S. Zhang et al. / Tetrahedron Letters 53 (2012) 1882–1884
1883
O
P
O
O
O
or
or
CO2R''
O
or
or
O
RO
RO
Li
Me
R'O2C
+
O
O
O
H
4b
4a
4c
4e
4d
dihydrocitronellal (3)
phosphonates or various nucleophiles used
HWE reaction or
the most commonly
employed approaches
aldehyde addition reaction
to form C4-C5 olefin
---Low 2E : 2Z ratio
ketone addition reaction
to form C2-C3 Olefin
---Low 2E : 2Z ratio
Disconnection A
O
O
5
3
5
+
Suzuki-Miyaura
O
2
cross-coupling
to form C3-C4 bond
---High 2E : 2Z ratio
4
6
LiCH2COOLi
or
(S)-hydroprene (1)
Disconnection B
BrMg
OEt 7
Disconnection C
This work
O
Br
+
B(OH)2
COOMe
TfO
O
8
10
11
9
Scheme 1. Previous synthetic strategies toward the synthesis of (S)-hydroprene and our retrosynthetic ananlysis.
presence of NMP,16 followed by LiAlH4 reduction/Swern oxidation
to furnish aldehyde 12 in high yield. Treatment of 12 with trip-
henylphosphite and bromine17 gave gem-dibromide 13 in an 88%
yield, which was eliminated with potassium 3-aminopropylamide
(KAPA)18 to afford terminal alkyne 10 in nearly quantitative yield,
with no isomerized internal alkyne detected. Hydroboration of
terminal alkyne 10 with HBBr2ÁSMe219 followed by in situ hydroly-
sis of the resulting dibromoborane produced the desired (E)-
alkenylboronic acid 9.20 As anticipated, the Suzuki–Miyaura
cross-coupling reaction between (E)-alkenylboronic acid 9 and
the known (E)-enol triflate 8 (E:Z = 24:1, prepared in an 82% yield
from 4c according to the literature procedure12) led to the target
molecule, (S)-hydroprene in a 79% yield (starting from 10).21 As de-
duced from 1H NMR, the ratio of (S)-hydroprene and its (2Z,4E)-iso-
mer was 22:1, which was in accordance with the E:Z ratio of the
(E)-enol triflate 8 used, indicating no isomerization of C2–C3 olefin
taking place in our key cross-coupling reaction.
In conclusion, we have developed a highly stereoselective syn-
thesis of the insect growth regulator (S)-(+)-hydroprene in seven
steps with a 50% overall yield starting from the easily available
bromoester 11. The synthesis reported herein is concise and effi-
cient and features Suzuki–Miyaura cross-coupling reaction as the
key transformation. This synthetic strategy should be applicable
to the stereocontrolled synthesis of other 2E,4E-dodecadienoates,
such as Methoprene, isopropyl (E,E)-11-methoxy-3,7,11-tri-
methyl-2,4-dodecadienoate, an active ingredient in Precor to
prevent indoor flea infestations.
a
Br
O
COOMe
11
12
b
c
Br
10
Br
13
d
OH
B
8
e
+
(S)-hydroprene
OH
9
Scheme 2. Stereoselective synthesis of (S)-hydroprene. Reagents and conditions:
(a) (i) isoamylMgBr, Li2CuCl4, NMP, THF, 86%; (ii) LAH, Et2O, 96%; (iii) Swern
oxidation, 88%; (b) P(OPh)3, Et3N, Br2, DCM, 88%; (c) H2N(CH2)3NH2, KH, 99%; (d) (i)
Br2BHÁSMe2, DCM; (ii) Et2O, H2O; (e) Na2CO3, Pd(PPh3)4, dioxane-H2O, 80 °C, 79%
from 10.
Therefore, an efficient method for the stereocontrolled synthesis of
(S)-(+)-hydroprene is still needed.
Transition-metal catalyzed cross-coupling reaction offers a ste-
reospecific way for the formation of the Csp2–Csp2 bonds.9 Among
the most versatile C–C bond forming cross-coupling reactions, Su-
zuki–Miyaura cross-coupling10 has been used much more exten-
sively in both academia and industry for its mild reaction
conditions and the easy, safe preparation and handling of boron-
containing chemicals.11 In the context of hydroprene synthesis,
we envisioned that the above mentioned stereocontrolled con-
struction of (S)-(+)-hydroprene could be realized through the Suzu-
ki–Miyaura cross-coupling between (E)-alkenylboronic acid 9 and
known (E)-enol triflate 812 (Disconnection C, Scheme 1), which
was expected to avoid the problem of C2-C3 olefin isomerization
in previous synthetic endeavors.13 In retrosynthetic format, the
(E)-alkenylboronic acid 9 could be prepared from the hydrobora-
tion of alkyne 10, which in turn might be synthesized from the
known compound bromoester 1114 in several simple procedures.
Bromoester 11 was easily produced from (R)-4-methyl-d-valero-
lactone (enantiomeric purity >95%), a tigogenin-degraded product
that could be obtained in kilograms.15
Supplementary data
Supplementary data (experimental procedures and analytic
data and copies of NMR spectra for all new compounds) associated
with this article can be found, in the online version, at doi:10.1016/
References and notes
2. (a) Siddall, J. B. Environ. Health Perspect. 1976, 14, 119; (b) Tunaz, H.; Uygun, N.
Turk. J. Agric. For. 2004, 28, 377.
3. Henrick, C. A.; Staal, G. B.; Siddall, J. B. J. Agric. Food Chem. 1973, 21, 354.
4. Henrick, C. A.; Willy, W. E.; Staal, G. B. J. Agric. Food Chem. 1976, 24, 207.
5. Henrick, C. A.; Willy, W. E.; Garcia, B. A.; Staal, G. B. J. Agric. Food Chem. 1975, 23,
396.
As depicted in Scheme 2, our synthesis of (S)-hydroprene com-
menced with the Cu-catalyzed alkylation of bromoester 11 in the