6106 J . Org. Chem., Vol. 61, No. 18, 1996
Chattopadhyay
the anti isomer (syn 7:anti 8 ) 3:97), which is higher than
our earlier observation3 that involves propargylation with
the Grignard under anhydrous conditions. The diastereo
alcohols were isolated in pure form after being separated
by column chromatography. This appears to be the first
report on metal-mediated Barbier-type stereoselective
propargylation of a chirally oxygenated carbonyl in the
presence of water.
(83%). Compound 15 with its three hydroxyl groups, two
of which are versatilely protected, in association with a
terminal alkene is supposed to be of interest as a possible
intermediate for the synthesis of sugar-modified nucleo-
sides18 as well as many carbohydrates and related
polyols.8e,f,19 Similarly, compounds 5, 6, and 8 with an
identical reaction sequence should give rise to other
functionalized triols of good synthetic potential.
Here we have accomplished an inexpensive and op-
erationally simple approach to the preparation of an
appreciable amount of four functionally rich alcohols 3,
5, 6, 8 in optically pure form. The efficacy of this method
is due to good reactivity of 1 in an aqueous environment
followed by easy isolation and separability of the result-
ing diastereo alcohols, in each case, by simple column
chromatography. The stable cyclohexylidene ketal func-
tionality remains unaffected even on mild acid treatment
during isolation of the product to dissolve the turbid
metal complex in order to facilitate the extraction.
Hence, the present approach is amenable to large scale
synthesis of these four alcohols, which hold good promise
in versatile synthetic manipulations.
The high anti selectivity during the formation of
alcohol for all the three reactions suggests that these
reactions proceed via a Felkin-Anh model11 rather than
by a chelation-Cram model12 as the water solvates the
metal ions and thereby competes with chelate complex.
The crotylation using crotyl bromide, whose (E)-stereo-
chemical purity is not available in detail, proceeds with
the formation of predominantly threo-6 (63.5%) and an
appreciable amount of erythro-5 (34.2%). Hence, it is not
clearly understood about the nature of the intermediate
during the reaction in aqueous medium, as the six-
membered cyclic transition state13 is expected to produce
threo-isomer from (E)-bromide and erythro-isomer from
(Z)-bromide stereoselectively, whereas the acyclic linear
transition state14 suggests erythro selectivity with (E)-
bromide and poor selectivity with (Z)-bromide.
Thus, a convenient procedure for stereoselective syn-
thesis of a series of chiral functionalized homoallylic 3,
5, 6 and homopropargylic 8 alcohols starting from the
aldehyde 1 has been presented. Hopefully, utilization of
this protocol with its available enantiomer20 will afford
stereoselective synthesis of another series of diastereo
alcohols with high optical purity.
Exp er im en ta l Section
All bps are uncorrected. All the anhydrous reactions were
carried out under argon atmosphere using freshly distilled
anhydrous solvents. Unless otherwise mentioned, the organic
extracts were dried over anhydrous Na2SO4.
Gen er a l P r oced u r e for Allyla tion , Cr otyla tion , a n d
P r op a r gyla tion of 1. To a cold (10 °C) and well-stirred
mixture of 1 (10.2 g, 0.06 mol), Zn dust (7.8 g, 0.12 mol for
allylation and crotylation; 14 g, 0.21 mol for propargylation),
and bromide (14.5 g for allylaion, 0.12 mol; 16.2 g for
crotylation, 0.12 mol; 21.4 g, 0.18 mol for propargylation) in
THF (50 mL) was added a saturated aqueous solution of NH4-
Cl (30 mL) dropwise over a period of 30 min. The mixture
was stirred for 4 h (allylation and crotylation) or for 8 h
(propargylation) at ambient temperature until the aldehyde
was totally consumed (by TLC). The mixture was filtered, and
the precipitate was thoroughly washed with CHCl3. The
aqueous layer was separated and treated with 5% HCl to
dissolve the suspended turbid material. The clear solution was
extracted with CHCl3. The combined organic layer was
washed successively with 10% NaHCO3, water, and brine.
After solvent removal under reduced pressure, the residue was
column chromatographed (silica gel), eluting with 0-25%
EtOAc in hexane resulting in isolation of the diastereomers
in pure form. Both for allylation and propargylation, the minor
isomers (2R,3R)-2 (0.33 g, 3%) and (2R,3R)-7 (0.28 g, 2%),
respectively, have been eluted first followed by the major
isomers (2R,3S)-3 (9.59 g, 75%) and (2R,3S)-8 (9.17 g, 73%),
respectively. The spectral and optical data of all these four
compounds (2, 3, 7, and 8) were found to be identical with those
reported by us.3 Column chromatography of the crotylated
product sequentially isolated (2R,3R,4R)-4, (2R,3S,4R)-5, and
(2R,3S,4S)-6.
Silylation of the hydroxy group of 8 followed by
C-alkylation of the terminal alkyne 9 gave 10. Semihy-
drogenation of 10 with P(2)-Ni catalyst15 produced 11.
Deketalization of 11 with aqueous trifluoroacetic acid
followed by NaIO4 cleavage of the resulting diol 12,
without purification, afforded the aldehyde (S)-13. (R)-
13 has been utilized16 for the synthesis of the leukotriene
(LTB4),17 the synthesis of which is of current interest.
The physical and spectral properties of (S)-13 ([R]24
-7.82°, (c 0.98, CHCl3)) were found to be in accordance
with those16 of the (R)-enantiomer ([R]D +7.9°, (c 1.0,
CHCl3)).
(2R,3R,4R)-1,2-O-Cycloh exylid en e-4-m eth yl-5-h exen e-
1,2,3-tr iol (4): yield 0.24 g (2%); Rf 0.83 (20% EtOAc/hexane);
[R]23 +47.14° (c 1.4, CHCl3); IR (film) 3400, 3005, 1650, 1475,
1
1390, 1130, 1060, 995, 920; H NMR (CDCl3) δ 1.09 (d, J )
6.6 Hz, 3H), 1.4-1.6 (m, 10H), 2.2-2.3 (m, 1H), 2.68 (br, s,
D2O exchangeable, 1H), 3.3-3.4 (m, 1H), 3.65-3.75 (m, 1H),
3.93-4.08 (m, 2H), 5.0-5.1 (m, 2H), 5.7-5.9 (m, 1H).
Silylation of the hydroxy group of 3 and subsequent
deketalization afforded the diol 14 in good yield (84%).
Selective monobenzoylation of the primary hydroxyl of
14 has been accomplished to give 15 in appreciable yield
(2R,3S,4R)-1,2-O-Cycloh exylid en e-4-m eth yl-5-h exen e-
1,2,3-tr iol (5): yield 3.6 g (27%); Rf 0.75 (20% EtOAc/hexane);
[R]23 +29.65° (c 1.45, CHCl3); IR (film) 3400, 3005, 1650, 1470,
1
1395, 1130, 1060, 995, 920; H NMR (CDCl3) δ 1.08 (d, J )
(11) (a) Anh, N. T. Top. Curr. Chem. 1980, 88, 145. (b) Cherest, M.;
Felkin, H. Tetrahedron Lett. 1968, 9, 2205.
(12) (a) Cram, D. J .; Kopecky, K. R. J . Am. Chem. Soc. 1959, 81,
2748. (b) Cram, D. J .; Abd Elhafez, F. A. J . Am. Chem. Soc. 1952, 74,
5828.
(13) Hoffman, R. W.; Zeiss, H. J . J . Org. Chem. 1981, 46, 1309.
(14) Hayashi, T.; Kabeta, K.; Hamachi, I.; Kumuda, M. Tetrahedron
Lett. 1983, 24, 2865.
(15) (a) Brown, C. A.; Ahuja, V. K. J . Chem. Soc., Chem. Commun.
1973, 553. (b) Chattopadhyay, A.; Mamdapur, V. R. Synth. Commun.
1990, 20, 2225.
6.6 Hz, 3H), 1.4-1.6 (m, 10H), 2.11 (bs, D2O exchangeable,
1H), 2.2-2.3 (m, 1H), 3.6-3.7 (m, 1H), 3.8-3.9 (m, 2H), 4.0-
4.1 (m, 1H), 5.0-5.06 (m, 2H), 5.7-5.9 (m, 1H).
(2R,3S,4S)-1,2-O-Cycloh exylid en e-4-m eth yl-5-h exen e-
1,2,3-tr iol (6): yield 6.65 g (49%); Rf 0.66 (20% EtOAc/hexane);
[R]23 +2.60° (c 2.05, CHCl3); IR (film) 3400, 3005, 1655, 1475,
1
1390, 1130, 1065, 995, 920; H NMR (CDCl3) δ 1.07 (d, J )
6.5 Hz, 3H), 1.4-1.6 (m, 10H), 2.15 (bs, 1H, D2O exchangeable),
(16) Solladie, G.; Hamdouchi, C.; Cherif, C. Tetrahedron Asymmetry
1991, 2, 457.
(17) (a) Kerdesky, F. A. J .; Schmidt, S. P.; Brooks, D. W. J . Org.
Chem. 1993, 58, 3516 and references cited therein. (b) Borgeat, P.;
Samuelson, B. J . Biol. Chem. 1979, 254, 2643.
(18) (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745. (b)
Dueholm, K. L.; Pedersen, E, B. Synthesis 1992, 1.
(19) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon Press: New York, 1983; Vol. 3.
(20) Grauert, M.; Schollkopf, U. Leibigs Ann. Chem. 1985, 1817.