Asymmetric total synthesis of (-)-stenine and 9a-epi-stenine

Article abstract of DOI:10.1002/chem.201200376

A route for the asymmetric synthesis of (-)-stenine, a member of the Stemona alkaloid family used as folk medicine in Asian countries, is described. The key features of the sequence employed include stereoselective transformations on a cyclohexane ring controlled by a chiral auxiliary unit and an intramolecular Mitsunobu reaction to construct the perhydroindole ring system. By using an intermediate in the route to (-)-stenine, an asymmetric synthesis of 9a-epi-stenine was also executed. The C(9a) stereocenter in 9a-epi-stenine was installed by using a Staudinger/aza-Wittig reaction of a keto-azide precursor followed by reduction of the resulting imine. The results of this effort demonstrate the applicability of the chiral auxiliary based strategy to the preparation of naturally occurring alkaloids that contain highly functionalized cyclohexane cores. Copyright

Full text of DOI:10.1002/chem.201200376

FULL PAPER
DOI: 10.1002/chem.201200376
Asymmetric Total Synthesis of (À)-Stenine and 9a-epi-Stenine
Hiromichi Fujioka,* Kenji Nakahara, Naoyuki Kotoku, Yusuke Ohba, Yasushi Nagatomi,
Tsung-Lung Wang, Yoshinari Sawama, Kenichi Murai, Kie Hirano, Tomohiro Oki,
Shintaro Wakamatsu, and Yasuyuki Kita[a]
Abstract: A route for the asymmetric
synthesis of (À)-stenine, a member of
the Stemona alkaloid family used as
folk medicine in Asian countries, is de-
scribed. The key features of the se-
quence employed include stereoselec-
tive transformations on a cyclohexane
ring controlled by a chiral auxiliary
unit and an intramolecular Mitsunobu
reaction to construct the perhydroin-
dole ring system. By using an inter-
mediate in the route to (À)-stenine, an
asymmetric synthesis of 9a-epi-stenine
was also executed. The C(9a) stereo-
center in 9a-epi-stenine was installed
by using a Staudinger/aza-Wittig reac-
tion of a keto–azide precursor followed
by reduction of the resulting imine.
The results of this effort demonstrate
the applicability of the chiral auxiliary
based strategy to the preparation of
naturally occurring alkaloids that con-
tain highly functionalized cyclohexane
cores.
Keywords: alkaloids · asymmetric
synthesis · chiral auxiliary · natural
products · stenine
Introduction
lective synthesis of this target that was based on an asym-
metric double Michael reaction.[9] Owing to its range of
potent biological activities and its structural complexity,
stenine continues to serve as a challenging synthetic target.
Below, we describe the results of an investigation that has
led to the development of a stereocontrolled total synthesis
of stenine and its C(9a) epimer, 9a-epi-stenine, that utilizes
a novel chiral auxiliary based strategy.
Extracts from the roots and rhizomes of plants in the Ste-
monaceae family (Stemona and Croomia spieces) have long
been used in Asian countries as remedies for the treatment
of respiratory diseases and as anthelmintics. These extracts
were found to be rich Stemona alkaloids, which possess
poly
The structures of most of the alkaloids in this family contain
a pyrrolo[1,2-a]azepine nucleus with different connection
ACHTUNGTRENNUNGcyclic structures containing multiple stereogenic centers.
ACHTUNGTRENNUNG
sites between the basic ring system and side chains that
serve as the foundation of subcategorization of members of
this family.[1] Stenine, a member of this group of alkaloids,
was isolated from the roots of Stemona tuberosa.[2] The
structure of this alkaloid contains a fully substituted cyclo-
hexane core unit fused to three other rings along with seven
contiguous stereogenic centers. This substance has attracted
considerable attention among synthetic chemists. For exam-
ple, Hart, Padwa, and Aubꢀ have developed routes for the
total syntheses of racemic stenine,[3–5] and several other in-
vestigations have been carried out by exploring general ap-
proaches to prepare this target.[6] To date, three asymmetric
syntheses of stenine have been described, including those of
Wipf and Morimoto that employ relatively lengthy sequen-
ces.[7,8] Recently, Zhang devised a highly concise enantiose-
The most demanding task in the synthesis of stenine is the
stereoselective construction of its densely substituted cyclo-
hexane core. In the course of recent efforts focusing on
asymmetric reactions using chiral acetals derived from C2-
symmetric diols,[10] we developed a new asymmetric desym-
metrization strategy that employs intramolecular haloetheri-
fication reactions of cyclohexadiene acetals 1 to generate
substituted cyclohexenes
2
(Scheme 1).[11] This process,
which enables installation of multiple chiral centers in cyclo-
hexane rings, proceeds via a rigid cationic intermediate
(Scheme 1) and utilizes the chiral auxiliary as a template
that remains in the product. We have already demonstrated
the usefulness of this haloetherification methodology by its
application to the synthesis of biologically active natural
products containing substituted cyclohexane frameworks.[12]
[a] Prof. Dr. H. Fujioka, K. Nakahara, N. Kotoku, Y. Ohba, Y. Nagatomi,
T.-L. Wang, Y. Sawama, K. Murai, K. Hirano, T. Oki, S. Wakamatsu,
Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences, Osaka University
1-6, Yamada-oka, Suita, Osaka, 565-0871 (Japan)
Fax : (+81)6-6879-8229
E-mail: fujioka@phs.osaka-u.ac.jp
Synthetic plan: The plan we have devised for the asymmet-
ric synthesis of (À)-stenine and 9a-epi-stenine employs the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200376.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

tions of the cyclohexene core of 3, guided by the steric envi-
ronment provided by the eight-membered acetal. These
processes will produce the cyclohexanone derivatives 4 and
5. In the pathway for synthesis of (À)-stenine, the tetracyclic
lactam 7 would be produced by using a 2-nitrobenzenesul-
AHCTUNGTRENGfNUN onamide (NsNH2)-based intramolecular Mitsunobu reac-
tion[13] of alcohol 6, prepared from 4, followed by manipula-
tion of the two terminal olefin moieties. Importantly, previ-
ous studies have shown that lactam 7 can be transformed to
stenine through sequential a-methylation of the lactone ring
and reduction of the lactam moiety.[5b,c,9] In contrast, the
C(9a) stereocenter in 9a-epi-stenine would be installed by
employing a Staudinger/aza-Wittig reaction of keto azide 8
and subsequent stereoselective reduction of the resulting
imine. Finally, 9a-epi-stenine would then be generated from
lactam 9 through conversion of the 8-membered acetal to
the required lactone.
Scheme 1. Intramolecular haloetherification of cyclohexadiene acetals 1.
Results and Discussion
Synthesis of (À)-stenine: The first phase of the synthetic ap-
proach to stenine focused on the stereoselective introduc-
tion of alkyl side chains on the cyclohexane ring of enone 3.
We observed that allylation at the a’-position of 3 takes
place readily to afford 10 in 92% yield (Scheme 4). CuCN-
promoted Michael addition of 4-pentenyl magnesium bro-
mide to 10 and a subsequent aldol reaction of the resulting
enolate with acetaldehyde gave alcohol 11 in 84% yield.[14]
Conventional two-step reduction of the alcohol moiety in 11
led to formation of the desired a-ethylcyclohexanone 4 as a
Scheme 2. Synthetic strategy for the preparation of (À)-stenine and 9a-
epi-stenine by using the common intermediate 3.
common intermediate 3 (Scheme 2), which can be obtained
by hydroboration and subsequent oxidation of the cyclohex-
ane derivative 2 (R1 =R2 =H, R=Me, X=Br in Sche-
me 1).[12b] We postulated that this enone would serve as a
suitable precursor for a variety
of highly functionalized cyclo-
hexanes containing multiple
asymmetric centers because it
possesses a variety of functional
groups that can undergo nucle-
ophilic and electrophilic addi-
tion reactions. Furthermore, we
believed that the sterically
bulky auxiliary present in
3
would govern the conformation
of the cyclohexene ring and
guide the stereochemical course
of ensuing transformations. Fi-
nally, we envisaged that two dif-
ferent routes would exist to
convert
3
to (À)-stenine
(Scheme 2, route A) and 9a-epi-
stenine (route B), through proc-
esses that lead to installation of
the nitrogen center.
The synthetic plans for the
preparation of (À)-stenine and
9a-epi-stenine,
outlined
in
Scheme 3, begin with a set of
stereoselective alkylation reac- Scheme 3. Detailed plan for the syntheses of (À)-stenine and 9a-epi-stenine. Ns=2-nitrobenzenesulfonyl.
&
2
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Total Synthesis of (À)-Stenine and 9a-epi-Stenine
FULL PAPER
Scheme 5. Mitsunobu cyclization of alcohol 6.
preventing Mitsunobu cyclization that would need to pro-
ceed through SN2 displacement of the hydroxyl group. Be-
cause this hydroxyl moiety is located in an axial position, a
severe 1,3-diaxial interaction exists between it and the 1,3-
disposed ethyl group (Figure 1).
Scheme 4. Synthesis of alcohol 6: a) LHMDS (1.2 equiv), allyl iodide
(3.0 equiv), HMPA (10 equiv), THF, À788C, 3 h, 92%; b) 4-pentenyl
magnesium bromide (2.0 equiv), CuCN (0.2 equiv), THF, À788C, 1 h,
then CH3CHO (1.5 equiv), À788C, 1 h, 84 %; c) i) O-phenyl chlorothio-
noformate (5.0 equiv), DMAP (1.0 equiv), pyridine, RT, 12 h; ii) AIBN
(0.1 equiv), Bu3SnH (3.0 equiv), benzene, 808C, 1 h; d) DDQ (0.5 equiv),
CH3CN/H2O 10:1, RT, 4 h, 85% (3 steps); e) i) 4-methoxybenzylamine
Figure 1. Proposed conformation of alcohol 6.
This reasoning led to a modification of the strategy in
which the Mitsunobu reaction would be conducted on alco-
hol 18, which does not suffer from this bad hydroxyl–ethyl
group interaction. To explore this proposal, alcohol 18 was
generated by using a procedure that is similar to the one
employed to prepare 6 (Scheme 6). Michael addition of 4-
pentenyl magnesium bromide to the enone 10 afforded 15 in
90% yield. DDQ-mediated hydrolysis of the acetal group in
15, followed by reductive amination of the resulting alde-
hyde 16 and protection of the amine as a Ns group led to
formation of cyclohexanone derivative 17 in 61% yield
(three steps). Treatment of 17 with CAN then furnished the
target alcohol 18 in 62% yield.
An investigation of the Mitsunobu cyclization of 18 led to
the results summarized in Table 1. Under standard condi-
tions (PPh3, DEAD, THF, or benzene), 18 reacted to form
19 in rather low yield (Table 1, entries 1 and 2). Also, when
nBu3P instead of PPh3 was used to promote this process,
only elimination of the alcohol group took place (Table 1,
entry 3). Finally, changing the solvent to 1,4-dioxane with
DIAD gave a higher yield of 19 (55% yield, entry 4).[18] The
presence of a trans ring fusion in 19 was demonstrated by
observing coupling constants of 11.2 and 4.0 Hz (shown in
Table 1, right figure).[19]
(1.1 equiv), NaBHACHTUNGTRENNUNG(OAc)3 (2.0 equiv), 1,2-DCE, RT, 1.5 h; ii) 2-nitroben-
zenesulfonyl chloride (1.5 equiv), Et3N (2.0 equiv), CH2Cl2, RT, 30 min,
72% (2 steps); f) CAN (5.0 equiv), CH3CN/H2O 2:1, RT, 5 h, 68%.
AIBN=azobisisobutyronitrile, CAN=cerium(IV) ammonium nitrate,
1,2-DCE=1,2-dichloroethane, DDQ=2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone, DMAP=N,N-4-dimethylaminopyridine, HMPA=hexame-
thylphosphoramide, LHMDS=lithium bis(trimethylsilyl)amide, PMB=
para-methoxybenzyl.
single diastereomer. Unfortunately, direct ethylation adja-
cent to the ketone did not proceed at all. An initial attempt
to hydrolyze the acetal group in 4, employing standard
Brønsted acid based procedures, gave aldehyde 12 in only
modest yields. However, when 4 was treated with a catalytic
amount of DDQ,[15] aldehyde 12 was obtained in high yield
(85%, three steps). Reductive amination of the aldehyde
moiety in 12 by using 4-methoxybenzylamine and NaBH-
ACHTUNGTRENNUNG
(OAc)3,[16] followed by protection of the amine as a 2-nitro-
benzenesulfonamide provided 13 in 72% yield (two steps).
Removal of the PMB and 2-hydroxyethyl groups in 13 was
accomplished by using CAN[17] and gave the desired alcohol
6 in 68% yield.
Methods to bring about Mitsunobu-type cyclization of 6
to construct the nitrogen-containing bicyclic system in sten-
ine was next examined (Scheme 5). However, extensive ef-
forts to promote the conversion of 6 to 14 were not success-
ful because under a variety of Mitsunobu cyclization condi-
tions either elimination of the hydroxyl group in 6 occurred
or starting material 6 was recovered. We reasoned that the
conformation of the cyclohexane ring in 6 was the factor
After having developed a route to prepare 19, attention
then focused on the assembly of the polycyclic framework
of stenine. a-Ethylation of 19 by using LHMDS and EtI
provided 14 in 80% yield (based on the recovered starting
material). As anticipated, this process took place selectively
from the b face of the cyclohexanone ring system (i.e., trans
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

H. Fujioka et al.
hexane ring, serves as an alter-
native for synthesis of enantio-
merically
(Scheme 7).
pure
(À)-stenine
Synthesis of 9a-epi-stenine: A
synthetic route to 9a-epi-stenine
was also developed by employ-
ing intermediate 3 used in the
approach to (À)-stenine. Ac-
cordingly, enone 3 reacted with
EtMgBr in the presence of CuI,
followed by TMSCl and Et3N-
promoted silylation of the re-
sulting enolate to afford silyl
enol ether 22 (Scheme 8).
Double a,a’-allylation of 22 was
achieved by using an excess of
MeLi and allyl iodide to pro-
vide 5, in which three stereo-
centers have been installed, in
Scheme 6. Synthesis of alcohol 18: a) 4-pentenyl magnesium bromide (2.0 equiv), CuI (0.5 equiv), THF,
À788C, 3 h, 90%; b) DDQ (0.5 equiv), CH3CN/H2O 10:1, RT, 4 h, 84%; c) i) 4-methoxybenzylamine
(1.1 equiv), NaBHACHTUNGTRENNUNG(OAc)3 (2.0 equiv), 1,2-DCE, RT, 1.5 h; ii) 2-nitrobenzenesulfonyl chloride (1.5 equiv), Et3N
(2.0 equiv), CH2Cl2, RT, 30 min, 73% (2 steps); d) CAN (5.0 equiv), CH3CN/H2O 2:1, RT, 5 h, 62%.
Table 1. Mitsunobu cyclization of alcohol 18 to form 19.[a]
44% overall yield. In this process, a dianion intermediate
is generated through reaction of 22 with MeLi, serving as a
strong base. Reduction of the ketone group in 5 with
LiAlH4 occurred selectively from the a face to generate al-
cohol 23.[21] Alcohol 23, containing a small amount of a
minor diastereoisomer, was purified by acetACHTNUTRGNEyNUG lation and a
LiAlH4 reduction process. Oxidative cleavage of both ter-
minal olefin moieties in 23, carried out by using the Le-
Entry
Azo compound
Solvent
Time
Yield [%][e]
1[b]
2[b]
3[c]
4[d]
5[d]
6[d]
DEAD
DEAD
DEAD
DEAD
DIAD
DTAD
THF
benzene
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1 h
1 h
24 h
15 min
15 min
15 min
18
19
n.d.[f]
47
55
28
[a] Unless otherwise noted, reactions were performed by using PPh3
(2.0 equiv) and azo compound (2.0 equiv) at room temperature. [b] The
reaction was performed at 08C. [c] nBu3P was used instead of PPh3.
[d] 1.5 equivalents of PPh3 and the azo compound were used. [e] Isolated
yield. [f] Compound 19 was not detected. DEAD=diethyl azodicarboxy-
late, DIAD=diisopropyl azodicarboxylate, DTAD=di-tert-butyl azodi-
carboxylate.
to the pre-existing pentenyl group). Conversion of 14 to
ester 20 was effected in 57% overall yield by using a se-
quence of reactions involving ozonolysis, PDC oxidation,
and trimethylsilyldiazomethane-promoted esterification.[20]
Removal of the Ns group in 20, by employing standard con-
ditions (PhSH, CsCO3), followed by lactam ring formation
in toluene heated at reflux gave the desired tricyclic lactam
21 in 95% yield. Finally, NaBH4-mediated reduction of the
ketone moiety in 21 afforded lactone 7, which has been pre-
viously employed by Aubꢀ[5b,c] and Zhang[9] as an intermedi-
ate in their total syntheses of stenine. All spectroscopic data
of 7 matched those reported by these workers.[5b,c,9] Conse-
quently, the route we have developed, which efficiently and
stereoselectively installs all stereogenic centers in the cyclo-
Scheme 7. Total synthesis of (À)-stenine: a) LHMDS (1.5 equiv), ethyl
iodide (10 equiv), HMPA (10 equiv), THF, À788C to RT, 24 h, 57%
(80% brsm); b) i) O3, CH2Cl2, À788C, 15 min, then PPh3 (8.0 equiv), RT,
1 h, 81%; ii) PDC (10 equiv), DMF, RT, 24 h; iii) TMSCHN2 (2.5 equiv),
benzene/MeOH 4:1, RT, 30 min, 70% (2 steps); c) i) CsCO3 (3.0 equiv),
PhSH (1.5 equiv), CH3CN, RT, 12 h; ii) toluene, reflux, 24 h, 95%
(2 steps); d) NaBH4 (3.0 equiv), MeOH, 08C, 1.5 h, 64%. PDC=pyridini-
um dichromate.
&
4
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Total Synthesis of (À)-Stenine and 9a-epi-Stenine
FULL PAPER
sired epimerization at C(1).[19]
In contrast, the desired primary
alcohol was obtained in 75%
yield by treatment with tris(di-
methylamino)sulfonium difluo-
AHCTUNGTERNGNrUN otrimethylsilicate (TAS-F), a
milder reagent for silyl ether
deprotection.[23] Alcohol to
azide conversion was performed
by using Mitsunobu conditions
to give 8 in 91% yield. A Stau-
dinger reaction of the keto
azide 8 occurred by using Et3P
and was followed by an intra-
molecular aza-Wittig reaction
that gave the corresponding
imine, which was reduced by
using NaBH4 from the convex
face to produce amine 27.
When we conducted the Stau-
dinger/aza-Wittig reaction by
using PPh3, the high tempera-
ture brought about
a slight
degree of epimerization. In tol-
uene heated at reflux, 27 was
transformed to lactam 9 in 53%
overall yield. The stereochemi-
cal assignment of 9 was based
Scheme 8. Synthesis of diol 25: a) i) EtMgBr (5.0 equiv), CuI (cat.), THF, À788C, 30 min; ii) TMSCl
(8.0 equiv), Et3N (9.0 equiv), HMPA (4.0 equiv), THF, 08C to RT, 30 min; b) i) MeLi (3.5 equiv), DME,
À158C, 15 min; ii) allyl iodide (4.0 equiv), 1 h, 08C, 44% (3 steps); c) i) LiAlH4 (1.2 equiv), THF, 08C to RT,
99% (9:1 d.r.); ii) Ac2O, DMAP, pyridine; iii) LiAlH4 (2 equiv), THF, 08C to RT, 85%; d) OsO4 (cat.), NaIO4
(4.2 equiv), THF/H2O 1:1, 1 h, 69% (d.r. 2.5:1); e) i) DIBAL (3.0 equiv), toluene, À788C, 1 h, 77% (d.r.
2.5:1); ii) Ph3P=CHCO2Et (1.5 equiv), benzene, reflux, 3 h; iii) Pd/C (cat.), H2, AcOEt, RT, 2 h, 92% (2 steps).
DIBAL=diisobutylaluminum hydride; DME=1,2-dimethoxyethane.
1
on the results of H NMR spec-
troscopic experiments, which
showed that an NOE interac-
tion exists between H(1) and
mieux–Johnson
procedure,[22]
gave the monoACHTUNGTRENNUNGacetal 24 exclu-
sively as a result of selective ad-
dition of the alcohol to the
equatorial aldehyde group in
the intermediate dialdehyde.
Conversion of the lactol 24 to
the corresponding ester 25 was
accomplished by utilizing
a
three-step sequence, including
DIBAL reduction of the free
aldehyde group, Horner–Was-
worth–Emmons reaction of the
lactol, and hydrogenetion of the
olefin moiety.
Sequential TBS protection of
the primary alcohol group and
oxidation of the secondary alco-
hol in 25 gave rise to the cyclo-
hexanone derivative 26 in 95%
overall yield (Scheme 9). Owing
to its basicity, tetra-n-butylam-
monium fluoride (TBAF), em-
ployed for deprotection of the
Scheme 9. Synthesis of lactam 9: a) i) TBSCl (1.2 equiv), imidazole (2.4 equiv), DMF, RT, 1 h, 100%; ii) PDC
(1.3 equiv), CH2Cl2, RT, overnight, 95%; b) i) TAS-F (2.1 equiv), DMF/H2O 20:1, RT, 24 h, 75%; ii) PPh3
(2.4 equiv), DEAD (2.4 equiv), DPPA (1.2 equiv), THF, RT, 1 h, 91%; c) i) Et3P (1.2 equiv), THF, RT, 3 h;
ii) NaBH4 (2.0 equiv), MeOH, 08C, 1 h; d) toluene, reflux, 2 h, 53% (3 steps). DPPA=diphenylphosphoryl
TBS group, promoted unde- azide, TAS-F=tris(dimethylamino)sulfonium difluorotrimethylsilicate.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

H. Fujioka et al.
fuse reflectance measurement of samples dispersed in KBr powder. Opti-
cal rotations were measured by JASCO P-1020. HRMS and elemental
analysis were performed by the Elemental Analysis Section of Graduate
School of Pharmaceutical Sciences in Osaka University. Melting points
were measured on Yanagimoto Micro Melting Point Apparatus and were
uncorrected. Column chromatography was performed with SiO2 (Merck
Silica Gel 60 (230–400 mesh) or Kanto Chemical Silicagel 60 (spherical,
63–210 mm). The organic layer was dried over Na2SO4 or MgSO4.
H(9a) and, therefore, that the five-membered ring is fused
to the cyclohexane ring in a cis manner.
In the final stage of the synthesis of 9a-epi-stenine, reduc-
tion of lactam 9 was achieved by employing BH3·THF to
afford aminoborane intermediate 28 (Scheme 10). The
(1R,3R,4R,6R,8R)-6-Methoxy-3,4-diphenyl-2,5-dioxabicycloACTHNUTRGNEUGN[6.4.0]dodec-
11-en-10-one (3) was prepared according to the known procedure.[12b]
(1R,3R,4R,6R,8R,9R)-9-Allyl-6-methoxy-3,4-diphenyl-2,5-dioxabicyclo-
AHCTUNGTREG[NNUN 6.4.0]dodec-11-en-10-one (10): LHMDS (1.0m in THF, 5.5 mL,
5.53 mmol) was added to a stirred solution of 3 (1.68 g, 4.61 mmol) in
THF (46 mL) at À788C under N2 and the resulting mixture was stirred
for 1 h. HMPA (8.0 mL, 46.1 mmol) and allyl iodide (1.26 mL,
13.8 mmol) were added at À788C and the resulting mixture was stirred at
À788C for 3 h. The reaction was quenched with sat. aq. NH4Cl and ex-
tracted with AcOEt. The organic layer was washed with brine, dried, and
concentrated in vacuo. The residue was purified by SiO2 column chroma-
tography (hexane/AcOEt=5:1) to give 10 (1.72 g, 92%) as a colorless
1
amorphous solid. [a]2D7:4 = +50.4 (c=1.04 in CHCl3); H NMR (400 MHz,
CDCl3): d=1.74 (1H, ddd, J=11.9, 8.2, 3.7 Hz), 2.22 (1H, dt, J=13.5,
5.0 Hz), 2.30–2.50 (3H, m), 3.27 (3H, s), 3.31 (1H, brs), 4.40 (1H, A in
ABq, J=6.9 Hz), 4.44 (B in ABq, J=6.9 Hz), 4.71 (1H, dd, J=2.7,
2.3 Hz), 5.17 (1H, d, J=16.9 Hz), 5.22 (1H, d, J=10.1 Hz), 5.29 (1H, dd,
J=5.0, 3.2 Hz), 5.82–5.90 (1H, m), 5.95 (1H, dd, J=10.1, 1.8 Hz), 6.74
(1H, d, J=10.1 Hz), 6.94 (2H, d, J=6.0 Hz), 6.99 (2H, d, J=6.0 Hz),
7.17–7.21 ppm (6H, m); 13C NMR (100 MHz, CDCl3): d=34.9, 36.4, 38.2,
51.1, 54.8, 75.0, 88.07, 88.11, 105.3, 117.4, 127.2, 127.5, 127.75, 127.79,
127.84, 127.9, 128.0, 135.5, 137.6, 138.3, 147.6, 200.1; IR (KBr): n˜ =2907,
Scheme 10. Total synthesis of 9a-epi-stenine: a) BH3·THF (5.0 equiv),
THF, RT, 3 h; b) i) Ca, NH3, EtOH, À788C, 1 h; ii) PDC (2.0 equiv),
CH2Cl2, overnight, 37% (3 steps); c) i) LDA (8.4 equiv), MeI (30 equiv),
HMPA (10 equiv), À788C, 1 h; ii) Na2CO3, MeOH, reflux, 1 h, 65%
(2 steps). LDA=lithium diisopropylamide.
1678, 1092 cmÀ1
; HRMS (FAB): m/z calcd for C26H29O4: 405.2066
[M+H]+; found: 405.2067.
(1R,3R,4R,6R,8R,9R,12R)-9-Allyl-6-methoxy-12-(pent-4-en-1-yl)-3,4-di-
phenyl-2,5-dioxabicycloACTHNUTRGNEUG[N 6.4.0]dodecan-10-one (15): 4-Pentenyl magnesi-
eight-membered cyclic acetal moiety in 28 was then convert-
ed to the corresponding lactol under Birch reduction condi-
tions. In addition, oxidation of the lactol with PDC gave lac-
tone 29 in 37% yield (three steps). Finally, a-methylation of
29 followed by deboration furnished 9a-epi-stenine in 65%
overall yield.
um bromide (1.0m in THF, 2.7 mL, 2.74 mmol) was added to a stirred
suspension of 10 (555 mg, 1.37 mmol) and CuI (131 mg, 0.686 mmol) in
THF (14 mL) at À788C under Ar and the resulting mixture was stirred
at À788C for 3 h. The reaction was quenched with sat. aq. NH4Cl and ex-
tracted with AcOEt. The organic layer was washed with brine, dried, and
concentrated in vacuo. The residue was purified by SiO2 column chroma-
tography (hexane/AcOEt=5:1) to give 15 (586 mg, 90%) as a colorless
amorphous solid. [a]2D7:7 =À50.8 (c=1.41 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.10–1.52 (4H, m), 1.87–2.00 (3H, m), 2.11–2.19 (3H, m),
2.37–2.44 (1H, m), 2.48–2.63 (2H, m), 2.67–2.75 (2H, m), 3.24 (3H, s),
3.99 (1H, dd, J=6.9, 2.3 Hz), 4.42 (2H, s), 4.92–4.97 (2H, m), 5.10–5.15
(2H, m), 5.27 (1H, dd, J=8.2, 2.7 Hz), 5.66–5.84 (2H, m), 6.91 (2H, dd,
J=6.4, 1.4 Hz), 7.00 (2H, dd, J=6.4, 1.4 Hz), 7.13–7.22 ppm (6H, m);
13C NMR (100 MHz, CDCl3): d=25.7, 31.9, 33.6, 33.7, 37.0, 38.0, 39.6,
41.6, 51.9, 54.6, 81.2, 87.9, 89.4, 105.1, 114.7, 117.2, 127.0, 127.5, 127.7,
127.8, 127.9, 135.3, 137.9, 138.4, 138.9, 211.9 ppm; IR (KBr): n˜ =2926,
1709, 1121, 1088 cmÀ1; HRMS (FAB): m/z calcd for C31H39O4: 475.2848
[M+H]+; found: 475.2864.
Conclusion
In the investigation described above, stereocontrolled syn-
theses of (À)-stenine and 9a-epi-stenine were achieved by
using strategies that rely on the common intermediate 3.
This effort showed that enone 3 serves as a useful intermedi-
ate in the preparation of complex naturally occurring alka-
loids, like stenine, that contain densely substituted cyclohex-
ane cores. In the routes developed, all six stereogenic cen-
ters in the cyclohexane rings of the targets are introduced
with a high degree of stereoselectivity by employing an in-
tramolecular bromoetherification reaction of cyclohexadiene
acetal 1 and efficient transformations of the chiral auxiliary
containing enone 3.
2-{(1R,2R,5R,6S)-2-Allyl-6-[(1R,2R)-2-hydroxy-1,2-diphenylethoxy]-3-
oxo-5-(pent-4-en-1-yl)cyclohexyl}acetaldehyde (16): DDQ (76.8 mg,
0.338 mmol) was added to a stirred solution of 15 (321 mg, 0.676 mmol)
in CH3CN/H2O (6.8 mL, v/v=10:1) at room temperature and the result-
ing mixture was stirred at this temperature for 4 h. The reaction was
quenched with sat. aq. Na2S2O3 and extracted with AcOEt. The organic
layer was washed with brine, dried, and concentrated in vacuo. The resi-
due was purified by SiO2 column chromatography (hexane/AcOEt=3:1)
to give 16 (262 mg, 84%) as a colorless oil. [a]2D9:5 =À17.9 (c=1.33 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=1.02–1.41 (4H, m), 1.85–2.24
(5H, m), 2.34–2.70 (4H, m), 2.85 (1H, dd, J=17.4, 6.9 Hz), 3.05 (1H, d,
J=3.2 Hz), 3.68 (1H, dd, J=4.6, 2.7 Hz), 4.33 (1H, d, J=7.3 Hz), 4.80
(1H, dd, J=7.3, 2.7 Hz), 4.93–5.04 (4H, m), 5.64–5.76 (2H, m), 6.89–7.22
(10H, m), 9.77 ppm (1H, s); 13C NMR (100 MHz, CDCl3): d=25.6, 31.2,
31.9, 33.3, 34.8, 39.1, 41.1, 42.8, 50.2, 78.5, 86.4, 114.8, 117.3, 126.8, 127.7,
127.8, 128.0, 128.15, 128.20, 134.9, 138.2, 138.4, 139.8, 201.5, 210.9 ppm;
Experimental Section
General: 1H and 13C NMR spectra were measured by JEOL JNM-AL
500, JEOL JNM-ECS 400, JEOL JNM-EX 300, and JEOL JNM-EX 270
spectrometers with tetramethylsilane as an internal standard. IR spectra
were recorded by Shimadzu FTIR 8400 and IRAffinity-1 by using a dif-
&
6
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Total Synthesis of (À)-Stenine and 9a-epi-Stenine
FULL PAPER
IR (KBr): n˜ =3422, 2928, 1709, 1074 cmÀ1; HRMS (FAB): m/z calcd for
C30H36O4Na: 483.2511 [M+Na]+; found: 483.2527.
0.21 mL, 0.208 mmol) was added to a stirred solution of 19 (74.8 mg,
0.173 mmol) in THF (1.7 mL) at À788C under Ar and the resulting mix-
ture was stirred for 1 h. HMPA (0.32 mL, 1.73 mmol) and ethyl iodide
(0.14 mL, 1.73 mmol) were added at À788C. The resulting mixture was
stirred and then allowed to warm to room temperature over 5 h. The re-
action was quenched with sat. aq. NH4Cl and extracted with AcOEt. The
organic layer was washed with brine, dried, and concentrated in vacuo.
The residue was purified by SiO2 column chromatography (hexane/
AcOEt=5:2) to give 5 (45.8 mg, 57%) as a colorless oil and 14 (21.4 mg,
29%) was recovered. [a]2D4:4 =À110.4 (c=0.55 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=0.92 (3H, t, J=7.3 Hz), 1.33–1.78 (7H, m), 1.87
(2H, d, J=6.9 Hz), 2.00–2.12 (2H, m), 2.26–2.48 (5H, m), 3.47 (1H, dd,
J=11.0, 5.5 Hz), 3.92 (1H, dd, J=11.0, 8.7 Hz), 3.98 (1H, dd, J=11.0,
4.1 Hz), 4.88–5.05 (4H, m), 5.62–5.82 (2H, m), 7.67–7.75 (3H, m),
8.07 ppm (1H, dd, J=6.9, 2.3 Hz); 13C NMR (100 MHz, CDCl3): d=12.5,
25.4, 26.8, 27.0, 28.7, 31.4, 33.8, 40.9, 44.3, 50.4, 50.8, 55.7, 64.4, 114.5,
116.8, 124.4, 131.1, 131.5, 132.6, 133.7, 135.7, 138.4, 148.3, 211.6 ppm; IR
(KBr): n˜ =2930, 1705, 1543, 1371, 1362, 1165 cmÀ1; HRMS (FAB): m/z
calcd for C24H33N2O5S: 461.2110 [M+H]+; found: 461.2093.
N-(2-{(1R,2R,5R,6S)-2-Allyl-6-[(1R,2R)-2-hydroxy-1,2-diphenylethoxy]-
3-oxo-5-(pent-4-en-1-yl)cyclohexyl}ethyl)-N-(4-methoxybenzyl)-2-nitro-
benzenesulfonamide (17): 4-Methoxybenzylamine (13.6 mL, 0.105 mmol)
and NaBHACHTUNGTRENNUNG(OAc)3 (40.5 mg, 0.191 mmol) were added to a solution of 16
(44.0 mg, 0.0955 mmol) in 1,2-DCE (1.0 mL) at 08C under N2 and the re-
sulting mixture was stirred at room temperature for 1.5 h. The reaction
was quenched with sat. aq. NaHCO3 and extracted with CH2Cl2. The or-
ganic layer was dried and concentrated in vacuo. 2-Nitrobenzenesulfonyl
chloride (31.7 mg, 0.143 mmol) and Et3N (26.5 mL, 0.191 mmol) were
added to a solution of residue in CH2Cl2 (1.0 mL) at 08C under N2 and
the resulting mixture was stirred at room temperature for 30 min. The
mixture was diluted with water and extracted with CH2Cl2. The organic
layer was dried and concentrated in vacuo. The residue was purified by
SiO2 column chromatography (hexane/AcOEt=2:1) to give 17 (51.6 mg,
73%) as a colorless amorphous soild. [a]2D7:8 =À12.7 (c=0.66 in CHCl3);
1H NMR (400 MHz, CDCl3): d=0.88–1.38 (5H, m), 1.86–2.07 (8H, m),
2.37–2.43 (2H, m), 3.15 (1H, d, J=1.4 Hz), 3.24 (1H, ddd, J=14.7, 9.6,
5.0 Hz), 3.51–3.62 (2H, m), 3.75 (3H, s), 4.40 (1H, d, J=8.2 Hz), 4.49
(1H, A in ABq, J=15.2 Hz), 4.58 (1H, B in ABq, J=15.2 Hz), 4.80 (1H,
dd, J=8.2, 2.7 Hz), 4.84 (1H, brs), 4.92–4.96 (3H, m), 5.50–5.59 (1H, m),
5.67–5.76 (1H, m), 6.81 (2H, d, J=8.7 Hz), 7.01–7.05 (4H, m), 7.14–7.20
(8H, m), 7.63–7.73 (3H, m), 8.05 ppm (1H, d, J=7.8 Hz); 13C NMR
(100 MHz, CDCl3): d=14.2, 21.0, 25.6, 31.4, 33.4, 38.7, 41.2, 45.7, 50.6,
55.2, 60.4, 78.7, 113.9, 114.1, 114.7, 117.0, 124.2, 127.17, 127.21, 127.6,
127.8, 128.0, 128.1, 128.3, 129.6, 129.7, 131.0, 131.8, 133.4, 133.7, 135.2,
138.3, 139.4, 147.9, 159.4, 211.5 ppm; IR (KBr): n˜ =3563, 2907, 1705,
Methyl 4-{(3aR,4R,6R,7R,7aR)-6-ethyl-4-(2-methoxy-2-oxoethyl)-1-[(2-
nitrophenyl)sulfonyl]-5-oxooctahydro-1H-indol-7-yl}butanoate (20):
A
solution of 14 (21.0 mg, 0.0456 mmol) in CH2Cl2 (1.0 mL) was bubbled
with ozone at À788C for 15 min. The reaction was quenched with PPh3
(95.7 mg, 0.365 mmol) at À788C and allowed to warm to room tempera-
ture. The mixture was stirred for 1 h and concentrated in vacuo. The resi-
due was purified by SiO2 column chromatography (hexane/AcOEt=1:2)
to give aldehyde 30 (17.2 mg, 81%) as a colorless oil. PDC (100 mg,
0.267 mmol) was added to a suspension of 30 (12.4 mg, 0.0267 mmol) and
Celite in DMF (0.3 mL) at room temperature under N2 and the resulting
mixture was stirred at room temperature for 24 h. Et2O and MgSO4 were
added, and the solution was filtered and concentrated in vacuo.
TMSCHN2 (2.0m in Et2O, 33.4 mL, 0.0667 mmol) was added to a solution
of the residue in benzene/MeOH (0.5 mL, v/v=4:1) at 08C under N2 and
the resulting mixture was stirred at room temperature for 15 min and
concentrated in vacuo. The residue was purified by SiO2 column chroma-
tography (hexane/AcOEt=1:2) to give 20 (9.8 mg, 70%) as a colorless
oil. [a]2D2:8 =À105.3 (c=0.28 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
0.93 (3H, t, J=7.3 Hz), 1.52–1.90 (9H, m), 2.03–2.14 (1H, m), 2.20 (2H,
t, J=7.8 Hz), 2.24 (1H, dd, J=16.5, 4.6 Hz), 2.33–2.41 (2H, m), 2.70
(1H, dd, J=16.9, 7.8 Hz), 2.95 (1H, ddd, J=12.8, 7.8, 5.0 Hz), 3.47 (1H,
dt, J=11.4, 5.9 Hz), 3.65 (3H, s), 3.66 (3H, s), 3.88 (1H, dd, J=10.5,
8.7 Hz), 4.00 (1H, dd, J=11.4, 4.1 Hz), 7.67–7.78 (3H, m), 8.04–8.07 ppm
(1H, m); 13C NMR (125 MHz, CDCl3): d=12.3, 22.9, 25.4, 26.5, 28.3,
31.6, 34.0, 41.1, 44.3, 47.2, 50.6, 51.5, 51.8, 55.2, 64.1, 124.4, 129.5, 131.2,
131.6, 133.9, 148.4, 172.4, 173.6, 210.3 ppm; IR (KBr): n˜ =2953, 2934,
1543 cmÀ1
; HRMS (FAB): m/z calcd for C44H50N2O8SNa: 789.3185
[M+Na]+; found: 789.3185.
N-{2-[(1R,2R,5R,6S)-2-Allyl-6-hydroxy-3-oxo-5-(pent-4-en-1-yl)cyclohex-
yl]ethyl}-2-nitrobenzenesulfonamide (18): CAN (404 mg, 0.737 mmol)
was added to a solution of 17 (113 mg, 0.147 mmol) in CH3CN/H2O
(1.5 mL, v/v=2:1) at room temperature and the resulting mixture was
stirred at room temperature for 5 h. The mixture was diluted with water
and extracted with AcOEt. The organic layer was washed with brine,
dried, and concentrated in vacuo. The residue was purified by SiO2
column chromatography (hexane/AcOEt=1:1) to give 18 (41.0 mg, 62%)
as a colorless oil. [a]2D5:7 =À18.0 (c=1.87 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.11–2.22 (12H, m), 2.16 (1H, dd, J=13.7, 5.0 Hz), 2.73 (1H,
dd, J=13.7, 5.5 Hz), 3.11–3.25 (2H, m), 3.94 (1H, brs), 4.93–5.02 (4H,
m), 5.63–5.80 (3H, m), 7.74–7.87 (3H, m), 8.12–8.14 ppm (1H, m);
13C NMR (125 MHz, CDCl3): d=26.0, 28.5, 31.1, 31.3, 33.5, 39.6, 40.7,
41.4, 42.5, 49.8, 69.9, 114.9, 116.9, 125.3, 131.1, 132.8, 133.56, 133.58,
135.4, 138.2, 148.0, 211.2 ppm; IR (KBr): n˜ =3339, 2928, 1701, 1541,
1167 cmÀ1; HRMS (FAB): m/z calcd for C22H31N2O6S: 451.1921 [M+H]+;
found: 451.1912.
1732, 1713, 1549, 1371, 1167 cmÀ1
; HRMS (FAB): m/z calcd for
C24H33N2O9S: 525.1907 [M+H]+; found: 525.1912.
Methyl 2-(5R,7aR,8R,10R,10aR)-10-ethyl-4,9-dioxododecahydroazipino-
AHCTUNGTRENNUNG
(3aR,4R,7R,7aR)-4-Allyl-1-[(2-nitrophenyl)sulfonyl]-7-(pent-4-en-1-yl)-
hexahydro-1H-indol-5(6H)-one (19): DIAD (1.9m in toluene, 0.15 mL,
0.272 mmol) and PPh3 (71.3 mg, 0.272 mmol) were added to a solution of
18 (81.7 mg, 0.181 mmol) in 1,4-dioxane (3.6 mL) at room temperature
under N2 and the resulting mixture was stirred at room temperature for
15 min. The mixture was concentrated in vacuo. The residue was purified
by SiO2 column chromatography (benzene/AcOEt=10:1) to give 19
(43.3 mg, 55%) as a colorless oil. [a]2D5:9 =À177.7 (c=0.77 in CHCl3);
1H NMR (400 MHz, C6D6): d=0.82–1.98 (9H, m), 1.87 (1H, dt, J=11.4,
5.0 Hz), 2.20–2.26 (1H, m), 2.30 (1H, dd, J=14.7, 5.5 Hz), 2.37–2.43 (1H,
m), 2.59 (1H, dd, J=14.7, 2.3 Hz), 2.66 (1H, brs), 3.34 (1H, dt, J=11.2,
5.9 Hz), 3.78 (1H, dd, J=11.0, 4.1 Hz), 3.89 (1H, dd, J=10.5, 8.7 Hz),
5.11–5.16 (4H, m), 5.75–5.85 (1H, m), 5.94–6.05 (1H, m), 6.78 (1H, dt,
J=7.8, 1.4 Hz), 6.88 (1H, dt, J=7.8, 1.4 Hz), 6.95 (1H, dt, J=7.8,
1.4 Hz), 7.90 ppm (1H, dt, J=7.8, 1.4 Hz); 13C NMR (100 MHz, CDCl3):
d=26.2, 26.8, 28.6, 31.3, 33.7, 37.2, 43.3, 43.8, 51.0, 53.3, 67.1, 114.5, 116.9,
124.3, 131.0, 131.6, 132.0, 133.8, 135.5, 138.3, 148.4, 208.5 ppm; IR (KBr):
n˜ =2928, 1713, 1547, 1373, 1167 cmÀ1; HRMS (FAB): m/z calcd for
C22H29N2O5S: 433.1772 [M+H]+; found: 433.1785.
a
0.0187 mmol) in CH3CN (0.3 mL) at 08C under N2 and the resulting mix-
ture was stirred at room temperature for 12 h. Sat. aq. NaHCO3 was
added and the resulting mixture was extracted with AcOEt. The organic
layer was washed with brine, dried, and concentrated in vacuo. The resi-
due was dissolved in toluene (1.0 mL) and stirred at reflux for 24 h. After
cooling, the mixture was concentrated in vacuo. The residue was purified
by SiO2 column chromatography (AcOEt/MeOH=10:1) to give 21
(5.5 mg, 95%) as a colorless oil. [a]1D7:4 =À45.8 (c=0.17 in CHCl3);
1H NMR (400 MHz, CDCl3): d=0.92 (3H, t, J=7.3 Hz), 1.39–1.50 (2H,
m), 1.66–2.08 (7H, m), 2.27–2.50 (5H, m), 2.59 (1H, dd, J=16.0, 5.5 Hz),
2.76 (1H, dd, J=16.0, 5.5 Hz), 3.47–3.55 (2H, m), 3.68 (3H, s), 3.72 ppm
(H, dd, J=11.9, 9.2 Hz); 13C NMR (100 MHz, CDCl3): d=12.4, 22.3,
22.6, 25.2, 26.7, 31.9, 34.4, 37.9, 42.4, 46.7, 49.1, 51.9, 53.2, 62.2, 170.9,
171.7, 212.8 ppm; IR (KBr): n˜ =2926, 2855, 1736, 1715, 1632, 1261 cmÀ1
;
HRMS (FAB): m/z calcd for C17H26NO4: 308.1862 [M+H]+; found:
308.1860.
(3aR,4R,6R,7R,7aR)-4-Allyl-6-ethyl-1-[(2-nitrophenyl)sulfonyl]-7-(pent-
4-en-1-yl)hexahydro-1H-indol-5(6H)-one (14): LHMDS (1.0m in THF,
13-Desmethyl-5-oxostenine (7): NaBH4 (1.8 mg, 0.0488 mmol) was added
to a solution of 21 (5.0 mg, 0.0162 mmol) in MeOH (0.3 mL) at 08C
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

H. Fujioka et al.
under N2 and the resulting mixture was stirred at 08C for 1.5 h. The reac-
tion was quenched with aq. 1n HCl and extracted with AcOEt. The or-
ganic layer was washed with brine, dried, and concentrated in vacuo. The
residue was purified by SiO2 column chromatography (AcOEt/MeOH=
10:1) to give 7 (2.9 mg, 64%) as a white solid. M.p. 1408C; [a]1D9:2 =À67.4
(c=0.13 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.97 (3H, t, J=
7.3 Hz), 1.44–1.68 (7H, m), 1.88–2.07 (4H, m), 2.30–2.57 (4H, m), 2.80
(1H, dd, J=17.9, 9.6 Hz), 3.40–3.75 (3H, m), 4.57 ppm (1H, dd, J=11.9,
9.6 Hz); 13C NMR (100 MHz, CDCl3): d=10.2, 22.4, 22.9, 27.8, 33.1 (2C),
35.5, 37.4, 42.5, 44.2, 46.7, 60.6, 81.5, 171.0, 176.0 ppm; IR (KBr): n˜ =
2961, 2928, 1775, 1634, 1263 cmÀ1; HRMS (EI): m/z calcd for C16H23NO3:
277.1687 [M]+; found: 277.1678; the spectroscopic data were identical to
the reported data.[5b,c,9]
Ethyl
4-[(1S,3R,4R,6R,8R,9R,10R,11R,12R)-12-ethyl-10-hydroxy-9-(2-
hydroxyethyl)-6-methoxy-3,4-diphenyl-2,5-dioxabicycloACTHNUTRGNEU[GN 6.4.0]dodecan-11-
yl]butanoate (25): A catalytic amount of OsO4 was added to a solution of
23 (136 mg, 0.286 mmol) in THF/H2O (16 mL. v/v=1:1) at room temper-
ature and the resulting mixture was stirred at room temperature for
15 min. NaIO4 (256 mg, 1.20 mmol) was added in several portions and
the resulting mixture was stirred for 1 h. The mixture was diluted with
water and AcOEt and extracted with AcOEt. The organic layer was
washed with brine, dried, and concentrated in vacuo. The residue was pu-
rified by SiO2 column chromatography (hexane/AcOEt=1:1) to give al-
dehyde 24 (95.0 mg, 69%, d.r. 2.5:1) as a colorless oil. DIBAL-H (0.95m
in hexane, 0.26 mL) was added to a solution of 24 (39.0 mg, 0.0812 mmol)
in toluene (1.5 mL) at À788C under N2 and the resulting mixture was
stirred at À788C for 1 h. The reaction was quenched with MeOH and
then allowed to warm to room temperature. Aq. 2n NaOH was added
and the resulting mixture was extracted with AcOEt. The organic layer
was washed with brine, dried, and concentrated in vacuo. The residue
was purified by SiO2 column chromatography (hexane/AcOEt=1:3) to
give alcohol 31 (30.3 mg, 77%, 2.5:1 d.r.) as a colorless oil. Ph3P=
(1R,3R,4R,6R,8R,9R,11R,12R)-9,11-Diallyl-12-ethyl-6-methoxy-3,4-di-
phenyl-2,5-dioxabicycloACHTUNGTRENNUNG[6.4.0]dodecan-10-one (5): EtMgBr (1.02m in
THF, 3.4 mL, 3.50 mmol) was added to a stirred suspension of 3 (255 mg,
0.700 mmol) and CuI (10.0 mg, 0.0525 mmol) in THF (7.0 mL) at À788C
under Ar and the resulting mixture was stirred for 30 min at À788C and
then allowed to warm to 08C. TMSCl (0.72 mL, 5.67 mmol), Et3N
(0.87 mL, 6.24 mmol), and HMPA (0.50 mL, 2.87 mmol) were added to
the mixture at 08C and the resulting mixture was allowed to warm to
room temperature and concentrated in vacuo. n-Pentane was then added
and the mixture was filtered and concentrated in vacuo. MeLi (1.14m in
Et2O, 2.2 mL, 2.51 mmol) was added to a solution of the residue in DME
(7.0 mL) at À108C under Ar and the resulting mixture was stirred for
15 min at À158C and allowed to warm to 08C. Allyl iodide (0.25 mL,
2.73 mmol) was added at 08C and the resulting mixture was stirred for
1 h. The reaction was quenched with sat. aq. Na2S2O3 and extracted with
Et2O. The organic layer was washed with brine, dried, and concentrated
in vacuo. The residue was purified by SiO2 column chromatography
CHCO2Et (19.9 mg, 0.0572 mmol) was added to
a solution of 31
(18.4 mg, 0.0381 mmol) in benzene (0.4 mL) at room temperature under
N2 and the resulting mixture was stirred at reflux for 3 h. After cooling,
the mixture was concentrated in vacuo. A catalytic amount of 10% Pd/C
was added to a solution of the residue in AcOEt (0.5 mL) at room tem-
perature and the resulting mixture was stirred at room temperature for
2 h under H2. The mixture was filtered and concentrated in vacuo. The
residue was purified by SiO2 column chromatography (hexane/AcOEt=
1:2) to give 25 (19.5 mg, 92%) as a colorless oil. [a]2D4:5 = +4.8 (c=1.01 in
1
CHCl3); H NMR (300 MHz, CDCl3): d=0.82 (3H, brs), 1.13–2.08 (15H,
m), 1.23 (3H, t, J=7.2 Hz), 2.04–2.33 (3H, m), 3.22 (3H, s), 3.66 (1H,
brs), 3.82 (2H, t, J=7.2 Hz), 3.94 (1H, brs), 4.12 (2H, q, J=7.1 Hz), 4.32
(1H, d, J=8.9 Hz), 4.50 (1H, d, J=8.9 Hz), 5.24 (1H, dd, J=6.4, 3.0 Hz),
6.90–6.99 (4H, m), 7.16–7.19 ppm (6H, m); 13C NMR (75.5 MHz,
CDCl3): d=14.2, 22.7, 28.6, 34.3, 35.3, 37.0, 37.3, 39.6, 40.9, 54.5, 60.2,
61.2, 71.1, 77.2, 88.6, 89.6, 106.3, 126.9, 127.4, 127.7, 127.9, 128.1, 127.9,
128.1, 137.9, 138.8, 173.8 ppm; IR (KBr): n˜ =3478, 2934, 1732, 1075,
1057 cmÀ1; HRMS (FAB): m/z calcd for C33H47O7: 555.3322 [M+H]+;
found: 555.3341.
(hexane/AcOEt=15:1) to give
5 (145 mg, 44%) as a colorless oil.
[a]2D4:7 =À76.9 (c=1.90 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.81
(3H, t, J=7.3 Hz), 1.38–1.43 (1H, m), 1.45–1.65 (1H, m), 1.84–2.04 (3H,
m), 2.20–2.51 (5H, m), 2.60–2.67 (2H, m), 3.21 (3H, s), 4.09 (1H, dd, J=
6.0, 2.3 Hz), 4.38 (2H, s), 4.80–4.86 (2H, m), 5.07–5.13 (2H, m), 5.22
(1H, dd, J=8.6, 2.8 Hz), 5.72 (2H, m), 6.82–7.21 ppm (10H, m);
13C NMR (75.5 MHz, CDCl3): d=9.9, 23.3, 32.4, 35.4, 36.9, 37.6, 44.7,
48.4, 51.2, 54.6, 79.7, 87.5, 90.0, 105.6, 116.2, 117.4, 127.0, 127.4, 127.5,
127.7, 127.8, 128.0, 135.0, 136.3, 137.9, 138.7, 213.2 ppm; IR (KBr): n˜ =
3034, 1713, 1455, 1121 cmÀ1; elemental analysis calcd (%) for C31H38O4:
C 78.45, H 8.07; found: C 78.44, H 8.08.
Ethyl
oxy]ethyl}-12-ethyl-6-methoxy-10-oxo-3,4-diphenyl-2,5-dioxabicyclo-
AHCTUNGERTG[NNUN 6.4.0]dodecan-11-yl]butanoate (26): Imidazole (62.2 mg, 0.914 mmol)
4-[(1S,3R,4R,6R,8R,9R,11R,12R)-9-{2-[(tert-butyldimethylsilyl)-
AHCTUNGTRENNUNG
and TBSCl (68.8 mg, 0.457 mmol) were added to a stirred solution of 25
(211 mg, 0.381 mmol) in DMF (0.8 mL) at room temperature under N2
and the resulting mixture was stirred at room temperature for 1 h. The
reaction was quenched with sat. aq. NH4Cl and extracted with Et2O. The
organic layer was washed with brine, dried, and concentrated in vacuo.
The residue was purified by SiO2 column chromatography (hexane/
AcOEt=4:1) to give TBS ether 32 (254 mg, 99%) as a colorless oil. A
suspension of PDC (180 mg, 0.478 mmol) in CH2Cl2 (2.0 mL) was added
(1R,3R,4R,6R,8R,9R,10R,11R,12R)-9,11-Diallyl-12-ethyl-6-methoxy-3,4-
diphenyl-2,5-dioxabicycloACHTUNTRGNE[UNG 6.4.0]dodecan-10-ol (23): LiAlH4 (21.2 mg,
0.556 mmol) in THF (3.0 mL) was added to a solution of 5 (220 mg,
0.464 mmol) in THF (3.0 mL) at 08C under N2 and the resulting mixture
was allowed to warm to room temperature. The reaction was quenched
with 15% aq. NaOH and filtered and concentrated in vacuo to give 23
containing the minor isomer (218 mg, 99%, d.r. 9:1). The obtained 23
was acetylated by Ac2O (1 mL), DMAP (cat.), and pyridine (2 mL) at
room temperature for 1 h. The reaction was quenched with sat. aq.
NaHCO3 and extracted with AcOEt. The organic layer was washed with
brine, dried, and concentrated in vacuo. The residue was purified by SiO2
column chromatography (hexane/AcOEt=8:1) to afford the acetylated
23 (199.4 mg, 85%). LiAlH4 (29.7 mg, 0.78 mmol) in THF (1.5 mL) was
added to a solution of the acetylated 23 (199.4 mg, 0.39 mmol) in THF
(3.0 mL) at 08C under N2 and the resulting mixture was allowed to warm
to room temperature. The reaction was quenched with 15% aq. NaOH
and filtered and concentrated in vacuo to give 23 (185.4 mg, 99%).
1H NMR (270 MHz, CDCl3): d=0.82 (3H, brs), 1.15–1.18 (2H, m), 1.57–
1.64 (2H, m), 1.92–2.41 (8H, m), 3.23 (3H, s), 3.67 (1H, d, J=7.4 Hz),
3.90 (1H, brs), 4.34 (1H, d, J=9.1 Hz), 4.48 (1H, d, J=9.1 Hz), 4.96–
5.13 (4H, m), 5.27 (1H, dd, J=7.7, 1.3 Hz), 5.70–5.89 (2H, m), 6.89–7.00
(4H, m), 7.12–7.19 ppm (6H, m); 13C NMR (75.5 MHz, CDCl3): d=14.1,
22.6, 31.5, 33.9, 35.9, 36.8, 37.4, 39.7, 43.6, 54.4, 70.4, 88.4, 89.6, 106.3,
115.9, 116.7, 126.9, 127.1, 127.3, 127.5, 127.6, 127.7, 127.9, 128.0, 136.7,
137.4, 137.9, 138.8 ppm; IR (KBr): n˜ =3472, 2934, 1455, 1121 cmÀ1; ele-
mental analysis calcd (%) for C31H40O4: C 78.11, H 8.46; found: C 77.96,
H 8.40.
to
a suspension of 32 (242 mg, 0.362 mmol) and Celite in CH2Cl2
(1.5 mL) at room temperature under N2 and the resulting mixture was
stirred at room temperature overnight. Et2O was then added, the solution
filtered, and concentrated in vacuo. The residue was purified by SiO2
column chromatography (hexane/AcOEt=5:1) to give 26 (230 mg, 95%)
as a colorless oil. [a]2D7:3 =À32.6 (c=1.64 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=0.05 (3H, s), 0.06 (3H, s), 0.79 (3H, t, J=8.2 Hz), 0.90 (9H,
s), 1.21 (3H, t, J=7.1 Hz), 1.25–2.55 (14H, m), 2.50–2.60 (1H, m), 2.65–
2.80 (1H, m), 3.18 (3H, s), 3.62 (2H, t, J=6.5 Hz), 4.00–4.15 (2H, m),
4.36 (2H, s), 5.18 (1H, d, J=5.6 Hz), 6.75–7.25 ppm (10H, m); 13C NMR
(75.5 MHz, CDCl3): d=À5.4, À5.3, 10.3, 14.2, 18.3, 22.8, 23.7, 26.0, 28.1,
33.7, 34.4, 36.9, 39.4, 46.2, 47.5, 48.5, 54.6, 60.1, 60.9, 80.5, 87.8, 90.1,
105.7, 127.0, 127.4, 127.6, 127.7, 127.8, 127.9, 137.9, 138.8, 173.4,
214.1 ppm; IR (KBr): n˜ =2928, 1736, 1711, 1090 cmÀ1; elemental analysis
calcd (%) for C39H58O7Si: C 70.23, H 8.77; found: C 70.42, H 8.72.
Ethyl 4-[(1S,3R,4R,6R,8R,9R,11R,12R)-9-(2-azidoethyl)-12-ethyl-6-me-
thoxy-10-oxo-3,4-diphenyl-2,5-dioxabicycloACTHNUTRGNE[UNG 6.4.0]dodecan-11-yl]buta-
noate (8): TAS-F (199 mg, 0.724 mmol) was added to a stirred solution of
26 (230 mg, 0.345 mmol) in DMF/H2O (3.0 mL, v/v=20:1) at 08C. The
resulting mixture was gradually allowed to warm to room temperature
&
8
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Total Synthesis of (À)-Stenine and 9a-epi-Stenine
FULL PAPER
and was then stirred for 24 h. The reaction was quenched with sat. aq.
NH4Cl and extracted with Et2O. The organic layer was washed with
brine, dried, and concentrated in vacuo. The residue was purified by SiO2
column chromatography (hexane/AcOEt=1:1) to give alcohol 33
(143 mg, 75%) as a colorless oil. PPh3 (133 mg, 0.508 mmol), DEAD
(50% in toluene, 0.22 mL, 0.508 mmol), and DPPA (55.0 mL,
0.254 mmol) were added to a stirred solution of 33 (117 mg, 0.212 mmol)
in THF (1.2 mL) at 08C under N2. The resulting mixture was gradually
allowed to warm to room temperature and stirred for 1 h at room tem-
perature. MeOH was added and concentrated in vacuo. The residue was
purified by SiO2 column chromatography (hexane/AcOEt=4:1) to give 8
(111 mg, 91%) as a colorless oil. [a]2D6:3 =À23.8 (c=1.68 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.84 (3H, t, J=7.3 Hz), 1.22 (3H, t, J=
7.2 Hz), 1.26–2.20 (14H, m), 2.45–2.47 (1H, m), 2.76 (1H, td, J=8.7,
4.9 Hz), 3.20 (3H, s), 3.35–3.41 (2H, m), 4.08 (2H, q, J=7.2 Hz), 4.38
(1H, A in ABq, J=9.0 Hz), 4.42 (1H, B in ABq, J=9.0 Hz), 5.20 (1H,
dd, J=7.1, 3.6 Hz), 6.84–7.20 ppm (10H, m); 13C NMR (75.5 MHz,
CDCl3): d=10.6, 14.1, 22.7, 24.1, 28.6, 29.2, 34.1, 36.8, 39.5, 46.7, 47.5,
49.3, 49.3, 54.5, 60.0, 81.0, 88.2, 89.9, 105.4, 126.9, 127.4, 127.6, 127.7,
127.8, 137.7, 128.6, 173.2, 213.4 ppm; IR (KBr): n˜ =2878, 2098, 1731,
1709 cmÀ1; elemental analysis calcd (%) for C33H43N3O6: C 68.61, H 7.50,
N 7.27; found: C 68.79, H 7.62, N 7.16.
9a-epi-Stenine: A solution of 29 (6.6 mg, 0.0238 mmol) in THF (1.0 mL)
was added to a solution of LDA (1.0m in THF, 0.20 mL, 0.200 mmol) at
À788C under N2 and the resulting mixture was stirred at À788C for
30 min. HMPA (40.0 mL, 0.230 mmol) and MeI (50.0 mL, 0.803 mmol)
were added and the resulting mixture was stirred at À788C for 1 h. The
reaction was quenched with sat. aq. NH4Cl and extracted with AcOEt.
The organic layer was washed with brine, dried, and concentrated in
vacuo. The residue was dissolved in MeOH (1.0 mL) and Na2CO3
(19.0 mg, 0.179 mmol) was added and the resulting mixture was stirred at
reflux for 1 h. After cooling, H2O was added and extracted with AcOEt.
The organic layer was washed with brine, dried, and concentrated in
vacuo. The residue was purified by SiO2 column chromatography
(CH2Cl2/MeOH=10:1) to give 9a-epi-stenine (4.3 mg, 65%) as a glassy
powder. [a]2D5:8 = +14.7 (c=0.83 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=0.92 (3H, t, J=7.1 Hz), 1.22–2.49 (18H, m), 1.34 (3H, d, J=7.5 Hz),
3.16–3.40 (2H, m), 4.53 ppm (1H, t, J=7.2 Hz); 13C NMR (75.5 MHz,
CDCl3): d=9.3, 16.6, 22.4, 25.3, 27.6, 29.6, 29.7, 38.5, 40.7, 42.3, 55.9, 57.4,
68.5, 71.1, 77.2, 81.6, 180.1 ppm; IR (KBr): n˜ =2931, 1769, 1219,
1188 cmÀ1; HRMS (FAB): m/z calcd for C17H28NO2: 278.2120 [M+H]+;
found: 278.2121.
(7aR,8R,8aS,10R,11R,13R,14aR,14bR,14cS)-8-Ethyl-13-methoxy-10,11-
diphenyltetradecahydroazepinoACHTUNGTRENNN[UG 3,2,1-hi]AHCTUNRTGEG[NNUN 1,4]dioxocinoCAHTNUGTREN[NNGU 6,5-e]indol-
Acknowledgements
4(5H)one (9): Et3P (20% in toluene, 90 mL, 0.157 mmol) was added to a
stirred solution of 8 (75.5 mg, 0.131 mmol) in THF (1.3 mL) at room tem-
perature under N2 and the resulting mixture was stirred at room tempera-
ture for 3 h. MeOH (1.3 mL) was added and then NaBH4 (10.0 mg,
0.264 mmol) was added at 08C and the resulting mixture was stirred at
room temperature for 1 h. The reaction was quenched with sat. aq.
NaHCO3 and extracted with AcOEt. The organic layer was washed with
brine, dried, and concentrated in vacuo. The residue was dissolved in tol-
uene (4.0 mL) and stirred at reflux for 2 h. After cooling, the mixture
was concentrated in vacuo. The residue was purified by SiO2 column
chromatography (AcOEt) to give 9 (34.0 mg, 53%) as a colorless oil.
[a]2D6:2 =À34.9 (c=1.14 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.62
(3H, t, J=7.3 Hz), 1.21–2.50 (15H, m), 1.26 (3H, t, J=7.2 Hz), 2.48 (2H,
t, J=5.0 Hz), 2.79 (1H, brs), 3.32 (1H, dd, J=11.7, 6.9 Hz), 3.27 (3H, s),
3.65 (1H, dd, J=11.7, 8.3 Hz), 3.71–3.77 (1H, m), 4.39 (1H, A in ABq,
This work was supported by a Grant-in-Aid for Scientific Research from
the Japan Society for the Promotion of Science (JSPS). K. N. acknowl-
edges a Research Fellowship for Young Scientists from JSPS.
[1] a) M. Gçtz, O. E. Edwards in The Alkaloids, Vol. 9 (Ed: R. H. F.
Manske), Academic Press, New York, 1967, pp. 545–551; b) M.
Gçtz, G. M. Strunz in Alkaloids, MTP International Review of Scien-
ces, Series 1, Vol. 9 (Ed: K. Wiesner), Butterworth, London, 1975,
pp. 143–160; c) R. A. Pilli, M. C. F. de Oliveira, Nat. Prod. Rep.
2000, 17, 117–127; d) R. A. Pilli, G. B. Rosso, M. C. F. de Oliveira
in The Alkaloids, Vol. 62 (Ed: G. A. Cordell), Elsevier, New York,
2005, pp. 77–173; e) H. Greger, Planta Med. 2006, 72, 99–113; f) R.
Alibꢀs, M. Figueredo, Eur. J. Org. Chem. 2009, 2421–2435; g) R. A.
Pilli, G. B. Rosso, M. C. F. de Oliveira, Nat. Prod. Rep. 2010, 27,
1908–1937.
[2] a) S. Uyeo, H. Irie, H. Harada, Chem. Pharm. Bull. 1967, 15, 768–
770; b) H. Harada, H. Irie, N. Masaki, K. Osaki, S. Uyeo, Chem.
Commun. (London) 1967, 460–462.
[3] a) C.-Y. Chen, D. J. Hart, J. Org. Chem. 1990, 55, 6236–6240; b) C.-
Y. Chen, D. J. Hart, J. Org. Chem. 1993, 58, 3840–3849.
J=9.3 Hz), 4.41 (1H,
B in ABq, J=9.3 Hz), 5.34 (1H, dd, J=8.9,
3.8 Hz), 6.90–7.19 ppm (10H, m); 13C NMR (75.5 MHz, CDCl3): d=9.1,
20.6, 23.8, 28.3, 35.2, 36.1, 37.7, 38.2, 40.2, 44.1, 45.2, 54.6, 60.5, 77.2, 78.2,
86.4, 89.3, 105.3, 127.1, 127.4, 127.5, 127.6, 127.8, 127.9, 138.0, 138.8,
174.3 ppm; IR (KBr): n˜ =3033, 1646, 1455, 1211, 1055 cmÀ1; HRMS
(FAB): m/z: calcd for C31H40NO4: 490.2958 [M+H]+; found: 490.2952.
(7aR,8R,8aS,11aR,11bR,11cR)-8-Ethyldodecahydroazepino
ACHTUNGTREN[NGNU 3,2,1-hi]furo-
ACHTUNGTRENNUNG[3,2-e]indol-10(2H)-one BH3 complex (29): BH3·THF (1.0m in THF,
[4] a) J. D. Ginn, A. Padwa, Org. Lett. 2002, 4, 1515–1517; b) A.
Padwa, J. D. Ginn, J. Org. Chem. 2005, 70, 5197–5206.
0.35 mL, 0.350 mmol) was added to a stirred solution of 9 (34.0 mg,
0.0694 mmol) in THF (1.0 mL) at 08C under N2. The resulting mixture
was gradually allowed to warm to room temperature and stirred for 3 h.
EtOH (0.3 mL) was added and the mixture was added to liq. NH3 at
À788C. Calcium (30.0 mg, 0.749 mmol) was added at À788C and the re-
sulting mixture was stirred at À788C for 1 h. The reaction was quenched
with sat. aq. NH4Cl and the resulting mixture was extracted with AcOEt.
The organic layer was washed with brine, dried, and concentrated in
vacuo. The residue was dissolved in CH2Cl2 (1.0 mL) and the mixture
was added to the suspension of PDC (50.0 mg, 0.133 mmol) and Celite in
CH2Cl2 (0.5 mL) at room temperature. The resulting mixture was stirred
at room temperature overnight. Et2O was added, filtered, and concentrat-
ed in vacuo. The residue was purified by SiO2 column chromatography
(benzene/AcOEt=4:1) to give 29 (7.2 mg, 37%) as a glassy powder.
[a]2D5:3 = +15.5 (c=1.32 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.89
(3H, t, J=7.5 Hz), 1.24–2.05 (13H, m), 2.27–2.42 (3H, m), 2.69–2.87
(5H, m), 3.17–3.25 (2H, m), 3.59 (1H, t, J=7.9 Hz), 4.46 ppm (1H, dd,
J=8.1, 6.3 Hz); 13C NMR (75.5 MHz, CDCl3): d=8.9, 22.4, 24.1, 27.6,
28.5, 30.5, 34.6, 35.3, 35.8, 39.8, 41.7, 61.9, 63.2, 77.8, 81.6, 175.6 ppm; IR
(KBr): n˜ =2965, 2382, 1782, 1165 cmÀ1; elemental analysis calcd (%) for
C16H28BNO2: C 69.32, H 10.18, N 5.05; found: C 69.11, H 9.99, N 4.94.
[5] a) J. E. Golden, J. Aubꢀ, Angew. Chem. 2002, 114, 4492–4494;
Angew. Chem. Int. Ed. 2002, 41, 4316–4318; b) Y. Zeng, J. Aubꢀ, J.
Am. Chem. Soc. 2005, 127, 15712–15713; c) K. J. Frankowski, J. E.
Golden, Y. Zeng, Y. Lei, J. Aubꢀ, J. Am. Chem. Soc. 2008, 130,
6018–6024.
[6] a) L. Xiang, A. P. Kozikowski, Synlett 1990, 279–281; b) J. H. Rigby,
S. Laurent, A. Cavezza, M. J. Heeg, J. Org. Chem. 1998, 63, 5587–
5591; c) S. H. Jung, J. E. Lee, H. J. Joo, S. H. Kim, H. Y. Koh, Bull.
Korean Chem. Soc. 2000, 21, 159–160; d) L. Zhu, R. Lauchli, M.
Loo, K. J. Shea, Org. Lett. 2007, 9, 2269–2271; e) A. J. M. Burrell, L.
Watson, N. G. Martin, N. Oram, I. Coldham, Org. Biomol. Chem.
2010, 8, 4530–4532; f) R. W. Bates, S. Sridhar, J. Org. Chem. 2011,
76, 5026–5036.
[7] a) P. Wipf, Y. Kim, D. M. Goldstein, J. Am. Chem. Soc. 1995, 117,
11106–11112; they have also reported the total synthesis of a relat-
ed Stemona alkaloid, tuberotemonine, see: b) P. Wipf, S. R. Rector,
H. Takahashi, J. Am. Chem. Soc. 2002, 124, 14848–14849; c) P.
Wipf, S. R. Spencer, J. Am. Chem. Soc. 2005, 127, 225–235.
[8] a) Y. Morimoto, M. Iwahashi, K. Nishida, Y. Hayashi, H. Shirahama,
Angew. Chem. 1996, 108, 968–970; Angew. Chem. Int. Ed. Engl.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!

H. Fujioka et al.
1996, 35, 904–906; b) Y. Morimoto, M. Iwahashi, T. Kinoshita, K.
Nishida, Chem. Eur. J. 2001, 7, 4107–4116.
[9] J. Chen, J. Chen, Y. Xie, H. Zhang, Angew. Chem. 2012, 124, 1048–
1051; Angew. Chem. Int. Ed. 2012, 51, 1024–1027.
[10] a) H. Fujioka, H. Kitagawa, N. Matsunaga, Y. Nagatomi, Y. Kita,
Tetrahedron Lett. 1996, 37, 2245–2248; b) H. Fujioka, H. Kitagawa,
Y. Nagatomi, Y. Kita, J. Org. Chem. 1996, 61, 7309–7315.
[11] a) H. Fujioka, N. Kotoku, Y. Sawama, H. Kitagawa, Y. Ohba, T.-L.
Wang, Y. Nagatomi, Y. Kita, Chem. Pharm. Bull. 2005, 53, 952–957;
for a related desymmetrization strategy for asymmetric synthesis de-
veloped in our laboratory, see: b) H. Fujioka, Y. Ohba, H. Hirose,
K. Murai, Y. Kita, Angew. Chem. 2005, 117, 744–747; Angew. Chem.
Int. Ed. 2005, 44, 734–737; c) H. Fujioka, Y. Ohba, H. Hirose, K.
Nakahara, K. Murai, Y. Kita, Tetrahedron 2008, 64, 4233–4245;
d) H. Fujioka, K. Murai, Y. Ohba, H. Hirose, Y. Kita, Chem.
Commun. 2006, 832–834; e) H. Fujioka, K. Nakahara, H. Hirose, T.
Oki, Y. Kita, Chem. Commun. 2011, 47, 1060–1062.
[12] a) H. Fujioka, Y. Sawama, N. Kotoku, T. Ohnaka, T. Okitsu, N.
Murata, O. Kubo, R. Li, Y. Kita, Chem. Eur. J. 2007, 13, 10225–
10238; b) H. Fujioka, Y. Ohba, K. Nakahara, M. Takatsuji, K.
Murai, M. Ito, Y. Kita, Org. Lett. 2007, 9, 5605–5608; c) H. Fujioka,
K. Nakahara, T. Oki, K. Hirano, T. Hayashi, Y. Kita, Tetrahedron
Lett. 2010, 51, 1945–1946; d) K. Nakahara, K. Hirano, R. Maehata,
Y. Kita, H. Fujioka, Org. Lett. 2011, 13, 2015–2017.
chi, Bull. Chem. Soc. Jpn. 1994, 67, 290–292; d) J. M. Garcꢂa
Fernꢃndez, C. O. Mellet, A. M. Marꢂn, J. Fuentes, Carbohydr. Res.
1995, 274, 263–268.
[16] A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff,
R. D. Shah, J. Org. Chem. 1996, 61, 3849–3862.
[17] a) H. Fujioka, Y. Ohba, H. Hirose, K. Murai, Y. Kita, Org. Lett.
2005, 7, 3303–3306; b) H. Fujioka, H. Hirose, Y. Ohba, K. Murai,
K. Nakahara, Y. Kita, Tetrahedron 2007, 63, 625–637.
[18] Other solvents, such as toluene, DMF, Et2O, CH3CN, and CH2Cl2
gave poor results. We also examined the effect of the protecting
group on the nitrogen atom (para-toluenesulfonyl (Ts), tert-butoxy-
carbonyl (Boc), benzyl (Bn), and p-Ns) under the optimized condi-
tions. However, the Mitsunobu cyclization did not occur.
[19] The numbering is the same as that for stenine.
[20] N. Hashimoto, T. Aoyama, T. Shioiri, Chem. Pharm. Bull. 1981, 29,
1475–1478.
[21] Although chiral 23 was a glassy powder, racemic 23 was crystalline
and a minor isomer was separated by recrystallization (AcOEt). The
relative stereochemistry of 23 was determined by using X-ray crys-
tallographic analysis of racemic 23. CCDC-199947 contains the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[22] R. Pappo, D. S. Allen, Jr., R. U. Remieux, W. S. Johnson, J. Org.
Chem. 1956, 21, 478–479.
[23] K. A. Scheidt, H. Chen, B. C. Follows, S. R. Chemler, D. S. Coffey,
W. R. Roush, J. Org. Chem. 1998, 63, 6436–6437.
[13] a) T. Kan, T. Fukuyama, Chem. Commun. 2004, 353–359; b) T. Kan,
T. Fukuyama, J. Synth. Org. Chem. Jpn. 2001, 59, 779–789.
[14] Compound 11 was obtained as a single isomer and the absolute con-
figuration of the secondary alcohol in 11 was deduced by a Zimmer-
man–Traxler model.
[15] a) K. Tanemura, T. Suzuki, T. Horaguchi, J. Chem. Soc. Chem.
Commun. 1992, 979–980; b) A. Oku, M. Kinugasa, T. Kamada,
Chem. Lett. 1993, 165–168; c) K. Tanemura, T. Suzuki, T. Horagu-
Received: February 4, 2012
Revised: July 14, 2012
Published online: && &&, 0000
&
10
&
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Asymmetric Total Synthesis of (À)-Stenine and 9a-epi-Stenine
FULL PAPER
Alkaloids
H. Fujioka,* K. Nakahara, N. Kotoku,
Y. Ohba, Y. Nagatomi, T.-L. Wang,
Y. Sawama, K. Murai, K. Hirano,
T. Oki, S. Wakamatsu,
Y. Kita .......................... &&&& — &&&&
Stereocontrolled synthesis: Stereocon-
trolled syntheses of (À)-stenine and
9a-epi-stenine have been developed by
using a common cyclohexenone inter-
mediate (see scheme). All six stereo-
Asymmetric Total Synthesis of (À)-
Stenine and 9a-epi-Stenine
genic centers in the cyclohexane ring
were introduced with a high degree of
stereoselectivity.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
11
&
ÞÞ
These are not the final page numbers!