.), and the National
Institutes of Health (CA40250) for generous financial support.
Supporting Information Available: Synthetic procedures and spec-
troscopic data for the preparation of D-threo-methylphenidate (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
Figure 1.
JA991466O
as indicated in either A or B, and the orientation shown in B
minimizes the interaction between the phenyl ring and the
indicated ester moiety (R′) on the pyrrolidine ring.19 Approach
of the equatorial C-H bond of the N-Boc piperidine20 to the
carbene can occur as shown in either C or D, in which the
protected piperidine nitrogen is oriented away from or toward
(19) For calculations on these structures and a discussion of steric and
electron effects in the C-H insertion reactions iazoacetates catalyzed by
dirhodium, see: Doyle, M. P.; Westrum, L. J.; Wolthuis, W.; See, M.; Boone,
W.; Bagheri, V.; Pearson, M. J. Am. Chem. Soc. 1993, 115, 958.
(20) (a) Doyle, M. P.; Dyatkin, A.; Roos, G.; Canas, F.; Pierson, D.; van
Basten, A.; Muller, P.; Polleux, P. J. Am. Chem. Soc. 1994, 116, 4507. (b)
Muller, P.; Polleux, P. HelV. Chim. Acta 1994, 77, 645.