Z-Enolate Geometry in the Thioamide Aldol Reaction Illuminated by the 7-Azaindoline Auxiliary

Article abstract of DOI:10.1021/acs.orglett.9b04120

Z or E enolate geometry is the primary determinant of diastereoselectivity in the aldol reaction. Although amide and thioamide enolates are anticipated to have predominantly the E geometry because of the intrinsic steric demand, spectroscopic confirmation of the geometry in solution has remained elusive, particularly in the realm of highly stereoselective catalytic asymmetric aldol reactions. Herein we demonstrate that the 7-azaindoline auxiliary enables direct observation of the exclusive formation of the Z-enolate of the thioamide en route to a highly syn-selective aldol reaction.

Full text of DOI:10.1021/acs.orglett.9b04120

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Z-Enolate Geometry in the Thioamide Aldol Reaction Illuminated by
the 7‑Azaindoline Auxiliary
Roman Pluta, Zhao Li, Naoya Kumagai,* and Masakatsu Shibasaki*
Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: Z or E enolate geometry is the primary
determinant of diastereoselectivity in the aldol reaction.
Although amide and thioamide enolates are anticipated to
have predominantly the E geometry because of the intrinsic
steric demand, spectroscopic confirmation of the geometry in
solution has remained elusive, particularly in the realm of highly
stereoselective catalytic asymmetric aldol reactions. Herein we
demonstrate that the 7-azaindoline auxiliary enables direct observation of the exclusive formation of the Z-enolate of the
thioamide en route to a highly syn-selective aldol reaction.
he aldol reaction, which involves coupling of acceptor
carbonyls (often aldehydes) and donor carbonyls,
stereoselectivity.9 Although there has been substantial progress
in amide and thioamide aldol reactions from a synthetic
standpoint,10 the geometry of in situ-generated enolate species
under catalytic conditions is underexplored. Direct observation
of the amide enolate in solution by spectroscopic means
remains elusive,11 and determination of the enolate geometry
under specific conditions with a chiral catalyst is a formidable
task. Herein we report that combining thioamide chemistry
with the 7-azaindoline auxiliary provided explicit evidence of
the involvement of the Z-configured thioamide enolate in
delivering syn-aldols (Scheme 1b). The 7-azaindoline thio-
amide donor accommodates various α-substituents with
sufficient reactivity, thereby expanding the scope of the direct
catalytic asymmetric aldol reactions of weakly acidic donors.
In the direct catalytic asymmetric aldol reaction of N,N-
diallylthiopropionamide (1), a cooperative catalytic system
comprising a chiral Cu(I) complex and LiOAr was effective,
with the former activating the thiocarbonyl functionality as a
soft Lewis acid and the latter deprotonating the α-proton for
enolization (Scheme 2).7 Ph-BPE is a privileged ligand in this
specific reaction and uniquely competent to afford high
enantioselectivity. We reasoned that thiopropionamide 2a
bearing a 7-azaindoline unit could stabilize the enolate
intermediate by additional chelation to Cu(I) to dissect the
geometry of the enolate.12 7-Azaindolinyl thiopropionamide 2a
was obtained from the parent 7-azaindolinyl amide via a
standard protocol using Lawesson’s reagent.13 The initial trial
of the direct aldol reaction of 2a and hydrocinnamaldehyde
(3a) under standard catalytic conditions ([Cu(CH3CN)4]PF6/
(S,S)-Ph-BPE/LiOAr) confirmed that 2a shares similar
reactivity with 1, as the corresponding product 5a was
obtained with high stereoselectivity and an identical absolute
configuration.
T
provides ready access to synthetically versatile β-hydroxycar-
bonyl units.1−3 Significant advances in the last two decades
have rendered this particular reaction asymmetric, catalytic,
and direct.4,5 A direct aldol reaction, although difficult to
attain, enables the direct use of donor substrates without
reagent-driven preactivation processes, thus enhancing the
reaction efficiency. Our group has been working to develop
direct catalytic asymmetric aldol reactions using weakly acidic
carbonyl compounds as aldol donors. In 2011, we disclosed
thioamides as competent aldol donors incorporated in
cooperative catalytic systems6 to deliver syn-aldols with high
enantioselectivity (Scheme 1a).7,8 Our continuous efforts in
this field later led us to identify that the 7-azaindoline auxiliary
engages amides in the direct aldol reaction with high
Scheme 1. Prior Art of the Thioamide Aldol Reaction and
Confirmation of Z-Enolate Formation with the 7-
Azaindoline Auxiliary
Received: November 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04120
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
PF6/(S,S)-Ph-BPE mixture (Figure 1b,c). Indeed, the newly
appearing quartet at 5.05 ppm (Hf) is the signature of the
olefinic proton corresponding to the formation of the
copper(I) enolate. Only one species was detected from the
clear spectral pattern, and prominent NOE signals between the
olefinic proton (Hf) and the protons on the pyrroline unit (He)
confirmed the exclusive formation of the Z-configured
enolate.15 The 7-azaindoline auxiliary played a pivotal role in
stabilizing the enolate and preventing the rotation of the C−N
single bond, which rendered the enolate discernible by NMR
spectroscopy even at room temperature.16 The Z-enolate
generated from mesitylcopper reacted with aldehyde 3a at −60
°C to reproduce comparable stereoselectivity (syn/anti > 20/1,
86% ee) in the catalytic system comprising [Cu(CH3CN)4]-
PF6/(S,S)-Ph-BPE/LiOAr.15 This observation supports the
general involvement of the Z-enolate and a cyclic transition
state to deliver syn-aldols in Cu(I)-catalyzed thioamide aldol
reactions.17
Scheme 2. Prior Art of the Thioamide Aldol Reaction and
Confirmation of Z-Enolate Formation with the 7-
Azaindoline Auxiliary
7-Azaindolinyl thiopropionamide 2a displayed a syntheti-
cally useful substrate scope (Figure 2).18 Further optimization
Having confirmed 2a as a competent thioamide model with
chelation capability, we next probed its interaction with the
Cu(I)/(S,S)-Ph-BPE complex and the subsequent enolization
process by NMR spectroscopy (Figure 1). The addition of
Figure 1. 1H NMR spectra of 7-azaindolinyl thiopropionamide 2a and
Cu(I) complexes in THF-d8: (a) 2a only; (b) 1/1/1 2a/
[Cu(CH3CN)4]PF6/(S,S)-Ph-BPE = 1/1/1 mixture. (c) 1/1.1/1.1
2a/mesitylcopper/(S,S)-Ph-BPE mixture.
[Cu(CH3CN)4]PF6 and (S,S)-Ph-BPE to a THF-d8 solution of
2a induced significant changes in the chemical shift that
correspond to the conformational flipping of the 7-azaindoline
unit for chelation to the Cu(I) complex (Figure 1a,b). The
characteristic upfield shift of the α-protons (Hf) indicates the
lack of intramolecular hydrogen bonding with the pyridyl
nitrogen, which was confirmed by the NOE with the protons
on the pyrroline unit (He). Subsequent addition of Li(OC6H4-
p-OMe) to the thioamide 2a/Cu(I) complex barely changed
the 1H NMR spectrum, presumably because enolization/
reprotonation is in equilibrium and the enolate species is
significantly less populated. To address this issue, irreversible
enolization was attempted with mesitylcopper14 as a highly
basic Cu(I) source. In contrast to the case with Li(OC6H4-p-
OMe), the thioamide 2a/mesitylcopper/(S,S)-Ph-BPE mixture
gave a different spectral pattern from the 2a/[Cu(CH3CN)4]-
Figure 2. Substrate generality of the direct aldol reaction using 7-
azaindolinyl thioamide 2. Isolated yields are shown. aReaction at −78
°C.
revealed that a slight excess of the base PhOLi with respect to
the Cu(I) complex provided a better yield.15 α-Nonsubstituted
aldehydes, which are generally prone to undesired self-aldol
reactions, gave syn-aldols 5a−d without the formation of self-
aldol products. Aldehydes bearing Lewis acid-sensitive or base-
sensitive functionalities are applicable to the present catalysis,
and an alkynyl group was tolerated (5e−i). An aldehyde with a
B
DOI: 10.1021/acs.orglett.9b04120
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fully saturated thiopyran, a soft Lewis base that could
competitively coordinate to Cu(I) complex to disturb the
catalysis, was accommodated to give product 5j with high
enantioselectivity but a slightly lower yield and syn selectivity.
The advantage of 7-azaindolinyl thioamide 2a compared with
N,N-diallylthioamide 1 is the engagement of various α-
substituted donors in direct aldol reactions. Along with
nonfunctionalized thiopropionamide and thiobutyramide (5k
and 5l), thioamides with an ether, ester, or trifluoromethyl
group were tractable donor substrates to deliver syn-aldol
products (5m−o).19 The stereoselectivity was slightly eroded,
but this was somewhat addressed by lowering the reaction
temperature to −78 °C. The reaction with (−)-citronellal
afforded the products 5p and 5q with similar diastereose-
lectivity irrespective of the R/S sense of the catalyst, indicating
that the stereoselection was determined by the asymmetric
environment of the catalyst via high-fidelity formation of the Z-
enolate.20 It is worthy of note that simple treatment of aldol
product 5a with 2 N HCl in MeOH at 60 °C converted it to
the corresponding methyl ester 6 without epimerization
(Scheme 3). Desulfurization with H2O2 in the presence of
ZrCl4 was another option to give 7-azaindolinyl amide 7,21
which is amenable to diverse functional group transforma-
tions.12
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: nkumagai@bikaken.or.jp.
*E-mail: mshibasa@bikaken.or.jp.
ORCID
Naoya Kumagai: 0000-0003-1843-2592
Masakatsu Shibasaki: 0000-0001-8862-582X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by KAKENHI (17H03025
and 18H04276 in Precisely Designed Catalysts with Custom-
ized Scaffolding) from JSPS and MEXT. We are grateful to Dr.
Tomoyuki Kimura, Dr. Ryuichi Sawa, Ms. Yumiko Kubota, and
Dr. Kiyoko Iijima at the Institute of Microbial Chemistry for
technical support with NMR and X-ray crystallographic
analysis.
REFERENCES
■
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a
Scheme 3. Transformation of the Product
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a
Reagents and conditions: (a) 2 N HCl/MeOH, 60 °C, 8 h, 85%; (b)
ZrCl4, 30% H2O2, rt, 1 h, 82%.
In summary, we utilized the 7-azaindoline auxiliary to probe
the enolate geometry in a direct catalytic asymmetric aldol
reaction of thioamides. The 7-azaindoline unit played a key
role in detecting the copper(I) enolate even at room
temperature, revealing the exclusive formation of a Z-
configured enolate. Considering the generally high syn
diastereoselectivity, a cyclic transition state is likely operative
in the C−C bond-forming process with aldehydes. A range of
α-substituted 7-azaindolinyl thioamides proved to be tractable
latent enolates, expanding the scope of direct aldol chemistry.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04120.
Experimental procedures, spectroscopic data for new
compounds, crystallographic data for 2a and 5a′, and
NMR spectra (PDF)
Accession Codes
CCDC 1966091 and 1966092 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.9b04120
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(15) See the Supporting Information for details.
(16) NMR experiments using N,N-diallylthioamide 1 resulted in
complicated spectra.
(17) In view of the identical absolute configurations of aldol
products 4 and 5a, the chelated Z-enolate presumably dissociates
prior to the aldol addition step, thereby forming a cyclic transition
state with an incoming aldehyde.
(18) The absolute configuration was determined by X-ray crystallo-
graphic analysis after conversion of the product into the 3,5-
dichlorobenzoate ester. See the Supporting Information for details.
(19) The geometries of the enolates derived from thioamides 2e and
2f (for products 5n and 5o) were determined to be Z in the same
manner as in Figure 1. See the Supporting Information for details.
(20) The reaction using α-branched aldehydes was sluggish and
failed to give reasonable amount of aldol products.
(21) Khodaei, M.; Bahrami, K.; Tirandaz, Y. Synthesis 2009, 2009,
369.
D
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