Stereospecific ester activation in nitrite-mediated carbohydrate epimerization

Article abstract of DOI:10.1021/jo052662i

The Lattrell-Dax method of nitrite-mediated substitution of carbohydrate triflates is an efficient method to generate structures of inverse configuration. In the present study, epimerization of gluco- and galactopyranoside derivatives to the corresponding

Full text of DOI:10.1021/jo052662i

SCHEME 1 a
Stereospecific Ester Activation in
Nitrite-Mediated Carbohydrate Epimerization
Hai Dong, Zhichao Pei, and Olof Ramstro¨m*
KTH-Royal Institute of Technology, Department of Chemistry,
Teknikringen 30, S-10044 Stockholm, Sweden
ramstrom@kth.se
ReceiVed December 28, 2005
a Reagents and conditions. (a) i: Tf2O, pyridine, CH2Cl2, -20 to 10 °C,
2 h. ii: KNO2, DMF, 50 °C, 3 h (2, 73%). (b) i: Tf2O, pyridine, CH2Cl2,
-20 to 10 °C, 2 h. ii: KNO2, DMF, 50 °C, 6 h, (4, 77%). (c) i: Tf2O,
pyridine, CH2Cl2, -20 to 10 °C, 2 h. ii: KNO2, DMF, 50 °C, 3 h.
under very mild conditions.6 Despite its reported efficiency,7-10
the Lattrell-Dax method has unfortunately not been extensively
adopted, likely because of difficulties in predicting the outcome
for specific structures. This fact has been addressed in the
present study, where it has been found that the protecting group
pattern is an essential element in the reaction, both with regard
to configuration and functionality.
Our first notion of the inversion reaction emanated from
studies in thiosaccharide synthesis,11-14 and whereas reported
studies suggested certain reactivity patterns,6,15-17 no detailed
explanations were given. As a first approach to investigate the
effect of the protecting group pattern to the inversion reaction,
the epimerization of galactopyranosides, where the hydroxyl
group in the 3-position was free and the other positions were
separately protected with acetyl (1), benzoyl (3), and benzyl/
benzylidene groups (5), respectively, was studied (Scheme 1).
These compounds were subjected to conventional triflation by
triflic anhydride, followed by treatment with potassium nitrite
in DMF at 50 °C. As can be seen, good yields were in these
cases obtained only on the condition that esters were chosen as
protecting groups, benzoyl groups being slightly less activating
than the acetyl counterparts. When the ester protecting groups
were replaced by benzyl/benzylidene groups, a mixture of
different products was instead obtained.
The Lattrell-Dax method of nitrite-mediated substitution of
carbohydrate triflates is an efficient method to generate
structures of inverse configuration. In the present study,
epimerization of gluco- and galactopyranoside derivatives
to the corresponding allo- and gulopyranoside structures by
triflation/nitrite treatment has been investigated. It was found
that a neighboring ester group was essential for the reactivity
of the nitrite-mediated triflate inversion. Furthermore, a good
inversion yield also depended on the relative configuration
of the neighboring ester group to the triflate. Only with the
ester group in the equatorial position, whatever the config-
uration of the triflate, did the reaction proceed smoothly,
whereas a neighboring axial ester group proved largely
inefficient. The results were subsequently used to predict the
inversion of glucopyranoside derivatives to the mannopy-
ranoside epimers.
Epimerization of carbohydrate structures to the corresponding
epi-hydroxy stereoisomers is an efficient means to generate
compounds with inverse configuration that may otherwise be
cumbersome to prepare.1 Several different synthetic methods
have been developed, including protocols based on the Mit-
sunobu reaction,2 sequential oxidation/reduction routes,3 as well
as enzymatic methods,4 all of which with their respective
advantages and shortcomings. A common route to stereocenter
inversion in carbohydrate chemistry involves the triflation of a
given hydroxyl group, followed by substitution using a variety
of nucleophilic reagents. This method was used by Dax and
co-workers who first reported that glycoside triflate displacement
by nitrite ion, a reaction first found by Lattrell and Lohaus,5
produced carbohydrates with inverse hydroxy configuration
Similar results were obtained from the epimerization of
glycopyranosides, where the hydroxyl group in the 4-position
(6) Albert, R.; Dax, K.; Link, R. W.; Stuetz, A. E. Carbohydr. Res. 1983,
118, C5-C6.
(7) Rich, J. R.; Bundle, D. R. Org. Lett. 2004, 6, 897-900.
(8) Trost, B. M.; Yang, H.; Probst, G. D. J. Am. Chem. Soc. 2004, 126,
48-49.
(9) Abdel-Rahman, A. A. H.; Jonke, S.; El Ashry, E. S. H.; Schmidt, R.
R. Angew. Chem., Int. Ed. 2002, 41, 2972-2974.
(10) Hoffmann, H. M. R.; Dunkel, R.; Mentzel, M.; Reuter, H.; Stark,
C. B. W. Chem.sEur. J. 2001, 7, 4771-4789.
(11) Pei, Z.; Dong, H.; Ramstro¨m, O. J. Org. Chem. 2005, 70, 6952-
6955.
(12) Witczak, Z. J. Curr. Med. Chem. 1999, 6, 165-178.
(13) Robina, I.; Vogel, P.; Witczak, Z. J. Curr. Org. Chem. 2001, 5,
1177-1214.
* Corresponding Author. Fax: +46-8-7912333.
(1) Lindhorst, T. K. Essentials of Carbohydrate Chemistry and Bio-
chemistry; Wiley-VCH: Weinheim, 2000.
(2) Weinges, K.; Haremsa, S.; Maurer, W. Carbohydr. Res. 1987, 164,
453-458.
(14) Driguez, H. ChemBioChem 2001, 2, 311-318.
(15) Binkley, R. W. J. Org. Chem. 1991, 56, 3892-3896.
(16) Binkley, R. W. J. Carbohydr. Chem. 1994, 13, 111-123.
(17) Liakatos, A.; Kiefel, M. J.; von Itzstein, M. Org. Lett. 2003, 5,
4365-4368.
(3) Chang, C. W. T.; Hui, Y.; Elchert, B. Tetrahedron Lett. 2001, 42,
7019-7023.
(4) Samuel, J.; Tanner, M. E. Nat. Prod. Rep. 2002, 19, 261-277.
(5) Lattrell, R.; Lohaus, G. Justus Liebigs Ann. Chem. 1974, 901-920.
10.1021/jo052662i CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/15/2006
3306
J. Org. Chem. 2006, 71, 3306-3309

SCHEME 2 a
3,4-cis configurations, where the ester groups are in the
equatorial positions, a structural situation largely excluding the
conventional neighboring group participation.18,19
The results obtained seem to point to the importance of a
neighboring group (acyloxonium) effect, where compounds 11
and 14 (3,4-trans) expressed a higher reactivity as a result of
activation from the neighboring ester group in inducing the
inversion reaction compared to compounds 12 and 15 (3,4-cis).
This is reflected in the longer reaction times for the 3,4-cis
compounds, as displayed in Table 1. However, acyloxonium
formation is still unlikely to be the sole explanation of the
results, contradictory to the results for two reasons: first, starting
compounds 6, 12, and 15 all have a cis relationship between
the ester and the leaving group, which largely disqualifies
acyloxonium formation;18,19 and second, formation of a car-
bocation intermediate would result in a nucleophilic displace-
ment from the triflate face of the compound leading to retention
(double inversion) of configuration rather than single inversion.
However, that acyloxonium formation is important in the
trans-configuration cases was further supported by studies with
added water. Thus, compounds 11 and 14, both with 3,4-trans-
diequatorial relationships, mainly yielded compounds 12 and
15 from reaction with potassium nitrite in dry DMF. If on the
other hand wet DMF was used, compounds 10 and 13 were
instead obtained as the main products (Table 2). This suggests
acyloxonium formation to the five-membered-ring intermediate,
which rapidly collapses in the presence of water to produce the
axial ester and the equatorial hydroxyl group. These results are
indicative of (partial) acyloxonium formation in the trans-
configuration cases, but that the nitrite ion is unable to open
the five-membered ring from either the triflate face or from
attacking the carbonyl cation, as has been suggested for water.15
More importantly, the ester group is, therefore, likely to induce
or stabilize the attacking nitrite ion regardless of the trans- or
cis-configurational relationships.
The effects observed for the ether-protected carbohydrates
are likely a result of their lower degree of positive charge
destabilization than the corresponding ester groups, leading to
side reactions such as ring contraction and elimination.20,21
To further test the hypothesis of ester activation in the nitrite-
mediated inversion reaction, glucopyranoside compounds 16 and
18 were synthesized (Scheme 3). Instead of observing the
inversion behavior in the 3- and 4-positions of the hexopyra-
nosides, the 2- and 3-positions were probed (2,3-trans). If the
induction argument would hold valid, the ester-protecting group
would prove efficient in inducing the inversion, whereas the
corresponding ether protecting group would fail to produce this
effect. The results are displayed in Scheme 3, and as can be
seen, the hypothesis was valid also for these compounds. The
ester-protected glucopyranoside compound 16 afforded the
inversion mannopyranoside product 17 in good yield, whereas
the ether-protected compound 18 proved inefficient. In this case,
slightly longer reaction times were, however, necessary due to
the lower reactivity of the 2-OTf derivative.
a Reagents and conditions. (a) i: Tf2O, pyridine, CH2Cl2, -20 to 10 °C,
2 h. ii: KNO2, DMF, 50 °C, 5 h, (7, 75%). (b) i: Tf2O, pyridine, CH2Cl2,
-20 to 10 °C, 2 h. ii: KNO2, DMF, 50 °C, 2 h, (6, 70%). (c) i: Tf2O,
pyridine, CH2Cl2, -20 to 10 °C, 2 h. ii: KNO2, DMF, 50 °C, 0.5 h.
was unprotected, and all other positions were protected with
either benzoyl or benzyl groups (Scheme 2). Only when an ester
group was present at the carbon adjacent to the carbon atom
carrying the leaving triflate group did the reaction proceed
smoothly, the axially oriented triflate being less reactive than
the equatorial leaving group. In contrast to this effect, no
efficient reaction occurred when benzyl groups were employed
where compound mixtures were instead rapidly obtained. These
results suggest that a neighboring ester group is able to induce
or activate the inversion reaction, whereas an ether derivative
is unable to produce this effect. The results also show that the
inversion reaction proceeded smoothly regardless of the triflate
configuration.
To further analyze these findings and explore the effect of
neighboring ester group configurations of triflate to the reactiv-
ity, other inversion systems were designed (Table 1). To avoid
the effects from the 2- and 6-positions and to isolate the effects
arising from ester groups in the 3- and 4-positions, the 2- and
6-positions were protected with benzyl ether groups. Thus, a
range of compounds where one of the hydroxyl groups in the
3- or 4-position was protected with an acetyl group were
prepared and subsequently tested in the nitrite-mediated inver-
sion reactions. The experimental results presented in Table 1
clearly indicate that the configuration of the neighboring ester
group was decisive for the reactivity of the epimerization
reaction. Good inversion yields depended mainly on the relative
configurations between the two groups, and only with the ester
group in the equatorial position, whatever the configuration of
the triflate, did the reaction proceed smoothly, whereas a
neighboring axial ester group proved inefficient.
Rapid internal triflate displacements by neighboring acetyl
or benzoyl groups have been reported when the ester group and
the leaving group have trans-diaxial relationships.11 This leads
to products where the configuration is retained, thus excluding
these combinations from the present investigation. This internal
displacement is indicative of the fast formation of an intermedi-
ate acyloxonium carbocation, stabilized by polar solvent. In our
cases, compounds 11 and 14 hold 3,4-trans configurations in
diequatorial relationships, where the internal triflate displace-
ment by the neighboring ester group is considerably less
efficient. Contrary to this situation, compounds 12 and 15 hold
In conclusion, it has been demonstrated that esters play highly
important roles in the Lattrell-Dax reaction, facilitating nitrite-
(18) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books: Sausalito, CA, 2006; pp 659-660.
(19) Winstein, S.; Grunwald, E.; Ingraham, L. L. J. Am. Chem. Soc. 1948,
70, 821-828.
(20) Kassou, M.; Castillon, S. J. Org. Chem. 1995, 60, 4353-4358.
(21) El Nemr, A.; Tsuchiya, T. Carbohydr. Res. 1997, 303, 267-281.
J. Org. Chem, Vol. 71, No. 8, 2006 3307

TABLE 1. Epimerization Reactions Studied
TABLE 2. Water Effects in Studied Nitrite-Mediated Inversion Reactions
a i: Tf2O, pyridine, CH2Cl2, -20 to 10 °C, 2 h. ii: KNO2, 50 °C, DMF, 0.5-1.5 h or H2O, rt, DMF, 6 h.
SCHEME 3 a
of inversion compounds in good yields. The reactions further
demonstrated stereospecificity, inasmuch as axially oriented
neighboring ester groups were unproductive and only equatorial
ester groups induced the nucleophilic displacement reaction.
These findings expand the utility of this highly useful reaction
in carbohydrate synthesis as well as for other compound classes.
Experimental Section
a Reagents and conditions. (a) i: Tf2O, pyridine, CH2Cl2, -20 to 10 °C,
2 h. ii: KNO2, DMF, 50 °C, 6 h, (17, 74%). (b) i: Tf2O, pyridine, CH2Cl2,
-20 to 10 °C, 2 h. ii: KNO2, DMF, 50 °C, 3 h.
General Synthesis of Triflate Derivatives. To a solution of the
suitably O-protected methyl â-D-glycoside, carrying an unprotected
OH at C3 or C4 (0.3 g, 0.94 mmol), in CH2Cl2 (5 mL) was added
pyridine (0.65 mL) at -20 °C. Trifluoromethanesulfonic anhy-
dride (0.53 g, 1.88 mol) in CH2Cl2 (2 mL) was added dropwise,
and the mixture was stirred while allowing to warm from -20 °C
to 10 °C over 2 h. The resulting mixture was subsequently diluted
with CH2Cl2 and washed with 1 M HCl, aqueous NaHCO3, water,
and brine. The organic phase was dried over Na2SO4 and concen-
mediated carbohydrate epimerizations. Despite the higher
reactivity of carbohydrate triflates protected with ether func-
tionalities, these compounds proved inefficient in these reactions,
where mixtures of compounds were rapidly obtained. Neighbor-
ing ester groups, on the other hand, could induce the formation
3308 J. Org. Chem., Vol. 71, No. 8, 2006

trated in vacuo at low temperature. The residue was used directly
in the next step without further purification.
70.4, 69.1, 68.7, 68.0, 57.1, 20.9. [R]20 ) +106 (c 0.5, CHCl3).
D
Anal. Calcd for C23H28O7‚1/2H2O: C, 64.93; H, 6.87. Found: C,
64.98; H, 7.08.
General Inversion of Triflate Derivatives. KNO2 (5 equiv) was
added to a solution of the protected triflate residue (20 mg) in dry
DMF (2.0 mL). After stirring at 50 °C for 1-6 h, the mixture was
diluted with CH2Cl2 and washed with brine. The organic phase was
dried with MgSO4 and concentrated in vacuo. Purification of the
residue by flash column chromatography (5:2, hexanes-ethyl
acetate) afforded the inversion products.
Methyl 3-O-Acetyl-2,6-di-O-benzyl-â-D-gulopyranoside (13).
1H NMR (CDCl3, 400 MHz): δ 7.25-7.36 (m, 10H, 2 × OBn),
5.61 (t, 1H, J2,3, J3,4 ) 3.1 Hz, H3), 4.65 (s, 2H, OCH2C6H5), 4.64
(d, 1H, J1,2 ) 7.6 Hz, H1), 4.61, 4.51 (d, 2H, Ja,b ) 12.1 Hz,
OCHaHbC6H5), 3.70-3.86 (m, 4H, H4, H5, H6a, H6b), 3.53 (s, 3H,
OMe), 3.34 (dd, 1H, J1,2 ) 7.6 Hz, J2,3 ) 3.1 Hz, H2), 2.62 (d, 1H,
J ) 4.53 Hz, OH), 2.14 (s, 3H, OAc). 13C NMR (CDCl3, 100
MHz): δ 171.0, 137.7, 137.6, 128.5, 128.4, 127.9, 127.8, 127.7,
1
Methyl 2,4,6-Tri-O-acetyl-â-D-gulopyranoside (2). H NMR
(CDCl3, 400 MHz): δ 4.98 (dd, 1H, J3,4 ) 3.9 Hz, J4,5 ) 1.6 Hz,
H4), 4.93 (dd, 1H, J1,2 ) 8.1 Hz, J2,3 ) 3.1 Hz, H2), 4.74 (d, 1H,
J1,2 ) 8.1 Hz, H1), 4.30 (td, 1H, J4,5 ) 1.6 Hz, J5,6 ) 6.5 Hz, H5),
4.14-4.33 (m, 3H, H3, H6a, H6b), 3.51 (s, 3H, OMe.), 2.13 (s, 3H,
OAc), 2.12 (s, 3H, OAc), 2.05 (s, 3H, OAc). 13C NMR (CDCl3,
125 MHz): δ 170.6, 170.2, 169.5, 99.1, 70.5, 69.9, 69.5, 67.6, 61.9,
56.8, 21.0, 20.8, 20.7. [R]20D ) -103 (c 2.0, CHCl3). Anal. Calcd
for C13H20O9‚1/2H2O: C, 47.42; H, 6.43. Found: C, 47.49; H, 6.42.
Methyl 2,4,6-Tri-O-benzoyl-â-D-gulopyranoside (4). 1H NMR
(CDCl3, 400 MHz): δ 7.38-8.14 (m, 15H, 3 × OBz), 5.43 (dd,
1H, J ) 4.0 Hz, J ) 1.0 Hz, H4), 5.30 (dd, 1H, J1,2 ) 8.0 Hz, J2,3
) 3.1 Hz, H2), 5.03 (d, 1H, J1,2 ) 8.0 Hz, H1), 4.59-4.68 (m, 2H,
H6a, H6b), 4.44-4.52 (m, 2H, H3, H5), 3.58 (s, 3H, OMe). 13C NMR
(CDCl3, 125 MHz): δ 166.1 165.5 165.2, 133.6, 133.5, 133.1,
130.0, 129.8, 129.7, 129.6, 129.5, 129.0, 128.6, 128.5, 128.4, 99.5,
101.4, 75.8, 73.7, 72.5, 72.3, 70.6, 70.5, 68.8, 56.9, 21.0. [R]20
)
D
-116 (c 0.5, CHCl3). HRMS for C23H28O7‚Na, 439.1733; found,
439.1723.
Methyl 3-O-Acetyl-2,6-di-O-benzyl-â-D-glucopyranoside (14).
1H NMR (CDCl3, 500 MHz): δ 7.25-7.36 (m, 10H, 2 × OBn),
4.97 (t, 1H, J2,3, J3,4 ) 9.3 Hz, H3), 4.83, 4.60, 4.59, 4.56 (d, 4H,
Ja,b ) 12.1 Hz, 2 × OCHaHbC6H5), 4.36 (d, 1H, J1,2 ) 7.9 Hz,
H1), 3.76 (dd, 2H, J ) 4.57 Hz, J ) 3.0 Hz, H6), 3.61 (td, 1H, J4,3
) 9.3 Hz, J ) 3.8 Hz, H4), 3.56 (s, 3H, OMe), 3.46-3.51 (m, 1H,
H5), 3.33 (dd, 1H, J2,1 ) 7.9 Hz, J2,3 ) 9.3 Hz, H2), 2.92 (d, 1H,
J ) 3.8 Hz, OH), 2.00 (s, 3H, OAc). 13C NMR (CDCl3, 125
MHz): δ 171.8, 138.3, 137.7, 128.4, 128.3, 127.9, 127.8, 127.7,
127.6, 104.5, 78.7, 77.2, 74.2, 74.1, 73.7, 71.0, 70.1, 57.2, 21.0.
[R]20 ) +21 (c 4.0, CHCl3). Anal. Calcd for C23H28O7‚1/2H2O:
D
71.3, 70.7, 70.1, 68.0, 62.6, 57.0. [R]20 ) +20 (c 1.0, CHCl3).
C, 64.93; H, 6.87. Found: C, 65.42; H, 7.01.
D
Anal. Calcd for C28H26O9: C, 66.40; H, 5.17. Found: C, 66.22; H,
5.08.
Methyl 3-O-Acetyl-2,6-di-O-benzyl-â-D-galactopyranoside (15).
1H NMR (CDCl3, 400 MHz): δ 7.26-7.36 (m, 10H, 2 × OBn),
4.88 (dd, 1H, J2,3 ) 10.20 Hz, J3,4 ) 3.2 Hz, H3), 4.84, 4.61, 4.59,
4.55 (d, 4H, Ja,b ) 12.0 Hz, 2 × OCHaHbC6H5), 4.35 (d, 1H, J1,2
) 7.8 Hz, H1), 4.11 (t, 1H, J3,4, J4,5 ) 3.25 Hz, H4), 3.61-3.81
(m, 4H, H2, H5, H6a, H6b), 3.58 (s, 3H, OMe), 2.65 (d, 1H, J ) 4.3
Hz, OH), 2.04 (s, 3H, OAc). 13C NMR (CDCl3, 125 MHz): δ 170.3,
138.3, 137.5, 128.5, 128.3, 127.9, 127.8, 127.6, 105.0, 76.6, 74.7,
Methyl 4-O-Acetyl-2,6-di-O-benzyl-â-D-glucopyranoside (11).
1H NMR (CDCl3, 400 MHz): δ 7.25-7.36 (m, 10H, 2 × OBn),
4.79-4.86 (m, 1H, H4), 4.85, 4.59, 4.50, 4.45 (d, 4H, Ja,b ) 12.0
Hz, 2 × OCHaHbC6H5), 4.25 (d, 1H, J1,2 ) 7.6 Hz, H1), 3.60 (td,
1H, J2,3 ) 9.2 Hz, J3,4 ) 2.8 Hz, H3), 3.45-3.55 (m, 3H, H5, H6a,
H6b), 3.57 (s, 3H, OMe), 3.22 (dd, 1H, J1,2 ) 7.6 Hz, J2,3 ) 9.2
Hz, H2), 2.33 (d, 1H, J ) 2.8 Hz, OH), 1.98 (s, 3 H, OAc). 13C
NMR (CDCl3, 100 MHz): δ 170.4, 138.2, 137.8, 128.5, 128.4,
128.1, 127.9, 127.8, 127.7, 104.2, 81.2, 74.4, 74.2, 73.6, 73.4, 71.1,
73.8, 72.6, 69.5, 68.4, 57.2, 21.0. [R]20 ) +88 (c 0.5, CHCl3).
D
Anal. Calcd for C23H28O7: C, 66.33; H, 6.78. Found: C, 66.11; H,
7.02.
69.2, 57.1, 20.9. [R]20 ) +66 (c 0.5, CHCl3). Anal. Calcd for
D
C23H28O7‚1/2H2O: C, 64.93; H, 6.87. Found: C, 64.85; H, 6.87.
Methyl 4-O-Acetyl-2,6-di-O-benzyl-â-D-gulopyranoside (12).
1H NMR (CDCl3, 500 MHz): δ 7.25-7.36 (m, 10H, 2 × OBn),
4.83 (dd, 1H, J3,4 ) 2.8 Hz, J4,5 ) 9.7 Hz, H4), 4.81, 4.65, 4.61,
4.47 (d, 4H, Ja,b ) 12.0 Hz, 2 × OCHaHbC6H5), 4.68 (d, 1H, J1,2
) 7.6 Hz, H1), 4.34 (t, 1H, J2,3, J3,4 ) 2.8 Hz, H3), 4.08 (m, 1H,
H5), 3.51-3.64 (m, 2H, H6a, H6b), 3.56 (s, 3H, OMe), 3.34 (dd,
1H, J1,2 ) 7.6 Hz, J2,3 ) 2.8 Hz, H2), 2.48 (s, 1H, OH), 1.97 (s,
3H, OAc). 13C NMR (CDCl3, 125 MHz): δ 169.9, 138.1, 137.7,
128.5, 128.3, 128.0, 127.9, 127.8, 127.6, 101.6, 77.1, 73.4, 73.0,
Acknowledgment. This study was supported by the Swedish
Research Council, the Swedish Foundation for International
Cooperation in Research and Higher Education, the Royal
Institute of Technology, and the Carl Trygger Foundation.
Supporting Information Available: General methods, 1H and
13C spectra of compound 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO052662I
J. Org. Chem, Vol. 71, No. 8, 2006 3309