A concise synthesis of protected (2S,4R)-4-hydroxyornithine

Article abstract of DOI:10.1016/j.tetlet.2008.03.076

A short synthesis of the nonproteinogenic amino acid, (2S,4R)-4-hydroxyornithine is described. Starting from racemic benzyl glycidol, the scaffold of the target compound was constructed in high enantio- and diastereoselectivity using Jacobsen's hydrolytic kinetic resolution (HKR) and regioselective opening of an epoxide as key steps.

Full text of DOI:10.1016/j.tetlet.2008.03.076

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Tetrahedron Letters 49 (2008) 3297–3299
A concise synthesis of protected (2S,4R)-4-hydroxyornithine
Satyendra Kumar Pandey, Menaka Pandey, Pradeep Kumar *
Division of Organic Chemistry, National Chemical, Laboratory, Pune 411 008, India
Received 5 February 2008; revised 12 March 2008; accepted 15 March 2008
Available online 20 March 2008
Abstract
A short synthesis of the nonproteinogenic amino acid, (2S,4R)-4-hydroxyornithine is described. Starting from racemic benzyl glycidol,
the scaffold of the target compound was constructed in high enantio- and diastereoselectivity using Jacobsen’s hydrolytic kinetic
resolution (HKR) and regioselective opening of an epoxide as key steps.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Hydroxyornithine; Jacobsen’s HKR; Epoxide; Grignard reaction; Natural product
COOH
NH2
COOH
4-Hydroxyornithine 1a–b is a nonproteinogenic amino
acid found abundantly in nature. It is a component of mar-
ine organism1 and plants,2 as well as a constituent of a
number of peptide natural products, such as the antifungal
lipopeptides echinocandin and pneumocandin,3 the K 582
type antibiotics,4 macrocyclic antibiotics such as the biphe-
nomycin A and B 2a–b,5 the b-lactam antibiotic clava-
lanine 36 and polyoxin M.7 Related 4-hydroxylated a-
amino acid, (2S,4S,6R)-4-hydroxy-5-phenylsulfinyl-norval-
ine 4 has also been identified as a key component of usti-
loxin A and B,8 a family of cyclic peptides with potent
antimitotic activity (Fig. 1).9
H2N
H2N
OH
OH
NH2
1a (2
S,4R
)-4-hydroxyornithine
1b (2
S
,4
S
)-4-hydroxyornithine
H2N
H
N
HO
OH
O
COOH
COOH
R
O
3
O
H
N
clavalanine
COOH
H2N
N
H
O
Ar
OH
S
Various methods for the synthesis of 4-hydroxyorni-
thine including stereoselective approaches have been
reported in the literature.10 Rudolph et al. described the
synthesis of the target compound from a chiral pool start-
ing material, (S)-N-Boc-aspartic acid tert-butyl ester. This
approach, which is based on an initial homologation of
the acid side chain to form an a-nitroketone and subse-
quent diastereoselective ketone reduction to the corres-
ponding b-nitro alcohol, involves the use of an excess of
starting material (10-fold of nitromethane) and suffers from
a low overall yield of the product.11 In another approach,
O
OH
NH2
NH2
4
2a biphenomycin A
2b biphenomycin B
R = OH
R = H
(2
S,4S,6R)-4-hydroxy-5-
phenylsulfinylnorvaline
Fig. 1.
the scaffold of 1 was constructed by multi-step synthesis
starting from (R)-1,2-O-isopropylideneglycerol.12 Very
recently, Paintner et al. developed
a stereoselective
approach to 1 based on a bis(oxazoline) copper(II)-com-
plex mediated diastereoselective Henry reaction of nitro-
methane with the homoserine-derived aldehyde in 11
steps.13
*
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.076

3298
S. K. Pandey et al. / Tetrahedron Letters 49 (2008) 3297–3299
OH
N3
OH
N3
OTBS
O
O
b
a
a
BnO
N3
N3
BnO
BnO
BnO
OH
8a
+
BnO
9
10
5
5a
5b
BocHN
OTBS
Scheme 1. Reagents and conditions: (a) (R,R)-Salen-CoIIIꢁ(OAc)
(0.5 mol %), distd H2O (0.55 equiv), 0 °C, 14 h, (47% for 5a, 43% for 5b).
BocHN
OTBS
d
c
NHBoc
HO
NHBoc
HO
O
12
11
As part of our research programme aimed at developing
enantioselective syntheses of naturally occurring amino-
alcohols,14 we recently developed the asymmetric synthesis
of b-hydroxyornithine using Sharpless asymmetric dihydr-
oxylation and cyclic sulfite chemistry.15 In continuation, we
herein report a new and feasible route to 4-hydroxyornith-
ines 1a–b using Jacobsen’s hydrolytic kinetic resolution
(HKR) as the key step.
Scheme 3. Reagents and conditions: (a) NaN3, NH4Cl, DMF, 50 °C, 14 h,
92%; (b) TBS–Cl (TBS = tert-butyldimethylsilyl), imidazole, DMAP,
CH2Cl2, 0 °C–rt, 4 h, 97%; (c) 20% Pd(OH)2/C, H2, Boc2O, EtOAc,
12 h, 86%; (d) TEMPO, NaOCl, NaClO2, CH3CN, 82%.
converted into its O-mesyl derivative, which on treatment
with sodium azide in dry DMF furnished azide 7 with
the desired inverted stereochemistry. Compound 7 was
then subjected to m-CPBA epoxidation, and epoxide 8 thus
obtained was found to be a mixture of two diastereomers in
almost equal amounts (syn:anti/1:1.18).17 In order to
improve the diastereoselectivity, we attempted the HKR
method as depicted in Scheme 2. Thus HKR was per-
formed on 8 with the (S,S)-Salen CoIIIꢁOAc complex
(Fig. 2) (0.5 mol %) and water (0.55 equiv) in THF
(0.55 equiv) to afford epoxide 8a as a single diastereoisomer
(as determined from 1H and 13C NMR spectral analyses)18
in 41% yield and diol 8b in 43% yield.
The ring opening of epoxide 8a was carried out with
NaN3 to give the diazido alcohol 9 in 92% yield (Scheme
3). Hydroxyl protection of 9 with tert-butyldimethylsilyl
chloride and imidazole in the presence of a catalytic
amount of DMAP afforded the silyl ether 10 in 97% yield.
Concomitant one-pot deprotection of benzyl group, reduc-
tion of both the azide groups and Boc protection of the
resulting diamine were carried out with H2/Pd(OH)2,
Boc2O to give alcohol 11 in 86% yield. Finally, amino-alco-
hol 11 was oxidized with TEMPO/NaOCl/NaClO2 to
furnish the desired protected amino acid 1219 in excellent
yield.
As illustrated in Scheme 1, racemic benzyl glycidol 5 was
subjected to Jacobsen’s HKR16a using (R,R)-Salen-CoIII
.
OAc as the catalyst to give (S)-benzyl glycidol 5a as a single
25
25
enantiomer {½aꢀD +8.63 (c 0.40, EtOH)}, {lit.16b ½aꢀD +7.82
(c 0.40, EtOH)}, which was easily isolated from the more
polar diol 5b by distillation.
With enantiomerically pure epoxide 5a in hand our next
aim was to construct the syn-1,3-amino-alcohol. To estab-
lish the second stereogenic centre with the required stereo-
chemistry, it was thought worthwhile to examine
stereoselective epoxidation of a homoallylic azide (Scheme
2). Thus, (S)-benzyl glycidol 5a was treated with vinylmag-
nesium bromide in the presence of CuI to give the homo-
allylic alcohol 6 in 88% yield. Compound 6 was then
H
H
N
O
N
O
Co
t-Bu
t-Bu
OAc
t-Bu
t-Bu
(
S,S)-Salen Co(III).OAc complex
In conclusion, we have developed a short approach to
protected (2S,4R)-4-hydroxyornithine in high enantio-
Fig. 2.
OH
N3
O
a
b
BnO
BnO
BnO
6
5a
7
N3
O
8a
8b
BnO
BnO
N3
O
d
c
+
BnO
OH
N3
8
OH
Scheme 2. Reagents and conditions: (a) vinylmagnesium bromide, CuI, THF, ꢂ20 °C, 12 h, 88%; (b) (i) MsCl, Et3N, DMAP, 0 °C–rt, 1.5 h; (ii) NaN3,
DMF, 70 °C, 9 h, 91%; (c) m-CPBA, CH2Cl2, 0 °C–rt, 10 h, 96%, ds, syn:anti/1:1.18; (d) (S,S)-Salen CoIIIꢁOAc (0.5 mol %), distd H2O (0.55 equiv), THF,
0 °C, 14 h (41% for 9a, 43% for 9b).

S. K. Pandey et al. / Tetrahedron Letters 49 (2008) 3297–3299
3299
Yaegashi, H.; Sato, Z. J. Antibiot. 1994, 47, 765; (d) Morisaki, N.;
Mitsui, Y.; Yamashita, Y.; Koiso, Y.; Shirai, R.; Hashimoto, Y.;
Iwasaki, S. J. Antibiot. 1998, 51, 423.
and diastereomeric excess using Jacobsen’s HKR as the key
step. The syn- and anti-configuration of the 1,3-amino-
alcohol moiety can be manipulated simply by changing
the Jacobsen’s catalyst in the hydrolytic kinetic resolution
step. The target compound 12 has been synthesized from
5 in 9 steps and in 9.3% overall yield. The synthetic strategy
described here has significant potential for stereochemical
variations and further extension to other stereoisomers,
and analogues, for example (2S,4S,6R)-4-hydroxy-5-phenyl-
sulfinyl-norvaline 4. Currently, studies are in progress in
this direction.
9. For recent use of this versatile chiral building block, see: Catalano, J.
G.; Deaton, D. N.; Furfine, E. S.; Hassell, A. M.; McFayden, R. B.;
Miller, A. B.; Miller, L. R.; Shewchuk, L. M.; Willard, D. H.; Wright,
L. L. Bioorg. Med. Chem. Lett. 2004, 14, 275.
10. (a) Talbot, G.; Gaudry, R.; Berlinguet, L. Can. J. Chem. 1956, 34,
911; (b) Mizusaki, K.; Makisumi, S. Bull. Chem. Soc. Jpn. 1981, 54,
470; (c) Jackson, R. F. W.; Wood, A.; Wythes, M. J. Synlett 1990,
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1 1994, 1719; (f) Girard, A.; Greck, C.; Genet, J. P.
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Acknowledgements
11. Rudolph, J.; Hannig, F.; Theis, H.; Wischnat, R. Org. Lett. 2001, 3,
3153.
12. (a) Schmidt, U.; Meyer, R.; Leitenberger, V.; Stabler, F.; Lieberkn-
echt, A. Synthesis 1991, 409; (b) Lepine, R.; Carbonnelle, A.-C.; Zhu,
J. Synlett 2003, 1455.
13. Paintner, F. F.; Allmendinger, L.; Bauschke, G.; Klemann, P. Org.
Lett. 2005, 7, 1423.
S.K.P. thanks CSIR New Delhi for a research fellow-
ship. We are grateful to Dr. Ganesh Pandey for his support
and encouragement. Financial support from DST, New
Delhi (Project Grant No. SR/S1/OC-40/2003) is gratefully
acknowledged. This is NCL Communication No. 6707.
14. Pandey, S. K.; Kumar, P. Synlett 2007, 1894 and references cited
therein.
15. Pandey, S. K.; Kumar, P. Tetrahedron Lett. 2006, 47, 4167.
16. (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307; (b) Hansen, T. V.; Vaagen, V.; Partali,
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6, 499.
References and notes
1. (a) Fujita, Y. Bull. Chem. Soc. Jpn. 1959, 32, 439; (b) Makisumi, S. J.
Biochem. 1961, 49, 284.
2. (a) Bell, E. A.; Tirimanna, A. S. L. Nature 1963, 197, 901; (b) Bell, E.
A.; Tirimanna, A. S. L. Biochem. J. 1964, 91, 356.
3. Denning, D. W. J. Antimicrob. Chemother. 1997, 40, 611.
4. Kondo, S.; Meguriya, N.; Mogi, H.; Aota, T.; Miura, K.; Fujii, T.;
Hayashi, I.; Makino, K.; Yamamoto, M.; Nakajima, N. J. Antibiot.
1980, 33, 533.
5. Ezaki, M.; Iwami, M.; Yamashita, M.; Hashimoto, S.; Komori, T.;
Umehara, K.; Mine, Y.; Kohsaka, M.; Aoki, H.; Imanaka, I. J.
Antibiot. 1985, 38, 1453.
6. (a) Pruess, D. L.; Kellett, M. J. Antibiot. 1983, 36, 208; (b) Evans, R.
H., Jr.; Ax, H.; Jacoby, A.; Williams, T. H.; Jenkis, E.; Scannell, J. P.
J. Antibiot. 1983, 36, 213; (c) Muller, J.-C.; Toome, V.; Pruess, D. L.;
Blount, J. F.; Weigele, M. J. Antibiot. 1983, 36, 217.
7. Shiro, Y.; Kato, K.; Fujii, M.; Idab, Y.; Akitaa, H. Tetrahedron 2006,
62, 8687 and references cited therein.
8. (a) Koiso, Y.; Natori, M.; Iwasaki, S.; Sato, S.; Sonoda, R.; Fujita,
Y.; Yaegashi, H.; Sato, Z. Tetrahedron Lett. 1992, 33, 4157; (b) Koiso,
Y.; Morisaki, N.; Yamashita, Y.; Mitsui, Y.; Shirai, R.; Hashimoto,
Y.; Iwasaki, S. J. Antibiot. 1998, 51, 418; (c) Koiso, Y.; Li, Y.;
Iwasaki, S.; Hanaoka, K.; Kobayashi, T.; Sonoda, R.; Fujita, Y.;
17. The diastereoselectivity was determined from 1H and 13C NMR
spectral data.
25
18. Spectral data of compound 8a: Pale yellow liquid, ½aꢀD +49 (c 1.00,
CHCl3). IR (CHCl3): ~m ¼ 2922, 2115, 1601, 1453, 1272 cmꢂ1
.
1H
NMR (200 MHz, CDCl3): dH 1.48–1.61 (m, 1H), 1.75–1.89 (m, 1H),
2.53 (dd, J = 2.78, 5.05 Hz, 1H), 2.84 (t, J = 4.04 Hz, 1H), 3.02–3.11
(m, 1H), 3.53 (dd, J = 7.07, 9.85 Hz, 1H), 3.66 (dd, J = 3.91, 6.31 Hz,
1H), 3.75–3.88 (m, 1H), 4.59 (s, 2H), 7.30–7.38 (m, 5H) ppm. 13C
NMR (50 MHz, CDCl3): dC 34.3, 47.2, 49.2, 59.4, 72.6, 73.2, 127.4,
127.7, 128.3, 137.6 ppm. Anal. Calcd for C12H15N3O2: C, 61.7; H,
6.48; N, 18.01. Found: C, 61.58; H, 6.67; N, 17.69.
25
19. Spectral data of compound 12: ½aꢀD +38 (c 0.50, CHCl3). IR (CHCl3):
~m ¼ 3346, 2910, 1716, 1453 cmꢂ1
.
1H NMR (200 MHz, CDCl3): dH
0.08 (s, 6H), 0.88 (s, 9H), 1.45 (s, 18H), 1.75–1.82 (m, 2H), 2.62–2.89
(m, 1H), 3.61–3.81 (m, 1H), 3.98–4.38 (m, 2H), 4.31–4.62 (m, 1H),
5.49–5.74 (m, 1H) ppm. 13C NMR (50 MHz, CDCl3): dC ꢂ5.1, ꢂ4.7
14.1, 18.0, 22.7, 28.3, 31.9, 42.5, 65.2, 66.3, 80.4, 163.3 ppm. Anal.
Calcd for C21H42N2O7Si: C, 54.52; H, 9.15; N, 6.05%. Found: C,
54.25; H, 9.37; N, 5.75%.