An Improved Methodology for the Synthesis of Enantiomerically Pure (S)-2,3-O-Cyclohexylideneglyceraldehyde

Article abstract of DOI:10.1080/10242430215702

An improved methodology to prepare (S)-2,3-O-cyclohexylideneglyceraldehdye is described. Starting from the commercially available (L)-cyclohexylidene protected ascorbic acid the enantiomerically pure aldehyde was synthesized inonly two steps in 41 percent overall yield. 5,6-O-cyclohexylidene-(L)-ascorbic acid -> (S)-2,3-O-cyclohexylideneglyceraldehyde

Full text of DOI:10.1080/10242430215702

Enantiomer
ISSN: 1024-2430 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/gena20
An Improved Methodology for the Synthesis
of Enantiomerically Pure ( S )-2,3- O -
Cyclohexylideneglyceraldehyde
M. Benaglia , M. Caporale & A. Puglisi
To cite this article: M. Benaglia , M. Caporale & A. Puglisi (2002) An Improved Methodology for
the Synthesis of Enantiomerically Pure ( S )-2,3- O -Cyclohexylideneglyceraldehyde, Enantiomer,
7:6, 383-385, DOI: 10.1080/10242430215702
To link to this article: http://dx.doi.org/10.1080/10242430215702
Published online: 17 Sep 2010.
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Date: 16 January 2017, At: 06:52

Enantiomer, Vol. 7, pp.383–385
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Copyright 2002 Taylor & Francis
1024-2430/02 $12.00 + .00
DOI: 10.1080/10242430290015953
An Improved Methodology
for the Synthesis of Enantiomerically Pure
(S )-2,3-O-Cyclohexylideneglyceraldehyde
M. Benaglia, M. Caporale,
and A. Puglisi
ABSTRACT An improved methodology to prepare (S )-2,3-O-
cyclohexylideneglyceraldehyde is described. Starting from the commer-
cially available (L)-cyclohexylidene protected ascorbic acid the enan-
tiomerically pure aldehyde was synthesized in only two steps in 41%
overall yield.
Dipartimento di Chimica
Organica e Industriale, Universita`
degli Studi di Milano, Via Golgi,
19, 20133 Milano (Italy)
KEYWORDS enantiomerically pure reagents, O-protected glyceraldehyde
RESULTS AND DISCUSSION
Enantiomerically pure reagents are extensively used in stereoselective
synthesis as starting materials for the stereo-controlled preparation of chi-
ral products. Their use is very advantageous since, in many cases, enables
precise planning and efficient realization of synthetic pathways [1].
In the course of a project devoted to the stereoselective synthe-
sis of the PSA inhibitor 1 [2] the imine 2 derived from (S)-2,3-O-
cyclohexylideneglyceraldehyde (CAS name: 1,4-dioxa-spiro(4.5)decane-
2-carbaldehyde) was required to stereo direct the crucial step in deter-
mining the correct configuration of all the stereocenters in the target
molecule (Scheme 1) [3].
(R)- and (S )-protected glyceraldehydes are commonly used reagents
in stereoselective synthesis [4] because of the synthetic versatility of the
aldehyde and protected diol groups. While the (R)-enantiomer of 2,3-O-
cyclohexylideneglyceraldehyde can be readily prepared in one step from
the commercially available bisprotected (D)-mannitol, the synthesis of
the (S )-enantiomer is more difficult and has been described only twice
[5,6].
Received April 14, 2002;
accepted September 29, 2002.
Corresponding author. Telephone:
++390250314171; Fax:
++390250314159; E-mail:
Maurizio.Benaglia@unimi.it
383

SCHEME 1 Synthesis of PSA inhibitor 1.
Here we report that a reinvestigation of Hino’s
method allowed us to prepare the enantiomerically
pure (S )-2,3-O-cyclohexylideneglyceraldehyde 4 in
41% distilled yield.
Preliminary and fruitless attempts to improve
Hino’s procedure involved variation of the nature
(LiAlH4 or NaBH4) [7] and the stoichiometry of the
reducing agents, the solvent, and the reaction time.
Similarly, extension to compound 4 of the proce-
dure described by Takano for the synthesis of 2,3-O-
isopropylideneglyceraldehyde [8] turned out to be
useless.
The method reported by Schollkopf [5] started
from (L)-arabinose (Scheme 2). This was reacted first
with benzylthiol to give the corresponding diben-
zylthioacetal, and then with cyclohexanone to give
compound 3. Treatment with Pb(OAc)4 afforded the
desired aldehyde 4 that was isolated by distillation in
26% overall yield. In our hands the method turned
out to be reliable and reproducible. Unfortunately
it required three steps, two crystallizations, and the
final distillation. Last but not least, the method suf-
fers also from the use of benzyl thiol, an unpleasant
reagent to handle.
A satisfactory solution was finally envisaged when
we observed that in the final step of the Schollkopf’s
procedure sodium carbonate was used together with
Pb(OAc)4, likely to buffer the acidity of this reagent.
When this modification was introduced in the ox-
idative cleavage step, we were pleased to see that the
reaction worked reasonably well, affording the final
aldehyde in 27% yield after purification by distilla-
tion. A further improvement was found in the use of
methylene chloride as the solvent of the oxidation
reaction. This allowed us to isolate pure compound
4 in 41% overall yield [9].
In conclusion, we have developed an improved
and reliable procedure for the synthesis of enantiom-
erically pure (S)-2,3-O-cyclohexylideneglyceralde-
hyde. The procedure has the advantage to start
from the commercially available (L)-cyclohexylidene
The method reported by Hino [6] started from
the commercially available (L)-cyclohexylidene pro-
tected ascorbic acid and involved reaction with
LiAlH4, followed by a basic workup and treatment
of the crude reaction product 5 with NaIO4 in ethy-
lacetate (Scheme 3).
It is worth mentioning that the procedure was not
described in detail and the aldehyde was not iso-
lated but used without further purification in a poor
yielding (18%) Wittig reaction. The authors surpris-
ingly pointed out that all the attempts to isolate 4
by distillation led to extensive decomposition of the
product; this was in contrast to Schollkopf’s obser-
vation (see above), and with the fact that (R)-4 can be
routinely distilled without any problem. Despite sev-
eral attempts, we were not able to obtain the desired
aldehyde in >5% yield.
SCHEME 2 Schollkopf’s synthesis of aldehyde 4.
384
M. BENAGLIA ET AL.

SCHEME 3 Improved Hino’s synthesis of aldehyde 4.
protected ascorbic acid, gives the final product after
only two steps, and requires a single distillation as
purification procedure. The whole protocol takes less
than 24 hours and is applicable on multigram scale.
rated. Purification of the crude residue by distilla-
tion under vacuum (b.p. 110–120 at 10 mm Hg) af-
fords the aldehyde in 41% overall yield starting from
the commercially available 5,6-O-cyclohexylidene-
(L)-ascorbic acid.
MATERIALS AND METHODS
REFERENCES
Synthesis of (S )-2,3-
O-cyclohexylideneglyceraldehyde
[1] E. L. Eliel, S. H. Wilen, and L. N. Mander, Stereochemistry
of Carbon Compounds, Wiley: New York, 1994.
[2] R. M. Adlington, J. E. Baldwin, B. Chen, S. L. Cooper,
W. McCoull, G. J. Pritchard, T. J. Howe, G. W. Becker,
B. Hermann, A. M. McNulty, and B. L. Neubauer, Bioorg.
Med. Chem. Lett. 1997, 7, 1689–1694.
[3] M. Benaglia, M. Cinquini, and F. Cozzi, Eur. J. Org. Chem.
2000, 563–572.
[4] J. Jurczak, S. Pikul, and T. Bauer, Tetrahedron 1986, 42,
447–488.
[5] M. Grauert and U. Shollkopft, Liebigs Ann. Chem. 1985,
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[6] J. Yoshida, M. Nakagawa, H. Seki, and T. Hino, J. Chem.
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[7] M. E. Jung and T. Shaw, J. Am. Chem. Soc. 1980, 102,
6304–6311.
[8] S. Takano, H. Numata, and K. Ogasawara, Heterocycles
1982, 19, 327–328.
To a suspension of NaBH4 (1.52 g., 40 mmol) in
ethanol (700 ml), under inert atmosphere, a solution
of 5,6-O-cyclohexylidene-(L)-ascorbic acid (10.14 g.,
40 mmol) in ethanol (170 ml), was added dropwise
in 1 hour; the crude mixture was allowed to stir at
20 C for 4 hours, then 100 ml of 1 M NaOH solution
were added; after 15 minutes 5 g. of NaOH pellets
[7] were added and the reaction mixture was stirred
at 20 C for 12 hours. The solution was neutralized
by addition of conc. HCl solution, evaporated un-
der reduced pressure and kept in high vacuum pump
(0.05 mm Hg) for 2 hours. The crude product 5 was
dissolved in methylene chloride (550 ml), Na2CO3
(150 g.) and Pb(OAc)4 (65 g.) were added; the mixture
was stirred for 2 hours at 20 C and filtered through
celite; the filter was washed with 350 ml of methy-
lene chloride and all the organic phase was evapo-
[9] The enantiomeric excess of the product was determined
by comparison of optical rotation value ([ ]D
=
60.1 ,
c = 3.0 in benzene) with the value reported for the enan-
tiomer (see A. Chattopadhyay and V. R. Mamdapur, J. Org.
Chem. 1995, 60, 3, 585–587; reported value for the (R)
enantiomer [ ]D = 60.5 , c = 3.5 in benzene).
SYNTHESIS OF ENANTIOMERICALLY PURE (S )-2,3-O-CYCLOHEXYLIDENEGLYCERALDEHYDE
385