Enantioselective Synthesis of Indolines, Benzodihydrothiophenes, and Indanes by C?H Insertion of Donor/Donor Carbenes

Article abstract of DOI:10.1002/anie.201809344

We employ a single catalyst/oxidant system to enable the asymmetric syntheses of indolines, benzodihydrothiophenes, and indanes by C?H insertion of donor/donor carbenes. This methodology enables the rapid construction of densely substituted five-membered rings that form the core of many drug targets and natural products. Furthermore, oxidation of hydrazones to the corresponding diazo compounds proceeds in situ, enabling a relatively facile one- or two-pot protocol in which isolation of potentially explosive diazo alkanes is avoided. Regioselectivity studies were performed to determine the impact of sterics and electronics in donor/donor metal carbene C?H insertions to form indolines. This methodology was applied to a variety of substrates in high yield, diastereomeric, and enantiomeric ratios and to the synthesis of a patented indane estrogen receptor agonist with anti-cancer activity.

Full text of DOI:10.1002/anie.201809344

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Enantioselective Synthesis of Indolines,
Benzodihydrothiophenes, and Indanes by C–H Insertion of
Donor/Donor Carbenes
Authors: Jared Thomas Shaw, Lucas W. Souza, Richard A. Squitieri,
Christine A. Dimirjian, Blanka M. Hodur, Leslie A. Nickerson,
Corinne N. Penrod, Jesús Cordova, and James C. Fettinger
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809344
Angew. Chem. 10.1002/ange.201809344
Link to VoR: http://dx.doi.org/10.1002/anie.201809344
http://dx.doi.org/10.1002/ange.201809344

10.1002/anie.201809344
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Synthesis of Indolines, Benzodihydrothiophenes,
and Indanes by C–H Insertion of Donor/Donor Carbenes
Lucas W. Souza,† Richard A. Squitieri,† Christine A. Dimirjian, Blanka M. Hodur, Leslie A. Nickerson,
Corinne N. Penrod, Jesus Cordova, James C. Fettinger, Jared T. Shaw*[a]
Abstract: We employ a single catalyst/oxidant system to enable the
asymmetric syntheses of indolines, benzodihydrothiophenes, and
indanes by C–H insertion of donor/donor carbenes. This methodology
enables the rapid construction of densely substituted five-membered
rings that form the core of many drug targets and natural products.
Furthermore, oxidation of hydrazones to the corresponding diazo
compounds proceeds in situ, enabling a relatively facile one- or two-
pot protocol in which isolation of potentially explosive diazo alkanes is
avoided. Regioselectivity studies were performed to determine the
impact of sterics and electronics in donor/donor metal carbene C–H
insertions to form indolines. This methodology was applied to a variety
of substrates in high yield, diastereomeric, and enantiomeric ratios
and to the synthesis of a patented indane estrogen receptor agonist
with anti-cancer activity.
Moreover, the requisite diazo precursor for the donor/donor
carbene can be produced in situ from the parent hydrazone.
Herein, we apply our methodology to the synthesis of three new
classes of products, i.e. indolines, benzodihydrothiophenes and
indanes.
Indolines represent a common core structure among natural
products and drug discovery candidates.[4] Although these
heterocycles can be prepared by a variety of strategies, formation
of the C2-C3 bond by C–H insertion offers the opportunity to
create two stereogenic centers.[5] Intramolecular C–H insertion
has been used previously for the synthesis of indolines, however
few examples of substrates containing basic nitrogen have been
shown to proceed with high levels of enantioselectivity.[6] We
documented the first enantioselective synthesis of an indoline
from a donor/donor carbene, albeit with modest enantioselectivity
on a substrate lacking a basic nitrogen atom.[3a] Recently, Zhu et.
al. reported the enantioselective synthesis of indolines from
donor/donor carbenes via a non-diazo approach.[5b]
The insertion of metal carbenes into otherwise unreactive C–H
bonds is a powerful method for the synthesis of complex
molecules. Chiral metal complexes, specifically rhodium
tetracarboxylates, can induce high levels of enantioselectivity for
both intra- and intermolecular reactions.[1] The asymmetric C–H
insertion reactions of metal carbenes flanked by electron
withdrawing groups have been well-documented since Teyssie’s
seminal publication in 1982.[2] Recently, our group has
demonstrated the utility of metal carbenes with two pendant
electron donating groups, or “donor/donor” metal carbenes, in the
A variety of indolines were synthesized with high levels of
diastereo- and enantioselectivity (Figure 2). Fused indolines
derived from cyclic anilines (2a-d) were formed in good to
excellent er, dr, and yield. C–H Insertion into primary centers is
known to be electronically unfavorable.[2, 7] However, indoline 2e
was produced in high yield and modest er. Changing from a
asymmetric synthesis of benzodihydrofurans (Figure 1).[3]
R2
R1
H2N
R2
N
N
R1
H2N
Rh2(R-PTAD)4 (1 mol%)
N
R2
2014
R2 Rh (R-PTAD)
O
2
(1 mol%)
4
N
O
Ph
MnO2, CH2Cl2,
0 °C to rt
R
MnO2
Ph
R
R= Ph
“donor/donor”
1a-g
2a-g
Ts
N
O
This work
N
N
N
H2N
R1
R1
R
Rh2(R-PTAD)4
(1 mol%)
N
X
X
O
H
Ph
2a, 70%
>95:5 dr; 96:4 er
Ph
Ph
2b, 66%
>95:5 dr; 99.5:0.5 er
O
O
Rh
Rh
R
N
MnO2
2c, 78%
93:7 dr; 99.5:0.5 er
O
R= Ph
R
indolines: X = NH or NR2
indanes: X = CH2
benzodihydrothiophenes: X = S
4
CH3
Rh2(R-PTAD)4
(R=1-adamantyl)
CH3
N
H3C
N
N
Figure 1. Additional cores accessible by C–H insertion reactions of donor/donor
metal carbenes.
Ph
Ph
Ph
2d, 97%
>95:5 dr; 99.5:0.5 er
2e, 99%
82:18 er
2f, 85%
>95:5 dr; 99.5:0.5 er
L. W. Souza,† Dr. R. A. Squitieri,† C. A. Dimirjian, B. M. Hodur, L. A.
Nickerson, C. N. Penrod, Prof. J. Cordova, Dr. J. C. Fettinger, Prof.
Jared T. Shaw*
X-ray crystal
structure of 2c
[a]
H
Ph
N
Chemistry Department
Ph
2g, 97%
>95:5 dr; 97:3 er
University of California, Davis
One Shields Ave, Davis, CA 95616
jtshaw@ucdavis.edu
[†]
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
Figure 2. Indolines synthesized by the C–H insertion reaction of donor/donor
metal carbenes.
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10.1002/anie.201809344
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Regioselectivity of indolines.
methyl to an ethyl substituent has a drastic effect on the
enantioselectivity of the reaction, as indoline 2f was produced as
primarily one enantiomer. This observation suggests that
increased steric bulk at the insertion center plays a role in the high
degree of stereoselectivity observed. An indoline derived from an
N-tosyl protected amine was also tolerated (2b) allowing for
further modification after deprotection. Additionally, indoline 2g
derived from a free amine was also synthesized in excellent er, dr
and yield. X-ray crystallography of 2c indicated that the relative
and absolute configurations of the product were consistent with
the sense of induction observed for the formation of
benzodihydrofurans.[3a, 8]
R
R
CH3
H2N
CH3
R
N
N
N
N
catalyst (1 mol%)
Ph
MnO2, CH2Cl2, 0 ºC
Ph
Ph
5a,b
6a,b
7a,b
Entry
R
catalyst
Rh2(OAc)4
6:7
1
2
3
4
5
6
Ph
7:93
[a]
Ph
Rh2(Mes)4
25:75
51:49
61:39
95:5
Ph
Rh2(R-PTAD)4
Rh2(OAc)4
Over the course of our synthesis of indolines, it became
apparent that unsymmetrical aniline substrates presented the
opportunity to insert into two chemically different C–H bonds. X-
ray crystal structures by Fürstner show that the π system of the
pendant phenyl group is in conjugation with the carbene center.[9]
Additionally, computational experiments in our previous work with
benzodihydrofurans have demonstrated that the electron
donation afforded by the phenyl ring reduces the electrophilicity
of the resultant metal carbene and stabilizes its formation.[3b]
These factors motivate a stepwise reaction mechanism unique to
our donor/donor system. In contrast, the mechanism of
donor/acceptor substituted carbenes is known to be concerted
asynchronous.[10] With this mechanistic framework in mind we set
out to test the effect of sterics and electronics on the
regiochemistry of C–H insertion reactions to form indolines. The
insertion begins with a hydride transfer followed by rapid collapse
of the resultant zwitterionic intermediate II.[3b] As such, insertion
is favored by substituents that stabilize cations at the insertion
carbon (Scheme 1). However, steric demand near the insertion
carbon can be unfavorable, especially with crowded chiral
catalysts.
i-Pr
i-Pr
i-Pr
[a]
Rh2(Mes)4
Rh2(R-PTAD)4
82:18
[a] Rh2(Mes)4 = Rh2(2, 4, 6-trimethylbenzoate)4
carbenes with acceptor-substituted diazo compounds.[13] The
authors of this study hypothesize that the lack of development of
this methodology is due to a propensity of the highly nucleophilic
sulfur atom to attack the carbene directly to form an ylide.[14] Due
to the reduced electrophilicity of our donor/donor carbenes we are
able to synthesize a variety of benzodihydrothiophenes with
excellent stereocontrol and high yields.
Similarly to benzodihydrofurans,[3b] 4a, b were synthesized
with excellent stereoselectivity and yield (Figure 3). Hydrazone 3c
was selectively oxidized to the diazo compound with MnO2 in the
presence of a benzylic alcohol. Furthermore, the corresponding
diazo-alcohol was tolerated well under our reaction conditions,
creating a useful chemical handle for further modification without
the use of a protecting group (4c). Sterically crowded insertion
centers were also tolerated allowing access to novel alkyl and
spirocyclic compounds 4d-f. In contrast, poor selectivity was
observed with 4g. This result supports our hypothesis that the
degree of stereoselectivity observed corresponds to the presence
of steric bulk near the insertion center as shown with indolines.
Interestingly, with sufficient activation from the neighboring acetal,
six-membered ring formation (4h) was achieved in high yield and
er.
[Rh]
[Rh]
H
H
H
H
H
O
O
R
O
R
R
III
I
II
zwitterionic intermediate
Scheme 1. Mechanism of benzodihydrofuran insertion.
To study the effects of sterics and electronics on the
regioselectivity of this chemistry, we synthesized two
unsymmetrical hydrazones (5a, b) with both sterically and
electronically favorable insertion sites (Table 1). In the presence
of Rh2(OAc)4, insertion at the benzylic carbon is favorable, to form
7a (entry 1). Treatment with Rh2(Mes)4 and Rh2(R-PTAD)4, shows
a decrease in selectivity for the electronically favorable center as
the bulk of the catalyst increases (entries 2, 3). When methyl is
contrasted with isopropyl (5b), selectivity for the less substituted
carbon is modest (entry 4) and use of the Rh2(Mes)4 catalyst
heavily favors methyl insertion (entry 5). Finally, the reaction of 5b
with Rh2(R-PTAD)4 also favors methyl insertion to a lesser extent
(entry 6). The results indicate that both steric and electronic
factors compete for the most favorable insertion pathway.
R
H2N
Ph
R
S
N
S
Rh2(R-PTAD)4 (1 mol%)
MnO2, CH2Cl2, 0 °C to rt
Ph
3a-h
4a-h
H3C
CH3
OH
S
R
S
S
S
Ph
Ph
Ph
4d, 84%
89:11 er
Ph
4a, R=Ph; 97%
>95:5 dr; 97:3 er
4b, R=PMP; 77%
4c, 85%
>95:5 dr; 97:3 er
4e, 69%
>95:5 dr; >99:1 er
>95:5 dr; 97:3 er
Ph
S
S
S
O
O
Benzodihydrothiophenes form an interesting class of
heterocycles for which there are currently few stereoselective
synthetic methods.[11] Growing interest in sulfur-containing
heterocycles as anti-tumor agents emphasizes the need for new
method development in this area.[12] To date, there is only a single
report of a benzodihydrothiophene synthesis employing rhodium
Ph
Ph
Ph
4f, 95%
99:1 er
4g, 77%
80:20 dr; 75:25 er
4h, 97%
97:3 er
Figure 3. Insertion reactions for the synthesis of benzodihydrothiophenes.
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10.1002/anie.201809344
Angewandte Chemie International Edition
COMMUNICATION
Indanes are rigid carbacycles that feature prominently in both
natural products and in drug discovery. Unlike their heterocyclic
counterparts, the electron-neutral benzene and benzylic carbon
are less easily oxidized by enzymes responsible for drug
clearance.[15] Enantioselective synthesis of indanes has been
achieved primarily by asymmetric reduction of indenes.[16]
Hashimoto and Lei have reported the enantioselective synthesis
of indanes by C–H insertion of donor/acceptor carbenes.[17] In our
seminal publication, we demonstrated that the formation of
indanes by C–H insertion of donor/donor metal carbenes was
with the cis diastereomer observed both in this and in our previous
work.[3a] We envisioned 9f as the direct synthetic precursor to a
class of indanes patented as an estrogen receptor agonist for the
treatment of breast, prostate and ovarian cancers.[18] Treatment
of substrate 9f under modified Ullman coupling conditions allowed
us to access the first enantioselective synthesis of drug lead
11a[19] in 34% overall yield (Figure 4B).
In conclusion, we have expanded the C–H insertion
methodology of donor/donor metal carbenes to the
enantioselective synthesis of
a
variety of indolines,
possible in good yield and with
a
modest degree of
benzodihydrothiophenes, and indanes. Preliminary results
suggest the regiochemistry of C–H insertions to form indolines is
influenced by competition between electronics that favor
carbocation stability and the steric demands of catalyst and
substrate. Our methodology allows for the facile synthesis of
complex and difficult-to-access benzodihydrothiophenes.
Furthermore, insertion into deactivated C–H bonds was
stereoselectivity.[3a] In this work, we expand the scope of this
chemistry to include a variety of indanes in excellent yield and
selectivity.
Aliphatic spirocyclic five- and six-membered rings were
particularly effective (Figure 4A, 9a, c). Heteroatoms were also
tolerated to generate the corresponding spirocycles 9d, e
accomplished, yielding
a variety of indanes. Finally, we
including
a Boc-protected amine as a
chemical handle.[8]
demonstrated the utility of this chemistry by carrying out the first
highly enantioselective synthesis of patented drug lead 11a in
good overall yield.[19]
Disubstitution at the inserting carbon creates a high level of steric
crowding, yet stabilizes carbocation formation at the insertion
center more readily. As such, these substrates react to form
quaternary carbons in high yield and with high levels of
stereoselectivity (9b). The absolute configuration of the new
stereogenic center was shown to be S upon treatment with Rh2(R-
PTAD)4, in agreement with the sense of induction for both
benzodihydrofurans and indolines.
Experimental Section
Experimental procedures and compound characterization can be
found in the Supporting Information (PDF). 1H and 13C NMR
spectra for all new compounds and HPLC traces for all
enantiomerically enriched insertion products (PDF). X-ray data for
compound 2c (CIF) and 9d (CIF).
Substitution of the carbene pendant groups with halogens
was also tolerated with excellent selectivity (9f, g). Furthermore,
J-values of the relevant protons of these products were consistent
A)
H2N
N
R1
R1
Acknowledgements
Rh2(R-PTAD)4 (1 mol%)
Ph
MnO2, CH2Cl2 or CH3CN
Ph
0
°C to rt
Research reported in this publication was supported by the
National Institute Of General Medical Sciences of the National
Institutes of Health under Award Number R01GM124234. The
content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
Institutes of Health. We thank Austin Kelly (Franz group, UC
Davis) for providing assistance with HPLC traces and Dr. William
Long (Agilent Technologies) for obtaining a chiral HPLC trace for
compound 4h. We also thank Zefan Hurley and Lee Dunlap
(Olson group, UC Davis) for use of their IR. C.N.P. thanks UC
Davis for providing a Provost’s Undergraduate Fellowship (PUF).
We thank the National Science Foundation (Grant CHE-1531193)
for the Dual source X-ray diffractometer.
8a-g
9a-9g
H3C
H3C
Ph
9b, 89%
92:8 er
Ph
Ph
9a, 89%
99:1 er
9c, 86%
93:7 er
Boc
N
O
Ph
9d, 91%
96:4 er
Ph
9e, 89%
94:6 er
Ph
X-ray crystal
structure of 9d
Keywords: asymmetric synthesis • C–H insertion •
OCH3
diastereoselectivity • enantioselectivity • rhodium carbenes
X
Rh2(S-PTAD)4
9f X= Br; 65%
>95:5 dr; 97:3 er
9g X= F; 87%
96:4 dr; 93:7 er
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COMMUNICATION
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10.1002/anie.201809344
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
H2N
Lucas W. Souza,† Richard A. Squitieri,† Christine A. Dimirjian, Blanka
M. Hodur, Leslie A. Nickerson, Corinne N. Penrod, Jesus Cordova,
James C. Fettinger, Jared T. Shaw*[a]
R1
Rh2(PTAD)4
(1 mol%)
R1
R
X
N
X
R
MnO2
22 examples!
up to: 99% yield
>95:5 dr
X = NH or NR2
X = CH2
† These authors contributed equally.
base/nucleophile
reduced reactivity
Lewis base
X = S
99.5:05 er
Page No. – Page No.
Enantioselective Synthesis of Indolines, Benzodihydrothiophenes,
and Indanes by C–H Insertion of Donor/Donor Carbenes
The Carbene Abides. Rhodium carbenes derived from substrates with no electron withdrawing groups enable the highly selective
syntheses of indolines, benzodihydrothiophenes, and indanes in the presence of many previously incompatible functional groups,
including strong bases/nucleophiles and free NH and OH groups. A single catalyst/oxidant system is employed for all substrates and
in most cases C–H insertion proceeds as a one-pot process from the hydrazone. In the case of indoline formation, regioselectivity
reflects a balance of both steric and electronic preferences. The reactions reported here represent the broadest level of functional
group tolerance yet demonstrated for enantioselective C–H insertion.
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