Asymmetric formal synthesis of (-)-pancracine via catalytic enantioselective C-H amination process

Article abstract of DOI:10.1016/j.tet.2008.10.091

The reaction of silyl enol ethers derived from cyclohexanone with [(4-nitrophenylsulfonyl)imino]phenyliodinane (pNsN{double bond, long}IPh) catalyzed by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh₂(S-TCPTTL)₄, provides, after desilylation, N-pNs-protected (S)-β-aminocyclohexanone in up?to 72% ee. This represents the first example of the insertion of nitrene species into an allylic C-H bond of silyl enol ethers. Using this process, a new catalytic asymmetric route to an advanced intermediate in Overman's synthesis of the montanine-type Amaryllidaceae alkaloid (-)-pancracine has been developed. The key steps involve (a) a one-pot Rh₂(R-TCPTTL)₄-catalyzed sequential 1,4-hydrosilylation/enantioselective C-H amination of 2-cyclohexen-1-one, (b) N-alkylation and subsequent intramolecular Mukaiyama aldol reaction/dehydration, and (c) a regio- and stereocontrolled reductive deoxygenation of?bicyclic enone 27 with migration of the double bond to create the C1/C11a double bond and the stereogenic center at C11 of 3-arylhexahydroindole 31.

Full text of DOI:10.1016/j.tet.2008.10.091

Tetrahedron 65 (2009) 3069–3077
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Tetrahedron
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Asymmetric formal synthesis of (ꢀ)-pancracine via catalytic enantioselective
C–H amination process
Masahiro Anada, Masahiko Tanaka, Naoyuki Shimada, Hisanori Nambu, Minoru Yamawaki,
*
Shunichi Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 October 2008
Received in revised form 28 October 2008
Accepted 28 October 2008
Available online 5 November 2008
The reaction of silyl enol ethers derived from cyclohexanone with [(4-nitrophenylsulfonyl)-
imino]phenyliodinane (pNsN]IPh) catalyzed by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-
leucinate], Rh2(S-TCPTTL)4, provides, after desilylation, N-pNs-protected (S)-b-aminocyclohexanone in
up to 72% ee. This represents the first example of the insertion of nitrene species into an allylic C–H bond
of silyl enol ethers. Using this process, a new catalytic asymmetric route to an advanced intermediate in
Overman’s synthesis of the montanine-type Amaryllidaceae alkaloid (ꢀ)-pancracine has been developed.
The key steps involve (a) a one-pot Rh2(R-TCPTTL)4-catalyzed sequential 1,4-hydrosilylation/enantio-
selective C–H amination of 2-cyclohexen-1-one, (b) N-alkylation and subsequent intramolecular
Mukaiyama aldol reaction/dehydration, and (c) a regio- and stereocontrolled reductive deoxygenation
of bicyclic enone 27 with migration of the double bond to create the C1/C11a double bond and the
stereogenic center at C11 of 3-arylhexahydroindole 31.
Dedicated to Professor Justin Du Bois on his
receipt of the 2008 Tetrahedron Young In-
vestigator Award
Keywords:
Amaryllidaceae alkaloids
C–H amination
Ó 2008 Elsevier Ltd. All rights reserved.
(ꢀ)-Pancracine
Chiral dirhodium(II) catalyst
1. Introduction
The montanine class of Amaryllidaceae alkaloids,1 includ-
ing (ꢀ)-montanine (1),2 (ꢀ)-coccinine (2),2 (ꢀ)-pancracine (3),3
(ꢀ)-brunsvigine (4),4 (ꢀ)-manthine (5),2 (ꢀ)-nangustine (6),5 and
(þ)-montabuphine (7),6 shares a 5,11-methanomorphanthridine core
with a C1/C11a double bond and differ only in the nature and stereo-
chemistry of the oxygen-based substituents at C2 and C3, except for
(ꢀ)-nangustine (6). These alkaloids have been shown to display anxio-
lytic, antidepressive, anticonvulsive and weak hypotensive activities.7
In the early 1990s, Overman and Shim accomplished the first
total synthesis of (ꢁ)- and (ꢀ)-pancracine employing a tandem aza-
Cope rearrangement/Mannich cyclization of B and a Pictet–Spengler
cyclization of A as the pivotal steps (Scheme 1).8 Hoshino and co-
workers described the first total synthesis of (ꢁ)-coccinine,
(ꢁ)-montanine, and (ꢁ)-pancracine utilizing an intramolecular re-
ductive cyclization of D as the key step to assemble the pentacyclic
framework.9 The same group also developed a radical cyclization
strategy (E/C) for the formal total synthesis of these alkaloids.10
Since their pioneering studies, this class of alkaloids has been the
subject of a considerable amount of innovative synthetic work.
Weinreb and Jin reported the enantioselective synthesis of alkaloids
1–4 exploiting an intramolecular concerted allenylsilane imino ene
cyclization of F.11 Pearson and Lian achieved the enantioselective
total synthesis of (þ)-coccinine employing an intramolecular cy-
cloaddition of the 2-azaallyl anion derived from H.12 Sha and co-
workers developed an anionic cyclization method (J/I) for the total
synthesis of (ꢀ)-brunsvigine13 and (ꢀ)-manthine.13b Banwell and
co-workers developed chemoenzymatic approaches including
a radical addition/elimination sequence (N/K–M) for the total
synthesis of (þ)-brunsvigine,14 (þ)-nangustine,15 and (þ)-mon-
tabuphine.16 In addition, several groups achieved a formal total
synthesis of these alkaloids by devising innovative strategies and
R1
1
1
OH
O
O
11
11a
11
11a
R2
R3
2
3
2
3
4a
4
4a
O
O
4
OMe
R4
N
5
N
H
H
R5
5
1–6
(+)-montabuphine (7)
R1 = H; R2 = OMe; R3 = OH; R4 = H; R5 = H: (–)-montanine (1)
R1 = OMe; R2 = H; R3 = OH; R4 = H; R5 = H: (–)-coccinine (2)
R1 = H; R2 = OH; R3 = OH; R4 = H; R5 = H: (–)-pancracine (3)
R1 = H; R2 = OH; R3 = H; R4 = OH; R5 = H: (–)-brunsvigine (4)
R1 = H; R2 = OMe; R3 = OMe; R4 = H; R5 = H: (–)-manthine (5)
R1 = H; R2 = H; R3 = H; R4 = OH; R5 = OH: (–)-nangustine (6)
* Corresponding author. Tel.: þ81 11 706 3236; fax: þ81 11 706 4981.
E-mail address: hsmt@pharm.hokudai.ac.jp (S. Hashimoto).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.091

3070
M. Anada et al. / Tetrahedron 65 (2009) 3069–3077
OH
H
SPh
O
Ph
H
SiMe2Ph
Br
O
O
O
O
H
O
O
O
H
N
N
OCH2Ph
H
Ts
N
H
H
H
O
OTBS
H
O
E
Ph
O
D
F
Hoshino 1993
O
O
Hoshino 1991, 1992
Weinreb 1997
O
N
H
O
C
O
O
O
OMe
OBn
O
O
O
R1
R2
O
SPh
N
O
O
H
O
SPh
R3
O
O
N
OMe
N
R4
H
N
H
R5
6
6
Bu3Sn
N
H
Overman's intermediate 8
N
H
OBn
Pearson 1998
montanine-type alkaloids 1–7
H
H
H
A
H
Me
G
Ph
O
O
O
Overman 1991, 1993
O
B
O
O
O
MeO
N
I
O
O
O
Me
SPh
N
Cl
R6
R7
R6
R7
O
O
TMS
O
O
N
O
PMB
Ts
N
N
Cl
OH
OBz
O
N
H
J
H
OH
O
R8
PMB R8
H
P
TMS
Pandey 2005
I
R6 = OMOM, R7 = OMOM, R8 = H: K (for 4)
Sha 2001, 2008
N
R6 = H, R7 = OMOM, R8 = OMOM: L (for 6)
Banwell 2007, 2008
R
6 = OMOM, R7 = OMe, R8 = H: M (for 7)
Scheme 1. Representative synthetic strategies toward montanine-type alkaloids 1–7.
tactics, wherein the key features include a 5-exo-trig radical cycli-
zation of N-(2-cyclohexenyl)- -aryl-
-(phenylthio)acetamide,17
acyclic ketones or enones with [(2-nitrophenylsulfonyl)
imino]phenyliodinane (NsN]IPh, 11a) provides N-(2-nitro-
a
a
a Mitsunobu-promoted nucleophilic displacement of an allylic
alcohol by a tethered sulfonamide,18 an intramolecular aldol
condensation of ketone prepared from trans-(2S,4R)-4-hydroxy-
proline,19 and an intramolecular 1,3-dipolar cycloaddition of non-
stabilized azomethine ylide derived from P.20 It is notable that all of
the reported synthetic strategies except for those by the Hoshino,
Weinreb, and Pandey groups rely on the construction of appropriate
3-arylperhydroindoles and the subjection of such intermediates to
a Pictet–Spengler cyclization so as to install the C6 methylene group
associated with the target framework as originally established in
Overman’s synthesis of (ꢁ)-pancracine.
phenylsulfonyl)-a-amino ketones 12 with enantioselectivities of up
to 95% ee (Eq. 1),26,27 the effectiveness of which has been demon-
strated by an asymmetric formal synthesis of (ꢀ)-metazocine26a
and (ꢀ)-ritodrine hydrochloride.26b In these processes, the use of
NsN]IPh (11a) as the nitrene precursor is not only crucial for high
levels of enantioselection but also synthetically advantageous since
the alkylation of resultant N-monosubstituted Ns-amides and
deprotection proceed under mild conditions as established by the
group of Fukuyama.28
1. Rh2(S-TFPTTL)4 (9a)
We have recently documented the utility of Rh2(S-TFPTTL)4 (9a)
and Rh2(S-TCPTTL)4 (9b),21 characterized by the substitution of
fluorine or chlorine atoms for four hydrogen atoms on the phtha-
limido group in the parent dirhodium(II) complex, Rh2(S-PTTL)4
(9c)22 (Fig. 1), in the catalysis of enantioselective nitrene transfer
reactions such as C–H amination23,24 and olefin aziridination.25
More recently, we have reported that Rh2(S-TFPTTL)4-catalyzed
enantioselective amination of silyl enol ethers 10 derived from
O
(3 mol %)
OSiEt3
R1
CH2Cl2, –40 °C
R1
+
R2
NHNs
12
NsN=IPh
R2
ð1Þ
2. aq TFA
11a
10
R1 = aryl, alkyl
R2 = Me, aryl
Ns = 2-NO2C6H4SO2
up to 95% ee
During the course of the above studies, we found that the re-
action of 1-triethylsiloxy-1-cyclohexene (13a) with NsN]IPh (11a)
in CH2Cl2 at 0 ꢂC in the presence of 2 mol % of Rh2(S-TCPTTL)4 (9b)
gave, after treatment with 10% HCl,
from allylic C–H insertion by rhodium(II) nitrene species in 74%
yield and 51% ee, with no trace of the expected -amino ketone
product 16a (Eq. 2). The surprising outcome with 13a adopting E-
geometry might be related to the fact that only Z-isomers of silyl
b-amino ketone 15a derived
X
Cl
O
Cl
X
O
N
O
N
a
Cl
X
H
H
O
O
X
Cl
O
O
O
enol ethers 10 are responsible for the formation of a-amino ketones
in the foregoing catalytic process, whereas the corresponding
E-isomers did not react under the same conditions.26a,27 Although
results of several studies on nitrene transfer from a suitable nitrene
source to silyl enol ether substrates by means of thermolysis,29
photolysis,30 and transition metal catalysts31,32 have been reported,
there have been no examples of the formation of an allylic C–H
amination product. It has been shown that nitrene species undergo
Rh
Rh
Rh
Rh
X = F: Rh2(S-TFPTTL)4 (9a)
X = Cl: Rh2(S-TCPTTL)4 (9b)
X = H: Rh2(S-PTTL)4 (9c)
Rh2(R-TCPTTL)4 (9d)
Figure 1. Chiral dirhodium(II) catalysts.
aziridinations of silyl enol ethers to produce N-substituted a-amino

M. Anada et al. / Tetrahedron 65 (2009) 3069–3077
3071
ketones via ring opening of the aziridine intermediates in modest
to good yields.
initial studies began with an evaluation of the performance of two
other chiral dirhodium(II) complexes, Rh2(S-TFPTTL)4 (9a) and
Rh2(S-PTTL)4 (9c).21 The reaction of 13a with NsN]IPh (11a) in
CH2Cl2 at 0 ꢂC in the presence of 2 mol % of the catalyst 9a or 9c
OSiEt3
OSiEt3
Rh2(S-TCPTTL)4 (9b)
(2 mol %)
afforded, after desilylation, b-amino ketone 15a in 57% and 52%
+
NsN=IPh
CH2Cl2, 0 °C, 1 h
yields with 41% and 19% ee, respectively (entries 2 and 3). From this
comparison, Rh2(S-TCPTTL)4 proved to be the catalyst of choice in
terms of both product yield and enantioselectivity (74% yield
and 51% ee, entry 1). Using Rh2(S-TCPTTL)4, we next evaluated
the effect of two other nitrene precursors, [(4-nitrophenyl-
sulfonyl)imino]phenyliodinane (pNsN]IPh, 11b) and [(2,4-dini-
trophenylsulfonyl)imino]phenyliodinane (DNsN]IPh, 11c), on
enantioselection and yield. This screening revealed that pNsN]IPh
(11b) was the optimal nitrene precursor for this transformation
(79% yield and 72% ee, entries 4 vs 1 and 5), although the reason for
the advantage of 11b is not clear at this time. It is noteworthy that
NHNs
11a
13a
14a
ð2Þ
O
O
NHNs
10% HCl
THF/H2O (7:3)
NHNs
rt, 1 h
15a
16a
74% yield (51% ee) not detected
Attracted by this unprecedented result, we set out to enhance
the enantioselectivity in this reaction system. Furthermore, taking
full advantage of Fukuyama’s Ns-strategy,28 we hoped to apply
a catalytic enantioselective C–H amination of this type to the syn-
thesis of the montanine-type Amaryllidaceae alkaloid (ꢀ)-pan-
cracine (3) as outlined in Scheme 2. Since a highly efficient
conversion of 8 to 3 had already been established by Overman and
Shim,8 we directed our efforts to the asymmetric synthesis of
Overman’s intermediate 8 via a Pictet–Spengler cyclization at a late
no signs of the corresponding a-amino ketone products could be
detected in the crude reaction mixture, regardless of the nature of
the nitrene precursors. A survey of solvents revealed that the use of
CH2Cl2 was the superior choice in terms of enantioselectivity (en-
tries 4 vs 6 and 7), although the product 15b was also formed with
similar yields in toluene and a,a,a-trifluorotoluene. Using the op-
timal combination of Rh2(S-TCPTTL)4 as the catalyst, pNsN]IPh as
the nitrene precursor, and CH2Cl2 as the solvent, we also examined
the effect of the silicon substituents of silyl enol ethers 13a–d. The
use of trimethylsilyl enol ether 13b exhibited nearly the same
enantioselectivity as that found with 13a but led to a marked de-
crease in product yield probably because of the instability of 13b
under these reaction conditions (47% yield and 67% ee, entry 8). The
use of 13c,d with larger silicon substituents relative to the tri-
ethylsilyl group resulted in lower product yields and enantiose-
lectivities (entries 9 and 10). Thus, the triethylsilyl functionality was
found to be optimal for this process, 72% ee being the highest
achievement.
stage. We anticipated that the N-Ns-protected b-amino silyl enol
ether ent-14 obtained by a one-pot Rh2(R-TCPTTL)4-sequential 1,4-
hydrosilylation/enantioselective C–H amination of 2-cyclohexen-1-
one (17) would undergo alkylation and subsequent Mukaiyama
aldol reaction/dehydration to produce aza bicyclic enone 20. The
most crucial step in the synthesis is conversion of 20 to 3-aryl-
hexahydroindole 21, which would require a regio- and stereo-
controlled reductive deoxygenation of enone with migration of the
double bond to create the C1/C11a double bond and the stereogenic
center at C11. Results of these studies are presented in this paper.
The preferred absolute configuration of the N-pNs-
20
O
O
protected
b
-aminocyclohexanone 15b with 72% ee {[
a
]
þ14.4 (c
D
1.12, THF)} was determined by its transformation to
the known 1-acetoxy-3-(benzyloxycarbonylamino)cyclohexane
(25)33 (Scheme 3). Reduction of 15b with NaBH4 in EtOH fol-
lowed by acetylation gave a 7:1 mixture of cis-acetate 22 and
N-acetyl-protected trans-acetate 23 in 96% combined yield.
O
O
O
1,4-hydrosilylation/
OSiR3
O
OSiR3
enantioselective
C–H amination
18
Br
O
Rh2(R-TCPTTL)4
N
NHNs
Treatment of 22 with CbzCl followed by removal of the pNs
23
17
ent-14
Ns 19
group under standard Fukuyama conditions afforded 25 {[a]
D
20
ꢀ6.5 (c 1.24, CHCl3); lit.33
[
a
]
þ9.1 (c 0.45, CHCl3) for (1R,3S)-
O
O
O
D
O
enantiomer} in 53% yield. Thus, the preferred absolute configu-
ration of 15b was established as R.
O
Mukaiyama aldol
reductive
H
1
reaction/dehydration
deoxygenation
11a
11
N
Ns
N
H
20
H
Ns
O
OAc
OAc
21
a,b
OH
OH
1
O
O
11
+
11a
1. removal of
Ns group
ref. 8
Ac
O
O
N
NHpNs
NHpNs
2. Pictet–Spengler
N
N
15b
22
23
pNs
H
H
cyclization
[α]D23 +14.4 (c 1.12, THF)
8
(–)-pancracine (3)
Overman's intermediate
Scheme 2. Synthetic strategy for (ꢀ)-pancracine (3).
for 72% ee
OAc
OAc
1S
c
d
22
3R
Cbz
N
pNs
NHCbz
2. Results and discussion
2.1. Enantioselective C–H amination of silyl enol ethers
24
25
[α]D23 –6.5 (c 1.24, CHCl3)
lit.33 [α]D20 +9.1 (c 0.45, CHCl3)
At the outset of this work, we explored the optimization of the
C–H amination of 1-triethylsiloxy-1-cyclohexene (13a), the enan-
tioselectivity of which was assayed by chiral HPLC (Table 1). Our
Scheme 3. Reagents and conditions: (a) NaBH4, EtOH, 0 ꢂC, 10 min; (b) Ac2O, pyridine,
CH2Cl2, 0 ꢂC, 1 h, 96% (22/23¼7:1, two steps); (c) NaH, CbzCl, CH2Cl2, 0 ꢂC, 1 h, 58%; (d)
PhSH, K2CO3, DMF, rt, 30 min, 91%.

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M. Anada et al. / Tetrahedron 65 (2009) 3069–3077
Table 1
Enantioselective C–H amination of silyl enol ethers 13 with [N-(arylsulfonyl)imino]phenyliodinanes 11 catalyzed by chiral dirhodium(II) carboxylatesa
OSiR3
OSiR3
O
Rh(II) catalyst
(2 mol %)
10% HCl
+
ArSO2N=IPh
CH2Cl2,0 °C
THF/H2O (7:3)
rt, 1 h
NHSO2Ar
NHSO2Ar
13
11
14
15
Entry
Silyl enol ether 13
Iminoiodinane 11
Rh(II) catalyst
Solvent
Time, h
b-Amino ketone 15
R3Si
Ar
Yield,b
%
ee, %
1
2
3
4
5
6
7
8
9
10
13a
13a
13a
13a
13a
13a
13a
13b
13c
13d
Et3Si
Et3Si
Et3Si
Et3Si
Et3Si
Et3Si
Et3Si
Me3Si
t-BuMe2Si
i-Pr3Si
11a
11a
11a
11b
11c
11b
11b
11b
11b
11b
2-NO2C6H4
Rh2(S-TCPTTL)4 (9b)
Rh2(S-TFPTTL)4 (9a)
Rh2(S-PTTL)4 (9c)
Rh2(S-TCPTTL)4 (9b)
Rh2(S-TCPTTL)4 (9b)
Rh2(S-TCPTTL)4 (9b)
Rh2(S-TCPTTL)4 (9b)
Rh2(S-TCPTTL)4 (9b)
Rh2(S-TCPTTL)4 (9b)
Rh2(S-TCPTTL)4 (9b)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CF3C6H5
CH2Cl2
CH2Cl2
CH2Cl2
1.5
1
3
1
2.5
3
3
1.5
2
15a
15a
15a
15b
15c
15b
15b
15b
15b
15b
74
57
52
79
53
65
73
47
55
51
51c
41c
19c
72d
46c
45d
52d
67d
60d
59d
2-NO2C6H4
2-NO2C6H4
4-NO2C6H4
2,4-(NO2)2C6H3
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2
a
All reactions were performed on a 0.2 mmol scale (0.1 M) with 1.2 equiv of 11.
Isolated yield.
Determined by HPLC (Daicel Chiralpak AD-H).
Determined by HPLC (Daicel Chiralpak IA).
b
c
d
2.2. One-pot sequential 1,4-hydrosilylation/enantioselective
C–H amination
elaboration of an advanced intermediate in Overman’s synthesis of
(ꢀ)-pancracine (Scheme 5). The one-pot 1,4-hydrosilylation/C–H
amination of 2-cyclohexen-1-one (17) with pNsN]IPh (11b) using
2 mol % of Rh2(R-TCPTTL)4 (9d) led to the formation of the N-pNs-
We previously reported that dirhodium(II) carboxylates are ef-
fective catalysts for 1,4-hydrosilylation of
a
,
b
-unsaturated ketones
protected b-amino silyl enol ether ent-14b. Since silyl enol ether
and aldehydes.34 Based on this work, we recently developed a
one-pot Rh2(S-TFPTTL)4-catalyzed sequential 1,4-hydrosilylation/
amination procedure for the enantioselective synthesis of N-Ns-
ent-14b was relatively unstable and could not be obtained in pure
form by column chromatography on Wakogel C-200, the crude
product of this process was used for the next step. N-Alkylation of
ent-14b with 1-(bromoacetyl)-3,4-methylenedioxybenzene (18)35
in the presence of K2CO3 was uneventfully followed by column
chromatography on Wakogel C-200 to give the N,N-disubstituted
protected a-amino ketones from a,b
-enones.26a In order to improve
the operation efficiency, we became interested in the possibility of
applying the one-pot methodology in the present system. Upon
completion of the 1,4-hydrosilylation reaction of 2-cyclohexen-1-
one (17) with triethylsilane (1.2 equiv) in the presence of 2 mol % of
Rh2(S-TCPTTL)4 (performed in CH2Cl2 under reflux for 0.5 h), the
reaction mixture was treated with pNsN]IPh (11b) (1.2 equiv) at
0 ꢂC for 2 h in the same reaction vessel. After the usual workup, the
b-amino silyl enol ether 26 in 58% yield in three steps from 17.
Intramolecular Mukaiyama aldol reaction of 26 and subsequent
dehydration were effected with the aid of BF3$OEt2, providing bi-
cyclic enone 27 in 81% yield. At this point, the enantiomeric excess
of 27 was confirmed to be 72% by HPLC analysis (Daicel Chiralpak
desired
b
-amino ketone 15b was obtained in 73% overall yield with
IA). Fortunately, two recrystallizations of 27 from EtOAc/hexane
23
72% ee, comparable to that obtained in the amination of 13a
(Scheme 4 vs Table 1, entry 4). While the mechanistic profile of the
dirhodium(II) carboxylate-catalyzed 1,4-hydrosilylation is unclear
at present, the result with this system again suggested that the
integrity of the ligands on the dirhodium framework was not
compromised during the 1,4-hydrosilylation process.
produced optically pure material, mp 146.0–147.0 ꢂC, [
1.06, CHCl3) in 53% yield.
a
]
D
ꢀ81.7 (c
The stage was now set for the reductive deoxygenation of enone
27 (>99% ee) with migration of the double bond to create the C1/
C11a double bond and the stereogenic center at C11 of 3-
arylhexahydroindole 31. After some experimentation,36 we were
gratified to find that this goal could be readily achieved by
employing Hutchins’ tosylhydrazone reduction protocol.36a Thus,
Et3SiH (1.2 equiv)
O
OSiEt3
OSiEt3
the
a,b-unsaturated tosylhydrazone 28 prepared from the cisoid
Rh2(S-TCPTTL)4 (9b)
pNsN=IPh (11b)
enone 27 was reduced with NaBH3CN in acidic DMF/sulfolane at
100 ꢂC to produce the desired alkene 31 in 64% yield, along with 6%
of its C11 epimer 32. Stereochemical assignments of 31 and 32 were
obtained from 1H NOE experiments. The stereochemical outcome
of this process can be rationalized from the mechanism of re-
duction of unsaturated hydrazones.36 Because of the steric hin-
drance of the 3,4-methylenedioxyphenyl group oriented
perpendicularly to the plane of the C11/C11a double bond, hydride
attack at C1 of the protonated tosylhydrazone occurs pre-
(2 mol %)
(1.2 equiv)
CH2Cl2, reflux, 0.5 h
0 °C, 2 h
NHpNs
13a
17
14b
O
10% HCl
THF/H2O (7:3)
rt, 1 h
NHpNs
15b
73% yield (72% ee)
dominantly from the a-side of the molecule to give the 1b-tosyl-
hydrazine intermediate 29, which subsequently decomposes to the
desired alkene 31 via a suprafacial 1,5-sigmatropic rearrangement
of the diazene intermediate 30 with loss of dinitrogen.37 Removal of
the pNs group in 31 under standard Fukuyama conditions28 fol-
lowed by the Pictet–Spengler cyclization of 3-arylhexahydroindole
33 under Banwell conditions18 furnished Overman’s intermediate
Scheme 4. One-pot sequential 1,4-hydrosilylation/enantioselective C–H amination.
2.3. Asymmetric formal synthesis of (L)-pancracine
With the process of 2-cyclohexen-1-one into the N-pNs-pro-
tected b-aminocyclohexanone optimized, we then proceeded to the

M. Anada et al. / Tetrahedron 65 (2009) 3069–3077
3073
O
TCPTTL)4-catalyzed sequential 1,4-hydrosilylation/enantioselective
C–H amination of 2-cyclohexen-1-one, (b) N-alkylation of the N-
O
O
OSiEt3
OSiEt3
pNs-protected
b-amino silyl enol ether, and subsequent
O
c
a
b
Mukaiyama aldol reaction/dehydration to construct aza bicyclic
enone 27, and (c) a regio- and stereocontrolled reductive de-
oxygenation of enone 27 employing Hutchins’ method to create the
C1/C11a double bond and the stereogenic center at C11 of 3-aryl-
hexahydroindole 31. Further extension of this and related meth-
odology to other natural products is currently in progress.
N
NHpNs
ent-14b
17
pNs 26
O
O
O
O
O
O
O
TsHNN
TsHNHN
1
4. Experimental
4.1. General
f
11a
H
e
11
N
pNs
N
pNs
N
pNs
H
27
H
Melting points were determined on a Bu¨chi 535 digital melting
point apparatus and are uncorrected. Optical rotations were mea-
sured on a JASCO P-1030 digital polarimeter with a sodium or
a mercury lamp. IR spectra were recorded on a JASCO FT/IR-5300
spectrometer and absorbance bands are reported in wavenumber
(cmꢀ1). 1H NMR spectra were recorded on JEOL EX 270 (270 MHz)
spectrometer, JEOL JNM-ECX 400P (400 MHz)spectrometer, or JNM-
ECA 500 (500 MHz) spectrometer. Chemical shifts are reported
relative to internal standard (tetramethylsilane at dH 0.00, CDCl3 at
dH 7.26, orC6D6 dH 7.20). Data are presented as follows: chemical shift
28
29
72% ee
>99% ee
d
O
H
O
O
O
O
O
1
H
11a
H
H
N
11
+
N
pNs
N
4.6% 3.2%
N
pNs
N
2.4% 2.6%
pNs
H
H
H
H
O
30
31
32
(
d
, ppm), multiplicity (s¼singlet, d¼doublet, t¼triplet, m¼multiplet,
br¼broad), coupling constant, integration, and assignment.13C NMR
spectra were recorded on JEOL JNM-ECX 400P (100 MHz) spec-
trometer or JEOL JNM-ECA 500 (125 MHz) spectrometer. The fol-
O
1
O
11
11a
g
h
1
31
lowing internal references wereused (CDCl3 at
d 77.0, C6D6 at d 128.0,
11a
11
H
O
CD2Cl2 at 53.8, or acetone-d6 at 30.3). EIMS spectra were obtained
d
d
N
H
N
H
8
on a JEOL JMS-FABmate spectrometer, operating with ionization
energy of 70 eV. FABMS spectra were obtained on a JEOL JMS-HX 110
spectrometer. Column chromatography was carried out on Kanto
H
33
[ ] 23 –100.6, [ ] 23 –111.8 (c 0.49, CHCl3)
α 577 α 546
lit.8b [α]57725 –96.6, [α]54623 –131.4 (c 0.21, CHCl3)
silica gel 60 N (63–210 mesh), WakogelÒ C-200 (75–200
mm), or Fuji
Scheme 5. Reagents and conditions: (a) Et3SiH (1.2 equiv), Rh2(R-TCPTTL)4 (9d)
(2 mol %), CH2Cl2, 40 ꢂC, 0.5 h, then pNsN]IPh (11b) (1.2 equiv), 0 ꢂC, 2 h; (b) 1-(bro-
moacetyl)-3,4-methylenedioxybenzene (18) (1.5 equiv), K2CO3, DMF, rt, 0.5 h, 58%
(three steps); (c) BF3$OEt2, CH2Cl2, ꢀ78 ꢂC to rt, 2 h, 81%; (d) recrystallization from
EtOAc/hexane, 53%; (e) TsNHNH2, TsOH, EtOH, reflux, 1.5 h; (f) NaBH3CN, concd HCl,
DMF/sulfolane (1:1), 100 ꢂC, 10 h, 64% of 31 and 6% of 32 from 27; (g) PhSH, LiOH$H2O,
DMF, rt, 0.5 h, 86%; (h) paraformaldehyde, HCO2H, reflux, 1.5 h, 72%.
Silysia ChromatorexÒ NH (100–200 mesh). Analytical thin layer
chromatography (TLC) was carried out on Merck Kieselgel 60 F254
plates. Visualization was accomplished with UV light, anisaldehyde
stain solution, or phosphomolybdic acid stain solution followed by
heating. Analytical high performance liquid chromatography (HPLC)
was performed on a JASCO PU-1580 intelligent HPLC pump with
JASCO UV-1575 intelligent UV/VIS detector. Detection was per-
formed at 254 nm. Chiralpak AD-H and IA columns
(0.46 cmꢃ25 cm) from Daicel were used. Retention times (tR) and
peak ratios were determined with JASCO–Borwin analysis system.
All non-aqueous reactions were carried out in flame-dried
glassware under argon atmosphere unless otherwise noted. Re-
agents and solvents were purified by standard means. Benzene was
distilled from sodium benzophenone ketyl. Chiral dirhodium(II)
carboxylates 9a–d,21,23a,40 arylsulfonyliminoiodinanes 11a–c,41 silyl
enol ethers 13a,34 13b,42 13c,43 and 13d,44 and 1-(bromoacetyl)-3,4-
methylenedioxybenzene (18)35 were prepared according to the
literature procedures.
88b in 72% yield. The spectroscopic data of our synthetic 8 were
identical to those reported by Overman and Shim (IR, 1H NMR, 13
C
23
23
NMR, HRMS). The optical rotation {[
0.49, CHCl3)} of our synthetic material was in good agreement with
that reported {[
fore, we have completed a catalytic, asymmetric formal synthesis of
(ꢀ)-pancracine.
a
]
ꢀ100.6, [
a
]
ꢀ111.8 (c
577
546
25
23
a]
–96.6, [
a
]
ꢀ131.4 (c 0.21, CHCl3)}.8b There-
577
546
3. Conclusion
We have developed an enantioselective C–H amination of silyl
enol ethers derived from cyclohexanone with pNs]IPh using
Rh2(S-TCPTTL)4 as a catalyst, which provides, after desilylation,
4.2. Representative procedure for the amination reaction of
silyl enol ether (Table 1, entry 4): (R)-3-[(4-nitrophenyl-
sulfonyl)amino]cyclohexan-1-one (15b)
N-pNs-protected (S)-b-aminocyclohexanone as the sole product in
up to 72% ee. To the best of our knowledge, this is the first example
of allylic C–H amination of silyl enol ethers by nitrene transfer re-
actions.38 However, we were greatly disappointed to find that the
protocol was successful only with silyl enol ethers from cyclohex-
anone as those from cyclopentanone and cycloheptanone gave
pNsN]IPh (11b) (97.0 mg, 0.24 mmol) was added in one
portion to a solution of silyl enol ether 13a (42.5 mg, 0.2 mmol) and
Rh2(S-TCPTTL)4$2EtOAc (9b) (7.8 mg, 0.004 mmol) in CH2Cl2 (2 mL,
0.1 M) at 0 ꢂC. After stirring at this temperature for 1 h, the reaction
mixture was evaporated in vacuo. The residue was dissolved in THF/
H2O (7:3, 1 mL) and then 10% aqueous HCl (0.1 mL) was added at
room temperature. After stirring for 1 h, the mixture was parti-
tioned between EtOAc (2 mL) and pH 7.0 phosphate buffer (3 mL),
and the whole was extracted with EtOAc (15 mL). The organic layer
a mixture of a- and b-amino ketones in modest yield, together with
a complex mixture of products.39
Using this process, we have developed a new, concise, and cat-
alytic asymmetric route to the 5,11-methanomorphanthridine
Amaryllidaceae (ꢀ)-pancracine from 2-cyclohexen-1-one. The key
features of the synthetic strategy include (a) a one-pot Rh2(R-

3074
M. Anada et al. / Tetrahedron 65 (2009) 3069–3077
was washed with H2O (2ꢃ3 mL) and brine (2ꢃ3 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo followed by
column chromatography (silica gel, 2:1 hexane/EtOAc) gave 15b
column (1:1 hexane/i-PrOH, 1.0 mL/min): tR¼9.7 min for major en-
antiomer; tR¼13.3 min for minorenantiomer. Thepreferred absolute
configuration of 15c was not determined.
(47.1 mg, 79%) as a white solid: Rf¼0.31 (1:1 hexane/EtOAc); mp
23
154.5–156.0 ꢂC; [
a
]
þ14.4 (c 1.12, THF) for 72% ee; IR (KBr) 3240,
4.5. (1S,3R)-1-Acetoxy-3-[(4-nitrophenylsulfonyl)amino]-
cyclohexane (22) and (1S,3S)-1-acetoxy-3-[acetyl-(4-
nitrophenylsulfonyl)amino]cyclohexane (23)
D
1708, 1527, 1350, 1313, 1159 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
1.69–1.75 (m, 2H, H-5), 1.95–2.02 (m, 2H, H-4), 2.24–2.39 (m, 3H,
H-2a, H-6), 2.56 (dd, J¼4.6, 13.9 Hz, 1H, H-2b), 3.70 (m, 1H, NCH),
5.41 (d, J¼7.5 Hz, 1H, NH), 8.08 (dt, J¼9.2, 2.0 Hz, 2H, Ar), 8.38 (dt,
A solution of sulfonamide 15b (68.2 mg, 0.17 mmol) in EtOH
(0.5 mL) was added to a suspension of NaBH4 (6.3 mg, 0.17 mmol) in
EtOH (1 mL) under argon atmosphere at 0 ꢂC. After stirring at this
temperature for 10 min, the reaction was quenched with saturated
aqueous NH4Cl (2 mL), and the whole was extracted with EtOAc
(2ꢃ10 mL). The combined organic layers were washed with brine
(2ꢃ5 mL) and dried over anhydrous Na2SO4. Filtration and evapo-
ration gave the crude amino alcohol product, which was dissolved in
pyridine (0.5 mL). Ac2O (24.6 mg, 0.242 mmol) was added to the
mixture at 0 ꢂC. Afterstirring at this temperature for 1 h, the reaction
was quenched with crushed ice. The reaction mixture was parti-
tioned between EtOAc (5 mL) and saturated aqueous NaHCO3
(5 mL), andthewholewas extractedwith EtOAc(10 mL). The organic
layer was washed with 10% aqueous HCl (2ꢃ3 mL) and brine
(2ꢃ3 mL), and dried over anhydrous Na2SO4. Filtration and evapo-
ration in vacuo followed by column chromatography (silica gel,
5:1/3:1 hexane/EtOAc) provided 22 (48.9 mg, 84%) as a colorless
J¼9.2, 2.0 Hz, 2H, Ar); 13C NMR (125 MHz, CDCl3)
d 21.5 (CH2), 31.7
(CH2), 40.5 (CH2), 48.3 (CH2), 52.8 (CH),124.5 (CH),128.2 (CH),146.5
(C), 150.1 (C), 207.8 (C]O); HRMS (EI) calcd for C12H14N2O5S (M)þ
298.0623, found 298.0611. Anal. Calcd for C12H14N2O5S: C, 48.31; H,
4.73; N, 9.39; S, 10.75. Found: C, 48.22; H, 4.66; N, 9.29; S, 10.75. The
enantiomeric excess of 15b was determined to be 72% by HPLC with
a
Chiralpak IA column (1:1 hexane/THF, 1.0 mL/min): tR
(major)¼5.9 min for (R)-15b; tR (minor)¼9.1 min for (S)-15b. The
preferred absolute configuration of 15b was determined to be R by
chemical correlation (vide infra).
4.3. (R)-3-[(2-Nitrophenylsulfonyl)amino]cyclohexan-
1-one (15a)
The b-amino ketone was prepared according to the represen-
tative procedure for amination reaction (2.0 mL of CH2Cl2, 1.5 h at
0 ꢂC) employing the silyl enol ether 13a (42.5 mg, 0.2 mmol), Rh2(S-
TCPTTL)4$2EtOAc (9b) (7.8 mg, 0.004 mmol), and NsN]IPh (11a)
(97.0 mg, 0.24 mmol) to provide 15a (44.4 mg, 74%) as a white solid
oil and 23 (7.2 mg,12%) as a colorless oil. Compound 22: Rf¼0.55 (1:1
24
hexane/EtOAc); [
a
]
D
þ8.4 (c 0.94, CHCl3); IR (CHCl3) 3382, 1732,
1534, 1365, 1350, 1165 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 1.09–1.28
after column chromatography (silica gel, 2:1 hexane/EtOAc);
(m, 4H),1.64–1.72 (m, 2H),1.80 (m,1H),1.94 (s, 3H, COCH3), 2.00 (m,
1H), 3.22 (m,1H, NCH), 4.58 (m,1H, OCH), 5.52 (d, J¼8.9 Hz,1H, NH),
8.01 (d, J¼8.6 Hz, 2H, Ar), 8.30 (d, J¼8.6 Hz, 2H, Ar); 13C NMR
23
Rf¼0.33 (1:1 hexane/EtOAc); mp 142.0–144.0 ꢂC; [
a
]
þ16.8 (c 1.03,
D
THF) for 51% ee; IR (KBr) 3356, 1709, 1536, 1362, 1342, 1163 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.59–1.77 (m, 2H, H-5), 2.03 (m, 1H, H-
(125 MHz, CDCl3) d 20.6 (CH2), 21.1 (CH3), 30.1 (CH2), 32.5 (CH2), 38.4
4a), 2.11 (m, 1H, H-4b), 2.23–2.38 (m, 3H, H-2a, H-6), 2.56 (ddt,
J¼4.5, 14.1, 1.8 Hz, 1H, H-2b), 3.75 (m, 1H, NCH), 5.43 (d, J¼7.7 Hz,
1H, NH), 7.74–7.80 (m, 2H, Ar), 7.90 (m, 1H, Ar), 8.16 (m, 1H, Ar); 13C
(CH2), 51.0 (CH), 70.5 (CH),124.4 (CH),128.0 (CH),146.9 (C),149.8 (C),
170.2 (C]O); HRMS (FAB) calcd for C14H19N2O6S (MþH)þ 343.0964,
24
found 343.0963. Compound 23: Rf¼0.63 (1:1 hexane/EtOAc); [
a]
D
NMR (125 MHz, CD2Cl2)
d
22.0 (CH2), 32.2 (CH2), 40.7 (CH2), 48.8
ꢀ3.5 (c 1.19, CHCl3); IR (CHCl3) 3020, 1731, 1718, 1536, 1365, 1351,
(CH2), 53.6 (CH), 125.8 (CH), 131.0 (CH), 133.5 (CH), 134.3 (CH), 134.4
(C), 148.1 (C), 207.5 (C]O); HRMS (EI) calcd for C12H14N2O5S (M)þ
298.0623, found 298.0618. Anal. Calcd for C12H14N2O5S: C, 48.31; H,
4.73; N, 9.39; S, 10.75. Found: C, 48.20; H, 4.67; N, 9.35; S, 10.66. The
enantiomeric excess of 15a was determined to be 51% by HPLC with
a Chiralpak AD-H (3:1 hexane/i-PrOH, 1.0 mL/min): tR¼14.7 min for
major enantiomer; tR¼20.0 min for minor enantiomer. The pre-
ferred absolute configuration of 15a was not determined.
1173 cmꢀ1; 1H NMR (270 MHz, CDCl3)
d
1.20–1.40 (m, 4H), 1.75 (m,
1H, CHH),1.85–2.01 (m, 3H), 2.03 (s, 3H, COCH3), 2.33 (s, 3H, COCH3),
2.44 (q, J¼11.2 Hz, 1H, H-2a), 4.09 (m, 1H, NCH), 4.66 (m, 1H, OCH),
8.10 (dt, J¼8.6, 2.3 Hz, 2H, Ar), 8.42 (dt, J¼8.6, 2.3 Hz, 2H, Ar); 13C
NMR (125 MHz, CDCl3)
d 21.2 (CH3), 22.4 (CH2), 26.4 (CH3), 29.3
(CH2), 30.4 (CH2), 35.6 (CH2), 58.7 (CH), 71.7 (CH), 124.5 (CH), 128.8
(CH), 145.5 (C), 150.5 (C), 170.2 (C]O), 170.3 (C]O); HRMS (FAB)
calcd for C16H20N2NaO7S (MþNa)þ 407.0889, found 407.0889.
4.4. (R)-3-[(2,4-Dinitrophenylsulfonyl)amino]cyclohexan-1-
4.6. (1S,3R)-1-Acetoxy-3-[benzyloxycarbonyl-(4-
one (15c)
nitrobenzenesulfonyl)amino]cyclohexane (24)
The
b
-amino ketone was prepared according to the representa-
A solution of 22 (42.4 mg, 0.124 mmol) in CH2Cl2 (1 mL) was
added to a suspension of NaH (7.4 mg, 0.186 mmol) in CH2Cl2
(1 mL) at 0 ꢂC. After stirring at this temperature for 0.5 h, CbzCl
(30.6 mg, 0.186 mmol) was added and stirred for 1 h and then the
reaction was quenched with crushed ice. The reaction mixture was
partitioned between EtOAc (3 mL) and saturated aqueous NaHCO3
(3 mL), and the whole was extracted with EtOAc (15 mL). The or-
ganic layer was washed with brine (2ꢃ3 mL) and dried over an-
hydrous Na2SO4. Filtration and evaporation in vacuo followed by
column chromatography (silica gel, 3:1 hexane/EtOAc) gave 24
tive procedure foraminationreaction(2.0 mL ofCH2Cl2, 2.5 h at 0 ꢂC)
employing the silyl enol ether 13a (42.5 mg, 0.2 mmol), Rh2(S-
TCPTTL)4$2EtOAc (9b) (7.8 mg, 0.004 mmol), and DNsN]IPh (11c)
(107.8 mg, 0.24 mmol) to provide 15c (36.4 mg, 53%) as a white solid
aftercolumn chromatography(silicagel, 2:1hexane/EtOAc);Rf¼0.36
22
(1:1 hexane/EtOAc); mp 167.0–170.0 ꢂC; [
a
]
þ13.7 (c 1.04, EtOAc)
D
for 46% ee; IR (KBr) 3333,1710,1548,1540,1351,1333,1165 cmꢀ1; 1H
NMR (500 MHz, CDCl3) 1.66–1.79 (m, 2H, H-5),1.99–2.13 (m, 2H, H-
d
4), 2.23–2.40 (m, 3H, H-2a, H-6), 2.58 (m,1H), 3.84 (m,1H, NCH), 5.46
(d, J¼7.5 Hz,1H, NH), 8.39 (d, J¼8.6 Hz,1H, Ar), 8.58 (dd, J¼2.3, 8.6 Hz,
1H, Ar), 8.70 (d, J¼2.3 Hz, 1H, Ar); 13C NMR (100 MHz, acetone-d6)
(34.0 mg, 58%) as a white solid; Rf¼0.53 (2:1 hexane/EtOAc); mp
24
130.5–134.0 ꢂC; [
a
]
D
ꢀ13.6 (c 1.34, CHCl3); IR (CHCl3) 3434, 1747,
d
22.7 (CH2), 33.0 (CH2), 41.2 (CH2), 49.4 (CH2), 54.4 (CH), 121.7 (CH),
1734, 1532, 1381, 1353, 1174 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 1.28
128.6 (CH), 133.5 (CH), 140.5 (C), 149.4 (C), 151.6 (C), 207.5 (C]O);
HRMS (FAB) calcd for C12H13N3O7S (M)þ 343.0474, found 343.0484.
Anal. Calcd for C12H13N3O7S: C, 41.98; H, 3.82; N, 12.24; S, 9.34.
Found: C, 41.77; H, 3.82; N,12.00; S, 9.37. The enantiomeric excess of
15c was determined to be 46% by HPLC with a Chiralpak AD-H
(m, 1H), 1.42 (m, 1H), 1.84–2.01 (m, 3H), 2.04 (s, 3H, COCH3), 2.08–
2.22 (m, 2H), 2.33 (q, J¼11.3 Hz, 1H, H-2a), 4.48 (tt, J¼3.6, 12.7 Hz,
1H, H-3), 4.77 (tt, J¼4.1, 11.3 Hz, 1H, H-1), 5.06 (s, 2H, PhCH2), 7.16
(m, 2H, Ar), 7.31–7.38 (m, 3H, Ar), 7.86 (d, J¼9.1 Hz, 2H, Ar), 8.09 (d,
J¼9.1 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d 21.2 (CH3), 22.0

M. Anada et al. / Tetrahedron 65 (2009) 3069–3077
3075
(CH2), 29.6 (CH2), 30.4 (CH2), 35.9 (CH2), 56.8 (CH), 69.5 (CH2), 71.6
(CH), 123.7 (CH), 128.6 (CH), 128.8 (CH), 129.01 (CH), 129.03 (CH),
133.6 (C), 145.4 (C), 150.0 (C), 151.2 (C]O), 170.3 (C]O); HRMS
(FAB) calcd for C22H25N2O8S (MþH)þ 477.1332, found 477.1343.
and saturated aqueous NaHCO3 (5 mL), and the whole was
extracted with EtOAc (30 mL). The organic layer was washed with
brine (2ꢃ5 mL) and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo followed by column chromatography
(WakogelÒ C-200, 5:1 hexane/EtOAc) provided 26 (803.1 mg, 58%)
23
4.7. (1S,3R)-1-Acetoxy-3-(benzyloxycarbonylamino)-
cyclohexane (25)
as a pale yellow oil; Rf¼0.34 (3:1 hexane/EtOAc); [
a
]
ꢀ34.5 (c 1.05,
D
CHCl3) for 72% ee; IR (film) 1697, 1657, 1348 cmꢀ1
;
1H NMR
0.56 (q, J¼7.7 Hz, 6H, SiCH2), 0.87 (t, J¼7.7 Hz,
(400 MHz, CDCl3)
d
K2CO3 (19.8 mg, 0.142 mmol) was added to a solution of 24
(34.0 mg, 0.072 mmol) and PhSH (9.5 mL, 0.092 mmol) in DMF
9H, SiCH2CH3), 1.21–1.30 (m, 2H), 1.65 (m, 1H), 1.81–2.00 (m, 3H),
4.51 (br s, 1H, H-2), 4.53 (m, 1H, NCH), 4.66 (d, J¼18.1 Hz, 1H,
NCHH), 4.72 (d, J¼18.1 Hz, 1H, NCHH), 6.06 (s, 2H, OCH2O), 6.87 (d,
J¼8.3 Hz, 1H, OCH2OCCHCH), 7.38 (d, J¼1.5 Hz, 1H, OCH2OCCHC),
7.51 (dd, J¼1.5, 8.3 Hz, 1H, OCH2OCCHCH), 8.22 (d, J¼8.6 Hz, 2H, Ar),
(0.3 mL) at room temperature. After stirring at this temperature for
30 min, the reaction mixture was partitioned between EtOAc
(2 mL) and 10% aqueous NaOH (2 mL), and the whole was extracted
with EtOAc (10 mL). The organic layer was washed with H2O
(2ꢃ3 mL) and brine (2ꢃ3 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo followed by column chroma-
tography (silica gel, 2:1 hexane/EtOAc) provided 25 (19.0 mg, 91%)
as a white solid; Rf¼0.53 (1:1 hexane/EtOAc); mp 101.5–104.0 ꢂC;
8.38 (d, J¼8.6 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d 4.8 (CH2), 6.5
(CH3), 20.6 (CH2), 28.0 (CH2), 29.1 (CH2), 48.7 (CH2), 55.3 (CH), 101.9
(CH2), 102.2 (CH), 107.4 (CH), 107.9 (CH), 123.7 (CH), 123.9 (CH),
128.8 (CH), 129.2 (C), 146.6 (C), 148.1 (C), 149.6 (C), 152.1 (C), 156.5
(C), 192.0 (C); HRMS (FAB) calcd for C27H34N2NaO8SSi (MþNa)þ
597.1703, found 597.1688.
23
20
[
a]
ꢀ6.5 (c 1.24, CHCl3) [lit.33
[
a
d
]
þ9.1 (c 0.45, CHCl3) for (1R,3S)-
D
D
25]; 1H NMR (270 MHz, CDCl3)
1.05–1.50 (m, 5H), 1.85–1.90 (m,
3H), 2.03 (s, 3H, COCH3), 2.22 (m, 1H), 3.63 (m, 1H, NCH), 4.79 (m,
4.10. (S)-3-(1,3-Benzodioxol-5-yl)-N-(4-nitrophenylsulfonyl)-
1,2,5,6,7,7a-hexahydroindol-4-one (27)
1H, OCH), 5.09 (s, 2H, PhCH2), 7.31–7.35 (m, 5H, Ar); 13C NMR
(100 MHz, CDCl3)
d 20.7 (CH2), 21.3 (CH3), 30.6 (CH2), 32.0 (CH2),
38.0 (CH2), 48.0 (CH), 66.5 (CH2), 71.0 (CH),128.07 (CH),128.10 (CH),
128.5 (CH), 136.4 (C), 155.3 (C]O), 170.1 (C]O).
BF3$OEt2 (0.38 mL, 3.0 mmol) was added to a solution of silyl
enol ether 26 (574.7 mg,1.0 mmol) in CH2Cl2 (5 mL) at ꢀ78 ꢂC. After
stirring at this temperature for 0.5 h, the reaction mixture was
allowed to warm to room temperature over 1 h and stirred for an
additional 1 h. The mixture was partitioned between EtOAc (2 mL)
and pH 7.0 phosphate buffer (5 mL), and the whole was extracted
with EtOAc (25 mL). The organic layer was washed with brine
(2ꢃ5 mL) and dried over anhydrous Na2SO4. Filtration and evapo-
ration in vacuo followed by column chromatography (silica gel, 5:1
4.8. One-pot 1,4-hydrosilylation/enantioselective C–H
amination of 2-cyclohexen-1-one catalyzed by 9b: (R)-3-[(4-
nitrophenylsulfonyl)amino]cyclohexanone (15b) from 2-
cyclohexen-1-one (17)
A mixture of triethylsilane (27.9 mg, 0.24 mmol), 2-cyclohexen-
1-one (17) (19.2 mg, 0.2 mmol), and Rh2(S-TCPTTL)4$2EtOAc (9b)
(7.8 mg, 0.004 mmol, 2 mol %) in CH2Cl2 (0.2 mL) was heated at
reflux for 0.5 h. The mixture was diluted with CH2Cl2 (2 mL) at
room temperature and then cooled to 0 ꢂC. pNsN]IPh (11b)
(97.0 mg, 0.24 mmol) was added in one portion to the mixture.
After stirring at this temperature for 2 h, the reaction mixture was
evaporated in vacuo. The residue was dissolved in THF/H2O (7:3,
1 mL) and then 10% aqueous HCl (0.1 mL) was added at room
temperature. After stirring for 1 h, the mixture was partitioned
between EtOAc (2 mL) and pH 7.0 phosphate buffer (3 mL), and the
whole was extracted with EtOAc (15 mL). The organic layer was
washed with water (2ꢃ3 mL) and brine (2ꢃ3 mL), and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo followed by
hexane/EtOAc) provided 27 (357.5 mg, 81%) as a pale yellow solid;
24
Rf¼0.54 (1:1 hexane/EtOAc); mp 136.5–139.0 ꢂC; [
a
]
D
ꢀ56.5 (c
1.00, CHCl3) for 72% ee; IR (KBr) 1683, 1530, 1352, 1167 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d 1.74–1.96 (m, 2H, H-6a, H-7a), 2.12 (m, 1H,
H-6b), 2.31 (ddd, J¼6.6, 12.9, 16.3 Hz, 1H, H-5a), 2.56 (m, 1H, H-5b),
2.75 (m, 1H, H-7b), 4.34 (dd, J¼3.2, 15.0 Hz, 1H, NCHH), 4.55 (m, 1H,
NCH), 4.70 (dd, J¼5.4, 15.0 Hz, 1H, NCHH), 5.97 (s, 2H, OCH2O), 6.76
(d, J¼8.2 Hz, 1H, OCCHCH), 6.99 (dd, J¼1.8, 8.2 Hz, 1H, OCCHCH),
7.08 (d, J¼1.8 Hz, 1H, OCCHC), 8.06 (dt, J¼9.1, 2.2 Hz, 2H, Ar), 8.41
(dt, J¼9.1, 2.2 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d 21.3 (CH2),
34.1 (CH2), 42.1 (CH2), 57.9 (CH2), 69.8 (CH), 101.4 (CH2), 107.9 (CH),
108.9 (CH), 122.9 (CH), 124.5 (C), 124.6 (CH), 128.7 (CH), 131.3 (C),
138.0 (C), 142.3 (C), 147.4 (C), 149.0 (C), 150.3 (C), 198.1 (C); HRMS
(EI) calcd for C21H18N2O7S (M)þ 442.0835, found 442.0837. Com-
pound 27 (300.0 mg, 72% ee) was recrystallized twice from hexane/
column chromatography (silica gel, 2:1 hexane/EtOAc) provided
20
15b (43.6 mg, 73%) as a white solid; mp¼155.0–157.0 ꢂC; [
a]
D
þ14.2 (c 1.07, THF) for 72% ee. The enantiomeric excess of 15b was
determined to be 72% by HPLC with a Chiralpak IA (1:1 hexane/THF,
1.0 mL/min).
EtOAc (1:1) to afford optically pure material (155.6 mg, 53% yield,
23
>99% ee) as pale yellow needles; mp 146.0–147.0 ꢂC; [
a
]
D
ꢀ81.7 (c
1.06, CHCl3). Anal. Calcd for C21H18N2O7S: C, 57.01; H, 4.10; N, 6.33;
S, 7.25. Found; C, 57.18; H, 4.22; N, 6.18; S, 7.18. The homochirality of
27 was established by comparison of retention time in HPLC
(Chiralpak IA, 1:1 hexane/THF, 1.0 mL/min) with a racemic sample:
tR (major)¼4.29 min for (S)-27 and tR (minor)¼5.00 min for (R)-27.
4.9. (S)-N-(2-Benzo[1,3]dioxol-5-yl-2-oxoethyl)-4-nitro-N-(3-
triethylsiloxycyclohex-2-enyl)benzenesulfonamide (26)
A mixture of triethylsilane (463.2 mL, 2.9 mmol), 2-cyclohexen-
1-one (17) (232.0 mg, 2.4 mmol), and Rh2(R-TCPTTL)4$2EtOAc (9d)
(90.4 mg, 0.048 mmol, 2 mol %) in CH2Cl2 (2 mL) was heated at
reflux for 0.5 h. The mixture was diluted with CH2Cl2 (12 mL) at
room temperature and then cooled to 0 ꢂC. pNsN]IPh (11b) (1.17 g,
2.9 mmol) was added in one portion to the mixture. After stirring at
this temperature for 2 h, the reaction mixture was filtered through
a CeliteÒ. The filtrate was evaporated in vacuo and diluted with
DMF (10 mL). 1-(Bromoacetyl)-3,4-methylenedioxybenzene (18)35
(875.0 mg, 3.6 mmol) and K2CO3 (663.4 mg, 4.8 mmol) were added
to the solution at room temperature. After stirring at this temper-
ature for 0.5 h, the mixture was partitioned between EtOAc (5 mL)
4.11. (3R,7aS)-3-(1,3-Benzodioxol-5-yl)-N-(4-nitrophenyl-
sulfonyl)-2,3,5,6,7,7a-hexahydro-1H-indole (31) and (3R,7aR)-
3-(1,3-benzodioxol-5-yl)-N-(4-nitrophenylsulfonyl)-
2,3,5,6,7,7a-hexahydro-1H-indole (32)
TsNHNH2 (22.3 mg, 0.12 mmol) was added to a solution of 27
(50.0 mg, 0.11 mmol) and TsOH$H2O (2.1 mg, 0.011 mmol) in EtOH
(1 mL) and the resulting mixture was heated at reflux for 1.5 h. The
solvent was evaporated in vacuo, and the reaction mixture was
partitioned between EtOAc (3 mL) and saturated aqueous NaHCO3
(3 mL). The whole was extracted with EtOAc (20 mL), and the

3076
M. Anada et al. / Tetrahedron 65 (2009) 3069–3077
organic layer was washed with brine (2ꢃ5 mL) and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished
the crude tosylhydrazone product, which was dissolved in DMF/
sulfolane (1:1, 2 mL). NaBH3CN (25.8 mg, 0.46 mmol) and small
amount of Methyl Yellow were added to the solution at room
temperature. The mixture was heated at 100 ꢂC in a preheated oil
bath and then a few drops of concd hydrochloric acid (ca. 50 mL)
were added cautiously until the pH was <2.9 as indicated by a color
change from yellow to red. After stirring at 100 ꢂC for 5 h, a few
4.13. (4aS,11R)-8,9-Methylenedioxy-D
1(11a)-5,11-
methanomorphanthridine (8)
Paraformaldehyde (16.2 mg, 0.54 mmol) was added to the so-
lution of 33 (22.0 mg, 0.09 mmol) in formic acid (1 mL). The re-
action mixture was heated at reflux for 1.5 h. The reaction mixture
was cooled to room temperature and then partitioned between
EtOAc (15 mL) and 10% aqueous NaOH (3 mL). The organic layer was
washed with brine (2ꢃ3 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo followed by column
chromatography (Chromatorex NH, 9:1 hexane/EtOAc) provided 8
(16.6 mg, 72%) as a white solid; Rf¼0.50 (9:1 CHCl3/MeOH); mp
drops of concd hydrochloric acid (ca. 50 mL) were added to maintain
the pH below 2.9 and heating was continued for 5 h. The reaction
mixture was partitioned between EtOAc (3 mL) and H2O (3 mL),
and the whole was extracted with EtOAc (20 mL). The organic layer
was washed with brine (2ꢃ5 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo followed by column
chromatography (silica gel, 4:1 hexane/EtOAc) gave 31 (30.2 mg,
23
23
100.5–102.0 ꢂC; [
a
]
ꢀ100.6, [
a
]
ꢀ111.8 (c 0.49, CHCl3) [lit.8b
577
546
25
25
[a
]
577 ꢀ96.6, [
a
]
546 ꢀ131.4 (c 0.21, CHCl3)]; IR (KBr) 2925,1501, 1477,
1234, 1223, 1037, 935 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d 1.27 (m,
1H), 1.51 (m, 1H), 1.84 (m, 1H), 2.02–2.12 (m, 3H), 2.99 (br s, 2H, H-
12), 3.15 (ddd, J¼2.5, 4.6, 11.5 Hz, 1H, C4a-H), 3.24 (br s, 1H, H-11),
3.82 (d, J¼16.6 Hz, 1H, H-5a), 4.34 (d, J¼16.6 Hz, 1H, H-5b), 5.50 (q,
J¼2.8 Hz, 1H, H-1), 5.86 (d, J¼1.4 Hz, 1H, OCHHO), 5.89 (d, J¼1.4 Hz,
1H, OCHHO), 6.49 (s, 1H, H-7), 6.56 (s, 1H, H-10); 13C NMR
64%) as a yellow oil and 32 (2.8 mg, 6%) as a yellow oil. Compound
21
31: Rf¼0.29 (4:1 hexane/EtOAc); [
a
]
D
ꢀ24.3 (c 1.13, CHCl3); IR (film)
1526, 1348, 1163 cmꢀ1
;
1H NMR (400 MHz, C6D6)
d 1.26–1.47 (m,
2H), 1.58 (m, 1H), 1.70–1.75 (m, 2H), 2.76 (m, 1H), 3.14 (d, J¼6.3 Hz,
1H, H-3), 3.31 (dd, J¼1.8, 11.3 Hz, 1H, H-2a), 3.51 (dd, J¼6.3,
11.3 Hz, 1H, H-2b), 3.67 (m, 1H, NCH), 5.25 (m, 1H, H-4), 5.30 (d,
J¼1.4 Hz, 1H, OCHHO), 5.33 (d, J¼1.4 Hz, 1H, OCHHO), 5.85 (d,
J¼1.8 Hz, 1H, OCCHC), 6.00 (m, 1H, OCCHCH), 6.27 (d, J¼8.2 Hz, 1H,
OCCHCH), 7.33 (dt, J¼9.1, 2.3 Hz, 2H, Ar), 7.56 (dt, J¼9.1, 2.3 Hz, 2H,
(125 MHz, CDCl3) d 21.1 (CH2), 24.3 (CH2), 28.3 (CH2), 45.9 (CH), 55.2
(CH2), 60.9 (CH2), 63.5 (CH), 100.7 (CH2), 106.8 (CH), 107.2 (CH),
115.1 (CH), 124.6 (C), 133.1 (C), 145.9 (C), 146.5 (C), 150.0 (C); HRMS
(EI) calcd for C16H17NO2 (M)þ 255.1259, found 255.1278.
Ar); 13C NMR (100 MHz, CDCl3)
d 20.1 (CH2), 24.4 (CH2), 30.3 (CH2),
Acknowledgements
47.0 (CH), 56.1 (CH2), 58.9 (CH), 101.2 (CH2), 106.8 (CH), 108.1 (CH),
120.1 (CH), 123.7 (CH), 125.5 (CH), 128.2 (CH), 135.2 (C), 138.2 (C),
143.0 (C), 146.2 (C), 147.4 (C), 149.6 (C); HRMS (EI) calcd for
This research was supported, in part, by a Grant-in-Aid for Sci-
entific Research on Priority Areas ‘Advanced Molecular Trans-
formations of Carbon Resources’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. We thank S. Oka, M.
Kiuchi, and T. Hirose of the Center for Instrumental Analysis at
Hokkaido University for mass measurements and elemental
analysis.
C21H20N2O6S (Mþ) 428.1042, found 428.1046. Compound 32:
23
Rf¼0.34 (4:1 hexane/EtOAc); [
a
]
þ19.7 (c 0.76, CHCl3); IR (film)
D
1527, 1347, 1219 cmꢀ1
;
1H NMR (500 MHz, C6D6)
d 1.24–1.40 (m,
2H), 1.56 (m, 1H), 1.63–1.66 (m, 2H), 2.67 (m, 1H), 2.99 (m, 1H, H-3),
3.18 (dd, J¼1.8, 11.3 Hz,1H, H-2a), 3.64 (dd, J¼6.3,11.3 Hz,1H, H-2b),
3.75 (m, 1H, NCH), 4.94 (m, 1H, H-4), 5.34 (d, J¼1.4 Hz, 1H, OCHHO),
6.30 (m, 1H, OCCHCH), 6.49 (d, J¼8.2 Hz, 1H, OCCH), 6.63 (d,
J¼8.0 Hz, 1H, OCCHCH), 7.53 (dt, J¼9.1, 2.3 Hz, 2H, Ar), 7.66 (dt,
References and notes
J¼9.1, 2.3 Hz, 2H, Ar); 13C NMR (125 MHz, C6D6)
d 20.2 (CH2), 24.1
(CH2), 30.2 (CH2), 47.2 (CH), 54.8 (CH2), 59.8 (CH), 101.1 (CH2), 108.5
(CH), 108.9 (CH), 122.2 (CH), 122.3 (CH), 124.1 (CH), 128.3 (CH), 131.6
(C), 141.5 (C), 144.1 (C), 147.4 (C), 148.4 (C), 149.8 (C); HRMS (EI)
calcd for C21H20N2O6S (M)þ 428.1042, found 428.1056.
1. For recent reviews, see: (a) Jin, Z. Nat. Prod. Rep. 2003, 20, 606–614; (b) Jin, Z.
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PhSH (72 mL, 0.70 mmol) was added to a suspension of 31
(51.0 mg, 0.12 mmol) and LiOH$H2O (40.4 mg, 0.96 mmol) in DMF
(0.5 mL) at room temperature. After stirring at this temperature for
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aqueous NaOH (2 mL), and the whole was extracted with EtOAc
(2ꢃ10 mL). The combined organic layers were washed with H2O
(2ꢃ3 mL) and brine (2ꢃ3 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo followed by column chromatog-
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raphy (Chromatorex NH, 9:1/4:1 hexane/EtOAc) provided 33
23
(25.2 mg, 86%) asayellowoil;Rf¼0.46(4:1CHCl3/MeOH); [
a
]
ꢀ52.9
D
(c 1.01, CHCl3); IR (film) 3250, 2929,1608,1103,1039, 936, 809 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
1.29 (m, 1H), 1.55 (m, 1H), 1.88 (m, 1H),
2.02–2.14 (m, 2H), 2.27 (m, 1H), 2.86 (dd, J¼8.6, 10.4 Hz, 1H, H-2a),
3.27 (br s, 1H, NH), 3.54 (m, 1H), 3.58 (dd, J¼8.6, 10.4 Hz, 1H, H-2b),
3.78(t, J¼8.6 Hz,1H, H-3), 5.51(m,1H,H-4), 5.93(s, 2H, OCH2O), 6.67–
6.75 (m, 3H, Ar); 13C NMR (125 MHz, CDCl3)
d 20.7 (CH2), 25.1 (CH2),
28.4 (CH2), 48.4 (CH), 54.1 (CH2), 59.5 (CH), 100.9 (CH2), 107.7 (CH),
108.2 (CH), 120.5 (CH), 121.6 (CH), 137.5 (C), 143.8 (C), 146.0 (C), 147.8
(C); HRMS (EI) calcd for C15H17NO2 (M)þ 243.1259, found 243.1260.

M. Anada et al. / Tetrahedron 65 (2009) 3069–3077
3077
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b
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