Highly regio-, diastereo-, and enantioselective C-H insertions of methyl aryldiazoacetates into cyclic N-BOC-protected amines. Asymmetric synthesis of novel C2-symmetric amines and threo-methylphenidate [7]

Full text of DOI:10.1021/ja9910715

J. Am. Chem. Soc. 1999, 121, 6509-6510
6509
The potential of this chemistry is illustrated by means of a
two-step asymmetric synthesis of a novel class of C2-symmetric
amines (3)8 and of threo-methylphenidate (Ritalin) (4).9 C2-
Symmetric amines are especially useful in organic synthesis,8 and
the direct approach to highly elaborate C2-symmetric amines
described here is likely to be of great interest. threo-Methylpheni-
date is an important pharmaceutical agent that is used in racemic
form for the treatment of attention deficit disorders.9 Considering
that, within the last year, two fairly lengthy asymmetric syntheses
(eight and nine steps) of threo-methylphenidate have been
reported,10,11 the two-step asymmetric synthesis reported herein
should be of considerable value.
Highly Regio-, Diastereo-, and Enantioselective C-H
Insertions of Methyl Aryldiazoacetates into Cyclic
N-Boc-Protected Amines. Asymmetric Synthesis of
Novel C2-Symmetric Amines and
threo-Methylphenidate
Huw M. L. Davies,* Tore Hansen, Darrin W. Hopper, and
Stephen A. Panaro
Department of Chemistry
State UniVersity of New York at Buffalo
Buffalo, New York 14260-3000
ReceiVed April 5, 1999
The development of selective methods for asymmetric C-H
activation is a challenging goal in organic synthesis.1 Metal-
stabilized carbenoid intermediates have been impressively used
for intramolecular asymmetric C-H activation,2 but the inter-
molecular version of this reaction is not generally considered to
be synthetically useful.2,3 We have previously communicated that
Rh2(S-DOSP)4 (1)4-catalyzed decomposition of aryldiazoacetates
results in asymmetric C-H insertion into cyclohexane and
tetrahydrofuran.5 This was the first report of enantioselective
intermolecular C-H insertion using metal carbenoid intermedi-
ates. In this paper we describe that highly regio-, diastereo-, and
enantioselective C-H insertions of aryldiazoacetates into cyclic
N-BOC-protected amines can be achieved (eq 1).6 The catalyst
that was used in most of this study was Rh2(S-DOSP)4 (1), but in
one case, the novel Rh2(S-biDOSP)2 (2) catalyst7 was used.
In the original study on asymmetric C-H insertion into
cycloalkanes and tetrahydrofuran, high levels of enantioselectivity
were achieved.5 In the current study with N-BOC-protected cyclic
amines, we discovered that high diastereoselectivity is also
feasible in intermolecular C-H insertions, although the issues
that control the diastereoselectivity in these reactions are subtle.
Rh2(S-DOSP)4-catalyzed (1% of catalyst) decomposition of 5a
in the presence of N-BOC-pyrrolidine (6, 2 equiv) in hexane at
-50 °C results in the formation of the C-H insertion product 7a
in 94% ee and 92% de (eq 2). The C-H insertion into N-BOC-
pyrrolidine is a general process that can be extended to a range
of aryldiazoacetates. In all cases, the diastereoselectivity and the
enantioselectivity in these reactions are greater than 90% de and
90% ee, respectively.12
The next issue that was examined was whether a second C-H
insertion was a feasible process. These reactions were carried out
(8) (a) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97, 3161. (b)
Whitesell, J. K. Chem. ReV. 1989, 89, 1581. (c) Takahata, H.; Kouno, S.;
Momose, T. Tetrahedron: Asymmetry 1995, 6, 1085.
(9) For racemic syntheses of 4, see: (a) Pannizon, L. HelV. Chim. Acta
1944, 27, 1748. (b) Deutsch, H.; Shi, Q.; Gruaszecka-Kowalik, E.; Schweri,
M. J. Med. Chem. 1996, 39, 1201. (c) Axten, J. M.; Krim, L.; Kung, H. F.;
Winkler, J. D. J. Org. Chem. 1998, 63, 9628.
(10) Thai, D. L.; Sapko, M. T.; Reiter, C. T.; Bierer, D. E.; Perel, J. M. J.
Med. Chem. 1998, 41, 591.
(11) Prashad, M.; Kim, H.-Y.; Lu, Y.; Liu, Y.; Har, D.; Repic, O.;
Blacklock, T. J.; Giannousis, P. J. Org. Chem. 1999, 64, 1750.
(12) The diastereoselectivity for the formation of 7 was determined from
the 1H NMR of the crude amine after extraction and removal of solvent. The
yields for 7a,c-e represents the amount of crystalline hydrochloride salt that
was obtained after treatment of the crude amine with ethereal HCl. The yield
of 7b represented the pure amine after purification by column chromatography.
The enantioselectivity was determined by conversion of the crude amine to
its trifluoroacetamide derivative, followed by chiral HPLC or GC analysis.
The relative stereochemistry of 7c was readily determined by conversion of
7c to a fused â-lactam, in which the cis arrangement of the two protons in
the â-lactam ring was assigned on the basis on a distinctive coupling (J )
5.1 Hz) and NOE experiments (Coulton, S.; Gilchrist, T. L.; Graham, K. J.
Chem. Soc., Perkin Trans. 1 1998, 1193). The absolute stereochemistry of 7a
was determined to be (2S,2′R) using the Mosher amide method developed by
Hoye (Hoye, T. R.; Renner, M. K. J. Org. Chem. 1996, 61, 8489).
(1) Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc.
Chem. Res. 1995, 28, 154.
(2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; Wiley-Interscience: New York,
1998; pp 112-162.
(3) For representative examples of intermolecular C-H insertions, see: (a)
Scott, L. T.; DeCicco, G. J. J. Am. Chem. Soc. 1974, 96, 322. (b)
Ambramovitch, R. A.; Roy, J. J. Chem. Soc., Chem. Commun. 1965, 542. (c)
Adams, J.; Poupart, M.-A.; Greainer, L.; Schaller, C.; Quimet, N.; Frenette,
R. Tetrahedron Lett. 1989, 30, 1749. (d) Demonceau, A.; Noels, A. F.; Hubert,
A. J.; Teyssie, P. J. Chem. Soc., Chem. Commun. 1981, 688. (e) Demonceau,
A.; Noels, A. F.; Hubert, A. J.; Teyssie, P. Bull. Soc. Chim. Belg. 1984, 93,
945. (f) Demonceau, A.; Noels, A. F.; Hubert, A. J.; Teyssie, P. J. Mol. Catal.
1988, 49, L13. (g) Callott, H. J.; Metz, F. Tetrahedron Lett. 1982, 23, 4321.
(h) Callott, H. J.; Metz, F. NouV. J. Chim. 1985, 9, 167.
(4) Davies, H, M. L. Aldrichim. Acta 1997, 30, 107.
(5) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(6) The majority of this Communication was presented previously: Davies,
H. M. L.; Hodges, L. M.; Hansen, T. Asymmetric synthesis of heterocycles
using rhodium-stabilized carbenoids. Abstracts of Papers, 216th National
Meeting of the Americal Chemical Society, Boston, MA, August 23-27, 1998;
ACS: Washington, DC, 1998; ORGN 254.
(7) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett., submitted.
10.1021/ja9910715 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/24/1999

6510 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
Communications to the Editor
on enantiomerically pure 8, which was obtained from 7a that was
first recrystallized as its hydrochloride salt to obtain enantiomeri-
cally pure material and then treated with (BOC)2O. Reaction of
8 with the phenyldiazoacetate 5a (4 equiv) using Rh2(S-DOSP)4
as catalyst in 2,3-dimethylbutane as solvent resulted in the
formation of 3a in 93% yield (eq 3). The compound was shown
to be C2-symmetric because in the 13C NMR only nine signals
were apparent, yet the compound was chiral, which rules out the
meso diastereomer. In contrast, reaction of 8 with excess 5a using
Rh2(R-DOSP)4 as catalyst resulted in the formation of a mixture
of diastereomers and/or regioisomers that were not resolvable (eq
4).
different from what was observed with N-BOC-pyrrolidine, which
gave bis C-H insertion when an excess of phenyldiazoacetate
was used. A major improvement in enantioselectivity and
diastereoselectivity was possible by carrying out the reaction with
the Rh2(S-biDOSP)2 (2) catalyst.7 The ratio of 4:10 (73% yield)
was improved to 2.5:1, and (2R, 2′R)-threo isomer 4 was formed
in 86% ee and 52% isolated yield. It is well established that Rh2-
(S-biDOSP)2 (2) results in opposite asymmetric induction to Rh2-
(S-DOSP)4,7 and in the reaction of 5a and 9 catalyzed by 2, the
biologically active enantiomer of threo-methylphenidate is formed.
Access to the erythro diastereomer of methylphenidate was
achieved by carrying out the reaction with tetrahydropyridine 11
as illustrated in eq 7. Rh2(S-DOSP)4-catalyzed decomposition of
5a in the presence of 11 (4 equiv) in 2,3-dimethylbutane at room
temperature, followed by treatment with TFA, resulted in a 63%
yield of C-H insertion products 12 and 13. Remarkably, the
erythro diastereomer 13 was the major diastereomer (62% de)
and was isolated in 53% yield and 80% ee. Determination of the
relative and absolute stereochemistry of 13 as (2S, 2′R) was readily
achieved by conversion of 13 to erythro-methylphenidate 1010
by catalytic hydrogenation.
Further experimentation demonstrated that the C2-symmetric
amines could be formed in a single step. Rh2(S-DOSP)4-catalyzed
decomposition of 5a (1.5 equiv) at -50 °C in the presence of
N-BOC-pyrrolidine, followed by heating of the mixture under
reflux and addition of a further 4.5 equiv of 5a, generated the
C2-symmetric amine 3a in 78% yield and 97% ee (eq 5). Similar
bis C-H insertion reactions were possible with aryldiazoacetates
5b-e, leading to the formation of the amines 3b-e. These amines
are appropriately functionalized for further conversion by ester
reduction or Grignard addition to highly functionalized and
potentially useful C2-symmetric bases. Further studies to evaluate
the synthetic utility of such C2-symmetric bases are in progress.
If a similar reaction would be feasible with N-BOC-piperidine,
In summary, the reaction of cyclic N-BOC-protected amines
with aryldiazoacetate catalyzed by Rh2(S-DOSP)4 or Rh2(S-
biDOSP)2 is an attractive method for the asymmetric synthesis
of elaborate chiral amines. The synthetic utility of this method
was demonstrated by means of a two-step asymmetric synthesis
of a novel class of C2-symmetric amines and of threo-meth-
ylphenidate. These studies demonstrate that the intermolecular
C-H insertions with aryldiazoacetates can be achieved with high
diastereoselectivity in addition to high enantioselectivity. These
studies also demonstrate that these carbenoids are especially
selective toward C-H insertions into methylene groups adjacent
to amide nitrogen functionality.15 The combination of regiose-
lectivity and stereoselectivity exhibited in these reactions would
indicate that aryldiazoacetate C-H insertions offer tremendous
opportunities in organic synthesis. Further studies to explore the
full scope of this chemistry and to determine the factors that
control the diastereoselectivity in these reactions are underway.
a very direct asymmetric synthesis of threo-methylphenidate
would be achieved. Rh2(S-DOSP)4 (1)-catalyzed decomposition
of methyl phenyldiazoacetate (5a) in the presence of N-BOC-
piperidine (9, 4 equiv) in 2,3-dimethylbutane at room temperature,
followed by treatment with trifluoroacetic acid, resulted in the
formation of a mixture of threo- and erythro-methylphenidate, 4
and 10, in 49% yield.13,14 However, the threo isomer 4 was the
minor diastereomer and was formed in only 34% ee. The
combined yield of 4 and 10 could be improved to 86% by using
N-BOC-piperidine as the limiting agent. This result is very
Acknowledgment. Financial support of this work by the National
Science Foundation (CHE 9726124) and the National Institutes of Health
(DA06301) is gratefully acknowledged. D.W.H. was supported by a
National Institutes of Health postdoctoral fellowship grant (DA05886).
Supporting Information Available: Full experimental data for
compounds 3, 4, 7, 10, and 13 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) Winkler and co-workers have described at the 217th ACS Meeting in
Anaheim, CA, March 21-25, 1999 (Organic Division Paper No. 142) that
decomposition of 5a in the presence of N-BOC-piperidine using Doyle’s Rh2-
(MEPY)4 catalyst generates threo-methylphenidate in 45% yield and 69% ee.
(14) The absolute stereochemistry of 4 and 10 was determined by
comparison of the optical rotation with the literature values (ref 10).
JA9910715
(15) For examples of intramolecular C-H insertions of aryldiazoacetates
into pyrrolines, see: Lim H. J.; Sulikowski, G. A. J. Org. Chem. 1995, 60,
2326.