Total Syntheses of (±)-(Z)- and (±)-(E)-9

716 J.-L. Zhu et al. PAPER
between 2-cyano-3-methylbut-2-enoic acid ethyl ester (4)
and the Danishefsky-type diene 5 could be used to create
the A-ring of 1 and 2 in a single step with the concomitant
introduction of the C-5 quaternary center and the C-1
methyl group. In addition, the silyl enol ether moiety of
the resulting adduct 6 would be easily converted into the
requisite enone functionality to afford the intermediate 7.
After protecting the carbonyl group of 7, the cyano group
would be elaborated into a but-3-enyl appendage through
a reductive alkylation operation to give the intermediate 8.
Then, the terminal vinyl moiety of 8 has to be changed
into a keto functionality while the ester moiety has to be
converted into a formyl group to afford the keto aldehyde
9. Subsequent intramolecular aldol condensation of 9
would allow the establishment of the spirocyclic core, by
giving rise to intermediate 10. Finally, Wittig reaction
of 10 with trimethylphosphonium bromomethylide
(Ph 3P=CHBr) followed by the respective deprotection of
the resulting E- and Z-isomers would complete the total
synthesis of 1 and 2.
O
9
8
1 and 2
7
EtO 2C CN
10
+
OPG
OTBS
OHC
EtO 2C
OTBS
5
6
4
Scheme 2 Retrosynthetic analysis of 1 and 2
In a modified procedure, our synthetic effort began with
the condensation of ethyl cyanoacetate with acetone to
provide the known compound 49 in 66% yield (Scheme 3).
After this, the Diels–Alder reaction of 4 with diene 510 was carried out. It was observed that with the assistance of
zinc chloride, 4 could readily undergo the cycloaddition
with 5 (5 equiv) in toluene at 80 °C, to afford the desired
adduct 6 as a diastereomeric mixture (ortho-like, 50:50) in
good yield (82%), together with the by-product 11 resulting
from the self-addition of 5 (0.6 out of 5 equiv) as a single
diastereomer. 11 As we designed, compound 6 should
be directly transformed into enone 7, and for this purpose,
two commonly employed reagent systems for converting
silyl enol ether into enone, including 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ)/benzene12a and Pd(OAc) 2/
Na2CO3/MeCN, 12b were respectively attempted on 6 at
different temperatures (r.t. to reflux). However, these reactions
only led to recovered starting material or complex
mixtures.
We envisaged that the failure met with the transformation
of 6 into 7 through the DDQ oxidation might be attributed
Synthesis 2011, No. 5, 715–722 © Thieme Stuttgart · New York
O
9
PG = protecting group
CN
OPG
EtO 2C
EtO 2C
8
CN
7
OPG
O
6
2C CN EtO a
66%
c or d
EtO2C
2C 2
EtO
1
4
CN
EtO2C
b
≡
OTBS
6 (50:50) (82%)
OTBS
H
O EtO
12
Scheme 3 Reagents and conditions: (a) LiBr (5.0 equiv), MS 3Å,
acetone, reflux, 18 h; (b) 5 (5.0 equiv), ZnCl2 (1.0 equiv), toluene, 80
°C, 20 h; (c) LN (3.5 equiv), THF, –45 °C, 30 min, then
H2C=CHCH2CH2Br (4 equiv), r.t., 24 h, 57% of 12; (d) LN (3.5
equiv), THF, –45 °C, 30 min, then H2C=CHCH2CH2Br (4 equiv),
HMPA (4 equiv), r.t., 12 h, 70% of 12.
to the unfavorable electronic effect of the cyano group to
the cation intermediate. In this regard, it was decided to
reroute our original scheme by conducting the reductive
alkylation of 6 first, to replace its cyano group with a but-
3-enyl appendage. Following the previously established
reaction conditions, 8 the reductive alkylation reaction was
initially performed by treating 6 with LN (3.5 equiv) 13 in
THF at –45 °C for 30 minutes, followed by trapping the
resulting enolate from the reductive decyanation with 4bromobut-1-ene
(4 equiv), affording the alkylated product
12 in 57% yield as a single diastereomer. The trans steric
relationship between C-1 butenyl and C-2 methyl groups
was verified by 2D NOESY correlations as illustrated in
Scheme 3. It was further discovered that a much better
yield of 12 (70%) could be obtained by the use of hexamethylphosphoramide
(HMPA) (4 equiv) as an activating
reagent.
With the cyano group having been replaced by the alkyl
group, treatment of 12 with DDQ (5 equiv) in benzene at
80 °C for 24 hours could indeed affect the formation of the
enone moiety as evidenced by the low yield (~10%) of 13
obtained. To improve the yield of 13, we continued to examine
several reaction conditions by combining DDQ respectively
with several bases, including K2CO3, 2,4,6collidine,
14 and 2,6-lutidine, in benzene. Among the bases
tested, the best result was obtained from the reaction of
DDQ (4.8 equiv) in 2,6-lutidine (5.1 equiv) affording 13
in 55% yield (brsm: 72%), plus 30% of recovered 12
(Scheme 4). Regarding the inherent instability of the
enone, we thought that the carbonyl group of 13 should be
protected before creating the B-ring. To this end, 13 was
first reduced under the Luche’s conditions to give the allyic
alcohol 14 in 79% yield as a diastereomeric mixture
(76:24). The formation of two isomers in this case should
O
CN
+
11
Me
H
H
EtO2C
OTBS
OTBS
H
CN
7
O