Lewis-Base-Catalyzed Reductive Aldol Reaction to Access Quaternary Carbons

Article abstract of DOI:10.1021/acs.orglett.8b00507

A synthetic method for the efficient construction of β-hydroxylactones and lactams bearing α-quaternary carbon centers is described. This transformation relies on an electronically differentiated Lewis base catalyst, which is uniquely capable of promoting

Full text of DOI:10.1021/acs.orglett.8b00507

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Lewis-Base-Catalyzed Reductive Aldol Reaction To Access
Quaternary Carbons
Yvonne C. DePorre,† James R. Annand,† Sukanta Bar, and Corinna S. Schindler*
Department of Chemistry, Willard Henry Dow Laboratory, University of Michigan, 930 North University Avenue, Ann Arbor,
Michigan 48109, United States
S
* Supporting Information
ABSTRACT: A synthetic method for the efficient con-
struction of β-hydroxylactones and lactams bearing α-
quaternary carbon centers is described. This transformation
relies on an electronically differentiated Lewis base catalyst,
which is uniquely capable of promoting a reductive aldol
reaction of α,α-disubstituted and α,α,β-trisubstituted enones.
This approach provides a valuable synthetic alternative for
carbon−carbon bond formation in complex molecular settings
due to its orthogonal reactivity compared to that of traditional
aldol reactions. Based on this method described herein, lactones, lactams, and morpholine amides bearing α-quaternary carbon
centers are accessible in yields up to 85% and 50:1 dr.
oxicity is known to be the leading cause for drug candidates
T
failing clinical trials.1 Recent studies suggest that
compounds of higher complexity, as measured by the saturation
and presence of sp3-hybridized quaternary carbon centers, have
fewer off-target effects, show less toxicity, and have a greater
success rate in the clinic.2 However, synthetic access to molecules
with increased complexity requires successful methods for the
construction of quaternary carbon centers.3 Despite recent
advances, synthetic challenges in the formation of quaternary
carbon centers still exist and prove even more difficult when the
desired quaternary carbons are chiral.3a Additionally, quaternary
carbon centers in acyclic molecules and molecular fragments
remain challenging to access.3b,c,4 Furthermore, most of the
methods currently available for the construction of quaternary
carbons rely on metal-based catalysts, and the development of
alternative catalytic systems was recently described as a future
challenge.3b Here, we describe a method for the diastereose-
lective construction of β-hydroxylactones and lactams bearing α-
quaternary carbon centers that relies on simple, electronically
differentiated phosphine oxides as Lewis base catalysts. The
reported strategy enables access to structural motifs prevalent in
many biologically relevant target structures.5,6
A synthesis project in our laboratory recently required
operational access to complex lactones and lactams 5 bearing
quaternary carbons from α,α,β-trisubstituted enones 1 (Figure
1A). A reductive aldol approach seemed particularly desirable, as
it would permit a select Michael acceptor such as 1 to react in the
presence of enolizable functional groups. Several successful
protocols for transition-metal-catalyzed reductive aldol reactions
for α,β-unsaturated carbonyl compounds 6 have been described
that rely on Rh,7 Ir,8 Cu,9 Co,10 Ru,11 or Pd12 in combination
with boranes, silanes, or hydrogen gas as suitable reductants.
Unfortunately, methods for converting α,α-disubstituted (7)13
or α,α,β-trisubstituted (8)14 and tetrasubstituted (9) enones to
Figure 1. Lewis-base-catalyzed reductive aldol reaction.
the reductive aldol products bearing α-quaternary carbons are
less common (Figure 1B).15 An inherent challenge to enones 7−
Received: March 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00507
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Letter
9 relates to the identification of potent catalyst systems that (1)
exhibit high levels of chemoselectivity for 1,4-reduction, (2)
activate both the resulting enolate nucleophile and aldehyde
electrophile for aldol addition while (3) minimizing competing
reduction of the aldehyde electrophile. Denmark’s pioneering
work has established Lewis bases as a powerful class of catalysts
capable of enhancing enolate nucleophilicity in asymmetric aldol
reactions.16 Recently, Nakajima has shown that Lewis bases, such
as triphenylphosphine oxide (TPPO) (12) and hexamethyl-
phosphoramide (HMPA) (13), are able to promote reductive
aldol reactions of α,β-disubstituted enones 6, though α,α-
disubstituted (7) and α,α,β-trisubstituted (8) enones still remain
elusive as substrates.17 We postulated that the reactivity of these
Lewis base catalysts can be tuned to the specific electronic and
steric requirements inherent to highly functionalized enones 7−
9, to enable both in situ conjugate reduction and activation of the
resulting enolate for a subsequent aldol reaction. Aryl phosphine
oxide derivatives seemed particularly desirable Lewis bases, as
they allow for facile electronic differentiation of the aryl
substituents to probe our hypothesis. Our initial studies with
lactone 10, bearing an exocyclic Michael acceptor, benzaldehyde
as an electrophile, and TPPO (12) or HMPA (13) as Lewis base
catalyst with HSiCl3 as the reductant, proved promising and
resulted in the formation of the reductive aldol product 11 in 43
and 45% yield, respectively (entries 1 and 2, Table 1). Although
optimization centered on electronic differentiation of triaryl
phosphine oxides to increase their reactivity in the initial 1,4-
reduction. Lewis bases 16, 20, and 21, bearing electron-donating
substituents in the ortho-position, formed lactone 11 in low yields
most likely due to the increased steric bulk compared to TPPO
12 (entries 5, 9, and 10, Table 1). The para-methyl
triarylphosphine oxide 17 showed a reaction profile similar to
that of Lewis base 12 and resulted in the formation of 11 in 39%
yield together with reisolated starting material (entry 6, Table 1).
In comparison, the corresponding Lewis base 18 bearing a
dimethylamine moiety in the para-position showed low solubility
in dichloromethane and resulted in diminished yields of 11
(entry 7, Table 1). However, para-methoxy triarylphosphine 19
led to formation of product 11 in 71% yield with minor
competing reduction (entry 8, Table 1) and was identified as the
optimal Lewis base catalyst. Subsequent reaction optimization
focused on the silane reductant. It was found that 2.5 equiv of
trichlorosilane was optimal, whereas increased amounts resulted
in diminished yields of the desired reductive aldol products due
to competing reduction side products. Additionally, 20 mol %
catalyst loadings proved superior with minimal reduction of the
aldehyde electrophile (<10%), whereas stoichiometric quantities
of Lewis base 19 resulted in diminished yields of 11 in 28%.
Notably, the diastereomeric ratio of aldol product 11 remained
constant despite changes in catalyst loading.18
Transition state models similar to those proposed by Denmark
for phosphoramide-catalyzed aldol reactions of preformed
trichlorosilyl enolates can justify the stereochemical outcome
observed in the reductive aldol reaction.19 Stereochemical
models are consistent with a boat transition state 25 resulting
in the major diastereomer 27 with both CH2R2 and hydroxyl
substituents being anti to one another. The minor diastereomer
with CH2R2 and hydroxyl group being syn to one another could
be formed via the less favorable boat transition state 26 or by a
chair transition state 22 (Figure 2A). The relative configuration
of both diastereomeric products of lactam 28 and tolualdehyde
29 was confirmed using X-ray analysis to result in the formation
of lactam anti-30 as the major diastereomer and syn-31 as the
minor diastereomer in combined 70% yield (Figure 2B).
a
Table 1. Catalyst Evaluation for the Sythesis of 11
The conditions developed proved efficient for construction of
a variety of α,α-disubstituted and α,α,β-trisubstituted lactones
and lactams (Scheme 1), affording yields and diastereomeric
ratios up to 85% and 50:1, respectively. For six-membered
monocyclic lactones and lactams, the anti-product was favored
with diastereomeric ratios up to 20:1 dr, increasing with both
aldehyde and alkene bulk (11, 32−34, 36−52, 54, and 55,
Scheme 1). Importantly, sterically encumbered tricyclic lactones
resulted in the formation of the corresponding β-hydroxylac-
tones 35 and 53 in up to 67% yield and 50:1 dr (Scheme 1). N-
Alkyl- or N-aryl-substituted lactams proved efficient under the
optimized reaction conditions and resulted in up to 85% yield
and 20:1 dr of the desired reductive aldol products (e.g., 32,
Scheme 1). Notably, lactams bearing removable para-methox-
yphenyl or benzyl protecting groups afforded high yields and
good to excellent diastereomeric ratios of the desired β-
hydroxylactams (34 and 48−51, Scheme 1). Aryl aldehydes
with varying substitution are viable electrophiles, and increased
hindrance on the aromatic moieties led to higher diastereomeric
ratios (e.g., 32 and 34, Scheme 1). Aldehydes conjugated to
heterocycles including furan and thiophene were tolerated well as
electrophiles rendering yields up to 77% (41 and 42, Scheme 1).
Initial efforts to extend the substrate scope to unsaturated
aldehydes, such as cinnamaldehyde, proved challenging due to
a
Reactions were run in 0.25 M DCM at 30 °C for 48 h with 1.2 equiv
of benzaldehyde.
both catalysts produced 11 in similar yields, the reaction profiles
differed. Unreacted starting material 10 was recovered when
employing 12, but 10 was consumed with 13, forming both 1,4-
reduced lactone and benzyl alcohol as side products. These
results suggest that HMPA is a potent catalyst for initial
conjugate reduction but is too sterically encumbering to fully
promote subsequent aldol addition. In comparison, TPPO is not
Lewis basic enough to complete the initial conjugate reduction
reaction, thus resulting in the reisolation of starting material 10.
Attempts to use the HMPA analogues 14 and 15 to decrease
steric bulk in the aldol addition resulted in either no reaction or
no improved yield of the desired reductive aldol product 11
(entries 3 and 4, Table 1). As a result, subsequent catalyst
B
DOI: 10.1021/acs.orglett.8b00507
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Letter
the formation of competing aldol condensation products.
However, conducting the reaction in toluene under otherwise
identical conditions attenuated this competing self-condensation
and resulted in good yields of the respective β-hydroxylactone
and -lactam adducts (42, 45, and 48, Scheme 1). Aliphatic
aldehydes lacking acidic α-protons, such as pivaldehyde, proved
viable under the conditions developed for reductive aldol
reactions of α,α,β-trisubstituted enones and lactams resulting
in the desired products in good yields in up to 65% (56−59,
Figure 3).20
Figure 3. Reductive aldol reactions using pivaldehyde.
Figure 2. Transition state models for aldol addition of enolate 3.
Furthermore, morpholine amides 60 and 61 proved viable
substrates for the Lewis-base-catalyzed reductive aldol reaction.
a
Scheme 1. Substrate Scope for Lactones and Lactams
a
Standard conditions: Michael acceptor (1 mmol), aldehyde (1.5 mmol), pOMe-TPPO (19, 20 mol %), HSiCl3 (2.5 equiv), in dichloromethane
b
c
d
(0.25 M) at 30 °C for 48 h. Reaction is complete in 12 h. In toluene (0.25 M). Aldehyde is added after 8 h. Reaction is quenched 12 h after
addition of the aldehyde.
C
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Morpholine amides are important synthetic alternatives to
Weinreb amides characterized by their ease of use.21 Upon
conversion of 60 with a variety of aldehydes under the optimized
conditions, the corresponding aldol products were obtained
bearing a methyl group syn and an ethyl group anti to the β-
hydoxyl group (61, 64, and 65, Figure 4).
In summary, a synthetic method for the efficient construction
of β-hydroxylactones, lactams, and morpholine amides bearing
α-quaternary carbon centers is described. The simple para-
methoxy triarylphosphine oxide 19 was identified as a Lewis base
catalyst uniquely effective in promoting the reductive aldol
reaction of α,α-disubstituted and α,α,β-trisubstituted enones to
form the desired products in up to 85% yield and 50:1 dr.
Importantly, this reaction complements existing protocols for the
conversion of morpholine amides relying on (Ipc)2BH as
reagent, resulting in the formation of diastereomeric products.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00507.
Experimental procedures and compound characterization
1
data, including the H/13C NMR spectra, as well as data
for deuterium labeling studies (PDF)
Accession Codes
CCDC 1831871−1831873 contain the supplementary crystallo-
graphic 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
*E-mail: corinnas@umich.edu.
ORCID
Figure 4. Reductive aldol reactions of morpholine amides.22
Corinna S. Schindler: 0000-0003-4968-8013
Author Contributions
Notably, the products of this reductive aldol approach are
formed in up to 60% yield and 10:1 dr, whereas the use of TPPO
12 as catalyst resulted in overall diminished yields. Importantly,
the products are diastereomeric to those obtained via an alternate
approach relying on (Ipc)2BH, thus providing a valuable
complementary synthetic alternative (62, Figure 5).21 The
†Y.C.D. and J.R.A. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Petroleum Research Fund (PRF#54688-DNI1),
the University of Michigan Office of Research and the NSF/
National Science Foundation (CHE-1654223) for financial
support. Y.C.D. thanks the National Science Foundation for a
predoctoral fellowship. We thank Dr. Jeff W. Kampf (Depart-
ment of Chemistry, Willard Henry Dow Laboratory, University
of Michigan) for X-ray crystallographic studies.
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