Enantioselective Iridium-Catalyzed Allylic Cyclizations

Article abstract of DOI:10.1021/acs.orglett.7b01346

A method for the enantioselective synthesis of carbo- and heterocyclic ring systems enabled through the combination of Lewis acid activation and iridium-catalyzed allylic substitution is described. The reaction proceeds with branched, allylic alcohols and carbon nucleophiles as well as heteronucleophiles to give a diverse set of ring systems in good yields and with high enantioselectivities. The utility of the method is highlighted by the asymmetric syntheses of erythrococcamides A and B.

Full text of DOI:10.1021/acs.orglett.7b01346

Letter
pubs.acs.org/OrgLett
Enantioselective Iridium-Catalyzed Allylic Cyclizations
Michael A. Schafroth, Stephan M. Rummelt, David Sarlah,† and Erick M. Carreira*
ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland
̈
̈
S
* Supporting Information
ABSTRACT: A method for the enantioselective synthesis of carbo- and heterocyclic ring systems enabled through the
combination of Lewis acid activation and iridium-catalyzed allylic substitution is described. The reaction proceeds with branched,
allylic alcohols and carbon nucleophiles as well as heteronucleophiles to give a diverse set of ring systems in good yields and with
high enantioselectivities. The utility of the method is highlighted by the asymmetric syntheses of erythrococcamides A and B.
Scheme 1. Enantioselective Iridium-Catalyzed Allylic
Cyclizations
etero- and carbocycles are ubiquitous in natural isolates
1
Hand in synthetic drugs with diverse modes of action. The
development and improvement of cross-coupling chemistry has
widened the availability of aromatic building blocks, which
ultimately led to an increased aromatic ring count in small
molecule drugs.2,3 However, recent data indicate that there is a
limit to the aromatic ring count beyond which it becomes
detrimental for the development of drug candidates.4 As a way
around such limitations, saturated rings can impart beneficial
effects in terms of pharmacokinetics, solubility, or bioavail-
ability.5 Hence, the discovery of simple catalytic methods that
rapidly provide sets of structurally diverse saturated (hetero)-
cyclic motifs is desirable. Herein, we report a general and direct
Ir-catalyzed, enantioselective, allylic cyclization of unactivated,
branched allylic alcohols with oxygen- and nitrogen-based
heteronucleophiles, as well as electron-rich aromatic substrates
(Scheme 1a and b).6 The practicality of the approach is
demonstrated with the enantioselective syntheses of eryth-
rococcamides A and B (Scheme 1c).
Significant research efforts have focused on the development
of enantioselective, catalytic methods for the preparation of N-
heterocycles (e.g., pyrrolidines, piperidines, piperazines,
tetrahydroquinolines), O-heterocycles (e.g., oxanes, dioxanes),
and carbocycles (tetrahydrocarbazole, tetrahydrobenzpyrane).7
Among them, the application of iridium-catalyzed, enantiose-
lective, allylic cyclization has recently attracted attention.
Helmchen has reported intramolecular Ir-catalyzed allylic
aminations using phosphoramidite ligands in combination
with bases to promote the formation of 5- to 7-membered
rings.8 An intramolecular allylic amidation reaction for the
synthesis of tetrahydroisoquinolines as well as 5- and 6-
membered rings was developed by Feringa and co-workers.9
Additionally, the You group recently disclosed several
approaches for intramolecular allylic substitution reactions
with amines and carbon nucleophiles (indoles, pyrroles, and
phenols).10
It is important to note, however, that common to these
protocols are different requirements in the reaction conditions
(solvents, promoters, ligands, or metal precursors) for
incorporation of various (hetero)nucleophiles and preparation
of different ring sizes. Furthermore, the use of a stoichiometric
amount of base and activation of the allylic alcohol as a
carbonate or acetate are often required. The incorporation of
activating groups leads to longer, less straightforward substrate
syntheses and to sequences that are suboptimal vis a vis atom
economy.
We have previously reported the direct substitution of
branched allylic alcohols with a variety of nucleophiles.11 In
Received: May 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01346
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Organic Letters
Letter
light of our report on Ir-catalyzed, zinc triflate promoted
polyene cyclizations we were interested in expanding this
approach to access a broader range of chiral, cyclic building
blocks.12 To evaluate the potential of the [Ir]/Zn(OTf)2
system to promote allylic cyclizations with various nucleophiles,
we subjected allylic alcohol substrate 1a to the reaction
conditions shown in Scheme 2, and we were pleased to observe
cyclization at the position para to the methoxy substituent.
This stands in contrast to our previous observations in a
polyene cyclization reaction where both regioisomers were
isolated (2:1 para/ortho selectivity). It also highlights a
difference to the method by You and co-workers where
product mixtures in favor of ortho functionalization were usually
observed (1:4 to 1:6 para/ortho selectivity).10d The formation
of five-membered rings employing this method was successful,
furnishing the fused rings with >99% ee (2d). Substrates
incorporating hetarenes smoothly underwent cyclization, as
showcased with the examples of indoles (2e−2f) and pyrrole
(2g). Next, we turned our attention to substrates that
incorporate heteroatom tethers, leading to saturated hetero-
cyclic products. Substrates derived from phenols (2h−2i) and
anilines (2j) provided the corresponding dihydrobenzopyran
and tetrahydroquinoline products, respectively. In a similar
manner, tetrahydroisoquinoline (2k) and furanopiperidine 2l
were obtained in good yields with excellent enantioselectivities.
For substrates 2h−2k no cyclization at the ortho position was
observed, and, consequently, the products were isolated as
single isomers.14 We suggest steric interactions between the
substituent on the aromatic ring of the substrate and the ligand
on the active iridium species as a possible explanation for this
exclusive para selectivity (Figure 1). This hypothesis is
Scheme 2. Initial Results
the formation of cyclization product 2a in 79% yield with
excellent enantioselectivity (>99% ee, Scheme 2). Phenol
substrate 3a bearing a nucleophilic alcohol readily cyclized
under identical conditions to give the corresponding
dihydrobenzopyran derivative 4a in 66% yield and >98% ee
(Scheme 2).13
With these promising results in hand, the generality and
scope of the reaction was examined. The initial focus was on
the use of sp2-carbon nucleophiles to generate fused ring
systems (Scheme 3). The reaction proceeded well with
electron-rich alkoxy-substituted substrates to give products
2a−2c in good yields and >99% ee (Scheme 3, entries 2a−2c).
Interestingly, the use of arenes 2b−2c led to exclusive
a b c
, ,
Scheme 3. Reaction Scope with Carbon Nucleophiles
Figure 1. Transition state models leading to the ortho or para
substituted products, respectively.
supported by a model based on our recent mechanistic studies
involving X-ray characterization of a catalytically active Ir(III)
species, which highlights steric repulsion between the azepine
moiety of the non-chelating ligand with the ortho substituent.15
Such repulsive interactions would be minimized for the
intermediate/transition state leading to the para substituted
product.
Next, we sought to examine the scope of oxygen and
nitrogen nucleophiles. The optimal conditions for the
production of 4a allowed a lower Ir-catalyst loading (2 mol
% [Ir(cod)Cl]2, 8 mol % (S)-L, 20 mol % Zn(OTf)2) while
affording higher yields of the cyclization product (79% yield,
98% ee, Scheme 4, entry 4a). In a similar manner, 5-membered
dihydrobenzofuran derivative 4b was obtained in 88% yield and
96.5% ee. The use of aliphatic alcohols as substrates for
cyclization was evaluated next. Under standard conditions, 6-
membered tetrahydropyran and dioxane derivatives were
obtained in good yield and with good enantioselectivities
(4c−4d). 1,6- and 1,7-Diol substrates readily cyclized to give
the corresponding 7- and 8-membered, medium-sized rings.
The set of products includes derivatives of oxepane (entry 4e),
a
Unless noted otherwise all reactions were conducted on 0.25 mmol
scale under standard conditions (4 mol % [Ir], 16 mol % (S)-L, 10 mol
% Zn(OTf)2 at 25 °C for 24 h). Yields of isolated products. % ee
determined by SFC on a chiral stationary phase. Conducted with 20
b
c
d
e
mol % Zn(OTf)2. Conducted at 50 °C.
B
DOI: 10.1021/acs.orglett.7b01346
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Organic Letters
Letter
Scheme 4. Reaction Scope with Heteroatom
Nucleophiles
Scheme 5. Total Syntheses of Erythrococcamides A and B
a b c
, ,
a
b
Standard conditions for [Ir]/Zn(OTf)2, 80%, 98.5% ee. 2.0 equiv of
9-BBN, THF, 60 °C, 16 h; then 10.0 equiv of NaBO3·4H2O, 0 to 25
c
°C, 24 h, 93%. 20 mol % TEMPO, 1.2 equiv of PhI(OAc)2, CH2Cl2,
d
25 °C, 2 h, 85%. Pinnick oxidation: 12.0 equiv of 2-methyl-2-butene,
5.0 equiv of NaClO2, H2O, 0 to 25 °C, 3 h; then subsequent amide
coupling, 4.0 equiv of 2-methylpropan-1-amine, 2.0 equiv of HATU,
e
DMF, 0 to 25 °C, 16 h, 87% over 2 steps. 2.0 equiv of (E)-methyl 4-
(triphenylphosphoranylidene)but-2-enoate, CH2Cl2, 25 °C, 2.5 h, then
f
1 mol % I2, benzene, reflux, 5 h, 65%, E/Z = 9:1. 3.0 equiv of LiOH,
THF/MeOH, 25 °C, 16 h, then 4.0 equiv of 2-methylpropan-1-amine,
2.0 equiv of HATU, DMF, 0 to 25 °C, 16 h, 92% yield over 2 steps.
with a stabilized ylidene resulted in an intermediate ester (1:1
mixture of diastereomers), which, following treatment with
iodine, furnished a 9:1 (E)/(Z)-mixture. Saponification of the
ester followed by amide bond formation with isobutylamine
afforded ent-erythrococcamide A (9) in 92% yield over 2 steps.
In conclusion, we have developed a uniform method for the
enantioselective, intramolecular allylic substitution reaction
with aliphatic alcohols, sulphonamides, and electron-rich arenes
as nucleophiles. The method enables the preparation of a
unique set of heterocyclic ring systems via user-friendly and
scalable conditions. The utility and generality of the method
was showcased through the syntheses of erythrococcamides A
and B.
a
Unless noted otherwise all reactions were conducted on 0.25 mmol
scale under standard conditions (4 mol % [Ir], 16 mol % (S)-L, 20 mol
% Zn(OTf)2 at 25 °C for 36 h). Yields of isolated products. % ee
determined by SFC on a chiral stationary phase. Conducted with 2
mol % [{Ir(cod)Cl}]2, 8 mol % (S)-L. Conducted at 50 °C. Due to
high volatility isolated as the corresponding benzoate, after hydro-
boration; see Supporting Information for further information. At 50
°C isolated in 84% yield with 90% ee. At 50 °C isolated in 92% yield
b
c
d
e
f
g
h
with 65% ee.
oxazepane (entries 4f−4g), and oxazocane (entry 4h). It is
important to note that formation of product resulting from the
alternative intermolecular pathway was only observed in one
instance (entry 4h). Conducting the reaction at higher dilution
did not improve the yield of the desired product. Nitrogen
based nucleophiles in the intramolecular allylic substitution
reaction were subsequently examined. The corresponding 1,4-,
1,5-, and 1,6-sulfonamide−alcohol substrates readily cyclized to
give enantioenriched pyrrolidine (entry 4i), piperidine (entry
4j), piperazine (entry 4k), and diazepane derivatives (entry 4l).
However, the yields for 4i and 4k were improved when the
reaction was performed at elevated temperature (50 °C), albeit
with reduction of enantioselectivities.
To highlight the synthetic utility of the [Ir]/Zn(OTf)2
cyclization method beyond the generation of simple building
blocks, enantioselective syntheses of erythrococcamides A and
B were conducted (Scheme 5). These isobutylamides were
isolated from Dinosperma erythrococca, and to date, only a single
enantioselective synthesis of erythrococcamide B has been
reported.16,17 Starting from sesamol, the cyclization substrate 5
was prepared in 3 steps, which when subjected to [Ir]/
Zn(OTf)2 afforded cyclization product 6 in 80% yield and
>98% ee (reaction was performed on >7.5 mmol scale). The
side chain was installed by hydroboration, followed by oxidative
workup and subsequent TEMPO oxidation of the alcohol to
the corresponding aldehyde 7 (79% yield over 2 steps). Pinnick
oxidation of aldehyde 7 and direct amide bond formation of the
crude carboxylic acid with isobutylamine afforded ent-
erythrococcamide B (8) in 87% yield over 2 steps. In the
synthesis of erythrococcamide A, Wittig reaction of aldehyde 7
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01346.
Detailed experimental procedures, and characterization
data and copies of 1H, 13C NMR spectra and SFC traces
of the products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: erickm.carreira@org.chem.ethz.ch.
ORCID
Michael A. Schafroth: 0000-0002-5864-6766
David Sarlah: 0000-0002-8736-8953
Erick M. Carreira: 0000-0003-1472-490X
Present Address
†Roger Adams Laboratory, Department of Chemistry, Uni-
versity of Illinois, Urbana, Illinois 61801, USA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to ETH Zurich and the Swiss National Science
Foundation (200020_152898) for financial support.
■
C
DOI: 10.1021/acs.orglett.7b01346
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
detectable byproduct is a linear ethyl ketone, resulting from
isomerization of the corresponding allylic alcohol that was observed
in some cases.
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D
DOI: 10.1021/acs.orglett.7b01346
Org. Lett. XXXX, XXX, XXX−XXX