Highly Regio- and Enantioselective Formal [3 + 2]-Annulation of Indoles with Electrophilic Enol Carbene Intermediates

Article abstract of DOI:10.1021/acs.orglett.6b02192

Chiral cyclopentane-fused indolines are synthesized with high regio- and enantiocontrol by formal [3 + 2]-annulation reactions of indoles and electrophilic enol carbenes. High enantioselectivity and exclusive regiocontrol occurred with enoldiazoacetamides using a less sterically encumbered prolinate-ligated dirhodium(II) catalyst in reactions with N-substituted indoles without substituents at the 2- or 3-positions via a selective vinylogous addition process. In this transformation, donor-acceptor cyclopropenes generated from enoldiazoacetamides serve as the carbene precursors to form metal carbene intermediates.

Full text of DOI:10.1021/acs.orglett.6b02192

Letter
pubs.acs.org/OrgLett
Highly Regio- and Enantioselective Formal [3 + 2]-Annulation of
Indoles with Electrophilic Enol Carbene Intermediates
Changcheng Jing,† Qing-Qing Cheng,‡ Yongming Deng,‡ Hadi Arman,‡ and Michael P. Doyle*,‡
†Shanghai Engineering Research Centre of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai 200062, P.R. China
‡Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
S
* Supporting Information
ABSTRACT: Chiral cyclopentane-fused indolines are synthe-
sized with high regio- and enantiocontrol by formal [3 + 2]-
annulation reactions of indoles and electrophilic enol carbenes.
High enantioselectivity and exclusive regiocontrol occurred
with enoldiazoacetamides using a less sterically encumbered
prolinate-ligated dirhodium(II) catalyst in reactions with N-
substituted indoles without substituents at the 2- or 3-positions via a selective vinylogous addition process. In this transformation,
donor−acceptor cyclopropenes generated from enoldiazoacetamides serve as the carbene precursors to form metal carbene
intermediates.
2,C3-Fused indole skeletons are key structural motifs of a
large number of alkaloid natural products and bioactive
styryl group orientations of zwitterionic intermediates in the [3
+ 2]-cycloaddition reaction.4b Dearomatizing [3 + 2]-
annulation of indoles without substitution at the 2- or 3-
positions that occurs with good chemo-, regio-, and
enantiocontrol has not been achieved.
Electrophilic enol carbene intermediates generated from
enoldiazo compounds are 1,3-dipole equivalents that possess
electrophilic character at the vinylogous position and
nucleophilic character at the metal carbene carbon. These
intermediates readily undergo [3 + 3]-annulation reactions with
1,3-dipoles6 or [3 + 2]-annulation reactions with unsaturated
compounds having nucleophilic character.7 Could vinylogous
reactivity from these vinylcarbene intermediates also provide
high regioselectivity and enantioselectivity for [3 + 2]-
annulation of indoles without substituents at either the 2- or
3-positions?
C
compounds,1 and considerable effort has been focused on the
development of chemo-, regio-, and enantioselective method-
ologies to form C2,C3-fused indoles and indolines.2−4 Of the
synthetic methods that have been developed, dearomatizing [3
+ 2]-annulation of indoles has proven to be an efficient and
effective approach to cyclopentane−fused indole-derived
alkaloids3,4 which are common structures in bioactive
compounds (Figure 1).1,5 However, in spite of longstanding
Treatment of 1.2 equiv of enol diazoacetate 1 with 1.0 equiv
of 1-methylindole 2a in the presence of 2 mol % of dirhodium
tetraacetate and 4 Å MS in CHCl3 at room temperature gave, as
expected from Davies’ prior report,4b two regioisomeric [3 +
2]-annulation products in a 44:56 ratio (68% yield). An
extensive screening of chiral dirhodium catalysts was conducted
in efforts to improve regioselectivity as well as to achieve
enantiocontrol (Scheme 1).8 Chiral phthalimidate-ligated
dirhodium carboxylate catalysts favored addition to indole
from the carbene carbon to give 4 as a major product in variable
ratios, but use of the more Lewis acidic Rh2(S-TFPTTL)4 gave
the highest regioselectivity and enantioselectivity for the
formation of this product. Switching to prolinate-derived
catalysts resulted in reversed regioselectivities with vinylogous
addition forming 3 as the major product. However, both chiral
Figure 1. Cyclopent[b]indole alkaloids.
efforts, only limited reports are available on catalytic
asymmetric methods for their synthesis.4 Barluenga reported
an enantioselective [3 + 2]-cycloaddition reaction of indoles
with tungsten Fischer alkynylcarbenes using (S)-menthol as a
chiral auxiliary,4a while Davies realized an enantioselective
dirhodium-catalyzed version with styryldiazoacetates,4b and
Tang developed a copper-catalyzed enantioselective intra-
molecular cyclopentane-annulation of indoles with donor−
acceptor cyclopropanes.4c,d However, in all of these cases,
indoles with electron-donating alkyl groups at the 2- or 3-
position were required in order to achieve regio- and
stereocontrol.4b Regioselectivity was explained by the steric
preferences of s-trans- and s-cis-metallo-styrylcarbenes in
reactions with 1,2- and 1,3-disubstituted indoles or by different
Received: July 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02192
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Organic Letters
Letter
Scheme 1. Catalytic [3 + 2]-Annulation of Indole 2a with
Enol Diazoacetate 1
Table 1. Optimization of the [3 + 2]-Annulation Reaction of
N-Methylindole 2a with N,N-Dimethyl Enoldiazoacetamide
a
5a
b
c
temp
(°C)
yield
ee
entry
1
Rh2L4 (x)
solvent
CHCl3
(%)
(%)
Rh2(S-TFPTTL)4
(1)
rt
33
0
2
Rh2(S-DOSP)4
CHCl3
CHCl3
rt
18
43
(1)
3
4
5
6
7
8
9
Rh2(S-BSP)4 (1)
rt
rt
rt
rt
0
49
32
55
13
11
61
45
82
48
46
80
90
88
88
91
94
Rh2(S-TBSP)4 (1) CHCl3
Rh2(S-MSP)4 (1)
Rh2(S-MSP)4 (1)
Rh2(S-MSP)4 (1)
Rh2(S-MSP)4 (2)
Rh2(S-MSP)4 (2)
Rh2(S-MSP)4 (2)
CHCl3
toluene
CHCl3
CHCl3
0
CHCl3/ toluene
CHCl3/ toluene
rt
0
d
10
a
Unless otherwise noted, all reactions were conducted on a 0.10 mmol
phthalimide rhodium carboxylate catalysts and chiral prolinate-
derived catalysts gave the [3 + 2]-annulation products with
poor enantioselectivities.
scale of 2a with 5a/2a = 1.2:1.0. Diazoamide 5a in 0.5 mL of solvent
was added to the mixture of catalyst, 2a, and 4 Å MS (100 mg) in 0.5
mL of solvent by syringe pump over 30 min, and then the reaction
b
Given our recent successes in the uses of enoldiazoaceta-
mides as highly selective reagents for vinylogous cycloaddition
reactions,6e,9 we considered their use for reactions with 1-
methylindole. Initial reactions were conducted in CHCl3 by
slowly adding a solution of enoldiazoacetamide 5a to a mixture
of indole 2a, 1.0 mol % Rh2(OAc)4, and 4 Å MS at room
temperature. After 4 h, the [3 + 2]-cycloaddition product 6a
was isolated in 18% yield as a single regioisomer. The screening
of different catalysts was conducted to maximize the efficiency
and selectivities of this [3 + 2]-annulation transformation.8 Use
of Cu(MeCN)4PF6 and Cu(OTf)2 with (S,S)-t-Bu-Box ligand
gave the desired product in low yield, but without any
enantioselectivity, and with AgSbF6 in place of copper catalysts
no activity was observed. The use of phthalimide-amino acid
ligated dirhodium catalysts did not give the [3 + 2]-annulation
product after 4 h at room temperature. However, the more
Lewis acidic Rh2(S-TFPTTL)4 catalyzed the formation of only
one regioisomer (6a) in 33% yield, but this catalyst did not
provide enantiocontrol (Table 1, entry 1). Switching to known
prolinate-derived catalysts resulted in significant increases in
both the yields and enantioselectivities for the [3 + 2]-
annulation product 6a (Table 1, entries 2−4), but enantiose-
lectivities remained low.
With recognition from a previously reported [3 + 3]-
cycloaddition reaction of enoldiazoacetates10 that a less
sterically encumbered catalyst could give higher enantioselec-
tivities, we prepared the methanesulfonyl analogue of the
arylsulfonylprolinate ligated dirhodium(II) carboxylates, Rh2(S-
MSP)4, and applied this catalyst to the reaction between 2a and
5a which gave the highest level of enantiocontrol (Table 1,
entry 5). Using Rh2(S-MSP)4, other reaction parameters
(solvent, reaction temperature, reaction time, and the loading
of the catalyst) were examined, and representative results are
reported in the table.8 Low reaction temperatures and use of
toluene gave higher enantioselectivities, but reactions were
sluggish (Table 1, entries 6 and 7). Increasing the catalyst
loading of Rh2(S-MSP)4 to 2 mol % in chloroform accelerated
the reaction rate (Table 1, entry 8). The [3 + 2]-annulation
mixture was stirred for 4 h. Isolated yields obtained after column
c
d
chromatography. Determined by HPLC using a chiral column. The
reaction mixture was stirred for 24 h.
product 6a was obtained in 45% yield and 91% ee when a
mixed solvent of 1:1 CHCl3 and toluene was used (Table 1,
entry 9). Prolonging the reaction time to 24 h and lowering the
reaction temperature to 0 °C further improved the yield and
enantioselectivity (82% yield, 94% ee; Table 1, entry 10), and
these conditions were optimal. Use of Rh2(S-MSP)4 with 1
gave 3 (31% ee) and 4 (−10% ee) in a 79:31 ratio (68%
yield).8
With the optimal conditions in hand, we probed the reaction
scope for this formal [3 + 2]-annulation transformation. The
size of the amide group had a significant impact on the level of
enantioselectivity. Enoldiazoacetamide 5b that bears a piper-
idine ring gave the [3 + 2]-annulation product with higher
enantioselectivity than did N,N-dimethyl enoldiazoacetamide
5a (Scheme 2, 6b vs 6a). In general, excellent regio- and
enantioselectivities were obtained regardless of the substituents
on nitrogen atom or on the benzene ring of the examined
indoles. N-Benzyl indole gave the [3 + 2]-annulation product in
lower yield than did N-methylindole although their enantiose-
lectivities were similar (Scheme 2, 6c vs 6b). Indoles bearing
different electron-withdrawing benzene substituents were
generally less reactive (Scheme 2, 6g−6j vs 6d−6f), probably
due to their reduced nucleophilicity. 6-Chloro- and 7-chloro-
substituted indoles gave slightly higher enantioselectivities than
did the 5-chloro-substituted indole; however, use of 7-chloro-
substituted indole resulted in a reduced yield (Scheme 2, 6h−
6j). Surprisingly, indoles possessing a methyl group at either
the 2- or 3-positions did not give the [3 + 2]-annulation
products with enoldiazoacetamides 5 as they did in reactions
with (E)-arylvinyldiazoacetates reported by Davies and co-
workers;4b instead 5 was converted to its derivative donor−
acceptor cyclopropene without reacting with 2.
B
DOI: 10.1021/acs.orglett.6b02192
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a c
Scheme 2. Reaction Scope −
cyclopropene is the carbene precursor in this transformation,
the reaction of 1-methylindole 2a with cyclopropene 5b′,
thermally preformed from enoldiazoacetamide 5b,13 was
performed under the same conditions as the reactions reported
in Scheme 2 (eq 1). The [3 + 2]-annulation product 6b was
obtained with the same selectivity in similar yield (67% yield,
98% ee) as with diazo compound 5b. Additionally, the optimal
catalyst in the present system [Rh2(S-MSP)4] was also
evaluated in other carbene-transfer reactions.12 In comparison
with the established dirhodium(II) prolinate catalyst Rh2(S-
DOSP)4, the sterically less demanding Rh2(S-MSP)4 provided
lower stereocontrol in cyclopropanation of styrene [65% ee,
13:1 dr with Rh2(S-MSP)4; 91% ee, > 20:1 dr with Rh2(S-
DOSP)414] and C−H insertion into cyclohexane with α-
phenyl-α-diazoacetate [15% ee with Rh2(S-MSP)4; 88% ee with
Rh2(S-DOSP)415], however, giving higher enantioselectivity in
[3 + 3]-cycloaddition of N,α-diphenyl nitrone with enoldia-
zoacetate [20% ee with Rh2(S-MSP)4; 0% ee with Rh2(S-
DOSP)410].
a
An explanation for the observed regio- and enantioselectivity
that is achieved with the metal carbene formed by catalytic
reactions of enoldiazoacetamides with N-substituted indoles is
given in Scheme 3. Rhodium-catalyzed metal carbene formation
Unless otherwise noted, all reactions were conducted on a 0.20 mmol
scale of 2 with 5/2 = 1.2:1.0. 5 in 1.0 mL of solvent (CHCl3/toluene =
1:1) was added to the mixture of Rh2(S-MSP)4 (2 mol %), 2, and 4 Å
MS (200 mg) in 1.0 mL of solvent (CHCl3/toluene = 1:1) by syringe
pump over 30 min at 0 °C, and then the reaction mixture was stirred
for 48 h at the same temperature. % yield refers to isolated yields of
the product after column chromatography, and the only other indole-
b
Scheme 3. Proposed Mechanism for [3 + 2]-Cycloaddition
derived material observed in the reaction mixture was the unreacted
c
d
indole 2. % ee was determined by HPLC using a chiral column. The
reaction mixture was stirred for 24 h.
The relative configuration of the product rac-6g was
determined by X-ray crystallographic analysis (Figure 2).11
from the enoldiazo compound or its derivative donor−acceptor
cyclopropene affords a preferred s-cis-vinylcarbene to minimize
the steric interaction between the internal OTBS group and the
“wall” of rhodium catalyst. Upon vinylogous attack by the
indole, a configurationally stable vinylrhodium intermediate
linked to the electrophilic indoleniminium ion is formed.
Indoleniminium ion addition to the vinyl carbon bound to
rhodium is facilitated by stabilization that is provided by the
OTBS group. Release of the rhodium catalyst gives the [3 + 2]-
annulation product. Note that this explanation is consistent
with the lower yield of cycloaddition product formed with N-
benzylindole than with N-methylindole and with the enhance-
ment of enantioselectivity from the piperidine amide 5b relative
to the dimethylamine 5a. Regioselectivity is imposed on the
cycloaddition process by the amide functionality of the metallo-
enolcarbene.
In conclusion, we have demonstrated the high regio- and
enantioselectivities for Rh2(S-MSP)4-catalyzed dearomatizing
[3 + 2]-annulation of indoles and enoldiazoacetamides and
metal carbene formation that produces the C2,C3-fused
indoline products occurs through the intermediate donor−
acceptor cyclopropene. The acyl group of the enol carbene
intermediate is a determining factor for selective vinylogous
reactivity. Reactions with indole substrates without methyl
substituents at either the 2- or 3-positions and less sterically
Figure 2. X-ray structure of [3 + 2]-annulation product rac-6g.
The absolute configuration of the [3 + 2]-annulation product
was determined as (3aR,8bS) by comparison of the observed
optical rotation with the sign of the specific rotation of similar
structures.4b,12
In our previous work, donor−acceptor cyclopropenes
generated from enoldiazo compounds have served as carbene
precursors to take part in cyclopropanation13 and C−H
insertion reactions.9a Close spectroscopic inspection of the
reaction of 1-methylindole 2a with enoldiazoacetamide 5b
indicated that formation of donor−acceptor cyclopropene was
much faster than the generation of [3 + 2]-annulation
products.12 To further determine if the donor−acceptor
C
DOI: 10.1021/acs.orglett.6b02192
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Organic Letters
Letter
J. 2010, 16, 5853−5857. (f) Wu, H.-X.; Xue, F.; Xiao, X.; Qin, Y. J. Am.
Chem. Soc. 2010, 132, 14052−14054.
encumbered catalyst ligands allow for the efficient synthesis of
enantioenriched cyclopentane-fused indoline building blocks
via a selective vinylogous addition process. Extending this
transformation to other nucleophiles, as well as exploring the
importance of donor−acceptor cyclopropenes and the effect of
different acyl groups on vinylcarbene intermediate, comprises
our future interests.
(4) For leading references on metal-catalyzed asymmetric reactions,
see: (a) Barluenga, J.; Tudela, E.; Ballesteros, A.; Tomas, M. J. Am.
Chem. Soc. 2009, 131, 2096−2097. (b) Lian, Y.; Davies, H. M. L. J. Am.
Chem. Soc. 2010, 132, 440−441. (c) Xiong, H.; Xu, H.; Liao, S.; Xie,
Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851−7854. (d) Zhu, J.;
Liang, Y.; Wang, L.; Zheng, Z.-B.; Houk, K. N.; Tang, Y. J. Am. Chem.
Soc. 2014, 136, 6900−6903.
ASSOCIATED CONTENT
* Supporting Information
(5) (a) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am.
Chem. Soc. 1994, 116, 9935−9942. (b) Lopchuk, J. M.; Green, I. L.;
Badenock, J. C.; Gribble, G. W. Org. Lett. 2013, 15, 4485−4487.
(c) Fehr, T.; Acklin, W. Helv. Chim. Acta 1966, 49, 1907−1910.
(6) For a review and selected references, see: (a) Xu, X.; Doyle, M. P.
Acc. Chem. Res. 2014, 47, 1396−1405. (b) Qian, Y.; Zavalij, P. Y.; Hu,
W.; Doyle, M. P. Org. Lett. 2013, 15, 1564−1567. (c) Xu, X.; Zavalij,
P. Y.; Doyle, M. P. Angew. Chem., Int. Ed. 2013, 52, 12664−12668.
(d) Xu, X.; Zavalij, P. Y.; Doyle, M. P. J. Am. Chem. Soc. 2013, 135,
12439−12447. (e) Cheng, Q.-Q.; Yedoyan, J.; Arman, H.; Doyle, M.
P. J. Am. Chem. Soc. 2016, 138, 44−47.
(7) Smith, A. G.; Davies, H. M. L. J. Am. Chem. Soc. 2012, 134,
18241−18244.
(8) See the Supporting Information for a detailed survey of yields and
enantioselectivities.
(9) (a) Xu, X.; Deng, Y.; Yim, D. N.; Zavalij, P. Y.; Doyle, M. P.
Chem. Sci. 2015, 6, 2196−2201. (b) Cheng, Q.-Q.; Yedoyan, J.;
Arman, H.; Doyle, M. P. Angew. Chem., Int. Ed. 2016, 55, 5573−5576.
(10) Wang, X.; Xu, X.; Zavalij, P. Y.; Doyle, M. P. J. Am. Chem. Soc.
2011, 133, 16402−16405.
(11) CCDC 1420593 (rac-6g) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02192.
General experimental procedures, results from detailed
surveys of yields and selectivities for reaction optimiza-
tions, and spectroscopic data for all new compounds
(PDF)
X-ray data for rac-6g (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: michael.doyle@utsa.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this research from the National Science Foundation
(CHE-1559715 and CHE-1464690) is gratefully acknowledged.
C.J. thanks ECNU for a grant from the Fund for Domestic and
International Visits.
(12) See the Supporting Information for details.
(13) Deng, Y.; Jing, C.; Doyle, M. P. Chem. Commun. 2015, 51,
12924−12927.
(14) Qin, C.; Boyarskikh, V.; Hansen, J. H.; Hardcastle, K. I.;
Musaev, D. G.; Davies, H. M. L. J. Am. Chem. Soc. 2011, 133, 19198−
19204.
(15) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119,
9075−9076.
REFERENCES
■
(1) (a) Dewick, P. M. In Medicinal Natural Products: A Biosynthetic
Approach; Wiley: New York, 2002. (b) Aiello, A.; Fattorusso, E.;
Menna, M.; Taglialatela-Scafati, O. In Modern Alkaloids; Wiley−VCH:
Weinheim, 2008. (c) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.;
Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004,
67, 78−81. (d) Wright, C. W. Nat. Prod. Rep. 2010, 27, 961−968.
(e) Elliott, J. M.; Broughton, H.; Cascieri, M. A.; Chicchi, G.; Huscroft,
I. T.; Kurtz, M.; MacLeod, A. M.; Sadowski, S.; Stevenson, G. I. Bioorg.
Med. Chem. Lett. 1998, 8, 1851−1856.
(2) For recent leading reviews and references, see: (a) Bonjoch, J.;
Sole, D. Chem. Rev. 2000, 100, 3455−3482. (b) Zhuo, C.-X.; Zhang,
W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662−12686. (c) Loh,
C. C. J.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 46−48. (d) Li, H.;
Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288−6296.
(e) Kawano, M.; Kiuchi, T.; Negishi, S.; Tanaka, H.; Hoshikawa, T.;
Matsuo, J.; Ishibashi, H. Angew. Chem., Int. Ed. 2013, 52, 906−910.
(f) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008,
130, 1814−1815. (g) Martin, D. B. C.; Vanderwal, C. D. Chem. Sci.
2011, 2, 649−651. (h) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J.
Am. Chem. Soc. 2007, 129, 9631−9634. (i) Mejía-Oneto, J. M.; Padwa,
A. Org. Lett. 2004, 6, 3241−3244. (j) Spangler, J. E.; Davies, H. M. L. J.
Am. Chem. Soc. 2013, 135, 6802−6805. (k) Li, Y.; Zhang, Q.; Du, Q.;
Zhai, H. Org. Lett. 2016, 18, 4076−4079.
(3) For leading references on organocatalytic reactions, see: (a) Cai,
Q.; Zheng, C.; Zhang, J. W.; You, S. L. Angew. Chem., Int. Ed. 2011, 50,
8665−8669. (b) Jones, S. B.; Simmons, B.; Mastracchio, A.;
MacMillan, D. W. C. Nature 2011, 475, 183−188. (c) Jones, S. B.;
Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
13606−13607. (d) Lozano, O.; Blessley, G.; Martinez del Campo, T.
M.; Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.;
Borman, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 8105−
8109. (e) Zheng, J.; Chen, X.; Chai, Z.; Ma, W.; Zhao, G. Chem. - Eur.
D
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