Sulfinyl moiety as an internal nucleophile. Part 6: Stereospecific synthesis of 3-amino-2-hydroxy-4-phenylbutanoate

Article abstract of DOI:10.1016/S0957-4166(03)00239-8

A novel and stereospecific synthesis of (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoate (AHPBA) is disclosed. The key step includes regio- and stereospecific functionalization of an alkene by the pendant sulfinyl group.

Full text of DOI:10.1016/S0957-4166(03)00239-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1371–1374
Sulfinyl moiety as an internal nucleophile. Part 6: Stereospecific
synthesis of 3-amino-2-hydroxy-4-phenylbutanoateꢀ
Sadagopan Raghavan* and M. Abdul Rasheed
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 January 2003; revised 10 March 2003; accepted 11 March 2003
Abstract—A novel and stereospecific synthesis of (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoate (AHPBA) is disclosed. The key
step includes regio- and stereospecific functionalization of an alkene by the pendant sulfinyl group. © 2003 Elsevier Science Ltd.
All rights reserved.
1. Introduction
because of their complexity, demand for unusual
reagents and synthetic intermediates. We have been
interested in the stereo- and regioselective functionaliza-
tion of olefins using the sulfinyl moiety as an internal
nucleophile.15 We disclose herein an efficient, stereospe-
cific synthesis of (2R,3S)-3-amino-2-hydroxy-4-phenyl
butanoic acid derivative exploiting this methodology.
b-Amino-a-hydroxy acid derivatives are important
because many of them occur in diverse natural and
synthetic compounds possessing significant biological
activity; for example in taxol 1,1 bestatin 2,2 microginin
3,3 HIV protease inhibitors,4 and renin inhibitors5 (Fig.
1).
Not surprisingly, a great deal of attention has been
devoted towards their efficient synthesis. The methods
include acid hydrolysis of cyanohydrins6 derived from
a-amino aldehydes, iodocyclocarbamation,7 b-lactam
ring opening,8 aldol condensation of chiral enolates,9
stereoselective reduction,10 epoxidation,11 conjugate
addition of amines12 and use of sugar derivatives as
starting materials.13 Bestatin, a dipeptide, isolated from
Streptomyces olivoreticuli contains a non-proteinogenic
2. Results and discussion
The synthesis of AHPBA commenced from the b-
hydroxy sulfoxide 6 obtained by diastereoselective
reduction (>95% d.e)16 of b-keto sulfoxide 5.17 Treat-
ment of the allyl alcohol 6 with NBS in toluene in the
presence of water afforded the bromodiol 8.15c Subject-
ing the bromodiol 8 to 2,2-dimethoxy propane in the
presence of cat. amounts of CSA yielded the acetonide
9, the 13C spectrum of which revealed resonances at l
19.4, 29.5 for the methyl groups and at l 100.7 for the
quaternary carbon of the acetonide proving unambigu-
ously the 1,3-syn disposition18 of the hydroxy groups in
8. The proton attached to the carbon bearing the
bromine atom in 8 appeared as a triplet with J=10.26
Hz indicating an anti disposition of bromine relative to
the hydroxy groups. The regio- and stereoselectivity of
the reaction can be rationalized by invoking the inter-
mediate sulfoxonium salt 7 arising from the 6-endo
nucleophilic attack of the sulfinyl moiety onto the
olefin, p complexed to the bromonium ion, and its
subsequent hydrolysis by attack of water at sulfur. The
benzylic carbon being better able to stabilize a partial
positive charge leads to the observed 6-endo opening
product (Scheme 1).
(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoic
acid
(AHPBA) residue. It is an aminopeptidase inhibitor
that exhibits immunostimulatory as well as cytotoxic
activity. Several synthetic routes to bestatin have been
reported.14 Many of the reported methods are non-
stereoselective and are of limited practical utility
Figure 1.
ꢀ IICT Communication No. 030126.
* Corresponding author. E-mail: purush101@yahoo.com
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00239-8

1372
S. Ragha6an, M. A. Rasheed / Tetrahedron: Asymmetry 14 (2003) 1371–1374
Scheme 1. Reaction conditions: (a) DIBAL, ZnCl2, THF, −78°C 1 h, 80%; (b) NBS, H2O, toluene, rt, 30 min 80%.
Scheme 2. Reaction conditions: (a) 2,2-DMP, cat. CSA, acetone, rt, 1 h, 90%; (b) NaN3, DMSO, 100°C, 8 h, 75%; (c) TFAA,
Et3N, CH3CN, 0°C, 10 min then aq. NaHCO3, NaBH4, 30 min, 85%; (d) PDC, DMF, rt, 16 h; (e) CH2N2, ether 70% for two
steps; (f) cat. CSA, MeOH, rt, 2 h, 85%; (g) Pd(OH)2/C, H2, (Boc)2O, MeOH, rt, 12 h, 80%.
3. Experimental
The amino group was introduced by nucleophilic dis-
placement of bromine by treatment of 9 with NaN3 in
DMSO. In addition to the expected azido acetonide 10,
another minor, less polar product, characterized as the
sulfide 11 was also isolated. Treatment of 10 with
TFAA in acetonitrile in the presence of Et3N afforded
the Pummerer intermediate,19 which without isolation
was treated in the same vessel with aq. saturated
NaHCO3 and NaBH4 to yield the alcohol 12 (Scheme
2).
Melting points were recorded on Buchi R-535 appara-
tus and are uncorrected. 1H NMR spectra were
recorded on Gemini-200 and Brucker 300 spectropho-
tometers in CDCl3 using TMS as internal standard.
Mass spectra were recorded on a Finnigan Matt 1200
mass spectrometer. Optical rotations were measured on
a Jasco Dip 360 digital polarimeter. Column chro-
matography was performed on silica gel (Merck, 100–
200 mesh).
Oxidation of 12 proceeded without incident with PDC
in DMF20 to afford the acid 13 which was characterized
as its methyl ester 14. The ester 14 was elaborated to
AHPBA as depicted in Scheme 2. Thus, deprotection of
the acetonide group by treatment with cat. amounts of
CSA in methanol afforded the diol 15 which upon
treatment with Pd(OH)2/C in the presence of (Boc)2O
in methanol under an atmosphere of hydrogen yielded
b-amino acid derivative 16.
3.1. (Ss)-1-(4-Methylphenylsulfinyl)-4-phenyl-(2R,3E)-3-
buten-2-ol, 6
To a solution of b-ketosulfoxide 5 (1.78 g, 6.25 mmol)
in THF (62 mL) was added the solution of anhydrous
ZnCl2 (6.9 mL, 6.9 mmol, 1 M/THF) and stirred at rt
for 1 h. The reaction mixture was then cooled to −78°C
and DIBAL-H (2 M/toluene, 3.46 mL 6.92 mmol) was
added dropwise. After 1 h at −78°C the reaction was
quenched by adding methanol (30 mL) and allowed to
attain ambient temperature. The solvent was then evap-
orated and the residue diluted with water and extracted
with ethyl acetate. The organic layer was washed suc-
cessively with 5% aq. NaOH, water, brine, dried over
anhydrous Na2SO4 and evaporated under reduced pres-
sure. The crude product was purified by column chro-
matography using 30% EtOAc/pet. ether as the eluent
In summary, we have disclosed a stereospecific synthe-
sis of (2R,3S)-AHPBA ester utilizing the sulfinyl moiety
as an internal nucleophile to stereo- and regioselectively
functionalize an olefin in the key step of the reaction
sequence. It is pertinent to note that starting from
(S)-tolyl methyl sulfoxide21 and following an identical
reaction sequence as detailed above, the (2S,3R)-
AHPBA, constituent of bestatin can be prepared.

S. Ragha6an, M. A. Rasheed / Tetrahedron: Asymmetry 14 (2003) 1371–1374
1373
to afford 6 (1.43 g, 5 mmol) in 80% yield. White solid.
matography using 30% EtOAc/pet. ether as the eluent
to afford initially the azido sulfide 11 (0.12 g, 0.33
mmol) in 10% yield and azido sulfoxide 10 (0.94 g, 2.43
1
Mp 95–97°C. H NMR (200 MHz, CDCl3) l 7.55 (d,
J=8.2 Hz, 2H), 7.40–7.20 (m, 7H), 6.70 (d, J=16.5 Hz,
1H), 6.15 (dd, J=16.5, 5.9 Hz, 1H), 5.0 (m, 1H), 3.90
(bs, 1H) 3.06 (dd, J=12.9, 8.2 Hz, 1H), 2.90 (dd,
J=12.9, 2.4 Hz, 1H), 2.45 (s, 3H). MS (FAB) 287
(M++H). [h]D +112.6 (c 0.6, CHCl3).
1
mmol) in 75% yield. Viscous oil. H NMR (200 MHz,
CDCl3) l 7.50 (d, J=8.2 Hz, 2H), 7.31 (m, 7H), 5.24
(d, J=1.5 Hz, 1H), 4.83 (dd, J=9.66, 2.23 Hz, 1H), 3.0
(dd, J=13.38, 9.66 Hz, 1H), 2.80 (dd, J=13.38, 2.23
Hz, 1H), 2.75 (d, J=1.5, Hz, 1H), 2.39 (s, 3H), 1.67 (s,
3H), 1.62 (s, 3H). 13C NMR (50 MHz, CDCl3) l 141.7,
140.9, 137.9, 130.1, 128.5, 127.4, 125.5, 123.7, 100.9,
74.5, 67.3, 61.8, 60.4, 28.5, 21.3, 19.1. MS (FAB) 386
(M++H), 328, 139. [h]D −131.75 (c 0.99, CHCl3).
3.2. 2-Bromo-(Ss)-4-(4-methylphenylsulfinyl)-1-phenyl-
(1R,2R,3S)-butane-1,3-diol, 8
To a solution of b-hydroxy sulfoxide 6 (1.43 g, 5.0
mmol) in toluene (20 mL) at rt was added water (153
ml, 8.5 mmol), N-bromosuccinimide (1.07g, 6 mmol)
and stirred for 30 min. The reaction mixture was taken
into ethyl acetate (50 mL) and washed successively with
10% aq. NaHCO3, water and brine. The organic layer
was dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude reaction mixture was
purified by column chromatography using 50% EtOAc/
pet. ether as the eluent to afford 8 (1.53 g, 4 mmol) in
3.5. 5-Azido-2,2-dimethyl-6-phenyl-(4R,5S,6R)-1,3-
dioxan-4-ylmethanol, 12
To a solution of the azido acetonide 10 (0.76 g, 1.98
mmol) in acetonitrile (10 mL) cooled at 0°C was added
triethylamine (0.83 mL, 5.94 mmol) followed by tri-
fluoroacetic anhydride (0.83 mL, 5.94 mmol) and
stirred for 10 min. A solution of NaHCO3 (1.67 g 19.8
mmol) in water (10 mL) was added at 0°C followed by
solid NaBH4 (0.15 g, 3.96 mmol) and the reaction
mixture stirred for another 30 min. The reaction mix-
ture was then extracted into ethyl acetate (40 mL) and
washed successively with water, brine and dried over
Na2SO4. The solvent was removed under reduced pres-
sure to afford a residue which was purified by column
chromatography using 30% EtOAc/pet. ether as the
eluent to afford 12 (0.44 g, 1.68 mmol) in 85% yield.
1
80% yield. White solid. Mp 123–125°C. H NMR (300
MHz, CDCl3) l 7.50 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2
Hz, 2H), 7.28 (bs, 5H), 5.0 (bs, 1H), 4.94 (d, J=8.0 Hz,
1H), 4.40 (m, 1H), 4.25 (t, J=8.0 Hz, 1H), 3.90 (bs,
1H), 3.27 (dd, J=13.4, 10.7 Hz, 1H), 3.18 (dd, J=13.4,
2.7 Hz, 1H), 2.45 (s, 3H). 13C NMR (50 MHz, CDCl3)
l 141.9, 140.4, 138.6, 130.2, 128.3, 126.9, 124.1, 74.2,
68.6, 61.8, 59.3, 21.4. MS (FAB) 383 (M++H), 365, 307,
154. [h]D −124.9 (c 1.47, CHCl3).
1
Viscous oil. H NMR (200 MHz, CDCl3) l 7.38 (m,
5H), 5.18 (d, J=2.23 Hz, 1H), 4.30 (m, 1H), 3.85 (dd,
J=11.15, 6.69 Hz, 1H), 3.72 (dd, J=11.15, 5.2 Hz,
1H), 2.94 (d, J=2.23 Hz, 1H), 2.20 (bs, 1H), 1.60 (s,
6H). 13C NMR (50 MHz, CDCl3) l 138.2, 128.5, 127.9,
125.6, 100.4, 74.5, 73.5, 63.2, 57.9, 28.6, 19.1. MS
(FAB) 264 (M++H), 246, 154. [h]D −147.0 (c 1.0,
CHCl3).
3.3. 5-Bromo-2,2-dimethyl-(Ss)-4-(4-methylphenylsulfinyl-
methyl)-6-phenyl-(4S,5R,6R)-1,3-dioxane, 9
To a solution of the bromodiol 8 (1.43 g, 3.74 mmol) in
acetone (7.5 mL) was added 2,2-dimethoxypropane (7.5
mL) and catalytic amounts of CSA and the mixture
stirred at rt for 1 h. Et3N, enough to neutralize CSA,
was added and the volatiles were removed under
reduced pressure. The residue was purified by column
chromatography using 30% EtOAc/pet. ether as the
eluent to afford 9 (1.43 g, 3.38 mmol) in 90% yield.
3.6. Methyl 5-azido-2,2-dimethyl-6-phenyl-(4R,5S,6R)-
1,3-dioxane-4-carboxylate, 14
To a solution of alcohol 12 (0.34 g, 1.29 mmol) in
DMF (2.6 mL) at rt was added pyridinium dichromate
(1.94 g, 5.18 mmol) and let stir for 16 h. The reaction
mixture was then extracted into ethyl acetate (30 mL)
and washed with water (2×10 mL). The organic layer
was washed with 10% aq. NaHCO3 (3×15 mL). The
bicarbonate layer was acidified to pH 2 with 5N HCl
and extracted with ethylacetate (3×15 mL). The com-
bined organic layers were washed successively with
water (10 mL) and brine. To this ethyl acetate layer was
added cold (0°C) ethereal CH2N2, generated in situ
from nitrosomethyl urea (0.28 g, 2.59 mmol) in ether
(10 mL) and 50% aq. KOH (4 mL) at 0°C, and stirred
at rt for 10 min. The solvent was removed under
reduced pressure to afford a residue which was purified
by column chromatography using 30% EtOAc/pet.
ether as the eluent to afford 14 (0.26 g, 0.9 mmol) in
70% overall yield for two steps. White crystalline solid.
1
Gummy liquid. H NMR (200 MHz, CDCl3) l 7.56 (d,
J=8.0 Hz, 2H), 7.36 (m, 7H), 4.90 (d, J=10.26 Hz,
1H), 4.67 (td, J=10.26, 2.2 Hz, 1H), 3.62 (t, J=10.26
Hz, 1H), 3.36 (dd, J=13.18, 2.2 Hz, 1H), 2.76 (dd,
J=13.18, 10.25 Hz, 1H), 2.45 (s, 3H), 1.76 (s, 3H), 1.57
(s, 3H). 13C NMR (50 MHz, CDCl3) l 141.6, 141.3,
138.1, 130.0, 128.3, 127.8, 124.0, 123.7, 100.7, 77.4,
69.3, 62.4, 52.4, 29.5, 21.4, 19.4. MS (FAB) 423 (M++
H), 365, 285. [h]D −127.5 (c 1.04, CHCl3).
3.4. 5-Azido-2,2-dimethyl-(Ss)-4-(4-methylphenylsulfinyl-
methyl)-6-phenyl-(4R,5S,6R)-1,3-dioxane, 10
To a solution of the bromo acetonide 9 (1.38 g, 3.25
mmol) in dimethyl sulfoxide (6.5 mL) was added
sodium azide (0.85 g, 13 mmol) and the reaction mix-
ture heated at 100°C for 8 h. The reaction mixture was
cooled to rt, diluted with ether (60 mL) and washed
successively with water, brine, dried over anhydrous
Na2SO4 and evaporated under reduced pressure to
afford a residue which was purified by column chro-
1
Mp 143–145°C. H NMR (300 MHz, CDCl3) l 7.40
(m, 5H), 5.23 (s, 1H), 4.83 (d, J=2.3 Hz, 1H), 3.83 (s,
3H), 3.34 (d, J=2.3 Hz, 1H), 1.69 (s, 3H), 1.61 (s, 3H).
13C NMR (75 MHz, CDCl3) l 168.6, 137.5, 128.6,

1374
S. Ragha6an, M. A. Rasheed / Tetrahedron: Asymmetry 14 (2003) 1371–1374
128.2, 125.6, 100.8, 74.0, 72.6, 58.5, 52.7, 28.6, 18.6. MS
(FAB) 292 (M++H), 264, 234. [h]D −94.95 (c 1.0,
CHCl3).
2. Suda, H.; Takita, T.; Aoyagi, T.; Umezawa, H. Antibi-
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3. Okino, T.; Matsuda, H.; Murakami, M.; Yamaguchi, K.
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5. (a) Abell, A. D.; Foulds, G. J. J. Chem. Soc., Perkin
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7. Kobayashi, S.; Isobe, T.; Ohno, M. Tetrahedron Lett.
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8. (a) Kobayashi, Y.; Takemoto, Y.; Ito, Y.; Terashima, S.
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A.; Cossio, F. P.; Aizpurua, J. M.; Mielgo, A.;
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9. (a) Pearson, W. H.; Hines, J. V. J. Org. Chem. 1989, 54,
4235; (b) Ha, H.-J.; Ahn, Y.-G.; Lee, G. S. Tetrahedron:
Asymmetry 1999, 10, 2327.
butanoate, 15
To the solution of the azido ester 14 (0.2 g, 0.73 mmol)
in methanol (1.5 mL) was added catalytic amounts of
CSA and the mixture stirred at rt for 2 h. Et3N was
added to neutralize CSA and methanol removed under
reduced pressure. The residue was purified by column
chromatography using 40% EtOAc/pet. ether as the
eluent to yield 15 (0.155 g, 0.62 mmol) in 85% yield.
White solid. Mp 154–156°C. 1H NMR (200 MHz,
CDCl3) l 7.40 (m, 5H), 5.02 (d, J=9.8 Hz, 1H), 3.83
(bs, 1H), 3.82 (s, 3H), 3.78 (d, J=9.8 Hz, 1H), 3.02 (bs,
1H), 2.6 (bs, 1H). MS (FAB) 252 (M++H), 234, 154.
[h]D −115.2 (c 1.0, CHCl3).
3.8. Methyl 3-N-t-butyloxycarbonylamino-2-hydroxy-4-
phenyl-(2R,3S)-butanoate, 16
10. Nozaki, K.; Sato, N.; Takaya, H. Tetrahedron: Asymme-
try 1993, 4, 2179.
To the solution of the diol ester 15 (50 mg, 0.2 mmol)
in methanol (0.8 mL) was added Pd(OH)2 (10 mg, 20%
by weight) and (Boc)2O (48 mg, 0.22 mmol) and stirred
under hydrogen atmosphere for 12 h. The catalyst was
filtered through a small pad of Celite and the filtrate
evaporated under reduced pressure. The residue was
purified by column chromatography using 30% EtOAc/
pet. ether as the eluent to yield 16 (50 mg, 0.16 mmol)
11. Saino, T.; Kato, S.; Nishizawa, R.; Takita, T.; Umezawa,
H. J. Chem. Soc., Perkin Trans. 1 1980, 1618.
12. Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. Synlett
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13. (a) Kang, S. H.; Ryu, D. H. Bioorg. Med. Chem. Lett.
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15. (a) Raghavan, S.; Joseph, S. C. Tetrahedron: Asymmetry
2003, 14, 101; (b) Raghavan, S.; Ramakrishna Reddy, S.;
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1
in 80% yield. White solid. Mp 96–97°C. H NMR (200
MHz, CDCl3) l 7.30 (m, 5H), 4.70 (d, J=10.4 Hz, 1H),
4.20 (m, 1H), 4.0 (bs, 1H), 3.70 (s, 3H), 3.0 (d, J=4.5
Hz, 1H), 2.90 (m, 2H), 1.40 (s, 9H). 13C NMR (75
MHz, CDCl3) l 174.0, 155.2, 137.5, 129.4, 128.6, 126.6,
79.6, 70.2, 54.2, 52.8, 38.2, 28.2. MS (FAB) 310 (M++
H), 254, 210. [h]D −73.4 (c 0.25, CHCl3).
16. (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)
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50, 1552.
18. Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945.
19. (a) Pummerer, R. Chem. Ber. 1909, 42, 2282; (b) Sugi-
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Acknowledgements
S.R. is thankful to Dr. J. S. Yadav, Head, Organic
Division I and Dr. K. V. Raghavan, Director, I.I.C.T,
for constant support and encouragement. M.A.R is
thankful to CSIR, New Delhi for a fellowship. Finan-
cial assistance from DST (New Delhi) is gratefully
acknowledged. We thank Dr. A. C. Kunwar for the
NMR spectra and Dr. M. Vairamani for the mass
spectra.
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