Total synthesis of cryptophycin-24 (arenastatin A) via Prins cyclization

Article abstract of DOI:10.1016/j.tetlet.2011.09.134

A stereoselective synthesis of fragment A of cryptophycin is achieved utilizing the versatile Prins cyclization. Subsequently, the total synthesis of cryptophycin-24 (arenastatin A) has been accomplished by coupling it with the depsipeptide subunit.

Full text of DOI:10.1016/j.tetlet.2011.09.134

Tetrahedron Letters 52 (2011) 6709–6712
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Tetrahedron Letters
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Total synthesis of cryptophycin-24 (arenastatin A) via Prins cyclization
J.S. Yadav a, , K.V. Purnima a, B.V. Subba Reddy a, K. Nagaiah a, A.K. Ghamdi b
⇑
a CSIR, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 May 2011
Revised 27 September 2011
Accepted 29 September 2011
Available online 6 October 2011
A stereoselective synthesis of fragment A of cryptophycin is achieved utilizing the versatile Prins cycliza-
tion. Subsequently, the total synthesis of cryptophycin-24 (arenastatin A) has been accomplished by cou-
pling it with the depsipeptide subunit.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cryptophycins
Cyclic depsipeptides
Prins cyclization
Olefin rearrangement
Grignard reaction
Cryptophycins were isolated by Schwartz and co-workers from
Nostoc sp. strains ATCC 53789.1 While these authors established
their structures, details of absolute stereochemistry were not dem-
onstrated. Subsequently, a variety of cytotoxins were isolated by
Moore and co-worker from a crude lipophilic extract of Nostoc
sp. GSV 224 and they established their absolute stereochemistry.2a
Cryptophycins are cyclic depsipeptides and are remarkably potent
against tumor cell lines.2b
Cryptophycin A (1) and B (2) exhibit cytotoxic IC50 values of 5
and 7 pg/mL, respectively, against KB cells. In 1994, arenastatin A
(3) (renamed as cryptophycin-24), another member of the crypto-
phycin family, was isolated 3 by Kobayashi et al. from the Okinawa
marine sponge Dysidea arenaria. It also exhibits cytotoxicity with
IC50 value of 5 pg/mL against KB cells.3 Moore and co-worker have
discovered that the synthetically derived cryptophycin 8 (4) is
more active in vivo than (1) (Fig. 1).4
Cryptophycin A (1) was found to be very active against the fun-
gus Cryptococcus, which causes immunodeficiency.2 The significant
clinical potential of cryptophycins and their low natural abundance
have made them attractive synthetic targets. Consequently, some
reports on the total synthesis of cryptophycins following multi-step
synthetic sequences have been published.5–13 However; many of
these syntheses employ asymmetric dihydroxylation as a key step
to generate syn-diols. In view of their fascinating structures and
biological activity, we were interested in the synthesis of crypto-
phycins using Prins cyclization as a key step for the synthesis of
non-peptidic part.14,15 We have explored the utility of Prins cycliza-
tion in the synthesis of various polyketide intermediates for the to-
tal synthesis of natural products16 and report the total synthesis of
cryptophycin-24. In our retrosynthetic analysis (Scheme 1), we
envisaged that cryptophycin-24 could be divided into two parts,
homoallyl alcohol with four stereogenic centers (Fragment A) and
a peptidic subunit (Fragment B). It was proposed to obtain an
anti-1,3-diol derivative from 2,4,5,6-tetrasubstituted tetrahydropy-
ran 8, which in turn could be obtained via the Prins cyclization of the
homoallylic alcohol 9 with an aldehyde 10. The synthesis of
O
O
HN
X
O
O
O
O
N
H
O
OMe
R
cryptophycin A (1) X=Cl, R=CH3
cryptophycin B (2) X=Cl, R=H
cryptophycin-24 (3) X=H, R=H
Cl
O
O
O
O
HN
Cl
HO
O
O
OMe
N
H
cryptophycin 8 (4)
⇑
Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160512
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Figure 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.134

6710
J. S. Yadav et al. / Tetrahedron Letters 52 (2011) 6709–6712
O
O
O
O
O
OH
O
OH
HN
Ph
O
O
+
O
O
HN
O
O
O
N
H
OMe
Ph
O
OMe
N
H
fragment A
6
5
fragment B
OH
OH
OH
O
OBn
HO
OBn
Ph
9
HO
O
O
11
O
OBn
+
7
O
O
OBn
8
OHC
10
Scheme 1. Retrosynthetic analysis of cryptophycin-24 (arenastatin A) (3).
fragment A began with the homoallylic alcohol 9 which was pre-
pared from (S)-benzyl glycidyl ether 11.17 Prins cyclization of 9 with
aldehyde 10 in the presence of TFA (10 equiv) followed by hydroly-
sis of the resulting trifluoroacetate with K2CO3 in methanol gave 4-
hydroxytetrahydropyran 8 with 94% de.
Ozonolysis of alkene 15 afforded the corresponding aldehyde
16, which on treatment with phenylmagnesium bromide in the
presence of magnesium bromide diethyl etherate in CH2Cl2 at
À78 °C afforded syn-selective alcohol 7 in 72% overall yield with
94% de. The presence of MgBr2 led to high syn-selectivity in phenyl
Grignard reaction, while in the absence of MgBr2 an inseparable
mixture of diastereomers was obtained in a 1:1 ratio.19 The
MOM group in 7 was deprotected using p-TSA in methanol to fur-
nish the corresponding diol in 65% yield, which in turn was
protected as its acetonide 17 by treatment with 1,2-dimethoxypro-
pane in the presence of catalytic amounts of PPTS in 92% yield. The
acetate 17 was hydrolyzed with K2CO3 in methanol to yield an
alcohol.
This was separated by column chromatography (Scheme 2). The
stereochemistry was assumed to be in line with previous results.16
It was later proved by the elaboration of compound 8 to the target
fragment which was found to be identical to a sample reported
earlier.13 Chemoselective tosylation of primary alcohol 8 with
1.1 equiv of tosyl chloride in the presence of TEA in CH2Cl2 gave
the corresponding tosylate 12 in 82% yield. MOM protection of
the secondary alcohol in 12 with methoxymethyl chloride pro-
vided the corresponding MOM ether 13 in 76% yield. Treatment
of tosylate 13 with NaI in refluxing acetone gave the respective
iodide 14 in 86% yield, which on exposure to potassium
t-butoxide18 in THF and a subsequent rearrangement on silica gel
gave the key intermediate 15 in 55% yield.16d
This was subsequently debenzylated with Pd/C under H2 atmo-
sphere in methanol to furnish diol 18 in 82% yield. Oxidation of pri-
mary hydroxyl group in 18 using TEMPO and BAIB in CH2Cl2
followed by Wittig olefination of the resulting aldehyde with an
excess C-1 ylide generated in situ by the reaction of ICH3PPh3 with
OH
OH
OH
HO
a
b
9
TsO
HO
+
O
OBn
O
OBn
OBn
12
OHC
c
8
10
OMOM
OMOM
OMOM
e
d
TsO
I
O
OBn
O
OBn
O
OBn
13
14
15
OH
g
h
f
OBn
OHC
OBn
Ph
O
OAc
16
O
OAc
O
7
O
O
OH
O
j
OAc
O
i
OH
O
O
O
OBn
OH
Ph
Ph
Ph
6
17
18
Scheme 2. Synthesis of 6. Reagents and conditions: (a) (i) TFA, CH2Cl2, 0 °C to rt, 4 h; (ii) K2CO3, MeOH, rt, 2 h, 65% over two steps; (b) p-TSCl, CH2Cl2, TEA, 0 °C to rt, 8 h, 82%;
(c) MOM-Cl, CH2Cl2, DIPEA, 0 °C to rt, 6 h, 76%; (d) NaI, acetone, reflux, 24 h, 86%; (e) t-BuOK, THF, 0 °C, 30 min, silica gel promoted rearrangement, 55%; (f) O3, CH2Cl2, À78 °C,
15 min; (g) PhMgBr in Et2O, MgBr2ÁEt2O, CH2Cl2, À78 °C, 45 min, 72% over two steps; (h) (i) p-TSA, MeOH, reflux, 6 h, 65%; (ii) 2,2-DMP, PPTS, rt, 3 h, 92%; (i) (i) K2CO3, MeOH,
rt, 2 h, quant; (ii) 5% Pd/C, MeOH, H2, 3 h, 82%; (j) (i) TEMPO, BAIB, CH2Cl2, rt, 1 h; (ii) ICH3PPh3, t-BuOK, THF, 0 °C to rt, 4 h, 76% from 18.

J. S. Yadav et al. / Tetrahedron Letters 52 (2011) 6709–6712
6711
O
Ph
O
O
O
OR
HN
b
O
O
O
O
O
HN
O
O
O
OMe
N
H
N
H
O
OMe
R=t-Bu
19
5
a
20
R=H
c
OH
Ph
O
O
Ph
e
d
O
OH
O
HN
3
O
O
O
HN
O
O
O
O
N
H
O
OMe
O
N
H
O
OMe
22
21
Scheme 3. Synthesis of 3. Reagents and conditions: (a) TFA, CH2Cl2, rt, 4 h, quant; (b) 2,4,6-trichlorobenzoyl chloride, DIPEA, THF, 0 °C to rt, 2 h, then 6, DMAP, rt, 18 h, 80%
from 19; (c) Grubbs’ II catalyst (10 mol %), CH2Cl2, reflux, 2 h, 75%; (d) TFA, CH2Cl2, 0 °C to rt, 4 h, 80%; (e) (i) (MeO)3CH, PPTS, CH2Cl2, rt, 1 h; (ii) AcBr, CH2Cl2, rt, 2 h; (iii)
KHCO3, DME/EtOH/MeOH (6:4:1), 40 °C, 6 h, 65% from 22.
3. (a) Kobayashi, M.; Aoki, S.; Ohyabu, N.; Kurosu, M.; Wang, W.; Kitagawa, I.
potassium t-butoxide gave the target fragment A of cryptophycin-
Tetrahedron Lett. 1994, 35, 7969–7972; (b) Koiso, Y.; Morita, K.; Kobayashi, M.;
Wang, W.; Ohyabu, N.; Iwasaki, S. Chem. Biol. Interact. 1996, 102, 183–191; (c)
Kobayashi, M.; Wang, W.; Ohyabu, N.; Kurosu, M.; Kitagawa, I. Chem. Pharm.
24 6 in 76% yield. The data of a target fragment A of cryptophycin-
24 were identical in all respects to that reported in literature.13
Bull. 1995, 43, 1598–1600.
4. Trimurtulu, G.; Ogino, J.; Heltzel, C. E.; Husebo, T. L.; Jensen, C. M.; Larsen, L. K.;
The depsipeptide subunit (Fragment B) was constructed from
(D)-N-Boc-tyrosine methyl ester, b-alanine, and L-leucic acid t-
Patterson, G. M. L.; Moore, R. E.; Mooberry, S. L.; Corbett, T. H.; Valeriote, F. A. J.
Am. Chem. Soc. 1995, 117, 12030–12049.
butyl ester.7d The t-butyl group of 19 was removed with TFA and
the resulting acid 5 was coupled with alcohol 6 under Yamaguchi
conditions to afford the compound 20 in 80% overall yield.7d The
diene 20 was subjected to Grubbs’ second generation catalyst in
CH2Cl2 under reflux conditions to afford the RCM product 21 in
75% yield (Scheme 3).11 The compound 21 was subjected to TFA
in CH2Cl2 to afford diol 22 (80%). The syn-diol 22 was then con-
verted into the epoxide in three sequential steps in 65% yield. Ini-
tially, the diol was treated with trimethylorthoformate in the
presence of PPTS in CH2Cl2, followed by acetyl bromide to produce
the anticipated bromohydrin formate, which was taken for the
next step without purification. The formation of the desired epox-
ide was achieved using solid KHCO3 in a mixture of DME/ethanol/
methanol (6:4:1) at 40 °C for 6 h.11 The data of the target molecule
3, cryptophycin-24 (arenastatin A) were identical in all respects to
that reported in.4
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In conclusion, we have proved the versatility of the Prins cycli-
zation in natural product synthesis by achieving the stereoselective
synthesis of cryptophycin-24 (arenastatin A). Further applications
of the Prins cyclization in the synthesis of natural products are in
progress.
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K.V.P. thanks CSIR New Delhi for the award of fellowships and
J.S.Y. is thankful to DST for the financial assistance under J.C. Bose
fellowship scheme. The author acknowledges the partial support
by King Saud University for Global Research Network for Organic
Synthesis (GRNOS).
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