Carbon-bridged trehalose. Synthesis of bis[C-β-D- galactopyranosyl)]methanol

Article abstract of DOI:10.1055/s-1998-4503

Reaction of 1-C-lithiated 2-phenylsulfinyl-D-galactals (R)- and (S)-3A as nucleophiles with dimethylformamide as electrophile furnished after workup 1-formyl derivatives (R)- and (S)-4. Their reaction with (R)- and (S)-3A then afforded C-trehalose interme

Full text of DOI:10.1055/s-1998-4503

SYNTHESIS
December 1998
1731
Carbon-Bridged Trehalose. Synthesis of Bis[C-(â-D-galactopyranosyl)]methanol
Balaram Patro, Richard R. Schmidt*
Fakultät Chemie, Universität Konstanz, Fach M 725, D-78457 Konstanz, Germany
Fax: +49-7531-88-3135
Received 28 April 1998
Abstract: Reaction of 1-C-lithiated 2-phenylsulfinyl-D-galactals
to this type of C-disaccharides. For two identical sugar
residues even the same nucleophile can be employed as
indicated in the retrosynthesis in Scheme 1. We would
like to demonstrate application of this method to galactose
and glucose; the method is based on ready access of het-
eroatom-stabilized vinyllithium species11 and, conse-
quently, to generation of 1-C-lithiated glycals A as C6-
nucleophiles12 and their reaction with C1-electrophile B.
In order to demonstrate the efficiency of this method, the
galactose derived C-trehalose intermediate is finally
transformed into the title compound 2a, having, in com-
parison with the parent compound 2, an additional hy-
droxy group in the bridge for further modifications.
(R)- and (S)-3A as nucleophiles with dimethylformamide as elec-
trophile furnished after workup 1-formyl derivatives (R)- and (S)-
4. Their reaction with (R)- and (S)-3A then afforded C-trehalose
intermediates (R,R)- and (S,S)-5, respectively. Ensuing treatment
with sodium cyanoborohydride and then with Raney nickel led to
removal of the phenylsulfinyl groups furnishing galactal interme-
diate 7, which on reaction with BH3•SMe2 and then H2O2/NaOH
followed by hydrogenolytic debenzylation resulted in target mole-
cule 2a. Extension of this convenient method to C-trehalose syn-
thesis is shown for the corresponding glucose derivative.
Key words: C-glycosides, C-disaccharides, trehaloses, vinyllith-
ium species, glycals
C-Disaccharides have become very popular target mole-
cules because they are potential reversible inhibitors of
glycosidases and disaccharidases which are, for example,
present in the digestive tract.1–3 Some glycosidase inhibi-
tors were also found to possess antiretroviral activity.4
Therefore, quite a few methods for the synthesis of car-
bon-bridged C-disaccharides have been developed.5
Unique disaccharides are trehaloses in which two carbo-
hydrate residues are linked via their anomeric hydroxy
groups. Some trehaloses also exhibit important biological
functions, such as ,for example, α,α-trehalose (i.e., α-D-
glucopyranosyl-α-D-glucopyranoside).6 Trehaloses pro-
vide also core structures for the generation of interesting
structural motifs, as recently shown.7 Also approaches to
the synthesis of corresponding C-trehalose have been al-
ready reported (for example, 1 in Scheme 1).8–10 The syn-
theses started from a C-glucopyranosyl derivative which
was used for the attachment of the second sugar chain;
then, via ring closure and protective group manipulations
the target molecules were obtained.8, 9
Tri-O-benzyl-D-galactal was readily converted into
known 2-phenylsulfinyl derivatives (R)- and (S)-3
(Scheme 2).13 Their treatment with LDA in THF at
–100°C afforded the corresponding 1-C-lithiated species
(R)- and (S)-3A, which gave with equivalent amounts of
DMF as C1-electrophile of type B in the presence of hex-
amethylphosphorous triamide (HMPA) 1-formyl deriva-
tives (R)-4 and (S)-4, respectively, in high yields.14 Imme-
diate formation of the bis-reaction products (R,R)-5 and
(S,S)-5 was not observed, even when excess (R)- or (S)-
3A was generated. This finding is presumably due to gen-
eration of the aldehyde 4 only after hydrolysis of the addi-
tion product between 3A and DMF during workup; thus,
the method employed should enable also combination of
two different sugar residues. Then, reaction of (R)-3A or
(S)-3A with (R)-4 and (S)-4 gave the desired C-trehalose
intermediates (R,R)-5 and (S,S)-5, respectively, in 73%
and 59% yields; based on consumed 3, yields were 89%
and 74%, respectively. Removal of the phenylsulfinyl
group in (R,R)-5 and (S,S)-5 was best performed in two
steps: reduction of the sulfoxide moiety with sodium cy-
anoborohydride (NaCNBH3) in acetic acid gave phenyl
sulfide 6 in high yields, which upon Raney nickel (WII)15
treatment led to the desired bis-galactal derivative 7. The
galactose structure was readily introduced into 7 by regio-
and diastereoselective hydrogen and hydroxy group addi-
tion to the enol ether moieties with borane–dimethyl sulf-
ide complex and then H2O2/NaOH treatment,16 thus fur-
nishing hydroxymethylene-bridged C-trehalose 8. Hydro-
genolytic removal of the benzyl groups in the presence of
Pd/C as catalyst afforded target molecule 2a. The structur-
Obviously, a more direct approach with a C1-electrophile
and two glycopyranosyl nucleophiles should readily lead
1
al assignment was based on the H NMR data (2-H: δ =
3.70, J1,2 = J2,3 = 9.4 Hz; 2'-H: δ = 3.72, J1',2' = J2',3'
=
9.4 Hz) which are in accordance with β-galactopyranosyl
residues in 4C1-conformation.
Similarly, from known glucal derivative (R)-917 (Scheme
3) the corresponding C-1 lithiated species (R)-9A was
generated; reaction with DMF under the same conditions
Scheme 1

SYNTHESIS
Papers
1732
Scheme 2
Solvents were purified in the usual way; petroleum ether bp 35–65°C.
Column chromatography: flash chromatography: silica gel (Baker, T.
J.; particle size 40 µm). TLC: DC plastikfolien Kieselgel 60F254
(Merck; layer thickness 0.2 mm). Mps were uncorrected. Optical ro-
tations: Perkin–Elmer 241 MC polarimeter; 1-dm cell. NMR Bruker
AC 250, Avanca-DRX 600; internal standard TMS or deuterated sol-
vent. FAB-MS: Finnigan MAT 312 (modified), 70 ev, 70°C.
Bis{1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-[(R)-phenylsulfi-
nyl]-D-lyxo-hex-1-enit-1-yl}methanol [(R,R)-5]:
To a well-stirred solution of freshly prepared LDA (1.1 equiv) in an-
hyd THF (200 mL) was added at –100°C a solution of 1,5-anhydro-
3,4,6-tri-O-benzyl-2-[(R)-phenylsulfinyl]-D-lyxo-hex-1-enitol [(R)-
3]13 (5.41 g, 10 mmol) in anhyd THF. After stirring for 1 h, HMPA
(1.5 mL, 8 mmol) was added and after another 30 min was added
dropwise a solution of 2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-3-
[(R)-phenylsulfinyl]-aldehydo-D-lyxo-hept-2-enose [(R)-4]14 (6.25 g,
11 mmol) in THF (50 mL). The mixture was stirred for 2 h at this
temperature and quenched with sat. NH4Cl and extracted with Et2O
(3 × 100 mL). The combined organic extract was washed with sat.
brine and then dried (MgSO4) and concentrated in vacuo. The residue
was purified by flash chromatography (petroleum ether/EtOAc 1:1)
to give colorless crystals; yield 8.08 g (73%) [89% based on con-
sumed (R)-3)]; mp 56.7°C; TLC (petroleum ether/EtOAc 4:6) Rf
0.19; [α]20 +46.9 (c = 1, CHCl3).
Scheme 3
afforded only aldehyde (R)-10. Upon further reaction with
(R)-9A the desired C-trehalose intermediate (R,R)-11 was
obtained in good yield, thus exhibiting the general appli-
cability of this method for C-trehalose synthesis.

SYNTHESIS
December 1998
1733
1H NMR (600 MHz, CDCl3): δ = 3.65–3.67 (m, 2 H, 3'-H, 6-H), 3.79
(dd, 1 H, H5,6a = 8.4, J6a,6b = 11.6 Hz, 6-H), 3.84 (d, 1 H, J = 10.4 Hz,
CHPh), 3.86–3.90 (m, 2 H, 6'-H), 3.96–3.98 (m, 2 H, CHPh, 3-H),
4.34 (d, 1 H, J = 12.1 Hz, CHPh), 4.37 (d, 1 H, J = 12.1 Hz, CHPh),
4.38–4.41 (m, 2 H, CHPh), 4.44 (d, 1 H, J = 12.1 Hz, CHPh), 4.47 (d,
1 H, J = 12.1 Hz, CHPh), 4.51 (d, 1 H, J = 12 Hz, CHPh), 4.54 (d, 1 H,
J = 11.9 Hz, CHPh), 4.55–4.58 (m, 3 H, CHPh, 4-H, 5'-H), 4.67–4.69
(m, 2 H, 5-H, CHPh), 4.75 (dd, 1 H, J3,4 = 3.5, J4,5 = 1 Hz, 4'-H), 6.27
(s, 1 H, 7-H), 6.52–6.54 (m, 2 H, ArH), 6.68, 6.69 (m, 2 H, ArH),
7.09–7.3 (m, 32 H, ArH), 7.61–7.65 (m, 4 H, ArH).
ether/EtOAc 8:2) to give a viscous liquid; yield: 4.68 g (86%); TLC
(petroleum ether/EtOAc 7:3) Rf 0.42; [α]D –17.7 (c = 1, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 3.75–3.76 (m, 2 H, 4'-H, 3'-H), 3.83
(dd, 2 H, J6'a,6'b = 10.9, J5',6' = 4.5 Hz, 6'-H), 3.91 (m, 2 H, 6-H), 4.03
(dd, 1 H, J3,4 = J4,5 = 3.5 Hz, 4-H), 4.09 (d, 1 H, J = 3.6 Hz, 3-H), 4.38
(d, 1 H, J = 12 Hz, CHPh), 4.41 (m, 1 H, 5'-H), 4.42 (d, 2 H, J = 11.9
Hz, CHPh), 4.47 (s, 1 H, CHPh), 4.49–4.50 (m, 3 H, CHPh), 4.53 (d,
1 H, J5,6a = 5.3 Hz, 5-H), 4.55 (d, 2 H, J = 11.7 Hz, CHPh), 4.65 (s, 2
H, CHPh), 4.74 (d, 1 H, J = 11.7 Hz, CHPh), 6.26 (s, 1 H, 7-H), 7.08–
7.31 (m, 40 H, Ph).
13C NMR (150 MHz, CDCl3): δ = 63.68 (4-C), 65.38 (5'-C), 66.89 (6-
C), 66.94 (6'-C), 68.04 (3'-C), 72.07, 72.54, 72.95, 73.27, 73.27,
73.43, 73.63, 73.86 (CH2), 74.55 (C-3), 76.92 (5'-C), 77.71 (5-C),
113.74, 115.48 (2-C, 2'-C), 124.30, 125.86, 126.72, 126.79, 126.99,
127.25, 127.47, 127.52, 127.67, 127.86, 127.92, 128.34, 128.44,
128.53, 129.39, 129.77, 137.37, 137.58, 137.95, 142.55, 143.23
(ArC), 156.96, 157.79 (1-C, 1'-C).
13C NMR (150 MHz, CDCl3): δ = 67.56 (6'-C), 68.1 (6-C), 68.19,
72.51, 72.70, 73.44 (CH3), 73.05 (4-C), 73.3 (4'-C), 74.00, 74.14,
74.42 (3-C, 3'-C), 76.2 (5'-C), 76.2 (5-C), 77.71, 101.44, 102.29 (2-C,
2'-C), 124.97, 126.95, 127.26, 127.29, 127.51, 127.63, 127.65,
127.73, 127.87, 127.98, 128.22, 128.31, 128.44, 128.50, 137.62,
138.02, 138.12, 138.15, 138.27, 138.56, 157.63, 158.36 (1-C, 1'-C).
MS (FAB, NaI): m/z = 1099 (M + Na).
MS (FAB, NaI): m/z = 1131 (M + Na).
Anal. calcd for C67H64O11S2 (1109.37): C, 72.54; H, 5.82. Found: C,
71.79; H, 5.95.
Anal. calcd for C67H64O9S2 (1077.37): C, 74.69; H, 5.99. Found: C,
74.77; H, 5.93.
Bis(1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-D-lyxo-hex-1-enit-1-
yl)methanol (7):
Bis{1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-[(S)-phenylsulfi-
nyl]-D-lyxo-hex-1-enit-1-yl}methanol [(S,S)-5]:
A solution of 6 (4.4 g, 4.08 mmol) in anhyd THF (50 mL) was stirred
with W-2 Raney Nickel (25 g) and monitored by TLC (45 min). When
the reaction was complete the solid was filtered out and washed with
EtOAc and the combined filtrate was evaporated to dryness. The res-
idue was chromatographed by flash chromatography (petroleum
ether/EtOAc 3:1) to give 7 as a colorless oil; yield: 2.87 g (86%); TLC
(petroleum ether/EtOAc 7:3) Rf 0.15; [α]D –20.3 (c = 1, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 2.72–2.78 (brs, 1 H, -OH), 3.61 (dd,
1 H, J3',4' = J4',5' = 2.9 Hz, 4'-H), 3.72–3.74 (m, 1 H, 3'-H), 3.83 (dd,
2 H, J6'a,6'b = 12, J5',6' = 5.5 Hz, 6'-H), 3.89–3.95 (m, 2 H, 6-H), 4.08–
4.13 (m, 2 H, 4-H, 3-H), 4.18–4.26 (m, 2 H, 7-H, CHPh), 4.42–4.46
(m, 4 H, CHPh, 5'-H), 4.48 (d, 2 H, J = 11.8 Hz, CHPh), 4.62–4.64
(m, 5 H, 5-H, CHPh), 4.80 (d, 1 H, J = 11.9 Hz, CHPh), 4.91 (d, 1 H,
J = 11.6 Hz, CHPh), 5.16 (d, 2 H, J = 3.2 Hz, 2-H, 2'-H), 7.19–7.32
(m, 30 H, Ph).
Compound (S,S)-5 was prepared in a similar manner to that described
for compound (R,R)-5 by starting from 1,5-anhydro-3,4,6-tri-O-
ben-zyl-2-[(R)-phenylsulfinyl]-D-lyxo-hex-1-enitol [(S)-3]13 (5.41 g,
10 mmol). A solution of 2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-3-
[(S)-phenylsulfinyl]-aldehydo-D-lyxo-hept-2-enose [(S)-4]14 (6.25 g,
11 mmol) in THF (50 mL) was added dropwise. The mixture was
stirred for 2 h at this temperature and in a similar work up and purifi-
cation by flash chromatography (petroleum ether/EtOAc 7:3), color-
less crystals were obtained; yield: 6.53 g (59%) [74% based on (S)-3
consumed]; mp 68.8°C; TLC (petroleum ether/EtOAc 6:4) Rf 0.14;
[α]D –31.8 (c = 1, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 3.31 (dd, 1 H, J4,5 = 3.2, J3,4
=
5.9 Hz, 4-H), 3.49 (dd, 1 H, J3',4' = 3.5, J4',5' = 1.7 Hz, 4'-H), 3.76 (d,
1 H, J = 2.9 Hz, 3-H), 3.84 (dd, 1 H, J5',6'a = 7.9, J6'a,6'b = 11.4 Hz, 6'-H),
3.91 (m, 2 H, CHPh, 6-H), 3.93 (m, 2 H, CHPh, 6'-H), 3.99 (d, 1 H, J
= 11.8 Hz, CHPh), 4.02 (dd, 1 H, J5,6a = 8.5, J6a,6b = 11.7 Hz, 6-H),
4.12 (brs, 1 H, 3'-H), 4.21 (d, 2 H, J = 11.7 Hz, CHPh), 4.31 (d, 2 H,
J = 11.7 Hz, CHPh), 4.38–4.43 (m, 3 H, CHPh), 4.52–4.56 (m, 2 H,
CHPh, 5'-H), 4.58 (dd, 1 H, J5,6a = J5,6b = 7 Hz, 5-H), 4.72 (d, 2 H, J
= 11.2 Hz, CHPh), 6.51 (s, 1 H, 7-H), 7.05–7.13 (m, 2 H, ArH), 7.16–
7.38 (m, 31 H, ArH), 7.43–7.46 (m, 3 H, ArH), 7.57–7.61 (m, 2 H,
ArH), 7.72–7.76 (m, 2 H, ArH).
MS (MALDI, NaI): m/z = 882 (M + Na).
Anal. calcd for C55H56O9 (861.044): C, 76.72; H, 6.56. Found: C,
76.35; H, 6.43.
Bis(3,4,6-tri-O-benzyl-α-D-galactopyranosyl)methanol (8):
A solution of 7 (2.0 g, 2.3 mmol) in THF (15 mL) was added to a cooled
(4°C) solution of BH3•SMe2 in anhyd THF (9.2 mL, 18.4 mmol) and
stirred at this temperature for 3 d. Then 10% aq NaOH (18 mL) was
added followed by 35% H2O2 (5.2 mL). After stirring for 30 min, the
mixture was poured into water (50 mL) and extracted with Et2O (5 ×
50 mL). The combined organic layers were neutralized with 20% aq so-
dium bisulfite (18 mL) and then sat. NH4Cl, followed by brine. The or-
ganic extract was dried (MgSO4) and concentrated. Purification by flash
chromatography of the residue afforded 8; yield: 1.18g (57%); TLC (pe-
troleum ether/EtOAc 1:1) Rf 0.33; [α]D –1.3 (c = 1, CHCl3).
13C NMR (150 MHz, CDCl3): δ = 66.21 (7-C), 67.63 (3-C), 68.3 (3'-
C), 68.74 (6-C), 69.15 (6'-C), 71.18, 72.00, 72.72, 72.95, 73.00, 73.27
(CH2), 72.44 (4'-C), 74.00 (4-C), 77.05 (5'-C), 77.45 (5-C), 116.14,
116.27 (2-C, 2'-C), 124.72, 124.88, 127.27, 127.41, 127.51, 127.76,
127.80, 127.89, 127.95, 127.98, 128.15, 128.17, 128.21, 128.28,
128.39, 128.85, 129.06, 130.19, 137.04, 137.19, 137.85, 138.14,
142.21, 143.48 (ArC), 157.80, 157.42 (1-C, 1'-C).
MS (FAB, NaI): m/z = 1131 (M + Na).
Anal. calcd for C67H64O11S2 (1109.37): C, 72.54; H, 5.82. Found: C,
72.22; H, 5.76.
1H NMR (250 MHz, CDCl3): δ = 3.32 (d, 1 H, J7,1 = 7.8, J1,2 = 9 Hz,
1-H), 3.40 (dd, 1 H, J2',3' = 10, J3',4' = 2.9 Hz, 3'-H), 3.46 (dd, 1 H, J2,3
= 9.4, J3,4 = 2.9 Hz, 3-H), 3.48 (dd, 1 H, J1',2' = 10, J7,1' = 2.5 Hz, 1'-
H), 3.44–3.52 (m, 2 H, 6-H), 3.52 (d, 1 H, J4,5 <1 Hz, 5-H), 3.52–3.56
(m, 2 H, 6'-H), 3.60 (d, 1 H, J4',5' <1 Hz, 5'-H), 3.70 (brs, 2 H, CHPh),
3.85 (d, 1 H, J3,4 = 2.9 Hz, 4-H), 3.93 (d, 1 H, J3',4' = 2.9 Hz, 4'-H),
Bis[1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-(phenylthio)-D-
lyxo-hex-1-enit-1-yl]methanol (6):
4.07 (dd, 1 H, J7,1 = 7.8, J1,2 = 9 Hz, 7-H), 4.15 (dd, 1 H, J1',2' = J2',3'
=
To a solution of (R,R)-5 or (S,S)-5 (5.51 g, 5 mmol) in HOAc (30 mL)
NaCNBH3 (2.5 g, 38 mmol) was added portionwise at r.t. When the
addition was complete the mixture was stirred at this temperature for
10 h and then heated to 50°C for 4 h and monitored by TLC. The
mixture was poured onto crushed ice (200 g) and brought to r.t. and
extracted with Et2O (4 × 50 mL). The combined extracts were washed
with brine (2 × 30 mL) and dried (MgSO4) and concentrated in vacuo.
The crude residue was purified by flash chromatography (petroleum
9.4 Hz, 2'-H), 4.23 (dd, 1 H, J2,3 = J3,4 = 9.4 Hz, 2-H), 4.40–4.95 (m,
4 H, CHPh), 4.54–4.58 (m, 3 H, CHPh), 4.71–4.74 (m, 2 H, CHPh),
4.80 (d, 1 H, J = 12 Hz, CHPh), 4.85 (d, 1 H, J = 11.6 Hz, CHPh), 4.90
(d, 1 H, J = 11.6 Hz, CHPh), 7.25–7.36 (m, 30 H, ArH).
13C NMR (150 MHz, CDCl3): δ = 66.3 (2'-C), 68.7 (6'-C), 69.2 (6-C),
71.1 (2-C), 72.8 (4'-C), 72.9 (7-C), 73.7 (4-C), 76.9 (5'-C), 77.0 (5-C),
77.1 (1-C), 78.1 (1'-C), 83.3 (3-C), 84.1 (3'-C).
MS (FAB, NaI): m/z = 919 (M + Na).

SYNTHESIS
Papers
1734
Anal. calcd for C55H60O11 (897.074): C, 73.64; H, 6.74. Found: C,
73.29; H, 6.92.
[72% based on (R)-9 consumed]; TLC (petroleum ether/EtOAc
6:4) Rf 0.12; [α]D –14.5 (c = 1, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 3.42 (dd, 1 H, J4,5 = 5, J3,4 = 9.6 Hz,
4-H), 3.53–3.55 (m, 2 H), 3.58–3.77 (m, 7 H, CH, CHPh), 3.81–3.91
(m, 2 H, CHPh, 6-H), 4.03 (dd, 2 H, J5,6a = 3.6, J6a,6b = 12 Hz, 6-H),
4.34 (d, 1 H, J = 11.7 Hz, CHPh), 4.36–4.46 (m, 5 H, CHPh), 4.58 (d,
1 H, J = 11.4 Hz, CHPh), 4.62 (d, 1 H, J = 11.6 Hz, CHPh), 6.60 (s,
1 H, 7-H), 6.72–6.74 (m, 2 H, ArH), 6.79–6.82 (m, 2 H, ArH), 6.97–
7.01 (m, 2 H, ArH), 7.12–7.29 (m, 30 H, ArH), 7.58–7.76 (m, 4 H,
ArH).
Bis[C-(â-D-galactopyranosyl)]methanol (2a):
Compound 8 (179 mg, 0.20 mmol) was dissolved in EtOAc/MeOH
(1:1) (20 mL) and to this 10% Pd/C (20 mg) was added. The suspen-
sion was stirred for 20 h under hydrogen at normal pressure. Then the
catalyst was filtered and washed repeatedly with MeOH and the com-
bined filtrate was evaporated to dryness. Flash chromatography
(CH2Cl2/MeOH, 7:3) of the residue afforded 2a; yield: 58 mg (81%).
TLC (CH2Cl2/MeOH 7:3) Rf 0.33; [α]D –1.6 (c = 0.42, dioxane).
MS (FAB, NaI): m/z = 1131 (M + Na).
Anal. calcd for C67H64O11S2 (1109.37): C, 72.54; H, 5.82. Found: C,
72.13; H, 5.88.
1H NMR (600 MHz, MeOH-d4): δ = 3.32 (dd, 1 H, J7,1' = 6.8, J1',2'
=
9.4 Hz, 1'-H), 3.38 (dd, 1 H, J2',3' = 9.4, J3',4' = 3.2 Hz, 3'-H), 3.40 (dd,
1 H, J7,1 = 2.5, J1,2 = 9.4 Hz, 1-H), 3.40–3.42 (m, 1 H, 5'-H), 3.42 (dd,
1 H, J2,3 = 9.4, J3,4 = 3.2 Hz, 3-H), 3.46 (1 H, J5,6a = 5, J5,6b = 7.6 Hz,
5-H), 3.55 (dd, 1 H, J5,6a = 5, J6a,6b = 11.4 Hz, 6-H), 3.58 (dd, 1 H, J5,6a
= 5, J6a,6b = 11.4 Hz, 6-H), 3.62 (dd, 1 H, J5',6'b = 7.0, J6'a,6'b = 11.4 Hz,
6'-H), 3.64 (dd, 1 H, J5',6'b = 7.3, J6'a,6'b = 11.4 Hz, 6'-H), 3.70 (dd, 1 H,
J1,2 = J2,3 = 9.4 Hz, 2-H), 3.72 (dd, 1 H, J1',2' = J2',3' = 9.4 Hz, 2'-H),
3.75 (m, 1 H, 4-H), 3.76 (m, 1 H, 4'-H), 4.05 (dd, 1 H, J7,1' = 6.8, J7,1
= 2.5 Hz, 7-H).
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. B.P. is grateful to the Alex-
ander von Humboldt Foundation for a research fellowship.
13C NMR (150 MHz, MeOH-d4): δ = 62.84, 62.94 (6-C, 6'-C), 67.97,
71.76 (2-C, 2-C), 70.66, 71.12 (4-C, 4'-C), 72.85 (7-C), 76.27, 76.75
(3-C, 3'-C), 79.0, 79.5 (1-C, 1'-C), 80.1, 80.4 (5-C, 5'-C).
MS (FAB, NaI): m/z = 379 (M + Na).
(1) Lalégerie, P.; Legler, G.; You, J. M. Biochemie 1982, 64, 977.
(2) Truscheit, E.; Frommer, W.; Junge, B.; Müller, L.; Schmidt, D.
D.; Wingender, W. Angew. Chem. 1981, 93, 738; Angew.
Chem., Int. Ed. Engl. 1981, 20, 744.
Anal. calcd for C13H24O11 (356.324): C, 43.82; H, 6.79. Found: C,
43.49; H, 6.43.
(3) Krohn, K.; Huns, H.; Wielckens, K. J. Med. Chem. 1992, 35,
511.
(4) Walker, B. D.; Kowalski, M.; Goh, W. C.; Kozarsky, K.; Krie-
ger, M.; Rosen, C.; Rohrschneider, L.; Haseltine, W. A.; Sodro-
ski, J. Proc. Nat. Acad. Sci. 1987, 84, 8210.
2,6-Anhydro-4,5,7-tri-O-benzyl-3-deoxy-3-[(R)-phenylsulfinyl]-
aldehydo-D-arabino-hept-2-enose [(R)-10]:
(R)-10 was prepared by following a similar procedure to that in the
case of 4.14 The analytical data for this compound are as follows.
Flash chromatography of the crude residue yielded 89% of (R)-10;
TLC (petroleum ether/EtOAc 7:3) Rf 0.26; [α]D +56.8 (c = 1, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 3.47 (dd, 1 H, J5,7a = J7a,7b = 5.4 Hz,
7a-H), 3.61 (dd, 1 H, J5,7b = 3.3, J7a,7b = 7.4 Hz, 7b-H), 3.85 (dd, 1 H,
J4,5 = 2.5, J5,6 <1 Hz, 5-H), 4.23–4.60 (m, 6 H, CHPh), 4.69–4.70 (m,
1 H, 6-H), 4.77 (dd, 1 H, J4,5 = 2.5, J4,6 <1 Hz, 4-H), 6.73, 6.77 (m,
2 H, ArH), 7.12–7.35 (m, 16 H, ArH), 7.53–7.57 (m, 2 H, ArH), 9.94
(s, 1 H, CHO).
Kameda, Y.; Asano, N.; Yamaguchi, T.; Matsui, K. J. Anti-
biotics 1987, 563.
Sunkara, P. S.; Bowlin, T. L.; Liu, P. S.; Sjoerdsma, A. Bio-
chem. Biophys. Res. Commun. 1987, 148, 206.
(5) Eisele, T.; Ishida, H.; Hummel, G.; Schmidt, R. R. Liebigs Ann.
Chem. 1995, 2113; and ref 7, 12–24 therein.
(6) Elbein, A. D. Adv. Carbohydr. Chem. Biochem. 1974, 30, 227;
and references therein.
(7) Geyer, A.; Reinhardt, S.; Bendas, G.; Rothe, U.; Schmidt, R. R.
J. Am. Chem. Soc. 1997, 119, 11707.
(8) Martin, O.; Lai, W. J. Org. Chem. 1990, 55, 5188.
Martin, O.; Lai, W. J. Org. Chem. 1993, 58, 176.
(9) Wei, A.; Kishi, Y. J. Org. Chem. 1994, 59, 88.
(10) Lubineau, A.; Grand, E.; Scherrmann, M.-C. Carbohydr. Res.
1997, 297, 169.
13C NMR (62.7 MHz, CDCl3): δ = 62.7, 63.91, 66.78, 70.96, 71.47,
72.03, 72.87, 76.49, 77.39, 124.70, 126.70, 127.30, 127.43, 127.47,
127.60, 127.86, 127.93, 128.24, 128.73, 129.94, 136.83, 137.02,
137.49, 143.70, 149.65 (C=C, ArC), 185.08 (CHO).
MS (FAB, NaI): m/z = 591 (M + Na).
(11) Schmidt, R. R.; Preuß, R.; Betz, R. Tetrahedron Lett. 1987, 28,
6591.
Preuß, R.; Schmidt, R. R. Liebigs Ann. Chem. 1989, 429 and
references therein.
(12) Dietrich, H.; Regele-Mayer, C.; Schmidt, R. R. Carbohydr.
Lett. 1994, 1, 115.
Dietrich, H.; Schmidt, R. R. Liebigs Ann. Chem. 1994, 975 and
references therein.
(13) Schmidt, R. R.; Beyerbach, A. Liebigs Ann. Chem. 1992, 983.
(14) Frische, K.; Schmidt, R. R. Liebigs Ann. Chem. 1994, 297.
(15) Mozingo, R. Organic Syntheses; Wiley & Sons: New York,
1955; Collect. Vol. 3, p 181.
(16) Zweifel, G.; Brown, H. C. Org. React. 1963, 13, 1.
Schmidt, R. R. Acc. Chem. Res. 1986, 19, 250.
Pure Appl. Chem. 1987, 59, 415.
Bis{1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-[(R)-phenylsulfi-
nyl]-D-arabino-hex-1-enit-1-yl}methanol [(R,R)-11]:
To a well-stirred solution of freshly prepared LDA (1.1 equiv) in an-
hyd THF (50 mL), a solution of 1,5-anhydro-3,4,6-tri-O-benzyl-2-
[(R)-phenylsulfinyl]-D-arabino-hex-1-enitol [(R)-9] (150 mg,
0.27 mmol) in anhyd THF was added at –100°C. After stirring for 1
h, HMPA (0.15 mL, 0.21 mmol) was added and after another 30 min
a solution of 2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-3-[(R)-phenyl-
sulfinyl]-aldehydo-D-arabino-hept-2-enose [(R)-10] (171 mg,
0.3 mmol) in THF (10 mL) was added dropwise. The mixture was
stirred for 2 h at this temperature and quenched with a sat. NH4Cl
solution and extracted with Et2O (3 × 25 mL). The combined organic
extract was washed with sat. brine and dried (MgSO4) and concentrat-
ed in vacuo. The residue was purified by flash chromatography (pe-
troleum ether/EtOAc 7:3) to give a viscous oil; yield: 106 mg (35%)
(17) Schmidt, R. R.; Preuß, R. Tetrahedron Lett. 1989, 30, 3409.