Using stereoelectronic effects to explain selective reactions of 4-substituted five-membered ring oxocarbenium ions

Article abstract of DOI:10.1021/ol0492647

Equation presented. The utility of the inside attack model to predict and analyze the stereoselectivities of nucleophilic additions to complex five-membered ring oxocarbenium ions is demonstrated in a systematic study of C-4-substituted acetals.

Full text of DOI:10.1021/ol0492647

ORGANIC
LETTERS
2004
Vol. 6, No. 12
2063-2066
Using Stereoelectronic Effects to
Explain Selective Reactions of
4-Substituted Five-Membered Ring
Oxocarbenium Ions
Deborah M. Smith and K. A. Woerpel*
Department of Chemistry, UniVersity of California-IrVine,
IrVine, California 92697-2025
kwoerpel@uci.edu
Received April 21, 2004
ABSTRACT
The utility of the inside attack model to predict and analyze the stereoselectivities of nucleophilic additions to complex five-membered ring
oxocarbenium ions is demonstrated in a systematic study of C-4-substituted acetals.
Stereoselective nucleophilic addition reactions to substituted
five-membered ring oxocarbenium ions continue to be
important transformations in bioorganic and synthetic organic
chemistry.1-5 Our laboratory recently developed a model to
explain the stereochemical outcomes resulting from these
transformations and, in particular, the strong dependence on
the substitution pattern at C-3 for high selectivity.6,7 This
model stipulates that a stereoelectronic preference directs the
nucleophile to attack the five-membered ring oxocarbenium
ion from the inside face of the envelope conformer, providing
the low-energy staggered product.8,9 Establishing that the
stereoelectronic principles of this model tolerate substrate
complexity would broaden its application toward highly
substituted molecules encountered in synthetic applications
and biological systems.10-13
Seemingly contradictory selectivities associated with sub-
stituted five-membered ring oxocarbenium ions suggest that
further efforts to understand the reactivities of these inter-
mediates are required.14,15 Reissig16 and others6,17 demon-
strated that the presence of a substituent at the C-4 position
of an oxocarbenium ion is not sufficient to obtain selectivity
in nucleophilic substitution reactions (Scheme 1). In a
separate account, the addition of Me3SiCN to acetal 3 in the
presence of a Lewis acid afforded the contrasteric 1,4-cis
product 4 with high selectivity.18 Because acetal 3 featured
(1) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004,
126, 998-999.
(2) Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374-2375.
(3) Cipolla, L.; Forni, E.; Jime´nez-Barbero, J.; Nicotra, F. Chem. Eur.
J. 2002, 8, 3976-3983.
(10) Tanaka, K. S. E.; Chen, X.-Y.; Ichikawa, Y.; Tyler, P. C.; Furneaux,
R. H.; Schramm, V. L. Biochemistry 2001, 40, 6845-6851.
(11) Chen, X.-Y.; Berti, P. J.; Schramm, V. L. J. Am. Chem. Soc. 2000,
122, 1609-1617.
(4) Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763-766.
(5) A¨ıssa, C.; Riveiros, R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc.
2003, 125, 15512-15520.
(12) Jiang, Y. L.; Ichikawa, Y.; Song, F.; Stivers, J. T. Biochemistry
2003, 42, 1922-1929.
(6) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208-12209.
(13) Houseknecht, J. B.; Lowary, T. L. Curr. Opin. Chem. Biol. 2001,
5, 677-682.
(7) Numbering used in this paper considers the carbocationic carbon as
C-1.
(14) Figade`re, B.; Peyrat, J.-F.; Cave´, A. J. Org. Chem. 1997, 62, 3428-
3429.
(8) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc. 2003,
125, 14149-14152.
(9) Other five-membered ring cations are believed to undergo nucleophilic
addition through similar low-energy staggered transition structures: (a) Bur,
S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221-3242. (b) Bach, T.;
Brummerhop, H.; Harms, K. Chem. Eur. J. 2000, 6, 3838-3848.
(15) Hanessian, S.; Grillo, T. A. J. Org. Chem. 1998, 63, 1049-1057.
(16) Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893-3901.
(17) Franck, X.; Hocquemiller, R.; Figade`re, B. Chem. Commun. 2002,
160-161.
(18) Nishiyama, Y.; Katoh, T.; Deguchi, K.; Morimoto, Y.; Itoh, K. J.
Org. Chem. 1997, 62, 9339-9341.
10.1021/ol0492647 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/08/2004

controlled selectivity and reveal the significance of geminal
substitution.22 Perturbation of the C-1 substituent of the
oxocarbenium ion intermediate has little effect on reaction
stereoselectivity, and analysis of this observation lends
additional support for stereoelectronically preferred inside
attack of the nucleophile. Our results demonstrate that
selective formation of the 1,4-cis product 4 does not require
a chelated transition structure, reinforcing the utility of the
inside attack model to analyze the reactivity of complex five-
membered ring oxocarbenium ion intermediates.
Scheme 1
Nucleophilic Substitution Reactions. Prior to the discus-
sion of the nucleophilic substitution reactions, details of the
experimental design deserve mention. Anomeric mixtures of
the desired acetals were prepared and employed as oxocar-
benium ion precursors.23 Allyltrimethylsilane24,25 was utilized
as the nucleophile in the majority of the addition reactions
to obviate product epimerization that may occur with
Me3SiCN.26-28 The stereochemistry of the substitution
products was assigned by analysis of NOE measurements
on the products or their derivatives.
Nucleophilic substitution reactions of acetates 7 and 9
indicate that a single substituent at C-2 is not the origin of
stereoselectivity for acetal 3 (Scheme 1). Treatment of the
trans acetate 7 with allyltrimethylsilane in the presence of
SnBr4 provided the 1,4-cis product 8 with 67:33 stereose-
lectivity (Scheme 3).29,30 The reaction of the related cis
acetate 9 also afforded a mixture of diastereomers.29,31
Both the conformational preference of the oxocarbenium
ion intermediate and steric interactions that arise in the
transition structure for nucleophilic attack influence the
stereochemical outcomes observed with acetates 7 and 9.
While the two ground state conformers of the cation derived
from trans acetate 7, namely, 11 and 12, are comparable in
energy, developing steric interactions between the approach-
ing nucleophile and the pseudoequatorial methyl of inter-
mediate 12 slightly disfavor the formation of the 1,4-trans
a single stereocenter at C-4, the selective formation of 4
contradicted the results observed for the nucleophilic sub-
stitution of acetal 1. The counterintuitive stereochemical
outcome for acetal 3 was attributed to the steric bias imparted
by Lewis acid coordination to the oxonium oxygen and the
C-2 heteroatom.18,19
While the unselective reaction of the C-4 phenyl acetal 1
is consistent with Reissig’s16 model and our model,6,8 the
correlation between substrates 1 and 3 remains unresolved.
We surmised that the sulfur substituents might not participate
in a chelated transition structure but would instead influence
the conformational preference of the oxocarbenium ion
intermediate. According to that hypothesis and the stereo-
electronic model,6,8 the contrasteric 1,4-cis product 4 would
arise from inside attack of the nucleophile to the lower energy
diequatorial oxocarbenium ion 5 (Scheme 2). This reaction
pathway would provide a lower energy transition structure
relative to inside attack of the nucleophile on the diaxial
conformer 6 (vide infra).20,21
Scheme 2
(19) An oxocarbenium ion intermediate with a Lewis acid blocking one
face has been invoked to account for the facial selectivity of a nucleophile:
Mukaiyama, T.; Shimpuku, T.; Takashima, T.; Kobayashi, S. Chem. Lett.
1989, 145-148.
(20) Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111-128.
(21) Seeman, J. I. Chem. ReV. 1983, 83, 83-134.
(22) Geminal substitution influenced the selectivity in other oxocarbenium
ion systems: Shaw, J. T.; Woerpel, K. A. Tetrahedron 1999, 55, 8747-
8756.
(23) Acetals 7, 9, 15, 24, and 26 were prepared from the corresponding
known lactones. Details of these experiments are provided as Supporting
Information.
To prove this hypothesis of inside attack and to elucidate
the factors that contribute to the selective reaction of acetal
3, alkyl analogues (R1, R2 ) Me, Figure 1) with various
(24) Bear, T. J.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 2002, 67,
2056-2064.
(25) Burfeindt, J.; Patz, M.; Mu¨ller, M.; Mayr, H. J. Am. Chem. Soc.
1998, 120, 3629-3634.
(26) Herranz, R.; Castro-Pichel, J.; Vinuesa, S.; Garc´ıa-Lo´pez, M. T. J.
Org. Chem. 1990, 55, 2232-2234.
(27) Herranz, R.; Sua´rez-Gea, M. L.; Vinuesa, S.; Garc´ıa-Lo´pez, M. T.
J. Org. Chem. 1993, 58, 5186-5191.
(28) Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P. Synthesis 1996,
123-132.
(29) Use of BF3‚OEt2 and Me3SiOTf as the Lewis acid provided similar
selectivities.
Figure 1. Substitution pattern of the alkyl analogue.
(30) For all experiments, stereoselectivities were determined by GC and/
or 1H NMR spectroscopic analysis of unpurified reaction mixtures. The
reported yields are based upon purified products (details of these experiments
are provided as Supporting Information).
(31) Low selectivity with C-2- and C-4-cis-substituted five-membered
ring oxocarbenium ions has been observed: see ref 22.
substitution patterns at C-1 and C-2 were investigated.
Experiments with alkyl substituents at C-2, in place of the
sulfur heteroatoms, eliminate the viability of a chelation-
2064
Org. Lett., Vol. 6, No. 12, 2004

Scheme 3
Scheme 5
product (Scheme 4). The low selectivity obtained from the
reaction of cis acetate 9 indicates that the difference in
attack, resulting in a similar selectivity for the reaction of
the C-1-unsubstituted substrate 9 (Scheme 3).
The selectivities for the reactions of acetate 9 and acetal
15 provide experimental support for stereoelectronically
preferred inside attack on five-membered ring oxocarbenium
ions, confirming the importance of torsional angle effects
in addition reactions.6,8,36 A potential reaction pathway
leading to the minor 1,4-trans product obtained with acetal
9 could involve outside attack of the nucleophile to the lower
energy conformer 13. The reaction of acetate 15 resolves
this ambiguity because formation of the 1,4-trans product
21 via outside attack on conformer 19 would be disfavored
due to a more severe eclipsing interaction (MeTMe and a
MeTH) that develops in the transition structure (Scheme
6).37 If outside attack occurred, acetal 15 should have shown
Scheme 4
transition state energies (∆∆Gq) is negligible. Inside attack
of the nucleophile to the two ground state conformers 13
and 14 each involve destabilized transition structures. The
transition structure for inside attack on the lower energy
conformer 13 develops a destabilizing gauche-butane interac-
tion between the nucleophile and the pseudoequatorial C-2
methyl substituent.31,32 While inside attack on conformer 14
circumvents an unfavorable interaction with the nucleophile,
the steric interactions between the methyl and phenyl groups
destabilize the transition structure leading to product.21,33
The origin of the contrasting selectivities exhibited by
acetal 116 and acetal 318 is not attributable to the presence of
an alkyl substituent at the acetal carbon (C-1). Treatment of
acetal 15 with allyltrimethylsilane in the presence of SnBr4
afforded tetrahydrofuran 16 with 65:35 stereoselectivity
(Scheme 5).34,35 The C-1 substituent exerts minimal influence
on the equilibrium of the ground-state conformers 17 and
18 and the respective transition state structures for inside
Scheme 6
considerably higher selectivity for the staggered 1,4-cis
product 20. The selectivity for the nucleophilic substitution
reaction of methyl-substituted acetal 15 confirms that the
minor product obtained with acetate 9 is the result of inside
attack on the higher energy conformer of the cation and not
outside attack on the lower energy conformer.38
Because the C-4-substituted acetals in this study exhibit
low selectivity as was observed for acetal 116 (Scheme 1),
the unique feature of acetal 318 that contributes to high
(32) For a study on the developing steric interactions between C-2
substituents and the incoming nucleophile in six-membered ring oxocar-
benim ion intermediates, see: Ayala, L.; Lucero, C. G.; Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521-
15528.
(33) In accordance with the Curtin-Hammett principle, the relative
energies of the transition state structures dictate the stereochemical outcome,
not the relative energies of the ground-state structures.
(34) The two anomers of acetal 15 were isolated in various ratios. Control
experiments demonstrate that the starting anomer ratio does not affect the
stereochemical outcome of the product, consistent with the intermediacy
of oxocarbenium ions.
(36) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J.
Science 1986, 231, 1108-1117.
(37) We estimate the energy difference between a MeTMe and a MeTH
eclipsing interaction to be 2 kcal/mol. This approximation was extrapolated
from the rotational barriers of n-butane and n-propane. For n-butane, see:
Allinger, N. L.; Fermann, J. T.; Allen, W. D.; Schaefer, H. F., III. J. Chem.
Phys. 1997, 106, 5143-5150. For n-propane, see: Bu¨rgi, H.-B.; Hounshell,
W. D.; Nachbar, R. B., Jr.; Mislow, K. J. Am. Chem. Soc. 1983, 105, 1427-
1438.
(38) For an investigation of torsional angle effects (eclipsing strain
energy) on the reaction selecitivity of hydroxymercuration of substituted
cyclohexenes, see: Pasto, D. J.; Gontarz, J. A. J. Am. Chem. Soc. 1971,
93, 6909-6913.
(35) Use of BF3‚OEt2 as the Lewis acid afforded a 54:46 ratio of cis:
trans isomers for the allylation of 15.
Org. Lett., Vol. 6, No. 12, 2004
2065

selectivity may be geminal substitution at C-2. With a
pseudoequatorial methyl in both ground state conformers 22
and 23, steric interactions with the approaching nucleophile
would be comparable in both transition structures (Scheme
7). Therefore, the energy difference between the transition
Scheme 8
Scheme 7
In conclusion, the dissimilar selectivities exhibited by the
two related tetrahydrofuran acetals shown in Scheme 1 are
not the result of chelation of the Lewis acid. Instead, the
substituent at C-4 biases the conformation of the oxocarbe-
nium ion, and inside attack provides the product with high
cis selectivity. This study demonstrates the capacity of the
model to analyze the stereochemical outcomes of nucleo-
philic addition reactions to complex five-membered ring
oxocarbenium ions.
structures of inside attack would reflect the relative energy
difference between the ground-state oxocarbenium ion
conformers 22 and 23. Inside attack on the favored diequa-
torial conformer 22 should afford the 1,4-cis product with
high selectivity, consistent with acetal 3.
Our experiments confirm that geminal substitution at the
C-2 position, regardless of the substitution pattern at C-1, is
required to obtain high stereoselectivity for this series of
substrates. Allylation of geminal dimethyl acetate 24 in the
presence of SnBr4 afforded the 1,4-cis product 25 with high
selectivity (Scheme 8).29,39 To mimic the experiments
reported for the nucleophilic substitution reaction of dithiane-
substituted acetal 3 (Scheme 1), the reaction of C-1 phenyl
acetal 26 with Me3SiCN was studied. In accord with
experiments described previously, the substituent at C-1
exerted little influence on the selectivity. The kinetically
controlled addition of Me3SiCN to 26 in the presence of
SnBr4 afforded the 1,4-cis product 27 with high selectiv-
ity.29,40
Acknowledgment. This research was supported by the
National Institutes of Health, National Institute of General
Medical Science (GM-61066), and by Johnson & Johnson.
D.M.S. thanks Johnson & Johnson for a graduate research
fellowship. K.A.W. thanks Merck Research Laboratories for
an award to support research. We thank Dr. John Greaves
and Dr. John Mudd for mass spectrometric data.
Supporting Information Available: Complete experi-
mental procedures, product characterization, stereochemical
proofs, and GC and spectral data for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0492647
(39) The solvent employed for these nucleophilic substitution reactions
was CH2Cl2. With toluene as the solvent, selectivities were optimized to a
96:4 ratio of cis:trans isomers for the reaction of acetate 24.
(40) Control experiments indicate that this reaction is irreversible at low
(-78 °C) reaction temperatures (details of these experiments are provided
as Supporting Information).
2066
Org. Lett., Vol. 6, No. 12, 2004