Correlations between nucleophilicities and selectivities in the substitutions of tetrahydropyran acetals

Article abstract of DOI:10.1021/jo901639b

(Chemical Equation Presented) Selectivities that deviate from S _N1 stereoelectronic models in the nucleophilic substitutions of tetrahydropyran acetals were investigated. When weak nucleophiles were employed, stereoselectivities conformed to kn

Full text of DOI:10.1021/jo901639b

pubs.acs.org/joc
Correlations Between Nucleophilicities and Selectivities in the
Substitutions of Tetrahydropyran Acetals
Jennifer R. Krumper, Walter A. Salamant, and K. A. Woerpel*
Department of Chemistry, University of California, Irvine, California 92697-2025
kwoerpel@uci.edu
Received July 28, 2009
Selectivities that deviate from SN1 stereoelectronic models in the nucleophilic substitutions of
tetrahydropyran acetals were investigated. When weak nucleophiles were employed, stereoselecti-
vities conformed to known SN1 stereoelectronic models. In contrast, stereoselectivities in the sub-
stitutions of acetals with strong nucleophiles depended on reaction conditions. Erosions in
selectivities were observed when strong nucleophiles were employed in the absence of coordinating
counterions. These erosions in selectivities are attributed to rates of nucleophilic additions to
oxocarbenium ion intermediates that approach the diffusion limit. When triflate counterions were
present, however, SN2-like pathways became accessible with strong nucleophiles. In most cases
examined, the major stereoisomers formed from reactions that proceeded through SN2-like pathways
were opposite to the major stereoisomers formed from the analogous reactions that proceeded
through SN1 pathways.
Introduction
substitutions can result from a change in the reaction me-
chanism. For example, allylation of a mannosyl donor,
which likely proceeds through an SN1 mechanism, afforded
the R-pyranoside as the major stereoisomer,14 while selecti-
vity for the β-pyranoside in the allylation of a modified
mannosyl donor is attributed to reaction through an SN2-
like mechanism.15,16 Significant effort, particularly in carbo-
hydrate synthesis, has been expended to develop conditions
that favor a single pathway in a predictive manner.7,17-23
The nucleophilic substitution reactions of functionalized
tetrahydropyran acetals and related pyranosyl donors can
proceed by either SN1-1-5 or SN2-like6-13 pathways. Devia-
tion in the stereochemical outcomes of two similar pyranosyl
(1) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1992, 114, 10998–
10999.
(2) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116, 7915–7916.
(3) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269–4279.
(4) Boebel, T. A.; Gin, D. Y. J. Org. Chem. 2005, 70, 5818–5826.
(5) Shenoy, S. R.; Woerpel, K. A. Org. Lett. 2005, 7, 1157–1160.
(6) The term “SN2-like” encompasses both nucleophilic displacement of a
covalently bound leaving group and nucleophilic addition to a contact ion-
pair in which one face of an oxocarbenium ion intermediate is blocked by a
counterion.
(14) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H. J. Am.
Chem. Soc. 2001, 123, 9545–9554.
(15) Crich, D.; Sharma, I. Org. Lett. 2008, 10, 4731–4734.
(16) Allylation of mannosyl phosphate with no selectivity has been
reported: Singh, G.; Vankayalapati, H. Tetrahedron: Asymmetry 2001, 12,
1727–1735.
(7) Kim, J.-H.; Yang, H.; Park, J.; Boons, G.-J. J. Am. Chem. Soc. 2005,
127, 12090–12097.
(8) Nukada, T.; Berces, A.; Zgierski, M. Z.; Whitfield, D. M. J. Am.
Chem. Soc. 1998, 120, 13291–13295.
(9) Berces, A.; Enright, G.; Nukada, T.; Whitfield, D. M. J. Am. Chem.
Soc. 2001, 123, 5460–5464.
(10) Fan, E.; Shi, W.; Lowary, T. L. J. Org. Chem. 2007, 72, 2917–2928.
(11) Banait, N. S.; Jencks, W. P. J. Am. Chem. Soc. 1991, 113, 7951–7958.
(12) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43,
5386–5389.
(17) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506–4507.
(18) McGarvey, G. J.; LeClair, C. A.; Schmidtmann, B. A. Org. Lett.
2008, 10, 4727–4730.
(19) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198–1199.
(20) Lam, S. N.; Gervay-Hague, J. Org. Lett. 2003, 5, 4219–4222.
(21) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056–4062.
ꢀ
(22) Codee, J. D. C.; de Jong, A. R.; Dinkelaar, J.; Overkleeft, H. S.; van
der Marel, G. A. Tetrahedron 2009, 65, 3780–3788.
(23) Dinkelaar, J.; de Jong, A. R.; van Meer, R.; Somers, M.; Lodder, G.;
ꢀ
Overkleeft, H. S.; Codee, J. D. C.; van der Marel, G. A. J. Org. Chem. 2009,
74, 4982–4991.
(13) El-Badri, M. H.; Willenbring, D.; Tantillo, D. J.; Gervay-Hague, J.
J. Org. Chem. 2007, 72, 4663–4672.
DOI: 10.1021/jo901639b
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Published on Web 10/08/2009
J. Org. Chem. 2009, 74, 8039–8050 8039
2009 American Chemical Society

Krumper et al.
JOCFeatured Article
For example, changes in the pyranosyl donor,17,22-24 nucleo-
phile,25-28 activator,3,24 and solvent29 can alter the predomi-
nant mechanistic pathway and the resulting stereoselectivity.
Stereoselectivity in tetrahydropyran acetal substitutions
that proceed through SN1 pathways can be predicted, or
rationalized, by stereoelectronic models involving half-chair
oxocarbenium ions.30-32 In accord with Curtin-Hammett
kinetics,33 the facial preference of nucleophilic addition onto
a substituted cyclic oxocarbenium ion depends upon which
diastereomeric half-chair conformer is preferred and any
developing interactions (e.g., 1,3-diaxial interactions) be-
tween the incoming nucleophile and the ring substituents.34
These stereochemical models fail when the rates of nucleo-
philic addition to the intermediate oxocarbenium ion ap-
proach the diffusion limit.35,36
FIGURE 1. π-Nucleophile panel.
Experimental Approach
The major stereoisomers generated by SN2-like nucleo-
philic substitutions of tetrahydropyran acetals can be pre-
dicted on the basis of the configurations at C1 of the
tetrahydropyran donors. The lower energy chair conforma-
tions of donors that can undergo SN2-like displacements,
such as tetrahydropyran triflates,3,37,38 iodides,20,27 and
fluorides,11 typically favor axial conformations for the leav-
ing groups at the anomeric (C1) positions.4,38,39 Subsequent
stereospecific displacements of these axial leaving groups
with inversion account for the major stereoisomers observed
in these transformations. Conditions and substrates that
favor reaction through either the tetrahydropyran donor
or a contact ion-pair over a solvent-separated oxocarbenium
ion are critical to access SN2-like pathways instead of SN1
pathways.4,17,40
In this paper, we analyze the impact of nucleophile
reactivity on the stereoselectivities of tetrahydropyran acetal
substitutions and discuss mechanistic implications of these
trends. We present evidence that suggests the substitutions of
acetals with weak nucleophiles generally favor SN1 mech-
anisms regardless of the conditions employed. In contrast, the
mechanisms and stereochemical outcomes in the substitutions
of acetals with strong nucleophiles appear highly dependent
To investigate the influence of nucleophilicity on stereose-
lectivity in the substitutions of tetrahydropyran acetals, a series
of neutral π-nucleophiles with varying nucleophilicities was
selected (Figure 1).41,42 The nucleophilicity values (N), derived
by Mayr and co-workers, correlate logarithmically with rates of
reactions with carbocationic electrophiles.41,43 The nucleo-
philes selected for this study represent a range in reactivity that
spans over eight orders of magnitude,41 from the least reactive,
allyltrimethylsilane 1 (N= 1.8), to the most reactive, alkylsilyl
ketene acetal 10 (N=10.2). Although the nucleophilicity values
of enoxy silane 6 and silyl thioketene acetal 7 are unknown, we
hypothesized they would lie between 6.2 and 8.2.44
Results and Discussion
C3 tert-Butyl Acetal. Reactions of C3 tert-butyl acetal 11
with allyltrimethylsilyl or enoxy silane nucleophiles (N =
1.8 - 6.2) in the presence of BF3 OEt2 afforded 1,3-trans
3
stereoisomers with high selectivities (Table 1, entries 1-4).
Although these reactions employed nucleophiles with reac-
tivities spanning four orders of magnitude, stereoselectivities
remained constant. When silyl ketene acetals 8 and 10 (N =
8.2 and 10.2, respectively) were employed, however, the
major 1,3-trans stereoisomers were produced with eroded
selectivities (Table 1, entries 5 and 6).
on which activator (BF3 OEt2 or Me3SiOTf) and which
3
tetrahydropyran acetal are employed.
The loss of stereoselectivity in the substitution of acetal 11
with silyl ketene acetals 8 and 10 cannot be explained by a
simple SN1 stereochemical model32 (Scheme 1). The 1,3-trans
stereoisomers observed as the major products of the substitu-
tions of acetal 11 with allyltrimethylsilyl and enoxy silane
nucleophiles 1, 2, 4, and 5 are assumed to result from
(24) Crich, D.; Pedersen, C. M.; Bowers, A. A.; Wink, D. J. J. Org. Chem.
2007, 72, 1553–1565.
(25) Minehan, T. G.; Kishi, Y. Tetrahedron Lett. 1997, 38, 6815–6818.
(26) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V. Tetrahedron
1989, 45, 4293–4308.
(27) Gervay, J.; Hadd, M. J. J. Org. Chem. 1997, 62, 6961–6967.
(28) Hinkle, R. J.; Lian, Y.; Litvinas, N. D.; Jenkins, A. T.; Burnette,
D. C. Tetrahedron 2005, 61, 11679–11685.
(29) Vankar, Y. D.; Vankar, P. S.; Behrendt, M.; Schmidt, R. R. Tetra-
hedron 1991, 47, 9985–9992.
(41) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77.
(42) Tokuyasu, T.; Mayr, H. Eur. J. Org. Chem. 2004, 2791–2796.
(43) Mayr and co-workers have elucidated an additional nucleophile
parameter, s, that we omit for the sake of clarity. Although the s value can
have a significant impact on the predicted rate of a nucleophile-electrophile
combination, the impact on relative rates between two different nucleo-
phile-electrophile combinations is minimal if the s values are similar. The
known s values for nucleophiles used in this study range from 0.79 to 1.0; see
ref 41.
(30) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032–
7035.
(31) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289–296.
(32) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983; pp 209-221.
(33) Seeman, J. I. Chem. Rev. 1983, 83, 83–134.
(34) Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641–2647.
(35) Shenoy, S. R.; Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2006,
128, 8671–8677.
(36) Krumper, J. R.; Salamant, W. A.; Woerpel, K. A. Org. Lett. 2008, 10,
4907–4910.
(37) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217–11223.
(38) Nokami, T.; Shibuya, A.; Tsuyama, H.; Suga, S.; Bowers, A. A.;
Crich, D.; Yoshida, J.-i. J. Am. Chem. Soc. 2007, 129, 10922–10928.
(39) Displacements of equatorial triflates at the anomeric position have
been reported to be favored over displacements of axial triflates: Stewart,
A. O.; Williams, R. M. J. Am. Chem. Soc. 1985, 107, 4289–4296.
(40) Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681–1690.
(44) The relative reactivities of enoxy silane 6 and silyl ketene thioacetal 7
to other nucleophiles employed in this study are estimated based upon
reactivities of related compounds detailed by Mayr and co-workers (e.g.,
furan is more nucleophilic than thiophene); see ref 41. These estimated
relative reactivities can also be inferred by reaction times in Mukaiyama
aldol and Mannich reactions; see: (a) Evans, D. A.; Kozlowski, M. C.;
Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J.
J. Am. Chem. Soc. 1999, 121, 669–685. (b) Sedelmeier, J.; Hammerer, T.;
Bolm, C. Org. Lett. 2008, 10, 917–920. (c) Hamada, T.; Manabe, K.;
Kobayashi, S. Chem.-Eur. J. 2006, 12, 1205–1215. (d) Dıez, E.; Prieto, A.;
´
ꢀ
Simon, M.; Vazquez, J.; Alvarez, E.; Fernandez, R.; Lassaletta, J. M.
ꢀ
Synthesis 2006, 540–550.
ꢀ
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TABLE 1. Nucleophilic Substitution of C3 tert-Butyl Acetal 11 Acti-
vated by BF3 OEt2
TABLE 2. Competition Reactions with Acetal 11
3
entry
Nu-SiMe3
Na
product
cis/transb
yieldc (%)
1
2
3
4
5
6
1
2
4
5
8
10
1.8
3.8
4.4
6.2
8.2
10.2
12
13
14
15
16
17
1:99
1:99
1:99
2:98
17:83
34:66
67
88
80
83
93
69
aN = nucleophilicity parameter.41 bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture. cIsolated
yield.
aFive equivalents of nucleophile. bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture.
SCHEME 1. Stereoelectronic Model for Oxocarbenium Ion 18
occurs when the rates of reactions by both paths a and b
approach the diffusion limit (Scheme 1). A statistical mixture of
stereoisomers is expected when all viable reaction paths reach
the diffusion limit.46
It was predicted that selectivity in a competition reaction
between two nucleophiles with a single oxocarbenium ion
electrophile (e.g., 18) would corroborate that the loss of
stereoselectivity in the addition of a nucleophile to a cyclic
oxocarbenium ion results from diffusion-limited reaction rates.
A competition experiment in which the rates of reaction are
below the diffusion limit should favor the product generated
from the more reactive znucleophile.46 The selectivity in this
competition reaction should reflect the logarithmic difference
between the nucleophilicities of the two nucleophiles (ΔN).43
For example, a difference of one order of magnitude between
two different nucleophiles (ΔN = 1) should result in an
approximate 10:1 difference in rates between the two nucleo-
phile-electrophile combinations.43 If two nucleophiles both
react at or near the diffusion limit, however, then a competition
reaction between these two nucleophiles with a single electro-
phile should give a mixture of the two products regardless of the
difference in nucleophilicities.46,49
nucleophilic additions to the stereoelectronically preferred
face32 of lower energy oxocarbenium ion conformer45 18eq
(Scheme 1, path a). In contrast, the 1,3-cis stereoisomers obser-
ved when silyl ketene acetals 8 and 10 are employed can arise
from either nucleophilic addition to the stereoelectronically
disfavored face of the lower energy conformer 18eq (path b) or
nucleophilic addition to the higher energy conformer 18ax (path
d). Nucleophilic attack on the bottom face of minor conformer
18ax (path d) is discounted because a significant 1,3-diaxial
interaction between the C3 tert-butyl group and the incoming
nucleophile develops in the transition state. On the basis of this
analysis, the two diastereomeric products arise from competitive
addition to both faces of conformer 18eq (paths a and b).
Extrapolation of the work of Mayr and co-workers suggests
that the loss of stereoselectivity observed in the substitutions of
acetal 11 could occur if reaction rates approach the diffusion
limit (k≈109 M-1 s-1).41,46,47 The diffusion limit represents the
maximum rate at which a bimolecular reaction can occur.48
Application of this concept to the stereoelectronic model for
oxocarbenium ion 18eq implies that erosion of stereoselectivity
A series of competition experiments were performed with
acetal 11 and several pairs of nucleophiles to explore the
diffusion-limit hypothesis (Table 2).50 Treatment of acetal 11
with nucleophiles 2 and 5 in the presence of BF3 OEt2
3
afforded tetrahydropyran 15 in high selectivity (Table 2,
entry 1). Tetrahydropyran 16 was obtained in high selectivity
when nucleophiles 2 and 8 were used in competition (Table 2,
entry 2). When two silyl ketene acetal nucleophiles (8 and 10)
were employed, however, tetrahydropyrans 16 and 17
were produced with selectivity lower than predicted by
(49) A third scenario is also possible: a competition reaction between two
nucleophiles with a single electrophile would still be selective if only one
nucleophile-electrophile combination proceeds with a rate near the diffu-
sion limit. In this case, the major product would arise from the more reactive
nucleophile, but the selectivity would be less than the expected from the
difference in nucleophilicities (ΔN).
(50) Ratios of stereoisomers for all products observed in the competition
experiments matched those observed in the individual reactions of a single
nucleophile with a single acetal.
(45) Manoharan, M.; Eliel, E. L. Tetrahedron Lett. 1984, 25, 3267–3268.
(46) Mayr, H.; Ofial, A. R. Angew. Chem., Int. Ed. 2006, 45, 1844–1854.
(47) Bartl, J.; Steenken, S.; Mayr, H.; McClelland, R. A. J. Am. Chem.
Soc. 1990, 112, 6918–6928.
(48) Atkins, P.; de Paula, J. Physical Chemistry; 7th ed.; Freeman:
New York, 2002; pp 951-954.
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Krumper et al.
JOCFeatured Article
the difference in the nucleophilicity values of 8 and 10
(Table 2, entry 3). These results are consistent with the con-
clusion that nucleophiles 2 and 5 add to oxocarbenium ion
18eq with rates below the diffusion limit, but nucleophiles 8
and 10 add to oxocarbenium ion 18eq near the diffusion limit.
Based upon observations by Crich and co-workers,37 we
hypothesized that activation of acetal 11 with Me3SiOTf,
C4 OBn Acetal. Inductive effects could alter the ratio of the
solvent-separated oxocarbenium ion intermediate (associated
with the SN1 pathway) to the tetrahydropyran triflate intermedi-
ate (associated with the SN2-like pathway).37,40 Destabilization
of a solvent-separated oxocarbenium ion (e.g., 19eq, Scheme 2)
would likely increase the relative concentration of the related
tetrahydropyran triflate (e.g., trans-20eq).40 This change in equi-
librium would increase the likelihood of accessing an SN2-like
pathway.40 Destabilization of a solvent-separated oxocarbe-
nium ion would also increase the likelihood of the competitive
SN1 pathway approaching diffusion-limited rates.46 Consistent
with this hypothesis, oxygenation of tetrahydropyran acetals is
known to reduce the rate of ionization due to inductive
destabilization of the intermediate oxocarbenium ions.54-57
To probe the influence of inductive effects on the displacement
reactions, substitutions of alkoxy-functionalized tetrahydropyr-
an acetals were examined.58 Nucleophilic substitution reactions
instead of BF3 OEt2, might form tetrahydropyran triflate
3
trans-20eq in situ (Scheme 2). Tetrahydropyran triflate trans-
20eq is predicted to be the preferred isomer because steric
strain is minimized when the C3 tert-butyl group adopts an
equatorial position,45 and anomeric donation from the en-
docyclic oxygen atom into the σ* of the C1-OTf bond is
maximized when the triflate is in an axial position.38,51-53 In
contrast to nucleophilic addition to oxocarbenium ion 19eq
by an SN1 pathway, nucleophilic attack on tetrahydropyran
triflate trans-20eq would provide 1,3-cis products as the
major stereoisomers (Scheme 2).
of C4 OBn acetal 21 in the presence of BF3 OEt2 resulted in a
3
stereoselectivity trend similar to that observed in the substitu-
tions of C3 t-butyl acetal 11 (Tables 1 and 3). Reactions of C4
OBn acetal 21 with enoxy silane 5 (N = 6.2) or weaker
nucleophiles afforded 1,4-trans tetrahydropyrans as the major
stereoisomers (Table 3, entries 1-4). Erosions in 1,4-trans selec-
tivities were observed when more reactive nucleophiles enoxy
silane 6 and silyl thioketene acetal 7 were employed (Table 3,
entries 5 and 6). The use of silyl ketene acetal 8 (N = 8.2)
afforded an equal mixture of stereoisomers (Table 3, entry 7).
A slight preference for formation of the 1,4-cis stereoisomer was
observed when the more reactive silyl ketene acetals 9 (N=9.0)
and 10 (N= 10.2) were employed (Table 3, entries 8 and 9).
The reactions of acetal 21 that proceed with high 1,4-trans
selectivities (Table 3, entries 1-4) match the accepted stereo-
electronic model (Scheme 3, paths a and d).59,60 These high
selectivities are observed when weak nucleophiles are employed,
and the major 1,4-trans stereoisomers arise from stereoelectro-
SCHEME 2. Potential Mechanistic Pathways Involving
Triflate Anion
61-64
Acetal 11 was treated with Me3SiOTf in the presence of
either silyl ketene acetal 8 or 10. Reaction with silyl ketene
acetal 8 afforded trans-16 as the major diastereomer in a ratio
similar to that observed for the reaction activated by
nically preferred additions to lower energy conformer 31ax
(51) Efforts to observe tetrahydropyran triflates generated from Me3-
SiOTf and the tetrahydropyran acetals employed in this study have been
unsuccessful to date.
BF3 OEt2 (eq 1). On the other hand, the reaction of the
3
more nucleophilic silyl ketene acetal 10 afforded cis-17 as the
major stereoisomer, albeit in low selectivity (eq 2). These two
Me3SiOTf-mediated reactions of acetal 11 suggest a transi-
tion from a single SN1 mechanism in operation with silyl
ketene acetal 8 (eq 1) to multiple mechanisms (competing SN1
and SN2-like pathways) in operation in the case of silyl ketene
acetal 10 (eq 2).
(52) Lemieux, R. U.; Koto, S. Tetrahedron 1974, 30, 1933–1944.
(53) Juaristi, E.; Cuevas, G. Tetrahedron 1992, 48, 5019–5087.
(54) Namchuk, M. N.; McCarter, J. D.; Becalski, A.; Andrews, T.;
Withers, S. G. J. Am. Chem. Soc. 2000, 122, 1270–1277.
(55) Withers, S. G.; Percival, M. D.; Street, I. P. Carbohydr. Res. 1989,
187, 43–66.
(56) Jensen, H. H.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205–9213.
(57) Jensen, H. H.; Bols, M. Org. Lett. 2003, 5, 3419–3421.
(58) Tetrahydropyran acetals with oxygen atom functionalization at C2
were not included in this study because the conditions employed to ionize the
acetate acetals (BF3 OEt2 or Me3SiOTf in CH2Cl2 at temperatures of up to
3
0 °C) failed to ionize C2 alkoxy acetals.
(59) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc.
2000, 122, 168–169.
(60) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528.
(61) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc. 1992,
114, 859–864.
ꢀ
(62) Miljkovic, M.; Yeagley, D.; Deslongchamps, P.; Dory, Y. L. J. Org.
Chem. 1997, 62, 7597–7604.
(63) Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am. Chem. Soc.
2005, 127, 5322–5323.
(64) Electrostatic effects on ring conformation equilibria and reactivity
have been experimentally observed in related systems: (a) Jensen, H. H.;
Bols, M. Acc. Chem. Res. 2006, 39, 259–265. (b) Bols, M.; Liang, X.; Jensen,
ꢀ
H. H. J. Org. Chem. 2002, 67, 8970–8974. (c) McDonnell, C.; Lopez, O.;
ꢀ
~
Murphy, P.; Fernandez Bolanos, J. G.; Hazell, R.; Bols, M. J. Am. Chem.
Soc. 2004, 126, 12374–12385. (d) Jensen, H. H.; Lyngbye, L.; Jensen, A.;
Bols, M. Chem.-Eur. J. 2002, 8, 1218–1226.
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JOCFeatured Article
TABLE 3. Nucleophilic Substitution of Acetal 21 Activated by
BF3 OEt2
SCHEME 3. Stereoelectronic Model for Oxocarbenium Ion 31
3
entry
Nu-SiMe3
Na
product
cis/transb
yieldc (%)
1
2
3
4
5
6
7
8
9
1
2
4
5
6
7
8
9
10
1.8
3.8
4.4
6.2
NA
NA
8.2
9.0
10.2
22
23
24
25
26
27
28
29
30
8:92
11:89
10:90
8:92
18:82
21:79
50:50
58:42
60:40
83
84
57
87
67
93
88
80
86
aN = nucleophilicity parameter.41 bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture. cIsolated
yield. dProduct was not isolated under these conditions.
SCHEME 4. Borate Contact Ion-Pair Model
(path a). The minor 1,4-cis stereoisomers likely arise from
stereoelectronically preferred additions to higher energy con-
former 31eq (pathd).59,60 Selectivities that conform to this model
(Table 3, entries 1-4) are believed to reflect the ground-state
ratio of conformers 31ax and 31eq,61,62 as described by a
Winstein-Holness kinetic scenario (Scheme 3).33
The erosion of selectivities in other reactions of acetal 21
(Table 3, entries 5-9) indicates a deficiency in the accepted
stereoelectronic model (Scheme 3).59,60 It is unlikely that the
increased amounts of 1,4-cis stereoisomers result from
stereoelectronic addition to higher energy conformer 31eq
alone: nucleophilic strength should not alter the equilibrium
of the oxocarbenium ion conformers. Similarly, there is no
immediately obvious reason why addition to the stereoelec-
tronically preferred face of higher energy conformer 31eq
(path d) would become a lower energy pathway than addi-
tion to the stereoelectronically preferred face of lower energy
conformer 31ax (path a) when strong nucleophiles are em-
ployed. The losses of stereoselectivities in these substitutions
are most consistent with near-diffusion-limited rates of
addition for both faces of oxocarbenium ions 31ax and 31eq
(paths a-d).
The slight 1,4-cis selectivities observed when silyl ketene
acetals 9 and 10 were employed (Table 3, entries 8 and 9)
cannot be wholly rationalized by diffusion-limited additions
of the nucleophile to oxocarbenium ion 31. An emergent
SN2-like mechanism (Scheme 4, path c) could, however,
account for increased formation of 1,4-cis stereoisomers.
In these reactions, an SN2-like mechanism requires the
BF3OAc- counterion, which is typically considered to be
noncoordinating,65 to block one face of oxocarbenium ion
31, likely as contact ion-pair 32.66-69 It is noteworthy in the
context of this hypothesis that the starting anomer does not
affect the observed selectivity in these reactions: starting with
either cis-21 or trans-21 leads to the same ratio of stereo-
isomers.70
Acetal 21 was treated with a panel of nucleophiles in the
presence of Me3SiOTf to examine the influence of a triflate
counterion on selectivity (Table 4). Substitution of C4 OBn
acetal 21 with enoxy silane 5 (N = 6.2) or less reactive
nucleophiles afforded 1,4-trans tetrahydropyrans as the
major stereoisomers (Table 4, entries 1-4). The eroded
stereoselectivities observed when enoxy silane 6 and silyl
ketene thioacetal 7 were employed (Table 4, entries 5 and 6)
also matched the selectivities in the analogous BF3
OEt2 mediated reactions (Table 3, entries 5 and 6). When
3
silyl ketene acetals 8-10 were employed, however, the
(70) This analysis implies that the diastereomeric contact ion-pairs gen-
erated from these tetrahydropyran acetals equilibrate faster than reactions of
the contact ion-pairs with the nucleophile. A similar independence of starting
anomeric ratios on stereoselectivities in related SN2-like acetal substitutions
have been reported. For example: (a) Reference 20. (b) Guindon, Y.; Ogilvie,
W. W.; Bordeleau, J.; Cui, W. L.; Durkin, K.; Gorys, V.; Juteau, H.; Lemieux, R.;
Liotta, D.; Simoneau, B.; Yoakim, C. J. Am. Chem. Soc. 2003, 125, 428–436.
(71) The stereoselectivities in the Me3SiOTf-mediated substitutions of
acetal 21 with silyl ketene acetals 8-10 were independent of the anomeric
ratio of acetal 21. Employing cis-21, trans-21, or a 50:50 mixture of anomers
afforded identical results.
(65) Suzuki, S.; Matsumoto, K.; Kawamura, K.; Suga, S.; Yoshida, J.-i.
Org. Lett. 2004, 6, 3755–3758.
(66) Winstein, S.; Grunwald, E.; Jones, H. W. J. Am. Chem. Soc. 1951, 73,
2700–2707.
(67) Winstein, S.; Klinedinst, P. E., Jr.; Robinson, G. C. J. Am. Chem.
Soc. 1961, 83, 885–895.
(68) Huang, X.; Surry, C.; Hiebert, T.; Bennet, A. J. J. Am. Chem. Soc.
1995, 117, 10614–10621.
(69) Bennet, A. J.; Kitos, T. E. J. Chem. Soc., Perkin Trans. 2 2002, 1207–
1222.
J. Org. Chem. Vol. 74, No. 21, 2009 8043

Krumper et al.
JOCFeatured Article
substitutions were selective for the 1,4-cis stereoisomers
(Table 4, entries 7-9).71,72
TABLE 4. Nucleophilic Substitution of Acetal 21 Activated by
Me3SiOTf
Divergence in stereoselectivities in the Me3SiOTf-acti-
vated substitutions of acetal 21 can be explained by three
scenarios: stereoselective SN1 pathways, diffusion-limited
unselective SN1 pathways, and SN2-like pathways.73-76
When weaker nucleophiles are employed (Table 4, entries
1-4), selectivity corresponds to the accepted stereoelec-
tronic model of an SN1 mechanism through solvent-sepa-
rated oxocarbenium ion 33 (eq 3). Because the eroded
selectivities with moderate strength nucleophiles 6 and 7
(Table 3, entries 5 and 6, and Table 4, entries 5 and 6) are
entry
Nu-SiMe3
Na
product
cis/transb
yieldc (%)
1
2
3
4
5
6
7
8
9
1
2
4
5
6
7
8
9
10
1.8
3.8
4.4
6.2
NA
NA
8.2
9.0
10.2
22
23
24
25
26
27
28
29
30
6:94
12:88
10:90
10:90
18:82
27:73
71:29
85:15
89:11
96
87
50
95
NAd
85
the same regardless of which activator (BF3 OEt2 or
3
83
93
96
Me3SiOTf) is used, the increased quantities of minor 1,4-
cis stereoisomers are likely due to near diffusion-limited
SN1 processes rather than emergent SN2-like pathways.
When stronger nucleophiles, such as silyl ketene acetals
8-10, are employed, SN2-type displacements of tetra-
hydropyran triflate 34 occur to afford the 1,4-cis products
(eq 3).
aN = nucleophilicity parameter.41 bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture. cIsolated
yield. dProduct was not isolated under these conditions.
SCHEME 5. SN2-like Pathway for Tetrahydropyran
Triflate 34
Selectivities for 1,4-cis stereoisomers in the substitutions
of C4 OBn acetal 21 that follow SN2-like pathways are
consistent with an electrostatic model (Scheme 5) similar to
that used to describe related SN1 pathways (Scheme 3).59,60
Kinetic isotope studies on related SN2-like substitutions of
pyranosyl donors indicate that significant cationic character
develops at C1 in the transition state.12,13,77,78 To account for
this kinetic data, the SN2-like substitutions of pyranosyl
donors have been suggested to proceed through either
“exploded” transition states (e.g., 35) or contact ion-pairs
(e.g., 36).12,13 Placement of the C4 OBn substituent axial in
both “exploded” transition state 35 and contact ion-pair 36 maxi-
mizes the electrostatic interaction between the cationic center at
C1 and the partially negative oxygen atom at C4.61,62
A series of competition experiments were performed with
C4 OBn acetal 21 to support the mechanistic rationales
presented for the nucleophilic substitutions of acetal 21
(Table 5).50 When enoxy silane 5 (N = 6.2) was placed in
competition with silyl ketene acetal 10 (N = 10.2), the pro-
duct arising from reaction with the more reactive silyl ketene
acetal 10, tetrahydropyran 30, was formed with high selec-
tivity (Table 5, entry 1). This result indicates that the addi-
tion of enoxy silane 5 to intermediate oxocarbenium ion
31 is significantly below the diffusion-limited rate of addi-
tion of silyl ketene acetal 10. In contrast, the eroded selec-
tivity between enoxy silane 6 and silyl ketene acetal 10
with acetal 21 (Table 5, entry 2), combined with the
eroded stereoselectivity observed in the reaction of enoxy
silane 6 with acetal 21 (Table 3, entry 5), suggest a near
diffusion-limited rate of addition of enoxy silane 6 to oxo-
carbenium ion 31.
(72) Two control experiments were performed to verify that diastereomer
ratios resulted from kinetic product distributions under these reaction
conditions. An isolated sample of trans-28 was treated with silyl ketene
acetal 10 (4.0 equiv) and Me3SiOTf (1.6 equiv) under standard reaction
conditions. The ester trans-28 did not react under these conditions: neither
stereochemical inversion to cis-28 nor chemical exchange to form cis- or
trans-30 was observed. In addition, an isolated sample of cis-28 was treated
with silyl ketene acetal 10 (4.0 equiv) and BF3 OEt2 (1.6 equiv) under
3
standard reaction conditions. The ester cis-28 did not react under these
conditions either.
A BF3 OEt2-mediated competition reaction between silyl
3
ketene acetals 8 (N = 8.2) and 10 (N = 10.2) with C4 OBn
acetal 21 resulted in low selectivity for products 28 and 30
(Table 5, entry 3). This low selectivity, which is below the
theoretical 100:1 ratio (ΔN = 2.0), remains consistent with
nucleophilic addition of both silyl ketene acetals 8 and 10 to
oxocarbenium ion 31 to be near the diffusion limit. Because
diffusion-limited reactions should afford statistical mixtures
(73) Jencks, W. P. Acc. Chem. Res. 1980, 13, 161–169.
(74) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104, 4689–4691.
(75) Ta-Shma, R.; Rappoport, Z. J. Am. Chem. Soc. 1983, 105, 6082–
6095.
(76) Denmark, S. E.; Almstead, N. G. J. Org. Chem. 1991, 56, 6485–6487.
(77) Bennet, A. J.; Sinnott, M. L. J. Am. Chem. Soc. 1986, 108, 7287–
7294.
(78) Zhang, Y.; Bommuswamy, J.; Sinnott, M. L. J. Am. Chem. Soc. 1994,
116, 7557–7563.
8044 J. Org. Chem. Vol. 74, No. 21, 2009

Krumper et al.
JOCFeatured Article
TABLE 5. Competition Reactions with Acetal 21
ketene acetals 8 and 10, a near-statistical mixture of tetra-
hydropyrans 28 and 30 was observed.79 This lack of selecti-
vity for the pivaloate (eq 4) as compared to the acetate
(Table 5, entry 3) supports near diffusion-limited additions
of nucleophiles 8 and 10 to solvent-separated oxocarbenium
ion 38ax.
aFive equivalents of nucleophile. bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture.
C3 OBn Acetal. We next examined the BF3 OEt2-acti-
3
vated substitutions of C3 OBn acetal 40 with members of a
panel of nucleophiles (Table 6). Similar to previous reports,
allylation of acetal 40 afforded tetrahydropyran cis-41 as the
major stereoisomer (Table 6, entry 1).59,60 Substitutions of
acetal 40 with nucleophiles more reactive than allyltrimethyl-
silane 1 (N=1.8) and less reactive than silyl ketene acetal 10
(N = 10.2), maintained modest, but lower, selectivities for
the 1,3-cis stereoisomers (Table 6, entries 2-5). A decrease in
stereoselectivity was again observed when C3 OBn acetal 40
of products, however, the low selectivity observed in this
competition experiment also supports an emergent SN2-like
mechanism (Scheme 4) as a viable alternative pathway to the
SN1 mechanism.
Competition experiments with acetal 21 activated by
Me3SiOTf in the presence of silyl ketene acetal 10 and one
other nucleophile were designed to differentiate between
was treated with BF3 OEt2 in the presence of silyl ketene 10
3
(Table 6, entry 6).
Me3SiOTf-mediated SN2-like pathways and BF3 OEt2-
3
The stereoselectivities in the substitutions of C3 OBn
acetal 40 provide insight into our previously reported elec-
trostatic stereochemical model59,60 (Scheme 6). In this mod-
el, the major 1,3-cis stereoisomer arises from nucleo-
philic addition to the stereoelectronically preferred face32
of lower energy conformer 47ax61,62 (Scheme 6, path b). The
minor 1,3-trans stereoisomer results from nucleophilic addi-
tion to the stereoelectronically preferred face of higher
energy conformer 47eq (path c). An increase in the quantity
of 1,3-trans stereoisomer formed could result from diffusion-
limited rates of addition to the stereoelectronically dis-
favored face of oxocarbenium ion 47ax (path a). Alterna-
tively, developing 1,3-diaxial interactions between the
C3 OBn group and the incoming nucleophile in the transition
state of path b would become more severe with larger
nucleophiles, which would lead to a greater relative pre-
ference for path c.
mediated SN1 pathways. Selectivity between enoxy silane 6
and silyl ketene acetal 10 in the substitution of acetal 21
increased when the Lewis acid employed was changed from
BF3 OEt2 (Table 5, entry 2) to Me3SiOTf (Table 5, entry 4).
3
Similarly, a Me3SiOTf-mediated competition reaction be-
tween silyl ketene acetals 8 and 10 (Table 5, entry 5) resulted
in higher selectivity than the analogous BF3 OEt2-mediated
3
reaction (Table 5, entry 3). These results support SN2-like
pathways proceeding at rates below the diffusion limit, but in
which the overall activation energies are lower than the
alternative diffusion-limited SN1 pathways. A corollary to
this conclusion is that tetrahydropyran triflate trans-34ax is
lower in energy, and thus higher in concentration, than
solvent-separated oxocarbenium ion 33ax.51
A final competition experiment between silyl ketene acet-
als 8 and 10 was designed to favor only SN1 pathways and
minimize alternative SN2-like pathways (eq 4). Ionization of
If the erosion of stereoselectivities observed in the sub-
stitutions of C3 OBn acetal 40 were solely due to reaction
rates approaching the diffusion limit, then stereoselec-
tivities should have steadily decreased as nucleophilicities
increased.46 This trend was not initially observed; stereose-
lectivities were modest but remained constant when nucleo-
philes 3, 5, 8, and 9 were employed despite a range in reactivity
of five orders of magnitude (Table 6, entries 2-5). The lower
stereoselectivities observed in the substitutions of acetal 40
pivaloate acetal 37 with BF3 OEt2 should generate a cyclic
3
oxocarbenium ion with a BF3OPiv- counterion. We hy-
pothesized that the steric bulk of this borate counterion
would serve to disfavor contact ion-pair 39ax and thus any
SN2-like pathways that would involve 39ax (eq 5). When
acetal 37 was treated with BF3 OEt2 in the presence of silyl
3
(79) Both substitution reactions afforded near statistical mixtures of
stereoisomers as well.
J. Org. Chem. Vol. 74, No. 21, 2009 8045

Krumper et al.
JOCFeatured Article
TABLE 6. Nucleophilic Substitution of Acetal 40 Activated by
BF3 OEt2
SCHEME 6. Stereoelectronic Model for Oxocarbenium Ion 47
3
entry
Nu-SiMe3
Na
product
cis/transb
yieldc (%)
1
2
3
4
5
6
1
3
5
8
9
10
1.8
3.9
6.2
8.2
9.0
10.2
41
42
43
44
45
46
88:12
79:21
79:21
80:20
77:23
63:37
70
98
92
93
97
96
aN = nucleophilicity parameter.41 bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture. cIsolated yield.
would maximize electrostatic stabilization between the
cationic center at C1 and the electronegative C3 oxygen
atom,61,62 steric and electrostatic repulsion between the
C3 oxygen atom and the triflate counterion would also
be maximized.80 In contrast, an SN2-like displacement of
tetrahydropyran triflate trans-48 would account for in-
creased 1,3-cis stereoselectivities in these transforma-
tions. It is unclear if the increase in 1,3-cis stereoisomers
in Me3SiOTf mediated reactions is the result of tetrahydro-
pyran triflate trans-48 being lower in energy than tetra-
hydropyran triflate cis-48, or if the SN2-like substitution
of tetrahydropyran triflate trans-48 is faster than that of
cis-48.
when nucleophiles 3, 5, 8, and 9 were employed (Table 6, entries
2-5) instead of when allyltrimethylsilane 1 was employed
(Table 6, entry 1) are likely due to a change in the steric bulk
of the nucleophiles compared to allyltrimethylsilane 1. In the
context of this hypothesis, however, it is surprising that other
nucleophile pairs with large steric differences (e.g., enoxy
silanes 3 and 5 or silyl ketene acetals 8 and 9) provided products
with similar levels of stereoselection.
The low stereoselectivity observed when silyl ketene acetal
10 was employed (Table 6, entry 6), however, is consistent
with rates of nucleophilic addition to oxocarbenium ion
half-chairs 47ax and 47eq approaching the diffusion limit
(Scheme 6). In this case, an increase in nucleophilicity
corresponded to a lower observed selectivity. Because silyl
ketene acetal 10 is no more bulky than nucleophiles 3, 5, 8,
or 9, a steric argument does not sufficiently rationalize the
low selectivity observed when silyl ketene acetal 10 was
employed.
Acetal 40 was treated with several strong nucleophiles in
the presence of Me3SiOTf to evaluate if changing the coun-
terion would result in stereoisomers originating from emer-
gent SN2-like pathways (Table 7). Based upon the trend
observed with C4 OBn acetal 21 (Tables 3 and 4), the SN2-
like substitution pathway of C3 OBn acetal 40 was expected
to favor formation of the opposite stereoisomer compared to
the SN1 pathway. In this case, the 1,3-trans tetrahydropyrans
were expected to be the major stereoisomers instead of the
1,3-cis tetrahydropyrans observed as the major products in
2-Deoxyglucose Acetal. Extension of these studies to
2-deoxyglucosyl acetal 50 provided a template for studying
the influence of several ring oxygen atoms on substitution
selectivities (Table 8). Unlike the previous monosubstituted
acetals 11, 21, and 40, the substitutions of 2-deoxyglucose
acetal 50 required relatively elevated temperatures (0 °C).81
Allylation of acetal 50 activated by BF3 OEt2 afforded 51r
3
as the major stereoisomer, correlating to the results of related
allylation reactions.82,83 Substitutions of acetal 50 with more
reactive nucleophiles under these conditions, however,
proved to be unselective.
Although the R-selectivity in the allylation of acetal 50
corresponds to the previously published stereochemical
model,82 the lack of selectivity with the other nucleophiles
employed represent a critical failure of this model (Scheme 8).
Developing 1,3-diaxial interactions in the transition
state between the incoming nucleophile and axial sub-
stituents at C3 and C5 disfavor addition to the stereo-
electronically preferred face of conformer 57ax, despite
BF3 OEt2-mediated reactions. Instead, not only did the 1,3-
3
cis tetrahydropyrans remain the major stereoisomers, but the
1,3-cis tetrahydropyrans were produced in higher selectivity
when Me3SiOTf was employed (Table 7) than when the
3
evidence that the H4 conformer 57ax is lower in energy
4
82
than the H3 conformer 57eq (Scheme 8, path c). In accord
with Curtin-Hammett kinetics,33 the major R-stereo-
isomer in the allylation of acetal 50 likely arises from
reaction was performed with BF3 OEt2 (Table 6). This trend
3
stands in marked contrast to the impact of employing
Me3SiOTf in the substitution reactions of C4 OBn acetal
21 (Tables 3 and 4).
(80) de Oliveira, P. R.; Rittner, R. Spectrochim. Acta, Part A 2005, 61,
1737–1745.
The surprisingly high 1,3-cis selectivities observed in
the Me3SiOTf-activated substitutions of acetal 40 can
be rationalized by considering hypothetical tetrahydro-
pyran triflate intermediates and the SN2-like reactions of
these species (Scheme 7). Although displacement of tetra-
hydropyran triflate cis-48 through contact ion-pair 49ax
(81) Selected substitutions were repeated at 0 °C and were observed to
have slightly lower selectivities than when the same reactions were performed
at -42 °C. Details are provided as Supporting Information.
(82) Yang, M. T.; Woerpel, K. A. J. Org. Chem. 2009, 74, 545–553.
(83) Fujiwara, K.; Sato, D.; Watanabe, M.; Morishita, H.; Murai, A.;
Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 5243–5246.
8046 J. Org. Chem. Vol. 74, No. 21, 2009

Krumper et al.
JOCFeatured Article
TABLE 7. Nucleophilic Substitution of Acetal 40 Activated by
Me3SiOTf
TABLE 8. Nucleophilic Substitution of Acetal 50 Activated by
BF3 OEt2
3
entry
Nu-SiMe3
Na
product
cis/transb
yieldc (%)
entry
Nu-SiMe3
Na
product
R/βb
yieldc (%)
1
2
3
4
1
5
8
10
1.8
6.2
8.2
10.2
41
43
44
46
87:13
89:11
88:12
79:21
87
84
86
88
1
2
3
4
5
6
1
4
5
8
9
10
1.8
4.4
6.2
8.2
9.0
10.2
51
52
53
54
55
56
89:11
43:57
61:39
45:55
43:57
NA
80
79
83
83
aN = nucleophilicity parameter.41 bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture. cIsolated yield.
57
decomp.
aN = nucleophilicity parameter.41 bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture. cIsolated yield.
SCHEME 7. SN2-like Pathways for Tetrahydropyran Triflate 48
SCHEME 8. Stereoelectronic Model for Oxocarbenium Ion 57
addition to the stereoelectronically preferred face of
4H3 conformer 57eq (Scheme 8, path b). The increased
ratios of β-stereoisomers observed when nucleophiles
stronger than allyltrimethylsilane are employed may
result from either addition to the stereoelectronically
preferred face of 3H4 conformer 57ax (path c), addition to
the stereoelectronically disfavored face of 4H3 con-
former 57eq (path a), or both. Regardless of which
pathway(s) is responsible for the formation of the
β-stereoisomer, however, the erosion of selectivities
observed is consistent with a near-diffusion-limited re-
action rate for the pathway that produces the R-stereo-
isomer (path b).
substitutions of acetal 50 can be explained by a change from
SN1- to SN2-like pathways (Scheme 9). When allyltri-
methylsilane is employed (Table 9, entry 1), the selectivity
observed suggests operation of an SN1 mechanism
(Scheme 8) and indicates reaction through solvent-sepa-
rated oxocarbenium ion 57 rather than tetrahydropyran
triflate 58. The low selectivities in the substitutions of acetal
50 with nucleophiles 4 and 5 (Table 8, entries 2 and 3, and
Table 9, entries 2 and 3), which are the same regardless of
The stereoselectivities in the substitutions of 2-deoxygluco-
syl acetal 50 in the presence of Me3SiOTf proved to be highly
dependent on the nucleophile employed (Table 9). Allylation
which activator (BF3 OEt2 or Me3SiOTf) is used, are likely
3
the result of near-diffusion-limited SN1 processes and not
emergent SN2-like pathways. This analysis is identical to
the one used to rationalize the selectivities in the reactions
of C4 OBn acetal 21 with nucleophiles 6 and 7 (Tables 3 and
4). When stronger nucleophiles, such as silyl ketene acetals
8 and 9, are employed, SN2 displacements of tetrahydro-
pyran triflate 58r occur to afford the β-stereoisomers
(Scheme 9).84
of acetal 50 with Me3SiOTf, as with BF3 OEt2 (Table 8, entry
3
1), afforded 51r as the major stereoisomer (Table 9, entry 1).
Similarly, the low stereoselectivities observed in the substitu-
tions of acetal 50 with methallyltrimethylsilane 4 and enoxy
silane 5 in the presence of Me3SiOTf (Table 9, entries 2 and 3)
matched the low selectivities observed in the analogous
BF3 OEt2 mediated reactions (Table 8, entries 2 and 3). When
3
silyl ketene acetals 8 and 9 were employed in the reaction,
however, β-stereoisomers 54β and 55β were generated with
good selectivities (Table 9, entries 4 and 5).
(84) Because relatively warm temperatures (0 °C) were employed in the
substitutions of acetal 50, the reactive intermediate in the SN2-like pathway
may be a contact ion-pair rather than tetrahydropyran triflate 58r. Pyrano-
syl triflates have been observed to be unstable on the NMR time scale above
-50 °C (ref 38).
As observed in the other systems described in this report,
divergence in stereoselectivities in the Me3SiOTf-activated
J. Org. Chem. Vol. 74, No. 21, 2009 8047

Krumper et al.
JOCFeatured Article
TABLE 9. Nucleophilic Substitution of Acetal 50 Activated by
Me3SiOTf
employed. The lowest energy pathway with weak nucleo-
philes in the cases studied, however, involves nucleophilic
attack of a solvent-separated oxocarbenium ion. Conditions
that allow access of SN2-like pathways in tetrahydropyran
acetal substitutions represent a complementary technique to
conditions that favor SN1 pathways because the two mecha-
nisms often favor opposite stereoisomers.
Na
product
R/βb
yieldc (%)
Experimental Section
entry
Nu-SiMe3
1
2
3
4
5
6
1
4
5
8
9
10
1.8
4.4
6.2
8.2
9.0
10.2
51
52
53
54
55
56
89:11
50:50
68:32
27:73
19:81
NA
57
73
94
78
General Procedure for Nucleophilic Substitution Reactions of
Acetals 11, 21, 37, 40, and 50. To a cooled (-78 °C) 0.1 M
solution of the acetal (0.4-0.8 mmol, 1.0 equiv) and nucleophile
(2.0-4.0 equiv) in CH2Cl2 was added the Lewis acid (1.4-1.6
equiv) dropwise. After being stirred at -78 °C for 1-5 min, the
reaction mixture was maintained at -42 °C for 1-2 h. A
saturated aqueous solution of NaHCO3 (4.0 mL) was added,
and the solution was warmed to 22 °C. The resulting biphasic
mixture was diluted with CH2Cl2 (2 mL) and H2O (2 mL), and
the layers were separated. The aqueous layer was extracted with
CH2Cl2 (3 ꢀ 2 mL), and the combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. The standard
procedure for nucleophilic substitution was modified when
2-deoxyglucose acetal 50 was employed: the reagents were
combined at -42 °C and then allowed to stir at 0 °C for 1-2 h
before addition of saturated NaHCO3. Diastereomeric ratios
were determined by GC and confirmed by GC/MS and 1H
NMR spectroscopy. Reported yields refer to purified material.
68
decomp.
aN = nucleophilicity parameter.41 bDetermined by GC and 1H NMR
spectroscopic analysis of the unpurified reaction mixture. cIsolated yield.
SCHEME 9. SN2-like Displacement of Pyranosyl Triflate 58
The nucleophilic substitutions of acetal 21 activated by BF3
3
OEt2 (Table 3) are reported here as representative examples.
2- Allyl-5-(benzyloxy)tetrahydro-2H-pyran (22).59 The condi-
tions for a standard nucleophilic substitution were followed
with acetal 21 (0.102 g, 0.407 mmol), allyltrimethylsilane 1
(0.260 mL, 1.64 mmol), and BF3 OEt2 (0.080 mL, 0.64 mmol).
3
Analysis of the crude mixture revealed an 8:92 ratio of cis-22 to
trans-22. Purification by flash chromatography (2.5:97.5 EtOAc/
hexanes) afforded the product as a colorless, clear oil (0.078 g,
83%). Characterization matches reported values59 and is
reported for the isomer trans-22: 1H NMR (500 MHz,
CDCl3) δ 7.35-7.24 (m, 5H), 5.80 (ddt, J = 17.2, 10.2, 7.0,
1H), 5.10-5.01 (m, 2H), 4.58 (d, J = 11.9, 1H), 4.52 (d, J =
11.9, 1H), 4.09 (ddd, J=10.8, 4.7, 2.3, 1H), 3.43 (tt, J=10.3,
4.6, 1H), 3.33-3.25 (m, 1H), 3.18 (t, J = 10.5, 1H), 2.30-
2.22 (m, 1H), 2.22-2.12 (m, 2H), 1.78-1.70 (m, 1H), 1.49-
1.38 (m, 1H), 1.36-1.25 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 138.7, 135.0, 128.6, 127.82, 127.78, 117.0, 77.1,
73.2, 70.94, 70.92, 40.4, 30.3, 30.2; HRMS (TOF MS ESþ)
m/z calcd for C15H20NaO2 (M þ Na)þ 255.1361, found
255.1369.
Conclusions
Examination of the substitutions of tetrahydropyran acet-
als reveals a dramatic impact of nucleophile reactivity and
the activating agent on the stereoselectivities of these trans-
formations. When BF3 OEt2 was employed, substitutions of
3
acetals appeared to proceed largely through SN1 mechan-
isms. Consequently, the selectivities in the nucleophilic addi-
tions to oxocarbenium ion intermediates follow stereoelec-
tronic models developed for these SN1 processes and remain
constant as nucleophilicity is increased until a threshold
nucleophilicity is reached. Beyond this point, however,
selectivities decrease until a statistical mixture is obtained.
This result is consistent with the emergence of diffusion-
limited reaction rates above this increased nucleophile acti-
vity threshold.
In contrast, when Me3SiOTf was employed in the sub-
stitution of tetrahydropyran acetals, SN2-like pathways,
likely through tetrahydropyran triflate intermediates, be-
come competitive with SN1 pathways when strong nucleo-
philes are employed. Although substitutions with weak
nucleophiles still follow SN1 mechanisms, substitutions with
stronger nucleophiles, notably silyl ketene acetals 8-10,
appear to intercept either tetrahydropyran triflates or the
associated contact ion-pairs through SN2-like mechanisms.
In this analysis, tetrahydropyran triflates or the associated
contact ion-pairs are present when weak nucleophiles are
1-[5-(Benzyloxy)tetrahydro-2H-pyran-2-yl]-3,3-dimethylbutan-
2-one (23). The conditions for a standard nucleophilic sub-
stitution were followed with acetal 21 (0.102 g, 0.407 mmol),
enoxy silane 2 (0.293 g, 1.70 mmol), and BF3 OEt2 (0.080 mL,
3
0.64 mmol). Analysis of the crude mixture revealed an 11:89
ratio of cis-23 to trans-23. Purification by flash chromato-
graphy (5:95 EtOAc/hexanes) afforded the product as a
colorless, clear oil (0.099 g, 84%). Characterization is
reported for the isomer trans-23: 1H NMR (500 MHz,
CDCl3) δ 7.36-7.24 (m, 5H), 4.58 (d, J = 11.9, 1H), 4.52
(d, J=12.0, 1H), 4.03 (ddd, J=10.8, 4.7, 2.3, 1H), 3.77 (dtd,
J=11.7, 6.4, 1.9, 1H), 3.43 (tt, J=9.6, 4.6, 1H), 3.21 (t, J=
10.5, 1H), 2.80 (dd, J=17.0, 6.6, 1H), 2.43 (dd, J=17.0, 5.8,
1H), 2.18 (br d, J = 12.5, 1H), 1.79 (br d, J = 13.3, 1H),
1.55-1.44 (m, 1H), 1.28 (tdd, J=13.4, 11.2, 3.8, 1H), 1.12 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 213.5, 138.6, 128.5,
127.7, 127.6, 73.7, 72.9, 70.8, 70.7, 44.3, 42.6, 30.5, 30.0,
26.2; IR (neat) 2966, 2868, 1707, 1454, 1365, 1097 cm-1
;
8048 J. Org. Chem. Vol. 74, No. 21, 2009

Krumper et al.
JOCFeatured Article
HRMS (TOF MS ESþ) m/z calcd for C18H26NaO3 (M þ
Na)þ 313.1780, found 313.1779.
5-(Benzyloxy)-2-(2-methylallyl)tetrahydro-2H-pyran (24). The
standard procedure for nucleophilic substitution was fol-
lowed with acetal 21 (0.127 g, 0.507 mmol), methallyltri-
30.9, 30.2; IR (thin film) 3064, 3031, 2937, 2861, 1671, 1600
cm-1; HRMS (TOF MS ESþ) m/z calcd for C21H24NaO4 (M þ
Na)þ 363.1572, found 363.1578. Anal. Calcd for C21H24O4: C,
74.09; H, 7.11. Found: C, 74.24; H, 7.12.
S-tert-Butyl 2-[5-(benzyloxy)tetrahydro-2H-pyran-2-yl]ethane-
thioate (27). The standard procedure for nucleophilic sub-
stitution was followed with acetal 21 (0.100 g, 0.400 mmol),
methylsilane 4 (0.350 mL, 1.99 mmol), and BF3 OEt2 (0.100 mL,
3
0.789 mmol). Analysis of the crude mixture revealed a 10:90
ratio of cis-24 to trans-24. Purification by flash chromato-
graphy (2.5:97.5 EtOAc/hexanes) afforded the product as a
colorless, clear oil (0.0703 g, 57%). Characterization is
reported for the isomer trans-24: 1H NMR (500 MHz, CDCl3) δ
7.36-7.24 (m, 5H), 4.79 (s, 1H), 4.73 (s, 1H), 4.58 (d, J =
11.9, 1H), 4.52 (d, J=11.9, 1H), 4.10 (ddd, J=10.8, 4.7, 2.3,
1H), 3.50-3.36 (m, 2H), 3.18 (t, J = 10.5, 1H), 2.24 (dd, J =
14.1, 7.5, 1H), 2.21-2.15 (m, 1H), 2.09 (dd, J = 14.1, 5.6,
1H), 1.74 (br s, 4H), 1.50-1.40 (m, 1H), 1.29 (tdd, J = 13.6,
11.0, 3.7, 1H); 13C NMR (125 MHz, CDCl3) δ 142.7, 138.7,
128.6, 127.82, 127.77, 112.6, 75.8, 73.2, 71.0, 70.9, 44.4,
30.7, 30.3, 22.8; IR (thin film) 3072, 3033, 2939, 2854, 1648,
thiosilyl ketene acetal 7 (0.198 g, 0.970 mmol), and BF3 OEt2
3
(0.080 mL, 0.64 mmol). Analysis of the crude mixture
revealed a 21:79 ratio of cis-27 to trans-27. Purification by
flash chromatography (10:90 EtOAc/hexanes) afforded the
product as a faint yellow oil (0.120 g, 93%). Characteriza-
tion is reported for a 27:73 mixture of cis-27 to trans-27: 1H
NMR (500 MHz, CDCl3; the major trans-27 isomer is
denoted by *) δ 7.38-7.23 (m, 5H* þ 5H), 4.57 (d, J =
12.1, 1H* þ 2H), 4.51 (d, J = 12.0, 1H*), 4.10-4.02 (m, 1H* þ
1H), 3.84-3.76 (m, 1H), 3.70 (dddd, J = 11.0, 7.4, 5.5, 2.0,
1H*), 3.49 (dd, J = 12.5, 1.4, 1H), 3.43 (tt, J = 10.1, 4.5,
1H*), 3.38 (br s, 1H), 3.19 (t, J = 10.5, 1H*), 2.80 (dd, J =
15.0, 7.0, 1H), 2.67 (dd, J = 14.8, 7.4, 1H*), 2.54 (dd, J =
15.0, 5.9, 1H), 2.48 (dd, J = 14.8, 5.5, 1H*), 2.17 (br d, J =
9.6, 1H*), 2.07-1.99 (m, 1H), 1.80-1.70 (m, 1H* þ 1H), 1.62
(tt, J = 13.6, 3.7, 1H), 1.52-1.46 (m, 1H*), 1.44 (s, 9H* þ 9H),
1.38-1.27 (m, 1H* þ1H); 13C NMR (125 MHz, CDCl3; the
major trans-27 isomer is denoted by *) δ 198.0, 197.7*,
138.8, 138.6*, 128.6*, 128.5, 127.8*, 127.7* (minor isomer
overlaps), 127.6, 74.21*, 74.16, 72.8*, 70.89*, 70.86*, 70.4,
70.1, 69.6, 50.9, 50.5*, 48.4*, 48.2, 30.4*, 30.0, 29.92*,
29.90*, 27.0, 26.4; IR (neat) 2960, 2861, 1681, 1454, 1095
cm-1; HRMS (TOF MS ESþ) m/z calcd for C18H26NaO3S
(M þ Na)þ 345.1500, found 345.1494. Anal. Calcd for
1455 cm-1; HRMS (TOF MS ESþ) m/z calcd for C16H22
-
NaO2 (M þ Na)þ 269.1518, found 269.1518.
2-[5-(Benzyloxy)tetrahydro-2H-pyran-2-yl]-1-phenylethanone
(25).36 The standard procedure for nucleophilic substitution was
followed with acetal 21 (0.099 g, 0.40 mmol), enoxy silane 5
(0.305 g, 1.59 mmol), and BF3 OEt2 (0.082 mL, 0.64 mmol).
3
Analysis of the crude mixture revealed an 8:92 ratio of cis-25 to
trans-25. Purification by flash chromatography (10:90 EtOAc/
hexanes) afforded the product as an oily, white solid (0.108 g,
87%). Characterization matches reported values36 and is repor-
ted for the isomer trans-25: mp 59-60.5 °C; 1H NMR (500 MHz,
CDCl3) δ 7.95 (d, J = 7.9, 2H), 7.57 (t, J = 7.3, 1H), 7.46 (t,
J=7.7, 2H), 7.37-7.27 (m, 5H), 4.59 (d, J=11.9, 1H), 4.53
(d, J = 11.9, 1H), 4.06 (ddd, J = 10.8, 4.6, 2.2, 1H), 3.98-
3.88 (m, 1H), 3.48 (tt, J = 10.0, 4.5, 1H), 3.29 (dd, J = 16.3,
6.7, 1H), 3.24 (t, J = 10.6, 1H), 2.93 (dd, J = 16.3, 5.8, 1H),
2.27-2.18 (m, 1H), 1.97-1.87 (m, 1H), 1.60-1.48 (m, 1H),
1.46-1.35 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 198.2,
138.7, 137.3, 133.4, 128.8, 128.6, 128.4, 127.9, 127.8, 74.2,
73.0, 71.0, 70.9, 44.7, 30.8, 30.2; IR (thin film) 3061, 2860,
2352, 1681, 1596 cm-1; HRMS (TOF MS ESþ) m/z calcd for
C
18H26O3S: C, 67.04; H, 8.13. Found: C, 67.19; H, 8.33.
Phenyl 2-[5-(Benzyloxy)tetrahydro-2H-pyran-2-yl]acetate (28).36
The standard procedure for nucleophilic substitution was
followed with acetal 21 (0.152 g, 0.607 mmol), silyl ketene
acetal 8 (0.252 g, 1.21 mmol), and BF3 OEt2 (0.120 mL,
3
0.947 mmol). Analysis of the crude mixture revealed a 50:50
ratio of cis-28 to trans-28. Purification by flash chromato-
graphy (20:80 EtOAc/hexanes) afforded the product as a
colorless, clear oil (0.175 g, 88%). Characterization matches
reported values36 and is reported for the isolated isomers
cis-28 and trans-28.
C
20H22NaO3 (M þ Na)þ 333.1467, found 333.1460. Anal.
Calcd for C20H22O3: C, 77.39; H, 7.14. Found: C, 77.14; H,
7.07.
1
cis-28: H NMR (500 MHz, CDCl3) δ 7.40-7.17 (m, 8H),
2-[5-(Benzyloxy)tetrahydro-2H-pyran-2-yl]-1-(4-methoxyphenyl)-
ethanone (26). The standard procedure for nucleophilic
substitution was followed with acetal 21 (0.203 g, 0.811 mmol),
7.07 (d, J=7.9, 2H), 4.62-4.54 (m, 2H), 4.11 (d, J=12.5, 1H),
3.92 (dddd, J = 10.4, 7.5, 5.3, 2.0, 1H), 3.54 (dd, J = 12.5, 1.2,
1H), 3.42 (br s, 1H), 2.86 (dd, J = 15.5, 7.9, 1H), 2.67 (dd, J =
15.5, 5.2, 1H), 2.12-2.06 (m, 1H), 1.86 (m, 1H), 1.71-1.63 (m,
1H), 1.62-1.55 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 170.0,
150.8, 138.8, 129.5, 128.5, 127.8, 127.7, 125.9, 121.8, 74.1, 70.4,
70.2, 69.7, 41.4, 27.0, 26.4; IR (thin film) 3066, 3031, 2944, 2858,
1756, 1594 cm-1; HRMS (TOF MS ESþ) m/z calcd for
C20H22NaO4 (M þ Na)þ 349.1416, found 349.1415.
enoxy silane 6 (0.762 g, 3.43 mmol), and BF3 OEt2 (0.165 mL,
3
1.30 mmol). Analysis of the crude mixture revealed an 18:82
ratio of cis-26 to trans-26. Purification by flash chromato-
graphy (20:80 EtOAc/hexanes) afforded the product as a
faint yellow solid (0.185 g, 67%). Characterization is repor-
ted for the isolated isomers cis-26 and trans-26.
cis-26: 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.8, 2H),
7.38-7.25 (m, 5H), 6.93 (d, J=8.8, 2H), 4.59 (s, 2H), 4.06 (d, J=
12.5, 1H), 4.03-3.98 (m, 1H), 3.87 (s, 3H), 3.55 (d, J=12.4, 1H),
3.42 (br s, 1H), 3.35 (dd, J = 16.3, 6.4, 1H), 2.93 (dd, J = 16.3,
6.0, 1H), 2.11-2.05 (m, 1H), 1.86-1.77 (m, 1H), 1.73-1.65 (m,
1H), 1.64-1.56 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 197.0,
163.7, 138.9, 130.8, 130.6, 128.6, 127.8, 127.7, 113.9, 74.3, 70.6,
70.2, 69.9, 55.7, 44.8, 27.1, 26.9.
trans-28: 1H NMR (500 MHz, CDCl3) δ 7.40-7.19 (m, 8H),
7.08 (d, J = 7.7, 2H), 4.60 (d, J = 11.9, 1H), 4.54 (d, J = 11.9,
1H), 4.12 (ddd, J=10.8, 4.7, 2.2, 1H), 3.84 (dddd, J=10.6, 7.6,
5.2, 2.1, 1H), 3.49 (tt, J=10.1, 4.5, 1H), 3.26 (t, J= 10.5, 1H),
2.74 (dd, J = 15.2, 7.9, 1H), 2.65 (dd, J = 15.2, 5.2, 1H),
2.27-2.19 (m, 1H), 1.92-1.84 (m, 1H), 1.57-1.40 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 169.9, 150.8, 138.6, 129.6, 128.7,
127.9, 127.8, 126.1, 121.8, 74.2, 72.8, 71.0, 70.9, 41.1, 30.5, 30.1;
IR (thin film) 3064, 3033, 2939, 2863, 1756, 1594 cm-1; HRMS
(TOF MS ESþ) m/z calcd for C20H22NaO4 (M þ Na)þ
349.1416, found 349.1420. Anal. Calcd for C20H22O4: C,
73.60; H, 6.79. Found: C, 73.22; H, 6.80.
trans-26: mp 69-70 °C; 1H NMR (500 MHz, CDCl3) δ 7.93
(d, J=8.7, 2H), 7.37-7.26 (m, 5H), 6.93 (d, J=8.7, 2H), 4.59 (d,
J = 11.9, 1H), 4.53 (d, J = 11.9, 1H), 4.09-4.03 (m, 1H),
3.93-3.89 (m, 1H), 3.86 (s, 3H), 3.47 (tt, J = 9.8, 4.4, 1H),
3.27-3.19 (m, 2H), 2.87 (dd, J=15.9, 5.8, 1H), 2.21 (d, J=12.3,
1H), 1.91 (d, J = 13.0, 1H), 1.57-1.48 (m, 1H), 1.44-1.35 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 196.7, 163.8, 138.7, 130.8,
130.4, 128.6, 127.9, 127.8, 113.9, 74.4, 73.1, 71.0, 70.9, 55.7, 44.3,
Methyl 2-[5-(Benzyloxy)tetrahydro-2H-pyran-2-yl]-2-methyl-
propanoate (29).36 The standard procedure for nucleophilic
substitution was followed with acetal 21 (0.101 g, 0.404 mmol),
silyl ketene acetal 9 (0.295 g, 1.69 mmol), and BF3 OEt2 (0.080 mL,
3
J. Org. Chem. Vol. 74, No. 21, 2009 8049

Krumper et al.
JOCFeatured Article
0.64 mmol). Analysis of the crude mixture revealed a 58:42
ratio of cis-29 to trans-29. Purification by flash chromato-
graphy (10:90 EtOAc/hexanes) afforded the product as a
colorless, clear oil (0.094 g, 80%). Characterization matches
reported values36 and is reported for the isolated isomers
cis-29 and trans-29.
(dd, J = 12.5, 1.1, 1H), 3.40 (br s, 1H), 2.62 (dd, J = 15.5, 7.7,
1H), 2.41 (dd, J = 15.5, 5.4, 1H), 2.10-2.01 (m, 1H), 1.77 (qd,
J=13.2, 3.6, 1H), 1.69-1.57 (m, 3H), 1.51 (d, J=12.0, 1H), 1.36
(sextet, J=7.6, 2H), 0.92 (t, J=7.5, 3H); 13C NMR (125 MHz,
CDCl3) δ 171.6, 138.8, 128.5, 127.7, 127.6, 74.2, 70.4, 70.1, 69.6,
64.5, 41.4, 30.8, 27.0, 26.4, 19.2, 13.9; IR (thin film) 2958,
2871, 1733, 1455, 1115 cm-1; HRMS (TOF MS ESþ) m/z calcd
for C18H26NaO4 (M þ Na)þ 329.1729, found 329.1718.
Anal. Calcd for C18H26O4: C, 70.56; H, 8.55. Found: C, 70.39;
H, 8.48.
1
cis-29: H NMR (500 MHz, CDCl3) δ 7.38-7.24 (m, 5H),
4.59 (d, J=12.3, 1H), 4.51 (d, J=12.3, 1H), 4.12 (d, J=12.5,
1H), 3.68 (s, 3H), 3.55 (dd, J=11.4, 1.7, 1H), 3.45 (dd, J=12.5,
1.3, 1H), 3.38 (br s, 1H), 2.10 (dt, J=13.9, 3.1, 1H), 1.81 (qd, J=
13.1, 3.7, 1H), 1.67-1.57 (m, 1H), 1.31 (br d, J=12.8, 1H), 1.23
(s, 3H), 1.14 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.7,
139.1, 128.5, 127.64, 127.58, 82.4, 70.8, 69.9, 69.8, 52.0, 46.9,
27.8, 21.3, 20.64, 20.56; IR (neat) 2950, 2858, 1730, 1454, 1143,
1115 cm-1; HRMS (TOF MS ESþ) m/z calcd for C17H24NaO4
(M þ Na)þ 315.1572, found 315.1569. Anal. Calcd for
C17H24O4: C, 69.84; H, 8.27. Found: C, 70.06; H, 8.32.
trans-30: 1H NMR (500 MHz, CDCl3) δ 7.35-7.25 (m, 5H),
4.58 (d, J=11.9, 1H), 4.52 (d, J=11.8, 1H), 4.14-4.04 (m, 3H),
3.75-3.68 (m, 1H), 3.45 (tt, J=10.0, 4.6, 1H), 3.21 (t, J=10.5,
1H), 2.49 (dd, J = 15.1, 7.8, 1H), 2.39 (dd, J = 15.1, 5.2, 1H),
2.19 (br d, J=12.4, 1H), 1.79 (br d, J=12.9, 1H), 1.61 (quintet,
J = 6.8, 2H), 1.54-1.44 (m, 1H), 1.42-1.32 (m, 3H), 0.92 (t,
J = 7.5, 3H); 13C NMR (125 MHz, CDCl3) δ 171.4, 138.6,
128.6, 127.9, 127.8, 74.2, 72.8, 71.0, 70.9, 64.6, 41.2, 30.8,
30.4, 30.1, 19.3, 13.9; IR (thin film) 2960, 2867, 1733, 1455,
1090 cm-1; HRMS (TOF MS ESþ) m/z calcd for C18H26-
trans-29: 1H NMR (500 MHz, CDCl3) δ 7.38-7.24 (m, 5H),
4.57 (d, J=12.0, 1H), 4.52 (d, J=12.0, 1H), 4.09 (ddd, J=10.7,
4.7, 2.3, 1H), 3.67 (s, 3H), 3.46-3.37 (m, 2H), 3.16 (t, J=10.5,
1H), 2.26-2.18 (m, 1H), 1.66-1.60 (m, 1H), 1.50-1.34 (m, 2H),
1.16 (s, 3H), 1.11 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 177.4,
138.8, 128.6, 127.9, 127.8, 82.3, 73.2, 71.3, 71.0, 52.1, 46.4, 30.3,
24.7, 21.7, 20.7; IR (neat) 2948, 2864, 1734, 1454, 1275, 1093
cm-1; HRMS (TOF MS ESþ) m/z calcd for C17H24NaO4 (M þ
Na)þ 315.1572, found 315.1577. Anal. Calcd for C17H24O4: C,
69.84; H, 8.27. Found: C, 70.00; H, 8.31.
NaO4 (M
þ
Na)þ 329.1729, found 329.1720. Anal.
Calcd for C18H26O4: C, 70.56; H, 8.55. Found: C, 70.49; H,
8.70.
Acknowledgment. This research was supported by the
National Institutes of Health, National Institute of General
Medical Sciences (Grant No. GM-61066 to K.A.W. and
Grant No. GM-081996 to J.R.K.). W.A.S. thanks the ARCS
foundation for a fellowship. K.A.W. thanks Amgen and
Lilly for generous support of this research. We thank Dr.
Phil Dennison (UCI) for assistance with NMR spectroscopy,
and Dr. John Greaves and Ms. Shirin Sorooshian (UCI) for
mass spectrometry.
Butyl 2-[5-(Benzyloxy)tetrahydro-2H-pyran-2-yl]acetate (30).36
The standard procedure for nucleophilic substitution was
followed with acetal 21 (0.105 g, 0.419 mmol), silyl ketene
acetal 10 (0.156 g, 0.828 mmol), and BF3 OEt2 (0.080 mL,
3
0.64 mmol). Analysis of the crude mixture revealed a 60:40
ratio of cis-30 to trans-30. Purification by flash chromatog-
raphy (5:95 EtOAc/hexanes) afforded the product as a
colorless, clear oil (0.110 g, 86%). Characterization matches
reported values36 and is reported for the isolated isomers
cis-30 and trans-30.
Supporting Information Available: Complete experimental
procedures, product characterization, stereochemical proofs,
GC and spectral data, and references. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
cis-30: H NMR (500 MHz, CDCl3) δ 7.38-7.24 (m, 5H),
4.60-4.53 (m, 2H), 4.12-4.03 (m, 3H), 3.85-3.77 (m, 1H), 3.51
8050 J. Org. Chem. Vol. 74, No. 21, 2009