Enantioselective Synthesis of Spiroindenes by Enol-Directed Rhodium(III)-Catalyzed C-H Functionalization and Spiroannulation

Article abstract of DOI:10.1002/anie.201507029

Chiral cyclopentadienyl rhodium complexes promote highly enantioselective enol-directed C(sp²)-H functionalization and oxidative annulation with alkynes to give spiroindenes containing all-carbon quaternary stereocenters. High selectivity betwe

Full text of DOI:10.1002/anie.201507029

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507029
German Edition: DOI: 10.1002/ange.201507029
Asymmetric Catalysis
Enantioselective Synthesis of Spiroindenes by Enol-Directed
À
Rhodium(III)-Catalyzed C H Functionalization and Spiroannulation
Suresh Reddy Chidipudi, David J. Burns, Imtiaz Khan, and Hon Wai Lam*
Abstract: Chiral cyclopentadienyl rhodium complexes pro-
mote highly enantioselective enol-directed C(sp2)-H function-
alization and oxidative annulation with alkynes to give
spiroindenes containing all-carbon quaternary stereocenters.
High selectivity between two possible directing groups, as well
as control of the direction of rotation in the isomerization of an
O-bound rhodium enolate into the C-bound isomer, appear to
be critical for high enantiomeric excesses.
C
yclopentadienyl rhodium(III) complexes are well-estab-
lished as highly active and versatile precatalysts in a diverse
[1]
À
array of C H functionalization reactions. However, enan-
tioselective variants of these reactions only became possible
with the development of chiral C2-symmetric cyclopenta-
dienyl ligands by Ye and Cramer,[2] and an artificial RhIII-
containing metalloenzyme by Ward, Rovis, and co-workers.[3]
To date, a handful of catalytic enantioselective RhIII-catalyzed
III
À
Scheme 1. Enantioselective Rh -catalyzed C H functionalizations.
[2–5]
À
C H functionalizations have been described,
but there is
a compelling need to develop new processes to access novel
classes of enantioenriched products.[6]
We recently reported Ru- and Pd-catalyzed oxidative
annulations of a-aryl cyclic 1,3-dicarbonyl compounds (or
their enol tautomers) with alkynes that provide achiral or
racemic spiroindenes.[7] Given that indenes appear in several
biologically active compounds,[8,9] the ability to prepare chiral
À
spiro-fused indenes 4 by asymmetric C H functionalization
would be valuable.[4d,10] Because we also found that
[{Cp*RhCl2}2] is an effective precatalyst,[7a,11] chiral cyclo-
pentadienyl rhodium complexes 3 appeared to be highly
promising for investigation. However, in contrast to existing
enantioselective RhIII-catalyzed C H functionalizations,
À
which all rely upon aryl C(sp2)–H activation of substrates
containing a single directing group (Scheme 1a),[2–5] the
substrates 1 required for our proposed study contain two
potential directing groups (Scheme 1b). Within the accepted
model for enantioinduction using complexes 3,[2b, 5] cyclo-
rhodation can generate up to four species, which differ in
which directing group participates in cyclometallation, and/or
Scheme 2. Possible species to consider upon cyclorhodation.
[*] Dr. S. Reddy Chidipudi, Dr. D. J. Burns, I. Khan, Prof. H. W. Lam
School of Chemistry, University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
E-mail: hon.lam@nottingham.ac.uk
the orientation of the rhodacycle within the chiral pocket
(Scheme 2). This situation contrasts with existing process-
es,[2–5] including the dearomatizing oxidative spiroannulations
of You and co-workers,[4d] in which only two conformations of
one rhodacycle need to be considered. Given the possibility of
other reaction pathways with potentially different stereo-
chemical outcomes, the development of a highly enantiose-
lective process was far from certain. Herein, we report the
successful realization of asymmetric [3+2] spiroannulations
to give a diverse range of spiroindenes in up to 97% ee.
Homepage: http://www.nottingham.ac.uk/~pczhl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507029.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Angew. Chem. Int. Ed. 2015, 54, 13975 –13979
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13975

.
Angewandte
Communications
Our investigations began with an evaluation of chiral
cyclopentadienyl rhodium complexes 3a–3 f[2b] in the reaction
of 4-hydroxy-6-methyl-3-phenyl-2H-pyran-2-one (1a) with 1-
phenylpropyne (2a, 1.5 equiv), using Cu(OAc)2 (2.1 equiv) in
DMF[12] at 508C for 24 h (Table 1). Benzoyl peroxide, which
was employed as an additive in previous enantioselective Rh-
catalyzed C H functionalizations,[2,4] was unnecessary,[13] and
À
in all cases, only one regioisomer of spiroindene 4a was
detected. The parent complex 3a (R = H) gave 4a in 93%
NMR yield, but the enantioselectivity was moderate
(entry 1).[14] Higher selectivities were obtained with com-
plexes 3b–3f containing larger groups at the 3,3’-positions
(entries 2–6). The OTBDPS- containing complex 3 f was
optimal, and provided 4a in high NMR yield and 95% ee
(entry 6).
With an effective chiral complex identified, the enantio-
selective spiroannulation of 1a with various alkynes was
explored (Scheme 3). With unsymmetrical alkynes, the regio-
selectivities of these reactions were excellent, and with the
exception of spiroindene 4d, which was formed as a 19:1
regioisomeric mixture, only single regioisomers were
detected. With 1-phenylpropyne (2a), spiroindene 4a was
isolated in 84% yield and 95% ee. The same reaction run at
room temperature provided 4a in 78% yield and 97% ee.
Diphenylacetylene reacted to give spiroindene 4b in 67%
yield and 93% ee, whereas a symmetrical dialkyl alkyne gave
spiroindene 4c in moderate yield and enantioselectivity.
However, other alkyl/(hetero)aryl alkynes were excellent
reaction partners. For example, alkynes containing 5-indolyl,
3-indolyl, or 2-thienyl substituents provided spiroindenes 4d–
4 f in 74–93% yield and 89–97% ee.
Various other substrates also underwent the spiroannula-
tion with a range of alkynes to give spiroindenes containing
ketoesters (4g–4l, 4q, and 4r), ketolactams (4m–4p and 4t–
4v), a diketone (4s), or a barbiturate (4w) with generally high
enantioselectivities (Scheme 4). Although complex 3 f was
generally effective, in some cases the less sterically hindered
complex 3b gave superior yields and enantioselectivities (4t–
Scheme 3. Enantioselective oxidative annulations of 1a with various
alkynes. Reactions were conducted with 0.30 mmol of 1a. Yields are of
isolated products. Enantiomeric excesses were determined by HPLC
analysis on a chiral stationary phase. [a] Conducted with 0.20 mmol of
1a at room temperature for 24 h. [b] Formed as a 19:1 mixture of
1
regioisomers as determined by H NMR of the unpurified reaction
mixture. The isolated product was also a 19:1 mixture of regioisomers.
4w). The reason for the superiority of complex 3b in these
cases is not currently known. Substitution at the meta- or
para-position of the a-phenyl group was tolerated (4g–4i).
À
With a meta-CF3 group, C H functionalization occurred at
the more sterically accessible site (4g).[14] In our previous
oxidative annulation work,[7] only six-membered cyclic 1,3-
dicarbonyl compounds were employed. Therefore, it is
notable that, for the first time, five- and seven-membered
substrates could be employed (4l, 4m, and 4o). The low yield
of 4l is attributed to its instability under the reaction
conditions. Products containing the 1,3-dicarbonyl compo-
nent within various polycyclic ring systems were also pre-
pared (4p–4r and 4v), although the enantioselectivities of 4p
and 4q were more modest. A substrate in which the two
possible directing groups are almost identical electronically,
but sterically well-differentiated, gave spiroindene 4s in 77%
yield and a reasonable 78% ee. 1-Methyl-5-phenylbarbituric
acid, in which the two carbonyl groups adjacent to the phenyl
group are electronically and sterically similar, gave spiroin-
dene 4w with low enantioselectivity. Finally, several of the
reactions could be carried out in dimethyl carbonate,
a significantly more environmentally friendly solvent than
DMF (4i, 4t, and 4u).[15]
Table 1: Catalyst evaluation in the reaction of 1a with 2a.[a]
Entry
Rh complex 3
NMR Yield [%][b]
ee [%][c]
1
2
3
4
5
6
3a R=H
93
97
33
41
84
98
58
90
78
88
92
95
3b R=OMe
3c R=OiPr
3d R=Ph
3e R=OTIPS
3 f R=OTBDPS
To gain further insight into these annulations, deuteration
reactions were conducted. Treatment of 1c under the
standard conditions in the absence of an alkyne but with the
addition of D2O for 4 h led to recovery of [D]n-1c with 5%
deuteration at the ortho-positions of the arene only (Sche-
me 5a). Furthermore, reaction of 1c with alkyne 2 f under the
[a] Reactions were conducted with 0.05 mmol of 1a. [b] Determined by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal
standard. [c] Determined by HPLC analysis on a chiral stationary phase.
TIPS=triisopropylsilyl, TBDPS=tert-butyldiphenylsilyl.
13976 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13975 –13979

Angewandte
Chemie
Scheme 5. Deuteration experiments.
etate complex 5, we assume that cyclorhodation of 1a is
promoted by the most enolizable of the two possible directing
groups, which is the enol derived from the ketone rather than
the ester, to give rhodacycle 6a. Coordination and migratory
insertion of the alkyne would then give rhodacycle 7a. The
alternative conformations 6b and 7b appear to be disfavored
because of steric interactions between the side wall of the
cyclopentadienyl ligand with the metallated arene of 6b or
the phenyl substituent of 7b (Scheme 6b). The next step is the
isomerization of the O-bound rhodium enolate 7a into the C-
bound isomer 8a, presumably through an oxa-p-allylrhodium
species, which requires a rotation of the 4-alkoxypyran-2-one
moiety. Because the rhodium alkoxide of this moiety is in
closest proximity to the chiral ligand, it experiences the
greatest steric interactions, and we propose there is a prefer-
ence for this group to rotate away from the ligand to give 8a.
Reductive elimination of 8a gives spiroindene 4a and RhI
species 9, which is oxidized by Cu(OAc)2 to regenerate 5. The
formation of the minor enantiomer from 7a requires an
unfavorable rotation of the rhodium alkoxide towards the
back wall of the chiral ligand (Scheme 6c).
Scheme 4. Reactions were conducted with 0.20 or 0.30 mmol of 1 (see
Supporting Information for details). Yields are of isolated products.
Enantiomeric excesses were determined by HPLC analysis on a chiral
stationary phase. [a] Dimethyl carbonate was used as the solvent.
[b] The absolute stereochemistry of the major enantiomer of 4w is not
known.
An alternative explanation that cannot be excluded is that
migratory insertion of 6a with the alkyne directly produces
a rhodacycle with a conformation closely related to that of 7a,
but with the rhodium alkoxide already partially rotated away
from the chiral ligand. Continued rotation of the 4-alkox-
ypyran-2-one moiety in the same direction, according to the
principle of least motion,[17] would then give 8a.
In conclusion, we have developed an enantioselective
synthesis of spiroindenes from the oxidative annulation of a-
aryl cyclic 1,3-dicarbonyl compounds (or their enol tauto-
mers) with alkynes, using chiral cyclopentadienyl rhodium
catalysts. The process tolerates a wide range of substrates to
give diverse products containing all carbon-quaternary ste-
reocenters with high enantioselectivities. Application of these
same conditions led to recovered 1c with no observable
deuteration, and spiroindene [D]n-4h that was partially
deuterated at the pyran-2,4-dione ring[16] but not at the
arene (Scheme 5b). Interestingly, the presence of D2O
decreased the regioselectivity of this reaction compared to
the one conducted in DMF only (Scheme 4), and [D]n-4h was
isolated as an 8:1 mixture of inseparable regioisomers. The
experiments shown in Scheme 5 suggest that cyclorhodation is
largely irreversible under these conditions.
A proposed catalytic cycle and stereochemical model[14]
for these reactions is shown in Scheme 6a, using 1a and 2a as
representative substrates. After formation of rhodium diac-
Angew. Chem. Int. Ed. 2015, 54, 13975 –13979
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13977

.
Angewandte
Communications
1460; b) F. W. Patureau, J. Wencel-Delord, F. Glorius, Aldrichi-
mica Acta 2012, 45, 31 – 41; c) T. Satoh, M. Miura, Chem. Eur. J.
2010, 16, 11212 – 11222.
[2] a) B. Ye, N. Cramer, Science 2012, 338, 504 – 506; b) B. Ye, N.
Cramer, J. Am. Chem. Soc. 2013, 135, 636 – 639; c) M. Die-
ckmann, Y.-S. Jang, N. Cramer, Angew. Chem. Int. Ed. 2015,
DOI: 10.1002/anie.201506483; Angew. Chem. 2015, DOI:
10.1002/ange.201506483. For references describing the develop-
ment of chiral cyclopentadienyl ligands, see references cited
within Ref. [2b] and [5].
[3] T. K. Hyster, L. Knçrr, T. R. Ward, T. Rovis, Science 2012, 338,
500 – 503.
[4] a) B. Ye, P. A. Donets, N. Cramer, Angew. Chem. Int. Ed. 2014,
53, 507 – 511; Angew. Chem. 2014, 126, 517 – 521; b) B. Ye, N.
Cramer, Angew. Chem. Int. Ed. 2014, 53, 7896 – 7899; Angew.
Chem. 2014, 126, 8030 – 8033; c) J. Zheng, S.-L. You, Angew.
Chem. Int. Ed. 2014, 53, 13244 – 13247; Angew. Chem. 2014, 126,
13460 – 13463; d) J. Zheng, S.-B. Wang, C. Zheng, S.-L. You, J.
Am. Chem. Soc. 2015, 137, 4880 – 4883; e) B. Ye, N. Cramer,
Synlett 2015, 1490 – 1495.
[5] For a review, see: B. Ye, N. Cramer, Acc. Chem. Res. 2015, 48,
1308 – 1318.
[6] For reviews of enantioselective C–H functionalization, see
Ref. [5] and: a) C. Zheng, S.-L. You, RSC Adv. 2014, 4, 6173 –
6214; b) J. Wencel-Delord, F. Colobert, Chem. Eur. J. 2013, 19,
14010 – 14017; c) L. Yang, H. Huang, Catal. Sci. Technol. 2012, 2,
1099 – 1112; d) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q.
Yu, Chem. Soc. Rev. 2009, 38, 3242 – 3272.
[7] a) S. Reddy Chidipudi, I. Khan, H. W. Lam, Angew. Chem. Int.
Ed. 2012, 51, 12115 – 12119; Angew. Chem. 2012, 124, 12281 –
12285; b) J. D. Dooley, S. Reddy Chidipudi, H. W. Lam, J. Am.
Chem. Soc. 2013, 135, 10829 – 10836.
[8] For examples of biologically active spiroindenes, see: T. A.
Blizzard, I. I. J. D. Morgan, R. T. Mosley, E. T. Birzin, K. Frisch,
S. P. Rohrer, M. L. Hammond, Bioorg. Med. Chem. Lett. 2003,
13, 479 – 483.
[9] For examples of biologically active indenes, see: a) Y. Ishiguro,
K. Okamoto, F. Ojima, Y. Sonoda, Chem. Lett. 1993, 1139 – 1140;
b) I. M. Karaguni, K. H. Glusenkamp, A. Langerak, C. Geisen,
V. Ullrich, G. Winde, T. Moroy, O. Müller, Bioorg. Med. Chem.
Lett. 2002, 12, 709 – 713; c) O. Müller, E. Gourzoulidou, M.
Carpintero, I. M. Karaguni, A. Langerak, C. Herrmann, T.
Moroy, L. Klein-Hitpass, H. Waldmann, Angew. Chem. Int. Ed.
2004, 43, 450 – 454; Angew. Chem. 2004, 116, 456 – 460; d) N. J.
Clegg, S. Paruthiyil, D. C. Leitman, T. S. Scanlan, J. Med. Chem.
2005, 48, 5989 – 6003.
Scheme 6. Proposed catalytic cycle and stereochemical model.
À
chiral complexes in other classes of C H functionalization/
oxidative annulation is underway, and these results will be
reported in due course.
[10] For other racemic examples of spiroindene formation by C–H
functionalization/oxidative annulation, see: a) J. Nan, Z. Zuo, L.
Luo, L. Bai, H. Zheng, Y. Yuan, J. Liu, X. Luan, Y. Wang, J. Am.
Chem. Soc. 2013, 135, 17306 – 17309; b) A. Seoane, N. Casanova,
N. QuiÇones, J. L. MascareÇas, M. Gulías, J. Am. Chem. Soc.
2014, 136, 7607 – 7610; c) S. Kujawa, D. Best, D. J. Burns, H. W.
Lam, Chem. Eur. J. 2014, 20, 8599 – 8602; d) M.-B. Zhou, R. Pi,
M. Hu, Y. Yang, R.-J. Song, Y. Xia, J.-H. Li, Angew. Chem. Int.
Ed. 2014, 53, 11338 – 11341; Angew. Chem. 2014, 126, 11520 –
11523; e) S. Gu, L. Luo, J. Liu, L. Bai, H. Zheng, Y. Wang, X.
Luan, Org. Lett. 2014, 16, 6132 – 6135; f) Z. Zuo, X. Yang, J. Liu,
J. Nan, L. Bai, Y. Wang, X. Luan, J. Org. Chem. 2015, 80, 3349 –
3356.
Acknowledgements
We thank the ERC (Starting Grant No. 258580), the EPSRC
(through grant number EP/L001500/2 and a Leadership
Fellowship to H.W.L.), and the University of Nottingham
for financial support. We thank Dr. William Lewis (University
of Nottingham) for X-ray crystallography.
Keywords: alkynes · catalysis · C–H activation ·
[11] a) D. J. Burns, H. W. Lam, Angew. Chem. Int. Ed. 2014, 53,
9931 – 9935; Angew. Chem. 2014, 126, 10089 – 10093; b) D. J.
Burns, D. Best, M. D. Wieczysty, H. W. Lam, Angew. Chem. Int.
Ed. 2015, 54, 9958 – 9962; Angew. Chem. 2015, 127, 10096 –
10100.
enantioselective · rhodium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13975–13979
Angew. Chem. 2015, 127, 14181–14185
[12] Dimethyl carbonate and toluene were also good solvents, but
DMF proved to be the most effective across a range of
substrates.
[1] For reviews of RhIII-catalyzed C–H functionalization, see: a) N.
Kuhl, N. Schrçder, F. Glorius, Adv. Synth. Catal. 2014, 356, 1443 –
13978 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13975 –13979

Angewandte
Chemie
[13] We assume Cu(OAc)2 oxidizes the precatalysts into the active
RhIII species.
S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks,
A. D. Curzons, Green Chem. 2011, 13, 854 – 862.
[14] The absolute configurations of the spiroindenes prepared in this
work were assigned by analogy to those of 4g – 4j, 4o, and 4r,
[16] Deuteration at the pyran-2,4-dione is likely to occur by
reversible dienolization after spiroindene formation.
which
were
determined
by
X-ray
crystallography.
[17] a) F. O. Rice, E. Teller, J. Chem. Phys. 1938, 6, 489 – 496; b) J.
Hine in Advances in Physical Organic Chemistry, Vol. 15 (Eds.:
V. Gold, D. Bethel), Academic Press, New York, 1978, pp. 1 – 61.
CCDC 1415390, 1415391, 1415392, 1415393, 1415394, and
1415395 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[15] a) P. Tundo, M. Selva, Acc. Chem. Res. 2002, 35, 706 – 716;
b) R. K. Henderson, C. Jimenez-Gonzalez, D. J. C. Constable,
Received: July 29, 2015
Published online: September 25, 2015
Angew. Chem. Int. Ed. 2015, 54, 13975 –13979
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13979