Highly stereoselective ring expansion reactions mediated by attractive cation-n interactions

Article abstract of DOI:10.1002/anie.200801591

Gaining control: An attractive electrostatic force stabilizes the conformation of an intermediate (see scheme; n=nonbonded electron), thus controlling the leaving group configuration to give superior diastereoselectivity in an asymmetric ring expansion. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200801591

Angewandte
Chemie
DOI: 10.1002/anie.200801591
Asymmetric Ring Expansion
Highly Stereoselective Ring Expansion Reactions Mediated by
Attractive Cation–n Interactions**
Timothy Ribelin, Christopher E. Katz, Donna G. English, Sherriel Smith, Anna K. Manukyan,
Victor W. Day, Benjamin Neuenswander, Jennifer L. Poutsma,* and Jeffrey AubØ*
Most stereoselective reactions are ruled by steric effects. In
particular, kinetically controlled asymmetric transformations
utilizing chiral reagents, auxiliaries, or catalysts succeed
because of energy differences in the transition states that
most often arise by the minimization of repulsive, nonbonded
interactions. Stereoelectronic considerations, which arise
when the alignment of particular orbitals are necessary for a
successful reaction, can also play a role.[1] An iconic stereo-
electronic effect in organic chemistry is the anomeric effect.[2]
Reactions controlled by the anomeric effect, such as glyco-
sidations, largely depend on the relative orientation of the
nonbonding or n electrons of a nearby alkoxy group. In recent
years, alkoxy group control of stereoselective reactions by
electrostatic interactions has received renewed scrutiny, led
by the Woerpel group.[3] In this communication, we report an
alternative and highly effective approach to stereocontrol
through the maximization of attractive nonbonded interac-
tions between an alkoxy or alkylthio group and a positively
charged leaving group.
The Lewis acid promoted reaction of a symmetrically
substituted cyclic ketone with a chiral hydroxyalkyl azide
provides a stereoselective route to lactams (Scheme 1).[4] In
this reaction, initial formation of a spirocyclic intermediate
sets up the selective migration of one of the methylene
groups, originally adjacent to the ketone carbonyl group.
+
À
Migration of a C C bond antiperiplanar to the N2 leaving
group (only possible when the latter is in an axial position as
shown) affords an iminium ether that is converted into lactam
Scheme 1. Origin of selectivity in asymmetric Schmidt reactions.
by workup with aqueous base. For 1- or 3-substituted
azidopropanols (not shown), 10:1 selectivities are obtained,
corresponding to preferential reaction through the most
stable chairlike heterocyclic ring (A or B) resulting from
equatorial addition of the azide group relative to the tert-butyl
group. Intermediates A and B can interconvert through
conformational reorganization or by reversion to the initially
formed oxonium ion and then reclosure. In this scenario,
selectivity has been generally attributed to the stabilization of
one intermediate over the other owing to traditional mini-
mization of 1,3-diaxial interactions (for example, favoring A
when R2 = alkyl).
2-Substituted 1,3-azidopropanols present a special case
that is unusually susceptible to stereoelectronic control
because of three factors: 1) the methylene groups near the
spiro linkage are locally isoelectronic, so the reaction cannot
be controlled by migratory aptitude, 2) the presence of either
an ether oxygen atom or an N-N2+ group in a 1,3 relationship
to the R2 group means that 1,3-diaxial steric interactions will
be minimized, and 3) the 1,3 relationship between the axial R2
[*] D. G. English, S. Smith, A. K. Manukyan, Prof. J. L. Poutsma
Department of Chemistry and Biochemistry
Old Dominion University
4541 Hampton Boulevard, Norfolk, Virginia 23529 (USA)
Fax: (+1)757-683-4628
E-mail: jradkiew@odu.edu
T. Ribelin, Dr. C. E. Katz, Dr. V. W. Day, B. Neuenswander, Prof. J. AubØ
Department of Medicinal Chemistry
University of Kansas
1251 Wescoe Hall Drive, Malott Hall, Room 4070
Lawrence, KS 66047 (USA)
Fax: (+1)785-864-5326
E-mail: jaube@ku.edu
[**] Financial support of this work by the Institute of General Medical
Sciences (NIH) is gratefully acknowledged (GM 49093, J.A.).
Acknowledgment is made to the donors of the American Chemical
Society Petroleum Research Fund for partial support of this research
(to J.L.P.). We also thank Prof. Paul Hanson and his group for their
gas chromatograph. n=nonbonded electrons.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.20001591.
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Communications
Table 1: Selectivity of reactions of substituted 1,3-hydroxyalkyl azides
(see Scheme 1a).
Schmidt reaction protocol. Remarkably, a greater than 98:2
d.r. was obtained for this system, favoring 3d. The selectivities
obtained with both the methoxy and methylthio groups, which
depend mainly on electrostatics and feature axially disposed
substituents, are higher than any previously reported, steri-
cally based, example of this ring-expansion reaction.[4,5]
Although the first example of an asymmetric azido-
Schmidt reaction reported utilized an azidoethanol reagent,
that series has typically provided lower selectivities relative to
the three-carbon-containing reagents like 1, and has more
recently been shown to occur by predominant steric control,
even when a phenyl group is in a position to participate in a
cation–p interaction.[5] In sharp contrast to these previous
results, the reaction using reagent 4 afforded a 97:3 ratio of 5
over 6; the major product is derived from an intermediate in
which a syn relationship between the methoxy group and the
leaving N2 + substituent is possible (Scheme 2a). A computa-
tional investigation showed that cation–n intermediate C is
Entry
Series
R2
2:3 ratio
Yield [%]
1
2
3
4
1a
1b
1c
1d
Me[a]
Ph[b]
OMe
SMe
74:26
60:40
4:96
98
98
98
90
1.8:98.2
[a] Reference [4]. [b] References [4] and [5].
+
group and the N2 group provides a strong opportunity for
attractive electrostatic interactions to occur between these
groups in intermediate B. In previous work, it was demon-
strated that unusually low selectivities obtained in this system,
when R = aryl, could be ascribed to preferential stabilization
of intermediate B by attractive, nonbonded cation–p inter-
+
actions between the aromatic group and the N2 leaving
group (Table 1).[5] Although such interactions are commonly
proposed in biological systems,[6] they are rarely invoked as
stereocontrolling features of stereoselective reactions of small
molecules.[7]
+
stabilized by 3.9 kcalmolÀ1. Notably, the O–N2 distances,
energy differences, and ratios are similar between systems B
and C. Previous work on the reactions of substituted 1,2-
azidoethanols has shown the predominant steric feature
affecting stereochemistry to exist between the migrating
carbon center and the substituents on the five-membered
heterocyclic ring.[4,5b] In cases where the alkyl group is
A computational study[8] and analogy to the well-known
ability of ether groups to bind to cations suggested that
intermediates like B should be even more enhanced in
compounds where R2 = alkoxy. As shown in Figure 1, isomer
B contains a diaxial relationship between a methoxy group
and a leaving group, and was calculated to be approximately
3.8 kcalmolÀ1 more stable than the equatorial isomer for
which no interaction between the methoxy and N2+ groups are
possible. To test this, 1-azido-2-methoxypropanol (1c, R2 =
OMe) was prepared and reacted with 4-tert-butylcyclohex-
anone by using BF3·OEt2 as the Lewis acid promoter. A
striking 24:1 selectivity in favor of the isomer emanating from
an axially disposed methoxy group was obtained in high yield
(Table 1, entry 3).
This result suggests that the methoxy cation–n interaction
is considerably stronger than the previously reported cation–
p effect, because of the fact that the highest 3:2 ratio observed
to date was 57:43 for the electron-rich 3,4,5-trimethoxyphenyl
group (not shown).[5] The fact that the small MeO group (A
value = 0.6[9]) pays a relatively small steric penalty in the axial
orientation is a likely contributor to the high selectivity of this
reaction as well. However, the much higher selectivity and the
opposite direction of the stereocontrol obtained for the
smaller MeO group as compared to alkyl or aryl substituents
(Table 1, entries 1 and 2) is strong evidence for the proposed
role of electrostatics in this reaction.
We proposed that a similar effect might be observed with
a more polarizable heteroatom.[3m] Accordingly, 1d, where
R = SMe, was prepared and submitted to the asymmetric
Scheme 2. a) Electrostatically controlled reaction of 1-azidoethanol
derivative 4 with 4-tert-butylcyclohexanone (including calculated ener-
gies of proposed, minimized intermediates C and D[8]) and b) a
cyclohexyl-containing control compound.[5b] The model systems used
for the calculations are given in the Supporting Information (Fig-
ure S1).
Figure 1. Calculations for proposed intermediates A and B performed
at the MP2/6-311+G**//MP2/6-31G* level of theory.[8]
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Angewandte
Chemie
adjacent to an oxygen atom (i.e. across the ring from the
migrating methylene group and the N2+ leaving group), steric
effects do not play an important role in determining the
reaction stereochemistry, as clearly demonstrated by the
nonselective cyclohexyl case shown in Scheme 2b.
attempted utilization of cation nonbonding electron stabili-
zation in other stereoselective processes.[10]
Received: April 4, 2008
Published online: July 9, 2008
The opposite situation occurs when the methoxymethyl
group is placed adjacent to the azido group (Scheme 3). In
this case, there is no substantial difference in distance
Keywords: azides · electrostatic interations ·
nonbonded interactions · ring expansion · Schmidt reaction
.
+
between the methoxy group and the N2 group in either
isomeric intermediate, so electrostatic considerations cannot
play a role, and the preference for syn E over anti F drops to
0.6 kcalmolÀ1 computationally. Instead, the usual steric
course of the reaction leads to the same product observed
for the analogous example to 14.
[1]P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon, Oxford, 1983.
[2]For reviews, see: a) E. Juaristi, G. Cuevas, Tetrahedron 1992, 48,
5019 – 5087; b) P. P. Graczyk, M. Mikolajczyk, Top. Stereochem.
1994, 21, 159 – 349.
[3]For a review on electrostatic interactions between ethers and
oxocarbenium ions, see: a) D. M. Smith, K. A. Woerpel, Org.
Biomol. Chem. 2006, 4, 1195–1201. For selected examples from
the recent literature, see: b) I. R. Dunkin, A. J. Paul, C. J.
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j) W. R. Judd, S. Ban, J. AubØ, J. Am. Chem. Soc. 2006, 128,
13736–13741; k) G. Baghdasarian, K. A. Woerpel, J. Org. Chem.
2006, 71, 6851–6858; l) S. R. Shenoy, D. M. Smith, K. A. Woerpel,
J. Am. Chem. Soc. 2006, 128, 8671–8677; m) M. G. Beaver, S. B.
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[4]a) V. Gracias, K. E. Frank, G. L. Milligan, J. AubØ, Tetrahedron
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Chem. Soc. 2003, 125, 7914 – 7922.
The most interesting elements of this approach are that:
1) intermediates are subject to nonbonded, attractive inter-
actions that are able to strongly favor one stereoisomeric form
over the other, 2) these intermediates lead to the correspond-
ing products in a process entirely controlled by stereoelec-
tronic considerations, and 3) the overall stereoselectivity
ultimately depends on the control of leaving group stereo-
slectivity at an epimerizable nitrogen atom. The high yields of
these reactions combined with the utility of the lactam
products suggests a high level of utility of the present ring
expansion. Of perhaps greater long-term interest will be the
[5]a) C. E. Katz, J. AubØ, J. Am. Chem. Soc. 2003, 125, 13948 –
13949; b) C. E. Katz, T. Ribelin, D. Withrow, Y. Basseri, A. K.
Manukyan, A. Bermudez, C. G. Nuera, V. W. Day, D. R. Powell,
J. L. Poutsma, J. AubØ, J. Org. Chem. 2008, in press.
[6]a) D. A. Dougherty, Science 1996, 271, 163 – 168; b) J. C. Ma,
D. A. Dougherty, Chem. Rev. 1997, 97, 1303 – 1324.
[7]For a review, see: a) S. Yamada, Org. Biomol. Chem. 2007, 5, 2903–
2912. For some leading references, see: b) P. Lakshminarasimhan,
R. B. Sunoj, J. Chandrasekhar, V. Ramamurthy, J. Am. Chem. Soc.
2000, 122, 4815 –4816; c) M. Stratakis, G. Froudakis, Org. Lett.
2000, 2, 1369–1372; d) S. Yamada, T. Misono, M. Ichikawa, C.
Morita, Tetrahedron 2001, 57, 8939 –8949; e) S. Yamada, C. Morita,
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[8]All calculations reported utilize MP2/6-311 + G(d,p)//MP2/6-
31G(d) free energies with CPCM dichloromethane solvent-
optimized geometries.
[9]E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of
OrganicCompounds , Wiley, New York, 1994, pp. 696 – 697,
and references therein.
[10]All experimental details and stereochemical assignments are
described in the Supporting Information. CCDC-647651 (3c),
647652 (O-benzyl derivative of 5), 647654 (O-p-nitrobenzoyl
derivative of 11), and 683831 (3d) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Scheme 3. Sterically controlled reactions of a) 10 and b) a previously
reported cyclohexane-containing substrate example.[5] The model sys-
tems used for the calculations are given in the Supporting Information
(Figure S1).
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