Stereoselective C-glycosylation reactions of ribose derivatives: Electronic effects of five-membered ring oxocarbenium ions

Article abstract of DOI:10.1021/ja0524043

The factors controlling the highly α-selective C-glycosylation of ribose derivatives were determined by examining the Stereoselective reactions of 18 ribose analogues differing in substitution at C-2, C-3, and C-4. The lowest energy conformers of the intermediate oxocarbenium ions display the C-3 alkoxy group in a pseudoaxial orientation to maximize electrostatic effects. To a lesser extent, the C-2 substituent prefers a pseudoequatorial position, and the alkyl group at C-4 has little influence on conformational preferences. In all cases, the product was formed by stereoelectronically preferred inside attack on the lowest energy conformer.

Full text of DOI:10.1021/ja0524043

Published on Web 07/13/2005
Stereoselective C-Glycosylation Reactions of Ribose
Derivatives: Electronic Effects of Five-Membered Ring
Oxocarbenium Ions
Catharine H. Larsen, Brian H. Ridgway, Jared T. Shaw, Deborah M. Smith, and
K. A. Woerpel*
Contribution from the Department of Chemistry, UniVersity of California,
IrVine, California 92697-2025
Received April 13, 2005; E-mail: kwoerpel@uci.edu
Abstract: The factors controlling the highly R-selective C-glycosylation of ribose derivatives were determined
by examining the stereoselective reactions of 18 ribose analogues differing in substitution at C-2, C-3, and
C-4. The lowest energy conformers of the intermediate oxocarbenium ions display the C-3 alkoxy group in
a pseudoaxial orientation to maximize electrostatic effects. To a lesser extent, the C-2 substituent prefers
a pseudoequatorial position, and the alkyl group at C-4 has little influence on conformational preferences.
In all cases, the product was formed by stereoelectronically preferred inside attack on the lowest energy
conformer.
Introduction
glycosyl fluoride 1 occurred from the R-face to provide the
R-glycoside 2 exclusively (eq 1).12 Because the configuration
The stereoselective synthesis of substituted tetrahydrofurans
remains an important synthetic challenge because this structural
motif is prevalent in many target structures. For example,
methods have been developed for the construction of the five-
membered ring form of carbohydrates, since this framework
emerges often in biological systems such as furanoses1 and
nucleosides.2 Interest in the synthesis of C-glycosides3,4 and
C-nucleosides5 has intensified because of the therapeutic
potential of these compounds.6,7 In addition, challenges posed
by natural products containing the tetrahydrofuran moiety, such
as the Annonaceous acetogenins,8,9 have heightened interest in
the stereocontrolled synthesis of this ring system.10
Because of the high level of stereochemical control that can
be observed, nucleophilic substitution reactions of five-
membered ring acetals are valuable transformations to access
highly substituted tetrahydrofurans and furanosides.10,11 For
example, the C-glycosylation reaction3 of the ribose-derived
at C-1 of the R-C-glycoside 2 is opposite to that for the naturally
occurring nucleosides, a complementary strategy has been
employed to obtain the biologically relevant â-C-glycoside.
Nucleophilic substitution by hydride onto a hemiacetal bearing
a carbon substituent at C-113 proceeded from the R-face to
provide the desired â-C-glycoside 4 (eq 2).14,15
The proclivity for R-selective substitutions of ribose-derived
acetals as exemplified by eqs 1 and 2 has never been adequately
explained, limiting the influence of these reactions on synthetic
and biological chemistry. Because the anomeric configuration
(1) Lowary, T. L. Curr. Opin. Chem. Biol. 2003, 7, 749-756.
(2) Knapp, S. Chem. ReV. 1995, 95, 1859-1876.
(3) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913-9959.
(4) For a recent example, see: Harvey, J. E.; Raw, S. A.; Taylor, R. J. K.
Org. Lett. 2004, 6, 2611-2614.
(5) Wu, Q.; Simons, C. Synthesis 2004, 1533-1553.
(6) Yang, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Angew. Chem., Int. Ed.
2004, 43, 3818-3822.
(7) el Kouni, M. H. Curr. Pharm. Des. 2002, 8, 581-593.
(8) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin,
J. L. Nat. Prod. Rep. 1996, 13, 275-306.
(11) For a review that includes nucleophilic substitution on five-membered ring
acetals, see: Harmange, J.-C.; Figade`re, B. Tetrahedron: Asymmetry 1993,
4, 1711-1754.
(9) For a recent total synthesis and citations to the recent literature in this field,
see: Nattrass, G. L.; D´ıez, E.; McLachlan, M. M.; Dixon, D. J.; Ley, S. V.
Angew. Chem., Int. Ed. 2005, 44, 580-584.
(12) Araki, Y.; Kobayashi, N.; Ishido, Y.; Nagasawa, J. Carbohydr. Res. 1987,
171, 125-139.
(13) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976-
(10) For example, the syntheses of members of the amphidinolide T natural
products utilize substitution reactions of acetals to introduce a substituent
and establish the stereochemistry of the tetrahydrofuran moiety: (a) Ghosh,
A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374-2375. (b) A¨ıssa, C.;
Riveiros, R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc. 2003, 125, 15512-
15520. (c) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc.
2005, 127, 4297-4307.
4978.
(14) Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610-612.
(15) For related examples, see: (a) Liu, W.; Walker, J. A., II; Chen, J. J.; Wise,
D. S.; Townsend, L. B. Tetrahedron Lett. 1996, 37, 5325-5328. (b)
Matulic-Adamic, J.; Beigelman, L. Tetrahedron Lett. 1997, 38, 1669-1672.
(c) Dondoni, A.; Formaglio, P.; Marra, A.; Massi, A. Tetrahedron 2001,
57, 7719-7727.
9
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J. AM. CHEM. SOC. 2005, 127, 10879-10884
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A R T I C L E S
Larsen et al.
(R or â) of the starting materials 1 and 3 does not determine
the stereochemistry of the products, these reactions likely
proceed via oxocarbenium ions 5.16 Evidently, the nucleophile
approaches the electrophilic carbon from the face bearing the
two alkoxy groups at C-2 and C-3. To explain the counter-
intuitive stereochemical outcome shown in eq 1, various
arguments have been offered, such as involvement of the
counterion and solvent.12,17,18 These arguments, however, are
unsatisfying because the selectivities are only marginally
affected by solvent, Lewis acid, anomeric leaving group, and
carbon-based nucleophile (eq 1).19-24 The generality of the
R-selective substitution suggests that the selectivity is the result
of an inherent stereochemical bias of the substituted oxocar-
benium ion 5 and not a result of external variables.
tronic effects should control the approach of the nucleophile to
a five-membered ring oxocarbenium ion.37-39 Experiments
involving conformationally constrained five-membered ring
oxocarbenium ions revealed that attack on the prototypical
oxocarbenium ion 6 occurred preferentially (up to 96:4 selectiv-
ity) from “inside” the envelope to form the staggered product
7 (eq 3).38 Destabilizing steric effects that emerge in transition
structures also influence selectivities,26,39 in accordance with
the Curtin-Hammett principle.40 The magnitude of such effects
is difficult to estimate a priori, since the precise transition
structures for nucleophilic attack on oxocarbenium ions have
not been located and are likely to depend on substitution
patterns.41
The conformational analysis of heteroatom-substituted six-
membered ring oxocarbenium ions allows for an understanding
of the behavior of five-membered ring analogues (vide infra).
While alkyl groups in six-membered ring oxocarbenium ions
prefer equatorially substituted conformers, heteroatom-contain-
ing functional groups reside in pseudoaxial orientations at certain
positions of the ring.25,26,42 With the alkoxy group situated in
the pseudoaxial position, an attractive electrostatic interaction
between the cationic carbon and partially negatively charged
substituent is maximized. This paradoxical conformational
preference is supported by computational43,44 and experimental
studies with six-membered ring oxocarbenium ions25,26,42,45-49
and iminium ions50-52 and operates in the rates of oxocarbenium
ion generation.53,54 As will be demonstrated, the selectivities
exhibited by ribose-derived oxocarbenium ions find close
analogy to our studies with the six-membered ring systems.25,26,42
The challenges associated with understanding the perplexing
selectivities shown in eqs 1 and 2 prompted us to investigate
the origin of stereoselective reactions of highly oxygenated five-
membered ring oxocarbenium ions such as 5. In this article,
we demonstrate that electronic 25,26 and stereoelectronic effects
dominate the selectivity exhibited by ribose-derived acetal 1
(eq 1). We also show that the conclusions gleaned from the
study of ribose-derived acetals allow for predictions of stereo-
chemical courses for new reactions.
Our earlier studies of oxocarbenium ions indicate that five-
and six-membered ring oxocarbenium ions display parallel
selectivity patterns, suggesting that similar influences control
the stereoselectivities of the two related systems. Because five-
membered ring systems undergo conformational interconver-
sions more rapidly than six-membered rings,1,27,28 it is more
challenging to develop stereochemical models, and therefore
few attempts to codify these reactions have emerged.29-32 Five-
membered rings do exhibit discrete minima, however, as has
been demonstrated for ribose systems.33 Consequently, as
established with six-membered ring systems,34-36 stereoelec-
(36) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Perga-
mon: New York, 1983; pp 209-221.
(37) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem.
Soc. 1999, 121, 12208-12209.
(38) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125,
14149-14152.
(16) Lowary has shown that O-glycosylation of furanosyl triflates occurs with
inversion of configuration: Callam, C. S.; Gadikota, R. R.; Krein, D. M.;
Lowary, T. L. J. Am. Chem. Soc. 2003, 125, 13112-13119.
(17) Jaouen, V.; Je´gou, A.; Leme´e, L.; Veyrie`res, A. Tetrahedron 1999, 55,
9245-9260.
(18) Nishiyama, Y.; Katoh, T.; Deguchi, K.; Morimoto, Y.; Itoh, K. J. Org.
Chem. 1997, 62, 9339-9341.
(19) Stewart, A. O.; Williams, R. M. J. Am. Chem. Soc. 1985, 107, 4289-
4296.
(39) Smith, D. M.; Woerpel, K. A. Org. Lett. 2004, 6, 2063-2066.
(40) Seeman, J. I. Chem. ReV. 1983, 83, 83-134.
(41) Five-membered ring iminium ions are believed to undergo nucleophilic
attack by similar transition structures to those for oxocarbenium ions: Bur,
S. K.; Martin, S. F. Org. Lett. 2000, 2, 3445-3447.
(42) Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am. Chem. Soc. 2005,
127, 5322-5323.
(43) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc. 1992, 114,
859-864.
(20) Bennek, J. A.; Gray, G. R. J. Org. Chem. 1987, 52, 892-897.
(21) Mukaiyama, T.; Kobayashi, S. Carbohydr. Res. 1987, 171, 81-87.
(22) Mukaiyama, T.; Shimpuku, T.; Takashima, T.; Kobayashi, S. Chem. Lett.
1989, 145-148.
(44) Miljkovic, M.; Yeagley, D.; Deslongchamps, P.; Dory, Y. L. J. Org. Chem.
1997, 62, 7597-7604.
(45) Roush, W. R.; Sebesta, D. P.; Bennett, C. E. Tetrahedron 1997, 53, 8825-
(23) O’Leary, D. J.; Kishi, Y. J. Org. Chem. 1994, 59, 6629-6636.
(24) Hachiya, I.; Kobayashi, S. Tetrahedron Lett. 1994, 35, 3319-3320.
(25) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000,
122, 168-169.
8836.
(46) Hosokawa, S.; Kirschbaum, B.; Isobe, M. Tetrahedron Lett. 1998, 39,
1917-1920.
(47) Isobe, M.; Saeeng, R.; Nishizawa, R.; Konobe, M.; Nishikawa, T. Chem.
Lett. 1999, 467-468.
(26) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel, K.
A. J. Am. Chem. Soc. 2003, 125, 15521-15528.
(48) Saeeng, R.; Isobe, M. Tetrahedron Lett. 1999, 40, 1911-1914.
(49) Chong, P. Y.; Roush, W. R. Org. Lett. 2002, 4, 4523-4526.
(50) Shono, T.; Matsumura, Y.; Onomura, O.; Sato, M. J. Org. Chem. 1988,
53, 4118-4121.
(27) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94, 8205-8212.
(28) Fuchs, B. Top. Stereochem. 1978, 10, 1-94.
(29) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40-42.
(30) Schmitt, A.; Reissig, H.-U. Chem. Ber. 1995, 128, 871-876.
(31) Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893-3901.
(32) Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2001, 1169-1174.
(33) Brameld, K. A.; Goddard, W. A., III. J. Am. Chem. Soc. 1999, 121, 985-
993.
(51) Herdeis, C.; Engel, W. Tetrahedron: Asymmetry 1991, 2, 945-948.
(52) Vink, M. K. S.; Schortinghuis, C. A.; Luten, J.; van Maarseveen, J. H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2002,
67, 7869-7871.
(53) Jensen, H. H.; Bols, M. Org. Lett. 2003, 5, 3419-3421.
(54) McDonnell, C.; Lo´pez, O.; Murphy, P.; Bolan˜os, J. G. F.; Hazell, R.; Bols,
M. J. Am. Chem. Soc. 2004, 126, 12374-12385.
(34) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032-7035.
(35) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289-296.
9
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Five-Membered Ring Oxocarbenium Ions
A R T I C L E S
Results
C-4 Alkyl Group. The C-4 alkyl group does not control the
stereoselectivity of nucleophilic attack for ribose-derived systems
(eq 1). Analogues resembling the 2-deoxyribose derivative 8a
with different substituents at the C-4 position were examined
to determine if the reaction outcome would deviate from the
anticipated 1,3-cis stereoselectivity. Whether the C-4 substituent
contained an oxygen atom or not, the nucleophile consistently
approached cis to the alkoxy substituent at C-3 (eq 6). In
Experimental Approach. To understand the stereoselective
nucleophilic substitution reactions of the ribose-derived acetal
1 (eq 1), we investigated how changing substituents at C-2, C-3,
and C-4 of the oxocarbenium ion intermediate 5 would influence
selectivity. All substrates were prepared as anomeric mixtures,
and control experiments revealed that the anomeric composition
did not influence the stereoselectivities, suggesting common
intermediates.55,56 Our studies focused on C-glycosylation of
anomeric acetates with allyltrimethylsilane in CH2Cl2 because
the reactions are rapid, high-yielding, and irreversible.57 The
products also cannot be epimerized, and the presence of the
pendant alkene in the product permits facile stereochemical
proof of the products.55 We have described in detail other
reasons for selecting experiments of this type.26
C-2 Alkoxy Group. Stereoselective nucleophilic substitution
reactions of 2-deoxyribose derivatives indicate that the electronic
nature of the C-2 substituent does not govern the high selectivity
of the ribose-derived system (eq 1). Replacing the oxygen at
the C-2 position with either hydrogen or fluorine led to the
analogous 1,3-cis products with comparable selectivities (eq 4).
addition, the relative stereochemistry between the substituent
at C-4 and the alkoxy group at C-3 did not strongly influence
the 1,3-cis selectivity (eq 7). In contrast to intuition, substitution
of acetal 14 provided a product where the nucleophile ap-
proached from the same face as the two substituents.37,66
Geminal substitution at C-4 also had little influence on the high
cis selectivity (eq 8).67,68
Experiments involving substrates bearing a single alkyl group
at C-4 support the notion that this substituent does not control
the approach of the nucleophile (eq 9). While 1,4-disubstituted
Similar observations for alkylations23,58-61 and reductions62 of
2-deoxyribosyl systems resembling 8a have been reported. In
the case of the fluoro compound 8b, TiCl4 was required to obtain
allylation products, presumably since the strongly electron-
withdrawing fluorine made formation of the oxocarbenium ion
difficult.63-65 Because these modifications did not equate to a
difference in selectivities, substitution at a position other than
C-2 must determine the stereochemical course of these reactions.
Examining the influence of the C-2 benzyloxy group in the
absence of other substituents revealed that this substituent
reinforces the stereochemical preference of the ribosyl oxocar-
benium ions 5. Allylation of the 2-benzyloxy acetate 10 was
cis-selective (eq 5), matching the selectivity pattern observed
tetrahydrofurans are found in natural products such as the
Annonaceous acetogenins,8,9 controlling this stereochemical
array has been challenging,11 as demonstrated by other research-
ers, since this position does not strongly influence selectivi-
ties.29-32,39,69
C-3 Alkoxy Group. The electronic nature of the substituent
at C-3 exerts a powerful effect upon selectivity. Replacing the
for the ribose system (eq 1). In contrast, additions of allyltri-
methylsilane to 2-methyl-substituted five-membered ring acetals
are modestly trans-selective.29-32 These experiments suggest that
the C-2 substituent exerts some control but is not responsible
for the high R-selectivity observed in eq 1.
(61) Jaouen, V.; Je´gou, A.; Veyrie`res, A. Synlett 1996, 1218-1220.
(62) Wichai, U.; Woski, S. A. Bioorg. Med. Chem. Lett. 1998, 8, 3465-3468.
(63) Namchuk, M. N.; McCarter, J. D.; Becalski, A.; Andrews, T.; Withers, S.
G. J. Am. Chem. Soc. 2000, 122, 1270-1277.
(64) Torsional effects can also influence the rate of ionization of acetals: Dean,
K. E. S.; Kirby, A. J.; Komarov, I. V. J. Chem. Soc., Perkin Trans. 2 2002,
337-341.
(65) Partial debenzylation was observed under these conditions: Hori, H.;
Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989, 54, 1346-1353.
(66) For clarity of presentation, this compound was drawn as one enantiomer.
Because this substrate was prepared from D-xylose, the material is the
enantiomer of the one presented.
(67) Wendeborn, S.; Binot, G.; Nina, M.; Winkler, T. Synlett 2002, 1683-1687.
(68) Paquette, L. A.; Seekamp, C. K.; Kahane, A. L.; Hilmey, D. G.; Galluci,
J. J. Org. Chem. 2004, 69, 7442-7447.
(55) The syntheses of substrates, determination of stereoselectivities, and
stereochemical proofs are provided as Supporting Information.
(56) Shenoy, S.; Woerpel, K. A. Org. Lett. 2005, 7, 1157-1160.
(57) Hagen, G.; Mayr, H. J. Am. Chem. Soc. 1991, 113, 4954-4961.
(58) Uenishi, J.; Sohma, A.; Yonemitsu, O. Chem. Lett. 1996, 595-596.
(59) Shimomura, N.; Saitoh, M.; Mukaiyama, T. Chem. Lett. 1994, 433-436.
(60) For example, see: Ichikawa, Y.-i.; Kubota, H.; Fujita, K.; Okauchi, T.;
Narasaka, K. Bull. Chem. Soc. Jpn. 1989, 62, 845-852.
9
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A R T I C L E S
Larsen et al.
alkoxy group at C-3 in the 2-deoxyribose system 8a with a
methyl group resulted in formation of the 1,3-trans product (eq
10), which is the opposite selectivity obtained with 8a (eq
steric effects are unlikely to control the stereochemical outcome
of the reaction.37,77
Discussion
The results obtained from previous investigations37-39 and
this current study of ribose-derived analogues support and shape
a general method of analysis applicable to the nucleophilic
substitution reactions of alkoxy-substituted five-membered ring
oxocarbenium ions. The monosubstituted acetals were examined
to understand the independent influence of each substituent on
the ground state conformer population of the oxocarbenium ion,
which is associated with the selectivity.78 To understand and
predict the selectivity of highly oxygenated systems such as 1,
the influence of each substituent is considered along with the
interactions that arise between the groups present.
The C-3 alkoxy group exerts the largest influence on
selectivity, leading to the 1,3-cis product. An alkoxy group at
C-3 prefers to adopt a pseudoaxial orientation (28, eq 13),
placing the partially negatively charged substituent in closest
proximity to the cationic carbon of the oxocarbenium ion.25,26,42-44
Nucleophilic attack on the lower energy conformer 28 from the
stereoelectronically favored inside face37-39 affords the observed
1,3-cis product (eq 13). This mode of attack develops a syn-
4).38,70,71 This divergence in diastereoselectivity between an
alkoxy group and a methyl group25,26 was independent of the
relative stereochemistry between the C-3 and C-4 positions (eq
11).72 The selectivities observed for acetates 2073,74 and 23 have
been observed by other workers.10
Experiments with monosubstituted acetals 26a-c confirmed
the powerful influence of a single alkoxy group at C-3 on
selectivity. Substitutions on acetals with an oxygen substituent
at C-3, regardless of the protecting group employed, provided
the 1,3-cis products with high selectivities (eq 12).26,75 The 1,3-
butanol interaction79 in the transition state, but this interaction
is considerably smaller than a syn-pentane interaction,80 so it
is not destabilizing enough to hinder attack from this trajectory.
In contrast, a C-3 alkyl-substituted oxocarbenium would experi-
ence a syn-pentane interaction80 upon attack of the C-3 axial
conformer, so attack occurs on the analogous equatorial cation,
leading to the 1,3-trans product.
Because five-membered ring iminium ions reside in similar
envelope conformations, the observations and analysis of the
3-alkoxy oxocarbenium ion 28 (eq 13) are relevant for the
related nitrogen-containing compounds.41 Seebach reported that
reactions of 3-silyloxyiminium ions derived from N,O-acetal
30 showed preferential 1,3-cis selectivity (eq 14).81,82 This result
cis selectivity contrasts with the preferred 1,3-trans selectivity
observed for 3-alkyl29-32 and 3-aryl31,76 substituted five-
membered ring acetals. These 1,3-cis selectivities indicate that
(69) Improved selectivity for C-4 substituted five-membered ring acetals can
be realized with either large substituents at C-4 (Buffet, M. F.; Dixon, D.
J.; Ley, S. V.; Reynolds, D. J.; Storer, R. I. Org. Biomol. Chem. 2004, 2,
1145-1154) or using large nucleophiles (Jalce, G.; Seck, M.; Franck, X.;
Hocquemiller, R.; Figade`re, B. J. Org. Chem. 2004, 69, 3240-3241).
(70) For both of these substrates, the two anomers of the starting material could
be separated. When each isomer was subjected separately to the reaction
conditions, the same product was obtained with the same diastereoselec-
tivity. These experiments suggest that the reactions of the two anomers
proceed via a common intermediate.
is matched by the selectivity of the 3-silyloxy oxocarbenium
system derived from acetal 26b (eq 12). Similar to the analysis
(71) This selectivity is independent of Lewis acid (TiCl4, SnCl4, or BF3‚OEt2).
(72) Addition of hydride to a structurally related five-membered ring oxocar-
benium ion bearing an alkyl group at C-2 occurs with high selectivity with
similar stereochemistry: Yoda, H.; Mizutani, M.; Takabe, K. Tetrahedron
Lett. 1999, 40, 4701-4702.
(77) Bear, T. J.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 2002, 67, 2056-
2064.
(78) Destabilizing steric effects developing in the transition states do not appear
to be large in these ribose-derived systems, probably since the alkoxy
substituents are not sterically large.
(79) Ohno, K.; Yoshida, H.; Watanabe, H.; Fujita, T.; Matsuura, H. J. Phys.
Chem. 1994, 98, 6924-6930.
(73) Ishihara, J.; Miyakawa, J.; Tsujimoto, T.; Murai, A. Synlett 1997, 1417-
1419.
(74) Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763-766.
(75) Control experiments performed using acetal 26b indicate that the polarity
of the solvent (CH2Cl2, hexane, and nitroethane) does not influence
selectivity. In addition, the same selectivity can be obtained using protic
acids to catalyze the reaction.
(80) Wiberg, K. B.; Murcko, M. A. J. Am. Chem. Soc. 1988, 110, 8029-8038.
(81) Renaud, P.; Seebach, D. HelV. Chim. Acta 1986, 69, 1704-1710.
(82) For other examples exhibiting similar selectivities, see: (a) Thaning, M.;
Wistrand, L.-G. Acta Chem. Scand. 1989, 43, 290-295. (b) Boto, A.;
Herna´ndez, R.; Sua´rez, E. Tetrahedron Lett. 2000, 41, 2495-2498. (c)
Yoda, H.; Egawa, T.; Takabe, K. Tetrahedron Lett. 2003, 44, 1643-1646.
(76) Mehta, G.; Sengupta, S. Tetrahedron Lett. 1996, 37, 8625-8626.
9
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Five-Membered Ring Oxocarbenium Ions
A R T I C L E S
in eq 13, the alkoxy group of the related iminium ion evidently
prefers an axial orientation, and nucleophilic attack through the
staggered transition state affords the observed cis product.
The contra-steric 1,2-cis product 11 obtained from the reaction
of the monosubstituted acetal 10 (eq 5) indicates that the
electronic nature of the C-2 alkoxy group contributes to the
selectivity. The oxocarbenium ion intermediate prefers to
position the C-2 alkoxy group in a pseudoequatorial orientation
(32, eq 15), consistent with the reactions of related C-2
the C-2 alkoxy group is replaced with either H or F as seen for
the 2-deoxyribose systems (eq 4), the conformational preference
is not dramatically perturbed, demonstrating the powerful
influence of the C-3 alkoxy substituent. This argument extends
to the selective reduction of the C-1 phenyl-substituted acetal
3 (eq 2), since the presence of a C-1 alkyl or aryl group does
not change the selectivities of reactions of five-membered ring
acetals.39
Extensions to Systems not Derived from Ribose. Our
detailed analysis of the stereoselective reactions of ribose-
derived electrophiles such as 1 (eq 1) indicates that the C-3
alkoxy substituent dominates the stereoselective reactions of
these cations (eq 12). The presence of an alkoxy group at C-2,
which favors 1,2-cis selectivity (eq 5), reinforces the selectivity
observed in eqs 1 and 2 because it is cis to the C-3 alkoxy
group. We anticipated that if a cation had only alkoxy groups
at C-2 and C-3 (as in eq 18), 1,3-cis selectivity would be
observed. Selectivity would be high if the substituents were cis
to each other, because the oxocarbenium ion would adopt the
conformer 38, retaining the preferred pseudoaxial orientation
at C-3 and pseudoequatorial orientation at C-2.25,26,43 On the
substituted six-membered ring oxocarbenium ions.43 This con-
former maximizes the overlap of the more electron-donating83,84
σC-H orbital at C-2 with the adjacent vacant orbital of the
oxocarbenium ion.25,26 Consequently, inside attack on the
favored equatorial conformer 32 provides the 1,2-cis product.
With an alkyl group at C-2, steric interactions are small,26 and
the hyperconjugative donating abilities of σC-H and σC-C orbitals
are similar,84 so both conformers have equivalent energies.
Inside attack on the pseudoaxial conformer alleviates destabiliz-
ing gauche-butane interactions that develop in the transition state
structure involving the pseudoequatorial conformer, providing
a moderate selectivity for the 1,2-trans product.
A C-4 alkyl substituent normally exerts little influence on
the selectivities resulting from reactions of oxocarbenium
ions.29-32 It does not strongly bias the conformational equilib-
rium,31 nor is it involved in destabilizing interactions in the
transition state for nucleophilic attack. As a result, both 1,4-
trans and 1,4-cis products are observed (eq 16). A substituent
at C-4, however, can exert significant control on selectivity
(favoring the 1,4-cis product) if it is constrained to an equatorial
position (as in conformer 35) by geminal substitution at C-2.18,39
Our observation that the selectivity is independent of the
electronic nature of the C-4 substituent (such as in eqs 6 and 9)
contrasts with observations of the influence on selectivity exerted
by the analogous C-5 substituent for tetrahydropyran cations.45,85
The aggregate influences of the appropriate substituents at
C-2, C-3, and C-4 account for the selectivities obtained from
nucleophilic substitution reactions of the ribose-derived systems.
Because the C-3 alkoxy group has a strong tendency to be
pseudoaxial and the C-2 alkoxy group favors pseudoequatorial
positions, conformer 36 is strongly favored when X ) OBn.
The C-4 alkyl group exerts no discernible influence on the
conformational preference. Inside attack on the lower energy
conformer 36 leads to the observed major product (eq 17). When
other hand, switching the stereochemistry at C-2 to the 2,3-
trans oxocarbenium ion would diminish the preference for
conformer 38, leading to lower selectivity because of the
unfavorable axial orientation of the alkoxy substituent at C-2.
These hypotheses were verified by experiments: substitutions
on the acetals 40 and 42 (eqs 1986 and 20) occur cis to the C-3
alkoxy group, and lower selectivity is observed when the two
substituents are trans.
The modest 1,3-cis selectivity for C-glycosylation of arabi-
nose-derived acetal87 44 (eq 21)78,88 illustrates further the
“mismatched” selectivities exhibited by trans-substituted acetal
(83) Apeloig, Y.; Schleyer, P. v. R.; Pople, J. A. J. Am. Chem. Soc. 1977, 99,
5901-5909.
(84) Alabugin, I. V.; Manoharan, M. J. Org. Chem. 2004, 69, 9011-9024.
(85) Larrosa, I.; Romea, P.; Urp´ı, F.; Balsells, D.; Vilarrasa, J.; Font-Bardia,
M.; Solans, X. Org. Lett. 2002, 4, 4651-4654.
(86) The selectivity can be improved to 98:2 by using toluene as the solvent.
(87) Barker, R.; Fletcher, H. G., Jr. J. Org. Chem. 1961, 26, 4605-4609.
(88) Peri, F.; Bassetti, R.; Caneva, E.; de Gioia, L.; La Ferla, B.; Presta, M.;
Tanghetti, E.; Nicotra, F. J. Chem. Soc., Perkin Trans. 1 2002, 638-644.
9
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A R T I C L E S
Larsen et al.
42. For the C-3 alkoxy group to occupy the preferred pseudo-
would not be anticipated based upon consideration of steric
effects alone, since the nucleophile approaches the electrophile
from the same face as the substituents.
Conclusion
By systematically varying the substitution of the ribose-
derived acetal 1 (eq 1), we determined that the alkoxy group at
C-3 principally governs the selectivity. As with six-membered
rings,25,26,42 the electronic nature of substituents exerted an
enormous influence on the selectivity of these reactions. The
lowest energy conformers bear the C-3 alkoxy group in a
pseudoaxial orientation. To a lesser extent, the C-2 substituent
prefers to occupy a pseudoequatorial position, a preference that
is accommodated by the ribose stereochemistry but not the
arabinose stereochemistry. The alkyl group at C-4 exerts no
influence on the stereoselective reactions of ribose-derived
acetals. In all cases, the product was formed by stereoelectroni-
cally preferred inside attack on the lowest energy conformer.
The studies reported in this paper indicate that a knowledge of
the unusual conformational preferences of alkoxy groups in
oxocarbenium ions25,26,42-44 and a stereoelectronic model to
explain reactions of five-membered ring oxocarbenium ions37-39
can be combined to predict selectivities in highly substituted
oxocarbenium ions and also iminium ions.
axial orientation, all substituents must be pseudoaxial (46, eq
22). This arrangement not only would place the C-2 alkoxy
group in the electronically disfavored pseudoaxial orientation
but also would create an unfavorable syn-butanol interaction79
between the benzyloxy substituent at C-2 and the alkoxymethyl
group at C-4. Although the magnitude of the syn-butanol
interaction is not high (approximately 1.8 kcal/mol),79 the
transition state leading to the observed product would involve
two such interactions. Considering these destabilizing interac-
tions, the reaction via the all-equatorial conformer 47 should
also be possible, leading to a poorly selective reaction.88-90
Because a single alkoxy group at C-3 is generally sufficient
to control the conformational equilibrium and provide high
selectivity, it was anticipated that the influence of a C-3 alkoxy
group would overwhelm the modest influence on selectivity
conferred by an alkyl group at C-2.29-32 A C-3 alkoxy
oxocarbenium ion substituted at C-2 with a methyl group either
cis or trans to it should adopt the electrostatically stabilized
conformer 48, and inside attack would lead to the 1,3-cis product
49 (eq 23). This prediction was also validated by experiments
(eqs 24 and 25). As with two other disubstituted substrates
examined (eqs 7 and 19), the major product obtained in eq 25
Acknowledgment. We dedicate this paper to the memory of
our friend and colleague Dr. Jacqueline Smitrovich, whose
insight and inspiration profoundly influenced us. This research
was supported by the National Institutes of Health, National
Institute of General Medical Sciences (GM-61066) and by
Johnson & Johnson. Acknowledgment is also made to the donors
of the Petroleum Research Fund, administered by the American
Chemical Society, for partial support of this research. C.H.L.
thanks Pfizer for a Summer Undergraduate Research Fellowship.
J.T.S. thanks the American Chemical Society Division of
Organic Chemistry, sponsored by Merck, for a graduate
fellowship. D.M.S. thanks Johnson & Johnson for a graduate
research fellowship. K.A.W. thanks Merck Research Labora-
tories and Johnson & Johnson for awards to support research.
We thank Michelle Tran-Dube´ for her contributions to this
project, Dr. John Greaves and Dr. John Mudd for mass
spectrometric data, and Dr. Phil Dennison for assistance with
NMR studies.
Supporting Information Available: Complete experimental
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.
JA0524043
(89) Addition of allyltrimethylsilane to a tetrabenzyl fructose-derived acetal,
which is stereochemically similar to the arabinose system except that it
bears an alkoxymethyl group at C-2, gives similar selectivity: Nicotra, F.;
Panza, L.; Russo, G. J. Org. Chem. 1987, 52, 5627-5630.
(90) Sharma, G. V. M.; Chander, A. S.; Krishnudu, K.; Krishna, P. R.
Tetrahedron Lett. 1997, 38, 9051-9054.
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10884 J. AM. CHEM. SOC. VOL. 127, NO. 31, 2005