Synthesis of unit-B of cryptophycin-24 via Sharpless asymmetric dihydroxylation

Article abstract of DOI:10.1016/j.tetlet.2012.10.078

A synthetic pathway for the synthesis of unit-B of cryptophycin-24 has been developed using Sharpless asymmetric dihydroxylation as the key step. This study shows that direct azidation of α-hydroxy acid ester using diphenylphosphoryl azide is beneficial to asymmetric synthesis of α-amino acid without the loss of chirality during the transformation.

Full text of DOI:10.1016/j.tetlet.2012.10.078

Tetrahedron Letters 53 (2012) 7128–7130
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Synthesis of unit-B of cryptophycin-24 via Sharpless asymmetric
dihydroxylation
Arun Jyoti Borah a, Progyashree Goswami a, Nabin C. Barua b, Prodeep Phukan a,
⇑
a Department of Chemistry, Gauhati University, Guwahati 781 014, Assam, India
b Natural Product Chemistry Division, CSIR-NEIST, Jorhat 785 006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic pathway for the synthesis of unit-B of cryptophycin-24 has been developed using Sharpless
asymmetric dihydroxylation as the key step. This study shows that direct azidation of -hydroxy acid
-amino acid without
Received 16 July 2012
Revised 19 October 2012
Accepted 21 October 2012
Available online 26 October 2012
a
ester using diphenylphosphoryl azide is beneficial to asymmetric synthesis of
the loss of chirality during the transformation.
a
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cryptophycin
Sharpless asymmetric dihydroxylation
Hydrogenolysis
Diphenylphosphoryl azide
a-Amino acid
The cryptophycins1 are potent tumour selective cytotoxins, iso-
Unit A
lated from the blue green algae Nostoc sp. ATCC 53,7892 and Nostoc
sp. GSV 224.3 The first representative of these depsipeptides, cryp-
tophycin-1, was isolated from the blue-green algae Nostoc sp. ATCC
53789.2 Several other cytotoxin analogues were also isolated from
blue green algae belonging to Nostocaceae.2,4 Structurally simpler
cryptophycin, cryptophycin-24 was isolated from an Okinawan
marine sponge, Dysidea arnaria.5 Though cryptophycin-24 lacks a
chlorine substituent on the aryl ring of the C-10 side chain and
the methyl group at C6 (Fig. 1), it was extremely potent against
KB cells (ED50 = 5 pm).5
O
Unit B
O
O
HN
O
O
O
O
OMe
N
H
Unit D
Unit C
Figure 1. Structure of cryptophycin-24.
To realize the synthesis of unit B of cryptophycin-24, we have
initiated the synthesis, using 4-methoxy cinnamic acid 1 as the
starting material (Scheme 2). The acid was converted into methyl
ester (2) in 87% yield using methanol and thionyl chloride (SOCl2).9
Ester 2 was then subjected to Sharpless asymmetric dihydroxyla-
tion procedure using (DHQ)2PHAL as the chiral ligand.10 The corre-
sponding diol 3 was obtained in 87% yield. The optical rotation of
the compound was found to be +5.2° (c 1, EtOH) [Lit11 +5.5° (c 1,
EtOH)]. Hydrogenolysis of diol 3 using Pd/C and hydrogen gas in
methanol12 produced the corresponding alcohol 4 in 65% yield.
The measured optical rotation of 4 was found to be +11.3° (c 1,
CHCl3). In the next step our strategy was to convert the alcohol
functionality into azide.
Retrosynthetically, cryptophycin-24 can be disconnected into
four units (Fig. 1). The unit-B of cryptophycin can be derived from
the commercially available
a
-amino acid, D-tyrosine.6 However,
few alternative pathways were also developed to synthesize the
target amino-acid fragment. Maier developed a synthetic strategy
for unit B via the asymmetric alkylation of a glycine imine in the
presence of a cinchonine derived phase transfer catalyst (PTC).7 Re-
cently, Sewald developed another strategy for this unit based on
the asymmetric hydrogenation in the presence of a chiral rhodium
catalyst.8 In this Letter, we are reporting a new synthetic strategy
for unit-B of cryptophycin-24 using Sharpless asymmetric dihydr-
oxylation as the key step. The retrosynthetic sequence is repre-
sented in Scheme 1.
Alcohol 4 was first transformed to the corresponding bromide 5
and then to the azido compound 6. Bromination was carried out
using CBr4 in the presence of PPh3. The optical rotation of the
⇑
Corresponding author.
E-mail addresses: baruanc@rrljorhat.res.in (N.C. Barua), pphukan@yahoo.com (P.
13
bromo compound 5 was measured to be ꢀ3.6° (c 1, CHCl3). Then
Phukan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.078

A. J. Borah et al. / Tetrahedron Letters 53 (2012) 7128–7130
7129
O
O
O
OH
OMe
OMe
NHBoc
N3
OH
MeO
MeO
MeO
O
OH
O
OH
OMe
OH
MeO
MeO
Scheme 1.
O
OH
O
O
OMe
OMe
b
OH
a
OH
MeO
MeO
MeO
1
3
2
O
O
e
OMe
d
c
OMe
Br
MeO
OH
MeO
5
4
O
O
O
OH
NHBoc
OMe
NHBoc
g
f
OMe
MeO
MeO
N3
MeO
8
7
6
Scheme 2. Reagents and condition: (a) MeOH, SOCl2, rt; (b) K2OsO2(OH)4, (DHQ)2PHAL, MeSO2NH2 tBuOH: H2O (1:1), 0 °C; (c) Pd/C, H2, MeOH; (d) CBr4, TPP, dry DCM, rt; (e)
NaN3, DMF, rt; (f) H2, EtOAc, Boc2O; (g) K2CO3, H2O, MeOH, rt.
the bromo ester 5 was converted into azide 6 using NaN3 in dry
method used previously to produce compound 10 with 67% yield.
The optical rotation of the compound recorded to be ꢀ11.9° (c, 1,
CHCl3). In the next step we synthesized the azide 11 directly from
10 by using diphenylphosphoryl azide (DPPA).18 The reaction was
carried out by treating compound 10 with DPPA in the presence of
DBU in THF under ice cool condition and continuing the reaction at
room temperature for 24 h. The corresponding azide 11 was ob-
tained in 75% yield and with high optical activity. The measured
optical rotation this time was found to be +48.1° which is much
better in comparison to the previous route (Scheme 2). Then we
DMF14 {½a 2D6
ꢁ
= + 14.9° (c 1, CHCl3)}. In the next step we converted
the azide 6 into Boc-protected amino compound 7 through one
pot synthesis.15 The optical rotation of compound 7 [ꢀ16.1° (c 1,
CHCl3)] was found to be very low as compared to that reported
in the literature [ꢀ58.4° (c 1, CHCl3)].16 This may be due to partial
racemization of the product during bromination of the hydroxyl
functionality of compound 4, located at
a-position to the ester
functionality. Hence, we designed a new strategy to synthesize
the target molecule. The new synthetic route is shown in Scheme 3.
Accordingly, we planned to synthesize the azido compound di-
rectly from monohydroxy compound 10 in one step. We have car-
ried out the AD reaction of compound 2, using (DHQD)2PHAL as the
chiral ligand. The product was obtained with 89% yield with high
optical purity. The measured optical rotation for the diol was found
to be ꢀ5.6° (c 1, CH2Cl2) [Lit.17 ꢀ5.8° (c 1, CH2Cl2)]. Thereafter com-
pound 9 was subjected to hyderogenolysis by following the same
continued the synthesis to produce the Boc-protected
a-amino
acid ester 12 under hydrogenation condition. The present method
resulted in improvement of the optical purity of compound 12 and
the optical rotation was found to be ꢀ58.1° (c 1, CHCl3). The enan-
tiomeric excess of the product was analysed by using HPLC and
found to be 99%. The amino ester was finally converted into corre-
sponding amino acid 8 using K2CO3 in methanol19 to yield the
O
O
OH
O
a
OMe
b
OMe
OMe
OH
MeO
OH
MeO
MeO
2
9
10
O
O
O
c
OMe
d
OH
NHBoc
e
OMe
NHBoc
N3
MeO
MeO
MeO
8
11
12
Scheme 3. Reagents and condition: (a) K2OsO2(OH)4, (DHQD)2PHAL, MeSO2NH2 tBuOH: H2O (1:1), 0 °C; (b) Pd/C, H2, MeOH; (c) DPPA, DBU, dry THF, 0 °C; (d) H2,
EtOAc,Boc2O; (e) K2CO3, H2O, MeOH, rt.

7130
A. J. Borah et al. / Tetrahedron Letters 53 (2012) 7128–7130
OH
OH
O
O
O
O
OMe
OMe
OMe
OH
c
a
b
OH
MeO
MeO
MeO
MeO
Cl
Cl
Cl
10
13
14
Scheme 4. Reagents and condition: (a) SOCl2, MeOH; (b) K2OsO2(OH)4, (DHQD)2PHAL, MeSO2NH2 tBuOH: H2O (1:1), 0 °C; (c) Pd/C, H2, MeOH.
product as a white solid. The optical rotation of the compound was
found to be ꢀ26.9° (c 1, EtOH).
References and notes
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In conclusion, we have developed a new asymmetric synthetic
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Sharpless asymmetric dihydroxylation as the key step. Initial at-
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a-hydroxy acid ester into the corresponding a-
amino acid ester via bromocompound was unsuccessful due to
partial racemization of the product during bromination. However,
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azidation using DPPA is beneficial for asymmetric synthesis of
a-
amino acid from -hydroxy acid ester without the loss of chirality
a
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Acknowledgments
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
078.