Improved E-selectivity in the Wittig reaction of stabilized ylides with alpha-alkoxyaldehydes and sugar lactols.

Article abstract of DOI:10.1021/ol016729+

[reaction: see text]. The Wittig reactions of alpha-alkoxyaldehydes and sugar lactols with stabilized ylides such as (alkoxycarbonylmethylene)triphenylphosphoranes typically proceed with low E-selectivities. However, we have discovered that the reaction o

Full text of DOI:10.1021/ol016729+

ORGANIC
LETTERS
2
001
Vol. 3, No. 22
591-3593
Improved E-Selectivity in the Wittig
Reaction of Stabilized Ylides with
r-Alkoxyaldehydes and Sugar Lactols
3
Christian Harcken and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received September 8, 2001
ABSTRACT
The Wittig reactions of r-alkoxyaldehydes and sugar lactols with stabilized ylides such as (alkoxycarbonylmethylene)triphenylphosphoranes
typically proceed with low E-selectivities. However, we have discovered that the reaction of such aldehydes with (methoxycarbonylmethylene)-
tributylphosphorane in toluene in the presence of catalytic amounts of benzoic acid proceeds to give the E-r,â-unsaturated esters with high
selectivities and in high yields.
3
The Wittig reaction of aldehyde 1 with a phosphorus ylide
boxylic acid have been observed to increase the E-selectivity
in certain cases. Protic solvents on the other hand appear to
promote Z-selective olefinations in some cases. The E-
selective Knoevenagel condensation and Horner-Wads-
worth-Emmons reaction cannot be applied to sugar lactols,
since the basic conditions often lead to racemization or
cyclization of the initially formed hydroxyenoates.
is one of the most commonly used constructions for forming
substituted olefins 2 (Scheme 1). When stabilized ylides (R
2
Scheme 1
In the course of our studies toward the synthesis of the
4
solandelactone oxylipins, it was necessary to convert the
arabinose derivative 3 to the R,â-unsaturated ester 4 (Scheme
2
). However, when 3 was subjected to standard Wittig
)
EWG) are employed for the preparation of R,â-unsaturated
2
carboxylic acid derivatives 2 (R ) EWG), the products are
generally obtained with very good levels of E-selectivity.
Scheme 2
1
However, such reactions with protected or unprotected
R-alkoxyaldehydes, especially those derived from carbohy-
drates and sugar lactols, appear anomalous as they typically
proceed with low selectivities. Indeed, the reactions are
oftentimes Z-selective.
Despite the longstanding nature of this problem, no general
solution has been described. The use of nonpolar solvents
2
and elevated temperatures or catalytic amounts of a car-
conditions with the triphenylphosphorane 5a, a 50:50 mixture
of geometric isomers of 4 was isolated in moderate yield.
(1) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
1
0.1021/ol016729+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001

Changes in solvent or temperature had little effect upon the
product ratio (Table 1, entries 1-3), but adding benzoic acid
more nucleophilic than the corresponding triarylphospho-
ranes, thus possibly explaining the increased yields.9
To define the scope and limitations of this improved
methodology, we examined the reactions of a variety of
R-alkoxyaldehydes and sugar lactols with 5b (1.3 equiv) in
the presence of benzoic acid (20 mol %) under standard
Table 1. Wittig Reactions of Lactol 3
1
0
equiv
temp
(°C)
% yield
(E/ Z)6
conditions (Scheme 3). We specifically selected those
entry
ylide
solvent
of acid
1
2
3
4
5
6
7
5a
5a
5a
5a
5a
5a
5b
CH2Cl2
toluene
DME
toluene
toluene
toluene
toluene
rt
90
90
90
90
90
90
59 (40:60)
55 (50:50)
50 (40:60)
70 (78:22)
48 (82:18)
49 (75:25)
78 (91:9)
Scheme 3
0.05
0.20
0.50
0.20
improved the E/Z ratio to 82:18 (entries 4-6). After some
experimentation, we discovered that using the tributylphos-
5
phorane 5b instead of 5a and catalytic amounts of benzoic
acid significantly increased the selectivity (E/Z ) 91:9) and
the yield of the reaction (78%) (entry 7). Pure 4 was readily
obtained by recrystallization.
The increased E-selectivity in reactions of nonstabilized
and semistabilized tributylphosphoranes with aldehydes has
7
been reported. It is also known that replacing the aryl rings
on the phosphorus atom of stabilized ylides with alkyl groups
can lead to increased E-selectivity in reactions with benz-
8
aldehyde. However, the utility of stabilized tributylphos-
phoranes as reagents for E-selective olefinations has not been
generally established. Tributylphosphoranes are known to be
(
2) Valverde, S.; Martin-Lomas, M.; Herradon, B.; Garcia-Ochoa, S.
Tetrahedron 1987, 43, 1895-1901.
3) The basis for the effect, which has been known for some time, of
(
carboxylic acids upon Wittig reactions of stabilized ylides is not well
understood. See: (a) Buchanan, J. G.; Edgar, A. R.; Power, M. J.; Theaker,
P. D. Carbohydr. Res. 1974, 38, C22-C24. (b) Corey, E. J.; Goto, G.
Tetrahedron Lett. 1980, 21, 3463-3466. (c) Marriott, D. P.; Bantick, J. R.
Tetrahedron Lett. 1981, 22, 3657-3658. (d) Mulzer, J.; Kappert, M. Angew.
Chem., Int. Ed. Engl. 1983, 22, 63-64.
substrates whose reactions with 5a under standard conditions
were known from the literature to proceed with low E-
selectivity.
(
4) Seo, Y.; Cho, K. W.; Rho, J.-R.; Shin, J.; Kwon, B.-M.; Bok, S.-H.;
Song, J.-I. Tetrahedron 1996, 52, 10583-10596.
5) Bu3PdCHCO2Me was freshly prepared from the corresponding
(
phosphonium bromide as a toluene solution according to Aspinall, I. A.;
Cowley, P. M.; Mitchell, G.; Raynor, C. M.; Stoodley, R. J. J. Chem. Soc.,
(12) Prepared in one step (90% yield) from L-arabinose: Perigaud, C.;
Gosselin, G.; Imbach, J.-L. J. Chem. Soc., Perkin Trans. 1 1992, 1943-
1952.
Perkin Trans. 1 1999, 2591-2599.
1
(
6) E/Z ratios were determined of the crude product by H NMR. All
yields are of the pure E/Z mixture after chromatography.
7) (a) Meyers, A. I.; Lawson, J. P.; Carver, D. R. J. Org. Chem. 1981,
(13) Prepared in two steps (67% yield) from (S)-ethyl lactate: Enders,
D.; Jandeleit, B.; von Berg, S. J. Organomet. Chem. 1997, 553, 219-236.
(14) Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron 1988,
44, 491-502. The reaction of 6 with 5a in MeOH provides 7 in 81% yield
(E/Z ) 20:80), see ref 2.
(15) Prepared in two steps (78%) from 2,3-O-isopropylidene-D-threitol:
Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 3337-3342.
(16) Prepared in one step (44%) from 1,2:3,4:5,6-tri-O-isopropylidene-
D-mannitol: Wu, W.-L.; Wu, Y.-L. J. Org. Chem. 1993, 58, 3586-3588.
(17) Horton, D.; Machinami, T.; Takagi, Y. Carbohydr. Res. 1983, 121,
135-161. The reaction of 10 with 5a in MeOH provides 11 in 70% yield
(E/Z ) 12:88), see ref 2.
(18) Prepared in two steps (68%) from 1,2:5,6-di-O-isopropylidene-R-
D-glucofuranose: Kov a´ r, J.; Baer, H. H. Can. J. Chem. 1973, 51, 1801-
1811.
(
4
1
2
3
6, 3119-3132. (b) Schlosser, M.; Schaub, B. J. Am. Chem. Soc. 1982,
04, 5821-5823. (c) Linderman, R. J.; Meyers, A. I. Heterocycles 1983,
0, 1737-1740. (d) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1988, 110,
948-3958. (e) Tamura, R.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org.
Chem. 1988, 53, 2723-2728.
(
(
(
8) Bissing, D. E. J. Org. Chem. 1965, 30, 1296-1298.
9) Johnson, A. W.; LaCount, R. B. Tetrahedron 1960, 9, 130-138.
10) Typical procedure: A solution of tributyl(methoxycarbonylmeth-
ylene)phosphonium bromide (17.8 g, 50.0 mmol) in CH2Cl2 (60 mL) was
washed with aqueous NaOH (1 M, 2 × 50 mL), dried (MgSO4), and diluted
with toluene (50 mL). The CH2Cl2 was successively evaporated. This
solution was then added to a stirred solution of 3 (7.60 g, 40.0 mmol) and
benzoic acid (976 mg, 8.00 mmol) in toluene (200 mL) at 90 °C. After 10
min the solvent was evaporated, and the residue was purified by flash
chromatography with hexanes/EtOAc (1:1 f 1:2) to give 7.71 g (78%) of
(19) Tronchet, J. M. J.; Gentile, B. HelV. Chim. Acta 1979, 62, 2091-
2098. The reaction of 12 with 5a in MeOH provides 13 in unknown yield
(E/Z ) 8:92).
4
(E/Z ) 91:9) as a pale yellow solid.
(
11) All reactions were run according to the conditions given for the
(20) Prepared in three steps (33%) from L-arabinose: Tejima, S.; Fletcher,
H. G., Jr. J. Org. Chem. 1963, 28, 2999-3004.
1
1
typical procedure. E/Z ratios were determined from the crude reaction
product by H NMR. All yields are of the pure E/Z mixture after
1
(21) For the tert-butyl ester: Wilcox, C. S.; Gaudino, J. J. J. Am. Chem.
Soc. 1986, 108, 3102-3104.
chromatography.
3592
Org. Lett., Vol. 3, No. 22, 2001

than those reported in the literature; the yields were also
generally higher. Simple substrates such as the lactate 6
underwent olefination with excellent E-selectivities (E/Z )
95:5). The ketal and silyl protecting groups in aldehydes 8,
Table 2. Wittig Reaction of R-Alkoxyaldehydes and Sugar
Lactols with (Methoxycarbonylmethylene)tributylphosphorane
10,11
(5b)
1
0, and 12 were stable to the reaction conditions, although
aldehyde
or lactol
% yield
% yield
the ketal protecting group in the ribose derivative 16 proved
somewhat labile. Prior protection of the primary hydroxyl
group in 16 with tert-butyldiphenylsilyl chloride had no effect
on the E/Z ratio.
olefin
(E/Z)
(E/Z) with 5a
312
4
7
9
11
13
15
17
78 (91:9)
94 (95:5)
83 (92:8)
73 (95:5)
80 (91:9)
95 (91:9)
64 (67:33)
55 (50:50)
613
14
70-75 (63:37)
815
15
87 (68:32)
1
1
1
1
016
218
420
622
47 (75:25)17
NA (80:20)19
92 (40:60)21
65 (38:62)23
In conclusion, we have developed a useful method for
transforming R-alkoxyaldehydes and sugar lactols to R,â-
unsaturated esters in good yields and E-selectivities. Thus,
this protocol nicely complements the known Z-selective
conditions for the Wittig reactions of these aldehydes with
The results of these experiments together with the literature
1
stabilized phosphoranes.
data for the reactions of these aldehydes with 5a are
summarized in Table 2. The E-selectivities in the olefinations
of all substrates except 16 with 5b were dramatically higher
Acknowledgment. We thank the Alexander von Hum-
boldt Foundation, the National Institutes of Health, and the
Robert A. Welch Foundation for their generous financial
support.
(
22) Prepared in one step (68%) from D-ribose: Kaskar, B.; Heise, G.
L.; Michalak, R. S.; Vishnuvajjala, B. R. Synthesis 1990, 1031-1032.
23) Herrera, F. J. L.; Gonzalez, M. S. P. Carbohydr. Res. 1986, 152,
83-291.
(
2
OL016729+
Org. Lett., Vol. 3, No. 22, 2001
3593