Rationally Designed Chiral Synthons Enabling Asymmetric Z- and E-Selective Vinylogous Aldol Reactions of Aldehydes

Article abstract of DOI:10.1021/acs.orglett.8b00230

In a conceptually different approach, highly stereoselective 2-oxonia-Cope rearrangement reactions between rationally designed nonracemic vinylogous aldolation synthons and aldehydes are described to provide δ-hydroxy-α,β-unsaturated esters with excellent

Full text of DOI:10.1021/acs.orglett.8b00230

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rationally Designed Chiral Synthons Enabling Asymmetric Z- and
E‑Selective Vinylogous Aldol Reactions of Aldehydes
Akhil Padarti and Hyunsoo Han*
Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas 78249, United States
S
* Supporting Information
ABSTRACT: In a conceptually different approach, highly stereoselective 2-oxonia-Cope rearrangement reactions between
rationally designed nonracemic vinylogous aldolation synthons and aldehydes are described to provide δ-hydroxy-α,β-
unsaturated esters with excellent enantioselectivities and, for the first time, unprecedented Z- and E-selectivities without the
regioselectivity issue.
Scheme 1. Approaches for the Asymmetric Synthesis of δ-
Hydroxy-α,β-Unsaturated Carbonyl Functionalities
δ-Hydroxy-α,β-unsaturated carbonyl functionalities occupy a
privileged status in organic synthesis due to their prevalence in
many natural and artificial products as well as their versatile
synthetic utilities as intermediates toward other (more
complex) useful structures.1−5 As such, a plethora of
asymmetric methodologies have been put forth, the vast
majority of which rely on the asymmetric vinylogous
(Mukaiyama) aldol reaction employing dienolates/dienol
ethers in combination with chiral catalysts1−4 or chiral
auxiliary-based dienol ethers in the presence of Lewis acids.5
Recently, an enantioselective Ir-catalyzed vinylogous Reformat-
sky aldol reaction was reported to circumvent some drawbacks
associated with the vinylogous (Mukaiyama) aldol reaction,
such as the formation and tractability of the required silyl
dienol ethers as well as potential background reactions
catalyzed by racemic silyl cations formed in the reaction.6
Even though good to excellent enantioselectivities have been
obtained in some cases, there still exists significant room for
improvement with respect to the scope of dienol ethers and
(functionalized) aliphatic aldehydes, and the regioselectivity
problem is an intrinsic shortcoming of the aforementioned
approaches (Scheme 1a,b). Furthermore, these methods are
inherently unable to control the double bond configuration of
enoate products. The Z- and E-selectivity issue has not been
addressed to date and, thus, represents a significant literature
gap, particularly considering that both 2Z- and 2E-δ-hydroxy-
α,β-unsaturated carbonyl functionalities have been found in
natural products,7 and they often exhibit disparate behaviors in
organic reactions.8
the vinylogous aldol reaction of aldehydes, which operate
through a 2-oxonia-[3,3]-Cope rearrangement (2-OCR)
In a distinctly different approach, we herein report the
development of rationally designed nonracemic synthons
enabling the at-will control of not only enantioselectivity, but
also Z- and E-selectivity without the regioselectivity concern in
Received: January 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00230
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Letter
mechanism (Scheme 1c).9 Also described is a convenient one-
pot asymmetric synthesis of 5,6-dihydropyran-2-ones,7 which
exploits the unprecedented Z-selective vinylogous aldolation.10
Scheme 2 describes the mechanism of the 2-OCR reaction
between vinylogous aldolation synthons 3R-2,3-syn-I and
On the basis of the above reasoning, the vinylogous
aldolation synthons 1a−d are devised, and their synthesis is
shown in Scheme 3. A Reformatsky reaction between 2,6-
Scheme 3. Preparation of Vinylogous Aldolation Synthons
Scheme 2. Mechanism and Chirality Transfer of 2-Oxonia-
Cope Rearrangement Reaction between Aldehydes and the
Synthons I
aldehydes under acidic conditions employing the Zimmer-
man−Traxler-type analysis of transition states.11 Assuming that
the key step in the mechanism is the [3,3]-sigmatropic
rearrangement of the initially formed oxocarbenium ions II to
the product-side oxocarbenium ions III, the relative stability of
III to II as well as the steric repulsion between the aryl group
and the ester group of II are expected to provide a major
driving force for the reaction. This led us to conjecture that
installing an aryl group with appropriate substituents at the C3
position of I could increase the relative stability of III to II and
the steric repulsion, driving the equilibrium reaction to the
product side. Sterically hindered aryl groups, such as a 2,6-
disubstituted phenyl group, would be most appropriate in this
regard. Moreover, the steric encumbrance by the 2,6-
substituents can prevent the aryl aldehyde byproducts V from
interfering with the desired 2-OCR reaction. The mechanism
also shows that the chirality of 3R-2,3-syn-I can be specifically
transferred to that of 5S-2E-IV. This analysis, when combined
with a similar analysis for 3R-2,3-anti-I, strongly indicates that
the C5 stereochemistry and the C2 double configuration of IV
can be easily predicted and controlled by the absolute and relative
stereochemistry of the C2 and C3 of I, respectively. The
synthons 3R-2,3-syn-I and 3R-2,3-anti-I are expected to be air-
stable and thus easy to handle.
Despite these attractive traits, a convenient and general
platform, such as I, which can enable efficient 2-oxonia-Cope
rearrangement reactions to deliver δ-hydroxy-α,β-unsaturated
carbonyl compounds IV in a highly stereoselective fashion, is
not currently available. In related work introducing bispropi-
onates to aldehydes, the McDonald group recently reported the
synthons containing a phenyl group tethered with a silyloxy
group, which was required not only to drive 2-OCR to the
product side, but also to facilitate purification; a synthon with a
phenyl group only did not work. Contrary to the synthons I,
their synthons worked in two stages through the formation of
acetal intermediates, followed by a 2-OCR, and only aliphatic
aldehydes were used.12a
dimethylbenzaldehyde and methyl 4-bromocrotonate at either
−20 or −20 to 0 °C generated the desired syn- and anti-aldol
products, respectively.13 When ( )-2,3-syn- and ( )-2,3-anti-1a
were subjected to the kinetic resolution conditions employing
Fu’s catalyst (−)-5,14 delightfully, the respective syn- and anti-
1a were obtained with >95% ee for both cases. The synthons
( )-1b−d were similarly prepared.
With ( )-anti-1a−d in hand, their 2-OCR reactions with n-
hexanal were studied to determine the best aryl group and the
optimal reaction conditions by screening various acids
[TMSOTf, TfOH, BF3·OEt2, SiCl4, SnCl4, TiCl4, Sn(OTf)2,
and Sc(OTf)3] and temperatures (−78, −20, 0 °C, and rt). The
conditions employing ( )-anti-1a and TMSOTf in CH2Cl2 at
−78 °C were determined to be optimal. Under the optimal
conditions, anti-1a (95% ee) delivered the expected Z-2a in
87% reaction yield with 94% ee and >25:1 Z/E-selectivity,
indicating nearly perfect chirality transfer in the reaction.
The determined optimal 2-OCR conditions involving anti-1a
and TMSOTf in CH2Cl2 at −78 °C are applied to a diverse
array of aldehydes, and the results are displayed in Table 1.
Linear, β-branched, α-branched, and cyclic aliphatic aldehydes
all worked well (entries 1−4). Sterically hindered pivalaldehyde
also reacted smoothly (entry 5). In the aliphatic aldehyde cases
studied, excellent reaction yields (≥87%) were obtained, and
chirality transfer was nearly perfect, as judged by the
exceptional Z/E- and enantioselectivities obtained. With
benzaldehyde, a diminished yield was observed due to the
formation of the corresponding 5,6-dihyropyran-2-one (entry
6), but the Z/E- and enantioselectivities remained excellent.
Particularly notable are almost exclusive Z-selectivities
observed, which are not possible by any other vinylogous
aldol reactions.
Table 2 describes a one-pot synthesis of 5,6-dihydropyran-2-
ones 3 via the Z-selective 2-OCR reaction between anti-1a and
aldehydes. After completing 2-OCR reactions at −78 °C, as
judged by TLC, the temperature was raised, and the initial
B
DOI: 10.1021/acs.orglett.8b00230
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Letter
products Z-2 spontaneously cyclized into the corresponding
5,6-dihydropyran-2-ones without compromising enantioselec-
tivities. The one-pot operation and excellent enantioselectivities
of the 2-OCR reactions, followed by spontaneous cyclization,
attest their superb synthetic efficiency, when compared with
other synthetic methods for the 5,6-dihydropyran-2-one ring
structures that have typically employed a three-step sequence of
aldehyde allylation/acylation/ring-closing metathesis (RCM)15
or aldehyde allylation/Z-selective cross-metathesis (CM)/
cyclization.16
Table 1. Enantio- and Z-Selective Vinylogous Aldol
Reactions between Aldehydes and anti-1a
a
Depicted in Table 3 are enantio- and E-selective vinylogous
aldol reactions between syn-1a and aldehydes. As in the cases of
Table 3. Enantio- and E-Selective Vinylogous Aldol
a
Reactions between Aldehydes and syn-1a
a
anti-1a (0.213 mmol), aldehyde (2.00 equiv), and TMSOTf (1.50
b
c
equiv) in DCM (4 mL) at −78 °C for 60 min. Isolated yields. Yield
at 1 mmol scale. The corresponding 5,6-dihydropyran-2-one was
obtained in 26% yield. Determined by H NMR. Determined by
d
e
f
1
measuring the ee’s of the corresponding 5,6-dihydropyran-2-ones by
g
chiral HPLC. Determined by chiral HPLC
Table 2. Enantioselective One-Pot Synthesis of 5,6-
Dihydropyran-2-ones via the 2-OCR Reaction of anti-1a
a
a
syn-1a (0.213 mmol), aldehyde (2.00 equiv), and TMSOTf (1.50
b
equiv) in CH2Cl2 (4 mL) at −78 °C for 60 min. Isolated yields.
c
d
e
1
Yield at 1 mmol scale. Determined by H NMR. Determined by
chiral HPLC
anti-1a in Table 1, excellent enantioselectivities and E-
selectivities were obtained with all aliphatic and aromatic
aldehydes. A notable difference is that the 2-OCR reactions of
aldehydes by syn-1a proceeded faster than those by anti-1a,
which is consistent with the analysis in Scheme 2.
As shown Scheme 4, functionalized aldehydes could be used
in the 2-OCR reaction. For example, 3-(benzyloxy)propanal
(6)17 reacted well with anti- and syn-1a to give the
corresponding 2Z- and 2E-δ-hydroxy-α,β-unsaturated esters,
Z- and E-7 (Scheme 4a).18 As anticipated, upon raising the
temperature, Z-7 spontaneously cyclized to the corresponding
5,6-dihyropyran-2-one 8 in 85% yield and with 99% ee
(Scheme 4a), which had been previously synthesized from 6
by the asymmetric aldehyde allylation/acylation/cross meta-
thesis sequence19a and used as an intermediate in the
asymmetric synthesis of natural products.19
a
Conditions A: same as Table 1 at −78 °C to rt for 5 h. Conditions B:
b
c
at −78 to −30 °C for 90 min. Isolated yields. Yield at 1 mmol scale.
d
e
Determined by chiral HPLC. See Table 1, entries 4 and 5.
To further demonstrate the power and synthetic utility of the
developed 2-OCR reaction by anti-1a, two stereoisomers of
euscapholide, syn-11 and anti-11, were prepared (Scheme 4b).
C
DOI: 10.1021/acs.orglett.8b00230
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Letter
Scheme 4. Synthetic Applications Utilizing syn- and anti-1a
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hyunsoo.han@utsa.edu.
ORCID
Hyunsoo Han: 0000-0001-7821-5851
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support by the National Science Foundation (CHE-1362964)
is greatly acknowledged.
■
REFERENCES
■
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■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00230.
Procedures, characterization data, HPLC chromato-
1
grams, and H/13C NMR spectra (PDF)
D
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