N-(9-(9-phenylfluorenyl))homoserine-derived cyclic sulfamidates: Novel chiral educts for the synthesis of enantiopure γ-substituted α-amino acids

Article abstract of DOI:10.1021/ol016225b

matrix presented nucleophile: NaN₃, RNH₂, RR'NH, ArNH₂, KSCN, NaSAr, NaOAr (4S)-tert-Butyl 2,2-dioxo-3-PhF-1,2,3-oxathiazainane-4-carboxylate reacted effectively with nitrogen, sulfur, and oxygen nucleophiles to provide en

Full text of DOI:10.1021/ol016225b

ORGANIC
LETTERS
2001
Vol. 3, No. 19
2965-2968
N-(9-(9-Phenylfluorenyl))homoserine-Derived
Cyclic Sulfamidates: Novel Chiral
Educts for the Synthesis of Enantiopure
γ-Substituted r-Amino Acids
Mohamed Atfani, Lan Wei, and William D. Lubell*
De´partement de chimie, UniVersite´ de Montre´al, C. P. 6128, Succursale Centre-Ville,
Montre´al, Que´bec, Canada H3C 3J7
lubell@chimie.umontreal.ca
Received June 4, 2001
ABSTRACT
(4S)-tert-Butyl 2,2-dioxo-3-PhF-1,2,3-oxathiazainane-4-carboxylate reacted effectively with nitrogen, sulfur, and oxygen nucleophiles to provide
enantiopure (>97% ee) γ-substituted r-amino acids.
R-Amino acids possessing remote electrophilic centers have
served as important precursors for the synthesis of amino
acid analogues and natural products.1-5 Although a variety
of ω-halogeno R-amino propanoates,2a,b butanoates,2b-h and
pentanoates2h-j have been effectively synthesized and em-
ployed in intermolecular reactions with various nucleophiles,
their utility has been compromised by side reactions involv-
ing eliminations,2a as well as intramolecular attack of amine
and R-carbanion groups to form cyclic products.2f,j In the
case of serine-derived electrophiles, the problem of intra-
molecular amine alkylation and aziridine formation has been
alleviated by the employment of serine-derived cyclic
sulfamidates1,3 and â-lactones,4 which have served as alanine
â-cation equivalents for the synthesis of a variety of amino
acid analogues. Employing N-(PhF)serine-derived sulfami-
date 1, we observed that weakly basic (conjugate acid pKa
e 7) nucleophiles reacted in nucleophilic displacements to
provide enantiopure (>97% ee) â-substituted alanines;
however, enolates of 1,3-dicarbonyl compounds added to
sulfamidate 1 by a mechanism featuring â-elimination to
provide a dehydroalanine intermediate that underwent sub-
sequent Michael addition and afforded racemized product
(PhF ) 9-(9-phenylfluorenyl), Figure 1).1
(1) (a) Wei, L.; Lubell, W. D. Org. Lett. 2000, 2, 2595 and refs 9-19
therein. (b) Wei, L.; Lubell, W. D. Can. J. Chem. 2001, 79, 94 and refs
1-3 therein.
(2) Representative examples include (a) Bajgrowicz, J. A.; El Hallaoui,
A.; Jacquier, R.; Pigiere, C.; Viallefont, P. Tetrahedron 1985, 41, 1833.
(b) Jackson, R. F. W.; Wishart, N.; Wythes, M. J. Synlett 1993, 219. (c)
Jost, K.; Rudinger, J. Collect. Czech. Chem. Commun. 1967, 32, 2485. (d)
Ciapetti, P.; Soccolini, F.; Taddei, M. Tetrahedron 1997, 53, 1167. (e)
Barton, D. H. R.; Crich, D.; Herve´, Y.; Poitier, P.; Thierry, J. Tetrahedron
1985, 41, 4347. (f) Strazewski, P.; Tamm, C. Synthesis 1987, 298. (g)
Hoffmann, M. G.; Zeis, H. J. Tetrahedron Lett. 1992, 33, 2669. (h) Barton,
D. H. R.; Herve´, Y.; Poitier, P.; Thierry, J. Tetrahedron 1988, 44, 5479. (i)
Maurer, P. J.; Miller, M. J. J. Am. Chem. Soc. 1982, 104, 3096. (j) Olsen,
R. K.; Ramasamy, K.; Emery, T. J. Org. Chem. 1984, 49, 3527.
(3) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetrahedron:
Asymmetry 1990, 1, 881.
Figure 1. N-(PhF)serine and N-(PhF)homoserine cyclic sulfami-
dates 1 and 2.
Seeking to expand the utility of amino-acid-derived cyclic
sulfamidates, we have now investigated the related six-
(4) Pansare, S. V.; Huyer, G.; Arnold, L. D.; Vederas, J. C. Org. Synth.
1992, 70, 1.
10.1021/ol016225b CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/24/2001

membered cyclic sulfamidate 2 derived from homoserine.
Although numerous examples of five-membered cyclic
sulfamidates have been presented in the literature,1,3 few
reports have been made of the synthesis and reactivity of
their six-membered counterparts.6,7 In the synthesis of
N-methyl-D-aspartate receptor antagonists, nucleophilic ring
opening of sulfamidate 3 was reported to proceed with
tetrabutylammonium fluoride at 70 °C to furnish both the
displacement product dibenzo[a,d]cycloalkenimine 4 and
vinyl elimination product 5 (Figure 2).6b To the best of our
homoserine 6,5 by using similar protocols as those reported
for the preparation of its five-membered counterpart (Scheme
1).1,8 Initially, amino alcohol 6 was treated with thionyl
chloride, triethylamine, and imidazole in dichloromethane
to furnish a 4:1 mixture of 2R:2S-sulfamidite diastereomers
7.8 When imidazole was omitted from the reaction mixture,
the major isolated product was symmetrical sulfite 8.9
Diastereomers 7 were separated by chromatography on silica
gel using an eluant of 0-20% EtOAc in hexane. Oxidation
of the major (2R,4S)-sulfamidite 7 with catalytic ruthenium
trichloride and sodium periodate in acetonitrile and water at
0 °C afforded sulfamidate 2 in 89% yield.10 On the other
hand, treatment of the minor (2S,4S)-sulfamidite 7 under the
same conditions gave no oxidation product 2 and the starting
material was recovered unchanged.
The configurational assignments for sulfamidites 7 were
made on the basis of their proton NMR spectra with
comparison to sulfamidate 2. Sulfamidites 7 and sulfamidate
2 were expected to adopt a chair conformation, which has
been shown by NMR studies to be the preferred conformation
of the related six-membered cyclic sulfates (Figure 3).11
Figure 2. Ring opening of six-membered sulfamidate 3.6
knowledge, no example of a homoserine-derived cyclic
sulfamidate had been reported prior to our study. In light of
the importance of γ-substituted amino acids, such as γ-amino
butyric acid (GABA), as well as the interesting reactivity
observed with serine-derived sulfamidate 1, we have now
explored the synthesis and reactivity of N-(PhF)homoserine-
derived sulfamidate 2. Our preliminary findings have dem-
onstrated that sulfamidate 2 reacts effectively with nitrogen,
sulfur, and oxygen nucleophiles to provide enantiopure
γ-substituted R-amino acids.
Scheme 1
Figure 3. Influence of S-O bond anisotropy on chemical shift in
sulfamidate 2 and sulfamidites 7.
Small coupling constants between the C-4 and C-5 protons
suggested that 2 and 7 adopt conformations with the tert-
butyl ester sitting axial, as has been previously observed for
related N-(PhF)pipecolate tert-butyl esters.12 In the proton
spectrum of 2, the anisotropy of the sulfamidate caused the
signals for the axial tert-butyl ester singlet (1.66 ppm), the
C-6 â-proton (4.88 ppm), and the PhF resonances (7.2-8.11
(6) (a) Lyle, T. A.; Magill, C. A.; Pitzenberger, S. M. J. Am. Chem.
Soc. 1987, 109, 7890. (b) 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, C. 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.
(7) (a) Lowe, G.; Reed, M. A. Tetrahedron: Asymmetry 1990, 1, 885.
(b) Meunier, N.; Veith, U.; Ja¨ger, V. Chem. Commun. 1996, 331. (c) Espino,
C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123,
6935.
(4S)-tert-Butyl 2,2-dioxo-3-PhF-1,2,3-oxathiazainane-4-
carboxylate (2) was synthesized from tert-butyl N-(PhF)-
(5) Gosselin, F.; Lubell, W. D. J. Org. Chem. 1998, 63, 7463 and ref 16
therein.
2966
Org. Lett., Vol. 3, No. 19, 2001

ppm) all to be shifted downfield.13 In the spectrum of (2S)-
7, the presence of the axial sulfoxide oxygen caused a similar
downfield shift of its tert-butyl ester singlet (1.61 ppm) and
C-6 â-proton (4.9 ppm). In the spectrum of (2R)-7, only the
PhF resonances (7.20-8.27 ppm) were shifted further
downfield by the presence of the equatorial sulfoxide oxygen,
and the signals for the tert-butyl ester singlet (1.40 ppm)
and C-6 â-proton (4.37 ppm) remained upfield. These
assignments also correlated with the fact that only the (2R)-
sulfamidite (2R)-7 was oxidized to sulfamidate 2, because
in sulfamidite (2S)-7, the S+-O- group sits in an axial
position and access of the oxidant to the sulfur was blocked
by the PhF group.
hexanes) was observed by TLC. Sodium azide and potassium
thiocyanate were used without additional NaH. The solution
was then cooled, poured into a 1 M NaH2PO4 solution, and
agitated to hydrolyze the sulfamic acid intermediate. The
desired γ-substituted R-N-(PhF)amino esters 9 were isolated
after extraction with EtOAc and column chromatography on
silica gel. Amine nucleophiles were later found to be
sufficiently reactive in the absence of NaH and provided
clean products after heating with 2 in acetonitrile at 70 °C
for 30 h. Phenolate and thiophenolate ions both reacted with
sulfamidate 2 to provide, respectively, O-phenylhomoserine
9i and S-phenylhomocysteine 9h. The related O-alkylho-
moserine and S-alkylhomocysteine analogues could not be
isolated from treatment of 2 with methoxide and benzylthi-
olate ions in preliminary experiments; instead, cursory
analyses of the reaction mixtures indicated decomposition
of sulfamidate 2.
Ring opening of sulfamidate 2 was examined using
nitrogen, sulfur, and oxygen nucleophiles (Table 1). In our
Table 1. Nucleophilic Opening of Sulfamidate 2
Scheme 2
entry
nucleophile
conditions
9 (%)
[R]20
D
a
b
NaN3
DMF, 60°, 24 h
NaH, DMF, 60°, 24 h
DMF, 60°, 24 h
83
50
56
65
85
95
80
90
85
91
68
56
0
-211°
-165°
-165°
-165°
-217°
-217°
-130°
-130°
-146°
-176°
-210°
-310°
imidazole
imidazole
imidazole
morpholine
morpholine
piperidine
piperidine
PhNH2
i-BuNH2
KSCN
PhSH
PhSH
PhOH
CH3CN, 75°, 30 h
NaH, DMF, 60°, 24 h
CH3CN, 75°, 30 h
DMF, 60°, 24 h
CH3CN, 75°, 30 h
CH3CN, 75°, 30 h
CH3CN, 75°, 30 h
CH3CN, 75°, 30 h
NaH, DMF, 60°, 24 h
CH3CN, 75°, 30 h
NaH, DMF, 60°, 60 h
c
d
e
f
g
h
i
56
-178°
Deprotection of γ-substituted R-N-(PhF)amino esters 9 was
demonstrated by treating piperidinyl analogue 9d with TFA
in dichloromethane for 18 h (Scheme 2). The trifluoroacetate
salt was obtained in acceptable purity by evaporation of the
volatiles, digestion of the residue into water, filtration of the
insoluble hydrocarbon, and evaporation of the aqueous phase.
Amino acid 10d was later isolated in zwiterionic form after
ion exchange chromatography.
initial procedure, sulfamidate 2 (100 mol %), the nucleophile
(2-300 mol %), and sodium hydride (2-300 mol %) were
heated in DMF at 60 °C for 24-48 h, when complete
consumption of starting material (Rf ) 0.3 in 1:3 EtOAc/
(8) A 0.05 M solution of N-(PhF)homoserine 6 (2 g, 4.7 mmol, prepared
according to ref 5) in dichloromethane was treated in the same manner as
described for the synthesis of serine-derived cyclic sulfamidites in ref 1.
Chromatography on silica gel with a gradient of 0-10% EtOAc in hexane
furnished 1.6 g (71%) of (2R,4S)-tert-butyl 2-oxo-3-PhF-1,2,3-oxathiaza-
inane-4-carboxylate (2R)-7 and 0.5 g (23%) of (2S)-7. First to elute was
(2S)-7: Rf ) 0.36 (30% EtOAc in hexanes); mp 166-167 °C; [R]20D 212°
(10) The same protocol described in ref 1 for the oxidation of serine-
derived sulfamidite to sulfamidate 1 was employed to convert (2R)-7 (500
mg) to 2. N-(PhF)homoserine-derived cyclic sulfamidate 2 (468 mg, 89%)
crystalized upon evaporation of the combined dried organic extractions:
1
(c 0.34, CHCl3); H NMR δ 1.26 (m, 1 H), 1.61 (s, 9 H), 1.78 (m, 1 H),
3.16 (dd, 1 H, J ) 2.5, 5.4), 3.53 (m, 1 H), 4.90 (m, 1 H), 7.19-7.77 (m,
13 H); 13C NMR δ 22.6, 27.9, 49.3, 54.6, 76.6, 81.7, 169.9; HRMS calcd
for C27H27O4NNaS (M + Na) 484.1559, found 484.1560. Second to elute
mp 188-188.5 °C; [R]20 268° (c 0.37, CHCl3); 1H NMR δ 1.10 (m, 1
D
H), 1.66 (s, 9 H), 1.74 (m, 1 H), 3.85 (br d, 1 H, J ) 5.3), 4.15 (m, 1 H),
4.88 (m, 1 H), 7.20-8.11 (m, 13 H); 13C NMR δ 22.4, 28.0, 58.3, 70.7,
78.6, 82.6, 168.3; HRMS calcd for C27H27O5NNaS (M + Na) 500.1508,
found 500.1489.
was (2R)-7: Rf ) 0.27 (20% EtOAc in hexanes); mp 172-173 °C; [R]20
D
132° (c 0.33, CHCl3); 1H NMR δ 1.40 (s, 9 H), 2.18 (m, 1 H), 2.69 (m, 1
H), 3.31 (dd, 1 H, J ) 3.4, 4.3), 3.94 (ddd, 1 H, J ) 9.7, 10.9, 16.4), 4.37
(m, 1 H), 7.20-8.27 (m, 13 H); 13C NMR δ 26.6, 27.8, 54.3, 57.0, 76.8,
81.3, 170.6; HRMS calcd for C27H27O4NNaS (M + Na) 484.1559, found
484.1541.
(11) (a) Reviewed in: Lohray, B. B. Synthesis 1992, 1035. (b) Wood,
G.; McIntosh, J. M.; Miskow, M Tetrahedron Lett. 1970, 4895.
(12) (a) Christie, B. D.; Rapoport, H. J. Org. Chem. 1985, 50, 1239. (b)
Swarbrick, M. E.; Gosselin, F.; Lubell, W. D. J. Org. Chem. 1999, 64,
1993. (c) Swarbrick, M. E.; Lubell, W. D. Chirality 2000, 12, 366.
(13) Deyrup, J. A.; Moyer, C. L. J. Org. Chem. 1969, 34, 175.
(9) HRMS calcd for C54H57O7N2S (MH+) 877.3887, found 877.3853.
Dimerization product 8 was best prevented under dilute conditions (0.05
M) using excess imidazole (400 mol %).
Org. Lett., Vol. 3, No. 19, 2001
2967

The enantiomeric purity of morpholine adduct 9c, prepared
from conditions in the presence of NaH, was examined after
its conversion to L- and D,L-N-(toluenesulfonyl)prolylamides
11 (Scheme 2). Hydrogenolytic cleavage of the PhF group
was performed at 10 atm of H2 with palladium-on-carbon
as catalyst in MeOH for 72 h. Subsequently, the amine
product was acylated with L- and D,L-N-(toluenesulfonyl)-
prolyl chloride and Et3N in CH2Cl2 for 1 h. After aqueous
washes and evaporation of the organic phase, the 400 MHz
1H NMR spectra of amides L- and D,L-11 were measured. In
the spectrum of D,L-11, diastereomeric tert-butyl ester signals
were observed at 1.48 and 1.57 ppm in C6D6 in a ∼1:1 ratio.
Measurement of the tert-butyl ester signals for material
prepared with L-proline under the same conditions demon-
strated amide L-11 to be of >97% diastereomeric purity.
Hence, γ-substituted R-N-(PhF)amino esters 9 and their
deprotection products 10 all are presumed to be of >97%
enantiomeric purity.
ee) γ-substituted R-amino acids. Homoserine-derived cyclic
sulfamidate 2 was readily synthesized from inexpensive
aspartic acid and was shown to react effectively with
nitrogen, sulfur, and oxygen nucleophiles. In light of the
utility and limitations of contemporary R-amino acid ana-
logues that possess remote electrophilic centers, sulfamidate
2 represents a practical alternative for the synthesis of novel
amino acids and natural products.
Acknowledgment. This research was supported in part
by the Natural Sciences and Engineering Research Council
of Canada, 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.
In conclusion, we have developed a novel configurationally
stable chiral educt for the synthesis of enantiopure (>97%
OL016225B
2968
Org. Lett., Vol. 3, No. 19, 2001