Grignard Additions to O-Protected Polyhydroxylated Ketones
J . Org. Chem., Vol. 62, No. 12, 1997 3943
8a -h were prepared via routine operations.10 The 1H and
13C NMR spectra were recorded on a 250 or 500 MHz Brucker
machine.
Sch em e 12a
Typ ica l P r oced u r e. A. Sw er n -Oxid a tion : (2R,4R,5R)-
4-O-Ben zoyl-1,2:5,6-di-O-isopr opyliden e-1,2,4,5,6-pen tah y-
d r oxy-3-h exa n on e (11). To a solution of oxalyl chloride
(17.16 g, 135 mmol, 1.1 mol equiv) in dry methylene chloride
(250 mL) was added slowly dry DMSO (23.05 g, 295 mmol,
2.4 mol equiv, dissolved in 100 mL of methylene chloride) at
-78 °C. The mixture was stirred strongly for 15 min. Then
alcohol 8c (45 g, 123 mmol, 5 mol equiv) was added. The
mixture was placed into an ice bath, and the reaction was
quenched by addition of an ether/water mixture (4:1, 400 mL).
The organic layer was separated, washed with water, and dried
(MgSO4). After concentration of the organic layer in vacuo the
crude product was purified by column chromatography (hex-
ane/ethyl acetate 2:1) to give 11 (42.1 g, 94%).
B. Gr ign a r d Rea ction . To a solution of the ketone in dry
THF (2-4 mL/mmol) were added slowly 3-4 mol equiv of the
Grignard compound (1 M THF solution) at 0 °C. After stirring
for 15 min (monitored by TLC) the reaction was stopped by
adding saturated ammonium chloride solution drop by drop.
The precipitated salts were removed by filtration and carefully
washed with THF. The filtrate was concentrated in vacuo,
and the residue was dissolved in ether and washed three times
with water and one time with brine. The organic phase was
dried (MgSO4) and concentrated in vacuo. The crude product
was purified by column chromatography (hexane/ethyl acetate
2:1).
All other experiments are analogous to the typical proce-
dures or routine operations. Characteristic analytical data of
the products are described in Supporting Information.
Su p p or tin g In for m a tion Ava ila ble: Analytical data of
compounds 8c,d ,e,g,h , 11-16, 19a -d , 20a -c, 21a -d , 22a ,b ,
23a ,c, 31c, 33a ,b,d , 37, 38, 40, 47, 50, 51a ,c, 53a -c, 55a /56a ,
55b/56b, 55c, 57a /58a , 57b/58b, 57c/58c, 59a ,b, 60a ,b 61a ,b,
62a , 63a , 63b/64b, 65a ,b, 66a ,b, 67, 68a -c, 68d /69d , 70, 71a -
d , 73, 74a , 74b/75b, 74c, 74d /75d , 77, 78, 79 (48 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
a
(a) 70% AcOH, 22 °C, 3-4 h; (b) BOM-Cl, (iPr)2NEt, CH2Cl2,
0 °C, 24 h, 80%; (c) 30% KOH/MeOH, CH2Cl2, 22 °C, 30 min, 82%;
(d) BzCl, DMAP, pyridine, 0 °C, 20 h, 67%, HPLC; (e) (COCl)2,
DMSO, NEt3, CH2Cl2, -68 °C, 93-97%; (f) TrCl, DMAP, pyridine,
22 °C, 2 d, 97%; (g) NaH, DMF, MeI, 0-22 °C, 20 h, 80%;
(h) HCO2H, CH2Cl2, 22 °C, 4 h, 65%; (i) NaH, DMF, BnBr, 0 °C,
92%.
tions may serve as a basis for interpreting the stereo-
chemical course of the addition. Furthermore, there is
no need to postulate metal chelate complexes as reactive
intermediates, which is surprising in view of the multi-
tude of oxygen functions available in the substrates. In
summary, it appears that the diastereoselectivity of
Grignard carbonyl additions is much less understood
than one might have thought, 45 years after the formula-
tion of Cram’s rule.2a
J O961542V
(8) Coxon, J . M.; Houk, K. N.; Luibrand, R. T. J . Org. Chem. 1995,
60, 418-427.
(9) Schmidt, C. R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J . L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem.
1991, 56, 4056-4058.
(10) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991.
(11) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
Exp er im en ta l Section
Di-O-isopropylidene-D-mannitol 7 was prepared from D-
mannitol by a well-known procedure.9 The protected alcohols