Improving the stereoselectivity of one-carbon atom homologation of hexoses at the terminal position

Article abstract of DOI:10.1016/S0040-4039(01)02376-0

A number of modifications of the original Grignard C₁ homologation of hexoses was examined, e.g. reactions of protected hexodialdo-1,5-pyranosides with benzyloxymethyllithium, transmetalation, precomplexation of the aldehydes. Some of the modif

Full text of DOI:10.1016/S0040-4039(01)02376-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1337–1340
Improving the stereoselectivity of one-carbon atom homologation
of hexoses at the terminal position
Mikhail Kim, Barbara Grzeszczyk and Aleksander Zamojski*
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
Received 10 September 2001; revised 7 December 2001; accepted 14 December 2001
Abstract—A number of modifications of the original Grignard C1 homologation of hexoses was examined, e.g. reactions of
protected hexodialdo-1,5-pyranosides with benzyloxymethyllithium, transmetalation, precomplexation of the aldehydes. Some of
the modifications, e.g. benzyloxymethyl Grignard addition in the presence of tert amines showed good to very good stereoselec-
tivity of the heptoside formation. © 2002 Elsevier Science Ltd. All rights reserved.
A practical method of homologation of hexoses 1,
preserving their natural configuration, consists of a
galacto aldehyde 8 led to the corresponding heptosides
in low yield. Only with Al(OiPr)3, the and -hep-
tosides were obtained in high yield and with good (10:1)
stereoselectivity. Attempts at transmetalation of the
lithium reagent with ZnCl2, ZrCp2Cl2, TiCl4,
Ti(OiPr)3Cl, CuBr·Me2S, CeCl3 and Et2AlCl led to
completely unreactive reagents.
D
D
,D
L,D
reaction between an alkoxymethyl Grignard reagent 3
and a C-6 aldehyde 2 (Scheme 1).1 Although the yields
of heptosides 4
D
,D
and 5 L,D are generally high or very
high, the stereoselectivities of the reactions are usually
in the range 1.5–4:1.1 Only (phenyldimethylsilyl)methyl-
magnesium chloride, a reagent introduced by van
Boom,2 secures very high yields of
L
,D
-heptosides.
We next examined precomplexation6 of the hexose alde-
hydes with some metal compounds. Moderate to good
Benzyloxymethyllithium, readily available from (benzyl-
oxymethyl)tributylstannane,3,4 reacted with four
yields (37–57%) of the corresponding D,D and L,D-hep-
tosides were obtained when all four hexose aldehydes
were precomplexed with Et2AlCl and reacted next with
benzyloxymethyllithium (Table 1, entry 3). The reaction
of benzyloxymethyllithium with Ti(OiPr)3Cl, Ti(OiPr)4
hexopyranose 6-aldehydes 6–9 to yield the expected
D,D
and -heptoses in good yields (72–76%)(Table 1,
L,D
entry 2). The stereoselectivity of the reactions was
substantially improved (9–10:1) in the galacto series 8,9,
slightly improved in the case of the allo aldehyde 6
(2:1), whereas no improvement was noted for the gluco
aldehyde 7. Transmetalation5 of benzyloxymethyl-
lithium with Ti(OiPr)4 or CuCN in reactions with the
or ZnCl2-precomplexed galacto aldehyde 8 led to
D,D
and -heptosides with high (9–15:1) stereoselectivity
L,D
but in low yields. The stereoselectivity of the heptoside
formation in the case of the allo aldehyde 6 was
increased to 1:2 and for both galacto aldehydes 8 and 9
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02376-0

Table 1. Stereoselectivity in chain-elongation reactions of terminal hexose-derived aldehydes 6–9 with a benzyloxymethyl unit under different conditions
Entry no.
Reagent
6 (allo)
7 (gluco)
8 (galactod)
9 (galacto)
Yield (%)
D
,
D
L
,
D
Yield (%)
D
,
D
L
,
D
Yield (%)
D
,
D
L
,
D
Yield (%)
D
,
D
L,D
/
1
2
3
4
5
6
7
BnOCH2MgCla
84b
76
52
79
90
86
–
38
34
31
14
21
35
–
51
66
69
86
79
65
–
89
72
37
78
79
80
57
60
48
48
20
30
47
2
40
52
52
80
70
53
98
80
74
49e
71
87
83
–
60
91
87
84
74
62
–
40
9
80
76
57
74
76
74
–
54
89
93
81
64
60
–
46
11
7
19
36
40
–
BnOCH2Li
BnOCH2Li+Et2AlClc
13
16
26
38
–
BnOCH2MgCl+TMEDA
BnOCH2MgCl+(R)-Me2N-CHPh-CH3
BnOCH2MgCl+(S)-Me2N-CHPh-CH3
BnOCH2MgCl+(S)-1-methyl-2-(piperidinemethyl)-pyrrolidine
4
a Data from Ref. 1.
(
b C-5 inverted heptosides (11%) were also isolated.1
c Precomplexation of the aldehydes (6–9) with Et2AlCl before reaction with BnOCH2Li.
1
d When the solution of BnOCH2Li was transmetalated before the reaction with aldehyde 8, the following results were obtained (metal derivative/heptoside yield%/
CuCN/9%/70:30, Al(OiPr)3/81%/91:9.
D,D:L,D):Ti(OiPr)4/14%/91:9,
1
e Precomplexation of the aldehyde (8) with ZnCl2 followed by the reaction with BnOCH2Li led to 45% of
gave 7% of heptosides in 94:6 proportion, and with Ti(OiPr)4—13% in 91:9 proportion.
D,D and L,D heptosides in 90:10 proportion. Analogous precomplexation of 8 with Ti(OiPr)3Cl

M. Kim et al. / Tetrahedron Letters 43 (2002) 1337–1340
1339
was very high (7–14:1), leaving the proportion of hep-
tosides obtained from the gluco aldehyde 7 unchanged.
series. We tend to interpret these results in terms of a-
and b-chelation control. Especially remarkable is the
effect of optically active diamine (entry 7) in enhancing
the yield of the
D,D-gluco-heptoside. This result is in
line with the observations of Mukaiyama16 on similar
addition reactions. Monoamines (entries 5 and 6 in
Table 1), although producing reactive Grignard
reagents, exert less steric control than diamines.
Acknowledgements
Finance for this investigation from a Grant No. 3
TO9A 056 19 obtained from the State Committee for
Scientific Research (KBN) is gratefully acknowledged.
References
Valuable results were obtained when tertiary amines
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magnesium chloride, before the reaction with the four
hexose aldehydes7 (Table 1, entries 4–7). The corre-
sponding heptosides were obtained in high yields and
with good to very good stereoselectivities. An especially
beneficial effect of amine addition was observed for the
recalcitrant gluco aldehyde (7): the proportion of
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2000, 56, 9319–9337 and references cited therein.
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ml) was mixed with an equimolar amount Ti(OiPr)4
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coordination sphere of the Grignard reagent.13–15
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Coordination with TMEDA formed a reagent which
12. Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Angew.
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improved the yield of -heptosides in the allo and
L
,
D
gluco aldehydes and D,D-stereoisomers in the galacto

1340
M. Kim et al. / Tetrahedron Letters 43 (2002) 1337–1340
13. Benn, R.; Rufinska, A. Angew. Chem., Int. Ed. Engl.
1986, 25, 861–881.
14. Blomberg, C. In Handbook of Grignard Reagents;
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