.
Angewandte
Communications
which the phenylselenide function would serve as a handle for
the introduction of the C14ÀC15 double bond. Further
cleavage of the C2ÀC7 bond would provide the intermediate
8
containing an enamine and transient aza-ortho-quinone
methide function. The latter would be generated in situ by
[14,15]
a retro-Diels–Alder reaction of the cyclic carbamate 9,
which in turn could be obtained by alkylation of the cyclic
imine 11 with iodide 10. The iodide 10 and enantioenriched 11
could be synthesized from 6-nitroveratraldehyde (12) and
allyl 2-oxocyclopentane-1-carboxylate (13), respectively. We
hoped to construct the hexacyclic structure of (À)-isoschizog-
amine in a one-pot manner from 10 and 11, and to control
both the relative and absolute configuration of three con-
tiguous stereogenic centers (C2, C7, C21) of the natural
product through the quaternary carbon center (C20) of 11.
According to this scheme there would be no need to prepare
the enantioenriched iodide 10 since its benzylic stereogenic
center (C7) would be destroyed and regenerated in the
process via the aza-ortho-quinone methide intermediate 8.
Synthesis of the alkyl iodide (Æ)-10 is shown in Scheme 3.
Scheme 4. Synthesis of the enantioenriched imine 11. a) Methyl bro-
moacetate, K CO , acetone, 508C, 95%; b) [Pd (dba) ], ligand 17,
2
3
2
3
toluene, 608C, yield: 90%, 83% ee; c) (PhSe) , NaN , PhI(OAc) ,
2
3
2
CH Cl , 72%, d.r.=1:1; d) Me P, THF, RT, 89%. dba=dibenzylidene-
2
2
3
acetone.
[17,18]
assigned based on literature precedents
and was further
confirmed by its conversion into (À)-isoschizogamine. Azido-
[19]
TiCl -mediated allylation of readily available 6-nitroveratral-
phenylselenenylation of the terminal double bond in (R)-18
under oxidative conditions regioselectively afforded the
desired alkyl azide 20 as a mixture of two diastereomers
4
(d.r. = 1:1). The lack of diastereoselectivity in this alkene
difunctionalization reaction was of no consequence since the
2
newly created chiral center will become an sp -hybridized
carbon atom upon elimination of phenylselenyl substituent.
Staudinger reduction 20 (Me P in THF) afforded a phospha-
3
zene intermediate which underwent in situ intramolecular
aza-Wittig reaction to provide 11 in 89% yield.
With the desired coupling partners in hand, the hetero-
annulation of 10 and 11 was examined (Scheme 5). After
Scheme 3. Synthesis of (Æ)-10. a) TMS allyl, TiCl , CH Cl , À788C;
4
2
2
b) O , MeOH, À788C; then NaBH , À788C to RT; c) Pd/C, H ,
3
4
2
(
EtOCO) O, MeOH; then K CO , 55% from 12; d) I , PPh , imidazole,
2 2 3 2 3
2 2
CH Cl /THF (1:1), RT, 76%. THF=tetrahydrofuran, TMS=trimethyl-
silyl.
dehyde (12) with allyltrimethylsilane afforded a homoallylic
alcohol, which was converted into the 1,3-diol 14 by ozonol-
ysis of the terminal olefin followed by reductive workup with
[
16]
NaBH4. Hydrogenation of 14 in the presence of diethyl
pyrocarbonate gave an unstable ethyl carbamate, and upon
addition of K CO it was cyclized in situ into the 1,4-dihydro-
2
3
2
H-benzo[d][1,3]oxazin-2-one derivative 15 in 55% yield
Scheme 5. Total synthesis of (À)-1. a) CH CN (c=0.5m), 1008C
3
over three steps. Treatment of 15 with iodine and triphenyl-
phosphine under Appel conditions provided the desired (Æ)-
(microwave); b) 1,2-dichloroethane/1,2-dichlorobenzene (1:3,
c=0.025m), PivOH, 1608C (microwave), 45%; c) NaIO
, NaHCO ,
3
4
MeOH; then Na S O , Et NH, 1,2-dichloroethane, 558C, 2.5 h, 46%.
1
0 in 76% yield.
2
2
3
2
Synthesis of the imine 11 is shown in Scheme 4. Alkylation
of allyl 2-oxocyclopentane-1-carboxylate (13), prepared in
two steps from adipic acid by a sequence of esterification and
Dieckmann condensation of the resulting diester (see the
Supporting Information), with methyl bromoacetate afforded
much experimentation, it was found that heating a solution of
10 and 11 [1.2 equiv in CH CN (0.5m), microwave irradiation]
3
for 1 hour afforded cleanly the desired iminium salt 9. After
removal of acetonitrile, the crude 9 and an excess of pivalic
acid (20.0 equiv) was dissolved in 1,2-dichloroethane/1,2-
dichlorobenzene (1:3, c = 0.025m). The resulting solution was
heated to 1608C for 30 minutes under microwave irradiation.
Under these optimized reaction conditions, the desired
hexacyclic compound 21 was isolated in 45% yield as
a mixture of two diastereomers (d.r. = 1:1) with the desired
1
6 in 95% yield. Asymmetric decarboxylative allylation of 16
under the Stoltz conditions using (R)-(p-CF ) -tBuPHOX
3
3
[17]
(17), as a ligand, afforded (R)-18 in 90% yield with 83% ee.
With (R)-tBuPHOX as ligand under otherwise identical
conditions, the desired (R)-18 was isolated with only 60%
[18]
ee. The ee value of 18 was determined by SFC analysis of its
UV-active derivative 19. The absolute configuration of 18 was
1
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 14937 –14940