Using Neighboring-Group Participation for Acyclic Stereocontrol in Diastereoselective Substitution Reactions of Acetals

Article abstract of DOI:10.1021/acs.orglett.0c01166

Neighboring-group participation of an ester enabled stereocontrol in substitution reactions of acyclic acetals. The ester group formed a trans-fused dioxolenium ion intermediate, which underwent a substitution reaction at the acetal carbon atom to afford the product with high diastereoselectivity. Neighboring-group participation was confirmed by isolating dioxolane products resulting from nucleophilic addition at C-2 of a 1,3-dioxolenium ion intermediate. Using a pivaloate ester as the participating group in combination with strong nucleophiles produced substitution products with diastereoselectivities of ≥90:10.

Full text of DOI:10.1021/acs.orglett.0c01166

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Letter
Using Neighboring-Group Participation for Acyclic Stereocontrol in
Diastereoselective Substitution Reactions of Acetals
Amanda Ramdular and K. A. Woerpel*
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ABSTRACT: Neighboring-group participation of an ester enabled
stereocontrol in substitution reactions of acyclic acetals. The ester
group formed a trans-fused dioxolenium ion intermediate, which
underwent a substitution reaction at the acetal carbon atom to afford
the product with high diastereoselectivity. Neighboring-group
participation was confirmed by isolating dioxolane products resulting
from nucleophilic addition at C-2 of a 1,3-dioxolenium ion intermediate. Using a pivaloate ester as the participating group in
combination with strong nucleophiles produced substitution products with diastereoselectivities of ≥90:10.
eighboring-group participation is a widely used approach
to control stereochemistry in substitution reactions of
Scheme 1. Rates of Hydrolysis of Acetals with Different
Neighboring Groups
N
carbohydrate compounds.1−3 Most commonly, acyloxy groups,
namely, the acetate, benzoate, and pivaloate esters,1,4,5 are used
to favor the 1,2-trans products with high selectivity.1,4,6
Neighboring-group participation has not emerged as a useful
approach for controlling stereochemistry in reactions involving
acyclic acetals, however.7−18 The use of neighboring-group
participation to control stereochemistry in acyclic systems, as
illustrated in eq 1, would be significant because it would
provide access to the products expected from nucleophilic
additions to α-alkoxy aldehydes that would be governed by the
Felkin−Anh or related19−21 stereochemical models. Such
transformations, however, often give products with modest
diastereoselectivity.8,16,22−24
In this paper, we demonstrate that neighboring-group
participation of an ester group adjacent to an acetal can
provide high diastereoselectivity in substitution reactions.
These reactions likely proceed through five-membered ring
intermediates, such as 2, which then undergo nucleophilic ring
opening to provide the 1,2-syn products 3 (eq 1).
considering that the magnitude of the acceleration is similar to
that observed for carbohydrates.5,26 As the donating ability of
the acyl group increased,5 the rate of ionization increased,
which is consistent with participation of the carbonyl group
(eq 1). The similar rates of hydrolysis of acetals bearing alkyl
and aryl groups (i.e., 4a and 4d) indicate that the generation of
the cationic intermediates in these reactions is dominated by
the donation of electrons from the acyloxy group.1,27 This
observation contrasts with those of studies of β-phenyl-
The rates of hydrolysis of acyclic acetals indicated that an
acyloxy group near an acetal can influence the rate of
ionization by neighboring-group participation, as observed
for cyclic acetals.25 The rates of hydrolysis of acetals 4a, 4d, 7a,
and 7b bearing α-acyloxy groups were accelerated compared to
the ionization of an acetal with an α-methoxy group, 6
(Scheme 1). This acceleration likely reflects stabilization of the
developing positive charge by neighboring-group participation,
Received: April 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01166
© XXXX American Chemical Society
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substituted acetals, where the phenyl group inductively
destabilized the cationic intermediate, leading to a >20-fold
slower ionization compared to an acetal without a phenyl
group.28
More direct evidence supporting the participation of the
acyloxy group was obtained upon treatment of pivaloate esters
4a−c with Me3SiCN in the presence of a Lewis acid (Scheme
2).29 The formation of dioxolane products 8a−c represents an
which is unlikely.33 This reversibility would require that the
acyclic oxocarbenium ion 10 not be too high in energy
compared to dioxolenium ions 9 and 11 (Scheme 3).2,3,34,35
Experiments with an acetal bearing a tert-butyl carbonate
group provided additional evidence that a dioxolenium ion was
an intermediate in these reactions.36 Upon treatment of
carbonate 12 with a Lewis acid or SiO2 gel, cyclic carbonate 14
was formed (Table 1), likely upon release of the tert-butyl
Scheme 2. Reactions of Pivaloate Esters to Give Dioxolane
Products
Table 1. Formation of Cyclic Carbonate
acid
nucleophile
dr (anti:syn)
% yield
Me3SiOTf
SiO2
Me3SiOTf
none
none
96:4
76:24
76:24
71
39
9
a
H2CCHCH2SnBu3
a
The low yield resulted from difficulty in purifying the product.
cation from dioxolenium ion 13.36 These products were prone
to epimerization upon purification using SiO2, so the
diastereoselectivities are likely not representative of the kinetic
products of cyclization.
unusual case of nucleophilic addition at the participating
pivaloyl group, which is generally sterically disfavored.1,4,5,30,31
Dioxolane-substituted products 8a and 8c were obtained as
97:3 mixtures of diastereomers (Scheme 2).25 The relative
stereochemical configurations of these compounds were
assigned by NOE measurements, and the structure of 8c was
confirmed by X-ray crystallography. These experiments reveal
that the dioxolane favors a 1,2-trans relationship between the
ethoxy and aryl groups (i.e., 11 in Scheme 3), likely because
With the demonstration that neighboring-group participa-
tion was possible with acyclic acetals, attention turned to the
development of the ring opening of dioxolenium ions with
carbon nucleophiles. The successful formation of acetal
substitution products using allyltributylstannane as the
nucleophile depended upon the reaction conditions. Sub-
stitutions of acetal 4a bearing the pivaloyl protecting group
using numerous Lewis acids were unsuccessful, likely because
of the strongly electron-withdrawing nature of the acetoxy
group.5,26 The Lewis acids BF3·OEt2, SiCl4, SnCl4, and
Et3SiOTf activated the acetal group, but only at temperatures
above −40 °C. The use of Me3SiOTf proved to be most
successful, although TiCl4 and Bi(OTf)3 could also be used to
form the desired products at low temperatures. The fact that
the presence of the triflate ion was not necessary for high
selectivity argues against a covalently bound triflate species as a
reactive intermediate. These reactions provided both the
desired product 15a and the undesired dioxolane 16a. With
the more polar solvents MeCN and EtCN, significant
quantities of undesired dioxolane product 16a were formed
(Table 2).37,38 The major diastereomer of acyclic substitution
product 15a in the nitrile solvents was the same as for reactions
with CH2Cl2 as the solvent, which indicates that there is no
special influence of the nitrile solvent.39−41 The nonpolar
solvent toluene gave the highest proportion of desired acyclic
product 15a (Table 2). This observation is consistent with
studies of product distributions as a function of solvent for
carbohydrates with neighboring acyloxy groups.37 Lower
concentrations (0.1 M), which favor neighboring-group
participation in reactions of carbohydrates,42 gave the highest
stereoselectivities. At temperatures below −45 °C, it is likely
that ionization was too slow (Table 2).43,44
Scheme 3. Equilibrium of Oxocarbenium and Dioxolenium
Ions
these groups would be eclipsed in the essentially planar five-
membered ring intermediate in the cis isomer (9).32 The
stereochemical configuration at the nitrile-bearing carbon atom
results from preferential nucleophilic attack on the major
dioxolenium ion 11 from the more accessible face. Substitution
reactions of acetal 4b with Me3SiCN, however, showed a
decrease in diastereoselectivity of the dioxolane product
(Scheme 2). The amount of the trans diastereomer of
dioxolenium ion 11 (Scheme 3) with the smaller substituent
decreases likely because the unfavorable eclipsing interactions
are not as prominent between the alkyl and ethoxy groups.
The high diastereoselectivities observed for the formation of
dioxolanes 8a and 8c (Scheme 2) suggest that formation of
dioxolenium ion 11 (Scheme 3) is reversible. If this ionization
step were not reversible, the Lewis acid would need to
differentiate between the two diastereotopic ethoxy groups,
A control experiment indicated the importance of
neighboring-group participation for obtaining the products
with high diastereoselectivity. The substitution reaction of
B
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consistent with the expected steric differences between
dioxolenium ions 9 and 11. The fact that ethyl acetal 4a
reacted with a diastereoselectivity [90:10 (Scheme 4)] lower
than that observed for the reaction with Me3SiCN [97:3
(Scheme 2)] confirms that an equilibrium is established with
dioxolenium ions 9 and 11 and acyclic oxocarbenium ion 10
(Scheme 3). Formation of both isomers of the product
requires that both cis- and trans-substituted dioxolenium ions 9
and 11 are present (Scheme 3) and that the product ratio
reflects different rates of reaction of these intermediates with
nucleophiles.
The ability of a carbonyl group to participate exerted a
strong influence on the outcomes of these substitution
reactions.5,26 For the ester participating groups, increasing
the donating ability of the participating group, as defined by
the kinetic studies (Scheme 1), resulted in an increased level of
formation of the undesired dioxolane regioisomer [acetal 7b
(Table 3)]. It is likely that the dioxolenium ion is more
Table 2. Optimization of Reaction Conditions
solvent polarity (ET) temp (°C) 15a:16a dr (15a) % yield (15a)
MeCN
EtCN
CH2Cl2
CH2Cl2
MePh
MePh
46
43.7
41
41
33.9
33.9
−40
−78
−45
−78
−45
−78
47:53
49:51
70:30
68:32
95:5
75:25
80:20
90:10
90:10
90:10
82:18
39
36
53
61
82
29
a
>99:1
a
Reaction proceeded to 30% completion.
acetal 6 (eq 2) afforded the substitution product with no
selectivity. This result confirms that reactions through an open
Table 3. Influence of Neighboring Groups on Selectivity
transition state resembling the Felkin−Anh transition state will
not be stereoselective.
Substitution reactions of pivaloyl-substituted acetals 4a, 18,
and 19 with different alkoxy groups (Scheme 4) under the
major
dr
% yield
(ester)
acetal
R
product
ester:dioxolane (ester)
7a
4a
7c
7b
7d
4-O2NC6H4
tBu
24a
15a
25a
26b
27a
>99:1
70:30
79:21
<1:99
>99:1
78:22
90:10
85:15
−
43
53
54
C6H5
Scheme 4. Influence of the Size of the Alkoxy Group on
Selectivity
a
4-MeOC6H4
NHtBu
72
78:22
88
a
Yield of dioxolane product 26b.
stabilized by the strong participating group, so the nucleophile
cannot readily open it to form the acyclic product. By contrast,
reactions of carbamate 7d did not give products derived from
attack at C-2 of dioxolenium ion 28, likely because it is too
stabilized.26
The stabilizing influence of the acyloxy group is reflected in
both the reactivity and stereoselectivity of these reactions.
Attempted substitution reactions with nucleophiles that are
weaker than allyltributylstannane,43 such as allyltrimethylsilane
and methallyltrimethylsilane, did not occur in PhMe. These
reactions did proceed in CH2Cl2, however, producing the
substitution products with little stereoselectivity (Table 4).
These results can be understood by postulating an increased
concentration of oxocarbenium ion 10 compared to that of
dioxolenium ion 11 in the more polar solvent (Scheme 5).
This change in concentration would result because oxocarbe-
nium ions, which have a higher charge density, would be more
favored in the polar medium. In the more polar solvent,
oxocarbenium ion 10, although formed in only small amounts,
optimized conditions provided additional support that these
reactions involve equilibration of dioxolenium ions 9 and 11
and acyclic oxocarbenium ion 10 (Scheme 3). Substitution
reactions of methyl acetal 18 gave small quantities of two
dioxolane products, 22 and 23. Benzyl acetal 19 reacted with
the highest diastereoselectivity, but the yields were lower
because this acetal was particularly prone to decomposition.
The observation that increasing the size of the alkoxy groups of
the acetal increased the diastereoselectivity of the products is
C
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Table 4. Influence of the Nucleophile and Solvent on
Scheme 6. Influence of Side Chain on Selectivity
Reactivity
N
%
Nu−M
factor43
7.48
solvent product
dr
yield
H2CC(Me)
MePh
29
93:7
45
CH2SnBu3
H2CCHCH2SnBu3
5.46
4.41
MePh
CH2Cl2
15a
29
90:10
70:30
82
89
H2CC(Me)
CH2SiMe3
H2CCHCH2SiMe3
1.68
CH2Cl2
15a
54:46
87
Scheme 5. Nucleophiles React by Different Pathways
This reaction provides a highly stereoselective alternative route
for preparing products expected from Felkin−Anh additions to
carbonyl compounds.
ASSOCIATED CONTENT
* Supporting Information
■
sı
would be electrophilic enough to react with the allylic silane
nucleophiles. Considering that these reactions would proceed
through open carbocations, it is reasonable that they would
react with diastereoselectivities comparable to that of the
reaction of the methyl ether 6a (eq 2).35 By contrast, reactions
with a stronger nucleophile, methallyltrimethylstannane,43
occurred with higher diastereoselectivity (Table 4). The
increased diastereoselectivity observed with an increase in
the nucleophilicity of the nucleophile suggests that this
reaction proceeds through the stabilized intermediate 11
(Scheme 5).45
The scope of the reaction demonstrates that the general
features of the substitution reaction hold for other substrates.
Substitution reactions of acetals 4a−f showed that increasing
the steric demand of the side chain in comparison to that of
the alkoxy group increased the diastereoselectivity of the
reaction (Scheme 6). This correlation of steric size and
reactivity could reflect a lower preference for the trans
diastereomer of the dioxolenium ion with smaller substituents.
Useful levels of stereochemical control can be achieved
provided that the substituent is branched. The similar
diastereomeric ratios of 15a and 15d, which have side chains
of similar size, suggest that steric effects of the side chain
influence stereoselectivity more so than electronic effects, a
finding that is supported by the kinetic data (Scheme 1). The
reaction of optically pure α-pivaloyloxy acetal 4f (Scheme 6),
which was readily prepared by enzymatic kinetic resolution,46
demonstrates that this reaction can be used to prepare
enantiomerically enriched products.12,15
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01166.
Experimental procedures, characterization of new
compounds, stereochemical proofs, kinetic data, X-ray
1
data, and H and 13C NMR spectra of new compounds
(PDF)
Accession Codes
CCDC 1987988 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
K. A. Woerpel − Department of Chemistry, New York
University, New York, New York 10003, United States;
orcid.org/0000-0002-8515-0301; Email: kwoerpel@
nyu.edu
Author
Amanda Ramdular − Department of Chemistry, New York
University, New York, New York 10003, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01166
In summary, neighboring-group participation to control the
diastereoselectivity of acetal substitution reactions can be
extended from carbohydrates to encompass acyclic acetals.
Notes
The authors declare no competing financial interest.
D
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Letter
(30) Fraser-Reid, B.; Grimme, S.; Piacenza, M.; Mach, M.; Schlueter,
ACKNOWLEDGMENTS
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This research was supported by the National Institutes of
Health (NIH), National Institute of General Medical Sciences
(1R01GM129286). The authors acknowledge New York
University’s Shared Instrumentation Facility and the support
provided by National Science Foundation Grant CHE-
01162222 and NIH Grant S10-OD016343. The authors
thank Dr. Chin Lin (New York University) and Dr. Chunhua
(Tony) Hu (New York University) for their help with NMR
and X-ray data, respectively.
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