A straightforward synthesis of perbenzylated conduritols from alditols by ring closing olefin metathesis

Article abstract of DOI:10.1039/a906626h

The synthesis of perbenzylated conduritols A, E and F has been achieved in six steps by formal conversion of galactitol, D-mannitol and D-glucitol into the respective terminal dienes, followed by ring closing olefin metathesis. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a906626h

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A straightforward synthesis of perbenzylated conduritols from
alditols by ring closing olefin metathesis
John K. Gallos,* Theocharis V. Koftis, Vassiliki C. Sarli and Konstantinos E. Litinas
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 540 06, Greece
Received (in Cambridge, UK) 16th August 1999, Accepted 20th September 1999
The synthesis of perbenzylated conduritols A, E and F
has been achieved in six steps by formal conversion of
galactitol, D-mannitol and D-glucitol into the respective
terminal dienes, followed by ring closing olefin metathesis.
the desired dienes 7, 10 and 13 in 50–53% overall yields (Scheme
1).† The presence of a catalytic amount of 12-crown-4 is crucial
in the Wittig olefination, since its absence dramatically reduces
the yields.
With the dienes 7, 10 and 13 in our hands our attention was
turned to establish the best conditions for RCM.6 In initial
experiments the easily handled ruthenium catalyst (Cy3P)2-
Ru(᎐CH-CH᎐CPh )Cl did not work at all and the dienes were
Conduritols (cyclohex-5-ene-1,2,3,4-tetrols) have recently
become fashionable synthetic targets, not only because of
the diverse biological activity of their simple derivatives such
as epoxides and conduramines but also because of their wide-
spread use as intermediates in chemical synthesis.1–4
᎐
᎐
2
2
quantitatively recovered. Schrock catalyst PhMe CCH᎐Mo᎐
᎐
᎐
2
N(2,6-(i-Pr)2C6H3)(OCMe(CF3)2)2 was also disappointing and
only traces of the cyclised products were formed. The results
were much better, however, when we switched to the Grubbs
catalyst 5: after several attempts, the best results were obtained
in a 0.01 M solution of dienes in refluxing CH2Cl2 for 72 h and
with the catalyst used in 30% molar ratio relative to diene. The
catalyst was added gradually in three equal portions.
In the case of the -mannitol derived diene 7, the per-
benzylated (Ϫ)-conduritol F 8 was obtained in 52% yield and
40% of the diene was recovered, while for diene 10 the protected
(Ϫ)-conduritol E 11 was formed in 77% yield and 18% of
unchanged 10 was recovered. Finally, the cyclisation of diene 13
was complete and the perbenzylated conduritol A 14 was
obtained in quantitative yield.† It is apparent that the relative
stereochemistry of the carbon backbone in dienes 7, 10 and 13
is responsible for their difference in reactivity, although we are
presently not able to point out the exact way the reaction is
affected by the substituents. Regarding the deprotection of the
perbenzylated conduritols prepared, a number of new and con-
venient methods for selective cleavage of benzyl ethers have
been developed in the last few last years,8 which do not affect an
existing double bond, since it is apparent that hydrogenolysis
(H2/Pd) would lead to saturation of the double bond.
Several approaches2–4 to the synthesis of conduritols have
been made, the most popular being the microbial oxidation of
benzene and halobenzenes and further manipulation of the
resulting cyclohexa-3,5-diene-1,2-diols.3 Carbohydrates and
related polyoxygenated compounds have also been used as
cheap commercially available starting materials.4 Moreover, a
number of unnatural analogs possessing the basic structure of
conduritols with interesting biological activities have been
prepared.5
Inspection of the general structure of conduritols such as 1–3
In conclusion, we have developed a simple and general
method for converting the commercially available alditols to
terminal dienes and then into the respective conduritols by
ring closing metathesis. When asymmetric alditols are used
(-mannitol, -glucitol) their chirality is transferred to the
products and enantiomerically pure conduritols are thus
prepared.
led us to the conclusion that they could be prepared by ring
closing olefin metathesis (RCM)6 of the appropriate dienes of
the general structure 4, which in turn could be prepared from
the respective alditols. While our study was in progress, a few
reports appeared in the literature applying the RCM in the syn-
thesis of carbocycles from carbohydrates,7 one of them referred
to the synthesis of conduritols B and F.4h However, our
approach to the synthesis of the diene precursor is totally
different.
Experimental
(3R*,4S*,5R*,6S*)-3,4,5,6-Tetra-O-benzylocta-1,7-diene-
3,4,5,6-tetrol, 13
A solution of dry DMSO (0.15 ml, 2.1 mmol) in dry CH2Cl2 (1
ml) was added to a solution of (COCl)2 (0.1 ml, 1.11 mmol) in
dry CH2Cl2 (2 ml) which had been cooled to Ϫ60 ЊC, under an
argon atmosphere. The resulting mixture was further stirred at
the same temperature for another 2 min before a solution of 12
(0.243 g, 0.448 mmol) in dry CH2Cl2 (2 ml) was added carefully
during a period of 5 min, while the temperature was kept
between Ϫ60 and Ϫ55 ЊC. The stirring was continued for 15
min and then Et3N (0.63 ml, 4.48 mmol) was added at the same
temperature. After another 10 min stirring at low temperature
the mixture was allowed to warm to room temperature. Satur-
ated aqueous NaCl (100 ml) was subsequently added and the
solution was extracted with CH2Cl2 (3 × 100 ml). The organic
layer was dried over Na2SO4, the solvent was removed on a
Starting from -mannitol, -glucitol and galactitol, which
have the stereochemistry of (Ϫ)-conduritol
E (2), (Ϫ)-
conduritol F (3) and conduritol A (1), respectively, their
derivatives 6, 9 and 12 were prepared in good overall yields by
standard sugar manipulations:5e protection of the primary
hydroxy groups by tritylation, then benzylation of the second-
ary hydroxy groups and finally selective removal of the trityl
group by acidic hydrolysis. Subsequent Swern oxidation of
diols 6, 9 and 12 led to the respective dialdehydes, which with-
out characterisation were subjected to Wittig olefination to give
J. Chem. Soc., Perkin Trans. 1, 1999, 3075–3077
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Scheme 1 Reagents and conditions: i, Ph3CCl, DMAP, Et3N, DMF, 20 ЊC, 24 h; ii, DMF, NaH, 0 ЊC, then BnCl, 0 to 20 ЊC, 24 h; iii, H2SO4, MeOH,
CH2Cl2, 20 ЊC, 1 h; iv, (COCl)2, DMSO, Et3N, Ϫ60 ЊC, 30 min; v, Ph3PϩCH3BrϪ, n-BuLi, 12-crown-4, THF, Ϫ60 ЊC to 20 ЊC, 12 h; vi, 5 (30 mol%),
CH2Cl2, 0.01 M, reflux, 72 h.
127.44, 127.56, 127.73, 127.88, 128.17, 138.58. Compound 10: oil, [α]D25
rotary evaporator and the resulting crude dialdehyde dried
ϩ15.2 (c 2.62, CHCl3); δH (300 MHz, CDCl3) 3.71 (1H, dd as t, J 5.2),
under vacuum and used without further purification. To a
stirring solution of Ph3PϩCH3BrϪ (0.8 g, 2.24 mmol) and 12-
3.81 (1H, dd as t, J 5.3), 3.96 (1H, dd as t, J 6.9), 4.05 (1H, dd as t,
J 6.7), 4.12 (1H, d, J 11.5), 4.34 (1H, d, J 11.9), 4.50 (1H, d, J 11.5), 4.57
(1H, d, J 11.2), 4.60 (1H, d, J 11.9), 4.64 (1H, d, J 11.1), 4.78 (1H, d,
crown-4 (0.079 g, 0.448 mmol) in THF (5 ml) n-BuLi (1.6 ml,
1.6 M in hexanes) was slowly added under argon at Ϫ78 ЊC. The
J 11.2), 4.80 (1H, d, J 11.1), 5.26 (4H, m), 5.90 (2H, m), 7.28 (20H, m);
mixture was allowed to reach 0 ЊC, then cooled again to Ϫ78 ЊC
δC (75 MHz, CDCl3) 69.94, 70.40, 73.96, 75.10, 80.50, 81.03, 81.28,
and a solution of the previous dialdehyde in THF (5 ml) was
added. The reaction mixture was stirred overnight at room
temperature, then water (100 ml) was added and extracted with
CH2Cl2 (3 × 100 ml). Drying (Na2SO4) of the organic phase and
removal of the solvent under vacuum, gave the crude product
which was purified by column chromatography (ethyl acetate–
hexane, 1:20), to give diene 13 (0.120 g, 50% overall yield).
Similarly, dienes 7 and 10 were prepared from 6 and 9, in 52
and 53% overall yields respectively.
81.50, 118.90, 119.38, 127.26, 127.34, 127.47, 127.79, 128.00, 128.09,
128.24, 135.59, 135.95, 138.24, 138.57, 138.98. Compound 11: oil
[Found: (M ϩ Na) (FAB) 529.2346. C34H34O4Na requires 529.2355];
[α]D25 Ϫ25 (c 0.5, MeOH); δH (300 MHz, CDCl3) 3.53 (1H, dd, J 9.9, 3.4),
4.05 (1H, d, J 3.4), 4.07 (1H, d, J 7.5), 4.21 (1H, dd, J 9.9, 7.5), 4.75
(8H, m), 4.84 (1H, d, J 11.0), 5.01 (1H, d, J 11.0), 7.32 (20H, m); δC (75
MHz, CDCl3) 71.31, 71.73, 71.83, 72.69, 75.09, 79.72, 80.04, 80.21,
126.17, 127.43, 127.51, 127.70, 127.86, 128.02, 128.28, 131.06, 138.59,
138.73, 138.92. Compound 13: Mp 85–86 ЊC (Et2O–hexane); δH (300
MHz, CDCl3) 3.83 (2H, s), 4.20 (2H, d, J 7.7), 4.30 (2H, d, J 12.0), 4.46
(2H, d, J 11.5), 4.61 (2H, d, J 11.5), 4.63 (2H, d, J 12.0), 5.26 (2H, d,
J 10.9), 5.35 (2H, d, J 17.3), 5.94 (2H, ddd, J 17.3, 10.9, 7.7), 7.28 (20H,
m); δC (75 MHz, CDCl3) 70.21, 74.35, 80.34, 81.50, 118.51, 127.31,
127.37, 127.62, 127.96, 128.12, 128.18, 136.59, 138.53, 138.69. Com-
pound 14: oil [Found: (M ϩ Na) (FAB) 529.2348. C34H34O4Na requires
529.2355]; δH (300 MHz, CDCl3) 3.90 (2H, d, J 5.0), 4.17 (2H, d, J 5.0),
4.57 (4H, s), 4.66 (4H, s), 5.84 (2H, s), 7.30 (20H, m); δC (75 MHz,
CDCl3) 71.65, 72.42, 75.34, 77.00 (overlapping with CDCl3), 127.30,
127.36, 127.58, 128.07, 128.22, 138.42.
(1R*,2S*,3R*,4S*)-1,2,3,4-Tetra-O-benzylcyclohex-5-ene-
1,2,3,4-tetrol (tetra-O-benzylconduritol A), 14
To a stirring and degassed 0.01 M in CH2Cl2 solution of diene
13 (59 mg, 0.11 mmol), Grubbs catalyst 5 (9 mg, 0.011 mmol)
was added and the mixture was refluxed for 72 h. The same
amount of catalyst was then added twice again (every 24 h,
total 27 mg, 30 mol%). The solvent was removed and the resi-
due was purified by column chromatography (ethyl acetate–
hexane, 1:20), to give compound 14 (0.055 g, 99%).
Perbenzylated conduritols 8 and 11 were also prepared from
7 and 10 by the same procedure, in 58 and 77% yields respect-
ively. Chromatographic separation (silica gel, ethyl acetate–
hexane, 1:20) of the mixture gave firstly the unchanged 7 or 10,
followed by the desired products 8 or 11.
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Notes and references
† All new compounds gave satisfactory microanalyses (C 0.25, H
0.2) and spectral and analytical data consistent with their assigned
structures. Selected analytical data (J values are given in Hz):
Compound 7: Mp 67–68 ЊC (Et2O–hexane); [α]D25 Ϫ37.5 (c 0.42, MeOH);
δH (300 MHz, CDCl3) 3.81 (2H, d, J 6.1), 4.03 (2H, dd, J 6.1, 7.3), 4.20
(2H, d, J 11.7), 4.51 (2H, d, J 11.1), 4.58 (2H, d, J 11.7), 4.68 (2H, d,
J 11.1), 5.32 (2H, d, J 17.0), 5.34 (2H, d, J 11.0), 5.93 (2H, ddd, J 17.0,
11.0, 7.3), 7.42 (20H, m); δC (75 MHz, CDCl3) 69.88, 74.44, 80.36,
81.10, 119.54, 127.27, 127.40, 127.66, 127.85, 128.05, 128.24, 136.17,
138.43, 138.85. Compound 8: oil [Found: (M ϩ Na) (FAB) 529.2348.
C34H34O4Na requires 529.2355]; [α]D25 Ϫ115.5 (c 0.42, MeOH); δH (300
MHz, CDCl3) 3.98 (2H, s), 4.25 (2H, s), 4.64 (8H, m), 5.83 (2H, s), 7.27
(20H, m); δC (75 MHz, CDCl3) 71.55, 73.17, 73.32, 76.03, 127.40,
3076
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Communication 9/06626H
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