Mechanistic studies on the stereoselective formation of β-mannosides from mannosyl iodides using α-deuterium kinetic isotope effects

Article abstract of DOI:10.1021/jo070229y

(Chemical Equation Presented) Stereoselective synthesis of β-mannosides is one of the most challenging linkages to achieve in carbohydrate chemistry. Both the anomeric effect and the C2 axial substituent favor the formation of the axial glycoside (α-produ

Full text of DOI:10.1021/jo070229y

Mechanistic Studies on the Stereoselective Formation of
â-Mannosides from Mannosyl Iodides Using r-Deuterium Kinetic
Isotope Effects
Mohamed H. El-Badri, Dan Willenbring, Dean J. Tantillo,* and Jacquelyn Gervay-Hague*
UniVersity of California, DaVis, Department of Chemistry, One Shields AVenue, DaVis, California 95616
gerVay@chem.ucdaVis.edu; tantillo@chem.ucdaVis.edu
ReceiVed February 2, 2007
Stereoselective synthesis of â-mannosides is one of the most challenging linkages to achieve in
carbohydrate chemistry. Both the anomeric effect and the C2 axial substituent favor the formation of the
axial glycoside (R-product). Herein, we describe mechanistic studies on the â-selective glycosidation of
trimethylene oxide (TMO) using mannosyl iodides. Density functional calculations (at the B3LYP/6-
31+G(d,p):LANL2DZ level) suggest that formation of both R- and â-mannosides involve loose SN2-
like transition-state structures with significant oxacarbenium character, although the transition structure
for formation of the R-mannoside is significantly looser. R-Deuterium kinetic isotope effects (R-DKIEs)
based upon these computed transition state geometries match reasonably well with the experimentally
measured values: 1.16 ( 0.02 for the â-linkage (computed to be 1.15) and 1.19 ( 0.05, see table 2 for
the R-analogue (computed to be 1.26). Since it was unclear if â-selectivity resulted from a conformational
constraint induced by the anomeric iodide, a 4,6-O-benzylidine acetal was used to lock the iodide into
a chairlike conformation. Both experiments and calculations on this analogue suggest that it does not
mirror the behavior of mannosyl iodides lacking bridging acetal protecting groups.
Introduction
Typically, a suitably protected electrophilic mannose analogue
possessing a leaving group at the anomeric center serves as a
glycosyl donor and reacts with a nucleophilic oxygen of an
acceptor. There remains a need for more effective, easily
prepared mannosyl donors that allow for the formation of
â-mannosides in high yields and good stereoselectivity with a
variety of acceptors. Our efforts in this direction have focused
on the use of glycosyl iodides.17-21 Our previous observation
that THF, but not diethyl ether, acts as a capable acceptor
â-Mannosides are major constituents in many biologically
important structures,1-5 and numerous efforts have focused on
synthesizing mannoside linkages with high â-selectivity.6-16
(1) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-173.
(2) Lam, S. N.; Gervay-Hague, J. J. Org. Chem. 2005, 70, 8772 -8779.
(3) Crich, D.; Banerjee, A.; Yao, Q. J. Am. Chem. Soc. 2004, 126,
14930-14934.
(4) Joshi, H.; Kapoor, V. P. Carbohydr. Res. 2003, 338, 1907-1912.
(5) Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1 2000,
1471-1791.
(6) Paulsen, H.; Lokhoff, O. Chem. Ber. 1981, 114, 3102-3114.
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1126.
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1086-1087.
(12) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
(13) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(14) Hodosi, G.; Kovac, P. J. Am. Chem. Soc. 1997, 119, 2335-2336.
(15) Kim, W.-S.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995, 60, 4-5.
(16) Toshima, K.; Kasumi, K.-I.; Matsumura, S. Synlett 1998, 643-645.
(17) Lam, S. N.; Gervay-Hague, J. Org. Lett. 2002, 4, 2039-2042.
(8) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9376-9377.
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10.1021/jo070229y CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/01/2007
J. Org. Chem. 2007, 72, 4663-4672
4663

El-Badri et al.
SCHEME 3. Synthesis of 1-Deuteromannose Diol
SCHEME 1. Mannosylation Reaction of Iodide 1 with
TMO under Neutral Conditions
SCHEME 2. Synthesis and Glycosylation Reaction of
6-O-PNB Mannosyl Iodide
mannoside 5 in 76% yield. Deprotection of the silyl protecting
group using tetrabutylammonium fluoride delivered 6 in quan-
titative yield,29 and subsequent p-nitrobenzylation of 630 fol-
lowed by acetylation at the anomeric center31 afforded mannosyl
acetate 8 in 64% yield over two steps.
We were now set to explore the effects of switching the O-6-
acetyl group for an O-6-PNB group on the TMO reaction.
Generation of the corresponding mannosyl iodide from 8
followed by reaction with TMO yielded mannosides 9 (86%
over two steps; Scheme 2). Upon characterization of the
anomeric ratio for these compounds, we found that the mannosyl
iodide bearing an O-6-PNB group displayed the same reactivity
and stereoselectivity observed for the O-6-acetyl analog, Scheme
1, indicating that participation of the C-6 acetate is not a
competing factor in these reactions.
Previously,25 we suggested that the â-mannoside arises from
nucleophilic displacement of the R-iodide in an SN2-like fashion,
while the R-mannoside results from either attack on an oxac-
arbenium intermediate or from direct displacement of the
â-glycosyl iodide generated from in situ anomerization,
Figure 1.32 We now describe additional experiments and
quantum chemical calculations aimed at testing the validity of
these hypotheses.
inspired us to investigate the reactivity of a variety of cyclic
ethers with glycosyl iodides.22 Preliminary studies in this area
showed that reactions with strained cyclic oxa- and thioethers
proceeded under neutral conditions yielding the corresponding
glycosides in excellent yields and with high â-selectivity.22
Of the acceptors explored so far, we are particularly interested
in trimethylene oxide (TMO) because of its potential versatility
in natural product synthesis.23,24 A representative reaction using
TMO is shown in Scheme 1. Mannosyl iodide 1, possesses an
acetate group at the O-6 position, which attenuates the reactivity
of the iodide giving greater stereocontrol.22 The reaction of TMO
with 1 produces mannosides 2 with 4:1 â-selectivity at room
temperature,22 and up to 10:1 â-selectivity at lower tempera-
tures.25 With the ultimate goal of increasing this selectivity, we
set out to examine the mechanism for this reaction.
To rule out the possibility that the acyl group at C6 is
participating in these substitution reactions,26,27 we replaced this
acetyl group with a p-nitrobenzyl (PNB) group, a “disarming”
functionality that lacks the ability to directly interact with the
anomeric carbon. The synthesis of this analogue (8) is shown
in Scheme 2. Selective protection of the O-6 hydroxyl group in
mannoside 3 was accomplished using tert-butyldimethylsilyl
chloride in dimethylformamide to afford compound 4 in 82%
yield.28 Benzylation of 4 yielded the fully protected methyl
Results and Discussion
First, we undertook the experimental determination of the
R-deuterium kinetic isotope effects (R-DKIEs, kH/kD) for the
transformation described in Scheme 1. Our approach was based
on studies previously described by Crich and co-workers of
â-mannoside formation using labeled mannosyl triflates.33
Crich’s experiment, along with other previous work, suggested
that very small R-DKIEs (kH/kD ∼ 1.0-1.1) are consistent with
SN2-like processes with relatively tight transition state structures,
while larger R-DKIEs (kH/kD ∼ 1.1-1.4) are consistent with
rate-determining transition state structures with significant
oxacarbenium ion character (i.e., SN1 or SN2 processes with
loose transition-state structures).34,35 Our synthesis of compound
(18) Lam, S. N.; Gervay-Hague, J. Carbohydr. Res. 2002, 337, 1953-
1965.
(19) Bhat, A. S.; Gervay-Hague, J. Org. Lett. 2001, 3, 2081-2084.
(20) Gervay, J. Org. Synth: Theory Appl. 1998, 4, 121-153.
(21) Hadd, M. J.; Gervay, J. Carbohydr. Res. 1999, 320, 61-69.
(22) Dabideen, D. R.; Gervay-Hague, J. Org. Lett. 2004, 6, 973-975.
(23) Proemmela, S.; Wartchowb, R.; Hoffmann, H. M. R. Tetrahedron
2002, 58, 6199-6206.
(29) Corey, E. J.; Venkateswalu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(30) Izumi, M.; Fukase, K. Chem. Lett. 2005, 34, 594-595.
(31) Morteza, M. V.; Bernacki, R. J.; Dalley, N. K.; Wilson, B.; Robins,
R. J. Med. Chem. 1987, 30, 1383-1391.
(32) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. Can. J.
Chem. 1955, 33, 134.
(33) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. Engl. 2004,
43, 5386-5389.
(34) Melander, L. C. S.; Saunders, W. H. Wiley-Interscience: New York
1980.
(24) Hamberg, M.; Svensson, J.; Samuelsson, B. Proc. Natl. Acad. Sci.
U.S.A. 1975, 72, 2994-2998.
(25) El-Badry, M. H.; Gervay-Hague, J. Tetrahedron Lett. 2005, 46,
6727-6728.
(26) Lin, C.-C.; Shimazaki, M.; Heck, M.; Aoki, S.; Wang, R.; Kimura,
T.; Ritzen, H.; Takayama, S.; Wu, S.; Weitz-Schmidt, G.; Wong, C. H. J.
Am. Chem. Soc. 1996, 118, 6826-6840.
(27) Lu, L.-D.; Shie, C.-R.; Kulkarni, S. S.; Pan, G.-R.; Lu, X.-A.; Hung,
S.-C. Org. Lett. 2006, 8, 5995-5998.
(35) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117,
9357-9358.
(28) Hernandez, O.; Chaudhary, S. K. Tetrahedron Lett. 1979, 95-98.
4664 J. Org. Chem., Vol. 72, No. 13, 2007

StereoselectiVe Formation of â-Mannosides from Mannosyl Iodides
FIGURE 1. Proposed mechanisms for the mannosylation reaction of TMO.
SCHEME 4. Synthesis of 6-O-Deuterated Acetyl Analogue
SCHEME 5. Mannosylation Reaction
as Internal Standard
14 possessing >95% deuterium at the anomeric center is
outlined in Scheme 3. Selective deacetylation of 1,6-di-O-acetyl-
2,3,4-tri-O-benzyl-R-D-mannopyranosemannoside 1036 at the
anomeric center using hydrazine acetate37 in DMF yielded
compound 11, which was oxidized in 82% yield to the
corresponding lactone 12 using tetrapropylammonium perruth-
enate and N-methyl-N-morpholine oxide.38 Treatment of 12 with
NaBD4 afforded 13 in 80% yield,39 which was then deacetylated
with sodium methoxide in methanol to yield diol 14 (in 45%
overall yield). For our kinetic studies, we required a 50/50
mixture of material with and without a deuterium label at the
anomeric carbon (vide infra), so the 1-deutero diol (14) was
then mixed in an equal quantity with unlabeled 15 to give a
mixture (14:15 1:1) enriched with ∼50% deuterium at the
anomeric carbon, H* (Scheme 4).
Separate portions of mixture 14:15 (1:1) were acetylated with
acetic anhydride and deuterated acetic anhydride to yield
mannosyl acetates 16 and 17, respectively (Scheme 4). Com-
bining acetates 16 and 17 in equimolar amounts afforded a
mixture of 16:17 (1:1) with ∼50% enrichment in deuterium at
C1 (H*) and, as internal standard to measure isotopic changes
at the anomeric center in the product, ∼50% enrichment in
deuterium at the C6 acetate, Ac* (Scheme 4).33
acetate peak and the anomeric hydrogens were measured against
the signal of benzaldehyde (see the Experimental Section).40
Mannosyl acetates 16:17 (1:1) were dissolved in CH2Cl2 (0.17
M), and trimethylsilyl iodide (1.1 equiv) was then added at
0 °C to produce iodides 18 quantitatively (Scheme 5). Next,
MgO (2 equiv; added to deactivate the TMSOAc byproduct),
followed by trimethylene oxide (1.5 equiv) were added to the
reaction mixture at the same temperature, and then the reaction
was allowed to proceed at room temperature for a particular
amount of time; experiments were performed for 4, 8, and 12 h.
After aqueous workup, 1H NMR spectra of the reaction
mixture, containing 50 mol % of benzaldehyde, showed
â-mannosides 19 as the major products and the R-anomers 20
as the minor products. The yield of the R- and â-mannosides
was obtained from 1H NMR integration of the C6 acetate signals
against the aldehydic signal of benzaldehyde.
1
After HPLC separation, the H NMR spectra of the â-man-
nosides were recorded with careful integration of the C6 acetates
and the anomeric protons. The R-DKIE for the â-mannosides
was then determined using eq 133where F is the fractional
KIE ) ln(1 - F)/ln[1 - (FR/R0)]
(1)
In the KIE experiments, mannosyl acetates 16:17 (1:1) and
50 mol % of benzaldehyde, an internal standard to measure the
percentage conversion of the product, were first dissolved in
conversion of the iodides 18 (yield of 19), R and R0 are the
ratios of the acetates to the anomeric resonances in the products
19 and the starting acetates 16 + 17, respectively, corresponding
to the D/H ratios in 19 and 16 + 17.
These experiments resulted in R-DKIEs of 1.16 ( 0.02,
suggesting that the rate-determining transition-state structure for
1
C6D6 and H NMR spectra were recorded; integration of the
(36) Tennant-Eyles, R. J.; Davis, B. G.; Fairbanks, A. J. Tetrahedron
Asymmetry 2000, 1, 231-243.
(37) Murakata, C.; Ogawa, T. Carbohydr. Res. 1992, 235, 95-114.
(38) Benhaddou, R.; Czernecki, S.; Ville, G.; Zegar, A. Carbohydr. Res.
1994, 260, 243-250.
(40) It was taken into consideration that a ratio of 1:3 (PhCHO/Ac) from
NMR integration resembles a ratio of 1:1 (PhCHO/mannosyl acetates 16:
17).
(39) Baker, D. C.; Defaye, J.; Horton, D. J. Org. Chem. 1976, 41, 3834-
3840.
J. Org. Chem, Vol. 72, No. 13, 2007 4665

El-Badri et al.
FIGURE 2. Computed geometries (B3LYP/6-31+G(d,p):LANL2DZ; selected distances in Å) of transition structures for trimethylene oxide attack
on R- and â-mannosyl iodide models. For clarity, hydrogen atoms on methyl and acetyl groups are not shown.
this reaction has significant oxacarbenium ion character.33
R-DKIEs for the R-anomers 20 were determined using the same
methodology. In these cases, values of 1.19 ( 0.04 were
obtained, also suggesting a transition-state structure with ox-
acarbenium ion character. As noted above, such values are
consistent with both SN1 and SN2 processes (providing the SN2
processes involve loose transition structures). Given the error
bars on our R-DKIE values, we cannot say with certainty
whether the rate-determining transition structures for formation
of the R- and â-mannosides differ significantly in the degree to
which their anomeric centers are rehybridized.
To explore these issues further, we carried out quantum
chemical calculations (at the B3LYP/6-31+G(d,p):LANL2DZ
level; see the Computational Methods for details) on the
transition-state structures for formation of R- and â-mannosyl
oxetanium ions. Figure 2 shows calculated transition-state
structures for the direct displacement of iodide by trimethylene
oxide to produce the two anomeric mannosides. In these
calculations, a simplified model of the experimental system was
used in which benzyl groups were replaced by methyl groups.
The calculated transition structures both exhibit loose SN2-like
geometries.41 With an O-C-I bond angle almost 20° greater
than that for B, one might argue that A is more SN2-like, but
this structural variation is likely related to the nature of the gas-
phase calculations used here, which should overestimate elec-
trostatic effects; as the negatively charged iodide departs,
electrostatic attraction brings it near to the somewhat positively
charged proton at the anomeric center. Note that although the
C-I distances are similar in both transition structures, the
forming C-O bond is nearly 0.5 Å longer in B (axial-like
attack at the anomeric carbon) than in A (equatorial-like
attack at the anomeric carbon). In both transition structures, the
C-O bond of the mannose ring is shortened, corresponding to
the development of oxacarbenium (oxonium) ion character.
The R-DKIEs calculated based on these transition structures
(see the Methods section for details) were 1.15 for A and 1.26
for B. These values match reasonably well with experimental
values, given the nature of the model systems used. Taken
together, the experimentally observed and theoretically com-
puted R-DKIEs imply that both reactions involve loose transition
structures with considerable rehybridization at the anomeric
center, both residing in the border regions between traditional
SN2 and SN1 transition state structures. The calculations do
suggest, though, that the transition-state structure for formation
of the R C-O bond is looser than that for formation of the â
C-O bond.
In order to investigate the possibility that the anomeric iodide
may be imposing an unusual conformational constraint on the
sugar ring, glycosylation reactions of conformationally locked
iodides were undertaken. Cyclic restraints42 have been used
previously to facilitate the stereoselective synthesis of â-man-
nosides.43,44 For example, the trans-fused protecting group in
structures such as 21 severely decreases the flexibility of the
attached sugar ring and thereby discourages formation of half-
chair transition-state structures.45,46
For comparison purposes, mannosyl acetates 23 were prepared
in 93% yield from mannopyranose 22, Scheme 6.47,48 Treatment
of 23 with TMSI in dichloromethane resulted in formation of
iodide 24, which was then coupled to TMO. The reaction was
sluggish, requiring 2 days for completion; however, only the
â-product (25) was obtained; no evidence was found for
R-mannoside formation. The significant difference in reactivity
and selectivity between 24 and 1 indicates differences in the
transition states.
We also modeled the 24 to 25 transformation computationally.
Our model system included a 4,6-O-methylene bridge rather
than the 4,6-O-benzylidine. The R- and â-transition structures
(42) Fraser-Reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.; Bowen,
J. P. J. Am. Chem. Soc. 1991, 113, 1434-1435.
(43) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(44) Crich, D.; Smith, M. J. Am. Chem. Soc. 2002, 124, 8867-8869.
(45) Jensen, H. H.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205-9213.
(46) Nukada, T.; Berces, A.; Whitfield, D. M. Carbohydr. Res. 2002,
337, 765-774.
(47) Wang, W.; Kong, F. Carbohydr. Res. 1999, 315, 128-136.
(48) Codee, J. D. C.; Hossain, L. H.; Seeberger, P. H. Org. Lett. 2005,
7, 3251-3254.
(41) This may be an artifact of the gas phase nature of the calculations.
The following paper nicely describes many of the issues associated with
locating transition state structures for heterolytic dissociation reactions:
Schreiner, P. R.; Schleyer, P. v. R.; Schaefer, H. F., III. J. Org. Chem.
1997, 62, 4216-4228. In addition, the work of Beauchamp and co-workers
provides relevant experimental data on the feasibility of gas phase ionization
processes; see, for example: Berman, D. W.; Anicich, V.; Beauchamp, J.
L. J. Am. Chem. Soc. 1979, 101, 1239-1248.
4666 J. Org. Chem., Vol. 72, No. 13, 2007

StereoselectiVe Formation of â-Mannosides from Mannosyl Iodides
FIGURE 3. Computed geometries (B3LYP/6-31+G(d,p):LANL2DZ; selected distances in Å) of transition structures for TMO attack on methylene-
bridged R- and â-mannosyl iodide models. For clarity, hydrogen atoms on methyl and acetyl groups are not shown.
FIGURE 4. Computed geometries (B3LYP/6-31+G(d,p):LANL2DZ; selected distances in Å) of transition structures for trimethylene oxide attack
on R- and â-mannosyl iodide models. For clarity, hydrogen atoms on methyl and acetyl groups are not shown.
SCHEME 6. Generation and Reaction of
4,6-O-Benzylidine-D-mannosyl Iodide with TMO
an acetal bridge. After a series of constrained calculations
starting with the geometries of C and D (see the Methods section
for details), the fully optimized transition structures shown in
Figure 4 were located. While structure F, leading to the
R-product, has a ring conformation similar to that of structure
D, structure E, despite all attempts, always fell back to a
structure with the same conformation of the sugar ring found
for A (compare with Figure 2).49
While experimental KIE measurements for the bridged system
were not explored, theoretical KIE values were calculated on
the basis of transition structures C and D (as well as E and F),
and these allow us to relate geometric differences to changes
in KIE values for a variety of similar systems. Calculated KIE
values for structures A, B, C, D, E, and F are 1.15, 1.26, 1.01,
1.31, 1.09, and 1.08, respectively. There is a rough correlation
between the C-O distances in these transition structures and
their calculated KIE valuessin general, larger KIE values are
associated with longer C-O (partial) bonds (Figure 5), although
the correlation is not perfect (since the KIEs depend on many
factors in addition to the degree of C-O bonding).
for this substrate are shown in Figure 3. These transition-state
structures can be thought of as ring-flipped analogues of the
corresponding transition structures in Figure 2. The geometries
around the anomeric carbon are notably different than those in
Figure 2; for example, the computed C-O distances of 1.72
and 2.32 Å for C and D, respectively, are significantly shorter
than their nonbridged counterparts. Nonetheless, the C-I
distance only differs by 0.01 Å across all four transition
structures, suggesting that in all four cases the C-I bond has
been effectively broken by the time the transition structure is
reached (i.e., although all four transition-state structures cor-
respond to concerted displacements of iodide by TMO, the bond-
breaking and -forming events happen asynchronously). In
addition, note that the conformations of C and D are consider-
ably different from each other, since the C-H group at the
anomeric center must orient itself differently in each case so as
to allow for C-O bond formation without excessive steric
problems.
In general, pairs of related transition structures (A and B; C
and D) were close to each other in energy (i.e., within a few
kcal/mol of each other), and the member of each pair with a
larger CsO distance was lower in energy (see the Supporting
(49) It is important to highlight that although the same ring conformation
is present in structures A and E, the methoxy and acetate groups adorning
these sugars assume different conformations. There is no doubt that these
two minima represent a narrow sampling of possible conformations for these
groups, but computational resources and the nature of the model system
itself, specifically the substitution of methyl groups for benzyl groups, made
an exhaustive search of this conformational space not only impractical, but
also unwarranted. Note also that both of the transition structures in Figure
4 are higher energy conformers than their analogs in Figure 2: E is 2.9
kcal/mol higher than A, and F is 14.2 kcal/mol higher than B.
Having located transition-state structures resembling ring-
flipped analogues of those in Figure 2, it was of particular
interest to see if ring-flipped versions of A and B exist without
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El-Badri et al.
6-O-tert-Butyldimethylsilyl-2,3,4-tri-O-benzyl-R-methyl-D-
mannopyranoside (5). To a stirred solution of 6-O-tert-butyldim-
ethylsilyl-R-methyl-D-mannopyranoside 4 (1.9 g, 6.15 mmol),
benzyl bromide (2.94 g, 24.6 mmol), and tetrabutylammonium
iodide (113 mg, 0.31 mmol) in DMF (23 mL) at 0 °C was added
NaH (0.81 g, 33.83 mmol). The reaction was then allowed to
continue at rt for 24 h. Upon reaction completion, the mixture was
quenched with methanol (5 mL) and diluted with ethyl acetate
(30 mL). The organic mixture was washed with water (10 mL),
and the aqueous extraction was washed with ether (2 × 30 mL).
The organic extract was combined and dried over Na2SO4 to afford
the title compound (67%) as a colorless syrup, Rf ) 0.77 (toluene/
ethyl acetate 85:15). The concentrated residue was then purified
by column chromatography (15% ethyl acetate in hexanes): [R]23
D
+21.6 (c 1.9 in CHCl3); IR ν 2929, 1102, 1059; 1H NMR
(600 MHz, C6D6) δ 0.07 (s, 3 H), 0.10 (s, 3 H), 0.97 (s, 9 H), 3.09
(s, 3 H), 3.71 (dd, 1 H, J ) 3.6 and 13.2 Hz), 3.74 (t, 1 H, J )
2.4 Hz), 3.85 (dd, 1 H, J ) 1.4 and 11.0 Hz), 3.91 (dd, 1 H, J )
4.8 and 11.4 Hz), 4.02 (dd, 1 H, J ) 3.0 and 9.6 Hz), 4.18 (t, 1 H,
J ) 9.6 Hz), 4.40-4.49 (m, 3 H), 4.58 (d, 1 H, J ) 12 Hz), 4.66
(d, 1 H, J ) 10.8 Hz), 4.68 (d, 1 H, J ) 1.8 Hz), 4.99 (d, 1 H, J
) 11.4 Hz), 7.03-7.33 (m, 15 H, ArH); 13C NMR (150 MHz, C6D6)
δ -4.8, -4.9, 18.7, 26.3, 54.5, 63.3, 72.4, 73.2, 73.9, 75.3, 75.4,
76.0, 81.1, 99.6, 127.7, 127.8, 127.83, 128.0, 128.02, 128.2, 128.3,
128.5, 128.6, 128.63, 128.7, 139.4, 139.5, 139.9; HR-EI-MS m/z
[M]+ calcd for C34H46O6Si1 578.3058, found 578.3055.
FIGURE 5. Correlation between computed KIEs and C-O distances.
Information for details). These relative energies do not cor-
respond to the experimental distributions of products, but this
is likely a result of the simplified model systems used and the
fact that these energies are for gas-phase structures. We have,
to this point, had impenetrable difficulties with solvation
calculations on these systems. Nonetheless, correspondence
between calculated and experimental isotope effects is still a
valid measure of the plausibility of the geometry of a transition-
state structure.
2,3,4-Tri-O-benzyl-R-methyl-D-mannopyranoside (6). To a
stirred solution of 6-O-tert-butyldimethylsilyl-2,3,4-tri-O-benzyl-
R-methyl-D-mannopyranoside 5 (1.7 g, 2.9 mmol) and MS, 4 Å
(40 mg) in THF was added tetrabutylammonium fluoride (8.8 mL,
1 M in THF) at 0 °C. The reaction was then allowed to proceed at
room temperature for 6 h. Upon reaction completion, the mixture
was concentrated in vacuo and diluted with ethyl acetate (50 mL),
and the organic mixture was washed with sodium bicarbonate
(10 mL) and water (10 mL). The aqueous extract was washed with
dichloromethane, and the combined organic extracts were dried over
Na2SO4. The concentrated residue was purified by column chro-
matography, Rf ) 0.57 (hexanes/ethyl acetate 1:1) to afford the
Conclusion
R-DKIEs for the mannosylation reaction of mannosyl iodide
with trimethylene oxide were determined experimentally to be
∼1.16 and ∼1.19 for the â- and R-mannosides, respectively.
These values suggest that both cases have rate-determining
transition structures with significant oxacarbenium ion character.
Acyl participation at the anomeric center does not take place
in these reactions, and the anomeric iodide present in these
systems does not bias the ring conformations as bridging acetal
protecting groups do. Quantum chemical calculations revealed
details of the transition structure geometries for these reactions,
showing that the observed KIEs are consistent with very loose
SN2-like processes.
title compound (67%) as a colorless syrup: [R]23 +42.4 (c 0.45
D
in CHCl3); IR ν 3467, 2906, 1454, 1109, 1071; 1H NMR (150 MHz,
CDCl3) δ 2.40 (brs, 1 H) 3.34 (s, 3 H), 3.67 (m, 1 H), 3.82-3.92
(m, 3 H), 3.97 (dd, 1 H, J ) 3.0 and 9.0 Hz), 4.04 (t, 1 H, J )
9.6 Hz), 4.68 (d, 1 H, J ) 2.4 Hz), 4.71-5.01 (m, 6 H, CH2Ph),
7.25-7.42 (m, 15 H, ArH); 13C NMR (150 MHz, CDCl3) δ 54.7,
62.3, 72.2, 72.22, 72.9, 74.7, 74.8, 75.2, 80.2, 99.3, 127.6, 127.7,
127.73, 127.9, 128.0, 128.4, 128.41, 138.2, 138.50. HR-EI-MS m/z
[M]+ calcd for C28H32O6 464.2193, found 464.2206.
Experimental
6-O-(4-Nitrobenzyl)-2,3,4-tri-O-benzyl-R-methyl-D-mannopy-
ranoside (7). To a stirred solution of 2,3,4-tri-O-benzyl-R-methyl-
D-mannopyranoside 6 (170 mg, 0.4 mmol) and chlorotrimethylsilane
(0.47 mL, 3.7 mmol) in CH2Cl2 (2.0 mL) were added 4-nitroben-
zaldehyde (55 mg, 0.4 mmol) and triethylsilane (0.12 mL,
0.7 mmol). The reaction was stirred at rt for 2 d. Upon reaction
completion, the reaction mixture was concentrated under vacuum
and the organic residue was subjected to column chromatography,
Rf ) 0.27 (hexane/ethyl acetate 75:25), to afford the benzylated
6-O-tert-Butyldimethylsilyl-R-methyl-D-mannopyranoside (4).
To a stirred solution of R-methyl-D-mannopyranoside 3 (1.5 g,
7.7 mmol), triethylamine (3.76 g, 27 mmol), and DMAP (47 mg,
0.39 mmol) in DMF (12 mL) at 0 °C was added TBDMSCl
(1.28 g, 8.5 mmol). The reaction was then allowed to proceed at
room temperature for 12 h. Upon reaction completion, the mixture
was poured over ice-water (10 mL) and extracted with dichlo-
romethane (50 mL), and the organic mixture was washed with
ammonium chloride and water (10 mL, each). The organic extract
was then dried over Na2SO4 and stripped of solvent in vacuo, and
the concentrated residue was purified by column chromatography,
Rf ) 0.25 (hexanes/ethyl acetate 1:4), to afford the title compound
compound (76%) as a colorless syrup: [R]23 +37.1 (c 1.0 in
D
1
CHCl3); IR ν 2900, 1520, 1106; H NMR (600 MHz, CDCl3) δ
3.35 (s, 3 H), 3.76-3.79 (m, 2 H), 3.83-3.86 (m, 2 H), 3.94 (dd,
1 H, J ) 3.0 and 9.6 Hz), 4.03 (t, 1 H, J ) 9.6 Hz), 4.57-4.64 (m,
4 H), 4.71-4.80 (m, 4 H), 4.96 (d, 1 H, J ) 11.4 Hz), 7.22-7.40
(m, 15 H, ArH), 7.47 (d, 2 H, J ) 8.4 Hz), 8.12 (d, 2 H, J )
8.4 Hz); 13C NMR (150 MHz, CDCl3) δ 55.1, 70.2, 71.9, 72.1,
72.3, 73.0, 74.8, 74.9, 75.3, 80.4, 99.3, 123.8, 127.8, 127.9, 127.93,
127.94, 128.0, 128.03, 128.1, 128.6, 128.63, 128.64, 138.5, 138.7,
138.72, 146.4, 147.4. HR-EI-MS m/z [M]+ calcd for C35H37O8N1
599.2514, found 599.2524.
(82%) as a white solid: mp 102.1-103.0; [R]23 +57 (c 0.3 in
D
CHCl3); IR ν 3386, 2938, 2857, 1100, 1049, 839; 1H NMR
(600 MHz, C6D6) δ 0.21 (s, 6 H), 1.04 (s, 9 H), 3.25 (s, 3 H),
3.82-3.86 (m, 1 H), 4.02-4.07 (m, 2 H), 4.11-4.14 (m, 1 H),
4.20 (d, 1 H, J ) 2.4 Hz), 4.22 (d, 1 H, J ) 3.0 Hz), 4.56 (d, 1 H,
J ) 4.8 Hz), 4.61 (d, 1 H, J ) 3.6 Hz), 4.84 (d, 1 H, 1.2 Hz,
H-1R), 5.12 (d, 1 H, J ) 5.4 Hz); 13C NMR (150 MHz, C6D6) δ
-5.2, -5.2, 18.5, 26.1, 54.4, 64.2, 68.9, 71.1, 72.5, 73.2, 101.3;
HR-EI-MS m/z [M]+ calcd for C13H28O6Si1 308.1650, found
308.1637.
6-O-(4-Nitrobenzyl)-2,3,4-tri-O-benzyl-1-O-acetyl-R-D-man-
nopyranoside (8). To a stirred solution of 6-O-(4-nitrobenzyl)-
4668 J. Org. Chem., Vol. 72, No. 13, 2007

StereoselectiVe Formation of â-Mannosides from Mannosyl Iodides
2,3,4-tri-O-benzyl-R-methyl-D-mannopyranoside (250 mg,
7
sulfite in brine, brine, and copper sulfate (10 mL, each). The
combined organic extract was dried over MgSO4, filtered through
Celite, and concentrated in vacuo, and the concentrated residue was
purified by column chromatography, Rf ) 0.53 (hexanes,ethyl
0.4 mmol) and acetic anhydride (0.19 mL, 1.9 mmol) in acetic acid
(0.83 mL) was added sulfuric acid (37 µL) dropwise at 0 °C for
30-60 min. Upon completion, the reaction was poured over ice-
water (10 mL) and stirred for 20 min. The reaction mixture was
then extracted with chloroform (50 mL) and washed with sodium
bicarbonate (10 mL) and then water (10 mL). The aqueous phase
was washed with chloroform (50 mL), the combined organic phase
was dried over sodium sulfate and concentrated in vacuo, and the
concentrated residue was then purified using column chromatog-
raphy, Rf ) 0.24 (hexane/ethyl acetate 75:25), to afford mannosyl
acetate/ 2:1), to afford the title compound (93%, as an oil): [R]23
D
1
+22 (c 0.1 in CHCl3); IR ν 2910, 1776, 1454, 1142, 1084; H
NMR (600 MHz, CDCl3) δ 2.02 (s, 3 H, Ac), 3.65 (d, 1 H, J )
7.8 Hz), 4.08 (m, 1 H), 4.17 (dd, 1 H, J ) 6.6 and 12.0 Hz), 4.22-
4.27 (m, 3 H), 4.36-4.38 (m, 2 H), 4.60 (d, 1 H, J ) 12 Hz), 4.67
(d, 1 H, J ) 12 Hz), 4.88 (d, 1 H, J ) 12 Hz), 4.08 (d, 1 H, J )
12 Hz), 7.15-7.41 (m, 15 H, ArH); 13C NMR (150 MHz, CDCl3)
δ 20.9, 63.4, 72.0, 73.2, 73.4, 75.6, 76.4, 76.5, 76.6, 128.1, 128.2,
128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 136.6, 137.2, 137.7, 169.1,
170.8. HR-EI-MS m/z [M]+ calcd for C29H30O7 490.1986, found
490.1995.
acetate 8 (84%) as a colorless syrup: [R]23 +31.6 (c 2.85 in
D
CHCl3); IR ν 2891, 1748, 1519, 1344; 1H NMR (600 MHz, CDCl3)
δ 2.04 (s, 3 H), 3.74 (d, 1 H, J ) 9.6 Hz), 3.77 (t, 1 H, J ) 2.4
Hz), 3.84 (m, 2 H), 3.90 (dd, 1 H, J ) 3.0 and 9.6 Hz), 4.12 (t, 1
H, J ) 9.3 Hz), 4.58-4.96 (m, 8 H, CH2Ph), 6.22 (d, 1 H, J )
2.4 Hz), 7.23-7.40 (m, 15 H, ArH), 7.44 (d, 2 H, J ) 7.8 Hz),
8.10 (d, 2 H, J ) 9.0 Hz); 13C NMR (150 MHz, CDCl3) δ 21.1,
69.6, 72.3, 72.33, 72.8, 73.6, 74.1, 74.5, 75.4, 79.3, 91.8, 123.6,
127.8, 127.9, 127.92, 127.94, 128.0, 128.03, 128.1, 128.5, 128.54,
137.8, 138.1, 138.3, 146.1, 147.3, 169.1; HR-EI-MS m/z [M]+ calcd
for C36H37O9N1 627.2463, found 627.2453.
1-Deutero-6-O-acetyl-2,3,4-tri-O-benzyl-D-mannopyranose (13).
To a mixture of 6-O-acetyl-2,3,4-tri-O-benzyl-R-D-manno-1-lactone
12 (684 mg, 1.4 mmol) and sodium borodeuteride (88 mg,
2.1 mmol) in methanol (50 mL, 0.028 M) was added water
(3.5 mL) at 0 °C. After 3 min, the reaction reached completion,
and the mixture was neutralized with CO2 gas bubbled in the
solution. The reaction mixture was azeotroped with methanol (4 ×
15 mL) to remove boric acid as its methyl ester followed by
azeotroping with toluene (3 × 15 mL). The mixture was concen-
trated and then diluted in chloroform (30 mL) and washed with
water (2 × 5 mL). The combined organic extract was dried over
Na2SO4 and concentrated in vacuo, and the concentrated residue
was purified by column chromatography, Rf ) 0.54 (hexanes/ethyl
acetate/ 1:1), to afford oil 13 (80%, 1:5 â:R). For the major product
(R-anomer): 1H NMR (600 MHz, CDCl3) δ 2.05 (s, 3 H, Ac),
3.84 (d, 1 H, J ) 4.2 Hz), 3.97 (t, 1 H, J ) 9.6 Hz), 4.02-4.09
(m, 2 H), 4.30 (dd, 1 H, J ) 5.4 and 11.4 Hz), 4.41 (dd, 1 H, J )
1.8 and 12.0 Hz), 4.64-4.67 (m, 3 H), 4.71 (d, 1 H, J ) 12.0 Hz),
4.77 (d, 1 H, J ) 12.6 Hz), 4.99 (d, 1 H, J ) 10.8 Hz), 7.31-7.42
(m, 15 H, ArH); 13C NMR (150 MHz, CDCl3) δ 20.9, 63.8, 70.0,
72.1, 72.6, 74.6, 74.8, 75.2, 79.6, 92.2 (t, 1JCD ) 79.03 Hz), 127.72,
127.73, 127.74, 127.81, 127.83, 128.0, 128.1, 128.2, 128.22, 128.3,
128.4, 128.42, 128.5, 128.53, 128.6, 128.62, 129.1, 137.8, 138.0,
138.2, 138.3, 138.33, 171.3. Some selected values for the minor
product (â-anomer): 1H NMR (600 MHz, CDCl3) δ 3.56 (m,
1 H), 3.67 (dd, 1 H, J ) 2.7 and 9.3 Hz), 3.90 (m, 1 H), 5.13 (d,
1 H, J ) 11.4 Hz); 13C NMR (150 MHz, CDCl3) δ 63.6, 72.7,
73.3, 74.2, 75.8, 83.0, 171.1. HR-EI-MS m/z [M]+ calcd for
C29H312H1O7 493.2205, found 493.2201.
1-Deutero-2,3,4-tri-O-benzyl-D-mannopyranose (14). To a
stirred solution of 1-deutero-6-O-acetyl-2,3,4-tri-O-benzyl-R-D-
mannopyranose 13 (440 mg, 0.9 mmol) in methanol (6 mL,
0.15 M) was added sodium methoxide, 30% in methanol (150 µL,
2.7 mmol) at 0-10 °C for 30 min. Upon reaction completion, the
mixture was neutralized with acidic resin, DOWEX 50wx 2-200,
the neutral mixture was filtered out, and the filtrate was concentrated
and then filtered through a short plug of silica gel, Rf ) 0.20
(hexanes/ethyl acetate/ 1:1), to afford syrup 14 (93%, 1:6 â/R). For
the major product (R-anomer): 1H NMR (400 MHz, C6D6) δ 3.55
(m, 1 Η), 3.80 (d, 2 H, J ) 2.4 Hz), 3.97 (m, 1 H), 4.04 (t, 1 H,
J ) 9.6 Hz), 4.15 (dd, 1 H, J ) 2.8 and 9.2 Hz), 4.19 (m, 1 H),
4.35-4.91 (m, 6 H, CH2Ph), 7.01-7.35 (m, 15 H, ArH); 13C NMR
(100 MHz, C6D6) δ 62.9, 72.3, 73.0, 73.3, 75.3, 76.0, 76.3, 80.5,
92.8 (m, C-D), 127.6, 127.63, 127.7, 127.72, 127.74, 127.9, 128.0,
128.03, 128.1, 128.2, 128.3, 128.4, 128.43, 128.5, 128.6, 128.62,
138.7, 138.72, 138.9, 139.0, 139.1. Some selected values for the
minor product (â-anomer): 1H NMR (400 MHz, C6D6) 3.19-3.22
(m, 1 H), 3.24 (dd, 1 H, J ) 2.8 and 2.0), 3.41 (t, 1 H, J )
6.0 Hz), 3.86 (d, 1 H, J ) 2.8), 3.89 (m, 1 H); 13C NMR
(100 MHz, C6D6) δ 62.2, 72.5, 75.0, 75.2, 76.4, 76.7, 83.2. 92.8;
HR-EI-MS m/z [M]+ calcd for C27H292H1O6 451.2100, found
451.2095.
1-O-(3-Iodopropyl)-6-O-(4-nitrobenzyl)-2,3,4-tri-O-benzyl-R-
D-mannopyranoside (9). To a stirred solution of 6-O-(4-nitroben-
zyl)-2,3,4-tri-O-benzyl-1-O-acetyl-R-D-mannopyranoside 8 (87 mg,
0.14 mmol) in dichloromethane (0.8 mL, 0.2 mmol) was added
trimethylsilyl iodide (21 µL, 0.2 mmol) at 0 °C for 1 h to show
complete formation of the iodide. MgO (11 mg, 0.28 mmol)
followed by trimethylene oxide (14 µL, 0.21 mmol) was added to
the reaction mixture at the same temperature, and then the reaction
was allowed to proceed at room temperature for 6 h. Upon
completion, the reaction was diluted with ethyl acetate (30 mL),
and the organic mixture was washed with sodium thiosulfate, brine,
and water (5 mL, each). The aqueous phase was washed with
dichloromethane (30 mL), and the combined organic phase was
dried over sodium sulfate and concentrated in vacuo to afford
mannoside 9 (86% of 1:4 R/â) as a colorless syrup. Purification of
the crude residue and separation of the anomers was achieved
successfully using column chromatography (15% ethyl acetate in
hexane). For the major product (â-anomer), Rf ) 0.63 (toluene/
1
ethyl acetate 85:15); H NMR (600 MHz, C6D6) δ 1.68 (m, 2 H),
2.85-2.92 (m, 2 H), 3.21 (m, 1 H), 3.27-3.30 (m, 2 H), 3.59 (d,
1 H, J ) 1.2 and 11.4 Hz), 3.67-3.72 (m, 3 H) 3.95 (s, 1 H), 4.06
(m, 1 H), 4.17-4.98 (m, 8 H, CH2Ph), 6.94-7.80 (m, 19 H, ArH);
13C NMR (150 MHz, C6D6) δ 3.1, 33.2, 68.8, 70.1, 71.3, 72.1,
74.5, 74.9, 75.0, 75.1, 76.2, 82.4, 101.9, 123.4, 127.6, 127.64, 127.7,
127.72, 127.74, 127.9, 128.1, 128.2, 128.4, 128.43, 128.6, 138.8,
139.2, 139.4, 146.0, 147.5; HR-EI-MS m/z [M]+ calcd for
C37H40O8I1N1 753.1793, found 753.1773. For the minor product
(R-anomer), Rf ) 0.62 (toluene/ethyl acetate 85:15); 1H NMR
(600 MHz, C6D6) δ 1.56 (m, 2 H), 2.75 (t, 2 H, J ) 6.6 Hz), 3.09
(m, 1 H), 3.55 (m, 1 H), 3.61 (dd, 1 H, J ) 1.8 and 6.3 Hz), 3.73-
3.77 (m, 2 H), 3.89 (dd, 1 H, J ) 3.6 and 9.6 Hz), 3.99 (dd, 1 H,
J ) 3.0 and 9.0 Hz), 4.14 (d, 1 H, J ) 13.2 Hz), 4.23 (t, 1 H, J )
9.6 Hz), 4.29 (d, 1 H, J ) 13.2 Hz), 4.44 (d, 1 H, J ) 3.6 Hz),
4.47 (d, 1 H, J ) 12.0 Hz), 4.55 (d, 1 H, J ) 11.4 Hz), 4.62 (d,
1 H, J ) 12.0 Hz), 4.81 (d, 1 H, J ) 1.2 Hz), 5.00 (d, 1 H, J )
11.4 Hz), 6.93-7.79 (m, 19 H, ArH); 13C NMR (150 MHz, C6D6)
δ 2.5, 33.0, 67.0, 70.2, 72.1, 72.2, 73.0, 73.2, 75.2, 75.6, 80.6, 98.6,
123.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3,
128.4, 128.5, 128.52, 183.8, 138.9, 139.2, 146.0, 147.5. HR-EI-
MS m/z [M]+ calcd for C37H40O8I1N1 753.1793, found 753.1762.
6-O-Acetyl-2,3,4-tri-O-benzyl-R-D-manno-1-lactone (12) A
mixture of 6-O-acetyl-2,3,4-tri-O-benzyl-R-D-mannopyranose 11
(1.14 g, 2.3 mmol), tetrapropylammonium perruthenate (81 mg,
0.231 mmol), N-methyl-N-morpholine oxide (0.54 g, 4.63 mmol)
and MS, 3 Å (0.57 g) in CH2Cl2 (19 mL) was stirred at room
temperature for 2 h. Upon reaction completion, the mixture was
diluted with dichloromethane (50 mL) and washed with 5% sodium
2,3,4-Tri-O-benzyl-D-mannopyranose (15). To a stirred solution
of 1,6-di-O-acetyl-2,3,4-tri-O-benzyl-R-D-mannopyranoside 10
J. Org. Chem, Vol. 72, No. 13, 2007 4669

El-Badri et al.
(0.74 g, 1.4 mmol) in methanol/THF, 3:1 (12 mL) was added
sodium methoxide (30% in methanol), 0.47 mL, 8.34 mmol, at
0-10 °C for 40 min. Upon reaction completion, the mixture was
neutralized with acidic resin, DOWEX 50wx 2-200, the neutral
mixture was filtered, and the filtrate was concentrated and then
filtered through a short plug of silica gel, Rf ) 0.20 (hexanes/ethyl
acetate 1:1), to afford syrup 8 (93%, 1:8 â/R). For the major product
(R-anomer): 1H NMR (400 MHz, CDCl3) δ 3.48 (t, 1 Η, J )
6.0 Hz), 3.70 (m, 1 H), 3.81-3.90 (m, 2 H), 3.97 (bd, 1 H J )
8.8 Hz), 4.03 (dd, 1 H, J ) 2.8 and 12.0 Hz), 4.63-4.98 (m, 6 H,
CH2Ph), 5.13 (bd, 1 H, J ) 1.2 Hz), 7.31-7.42 (m, 15 H, ArH);
13C NMR (100 MHz, CDCl3) 62.5, 72.1, 72.2, 73.0, 75.2, 75.3,
75.5, 79.9, 92.6, 127.6, 127.7, 127.8, 127.83, 127.9, 128.0, 128.1,
128.2, 128.2, 128.4, 128.5, 128.53, 128.6, 138.2, 138.24, 138.4.
Some selected values for the minor product (â-anomer): 1H NMR
(400 MHz, CDCl3) 3.25 (t, 1 H, J ) 6.4 Hz), 3.34-3.38 (m, 1 H),
3.42 (d, 1 H, J ) 6.0 Hz), 3.61 (m, 1 H); 13C NMR (100 MHz,
CDCl3) δ 62.0, 72.6, 74.4, 75.5, 75.8, 82.8, 94.1; HR-EI-MS m/z
[M]+ calcd for C27H30O6 450.2037, found 450.2043.
for 4, 8, and 12 h. The reaction mixture was diluted with CH2Cl2
(20 mL) and washed with satd Na2S2O3 (2 × 5 mL) and brine (2
× 5 mL). The organic extract was dried (Na2SO4) and concentrated
in vacuo to afford mixture of anomers 19 + 20, Rf ) 0.57 (toluene/
ethyl acetate 85:15). Benzaldehyde (8.2 µL) was added to the
1
reaction mixture, and the H NMR spectrum was recorded. The
crude mixture was then purified using analytical normal-phase
HPLC (Si phase, isocratic elution with ethyl acetate:petroleum ether
(15:85), 1 mL/min. flow, detection at 260 nm) to give complete
separation of the R and the â anomers as colorless oils. For the
major product (â-anomer): [R]23 -2.4 (c 0.5 in CHCl3); IR ν
D
3031, 2893, 1738, 1346, 1092; 1H NMR (600 MHz, C6D6) δ 1.63
(m, 1 H), 1.66 (s, 1.5 H), 1.73 (m, 1 H), 2.85 (m, 1 H), 2.97 (m,
1 H), 3.27 (m, 3 H), 3.68 (m, 2 H), 3.94 (s, 0.5 H), 4.02 (t, 1 H, J
) 9.6 Hz), 4.30 (d, 1 H, J ) 11.4 Hz), 4.36 (dd, 1 H, J ) 6.0 and
12.0 Hz), 4.39 (d, 1 H, J ) 11.4 Hz), 4.48 (d, 1 H, J ) 11.4 Hz),
4.54 (d, 1 H, J ) 11.4 Hz), 4.77 (d, 1 H, J ) 12.0 Hz), 4.92 (d, 1
H, J ) 10.8 Hz), 4.95 (d, 1 H, J ) 12.0 Hz), 7.05-7.51 (m, 15 H,
ArH); 13C NMR (150 MHz, C6D6) δ 3.3, 20.5, 33.7, 63.6, 69.0,
71.4, 74.2, 74.5, 74.8, 74.84, 75.2, 82.6, 102.0, 127.5, 127.6, 127.7,
127.9, 128.1, 128.2, 128.3, 128.4, 128.5, 138.8, 138.9, 139.5, 170.0.
HR-EI-MS m/z [M]+ calcd for C32H37O7I1 660.1578, C32H362H1O7I1
661.1641, C32H342H3O7I1 663.1767 and C32H332H4O7I1 664.1830,
found 660.1562, 661.1648, 663.1758 and 664.1801 respectively.
For the minor product (R-anomer): [R]23D -4.7 (c 0.3 in CHCl3);
IR ν 3031, 2921, 1737, 1345, 1085; 1H NMR (600 MHz, C6D6) δ
1.57 (m, 2 H), 1.71 (s, 1.5 H), 2.76 (t, 2 H, J ) 6.9 Hz), 3.06 (m,
1 H), 3.49 (m, 1 H), 3.74 (d, 1 H, J ) 3.0 Hz), 3.92 (m, 1 H), 3.97
(dd, 1 H, J ) 3.0 and 9.6 Hz), 4.17 (t, 1 H, J ) 9.0 Hz), 4.41-
4.63 (m, 7 H, CH2Ph), 4.79 (d, 0.5 H, J ) 1.2 Hz, H-1), 4.95 (d,
1 H, J ) 10.8 Hz, CH2Ph), 7.03-7.36 (m, 15 H, ArH); 13C NMR
(150 MHz, C6D6) δ 2.6, 20.6, 33.2, 63.7, 67.1, 71.2, 72.2, 73.1,
75.1, 75.3, 75.5, 80.7, 98.6, 127.5, 127.6, 127.7, 127.9, 128.1, 128.2,
128.3, 128.4, 128.5, 138.8, 138.9, 139.5, 170.0. HR-EI-MS m/z
[M]+ calcd for C32H37O7I1 660.1578, C32H362H1O7I1 661.1641,
C32H342H3O7I1 663.1767 and C32H332H4O7I1 664.1830, found
660.1585, 661.1654, 663.1770 and 664.1830, respectively.
Calculation of the Kinetic Isotope Effect. The 1H NMR spectra
of the starting acetates 16:17 (1:1), the crude mixture, the â- and
R-mannoside products and the internal standard were recorded in
C6D6 using 600 MHz. For each of these materials, the acetate
protons at C6, the anomeric and the internal standard protons were
carefully integrated on an expanded region of the desired peak with
a standard one pulse sequence. Each spectrum was integrated
10 times and the average value of these integrations was recorded
in Table 1 and 2. The R-DKIE of the â-mannoside 19 was
determined using the equation KIE ) ln(1 - F)/ln[1 - (FR/R0)],
where F is the percentage conversion of iodide 18 to the â-man-
noside 19 (yield of [16 + 17]). R and R0 are the ratios of the acetate
to the anomeric proton integrations in the product 19 and the starting
acetates (16 + 17) respectively.
1-(50% Deutero)-1,6-di-O-acetyl-2,3,4-tri-O-benzyl-R-D-man-
nopyranoside (16). To a stirred solution of a 1:1 mixture of
mannopyranoses 14 and 15 (100 mg, 0.22 mmol) in pyridine
(1.5 mL) was added acetic anhydride (0.82 µL, 0.9 mmol) at rt for
5 h. Upon reaction completion, the mixture was diluted with ethyl
acetate (25 mL), neutralized with aqueous HCl (10%), washed with
water (5 mL), and dried (Na2SO4). The residue was purified by
column chromatography, Rf ) 0.66 (hexanes/ethyl acetate 3:2), to
afford the title compound (80%) as a white solid: mp 88.3-
91.6 °C; [R]23 +31.8 (c 0.55 in CHCl3); IR ν 3031, 2902, 1743,
D
1231, 1094; 1H NMR (400 MHz, CDCl3) δ 2.06 (s, 3 H, Ac), 2.08
(s, 3H, Ac), 3.79 (t, 1 H, J ) 2.8 Hz), 3.93 (m, 2 H), 4.05 (dd,
1 H, J ) 9.6, 9.6 Hz), 4.37 (m, 2 H), 4.63-4.67 (m, 3 H), 4.80 (q,
2 H, J ) 12.4 and 9.2 Hz), 5.00 (d, 1 H, J ) 10.8 Hz), 6.24 (d,
0.5 H, J ) 2.00 Hz, H-1R), 7.26-7.41 (m, 15 H, ArH); 13C NMR
(100 MHz, CDCl3) δ 20.9, 21.0, 63.1, 72.0, 72.3, 73.0, 73.1, 73.7,
75.3, 79.0, 91.5, 127.7, 127.8, 127.82, 127.9, 128.1, 128.3, 128.4,
128.5, 137.7, 137.9, 168.8, 170.8. HR-EI-MS m/z [M]+ calcd for
C31H34O8 534.2248 and C31H332H1O8 535.2311, found 534.2255
and 535.2308, respectively.
1-(50% Deutero)-1,6-di-O-(acetyl-d3)-2,3,4-tri-O-benzyl-R-D-
mannopyranoside (17). To a stirred solution of a 1:1 mixture of
mannopyranoses 14 and 15 (200 mg, 0.44 mmol) in pyridine
(3 mL, 0.15 M) was added deuterated acetic anhydride (0.17 mL,
1.76 mmol) at rt for 4 h. Upon reaction completion, the mixture
was diluted with ethyl acetate (30 mL), neutralized with aqueous
HCl (10%), washed with water (2 × 5 mL), and dried (Na2SO4).
The residue was purified by column chromatography, Rf ) 0.66
(hexanes:ethyl acetate 3:2), to afford the title compound (81%) as
white crystals: mp 88.5-93.9; 1H NMR (400 MHz, CDCl3) δ 3.76
(d, 1 H, J ) 2.4 Hz), 3.90 (dd, 2 H, J ) 2.8, 9.2 Hz), 4.01 (m,
1 H), 4.34 (m, 2 H), 4.62 (m, 3 H), 4.76 (q, 2 H, J ) 12.40 and
9.6 Hz), 4.97 (d, 1 H, J ) 10.8 Hz), 6.21 (d, 0.5 H, J ) 2.4 Hz,
H-1R), 7.26-7.41 (m, 15 H, ArH); 13C NMR (100 MHz, CDCl3)
δ 21.05 (m, C-D3), 63.2, 72.1, 72.4, 72.41, 72.42, 73.1, 73.2, 73.8,
75.5, 79.1, 91.6, 127.8, 127.9, 127.9, 128.0, 128.3, 128.5, 128.54,
128.6, 137.8, 138.0, 138.02, 167.0, 171.0. HR-EI-MS m/z [M]+
calcd for C31H282H6O8 540.2472 and C31H272H7O8 541.2688, found
540.2474 and 541.2683, respectively.
KIE of the R-mannoside was determined using the same equation,
ln(1 - F)/ln[1 - (FR/R0)], where F is the percentage conversion
of the iodide 18 to the R-mannoside 20 (yield of 16 + 17), and R
TABLE 1. KIEs Measured for the â-Anomera
reaction KIE
F
R
R0
S
S0
N
N0
â1
â2
â3
â4
1.13
1.17
1.16
1.16
0.493 1.019 1.109 0.415 0.841 0.407 0.758
1-(50% Deutero)-1-â-O-(3-iodopropyl)-2,3,4-tri-O-benzyl-6-
O-(acetyl-50% d)-D-mannopyranoside (19) and 1-(50% Deu-
tero)-1-R-O-(3-iodo-propyl)-2,3,4-tri-O-benzyl-6-O-(acetyl-
50% d)-D-mannopyranoside (20). A mixture of a 1:1 ratio of
mannopyranosides 16 and 17 (86 mg, 0.16 mmol) and benzaldehyde
0.564 1.000 1.109 0.48
0.587 1.006 1.108 0.493 0.839 0.49
0.849 0.48
0.765
0.756
0.444 0.991 1.109 0.377 0.848 0.380 0.764
average 1.155
STDEV 0.020
1
a S ) ratio of acetate peak of product/internal standard peak. S0 ) ratio
of acetate peak of starting material/internal standard peak. R ) ratio of
acetate peak/anomeric peak in the product. R0 ) ratio of acetate peak/
anomeric peak in the starting material. N ) ratio of anomeric peak of
product/internal standard peak. N0 ) ratio of anomeric peak of starting
material/internal standard peak.
(8.2 µL, 0.08 mmol) were dissolved in C6D6, and the H NMR
spectrum was recorded. Mannosyl acetates 16 + 17 were dissolved
in CH2Cl2 (0.9 mL) at 0 °C, and TMSI (26 µL, 0.19 mmol) was
added to produce iodides 18 with complete conversion. MgO
(13 mg, 0.3 mmol) followed by trimethylene oxide (16 mg, 0.2
mmol) were added at 0 °C, and the mixture was then stirred at rt
4670 J. Org. Chem., Vol. 72, No. 13, 2007

StereoselectiVe Formation of â-Mannosides from Mannosyl Iodides
TABLE 2. KIEs Measured for the r-Anomera
12.0 Hz), 4.95 (d, 1 H, J ) 12.0 Hz), 5.25 (s, 1 H) 7.03-7.63 (m,
15 H, ArH); 13C NMR (150 MHz, C6D6) δ 3.2, 33.7, 67.9, 68.8,
68.9, 72.6, 75.6, 77.7, 78.4, 79.3, 101.7, 102.4, 126.7, 127.8, 127.9,
127.94, 128.0, 128.1, 128.2, 128.3, 128.4, 128.43, 128.5, 128.6,
128.9, 138.7, 139.5, 139.6; HR-MADI [M + Na]+ m/z calcd for
C30H33INaO6 639.1220, found 639.1190.
reaction KIE
F
R
R0
S
S0
N
N0
R1
R2
R3
R4
1.26 0.039
1.13 0.086
1.19 0.07
0.878 1.109 0.033 0.841 0.038 0.758
0.990 1.109 0.073 0.849 0.074 0.765
0.935 1.108 0.066 0.839 0.071 0.756
1.18 0.0487 0.938 1.109 0.041 0.847 0.044 0.763
average 1.19
STDEV 0.05
Computational Methods
a S ) ratio of acetate peak of product/internal standard peak. S0 ) ratio
of acetate peak of starting material/internal standard peak. R ) ratio of
acetate peak/anomeric peak in the product. R0 ) ratio of acetate peak/
anomeric peak in the starting material. N ) ratio of anomeric peak of
product/internal standard peak. N0 ) ratio of anomeric peak of starting
material/internal standard peak.
The structures reported herein (images generated with Ball &
Stick 4.0a1250) were optimized in the gas phase using the Gaussian
03 suite of programs51 utilizing the Becke three-parameter hybrid
functional combined with the Lee-Yang-Parr correlation func-
tional.52-55 The 6-31+G(d,p) basis set was used for C, O, and H
atoms and the LANL2DZ basis set56 was used for I atoms. This
level of theory is referred to throughout as B3LYP/6-31+G(d,p):
LANL2DZ.
An exhaustive search of conformational space was not practical
at this level of theory, so the substituents on the mannose oxygens
were initially oriented in what appeared to be the least sterically
crowded directions and then allowed to relax during the geometry
optimization procedure; the same initial orientations were used for
all structures.
and R0 are the ratios of the acetate to the anomeric protons
integrations in the product 20 and the starting acetates (16 + 17),
respectively.
Acetyl 2,3-Di-O-benzyl-4,6-O-benzylidine-R/â-D-mannopyra-
noside (23). To a stirred solution of 2,3-di-O-benzyl-4,6-O-
benzylidine-R-D-mannopyranose 22 (40 mg, 0.09 mmol) in DCM
(0.5 mL, 0.18 mmol) was added acetic anhydride (30 µL,
0.32 mmol) followed by triethylamine (0.1 mL, 0.68 mmol) at rt
for 4 h. Upon reaction completion, the mixture was quenched with
methanol (2 mL) and concentrated in vacuo, and the concentrated
residue was subjected to column chromatography (85:15 hexane/
ethyl acetate) to afford the title compound (93%, 1:2 R/â) as a
colorless syrup. For the â anomer Rf ) 0.59 (15% ethyl acetate in
SCHEME 7. Series of Partially Constrained Optimizations
Leading to Structure Ea
toluene): [R]23 +6.4 (c 1.65 in CHCl3); IR ν 2897, 1757, 1370,
D
1
1219, 1083; H NMR (600 MHz, C6D6) δ 1.62 (s, 3 H), 3.17 (m,
1 H), 3.34 (dd, 1 H, J ) 3.0 and 9.6 Hz), 3.48 (t, 1 H, J )
10.2 Hz), 3.56 (d, 1 H, J ) 3.0 Hz), 4.07 (dd, 1 H, J ) 4.8 and
10.2 Hz), 4.22 (t, 1 H, J ) 9.6 Hz), 4.50 (d, 1 H, J ) 12.6 Hz),
4.73 (d, 1 H, J ) 12.6 Hz), 4.77 (d, 1 H, J ) 11.4 Hz), 4.84 (d, 1
H, J ) 11.4 Hz), 5.14 (s, 1 H), 5.46 (d, 1 H, J ) 1.2 Hz), 7.06-
7.63 (m, 15 H, ArH); 13C NMR (150 MHz, C6D6) δ 20.4, 68.3,
68.5, 73.1, 75.7, 77.1, 78.8, 78.9, 93.5, 101.7, 126.7, 127.7, 127.8,
127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.7, 129.0, 138.6,
139.3, 139.32, 168.4; HR-MALDI m/z [M + Na]+ calcd for C29H30-
NaO7 513.1889, found 513.1780. For the R-anomer, Rf ) 0.65 (15%
ethyl acetate in toluene): 1H NMR (600 MHz, C6D6) δ 1.65 (s, 3
H), 3.73 (t, 1 H, J ) 10.2 Hz), 3.92 (m, 1 H), 4.17 (m, 2 H), 4.31
(dd, 1 H, J ) 4.8 and 10.2 Hz), 4.64 (t, 1 H, J ) 10.0 Hz), 4.72
(d, 1 H, J ) 12.0 Hz), 4.75 (d, 1 H, J ) 12.0 Hz), 4.85 (d, 1 H, J
) 12.0 Hz), 5.00 (d, 1 H, J ) 12.0 Hz), 5. 46 (s, 1 H), 6.62 (d, 1
H, J ) 1.2 Hz), 7.23-7.76 (m, 15 H, ArH); 13C NMR (150 MHz,
C6D6) δ 20.3, 67.0, 68.8, 73.4, 74.0, 76.4, 76.5, 79.3, 93.0, 101.9,
126.7, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5,
128.6, 128.7, 129.0, 138.5, 138.6, 139.3, 168.2; HR-MALDI m/z
[M + Na]+ calcd for C29H30NaO7 513.1889, found 513.1562.
1-O-(3-Iodopropyl)-2,3-di-O-benzyl-4,6-O-benzylidine-â-D-
mannopyranoside (25). To a stirred solution of acetyl 2,3-di-O-
benzyl-4,6-O-benzylidine-R/â-D-mannopyranoside 23 (99 mg,
0.20 mmol) in DCM (1 mL, 0.17 mmol) at 0 °C was added TMSI
(31 µL, 2.2 mmol). After 30 min, MgO (16 mg, 0.4 mmol) and
trimethylene oxide (20 µL, 0.3 mmol) were added at the same
temperature, and then the reaction was stirred at room temperature
for 2d. Upon reaction completion, the mixture was diluted with
DCM (15 mL) and washed with satd Na2S2O3 (2 × 5 mL) and
brine (2 × 5 mL). The organic extract was dried (Na2SO4),
concentrated in vacuo and subjected to column chromatography
(hexane/ethyl acetate 90:10) to afford the title compound (65% over
a An analogous procedure was used to locate structure F. Bolded red
bonds and lines indicate a constrained bond length, angle, or dihedral angle
during the optimization procedure.
Geometries from structures C and D (Figure 3) were used as
starting points for a series of constrained optimizations (Scheme
7) aimed at finding analogous conformers of A and B. The
methylene bridge was removed and replaced with methyl and
(50) Mu¨ller, N.; Falk, A.Ball & Stick 4.0a12, Molecular Graphics
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Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M. L.
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
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Revision B.04: Gaussian, Inc.: Pittsburgh PA 2003.
two steps) as a colorless syrup: Rf ) 0.69 (15% ethyl acetate in
1
toluene); [R]23 -31.3 (c 0.15 in CHCl3); IR ν 2923, 1092; H
D
(52) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
NMR (600 MHz, C6D6) δ 1.66 (m, 2 H), 2.86 (m, 1 H), 2.95 (m,
1 H), 3.06 (m, 1 H), 3.19 (m, 1 H), 3.39 (dd, 1 H, J ) 3.0 and 9.6
Hz), 3.61 (m, 2 H), 3.66 (d, 1 H, J ) 3.0 Hz), 3.86 (s, 1 H), 4.17
(dd, 1 H, J ) 4.8 and 10.2 Hz), 4.29 (t, 1 H, J ) 9.5 Hz), 4.63 (d,
1 H, J ) 12.6 Hz), 4.78 (d, 1 H, J ) 12.0 Hz), 4.86 (d, 1 H, J )
(53) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J.
Phys. Chem. 1994, 98, 11623-11627.
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J. Org. Chem, Vol. 72, No. 13, 2007 4671

El-Badri et al.
acetate groups and an optimization was performed allowing
everything to relax with the exception of the indicated O-C-C-C
dihedral angle and indicated bonds and angles around the anomeric
carbon. The resulting geometry was then allowed to relax with the
exception of the indicated O-C-C-C dihedral angle. Finally all
constraints were removed, and the atoms were allowed to relax to
the transition structures shown in Figure 4.
OSTI 97-24412, and NIH Grant RR11973 provided funding for
the NMR spectrometers used in this project. D.J.T. and D.W.
gratefully acknowledge support from UC Davis and the
American Chemical Society’s Petroleum Research Fund and
thank Prof. Dan Singleton for information on processing the
computational KIE data.
Saddle points A and B were connected to reactant complexes
using intrinsic reaction coordinate57,58 searches (see the Supporting
Information for details). Energy values reported are in kcal/mol
and zero-point corrected (with no scaling factor applied). Vibrational
frequency analysis on the stationary points provided the frequencies
for the KIE calculations which were processed with QUIVER, a
program59 employing the method introduced by Bigeleisen and
Mayer.60 Tunneling corrections, while minimal, were applied using
the one-dimensional infinite parabolic barrier model.61,62
Supporting Information Available: NMR spectra and ad-
ditional details on computations. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO070229Y
(59) Saunders, W.; Laidig, K. E.; Wolfsberg, M. J. Am. Chem. Soc. 1989,
111, 8989-8994.
(60) Bigeleisen, J.; Mayer, M. G. J. Chem. Phys. 1947, 15, 261-267.
(61) Bell, R. P. Chem. Soc. ReV. 1974, 3, 513-544.
(62) Bell, R. P. The Tunnel Effect in Chemistry; Chapman and Hall:
London, 1980; pp 60-63.
Acknowledgment. National Science Foundation CHE-
0196482, NSF CRIF program (CHE-9808 183), NSF Grant
(57) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523-5527.
(58) Fukui, K. Acc. Chem. Res. 1981, 14, 363-368.
4672 J. Org. Chem., Vol. 72, No. 13, 2007