Regioselective esterification of vicinal diols on monosaccharide derivatives via Mitsunobu reactions

Article abstract of DOI:10.1021/ol801316f

(Chemical Equation Presented) We have carried out a series of esterification reactions of secondary alcohols derived from D-glucose, D-mannose, and D-galaclose via the Mitsunobu reaction. The benzoylation reaction of vicinal diols derived from monosacchar

Full text of DOI:10.1021/ol801316f

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4203-4206
Regioselective Esterification of Vicinal
Diols on Monosaccharide Derivatives via
Mitsunobu Reactions
Guijun Wang,* Jean-Rene Ella-Menye, Michael St. Martin, Hao Yang, and
Kristopher Williams
Department of Chemistry, UniVeristy of New Orleans, New Orleans, Louisiana 70148
gwang2@uno.edu
Received June 10, 2008
ABSTRACT
We have carried out a series of esterification reactions of secondary alcohols derived from D-glucose, D-mannose, and D-galactose via the
Mitsunobu reaction. The benzoylation reaction of vicinal diols derived from monosaccharides under Mitsunobu conditions afforded monobenzoates
with retention of stereochemistry only. The regioselectivity of these reactions depends on the stereochemistry of the sugar starting material.
The Mitsunobu reactions on these diols may be used for the selective protection of other vicinal secondary hydroxyl groups.
The Mitsunobu reaction is widely used in organic synthesis
to introduce various functional groups under mild condi-
tions.1-3 An especially useful aspect of the reaction is the
inversion of stereogenic centers via an SN2 mechanism.
Typically, a secondary hydroxyl group can be converted to
the corresponding ester with inverted stereochemistry using
triphenylphosphine (TPP) and diethyl azodicarboxylate
(DEAD) as shown in Scheme 1.4,5 The alcohol 1 is converted
to the ester 2, and TPP and DEAD are converted to
triphenylphosphine oxide (TPPO) and diethyl hydrazinedi-
carboxylate (EtO2CNHNHCO2Et). The normal reaction
(mechanism 1) generally involves the formation of an initial
complex 3 which can then deprotonate benzoic acid to give
intermediate 4. Compound 4 then reacts with the alcohol 1
to afford the key triphenylphosphonium ion 5. The benzoate
nucleophile then reacts with intermediate 5 to afford the ester
2 with inverted stereochemistry by an SN2 mechanism.
Although inversion of stereochemistry is expected in general,
retention of configuration has also been reported.6-10 Mit-
sunobu reactions can give products with retention of the
stereochemistry when the secondary hydroxyl group is in a
sterically hindered environment via mechanism 2. In this
case, the hydroxyl group acts as the nucleophile, and benzoic
acid is activated into a phosphonium ion intermediate with
a better leaving group.
(1) Mitsunobu, Z. O. Synthesis 1981, 1–28
.
(6) Ahn, C.; DeShong, P. J. Org. Chem. 2002, 67, 1754–1759
.
(2) Huges, D. L. Organic Reactions; Beak, P. et al., Eds.; John Wiley
& Sons, Inc.: New York, 1992; Vol. 42, 335-656.
(7) Hughes, A. B.; Sleebs, M. M. J. Org. Chem. 2005, 70, 3079–3088
.
(8) Achmatowicz, M.; Hegedus, L. S. J. Org. Chem. 2004, 69, 2229–
(3) Dembinski, R. Eur. J. Org. Chem. 2004, 2763–2772
.
2234
.
(4) Camp, D.; Jenkins, I. D. Aust. J. Chem., 1992, 45, 47–55
.
(9) Dinsmore, C. J.; Mercer, S. P. Org. Lett. 2004, 6, 2885–2888
(10) Smith, A. B.; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
.
(5) Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67, 1751–
1753
.
2002, 124, 11102–11113.
10.1021/ol801316f CCC: $40.75
Published on Web 08/30/2008
2008 American Chemical Society

Scheme 1. Example of Mitsunobu Reaction and the General
Mechanisms to Inversion or Retention of Stereochemistry
Figure 1
products.
. Examples of vicinal diols and their Mitsunobu reaction
Compared to the vast amount of Mitsunobu reactions
performed on compounds containing monohydroxyl groups,1-3
there are fewer Mitsunobu reactions done on compounds
containing multiple hydroxyl groups, especially those with
two vicinal chiral hydroxyl groups.11-17 Two examples of
Mitsunobu esterification of diols are shown in Figure 1. The
esterification of the 1,2-diol 6 using TPP, DEAD, and benzoic
acid afforded ester 7 in 79.7% yield, along with 12% primary
ester 8 and 8.3% of diester 9.11b The regioselectivity is such
that the esterification occurs primarily at the secondary center.
However, butane 1,3- diol was esterified predominantly at
the primary center, in over 90% yield. The syn-dihydroxy
ester 10 gives only the ꢀ-functionalized derivative 11 with
inverted stereochemistry.12
diaxial hydroxyl groups afford the corresponding epoxide
18 with relative ease, compound 15 diequatorial hydroxyl
groups is more difficult to convert to the epoxide 16.18
Carbohydrates are useful chiral pool materials and renew-
able resources. They contain multiple chiral centers and can
be used as starting materials for the synthesis of many
complex bioactive compounds. Mitsunobu esterification has
been applied to the C-6 and C-1 positions of sugars and their
derivatives.19 Previously, we synthesized bicyclic amino
acids from D-glucose and D-mannose and organogelators
from glucose derivatives.20-22 During these syntheses, it was
necessary for us to differentiate between the hydroxyl groups
at the C2 and C3 positions of various D-glucose derivatives.
For example, the acylation of compound 15 using acyl
chloride and pyridine afforded mainly the 2-ester along with
a small amount of the 3-ester and diester. Depending on the
choice of acylating agents, the 2-esters and 3-esters are good
organo/hydrogelators.21
1,2-Diols have also been shown to form epoxides under
Mitsunobu conditions when no additional nucleophiles are
used.15-18 For example, the diol 12 can be converted to either
of the epoxides 13 or 14 depending on the type of phosphine
agent used (Figure 1). When triphenylphosphine and diiso-
propylazodicarboxylate (DIAD) were used, the epoxide 13
with retention of configuration was obtained, while tri-n-
butyl phosphine and DIAD afforded epoxide 14 instead.17
Cyclic vicinal diols can also be converted to the correspond-
ing epoxides; for example, the monosaccharide derived
compounds 15 and 17 can be converted into epoxides 16
and 18, respectively (Figure 1). While compound 17 with
Here we wish to report the results of Mitsunobu benzoy-
lation reactions of alcohols, especially vicinal diols derived
from D-glucose, D-mannose, and D-galactose. We studied the
acylation reactions of vicinal diols under Mitsunobu condi-
tions using benzoic acid, TPP, and DEAD and found that
the benzoylation reactions proceeded with interesting regi-
oselectivity and stereoselectivity. The regioselectivity and
(11) (a) Mistunobu, Z. O. Bull. Chem. Soc. Jpn. 1976, 49, 510–513. (b)
Pautard, A. M.; Evans, S. A, Jr. J. Org. Chem. 1988, 53, 2300–2303
.
(12) Ko, S. Y. J. Org. Chem. 2002, 67, 2689–2691
(13) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R. Tetrahe-
dron Lett. 2000, 41, 1959–1962
(14) He, L.; Wanunu, M.; Byun, H. S.; Bittman, R. J. Org. Chem. 1999,
64, 6049–6055
(15) Robinson, P. L.; Barry, C. N.; Bass, S. W.; Jarvis, S. E.; Evans, S.
A, Jr. J. Org. Chem. 1983, 48, 5396–5398
(16) Callam, C. S.; Gadikota, R. R.; Lowary, T. L. J. Org. Chem. 2001,
66, 4549–4558
.
.
(19) (a) Besset, C.; Chambert, S.; Quenuau, Y.; Kerverdo, S; Rolland,
H.; Guilbot, J. Carbohydr. Res. 2008, 343, 929–935. (b) Baczko, K.;
Nugierchauvin, C.; Banoub, J.; Thibault, P.; Plusquellec, D. Carbohydr.
Res. 1995, 269, 79085. (c) Smith, A. B.; Rivero, R. A.; Hale, K. J.; Vaccaro,
H. A. J. Am. Chem. Soc. 1991, 113, 2092–2112.
.
.
(20) Nie, X.; Wang, G. J. Org. Chem. 2005, 70, 8687–8692
.
.
(21) (a) Wang, G.; Sharma, V.; Cheuk, S.; Williams, K.; Dakessian,
(17) Garcia-Delgado, N.; Riera, A.; Verdaguer, X. Org. Lett. 2007, 9,
L.; Thorton, Z. Carbohydr. Res. 2006, 341, 705–716. (b) Nie, X; Wang,
635–638
.
G. J. Org. Chem. 2006, 71, 4734–4741.
(18) Guthrie, R. D.; Jenkins, I. D. Aust. J. Chem. 1981, 34, 1997–2000
.
(22) Nie, X.; Wang, G. Tetrahedron 2008, 64, 5784–5793
.
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Org. Lett., Vol. 10, No. 19, 2008

stereochemistry of the reactions are determined by the
structures of the monosaccharides. To our surprise, the
reactions utilizing vicinal diols produced monobenzoates with
retention of stereochemistry only. The results for a series of
glucose-derived alcohols are shown in Table 1.
95% yield, but the product is difficult to separate from the
byproduct of DEAD. We found that the solvent system using
hexane:DCM:THF (30:1:1) gave the best separation. The
4-methoxyphenyl acetal 26 also gives the 2-ester exclusively
1
with over 90% conversion (estimated from H NMR spec-
trum).
These results indicate that the esterification of compounds
15, 21, 23, and 26 proceeds via a different mechanism from
the classical Mitsunobu reaction (mechanism 2 shown in
Scheme 1). This mechanism was also postulated for other
Mitsunobu esterification reactions.5,6,23 Here the nucleophile
is the 2-alkoxide or 2-hydroxyl group of the diol, which
undergoes acylation with the activated acid to form the
benzoate with retention of configuration. The 2-hydroxyl
group of compound 19 is in a less hindered environment
compared to other substrates in Table 1, thus it proceeds
via mechanism 1 shown in Scheme 1, leading to inversion
of the C-2 stereocenter. It seems that an epoxide intermediate
is not formed when the diol was subjected to the same
Mitsunobu conditions in the absence of an acid for 2 days,
and no reaction took place.
Table 1. Mitsunobu Esterification of Various Glucose
Derivatives Using TPP and DEAD and the Acylating Agent Is
Benzoic Acid for All Compounds
To confirm the mechanism and further understand the
reaction, we also used thiobenzoic acid (PhCOSH) as the
acylating agent for compound 26. The same product, 2-O-
benzoate 27, was obtained, and no incorporation of thio group
(28, Figure 2) was observed. This reaction outcome supports
1
* Estimated conversion based on H NMR spectrum.
Monohydroxyl compound 19 was synthesized from D-
glucose22 and can be cleanly converted to the corresponding
benzoate 20 with inversion of stereochemistry. Compound
2121 also has one free secondary hydroxyl group, but under
similar conditions afforded the ester 22 with retention of
stereochemistry. The structure of 22 was confirmed by
hydrolysis of the benzoate ester, and the hydrolyzed product
of 22 was found to have the same structure as the starting
material according to NMR spectra. It is reasonable to view
compound 21 as a sterically hindered secondary alcohol, and
retention of configuration was expected when the hydroxyl
group is in a hindered environment in accordance to the
results reported by several researchers.6-10 The 1,3-dideoxy
derivative 19 is less sterically hindered compared to 21 and
therefore produced the inverted ester.
The 1-deoxy-glucose derivative 23 was converted exclu-
sively to the 2-O-benzoate 24 with retention of stereochem-
istry using 2 equiv of benzoic acid, TPP and DEAD. No
other regioisomers were observed. The structure of the
product was confirmed by NMR spectra of the product and
the hydrolysis of ester 24. Hydrolysis of 24 with NaOMe in
MeOH gave a single product whose 1H and 13C NMR spectra
exactly match those of compound 23, not the compound with
inverted C-2 configuration. For the 1-methoxy glucoside 15,
a similar pattern was observed. The 2-O-benzoate 25 was
Figure 2. Structures of compound 28 and D-mannose and D-
galactose derivatives and their acylation products 29-41.
the mechanism 2 in Scheme 1 where the nucleophile is the
2-hydroxy group, not the benzoate. However, the reaction
conversion was only around 35%, with about 65% of unreacted
starting materials. The reason for the lower conversion was
perhaps due to the bulkiness of the sulfur group compared to
1
formed with retention of configuration. On the basis of H
NMR, the starting material is converted to the 2-ester in over
(23) Fitzjarrald, V. P.; Pongdee, R. Tetrahedron Lett. 2007, 48, 3553–
3557.
Org. Lett., Vol. 10, No. 19, 2008
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an oxygen atom. In addition, the elimination of Ph3PdS is not
as thermodynamically favorable as that of Ph3PdO, as the
phosphorus-sulfur double bond is not as strong as the
phosphorus-oxygen double bond (PdO bond energy ∼ 544
kJ/mol, whereas PdS ∼ 335 kJ/mol).24
complementary regioselectivity to standard esterification
conditions. The reason for the different regioselectivity is
perhaps due to the stereoelectronic differences between the
two positions. The 2-position is less hindered in comparison
to the 3-hydroxyl group and is acylated more favorably under
the mild conditions of the Mitsunobu reaction. The 3-position
is favored under normal esterification conditions, perhaps
due to the hydrogen bonding of the cis-3- and 4-hydroxyl
groups, increasing the nucleophilicity of the 3-position.
This exceptional selectivity disappears when using the
1-methoxy derivative 38. The direct esterification also favors
the 3-ester (45% 39, 12% 40, and 17% 41) but to a lesser
degree than the 1-deoxy compound 34. Under Mitsunobu
conditions, when using 2 equiv of reagents, the reaction leads
to almost equal amounts of the 3-ester 39 and 2-ester 40
and some unreacted starting material. The reaction can reach
completion by adding triethylamine as a coreactant giving
the 2- and 3-esters in a 1:1 ratio. When a larger excess of
reagents was used (4 equiv of each and stirring for 4 days),
the reaction gave about 5% diester 41, 35% 2-ester 40, and
60% 3-ester 39. The regioselectivity for the 2-ester decreases
probably due to the presence of the large excess of reagents.
In summary, we have carried out a series of esterification
reactions on chiral alcohols including vicinal diols derived
from monosaccharides under Mitsunobu conditions. The
Mitsunobu esterifications of the diols derived from D-glucose,
D-galactose, and D-mannose all proceeded with retention of
configuration. The glucose based diols 23, 15, and 26 and
1-deoxy galactose derivative 34 afforded 2-OBz with high
regioselectivity. The D-glucose derivatives regioselectively
afforded the 2-benzoate esters with excellent yields. How-
ever, D-mannose derivatives and 1-methoxy D-galactose
derivatives did not show good regioselectivity. The 1-deoxy
D-galactose 34 afforded excellent regioselectivity, and the
Mitsunobu esterification gave opposite regioselectivity com-
pared to that of the direct esterification reactions. The
stereochemistry of Mitsunobu reactions is very sensitive to
the environment, and hindered substrates tend to yield
products with retention of configuration. The interesting
regioselectivity and stereoselectivity of these Mitsunobu
reactions on diols derived from common sugars can be
applied to other chiral cyclic diols.
The regioselectivities of 15, 23, and 26 can be ration-
alized by stereoelectronic factors. In the diol 23, the 2-OH
is less hindered than the 3-OH since it is next to a primary
carbon. Therefore, the regioselectivity favors the formation
of the 2-ester. In compounds 15 and 26, the cis relationship
with the methoxyl group presumably promotes hydrogen
bonding and leads to the enhanced nucleophilicity of the
2-hydroxyl group. This makes the 2-hydroxyl group more
reactive, and under mild Mitsunobu conditions, the 2-ester
is the major product.
When the substrates are derivatives from D-mannose (29,
30), the Mitsunobu reaction results are quite different. Unlike
the D-glucose derivatives shown in Table 1, here the regiose-
lectivity and yields are low perhaps due to the 2-hydroxy
group being in the axial position and more sterically
hindered.25 For the 1-deoxy derivative 29, using the same
conditions utilized in the glucose series, only a very small
amount of the starting material was esterified. Two esteri-
fication products were obtained in equal ratio, affording no
regioselectivity, and the majority (>80%) of the reaction
mixture was unchanged starting material.
For the 1-methoxy mannoside 30, depending on the
reaction conditions, different esterification products with
retention of stereochemistry were obtained (Figure 2). Under
mild conditions, using 2 equiv of reagents, and heating at
∼45 °C for 24 h, the 2-ester was obtained in 38% yield along
with 62% unreacted starting materials. Under more harsh
conditions, using 3 equiv of each reagent and heating to about
80 °C for 3 days, the starting material was completely
converted to three products: the diester 31 in 40%, 2-ester
32 in 45%, and 15% 3-ester 33. The reaction is no longer
regioselective under these conditions; however, both condi-
tions lead to retention of configuration. This is confirmed
1
by analysis of the H NMR spectra. Additionally, simple
hydrolysis of 32 led to the starting material 30 as indicated
1
by H NMR spectra.
For D-galactose derivatives, an interesting regioselectivity
was observed. The direct esterification of 1-deoxy galactose
acetal 34 using benzoyl chloride26 led to the 3-ester 36 as
the major product in 85-95% yield along with a small
amount of diester 37. However, under Mitsunobu reaction
conditions using TPP and either DEAD or DMEAD,27 the
opposite regioselectivity was observed. The 2-ester 35 was
obtained as the major product in 90% yield along with about
5-10% of 36. Thus, the Mitsunobu reaction provides
Acknowledgment. This research is supported in part by
the National Science Foundation (Grant 518283), the Ameri-
can Heart Association (Grant 043285N), and Louisiana Board
of Regents Graduate Fellowship to K. Williams.
Supporting Information Available: The experimental
data for the preparation of 20, 22, 24, 25, 27, 35, 36, and
39-41 are provided. The 1H NMR and 13C NMR spectra of
these compounds and some starting materials are also
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Huheey, J. E.; Keiter, E. A.; Keiter, R. L. Inorganic chemistry,
ISBN 0-06-042995-X, 4th ed., page, A 31.
(25) Davis, A. P.; Dresen, S.; Lawless, L. J. Tetrahedron Lett. 1997,
38, 4305–4308.
(26) Kondo, Y. Carbohydr. Res. 1989, 193, 279–282.
(27) Sugimura, T.; Hagiya1, K. Chem. Lett. 2007, 36, 566–567.
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