The stereoselective total synthesis of (+)-18-(6S,9R,10R)-bovidic acid

Article abstract of DOI:10.1016/j.tetlet.2011.03.089

An expedient stereoselective total synthesis of 18-carbon (+)-(6S,9R,10R)-bovidic acid, isolated from the pelage and skin of a gaur B. frontalis is described using l-proline catalysed sequential α- aminoxylation and Horner-Wadsworth-Emmons olefination of

Full text of DOI:10.1016/j.tetlet.2011.03.089

Tetrahedron Letters 52 (2011) 2943–2945
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Tetrahedron Letters
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The stereoselective total synthesis of (+)-18-(6S,9R,10R)-bovidic acid
J. S. Yadav a, , K. Ramesh a, U. V. Subba Reddy a, B. V. Subba Reddy a, Ahamad Al Khazim Al Ghamdi b
⇑
a Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Engineer Abdullah Baqshan for Bee Research, King Saudi University, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient stereoselective total synthesis of 18-carbon (+)-(6S,9R,10R)-bovidic acid, isolated from the
Received 4 February 2011
Revised 13 March 2011
Accepted 16 March 2011
Available online 31 March 2011
pelage and skin of a gaur B. frontalis is described using L-proline catalysed sequential a-aminoxylation
and Horner–Wadsworth–Emmons olefination of aldehyde, cross metathesis and tandem Sharpless asym-
metric dihydroxylation-SN2 cyclization reaction as the key steps.
Ó 2011 Published by Elsevier Ltd.
Keywords:
Bovidic acid
MacMillan a-hydroxylation
Horner–Wadsworth–Emmons reaction
Cross metathesis
Tandem dihydroxylation-SN2 cyclization
New repellents against biting insects need to be developed to
protect people from insect-transmitted diseases. The natural prod-
ucts present in preferred and non-preferred animal hosts of biting
insects can exhibit interesting semi-chemical properties. Numer-
ous pathogens of both man and livestock are transmitted by mos-
quitoes and other biting arthropods. Repellents have proven to be a
reliable means of preventing biting insects.
While repellents have been isolated from many naturally occur-
ring plants and animals, recent studies by Oliver and Ishii reported
identification and isolation of the natural repellent, (+)-bovidic
acid 1 from the pelage and skin of a gaur B. Frontalis.1,2 Decades
ago, a shorter 16-carbon analogue (3) was isolated from sheep
O
OH
10
O
HO
6
9
O
OH
10
O
6
HO
(+)-(6S,9R,10R)-Bovidic acid 1
9
(+)-(6S,9R,10R)-Bovidic acid 1
O
OH
10
O
HO
6
9
BnO
16-C-Bovidic acid 3
OMs
14
O
OH
10
O
CO2Et
HO
6
9
BnO
OH
6
(-)-(6R,9S,10S)-Gaur acid 2
Figure 1. Examples of bovidic acid and its derivatives.
HO
OH
⇑
Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160387.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Scheme 1. Retrosynthesis of (+)-bovidic acid.
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.03.089

2944
J. S. Yadav et al. / Tetrahedron Letters 52 (2011) 2943–2945
wool (Fig. 1).3 These hydroxy furanoid fatty acids and their ana-
logues were evaluated against Aedes aegypti (L) mosquitoes and
the results reveal that this may generate a class of tropical repel-
lents for use against insects that transmit pathogens to humans.4
The (ꢀ) isomer of bovidic acid, that is, gaur acid 2 has been syn-
thesised by Evans and co-workers.5
a
b
OH
O
BnO
HO
OH
4
CO2Et
CO2Et
c
BnO
BnO
OH
6
7
5
d
CO2Et
e
BnO
BnO
OH
OMOM
8
f
g
BnO
O
BnO
BnO
OH
OMOM
10
OMOM
OH
9
h
i
BnO
12
OMOM
11
j
+
BnO
OMs
13
k
BnO
OMs
14
l
m
n
OH
O
BnO
HO
15
OH
O
16
O
OH
O
HO
1
(+)-(6S,9R,10R)-Bovidic acid
Scheme 2. Reagents and conditions: (a) (i) NaH, THF, 0–25 °C, 0.5 h; (ii) BnBr, 0–25 °C, 3 h, 90%; (b) oxalyl chloride, dry DMSO, dry DCM, ꢀ78 °C, Et3N, 1 h, 87%; (c)
nitrosobenzene (1.2 equiv), -proline (0.4 equiv), DMSO, 20 °C, 25 min, then triethylphosphonoacetate, DBU, LiCl, 0 °C, 15 min, then MeOH, NH4Cl, Cu(OAc)2, rt, 24 h, 48% (one
L
pot); (d) NaBH4, NiCl2.6H2O, MeOH, 0 °C–rt; 3 h, 90%; (e) MOMCl, DIPEA, dry DCM, 0 °C–rt, 6 h, 94%; (f), DIBAL-H, DCM, 0 °C, 15 min, 88%; (g) oxalyl chloride, dry DMSO, dry
DCM, ꢀ78 °C, Et3N, 1 h 85%; (h) n-BuLi, Ph3P+CH3Iꢀ, THF, 0 °C–rt, over night, 85%; (i) p-TSA, MeOH, reflux, 30 min, 90%; (j) MsCl, Et3N, DCM, 0 °C–rt, 4 h, 90%; (k) Grubbs II
generation catalyst (3 mol %), DCM, reflux, 10 h, 75%; (l) admix-b, MeSO2NH2, t-BuOH/H2O (1:1), 30 h, 85%, 0 °C–rt; (m) 10% Pd/C, H2, EtOAc, rt, 10 h, 92%; (n) TEMPO, BAIB,
DCM/H2O (1:1), 0 °C–rt, 2 h, 84%.

J. S. Yadav et al. / Tetrahedron Letters 52 (2011) 2943–2945
2945
In continuation of our ongoing research programme on the total
synthesis of biologically active molecules by desymmetrization
strategy,6 and also the inherent biological property of bovidic acid
encouraged us to initiate the total synthesis of this molecule. Here-
in, we report a concise and flexible stereoselective synthetic route
for the total synthesis of (+)-bovidic acid (1) starting from the read-
1,7-heptanediol. The salient features of this synthesis include the
use of the MacMillan -hydroxylation and HWE reaction for the
construction of -hydroxy- ,b-unsaturated ester in a single step,
Grubbs cross metathesis and tandem Sharpless asymmetric
dihydroxylation-SN2 cyclization, which allow the preparation of a
target molecule in a short and flexible route.
a
c
a
ily available heptanediol by employing the MacMillan
ation, Horner–Wadsworth–Emmons olefination, cross metathesis
and tandem Sharpless asymmetric dihydroxylation-SN2
cyclization.
In our retrosynthetic analysis, we envisioned that the synthesis
of bovidic acid could be accomplished from intermediate 14, which
can be synthesized by means of cross metathesis of compound 12
and 1-decene. The compound 12 could in turn be obtained from 6
a-hydroxyl-
Acknowledgements
K.R. thanks CSIR, New Delhi and U.V.S.R. thanks UGC, New
Delhi, for the award of fellowships.
References and notes
1. Oliver, J. E.; Weldon, P. J.; Peterson, K. S.; Schmidt, W. F.; Debboun, M. Abstracts
of Papers, 225th ACS National Meeting, New Orleans, LA, USA, March 23-27,
2003.
by reduction and C1Wittig of compound 6. This
c-hydroxy-a,b-
unsaturated ester 6 can be prepared through MacMillan
a-hydrox-
ylation followed by Horner–Wadsworth–Emmons olefination of
the corresponding aldehyde (Scheme 1).
2. Hideki, I.; Sonja, K.; Yasuhiro, I.; Nina, B.; Koji, N.; Paul, J. W. J. Nat. Prod. 2004,
67, 1426.
3. Ito, S.; Endo, K.; Inoue, S.; Nozoe, T. Tetrahedron Lett. 1971, 12, 4011.
4. Tran, K.; Chauhan, K. R. Biopestic. Int. 2007, 3, 53.
5. Evans, P. A.; Leahy, D. K.; Andrews, W. J.; Uraguchi, D. Angew. Chem., Int. Ed.
2004, 43, 4788.
6. For recent publications see: (a) Yadav, J. S.; Satheesh, G.; Murthy, C. V. S. R. Org.
Lett. 2010, 12, 2544; (b) Yadav, J. S.; Rajender, V.; Gangadhar, Y. Org. Lett. 2010,
12, 348; (c) Yadav, J. S.; Mohapatra, D. K.; Hossain, S. S.; Dhara, S. Tetrahedron
Lett. 2010, 51, 3079; (d) Yadav, J. S.; Narasimhulu, G.; Reddy, N. M.; Reddy, B. V.
S. Tetrahedron Lett. 2010, 51, 1574.
Accordingly, our synthetic approach began with mono protec-
tion of 1,7-heptanediol with benzyl bromide using NaH and TBAI
to give mono-benzyl ether 4 in 90% yield.7 This monoprotected
alcohol 4 was subjected to Swern oxidation to afford the corre-
sponding aldehyde 5 in 88% yield.8 The direct catalytic asymmetric
aminoxylation of aldehyde 5 with nitrosobenzene using
as a catalyst gave an intermediate -oxyamino aldehyde with high
levels of enantioselectivity9,10 by means of
-oxidation. Subse-
L-proline
a
7. Jun, I. S.; Lee, J. W.; Sakamoto, S.; Yamaguchi, K.; Kimoon, K. Tetrahedron Lett.
2000, 41, 471.
a
8. Corey, E. J.; Marafat, A.; Laguzza, B. C. Tetrahedron Lett. 1981, 22, 3339.
9. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am Chem. Soc. 2003,
125, 10808.
10. For other reports on proline-catalyzed oxidation of aldehydes see: (a)
Chandrasekhar, S.; Mahipal, B.; Kavitha, M. J. Org. Chem. 2009, 74, 9531; (b)
Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (c) Hayashi, Y.; Yamaguchi, J.;
Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293; (d) Chandrasekhar, S.;
Yaragorla, S. R.; Sreelakshmi, L. Tetrahedron Lett. 2007, 48, 7339; (e) Zhong, G.
Chem. Commun. 2004, 606.
11. (a) Yadav, J. S.; Reddy, U. V. S.; Anusha, B.; Reddy, B. V. S. Tetrahedron Lett. 2010,
51, 5529; (b) Sabitha, G.; Chandrashekhar, G.; Yadagiri, K.; Yadav, J. S.
Tetrahedron Lett. 2010, 51, 3824; (c) Yadav, J. S.; Reddy, U. V. S.; Reddy, B. V.
S. Tetrahedron Lett. 2009, 50, 5984; (d) Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637;
(e) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696; (f)
Varseev, G. N.; Maier, M. E. Org. Lett. 2007, 9, 1461.
quent olefination of aminoxy aldehyde under Horner–Wads-
worth–Emmons conditions followed by the cleavage of aminoxy
bond with Cu(OAc)2 in MeOH at room temperature gave the
droxy-
,b-unsaturated ester 6 (96% ee, HPLC) in 48% yield.11 The
selective reduction of the double bond in -hydroxy- ,b-unsatu-
c-hy-
a
c
a
12
rated ester 6 using NiCl2.6H2O and NaBH4 afforded the com-
pound 7 in 90% yield. Thereafter, alcohol 7 was protected as its
MOM ether 8 using MOMCl in the presence of the Hunig’s base
in dry dichloromethane. The reduction of ester 8 with DIBAL-H in
DCM gave the primary alcohol 9 in 88% yield, which was further
oxidized to aldehyde 10 under Swern oxidation conditions. Upon
treatment of aldehyde 10 with methylene-triphenylphosphorane
(generated in situ from CH3P+Ph3I- and n-BuLi) in THF gave the ole-
fin 11 in 85% yield. The deprotection of MOM ether was achieved
by p-TSA in methanol to give the secondary alcohol 12 in 90% yield.
The hydroxyl compound 12 was converted into its mesylate13 13
using MeSO2Cl, Et3N and DMAP (catalytic) in CH2Cl2. The mesyl es-
ter plays a dual role as a protecting group as well as a leaving group
at a later stage. Then substrate 13 was treated with 0.03 equiv of
second generation Grubbs’ catalyst in the presence of 4 equiv of
1-decene in dichloromethane for 10 h at reflux. The reaction pro-
ceeded smoothly and the desired cross coupled product 14 was ob-
tained in 75% yield as E/Z isomers in 15:1 ratio.14 A careful flash
chromatography on silica gel allowed the separation of the E and
Z isomers. The major trans isomer of cross metathesis product 14
was subjected to the Sharpless asymmetric dihydroxylation15
using (DHQD)2 PHAL, K3Fe(CN)6, K2CO3, and MeSONH2, in t-
BuOH/H2O (1:1) over 30 h to afford the key tetrahydrofuran 15
in 85% yield (no traces of the other isomer was detected by 1H
NMR, since no further experiments were carried out on the enan-
tiomerically pure compound.). Debenzylation of ether 15 with
10% Pd/C under H2 atmosphere gave the primary alcohol 16 in
good yield. Eventual oxidation of primary alcohol 16 using TEMPO
and BAIB in DCM/H2O(1:1) afforded the target acid 1 in 84% yield
as a semi-solid without affecting the secondary alcohol (Scheme
2).16 The analytical and spectral properties of the compound 1
were in good agreement with the data reported in literature.17
In conclusion, we have developed an efficient stereoselective
route for the total synthesis of bovidic acid from a readily available
12. Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19, 817.
13. Marshal, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819.
14. Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Germany, 2003; (b) Connon,
S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900; (c) Chatterjee, A. K.; Choi,
T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360; (d)
Tetsuya, Y.; Hiroko, H.; Toshikazu, H.; Shigeo, K. Org. Lett. 2006, 8, 5569.
15. (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.;
Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X. L. J. Org.
Chem. 1992, 57, 2768; (b) Kolb, H. C.; Van-Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483; (c) Mohapatra, D. K.; Pavankumar, D.; Hasibur, R.;
Pal, R. Tetrahedron Lett. 2009, 50, 6276.
16. (a) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293; (b) De Mico, A.;
Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62,
6974.
17. Spectral data for compound 6: Light yellow liquid, ½a D25
ꢁ
+3 (c 0.75, CHCl3); IR
(neat): t ;
max 3430, 2922, 2852, 1717, 1655, 1641, 1262, 1096, 803, 737 cmꢀ1 1H
NMR (CDCl3, 300 MHz): d 7.29–7.21 (m, 5H), 6.87 (dd, 1H, J = 4.5, 15.8 Hz), 5.96
(dd, 1H, J = 1.5, 15.1 Hz), 4.4 (s, 2H), 4.21–4.11 (m, 3H), 3.42 (t, 2H, J = 6.0 Hz),
1.61–1.24 (m, 11H). 13C NMR (CDCl3, 75 MHz): d 166.5, 150.0, 138.5, 128.3,
127.6, 127.4, 120.1, 72.8, 70.9, 70.1, 60.4, 36.5, 29.5, 26.0, 24.9, 14.2; ESI-MS:
m/z: 307 (M+H)+, 324 (M+NH4)+, 329 (M+Na)+; Compound 15: Colourless
liquid, ½a 2D5
ꢁ
+8.4 (c 0.4, CHCl3); IR (neat): tmax 3449, 2922, 2852, 1637, 1461,
1098, 726 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 7.30–7.27 (m, 5H), 4.46 (s, 2H),
3.89-3.81 (m, 1H), 3.72 (q, 1H, J = 7.5 Hz), 3.46–3.40 (m, 2H), 3.34–3.26 (m, 1H),
2.26–2.22 (m, 1H), 2.04–1.89 (m, 2H), 1.63–1.23 (m, 24H), 0.88 (t, 3H,
J = 6.9 Hz); 13C NMR (CDCl3, 75 MHz): d 128.3, 127.6, 127.4, 81.9, 79.1, 74.1,
72.8, 70.3, 35.6, 33.4, 32.5, 31.9, 30.2, 29.8, 29.6, 29.3, 28.4, 26.3, 26.1, 25.7,
22.7, 14.2; ESI-MS: m/z: 390 (M)+, 391 (M+H)+; Compound 1: Colourless semi
solid, ½a 2D5
ꢁ
+7.3 (c 0.2, CHCl3); IR (neat): tmax 3447, 2921, 2852, 1716, 1461,
1260, 1081, 722 cm-1
;
1H NMR (CDCl3, 300 MHz): d 3.93–3.83 (m, 1H), 3.74 (q,
1H, J = 7.5 Hz), 3.36–3.28 (m, 1H), 2.34 (t, 2H, J = 7.5 Hz), 2.09–1.90 (m, 2H),
1.69–1.32 (m, 12 H), 1.27 (s, 12H), 0.88 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3,
75 MHz): d 82.1, 78.9, 74.0, 35.3, 33.9, 33.5, 32.7, 32.1, 29.9, 29.8, 29.5, 28.6,
25.8, 25.7, 24.8, 22.9, 14.3; ESI-MS: m/z: 315 (M+H) +, 337 (M+Na)+.