Enantioselective total synthesis of cis-(+)- and trans-(+)-disparlure

Article abstract of DOI:10.1016/j.tetlet.2017.07.024

An expedient enantioselective synthetic approach for the gypsy moth sex-attractant pheromone cis-(+)-1 and trans-(+)-disparlure 2 is described employing the optimized combination of organocatalytic MacMillan's self aldol reaction, Wittig olefination, regioselective ring opening of an epoxide and Mitsunobu esterification reactions as key steps.

Full text of DOI:10.1016/j.tetlet.2017.07.024

Accepted Manuscript
Enantioselective total synthesis of cis-(+)- and trans-(+)-disparlure
Yuvraj Garg, Anand Kumar Tiwari, Satyendra Kumar Pandey
PII:
S0040-4039(17)30870-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.024
TETL 49106
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 June 2017
4 July 2017
5 July 2017
Please cite this article as: Garg, Y., Kumar Tiwari, A., Kumar Pandey, S., Enantioselective total synthesis of cis-
+)- and trans-(+)-disparlure, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.024
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Tetrahedron Letters
Enantioselective total synthesis of cis-(+)- and trans-(+)-disparlure
Yuvraj Garg, Anand Kumar Tiwari and Satyendra Kumar Pandey
School of Chemistry and Biochemistry, Thapar University, Patiala 147001, India
Dedicated to Dr. Pradeep Kumar (CSIR-NCL, Pune, India) on his 60th Birthday.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An expedient enantioselective synthetic approach for the gypsy moth sex-attractant pheromone
cis-(+)-1 and trans-(+)-disparlure 2 is described employing the optimized combination of
organocatalytic MacMillan’s self aldol reaction, Wittig olefination, regioselective ring opening
of an epoxide and Mitsunobu esterification reactions as key steps.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
sex-attractant pheromone
disparlure
MacMillan’s self aldol reaction
Wittig olefination
Mitsunobu esterification
Introduction
Therefore, cis-(+)-disparlure 1 has been used to confuse and
preventing male moths from locating and mating with females or
leading male moths into traps for the protection of forests. The
cis-(+)-disparlure 1 and its analogues (2-4) have been synthetic
targets of considerable interest for academia and agriculture due
to their astonishing biological properties combined with
attractive structural features. Various elegant syntheses of cis-
Over the last decades, cis-(+)-disparlure 1 has been used
worldwide as a pesticide against the gypsy moth, Lymantria disar
L., a widespread pest causing damage to the wild ecosystem of
5
1
Europe, Africa, and North America (Figure 1). The straight
chain lepidopteran sex pheromone cis-(+)-disparlure 1 was
isolated by Bierl and co-workers from the Porthetria disar L.,
(
+)-disparlure 1 and its analogues (2-4) mainly based on chiral
2
female gypsy moths. Iwaki and co-workers established the
6
pool approaches have been documented in the literature. Very
recently, Fernandes and co-workers reported the stereoselective
synthesis of cis-(+)-disparlure 1 and its analogues (2-3) using a
domino Pd-catalyzed recombinant -isomerization/Wacker
absolute configuration of cis-(+)-disparlure 1 via its synthesis
3
from (S)-glutamic acid. The cis-(+)-disparlure 1 is required for
the upwind flight of male moths to the pheromone releasing
females and binds selectively to PBP1 protein, while the cis-(-)-
disparlure 3 cancels the upwind flight behavior in the males
6a
oxidation reactions of -vinyl--butyrolactone as key steps. As
part of our research program towards the asymmetric synthesis of
4
which binds selectively to PBP2 protein of gypsy moth.
7
bioactive compounds, we report herein, a novel synthesis of cis-
(+)-1 and trans-(+)-disparlure 2 employing the MacMillan’s self
H
H
aldol reaction, Wittig olefination, regioselective ring opening of
an epoxide and Mitsunobu esterification reactions as key steps.
O
O
Results and Discussion
H
H
Our synthetic approach for the enantioselective synthesis of
disparlure (1-4) was envisioned via the retrosynthetic route as
shown in Scheme 1. The epoxide derivative 5 was visualized as a
synthetic intermediate from which disparlure (1-4) could be
synthesized via Grignard reaction followed by functional group
manipulations. The epoxide derivative 5 in turn could be
obtained from triol derivative 6 via terminal epoxide formation
and subsequent standard organic transformations. The triol
derivative 6 could be assembled from mono-protected terminal
alcohol 7 by oxidation followed by MacMillan’s self-aldol
(
R,S)-(+)-disparlure 1
(R,R)-(+)-disparlure 2
H
H
O
O
H
H
(
S,R)-(-)-disparlure 3
(S,S)-(-)-disparlure 4
Figure 1: Structures of stereoisomers of disparlures (1-4).
—
——

Corresponding author. Tel.: +91-175-239-3832; fax: +91-175-236-4498; e-mail: skpandey@thapar.edu

2
Tetrahedron Letters
reaction and subsequently Wittig olefination. All the
The cleavage of silyl ether in compound 9 with TBAF and
subsequent hydrogenation under 1 atm pressure in the presence
of a catalytic amount of Pd/C furnished the triol derivative 10 in
90% yield. Our next endeavour was to carry out the terminal
epoxide formation using 1,2-diol. Towards this end, triol 10 on
stereoisomers of disparlure (1-4) could be synthesized using this
approach by simply changing the L- and D-proline, respectively,
during organocatalyzed MacMillan’s self aldol reaction and/or by
Mitsunobu inversion reaction.
3
base catalyzed selective monotosylation with TsCl/NEt in the
presence of catalytic amount of dibutyltin oxide followed by base
treatment delivered the terminal epoxide 11 in 76% yield. The
free hydroxyl group of compound 11 on treatment with p-
nitrobenzoic acid (PNBA) and diisopropyl azodicarboxylate
H
O
O
*
*
* *
OTBS
H
(DIAD) under the Mitsunobu esterification conditions
disparlure
OH
5
successfully furnished the ester 12, which on basic hydrolysis
synthesized the inverted alcohol 13 in 95% yield. Treatment of
alcohol 13 with TBSCl using the basic conditions of
imidazole/DMAP synthesized the protected derivative 14 in 89%
yield. The epoxide 14 on Cu(I)-catalyzed regioselective ring-
TIPSO
HO
OH
*
*
OH
6
7
o
opening with iso-hexylMgBr at -60 C, furnished the alcohol 15
in 81% yield. Finally, the free hydroxyl group of compound 15
was subjected to O-tosylation using TsCl/DMAP and subsequent
silyl ether cleavage using TBAF delivered the sex pheromone
Scheme 1: Retrosynthetic approach for disparlure (1-4).
2
5
6a
As outlined in Scheme 2, the synthesis of cis-(+)-disparlure 1
commenced with readily available monosilylated ethylene glycol
cis-(+)-disparlure 1 in 85% yield {[α]
1.6 (c 1.1, CCl )]}. The spectroscopic and physical data of cis-
+)-disparlure 1 were found to be in full accordance with those
D
4
+1.2 (c 1.1, CCl ) [Lit.
+
4
7
, which can be easily synthesized from base catalyzed selective
(
3
,6
protection of ethylene glycol with TIPSCl. Oxidation of
documented in the literature.
8
monosilylated alcohol 7 under Swern conditions, subsequent
For synthesis of trans-(+)-disparlure 2, the free hydroxyl group
of compound 11 on treatment with TBSCl under the basic
conditions of imidazole/DMAP furnished the silyl ether
derivative 16 in 87% yield (Scheme 3). The trans-(+)-disparlure
asymmetric MacMillan’s self aldol reaction in the presence of
catalytic amount of L-proline afforded the anti-diastereomer 8 as
the major product along with its column separable syn-
diastereomer in 4:1 ratio and 90% combined isolated yield,
9
2
was synthesized from compound 16 following an analogous
following the known literature procedure. With enantiomerically
25
series of reactions as shown in Scheme 2, {[α]
CCl
D
+27.8 (c 0.5,
)]}. The spectroscopic and physical
pure anti-diastereomer 8 in hand, it was then subjected to Wittig
olefination with (nonyl)triphenylphosphonium bromide using
KHMDS to furnish the olefin 9 in 65% yield. Since the incipient
olefin would be eventually hydrogenated for the synthesis of the
target compound, we did not analyse the olefin geometry of 9.
3
4
) [Lit. +27.5 (c 0.5, CCl
4
data of trans-(+)-disparlure 2 were found to be in full accordance
3,6
with the literature data.
OH
OH
a
b
c
TIPSO
TIPSO
TIPSO
OH
O
OTIPS
OTIPS
7
8
9
OH
d
O
e
O
f
g
HO
OH
OR
OH
10
11
12 R = COC H NO
6 4
2
1
3 R = H
H
TBSO
HO
O
h
i
O
OTBS
H
14
15
cis-(+)-disparlure 1
o
Scheme 2: Reagents and conditions: (a) i) (COCl)
2
, DMSO, NEt
3
, CH
2
Cl
2
, -78 C, 2 h, ii) L-proline (10 mol%), DMF, rt, 24 h, 72%; (b)
, Pd/C, EtOAc, rt, 8 h, 90% (over two steps); (d)
O, rt, 12 h, 76% (over two steps); (e) PPh , PNBA, DIAD,
O (3:2:1), rt, 1 h, 95%; (g) TBSCl, imidazole, DMAP, dry CH
o
KHMDS, C
i) TsCl, NEt
9
H
19PPh
3
Br, THF, -78 C to rt, 4 h, 65%; (c) i) TBAF, THF, rt, 12 h; ii) H
2
o
3
, Bu
2
SnO (10 mol%), dry CH
2
Cl
2
, 0 C to rt, 2 h, ii) KOH, Et
2
3
o
o
toluene, 0 C to rt, 2 h, 97%; (f) LiOH.H O, THF:MeOH:H
2
2
2
Cl
2
, 0 C to
o
o
rt, 14 h, 89%; (h) iso-hexylMgBr, dry THF, CuI, -60 C, 6 h, 81%; (i) i) TsCl, DMAP, dry CH Cl , 0 C to rt, 24 h, ii) TBAF, THF, rt, 6
2 2
h, 85% (over two steps).

4
5
.
.
Plettner, E.; Lazar, J.; Prestwich, E. G.; Prestwich, G. D. Biochemistry
2000, 39, 8953.
(a) Vergassola, M.; Villermaux, E.; Shraiman, B. I. Nature 2007, 445,
O
a
O
b
4
2
06; (b) Miller, J. R.; Mori, K.; Roelofs, W. L. J. Insect Physiol. 1977,
3, 1447.
OH
OTBS
11
16
6.
(a) Bethi, V.; Kattanguru, P.; Fernandes, R. A. Eur. J. Org. Chem. 2014,
3
3
2
249; (b) Zhigang, W.; Jianfeng, Z.; Peiqiang, H. Chin. J. Chem. 2012,
0, 23; (c) Dubey, A. K.; Chattopadhyay, A. Tetrahedron: Asymmetry
011, 22, 1516; (d) Chen, H.; Gong, V.; Gries, R.; Plettner, E. Bioorg.
H
O
TBSO
HO
c
Med. Chem. 2010, 18, 2920; (e) Kim, S. G. Synthesis 2009, 14, 2418;
f) Kovalenko, V. N.; Masalov, N. V.; Kulinkovich, O. G. Russ. J. Org.
Chem. 2009, 45, 1318; (g) Prasad, K. R.; Anbarasan, P. J. Org. Chem.
007, 72, 3155; (h) Zhang, C. X.; Da, S. J.; Zhang, H. B.; Sun, B.; Li,
(
H
2
1
7
trans-(+)-disparlure 2
Y. Acta Chim. Sinica 2007, 65, 2433; (i) Inkster, J. A. H.; Ling, I.;
Honson, N. S.; Jacquet, L.; Gries, R.; Plettner, E. Tetrahedron:
Asymmetry 2005, 16, 3773; (j) Koumbis, A. E.; Chronopoulos, D. D.
Tetrahedron Lett. 2005, 46, 4353; (k) Hu, S.; Jayaraman, S.;
Oehlschlager, A. C. J. Org. Chem. 1999, 64, 3719; (l) Li, L. H.; Wang,
D.; Chan, T. H. Tetrahedron Lett. 1997, 38, 101; (m) Tsuboi, S.;
Yamafuji, N.; Utaka, M. Tetrahedron: Asymmetry 1997, 8, 375; (n) Ko,
S. Y. Tetrahedron Lett. 1994, 35, 3601; (o) Brevet, J. L.; Mori, K.
Synthesis 1992, 1007; (p) Mori, K.; Takigawa, T.; Matsui, M.
Tetrahedron 1979, 35, 833; (q) Mori, K.; Takigawa, T.; Matsui, M.
Tetrahedron Lett. 1976, 44, 3953.
(a) Gahalawat S.; Pandey, S. K. Org. Biomol. Chem. 2016, 14, 9287; (b)
Kaur R.; Garg Y.; Pandey, S. K. ChemistrySelect 2016, 1, 4286; (c)
Kaur R.; Pandey, S. K. Tetrahedron: Asymmetry 2016, 27, 338; (d)
Garg Y.; Pandey, S. K. RSC Adv. 2016, 6, 25913; (e) Gahalawat S.;
Garg Y.; Pandey, S. K. Asian J. Org. Chem. 2015, 4, 1025; (f)
Gahalawat S.; Pandey, S. K. RSC Adv. 2015, 5, 41013; (g) Garg, Y.;
Gahalawat S.; Pandey, S. K. RSC Adv. 2015, 5, 38846; (h) Garg Y.;
Pandey, S. K. J. Org. Chem. 2015, 80, 4201.
Scheme 3. Reagents and conditions: (a) TBSCl, imidazole,
Cl , 0 C to rt, 14 h, 87%; (b) iso-hexylMgBr,
dry THF, CuI, -60 C, 6 h, 85%; (c) i) TsCl, DMAP, dry CH
o
DMAP, dry CH
2 2
o
2 2
Cl ,
o
0
C to rt, 24 h, ii) TBAF, THF, rt, 6 h, 84% (over two steps).
In conclusion, enantioselective synthesis of cis-(+)-1 and
trans-(+)-disparlure 2 have been achieved from readily available
starting materials employing the organocatalyzed MacMillan’s
self aldol reaction, Wittig olefination, regioselective ring opening
of an epoxide and Mitsunobu esterification reactions as key steps.
Moreover, the synthetic strategy described has significant
potential for stereochemical variation and gives further access to
other stereoisomers as well as various other analogues of
disparlure.
7
8
.
.
(a) Tidwell, T. T. Synthesis 1990, 10, 857; (b) Tidwell, T. T. Org.
React. 1990, 39, 297.
Acknowledgments
9.
Northurp, A. B.; Mangoin, I. K.; MacMillan, D. W. C. Angew. Chem.,
Int. Ed., 2004, 43, 2152.
S.K.P. is thankful to Department of Science and Technology,
New Delhi, for generous funding of the project (Grant No.
EMR/2016/003649). Y.G. thanks UGC, New Delhi for a senior
research fellowship.
Supplementary Material
Supplementary Supplementary material (detailed experimental
and spectral analysis) associated with this article can be found in
the online version, at http://....
References and notes
1
.
Montgomery, M. E.; Wallner, W. E. In Dynamics of Forest Insect
Populations. Patterns, Causes, Implications; Berryman, A. A., Ed.;
Plenum: New York, 1988; p 353.
.
2
3
.
.
(a) Bierl, B. A.; Beroza, M.; Collier, C. W. J. Econ. Entomol. 1972, 65,
6
59; (b) Bierl, B.; Beroza, M.; Collier, C. W. Science 1970, 170, 87.
Iwaki, S.; Marumo, S.; Saito, T.; Yamada, M.; Katagiri, K. J. Am.
Chem. Soc. 1974, 96, 7842.
4
. Regioselective ring opening of an epoxide
and Mitsunobu esterification reactions
Highlights
1
2
3
. cis-(+)-Disparlure, a female gypsy moths
sex pheromone
. A concise and efficient asymmetric general
approach for disparlure
. Organocatalytic MacMillan’s self aldol
reaction and Wittig olefination key steps

4
Tetrahedron Letters