Enantiospecific synthesis of sex pheromone of the obscure mealybug from pantolactone via tandem conjugate addition/cyclization

Article abstract of DOI:10.1016/j.tetlet.2010.07.166

An efficient synthesis of an enantiomer of insect's natural pheromone is reported starting from chiral pool d-(-)-pantolactone. Highly stereoselective tandem conjugate addition/cyclization sequence and hydrogenation of exocyclic double bond are the key st

Full text of DOI:10.1016/j.tetlet.2010.07.166

Tetrahedron Letters 51 (2010) 5291–5293
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Tetrahedron Letters
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Enantiospecific synthesis of sex pheromone of the obscure mealybug from
pantolactone via tandem conjugate addition/cyclization
*
Atul K. Hajare, Laxmikant S. Datrange, Samir Vyas, Debnath Bhuniya, D. Srinivasa Reddy
Discovery Chemistry, Advinus Therapeutics Pvt. Ltd, Quantum Towers, Plot No. 9, Rajiv Gandhi Infotech Park, Phase-I, Hinjewadi, Pune 411057, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of an enantiomer of insect’s natural pheromone is reported starting from chiral pool
Received 29 June 2010
Revised 27 July 2010
Accepted 29 July 2010
Available online 5 August 2010
D
-(ꢀ)-pantolactone. Highly stereoselective tandem conjugate addition/cyclization sequence and hydroge-
nation of exocyclic double bond are the key steps in the present synthesis.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pheromone
Enantiospecific synthesis
Tandem reaction
Pantolactone
Synthesis of pheromones is an important and exciting area in
organic chemistry which helps in establishing their stereochemical
assignments. The synthesis also provides sufficient quantities to
carry out extensive biological tests, as pheromones are available
in limited quantities from nature (usually in microgram). While
constructing such low molecular weight pheromones, several
stereoselective methods have been reported in the literature.1
Recently, pioneering work from Millar’s group led to the identifica-
tion,2 the diastereoselective racemic synthesis,3 and the determi-
nation of absolute configuration using vibrational circular
dichroism (VCD)4 of 1S,2S,3R-1-acetoxymethyl-2,3,4,4-tetrameth-
ylcyclopentane (+)-1 (Fig. 1). This powerful sex pheromone (+)-1
was isolated from the female mealybug, Pseudococcus viburni
(Homoptera: Pseudoccidae), a common and widely distributed
pest that damages a range of economically important plants like
grape vines, glasshouse crops, and ornamental plants. Soon after
Millar’s synthesis, the first and unique enantioselective synthesis
of (+)-1 was reported by Kuwahara’s group.5 The interesting chem-
ical structure of 1 and its potential use in pest management
prompted our efforts toward its synthesis. Herein, we disclose
the first enantiospecific synthesis of (ꢀ)-1 starting from an inex-
pensive and commercially available
D
-(ꢀ)-pantolactone.6
We set out to synthesize the sex pheromone (ꢀ)-1 as a means of
developing chemistry that might be useful for more complex nat-
ural products. Retrosynthetically, the pheromone (ꢀ)-1 could be
prepared from the final precursor 2 through stereoselective hydro-
genation of the exocyclic double bond which in turn can be ob-
tained from 3. The intermediate 3 could be derived from an
acyclic intermediate 4 through a tandem intermolecular conjugate
addition followed by intramolecular cyclization. The intermediate
OAc
COOEt
(-)-1
BnO
OAc
OAc
2
3
1
4
2
3
5
"Me"
conjugate
addition
COOEt
O
O
cyclization
(+)-1
(-)-1
Figure 1. Structures of both enantiomers of sex pheromone.
HO
BnO
OTs
* Corresponding author. Tel.: +91 20 66539600; fax: +91 20 66539620.
E-mail addresses: dsrinivas.reddy@advinus.com, dsreddy88@yahoo.com (D.S.
Reddy).
4
(-)-Pantolactone
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.166

5292
A. K. Hajare et al. / Tetrahedron Letters 51 (2010) 5291–5293
Nu
H
OTBDPS
OTBDPS
OBn
a
b
3
COOEt
H
OBn
EtO
OTs
BnO
O
TMSO
8
9
OTs
OTBDPS
OTBDPS
A
c
d
e
TMSO
OEt
(-)-1
COOEt
BnO
OTs
10
11
BnO
Scheme 3. Reagents and conditions: (a) (i) LiAlH4, THF, 0 °C, 0.5 h, 95%; (ii) TBDPSCl,
imidazole, py, rt, 93%; (b) (i) 10% Pd/C, H2, MeOH, 91%; (ii) Dess–Martin
periodinane, DCM, 0 °C, 1 h, 89%; (c) Tebbe’s reagent, THF, 0 °C, 45 min, 89%; (d)
Rh(PPh3)3Cl, H2, THF-tBuOH (1:1), rt; 85%; (e) (i) TBAF, THF, 60 °C, 1 h; 86%; (ii)
Ac2O, py, DMAP, DCM, rt, 1 h, 87%.
3
B
Figure 2. Plausible explanation for the observed stereoselectivity.
COOEt
COOEt
HO
BnO
O
was not possible in our hands. The formation of desired olefin 2
was observed using Tebbe’s reagent, however, we could not isolate
it in pure form due to its volatile nature.
a
b
BnO
OTs
BnO
To circumvent this problem, we have protected the primary alco-
hol obtained from 3 with bulky TBDPS group to provide 8. Deprotec-
tion of benzyl group followed by oxidation resulted in ketone 9,
which was subjected to Tebbe’s olefination to furnish the compound
10. After several attempts,13 it was found that hydrogenation of the
exocyclic double bond using Wilkinson’s catalyst furnished the de-
sired stereoisomer 11 in a highly diastereoselective fashion (>95%
de, judged by NMR).14 Removal of TBDPS group in 11 using TBAF
and acetylation of resulting primary alcohol furnished the target
compound pheromone (ꢀ)-1 (Scheme 3). The spectral data (1H
and 13C NMR) of the synthetic pheromone (ꢀ)-1 from our lab were
compared with that of synthetic (+)-1 from Kuwahara’s group5 and
both were found identical. Specific rotation of our sample (ꢀ)-1
5
4
3
OAc
OAc
c
d
(-)-1
BnO
O
6
7
Scheme 2. Reagents and conditions: (a) (i) Ph3P = CHCOOEt, toluene, reflux, 8 h, 75%;
(ii) TsCl, py, DMAP, rt, 24 h, 88%; (b) Me2CuLi, TMSCl, ꢀ78 °C to rt, THF, 24 h, 94%;
(c) (i) LiAlH4, THF, 0 °C, 0.5 h, 95%; (ii) Ac2O, DMAP, py, DCM, rt, 92%; (d) (i) 10% Pd/
C, H2, MeOH, 24 h, 96%; (ii) Dess–Martin periodinane, DCM, 0 °C, 1 h, 93%.
showed ½a 2D4:5
ꢀ8.96 (c 0.50, CDCl3) compared to that of natural
ꢁ
4 could be prepared from commercially available
tone using routine functional group transformations (Scheme 1).
D
-(ꢀ)-pantolac-
enantiomer ½a D23:3
ꢁ
+9.1 (c 0.4, CDCl3)4 and ½a D27
ꢁ
+15.1 (c 1.50, CDCl3).5
The natural enantiomer (+)-1 can be synthesized starting from cor-
Our synthesis commenced from the benzyl-protected lactol 5
responding L-(+)-pantolactone in a similar manner.
obtained from commercially available
tol 5 was transformed into an acyclic
D
-(ꢀ)-pantolactone.7 The lac-
In short, we have achieved the enantiospecific synthesis of
a,b-unsaturated ester 4 (pure
(ꢀ)-1, an isomer of insect’s natural sex pheromone starting from
E-isomer) using Horner–Wittig olefination followed by tosylation of
resulting primary alcohol. Having 4 in hand, the desired conjugate
addition followed by cyclization was carried out using Me2CuLi/
TMSCl to furnish the cyclopentane derivative 3 in excellent
yield.5,8–10 The cyclic compound 3 was characterized by NOE and
1H–1H COSY NMR experiments. The stereoselectivity obtained dur-
ing the conjugate addition could be explained by the modified Fel-
kin–Anh model.8c The transition state/intermediate is proposed as
shown in Figure 2, where the attack of a nucleophile (cuprate) re-
sults in an anti (or in our cyclic case, syn) relationship between ben-
zyloxy and the newly formed adjacent stereocenter. In the case of
cyclization, simple thermodynamic stability may be providing the
desired selectivity and probably the Thorpe–Ingold effect (gem-di-
methyl effect on cyclization) driving the reaction.12 The pleasing
outcome from this reaction is the very high diastereoselectivity dur-
ing both carbon–carbon bond-forming reactions, which installed
two required chiral centers in one-pot for the synthesis of (ꢀ)-1.11
The similar observations were made by Kuwahara’s group, however,
it was derived in two independent steps on related substrates.5
The primary alcohol obtained by LAH reduction of ester 3 was
acetylated to provide compound 6. Debenzylation (10% Pd/C, H2)
followed by oxidation using Dess–Martin’s reagent resulted in ke-
tone 7 in very high yield (Scheme 2). Olefination of ketone 7 fol-
lowed by reduction of the double bond would have provided the
final compound (ꢀ)-1, however, despite several attempts this
readily available
D
-(ꢀ)-pantolactone chiral pool. An unprecedented
tandem sequence of conjugate addition followed by cyclization
using Me2CuLi and a stereoselective reduction of exocyclic olefin
are the key steps in our synthesis. This diastereoselective tandem
sequence can be applied to the synthesis of more complex natural
products.
Acknowledgments
We are grateful to Drs. Rashmi Barbhaiya, Kasim Mookhtiar,
and Venkata P. Palle for their support and encouragement.
Supplementary data
Supplementary data (general methods, experimental details and
analytical data for compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.07.166.
References and notes
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cyclopentanecarboxylic acid ethyl ester (3). To a stirred suspension of CuI (6.4 g,
33.6 mmol) in THF (50 ml) was added methyl lithium (5% in diethyl ether,
20 ml, 44.8 mmol) at ꢀ78 °C, and the resulting mixture was stirred for 1 h.
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ester 3 as a colorless oil. ½a D24:3
ꢁ
ꢀ12.8 (c 0.60, CHCl3); IR (CHCl3) 1730 cmꢀ1
;
1H
NMR (400 MHz, CDCl3) d 1.04 (s, 3H), 1.07 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.25
(t, J = 7.2 Hz, 3H), 1.62 (dd, J = 7.6, 13.2 Hz, 1H), 1.88 (dd, J = 9.6, 13.2 Hz, 1H),
2.50–2.69 (m, 2H), 3.34 (d, J = 5.6 Hz, 1H), 4.12 (d q, J = 1.2, 6.8 Hz, 2H), 4.55 (s,
2H), 7.28–7.37 (m, 5H); 13C NMR (100 MHz, CDCl3) d 14.4, 14.8, 23.8, 29.2, 41.4,
42.1, 43.5, 49.1, 60.3, 74.2, 91.0, 127.5, 127.7, 128.3, 139.1, 176.6; LCMS = 291.3
(M+1); HRMS (ESI): m/z calculated for
C
18H27O3[M+H]+ 291.1960, found
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291.1965. See Supplementary data for other experimental procedures.
11. See Supplementary data for details and copies of NMR spectra.
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13. Hydrogenation using Adam’s catalyst (PtO2) gave 60:40 diastereoselectivty.
14. The olefin was hydrogenated using 10 mol % of chlorotris(triphenylphosphine)-
rhodium(I) catalyst in 1:1 mixture of THF:tBuOH under hydrogen-balloon
pressure.