A carbohydrate based straightforward approach to trans-4-hydroxy-D-proline and trans-4-hydroxy-D-prolinol

Article abstract of DOI:10.1016/j.tetlet.2020.152081

Synthesis of trans-4-hydroxy-D-proline and the corresponding prolinol has been accomplished starting from 4,6-di-O-benzyl-3-deoxy-D-glucal, an enol-ether derived from D-glucose, through oxidative cleavage of a vicinal diol intermediate as the key step. This work represents a practical approach to an unnatural, yet synthetically and biologically very significant, amino acid.

Full text of DOI:10.1016/j.tetlet.2020.152081

Journal Pre-proofs
A carbohydrate based straightforward approach to trans-4-hydroxy-D-proline
and trans-4-hydroxy-D-prolinol
Umesh Kumar Mishra, Namakkal G. Ramesh
PII:
S0040-4039(20)30532-3
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152081
TETL 152081
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 April 2020
21 May 2020
23 May 2020
Please cite this article as: Kumar Mishra, U., Ramesh, N.G., A carbohydrate based straightforward approach to
trans-4-hydroxy-D-proline and trans-4-hydroxy-D-prolinol, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.152081
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Graphical Abstract
A carbohydrate based straightforward
approach to trans-4-hydroxy-D-proline and
trans-4-hydroxy-D-prolinol
Leave this area blank for abstract info.
Umesh Kumar Mishra and Namakkal G Ramesh
OBn
HO
OBn
6
6
5
4
5
3
OH
O
BnO
OH
N
4
2
OH
3
1
TsHN
1
R2 R1
H
2
OH
R1 = R2 = H
R1R2 = O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A carbohydrate based straightforward approach to trans-4-hydroxy-D-proline and
trans-4-hydroxy-D-prolinol
Umesh Kumar Mishra and Namakkal G. Ramesha, 
a Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi – 110016, India.
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +91-11-26596584; fax: +91-11-26581102; e-mail: ramesh@chemistry.iitd.ac.in
Article history:
Received
Synthesis of trans-4-hydroxy-D-proline and the corresponding prolinol has been accomplished
starting from 4,6-di-O-benzyl-3-deoxy-D-glucal, an enol-ether derived from D-glucose, through
Received in revised form
Accepted
oxidative cleavage of a vicinal diol intermediate as the key step. This work represents a practical
approach to this unnatural, yet synthetically and biologically very significant, amino acid.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Trans-4-hydroxy-D-proline
4,6-Di-O-benzyl-3-deoxy-D-glucal
Oxidative cleavage
Carbohydrates
Unnatural amino acid
Introduction
Trans-4-hydroxy-L-proline 1 (Hyp) (Figure 1) is a non-proteinogenic amino acid produced by hydroxylation of proline by the
enzyme prolyl 4-hydroxylase during the post translational modification following protein synthesis.1 Hyp is a major component of
the protein collagen and plays a key role in the stabilization of triple helical supercoil of collagen.2 Hyp rich glycoproteins are vital
structural ingredients in the plant cell wall. They participate in the formation of crosslinked networks in the cell wall which is
significant for wall strengthening as well as disease resistance.2 Hydroxyproline is a rich source of reduced carbon and nitrogen.2 Trans-
4-hydroxy-D-proline (D-Hyp) 2, enantiomer of natural Hyp 1, has also found enormous chemical and biological applications. In 2007,
Waffenschmidt reported the isolation of linear hydroxyproline bound O-glycans of unicellular green alga Chlamydomonas reinhardtii
from the outer cell wall of glycoproteins.3 Through structural identification3 as well as chemical synthesis,4 it was established that some
of these hydroxyproline bound O-glycans such as 3 and 4 are constituted of D-Hyp. It has also been shown that D-Hyp is a promising
candidate for the tuning of pharmaceutical, biological or physiochemical properties of de novo designed or naturally occurring peptides.
Nishizawa et al have shown that an analogue of peptide PYY possessing a combination of N-terminal 4-imidazolecarbonyl moiety and
three amino acid substitutions D-Hyp, isovalin and c-methylleucine, not only improved the binding affinity of the peptide for Y2R but
also increased its anorectic activity in lean mice.5 D-Hyp based amide 5 has been
developed by Pippel et al as histamine H3 receptor antagonist.6 Quinoline bearing proline derivatives such as 6 derived from D-Hyp
displayed significant -amylase inhibitory activity.7 A series of carboxamides derived from D-Hyp have been tested for their
antimicrobial and antifungal activities amongst which compound 7 was found to be the most potent.8 Conformationally constrained
diethylenetriaminepentaacetic acid (DTPA) analogues derived from both Hyp and D-Hyp have been investigated for their complexation
with paramagnetic metals such as gadolinium and lutetium.9 Stereoselective synthesis of N-protected alkoxy prolines, including
examples from D-Hyp, as potential serine protease factor Xa inhibitors has been reported by Vrieze.10 Synthesis of novel peptide nucleic
acids through the replacement of the hydroxyl group of Boc-protected Hyp and D-Hyp by nucleobases was reported by Lowe.11 Several
N-acyl carboxamide derivatives were synthesized from various hydroxyprolines, including D-Hyp, and investigated for their efficacies
as inhibitors of human plasma kallikrein.12 Compound 8, an inhibitor of cathepsin C, a dipeptidase I, was synthesized from D-Hyp.13
Hyp and D-Hyp have also found applications as asymmetric catalysts in organic synthesis.14 As D-Hyp is not naturally occurring, it has
to be synthesized and is about 75 times more expensive than natural Hyp. The method originally developed by Robinson,15 involving
epimerization of both the chiral centres of natural Hyp 1, through a sequence of steps is long, tedious, expensive and low yielding
besides formation of an unwanted olefin by-product that further complicated the purification process as claimed by Stille.16 Despite
these limitations, this strategy is the only one that has been followed by other groups mostly for the synthesis of

2
Tetrahedron Letters
HO
O
HO
O
O
O
O
O
O
HO
HO
HO
HO
OH
OH
NH
NH
O
HO
HO
COOH
O
HO
O
O
O
HO
HO
HO
COOH
N
H
Hyp
N
H
O
O
HO
HO
HO
O
O
D-Hyp
HO
HO
HO
1
2
3
4
F
HO
Cl
Br
O
S
NHAr
N
O
HO
Br
HN
Br
O
O
N
NH
N
N
N
N
N
8
O
CF3
N
O
O
CH3
F
O
5
6
7
Figure 1. Structures of hydroxyl proline and relevant compounds of biological significance
protected D-Hyp and not D-Hyp itself.4,11 Two other strategies reported by Arai17 and Pilli18 are synthetically not attractive as D-Hyp
was obtained as one of the many possible products from mixtures.
Trans-4-hydroxy-D-prolinol 9, the reduced form of D-Hyp 2, also plays significant roles in the areas of synthetic organic chemistry
and biology. Synthesis of biologically important pyrrolidine based nucleosides derived from trans-4-hydroxy-D-prolinol and its
derivatives are known.19 Constrained FTY720 analogue 10, benzyl ether derivative of trans-4-hydroxy-D-prolinol, possess anticancer
activity.20 Trans-4-hydroxy-D-prolinol and its derivatives such as 11 have been successfully employed as chiral catalysts in various
asymmetric synthesis21 and receptor binding studies.22 The only method available for trans-4-hydroxy-D-prolinol is through reduction
of the ester of D-Hyp.
HO
O
TESO
Ar
Ar
OTES
N
H
N
H
N
H
OH
OH
9
10
11
Figure 2. Structures of 4-hydroxy-D-prolinol and its derivatives.
Given this background and due to paucity of enough strategies to access D-Hyp and 4-hydroxy-D-prolinol, it was considered
worthwhile to develop a new chiron based approach for the synthesis of both of them starting from a substrate that already possesses all
the required absolute stereocentres and proceeds with complete stereochemical integrity.
Results and Discussion
Recently, we have reported a divergent synthesis of 1,4-dideoxy-1,4-imino-L-xylitol and deacetyl (+)-anisomycin wherein their key
pyrrolidine moiety was installed through an oxidative cleavage cum concomitant intramolecular cyclization of a vicinal diol derived
from tri-O-benzyl-D-glucal.23 It was envisaged that a similar reaction on 4,6-di-O-benzyl-3-deoxy-D-glucal 1224,25 derived vicinal diol
would offer a straightforward approach to D-Hyp and its corresponding prolinol. With this idea, we started our synthesis with the
chemoselective debenzylation of the primary benzyloxy group of hemiacetal 13, which, in turn, was synthesized in one-pot two steps
from 4,6-di-O-benzyl-3-deoxy-D-glucal 12 as reported by us earlier.25 Exposure of hemiacetal 13 to ZnCl2 in presence of Ac2O and
AcOH26 resulted in a facile debenzylative acetolysis of primary benzylozy group that was also accompanied with acetylation of the
anomeric hydroxyl group to give the diacetate 14 in 78% yield. Next, reduction of the acetate groups of 14 and in situ reductive ring
opening of

3
OBn
OBn
O
6
3
5
Ref. 24
O
4
BnO
BnO
1
two steps
42 %
2
TsHN
OH
12
13
ZnCl2
Ac2O:AcOH
78%
rt, 40 °C, 5 h
OBn
4
HO
5
OAc
O
LiAlH4, THF
reflux, 10 h
3
2
6
BnO
1
HO HN
Ts OH
15
Scheme 1. Synthesis of intermediate 15 from glucal 12.
the resulting hemiacetal to triol 15 (84% yield) was accomplished by refluxing it with LiAlH4 in THF (Scheme 1).
84%
TsHN
OAc
14
As planned, oxidative cleavage of vicinal diol group of 15 was then carried out with NaIO4 in dichloromethane at 0 ºC–rt for 12 h.
The reaction directly afforded a diastereomeric mixture of cyclic hemiaminal 17, in 92% yield, formed through concomitant cyclization
of the initially formed aldehyde 16, as evidenced from the crude NMR (1H and 13C) spectra of the product. Absence of signal due to
aldehydic proton and carbonyl carbon as well as appearance of a signal at  5.45 ppm (due to hemiaminal proton) and  88.24 ppm (due
to hemiaminal carbon) in its 1H and 13C NMR spectra respectively confirmed the formation of pyrrolidine ring. The product was filtered
through a short silica gel column and was taken forward for the next step as such. Deoxygenation of hemiaminal 17 was next performed
with Et3SiH in presence of BF3.Et2O to get 18 in 85% yield. Oxidation of side chain primary hydroxyl group of 18 under Jones’
condition (CrO3, aq. H2SO4) smoothly delivered the corresponding carboxylic acid 19. One step deprotection of both the benzyl and
tosyl groups of 19 was conveniently achieved under Birch condition to obtain the target molecule, trans-4-hydroxy-D-proline, 2 in 79%
yield (Scheme 2). Its specific rotation []29D +72.0 (c 1.0, H2O) is in complete agreement with the literature reported values []25D +76.0
(c 2.0, H2O)}15 and {[]21D +79.3 (c 2.0, H2O)},16 so also its 1H and 13C NMR spectral data.18 On the other hand, direct Birch reduction
on 18 afforded trans-4-hydroxy-D-prolinol 9 in 71% yield (Scheme 2).
BnO
O
BnO
HO
NaIO4,
aq. NaHCO3
15
HN
Ts
16
CH2Cl2
30 oC, 12 h
N
OH
OH
Ts
92%, crude
17
BF3.Et2O
Et3SiH
CH2Cl2, 0-30 oC
85%
3 h
CrO3, aq. H2SO4
acetone, 0 oC
4 h
BnO
BnO
O
N
N
81%
OH
OH
Ts
19
Ts
18
Na, liq. NH3
78 oC, 3.5 h
Na, liq. NH3
78 oC, 4 h
79%
71%
HO
HO
O
N
N
H
9
OH
OH
H
2
trans-4-hydroxy-D-proline
trans-4-hydroxy-D-prolinol
Scheme 2. Synthesis of trans-4-hydroxy-D-proline and prolinol.

4
Tetrahedron
Conclusions
In conclusion, we have accomplished a practical synthesis of 4-hydroxy-D-proline and prolinol starting from 4,6-di-O-benzyl-3-
deoxy-D-glucal through oxidative cleavage as the key step. The novelty of the work is that the whole synthetic sequence proceeds
through complete stereochemical integrity. Notably, there was no formation of unwanted side products/mixtures in any of the steps.
Synthesis of 4-hydroxy-D-proline has been accomplished in 11 steps from commercially available 3,4,6-tri-O-acetyl-D-glucal with an
overall yield of 9.6%. It may be noted that the literature reliable method16 to obtain 4-hydroxy-D-proline was carried out in 10 steps
from trans-4-hydroxy-L-proline with an overall yield of 4.2% and required excess of expensive silver carbonate as well as hazardous
diazomethane. As all the steps described herein are well established and also do not require any special reaction condition, this
methodology should be easily amenable for scale up. This synthetic protocol is thus expected to serve as an attractive alternative to the
existing ones for the synthesis of D-Hyp.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgments
The authors are grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India for financial support in the
form of a research grant (02(243)/15/EMR-II) and a research fellowship to U.K.M. The authors also thank the Department of Science
and Technology (DST) and the Indian Institute of Technology Delhi (IITD) for funding of the ESI-HRMS facility at IIT Delhi.
Appendix A. Supplementary data
1
Supplementary data (experimental procedures, characterization data and copies of H and 13C NMR spectra of all new compounds)
to this article can be found at https://doi.org/10.1016/j.tetlet.2020
References and notes
1.
2.
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(a) Ramshaw, J. A. M.; Shah, N. K.; Brodsky, B. J. Struct. Biol. 1998, 122, 86-91. (b) McCaldon, P.; Argos, P. Proteins 1988, 4, 99–122. (c) White,
C. E.; Gavina, J. M. A.; Morton, R.; Britz-McKibbin.; Finan, T. M. Mol. Microbiol. 2012, 85, 1133–1147. (d) Srivastava, A. K.; Khare, P.; Nagar, H.
K.; Raghuwanshi, N.; Srivastava, R. Curr. Prot. Pept. Sci. 2016, 17 596–602.
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5.
Bollig, K.; Lamshöft, M.; Schweimer, K.; Marner, F. –J.; Budzikiewicz, H.; Waffenschmidt, S. Carbohydr. Res. 2007, 342, 2557–2566.
Zhu, K.; Yang, J. –S. Tetrahedron 2016, 72, 3113–3123.
Nishizawa, N.; Niida, A.; Adachi, Y.; Kanematsu-Yamaki, Y.; Masuda, Y.; Kumano, S.; Yokoyama, K.; Noguchi, Y.; Asakawa, T.; Hirabayashi, H.;
Amano, N.; Takekawa, S.; Ohtaki, T.; Asami, T. Bioorg. Med. Chem. 2017, 25, 5718–5725.
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.
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9.
Ganesan, M. S.; Raja, K. K.; Narasimhan, K.; Murugesan, S.; Kumar, B. K. J. Mol. Struct. 2020, 1208, 127873.
Darehkordi, A.; Ramezani, M. Mol. Divers. 2017, 21, 305–315.
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10. Vrieze, D. C. WO 200638119 2006.
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13. Lainé, D.; Palovich, M.; McCleland, B.; Petitjean, E.; Delhom, I.; Xie, H.; Deng, J.; Lin, G.; Davis, R.; Jolit, A.; Nevins, N.; Zhao, B.; Villa, J.;
Schneck, J.; McDevitt, P.; Midgett, R.; Kmett, C.; Umbrecht, S.; Peck, B.; Davis, A. B.; Bettoun, D. ACS Med. Chem. Lett. 2011, 2, 142–147.
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15. Robinson, D. S.; Greenstein, J. P. J. Biol. Chem. 1952, 195, 383–388.
16. Baker, G. L.; Fritschel, S.; Stille, J. R.; Stille, J. K. J. Org. Chem. 1981, 46, 2954–2960.
17. Krishnamurthy, S.; Arai, T.; Nakanishi, K.; Nishino, N. RSC Advances 2014, 4, 2482–2490.
18. Schuch, C. M.; Pilli, R. A. Tetrahedron Asymmetry 2002, 13, 1973–1980.
19. (a) Peterson, M. L.; Vince, R. J. Med. Chem. 1991, 34, 2787–2797. (b) Ng, K. –m. E.; Orgel, L. E. J. Med. Chem. 1989, 32, 1754–1757. (c),
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24. 4,6-Di-O-benzyl-3-deoxy-D-glucal 12 was synthesized, in three steps, from commercially available tri-O-acetyl-D-glucal with an overall yield of
69.5% as per the procedure described in the following papers. (a) Clark, J. S.; Romiti, F.; Sieng, B.; Paterson, L. C.; Stewaart, A.; Chaudhury, S.;
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5
Graphical Abstract
OBn
HO
OBn
6
5
4
6
5
3
OH
O
BnO
OH
R2 R1
4
3
2
OH
N
1
TsHN
1
H
2
OH
R1 = R2 = H
R1R2 = O
HIGHLIGHTS
Trans-4-hydroxy-L-proline (Hyp) is a non-proteinogenic amino acid.
Trans-4-hydroxy-D-proline (D-Hyp) is a non-natural enantiomer of Hyp.
Hyp and D-Hyp have found various biological applications.
4,6-Di-O-benzyl-3-deoxy-D-glucal has been utilized to synthesize D-Hyp.
The reported synthetic protocol proceeds with complete stereochemical integrity.