Highly Stereoselective 2-Oxonia-Cope Rearrangement: A Platform Enabling At-Will Control of Regio-, Enantio-, and Diastereoselectivity in the Vinylogous Aldol Reactions of Aldehydes

Article abstract of DOI:10.1021/acs.orglett.7b03895

A distinctly different approach for the vinylogous aldolation of aldehydes is described, which exploits 2-oxonia-Cope rearrangement reactions between two readily available partners, a set of rationally designed chiral homoallylic alcohol synthons and aldehydes, under simple conditions. In these processes, chirality transfer from the former to the latter is nearly perfect, giving rise to excellent enantio- and diastereoselectivity without the regioselectivity issue associated with traditional vinylogous aldol reactions.

Full text of DOI:10.1021/acs.orglett.7b03895

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Stereoselective 2‑Oxonia-Cope Rearrangement: A Platform
Enabling At-Will Control of Regio‑, Enantio‑, and Diastereoselectivity
in the Vinylogous Aldol Reactions of Aldehydes
Akhil Padarti, Dongeun Kim, and Hyunsoo Han*
Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas 78249, United States
S
* Supporting Information
ABSTRACT: A distinctly different approach for the vinylogous aldolation of aldehydes is described, which exploits 2-oxonia-
Cope rearrangement reactions between two readily available partners, a set of rationally designed chiral homoallylic alcohol
synthons and aldehydes, under simple conditions. In these processes, chirality transfer from the former to the latter is nearly
perfect, giving rise to excellent enantio- and diastereoselectivity without the regioselectivity issue associated with traditional
vinylogous aldol reactions.
of aldehydes was limited with respect to diastereoselectivity
(Figure 1b).7 Vinylogous aldol reactions utilizing chiral
crotylsilanes led to only syn-II, and modest diastereoselectivities
were observed with most aldehydes used (Figure 1c).8 Finally,
Kobayashi vinylogous aldol reactions using Evans’ chiral
auxiliary-based silyl dienyl N,O-acetals deliver either syn- or
anti-II depending upon the reaction conditions and the starting
materials employed.4b,c The diastereoselectivity issue still persists
with aliphatic aldehydes,4b and acetals (or in situ formation of
acetals) need to be used for the generation of syn-II (Figure
1d).4c
In this paper, we describe a distinct, general method enabling
the enantio- and diastereoselective synthesis of both I and II
without the regioselectivity issue, which takes advantage of
underexploited 2-oxonia-Cope rearrangement (2-OCR) reac-
tions9 between rationally designed homoallylic alcohol synthons
III and aldehydes (Figure 2). If the 2-OCR reaction follows the
Zimmerman−Traxler model employing “closed” six-membered
ring transition states,10 the chirality of III is expected to be
specifically transferred to that of VI: 1′E-III to anti-VI and 1′Z-
III to syn-VI along with the control of the C5 stereochemistry of
VI by the C3 stereochemistry of III. In addition, since the overall
transformation of III to VI is mainly governed by the [3,3]-
sigmatropic rearrangement of IV to V, selective stabilization of V
5-Hydroxy-2,3-unsaturated carbonyl compounds I and their
“crotyl” analogues II are valuable synthetic targets, both as final
structures and as intermediates in the total synthesis of
(bio)chemically relevant compounds, particularly polyketide
natural products.1,2 The vinylogous (Mukaiyama) aldol reaction
employing enolates/dienol ethers in combination with chiral
catalysts has been most widely used,2 and other innovative
protocols such as iridium-catalyzed vinylogous Reformatsky
reaction3 and Kobayashi aldol reactions employing Evans’ chiral
auxiliary-based silyl dienyl N,O-acetals4 have been put forth in
recent years. Excellent regio- and enantioselectivities have been
obtained with a diverse array of aliphatic and aromatic aldehydes
in the case of I.5,6
In contrast, the synthesis of II has proven to be challenging due
to the requirement to control diastereoselectivity in addition to
regio- and enantioselectivity. As shown in Figure 1, a literature
survey surprisingly revealed a lack of a general platform to control
all three selectivities simultaneously. Chiral silicon-catalyzed
vinylogous Mukaiyama aldol reactions gave rise to only anti-II
and, more significantly, did not work with aliphatic aldehydes
(Figure 1a).6 In the chiral boron-catalyzed vinylogous
Mukaiyama aldol reactions, only syn-II was obtained from both
4E- and 4Z-methyl-substituted silyl dienyl acetals, and the scope
Received: December 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03895
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Asymmetric Synthesis of the Synthons 3 and 6
experiments using different Evans’ auxiliaries (R= i-Pr-, Bn-, Ph-)
and B-/Ti-enolates in the deconjugative aldol reactions between
1 and 2,6-dimethylbenzaldehyde, the reaction conditions
involving the Ti enolates of 1 derived from 4-phenyloxazolidin-
2-one was determined to be optimal in terms of Evans syn
selectivity and reaction yield. The use of 1.1−1.2 equiv of TiCl4
relative to 1 was also found to be crucial for high stereo-
selectivities. All other synthons were similarly prepared from
either 1 or 4. In the aldol reactions of 4, the C3 geometry of 4 was
maintained without isomerization and rearrangement. The
synthons 3 and 6 are crystalline solids and can be stored at
ambient temperatures under air without any precautions.
With the synthons 3a−e in hand, we set out to explore their 2-
OCR reactions with benzaldehyde under the reaction conditions
involving TfOH in CH2Cl2 at −78 °C previously determined for
similar 2-OCR reactions.13 When the synthon 3a was used, the
corresponding 4-hydroxy-2,3-unsaturated imide 7 was obtained
in 83% yield (Table 1, entry 1). Lewis acids such as BF3·OEt2,
SiCl4, TiCl4, Sn(OTf)2, Sc(OTf)3, and TMSOTf were also
screened (entries 2−7),8 and TMSOTf was determined to be a
choice of acids, giving rise to 7 in 93% yield and with 99:1 dr
(entry 7). Under the optimal conditions, the synthon 3b
produced as high a reaction yield and dr as did 3a but resulted in a
faster 2-OCR reaction than 3a (entry 8). The other synthons,
3c−e, were found to be inferior to 3a and 3b. During the
optimization study, it was found that the “endogenous”
aldehydes, which were generated from the synthons used in
the 2-OCR reactions, also participated in the reactions to
produce byproducts 8 (entries 9−11), and epimerization took
place to some extent at the benzylic position in the case of 3c.
These results indicate that 3a and 3b are sterically and
electronically well-balanced in that their 2,6-dialkyl-substituted
phenyl group is a sufficient oxocarbenium stabilizer to facilitate
the 2-OCR reaction but not as strong as to cause epimerization at
the benzylic position. Furthermore, the steric encumbrance by
the 2,6-substituents can not only facilitate the rearrangement, but
also prevent the endogenous aldehydes from interfering with the
desired 2-OCR reaction. Otherwise mentioned, the synthons
derived from 2,6-diethylbenzaldehdye (3b, 1′E-6, and 1′Z-6)
were used in the 2-OCR reactions with aldehydes.
Figure 1. Prior approaches for the asymmetric synthesis of II and their
drawbacks.
Figure 2. Stereospecific 2-oxonia-Cope rearrangement reaction
between the chiral synthons III and aldehydes.
over IV is necessary to drive the reaction to the product side. We
envisioned that such a selective stabilization could be attained by
equipping the chiral synthons III with an aryl group with
strategically positioned substituents to create more favorable
electronic and steric environments for the formation of V.9,11
On the basis of the above reasoning, the chiral synthons 3 and
6 containing a substituted phenyl group were designed, wherein
an Evans’ chiral auxiliary was also incorporated for their
convenient asymmetric synthesis (Scheme 1). The synthons 3
were prepared by the aldol reactions between aromatic aldehydes
and the Evans-type imides 1 (Scheme 1).12 After numerous
The determined optimal 2-OCR conditions involving 3b and
TMSOTf in CH2Cl2 at −78 °C are applied to a diverse array of
aldehydes, and the results are displayed in Table 2. Linear and
functionalized linear aliphatic aldehydes worked well (entries 1,
6, and 7). β-Branched, α-branched, and cyclic aliphatic aldehydes
B
DOI: 10.1021/acs.orglett.7b03895
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Determination of the Optimal Reaction Conditions
for the 2-OCR Reaction between 3a and Benzaldehyde
Table 3. Asymmetric Anti- and Syn-Selective 2-Oxonia-Cope
Rearrangement Reactions by 1′E-6 and 1′Z-6
a
a
c
d
e
entry
synthon
acid
TfOH
7/8
yield (%)
dr of 7
g
1
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
>25:1
>25:1
83
ND
b
2
BF3·OEt2
SiCl4
83
ND
ND
ND
ND
ND
99:1
99:1
f
3
NR
ND
ND
ND
ND
93
4
TiCl4
NR
NR
5
Sn(OTf)2
Sc(OTf)3
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
6
NR
7
>25:1
>25:1
20:1
7:3
8
93
c
9
76
95:5
10
11
83
ND
ND
6:4
73
a
3a−e (0.15 mmol), benzaldehyde (1.1 equiv), and acid (1.50 equiv)
b
in CH2Cl2 (3 mL). 2.50 equiv of the acid was used at −50 °C.
c
d
e
Determined by 1H NMR. Combined yields of 7 and 8. Determined
f
g
by chiral HPLC. No reaction. Not determined.
Table 2. Asymmetric 2-Oxonia-Cope Rearrangement
a
Reactions between 3b and Aldehydes
a
6 (0.15 mmol), aldehyde (2.0 equiv), and TMSOTf (1.5 equiv) in
b
c
CH2Cl2 (4 mL). Isolated yields. Determined by H and 13C NMR.
1
d
e
1.5 equiv of TMSOTf at −15 to +4 °C (180 min). Yield at 1 mmol
scale.
Table 3 describes the asymmetric anti-selective 2-OCR
reactions between 1′E-6 and aldehydes. As in the case of 3b in
Table 2, structurally diverse aliphatic and aromatic aldehydes
were well accommodated to give good reaction yields and
excellent diastereoselectivities (entries 1, 3, 5, 7, 9, and 11). As
expected, the 1′E geometry and 2,3-syn stereochemistry of the
synthon 1′E-6 were specifically transferred to the 4,5-anti
stereochemistry and 2E geometry of 10, respectively.
Table 3 also describes the asymmetric syn-selective 2-OCR
reactions between 1′Z-6 and aldehydes. Again, the scope of the 2-
OCR reaction was quite broad, accommodating diverse
structural variations of aliphatic and aromatic aldehydes (entries
2, 4, 6, 8, 10, and 12). In addition to good reaction yields and
exclusive E-selectivities, excellent 4,5-syn selectivities (>25:1)
were obtained in all cases studied.
The results in Table 3, taken together with the data in Table 2,
convincingly indicate that the 2-OCR reactions of the developed
chiral synthons (3b, 1′E-6, and 1′Z-6) proceed with nearly
perfect chirality transfer, permitting total control of enantio- and
diastereoselectivity without the regioselectivity issue; this is not
possible with all other reported methods. A priori predictability
of the reaction stereochemistry is an additional advantage of the
2-OCR reaction.
As synthetic applications and to determine the stereo-
chemistry of 9 and 10, 9a, anti-10c, and syn-10c were converted
to the corresponding δ-lactones through a hydrogenation
reaction followed by an acid-catalyzed lactonization reaction in
a
3b (0.15 mmol), aldehyde (2.0 equiv to suppress the competing
reaction by 2,6-diethylbenzaldehyde generated), and TMSOTf (1.0
equiv) in CH2Cl2 (4 mL). Isolated yields. Determined by chiral
HPLC. Yield at 1 mmol scale.
b
c
d
performed as well (entries 2−4). Even sterically hindered
pivalaldehyde reacted smoothly. In all cases studied, excellent
reaction yields (≥89%) were obtained, and chirality transfer was
nearly perfect as evidenced by exceptional dr’s (≥98:2) and
exclusive E-selectivities.
C
DOI: 10.1021/acs.orglett.7b03895
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03895.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
A. V.; Kabeshov, M. A.; Barlog, M.; Koco
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hyunsoo.han@utsa.edu.
ORCID
Hyunsoo Han: 0000-0001-7821-5851
Notes
(12) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J.
Org. Chem. 2001, 66, 894−902. (b) Evans, D. A.; Sjogren, E. B.; Bartroli,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support by the National Science Foundation (CHE-1362964) is
greatly acknowledged.
(13) (a) Lee, J. S.; Kim, D.; Kong, S. B.; Han, H. Chem. - Eur. J. 2013,
19, 4135−4238. (b) Lee, J. S.; Kim, D.; Lozano, L.; Kong, S. B.; Han, H.
Org. Lett. 2013, 15, 554−557.
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DOI: 10.1021/acs.orglett.7b03895
Org. Lett. XXXX, XXX, XXX−XXX