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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

54, 1260 (1976).
Starting from mannitol diacetonide, a simple, I ~ i gyield
l ~ preparation of the title compounds
is described.
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
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. 1261

only. A careful study of the reaction indicated ethanolamine in 5OOml benzene was heated to reflux
that at p~ 5, mannitol diacetonide had dis- 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/
appeared within 5 min, and that glyceraldehyde 0,5 torr,
acetOnidehad started decomposing very rapidly When N-methylthioethanolamine was used instead of
due to the slightly acidic conditions. When the N-methylethanolamine, thiazolidine 6, bp 98-101 "C/0.05
periodate reaction was carried out at p H 6, the torr was obtained in 90% yield. A~lcrl. calcd. for
reaction was complete after 30 with little 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+).
degradation of 2. Reaction of the aqueous solu-
tion of 2 with aqueous formaldehyde and Mes~lufe8
A solution of 11.65 g of 6 and 7.6 g of triethylamine
potassium for l 6 h' by (1.5 equiv.) in 2OOml of methylene chloride was cooled
extraction, gave pure in to -50 alld 6.3 g (1.1 equiv,) of freshly distilled
70-80% yield. A benzene solution of 3 was then methanesulfonvl chloride in 100 ml of methvlene chloride
boiled for 1 h with continuous removal of water added dropwik over a ~ e r i o dof 3 h. The clbudv solution
with 2 equiv. of N-inethylethanolan~ine.Distilla- was into 300 hl of cold water, separated, and
washed twice with cold water. Drying and evaporation
tion gave a 95% yield of pure oxazolidine 5, gave a quantitative yield of oily mesylate. The oily residue
uncontaminated by diol 10a. It was converted to was shaken vigorously with ether, and the solvent
its crystalline mesylate 7 in high yield. pumped otl' under high vacuum to give a solid. Treatment
Similarly, treatment of 3 with N-methylthio- with ether and filtration after cooling to - 10 'C for 2 h
ethanolamine (3) gave 6 in high yield as a mixture 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.
of two epimers. No attempt was made to deter- S20.58; found: C42.25,H 6.59,N4.62, S20.32.
mine the relative stereochemistry of two epimers
of 6. Mesylation of 6 gave 8. Alde11).de 9 frorn 8
Conversion of the oxazolidine function in 7 to Usirlg Merclrric Clrloricle
To a solution of 31 1 mg of 8 in 80Y6 aqueous acetoni-
the free aldehyde 9 could be effected by treat- trile or tetrahydrofuran (IOml) was added mercuric
ment with aqueous acetic acid (1). The same chloride (280 mg, 1 .I equiv.). The white milky suspension
aldehyde 9 was obtained from the thiazolidine 8 was refluxed for 1 11 and filtered. The filtrate was evapo-
by hydrolysis with mercuric chloride either in rated irr vnc~roand the residue extracted with benzene.
The benzene solution was washed with dilute hydro-
aqueous acetonitrile (4) or tetrahydrofuran. chloric acid and water, dried over anhydrous sodium
Alternatively, the thiazolidine group could be sulfate, and evaporated to dryness i r ~ vucrro, giving
removed under virtually aprotic conditions by 248 mg (96%) of 9 as a white oil.
oxidation of 8 at 0 OC with 2 equiv. of m-chloro- Usirrg rr~-Cl~loroperber~~oic Acid
perbenzoic acid in methylene chloride for 5 min. A solution of 31 1 mg of 8 in methylene chloride (5 ml)
Direct chromatography of the reaction product was cooled to 0 "C and nl-cl~loroperbenzoicacid (344 mg,
2 equiv.) was added. The mixture was stirred for 5 min
or washing with aqueous sodium bicarbonate and washed with sodium bicarbonate solution. Drying
gave the free aldehyde 9 in 70% yield. 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.
Experimental The nmr and ir spectra were the same as those of the
Melting points were determined on a Gallenkamp product ( I ) from the acidic hydrolysis of the oxazolidine
block and are uncorrected. Mass spectra were obtained mesylate. Annl. calcd. for CsH14O6S: C 40.34, H 5.88,
on an AEI-MS-902 mass spectrometer at 70 eV using a S 13.46; found: C 4 0 . 1 0 , H 6.11, S 13.35.
direct insertion probe. Microanalyses were carried out
by C. Daessle, Montreal.
Formuldel~~~de Arl~lrrcf3 from Mur~r~irol
To a solution of 24 g of mannitol diacetonide in 400 ml We wish to thank the National Research
phosphate buffer ( p H 6 ) was added 20.4g of sodium Council of Canada and Bristol Laboratories for
metaperiodate. The mixture was stirred for 30 min, generous financial support.
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 1. G . Jus-rand P. Rossu. J. Org. Chem. 38, 1534 (1973).
chloride extraction and evaporation gave 25.5 g (73O4,) 2. G. KOHAN and G. JUST.Synthesis, 192 (1974).
of pure 3 (I), mp 89-90 "C. 3. D. S. TARBELL and D. P. CAMERON. J. Am. Chem.
SOC.78, 2731 (1956).
6frorn 3
Oxuzolidirre 5 arrcl Tl~iurolidir~e 4. A. I. MEYERS,R. MUNAVU, and J. DURANDETTA.
A solution of 0.1 mol of 3 and 2.2 equiv. of N-methyl- Tetrahedron Lett. 3929 (1972).