Racemization in the use of N-(9-(9-phenylfluorenyl))serine-derived cyclic sulfamidates in the synthesis of delta-keto alpha-amino carboxylates and prolines.

Article abstract of DOI:10.1021/ol006102b

[reaction: see text]Ring opening of enantiopure N-(9-(9-phenylfluorenyl)serine-derived cyclic sulfamidates with beta-keto esters, beta-keto ketones, and dimethyl malonate gave a variety of gamma-substituted amino acid analogues in racemic form. Investigat

Full text of DOI:10.1021/ol006102b

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2595-2598
Racemization in the Use of
N-(9-(9-Phenylfluorenyl))Serine-Derived
Cyclic Sulfamidates in the Synthesis of
δ-Keto r-Amino Carboxylates and
Prolines
Lan Wei and William D. Lubell*
De´partement de chimie, UniVersite´ de Montre´al, C. P. 6128, Succursale Centre Ville,
Montre´al, Que´bec H3C 3J7, Canada
lubell@chimie.umontreal.ca
Received May 24, 2000
ABSTRACT
Ring opening of enantiopure N-(9-(9-phenylfluorenyl)serine-derived cyclic sulfamidates with â-keto esters, â-keto ketones, and dimethyl malonate
gave a variety of γ-substituted amino acid analogues in racemic form. Investigation of the mechanism for racemization revealed that â-elimination
occurred to form a dehydroalanine intermediate that underwent subsequent Michael addition.
In the context of our research in the fields of peptide
mimicry1-3 and excitatory amino acid synthesis,4 we have
made extensive use of aminodicarboxylate-derived â-keto
esters.1-8 Previously, â-keto esters were obtained via acy-
lation of the ω-enolate of γ-methyl N-(PhF)glutamate deriva-
tives (PhF ) 9-(9-phenylfluorenyl)).4-8 Although this method
proved effective for synthesizing â-keto esters on variable
scales depending on the electrophile, an alternative approach
was sought that would be more amenable to large scale
synthesis and library generation. We envisioned that a
method based on ring opening of cyclic sulfamidates derived
from serine could be used to prepare the desired â-keto esters
and â-keto ketones.
Serine-derived cyclic sulfamidates have been effectively
used as “â-alanyl cation” synthons for the synthesis of
R-amino acids because the cyclic sulfamidate can simulta-
neously activate the â-position to nucleophilic attack and
protect the amino group.9-19 Several examples of nucleophilic
(9) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetrahedron:
Asymmetry 1990, 1, 881.
(10) Alker, D.; Doyle, K. J.; Harwood, L. M.; McGregor, A. Tetrahe-
dron: Asymmetry 1990, 1, 877.
(11) Boulton, L. T.; Stock, H. T.; Raphy, J.; Horwell, D. C. J. Chem.
Soc., Perkin Trans. 1 1999, 1421.
(12) Kim, B. M.; So, S. M. Tetrahedron Lett. 1998, 39, 5381.
(13) White, G. J.; Garst, M. E. J. Org. Chem. 1991, 56, 3178.
(14) Aguilera, B.; Fernandez-Mayoralas, A.; Jaramillo, C. Tetrahedron
1997, 53, 5863.
(15) Okuda, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4585.
(16) (a) Andersen, K. K.; Bray, D. D.; Champradit, S.; Clark, M. E.;
Habgood, G. J.; Hubbard, C. D.; Young, K, M. J. Org. Chem. 1991, 56,
6508. (b) Andersen, K. K.; Kociolek, M. J. Org. Chem. 1995, 60, 2003.
(17) Van Dort, M. E.; Jung, Y. W.; Sherman, P. S.; Kilbourn, M. R.;
Wieland, D. M. J. Med. Chem. 1995, 38, 810.
(1) Beausoleil, E.; Lubell, W. D. Biopolymers 2000, 53, 249.
(2) Be´le´c, L.; Slaninova, J.; Lubell, W. D. J. Med. Chem. 2000, 43, 1448.
(3) Halab, L.; Lubell, W. D. J. Org. Chem. 1999, 64, 3312.
(4) Atfani, M.; Lubell, W. D. J. Org. Chem. 1995, 60, 3184.
(5) Ibrahim, H. H.; Lubell, W. D. J. Org, Chem. 1993, 58, 6438.
(6) Beausoleil, E.; L’Archeveˆque, B.; Be´lec, L.; Atfani, M.; Lubell, W.
D. J. Org. Chem. 1996, 61, 9447.
(18) Ok, D.; Fisher, M. H.; Wyvratt, M. J.; Meinke, P. T. Tetrahedron
Lett. 1999, 40, 3831.
(7) Lombart, H. G.; Lubell, W. D. J. Org. Chem. 1994, 59, 6147.
(8) Lombart, H. G.; Lubell, W. D. J. Org. Chem. 1996, 61, 9437.
(19) Lyle, T. A.; Magill, C. A.; Pitzenberger, S. M. J. Am. Chem. Soc.
1987, 109, 7890.
10.1021/ol006102b CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/02/2000

ring opening of cyclic sulfamidates derived from serine have
been described with nitrogen,9-14 oxygen,9-11,14,15 sulfur,9,11,14
and fluoride11,13,17-19 nucleophiles. On the other hand, ring-
opened products have rarely been synthesized with carbon
nucleophiles16a other than cyanide.9,11,13,16a An exception to
this trend was the ring opening of (4S)-tert-butyl 2,2-dioxo-
3-benzyl-1,2,3-oxathiazolidine-4-carboxylate with diethyl
malonate which produced tert-butyl N-benzyl-4-ethoxycar-
bonyl pyroglutamate as well as a dehydroalanine side
product.9 Attempting to extend this reactivity with carbon
nucleophiles, we have studied N-(PhF)serine-derived cyclic
sulfamidate 1 and have discovered a â-elimination/Michael
addition pathway that furnished racemic γ-substituted amino
acid products.
periodate and catalytic ruthenium trichloride in acetonitrile
and water at 0 °C afforded cyclic sulfamidate 1 in 86%
overall yield.22
Ring opening of sulfamidate 1 was examined under various
conditions using enolates derived from â-keto esters, â-keto
ketones, and dimethyl malonate as nucleophiles (Scheme 2).
Scheme 2. Synthesis of γ-Acyl Amino Acids 2 by Ring
Opening of Cyclic Sulfamidate 1
(4S)-Methyl 2,2-dioxo-3-PhF-1,2,3-oxathiazolidine-4-car-
boxylate (1) was synthesized in two steps from N-(PhF)-
serine methyl ester 3 (Scheme 1).20 Treatment of serine 3
Scheme 1. Synthesis of N-(PhF)Serine-Derived Cyclic
Sulfamidate 1
We found that the desired amino acid derivatives 2 were
best prepared on treatment of sulfamidate 1 with a premixed
solution containing 400 mol % of â-keto ester or â-keto
ketone and 220 mol % of sodium hydride in DME, followed
by heating at 60 °C for 18 h and cooling to room temperature
before hydrolysis of the reaction mixture with 1 M KH2PO4
and chromatography (Table 1).23 Dehydroalanine 5 was also
encountered as a significant side product.
â-Keto esters 2a and 2c were respectively converted to
5-methylproline24,25 and δ-keto R-amino ester 6c,6 an inter-
mediate in the synthesis of N-BOC-5-tert-butylproline 8c
(Scheme 3). Hydrolysis and decarboxylation of â-keto esters
with thionyl chloride, triethylamine, and imidazole in dichlo-
romethane furnished quantitatively a 1:2 mixture of diaste-
reoisomeric sulfamidites 4 that could be separated by
chromatography on silica gel using an eluent of EtOAc in
hexane.21 Subsequent oxidation of sufamidites 4 with sodium
(22) (4S)-Methyl 2,2-Dioxo-3-PhF-1,2,3-oxathiazolidine-4-carboxylate
(1). A solution of 2-oxo-1,2,3-oxathiazolidine 4 (1.25 g, 3.1 mmol) in 100
mL of acetonitrile was cooled to 0 °C, treated with ruthenium(III) chloride
monhydrate (10 mg) followed by sodium periodate (1.28 g, 6 mmol), stirred
for 10 min, and quenched with water (100 mL). After stirring for 4 h, the
reaction mixture was diluted with ether (100 mL) and the phases were
separated. The aqueous phase was extracted with ether (3 × 60 mL). The
combined organic fractions were washed with saturated aqueous sodium
bicarbonate (100 mL) and brine (50 mL), dried, filtered, and evaporated to
a residue that was purified by chromatography on silica gel with an eluant
of 0-20% EtOAc in hexane. Evaporation of the collected fractions provided
1.14 g (87%) of 1: mp 155-156 °C; [R]20D 244° (c 0.1, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 3.64 (dd, 1 H, J ) 4.0, 8.2), 3.69 (s, 3 H), 4.02 (dd,
(20) Lubell, W. D.; Rapoport, H. J. Org. Chem. 1989, 54, 3824.
(21) (2R,4S)-Methyl 2-Oxo-3-(PhF)-1,2,3-oxathiazolidine-4-carboxy-
late ((2R)-4) and (2S,4S)-Methyl 2-Oxo-3-(PhF)-1,2,3-oxathiazolidine-
4-carboxylate ((2S)-4). A solution of N-PhF-L-serine methyl ester ((S)-3,
3.57 g, 10 mmol, prepared according to ref 20) in 150 mL of dichlo-
romethane was cooled to 0 °C, treated with imidazole (2.7 g, 40 mmol)
followed by triethylamine (2.8 mL, 20 mmol), stirred for 10 min, and then
treated with thionyl chloride (0.8 mL, 11 mmol). After stirring an additional
45 min, water (100 mL) was added and the phases were separated. The
aqueous phase was extracted with dichloromethane (3 × 50 mL), and the
combined organic fractions were washed with water (2 × 50 mL), dried,
filitered, and evaporated. The residue was normally used without purification
in the next reaction. Purification of the residue by chromatography on silica
gel with an eluant of 20-30% EtOAc in hexane provided 4 g (99%) of a
1:2 mixture of diastereomers, (2R)-4 and (2S)-4. First to elute was (2R)-4:
1 H, J ) 8.2, 8.7), 4.38 (dd, 1 H, J ) 4.0, 8.7), 7.19-8.22 (m, 13 H); 13
C
NMR (75 MHz, CDCl3) (52.9, 58.8, 66.8, 77.9, 169.2; HRMS calcd for
C23H19O5NS (M+) 421.0984, found 421.0997.
(23) General Procedure for Ring Opening of Five-Membered Cyclic
Sulfamidates with â-Keto Esters, â-Keto Ketones, and Dimethyl
Malonate. A solution of sodium hydride (prewashed with hexane, 60 wt
% in oil, 85 mg, 2.1 mmol) in DME (15 mL) was treated with the respective
â-keto ester, â-keto ketone, or dimethyl malonate (3.6 mmol), stirred for
10 min, treated with (4S)-methyl 2,2-dioxo-3-PhF-1,2,3-oxathiazolidine-4-
carboxylate (1, 380 mg, 0.9 mmol), heated at 60 °C for 18 h, cooled to
room temperature, and poured into 1 M NaH2PO4 (50 mL). The mixture
was extracted with EtOAc (3 × 50 mL). The combined organic phases
were washed with brine (2 × 30 mL), dried, filtered, and evaporated to a
residue. Isolation protocols as well as spectral characterization data for 2a-f
are presented in the Supporting Information.
TLC Rf ) 0.54 (30% EtOAc in hexanes); mp 83-84 °C; [R]20 121° (c
D
0.14, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.42 (s, 3 H), 3.51 (dd, 1 H,
J ) 1.4, 7.1), 4.41 (dd, 1 H, J ) 1.4, 9.4), 4.75 (dd, 1 H, J ) 7.1, 9.4),
7.17-8.17 (m, 13 H); 13C NMR (75 MHz, CDCl3) δ 52.1, 59.0, 72.2, 75.2,
171.4; HRMS calcd for C23H20O4NS (MH+) 406.1113, found 406.1130.
Next to elute was (2S)-4: TLC Rf ) 0.37 (30% EtOAc in hexanes); mp
71-72 °C; [R]20 243° (c 0.38, CHCl3); 1H NMR (400 MHz, CDCl3) δ
3.37 (t, 1 H, J )D7.9), 3.57 (s, 3 H), 4.32 (t, 1 H, J ) 7.9), 4.95 (t, 1 H, J
) 7.9), 7.19-7.77 (m, 13 H); 13C NMR (75 MHz, CDCl3) δ 52.5, 61.3,
73.5, 76.2, 170.3; HRMS calcd for C23H19O4NS (M+) 405.1035, found
405.1046. Stereochemistry was ascertained by a combination of NMR
spectroscopy and X-ray crystallography experiments to be reported in a
forthcoming manuscript in preparation.
(24) Ho, T. L.; Gopalan, B.; Nestor, J. J. J. Org. Chem. 1986, 51, 2405.
(25) Mauger, A. B.; Witkop, B. Chem. ReV. 1966, 66, 47.
2596
Org. Lett., Vol. 2, No. 17, 2000

meric R-methylbenzylamides 9a, which were synthesized by
coupling cis-N-(BOC)-5-methylproline 8a to L- and D-R-
methylbenzylamine followed by removal of the BOC group
Table 1. Synthesis of γ-Acyl Amino Acids 2 by Ring Opening
of Cyclic Sulfamidate 1 with Enolates of â-Keto Ester, â-Keto
Ketone, and Dimethyl Malonate
1
with 10% TFA in CH2Cl2 (Scheme 3). In the H NMR
spectra of R-methylbenzylamides 9a, the disteromeric methyl
doublet peaks were resolved and came at 1.50 and 1.49 ppm,
as well as at 1.46 and 1.42 ppm. Integration of these doublets
indicated that 9a was of only 10% diasteromeric excess.
Racemization had evidently occurred during the synthesis
of cis-N-(BOC)-5-methylproline 8a. The cause of this loss
of configurational integrity was narrowed down to the ring-
opening step by subsequent investigation of the purity of
heptanoate 6c. Measurement of the specific rotation of δ-keto
R-amino ester 6c showed a considerable drop in optical purity
([R]20 -1.2° (c 0.8, CHCl3); lit.6 [R]20 -137.7° (c 1,
nucleophile
entry
a
R1
R2
conditions
2a (%) 5 (%)
Me
Me
Me
Me
Me
Me
Me
Et
OMe K2CO3, DMF, rt, 3 d
OMe K2CO3, THF, rt, 3 d
OMe Cs2CO3, THF, rt, 5 d
OMe K3PO4, DME, rt, 18 h
OMe NaH, THF, 60 °C, 6 h
OMe NaH, DME, 60 °C, 4 h
OMe NaH, DME, 60 °C, 18 h
OEt
OEt
Me
100c
30b
d
100c
d
43b
51b
67b
86b
82
b
c
d
e
f
NaH, DME, 60 °C, 18 h
NaH, DME, 60 °C, 18 h
NaH, DME, 60 °C, 18 h
NaH, DME, 60 °C, 18 h
D
D
t-Bu
Me
Ph
63
66b
d
MeOH)). Because hydrolysis and decarboxylation of â-keto
ester 2c, prepared from a route featuring acylation of
N-(PhF)glutamate γ-methyl ester,5 produced enantiopure 6c
Me
45
65b
OMe OMe NaH, DME, 60 °C, 18 h
([R]20 -139.2° (c 0.8, MeOH)), we considered that race-
a Isolated yield. b Caculated yield from an isolated mixture of 2 and
â-dicarbonyl starting material. c Determined by 1H NMR spectroscopy.
d Observed by TLC.
D
mization occurred prior to or during the nucleophilic addition
to cyclic sulfamidate 1 and not at the hydrolysis and
decarboxylation steps. In addition, the low specific rotation
value ([R]20 -9.0° (c 0.15, CHCl3)) for glutamate 2f also
D
2a and 2c with sodium hydroxide in ethanol heated at a reflux
provided their respective δ-oxo-R-N-(PhF)amino acids that
were esterified with iodomethane and potassium carbonate
in acetonitrile to provide respectively methyl 5-oxo-2-[N-
(PhF)amino]hexanoate (6a) and methyl 6,6-dimethyl-5-oxo-
2-[N-(PhF)amino]heptanoate (6c).6 Hydrogenation of δ-oxo-
heptanoate 6a with palladium-on-carbon and di-tert-butyl
dicarbonate in methanol proceeded by cleavage of the PhF
protection, N-acylation, imine formation, and hydrogenation
to furnish N-(BOC)-5-methylproline methyl ester 7a as the
cis-diastereomer. Hydrolysis of methyl ester cis-7a with
potassium trimethylsilanolate in Et2O furnished N-(BOC)-
5-methylproline cis-8a in 96% yield.
suggested loss of configurational integrity during additon of
dimethyl malonate to cyclic sulfamidate 1.
Because dehydroalanine intermediates were detected dur-
ing the reactions of five-member cyclic sulfamidate 1, we
synthesized dehydroalanine 5 by â-elimination induced with
sodium hydride as a poor nucleophile (Scheme 4). We next
Scheme 4. Michael Addition of Methyl Acetoacetate Enolate
to Dehydroalanine Sulfamic Acid 10
The enantiomeric purity of cis-N-(BOC)-5-methylproline
(cis-8a) was ascertained by spectral analysis of its diastero-
Scheme 3. Synthesis and Enantiomeric Purity of
5-Alkylprolines 8
tried to determine if the presumed dehydroalanine intermedi-
ate 10 could serve as a Michael acceptor for the formation
of racemic â-keto ester. Sulfamidate 1 was treated with 300
mol % of sodium hydride in DME to form the elimination
product 10. Treatment of 10 with a premixed solution of
methyl acetoacetate (300 mol %) and NaH (400 mol %) in
DME, heating at 60 °C for 18 h, followed by hydrolysis of
Org. Lett., Vol. 2, No. 17, 2000
2597

Scheme 5. Proposed Mechanism for the Ring Opening of Sulfamidate 1 with â-Keto Ester
the polar sulfamic acid intermediate with 1 M KH2PO4,
with elimination. Preliminary experiments indicate that
elimination may be induced by residual base or by the enolate
itself. Enolate may then attack 10 by a Michael addition to
furnish after workup â-keto ester 2 (Scheme 5).26 Further
investigations are now in progress to define the scope and
limitations of N-(PhF)serine-derived sulfamidates as con-
figurationally labile chiral educts.
furnished (5RS)-methyl N-PhF-2-methyl-3-(methyloxy)car-
bonyl-∆2-pyrroline (11) in 87% yield (Scheme 4). Previously,
we encountered pyrroline 11 in the direct ring opening of
sulfamidate 1 with the preformed enolate of methyl aceto-
acetate when the hot reaction mixture was quenched with 1
M KH2PO4. Although formation of 11 can be avoided by
cooling the reaction mixture to room temperature prior to
hydrolysis of the sulfamic acid, we elected to form 11 in
this sequence because it was easier to characterize. The
formation of 11 demonstrated thus that dehydroalanine 10
could serve as a prochiral intermediate for the formation of
racemic 2. To verify if sulfamidate 1 racemized prior to ring
opening, we removed aliquots of the reaction mixture
containing 1 and the preformed sodium enolate of methyl
acetoacetate in DME at 60 °C. No loss of configurational
integrity of sulfamidate 1 was observed after 1 and 2 h of
reaction as determined by measurement of its specific rotation
after isolation by chromatography. Hence, R-deprotonation
triggers â-elimination prior to reprotonation and racemization
of 1.
Acknowledgment. This research was supported in part
by the Natural Sciences and Engineering Research Council
(NSERC) of Canada and the Ministe`re de l′EÄ ducation du
Que´bec.
Supporting Information Available: Descriptions of
experimental procedures and spectral data for key com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006102B
A mechanism that may explain the cause of this racem-
ization involves R-proton removal to trigger ring opening
(26) Dugave, C.; Cluzeau, J.; Me´nez, A.; Gaudry, M.; Marquet, A.
Tetrahedron Lett. 1998, 39, 5775.
2598
Org. Lett., Vol. 2, No. 17, 2000