Synthesis of chiral non-proteinogenic 4,5-dihydroxytetrahydropyran derived α-amino acids from d-mannitol

Article abstract of DOI:10.1016/j.tetlet.2006.10.099

Starting from R-2,3-O-cyclohexylideneglyceraldehyde, which was obtained from d-mannitol, four tetrahydropyran derived chiral, non-proteinogenic α-amino acids have been synthesized. The key step in these syntheses is the ring closing metathesis using the f

Full text of DOI:10.1016/j.tetlet.2006.10.099

Tetrahedron Letters 47 (2006) 9035–9038
Synthesis of chiral non-proteinogenic
4,5-dihydroxytetrahydropyran derived a-amino acids
from D-mannitol
Anita Brar and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, India
Received 5 September 2006; revised 10 October 2006; accepted 19 October 2006
Abstract—Starting from R-2,3-O-cyclohexylideneglyceraldehyde, which was obtained from D-mannitol, four tetrahydropyran
derived chiral, non-proteinogenic a-amino acids have been synthesized. The key step in these syntheses is the ring closing metathesis
using the first generation Grubbs’ catalyst.
Ó 2006 Published by Elsevier Ltd.
Alpha-amino acids are the fundamental building blocks
of proteins as well as peptides which carry out various
biological processes including catalysis, gene regulation,
signal transduction and immune response.1 In order to
modify and improve the physical properties such as sta-
bility and bioavailability, and biological properties such
as receptor affinity, DNA-binding specificity, antibiotic
and antitumour activity of peptides, there have been
many reports2 in the literature on the use of non-protein-
ogenic a-amino acids.3,4 Additionally, non-proteinogenic
N3
BocHN
OH
OBn
OBn
OBn
OBn
MeO2C
MeO2C
MeO2C
O
O
O
OBn
OBn
OH
HO
OBn
OBn
O
O
O
O
OBn
OBn
O
O
O
O
O
O
Mannitol
O
O
O
H
O
OH
O
Scheme 1.
Keywords: a-Amino acids; Non-proteinogenic; D-Mannitol; R-2,3-O-Cyclohexylideneglyceraldehyde.
*
Corresponding author. Tel.: +91 512 2597169; fax: +91 512 259 7436; e-mail: vankar@iitk.ac.in
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.10.099

9036
A. Brar, Y. D. Vankar / Tetrahedron Letters 47 (2006) 9035–9038
amino acids also serve5 as useful building blocks in
the synthesis of alkaloids and other natural products.
Clearly, the development of new non-proteinogenic
amino acids is important in view of the above described
usefulness in organic synthesis. In this letter, we wish to
report the synthesis of four new 4,5-dihydroxytetra-
hydropyran based amino acid analogs starting from R-
2,3-O-cyclohexylideneglyceraldehyde.6 It was expected
that the protected 1,2-diol unit in R-2,3-O-cyclohexylid-
eneglyceraldehyde would enable the formation of the a-
amino acid part. Retrosynthetic analysis towards the
synthesis of pyranoid based sugar amino acids is shown
in Scheme 1.
bromide to give a 7:3 diastereomeric mixture of anti–
syn allylic alcohols 2 and 3 in a 78% yield. The two
diastereomers were separated and allylic alcohol 2 was
reacted with allyl bromide in the presence of NaH to
afford diene 4 (Scheme 2) in a 78% yield. Ring closing
metathesis of diene 4 using 2 mol % of the first genera-
tion Grubbs’ catalyst7 5 led to the formation of the cor-
responding dihydropyran derivative 6 in a 92% yield.
Dihydroxylation of 6 with OsO4/NMO gave a 1:1.6 mix-
ture of diols 7 and 8 in a quantitative yield, which were
readily separated by column chromatography. Attempts
to improve the diastereoselectivity using ADmix-b did
not lead to positive results. The indicated stereochemis-
1
try of 7 at C-4 and C-5 was assigned on the basis of H
R-2,3-O-Cyclohexylideneglyceraldehyde 1 (Scheme 2),
NMR spectral analysis, and COSY and NOE data of
mesylate 13, obtained later (vide infra). At this stage,
obtained6 from D-mannitol, was reacted with allyl zinc
R
R
+
(i)
R
ref.6
O
O
D-Mannitol
H
OH
OH
where
R
O
O
O
1
2
3
R
2
R
O
OH
4
5
R
OH
OH
(ii)
(iii)
92%
(iv)
2
+
quant.
O
O
78%
O
1
OH
6
4
6
7
8
OH
OH
HO
R
O
OBn
OBn
(v)
(vii)
(vi)
OBn
OBn
OBn
OBn
7
RO2C
73%
78%
84%
O
O
9
10
(viii)
67%
R = H = 11
R = Me = 12
N3
OMs
(ix)
3
6
(x)
95%
OBn
OBn
4
5
2
OBn
OBn
PCy3
Ru
12
MeO2C 1'
2'
MeO2C
Cl
Cl
85%
O
O
1
Ph
PCy3
14
13
5
NHBoc
(xi)
(xii)
OBn
OBn
MeO2C
86%
O
15
NHBoc
O
OMs
O
OBn
OBn
OBn
8
MeO2C
MeO2C
OBn
16
8e
Scheme 2. Reagents and conditions: (i) allyl bromide, Zn dust, aq NH4Cl, THF, rt, 4 h; (ii) allyl bromide, NaH, THF, rt, 1.5 h; (iii) 2 mol % Grubbs’
catalyst 5, rt, 20 min; (iv) OsO4, NMO, (CH3)2CO/H2O/t-BuOH (1:1:0.5), Na2S2O5, quantitative yield, 2 h; (v) NaH, BnBr, DMSO, rt, 7 h;
(vi) MeOH/HCl, rt, 1 h; (vii) TEMPO, NaOCl, NaHCO3, KBr, (CH3)2CO, 0 °C, 2 h; (viii) CH2N2, THF, rt, 20 min; (ix) MsCl, pyridine, CH2Cl2, rt,
1 h; (x) NaN3, DMF, rt, 4 h; (xi) PPh3, H2O, THF, rt, 1.5 h; (xii) (Boc)2O, Et3N, DCM, rt, 5 h.

A. Brar, Y. D. Vankar / Tetrahedron Letters 47 (2006) 9035–9038
9037
however, diol 7 was protected as the corresponding di-
benzyl ether 9 followed by the cleavage of the cyclohexyl-
idene unit with MeOH/HCl to form diol 10 in an 84%
yield. The primary hydroxyl group was oxidized with
NaOCl/TEMPO8 and the corresponding a-hydroxy acid
11, obtained in a 78% yield, was then esterified with di-
azomethane to give methyl ester 12 in a 67% yield. In
order to introduce an amino functionality, the hydroxyl
group was mesylated in a 85% yield with methanesulfo-
nyl chloride in the presence of pyridine. Mesylate 13 was
used for establishing the stereochemistry since the ste-
reochemistry at C-2 was not expected to change during
the course of these reactions. COSY data was used to
assign the proton chemical shifts following which NOE
experiments and homonuclear decoupling permitted
the absolute stereochemical assignments (Fig. 1). The
homonuclear decoupling of H-10 at d 5.18 converted a
triplet of doublets for H-2 at d 3.89 to a doublet of doub-
lets (J = 11.7 and 2.7 Hz) indicating that H-2 was axi-
ally oriented. In the NOE experiment, irradiation of
the signal as peak at d 3.51 for H-4 led to the enhance-
ment of the signals for H-2 at d 3.89 and for H-5 at d
3.68, thereby establishing the cis relationship between
H-2, H-4 and H-5. Further, in this NOE experiment,
resonances corresponding to one of the two methylene
protons at C-3 and C-6 at d 1.70 and 3.36, respectively,
were also enhanced. In addition, the irradiation of H-2
at d 3.89 led to the enhancement of the signals at d
3.51 for H-4 and resonances corresponding to one of
the two methylene protons at C-3 and C-6 at d 1.70
and 3.36, respectively. These data favour the structure
indicated for compound 13. Treatment of mesylate 13
with NaN3 in DMF at room temperature gave azido es-
ter 14 in a 95% yield.
Reduction of the azido moiety with Ph3P–H2O followed
by the protection of the amino group as –NHBoc even-
tually gave the desired a-amino acid derivative 15 in an
86% yield.
Likewise, isomeric diol 8 was transformed into Boc pro-
tected a-amino acid 16 using an analogous sequence of
reactions (Scheme 2). The spectroscopic and analytical
data for all the compounds in this sequence of reactions
(8 to 16) are given in the Supplementary data. The abso-
lute stereochemistry of mesylate 8e was confirmed by
NOESY data, which showed that H-2 and H-4, as well
as H-2 and H-5 were anti to each other.
H
H
OMs
H
6
1'
1
O
2'
2
H
Allylic alcohol 3 was converted to dihydropyran deriva-
tives 18 and 19 via syn diastereomeric diene 3a using
allylation and subsequent ring closing metathesis
(Scheme 3) in an analogous manner to compounds 7
and 8. Dihydroxylation of compound 17 with OsO4/
NMO led to formation of the two diastereomers 18
and 19 in a 1.3:1 ratio and in a quantitative yield. These
COOMe
H
H
H
4
5
3
BnO
H
OBn
Figure 1. NOE correlations for compound 13.
OR'
OR'
OR'
OR'
R
R
R
R
(i)
(iii)
5
3
O
O
O
O
65%
quant.
90%
3a
17
19: R' = H
19a: R' = Bn
(iv)
74%
18: R' = H
18a: R' = Bn
(iv)
73%
OMs
NHBoc
3
2
OBn
OBn
4
5
OBn
OBn
MeO2C
18a
MeO2C
R
1
O
O
O
O
6
18e
20
OMs
O
NHBoc
O
OBn
OBn
OBn
OBn
MeO2C
MeO2C
19a
19e
21
Scheme 3. Reagents and conditions: (i) allyl bromide, NaH, THF; (ii) 2 mol % Grubbs’ catalyst 5, rt; (iii) OsO4, NMO, (CH3)2CO/H2O/t-BuOH
(1:1:0.5), Na2S2O5, quantitative yield; (iv) NaH, BnBr, DMSO, rt.

9038
A. Brar, Y. D. Vankar / Tetrahedron Letters 47 (2006) 9035–9038
Acknowledgements
BnO
H
3
H
1
O
6
OMs
1'
We thank the Council of Scientific and Industrial
Research, New Delhi, for financial support through a
project [01(1892)/03/EMR-II]. One of us (A.B.) thanks
the Centre for Development of Technical Education
for a Research Scholarship.
5
H
2'
2
BnO
CO2Me
4
H
H
H
H
H
Supplementary data
Figure 2. NOE correlations for compound 18e.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.10.099.
two diastereomers were separated by column chromato-
graphy and the hydroxyl groups of the diols were pro-
tected as benzyl ethers to form 18a and 19a, respectively,
which were subsequently converted to the desired amino
acid derivatives 20 and 21 following a similar sequence
of reactions as followed for converting compound
12–15. The analytical and spectroscopic data for all the
intermediate compounds are given in the Supplementary
data. In order to assign the absolute stereochemistry of
the newly generated stereogenic centres, mesylates 18e
and 19e were analyzed spectroscopically using COSY,
NOESY, and homonuclear decoupling data. Thus,
homonuclear decoupling of H-10 in compound 18e at d
5.00 converted the triplet of doublets for H-2 at d 3.86
to a doublet of doublets (J = 12.0 and 1.9 Hz) indicating
that H-2 was axially oriented with a diaxial coupling of
12.0 Hz. Further, the NOESY data suggested a cis rela-
tionship between H-2, H-4 and H-5. Clearly, the other
diastereomer 19e will have H-2 and H-4, as well as
H-2 and H-5 trans to each other; this was also confirmed
from the NOESY data. These are in accordance with
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4
structure 18e (Fig. 2) with C1 conformation. Thus, in
all the structures, it appears that the group at C-2
prefers to occupy an equatorial position.
In summary, D-mannitol, a cheap and commercially
available chiral compound can be readily transformed
into four different tetrahydropyran derived a-amino acid
derivatives of non-proteinogenic origin. These molecules
could also be regarded as C-glycosyl amino acid deriva-
tives of non-natural origin considering that the sugar
moiety is a 5-nor-2-deoxy sugar. While our work was
in progress, a report on converting D-serine to glycosyl
nucleoside amino acid cores appeared9 in the literature
with the stereochemistry of the serine dictating the ste-
reochemistry of the final products. However, the present
approach leads to the formation of stereochemically
different amino acids from D-mannitol.
7. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH,
2003; vol. 2.
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