Stereoselective synthesis of the C1-C12 subunit of (-)-callystatin A

Article abstract of DOI:10.1016/j.tetlet.2015.05.089

A stereoselective synthesis of the C1-C12 fragment of callystatin A is disclosed. The two stereocenters at C5 and C10 were created by an organocatalytic reaction and a diastereoselective alkylation, respectively. The trisubstituted double bond was introdu

Full text of DOI:10.1016/j.tetlet.2015.05.089

Accepted Manuscript
Stereoselective synthesis of the C1-C12 subunit of (-)-callystatin A
Sadagopan Raghavan, Sheelamanthula Rajendar
PII:
S0040-4039(15)00922-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.089
TETL 46361
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 April 2015
22 May 2015
23 May 2015
Please cite this article as: Raghavan, S., Rajendar, S., Stereoselective synthesis of the C1-C12 subunit of (-)-
callystatin A, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.05.089
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Stereoselective synthesis of the C1-C12
subunit of (-)-callystatin A
Leave this area blank for abstract info.
Sadagopan Raghavan and Sheelamanthula Rajendar
A stereoselective synthesis of the C1-C12 subunit of callystatin A is described.
Wittig olefination
Me
RCM
1
O
O
H
Me
Negishi coupling
PhS
Organocatalytic reaction
Myer's/Evan's protocol
12

1
Tetrahedron Letters
journal homepage: www.els evier.com
Stereoselective synthesis of the C1-C12 subunit of (-)-callystatin A
Sadagopan Raghavana* and Sheelamanthula Rajendara
a
Natural Product Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India.
ARTICLE INFO
ABSTRACT
A stereoselective synthesis of the C1-C12 fragment of callystatin A is disclosed. The two
stereocenters at C5 and C10 were created by an organocatalytic reaction and a diasteroselective
alkylation respectively. The trisubstituted double bond was introduced by a hydroxy directed
hydrostannylation followed by Negishi reaction. The lactone ring resulted from a ring-closing
metathesis reaction.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Callystatin-A
organocatalytic aminooxylation reaction
ring-closing metathesis
hydroxy directed hydrometalation
Negishi reaction
Wittig olefination
(–)-Callystatin A 1, was isolated by Kobayashi and co-
workers from
marine sponge, Callyspongia truncata.1
quantity of PPTS delivered compound 15 (dr >95:<5).
Deprotection of the silyl ether using TBAF yielded alcohol 16
which on oxidation using TEMPO and PhI(OAc)8 yielded
aldehyde 4, Scheme 2.
a
Callystatin exhibits remarkable cytotoxicity against KB (IC50
=
10 pg mL-1) and L1210 (IC50 = 20 pg mL-1) cell lines which is
attributed to its inhibition of CRM1 (chromosome region
maintenance 1) protein.2 The structure of callystatin consists of
an unsaturated δ-lactone, two (Z, E)- and (E, E)-1,3-diene units, a
The alcohol 8 was synthesized by a diastereoselective
alkylation. In the initial attempt, imide 19,9 prepared by the
reaction of oxazolidine 17 with the mixed anhydride prepared
from carboxylic acid 18,10 was subjected to methylation to
furnish compound 20 (dr >95:<5). Reductive cleavage using
stereogenic center at C10 and
a polypropionate subunit
incorporating four chiral centers.
Its potent cytotoxicity combined with its complex
structure has stimulated much attention leading to several total
syntheses.3 We disclose herein, our efforts toward the
stereoselective synthesis of the C1-C12 subunit of callystatin. By
a retrosynthetic disconnection, callystatin was envisioned to be
synthesized by the union of the sulfone derived from 2 and
aldehyde 3, employing the Julia-olefination, Scheme 1. The
stereoselective synthesis of aldehyde 3 by a non-aldol approach
was recently described.4 The sulfide 2 was envisaged to be
obtained by a Wittig olefination between aldehyde 4 and the
phosphonium salt derived from bromide 5. The aldehyde 4 can
be obtained from homoallyl alcohol 6 and bromide 5 was
envisioned to be obtained from alkyne 7 which inturn can be
traced to sulfide 8.
LAH yielded alcohol
8 and 17. In another approach,
propionamide derivative 21, prepared using Myer's auxiliary,11
was subjected to alkylation with 2-thiophenyl iodoethane 22, to
yield compound 23. Reductive cleavage of the auxiliary12 using
LiNH2.BH3 furnished alcohol 8. While the temperature had to be
maintained around -78 oC using imide 19, the alkylation could be
o
carried out at 0 C using amide 21. Oxidation of the carbinol
using Swern prootocol13 afforded aldehyde 24. Homologation
using Corey-Fuchs protocol14 furnished dibromoalkene 25.
Alkyne formation using n-BuLi in the presence of an excess of
paraformaldehyde yielded propargylic alcohol 7 (99% ee),
Scheme 3. A highly regio- and stereoselective hydrostannylation
of alkyne was exploited for the creation of the (Z)-trisubstituted
alkene. Thus treatment of 7 with tributyltin hydride in the
presence of Pd(II)15 followed by iodine quench yielded allyl
alcohol 26 (regioisomer ratio 16:1). Negishi coupling16 of 26 and
diethylzinc using Pd(0) furnished alkene 27 in good yield. The
alcohol 27 was transformed to bromide 5 under Mitsunobu
conditions using CBr4.17 Further phosphonium salt formation by
reaction of 5 with tributylphosphine and reaction of the
corresponding ylide generated following a reported procedure,3b
with aldehyde 4 furnished diene sulfide 2 (E:Z = >95:<5),
corresponding to the C1-C12 subunit of callystatin A.
The synthesis began from commercially available 4-
pentenal
9 which was subjected to L-proline catalyzed
aminooxylation using nitrosobenzene5 and reduction using
sodium borohydride in the same pot to afford alcohol 10 (99%
ee). Protection of the carbinol under standard conditions as its
silyl ether 11 followed by cleavage of the O-N bond6 furnished
alcohol 6. The acrylate ester 12 obtained from 6 was subjected to
ring-closing metathesis reaction using Grubbs' first generation
catalyst 13 to furnish lactone 14.7 Reduction to lactal using
DIBAL-H and acetal formation using isopropanol and catalytic

2
Tetrahedron
O
OiPr
1
1
O
5
O
5
O
+
16
20
13
OP OP
12
16
20
12
SPh
9
9
O
OH
1
3
2
Br
OiPr
SPh
1
+
12
SPh
OH
OP
O
5
5
12
12
SPh
8
9
9
OH
OH
O
7
8
5
6
4
Scheme 1. Retrosynthetic disconnection of callystatin A.
Scheme 2. Synthesis of aldehyde 4.

3
HO2C
SPh 18
O
O
Cl
O
SPh
O
O
NH
O
N
LAH, THF,
0 oC, 3 h, 78%
R
LiCl, CH2Cl2, Et3N,
0 oC to rt,12 h, 75%
Ph
17
Ph
SPh
19
, R = H
NaHMDS, MeI,
THF, -78 oC,
4 h, 80%
20, R = Me (>95:<5)
OH
8
LiNH2.BH3, THF,
0 oC, 6 h, 83%
O
O
LDA, LiCl
SPh
Ph
Ph
SPh
N
N
22
I
OH
OH
THF, 2 h, 85%
23
21
(COCl)2, DMSO,
CH2Cl2, -78 oC,
1 h, then iPr2NEt,
15 min, 90%
n-BuLi, (CH2O)n,
THF, -78 oC,
2 h, 80%
n-Bu3SnH, PdCl2(PPh3)2,
THF, rt, 3 h, then I2,
CH2Cl2, rt, 1 h, 64%
X
SPh
SPh
24
, X = O
CBr4, PPh3,
CH2Cl2, 0 oC,
OH
7
(99% ee)
25, X = CBr2
1 h, 74%
PBu3, CH3CN,
rt, 1 h, then,
OiPr
CBr4, PPh3,
CH2Cl2, 0 oC,
1 h, 80%
KOtBu, Toluene,
aldehyde 4,
0 oC, 1h, 48%
O
HO
R
Br
SPh
R
SPh
SPh
26
, R = I (16:1)
5
Et2Zn, Pd(PPh3)4,
DMF, rt, 3h, 79%
2 (>95:<5)
27
, R = Et
Acknowledgement
Scheme 3. Synthesis of sulfide 2.
In conclusion, we have devised a stereoselective route
S. Rajendar is thankful to CSIR, New Delhi, for SRF
fellowship. S.R acknowledges funding from DST and CSIR,
New Delhi as a part of XII five year plan programme under the
title ORIGIN (CSC-108). We thank Dr. B. Jagadeesh, Head,
NMR center, for NMR spectra and Dr. R. Srinivas, Head, NCMS
division, for mass spectra.
to the C1-C12 fragment of callystatin employing
A
organocatalytic reaction to introduce the C5 stereocenter, a
diastereoselective auxiliary controlled alkylation to introduce the
C10 stereocenter. Ring-closing metathesis, hydroxy directed
regio- and stereoselective hydrostannylation and Negishi
coupling are other metal catalyzed/promoted reactions that have
been used to advantage. The C6-C7 double bond was introduced
by a Wittig olefination. Efforts are in progress to complete the
synthesis of callystatin A.
References and notes
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Supplementary Material
Deatailed experimental procedures are available as
supplementary material.