Preparation and reactions of 2-allyl-5-deoxymannose derivatives

Article abstract of DOI:10.1016/S0040-4020(02)00150-3

Reaction of Danishefsky diene with benzyloxyethanal led to a pyrone which was transformed in 4-6 steps to different 5-deoxymannose derivatives, useful intermediates for the synthesis of natural product such as hemibrevetoxin.

Full text of DOI:10.1016/S0040-4020(02)00150-3

TETRAHEDRON
Pergamon
Tetrahedron 58 52002) 2891±2897
Preparation and reactions of 2-allyl-5-deoxymannose derivatives
p
Â
Twana Saleh and Gerard Rousseau
  à Â
Laboratoire des Carbocycles, Institut de Chimie Moleculaire d'Orsay, Universite de Paris-Sud, Bat.420, $Associe au CNRS),
91405 Orsay, France
Received 19 October 2001; revised 14 January 2002; accepted 4 February 2002
AbstractÐReaction of Danishefsky diene with benzyloxyethanal led to a pyrone which was transformed in 4±6 steps to different
5-deoxymannose derivatives, useful intermediates for the synthesis of natural product such as hemibrevetoxin. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
2. Results
Hemibrevetoxin B is a natural marine product of a family of
red tide toxins possessing biological properties including
antimicrobial activity and neurotoxicity.1 This 6,6,7,7-tetra-
cyclic ether contains 10 stereogenic centres. 5Fig. 1) More
complex structures including the brevetoxins, maitotoxins,
ciguatoxins or others have been reported.2
2.1. Preparation of racemic 2-a-allyl-6-benzyloxy-5-
deoxymannose derivatives
Our approach was based on the work of Danishefsky
concerning the hetero Diels±Alder reaction of aldehydes
with 1-methoxy-3-5trimethylsilyloxy)-1,3-butadiene. Follow-
ing the already described procedure,6 the racemic enone 1
was prepared and stereoselectively reduced by diisobutyl-
aluminum hydride to the allylic alcohol 2 5Scheme 2).
Reaction of this latter compound with m-chloroperbenzoic
acid in the presence of methanol gave the diol 3a. Only one
diastereoisomer was obtained, the stereochemistry of which
was deduced from its 1H NMR spectra. Similarly, the
reactions were conducted in the presence of 2-methoxy-
ethanol and benzylalcohol to give, respectively, the diols
3b and 3c. In view of the subsequent allylation reaction,
different protecting groups for the diols were then
examined. Reaction of diols 3a±c with excess of acetic
anhydride led to the diacetates 4a±c. In acetonitrile, in the
presence of a catalytic amount of boron tri¯uoride diethyl
etherate, only the diacetate 4b led to the desired allylic
compounds 5 and 6, in seven days. The structure of these
HO
H
H
CH3
O
H
A
O
O
H
O
O
H
H
H
CH3
OH
Figure 1.
The total synthesis of hemibrevetoxin B has been accom-
plished by several groups.3 Except for the Nakata strategy,3d
the approaches required the construction of the A-ring ®rst.
For example, Nicolaou3b reported the preparation of this
ring in 12 steps from d-mannose 5Scheme 1). Our interest
in the synthesis of hemibrevetoxin, by a iterative method,4
led us to research a shorter preparation of 2-alkyl-5-
deoxymannose derivatives.5
1
two diastereoisomers was determined from their H NMR
spectra, and con®rmed in the case of compound 5, by
comparison to the spectra of diol 7 5Scheme 2), formed by
cleavage of the two acetate functions, with those reported in
the literature.3b
OH
OBn
HO
HO
OH
OH
OTBS
BnO
To improve the rate of the allylation reaction, we decided
next to examine the behaviour of the dibenzyl ethers 8a,b.
As expected, these compounds were much more reactive 52
days for compound 8a and 12 h for compound 8b) and in
both cases the allylic compounds 9, 10 were obtained in
good yields 5Scheme 2). The stereochemistry of these two
O
O
D-mannose
Scheme 1.
Keywords: 2-allyl-5-deoxymannose; Danishefsky diene; hemibrevetoxin.
Corresponding author. Tel.: 133-1-69-15-7860; fax: 133-1-69-15-62-
78; e-mail: grousseau@icmo.u-psud.fr
1
p
diastereoisomers was deduced from their H NMR spectra,
2D NOESY experiment and con®rmed in the case of
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020502)00150-3

2892
T.Saleh, G.Rousseau / Tetrahedron 58 $2002) 2891±2897
OCH3
O
OH
O
DIBAL-H
ZnCl2/ C6H6
+
BnO
toluene
-78 ˚C
0 ˚C to rt, 36 h
OSi(CH3)3
H
BnO
BnO
O
O
2(100 %)
(92%)
1
OH
OAc
OH
OR
OAc
OR
Ac2O
pyridine
mCPBA/ROH
0 ˚C, 2 h
BnO
BnO
O
O
(95%)
R = CH
3a
3b
3
4a-c (100 %)
R = CH3OCH2CH
2 (83%)
3c R = Bn (62%)
OAc
OAc
OAc
SiMe3
OAc
BF3.Et2O/CH3CN
+
BnO
BnO
rt, 7 days
O
O
(for 4b)
5 (73%)
6 (3%)
96: 4
OH
OH
K2CO3
MeOH
5
BnO
O
7 (100%)
OBn
OBn
OBn
SiMe3
OBn
OR
OBn
OBn
BrBn/NaH
THF, 12 h
BF3.Et2O/CH3CN
rt, 2 days
+
3a,b
O
O
O
BnO
BnO
BnO
9
10
96: 4
8a
(89%)
R = CH3
total yield: 80 % from 8a, 74 % from 8b
8b R = CH3OCH2CH2
(96%)
Scheme 2.
compound 9 by comparison of its NMR spectra with those
of the product formed by dibenzylation of the diol 7.
three benzyl ether functions of compound 9. Differentiation
between the two benzyl functions in the 3 and 4 position was
easily realised by iodoetheri®cation.7 In acetonitrile in the
presence of iodine compound 9 led to a mixture of the two
products 11, 12 5mixture of two diastereoisomers) which
after reaction with zinc in methanol±THFwas converted
to the 3-hydroxy compound 13 5Scheme 3). This two step
selective cleavage of a benzyl ether has precedent in the
literature.8
2.2. Differentiation of the alcohol functions of 2-a-allyl-
5-deoxymannose derivatives
In our objective to prepare intermediates which can be
useful for the synthesis of hemibrevetoxin, it would be
interesting to ®nd procedures to discriminate between the
OBn
OBn
OBn
OBn
I2/MeCN
O
O
+
0 ˚C to rt, 12 h
RO
RO
O
RO
O
I
O
I
11 (50:50)
16 (50:50)
12
17
9 R = Bn
14 R = Ac
OBn
OH
Zn/MeOH/MeCN
rt, 12 h
RO
O
13 R = Bn (74 % from 9)
18 R = Ac (79 % from 14)
Scheme 3.

T.Saleh, G.Rousseau / Tetrahedron 58 $2002) 2891±2897
2893
OBn
O
OBn
SiMe3
OBn
OBn
BF3.Et2O then Ac2O
0 ˚C to rt, 48 h
8b
+
AcO
AcO
O
15 (4%)
14 (77%)
Scheme 4.
Wong reported that allylation of 6-benzyloxymethyl
sugars led in one pot to 6-acetyloxymethyl derivatives
if, the reaction was quenched by addition of acetic
anhydride.9 We applied this procedure to the allylation of
compound 8b, and obtained a mixture 595:5) of the two
diastereoisomers 14, 15 5Scheme 4). As in the case of
compound 9, reaction of compound 14 with iodine in
acetonitrile led to a mixture of the two iodoethers 16, 17
which after reaction with zinc led to the monoalcohol 18
5Scheme 3).
reduction step. After benzylation, enantiomerically enriched
compound 52S,3S,4S,6S)-8b 5[a]Dˆ117.0, cˆ1, CHCl3)
was transformed, as in the racemic series, into the allylic
compounds 9, 10 596:4) 5overall yield: 76%). The major
diastereoisomer 9 was treated with iodine in acetonitrile
leading to a mixture of compounds 11, 12 5see Scheme 3)
which after reaction with zinc provided the desired enantio-
merically enriched monoalcohol 52R,3S,4S,6S)-13 5overall
yield: 74%) [a]Dˆ119.5 5cˆ1, CHCl3).
2.4. Preparation of 2-b-allyl-6-benzyloxy-5-deoxy-
mannose derivatives
Cleavage of the acetate function on the mixture of products
16, 17 and protection as a t-butyldiphenylsilylether led to a
mixture of compounds 19, 20 which by reaction with zinc
yielded the alcohol 21 5Scheme 5).
b-C-Glycosidic natural products have been reported,13 and
due to the interesting biological properties of compounds
possessing this stereochemistry,14 it seemed interesting to
prepare the still unknown 2-b-allyl-5-deoxymannose
derivatives. Numerous methods have been reported to
prepare 2-b-C-glycosides.15 We decided to use the method
published by Kishi.16 Reaction 5808C, 36 h) of 8a or 8b with
a mixture 51:1) of sulphuric acid 51N) and acetic acid led to
the hemiacetal 22 5Scheme 6). This compound was oxidised
into the unstable lactone 23 by PCC in methylene chloride.
Without puri®cation, the addition of allylmagnesium
chloride at 2408C to this lactone led to the desired unstable
alcohol 24, whose stereochemistry was deduced from its 1H,
13C and 2D spectra. Reduction of the alcohol function using
a large excess of triethylsilane in methylene chloride in the
presence of boron tri¯uoride led to a 80:20 mixture of the
two diastereoisomers 10, 9.
2.3. Preparation of enantiomerically enriched 2-a-allyl-
6-benzyloxy-5-deoxymannose derivatives
Numerous methods have been reported for asymmetric
hetero-Diels±Alder.10 We chose the method described by
Jacobsen, for the simplicity of the reaction conditions.11
Reaction of the Danishefsky diene with benzyloxyethanal
in the presence of the Jacobsen catalyst12 led to enone 5S)-1
in moderate yield 560%). Its enantiomeric excess 590%) was
determined by chiral gas chromatography on 4,4-
dimethoxy-2-hydroxymethyltetrahydropyran. This latter
was formed by reduction of enone 5S)-1 by hydrogen in
methanol in the presence of Pd/C. Reduction of the ketone
function of enone 1 with DIBAL±H at 2788C led to allylic
alcohol 52S,4S)-2 5[a]Dˆ19.1, cˆ1, CHCl3) followed by
epoxidation using m-chloroperbenzoic acid in the presence
of methoxyethanol led in quantitative yield to the enantio-
merically enriched diol 52S,3S,4S,6S)-3b 5[a]Dˆ126.6,
cˆ1, CHCl3) 5see Scheme 2). Its enantiomeric excess
measured by chiral HPLC was found to be 76%. The partial
racemisation observed seemed to occur during the enone
In conclusion, in this study we have shown that we were
able to prepare different 5-deoxymannose derivatives in
racemic and enantiomerically enriched forms. These
compounds should be interesting intermediates for the
synthesis of products possessing this deoxy sugar.
OBn
OBn
O
O
1) K2CO3/MeOH
+
2) ClSiPh2t-Bu
16,17
t-BuPh2SiO
t-BuPh2SiO
I
O
O
I
19
20
OBn
O
OH
Zn/MeOH/MeCN
rt, 12 h
t-BuPh2SiO
21 (75 %)
Scheme 5.

2894
T.Saleh, G.Rousseau / Tetrahedron 58 $2002) 2891±2897
OBn
O
OBn
OBn
O
OBn
OH
PCC / CH2Cl2
rt, 30 min
CH3COOH / H2SO4
8a,8b
BnO
75 ˚C, 3 h
BnO
O
23 78 %
22
(88% from 8a; 81 % from 8b)
OBn
MgCl
OBn
OH
/THF
HSiEt3/BF3.Et2O
- 50 ˚C to - 20 ˚C, 30 min
10 (42%) + 9 (12%)
BnO
-78 ˚C to 0 ˚C, 6 h
O
24 (61%)
Scheme 6.
3. Experimental
3.1.3. Preparation of ,2Sp,3Sp,4Sp,6Sp)-6-benzyloxy-
methyl-2-,2-methoxyethoxy)-tetrahydropyran-3,4-diol
3b. The reaction was conducted as reported for the prepara-
tion of compound 3a using methoxyethanol as alcohol. Oil,
3.1. General
1
83%. H NMR 5250 MHz, CDCl3) d 1.61±1.69 5m, 2H),
NMR spectra were recorded on 250 and 400 MHz spectro-
meters. Tetrahydrofuran and ether were distilled under
argon from sodium-benzophenone. Dichloromethane was
distilled from calcium hydride. Acetonitrile and pentane
were distilled from phosphoric anhydride. 51)-Dihydro-
pyrone 1 was prepared as previously reported6 in 93%
yield.
2.25 5bs, 1H), 2.41 5bs, 1H), 3.33 5s, 3H), 3.49±3.58 5m,
5H), 3.37±3.81 5m, 2H), 3.95 5m, 2H), 4.45 5s, 2H), 4.80 5d,
Jˆ1.3 Hz, 1H), 7.30 5s, 5H). 13C NMR 550 MHz, CDCl3) d
30.4, 58.6, 65.2, 66.1, 67.2, 68.4, 71.2, 72.4, 73.0, 100.3,
127.4±128.1 55C), 137.7. IR 5®lm) 3400, 3080, 2920, 1490,
1450, 740±695 cm21
. HMRS calcd for C16H24O6Na
5MNa1): 335.147056. Found: 335.147058. Anal. calcd for
C16H24O6: C, 61.03; H, 7.72. Found: C, 61.52; H, 7.74.
3.1.1. Preparation of ,2Sp,4Sp)-2-benzyloxymethyl-3,4-
dihydro-2H-pyran-4-ol 2. A solution of enone 1 50.86 g,
3.94 mmol) in toluene 58 mL) was cooled to 2788C. To this
was added dropwise a 1 M solution in toluene of diisobutyl-
aluminum hydride 55 mL, 5 mmol). After 15 min, methanol
was added 510 mL), followed by a saturated solution of
Rochelle salt 515 mL) and the mixture was allowed to
warm to rt. The reaction mixture was extracted with ethyl
acetate 54£20 mL), dried 5MgSO4) and concentrated. Flash
chromatography 570:30 ether±hexane) afforded 0.87 g
5100%) of pyranol 2.
3.1.4. Preparation of ,2Sp,3Sp,4Sp,6Sp)-2-benzyloxy-6-
benzyloxymethyltetrahydropyran-3,4-diol 3c. This
compound was prepared using the procedure reported for
1
the diol 3a using benzyl alcohol. Oil. H NMR 5250 MHz,
D2O±CDCl3) d 1.70 5m, 2H), 3.53 5d, Jˆ4.4 Hz, 2H), 3.74
5t, Jˆ2.2 Hz, 1H), 3.97 5m, 2H), 4.49 5d, Jˆ11.8 Hz, 1H),
4.57 5s, 2H), 4.72 5d, Jˆ11.8 Hz, 1H), 4.96 5d, J#0.5 Hz,
1H), 7.33 5m, 10H).
3.1.5. Preparation of ,2Sp,3Sp,4Sp,6Sp)-6-benzyloxy-
methyl-3,4-bisacetyloxy-2-methoxytetrahydropyran 4a.
To diol 3a 50.3 g, 1.12 mmol) was added acetic anhydride
50.316 mL, 3.36 mmol) and triethylamine 50.622 mL,
4.48 mmol). After one night at rt, the mixture was concen-
trated under vacuum and the residue was puri®ed by ¯ash
chromatography 5SiO2, 35:65 ether±pentane) to give
0.375 g of diacetate 4a as an oil 595%). 1H NMR
5200 MHz, CDCl3) d 1.72 5m, 2H), 1.91 5s, 3H), 2.03 5s,
3H), 3.28 5s, 3H), 3.46 5m, 2H), 3.94 5m, 1H), 4.50 5s, 2H),
4.66 5d, Jˆ1.6 Hz, 1H), 5.00 5d, Jˆ3.2 Hz, 1H), 5.60 5ddd,
Jˆ11.9, 5.3, 3.2 Hz, 1H), 7.23 5s, 5H). 13C NMR 550 MHz,
CDCl3) d 20.7, 28.0, 54.7, 66.5, 67.1, 67.6, 72.1, 73.0, 99.0,
127.8±128.1 55C), 137.9, 169.7, 170.0. MS m/z: 352, 320,
292, 277, 149, 133, 121, 92, 91, 75, 43. Anal. calcd for
C18H24O7: C, 61.55; H, 6.95. Found: C, 61.35; H, 6.86.
3.1.2. Preparation of ,2Sp,3Sp,4Sp,6Sp)-6-benzyloxy-
methyl-2-methoxy-tetrahydropyran-3,4-diol 3a. A solu-
tion of pyranol 2 52.0 g, 9.09 mmol) in methanol 560 mL)
was stirred for 10 min at 08C before addition dropwise of a
solution of m-chloroperbenzoic acid 52.6 g, 9.90 mmol) in
methanol. The solution was maintained at 08C for 2 h
before addition of a saturated solution of sodium bicarbo-
nate 530 mL). The mixture was stirred for 12 h at rt. The pH
of the solution was found to be between 7 and 8 and was
extracted with methylene chloride 52£50 mL). The organic
phase was then washed with brine, dried 5MgSO4) and
concentrated. Flash chromatography 52.5:97.5 methanol±
ether) afforded 2.31 g of diol 3a as a white solid. Mp: 80±
1
858C. H NMR 5250 MHz, D2O±CDCl3) d 1.59 5m, 2H),
3.36 5s, 3H), 3.54 5d, Jˆ4.5 Hz, 2H), 3.70 5dd, Jˆ1.9,
3.3 Hz, 1H), 3.91 5m, 2H), 4.58 5s, 2H), 4.77 5d,
Jˆ1.5 Hz, 1H), 7.30 5s, 5H). 13C NMR 550 MHz, CDCl3)
d 30.4, 54.7, 65.4, 67.1, 68.6, 72.5, 73.3, 101.4, 127.6±
128.3 55C), 137.7. IR 5®lm) 3395, 3020, 1450, 1360,
1020±1100 cm21. Anal. calcd for C14H20O5: C, 62.18; H,
7.41. Found: C, 62.67; H, 7.51.
3.1.6. Preparation of ,2Sp,3Sp,4Sp,6Sp)-6-benzyloxy-
methyl-3,4-bisacetyloxy-2-,2-methoxyethoxy)-tetrahydro-
pyran 4b. This compound was obtained using the procedure
reported for the diacetate 4a. Oil, 100%. 1H NMR
5250 MHz, CDCl3) d 1.80 5m, 2H), 2.00 5s, 3H), 2.08 5s,

T.Saleh, G.Rousseau / Tetrahedron 58 $2002) 2891±2897
2895
3H), 3.36 5s, 3H), 3.59 5m, 5H), 3.79 5m, 1H), 4.09 5m, 1H),
4.50 52d, Jˆ12.1 Hz, 2H), 4.88±4.89 5d, Jˆ1.3 Hz, 1H),
5.12 5d, Jˆ2.0 Hz, 1H), 5.29 5ddd, Jˆ3.2, 5.4, 11.6 Hz,
1H), 7.32 5s, 5H). 13C NMR 562.9 MHz, CDCl3) d 20.8,
28.1, 58.8, 66.7, 67.3, 67.8, 71.3, 72.2, 73.2, 98.2, 127.4±
128.2 55C), 138.0, 169.8, 170.0. Anal. calcd for C20H28O8:
C, 60.61; H, 7.18. Found: C, 60.59; H, 7.12.
After ®ltration over Celite, the solution was concentrated
under vacuum and the residue was puri®ed by ¯ash chro-
matography 530:70 ether±pentane) to give 3.88 g 598%) of
1
compound 8a. Oil H NMR 5400 MHz, CDCl3) d 1.90 5m,
1H), 1.93 5d, Jˆ12 Hz, 1H), 3.30 5s, 3H), 3.53 5ddd, Jˆ4.4,
6.3, 10.0 Hz, 2H), 3.67 5bs, 1H), 3.81 5dt, Jˆ4.4, 10.6 Hz,
1H), 3.88 5m, 1H), 4.50 5bs, 2H), 4.59 52d, Jˆ12.0 Hz, 2H),
4.73 52d, Jˆ12.4 Hz, 2H), 4.77 5s, 1H), 7.33 5m, 15H). 13C
NMR 550.3 MHz, CDCl3) d 28.7, 54.1, 67.7, 69.6, 71.6,
72.2, 72.8 52C), 73.5, 99.6, 126.8±127.9 515C), 138.0
53C). Anal. calcd for C27H30O5: C, 74.68; H, 7.14. Found:
C, 74.62; H, 6.96.
3.2. Allylation of compound 4b
To a solution of diacetate 4b 50.06 g, 0.15 mmol) in aceto-
nitrile 52 mL) at 08C was added allyltrimethylsilane
50.25 mL, 0.15 mmol), followed 15 min later by BF3´Et2O
50.125 mL, 0.1 mmol). The reaction was warmed to rt and
stirred for 12 h. Then allyltrimethylsilane 50.25 mL,
0.15 mmol) and BF3´Et2O 50.125 mL, 0.1 mmol) were
added and the reaction was stirred for another 12 h. The
reaction mixture was stirred for 7 days more, with sequential
addition each 12 h of allyltrimethylsilane and BF3´Et2O.
The reaction was quenched with NaHCO3 5sat., 2 mL),
extracted with methylene chloride 52£10 mL), washed
with brine, dried 5Na2SO4) and concentrated. Flash chroma-
tography 530:70 ether±pentane) afforded 40 mg 574%) of
allyl compounds 5, 6 5mixture 96:4 of two diastereoisomers
3.2.4. Preparation of ,2Sp,3Sp,4Sp,6Sp)-3,4-bisbenzyloxy-
6-benzyloxymethyl-2-,2-methoxy-ethoxy)-tetrahydro-
pyran 8b. This compound was obtained using the procedure
reported for the dibenzyl ether 8a. Oil. 1H NMR 5400 MHz,
CDCl3) d 1.85 5m, 2H), 3.34 5s, 3H), 3.47±3.62 5m, 6H),
3.80 5m, 1H), 3.92 5m, 2H), 4.52 5s, 2H), 4.58 5d,
Jˆ12.0 Hz, 2H), 4.75 52d, Jˆ12.4 Hz, 2H), 4.94 5d,
Jˆ1.0 Hz, 1H), 7.32 5m, 15H). 13C NMR 550 MHz,
CDCl3) d 28.9, 58.7, 66.0, 67.9, 69.9, 71.3, 72.4, 72.7,
72.9, 73.0, 73.7, 98.8, 127.5 515C), 138.2 52C). Anal.
calcd for C30H36O6: C, 73.15; H, 7.39. Found: C, 73.35;
H, 7.37. HMRS calcd for C30H36O6Na 5MNa1) 515.24095.
Found: 515.24095.
1
in H NMR spectra).
3.2.1. ,2Rp,3Sp,4Sp,6Sp)-2-Allyl-6-benzyloxymethyl-3,4-
bisacetyloxytetrahydropyran 5. 5Major diastereoisomer)
1H NMR 5250 MHz, CDCl3) d 1.88 5m, 2H), 2.02 5s, 3H),
2.12 5s, 3H), 2.46 5m, 2H), 3.56 5ddd, Jˆ4.5, 6.0, 10.1 Hz,
2H), 4.00 5m, 2H), 4.58 5s, 2H), 5.16 5m, 4H), 5.79 5m, 1H),
7.33 5s, 5H). 13C NMR 550.3 MHz, CDCl3) d 20.9, 21.0,
28.8, 33.8, 66.7, 68.6, 69.0, 72.2, 73.3, 75.0, 117.2, 127.5±
128.3 55C), 133.1, 138.0, 170.0, 170.3. Anal. calcd for
C20H26O6: C, 66.26; H, 7.23. Found: C, 65.95; H, 7.33.
HMRS calcd for C20H30O6N 5MNH41) 380.20729. Found:
380.20731.
3.3. Allylation of compound 8a
To a solution of tribenzyl ether 8a 50.117 g, 2.37 mmol) in
acetonitrile 56 mL) was added allyltrimethylsilane
50.81 mL, 5.11 mmol) at 08C, followed 15 min later by
BF3´Et2O 50.2 mL, 1.64 mmol). The reaction was warmed
to rt and stirred for 12 h. Then allyltrimethylsilane
50.414 mL,
2.61 mmol)
and
BF3´Et2O
50.1 mL,
0.83 mmol) were added and the reaction was stirred for
another 12 h. The same amounts of silane and BF3´Et2O
were again added and after 12 h the reaction was quenched
with NaHCO3 solution 5sat., 4 mL), extracted with methyl-
ene chloride 52£15 mL), washed with brine, dried 5Na2SO4)
and concentrated. Flash chromatography 520:80 ether±
pentane) afforded 0.815 g 580%) of allyl compounds 9, 10
3.2.2. Preparation of ,2Rp,3Sp,4Sp,6Sp)-2-allyl-6-benzyl-
oxymethyl-tetrahydropyran-3,4-diol 7. To a solution of
diacetate 5 50.04 g, 0.11 mmol) in methanol 52 mL) was
added K2CO3 52 mg). The mixture was stirred for 2 h at rt.
The solvent was removed under vacuum and THF53 mL)
was added to the residue. After ®ltration the solvent was
removed under vacuum. The crude allyl diol 7 533 mg,
100%) could be used without puri®cation. 1H NMR
5250 MHz, CDCl3) d 1.75 5m, 1H), 1.98 5dt, Jˆ5.0,
13.8 Hz, 1H), 2.35 5m, 2H), 3.15 5bs, 1H), 3.19 5bs, 1H),
3.41±3.62 5m, 4H), 3.84±3.96 5m, 2H), 4.56 5bs, 2H), 5.05±
5.15 5m, 2H), 5.81 5m, 1H), 7.24±7.37 5m, 5H). 13C NMR
562.9 MHz, CDCl3) d 32.0, 34.7, 65.6, 68.9, 69.9, 73.2,
73.5, 75.2, 117.2, 127.6±128.4 55C), 134.2, 137.5. HMRS
calcd for C16H22NaO45MNa1) 301.14157. Found:
301.14157.
1
5mixture 96:4 of the two diastereoisomers from H NMR
spectra).
3.3.1. ,2Rp,3Sp,4Sp,6Sp)-2-Allyl-3,4-bisbenzyloxy-6-benzyl-
oxymethyl-tetrahydropyran 9. 5Major diastereoisomer):
1H NMR 5250 MHz, CDCl3) 1.78 5dt, Jˆ4.0, 13.0 Hz,
1H), 2.00 5m, 1H), 2.32 5m, 2H), 3.46 5t, Jˆ3.0 Hz, 1H),
3.50 and 3.74 5ddd, Jˆ5.1, 6.7, 10.0 Hz, 2H), 3.78 5m, 1H),
3.90 5m, 1H), 4.08 5m, 1H), 4.43±4.65 5m, 6H), 5.04 5m,
2H), 5.78 5m, 1H), 7.32 5m, 15H). 13C NMR 562.9 MHz,
CDCl3) d 28.8, 34.3, 69.3, 69.6, 70.8, 71.3, 71.6, 72.4, 72.7,
74.3, 116.5, 126.1±127.7 515C), 133.8, 137.8 53C). Anal.
calcd for C30H34O4: C, 78.57; H, 7.47. Found: C, 77.97; H,
7.48.
3.2.3. Preparation of ,2Sp,3Sp,4Sp,6Sp)-3,4-bisbenzyloxy-
6-benzyloxymethyl-2-methoxy-tetrahydropyran 8a. To
sodium hydride 52 g, 83.7 mmol) washed twice with pen-
tane under argon, was added, at 08C THF550 mL), and
dropwise a solution of diol 3a 52.9 g, 11.9 mmol) in THF
550 mL). Thirty minutes after the end of the addition of the
diol, benzyl bromide 54.25 mL, 35.6 mmol) was introduced.
After one night at rt, methanol 510 mL) was added at 08C.
3.3.2. ,2Sp,3Sp,4Sp,6Sp)-2-Allyl-3,4-bisbenzyloxy-6-benzyl-
oxymethyl-tetrahydropyran 10. 5Minor diastereo-
isomer):1H NMR 5400 MHz, CDCl3) 1.90 5m, 2H), 2.31
5m, 1H), 2.47 5m, 1H), 3.28 5t, Jˆ7.0 Hz, 1H), 3.47 5dd,
Jˆ4.0, 9.2 Hz, 1H), 3.57±3.69 5m, 4H), 4.52±4.68 5m, 6H),
5.02 5m, 2H), 5.66 5m, 1H), 7.26±7.41 5m, 15H). 13C NMR

2896
T.Saleh, G.Rousseau / Tetrahedron 58 $2002) 2891±2897
550 MHz, CDCl3) d 29.3, 35.9, 70.0, 72.9, 73.3, 73.4, 74.0,
75.6, 78.5, 79.2, 117.0, 127.1±128.7 515C), 134.6, 138.2,
138.4, 138.8. HMRS 5MNa1) calcd 481.23547. Found:
481.23547.
with iodine 51.48 g, 5.80 mmol) in acetonitrile 530 mL), as
reported for the preparation of compound 8a, the crude
mixture of iodo ethers 16, 17 was diluted with methanol
540 mL) and a catalytic amount of K2CO3 50.05 g) was
added. After stirring for one night at rt, the methanol was
removed under vacuum and the residue was diluted in THF
530 mL). After ®ltration over Celite, the solvent was
removed under vacuum. The crude mixture of iodo alcohols
5100% yield) was diluted in dry THF530 mL), and imida-
zole 50.544 g, 8 mmol) and DMAP 540 mg) were added.
After 1 h of stirring at rt, the mixture was cooled at 08C
and t-butyldiphenylchlorosilane 50.9 mL, 4 mmol) was
added. The solution was stirred for 12 h at rt. The solvent
was removed, and the residue was puri®ed by ¯ash chroma-
tography 510:90 ether±pentane). Then the mixture of silyl-
iodo ether was treated with zinc as reported for the
3.3.3. Preparation of ,2Rp,3Sp,4Sp,6Sp)-2-allyl-4-benzyl-
oxy-6-benzyloxymethyl-tetrahydropyran-3-ol 13. To a
solution of tribenzyl ether 9 50.59 g, 1.29 mmol) in aceto-
nitrile 520 mL) was added at 08C iodine 50.982 g,
3.86 mmol). After stirring for 14 h in the dark, ether
5150 mL) and sodium sulphite 5sat. solution, 20 mL) were
added. The aqueous phase was extracted with ether
52£100 mL) and the organic phase was washed with brine
5sat. solution, 50 mL), dried 5MgSO4) and concentrated. The
crude residue was dissolved in a 1:1 mixture methanol±THF
510 mL), and zinc powder 50.6 g) was added. After 15 min,
®ve drops of acetic acid were added, and the mixture stirred
for 48 h. The mixture was ®ltered with Celite. The solution
was extracted with ether 53£300 mL), and the organic phase
was dried 5MgSO4) and concentrated. The residue was puri-
®ed by ¯ash chromatography 540:60 pentane±ether) to
afford 0.35 g 574%) of alcohol 13 as an oil. 1H NMR
5250 MHz, CDCl3) d 1.88 5m, 2H), 2.36 5m, 3H), 3.48
5dd, Jˆ5.3, 10.0 Hz, 1H), 3.69 5m, 2H), 3.79 5m, 1H),
3.90 5m, 1H), 3.98 5m, 1H), 4.58 5m, 4H), 5.10 5m, 2H),
5.84 5m, 1H), 7.33 5m, 5H). 13C NMR 563 MHz, CDCl3) d
28.2, 34.2, 67.6, 68.7, 69.8, 71.8, 72.9, 74.6, 116.7, 127.2±
128.1 510C), 134.1, 137.5, 137.9. HMRS 5MNa1) calcd
391.18852. Found: 391.18852.
1
preparation of alcohol 13. H NMR 5250 MHz, CDCl3) d
1.06 5s, 9H), 1.88 5m, 2H), 2.32 5m, 2H), 2.38 5m, 1H),
3.82±3.96 5m, 6H), 4.53±4.64 52d, Jˆ12 Hz, 2H), 5.06
5m, 2H), 5.81 5m, 1H), 7.37 5m, 11H), 7.56 5m, 4H). 13C
NMR 563 MHz, CDCl3) d 19.2, 26.8 53C), 28.4, 65.8, 68.2,
70.2, 70.3, 73.4, 74.9, 117.0, 127.6±129.6 515C), 133.5
52C), 134.4, 135.6, 137.7. HMRS calcd for C32H40NaSiO4:
5MNa1) 539.25935. Found: 539.25935.
3.3.7. Preparation of ,2Sp,3Sp,4Sp,6Sp)-3,4-bisbenzyloxy-
6-benzyloxymethyltetrahydropyran-2-ol 22. A solution
compound 8a 50.146 g, 0.32 mmol) in a mixture of
acetic acid 530 mL) and sulphuric acid 51 M sol, 0.65 mL)
was heated at 758C for 48 h. The solution was then con-
centrated under vacuum and the residue was dissolved in
methylene chloride 5100 mL). The organic phase was
washed with sodium bicarbonate 5sat. sol., 20 mL), dried
5MgSO4) and concentrated. Flash chromatography
530:70 ether±pentane) afforded 0.114 g 581%) of
3.3.4. Preparation of ,2Rp,3Sp,4Sp,6Sp)-2-allyl-6-acetyl-
oxymethyl-3,4-bisbenzyloxytetrahydropyran-3-ol
14.
The reaction was carried out as reported for the allylation
of compound 8a. However, before the quenching of the
reaction, acetic anhydride was added 56 mL for 4 mmol of
compound 8b) and the solution was stirred 3 h. Work-up
was then carried out as for the allylation of compound 8a.
After ¯ash chromatography 520:80 ether±pentane) a
mixture 96:4 of the two diastereoisomers 14, 15 was
obtained 577%). 1H NMR for 14 5250 MHz, CDCl3) d
1.74 5dt, Jˆ4.0, 13.0 Hz, 1H), 1.95 5m, 1H), 2.08 5s, 3H),
2.29 5t, Jˆ7.0 Hz, 2H), 3.42 5dd, Jˆ2.8, 4.7 Hz, 1H), 3.76±
3.95 5m, 2H), 4.06±4.16 5m, 2H), 4.35 5dd, Jˆ8.0, 11.7 Hz,
1H), 4.56 5s, 2H), 4.62 5s, 2H), 5.00 5m, 2H), 5.73 5m, 1H),
7.37 5m, 10H). 13C NMR 563 MHz, CDCl3) d 20.8, 29.1,
34.7, 65.7, 68.6, 70.5, 71.3, 71.7, 72.4, 75.1, 117.0, 127.5±
128.8 510C), 134.2, 138.1, 138.2, 170.9. HMRS 5MNa1)
calcd 433.19909. Found: 433.19909.
1
compound 22 as a white solid. Mp 108±1108C. H NMR
5250 MHz, CDCl3) d 1.85 5m, 2H), 2.55 5d, 1H), 3.55 5ddd,
Jˆ3.5, 6.0, 10.6 Hz, 2H), 3.72 5bs, 1H), 3.92 5ddd, Jˆ2.9,
4.4, 11.7 Hz, 1H), 4.17 5m, 1H), 4.59 5m, 4H), 4.75 52d,
Jˆ12.5 Hz, 2H), 5.28 5d, Jˆ1.5 Hz, 1H), 7.30 5m, 15H).
13C NMR 550 MHz, CDCl3) d 28.7, 67.5, 69.8, 72.3, 72.8,
72.9, 73.2, 93.1, 127.5 515C), 137.6, 138.0 53C), 138.2.
Anal. calcd for C27H30O5: C, 74.68; H, 7.14. Found: C,
74.62; H, 6.96.
3.3.8. Preparation of ,3Sp,4Sp,6Sp)-3,4-bisbenzyloxy-6-
benzyloxymethyltetrahydropyran-2-one 23. To a solution
of hemiketal 22 50.15 g, 0.355 mmol) in methylene chloride
Ê
512 mL) was added molecular sieve 4 A in powder 50.4 g).
3.3.5. Preparation of ,2Rp,3Sp,4Sp,6Sp)-2-allyl-4-benzyl-
oxy-6-acetyloxymethyltetrahydropyran-3-ol 18. The
reaction was carried out from compound 14 as reported
for the preparation of alcohol 13 579%). 1H NMR
5250 MHz, CDCl3) d 1.84 5m, 2H), 2.08 5s, 3H), 2.32 5m,
3H), 3.67 5m, 1H), 3.81 5m, 1H), 3.91 5m, 1H), 4.00 5m, 1H),
4.07 and 4.68 5ddd, Jˆ3.6, 3.8, 11.6 Hz, 2H), 4.54 5d,
Jˆ11.6 Hz, 1H), 4.65 5d, Jˆ11.6 Hz, 1H), 5.11 5m, 2H),
5.84 5m, 1H), 7.35 5m, 5H). Anal. calcd for C18H24O5: C,
67.48; H, 7.55. Found: C, 67.55; H, 7.61.
The mixture was stirred for 15 min at rt, then cooled at 08C,
and PCC 50.344 g, 1.6 mmol) was added. After 50 min, the
reaction was quenched by addition of a mixture pentane±
ether 51:2). After ®ltration, the ®ltrate was concentrated
under vacuum. The residue was washed with a mixture
pentane±ether 51:2) 5150 mL). Concentration of the organic
1
phase afforded the unstable lactone 23 as an oil. H NMR
5250 MHz, CDCl3) d 2.06 5m, 1H), 2.20 5m, 1H), 3.55 5ddd,
Jˆ4.5, 6.0, 10.4 Hz, 2H), 4.13 5m, 2H), 4.40 5m, 1H), 4.60
5m, 4H), 4.81 5d, Jˆ12.3 Hz, 1H), 5.03 5d, Jˆ12.3 Hz, 1H),
7.34 5m, 15H). 13C NMR 550 MHz, CDCl3) d 30.9, 71.2,
72.1, 72.2, 73.2, 73.9, 75.9, 128.0 515C), 137.3 53C), 169.3.
HMRS calcd for C27H28O5Na 5MNa1) 455.18344. Found:
455.18344.
3.3.6. Preparation of ,2Rp,3Sp,4Sp,6Sp)-2-allyl-4-benzyl-
oxy-6-,t-butyldiphenylsilanyloxymethyl)-tetrahydro-
pyran-3-ol 21. After reaction of acetate 14 51 g, 2.03 mmol)

T.Saleh, G.Rousseau / Tetrahedron 58 $2002) 2891±2897
2897
3.3.9. Preparation of ,2Sp,3Sp,4Sp,6Sp)-2-allyl-3,4-bis-
benzyloxy-6-benzyloxymethyl-tetrahydropyran-2-ol 24.
A solution of lactone 23 50.16 g, 0.347 mmol) in THF
520 mL) was cooled at 2788C, and a solution 50.5 M in
THF) of allylmagnesium chloride 50.345 mL, 0.173 mmol)
was added. The mixture was warmed to rt and stirred for
15 h. The mixture was cooled at 2788C and another
solution of Grignard reagent was added 50.173 mL,
0.0865 mmol). The mixture was warmed to 2208C then
cooled again to 2788C. The same addition protocol was
carried out 10 times. The reaction was then quenched at
2788C by addition of ammonium chloride 5sat. sol.,
5 mL) and warmed to rt. The aqueous phase was extracted
with dichloromethane 5100 mL). The organic phase was
dried 5MgSO4), and concentrated. The residue was puri®ed
by ¯ash chromatography 530:70 ether±pentane) to afford
3. 5a) Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.;
Xiao, X.-Y. J.Am.Chem.Soc. 1992, 114, 7935±7936.
5b) Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.;
Xiao, X.-Y.; Hwang, C.-K. J.Am.Chem.Soc. 1993, 115,
3558±3575. 5c) Kadota, I.; Yamamoto, Y. J.Org.Chem.
1998, 63, 6597±6606. 5d) Morimoto, M.; Matsukura, H.;
Nakata, T. Tetrahedron Lett. 1996, 37, 6365±6368.
5e) Mori, Y.; Yaegashi, K.; Furukawa, H. J.Org.Chem.
1998, 63, 6200±6209. 5f) Rainier, J. D.; Allwein, S. P.; Cox,
J. M. J.Org.Chem. 2001, 66, 1380±1386.
4. Simart, F.; Brunel, Y.; Robin, S.; Rousseau, G. Tetrahedron
1998, 54, 13557±13566.
5. For a preliminary report of this work see: Saleh, T.; Rousseau,
G. Synlett 1999, 617±619.
6. Danishefsky, S.; Kerwin, J. F.; Kobayashi, S. J.Am.Chem.
Soc. 1982, 104, 358±360.
1
7. Rychnovsky, S. D.; Bartlett, P. A. J.Am.Chem.Soc. 1981,
103, 3963±3964.
8. 5a) Cipolla, L.; Lay, L.; Nicotra, F. J.Org.Chem. 1997, 62,
the unstable allyl alcohol 24 561%). H NMR 5400 MHz,
CDCl3) d 1.87 5m, 2H), 2.19 5dd, Jˆ9.5, 13.7 Hz, 1H), 2.51
5m, 1H), 2.75 5dd, Jˆ5.3, 13.7 Hz, 1H), 3.43±3.68 5ddd,
Jˆ4.4, 6.0, 10.0 Hz, 2H), 3.67 5d, Jˆ2 Hz, 1H), 4.05 5m,
2H), 4.51±5.00 52d1m, Jˆ11.4 Hz, 6H), 5.18 5m, 2H), 5.80
5m, 1H), 7.24±7.36 5m, 15H). 13C NMR 563 MHz, CDCl3) d
29.0, 43.4, 69.3, 70.6, 73.1, 73.4, 74.5, 75.9, 76.1, 98.5,
120.4, 128.0 515C), 132.5, 139.0 53C). HMRS calcd for
C30H34O5Na 5MNa1) 497.23038. Found: 497.23039.
 Á
6678±6681. 5b) Jegou, A.; Pacheco, C.; Veyrieres, A.
Tetrahedron 1998, 54, 14779±14790.
9. Hung, S.-C.; Lin, C.-C.; Wong, C.-H. Tetrahedron Lett. 1997,
38, 5419±5422.
10. 5a) Waldmann, H. Synthesis 1994, 535±551. 5b) Jorgensen,
K. A.; Johannsen, M.; Yao, S. L.; Audrain, H.; Thorhauge,
J. Acc.Chem.Res. 1999, 32, 605±613.
3.3.10. Preparation of ,2Sp,3Sp,4Sp,6Sp)-2-allyl-3,4-
bisbenzyloxy-6-benzyloxymethyl-tetrahydropyran 10.
To a solution of alcohol 24 50.149 g, 0.134 mmol) in
methylene chloride 56 mL) and triethylsilane 54 mL) at
2358C was added slowly BF3´Et2O 50.125 mL, 1.1 mmol).
The solution was stirred for 45 min after the end of the
addition and sodium bicarbonate 5sat. solution, 2.5 mL)
was added dropwise. After warming to rt, the aqueous
phase was extracted with methylene chloride 53£20 mL).
The organic phases were dried 5MgSO4), and concentrated.
The residue was puri®ed by ¯ash chromatography 515:85
ether±pentane) to afford a mixture 580:20) of the two
diastereoisomers 10 and 9 554%).
Ã
11. Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J.Org.Chem. 1998,
63, 4876±4877.
12. Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J.Org.Chem. 1998,
63, 403±405.
Ã
13. 5a) Zheng, W.; De Mattei, J.-P.; Wu, J.-W.; Duan, J.-W.;
Cook, L. H.; Oinuma, H.; Kishi, Y. J.Am.Chem.Soc. 1996,
118, 7946±7968. 5b) Loubinoux, B.; Sinnes, J.-L.; O'Sullivan,
A. C.; Winkler, T. J.Org.Chem.
1995, 60, 953±959.
5c) Minehan, T. G.; Kishi, Y. Tetrahedron Lett. 1997, 38,
6811±6814.
14. 5a) Bertozzi, C.; Bednarski, M. Carbohydr.Res. 1992, 223,
243±253. 5b) Kraus, G. A.; Molina, M. T. J.Org.Chem. 1988,
53, 752±753. 5c) Cipolla, F.; Nicotra, F.; Vismara, E.;
Guerrini, M. Tetrahedron 1997, 53, 6163±6170.
15. 5a) Postema, M. H. D. Tetrahedron 1992, 48, 8545±8599.
5b) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998,
54, 9913±9959.
References
1. Prasad, A. V. K.; Shimizu, Y. J.Am.Chem.Soc. 1989, 111,
6476±6477.
16. Lewis, M. D.; Cha, J. K.; Kishi, Y. J.Am.Chem.Soc. 1982,
104, 4976±4978.
2. Faulkner, D. J. Nat.Prod.Rep. 2001, 18, 1±49 and references
cited.