Enantioselective synthesis of (2R,3R)- and (2S,3S)-β-hydroxyornithine

Article abstract of DOI:10.1016/j.tetlet.2006.04.055

An efficient and short synthesis of (2R,3R)- and (2S,3S)-β-hydroxyornithine 1a-b is described using Sharpless asymmetric dihydroxylation and regioselective nucleophilic opening of a cyclic sulfite as the key steps.

Full text of DOI:10.1016/j.tetlet.2006.04.055

Tetrahedron Letters 47 (2006) 4167–4169
Enantioselective synthesis of (2R,3R)- and
(2S,3S)-b-hydroxyornithineq
Satyendra Kumar Pandey and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Homi Bhabha Road, Pune 411 008, India
Received 13 March 2006; revised 3 April 2006; accepted 12 April 2006
Abstract—An efficient and short synthesis of (2R,3R)- and (2S,3S)-b-hydroxyornithine 1a–b is described using Sharpless asymmetric
dihydroxylation and regioselective nucleophilic opening of a cyclic sulfite as the key steps.
Ó 2006 Elsevier Ltd. All rights reserved.
b-Hydroxyornithines 1a–b serve as intermediates in the
synthesis of important natural products like b-lactams
and amino polyols1 and as biosynthetic precursors to
both the b-lactamase inhibitor clavulanic acid 2 and
the anticancer agent, acivicin 3.2 Proclavaminic acid 4
has been recognized as the biosynthetic precursor of
clavulanic acid 2, a potent inhibitor of bacterial b-lacta-
mase (Fig. 1). Various methods for the synthesis of b-
hydroxyornithine in its different stereoisomeric forms,
mainly based on auxiliary supported or chiral pool
approaches, have been documented in the literature.3
Very recently, Williams et al. reported the asymmetric
synthesis of b-hydroxyornithines 1a–b via an aldol reac-
tion with a chiral oxazinone.4
As part of our research program aimed at developing
enantioselective syntheses of naturally occurring amino
alcohols and lactones,5 the Sharpless asymmetric
dihydroxylation and subsequent transformation of the
diol formed via a cyclic sulfite/sulfate were envisioned
as powerful tools offering considerable opportunities
for synthetic manipulations. Herein, we report a new
OH
O
OH
O
OH
H2N
OH
H2N
NH2
NH2
1b
(2S,3S)-β−hydroxyornithine
1a
(2
R
,3
R
)-β−hydroxyornithine
OH
O
HO
OH
O
OH
O
H2N
N
O
COOH
NH2
acivicin
N
N
O
COOH
clavulanic acid
3
4
2
(2S,3R)-proclavaminic acid
Figure 1.
q NCL Communication No. 80.
*
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629; e-mail: pk.tripathi@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.055

4168
S. K. Pandey, P. Kumar / Tetrahedron Letters 47 (2006) 4167–4169
b
a
BocHN
OH
H2N
OH
6
5
OH
O
O
O
d
c
OEt
BocHN
OEt
BocHN
BocHN
8
7
OH
O
OH
O
f
e
OEt
OEt
BocHN
S
O
O
N3
10
9
OH
O
OH
O
g
OH
HCl.H2N
OEt
BocHN
NH2
NH2
11
1a
Scheme 1. Reagents and conditions: (a) Boc2O, NaOH, 1,4-dioxane, H2O, 0 °C–rt; then KHSO4, 3 h, 94%; (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2,
ꢁ78 °C to ꢁ60 °C, 2 h; (ii) Ph3P@CHCOOEt, dry THF, rt, 24 h, 88%; (c) (DHQD)2PHAL, OsO4, CH3SO2NH2, K3FeCN6, K2CO3, t-BuOH–H2O
(1:1), 24 h, 0 °C, 95%; (d) SOCl2, Et3N, 30 min, 97%; (e) NaN3, dry DMF, 60 °C, 20 h, 93%; (f) 10% Pd–C, H2, EtOAc, rt, 98%; (g) 6 N HCl, reflux,
6 h, 88%.
and short synthesis of b-hydroxyornithines 1a–b by
employing cyclic sulfite methodology and Sharpless
asymmetric dihydroxylation as the source of chirality.
In conclusion, a practical, short and highly enantioselec-
tive synthesis of (2R,3R)- and (2S,3S)-b-hydroxyorni-
thine has been achieved by employing Sharpless
asymmetric dihydroxylation and cyclic sulfite methodol-
ogy as the key steps. The merits of this synthesis are high
enantioselectivity with high yielding reaction steps. The
synthetic strategy described has significant potential for
further extension to other stereoisomers via double
inversion at the a-carbon. Currently, work is in progress
in this direction.
The synthesis of b-hydroxyornithine 1a started from the
commercially available 3-aminopropanol 5, as illus-
trated in Scheme 1. Amino group protection of 5 with
(Boc)2O led to compound 6 in 94% yield, which was
oxidized to the aldehyde under Swern conditions6 and
subsequently treated with (ethoxycarbonylmethyl-
ene)triphenylphosphorane in dry THF to furnish the
Wittig product 7 in 88% yield. Subsequent treatment
of olefin 7 with osmium tetroxide and potassium ferricy-
anide as co-oxidant, in the presence of (DHQD)2PHAL
under Sharpless asymmetric conditions,7 gave diol 8 in
95% yield with 98% ee.8 Diol 8 was then treated with
thionyl chloride and Et3N to give the cyclic sulfite 9 in
97% yield. The synthetic strategy shown in Scheme 1
was based on the presumption that the nucleophilic
opening of cyclic sulfite 9 would occur in a regiospecific
manner at the a-carbon atom. Indeed, the cyclic sulfite
reacted with NaN3 with apparent complete selectivity
for attack at C-2 to furnish azido alcohol 109 in 93%
yield. The carbonyl group must be responsible for the
increased reactivity of the a-position.10 Hydrogenation
of azido alcohol 10 with 10% Pd–C led to amino alcohol
11 in 98% yield. Finally, concomitant deprotection of
Acknowledgements
S.K.P. thanks CSIR, New Delhi, for a research fellow-
ship. We are grateful to Dr. M. K. Gurjar for his sup-
port and encouragement. Financial support from DST,
New Delhi (Project Grant No. SR/S1/OC-40/2003), is
gratefully acknowledged.
References and notes
1. (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis.
Construction of Chiral Molecules Using Amino Acids; J.
Wiley and Sons: New York, 1987; (b) Miller, M. J. Acc.
Chem. Res. 1986, 19, 49–56, and references cited therein.
2. (a) Elson, S. W.; Baggaley, K. H.; Gillett, J.; Holland, S.;
Nicholson, N. H.; Sime, J. T.; Woroniecki, S. R. J. Chem.
Soc., Chem. Commun. 1987, 1736–1738; (b) Baldwin, J. E.;
Adlington, R. M.; Bryans, J. S.; Bringhen, A. O.; Coates,
J. B.; Crouch, N. P.; Lloyd, M. D.; Schofield, C. J.; Elson,
S. W.; Baggaley, K. H.; Cassels, R.; Nicholson, N. J.
Chem. Soc., Chem. Commun. 1990, 617–619.
the Boc group and ester hydrolysis were carried out with
25
6 N HCl to furnish 1a in excellent yield; ½aꢀD ꢁ21.32
25
(c 0.47, 6 N HCl), {lit.4 ½aꢀD ꢁ20.20 (c 0.47, 6 N
HCl)}. The physical and spectroscopic data were in full
agreement with the literature.4
In a similar way, (2S,3S)-b-hydroxyornithine 1b was
synthesized using (DHQ)2PHAL in the Sharpless
asymmetric dihydroxylation step and following a series
of reactions analogous to those shown in Scheme 1.
3. (a) Wityak, S. J.; Gould, S. J.; Hein, S. J.; Keszler, D. A. J.
Org. Chem. 1987, 52, 2179–2183; (b) Krol, W. J.; Mao, S.;
Steele, D. L.; Townsend, C. A. J. Org. Chem. 1991, 56,
728–731; (c) Di Giovanni, M. C.; Misiti, D.; Zappia, G.

S. K. Pandey, P. Kumar / Tetrahedron Letters 47 (2006) 4167–4169
4169
Tetrahedron 1993, 49, 11321–11328; (d) Rao, V. B.;
Krishna, U. M.; Gurjar, M. K. Synth. Commun. 1997,
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analysis using Cyclobond I beta 25 cm, 4.6 mm, HPLC-
Cartridge (R.R.-Whelk-01), MeOH–H2O, wavelength
254 nm, 1.0 mL/min. Spectral data of compound 8: white
25
4. DeMong, D. E.; Williams, R. M. Tetrahedron Lett. 2001,
42, 183–185.
solid, mp 178 °C, ½aꢀD +15.89 (c 1.0, CHCl3); IR (neat):
1
mmax 3340, 2972, 1751, 1681, 1524, 1214 cmꢁ1; H NMR
5. (a) Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44,
1035–1037; (b) Pandey, S. K.; Kandula, S. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 5877–5879; (c) Pandey, S. K.;
Kumar, P. Tetrahedron Lett. 2005, 46, 4091–4093; (d)
Kumar, P.; Bodas, M. S. J. Org. Chem. 2005, 70, 360–363;
(e) Kumar, P.; Naidu, S. V. J. Org. Chem. 2005, 70, 4207–
4210; (f) Kumar, P.; Naidu, S. V.; Gupta, P. J. Org. Chem.
2005, 70, 2843–2846; (g) Kumar, P.; Gupta, P.; Naidu, S.
V. Chem. Eur. J. 2006, 12, 1397–1402; (h) Pandey, S. K.;
Kumar, P. Tetrahedron Lett. 2005, 46, 6625–6627.
6. For reviews on the Swern oxidation, see: (a) Tidwell, T. T.
Synthesis 1990, 857–870; (b) Tidwell, T. T. Org. React.
1990, 39, 297–572.
(200 MHz, CDCl3): d 1.31 (t, J = 7.1 Hz, 3H), 1.45 (s,
9H), 1.59–1.95 (m, 2H), 2.92 (br s, 2H), 3.11–3.27 (m, 1H),
3.37–3.51 (m, 1H), 4.01 (dt, J = 10.1, 3.5 Hz, 1H), 4.07 (d,
J = 2.4 Hz, 1H) 4.29 (q, J = 7.2 Hz, 2H), 4.83 (br s, 1H);
13C NMR (50 MHz, CDCl3): d 14.0, 28.2, 33.8, 37.1, 61.7,
69.8, 73.7, 79.4, 156.8, 173.1, Anal. Calcd for C12H23NO6
(277.31): C, 51.97; H, 8.36; N, 5.05. Found: C, 51.89; H,
8.33; N, 5.08.
25
9. Spectral data of compound 10: ½aꢀD +8.27 (c 1.0, CHCl3);
IR (neat): mmax 3389, 2980, 2109, 1689, 1520, 1253 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 1.33 (t, J = 7.2 Hz, 3H),
1.44 (s, 9H), 1.59–1.85 (m, 2H), 3.10–3.24 (m, 1H), 3.46
(br s, 1H), 3.77 (d, J = 3.1 Hz, 1H), 3.95–4.06 (m, 1H),
4.15 (dt, J = 10.4, 3.2 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H),
4.86 (br s, 1H); 13C NMR (50 MHz, CDCl3): d 13.9, 28.1,
34.3, 36.6, 61.8, 65.8, 69.4, 79.5, 156.9, 169.1, Anal. Calcd
for C12H22N4O5 (302.33): C, 47.67; H, 7.33; N, 18.53.
Found: 47.70; H, 7.35; N, 18.51.
7. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed.
1996, 35, 448–451; (b) Kolb, H. C.; VanNieuwenhze, M.
S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547; (c)
Torri, S.; Liu, P.; Bhuvaneswari, N.; Amatore, C.; Jutand,
A. J. Org. Chem. 1996, 61, 3055–3060.
8. For the measurement of the enantiomeric excess, diol 8
was converted into its dibenzoate. The enantiomeric purity
of the dibenzoate was estimated to be 98% by chiral HPLC
10. Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper & Row: New York,
1987; p 321, and references therein.