Communications
cidal agent and root growth inhibitor[4] that was first isolated
OH
O
O
CH2OH
O
in 1973 from Teucrium viscidum Blume byFuijta and co-
workers,[3a] and 12-epi-teucvin (3),[5] a congener of teucvin
isolated eleven years later also from a Teucrium species by
Rodriguez and Savona, et al. These 19-norclerodane diterpe-
noids are of considerable structural complexity. In addition to
the presence of five stereogenic centers, challenging structural
features in 2 and 3 comprise a decalin core attached to an a,b-
unsaturated-g-lactone unit and a spiro g-lactone moiety
containing a pendant furyl group.
a
4
+
CO2Et
CO2Et
CO2Et
CO2Et
9
10
b
OAc
O
OAc
O
O
O
CH2OH
O
H
c
d
The present work began with the synthesis of dienophile 4
(Scheme 1). Its Diels–Alder addition to trans-2,4-pentadien-
CO2Et
CO2Et
CO2Et
CO2Et
CO2H
CO2Et
11
12
13
O
CHO
O
CO2H
a
b
O
CH2OH
EtO2C
H
H
EtO2C
CO2Et
CO2Et
O
CO2Et
CO2Et
g
f
e
5
6
CO2Et
CO2H
CO2Et
CO2H
O
O
O
14
15
CHO
CHO
c
d
e
O
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
h, i
j, k
2
+
3
4
8
7
CO2Et
CO2H
16
CO2Et
CHO
17
Scheme 1. Synthesis of dienophile 4. a) NaH, EtOCHO, EtOH (cat.),
¼
THF, RT, 10 h, 90%; b) CH2 CHCOCH3, DABCO, THF, RT, 10 h, 86%;
c) p-TsOH, PhH, reflux, ꢁH2O, 8 h, 89%; d) NaH, EtOCHO, EtOH
(cat.), THF, RT, 10 h, 89%; e) DDQ, K2CO3, THF, 08C, 20 min, 90%.
Scheme 2. Synthesis of target compounds 2 and 3. a) ZnCl2, trans-2,4-
pentadien-1-ol, CH2Cl2, 08C, 1 h, 90% (9:10=11:1); b) Ac2O, py,
DMAP (cat.), RT, 10 h, 90%; c) (CH3)2CuLi, Et2O, 08C, 0.5 h, 82%;
d) NaOH, EtOH, H2O, RT, 10 h, 90%; e) H2 (60 psi), 10% Pd/C,
EtOAc, RT, 6 h, 89%; f) Jones reagent, acetone, 08C, 1 h, 90%; g) p-
TsOH, PhH, reflux, 5 h, 85%; h) (COCl)2, PhH, reflux, 10 min; i) LiAl
(tBuO)3H, THF, ꢁ408C, 1 h, 70% over two steps; j) 3-lithiofuran,
Et2O, ꢁ788C, 20 min; k) LiH, THF, RT, 10 h, 45% over two steps
(2:3=1:3).
1-ol (see Scheme 2), which provided a rapid access to the
required decalin core with suitable functionalities at strategic
positions, served as a keyoperation to tackle the synthetic
problems associated with the title compounds. Dienophile 4
was prepared from diethyl succinate in five steps in an overall
yield of 55% (Scheme 1). Formylation of diethyl succinate
with ethyl formate in THF in the presence of sodium hydride
and a small amount of ethanol gave the corresponding
aldehyde 5, which was subjected to Michael addition with
methyl vinyl ketone using 1,4-diazabicyclo[2.2.2]octane
(DABCO) as a base to give the keto aldehyde 6. The aldol
condensation of 6 was subsequentlyinduced under acidic
conditions using p-toluenesulfonic acid (p-TsOH). The
resulting enone 7 was formylated with ethyl formate as
Alder reaction; the addition of the diene was found to take
[7]
place specificallyfrom the side containing the ester group.
To our delight, this interesting phenomenon of face-control,
central to our synthetic design, was also realized experimen-
tallyin the Diels–Alder addition of trans-2,4-pentadien-1-ol
to compound 4. This reaction occurred in a completelyface-
selective manner in favor of the face containing the carbe-
thoxygroup, thus allowing full control of the two crucial
before to give the formyl enone 8. Finally, the dienophilic stereogenic centers (C9 and C10 (clerodane numbering)).
double bond was introduced bydehydrogenation with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to give the
desired dienophile 4.
This keyreaction also proceeded with complete stereo- ( cis-
addition and endo-addition with respect to the ketone
carbonyl group) and regioselectivity (ortho-addition); both
the observed products originated from the same adduct whose
structure was unequivocallyestablished after further trans-
formations (vide infra).
For the incorporation of the required methyl group at
C17, the hemiacetal group of 9 was protected as the acetate by
using acetic anhydride, pyridine, and a small amount of 4-
dimethylaminopyridine (DMAP). The resulting acetate 11
(90% yield) was subsequently treated with lithium dimethyl
cuprate. The conjugate addition took place preferentially
Under zinc chloride catalysis, dienophile 4 was found to
undergo Diels–Alder reaction rapidly(0 8C, 1 h, in CH2Cl2)
with trans-2,4-pentadien-1-ol[6] to give compound 9 in a 83%
yield, as a result of concomitant intramolecular hemiacetal
formation, together with a small amount (ꢀ 7%) of the
deformylation by-product 10 (Scheme 2). Before the outset of
the current work, we had observed that the placement of an
ester group at C4 of various cyclohexenone dienophiles could
induce a profound effect on the face-selectivityof the Diels–
1852
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2003, 42, 1851 – 1853