Stereoselective synthesis of protected ketohexoses via aldol reaction of chiral dioxanone enolate

Article abstract of DOI:10.1055/s-1999-2862

Lithium and boron enolates of 2,2-dialkyl-1,3-dioxa-5-ones react with aldehydes to give aldol products in high diastereoselectivity and, when chiral lithium enolates are generated using optically pure chiral lithium amide bases, in high enantioselectivity. Dioxanone lithium enolates react readily with protected glyceraldehyde affording protected ketohexoses in high diastereo- and enantiomeric purity.

Full text of DOI:10.1055/s-1999-2862

LETTER
1447
Stereoselective Synthesis of Protected Ketohexoses via Aldol Reaction of
Chiral Dioxanone Enolate
Marek Majewski*, Pawel Nowak
Department of Chemistry, University of Saskatchewan, 110 Science Pl., Saskatoon, SK, S7N 5C9, Canada
Received 30 June 1999
tries 1 and 3, 5 and 6). Of several aldehydes tested, only
aliphatic aldehydes having an a-substituent were diastere-
oselective (c.f., entries 1, 4 and 5). In particular, cyclohex-
Abstract: Lithium and boron enolates of 2,2-dialkyl-1,3-dioxa-5-
ones react with aldehydes to give aldol products in high diastereo-
selectivity and, when chiral lithium enolates are generated using op-
tically pure chiral lithium amide bases, in high enantioselectivity. anecarboxaldehyde reacted with lithium enolate of 2-tert-
Dioxanone lithium enolates react readily with protected glyceralde- butyl-2-methyl-1,3-dioxa-5-one 1b to give only one prod-
hyde affording protected ketohexoses in high diastereo- and enan- uct which was identified by NMR and X-ray crystallogra-
tiomeric purity.
phy as the anti-cis isomer 2b. Boron enolates are well
Keywords: dioxanone, enantioselective deprotonation, chiral lithi- known to be more diastereoselective than the correspond-
4
um amides.
ing lithium enolates in aldol reactions. We synthesized
several boron enolates of dioxanone 1a and examined
briefly their reactions with benzaldehyde. Dicyclohexyl-
A few years ago we initiated a study of 2,2-dialkyl-1,3-di- boron enolate was the most diastereoselective and afford-
oxa-5-ones hoping that these compounds could be used as ed the corresponding aldols anti-4a and syn-4a in a 96 : 4
building blocks for synthesis of polyoxygenated natural ratio (Scheme 2). Two consecutive aldol reactions could
1
products. In particular, a double aldol reaction of 2,2-di- be done in ‘one pot’ and yielded 4 diastereoisomeric bis-
alkyldioxanone 1 could lead to a polyhydroxyalkane 3 aldols in a 83 : 09 : 06 : 02 ratio. After column chromato-
having a number of stereogenic centers. If relative and ab- graphy a single isomer 5 was isolated in 64 % yield.
solute stereochemistry of the process could be controlled
chiral polyoxygenated natural products could be con-
structed quickly and efficiently (Scheme 1). This ap-
proach could also provide a quick entry into synthesis of
carbohydrates. Although the main themes in carbohydrate
synthesis involve manipulation of readily available
monosaccharides and synthesis of oligosaccharides the
stereoselective total synthesis of ‘rare’ sugars is a topic of
2
current interest.
Scheme 1
Lithium enolates of cyclic ketones, being by necessity
E-isomers, normally react with aldehydes to give predom-
inantly anti aldols in agreement with the Zimmerman-
3
Traxler model. However, dioxanone lithium enolates,
generated by treatment of the dioxanones with LDA, af-
forded the corresponding aldols (2) with low diastereose-
lectivity. The outcome was dependent on the structures of
Scheme 2
both the dioxanone and the aldehyde. Selected results are
presented in Table 1. Larger groups in the acetal moiety of
the dioxanone increased the diastereoselectivity (c.f., en-
Synlett 1999, No. 9, 1447–1449 ISSN 0936-5214 © Thieme Stuttgart · New York

1
448
M. Majewski, P. Nowak
LETTER
Enantioselective deprotonation of 1b: Dioxanones having
C symmetry can be deprotonated enantioselectively with
S
chiral lithium amides to give non-racemic mixture of two
5
enantiomeric enolates. These enolates can be trapped
with electrophiles. We have undertaken a systematic
study aimed at finding the most effective (in this system)
lithium amide base derived from a-methylbenzylamine
(
general structure 7). Since we had determined earlier that
1
b
addition of LiCl was beneficial to selectivity, all reac-
tions were run with one equivalent of LiCl and one equiv-
alent of Li-amide. Fortunately, the reaction of lithium
enolate of dioxanone 1b with cyclohexanecarboxalde-
hyde proved very diastereoselective and only one diaste-
reoisomer of the aldol 6, namely the anti-cis isomer, was
obtained in each reaction. The relative stereochemistry of
this product was determined by x-ray crystallography on
a derivative. The enantiomeric ratio was measured by
NMR in the presence of the optically active shift reagent
Scheme 3
Eu(hfc) . The absolute stereochemistry of deprotonation
3
9
was determined by degrading a sample of the non-racemic D-psicose (10) and it was noted that the reaction was not
product 6 to a derivative of glyceraldehyde of known ab- overly stereoselective (Scheme 4 and Table 3, entry 1).
9
solute configuration. It was established that lithium The corresponding boron enolate, generated with dicyclo-
amides of general structure 7 having the R configuration hexylboron chloride, reacted much more selectively to
abstracted preferentially the H proton in 1b, whereas give a mixture of only two isomers with the D-tagatose
R
analogous amides having the S configuration preferred the derivative 9 predominating (entry 2). Chiral dioxanone
H proton. Overall, the aldol reaction of dioxanone eno- lithium enolate, generated from 1b by using the chiral
S
late with cyclohexanecarboxaldehyde provided a good base 7h, combined with R-8, resulted in a system capable
7
model system for our studies.
of double stereodifferentiation. Isopropylidene glyceral-
dehyde is known to have rather low diastereotopic face se-
The parameter to which we paid most attention in this
study was the structure of the lithium amide. In the group
of lithium amides that were investigated there seemed to
be a correlation between the size of the substituent on ni-
trogen (c.f., structure 7 in Scheme 3) and enantioselectiv-
ity. As the group R was changed from isopropyl to
neopentyl to diphenylmethyl to bis-naphtylmethyl the
enantioselectivity increased (Table 2, entries 1, 2, 3 and
8
lectivity in reactions with nucleophiles. In our system the
enolate clearly exerts much more control than the alde-
hyde with a small ‘matched-mismatched’ effect (Table 3,
entries 3 and 4). Overall, enantioselective deprotonation
of dioxanones followed by a reaction of the resulting lith-
ium enolate with a chiral aldehyde provided an easy entry
into carbohydrate derivatives.
6
). Bases 7f and 7h, having a large (and, in the latter case,
electron-withdrawing) substituent on nitrogen, were espe-
6
cially selective. The contribution of electronic effects
was clearly visible in the series 7i, 7j and 7k – the pres-
ence of electron-withdrawing fluorine substituent on the
benzene ring in 7j led to a more selective deprotonation,
whereas the electron-donating methoxy group in 7k
1
0
caused the decrease in enantioselectivity. Reactions of
dioxanone 1d with chiral lithium amides were much less
enantioselective than the corresponding reaction of 1b
(
c.f., entries 3 and 12, 8 and 13). It seems that a fairly large
conformational bias is necessary for the reaction to pro-
ceed with high enantioselectivity, this is a general trend in
5
chemistry of cyclic ketones.
Synthesis of carbohydrate derivatives: After developing
the conditions for efficient and stereoselective deprotona-
tion of C symmetrical dioxanones the stage was set for
S
applying the method to carbohydrate synthesis. Isopropy-
lidene R-glyceraldehyde 8 reacted readily with the achiral
lithium enolate of dimethyldioxanone 1a and afforded a
mixture of four diastereoisomers. The two major products
were identified as protected D-tagatose (9) and protected
Synlett 1999, No. 9, 1447–1449 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of Protected Ketohexoses via Aldol Reaction of Chiral Dioxanone Enolate
1449
Acknowledgement
Financial support was provided by the National Science and Engi-
neering Research Council of Canada and by the University of Sas-
katchewan.
References and Notes
(
1) (a) Majewski, M.; Gleave, D. M.; Nowak, P. Can. J. Chem.
1995, 73, 1616. (b) Majewski, M.; Lazny, R.; Nowak, P.
Tetrahedron Lett. 1995, 36, 5465.
Scheme 4
(2) (a) Jurczak, J. and Zamojski, A. in Preparative Carbohydrate
Chemistry, Hanessian, S., Ed.; Marcel Dekker, New York,
1997; p. 593. (b) Collins, P.; Ferrier, R. Monosaccharides:
Their Chemistry and Their Roles in Natural Products, Wiley,
New York 1995; p. 53.
(3) Majewski, M.; Gleave, D. M. Tetrahedron Lett. 1989, 30,
5681.
(
4) Moon Kim, B.; Williams, S. F.; Masamune, S. in
Comprehensive Organic Synthesis, vol. 2, Heathcock, C. H.,
Ed.; Pergamon, Oxford, 1991; p. 239.
(
(
5) Review: O’Brien, P. J. J. Chem. Soc., Perkin Trans. 1, 1998,
1439.
6) Chiral lithium amides having a fluoroalkyl substituent were
developed by Koga: Aoki, K.; Koga, K. Tetrahedron Lett.
1
997, 38, 2505 and references therein.
In summary, we have demonstrated that lithium and boron
enolates of dioxanones react with aldehydes with useful
diastereselectivity. Dioxanones having CS symmetry
could be deprotonated with chiral lithium amides with
high enantioselectivity. Aldol reaction of a chiral diox-
anone lithium enolate with protected glyceraldehyde pro-
vided a stereoselective method of synthesis of protected
ketohexoses.
(
7) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem. Int. Ed. Engl. 1985, 24, 1; see also ref. 4, p. 181.
(8) (a) Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron, 1986, 42,
447. (b) Roush, W.; Halterman, R. L. J. Am. Chem. Soc. 1986,
108, 294.
(
9) These studies will be described in the full paper
(
10) The differences in ee reported in Table 2, entries 9-11 are
small but statistically significant. Each experiment was
repeated 3-5 times and with careful control of experimental
conditions reproducibility within 2% was obtained.
Article Identifier:
437-2096,E;1999,0,09,1447,1449,ftx,en;S03499ST.pdf
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Synlett 1999, No. 9, 1447–1449 ISSN 0936-5214 © Thieme Stuttgart · New York