Vinylogous Mukaiyama-Michael Reactions of Dihydropyridinones

Article abstract of DOI:10.1021/acs.orglett.5b02778

An In(III)-catalyzed vinylogous addition of O-silyl vinylketene acetals to 2,3-dihydro-4-pyridinones has been developed. The method features the unprecedented employment of supersilyl groups to influence the γ versus α regiochemical control of vinylogous Mukaiyama-Michael (vM-Michael) reactions when γ-substituted O-silyl vinylketene acetals are used. We also demonstrate that these reactions allow facile access to quinolizidine-based alkaloids such as deoxynupharidine and well as lasubine I and II.

Full text of DOI:10.1021/acs.orglett.5b02778

Letter
pubs.acs.org/OrgLett
Vinylogous Mukaiyama−Michael Reactions of Dihydropyridinones
Hui Li and Jimmy Wu*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States
S
* Supporting Information
ABSTRACT: An In(III)-catalyzed vinylogous addition of O-silyl
vinylketene acetals to 2,3-dihydro-4-pyridinones has been
developed. The method features the unprecedented employment
of supersilyl groups to influence the γ versus α regiochemical
control of vinylogous Mukaiyama−Michael (vM−Michael)
reactions when γ-substituted O-silyl vinylketene acetals are used.
We also demonstrate that these reactions allow facile access to
quinolizidine-based alkaloids such as deoxynupharidine and well
as lasubine I and II.
as (+)-6-hydroxythiobinupharidine and others (recently synthe-
sized by our group).8 The lack of knowledge about this reaction
type may be because the vinylogous process is a more challenging
bond construction since synthetically useful vinylogous
Mukaiyama−Michael (vM−Michael) reactions must simulta-
neously address both regioselectivity (i.e., α- vs γ-attack and 1,2- vs
1,4-addition) and diastereoselectivity during C−C bond con-
struction.9 In order to diminish the amount of α-alkylated
products, nearly all of the previous reports elected to use cyclic
vinylogous substrates (e.g., silyloxyfurans) with a strong inherent
preference for γ-selectivity.9d In contrast, the use of linear
substrates such as 3 remains elusive due to poor regioselectivity
(α- vs γ-attack), reactivity, and diastereoselectivity. To the best of
our knowledge, only limited reports have employed linear
substrates in vM−Michael reactions.9b−g
2,3-Dihydro-4-pyridinones 1 (Scheme 1) are versatile building
blocks used to construct nitrogen-containing heterocyclic
frameworks.1 They have been described to undergo 1,4-
conjugate addition with various aryl,2 alkyl,3 and alkenyl4
nucleophiles. In addition, their capacity to participate in
Mukaiyama−Michael reactions has been shown by Comins
and co-workers using O-silyl ketene acetal 2.5
Scheme 1. Michael Reactions of 2,3-Dihydro-4-pyridinone
We initiated our study by examining the reaction between
dihydropyridinone 5a and γ-substituted 3,4-E silyl vinylketene
acetal 3a (Table 1, entry 1). In(OTf)3 is an air and moisture
stable catalyst that we identified to be effective in promoting the
vinylogous addition to form 6a as the major product (see
Supporting Information for a complete survey of Lewis acids).
No 1,2-addition product was isolated. The reaction, however,
only showed moderate regiochemical control with respect to the
silyl ketene acetal (γ- vs α-attack). Performing the reaction at
−20 °C resulted in diminished γ vs α regioselectivity but slightly
increased diastereoselectivity (entry 2). Interestingly, the use of
3,4-Z silyl ketene acetal 3b reversed the diastereoselectivity
(entry 3), which suggested that the geometry of 3,4-double bond
of 3 plays a role in the stereochemical outcome of the vinylogous
addition.
To address the issue of α- vs γ-attack, we reasoned that
differentiating the steric properties of chemical space around the
α- and γ-positions of 3 may alter their inherent nucleophilicities.
Inspired by the pioneering studies of Yamamoto with regards to
using supersilyl groups to influence the chemo- and stereo-
Nonetheless, little is known about the reactivity of 1 with
vinylogous silyl ketene acetals 3 although (1) the presence of an
extra alkene in the products renders this type of reaction more
efficient in increasing molecular complexity as compared to its
Mukaiyama−Michael counterpart and (2) the resulting piper-
idines 4 may be transformed into highly functionalized
quinolizidines (Scheme 1), thus providing potential approaches
toward lasubine I and II,6 and the dimeric nuphar alkaloids,7 such
Received: September 24, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02778
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Letter
a
Table 1. Optimization of Reaction Conditions
3 (E:Z)
yield (%)
b
c
d
entry
3
Si
TBS
1,2
3,4
temp (°C)
time (h)
γ
α
dr
1
2
3
4
5
6
3a
3a
3b
3c
3d
3d
1:2.7
1:2.7
1:8.0
1:5.0
<1:20
<1:20
>20:1
>20:1
<1:20
>20:1
>20:1
>20:1
rt
0.5
1.0
0.5
2.0
1.0
2.0
46
31
60
83
83
81
43
56
29
<5
<5
<5
5.2:1
5.7:1
1:6.8
2.7:1
5.8:1
7.1:1
TBS
−20
rt
TBS
TTESS
TTMSS
TTMSS
−30
rt
−20
a
b
c
3 (2 equiv), 5a (1 equiv), catalyst (5 mol %), reaction concentration 0.2 M. Isolated yield for γ-alkylated 1,4-adducts. Isolated yield for α-alkylated
d
1
1,4-adducts. Ratio of 6a:6a-minor as determined by H NMR spectroscopy.
selectivity of various reactions,10 we investigated the tris-
(triethylsilyl)silyl (TTESS) and tris(trimethylsilyl)silyl
(TTMSS) groups (entries 4, 5) and discovered that their use
substantially favors. Their use substantially favors the formation
of γ-alkylated products. After surveying different temperatures
(see Supporting Information), the best regio- and diastereose-
lectivity were obtained by conducting the reaction at −20 °C in
toluene and using TTMSS as a protecting group (entry 6).
As shown in Table 2, the vinylogous addition of vinylketene
acetals with diverse γ-substituents (alkyl, aryl, benzyl) proceeded
smoothly. The employment of the TTMSS group greatly
enhanced γ-regioselectivity (<5% of α-products were isolated
in all cases). Notably, the use of a TBS group in place of TTMSS
resulted in very poor α- vs γ-selectivity.11 Smaller protecting
groups at the nitrogen of dihydropyridinone 5 tended to give
better stereochemical control (entry 1 vs 2). In some cases, a
higher catalyst loading (10 mol %) was necessary to drive the
reaction to completion (entries 3, 5−10). The reactions yielded a
diverse range of piperidines 6b−k with good diastereoselectivity.
The relative stereochemical configurations of 6a, minor
diastereomer 6a-minor, and 6c were assigned by converting
them to known quinolizidine compounds (vide infra and also see
Supporting Information) while the relative stereochemical
relationships of the remaining products were assigned by
analogy.
Scheme 2 illustrates our proposed transition-state model to
rationalize the observed stereochemical outcome. We assume
Scheme 2. Stereochemical Models for 3d + 5a
Table 2. vM−Michael Reactions of Dihydropyridinones with
a
γ-Substituted Vinylketene Acetals
that the reaction between 3d and 5a may preferentially adopt an
antiperiplanar transition state TS1,12 which could be stabilized
by secondary orbital overlap (i.e., π−π stacking interactions)13
between the vinylketene moiety of 3d and the carbamate of 5a.
The model TS2, which proceeds through a synclinal transition
state, could be unfavored because the tetrahedral methyl group
on 3d may experience strong nonbonding interactions with the
carbamate of 5a.
With regard to the vinylogous addition of γ-unsubstituted O-
TBS vinylketene acetals 914 to various 2-substituted dihydropyr-
idinones (Table 3; see Supporting Information for optimization
details), a range of trans-disubstituted 4-piperidinones were
derived with high γ-selectivity without the need for employing a
supersilyl group (<5% of α-products were isolated in all cases).
This is likely because the absence of a substituent on the γ-
position of 9 renders it more nucleophilic than the α-position
toward Michael addition. Moreover, larger C2-substituents on 8
resulted in relatively higher diastereoselectivity (e.g., entry 1 vs
6). The catalyst loading may be lowered to 2.5 mol % in the
a
b
5 (1 equiv), 7 (2 equiv), reaction concentration 0.2 M. Isolated yield
c
1
for γ-alkylated 1,4-adducts. Determined by H NMR spectroscopy.
d
e
−20 to 0 °C. 2,3-E/Z > 20:1.
B
DOI: 10.1021/acs.orglett.5b02778
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Letter
consistent with the model proposed previously of trans-addition
of aryl cuprates to dihydropyridinones.15
Having developed the vM−Michael reaction of 2,3-dihydro-4-
pyridinones with vinylogous silyl ketene acetals, we turned our
attention to its incorporation in the syntheses of related
quinolizidine alkaloids, including deoxynupharidine, lasubine I
and II.
Table 3. vM−Michael Reactions of 2-Substituted
Dihydropyridinone with γ-Unsubstituted Vinylketene
Acetals
a
A formal synthesis of deoxynupharidine is shown in Scheme 4,
which began with the hydrogenation/hydrogenolysis of 6a to
Scheme 4. Formal Synthesis of Deoxynupharidine
simultaneously reduce the alkene and remove the Cbz group.
This was followed by spontaneous lactam formation to give
quinolizidine 11 in a single step from 6a. Our initial attempt to
obtain compound 12 via direct α-methylation of the C3 position
of 11 was unsuccessful as the reactions gave complex mixtures.
We then elected to pursue an alternative route by first installing a
methylene group at C3 of 11. After screening various reaction
conditions, morpholine-TFA salt was identified as an effective
catalyst to promote regioselective C3-methylenation to give
enone 13.17 Its C1-methylenated isomer was not observed based
on 1H NMR spectroscopic analysis. Compound 13 then
underwent diastereoselective hydrogenation to give intermediate
12, which was followed by modified Wolff−Kishner reduction to
yield a mixture of 14 and a minimal amount of its C3-epimer
(15.6:1). Quinolizidine 14 can be converted to deoxynuphar-
idine in one step as described by Harrity and others.18
a
b
9 (2 equiv), 8 (1 equiv), reaction concentration was 0.2 M. Isolated
c
yield for γ-alkylated products. Determined by 1H NMR spectroscopy.
d
e
f
Solvent: toluene/DCM (v/v = 9:1). 10: 2,3-E:Z > 20:1. The relative
stereochemical configuration of all the products were established by
NOESY experiments (see Supporting Information).
reaction starting from 2-vinyl dihydropyridinone (entry 4), while
10 mol % was necessary to drive the reaction to completion when
using 9d as a nucleophile (entry 12).
We hypothesize that the observed anti-facial selectivity arises
from a combination of stereoelectronic and steric control. Based
on the reported X-ray crystal structure of N-Cbz-2- phenyl-3,4-
dihydro-4-pyridinone,15 we propose that 8a exists in a half-boat
conformation (Scheme 3), with the C2 phenyl group adopting a
Scheme 3. Stereochemical Models for 8a + 9a
To achieve the synthesis of lasubine I and II (Scheme 5), a
mixture of disubstituted piperidinones 10i and its cis-
diastereomer (10i:10i-cis = 4.5:1) was subjected to simultaneous
hydrogenation and hydrogenolysis, followed by acid-mediated
Scheme 5. Formal Synthesis of Lasubine I and II
pseudoaxial position to avoid A(1,3) interactions with the N-Boc
group. Axial attack of vinylketene acetal 9a from either top or
bottom would generate, respectively, the chairlike syn-adduct
10a-cis or the higher energy twist boat-like anti-adduct 10a.16 But
although the delivery of 9a from the top is predicted to be favored
based on stereoelectronic considerations, it may experience
greater steric repulsion from the C2 phenyl group of 8a, thus
making bottom-face attack energetically more favorable. This is
C
DOI: 10.1021/acs.orglett.5b02778
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In conclusion, we have developed In(III)-catalyzed stereo-
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which provide diversified synthetic approaches to access
quinolizidine alkaloids. We have also demonstrated the first
use of the supersilyl group to govern the γ-vs-α regiochemical
outcome of vM−Michael reactions. This “supersilyl” strategy
may be extended to analogous processes in which γ-substituted
silyl vinylketene acetals are utilized.
ASSOCIATED CONTENT
* Supporting Information
■
S
́
(f) Casamitjana, H.; Jorge, A.; Perez, C. G.; Bosch, J.; Espinosa, E.;
Molins, E. Tetrahedron Lett. 1997, 38, 2295−2298. (g) Chan, T. H.;
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02778.
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Experimental details and characterization of all new
compounds, including 1H, 13C, and selected 2D-NOESY,
2D-COSY, HMBC, and HMQC data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jimmy.wu@dartmouth.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11)
J.W. was supported, in part, by a Research Scholar Grant (RSG-
13-011-01-CDD) from the American Cancer Society.
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