Enantioselective synthesis of (-)-pinellic acid

Article abstract of DOI:10.1016/j.tetlet.2007.01.163

An enantioselective convergent approach toward the total synthesis of pinellic acid 1 from 1,9-nonanediol is described. The synthetic strategy features iterative Sharpless asymmetric dihydroxylation, Sonogashira coupling and Birch reduction.

Full text of DOI:10.1016/j.tetlet.2007.01.163

Tetrahedron Letters 48 (2007) 2279–2282
Enantioselective synthesis of (ꢀ)-pinellic acid
S. Vasudeva Naidu and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 13 December 2006; revised 25 January 2007; accepted 31 January 2007
Available online 3 February 2007
Abstract—An enantioselective convergent approach toward the total synthesis of pinellic acid 1 from 1,9-nonanediol is described.
The synthetic strategy features iterative Sharpless asymmetric dihydroxylation, Sonogashira coupling and Birch reduction.
Ó 2007 Elsevier Ltd. All rights reserved.
ꢀ
Influenza, is an infectious disease that infects birds and
mammals (primarily the upper airways and lungs in
mammals) and is caused by an RNA virus of the Ortho-
myxoviridae family (the influenza viruses). The most
common and characteristic symptoms of influenza in
humans are fever, pharyngitis, myalgia, severe head-
ache, coughing, and malaise. Flu rapidly spreads around
the world in seasonal epidemics,1 killing millions of
people in pandemic years and hundreds of thousands
in nonpandemic years.
Omura and co-workers reported the first synthesis of
(ꢀ)-pinellic acid 1 and determined its absolute configu-
ration by synthesizing all its isomers via regioselective
Sharpless asymmetric dihydroxylation and stereoselec-
tive reduction.5 As a part of our research program
aimed at developing enantioselective syntheses of natu-
rally occurring lactones6 and amino alcohols,7 we have
accomplished the enantioselective synthesis of (ꢀ)-pinel-
lic acid 1 employing the Sharpless asymmetric dihydr-
oxylation as the source of chirality starting from
commercially available 1,9-nonanediol.
Kampo medicine, ‘Sho-seiryu-to’ was found to possess
potent adjuvant activity by oral administration on nasal
influenza infection and nasal influenza vaccination.2
Pinellic acid (9S,12S,13S-trihydroxy-10E-octadecenoic
acid, Fig. 1) was isolated from the tubers of Pinellia
ternata, one of the eight component herbs of the Kampo
formula, Sho-seiryu-to (SST).3 Pinellic acid is a novel
and potentially useful oral adjuvant when used in
conjunction with intranasal inoculation of influenza
HA vaccines.3a Pinellic acid showed no hemolytic
activity.3a Among the series of pinellic acid isomers,
the (9S,12S,13S)-compound, which is a natural product,
exhibited the most potent adjuvant activity.4
Our retrosynthetic strategy for the synthesis of (ꢀ)-
pinellic acid 1 is outlined in Scheme 1. We envisioned
that the 12S,13S syn-diol could be prepared from 1,3-
enyne 12, which in turn could be prepared from acetyl-
ene 10 by Sonogashira coupling with vinyl iodide 11.
Acetylene 10 could be obtained from 1,9-nonane diol
2. In this strategy, the 9S hydroxy could be installed
through Sharpless asymmetric dihydroxylation of an
olefin, which in turn would be prepared from 1,9-non-
ane diol 2.
The synthesis of (ꢀ)-pinellic acid 1 started from com-
mercially available 1,9-nonane diol 2 as illustrated in
Schemes 2 and 3. Thus, selective mono hydroxyl protec-
tion of 2 with p-methoxybenzyl bromide in the presence
of NaH gave the monoprotected diol 3 in 95% yield,
which was oxidized to the corresponding aldehyde under
Swern conditions8 and subsequently treated with
OH
OH
O
12S
HO
13S
9S
OH
(ethoxycarbonylmethylene)triphenylphosphorane
in
Pinellic acid (1)
benzene under reflux to furnish trans-olefin 4 in 91%
yield.
Figure 1.
*
Olefin 4 was treated with osmium tetroxide and potas-
sium ferricyanide as co-oxidant in the presence of
Corresponding author. Tel.: +91 20 25902050; fax: +91 20
25902629; e-mail: pk.tripathi@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.163

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S. V. Naidu, P. Kumar / Tetrahedron Letters 48 (2007) 2279–2282
Sonogashira
coupling
Reduction
OH
OH
O
HO
AD
OH
AD
1
OTBDPS
OTBDPS
OH
PMBO
PMBO
7
7
12
OH
13
OTBDPS
PMBO
I
+
7
11
10
OH
7
O
PMBO
HO
OH
OEt
7
OH
5
2
Scheme 1. Retrosynthetic analysis of pinellic acid (1).
b
a
HO
7
OH
PMBO
OH
7
3
2
OH
7
O
O
c
PMBO
OEt
PMBO
7
OEt
O
5
OH
O
4
O
e
O
d
PMBO
PMBO
7
7
7
6
OH
O
OEt
OP
7
O
g
O
f
PMBO
h
PMBO
7
8
Cl
9 : P = H
10: P = TBDPS
Scheme 2. Reagents and conditions: (a) (i) p-CH3OC6H4CH2Br, NaH, dry DMF, cat. TBAI, 0 °C–rt, 1 h, 95%; (b) (i) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 to ꢀ60 °C; (ii) Ph3P@CHCO2Et, benzene, reflux, 4 h, 91%; (c) (DHQ)2PHAL, K2CO3, K3Fe(CN)6, MeSO2NH2, OsO4 (0.1 M solution
in toluene), t-BuOH/H2O (1:1), 0 °C, 24 h, 96%; (d) p-TSA, 2,2-DMP, CH2Cl2, overnight, 96%; (e) DIBAL-H, CH2Cl2, 0 °C–rt, 2 h, 96%; (f) N-
chlorosuccinimide, PPh3, CH2Cl2, 0 °C to rt, 3 h, 89%; (g) (i) n-BuLi, HMPA, THF, ꢀ42 °C–rt, 30 min, 82%; (ii) TBDPSCl, imidazole, CH2Cl2,
0 °C–rt, overnight, 98%.
(DHQ)2PHAL ligand under asymmetric dihydroxyl-
ation (AD) conditions9 to give diol 5 in 96% yield with
99% ee.10 Treatment of diol 5 with 2,2-dimethoxypro-
pane in the presence of p-TSA gave compound 6, which
on reduction with DIBAL-H furnished alcohol 7 in
excellent yield. Alcohol 7 was converted to chloride 8
in 89% yield via Mitsunobu reaction.11 Propargylic alco-
hol 9 was obtained by treatment of 8 with n-BuLi in the

S. V. Naidu, P. Kumar / Tetrahedron Letters 48 (2007) 2279–2282
2281
OTBDPS
OTBDPS
OH
b
a
PMBO
PMBO
7
10 + 11
7
12
13
OH
OTBDPS
OTBDPS
OH
d
c
HO
O
HO
7
7
O
15
OH
14
O
OH
O
OTBDPS
OH
f
e
HO
HO
O
7
7
OH
(-)-Pinellic acid (1)
O
16
Scheme 3. Reagents and conditions: (a) Pd(PPh3)2Cl2, CuI, Et3N, 6 h, 86%; (b) (DHQ)2PHAL, K2CO3, K3Fe(CN)6, MeSO2NH2, OsO4 (0.1 M in
toluene), t-BuOH/H2O 1:1, 0 °C, 24 h, 96%; (c) Na/liq NH3, THF, ꢀ40 °C, 89%; (d) p-TSA, 2,2-DMP, CH2Cl2, overnight, 92%; (e) (i) (COCl)2,
DMSO, Et3N, CH2Cl2, ꢀ78 to ꢀ60 °C; (ii) NaClO2, DMSO, NaH2PO4, rt, overnight; (f) HCl (cat), MeOH, rt, overnight, 78% overall yield from 15.
presence of HMPA12 in 82% yield. The free hydroxy
group of 9 was protected with TBDPSCl to furnish com-
pound 10.13
for structure activity relationship studies is currently
underway in our laboratory.
In order to generate the trans-olefin to execute the second
Sharpless asymmetric dihydroxylation, Sonogashira
coupling14 was employed in the next step. Thus, coupling
of 10 with trans-vinyl iodide 1115 using Pd(PPh3)2Cl2 and
CuI in triethylamine furnished 1,3-enyne product 12 in
excellent yield. Enantioselective AD of 1,3-enyne 12
under standard conditions gave acetylenic diol 1316 in
good yield with high diastereomeric excess (de = >96%)
as judged by 1H and 13C NMR spectral analysis. Reduc-
tion of alkyne 13 to the E-alkene and concomitant
removal of the PMB group proceeded smoothly under
Acknowledgments
S.V.N. thanks the CSIR, New Delhi, for financial assis-
tance. We are grateful to Dr. M. K. Gurjar for his sup-
port and encouragement. The financial support from the
DST, New Delhi (Grant No. SR/S1/OC-40/2003), is
gratefully acknowledged. This is NCL communication
No. 6699.
References and notes
17
Birch conditions using Na/liq NH3 to afford 14 in
89% yield. Diol 14 was protected as its isopropylidene
derivative 15 in the presence of 2,2-dimethoxypropane
and a catalytic amount of p-TSA in good yield.
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sponding aldehyde using Swern conditions and further
oxidation using NaClO2 in DMSO under buffered condi-
tions18 furnished acid 16. Finally, the acetonide and
TBDPS groups were deprotected under acidic conditions
(catalytic HCl in MeOH) to afford the target molecule 1
in 78% overall yield from 15. The physical and spectro-
scopic data of 1 were identical with those reported.4,5
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In conclusion, a convergent and efficient total synthesis
of (ꢀ)-pinellic acid 1, with high enantioselectivities has
been developed in which all the stereocenters were estab-
lished by Sharpless asymmetric dihydroxylation. Nota-
ble features of this approach include Sonogashira
coupling and Birch reduction to establish the C10–C11
trans-olefin geometry. Further application of this
methodology to the syntheses of related compounds
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2282
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25
13. Spectral data of compound 10: colorless oil, ½aꢁD ꢀ1.75 (c
0.8, CHCl3); IR (CHCl3): mmax 3440, 2938, 2864, 1736, 1612,
1513, 1248, 1130, 1032 cmꢀ1; 1H NMR (200 MHz, CDCl3):
d 1.10 (s, 9H), 1.24 (br s, 10H), 1.53–1.72 (m, 4H), 2.33 (d,
J = 2.0 Hz, 1H), 3.44 (t, J = 6.6 Hz, 2H), 3.82 (s, 3H), 3.35
(dd, J = 6.1, 1.9 Hz, 1H), 4.45 (s, 2H), 6.92 (d, J = 8.7 Hz,
2H), 7.31 (d, J = 8.6 Hz, 2H), 7.37–7.45 (m, 6H), 7.64–7.79
(m, 4H); 13C NMR (50 MHz, CDCl3): d 19.2, 24.3, 24.5,
26.1, 26.5, 26.8, 28.9, 29.25, 29.28, 29.7, 37.2, 38.1, 55.0,
63.6, 69.2, 70.0, 72.4, 85.0, 113.6, 117.0, 127.3, 127.5, 129.1,
129.4, 129.56, 129.65, 129.7, 130.7, 133.9, 134.7, 135.7,
135.9, 159.0. Anal. Calcd for C35H46O3Si (542.82): C,
77.44; H, 8.54. Found: C, 77.51; H, 8.45.
7. (a) Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44,
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8. For reviews on the Swern oxidation, see: (a) Tidwell, T. T.
Synthesis 1990, 857–870; (b) Tidwell, T. T. Org. React.
1990, 39, 297–572.
9. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed.
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Lett. 1975, 16, 4467–4470; (b) Yu, Q.; Wu, Y.; Ding, H.;
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108, 7408–7410.
25
16. Spectral data of compound 13: colorless oil, ½aꢁD +8.8 (c
10. The enantiomeric purity of diol 5 was estimated to be
>99% by chiral HPLC analysis (Chiralcel OD, petroleum
ether/i-PrOH (96:4), 1 mL/min, 240 nm). Spectral data of
0.9, CHCl3); IR (CHCl3): mmax 3440, 2938, 2864, 1736,
1
1612, 1513, 1248, 1130, 1032 cmꢀ1; H NMR (200 MHz,
CDCl3): d 0.90 (t, J = 6.8 Hz, 3H), 1.07 (s, 9H), 1.27 (br s,
18H), 1.57–1.73 (m, 4H), 2.34 (br s, 2H), 3.29–3.34 (m,
2H), 3.81 (s, 3H), 3.90 (t, J = 7.3 Hz, 2H), 4.23–4.34 (m,
1H), 4.45 (s, 2H), 6.91 (d, J = 8.7 Hz, 2H), 7.30 (d,
J = 8.7 Hz, 2H), 7.35–7.49 (m, 6H), 7.69–7.78 (m, 4H);
13C NMR (50 MHz, CDCl3): d 13.9, 19.1, 22.5, 24.8, 25.1,
26.1, 26.8, 29.0, 29.3, 29.4, 29.7, 31.7, 32.1, 38.2, 55.2, 63.7,
65.9, 70.1, 72.4, 74.5, 83.2, 87.7, 113.7, 127.3, 127.6, 129.2,
129.6, 129.8, 130.7, 133.4, 134.1, 135.8, 135.9, 159.1. Anal.
Calcd for C42H60O5Si (673.01): C, 74.95; H, 8.99; Si, 4.17.
Found: C, 75.10; H, 8.80; Si, 4.09.
25
compound 5: ½aꢁD ꢀ6.7 (c 1.7, CHCl3); IR (CHCl3): mmax
3440, 2938, 2864, 1736, 1612, 1513, 1248, 1130, 1032 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 1.25–1.36 (m, 13H), 1.50–
1.74 (m, 4H), 2.51 (br s, 2H), 3.46 (t, J = 6.6 Hz, 2H), 3.82
(s, 3H), 3.90 (d, J = 6.6 Hz, 1H), 4.06–4.16 (m, 1H), 4.32
(q, J = 7.0 Hz, 2H), 4.46 (s, 2H), 6.93 (d, J = 8.5 Hz, 2H),
7.31 (d, J = 8.5 Hz, 2H); 13C NMR (50 MHz, CDCl3): d
14.0, 25.5, 26.0, 29.2, 29.3, 29.5, 33.5, 55.0, 61.6, 70.0, 72.3,
73.0, 73.1, 113.6, 128.9, 130.7, 158.9, 173.4. Anal. Calcd
for C21H34O6 (382.50): C, 65.94; H, 8.96. Found: C, 66.09;
H, 8.81.
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