Development and Scope of the Arene-Fused Domino Michael/Mannich Reaction: Application to the Total Syntheses of Aspidosperma Alkaloids (-)-Aspidospermidine, (-)-Tabersonine, and (-)-Vincadifformine

Article abstract of DOI:10.1021/acs.joc.6b02551

The development and application of the arene-fused domino Michael/Mannich route to the tetrahydrocarbazole (ABE) core of Aspidosperma alkaloids is described. The scope of this novel transformation was studied in terms of the nucleophilic component (i.e., N-sulfinyl metallodienamine) and the electrophilic component (i.e., Michael acceptor). The successful application of this methodology toward the concise total syntheses of classical indole alkaloids (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine in 10-11 steps, respectively, is also discussed.

Full text of DOI:10.1021/acs.joc.6b02551

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Article
Development and Scope of the Arene-Fused Domino Michael/Mannich
Reaction: Application to the Total Syntheses of Aspidosperma
Alkaloids (-)-Aspidospermidine, (-)-Tabersonine, and (-)-Vincadifformine
Senzhi Zhao, and Rodrigo B. Andrade
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02551 • Publication Date (Web): 29 Nov 2016
Downloaded from http://pubs.acs.org on December 6, 2016
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Development and Scope of the AreneꢀFused Domino Michael/Mannich Reaction:
Application to the Total Syntheses of Aspidosperma Alkaloids (−)ꢀAspidospermidine,
(−)ꢀTabersonine, and (−)ꢀVincadifformine
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Senzhi Zhao and Rodrigo B. Andrade*
Temple University, Department of Chemistry
Philadelphia, PA 19122
* Corresponding author: tel: +1 215 204 7155; fax: +1 215 204 9851; eꢀmail:
randrade@temple.edu
Abstract:
The development and application of the areneꢀfused domino
Michael/Mannich route to the tetrahydrocarbazole (ABE) core of Aspidosperma alkaloids
is described. The scope of this novel transformation was studied in terms of the
nucleophilic component (i.e., Nꢀsulfinyl metallodienamine) and the electrophilic
component (i.e., Michael acceptor). The successful application of this methodology
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toward the concise total syntheses of classical indole alkaloids (−)ꢀaspidospermidine, (−)ꢀ
tabersonine, and (−)ꢀvincadifformine in 10−11 steps, respectively, is also discussed.
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Key Words: total synthesis · areneꢀfused domino Michael/Mannich reaction ·
tetrahydrocarbazole · Aspidosperma alkaloids
1. INTRODUCTION
Aspidosperma alkaloids, along with other monoterpene indole alkaloids, have been
inspiring research targets for generations of synthetic organic chemists.1ꢀ3 Numerous
synthetic strategies have been developed for the construction of complex indole alkaloids,
and our efforts in this field have led to the total syntheses of Strychnos,4ꢀ8 bis-Strychnos9
and rearranged Aspidosperma10 indole alkaloids.
In 2013, we reported concise asymmetric total syntheses of three classical members
of the Aspidosperma alkaloids via a novel areneꢀfused domino Michael/Mannich/Nꢀ
alkylation route.11 To the best of our knowledge, this is one of the most efficient routes to
(−)ꢀaspidospermidine, (−)ꢀtabersonine, and (−)ꢀvincadifformine (Figure 1). Herein, we
present a detailed discussion on the development and the application of the domino
Michael/Mannich/Nꢀalkylation sequence. Moreover, we discuss the scope of this method
as applied to other areneꢀfused Nꢀsulfinyl metallodienamines.
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N
N
N
D
C
D
D
C
C
A
E
Et
E
A
E
A
B
Et
Et
B
B
N
N
N
H
H
H
H
CO2Me
CO2Me
9
1: (−)ꢀaspidospermidine
2: (−)ꢀtabersonine
3: (−)ꢀvincadifformine
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Figure 1. Structures of (−)ꢀaspidospermidine (1), (−)ꢀtabersonine (2), and (−)ꢀ
vincadifformine (3).
As shown in Figure 1, the structures of three classical Aspidosperma alkaloids share a
common ABCDE ring system with at least three contiguous stereogenic centers. To
develop an efficient and divergent synthetic route to the aforementioned targets, we
devoted ourselves to the construction of the ABE tetrahydrocarbazole with suitable
functional group handles, which could be further manipulated to install the C and D rings.
To readily access the ABE tetrahydrocarbazole nucleus, we were inspired by
Magnus’s stepꢀefficient indoleꢀ2,3ꢀquinodimethane strategy toward Aspidosperma and
Kopsia alkaloids.12 The asymmetric sulfinimine methodology developed by Davis13ꢀ16
and expanded by Ellman,17,18 which remains unparalleled in the construction of nitrogenꢀ
containing stereogenic centers, was recruited to render the syntheses enantiospecific. The
conjugate addition reactions of Nꢀsulfinyl metalloenamines and α,βꢀunsaturated ketones
reported by Ellman and coworkers in 2005 further inspired us to test the chemistry of 2,3ꢀ
indole fused Nꢀsulfinyl metalloenamines, which are readily prepared from commercial
starting materials.19 In analogy to Ellman’s work, we reasoned the Michael reaction of
the Nꢀsulfinyl metallodienamine 4 with suitable Michael acceptors would trigger a
Mannich reaction, thus making possible the formation of ABE tetrahydrocarbazole 6 via
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the intermediary enolate 5 (Scheme 1); moreover, the relative and absolute
stereochemistry of 6 could be controlled by the Nꢀsulfinyl group.
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Scheme 1. The proposed dominoꢀfused Michael/Mannich reaction of Nꢀsulfinyl
metallodienamines 4.
O
S
O
S
O
S
M
N
tꢀBu
N
tꢀBu
NH
tꢀBu
Mannich
reaction
Michael addition
EWG
R
EWG
R
E
A
B
N
EWG
R
CH2
N
N
PhO2S
PhO2S
PhO2S
5
6
4
R = H or alkyl groups
EWG = electron withdrawing groups
2. RESULTS AND DISCUSSION
2.1. Synthesis of NꢀSulfinylimine 7.
To test the feasibility of our idea, we first needed to generate the Nꢀsulfinyl
metallodienamines, which were assumed to obtainable from the treatment of the
corresponding Nꢀsulfinimines with a strong base. As shown in Scheme 2, Nꢀsulfinylimine
7 was easily prepared from the commercially available 2ꢀmethylꢀindoleꢀ3ꢀ
carboxaldehyde (8) by following known methods.20ꢀ22 However, the Nꢀsulfonylation
reaction of indole 8 was found to be fickle and desired product 9 was obtained in yields
ranging from 41% to 71%. Alternatively, reversing the order of events (i.e., first
condensing with Nꢀsulfinamide followed by Nꢀsulfonylation) remedied this problem, thus
favorably furnishing Nꢀsulfinylimine 7 in high yield and on multigram scale (Scheme 2).
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Scheme 2. Synthesis of Nꢀsulfinylimine 7.
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8
Original synthetic sequence:
O
S
(R)ꢀN-tert-
butanesulfinamide
Ti(OEt)4
N
tꢀBu
O
O
9
H
H
H
NaH, imidazole
THF, PhSO2Cl
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THF, rt, 24h
N
N
CH3
CH3
N
CH3
H
SO2Ph
SO2Ph
41% to 71%
97%
8
7
9
Optimized synthetic sequence:
(R)ꢀN-tert-
O
S
O
S
O
N
tꢀBu
N
tꢀBu
butanesulfinamide
Ti(OEt)4
NaH, imidazole
THF, PhSO2Cl
95%
H
H
H
THF, reflux, 24h
N
CH3
N
CH3
N
CH3
H
88%
SO2Ph
H
10
8
7
2.2. Initial experiments and optimization of the areneꢀfused domino
Michael/Mannich reaction.
With Nꢀsulfinylimine 7 in hand, our focus was turned to optimal conditions for
generating the requisite Nꢀsulfinyl metallodienamine for the proposed areneꢀfused
domino Michael/Mannich reactions. The common strong base, lithium diisopropylamide
(LDA), was initially screened, followed by treatment with methyl vinyl ketone (MVK) as
the first Michael acceptor. In the event, deprotonation of 7 with LDA followed by
addition of MVK led to a complex mixture with no sign of the domino Michael/Mannich
products. However, due to the fact that 7 was completely consumed, it was believed that
the metallodienamine did form and react with MVK, but the product 11 might still be in
its deprotonated form. This anion would have the ability to undergo further reactions with
the reactive Michael acceptor MVK. To test this hypothesis, MVK was replaced with
methyl acrylate, a less reactive Michael acceptor, for the domino Michael/Mannich
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reaction of 7 under the same conditions. To our delight, the desired product 11 was
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isolated in 46% yield (Scheme 3). No other isomers were able to be isolated at that time.
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Scheme 3. Initial domino Michael/Mannich reactions of Nꢀsulfinylimine 7.
O
S
tꢀBu
NH
O
H
LDA (1.1 equiv), THF, ꢀ78 °C
CH3
O
S
then, MVK (1.2 equiv)
ꢀ78 °C to rt
N
N
tꢀBu
SO2Ph
H
19
O
S
N
CH3
SO2Ph
tꢀBu
NH
O
7
LDA (1.1 equiv), THF, ꢀ78 °C
OCH3
H
then, methyl acrylate
(1.2 equiv)
N
SO2Ph
ꢀ78 °C to rt
46 % (dr > 20:1)
11
We reasoned that the treatment of 7 with LDA resulted in the formation of
metallodienamine 12, and the relative and absolute stereocontrol in the domino process
can be rationalized by invoking transition state 13, which is consistent with those posited
by both Ellman23 and Davis (Scheme 4).13
Scheme 4. The proposed mechanism and transition state for the formation of 11.
‡
O
S
O
S
PhO2S
Li
H
tꢀBu
N
HN
N
tꢀBu
CO2Me
H
CO2Me
OMe
Li
H
N
S
N
N
H
tꢀBu
O
O
SO2Ph
SO2Ph
H
13
11
12
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Cognizant of the acidity of the protons at the 2ꢀmethyl indole moiety of Nꢀ
sulfinylimine 7, which is enhanced due to the electronꢀwithdrawing arenesulfonyl group
on indole nitrogen, we started the optimization of the areneꢀfused domino
Michael/Mannich reaction by screening other, slightly weaker bases. Meanwhile, it was
speculated that the acidic hydrogen α to the carbomethoxyl group in 11 might cause side
reactions, particularly elimination of Nꢀsulfinylamine. Thus, the reaction of Nꢀ
sulfinylimine 7 and methyl ethacrylate was selected as the model reaction since the
product would bear a quaternary carbon, thus precluding elimination. Furthermore,
Aspidosperma alkaloids 1−3 all have possess an ethyl group at C20.
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Table 1. Optimization of the areneꢀfused domino Michael/Mannich reaction.a
O
S
O
S
tꢀBu
N
tꢀBu
HN
base, then
methyl ethacrylate
CO2Me
Et
H
N
CH3
N
solvent, ꢀ78 °C
SO2Ph
7
SO2Ph
14
drc
Yield (%)d
Entry
Base
LDA
Solvent
THF
1
2
3
4
10:1
11:1
6:1
40
93
79
77
98
13
THF
LHMDS
NaHMDS
KHMDS
LHMDS
LHMDS
THF
THF
12:1
11:1
7:1
5b
6
THF
Et2O
a. Unless otherwise specified, reaction conditions are as follows: 7 (1 equiv, 0.1 mmol)
in solvent (3 mL) with base (1.2 equiv), ꢀ78 °C, 1 h; then, methyl ethacrylate (1.5 equiv)
in solvent (1 mL), ꢀ78 °C, 2 h. b. 2.2 equivalents of base was used. c. Determined by
1H NMR. d. Isolated yields of the major product.
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The hexamethyldisilazide bases LHMDS, NaHMDS, and KHMDS were screened,
and all provided better results than LDA did. Of the three, LHMDS gave the best result
(Table 1, Entry 2). Additional equivalents of LHMDS shortened the reaction time and
slightly increased the yield but had a negligible effect on the dr (Table 1, Entry 5). The
effect of solvents on the reaction was also examined. The use of Et2O as solvent resulted
in low chemical yields, which is attributed to the low solubility of 7 (Table 1, Entry 6).
Since satisfactory results were obtained, no attempts were made to further optimize the
reaction conditions.
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2.3. Scope of the areneꢀfused domino Michael/Mannich reaction with various
electrophiles.
To determine the substrate scope and limitations of our domino Michael/Mannich
reaction, a number of Michael acceptors were evaluated (Table 2). As depicted in Table
2, under optimized conditions our areneꢀfused domino Michael/Mannich reaction
appeared to be tolerant towards a variety of functionalities such as esters, lactones,
ketones, aldehydes and Weinreb amides.
Table 2. The scope of Michael acceptors.a
LHMDS (1.2 equiv), then
O
S
O
S
EWG
N
tꢀBu
tꢀBu
EWG
R
HN
R
Michael acceptor (1.5 equiv)
H
THF, ꢀ78 °C
N
CH3
N
SO2Ph
SO2Ph
R = H or alkyl groups
7
EWG = electron withdrawing groups
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Michael
acceptor
Major product
(yieldb, drc)
Michael
acceptor
Major product
(yieldb, drc)
Entry
Entry
O
O
S
S
7
8
9
tꢀBu
HN
tꢀBu
CHO
Et
HN
CO2Me
H
Et
1
6
10
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12
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CO2Me
CHO
N
N
SO2Ph
SO2Ph
18 (86%, 18:1)
11 (70%, >20:1)
O
O
S
S
tꢀBu
tꢀBu
CO2Me
Me
HN
NH
O
Me
CO2Me
Me
Me
2
3
4
5
7
O
N
N
SO2Ph
SO2Ph
19 (40%, n.d.d)
15 (93%, 20:1)
O
S
CO2Me
tꢀBu
CO2Me
Et
HN
Et
CO2Me
N
8
SO2Ph
CO2Me
N
SO2Ph
20 (68%)
14 (93%, 11:1)
O
S
O
S
Et
tꢀBu
NH
O
tꢀBu
NH
O
O
O
O
O
OMe
N
9e
Et
N
Me
Me
21f
OMe
N
N
H
SO2Ph
22 (35%, 1.2:1)
SO2Ph
16 (73%, 9:1)
O
S
tꢀBu
CHO
Me
HN
Me
CHO
N
SO2Ph
17 (84%, >20:1)
a. Unless otherwise specified, reaction conditions are as follows:
7
(1 equiv, 0.1 mmol) in THF (3
mL) with base (1.2 equiv), ꢀ78 °C, 1h; then, methyl ethacrylate (1.5 equiv) in THF (1 mL), ꢀ78 °C,
2h. b. The isolated yield. c. Determined by 1HNMR. d. The other diastereomer was not isolated. e.
Reaction temperature: ꢀ78 °C to ꢀ20 °C. f. See experimental section for the synthesis of 21
.
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Of all the Michael acceptors screened, acrylates were shown to be the best Michael
acceptors in providing products in high chemical yields and good diastereoselectivities
(Table 2, Entries 2−3). However, 11 was obtained in relatively low yield (Table 2, Entry
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1), mainly owing to the deleterious effect of the acidic proton α to the ester group in the
product. An interesting trend of diastereoselectivity was also noticed; that is, the larger
the alkyl group α to the ester group, the less diastereoselective the reaction. This can be
rationalized by analyzing transition state 13 (Scheme 4). Since the alkyl group occupies
the axial position in the transition state, as steric bulk increases, the transition state
becomes less favorable.13,23
Significantly, the use of the α,β−unsaturated lactone 5,6ꢀdihydroꢀ2ꢀHꢀpyraneꢀ2ꢀone
led to the formation of the tetracyclic product 16, with formation of three new contiguous
stereogenic centers, in good yield (73%) and good diastereoselectivity (dr = 9:1, Table 2,
Entry 4). The structure of 16 was further confirmed by Xꢀray analysis, so was the
stereochemical course of the areneꢀfused domino Michael/Mannich reaction (see
Supporting Information for details).
It is noteworthy that more electrophilic Michael acceptors such as α,βꢀ
unsaturated aldehydes and ketones were also compatible with the optimized reaction
conditions (Table 2, Entries 5−7). While a modest 40% yield was obtained with α,βꢀ
unsaturated ketone MVK, this was a vast improvement over previous efforts using LDA
that resulted in no desired product (Scheme 4). We attribute this to the kinetic and
thermodynamic acidity of the αꢀprotons on the methyl group of the product 19. Lastly,
the successful use of α,βꢀunsaturated aldehydes as Michael acceptors (e.g., ethacrolein)
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would further streamline our syntheses of Aspidosperma alkaloids 1−3 by obviating
additional redox operations.
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8
9
Interestingly, when methyl propiolate was used as the Michael acceptor, carbazole 20
was obtained in good yield (Table 2, Entry 8), which was believed to be the elimination
product of the corresponding tetrahydrocarbazole (Scheme 5). Even though the formation
of 20 is not valuable in terms of asymmetric synthesis, it holds great potential for the
facile, stepꢀefficient preparation of carbazoles.24,25
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Scheme 5. The proposed formation of carbazole 20 from 7 and methyl propiolate.
O
S
O
S
O
S
LHMDS
(1.2 equiv)
then
tꢀBu
tꢀBu
N
tꢀBu
N
HN
H+
CO2Me
CO2Me
H
20
transfer
CO2Me
N
CH3
N
N
(1.5 equiv)
SO2Ph
SO2Ph
PhO2S
THF, ꢀ78 °C
7
Finally, when N,Oꢀdimethyl (i.e., Weinreb) acrylamide was used as the Michael
acceptor, no domino Michael/Mannich product was formed at –78 °C, which is consistent
with the decreased reactivity of acrylamides visꢀàꢀvis acrylates and acroleins.26 However,
raising the reaction temperature to –20 °C resulted effected the desired process wherein
two diastereoisomers were isolated in 62% yield (dr = 1.2:1). The relative
stereochemistry of each diastereoisomer was determined by NOE analysis (Figure 2). The
poor diastereoselectivity could be attributed to a disrupted transition state caused by the
extra chelating group of the Weinreb amide, as well as the higher reaction temperature.
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2
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8
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10
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12
13
14
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18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. NOE analysis of the diastereoisomers from the areneꢀfused domino
Michael/Mannich reaction with Weinreb amide 21.
2.4. Scope of the areneꢀfused domino Michael/Mannich reaction.
Areneꢀfused Nꢀsulfinimines 24–26 were synthesized from their corresponding
aldehydes with (R)ꢀNꢀtertꢀbutanesulfinamide to test the compatibility of these substrates
with our 2,3ꢀindoleꢀfused domino Michael/Mannich reaction conditions (Schemes 6). Nꢀ
sulfinimine 24 was obtained in 79% from the condensation of oꢀtolualdehyde (27) with
(R)ꢀNꢀtertꢀbutanesulfinamide.20,21 Similarly, Nꢀsulfinimine 25 was obtained from the
condensation of 2ꢀmethylpyridineꢀ3ꢀcarbaldehyde (28)27 in 75% yield. The synthesis of
furanꢀfused Nꢀsulfinimine 26 started from ethyl 2ꢀmethylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate 29.28
Nitrogen protection of 29 with benzenesulfonyl chloride afforded Nꢀbenzenesulfonylꢀ
protected pyrrole 30 in 96% yield, which was reduced with DIBALꢀH and followed by
ParikhꢀDoering oxidation to deliver 31 in 86% overall yield.29 The subsequent Tiꢀ
promoted condensation with (R)ꢀNꢀtertꢀbutanesulfinamide afforded Nꢀsulfinimine 26 in
97% yield (Scheme 6).
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Scheme 6. Syntheses of benzeneꢀ, pyridineꢀ, and pyrroleꢀfused Nꢀsulfinimines 24–26.
5
6
7
8
O
S
O
(R)ꢀN-tert-
butanesulfinamide
Ti(OEt)4
(R)ꢀN-tert-
butanesulfinamide
Ti(OEt)4
S
N
O
tꢀBu
N
O
tꢀBu
H
H
9
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
THF, rt, 24h
THF, rt, 24h
N
CH3
N
CH3
O
CH3
CH3
27
24
28
75%
25
79%
O
S
O
O
tꢀBu
(R)ꢀN-tert-
butanesulfinamide
N
NaH,DMF
PhSO2Cl
1) DIBALꢀH
ꢀ78 °C
OEt
OEt
H
H
Ti(OEt)4
N
N
N
N
CH3
SO2Ph
CH3
2) SO3•pyridine,
DMSO, DIPEA
CH3
CH3
0 °C to rt
THF, rt, 24h
SO2Ph
SO2Ph
SO2Ph
96%
97%
29
30
86%
31
26
When Nꢀsulfinimines 24 and 25 were subjected to the optimal conditions with methyl
ethacrylate as Michael acceptor, no desired product 32 or 33 was detected (Scheme 7).
Considering the difficulty with the formation of the corresponding metallodienamines,
we also tried other stronger bases (e.g., LDA, nꢀBuLi/diisopropylamine/tꢀBuOK,30 and nꢀ
BuLi/TMP31). However, those stronger bases either led to the decomposition of Nꢀ
sulfinimines 24 and 25, or left them intact. Increasing the reaction temperature also
proved ineffective.
Scheme 7. The attempted domino Michael/Mannich reaction of (A) benzeneꢀ and (B)
pyridineꢀfused Nꢀsulfinimines.
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7
8
9
A
B
O
S
O
S
tꢀBu
N
tꢀBu
HN
LHMDS, ꢀ78 °C
THF, then
CO2Me
Et
H
methyl ethacrylate
THF, ꢀ78 °C
CH3
32
24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(24 was recovered)
O
O
S
S
tꢀBu
N
tꢀBu
HN
LHMDS, ꢀ78 °C,
THF, then
CO2Me
Et
H
methyl ethacrylate
THF, ꢀ78 °C
N
CH3
N
33
25
(25 was recovered)
When pyrroleꢀfused Nꢀsulfinimine 26 was subjected to the optimal conditions for
the indoleꢀfused analog, no desired products were isolated and Nꢀsulfinimine 26 was
recovered. However, increasing the reaction temperature to rt after the addition of methyl
ethacrylate—much like the case of acrylamide electrophiles in Table 1, Entry 9—resulted
in the isolation of the domino Michael/Mannich products 34 and 35 in modest yield and
diastereoselectivity (dr = 2:1, Scheme 8). The relative stereochemical assignments of 34
and 35 were made from NOE experiments performed on the latter. The absolute
stereochemical assignments were based on analogy to the indoleꢀfused variant (Table 1).
Scheme 8. The domino Michael/Mannich reaction of pyrroleꢀfused Nꢀsulfinimines.
O
S
O
S
O
S
Me
O
O
N
tꢀBu
tꢀBu
tꢀBu
Et
CO2Me
N
HN
HN
Me
H
LHMDS, ꢀ78 °C
THF, then
O
CO2Me
S
H
+
H
Et
N
tꢀBu
methyl ethacrylate
THF, ꢀ78 °C to rt
N
N
N
CH3
SO2Ph
SO2Ph
SO2Ph
34 (major)
SO2Ph
35 (minor)
43% (BRSM 52%)
35 (NOE analysis)
26
dr = 2:1
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2.5. The 2,3ꢀindoleꢀfused domino Michael/Mannich/Nꢀalkylation sequence.
After exploring the substrate scope of the areneꢀfused domino Michael/Mannich
sequence, we proposed that there was a possibility to further improve the efficiency of
the reaction by trapping the direct domino Michael/Mannich product, the Nꢀsulfinyl anion
intermediate, with allyl bromide. The resulting domino Michael/Mannich/Nꢀalkylation
sequence would deliver the tetrahydrocarbazole with an Nꢀallyl group which was proved
to be useful for the construction of the D ring in Aspidosperma alkaloids 1–3.32,33
Table 3 shows some of the results from the areneꢀfused domino Michael/Mannich/Nꢀ
alkylation reaction where Nꢀsulfinyl anion intermediate 35 was trapped with allyl
bromide. Solvents were found to have a profound effect on the outcome of the telescoped
reaction sequence. When using only THF for both the Michael/Mannich and Nꢀallylation
reactions, no desired Nꢀallylated tetrahydrocarbazole 36 was isolated. Instead, the domino
Michael/Mannich product 14 was isolated in 90% yield (Table 3, Entry 1). To improve
the nucleophilicity of Nꢀsulfinyl anion 37, the polar aprotic solvent DMF was used.34
However, its incompatibility with the domino Michael/Mannich reaction resulted in
complete decomposition of Nꢀsulfinylimine 7 (Table 3, Entry 2). A 79% yield of the
desired product 36 was obtained when THF was used for the Michael/Mannich reaction
and DMF was used for the Nꢀallylation step (Table 3, Entry 3). Increasing the ratio of
THF/DMF to 1:2 led to a higher yield of 36. However, the yield was not improved by
further increasing the ratio of the solvents (Table 3, Entry 4ꢀ5). Finally, the highest yield
(up to 90%) was achieved by increasing the equivalents of LHMDS (Table 3, Entry 6).
9
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12
13
14
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19
20
21
22
23
24
25
26
27
28
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32
33
34
35
36
37
38
39
40
41
42
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45
46
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48
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50
51
52
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54
55
56
57
58
59
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Table 3. Optimization of the 2,3ꢀindoleꢀfused domino Michael/Mannich/Nꢀalkylation
5
6
reaction.a
7
8
9
O
S
O
S
O
S
LHMDS, then
tꢀBu
methyl
allyl
bromide
solvent 2
Li
N
tꢀBu
tꢀBu
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CO2Me
Et
ethacrylate
CO2Me
Et
H
ꢀ78 °C
to rt
solvent 1
ꢀ78 °C
N
CH3
N
SO2Ph
SO2Ph
SO2Ph
37
36
7
LHMDS
(equiv)
Allyl bromide
(equiv)
Solvent 1/Solvent 2
(v/v)
Yield (%)b
Entry
c
THF/THF
1
1.2
5
−
d
2
3
4
5
1.2
1.2
1.2
1.2
2.2
5
5
5
5
5
DMF/DMF
−
THF/DMF (1:1)
THF/DMF (1:2)
THF/DMF (1:4)
THF/DMF (1:4)
83
88
79
90
6e
a. Unless otherwise specified, reaction conditions are as follows: 7 (1 equiv, 0.1 mmol) in solvent 1,
LHMDS (1.2 or 2.2 equiv), ꢀ78 °C, 1 h; then, methyl ethacrylate (1.5 or 3 equiv), ꢀ78 °C, 2 h; then
allyl bromide (5 equiv) in solvent 2, ꢀ20 °C to rt, 16 h. b. Isolated yields. c. The domino product 14
was isolated (90% yield). d. No product was isolated. e. 3 equivalents of methyl ethacrylate was used.
2.6. Application of the 2,3ꢀindoleꢀfused Michael/Mannich reaction in the
syntheses of Aspidosperma alkaloids 1−3.
After developing new methodology for the construction of ABE tetrahydrocarbazole
framework of Aspidosperma alkaloids, and exploring its generality with different
Michael acceptors and donors, we applied this methodology toward the stepꢀefficient,
asymmetric total syntheses of (−)ꢀaspidospermidine (1), (−)ꢀtabersonine (2), and (−)ꢀ
vincadifformine (3).11
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Since we had established facile access to 2,3ꢀindoleꢀfused domino
Michael/Mannich/Nꢀalkylation product 36, the next stage of the synthesis called for ringꢀ
closing metathesis (RCM) of the D ring, a strategy employed by Rawal in the
Aspidosperma series.32,33 To this end, the methyl ester group in 36 was converted to a
requisite terminal olefin via the intermediary aldehyde 38. This goal was best
accomplished by sequential reduction to the alcohol with DIBALꢀH and oxidation with
the Dess−Martin periodinane (DMP) in 98% overall yield.35 Wittig methylenation of 38
and ringꢀclosing metathesis under the agency of 10 mol% Hoveyda−Grubbs second
generation catalyst (HGꢀII)36 delivered ABDE tetracycle 39 in 90% overall yield
(Scheme 9).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 9. Construction of the Aspidosperma dehydropiperidine D ring.
As previously noted, a more stepꢀefficient route would be possible if an α,βꢀ
unsaturated aldehyde (i.e., ethacrolein) was used for the 2,3ꢀindoleꢀfused domino
Michael/Mannich/Nꢀallylation, which would lead to aldehyde 38 in one step and avoid
redox processes. Thus, anion 40 from the 2,3ꢀindoleꢀfused domino Michael/Mannich
reaction sequence could be trapped with allyl bromide to give 38 in one step from Nꢀ
sulfinimine 7. However, the yield of this more direct route to 38 was lower (50ꢀ57%
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overall) than the acrylate variant (83ꢀ90% overall), which is attributed to the reactivity of
the aldehyde moiety under the reaction conditions (Scheme 10).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 10. Alternative route to aldehyde 38.
O
S
O
S
O
S
Li
tꢀBu
tꢀBu
allyl
bromide
DMF
N
N
N
tꢀBu
LHMDS, then
ethacrolein
CHO
Et
CHO
Et
H
ꢀ78 °C
to rt
THF
ꢀ78 °C
N
N
N
CH3
SO2Ph
SO2Ph
SO2Ph
50-57%
overall
40
38
7
With ABDE tetracycle 39 in hand, we were poised to construct the final C ring
(Scheme 11). To this end, we recruited the stepꢀefficient process developed by Bosch and
Rubiralta wherein tꢀBuOK was utilized for transferring the Nꢀbenzenesulfonyl protecting
group from indole to the primary hydroxyl group in 41, which resulted in spirocyclization
leading to pentacyclic indolenine 42.37,38
Scheme 11. Construction of the C ring.
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To access substrate 41 for the Bosch−Rubiralta process, the Nꢀsulfinyl group in 39
was first removed with methanolic HCl. Subsequent Nꢀalkylation of the gramine
intermediate was effected with 2ꢀbromoethanol and Na2CO3 (refluxing EtOH) to deliver
alcohol 41 in 80% overall yield. Thus, the Bosch−Rubiralta spirocyclization was realized
by the addition of 2 equivalents of tꢀBuOK in THF at 0 °C to afford indolenine 42 in 60%
yield (Scheme 11).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Indolenine 42 served as a key intermediate in the endgame of Aspidosperma alkaloids
1−3. Global hydrogenation of 42 with Adams’s catalyst and H2 in EtOH at room
temperature delivered (−)ꢀaspidospermidine (1) in a single step (75% yield).
Alternatively, metalation of indolenine 42 with LDA to access a metalloenamine
intermediate and subsequent addition of Mander’s reagent furnished (−)ꢀtabersonine (2)
in 73% yield.39ꢀ41,42 The hydrogenation of 2 with Adams’s catalyst and H2 in EtOAc
afforded (−)ꢀvincadifformine (2) in 81% yield (Scheme 12). Spectral data for 1−3 (e.g.,
1H and 13C NMR, IR, optical rotation) were in complete agreement with those reported in
the literature.11
Scheme 12. Endgame for Aspidosperma alkaloids 1−3.
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3
4
5
6
N
H2
PtO2
Et
7
8
9
EtOH
N
75%
H
H
N
1: (−)ꢀaspidospermidine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Et
N
N
N
H2
PtO2
42
LDA
NCCO2Me
Et
Et
THF, ꢀ78 °C
EtOAc
N
N
H
H
73%
CO2Me
81%
CO2Me
3: (−)ꢀvincadifformine
2: (−)ꢀtabersonine
3. CONCLUSION
In summary, a novel asymmetric 2,3ꢀindoleꢀfused domino Michael/Mannich
reaction sequence for the rapid assembly of the tetrahydrocarbazole (ABE) framework of
Aspidosperma alkaloids was developed. The reaction scope of both nucelophilic and
electrophilic partners was explored. The methodology was employed in the concise
asymmetric total syntheses of classical targets (−)ꢀaspidospermidine (1, 10 steps, 27%
overall yield), (−)ꢀtabersonine (2, 10 steps, 26% overall yield), and (−)ꢀvincadifformine
(3, 11 steps, 22% overall yield) from commercial starting materials. Other key steps
include (1) ringꢀclosing metathesis to prepare the D ring and (2) the Bosch−Rubiralta
spirocyclization to prepare the C ring.
4. EXPERIMENTAL SECTION
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General Information. All reactions containing moisture or air sensitive reagents
were performed in ovenꢀdried glassware under nitrogen or Argon. Tetrahydrofuran,
diethyl ether and dichloromethane were passed through two columns of neutral alumina
prior to use. 2ꢀMethylenebutyric acid and methyl ethacrylate were prepared according to
the procedure of Chen.43 All other reagents were purchased from commercial sources and
used without further purification. All solvents for workꢀup procedures were used as
received. Flash column chromatography was performed according to the procedure of
Still44 using 60Å silica gel with the indicated solvents. For all ringꢀclosing metathesis
reactions, CH2Cl2 was deaerated by bubbling argon (1 min/mL). Thin layer
chromatography was performed on 60F254 silica gel plates. Detection was performed
using UV light, KMnO4 stain, PMA stain and subsequent heating. Infrared spectra (IR)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
13
were measured on a Fourier transform infrared spectrometer (FTꢀIR). H and C NMR
spectra were recorded on a 500 MHz instrument in CDCl3 at 298K. Chemical shifts are
indicated in parts per million (ppm) and internally referenced to residual solvent signals.
Splitting patterns are abbreviated as follows: s (singlet), d (doublet), bs (broad singlet), bd
(broad doublet), t (triplet), q (quartet) and m (multiplet). Highꢀresolution mass spectra
(HRMS) were obtained on a timeꢀofꢀflight (TOF) mass spectrometer using an
electrospray ionization (ESI) source.
(R,E)-2-Methyl-N-((2-methyl-1H-indol-3-yl)methylene)propane-2-sulfinamide (10):
A mixture of 2ꢀmethylꢀ3ꢀformylindole 8 (2 g, 12.56 mmol), (R)ꢀtertꢀbutanesulfinamide
(1.83 g, 15.1 mmol) and Ti(OEt)4 (8.6 g, 37.7 mmol) in THF (50 mL) was stirred at 70
°C overnight. The reaction was quenched with brine (30 mL) and the resulting
suspension was filtered through a short pad of Celite. The solid cake was washed with
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ethyl acetate, and the separated organic layer was washed with brine. The organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography eluting with EtOAc/hexanes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
(1:4 to 1:1) to afford 2.9 g (88% yield) of Nꢀsulfinimine 10 as an offꢀwhite foam. [α]D
+74.9 (c 1.1, CHCl3); IR (neat) 3197, 2980, 2361, 2341, 1592, 1572, 1459, 1362, 1339,
1247, 1048, 745 cmꢀ1; H NMR (500 MHz, CDCl3) δ 9.74 (s, 1H), 8.83 (s, 1H), 8.26 –
1
13
8.19 (m, 1H), 7.38 – 7.33 (m, 1H), 7.26 – 7.20 (m, 2H), 2.57 (s, 3H), 1.33 (s, 9H); C
NMR (126 MHz, CDCl3) δ 155.3, 144.2, 135.8, 126.1, 123.0, 122.0, 121.2, 110.9, 110.9,
56.9, 22.4, 12.1; HRMS (ESI) calc’d for C14H18N2OS + H = 263.1218, found 263.1227.
General procedure for the optimization of the areneꢀfused domino
Michael/Mannich reaction: To a stirred solution of sulfinimine 7 (40 mg, 0.1 mmol) in
THF or diethyl ether (3 mL) was added base (0.12 or 0.22 mmol) at –78 °C. The resulting
mixture was stirred at –78 °C for 1 h. Then a solution of methyl ethacrylate (17 mg, 0.15
mmol) in THF or diethyl ether (1 mL) was added at –78 °C. Stirring was continued at –
78°C for 2 h. The reaction was quenched with saturated aq. NH4Cl (4 mL) at –78°C. The
cooling bath was removed and the mixture was warmed to rt. The organic layer was
separated, washed with brine (4 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography eluting with
EtOAc/hexanes (1:1 to 4:1) to afford 14 as a white foam.
General procedure for the the areneꢀfused domino Michael/Mannich reaction
with various electrophiles: To a stirred solution of Nꢀsulfinimine 7 (40 mg, 0.1 mmol)
in THF (3 mL) was added LHMDS (1.0M in THF, 0.12 mL, 0.12 mmol) at –78 °C. The
resulting mixture was stirred at –78 °C for 1 h. Then a solution of Michael acceptor (0.15
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mmol) in THF (1 mL) was added at –78 °C. Stirring was continued at –78 °C for 2 h. The
reaction was quenched with saturated aq. NH4Cl (4 mL) at –78 °C. The cooling bath was
removed and the mixture was warmed to rt. The organic layer was separated, washed
with brine (4 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel flash column chromatography.
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Methyl
(3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-9-(phenylsulfonyl)-2,3,4,9-tetra-
hydro-1H-carbazole-3-carboxylate (11): The title product 11 was obtained as a white
foam (34 mg, 70% yield) after purification by silica gel flash column chromatography
eluting with EtOAc/hexanes (1:1 to 4:5). [α]D 20 +16.4 (c 1.1, CHCl3); IR (neat) 3287,
2954, 2359, 1724, 1449, 1371, 1203, 11173, 1066, 984, 750, 727, 687, 593 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 7.3, 1.2 Hz, 1H), 7.75 – 7.67 (m, 3H), 7.57 –
7.51 (m, 1H), 7.42 (dt, J = 7.5, 1.7 Hz, 2H), 7.33 – 7.23 (m, 2H), 4.98 (dd, J = 7.2, 3.9
Hz, 1H), 4.53 (d, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.20 (dt, J = 18.5, 5.1 Hz, 1H), 3.06 –
13
2.92 (m, 2H), 2.33 – 2.17 (m, 2H), 1.13 (s, 9H); C NMR (125 MHz, CDCl3) δ 173.3,
138.9, 136.4, 136.4, 133.7, 129.3, 128.8, 126.2, 124.6, 123.6, 119.8, 117.8, 114.2, 56.2,
52.1, 49.7, 45.1, 23.5, 22.8, 21.2; HRMS (ESI) calc’d for C24H28N2O5S2 + H = 489.1518,
found 489.1513.
Methyl (3S,4R)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-9-(phenylsulfonyl)-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylate (15): The title product 15 was obtained as a
white foam (47 mg, 93% yield) after purification by silica gel flash column
chromatography eluting with EtOAc/hexanes (1:1 to 4:5). [α]D 20 –7.5 (c 1.55, CHCl3); IR
(neat) 3314, 2954, 2359, 1733, 1449, 1371, 1172, 1145, 1066, 749, 728, 594 cmꢀ1; 1H
NMR (500 MHz, CDCl3) δ 8.16 (dt, J = 5.9, 3.5 Hz, 1H), 7.73 – 7.69 (m, 2H), 7.65 (dt, J
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= 7.7, 3.5 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.43 – 7.38 (m, 2H), 7.34 – 7.28 (m, 2H), 4.72
(d, J = 6.1 Hz, 1H), 4.07 (d, J = 6.1 Hz, 1H), 3.79 (s, 3H), 3.26 (ddd, J = 18.8, 6.4, 1.6
Hz, 1H), 2.91 – 2.82 (m, 1H), 2.24 (ddd, J = 14.0, 11.4, 6.4 Hz, 1H), 2.11 – 2.03 (m, 1H),
1.07 (s, 3H), 1.02 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 176.1, 138.9, 136.8, 136.1,
133.7, 129.2, 126.0, 124.8, 123.7, 119.4, 115.9, 114.2, 56.0, 53.7, 52.2, 47.3, 24.4, 22.7,
21.4, 19.6; HRMS (ESI) calc’d for C25H30N2O5S2 + H = 503.1674, found 503.1681.
(R)-2-methyl-N-((4aR,11S,11aS)-1-oxo-6-(phenylsulfonyl)-1,3,4,4a,5,6,11,11a-
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octahydropyrano[4,3-b]carbazol-11-yl)propane-2-sulfinamide (16): The title product 16
was obtained as a white foam (37 mg, 73% yield) after purification by silica gel flash
column chromatography eluting with EtOAc/dichloromethane (1:1 to 4:5). [α]D 20 +18.1
(c 1.38, CHCl3); IR (neat) 3277, 2980, 2361, 1730, 1448, 1389, 1370, 1228, 1182, 1151,
1
1127, 1062, 1035, 750, 729, 686, 593 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.07 (d, J =
8.4 Hz, 1H), 7.70 – 7.63 (m, 3H), 7.53 – 7.47 (m, 1H), 7.41 (dd, J = 10.7, 4.8 Hz, 2H),
7.29 – 7.22 (m, 1H), 7.21 – 7.14 (m, 1H), 5.86 (d, J = 11.2 Hz, 1H), 4.90 (dd, J = 11.2,
4.8 Hz, 1H), 4.52 – 4.37 (m, 2H), 3.76 (t, J = 4.8 Hz, 1H), 3.48 – 3.33 (m, 1H), 2.79 –
2.69 (m, 2H), 2.36– 2.30 (m, 1H), 2.01 – 1.90 (m, 1H), 1.32 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 173.7, 138.4, 136.5, 133.8, 133.5, 129.3, 128.6, 126.2, 124.4, 123.3,
120.9, 118.0, 114.3, 65.5, 56.3, 54.0, 44.3, 30.4, 30.3, 27.2, 22.9; HRMS (ESI) calc’d for
C25H28N2O5S2 + Na = 523.1337, found 523.1322.
(R)-N-((3S,4R)-3-formyl-3-methyl-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-
carbazol-4-yl)-2-methylpropane-2-sulfinamide (17): The title product 17 was obtained as
a white foam (40 mg, 84% yield) after purification by silica gel flash column
chromatography. [α]D 20 –15.5 (c 2.8, CHCl3); IR (neat) 3218, 2960, 2361, 1722, 1448,
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1370, 1172, 1149, 1051, 982, 749, 728, 686, 591, 573 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ 9.64 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 7.0 Hz, 1H),
7.53 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.35 – 7.27 (m, 2H), 4.69 (d, J = 6.2 Hz,
1H), 4.17 (d, J = 6.2 Hz, 1H), 3.29 (dd, J = 19.0, 4.6 Hz, 1H), 3.00 – 2.86 (m, 1H), 2.23 –
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2.09 (m, 1H), 1.93 (dd, J = 13.9, 6.1 Hz, 1H), 1.04 (s, 9H), 1.00 (s, 3H); C NMR (101
MHz, CDCl3) δ 204.7, 139.2, 137.1, 136.4, 134.2, 129.7, 129.5, 126.5, 125.3, 124.2,
119.8, 116.8, 114.7, 56.6, 52.6, 50.2, 23.7, 23.1, 21.5, 17.1; HRMS (ESI) calc’d for
C24H28N2O4S2 + H = 473.1569, found 473.1577.
(R)-N-((3S,4R)-3-ethyl-3-formyl-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-
4-yl)-2-methylpropane-2-sulfinamide (18): The title product 18 was obtained as a white
foam (42 mg, 86% yield) after purification by silica gel flash column chromatography
eluting with EtOAc/hexanes (1:1 to 4:5). [α]D 20 –39.0 (c 2.2, CHCl3); IR (neat) 3215,
2966, 2361, 1721, 1449, 1370, 1213, 1171, 1149, 1055, 1026, 982, 749, 727, 686, 592,
573 cmꢀ1; H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H), 8.19 – 8.13 (m, 1H), 7.71 (dt, J =
1
8.6, 1.6 Hz, 2H), 7.66 – 7.62 (m, 1H), 7.56 – 7.50 (m, 1H), 7.43 – 7.37 (m, 2H), 7.34 –
7.25 (m, 2H), 4.76 (d, J = 6.2 Hz, 1H), 4.02 (d, J = 6.2 Hz, 1H), 3.30 – 3.21 (m, 1H), 2.91
– 2.79 (m, 1H), 2.10 – 2.06 (m, 2H), 1.54 (dq, J = 15.0, 7.5 Hz, 1H), 1.43 – 1.34 (m, 1H),
1.02 (s, 9H), 0.76 (t, J = 7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 204.8, 138.8, 136.7,
136.4, 133.8, 129.3, 129.1, 126.1, 124.8, 123.9, 119.2, 116.5, 114.3, 56.2, 53.6, 50.9,
22.9, 22.6, 21.1, 20.2, 8.4; HRMS (ESI) calc’d for C25H30N2O4S2 + H = 487.1725, found
487.1716.
(R)-N-((3S,4S)-3-acetyl-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-2-
methylpropane-2-sulfinamide (19): The title product 19 was obtained as a colorless gum
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(19 mg, 40% yield) after purification by silica gel flash column chromatography eluting
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with 100% diethyl ether. [α]D 20 –8.8 (c 1.38, CHCl3); IR (neat) 2980, 2360, 2341, 1701,
1
1449, 1371, 1173, 1148, 1090, 1063, 985, 750, 726, 687, 592, 574 cmꢀ1; H NMR (500
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MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 1H), 7.74 – 7.67 (m, 3H), 7.55 – 7.50 (m, 1H), 7.45 –
7.40 (m, 2H), 7.30 – 7.21 (m, 2H), 4.86 (dd, J = 8.1, 4.4 Hz, 1H), 4.59 (d, J = 8.1 Hz, 1H),
3.38 – 3.32 (m, 1H), 3.11 (dt, J = 18.3, 6.0 Hz, 1H), 3.00 (dt, J = 12.7, 6.0 Hz, 1H), 2.39
– 2.30 (m, 1H), 2.29 (s, 3H), 2.17– 2.11 (m, 1H), 1.16 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 210.1, 138.8, 136.3, 136.0, 133.7, 129.2, 128.8, 126.2, 124.4, 123.5, 120.1,
118.1, 114.2, 56.0, 51.7, 50.4, 29.2, 22.8, 22.7, 22.4; HRMS (ESI) calc’d for
C24H28N2O4S2 + Na = 495.1388, found 495.1391.
Methyl 9-(phenylsulfonyl)-9H-carbazole-3-carboxylate (20): The title product 20 was
obtained as a white foam (25 mg, 68% yield) after purification by silica gel flash column
chromatography eluting with EtOAc/hexanes (3:7). IR (neat) 2949, 2361, 1716, 1446,
1
1366, 1250, 1176, 1120, 1099, 975, 756, 745, 729, 685, 599 cmꢀ1; H NMR (500 MHz,
CDCl3) δ 8.63 – 8.59 (m, 1H), 8.40 – 8.37 (m, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.21 – 8.17
(m, 1H), 7.99 – 7.95 (m, 1H), 7.86 – 7.82 (m, 2H), 7.54 (dd, J = 8.4, 7.4 Hz, 1H), 7.51 –
7.45 (m, 1H), 7.43 – 7.39 (m, 1H), 7.37 – 7.32 (m, 2H), 3.97 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 166.8, 141.0, 138.8, 137.7, 134.1, 129.2, 128.7, 128.0, 126.4, 126.3,
125.9, 125.7, 124.3, 122.0, 120.3, 115.0, 114.6, 52.2; HRMS (ESI) calc’d for
C20H15NO4S + H = 366.0800, found 366.0802.
N-methoxy-N-methyl-2-methylenebutanamide (21): N,NꢀCarbonyldiimidazole (501
mg, 3.09 mmol) was added slowly to a stirred solution of 2ꢀmethylenebutyric acid (300
mg, 3 mmol) in acetonitrile (2 mL) at rt. After 30 min, N,Oꢀdimethylhydroxylamine (351
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mg, 3.6 mmol) was added, followed by addition of a solution of trimethylamine (0.51
mL, 3.6 mmol) in acetonitrile (1 mL). The stirring was continued at rt for 24h. The
resulting suspension was filtered through a short pad of Celite and the filter cake was
washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was
redissolved in ethyl acetate (20 mL) and washed with a 5% solution of sodium carbonate
(10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was used in the next reaction without
further purification. The residue was purified by flash column chromatography eluting
with EtOAc/hexanes (3:7 to 1:1) to afford 281 mg (65% over 2 steps) of the Weinreb
amide as a colorless oil. IR (neat) 2921, 2360, 2342, 1654, 1559, 1458, 1378, 999 cmꢀ1;
1H NMR (400 MHz, CDCl3) δ 5.26 (s, 1H), 5.21 (s, 1H), 3.65 (s, 3H), 3.24 (s, 3H), 2.35
(q, J = 7.4 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.5, 146.2,
114.4, 61.1, 33.4, 26.4, 11.8; HRMS (ESI) calc’d for C7H13NO2 + H = 144.1025, found
144.1015.
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(3S,4R)-4-(((R)-tert-butylsulfinyl)amino)-3-ethyl-N-methoxy-N-methyl-9-
(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (22): The title product
22 was obtained as an offꢀwhite gum (19 mg, 35% yield) after purification by silica gel
20
flash column chromatography eluting with EtOAc/hexanes (1:1 to 100% EtOAc). [α]D
–65.8 (c 0.95, CHCl3); IR (neat) 2964, 1647, 1453, 1371, 1174, 1148, 1089, 1068, 995,
750, 728, 595 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.18 – 8.12 (m, 1H), 7.69 (dd, J = 8.5,
1.1 Hz, 2H), 7.67– 7.65 (m, 1H), 7.54 – 7.49 (m, 1H), 7.41 – 7.37 (m, 2H), 7.33 – 7.27
(m, 2H), 5.06 (d, J = 5.7 Hz, 1H), 3.90 (d, J = 5.7 Hz, 1H), 3.78 (s, 3H), 3.27 (s, 3H),
3.24 – 3.18 (m, 1H), 2.77 (ddd, J = 18.7, 12.2, 6.2 Hz, 1H), 2.31 (dd, J = 14.6, 6.2 Hz,
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1H), 2.14 – 2.06 (m, 1H), 1.60 (dq, J = 14.6, 7.5 Hz, 1H), 1.30 – 1.24 (m, 1H), 0.99 (s,
9H), 0.82 (t, J = 7.5 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 175.3, 138.9, 136.9, 136.7,
133.6, 129.5, 129.2, 126.0, 124.7, 123.6, 119.5, 116.6, 114.3, 60.6, 56.1, 53.0, 52.5, 34.0,
22.7, 22.6, 21.8, 21.5, 9.3; HRMS (ESI) calc’d for C27H35N3O5S2 + Na = 568.1916, found
568.1932.
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(3R,4R)-4-(((R)-tert-butylsulfinyl)amino)-3-ethyl-N-methoxy-N-methyl-9-
(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (23): The title product
23 was obtained as an offꢀwhite gum (15 mg, 27% yield) after purification by silica gel
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flash column chromatography eluting with EtOAc/hexanes (1:1 to 100% EtOAc). [α]D
–14.0 (c 0.73, CHCl3); IR (neat) 2965, 1638, 1452, 1368, 1172, 1150, 1092, 1056, 998,
750, 728, 686, 596 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.11 – 8.05 (m, 1H), 7.64 (d, J =
7.5 Hz, 2H), 7.59 – 7.56 (m, 1H), 7.49 – 7.43 (m, 1H), 7.38 – 7.32 (m, 2H), 7.25 – 7.22
(m, 2H), 5.26 (d, J = 6.5 Hz, 1H), 3.66 (s, 3H), 3.39 – 3.33 (m, 1H), 3.16 (d, J = 6.5 Hz,
2H), 2.90 (s, 3H), 2.59 – 2.46 (m, 1H), 2.10 (dq, J = 14.8, 7.5 Hz, 1H), 1.85 – 1.75 (m,
13
2H), 1.08 (s, 9H), 0.95 (t, J = 7.5 Hz, 3H); C NMR (126 MHz, CDCl3) δ 173.9, 139.4,
136.8, 136.7, 133.2, 128.9, 128.8, 126.2, 124.3, 123.5, 120.2, 118.9, 114.4, 60.3, 56.5,
52.5, 51.2, 33.3, 26.6, 26.1, 23.3, 22.7, 8.7; HRMS (ESI) calc’d for C27H35N3O5S2 + Na =
568.1916, found 568.1900.
General procedure for the oneꢀpot areneꢀfused domino Michael/Mannich/N-
allylation reaction: To a stirred solution of sulfinimine 7 (40 mg, 0.1 mmol) in THF (3
mL) was added LHMDS (0.12 or 0.22 mmol) at –78 °C. The resulting mixture was
stirred at –78 °C for 1 h. A solution of methyl ethacrylate (0.15 or 0.3 mmol) in THF (1
mL) was added at –78 °C. Stirring was continued at –78 °C for 2 h. Then a solution of
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allyl bromide (60.5 mg, 0.5 mmol) in DMF was added. The reaction mixture was warmed
to rt and stirred overnight. The reaction was quenched with saturated aq. NH4Cl (20 mL)
and diluted with H2O (12 mL), followed by extraction with EtOAc (3 × 30 mL). The
combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified by flash
chromatography eluting EtOAc/hexanes (3:7) to afford 31 as a white foam.
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o-Tolualdehyde N-t-butyl sulfinimine (24): A mixture of oꢀtolualdehyde 27 (1.15 mL,
10 mmol), (R)ꢀtertꢀbutanesulfinamide (1.45 g, 12 mmol) and Ti(OEt)4 (6.2 mL, 30 mmol)
in THF (50 mL) was stirred at rt overnight. The reaction was quenched with brine (10
mL) and the resulting suspension was filtered through a short pad of Celite. The solid
cake was washed with ethyl acetate, and the separated organic layer was washed with
brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column chromatography
eluting with EtOAc/hexanes (1:9) to afford 1.76 g (79 %) of 24 as a pale yellow oil. [α]D
20 –141.8 (c 2.75, CHCl3); IR (neat) 3491, 2959, 2925, 2359, 1604, 1589, 1567, 1456,
1362, 1082, 758, 716 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 7.91 (dd, J = 7.5,
1.1 Hz, 1H), 7.39 (td, J = 7.5, 1.3 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 3.8 Hz,
1H), 2.61 (s, 3H), 1.27 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 161.6, 139.4, 132.1,
131.9, 131.3, 129.4, 126.3, 57.5, 22.5, 19.9; HRMS (ESI) calc’d for C12H17NOS + H =
224.1109, found 224.1102.
2-Methylpyridine-3-carboxaldehyde N-t-butyl sulfinimine (25): A mixture of 2ꢀ
methylpyridineꢀ3ꢀcarboxaldehyde 28 (0.28 g, 2.31 mmol), (R)ꢀtertꢀbutanesulfinamide
(0.34 g, 2.8 mmol) and Ti(OEt)4 (1.9 mL, 9.16 mmol) in THF (20 mL) was stirred at rt
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