De novo synthesis of galacto-sugar δ-lactones via a catalytic osmium/palladium/osmium reaction sequence

Article abstract of DOI:10.1016/j.tetlet.2005.03.029

A highly efficient route to various 1,5-galacto-sugar lactones from dienoates has been developed by using three catalytic reactions. These reactions include (i) an enantioselective osmium-catalyzed dihydroxylation, (ii) a regio- and diastereoselective pal

Full text of DOI:10.1016/j.tetlet.2005.03.029

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3015–3019
De novo synthesis of galacto-sugar d-lactones via a
catalytic osmium/palladium/osmium reaction sequence
Md. Moinuddin Ahmed and George A. OꢀDoherty*
Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
Received 14 February 2005; accepted 3 March 2005
Abstract—A highly efficient route to various 1,5-galacto-sugar lactones from dienoates has been developed by using three catalytic
reactions. These reactions include (i) an enantioselective osmium-catalyzed dihydroxylation, (ii) a regio- and diastereoselective
palladium-catalyzed p-allyl alkylation with p-methoxyphenol for alcohol differentiation and protection, and (iii) a diastereoselective
dihydroxylation that can be improved using matched enantioselective osmium-catalyzed dihydroxylation condition.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
protected galacto-sugar d-lactones via the use of a cata-
lytic Os/Pd/Os reaction sequence. A limitation to the
above approach (Scheme 1) is the limit to five membered
galacto-lactones. This problem was resolved when the
C-4 hydroxyl group was removed, in which a Pd-p-
allyl-catalyzed reduction was added to the sequence
and resulted in a 5-step synthesis of either altro- or glu-
co-C-4 deoxy sugar lactones 3 and 4 (Scheme 2).4
The de novo enantioselective synthesis of carbohydrates
and their analogous stands as a challenge to asymmetric
synthesis,2–5 as these compounds are integral compo-
nents of many important pharmaceuticals and biomole-
cules.1 Most existing syntheses are based on chemical
manipulation of naturally occurring sugars, where most,
if not all, of the stereocenters in the products are derived
directly from the starting material. Despite some notable
efforts by many, there still does not exist a practical
route to all the hexoses.2,3
In order to prevent five membered ring lactonization, a
selective protection of the C-4 hydroxyl group was
required. We were intrigued by the possibility of accom-
plishing this alcohol differentiation by means of the
same Pd-p-allyl intermediate that was used for the
deoxy-sugar synthesis (Scheme 2).
Recently we reported an expedient and practical synthe-
sis of galacto-sugars from simple achiral precursors with
complete stereocontrol.4,5 This powerful new approach
is based on the tandem use of the osmium-catalyzed
Sharpless asymmetric dihydroxylation (AD) reaction
(Scheme 1).4 Herein we report our discovery of a practi-
cal and highly stereocontrolled synthesis of various C-4
While many oxygen nucleophiles were investigated, only
phenols gave good yields, reacting with excellent regio-
and stereocontrol.6 Because of its ability for oxidative
removal, we pursued our synthetic investigations with
p-methoxyphenol (vide infra).
O
As in our previous syntheses the diols 5a–c can be easily
synthesized from dienoate 1a/b or from the commercially
available ethyl sorbate 1c in good yields and enantiomeric
HO
O
O
1-3 Steps
OBn
EtO
OBn
HO
OH
1
O
O
2
HO
HO
HO
HO
D-, L-, or rac-galacto-γ-lactone
5 Steps
O
O
or
1
OBn
OBn
Scheme 1. Synthesis (1- to 3-step) of galacto-c-sugar lactone.
4
3
deoxy-gluco-δ-lactone
deoxy-altro-δ-lactone
*
Corresponding author. Tel.: +1 304 293 3435x6444; fax: +1 800 293
4904; e-mail: george.odoherty@mail.wvu.edu
Scheme 2. Synthesis (5-step) of C-4 deoxy-d-sugar lactone.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.029

3016
Md. M. Ahmed, G. A. OꢀDoherty / Tetrahedron Letters 46 (2005) 3015–3019
O
O
OH
AD-α*
t-BuOH/H2O
R
R
EtO
EtO
OH
1a: R = OBn
5a: R = OBn; 89%, 90% ee
5b: R = CH3; 84%, 85% ee
5c: R = H; 80%, 80% ee
1b: R = CH3
1c: R = H
O
O
O
H3CO
OH
/ Et3N
(Cl3CO)2CO
Py/CH2Cl2
7a-c
EtO
R
5a-c
0.5% Pd2(DBA)3•CHCl3
2% PPh3
O
6a: R = OBn; 87%
6b: R = CH3; 96%
6c: R = H; 90%
O
OH
O
OH OH
2% OsO4/NMO
t-BuOH/Acetone
R
R
EtO
EtO
OPMP
OH OPMP
7a: R = OBn; 90%
7b: R = CH3; 90%
7c: R = H; 85%
8a: R = OBn; 82%; dr = 7:1
8b: R = CH3; 80%; dr = 6:1
8c: R = H; 77%; dr = 6:1
AD-α* = 2% OsO4, 4% (DHQ)2PHAL, 3 eq K3Fe(CN)6, 3 eq K2CO3, 1 eq MeSO2NH2
Scheme 3. Palladium-catalyzed hydroxyl protection at C-4.
excess (80–90% ee) (Scheme 3). The diol 5a was converted
into cyclic carbonate 6a (87% yield). Treatment of 6a with
a catalytic amount of palladium(0) (1 mol% Pd(0)/
2 mol% PPh3) and p-methoxyphenol as the nucleophile
provided the protected alcohol 7a in 90% yield, with no
loss of enantiomeric excess.7 Finally the C-2/C-3 hydroxyl
groups were installed, with galacto-stereochemistry, by
means of a diastereoselective dihydroxylation of 7a.
Thus, exposure of 7a to the Upjohn conditions (OsO4/
NMO) provided 8a in a 7:1 diastereomeric ratio. Similar
yields and selectivities were observed for the conversion
of dienoates 1b/c to galacto-triols 8b/c (58% and 47%
overall yield of 8b and 8c, respectively; Scheme 3). In all
three cases (8a–c) the minor diastereomer was easily
removed by silica gel chromatography.
the reaction in concert (matched case); therefore, the
product enantiopurity is even greater than the original
starting material enantiopurity.8,10,11 This presumably
results from the fact that the minor enantiomers
(ent-7a–c) do not react with the mismatched OsO4/
(DHQD)2PHAL catalyst system.
With the C-4 position differentiated, the triols 8a–c
could easily be lactonized giving the d-lactones 9a–c
(Scheme 4). When triols 8a–c were treated with 5%
PyÆTsOH/C6H6, the desired lactonization readily
occurred providing the galacto-pyranones 9a–c in
80–86% yield.12 At this stage the relative stereochemistry
1
could be assigned by analysis of H–1H-coupling con-
stants.13 This was easily accomplished on the diacetates
10a–c, which were readily prepared using Ac2O/Py in
90–95% yield (Scheme 4).14
While the triols 8a–c were easily obtained in diastereo-
merically pure form, we were interested in improving
both the diastereo- and enantiopurity of these triols.
Thus we investigated the use of the Sharpless reagent
for the second dihydroxylation (7 to 8).8 In this im-
proved procedure the triols 8a–c were isolated to all
practical purposes in both enantiomerically and diaste-
romerically pure form. When the alcohols 7a–c were
subjected to Sharpless asymmetric dihydroxylation reac-
tions using the matched reagent system (2% OsO4 and
4% (DHQD)2 PHAL) triols 8a–c were afforded as a sin-
gle diastereomer and enantiomer.9,10 Triol 8a was iso-
lated in 86% yield (>96% ee), triol 8b was isolated in
85% yield (>96% ee) and triol 8c was isolated in 83%
yield (>96% ee). The pseudo-enantiomeric catalyst sys-
tem (2% OsO4/4% (DHQ)2PHAL) reacted with the
enantiomers of 7a–c (ent-7a–c) to give ent-8a–c in simi-
lar yields and stereoselectivities (Scheme 4).
In summary, a highly enantio- and diastereoselective
procedure for the preparation of various galacto-sugar
d-lactones has been developed. Critical to the success
of this approach was the unique use of a regio- and ste-
reospecific Pd-p-allyl reaction for alcohol differentiation
and protection. Finally, by selecting the order in which
the Sharpless reagents were used, both D- and L-sugars
were produced. Further investigation for the develop-
ment of this methodology for the synthesis of biologi-
cally important carbohydrates is ongoing.
2. Experimental section
2.1. (E)-Ethyl 3-((4S,5S)-5-((benzyloxy)methyl)-2-oxo-
1,3-dioxolan-4-yl)acrylate (6a)
This improvement of enantiopurity results from the fact
that both the substrates 7a–c and the catalyst (OsO4/
(DHQD)2PHAL) direct the stereochemical course of
Into a 250 mL round-bottomed flask was placed 6.5 g
(23.2 mmol) of (E,4S,5S)-ethyl 6-(benzyloxy)-4,5-
dihydroxyhex-2-enoate 5a in 25 mL of dichloromethane

Md. M. Ahmed, G. A. OꢀDoherty / Tetrahedron Letters 46 (2005) 3015–3019
3017
O
OH OH
O
OH
AD-β*
t-BuOH/H2O
R
R
EtO
EtO
OH OPMP
OPMP
8a: R = OBn; 86%
8b: R = CH3; 85%
8c: R = H; 83%
7a-c
O
OH OH
1) AD-β*
AD-α*
t-BuOH/H2O
R
2) (Cl2CO)3
3) PMPOH
Pd(PPh3)2
1a-c
EtO
(ent)-7a-c
OH OPMP
(ent)-7a: 92% ee
(ent)-7b: 91% ee
(ent)-7c: 92% ee
(ent)-8a: R = OBn; 80%
(ent)-8b: R = CH3; 87%
(ent)-8c: R = H; 84%
O
O
HO
AcO
O
O
Py•TsOH
C6H6
Ac2O/Py
8a-c
R
R
HO
AcO
OPMP
OPMP
10a: R = OBn; 95%
10b: R = CH3; 94%
10c: R = H; 90%
9a: R = OBn; 85%
9b: R = CH3; 86%
9c: R = H; 80%
AD-β* = 2% OsO4, 4% (DHQD)2PHAL, 3 eq K3Fe(CN)6, 3 eq K2CO3, 1 eq MeSO2NH2
AD-α* = 2% OsO4, 4% (DHQ)2PHAL, 3 eq K3Fe(CN)6, 3 eq K2CO3, 1 eq MeSO2NH2
Scheme 4. Enantioselective synthesis of L-galacto-d-lactone.
and 10 mL (116 mmol) of pyridine. The solution was
cooled to 0 ꢁC and 7.6 g (25.6 mmol) of triphosgene in
50 mL of dichloromethane was added slowly with an
addition funnel. The reaction was stirred for 1.5 h and
quenched with saturated aqueous NH4Cl (40 mL). The
layers were separated and the aqueous layer was ex-
tracted with ether (3 · 50 mL). The combined organic
layers were washed with saturated aqueous sodium
bicarbonate (30 mL), brine (25 mL), 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 (E)-ethyl 3-((4S,5S)-5-((benz-
yloxy)methyl)-2-oxo-1,3-dioxolan-4-yl)acrylate 6a as a
(0.19 mmol, 2 mol%) of PPh3, and 30 mL of CH2Cl2.
Triethylamine 1.3 mL, (9.8 mmol) and p-methoxy phe-
nol 2.43 g (19.6 mmol) were added and the mixture
was allowed to reflux for 30 min. The reaction was
cooled to room temperature and quenched with satu-
rated aqueous sodium bicarbonate (20 mL). The aque-
ous layer was extracted with ether (3 · 30 mL). The
organic layer was washed with brine (20 mL) and dried
with anhydrous sodium sulfate. After removal of the
solvents in vacuo, flash chromatography on silica gel
(7:3 (v/v) hexanes/EtOAc) afforded (E,4S,5S)-ethyl 4-
(4-methoxyphenoxy)-6-(benzyloxy)-5-hydroxyhex-2-eno-
ate 7a as a yellow oil (3.4 g, 90%): Mosher ester analysis
clear, colorless oil (6.17 g, 87%): Rf (30% EtOAc/hex-
of this alcohol shows 90% ee; Rf (30% EtOAc/hex-
25
D
25
anes) = 0.37; ½aꢀ ꢁ54.7 (c 1.03, CH2Cl2); IR (thin film,
anes) = 0.32; ½aꢀ 22.5 (c 1.1, CH2Cl2); IR (thin film,
D
cmꢁ1) 2983, 2938, 2908, 2872, 1806, 1721, 1665, 1496,
cmꢁ1) 3484, 2980, 2954, 2923, 2869, 1716, 1660, 1506,
1454, 1368, 1303, 1276, 1227, 1180, 1109, 1036, 983;
1H NMR (CDCl3, 600 MHz) d 7.33 (m, 5H), 6.98 (dd,
J = 15.6, 5.4 Hz, 1H), 6.81 (m, 4H), 6.07 (dd, J = 15.6,
1.8 Hz, 1H), 4.86 (ddd, J = 5.4, 4.8, 1.8 Hz, 1H), 4.56
(d, J = 12 Hz, 1H), 4.53 (d, J = 12 Hz, 1H), 4.18 (q,
J = 7.8 Hz, 1H), 4.16 (q, J = 7.8 Hz, 1H), 4.01 (ddd,
J = 10.2, 6, 5.4 Hz, 1H), 3.76 (s, 3H), 3.68 (dd, J = 9.6,
4.8 Hz, 1H), 3.60 (dd, J = 9.6, 5.4 Hz, 1H), 2.58 (d,
J = 5.4 Hz, 1H), 1.27 (t, J = 7.8 Hz, 3H); 13C NMR
(CDCl3, 67.5 MHz) d 165.7, 154.5, 151.6, 143.5, 137.6,
128.4 (2C), 127.8 (3C), 123.8, 117.0 (2C), 114.6 (2C),
78.4, 73.6, 72.3, 69.9, 60.6, 55.6, 14.1; CIHRMS: Calcd
for [C22H26O6+Na]+: 409.1627. Found: 409.1621.
1454, 1369, 1304, 1272, 1174, 1111, 1032, 978 cmꢁ1
;
1H NMR (CDCl3, 600 MHz) d 7.34 (m, 5H), 6.83 (dd,
J = 15.6, 5.4 Hz, 1H), 6.14 (dd, J = 15.6, 1.4 Hz, 1H),
5.17 (ddd, J = 6.6, 5.4, 1.2 Hz, 1H), 4.64 (d, J = 12 Hz,
1H), 4.58 (d, J = 12 Hz, 1H), 4.46 (ddd, J = 6.6, 3.6,
3.6 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.75 (dd,
J = 11.4, 3.6 Hz, 1H), 3.66 (dd, J = 11.4, 3.6 Hz, 1H),
1.30 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
67.5 MHz): d 164.9, 153.5, 139.7, 136.7, 128.5 (2C),
128.1, 127.7 (2C), 124.5, 79.3, 76.4, 73.7, 67.7, 61.0,
14.1; CIHRMS: Calcd for [C16H18O6+Na]+: 329.1001.
Found: 329.1003.
2.2. (E,4S,5S)-Ethyl 4-(4-methoxyphenoxy)-6-(benzyl-
oxy)-5-hydroxyhex-2-enoate (7a)
2.3. (2S,3S,4R,5S)-Ethyl 4-(4-methoxyphenoxy)-6-(benz-
yloxy)-2,3,5-trihydroxyhexanoate (8a)
Into a 100 mL, round bottomed flask fitted with a
condenser and maintained under nitrogen was placed
3 g (9.8 mmol) of (E)-ethyl 3-((4S,5S)-5-((benzyl-
oxy)methyl)-2-oxo-1,3-dioxolan-4-yl)acrylate 6a, 50.7 mg
(0.49 mmol, 0.5 mol%) of Pd2(DBA)3ÆCHCl3, 51 mg
Into a 50 mL round bottom flask was added 10 mL of
t-BuOH, 10 mL of water, K3Fe(CN)6 (4.93 g,
15 mmol), K2CO3 (2.07 g, 15 mmol), MeSO2NH2
(475 mg, 5 mmol), (DHQD)2PHAL (155 mg, 0.2 mmol,

3018
Md. M. Ahmed, G. A. OꢀDoherty / Tetrahedron Letters 46 (2005) 3015–3019
4 mol%), and OsO4 (25 mg, 0.1 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 (E,4S,5S)-ethyl 4-(4-methoxyphenoxy)-6-(benzyl-
oxy)-5-hydroxyhex-2-enoate 7a (2.00 g, 5 mmol) in
4 mL CH2Cl2 and the reaction was stirred vigorously
at 0 ꢁC overnight. The reaction was quenched with
solid sodium sulfite (100 mg) at room temperature
and stirred for 15 min. Then the mixture was filtered
through a pad of Celite/Florisil and eluted with
50 mL 50% Ethyl acetate/MeOH. The combined organ-
ic layers were dried over anhydrous sodium sulfate.
After removal of the solvents in vacuo, flash chroma-
tography on silica gel (6:4 (v/v) hexanes/EtOAc) affor-
ded 1.8 g (86% yield) of (2S,3S,4R,5S)-ethyl 4-(4-
methoxyphenoxy)-6-(benzyloxy)-2,3,5-trihydroxyhexano-
2.5. (3S,4R,5R,6S)-5-(4-Methoxyphenoxy)-6-((benzyl-
oxy)methyl)-tetrahydro-3,4-diacetoxypyran-2-one (10a)
To a solution of (3S,4S,5S,6S)-5-(4-methoxyphenoxy)-
6-((benzyloxy)methyl)-tetrahydro-3,4-dihydroxypyran-
2-one 9a (150 mg, 0.4 mmol) in CH2Cl2 (2 mL) was
added excess Ac2O (0.6 mL, 2 mmol), pyridine (0.3 mL,
4 mmol) and a catalytic amount of DMAP (2.5 mg,
5 mol%). The reaction was stirred for an hour, after
which 10 mL ether and 10 mL of NH4Cl was added to re-
move excess base. The organic layer was washed with
10 mL CuSO4 solution, 10 mL brine and the aqueous
layer was further extracted with ether (3 · 10 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 (4:1
(v/v) hexanes/EtOAc) to yield (3S,4R,5R,6S)-5-(4-meth-
oxyphenoxy)-6-((benzyloxy)methyl)-tetrahydro-3,4-diac-
ate 8a as a viscous oil: Rf (90% EtOAc/hexanes) = 0.43;
25
D
½aꢀ 5.4 (c 1.0, CH2Cl2); IR (thin film, cmꢁ1) 3533,
2983, 2957, 2869, 1747, 1653, 1593, 1506, 1466, 1455,
1372, 1296, 1220, 1184, 1044 ; 1H NMR (CDCl3,
600 MHz) d 7.28 (m, 5H), 6.98 (m, 2H), 6.80 (m,
2H), 4.49 (dd, J = 9, 1.8 Hz, 1H), 4.46 (d,
J = 11.4 Hz, 1H), 4.43 (d, J = 11.4 Hz, 1H), 4.35–4.29
(m, 3H), 3.76 (s, 3H), 4.28 (q, J = 7.2 Hz, 1H), 4.26
(q, J = 7.2 Hz, 1H), 3.67 (dd, J = 9.6, 6 Hz, 1H), 3.55
(dd, J = 9.6, 6 Hz, 1H), 3.18 (d, J = 5.4 Hz, 1H), 2.89
(d, J = 8.4 Hz, 1H), 2.62 (d, J = 7.8 Hz, 1H), 1.29 (t,
J = 7.2 Hz, 3H) ; 13C NMR (CDCl3, 67.5 MHz) d
173.4, 154.4, 152.4, 137.5, 128.4 (2C), 127.8 (3C),
117.1 (2C), 114.7 (2C), 76.6, 73.4, 71.1, 70.6, 70.1,
69.3, 62.1, 55.6, 14.1; CIHRMS: Calcd for
[C22H28O8+Na]+: 443.1682. Found: 443.1668.
etoxypyran-2-one 10a (174 mg, 95% yield) as viscous oil.
25
Rf (40% EtOAc/hexanes) = 0.38; ½aꢀ ꢁ59.7 (c 1.0,
D
CH2Cl2); IR (thin film, cmꢁ1) 2953, 2922, 2876, 2863,
1754, 1507, 1455, 1373, 1209, 1087, 1034, 929; 1H
NMR (CDCl3, 270 MHz): d 7.29 (m, 3H), 7.19 (m,
2H), 6.94 (m, 2H), 6.79 (m, 2H), 5.49 (d, J = 10.2 Hz,
1H), 5.41 (dd, J = 10.2, 2.4 Hz, 1H), 5.04 (dd, J = 2.4,
1.4 Hz, 1H), 4.73 (ddd, J = 7.3, 7.1, 1.4 Hz, 1H), 4.46
(d, J = 11.4 Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 3.78 (d,
J = 7.1 Hz, 2H), 3.77 (s, 3H), 2.15 (s, 3H), 1.82 (s, 3H);
13C NMR (CDCl3, 67.5 MHz): d 170.2, 170.1, 165.7,
154.9, 152.9, 136.9, 128.4 (2C), 128.0, 127.9 (2C), 117.7
(2C), 114.6 (2C), 76.5, 73.6, 73.2, 71.4, 69.4, 66.3, 55.6,
20.5, 20.4; CIHRMS: Calcd for [C24H26O9+Na]+:
481.1475. Found: 481.1466.
2.4. (3S,4S,5S,6S)-5-(4-Methoxyphenoxy)-6-((benzyl-
oxy)methyl)-tetrahydro-3,4-dihydroxypyran-2-one (9a)
Acknowledgements
To a solution of (2S,3S,4R,5S)-ethyl 4-(4-methoxyphen-
oxy)-6-(benzyloxy)-2,3,5-trihydroxyhexanoate 8a (200
mg, 0.48 mmol) in benzene (3 mL), was added PyÆTsOH
(6 mg, 0.03 mmol, 5 mol%) and the mixture was allowed
to reflux for 5 h. The reaction was cooled to room tem-
perature and quenched with saturated aqueous sodium
bicarbonate (2 mL). The aqueous layer was extracted
with ether (3 · 10 mL). The organic layer was washed
with brine (10 mL) and dried with anhydrous sodium
sulfate. After removal of the solvents in vacuo, flash
chromatography on silica gel (4:6 (v/v) hexanes/EtOAc)
afforded (3S,4S,5S,6S)-5-(4-methoxyphenoxy)-6-((ben-
zyloxy)methyl)-tetrahydro-3,4-dihydroxypyran-2-one 9a
We are grateful to NIH (GM63150) and NSF (CHE-
0415469) for the support of our research program and
NSF-EPSCoR (0314742) for a 600 MHz NMR at
WVU.
References and notes
1. (a) Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G. W., Sinay, P., Eds.; Wiley-VCH: New York,
2000; (b) Glycochemistry. Principles, Synthesis and Appli-
cations; Wong, P. G., Bertozzi, C. P., Eds.; Marcel
Dekker: New York, 2001; (c) Vogel, P. In Glycoscience;
Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.; Springer:
Berlin, 2001; Vol. 2, pp 1023–1174.
as a viscous oil (160 mg, 85%): Rf (90% EtOAc/ hex-
25
anes) = 0.40; ½aꢀ ꢁ26.8 (c 2, CH2Cl2); IR (thin film,
D
cmꢁ1) 3396, 2929, 2922, 1740, 1506, 1455, 1368, 1328,
1220, 1103, 1034, 923, 830; 1H NMR (CDCl3,
600 MHz) d 7.26 (m, 3H), 7.03 (m, 4H), 6.78 (m, 2H),
4.8 (dd, J = 2.4, 1.8 Hz, 1H), 4.59 (d, J = 10.2 Hz, 1H),
4.54 (ddd, J = 7.2, 6.6, 1.8 Hz, 1H), 4.36 (d,
J = 11.4 Hz, 1H), 4.28 (d, J = 11.4 Hz, 1H), 4.17 (ddd,
J = 10.2, 1.8, 1.2 Hz, 1H), 3.81 (br s, 1H), 3.74 (s, 3H),
3.72 (d, J = 6.6 Hz, 2H), 3.21 (br s, 1H); 13C NMR
(CDCl3, 150 MHz) d 172.1, 154.8, 153.5, 137.0, 128.4
(2C), 127.9 (2C), 127.8, 117.7 (2C), 114.6 (2C), 78.2,
76.7, 73.5, 71.8, 70.4, 67.0, 55.7; CIHRMS: Calcd for
[C20H22O7+Na]+: 397.1257. Found: 397.1285.
2. Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.;
Sharpless, K. B. Science 1983, 220, 949–951.
3. For a review of other approaches to hexoses, see: (a)
Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J.
Chem. Rev. 1996, 96, 1195–1220; For related work
published since 1996, see: (b) Northrup, A. B.; MacMillan,
D. W. C. Science 2004, 305, 1752–1755; (c) Taniguchi, T.;
Nakamura, K.; Ogasawara, K. Synlett 1999, 341–354; (d)
Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem.
Rev. 1996, 96, 443–474; (e) Davies, S. G.; Nicholson, R.
L.; Smith, A. D. Synlett 2002, 1637–1640; (f) Bataille, C.;
Begin, G.; Guillam, A.; Lemiegre, L.; Lys, C.; Maddaluno,
J.; Toupet, L. J. Org. Chem. 2002, 67, 8054–8062; (g)

Md. M. Ahmed, G. A. OꢀDoherty / Tetrahedron Letters 46 (2005) 3015–3019
3019
Harris, J. M.; Kera¨nen, M. D.; Nguyen, H.; Young, V. G.;
OꢀDoherty, G. A. Carbohydr. Res. 2000, 328, 17–36.
4. (a) Ahmed, Md. M.; Berry, B. P.; Hunter, T. J.; Tomcik,
D. J.; OꢀDoherty, G. A. Org. Lett. 2005, 7, 745–748; For
its use in synthesis see: (b) Gao, D.; OꢀDoherty, G. A. Org.
Lett. 2005, 7, 1069–1072.
5. For related Achmatowicz approach to oligosaccharides
see: (a) Babu, R. S.; OꢀDoherty, G. A. J. Am. Chem. Soc.
2003, 125, 12406–12407; (b) Babu, R. S.; Zhou, M.;
OꢀDoherty, G. A. J. Am. Chem. Soc. 2004, 126, 3428–
3429.
6. (a) Evans, P. A.; Leahy, D. K.; Slieker, L. M. Tetrahedron:
Asymmetry 2003, 14, 3613–3618; (b) Evans, P. A.; Leahy,
D. K. J. Am. Chem. Soc. 2000, 122, 5012–5013; (c) Kim,
H.; Lee, C. Org. Lett. 2002, 4, 4369–4371.
7. We have found that this reaction works for various
phenols, however, simple alcohols (e.g., BnOH) did not
participate in this reaction.
9. Masamune, S.; Choy, W.; Petersen, J.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1–76.
10. For a discussion of the use of the Sharpless AD-mix
reagent in a matched/mismatched case see: Ref. 4 and
Morikawa, K.; Sharpless, K. B. Tetrahedron Lett. 1993,
34, 5575–5578.
1
11. All enantioexcesses were determined by examining the H
NMR and/or 19F NMR of a corresponding Mosher esters,
see: Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org.
Chem. 1973, 38, 2143–2147.
12. The overall sequence requires fewer steps (five vs eight) to
a galacto-d-lactone and occurs in a greater overall yield
(40% vs 14%) than a related iterative aldol approach, see:
Ref. 3e.
13. Particularly revealing coupling constants were the Jꢀs
between the two axial protons at C-2 and C-3 (e.g., for
10a, J2,3 = 10.2 Hz) and between the equatorial proton at
C-4 and the two axial protons at C-3 and C-5 (e.g., for
10a, J3,4 = 2.4 Hz and J4,5 = 1.4 Hz).
8. Recently we have found that when the Sharpless reagent
was used in a matched fashion on diols 5a/c, tetrols were
obtained in both excellent diastereoselectivity and enantio-
selectivity, see: Ref. 4.
14. As a representative example of this approach we have
included experimental details and spectral data for the
conversion of 6a to 10a.