First stereoselective total synthesis of pectinolide

Article abstract of DOI:10.1016/j.tetlet.2011.08.036

The enantioselective synthesis of bio-active 5,6-dihydro-α-pyrone, pectinolide A, has been achieved in 10 steps in good overall yield. Of the three stereogenic centres, the C-5/C-6 vic-diol was obtained using diastereo- and enantioselective Brown hydroxyl

Full text of DOI:10.1016/j.tetlet.2011.08.036

Tetrahedron Letters 52 (2011) 5747–5749
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Tetrahedron Letters
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First stereoselective total synthesis of pectinolide A
⇑
,
J. S. Yadav , S. S. Mandal
Organic Division—I, CSIR, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective synthesis of bio-active 5,6-dihydro-a-pyrone, pectinolide A, has been achieved in 10
Received 10 June 2011
Revised 5 August 2011
Accepted 7 August 2011
Available online 22 August 2011
steps in good overall yield. Of the three stereogenic centres, the C-5/C-6 vic-diol was obtained using dia-
stereo- and enantioselective Brown hydroxyl crotylation, while the C-30 stereocentre was created by Jac-
obsen hydrolytic kinetic resolution method.
Ó 2011 Elsevier Ltd. All rights reserved.
Pectinolides A–C are a class of 5,6-dihydro-
from Hyptis pectinata (Lamiaceae),1 and possess an antimicrobial
as well as cytotoxic activity (ED50 <4 g/mL) against a variety of tu-
a-pyrones, isolated
O
O
O
OAc
O
OH
O
l
OAc
O
mour cell lines (Fig. 1). Staphylococcous aureus and Bacillus subtilis
were sensitive to pectinolide A (1) in the concentration range of
OH
OAc
OAc
6.25–12.5
the absolute stereochemistry of pectinolide A2 (1) was established
as 6S-[(3S-acetyloxy)-1Z-heptenyl]-5S-(acetyloxy)-5,6-dihydro-
2H-pyran-2-one containing an ,b-unsaturated d-lactone. As these
lg/mL. Based on spectral study and chemical evidence,
Pectinolide B
2
Pectinolide A
1
Pectinolide C
3
a
Figure 1. Structures of pectinolides.
natural products are available in scarce amounts, the synthesis of
pectinolides is an attractive goal for further biological activity
studies. To date there is no report on the synthesis of these natural
products. Intrigued by the biological properties of this class of pyr-
ones as well as, in continuation of our work on the synthesis of lac-
tone containing natural products,3 we have taken up the total
synthesis of pectinolide A. Herein, we report the first stereoselec-
tive total synthesis of pectinolide A.
Retrosynthetically, we envisioned that the target molecule pec-
tinolide A can be obtained from the intermediate 4 by ring-closing
metathesis. In turn the intermediate 4 could be envisioned from
diastereo and enantioselective hydroxy crotylation of aldehyde ob-
tained from TBS protected Z alkenol 5 followed by esterification
with acrylol chloride. The compound 5 could be achieved from
(S)-2-(benzyl oxymethyl) oxirane 6. Thus, of the three stereogenic
centres, the vic-diol is obtained from alkenol 5, while the other chi-
ral centre is introduced by Jacobsen hydrolytic kinetic resolution4
of 2-(benzyl oxymethyl) oxirane (Scheme 1).
O
O
Still-Gennari reaction
OR1
3'
O
2
OAc
O
4
6
RCM
1'
4
OAc
OR2
Brown hydroxy
Crotylation
Jacobsen HKR
Pectinolide A; R1=R2=Ac
1
OTBS
OH
5
O
OBn
6
Scheme 1. Retrosynthetic analysis of pectinolide A.
dized under Swern oxidation conditions to afford the correspond-
ing aldehyde 10 with 92% yield. Aldehyde 10 was subjected to a
Still–Gennari reaction5 in the presence of NaH in THF to provide
Towards the synthesis of 1, initially the chiral epoxide 6 was
regioselectively opened with n-propylmagnesium bromide in
THF, in the presence of CuI to afford secondary alcohol 7 (85%),
which was protected as corresponding TBS ether 8 in 92% yield.
Debenzylation of the benzyl ether 8 using 20% Pd(OH)2/C afforded
the primary alcohol 9 in 89% yield. The primary alcohol 9 was oxi-
the
a,b-unsaturated ester compound 11 in 90% yield (Scheme 2).
The chemoselective reduction of
a,b-unsaturated ester 11 with
DIBAL-H was achieved at ꢀ20 °C to afford the allyl alcohol 5 in 95%
yield. The allyl alcohol 5 was oxidized under Swern oxidation con-
ditions to the corresponding aldehyde 12 with 90% yield. The treat-
⇑
Corresponding author. Fax: +91 40 27160387.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
ment of aldehyde 12 with in situ generated [(Z)-c-(methoxymetho
xy)allyl]-diisopinocampheylborane, [prepared from methoxy-
King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.036

5748
J. S. Yadav, S. S. Mandal / Tetrahedron Letters 52 (2011) 5747–5749
Br
OH
In conclusion, a concise and efficient first total synthesis of pec-
TBS-OTf
O
OBn
OBn
tinolide A has been achieved. Notable features include: (i) highly
diastereo- and enantioselective hydroxy crotylation to control
the configuration of the stereogenic centres. (ii) Still–Gennari reac-
tion for the generation of cis-olefin.
Mg, CuI
THF, -30 0C
3 h, 85%
2,6-Lutidine
CH2Cl2, rt, 3 h
6
7
92%
20% Pd(OH)2/ C
H2, THF
(COCl)2, DMSO
Et3N, CH2Cl2
OTBS
OTBS
OH
OBn
Acknowledgments
rt, 3 h, 92%
rt, 4 h, 89%
9
8
S.S.M. thank CSIR, New Delhi for financial assistance in the form
of fellowship. The author (J.S.Y.) acknowledges the partial support
by King Saud University for Global Research Network for Organic
Synthesis (GRNOS).
NaH, THF
-78 oC, 1 h
O
OTBS
OTBS
H
OEt
A, 90%
O
11
10
A = EtO2CCH2P(O)(OCH2CF3)2
Supplementary data
Scheme 2.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.036.
(COCl)2, DMSO
Et3N, CH2Cl2
OTBS
O
O
OTBS
DIBAl-H
References and notes
OH
OEt
CH2Cl2, -20 o
3 h, 95%
C
rt, 3 h, 90%
5
11
1. (a) Collett, L. A.; Davies-Coleman, M. T.; Rivett, D. E. A. Naturally Occurring 6-
Substituted 5,6-Dihydro-R-Pyrones In Progress in the Chemistry of Organic
Natural Products; Herz, W., Falk, H., Kirby, G. W., Moore, R. E., Tamm, Ch., Eds.;
Springer: New York, 1998; Vol. 75, pp 182–209; (b) Pereda-Miranda, R. Bioactive
Natural Products from Traditionally Used Mexican Plants. In Phytochemistry of
Medicinal Plants; Arnason, J. T., Mata, R., Romeo, J. T., Eds.; Plenum: New York,
1995; pp 83–112.
i)
OMOM
ii) sec-BuLi, B-Methoxy
OTBS
OTBS OH
diisopinocamphenyl borane
H
iii) BF3.Et2O , -78 o
iv) NaOH / H2O2 ,THF
3 h,
C
OMOM
12
13
2. (a) Pereda-Miranda, R.; Hernández, L.; Villavicencio, M. J.; Novelo, M.; Ibarra, P.;
62%
Chai, H.; Pezzuto, J. M. J. Nat. Prod. 1993, 56, 583–593; (b) Mendoza-Espinoza, J.
9
i
A.; López-Vallejo, F.; Fragoso-Serrano, M.; Pereda-Miranda, R.; Cerda-Garc
Rojas, C. M. J. Nat. Prod. 2009, 72, 700–708.
a-
Scheme 3.
3. For our contributions on lactone containing molecules see (a) Yadav, J. S.;
Mandal, S. S.; Reddy, J. S. S.; Srihari, P. Tetrahedron 2011, 67, 4620–4627; (b)
Yadav, J. S.; Reddy, J. S. S.; Mandal, S. S.; Srihari, P. Synlett 2010, 2636–2638; (c)
Srihari, P.; Kumaraswamy, B.; Rao, G. M.; Yadav, J. S. Tetrahedron: Asymmetry
2010, 21, 106–111; (d) Srihari, P.; Bhasker, E. V.; Reddy, A. B.; Yadav, J. S.
Tetrahedron Lett. 2009, 50, 2420–2424; (e) Yadav, J. S.; Kumar, V. N.; Rao, R. S.;
Srihari, P. Synthesis 2008, 1938–1942; (f) Srihari, P.; Kumar, B. P.; Subbarayudu,
K.; Yadav, J. S. Tetrahedron Lett. 2007, 48, 6977–6981; (g) Srihari, P.; Bhasker, E.
V.; Harshavardhan, S. J.; Yadav, J. S. Synthesis 2006, 4041–4045; (h) Yadav, J. S.;
Rao, K. V.; Sridhar Reddy, M.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 4393–
4395; (i) Yadav, J. S.; Prathap, I.; Padmaja, T. B. Tetrahedron Lett. 2006, 47, 3773–
3776.
4. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936–
938.
5. Still-Gennari olefination of the aldehyde 10 derived from 9 leading to 11 was
performed according to the literature procedure Still, W. C.; Gennari, C.
Tetrahedron Lett. 1983, 24, 4405–4408.
methyl allyl ether, sec-BuLi, IPC2-BOMe (derived from (+)-a-
pinene) and BF3ꢁOEt2] in THF at ꢀ78 to 25 °C in a regioselective
and stereoselective manner to yield the corresponding threo-b-
methoxymethylhomoallyl alcohol 13 in P99% diastereoselectivity
and >95% enantioselectivity (Scheme 3).6
The esterification of the secondary alcohol in 13 with acryloyl
chloride was achieved in the presence of Hünig’s base to afford
compound 14 in 92% yield. Deprotection of TBS and MOM groups
was achieved using 6 N HCl in THF at room temperature, to afford
the diol compound 15 in 85% yield. Acetylation of the diol 15 was
achieved with acetic anhydride and Et3N to yield compound 4
(89%). Finally, ring-closing metathesis of the compound 4 was
accomplished using Grubbs 2nd generation7 catalyst for 3 h at
40 °C in CH2Cl2 to afford the required 5,6 dihydro-2H pyran-2-
one 1 in 90% yield (Scheme 4). The 1H NMR and 13C NMR spectral
data and optical rotation of our synthetic compound8 were in good
agreement with the data previously reported in literature.2a
6. Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110, 1535–1538. The
de was determined to be >99% by Reverse phase HPLC column: Water HRC18,
300 ꢂ 3.9 mm, 6 micron. Mobile phase used was 30% acetonitrile + 70% water.
Flow rate: 1.0 mL/min. The ee was analyzed on chiral column using chiral pack
IA, 250 ꢂ 4.6 mm, 5
lm, UV254 nm, hexane/2-propanol (85:15) as mobile phase,
flow rate—1.0 mL/min..
7. Crimmins, M. T.; Haley, M. W. Org. Lett. 2006, 8, 4223–4225.
8. The 1H and 13C NMR spectral data and optical rotation, matched in comparison
with the reported data for pectinolide A.2a
Spectroscopic data for representative compounds 1: colourless oil, ½a D29
ꢃ
+196.8
+202.0 (c 0.15, MeOH)]. 1H NMR (300 MHz, CDCl3): d 0.91
O
(c 0.5, MeOH), [lit. ½a D
ꢃ
O
O
Cl
(t, 3H, J = 6.8 Hz), 1.20–1.40 (m, 5H), 1.46–1.77 (m, 1H), 2.04 (s, 3H), 2.09 (s, 3H),
5.16 (dd, 1H, J = 3.02, 6.0 Hz), 5.33 (ddd, 1H, J = 6.0, 7.6, 9.8 Hz), 5.57 (dd, 1H,
J = 3.0, 8.3 Hz), 5.61 (d, 1H, J = 9.8 Hz), 5.71 (dd, 1H, J = 8.3, 11.3 Hz), 6.23 (d, 1H,
J = 9.8 Hz), 6.93 (dd, 1H, J = 6.0, 9.8 Hz). 13C NMR (75 MHz, CDCl3): d 13.9, 20.5,
21.1, 22.4, 27.2, 34.0, 64.2, 69.3, 75.0, 125.1, 126.2, 133.1, 139.9, 162.1, 169.8,
170.3; IR (neat): 2925, 2855, 1740, 1460, 1337, 1226, 1028, 823 cmꢀ1. Mass (ESI-
MS): m/z 333 (M+Na)+. HRMS (ESI) calcd for C16H22O6Na (M+Na)+, 333.1314;
found 333.1324.
OTBS O
6N HCl
OH
O
DIPEA, DMAP
13
THF, rt, 3 h
85%
CH2Cl2
rt, 3 h, 92%
OH
O
OMOM
14
15
Grubbs'
O
O
O
2ndgeneration
(10 mol%)
OAc
O
Ac2O,Et3N
Compound 11: ½a 3D1
ꢃ
+83.6 (c 1.5, CHCl3).1H NMR (300 MHz, CDCl3): d 0.02 (s,
O
6H), 0.87 (s, 12H), 1.29 (t, 3H, J = 7.2 Hz), 1.22–1.59 (m, 6H), 4.16 (q, 2H,
J = 7.2 Hz), 5.23–5.33(m, 1H), 5.66 (dd, 1H, J = 1.0, 11.7 Hz), 6.13 (dd, 1H, J = 8.3,
11.7 Hz); 13C NMR (75 MHz, CDCl3) d ꢀ4.9, ꢀ4.6, 14.0, 14.2, 18.1, 22.6, 25.8, 27.3,
37.0, 60.0, 68.7, 117.4, 153.8, 165.9; IR (neat): 3473, 2934, 1722, 1661, 1371,
1174, 1036, 979 cmꢀ1. Mass (ESI-MS): m/z 323 (M+Na)+.
CH2Cl2, 40oC
DMAP, CH2Cl2
rt, 1 h, 89%
OAc
Pectinolide A
O
O
3 h, 90%
4
1
Compound 13: colourless syrup, ½a D29
ꢃ
+56.6 (c 1.5, CHCl3), 1H NMR (300 MHz,
N
N
Mes
Ph
Mes
Cl
CDCl3): d 0.04 (s, 6H), 0.88 (s, 12H), 1.20–1.60 (m, 6H), 2.59 (bs, -OH), 3.39 (s,
3H), 3.84–3.94 (m, 1H), 4.16–4.30 (m, 1H), 4.35–4.51 (m, 1H), 4.57 (d, 1H,
J = 6.6 Hz), 4.70 (d, 1H, J = 6.6 Hz), 5.22–5.37 (m, 3H), 5.45–5.75(m, 2H); 13C
NMR (75 MHz, CDCl3): d ꢀ4.9, ꢀ4.3, 14.0, 17.6, 22.5, 25.8, 27.5, 37.7, 55.7, 68.7,
69.8, 80.9, 94.1, 119.6, 126.2, 134.2, 138.0; IR (neat): 3447, 2926, 2857, 1757,
1462, 1252, 1110, 1034, 931, 838, 775 cmꢀ1. Mass (ESI-MS): m/z 359 (M+H)+;
Ru
Cl
PCy3
2
ndgeneration Grubbs' catalyst
Scheme 4.

J. S. Yadav, S. S. Mandal / Tetrahedron Letters 52 (2011) 5747–5749
5749
HRMS (ESI) calcd for C19H38NaO4Si (M+Na)+, 381.2437; found 381.2442.
13.9, 20.9, 22.5, 27.1, 29.7, 34.3, 70.2, 74.5, 77.2, 119.3, 126.2, 128.1, 131.3,
131.8, 134.4, 164.6, 169.7, 170.1; IR (neat): 3445, 2926, 2856, 1720, 1496, 1499,
1374, 1243, 1167, 1060, 864, 794, 519 cmꢀ1. Mass (ESI-MS): m/z 361 (M+Na)+;
HRMS (ESI) calcd for C18H26O6Na (M+Na)+, 361.1618; found 361.1614.
Compound 4: ½a 3D0
ꢃ
+68.7 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d 0.90 (t, 3H,
J = 6.6 Hz), 1.19–1.41 (m, 5H), 1.46–1.77 (m, 1H), 2.03 (s, 3H), 2.06 (s, 3H), 5.22–
5.39 (m, 2H), 5.40–5.49 (m, 2H), 5.52–5.62 (m, 2H), 5.68–5.87 (m, 3H), 6.11 (dd,
1H, J = 10.4, 17.4 Hz), 6.41 (dd, 1H, J = 7.0, 17.4 Hz); 13C NMR (75 MHz, CDCl3): d