Diastereoselective construction of continuous all-carbon quaternary centers via intramolecular oxidative coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2013.05.146

Construction of continuous all-carbon quaternary centers via intramolecular oxidative coupling was described. Intramolecular oxidative coupling of bisoxindole linked by diol derived from d-tartaric acid diastereoselectively produced C₁ or C

Full text of DOI:10.1016/j.tetlet.2013.05.146

Tetrahedron Letters 54 (2013) 4392–4396
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Tetrahedron Letters
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Diastereoselective construction of continuous all-carbon quaternary
centers via intramolecular oxidative coupling reaction
b
c
a
a
a
b,
Weiqing Xie a, , Hexiang Wang , Feng Fan , Junshan Tian , Zhiwei Zuo , Weiwei Zi , Kun Gao
⇑
⇑
,
Dawei Ma a,
⇑
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
b State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
c School of Pharmacy, East China University o f Science and Technology, 130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Construction of continuous all-carbon quaternary centers via intramolecular oxidative coupling was
Received 17 April 2013
Revised 23 May 2013
Accepted 30 May 2013
Available online 10 June 2013
described. Intramolecular oxidative coupling of bisoxindole linked by diol derived from D-tartaric acid
diastereoselectively produced C1 or C2 isomers of the annulation product. The selectivity was realized
by judiciously choosing base and solvent employed in the reaction. As key intermediates for the synthesis
of cyclotryptamine alkaloids, the resulting bisoxindole should be applicable to the total syntheses of com-
plex indole alkaloids with continuous all-carbon quaternary centers.
Keywords:
Bisoxindole
Ó 2013 Elsevier Ltd. All rights reserved.
Intramolecular oxidative coupling
Continuous all-carbon quaternary center
Cyclotryptamine alkaloids
Although elegant synthetic methodologies have been developed
for constructing quaternary carbon center, new strategy is still
continuously being invented to provide a convenient, efficient,
and general way for assembling asymmetric quaternary carbon
center.1 Since asymmetric all-carbon quaternary center is com-
monly found in natural products and pharmaceutical molecules,
designing methodologies for stereocontrolled construction of all-
carbon quaternary center remains to be attractive but a significant
challenge for synthetic chemists.2 Especially when culminating
complex natural products with continuous all-carbon quaternary
centers (such as Communesin and Perophoramidine),2 one faces
much more challenges in stereocontrolled construction of continu-
ous all-carbon quaternary centers because of the increasing steric
repulsion and the intrinsic difficulty in controlling diastereoselec-
tivity and enantioselectivity.
all-carbon quaternary centers and polycyclic structure of trypt-
amine alkaloids pose formidable challenges for synthetic chemists.4
Extensive synthetic studies of cyclotryptamine alkaloids have been
reported and elegant strategies have been developed to enantiose-
lectively construct the vicinal all-carbon quaternary centers.4
Although biomimetic synthesis of ( ) and meso-Chimonanthine, di-
mer of tryptamine, has been achieved by oxidative coupling of
tryptamine or oxindole,5a–c the first enantioselective synthesis of
Chimonanthine was reported by Overman until 1999, who estab-
lished the quaternary carbon centers by domino Heck reaction or
later by dialkylation of isoindigo.5d,5e In 2007, Movassaghi et al.
developed the reductive coupling of 3-bromopyrrolo[2,3-b]indole
mediated by Co(PPh3)2Cl to dimerize pyrroloindoline units, which
enabled an efficient synthesis of Chimmonanthine.5f Recently the
catalytic construction of one of the quaternary carbon centers of
Folicanthine was reported by Gong,5g which relied on the substitu-
tion of hydroxyoxindole with enamide catalyzed by chiral phospho-
ric acid. Kanai and coworkers made use of asymmetric Michael
reaction of isoindigo with vinylnitrate catalyzed by chiral bimetallic
catalyst to establish one of the all-carbon quaternary centers of
Chimonanthine.5h However both strategies needed additional
transformations to install the other quaternary carbon center,
which made the synthetic routine much longer and less efficient
compared with Overman’s and Movassaghi’s method.
Cyclotrytamine alkaloids are a large family of indole alkaloids
with complex structure and potent biological activities, which
could be biosynthetically considered as oligomers of tryptamines.3
Hexahydropyrrolo[2,3-b]indole is the structural unit of cyclotrypta-
mine alkaloids, which are mainly connected by forming C3–C30
bond or C3–C70 bond between the two units. The vicinal and biaryl
⇑
Corresponding authors. Tel.: +86 21 57495341; fax: +86 21 64166128 (W.X.);
tel.: +86 931 8912592; fax: +86 931 8915557 (K.G.); tel.: +86 21 57495130; fax: +86
21 64166128 (D.M.).
Recently we developed intramolecular oxidative coupling
reactions of indole incorporated substrates to build up complex in-
dole scaffolds including the frameworks of Communesin A, F, and
E-mail addresses: xiewq@sioc.ac.cn (W. Xie), npchem@lzu.edu.cn (K. Gao),
madw@sioc.ac.cn (D. Ma).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.146

W. Xie et al. / Tetrahedron Letters 54 (2013) 4392–4396
4393
Me
N
O
O
O
H
N
H
O
NBn
OTf
BnN
TfO
O
BnN
O
NBn
ref. 5e
3
N
H
N
Me
H
dialkylation
O
O
O
C1-1
(+)-Chimonanthine
4
O
Me
N
O
O
this work
H
N
H
O
O
O
intramolecular
oxidative
BnN
BnN
coupling
NBn
NBn
O
N
Me
N
H
H
5
C2-2
meso-Chimonanthine
Figure 1. Strategies for synthesis of Chimonanthine alkaloids.
(ꢀ)-Vincorine,2c,d,6 which demonstrated the powerful potential of
intramolecular oxidative coupling on the synthesis of complex in-
dole alkaloid motifs. Despite of the recent advances of intramolec-
ular oxidative coupling,7 diastereoselective formation of
continuous all-carbon quaternary centers via intramolecular oxi-
dative coupling is still less explored. Herein we would like to report
on diatereoselectively constructing continuous all-carbon quater-
nary centers of cyclotryptamine alkaloids via intramolecular oxida-
tive coupling.
During the course of the synthesis of cyclotryptamine alkaloids,
we encountered the problem of establishing both stereoisomers of
the continuous all-carbon quaternary centers. To this end,
Oveman’s dialkylation strategy seemed more appealing, since both
bisoxindole C1-1 and C2-2, which were the key intermediate to cyc-
lotryptamine alkaloids (Fig. 1),4b were accessible by dialkylation of
isdingo 3 with ditriflate 4 under different reaction conditions.4b,5d,9
o
7
1. n-BuLi, , -78 C
2. MsCl, Et3N, -78oC to 0oC
OTBS
N
Bn
6
O
67% for two steps
O
O
N
Bn
O
TBSO
O
O
O
8
7
1. Swern oxidation
1. Pd/C, MeOH
2. TBAF, HOAc
OH
2. 6, BuLi, THF, -78oC
O
O
3. MsCl, Et3N, -78oC to 0oC
55% for three steps
4. Raney Ni, MeOH, 82%
N
Bn
O
O
83% for two steps
9
O
BnN
NBn
O
O
5
Scheme 1. Synthesis of bisoxindole 5.
Table 1
Optimization of intramolecular oxidative coupling condition for bisoxindole C1-1
O
O
O
O
O
O
(S)(S)
conditionsa
BnN
NBn
BnN
O
O
NBn
5
C1-1
Entry
Solvent
Base
Oxidant
Fe(acac)3 (2.2 equiv)
Cu(2-ethylhexanate)2 (2.2 equiv)
I2 (2.2 equiv)
Temperature (°C)
Concentration (M)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
THF
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
Et2O
THF
THF
LDA
LDA
LDA
LDA
LDA
LDA
LiHMDS
NaHMDS
KHMDS
NaHMDS
NaH MDS
NaHMDS
NaHMDS
ꢀ78 to rt
ꢀ78 to rt
ꢀ78 to rt
ꢀ78
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.005
0.005
NDc
NDc
47
54
37
I2 (1.1 equiv)
NBS (1.1 equiv)
NIS (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
ꢀ78
ꢀ78
53
30
ꢀ78
ꢀ78
63
ꢀ78
NDc
47
ꢀ78 to rt
ꢀ78 to rt
ꢀ78
43
77
84
ꢀ78 to rt
a
5 (1.0 equiv), Base (2.2 equiv), THF, ꢀ78 °C, 30 min, then addition of oxidant, ꢀ78 °C 2 h or ꢀ78 °C to rt 30 min.
b
Isolated yield.
c
Complex mixture, no desired product was isolated.

4394
W. Xie et al. / Tetrahedron Letters 54 (2013) 4392–4396
Table 2
Screening of intramolecular oxidative coupling condition for bisoxindole C2-2
O
O
O
O
O
O
O
O
O
O
O
O
conditionsa
BnN
NBn
BnN
O
O
BnN
+
NBn
BnN
+
NBn
NBn
O
O
1
C1-
5
2
3
C2-
C2-
Entry
Solvent
Base
Oxidant
Temperature (°C)
Concentration (M)
Ratio (1:2 + 3)
Ratio 2:3
Yield (2 + 3)c (%)
1
2
3
4
5
6
9
8
9
THF/HMPA 9:1
THF/HMPA 9:1
THF/HMPA 9:1
THF/HMPA 9:1
THF/HMPA 9:1
THF/HMPA 9:1
THF/HMPA 9:1
THF/HMPA 9:1
THF/HMPA 8:2
THF/HMPA 7:3
LDA
LDA
LDA
LiHMDS
NaHMDS
KHMDS
LDA
LDA
LDA
LDA
I2 (2.2 equiv)
I2 (1.1 equiv)
NBS (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
I2 (1.1 equiv)
ꢀ78
0.05
0.05
0.05
0.05
0.05
0.05
0.005
0.005
0.005
0.005
1:2
1:2
1:6
1:5
5.8:1
4.0:1
3.4:1
3.7:1
1.8:1
NA
9:1
7:1
5.:1
4.4:1
37
68
60
60
27
NDd
80
73
70
63
ꢀ78
ꢀ78
ꢀ78
ꢀ78
1.4:1
b
ꢀ78
—
—
—
—
b
ꢀ78
b
ꢀ78 to rt
ꢀ55
b
b
10
ꢀ50
—
a4 (1.0 equiv), Base (2.2 equiv), THF/HMPA, ꢀ78 °C, 30 min, then addition of oxidant, ꢀ78 °C 2 h or ꢀ78 °C to rt 30 min.
b
No C1-1 was detected.
Isolated yield.
Complex mixture, no desired product was isolated.
c
d
For C1-1:
In their procedure, bisoxindole C1-1 could be obtained in 90% yield
Bn
using NaHMDS as base, while bisoxindole C2-2 was only achieved
in moderate yield (58%) under the optimal condition (LiHMDS as
base). To develop an alternative route to bisoxindole C1-1 and C2-
2, we envisaged that they could be constructed by intramolecular
O
Na
B
N
(R)O
O
O
H
H
(R)
O
NBn
A
O
B
O
O
O
NBn
O
BnN
O
(R) NBn
H
(S)
H
oxidative coupling of bisoxindole 5. By employing D-tartaric acid
N
Na
O
A
Bn
TS2
derived diol as linker, a tighter transient state could be produced
in the oxidative coupling reaction, which would result in good
diastereoselectivity.
TS1
1
C1-
For C2-2:
As depicted in Scheme 1, the synthesis of bisoxindole 5 com-
menced with aldol condensation of oxindole 6 with aldehyde 78
Bn
N
Li
O
derived from
D-tartaric acid followed by dehydration with MsCl/
H
Li
NBn
O
H
Et3N to afford alkylidene oxindole 8 in 67% yield. Hydrogenation
catalyzed by Pd/C and desilylation by TBAF which was neutralized
with HOAc smoothly gave primary alcohol 9. The addition of HOAc
proved critical since hydroxyl indole was isolated as the main
product owing to the oxidation of oxindole by air. Swern oxidation
of the primary alcohol and the second aldol condensation with
oxindole 6 furnished bisoxindole which was dehydrated and
hydrogenated by Raney Nickel to provide bisonindole 5 in accept-
able yield.
O
O
Li
O
O
NBn
O
H
H
NBn
O
Li
TS3
major
TS4
minor
O
O
(R)
O
O
(R)
(R)
(R)
O
O
(S)
(R)(R)
BnN
With bisoxindole 5 in hand, various reactions conditions were
screened to deliver the oxidative coupling product (Table 1). We
first followed Baran’s condition by using Fe(III) or Cu(II) salts as
oxidant (entries 1 and 2).9 To our disappointment, no product
could be isolated and only decomposition of starting material
was detected due to the sensitivity of substrate to Lewis acids.
After series of trials, halogen reagents were found to be effective
for the oxidative coupling (entries 3–6). Iodine gave slightly better
yield (54%) than NBS (37%) and NIS (43%). To our delight, only one
isomer was isolated and determined to be C1 symmetric isomer C1-
111 by comparison of NMR spectra with those of reported com-
pound.5d,10 The yield of the reaction were also depended on the
base used in the reaction (entries 6–9). NaHMDS afforded the best
results (entry 8) and too strong base KHMDS led to decomposition
of starting material. Other solvents such as toluene, ether was less
efficient than THF as shown in entries 10 and 11. Fortunately, the
yield was improved to 77% by diluting the reaction to 0.005 M (en-
try 12) and eventually 84% yield could be achieved by immediate
removal the reaction flask from cold bath after addition of oxidant.
BnN
(S)
NBn
NBn
O
O
C2 -2
C2-3
Figure 2. Rationale for the observed diastereoselectivity.
Interestingly, when adding HMPA as co-solvent, C2 symmetric
isomer C2-212 was generated as the major product albeit in low
yield and diastereoselectivity (Table 2, entry 1). This result was
quite encouraging since like Overman’s procedure we could obtain
both stereoisomers from the same starting material just by chang-
ing reaction conditions. I2 was also proved to be the best oxidant
(entries 2 and 3). On the contrast, LDA was found to be the optimal
base as other base gave deleterious results (entries 4–6). The dia-
stereoselectivity was greatly enhanced (only C2 isomer, C2-2/C2-3
9:1) when lowing the concentration of the reaction mixture to
0.005 M (entry 9). It was also found that higher temperature have

W. Xie et al. / Tetrahedron Letters 54 (2013) 4392–4396
4395
HO
O
OH
HO
O
OH
O
O
O
CSA, MeOH, CH2Cl2 BnN
72 11
BnN
BnN
NBn
NBn
% for 10, 8% for
O
O
NBn
C2-2, dr 9:1
O
11
10
Scheme 2. Deprotection of C2-2 and ORTEP drawing of diol 10.
negative influence on the diastereoselectivity as well as yield
(entry 8). Increasing the ratio of HMPA led to decreased diastere-
oselectivity as the reaction had to be run at higher temperature be-
cause of solidification of reaction mixture at ꢀ78 °C. To establish
the absolute configuration of C2-2 and C2-3, removal of acedonide
of oxidative coupling product with CAS in MeOH and CH2Cl2 affor-
ded two separable isomers, diol 10 together with the minor isomer
11 (Scheme 2). X-ray crystallography of diol 1013 showed that the
absolute configuration of the newly formed stereocenters of C2-2
were R,R, while C2-3 had S,S configuration as determined by diol
11, which was a known compound.5e,10
To explain the observed diastereoselectivity, we proposed the
transition state of the reaction as shown in Figure 2. In the course
of forming C1-1, both enolates coordinated to sodium cation
despite the electronic repulsion between the two enolates in the
presence of NaHMDS, which was similar to Overman’s pro-
posal.5d,10 Additionally the backbone of the transition species
adopted a six-membered chair conformation which was fixed by
the acetonide protected diol. Although two enolates could point
up or down to the six-membered ring, the two transition states
TS1 and TS2 were equal to each other. After oxidative coupling,
both transition states led to C1 symmetric isomer C1-1. On the con-
trary, when LDA was used as base and THF/HMPA as solvent, two
enolates of oxindole had to be pointed against each other for elec-
tronic repulsion between the two enolates and two unequal tran-
sition states TS3 and TS4 thus were formed. As the two aromatic
rings of oxindoles in TS4 suffered more seriously steric repulsion
than those in TS3, TS4 had a greater energy barrier and the reaction
preferred to proceed along with TS3 pathway. After oxidative cou-
pling, TS3 went to the major product C2-2 isomer while TS4 led to
the minor product C2-3 isomer.
Acknowledgments
The authors are grateful to the Chinese Academy of Sciences,
National Natural Science Foundation of China (Grants 20921091
&
20572119), and Ministry of Science & Technology (Grant
2009CB940900) for their financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
146.
References and notes
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In conclusion, a highly diastereoselective synthesis of continu-
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oxidative coupling of bisoxindole linked by diol derived from D-tar-
taric acid. From the same cyclization precursor, both stereoisomers
could be obtained under different reaction conditions in excellent
yield and diastereoselectivity. This reaction represents one of the
few examples of diastereoselective construction of continuous
all-carbon quaternary centers in one step. As the cyclized bisoxin-
doles were the key intermediates for asymmetric syntheses of
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alternative route to those alkaloids. The further application of this
methodology on the syntheses of complex indole alkaloids is ac-
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4396
W. Xie et al. / Tetrahedron Letters 54 (2013) 4392–4396
A. J. Am. Chem. Soc. 1999, 121, 7702–7703; (e) Overman, L. E.; Larrow, J. F.;
7.30 (m, 2H), 7.25–7.15 (m, 5), 7.07 (t, J = 7.8 Hz, 2H), 6.96 (t, J = 7.2 Hz, 2H),
6.57–6.48 (m, 4H), 6.31 (d, J = 7.5 Hz, 2H), 6.05 (d, J = 7.5 Hz, 1H), 5.30–5.28 (m,
1H), 5.17 (d, J = 15.9 Hz, 1H), 5.01 (d, J = 15.7 Hz, 1H), 4.89 (d, J = 15.6 Hz, 1H),
4.52–4.43 (m, 1H), 4.30 (d, J = 16.2 Hz, 1H), 3.28 (t, J = 12.0 Hz, 1H), 2.36 (t,
J = 12.9 Hz, 1H), 2.30 (dd, J = 13.2, 4.8 Hz, 1H), 2.04 (dd, J = 13.2, 4.5 Hz, 1H),
1.59 (s, 6H); ESIMS m/z 593.1 (M+Na)+; HRMS calcd for C37H34N2O4 Na
(M+Na)+ requires 593.2421, found: 593.2422.
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12. C2-2 (Mixture of two inseparable isomers), major isomer: 1H NMR (400 MHz,
CDCl3) d 7.27 (m, 8H), 7.09 (m, 4H), 6.98 (t, J = 8.0 Hz, 2H), 6.77 (t, J = 7.6 Hz,
2H), 6.41 (d, J = 7.6 Hz, 2H), 5.10 (m, H), 4.96 (d, J = 15.6 Hz, 2H), 4.47 (d,
J = 15.6 Hz, 2H), 2.55 (dd, d, J = 13.4, 6.8 Hz, 2H), 2.28 (dd, J = 13.2, 9.6 Hz, 2H),
1.55 (s, 6H); 13C NMR (100 MHz, CDCl3) d 178.2, 142.0, 135.3, 130.3, 128.7,
128.5, 127.6, 127.4, 127.3, 125.1, 122.6, 110.5, 108.6, 74.7, 53.1, 43.8, 34.3,
27.5; ESIMS m/z 593.1 (M+Na)+; HRMS calcd for C37H34N2O4 Na (M+Na)+
requires 593.2421, found: 593.2422.
6. (a) Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 132, 9126–9129; (b) Fan, F.;
Xie, W.; Ma, D. Org. Lett. 2012, 14, 1405–1407; (c) Fan, F.; Xie, W.; Ma, D. Chem.
Commun. 2012, 48, 7571–7573.
7. (a) Guo, F.; Clift, M. D.; Thomson, R. J. Eur. J. Org. Chem. 2012, 26, 4881–4896; (b)
Xie, W.; Zuo, Z.; Zi, W.; Ma, D. Chin. J. Org. Chem. 2013. http://dx.doi.org/
10.6023/cjoc201301035.
8. Fürstner, A.; Wuchrer, M. Chem. Eur. J. 2006, 12, 76–89.
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9. (a) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed. 2005, 44, 609–
612; (b) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45, 7083–
7086; (c) Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin, D. W.; Castroviejo, P.;
Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857–12869; (d) DeMartino, M. P.;
Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546–11560.
10. Stearns, B. A. Ph D. Dissertation, University of California, Irvine, 2000.
13. ½aꢁD 172.7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.27 (m, 7H), 7.11 (m,
3H), 7.05 (t, J = 7.6 Hz, 2H), 6.82 (t, J = 7.6 Hz, 2H), 6.48 (d, J = 7.6 Hz, 2H), 6.14
6.48 (d, J = 11.6 Hz, 2H), 4.96 (d, J = 15.6 Hz, 2H), 4.63 (d, J = 16.0 Hz, 2H), 4.23
(d, J = 11.2 Hz, 2H). 3.25 (dd, d, J = 15.6, 3.2 Hz, 2H), 2.43 (br s, 2H), 1.93 (d,
J = 15.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 180.4, 142.0, 134.8, 129.4, 129.1,
128.1, 127.1, 127.6, 124.8, 123.8, 109.7, 71.4, 51.8, 44.2, 30.1; IR (film) 3368,
1678, 1610, 1384, 1083, 763 cmꢀ1; ESIMS m/z 531.1 (M+H)+, 553.1 (M+Na)+;
HRMS calcd for C34H31N2O4 (M+H)+ requires 531.2778, found: 531.2268.
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11. C1-1: ½aꢁD ꢀ264.0 (c 0.95, CHCl3), (lit. ½aꢁD +290 (c 0. 5, CHCl3),10 for the
enantiomer of C1-1; 1H NMR (300 MHz, CDCl3) d 7.88 (d, J = 7.2 Hz, 1H), 7.32–