A convenient route to higher sugars by two-carbon chain elongation using Wittig/dihydroxylation reactions

Article abstract of DOI:10.1021/jo010128e

The combination of a Wittig olefination and a dihydroxylation reaction constitutes a facile synthetic protocol for the transformation of unprotected carbohydrates into higher sugars. The Wittig reaction is carried out with tert-butyl or diphenylmethyl ester stabilized phosphoranes to give (E)-configured α,β-unsaturated esters as the only products in most cases. These are dihydroxylated in a diastereoselective fashion using OsO₄/NMO. The stereochemical outcome in the dihydroxylation follows Kishi's empirical rule and gives high diastereoselectivity (5:1-8:1) when starting from sugars with the 2,3-threo configuration. When starting from sugars with the 2,3-erythro configuration, the diastereoselectivity in the dihydroxylation is low (2:1-2.5:1). As a result, the Wittig/dihydroxylation protocol is most effective for producing higher sugars with the galacto configuration at the reducing end. The two steps can either be carried out individually or, more efficiently, as a one-pot procedure.

Full text of DOI:10.1021/jo010128e

J . Org. Chem. 2001, 66, 4625-4629
4625
A Con ven ien t Rou te to High er Su ga r s by Tw o-Ca r bon Ch a in
Elon ga tion Usin g Wittig/Dih yd r oxyla tion Rea ction s
Morten J ørgensen, Erik H. Iversen, and Robert Madsen*
Department of Organic Chemistry, Technical University of Denmark, DK-2800 Lyngby, Denmark
rm@kemi.dtu.dk
Received February 1, 2001
The combination of a Wittig olefination and a dihydroxylation reaction constitutes a facile synthetic
protocol for the transformation of unprotected carbohydrates into higher sugars. The Wittig reaction
is carried out with tert-butyl or diphenylmethyl ester stabilized phosphoranes to give (E)-configured
R,â-unsaturated esters as the only products in most cases. These are dihydroxylated in a
diastereoselective fashion using OsO4/NMO. The stereochemical outcome in the dihydroxylation
follows Kishi’s empirical rule and gives high diastereoselectivity (5:1-8:1) when starting from sugars
with the 2,3-threo configuration. When starting from sugars with the 2,3-erythro configuration,
the diastereoselectivity in the dihydroxylation is low (2:1-2.5:1). As a result, the Wittig/
dihydroxylation protocol is most effective for producing higher sugars with the galacto configuration
at the reducing end. The two steps can either be carried out individually or, more efficiently, as a
one-pot procedure.
In tr od u ction
However, with the employed phosphorane, Ph3PdCHCO2-
Et, the yield in the Wittig reaction was moderate (30-
60%) due to a concomitant intramolecular Michael ad-
dition in the products. In addition, the dihydroxylation
of the unsaturated ester proceeded with only about 3:1
diastereoselectivity. The Michael addition side reaction
is a well-known problem in Wittig reactions on unpro-
tected aldoses with methyl or ethyl ester stabilized
phosphoranes.3 Addition of cupric acetate has been
reported to diminish this side reaction to some extent.7
However, in 1996, Railton and Clive reported that the
Michael addition could be virtually completely sup-
pressed by employing bulky tert-butyl and diphenyl-
methyl ester stabilized phosphoranes.8 In addition, the
bulky ester groups, particularly the diphenylmethyl
group, also gave very high (E)-selectivity in the Wittig
reactions. We speculated that the use of bulky ester
groups would not only improve the selectivity and yield
in the Wittig reaction but also might enhance the
diastereoselectivity in the subsequent dihydroxylation
reaction. Herein, we report an improved strategy for
synthesis of higher sugars by Wittig/dihydroxylation of
unprotected aldoses.
Higher carbon sugars are carbohydrates containing
seven or more consecutive carbon atoms. They have been
identified as subunits in a number of natural products
of biological significance1 and have found important use
as chiral synthons.2 However, the synthesis of higher
sugars has been a challenge in carbohydrate chemistry
for more than a century.3 The addition of more carbon
atoms to unprotected pentoses and hexoses is often
plagued by low yield, poor diastereoselectivity, and
troublesome isolation of the products. The classical
methods for one carbon chain extension of aldoses are
the Kiliani and the Sowden reactions using addition of
cyanide and nitromethane, respectively.3,4 More recently,
a number of different methods have been developed for
elongation of partially protected sugars.3,5
In 1965, Kochetkov and Dmitriev demonstrated that
higher sugars could be obtained by Wittig reaction of
unprotected aldoses followed by OsO4-catalyzed dihy-
droxylation of the resulting R,â-unsaturated esters.6
(1) Secrist, J . A., III; Barnes, K. D.; Wu, S.-R. In Trends in Synthetic
Carbohydrate Chemistry; Horton, D., Hawkins, L. D., McGarvey, G.
J ., Eds.; ACS Symposium Series 386; American Chemical Society:
Washington, DC, 1989; p 93. Danishefsky, S. J .; DeNinno, M. P. Angew.
Chem., Int. Ed. Engl. 1987, 26, 15.
Resu lts a n d Discu ssion
(2) Lundt, I. Top. Curr. Chem. 1997, 187, 117. Casiraghi, G.;
Zanardi, F.; Rassu, G.; Spanu, P. Chem. Rev. 1995, 95, 1677. Fleet, G.
W. J . In Antibiotics and Antiviral Compounds - Chemical Synthesis
and Modification; Krohn, K., Kirst, H. A., Maag, H., Eds.; VCH:
Weinheim, 1993; p 333. Hanessian, S. Total Synthesis of Natural
Products: The ‘Chiron’ Approach; Pergamon Press: Oxford, 1983.
(3) Gyo¨rgydea´k, Z.; Pelyva´s, I. F. Monosaccharide Sugars - Chemi-
cal Synthesis by Chain Elongation, Degradation and Epimerization;
Academic Press: San Diego, 1998.
(4) For some recent examples, see: Dromowicz, M.; Ko¨ll, P. Carbo-
hydr. Res. 1998, 308, 169. Bell, A. A.; Nash, R. J .; Fleet, G. W. J .
Tetrahedron: Asymmetry 1996, 7, 595. Lundt, I.; Madsen, R. Synthesis
1995, 787. Sato, K.-i.; Miyata, T.; Tanai, I.; Yonezawa, Y. Chem. Lett.
1994, 129.
We first decided to probe the strategy by studying the
chain elongation of D-galactose. Railton and Clive have
already described the Wittig reactions on D-galactose with
phosphoranes 1a and 1b8 (Scheme 1). The liberated
triphenylphosphine oxide is conveniently removed from
the products by partitioning between dichloromethane
and water. Unsaturated tert-butyl ester 2a stays in the
aqueous layer from which it can be isolated by crystal-
lization, while the diphenylmethyl ester 2b crystallizes
directly at the interface of the organic and the aqueous
(5) Dondoni, A.; Marra, A. In Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; p 173. Casiraghi,
G.; Rassu, G. In Studies in Natural Product Chemistry; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1992; p 429.
(6) Kochetkov, N. K.; Dmitriev, B. A. Tetrahedron 1965, 21, 803.
(7) Horton, D.; Koh, D. Carbohydr. Res. 1993, 250, 231.
(8) Railton, C. J .; Clive, D. L. J . Carbohydr. Res. 1996, 281, 69.
10.1021/jo010128e CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/01/2001

4626 J . Org. Chem., Vol. 66, No. 13, 2001
J ørgensen et al.
Sch em e 1
Ch a r t 1
Ta ble 1. Wittig Rea ction s on Un p r otected Ald oses w ith
P h osp h or a n es 1a a n d 1b
layer.8 This turns out to be general for many Wittig
reactions on unprotected aldoses with bulky phospho-
ranes 1a and 1b.
The OsO4-catalyzed dihydroxylation of 2a and 2b
proceeded smoothly in an acetone-water mixture with
NMO as reoxidant.9 A 8:1 diastereomeric ratio between
the two possible octonic acid esters was obtained in both
cases as determined by means of 13C NMR spectroscopy.
For the tert-butyl ester, the major diastereomer 3 crystal-
lized directly from the reaction mixture in 85% yield. For
the more labile diphenylmethyl ester, the octonolactone
4 was isolated by crystallization after workup with acidic
ion-exchange resin. Octonolactone 4 has previously been
prepared by the Kiliani reaction.10 It could also be
obtained from tert-butyl ester 3 after reflux in dilute
hydrochloric acid. The high diastereomeric ratio is a
significant improvement over the 3:1 ratio obtained pre-
viously on the corresponding unsaturated ethyl ester or
free acid.6 The observed diastereoselectivity obeys Kishi’s
empirical rule.11 This predicts that for dihydroxylation
of acyclic allylic alcohols the relative stereochemistry
between the preexisting hydroxy group and the adjacent
newly introduced hydroxy group in the major product is
erythro. Kishi’s rule has previously been shown to apply
in dihydroxylation of a variety of carbohydrate allylic
systems and has also been exploited for the synthesis of
complex natural products.12
Following the successful chain elongation of D-galac-
tose, we now decided to explore the strategy on a wide
assortment of substrates. Railton and Clive have also
reacted D-glucose and D-mannose with phosphoranes 1a
and 1b to give unsaturated esters 5 and 68 (Chart 1). In
addition, D-ribose and D-arabinose have been reacted with
tert-butyl ester phosphorane 1a to give 7a and 8a ,
respectively.8 Notably, the reactions between D-mannose
and D-ribose with 1a give in both cases a mixture of
(E)- and (Z)-olefins.8 When we treated D-ribose with
diphenylmethyl ester phosphorane 1b, we obtained 7b
in 62% yield as the pure (E)-conjugated ester (Chart 1).
Under the same conditions, D-arabinose gave (E)-config-
ured ester 8b in 75% yield. In a similar way, we have
treated D-xylose and D-lyxose with phosphoranes 1a and
1b to obtain the corresponding Wittig adducts (Table 1,
entries 1-4). In addition, the heptoses D-glycero-D-gulo-
heptose and D-glycero-D-galacto-heptose have also been
homologated, but only with phosphorane 1a (Table 1,
entries 5 and 6).
These reactions were all carried out in dioxane or
dioxane-DMF mixtures at 50-90 °C, and the Wittig
products were separated from triphenylphosphine oxide
after partitioning between dichloromethane and water.
Finally, the products were purified by crystallization or
flash chromatography. In all cases, good yields of the
desired Wittig products were obtained. Byproducts aris-
ing from the intramolecular Michael addition were either
not observed at all or only in minor amounts. The
diphenylmethyl phosphorane 1b always gave the (E)-
(9) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(10) Maclay, W. D.; Hann, R. M.; Hudson, C. S. J . Am. Chem. Soc.
1938, 60, 1035.
(11) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron 1984, 40, 2247.
(12) Cha, J . K.; Kim, N.-S. Chem. Rev. 1995, 95, 1761. Prenner, R.
H.; Binder, W. H.; Schmid, W. Liebigs Ann. Chem. 1994, 73. Brima-
combe, J . S.; Kabir, A. K. M. S. Carbohydr. Res. 1988, 179, 21.

Wittig/Dihydroxylation Reactions
J . Org. Chem., Vol. 66, No. 13, 2001 4627
Ch a r t 2
substrates featuring erythro-configured hydroxy groups
adjacent to the alkene moiety provided significantly
poorer diastereoselectivities in the dihydroxylation reac-
tion (ranging from 2:1 to 2.5:1). In these cases, no attempt
has been made to isolate or identify the major products.
The last entry in Table 2 is noteworthy. The starting
material for the elongation, D-glycero-D-galacto-heptose,
is prepared by reduction of lactone 15,17 which itself is
available by the two step elongation of D-arabinose in
entry 8. This shows that the Wittig/dihydroxylation
method can be used in an iterative process to form higher
sugars in a repetitive fashion.
On the basis of these findings, some general rules can
be established for preparation of higher sugars with this
two-step methodology. With diphenylmethyl phosphorane
1b, the Wittig reaction always gives the (E)-olefin. For
the tert-butyl phosphorane 1a , pure (E)-olefins are only
obtained with 2,3-threo sugars while 2,3-erythro sugars
give mixtures of (E)- and (Z)-olefins. In the dihydroxyla-
tion, however, the same selectivity is obtained for both
bulky ester groups. Instead, the diastereoselectivity is
controlled by the two hydroxy groups adjacent to the
olefin. When these have the threo configuration the
dihydroxylation occurs with high diasteroselectivity. On
the contrary, when these hydroxy groups have the
erythro configuration the selectivity in the dihydroxyla-
tion is poor. Hence, the dihydroxylation becomes an
efficient protocol for preparing higher sugars with the
galacto configuration at these four stereogenic centers.
Attempts at improving or reversing the diastereomeric
ratio by the use of Sharpless’ chiral hydroquini(di)ne
phthalazine and pyrimidine ligands were unsuccessful.18
With NMO as reoxidant, the same diastereomeric ratio
and rate were observed as in the absence of the ligands.
With potassium ferricyanide as reoxidant it proved
impossible to remove the iron salts from the products.
Furthermore, we speculated whether it would be
possible to develop a one-pot procedure to allow a more
rapid access to higher carbohydrates. Although the
intermediate R,â-unsaturated esters are generally crys-
talline, their isolation from triphenylphosphine oxide can
still in some cases be a little tedious. We decided to
concentrate on the tert-butyl phosphorane 1a for these
one-pot studies because some of the corresponding
dihydroxylation products crystallize directly during the
oxidation reaction. First, D-galactose was treated with 1a
in dioxane according to the procedure of Railton and
Clive.8 However, instead of isolating the generated ester
2a , the mixture was cooled to room temperature followed
by addition of OsO4 (0.5%) and NMO (1.5 equiv). This
mixture was then stirred at room temperature for 6 h
during which time the dihydroxylation product 3 crystal-
lized out directly. Simple filtration gave 77% yield of 3
based on D-galactose (Table 3, entry 1). This has to be
compared with the 65% yield for the two-step sequence
as shown in Scheme 1. Encouraged by this result, we also
treated D-glucose, D-arabinose, and D-xylose with phos-
phorane 1a followed by direct dihydroxylation. With
D-glucose, the octonolactone 13 was isolated after workup
to separate triphenylphosphine oxide, while with D-
Ta ble 2. Dih yd r oxyla tion of Un sa tu r a ted Ald on ic Acid
Ester s
major
(E)-unsat. diastereo- product yield
entry
original aldose
D-glucose
ester
meric ratio isolated (%)
1
2
5a
5b
5:1
13
13
76
60
D-glucose
5:1
3
4
5
6
7
8
9
D-mannose
D-mannose
D-ribose
6a
6b
7a
7b
8a
8b
9a
2.5:1
2.5:1
2.5:1
2.5:1
7:1
D-ribose
D-arabinose
D-arabinose
D-xylose
14
15
16
17
69
74
53
51
7:1
6:1
10
11
12
13
D-xylose
D-lyxose
D-lyxose
D-glycero-D-gulo-
heptose
9b
6:1
10a
10b
11a
2.0:1
2.0:1
2.5:1
14
D-glycero-D-galacto-
heptose
12a
5:1
18
54
configurated olefin. The tert-butyl phosphorane 1a , on the
other hand, only gave (E)-olefins with sugars having the
2- and 3-hydroxy group in the threo configuration. Sugars
with these two hydroxy groups in the erythro configura-
tion all gave mixtures of (E)- and (Z)-olefins with phos-
phorane 1a , although these E/Z mixtures could be
separated by crystallization or flash chromatography.
Having prepared a variety of unsaturated aldonic acid
esters we were now ready to carry out a more systematic
study on the dihydroxylation of these (Chart 2, Table 2).
The reactions were again performed in an acetone-water
mixture with 0.5% OsO4 and 1.2 equiv of NMO.
For both unsaturated (E)-esters derived from a given
carbohydrate, we observed the same diastereoselectivity
(Table 2, entries 1-12). All the substrates having the
two hydroxy groups adjacent to the R,â-unsaturated
ester in a relative threo configuration gave rise to high
diastereoselectivities (ranging from 5:1 to 8:1). The
diastereoselectivities were found to be in accordance
with Kishi’s rule in all cases.11 In these cases, the di-
hydroxylation products could be isolated in good yields
either as esters, lactones, or metal salts of the carboxylic
acid. The structures of these products were verified by
comparing the melting points and optical rotations with
literature data.13-16 As opposed to this, all (E)-ester
(16) Fischer, E.; Passmore, F. Chem. Ber. 1890, 23, 2226. Karabinos,
J . V.; Hann, R. M.; Hudson, C. S. J . Am. Chem. Soc. 1953, 75, 4320.
(17) de Lederkremer, R. M.; Deferrari, J . O. J . Org. Chem. 1962,
27, 2561.
(18) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(13) Hockett, R. C.; Hudson, C. S. J . Am. Chem. Soc. 1938, 60, 622.
(14) Montgomery, E. M.; Hudson, C. S. J . Am. Chem. Soc. 1942,
64, 247.
(15) Isbell, H. S. J . Res. Natl. Bur. Stand. 1937, 19, 639.

4628 J . Org. Chem., Vol. 66, No. 13, 2001
J ørgensen et al.
Ta ble 3. On e-P ot Wittig/Dih yd r oxyla tion Usin g
P h osp h or a n e 1a
Gen er a l P r oced u r e for Dih yd r oxyla tion s. The substrate
(2.00 g) was dissolved in acetone/water (3 mL/1 mL), and NMO
(1.2 equiv as a 50% aqueous solution) was added. Finally, OsO4
(0.5% as a 5% aqueous solution) was added and the reaction
stirred at room temperature for 5-6 h. During workup, the
mixture was concentrated. The residue was dissolved in water
(5 mL, a -series) or water/Et2O (1:1, 10 mL, b-series) and
treated with acidic ion-exchange resin (5 mL, Amberlite IR-
120-H+) for 2 h. The resin was filtered off and the aqueous
phase concentrated. The products were isolated by crystal-
lization.
Gen er a l P r oced u r e for On e-P ot Wittig/Dih yd r oxyla -
tion s. The olefination was performed with phosphorane 1a
as described above with only dioxane as the solvent. After the
solution was cooled to room temperature, 0.5% OsO4 and
NMO‚H2O (1.5 equiv) were added. The mixture was then
stirred at room temperature for 5-6 h. The higher sugars
crystallized directly during the reaction as the tert-butyl esters,
except when starting from D-glucose where octonolactone 13
was isolated after partitioning between water and CH2Cl2 and
treatment of the aqueous layer with acid.
entry
original aldose
isolated product
yield (%)
1
2
3
4
D-galactose
D-glucose
D-arabinose
D-xylose
3
13
14
16
77
68
73
63
arabinose and D-xylose the heptonic acid esters 14 and
16 were isolated by direct crystallization from the reac-
tion mixture (Table 3, entries 2-4). In all cases, the yields
for these one-pot procedures were higher than for the
two-step sequence. In this way, two carbon atoms and
two new stereogenic centers have been added to unpro-
tected sugars in a one-pot procedure with excellent
diastereocontrol and good overall chemical yield. This
clearly demonstrates that the one-pot protocol is a
superior method for this two-carbon chain elongation
procedure.
In conclusion, we have further developed an efficient
and facile route from unprotected aldoses to higher
sugars using Wittig and dihydroxylation reactions. The
two reactions can be carried out independently or as a
one-pot transformation. The outcome of the overall
transformation is predictable, and the protocol is par-
ticularly effective for the construction of higher sugars
featuring the galacto configuration at the reducing end.
ter t-Bu t yl D-th r eo-L-ga la cto-Oct on a t e (3). Rf ) 0.30
(CHCl3/MeOH ) 3:1). Mp: 167-169 °C (H2O). [R]D: +10.1 (c
2, H2O). 1H NMR (D2O, 300 MHz): δ 4.55 (d, J ) 1.7 Hz, 1H),
4.13 (dd, J ) 9.7, 1.6 Hz, 1H), 4.07 (ddd, J ) 7.5, 6.8, 1.5 Hz,
1H), 3.98 (m, 2H), 3.77 (m, 3H), 1.57 (s, 9H). 13C NMR (D2O,
75 MHz): δ 174.2, 84.0, 71.4, 71.3, 70.6, 69.7, 68.5, 68.3, 63.6,
27.5 (3C). Anal. Calcd for C12H24O9: C, 45.89; H, 7.54. Found:
C, 46.15; H, 7.75.
D-th r eo-L-ga la cto-Oct on o-1,4-la ct on e (4). Rf ) 0.09
(CHCl3/MeOH ) 5:1). Mp: 218-220 °C (H2O). [R]D: +51.0 (c
2, H2O) (lit.10 mp 219-220 °C (H2O); [R]D +64.8 (c 0.8, H2O)).
1H NMR (D2O, 300 MHz): δ 4.47 (d, J ) 9.1 Hz, 1H), 4.38
(dd, J ) 8.4, 5.1 Hz, 1H), 4.22 (dd, J ) 8.7, 8.6 Hz, 1H), 3.96
(m, 1H), 3.80-3.56 (m, 4H). 13C NMR (D2O, 75 MHz): δ 176.3,
79.8, 74.1, 72.8, 70.2, 69.5, 66.7, 63.3.
Dip h en ylm eth yl (E)-2,3-Did eoxy-D-r ibo-h ep t-2-en oa te
(7b). Rf ) 0.47 (CHCl3/MeOH ) 5:1). Syrup purified by flash
chromatography (CHCl3 f CHCl3/MeOH ) 9:1). [R]D: +8.47
(c 1, MeOH). 1H NMR (DMSO-d6 + 1% D2O, 300 MHz): δ
7.41-7.20 (m, 10H), 7.11 (dd, J ) 15.7, 4.8 Hz, 1H), 6.81 (s,
1H), 6.08 (dd, J ) 15.7, 1.7 Hz, 1H), 4.34 (dt, J ) 4.7, 1.7 Hz,
1H), 3.50-3.25 (m, 4H). 13C NMR (DMSO-d6 + 1% D2O, 75
MHz): δ 164.6, 150.7, 140.5, 128.4, 127.6, 126.4, 119.8, 76.0,
74.9, 72.4, 70.9, 63.1. Anal. Calcd for C20H22O6: C, 67.03; H,
6.19. Found: C, 66.74; H, 6.01.
Diph en ylm eth yl (E)-2,3-Dideoxy-D-a r a bin o-h ept-2-en o-
a te (8b). Rf ) 0.67 (CHCl3/MeOH ) 5:1). Isolated directly as
a solid at the phase boundary between water and CH2Cl2.
Mp: 175-177 °C (MeOH/CHCl3). [R]D: -11.2 (c 1, MeOH). 1H
NMR (DMSO-d6 + 1% D2O, 300 MHz): δ 7.42-7.23 (m, 10H),
7.10 (dd, J ) 15.8, 4.2 Hz, 1H), 6.80 (s, 1H), 6.12 (dd, J )
15.7, 2.0 Hz, 1H), 4.46 (ddd, J ) 4.2, 2.0, 1.9 Hz, 1H), 3.50
(dd, J ) 9.1, 1.9 Hz, 1H), 3.46 (dd, J ) 9.2, 1.1 Hz, 1H), 3.40
(bs, 1H), 3.37 (bd, J ) 1.5 Hz, 1H). 13C NMR (DMSO-d6 + 1%
D2O, 75 MHz): δ 164.6, 152.4, 140.5, 128.4, 127.6, 126.4, 119.4,
76.0, 73.0, 71.4, 70.0, 63.3. Anal. Calcd for C20H22O6: C, 67.03;
H, 6.19. Found: C, 66.80; H, 6.17.
ter t-Bu tyl (E)-2,3-Did eoxy-D-xylo-h ep t-2-en oa te (9a ). Rf
) 0.67 (CHCl3/MeOH ) 3:1). Isolated as a syrup after flash
chromatography (CHCl3/MeOH ) 9:1 f 5:1). The syrup
crystallized from Et2O on standing. Mp: 133-135 °C (MeOH/
CHCl3). [R]D: -9.3 (c 1, MeOH). 1H NMR (DMSO-d6 + 1% D2O,
300 MHz): δ 6.80 (dd, J ) 15.5, 4.9 Hz, 1H), 5.84 (dd, J )
15.5, 1.7 Hz, 1H), 4.18 (ddd, J ) 5.2, 4.9, 1.7 Hz, 1H), 3.45-
3.25 (m, 4H), 1.39 (s, 9H). 13C NMR (DMSO-d6 + 1% D2O, 75
MHz): δ 165.9, 149.3, 122.3, 80.3, 73.7, 72.1, 71.9, 63.1, 28.5
(3C). Anal. Calcd for C11H20O6: C, 53.33; H, 8.12. Found: C,
53.22; H, 8.08.
Dip h en ylm eth yl (E)-2,3-Did eoxy-D-xylo-h ep t-2-en oa te
(9b). Rf ) 0.56 (CHCl3/MeOH ) 5:1). Isolated as a crystalline
product after flash chromatography (CHCl3/MeOH ) 9:1 f
5:1). Mp: 114-118 °C (EtOAc/hexane). [R]D: -9.43 (c 2,
MeOH). 1H NMR (DMSO-d6 + 1% D2O, 300 MHz): δ 7.50-
7.25 (m, 10H), 7.17 (dd, J ) 15.8, 4.5 Hz, 1H), 6.83 (s, 1H),
Exp er im en ta l Section
Gen er a l P r oced u r es. Thin-layer chromatography was
performed on aluminum plates precoated with silica gel (Merck
1.05554). Compounds were visualized by charring after dipping
in a solution of ammonium molybdate (6.25 g) and cerium(IV)
sulfate (2.5 g) in 10% aqueous H2SO4 (250 mL). Flash chro-
matography was performed using silica gel 60 (Amicon 85040).
Microanalyses were conducted by the Department of Chem-
istry at the University of Copenhagen.
Dip h en ylm et h yl 2-(Tr ip h en ylp h osp h on iu m )a cet a t e
Br om id e (1b‚HBr ). Benzhydrol (26.0 g, 141 mmol) was
dissolved in a mixture of redistilled dimethyl aniline (20 mL)
and Et2O (50 mL) at 0 °C. Bromoacetyl bromide (28.5 g, 141
mmol) was added dropwise to the vigorously stirred solution
during 10 min (after 5 min a white solid precipitated). The
stirring was continued for 1.5 h and the mixture allowed to
warm to room temperature. TLC (hexane/EtOAc ) 5:1) showed
consumption of most of the benzhydrol. The mixture was
washed with water (50 mL). The organic phase was washed
further with 10% aqueous H2SO4 (25 mL) and dried (MgSO4).
A solution of PPh3 (37.5 g, 141 mmol) in Et2O (200 mL) was
then added. The cloudy solution was allowed to stand over-
night at room temperature to precipitate 1b‚HBr. After
filtration and washing with Et2O, the phosphonium salt 1b‚
HBr was obtained as a white solid (66.3 g, 117 mmol, 83%)
with NMR data in accordance with literature values.8
Gen er a l P r oced u r e for Wittig Rea ction s. Following a
slightly modified version of Railton and Clive’s method,8 the
phosphonium salt 1a ‚HBr (5.64 g, 12 mmol) or 1b‚HBr (6.83
g, 12 mmol) was dissolved in CHCl3 (25 mL) and shaken gently
with 2 M aqueous NaOH (25 mL) in a separatory funnel for 5
min. The organic phase was dried (MgSO4) and concentrated.
The aldose (10 mmol) was added to the residue. Finally,
dioxane (25 mL) or dioxane/DMF (1:1, 25 mL) was added. The
resulting solution was stirred for 6 h at 90 or 70 °C and then
at 50 °C overnight. During workup, the solution was concen-
trated and the residue partitioned between water and CH2Cl2.
The products from the a -series were crystallized from MeOH/
CHCl3 after concentration of the aqueous layer. Generally, the
products from the b-series crystallized directly at the phase
boundary in the separatory funnel and were recrystallized
from MeOH/CHCl3. In a few cases, the products had to be
purified by flash chromatography.

Wittig/Dihydroxylation Reactions
J . Org. Chem., Vol. 66, No. 13, 2001 4629
6.10 (dd, J ) 15.8, 1.7 Hz, 1H), 4.31 (ddd, J ) 4.5, 3.0, 1.7 Hz,
1H), 3.55-3.30 (m, 4H). 13C NMR (DMSO-d6 + 1% D2O, 75
MHz): δ 164.7, 151.1, 140.6, 128.5, 127.7, 126.5, 119.3, 76.1,
73.1, 71.5, 71.5, 62.6. Anal. Calcd for C20H22O6: C, 67.03; H,
6.19. Found: C, 67.06; H, 6.10.
D-er yth r o-L-ga la cto-Octon o-1,4-la cton e (13). Rf ) 0.30
(CHCl3/MeOH ) 3:1). Mp: 142-144 °C (EtOH). [R]D: +51.3
(c 2, H2O) (lit.13 mp 151-152 °C (EtOH); [R]D +53.7 (c 1.65,
1
H2O)). H NMR (D2O, 300 MHz): δ 4.55 (d, J ) 9.1 Hz, 1H),
4.36 (dd, J ) 8.5, 5.1 Hz, 1H), 4.22 (t, J ) 8.8 Hz, 1H), 3.97
(dd, J ) 5.1, 1.4 Hz, 1H), 3.75 (m, 1H), 3.73-3.62 (m, 2H),
3.60 (m, 1H). 13C NMR (D2O, 75 MHz): δ 176.2, 81.9, 74.0,
73.9, 70.1, 70.1, 69.3, 63.0.
ter t-Bu tyl (E)-2,3-Did eoxy-D-lyxo-h ep t-2-en oa te (10a ).
Rf ) 0.53 (CHCl3/MeOH ) 3:1). The product was isolated by
flash chromatography (hexane f EtOAc). Yield 75% as a 3:1
(E)/(Z) mixture. Further purification by flash chromatography
gave pure (E)-isomer with the following data. [R]D: +24.8 (c
ter t-Bu tyl D-glycer o-D-ga la cto-Hep ton a te (14). Rf ) 0.43
(CHCl3/MeOH ) 3:1). The product precipitated directly during
the dihydroxylation reaction when using acetone as the
1
1, MeOH). H NMR (DMSO-d6 + 1% D2O, 300 MHz): δ 6.99
1
(dd, J ) 15.8, 4.6 Hz, 1H), 5.83 (dd, J ) 15.6, 1.7 Hz, 1H),
4.11 (ddd, J ) 8.1, 4.5, 1.7 Hz, 1H), 3.65 (dt, J ) 6.6, 2.0 Hz,
1H), 3.42-3.30 (m, 2H), 3.24 (dd, J ) 8.2, 1.9 Hz, 1H), 1.41 (s,
9H). 13C NMR (DMSO-d6 + 1% D2O, 75 MHz): δ 165.9, 150.6,
121.8, 80.2, 73.1, 70.3, 70.2, 62.9, 28.2 (3C). Anal. Calcd for
solvent. Mp: 175-177 °C (H2O). [R]D: -7.91 (c 1, MeOH). H
NMR (DMSO-d6 + 1% D2O, 300 MHz): δ 4.21 (bs, 1H), 3.83-
3.38 (m, 6H), 1.37 (s, 9H). 13C NMR (DMSO-d6 + 1% D2O, 75
MHz): δ 174.5, 83.6, 72.3, 72.1, 71.9, 70.0, 69.2, 64.5, 28.8 (3C).
Anal. Calcd for C11H22O8: C, 46.80; H, 7.86. Found: C, 46.48;
H, 7.74.
C
11H20O6: C, 53.33; H, 8.12. Found: C, 53.31; H, 8.38.
Dip h en ylm eth yl (E)-2,3-Did eoxy-D-lyxo-h ep t-2-en oa te
D-glycer o-D-ga la cto-Hep ton o-1,4-la cton e (15). Rf ) 0.33
(CHCl3/MeOH ) 3:1). Mp: 145-147 °C (EtOH). [R]D: -72.3
(c 2, H2O) (lit.14 mp 149-151 °C (EtOH); [R]D -74.2 (c 2, H2O)).
1H NMR (D2O, 300 MHz): δ 4.57 (d, J ) 9.2 Hz, 1H), 4.48 (d,
J ) 8.6 Hz, 1H), 4.33 (dd, J ) 9.2, 8.6 Hz, 1H), 3.79 (bd, J )
10.9 Hz, 1H), 3.73-3.58 (m, 3H). 13C NMR (D2O, 75 MHz): δ
176.2, 79.6, 74.0, 72.7, 70.9, 67.6, 63.1.
(10b). Rf ) 0.63 (CHCl3/MeOH ) 5:1). Mp: 98-100 °C (MeOH/
CHCl3). [R]D: -7.5 (c 1, MeOH). 1H NMR (DMSO-d6 + 1% D2O,
300 MHz): δ 7.43-7.20 (m, 11H), 6.80 (s, 1H), 6.17 (dd, J )
15.7, 0.1 Hz, 1H), 4.20 (m, 1H), 3.67 (m, 1H), 3.45-3.22 (m,
3H). 13C NMR (DMSO-d6 + 1% D2O, 75 MHz): δ 165.5, 153.2,
141.0, 129.2, 128.4, 126.9, 119.7, 76.9, 73.1, 70.4, 70.3, 63.1.
Anal. Calcd for C20H22O6: C, 67.03; H, 6.19. Found: C, 66.71;
H, 5.97.
ter t-Bu tyl D-glycer o-L-ga la cto-Hep ton a te (16). Rf ) 0.42
(CHCl3/MeOH ) 3:1). Mp: 130-132 °C (EtOH). [R]D: +2.5 (c
1
ter t-Bu tyl (E)-2,3-Dideoxy-D-glycer o-D-gu lo-n on -2-en oate
(11a ). Rf ) 0.23 (CHCl3/MeOH ) 3:1). The product was
isolated as a 3:1 mixture of (E)- and (Z)-isomers. Further
purification by flash chromatography gave pure (E)-isomer.
[R]D: -12.4 (c 2, H2O). 1H NMR (DMSO-d6 + 1% D2O, 300
MHz): δ 6.86 (dd, J ) 15.7, 4.3 Hz, 1H), 5.82 (dd, J ) 15.7,
1, H2O). H NMR (DMSO-d6 + 1% D2O, 300 MHz): δ 4.15 (d,
J ) 1.7 Hz, 1H), 3.72 (dd, J ) 9.5, 1.6 Hz, 1H), 3.54 (dd, J )
10.5, 5.0 Hz, 1H), 3.52-3.38 (m, 3H), 3.34 (dd, J ) 11.0, 5.9
Hz, 1H), 1.39 (s, 9H). Anal. Calcd for C11H22O8: C, 46.80; H,
7.86. Found: C, 46.35; H, 7.71.
Ba r iu m D-glycer o-L-ga la cto-Hep ton a te (17). Rf ) 0.02
1.6 Hz, 1H), 4.38 (m, 1H), 3.70-3.20 (m, 6H), 1.38 (s, 9H). 13
C
(CHCl3/MeOH ) 3:1). [R]D: +1.4 (c 1, H2O) (lit.15 [R]20 +1.5
D
1
NMR (DMSO-d6 + 1% D2O, 75 MHz): δ 165.7, 150.8, 121.8,
80.1, 71.8, 71.5, 70.1, 69.6, 69.0, 64.0, 28.1 (3C). Anal. Calcd
for C13H24O8: C, 50.64; H, 7.85. Found: C, 50.68; H, 7.75.
ter t-Bu t yl (E)-2,3-Did eoxy-D-glycer o-D-ga la cto-n on -2-
en oa te (12a ). Rf ) 0.26 (CHCl3/MeOH ) 3:1). Isolated as a
crystalline 7:1 mixture of the (E)-olefin and the corresponding
Michael product. Recrystallization from MeOH/CHCl3 afforded
the desired product in 52% yield. Mp: 175-177 °C (H2O). [R]D:
(c 3, H2O)). H NMR (D2O, 300 MHz): δ 4.32 (d, J ) 1.7 Hz,
1H), 4.01 (dd, J ) 9.2, 1.6 Hz, 1H), 3.92-3.87 (m, 2H), 3.81-
3.74 (m, 2H), 3.66 (m, 1H). 13C NMR (D2O, 75 MHz): δ 180.2,
73.5, 72.1, 72.1, 71.1, 69.9, 62.8.
D-a r a bin o-L-ga la cto-Non on o-1,4-la cton e (18). Rf ) 0.04
(CHCl3/MeOH ) 2:1). Mp: 174-176 °C (EtOH/H2O). [R]D:
-37.5 (c 0.5, H2O) (lit.16 mp 175-177 °C (EtOH). [R]20D: -41.0
(c 10, H2O)). 1H NMR (D2O, 300 MHz): δ 4.55 (d, J ) 11.5 Hz,
1H), 4.20 (dd, J ) 7.0, 14.2 Hz, 1H), 4.02 (d, J ) 10.0 Hz, 1H),
3.96-3.52 (m, 6H). 13C NMR (D2O, 75 MHz): δ 175.3, 79.9,
71.5, 71.3, 71.2, 69.6, 68.6, 68.2, 63.5.
1
-7.86 (c 1, MeOH). H NMR (D2O, 300 MHz): δ 6.93 (dd, J
) 15.7, 4.3 Hz, 1H), 6.02 (dd, J ) 15.7, 1.8 Hz, 1H), 4.59 (ddd,
J ) 4.3, 2.5, 1.8 Hz, 1H), 3.87 (d, J ) 9.2 Hz, 1H), 3.79 (dd, J
) 11.5, 2.3 Hz, 1H), 3.77-3.64 (m, 3H), 3.60 (dd, J ) 11.5, 5.6
Hz, 1H), 1.43 (s, 9H). 13C NMR (CD3OD, 75 MHz): δ 167.7,
150.2, 123.6, 81.5, 73.4, 73.2, 71.7, 71.2, 70.7, 65.2, 28.4 (3C).
Anal. Calcd for C13H24O8‚1/2H2O: C, 49.20; H, 7.74. Found: C,
49.56; H, 7.65.
Ack n ow led gm en t. We thank the Danish Natural
Science Research Council for financial support.
J O010128E