Stereoselective synthesis of (2R,3R) and (2R,3S)-3-hydroxyleucines

Article abstract of DOI:10.1016/j.tetlet.2004.01.117

A stereoselective synthesis of (2R,3R) and (2R,3S)-3-hydroxyleucine is disclosed. The key step of the reaction sequence involves, stereo- and regioselective bromohydration of 7, using a brominating agent derived in situ from N-bromosuccinimide and 2,6-lutidine, via intramolecular sulfinyl group participation.

Full text of DOI:10.1016/j.tetlet.2004.01.117

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2639–2641
Stereoselective synthesis of (2R,3R) and (2R,3S)-
3-hydroxyleucinesq
Sadagopan Raghavan* and K. A. Tony
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 22 November 2003; revised 19 January 2004; accepted 26 January 2004
Abstract—A stereoselective synthesis of (2R,3R) and (2R,3S)-3-hydroxyleucine is disclosed. The key step of the reaction sequence
involves, stereo- and regioselective bromohydration of 7, using a brominating agent derived in situ from N-bromosuccinimide and
2,6-lutidine, via intramolecular sulfinyl group participation.
Ó 2004 Elsevier Ltd. All rights reserved.
b-Hydroxy a-amino acids are constituents of many
bioactive natural products. (2S,3S)-3-Hydroxyleucine is
a key constituent of a range of naturally occurring cyclic
depsipeptides that include telomycin,1 A-83586C,2 azi-
nothricin,3 citropeptin,4 varicapeptin,4 L-156602,5 ver-
ucopeptin,6 and sanjoinine.7 Lysobactin8 contains the
the (2S,3R) diastereoisomer while lactacystin9 incorpo-
rates the (2R,3S) isomer. As a consequence of the
essential role played by this amino acid in biological
systems and its utility as a synthon, a number of useful
strategies have been disclosed for its preparation.10 The
majority of the reported methods utilize, Sharpless
asymmetric epoxidation/dihydroxylation reaction or
chiral pool starting materials for the introduction of the
desired stereocenters. In continuation of our interest in
utilizing the sulfinyl group as an intramolecular nucleo-
phile to heterofunctionalize olefins,11 we disclose herein
a stereoselective approach to (2R,3R) and (2R,3S)-3-
hydroxyleucine (Fig. 1).
NH2
NH2
S
S
CO2H
CO2H
S
R
S
OH
OH
NH2
NH2
R
R
CO2H
CO2H
R
OH
OH
Figure 1.
ethanol as the solvent yielded cleanly the urethane 4
(Scheme 1), whose physical characteristics13 were in
good agreement with the data reported in the litera-
ture.14
Aldehyde 511e on treatment with methyl(triphenylphos-
phoranylidene)acetate in benzene as the solvent afforded
the trans a,b-unsaturated ester 6 exclusively.15 Oxidation
16
of the sulfide with NaIO4 yielded an epimeric mixture
The bromohydrin 2, elaborated stereoselectively from
the unsaturated ester 1,11e was subjected to treatment
with tetramethylguanidinium azide (TMGA)12 in dichloro-
methane to yield stereoselectively the azidoester 3.10k
Treatment of 3 with di tert-butyldicarbonate and
Raney-Nickel under an atmosphere of hydrogen in
of sulfoxides 7 in equimolar proportions as an insepa-
rable mixture. Bromohydration of 7 with NBS yielded a
product mixture of 8 and 9, stereoisomeric at C3 and C4
in a 3:1 ratio, respectively.17 After much experimenta-
tion varying the solvents, temperature, and the haloge-
nating agent bromohydration, when carried out with
NBS in the presence of an equivalent of 2,6-lutidine
(relative to NBS), yielded cleanly the bromohydrin 8
(Scheme 2). Probably a new sterically bulkier bromi-
nating agent is formed (as an indication of which the
reaction proceeds slower) in situ by the reaction of NBS
with 2,6-lutidine, which reacts with 7 in a stereoselective
fashion.
Keywords: 3-Hydroxyleucine; Intramolecular participation; Bromo-
hydration.
q IICT Communication No. 040110.
* Corresponding author. Tel.: +91-40-2716-0123; e-mail: sraghavan@
iict.ap.nic.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.117

2640
S. Raghavan, K. A. Tony / Tetrahedron Letters 45 (2004) 2639–2641
O
S
Br
O
S
b
a
CO2Me
Ph
CO2Me
Ph
OH
1
2
O
S
N3
NHBoc
c
R
Ph
CO2Me
CO2Me
R
OH
3
OH
[α]D = _19.0 (c 1, CHCl3)
4
Scheme 1. Reagents and conditions: (a) NBS, H2O, toluene, rt, 3 h, 80%; (b) TMGA, CH2Cl2, 0 °C to rt, 1 h, 80%; (c) H2, (Boc)2O, Raney-Ni, EtOH,
60 °C, 2 h, 70%.
O
S
X
S
a
c
or d
O
Ph
Ph
CO2Me
64.0 (c 1.5, CHCl )
5
_
[α]
=
6, X =
D
3
b
7, X = O
O
S
Br
O
S
Br
+
4
4
2
Ph
CO2Me
2
Ph
CO2Me
OH
OH
9
8
Scheme 2. Reagents and conditions: (a) Ph3PCHCO2Me, PhH, rt, 3 h, 85%; (b) NaIO4, MeOH/H2O (2:1), 0 °C to rt, 5 h, 85%; (c) NBS, H2O,
toluene, rt, 3 h, 75% 3:1 of 8:9; (d) NBS, H2O, 2,6-lutidine, toluene, rt, 6 h, 65% of 8 only.
The bromohydrin 8 on treatment with NaN3 in DMF at
rt afforded a mixture of products18 epimeric at C4. Co-
rey et al.10h in their study aimed at the preparation of
(2S,3S)-3-hydroxyleucine made a similar observation,
when attempted displacement of the bromide a to the
ester by the azido group, yielded the epimeric azides and
the epoxide. The side reaction could be averted by silyl
protection. Attempted protection of the hydroxy group
in 8 as its silyl ether by treatment with tert-butyldi-
methylsilyl triflate and 2,6-lutidine yielded a mixture of
products resulting from the activation of the sulfinyl
group by the reagent. Therefore the sulfinyl group was
reduced19 to yield the sulfide 10, which on treatment
with tert-butyldimethylsilyl triflate cleanly afforded the
silyl ether 11. Displacement of the bromide in 11 pro-
ceeded without incident to yield the azide 12 on warm-
ing the DMF solution with excess of sodium azide.
Treatment of 12 with excess of Raney-Nickel in the
presence of (Boc)2O under an atmosphere of hydrogen
in ethanol as the solvent yielded the silyl ether 13.
Deprotection of the silyl group with TBAF afforded
urethane 1420 (Scheme 3).
In conclusion we have devised a very stereoselective
route to (2R,3R) and (2R,3S)-3-hydroxyleucine diaste-
reomers from the cis and trans a,b-unsaturated esters 1
and 7, respectively. The brominating agent generated in
situ from NBS and 2,6-lutidine proved to more stereo-
selective in the reaction with ester 7.
Acknowledgements
S.R. is thankful to Dr. J. S. Yadav, Director, I.I.C.T, for
constant support and encouragement. K.A.T is thankful
to CSIR, New Delhi for a fellowship. Financial assis-
Br
N3
X
S
Br
b
c
S
S
Ph
CO2Me
Ph
CO2Me
OTBS
[α] = + 11.0 (c 1.5, CHCl )
Ph
CO2Me
OTBS
OH
_
[α]
=
15.0 (c 1, CHCl )
8, X = O
10, X =
11
12
D
3
D
3
a
_
[α]
= 8.0 (c 2, CHCl )
3
D
NHBoc
NHBoc
d
e
R
CO2Me
OTBS
[α] = + 4.0 (c 1, CHCl )
CO2Me
S
OH
[α] = + 8.0 (c 0.5, CHCl )
14
D
3
13
D
3
Scheme 3. Reagents and conditions: (a) TiCl3, EtOH, rt, 30 min 65%; (b) TBS-OTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 1 h, 70%; (c) NaN3, DMF, 50 °C,
3 h, 65%; (d) H2, (Boc)2O, Raney-Ni, EtOH, 60 °C, 2 h, 70%; (e) n-Bu4NF, THF, rt, 2 h, 85%.

S. Raghavan, K. A. Tony / Tetrahedron Letters 45 (2004) 2639–2641
2641
Y. H. Tetrahedron Lett. 1989, 30, 6637; (k) Evans, D. A.;
Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron
Lett. 1987, 28, 39; (l) Seebach, D.; Juaristi, E.; Miller, D.
D.; Schickli, C.; Weber, T. Helv. Chim. Acta 1987, 70, 237.
11. (a) Raghavan, S.; Rasheed, M. A. Tetrahedron 2003, 59,
10307; (b) Raghavan, S.; Joseph, S. C. Tetrahedron Lett.
2003, 44, 8237; (c) Raghavan, S.; Rajender, A. J. Org.
Chem. 2003, 68, 7094; (d) Raghavan, S.; Ramakrishna
Reddy, S.; Tony, K. A.; Naveen Kumar, Ch.; Varma,
A. K.; Nangia, A. J. Org. Chem. 2002, 67, 5838; (e)
Raghavan, S.; Tony, K. A. J. Org. Chem. 2003, 68, 5002;
(f) Raghavan, S.; Rasheed, M. A.; Joseph, S. C.; Rajender,
A. J. Chem. Soc., Chem. Commun. 1999, 1845.
tance from DST (New Delhi) is gratefully acknowl-
edged. We thank Dr. A. C. Kunwar for the NMR
spectra and Dr. M. Vairamani for the mass spectra.
References and notes
1. Sheehan, J. C.; Maeda, K.; Sen, A. K.; Stock, A. K. J. Am.
Chem. Soc. 1962, 84, 1303.
2. Smita, T. A.; Deeter, J. B.; Hunt, A. H.; Mertz, F. P.; Ellis,
R. M.; Boeck, L. D.; Yao, R. C. J. Antibiot. 1988, 41, 726.
3. Maehr, H.; Liu, C.-M.; Pallerow, N. J.; Smallheer, J.;
Todaro, L.; Williams, T. H.; Blout, J. F. J. Antibiot. 1986,
39, 17.
4. (a) Nakagawa, M.; Hayakawa, Y.; Furihita, K.; Seto, H.
J. Antibiot. 1990, 43, 477; (b) Hayakawa, Y.; Nakagawa,
M.; Toda, Y.; Seto, H. Agric. Biol. Chem. 1990, 54, 1007.
5. Heusens, O. D.; Borris, R. P.; Koupal, L. R.; Caldwell, L.
G.; Currie, S. A.; Haidri, A. A.; Honnick, C. F.;
Honeysutt, S. S.; Lindenmayer, H. B.; Zink, O. L.;
Zitano, L.; Fieldhouse, J. M.; Rollins, T.; Springer, M.
S.; Springer, J. P. J. Antibiot. 1991, 44, 249.
12. Evans, D. A.; Britton, T. C.; Ellmann, J. A.; Dorow, R. L.
J. Am. Chem. Soc. 1990, 112, 4011.
13. 1H NMR (200 MHz, CDCl3) d 5.4 (d, J ¼ 6:8 Hz, 1H),
4.40 (dd, J ¼ 7:9, 3.4 Hz, 1H), 3.75 (s, 3H), 3.42 (br s, 1H),
1.7 (m, 1H), 1.45 (s, 9H), 1.02 (d, J ¼ 6:4 Hz, 3H), 0.96 (d,
J ¼ 6:8 Hz, 3H). 13C NMR (75 MHz, CDCl3) 19.0, 19.2,
28.1, 30.6, 52.2, 78.6, 80.1, 153.4, 171.7.
14. Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werener,
J.; Fischer, P. Synthesis 1989, 256.
15. The stereochemical integrity of the chiral center during the
transformation of the aldehyde 5 to the unsaturated ester 6
was proven by a two step transformation of the latter
including (i) reduction to the allyl alcohol using DIBAL-H
and (ii) reaction of the allyl alcohol with (S)-O-methyl
mandelic acid using DCC, to yield diastereomerically pure
mandelate ester.
6. Nishiyama, Y.; Sugawara, K.; Tomita, K.; Yamamoto,
H.; Kamei, H.; Oki, T. J. Antibiot. 1993, 46, 921.
7. Han, B. H.; Park, M. H.; Park, J. H. Pure Appl. Chem.
1989, 61, 443.
8. Tywiak, A. A.; McCormick, T. T.; Unger, S. E. J. Org.
Chem. 1989, 54, 1149.
9. Omura, S.; Fujimoto, T.; Otoguro, K.; Moriguchi, R.;
Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113.
10. (a) Xiong, C.; Wang, W.; Hruby, V. J. J. Org. Chem. 2002,
67, 3514; (b) Davis, F. A.; Srirajan, V.; Fanelli, D. L.;
Portonovo, P. J. Org. Chem. 2000, 65, 7663; (c) Williams,
L.; Zhang, Z.; Shao, F.; Carroll, P. J.; Joullie, M. M.
Tetrahedron 1996, 52, 11673; (d) Nagamitsu, T.; Sun-
azuka, T.; Tanaka, H.; Omura, S.; Sprengeler, P. A.;
Smith, A. B., III. J. Am. Chem. Soc. 1996, 118, 3584; (e)
Yadav, J. S.; Chandrasekhar, S.; Ravindra Reddy, Y.;
Rama Rao, A. V. Tetrahedron 1995, 51, 2749; (f) Hale, K.
J.; Manaviazar, S.; Delisser, V. M. Tetrahedron 1994, 50,
9181; (g) Kanemasa, S.; Mori, T.; Tatsukawa, A. Tetra-
hedron Lett. 1993, 34, 8292; (h) Corey, E. J.; Lee, D.-H.;
Choi, S. Tetrahedron Lett. 1992, 33, 6735; (i) Caldwell, C.
G.; Bondy, S. S. Synthesis 1990, 34; (j) Jung, M. E.; Jung,
16. Leonard, N. J.; Johnson, C. R. J. Org. Chem. 1962, 27,
282.
17. Oxidation of the mixture of sulfoxides 8 and 9 with
m-CPBA afforded the corresponding sulfones. Integration
of the C3 methine proton signal of the sulfone mixture
revealed the presence of the stereoisomers in a 3:1 ratio.
18. The product distribution was not any different using
TMGA in dichloromethane.
19. Takahashi, T.; Iyobe, A.; Arai, Y.; Koizumi, T. Synthesis
1989, 189.
20. 1H NMR (200 MHz, CDCl3) d 5.20 (d, J ¼ 9:5 Hz, 1H),
4.40 (d, J ¼ 8:8 Hz, 1H), 3.75 (s, 3H), 3.65 (d, J ¼ 9:5 Hz,
1H), 1.70 (m, 1H), 1.45 (s, 9H), 1.0 (d, J ¼ 6:6 Hz, 3H),
0.90 (d, J ¼ 6:6 Hz, 3H). 13C NMR (75 MHz, CDCl3) d
18.9, 28.3, 30.8, 52.4, 55.6, 80.0, 156.0, 172.7.