Stereoselective synthesis of the C33-C44 fragment of palau'amide

Article abstract of DOI:10.1016/j.tetlet.2007.11.200

An efficient stereoselective synthesis of the C33-C44 fragment of palau'amide is described using a Sharpless asymmetric epoxidation, a regioselective nucleophilic ring opening of the epoxide, a Grignard reaction and a Luche stereoselective reduction of a

Full text of DOI:10.1016/j.tetlet.2007.11.200

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 786–789
Stereoselective synthesis of the C33–C44 fragment of palau’amide
Debendra K. Mohapatra *, Sabita Nayak
Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
Received 21 October 2007; revised 17 November 2007; accepted 30 November 2007
Available online 4 December 2007
Abstract
An efficient stereoselective synthesis of the C33–C44 fragment of palau’amide is described using a Sharpless asymmetric epoxidation,
a regioselective nucleophilic ring opening of the epoxide, a Grignard reaction and a Luche stereoselective reduction of a keto compound
as the key steps.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Palau’amide; Cytotoxic; Stereoselective; Sharpless asymmetric epoxidation; Luche’s stereoselective reduction
H
In 2003, Moore and co-workers reported the isolation,
N
structure elucidation, and biological activity (cytotoxicity
N
to KB cells, IC50 = 13 nM) of palau’amide (1), an architec-
O
O
O
turally novel cyclic depsipeptide from the bioassay-guided
fractionation of the extract species of Lyngbya from
Palau.1 Key structural elements include a five amino acid
backbone fused together in a macrocycle and a novel poly-
ketide chain incorporated into the molecule. The molecular
architecture of the polyketide comprises three contiguous
chiral centres, a 1,3-syn diol flanking an anti methyl group,
a terminal alkyne and an a,b-unsaturated acid (Fig. 1).
Potent biological activity coupled with unique structural
features and limited availability prompted us to explore
the synthesis of palau’amide (1). The first synthesis of
palau’amide was reported by Ma et al.2 The polyketide
chain was synthesized following Oppolzer’s protocol and
utilized a vinylogous Mukaiyama aldol reaction as a key
reaction. The ‘anti’ aldolization strategy to build the C38
and C39 stereocentres was not successful. ‘syn’ Aldoliza-
tion and Mitsunobu inversion were required to obtain the
required stereochemistry. However, the data for the syn-
thetic palau’amide (1) did not match the reported values.
A highly stereoselective and practical approach to con-
struct the three contiguous chiral centres present in the
O
O
N
O
NH
O
O
OH
N
O
1 Palau'amide
Fig. 1. Structure of palau’amide 1.
C33–C44 fragment was therefore required to establish con-
clusively the structure of the natural product and to furnish
additional analogues for testing.
Our retrosynthetic analysis of fragment 2 (Scheme 1)
revealed that it could be synthesized from intermediate 3
which, in turn, could be prepared from fragment 4 follow-
ing oxidation and a Grignard reaction with pentynyl-
magnesium bromide. Intermediate 4 was envisaged to be
obtained by regioselective opening of epoxide 5, which in
turn could be prepared from commercially available 1,3-
propane diol following a known protocol.
*
Corresponding author. Tel.: +91 20 25902627; fax: +91 20 25902629.
E-mail address: dk.mohapatra@ncl.res.in (D. K. Mohapatra).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.200

D. K. Mohapatra, S. Nayak / Tetrahedron Letters 49 (2008) 786–789
787
OH
H
N
O
1. Me2CuCNLi2
PMBO
OH
N
PMBO
OH THF
-20 oC, 6 h
O
O
O
6
5
2. NaIO4, 30 min
70% over two steps
1. BzCl, Et3N
O
O
CH2Cl2, 0 oC
N
1 h, 97%
2. TBSOTf,CH2Cl2
2,6-Lutidine
0 oC, 1 h, 98%
3. K2CO3, MeOH
rt, 4 h, 98%
OTBS
O
NH
O
O
OH
1. (COCl)2, DMSO, CH2Cl2
Et3N, -78 oC, 3 h
N
O
2. TMS-C5H6MgBr, THF
PMBO
OH
0 oC-rt, 2 h, 84% for two steps
1 Palau'amide
4
OH
OTBS
TMS
PMBO
PMBO
OMOM
O
OH
7
+
OTBS
O
OH
TMS
2
8
OMOM
OTBS
1. TBAF, THF
2. DMP, p-TSA, CH2Cl2
78% over two steps
HO
3
O
O
PMBO
OTBS
O
C2 = 97.93 ppm
C1-C3 = 10.12 ppm
9
PMBO
OH
PMBO
OH
5
4
O
O
Scheme 1. Retrosynthetic analysis.
PMBO
C2 = 100.64 ppm
C1-C3 = 0.09 ppm
10
Chiral epoxide 5 was elaborated from 1,3-propane diol
via a five-step sequence following the literature methods.3
A key reaction was the Sharpless asymmetric epoxidation
with titanium tetraisopropoxide and t-butylhydroperoxide
in the presence of (ꢀ)-DIPT. The enantiomeric excess of
epoxide 54 was determined by HPLC analysis5 and was
found to be greater than 97%. Regioselective nucleophilic
Scheme 2. Synthesis of 7 and 8.
on a model proposed by Evans and co-workers.12 This
assumption was further confirmed using the method
reported by Rychnovsky and co-workers.13 Accordingly,
cleavage of the silyl ether in 7 and 8 produced diols, which
were protected as 1,3-diol acetonides 9 and 10 by treatment
with dimethoxypropane in the presence of a catalytic
amount of p-TSA. Since the C(2)-acetals in 9 and 10
showed 13C chemical shifts at d 97.94 and 100.62 ppm
and the differences between the two 13C methyl signals in
9 and 10 were 10.12 and 0.09 ppm, respectively, the syn
and anti juxtaposition of the acetonide moieties was con-
firmed (Scheme 2).
To obtain the desired alcohol 13 exclusively, the mixture
of alcohols 7 and 8 was treated with K2CO3 and MeOH to
effect TMS deprotection. The resulting secondary hydroxyl
group was oxidized by the Swern oxidation protocol to give
keto compound 12, which was reduced by Luche’s14 proce-
dure using NaBH4 and CeCl3 in MeOH at ꢀ100 °C to
6
opening of 5 with Me2CuCNLi2 afforded a mixture of
the desired 1,3-diol 6 and the corresponding 1,2-diol in a
ratio of 8:1. The minor product was easily removed by
treatment with NaIO4 (Scheme 2). Chemoselective benzoyl-
ation of the primary hydroxyl group of 6, followed by sily-
lation of the secondary hydroxyl group using TBSOTf7 and
2,6-lutidine in dichloromethane and subsequent hydrolysis
of the benzoyl ester, afforded alcohol 48 in excellent yield.
Oxidation of the primary hydroxyl group of 4 under
Swern oxidation conditions9 gave an aldehyde, which on
treatment with trimethylsilyl protected pentynylmagnesium
bromide in THF at 0 °C furnished diastereomeric alcohols
7 and 8 in a ratio of 1:1.5. The stereochemistry at the newly
created stereogenic centers in 710 and 811 was assumed to be
R and S resulting from 1,3-asymmetric induction based

788
D. K. Mohapatra, S. Nayak / Tetrahedron Letters 49 (2008) 786–789
afford 13 as a single isomer (Scheme 3). The secondary
alcohol moiety of 13 was protected as its methoxymethyl
ether using MOMCl and DIPEA to afford 14 in 82% yield.
The p-methoxybenzylether of 14 was cleaved using DDQ in
CH2Cl2 to furnish alcohol 3 in 91% yield. Alcohol 3 was
oxidized to the aldehyde with IBX; further treatment with
the Wittig reagent allyloxycarbonylethylenetriphenylphos-
phorane in refluxing THF gave only E-isomer 15 as a single
product in an 80% yield over two steps. Finally, deprotec-
tion of the tert-butyldimethylsilyl group with tetrabutyl-
ammonium fluoride afforded the C33–C44 core fragment
1
2 with the required stereocenters in 86% yield. The H,
13C NMR and elemental analysis of fragment 215 were in
good agreement with the assigned structure. For example,
1
the H NMR spectrum revealed signals due to the olefinic
protons at d 6.94 (m, 1H), 5.97 (m, 1H) and 5.39–5.20 (m,
2H), which were characteristic of an a,b-unsaturated ester
and a terminal olefin group. A signal due to the alkyne pro-
ton appeared at d 1.97 (t, J = 2.6 Hz), the methyl group
attached to the double bond carbon appeared as a singlet
at d 1.89 and the methyl group present between the two
hydroxyl groups appeared as a doublet at d 0.88 (d,
J = 6.9 Hz). In the 13C NMR spectrum, the corresponding
olefinic carbons appeared at 138.9, 132.4, 129.5 and
117.7 ppm, respectively. The carbonyl carbon of the ester
group resonated at d 167.5 ppm.
OH
OTBS
TMS
PMBO
11
2. (COCl)2, DMSO
CH2Cl2, Et3N
-78 oC, 3 h, 86%
1. K2CO3, MeOH
rt, 2 h, 92%
O
OTBS
In conclusion, a practical and stereoselective synthesis of
the C33–C44 fragment of palau’amide has been achieved
using a Sharpless asymmetric epoxidation, a regioselective
nucleophilic epoxide opening, a Grignard reaction, a Luche
stereoselective reduction and an E-selective Wittig reaction.
Further investigations towards the total synthesis of
palau’amide are in progress.
PMBO
12
NaBH4, CeCl3
MeOH, -100 oC
1 h, 90%
OH
OTBS
Acknowledgements
PMBO
13
We thank Dr. Mukund K. Gurjar for his support and
encouragement. S.N. thanks CSIR, New Delhi, for finan-
cial support in the form of a research fellowship. We also
thank Dr. P. R. Rajmohanan for the NMR data.
MOMCl, DIPEA
cat. AgNO3, CH2Cl2
rt, 4 h, 82%
OMOM
OTBS
PMBO
References and notes
14
DDQ, CH2Cl2
H2O, rt, 2 h, 91%
1. Williams, P. G.; Yoshida, W. Y.; Quon, M. K.; Moore, R. E.; Paul,
V. J. J. Nat. Prod. 2003, 66, 1545–1549.
2. Zou, B.; Long, K.; Ma, D. Org. Lett. 2005, 7, 4237–4240.
3. Pandey, S. K.; Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2004, 45,
5877–5879.
OMOM
OTBS
HO
25
4. Analytical and spectral data of 5: ½aꢁD ꢀ20.34 (c 1.7, CHCl3); 1H
NMR (200 MHz, CDCl3): d 7.24 (d, J = 8.7 Hz, 2H), 6.86 (d,
J = 8.7 Hz, 2H), 4.44 (s, 2H), 3.87 (dd, J = 2.6, 12.6 Hz, 1H), 3.80 (s,
3H), 3.64–3.53 (m, 3H), 3.08 (m, 1H), 2.95 (m, 1H), 2.00–1.74 (m,
3H); 13C NMR (50 MHz, CDCl3): d 158.9, 129.9, 128.9, 113.5, 72.3,
66.2, 61.5, 58.3, 54.8, 53.4, 31.7. Anal. Calcd for C13H18O4: C, 65.50;
H, 7.56. Found: C, 65.35; H, 7.48.
3
1. IBX, DMSO,
THF, rt, 2 h
2. Ph3P=CH(CH3)CO2Allyl
THF, reflux, 2 h, 80% two steps
OMOM
O
OTBS
5. Enantiomeric purity of the product formed was verified by HPLC
analysis. HPLC conditions: column, CHIRALCEL [OJ-H (5 lm
spherical) 250 ꢂ 4.6 mm]; mobile phase, IPA–petroleum ether (1:9);
flow rate, 0.5 mL/min; UV detection at 220 nm.
6. Johnson, M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979, 20,
4343–4346.
O
15
TBAF, THF, cat. AcOH
rt, 3 h, 86%
7. Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett. 1981,
¨
OMOM
22, 3455–3458.
O
OH
25
8. Analytical and spectral data of 4: ½aꢁD ꢀ1.32 (c 1.7, CHCl3); 1H NMR
(200 MHz, CDCl3): d 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.6 Hz,
2H), 4.41 (ABq, J = 11.6, 13.1 Hz, 2H), 3.89 (q, J = 5.9 Hz, 1H), 3.81
(s, 3H), 3.69 (dd, J = 3.9, 10.9 Hz, 1H), 3.50 (t, J = 6.5 Hz, 3H), 2.69
(br s, 1H), 1.88–1.74 (m, 3H), 0.97 (d, J = 7.1 Hz, 3H), 0.90 (s, 9H),
0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (50 MHz, CDCl3): d 159.1, 130.3,
O
2
Scheme 3. Synthesis of 2.

D. K. Mohapatra, S. Nayak / Tetrahedron Letters 49 (2008) 786–789
789
129.2, 113.7, 73.6, 72.7, 66.4, 65.1, 55.1, 39.1, 34.2, 25.8, 18.0, 13.7,
ꢀ4.4, ꢀ4.6. Anal. Calcd for C20H36O4Si: C, 65.21; H, 9.78. Found: C,
65.24; H, 9.69.
2.26 (t, J = 6.9 Hz, 2H), 1.94 (q, J = 6.7 Hz, 2H), 1.81–1.63 (m, 2H),
1.55–1.25 (m, 3H), 0.99 (d, J = 7.1 Hz, 3H), 0.88 (s, 9H), 0.13 (s, 9H),
0.09 (s, 6H); 13C NMR (50 MHz, CDCl3): d 159.1, 130.2, 129.2, 113.7,
107.1, 84.5, 76.0, 72.6, 69.1, 66.2, 55.1, 38.6, 35.0, 33.5, 25.8, 17.9,
16.6, 11.3, 0.2, ꢀ4.4, ꢀ4.7. Anal. Calcd for C28H50Si2O4: C, 66.40; H,
9.88. Found: C, 66.51; H, 10.02.
9. (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660; (b)
Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482; (c) Tidwell, T. T. Synthesis 1990, 857–870; (d) Tidwell, T.
T. Org. React. 1990, 39, 297–306.
12. Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35,
8537–8540.
13. Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511–3515.
25
10. Analytical and spectral data of 7: ½aꢁD +3.05 (c 1.3, CH2Cl2); 1H NMR
(200 MHz, CDCl3): d 7.22 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz,
2H), 4.40 (s, 2H), 4.02 (m, 1H), 3.78 (s, 3H), 3.53–3.44 (m, 3H), 2.33
(dt, J = 2.02, 7.07 Hz, 2H), 2.20 (m, 1H), 1.94–1.44 (m, 7H), 0.86 (s,
9H), 0.82 (d, J = 6.9 Hz, 3H), 0.12 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H);
13C NMR (50 MHz, CDCl3): d 159.1, 130.2, 129.3, 113.7, 107.5, 84.7,
72.8, 72.7, 71.5 67.0, 55.1, 44.2, 33.6, 33.3, 25.8, 18.0, 16.2, 11.6, 0.18,
ꢀ4.4, ꢀ4.5. Anal. Calcd for C28H50Si2O4: C, 66.40; H, 9.88. Found:
C, 66.32; H, 10.14.
14. Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–5459.
25
15. Analytical and spectral data of 2: ½aꢁD ꢀ16.71 (c 1.0, CH2Cl2); 1H
NMR (200 MHz, CDCl3): d 6.94 (m, 1H), 5.97 (m, 1H), 5.39–5.20 (m,
2H), 4.68–4.66 (m, 3H), 4.64 (t, J = 1.3 Hz, 1H), 3.81–3.63 (m, 2H),
3.40 (s, 3H), 2.78 (br s, 1H), 2.48–2.16 (m, 4H), 1.97 (t, J = 2.6 Hz,
1H), 1.89 (s, 3H), 1.76–1.55 (m, 5H), 0.88 (d, J = 6.9 Hz, 3H); 13C
NMR (125 MHz, CDCl3); d 167.5, 138.9, 132.4, 129.5, 117.7, 95.7,
84.1, 79.7, 73.2, 68.5, 65.1, 55.9, 41.5, 34.1, 29.3, 23.6, 18.3, 12.6, 12.0.
Anal. Calcd for C19H30O5: C, 67.40; H, 8.87. Found: C, 67.54; H,
8.69.
25
11. Analytical and spectral data of 8: ½aꢁD ꢀ2.85 (c 0.7, CH2Cl2); 1H NMR
(200 MHz, CDCl3): d 7.22 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz,
2H), 4.39 (ABq, J = 11.6, 19.4 Hz, 2H), 4.12 (m, 1H), 3.95 (dt,
J = 2.4, 6.8 Hz, 1H), 3.80 (s, 3H), 3.54 (m, 1H), 3.46–3.38 (m, 2H),