Cycloheptanic sugar mimetics, bridging the gap in the homologous series of carbocyclic analogues

Article abstract of DOI:10.1016/S0040-4020(02)01402-3

The cycloheptanic analogues of α-D-glucopyranose and β-D-mannopyranose have been synthesized. These two members of a new class of carbocyclic sugar mimetics are filling the gap between already existing cyclohexanic and cyclooctanic classes of sugar mimetics.

Full text of DOI:10.1016/S0040-4020(02)01402-3

Tetrahedron 58 (2002) 10189–10196
Cycloheptanic sugar mimetics, bridging the gap in the
homologous series of carbocyclic analogues
†
Eugen Sisu, Matthieu Sollogoub, Jean-Maurice Mallet and Pierre Sinay¨
*
´ ´ ´
Ecole Normale Superieure, Departement de Chimie, associe au CNRS, UMR 8642, 24 rue Lhomond, 75231 Paris Cedex 05, France
Received 22 July 2002; revised 7 October 2002; accepted 23 October 2002
Abstract—The cycloheptanic analogues of a-D-glucopyranose and b-D-mannopyranose have been synthesized. These two members of a
new class of carbocyclic sugar mimetics are filling the gap between already existing cyclohexanic and cyclooctanic classes of sugar
mimetics. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Carbasugars are a class of sugar mimetics in which the ring
oxygen has been replaced by a methylene group. We have
recently described the synthesis of such cyclohexanic
compounds1 using the triisobutylaluminium (TIBAL)-
promoted carbocyclisation developed by us.2 During a
study of the scope of this reaction, we have synthesized
cyclooctanic mimetics of sugars using a TIBAL-mediated
Claisen rearrangement.3,4 We now want to bridge the gap
between these two families of carbocycles, describing the
synthesis of cycloheptanic sugar mimetics, as shown in
Scheme 1.
Various methods have been used for the conversion of
sugars into seven-membered carbocycles including ring-
closing metathesis,5,6 free radical-mediated cyclization,5,7
1,3-dipolar cycloadditions,8 intramolecular nucleophilic
attack,9 and ring enlargement of cyclohexanones.10
Although the Claisen rearrangement has been extensively
studied in sugar chemistry,11 it has not been used for
cycloheptane synthesis from sugars. Similarly, TIBAL
promoted Claisen rearrangement has been widely used for
cyclooctane formation,12 but only one report of such a
reaction has been found for a cycloheptane synthesis.13 As
we previously developed a TIBAL promoted reductive
Scheme 1. Carbocyclic sugar mimetics.
2. Results and discussion
Claisen rearrangement for cyclooctene formation from
The synthesis of the key diene 1 was achieved as shown in
pyranic rings,3,4 we assumed that a similar reaction could
be used for the construction of a cycloheptene ring from
furanic compounds (Scheme 2).
Scheme 3. The known alcohol 2,14 was paramethoxy
benzylated to afford 3 in almost quantitative yield.
Compound 3 was then hydrolysed in the presence of silver
nitrate in an acetone/water mixture; Wittig olefination on
the resulting hexose 4 gave the unsaturated alcohol 5 in 66%
yield and this alcohol was converted into the corresponding
triflate using triflic anhydride and pyridine in dichloro-
methane at 2408C. On heating, this triflate was displaced by
nucleophilic attack of O-2, and subsequent debenzylation
Keywords: carbohydrates; carbasugars; cycloheptanes; Claisen
rearrangement; triisobutylaluminium.
*
Corresponding author. Tel.: þ33-1-44-32-33-90; fax: þ33-1-44-32-33-
97; e-mail: pierre.sinay@ens.fr
Present address: Institutul de chimie, Bv. Mihai Vitaezul 24, 1900
Timisoara, Roumania.
†
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01402-3

10190
E. Sisu et al. / Tetrahedron 58 (2002) 10189–10196
Dihydroxylation of the mixture of 9 and 10 with osmium
tetroxide, followed by conventional acetonide protection of
the resulting diol, and oxidation of the resulting alcohol with
pyridinium chlorochromate, afforded 12 and 13 in 55%
overall yield as a 5:4 separable mixture. Ketones 12 and 13
were then converted into cycloheptanic mimetics using the
same sequence: Tebbe olefination of the carbonyl, hydro-
boration/oxidation of the resulting alkene, and final
deprotection. (Scheme 5)
The hydroboration/oxidation step afforded a mixture of
isomers for both compounds 14 and 19. Assignment of the
stereochemistry of the cycloheptanic compounds was
achieved at this point by NMR spectroscopy. The coupling
constants: J1,2<J2,3<J3,4<9 Hz for a-D-glucopyranose
mimic 15 and J1,2<J2,3<8 Hz and J3,4<2 Hz for b-D-
mannopyranose mimic 20 were consistent with the data for
similar compounds17 and in agreement with the twist chair
conformation described for seven-membered rings.18 15 and
20 were then fully deprotected: acetonide removal with
TFA in a dioxane/water mixture, and benzyl removal
by hydrogenolysis afforded 18 (75%) and 23 (82%),
respectively. (Scheme 6)
Scheme 2. TIBAL promoted reductive Claisen rearrangement on sugars.
afforded 6 in 68% yield.15 Selective deprotection of C-7,
followed by tosylation, iodination and elimination16
uneventfully afforded the expected diene 1 in 30% overall
yield from the starting alcohol 2.
Not unexpectedly, diene 1 underwent a smooth Claisen
rearrangement catalyzed by TIBAL affording 9 and 10 in
76% yield as a 2:1 unseparable mixture, a side open-chain
product 11 being also isolated in 7% yield (Scheme 4).
Product 11 is the result of an hydroalumination–elimination
process, that has already been reported in related cases.3 The
Claisen rearrangement into cycloheptene is not quite as
efficient as for cyclooctene, probably due to the strain
induced by the furanic ring.
As expected, the 1H NMR spectrum of 18 and 23 has a close
analogy with that of a-D-glucopyranose19 and b-D-manno-
pyranose,20 respectively, a feature which fully qualifies 18
and 23 as cycloheptanic mimetics of their related sugars
(Table 1). Compounds 18 and 23 represent the first two
members of a new class of homologous carbasugars, which
Scheme 3. Synthesis of the key diene 1. Reagents and conditions: (i) PMBCl, NaH, DMF, rt, 12 h, (99%); (ii) AgNO3, acetone, H2O, rt, 48 h, (98%);
(iii) Ph3PMeBr/BuLi, DME, rt!808C, 25 min, (66%); (iv) Tf2O, Pyr, dichloromethane, 2408C!rt, 6 h, (68%); (v) DDQ, dichloromethane, H2O, rt, 4 h,
˚
(87%); (vi) TsCl, DMAP, Pyr, dichloromethane, rt, 8 h, (87%); (vii) (a) NaI, Bu4NI, DMSO, MS 4 A, 808C, 12 h; (b) DBU, DMSO, 4 A MS, 808C, 6 h, (93%,
˚
two steps).
Scheme 4. Action of TIBAL on diene 1. Reagents and conditions: (i) iBu3Al, toluene, 608C, 12 h, (9/10/11, 62:30:8, 83%).

E. Sisu et al. / Tetrahedron 58 (2002) 10189–10196
10191
Scheme 5. Chain elongation of cycloheptanes 9 and 10. Reagents and conditions: (i) (a) OsO4, NMO, MeCOMe/H2O, rt, 24 h; (b) Me2C(OMe)2, CSA CH2Cl2,
˚
rt, 15 h; (c) PCC, 4 A MS, CH2Cl2, rt, 2 h (12/13, 55:45, 56%, 3 steps); (ii) Tebbe reagent, THF/pyr. 2408C!rt, 36 h, (14, 63%; 19, 71%); (iii) BH3.THF, rt,
5 h then H2O2, aq NaOH, 508C, 3 h, (15/16, 75:25, 69%; 20/21, 7:3, 65%).
Scheme 6. Final deprotection in the synthesis of cycloheptanic sugar mimetics. Reagents and conditions: (i) TFA, dioxane/H2O, rt, 24 h, (17, 82%; 22 89%);
(ii) H2, Pd/C, EtOH/MeOH, rt, 5 h, (18, 92%; 23, 92%).
Table 1. Comparison of the coupling constants between the sugars and their analogues
Coupling constants (Hz)
a-D-glucopyranose19
18
b-D-mannopyranose20
23
J1,2
J2,3
J3,4
J4,5
3.6
9.5
9.5
9.5
2.6
7.8
7.8
9.3
1.5
3.8
10.0
9.8
2
2
8.8
8.6
We used carbasugar numbering for the cycloheptanic mimetic as shown on Scheme 6.
fills the gap between previously described cyclohexanic and
cyclooctanic sugar mimetics.
measured at 20^28C with a Perkin–Elmer Model 241
digital polarimeter, using a 10 cm, 1 mL cell. Chemical
Ionization Mass Spectra (CI-MS ammonia) and Fast Atom
Bombardment Mass Spectra (FAB-MS) were obtained with
a JMS-700 spectrometer. Elemental analyses were per-
3. Experimental
3.1. General
0
´
formed by Service de Microanalyse de l Universite Pierre et
Marie Curie, 4 Place Jussieu, 75005 Paris, France. 1H NMR
spectra were recorded with a Bruker AC 250 or a Bruker
DRX 400 or a Bruker Avance 600 spectrometer for
solutions in CDCl3 or CD3OD or D2O at ambient
Melting points were determined with a Bu¨chi model 535 mp
apparatus and are uncorrected. Optical rotations were

10192
E. Sisu et al. / Tetrahedron 58 (2002) 10189–10196
4.97 (d, 1H, J¼11 Hz, CH2Ph); 4.88 (d, 1H, J¼11 Hz,
CH2Ph); 4.85 (d, 1H, J¼10.8 Hz, CH2Ph); 4.84 (d, 1H,
J¼10 Hz, CH2Ph); 4.81 (d, 1H, J¼11.7 Hz, CH2Ph); 4.77
(d, 1H, J1,2¼8 Hz, H-1b); 4.73 (d, 1H, J¼11.9 Hz, CH2Ph);
4.60 (d, 1H, J¼11.9 Hz, CH2Ph); 4.57 (d, 1H, J¼11 Hz,
CH2Ph); 4.50 (d, 1H, J¼11.4 Hz, CH2Ph); 4.48 (d, 1H,
J¼10.8 Hz, CH2Ph); 4.45 (d, 1H, J¼11.9 Hz, CH2Ph); 4.07
(ddd, 1H, H-5a); 4.01 (t, 1H, J3,2¼9.2 Hz, H-3a); 3.82 (s,
3H, OCH3b); 3.80 (s, 3H, OCH3a); 3.72 (dd, 1H, J6b,5
¼
3.8 Hz, H-6ba); 3.65 (dd, 1H, J5,6a¼2 Hz, J6a,6b¼10 Hz,
H-6aa); 3.64 (t, 1H, J4,3¼J4,5¼9.2 Hz, H-4a); 3.63 (dd, 1H,
J1,2¼3.5 Hz, H-2a); 3.44 (dd, 1H, J1,2¼8 Hz, J2,3¼7.8 Hz,
H-2b); 3.21 (bs, 1H, OH). MS (CI): m/z¼588 (MþNH4).
Anal. calcd for C35H38O7: C%¼73.66, H%¼6.71; found
C%¼73.55, H%¼6.68.
Figure 1. Cycloheptane numbering for NMR assignment.
temperature. Assignment were aided by COSY experi-
ments. 13C NMR spectra were recorded at 62.9 MHz with a
Bruker AC 250 or at 100.6 MHz with a Bruker DRX 400 or
at 150.9 MHz with a Bruker DRX 600 spectrometer for
solutions in CDCl3 adopting 77.00 ppm for the central line
of CDCl3. Assignments were aided by J-mod technique and
proton–carbon correlation. Numbering of cycloheptanic
compounds is indicated on Fig. 1 (for compounds 18 and 23
see Scheme 6). Reactions were monitored by thin-layer
chromatography (TLC) on a precoated plate of silica gel 60
F254 (layer thickness 0.2 mm; E. Merck, Darmstadt,
Germany) and detection by charring with sulfuric acid.
Flash column chromatography was performed on silica gel
60 (230–400 mesh, E. Merck).
3.1.3. 7-O-(4-Methoxybenzyl)-3,4,5-tri-O-benzyl-D-
gluco-hept-1-enitol (5). A solution of Ph3PvCH2 in
DME (prepared by mixing Ph3PMeBr (9.8 g, 27.6 mmol),
BuLi (1.6 M in hexane, 17.25 mL, 27.6 mmol) in dry DME
(25 mL) at 2208C and then stirring for 3 h at room
temperature) was added dropwise at 08C to a solution of 4
(5.1 g, 9.2 mmol) and BuLi (1.6 M in hexane, 5.75 mL,
9.2 mmol) in dry DME (25 mL). The temperature was
raised to 808C for 20 min then cooled to 08C. The reaction
mixture was quenched with acetone (15 mL), filtered,
concentrated. Chromatography (toluene/AcOEt¼9:1) of
the residue gave 5 (3.38 g, 66%). [a]D¼þ24 (c¼1,
CHCl3). 1H NMR (CDCl3, 400 MHz): 7.75–7.30 (m,
3.1.1. Phenyl 2,3,4-tri-O-benzyl-6-O-(4-methoxybenzyl)-
1-thio-b-D-glucopyranoside (3). Sodium hydride (60% in
mineral oil, 0.9 g, 21.5 mmol) was added portionwise to a
cooled (08C) solution of 2 (5.3 g, 9.77 mmol) and
p-methoxybenzyl chloride (2.9 mL, 21.5 mmol) in DMF
(100 mL). The reaction mixture was stirred at rt overnight.
MeOH (5 mL) was added. The reaction mixture was stirred
for 1 h then concentrated. A solution of the residue in
dichloromethane was washed with water, dried (MgSO4)
and concentrated. The residue was chromatographed
(cyclohexane/AcOEt¼5:1) to give 3 (6.4 g, 99%). Mp
14H, H-arom.); 5.90 (ddd, 1H, J2,1a¼10 Hz, J2,1b
¼
17.2 Hz, J2,3¼7.3 Hz, H-2); 5.37 (dd, 1H, J1a,1b¼1.8 Hz,
H-1a); 5.32 (dd, 1H, H-1b); 4.89 (d, 1H, J¼11.3 Hz,
CH2Ph); 4.75 (d, 1H, J¼11.3 Hz, CH2Ph); 4.74 (d, 1H,
J¼11.7 Hz, CH2Ph); 4.68 (d, 1H, J¼11.6 Hz, CH2Ph); 4.64
(d, 1H, J¼11.5 Hz, CH2Ph); 4.59 (d, 1H, J¼11.5 Hz,
CH2Ph); 4.51 (d, 1H, J¼11.5 Hz, CH2Ph); 4.48 (d, 1H,
J¼11.6 Hz, CH2Ph); 4.27 (dd, 1H, J4,3¼6.2 Hz, H-3); 4.08
(quin, 1H, J6,7a¼J6,7b¼J6,5¼J6,OH¼5 Hz, H-6); 3.85 (s, 1H,
OCH3); 3.82 (dd, 1H, J4,5¼3.6 Hz, H-4); 3.78 (dd, 1H, H-5);
3.67–3.60 (m, 2H, H-7a, H-7b); 2.91 (d, 1H, OH). MS (CI):
m/z¼586 (MþNH4). Anal. calcd for C36H40O6: C%¼76.03,
H%¼7.09; found C%¼75.97, H%¼7.18.
1
65–668C, [a]D¼þ6 (c¼0.75, CHCl3). H NMR (CDCl3,
400 MHz): 7.70–6.90 (m, 24H, H-arom); 4.93 (d, 1H,
J¼11 Hz, CH2Ph); 4.91 (d, 1H, J¼10.2 Hz, CH2Ph); 4.89
(d, 1H, J¼11 Hz, CH2Ph); 4.85 (d, 1H, J¼10.8 Hz, CH2Ph);
4.78 (d, 1H, J¼10.3 Hz, CH2Ph); 4.72 (d, 1H, J1,2¼9.8 Hz,
H-1); 4.61 (d, 1H, J¼10.8 Hz, CH2Ph); 4.60 (d, 1H,
J¼11.6 Hz, CH2Ph); 4.52 (d, 1H, J¼11.6 Hz, CH2Ph);
3.85 (s, 3H, OCH3); 3.80 (dd, 1H, J6a,6b¼11 Hz, J6a,5¼2 Hz,
H-6a); 3.78 (dd, 1H, J6a,5¼4 Hz, H-6b); 3.75 (t, 1H,
J3,4¼J3,2¼9 Hz, H-3); 3.68 (t, 1H, J4,5¼9 Hz, H-4); 3.55
(dd, 1H, H-2); 3.53 (ddd, 1H, H-5). MS (CI): m/z¼680
(MþNH4). Anal. calcd for C41H42O6S: C%¼74.29,
H%¼6.38; found C%¼74.29, H%¼6.39.
3.1.4. 7-O-(4-Methoxybenzyl)-4,5-di-O-benzyl-3,6-an-
hydro-L-ido-hept-1-enitol (6). Triflic anhydride (2.2 mL,
13 mmol) was added dropwise at 2408C to a solution of 5
(1.91 g, 3.46 mmol) in a mixture of dichloromethane
(25 mL) and pyridine (5 mL). The temperature was
maintained at 240 to 2208 C for 4 h, then slowly raised
to room temperature over night. MeOH (10 mL) was added
at 08C. The reaction mixture was concentrated. A solution of
the residue in dichloromethane was washed with water, aq
NaHCO3, dried (MgSO4) and concentrated. Chromato-
graphy on silica gel (cyclohexane/AcOEt¼5:1) of the
residue gave 6 (1.08 g, 68%). [a]D¼þ37 (c¼1.5, CHCl3).
1H NMR (CDCl3, 400 MHz): 7.40–7.60 (m, 14H, H-arom);
6.11 (ddd, 1H, J2,1a¼17 Hz, J2,1b¼10 Hz, J2,3¼7.7 Hz,
H-2); 5.43 (dt, 1H, J1a,1b¼J1a,3¼1.6 Hz, H-1a); 5.33
(dddd, 1H, J1b,3¼0.8 Hz, H-1b); 4.65 (dd, 1H, J3,4¼4 Hz,
H-3); 4.66 (d, 1H, J¼11.5 Hz, CH2Ph); 4.62 (d, 1H,
J¼12.2 Hz, CH2Ph); 4.60 (d, 1H, J¼12.3 Hz, CH2Ph);
4.56 (d, 1H, J¼12 Hz, CH2Ph); 4.55 (d, 1H, J¼12.2 Hz,
CH2Ph); 4.52 (d, 1H, J¼11.5 Hz, CH2Ph); 4.50 (dt, 1H
3.1.2. 2,3,4-Tri-O-benzyl-6-O-(4-methoxybenzyl)-a,b-D-
glucopyranose (4). Silver nitrate (5 g, 29.4 mmol) was
added to a solution of 3 (6.4 g, 11.5 mmol) in acetone/water
(120 mL, v/v 5:1). The mixture was stirred for 3 days,
filtered and concentrated. A solution of the residue in
dichloromethane was washed with water, aq. NaHCO3,
dried (MgSO4) and concentrated. Chromatography of the
residue on silica gel (cyclohexane/AcOEt 2:1), gave 4
(5.24 g, 98%). 1H NMR (CDCl3, 400 MHz): 7.50–6.70 (m,
19H, H-arom); 5.27 (d, 1H, J1,2¼3.4 Hz, H-1a); 4.99 (d,
1H, J¼11 Hz, CH2Ph); 4.98 (d, 1H, J¼10.9 Hz, CH2Ph);

E. Sisu et al. / Tetrahedron 58 (2002) 10189–10196
10193
J6,7¼6.2 Hz, J6,5¼4 Hz, H-6); 4.15 (dd, 1H, J5,4¼1.5 Hz,
H-5); 4.01 (dd, 1H, H-4); 3.86 (s, 3H, OCH3); 3.82 (dd, 1H,
J7a,7b¼9.7 Hz, H-7a); 3.77 (dd, 1H, H-7b). MS (CI):
m/z¼478 (MþNH4). Anal. calcd for C29H32O5:
C%¼75.62, H%¼7.00; found C%¼75.62, H%¼6.95.
CH2Ph); 4.50 (d, 1H, J1a,1b¼1.7 Hz, H-1a); 4.44 (d, 1H,
J¼12.2 Hz, CH2Ph); 4.43 (d, 1H, J¼11.8 Hz, CH2Ph); 4.20
(d, 1H, J3,4¼1.5 Hz, H-3); 4.10(d, 1H, H-1b);3.90(dd, 1H, H-
4). MS (CI): m/z¼340 (MþNH4). Anal. calcd for C21H22O3:
C%¼78.23, H%¼6.88; found C%¼78.11, H%¼7.08.
3.1.5. 4,5-Di-O-benzyl-3,6-anhydro-L-ido-hept-1-enitol
(7). A solution of DDQ (518 mg, 2.28 mmol), 6 (700 mg,
1.52 mmol) in dichloromethane/water (21 mL, 20:1 v/v)
was stirred overnight, diluted with dichloromethane
(25 mL), washed with 20% aq NaOH, water, dried
(MgSO4) and concentrated. Column chromatography
(cyclohexane/AcOEt¼3:1) of the residue gave 7 (450 mg,
87%). [a]D¼þ41 (c¼0.65 CHCl3). 1H NMR (CDCl3,
400 MHz): 7.20–7.40 (m, 10H, H-arom); 6.10 (ddd, 1H,
J2,1a¼10 Hz, J2,1b¼17 Hz, J2,3¼7 Hz, H-2); 5.46 (dt, 1H,
J1b,1a¼J1a,3¼1.2 Hz, H-1a); 5.35 (dt, 1H, J1b,3¼1.2 Hz,
H-1b); 4.67 (dd, 1H, J3,4¼4 Hz, H-3); 4.63 (d, 1H,
J¼11.9 Hz, CH2Ph); 4.62 (d, 1H, J¼12.2 Hz, CH2Ph);
4.58 (d, 1H, J¼12.2 Hz, CH2Ph); 4.48 (d, 1H, J¼11.9 Hz,
CH2Ph); 4.36 (q, 1H, J6,5¼J6,7a¼J6,7b¼5 Hz, H-6); 4.19
(dd, 1H, J5,4¼2 Hz, H-5); 4.05 (dd, 1H, H-4); 3.92 (dd, 1H,
J7a,7b¼11.8 Hz, H-7a); 3.84 (dd, 1H, H-7b); 2.40 (s, 1H,
OH). MS (CI): m/z¼358 (MþNH4). Anal. calcd for
C21H24O4: C%¼74.09, H%¼7.10; found C%¼73.94,
H%¼7.13.
3.1.8. (1R and 1S,2R,3S)-1-Hydroxy-2,3-dibenzyloxy-
cyclohept-4-ene (9) and (10). A mixture of a triisobutyl-
aluminum (1 M solution in toluene, 6.5 mL, 6.5 mmol), 1
(600 mg, 1.85 mmol) in dry dichloromethane (8 mL) was
stirred in a Schlenk tube under argon for 12 h at 608C, then
cooled (08C) and diluted with ethyl acetate (10 mL) and
water (2 mL), filtered dried (MgSO4) and concentrated. The
residue was chromatographed (toluene/AcOEt/MeCOMe¼
95:4:1) to give a mixture of 9 and 10 (430 mg, 76%,
1
9/10¼2:1 from H NMR), 11 (40 mg, 7%) and 1 (40 mg,
7%). 9þ10 (0): 1H NMR (CDCl3, 400 MHz): 7.30–7.50 (m,
20H, H-arom); 6.02–5.95 (m, 2H, H-5, H-50); 5.80 (ddd,
0
0
0
0
0
0
0
1H, J4 ,5 ¼11.5 Hz, J4 ,3 ¼3.4 Hz, J4 ,6a ¼2 Hz, H-4 ); 5.75
(dd, 1H, J4,5¼11.4 Hz, J4,3¼4 Hz, H-4); 5.12 (d, 1H,
J¼11.2 Hz, CH2Ph0); 4.90 (d, 1H, J¼11.5 Hz, CH2Ph);
4.79 (d, 1H, J¼11.7 Hz, CH2Ph0); 4.72 (d, 1H, J¼11.7 Hz,
CH2Ph); 4.70 (d, 1H, J¼11.7 Hz, CH2Ph0); 4.69 (d, 1H,
J¼11.6 Hz, CH2Ph); 4.66 (d, 1H, J¼11.7 Hz, CH2Ph); 4.65
(d, 1H, J¼11.2 Hz, CH2Ph0); 4.50 (dd, 1H, J3,2¼8.5 Hz,
H-3); 4.23–4.18 (m, 2H, H-30, H-1); 3.70 (td, 1H, J1 ,7a
¼
0
0
J1 ,2 ¼8.5 Hz, J1 ,7b ¼3.5 Hz, H-10); 3.67 (dd, 1H,
0
0
0
0
0
0
0
0
3.1.6. 7-O-Tosyl-4,5-di-O-benzyl-3,6-anhydro-L-ido-
hept-1-enitol (8). A solution of 7 (450 mg, 1.32 mmol),
tosyl chloride (1.26 g) and DMAP (cat.) in dry pyridine
(5 mL) was stirred 24 h at rt, diluted with MeOH (5 mL)
and concentrated. Column chromatography (cyclo-
hexane/AcOEt¼4:1) of the residue gave 8 (570 mg, 87%).
Mp 50–518C [a]D¼þ14 (c¼1.7, CHCl3). 1H NMR (CDCl3,
400 MHz): 7.90 (d, 2H, Ts); 7.20–7.40 (m, 12H, H-arom);
6.01 (ddd, 1H, J2,1a¼10 Hz, J2,1b¼17.5 Hz, J2,3¼7 Hz H-2);
5.37 (dt, 1H, J1b,1a¼J1a,3¼1.5 Hz, H-1a); 5.30 (dt, 1H,
J1b,3¼1.5 Hz, H-1b); 4.53 (d, 1H, J¼12.2 Hz, CH2Ph); 4.52
(d, 1H, J¼11.8 Hz, CH2Ph); 4.51 (dd, 1H, H-3); 4.50 (d, 1H,
J¼12.2 Hz, CH2Ph); 4.45 (d, 1H, J¼11.8 Hz, CH2Ph); 4.44
(td, 1H, J6,7a¼J6,7b¼6.5 Hz, J6,5¼4.2 Hz, H-6); 4.32 (dd,
1H, J7a,7b¼9.7 Hz, H-7b); 4.20 (dd, 1H, H-7a); 4.09 (dd, 1H,
J5,6¼4.1 Hz, J5,4¼1.4 Hz, H-5); 3.92 (dd, 1H, J4,3¼3.7 Hz,
H-4); 2.50 (s, 3H, Tos). MS (CI): m/z¼512 (MþNH4). Anal.
calcd for C28H30O6S: C%¼67.99, H%¼6.11; found
C%¼67.91, H%¼5.78.
J2,1¼3.1 Hz, H-2); 3.40 (t, 1H, J2 ,1 ¼J2’,3 ¼8.5 Hz, H-2 );
3.10 (s br, 1H, OH0); 2.70 (s br, 1H, OH); 2.41–2.31 (m, 1H,
H-6a); 2.30–2.21 (m, 1H, H-6a0); 2.08–1.97 (m, 3H, H-7a0,
H-6b0, H-6b); 1.87 (dtd, 1H, J7a,7b¼13.6 Hz, J¼8.2, 8.2,
2.4 Hz, H-7a); 1.76 87 0(ddt, 1H, J¼10.5, 3, 3 Hz, H-7b);
1.60–1.50 (m, 1H, H-7 b). MS (CI): m/z¼342 (MþNH4).
Anal. calcd for C21H24O3: C%¼77.74, H%¼7.45; found
C%¼77.61, H%¼7.61.
3.1.9. (3S,4S,5R)-3,4-Dibenzyloxy-5-hydroxy hepta-1,6-
1
diene (11). [a]D¼223 (c¼1.3, CHCl3). H NMR (CDCl3,
400 MHz): 7.35 (m, 10H, H-arom); 5.95 (ddd, 1H,
J2,1a¼17.5 Hz, J2,1b¼10 Hz, J2,3¼7.5 Hz, H-2); 5.90 (ddd,
1H, J6,7a¼17.2 Hz, J6,7b¼10.4 Hz, J6,5¼5.3 Hz, H-6);
5.46–5.39 (m, 2H, H-1); 5.32 (dt, 1H, J7a,7b¼J7a,5¼1.6 Hz,
H-7a); 5.19 (dt, 1H, J7b,6¼1.5 Hz, H-7b); 4.88 (d, 1H,
J¼11.1 Hz, CH2Ph); 4.69 (d, 1H, J¼10.9 Hz, CH2Ph); 4.43
(d, 1H, J¼11.7 Hz, CH2Ph); 4.33–4.29 (m, 1H, H-5); 4.10
(dd, 1H, J3,4¼6 Hz, H-3); 3.47 (dd, 1H, J4,5¼3.5 Hz, H-4);
2.54 (d, 1H, JOH,5¼6.9 Hz, OH); MS (CI): m/z¼342
(MþNH4); Anal. calcd for C21H24O3: C%¼77.74,
H%¼7.45; found C%¼77.70, H%¼7.64.
3.1.7. (3S,4R,5S)-3,4-Di-benzyloxy-2-methylene-5-vinyl-
(560 mg,
tetrahydrofurane (1).
A
mixture of
8
˚
1.13 mmol), 4 A molecular sieve (0.5 g), NaI (1.1 g,
6.78 mmol) and Bu4NI (6.30 mg, 1.69 mmol) in anhydrous
DMSO (6 mL) was stirred at 808C for 7 h. The mixture was
cooled to room temperature, and DBU (0.7 mL, 2.26 mmol)
was added, the mixture was then stirred overnight at 908C,
cooled to room temperature, diluted with AcOEt (25 mL),
filtered through Celite, concentrated. Chromatography
3.1.10. (2R and 2S,3R,4S,5S)-4,5-Dihydroxy-4,5-O-iso-
propylidene-2,3-di-benzyloxy-cylohept-1-one (12 and
13).
A
solution of N-morpholin-oxide (130 mg,
0.96 mmol) and OsO4 (2.5% solution in tertbutanol,
0.048 mL, 0.005 mmol) and (9þ10, 155 mg) in acetone/
water (20 mL, 8:1¼v/v) was stirred for 24 h at room
temperature, diluted with dichloromethane (20 mL) and
1 M aq HCl (3 mL), stirred for 30 min. The organic layer
was separated, concentrated to 5 mL treated for 1 h with
1.5 mL 10% aq. Na2S2O5, washed with water, dried
(MgSO4) and concentrated. Column chromatography
(cyclohexane/AcOEt¼1:2) gave to an mixture of diols
(95 mg) directly engaged in the next step.
(cyclohexane/AcOEt¼95:5) of the residue gave
1
(340 mg, 93%). [a]Dþ3 (c¼1.3, CHCl3). 1H NMR
(CDCl3, 250 MHz): 7.50–7.20 (m, 10H, H-arom); 6.00
(ddd, 1H, J6,7a¼17 Hz, J6,7b¼10.3 Hz, J5,6¼7.6 Hz, H-6);
5.35 (dt, 1H, J7a,7b¼J7a,5¼1.5 Hz, H-7a); 5.25 (ddd, 1H,
J7b,5¼1.5 Hz, H-7b); 4.75 (dd, 1H, J4,5¼3.8 Hz, H-5); 4.63
(d, 1H, J¼11.8 Hz, CH2Ph); 4.51 (d, 1H, J¼12.2 Hz,

10194
E. Sisu et al. / Tetrahedron 58 (2002) 10189–10196
A solution of diols (95 mg, 0.27 mmol), 2,2-dimethoxy
propane (3.5 mL) and CSA (cat) in dry dichloromethane
(3.5 mL) was stirred overnight at room temperature, diluted
with dichloromethane (25 mL), washed with sat. aq.
NaHCO3, dried (MgSO4) and concentrated. Chromato-
graphy (cyclohexane/AcOEt¼3.5:1) gave a mixture of
isopropylidene derivatives (90 mg, 85%).
ether (30 mL), filtered through Celite. The organic solution
was concentrated. Flash chromatography (cyclohexane/
AcOET/EtOH¼6:1:0.1) of the residue gave 14 (126 mg,
63%). [a]D¼þ85 (c¼0.8, CHCl3). 1H NMR (CDCl3,
400 MHz): 7.50–7.30 (m, 10H, H-arom); 5.18 (t, 1H,
J8a,8b¼J8a,2¼1.9 Hz, H-8a); 5.10 (t, 1H, J8b,2¼1.9 Hz,
H-8b); 4.84 (d, 1H, J¼11.9 Hz, CH2Ph); 4.78 (d, 1H,
J¼11.9 Hz, CH2Ph); 4.53 (d, 1H, J¼11.8 Hz, CH2Ph); 4.31
A
mixture of isopropylidene derivatives (90 mg,
(d, 1H, J¼11.8 Hz, CH2Ph); 4.20 (dt, 1H, J5,4¼ J5,6a¼
˚
0.226 mmol), PCC (155 mg, 0.7 mmol), 4 A molecular
sieve (150 mg) in anhydrous dichloromethane (5 mL) under
argon was stirred for 2 h., diluted with dichloromethane
(25 mL) and ether (10 mL), filtered through Celite. The
organic phase was dried (MgSO4), concentrated and the
residue was chromatographed (cyclohexane/AcOEt¼5:1) to
give 12 and 13 (58 mg, 65% ratio 12/13¼5/4).
7.1 Hz, J5,6b¼8.7 Hz, H-5); 4.12 (dd, 1H, J4,3¼10 Hz, H-4);
4.10 (d, 1H, J2,3¼4 Hz, H-2); 3.85 (dd, 1H, H-3); 2.53–2.45
(m, 1H, H-7a); 2.24 (ddd, 1H, J7a,7b¼14.7 Hz, J7b,6a
¼
10.8 Hz, J7b,6b¼8.2 Hz, H-7b); 2.04–1.97 (m, 2H, H-6a,
H-6b). 13C NMR (CDCl3, 150 MHz): 144.1 (1C, C1); 138.6,
138.0 (2C, Cquat. CH2Ph); 128.3, 128.1, 128.1, 127.9,
127.6, 127.3, (10C, 2£CH2Ph); 108.2 (1C, CMe2); 87.8 (1C,
C2); 82.6 (1C, C3); 76.8 (1C, C4); 75.2 (1C, C5); 73.1 69.6
(2C, CH2Ph); 27.6 (12C, C7); 27.1, 24.0 (2C, C (CH3)2);
26.2 (1C, C6). MS (CI): m/z¼412 (MþNH4). Anal. calcd
for C25H30O4: C%¼76.11, H%¼7.66; found C%¼75.51,
H%¼7.89.
12: [a]D¼þ10 (c¼0.5, CHCl3). 1H NMR (CDCl3,
400 MHz): 7.30–7.50 (m, 10H, H-arom); 4.71 (d, 1H,
J¼11.6 Hz, CH2Ph); 4.70 (d, 1H, J¼11.8 Hz, CH2Ph); 4.64
(d, 1H, J¼11.8 Hz, CH2Ph); 4.41 (d, 1H, J¼11.6 Hz,
CH2Ph); 4.40 (dt, 1H, J5,4¼6.8 Hz, J5,6¼3.5 Hz, H-5); 4.34
(t, 1H, J4,3¼7.1 Hz, H-4); 4.29 (d, 1H, J2,3¼3.4 Hz, H-2);
4.01 (dd, 1H, H-3); 2.85 (ddd, 1H, J7a,6b¼5.2 Hz,
J7a,6a¼8.5 Hz, J7a,7b¼16.5 Hz, H-7a); 2.35 (ddd, 1H,
J7b,6a¼4.6 Hz, J7b,6b¼7.5 Hz, H-7b); 2.22–2.10 (m, 2H,
H-6a, H-6b); 1.46, 1.25 (2 s, 6H, C(CH3)2). 13C NMR
(CDCl3, 150 MHz): 206.7 (1C, CO); 137.6, 137.1 (2C,
Cquat. CH2Ph); 128.4, 128.3, 128.2, 128.0, 127.9, 127.8
(10C, CH2Ph); 108.5 (1C, C (CH3)2); 87.2 (1C, C2); 80.2
(1C, C3); 76.6 (1C, C4); 74.4 (1C, C5); 72.8, 72.1 (2C,
2£CH2Ph); 36.6 (1C, C7); 25.9, 24.6 (2C, C(CH3)2); 23.7
(1C, C6). MS (CI): m/z¼414 (MþNH4). Anal. calcd for
C24H28O5: C%¼72.70, H%¼7.11; found C%¼72.58,
H%¼7.31.
3.1.12. (1R and 1S,2R,3S,4S)-1-Hydroxymethyl-2,3-
dibenzyloxy-4,5-isopropylidene-cycloheptane (15 and
16). BH3 (1 M solution in THF 0.5 mL, 0.5 mmol) was
added to solution of 14 (100 mg, 0.25 mmol) in THF (2 mL)
at 08C. The reaction mixture was stirred for 5 h at rt,
quenched with water (0.2 mL). Aq 3N NaOH (0.17 mL,
0.5 mmol) and H2O2 (30%, 0.15 mL, 1.5 mmol) were added
to the cooled (08C) solution. The reaction mixture was
stirred for 1 h at rt then 3 h at 45–508C. The cooled (208C)
solution was extracted with ethyl ether (50 mL), dried
(MgSO4), and concentrated. Column chromatography
(chloroform/AcOEt¼9:1) of the residue gave 15 and 16
(73 mg, 69%), (15/16¼11:3).
13: [a]D¼228 (c¼0.8, CHCl3). 1H NMR (CDCl3,
400 MHz): 7.40 (m, 10H, H-arom); 4.75 (d, 1H, J¼12 Hz,
CH2Ph); 4.69 (dd, 1H, J4,3¼2.5 Hz, J4,5¼7.7 Hz, H-4); 4.69
(d, 1H, J¼12 Hz, CH2Ph); 4.55 (d, 1H, J¼11.6 Hz, CH2Ph);
4.50 (ddd, 1H, J5,6a¼9.4 Hz, J5,6b¼4 Hz, H-5); 4.43 (d, 1H,
15: [a]D¼þ74 (c¼0.3, CHCl3). 1H NMR (CDCl3,
400 MHz): 7.40 (m, 10H, H-arom); 5.06 (d, 1H,
J¼10.9 Hz, CH2Ph); 4.93 (d, 1H, J¼11.2 Hz, CH2Ph);
4.88 (d, 1H, J¼11.2 Hz, CH2Ph); 4.60 (d, 1H, J¼10.9 Hz,
CH2Ph); 4.33 (dd, 1H, J4,3¼8.6 Hz, J4,5¼7 Hz, H-4); 4.15
(ddd, 1H, J5,6a¼11 Hz, J5,6b¼4 Hz, H-5); 3.72 (t, 1H,
J3,2¼9 Hz, H-3); 3.63–3.58 (m, 2H, H-8a, H-8b); 3.29 (t,
1H, J2,1¼9.5 Hz, H-2); 2.50 (br s, 1H, OH); 1.95–1.88 (m,
1H, H-6a,); 1.88–1.75 (m, 2H, H-1, H-7a); 1.66–1.55 (m,
1H, H-6b); 1.50, 1.40 (2s, 2£CH3); 1.21–1.10 (m, 1H,
H-7b). 13C NMR (CDCl3, 100 MHz): 138.7, 137.8, (2C,
Cquat. CH2Ph); 128.5, 128.5, 128.2, 128.1, 127.9, 127.4,
(10C, CH2Ph); 107.9 (1C, C(CH3)2); 83.8 (1C, C3); 82.3
(1C, C2); 80.5 (1C, C4); 76.7 (1C, C1); 75.8 (1C, CH2Ph);
75.5 (1C, CH2Ph); 66.7 (1C, C8); 47.4 (1C, C1); 28.9 (1C,
C6); 27.6, 24.8 (2C, C(CH3)2); 24.9 (1C, C7). MS (CI)
m/z¼413 (MþH). Anal. calcd for C25H32O5: C%¼72.79,
H%¼7.82; found C%¼72.67, H%¼8.00.
16: [a]D¼þ35 (c¼0.5, CHCl3). 1H NMR (CDCl3,
400 MHz): 7.50–7.20 (m, 10H, H-arom); 5.31 (d, 1H,
J¼11.4 Hz, CH2Ph); 4.88 (d, 1H, J¼11.8 Hz, CH2Ph); 4.75
(d, 1H, J¼11.4 Hz, CH2Ph); 4.60 (d, 1H, J¼11.8 Hz,
CH2Ph); 4.25 (dd, 1H, J4,3¼10 Hz, J4,5¼7 Hz, H-4); 4.10–
4.00 (m, 3H, H-2, H-3, H-5); 3.55 (dd, 1H, J8a,8b¼10.4 Hz,
J8a,1¼8 Hz, H-8a); 3.40 (dd, 1H, J8b,1¼4.8 Hz, H-8b);
2.05–1.98 (m, 2H, H-6a, H-6b); 1.73–1.63 (m, 1H, H-7a);
J¼11.6 Hz, CH2Ph); 4.15 (dd, 1H, J2,3¼6.6 Hz, J2,7b
¼
1.2 Hz, H-2); 4.09 (dd, 1H, H-3); 2.70 (ddd, 1H,
J7a,7b¼14.2 Hz, J7a,6a¼10.8 Hz, J7a,6b¼3.3 Hz, H-7a); 2.53
(dddd, 1H, J7b,6a¼2.6 Hz, J7b,6b¼8.6 Hz, J7b,2¼1.2 Hz,
H-7b); 2.26 (dddd, 1H, J6a,6b¼13.8 Hz, H-6a); 2.10 (dddd,
1H, H-6b); 1.52, 1.40 (2s, 1H, C (CH3)2). 13C NMR (CDCl3,
150 MHz): 208.0 (1C, CO); 137.8, 136.8 (2C, Cquat.
CH2Ph); 127.6, 127.5, 128.5, 128.2, 128.2, 128.1, (10C,
2£CH2Ph); 107.8 (1C, CMe2); 84.9 (1C, C2); 77.4 (1C, C3);
76.9 (1C, C4); 76.2 (1C, C5); 73.8 (1C, CH2Ph); 72.5 (1C,
CH2Ph); 35.3 (1C, C7); 26.1 (1C, CH3); 25.5 (1C, C6); 24.3
(1C, CH3), MS (CI): m/z¼414 (MþNH4). Anal. calcd for
C24H28O5: C%¼72.70, H%¼7.11; found C%¼72.78,
H%¼7.19.
3.1.11. (2R,3R,4S,5S)-2,3-Di-benzyloxy-4,5-O-isopropyl-
idene-methylenecycloheptane (14). Tebbe reagent (1 M in
toluene, 2, mL, 2 mmol) was added to a solution of 12
(150 mg, 0.378 mmol) in THF/Pyridine (2 mL 1:1 v/v) at
2408C. The reaction mixture was stirred at 2408C for
30 min, at rt for 1.5 day, cooled to -258C and diluted with
acetone (2 mL) and triethylamine (2 mL) then with ethyl

E. Sisu et al. / Tetrahedron 58 (2002) 10189–10196
10195
1.62, 1.38 (2s, 6H C(CH3)2); 1.5–1.42 (m, 1H, H-1); 1.21
(ddt, 1H, J7a,7b¼18.5 Hz, J7b,6a¼7.5 Hz, J7b,6b¼J7b,5¼5.3
Hz, H-7b). 13C NMR (CDCl3, 100 MHz): 140.3, 139.8 (2C,
Cquat. CH2Ph); (10C, 2£CH2Ph); 107.7 (1C, CMe2); 85.3
(1C, C3); 82.2 (1C, C2); 79.8 (1C, C4); 76.1 (1C, C5); 74.7
(1C, CH2Ph); 73.2 (1C, CH2Ph); 65.4 (1C, C8); 41.3 (1C,
C1); 27.8, 24.4 (2C, CMe2); 27.0 (1C, C6); 21.1 (1C, C7);
MS (CI): m/z¼430 (MþNH4); Anal. calcd for for
C25H32O5: C%¼72.79, H%¼7.82; found C%¼72.39,
H%¼8.20.
1H, J2,3¼6.3 Hz, H-2); 4.04 (dd, 1H, H-3); 2.35 (br dd, 1H,
J6a,7a¼6.8 Hz, J6a,6b¼12 Hz, H-6a); 2.25–2.09 (m, 3H,
H-6b, H-7a, H-7b); 1.53, 1.40 (2s, 6H, CMe2). 13C NMR
(CDCl3, 150 MHz): 145.6 (1C, C1); 139.9, 138.3 (2C,
Cquat. CH2Ph); 128.3, 128.0, 127.4, 127.4, 127.3, 127.1,
(10C, 2£CH2Ph); 117.5 (1C, C8); 107.6 (1C, CMe2); 81.9
(1C, C2); 79.5 (1C, C3); 77.3 (1C, C4); 76.9 (1C, C5); 73.7,
69.9 (2C, 2£CH2Ph); 29.4 (1C, C7); 27.3 (1C, C6); 26.5,
24.4 (2C, CMe2); MS (CI): m/z¼412 (MþNH4); Anal.
calcd for (C25H30O4)·H2O: C%¼72.79, H%¼7.82; found
C%¼72.99, H%¼7.62.
3.1.13. (1R,2R,3S,4S)-1-Hydroxymethyl-2,3-dibenzyl-
oxy-4,5-dihydroxy-cycloheptane (17). Trifluoroacetic
acid (2 mL) was added to a solution of 15 (38 mg,
0.09 mmol) in dioxane/water (0.1 mL, 4:1 v/v) at room
temperature. After 24 h, the mixture is neutralized with
concentrated aq NH3 and concentrated, the residue was
chromatographed (cyclohexane/AcOEt¼1:2) to afford 17
3.1.16. (1R and 1S,2R,3R,4R)-1-Hydroxymethyl-2,3-
dibenzyloxy-4,5-isopropylidene-cycloheptane (20 and
21). 19 (80 mg, 0.2 mmol) was treated with BH3 as
described for 15 and 16 to give after flash chromatography
(cyclohexane/AcOEt¼3:1) 20 and 21 (54 mg, 65%,
20/21¼2.7:1).
1
(28 mg, 82%) as a an oil. H NMR (CDCl3, 400 MHz):
7.41–7.30 (m, 10H, H-arom); 4.84 (d, 1H, J¼11.5 Hz,
CH2Ph); 4.80 (d, 1H, J¼11.4 Hz, CH2Ph); 4.67 (d, 1H,
J¼11.4 Hz, CH2Ph); 4.62 (d, 1H, J¼11.5 Hz, CH2Ph);
4.07–4.02 (m, 1H, H-5); 3.92 (dd, J2,1¼J2,3¼7 Hz, H-2);
3.90 (dd, 1H, J4,3¼7 Hz, J4,5¼3 Hz, H-4); 3.65 (dd, 1H,
H-3); 3.65 (dd, J8a,1¼7 Hz, J8a,8b¼11 Hz, H-8a); 3.58 (dd,
J8b,1¼5 Hz, H-8b); 2.12–2.07 (m, 1H, H-1); 1.92–1.75 (m,
3H, H-6a, H-6b, H-7a); 1.50–1.39 (m, 1H, H-7b). 13C NMR
(CDCl3, 100 MHz): 137.5, 137.4 (2C, Cquat. CH2Ph);
128.6, 128.5, 128.079, 128.0, 127.9, (10C, 2£CH2Ph); 82.1
(1C, C3); 80.6 (1C, C2); 74.7 (1C, C4); 74.3, 73.7 (2C,
2£CH2Ph); 70.4 (1C, C5); 65.6 (1C, C8); 44.7 (1C, C1);
28.8 (1C, C6); 21.2 (1C, C7); HRMS, m/z¼373.201
(MþH): calcd for C22H29O5¼373.472.
20: [a]D¼þ37 (c¼0.5, CHCl3). 1H NMR (CDCl3,
400 MHz): 7.40 (m, 10H, H-arom); 4.98 (d, 1H, J¼11 Hz,
CH2Ph); 4.90 (d, 1H, J¼12 Hz, CH2Ph); 4.79 (d, 1H,
J¼12 Hz, CH2Ph); 4.62 (d, 1H, J¼11 Hz, CH2Ph); 4.55 (dd,
1H, J4,5¼8.4 Hz, J4,3¼1.8 Hz, H-4); 4.30 (ddd, 1H,
J5,6a¼2 Hz, J5,6b¼6 Hz, H-5); 3.88 (dd, 1H, J1,2¼8.3 Hz,
J2,3¼8 Hz, H-2); 3.68 (dd, 1H, J8a,8b¼10.9 Hz,
J8a,1¼6.2 Hz, H-8a); 3.63 (dd, 1H, H-3); 3.61 (dd, 1H,
J8b,1¼4 Hz, H-8b); 2.60 (s, 1H, OH); 2.10 (m, 1H,
J6a,7b¼6 Hz, J6a,7a¼4.7 Hz, J6a,6b¼10 Hz, H-6a); 1.78–
1.69 (m, 1H, H-1); 1.45–1.58 (m, 3H, H-6b, H-7a, H-7b).
13C NMR (CDCl3, 100 MHz): 138.2, 137.9 (2C, Cquat.
CH2Ph); 128.5, 128.4, 128.3, 128.0, 127.8, 127.6 (10C,
2£CH2Ph); 81.5 (1C, C3); 80.7 (1C, C2); 77.8 (1C, C4);
74.6 (1C, CH2Ph); 74.5 (1C, CH2Ph); 74.1 (1C, C5); 66.9
(1C, C8); 46.6 (1C, C1); 28.2 (1C, C6); 23.7, 25.9 (2£CH3);
21.1 (1C, C7). MS (CI) m/z¼413 (MþH). Anal. calcd for
C25H32O5: C%¼72.78, H%¼7.81; found C%¼72.64,
H%¼8.00.
3.1.14. Cycloheptanic a-D-glucopyranose mimetic (18).
A solution of 17 (33 mg) in EtOH/MeOH (0.3 mL, 1:1) was
stirred under hydrogen for 5 h in the presence of 10% Pd/C
(cat) at rt. The reaction mixture was filtered, concentrated to
1
give 18 (19 mg, 92%). H NMR (D2O, 600 MHz): 3.99
21: [a]D¼221 (c¼0.4, CHCl3). 1H NMR (C6D6,
400 MHz): 7.40–7.20 (m, 10H, H-arom); 5.08 (d, 1H,
J¼11.9 Hz, CH2Ph); 4.80 (dd, 1H, J4,5¼7.8 Hz,
J4,3¼2.6 Hz, H-4); 4.65 (d, 1H, J¼11.9 Hz, CH2Ph); 4.45
(d, 1H, J¼11.4 Hz, CH2Ph); 4.40 (ddd, 1H, 4.28 (dd, 1H,
J3,2¼6.8 Hz, H-3); 4.04 (dd, 1H, J5,6a¼11.1 Hz,
J5,6b¼5.5 Hz, H-5); 4.38 (d, 1H, J¼11.4 Hz, CH2Ph); 4.28
(dd, 1H, J3,2¼6.8 Hz, H-3); 4.04 (dd, 1H, J2,1¼2.5 Hz, H-2);
3.55 (dd, 1H, J8a,8b¼10.4 Hz, J8a,1¼8 Hz, H-8a); 3.4 (dd,
1H, J8b,1¼5.1 Hz, H-8b); 2.48–2.38 (m, 1H, H-6a); 2.27–
2.18 (m, 1H, H-6b); 2.18–2.10 (m, 1H, H-1); 1.71, 1.42 (2 s,
6H, CMe2); 1.50–1.35 (m, 2H, H-7a, H-7b). 13C NMR
(C6D6, 100 MHz): 140.1, 139.1 (2C, Cquat. CH2Ph); 129.1,
129.0, 128.8, 128.5, 128.1 (10C, 2£CH2Ph); 108.3 (1C,
CMe2); 78.7 (1C, C5); 78.1 (1C, C3); 77.9 (1C, C4); 77.4
(1C, C2); 75.3 (1C, CH2Ph); 73.2 (1C, CH2Ph); 66.0 (1C,
C8); 43.4 (1C, C1); 30.2 (1C, C6); 27.6, 24.9 (2C, CMe2);
21.3 (1C, C7); MS (CI) m/z¼413 (MþH). Anal. calcd for
C25H32O5: C%¼72.79, H%¼7.82; found C%¼72.72,
H%¼8.13.
00
00
(ddd, 1H, J1,5 a¼8 Hz, J1,5 b¼5 Hz, J1,2¼2.7 Hz, H-1); 3.69
(dd, 1H, J6a,6b¼11 Hz, J6a,5¼4.1 Hz, H-6a); 3.66 (t, 1H,
J3,2¼J3,4¼7.8 Hz, H-3); 3.63 (dd, 1H, H-2); 3.57 (dd, 1H,
J6b,1¼6.5 Hz, H-6b); 3.33 (dd, 1H, J4,5¼9.3 Hz, H-4);
1.90–1.84 (m, 1H, H-500a); 1.79–1.75 (m, 1H, H-50a); 1.74–
00
00
1.68 (m, 1H, H-5); 1.64 (dddd, 1H, J5 b,5 a¼18.4 Hz,
J¼10.4 Hz, J¼8 Hz, J¼3.2 Hz, H-500b); 1.35 (dddd, 1H,
J5 b,5 a¼17.8 Hz, J¼10.3 Hz, J¼9.3 Hz, J¼3.1 Hz, H-50b).
13C NMR (D2O, 150 MHz): 74.9 (1C, C4); 74.7 (2C, C2,
C3); 70.4 (1C, C1);044.4 (1C, C6); 44.4 (1C, C5); 28.7 (1C,
C500); 22.4 (1C, C5 ). HRMS, m/z¼193.107 (MþH) calcd
for C8H17O5¼193.221.
0
0
3.1.15. (2R,3R,4R,5R)-2,3-Di-benzyloxy-4,5-O-isopropyl-
idene methylenecycloheptane (19). The ketone 13
(140 mg, 0.352 mmol) was treated with Tebbe reagent as
described for 14. Chromatography (cyclohexane/AcOEt¼
6:1) gave 19 (100 mg, 71%). [a]D¼242 (c¼1.2, CHCl3).
1H NMR (CDCl3, 400 MHz): 7.20–7.40 (m, 10H, H-arom);
5.16 (d, 1H, J8a,8b¼2 Hz, H-8a); 4.97 (d, 1H, H-8b); 4.79 (d,
1H, J¼12.1 Hz, CH2Ph); 4.74 (dd, 1H, J4,5¼7.8 Hz,
J4,3¼2.5 Hz, H-4); 4.67 (d, 1H, J¼12.1 Hz, CH2Ph); 4.54
(d, 1H, J¼12 Hz, CH2Ph); 4.42 (ddd, 1H, J5,6a¼5.9 Hz,
J5,6b¼9.3 Hz, H-5); 4.29 (d, 1H, J¼12 Hz, CH2Ph); 4.12 (d,
3.1.17. 1-Hydroxymethyl-2,3-dibenzyloxy-4,5-dihydroxy
cycloheptane (22). 20 (35 mg, 0.084 mmol) was reacted
with trifluoroacetic acid as described for 17 to give 22

10196
E. Sisu et al. / Tetrahedron 58 (2002) 10189–10196
(28 mg, 89%). 1H NMR (CDCl3, 400 MHz): 7.30–7.40 (m,
10H, H-arom); 4.78 (d, 1H, J¼11.6 Hz, CH2Ph); 4.68 (d,
1H, J¼11.3 Hz, CH2Ph); 4.66 (d, 1H, J¼11.3 Hz, CH2Ph);
2. Das, S. K.; Mallet, J.-M.; Sinay¨, P. Angew. Chem., Int. Ed.
Engl. 1997, 36, 493–496.
3. Sollogoub, M.; Mallet, J.-M.; Sinay¨, P. Angew. Chem., Int. Ed.
Engl. 2000, 39, 360–363.
4.49 (d, 1H, J¼11.6 Hz, CH2Ph); 4.10 (br d, 1H, J3,2
¼
4. Wang, W.; Zhang, Y.; Sollogoub, M.; Sinay¨, P. Angew. Chem.,
Int. Ed. Engl. 2000, 39, 2466–2467. Wang, W.; Zhang, Y.;
4.5 Hz, H-3); 4.04 (br m, 1H, H-5); 4.00 (br s, 1H, H-4);
3.68 (dd, 1H, J2,1¼6 Hz, H-2); 3.65 (dd, 1H, J8a,8b
¼
´
Zhou, H.; Bleriot, Y.; Sinay¨, P. Eur. J. Org. Chem. 2001,
1053–1059.
10.5 Hz, J8a,1¼4.6 Hz, H-8a); 3.57 (dd, 1H, J8b,1¼5.2 Hz,
H-8b); 2.12–2.05 (m, 1H, H-6a); 1.82–1.65 (m, 3H, H-7b,
H-6b, H-1); 1.55–1.45 (m, 1H, H-7a). 13C NMR (CDCl3,
100 MHz): 137.7, 137.2 (2C, Cquat. CH2Ph); 128.8, 128.7,
128.5, 128.3, 128.1, 127.9, 127.9 (10C, 2£CH2Ph); 86.7
(1C, C3); 78.3 (1C, C2); 74.2 (1C, CH2Ph); 73.7 (1C, C5);
72.5 (1C, CH2Ph); 86.7 (1C, C3); 78.3 (1C, C2); 74.2 (1C,
CH2Ph); 73.7 (1C, C5); 72.5 (1C, CH2Ph); 71.0 (1C, C4);
66.7 (1C, C8); 32.5 (1C, C6); 20.5 (1C, C7). HRMS,
m/z¼373.201 (MþH), calcd for C22H28O5¼373.472.
5. Marco-Contelles, J.; de Opazo, E. J. Org. Chem. 2002, 67,
3705–3717.
6. Marco-Contelles, J.; de Opazo, E. Tetrahedron Lett. 2000, 41,
2439–2441. Hanna, I.; Ricard, L. Org. Lett. 2000, 2,
2651–2654.
7. Marco-Contelles, J.; de Opazo, E. Tetrahedron Lett. 2000, 41,
5341–5345.
´
8. Duclos, O.; Dureault, A.; Depezay, J. C. Tetrahedron Lett.
1992, 33, 1059–1062. Marco-Contelles, J.; de Opazo, E.
Tetrahedron Lett. 1999, 40, 4445–4448.
9. Dyong, I.; Bonn, R. Chem. Ber. 1973, 106, 944–955. Krohn,
3.1.18. Cycloheptanic b-D-mannopyranose mimetic (23).
Deprotection of 22 (26 mg) as described for 18 gave 23
(15 mg, 92%). 1H NMR (D2O, 600 MHz): 4.02 (t, 1H,
¨
K.; Borner, G. J. Org. Chem. 1994, 59, 6063–6068.
00
10. Cocu, F. G.; Pochelon, B.; Giddey, A.; Posternak, T. Helv.
Chim. Acta 1974, 57, 1974–1987. Boyer, F.-D.; Lallemand,
J.-Y. Tetrahedron 1994, 50, 10443–10458.
J2,1¼J2,3¼2 Hz, H-2); 3.83 (td, 1H, J1,5 b¼7.4 Hz, H-1);
3.69 (dd, 1H, J6a,6b¼11 Hz, J6a,5¼4 Hz, H-6a); 3.60 (dd,
1H, J3,4¼8.8 Hz, H-3); 3.52 (dd, 1H, J6b,5¼7 Hz, H-6b);
3.50 (t, 1H, J4,5¼8.6 Hz, H-4); 1.88–1.65 (m, 2H, H-6a,
H-7a); 1.61–1.55 (m, 3H, H-6b, H-7b, H-1). 13C NMR
(D2O, 150 MHz): 76.2 (1C, C2); 75.7 (1C, C3); 75.2 (1C,
C4); 71.8 (1C, C1); 64.3 (1C, C6); 43.5 (1C, C5); 27.5 (1C,
C50); 22.1 (1C, C500); HRMS, m/z¼193.107 (MþH): calcd
for C8H16O5¼193.221.
11. Wershkun, B.; Thiem, T. Top. Curr. Chem. 2001, 215,
293–325.
12. Paquette, L. A.; Friedrich, D.; Rogers, R. D. J. Org. Chem.
1991, 56, 3841–3849. Paquette, L. A.; Philippo, C. M. G.; Vo,
N. H. Can. J. Chem. 1992, 70, 1356–1365.
13. Mori, I.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron 1984,
40, 4013–4018.
14. Motawia, M. S.; Marcussen, J.; Møller, B. L. J. Carbohydr.
Chem. 1995, 14, 1279–1294.
References
15. Martin, O. R.; Yang, F.; Xie, F. Tetrahedron Lett. 1995, 36,
47–50.
´
1. Sollogoub, M.; Pearce, A. J.; Herault, A.; Sinay¨, P.
16. Sato, K.-I.; Kubo, N.; Takada, R.; Sakuma, S. Bull. Chem. Soc.
Jpn. 1993, 66, 1156–1165.
Tetrahedron: Asymmetry 2000, 11, 283–294. Recent
syntheses of carbasugars: Gomez, A. M.; Moreno, E.;
Valverde, S.; Lopez, J. C. Tetrahedron Lett. 2002, 43,
5559–5562. Zanardi, F.; Battistini, L.; Marzocchi, L.;
Acquotti, D.; Rassu, G.; Pinna, L.; Auzzas, L.; Zambrano,
V.; Casiraghi, G. Eur. J. Org. Chem. 2002, 1956–1965.
Perlmutter, P.; Rose, M. J. Carbohydr. Chem. 2002, 21, 1–10.
Mehta, G.; Lakshminath, S.; Talukdar, P. Tetrahedron Lett.
2002, 43, 335–338. Ferrier, R. J. Top. Curr. Chem. 2001, 215,
277–291. Mehta, G.; Talukdar, P.; Mohal, N. Tetrahedron
Lett. 2001, 42, 7663–7666. Gravier-Pelletier, C.; Maton, W.;
Lecourt, T.; Le Merrer, Y. Tetrahedron Lett. 2001, 42,
4475–4778.
17. Redlich, H.; Sudau, W.; Szardenings, A. K.; Vollerthum, R.
Carbohydr. Res. 1992, 226, 57–78. Boyer, F.-D.; Lallemand,
J.-Y. Tetrahedron 1994, 50, 10443–10458. Pearson, A. J.;
Katiyar, S. Tetrahedron 2000, 56, 2297–2304. Duclos, O.;
´
Mondange, M.; Dureault, A.; Depezay, J. C. Tetrahedron Lett.
1992, 33, 8061–8064.
18. Bocian, D. F.; Strauss, H. L. J. Am. Chem. Soc. 1977, 99,
2876–2882. Dell’Erba, A.; Melandri, S.; Caminati, W.;
Favero, P. G. Chem. Phys. Lett. 1997, 278, 31–34.
19. Koch, H. J.; Perlin, A. S. Carbohydr. Res. 1970, 15, 403–410.
20. Angyal, S. J.; Pickles, V. A. Aust. J. Chem. 1972, 25,
1695–1710.