Stereoselective synthesis of the common polyketide fragment of hoiamides

Article abstract of DOI:10.1016/j.tetlet.2012.05.103

Stereoselective synthesis of the polyketide fragment commonly present in hoiamide A, B, and C is described using iterative Crimmins aldol reaction as the key reaction.

Full text of DOI:10.1016/j.tetlet.2012.05.103

Tetrahedron Letters 53 (2012) 4087–4089
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Stereoselective synthesis of the common polyketide fragment of hoiamides
⇑
M. Seenaiah, S. Chandrasekhar
Division of Natural Products Chemistry, CSIR—Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of the polyketide fragment commonly present in hoiamide A, B, and C is
described using iterative Crimmins aldol reaction as the key reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 April 2012
Revised 21 May 2012
Accepted 23 May 2012
Available online 29 May 2012
Keywords:
Hoiamide
Polyketides
Crimmins aldol
Wittig olefination
Hoiamides, a new class of marine natural products which are
isolated from cyanobacteria collected in Papua New Guinea and
their structures were determined by spectral techniques.1 This
unusual structural complexity must have been derived from pep-
tide–polyketide biogenetic pathway. The structure and stereo-
chemical assignments were made by using extensive NMR
studies, chemical degradation methods, and modified Mosher ester
analysis (Fig. 1). Hoiamide A and B exhibited sodium influx with
EC50 values of 1.7 and 3.9 lM, where as hoiamide C showed no sig-
nificant pharmacological activity in these assays.
The natural products hoiamide A and B are cyclic depsipeptides,
whereas hoiamide C is a linear compound. The structural complex-
ity of these molecules includes 15 asymmetric carbons, peptide
link, and three thiazole rings. The common structural feature in
S
S
N
N
HO
S
MeO
N
HO
O
O
NH
HN
OH
R = H, Hoiamide A (1)
R = Me, Hoiamide B (2)
O
O
R
HO
O
S
S
N
S
all three natural products is the polyketide fragment that is C30
40 of hoiamide A, C31–C41 of hoiamide B, and C21–C31 of hoiamide
C. To date there is only one total synthesis of hoiamide C.2
–
OMe OH OH
N
N
C
HO HN
O
O
O
In continuation of our work in the synthesis of marine cyclic
peptides,3 we were interested in the synthesis of hoiamides. Here-
in, we present the synthesis of polyketide fragment of hoiamides.
The retrosynthetic analysis showed that the fragment 4 could be
derived from thiazolidine system 5, which in turn is envisioned
from Crimmins aldol adduct 6. The adduct 6 in turn could arise
from known 1, -3-diol 7, which can be obtained from propane-1,
-3-diol 8 (Scheme 1).
Hoiamide C (3)
Figure 1. Structures of hoiamide A, B, and C.
protected as tert-butyldimethylsilyl ether 9 (86%) by treating with
TBS-Cl and Et3N in CH2Cl2 and subsequent protection of the sec-
ondary alcohol using MeI and NaH in THF resulted in the methyl
ether 10 (71%). In compound 10, the silyl group was deprotected
by treatment TBAF (1 M) in THF at 0 °C to afford the alcohol 11.
Alcohol 11 was efficiently oxidized with IBX in DMSO/THF at room
temperature to provide the aldehyde 12.
Synthesis of the polyketide fragment 4 (Scheme 2) began from
the known 1,3-diol 7.4 Next, the primary alcohol group in 7 was
⇑
Corresponding author. Tel.: +91 040 27193210; fax: +91 040 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.103

4088
M. Seenaiah, S. Chandrasekhar / Tetrahedron Letters 53 (2012) 4087–4089
O
MeO
OTBS
O
O
MeO
OTBSOMOM
S
BnO
N
HO
S
Polyketide fragment
5
Ph
4
OH
MeO
OH
O
S
BnO
OH
BnO
N
HO
OH
S
6
8
7
Ph
Scheme 1. Retrosynthetic analysis of polyketide fragment.
OH
OH
a
b
c
HO
OH
BnO
OH
BnO
OTBS
O
9
7
8
OMe
OMe
OMe
d
e
f
BnO
g
OH
BnO
BnO
OTBS
O
12
11
10
MeO
OTBSO
MeO
OH
S
S
MeO
OTBS
h
BnO
N
BnO
N
BnO
S
S
O
14
6
15
Ph
MeO
Ph
OMOM
O
OTBS
MeO
OTBS
S
OH
O
l
S
k
i
j
BnO
MeO
N
S
BnO
N
S
16
5
Ph
Ph
OTBSOMOM
MeO
OTBS
OMOM
m
BnO
BnO
O
17
18
S
N
O
S
MeO
OTBSOMOM
Ph
HO
13
4
Scheme 2. Reagents and conditions: (a) Ref. 4; (b) TBS-Cl, Et3N, CH2Cl2, rt, 2 h, 86%; (c) NaH, Mel, THF, 0 °C, 3 h, 71%; (d) TBAF (1 M in THF), THF, 0 °C to rt, 2 h, 88%; (e) IBX,
DMSO, THF, 0 °C to rt, 3 h, 85%; (f) 13, TiCl4 (1 M in CH2Cl2), DIPEA, CH2Cl2, 0 °C, 4 h, 70%, (95:5 dr); (g) TBSOTf, DIPEA, CH2Cl2, 0 °C, 2 h, 88%; (h) DIBAL-H, CH2Cl2, À78 °C,
10 min, 90%; (i) 13, TiCl4 (À)-Sparteine (2 equiv), CH2Cl2, 0 °C, 12 h, 63%; (94:6 dr); (j) MOM-Cl, DIPEA, CH2Cl2, 0 °C, 3 h, 70%; (k) DIBAL-H, CH2Cl2, À78 °C, 10 min, 90%; (l)
PPh3C2H5, n-BuLi (1.6 M), THF, À78 °C, 2 h, 70%; (m) 10% Pd-C, H2 (gas), EtOH, rt, 12 h, 80% .
According to the envisaged plan, the next task was a non-Evans
syn-aldol reaction5 of aldehyde 12 with the versatile Crimmins chi-
ral auxiliary 13. The chlorotitanium enolate of 13 was formed by
addition of 1.05 equiv of TiCl4, followed by 1.1 equiv of i-Pr2NEt
and subsequent addition of aldehyde 12 gave the alcohol 6 in
70% yield (95:5 dr).
Alcohol 6 was silylated by the action of TBSOTf and lutidine in
CH2Cl2 at 0 °C to get compound 14 in 88% yield and 1, 2-syn stereo-

M. Seenaiah, S. Chandrasekhar / Tetrahedron Letters 53 (2012) 4087–4089
4089
ric carbons present in the polypropionate part of the target
molecules.
Acknowledgments
M.S. thanks CSIR, New Delhi, for financial support in the form of
a fellowship. The help of Balasubramanian Sridhar (the Laboratory
of X-ray Crystallography, IICT) in X-ray crystal structure determi-
nation is acknowledged.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data for all new compounds) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.05.103.
References and notes
1. (a) Pereira, A.; Cao, Z.; Murray, T. F.; Gerwick, W. H. Chem. Biol. 2009, 16, 893–
906; (b) Choi, H.; Pereira, A. R.; Cao, Z.; Shuman, C. F.; Engene, N.; Byrum, T.;
Matainaho, T.; Murray, T. F.; Mangoni, A.; Gerwick, W. H. J. Nat. Prod. 2010, 73,
1411–1421.
2. Wang, L.; Xu, Z.; Ye, T. Org. Lett. 2011, 13, 2506–2509.
3. (a) Chandrasekhar, S.; Lohitha Rao, Ch.; Seenaiah, M.; Naresh, P.; Jagadeesh, B.;
Manjeera, D.; Sarkar, A.; Bhadra, M. P. J. Org. Chem. 2009, 74, 401–404; (b)
Chandrasekhar, S.; Reddy, G. P. K.; Sathish, K. Tetrahedron Lett. 2009, 50, 6851–
6854; (c) Sathish, K.; Reddy, G. P. K.; Mainkar, P. S.; Chandrasekhar, S.
Tetrahedron: Asymmetry 2011, 22, 1568–1573; (d) Chandrasekhar, S.; Sultana,
S. S. Tetrahedron Lett. 2006, 47, 7255–7258.
Figure 2. X-ray crystal structure of 14.6 Displacement ellipsoids are drawn at 30%
probability level.
4. (a) Chattopadhyay, S. K.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 2000, 2429–
2454; (b) Ishihara, J.; Ishizaka, T.; Suzuki, T.; Hatakeyama, S. Tetrahedron Lett.
2004, 45, 7855–7858; (c) The enantiomeric excess in Sharpless asymmetric
epoxidation was 94% ee.
5. (a) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084–9085; (b)
Crimmins, M. T.; Choudary, K. Org. Lett. 2000, 2, 775–777; (c) Crimmins, M. T.;
Slade, D. J. Org. Lett. 2006, 8, 2191–2194; (d) Crimmins, M. T.; She, J. Synlett 2004,
1371–1374.
chemistry of the newly created asymmetric carbons was deter-
mined by X-ray crystallography.6 Reduction of the imide with i-
Bu2AlH in CH2Cl2 at À78 °C provided the aldehyde 15 in 90% yield.
Aldehyde 15 underwent a second Evans syn-aldol reaction5 with
propionylthiazolidinethione 13, TiCl4 (1.05 equiv), and (À)-Sparti-
ene (2.2 equiv) in CH2Cl2 at 0 °C gave syn aldol product 16 in 63%
yield (94:6 dr). Protection of secondary alcohol 16 by treatment
with MOM-Cl and DIPEA in CH2Cl2 at 0 °C resulted in 5 (70% yield).
Reductive removal of the chiral auxiliary of 5 with DIBAL-H in
CH2Cl2 at À78 °C provided the corresponding aldehyde 17 in 90%
yield.7 Wittig reaction8 of the aldehyde 17 with PPh3C2H5I and n-
BuLi in THF at À78 °C led to olefin 18 as a mixture of E/Z isomers
in 70% yield. The mixture of stereoisomers was converted into
compound 4 in 80% yield by hydrogenation of the double bond
and benzyl deprotection with 10% Pd-C in EtOH in one-pot. This
constitutes the key polyketide fragment of hoiamides.
6. Crystal data of compound (14): C33H49NO4S2Si, M = 277.35, monoclinic, space
group P21, a = 13.3475(10) Å, b = 8.2602(6) Å, c = 16.6536(13) Å, b = 113.082(1),
V = 1689.1(2) Å3, Z = 2, Dcalcd = 1.211 mg mÀ3
,
T = 294(2) K,
F(000) = 664, k = 0.71073Å. Data collection yielded 16,323 reflections resulting
in 5935 unique, averaged reflection, 5804 with I > 2 (I). Full-matrix least-
l ,
= 0.229 mmÀ1
r
squares refinement led to a final R = 0.0263, wR = 0.0737, and GOF = 1.046. .
CCDC 859873 contains supplementary Crystallographic data for the structure
(Fig. 2). These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/data_request/cif.
7. The asymmetric aldol reaction which was performed twice in conversion of 12
into 6 and 5 into 17 is a matched pair as the existing chirality in aldehyde 12 and
5 and also the reaction conditions induced the chirality in an anti fashion, see
Ref. 5c.
8. Lamers, Y. M. A. W.; Rusu, G.; Wijnberg, J. B. P. A.; Groot, A. Tetrahedron 2003, 59,
9361–9369.
In summary, asymmetric aldol reaction has been utilized
twice in a linear synthesis to generate all the required asymmet-