A concise organocatalytic route to protected (2 S,4 R)-4-hydroxyornithine and (+)-pseudohygroline

Article abstract of DOI:10.1055/s-0033-1340977

A practical, efficient, and organocatalytic approach to the synthesis of (2S,4R)-4-hydroxyornithine and (+)-pseudohygroline is reported using proline-catalyzed sequential α-aminoxylation/α-amination reaction and Horner-Wadsworth-Emmons olefination reaction of an aldehyde as the key step. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340977

LETTER
▌1089
lAetteCr oncise Organocatalytic Route to Protected (2S,4R)-4-Hydroxyornithine
and (+)-Pseudohygroline
Synthesis of (2S,4R)-4-Hydroxyornithine and (+)-Pseudohygroline
Vishwajeet Jha, Pradeep Kumar*
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Homi Bhabha Road, Pune – 411008, India
Fax +91(20)25902629; E-mail: pk.tripathi@ncl.res.in
Received: 27.12.2013; Accepted after revision: 19.02.2014
another approach, Zhu et al. have constructed the scaffold
Abstract: A practical, efficient, and organocatalytic approach to
of 1 in nine steps starting from (R)-1,2-O-isopropylidene-
the synthesis of (2S,4R)-4-hydroxyornithine and (+)-pseudohygro-
glycerol,12i while Paintner et al. developed a stereoselec-
line is reported using proline-catalyzed sequential α-aminoxyl-
tive approach to 1 based on a bis(oxazoline) copper(II)-
complex-mediated diastereoselective Henry reaction of
nitromethane with the homoserine-derived aldehyde in 11
steps.12j Recently, our group has reported a synthesis em-
ploying Jacobsen hydrolytic kinetic resolution of terminal
racemic epoxides.12k For (+)-pseudohygroline (5a), Tilve
et al. have reported a chiral-pool approach starting from
proline which suffers from low to moderate diastereomer-
ic ratios,13a whilst Yadav et al. have reported a synthesis
using a Prins cyclization in ten steps.13b In another report,
Davies et al. have employed lithium amide conjugate ad-
dition to an alkyl hexa-2,4-dienoate followed by a ring-
closing metathesis strategy to complete the synthesis in
eight steps.13c
ation/α-amination reaction and Horner–Wadsworth–Emmons
olefination reaction of an aldehyde as the key step.
Key words: aldehydes, amination, amino alcohols, Wittig reaction,
cyclization, enantioselectivity
Many natural products and pharmaceuticals include 1,3-
amino alcohols as a principal skeletal array.1 Additional-
ly, 1,3-amino alcohols have also been used as ligands for
asymmetric catalysis, as chiral auxiliaries, resolving
agents and phase-transfer catalysts.2 Thus, numerous
strategies3 for their synthesis have been developed due to
the lack of their availability from natural sources. Among
them, the nonproteinogenic amino acid (2S,4R)-4-hy-
droxyornithine (1a) and pyrrolidine alkaloid (+)-pseudo-
hygroline (5a) have attracted a great deal of interest due to
their potent biological activities and importance as syn-
thetic building blocks.
H2N
H
COOH
COOH
H2N
COOH
H2N
O
OH NH2
OH NH2
N
O
2
1a
1b
4-Hydroxyornithine (1) is a rare nonproteinogenic amino
acid found in lentils4 (e.g., Lens culinaris Medik.) and
some members of the genus Vicia5 (e.g., V. unijuga A.
Br.). It is a constituent of a number of peptide natural
products, such as the antifungal lipopeptides echinocan-
din and pneumocandin,6 the K 582 type antibiotics,7 the β-
lactam antibiotics clavalanine (2)8a–c and polyoxin M
(4),8d and macrocyclic antibiotics such as biphenomycin
A and B (3),9 that have high in vitro and in vivo antibac-
terial activity against multiresistant gram-positive patho-
gens (Figure 1).10 (+)-Pseudohygroline (5a) and (–)-
hygroline (5b), 2-substituted pyrrolidines have been iso-
lated from Carallia brachiata,11a Erythroxylon coca,11b
and Schizanthus hookeri.11c
clavalanine
(2S,4R)-4-hydroxyornithine (2S,4S)-4-hydroxyornithine
HO
OH
R
H
O
O
O
COOH
N
COOH
H2N
N
H
OH
O
O
N
NH
H2N
O
N
H
O
OH NH2
O
HO
OH
NH2
3
4
biphenomycin A
biphenomycin B
R = OH
R = H
polyoxin M
Me
OH
Me
OH
N
N
5a
(+)-pseudohygroline
5b
(–)-hygroline
Considering their potent biological activity and fascinat-
ing structural features, several approaches have been re-
ported for the synthesis of (2S,4R)-4-hydroxyornithine12
and (+)-pseudohygroline.13 Rudolph et al. have described
the synthesis of protected (2S,4R)-4-hydroxyornithine
from a chiral-pool starting material that involves the use
of an excess of starting material (tenfold of nitromethane)
and suffers from a low overall yield of the product.12h In
Figure 1 1,3-Amino alcohol containing bioactive compounds
In recent years, the area of organocatalysis has emerged as
an alternative to enzyme catalysis and metal catalysis in
the field of asymmetric synthesis.14,15 Recently, we have
developed an efficient approach to the asymmetric syn-
thesis of 1,3-amino alcohols using sequential α-aminoxyl-
ation/α-amination and Horner–Wadsworth–Emmons
(HWE) olefination reaction catalyzed by proline.16 In con-
tinuation of our interest in organocatalysis17 and asym-
metric synthesis of amino alcohols,18 we became
SYNLETT 2014, 25, 1089–1092
Advanced online publication: 14.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340977; Art ID: ST-2013-D1170-L
© Georg Thieme Verlag Stuttgart · New York

1090
V. Jha, P. Kumar
LETTER
interested in devising a flexible approach to the synthesis
of 1,3-amino alcohol containing compounds. Herein we
report our successful endeavors to devise a simple route
towards the synthesis of (2S,4R)-4-hydroxyornithine and
Cbz
Cbz
Cbz
Cbz
NH
NaBH4
EtOH
NH
H2, Raney Ni
TBS
TBS
R
O
N
O
N
OH
BocHN
O
Boc2O, Et3N
74%
10
(+)-pseudohygroline,
employing
sequential
α-
9a
aminoxylation19/α-amination20 reactions and HWE olefi-
Boc
O
Boc
TBS
TBS
nation of an aldehyde catalyzed by proline.
NH
O
NH
TEMPO, NaOCl
NaClO2, MeCN
BocHN
OH
BocHN
As shown in Scheme 1, the synthesis started from alde-
hyde 6 which on sequential α-aminoxylation using nitroso
benzene as oxygen source and D-proline as catalyst and
subsequent HWE olefination using the ylide generated
from triethyl phosphonoacetate, followed by hydrogena-
tion using catalytic amount of Pd/C furnished the γ-hy-
droxy esters 7 (7a: 68% yield, 96% ee; 7b: 72% yield and
94% ee).21 The free hydroxy group of γ-hydroxy esters 7
was protected as the TBS ether using TBSCl in DMF to
furnish compound 8. DIBAL-H reduction of ester 8 at –
78 °C furnished the corresponding aldehyde that was then
subjected to α-amination using commercially available
dibenzyl azodicarboxylate (DBAD) as a nitrogen source
and D-proline as a catalyst to furnish the α-amino alde-
hyde 9.
COOH
82%
11
12
Scheme 2 Synthesis of (2S,4R)-4-hydroxyornithine
amino alcohol 13 in 19:1 diastereomeric ratio.21 The N–N
bond of diastereomerically pure 1,3-syn-amino alcohol
1322 was readily cleaved with concomitant reduction of
the double bond under hydrogenation conditions using
freshly prepared Raney nickel at 60 psi of H2 to give the
free amine that was refluxed in ethanol to afford the lac-
tam 14 in 72% yield (over two steps). Methylation of 14
using MeI and NaH furnished the N-methylated com-
pound 15 in 93% yield. LAH reduction of amide 15 fur-
nished amine 16 in 87% yield. Finally, TBS deprotection
using PTSA in methanol afforded the target compound
5a23 in 95% yield (Scheme 3).
(a) nitrosobenzene
D-proline, DMSO
then HWE salt
OH
R
CHO
DBU, LiCl, MeCN
R
COOEt
TBSCl, imidazole
DMF, overnight
6
Cbz
Cbz
Cbz
NH
(i) Raney Ni, EtOAc
2 (60 psi), 12 h
7
(b) H2, Pd/C, EtOAc
Cbz
TBS
H
HWE ester
DBU, LiCl
NH
TBS
R
O
N
6a R = CH2NHBoc
6b R = Me
7a R = CH2NHBoc
7b R = Me
O
N
(ii) EtOH, 50 °C, 5 h
72% over two steps
O
COOEt
9b
13
O
O
TBS
Me
TBS
NaH, MeI
OTBS
Cbz
NH
O
HN
O
N
LAH, THF
87%
(a) DIBAL-H, CH2Cl2
–78 °C
toluene
93%
Cbz
O
R
COOEt
TBS
R
N
(b) DBAD, D-proline
MeCN
8
O
15
14
8a R = CH2NHBoc
8b R = Me
9
Me
OH
TBS
Me
PTSA
9a R = CH2NHBoc
9b R = Me
N
O
N
MeOH
95%
Scheme 1 Synthesis of α-amino aldehydes
16
5a
Scheme 3 Synthesis of (+)-pseudohygroline
For the synthesis of (2S,4R)-4-hydroxyornithine, amino
aldehyde 9a was reduced using NaBH4 in ethanol to af-
ford the substituted hydrazine 1022 in 88:12 diastereomer-
ic ratio.21 Both the diastereomers can be easily separated
using flash column chromatography. The N–N bond of di-
astereomerically pure substituted hydrazine 10 was
cleaved hydrogenolytically using freshly prepared Raney
nickel at 60 psi of H2, and the free amine was subsequent-
ly converted into its Boc derivative using Boc2O to fur-
nish 1,3-amino alcohol 11 in 74% yield. Finally amino
alcohol 11 was oxidized with TEMPO, NaOCl, and
NaClO2 to furnish the desired protected (2S,4R)-4-hy-
droxyornithine 1223 in 82% yield (Scheme 2).
In conclusion, a short and efficient asymmetric synthesis
of protected (2S,4R)-4-hydroxyornithine and (+)-pseudo-
hygroline has been achieved using proline-catalyzed se-
quential α-aminoxylation/α-amination and Horner–
Wadsworth–Emmons olefination reaction of an aldehyde
as the key step. The syn and anti configuration of the 1,3-
amino alcohol moiety can be manipulated simply by
changing the proline in the α-aminoxylation/α-amination
step. The target compound 12 was synthesized from alde-
hyde 6a in ca. 22% overall yield; whilst compound 5a was
synthesized in ca. 24% overall yield. The synthetic strate-
gy described herein has significant potential for stereo-
chemical variations and gives further access to other
stereoisomers and analogues.
For the synthesis of (+)-pseudohygroline, aminoaldehyde
9b was treated with triethyl phosphonoacetate (HWE ole-
fination) in the presence of DBU to furnish the syn-1,3-
Synlett 2014, 25, 1089–1092
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (2S,4R)-4-Hydroxyornithine and (+)-Pseudohygroline
(11) (a) Platonava, T. F. Kuzovkov A. D. 1963, 17, 19.
1091
Acknowledgment
(b) Fitzgerald, J. S. Aust. J. Chem. 1965, 18, 589. (c) Martin,
S. A.; Rovirosa, J.; Gambaro, V.; Castillo, M.
Phytochemistry 1980, 19, 2007. (d) Pomilio, A. B.;
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41, 1393.
V.J. thanks UGC New Delhi for fellowship. We thank Ms. S. Kunte
for HPLC analysis. The authors thank the CSIR, New Delhi for fi-
nancial support as part of XII Five Year Plan under title ORIGIN
(CSC0108).
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Supporting Information for this article is available online at
http://www.thiemeconnect.com/ejournals/toc/synlett. Included are
experimental procedures and spectral data for compounds 7–15.SnugIoipfn
m
r
iot
SatrnufpgIorpi
o
nmitrat
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(21) The ee of 7a was determined by derivatizing it with
Mosher’s acid and analyzing the 19F NMR spectrum. The ee
of 7b was determined by comparing its specific rotation with
the literature value.24a The diastereomeric ratios of 10 and 13
were determined using HPLC analysis (see Supporting
Information).
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(22) Dibenzyl 1-{(2S,4R)-5-[(tert-Butoxycarbonyl)amino]-4-
[(tert-butyldimethylsilyl)oxy]-1-hydroxypentan-2-
yl}hydrazine-1,2-dicarboxylate (10)
Colorless oil; yield 2.122 g (63%). [α]D25 –9.56 (c 1.0,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1089–1092

1092
V. Jha, P. Kumar
LETTER
CHCl3). IR (CHCl3): νmax = 3019, 2956, 1712, 1505, 1216
cm–1. 1H NMR (200 MHz, CDCl3): δ = 0.00 (s, 3 H), 0.02 (s,
3 H), 0.90 (s, 9 H), 1.45 (s, 9 H), 1.66–1.82 (m, 2 H), 3.24–
3.48 (m, 2 H), 3.90–4.15 (m, 3 H), 4.40–4.73 (m,1 H), 5.07–
5.34 (m, 4 H), 6.11–6.19 (m, 1 H), 7.22–7.36 (m, 10 H) ppm.
13C NMR (50 MHz, CDCl3): δ = –4.8, –4.7, 17.9, 25.8, 28.6,
31.8, 32.6, 53.3, 62.3, 62.5, 67.9, 71.8, 71.9, 79.7, 126.4,
127.8, 128.1, 128.5, 129.3, 135.3, 135.5, 135.9, 138.1,
138.3, 155.9, 156.5, 158.1, 158.6 ppm. ESI-MS: m/z =
654.43 [M + Na]+. Anal. Calcd (%) for C32H49N3O8Si: C,
60.83; H, 7.82; N, 6.65. Found: C, 60.70; H, 7.91; N, 6.57.
Dibenzyl 1-{(4S,6S,E)-6-[(tert-butyldimethylsilyl)oxy]-1-
ethoxy-1-oxohept-2-en-4-yl}hydrazine-1,2-dicarboxylate
(13)
C31H44N2O7Si: C, 63.67; H, 7.58; N, 4.79. Found: C, 63.39;
H, 7.43; N, 4.92.
(23) (2S,4R)-2,5-Bis{(tert-butoxycarbonyl)amino)-4-[(tert-
butyldimethylsilyl]oxy}pentanoic Acid (12)
Viscous oil; yield 42 mg (82%). [α]D25 –34.56 (c 1, CHCl3).
IR (CHCl3): νmax = 3346, 2910, 1716, 1453 cm–1. 1H NMR
(200 MHz, CDCl3): δ = 0.08 (s, 6 H), 0.88 (s, 9 H), 1.45 (s,
18 H), 1.73–1.79 (m, 2 H), 3.07–3.28 (m, 1 H), 3.55–3.80
(m, 1 H), 3.90–4.11 (m, 2 H), 5.59 (br s, 1 H), 5.74 (br s, 1
H) ppm. 13C NMR (50 MHz, CDCl3): δ = –5.1, –4.7, 14.1,
18.0, 22.7, 28.3, 31.9, 42.5, 65.2, 66.4, 80.4, 163.3 ppm.
ESI-MS: m/z = 485.21 [M + Na]+. Anal. Calcd (%) for
C21H42N2O7Si: C, 54.52; H, 9.15; N, 6.05. Found: C, 54.25;
H, 9.37; N, 5.75.
Colorless oil; yield 1.33 g (65%). [α]D25 +2.32 (c 0.5,
CHCl3). IR (CHCl3): νmax = 3295, 2956, 1755, 1719, 1406,
1043 cm–1. 1H NMR (200 MHz, CDCl3): δ = –0.02 (s, 3 H),
0.03 (s, 3 H), 0.85 (s, 9 H), 1.16 (d, J = 6.2 Hz, 3 H), 1.28 (t,
J = 7.1 Hz, 2 H), 1.64–1.72 (m, 2 H), 3.76–3.93 (m, 1 H),
4.19 (q, J = 7.1 Hz, 2 H), 4.91–5.15 (m, 5 H), 5.94 (m, 1 H),
6.57 (br s, 1 H), 6.83 (dd, J = 6.8, 15.6 Hz, 1 H), 7.31 (m, 10
H) ppm. 13C NMR (50 MHz, CDCl3): δ = –4.8, –4.1, 14.1,
17.9, 24.1, 29.9, 40.6, 56.5, 60.5, 67.4, 67.7, 68.3, 122.9,
128.0, 128.1, 128.3, 128.4, 135.5, 144.6, 155.3, 156.3, 166.1
ppm. ESI-MS: m/z = 607.32 [M + Na]+. Anal. Calcd (%) for
(+)-Pseudohygroline (5a)
Colorless liquid; yield 0.02 g (95%). [α]D25 –48.12 (c 0.5,
EtOH). 1H NMR (200 MHz, CDCl3): δ = 1.17 (d, J = 6.2 Hz,
3 H), 1.31–1.45 (m, 3 H), 1.71–1.78 (m, 2 H), 1.98–2.04 (m,
1 H), 2.31–2.40 (m, 1 H), 2.37 (s, 3 H), 2.69–2.77 (m, 1 H),
3.00–3.08 (m, 1 H), 3.87–3.96 (m, 1 H) ppm. 13C NMR (50
MHz, CDCl3): δ = 21.9, 22.8, 29.1, 38.1, 40.6, 56.5, 67.1,
68.2 ppm. ESI-MS: m/z = 144.22 [M + H]+.
(24) (a) Jacobs, H.; Berryman, K.; Jones, J.; Gopalan, A. Synth.
Commun. 1990, 20, 999. (b) Reddy, C. R.; Srikanth, B.;
Dilipkumar, U.; Rao, K. V. M.; Jagadeesh, B. Eur. J. Org.
Chem. 2013, 525.
Synlett 2014, 25, 1089–1092
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