A short diastereoselective synthesis of cis-(2S,4S) and cis-(2R,4R)-4-hydroxyprolines

Article abstract of DOI:10.1016/j.tetlet.2015.03.119

A concise synthesis of (2R,4R)-4-hydroxyproline (1) and (2S,4S)-4-hydroxyproline (2) has been developed in enantiomerically pure form from commercially available starting materials with excellent diastereoselectivity. The tightly bound chelation controlled transition state formed during the 5-exo-tet ring closure reaction is assumed to be the origin of high diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2015.03.119

Accepted Manuscript
A short diastereoselective synthesis of cis-(2S,4S) and cis-(2R,4R)-4-hydroxy-
prolines
Vikas S. Gajare, Sandip R. Khobare, B. Malavika, R. Nagaraju, B.
VenkateswaraRao, U.K. Syam Kumar
PII:
S0040-4039(15)00589-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.03.119
TETL 46122
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 February 2015
23 March 2015
25 March 2015
Please cite this article as: Gajare, V.S., Khobare, S.R., Malavika, B., Nagaraju, R., VenkateswaraRao, B., Syam
Kumar, U.K., A short diastereoselective synthesis of cis-(2S,4S) and cis-(2R,4R)-4-hydroxyprolines, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.03.119
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Graphical Abstract
A short diastereoselective synthesis of cis-(2S,4S)-4-
and cis-(2R,4R)-4-hydroxyproline
Leave this area blank for abstract info.
Vikas S. Gajare, Sandip R. Khobare, B. Malavika, R. Nagaraju, B. Venkateswara Rao, U. K. Syam Kumar*
HO
O
O
1. LiHMDS
O
N
H
N
Bn
MgBr2/THF
OH
O
2. deprotection
O
de = 99.5%
HO
Cl
Cl
HO
1. LiHMDS
O
O
N
R1
R2
N
H
2. deprotection
O
OH
R1 = Boc, Bn
R2 = Bn, Et
de = 78-99.5%

1
Tetrahedron Letters
journal homepage: www.els evier.com
A short diastereoselective synthesis of cis-(2S,4S) and cis-(2R,4R)-4-
hydroxyprolines
Vikas S.Gajare,ab Sandip R. Khobare,a B. Malavika,a R. Nagaraju,a B. VenkateswaraRao,b U. K. Syam Kumar
a
*
aTechnology Development Center, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Miyapur, Hyderabad 500049, India.
bAU College of engineering (A), Andhra University, Visakhapatanum 530003, India
Fax: 914023045439 / 5438
E-mail: syam_kmr@yahoo.com
Received: The date will be inserted once the manuscript is accepted.
ARTICLE INFO
ABSTRACT
Article history:
Received
A concise synthesis of (2R,4R)-4-hydroxyproline (1) and (2S,4S)-4-hydroxyproline (2)
have been developed in enantiomerically pure form from commercially available starting
materials with excellent diastereoselectivity. The tightly bound chelation controlled
transition state formed during the 5-exo-tet ring closure reaction is assumed to be the origin
for high diastereoselectivity.
Received in revised form
Accepted
Available online
Keywords:
Diastereoselective synthesis
cis-4-Hydroxyproline,
2009 Elsevier Ltd. All rights reserved
.
Diastereoselective epoxide opening
Six membered transition state
Zinc and magnesium enolates
trans alkylation of (6S)-methyl-4-(1S)-phenylethyl-1,4-
morpholine-2,5-diones is
noteworthy approach.13
Synthesis of 1 and 2 are also reported from the amino
3- and 4-Hydroxyprolines has attracted widespread attention
in the recent past as a useful chiral building block in organic
synthesis. These chiral building blocks were extensively
used for the synthesis of glycopeptides,1 antimetabolite of
a
acid,14a
carbohydrates,14b
and
4-oxo-1,2-
pyrrolidinedicarboxylic acid dimethyl ester.15 Recently
Kimura et al. demonstrated the synthesis of both
enantiomers of cis-4-hydroxyproline using Wittig
olefination protocol.16
glutamic
acid,
ACE
inhibitors,2
and
1-β-
methylacarbapenem antibiotics. 3- and 4-Hydroxyprolines
are also used in the agrochemical industry.3 Recently the
application of cis-4-hydroxyproline in topical medication is
also disclosed.4 One of the key structural fragment of
naturally occurring phalloidine alkaloid is cis-(2S,4S)-4-
hydroxyproline (2).5 Chiraly pure 4-hydroxyproline was
first isolated from gelatin hydrolyzates6 and Luechs et al.
reported the first synthesis of racemic 4-hydroxyproline in
1937.7 Subsequently numerous methodologies were
reported in literature for the synthesis of racemic 4-
hydroxy-prolines.8 The diastereo as well as enantioselective
synthesis of (2R,4R)-hydroxyproline (1) and (2S,4S)-4-
hydroxyproline (2) are rarely disclosed in the literature.
HO
HO
HO
HO
OH
OH
OH
OH
N
H
1
N
H
2
N
H
3
N
H
4
O
O
O
O
(2R,4R)-4-
hydroxypyrrolidine-2- hydroxypyrrolidine-2-
carboxylic acid carboxylic acid
(2S,4S)-4-
(2S,4R)-4-
hydroxypyrrolidine- hydroxypyrrolidine-2-
2-carboxylic acid carboxylic acid
(2R,4S)-4-
Figure 1. Stereoisomer’s of 4-hydroxyproline
Though some of these syntheses commenced with chirally
pure starting materials, the product 4-hydoxyproline is
obtained with low diastereomeric excess. The lengthy
synthetic sequence, use of complex and expensive reagents,
and tedious purification procedures adapted for enriching
the diastereomeric excess in these synthesis demands
efficient protocols for the preparation of cis-(2R,4R)-4-
hydroxyproline (1) and cis-(2S,4S)-4-hydroxyproline (2) in
minimum number of stages. As a part of our efforts to
develop new methodologies for the total synthesis of natural
products,17 herein we disclose our successful efforts towards
Papaioannou et al.9 and Seki et al.10 reported the synthesis
of (2R,4R)-4-hydroxy-proline
1 by the inversion of
stereocenter in (2R,4S)-4-hydroxyproline under Mitsunobu
reaction conditions. The synthesis of 1 is also reported by
Thirring et al.11 from (-)-menthyl ester of hippuric acid.12
However; both syntheses use the separation techniques for
enriching the de of the required cis isomer. The
enantioselective synthesis of 1 through stereocontrolled 1,4-

Tetrahedron Letters
2
the development of a concise and highly diastereoselective
synthesis of cis-(2R,4R)-4-hydroxyproline (1) and cis-
(2S,4S)-4-hydroxyproline (2).
various percentages as summarized in Table 1. The best
diastereoselectivity and yield was obtained when the
oxirane ring opening in 6a, was attempted with 1.5 equiv of
The retro synthetic approach for the diastereoselective
synthesis of cis-(2R,4R)-4-hydroxyproline (1) is outlined in
Scheme 1. The deprotection of N-Boc/N-benzyl proline
ester 3 under standard deprotection conditions could easily
generate (2R,4R)-4-hydroxyproline (1). The required
proline ester 5 could be obtained from enantiomerically
pure amino epoxide 6 under intramolecular 5-exo-tet ring
closure conditions (path A) from a highly chelated Zn(II) or
Mg(II) complexes. The reaction of optically pure (S)-
epichlorohydrin (8a) and glycine ester 7 would generate
chiral epoxide 6. In Path-B, (2R,4R)-4-hydroxyproline (1) is
envisaged to obtain from chirally pure chlorohydrins 7 by
using the memory of chirality protocol.18 The chlorohydrins
7 required for the synthesis of 1 could easily synthesized by
the reaction of epichlorohydrin 8a with glycine ester 9.
LIHMDS in the presence of 1 equiv of MgBr2. The product
20
hydroxypyrrolidine-2-carboxylate 5a with SOR [α]D
=
+37.9° (c 1.0, CHCl3)20 was isolated in 78% yield with
99.5% de.20 In-order to check the chiral purity of the ethyl
(2R,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate (5a)
by HPLC method, other diastereomers were synthesized as
per the reported literature protocols.
O
HO
Path A
OR1
OR1
via insitu
halohydrin synthesis
N
N
R2
6
O
R2
O
HO
5
OH
N
H
Path B
O
1
Cl
HO
OR1
Cl
HN
+
OR1
O
R2
O
N
R2
7
O
8a
9
R1 = alkyl/benzyl group
R2 = Boc/benzyl
Scheme 2. Synthesis of cis-4-hydroxyproline from chiral
epoxide 6a
Scheme 1. Retro synthetic analysis of cis-4-hydroxyproline
The synthesis of 1 initiated using commercially available
enantiomerically pure (S)-epichlorohydrin (8a) and N-
benzyl glycine ethyl ester 9a (Scheme 2). The N-Benzyl
glycine ethyl ester 9a was reacted with (S)-epichlorohydrin
8a at ambient temperature to yield the chlorohydrin 7a,
which was then in situ converted to the amino epoxide 6a
using potassium carbonate and DMF at elevated
temperature in 50% yield.19 The key step, the intramolecular
oxirane ring opening of 6a leading to the formation of ethyl
(2R,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate (5a)
was designed under 5-endo-tet ring opening reaction
conditions. Thus, amino epoxide 6a was reacted with bases
like NaH, KOtBu, NaOEt and LDA over a wide range of
temperatures; however these reactions were failed to yield
the required product 5a. The oxirane ring opening in 6a,
was also attempted with 1.5 equiv of LiHMDS in THF in
the temperature range of -60 °C to 0 °C, however, this
reaction also resulted in the formation of a complex mixture
of products. The experiments conducted with higher equiv
of LiHMDS at different temperatures in solvents like 2-
MeTHF, CPME, toluene, as well as in MTBE were also
failed to yield 4-hydroxypyrrolidine-2-carboxylate 5a. The
inability of the oxirane 6a to undergo disfavored 5-endo-tet
ring closure reaction prompted us to use oxophilic metal
halide as additive in the reaction to stabilize the lithium
enolate as well as for the in situ generation of halohydrin
(Scheme2). Thus, when the oxirane ring opening was
carried out in presence of Zn(II), Mg(II), Li(I), as well as
Cu(II) halides, the required product 5a was obtained in
The diastereoselective intramolecular 5-exo-tet ring closure
reaction of 6a leading to the formation of ethyl (2R,4R)-1-
benzyl-4-hydroxypyrrolidine-2-carboxylate (5a) is assumed
to proceed via tightly bound chelation controlled transition
states. The lithium enolate formed from chiral epoxide 6a
by deprotonation with LiHMDS forms a highly stabilized
magnesium enolate with MgBr2 along with the liberation of
halide ion. The magnesium enolate then activates the
epoxide via coordination and forms halohydrin 10b. The
hydroxyl oxygen of halohydrin, enolate oxygen, and tertiary
amine together forms a tricoordinate complex with the
magnesium ion. The metal coordinated transition states
such as 10a, 10b, and 11a ensure that the enolate oxygen
and the hydroxyl oxygen will have syn facial orientation.
The formation of these tightly bound magnesium coordinate
complexes 10a, 10b, and 11a drives the diastereoselectivity
in the reaction. (Scheme 2)
Table 1. Synthesis of cis-4-hydroxyproline from chiral
epoxide 6a
Equiv of
LiHMDS/
metal halide
Ent Substra
ry
Metal
halide
Yield
(%)
de(%)
te
1
2
3
4
6a
6a
6a
6a
ZnBr2
ZnI2
1.5/1.0
1.5/1.0
1.5/1.0
1.5/1.0
55a
63 a
78 a
30b
98.5
99.5
99.5
98.0
MgBr2
LiBr

Tetrahedron Letters
3
Not
Table 2. Synthesis of 3 from halohydrin 7 in DMF/THF
at -50 °C
5
6
6a
6a
LiCl
1.5/1.0
1.5/1.0
< 5%
< 5%
analyzed
Not
analyzed
CuCl2
aThe reaction terminated after 4h
bThe reaction terminated after completion as per TLC
de
(%)
Yield
(%)
Entry
Substrate
Product
HO
Cl
HO
O
OEt
1
To get more mechanistic insight about the diastereoselective
synthesis of (2R,4R)-1-benzyl-4-hydroxypyrrolidine-2-
carboxylate (5a), we decided to use chiral chlorohydrin 7
instead of the epoxide 6 in the synthesis. For the synthesis
of key intermediate ethyl-(S)-N-benzyl-N-(3-chloro-2-
hydroxypropyl)glycinate(7a), ethyl benzyl glycinate 9a was
reacted with (S)-epichlorohydrin (8a) in neat conditions at
25-30 °C. When the 5-exo tet ring closure was attempted
with LiHMDS in DMF at -60 °C, the required product
(2R,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate (5a)
was obtained approximately in 15% yield. Encouraged by
this result, the reaction was attempted to optimize to
improve the yield of required product 5a. The use of excess
equiv of LiHMDS didn’t improve the yield of the reaction
further. Surprisingly, when the reaction was conducted at
slightly higher temperature (-50 °C), the required product
(2R,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate (5a)
was isolated in 51% yield with 99.5% de. The ring closure
reaction went equally well when conducted in THF with
LiHMDS at -50 °C and further maintenance at -5 °C over a
period of 4h. The moderate yield as well as high
diastereoselectivity achieved in this reaction is believed to
be occurred by the syn complexation between the lithium
enolate with –OH group, which is further stabilized by the
coordinating solvents like DMF. (Scheme 3) Further
variations in reaction conditions, and mol equiv of reagents
didn’t improve the yield of cis-4-hydroxy proline derivative
5a. The synthesis of benzyl (S)-N-(tert-butoxycarbonyl)-N-
(3-chloro-2-hydroxypropyl)glycinate (7c) was carried out
by reacting glycine benzyl ester tosylate salt with (S)-
epichlorohydrin (8a) in IPA followed by in situ Boc-
protection in 51% overall yield. (Table-2)
N
N
Bn
99.5
88.0
51
72
OEt
O
Bn
5a
7a
Cl
HO
HO
O
OEt
N
2
N
Boc O
OEt
Boc
5b
7b
Cl
HO
HO
HO
O
OBn
3
4
77.3
99.0
54
49
N
N
Boc O
OBn
Boc
5c
7c
Cl
HO
O
OMe
N
N
Bn
7d
OMe
Bn
5d
O
The formation of hydroxyl proline ester 5b and 5c with
lesser de are probably due to the increased steric repulsion
between the bulky amine and acid protecting groups which
partially block the syn facial metal complexation between
the lithium enolate and hydroxyl groups in the transition
states of 14 and 15 respectively. (Figure 2)
Cl
Cl
O
Cl
O
Cl
O
O
O
O
O
O
O
O
O
N
N
O
N
O
O
Li
N
Li
Li
Li
O
O
13
14
15
16
Figure 2. Transition state for the formation of 5a, 5b, 5c, and
5d
Cl
HO
O
O
The chiral epoxide 6a when subjected to hetero annulation
reaction using DMF/LiHMDS/THF, it failed to yield cis-4-
hydroxy proline derivative 5a, which clearly proves that
reaction didn’t proceed as per less preferred 5-endo tet
Baldwin cyclization pathway. React IR studies were also
conducted to check the intermediacy of epoxide 6a during
the conversion of halohydrin 7a to cis-4-hydroxy proline
derivative 5. These studies clearly rule out the intermediacy
of epoxide 6a during the conversion of chlorohydrin 7a to
cis-proline derivative 5a and the reaction proceed through
the preferred Baldwin’s 5-exo tet pathway.22 (Scheme 4)
RT
HN
Bn
+
O
O
Cl
O
N
O
Bn
8a
9a
7a
HO
+
HO
LiHMDS/DMF
-58 °C to -50 °C
O
N
N
51% in two step
O
O
Bn
12a
Bn
5a
Scheme 3. Synthesis of cis-4-hydroxyproline from
chlorohydrin 7a
To understand the impact of protecting groups in 4-
hydroxypyrrolidine-2-carboxylate (5) synthesis, the reaction
was carried out with different amine and acid protecting
groups as described in Table 2. Amongst the protecting
groups, the best yield (72%) of cis-proline derivative 5b
was obtained when the amine and acid functionality were
protected with Boc and ethyl ester respectively; however a
diminished de of 88% was obtained with these substrates.
Scheme 4. Attempted Synthesis of 4-hydroxyproline from
epoxide 6a

Tetrahedron Letters
4
Interestingly, during the course of the purification of
halohydrin 7a by silica gel column chromatography, lactone
17 was isolated in 20% yield. This silica gel assisted
lactonization of 7a is probably due to the favored
conformational orientation of 7a via hydrogen bonding
between the carbonyl carbon of ethyl ester and the hydroxyl
group, which favors the intramolecular lactonization. The
halohydrin 7b has failed to yield the lactone 18 even after
stirring 7b with silica gel in various percentage of hexane
and ethyl acetate mixture (Scheme 5) on prolonged time, as
well as at elevated temperature.
synthesis of densely functionalized diverse products is
under progress and will report in due course of time.
Acknowledgments
The authors would like to thank Dr. Vilas Dahanukar of Dr.
Reddy’s Laboratories for useful discussions. We also thank
the analytical department, Dr. Reddy’s Laboratories, for
providing the analytical support.
References and notes
Cl
Cl
1. (a) Kaeothip, S.; Ishiwata, A.; Ito Y. Org. Biomol. Chem. 2013, 11,
5892-5907; (b) Shinohara, H.; Matsubayashi, Y. Plant Cell Physiol.
2013, 54, 369-374; (c) Wakamiya, T.; Yamanoi, K.; Kanou, K.; Shiba,
T. Tetrahedron Lett. 1987, 28, 5887-5888.
O
O
Silica gel
O
O
Bn
H
N
N
EtO
7a
Bn
2. (a) Pippel, D. J.; Young L. K.; Letavic, M. A.; Ly, K. S.; Naderi, B.;
Soyode-Johnson, A.; Stocking, E. M.; Carruthers, N. I.; Mani, N. S. J.
Org. Chem. 2010, 75, 4463-4471; (b) Thottathil, J. K.; Moniot, J. L.
Tetrahedron Lett. 1986, 27, 151-154; (c) Kronenthal, D. R.; Mueller,
R. H.; Kuester, P. L.; Kissick, T. P.; Johnson, E. J. Tetrahedron Lett.
1990, 31, 1241-1244.
17
Cl
Cl
Cl
O
O
EtOOC
O
O
N
O
N
Silica gel
O
O
O
O
N
EtO
H
H
3. (a) Ducho, C.; Hamed, R. B.; Batchelar, E. T.; Sorensen, J. L.; Odell,
B.; Schofield, C. J. Org. Biomol. Chem. 2009, 7, 2770-2779; (b)
Remuzon, P. Tetrahedron, 1996, 52, 13803-13835.
Boc
7b
7b
18
4. Suzuki, R.; Tojo, Y.; Mizumoto, C.; Hasegawa, K.; Ashida, Y.; Hosoi,
Jun-ichi.; Sato, K, US20120122951 A1.
Scheme 5. The lactonization of chlorohydrin 7a
The ethyl (2R,4R)-1-benzyl-4-hydroxypyrrolidine-2-
carboxylate 5a was then converted to (2R, 4R)-4-hydroxy-
proline (1) by debenzylation with Pd(OH)2 followed by
hydrolysis of ester with aqueous sodium hydroxide in 80%
yield (Scheme 6) over two steps. The SOR, spectral and
5. (a) Wieland, H.; Witkop, B. Liebigs. Ann. Chem. 1940, 543, 171-183;
(b) Yu M.; Deming, T. J. Macromolecules, 1998, 31, 4739-4745; (c)
Ohtani, I.; Kusumi, T.; Kakisawa, H.; Kashman, Y.; Hirsh S. J. Am.
Chem. Soc. 1992, 114, 8472-8479.
6. Irreverre, F.; Morita, K.; Robertson, A. V.; Witkop, B. J. Am. Chem.
Soc. 1963, 85, 2824-2831.
7. Leuchs H., Berlin. 1905, 38, 1937-1943.
8. Roberson, A.V.; Katz, E.; Witkop, B. J. Org. Chem. 1962, 27, 2676-
2677.
analytical
carboxylic acid 1 thus obtained is identical to the values
data of
(2R,4R)-4-hydroxypyrrolidine-2-
9. Papaioannou, D.; Stavropoulos, G.; Kargiannis, K.; Francis, G. W.;
Brekke, T.; Aksnes, D. W. Acta Chem. Scand. 1990, 44, 243-251.
10. (a) Seki, M.; Matsumoto, K. Biosci. Biotech. Biochem. 1995, 59, 1161-
1162; (b) Madau, A.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry,
1996, 7, 825-830.
reported in the literature.
HO
HO
1. Pd(OH)2 / MeOH
11. Mehlfuhrer, M.; Berner, H.; Thirring, K. J. Chem. Soc., Chem.
Commun. 1994, 1291.
OH
OEt
N
H
N
2. NaOH/Water/EtOH
12. Kober, R.; Papadopoulos, K.; Miltz, W.; Enders, D.; Steglish, W.;
Reuter, H.; Puff, H. Tetrahedron, 1985, 41, 1693-1701.
13. Graziani, L.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1996, 1341-
1346.
O
O
Bn
1
5a
Scheme 6. Synthesis of (2R, 4R)-4-hydroxy-proline (1)
14. (a) Burger, K.; Rudolph, M.; Fehn, S. Angew. Chem. Int. Ed. Engl.
1993, 32, 285-287; (b) Mereyala, H. B.; Pathuri, G.; Nagarapu, L.
Synthetic Comm. 2012, 42, 1278-1287.
In a similar way, (2S,4S)-4-hydroxypyrrolidine-2-carboxylic
acid 2 was also synthesized in high de (99.5%) in moderate
yields starting from (R)-epichlorohydrin 8b and glycine
ester 9a as described in Scheme 7.
15. (a) Sigmund, A. E.; Hong, W.; Shapiro, R.; Dicosimo, R. Adv. Synth.
Catal. 2001, 343, 587-590; (b) Christian, K.; Wolfgang, H. Beilstein J.
Org. Chem. 2011, 7, 1643-1647.
16. Kimura, R.; Nagano, T.; Kinoshita, H. Bull. Chem. Soc. Jpn, 2002, 75,
2517-2525.
HO
17. (a) Srinivasan, A. K.; Shyamapada, B.; Syam Kumar, U. K, Org.
Biomol. Chem. 2014, 12, 6105-6113 (b) Suresh Babu, M.;
Ramamohan, M.; Raghunadh, A.; Raghavendra Rao, K.; Vilas H.
Dahanukar, Pratap, T. V.; Syam Kumar, U. K.; Dubey P. K. Tet Lett,
O
O
HN
Bn
OH
+
Cl
O
N
H
O
2014, 55, 4739-4741
(c) Raghunadh, A.;
Suresh Babu, M.;
9a
8b
2
Ramamohan, M.; Raghavendra Rao, K.; Krishna, T.; Gangadhara
Chary, R.; Rao, V. L.; Syam Kumar U. K. Tet Lett, 2014, 55, 2986-
2990 (d) Sandip. R. K.; Vikas, S. G.; Subbarao, J.; Syam Kumar U. K.;
Y. L. N. Murthy, Tet Lett, 2013, 54, 2909-2912 (e) Shankar, R.; More,
Satish S.; Madhubabu, M. V.; Vembu, N.; Syam Kumar, U. K. Synlett,
2012, 23, 1013–1020 (f) Raghunadh, A.; Suresh Babu, M.; Anil
Kumar, N.; Santosh, G.; Rao, V.L.; SyamꢀKumar, U. K. Synthesis,
2012, 44, 283–289 (g) Shankar, R.; Manoj, B. W.; Madhubabu, M. V.;
Vembu, N.; Syam Kumar, U. K. Synlett, 2011, 6, 844–0848 (h) Manoj
B. W.; Shankar, R.; Syam Kumar U. K.; Gill, C. H. Synlett, 2011, 1,
84–88 (i) Shanmugapriya, D.; Shankar, R.; Satyanarayana, G.; Vilas,
H. D.; Syam Kumar, U. K.; Vembu, N. Synlett, 2008, 19, 2945–2950
18. Kolaczkowski, L.; Barnes, D. M. Org. Lett. 2007, 9, 3029-3032.
Scheme 7. Synthesis of (2S, 4S)-4-hydroxy-proline (2)
In conclusion, a concise and highly diastereoselective
synthesis of (2R,4R)-4-hydroxyprolineand (2S,4S)-4-
hydroxyprolinein high de have been developed from readily
accessible starting materials in moderate yields. The high de
observed in the synthesis of cis 4-hydroxyproline is
probably due to the highly chelated complex formed during
the exo tet ring closure process, as well as via the
stabilization of the enolate by coordinating solvent. The
application of this methodology for the diastereoselective

Tetrahedron Letters
5
19. (S)-ethyl 2-(benzyl (oxiran-2-ylmethyl)amino)acetate) (6a): pale
yellow viscous liquid. (Yield = 50%)1H NMR (400 MHz, CDCl3): δ
ppm 1.26 (t, J = 7.3 Hz, 3H), 2.47 (dd, J = 2.9 Hz, 1H), 2.63 – 2.73
(m, 2H), 2.98 (dd, J = 3.4, 1H), 3.01 – 3.11 (m, 1H), 3.45 (s, 2H), 3.81
(d, J = 13.7 Hz, 1H), 3.92 (d, J = 13.7 Hz, 1H), 4.14 (q, J = 7.4 & 6.8
Hz, 2H), 7.25 (m, 5H). 13C NMR (100 MHz, CDCl3): δ ppm 14.2,
44.69, 51.08, 54.66, 56.03, 58.76, 60.24, 127.17, 128.27, 128.89,
138.55, 171.27. IR: 3685, 3019, 2400, 1732, 1520, 1495, 1477, 1214,
775, 669. HRMS (ESI): Calcd for C14H20NO3 (M+H)+ 250.1443, found
250.1433. [α]D25 = 1.22 ° (c 0.5, CHCl3).
liquid. Yield: 78% (MgBr2), 63 % ( ZnI2). 1H NMR (400 MHz, CDCl3):
δ ppm 1.21 (t, J = 7.4 Hz, 3H), 1.9 - 2.0 (m, 1H), 2.33 – 2.4 (m, 1H),
2.64 (dd, J = 3.9 and 4.4 Hz, 1H), 3.01 (d, J = 9.8 Hz, 1H), 3.2 (brs,
1H), 3.33 (dd, 3.5 and 3.4 Hz, 1H), 3.71 (d, J = 13.2 Hz, 1H), 3.87 (d, J
= 13.2 Hz, 1H), 4.07 (m, 2H), 4.24 (m, 1H), 7.2-7.31 (m, 5H). 13C
NMR (100 MHz, CDCl3): δ ppm 14.06, 39.11, 58.07, 60.96, 61.78,
63.39, 70.91, 127.18, 128.2, 128.92, 138.01, 175.10. IR: 3451, 1729,
1454, 1376, 1216, 756, 700. HRMS (ESI): Calcd for C14H20NO3
20
(M+H)+ 250.1443, found 250.1436. [α]D = +39.04° (c 1.0, CHCl3),
[α]D20 = +37.9° (c 1.0, CHCl3). % de (HPLC) = 99.5.
22. Nicolaou, K. C, Prasad, C. V. C.; Somer, P. K.; Hwang, C.-K. J. Am.
Chem, Soc. 1989, 111, 5331-5334.
20. Heindl, C.; Hubner, H.; Gmeiner, P. Tetrahedron: Asymmetry, 2003,
14, 3141-3152.
21. Procedure for the synthesis of 5a: A solution of (S)-ethyl 2-(benzyl
(oxiran-2-ylmethyl)amino)acetate) 6a (500 mg, 2.01 mmol) in THF
(7.5 mL, 15 vol) was cooled to – 60 °C and was added 1.5 equiv of 1 M
LiHMDS in THF (3 mL, 3.01 mmol). The reaction mixture was then
allowed to warm to – 15 °C for 10 minutes and cooled to -60 °C.
MgBr2.: etherate (622 mg, 2.41 mmol, 1 equiv) or Zn(II)I2 (1 equiv) in
THF (2.5 v) was added into the reaction mixture over a period of 30
minutes. The reaction mixture was then maintained at room
temperature and was stirred for 3 h. It was then cooled to -10 °C,
quenched with aqueous saturated NH4Cl solution (50 mL) and diluted
with ethyl acetate (25 mL). The layers were separated, the aqueous
layer extracted with ethyl acetate (2X 10 mL). The combined organic
layers were washed with water, 10% brine solution, dried over sodium
sulfate and evaporated. Crude product was then purified by column
chromatography on silica gel (230-400 mesh) using ethyl acetate and
hexane (1:4) to afford 390 mg of title compound as a pale yellow
Supplementary Material
Supplementary data (detailed experimental analysis and
1
spectral analysis including H, 13C, and HRMS associated
with this article can be found, in the online version, at http://