Stereoselective synthesis of methyl branched chiral deoxypropionate units: A new route for synthesis of insect pheromone (-)-lardolure and (2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid

Article abstract of DOI:10.1016/j.tetlet.2012.08.112

(-)-Lardolure and (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been synthesized via lipase catalyzed desymmetrization strategy to create two methyl chiral centers. Other key steps involved in the synthesis are Wittig reaction, Evan's asymmetric alkylation, Grignard reaction, Pd-catalyzed isomerization of primary allylic alcohol to corresponding saturated aldehyde, and PhNO/proline catalyzed MacMillan α-hydroxylation.

Full text of DOI:10.1016/j.tetlet.2012.08.112

Tetrahedron Letters 53 (2012) 5952–5954
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of methyl branched chiral deoxypropionate units: a
new route for synthesis of insect pheromone (ꢀ)-lardolure and
(2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid
J. S. Yadav a, , Sandip Sengupta a,b, Nagendra Nath Yadav a,b, D. Narasimha Chary a,b
,
⇑
Ahmad Alkhazim Al Ghamdi b
a Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
b Engineer Abdullah Baqshan for Bee Research, King Saud University, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
(ꢀ)-Lardolure and (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been synthesized via lipase
catalyzed desymmetrization strategy to create two methyl chiral centers. Other key steps involved in
the synthesis are Wittig reaction, Evan’s asymmetric alkylation, Grignard reaction, Pd-catalyzed isomer-
ization of primary allylic alcohol to corresponding saturated aldehyde, and PhNO/proline catalyzed Mac-
Received 29 May 2012
Revised 23 August 2012
Accepted 25 August 2012
Available online 4 September 2012
Millan a-hydroxylation.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Enzymatic resolution
Wittig reaction
Alkylation
a
-Hydroxylation
Deoxypropionates
Pheromones
Preen-gland wax
Polydeoxypropionatechainshave beenfoundinnumerousbiolog-
ically relevant compounds and are of great interest for the last few
decades in respect of their stereocontrolled synthesis.1 A syn/syn-
deoxypropionate unit can be found in many natural products, such
as lardolure (1), (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid
(2), siphonareinal (3), siphonarienone (4), pectinatone (5), siphonari-
enolone (6), and supellapyrone (7). Mite pheromones have been
intensively investigated predominantly by Kuwahara’s group.2,3 They
isolated (ꢀ)-lardolure (1) as the aggregation pheromone of the acarid
mite, Lardoglyphus konoi, identified as the primary pest for stored
products with high protein content in 1982.4 The relative and abso-
lute stereochemistry of (ꢀ)-lardolure was confirmed by Mori and
Kuwahara.5 Extensive studies in 1960s on the preen gland waxes of
water fowl revealed the chemotaxonomic utility of waxes. During
the studies (2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid (2)
was isolated as preen secretion of graylag goose anser anser by
Murray6 and Odham7 independently. The structure and stereochem-
istry was established synthetically by Mori et al.8 and absolute
configuration was proposed by Odham7 (Fig. 1).
OCHO
COOH
Lardolure (1)
(2R, 4R, 6R, 8R)-2, 4, 6, 8-Tetramethyl-
undecanoic acid (2)
O
O
O
Siphonareinal (3)
Siphonarienone (4)
O
O
OH
Siphonarienolone (6)
OH
Pectinatone (5)
O
O
Supellapyrone (7)
Figure 1. Chemical structures of lardolure (1), acid (2), and some related natural
products containing deoxypropionates.
There are fourreports9 forthetotalsynthesis of(ꢀ)-1 sofarinclud-
ing iterative conjugate addition of MeMgBr to
a,b-unsaturated
thioesters and interconversion of 1 to 2 and vice versa.10 Recently,
we have demonstrated enzymatic desymmetrization strategy for
⇑
Corresponding author. Fax: +91 40 27160387.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.112

J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 5952–5954
5953
1.Pre activated Pd(OH)2/C
Et3N, Benzene, rt, 92%
OCHO
COOH
OH
OH
2.D-Proline, PhNO, CHCl3
CuSO4, MeOH, rt
50% for three steps
-
1
(2R,4R,6R,8R)-2,4,6,8-tetramethyl
( )-Lardolure ( )
8
2
undecanoic acid ( )
1.TsCl, Et3N, (nBu)2SnO
CH2Cl2, 0 oC-rt
OH
OH
OH
2.LAH, THF, 0 o
C
8
13
82% for two steps
14
HCOOH, 65 o
85%
C
OCHO
HO
OTBS
(-)-Lardolure (1)
9
Scheme 3. Synthesis of (ꢀ)-lardolure (1).
Wittig reaction to obtain a,b-unsaturated ester 12 in 80% yield over
three steps. The ester 12 was reduced with DIBAL-H in CH2Cl2 to
afford the corresponding common allylic alcohol intermediate 8
in 90% yield (Scheme 2).
At first we targeted the total synthesis of 1 from the common
intermediate 8 (Scheme 3). Pd(OH)2/C in benzene was used for
the conversion of allylic alcohol 8 to the saturated aldehyde16
OAc
OH
10
Scheme 1. Retrosynthetic analysis of (ꢀ)-lardolure (1) and (2R,4R,6R,8R)- 2,4,6,8-
tetramethylundecanoic acid (2).
the total synthesis of biologically active natural products containing
polydeoxypropeonates.11
To further highlight the synthetic utility of the protocol, herein,
we report the syntheses of both the pheromone 1 and 2 of preen
gland waxes from a common methyl branched chiral allylic alcohol
intermediate 8.
The retrosynthetic path (Scheme 1) shows that the targeted
molecules 1 and 2 could be easily synthesized from the common
allylic alcohol intermediate 8 which has three chiral methyl
groups. Furthermore, 8 could be obtained from the known primary
alcohol 9, which was synthesized earlier in our group using a
known precursor 10 by means of Wittig reaction and Evan’s alkyl-
ation reaction.11a
(which was not isolated) and subsequent
a-hydroxylation with
PhNO and 10 mol % -proline afforded the desired diol 13 as a ma-
D
jor diastereomer17 with 50% yield in three steps (d.r., >99%, as
determined by HPLC analysis). Selective tosyl protection of the pri-
mary alcohol of 1,2-diol 13 was achieved by TsCl, Et3N and the cat-
alytic amount of Bu2SnO and then LiAlH4 reduction of the tosylate
yielded secondary alcohol 14 in 82% yield over two steps. Second-
ary alcohol 14 was formylated by mixing 14 with formic acid at
65 °C to furnish the targeted pheromone (ꢀ)-lardolure (1) in 85%
yield. The NMR (1H and 13C) analysis and optical rotation
(½a 2D5
ꢁ
= ꢀ3.2) of 118 were in good agreement with the literature
value.9
Next we initiated the total synthesis of (2R,4R,6R,8R)-2,4,6,8-
Our synthesis began with the known precursor 10 which was
synthesized in four steps starting from cis-4,6-dimethyl cyclohex-
an-1,3-dione following a known protocol.12–14 Primary alcohol 9
was synthesized from 10 by following a reported protocol devel-
oped in our group.11a Primary hydroxyl group present in 9 was pro-
tected as its tosyl derivative by TsCl/Et3N in the presence of
catalytic amount of DMAP. It was then subjected to Grignard reac-
tion15 with EtMgBr in Et2O in the presence of 5 mol % Li2CuCl4 to
afford 11 in 90% yield. Silyl deprotection of 11 by TBAF yielded long
chain alcohol which was subjected to Swern oxidation followed by
tetramethyl undecanoic acid 2 starting from the common allylic
alcohol intermediate 8 (Scheme 4).
Accordingly, the allylic alcohol 8 was subjected to Pd-mediated
oxidation as mentioned earlier,16 followed by transformation of
1.Pre activated Pd(OH)2/C
Et3N, Benzene, rt
OH
2.NaClO2, NaH2PO4, tBuOH
8
rt, 75% for two steps
(R)-Oxazolidinone
O
PivCl, Et3N, LiCl
THF,-20 oC -0 oC, 95%
15
OH
Ph
O
ref. 11a
ref. 12, 13, 14
OAc
OH
OH
OTBS
C
9
10
NaHMDS,MeI
ee >95%
dr >97:3
O
N
THF, -78 oC
91%, >95:5
O
O
1.TBAF, THF, 0 o
16
1.TsCl, Et3N, DMAP
CH2Cl2, 0 oC
2.(COCl)2, DMSO, Et3N
Ph
CH2Cl2, -78 0
C
2.EtMgBr, Li2CuCl4
Et2O, -78 oC, 90%
H2O2, LiOH
11
OTBS
O
3.Ph3P=CHCOOEt
80% for three steps
N
THF:H2O(4:1)
91%
O
17
O
DIBAL-H
CH2Cl2
OEt
OH
OH
-78 oC, 90%
O
12
8
2
O
Scheme 2. Synthesis of allylic alcohol intermediate 8.
Scheme 4. Synthesis of (2R,4R,6R,8R)-2,4,6,8- tetramethylundecanoic acid (2).

5954
J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 5952–5954
11. (a) Yadav, J. S.; Yadav, N. N.; Rao, T. S.; Reddy, B. V. S.; Al Ghamdi, A. A. Eur. J.
Org. Chem. 2011, 4603–4608; (b) Yadav, J. S.; Rao, T. S.; Yadav, N. N.; Rao, K. V.
R.; Reddy, B. V. S.; Al Ghamdi, A. A. Synthesis 2012, 5, 788–792.
12. (a) Miller, J. J.; De Benneville, P. L. J. Org. Chem. 1957, 22, 1268; (b) Stork, G.;
Nair, V. J. Am. Chem. Soc. 1979, 101, 1315.
13. Wolfrom, M. L.; Bobbitt, J. M. J. Am. Chem. Soc. 1956, 78, 2489.
14. (a) Tsuji, K.; Terao, Y.; Achiwa, K. Tetrahedron Lett. 1989, 30, 6189; (b) Lin, G.;
Xu, W. Tetrahedron 1996, 52, 5907; (c) Anderson, J. C.; Ley, S. V.; Marsden, S. P.
Tetrahedron Lett. 1994, 35, 2087; (d) Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001,
493; (e) McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 2551.
15. Breit, B.; Schmidt, Y. Org. Lett. 2009, 11, 4767–4769.
aldehyde to the corresponding acid 15 under Pinnick conditions
using NaClO2, NaH2PO4, in tBuOH/H2O (2:1) with 75% yield in
two steps. Coupling of acid 15 with Evan’s (R)-oxazolidinone using
pivaloyl chloride in the presence of Et3N and LiCl furnished the re-
quired compound 16 in 95% yield. Methylation of the Na-enolate of
compound 16 with MeI afforded compound 17 in 91% yield. Final-
ly, treatment of compound 17 with LiOH/H2O2 in THF/H2O (4:1)
furnished the desired (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic
acid (2)7,8,18 in 91% yield and >99% d.r. and ee (as determined by
HPLC analysis).
In conclusion, concise total syntheses of (ꢀ)-lardolure and
(2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been
accomplished from a common intermediate. The key reactions in-
volved for the syntheses of 1 and 2 are enzymatic desymmetriza-
tion of meso-diol, Wittig reaction, Evan’s alkylation, palladium
hydroxide catalyzed isomerization of primary allylic alcohol to
16. Sabitha, G.; Nayak, S.; Bhikshapati, M.; Yadav, J. S. Org. Lett. 2011, 13, 382–385.
17. MacMillan, D. W. C.; Sinz, C. J.; Brochu, M. P.; Brown, S. P. J. Am. Chem. Soc. 2003,
125, 10808–10809.
18. The 1H and 13C NMR spectral data and optical rotation, of the synthetic
compounds 1 and 2 are identical with the reported values. Spectroscopic data
for selected compounds are given below.
Compound 11: colorless oil, ½a D25
ꢁ
= +0.8 (c = 0.6, CHCl3); IR (KBr):
tmax = 2956,
2929, 2958, 1466, 1254, 1073, 837 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d = 3.43
(dd, J = 9.6, 5.1 Hz, 1H), 3.33 (dd, J = 9.6, 6.2 Hz, 1H), 1.72–1.46 (m, 3H), 1.38–
0.97 (m, 8H), 0.89 (s, 9H), 0.89–0.82 (m, 12H), 0.03 (s, 6H); 13C NMR (CDCl3,
75 MHz) d = 68.1, 45.4, 41.3, 39.0, 33.2, 29.8, 27.6, 26.0, 21.0, 20.4, 20.0, 18.3,
aldehyde, and a-hydroxylation.
17.9, 14.4, -5.4; Compound 8: colorless oil, ½a D25
ꢁ
= –9.1 (c = 0.57, CHCl3); IR
(KBr): t ;
max = 3327, 2957, 2923, 2870, 1725, 1460, 1376, 1088, 972, 768 cmꢀ1
1H NMR (300 MHz, CDCl3): d = 5.58 (dt, J = 15.3, 5.6 Hz, 1H), 5.45 (dd, J = 15.5,
7.7 Hz, 1H), 4.05 (d, J = 5.5 Hz, 2H), 2.32–2.17 (m, 1H), 1.55–1.44 (m, 3H), 1.39–
1.03 (m, 8H), 0.97 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H), 0.83 (d, J = 6.4 Hz,
3H), 0.82 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d = 139.0, 127.3, 63.8,
45.5, 44.3, 39.2, 33.9, 29.6, 27.5, 21.5, 20.2, 20.1, 20.0, 14.4; Compound 13:
Acknowledgements
S.S. and N.N.Y. thank CSIR and D.N.C. thanks UGC, New Delhi for
financial assistance in the form of fellowship.
yellow oil, ½a 2D5
ꢁ
= ꢀ5.4 (c = 0.95, CHCl3). IR (KBr):
tmax = 3446, 2957, 2925,
1633, 1458, 1081 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d = 3.82-3.74 (m, 1H), 3.65-
References and notes
3.56 (m, 1H), 3.41–3.35 (m, 1H), 1.82–1.44 (m, 5H), 1.35–1.14 (m, 8H), 0.97–
0.82 (m, 6H), 0.89 (d, J = 6.9 Hz, 3H), 0.85 (t, J = 5.9 Hz, 3H); 13C NMR (CDCl3,
75 MHz) d = 69.9, 67.4, 45.8, 45.5, 41.4, 39.8, 27.7, 27.2, 26.2, 22.2, 20.4, 19.8,
18.6, 14.4; Mass (ESI–MS) m/z: 253 [M + Na]+; Compound 1: yellow oil,
1. For recent synthesis of deoxypropionate-containing natural products, see (a)
Hanessian, S.; Yang, Y.; Giroux, S.; Mascitti, V.; Ma, J.; Raeppel, F. J. Am. Chem.
Soc. 2003, 125, 13784–13792; (b) Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith,
N. D.; Bouchain, G. Org. Lett. 2002, 4, 1879–1882; (c) Lachaux, M.; Tan, Z.; Liang,
B.; Negishi, E. Org. Lett. 2004, 6, 1425–1427; synthesis of polypropionate-
containing natural products by our group (d) Birkbeck, A. A.; Enders, D.
Tetrahedron Lett. 1998, 39, 7823–7826; (e) Yadav, J. S.; Rao, K. V. R.; Ravindar,
K.; Reddy, B. V. S. Eur. J. Org. Chem. 2011, 58–61; (f) Yadav, J. S.; Rajendar, V.;
Rao, Y. G. Org. Lett. 2010, 12, 348–350; (g) Yadav, J. S.; Hossain, S. S.; Madhu, M.;
Mohapatra, D. K. J. Org. Chem. 2009, 74, 8822; (h) Yadav, J. S.; Reddy, R. N.
Tetrahedron 2010, 66, 3265.
2. Kuwahara, Y. In Advances in Insect Chemical Ecology; Carde, R. T., Millar, J., Eds.;
Cambridge Press: Cambridge, 2004; pp 110–140.
3. Kuwahara, Y. In Modern Acarology; Dusbabek, F., Bukva, V., Eds.; Academia:
Prague, 1991; vol 1, pp 43–52.
4. Kuwahara, Y.; Yen, L. T. M.; Tominaga, Y.; Matsumoto, K.; Wada, Y. Agric. Biol.
Chem. 1982, 46, 2283.
5. Mori, K.; Kuwahara, S. Tetrahedron 1986, 42, 5545–5550.
6. Murray, K. E. Aust. J. Chem. 1962, 15, 510.
½
a 2D5
ꢁ
= ꢀ3.2 (c = 0.25, Hexane). IR (KBr):
tmax = 3424, 2957, 2924, 2854, 1723,
1461, 1376, 1260, 1097 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 8.06 (s, 1H), 5.19–
;
5.09 (m, 1H), 1.75–1.68 (m, 1H), 1.63-1.55 (m, 1H), 1.52–1.45 (m, 2H), 1.40–
0.85 (m, 12H), 0.88 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz,
3H), 0.83 (d, J = 6.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d = 160.9, 69.1, 45.4,
45.2, 42.9, 38.9, 29.6, 27.2, 26.4, 20.9, 20.5, 20.4, 20.2, 19.9, 14.4; HRMS (ESI):
calcd for C15H30O2 242.22403, found 242.28444; Compound 17: yellow oil,
½
a 2D5
ꢁ
= ꢀ30.9 (c = 0.8, CHCl3). IR (KBr):
t
max = 3448, 2956, 2923, 2853, 1784,
1698, 1634, 1459, 1383, 1099, 972, 765 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d = 7.26 (t, J = 7.3, 2H), 7.20 (t, J = 6.5 Hz, 1H), 7.14 (d, J = 7.3, 2H), 4.65–4.59 (m,
1H), 4.15–4.08 (m, 2H), 3.86–3.79 (m, 1H), 3.18 (dd, J = 13.7, 3.2 Hz, 1H), 2.69
(dd, J = 13.7, 9.7 Hz, 1H), 1.88–1.79 (m, 1H), 1.61–1.38 (m, 4H), 1.30–1.09 (m,
8H), 1.15 (d, J = 7.3 Hz, 3H), 0.89–0.75 (m, 6H), 0.81 (t, J = 6.5 Hz, 3H), 0.77 (d,
J = 6.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d = 177.3, 162.8, 135.2, 129.4, 128.9,
127.3, 65.9, 55.2, 46.5, 45.5, 45.3, 45.2, 40.4, 40.3, 29.6, 28.0, 27.2, 20.7, 20.5,
20.4, 20.0, 18.7, 14.4; Mass (ESI–MS) m/z: 424 [M + Na]+; Compound 2: yellow
oil, ½a 2D5
ꢁ
= ꢀ28 (c = 0.25, CHCl3). IR (KBr):
tmax = 2959, 2925, 1707, 1461, 1378,
7. Odham, G. Arkio Kemi 1963, 21, 379.
1227, 944, 889 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d = 2.63–2.52 (m, 1H), 2.01–
8. Mori, K.; Kuwahara, S. Liebigs Ann. Chem. 1987, 555–556.
9. (a) Mori, K.; Kuwahara, S. Tetrahedron 1986, 42, 5539–5544; (b) Kaino, M.;
Naruse, Y.; Yamamoto, H. Tetrahedron 1996, 52, 7297–7320; Feringa, B. L.;
Minnaard, A. J.; Harutyunyan, S. R.; Lopez, F.; Pullez, M.; Mazery, R. D. J. Am.
Chem. Soc. 2005, 127, 9966–9967; (c) Kaino, M.; Naruse, Y.; Yamamoto, H. J. Org.
Chem. 1990, 55, 5814–5815.
1.61 (m, 3H), 1.61–1.44 (m, 2H), 1.37–1.00 (m, 8H), 1.18 (d, J = 6.8 Hz, 3H), 0.98
(d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H), 0.87 (d, J = 6.0 Hz, 3H), 0.84 (t,
J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d = 183.4, 46.0, 45.2, 40.8, 39.1, 37.3,
29.7, 29.5, 28.5, 20.2, 20.1, 20.0, 19.4, 17.9, 14.4; HRMS (ESI): calcd for
C
15H31O2 243.23186, found 243.21023.
10. (a) Morr, M.; Proppe, C.; Wray, V. Liebigs Ann. Chem. 1995, 2001–2004; (b)
Morr, M.; Wray, V.; Fortkamp, J.; Schmid, R. D. Liebigs Ann. Chem. 1992, 433–
439.