Stereoselective synthesis of tertiary ethers through geometric control of highly substituted oxocarbenium ions

Article abstract of DOI:10.1002/anie.201002281

Fully substituted, fully controlled I The geometries of 1,1-disubstituted oxocarbenium ions and the conformations of oxocarbenium ions that contain a tertiary stereocenter can be predicted based on simple models. These models have been applied to highly stereoselective syntheses of tetrahydropyran derivatives that contain tertiary ethers (see scheme; RL, R_s, and R_N represent large, small, and nucleophilic groups, respectively). (Figure Presented)

Full text of DOI:10.1002/anie.201002281

Communications
DOI: 10.1002/anie.201002281
Oxocarbenium Ions
Stereoselective Synthesis of Tertiary Ethers through Geometric Control
of Highly Substituted Oxocarbenium Ions**
Lei Liu and Paul E. Floreancig*
Oxocarbenium ions are intermediates in a number of
synthetic processes including Prins cyclizations,[1] acid-medi-
ated additions to acetals,[2] allyl group transfers,[3] and
additions of carbonyls to electrophiles.[4] Stereocontrol in
these transformations can be quite high as a result of the
strong preference, calculated at approximately 2 kcalmolÀ1,[5]
for monosubstituted oxocarbenium ions to exist in E confi-
gurations. However, reports of geometric control for 1,1-
disubstituted oxocarbenium ions are rare[6] because the steric
difference between the alkyl groups is generally smaller than
the steric difference between an alkyl group and a hydrogen
atom. General models that predict the geometry of disub-
stituted oxocarbenium ions would be valuable for designing
syntheses of natural products or natural-product-like libra-
ries[7] that contain tertiary ether groups. Recently, our
research group reported[8] that intramolecular nucleophilic
additions to alkynyl-substituted oxocarbenium ions proceed
with minimal stereocontrol to provide cis- and trans-2,6-
disubstituted tetrahydropyrans. This unusual lack of stereo-
control results from the approximate energetic equivalence of
the E and Z oxocarbenium ions, which is a result of the small
steric difference between an alkynyl group and a hydrogen
atom (Scheme 1). Herein, we describe a rare application of
model that illustrates stereocontrol in intramolecular addi-
tions to monosubstituted oxocarbenium ions relative to a
tertiary ether.
We postulated that 1,1-disubstituted oxocarbenium ions
containing an alkyl group and an alkynyl group should exist in
a conformation in which the two alkyl groups have a
trans relationship in consideration of the minimal steric
demands of alkynyl groups. We chose to employ a DDQ-
mediated ether oxidation[9] protocol for carbocation forma-
tion to test this hypothesis because these conditions eliminate
the potential for acid-induced solvolytic product decomposi-
tion[10] The synthesis of the ether linkage between the two
branched carbon atoms in 2 (Scheme 2) was readily con-
Scheme 1. Alkynyl-substituted oxocarbenium ions.
Scheme 2. Stereocontrolled tertiary ether synthesis. Reagents and con-
ditions: a) Me3Al, toluene, 75%. b) Py·SO3, Et3N, DMSO, 92%.
c) Bestmann–Ohira reagent,[13] K2CO3, MeOH. d) HOAc, [{(p-cyme-
ne)RuCl2}2], Fur3P, Na2CO3, toluene,[14] 65%, two steps. e) DDQ, M.S.
(4 ꢀ), 2,6-Cl2Py, 1,2-dichloroethane, 72%. DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, DMSO=dimethyl sulfoxide, Fur3P=tri(2-
furyl)phosphine, M.S.=molecular sieves, Py=pyridine.
carbon–hydrogen bond functionalization for stereoselective
syntheses of molecules that contain fully substituted carbon
atoms. The approach is based on the development of a model
that is able to predict the geometries of 1,1-disubstituted
oxocarbenium ions involved in nucleophilic additions that
form tertiary ethers with high stereocontrol. We also report a
[*] L. Liu, Prof. Dr. P. E. Floreancig
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
structed by applying Yamamotoꢀs Me3Al-mediated acetal
opening protocol[11] to alkynyl acetal 1. Functional group
manipulations provided the cyclization substrate 3, which was
exposed to DDQ at room temperature and provided tetrahy-
dropyran 4 as a single stereoisomer in 72% yield. This
stereochemical outcome is consistent with our hypothesis that
the reaction proceeds through the oxocarbenium ion 5.
Although tertiary and spirocyclic ethers have been prepared
through intramolecular Prins-type additions to disubstituted
Fax: (+1)412-624-8611
E-mail: florean@pitt.edu
[**] We thank the National Institutes of Health and the Institute of
General Medicine (GM062924) for their generous support of this
work. We thank Prof. Paul Wender for valuable discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002281.
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oxocarbenium ions,[12] stereoselectivity has not been
addressed aside from reactions that proceed through a
specific isatin-derived ion.[6d–f]
This result led us to devise more generalized models of
oxocarbenium ion geometry to guide substrate design for the
stereocontrolled formation of cyclic tertiary ethers. One
approach was based on expanding the model for the geo-
metric control over 1,1-disubstituted oxocarbenium ions, and
the other was based on control over the trajectory of
nucleophilic approach by preexisting tertiary stereocenters
(Figure 1). The generalized model for 1,1-disubstituted oxo-
Table 1: Synthesis of tertiary ethers from oxidation of allylic and benzylic
ethers.[a]
Entry Substrate[b]
Product
t [h] d.r.[c] Yield
[%][d]
1
12
26:1 84
2
3
4
2.5 100:0 86
2
2
100:0 78
100:0 74
Figure 1. Models for geometrical control in highly substituted oxocar-
benium ions. The large, small, and nucleophilic groups on the tertiary
ether are labeled as RL, RS, and RN, respectively.
carbenium ion geometric control (model A) places the
smaller group (RS) in a cis relationship with the opposite
alkyl group and the larger group (RL) in a trans relationship.
Model B illustrates the manner by which preexisting tertiary
stereocenters can influence the sense of nucleophilic addition
into oxocarbenium ions. Thus RS occupies an eclipsed
orientation with the hydrogen atom of a monoalkyl oxocar-
benium ion. These models are similar to the reactive
conformation for the well-studied Corey–Bakshi–Shibata
(CBS) ketone reduction (model C),[15] and successful struc-
tural classes for CBS reactions were used to guide substrate
design in this study.
Alkynes serve as the RS substituent when compared to
alkyl groups in model A, but alkenes and arenes could serve
as the RL group. Thus, secondary allylic and benzylic ethers
should yield products that place the unsaturated groups in
equatorial orientations. These substrates reacted with mod-
erate stereocontrol in dichloroethane (not shown), but
changing the reaction solvent to nitromethane led to a
substantial improvement in selectivity. We postulate that the
more polar solvent stabilizes the intermediate oxocarbenium
ion, thus slowing the cyclization and lowering the barrier of
oxocarbenium-ion rotation,[16] and thereby allowing the ions
to equilibrate to their more stable isomers prior to ring
closure.
Representative examples of these cyclization reactions
are shown in Table 1. In each of these examples the alkenyl or
aryl group is the RL group. Allylic ethers 6 and 8 reacted quite
efficiently and provided tetrahydropyrans 7 and 9 with
excellent stereocontrol (Table 1, entries 1 and 2). Aryl
analogues were effective substrates, with diastereomeric
ethers 10 and 12 yielding 11 as a single stereoisomer
(Table 1, entries 3 and 4). The formation of the same isomer
starting from diasteromeric reagents provides support for a
planar oxocarbenium ion intermediate. Spirocyclic ethers,
which are subunits in many natural products,[17] are also
accessible through this protocol as shown in entries 5, 6, and 7
5
6
7
0.67 100:0 82
0.5 100:0 84
7
100:0 67
3:1 85[e]
10:1 82
8
5.5
4
9[f]
[a] Typical procedure: a 0.1 m solution of the substrate and 2,6-dichloropyr-
idine in MeNO2 was treated with DDQ and stirred at 08C or at RT for the
indicated time period. See the Supporting Information for details on specific
reactions. [b] See the Supporting Information for details on substrate
synthesis. [c] d.r.=diastereomer ratio normalized to 100. [d] Yields refer to
isolated, purified material unless otherwise noted. [e] Yield corresponding to
the mixture of stereoisomers.[f] Reaction was conducted at À608C in EtNO2.
of Table 1. These reactions were quite fast and extremely
stereoselective. Entries 8 and 9 of Table 1 show the effect of
using trans-1,2-disubstituted alkene substrates. Allylic ether
19 reacted with excellent efficiency, though the diastereocon-
trol was modest (3:1). This outcome is consistent with the
lower steric demand of a disubstituted alkene relative to a
trisubstituted alkene. The diastereomeric products were
separable, however, and the major product could be isolated
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as a pure compound in good yield. Cinnamyl ethers are
and 3). The potential for alkyl groups to occupy the RS site
was demonstrated through the cyclization of 29 to form
spirocycle 30 (Table 2, entry 4). While diastereocontrol was
not an issue for this reaction, the transformation was
important for expanding the scope of the process to include
saturated tertiary ether substrates. Diastereocontrol was
demonstrated in the cyclization of 31 to 32 (Table 2,
entry 5), in which the unbranched group was the
RS substituent and the branched group was the
RL substituent. These spirocyclization reactions were quite
rapid, and allowed the transformations to be conducted at
À308C to maximize stereocontrol. Unfortunately, attempts to
prepare tetrahydropyrans with two quaternary stereocenters
failed, as demonstrated by the DDQ oxidation of 33 (Table 2,
entry 6). No reaction was observed at room temperature and
nonspecific decomposition of the starting material was
observed at elevated temperatures. Presumably the steric
interactions in this system are simply too significant to
overcome through ether oxidation.
significantly more reactive than allylic ethers, and allowed the
reaction of 21 to be conducted at À608C in nitroethane to
provide 22 in 82% yield as a 10:1 mixture of diastereomers
within 4 hours.
Our success in this phase of the project led us to explore
applications of model B, in which tertiary ethers serve to
direct the generation of new stereocenters. Prenyl ethers were
used in this study because of their exceptional efficiency in
these reactions. The results of these cyclization reactions are
shown in Table 2. Propargylic ether 23 smoothly reacted to
form 24 as a single stereoisomer (Table 2, entry 1). The
stereochemical outcome of this reaction is consistent with the
alkynyl group serving as the RS substituent. In contrast to
model A, alkenyl groups act as the RS substituent in this
model, as shown in the cyclizations of 25 and 27 to form
tetrahydropyrans 26 and 28, respectively (Table 2, entries 2
Table 2: Tertiary ether substrates in stereoselective cyclization reac-
A postulate for the steric differences of alkenes in
models A and B is shown in Figure 2. The conjugation
between the alkene and the oxocarbenium ion in model A
forces the substituent on the alkene to project across the ether
tions.[a]
Entry Substrate[b]
Product
t [h] d.r.[c] Yield
[%][d]
1
2.5 100:0 79
2
3
2
15.7:1 95
0.5 100:0 76
Figure 2. Steric interactions for alkenes in models A and B.
linkage in the disfavored configuration. The alkenyl groups in
model B can orient their sterically undemanding flat faces
toward the substituents across the ether linkage to minimize
steric interactions. An electrostatic attraction between the
p electrons and the electron deficient formyl hydrogen
atom[18] could further stabilize this conformation. From a
synthesis perspective the fact that alkenyl groups serve as the
smaller substituent in this model illustrates that stereochem-
ically complementary unsaturated products can be prepared
by judicious substrate design.
4
0.3
–
88
5[e]
5
–
100:0 81
The applicability of models A and B to related reactions is
shown in Scheme 3. The condensation of acetophenone (34)
with homoallylic alcohol 35 in the presence of TMSCl and
NaI[12c] provided, after radical-mediated removal of iodide,
6[f]
–
–
–
tetrahydropyran 36 as a single isomer. Aldehyde 38 con-
[a] Typical procedure: a solution of the substrate and 2,6-dichloropyr-
idine in 1,2-dichloroethane was treated with DDQ and stirred for the
indicated time period. [b] See the Supporting Information for details on
substrate synthesis. [c] d.r.=diastereomer ratio normalized to 100.
[d] Yields refer to isolated, purified material. [e] Reaction was conducted
at À308C. [f] no reaction occurred.
[19]
densed with tertiary alcohol 37 and AlCl3
and yielded
chlorotetrahydropyran 39, also as a single stereoisomer. The
yields of these reactions were rather low because of the
competitive ionization and of the oxonia-Cope-type reac-
tions,[20] but the procedures were not optimized because our
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Scheme 3. Applications to acid-mediated Prins reactions. AIBN=azo-
bisisobutyronitrile, TMS=trimethylsilyl.
main interest was focused on determining the stereochemical
outcomes of these transformations.
In conclusion, we have shown that two models can be
applied to design stereocontrolled reactions that yield tetra-
hydropyrans with tertiary ethers. In one model the geometry
of unsaturated 1,1-disubstituted oxocarbenium ions can be
predicted based on the steric differences between the two
substituents. The other model uses preexisting quaternary
centers to control the geometry of oxocarbenium ions. While
oxidative carbocation formation was employed to initiate the
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Received: April 16, 2010
Revised: June 9, 2010
Published online: July 13, 2010
À
Keywords: carbocations · C H activation ·
conformational analysis · oxidation · stereoselectivity
.
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