Highly stereoselective allylic ethylation with alkoxytitanacyclopropane reagents. Synthesis of (1R/S,7R)-1,7-dimethylnonyl propanoate, the Western corn rootworm sex attractant

Article abstract of DOI:10.1016/j.tetlet.2008.08.063

Allylic ethylation of 2-((E)-dodec-2-en-4-yloxy)tetrahydro-2H-pyran with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide proceeds via a S_N2′ pathway to afford (E)-3-methyltridec-4-ene with excellent syn-diastereoselecivity. This transformation is used as a key step in the synthesis of (1R/S,7R)-1,7-dimethylnonyl propanoate, the Western corn rootworm (Diabrotica virgifera virgifera) sex attractant.

Full text of DOI:10.1016/j.tetlet.2008.08.063

Tetrahedron Letters 49 (2008) 6959–6961
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Highly stereoselective allylic ethylation with alkoxytitanacyclopropane
reagents. Synthesis of (1R/S,7R)-1,7-dimethylnonyl propanoate,
the Western corn rootworm sex attractant
Vladimir E. Isakov, Oleg G. Kulinkovich *
Department of Organic Chemistry, Belarusian State University, Nezavisimosti Av. 4, Minsk 220030, Belarus
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2008
Revised 11 August 2008
Accepted 19 August 2008
Available online 23 August 2008
Allylic ethylation of 2-((E)-dodec-2-en-4-yloxy)tetrahydro-2H-pyran with ethylmagnesium bromide in
0
the presence of titanium(IV) isopropoxide proceeds via a S
N
2 pathway to afford (E)-3-methyltridec-4-
ene with excellent syn-diastereoselecivity. This transformation is used as a key step in the synthesis of
1R/S,7R)-1,7-dimethylnonyl propanoate, the Western corn rootworm (Diabrotica virgifera virgifera) sex
attractant.
(
Ó 2008 Published by Elsevier Ltd.
Keywords:
Alkoxytitanacyclopropane reagents
Allylic ethers
Allylic ethylation
Diastereoselectivity
Pheromones
The development of efficient methods for the preparation of
chiral allylic alcohols and their derivatives2 increases the syn-
the substrate 1 with alkoxytitanacyclopropane species A, followed
by transformation of the resulting complex B to titanacyclopentane
ate-complex C, intramolecular 1,2-elimination of a metal oxide
fragment, and disproportionation of dialkyltitanium intermediate
1
thetic importance of stereoselective carbon–carbon bond forming
0
reactions. Highly anti-S
N
2
stereoselective alkylations of allylic
2k–o
7a
esters have been observed in copper-catalyzed
and hetero-
D (Scheme 1). Among the compounds 1a–c, only tetrahydro-
atom-assisted noncatalyzed reactions of organomagnesium com-
pounds. In contrast, the use of o-diphenylphosphanylbenzoate
pyranyl derivative 1c gave alkene
diastereoselectivity.
2
with high trans-
3
as a reagent-directing leaving group permits reactions of the
corresponding allylic esters with organomagnesium compounds
Herein, we report the trans-diastereoselectivity of the allylic
ethylation of tetrahydropyranyl derivative 1c combined with high
0
2p–s
in a highly syn-S
N
2 stereoselective fashion.
Herein, we disclose
1,3-asymmetric induction during the formation of a stereogenic
0
the ability of a tetrahydropyranyloxy group to play the same
directing role toward alkoxytitanacyclopropane reagents. As an
application of this method of regio- and diastereoselective
ethylation of THP-protected allylic alcohols, we have synthesized
center in a syn-S
N
2 stereoselective fashion. Thus, treatment of a
8
0.4 M solution of allylic alcohol (2E,4R)-1a (ee 88%) and tita-
nium(IV) isopropoxide in ether with a 1.2 M solution of ethylmag-
nesium bromide gave alkene (3R,4E)-2 with a de of 15% and an ee
of 14%, whereas its THP analogue (2E,4R)-1c (a mixture of diaste-
reomers) afforded the same product with much better stereoselec-
tivity (de 90%, ee 69%). The concentration of the reagent solutions
influenced the stereoselective formation of the stereogenic center
significantly. Thus, the use of fourfold diluted solutions of tetrahy-
dropyranyl derivative 1c, titanium(IV) isopropoxide, and ethyl-
magnesium bromide led to the formation of alkene (3R,4E)-2
(
1R/S,7R)-1,7-dimethylnonyl propanoate 3, the Western corn root-
4
worm sex attractant.
Recently, we reported that interaction of racemic allylic alco-
hols and their ethers with alkoxytitanacyclopropane reagents, gen-
5
,6
erated in situ by treatment of titanium(IV) alkoxides
with
0
ethylmagnesium bromide, afforded the products of S
N
2 substitu-
7
tion of hydroxy or alkoxy groups with an ethyl group. For exam-
ple, allylic alcohol 1a and its derivatives 1b,c were converted
under these conditions into methyl-branched alkenes 2. The
suggested mechanism of the reaction includes coordination of
9
0
with de 90% and ee 87%, corresponding to 99% syn-S 2 chirality
N
transfer (Scheme 2). The enantiomeric purity and absolute config-
uration of the mixture of alkenes 2 obtained were ascertained by
ozonolysis, followed by reduction with sodium borohydride and
1
analysis of the H NMR spectrum of the (+)-MTPA ester of the
*
Corresponding author. Tel.: +375 17 2095459; fax: +375 17 2265609.
1
0,11
E-mail address: kulinkovich@bsu.by (O. G. Kulinkovich).
resulting 2-methylbutanol (Scheme 2).
0
040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.08.063

6
960
V. E. Isakov, O. G. Kulinkovich / Tetrahedron Letters 49 (2008) 6959–6961
EtMgBr, Ti(Oi-Pr) , Et O
TiLn,
A
OR
C H
4
2
C H
8
17
8
17
1
2
(E)-
2,(de) Yield 2,(%)[7a]
R
A
1
a
H
15
87
72
71
A
1
1
b
c
Me
40
90
THP
EtMgBr
-
TiLn
TiLn
TiLn
C H
C H
8
17
MgBr+
-
BrMgOMLm
OMLm
OMLm
H17C8
8
17
B
C
D
M = Mg or Ti, L = Oi-Pr or another ligand
Scheme 1.
O
O
O
TiL , EtMgBr
n
O
H
O
+MgBr
C H
8 17
O
A
C H
8
17
C H
8
17
syn-S 2`
TiLn
-
H
+MgBr
TiLn
N
-
H
skew-(2
E R)-1c
,4
E
F
ee
(R) 88%
syn-1,2-elimination
anti-1,2-elimination
o
1
. O , -70 C
MeO CF3
3
O
2. NaBH
3
4
C H
8 17
Ph
. (+)-MTPA Cl
O
+
C H
8
17
ee
(R
) 87%
(3R,4E
)-2
(3R,4Z)-2
Scheme 2.
The conversion of allylic alcohol derivative (2E,4R)-1c to the
synthetic applications. In this work, we employed this transforma-
tion in the synthesis of propanoate (1R/S,7R)-3, the pheromone of
the Western corn rootworm (Diabrotica virgifera virgifera). The
attractive activity of this compound in field testing was comparable
alkenes 2 with (R) configuration at the stereogenic center at C-3
corresponds to addition of alkoxytitanacyclopropane reagent A to
the disubstituted double bond in syn-fashion with respect to the
leaving THPO-group in a skew-conformation12 of the substrate.
Such a stereochemical pathway of the reaction suggests the forma-
tion of putative tricyclic complex E, where the octyl substituent
occupies the less hindered exo-position (Scheme 2). It should be
4
with the activity of the natural pheromone (1R,7R)-3 (Scheme 3).
rac-Alcohol 4 was prepared by the reaction of crotonic aldehyde
with 4-(tetrahydro-2H-pyranyl-2-oxy)pentylmagnesium chloride
(5). After resolution of rac-4 by stoichiometric Sharpless asymmet-
1
3
mentioned that the allylic ethylation of compound 1c proceeded
ric epoxidation, alcohol (2R/S,6R)-4 was obtained with ee 90%
0
14
with higher syn-S
N
2 stereoselectivity than trans-stereoselectivity
(Scheme 3). Protection of the hydroxyl group in the latter and
(
99% and 90%, correspondingly), evidencing the ability for forma-
treatment of resulting THP-ether 7 with an excess of ethylmagne-
sium bromide in the presence of 1 equiv of titanium(IV) isopropox-
ide led to olefin (2R/S,8R)-6 (de 90%, ee 89%) in 70% yield.15
Palladium-catalyzed hydrogenation of the double bond in (2R/
tion of (3R,4Z)-olefin 2 via an anti-1,2-elimination of the metal
oxide fragment in titanacyclopentane intermediate F.
As mentioned above, the ready availability of chiral allylic alco-
hols1 makes the allylic ethylation of their THP derivatives with
alkoxytitanacyclopropane reagents A a potentially useful tool for
16
S,8R)-6, followed by deprotection and esterification of alcohol
1
7
4,18
(2R/S,8R)-8 led to the target propanoate (1R/S,7R)-3.

V. E. Isakov, O. G. Kulinkovich / Tetrahedron Letters 49 (2008) 6959–6961
6961
THPO
1
. (
Ti(O
L
)-(+)-DIPT,
ClMg
(
)3
EtMgBr,
Ti(Oi
-Pr)4
i
-Pr)4, -BuO H
t
2
OH OTHP
THPO
OTHP
5
2. DHP, PPTS
CHO
(
)3
( )3
)-7
80%
29%
70%
4
(2R/S,6
R
1
2
. H , Pd / C, EtOH
2
. PPTS, EtOH, 50 C
OTHP
)3
OH
( )5
OCOEt
o
EtCOCl, NEt3
89%
(
( )5
90%
(2R/S,8R
)-6
(2R/S,8
R
)-8
(1R/S,7R)-3
ee (8 ) 89%
R
Scheme 3.
In conclusion, we have reported a highly stereoselective syn-
2 allylic ethylation reaction of the THP-derivatives 1c and 7 with
alkoxytitanacyclopropane reagents and the use of this transforma-
tion in the key step of the synthesis of (1R/S,7R)-1,7-dimethylnonyl
propanoate, the Western corn rootworm sex attractant.
1991, 27, 1249; (d) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A. Synthesis
1991, 234.
For reviews, see: (a) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100,
0
S
N
6
7
.
.
2789; (b) Kulinkovich, O. G. Izv. AN Ser. Chim. 2004, 1022; Russ. Chem. Bull., Int.
Ed. 2004, 1065.
(a) Kulinkovich, O. G.; Epstein, O. L.; Isakov, V. E.; Khmel‘nitskaya, E. A. Synlett
2
001; (b) Kulinkovich, O. G. Pure Appl. Chem. 2000, 72, 1715; (c) Matyushenkov,
E. A.; Churikov, D. G.; Sokolov, N. A.; Kulinkovich, O. G. Zh. Org. Khim. 2003, 39,
14.
5
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8
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4
2
(
1
1
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2
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4
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2
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1
H NMR spectroscopy after the
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2
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4
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4
,
(
2
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3
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1
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.
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4
ꢁ
1
(
8
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4
8
8b–d
2
5
.
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