Catalytic C-CN activation and asymmetric cyanoamidation of alkenes: Total syntheses of (+)-horsfiline, (-)-coerulescine, and (-)-esermethole

Article abstract of DOI:10.1016/j.tet.2010.02.096

The detailed study of Pd-catalyzed asymmetric cyanoamidation is reported. Excellent enantioselectivities are attributed to a chiral phosphosphoramidite ligand synthesized in one step from the commercially available materials. Cyanoamidation substrates are easy to prepare from the corresponding anilines. The 3,3-disubstituted oxindole products bear all-carbon quaternary stereocenters and contain a nitrile and an amide, which are valuable functional handles for the synthesis of many indole-containing natural products. Cyanoamidation tolerates free N-H groups, as demonstrated by the successful use of cyanoamidation in the syntheses of (+)-horsfiline and (-)-coerulescine.

Full text of DOI:10.1016/j.tet.2010.02.096

Tetrahedron 66 (2010) 4719–4729
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic C–CN activation and asymmetric cyanoamidation of alkenes:
total syntheses of (þ)-horsfiline, (ꢀ)-coerulescine, and (ꢀ)-esermethole
*
Venkata Jaganmohan Reddy, Christopher J. Douglas
Department of Chemistry, University of Minnesota – Twin Cities, 207 Pleasant St SE, Minneapolis MN 55455, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The detailed study of Pd-catalyzed asymmetric cyanoamidation is reported. Excellent enantioselectivities
are attributed to a chiral phosphosphoramidite ligand synthesized in one step from the commercially
available materials. Cyanoamidation substrates are easy to prepare from the corresponding anilines. The
3,3-disubstituted oxindole products bear all-carbon quaternary stereocenters and contain a nitrile and an
amide, which are valuable functional handles for the synthesis of many indole-containing natural products.
Cyanoamidation tolerates free N–H groups, as demonstrated by the successful use of cyanoamidation in the
syntheses of (þ)-horsfiline and (ꢀ)-coerulescine.
Received 20 January 2010
Received in revised form
24 February 2010
Accepted 25 February 2010
Available online 6 March 2010
Dedicated to Professor Brian M. Stoltz for his
many contributions to organic chemistry
and his receipt of the 2010 Tetrahedron
Young Investigator Award for Organic
Synthesis
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
C–C bond activation
Asymmetric catalysis
Total synthesis
Alkaloids
1. Introduction
quaternary stereocenters5 with ee’s up to 99% and our syntheses of
(ꢀ)-esermethole, (þ)-horsfiline, and (ꢀ)-coerulescine.6
Increasingly complex pharmaceutical alkaloid targets require
the continued development of new strategies and methodologies to
synthesize them efficiently. One potential new strategy is the ac-
tivation of C–C sigma bonds and functionalization of alkenes or
alkynes (cyanoamidation),1 allowing for rapid increase in molecular
complexity. Recent work from Nakao and Hiyama2 and Jacobsen3
highlights the utility of activating aryl nitriles, while Takemoto
has reported the activation of cyanoformamide C–CN bonds and
asymmetric cyanoamidation of alkenes providing 3,3-disubstituted
oxindoles with ee’s up to 86%.4
R
R
R
Pd0 cat.
CN
O
CN
Ln
Pd
ligand
NR'
N
N
additive
R'
R'
O
O
1
CN
2
3
Scheme 1.
The reactivity of cyanoformamides toward activation (1 to 2,
Scheme 1) and cyanoamidation (2 to 3), their ease of preparation
(discussed in this report), and their synthetic potential in preparing
indole-containing natural products (Fig. 1) led us to continue pur-
suing cyanoamidation conditions giving products with synthetically
useful ee’s. We now report our comprehensive account of cyanoa-
midation conditions that give oxindoles bearing all-carbon
2. Results and discussion
2.1. Optimization of asymmetric cyanoamidation
Our laboratory independently observed many of the same fea-
tures of cyanoamidation as reported in a previous report.4 Detailed
in this section is our quest for synthetically useful enantiose-
lectivities of oxindoles, which we eventually achieved by synthe-
sizing a chiral ligand and using it in cyanoamidation. We also detail
our observations in probing the role of additives.
* Corresponding author. Tel.: þ1 612 625 0922; fax: þ1 612 626 7541; e-mail
address: cdouglas@umn.edu (C.J. Douglas).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.096

4720
V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
O
R
H
Ph
Ph
Ph
O
O
O
H
Me
H
N
H
Me
Me
N
O
O
Me
Me
Me
P(Ph)2
P(Ph)2
O
O
N
O
O
O
P
N
P N
Me
Me
N
O
Me
Me
Me
NH
Ph
Me
R
O
NH
N
O
Me
L1
L2, R = H
L4
N
NH
Me
L3, R = Me
(–)-communesin A
X
(+)-alstonisine
MeO
spirotryprostatin B
Me
N
Me
NMe
H
O
N
R
R
R
O
O
O
O
O
O
N
H
Me
P
N
P N
P
N
R
R
R
(+)-horsfiline, X = OMe
(–)-esermethole
(–)-coerulescine, X = H
Me
Ph
L5, R = Me
L8, R = Me
L9, R = i-Pr
Figure 1.
L7, R =
Me
L6, R =
Ph
We initiated our study by synthesizing cyanoformamide 6 via
the reductive amination of aniline 47 with benzaldehyde to give the
N-benzyl aniline 5 (Scheme 2). Subsequent treatment of 5 with
carbonyl cyanide8 provided the cyanoformamide 6 in 70% yield.
We observed that catalytic Pd2dba3, phosphoramidite ligands,
Lewis basic additives, and solvents THF or decalin4 cyclized cyano-
formamide 6 to oxindole 8, presumably via intermediate 7. We found
that absence of ligand gave poor yield of 8 (entry 1, Table 1). Addition
of bidentate BINAP L1 (entry 2) and monodentate MonoPhos L2
(entry 3) gave yields of 8 exceeding 80%, with MonoPhos also pro-
viding some enantioinduction. After screening several commercially
available phosphoramidites (L2–L8, entries 3–9),9 we identified
octahydro-MonoPhos L8 (entry 9, ee¼66%) as a promising lead to
optimize. Attempting cyanoamidation with various solvents (xylene,
toluene, DCE, THF, entries 9–12) showed that THF was the preferred
option. Additives such as N-methylpyrrolidinone (NMP), N,N-dime-
thylpropylene urea (DMPU), and hexamethylphosphoramide
(HMPA) enhanced enantioselectivity (entries 12–14 and 19), partic-
ularly with decalin4 (entries 15–16). We concluded that commer-
cially available ligands would only give our desired oxindole 8 in ee’s
up to 86–91%, only slightly better than the previous study.4
Me
O
Me
PhCHO
Me
NaBH3CN
NC
CN
80%
70%
NBn
NH2
NHBn
4
5
6
O
CN
Scheme 2.
Table 1
Optimization of asymmetric cyanoamidation.a
Me
Me
Me
Pd2dba3
ligand
CN
CN
Ln
O
Pd
NBn
N
N
solvent, additive
Bn
Bn
O
temp.
O
6
CN
7
8
Postulating that increasing ligand nitrogen substituent bulk
would improve selectivity, we prepared the N,N-(i-Pr)2 derivative of
octahydro-MonoPhos L9 in one step from the corresponding amine
and phosphorochloridite.10 We were able to achieve ee’s up to 94%
using L9 (entries 17–22). Screening various additives showed that
usage of DMPU gave the highest enantioselectivity (entry 18). The
comparable yields and enantioinduction with THF and decalin as
solvents (entries 18–21) prompted us to continue using THF because
of its ease of removal during work-up. Reducing the concentration of
L9 to 8 mol % decreased the ee of 8 from 94% to 86% (entry 22).
Therefore, we used the conditions shown in entry 18 for the re-
mainder of our study.
We briefly probed the role of the Lewis base additive by using our
optimized conditions while substituting DMPU with stoichiometric
chiral phosphoramide (Scheme 3).11 We were able to obtain the
opposite enantiomer of 8 in 63% yield (ee¼93%). Based on the limited
results, we hypothesize that the phosphoramide oxygen may co-
ordinate to the palladium complex and impart stereocontrol during
Entry
Solvent
Ligand
Temp (ꢁC)
Additive
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
PhMe
DCE
THF
THF
THF
Decalin
Decalin
THF
THF
THF
None
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L9
L9
L9
L9
L9
L9
130
130
130
130
130
130
130
130
130
120
100
100
100
100
100
100
100
100
100
100
100
100
None
None
None
None
None
None
None
None
None
None
None
None
NMP
DMPU
NMP
DMPU
NMP
DMPU
HMPA
NMP
DMPU
DMPU
28
81
89
40
58
42
51
58
51
50
0
70
69
80
80
81
68
72
64
66
68
70
d
<5
23
<5
33
<5
52
48
62
52
d
9
10
11
12
13
14
15
16
17
18d
19
20
21
22e
68
73
86
91
87
90
94
91
89
95
86
Decalin
Decalin
THF
Pd2dba3 (2 mol %)
Me
L9 (16 mol %)
THF, 100 °C
Me
a
Entries 1–12: 10 mol % Pd2dba3, 20 mol % ligand. Entries 13–21: 2 mol %
Pd2dba3, 16 mol % ligand. THF¼tetrahydrofuran, DCE¼1,2-dichloroethane,
NMP¼N-methylpyrrolidinone, DMPU¼N,N-dimethylpropylene urea, HMPA¼
Hexamethylphosphoramide.
Additive
CN
O
additive (1 equiv)
Me
N
O
P
NBn
63%
N
Ph
N
Bn
N
b
O
6
CN
Me
Ph
Yields after silica gel chromatography.
ee determined by HPLC (Chiralcel OD-H, n-hexane/isopropanol (9:1),
ent-8
(ee = 93%)
c
l
¼220 nm).
d
Scheme 3.
Conditions in entry 18 were used for the remainder of the study.
8 mol % L9.
e

V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
4721
the enantioinduction step. Our brief study suggested that chiral
‘additives’ might be useful upon further optimization. We plan to
continue studying the role of these additives in cyanoamidation.
N-benzyl anilines 22 and 23. Cyanoformamides 24a–27a were
generated from the appropriate precursor using carbonyl cyanide in
67 to 81% yield.
2.2. Substrate synthesis for exploring the scope of
asymmetric cyanoamidation
R
R
Ph3P+CH3Br-
PhCHO
O
t-BuOK
NaBH3CN
NH2
NH2
An advantage of cyanoamidation is the ease in preparing the
cyanoformamides. Unprotected cyanoformamides are typically
available in two to four steps from commercially available com-
pounds, while N-protected cyanoformamides require an additional
step. When coupled with cyanoamidation, oxindoles bearing all-
carbon quaternary stereocenters can be rapidly synthesized. This
section details the preparation of our substrates for exploring the
scope of cyanoamidation.
Substrates with a methyl alkene substituent (12a–15a) were
synthesized similar to cyanoformamide 6 in two to three steps from
commercially available substances (Scheme 4). Beginning with the
corresponding methyl anthranilates, anilines 4/9 were synthesized
in one step according to Spaeth.7 To generate the N-methyl cya-
noformamides, anilines 4 and 9 were treated with formaldehyde
and NaBH3CN to form the N-methyl anilines 10–11. The cyano-
formamides 12a–15a were generated from the appropriate pre-
cursor using carbonyl cyanide in 57 to 67% yield.
16: R = t-Bu
17: R = CH2Cy
18: R = Ph
19: R = t-Bu, 72%
20: R = CH2Cy, 70%
21: R = Ph, 65%
O
NC
R
CN
O
R
24a: R = CH2Cy, R' = Bn,71%
25a: R = CH2Cy, R' = H, 67%
26a: R = Ph, R' = Bn, 77%
27a: R = t-Bu, R' = H, 81%
NC
CN
NR'
CN
NHR'
O
22: R = CH2Cy, R' = Bn
23: R = Ph, R' = Bn
Scheme 5.
We opted for a three- to four-step approach via an aryl/vinyl
Pd-catalyzed cross-coupling reaction to build substrates with siloxy
methyl substituents on the alkene (R¼CH2OTBS). The cross-coupling
proved quite difficult, likely due to the presence of the ortho-aniline
(Table 2). Our initial goal was to avoid protecting group manipulations
by using the free aniline 28 to generate organometallic reagents for
the cross-coupling. Producing the corresponding metalloaniline was
unexpectedly difficult (entries 1 and 2); evenwhen the metalloaniline
was formed, the Suzuki cross-coupling15 with vinyl iodide 3314 gave
the styrene 34 in 15% yield (entry 2). A Negishi cross-coupling strat-
egy16 beginning with 1-bromo-2-nitrobenzene 29 fared no better
(entry 3). Hypothesizing that the nitro group or free aniline was in-
terfering with successful cross-coupling, we chose to work with N-
Boc-aniline 30.17 Arene deprotonation of 30 with t-BuLi followed by
a (n-Bu)3SnCl (entry 4) or B(OMe)3 (entry 5) quench provided the
corresponding metalloanilines. Attempted Stille (entry 4)18 and
Suzuki cross-couplings (entry 5) with the metalloanilines and vinyl
iodide 33 provided minor amounts of styrene 36. Qualitatively, it
appeared that sluggish arene deprotonation was hampering forma-
tion of the metalloaniline. Switching cross-coupling partners was one
alternative to circumvent arene deprotonation: we generated vinyl-
borolane 3719 from vinyl iodide 33, followed by cross-coupling with
Me
O
Me
Me
X
HCHO
NC
CN
X
X
NaBH3CN
NR'
NH2
NHR
O
CN
4: X = H
9: X = OMe
10: X = H, R' = Me
11: X = OMe, R' = Me
12a: X = H, R' = Me, 67%
13a: X = H, R' = H, 58%
14a: X = OMe, R' = Me, 64%
15a: X = OMe, R' = H, 57%
O
NC
CN
Scheme 4.
Substrates with alkene substituents R¼CH2Cy, phenyl, and tert-
butyl (24a–27a) were synthesized in three to four steps from com-
merciallyavailable substances (Scheme 5). Ketones 16 (R¼t-Bu)12 and
17 (R¼CH2Cy)13 were synthesized in one step from 2-amino-
benzonitrile; 2-aminobenzophenone 18 (R¼Ph) is commercially
available. Wittig reaction installs the styrene to produce 19–21 in 65
to 72% yield. Reductive amination with benzaldehyde forms the
Table 2
Palladium-catalyzed cross-coupling of metalloanilines and a vinyl iodide
TBSO
28: X = Br, N = NH2
29: X = Br, N = NO2
30: X = H, N = NHBoc
31: X = Br, N = NHBoc
X
MLn
34: N = NH2
35: N = NO2
36: N = NHBoc
conditions A
conditions B
TBSO
N
N
33
N
32
I
Entry
Aniline
Conditions Aa
32b
Conditions B
Product, yieldc
1
2
28
28
Pd(dppf)2 (10 mol %), pinB(Oi-Pr) (1.3 equiv), THF
Pd(dppf)2 (5 mol %), (pinB)2 (1.3 equiv), THF
Not obs
Obs
d
d
Pd(PPh3)4 (5 mol %), CuBr (5 mol %), LiCl (2.4 equiv),
33 (1.5 equiv), dioxane
34, 15%
3
4
5
6
29
30
30
31
(i) t-BuLi (1.65 equiv), THF (ii) ZnBr2 (1.8 equiv)
(i) t-BuLi (2.5 equiv), THF (ii) (n-Bu)3SnCl (1.1 equiv)
(i) t-BuLi (2.5 equiv), THF (ii) B(OMe)3 (1.1 equiv)
(i) t-BuLi (2.5 equiv), THF (ii) pinB(Oi-Pr) (1.5 equiv)
d
Pd(PPh3)4 (5 mol %), 33 (1.5 equiv), THF
Pd(PPh3)4 (10 mol %), 33 (1.5 equiv), dioxane
Pd(PPh3)4 (10 mol %), 33 (1.5 equiv), dioxane
Pd(PPh3)4 (10 mol %), CuBr (5 mol %), LiCl (2.4 equiv),
33 (1.5 equiv), dioxane
35, 10%
36, 10%
36, 15%
36, 25%
d
Obs
Obs
7
31
(i) t-BuLi (2.5 equiv), THF (ii) pinB(Oi-Pr) (1.5 equiv)
Obs
Pd(PPh3)4 (20 mol %), Na2CO3 (2 M),
33 (1.5 equiv), MeOH:PhH (1:3)
36, 75%
a
pin¼pinacolato.
Obs¼observed.
b
c
Yields after silica gel chromatography.

4722
V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
bromoaniline 3120 to provide a 12% yield of 36 (Scheme 6). The poor
yield prompted us to generate lithioanilines via a lithium–halogen
exchange of bromoaniline 31 (Table 2, entries 6 and 7). Treatment of
the metalloaniline 39 with Stoltz’s modified Suzuki cross-coupling
conditions21 provided styrene 36 in good yield (Scheme 7). Apply-
ing the same conditions beginning with 4-methoxyaniline 38 gave
the styrene 41 in 80% yield.
Table 3
Formation of oxindolesa
Entry
Substrate
Product
Yieldb
(%)
eec
(%)
Me
Me
CN
O
6
8
1
72
72
94
88
NBn
N
Bn
TBSO
TBSO
O
CN
TBSO
Me
Pd(PPh3)4
i) t-BuLi
Me
Me
Me
O
Me
Me
B
O
CN
O
ii)
Me
Me
Br
I
12b
O
O
31
12a
2
NHBoc
Me
B
Oi-Pr
NMe
N
NHBoc
12%
Me
Me
33
37
36
Me
O
CN
Me
Scheme 6.
CN
O
13b
3
4
48
82
82
99
Me
O
NH 13a
CN
Me
Me
Me
N
H
ii) Pd(PPh3)4
Na2CO3
X
Br
NHBoc
i) t-BuLi
O
X
B
O
Me
O
TBSO
Me
33
Me
Me
OiPr
Me
B
O
MeO
MeO
NHBoc
39: X = H
40: X = OMe
CN
MeO
MeO
I
31: X = H
38: X = OMe
14a
14b
O
Me
NMe
CN
N
Me
O
TBSO
TBSO
TBSO
PhCHO or
HCHO
TBSOTf
Me
2,6-lutidine
X
X
X
Me
CN
O
NaBH3CN
15a
15b
5
6
72
68
98
98
NH2
NHR'
NHBoc
36: X = H, 75%
41: X = OMe, 80%
NH
N
H
43: X = H, R' = Bn
34: X = H, 90%
42: X = OMe, 90%
44: X = H, R' = Me
O
CN
45: X = OMe, R' = Bn
46: X = OMe, R' = Me
O
Cy
NC
CN
TBSO
X
Cy
CN
O
24a
24b
47a: X = H, R' = Bn, 75%
48a: X = H, R' = Me, 76%
49a: X = H, R' = H, 90%
50a: X = OMe, R' = Bn, 70%
51a: X = OMe, R' = Me, 60%
52a: X = OMe, R' = H, 85%
NBn
N
O
Bn
O
CN
NC
CN
NR'
Cy
O
CN
Cy
Scheme 7.
CN
25a
7
53
94
25b
NH
CN
O
N
H
The remainder of the synthetic sequence for forming substrates
O
with siloxymethyl substituents on the alkene (R¼CH2OTBS) was
straightforward. The Boc groups were removed using TBSOTf in
2,6-lutidine to provide the free anilines 34 and 42. To provide alkyl-
protected cyanoformamides for our comparative study, we pro-
tected the anilines using benzaldehyde or formaldehyde in the
presence of NaBH3CN to give the methyl and benzyl anilines 43–46.
Finally, cyanoformamides 47a–52a were generated from the appro-
priate precursors using carbonyl cyanide.
Ph
Ph
CN
O
26a
26b
8
9
29
10
32
32
NBn
CN
N
Bn
O
O
t-Bu
t-Bu
CN
O
27a
27b
NH
N
H
2.3. Scope of asymmetric cyanoamidation
CN
When we subjected our cyanoformamides to our previously
optimized conditions (Table 1, entry 18), we observed superb
enantioselectivities (ee’s up to 99%) with less sterically demanding
alkene substituents as detailed in this section.
When the alkene was substituted with methyl (Table 3, entries
1–5), only slight differences in enantioselectivity were observed be-
tween N-benzyl and N-methyl cyanoformamides (entries 1 and 2).
Substantial decrease inyield and modest decrease in enantioselectivity
was observed when the cyanoformamide was unprotected compared
to the protected cyanoformamides (entries 1–3). Addition of
a methoxy substituent para to the cyanoformamide caused a dramatic
increase in yield and enantioselectivity for N-methyl cyanoforma-
mides (entries 2 and 4) and unprotected cyanoformamides (entries 3
TBSO
TBSO
TBSO
CN
47a
10
11
80
73
97
94
47b
O
NBn
CN
N
Bn
O
TBSO
CN
48a
O
48b
NMe
CN
N
Me
O

V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
4723
Table 3 (continued)
substituent para to the cyanoformamide was added (entries 13–15),
yields for all substrates increased above 70%, while enantiose-
lectivities were exceptional (ee’s of 98% and greater).
Entry
Substrate
Product
Yieldb
(%)
eec
(%)
We conclude that substituents on the alkene R have a large
influence on cyanoamidation. Sterically bulky phenyl and tert-butyl
substituents performed poorly compared to their less sterically de-
manding counterparts. For yield, the substituents R displayed the
following trend: CH2OTBS¼Me>CH2Cy>Ph>t-Bu. Enantioselectivity
TBSO
TBSO
CN
49a
12
56
88
78
72
93
99
98
98
O
49b
NH
CN
N
H
O
followed
a
slightly different pattern: CH2OTBS¼CH2Cy>Me>
TBSO
Ph¼t-Bu. One allylic substituent improved enantioselectivity,
TBSO
whereas two or more substituents markedly decreased it.
MeO
MeO
MeO
CN
MeO
MeO
MeO
50a
50b
13
14
O
NBn
CN
N
2.4. Absolute configuration via synthesis of (L)-esermethole
Bn
O
To confirm the absolute configuration of our cyanoamidation
products, we synthesized (ꢀ)-esermethole.22,23 (ꢀ)-Esermethole is
a pyrrolidinoindoline natural product containing an all-carbon qua-
ternarystereocenterat the C-3aposition. It is a key intermediateinthe
synthesis of (ꢀ)-physostigmine,24 a potent reversible inhibitor of
acetyl- and butyrylcholinesterase and used clinically to treat to glau-
coma.25 (ꢀ)-Esermethole is also a key intermediate in the synthesis of
(ꢀ)-phenserine (Fig. 2),24 a congener of physostigmine. (ꢀ)-Phen-
serinedisplays acetylcholinesterase inhibition,26 beta-amyloid plaque
deposition in the brain,27 and was in Phase III clinical trials as
a treatment for Alzheimer’s Disease until the previous year.28 The
potency of the structurally similar pyrrolidinoindolines makes the
efficient preparation of the key precursor critically important.
TBSO
TBSO
TBSO
CN
51a
51b
O
NMe
CN
N
Me
O
TBSO
CN
O
52a
52b
15
NH
CN
N
H
O
a
Pd2dba3 (2 mol %), L9 (16 mol %), DMPU (1 equiv), THF (0.25 M), 100 ꢁC.
TBS¼tert-butyl-dimethylsilyl, Cy¼cyclohexyl.
b
Yields after silica gel chromatography.
c
RHN
MeO
ee determined by HPLC.
Me
O
Me
N
O
NMe
NMe
N
H
and 5). The yield for unprotected cyanoformamides was still sub-
stantially lower than the N-methyl compound, even with the addi-
tional methoxy substituent (entries 4 and 5). Yields for methyl-
substituted alkenes ranged from 48 to 72%, while ee’s ranged from
82 to 99%.
Me
H
Me
(–)-esermethole
R = Me, (–)-physostigmine
R = Ph, (–)-phenserine
Figure 2.
Similarly, when the alkene was substituted with CH2Cy, better
yields and ee’s were observed with the N-benzyl cyanoformamide
(entry 6) compared to the unprotected cyanoformamide (entry 7).
The unprotected cyanoformamide 25a with R¼CH2Cy had much
better yields and enantioselectivities of the oxindole compared to
cyanoformamide 13a with R¼Me (53%, ee¼94%, compared to 48%,
ee¼82%, respectively). As the alkene substituent became more
sterically demanding (R¼phenyl, entry 8) and (R¼t-Bu, entry 9),
much poorer yields and enantioselectivities were observed com-
pared to their less sterically demanding counterparts.
Substrates with siloxymethyl ether substituents (entries 10–15)
consistently gave the highest yields and enantioselectivities of all
the substrates we examined. Erosion in yield occurred from
N-benzyl to N-methyl to unprotected cyanoformamides, though
ee’s for oxindoles remained greater than 90%. When the methoxy
To begin our synthesis of (ꢀ)-esermethole, we made slight
changes to our general substrate syntheses to furnish cyanoforma-
mide 14a (Scheme 8). 5-Hydroxymethylanthranilate 53 was avail-
able in one step29 from commercially available 5-hydroxyanthranilic
acid. Treatment of 53 with NaH and MeI provided 54 in 56% yield.
The alpha-methyl styrene was installed by treating 54 with excess
MeMgBr, followed by dehydration7 to produce 11 in 72% yield. In-
stallation of the cyanoformamide using carbonyl cyanide provided
14a in 64% yield. Cyanoamidation of 14a using our standard condi-
tions gave the 3,3-disubstituted oxindole 14b in 82% yield (ee¼99%).
Following the cyanoamidation, LiAlH4 reduction of oxindole 14b
generated the pyrrolidinoindoline core 55, and subsequent re-
ductive amination with formaldehyde gave our targeted molecule
(ꢀ)-esermethole in 92% yield over two steps.2 Our targeted
Me
O
i) MeMgBr
ii) I2, PhMe (Dean-Stark)
72%
Me
MeO
HO
CO2Me
NH2
MeO
CO2Me
NHMe
NaH, MeI
56%
NC
CN
MeO
64%
NMe
NHMe
53
54
11
14a
O
CN
Pd2dba3 (2 mol %)
MeO
MeO
Me
HCHO
L9 (16 mol %), DMPU (1 equiv)
Me
Me
MeO
NaBH(OAc)3
LiAlH4
CN
O
°C
NMe
NH
92% over 2 steps
82%
N
N
N
H
H
Me
Me
Me
(−)-esermethole
(ee = 99%)
55
14b
(ee = 99%)
Scheme 8.

4724
V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
compound was produced in seven steps from commercially avail-
able materials, in 19.5% overall yield from methylanthralinate 53,
and with high enantiopurity.
Based on the optical rotation of our (ꢀ)-esermethole product,
were able to assign the absolute stereochemistry of oxindole 14b.
The absolute stereochemistry of many of the remaining oxindoles
shown in Table 3 was assigned by analogy to oxindole 14b.
the aldehyde 56. We anticipated that chemoselective reduction of the
nitrile in the presence of the aldehyde of 56 would allow efficient
reductive amination. Unfortunately, treatmentof nitrile 56with PtO2/
1 M HCl in methanol gave a mixture of compounds 57–60, and sub-
jecting the mixture to reductive amination conditions (NaBH3CN,
AcOH, MeOH) caused extensive racemization, presumably via the
Mannich/retro-Mannich pathway.
Our alternative route, incorporating an intramolecular SN2 re-
action, was much more successful (Scheme 11). The oxindoles 49b
and 52b were treated with TBAF, and the resulting crude alcohols
exposed to MsCl. Chemoselective reduction of the nitrile was ach-
ieved with NaBH4/CoCl2$6H2O,33 allowing closure of the spirocycle
via 61 and 62. Addition of formaldehyde to the reaction mixture
installed the amino methyl groups and completed the syntheses of
(ꢀ)-coerulescine (54% from 49b, ee¼91%) and (þ)-horsfiline (49%
from 52b, ee¼98%). Only one purification was performed during
the last three steps. The slight decrease in ee during the synthesis of
(ꢀ)-coerulescine might be attributed to the slightly acidic condi-
tions during workup.
We conclude that cyanoamidation allows (ꢀ)-coerulescine to be
synthesized in 18% overall yield (ee¼91%) in seven steps from an-
iline 31, and eight steps from commercially 2-bromoaniline.
(þ)-Horsfiline was synthesized in 22% overall yield (ee¼99%) in
seven steps from aniline 38,34 and nine steps from commercially
available 4-methoxyaniline.
2.5. Syntheses of (D)-horsfiline and (L)-coerulescine
In addition to synthesizing (ꢀ)-esermethole, we also targeted
(þ)-horsfiline and (ꢀ)-coerulescine, which are oxindole natural
products with unique spiro stereogenic centers. Their spirocyclic
oxindolecoresarestructurallysimilartothespirotryprostatins(Fig.1),
which are cell-cycle inhibitors at micromolar concentrations.30 The
unique structures of horsfiline has inspired synthetic chemists to
pursue more efficient strategies toward its construction.31,32 Notable
syntheses include Trost’s palladium-catalyzed asymmetric allylic al-
kylation approach to generate the quaternary stereocenter.31a Palm-
isano utilized a chiral auxiliary-directed 1,3-dipolar cycloaddition of
anazomethineylidetoformthequaternarystereocenter.31b Onewell-
known synthetic challenge of both (þ)-horsfiline and (ꢀ)-coeru-
lescine is the acid-promoted retro-Mannich/Mannich, which can
racemize the natural product (Scheme 9).
Me
N
Me
N
Me
N
3. Conclusion
MeO
MeO
MeO
H
We have reported the detailed study of Pd-catalyzed asym-
metric cyanoamidation. We attribute our high enantioselectivities
to a chiral phosphoramidite ligand synthesized in one step from the
commercially available phosphorochloridite and amine. We dem-
onstrated that diverse cyanoformamides are easy to prepare. The
3,3-disubstituted oxindoles resulting from cyanoamidation bear
all-carbon quaternary stereocenters, a nitrile, and an amide, which
can be valuable functional handles in the synthesis of indole-
containing natural products. Cyanoamidation tolerates free N–H
groups, as demonstrated by our syntheses of (þ)-horsfiline and
(ꢀ)-coerulescine. Future work on asymmetric cyanoamidation-
based strategies for the synthesis of complex alkaloids is ongoing.
O
O
O
H
N
H
N
H
–H
N
H
Scheme 9.
Our oxindoles 49b (ee¼93%) and 52b (ee¼98%) contained ideally
situated functional groups to enable rapid syntheses of (ꢀ)-coeru-
lescine and (þ)-horsfiline, respectively. We originally envisioned
constructing the spirocycle via a reductive amination route as shown
in Scheme 10. Treatment of oxindole 52b with TBAF exposed
the alcohol, which was subsequently oxidized with IBX to generate
H
N
N
HO
1. NaBH3CN
AcOH
MeO
MeO
Me
N
H
MeOH
+
TBSO
O
1. TBAF
CN 2. IBX
O
PtO2, MeOH,
HCl (1 mol %)
O
2. CH2O
N
H
N
H
MeO
CN
O
MeO
MeO
58
57
O
78%
15%
O
O
OH
N
H
N
H
H
N
H
NH2
NH2
MeO
MeO
52b
56
horsfiline
O
+
(ee = 98%)
(ee = 98%)
(ee = 8%)
O
N
H
N
H
59
60
Scheme 10.
H2N
1. TBAF
Me
N
Me
N
TBSO
2. MsCl, Et3N
CH2Cl2
CN
O
3ii. CH2O
R = H, 54% from 49b
X
MsO
X
MeO
or
3i. CoCl2 6H2O,
NaBH4, MeOH,
O
O
N
H
O
R = OMe, 49% from 52b
N
H
N
H
N
H
49b: X = H (ee = 93%)
61: X = H
62: X = OMe
(–)-coerulescine
(ee = 91%)
(+)-horsfiline
(ee = 99%)
52b: X = OMe (ee = 98%)
Scheme 11.

V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
4725
4. Experimental section
4.1. General
was allowed to stir for 8 h at room temperature. The reaction was
filtered through a Celite pad and solvent was evaporated to dryness.
The crude product was purified by silica gel chromatography (15:85,
EtOAc/Hex) to provide 6 as clear oil (0.375 g, 1.42 mmol, 70%).
All reactions were carried out using flame-dried glassware under
a nitrogen or argon atmosphere unless aqueous solutions were
employed as reagents or dimethylformamide was used as a solvent.
Tetrahydrofuran (THF), dichloromethane (CH2Cl2), xylene, diethyl
ether and toluene (PhMe) were dried according to published pro-
cedures. THF was further degassed by bubbling a stream of argon
through the liquid in a Strauss flask and then stored in a nitrogen-
filled glove box. Palladium complexes were purchased from Strem
and used as received. Phosphoramidite ligands were purchased form
Strem or prepared by using the literature procedure and stored in
nitrogen-filled glove box. Phosphonium salts for Wittig reactions
were purchased from Aldrich and used as received. All types of an-
ilines compounds were purchased from Aldrich and used as re-
ceived. Tetracyanoethyleneoxide was prepared according to Linn.35
All cyanoamidation reactions were out in a Vacuum Atmospheres
nitrogen-filled glove box in 1 dram vials with PTFE lined caps and
heating was applied by aluminum block heaters. Analytical thin layer
chromatography (TLC) was carried out using 0.25 mm silica plates
from E. Merck. Eluted plates were visualized first with UV light and
then by staining with ceric sulfate/molybdic acid or potassium per-
manganate/potassium carbonate. Flash chromatography was per-
formed using 230–400 mesh (particle size 0.04–0.063 mm) silica gel
purchased from Merck unless otherwise indicated. 1H NMR (300 and
500 MHz) and 13C NMR (75 and 125 MHz) spectra were obtained on
4.3.2. Method B. A solution of (2-isopropenyl-phenyl)-methyl-
amine 10 (0.246 g, 1.4 mmol) in Et2O (2.2 mL) was cooled to 0 ꢁC
and carbonyl cyanide8 (3.0 mL, 3.0 mmol, 1.0 M in Et2O) was
added. The resulting suspension was stirred for 8 h at rt. The
reaction mixture was filtered through a pad of Celite and con-
centrated. The crude product was purified by silica gel chroma-
tography (25:75, EtOAc/Hex) to provide 12a as a clear oil (0.187 g,
0.93 mmol, 67%).
4.3.3. N-Benzyl(2-(prop-en-2yl) phenyl)carbamoyl cyanide(6). Pre-
pared via Method A (Section 4.3.1): 1H NMR (300 MHz, CDCl3)
d 7.44–
7.38 (m, 2H), 7.35–7.26 (m, 3H), 7.25–7.16 (m, 3H), 6.80–6.77 (m,1H),
5.54 (d, J¼14.1 Hz, 1H), 5.38 (q, J¼3.2 Hz, 1H), 5.12 (s, 1H), 4.13
(d, J¼14.1 Hz, 1H), 2.15 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 145.5,
142.0, 135.0, 134.7, 130.6, 130.4, 130.3, 129.4, 128.8, 128.5, 128.4,
118.3, 110.9, 53.3, 23.7; IR (thin film) 2841, 2023, 1614, 1545, 1504,
1450, 1380, 1016, 912, 660; HRMS (ESI) calcd for [C17H15N2OþNa]þ
286.1082, found 286.1081. (Mixture of rotamers w92:8).
4.3.4. N-Methyl(2-(prop-en-2yl) phenyl)carbamoyl cyanide
(12a). Prepared via Method B (Section 4.3.2): 1H NMR (300 MHz,
CDCl3)
d
7.46 (dd, J¼7.7, 1.2 Hz, 1H), 7.40 (dd, J¼7.7, 1.6 Hz, 1H), 7.24
(dd, J¼7.7, 1.2 Hz, 1H), 5.31 (dq, J¼3.2, 1.5 Hz, 1H), 5.03 (d, J¼3.2 Hz,
Varian FT NMR instruments. NMR spectra were reported as d values
1H), 3.27 (s, 3H), 2.08 (d, J¼1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
in parts per million relative to chloroform or tetramethylsilane. 1H
NMR coupling constants are reported in hertz; multiplicity was in-
dicated as follows; s (singlet); d (doublet); t (triplet); q (quartet);
quint (quintet); m (multiplet); dd (doublet of doublets); ddd (dou-
blet of doublet of doublets); dddd (doublet of doublet of doublet of
doublets); dt (doublet of triplets); dq (doublet of quartets); td (triplet
of doublets); ddt (doublet of doublet of triplets); app (apparent); br
(broad). Infrared (IR) spectra were obtained as films from CH2Cl2 or
CDCl3. LRMS and high-resolution mass spectra (HRMS) in electro-
spray (ESI) experiments were performed on a Bruker BioTOF II. Op-
tical rotation experiments were performed on Rudolph Polarimeter.
The ee’s were determined by using HPLC with Chiralpak OD-H or
AD-H columns by using combination of hexanes and isopropanol as
a mobile phase. For oxindoles 14b, 52b, and 49b, the absolute ste-
reochemistry was assigned by chemical correlation to (ꢀ)-eser-
methole, (þ)-horsfiline, and (ꢀ)-coerulescine, respectively. Other
absolute configurations of oxindoles were assigned in analogy.
d 145.4, 142.6, 141.8, 137.1, 130.5, 130.4, 128.9, 118.3, 111.0, 36.8, 23.7;
IR (thin film) 2861, 2003, 1604, 1525, 1504, 1470, 1300, 1016, 912,
665; HRMS (ESI) calcd for [C12H12N2OþNa]þ 223.0847, found
223.0842. (Mixture of rotamers w93:7).
4.3.5. (2-(Prop-en-2yl) phenyl)carbamoyl cyanide (13a). Prepared
via Method B (Section 4.3.2): 1H NMR (300 MHz, CDCl3)
d 8.31 (br s,
1H), 8.10 (d, J¼8.2 Hz, 1H), 7.31–7.28 (m, 1H), 7.24–7.22 (m, 2H),
5.49–5.47 (m, 1H), 5.07–4.99 (m, 1H), 2.11 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 141.6, 140.4, 134.5, 131.4, 128.4, 126.3, 121.8, 121.7,
111.6, 24.3; IR (thin film) 2841, 2023, 1614, 1535, 1504, 1470, 1300,
1016, 912, 665; HRMS (ESI) calcd for [C11H10N2OþNa]þ 209.0691,
found 209.0685. (Mixture of rotamers w92:8).
4.3.6. N-Methyl(4-methoxy-2-(prop-1-en-2-yl)phenyl)carbamoyl
cyanide (14a). Prepared via Method B (Section 4.3.2): 1H NMR
(300 MHz, CDCl3)
J¼1.5 Hz, 1H), 5.02 (d, J¼1.0 Hz, 1H), 3.84 (s, 3H), 3.23 (s, 3H), 2.07
(s, 3H); 13C NMR (75 MHz, CDCl3)
179.7, 156.6, 133.1, 132.9, 116.7,
d
7.16 (d, J¼8.7 Hz,1H), 6.90–6.84 (m, 2H), 5.29 (d,
4.2. Preparation of carbonyl cyanide (w1 M in ether)8
d
114.1, 111.1, 110.7, 56.1, 53.3, 46.0, 26.5, 22.5; IR (thin film) 2841,
2023, 1614, 1535, 1504, 1470, 1300, 1280, 1050, 1016, 912, 668;
HRMS (ESI) calcd for [C13H14N2O2þNa]þ 253.0953, found 253.0952.
(Mixture of rotamers w93:7).
To a suspension of tetracyanoethyleneoxide (TCEO) (10.00 g,
69.4 mmol) in ether (40 mL) was added Me2S (5.19 mL, 68.0 mmol)
at 0 ꢁC. After stirring at 0 ꢁC for 1 h, the precipitate was removed by
filtration and the filtrate was diluted with ether (30 mL) to give the
carbonyl cyanide solution (w1.0 M) in ether, which was used for
the following reactions without further purification.
4.3.7. (4-Methoxy-2-(prop-1-en-2-yl)phenyl)carbamoyl cyanide
(15a). Prepared via Method A (Section 4.3.1): 1H NMR (300 MHz,
Note: The solution of carbonyl cyanide can be used in-
terchangeably with TCEO/Me2S. Based on our experience, the so-
lution was stable for a few months in the refrigerator (w5 ꢁC).
CDCl3)
3.0 Hz, 1H), 5.46 (dd, J¼3.3, 1.8 Hz, 1H), 5.05 (dd, J¼3.3, 1.8 Hz, 1H),
3.80 (s, 3H), 2.07 (s, 3H); 13C NMR (75 MHz, CDCl3)
158.3, 142.3,
d
8.02 (d, J¼9.0 Hz, 1H), 6.85–6.80 (m, 2H), 6.74 (t, J¼4.8,
d
136.8, 125.2, 123.9, 119.0,118.7, 114.4, 113.6, 112.4, 56.2, 25.1; IR (thin
film) 2841, 2023, 1614, 1535, 1504, 1470, 1300, 1280, 1050, 1016, 912,
668; HRMS (ESI) calcd for [C12H12N2O2þNa]þ 239.0796, found
239.0792. (Mixture of rotamers w95:5).
4.3. General procedure to generate cyanoformamides
4.3.1. Method A. To a solution of TCEO (0.347 g, 2.4 mmol) in dry
Et2O in a flame-dried round bottom flask was added methyl sulfide
(0.25 mL, 3.0 mmol) at 0 ꢁC.35 The reaction mixture was stirred for
one hour at 0 ꢁC, and a solution of benzyl-(2-isopropenyl-phenyl)-
amine 5 (0.446 g, 2.0 mmol) in Et2O was added at 0 ꢁC. The reaction
4.3.8. N-Benzyl(2-(3-cyclohexylprop-1-en-2-yl)phenyl)carbamoyl
cyanide (24a). Prepared via Method A (Section 4.3.1): 1H NMR
(300 MHz, CDCl3)
d 7.44–7.38 (m, 2H), 7.35–7.26 (m, 3H), 7.25–7.16

4726
V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
(m, 3H), 6.80–6.77 (m, 1H), 5.54 (d, J¼14.1 Hz, 1H), 5.38 (q, J¼3.2 Hz,
1H), 5.12 (s, 1H), 4.13 (d, J¼14.1 Hz, 1H), 2.25 (dd, J¼7.2, 0.9 Hz, 2H),
1.71–1.67 (m, 5H), 1.29–0.87 (m, 6H); 13C NMR (75 MHz, CDCl3)
1H), 4.33 (s, 2H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR
(75 MHz, CDCl3) 145.8, 145.7,139.9,138.2,131.5,130.7,129.9, 129.7,
116.6, 111.4, 37.5, 26.5, 19.0, ꢀ4.6, ꢀ4.7; IR (thin film) 2831, 2033,
1600, 1535, 1504, 1470, 1300, 1280, 1050, 1016, 912, 678; HRMS (ESI)
calcd for [C17H24N2O2SiþNa]þ 339.1505, found 339.1507. (Mixture
of rotamers w95:5).
d
d
158.9, 145.3, 134.4, 132.6, 129.1, 128.9, 126.8, 122.0, 119.1, 112.2, 46.8,
35.9, 34.2, 34.0, 27.0, 26.7; IR (thin film) 2841, 2023, 1614,1535,1504,
1470, 1300, 1280, 1050, 1016, 912, 668; HRMS (ESI) calcd for
[C24H26N2OþNa]þ 381.1943, found 381.1948. (Mixture of
rotamers w94:6).
4.3.15. N-Benzyl(2-(3-(tert-butyldimethylsilyloxy)prop-1-en-2-yl)-4-
methoxyphenyl)carbamoyl cyanide (50a). Prepared via Method B
4.3.9. (2-(3-Cyclohexylprop-1-en-2-yl)phenyl)carbamoyl cyanide
(Section 4.3.2): 1H NMR (300 MHz, CDCl3)
d 7.38–7.24 (m, 5H), 6.72–
(25a). Prepared via Method A (Section 4.3.1): 1H NMR (300 MHz,
6.69 (m, 1H), 6.61–6.52 (m, 2H), 5.60 (d, J¼1.8 Hz, 1H), 5.18
CDCl3)
1.0 Hz,1H), 5.10 (d, J¼1.5 Hz,1H), 2.25(dd, J¼7.2, 0.9 Hz, 2H),1.71–1.67
(m, 5H), 1.29–0.87 (m, 6H); 13C NMR (75 MHz, CDCl3)
158.9, 145.3,
d
8.13 (dd, J¼7.1, 1.5 Hz, 1H), 7.39–7.14 (m, 3H), 5.42 (dd, J¼1.5,
(d, J¼1.8 Hz, 1H), 4.72 (d, J¼7.5 Hz, 2H), 4.28 (s, 2H), 3.73 (s, 3H), 0.91
(s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 146.1, 146.0, 138.8,
d
136.2,135.3,131.5,131.4,130.8,129.7,116.9,111.5, 66.3, 53.8, 30.5, 26.6,
26.5,19.1, ꢀ4.6; IR (thin film) 3021, 2841, 2023,1614,1535,1504,1470,
1300, 1280, 1050, 1016, 912, 668; HRMS (ESI) calcd for
[C25H32N2O3SiþNa]þ 459.1974, found 459.1970. (Mixture of rotamers
w95:5).
134.4,132.6,129.1,128.9,126.8,122.0,119.1,112.2, 46.8, 35.9, 34.2, 34.0,
27.0, 26.7; IR (thin film) 2841, 2023,1614,1535,1504,1470,1300,1280,
1050,1016, 912, 668; HRMS (ESI) calcdfor [C17H20N2OþNa]þ 291.1473,
found 291.1480. (Mixture of rotamers w93:7).
4.3.10. N-Benzyl(2-(1-phenylvinyl)phenyl)carbamoylcyanide
4.3.16. N-Methyl(2-(3-(tert-butyldimethylsilyloxy)prop-1-en-2-yl)-
(26a). Prepared via Method A (Section 4.3.1): 1H NMR (300 MHz,
4-methoxyphenyl)carbamoyl cyanide (51a). Prepared via Method B
CDCl3)
d
7.60–7.43 (m, 2H), 7.42–7.22 (m, 9H), 7.15–7.06 (m, 2H), 6.80–
(Section 4.3.2): 1H NMR (300 MHz, CDCl3)
d
8.09–8.06 (m, 1H), 7.16–
7.35 (m, 2H), 5.59 (s, 1H), 5.14 (s, 1H), 4.34 (s, 2H), 3.76 (s, 3H), 3.30
(s, 3H), 0.83 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3)
152.9,
6.77 (m, 1H), 5.77 (s, 1H), 5.45 (s, 1H), 5.04 (d, J¼14.1 Hz, 1H), 3.68
(d, J¼14.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
156.5, 143.4, 137.3,
d
135.8, 130.3, 129.8, 129.6, 129.1, 128.5, 127.8, 127.4, 125.9, 124.1, 117.1,
110.8, 53.4, 44.9, 26.9; IR (thin film) 2841, 2003, 1604, 1515, 1513, 1460,
1300, 1006, 902, 655; HRMS (ESI) calcd for [C23H19N2OþH]þ
339.1497, found 339.1497. (Mixture of rotamers: 98:2).
147.3, 138.0, 127.8, 117.2, 115.4,114.6,114.2, 66.0, 56.4, 31.8, 26.6, 26.3,
19.1, ꢀ4.6; IR (thin film) 3021, 2841, 2023, 1614, 1535, 1504, 1470,
1300, 1280, 1050, 1016, 912, 668; HRMS (ESI) calcd for
[C19H28N2O3SiþNa]þ 383.1767, found 383.1760. (Mixture of rotamers
w94:6).
4.3.11. (2-(3,3-Dimethylbut-1-en-2-yl)phenyl)carbamoyl cyani-
de(27a). Prepared via Method B (Section 4.3.2): 1H NMR (300 MHz,
4.3.17. (2-(3-(tert-Butyldimethylsilyloxy)prop-1-en-2-yl)-4-methoxy
CDCl3)
7.12 (m, 2H), 5.57 (d, J¼0.9 Hz,1H), 4.99 (d, J¼0.9 Hz,1H),1.14 (s, 9H);
13C NMR (75 MHz, CDCl3)
155.4, 140.4, 133.6, 130.5, 128.7, 126.0,
121.8, 111.6, 112.7, 37.9, 30.7; IR (thin film) 2840, 2013, 1610, 1530,
1504, 1470, 1300, 1016, 912, 665; HRMS (ESI) calcd for
[C14H16N2OþNa]þ 251.1160, found 251.1160. (Mixture of rotamers
w93:7).
d
8.13 (d, J¼8.4 Hz,1H), 7.93 (br s,1H), 7.36–7.31 (m,1H), 7.22–
phenyl)carbamoyl cyanide (52a). Prepared via Method B (Section
4.3.2): 1H NMR (300 MHz, CDCl3)
d
9.16 (br s,1H), 8.09–8.06 (m,1H),
7.16–7.35 (m, 2H), 5.59 (s, 1H), 5.14 (s, 1H), 4.34 (s, 2H), 3.76 (s, 3H),
0.83 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3)
152.9,147.3, 8.0,
d
d
127.8, 117.2, 115.4, 114.6, 114.2, 66.0, 56.4, 26.6, 26.3, 19.1, ꢀ4.6; IR
(thin film) 3021, 2841, 2023,1614,1535,1504,1470,1300,1280,1050,
1016, 912, 668; HRMS (ESI) calcd for [C18H26N2O3SiþNa]þ 369.1610,
found 369.1610. (Mixture of rotamers w95:5).
4.3.12. N-Benzyl(2-(3-(tertbutyldimethylsilyloxy)prop-1-en-2-yl)-
phenyl)carbamoyl cyanide (47a). Prepared via Method B (Section
4.4. General procedure for cyanoamidation
4.3.2): 1H NMR (300 MHz, CDCl3)
d 7.45–7.08 (m, 8H), 6.73 (dd,
J¼7.8,1.2 Hz,1H), 5.64 (dd, J¼3.3,1.5 Hz,1H), 5.50 (d, J¼14.8 Hz,1H),
In a N2 filled glove box, cyanoformamide (1.0 equiv), Pd2dba3
(0.02 equiv), L9 (0.16 equiv), DMPU (1.0 equiv) were combined in
a PTFE-lined screw-cap vial. THF was added (0.25 M in cyano-
formamide) and the vial was sealed. The resulting solution was
maintained at 100 ꢁC for 24 h, after which the reaction was removed
from the glove box. The reaction mixture was diluted with CH2Cl2
(2ꢂvolume), filtered through Celite and concentrated in vacuo. The
resulting crude product was purified by flash chromatography and
the resulting product analyzed by HPLC.
5.23 (dd, J¼3.3, 1.5 Hz, 1H), 4.40 (s, 2H), 4.14 (d, J¼14.8 Hz, 1H), 0.89
(s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 146.1, 146.0, 139.8,
135.3,131.5,131.4,130.8,130.7,130.1,129.7,129.7,129.6,129.5,129.4,
129.3, 129.0, 116.9, 111.5, 66.4, 53.8, 26.6, 26.5, 19.1, ꢀ4.5, ꢀ4.6; IR
(thin film) 2881, 2033, 1600, 1535, 1504, 1470, 1300, 1280, 1050,
1016, 912, 678; HRMS (ESI) calcd for [C24H30N2O2SiþNa]þ 429.1974,
found 429.1970. (Mixture of rotamers w95:5).
4.3.13. N-Methyl(2-(3-(tert-butyldimethylsilyloxy)prop-1-en-2-yl)-
phenyl)carbamoyl cyanide (48a). Prepared via Method B (Section
4.4.1. (S) 2-(1-Benzyl-3-methyl-2-oxoindolin-3-yl)acetonitrile (8). 1H
4.3.2): 1H NMR (300 MHz, CDCl3)
d
7.49–7.34 (m, 3H), 7.29–7.24 (m,
NMR (300 MHz, CDCl3)
d
7.50 (td, J¼7.5, 0.9 Hz, 1H), 7.37–7.22 (m,
1H), 5.58 (dd, J¼3.3, 1.8 Hz, 1H), 5.17 (dd, J¼3.0, 1.5 Hz, 1H), 4.33 (s,
6H), 7.11 (dt, J¼7.5, 1.2 Hz, 1H), 6.80 (d, J¼7.8 Hz, 1H), 4.95 (s, 2H),
2H), 3.26 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR
2.93 (d, J¼16.8 Hz, 1H), 2.66 (d, J¼16.8 Hz,1H), 1.60 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d
145.8,145.7,139.9, 138.2, 131.5, 130.7, 129.9, 129.7,
(75 MHz, CDCl3) d 179.8, 141.8, 135.4, 131.0, 129.2, 129.0, 127.9, 127.2,
116.6, 111.4, 66.2, 37.5, 26.5, 19.0, ꢀ4.6, ꢀ4.7; IR (thin film) 2831,
2033, 1600, 1535, 1504, 1470, 1300, 1280, 1050, 1016, 912, 678;
HRMS (ESI) calcd for [C18H26N2O2SiþNa]þ 353.1661, found
353.1660. (Mixture of rotamers w94:6).
123.3, 123.3, 123.2, 116.6, 45.0, 44.0, 26.4, 22.6; IR (thin film) 2841,
2023, 1614, 1545, 1504, 1450, 1380, 1016, 912, 660; HRMS (ESI) calcd
for [C17H15N2OþNa]þ 286.1082, found 286.1081; HPLC [Chiralcel
23
OD-H, Hex/IPA¼90/10, 1.0 mL/min,
l¼220 nm] 95% ee, [
a]
ꢀ32.0
D
(0.45 in CHCl3).
4.3.14. (2-(3-(tert-Butyldimethylsilyloxy)prop-1-en-2-yl)phe-
nyl)carbamoyl cyanide (49a). Prepared via Method B (Section 4.3.2):
4.4.2. (S) 2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetonitrile (12b). 1H
NMR (300 MHz, CDCl3)
7.48 (d, J¼8.0 Hz, 1H), 7.36 (d, J¼8.0 Hz,
1H), 7.14 (dd, J¼8.0 Hz, 1H), 6.90 (d, J¼7.9 Hz, 1H), 3.25 (s, 3H), 2.85
1H NMR (300 MHz, CDCl3)
d
7.49–7.43 (m, 2H), 7.41–7.34 (m, 1H),
d
7.29–7.24 (m, 1H), 5.58 (dd, J¼3.3, 1.8 Hz, 1H), 5.17 (dd, J¼3.0, 1.5 Hz,

V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
4727
(d, J¼16.8 Hz, 1H), 2.58 (d, J¼16.4 Hz, 1H), 1.53 (s, 3H); 13C NMR
129.1, 128.5, 127.8, 127.4, 125.9, 124.1, 117.1, 110.8, 53.4, 44.9, 26.9; IR
(thin film) 2881, 2123, 1600, 1585, 1504, 1400, 1380, 1016, 912, 665;
HRMS (ESI) calcd for [C23H19N2OþH]þ 339.1497, found 339.1497.
(75 MHz, CDCl3) d 171.5,142.9, 131.2,129.3,123.4,123.3,116.8,108.8,
44.9, 26.6, 26.3, 22.2; IR (thin film) 2861, 2003, 1604, 1525, 1504,
1470, 1300, 1016, 912, 665; HRMS (ESI) calcd for [C12H12N2OþNa]þ
HPLC [Chiralcel OD-H, hexane/isopropanol¼90/10, 1.0 mL/min,
23
223.0847, found 223.0844; HPLC [Chiralcel OD-H, Hex/IPA¼90/10,
l
¼220 nm] 32% ee [
a
]
þ83.6 (0.5 in CHCl3).
D
23
1.0 mL/min,
l
¼220 nm] 88% ee, [
a
]
þ64.1 (0.45 in CHCl3).
D
4.4.9. (R)-2-(3-tert-Butyl-2-oxoindolin-3-yl)acetonitrile (27b). 1H
NMR (300 MHz, CDCl3) 7.60 (br s, 1H), 7.32–7.26 (m, 2H), 7.24–
7.08 (m, 1H), 2.99 (d, J¼16.2 Hz, 1H), 2.89 (d, J¼16.5 Hz, 1H), 1.03
(s, 9H); 13C NMR (75 MHz, CDCl3)
180.2, 139.9, 131.4, 123.4,
4.4.3. (S) 2-(3-Methyl-2-oxoindolin-3-yl)acetonitrile (13b). 1H NMR
(300 MHz, CDCl3)
d
d
9.15 (br s, 1H), 7.45 (d, J¼7.3 Hz, 1H), 7.30
(t, J¼7.8 Hz, 1H), 7.12 (t, J¼7.6 Hz, 1H), 7.00 (d, J¼7.6 Hz, 1H), 2.85
d
(d, J¼16.5 Hz, 1H), 2.64 (d, J¼16.8 Hz, 1H), 1.56 (s, 3H); 13C NMR
123.2, 116.5, 110.6, 45.3, 26.1, 37.1, 30.1; IR (thin film) 3000, 2861,
2003, 1604, 1525, 1504, 1470, 1300, 1016, 912, 665; HRMS (ESI)
calcd for [C14H16N2OþNa]þ 251.1160, found 251.1160; HPLC
(75 MHz, CDCl3) d 180.2, 139.9, 131.4, 123.4, 123.2, 116.5, 110.6, 45.3,
26.1, 22.1; IR (thin film) 3000, 2861, 2003, 1604, 1525, 1504, 1470,
1300, 1016, 912, 665; HRMS (ESI) calcd for [C11H10N2OþNa]þ
[Chiralcel OD-H, Hex/IPA¼90/10, 1.0 mL/min, ¼220 nm] 32% ee,
l
23
209.0691, found 209.0690; HPLC [Chiralcel OD-H, Hex/IPA¼90/10,
[
a
]
þ32.0 (0.65 in CHCl3).
D
23
1.0 mL/min,
l
¼220 nm] 82% ee, [
a
]
þ52.0 (0.65 in CHCl3).
D
4.4.10. (S)-2-(1-Benzyl-3-((tert-butyldimethylsilyloxy)methyl)-2-oxo-
indolin-3-yl)acetonitrile (47b). 1H NMR (300 MHz, CDCl3)
7.45–7.02
4.4.4. (S)-2-(5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)acetonitrile
(14b). 1H NMR (300 MHz, CDCl3)
7.07 (d, J¼2.4 Hz, 1H), 6.87–6.78
d
d
(m, 7H), 7.15–7.10 (m, 1H), 6.80 (d, J¼2.4 Hz, 1H), 4.91 (s, 2H) 3.98 (d,
J¼9.6 Hz,1H), 3.79 (d, J¼12.0 Hz, 1H), 3.04 (d, J¼16.8 Hz, 1H), 2.81 (d,
J¼16.3 Hz, 1H), 0.82 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3)
(m, 2H), 3.80 (s, 3H), 3.20 (s, 3H), 2.82 (d, J¼16.8 Hz, 1H), 2.58
(d, J¼16.5 Hz, 1H), 1.54 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 177.8,
157.1,136.7,132.9,117.3,114.1,111.1,109.8, 56.5, 45.9, 27.2, 26.9, 22.8;
IR (thin film) 3000, 2861, 2003, 1604, 1525, 1504, 1470, 1300, 1280,
1180, 1016, 912, 665; HRMS (ESI) calcd for [C13H14N2O2þNa]þ
d 175.7, 143.1, 136.4, 129.4, 129.0, 127.3, 124.2, 123.1, 116.5, 109.7, 66.7,
51.1, 25.7, 21.7, 18.2, ꢀ5.5; IR (thin film) 2881, 2033, 1600, 1535, 1504,
1470, 1300, 1280, 1050, 1016, 912, 678; HRMS (ESI) calcd for
253.0953, found 253.0951; HPLC [Chiralcel OD-H, Hex/IPA¼90/10,
[C24H30N2O2SiþNa]þ 429.1974, found 429.1972; HPLC [Chiralcel OD-
23
23
1.0 mL/min,
l
¼220 nm] 99% ee, [
a
]
þ57.0 (1.0 in CHCl3).
H, Hex/IPA¼90/10, 1.0 mL/min,
l
¼220 nm] 97% ee, [
a
]
ꢀ7.6 (0.5 in
D
D
CHCl3).
4.4.5. (S)-2-(5-Methoxy-3-methyl-2-oxoindolin-3-yl)acetonitrile
(15b). 1H NMR (300 MHz, CDCl3)
8.25 (br s, 1H), 7.04 (d, J¼1.8 Hz,
d
4.4.11. (S)-2-(3-((tert-Butyldimethylsilyloxy)methyl)-1-methyl-2-oxo-
indolin-3-yl)acetonitrile (48b). 1H NMR (300 MHz, CDCl3)
7.52–7.33
1H), 6.87–6.78 (m, 2H), 3.80 (s, 1H), 2.82 (d, J¼12.4 Hz, 1H), 2.64 (d,
d
J¼13.1 Hz, 1H), 1.54 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
179.7, 156.6,
(m, 2H), 7.23–6.87 (m, 2H), 3.93 (d, J¼9.6 Hz, 1H), 3.75 (d, J¼9.6 Hz,
133.1,132.9,116.7,114.1,111.1,110.7, 56.1, 46.0, 26.5, 22.5; IR (thin film)
3000, 2861, 2003, 1604, 1525, 1504, 1470, 1300, 1280, 1180, 1016, 912,
665; HRMS (ESI) calcd for [C12H12N2O2þNa]þ 239.0796, found
1H), 3.23 (s, 3H) 3.04 (d, J¼16.8 Hz, 1H), 2.81 (d, J¼16.3 Hz, 1H), 2.10
(s, 3H), 0.89 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 175.5,
144.0, 134.8, 129.6, 128.7, 128.2, 124.4, 123.2, 116.7, 108.7, 66.7, 51.2,
31.2, 25.7, 21.7, 18.2, ꢀ5.3, ꢀ5.4; IR (thin film) 2831, 2033, 1600, 1535,
1504, 1470, 1300, 1280, 1050, 1016, 912, 678; HRMS (ESI) calcd for
239.0794; HPLC [Chiralcel OD-H, Hex/IPA¼90/10, 1.0 mL/min,
23
l
¼220 nm] 98% ee, [
a
]
þ48.2 (1.5 in CHCl3).
D
[C18H26N2O2SiþNa]þ 353.1661, found 353.1660; HPLC [Chiralcel OD-
23
4.4.6. (S) 2-(1-Benzyl-3-(cyclohexylmethyl)-2-oxoindolin-3-yl)ace-
tonitrile (24b). 1H NMR (300 MHz, CDCl3)
H, Hex/IPA¼90/10,1.0 mL/min,
l
¼220 nm] 94% ee, [
a
]
ꢀ21.6 (0.3 in
D
d
7.50 (td, J¼7.5, 0.9 Hz,
CHCl3).
1H), 7.37–7.22 (m, 6H), 7.11 (dt, J¼7.5, 1.2 Hz, 1H), 6.80 (d, J¼7.8 Hz,
1H), 4.95 (s, 2H), 2.93 (d, J¼16.8 Hz, 1H), 2.66 (d, J¼16.8 Hz, 1H),
2.25 (d, J¼7.2 Hz, 2H), 1.71–1.67 (m, 5H), 1.29–0.87 (m, 6H); 13C
4.4.12. (S)-2-(3-((tert-Butyldimethylsilyloxy)methyl)-2-oxoindolin-
3-yl)acetonitrile (49b). 1H NMR (300 MHz, CDCl3)
7.52–7.33
d
NMR (75 MHz, CDCl3)
d
179.8, 145.3, 134.4, 132.6, 129.1, 128.9, 126.8,
(m, 2H), 7.23–6.87 (m, 2H), 3.90 (d, J¼9.6 Hz, 1H), 3.77 (d, J¼9.6 Hz,
122.0, 119.1, 112.2, 46.8, 35.9, 34.2, 34.0, 27.0, 26.7; IR (thin film)
2841, 2023, 1614, 1535, 1504, 1470, 1300, 1280, 1050, 1016, 912, 668;
HRMS (ESI) calcd for [C17H20N2OþNa]þ 381.1943, found 381.1943.
1H), 3.23 (s, 3H) 3.04 (d, J¼16.8 Hz, 1H), 2.81 (d, J¼16.3 Hz, 1H), 0.89
(s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 175.5, 144.0, 134.8,
129.6, 128.7, 128.2, 124.4, 123.2, 116.7, 108.7, 66.7, 51.2, 25.7, 21.7, 18.2,
ꢀ5.3, ꢀ5.4; IR (thin film) 2831, 2033, 1600, 1535, 1504, 1470, 1300,
1280,1050,1016, 912, 678; HRMS (ESI) calcd for [C17H24N2O2SiþNa]þ
HPLC [Chiralcel OD-H Hex/IPA¼90/10, 1.0 mL/min, ¼220 nm] 98%
l
23
ee; [
a]
þ40.6 (0.6 in CHCl3).
D
339.1505, found 339.1507; HPLC [Chiralcel OD-H, Hex/IPA¼90/10,
23
4.4.7. (S)-2-(3-(Cyclohexylmethyl)-2-oxoindolin-3-yl)acetonitrile
(25b). 1H NMR (300 MHz, CDCl3)
1.0 mL/min,
l
¼220 nm] 93% ee, [
a
]
þ21.6 (0.5 in CHCl3).
D
d
7.45 (d, J¼7.3 Hz, 1H), 7.30
(t, J¼7.8 Hz, 1H), 7.12 (t, J¼7.6 Hz, 1H), 7.00 (d, J¼7.6 Hz, 1H), 2.85
(d, J¼16.5 Hz, 1H), 2.64 (d, J¼16.8 Hz, 1H), 2.25 (d, J¼7.2 Hz, 2H),
1.71–1.67 (m, 5H), 1.29–0.87 (m, 6H); 13C NMR (75 MHz, CDCl3)
4.4.13. (S)-2-(1-Benzyl-3-((tert-butyldimethylsilyloxy)methyl)-5-
methoxy-2-oxoindolin-3-yl)acetonitrile (50b). 1H NMR (300 MHz,
CDCl3)
d
7.31–7.25 (m, 5H), 7.08 (d, J¼2.7 Hz, 1H), 6.76–6.61 (m, 2H),
d
158.9, 145.3, 134.4, 132.6, 129.1, 128.9, 126.8, 122.0, 119.1, 112.2,
4.91 (s, 2H), 3.98 (d, J¼9.6 Hz,1H), 3.83 (s, 3H), 3.79 (d, J¼9.6 Hz, 1H),
46.8, 35.9, 34.2, 34.0, 27.0, 26.7; IR (thin film) 2841, 2023, 1614,
1535, 1504, 1470, 1300, 1280, 1050, 1016, 912, 668; HRMS (ESI) calcd
3.04 (d, J¼16.8 Hz, 1H), 2.81 (d, J¼16.3 Hz, 1H), 0.83 (s, 9H), 0.01
(s, 6H); 13C NMR (75 MHz, CDCl3)
d 175.7, 143.1, 136.4, 129.4, 129.0,
for [C17H20N2OþNa]þ 291.1473, found 291.1480; HPLC [Chiralcel
127.3, 124.2,123.1,116.5,109.7, 66.7, 56.7, 51.1, 25.7, 21.7,18.2, ꢀ5.5; IR
(thin film) 3021, 2841, 2023, 1614,1535, 1504, 1470, 1300, 1280, 1050,
1016, 912, 668; HRMS (ESI) calcd for [C25H32N2O3SiþNa]þ 459.1974,
23
OD-H, Hex/IPA¼90/10, 1.0 mL/min,
l
¼220 nm] 94% ee; [
a
]
ꢀ20.6
D
(1.0 in CHCl3).
found 459.1970; HPLC [Chiralcel OD-H, Hex/IPA¼90/10, 1.0 mL/min,
23
4.4.8. (R)-2-(1-Benzyl-2-oxo-3-phenylindolin-3-yl)acetonitrile
(26b). 1H NMR (300 MHz, CDCl3)
l
¼220 nm] 99% ee, [
a
]
þ42.6 (0.5 in CHCl3).
D
d
7.59–7.49 (dd, J¼7.2, 1.0 Hz, 1H),
7.37–7.25 (m, 11H), 7.20–7.15 (dt, J¼7.5, 0.9 Hz, 1H), 6.85 (d, J¼7.5 Hz,
4.4.14. (S)-2-(3-((tert-Butyldimethylsilyloxy)methyl)-5-methoxy-1-
1H), 4.99 (s, 2H), 2.93 (d, J¼16.5 Hz, 1H), 2.66 (d, J¼16.5 Hz, 1H); 13C
methyl-2-oxoindolin-3-yl)acetonitrile (51b). 1H NMR (300 MHz,
NMR (75 MHz, CDCl3)
d
176.5, 143.4, 137.3, 135.8, 130.3, 129.8, 129.6,
CDCl3)
d
7.08 (d, J¼2.7 Hz, 1H), 6.76–6.61 (m, 2H), 3.96 (d, J¼9.6 Hz,

4728
V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
1H), 3.82 (s, 3H), 3.80 (d, J¼9.6 Hz, 1H), 3.04 (d, J¼16.8 Hz, 1H), 2.83
(d, J¼16.3 Hz, 1H), 2.70 (s, 3H), 0.83 (s, 9H), 0.01 (s, 6H); 13C NMR
then the THF removed under reduced pressure. The crude product
was immediately carried on to next step without purification. The
free alcohol (1.0 equiv) in methylene chloride was then treated
with MsCl (1.1 equiv) and triethylamine (2.5 equiv) at rt and stirred
for 15 min then quenched with saturated NH4Cl solution, separated
two layers and extracted the aqueous layer with methylene chlo-
ride (2ꢂ10 mL) and combined organic portions were dried over
anhydrous Na2SO4 and evaporated under vacuum. The mesylate
was then treated with CoCl2$6H2O (1.5 equiv), NaBH4 (3.0 equiv) in
MeOH (10 mL) at rt and stirred for 2 h and then added HCHO
(2.0 equiv), and the suspension was stirred for 6 h at room tem-
perature. The reaction was quenched with saturated aqueous NH4Cl
solution, evaporated MeOH, then EtOAc (10 mL) was added and
washed with 2 N aqueous EDTA solution and evaporated the sol-
vent after drying with anhydrous Na2SO4. The crude compound was
purified by silica-gel chromatography using EtOAc/MeOH (95:5 and
added 2–3 drops of triethylamine).
(75 MHz, CDCl3)
d 175.5, 144.0, 134.8, 129.6, 128.3, 124.4, 123.2,
116.7, 108.7, 66.7, 56.7, 51.1, 31.2, 26.7, 25.8, 18.3, ꢀ5.3, ꢀ5.4; IR (thin
film) 3021, 2841, 2023, 1614, 1535, 1504, 1470, 1300, 1280, 1050,
1016, 912, 668; HRMS (ESI) calcd for [C19H28N2O3SiþNa]þ 383.1767,
found 383.1760; HPLC [Chiralcel OD-H, Hex/IPA¼90/10, 1.0 mL/min,
23
l¼220 nm] 98% ee, [
a
]
ꢀ42.8 (0.1 in CHCl3).
D
4.4.15. (S)-2-(3-((tert-Butyldimethylsilyloxy)methyl)-5-methoxy-2-
oxoindolin-3-yl)acetonitrile (52b). 1H NMR (300 MHz, CDCl3)
7.08
d
(d, J¼2.7 Hz, 1H), 6.76–6.61 (m, 2H), 4.01 (d, J¼9.6 Hz, 1H), 3.82
(d, J¼9.6 Hz, 1H), 3.80 (s, 3H), 3.04 (d, J¼16.8 Hz, 1H), 2.83
(d, J¼16.3 Hz, 1H), 0.83 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz,
CDCl3)
d 175.5, 144.0, 134.8, 129.6, 128.3, 124.4, 123.2, 116.7, 108.7,
66.7, 56.7, 51.1, 26.7, 25.8, 18.3, ꢀ5.3, ꢀ5.4; IR (thin film) 3021, 2841,
2023, 1614, 1535, 1504, 1470, 1300, 1280, 1050, 1016, 912, 668;
HRMS (ESI) calcd for [C18H26N2O3SiþNa]þ 366.1713, found
366.1710; HPLC [Chiralcel OD-H, Hex/IPA¼90/10, 1.0 mL/min,
4.6.1. (ꢀ)-Coerulescine. 1H NMR (300 MHz, CDCl3):
d 8.16 (1H, br s,
23
l¼220 nm] 98% ee, [
a
]
ꢀ88.1 (0.5 in CHCl3).
NH), 7.42 (d, J¼7.2 Hz, 1H), 7.20 (m, 1H), 7.07 (m, 1H), 6.88 (d,
J¼8.0 Hz, 1H), 3.11–3.05 (m, 1H), 2.96–2.89 (m, 2H), 2.86–2.80 (m,
1H), 2.50 (s, 3H), 2.45–2.39 (m, 1H), 2.18–2.10 (m, 1H); 13C NMR
D
4.5. General procedure for Suzuki cross-coupling
(125 MHz, CDCl3):
d 183.4, 140.4, 136.1, 128.0, 123.5, 123.1, 109.7,
A solution of (2-bromo-phenyl)-carbamic acid tert-butyl ester 31
(1.65 g, 6.06 mmol) in THF (103 mL) was prepared in a flame-dry
500-mL 3-neck round bottom flask and cooled to ꢀ78 ꢁC. A solu-
tion of t-BuLi (12.5 mL, 21.21 mmol, 1.7 M in pentane) was added
drop-wise and the solution was maintained at ꢀ78 ꢁC for an addi-
tional 15 min. Isopropoxy pinacolborane (2.25 g, 12.12 mmol) was
added drop-wise and the solution was maintained for 1 h at ꢀ78 ꢁC.
After that the reaction was allowed to warm to rt and then quenched
with satd aqueous NH4Cl (20 mL). The resulting two layers were
separated and the aqueous portion was extracted with Et2O
(2ꢂ50 mL). The combined organic portions were dried over Na2SO4
and concentrated under reduced pressure. The crude boronic ester 39
was carried forward directly by dissolving in benzene/MeOH (5:1,
120 mL), and adding tert-butyl-(2-iodo-allyloxy)-dimethyl-silane 33
(3.41 g, 11.45 mmol) followed by 10 mL of 2 M aqueous Na2CO3 so-
lution. A stream of N2 was bubbled through the reaction mixture for
5 min and Pd(PPh3)4 (0.991 g, 0.858 mmol) was added in one portion.
The resulting mixture was heated to reflux (w80 ꢁC) and maintained
for 90 min, after which TLC indicated the reaction was complete. The
mixture was allowed to cool to RT and Na2SO4 (15 g) was added. The
mixture allowed to stand for 10 min and then filtered through Celite.
The filtrate was concentrated and the resulting crude product was
purified by silica gel chromatography (5:95, EtOAc/Hex).
66.4, 56.7, 55.9, 54.1, 41.8, 38.1; IR (thin film): 3223, 2940, 2835,
1707, 1603, 1484; HRMS (ESI) calcd for [C12H14N2OþNa]þ 225.1004,
found 225.1000; HPLC [Chiralcel OD-H, Hex/IPA¼90/10,1.0 mL/min,
23
l¼220 nm] 91% ee, [
a
]
ꢀ0.9 (0.10 in MeOH).
D
4.6.2. (þ)-Horsfiline. 1H NMR (300 MHz, CDCl3):
d 7.47 (br s, 1H),
7.04 (d, J¼2.0 Hz, 1H), 6.76 (d, J¼8.0 Hz, 1H), 6.72 (dd, J¼8.0, 2.0 Hz,
1H), 3.80 (s, 3H), 2.98–3.03 (m, 1H), 2.86 (s, 2H), 2.76 (dd, J¼9.0,8.0,
9.0 Hz, 1H), 2.45 (s, 3H), 2.40 (ddd, J¼12.0, 7.5, 4.5 Hz, 1H), 2.08
(dt, J¼13.0, 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d 182.6, 156.1,
137.7, 133.3, 112.4, 110.3, 109.7, 66.4, 56.7, 55.9, 54.1, 41.8, 38.1; IR
(neat): 3223, 2940, 2835, 1707, 1603, 1484 cmꢀ1; HRMS (ESI) calcd
for [C13H16N2O2þNa]þ 255.1109, found 255.1110; HPLC [Chiralcel
23
OD-H, Hex/IPA¼90/10, 1.0 mL/min,
l¼220 nm], 99% ee, [
a
]
ꢀ5.9
D
(0.40 in MeOH).
4.7. Synthesis of (L)-esermethole
Procedure: this procedure is adapted from Nakao and Hiyama:2
a
solution of (S)-2-(5-methoxy-1,3-dimethyl-2-oxoindolin-3-yl)
acetonitrile 14b (78 mg, 0.34 mmol) and LiAlH4 (52 mg, 1.36 mmol)
in THF (12 mL) were stirred under an argon atmosphere at rt for 1 h,
and then heated at the reflux temperature for 0.5 h. The reaction
was quenched by careful addition of 2 mL of THF–H2O (10:1) so-
lution at 0 ꢁC, and the resulting mixture was diluted with CH2Cl2
and filtered through a fritted-glass filter. The resulting precipitates
were washed thoroughly with CH2Cl2, and the filtrate was con-
centrated in vacuo. The residue was dissolved in EtOAc (5 mL) and
added 1 M HCl aqueous solution (5 mL). After being stirred for
5 min, the solution was neutralized by adding solid K2CO3, and then
extracted with EtOAc. The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered through a Celite
pad, and concentrated in vacuo.
4.5.1. {2-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-vinyl]-phenyl}-
carbamic acid tert-butyl ester (36). 1H NMR (300 MHz, CDCl3)
d 8.04
(d, J¼8.4, 1H), 7.27–7.18 (m, 1H), 7.14 (br s, 1H), 7.02–6.98 (m, 2H),
5.61 (dd, J¼3.6, 1.5 Hz, 1H), 5.15 (dd, J¼3.3, 1.5 Hz, 1H), 4.26 (s, 2H),
1.50 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H); HRMS (ESI) calcd for
[C20H33NO3SiþNa]þ 386.2127, found 386.2126.
4.5.2. {2-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-vinyl]-4-me-
thoxy-phenyl}-carbamic acid tert-butyl ester (41). 1H NMR
(300 MHz, CDCl3)
d
8.04 (d, J¼8.4, 1H), 7.27–7.18 (m, 1H), 7.14 (br s,
A solution of above crude (47 mg, 0.21 mmol) in MeOH (12 mL)
was added HCHO aqueous solution (37 wt %, 79 ml, 1.07 mmol) at
1H), 7.02–6.98 (m, 2H), 5.61 (dd, J¼3.6, 1.5, 1H), 5.15 (dd, J¼3.3,
1.5 Hz, 1H), 4.26 (s, 2H), 1.50 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H); HRMS
(ESI) calcd for [C21H35NO4SiþNa]þ 416.2233, found 416.2234.
0 ꢁC under an argon atmosphere, and the whole was stirred for
5 min. NaBH(OAc)3 (1.07 mmol, 230 mg) was added to the resulting
mixture, and the solution was stirred at rt for 1.5 h. The solution
was diluted with EtOAc and concentrated. The residue was treated
with a saturated NaHCO3 aqueous solution and extracted with
CH2Cl2 for three times. Combined organic layers were washed with
water and brine, dried over anhydrous Na2SO4, filtered through
Celite, and then concentrated in vacuum. The residue was purified
4.6. Synthesis of (L)-coerulescine and (D)-horsfiline
The oxindole (1.0 equiv) was dissolved in dry THF (10 mL) in
flame dried RBF and then added TBAF (5.0 equiv) (1.0 M solution in
THF) and stirred at rt for 2 h. TLC checked (reaction completed) and

V.J. Reddy, C.J. Douglas / Tetrahedron 66 (2010) 4719–4729
4729
13. McDonald, I. M.; Austin, C.; Buck, I. M.; Dunstone, D. J.; Gaffen, J.; Griffin, E.;
Harper, E. A.; Hull, R. A. D.; Kalindjian, S. B.; Linney, I. D.; Low, C. M. R.; Patel, D.;
Pether, M. J.; Raynor, M.; Roberts, S. P.; Shaxted, M. E.; Spencer, J.; Steel, K. I. M.;
Sykes, D. A.; Wright, P. T.; Xun, W. J. Med. Chem. 2007, 50, 4789.
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(b) Go´mez-Bengoa, E.; Echavarren, A. M. J. Org. Chem. 1991, 56, 3497.
15. Preparation of 32: (a) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675;
(b) Nicolaou, K. C.; Li, Y.; Uesaka, N.; Koftis, T. V.; Vyskocil, S.; Ling, T.;
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Ed. 2003, 42, 3643.
16. Clay, M. D.; Fallis, A. G. Angew. Chem., Int. Ed. 2005, 44, 4039.
17. Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798.
18. Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem. Soc.
1997, 119, 6072.
19. (a) Renaud, J.; Ouellet, S. G. J. Am. Chem. Soc. 1998, 120, 7995; (b) Takahashi, K.;
Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001, 625, 47.
by flash column chromatography on silica gel (MeOH/CHCl3, 5:95
and few drops of triethylamine) to give (ꢀ)-esermethole (46 mg,
92% over the two steps) as an amorphous solid: Rf¼0.49 (CHCl3/
MeOH, 50:1) 1H NMR (300 MHz, CDCl3)
d 6.68–6.62 (m, 2H), 6.36
(d, J¼8.4 Hz, 1H), 4.05 (s, 1H), 3.75 (s, 3H), 2.90 (s, 3H), 2.72 (dt,
J¼8.8, 5.3 Hz, 1H), 2.64 (dt, J¼9.0, 7.4 Hz, 1H), 2.54 (s, 3H), 1.95
(dd, J¼7.5, 5.5 Hz, 2H), 1.44 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
152.7, 146.4, 138.1, 112.0, 109.7, 107.3, 98.3, 56.0, 53.2, 52.8, 40.9,
38.3, 38.1, 27.6; HRMS (ESI) calcd for [C14H20N2OþNa]þ 255.1473,
found 255.1470. HPLC [Chiralcel OD-H, Hex/IPA¼90/10, 1.0 mL/min,
23
l
¼220 nm, 99% ee, [
a
]
ꢀ130.0 (1.0 in MeOH).
D
20. Youn, S. W.; Song, J.-H.; Jung, D.-I. J. Org. Chem. 2008, 73, 5658.
21. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179.
22. Selected recent enantioselective syntheses: (a) Bui, T.; Syed, S.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2009, 131, 8758; (b) See Ref. 1. (c) Pinto, A.; Jia, Y.; Neuville,
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14043.
Acknowledgements
We thank the University of Minnesota (UMN) for start-up funds,
Prof. Andrew Harned (UMN) for use of a shared HPLC, and Ms.
Rosalind Douglas (UMN) for assistance in manuscript preparation.
23. Selected recent syntheses of (ꢃ)-esermethole: (a) Kulkarni, M. G.; Dhondge, A. P.;
Borhade, A. S.; Gaikwad, D. D.; Chavhan, S. W.; Shaikh, Y. B.; Ningdale, V. B.; Desai,
M. P.; Birhade, D. R.; Shinde, M. P. Tetrahedron Lett. 2009, 50, 2411; (b) Rigby, J. H.;
Sidique, S. Org. Lett. 2007, 9, 1219; (c) See Ref 4b; (d) Nishida, A.; Ushigome, S.;
Sugimoto, A.; Arai, S. Heterocycles 2005, 66, 181; (e) Mukai, C.; Yoshida, T.; Sor-
imachi, M.; Odani, A. Org. Lett. 2006, 8, 83.
Supplementary data
1H and 13C NMR spectra and HPLC chromatograms for chiral
compounds not previously reported. Spectra and chromatograms
for many compounds were already reported in a recent commu-
nication.5a Supplementary data associated with this article can be
found in online version at doi:10.1016/j.tet.2010.02.096.
24. See Ref. 22f.
25. (a) Greig, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.; Brossi, A. Med. Res. Rev.
1995, 15, 3; (b) Sano, N.; Bell, K.; Marder, K.; Stricks, L.; Stern, Y.; Mayeux, R. Clin.
Neuropharmacol. 1993, 16, 61.
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Greig, N. H. J. Med. Chem. 2001, 44, 4062.
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