Catalytic Intramolecular Conjugate Additions of Aldehyde-Derived Enamines to α,β-Unsaturated Esters

Article abstract of DOI:10.1021/acs.orglett.0c01666

We report a pairing of known catalysts that enables intramolecular conjugate additions of aldehyde-derived enamines to α,β-unsaturated esters. Despite extensive prior exploration of conjugate additions of aldehyde-derived enamines, catalytic conjugate additions to unactivated enoate esters are unprecedented. Achieving enantioselective and diastereoselective six-membered ring formation requires the coordinated action of a chiral pyrrolidine, for nucleophilic activation of the aldehyde via enamine formation, and a hydrogen bond donor, for electrophilic activation of the enoate ester. Proper selection of the hydrogen bond donor is essential for chemoselectivity, which requires minimizing competition from homoaldol reaction. Utility is demonstrated in a six-step synthesis of (-)-yohimbane from cycloheptene.

Full text of DOI:10.1021/acs.orglett.0c01666

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Letter
Catalytic Intramolecular Conjugate Additions of Aldehyde-Derived
Enamines to α,β-Unsaturated Esters
Zebediah C. Girvin, Philip P. Lampkin, Xinyu Liu, and Samuel H. Gellman*
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ABSTRACT: We report a pairing of known catalysts that enables
intramolecular conjugate additions of aldehyde-derived enamines
to α,β-unsaturated esters. Despite extensive prior exploration of
conjugate additions of aldehyde-derived enamines, catalytic
conjugate additions to unactivated enoate esters are unprecedented.
Achieving enantioselective and diastereoselective six-membered
ring formation requires the coordinated action of a chiral
pyrrolidine, for nucleophilic activation of the aldehyde via enamine formation, and a hydrogen bond donor, for electrophilic
activation of the enoate ester. Proper selection of the hydrogen bond donor is essential for chemoselectivity, which requires
minimizing competition from homoaldol reaction. Utility is demonstrated in a six-step synthesis of (−)-yohimbane from
cycloheptene.
iscrimination among competing reaction pathways to
favor desired transformations is a central challenge in
D
preparative organic chemistry. Enzymes often exert strict
regulation of chemical reactivity because of the highly
controlled environment provided to substrates by active sites.
Discovering strategies to select among competing reaction
pathways via small-molecule catalysts, which cannot envelop
substrates, is a driving force for development of new synthetic
methods.1−7
Prior examples of aldehyde-derived enamines reacting with
unactivated α,β-unsaturated esters have involved preformed
enamines generated with excess achiral amine.8 Catalytic
addition of aldehydes to unactivated α,β-unsaturated esters, via
transient enamine formation, was apparently unknown when
we began this work.9 This reactivity lacuna is surprising
because conjugate additions have been explored for over 130
years.10 Many examples of catalytic conjugate additions of
enamine-based nucleophiles to electron-deficient alkenes are
known (Figure 1A).11 The absence of catalytic aldehyde
enamine conjugate additions to conventional enoate esters
likely stems from the low electrophilicity of these enoate esters,
as established by Mayr et al.,12,13 along with the high
electrophilicity of aldehydes, which leads to preference for
homoaldol products.14 The synthetic value of this unknown
transformation arises from the potential utility of the
products.9,15−18
Figure 1. (a) Conjugate addition of aldehyde-derived enamines to
electron-deficient olefins is widely practiced but limited by electro-
philic reactivity (scale on right adapted from ref 18). (b) For the
desired cyclization, conjugate addition to a weak electrophile (α,β-
unsaturated ester) must be favored over the competing homoaldol
pathway reaction, which is achieved with a specific cocatalyst pairing.
A few examples of intramolecular conjugate additions of
ketone-derived enamines to an enoate ester have been
reported. These reactions rely upon use of stoichiometric
amine and extended reaction times,19 or on a carefully chosen
bifunctional catalyst.16,17,20 The diminished electrophilicity of a
ketone relative to an aldehyde curtails formation of homoaldol
byproducts in these cases.13,14 Therefore, achieving chemo-
Received: May 15, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01666
© XXXX American Chemical Society
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selective conjugate addition of a ketone-derived enamine to an
enoate ester does not involve the challenges inherent in
comparable aldehyde reactions.
We report the identification of an amine−urea catalyst pair
that enables efficient and stereoselective six-membered ring
formation via intramolecular conjugate addition of an
aldehyde-derived enamine to an α,β-unsaturated ester. Many
reaction conditions we examined led to substantial homoaldol
product or no reaction at all. Proper choice of the two
catalysts, however, enabled useful control over chemo-,
diastereo-, and enantioselectivity. The reactivity demonstrated
here fills a long-standing void in conjugate additions, extending
this reaction mode to the poorest electrophile yet employed
with an aldehyde-derived enamine nucleophile.
Our initial studies focused on the cyclization of aldehyde-
enoate substrate 1, which allowed us to evaluate secondary
amines for the ability to catalyze the desired cyclization via
transient enamine formation.21 Pyrrolidine cleanly provided
racemic 3, but only a trace of 3 was detected with the widely
used Hayashi-Jørgensen catalyst, 2 (Figure S1).22,23 Com-
pound 2 and related 2-substituted pyrrolidines have enabled a
wide range of enantioselective conjugate additions of aldehydes
to electrophiles more reactive than enoate esters.24,25 However,
the increased steric hindrance arising from the bulky
substituent adjacent to nitrogen, relative to pyrrolidine itself,
apparently inhibits reaction with an enoate ester, a weak
electrophile.12,13
Figure 2. Effect of acidic/hydrogen bond donor additives on reaction
pathway. Reactions run on 0.05 mmol scale. Percent conversion of 1
(conv.), d.r. (diastereomeric ratio) of 3, and percent of crude product
that corresponds to the homoaldol product (4), as determined by 1H
NMR analysis. Percent enantiomeric excess (ee) determined by chiral
HPLC. For calculation of percent conversion, see the Supporting
Information.
We hypothesized that the desired conjugate addition would
require electrophilic activation of the enoate ester in
conjunction with enamine-based (nucleophilic) activation of
the aldehyde. Brønsted acid and hydrogen bond donor
additives have been employed to enhance carbonyl electro-
philicity,26,27 but use of such of such catalysts in our case could
create a chemoselectivity problem. The ideal catalyst should
activate the ester in preference to the aldehyde to favor
cyclization over the intermolecular homoaldol pathway.
Yamamoto et al. were able to activate aldehydes relative to
ketones with exotic Lewis acids,28 but we are not aware that
Brønsted acids or hydrogen bond donors have demonstrated
this type of chemoselectivity. We surveyed candidate
cocatalysts under a consistent set of conditions (Figure 2).
Brønsted acids were not effective as cocatalysts. The
strongest acids we examined, trifluoroacetic acid (5), squaric
acid (6), and BINOL phosphoric acid (7), gave low
conversions and mostly homoaldol product. Weaker acids,
benzoic acid (8) and propionic acid (9), gave high conversions
but again mostly the undesired homoaldol product. Among
simple phenolic compounds, which may be considered as
hydrogen bond donors rather than Brønsted acids under these
conditions, better outcomes were observed. Thus, p-nitro-
phenol (10), catechol (11) and ethyl protocatechuate (12)
supported formation of cyclized product 3 with high diastereo-
and enantioselectivity, but in each case, a substantial fraction of
the starting material was directed along the undesired
homoaldol pathway. BINOL (13) and TADDOL (14) were
poor cocatalysts, each providing relatively low yields of 3, with
little diastereoselectivity and significant homoaldol byproduct.
Placing our observations in the context of related reports
highlights the chemoselectivity challenge inherent in cyclizing
aldehyde-enoate ester 1. Dixon et al. reported enantioselective
formation of a six-membered ring via addition of a ketone-
derived enamine to an enoate ester with benzoic acid as a
cocatalyst.17 Scheidt et al. used catechol as a cocatalyst for six-
membered ring formation in a comparable process.16 Chemo-
selectivity was not a major concern in these systems because
homoaldol reactions of ketones are generally unfavorable.
Ethyl protocatechuate was an effective cocatalyst for
intermolecular conjugate additions of aldehydes to enones,29
which are more electrophilic than enoate esters.12,13 4-
Nitrophenol has been used for conjugate additions of
enamines derived from 2 to nitro-alkenes,11i which are strong
electrophiles.12,13
We identified three hydrogen bond donor cocatalysts that, in
combination with chiral amine 2, displayed favorable chemo-,
enantio-, and diastereoselectivity profiles. Chiral 1,2-bistri-
flamide (15) provided high conversion to 3 with excellent
enantio- and diastereoselectivity. Only a modest amount of
homoaldol product (8%) was formed. Compound 15 was
reported to catalyze aza-conjugate additions to enoate esters,30
which suggests that the 1,2-bistriflamide unit may be generally
effective for electrophilic activation of this substrate class.
Schreiner’s thiourea (16)31 and the corresponding urea (17)
both resulted in total conversion of 1, with near-complete
selectivity for the cyclization product (98%).
The electron-deficient aromatic rings in thiourea 16 are
critical because replacing one with an alkyl group (18) or
replacing both with phenyl rings (19) led to much poorer
outcomes relative to 16 as cocatalyst. Urea 17 and thiourea 19
are expected to have very similar pKa values,32 but they
perform very differently as cocatalysts for cyclization of 1. In
contrast, thiourea 16 is considerably more acidic than urea 17,
but they perform similarly as cocatalysts. Thus, pKa is not a
principal determinant of enoate ester activation in this
reaction. These results suggest that the factors determining
the efficacy of catalysis via hydrogen bond donation are
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complex and deserve further attention. The substantial
variation in proportion of homoaldol versus intramolecular
conjugate addition products observed across the cocatalysts we
surveyed raises the possibility that site-selective carbonyl
activation might offer a strategy for late-stage functionalization
of complex substrates.33
We examined a few variants of pyrrolidine 2 (Figure S1).
Replacing the trimethylsilyl group with t-butyldimethylsilyl led
to slight increases in enantioselectivity. Further increases in
steric bulk on the pyrrolidine ring substituent, however, caused
an erosion in reactivity. The pyrrolidine could not be replaced
with an imidazolidinone, which is consistent with earlier
studies involving intramolecular conjugate additions of
aldehydes.11d Trace conversion of starting material 1 was
observed in the presence of S-methylbenzylamine, which
highlights an important distinction between aldehyde-enoate
ester and ketone-enoate ester cyclizations. All known ketone-
enoate ester cyclizations have relied on primary amine
catalysts,16,17,19,20 presumably because primary amines are
more effective than secondary amines at forming ketone-
derived enamines.21,34
Toluene and chlorinated solvents were optimal for the
cyclization of 1 (Figure S2). Polar solvents, including alcohols,
ethers, nitriles, and amides, gave poor overall conversion,
which may indicate that Lewis basic groups in the solvent
molecules compete with the enoate ester as hydrogen bond
acceptors.
Additional studies were carried out to determine whether
useful chemoselectivity could be maintained at higher substrate
concentrations. The reactions described above were conducted
with 0.05 M 1; Figure 3 summarizes results obtained with 0.5
Figure 4. Substrate scope and X-ray structures. Reactions run on 0.5
mmol scale. Yields refer to isolated values. Diastereomeric ratio (d.r.)
1
was determined via H NMR analysis of the crude reaction mixture.
(a) 20 mol % 2, 20 mol % 17, 0.025 M toluene, 48 h, 0 °C. (b) 30
mol % 2, 30 mol % 17, 0.025 M toluene, 72 h, 0 °C. (c) 20 mol % 2,
20 mol % 16, 0.05 M toluene, 24 h, rt. Ts = p-toluenesulfonyl. Red
indicates bond formed.
cyclization products were formed in similar yields, but
enantioselectivity diminished as the ester group became
bulkier. Cis versus trans configurations of the products were
assigned via NMR analysis (Figures S18−S53). Absolute
configuration was determined by X-ray diffraction for
derivatives 3A and 21A (Figures 4 and S12−S14); other
absolute configurations were assigned by analogy.
Figure 3. Effect of high substrate concentration on reaction pathway
in the presence of lead cocatalysts from Figure 2. Reactions run on
0.05 mmol scale (0.5 M substrate).
Tetrahydropyran product 22 was obtained with high
enantioselectivity, although higher catalyst loadings were
required to achieve this outcome. We speculate that the
Lewis basic oxygen in the substrate may compete with the ester
carbonyl for hydrogen bonding to urea 17. The enoate ester
could be replaced with an α,β-unsaturated Weinreb amide
(23),35 although the product was formed with only moderate
enantioselectivity. When the length of the substrate was
reduced, cyclopentyl product 24 was obtained in good yield
and diasteroselectivity, but without any enantioselectivity.
Compound 24 has been previously used in prostaglandin
syntheses.36,37 The aldehyde-enoate ester substrate (25) that
might have formed a seven-membered ring did not cyclize
under our reaction conditions. Enoate ester 26, too, was
unreactive, which is consistent with Baldwin’s ring closure
rules.38 This observation prompted us to evaluate dienoate
ester substrate 27, which underwent regioselective cyclization
to form 28.
M 1. In each case, 15 mol % pyrrolidine 2 and cocatalyst were
used. Although competition from the undesired homoaldol
pathway was more apparent with the 10-fold increase in
substate concentration, as would be expected, these conditions
highlight the superiority of urea cocatalyst 17, with which the
homoaldol product was formed in only 13% yield. This
byproduct was formed in slightly higher yield with thiourea 16,
and in much higher yield with bis-triflamide 15 or with
catechol (11). Retention of selectivity for cyclization at this
substrate concentration suggests that urea 17 is highly selective
for electrophilic activation of the enoate ester relative to the
aldehyde.
We explored substrate scope with catalyst pair 2 + 17
(Figure 4). Methyl (3), ethyl (20), and benzyl (21) ester
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Accession Codes
Our new method of generating cyclohexyl aldehyde esters
enabled a concise total synthesis of (−)-yohimbane from
cycloheptene (Figure 5). (−)-Yohimbane, an indole alkaloid of
CCDC 2004981−2004982 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Samuel H. Gellman − Department of Chemistry, University of
Wisconsin, Madison, Wisconsin 53706, United States;
orcid.org/0000-0001-5617-0058; Email: gellman@
chem.wisc.edu
Figure 5. Six-step synthesis of (−)-yohimbane.
Authors
Zebediah C. Girvin − Department of Chemistry, University of
Wisconsin, Madison, Wisconsin 53706, United States;
orcid.org/0000-0001-5338-1319
Philip P. Lampkin − Department of Chemistry, University of
Wisconsin, Madison, Wisconsin 53706, United States
Xinyu Liu − Department of Chemistry, University of Wisconsin,
Madison, Wisconsin 53706, United States
the rauwalfia family, displays antipsychotic and antihyperten-
sive activities.39 The elegant prior enantioselective syntheses of
(−)-yohimbane rely on substrate diastereocontrol,40 enzymatic
resolution,41 or multiple stereodefining steps42 to control the
absolute configuration of the final product. Our cyclization
simultaneously sets two adjacent C-sp3 stereocenters, control-
ling both relative and absolute configurations, which supports a
streamlined route.
Compound 1 could be prepared in gram quantities from
cycloheptene via ozonlysis to generate the monodimethyl
acetal,43 followed by Horner-Wadsworth-Emmons olefination
and acetal hydrolysis. Use of pyrrolidine catalyst ent-2 along
with urea cocatalyst 17 produced ent-3, which was combined
with tryptamine in a one-pot reductive amination-cyclization
cascade44 to form lactam 29. Bischler-Napieralski reaction45 of
29 generated (−)-yohimbane in 95% ee.
Our results demonstrate that the reaction pathway followed
by an aldehyde-derived enamine can be controlled through
careful choice of the electrophile-activating cocatalyst. These
findings can be seen as part of an increasing communal interest
in the development of catalysts that influence selectivity among
alternative reaction pathways.46 Our work reveals surprising
variation among diverse Brønsted acid/hydrogen bond donor
cocatalysts in terms of the reactivity channel followed by
aldehyde-enoate ester 1 in the presence of the widely used
Hayashi-Jørgensen catalyst (2; Figure 2). Some cocatalysts
favor the intramolecular conjugate addition channel to form
cyclohexane derivative 3, while others favor the intermolecular
homoaldol condensation channel. A third set of cocatalyst
candidates does not promote either reaction. The distinctive
ability of urea 17 to provide 3 with superior diastereo- and
enantioselectivity could not have been predicted. The
enantioselective cyclization mode we have identified represents
a new frontier in conjugate additions of aldehyde-derived
enamines, which have been extremely widely examined with
intrinsically reactive electrophiles such as nitro-alkenes but
largely unexplored with the more inert enoate esters.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01666
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported in part by the US National
Science Foundation (CHE-1904940). We thank Dr. Ilia Guzei,
Amelia Wheaton, Dr. Bruce Noll (Bruker AXS Inc.), and Dr.
Matt Benning (Bruker AXS Inc.) for X-ray structure
determination of 3A and 21A. We thank the Weix group for
use of their chiral SFC.
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