Stereoselective synthesis of α-hydroxy-β-amino acid derivatives from β-hydroxy-γ,δ-unsaturated sulfilimine

Article abstract of DOI:10.1016/j.tetlet.2008.03.114

The first report on the use of N-sulfinyl benzylcarbamate for the preparation of N-Cbz sulfilimine from the corresponding sulfoxide is reported. The sulfilimine moiety is utilized as an intramolecular nucleophile for the regio- and stereoselective heterofunctionalization of an alkene to furnish a bromo carbamate which is used as a key advanced intermediate in the synthesis of representative α-hydroxy-β-amino acid derivatives.

Full text of DOI:10.1016/j.tetlet.2008.03.114

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3216–3220
Stereoselective synthesis of a-hydroxy-b-amino acid derivatives
from b-hydroxy-c,d-unsaturated sulfilimine
Sadagopan Raghavan *, Shaik Mustafa
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 25 February 2008; revised 17 March 2008; accepted 21 March 2008
Available online 28 March 2008
Abstract
The first report on the use of N-sulfinyl benzylcarbamate for the preparation of N-Cbz sulfilimine from the corresponding sulfoxide is
reported. The sulfilimine moiety is utilized as an intramolecular nucleophile for the regio- and stereoselective heterofunctionalization of
an alkene to furnish a bromo carbamate which is used as a key advanced intermediate in the synthesis of representative a-hydroxy-b-
amino acid derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: N-Sulfinyl benzylcarbamate; Sulfoxide; N-Cbz sulfilimine; Bromo carbamate; (2S,3R)-AHDA; (2S,3R)-AHPBA
a-Hydroxy-b-amino acids are an important class of
compounds that occur in diverse natural and synthetic
molecules possessing significant biological activity; for
example, paclitaxel,1 the aminopeptidase inhibitor amasta-
tin,2 the renin inhibitor KRI-13143 and the anti-bacterial
agent dideoxy-kanamycin.4 Not surprisingly, much effort
has been expended on the asymmetric synthesis of this
structural unit.5 Though relative stereocontrol in the syn-
thesis of the amino alcohol subunit has been satisfactory,
particularly one that employs a common advanced inter-
mediate, for the synthesis of a-hydroxy-b-amino acids.
In 2004, we reported a novel method for the preparation
of amino alcohol derivatives6 from b-hydroxy/siloxy-c,d-
unsaturated N-Ts sulfilimines. The synthetic methodology
demonstrated the potential of the sulfilimine as an intramo-
lecular nucleophile; however, the products bearing a N-Ts
group could only be transformed into free NH-derivatives
under harsh conditions (Eq. 1).
O
S
OH Br
NHTs
NTs OH
NBS, H2O
OBn
S
OBn
ð1Þ
Ph
Toluene, 90%
Ph
many of the reported methods suffer from limited practical
utility because of the multi-step reaction sequences and
demand for unusual reagents and synthetic intermediates.
Therefore, it is of interest to develop new efficient routes,
To fully exploit the potential of our methodology, it was
imperative to prepare sulfilimines possessing protecting
groups that are readily removable under mild conditions.
To the best of our knowledge, only N-Ts sulfilimines have
been prepared from the corresponding optically active sulf-
oxides either with retention or inversion of configuration.7
We report herein for the first time, the synthesis of
b-hydroxy-c,d-unsaturated N-Cbz sulfilimine from the
*
Corresponding author. Tel.: +91 040 27160123; fax: +91 040
27160512.
E-mail addresses: purush101@yahoo.com, sraghavan@iict.res.in
(S. Raghavan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.114

S. Raghavan, S. Mustafa / Tetrahedron Letters 49 (2008) 3216–3220
3217
CbzN
OP
O
S
OP
O
S
OP
NBS, H2O
Toluene
CbzNSO
CH3CN
S
Ar
Br
NHCbz
Bromo carbamate
Ar
Ar
Sulfoxide
N-Cbz Sulfilimine
OH
HO2C
R
P = H/Protecting group
NH2
1; (2S,3R)-AHDA, R = Hexyl
2; (2S,3R)-AHPBA, R = Phenyl
Scheme 1.
corresponding readily available sulfoxide,8 its further
conversion to a bromo carbamate en route to the synthesis
of (2S,3R)-3-amino-2-hydroxydecanoic acid ((2S,3R)-
AHDA) and (2S,3R)-3-amino-2-hydroxy-4-phenylbuta-
noic acid (2S,3R-AHPBA), Scheme 1.
that were separated by column chromatography on silica
gel. The individual sulfilimines 5a and 5s were subjected
to treatment with freshly recrystallized N-bromosuccin-
imide (NBS) to yield bromocarbamates 7s (70%) and 7a
(72%), respectively. The reaction proceeded highly regio-
and stereoselectively.21 The oxidation of 7s and 7a using
mCPBA yielded sulfone 8 (85%), thereby proving the ste-
reoconvergency (at carbon) in the reactions of 5a and 5s,
Scheme 2.
Further reactions were initially attempted on the bro-
mocarbamate 7s (though both 7s and 7a can be utilized).
Thus, on treatment of 7s with excess Hex2CuLi in THF
the chain elongated amino alcohol derivative 9s was
obtained in good yield (70%). Further elaboration to the
target required transformation of the sulfinyl moiety into
a hydroxyl group. The treatment of 9s with trifluoroacetic
anhydride (TFAA) in DCM afforded a less polar product,
assumed to be the Pummerer intermediate 10, which with-
out isolation was treated with aq satd NaHCO3 solution
and NaBH4 in an attempt to obtain primary alcohol 11.
However, we only isolated the inverted sulfoxide 9a as
the sole product (75%). The reaction probably proceeds
via sulfurane intermediate 12, which is the less polar inter-
mediate observed by TLC. Treatment with aq satd
NaHCO3 then leads to the displacement of the trifluoro-
acetate group with inversion of the sulfur configuration
to yield intermediate 13 which then ring opens to afford
the inverted sulfoxide 9a, Scheme 3.22
(2S,3R)-AHDA is an unusual amino acid constituent of
microginin,9 an ACE inhibitor, and several other linear
peptides10 isolated from the cyanobacterium Microcystis
aeruginosa. (2S,3R)-AHPBA is a non-proteinogenic con-
stituent of the dipeptide bestatin,11 an aminopeptidase
inhibitor, isolated from Streptomyces olivoreticuli. The syn-
thesis of AHDA has been reported by many groups using,
(a) asymmetric functionalization of olefins12 via asym-
metric epoxidation/dihydroxylation, (b) a chiral pool strat-
egy,13 (c) Lewis acid-mediated nucleophilic addition of
ketene acetals to non-racemic imines,14 (d) conjugate addi-
tion of chiral amines to enoates15 and other routes.16 Like-
wise, the synthesis of (2S,3R)-AHPBA has been reported
by many groups.5b,17
The synthesis of AHDA commenced from the b-
hydroxy sulfoxide18 3, obtained in two steps from (R)-
methyl p-tolyl sulfoxide. Protection of 3 as its silyl ether
25
4 (90%, ½aꢀD þ108:7 (c 0.67, CHCl3)) by treatment with
TBS–Cl followed by reaction with N-sulfinyl benzylcarb-
amate19 (CbzNSO) in acetonitrile20 afforded a 7:3 mixture
25
of diastereomeric sulfilimines 5s (½aꢀD ꢁ17.5 (c 1, CHCl3))
25
and 5a (½aꢀD +8.5 (c 0.35, CHCl3)), respectively, in 75%
yield along with the corresponding sulfide 6 (10% yield)
O
CbzN
CbzN
OTBS
O
S
OP
OTBS
Ref. 17
CbzNSO
S
+
S
S
p
-Tol
Me
p
-Tol
p
-Tol
p-Tol
CH3CN, 75%
3, P = H
4, P = TBS
5a
5s
TBS-Cl, Imid.,
DCM, 90%
OTBS
S
p
-Tol
CbzN
OTBS
O
S
OTBS
6
NBS, H2O
S
p
-Tol
p
p
-Tol
-Tol
Br
NHCbz
Toluene, 70%
5a
7s
O
S
OTBS
m
CPBA
p
-Tol
Br
NHCbz
CHCl3, 85%
O
CbzN
O
S
OTBS
OTBS
8
NBS, H2O
S
Br
NHCbz
p
-Tol
Toluene, 72%
5s
7a
Scheme 2.

3218
S. Raghavan, S. Mustafa / Tetrahedron Letters 49 (2008) 3216–3220
O
S
OTBS
O
S
OTBS
Hex2CuLi, THF
70%
p
-Tol
Br
NHCbz
p-Tol
NHCbz
7s
9s
OTBS
OTBS
S
HO
p-Tol
F3C(O)CO
NHCbz
NHCbz
Aq. NaHCO3, NaBH4
11
10
9s
TFAA, DCM
H
OC(O)CF3
O
S
N
p
-Tol
Cbz
S
N
OTBS
OTBS
H2O
p
-Tol
Cbz
12
OTBS
13
O
S
75%
p-Tol
NHCbz
9a
Scheme 3.
CbzN
OP
O
S
OH
O
S
OH
NBS, H2O
Toluene, 85%
R2CuLi, THF
S
p
-Tol
p
-Tol
Br
NHCbz
p
-Tol
R
NHCbz
5s, P = TBS
14, P = H
TBAF,
THF, 93%
15
16a, R = Me, 92%; 16b, R = Bu, 95%
16c, R = Hex, 92%; 16d, R = Ph, 85%
Scheme 4.
This unexpected result called for a revision of the syn-
thetic strategy and further experiments were carried out
with sulfilimine 5s. Deprotection of the silyl group in 5s
by treatment with n-tetrabutylammonium fluoride (TBAF)
This strategy obviates the necessity of starting from
different (amino acid) precursors to synthesize 1,2-amino
alcohols5a,12b,c,15 and is versatile for its flexibility for the
introduction of various carbon side chains and hetero-
atoms at a later stage in the synthesis on an advanced inter-
mediate. Compound 16c was transformed into AHDA as
25
furnished the allyl alcohol 14 (93%, ½aꢀD ꢁ103 (c 2.25,
CHCl3)). The reaction of 14 with NBS proceeded regio-
25
25
and stereoselectively to yield bromohydrin 15 (85%, ½aꢀD
depicted in Scheme 5. The treatment of 16c (½aꢀD +10.7
+11.3 (c 0.20, CHCl3)), which served as the common
advanced intermediate for the preparation of both AHDA
and AHPBA. Thus, treatment with excess cuprate reagents
in THF cleanly afforded the amino alcohol derivatives
16a–d in 85–95% yields, Scheme 4.
(c 0.15, CHCl3)) with excess 2,2-dimethoxypropane in the
25
presence of cat. CSA yielded acetonide 17c (85%, ½aꢀD
+53.1 (c 1.3, CHCl3)). Subjecting 17c to TFAA led to
formation of intermediate 18c which without isolation
was hydrolyzed by the treatment with aq satd NaHCO3
OMe
O
O
O
O
S
OH
NCbz
R
NCbz
R
TFAA, DCM
S
S
OMe
p-Tol
p
-Tol
p
-Tol
R
Cat. CSA, DCM
F3C(O)CO
NHCbz
16c, R = Hex
16d, R = Ph
17c, R = Hex, 85%
17d, R = Ph, 83%
18c, R = Hex
18d, R = Ph
OH
O
O
NaClO2,
NCbz Cat. CSA, MeOH
NCbz
R
Aq. NaHCO3
MeO2C
R
MeO2C
OHC
NaH2PO4, t-BuOH
NHCbz
R
then CH2N2, ether
19c, R = Hex,
19d, R = Ph
20c, R = Hex, 65% overall
20d, R = Ph,
21c, R = Hex, 95%
21d, R = Ph, 60% overall
Scheme 5.

S. Raghavan, S. Mustafa / Tetrahedron Letters 49 (2008) 3216–3220
3219
to furnish aldehyde 19c. Pinnick oxidation23 afforded the
acid which was characterized as its methyl ester 20c (65%
7. For the preparation of optically active sulfilimines from sulfoxides
using N-sulfinyl-p-toluenesulfonamide see: (a) Yamgishi, F. G.; Ray-
ner, D. R.; Zwicker, E. T.; Cram, D. J. J. Am. Chem. Soc. 1973, 95,
1916; (b) Christensen, B. W. J. Chem. Soc. D 1971, 597; (c) Cram, D. J.;
Day, J.; Rayner, D. R.; von Schriltz, D. M.; Duchamp, D. J.; Garwood,
D. C. J. Am. Chem. Soc. 1970, 92, 7369; (d) Christensen, B. W.; Kjaer,
A. Chem. Commun. 1969, 934; (e) Johnson, C. R.; Rigau, J. J. J. Org.
Chem. 1968, 33, 4340; (f) Using N,N0-bis(p-toluenesulfonyl)sulfur
diimide see Ref. 7a. Using p-tosyl isocyanate see: (g) Garwood, D. C.;
Jones, M. R.; Cram, D. J. J. Am. Chem. Soc. 1973, 95, 1925.
8. The b-hydroxy sulfoxides can be prepared readily from the keto
sulfoxide by diastereoselective reduction following Solladie’s proto-
col, see: (a) Solladie, G.; Demailly, G.; Greck, C. Tetrahedron Lett.
1985, 26, 435; (b) Solladie, G.; Frechou, C.; Demailly, G.; Greck, C. J.
Org. Chem. 1986, 51, 1912; (c) Carreno, M. C.; Garcia Ruano, J. L.;
Martin, A.; Pedregal, C.; Rodrigues, J. H.; Rubio, A.; Sanchez, J.;
Solladie, G. J. Org. Chem. 1990, 55, 2120.
25
overall yield for 3 steps, ½aꢀD +6.5 (c 1, CHCl3)). Deprotec-
tion of the acetonide furnished AHDA derivative 21c (95%,
25
½aꢀD +12.5 (c 1.4, CHCl3, 25% overall yield from 3 in 10
steps)). A similar sequence of reactions starting from 16d
gave AHPBA derivative 21d (60% overall yield for 3 steps,
25
½aꢀD +80 (c 0.40, MeOH, 18.6% overall yield from 3 in 10
steps)) with spectral characteristics in excellent agreement
to those reported in the literature.24
To summarize, N-Cbz sulfilimines were readily prepared
from the corresponding sulfoxide with modest stereoselec-
tivity. Further, it was used as an intramolecular nucleo-
phile to oxidatively functionalize an alkene. Also, we
have disclosed an efficient route to a-hydroxy-b-amino acid
derivatives, a class of compounds with widely varying
biological activities, starting from a common advanced
intermediate.
9. Okino, T.; Matsuda, H.; Murakami, M.; Yamaguchi, K. Tetrahedron
Lett. 1993, 34, 501.
10. (a) Ishida, K.; Kato, T.; Murakami, M.; Watanabe, M.; Watanabe,
M. F. Tetrahedron 2000, 56, 8643; (b) Ishida, K.; Matsuda, H.;
Murakami, M. Tetrahedron 1998, 54, 13475.
11. Suda, H.; Takita, T.; Aoyagi, T.; Umezawa, H. Antibiotics 1976, 26,
100.
Acknowledgements
12. (a) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999, 64, 2852;
(b) Sugimura, H.; Miura, M.; Yamada, N. Tetrahedron: Asymmetry
1997, 8, 4089; (c) Righi, G.; Chionne, A.; D’Achille, R.; Bonini, C.
Tetrahedron: Asymmetry 1997, 8, 903.
13. (a) Wee, A. G. H.; McLeod, D. D. J. Org. Chem. 2003, 68, 6268; (b)
Jefford, C. W.; Mcnulty, J.; Lu, Z. H.; Wang, J. B. Helv. Chim. Acta
1996, 79, 1203; (c) Tuch, A.; Saniere, M.; Merrer, Y. L.; Depezay, J.
Tetrahedron: Asymmetry 1996, 7, 2901.
S.R. is thankful to Dr. J. M. Rao, Head, Org. Div. I and
Dr. J. S. Yadav, Director, IICT for constant support and
encouragement. S.M. is thankful to the CSIR, New Delhi,
for a fellowship. Financial assistance from DST (New
Delhi) is gratefully acknowledged.
14. Ha, H. J.; Ahn, Y.-G.; Woo, J.-S.; Lee, G. S.; Lee, W. K. Bull. Chem.
Soc. Jpn. 2001, 74, 1667.
References and notes
15. Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Goodwin, C. J.
Tetrahedron: Asymmetry 1994, 5, 203–206.
16. (a) Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron 1994, 50,
11303; (b) Shirode, N. M.; Rakeeb, A.; Deshmukh, A. S. Tetrahedron
2006, 62, 4615.
1. Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed.
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2. Aoyagi, T.; Tobe, H.; Kojima, F.; Hamada, M.; Takeuchi, T.;
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17. Wassermann, H. H.; Xia, M.; Peterson, A. K.; Jorgensen, M. R.;
Curtis, E. A. Tetrahedron Lett. 1999, 40, 6163 and references cited
therein.
18. Raghavan, S.; Joseph, S. C. Tetrahedron: Asymmetry 2003, 14, 101.
19. (a) Weinreb, S. M.; Garigapati, R. S.; Gainor, J. A. Heterocycles
1984, 21, 309; (b) Garigipati, R. S.; Freyer, A. J.; Whittle, R. R.;
Weinreb, S. M. J. Am. Chem. Soc. 1984, 106, 7861.
20. The reaction of 4 with CbzNSO was attempted in different solvents to
determine the stereoselectivity and acetonitrile was found to be the
best in terms of yield and diastereoselectivity.
3. Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.;
Umeyama, H.; Kiso, Y. Chem. Commun. 1989, 1678.
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´
´
5. (a) Sanchez-Obregon, R.; Salgado, F.; Ortiz, B.; Dıaz, E.; Yuste, F.;
´
Walls, F.; Garcıa Ruano, J. L. Tetrahedron 2007, 63, 10521 and
references cited therein; (b) Raghavan, S.; Rasheed, M. A. Tetrahe-
dron: Asymmetry 2003, 14, 1371 and references cited therein.
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Reaction of sulfoxides with CbzNSO in different solvents
Entry
Sulfoxide
Solvent
Stereoselectivity
Yield (%)
inversion:retention
1
2
3
4
4
4
DCM
THF
PhH
1:1
1:1
1:1
50
20
20
O
S
OTBS
OTBS
OTBS
4
5
6
CH3CN
CH3CN
CH3CN
3:2
1:1
1:1
75
70
70
p
p
p
-Tol
-Tol
-Tol
O
S
O
S
OBn

3220
S. Raghavan, S. Mustafa / Tetrahedron Letters 49 (2008) 3216–3220
21. The inversion of sulfur configuration is based on our earlier
work using N-Ts sulfilimine as the intramolecular nucleophile, see
Ref. 6. The syn disposition of the substituents at C2 and C3 in 7a was
proven by NOE studies on the acetonide derived from 15.
recovery of the starting material from
derivative.
23. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
a syn-amino alcohol
2091.
22. The result obtained herein is in contrast to that reported
by Garcia-Ruano and co-workers (Ref. 5a) who report
24. Herranz, R.; Castro-Pichel, J.; Garcia-Lopez, T. Synthesis 1989,
703.