Asymmetric synthesis of substituted prolines from delta-amino beta-ketoesters. Methyl (2S,5R)-(+)-5-phenylpyrrolidine-2-carboxylate.

Article abstract of DOI:10.1021/ol025831j

[reaction: see text]. Metal carbenoid chemistry is used to convert delta-amino beta-ketoesters into 5-substituted 3-oxo prolines, which expands the utility of this class of polyfunctionalized chiral building blocks.

Full text of DOI:10.1021/ol025831j

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1599-1602
Asymmetric Synthesis of Substituted
Prolines from δ-Amino â-Ketoesters.
Methyl
(2S,5R)-(+)-5-Phenylpyrrolidine-2-carboxylate
Franklin A. Davis,* Tianan Fang, and Rajesh Goswami
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received March 6, 2002
ABSTRACT
Metal carbenoid chemistry is used to convert δ-amino â-ketoesters into 5-substituted 3-oxo prolines, which expands the utility of this class
of polyfunctionalized chiral building blocks.
Recent efforts in our laboratory have focused on the
applications of N-sulfinyl δ-amino â-ketoesters 1, a new
polyfunctionalized chiral building block for piperidine 2
alkaloid synthesis (Scheme 1). These building blocks can
chemistry. In this manner expeditious enantioselective
syntheses of (R)-(-)-2-phenylpiperidine,1 (-)-(2S,4S)-
SS20846A,1 the proposed biosynthetic intermediate of the
antimicrobial agent streptazolin, the quinolizidine alkaloid
(-)-lasubine II,2 all four stereoisomers of 4-hydroxypipecolic
acid,3 and the dendrobate alkaloid (+)-241D and its C-4
epimer have resulted.4 The versatility of these building blocks
could be greatly expanded if methods could be devised for
linking the δ-amino group with the R-carbon, which should
result in a functionalized 5-substituted 3-oxo proline 3
(Scheme 1). Substituted prolines are examples of confor-
mationally restricted R-amino acids and as such are in
demand for modifications of peptides that result in their
enhanced bioavailability and metabolic stability. In this paper
we report studies aimed at preparing substituted prolines from
1, as well as a concise asymmetric synthesis of methyl
(2S,5R)-(+)-5-phenylpyrrolidine-2-carboxylate (18).
Scheme 1
A method that appears to be ideally suited for linking the
nitrogen and R-carbon atoms in (SS,R)-(+)-methyl 3-oxo-
5-phenyl-5-(p-toluenesulfinylamino)pentanoate (4)3 is metal
carbenoid chemistry.5 Indeed the intramolecular N-H inser-
(1) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000,
2, 1041.
(2) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
(3) Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000, 2106.
(4) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169.
be prepared in one pot from sulfinimines (N-sulfinyl imines)
and can be readily converted to the target piperidine with a
minimum of chemical manipulation and protecting group
10.1021/ol025831j CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/10/2002

tion reactions of amino R-diazoketones catalyzed by metals
have been used to prepare nitrogen heterocycles,5,6 such as
â-lactams,7 pyrrolidinones,8,9 piperidinones,8,9 and pipecolic
acid.10 The requisite R-diazo compound (SS,R)-(+)-5 was
readily prepared in 91% yield by diazo transfer from
commercially available (4-carboxybenzene)sulfonyl azide (p-
CBSA) and triethylamine (Scheme 2). Since metal carbenoid
Scheme 3
Scheme 2
insertion into the N-H bond of a sulfinamide has not been
reported, the corresponding N-tosyl derivative (R)-(+)-7 was
prepared via two different methods.11 First the diazo sulfi-
namide 5 was oxidized to 7 in 98% yield using m-
chloroperbenzoic acid (m-CPBA). Alternatively this material
was prepared by diazo transfer from N-tosyl δ-amino
â-ketoester 6 (Scheme 2). The diazo compounds are stable
and readily purified by flash chromatography.
Diazo compounds (+)-5 or (+)-7 were treated in DCM
or benzene with 3 mol % of Rh2(OAc)4 at room temperature
or reflux for 2 h. Removal of the solvent and chromatography
gave a complex mixture of products that could not be
characterized. Since the majority of intramolecular carbenoid
N-H insertions involve amides,7-10 the N-Boc derivative
(R)-(+)-9 was prepared as outlined in Scheme 3. The sulfinyl
group in (+)-4 was removed with 5.0 equiv of TFA in MeOH
to give the amine salt (not shown). The solution was
concentrated, dissolved in THF, and treated with Boc2O/Et3N
and a catalytic amount of DMAP. The N-Boc-protected
δ-amino â-ketoester (R)-(+)-8 was obtained in 90% yield
for the two steps. Next, diazo transfer using 4-CBSA/Et3N
gave (R)-(+)-9 in nearly quantitative yield. Remarkably, (R)-
(+)-9 can also be prepared from the N-sulfinyl diazo
compound (+)-5 in 90% yield using the one-pot deprotection/
protection protocol (Scheme 3). It is reported that R-keto
diazo compounds are unstable in the presence of strong acids
such as TFA.9
With 3 mol % of Rh2(OAc)4, (R)-(+)-9 gave the desired
oxo proline 10 as a single diastereoisomer in near quantitative
crude yield (Scheme 3). In solution this material reverts to
an 85:15 mixture of cis:trans isomers and, on chromato-
graphic purification, a 60:40 isomer mixture 11 (vide infra).
NOE and NOESY experiments to determine the structure
of crude 10 were inconclusive. However, reduction of 10
(85:15 mixture) with NaBH4/MeOH gave a 76:14:10 mixture
of alcohols 12 in 85%. Deprotection, TFA/DCM, and
purification gave the major isomer (2S,3R,5R)-(+)-13 in 73%
yield. NOSEY experiments revealed that 13 had the cis
arrangement of substituents (Scheme 3) and strongly sug-
gested that the rhodium carbenoid species inserts into the
N-H bond of 9 to furnish the cis proline derivative 10.
(5) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds, Wiley-Interscience: New
York, 1998. (b) Doyle, M. P.; McKervey, M. A. Chem. Commun. 1997,
983. (c) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091.
(6) Wang, J.; Hou, Y.; Wu, P. J. Chem. Soc., Perkin Trans. 1 1999,
2277.
(7) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F.
A. J. Am. Chem. Soc. 1980, 102, 6161.
(8) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985,
50, 5223.
(9) Yang, H.; Jurkauskas, V.; Mackintosh, N.; Mogren, T.; Stephenson,
C. R. J.; Foster, K.; Brown, W.; Roberts, E. Can. J. Chem. 2000, 78, 800.
(10) Garcia, C. F.; McKervey, M. A.; Ye, T. Chem. Commun. 1996,
1565.
(11) For examples of carbenoid insertion into the N-H bond of a
sulfonamide, see: (a) Benati, L.; Calestani, G.; Nanni, D.; Spagnolo, P. J.
Org. Chem. 1998, 63, 4679. See also ref 215 in ref 5c.
1600
Org. Lett., Vol. 4, No. 9, 2002

The 60:40 oxo proline mixture 11 was treated with 10
equiv of 1,2-ethanedithiol and 2.5 equiv of BF3‚OEt2 to give
a separable cis:trans mixture of thioketals (-)-14 and (-)-
15 in 41% and 37% yield, respectively (Scheme 4). The cis
geometry was assigned to (-)-14 on the basis of its
conversion to (+)-18 and further supports an assertion that
the major isomer in 11 has the same cis geometry. Next
Raney-nickel desulfurization of (-)-15 in ethanol, expected
to furnish trans-19, resulted in a ring opening to produce
the N-ethyl and N,N-diethyl R-amino acids (R)-(-)-16 and
(R)-(+)-17 in 25% and 41% yield. While metal-catalyzed
reductive ring opening of aziridines to R-amino acids is well-
known,14 opening of larger ring systems such as pyrrolidines
under these conditions is, to the best of our knowledge,
unknown. Reductive amination, resulting from acetaldehyde
in the ethanol solvent, is the likely source of 16 and 17.
Desulfurization of (-)-14 and (-)-15 using tributyltin
hydride15 gave cis-(2S,5R)-(+)-1813 and trans-(2R,5R)-(+)-
1912 in 53% and 43% isolated yields, respectively (Scheme
4).
Scheme 4
Although our asymmetric synthesis of (+)-18 was more
efficient than those reported earlier,12,13 it was not as concise
as first envisioned: epimerization at C-2 in 10 required
separation of an almost 1:1 mixture of dithiane isomers 14
and 15. The reduction of a vinyl triflate to an alkane, as
described by Comins,15 could provide a more efficient route
to (+)-18 (Scheme 5). Thus reaction of 11 (60:40 mixture)
Scheme 5
(+)-RP 66803 is a nonpeptide cholecystokinin (CCK)
antagonist that contains a cis-(2S,5R)-(+)-5-phenylpyrroli-
dine-2-carboxylate segment.12 Cholecystokinin is a brain-
gut peptide hormone that is thought to regulate a number of
physiological process in mammalian species. This proline
has been prepared in enantiopure form by a Friedel-Crafts
reaction that employs a protected 5-methoxy L-proline to give
a cis/trans mixture that could be separated by chromatog-
raphy.12 A 13-step asymmetric synthesis of methyl cis-
(2R,5R)-(+)-5-phenylpyrrolidine-2-carboxylate (18) was re-
cently described by Larcheveque and co-workers starting
from an optically pure R-hydroxy acid.13 Removal of the
3-oxo group in 11 could result in a more expeditious
synthesis of (+)-18 provided that the cis and trans isomers
can be efficiently separated somewhere in the synthesis.
with 1.1 equiv of Et3N at -78 °C in DCM followed by
addition of Tf2O and a catalytic amount of DMAP resulted
after 1.5 h in a 93:7 inseparable regioisomeric mixture of
vinyl triflates 20 and 21 in 56% yield (Scheme 5). Starting
material 11 (36%) was also recovered. All attempts to date
to improve the yield by varying the reaction conditions
resulted in much poorer ratios of 20 and 21. Hydrogenation
of 20 and 21 over a platinum catalyst afforded an 85:15 ratio
of cis:trans 22. The fact that the cis:trans ratio of 22 is less
than 20:21 suggests that the hydrogenation was not com-
pletely stereospecific. Deprotection (TFA) afforded (+)-18
and (+)-19 and purification by preparative TLC furnished
an 80% yield of cis-(2S,5R)-18 for the two steps.
(12) Manfre, F.; Pulicani, J. P. Tetrahedron: Asymmetry 1994, 5, 235.
(13) Haddad, M.; Imogai, H.; Larcheveque, M. J. Org. Chem. 1998, 63,
5680.
(14) McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
(15) (a) Comins, D. L.; LaMunyon, D. H.; Chen, X. J. Org. Chem. 1997,
62, 8182. (b) Comins, D. L.; Dehghani, A. J. Org. Chem. 1995, 60, 794.
Org. Lett., Vol. 4, No. 9, 2002
1601

In summary, methodology has been devised for the
asymmetric construction of 5-substituted 3-oxo prolines from
δ-amino â-ketoesters by linking the nitrogen and R-carbon
atoms using metal carbenoid chemistry. This new protocol
greatly expands the utility of these versatile polyfunction-
alized chiral building blocks. A concise enantioselective
synthesis of methyl (2S,5R)-(+)-5-phenylpyrrolidine-2-car-
boxylate (18) has been achieved.
was supported by a grant from the National Institutes of
Health (GM 51982).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 5-19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Professor Douglas F. Taber,
University of Delaware, for helpful discussions. This work
OL025831J
1602
Org. Lett., Vol. 4, No. 9, 2002