Two efficient syntheses of protected 4-deoxy-D-lyxo-hexose (4-desoxy-D-mannose)

Article abstract of DOI:10.1080/07328300600770519

The formation of four differently protected 4-deoxy-D-lyxo-hexose derivatives 7, 8, 12, and 14 is described. In the first procedure, a nucleophilic displacement of the allylic mesylate 4 by hydride was combined with a highly stereoselective osmylation of

Full text of DOI:10.1080/07328300600770519

Journal of Carbohydrate Chemistry, 25:331–343, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300600770519
Two Efficient Syntheses of
Protected 4-Deoxy-D-lyxo-
hexose (4-Desoxy-D-
mannose)
Karsten Krohn and Ivan Shuklov
Department of Chemistry, University of Paderborn, Paderborn, Germany
The formation of four differently protected 4-deoxy-D-lyxo-hexose derivatives 7, 8, 12,
and 14 is described. In the first procedure, a nucleophilic displacement of the allylic
mesylate 4 by hydride was combined with a highly stereoselective osmylation of olefin
6 to afford diol 7. In the second radical procedure, tributyl tin hydride was substituted
by the cheap and environmentally friendly hypophosphorous acid as a hydrogen donor
in the reduction of xanthate 13 to 4-deoxy lyxo-hexose 14.
Keywords 4-Deoxy-D-lyxo-hexose, LiAlH4 reduction of allylic mesylate, Stereoselec-
tive cis-hydroxylation, Hypophosphorous acid, Deoxygenation
INTRODUCTION
3-Deoxy- and 4-deoxy-hexoses are rare sugar derivatives but are occasionally
found as components in natural products such as neosidomycin and SF-2140,
two indole nucleoside antibiotics.[1] Other 4-deoxy derivatives of oligosacchar-
ides[2] and antibodies[3] are useful tools in the study of biological and biochemi-
cal properties. 4-Deoxy-D-lyxo-hexose (4-deoxy-D-mannose) was of particular
value as a chiral starting material in natural product synthesis. For
example, Nikolaou et al. used this sugar as starting material for the synthesis
of brevetoxin B.[4] It was also used for the synthesis of hemibrevetoxin,
myxovirecin B, neosidomycin, and SF-2140.[5] 4-Deoxy-D-lyxo-hexose is not
commercially available; however, several methods for the synthesis of
Received February 13, 2006; accepted March 20, 2006.
Dedicated to Prof. Siegfried Blechert on the occasion of his 60th birthday.
Address correspondence to Karsten Krohn, Department of Chemistry, University of
Paderborn, Warburger Str. 100, D-33098 Paderborn, Germany. E-mail: karsten.
krohn@uni-paderborn.de
331

K. Krohn and I. Shuklov
332
4-deoxylyxo-hexoses are known.[1b,4–7] The 4-deoxy sugar was first prepared by
ˇ
´
Cerny et al. in a multi-step sequence employing 1,6-anhydro-b-D-glucopyra-
nose as the starting material.[6] Mostly, the deoxygenation step was carried
out by a Barton-McCombie reaction using tributylstannane as the hydrogen
radical donor.[5,8] In connection with the synthesis of the macrolide
LL-Z1640-2[9], we needed larger amounts of 4-deoxy-D-lyxo-hexose in different
protected forms and therefore examined three new variations, two of them
resulting in efficient, economical, and environmentally friendly routes to the
target molecule in protected form.
RESULTS AND DISCUSSION
Our first synthetic approach used 3,4,6-triacetyl-D-glucal (1) as the staring
material, easily available from D-glucose.[10] The idea behind this approach
was placing the 4-hydroxyl group into an allylic position to make it easily redu-
cible, for example, as a sulfonate by hydride donating agents. For this purpose,
3,4,6-triacetyl-D-glucal (1) was subjected to the Ferrier-type allylic rearrange-
ment.[11,12] We recently employed that reaction in the a-selective synthesis of
the benzyl glycoside 2,[13] using iron trichloride as a very efficient catalyst.[14]
Subsequent selective benzoylation of the primary hydroxyl group at C-6
afforded the monobenzoate 3. Mesylation at C-4 then led to the allylic
mesylate 4, perfectly suited for nucleophilic hydride reduction (Sch. 1). In
fact, upon treatment with lithium aluminum hydride, the mesylate reduction
occurred concurrently with conversion of the benzoate into the alcohol to
yield the deoxygenated unsaturated sugar 5 in good overall yield (60%).
Next, the hydroxyl group at C-6 was protected as a tosylate 6, facilitating the
purification in the subsequent step. Gratifyingly, the anomeric a-benzyloxy
group efficiently shielded the molecule from attack from the a-side in the
Scheme 1: Synthesis of 4-deoxy-lyxo-hexopyranosides 7 and 8. Reagents and conditions:
a) BzCl, 2,6-lutidine, 70%; b) MsCl, TEA, 4-DMAP, 95%; c) LiAlH4, 60%; d) TsCl, TEA, DMAP, 98%;
e) OsO4, NMO, 90%; f) 1,3-dimethoxypropane, PPTS, 95%.

Syntheses of Protected 4-Deoxy-D-lyxo-hexose
333
following cis-dihydroxylation step,[1b] using osmium tetroxide and N-morpho-
line-N-oxide (NMO) as the cooxidant.[15] Benzyl 4-deoxy-6-tosyl-a-D-lyxo-hexo-
pyranoside (7) was isolated in 90% yield and 99% de (NMR). The two vicinal
hydroxyl groups at C-2 and C-3 can be protected easily as an acetonide to
yield the fully protected 4-deoxy-D-lyxo-hexose derivative (8) in 95% yield.
Encouraged by the facile LiAlH4 reduction of mesylate 4 to the deoxy sugar
5, we wanted to probe a related reduction of non allylic sulfonates. Thus, the
second route required conversion of an appropriately protected known
mannose derivative 9[16] into the corresponding unknown mesylate 10a or
triflate 10b, which could be achieved in 98% and 90% yield, respectively
(Sch. 2).
However, not unexpectedly, the mesylate 10a was completely inert to
LiAlH4 as well as NaBH4 reduction, even at reflux in THF. This procedure
was also applied to the corresponding alcohols 11a/11b and an anchimeric
assistance of the free hydroxyl group in the reduction process to 12 could not
be observed. Although the triflate 10a reacted with NaBH4 to give deoxysugar
14 in moderate yield (35%), this procedure did not meet our requirements for
a larger scale production of 14.
In the third attempt, we therefore turned our attention to the radical pro-
cedure and converted the alcohol 9 into the xanthate 13. In fact, this compound
was shown to be a good substrate for the Barton-McCombie reaction[17]
(review[18]). However, the tributyl tin hydride used in this procedure was
Scheme 2: Reagents and conditions: a) Tf2O, Et3N, -408C, 65%; b) MsCl, NEt3, rt, 95%; c) TMSCl,
MeOH, 11a ¼ 90%, 11b ¼ 95%; d) LiAlH4, or NaBH4; e) NaBH4, 35%; f) 1. NaH; 2. CS2, 3. MeI, 98%;
g) H3PO2/AlBN, Et3N, dioxane, reflux, 90%; h) p-TsOH, acetone, 90%.

K. Krohn and I. Shuklov
334
neither an ideal reagent for large-scale production nor environmentally
friendly. We then tried the use of hypophosphorous acid, already suggested
by Barton et al. as a hydrogen donor.[19] We were pleased to observe that the
reaction of xanthate 13 with hypophosphorous acid produced the deoxysugar
14 nearly quantitatively. In the final step, the precursor 14 could be
detritylated selectively using p-TsOH in 90% yield to give the desired partially
protected 4-deoxy-D-lyxo-hexose derivative 12.
In conclusion, two efficient routes, amenable to larger scale, for the synthesis
of 4-deoxy-D-lyxo-hexose derivatives are proposed. In the first procedure, the
facile nucleophilic displacement of an allylic mesylate group in 4 by hydride
was combined with a highly stereoselective osmylation of 6. In the second pro-
cedure, the cheap and environmentally friendly hypophosphorous acid was
used as a hydrogen donor in the reduction of xanthate 13. Another advantage
of the two alternative approaches was the formation of differently protected
4-deoxy-D-lyxo-hexose derivatives such as 7, 8, 12, and 14.
EXPERIMENTAL
General
Thin-layer chromatography was performed on precoated TLC plates (silica
gel). Melting points were measured with a Gallenkamp apparatus and are cor-
rected. NMR spectra were recorded on Bruker Avance 500 at the following fre-
1
quencies: 500.13 MHz (1H) and 125.76 MHz. (13C). Chemical shifts of H and
13C NMR spectra are reported in ppm downfield from TMS as an internal
standard. Elemental analyses were performed with a Perkin-Elmer Elemental
Analyzer 2400. Optical rotations were measured at 258C on a Perkin-Elmer
Polarimeter 241. Mass spectra were recorded using a Finnigan MAT 8430 spec-
trometer in the electron-impact mode at 70 eV and chemical ionization are
given as m/z values and relative abundances. The infrared spectra were
recorded using a FT-IR Spectrometer Nicolet 510 P.
Benzyl 6-O-benzoyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranoside (3)
Benzoyl chloride (2 mL, 17 mmol) was added to a solution of benzyl 2,3-
dideoxy-a-D-erythro-hex-2-enopyranoside (2) (2.20 g., 9.3 mmol) in a mixture
of 2,6-lutidine (2 mL, 17 mmol) and dry CH2Cl2 (150 mL). The reaction
mixture was stirred at rt for 18 h and the conversion was monitored by TLC
(CH2Cl2/MeOH, 98:2). The mixture was then washed with saturated
aqueous NaHCO3 solution and brine. The combined organic layers were
dried over MgSO4, filtered, and concentrated at reduced pressure. Purification
by silica gel column chromatography (CH2Cl2) gave the benzoate 3 (2.20 g, 70%)
as a colorless solid Rf ¼ 0.25 (CH2Cl2/MeOH, 98:2). m.p. ¼ 658C. [a]2D0 244.5

Syntheses of Protected 4-Deoxy-D-lyxo-hexose
335
(c 1.0, CHCl3). IR (KBr): 3462, 1720, 1277, 1051, 1039, 1026. 1H NMR
(500 MHz, CDCl3): 4.00–4.03 (m, 1H, H-5), 4.15 (d, 1H, J ¼ 8.6 Hz, H-4), 4.45
(dd, 1H, J6a,5 ¼ 1.7 Hz Jgem ¼ 12.0 Hz, H-6a), 4.60 (d, 1H, Jgem ¼ 11.7 Hz,
OCH2Ph), 4.75 (dd, 1H, J6b,5 ¼ 5.0 Hz, Jgem ¼ 12.0 Hz, H-6b), 4.81 (d, 1H,
Jgem ¼ 11.7 Hz, OCH2Ph), 5.12 (s, 1H, H-1) 5.79–5.82 (m, 1H, H-2), 6.00
(d, 1H, J3,2 ¼ 10.1 Hz, H-3), 7.27–7.34 (m, 5H, Ph), 7.41–7.45 (m, 2H, Ph),
7.55–7.59 (m, 1H, Ph), 8.08 (m, 2H, Ph). 13C NMR (125 MHz, CDCl3): 64.0
(C-6), 64.2 (C-4), 70.2 (CH2Ph), 70.8 (C-5), 77.2 (CPh3), 93.8 (C-1), 126.6
(C-2), 127.8 (CAr), 127.9 (CAr), 128.4 (CAr), 129.7 (CAr), 129.8 (CAr), 133.1
(C-3), 133.3 (CAr), 137.8 (CAr), 167.3 (COO). Anal. Calc. for C20H20O5;
C, 70.57; H, 5.92. Found; C, 70.57; H, 5.72.
Benzyl 6-O-benzoyl-2,3-dideoxy-4-O-methanesulfonyl-a-D-erythro-hex-2-
enopyranoside (4)
Methanesulfonyl chloride (1.4 mL, 18 mmol) was added to a solution of 2,3-
dideoxy-a-D-erythro-hex-2-enopyranoside 3 (2.20 g, 6.4 mmol) in a mixture of
dry pyridine (1.5 mL, 18 mmol) and dry CH2Cl2 (150 mL). The reaction
mixture was stirred at rt for 12 h and the conversion was monitored by TLC
(CH2Cl2/MeOH, 98:2). The reaction mixture was then washed with saturated
aqueous NaHCO3 solution and brine. The combined organic layers were dried
over MgSO4, filtered, and concentrated at reduced pressure. Purification by
silica gel column chromatography (CH2Cl2/MeOH, 98:2) gave methanesulfo-
nate 4 (2.50 g, 95%) as a colorless solid Rf ¼ 0.7 (CH2Cl2/MeOH, 98:2).
m.p. ¼ 82–848C (decomp.). [a]2D0 þ 45.8 (c 1.0, CHCl3). IR (KBr): 2920, 2360,
2339, 1724, 1346, 1277, 1217, 1176, 1117, 1095, 1041, 1016, 949. 1H NMR
(500 MHz, CDCl3): 3.07 (s, 3H, SO2CH3), 4.31 (ddd, 1H, J5,6a ¼ 2.2 Hz,
J5,6b ¼ 5.2 Hz,
J5,4 ¼ 9.4 Hz,
H-5),
4.50
(dd,
1H,
J6b,5 ¼ 5.2 Hz,
Jgem ¼ 12.2 Hz, H-6b), 4.57–4.60 (m, 2H, OCH2Ph, H-6a), 4.79 (d, 1H,
Jgem ¼ 11.8 Hz, OCH2Ph), 5.12 (d, 1H, J1,2 ¼ 2.0 Hz, H-1), 5.31 (m, 1H, H-4),
5.93–5.96 (m, 1H, H-2), 6.11 (d, 1H, J2,3 ¼ 10.3 Hz, H-3), 7.27–7.34 (m, 5H,
Ph), 7.41–7.45 (m, 2H, Ph), 7.55–7.59 (m, 1H, Ph), 8.06–8.08 (m, 2H, Ph).
13C NMR (125 MHz, CDCl3): 38.7 (CH3SO2), 62.9 (C-6), 67.1 (C-4), 70.5
(CH2Ph), 70.8 (C-5), 93.5 (C-1), 127.9 (C-2), 128.0 (CAr), 128.5 (CAr), 128.6
(CAr), 129.3 (CAr), 129.7 (CAr), 129.8 (CAr), 133.2 (C-3), 137.3 (CAr), 166.2
(COO). MS (EI, 70 eV): m/z (%): 417 [M]þ (0.3), 232 [M-PhCH2-CH3SO2]þ,
91 [PhCH2]þ (27). Anal. Calc. for C30H34O8S: C, 60.27; H, 5.30. Found: C,
60.26; H, 5.01.
Benzyl 2,3,4-trideoxy-a-D-glycero-hex-2-enopyranoside (5)
Lithium aluminium hydride (0.30 g, 8 mmol) was added to the solution of
4 (0.55 g, 1.4 mmol) in dry THF (50 mL) under nitrogen. The reaction mixture
was stirred at rt for 5 h. The conversion was monitored by TLC (CH2Cl2/
MeOH, 98:2). Excess LiAlH4 was destroyed by addition of water (1 mL).

K. Krohn and I. Shuklov
336
The reaction mixture was extracted with diethyl ether (3 ꢀ 50 mL) and the
combined organic layers were dried over MgSO4, filtered, and concentrated.
Purification by silica gel column chromatography (CH2Cl2) gave 5 (0.20 g,
70%) as a colorless oil. Rf ¼ 0.5 (CH2Cl2/MeOH, 98:2). [a]2D0 235.7 (c 0.33,
CHCl3). IR (KBr): 3448, 2924, 2881, 1454, 1400, 1219, 1184, 1113, 1086,
1
1043, 1022, 953; H NMR (500 MHz, CDCl3): 1.88 (dddd, 1H, J4a,2 ¼ 1.4 Hz,
J4a,2 ¼ 3.4 Hz, J4a,3 ¼ 5.7 Hz, Jgem ¼ 17.7 Hz, H-4a), 2.11–2.19 (m, 1H, H-4b),
3.57 (dd, 1H, J6a,5 ¼ 3.1 Hz, Jgem ¼ 11.6 Hz, H-6a), 3.67 (dd, 1H,
J6b,5 ¼ 6.2 Hz, Jgem ¼ 11.6 Hz, H-6b), 4.06 (ddd, 1H, J5,6a ¼ 3.1 Hz,
J5,6b ¼ 6.2 Hz, J5,4b ¼ 11.3 Hz, H-5), 4.61 (d, 1H, Jgem ¼ 12.0 Hz, CH2Ph),
4.78 (d, 1H, Jgem ¼ 12.0 Hz, CH2Ph), 5.11 (t, 1H, J ¼ 1.3 Hz, H-1), 5.77 (dddd,
1H, J2,1 ¼ 1.4 Hz, J2,4a ¼ 1.3 Hz, J2,4b ¼ 4.3 Hz, J2,3 ¼ 10.1 Hz, H-2), 6.03
(dddd, 1H, J3,1 ¼ 1.4 Hz, J3,4b ¼ 1.4 Hz, J3,4a ¼ 5.7 Hz, J3,2 ¼ 10.1 Hz, H-3),
7.28–7.39 (m, 5H, Ph). 13C NMR (125 MHz, CDCl3): 26.0 (C-4), 65.2 (C-6),
65.3 (CAr), 67.2 (C-5), 69.8 (CH2Ph), 94.2 (C-1), 125.4 (C-2), 127.0 (CAr), 127.6
(C-3), 127.7, 128.6, 138.2, 140.1 (4 ꢀ CAr). MS (EI, 70 eV): m/z (%) ¼ 220 (1)
[M]þ, 203 (2) [M-OH], 129 (10) [M-PhCH2]þ, 91 (100), [PhCH2]þ, 77 (60) [Ph]þ.
Benzyl 6-O-tosyl-2,3,4-trideoxy-a-D-glycero-hex-2-enopyranoside (6)
Tosyl chloride (0.26 g, 1.2 mol) was added to the solution of 5 (0.25 g,
1.2 mmol), a catalytic amount of 4-DMAP, and pyridine (0.15 mL, 1.5 mmol)
in dry CH2Cl2 (100 mL). The reaction mixture was stirred at rt for 12 h and
the conversion was monitored by TLC (CH2Cl2/MeOH, 98:2). The reaction
mixture was washed with saturated aqueous NaHCO3 solution and brine.
The combined organic layers were dried over MgSO4, filtered, and concen-
trated. Purification by silica gel column chromatography (CH2Cl2) gave
tosylate 6 (0.40 g, 95%) as a colorless oil. Rf ¼ 0.9 (CH2Cl2/MeOH, 98:2). [a]D20
228.7 (c 0.8, CHCl3). IR (KBr): 3367, 2974, 2891, 1361, 1190, 1176, 1093,
1
1047, 1022, 1003, 991, 966, 949, 814. H NMR (500 MHz, CDCl3): 1.92 (dddd,
1H, J4a,2 ¼ 1.4 Hz, J4a,5 ¼ 3.6 Hz, J4a,3 ¼ 5.7 Hz, Jgem ¼ 17.5 Hz, H-4a), 2.02–
2.10 (m, 1H, H-4b), 2.44 (s, 3H, CH3Ph), 4.03–4.13 (m, 2H, H-6a, H-6b),
4.15–4.20 (m, 1H, H-5), 4.51 (d, 1H, Jgem ¼ 11.8 Hz, CH2Ph), 4.60 (d, 1H,
Jgem ¼ 11.8 Hz, CH2Ph), 5.01 (t, 1H, J ¼ 1.3 Hz, H-1), 5.72–5.76 (m, 1H,
H-2), 5.95–6.00 (m, 1H, H-3), 7.26–7.36 (m, 7H, Ph, Ts), 7.80–7.83 (m, 2H,
Ts). 13C NMR (125 MHz, CDCl3): 21.7 (C-4), 26.2 (CH3), 64.4 (C-5), 69.5
(CH2Ph), 71.4 (C-6), 93.7 (C-1), 125.6 (C-2), 127.6 (C-3), 127.7, 127.8, 128.0,
128.2 (4 ꢀ CAr), 128.4 (CAr, Ts), 133.1, 137.9, 144.8 (3 ꢀ CAr). MS (EI, 70 eV):
m/z (%) ¼ 375 [M]þ (1), 172 [CH3C6H4SO3H]þ (18), 91 [C6H5CH2]þ (100).
Benzyl 4-deoxy-6-O-tosyl-a-D-lyxo-hexopyranoside (7)
A 25-mL three-necked round-bottomed flask, with a magnetic stirrer and
a nitrogen inlet, was charged with the monohydrate of N-methylmorpholin
(0.16 g, 1.3 mmol), water (10 mL), and acetone (10 mL). To this solution was

Syntheses of Protected 4-Deoxy-D-lyxo-hexose
337
added a solution of osmium tetroxide (0.005 g, 0.02 mmol) in tert-butanol
(0.05 mL) and then olefin 6 (0.40 g, 1.3 mmol). This two-phase solution was
stirred vigorously under N2 at rt. After 18 h of stirring, TLC monitoring
showed the reaction to be complete. Sodium hydrogensulfite (0.1 g.) and 0.5 g
of Fluorosil in water (20 mL) were added, the slurry was stirred for 10
minutes, and the mixture was filtered through a pad of Celite (5g) on a 150-mL
sintered-glass funnel. The Celite cake was washed with acetone (3 ꢀ 15 mL).
The filtrate, combined with the acetone wash, was neutralized to pH 7 by
addition of 2 N sulfuric acid. The acetone was removed in vacuum and the
aqueous phase was washed with butanol (50 mL). The butanol extracts were
evaporated under vacuum, giving the crude product as a white solid, which
was recrystallized from chloroform to yield diol 7 as a white solid (0.40 g,
90%). m.p. 136–138 8C. Rf ¼ 0.3 (CH2Cl2/MeOH, 98:2). [a]2D0 þ62.2 (c 0.5,
CHCl3). IR (KBr): 3346, 2916, 2360, 2341, 1363, 1186, 1173, 1080, 1061,
1047, 1020, 987, 960, 847, 810. 1H NMR (500 MHz, CDCl3): 1.53–1.60
(m, 1H, H-4a). 1.70 (ddd, 1H, J ¼ 2.5 Hz, J ¼ 5.2 Hz, Jgem ¼ 12.6 Hz, H-4b),
2.12 (s br, 2H, OH), 2.43 (s, 3H, Ph-CH3), 3.74–3.76 (m, 1H, H-2), 3.97–4.04
(m, 3H, H-3, H-5, H-6a), 4.12 (m, 1H, H-6b), 4.46 (d, 1H, Jgem ¼ 11.7 Hz,
OCH2Ph), 4.66 (d, 1H, Jgem ¼ 11.7 Hz, OCH2Ph), 4.90 (d, 1H, J1,2 ¼ 1.6 Hz,
H-1), 4.26–4.35 (m, 7H, HTs, HBn), 7.81 (d, 2H, J ¼ 7.8 Hz, Ho,Ts). 13C NMR
(125 MHz, CDCl3): 21.6 (PhCH3), 30.3 (C-4), 65.2 (C-3), 66.1 (C-2), 68.9 (C-5),
69.3 (CH2Ph), 71.5 (C-6), 99.2 (C-1), 128.0, 128.1, 128.5, 129.9, 133.0, 136.9,
145.0 (7 ꢀ CAr). MS (70 eV) m/z (%) ¼ 448 [M]þ. Anal. Calc. for C23H28O7S:
C, 58.81; H, 5.93. Found: C, 58.23; H, 5.78.
Benzyl 2,3-O-isopropylidene 4-deoxy-6-O-tosyl-a-D-lyxo-hexopyranoside (8)
p-Toluenesulfonic acid (0.1 g, 0.52 mmol.) was added to the solution of 7
(0.90 g., 2.6 mmol) in 1,1-dimethoxypropane (5 mL). The reaction mixture was
stirred at rt for 3 h and the conversion was monitored by TLC (CH2Cl2/
MeOH, 98:2). The reaction mixture was subsequently washed with saturated
aqueous NaHCO3 solution and brine. The combined organic layers were
dried over MgSO4, filtered, and concentrated. Purification by silica gel
column chromatography (CH2Cl2) gave acetonide 8 (0.94 g, 95%) as a colorless
oil, Rf ¼ 0.6 (CH2Cl2/MeOH, 98:2). [a]2D0 þ43 (c 1.0, CHCl3). IR (KBr): 2931,
1363, 1190, 1176, 1138, 1090, 1065, 987. 1H NMR (500 MHz, CDCl3): 1.29
(s, 3H, CCH3), 1.42 (s, 3H, CC’H3), 1.47–1.53 (m, 1H, H-4a), 1.91 (ddd, 1H,
J4b,5 ¼ 3.3 Hz, J4b,3 ¼ 6.0 Hz, Jgem ¼ 13.4 Hz, H-4b), 2.43 (s, 3H, Ph-CH3),
3.97–4.04 (m, 3H, H-2, H-5, H-6b), 3.97–4.04 (m, 3H, H-2, H-5, H-6b), 4.32–
4.36 (ddd, 1H, J3,4b ¼ 6.0 Hz, J3,4a ¼ 6.0 Hz, J3,2 ¼ 8.2 Hz, H-3), 4.46 (d, 1H,
Jgem ¼ 11.7 Hz, OCH2Ph), 4.66 (d, 1H, Jgem ¼ 11.7 Hz, OCH2Ph), 4.99 (d, 1H,
J1,2 ¼ 1.6 Hz, H-1), 4.26–4.35 (m, 7H, HTs, HBn), 7.81 (d, 2H, J ¼ 7.82 Hz, Ho-Ts). 13C NMR
(125 MHz, CDCl3): 21.6 (PhCH3), 25.9 (CCH3), 27.7 (CC’H3), 28.9 (C-4), 64.6 (C-2), 69.3
(CH2Ph), 70.0 (C-3), 72.0 (C-6), 73.0 (C-5), 96.63 (CMe2), 109.13 (C-1), 127.99,

K. Krohn and I. Shuklov
338
128.27, 128.49, 129.84, 133.08, 136.98, 144.85 (7 ꢀ CAr). MS (CI) m/z (%) ¼ 446
[M-H2]þ (1). Anal. Calc. for C20H24O7S: C, 61.59; H, 6.29. Found: C, 61.43; H,
6.18.
Methyl 2,3-O-isopropylidene-4-O-methanesulfonyl-6-O-triphenylmethyl-a-D-
mannopyranoside (10a)
A 50-mL flask equipped with a magnetic stirring bar and septum was
charged with 1.3 g (2.7 mmol) of mannopyranoside 9, triethylamine (0.5 mL,
3.1 mmol), and anhydrous CH2Cl2 (30 mL). Mesylchloride (0.25 mL, 3.1 mmol)
was added slowly to the reaction mixture at 08C. The reaction was allowed to
warm to rt, stirred for 1 h, and then quenched by addition of saturated
NaHCO3 (2 mL) solution. The organic phase was dried with Na2SO4 and the
solvent removed at reduced pressure. The crude product was purified by
silica gel column chromatography (CH2Cl2) to afford mesylate 10a (1.5 g,
93%) as white crystals. Yield: 95%. m.p. 1838C (decomposition). Rf ¼ 0.8
(CH2Cl2). [a]2D0 þ7.2 (c 1.0, CHCl3). IR (KBr): 1635, 1612, 1464, 1454, 1261,
1203, 1167. 1H NMR (500 MHz, CDCl3): 1.40 (s, 3H, CCH3), 1.61 (s, 3H,
CC’H3), 2.97 (s, 3H, OCH3), 3.33–3.37 (m, 1H, H-6b), 3.42–3.45 (m, 1H,
H-6a), 3.55 (s, 3H, CH3SO2), 3.85–3.88 (m, 1H, H-5), 4.21–4.22 (m, 1H, H-2),
4.26–4.29 (m, 1H, H-3), 4.57–4.61 (m, 1H, H-4), 5.05 (s, 1H, H-1), 7.24–7.29
(m, 3H, Ho, Trt), 7.30–7.35 (m, 6H, Hp, Trt), 7.50–7.53 (m, 6H, Hm, Trt). 13C
NMR (125 MHz, CDCl3): 26.3 (CCH3), 27.7 (CC’H3), 38.8 (CH3SO2), 55.0
(OCH3), 62.7 (C-6), 67.2 (C-5), 76.2 (C-3), 76.23 (C-2), 78.8 (C-4), 86.9 (CPh3),
97.8 (C-1), 110.3 (CMe2), 127.0 (Trt, Cp), 127.8 (Trt, Co), 127.9 (Trt, Cm),
128.8 (Trt, Cm), 143.8 (Trt, Cipso). MS (CI) m/z (%): 554 (66) [M]þ, 522 (11)
[M-CH4O]þ, 477 (68) [M-C6H5]þ, 311 (60) [M-Ph3C]þ, 243 [Ph3C]þ, 77 (42)
[C6H5]þ. Anal. Calc. for C30H34O8S: C, 64.96; H, 6.18. Found: C, 64.83; H, 6.12.
Methyl 2,3-O-isopropylidene-4-O-trifluoromethanesulfonyl-6-O-
triphenylmethyl-a-D-mannopyranoside (10b)
A 50-mL flask equipped with a magnetic stirring bar and septum was
charged with methyl mannopyranoside 9 (1.80 g, 3.2 mmol), pyridine (0.3 mL,
3.5 mmol), and anhydrous CH2Cl2 (50 mL). Trifluoromethanesulfonic anhy-
dride (0.6 mL, 0.035 mmol) was added slowly to the reaction mixture at
2408C. The reaction mixture was allowed to warm to 08C and stirring was con-
tinued for 1 h at this temperature. The reaction was quenched by addition of a
saturated aqueous NaHCO3 solution (2 mL). The organic phase was dried with
Na2SO4 and the solvent removed in vacuum. The crude product was recrystal-
lized from CH2Cl2-hexane to afford the triflate 10b (1.50 g, 65%) as white
crystals, m.p. 508C (decomposition). Rf ¼ 0.9 (CH2Cl2). [a]2D0 21.9 (c 1.1,
CHCl3). IR (KBr): 3535, 2987, 2937, 1354, 1174, 1090, 960, 858. 1H NMR
(500 MHz, CDCl3): 1.38 (s, 1H, 3H, CCH3), 1.55 (s, 1H, 3H, CC’H3), 3.30
(dd, 1H, J6a,5 ¼ 6.5 Hz, Jgem ¼ 10.5 Hz, H-6a), 3.37 (dd, 1H, J6b,5 ¼ 2.4 Hz,

Syntheses of Protected 4-Deoxy-D-lyxo-hexose
339
Jgem ¼ 10.5 Hz, H-6b), 3.53 (s, 1H, 3H, OCH3), 3.95 (ddd, 1H, J5,6b ¼ 2.4 Hz,
J5,6a ¼ 6.5 Hz, J5,4 ¼ 10.4 Hz, H-5), 4.21 (d, 1H, J2,3 ¼ 5.5 Hz, H-2), 4.29 (dd,
1H, J3,2 ¼ 5.5 Hz, J3,4 ¼7.2 Hz, H-3), 4.80 (dd, 1H, J4,3 ¼ 7.2 Hz,
J5,4 ¼ 10.4 Hz, H-4), 5.03 (s, 1H, H-1), 7.23–7.26 (m, 6H, Trt), 7.28–7.33
(m, 6H, Trt), 7.47–7.49 (m, 3H, Trt). 13C NMR (125 MHz, CDCl3): 26.2
(CCH3), 27.5 (CC’H3), 55.2 (OCH3), 62.4 (C-6), 66.6 (C-5), 75.4 (C-3), 76.6 (C-
2), 83.9 (C-4), 97.8 (C-1), 127.1, 127.3, 127.8, 127.9, 128.8 (5 ꢀ CAr, Tr),
(5 ꢀ CAr,Tr), 118.5 (q, JC,F ¼ 319 Hz, CF3). MS (EI, 70 eV): m/z (%) ¼ 608 (0.1)
[M]þ, 244 (100) [Ph3CH]þ.
Methyl 2,3-O-isopropylidene-4-O-methanesulfonyl-a-D-mannopyranoside (11a)
Trimethylsilyl chloride (0.1 mL, 8 mmol) was added to the solution of 10a
(0.40 g, 0.7 mmol) in anhydrous CH2Cl2 (50 mL) and MeOH (1 mL, 25 mmol).
After 1 h, the reaction was completed and quenched by addition of saturated
aqueous NaHCO3 solution (2 mL). The organic solution was washed with
brine and the combined organic layers were dried over MgSO4, filtered, and
concentrated. Product 11a was isolated as a white solid after column chromato-
graphy on SiO2 (CH2Cl2/MeOH 98:2), 1.30 mg (60%). Rf ¼ 0.35 (CH2Cl2/MeOH
98:2). m.p. ¼ 908C. [a]2D0 248 (c 0.6, CHCl3). IR (KBr): 1373, 1354, 1223, 1174,
1140, 1090, 1020, 1005, 960, 858, 802. 1H NMR (500 MHz, CDCl3): 1.37 (s, 3H,
CCH3), 1.59 (s, 3H, CC’H3), 3.21 (s, 3H, SO2CH3), 3.42 (s, 3H, OCH3), 3.68–3.73
(m, 1H, H-5), 3.88 (m, 2H, H-6), 4.20 (d, 1H, J2,3 ¼ 5.6 Hz, H-2), 4.33 (m, 1H,
H-3), 4.61 (dd, J4,3 ¼ 7.6 Hz, J4,5 ¼ 10.4 Hz, H-4), 5.0 (s, 1H, H-1). 13C NMR
(125 MHz, CDCl3): 26.2 (CCH3), 27.8 (CC’H3), 38.9 (SO2CH3), 55.2 (OCH3),
60.8 (CH2OH), 67.5 (C-5), 75.8 (C-3), 76.2 (C-2), 78.9 (C-4), 97.9 (C-1), 110.3
(CMe2). MS (CI) m/z (%) ¼ 313 (35) [M þ H]þ, 281 (3) [M-CH4O]þ. Anal.
Calc. for C11H20O8S: C; 42.30; H, 6.45. Found: C, 42.35; H, 6.51.
Methyl 2,3-O-isopropylidene-4-O-trifluoromethanesulfonyl-a-D-
mannopyranoside (11b)
Trimethylsilyl chloride (0.1 mL, 8 mmol) was added to the solution of 10b
(0.40 g, 0.66 mmol) in anhydrous CH2Cl2 (50 mL) and MeOH (1 mL, 25 mmol).
After 1 h the reaction was completed and quenched by addition of saturated
aqueous NaHCO3 solution. The reaction mixture was washed with brine and
the combined organic layers were dried over MgSO4, filtered, and concen-
trated. Product 11b was isolated as an oil after column chromatography on
SiO2 (CH2Cl2/MeOH 98:2), 0.16 g (67%). Rf ¼ 0.3 (CH2Cl2/MeOH 98:2).
[a]2D0 þ23 (c 1.1, CHCl3). IR (KBr): 3471, 1714, 1414, 1363, 1221, 1140, 1092.
1H NMR (500 MHz, CDCl3): 1.38 (s, 1H, 3H, CCH3), 1.55 (s, 1H, 3H, CC’H3),
3.30 (dd, 1H, J6a,5 ¼ 6.5 Hz, Jgem ¼ 10.5 Hz, H-6a), 3.37 (dd, 1H,
J6b,5 ¼ 2.4 Hz, Jgem ¼ 10.5 Hz, H-6b), 3.53 (s, 1H, 3H, H-10), 3,95 (ddd, 1H,
J5,6b ¼ 2.4 Hz, J5,6a ¼ 6.5 Hz, J5,4 ¼ 10.4 Hz, H-5), 4.21 (d, 1H, J2,3 ¼ 5.5 Hz,
H-2), 4.29 (dd, 1H, J3,2 ¼ 5.5 Hz, J3,4 ¼ 7.2 Hz, H-3), 4.78 (dd, 1H,

K. Krohn and I. Shuklov
340
J4,3 ¼ 7.2 Hz, J5,4 ¼ 10.4 Hz, H-4), 5.01 (s, 1H, H-1). 13C NMR (125.76 MHz,
CDCl3): 26.3 (CCH3), 27.4 (CC’H3), 55.2 (OCH3), 62.4 (C-6), 66.6 (C-5), 75.4
(C-3), 76.7 (C-2), 83.9 (C-4), 97.8 (C-1), 118.4 (q, JC,F ¼ 319 Hz, CF3). MS
(CI) m/z (%) ¼ 367 [M þ 1]þ (13), 233 [M-CF3SO2]þ (12), 217 [M-CF3SO3]þ
(46). Fluor, kein E.a.
Methyl 2,3-O-isopropylidene-4-deoxy-6-O-triphenylmethyl-a-D-lyxo-
hexopyranoside (14)
Method A: NaBH4 (0.20 g, 5.3 mmol) was added to the solution of triflate
10b (1.80 g, 2.9 mmol) in dry acetonitrile (100 mL). The reaction mixture was
stirred for 2 h at rt and the excess of sodium borohydride was destroyed by
addition of water. The mixture was extracted with dichloromethane
(3 ꢀ 100 mL), and the combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. The residue was purified by
column chromatography (CH2Cl2) to give the deoxy compound 14 (0.48 g,
35%) as a white foam.
Method B: A solution of xanthate 11 (0.70 g, 1.25 mmol), hypophosphorous
acid (50% solution in water, 0.64 mL, 6.2 mmol), and triethylamine (0.69 mL,
6.82 mmol) in dioxane (15 mL) was degassed and refluxed under an argon
atmosphere for 0.25 h. The reaction mixture was cooled to rt. A 0.2 M
solution of AIBN in dioxane (1 mL) was then added slowly by refluxing with
a help of syringe pump. The reaction mixture was cooled and poured into
water. Extraction with ether and subsequent flash chromatography afforded
the reduced compound 14 (0.55 g, 95%). Rf ¼ 0.55 (CH2Cl2). m.p. 1868C. [a]D20
þ15 (c 0.6, CHCl3). IR (KBr): 1730, 1599, 1433, 1267, 1153, 1043, 1020, 922.
1H NMR (500 MHz, CDCl3): 1.36 (s, 3H, CCH3), 1.50 (s, 3H, CC’H3), 1.52–
1.57 (m, 1H, H-4a), 1.85–1.89 (m, 1H, H-4b), 3.04 (dd, 1H, J6a,5 ¼ 4.2 Hz,
Jgem ¼9.6, H-6a), 3.35 (dd, 1H, J6b,5 ¼ 6.8 Hz, Jgem ¼ 9.6, H-6b), 3.50 (s, 3H,
OCH3), 3.87-3.91 (m, 1H, H-5), 3.9 (d, 1H, J2,3 ¼ 5.7 Hz, H-2), 4.25 (m, 1H,
H-3), 5.00 (s, 1H, H-1), 7.25–7.28 (m, 3H, Hp, Trt), 7.30–7.36 (m, 6H, Ho,
Trt), 7.50–7.52 (m, 6H, Hm, Trt). 13C NMR (125.76 MHz, CDCl3): 26.3
(CCH3), 28.1 (CC’H3), 31.1 (C-4), 54.9 (C-5), 66.6 (C-6), 70.9 (C-3), 73.2 (C-2),
86.6 (CPh3), 98.7 (C-1), 108.9 (CMe2), 127.0, 127.3, 127.8, 127.9, 128.8, 144.1
(6 ꢀ CAr, Trt). MS (EI, 70 eV): m/z (%) ¼ 458 (10) [M-H2]þ, 243 (100) [CPh3þ],
215 (10) [M-H2-CPh3]þ, 185 (80) [M-CH3OH-CPh3]þ. Anal. Calc. for
C29H32O5: C, 75.60; H, 7.00. Found: C, 75.40; H, 6.87.
Methyl 2,3-O-isopropylidene-4-O-(methylthio)thiocarbonyl-6-O-
triphenylmethyl-a-D-mannopyranoside (13)
A 250-mL three-necked round-bottomed flask equipped with a magnetic
stirring bar, a nitrogen-inlet adapter, pressure-equalizing addition funnel,
and stopper was charged with methyl mannopyranoside
9 (5.05 g,
10.6 mmol), imidazole (0.025 g, 4 mmol), and anhydrous THF (100 mL). The

Syntheses of Protected 4-Deoxy-D-lyxo-hexose
341
reaction vessel was flushed with nitrogen and a nitrogen atmosphere was
maintained during the ensuing steps. Over a 5-min period, a 50% sodium
hydride dispersion (0.76 g, 15 mmol) was added. Vigorous gas evolution was
observed. After the reaction mixture was stirred for 20 min, CS2 (2.3 mL,
15.0 mmol) was added all at once. Stirring was continued for 30 min, after
which time iodomethane (1.2 mL, 17.7 mmol) was added in a single portion.
The reaction mixture was stirred for another 15 min, and acetic acid (5.0 mL)
was added dropwise to destroy the excess of sodium hydride. The solution
was filtered and the filtrate was concentrated on a rotary evaporator. The semi-
solid residue was extracted with three portions of ether (each 100 mL), and the
combined organic extracts were washed with two 100-mL portions of saturated
NaHCO3 solution and two 100-mL portions of water. The etheral solution was
dried over anhydrous magnesium sulfate, the drying agent was removed by fil-
tration, and the solvent was removed by rotary evaporation. Product 13 was
isolated by column chromatography to give xanthate 13 (5.96 g, 98%).
Rf ¼ 0.85 (CH2Cl2). m.p. 2048C. [a]D þ22.0 (c 1.2, CHCl3). IR (KBr): 1630,
1
1265. H NMR (500 MHz, CDCl3): 1.26 (s, 3H, CCH3), 1.47 (s, 3H, CC’H3),
2.31 (s, 3H, SCH3), 2.97 (dd, 1H, J6a,5 ¼ 2.2 Hz, Jgem ¼ 10.4, H-6a), 3.16 (dd,
1H, J6b,5 ¼ 7.1 Hz, Jgem ¼ 10.4, H-6b), 3.47 (s, 3H, OCH3), 3.85 (ddd,
J5,6a ¼ 2.2 Hz, J5,6b ¼ 7.1 Hz, J5,4 ¼ 10.4 Hz, 1H, H-5), 4.11 (d, 1H,
J2,3 ¼ 5.6 Hz, H-2), 4.25 (m, 1H, H-3), 4.95 (s, 1H, H-1), 5.78 (dd, 1H, J4,3
¼7.4, J4,5 ¼ 10.4, H-4), 7.11–7.16 (m, 3H, Hp, Trt), 7.17–7.21 (m, 6H, Ho,
Trt), 7.37–7.39 (m, 6H, Hm, Trt). 13C NMR (125 MHz, CDCl3): 19.2 (CCH3),
26.4 (CC’H3), 27.6 (SCH3), 55.0 (OCH3), 63.2 (C-6), 68.1 (C-5), 75.8 (C-3), 76.0
(C-2), 78.4 (C-4), 86.8 (CPh3), 98.0 (C-1), 110.1, 126.9, 127.8, 128.0, 128.8,
143.8, 215.6 (7 ꢀ CAr, Tr). MS (70 eV) m/z (%): 566 (0.1) [M]þ, 551 (10) [M-
CH3]þ, 458 (71) [M-C2H4OS2]þ, 398 (32) [M-C8H5S2]þ, 323 (19) [M-CPh3]þ,
243 (100) [Ph3C]þ, 228 (59) [M-CH3-CPh3]þ, 185 (94) [M-CH4O-CPh3-
C2H4OS2]þ, 165 (98). Anal. Calc. for C31H34O6S2: C, 65.70; H, 6.05. Found: C,
65.40; H, 5.83.
Methyl 2,3-O-isopropylidene-4-deoxy-a-D-lyxo-hexopyranoside (12)
p-TsOH (1.0 g, 5.2 mmol) was added to the solution of methyl lyxo-hexopy-
ranoside 14 (5.00 g, 10.9 mmol) in a mixture of acetone (100 mL) and 2,2-
dimethoxypropane (10 mL). After 12 h the reaction was completed and
diluted with dichloromethane (300 mL), and the organic solution was washed
with NaHCO3 (50 mL) and brine (50 mL) solution. The solution was dried
and evaporated, and the alcohol 14 (1.91 g, 80%) was isolated as a colorless
oil after flash chromatography on SiO2 (CH2Cl2/MeOH 98:2). [a]2D0 þ70.0 (c
0.8, CHCl3), lit. [a]2D0 þ66.0[7]
,
1H NMR (500 MHz, CDCl3): 1.35 (s, 3H,
CCH3), 1.53 (s, 3H, CC’H3), 1.66 (ddd, 1H, J4a,3 ¼ 8.6 Hz, J4a,5 ¼ 9.8 Hz,
Jgem ¼ 13.6 Hz, H-4a), 1.88 (ddd, 1H, J ¼ 3.5 Hz, J ¼ 4.5 Hz, Jgem ¼ 13.6 Hz,
H-4b), 2,17 (s, br, 1H, OH), 3.42 (s, 3H, OCH3), 3.63 (dd, 1H, Jgem ¼ 11.6 Hz,

K. Krohn and I. Shuklov
342
H-6a), 3.66 (dd, 1H, Jgem ¼ 11.6 Hz, H-6a), 3.80–3.84 (m, 1H, H-5), 3.93 (d, 1H,
J2,3 ¼ 5.9 Hz, H-2), 4.36 (dt, 1H, J3,4a ¼ 8.6 Hz, J3,2 ¼ 5.9 Hz, H-3), 4.92 (s, 1H,
H-1). 13C NMR (125 MHz, CDCl3): 26.1 (CCH3), 27.9 (CC’H3), 29.1 (C-4), 55.2
(OCH3), 65.6 (C-6), 66.8 (C-5), 70.4 (C-3), 73.1 (C-2), 98.9 (CMe2), 109.1 (C-1).
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