Stereoelectronic Model to Explain Highly Stereoselective Reactions of Seven-Membered-Ring Oxocarbenium-Ion Intermediates

Article abstract of DOI:10.1002/anie.201507806

Nucleophilic attack on seven-membered-ring oxocarbenium ions is generally highly stereoselective. The preferred mode of nucleophilic attack forms the product in a conformation that minimizes transannular interactions, thus leading to different stereoselectivity as compared to that of reactions involving six-membered-ring oxocarbenium ions.

Full text of DOI:10.1002/anie.201507806

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International Edition: DOI: 10.1002/anie.201507806
German Edition: DOI: 10.1002/ange.201507806
Carbocation Intermediates
Stereoelectronic Model To Explain Highly Stereoselective Reactions of
Seven-Membered-Ring Oxocarbenium-Ion Intermediates
Matthew G. Beaver, Trixia M. Buscagan, Olga Lavinda, and K. A. Woerpel*
Abstract: Nucleophilic attack on seven-membered-ring oxo-
carbenium ions is generally highly stereoselective. The pre-
ferred mode of nucleophilic attack forms the product in
a conformation that minimizes transannular interactions, thus
leading to different stereoselectivity as compared to that of
reactions involving six-membered-ring oxocarbenium ions.
substituted acetal 1 (X = OBn; Bn = benzyl) gave the product
with the opposite relative configuration.[8,9] These selectivities
are also opposite to those observed in reactions of six-
membered-ring oxocarbenium ions:[8] in the six-membered-
ring series, the alkyl-substituted acetal favored the 1,4-cis
product, and the alkoxy-substituted acetal formed the 1,4-
trans product.
B
ecause of their biological significance and the challenges
inherent to the synthesis of medium-ring compounds,[1] seven-
membered-ring ethers (oxepanes) are important synthetic
targets.[1,2] Substitution reactions of oxepane acetals, which
probably proceed via oxocarbenium-ion intermediates, are
particularly useful methods for the stereoselective construc-
tion of natural products and seven-membered-ring sugar
derivatives.[3] The origin of stereoselectivity in these trans-
formations remains poorly understood, however, because of
the conformational complexity of seven-membered-ring sys-
tems.[4,5] No systematic study of nucleophilic addition reac-
tions to simple seven-membered-ring oxocarbenium ions has
appeared, and no general explanation has been forwarded to
explain the reactions of these intermediates.[6]
Because the diverging stereochemical outcomes illus-
trated in Equation (1) are similar to observations regarding
the reactions of five- and six-membered-ring oxocarbenium
ions,[8,9] the factors that govern selectivity in those systems
should apply to the seven-membered-ring system. Models
used to explain selective reactions of oxocarbenium ions and
iminium ions[8–12] consider the conformations of these reactive
intermediates and how those conformations change in the
transition state of nucleophilic attack, which, in the case of p-
nucleophiles, is irreversible.[13] Although it would be desirable
to model this step computationally,[14] calculations involving
interactions of cations with electron-rich species are challeng-
ing.[15–17] Nevertheless, models derived by conformational
analysis of the first-formed products that result from nucle-
ophilic attack can be useful.[9,11,12]
A model to explain and predict the outcomes of reactions
involving seven-membered-ring oxocarbenium ions is illus-
trated for oxocarbenium ion 3 [Eq. (2)]. The oxocarbenium
ion probably adopts a chair-like conformation[18] with the
methyl group in a pseudoequatorial position.[19,20] Steric
interactions between the approaching nucleophile and the
substituent should be minimal, so the major product is likely
to be formed from this lowest-energy conformer.[21] The two
different modes of nucleophilic attack, A and B, give the
products in twist-chair-like conformations, but the interac-
tions that develop in the two transition states are different.
Nucleophilic attack along trajectory A would pyramidalize
the carbon and oxygen atoms in opposite directions,[8,12] thus
leading to an initial twist-chair conformation of product 4 (the
TC6 conformation[5]). Conversely, attack along trajectory B
would form product 5 in a different twist-chair conformation
We report herein that nucleophilic substitution reactions
of oxepane acetals are highly stereoselective in most cases.
We propose a model to explain these selectivities by consid-
ering that nucleophilic attack should occur from the face that
minimizes transannular interactions in the first-formed prod-
uct. We also demonstrate that acetal substitution reactions
that proceed by SN2-like mechanisms generally result in
products with the opposite stereochemical configuration to
that of products resulting from the corresponding SN1-like
reactions.
Initial studies revealed that nucleophilic substitution
reactions of acetals that proceed via seven-membered-ring
oxocarbenium ions are highly diastereoselective. Under
dissociative (SN1-like) conditions, the substitution reaction
of acetal 1 (X = Me) occurred with high trans selectivity
[Eq. (1)].[7] By contrast, the substitution reaction of alkoxy-
[*] Dr. M. G. Beaver
Amgen
360 Binney Street, Cambridge, MA 02142 (USA)
T. M. Buscagan
Department of Chemistry and Chemical Engineering
California Institute of Technology
1200 E. California Blvd, MNC 101-20, Pasadena, CA 91125 (USA)
O. Lavinda, Prof. K. A. Woerpel
Department of Chemistry, New York University
100 Washington Square East, New York, NY 10003 (USA)
E-mail: kwoerpel@nyu.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507806.
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(TC5). Attack by mode B is preferred because the resulting
product is formed with the carbon atom bearing the
nucleophile (C1) in a position that minimizes steric inter-
actions.[22] In the first-formed product 5, the nucleophile and
the hydrogen atom at C1 would occupy isoclinal positions, so
neither group is axial. As a result, steric interactions with the
other atoms of the ring are minimized.[4] By contrast,
conformer 4 is higher in energy because it places C1 in
a more sterically hindered position,[4] with destabilizing
interactions between the nucleophile and axial hydrogen
atoms at C3 and C5 [Eq. (2)].[4,5,22] As a result, the transition
state leading to conformer 4 should be higher in energy than
that leading to 5.[23,24]
bered-ring acetals. The lower selectivity for the formation of
the 1,3-trans product trans-12 probably results from the low
The preferred attack on the oxocarbenium ion along
trajectory B also explains the selective formation of the 1,4-cis
product when an alkoxy group is located at C4. The cation
should adopt a pseudoaxial conformation 6 [Eq. (3)] to
maximize electrostatic attraction between the positively
charged carbon atom and the partially negatively charged
oxygen atom of the benzyloxy group.[8,16,25,26] Computational
studies reinforce this prediction: 6 was calculated to be
favored by 1.4 kcalmolÀ1 as compared to an equatorial
conformer.[19] Nucleophilic attack from the torsionally
favored direction would form the 1,4-cis product 7 in the
preferred twist-chair conformation.
axial preference for the oxocarbenium ion 14 (calculated to
be 0.3 kcalmolÀ1)[19] owing to competing electrostatic stabili-
zation and steric destabilization [Eq. (6)]. The selectivity
observed for the formation of trans-13 results from the
preference[8,9,16,25,26] for the alkoxy group to adopt a pseudoax-
ial orientation in the oxocarbenium ion 16 [Eq. (7)], which is
consistent with the calculated preference of 0.8 kcalmolÀ1 for
this conformer.[19]
Other results support the prediction that the favored
transition state for nucleophilic attack develops the fewest
transannular interactions. Nucleophilic addition reactions to
oxocarbenium ions bearing an alkyl or an alkoxy group at C2
are highly trans-selective [Eq. (4)], in contrast to results with
five- and six-membered-ring acetals, for which selectivity is
low.[8,9] These reactions probably proceed via an equatorially
substituted oxocarbenium ion 10 [Eq. (5)]. In the case of X =
OBn, this conformation, which computational studies indi-
cate is favored by 2.5 kcalmolÀ1,[19] maximizes hyperconjuga-
tive stabilization from the pseudoaxial sCÀ orbital.[8,16]
Because many substitution reactions in carbohydrate
chemistry utilize stronger nucleophiles with either ion pairs
or covalent intermediates,[29–31] we examined reactions under
similar conditions. For example, the use of a highly reactive
nucleophile (silyl ketene acetal 19) in the presence of triflate
ions in a nonpolar solvent (trichloroethylene)[31] gave the cis
H
Attack along the preferred trajectory leads to the twist-
chair product 11.[27]
Considering the importance of seven-membered-ring
sugars in glycobiology,[2,28] we examined the substitution
reactions of two additional alkoxy-substituted seven-mem-
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isomer in the case of 5-benzyloxy acetal 18 [Eq. (8)].[32] The
relative configuration of the product is opposite to that
observed for the allylation (see trans-13). The switch in
selectivity for the SN2-type C-glycosylation reactions as
compared to SN1-type reactions was also observed for
reactions of 2- and 3-alkoxyoxepane acetals (see products
cis-21 and cis-22) and parallels observations for six-mem-
bered-ring systems.[31] In the case of the 4-benzyloxy acetal
1 (X = OBn), however, the cis isomer is the major product
regardless of the reaction type [cis-2, Eq. (1) and cis-23]. The
benzyloxy group at C4 may be too far from the oxygen and
carbon atoms of the oxocarbenium-ion intermediate to
destabilize it inductively,[33] so reactions proceed via oxocar-
benium ions even in the presence of the triflate ion.[31]
one conformer of the product as it is formed upon nucleo-
philic attack.
Acknowledgements
This research was supported by the National Institutes of
Health, National Institute of General Medical Sciences (GM-
61066). We thank Dr. Chin Lin (NYU) for assistance with
NMR spectroscopy and mass spectrometry, and Dr. Chunhua
Hu (NYU) for assistance with crystallographic studies.
Keywords: carbocations · carbohydrates ·
conformational analysis · electrostatic effects · stereoselectivity
How to cite: Angew. Chem. Int. Ed. 2016, 55, 1816–1819
Angew. Chem. 2016, 128, 1848–1851
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In conclusion, the substitution reactions of seven-mem-
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tivity, regardless of whether reactions involve free ions or
intermediates with close contact between the electrophile and
the leaving group. The reactions are selective because of
strong conformational preferences of oxepanes, which favor
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[21] In cases in which the nucleophile approaches a substituent
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can be important (see, for example, Ref. [8]).
[22] The computed structures for 4 and 5 (Nu = Me) illustrate the
different steric interactions in the two conformers. In 4, trans-
annular interactions occur between the nucleophile and two
hydrogen atoms of the ring. The distance between the carbon
atom of Nu and 3-H is 2.71 Š, and the distance to 5-H is 2.88 Š.
In 5, there is only one transannular interaction (with 6-H), and
the distance is 2.90 Š.
[23] A model assuming that selectivity is controlled by attack trans to
the axial hydrogen atom at C3 would not be consistent with the
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ring systems (see Refs. [9,12]).
[32] When BF3·OEt2 was used as the Lewis acid, the selectivity was
low (55:45), as expected for reactions of a strong nucleophile
with an oxocarbenium ion (see Ref. [31]).
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[24] Computational studies also suggest that attack by mode B should
be favored. A methyl group was used as the carbon nucleophile
to simplify the calculation. The twist-chair isomer 5 was found to
be lower in energy than 4 by 4.7 kcalmolÀ1, so transition states
leading to this conformer should be lower in energy.
Received: August 20, 2015
Revised: October 20, 2015
Published online: January 6, 2016
´
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