Synthesis of α,α′-trans-oxepanes through an organocatalytic oxa-conjugate addition reaction

Article abstract of DOI:10.1021/ol500773w

Oxepanes are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. Organocatalytic oxa-conjugate addition reactions promoted by the gem-disubstituent (Thorpe-Ingold) effect stereoselectively provided α,α′-trans-oxepanes. In addition, the potential of an organocatalytic tandem oxa-conjugate addition/α-oxidation was demonstrated in a rapid generation of molecular complexity. These organocatalytic oxa-conjugate addition reactions would provide powerful tools for the synthesis of natural products that contain highly functionalized oxepanes.

Full text of DOI:10.1021/ol500773w

Letter
pubs.acs.org/OrgLett
Synthesis of α,α′-trans-Oxepanes through an Organocatalytic Oxa-
conjugate Addition Reaction
Megan L. Lanier, Amanda C. Kasper, Hyoungsu Kim,† and Jiyong Hong*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
S
* Supporting Information
ABSTRACT: Oxepanes are found in a wide range of natural
products; however, they are challenging synthetic targets due
to enthalpic and entropic barriers. Organocatalytic oxa-
conjugate addition reactions promoted by the gem-disubstitu-
ent (Thorpe−Ingold) effect stereoselectively provided α,α′-
trans-oxepanes. In addition, the potential of an organocatalytic
tandem oxa-conjugate addition/α-oxidation was demonstrated
in a rapid generation of molecular complexity. These
organocatalytic oxa-conjugate addition reactions would
provide powerful tools for the synthesis of natural products that contain highly functionalized oxepanes.
Given the continued interest and challenges these molecules
present as potential synthetic targets, the number of methods
available for the construction of oxepanes has steadily
increased.3,4 Despite progress toward this goal, currently
available methods for the synthesis of oxepanes possess several
limitations. For example, with the notable exception of ring-
closing metathesis (RCM),3c,k catalytic methods remain scarce.
In addition, the stereoselective synthesis of α,α′-trans-oxepanes
remains a challenging task since they are thermodynamically
less favorable than the corresponding cis isomers.5 Further
limitations include the challenges associated with preparation of
chiral substrates with preinstalled stereocenters, limited
substrate scope, and competitive formation of smaller size
rings according to Baldwin’s rules.6 Therefore, despite the
advances of the past decade, there still exists a great need for
synthetic approaches toward α,α′-trans-oxepanes that address
these limitations.
rchitecturally complex 7-membered cyclic ethers (oxe-
Apanes) are found in a wide range of structurally or
biologically interesting natural products (Figure 1).1 Relative to
tetrahydrofurans and tetrahydropyrans, oxepanes are challeng-
ing synthetic targets due to enthalpic and entropic barriers.2
During the last century, considerable progress has been made
in the conjugate addition of carbon nucleophiles to a diverse set
of acceptors for C−C bond formation.7 However, there has
been far less interest in the analogous conjugate addition of
alcohols to α,β-unsaturated carbonyl compounds (oxa-con-
jugate addition reaction) and its application to the stereo-
selective synthesis of acyclic and cyclic ethers.8 This is especially
true with respect to the synthesis of medium-sized cyclic ethers.
This can be attributed to the low reactivity of oxygen
nucleophiles, the reversibility of the reaction, and the lack of
control in the stereoselectivity.8 To date, there have been only a
few reports on the synthesis of medium-sized cyclic ethers
through an intramolecular oxa-conjugate addition reaction.9 As
an example, Martin and co-workers reported the synthesis of an
oxepane through the oxa-conjugate addition reaction of a
Figure 1. Examples of natural products containing 7-membered cyclic
ethers.
Received: March 13, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Letter
hydroxy ester.9a However, the reaction suffered from competing
tetrahydropyran formation, required an internal (Z)-double
bond to achieve good yields, and had a narrow substrate scope.
Despite the scarcity of successful examples, however, the oxa-
conjugate addition reaction has the potential to be a highly
straightforward and efficient method for the synthesis of
medium-sized cyclic ethers. Herein, we describe our inves-
tigation of the organocatalytic oxa-conjugate addition reaction
promoted by the gem-disubstituent (Thorpe−Ingold) effect in
the stereoselective synthesis of α,α′-trans-oxepanes.
Scheme 2. Effect of the 1,3-Dithiane Group on the Oxa-
conjugate Addition Reaction
To test the feasibility of the oxa-conjugate addition reaction
for the stereoselective synthesis of oxepanes, we prepared α,β-
unsaturated aldehyde 5 and subjected it to the conditions
shown in Scheme 1. Our initial attempts at the oxa-conjugate
Scheme 1. Initial Attempts for the Oxa-conjugate Addition
Reaction
disubstituent effect as well as the iminium activation would help
overcome the ring strain and accelerate the cyclization step.15,16
After an extensive search for reaction conditions, treatment of
11 with (R)-6 (20 mol %) and BzOH provided the α,α′-trans-
oxepane 12 as the major diastereomer17 in good stereo-
selectivity (α,α′-trans:α,α′-cis = 7:1), but in low yield (19%).18
Encouraged by this initial success in the stereoselective
synthesis of α,α′-trans-oxepane 12, we decided to test the
hypothesis that the position of 1,3-dithiane group might effect
the reactivity and stereoselectivity.19 We prepared α,β-
unsaturated aldehyde 15a with the 1,3-dithiane group at the
C4 position by coupling 13 with (S)-glycidyl benzyl ether ((S)-
1a) followed by MnO2 oxidation (Scheme 3). We were
delighted to find that the organocatalytic oxa-conjugate
addition reaction of 15a in the presence of (R)-6 (20 mol %)
and BzOH followed by NaBH4 reduction successfully provided
the desired α,α′-trans-oxepane 18a through the more favorable
iminium intermediate 16B20 (dr = 8:1, 67% for two steps).21−24
Scheme 3. Synthesis of an α,α′-trans-Oxepane via the
addition reaction, under a variety of reaction conditions
(pyrrolidine, (R)-6, (S)-6, DBU, Et3N, KOtBu, NaH, or
Tf2NH), failed to provide the desired oxepane 7. We attributed
the unsuccessful results to the low reactivity of the oxygen
nucleophile, entropic factors, and/or transannular and torsional
strain.
Organocatalytic Oxa-conjugate Addition Reaction
To overcome these obstacles, we envisioned the introduction
of a structural element that would promote conformational
preorganization of α,β-unsaturated aldehydes for an intra-
molecular oxa-conjugate addition reaction. We hypothesized
that a 1,3-dithiane group installed on α,β-unsaturated aldehydes
could satisfy these requirements on the basis of the gem-
disubstituent effect (Thorpe−Ingold effect).10 The gem-
disubstituent effect has been shown to have a profound effect
on the formation of medium-sized rings.10,11 Among the
functional groups used to elicit the gem-disubstituent effect, the
1,3-dithiane group is one of the most effective.12 The 1,3-
dithiane group is an acyl anion equivalent with impressive
reactivity which allows umpolung-based strategies and serves as
a latent functional group for a carbonyl, hydroxy, or olefinic
group or hydrogen atoms.13
To explore the feasibility of the oxa-conjugate addition
reaction promoted by the gem-disubstituent effect in the
synthesis of oxepanes, we prepared the α,β-unsaturated
aldehyde 11 with a 1,3-dithiane group by coupling dithiane 8
with alkyl iodide 9 followed by MnO2 oxidation (Scheme 2).14
Aldehyde 11 was then subjected to a secondary amine-catalyzed
oxa-conjugate addition reaction. We anticipated that the gem-
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Letter
Surprisingly, when the reaction was run for a prolonged
period, the stereoselectivity was reduced to provide a 1:1
mixture of 17a and the corresponding α,α′-cis-oxepane,
suggesting that the organocatalytic oxa-conjugate addition
reaction was reversible. Probing the reaction further, 15a was
treated with (R)-6 and BzOH and monitored for the formation
and ratio of α,α′-trans- and α,α′-cis-oxepanes at different time
points using NMR. We observed that the α,α′-trans-oxepane
17a was initially formed as the major diastereomer. However,
after 24 h, the reaction provided a 1:1 mixture of 17a and the
corresponding α,α′-cis-oxepane. This data suggests that the
formation of the α,α′-trans-oxepane 17a through the organo-
catalytic oxa-conjugate addition is a kinetically controlled
process.
Scheme 4. Organocatalytic Tandem Oxa-conjugate
Addition/α-Oxidation
To investigate the substrate scope and stereoselectivity of the
reaction, α,β-unsaturated aldehydes 15b−e with a variety of
substituents at the C2 position were prepared25 and subjected
to the standard reaction conditions (Table 1). We were pleased
Table 1. Substrate Scope of the Organocatalytic Oxa-
conjugate Addition Reaction
organocatalytic tandem reaction would provide a powerful tool
for the rapid synthesis of natural products since these α-
functionalized medium-sized cyclic ethers are abundant in
natural products.
In summary, we have established an efficient method for the
stereoselective synthesis of oxepanes based on the organo-
catalytic oxa-conjugate addition reaction promoted by the gem-
disubstituent effect. It is noteworthy that the organocatalytic
oxa-conjugate addition reaction of α,β-unsaturated aldehydes
allows for the formation of α,α′-trans-oxepanes, which has
proven challenging in other approaches. We have also
demonstrated the potential of the organocatalytic tandem
oxa-conjugate addition/α-oxidation in a rapid generation of
molecular complexity. We plan to extend this organocatalytic
oxa-conjugate addition reaction to the stereoselective synthesis
of biologically important natural products.
a
b
entry
R
yield (%)
dr
a
b
c
CH2OBn
67
87
56
82
64
8:1
6:1
ASSOCIATED CONTENT
* Supporting Information
■
Et
Ph
S
6:1
d
e
C(CH3)2CH2OBn
CH((R)-OPMB)CH2OBn
17:1
20:1
General experimental procedures including spectroscopic and
analytical data along with copies of H and 13C NMR spectra.
1
a
This material is available free of charge via the Internet at
http://pubs.acs.org.
Combined yield of the isolated α,α′-trans- and α,α′-cis-oxepane
alcohols after NaBH4-reduction of the corresponding oxepane
aldehydes. The diastereomeric ratio (α,α′-trans/α,α′-cis) was
determined by integration of relevant H NMR spectroscopic signals
b
1
AUTHOR INFORMATION
■
of the crude oxepane aldehydes.
Corresponding Author
*E-mail: jiyong.hong@duke.edu.
Present Address
to find that the organocatalytic oxa-conjugate addition reaction
of 15b−e in the presence of (R)-6 provided α,α′-trans-
oxepanes 17b−e in good-to-excellent stereoselectivities (dr =
6−20:1).
†Ajou University, College of Pharmacy, Suwon 443-749, South
Korea.
Notes
Recently, the organocatalytic tandem reaction, which carries
out at least two reactions under the same reaction conditions,
has drawn a considerable amount of attention.26 It avoids time-
consuming, costly protecting-group manipulations as well as
the isolation of reaction intermediates. In this way, molecular
complexity is achieved quickly and often accompanied by high
levels of stereoselectivity. Building on the aforementioned
work, we attempted an organocatalytic tandem oxa-conjugate
addition/α-oxidation (Scheme 4).27 The organocatalytic
tandem oxa-conjugate addition/α-oxidation of 15a in the
presence of (R)-6 and PhNO followed by NaBH4 reduction
afforded 20 (62% for two steps) as a single diastereomer.28 The
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Duke University for funding this work, to the
North Carolina Biotechnology Center (NCBC; Grant No.
2008-IDG-1010) for funding of the NMR instrumentation, and
to the National Science Foundation (NSF) MRI Program
(Award ID No. 0923097) for funding mass spectrometry
instrumentation. M.L.L. was supported by the NIGMS
Pharmacological Sciences Training Program (NIH
GM007105).
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Letter
(14) Our analogous approaches to tetrahydropyran synthesis via the
tandem allylic oxidation/oxa-conjugate addition reaction were
successful, suggesting that oxepanes are generally more challenging
synthetic targets than tetrahydropyrans. See ref 15.
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