Erosion of stereochemical control with increasing nucleophilicity: O-glycosylation at the diffusion limit

Article abstract of DOI:10.1021/jo902222a

(Chemical Equation Presented) Nucleophilic substitution reactions of 2-deoxyglycosyl donors indicated that the reactivity of the oxygen nucleophile has a significant impact on stereoselectivity. Employing ethanol as the nucleophile resulted in a 1:1 (α:β) ratio of diastereomers under S_N1-like reaction conditions. Stereoselective formation of the 2-deoxy-α-O-glycoside was only observed when weaker nucleophiles, such as trifluoroethanol, were employed. The lack of stereoselectivity observed in reactions of common oxygen nucleophiles can be attributed to reaction rates of the stereochemistry-determining step that approach the diffusion limit. In this scenario, both faces of the prochiral oxocarbenium ion are subject to nucleophilic addition to afford a statistical mixture of diastereomeric products. Control experiments confirmed that all nucleophilic substitution reactions were performed under kinetic control.

Full text of DOI:10.1021/jo902222a

pubs.acs.org/joc
Erosion of Stereochemical Control with Increasing Nucleophilicity:
O-Glycosylation at the Diffusion Limit
Matthew G. Beaver and K. A. Woerpel*
Department of Chemistry, University of California, Irvine, California 92697-2025
kwoerpel@uci.edu
Received October 15, 2009
Nucleophilic substitution reactions of 2-deoxyglycosyl donors indicated that the reactivity of the
oxygen nucleophile has a significant impact on stereoselectivity. Employing ethanol as the nucleo-
phile resulted in a 1:1 (R:β) ratio of diastereomers under SN1-like reaction conditions. Stereoselective
formation of the 2-deoxy-R-O-glycoside was only observed when weaker nucleophiles, such as
trifluoroethanol, were employed. The lack of stereoselectivity observed in reactions of common
oxygen nucleophiles can be attributed to reaction rates of the stereochemistry-determining step that
approach the diffusion limit. In this scenario, both faces of the prochiral oxocarbenium ion are
subject to nucleophilic addition to afford a statistical mixture of diastereomeric products. Control
experiments confirmed that all nucleophilic substitution reactions were performed under kinetic
control.
Introduction
active natural products.2 Although the use of participating
groups at C-2 and their later removal can lead to selective
reactions, the direct synthesis of 2-deoxy-R-O-glycosides
from 2-deoxyglycosyl donors is not generally stereoselec-
tive.3 We have observed that the corresponding reactions
with carbon nucleophiles to form 2-deoxy-R-C-glycosides,
however, occur with high selectivity under comparable SN1-like
conditions (Scheme 1).4 A similar situation holds for C-
glycosylations of other glycosyl donors, such as glucose-,5
mannose-,6 and ribose-derived systems,7 where the C-glycosylation
The development of new methods for the synthesis of
carbohydrates has been particularly challenging because
glycosylation reactions often proceed with low or unpredict-
able selectivity.1 The problem of low selectivity has been
especially difficult to surmount for the synthesis of 2-deoxy-
sugars, which are common structures found in biologically
(1) For reviews on common glycosylation methods, see: (a) Boons, G.-J.
Contemp. Org. Syn. 1996, 3, 173–200. (b) Davis, B. G. J. Chem. Soc., Perkin
Trans. 1 2000, 2137–2160. (c) Demchenko, A. V. Synlett 2003, 1225–1240.
(d) Demchenko, A. V. Handbook of Chemical Glycosylation; Wiley-VCH:
Weinheim, 2008. (e) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009,
48, 1900–1934.
(2) (a) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531.
(b) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385–8417.
(3) For examples of recent methods for the preparation of 2-deoxy-R-
glycosides, see: (a) Lear, M. J.; Yoshimura, F.; Hirama, M. Angew. Chem.,
Int. Ed. 2001, 40, 946–949. (b) Kim, K. S.; Park, J.; Lee, Y. J.; Seo, Y. S.
Angew. Chem., Int. Ed. 2003, 42, 459–462. (c) Jaunzems, J.; Hofer, E.;
Jesberger, M.; Sourkouni-Argirusi, G.; Kirschning, A. Angew. Chem., Int.
Ed. 2003, 42, 1166–1170. (d) Lu, Y.-S.; Li, Q.; Zhang, L.-H.; Ye, X.-S. Org.
Lett. 2008, 10, 3445–3448. (e) Park, J.; Boltje, T. J.; Boons, G.-J. Org. Lett.
2008, 10, 4367–4370.
(4) Varying the Lewis acid, solvent, and protecting groups did not affect
the preference for the stereoelectronically preferred R-product: (a) Fujiwara,
K.; Sato, D.; Watanabe, M.; Morishita, H.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2004, 45, 5243–5246. (b) Yang, M. T.; Woerpel, K. A.
J. Org. Chem. 2009, 74, 545–553.
(5) (a) Kim, K. S.; Kang, S. S.; Seo, Y. S.; Kim, H. J.; Lee, Y. J.; Jeong, K.-S.
Synlett 2003, 1311–1314. (b) Lee, Y. J.; Baek, J. Y.; Lee, B.-Y.; Kang, S. S.;
Park, H.-S.; Jeon, H. B.; Kim, K. S. Carbohydr. Res. 2006, 341, 1708–1716.
(6) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H. J. Am.
Chem. Soc. 2001, 123, 9545–9554.
(7) (a) Araki, Y.; Kobayashi, N.; Ishido, Y.; Nagasawa, J. Carbohydr.
Res. 1987, 171, 125–139. (b) Ginisty, M.; Gravier-Pelletier, C.; Le Merrer, Y.
Tetrahedron: Asymmetry 2006, 17, 142–150.
DOI: 10.1021/jo902222a
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Published on Web 01/28/2010
J. Org. Chem. 2010, 75, 1107–1118 1107
2010 American Chemical Society

Beaver and Woerpel
JOCArticle
SCHEME 1. Nucleophilic Substitutions of 2-Deoxyglycoside 1
at rates approaching the diffusion limit9), the reactions of
alcohols should be comparably rapid.16 In this Article,
we provide evidence that the low stereoselectivity of some
O-glycosylation reactions are the result of reactions of
oxocarbenium ion intermediates that approach the diffu-
sion-controlled rate limit.
Results and Discussion
Details of the Experimental Approach. Details of the
experimental approach deserve mention prior to discussing
the results of nucleophilic substitution:
1. 2-Deoxythioglycosides and related monosubstituted
model systems were chosen as substrates for this study.
Our previous experience with these systems provided
evidence that the reaction pathway (SN1 versus SN2)
could be controlled with careful choice of leaving group
and activation conditions.9
2. In all cases, anomeric sulfides were employed as the oxo-
carbenium ion precursors.17 N-Iodosuccinimide (NIS) was
chosen as the thioglycoside activating agent. This combina-
tion of C-1 leaving group and activating agent provided
results consistent with SN1-like additions to intermediate
oxocarbenium ions.18,19 Where indicated, 2,6-di-tert-butyl-
4-methylpyridine (DTBMP) was employed as an additive to
prohibit the epimerization of the acid-labile O-glycosylation
products. Rigorous control experiments were conducted to
verify that product ratios were obtained under kinetic
control (vide infra, eq 5, Table 4).
was selective, but the O-glycosylation was not.8 No explana-
tion has been provided to reconcile the different selectivities
observed with the two types of nucleophiles.
Our studies of the reactions of six-membered ring oxocar-
benium ions with carbon nucleophiles of varying reactivity
suggest a possible explanation.9 The stereoselectivities of
these reactions are generally analyzed by considering stereo-
electronic effects. In the absence of participating counter-
ions,10 both faces of the prochiral oxocarbenium ion can be
attacked by a nucleophile (Scheme 2). Nucleophilic addition
SCHEME 2. Modes of Addition to the 2-Deoxyglucose-Derived
Oxocarbenium Ion 5
3. Ethanol served as a model nucleophile due to its small
size and because its nucleophilicity could be modified
by incorporating electron-withdrawing halogen sub-
stituents.14,20-23 Field inductive effect parameters
(F) were used as a quantitative measurement of the
electron-withdrawing ability of the halogen substitu-
ents on the alcohol nucleophiles.24,25 As the F-value
along the stereoelectronically preferred trajectory would
provide the R-product
4 in a chair conformation
(Scheme 2, path a).4b,11,12 As the nucleophile becomes more
reactive, the rates of nucleophilic addition to the cationic
intermediate increase and approach the diffusion limit.13 In
this case, both paths a and b result in product formation,
affording a statistical mixture of diastereomeric products.
We recently provided evidence for this divergence between
stereoelectronically controlled and diffusion-controlled
diastereoselectivity in C-glycosylation reactions.9 Because
of the similar nucleophilicity of alcohols14 and silyl enol
ethers15 (C-nucleophiles that react with oxocarbenium ions
(17) The Supporting Information describes the synthesis of substrates
and complete experimental details.
(18) The general procedure for nucleophilic substitution was performed
as follows: NIS (2 equiv) was added to a solution of the thioglycoside and
nucleophile (4 equiv). Neither the starting anomeric ratio of the thioglyco-
side, the equivalents of nucleophile or NIS, nor the addition of DTBMP were
found to affect the product diastereomeric ratio.
(19) (a) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;
€
Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734–753. (b) Bulow, A.; Meyer,
T.; Olszewski, T. K.; Bols, M. Eur. J. Org. Chem. 2004, 323–329. (c) This
mechanism has served as the basis for armed-disarmed effects in glycosyl
donors: Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org.
Chem. 1990, 55, 6068–6070. (d) Crich, D.; Li, M. Org. Lett. 2007, 9, 4115–
4118.
(8) O-Glycosylations and C-glycosylations, however, can exhibit similar
selectivities. See, for example: Crich, D.; Sharma, I. Org. Lett. 2008, 10,
4731–4734.
(9) (a) Krumper, J. R.; Salamant, W. A.; Woerpel, K. A. Org. Lett. 2008,
10, 4907–4910. (b) Krumper, J. R.; Salamant, W. A.; Woerpel, K. A. J. Org.
Chem. 2009, 74, 8039–8050.
(20) Sinnott, M. L.; Jencks, W. P. J. Am. Chem. Soc. 1980, 102,
2026–2032.
€
(21) Garegg, P. J.; Konradsson, P.; Kvarnstrom, I.; Norberg, T.; Svens-
(10) In the presence of participating counterions, such as the triflate ion,
SN1 and SN2 pathways become competitive, which can alter diastereo-
selectivies: (a) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015–
9020. (b) See ref 8.
(11) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983.
(12) At rates below the diffusion limit, the minor product is expected to
arise from the stereoelectronically preferred addition to the pseudoaxial
oriented half-chair oxocarbenium ion conformer (ref 4b).
(13) Mayr, H.; Ofial, A. R. Angew. Chem., Int. Ed. 2006, 45, 1844–1854.
(14) Minegishi, S.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2004, 126,
5174–5181.
(15) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77.
(16) Data supporting the hypothesis that oxygen nucleophiles react with
carbohydrate-derived oxocarbenium ions at the diffusion limit have been
reported: (a) Amyes, T. L.; Jencks, W. P. J. Am. Chem. Soc. 1989, 111, 7888–
7900. (b) Banait, N. S.; Jencks, W. P. J. Am. Chem. Soc. 1991, 113, 7951–
7958.
son, S. C. T.; Wigilius, B. Acta Chem. Scand. 1985, B39, 569–577.
(22) Bowden, T.; Garegg, P. J.; Maloisel, J.-L.; Konradsson, P. Isr. J.
Chem. 2000, 40, 271–277.
(23) Ethanol derivatives containing a single halogen substituent, parti-
cularly bromine, have been employed as nucleophiles in glycosylation
reactions en route to highly functionalized structures: (a) Ray, A. K.;
Nilsson, U.; Magnusson, G. J. Am. Chem. Soc. 1992, 114, 2256–2257.
(b) Stevenson, D. E.; Woolhouse, A. D.; Furneaux, R. H.; Batcheler, D.;
Eason, C. T. Carbohydr. Res. 1994, 256, 185–188. (c) Jung, M. E.; Yang, E.
C.; Vu, B. T.; Kiankarimi, M.; Spyrou, E.; Kaunitz, J. J. Med. Chem. 1999,
ꢀ
42, 3899–3909. (d) Momenteau, M.; Maillard, P.; De Belinay, M.-A.; Carrez,
D.; Croisy, A. J. Biomed. Opt. 1999, 4, 298–318. (e) Ohlsson, J.; Magnusson,
G. Carbohydr. Res. 2000, 329, 49–55. (f) Hirschmann, R.; Ducry, L.; Smith,
A. B., III J. Org. Chem. 2000, 65, 8307–8316. (g) Maschauer, S.; Prante, O.
Carbohydr. Res. 2009, 344, 753–761.
(24) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.
(25) An alternative measurement of nucleophilicity using alcohol pKa is
described in Supporting Information and ref 43.
1108 J. Org. Chem. Vol. 75, No. 4, 2010

Beaver and Woerpel
increased, the alcohol should be rendered less nucleo-
JOCArticle
SCHEME 3. Reactive Intermediates Involved in Nucleophilic
Substitutions
philic; competition experiments verified this hypothesis
(vide infra, eq 4, Table 3).
4. Both CH3CN and CH2Cl2 were employed as solvents.
Comparable yields and stereochemical trends were
observed in either solvent, but CH3CN generally pro-
vided higher diastereoselectivities consistent with
stereoelectronically controlled attack on an oxocarbe-
nium ion intermediate.26
5. Diastereomeric ratios were obtained by analysis of GC
and 1H NMR spectroscopy of the unpurified reaction
mixtures. The product stereochemistry was determined
by analysis of 1H NMR coupling constants and NOE
measurements of the purified products.
chanism for activation of thioglycoside 1c involves two
types of intermediates. Activation of the sulfur atom
occurs to form sulfonium ion A, followed by rate-deter-
mining ionization of A to form oxocarbenium ion B
(Scheme 3).19 The low diastereoselectivities observed with
strong nucleophiles could result from competitive
SN2-like pathways9,10,30 involving displacement of the
activated starting material A (Scheme 3)31 or analogous
compounds, such as the glycosyl iodide.30c,32 This expla-
nation, however, does not explain the stereochemical
data (eq 1, Table 1), because the β-substitution products
expected from direct displacement reactions of thio-
glycoside 1c30 are not the major products in any case
observed. Direct displacement of an adduct with CH3CN
(a nitrilium ion), which has been invoked in other glyco-
sylation reactions,33 also does not satisfactorily explain
the observed diastereoselectivities. First, the expected
β-glycoside products arising from direct displacement of
an R-nitrilium species33 are not favored for any of the
substrates examined. Second, invoking an interme-
diate nitrilium species does not account for the similar
selectivity trends observed in CH2Cl2 as in CH3CN. The
loss of selectivity with increasing reactivity, however, is
consistent with erosion of diastereoselectivity by an SN1-
like pathway involving oxocarbenium ion B (Scheme 3),
which has been observed for C-nucleophiles.9
Nucleophilic Substitution Reactions of 2-Deoxythioglyco-
sides. Experiments using 2-deoxyglucosyl donor 1c and a
range of oxygen nucleophiles demonstrated an erosion
of stereoselectivity with increasing nucleophilicity (eq 1,
Table 1). For example, substitution with the weakest nucleo-
phile examined, trifluoroethanol,14 resulted in an 83:17 (R:β)
mixture of products (Table 1, entry 1).27 This stereochemical
outcome is consistent with stereoelectronically controlled
attack (Scheme 2, path a), and the selectivity compares to
those observed for reactions of less reactive carbon nucleo-
philes (Scheme 1). Nucleophiles with fewer electron-with-
drawing groups, which should be more nucleophilic,14
exhibit lower selectivity. The strongest nucleophile employed,
ethanol,14 afforded the 2-deoxy-R-O-glycoside 11 in a 51:49 (R:β)
mixture of diastereomers (Table 1, entry 6).28 The same substitu-
tion reaction performed in CH2Cl2 resulted in a 52:48 (R:β)
mixture of diastereomeric products, suggesting that both reactions
proceed through a similar SN1-like mechanism (vide infra). These
results clearly indicate that the nucleophilicity of alcohols impacts
the stereoselectivity of glycosylation reactions.29
The stronger nucleophiles employed in the substitution
reactions of 2-deoxyglycosyl donor 1c follow the level of
stereocontrol observed in a common glycosylation reaction.
Substitution using the glucose-derived nucleophile 1334
afforded a 57:43 (R:β) mixture of products (12, eq 2),
comparable to the diastereoselectivities observed for reactions
(28) Loss of chemoselectivity with increasing reactivity has been reported:
Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1373–1383.
(29) Steric interactions that develop in the transition state can also
influence diastereoselectivity, as exhibited by matched and mismatched
donor-acceptor combinations: (a) Spijker, N. M.; van Boeckel, C. A. A.
Angew. Chem., Int. Ed. 1991, 30, 180–183. (b) Cid, M. B.; Alonso, I.; Alfonso,
TABLE 1. Effect of Nucleophile Strength on Substitution Reactions of
2-Deoxythioglycoside 1c
entry
compound
R
Fa
dr (R:β)b
yield (%)c
1
2
3
4
5
6
6
7
8
9
10
11
CF3
0.38
0.29
0.15
0.14
0.13
0.00
83:17
67:33
56:44
55:45
56:44
51:49
80
78
69
72
72
82
CF2H
CH2F
CH2Br
CH2Cl
CH3
ꢀ
F.; Bonilla, J. B.; Lopez-Prados, J.; Martın-Lomas, M. Eur. J. Org. Chem.
2006, 3947–3959.
(30) The SN2-like pathway would provide β-glycosides predominantly for
2-deoxyglycosyl donors: (a) Hashimoto, S.; Sano, A.; Sakamoto, H.;
Nakajima, M.; Yanagiya, Y.; Ikegami, S. Synlett 1995, 1271–1273.
(b) Pongdee, R.; Wu, B.; Sulikowski, G. A. Org. Lett. 2001, 3, 3523–3525.
(c) Lam, S. N.; Gervay-Hague, J. Org. Lett. 2003, 5, 4219–4222. (d) Crich, D.;
Vinogradova, O. J. Org. Chem. 2006, 71, 8473–8480.
aField inductive effect parameter; see ref 24. bDetermined by GC and 1H
NMR spectroscopy of the unpurified reaction mixture. cIsolated yield.
(31) Sun, L.; Li, P.; Zhao, K. Tetrahedron Lett. 1994, 35, 7147–7150.
(32) Gervay, J.; Hadd, M. J. J. Org. Chem. 1997, 62, 6961–6967. (b) El-Badri,
M. H.; Willenbring, D.; Tantillo, D. J.; Gervay-Hague, J. J. Org. Chem. 2007,
72, 4663–4672.
€
(33) (a) Schmidt, R. R.; Rucker, E. Tetrahedron Lett. 1980, 21, 1421–
1424. (b) Braccini, I.; Derouet, C.; Esnault, J.; du Penhoat, C. H.; Mallet, J.-M.;
Several factors were considered to explain the trend of
decreasing selectivity with increasing reactivity. The me-
.
(26) We have previously observed that reactions of oxocarbenium ions
with highly reactive nucleophiles in CH3CN as solvent exhibit greater
stereoselectivities for the stereoelectronically preferred product than reac-
tions in CH2Cl2: Shenoy, S. R.; Smith, D. M.; Woerpel, K. A. J. Am. Chem.
Soc. 2006, 128, 8671–8677.
(27) The nucleophilic substitution reaction of trifluoroethanol performed
in CH2Cl2 resulted in a 58:42 (R:β) mixture of anomers.
Michon, V.; Sinay, P. Carbohydr. Res. 1993, 246, 23–41. (c) Vankar, Y. D.;
Vankar, P. S.; Behrendt, M.; Schmidt, R. R. Tetrahedron 1991, 47, 9985–
9992. (d) Crich, D.; Vinogradova, O. J. Org. Chem. 2007, 72, 6513–6520.
(34) 2,3,4-Tri-O-benzyl-R-D-glucopyranoside 13 was prepared following
literature procedures: (a) Lam, S. N.; Gervay-Hague, J. Carbohdr. Res. 2002,
337, 1953–1965. (b) Reitz, A. B.; Tuman, R. W.; Marchione, C. S.; Jordan, A.
D., Jr.; Bowden, C. R.; Maryanoff, B. E. J. Med. Chem. 1989, 32, 2110–2116.
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of alcohols containing a single electron-withdrawing substituent
experiment between fluoroethanol and trifluoroethanol pro-
vided incorporation of the more nucleophilic alcohol with
nearly complete chemoselectivity (Table 3, entry 3). These
results confirm that the stereochemistry-determining step of
the substitution reaction of trifluoroethanol with 2-deoxy-
glycosyl donor 1c occurs at a rate below the diffusion limit.
Lastly, ethanol and fluoroethanol were subjected to a com-
petition experiment in CH3CN. This experiment afforded
the ethanol adduct 11 as the major product, but with
diminished chemoselectivity (Table 3, entry 4). This result
is consistent with the hypothesis that both nucleophiles react
at rates near the diffusion limit, in accord with the stereo-
chemical data (eq 1, Table 1).
(Table 1, entries 3-5).23
Varying the protecting groups on the 2-deoxyglycosyl
donor had a minimal effect on the stereoselectivity of
nucleophilic substitution. In all cases, reactions of trifluoro-
ethanol provided the highest level of stereocontrol favoring
the stereoelectronically preferred R-product, whereas use of
ethanol as the nucleophile resulted in a near statistical
mixture of diastereomers (eq 3, Table 2). The relationship
between nucleophilicity and stereoselectivity appears to be a
general characteristic of O-glycosylation reactions under
SN1-like conditions.19
TABLE 3. Competition Experiments Confirm the Relative Reactivities
of the Alcohol Nucleophiles
entry
solvent
R1a
R2a
product ratio (R1:R2)b
1
2
3
4
CH3CN
CH2Cl2
CH3CN
CH3CN
CH3
CH3
CH2F
CH3
CF3
CF3
CF3
CH2F
98:2 (11:6)
87:13 (11:6)
97:3 (8:6)
70:30 (11:8)
a10 equiv of nucleophile. bDetermined by GC analysis of the unpur-
ified reaction mixture.
TABLE 2. Effect of the Glycosyl Donor Protecting Group
entry
compound
R
R1
dr (R:β)a
yield (%)b
1
2
3
4
14
2
15
16
Bn
Bn
Ac
Ac
CF3
CH3
CF3
CH3
81:19
50:50
75:25
56:44
68
80
69
80
Comparison of the relative rates of reaction (kEtOH/kTFE) to
the rates of nucleophilic addition to analogous oxocarbenium
ion intermediates supports the transition to diffusion-limited
diastereoselectivity with more nucleophilic alcohols. Additions
of water to a propionaldehyde-derived oxocarbenium ion occur
at rates of approximately 4 ꢀ 108 M-1 s-1, a rate at which
diffusional processes begin to be important.16a,38 The 50-fold
decrease in reactivity of trifluoroethanol (Table 3, entry 1)
would suggest that the rate of addition to the oxocarbenium
ion intermediate is approximately 8 ꢀ 106 M-1 s-1, which is
about 1000-fold slower than the diffusion rate limit.
The competitionexperiment between ethanoland trifluoro-
ethanol in CH2Cl2 resulted in chemoselectivity lower than
that of the identical reaction performed in CH3CN (Table 3,
entry 2). This result can be explained by considering that the
rate of addition of trifluoroethanol to oxocarbenium ion 5
(Scheme 2) approaches the diffusion rate limit in CH2Cl2.13
The dependence of chemoselectivity on solvent choice is
consistent with the stereochemical data, in which stereo-
selectivity was greater in CH3CN than in CH2Cl2. Increasing
the polarity of the solvent results in the stabilization of the
cationic intermediate and subsequently reduces the rate of
nucleophilic addition.26 As the rate of nucleophilic addition
is decreased from the diffusion limit regime, greater facial
selectivity for the stereoelectronically preferred product
would be observed.
aDetermined by 1H NMR spectroscopy of the unpurified reaction
mixture. bIsolated yield.
Competition experiments between selected alcohol nucleo-
philes confirmed the relative reactivities of the ethanol
derivatives. Nucleophilic substitution reactions of 2-deoxy-
glycosyl donor 1c were performed in the presence of an
equimolar mixture of two nucleophiles of differing reactivity
(eq 4, Table 3).35 As expected, increasing the number of
electron-withdrawing substituents on the alcohol resulted in
a decrease of nucleophilicity. For example, a competition
experiment performed in CH3CN between ethanol and
trifluoroethanol resulted in near complete incorporation of
ethanol, reflecting the relative nucleophilicities of the two
nucleophiles (Table 3, entry 1).36,37 Similarly, a competition
(35) Competition experiments were performed in the presence of either 4
or 10 equiv of each nucleophile. Comparable results were obtained regardless
of the excess of nucleophile employed. Using DTBMP as an additive did not
affect the outcome of the competition experiments.
(36) For comparison, the differences in reactivity between ethanol and
trifluoroethanol is approximately 220,000 for reactions with benzhydryl
carbocations that occur at rates much below the diffusion rate limit (ref 14).
(37) Secondary benzylic carbocations exhibit selectivities for kEtOH/kTFE
from 17 for the less stable carbocations to 140 for the most stable (ref 28). The
k
EtOH/kTFE values (2.4-5.4) for reactions involving simple acyclic oxocarbenium
ions (ref 16a) in water differ significantly from the 50-fold selectivity reported in
this Article for 2-deoxyglucosyloxocarbenium ions in CH3CN but are similar to
the 6.7-fold selectivity observed in CH2Cl2. Given the differences in substrates
and conditions, it is not possible to reconcile these values.
(38) These rate data provide a conservative estimate of the nucleophilicity
of ethanol, as the reactivity of ethanol appears to be greater than that of water
in additions to oxocarbenium ion intermediates (ref 28).
1110 J. Org. Chem. Vol. 75, No. 4, 2010

Beaver and Woerpel
JOCArticle
Control experiments confirmed that the products derived
from nucleophilic substitution of 2-deoxythioglycoside 1c
were formed under kinetic control.39,40 The presence or
absence of epimerization could be tested by resubjecting the
products of nucleophilic substitution to the reaction con-
ditions (eq 5, Table 4). For example, acetal 6 and tri-O-
ethylthioglycoside 17 were subjected to difluoroethanol
and N-iodosuccinimide in CH3CN at -42 °C. Of the four
possible products, only acetal 6 (which did not undergo
epimerization) and nucleophilic substitution product 18
were observed (Table 4, entry 1). Increasing the tempera-
ture to 0 °C resulted in neither epimerization nor incorpora-
tion of difluoroethanol into acetal 6. At 25 °C, however,
small amounts of epimerization of the trifluoroethanol
addition product 6 was observed.41 Therefore, it was
deemed critical to perform all nucleophilic substitution
reactions at or below 0 °C. Following this model, control
experiments were performed for each pyran system inves-
tigated; those results are provided as Supporting Informa-
tion.
FIGURE 1. Stereoselectivity (dr) vs nucleophilicity (F)24 in pyran
systems.
which has a nucleophilicity parameter comparable to that of
trifluoroethanol.14,15
A graphical summary of the nucleophilic substitution data
for the monosubstituted tetrahydropyran acetals is pre-
sented in Figure 1. Data for the nucleophilic substitution
of 2-deoxythioglycosides (eq 1, Table 1) are included for
comparison purposes. Clearly, the nucleophilicity-selectivity
relationship is not restricted to highly oxygenated carbohy-
drate systems but must be considered for any substitution
reactions of acetals that proceed through oxocarbenium ion
intermediates. Specific details concerning the origin of
stereoselectivity (or lack thereof) of these nucleophilic sub-
stitutions provide additional insight into the trends depicted
in Figure 1.43
TABLE 4. Control Experiments Confirm Kinetic Product Formation
entry temp (°C) 6 (R:β)a 18 (R:β)a incorporation products (7, 19)
The stereochemical trend observed upon nucleophilic
substitution of the C5-benzyloxymethyl-substituted acetal
20 with various nucleophiles was consistent with reaction
rates that approach the diffusion limit (eq 6, Table 5).
Activation of acetal 20 occurred readily at -78 °C in
CH2Cl2, and control experiments indicated that these
conditions provided kinetic product ratios.39,44 Formation
of the favored 1,5-trans product (21-26) is consistent with
stereoelectronically controlled addition to the lowest en-
ergy oxocarbenium ion conformer 27 (Scheme 4, path a).4b
At reaction rates below the diffusion limit, the minor 1,5-
cis product arises from stereoelectronically controlled
addition to the higher energy half-chair conformer 28 in
which the C-5 substituent resides in a pseudoaxial orienta-
tion (Scheme 4, path c).4b The erosion of stereoselectivity
observed upon substitution with more reactive alcohols
can be explained by considering the diffusion-controlled
1
2
3
-42
0
25
61:39
62:38
71:29
58:42
59:41
59:41
none
none
none
aDetermined by GC analysis of the unpurified reaction mixture.
Nucleophilic Substitution Reactions of Monosubstituted
Tetrahydropyran Acetals. The inverse relationship between
nucleophilicity and selectivity was also observed for
the nucleophilic substitution reactions of monosubsti-
tuted tetrahydropyran acetals.17 In all cases examined,
reactions of trifluoroethanol provided the highest level
of stereocontrol, favoring the stereoelectronically pre-
ferred product, whereas use of ethanol as the nucleo-
phile resulted in a 1:1 mixture of diastereomers. The major
products of addition to each model system matched those
products previously obtained with allyltrimethylsilane,42
(43) A plot of log(dr) versus pKa of the alcohol nucleophile (a Brønsted
(39) Details of control experiments are provided as Supporting Informa-
tion.
(40) Thermodynamic product ratios were obtained for select substrates,
and these results do not account for the observed selectivity trends. Details
are provided as Supporting Information.
(41) Control experiments performed in the presence of (()-camphorsul-
fonic acid resulted in significant epimerization of starting material 6 and
product 15 at 0 °C. The incorporation product 7 was also observed at this
temperature, indicating complete ionization of the acetal center.
(42) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528.
plot) was also performed. These plots display poor linearity (R2
=
0.76-0.95), so it cannot be established that basicity is the dominant factor
responsible for selectivities. If βnuc numbers are extracted from these non-
linear plots, the values (0.18-0.25) are within the range observed for
reactions of the most reactive benzylic carbocations (ref 28). This value is
consistent with an early transition state for nucleophilic addition to the
cationic intermediate, but no clear trends in βnuc can be discerned. Details are
provided as Supporting Information.
(44) Control experiments indicated that the identical substitution reac-
tions performed in CH3CN resulted in rapid epimerization of the acetal
product.
J. Org. Chem. Vol. 75, No. 4, 2010 1111

Beaver and Woerpel
JOCArticle
addition to oxocarbenium ions 27 and 28 through compet-
ing pathways a-d.
SCHEME 4. Modes of Addition to the 5-CH2OBn-Substituted
Oxocarbenium Ions 27 and 28
TABLE 5. Effect of Nucleophile Strength on Substitution Reactions of
5-CH2OBn-Substituted Acetal 20
entry
compound
X
Fa
dr (trans:cis)b
yield (%)c
1
2
3
4
5
6
21
22
23
24
25
26
CF3
0.38
0.29
0.15
0.14
0.13
0.00
83:17
74:26
62:38
62:38
65:35
49:51
65
79
91
85
85
81
CF2H
CH2F
CH2Br
CH2Cl
CH3
SCHEME 5. Modes of Addition to the 4-OBn-Substituted
Oxocarbenium Ions 36 and 37
aField inductive effect parameter; see ref 24. bDetermined by GCand1H
NMR spectroscopy of the unpurified reaction mixture. cIsolated yield.
Nucleophilic substitution reactions of the C4-benzyloxy-
substituted acetal 29 proceeded under identical conditions to
provide the expected stereochemical trend (eq 7, Table 6). As
with the C5-benzyloxymethyl-substituted acetal model sys-
tem (20), CH2Cl2 was employed as the solvent because it
reliably provided kinetically derived diastereomeric ratios.39,44
The low-energy oxocarbenium ion 36, in which the C4-
benzyloxy substituent resides in the pseudoaxial position to
maximize electrostatic stabilization of the cationic center,42
is shown in Scheme 5. Upon addition of trifluoroethanol,
the major product 1,4-trans-30 arises from addition to the
stereoelectronically favored face (Scheme 5, path a). The
minor product 1,4-cis-30 arises from addition to the higher
energy oxocarbenium ion 37 (path c) at rates below the
diffusion limit. As nucleophilicity increases, reaction rates
for addition to oxocarbenium ion 36 approach the diffusion
rate limit. In this scenario, path b becomes a viable pathway
for the formation of the 1,4-cis product. Therefore, the
substitution reaction of ethanol results in a statistical
mixture of products (35, Table 6, entry 6) arising from
competing pathways a-d (Scheme 5).
examined (eq 8). Substitution reactions employing both ethanol
and trifluoroethanol as the nucleophile resulted in a 49:51
(cis:trans) ratio of diastereomers under conditions optimized
for the C4- and C5-substituted acetals (20 and 29).45,46
Performing the nucleophilic substitution reactions of
C3-benzyloxy-substituted acetal 38 in CH3CN, however,
resulted in the stereochemical trend observed for other sub-
strates (eq 9, Table 7).47 The more polar solvent is expected
TABLE 6. Effect of Nucleophile Strength on Substitution Reactions of
4-OBn-Substituted Acetal 29
entry
compound
X
Fa
dr (trans:cis)b
yield (%)c
(45) Nucleophilic addition to the lowest energy oxocarbenium ion (41)
results in destabilizing steric interactions with the axially oriented C3-
benzyloxy substituent (ref 42). In addition, electronic repulsion between
the oxygen atoms of the substrate and the nucleophile destabilize the
transition state leading to the 1,3-cis product: (a) Smith, G. D.; Jaffe,
R. L.; Yoon, D. Y. J. Phys. Chem. 1996, 100, 13439–13446. (b) de Oliveira,
P. R.; Rittner, R. Spectrochim. Acta, Part A 2005, 61, 1737–1745. (c) de
Oliveira, P. R.; Rittner, R. J. Mol. Struct. 2005, 743, 69–72.
1
2
3
4
5
6
30
31
32
33
34
35
CF3
0.38
0.29
0.15
0.14
0.13
0.00
88:12
82:18
71:29
61:39
67:33
51:49
81
68
72
83
79
70
CF2H
CH2F
CH2Br
CH2Cl
CH3
(46) The halogen substituents on the alcohol nucleophiles may also
experience lone pair-lone pair electron repulsion with the C3-benzyloxy
substituent, further destabilizing the stereoelectronically favored transition
state: Hu, T.; Shen, M.; Chen, Q.; Li, C. Org. Lett. 2006, 8, 2647–2650.
(47) Control experiments indicated that the nucleophilic substitution
products of C3-benzyloxy-substituted acetal 38 were susceptible to epimer-
ization. DTBMP was employed as an additive to prohibit epimerization of
the acetal center.
aField inductive effect parameter; see ref 24. bDetermined by GC and
1H NMR spectroscopy of the unpurified reaction mixture. cIsolated
yield.
In stark contrast, the C3-benzyloxy-substituted acetal 38 dis-
played no stereoselectivity in CH2Cl2 for any of the nucleophiles
1112 J. Org. Chem. Vol. 75, No. 4, 2010

Beaver and Woerpel
JOCArticle
SCHEME 6. Modes of Addition to the 3-OBn-Substituted Ox-
ocarbenium Ion
attributed to reaction rates of the stereochemistry-determin-
ing step at or near the diffusion limit.
Experimental Section
General Procedure for the Nucleophilic Substitution of Acetals
1c, 20, 29, and 38. To a cooled (-78 or 0 °C) solution of the
sulfide in CH3CN or CH2Cl2 (0.10 M) were added a nucleophile
(4.0 equiv) and then N-iodosuccinimide (2.0 equiv). 2,6-Di-tert-
butyl-4-methylpyridine (2.0 equiv) was added, where indicated.
After 1 h, the cooled solution was washed with 10% aqueous
Na2S2O3 (1 mL per mL of reaction volume), and the aqueous
layer was extracted with two portions of Et2O (2 mL per mL of
reaction volume). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The unpurified product was
analyzed by GC and 1H NMR spectroscopy and then purified as
indicated.
2-Deoxyglycoside Trifluoroethanol Substitution Product r-6/
β-6. The standard procedure for nucleophilic substitution of
acetals was followed with thioglycoside 1c (0.050 g, 0.20 mmol),
trifluoroethanol (0.058 mL, 0.80 mmol), and N-iodosuccinimide
to stabilize the oxocarbenium ions 41 and 42 (Scheme 6), thus
decreasing their electrophilicities and lowering rates of
nucleophilic addition from the diffusion-limit regime.26 Of
note, the nucleophilic substitution reaction of bromoethanol
resulted in a data point that did not fit the expected trend
(Table 7, entry 4). Because the destabilizing steric interac-
tions encountered in the favored transition state are sensitive
to nucleophile size,42 the unexpected erosion of selectivity
may be the result of the size of the bromine atom as compared
to the other halogen substituents.48
1
(0.090 g, 0.40 mmol) in CH3CN at 0 °C. GC and H NMR
spectroscopic analysis of the unpurified product indicated a pair
of diastereomers in a 83:17 (R:β) ratio. Purification by flash
chromatography (3:1 pentane/Et2O) afforded an inseparable
mixture of diastereomers R-6/β-6 as a colorless oil (0.047 g,
81%): GC tR(major) 8.4 min, tR(minor) 8.7 min; [R]22D þ80.2 (c
1.12, CHCl3); IR (thin film) 2934, 2830, 1468, 1267, 1067 cm-1
;
HRMS (ESI) m/z calcd for C11H19F3O5Na (M þ Na)þ
311.1082, found 311.1086. Anal. Calcd for C11H19F3O5: C,
45.83; H, 6.64. Found: C, 45.61; H, 6.66.
Major Isomer (r-6). 1H NMR (500 MHz, CDCl3) δ 5.01 (d,
J = 3.4 Hz, 1H), 3.88 (m, 2H), 3.56-3.64 (m, 4H), 3.55 (s, 3H),
3.45 (s, 3H), 3.42 (s, 3H), 3.18 (t, J = 9.2 Hz, 1H), 2.31 (ddd, J =
13.3, 5.1, 1.2 Hz, 1H), 1.60 (ddd, J = 13.2, 11.4, 3.5 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 123.9 (q, J = 278.4 Hz), 98.1, 79.6,
78.1, 71.3, 71.1, 64.1 (q, J = 26.0 Hz), 60.57, 59.3, 57.5, 34.4.
Minor Isomer (β-6). 1H NMR (500 MHz, CDCl3, distinctive
peaks) δ 4.55 (dd, J = 9.8, 1.8 Hz, 1H), 4.13 (dq, J = 12.6, 8.9 Hz,
2H), 3.54 (s, 3H), 3.43 (s, 3H), 3.30 (m, 2H), 3.13 (t, J = 9.2 Hz,
1H), 2.38 (dd, J = 12.7, 5.1, 2.1 Hz, 1H), 1.53 (td, J = 11.9,
9.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 123.8 (q, J =
278.4 Hz), 99.9, 80.6, 79.2, 75.2, 71.5, 65.5 (q, J = 34.7 Hz),
60.61, 59.4, 57.0, 35.5.
TABLE 7. Effect of Nucleophile Strength on Substitution Reactions of
3-OBn-Substituted Acetal 38
entry
compound
X
Fa
dr (cis:trans)b
yield (%)c
1
2
3
4
5
6
39
43
44
45
46
40
CF3
0.38
0.29
0.15
0.14
0.13
0.00
86:14
84:16
74:26
60:40
75:25
52:48
69
68
63
46
64
89
CF2H
CH2F
CH2Br
CH2Cl
CH3
2-Deoxyglycoside Difluoroethanol Substitution Product r-7/
β-7. The standard procedure for nucleophilic substitution of
acetals was followed with thioglycoside 1c (0.050 g, 0.20 mmol),
difluoroethanol (0.050 mL, 0.80 mmol), and N-iodosuccinimide
aField inductive effect parameter; see ref 24. bDetermined by GC and
1H NMR spectroscopy of the unpurified reaction mixture. cIsolated
yield.
1
(0.090 g, 0.40 mmol) in CH3CN at 0 °C. GC and H NMR
spectroscopic analysis of the unpurified product indicated a pair
of diastereomers in a 66:34 (R:β) ratio. Purification by flash
chromatography (3:1 pentane/Et2O) afforded an inseparable
mixture of diastereomers R-7/β-7 as a colorless oil (0.042 g,
Conclusion
78%): GC tR(major) 9.7 min, tR(minor) 9.9 min; [R]22 þ58
The stereoselectivity of O-glycosylation reactions are sig-
nificantly affected by the nucleophilicity of the glycosyl
acceptor. Common oxygen nucleophiles, such as ethanol,
result in diastereomeric mixtures of products, regardless of
the glycosyl donor. Only upon the addition of weaker
nucleophiles, such as trifluoroethanol, is stereoselectivity
observed favoring the product of stereoelectronically controlled
addition (Figure 1). In many cases, the complete lack of
stereocontrol observed for nucleophilic substitution may be
D
(c 0.80, CHCl3); IR (thin film) 2935, 2832, 1449, 1111 cm-1
;
HRMS (ESI) m/z calcd for C11H20F2O5Na (M þ Na)þ
293.1176, found 293.1169.
Major Isomer (r-7). 1H NMR (500 MHz, CDCl3) δ 5.89 (tt,
J = 55.5, 4.1 Hz, 1H), 4.96 (d, J = 3.4 Hz, 1H), 3.76 (dtd, J =
15.0, 11.9, 3.7 Hz, 1H), 3.55-3.67 (m, 4H), 3.54 (s, 3H), 3.44
(s, 3H), 3.42 (s, 3H), 3.29 (m, 1H), 3.14 (m, 1H), 2.27 (ddd, J =
13.3, 5.1, 1.0 Hz, 1H), 1.58 (ddd, J = 13.3, 11.7, 3.7 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 114.2 (t, J = 241.1 Hz), 98.3,
79.7, 78.2, 71.2, 71.0, 66.5 (t, J = 28.0 Hz), 60.55, 59.3, 57.4,
34.6.
(48) The halogen substituent influences the ground-state conformation of
the alcohol nucleophile, which may change its effective size: (a) Thomassen,
H.; Samdal, S.; Hedberg, K. J. Phys. Chem. 1993, 97, 4004–4010. (b) Durig,
J. R.; Shen, S.; Guirgis, G. A. J. Mol. Struct. 2001, 560, 295–314. (c) Trindle,
C.; Crum, P.; Douglass, K. J. Phys. Chem. A 2003, 107, 6236–6242.
Minor Isomer (β-7). 1H NMR (500 MHz, CDCl3, distinctive
peaks) δ 5.90 (m, 1H), 4.49 (dd, J = 9.7, 1.7 Hz, 1H), 3.99 (m,
1H), 3.53 (s, 3H), 3.43 (s, 3H), 3.41 (s, 3H), 2.35 (ddd, J = 12.7,
J. Org. Chem. Vol. 75, No. 4, 2010 1113

Beaver and Woerpel
JOCArticle
5.0, 1.8 Hz, 1H), 1.51 (td, J = 11.9, 9.7 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 114.4 (t, J = 240.7 Hz), 100.2, 80.8,
79.4, 75.1, 71.6, 68.1 (dd, J = 30.5, 26.4 Hz), 60.60, 59.4, 57.0,
35.7.
chromatography (1:1 pentane/Et2O) afforded an inseparable
mixture of diastereomers R-10/β-10 as a colorless oil (0.023 g,
72%): GC tR(major) 12.3 min, tR(minor) 12.4 min; [R]22D þ26.5
(c 0.900, CHCl3); IR (thin film) 2933, 2831, 1448, 1112 cm-1
;
2-Deoxyglycoside Fluoroethanol Substitution Product r-8/β-
8. The standard procedure for nucleophilic substitution of
acetals was followed with thioglycoside 1c (0.030 g, 0.12 mmol),
fluoroethanol (0.028 mL, 0.48 mmol), and N-iodosuccinimide
HRMS (ESI) m/z calcd for C11H21ClO5Na (M þ Na)þ
291.0975, found 291.0975. Anal. Calcd for C11H21ClO5: C,
49.16; H, 7.88. Found: C, 49.12; H, 7.77.
Major Isomer (r-10). 1H NMR (500 MHz, CDCl3) δ 4.97 (d,
J = 3.4 Hz, 1H), 3.86 (m, 1H), 3.55-3.75 (m, 7H), 3.54 (s, 3H),
3.45 (s, 3H), 3.42 (s, 3H), 3.17 (t, J = 9.4 Hz, 1H), 2.26 (ddd, J =
1
(0.054 g, 0.24 mmol) in CH3CN at 0 °C. GC and H NMR
spectroscopic analysis of the unpurified product indicated a pair
of diastereomers in a 56:44 (R:β) ratio. Purification by flash
chromatography (3:1 pentane/Et2O) afforded an inseparable
mixture of diastereomers R-8/β-8 as a colorless oil (0.021 g,
69%): GC tR(major) 10.4 min, tR(minor) 10.6 min; [R]22D þ41
13.1, 5.1, 1.1 Hz, 1H), 1.57 (ddd, J = 13.1, 11.5, 3.7 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 97.8, 79.9, 78.4, 71.4, 70.8, 67.5,
60.5, 59.3, 57.4, 43.0, 34.8.
Minor Isomer (β-10). 1H NMR (500 MHz, CDCl3, distinctive
peaks) δ 4.49 (dd, J = 9.8, 1.8 Hz, 1H), 4.28 (m, 1H), 4.11 (dt,
J = 10.8, 5.3 Hz, 1H), 3.54 (s, 3H), 3.43 (s, 3H), 3.41 (s, 3H), 3.30
(m, 2H), 3.10 (t, J = 9.0 Hz, 1H), 2.82 (m, 1H), 2.35 (ddd, J =
12.6, 5.1, 1.8 Hz, 1H), 1.51 (td, J = 12.5, 9.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 100.2, 80.9, 79.5, 75.1, 71.7, 69.3, 60.6,
59.4, 57.0, 42.8, 35.8.
(c 0.39, CHCl3); IR (thin film) 2934, 2830, 1450, 1110 cm-1
;
HRMS (ESI) m/z calcd for C11H21FO5Na (M þ Na)þ 275.1271,
found 275.1266. Anal. Calcd for C11H21FO5: C, 52.37; H, 8.39.
Found: C, 52.38; H, 8.35.
Major Isomer (r-8). 1H NMR (500 MHz, CDCl3) δ 4.97 (d,
J = 3.4 Hz, 1H), 4.49-4.61 (m, 2H), 3.81 (m, 2H), 3.56-3.66
(m, 4H), 3.55 (s, 3H), 3.45 (s, 3H), 3.41 (s, 3H), 3.17 (t, J = 9.2
Hz, 1H), 2.28 (dd, J = 12.8, 5.2 Hz, 1H), 1.58 (ddd, J = 13.1,
11.6, 3.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 97.7, 82.7 (d,
J = 165.3 Hz), 79.9, 78.4, 71.4, 70.6, 66.3 (d, J = 19.9 Hz), 60.5,
59.2, 57.4, 34.8.
2-Deoxyglycoside Ethanol Substitution Product r-11/β-11.
The standard procedure for nucleophilic substitution of acetals
was followed with thioglycoside 1c (0.030 g, 0.12 mmol), ethanol
(0.028 mL, 0.48 mmol), and N-iodosuccinimide (0.054 g,
0.24 mmol) in CH3CN at 0 °C. GC and 1H NMR spectroscopic
analysis of the unpurified product indicated a pair of diastereo-
mers in a 51:49 (R:β) ratio. Purification by flash chromato-
graphy (1:1 pentane/Et2O) afforded an inseparable mixture of
diastereomers R-11/β-11 as a colorless oil (0.023 g, 82%): GC
Minor Isomer (β-8). 1H NMR (500 MHz, CDCl3, distinctive
peaks) δ 4.52-4.70 (m, 3H), 4.26 (m, 1H), 4.06 (dddd, J = 35.0,
12.1, 4.3, 2.6 Hz, 1H), 3.69 (m, 1H), 3.54 (s, 3H), 3.43 (s, 3H),
3.41 (s, 3H), 3.30 (m, 2H), 3.10 (t, J = 9.2 Hz, 1H), 2.81 (dtt, J =
21.0, 13.6, 7.5 Hz, 1H), 2.38 (ddd, J = 12.6, 5.1, 1.8 Hz, 1H), 1.52
(td, J = 12.0, 9.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 100.0,
82.9 (d, J = 165.8 Hz), 80.9, 79.6, 75.1, 71.7, 68.1 (d, J = 19.9 Hz),
60.6, 59.4, 56.9, 35.9.
tR(major) 9.4 min, tR(minor) 9.7 min; [R]22 þ1.0 (c 0.43,
D
CHCl3); 1H NMR (500 MHz, CDCl3, mixture of anomers)
δ 4.93 (d, J = 3.7 Hz, 1H), 4.44 (dd, J = 9.7, 1.8 Hz, 1H),
3.95 (dq, J = 9.3, 7.0 Hz, 1H), 3.55-3.70 (m, 9H), 3.55 (s, 3H),
3.54 (s, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 3.41 (s, 6H), 3.30 (m, 2H),
3.16 (t, J = 9.2 Hz, 1H), 3.08 (t, J = 9.2 Hz, 1H), 2.30 (ddd, J =
12.5, 5.0, 1.8 Hz, 1H), 2.21 (dd, J = 12.8, 5.2 Hz, 1H), 1.52 (m,
2H), 1.21 (m, 6H); 13C NMR (125 MHz, CDCl3, mixture of
anomers) δ 99.6, 97.1, 81.1, 80.1, 79.7, 78.7, 75.1, 71.8, 71.5,
70.4, 64.7, 62.6, 60.6, 60.5, 59.4, 59.2, 57.3, 56.9, 36.1, 35.0,
15.13, 15.07; IR (thin film) 2932, 2830, 1446, 1113 cm-1; HRMS
(ESI) m/z calcd for C11H22O5Na (M þ Na)þ 257.1365, found
257.1361. Anal. Calcd for C11H22O5: C, 56.39; H, 9.46. Found:
C, 56.47; H, 9.56.
2-Deoxyglycoside Bromoethanol Substitution Product r-9/β-
9. The standard procedure for nucleophilic substitution of
acetals was followed with thioglycoside 1c (0.030 g, 0.12 mmol),
bromoethanol (0.034 mL, 0.48 mmol), and N-iodosuccinimide
1
(0.054 g, 0.24 mmol) in CH3CN at 0 °C. GC and H NMR
spectroscopic analysis of the unpurified product indicated a pair
of diastereomers in a 55:45 (R:β) ratio. Purification by flash
chromatography (1:1 pentane/Et2O) afforded an inseparable
mixture of diastereomers R-9/β-9 as a colorless oil (0.028 g,
74%): GC tR(major) 13.2 min, tR(minor) 13.4 min; [R]22D þ21.8
(c 0.805, CHCl3); IR (thin film) 2932, 2830, 1459, 1113 cm-1
;
2-Deoxyglycoside
2,3,4-Tri-O-benzyl-r-D-glucopyranoside
HRMS (ESI) m/z calcd for C11H21BrO5Na (MþNa)þ 335.0470,
found 335.0464. Anal. Calcd for C11H21BrO5: C, 42.19; H, 6.76.
Found: C, 41.94; H, 6.60.
Substitution Product r-12/β-12. The standard procedure for
nucleophilic substitution of acetals was followed with thioglyco-
side 1c (0.010 g, 0.040 mmol), 2,3,4-tri-O-benzyl-R-D-glucopyr-
anoside 1334 (0.020 g, 0.044 mmol), N-iodosuccinimide (0.018 g,
0.080 mmol), and 2,6-di-tert-butyl-4-methylpyridine (0.017 g,
0.080 mmol) in CH3CN at 0 °C. 1H NMR spectroscopic analysis
of the unpurified product indicated a pair of diastereomers in a
57:43 (R:β) ratio. Purification by flash chromatography (1:1
hexanes/EtOAc) afforded an inseparable mixture of diastereo-
Major Isomer (r-9). 1H NMR (500 MHz, CDCl3) δ 4.98 (d,
J = 3.4 Hz, 1H), 3.92 (dt, J = 11.6, 6.1 Hz, 1H), 3.76 (m, 2H),
3.55-3.70 (m, 3H), 3.55 (s, 3H), 3.48 (m, 2H), 3.45 (s, 3H), 3.42
(s, 3H), 3.17 (t, J = 9.4 Hz, 1H), 2.26 (ddd, J = 13.1, 5.1, 1.0 Hz,
1H), 1.57 (ddd, J = 13.1, 11.5, 3.7 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 97.8, 79.9, 78.4, 75.1, 70.9, 67.4, 60.5,
59.3, 57.4, 34.8, 30.6.
mers R-12/β-12 as a colorless oil (0.014 g, 52%): [R]22 þ20
D
Minor Isomer (β-9). 1H NMR (500 MHz, CDCl3, distinctive
peaks) δ 4.49 (dd, J = 9.7, 2.1 Hz, 1H), 4.33 (m, 1H), 4.17 (ddd,
J = 11.6, 6.6, 5.3 Hz, 1H), 3.54 (s, 3H), 3.43 (s, 3H), 3.41 (s, 3H),
3.30 (m, 2H), 3.11 (t, J = 9.2 Hz, 1H), 2.82 (m, 1H), 2.35 (ddd,
(c 0.47, CHCl3); 13C NMR (125 MHz, CDCl3, mixture of
anomers) δ 138.8, 138.7, 138.5, 138.4, 138.21, 138.18, 128.54,
128.52, 128.51, 128.48, 128.47, 128.44, 128.2, 128.12, 128.07,
127.99, 127.98, 127.97, 127.8, 127.74, 127.70, 127.68, 127.66,
100.1, 98.03, 97.99, 97.9, 82.29, 82.26, 81.0, 80.1, 79.9, 79.8, 79.7,
78.6, 77.8, 77.4, 77.3, 75.9, 75.8, 75.2, 74.9, 74.8, 73.41, 73.37,
71.9, 71.2, 70.7, 69.8, 69.7, 67.6, 65.8, 60.6, 60.5, 59.4, 59.2, 57.3,
56.9, 55.2, 35.8, 34.8; IR (thin film) 3063, 3030, 2930, 2834, 1454,
1097 cm-1; HRMS (ESI) m/z calcd for C37H48O10Na (M þ
Na)þ 675.3145, found 675.3151. Anal. Calcd for C37H48O10:
C, 68.08; H, 7.41. Found: C, 68.09; H, 7.64.
J = 12.6, 5.1, 2.0 Hz, 1H), 1.51 (td, J = 12.3, 9.9 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 100.1, 80.9, 79.5, 71.6, 71.3, 69.2,
60.6, 59.4, 57.0, 35.8, 30.4.
2-Deoxyglycoside Chloroethanol Substitution Product r-10β-
10. The standard procedure for nucleophilic substitution of
acetals was followed with thioglycoside 1c (0.030 g, 0.12 mmol),
chloroethanol (0.032 mL, 0.48 mmol), and N-iodosuccinimide
1
(0.054 g, 0.24 mmol) in CH3CN at 0 °C. GC and H NMR
spectroscopic analysis of the unpurified product indicated a pair
Major Isomer (r-12). 1H NMR (500 MHz, CDCl3) δ
7.26-7.38 (m, 15H), 4.57-5.00 (m, 8H), 3.99 (m, 1H), 3.83
(dd, J = 11.4, 4.2 Hz, 1H), 3.74 (dd, J = 10.0, 3.1 Hz, 1H),
of diastereomers in a 56:44 (R:β) ratio. Purification by flash
1114 J. Org. Chem. Vol. 75, No. 4, 2010

Beaver and Woerpel
JOCArticle
3.46-3.62 (m, 7H), 3.50 (s, 3H), 3.42 (s, 3H), 3.37 (s, 3H), 3.34
(s, 3H), 3.20 (m, 1H), 3.15 (t, J = 9.4 Hz, 1H), 2.24 (dd, J = 13.0,
5.0 Hz, 1H), 1.53 (ddd, J = 13.0, 11.6, 3.7 Hz, 1H).
spectroscopic analysis of the unpurified product indicated a pair of
diastereomers in a 62:38 (trans:cis) ratio. Purification by flash
chromatography (3:1 hexane/EtOAc) afforded an inseparable
mixture of diastereomers trans-23/cis-23 as a colorless oil (0.046 g,
91%): GC tR(major) 14.7 min, tR(minor) 14.9 min; IR (thin film)
3030, 2946, 2865, 1453, 1041 cm-1; HRMS (ESI) m/z calcd for
C15H21FO3Na (M þ Na)þ 291.1372, found 291.1372. Anal. Calcd
for C15H21FO3: C, 67.14; H, 7.89. Found: C, 67.44; H, 7.95.
Major Isomer (trans-23). 1H NMR (500 MHz, CDCl3) δ
7.25-7.37 (m, 5H), 4.92 (d, J = 2.7 Hz, 1H), 4.50-4.68 (m, 4H),
3.98 (m, 1H), 3.92 (ddd, J = 32.3, 5.1, 2.7 Hz, 1H), 3.70 (m, 1H),
3.45 (m, 2H), 1.88 (m, 1H), 1.75 (m, 1H), 1.67 (m, 1H), 1.59
(m, 1H), 1.43 (m, 1H), 1.25 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ138.5, 128.43, 127.70, 127.60, 97.6, 83.02 (d, J= 168.8 Hz),
73.53, 73.3, 68.2, 66.0 (d, J = 19.9 Hz), 29.5, 27.5, 17.7.
Minor Isomer (cis-23). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 4.49 (dd, J = 9.4, 1.8 Hz, 1H), 4.07 (ddd, J = 33.8,
4.4, 2.7 Hz, 1H), 3.80 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 138.4, 128.33, 127.66, 127.57, 102.3, 83.04 (d, J = 168.8 Hz),
75.5, 73.50, 67.6 (d, J = 19.9), 31.0, 21.7.
C5-OBn Pyranoside Bromoethanol Substitution Product
trans-24/cis-24. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 20 (0.050 g,
0.19 mmol), bromoethanol (0.053 mL, 0.75 mmol), and N-
iodosuccinimide (0.084 g, 0.38 mmol) in CH2Cl2 at -78 °C.
GC and 1H NMR spectroscopic analysis of the unpurified
product indicated a pair of diastereomers in a 62:38 (trans:cis)
ratio. Purification by flash chromatography (3:1 hexane/
EtOAc) afforded an inseparable mixture of diastereomers
trans-24/cis-24 as a colorless oil (0.053 g, 85%): GC tR(major)
17.2 min, tR(minor) 17.4 min; IR (thin film) 3029, 2942, 2861,
1454, 1124 cm-1;HRMS(ESI) m/z calcd for C15H21BrO3Na (M þ
Na)þ 351.0572, found 351.0574. Anal. Calcd for C15H21BrO3:
C, 54.72; H, 6.43. Found: C, 54.95; H, 6.59.
Minor Isomer (β-12). 1H NMR (500 MHz, CDCl3) δ
7.26-7.38 (m, 15H), 4.57-5.00 (m, 8H), 4.18 (dd, J = 9.8, 1.2 Hz,
1H), 4.08 (dd, J = 11.0, 1.6 Hz, 1H), 3.99 (m, 1H), 3.46-3.62
(m, 7H), 3.51 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 3.35 (s, 3H), 3.20
(m, 1H), 2.99 (t, J = 9.1 Hz, 1H), 2.13 (dd, J = 12.5, 4.9 Hz, 1H),
1.47 (td, J = 12.2, 9.9 Hz, 1H)
C5-OBn Pyranoside Trifluoroethanol Substitution Product
trans-21/cis-21. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 20 (0.050 g,
0.19 mmol), trifluoroethanol (0.050 mL, 0.75 mmol), and N-
iodosuccinimide (0.084 g, 0.38 mmol) in CH2Cl2 at -78 °C. GC
and 1H NMR spectroscopic analysis of the unpurified product
indicated a pair of diastereomers in a 83:17 (trans:cis) ratio.
Purification by flash chromatography (3:1 hexane/EtOAc)
afforded an inseparable mixture of diastereomers trans-21/cis-
21 as a colorless oil (0.037 g, 65%): GC tR(major) 12.9 min,
tR(minor) 13.2 min; IR (thin film) 3034, 2940, 1445, 1282, 1156
cm-1; HRMS (ESI) m/z calcd for C15H19F3O3Na (M þ Na)þ
327.1184, found 327.1174. Anal. Calcd for C15H19F3O3: C,
59.20; H, 6.29. Found: C, 59.50; H, 6.37.
Major Isomer (trans-21). 1H NMR (500 MHz, CDCl3) δ
7.25-7.37 (m, 5H), 4.96 (d, J = 2.6 Hz, 1H), 4.57 (m, 2H),
3.82-4.05 (m, 3H), 3.45 (m, 2H), 1.86 (m, 1H), 1.78 (m, 1H),
1.55-1.70 (m, 3H), 1.45 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 138.33, 128.4, 127.64, 127.59, 124.3 (q, J = 278.4 Hz), 97.8,
73.4, 73.2, 68.8, 63.7 (q, J = 25.8 Hz), 29.0, 27.19, 17.4.
Minor Isomer (cis-21). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 4.53 (dd, J = 8.8, 2.2 Hz, 1H), 4.14 (dq, J = 12.6,
9.2 Hz, 1H), 3.65 (dddd, J = 10.8, 6.2, 4.5, 2.0 Hz, 1H), 3.57 (dd,
J = 10.1, 6.2 Hz, 1H); 13C NMR (125 MHz, CDCl3, distinctive
peaks) δ 138.30, 128.5, 127.72, 127.69, 124.0 (q, J = 277.9 Hz),
102.1, 75.7, 73.5, 73.1, 65.0 (q, J = 34.7 Hz), 30.6, 27.15, 21.3.
C5-OBn Pyranoside Difluoroethanol Substitution Product
trans-22/cis-22. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 20 (0.050 g,
0.19 mmol), difluoroethanol (0.048 mL, 0.75 mmol), and N-
iodosuccinimide (0.084 g, 0.38 mmol) in CH2Cl2 at -78 °C. GC
and 1H NMR spectroscopic analysis of the unpurified product
indicated a pair of diastereomers in an 74:26 (trans:cis) ratio.
Purification by flash chromatography (5:1 hexane/EtOAc) af-
forded an inseparable mixture of diastereomers trans-22/cis-22
as a colorless oil (0.045 g, 79%): GC tR(major) 14.1 min,
tR(minor) 14.3 min; IR (thin film) 3031, 2943, 2867, 1455,
1075 cm-1; HRMS (ESI) m/z calcd for C15H20F2O3Na (M þ
Na)þ 309.1278, found 309.1281. Anal. Calcd for C15H20F2O3:
C, 62.92; H, 7.04. Found: C, 63.20; H, 7.18.
Major Isomer (trans-24). 1H NMR (500 MHz, CDCl3) δ
7.26-7.35 (m, 5H), 4.93 (d, J = 2.3 Hz, 1H), 4.57 (m, 2H),
4.01 (dddd, J = 12.0, 6.1, 4.0, 2.6 Hz, 1H), 3.98 (m, 1H), 3.81
(m, 1H), 3.41-3.58 (m, 4H), 1.88 (m, 1H), 1.73 (m, 1H),
1.50-1.69 (m, 2H), 1.42 (m, 1H), 1.25 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 138.44, 128.4, 127.71, 127.59, 97.7, 73.5,
73.33, 68.5, 67.3, 31.2, 29.5, 27.5, 17.7.
Minor Isomer (cis-24). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 4.48 (dd, J = 9.5, 2.0 Hz, 1H), 4.14 (ddd, J = 11.3,
7.1, 5.4 Hz, 1H), 3.66 (dddd, J = 10.9, 6.4, 4.8, 2.0 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 138.37, 128.5, 127.67, 127.57, 102.6,
75.6, 73.28, 68.9, 30.9, 30.7, 27.4, 21.7.
C5-OBn Pyranoside Chloroethanol Substitution Product
trans-25/cis-25. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 20 (0.050 g,
0.19 mmol), chloroethanol (0.050 mL, 0.75 mmol), and N-
iodosuccinimide (0.084 g, 0.38 mmol) in CH2Cl2 at -78 °C.
GC and 1H NMR spectroscopic analysis of the unpurified
product indicated a pair of diastereomers in a 65:35 (trans:cis)
ratio. Purification by flash chromatography (3:1 hexane/
EtOAc) afforded an inseparable mixture of diastereomers
trans-25/cis-25 as a colorless oil (0.046 g, 85%): GC tR(major)
16.4 min, tR(minor) 16.6 min; IR (thin film) 3030, 2944, 2864,
1353, 1035 cm-1; HRMS (ESI) m/z calcd for C15H21ClO3Na (M þ
Na)þ 307.1077, found 307.1074. Anal. Calcd for C15H21ClO3: C,
63.26; H, 7.43. Found: C, 63.24; H, 7.53.
Major Isomer (trans-22). 1H NMR (500 MHz, CDCl3) δ
7.25-7.38 (m, 5H), 5.97 (tt, J = 55.8, 8.4 Hz, 1H), 4.91 (d,
J = 2.3 Hz, 1H), 4.57 (s, 2H), 3.95 (m, 1H), 3.84 (tdd, J = 15.8,
12.0, 3.9 Hz, 1H), 3.70 (m, 1H), 3.45 (m, 2H), 1.85 (m, 1H), 1.75
(m, 1H), 1.55-1.70 (m, 2H), 1.43 (m, 1H), 1.25 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 138.35, 128.4, 127.61, 127.58, 114.6
(t, J = 240.7 Hz), 98.3, 73.4, 68.5, 66.5 (t, J = 28.0 Hz), 29.3,
27.3, 17.5.
Minor Isomer (cis-22). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 5.95 (tdd, J = 56.0, 5.4, 3.1 Hz, 1H), 4.47 (dd, J =
9.4, 1.8 Hz, 1H), 3.56 (dd, J= 10.2, 6.1 Hz, 1H); 13CNMR(125MHz,
CDCl3) δ 138.29, 128.5, 127.72, 127.70, 114.7 (t, J = 240.9 Hz),
102.7, 75.6, 73.5, 73.2, 67.8 (dd, J = 29.6, 26.8 Hz), 30.7, 27.2,
21.5.
Major Isomer (trans-25). 1H NMR (500 MHz, CDCl3) δ
7.26-7.36 (m, 5H), 4.93 (d, J = 2.3 Hz, 1H), 4.57 (m, 2H),
4.01 (dddd, J = 12.0, 6.1, 4.5, 2.3 Hz, 1H), 3.94 (ddd, J = 10.9,
6.1, 5.3 Hz, 1H), 3.64-3.80 (m, 3H), 3.45 (m, 2H), 1.88 (m, 1H),
1.74 (m, 1H), 1.50-1.68 (m, 2H), 1.43 (m, 1H), 1.25 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 138.44, 128.4, 127.71, 127.59,
97.8, 73.5, 73.33, 68.4, 67.3, 43.4, 29.5, 27.5, 17.7.
C5-OBn Pyranoside Fluoroethanol Substitution Product trans-
23/cis-23. The standard procedure for nucleophilic substitution
of acetals was followed with thioglycoside 20 (0.050 g, 0.19 mmol),
fluoroethanol (0.044 mL, 0.75 mmol), and N-iodosuccinimide
1
(0.084 g, 0.38 mmol) in CH2Cl2 at -78 °C. GC and H NMR
J. Org. Chem. Vol. 75, No. 4, 2010 1115

Beaver and Woerpel
JOCArticle
Minor Isomer (cis-25). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 4.48 (dd, J = 9.4, 2.1 Hz, 1H), 4.10 (ddd, J = 11.0,
5.9, 5.3 Hz, 1H), 3.56 (dd, J = 10.0, 6.1 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 138.38, 128.5, 127.67, 127.57, 102.6, 75.6,
73.29, 68.9, 43.0, 30.9, 27.4, 21.7.
J = 3.1 Hz, 1H), 4.57 (m, 2H), 3.86 (m, 2H), 3.70 (m, 1H), 3.62
(ddd, J = 12.0, 3.8, 1.6 Hz, 1H), 3.48 (bs, 1H), 2.09 (tt, J = 12.3,
3.6 Hz, 1H), 2.00 (tt, J = 12.2, 3.7 Hz, 1H), 1.75 (m, 1H), 1.58
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 138.50, 128.47, 127.7,
127.6, 114.5 (t, J = 240.7 Hz), 98.7, 71.0, 70.4, 66.8 (t, J =28.0 Hz),
63.1, 25.6, 22.9.
C5-OBn Pyranoside Ethanol Substitution Product trans-26/
cis-26. The standard procedure for nucleophilic substitution of
acetals was followed with thioglycoside 20 (0.050 g, 0.19 mmol),
ethanol (0.043 mL, 0.75 mmol), and N-iodosuccinimide (0.084 g,
Minor Isomer (cis-31). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 4.70 (t, J = 2.7 Hz, 1H), 1.91 (m, 2H), 1.83 (m, 1H);
13C NMR (125 MHz, CDCl3, distinctive peaks) δ 138.46,
128.49, 127.8, 127.7, 97.3, 72.1, 70.6, 66.4 (t, J = 28.6), 28.3,
24.8.
1
0.38 mmol) in CH2Cl2 at -78 °C. GC and H NMR spectro-
scopic analysis of the unpurified product indicated a pair of
diastereomers in a 49:51 (trans:cis) ratio. Purification by flash
chromatography (3:1 hexane/EtOAc) afforded an inseparable
mixture of diastereomers trans-26/cis-26 as a colorless oil (0.038 g,
C4-OBn Pyranoside Fluoroethanol Substitution Product trans-
32/cis-32. The standard procedure for nucleophilic substitution
of acetals was followed with thioglycoside 29 (0.10 g, 0.40 mmol),
fluoroethanol (0.044 mL, 0.16 mmol), and N-iodosuccinimide
(0.18 g, 0.79 mmol) in CH2Cl2 at -78 °C. 1H NMR spectroscopic
analysis of the unpurified product indicated a pair of diastereomers
in a 71:29 (trans:cis) ratio. Purification by flash chromatography
(5:1 hexane/EtOAc) afforded an inseparable mixture of diastereo-
mers trans-32/cis-32 as a colorless oil (0.072 g, 72%): GC tR(major
and minor) 14.4 min; IR (thin film) 3031, 2952, 2970, 1454,
1041 cm-1; HRMS (ESI) m/z calcd for C14H19FO3Na (M þ Na)þ
277.1216, found 277.1217. Anal. Calcd for C14H19FO3: C, 66.12; H,
7.53. Found: C, 66.31; H, 7.59.
1
81%): GC tR(major) 13.8 min, tR(minor) 14.1 min; H NMR
(500 MHz, CDCl3, mixture of anomers) δ 7.25-7.36 (10H), 4.88
(s, 1H), 4.57 (m, 4H), 4.43 (dd, J = 9.4, 2.1 Hz, 1H), 3.97 (m, 2H),
3.76 (ddd, J = 14.3, 9.8, 7.3 Hz, 1H), 3.66 (m, 1H), 3.41-3.60 (m,
6H), 1.86 (m, 2H), 1.78 (m, 1H), 1.48-1.69 (m, 7H), 1.41 (m, 2H),
1.23 (m, 6H); 13C NMR (125 MHz, CDCl3, mixture of anomers)
δ 138.53, 138.49, 128.41, 128.37, 127.7, 127.6, 127.5, 102.0, 97.0,
75.5, 73.7, 73.51, 73.46, 73.3, 67.9, 64.2, 62.2, 31.3, 29.8, 27.7, 27.6,
21.9, 17.8, 15.3, 15.2; IR (thin film) 3029, 2933, 2870, 1450, 1111
cm-1; HRMS (ESI) m/z calcd for C15H22O3Na (M þNa)þ
273.1467, found 273.1465. Anal. Calcd for C15H22O3: C, 71.97;
H, 8.86. Found: C, 72.22; H, 9.00.
C4-OBn Pyranoside Trifluoroethanol Substitution Product
trans-30/cis-30. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 29 (0.050 g,
0.20 mmol), trifluoroethanol (0.057 mL, 0.80 mmol), and N-
iodosuccinimide (0.089 g, 0.40 mmol) in CH2Cl2 at -78 °C. 1H
NMR spectroscopic analysis of the unpurified product indi-
cated a pair of diastereomers in an 88:12 (trans:cis) ratio.
Purification by flash chromatography (3:1 hexane/EtOAc)
afforded a inseparable mixture of diastereomers trans-30/cis-
30 as a colorless oil (0.046 g, 81%): GC tR(major and minor) 12.6
min; IR (thin film) 3033, 2928, 1445, 1282, 1156 cm-1; HRMS
(ESI) m/z calcd for C14H17F3O3Na (M þ Na)þ 313.1028, found
313.1031. Anal. Calcd for C14H17F3O3: C, 57.93; H, 5.90.
Found: C, 58.19; H, 6.02.
Major Isomer (trans-32). 1H NMR (500 MHz, CDCl3) δ
7.25-7.37 (m, 5H), 4.75 (t, J = 3.1 Hz, 1H), 4.51-4.64 (m, 4H),
3.90 (dd, J = 11.7, 2.4 Hz, 1H), 3.62-3.77 (m, 2H), 3.59 (ddd,
J = 12.0, 4.3, 1.5 Hz, 1H), 3.48 (bs, 1H), 2.06 (m, 1H), 1.91
(m, 1H), 1.73 (m, 1H), 1.58 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 138.59, 128.45, 127.6, 98.4, 83.0 (d, J = 169.2 Hz),
71.3, 70.4, 66.7 (d, J = 19.9 Hz), 63.2, 26.1, 23.4.
Minor Isomer (cis-32). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 4.71 (t, J = 3.2 Hz, 1H), 3.97 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 138.56, 128.47, 127.7, 96.9, 82.9 (d, J =
169.2 Hz), 72.3, 70.5, 66.2 (d, J = 19.9 Hz), 62.9, 28.5, 24.9.
C4-OBn Pyranoside Bromoethanol Substitution Product
trans-33/cis-33. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 29 (0.10 g,
0.40 mmol), bromoethanol (0.11 mL, 1.6 mmol), and N-iodo-
succinimide (0.18 g, 0.80 mmol) in CH2Cl2 at -78 °C. GC and
1H NMR spectroscopic analysis of the unpurified product
indicated a pair of diastereomers in n 61:39 (trans:cis) ratio.
Purification by flash chromatography (5:1 hexane/EtOAc) af-
forded an inseparable mixture of diastereomers trans-33/cis-33
as a colorless oil (0.10 g, 83%): GC tR(major) 17.1 min, tR-
Major Isomer (trans-30). 1H NMR (500 MHz, CDCl3) δ
7.26-7.37 (m, 5H), 4.83 (t, J = 2.9 Hz, 1H), 4.57 (m, 2H),
4.00 (dq, J = 12.2, 8.9 Hz, 1H), 3.88 (dq, J = 12.2, 8.6 Hz, 1H),
3.84 (dd, J = 12.0, 2.2 Hz, 1H), 3.66 (dt, J = 12.4, 2.5 Hz, 1H),
3.49 (bs, 1H), 2.12 (tt, J = 12.6, 3.8 Hz, 1H), 2.00 (tt, J = 12.7,
3.7 Hz, 1H), 1.79 (m, 1H), 1.62 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 138.5, 128.5, 127.7, 127.6, 125.1 (q, J = 278.3 Hz),
98.1, 70.8, 70.4, 64.3 (q, J = 25.9 Hz), 62.8, 25.0, 22.3.
(minor) 17.2 min; IR (thin film) 3030, 2935, 2868, 1456, 1027 cm-1
;
HRMS (ESI) m/z calcd for C14H19BrO3Na (M þ Na)þ
337.0415, found 337.0415. Anal. Calcd for C14H19BrO3: C,
53.35; H, 6.08. Found: C, 53.45; H, 6.11.
Minor Isomer (cis-30). 1H NMR (500 MHz, CDCl3, distinctive
peaks) δ 4.76 (s, 1H), 3.71 (dd, J = 10.5, 4.4 Hz, 1H), 3.58 (t, J =
10.2 Hz, 1H); 13C NMR (125 MHz, CDCl3, distinctive peaks) δ
138.4, 96.9, 72.0, 70.6, 64.0 (q, J = 34.5 Hz), 63.1, 28.2, 24.6.
C4-OBn Pyranoside Difluoroethanol Substitution Product
trans-31/cis-31. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 29 (0.050 g,
0.20 mmol), difluoroethanol (0.050 mL, 0.80 mmol), and N-
iodosuccinimide (0.089 g, 0.40 mmol) in CH2Cl2 at -78 °C. 1H
NMR spectroscopic analysis of the unpurified product indi-
cated a pair of diastereomers in a 82:18 (trans:cis) ratio. Pur-
ification by flash chromatography (3:1 pentane/Et2O) afforded
an inseparable mixture of diastereomers trans-31/cis-31 as a
colorless oil (0.037 g, 68%): GC tR(major and minor) 13.7 min;
IR (thin film) 3029, 2935, 2867, 1062 cm-1; HRMS (ESI) m/z
calcd for C14H18F2O3Na (M þ Na)þ 295.1122, found 295.1126.
Anal. Calcd for C14H18F2O3: C, 61.75; H, 6.66. Found: C, 62.04;
H, 6.76.
Major Isomer (trans-33). 1H NMR (500 MHz, CDCl3) δ 7.25
(m, 5H), 4.75 (t, J = 3.1 Hz, 1H), 4.57 (m, 2H), 3.99 (m, 1H),
3.93 (dd, J = 12.0, 2.3 Hz, 1H), 3.79 (m, 1H), 3.60 (ddd, J =
11.9, 4.0, 1.7 Hz, 1H), 3.50 (m, 3H), 2.06 (m, 1H), 1.91 (m, 1H),
1.75 (m, 1H), 1.57 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
138.6, 128.4, 127.653, 127.646, 98.4, 71.2, 70.4, 67.7, 63.4, 31.0,
26.0, 23.4.
Minor Isomer (cis-33). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 4.71 (t, J = 2.6 Hz, 1H), 4.57 (m, 2H), 3.74 (m, 1H),
3.66 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 138.5, 128.5,
127.7, 97.0, 72.2, 70.6, 67.3, 63.2, 30.7, 28.5, 24.9.
C4-OBn Pyranoside Chloroethanol Substitution Product
trans-34/cis-34. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 29 (0.10 g,
0.40 mmol), chloroethanol (0.11 mL, 1.6 mmol), and N-iodo-
succinimide (0.18 g, 0.80 mmol) in CH2Cl2 at -78 °C. 1H NMR
spectroscopic analysis of the unpurified product indicated a pair
of diastereomers in a 67:33 (trans:cis) ratio. Purification by flash
chromatography (5:1 hexane/EtOAc) afforded an inseparable
Major Isomer (trans-31). 1H NMR (500 MHz, CDCl3) δ
7.26-7.37 (m, 5H), 5.91 (tt, J = 55.7, 4.1 Hz, 1H), 4.75 (t,
1116 J. Org. Chem. Vol. 75, No. 4, 2010

Beaver and Woerpel
JOCArticle
mixture of diastereomers trans-34/cis-34 as a colorless oil (0.085 g,
79%): GC tR(major) 16.2 min, tR(minor) 16.3 min; IR (thin film)
3031, 2937, 2869, 1454, 1038 cm-1; HRMS (ESI) m/z calcd for
C14H19ClO3Na (M þ Na)þ 293.0920, found 293.0925. Anal.
CalcdforC14H19ClO3: C, 62.10; H, 7.07. Found: C, 61.86; H, 7.08.
Major Isomer (trans-34). 1H NMR (500 MHz, CDCl3) δ
7.25-7.37 (m, 5H), 4.75 (t, J = 3.1 Hz, 1H), 4.57 (m, 2H),
3.95 (m, 1H), 3.92 (m, 1H), 3.73 (m, 1H), 3.67 (m, 2H), 3.59
(ddd, J = 11.9, 4.0, 1.6 Hz, 1H), 3.48 (bs, 1H), 2.06 (m, 1H), 1.91
(m, 1H), 1.75 (m, 1H), 1.57 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 138.6, 128.45, 127.653, 127.646, 98.5, 71.2, 70.4, 67.9,
63.4, 43.2, 26.0, 23.4.
of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol),
difluoroethanol (0.030 mL, 0.48 mmol), 2,6-di-tert-butyl-4-
methylpyridine (0.054 g, 0.24 mmol), and N-iodosuccinimide
(0.049 g, 0.24 mmol) in CH3CN at 0 °C. GC and 1H NMR
spectroscopic analysis of the unpurified product indicated a pair of
diastereomers in a 84:16 (cis:trans) ratio. Purification by flash
chromatography (3:1 pentane/Et2O) afforded a separable mixture
of diastereomers cis-43/trans-43 as a colorless oil (0.022 g, 68%).
IR, mass spectrometry, and combustion analysis data was
obtained for major isomer (cis-43) and minor isomer (trans-43) as
a mixture of diastereomers: GC tR(major) 13.7 min, tR(minor)
13.3 min; IR (thin film) 3029, 2931, 2851, 1359, 1072 cm-1; HRMS
(ESI) m/z calcd for C14H18F2O3Na (M þ Na)þ 295.1122, found
295.1120.
Minor Isomer (cis-34). 1H NMR (500 MHz, CDCl3, distinc-
tive peaks) δ 4.71 (t, J = 2.6 Hz, 1H), 4.57 (m, 2H), 3.49 (m, 1H),
1.85 (m, 1H), 1.67 (m, 1H); 13C NMR (125 MHz, CDCl3,) δ
138.5, 128.48, 127.7, 97.0, 72.2, 70.6, 67.4, 63.1, 43.0, 28.5, 24.9.
C4-OBn Pyranoside Ethanol Substitution Product trans-35/
cis-35. The standard procedure for nucleophilic substitution of
acetals was followed with thioglycoside 29 (0.050 g, 0.20 mmol),
ethanol (0.046 mL, 0.80 mmol), and N-iodosuccinimide (0.089 g,
Major Isomer (cis-43). 1H NMR (500 MHz, CDCl3) δ
7.24-7.37 (m, 5H), 5.93 (tdd, J = 55.7, 5.4, 3.1 Hz, 1H), 4.58
(m, 2H), 4.47 (dd, J = 8.2, 2.6 Hz, 1H), 4.08 (dt, J = 12.4,
4.1 Hz, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.61 (tt, J = 9.4, 4.3 Hz,
1H), 3.38 (ddd, J = 12.0, 10.9, 2.7 Hz, 1H), 2.24 (ddt, J = 12.7,
4.2, 2.1 Hz, 1H), 1.94 (m, 1H), 1.62 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 138.4, 128.5, 127.7, 127.6, 114.5 (t, J = 240.9 Hz),
100.5, 72.3, 69.8, 67.7 (t, J = 28.5 Hz), 61.1, 36.9, 31.4.
Minor Isomer (trans-43). 1H NMR (500 MHz, CDCl3) δ
7.24-7.36 (m, 5H), 5.90 (tdd, J = 55.6, 4.6, 3.7 Hz, 1H), 4.96
(t, J = 3.2 Hz, 1H), 4.55 (m, 2H), 3.88 (tt, J = 9.2, 4.2 Hz, 1H),
3.82 (m, 1H), 3.76 (m, 2H), 3.66 (m, 1H), 2.14 (dddd, J = 13.0,
4.5, 2.8, 2.0 Hz, 1H), 1.98 (m, 1H), 1.71 (ddd, J = 13.3, 10.0, 3.4
Hz, 1H), 1.64 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 138.8,
128.7, 127.81, 127.76, 114.6 (t, J = 241.0 Hz), 99.2, 70.8, 70.2,
66.8 (t, J = 28.0 Hz), 59.5, 36.7, 32.0.
C3-OBn Pyranoside Fluoroethanol Substitution Product cis-
44/trans-44. The standard procedure for nucleophilic substitution
of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol),
fluoroethanol (0.028 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methyl-
pyridine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g,
0.24 mmol) in CH3CN at 0 °C. GC and 1H NMR spectroscopic
analysis of the unpurified product indicated a pair of diastereomers
in a 74:26 (cis:trans) ratio. Purification by flash chromatography
(3:1 pentane/Et2O) afforded a separable mixture of diastereomers
cis-44/trans-44 as a colorless oil (0.019 g, 63%). IR, mass spectro-
metry, and combustion analysis data was obtained for major
isomer (cis-44) and minor isomer (trans-44) as a mixture of
diastereomers: GC tR(major) 14.3 min, tR(minor) 14.0 min; IR
(thin film) 3028, 2959, 2864, 1359, 1058 cm-1; HRMS (ESI) m/z
calcd for C14H19FO3Na (M þ Na)þ 277.1216, found 277.1215.
Major Isomer (cis-44). 1H NMR (500 MHz, CDCl3) δ
7.23-7.38 (m, 5H), 4.50-4.69 (m, 4H), 4.45 (dd, J = 8.7, 2.4 Hz,
1H), 4.07 (m, 1H), 3.71-3.85 (m, 2H), 3.60 (tt, J = 9.9, 4.3 Hz,
1H), 3.37 (td, J = 11.7, 2.5 Hz, 1H), 2.29 (ddt, J = 12.4, 4.2,
2.1 Hz, 1H), 1.94 (m, 1H), 1.60 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 138.5, 128.5, 127.7, 127.6, 100.4, 83.0 (d, J = 169.2 Hz),
72.8, 69.8, 67.7 (d, J = 19.4 Hz), 61.5, 37.4, 31.7.
1
0.40 mmol) in CH2Cl2 at -78 °C. GC and H NMR spectro-
scopic analysis of the unpurified product indicated a pair of
diastereomers in a 51:49 (trans:cis) ratio. Purification by flash
chromatography (3:1 hexane/EtOAc) afforded an inseparable
mixture of diastereomers trans-35/cis-35 as a colorless oil (0.033 g,
1
70%): GC tR(major) 13.5 min, tR(minor) 13.6 min; H NMR
(500 MHz, CDCl3, mixture of anomers) δ 7.25-7.37 (m, 10H),
4.66 (bs, 2H), 4.57 (m, 4H), 3.91 (dd, J = 11.7, 2.4 Hz, 1H),
3.71-3.83 (m, 2H), 3.65 (m, 2H), 3.40-3.56 (m, 5H), 2.04 (m,
2H), 1.80-1.94 (m, 3H), 1.67 (m, 2H), 1.58 (m, 1H), 1.22 (m, 6H);
13C NMR (125 MHz, CDCl3, mixture of anomers) δ 138.64,
138.63, 128.45, 128.44, 127.66, 127.65, 127.64, 127.63, 98.4, 96.4,
72.4, 71.6, 70.50, 70.47, 63.8, 63.3, 62.9, 62.6, 28.8, 26.9, 25.1, 24.2,
15.3, 15.2; IR (thin film) 3030, 2934, 2872, 1364, 1090 cm-1
;
HRMS (ESI) m/z calcd for C14H20O3Na (M þ Na)þ 259.1310,
found 259.1311. Anal. Calcd for C14H20O3: C, 71.16; H, 8.53.
Found: C, 71.35; H, 8.47.
C3-OBn Pyranoside Trifluoroethanol Substitution Product
cis-39/trans-39. The standard procedure for nucleophilic sub-
stitution of acetals was followed with thioglycoside 38 (0.030 g,
0.12 mmol), trifluoroethanol (0.034 mL, 0.48 mmol), 2,6-di-tert-
butyl-4-methylpyridine (0.049 g, 0.24 mmol), and N-iodosucci-
1
nimide (0.054 g, 0.24 mmol) in CH3CN at 0 °C. GC and H
NMR spectroscopic analysis of the unpurified product indi-
cated a pair of diastereomers in an 86:14 (cis:trans) ratio.
Purification by flash chromatography (3:1 pentane/Et2O) af-
forded a separable mixture of diastereomers cis-39/trans-39 as a
colorless oil (0.024 g, 69%). IR, mass spectrometry, and com-
bustion analysis data was obtained for major isomer (cis-39) and
minor isomer (trans-39) as a mixture of diastereomers: GC
tR(major) 12.5 min, tR(minor) 12.1 min; IR (thin film) 3029.8,
2954, 2861, 1280, 1162 cm-1; HRMS (ESI) m/z calcd for
C14H17F3O3Na (M þ Na)þ 313.1028, found 313.1027.
Minor Isomer (trans-44). 1H NMR (500 MHz, CDCl3) δ
7.21-7.40 (m, 5H), 4.96 (t, J = 3.1 Hz, 1H), 4.56 (dt, J =
47.6, 4.3 Hz, 2H), 4.55 (m, 2H), 3.92 (m, 2H), 3.85 (m, 1H), 3.72
(m, 2H), 2.16 (ddd, J = 13.1, 4.6, 2.2 Hz, 1H), 1.99 (m, 1H),
1.56-1.75 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 138.7, 128.5,
127.7, 127.6, 98.5, 82.9 (d, J = 169.2 Hz), 70.9, 70.0, 66.4 (d, J =
19.9 Hz), 59.1, 36.7, 32.0.
C3-OBn Pyranoside Bromoethanol Substitution Product cis-
45/trans-45. The standard procedure for nucleophilic substitution
of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol),
bromoethanol (0.033 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methyl-
pyridine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g,
0.24 mmol) in CH3CN at 0 °C. GC and 1H NMR spectroscopic
analysis of the unpurified product indicated a pair of diastereomers
in a 60:40 (cis:trans) ratio. Purification by flash chromatography
(3:1 pentane/Et2O) afforded a separable mixture of diastereomers
Major Isomer (cis-39). 1H NMR (500 MHz, CDCl3) δ
7.26-7.38 (m, 5H), 4.58 (m, 2H), 4.56 (dd, J = 7.5, 2.2 Hz,
1H), 4.10 (m, 2H), 3.92 (m, 1H), 3.64 (tt, J = 8.9, 4.2 Hz, 1H),
3.40 (ddd, J = 12.2, 9.9, 2.8 Hz, 1H), 2.23 (m, 1H), 1.94 (m, 1H),
1.61-1.73 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 138.4, 128.5,
127.7, 127.6, 124.0 (q, J = 278.4 Hz), 99.9, 71.9, 69.9, 65.0 (q,
J = 25.9 Hz), 60.8, 36.3, 31.3.
Minor Isomer (trans-39). 1H NMR (500 MHz, CDCl3) δ
7.22-7.39 (m, 5H), 5.01 (t, J = 2.8 Hz, 1H), 4.55 (m, 2H),
3.80-4.00 (m, 3H), 3.76 (m, 2H), 2.19 (ddt, J = 13.1, 4.5, 2.3 Hz,
1H), 2.0 (d, J = 12.2 Hz, 1H), 1.69 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 138.5, 128.5, 127.7, 127.6, 124.0 (q, J = 278.4
Hz), 98.8, 70.4, 70.1, 64.1 (q, J = 34.2 Hz), 59.4, 36.3, 31.9.
C3-OBn Pyranoside Difluoroethanol Substitution Product cis-
43/trans-43. The standard procedure for nucleophilic substitution
J. Org. Chem. Vol. 75, No. 4, 2010 1117

Beaver and Woerpel
JOCArticle
cis-45/trans-45 as a colorless oil (0.017 g, 46%). IR, mass spectro-
metry, and combustion analysis data was obtained for major
isomer (cis-45) and minor isomer (trans-45) as a mixture of
diastereomers: GC tR(major) 17.1 min, tR(minor) 16.8 min; IR
(thin film) 3030, 2930, 2858, 1362, 1097 cm-1; HRMS (ESI) m/z
calcd for C14H19BrO3Na (M þ Na)þ 337.0415, found 337.0410.
Major Isomer (cis-45). 1H NMR (500 MHz, CDCl3) δ
7.22-7.40 (m, 5H), 4.55 (m, 2H), 4.44 (dd, J = 8.6, 2.4 Hz,
1H), 4.06 (m, 1H), 3.82 (m, 1H), 3.75 (m, 1H), 3.59 (tt, J = 9.6,
4.3 Hz, 1H), 3.51 (m, 2H), 3.36 (td, J = 11.6, 2.6 Hz, 1H), 2.25
(ddt, J = 12.5, 4.2, 2.0 Hz, 1H), 1.92 (m, 1H), 1.58-1.72
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 138.5, 128.5, 127.6,
127.6, 100.5, 72.7, 69.8, 68.9, 61.4, 37.3, 31.6, 30.6.
(m, 3H), 2.13 (m, 1H), 1.97 (m, 1H), 1.71 (ddd, J = 13.2,
10.2, 3.5 Hz, 1H), 1.59 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
138.7, 128.5, 127.7, 127.6, 98.6, 70.9, 70.0, 67.6, 59.3, 43.1, 37.7,
31.9.
C3-OBn Pyranoside Ethanol Substitution Product cis-40/
trans-40. The standard procedure for nucleophilic substitution
of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol),
ethanol (0.028 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methylpyri-
dine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g,
0.24 mmol) in CH3CN at 0 °C. GC and 1H NMR spectroscopic
analysis of the unpurified product indicated a pair of diastereo-
mers in a 52:48 (cis:trans) ratio. Purification by flash chromatog-
raphy (3:1 pentane/Et2O) afforded a separable mixture of
diastereomers cis-40/trans-40 as a colorless oil (0.027 g, 89%).
IR, mass spectrometry, and combustion analysis data was ob-
tained for major isomer (cis-40) and minor isomer (trans-40) as a
mixture of diastereomers: GC tR(major) 13.6 min, tR(minor)
Minor Isomer (trans-45). 1H NMR (500 MHz, CDCl3) δ
7.22-7.40 (m, 5H), 4.97 (t, J = 3.1 Hz, 1H), 4.55 (m, 2H),
4.07 (m, 1H), 3.96 (m, 1H), 3.90 (tt, J = 9.4, 4.2 Hz, 1H), 3.82
(td, J= 11.2, 3.2 Hz, 1H), 3.74 (m, 1H), 3.49 (m, 2H), 2.12 (m, 1H),
1.98 (m, 1H), 1.70 (ddd, J = 13.0, 9.7, 3.1 Hz, 1H), 1.64 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 138.7, 128.5, 127.7, 127.6, 98.5,
70.9, 70.0, 67.5, 59.3, 36.7, 31.9, 30.8.
C3-OBn Pyranoside Chloroethanol Substitution Product cis-
46/trans-46. The standard procedure for nucleophilic substitution
of acetals was followed with thioglycoside 38 (0.030 g, 0.12 mmol),
chloroethanol (0.032 mL, 0.48 mmol), 2,6-di-tert-butyl-4-methyl-
pyridine (0.049 g, 0.24 mmol), and N-iodosuccinimide (0.054 g,
0.24 mmol) in CH3CN at 0 °C. GC and 1H NMR spectroscopic
analysis of the unpurified product indicated a pair of diastereomers
in a 75:25 (cis:trans) ratio. Purification by flash chromatography
(3:1 pentane/Et2O) afforded a separable mixture of diastereomers
cis-46/trans-46 as a colorless oil (0.021 g, 64%). IR, mass spectro-
metry, and combustion analysis data was obtained for major
isomer (cis-46) and minor isomer (trans-46) as a mixture of
diastereomers: GC tR(major) 16.2 min, tR(minor) 15.9 min; IR
(thin film) 3030, 2929, 2856, 1454, 1065 cm-1; HRMS (ESI)
m/z calcd for C14H19ClO3Na (M þ Na)þ 293.0920, found
293.0919.
1
13.2 min; H NMR (500 MHz, CDCl3, mixture of anomers) δ
7.25-7.37 (m, 10H), 4.92 (t, J = 3.2 Hz, 1H), 4.56 (m, 4H), 4.35
(dd, J = 9.0, 2.3 Hz, 1H), 4.05 (ddd, J = 12.1, 4.7, 2.6 Hz, 1H),
3.90 (m, 2H), 3.70-3.80 (m, 3H), 3.57 (ddd, J = 14.8, 9.8, 4.4 Hz,
1H), 3.52 (dq, J = 9.4, 7.0 Hz, 1H), 3.44 (dq, J = 9.9, 7.1 Hz, 1H),
3.35 (td, J = 11.9, 2.4 Hz, 1H), 2.24 (ddt, J = 12.2, 4.0, 2.0 Hz,
1H), 2.07 (m, 1H), 1.89-1.98 (m, 2H), 1.71 (ddd, J = 13.1, 9.8,
3.3 Hz, 1H), 1.61 (m, 2H), 1.53 (m, 1H), 1.22 (m, 6H); 13C NMR
(125 MHz, CDCl3, mixture of anomers) δ 138.8, 138.5, 128.5,
128.4, 127.66, 127.65, 127.59, 127.56, 100.2, 97.9, 73.2, 71.2, 70.0,
69.7, 64.4, 62.9, 61.7, 59.0, 38.0, 37.0, 32.0, 31.9, 15.3, 15.2; IR
(thin film) 3030, 2930, 2871, 1361, 1070 cm-1; HRMS (ESI) m/z
calcd for C14H20O3Na (M þ Na)þ 259.1310, found 259.1317.
Acknowledgment. This research was supported by the
National Institutes of Health, National Institute of General
Medical Science (GM-61066). M.G.B. thanks Eli Lilly for a
graduate fellowship. K.A.W. thanks Amgen and Eli Lilly for
generous support for research. We thank Dr. John Greaves
and Ms. Shirin Sorooshian (UCI) for mass spectrometric
data and Dr. Phil Dennison (UCI) for assistance with NMR
spectroscopy.
Major Isomer (cis-46). 1H NMR (500 MHz, CDCl3) δ
7.24-7.38 (m, 5H), 4.58 (m, 2H), 4.45 (dd, J = 8.4, 2.4 Hz,
1H), 4.07 (m, 2H), 3.75 (m, 1H), 3.67 (m, 2H), 3.60 (tt, J = 9.8,
4.4 Hz, 1H), 3.37 (td, J = 11.6, 2.6 Hz, 1H), 2.26 (ddt, J = 12.5,
4.2, 2.0 Hz, 1H), 1.93 (m, 1H), 1.60 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 138.5, 128.5, 127.7, 127.6, 100.5, 72.7, 69.8, 69.0, 61.4,
43.0, 37.3, 31.6.
Supporting Information Available: Complete experimental
procedures, product characterization, stereochemical proofs,
details of control experiments, and GC and spectral data for
selected compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Minor Isomer (trans-46). 1H NMR (500 MHz, CDCl3) δ
7.23-7.38 (m, 5H), 4.96 (t, J = 3.1 Hz, 1H), 4.57 (m, 2H),
3.90 (m, 2H), 3.81 (td, J = 11.1, 2.8 Hz 1H), 3.74 (m, 1H), 3.66
1118 J. Org. Chem. Vol. 75, No. 4, 2010