Domino Michael/Mannich/ N-alkylation route to the tetrahydrocarbazole framework of Aspidosperma alkaloids: Concise total syntheses of (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine

Article abstract of DOI:10.1021/ja408114u

We report a novel, asymmetric domino Michael/Mannich/N-alkylation sequence for the rapid assembly of the tetrahydrocarbazole framework of Aspidosperma alkaloids. This method was utilized in the concise total syntheses of classical targets (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine in 10 or 11 steps. Additional key steps include ring-closing metathesis to prepare the D-ring and Bosch-Rubiralta spirocyclization to prepare the C-ring.

Full text of DOI:10.1021/ja408114u

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Communication
Domino Michael/Mannich/N-Alkylation Route to the Tetrahydrocarbazole
Framework of Aspidosperma Alkaloids: Concise Total Syntheses
of (-)-Aspidospermidine, (-)-Tabersonine, and (-)-Vincadifformine
Senzhi Zhao, and Rodrigo B. Andrade
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja408114u • Publication Date (Web): 23 Aug 2013
Downloaded from http://pubs.acs.org on August 23, 2013
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Domino Mic ha el/Ma nnic h/N-A lkylatio n Ro ut e to the T et-
rahydrocarba zo le Framework o f Aspid osp erma A lk a lo ids:
Conc is e Tota l Synthes es o f ( −)- Asp id osp ermid ine, (−) -
Tab ersonine, a nd (−)-Vinc a d ifformine
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Senzhi Zhao and Rodrigo B. Andrade*
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
Supporting Information Placeholder
ABSTRACT: We report a novel, asymmetric domino Mi-
Although we have been engaged in the total synthesis of
chael/Mannich/Ν-alkylation sequence for the rapid assem-
6
complex indole alkaloids of the Strychnos class and most
bly of the tetrahydrocarbazole (ABE) framework of Aspi-
7
recently rearranged Aspidosperma alkaloids, our methods
were ill suited for preparing targets such as 1-4. We were,
nonetheless, intrigued by two disparate bodies of work
whose merger, if successful, would offer facile, concise ac-
cess to appropriately functionalized ABE tetrahydrocarba-
zole cores of 1-4 with satisfactory control over relative and
absolute stereochemistry. Specifically, we were inspired by
(1) Magnus’s elegant and step-efficient indole-2,3-
dosperma alkaloids. This method was utilized in the concise
total syntheses of classical targets (−)-aspidospermidine
(1b), (−)-tabersonine (2), and (−)-vincadifformine (3) in
10−11 steps. Additional key steps include (1) ring-closing
metathesis to prepare the D-ring and (2) the
Bosch−Rubiralta spirocyclization to prepare the C-ring.
quinodimethane approach to Aspidosperma and Kospia
8,3h
alkaloids; and, (2) Ellman’s clever use of metalloe-
Monoterpene indole alkaloids of the Aspidosperma class,
which include over 250 unique members, are fascinating
natural products endowed with an irresistible combination
namines derived from tert-butanesulfinylimines as asym-
9
metric nucleophiles. Retrosynthetically, we reasoned that
tetrahydrocarbazole 4 could be obtained in one operation
1
of architectural complexity and pharmacological activity.
by means of a domino Michael/Mannich sequence
Moreover, these intriguing molecules have greatly bene-
fited both organic chemistry and medicine. The structures
of four classical members of the Aspidosperma family,
namely (−)-aspidospermine (1a), (−)-aspidospermidine
(1b), (−)-tabersonine (2), and (−)-vincadifformine (3),
are shown in Figure 1. Of these, aspidospermidine (1b) is
(Scheme 1) from the reaction of azadienolate 5 and methyl
10
ethacrylate (6). The efficiency of the operation could be
2
enhanced in the forward sense by productive trapping the
N-sulfinylanion intermediate with allyl bromide (7). Azadi-
enolate 5 would in turn be derived from N-sulfinylimine 8,
which was readily accessible from commercial 9 and (R)-
3
4
5
the most representative insofar as it possesses the hallmark
ABCDE pentacyclic framework and common structural
denominator amongst the Aspidosperma alkaloids. Accord-
ingly, targets 1-4 have stimulated considerable interest in
the synthetic community dating back to Stork’s elegant,
stereoselective total synthesis of 1a in 1963 and continues
9
N-tert-butanesulfinamide (10).
Scheme 1. Retrosynthetic analysis of tetrahydrocarbazole
4 via novel Domino Michael/Mannich/N-alkylation route.
2a
unabated to this day.
Br
O
O
7
S
Li
S
N
Domino
Michael/
Mannich/
t-Bu
N
t-Bu
Figure 1. Structures of (−)-aspidospermine (1a), (−)-
aspidospermidine (1b), (−)-tabersonine (2), and (−)-
vincadifformine (3).
CO2Me
Et
Et
MeO2C
+
N-alkylation
CH2
N
N
6
PhO2S
PhO2S
4
5
O
N
N
14
15
S
D
C
N
t-Bu
O
S
CHO
CH3
A
E
B
Et
Et
+
H2N
t-Bu
N
N
H
H
N
N
CH3
R1
R2
CO2Me
10
PhO2S
PhO2S
8
9
1a: (!)-aspidospermine (R1=OMe; R2=Ac)
1b: (!)-aspidospermidine (R1=R2=H)
2: (!)-tabersonine, "14,15
3: (!)-vincadifformine
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Scheme 2. Total syntheses of (−)-aspidospermidine (1b), (−)-tabersonine (2), and (−)-vincadifformine (3).
3
4
5
6
7
8
9
O
S
O
S
O
S
O
S
Li
5 equiv
allyl
bromide
(7)
PhO2S
N
t-Bu
N
t-Bu
CO2Me
N
t-Bu
1.2-2.2
equiv
LHMDS
N
H2N
t-Bu
CO2Me
Et
6
10
Et
9
DMF
81-90%
dr=11:1
OMe
Li
THF
-78 °C
Ti(OEt)4
CH2Cl2
97%
N
CH3
CH2
N
N
N
S
H
PhO2S
PhO2S
PhO2S
O
O
t-Bu
4
5
8
Et
10
11
12
13
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15
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11
HO
O
O
S
S
N
t-Bu
N
t-Bu
1.) HCl, MeOH
2.) Br(CH2)2OH
Na2CO3
N
N
t-BuOK
(2 equiv)
CHO
1.) Ph3P=CH2
2.) 10 mol%
HG-II
1.) DIBAL-H
Et
Et
Et
Et
THF
-78 °C
60%
2.) DMP
EtOH, reflux
80% overall
N
N
N
N
PhO2S
98% overall
90% overall
PhO2S
PhO2S
12
13
14
15
N
N
N
H2
PtO2
H2
PtO2
LDA
NCCO2Me
Et
Et
Et
EtOAc
81%
EtOAc
75%
THF, -78 °C
73%
N
H
N
H
H
N
H
CO2Me
CO2Me
3: (!)-vincadifformine
2: (!)-tabersonine
1b: (!)-aspidospermidine
The synthesis began with the condensation of N-
benezensulfonyl-2-methylindole-3-carboxaldehye (9),
sulfinamide 10, and Ti(OEt)4 to afford N-sulfinylimine 8
to an appropriately positioned primary hydroxyl group by
the action of t-BuOK; spirocyclization of the ensuing in-
dolyl anion at C3 with the benzenesulfonate ester estab-
17,18
in 97% yield (Scheme 2). Treatment of 8 with 1.2−2.2
equivalents of LHMDS in THF at -78 ºC generated di-
enolate 5 via deprotonation of the acidic 2-methyl group.
lishes the C-ring.
Accordingly, removal of the N-sulfinyl
group in 13 with HCl in MeOH and N-alkylation with 2-
bromoethanol, Na2CO3 in refluxing EtOH gave substrate
14 in 80% overall yield. Addition of 2 equivalents of t-
11
Addition of methyl ethacrylate (6) triggered a Michael
reaction whose enolate stereoselectively cyclized onto the
regenerated N-sulfinylimine moiety in a Mannich fashion;
trapping the resulting anion with 5 equivalents of allyl
bromide in DMF furnished tetrahydrocarbazole 4 in 81-
BuOK in THF at 0 ºC effected the Bosch−Rubiralta spiro-
cyclization to afford ABCDE pentacycle 15 in 60% yield.
Endgame for 1b, 3, and 4 commenced with indolenine
15. Whereas previous reports had employed a two-step
protocol (i.e., hydride reduction of the imine and metal-
catalyzed hydrogenation of the D-ring olefin), we found
hydrogenation of 15 over Adams’s catalyst in EtOAc at rt
delivered (−)-aspidospermidine (1b) in a single step (75%
yield). The synthesis of 2 employed tactics first employed
in Overman’s elegant synthesis of classical Strychnos alka-
12
90% yield (dr=11:1). We rationalized the relative and
absolute stereocontrol in the domino Michael/Mannich
sequence by means of transition state 11, which is consis-
13
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tent with those posited by Ellman and Davis. To the best
of our knowledge, this method represents the first (1) use of a
vinylogue of an N-sulfinyl metalloenamide; (2) domino proc-
ess wherein the in situ-generated nucleophile cyclizes onto an
N-sulfinyl imine; and (3) intramolecular process wherein β-
amino esters (i.e., Mannich bases) bearing α-quaternary
stereocenters are prepared in both high yield and diastereose-
lectivity.
19
loid akuammicine. Specifically, treatment of 15 with LDA
at -78 ºC and quenching the intermediary azaenolate spe-
20
cies with Mander’s reagent furnished (−)-tabersonine (2)
in 73% yield. Hydrogenation of 2 over Adams’s catalyst in
EtOAc afforded (−)-vincadifformine (3) in 81% yield.
Spectral data for 1a, 2, and 3 (e.g., 1H and 13C NMR, IR,
optical rotation) were in complete agreement with those
The next stage of the synthesis called for ring-closing me-
tathesis (RCM) of the D-ring, a strategy employed by
Rawal in the Aspidosperma series.
3ag,4j
3,4,5
To this end, we con-
reported in the literature.
verted the methyl ester in 12 to a requisite terminal olefin
via the intermediary aldehyde. This goal was best accom-
plished by sequential reduction to the alcohol with DIBAL-
In summary, we have completed concise, asymmetric to-
tal syntheses of classical Aspidosperma alkaloids (−)-
aspidospermidine (1b, 10 steps, 27% overall yield), (−)-
tabersonine (2, 10 steps, 26% overall yield), and (−)-
vincadifformine (3, 11 steps, 22% overall yield) from
commercial starting materials. Key steps include (1) a
H and oxidation with the Dess−Martin periodinane
15
(DMP) in 98% overall yield. Wittig methylenation of 12
and ring-closing metathesis under the agency of 10 mol%
16
Hoveyda−Grubbs 2nd generation catalyst (HG-II) deliv-
novel domino Michael/Mannich/N-alkylation sequence to
access the tetrahydrocarbazole framework of the Aspi-
dosperma alkaloids; (2) ring-closing metathesis to prepare
ered ABDE tetracycle 13 in 90% overall yield.
We envisioned installing the C-ring with a step-efficient
process discovered by Bosch and Rubiralta wherein an N-
benzenesulfonyl protecting group on indole is transferred
the D-ring; and, (3) the Bosch−Rubiralta spirocyclization
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of this novel process and applying it toward the total syn-
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AS S O CI AT ED CON TENT
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Supporting Information. Experimental details and spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INF ORM ATI ON
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C or resp o n di n g Au t h or
randrade@temple.edu
N o tes
The authors declare no competing financial interest.
ACKN OWL EDGMENT
This research was supported by the National Science Founda-
tion (CHE-1111558). We thank Dr. Charles DeBrosse, Direc-
tor of the NMR Facilities at Temple Chemistry, for kind assis-
tance with NMR experiments. We thank Prof. Chris
Schafmeister (Temple University) for access to LC-MS in-
strumentation. We thank Prof. David Dalton for carefully
reading our manuscript, Dr. Richard Pederson (Materia, Inc.)
for catalyst support, and the reviewers for helpful comments.
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6008; (h) Kobayashi, S.; Peng, G.; Fukuyama, T. Tetrahedron
Lett. 1999, 40, 1519−1522. For asymmetric syntheses of 3 see:
(i) Pandey, G.; Kumara, P. C. Org. Lett. 2011, 13, 4672−4675.
See also refs 4k, 4l, 3ag, and 3am.
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6 (a) Sirasani, G.; Andrade, R. B. Org. Lett. 2009, 11, 2085−
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(d) Sirasani, G.; Andrade, R. B. In Strategies and Tactics in
Organic Synthesis; Harmata, M., Ed.; Academic Press: New
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7 Zhao, S.; Sirasani, G.; Vaddypally, S.; Zdilla, M.; Andrade, R.
B. Angew. Chem. Int. Ed. 2013, 52, 8309−8311.
8 (a) Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P. Acc.
Chem. Res. 1984, 17, 35−41; (b) Cardwell, K.; Hewitt, B.;
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9 Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
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11 Kuang, Y.-Y.; Chen, F.-E. Org. Prep. Proced. Int. 2005, 37,
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12 The relative and absolute stereochemistry of tetrahydrocar-
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13 Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12−13.
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17 Rubiralta, M.; Diez, A.; Bosch, J.; Solans, S. J. Org. Chem.
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18 For a similar use of this tactic applied toward ( ) pseudo-
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19 Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W., Jr.;
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70, 256−264.
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Graphical Table of Contents:
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Domino Michael/Mannich/N-alkylation
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7
8
9
O
O
Ph
S
Li
S
5 equiv
allyl
bromide
CO2Me
t-Bu
N
N
t-Bu
O2S
N
H
CO2Me
Et
Et
THF
OMe
Li
DMF
81-90%
dr=11:1
CH2
N
N
-78 °C
N
S
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11
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PhO2S
O
PhO2S
O
t-Bu
(from 2-methylindole
3-carboxaldehyde)
Et
steps
Aspidosperma Alkaloids
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