De novo asymmetric syntheses of D- and L-talose via an iterative dihydroxylation of dienoates

Article abstract of DOI:10.1021/jo051476+

A short and highly efficient route to D- and L-tafo-γ-lactones has been developed. The key transformation was the sequential osmium-catalyzed bis-dihydroxylation reaction of substituted 2,4-dienoates. When the first dihydroxylation reaction is performed o

Full text of DOI:10.1021/jo051476+

SCHEME 1. 1- to 3-Step Stereoselective Synthesis
of galacto-γ-Lactone
De Novo Asymmetric Syntheses of D- and
L-Talose via an Iterative Dihydroxylation
of Dienoates
Md. Moinuddin Ahmed and George A. O′Doherty*
Department of Chemistry, West Virginia University,
Morgantown, West Virginia 26506
george.odoherty@mail.wvu.edu
Received July 16, 2005
dihydroxylation strategy5,6). In contrast to the diastereo-
selective aldol approach to hexoses of MacMillan and
others, we investigated the possibility of using a dia-
stereoselective osmium-catalyzed dihydroxylation ap-
proach to the hexoses (Scheme 1). These efforts resulted
in our recently reported synthesis of galacto-sugars from
simple achiral precursors with complete stereocontrol.5
Our optimized procedure affords either D-galacto-γ-
lactone (conditions a, Scheme 1) or L-galacto-γ-lactone
(conditions b, Scheme 1) in three steps.7,8 Alternatively,
racemic galacto-γ-lactone (conditions c, Scheme 1) can be
prepared in only one step. Key to the success of these
transformations is the in situ lactonization of the initially
formed tetraol products. The in situ lactonization along
with peracylation significantly aid in isolation of the
galacto-lactones 2.
A short and highly efficient route to D- and L-talo-γ-lactones
has been developed. The key transformation was the se-
quential osmium-catalyzed bis-dihydroxylation reaction of
substituted 2,4-dienoates. When the first dihydroxylation
reaction is performed on (2Z,4E)-dienoates with use of the
Sharpless AD-mix procedure, a regio- and enantioselective
dihydroxylation resulted along with an in situ lactonization.
A subsequent dihydroxylation, using OsO4/NMO in MeOH
conditions, resulted in an exceedingly diastereo- and enan-
tioselective synthesis of talo-γ-lactone.
Herein, we present the expansion this iterative dihy-
droxylation strategy to the talo-γ-lactones using the
Sharpless dihydroxylation for enantiocontrol.9 These
studies resulted in a three-step synthesis of talo-γ-
lactones, which are amenable to various C-6 substituents.
Conceptually a bis-dihydroxylation reaction, which
installs a hydroxyl group at every carbon atom, appears
to be an ideal method for an efficient carbohydrate
synthesis. In practice, however, there were issues associ-
ated with regioselectivity (which double bond reacts first),
enantioselectivity (the facial selectivity of the first dihy-
droxylation) and double diastereoselectivity (a balance
between substrate and catalyst stereocontrol).10,11 The
solution to these problems emerged from our continuing
study of the Sharpless dihydroxylation of di- and
In response to the growing importance carbohydrate
structures play in biology,1 considerable efforts have been
made to develop new synthetic routes to monosaccha-
rides. This need in particular is driven by medicinal
chemist’s desire for unnatural sugar analogues for struc-
ture activity relationship studies. For the unnatural
sugars in particular, there has been a growing interest
in preparing these carbohydrates from achiral starting
material, using enantioselective catalysis to set the
asymmetry (de novo synthesis). This interest in de novo
approach to the hexoses goes back to the seminal work
of Sharpless and Masamune.2 More recently this chal-
lenge has been taken up by MacMillan (iterative aldol
strategy)3 and us (both an Achmatowicz4 and an iterative
(5) (a) Ahmed, Md. M.; O’Doherty, G. A. Tetrahedron Lett. 2005,
46, 3015-3019. (b) Ahmed, Md. M.; Berry, B. P.; Hunter, T. J.; Tomcik,
D. J.; O’Doherty, G. A. Org. Lett. 2005, 7, 745-748.
(6) For its application in synthesis, see: (a) Ahmed, Md. M.;
O’Doherty, G. A. Tetrahedron Lett. 2005, 46, 4151-4155. (b) Gao, D.;
O’Doherty, G. A. Org. Lett. 2005, 7, 1069-1072.
(7) Although it is a rare sugar, L-galacto-γ-lactone is a naturally
occurring metabolite produced in plants as an intermediate in the
biosynthesis of vitamin C, see: Smirnoff, N. Nat. Biotechnol. 2003,
21, 134-136.
(8) It has been suggested that the level of the important antioxidant
ascorbic acid can be increased by treatment with L-galacto-γ-lactone,
see: Smirnoff, N. Philos. Trans. R. Soc. London 2001, 335, 1455-1464.
(9) (a) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc.
1992, 114, 7570-7571. (b) Heinrich, B.; Marcos, S. A.; Sharpless, K.
B. Tetrahedron 1995, 51, 1345-76.
(1) (a) Ernst, B.; Hart, G. W.; Sinay, P., Eds. Carbohydrates in
Chemistry and Biology; Wiley-VCH: New York, 2000. (b) Wong, P. G.;
Bertozzi, C. P., Eds. Glycochemistry. Principles, Synthesis and Ap-
plications; Marcel Dekker Inc.: New York, 2001. (c) Vogel, P. In
Glycoscience; Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.;
Springer: Berlin, Germany, 2001; Vol. 2, pp 1023-1174.
(2) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless,
K. B. Science 1983, 220, 949-951.
(3) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752-
1755.
(4) An Achmatowicz reaction is the oxidative rearrangement of
furfuryl alcohols to 2-substituted 6-hydroxy-2H-pyran-3(6H)-ones. For
examples of its use in de novo carbohydrate synthesis see: (a) Harris,
J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem. 1999, 64, 2982-
2983. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young, V. G.;
O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17-36. (c) Babu, R. S.;
O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125, 12406-12407. For its
use in oligosaccharide synthesis see: (d) Babu, R. S.; Zhou, M.;
O’Doherty, G. A. J. Am. Chem. Soc. 2004, 126, 3428-3429.
(10) Masamune, S.; Choy, W.; Petersen, J.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1-76.
(11) Morikawa, K.; Sharpless, K. B. Tetrahedron Lett. 1993, 34,
5575-5578.
10.1021/jo051476+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/11/2005
10576
J. Org. Chem. 2005, 70, 10576-10578

SCHEME 2. Retrosynthesis of talo-γ-Lactones
SCHEME 4. Four-Step Synthesis of talo-γ-Lactone
trienoates.12,13 As with the galacto-lactones, we planned
to establish the C-2 to C-5 tetrol stereochemistry of the
talo-lactones from (Z,E)-dienoates (i.e., 3 from 6, Scheme
2).14 These (Z,E)-dienoates were easily prepared by a
Still-Gennari olefination of 4-substituted crotyl alde-
hydes.15 Once again we targeted the γ-lactone 3, for ease
of isolation (Scheme 2).5
Encouraged by our success with the de novo synthesis
of galacto-lactones 2, we decided to next examine the
possibility of an iterative dihydroxylation on a double
bond isomer for the preparation of sugar stereoisomers.
Because the Sharpless dihydroxylation occurs with greater
selectivity for trans double bonds, we selected (2Z,4E)-
dienoate 6 to study.14 To our surprise, when dienoate 6
was dihydroxylated neither diol 5 nor tetrol 4 was
detected, instead a concomitant lactonization reaction
also occurred.
In practice, the dienoate 6 was prepared by treating a
THF solution of crotyl aldehyde 7 with both EtO2-
CCH2P(O)(OCH2CF3)2 and KOt-Bu in the presence of
excess 18-crown-6 (Scheme 3). This procedure reliably
prepared dienoate 6 in both excellent yield (95%) and
double bond stereoselectivity (12:1 Z/E-ratio). Exposing
(2Z,4E)-dienoate 6 to the typical Sharpless AD-mix
procedure (2% OsO4/2.1% (DHQ)2PHAL, 3 equiv of
K3Fe(CN)6/K2CO3, 1 equiv of MeSO2NH2)9 afforded lac-
tone 8 in good yield (70%) and enantiomeric excess (90%
ee). When the lactone 8 was further dihydroxylated under
ligandless conditions (OsO4/NMO in MeOH), the talo-γ-
lactone 3 was produced in good yield (65%, 5:1 dr). As
with the galacto-lactones (cf. Scheme 1), the triol 3 was
per-acylated giving 9 in an excellent yield (95%).
We next looked to improve the diastereoselectivity of
the second dihydroxylation in the sequence by making
the alcohol of 8 more sterically hindered (Scheme 4). To
these ends, we protected the alcohol with TBSCl, afford-
ing 10 in good yield (80%). When the TBS-protected
alcohol 10 was exposed to the same dihydroxylation
conditions improved diastereoselectivity was observed
(10:1 instead of 5:1). The talo-lactone 11 was isolated in
good yield (70%). To prove the stereochemistry the
lactone 11 was deprotected with TBAF to afford the
identical talo-γ-lactone 3 in good yield (80%).
SCHEME 3. Two-Step Highly Enantio- and
Diastereoselective Synthesis of talo-γ-Lactone
To perform a Mosher ester analysis, the diol 11 was
protected as the acetonide and the TBS group was
deprotected to give the alcohol 12 in good yield (70% for
2 steps). Conversion of 12 to the corresponding Mosher
esters followed by NMR analysis indicated that 12 was
formed in 91% ee. The talo-stereochemistry of 12 was
assigned by a series of nOe experiments (see the Sup-
porting Information). Finally, this procedure was also
used to produce the enantiomer of 3 (D-talo-γ-lactone) in
similar overall yield and enantiopurity (43% and 93% ee),
by simply switching to the (DHQD)2PHAL ligand system
in the initial dihydroxylation.
In conclusion, our strategy for the synthesis of either
enantiomer of talo-sugars provides rapid and practical
access to important sugars, which should be of further
use for oligosaccharide synthesis. In contrast to the
recently reported enantioselective aldol approach3 to
hexoses, which uses a change in aldol mechanism to
prepare stereoisomers, this approach can be used to
prepare either galacto- or talo-sugars by simply changing
the dienoate double bond geometry. Thus, by simply
changing one of the double bond geometries, optically
pure 3 was prepared in two steps from (2Z,4E)-dienoate
8 (45% overall yield).
(12) Zhang, Y.; O’Doherty, G. A. Tetrahedron 2005, 61, 6337-6351.
(13) (a) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959-
1962. (b) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002, 4, 4447-
4450.
(14) Thus the order of double bond reactivity in dienoate 6 is
controlled by taking advantage of the differing electronic nature of the
two double bonds, along with the preference for the AD-mix reagent
system to react with trans olefins, see ref 9.
(15) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
J. Org. Chem, Vol. 70, No. 25, 2005 10577

Experimental Section16
bottom flask was added (S)-5-((S)-2′-(benzyloxy)-1′-hydroxyethyl)-
furan-2(5H)-one (8) (100 mg, 0.42 mmol) and 1 mL of MeOH
and then the mixture was cooled to 0 °C. To this solution were
added 0.3 mL of 50% NMO in H2O (1.28 mmol) and OsO4 (2.1
mg, 8 µmol, 2 mol %) and the reaction was stirred vigorously at
0 °C overnight. The reaction was quenched with solid sodium
sulfite (150 mg) at room temperature. Then the reaction mixture
was filtered through a pad of Celite/florisil and eluted with 20
mL of 50% ethyl acetate/MeOH. The combined organic layers
were dried over anhydrous sodium sulfate. Removal of the
solvents in vacuo and flash chromatography on silica gel (1:9
(v/v) MeOH/EtOAc) afforded (3R,4S,5R)-5-((S)-2′-(benzyloxy)-1′-
hydroxyethyl)-3,4-dihydroxydihydrofuran-2(3H)-one (3) (74 mg,
5:1 dr, 65% yield) as a viscous oil. Rf (2% MeOH/EtOAc) 0.14;
[R]25D 41.2 (c 1.1, MeOH); IR (thin film, cm-1) 3396, 2928, 2874,
1779, 1455, 1366, 1316, 1215, 1179, 1092, 1027, 978, 905; 1H
NMR (CD3OD, 600 MHz) δ 7.37 (m, 5H), 4.67 (d, J ) 6 Hz, 1H),
4.61 (s, 2H), 4.52 (d, J ) 1.8 Hz, 1H), 4.38 (dd, J ) 6, 0.6 Hz,
1H), 4.02 (ddd, J ) 7.2, 6.6, 1.8 Hz, 1H), 3.60 (dd, J ) 9, 7.2 Hz,
1H), 3.56 (dd, J ) 9, 6.6 Hz, 1H), 3.76 (br s, 3H); 13C NMR
(CD3OD, 150 MHz) δ 178.9, 139.6, 129.5 (2C), 129.0, 128.9 (2C),
86.9, 74.5, 72.0, 71.7, 70.3, 70.2; CIHRMS calcd for [C13H16O6 +
Na]+ 291.0839, found 291.0830.
(2Z,4E)-Ethyl 6-(Benzyloxy)hexa-2,4-dienoate (6). A solu-
tion of (CF3CH2O)2P(O)CH2CO2CH2CH3 (3 g, 9.0 mmol) and 18-
crown-6 (7.1 g, 27.0 mmol) in THF (60 mL) was cooled to -78
°C and treated with t-BuOK (1.2 g, 10.8 mmol). After the mixture
was stirred for 15 min, a solution of the aldehyde 7 (1.6 g, 9.1
mmol) in THF (10 mL, plus 5 mL of rinse) was added by cannula.
The resulting mixture was stirred at -78 °C for 2.5 h, the
reaction mixture was quenched by the addition of saturated
aqueous NH4Cl, and the bulk of THF was removed under
reduced pressure. The residue was extracted with ether (3 × 30
mL) and the organic extracts were washed with brine, dried
(Na2SO4), filtered, and concentrated. The crude product was
purified by flash chromatography on silica gel (25:1 (v/v) hexane/
EtOAc) to yield (2Z,4E)-ethyl 6-(benzyloxy)hexa-2,4-dienoate 6
(2.1 g, 12:1 Z/E ratio, 95% yield) as a viscous oil. Major isomer
6: Rf (30% EtOAc/ hexanes) 0.6; IR (thin film, cm-1) 2983, 2928,
2872, 1766, 1650, 1620, 1496, 1454, 1436, 1362, 1268, 1141,
1
1073, 1029, 953; H NMR (CDCl3, 600 MHz) δ 7.58 (dddd, J )
15.6, 11.4, 1.2, 1.2 Hz, 1H), 7.33 (m, 5H), 6.59 (dd, J ) 11.4,
11.4 Hz, 1H), 6.12 (ddd, J ) 15.6, 6, 6 Hz, 1H), 5.68 (d, J ) 11.4
Hz, 1H), 4.54 (br s, 2H), 4.20 (q, J ) 7.2 Hz, 2H), 4.17 (d, J ) 6
Hz, 1H), 4.16 (d, J ) 6 Hz, 1H), 1.30 (t, J ) 7.2 Hz, 3H); 13C
NMR (CDCl3, 150 MHz) δ 166.2, 143.6, 139.3, 137.9, 128.4 (2C),
128.1, 127.7 (2C), 127.6, 118.1, 72.5, 70.0, 60.0, 14.2; CIHRMS
calcd for [C15H18O3 + Na]+ 269.2914, found 269.2917.
(3R,4S,5R)-5-((S)-2′-(Benzyloxy)-1′-acetoxyethyl)-3,4-
diacetoxydihydrofuran-2(3H)-one (9). To a solution of
(3R,4S,5R)-5-((S)-2′-(benzyloxy)-1′-hydroxyethyl)dihydro-3,4-di-
hydroxyfuran-2(3H)-one (3) (50 mg, 0.18 mmol) in CH2Cl2 (1 mL)
was added excess Ac2O (80 µL, 0.74 mmol), pyridine (120 µL,
1.5 mmol), and a catalytic amount of DMAP (1.1 mg, 5 mol %).
The reaction was stirred for 6 h, after which 5 mL of ether and
5 mL of NH4Cl were added to remove excess base. The organic
layer was washed with 5 mL of CuSO4 solution and 5 mL of
brine and the aqueous layer was further extracted with ether
(3 × 5 mL). The combined organic layers were dried over Na2SO4
and the solvent was removed in vacuo. The crude product was
purified by flash chromatography on silica gel (7:3 (v/v) hexane/
EtOAc) to yield (3R,4S,5R)-5-((S)-2′-(benzyloxy)-1′-acetoxyethyl)-
3,4-diacetoxydihydrofuran-2(3H)-one (9) (70 mg, 95% yield) as
(S)-5-((S)-2′-(Benzyloxy)-1′-hydroxyethyl)furan-2(5H)-
one (8). Into a 100-mL round-bottom flask was added 20 mL of
t-BuOH, 20 mL of water, K3Fe(CN)6 (9.6 g, 29 mmol), K2CO3
(4.03 g, 29 mmol), MeSO2NH2 (0.93 g, 9.7 mmol), (DHQ)2PHAL
(158 mg, 0.2 mmol, 2.1 mol %), and OsO4 (49 mg, 0.19 mmol, 2
mol %). The mixture was stirred at room temperature for about
15 min and then cooled to 0 °C. To this solution was added
(2Z,4E)-ethyl 6-(benzyloxy)hexa-2,4-dienoate (6) (2.4 g, 9.7 mmol)
and the reaction was stirred vigorously at 0 °C overnight. The
reaction was quenched with solid sodium sulfite (100 mg) at
room temperature. Ethyl acetate (30 mL) was added to the
reaction mixture, and after separation of the layers, the aqueous
phase was further extracted with the organic solvent (2 × 20
mL). The combined organic layers were washed with brine and
dried over anhydrous sodium sulfate. After removal of the
solvents in vacuo, flash chromatography on silica gel (7:3 (v/v)
hexanes/EtOAc) afforded 1.6 g (70% yield) of (S)-5-((S)-2′-
(benzyloxy)-1′-hydroxyethyl)furan-2(5H)-one (8) as a white
solid: mp 74-75 °C; Rf (50% EtOAc/hexanes) 0.16; [R]25D -52.33
(c 1.2, CH2Cl2); IR (thin film, cm-1) 3424, 2927, 2899, 1745, 1602,
1500, 1475, 1454, 1399, 1365, 1340, 1266, 1217, 1167, 1096,
1072, 993, 913 cm-1; 1H NMR (CDCl3, 600 MHz) δ 7.47 (dd, J )
6, 1.2 Hz, 1 H), 7.33 (m, 5H), 6.14 (dd, J ) 6, 1.8 Hz, 1 H), 5.16
(ddd, J ) 4.2, 1.8, 1.8 Hz, 1 H), 4.58 (d, J ) 12 Hz, 1H), 4.54 (d,
J ) 12 Hz, 1H), 4.01 (dddd, J ) 6, 5.4, 4.8, 4.2 Hz, 1H), 3.64
(dd, J ) 9.6, 5.4 Hz, 1 H), 3.58 (dd, J ) 9.6, 5.4 Hz, 1H), 2.42 (d,
J ) 6 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 172.9, 153.8, 137.2,
128.5 (2C), 128.0, 127.8 (2C), 122.2, 83.7, 73.6, 70.2, 70.0;
CIHRMS calcd for [C13H14O4 + Na]+ 257.0784, found 257.0782;
the COSY spectral analysis confirmed the formation of γ-lactone.
(3R,4S,5R)-5-((S)-2′-(Benzyloxy)-1′-hydroxyethyl)-3,4-di-
hydroxydihydrofuran-2(3H)-one (3). Into a 25-mL round-
a viscous oil. Rf (40% EtOAc/hexanes) 0.3; [R]25 8.6 (c 1.0,
D
CH2Cl2); IR (thin film, cm-1) 2953, 2922, 2876, 2863, 1808, 1749,
1373, 1234, 1179, 1100, 1069, 1044; 1H NMR (CDCl3, 600 MHz)
δ 7.33 (m, 5H), 5.69 (d, J ) 6 Hz, 1H), 5.39 (d, J ) 6 Hz, 1H),
5.27 (ddd, J ) 7.8, 5.4, 3 Hz, 1H), 4.86 (d, J ) 3 Hz, 1H), 4.57
(d, J ) 12 Hz, 1H), 4.54 (d, J ) 12 Hz, 1H), 3.65 (dd, J ) 9.6,
5.4 Hz, 1H), 3.60 (dd, J ) 9.6, 7.8 Hz, 1H), 2.14 (s, 3H), 2.13 (s,
3H), 2.11 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 170.2, 169.5,
169.3, 169.1, 137.2, 128.5 (2C), 128.0, 127.8 (2C), 80.7, 73.6, 70.3,
69.8, 66.4, 66.1, 20.8, 20.4, 20.1; CIHRMS calcd for [C19H22O9 +
Na]+ 417.1156, found 417.1158.
Acknowledgment. We would like to thank Dirk
Friedrich for his helpful discussions regarding the NMR
assignment of the stereochemistry of 12. We are grateful
to NIH (GM63150) and NSF (CHE-0415469) for support
of our research program and NSF-EPSCoR (0314742)
for the 600-MHz NMR at WVU.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Only the procedures for our initial preparation of talo-sugar 9
are presented in the Experimental Section (Scheme 3). Complete
experimental procedures and spectral data for all new compounds
(Schemes 3 and 4) are presented in the Supporting Information.
JO051476+
10578 J. Org. Chem., Vol. 70, No. 25, 2005