Reductive openings of benzylidene acetals revisited: A mechanistic scheme for regio- and stereoselectivity

Article abstract of DOI:10.1021/jo101184d

Despite the importance of regioselective reductive openings of cyclic acetals, mechanistic details are scarce. In this study 4,6-O-benzylidene acetals were used as model compounds for deciphering the mechanism of regioselective openings using a variety of

Full text of DOI:10.1021/jo101184d

pubs.acs.org/joc
Reductive Openings of Benzylidene Acetals Revisited: A Mechanistic
Scheme for Regio- and Stereoselectivity
Richard Johnsson,† Markus Ohlin,† and Ulf Ellervik*
Organic Chemistry, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden.
†These authors contributed equally to this work
ulf.ellervik@organic.lu.se
Received March 10, 2010
Despite the importance of regioselective reductive openings of cyclic acetals, mechanistic details are
scarce. In this study 4,6-O-benzylidene acetals were used as model compounds for deciphering the
mechanism of regioselective openings using a variety of reducing agents. Competitive isotopic studies
aiming at primary and secondary isotope effects, as well as an electron-deficient substrate, were used to
evaluate stereo- and regioselectivity. We show that there are three distinctly different mechanistic pathways.
In nonpolar solvents, such as toluene, the acetal is activated by the very reactive naked Lewis acid to give a
fully developed oxocarbenium ion that is then reduced by the borane, with low stereoselectivity. In THF the
reactivity of the Lewis acid is moderated by complex formation with the solvent. These reactions are thus
much slower and proceed through an intimate ion pair and thereby show high stereoselectivities. The
regioselectivity in these reactions is directed by the interaction between the Lewis acid and the most nucleo-
philic oxygen of the acetal, thus yielding a free 6-hydroxyl group. Finally, boranes such as BH3 NMe3 are
3
activated by Lewis acid, which results in the borane being the most electrophilic species, and consequently
the reaction shows inversed regioselectivity to give a free 4-hydroxyl group. These reactions proceed
through an oxocarbenium ion and thus show low stereoselectivity.
ꢀ
Introduction
and 1,3-dioxane systems and by Liptak et al. to open 4,6-O-
benzylidene acetals of various carbohydrate derivatives to
give 4-O-benzyl ethers and free 6-hydroxyl groups.2 Later
on, Garegg and co-workers introduced the milder reagent
combination NaCNBH3-HCl,3 which, interestingly, gave
the opposite regioselectivity, i.e. free 4-hydroxyl groups. To
get back to the original regioselectivity the Garegg group
turned to boranes and found that the reagent combination
Regioselective reductive openings of cyclic acetals have
emerged into a crucial tool for protective group introduc-
tion and manipulation, widely used in modern synthetic
organic chemistry. The reaction was first performed by
Doukas and Fontaine in 1951 to open the acetal diosgenin
by the reagent combination LiAlH4 and HCl.1 The active
Lewis acid in this reaction was later established as AlCl3
and the reagent combination LiAlH4-AlCl3 was intensely
explored by Brown et al. for openings of both 1,3-dioxolane
BH3 NMe3-AlCl3 gave different regioselectivity in differ-
3
ent solvents, i.e. free 4-OH in THF and free 6-OH in toluene
or dichloromethane/ether mixtures.4
(1) Doukas, H. M.; Fontaine, T. D. J. Am. Chem. Soc. 1951, 73, 5917–
5918.
(2) (a) Legetter, B. E.; Brown, R. K. Can. J. Chem. 1964, 42, 990–1004. (b)
Legetter, B. E.; Diner, U. E.; Brown, R. K. Can. J. Chem. 1964, 42, 2113–
(3) (a) Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1981, 93, C10–C11. (b)
Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97–101.
(4) (a) Ek, M.; Garegg, P. J.; Hultberg, H.; Oscarson, S. J. Carbohydr.
ꢀ
2118. (c) Liptak, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975, 44, 1–11. (d)
Liptak, A.; Imre, J.; Harangi, J.; Nanasi, P.; Neszmelyi, A. Tetrahedron 1982,
38, 3721–3727.
ꢀ
ꢀ ꢀ
ꢀ ꢀ
€
€
Chem. 1983, 2, 305–311. (b) Fugedi, P.; Garegg, P. J.; Kvarnstrom, I.;
Svansson, L. J. Carbohydr. Chem. 1988, 7, 389–397. (c) Fugedi, P.; Birberg,
W.; Garegg, P. J.; Pilotti, A. Carbohydr. Res. 1987, 164, 297–312.
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DOI: 10.1021/jo101184d
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Published on Web 11/01/2010
J. Org. Chem. 2010, 75, 8003–8011 8003
2010 American Chemical Society

Johnsson et al.
JOCArticle
Today, a plethora of reagent combinations is available for
regioselective reductive openings of cyclic acetals.5 Despite
the importance of these reactions for organic chemistry in
general and carbohydrate chemistry in particular, the rationale
for the regioselectivity is not fully understood and details for the
reductive steps are scarce.5b In an early mechanistic proposal by
Garegg6 the regioselective outcome was explained by the dif-
ference in steric bulk between AlCl3 and a proton. However,
there are several problems associated with this mechanistic
SCHEME 1. The Regioselectivity of Reductive Openings of
Benzylidene Acetals in THF Is Dependent on the Borane Rather
than the Lewis Acid
explanation. For example, BH3 NMe3-AlCl3 in THF gives
3
6-O-benzyl ethers, despite the obvious conclusion that the
strongly solvated AlCl3 THF would preferably associate with
3
the less sterically hindered O-6 to give 4-O-benzyl ethers.
Unlike reductive openings of cyclic acetals, there is a sub-
stantial body of experiments performed on acid-mediated
additions of carbon nucleophiles to acetals. This reaction
was initially introduced by Mukaiyama in 19747 and the
mechanistic details have later on been thoroughly investigated
by several groups. The reaction is usually performed at low
temperature, i.e. -78 °C, using the strong Lewis acid TiCl4 in
the nonpolar solvent CH2Cl2.
In a series of beautiful experiments, Denmark et al.
investigated the Lewis acid-catalyzed additions of carbon
nucleophiles to cyclic acetals.8 By using low-temperature
NMR experiments they observed the formation of an initial
complex between the Lewis acid and the acetal.9 Further on,
Denmark and co-workers showed that this initial complex
was not the reactive intermediate. Instead, the complex
rapidly equilibrated with intimate and external ion pairs as
well as oxocarbenium ions. This led to a stereochemical
continuum from high stereoselectivity in the case of intimate
ion pairs, i.e. SN2-like reactions, to stereo randomization in
the case of fully developed oxocarbenium ions.
The stereoselectivity of these nucleophilic reactions was
thus shown to be dependent on steric effects in the substrate,
the acetal configuration, the Lewis acid type, and stoichio-
metry, as well as solvent, temperature, and nucleophile
concentration. Generally, reactions between sterically un-
hindered acetals and weak Lewis acids proceeded through
intimate ion pairs while stronger Lewis acids, cation stabili-
zation, and sterically demanding acetals resulted in the
formation of oxocarbenium species. All reactions were per-
formed at low temperatures and only solvents without the
ability to form complexes with the Lewis acids were used (i.e.,
CH2Cl2, CHCl3, toluene, nitroethane, and hexane).
However, the situation is completely different in polar
solvents, such as THF, that will form complexes with the
Lewis acids. For example, AlCl3, a Lewis acid commonly used
in the acid-mediated reductive openings of cyclic acetals, forms
both mono- and dicoordinated complexes with THF.10 The
dissociation energy is estimated to be 90 kJ/mol for AlCl3 THF
3
and 132 kJ/mol for AlCl3 2THF.11 The formation of these com-
3
plexes moderates the reactivity of the Lewis acid. For example,
in the studies of Corcoran, it was found that the addition of even
moderate amounts of THF to the acid-mediated additions of
carbon nucleophiles resulted in a distinctly lowered reactivity.12
While reactions in CH2Cl2 generally were completed in less than
2.5 h at -78 °C, the addition of 20% THF resulted in reaction
times of 6 h at 0 °C. It is thus highly reasonable to assume that
the mechanism of Lewis acid-mediated reductions of cyclic
acetals, which are usually performed in THF at room tempera-
ture, differ from reactions with carbon nucleophiles in nonpolar
solvents at low temperatures.
The reductive opening of methyl 2,3-di-O-benzyl-4,6-O-ben-
zylidene-R-D-glucopyranoside (1) to give either the free 6-OH
(i.e., compound 2) or the free 4-OH (i.e., compound 3) is often
used as a model system for these reactions (Scheme 1). From our
own investigations as well as examples from the literature, we
found that the regioselectivity in THF is dependent on the type
of borane (i.e., BH3 complexed to NMe3 or THF) used for the
reduction rather than the Lewis acid (e.g., AlCl3, BF3 OEt2,
3
In(OTf)3, AgOTf, or Cu(OTf)2).13-15
This led us to the conclusion that the selectivity can be found
in the activation of certain borane complexes by Lewis acids, and
in previous publications we have explored a mechanism based
on borane activation.13 In nonpolar solvents, such as toluene,
the unsolvated AlCl3 is by far the strongest Lewis acid and it
will form an initial complex with the most nucleophilic acetal
oxygen, i.e. O-6 of the model compound 1 (Scheme 2, Path A).
The importance of the nucleophilicity of O-6 for the rate and
regioselectivity of acid-mediated reductive openings of benzyli-
dene acetals has been discussed in several recent reports13b,14,15
and is supported by calculations.16 The situation in THF is
(11) (a) Richards, R. L.; Thompson, A. J. Chem. Soc. A 1967, 1244–1248.
(b) Glavincevski, B.; Brownstein, S. K. Can. J. Chem. 1981, 59, 3012–3015.
(12) Corcoran, R. C. Tetrahedron Lett. 1990, 31, 2101–2104.
(13) (a) Johnsson, R.; Mani, K.; Cheng, F.; Ellervik, U. J. Org. Chem.
2006, 71, 3444–3451. (b) Johnsson, R.; Olsson, D.; Ellervik, U. J. Org. Chem.
(5) (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organci Chemistry, 4th ed.; Wiley-Interscience: Hoboken, NJ, 2007; pp
323-327. (b) Stick, R. V.; Williams, S. J. Carbohydrates: The Essential
Molecules of Life; Elsevier, London, UK, 2009; pp 51-52.
(6) Garegg, P. J. In Preparative Carbohydrate Chemistry; Hanessian, S.,
Ed.; Marcel Dekker: New York, 1996; pp 53-67.
ꢀ
2008, 73, 5226–5232. (c) Johnsson, R.; Cukalevski, R.; Dragen, F.; Ivaisevic,
D.; Johansson, I.; Petersson, L.; Elgstrand Wettergren, E.; Yam, K. B.;
Yang, B.; Ellervik, U. Carbohydr. Res. 2008, 343, 2997–3000.
(14) Shie, C.-R.; Tzeng, Z.-H.; Kulkarni, S. S.; Uang, B.-J.; Hsu, C.-Y.;
Hung, S.-C. Angew. Chem., Int. Ed. 2005, 44, 1665–1668.
(15) Wang, C.-C.; Luo, S.-Y.; Shie, C.-R.; Hung, S. C. Org. Lett. 2002, 4,
847–849.
(16) The electrostatic potential for compound 1 was calculated by using
density functional theory at the B3LYP/6-31G* level and default settings in
Spartan ’02 for Macintosh, Wave function, Inc., Irvine, CA. O-4: -32.9040
kcal/mol; O-6: -36.5412 kcal/mol.
(7) Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15–16.
(8) Denmark, S. E.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089–
8110.
(9) Denmark, S. E.; Willson, T. M.; Almstead, N. G. J. Am. Chem. Soc.
1989, 111, 9258–9260.
(10) (a) Derouault, J.; Granger, P.; Forel, M. T. Inorg. Chem. 1977, 16,
3214–3218. (b) Cowley, A. H.; Cushner, M. C.; Davies, R. E.; Riley, P. E.
Inorg. Chem. 1981, 20, 1179–1181.
8004 J. Org. Chem. Vol. 75, No. 23, 2010

Johnsson et al.
JOCArticle
SCHEME 2. The Regiochemical Outcome Is Directed by the
Relative Nucleophilicity of the Acetal Oxygens Toward the Free
Lewis Acid in Toluene (Path A), the Solvated Lewis Acid in THF
(Path B), or the Activated Borane (Path C)
slightly different. The strongly solvated AlCl3 THF is a stronger
3
Lewis acid compared to BH3 THF but both are relatively
3
inactive compared to the naked Lewis acid in nonpolar solvents
(Scheme 2, Path B). The reaction in THF is thus slow and might
take several hours to reach completion, even at room tempera-
ture, whereas reactions in toluene are usually completed within
minutes. The regioselectivities in these two cases are both
directed by the initial complex between the Lewis acid and the
more nucleophilic O-6.
FIGURE 1. Summary of kinetic studies of acetal openings. Reactions
opening the acetal to a free 6-hydroxyl group follow first order kinetics
(top graph: LiAlH4, black diamonds [right y-axis];, BH3 SMe2, red
circles; and BH3 THF, blue squares), while reactions to a free 4-hydro-
3
3
xyl group follow higher order kinetics (bottom graph: BH3 NMe3-
3
AlCl3, black diamonds; BH3 SMe2-AlCl3, red circles; and BH3
3
3
NMe3-AlCl3, blue squares). Graphs derived from data in ref 13c
.
The use of BH3 NMe3 as the reducing agent results in the
using BH3 NMe3-AlCl3-THF or BH3 NMe3-BF3 OEt2-
3
3
3
3
opposite regioselectivity. To deduce the mechanism for this
reaction we performed a series of kinetic experiments, 11BNMR
spectroscopy, and Hammett plots.13b At the beginning of the
THF, follow higher order kinetics. The higher order dependency
with respect to AlCl3 can be explained from the necessity of a
second Lewis acid molecule for activation of the initial complex.
reaction, only BH3 NMe3 was seen in the 11B NMR spectrum.
This mechanism will be further discussed (vide infra). The BH3
SMe2-AlCl3-THF system constitutes a borderline case (disso-
3
3
However, over the course of the reaction we observed the build-
up of a new peak, which corresponded to a BH2 group bound
to oxygen. We could not detect any traces of Me3NBH2þ. These
data suggest that the borane is cleaved from the amine during
the course of the reaction. Interestingly, when we added AlCl3
ciation energies: BH3 THF 83 kJ/mol; BH3 SMe2 101 kJ/mol;
3
3
BH3 NMe3 160 kJ/mol) yielding mostly free 6-OH (by a first
3
order reaction) but also free 4-OH (by a higher order reaction).
These results are summarized in Figure 1. Due to the very fast
reaction rates of both the original (i.e., NaCNBH3) and the
to a solution of BH3 NMe3 in THF, we could not detect any
3
reaction. However, on addition of the acetal, the reaction took
place. Our conclusion is that, in the presence of the acetal,
AlCl3 THF activates BH3 NMe3, which renders the borane
modified (i.e., BH3 NMe3 in toluene) Garegg conditions, we
3
were not able to investigate the kinetics of these reactions.
Clearly, reactions using activated and unactivated boranes
follow different mechanistic routes and cannot be described by
one unifying mechanism, but rather by a mechanistic scheme.
The aims of this investigation are to (i) investigate reactions in
nonpolar solvents to position them in the frame of the Denmark
mechanistic scheme; (ii) to investigate reactions with unacti-
vated boranes in THF with respect to regio- and stereoselectiv-
ity, (iii) to investigate reactions with activated boranes in THF to
explore the mechanistic details, and (iv) to categorize the
original and the modified Garegg reactions.
3
3
the most electrophilic species.13b Consequently, the regioselec-
tivity is now directed by addition of the borane to the more
nucleophilic O-6, giving the opposite product (Scheme 2, Path
C). This suggestion is further backed up by similar experiments
using BF3 OEt2 or metal triflates as the Lewis acid. The
3
complex AlCl3 NMe3 is very strong (199 kJ mol-1) compared
3
to the analogous BF3 NMe3 (130 kJ mol-1). According to our
activation theory, reactions using BF3 OEt2 should thus not
3
3
activate the reaction to the same degree, and indeed we observed
a much slower reaction rate using BF3 OEt2 compared to
3
Results and Discussion
AlCl3 THF.13c
3
To further explore the mechanism and to categorize different
reagent combinations, we investigated the reaction kinetics for a
number of reductive openings of compound 1.13c Openings to
To explore the stereochemical outcomes of these reduc-
tions, as well as secondary isotope effects, we synthesized the
deuterium-labeled benzylidene acetal, i.e. methyl 2,3-di-O-ben-
zyl-4,6-O-(benzylidene-1-d)-R-D-glucopyranoside (4) from ben-
zaldehyde-R-d1. In addition, methyl 2,3-di-O-benzyl-4,6-O-(p-
bromobenzylidene)-R-D-glucopyranoside (5) was synthesized to
give free 6-OH (i.e., compound 2), using BH3 THF-AlCl3-
3
THF or LiAlH4-AlCl3-Et2O, follow first order kinetics. On
the contrary, reactions yielding free 4-OH (i.e., compound 3),
J. Org. Chem. Vol. 75, No. 23, 2010 8005

Johnsson et al.
JOCArticle
SCHEME 3. Reductive Openings of Benzylidene Acetals: (a)
Openings To Free 6-OH and (b) Openings To Free 4-OHa
TABLE 1. Reductive Openings To Free 6-OH in Toluene
reagent
combination
ratio
6S:6Ra
2° KIE
(2:6)b
1° IE
(2:6)c
ratio
2:9d
entry
1
BH3 NMe3-
42:58
0.92
2.8
58:42
3
AlCl3-toluene
a4 was opened with undeuterated reagents. bEquimolar mixtures of 1
and 4 were reductively opened using undeuterated reducing agents. 1
c
was opened using equimolar mixtures of deuterated and undeuterated
reagents. dEquimolar mixtures of 1 and 5 were opened using undeuter-
ated reducing agents.
SCHEME 4. Mechanistic Details of Reductive Opening To
Give a Free 6-OH in Toluene
aProduct distributions were determined based on NMR spectrosco-
py. The stereochemical assignments of 6R and 6S were made by
2-dimensional NMR (COSY and NOESY experiments) and confirmed
by previously published data.14 The shift for benzylic proton on 6S is
4.63 ppm and the benzylic proton on 6R is 4.86 ppm. The absolute
stereochemistry for 7 could not be determined and the r and s designa-
tion is arbitrary. The shift for the benzylic proton of 7r is 4.57 ppm and
the benzylic proton of 7s is 4.53 ppm.17
.
explore electronic effects (Scheme 3). The p-bromobenzylidene
group was chosen to give a small but measurable electron-
withdrawing effect compared to the unsubstituted compound 1
(Hammett σpara(Br) = 0.26).
reductive step. However, since this competitive experiment
only shows the relative reaction rates of the reduction of
the intermediate oxocarbenium ion, the data are not con-
clusive for determination of the RCS. Finally, to investigate
electronic effects, we performed a competitive study using
equimolar mixtures of 1 and the p-bromobenzylidene analo-
gue 5 (Scheme 2, Table 1). This reaction gave a 2:9 ratio
of 58:42, i.e. a modest discrimination for the more electron
rich 1 over 5.
The low stereoselectivity, in combination with the inverse
secondary isotope effect and the low discrimination shown
by the electron-withdrawing group suggest that the reaction
proceeds with a fast formation of an oxocarbenium ion
followed by a rate-controlling reductive step (Scheme 4).
Lewis acid-mediated nucleophilic substitutions of cyclic
acetals using TiCl4 in nonpolar solvents, usually CH2Cl2,
have been investigated by several groups. Mori et al.18
showed that nucleophilic substitutions, which are similar to
the reductive openings using AlCl3 in toluene, proceed
through an oxocarbenium ion. Further on, Yamamoto
et al. investigated the importance of the nucleophilicity of
the carbon nucleophiles used in Lewis acid-mediated nu-
cleophilic substitutions to cyclic acetals.19 The results indi-
cated that, in nonpolar solvents (CH2Cl2) using the strong
Lewis acid TiCl4, carbon nucleophiles with low nucleophi-
licity, i.e. silicon- and boron-substituted compounds, gen-
erally react through the oxocarbenium ion pathway while
strong nucleophiles, i.e. tributylstannyl derivatives, react
through an SN2 pathway. Denmark and Almstead also
A. Reactions in Nonpolar Solvents. We first investigated
the modified Garegg conditions, i.e. BH3 NMe3-AlCl3 in
3
toluene. The deuterium-labeled compound 4 was thus
opened using undeuterated BH3 NMe3 and AlCl3 in toluene
3
at room temperature. These reactions were completed in less
than 5 min, which further demonstrate the high reactivity of
the naked Lewis acid in the nonpolar solvent toluene. The
product distribution was determined based on NMR spec-
troscopy.17 The results are summarized in Table 1. The reac-
tion gave a stereoisomeric ratio 6S:6R of 42:58, which points
to a significant degree of oxocarbenium ion character of the
reactive intermediate. To further investigate the mechanism,
we performed competitive isotope studies where equimolar
mixtures of 1 and 4 were reductively opened using BH3
3
NMe3-AlCl3 in toluene and the distribution between 2 and
6S/R was determined by NMR spectroscopy.17 We thus
observed an inverse secondary isotope effect of 0.92. An
inverse, rather than a normal, secondary kinetic isotope
effect can be explained by either an SN2-type reaction, where
the carbon is more available for the deuterated compound,
or a reaction mechanism where the rate-controlling step
(RCS) involves a change in hybridization of the former acetal
carbon from sp2 to sp3. In our case, the latter explanation is
the most plausible, taken into consideration the low stereo-
selectivity observed in the reaction. Primary isotope effects
were determined for the opening of 1 using equimolar
mixtures of BH3 NMe3/BD3 NMe3 under the conditions
3
3
of entry 1 in Table 1 to give mixtures of 2 and 6. Reaction for
4 min (34% yield) gave an isotope effect of 2.8, while shorter
reaction time (2 min, 29% yield) gave a similar effect (2.6).
This primary isotope effect can be explained by a very fast
formation of the oxocarbenium ion followed by a slower
(17) The peaks were overlapping and the areas for each compound were
calculated from several 1H NMR spectra at 400 or 500 MHz in CDCl3 and C6D6.
(18) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.; Yamamoto, H.;
Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107–6115.
(19) Yamamoto, Y.; Nishii, S.; Yamada, J.-i. J. Am. Chem. Soc. 1986,
108, 7116–7117.
8006 J. Org. Chem. Vol. 75, No. 23, 2010

Johnsson et al.
JOCArticle
TABLE 2. Reductive Openings To Free 6-OH
ratio 2° KIE 1° IE ratio
6S:6Ra (2:6)b (2:6)c 2:9d
entry
reagent combination
BH3 THF-AlCl3-THF
1
2
3
97:3
97:3
0.85
2.4 73:27
3
BH3 SMe2-AlCl3-THF
3
LiAlH4-AlCl3-Et2O-CH2Cl2 96:4
0.92
a4 was opened with undeuterated reagents. bEquimolar mixtures of 1
and 4 were reductively opened using undeuterated reducing agents. c1
was opened using equimolar mixtures of deuterated and undeuterated
reagents. dEquimolar mixtures of 1 and 5 were opened using undeut-
erated reducing agents.
FIGURE 2. Competitive isotope study of reductive opening of equi-
investigated the importance of the nucleophile and came to
similar conclusions.20
Finally, in an ingeniously designed experiment using a
deuterated acetal, Sammakia and Smith showed that nucleo-
philic addition of allylstannes, mediated by TiCl4 in CH2Cl2,
proceeds through an oxocarbenium intermediate.21 Reduc-
molar mixtures of 1 and 4 using (a) BH3 THF-AlCl3-THF and
3
(b) BH3 NMe3-AlCl3-THF.
3
SCHEME 5. Mechanistic Details of Reductive Opening To
Give a Free 6-OH in THF
tive openings using BH3 NMe3-AlCl3 in the nonpolar
3
solvent toluene thus represent one extreme in the mechanistic
scheme presented by Denmark et al. Since no strong com-
plexes can be formed between toluene and AlCl3, reactions in
this solvent give “naked” and very reactive Lewis acids and
consequently proceed via fully developed oxocarbenium ions
with low stereoselectivity in the reductive step.
To further emphasize the importance of the naked Lewis acid
in nonpolar solvents we repeated the reductive opening of
the model compound 1 using AlCl3 THF and BH3 NMe3 in
3
3
toluene. Thus, AlCl3 was dissolved in THF, stirred at room tem-
perature for 1 h, and then dried under vacuum to yield AlCl3
3
THF. Compound 1 was then opened with this reagent to give a
63:37 mixture of 2 and 3. Thus, by simply using AlCl3 THF
3
instead of AlCl3 we were able to partly reverse the regioselec-
tivity. To conclude, since AlCl3 is very reactive in nonpolar
solvents such as toluene, it will react with the more nucleophilic
oxygen of the acetal rather than activate BH3 NMe3. Thus, the
3
Lewis acid will form an initial complex with the acetal oxygen,
and the acetal is opened to an oxocarbenium ion. On the con-
trary, by complexation with THF, the reactivity is lowered and a
viable reaction pathway is a tandem reaction with formation of
observed a secondary isotope effect of 0.85, independent of
reaction time (Figure 2a). A similar result was obtained for the
AlCl3 NMe3 resulting in reversed regioselectivity as discussed in
3
detail in section C below, as well as a normal complexation with
the acetal as described in section B.
ꢀ
original Liptak conditions (Table 2, entry 3).
The combination of high stereoselectivities and a strong
inverse secondary kinetic isotope effect can be explained by an
SN2-type reaction, where the carbon is more available for the
deuterated compound. Primary isotope effects were determined
B. Reductive Openings Using Unactivated Boranes in THF.
Compound 4 was opened by reductive conditions aiming at a
free 6-OH (Scheme 3, path a) and the product distribution was
determined based on NMR spectroscopy.17 The results are
summarized in Table 2.
for the opening of 1 using equimolar mixtures of BH3 THF/
3
BD3 THF under the conditions of entry 1 in Table 2 to give
3
The reagent combinations BH3 THF-AlCl3-THF and
mixtures of 2 and 6. Reaction for 40 min (11% yield) gave an
isotope effect of 2.4, while longer reaction times (60 min, 20%
yield) lowered the effect to 1.4. This weak primary isotope effect
may indicate that the reductive step is not the rate-controlling
step. Finally, to investigate electronic effects, we performed
a competitive study using equimolar mixtures of 1 and the
p-bromobenzylidene analogue 5 (Scheme 3). The reaction was
run for 2 h (17% isolated yield) to give a 73:27 ratio of 2:9.
Longer reaction times (7.5 h) gave only minor changes (ratio
76:24). Since the reaction is slow, compared to reactions in
nonpolar solvents, and shows first-order kinetics with respect to
AlCl3, we propose that the rate-controlling step is the formation
of an initial complex (Scheme 5). This initial complex is then, in
full accordance with Denmark’s findings,9 equilibrated into
an intimate ion pair, with low oxocarbenium ion character.
3
ꢀ
BH3 SMe2-AlCl3-THF, as well as the original Liptak condi-
3
tions using LiAlH4-AlCl3-Et2O-CH2Cl2, resulted in high
stereoselectivities (approximately 97:3). Since the three different
reagents result in similar stereoselectivities we assume that they
follow a reaction mechanism with a highly ordered reactive inter-
mediate. To further investigate the mechanism, we performed
competitive isotope studies where equimolar mixtures of 1 and 4
were reductively opened using BH3 THF-AlCl3-THF. Reac-
3
tions were run for different times and the distribution between
2 and 6S/R was determined by NMR spectroscopy.17 We thus
(20) Denmark, S. E.; Almstead, N. G. J. Org. Chem. 1991, 56, 6485–6487.
(21) (a) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1992, 114, 10998–
10999. (b) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116, 7915–
7916.
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Johnsson et al.
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The intimate ion pair is subsequently reduced by the reductive
agent, resulting in high stereoselectivity. The major diastereomer
is the one expected from a direct attack on the intimate ion pair.
These data then represent the other extreme in the Denmark
mechanistic scheme, i.e. the intimate ion pair. Our observations
are thus in full accordance with earlier studies, where reactions
between sterically unhindered acetals and weak Lewis acids
usually proceeded through intimate ion pairs.8 It is reasonable
TABLE 3. Reductive Openings To Free 4-OH in THF
ratio 2° KIE 1° IE ratio
7r:7sa (3:7)b (3:7)c 3:8d
entry
reagent
BH3 NMe3-AlCl3-THF
1
2
3
4
57:43
1.4
4.9 87:13
3
BH3 NMe3-AlCl3-H2O-THF 58:42
3
3
BH3 SMe2-AlCl3-THF
52:48
56:44
NaCNBH3-HCl-Et2O-THF
1.4
a4 was opened with undeuterated reagents. bEquimolar mixtures of 1and
4 were opened using undeuterated reducing agents. 1 was opened using
c
equimolar mixtures of deuterated and undeuterated reagents. dEquimolar
mixtures of 1 and 5 were opened using undeuterated reducing agents.
to assume that the complex AlCl3 THF is a substantially
3
weaker Lewis acid compared to AlCl3 in toluene.
C. Reductive Openings Using Activated Boranes in THF.
Amine boranes are versatile reducing agents and their reac-
tions have been thoroughly studied in reactions such as
hydroboration, reduction of ketones, and hydrolysis. Despite
their importance, mechanistic details of the reductive openings
of acetals are nonexistent. However, some conclusions can be
drawn from the results by Brown and co-workers on acid-
catalyzed reduction of ketones.22 Brown propose three different
mechanistic possibilities for reactions using borane-amine
complexes in combination with acids: (A) prior dissociation of
the borane-amine complex in the presence of acidic solvents,
(B) activation of the reducible group by interaction with the
acid, or (C) activation of the borane-amine complex by
association with the Lewis acid. In a series of experiments Brown
et al. observed that the mechanism of reduction of cyclohex-
the mechanistic proposal by Saito et al.26 This was obviously an
oversimplified picture and we now present a more detailed study
of the reaction mechanism. Compound 1 was thus opened by
conditions aiming at a free 4-OH, as illustrated in Scheme 3,
Path b. The distribution between 7r/s was determined by NMR
spectroscopy (Table 3).
The opening of compound 4, using BH3 NMe3 activated
3
by AlCl3, gave a 57:43 ratio of 7r:7s (Table 3, entry 1). We have
earlier shown that BH3 NMe3 can be activated by Lewis acids
3
(i.e., AlCl3 or BF3 OEt2) as well as Brønsted acids (i.e., water in
3
combination with AlCl3) and it is well-known that a small
amount of water speeds up the reductive openings of benzyli-
dene acetals.27 Reduction of 4, using BH3 NMe3 activated by
AlCl3 and water gave a similar ratio of 7r:7s (Table 3, entry 2).
3
The opening of 4 using BH3 SMe2-AlCl3 gave 6 as the major
3
anone using BH3 NMe3 was drastically different in THF
3
product (Table 2, 72%). In addition we isolated 7 (11%) in a
52:48 ratio of r:s (Table 3, entry 3). Finally, the original Garegg
conditions (Table 2, entry 4) gave similar stereochemical out-
come and it is reasonable that NaCNBH3 is activated by the
Brønsted acid to give H2BCN that reacts analogous to BH3.28
These data indicate a less ordered reactive intermediate, possibly
an oxocarbenium ion, in reactions yielding a free 4-OH. Further
on, we performed competitive isotope studies with equimolar
compared to that in acetic acid. This is similar to findings by
Jones, who observed the same stereoselectivity in the reduction
of 4-tert-butylcyclohexanone by diborane or BH3 NMe3 in the
3
absence of acid.23 However, in the presence of BF3 OEt2, the
3
stereochemical outcome was essentially the same using diborane
but changed dramatically using the BH3 NMe3. Similar to our
3
findings, Jones also observed a strong rate enhancement in the
acid-catalyzed reactions. Other clues can be found in the
hydrolysis reactions of borane-amine complexes, where the
mixtures of 1 and 4, opened by BH3 NMe3-AlCl3-THF
3
(Table 3, entry 1). Reactions were run for different times and
the distribution between 3, 7s, and 7r was determined by NMR
spectroscopy.17 We thus found the isotope effect to be time
dependent (Figure 2b) and a normal secondary isotope effect of
1.4 was determined from the kinetic region. Similar experiments
using NaCNBH3-HCl-THF gave comparable isotope effects
(Table 3, entry 4). A normal secondary isotope effect indicates
that the rehybridization in the transition state goes from sp3
to sp2. In this case it would point to formation of an oxocarbe-
nium ion as the rate-controlling step.
hydrolysis of BH3 NMe3 follows first order dependency in both
3
acid and borane, which indicates initial association of the acid to
the complex.24 Later investigations of the reactions with amine
boranes with carbenium ions showed first order dependency
with respect to both the borane-amine complex and the
carbenium ion, and a primary kinetic isotope effect of 1.81,
which points toward a polar transition state.25 In an interesting
paper by Hung and co-workers, compound 1 was reductively
opened using a variety of borane reagents in combination with a
catalytic amount of Cu(OTf)2.14 The regioselectivities were
similar to our findings and the reaction rates were closely
associated with the nucleophilicity of O-6. Furthermore, the
Primary isotope effects were determined for the opening of
1 using equimolar mixtures of BH3 NMe3/BD3 NMe3. The
BD3 NMe3 reagent was prepared by mixing BD3 THF with an
3
3
3
3
use of BD3 THF in combination with Cu(OTf)2 in THF gave a
3
equal amount of NMe3 in THF prior to the reaction. The
primary isotope effects were time dependent and shifted from
4.9 (2 min) to 1.6 (10 min). Several different effects can explain
the origin of these rather strong “primary” isotope effects. First,
a normal primary kinetic isotope effect can probably be seen
from the transfer of the hydride/deuteride. Second, other iso-
tope effects may arise from differences in dissociation constants
for BD3 NMe3 and BH3 NMe3. Similar experiments using 1:1
stereoselectivity (i.e., 5:1) in full agreement with our results for
unactivated boranes (section B). Reduction using Et3SiH and a
catalytic amount of Cu(OTf)2 gave regioselective opening to a
free 4-OH. Interestingly, this reaction showed stereo randomiza-
tion, similar to openings using activated boranes.
We have earlier proposed a mechanistic explanation for the
regioselectivity for the reduction using BH3 NMe3,13b where
the addition of the hydrogen took place in a similar fashion as
3
3
3
mixtures of NaCNBH3/NaCNBD3 indicated an exchange of
deuterium in the reducing agent and no primary effects could be
(22) Brown, H. C.; Murray, L. T. Inorg. Chem. 1984, 23, 2746–2753.
(23) Jones, W. M. J. Am. Chem. Soc. 1960, 82, 2528–2532.
(24) Ryschkewitsch, G. E. J. Am. Chem. Soc. 1960, 82, 3290–3294.
(25) Funke, M.-A.; Mayr, H. Chem.;Eur. J. 1997, 3, 1214–1222.
(26) Saito, S.; Kuroda, A.; Tanaka, K.; Kimura, R. Synlett 1996, 231–
233.
ꢀ
(27) (a) Hernandez-Torres, J. M.; Achkar, J.; Wei, A. J. Org. Chem. 2004,
69, 7206–7211. (b) Sherman, A. A.; Mironov, Y. V.; Yudina, O. N.;
Nifantiev, N. E. Carbohydr. Res. 2003, 338, 697–703.
(28) Lane, C. F. Aldrichim. Acta 1975, 8, 3–10.
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Johnsson et al.
JOCArticle
SCHEME 7. Reductive Openings of Galactose Derivativesa
SCHEME 6. Mechanistic Details of Reductive Opening To
Give a Free 4-OH in THF
aConditions: (a) BH3 NMe3, AlCl3, THF.
3
data render a steric explanation for the regioselectivity less
plausible. The analogous reductive opening of compound 10
using unactivated BD3 THF and AlCl3 resulted in a free 6-OH
3
group with a high stereoselectivity of 87:13 (Supporting
Information), in full accordance with our results described
in section B.2c
Conclusions
We conclude that the regioselectivity of Lewis acid-catalyzed
reductive openings of benzylidene acetals can be directed by the
reducing reagent. In the case of unactivated boranes and alanes
(e.g., BH3 THF or LiAlH4), the regioselectivity is directed by
3
the complexation of the Lewis acid (e.g., AlCl3) with the most
electron-rich oxygen of the acetal to give free 6-OH. The
stereoselectivities depend on the solvent and represent a mechan-
istic continuum from an intimate ion pair in THF, resulting in
high stereoselectivity, to fully developed oxocarbenium ions in
toluene. The latter reaction, which is very fast due to naked Lewis
acids, results in stereo randomization. In THF, the Lewis acid is
reliably measured, i.e. reactions with HCl gave an isotope effect
of 2.7 while DCl lowered the effect to 1.1. A control experiment
using only NaCNBD3 (96% D) gave a large proportion (43%)
of the unlabeled compound 3. It is thus reasonable to assume
that the Brønsted acid catalyzed the exchange of deuterium for
hydrogen in the reducing agent. The reverse reaction with DCl
has been reported for BH3 NMe3.29 Finally, to investigate
3
complexed to the solvent (e.g., AlCl3 THF) and these reactions
3
electronic effects, we performed a competitive study using a
1:1 mixture of 1 and the p-bromobenzylidene analogue 5. Short
reaction times (4 min) gave an 87:13 ratio of 3:8 while longer
reaction times (2.5 h) diminished the ratio slightly to 83:17. The
rather strong influence of the electron-withdrawing group also
points toward a rate-controlling formation of an oxocarbenium
ion. We thus propose a mechanistic scheme where the regios-
electivity is determined by the fast formation of an initial com-
plex with the borane, activated by the Lewis acid. This initial
complex is then transformed into an oxocarbenium ion, aided
by a second equivalent of the Lewis acid, in the rate-controlling
step. Hence the π-electrons are considered to be donated into the
vacant p-orbital of the borane prior to the fast reduction
(Scheme 6). The oxocarbenium ion is then reduced with low
stereoselectivity to give the free 4-OH.
are thus significantly slower and much more selective compared
to reactions in nonpolar solvents. On the contrary, activation of
boranes (e.g., BH3 NMe3) using Lewis or Brønsted acids results
3
in the borane being the most electrophilic species that will form
an initial complex with the most electron-rich oxygen of the
acetal. These reactions, which result in free 4-OH, proceed
through an oxocarbenium ion, and thus give low stereoselectiv-
ity. The mechanistic scheme is summarized in Scheme 8.
These mechanistic details provide a foundation for the
design and limitations of new reducing agents for acetals. It is
most certainly possible to fine-tune the reactivity and selec-
tivity by a well-designed combination of borane, solvent,
Lewis acid, and temperature as indicated by the plethora of
reagents presented for this reaction.13b
To exclude the possibility of steric rather than stereoelec-
tronic explanations for these results, we also included reductive
openings of two galactose derivatives with different degrees of
steric hindrance toward O-4 (Scheme 7).
Experimental Section
For general experimental details and detailed experimental
conditions see the Supporting Information.
Opening of methyl 2,3-di-O-benzyl-4,6-O-(benzylidene)-
β-D-galactopyranoside (10) using BD3 NMe3 and AlCl3
gave, as expected, a free 4-hydroxyl group (i.e compound 12)
with low stereoselectivity, i.e. 61:39 (Supporting Information),
similar to earlier results using compound 1.3b,4a Reductive
General Procedure for Reductive Openings of Compounds 1, 4,
and 5. Compounds 1, 4, or mixtures of 1:4 or 1:5 (0.11 mmol) were
dissolved in suitable solvents (THF, CH2Cl2:Et2O, or toluene). The
reducing agent (BH3 NMe3, BD3 NMe3, BH3 SMe2, BH3 THF,
3
3
3
3
3
BD3 THF, LiAlH4, LiAlD4, NaCNBH3, or NaCNBD3) was
3
added followed by the acid (AlCl3, HCl, or DCl) and the mixtures
were stirred for suitable time periods (2 min to 3.5 h). The mixtures
were diluted with ether and washed once with NaHCO3 (sat. aq.)
and concentrated from toluene. The residue was chromatographed
(SiO2, toluene/EtOAc 5:1) to give the product.
openings of the less sterically hindered 11 using BH3 NMe3
3
and AlCl3 gave mainly opening to free 4-OH (i.e., compound
13, 94%) with only minor reverse opening (6%). This means
that, despite the lowered steric hindrance for O-4, the reaction
still proceeds to give free 4-OH rather than 6-OH. Thus, these
Methyl 2,3-Di-O-benzyl-4,6-O-(benzylidene-1-d)-r-D-glucopyra-
noside (4). Benzaldehyde-R-d1 (0.45 mL, 4.43 mmol) was dissolved
in MeOH (4 mL). CH(OCH3)3 (0.83 mL, 7.59 mmol) was added
followed by Amberlite IR-120 Hþ (19 mg). The mixture was heated
(29) Davis, R. E.; Brown, A. E.; Hopmann, R.; Kibby, C. L. J. Am. Chem.
Soc. 1963, 85, 487.
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Johnsson et al.
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SCHEME 8. Mechanistic Proposal for Reductive Openings of 4,6-O-Benzylidene Acetals
in a microwave to 75 °C for 30 min, filtered, and concentrated to
give the corresponding R,R-dimethoxy acetal. The R,R-dimethoxy
acetal was dissolved in MeCN (10 mL) followed by addition
of methyl R-D-glucopyranoside (723 mg, 3.72 mmol) and pTSA
(29 mg, 0.15 mmol). The mixture was stirred at rt and then refluxed
for 21 h. NEt3 (2 mL) was added and the mixture was concentrated.
The residue was chromatographed (SiO2, toluene/EtOAc 1:2) to
give methyl 4,6-O-(benzylidene-1-d)-R-D-glucopyranoside (365 mg,
Hz), 99.4, 82.2, 79.3, 78.7, 75.5, 73.9, 69.2, 62.5, 55.5. HRMS calcd
for C28H29DO6Na (M þ Na) 486.2003, found 486.2003.
Methyl 2,3-Di-O-benzyl-4,6-O-(p-bromobenzylidene)-r-D-gluco-
pyranoside (5). p-Bromobenzaldehyde (513 mg, 2.77 mmol) was
dissolved in MeOH (4 mL). CH(OCH3)3 (0.52 mL, 4.74 mmol) was
added followed by Amberlite IR-120 Hþ (11 mg). The mixture was
heated in a sealed tube to 75 °C for 3 h, filtered, and concentrated to
give the corresponding R,R-dimethoxy acetal. The R,R-dimethoxy
acetal was dissolved in MeCN (7 mL) followed by addition of
methyl R-D-glucopyranoside (456 mg, 2.35 mmol) and pTSA
(36 mg, 0.21 mmol). The mixture was stirred at rt for 30 min and
then refluxed for 24 h. NEt3 (2 mL) was added and the mixture was
concentrated. The residue was chromatographed (SiO2, toluene/
EtOAc 1:2) to give methyl 4,6-O-(p-bromobenzylidene)-R-D-gluco-
pyranoside (164 mg, 19%). [R]23D þ75.3 (c 0.7, CHCl3). 1H NMR
(CDCl3) δ 7.50, 7.37 (ABq, 2H each, J = 8.4 Hz, Ar), 5.49 (s, 1H,
ArCH[OR]2), 4.80 (d, 1H, J=3.9Hz, H-1), 4.29 (dd, 1H, J=9.5, 4.0
Hz, H-6), 3.92 (t, 1H, J=9.2 Hz, H-3), 3.71-3.82 (m, 2H, H-5, H-6),
3.63 (dd, 1H, J=8.9, 3.7 Hz, H-2), 3.49 (t, 1H, J=9.2 Hz, H-4),
3.46 (s, 3H, CH3). 13C NMR (CDCl3) δ 136.2, 131.6, 128.2, 123.5,
101.3, 99.9, 81.0, 73.1, 71.9, 69.0, 62.4, 55.8. HRMS calcd for
C14H17O6BrNa (M þ Na) 383.0106, found 383.0100. Methyl 4,6-O-
(p-bromobenzylidene)-R-D-glucopyranoside (112 mg, 0.31 mmol)
and TBAI (12 mg, 0.03 mmol) were dissolved in DMF (3 mL), then
the mixture was cooled to 0 °C under N2. After 17 min NaH (95 mg,
60% in oil) was added and after an additional 34 min benzyl
bromide (0.09 mL, 0.77 mmol), then the mixture was stirred for 2 h.
NH4Cl (satd.) was added and the mixture was extracted two times
with ether. The combined organic phases were dried (MgSO4) and
concentrated. The residue was chromatographed (SiO2, toluene/
EtOAc 4:1) to give 5 (42 mg, 25%). [R]22D -36.8 (c 0.8, CHCl3). 1H
NMR (CDCl3) δ 7.51 (d, 2H, J=1.9, Ar), 7.28-7.40 (m, 12H, Ar),
5.49 (s, 1H, ArCH[OR]2), 4.87, 4.84 (ABq, 1H each, J=11.3 Hz,
35%). [R]20 þ112.0 (c 0.4, CDCl3). 1H NMR (CDCl3) δ 7.48-
D
7.50 (m, 2H, Ar), 7.35-7.39 (m, 3H, Ar), 4.79 (d, 1H, J = 3.9 Hz,
H-1), 4.29 (dd, 1H, J = 9.6, 4.3 Hz, H-6), 3.92 (t, 1H, J = 9.2 Hz,
H-3), 3.71-3.84 (m, 2H, H-5, H-6), 3.62 (dd, 1H, J = 9.0, 3.7 Hz,
H-2), 3.49 (t, 1H, J = 9.3 Hz, H-4), 3.45 (s, 3H, CH3). 13C NMR
(CDCl3) δ 137.1, 129.4, 128.5, 126.4, 101.7 (t, J = 24.8 Hz), 99.9,
81.0, 73.0, 71.9, 69.0, 62.5, 55.7. HRMS calcd for C14H17DO6Na
(M þ Na) 306.1064, found 306.1065. Methyl 4,6-O-(benzylidene-1-
d)-R-D-glucopyranoside (362 mg, 1.28 mmol) and TBAI (49 mg,
0.13 mmol) were dissolved in DMF (10 mL) and the mixture was
cooled to 0 °C under N2. After 15 min, NaH (381 mg, 60% in oil)
was added, and after an additional 30 min benzyl bromide (0.38 mL,
3.19 mmol), then the mixture was stirred for 105 min. NH4Cl (sat.
aq.) was added and the mixture was extracted two times with ether.
The combined organic phases were washed once with brine, dried
(MgSO4), and concentrated. The residue was chromatographed
(SiO2, toluene/EtOAc 4:1) to give 4 (578 mg, 97%). [R]20D -25.0
(c 1.0, CDCl3). 1H NMR (CDCl3) δ 7.48-7.50 (m, 2H, Ar), 7.28-
7.41 (m, 13H, Ar), 4.84, 4.91 (ABq, 1H each, J = 11.2 Hz, PhCH2),
4.70, 4.86 (ABq, 1H each, J=12.2 Hz, PhCH2), 4.59 (d, 1H, J=3.7
Hz, H-1), 4.27(dd, 1H,J=10.1, 4.7 Hz, H-6), 4.05 (t, 1H, J=9.3 Hz,
H-3), 3.80-3.86 (m, 1H, H-5), 3.71 (t, 1H, J=10.2 Hz, H-6), 3.60
(t, 1H, J=9.4 Hz, H-4), 3.56 (dd, 1H, J=9.3, 3.7 Hz, H-2), 3.41
(s, 3H, CH3). 13C NMR (CDCl3) δ 138.9, 138.3, 137.5, 129.1, 128.6,
128.44, 128.35, 128.3, 128.2, 128.1, 127.7, 126.2, 101.0 (t, J=24.7
8010 J. Org. Chem. Vol. 75, No. 23, 2010

Johnsson et al.
JOCArticle
PhCH2), 4.85 (d, 1H, J=12.2 Hz, PhCH2), 4.70 (d, 1H, J=12.2 Hz,
PhCH2), 4.59 (d, 1H, J=3.7Hz, H-1), 4.25(dd, 1H, J=10.0, 4.7 Hz,
H-6), 4.02 (t, 1H, J=9.3 Hz, H-3), 3.80 (dt, 1H, J=9.9, 4.7 Hz,
H-5), 3.68 (t, 1H, J=10.2 Hz, H-6), 3.57 (t, 1H, J=9.4 Hz, H-4),
3.55 (dd, 1H, J = 9.3, 3.7 Hz, H-2), 3.40 (s, 3H, CH3). 13C NMR
(CDCl3) δ 138.8, 138.2, 136.6, 131.5, 128.6, 128.5, 128.3, 128.1,
127.97, 127.95, 127.8, 123.2, 100.7, 99.4, 82.2, 79.4, 78.7, 75.5,
73.9, 69.2, 62.4, 55.5. HRMS calcd for C28H29O6BrNa (MþNa)
563.1045, found 563.1028.
Acknowledgment. The Swedish Research Council, Lund
University, The Lennander Foundation, and The Crafoord
Foundation supported this work
Supporting Information Available: Experimental details,
compound characterization data, and NMR spectra of reaction
mixtures. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 23, 2010 8011