First stereoselective total synthesis of pectinolide H

Article abstract of DOI:10.1016/j.tetlet.2011.12.122

The stereoselective total synthesis of bio-active pectinolide H (1) is described. Midland's asymmetric reduction, Sharpless dihydroxylation reactions are involved in generating the stereogenic centers at C-4′, C-5 and C-1′. Other key steps in the synthesi

Full text of DOI:10.1016/j.tetlet.2011.12.122

Tetrahedron Letters 53 (2012) 1258–1260
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First stereoselective total synthesis of pectinolide H
⇑
D. Ramesh, V. Shekhar, D. Chantibabu, S. Rajaram, U. Ramulu, Y. Venkateswarlu
Division of Natural Product Chemistry, 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:
The stereoselective total synthesis of bio-active pectinolide H (1) is described. Midland’s asymmetric
reduction, Sharpless dihydroxylation reactions are involved in generating the stereogenic centers at
C-40, C-5 and C-10. Other key steps in the synthesis are Sonogashira cross coupling, Z-selective Still–Gen-
nari olefination, one-pot acetonide deprotection–lactonization, and Lindlar’s reaction. This offers a dis-
Received 21 November 2011
Revised 27 December 2011
Accepted 28 December 2011
Available online 5 January 2012
tinctive strategy for the synthesis of c-lactones.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric reduction
Sonogashira coupling
Sharpless dihydroxylation
Still–Gennari olefination
c
-Lactones
Five membered lactone having a substitution at the
c
-position
reactions of diol (6). The compound 6 was prepared from the Sono-
gashira cross coupling of alkyne (7) and iodoallylic alcohol (17).
Further, compound 7 was prepared from the acetylenic ketone
(8) by stereoselective asymmetric reduction (Scheme 1).
is an important structural subunit in many bio-active compounds.1
c
-Lactone containing natural products are known to exhibit vari-
ous biological activities,2 including anti-fungal, anti-bacterial,3 anti
tumor,4 cytotoxic,5 cyclooxygenase, or phospholipase A2 inihibi-
As outlined in Scheme 2, the synthesis of 1 commenced from
the acetylenic ketone (8)12 and the first stereogenic center was
generated by the enantioselective reduction of 8 with (S)-alpine
borane (18) and provided the chiral propargyl alcohol (9) in a
75% yield (enantiomeric ratio S:R = 87:13).13 The alcohol (9) was
protected as corresponding TBS ether (7).12b Thus obtained
compound (7) was subjected to Sonogashira cross coupling with
(17)14,15a in the presence of [Pd(PPh3)4], CuI to afford allylic alcohol
(10)15 in an 88% yield. The primary alcohol in 10 was protected
with p-methoxybenzyl chloride using NaH in dry THF to afford
compound 11 in a 93% yield. Sharpless dihydroxylation of (11)
tion.6 Pectinolide H (1), a structurally distinctive
c-lactone having
three stereogenic centers has been isolated from the chloroform
extract of the aerial parts of a Mexican terrestrial plant Hyptis
pectinata,7 which is used in traditional Mexican medicine for a
multipurpose remedies in the treatment of skin infections, fevers,
gastric disturbances,8 and lung congestion.9 Pectinolides A–C
(2–4; Fig. 1) are also isolated from the same plant and known to
show cytotoxic and antimicrobial properties.10 In particular, pecti-
nolide H (1) displayed significant antimicrobial activity against a
panel of multidrug-resistant strains of Staphylococcus aureus.7
The structure and stereo chemistry of 1 were established on the
basis of spectral, chiroptical data, and chemical evidence.
with AD-mix-
a
at 0 °C furnished diol (6)16 in an 82% yield (de
96%), which was protected with 2,2-dimethoxy propane in the
In continuation of our interest in the total synthesis of bio-active
natural products,11 the significant biological properties and impor-
tant structural features of 1 prompted us to explore the synthesis
of this molecule. To the best of our knowledge, there is no report
on the synthesis of 1. Herein, we describe a simple and efficient
approach for the stereoselective total synthesis of 1.
The retro synthetic analysis of 1 is depicted in Scheme 1. The
target molecule 1 can be easily envisaged from the cis olefinic ester
(5) by one pot acetonide deprotection and lactonization followed
by Lindlar’s reaction. The intermediate 5 in turn can be obtained
from the Z-selective Still–Gennari olefination and other sequential
presence of a catalytic amount of PTSA to yield compound (12)
O
OH
1'
OAc
4'
OR2
O
O
1
5
O
OR1
Pectinolide H
Pectinolide A; R1=R2=Ac 2
Pectinolide B; R1=Ac, R2=H 3
Pectinolide C; R1=H, R2=Ac 4
1
⇑
Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
Figure 1. Structures of pectinolides H and A–C.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.122

D. Ramesh et al. / Tetrahedron Letters 53 (2012) 1258–1260
1259
OAc
OAc
OH
O
O
O
5
1
O
O
O
OTBS
OTBS
OH
I
OH
+
OPMB
7
6
17
OH
O
8
Scheme 1. Retrosynthetic analysis of pectinolide H.
OH
OTBS
O
b
c
a
9
7
8
OTBS
OTBS
OTBS
OH
e
d
OPMB
OH
OPMB
6
10
OH
11
OTBS
OH
h
f
g
OPMB
12
OPMB
13
O
O
O
O
OAc
OAc
OAc
i
j
OPMB
OH
O
5
15
14
O
O
O
O
O
O
O
OAc
OH
O
OAc
l
k
O
O
O
16
1
OH
B
(S)-18
Scheme 2. Reagents and conditions: (a) (S)-18, THF, 8 h, rt, 75%; (b) imidazole, TBDMSCl, DCM, rt, 3 h; (c) 17, iPr2NH, Pd(PPh3)4, CuI, dry benzene, rt, 2 h, 88%; (d) NaH, PMBCl,
dry THF, 0 °C to rt, 4 h, 93%; (e) AD-mix- , MeSO2NH2, t-BuOH/H2O (1:1), 0 °C, 24 h, 82%; (f) 2,2-dimethoxypropane, PTSA, dry DCM, rt, 12 h, 90%; (g) TBAF, THF, rt, 2 h, 97%;
a
(h) Ac2O, pyridine, rt, 4 h, 96%; (i) DDQ, DCM/H2O (10:1), rt, 2 h, 95%; (j) (1) Dess–Martin periodinane, DCM, 0 °C to rt, 2 h, 94%; (2) (F3CCH2O)2POCH2COOMe, 18-crown ether,
KHMDS, dry THF, ꢀ78 °C, 4 h, 86%; (k) 80% AcOH, 0 °C to rt, 20 h, 96%; (l) Lindlar’s catalyst, quinoline, ethyl acetate, rt, 2 h, 88%.

1260
D. Ramesh et al. / Tetrahedron Letters 53 (2012) 1258–1260
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with a 90% yield. The tert-butyldimethylsilyl ether group in (12)
was removed using TBAF in THF to give secondary alcohol (13) in
a 97% yield, which was acetylated using acetic anhydride in pyri-
dine to afford compound 14 in a 96% yield. The p-methoxybenzyl
group in 14 was removed employing DDQ in DCM/H2O (10:1) to
give primary alcohol 15 in a 95% yield. The alcohol (15) was oxi-
dized with Dess–Martin periodinane (DMP) in DCM to afford alde-
hyde, which was further subjected to Z-selective Still–Gennari
olefination17 by employing bis((2,2,2-trifluoroethyl)(methoxycar-
bonylmethyl phosphonate)), 18-crown ether, KHMDS in THF to af-
ford cis-olefinic ester (5) in an 86% yield. Deprotection of acetonide
group and lactonization were achieved in one pot using 80% AcOH
to give acetylenic lactone (16) with a 96% yield. Finally, partial
hydrogenation of triple bond in compound 16 over Lindlar’s cata-
lyst furnished the target natural product, pectinolide H (1) in an
88% yield (Scheme 2). The spectral data18 and optical rotation
{½a 2D5
ꢀ43.7 (c 0.18, CHCl3)} of synthetic pectinolide H (1) were
ꢁ
in good agreement with the reported data of the natural product.7
In conclusion we have reported a simple and efficient approach
for the total synthesis of pectinolide H (1) in a stereoselective man-
ner. This protocol involves the use of enantioselective Midland’s
asymmetric reduction, Sonogashira cross coupling, Sharpless
dihydroxylation, Z-selective Still–Gennari olefination, one pot ace-
tonide deprotection–lactonization, and Lindlar’s reaction as key
steps.
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Acknowledgments
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U. M. Tetrahedron 2003, 59, 1293–1299.
The authors DR, VS, DCB, SR and UR are thankful to CSIR, New
Delhi, for the financial support and to Director IICT for constant
encouragement.
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18. Spectral data for selected compounds:
References and notes
Compound 6: ½a 2D5
ꢁ
ꢀ40.4 (c 2.1, CHCl3); IR (neat): 3413, 2932, 2860, 1613,
1249, 1083, 838, 777 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d = 7.21 (d, 2H,
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J = 8.3 Hz), 6.84 (d, 2H, J = 8.3 Hz), 4.47 (s, 2H), 4.39–4.30 (m, 2H), 3.79 (s, 3H),
3.78–3.72 (m, 1H) 3.67–3.50 (m, 2H), 2.62 (br s, 2H), 1.69–1.56 (m, 2H), 1.44–
1.26 (m, 4H), 0.91 (t, 3H, J = 6.8 Hz), 0.89 (s, 9H), 0.09 (d, 6H, J = 6.0 Hz); 13C
NMR (75 MHz, CDCl3): d = 159.2, 129.6, 129.3, 113.7, 88.0, 81.4, 73.3, 73.1, 70.2,
63.5, 62.7, 55.1, 38.1, 27.2, 25.6, 22.2, 18.1, 13.9, -4.6, -5.1; HRMS (ESI): calcd
for C24H40O5NaSi [M+Na]+ 459.2537; found 459.2523; Compound 5: ½a 2D5
ꢁ
ꢀ44.3
(c 1.2, CHCl3); IR (neat): 2956, 2867, 1731, 1374, 1230, 1054 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d = 6.18–6.08 (m, 1H), 5.95 (d, 1H, J = 11.3 Hz), 5.65 (t, 1H,
J = 6.8 Hz), 5.39 (t, 1H, J = 6.8 Hz), 4.42 (d, 1H, J = 6.0 Hz), 3.76 (s, 3H), 2.07 (s,
3H), 1.81–1.71 (m, 2H), 1.55–1.24 (m, 10H), 0.91 (t, 3H, J = 6.8 Hz); 13C NMR
(75 MHz, CDCl3): d = 169.8, 165.4, 144.3, 123.3, 111.4, 84.1, 81.6, 77.1, 70.8,
63.8, 51.5, 34.2, 27.2, 26.9, 26.4, 22.1, 20.9, 13.8; HRMS (ESI): calcd. for
C
18H26O6Na [M + Na]+ 361.1621; found 361.1617; Compound 1: ½a 2D5
ꢁ
ꢀ43.7 (c
0.18, CHCl3); IR (neat): 3444, 2924, 2855, 1752, 1243, 1044 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d = 7.55 (dd, 1H, J = 6.1, 1.8 Hz), 6.22 (dd, 1H, J = 6.1, 1.8 Hz),
5.56–5.33 (m, 3H), 5.16 (dt, 1H, J = 6.1, 1.8 Hz), 4.96 (dd, 1H, J = 7.8, 6.1 Hz),
3.70 (d, 1H, J = 3.8 Hz), 2.05 (s, 3H), 1.79-1.48 (m, 2H), 1.44–1.18 (m, 4H), 0.92
(t, 3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3): d = 172.5, 171.8, 153.3, 133.1,
129.3, 123.2, 84.1, 71.0, 67.1, 33.6, 27.1, 22.4, 21.3, 13.9; HRMS (ESI): calcd for
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C
14H20O5Na [M+Na]+ 291.1202; found 291.1200.