A simple synthesis of oxazolidine and thiazolidine derivatives

of hydroxymethylglyceraldehyde acetonide

Depnrtme~lrof Cl~ernisrry,MrGill U I I ~ V E I :I YM~~I I~I, ~ ~Q11e0ec

E N I , H3C 3GI
Received December 19, 1975

GEORGE
JUST,BONG YOUNGCHUNG,
GERALD and MICHELDUPRC.Can. J. Chern.
ROSEBERY,
54, 1260 (1976).
Starting from mannitol diacetonide, a simple, I ~ i gyield
l ~ preparation of the title compounds
is described.
GEORGE
JUST,BONG YOUNGCHUNG,
GERALD et ~VIICHEL
ROSEBERY ~ . J. Chem.
D U P R Can.
54, 1260 (1976).
A partir du diacitonide du mannitol, on dCcrit une synthkse simple et ?I rendement ClevC des
composCs mentionnis ci-haut.

In connection with a synthesis of cephalo-

sporin and oxacephalosporin derivatives, we re-
quired a large amount of hydroxylnethylglycer-
aldehyde acetonide, in which the aldehyde group
was protected as an oxazolidine or thiazolidine
derivative.
We recently reported (1) that 5 could be
obtained from mannitol diacetonide (2) 1 via the
sequence 1 + 2 >- 3 + 4 + 5. When these re-
actions were carried out on a large scale, it
became apparent that (i) the lead tetraacetate
oxidation of 1 was unwieldy; (ii) the distillation
of dioxolane 3 t o hydroxyaldehyde 4 could not be
scaled u p because of polymerization of 4 ; (iii)
that, because of this polymerization, the yield of
4 was low; and (iv) that 5 was contaminated with
varying amounts (5-50%) of an impurity.
The nature of this impurity became apparent
when 5, containing a particularly large amount of
side product, was mesylated. In addition t o the
expected inesylate 7, dirnesylate lob, m p 74-
75 "C, was isolated. Its structure followed from
its analytical and nmr data and it obviously was
derived from a Cannizzaro reaction occurring
during the work-up of 3, which had involved the was liberated during that transformation. Based
removal of methanol in the presence of potas- on this information, it was dccided to investigate
sium carbonate and formaldehyde. the periodate oxidation of mannitol diacetonide,
Although remaining highly crystalline, it was t o use reaction conditions which minimized the
noted that 3 decomposed at room temperature in undesired Cannizzaro reaction in the trans-
a period of several weeks, and that formaldehyde for~iiationof 2 to 3, and to make usc of the
equilibrium between 3 and 4 and formaldehyde
'Holder of a National Research Council of Canada
Scholarship, 1974-1975.
to trap 4 directly as its oxazolidine derivative 5.
'Holder of a National Research Council of Canada Initial attempts to cleavc mannitol diacetonide
Scholarship, 1970-1973. with aqucous periodate gave 2 in 10-2070 yield
 JUST ET AL.
only. A careful study of the reaction indicated
that at p~ 5, mannitol diacetonide had dis-
appeared within 5 min, and that glyceraldehyde
acetOnidehad started decomposing very rapidly
due to the slightly acidic conditions. When the
periodate reaction was carried out at p H 6, the
reaction was complete after 30 with little
degradation of 2. Reaction of the aqueous solu-
tion of 2 with aqueous formaldehyde and
potassium for l 6 h' by
extraction, gave pure in
70-80% yield. A benzene solution of 3 was then
boiled for 1 h with continuous removal of water
with 2 equiv. of N-inethylethanolan~ine.Distilla-
tion gave a 95% yield of pure oxazolidine 5,
uncontaminated by diol 10a. It was converted to
its crystalline mesylate 7 in high yield.
Similarly, treatment of 3 with N-methylthio-
ethanolamine (3) gave 6 in high yield as a mixture
of two epimers. No attempt was made to deter-
mine the relative stereochemistry of two epimers
of 6. Mesylation of 6 gave 8.
Conversion of the oxazolidine function in 7 to
the free aldehyde 9 could be effected by treat-
ment with aqueous acetic acid (1). The same
aldehyde 9 was obtained from the thiazolidine 8
by hydrolysis with mercuric chloride either in
aqueous acetonitrile (4) or tetrahydrofuran.
Alternatively, the thiazolidine group could be
removed under virtually aprotic conditions by
oxidation of 8 at 0 OC with 2 equiv. of m-chloro-
perbenzoic acid in methylene chloride for 5 min.
Direct chromatography of the reaction product
or washing with aqueous sodium bicarbonate
gave the free aldehyde 9 in 70% yield.
Experimental
Melting points were determined on a Gallenkamp
block and are uncorrected. Mass spectra were obtained
on an AEI-MS-902 mass spectrometer at 70 eV using a
direct insertion probe. Microanalyses were carried out
by C. Daessle, Montreal.
Formuldel~~~de Arl~lrrcf3 from Mur~r~irol
Dinreforlicle
To a solution of 24 g of mannitol diacetonide in 400 ml
phosphate buffer ( p H 6 ) was added 20.4g of sodium
metaperiodate. The mixture was stirred for 30 min,
23.1 g of potassium carbonate in 70 ml water and 74 ml
of aqueous 40'/" formaldehyde were added, and the
mixture stirred overnight at room temperature. Methylene
chloride extraction and evaporation gave 25.5 g (73O4,)
of pure 3 (I), mp 89-90 "C.
6frorn 3
Oxuzolidirre 5 arrcl Tl~iurolidir~e
A solution of 0.1 mol of 3 and 2.2 equiv. of N-methyl-
1261
ethanolamine in 5OOml benzene was heated to reflux
and the benzene slowly distilled off over a period of 2 h.
Distillation gave a 90-95%. yield of 5 ( I ) , bp 100-103 "C/
0,5 torr,
When N-methylthioethanolamine was used instead of
N-methylethanolamine, thiazolidine 6, bp 98-101 "C/0.05
torr was obtained in 90% yield. A~lcrl. calcd. for
C I O H I ~ O C ~51.49,
: H 8.21, N 6.01, S 13.72; found:
C51.53,H8.17,N6.13,S 13.63; rn/e233(M+).
Mes~lufe8
A solution of 11.65 g of 6 and 7.6 g of triethylamine
(1.5 equiv.) in 2OOml of methylene chloride was cooled
to -50 alld 6.3 g (1.1 equiv,) of freshly distilled
methanesulfonvl chloride in 100 ml of methvlene chloride
added dropwik over a ~ e r i o dof 3 h. The clbudv solution
was into 300 hl of cold water, separated, and
washed twice with cold water. Drying and evaporation
gave a quantitative yield of oily mesylate. The oily residue
was shaken vigorously with ether, and the solvent
pumped otl' under high vacuum to give a solid. Treatment
with ether and filtration after cooling to - 10 'C for 2 h
gave 14 g (90:/;,) of 8, mp 65-66 'C (mixture of epimers).
Arlcll. calcd. for C l l H ~ I N 0 5 S ?C: 42.45, H 6.75, N 4.50.
S20.58; found: C42.25,H 6.59,N4.62, S20.32.
Alde11).de 9 frorn 8
Usirlg Merclrric Clrloricle
To a solution of 31 1 mg of 8 in 80Y6 aqueous acetoni-
trile or tetrahydrofuran (IOml) was added mercuric
chloride (280 mg, 1 .I equiv.). The white milky suspension
was refluxed for 1 11 and filtered. The filtrate was evapo-
rated irr vnc~roand the residue extracted with benzene.
The benzene solution was washed with dilute hydro-
chloric acid and water, dried over anhydrous sodium
sulfate, and evaporated to dryness i r ~ vucrro, giving
248 mg (96%) of 9 as a white oil.
Usirrg rr~-Cl~loroperber~~oic Acid
A solution of 31 1 mg of 8 in methylene chloride (5 ml)
was cooled to 0 "C and nl-cl~loroperbenzoicacid (344 mg,
2 equiv.) was added. The mixture was stirred for 5 min
and washed with sodium bicarbonate solution. Drying
over anhydrous sodium sulfate, evaporation, passing
through a silica gel column using ethyl ether as eluant,
and evaporation gave 188 mg (72vc) of 9 as a white oil.
The nmr and ir spectra were the same as those of the
product ( I ) from the acidic hydrolysis of the oxazolidine
mesylate. Annl. calcd. for CsH14O6S: C 40.34, H 5.88,
S 13.46; found: C 4 0 . 1 0 , H 6.11, S 13.35.
Acknowledgements
We wish to thank the National Research
Council of Canada and Bristol Laboratories for
generous financial support.
1. G . Jus-rand P. Rossu. J. Org. Chem. 38, 1534 (1973).
2. G. KOHAN and G. JUST.Synthesis, 192 (1974).
3. D. S. TARBELL and D. P. CAMERON. J. Am. Chem.
SOC.78, 2731 (1956).
4. A. I. MEYERS,R. MUNAVU, and J. DURANDETTA.
Tetrahedron Lett. 3929 (1972).