A chemoenzymatic asymmetric synthesis of (9S,12S,13S)- and (9S,12RS,13S)-pinellic acids

Article abstract of DOI:10.1016/j.tetlet.2009.06.069

A brief and facile synthesis of the title compounds has been developed by using an efficient lipase-catalyzed acylation and a chiral template-directed diastereoselective alkylation for incorporating the stereogenic centres. A cross-metathesis was employed to get the required E-olefin geometry.

Full text of DOI:10.1016/j.tetlet.2009.06.069

Tetrahedron Letters 50 (2009) 4986–4988
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A chemoenzymatic asymmetric synthesis of (9S,12S,13S)- and
(9S,12RS,13S)-pinellic acids
*
Anubha Sharma , Seema Mahato, Subrata Chattopadhyay
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A brief and facile synthesis of the title compounds has been developed by using an efficient lipase-cata-
lyzed acylation and a chiral template-directed diastereoselective alkylation for incorporating the stereo-
genic centres. A cross-metathesis was employed to get the required E-olefin geometry.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 April 2009
Revised 10 June 2009
Accepted 12 June 2009
Available online 16 June 2009
Influenza is an infectious viral disease of the respiratory tract
among human beings. It is associated with fever, myalgia, pharyn-
gitis and severe headache. The symptoms are especially acute for
patients afflicted by bronchial asthma and immunosuppressive
syndromes such as AIDS1 and cardiopulmonary diseases and can
assume lethal proportions. Intranasal inoculation of influenza vac-
cine2 is a useful and safe prophylactic measure to treat the infec-
tion. However, it is not adequately effective to induce high levels
of immunity. Therefore, novel and effective adjuvants for the vac-
cine are sought for potency enhancement. The Kampo medicine,
Sho-seiryu-to (SST) was found to exhibit adjuvant activity by oral
intake for nasally administered influenza vaccine. The activity of
SST was attributed to ingredients from Pinelliae tuber, a component
herb. Pinellic acid (9,12,13-trihydroxy-10E-octadecenoic acid, 1) is
the active principle of the same.3 The initial syntheses4a,b of the
stereomers of 1 were aimed at elucidation of absolute stereochem-
istry of its stereogenic centres and establishing the structure–
activity relationship. These employed (i) Sharpless asymmetric
dihydroxylation and a stereoselective reduction with BINAL-H as
the key steps. Among the eight possible stereomers of pinellic acid,
(9S,12S,13S)-1 exhibited the most potent adjuvant activity.4c
Among the 9S-derivatives, the adjuvant activities of the 13S-com-
pounds were stronger than those of the 13R-compounds, while
the adjuvant activity was indifferent to the stereochemistry of C-
12 carbinol centre.4a,b In view of this, and the medicinal value of
1, several syntheses of its different stereomers via (i) Sharpless
asymmetric dihydroxylation, Sonogashira coupling and Birch
reduction,5a,b (ii) Sharpless asymmetric epoxidation and alkyne
coupling5c and (iii) tartaric acid as the chiral template have been
reported.5d
synthesis.6b,c To this end, we have extensively used inexpensive
and easily accessible (R)-cyclohexylideneglyceraldehyde 7 as a ver-
satile chiral template7a–f and/or employed biocatalytic routes8a–d
for the asymmetric syntheses of a diverse array of natural com-
pounds. A chemoenzymatic approach, combining both these meth-
odologies may often provide easy access to the target compounds,
as illustrated in this Letter for the syntheses of the title
compounds.
For the synthesis (Scheme 1), the commercially available 1,9-
nonanediol 2 was monoprotected with para-methoxybenzyl chlo-
ride (PMBCl) in the presence of NaH to furnish compound 3. On
oxidation with pyridinium chlorochromate (PCC), the aldehyde 4
was obtained. Its reaction with vinylmagnesium bromide afforded
the allylic alcohol 5. A Novozyme 435Ò-catalyzed acetylation of 5
with vinyl acetate proceeded smoothly to furnish the (S)-acetate
6 (41%) and (R)-alcohol 5 (38%) in 97% and 95% ees, respectively,
after ꢀ50% conversion. The % ees of the enantiomeric alcohols
(R)-5 and (S)-5 were determined from the relative intensities of
the methoxyl resonances of the corresponding MTPA esters, pre-
pared using (R)-MTPA chloride.9 Alkaline hydrolysis of (S)-6 gave
the alcohol (S)-5, while the resolved alcohol (R)-5 could be con-
verted to its antipode via a Mitsunobu inversion (PhCO2H/Ph3P/
DIAD/THF, 87%).10
For the other synthon, following our own methodology, the
known aldehyde 7 was reacted with CH3(CH2)4Li to furnish the
anti-triol derivative 8 almost exclusively (dr = 97:3). The anti-com-
pound 8 could be easily obtained in stereochemically pure form by
column chromatography, and characterized by its typical 1H NMR
resonances.7e,f Its carbinol function was protected with tert-butyldi-
phenylsilyl chloride (TPSCl)/imidazole in the presence of 4-dimeth-
ylaminopyridine (DMAP) in anhydrous CH2Cl2 to furnish the silyl
derivative 9. The acetal function of 9 was conveniently removed
with aqueous trifluoroacetic acid (TFA) to furnish the diol 10. Treat-
ment of 10 with NaIO4 led to cleavage of the 1,2-diol function afford-
ing the aldehyde 11, which on reaction with vinylmagnesium
Despite the impressive progress,6a the development of simple
and efficient strategies remains a challenging area in asymmetric
* Corresponding author. Tel.: +91 22 25590267; fax: +91 22 25505151.
E-mail address: anubhas@barc.gov.in (A. Sharma).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.069

A. Sharma et al. / Tetrahedron Letters 50 (2009) 4986–4988
4987
i
iii
(CH2)8OPMB
iv
HO(CH2)9OH
PMBO(CH2)8X
(CH2)8OPMB
OR
(R)-5 +
OH
2
3 X = CH2OH
ii
5
4 X = CHO
6 R = Ac
v
(S)-5 R =H
OH
O
vi
viii
O
HO
(CH2)4CH3
O
(CH2)4CH3
O
CHO
OTPS
10
OR
7
8 R = H
vii
9 R =TPS
OH
RO
ix
OHC
(CH2)4CH3
OTPS
11
iii
x
(CH2)4CH3
OTPS
12
(CH2)8OPMB
OR
CH3(CH2)4
vii
OTPS
13 R = H
14 R =TPS
TPSO
CH3(CH2)4
HO
xiii
xi
(CH2)7R
OTPS
(CH2)7CO2H
OH
CH3(CH2)4
OTPS
OH
1
15 R = CH2OH
16 R =CO2H
xii
Scheme 1. Reagents and conditions: (i) NaH/PMBCl/DMF/25 °C/12 h (71%); (ii) PCC/NaOAc/CH2Cl2/25 °C/3 h (92%); (iii) CH2@CHMgBr/THF/25 °C/3 h (79% for 5, 81% for 12);
(iv) vinyl acetate/Novozyme 435/diisopropyl ether/25 °C/26 h (50% conversion); (v) K2CO3/MeOH/25 °C/6 h (86%); (vi) CH3(CH2)4Li/THF/25 °C/4 h (87%); (vii) TPSCl/
imidazole/DMAP/CH2Cl2/25 °C/18 h (84% for 9, 80% for 14); (viii) 80% aqueous TFA/0 °C/3 h (81%); (ix) NaIO4/MeCN–H2O (6:4)/0 °C/2 h (90%); (x) (S)-5/CH2Cl2/Grubbs 2nd
generation catalyst/25 °C/18 h (78% based on 5); (xi) DDQ/CH2Cl2–H2O/25 °C/12 h (77%); (xii) PDC/DMF/25 °C/24 h (71%); (xiii) Bu4NF/THF/0 °C/12 h (89%).
OH
O
HO
OH
i,ii
(CH2)4CH3
iii
iv
(CH2)4CH3
(CH2)7CO2H
OH
CH3(CH2)4
10
OTPS
(3S,4S)-12
OTPS
17
(9S,12S,13S)-1
Scheme 2. Reagents and conditions: (i) TMSCl/EtOAc/ꢁ20 °C/20 min; MsCl/Et3N/ꢁ20 °C/30 min; 2 N aqueous HCl/25 °C/40 min (78%); (ii) NaH/THF/0–25 °C/3 h (89%); (iii)
Me3SI/BuLi/THF/ꢁ25 °C/1 h then 25 °C/6 h (84%); (iv) As in Scheme 1.
bromide furnished the allylic alcohol 12 (syn:anti 78:22). As envi-
sioned in our synthetic plan, the C-3 carbinol centre of 12 would
eventually provide the C-12 carbinol centre of the target compound.
Since, the stereochemistry at C-12 of 1 was inconsequential to its
adjuvant activity, the diastereomeric mixture of 12 was used as such
for the synthesis. A cross-metathesis reaction between (S)-5 and 12
(1.7 equiv) in the presence of Grubbs 2nd generation catalyst
proceeded smoothly to furnish the desired diol 13 in good yield.
However, the Grubbs 1st and Grubbs–Hoveyda 2nd generation cat-
alysts were ineffective for the transformation. The E-geometry of the
olefin 13 as ascertained from its 1H NMR spectrum was consistent
with the proposed model for the cross-metathesis reaction.11 Silyla-
tion of the carbinol function of 13 as above gave the trisilylated
compound 14. Oxidative removal of the PMB protection in 14 with
dichlorodicyanobenzoquinone (DDQ) furnished the alcohol 15. This
was oxidized with pyridinium dichromate (PDC) in DMF to furnish
the acid 16, which on desilylation afforded the title acid
(9S,12RS,13S)-1.12
For the synthesis of natural (9S,12S,13S)-1, the diol 10 was
monosilylated at its primary carbinol site with trimethylchlorosi-
lane (TMSCl), the adjacent hydroxyl function was mesylated with
methanesulphonyl chloride (MsCl) and was subsequently desily-
lated in one pot. The resultant hydroxymesyl compound was trea-
ted with NaH to furnish the epoxide (2S,3S)-17. This on a base (n-
BuLi)-mediated reaction Me3S+Iꢁ afforded (3S,4S)-12, which was
subsequently converted to the target compound in five steps and
27% yield (Scheme 2).
References and notes
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oil; ½a 2D4
ꢂ
+8.6 (c 1.20, CHCl3); IR: 3444 cmꢁ1 1H NMR: d 0.88 (dist. t, J = 6.4 Hz,
;
3H), 1.29–1.47 (m, 10H), 1.58–1.68 (m, 8H), 2.10 (br s, 1H), 3.72–3.79 (m, 1H),
3.83–4.06 (m, 3H); 13C NMR: d 13.9, 22.4, 23.6, 23.8, 25.0, 25.3, 31.7, 32.7, 34.7,
36.0, 64.4, 70.7, 78.3, 109.3. Anal. Calcd for C14H26O3: C, 69.38; H, 10.81. Found:
C, 69.22; H, 10.98. Data for 13: Colourless oil; ½a D24
ꢂ
+10.56 (c 1.42, CHCl3); IR:
3444 cmꢁ1 1H NMR: d 0.80 (dist. t, J = 6.8 Hz, 3H), 1.06–1.59 (m containing a s
;
11. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
at d 1.09, 31H), 2.05 (br s, 2H), 3.43 (t, J = 6.6 Hz, 2H), 3.60–3.69 (m, 1H), 3.80 (s,
3H), 4.02–4.14 (m, 2H), 4.43 (s, 2H), 5.67 (dd, J = 15.4, 5.6 Hz, 2H), 6.87 (d,
J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.35–7.44 (m, 6H), 7.67–7.71 (m, 4H);
13C NMR: d 13.8, 19.4, 22.3, 24.4, 25.2, 26.0, 27.0, 29.3, 29.6, 31.6, 33.2, 36.9,
55.1, 70.1, 72.0, 72.4, 73.3, 77.5, 113.6, 127.4, 127.5, 129.1, 129.6, 130.5, 130.7,
133.4, 134.8, 135.8, 158.9. Anal. Calcd for C42H62O5Si: C, 74.73; H, 9.26. Found:
C, 74.59; H, 9.10.
12. All the compounds were fully characterized from their spectral, optical and
microanalytical data. Representative data are included. Data for 5: Colourless
oil; ½a 2D3
ꢂ
ꢁ3.94 (c 1.41, CHCl3). IR: 3427, 3074, 918 cmꢁ1
;
1H NMR: d 1.29 (br s,
10H), 1.45–1.61 (m, 4H), 2.06 (br s, 1H), 3.44 (t, J = 6.6 Hz, 2H), 3.80 (s, 3H),
4.06–4.10 (m, 1H), 4..43 (s, 2H), 5.06–5.26 (m, 2H), 5.77–5.94 (m, 1H), 6.88 (d,
J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H); 13C NMR: d 25.3, 26.1, 29.4, 29.5, 29.6,