A Novel Catalytic and Highly Enantioselective Approach for the Synthesis of Optically Active Carbohydrate Derivatives

Article abstract of DOI:10.1021/jo9918596

A catalytic enantioselective inverse-electron demand hetero-Diels-Alder reaction of α,β-unsaturated carbonyl compounds with electron-rich alkenes catalyzed by chiral bisoxazolines in combination with Cu(OTf)₂ as the Lewis acid is presented. The reaction of γ-substituted β,γ-unsaturated α-keto esters with vinyl ethers and various types of cis-disubstituted alkenes proceeds in good yield, high diastereoselectivity, and excellent enantioselectivity. The potential of the reaction is demonstrated by the synthesis of optically active carbohydrates such as spiro-carbohydrates, an ethyl β-D-mannoside tetraacetate, and acetal-protected C-2-branched carbohydrates. On the basis of X-ray crystallographic data and the absolute configuration of the products, it is proposed that the alkene approaches the si-face of the reacting α,β-unsaturated carbonyl functionality when coordinated to the catalyst.

Full text of DOI:10.1021/jo9918596

J . Org. Chem. 2000, 65, 4487-4497
4487
A Novel Ca ta lytic a n d High ly En a n tioselective Ap p r oa ch for th e
Syn th esis of Op tica lly Active Ca r boh yd r a te Der iva tives
He´le`ne Audrain, J acob Thorhauge, Rita G. Hazell, and Karl Anker J ørgensen*
Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University,
DK-8000 Aarhus C, Denmark
kaj@kemi.aau.dk
Received December 3, 1999
A catalytic enantioselective inverse-electron demand hetero-Diels-Alder reaction of R,â-unsaturated
carbonyl compounds with electron-rich alkenes catalyzed by chiral bisoxazolines in combination
with Cu(OTf)2 as the Lewis acid is presented. The reaction of γ-substituted â,γ-unsaturated R-keto
esters with vinyl ethers and various types of cis-disubstituted alkenes proceeds in good yield, high
diastereoselectivity, and excellent enantioselectivity. The potential of the reaction is demonstrated
by the synthesis of optically active carbohydrates such as spiro-carbohydrates, an ethyl â-D-
mannoside tetraacetate, and acetal-protected C-2-branched carbohydrates. On the basis of X-ray
crystallographic data and the absolute configuration of the products, it is proposed that the alkene
approaches the si-face of the reacting R,â-unsaturated carbonyl functionality when coordinated to
the catalyst.
Sch em e 1
In tr od u ction
The interest in the development of new synthetic
procedures for the preparation of natural and unnatural
carbohydrates is due to the abundance of carbohydrates
in living cells. The most common synthetic approach for
the formation of these compounds has been to derivatize
naturally occurring carbohydrates. However, there are
limitations with this approach: (i) few monosaccharides
are readily available from natural sources; (ii) mainly
D-sugars are found in the chiral pool; (iii) a large number
of protection and deprotection steps makes the synthesis
less efficient; and (iv) the choice of substituents is limited.
Alternative procedures for the preparation of these
carbohydrate analogues from acyclic precursors would
therefore be of great value.
An attractive synthetic procedure for the preparation
of novel optically active carbohydrate derivatives is the
hetero-Diels-Alder (HDA) reaction of R,â-unsaturated
carbonyls with electron-rich alkenes, i.e., enol ethers.1
The retrosynthetic analysis presented in Scheme 1 il-
lustrates this approach for the formation of carbohydrate
derivatives. This procedure allows control of up to three
stereocenters in a single step, as well as incorporating a
broad choice of substituents in the final six-membered
ring. Furthermore, the substituents introduced might
eventually be transformed into other functional groups
allowing coupling reactions.
enantioselective reaction is necessary. The diastereose-
lective reaction requires an optically active R,â-unsatur-
ated carbonyl compound and/or an optically active alkene.
In recent years, several diastereoselective HDA reactions
of R,â-unsaturated carbonyl compounds with electron-
rich alkenes have appeared, leading to carbohydrate
derivatives with good diastereomeric excess.3 A problem
with this process is that it is usual to remove the chiral
auxiliary after reaction, which can lead to a lowering of
(2) For references of inverse hetero-Diels-Alder reactions in an
achiral environment, see, for example: (a) Tietze, L. F.; Voss, E.
Tetrahedron Lett. 1986, 27, 6181-6184. (b) Boger, D. L.; Robarge, K.
D. J . Org. Chem. 1988, 53, 3373-3377. (c) Boger, D. L.; Robarge, K.
D. J . Org. Chem. 1988, 53, 5793- 5796. (d) Wada, E.; Kanemasa, S.;
Tsuge, O. Chem. Lett. 1989, 675-678. (e) Tietze, L. F.; Hartfiel, U.
Tetrahedron Lett. 1990, 31, 1697-1700. (f) Sera, A.; Ohara, M.;
Yamada, H.; Egashira, E.; Ueda, N.; Setsune, J . Chem. Lett. 1990,
2043-2046. (g) Tietze, L. F.; Schneider, C. Synlett, 1992, 755-756.
(h) Sera, A.; Ohara, M.; Yamada, H.; Egashira, E.; Ueda, N.; Setsune,
J . Bull. Chem. Soc. J pn. 1994, 67, 1912-1917.
(3) For examples of diastereoselective hetero-Diels-Alder reaction
of R,â-unsaturated carbonyl compounds with electron-rich alkenes, see,
for example: (a) Schmidt, R. R.; Maier, M. Tetrahedron Lett. 1985,
26, 2065-2068. (b) Schmidt, R. R.; Haag-Zeino, B.; Hoch, M. Liebigs
Ann. Chem. 1988, 885-889. (c) Dujardin, G.; Molato, S.; Brown, E.
Tetrahedron: Asymmetry 1993, 4, 193-196. (d) Tietze, L. F.; Monten-
bruck, A.; Schneider, C. Synlett 1994, 509-510. (e) Tietze, L. F.;
Schneider, C.; Grote, A. Chem. Eur. J . 1996, 2, 139-148. (f) Wada, E.;
Pei, W.; Yasuoka, H.; Chin, U.; Kanemasa, S. Tetrahedron 1996, 52,
1205-1220. (g) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron
1996, 52, 4007-4010. (h) Dujardin, G.; Rossignol, S.; Brown, E.
Synthesis 1998, 763-770.
The type of reaction outlined in Scheme 1 has already
been shown to proceed in an achiral environment.2
However, to obtain optically active carbohydrate deriva-
tives by the HDA approach, either a chiral transforma-
tion via the use of a chiral auxiliary or a catalytic
* To whom correspondence should be addressed. Fax: 45 86 19 61
99.
(1) For leading references of inverse-electron demand hetero-Diels-
Alder reactions, see, for example: (a) Desimoni, G.; Tacconi, G. Chem.
Rev. 1975, 75, 651-692. (b) Boger, D. L.; Weinreb, S. M. Hetero Diels-
Alder Methodology in Organic Synthesis; Academic Press: New York,
1987. (c) Tietze, L. F.; Kettschau, G. Stereoselective Heterocyclic
Synthesis I; Metz, P., Ed.; Springer: Berlin, 1997; Vol. 189, pp 1-120.
(d) Ager, D. J .; East, M. B. Tetrahedron 1993, 49, 5683-5765.
10.1021/jo9918596 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/30/2000

4488 J . Org. Chem., Vol. 65, No. 15, 2000
Audrain et al.
the yield of the desired product. The catalytic enantiose-
lective HDA approach has several advantages compared
with the diastereoselective reactions. First, the substrate
does not require a chiral auxiliary, so the preparation
and cleavage steps associated with this technique are
now removed. Second, only catalytic amounts of chiral
complex are required to promote the reaction. The only
work published until recently using the catalytic enan-
tioselective approach for intermolecular HDA reactions
has, according to our knowledge, been published by Wada
et al.4
The use of chiral Lewis acids for the HDA reaction of
dicarbonyl compounds with dienes has recently been
shown to be a useful procedure for preparing products
with good enantioselectivity.5,6 Among the chiral Lewis
acids used as catalysts, the chiral bisoxazoline copper-
(II) complexes have been shown to be effective catalysts
for addition reactions to R-dicarbonyl compounds.6-8 The
bisoxazoline copper(II) catalysts can catalyze highly
diastereo- and enantioselective HDA reactions of acti-
vated aldehydes with conjugated dienes or ketones with
activated dienes.6 These reactions can be considered as
normal-electron demand HDA reactions where the di-
enophile, activated by the chiral Lewis acid, interacts by
its LUMO, with the HOMO of the diene.9 Recently, it was
communicated that the chiral bisoxazoline copper(II)
complexes can catalyze highly enantioselective inverse-
electron demand HDA reactions.10 In two independent
communications from Evans et al.10c and from us10b it was
demonstrated that â,γ-unsaturated R-keto esters react
with ethyl vinyl ether in the presence of chiral bisoxazo-
line copper(II) complexes as catalysts leading to enan-
tiomerically enriched dihydropyrans (eq 1).10b-d
This paper presents the development of highly dia-
stereo- and enantioselective catalytic HDA reactions of
R,â-unsaturated dicarbonyl compounds with electron-rich
alkenes. The products of this reaction are carbohydrate
precursors which can be converted into attractive carbo-
hydrate derivatives.
Resu lts a n d Discu ssion
Several different chiral bisoxazoline copper(II) com-
plexes can catalyze the HDA reaction of the â,γ-unsatur-
ated R-keto ester 1a with ethyl vinyl ether 2a (eq 2) and
among them, the tert-butyl-substituted bisoxazoline cop-
per(II) triflate catalyst (t-Bu-Box-Cu(OTf)2) 4a , has been
found to have the most promising properties.7,10b Some
representative results for the reaction of (E)-2-oxo-4-
phenylbut-3-enoic acid methyl ester 1a with 2a in the
presence of different C2-bisoxazoline ligands and copper-
(II) salts are presented in Table 1.
(4) Wada, E.; Yasuoka, H.; Kanemasa, S. Chem. Lett. 1994, 1637-
1640.
(5) The use of chiral Lewis acids in HDA reactions, see, for
example: (a) Graven, A.; J ohannsen, M.; J ørgensen, K. A. J . Chem.
Soc., Chem. Commun. 1996, 2373-2374. (b) Yao, S.; J ohannsen, M.;
J ørgensen, K. A. J . Chem. Soc., Perkin Trans. 1. 1997, 2345-2349. (c)
J ohannsen, M.; J ørgensen, K. A.; Zheng, X. F.; Hu, Q. S.; Pu, L. J .
Org. Chem. 1999, 64, 299-301. (d) Dossetter, A. G.; J amison, T. F.;
J acobsen, E. N. Angew. Chem. 1999, 111, 2459-2553; Angew. Chem.,
Int. Ed. 1999, 38, 2398-2400. (e) Desimoni, G.; Faita, G.; Righetti, P.;
Sardone, N. Tetrahedron 1996, 52, 12019-12030. (f) Maruoka, K.; Itoh,
T.; Shirasaka, T.; Yamamoto, H. J . Am. Chem. Soc. 1988, 110, 310-
312. (g) Gao, Q.; Maruyama, T.; Mouri, M.; Yamamoto, H. J . Org.
Chem. 1992, 57, 1951-1952. (h) Gao, Q.; Ishihara, K.; Maruyama, T.;
Mouri, M.; Yamamoto, H. Tetrahedron 1994, 50, 979-988. (i) Schauss,
S.; Bra˚nalt, J .; J acobsen, E. N. J . Org. Chem. 1998, 63, 403-405. (j)
Motoyama, Y.; Mikami, K. J . Chem. Soc., Chem. Commun. 1994, 1563-
1564. (k) Bednarski, M.; Danishefsky, S. J . Am. Chem. Soc. 1986, 108,
7060-7067. (l) Ghosh, A. K.; Mathivanan, P.; Cappiello, J . Tetrahedron
Lett. 1997, 38, 2427-2430. (m) Li, L.-S.; Wu, Y.; Hu, Y.-J . Xia, L.-J .;
Wu, Y.-L. Tetrahedron: Asymemtry 1998, 9, 2271- 2277. (n) Corey, E.
J .; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907-6910.
(o) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J . Org. Chem. 1995, 60,
5998-5999. (p) Togni, A. Organometallics 1990, 9, 3106-3113.
(6) Hetero-Diels-Alder reactions of aldehydes/ketones with dienes
catalyzed by chiral bisoxazoline-copper(II): (a) J ohannsen, M.; J ør-
gensen, K. A. J . Org. Chem. 1995, 60, 5757-5762. (b) J ohannsen, M.;
J ørgensen, K. A. Tetrahedron 1996, 52, 7321-7328. (c) J ohannsen, M.;
J ørgensen, K. A. J . Chem. Soc., Perkin Trans. 2 1997, 1183-1185. (d)
J ohannsen, M.; Yao, S.; J ørgensen, K. A. J . Chem. Soc., Chem.
Commun. 1997, 2169-2170. (e) Yao, S.; J ohannsen, M.; Hazell, R. G.;
J ørgensen, K. A. J . Org. Chem. 1998, 63, 118-121. (f) J ohannsen, M.;
Yao, S.; Graven, A.; J ørgensen, K. A. Pure Appl. Chem. 1998, 70, 1117-
1122. (g) Yao, S.; J ohannsen, M.; Audrain, H.; Hazell, R. G.; J ørgensen,
K. A. J . Am. Chem. Soc. 1998, 120, 8599-8605. (h) Ghosh, A. K.;
Mathivanan, P.; Cappiello, J .; Krishnan, K. Tetrahedron: Asymmetry
1996, 7, 2165-2168.
The results in Table 1 show that t-Bu-Box-Cu(OTf)2
4a catalyzes a highly diastereo- and enantioselective
HDA reaction giving the dihydropyran 3a in very high
yield. In THF, compound 3a is isolated in 95% yield,
predominantly as one diastereomer (the diastereoselec-
tivity is >98%) and with a very high ee, 99.5% (entry 1).
Changing the solvent from THF to CH2Cl2 or Et2O gives
similar results (entries 2, 3). When MeNO2 is the solvent
at 0 °C, lower diastereoselectivity of 3a was observed
(entry 4). At ambient temperatures and at 0 °C, the
reaction proceeds well in Et2O with no loss of yield and
selectivity even with only 0.5 mol % catalyst loading
(entries 5-10). We have previously reported10b that THF
was the solvent of choice, but in many cases further
studies have shown that Et2O gives better results. By
the use of Ph-Box-Cu(OTf)2 4b in Et2O at 0 °C as the
(7) For chiral bisoxazoline copper(II) complex used to catalyze
addition to R-dicarbonyls, see, for example: (a) J ørgensen, K. A.;
J ohannsen, M.; Yao, S.; Audrain, H.; Thorhauge, J . Acc. Chem. Res.
1999, 32, 605-613. (b) Evans, D. A.; J ohnson, J . S. Acc. Chem. Res.
2000, 33, in press.
(8) For pioneering work using bisoxazoline ligands, see: (a) Fritschi,
H.; Leutenegger, U.; Siegmann, K.; Pfaltz, A.; Keller, W.; Kratky, C.
Helv. Chim. Acta 1988, 71, 1541-1552. (b) Evans, D. A.; Woerpel, K.
A.; Hinman, M. M.; Faul, M. M. J . Am. Chem. Soc. 1991, 113, 726-
728.
(9) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Verlag Chemie: Weinhein, 1970.
(10) (a) Evans, D. A.; J ohnson, J . S. J . Am. Chem. Soc. 1998, 120,
4895-4896. (b) Thorhauge, J .; J ohannsen, M.; J ørgensen, K. A. Angew.
Chem. 1998, 110, 2543-2546; Angew. Chem., Int. Ed. 1998, 37, 2404-
2406. (c) Evans, D. A.; Olhava, E. J .; J ohnson, J . S.; J aney, J . M. Angew.
Chem. 1998, 110, 3554-3557; Angew. Chem., Int. Ed. 1998, 37, 3372-
3375. (d) Evans, D. A.; J ohnson, J . S.; Olhava, E. J . J . Am. Chem. Soc.
2000, 122, 1635-1649.

Synthesis of Optically Active Carbohydrate Derivatives
J . Org. Chem., Vol. 65, No. 15, 2000 4489
Ta ble 1. Resu lts for th e Rea ction of 1a w ith 2a Givin g
th e Heter o-Diels-Ald er Ad d u ct 3a in th e P r esen ce of th e
Ca ta lysts 4a ,b
of the enantioselectivity is found for the reaction of 1b
and 2b in the presence of catalyst 4a , when performed
in Et2O at -78 °C (>99.5% ee). This correlates well with
the findings in Table 1.
The catalytic enantioselective HDA reaction can be
used for the preparation of optically active spiro carbo-
hydrates, which are found in a variety of natural products
such as pheromones, steroid derivatives, antiparasitic
agents or polyether antibiotics.11 Equation 4 shows the
reaction of 1b and 1d with the exo-cyclic vinyl ether 2c
catalyzed by t-Bu-Box-Cu(OTf)2 4a . It appears that by
the use of the HDA methodology, it is possible to obtain
the spiroacetal functionality in a convergent way, avoid-
ing a stepwise spirocyclization.12,13 The catalytic enanti-
oselective HDA reaction of the exo-cyclic vinyl ether 2c
with enone 1b or 1d proceeds with moderate yield with
the endo-3e and endo-3f formed in 74% and 76% ee
respectively, as the major product.14 The minor diaster-
eomers exo-3e and exo-3f are formed in 84% and 95% ee,
respectively (eq 4).
loading,
temp, yield,a de,b,c eeb/%
entry
catalyst
mol % solvent
°C
%
%
endo/exo
1
2
3
4
5
6
7
8
9
(S)-4a X ) OTf 10
(S)-4a X ) OTf 10
(S)-4a X ) OTf 10
(S)-4a X ) OTf 10
(S)-4a X ) OTf 10
(S)-4a X ) OTf 10
THF
-78
95d >98 >99
CH2Cl2 -78
99
93
99
93
99e
96
98
98
99
99
99
97
99
34
98
99
Et2O
CH3NO2
Et2O
Et2O
Et2O
-78
99
87/58
99
0
0
rt
0
0
0
0
97 >99
99 >99
99 >99
99 >99
(S)-4a X ) OTf
(S)-4a X ) OTf
(S)-4a X ) OTf
5
2
1
Et2O
Et2O
10 (S)-4a X ) OTf
0.5 Et2O
98
99
11 (R)-4b X ) OTf 10
Et2O
CH2Cl2
0
0
71f
84f
12/5
-/93
12 (S)-4a X ) PF6
10
a
b
Isolated yield after 1 d. Determined by chiral HPLC. c Endo
diastereomer major product. Isolated yield after 2 d. e Isolated
d
yield after 2 h. f Other diastereomer.
catalyst, the diastereoselectivity changed and the enan-
tioselectivity was low (entry 11). The use of the PF6-salt
of the t-Bu-Box-CuX2 4a catalyst also changes the de of
the reaction (entry 12).
The catalytic enantioselective properties of t-Bu-Box-
Cu(OTf)2 4a for the HDA reaction of â,γ-unsaturated
R-keto esters with activated alkenes leading to precursors
for carbohydrates and carbohydrate derivatives will be
presented in the following. The reaction of the â,γ-
unsaturated R-keto esters 1a -c with 2,3-dihydrofuran
2b (eq 3) will be studied first.
To obtain derivatives which more closely resembles a
carbohydrate structure, the introduction of an alcohol in
an anti-Markovnikov sense on the double bond at the
carbon-4 position (carbohydrate numbering), as well as
the reduction of the ester to an alcohol at the carbon-6
position, are required. The introduction of the alcohol can
be achieved in endo-3e using TiCl4-NaBH4.15 However,
when this approach was used, a mixture of diastereomers
was formed in low yield. Using an alternative method
developed by Boger et al., we could obtain diastereomer
5, in which the alcohol at carbon-4 has been introduced
anti compared to the substituents on carbon-3 and
(11) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617-1661;
see also: Bartolozzi, A.; Capozzi, G.; Falciani, C.; Menichetti, S.; Naitvi,
C.; Bacialli, A. P. J . Org. Chem. 1999, 64, 6490-6494.
(12) For spirosugars made using HDA, see: Ireland, R. E.; Ha¨bich,
D. Chem. Ber. 1981, 114, 1418-1427.
(13) For other methodes to synthesize spirosugars, see, for ex-
ample: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362. (b)
Martin, A.; Salazar, J . A.; Suarez, E. J . Org. Chem. 1996, 61, 3999-
4006. (c) Van Hooft, P. A. V.; Leeuwenburgh, M. A.; Overkleeft, H. S.;
Van der Marel, G. A.; Van Boeckel, C. A. A.; Van Boom, J . H.
Tetrahedron Lett. 1998, 39, 6061-6064.
(14) The attribution of endo and exo to the products 3e and 3f were
made according to previous results where we observed that the endo
product is the major compound formed under the reaction conditions
(see eq 3 and ref 10b, as well as following results in this article
(compound endo-3g)).
(15) Kano, S.; Tanaka, Y.; Hibino, S. J . Chem. Soc., Chem. Commun.
1980, 414-415.
2,3-Dihydrofuran 2b reacts with (E)-2-oxo-4-phenylbut-
3-enoic acid methyl ester 1a , (E)-4-ethoxy-2-oxobut-3-
enoic acid ethyl ester 1b and (E)-2-oxopent-3-enoic ethyl
acid ester 1c in the presence of t-Bu-Box-Cu(OTf)2 4a (10
mol %) as the catalyst in THF. The bicyclic unsaturated
esters products 3b-d are formed in good yield, high
diastereoselectivity (de >95%, only traces of the minor
1
diastereomer can be detected by H NMR spectroscopy)
and enantioselectivity (up to 99.5% ee), results which are
similar to those observed by Evans et al.10c,d An increase

4490 J . Org. Chem., Vol. 65, No. 15, 2000
Audrain et al.
carbon-5 (eq 5) (stereochemistry vide infra).2c These
reactions, which have not been optimized, proceed well
giving the spiro-carbohydrate derivative 5 in satisfactory
overall yield. The catalytic enantioselective reaction of
â,γ-unsaturated R-keto esters with the exo-cyclic vinyl
ether catalyzed by t-Bu-Box-Cu(OTf)2 4a is a convenient
new synthetic procedure for the preparation of optically
active spiro-carbohydrates.
Ta ble 2. Resu lts for th e Rea ction of 1a , 1b a n d 1d w ith
2d a n d 2e in th e P r esen ce of (S)-t-Bu -Box-Cu (OTf)2 4a a s
th e Ca ta lyst in Et2O a t Room Tem p er a tu r e
For the catalytic enantioselective reactions of the â,γ-
unsaturated R-keto esters presented until now, an oxygen
substituent is lacking in the 2-position. In the following
we will consider cis-dihydroxy-substituted alkenes for the
introduction of the oxygen atom in the 2-position. To
control the regioselectivity in the HDA step when alkenes
with two different oxygen substituents are used, cis-1-
acetoxy-2-ethoxyethene 2d and cis-1-acetoxy-2-(benzyl-
oxy)ethene 2e have been chosen. However, a symmetrical
cis-alkene is also interesting and 2,2-dimethyl-1,3-dioxole
2f (vide infra) has been used. Both cis-alkenes 2d and 2f
were prepared in gram scale by a retro-Diels-Alder
reaction, and alkene 2e was synthesized following a
procedure developed by Boger et al.2c
catalyst
entry enone alkene load/% solvent
yielda/%
eeb/%
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1b
1a
1d
1b
2d
2d
2d
2d
2d
2d
2d
2d
2d
2e
10
20
20
20
20
15
10
20
20
20
THF
THF
endo-3h /nd
endo-3h /45
dioxane endo-3h /41
CH2Cl2 endo-3h /30
7
81
90
94
99.5
99
83
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
endo-3h /70
endo-3h /69
endo-3h /69
endo-3g/76c 99.5
endo-3i/60
endo-3j/61
96.5
66
10
Isolated yield. Determined by chiral GC or HPLC. c 4% of
exo-diastereomer, no determination of the ee.
a
b
F igu r e 1. The X-ray structure of endo-3g.
The results for the reaction of 2d and 2e with the â,γ-
unsaturated R-keto esters 1a ,b,d (eq 6) are presented in
Table 2. The reaction requires room temperature to
proceed and a 20 mol % loading of the t-Bu-Box-Cu(OTf)2
4a catalyst is necessary, as the reaction proceeds with a
decrease of enantioselectivity when only 10 mol % of the
catalyst is applied (entry 1). The reason for the higher
catalyst loading might be due to the binding of 2d to the
catalyst 4a , which causes its deactivation. However,
using 20 mol % of 4a as the catalyst leads to a highly
regio-, diastereo-, and enantioselective reaction (entry 2).
The reaction of 1b with 2d gives only one regioisomer of
the HDA adduct and only the endo-diastereomer, endo-
3h , could be observed by 1H NMR spectroscopy. Changing
the solvent to dioxane, CH2Cl2, or Et2O leads to higher
enantioselectivity in the reaction, with the best results
in Et2O (entries 3-5). The ee of endo-3h under these
reaction conditions is measured as 99.5% (entry 5).
However, trying to reduce the catalyst loading for the
reaction in Et2O from 20 mol % to 15 mol % and 10 mol
%, leads to a decrease in enantioselectivity (entries 6, 7).
Applying the optimal condition to the phenyl-substituted
enone 1a leads to product endo-3g in 76% yield and with
excellent ee of 99.5% (entry 8). However, in this case, the
formation of 4% of the exo-product is observed. An X-ray
analysis of endo-3g proved that the major diastereomer
has a cis-relationship with the three substituents in the
ring, corresponding to the endo-product (Figure 1).
An exchange of the 4-ethoxy substituent with a ben-
zyloxy substituent in the â,γ-unsaturated R-keto ester,
(E)-4-(benzyloxy)-2-oxobut-3-enoic acid ethyl ester 1d ,

Synthesis of Optically Active Carbohydrate Derivatives
J . Org. Chem., Vol. 65, No. 15, 2000 4491
Sch em e 2
The first step in the synthesis of the ethyl â-D-
mannoside tetraacetate 8 from endo-3i is the reduction
of the ester followed by protection of the resulting alcohol
into an acetate which gives compound 6 with 92% overall
yield. Hydroboration of the double bond in 6, which
proceeds in moderate yield, gives the sugar derivative 7
after acetylation of the hydroxyl groups. Finally, com-
pound 8 is obtained after a palladium-catalyzed reduction
of the benzyl group and acetylation of the resulting
hydroxyl group. After measurement of the optical rotation
of 8, we were able to assign the absolute stereochemistry
of this compound by comparison with the optical rotation
of ethyl â-D-mannoside tetraacetate found in the litera-
ture ([R]D exp ) -48.8°; [R]D lit ) -49°).22 This stereochem-
istry is used for the assignment of the absolute configu-
ration of the HDA adducts.
The symmetric activated cyclic alkene 2,2-dimethyl-
1,3-dioxole 2f also reacts smoothly with 1a and 1b in the
presence of t-Bu-Box-Cu(OTf)2 4a (20 mol %) (eq 7). When
1a is the substrate, endo-3k is isolated in 76% yield
having an ee of 99%, while 1b gives similar results with
endo-3l isolated in 63% yield and 99% ee. Exo-3k and
exo-3l are also formed in 22% and 16% yield, and with
92% and 82% ee, respectively.
leads to a substrate which contains a protecting group
on the C-3 alcohol. The reaction of 1d with 2d in the
presence of t-Bu-Box-Cu(OTf)2 4a as the catalyst gave
endo-3i as the only diastereomer in 60% isolated yield
and with an ee of 96.5% (entry 9). The three different
protecting groups on the three alcohols in endo-3i are
orthogonal and make endo-3i a useful synthon for
carbohydrate derivatives. The reaction of 1b with 2e
catalyzed by t-Bu-Box-Cu(OTf)2 4a proceeds also with
high diastereoselectivity (only the endo-product is ob-
served) and in reasonable yield in Et2O as the solvent.
However, a decrease to 66% ee of endo-3j was found
(entry 10).
The catalytic enantioselective HDA reactions presented
in Table 2 can be used for the preparation of â-D-
mannopyranosides. The stereoselective synthesis of this
class of carbohydrates has been a long standing problem
in carbohydrate chemistry16 which has attracted the
attention of numerous groups worldwide and has suc-
cessfully been carried out by, for example, Crich et al.,17
Hindsgaul et al.,18 Stork et al.,19 Ogawa et al.,20 and
others.21 We will in the following present the synthesis
of ethyl â-D-mannoside tetraacetate 8 using the HDA
approach. Furthermore, the synthesis of 8 allows us to
assign the absolute stereochemistry of the product by
comparison to literature.22 The synthesis of 8 from endo-
3i is presented in Scheme 2.
To obtain the carbohydrate derivative, the methodology
described in eq 5 was applied to endo-3k for the introduc-
tion of the alcohol at the carbon-4 position and reduction
of the ester. The carbohydrate derivative 9 was isolated
in 63% overall yield and as an optically pure compound
(eq 8). Furthermore, an X-ray structure analysis of 9
(16) See, for example: Barresi, F.; Hindsgaul, O. Synthesis of â-D-
mannose Containing Oligosaccharides. In Modern Methods in Carbo-
hydrate Synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic
Publishers: Amsterdam, 1996; pp 251-276.
(17) See, for example: (a) Crich, D.; Sun, S. J . Am. Chem. Soc. 1998,
120, 435-436. (b) Crich, D.; Sun, S. J . Org. Chem. 1996, 61, 4506-
4508. (c) Crich, D.; Sun, S. J . Org. Chem. 1997, 62, 1198-1199. (d)
Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(18) (a) Barresi, F.; Hindsgaul, O. J . Am. Chem. Soc. 1991, 113,
9376-9377. (b) Barresi, F.; Hindsgaul, O. Synlett 1992, 759-761. (c)
Barresi, F.; Hindsgaul, O. Can. J . Chem. 1994, 72, 1447-1465.
(19) (a) Stork, G.; Kim, G. J . Am. Chem. Soc. 1992, 114, 1087-1088.
(b) Stork, G.; La Clair J . J . J . Am. Chem. Soc. 1996, 118, 247-248.
(20) (a) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33,
1765-1767. (b) Ito, Y.; Ogawa, T. J . Am. Chem. Soc. 1997, 119, 5562-
5566.
showed the anti-relationship of the alcohol on carbon-4,
formed in the hydroboration/oxidation step, with the
substituents on carbon-3 and carbon-5 (Figure 2).
To show the potential of the catalytic enantioselective
HDA reaction, the enones 1a , 1b, and 1d were reacted
(21) See also: (a) Hodosi, G.; Kova´c, P. J . Am. Chem. Soc. 1997,
119, 2335-2336. (b) Srivastava, V. K.; Schuerch, C. Tetrahedron Lett.
1979, 20, 3269-3272.
(22) Asp, L.; Lindberg, B. Acta Chem. Scand. 1952, 6, 947-948.

4492 J . Org. Chem., Vol. 65, No. 15, 2000
Audrain et al.
F igu r e 2. The X-ray structure of 9.
with 4H-1,3-dioxine 2g23 catalyzed by t-Bu-Box-Cu(OTf)2
4a (eq 9). The alkene 2g can lead to a new procedure for
the synthesis of C-branched sugars, subunits which are
found in numerous natural compounds.24 The HDA
reaction between 1a ,b,d and 2g can facilitate the syn-
thesis of 2-C-analogues of carbohydrates. Two recent
articles showed new methods to get to these particular
compounds.25 The present HDA reaction could be an
alternative: it proceeds smoothly, giving the three endo-
diastereomers 3m , 3n , and 3o in 66%, 65%, and 81%
yield, and high ee’s 93%, 96%, and 91%, respectively. The
formation of the exo-diastereomer is also observed, but
only for the reaction of enone 1a where exo-3m is formed
in 11% yield.
F igu r e 3. The four different diastereoselective approaches
of an alkene such as ethyl vinyl ether to γ-substituted â,γ-
unsaturated R-keto ester (E ) EtOOC).
The catalytic HDA method developed has a high regio-,
diastereo-, and enantioselectivity. The regioselectivity in
this reaction is controlled by the electronic effects in the
alkene, thus alkenes 2d and 2e have been chosen so that
the most electron-rich oxygen becomes the one at the
anomeric position in the product. The diastereoselectivity
is controlled by both electronic and steric factors. Elec-
tronic effects favor the formation of the endo-product, but
when the size and shape of the alkene interact with the
enantiodirecting ligand the exo-product is formed. This
can be rationalized from the different diastereoselectivi-
ties obtained by reaction with the different alkenes: ethyl
vinyl ether 2a (99% de), 2,3-dihydro-furan 2b (96% -
locked), 4H-1,3-dioxine 2g (75% - locked and more bulky
than 2b), tert-butyl vinyl ether (60% - very bulky),10b 2,2-
dimethyl-1,3-dioxole 2f (60% - bulky and locked).
The diastereochemistry of the product formed in the
HDA reaction depends on the geometry of the transition
structures. There are four different transition states
through which the HDA reaction can proceed, the two
endo- and two exo-orientations. The four transition
structures1c leading to the two diastereomers of the
reaction of γ-substituted â,γ-unsaturated R-keto esters
with ethyl vinyl ether are outlined in Figure 3. The cis-
adduct can be formed by either an endo-E-syn or exo-Z-
syn orientation, whereas the trans-adduct is obtained by
either an exo-E-anti or endo-Z-anti orientation.
The results for the catalytic enantioselective reactions
presented in this paper have shown that the cis-cycload-
duct is the diastereomer formed, by either an endo-E-
syn or exo-Z-syn orientation of the electron-rich alkene
in the transition state. The γ-substituted â,γ-unsaturated
R-keto esters substrates all have the γ-substituent trans
[(E)] and therefore the endo-E-syn orientation is the
preferred orientation of the alkene when approaching the
â,γ-unsaturated R-keto ester.
The reaction presented in eq 9 leads to a synthetic
procedure for the preparation of unnatural synthetic
acetal-protected 2-C-branched carbohydrates 10 as out-
lined in eq 10. The acetal functionality of compound 10
Preparing crystals of dicarbonyl compounds coordi-
nated to the catalyst has proved illusive with only
crystals with 2 equiv of water per copper center, which
are similar to those published by Evans et al.10c,d,26 From
the X-ray structures it appears that chiral bisoxazoline
copper(II) coordinated complexes can have different geo-
metrical structures depending on the coordination num-
ber of copper. When the coordination number is four,
can then be removed, forming a CH2OH group on carbon-
2, which is attractive for further coupling reactions, e.g.,
unnatural oligosaccharide synthesis.
(23) Groth, U.; Scho¨llkopf, U.; Tiller, T. Tetrahedron 1991, 47, 2835-
2842.
(24) (a) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach; Pergamon Press: Oxford, 1983. (b) Fraser-Reid, B.
Acc. Chem. Res. 1996, 29, 57-66.
(25) (a) Linker, T.; Sommermann, T.; Kahlenberg, F. J . Am. Chem.
Soc. 1997, 119, 9377-9384. (b) Beyer, J .; Madsen, R. J . Am. Chem.
Soc. 1998, 120, 12137-12138.

Synthesis of Optically Active Carbohydrate Derivatives
J . Org. Chem., Vol. 65, No. 15, 2000 4493
This approach is in accordance with the absolute config-
uration of the HDA adduct obtained using the (S)-t-Bu-
Box-Cu(II) (S)-4a catalyst. The preferred endo-E-syn
orientation of the electron-rich alkene might be due to a
favorable electronic interaction between the oxygen atom
of the alkene and the metal center of the catalyst.
However, when the steric bulk of the substituent at the
oxygen atom of the vinyl ether increases, e.g., from ethyl
vinyl ether to tert-butyl vinyl ether,10b the diastereose-
lectivity of the reaction is reduced. This reduction might
be caused by an increased steric repulsion between the
tert-butyl substituent of the vinyl ether and the tert-butyl
of the chiral ligand located on the same side as the alkene
approaches.
The reason for the high enantioselectivity is (i) the near
perfect shielding of the reacting enone; (ii) the low degree
of freedom of the enones due to the bidentate coordination
and the required s-cis conformation for the reaction to
proceed.
F igu r e 4. The X-ray structure of the hydrolyzed enone 1b
coordinated to the chiral catalyst (S)-t-Bu-Box-Cu(II) 11.
Su m m a r y
We have shown that it is possible to use a highly
enantioselective hetero-Diels-Alder (HDA) reaction cata-
lyzed by the tert-butyl-substituted bisoxazoline copper-
(II) complex (S)-4a for the synthesis of carbohydrate
derivatives. In one reaction step, substituted dihydropy-
ran compounds with useful chemical handles are ob-
tained with high ee from two simple acyclic precursors.
The reagents can have different substituents, and the
reactions proceed generally in good to high yield. In the
HDA step, up to three chiral centers are formed with a
high degree of stereoselectivity at each center. The HDA
product can be converted in a few steps to interesting
derivatives of both natural and unnatural carbohydrates
and it is shown how a â-D-mannoside can be synthesized.
Other derivatives synthesized include optically active
spirosugars and C-branched sugars. The absolute con-
figuration of the products, and isolation of a chiral
bisoxazoline copper(II)-hydrolyzed enone complex, indi-
cate a reaction mechanism by which the â,γ-unsaturated
R-keto ester coordinates to the copper(II) center in a
bidentate fashion. This leads to a square-planar inter-
mediate in which the si-face of the reacting carbonyl is
available for approach of the alkene.
F igu r e 5. The endo-E-syn approach to ethyl vinyl ether to a
bidentate coordinated (E)-4-ethoxy-2-oxobut-3-enoic acid ethyl
ester to the (S)-t-Bu-Box-Cu(II) catalyst.
copper(II) exhibits distorted square-planar geometry with
a dihedral angle for the O(H2O)-Cu-N-C(chiral carbon
atom in ligand) in the range from +33.3° for t-Bu-Box-
2+
2+ 26a
Cu(OH2)2 to -9.3° for Ph-Box-Cu(OH2)2
.
A penta-
coordinated complex t-Bu-Box-Cu(OH2)2(OTf)2+ has also
been characterizedandshowsa square-pyramidalgeometry.10c,d
A chiral bisoxazoline copper(II) complex, with an alky-
lidene malonate coordinated to copper, has also been
isolated and characterized by X-ray analysis and shows
a distorted square-planar geometry.26b By chance a failed
reaction with enone 1b gave a crystal of the anion of the
hydrolyzed enone bound to the chiral bisoxazoline copper-
(II) catalyst 11 and is shown in Figure 4. The structure
of complex 11 also shows a distorted square-planar
geometry at the copper(II) center with a dihedral angle
of 16.1° and 14.0° for the O(enol/ketone)-Cu-N-C(chiral
carbon atom in the ligand) angles, respectively.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under an
atmosphere of N2 using anhydrous solvents and flame-dried
glassware. Commercially available compounds were used
without further purification, except for the vinyl ethers 2a ,b
which were distilled over sodium before use. Solvents were
dried according to standard procedures. Purification of the
products was carried out either by kugelrohr distillation or
by flash-chromatography (FC) using Merck silica gel 60 (230-
400 mesh). 1H and 13C NMR spectra were recorded at 300 and
75 MHz respectively, using CDCl3 as the solvent and are
The postulated intermediate presented in Figure 5 is
based on the assumption that the γ-substituted â,γ-
unsaturated R-keto ester 1b coordinates in a bidentate
fashion by the carbonyl oxygen atoms to the (S)-t-Bu-
Box-Cu(II) catalyst similar to the structure in Figure 4.
The approach of the electron-rich alkene to 1b when
coordinated to the catalyst will thus take place toward
the si-face of the reacting carbonyl, as the re-face is
shielded by the tert-butyl substituent of the chiral ligand.
1
reported in ppm downfield from TMS (δ ) 0) for H NMR and
relative to the central CDCl3 resonance (δ ) 77.00) for 13C
NMR. The enantiomeric excess (ee) of the products were
determined by chiral GC and GC-MS using a Chrompack
Chiralsil-Dex CB column, or by HPLC using a Daicel Chiral-
pak AD column, a Chiralcel OD column, or a Chiralcel OJ
column.
(26) (a) Evans, D. A.; J ohnson, J . A.; Burgey, C. S.; Compos, K. R.
Tetrahedron Lett. 1999, 40, 2879-2882. (b) Evans, D. A.; Rovis, T.;
Kozlowski, M. C.; Tedow, J . S. J . Am. Chem. Soc. 1999, 121, 1994-
1995.
Ma ter ia ls. 2,2′-Isopropylidenebis[(4S)-4-tert-butyl-2-oxazo-
line], (R)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline), CuBr2,
Cu(OTf)2, and AgPF6 from Aldrich were stored under an inert

4494 J . Org. Chem., Vol. 65, No. 15, 2000
Audrain et al.
atmosphere and used without further purification. Ethyl
oxochloro acetate and the alkenes 2a and 2b were com-
mercially available from Aldrich and Fluka. The alkenes 2c,12
2d , 2e,27a,b 2f,2c and 2g27c were prepared according to literature
procedures. The enones (E)-4-ethoxy-2-oxobut-3-enoic acid
ethyl ester 1b28a,b and (E)-2-oxopent-3-enoic acid ethyl ester
1c28c,d were prepared according to literature procedures.
(E)-2-Oxo-4-p h en ylbu t-3-en oic Acid Meth yl Ester (1a ).
Acetyl chloride (12 mL) was added dropwise to MeOH (70 mL)
cooled in an ice bath to produce dry hydrochloric acid.
Potassium benzylidene pyruvate29 (10.7 g, 50 mmol) was added
at 0 °C. The reaction was warmed to room temperature and
stirred for 2 h and then refluxed overnight. The solvent was
removed by evaporation. Water (25 mL) was added to the crude
product which was then extracted with CH2Cl2 (25 mL × 2).
The combined organic phases were washed with NaHCO3 (25
mL × 2) and then with water (25 mL) to give 1a in 91% yield.
The yellow solid was recrystallized from abs EtOH: mp 70-
71 °C; 1H NMR δ 7.88 (d, 1H, J ) 16.3 Hz), 7.63 (dd, 2H, J )
7.4, 1.7 Hz), 7.46-7.40 (m, 3H), 7.37 (d, 1H, J ) 16.3 Hz), 3.93
(s, 3H); 13C NMR δ 182.4, 162.5, 148.7, 134.0, 131.7, 129.1,
129.1, 120.4, 53.1; mass (TOF ES+): m/z 213 (M + Na)+;
HRMS calcd for C11H10NaO3 213.0528, found 213.0517.
(E)-4-(Ben zyloxy)-2-oxob u t -3-en oic Acid E t h yl E st er
(1d ). Ethyl oxochloro acetate (20.5 g, 150 mmol) and benzyl
vinyl ether30 (23.5 g, 175 mmol) were mixed and stirred for 1
day at 0 °C. The solution was evaporated and kugelrohr
distilled under reduced pressure (0.1 mBar) at 230 °C to give
a yellow oil of 1d in 50% yield (17.6 g). Though 1d is unstable
on silica, the oil could be further purified by flash chromatog-
raphy (FC) using EtOAc:pentane 1:10 as eluent. The FC of
2.25 g oil gave 1.01 g of a pale yellow oil which crystallized
into a white solid in the freezer: 1H NMR δ 7.96 (d, 1H, J )
12.4 Hz), 7.43-7.30 (m, 5H), 6.31 (d, 1H, J ) 12.4 Hz), 5.03
(s, 2H), 4.32 (q, 2H, J ) 7.1 Hz), 1.37 (t, 3H, J ) 7.1 Hz); 13C
NMR δ 182.2, 166.7, 162.3, 134.5, 128.90, 128.85, 127.9, 102.7,
74.1, 62.4, 14.4; mass (TOF ES+): m/z 257 (M + Na)+; HRMS
calcd for C13H14NaO4 257.0790, found 257.0791.
δ 163.2, 142.8, 142.3, 128.5, 127.5, 126.8, 114.5, 100.0, 64.7,
52.2, 37.8, 36.0, 15.1; mass (TOF ES+): m/z 285 (M + Na)+;
HRMS calcd for C15H18NaO4 285.1103, found 285.1111.
P r ep a r a tion of Ca ta lyst (S)-4a -Cu (P F 6)2. To a flame-
dried Schlenk tube were added CuBr2 (22.3 mg, 0.10 mmol),
AgPF6 (50.6 mg, 0.20 mmol), and 2,2′-isopropylidenebis[(4S)-
4-tert-butyl-2-oxazoline] (30.9 mg, 0.105 mmol) under N2. The
Schlenk tube was kept in darkness, and the mixture was dried
under vacuum for 1-2 h. Anhydrous CH2Cl2 (2.0 mL) was
added, and the resulting suspension was stirred vigorously
overnight. The white precipitate was filtered from the green
catalyst solution through a Celite plug in a Pasteur pipet with
N2 pressure.
4-P h en yl-2,3,3a ,7a -t et r a h yd r o-4H-fu r o[2,3-b]p yr a n -6-
ca r boxylic Acid Meth yl Ester (3b). According to the general
procedure dihydrofuran 2b (113 µL, 1.50 mmol) was reacted
with 1a (190 mg, 1.0 mmol) in THF (2 mL) at -78 °C in 2
days with 10 mol % catalyst. Purification by FC on silica gel
(30% Et2O in heptane) gave endo-3b as a colorless oil in 96%
yield in 95% de with >99% ee detected by chiral GC. [R]rt
)
D
-65.7° (c ) 0.0127 g/mL, Et2O); 1H NMR δ 7.37-7.20 (m, 5H),
6.20 (dd, 1H, J ) 2.7, 1.1 Hz), 5.64 (d, 1H, J ) 3.7 Hz), 4.17
(td, 1H, J ) 9.0, 2.0 Hz), 4.16 (dd, 1H, J ) 7.6, 2.7 Hz), 3.86
(ddd, 1H, J ) 9.7, 9.0, 7.3 Hz), 3.83 (s, 3H), 2.65 (m, 1H), 1.71
(tt, 1H, J ) 12.3, 7.3 Hz), 1.34 (dtd, 1H, J ) 12.3, 7.3, 2.0 Hz);
13C NMR δ 162.9, 142.4, 141.0, 128.6, 127.5, 127.0, 110.0,
101.3, 68.4, 52.3, 43.9, 38.1, 24.5; mass (TOF ES+): m/z 283
(M + Na)+; HRMS calcd for C15H16NaO4 283.0946, found
283.0939.
4-Eth oxy-2,3,3a ,7a -tetr a h yd r o-4H-fu r o[2,3-b]p yr a n -6-
ca r boxylic Acid Eth yl Ester (3c). According to the general
procedure dihydrofuran 2b (113 µL, 1.50 mmol) was reacted
with 1b (172 mg, 1.0 mmol) in THF (2 mL) at -45 °C in 2
days with 10 mol % catalyst. Purification by FC on silica gel
(30% Et2O in heptane) gave endo-3c as a colorless crystalline
compound in 84% yield in >98% de with 98% ee detected by
chiral GC. [R]rt ) -32.1° (c ) 0.0106 g/mL, CHCl3); 1H NMR
D
δ 6.01 (dd, 1H, J ) 2.2, 1.5 Hz), 5.66 (d, 1H, J ) 4.0 Hz), 4.50
(dd, 1H, J ) 6.6, 2.2 Hz), 4.26 (qd, 2H, J ) 7.1, 4.4 Hz), 4.24
(ddd, 1H, J ) 17.9, 9.2, 3.5 Hz), 3.97 (dt, 1H, J ) 9.2, 8.1 Hz),
3.60 (q, 2H, J ) 7.1 Hz), 2.75 (m, 1H), 2.01 (m, 2H), 1.31 (t,
3H, J ) 7.1 Hz), 1.24 (t, 3H, J ) 7.1 Hz); 13C NMR δ 162.1,
141.6, 108.6, 102.2, 70.6, 68.4, 64.3, 61.4, 42.5, 23.7, 15.4, 14.2;
Gen er a l P r oced u r e for th e Heter o-Diels-Ald er Rea c-
tion s of En on es w ith Alk en es Ca ta lyzed by (S)-4a -Cu -
(OTf)2. P r ep a r a tion of 6-Eth oxy-4-p h en yl-5,6-d ih yd r o-
4H-p yr a n -2-ca r boxylic Acid Meth yl Ester (3a ). To a flame-
dried Schlenk tube was added Cu(OTf)2 (36.1 mg, 0.1 mmol)
and 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (30.9
mg, 0.105 mmol) under N2. The mixture was dried under
vacuum for 1-2 h, anhydrous solvent (2.0 mL) was added, and
the resulting suspension was stirred vigorously for 1-5 h. The
catalysts are green and homogeneous in all the solvents used
except in Et2O in which the catalysts were heterogeneous. To
the catalyst in solution at 0 °C were added the enone 1a (190
mg, 1.0 mmol) and then 1.5 equiv of ethyl vinyl ether 2a (143
µL, 1.50 mmol), and the reaction was stirred at 0 °C overnight.
Purification by FC on silica gel (CH2Cl2) gave endo-3a as a
colorless oil in 93% yield in 98% de with 99% ee detected by
HPLC using a Chiralpak OJ column (hexane:i-PrOH 98:2), 0.5
mass (TOF ES+): m/z 265 (M + Na)+; HRMS calcd for C12H18
NaO5 265.1052, found 265.1042.
-
4-Met h yl-2,3,3a ,7a -t et r a h yd r o-4H -fu r o[2,3-b]p yr a n -6-
ca r boxylic Acid Eth yl Ester (3d ). According to the general
procedure, dihydrofuran 2b (113 µL, 1.50 mmol) was reacted
with 1c (142 mg, 1.0 mmol) in THF (2 mL) at -78 °C in 2
days with 10 mol % catalyst. Purification by FC on silica gel
(25% Et2O in hexane) gave endo-3d as an oil in 51% yield in
>98% de with >99% ee detected by chiral GC. [R]rt ) -42.3°
D
(c ) 0.0052 g/mL, Et2O); 1H NMR δ 5.77 (dd, 1H, J ) 2.4, 1.4
Hz), 5.47 (d, 1H, J ) 3.8 Hz), 4.22 (qd, 2H, J ) 7.1, 1.7 Hz),
4.18 (ddd, 1H, J ) 9.7, 8.2, 2.3 Hz), 3.93 (ddd, 1H, J ) 9.7,
8.2, 7.3 Hz), 2.86 (qd, 1H, J ) 7.3, 2.4 Hz), 2.37 (m, 1H), 1.88
(dtd, 1H, J ) 12.4, 7.3, 2.3 Hz), 1.67 (tt, 1H, J ) 12.4, 9.7 Hz),
1.28 (t, 3H, J ) 7.1 Hz), 1.10 (d, 3H, J ) 7.3 Hz); 13C NMR δ
162.6, 140.9, 112.8, 101.2, 68.3, 61.2, 43.1, 26.7, 23,5 17.9, 14.2.
9-Eth oxy-1,6-dioxaspir o[4.5]dec-7-en e-7-car boxylic Acid
Eth yl Ester (3e). According to the general procedure, the exo-
cyclic vinyl ether 2c (84 mg, 1.0 mmol) was reacted with 1b
(86 mg, 0.5 mmol) in Et2O (2 mL) at -78 °C in 16 h with 20
mol % catalyst. Purification by FC on silica gel (pentane:EtOAc
5:1) gave 2 products: endo-3e as a colorless oil isolated in
62.5% yield with 74% ee detected by HPLC using a Chiralpak
mL/min: [R]rt ) +1.5° (c ) 0.0103 g/mL, CH2Cl2); 1H NMR δ
D
7.34-7.20 (m, 5H), 6.16 (dd, 1H, J ) 3.2, 1.1 Hz), 5.16 (dd,
1H, J ) 7.7, 2.2 Hz), 4.04 (dq, 1H, J ) 9.3, 7.1 Hz), 3.81 (s,
3H), 3.73 (ddd, 1H, J ) 9.5, 7.0, 3.2 Hz), 3.63 (dq, 1H, J ) 9.3,
7.1 Hz), 2.31 (dddd, 1H, J ) 13.5, 7.0, 2.2, 1.1 Hz), 1.97 (ddd,
1H, J ) 13.5, 9.5, 7.7 Hz), 1.23 (t, 3H, J ) 7.1 Hz); 13C NMR
(27) (a) Wulff, G.; Birnbrich, P. Chem. Ber. 1992, 125, 473-477. (b)
Posner, G. H.; Nelson, T. D. Tetrahedron 1990, 46, 4573-4586. (c)
Groth, U.; Scho¨llkopf, U.; Tller, T. Tetrahedron 1991, 47, 2835-2842.
(28) (a) Tietze, L. F.; Meier, H.; Voss, E. Synthesis 1988, 274-277.
(b) Effenberg, F.; Maier, R.; Scho¨nwa¨lder, K. H.; Ziegler, T.; Chem.
Ber. 1982, 115, 2766-2782. (c) Rambaud, M.; Bakasse, M.; Duguay,
G.; Villieras, J . Synthesis 1988, 564-566. (d) Schummer, A.; Yu, H.;
Simon, H. Tetrahedron 1991, 47, 9019-9034.
(29) Stecher, E. D.; Ryder, H. F. J . Am. Chem. Soc. 1952, 74, 4392-
4395.
(30) Corey, E. J .; Bass, J . D.; LeMahieu, R.; Mitra, R. B. J . Am.
Chem. Soc. 1964, 86, 5570-5583.
(31) Cascarno, G.; Altomare, A.; Giacivazzo, C.; Guagliardi, A.;
Moliterni, A. G. G.; Siliqi, D. Burla, M. C.; Polidori, G.; Camilli, M. J .
Appl. Chem. 1996, A52, C-50.
OD column (hexane:i-PrOH 99.5:0.5), 0.2 mL/min: [R]rt
)
D
+125.31° (c ) 0.0113 g/mL; CH2Cl2); 1H NMR δ 6.13 (dd, 1H,
J ) 2.2, 1.6 Hz), 4.29 (ddd, 1H, J ) 8.8, 6.1, 2.2 Hz), 4.20 (q,
2H, J ) 7.1 Hz), 4.08-3.90 (m, 2H), 3.64-3.48 (m, 2H), 2.34-
2.25 (m, 1H), 2.22-2.11 (m, 2H), 2.00-1.77 (m, 3H), 1.27 (t,
3H, J ) 7.1 Hz), 1.20 (t, 3H, J ) 7.1 Hz); 13C NMR δ 162.6,
142.4, 110.7, 108.7, 69.1, 68.5, 63.9, 61.1, 36.7, 35.4, 23.59, 15.4,
14.1; mass (TOF ES+): m/z 279 (M + Na)+; HRMS calcd for
C
13H20O5Na 279.1208, found 279.1215. exo-3e as a yellowish

Synthesis of Optically Active Carbohydrate Derivatives
oil isolated in 21% yield with 84% ee detected by HPLC using
J . Org. Chem., Vol. 65, No. 15, 2000 4495
3-Acet oxy-4-(b en zyloxy)-2-et h oxy-3,4-d ih yd r o-2H-p y-
r a n -6-ca r boxylic Acid Eth yl Ester (en d o-3i). According to
the general procedure, cis-1-acetoxy-2-ethoxyethene 2d (100
mg, 0.75 mmol) was reacted with 1d (117 mg, 0.5 mmol) in
Et2O (2 mL) at room temperature in 16 h with 20 mol %
catalyst. Purification by FC on silica gel (pentane:EtOAc 10:
1) gave the product as a pale yellow oil isolated in 60% yield
with 96.5% ee detected by HPLC using a Chiralcel OJ column
a Chiralpak OD column (hexane:i-PrOH 99.5:0.5), 0.3 mL/
1
min: [R]rt ) -5.12° (c ) 0.00508 g/mL; CHCl3); H NMR δ
D
6.24 (d, 1H, J ) 4.4 Hz), 4.22 (q, 2H, J ) 7.1 Hz), 4.14-3.98
(m, 3H), 3.69-3.50 (m, 2H), 2.26-2.08 (m, 4H), 2.03-1.87 (m,
1H), 1.85-1.74 (m, 1H), 1.28 (t, 3H, J ) 7.1 Hz), 1.23 (t, 3H,
J ) 7.1 Hz); 13C NMR δ 162.8, 143.1, 109.6, 107.2, 69.0, 68.11,
64.3, 61.2, 36.7, 35.7, 23.0, 15.4, 14.1; mass (TOF ES+): m/z
279 (M + Na)+; HRMS calcd for C13H20O5Na 279.1208, found
279.1220.
(hexane:i-PrOH 95:5), 0.4 mL/min: [R]rt ) -2.89° (CH2Cl2, c
D
1
) 0.0135 g/mL); H NMR δ 7.42-7.28 (m, 5H), 6.02 (dd, 1H,
9-(Ben zyloxy)-1,6-d ioxa sp ir o[4.5]d ec-7-en e-7-ca r boxyl-
ic Acid Eth yl Ester (3f): According to the general procedure
the exo-cyclic vinyl ether 2c (84 mg, 1.0 mmol) was reacted
with 1d (117 mg, 0.5 mmol) in Et2O (2 mL) at -78 °C in 16 h
with 20 mol % catalyst. Purification by FC on silica gel
(pentane:EtOAc 10:1 then 5:1) gave 2 products: endo-3f as a
colorless oil isolated in 40% yield with 76% ee detected by
HPLC using a Chiralpak OD column (hexane:i-PrOH 99.5:0.5),
J ) 2.8, 1.1 Hz), 5.39 (d, 1H, J ) 4.9 Hz), 5.09 (s, 1H), 4.69 (d,
1H, J ) 12.1 Hz), 4.55 (d, 1H, J ) 12.1 Hz), 4.34 (m, 1H), 4.25
(dq, 2H, J ) 7.1, 1.6 Hz), 3.99 (dq, 1H, J ) 9.9, 7.2 Hz), 3.68
(dq, 1H, J ) 9.9, 7.2 Hz), 2.15 (s, 3H), 1.30 (t, 3H, J ) 7.1 Hz),
1.25 (t, 3H, J ) 7.1 Hz); 13C NMR δ 170.6, 161.8, 142.3, 137.6,
128.5, 127.9, 127.8, 109.3, 97.9, 71.7, 68.8, 65.8, 65.7, 61.6, 21.0,
14.9, 14.2; mass (TOF ES+): m/z 387 (M + Na)+; HRMS calcd
for C19H24O7Na 387.1420, found 387.1370.
0.3 mL/min: [R]rt ) +114.22° (c ) 0.00914 g/mL; CH2Cl2);
3-Acet oxy-2-(b en zyloxy)-4-et h oxy-3,4-d ih yd r o-2H-p y-
r a n -6-ca r boxylic Acid Eth yl Ester (en d o-3j). According to
the general procedure, cis-1-acetoxy-2-(benzyloxy)ethene 2e
(144 mg, 0.75 mmol) was reacted with 1b (86 mg, 0.5 mmol)
in Et2O (2 mL) at room temperature in 36 h with 20 mol %
catalyst. Purification by FC on silica gel (pentane:EtOAc 10:
1) gave the product as a pale yellow oil, isolated in 61% yield
with 66% ee detected by HPLC using a Chiralcel OD column
D
1H NMR δ 7.38-7.28 (m, 5H), 6.21 (dd, 1H, J ) 2.7, 1.1 Hz),
4.64 (d, 1H, J ) 12.1 Hz), 4.58 (d, 1H, J ) 11.5 Hz), 4.43 (ddd,
1H, J ) 9.4, 6.6, 2.8 Hz), 4.23 (q, 2H, J ) 7.1 Hz), 4.11-4.01
(m, 1H), 4.00-3.91 (m, 1H), 2.40-2.28 (m, 1H), 2.26-2.13 (m,
2H), 2.06 (dd, 1H, J ) 12.7, 9.3 Hz), 2.02-1.80 (m, 2H), 1.30
(t, 3H, J ) 7.1 Hz); 13C NMR δ 162.6, 142.7, 138.1, 128.4, 127.7,
127.6, 110.3, 108.7, 70.6, 69.1, 68.6, 61.2, 36.6, 35.5, 23.6, 14.1;
mass (TOF ES+): m/z 341 (M + Na)+; HRMS calcd for
1
(hexane:i-PrOH 98:2), 0.6 mL/min; H NMR δ 7.40-7.25 (m,
C
18H22O5Na 341.1365, found 341.1343. exo-3f as a colorless oil
5H), 6.05 (d, 1H, J ) 3.3 Hz), 5.32 (dd, 1H, J ) 4.9, 1.1 Hz),
5.09 (d, 1H, J ) 1.1 Hz), 4.96 (d, 1H, J ) 12.6 Hz), 4.76 (d,
1H, J ) 12.6 Hz), 4.33-4.17 (m, 3H), 3.65 (dq, 1H, J ) 8.8,
7.2 Hz), 3.55 (dq, 1H, J ) 8.8, 7.2 Hz), 2.15 (s, 3H), 1.31 (t,
3H, J ) 7.2 Hz), 1.18 (t, 3H, J ) 7.2 Hz); 13C NMR δ 170.5,
161.7, 142.0, 136.6, 128.4, 128.0, 127.9, 109.8, 96.4, 70.6, 69.6,
66.0, 65.9, 61.5, 20.9, 15.3, 14.2; mass (TOF ES+): m/z 387 (M
+ Na)+; HRMS calcd for C19H24O7Na 387.1420, found 387.1314.
2,2-Dim eth yl-7-p h en yl-7,7a -d ih yd r o-3a H-[1,3]d ioxolo-
[4,5-b]p yr a n -5-ca r boxylic Acid Meth yl Ester (3k ). Accord-
ing to the general procedure 2,2-dimethyl-1,3-dioxole 2f (75
mg, 0.75 mmol) was reacted with 1a (95 mg, 0.5 mmol) in Et2O
(2 mL) at room temperature in 16 h with 20 mol % catalyst.
Purification by FC on silica gel (pentane:EtOAc 5:1) gave 2
products: exo-3k as a colorless oil, isolated in 22% yield with
isolated in 12% yield with 95% ee detected by HPLC using a
Chiralpak OD column (hexane:i-PrOH 99.5:0.5), 0.3 mL/min:
[R]rt ) +8.43° (c ) 0.00332 g/mL; CH2Cl2); 1H NMR δ 7.42-
D
7.28 (m, 5H), 6.25 (d, 1H, J ) 3.9 Hz), 4.68 (d, 1H, J ) 12.6
Hz), 4.63 (d, 1H, J ) 12.1 Hz), 4.24 (q, 2H, J ) 7.1 Hz), 4.17-
4.00 (m, 3H), 2.28-2.19 (m, 3H), 2.18-2.09 (dd, 1H, J ) 14.2,
6.6 Hz), 2.03-1.89 (m, 1H), 1.87-1.75 (m, 1H), 1.30 (t, 3H, J
) 7.1 Hz); 13C NMR δ 162.8, 143.4, 138.2, 128.4, 127.8, 127.7,
109.3, 107.2, 70.3, 69.1, 66.8, 61.2, 36.8, 35.6, 23.1, 14.2; mass
(TOF ES+): m/z 341 (M + Na)+; HRMS calcd for C18H22O5Na
341.1365, found 341.1367.
3-Acetoxy-2-eth oxy-4-p h en yl-3,4-d ih yd r o-2H-p yr a n -6-
ca r boxylic Acid Meth yl Ester (3g). According to the general
procedure cis-1-acetoxy-2-ethoxyethene 2d (100 mg, 0.75
mmol) was reacted with 1a (95 mg, 0.5 mmol) in Et2O (2 mL)
at room temperature in 16 h with 20 mol % catalyst. Purifica-
tion by FC on silica gel (pentane:EtOAc 10:1) gave two
products (80% yield): exo-3g as a colorless oil isolated in 4%
yield: 1H NMR δ 7.36-7.19 (m, 5H), 6.17 (d, 1H, J ) 2.8 Hz),
5.30 (d, 1H, J ) 2.2 Hz), 5.01 (dd, 1H, J ) 9.9, 2.2 Hz), 3.98-
3.78 (m, 5H), 3.71 (dq, 1H, J ) 9.9, 7.2 Hz), 1.97 (s, 3H), 1.25
(t, 3H, J ) 7.2 Hz); 13C NMR δ 170.1, 162.7, 140.1, 139.4, 128.7,
128.4, 127.5, 113.8, 95.6, 72.1, 64.9, 52.4, 40.1, 20.7, 15.0; mass
(EI): m/z 320 (M+•), 260, 215, 201, 172. endo-3g as a white
solid isolated in 76% yield with 99.5% ee according to chiral
92% ee according to chiral GC: [R]rt ) +166.92° (c ) 0.0026
D
1
g/mL; CHCl3); H NMR δ 7.40-7.18 (m, 5H), 6.24 (dd, 1H, J
) 5.5, 1.6 Hz), 5.55 (d, 1H, J ) 2.7 Hz), 4.25 (ddd, 1H, J )
2.7, 1.6, 1.6 Hz), 3.84 (m, 4H), 1.52 (s, 3H), 1.39 (s, 3H); 13C
NMR δ 162.7, 141.7, 138.8, 129.1, 128.0, 127.7, 111.4, 109.2,
95.3, 78.3, 52.4, 40.3, 27.9, 25.9; mass (EI): m/z 290 M+•. endo-
3k was isolated as a white solid in 76% yield with >99% ee
detected by HPLC using a Chiralcel OD column (hexane:i-
PrOH 99.5:0.5), 0.2 mL/min: [R]rtD ) -69.87° (c ) 0.008 g/mL;
1
CHCl3); H NMR δ 7.40-7.25 (m, 5H), 6.33 (dd, 1H, J ) 4.0,
2.2 Hz), 5.87 (d, 1H, J ) 3.3 Hz), 4.50 (ddd, 1H, J ) 5.0, 3.3,
1.7 Hz), 3.83 (m, 4H), 1.45 (s, 3H), 1.29 (s, 3H); 13C NMR δ
162.5, 142.2, 138.9, 128.7, 128.4, 127.2, 114.0, 111.8, 98.3, 77.4,
52.3, 40.2, 27.4, 25.9; mass (EI): m/z 290 (M+•), 275 (M - CH3),
231 (M - CO2Me), 173, 144, 100; HRMS (TOF ES+) calcd for
GC: [R]rt ) +31.33° (CHCl3, c ) 0.024 g/mL); 1H NMR δ
D
7.30-7.16 (m, 5H), 6.19 (d, 1H, J ) 3.3 Hz), 5.39 (d, 1H, J )
6.0 Hz), 5.18 (bs, 1H), 4.06-3.93 (m, 2H), 3.83 (s, 3H), 3.65
(dq, 1H, J ) 9.9, 7.1 Hz), 1.83 (s, 3H), 1.22 (t, 3H, J ) 7.1 Hz);
13C NMR δ 169.9, 162.6, 142.4, 137.0, 129.3, 128.1, 127.4,
112.2, 98.5, 67.7, 65.3, 52.3, 41.6, 20.6, 14.9; mass (EI): m/z
320 (M+•), 277, 260, 214, 172.
C
16H18O5Na 313.1052, found 313.1045.
7-Eth oxy-2,2-d im eth yl-7,7a -d ih yd r o-3a H-[1,3]d ioxolo-
[4,5-b]p yr a n -5-ca r boxylic Acid Eth yl Ester (3l). According
to the general procedure 2,2-dimethyl-1,3-dioxole 2f (75 mg,
0.75 mmol) was reacted with 1b (86 mg, 0.5 mmol) in Et2O (2
mL) at room temperature in 16 h with 20 mol % catalyst.
Purification by FC on silica gel (pentane:EtOAc 5:1) gave 2.
products: Exo-3l as a colorless oil, isolated in 16% yield with
3-Acet oxy-2,4-d iet h oxy-3,4-d ih yd r o-2H -p yr a n -6-ca r -
boxylic Acid Eth yl Ester (en d o-3h ). According to the
general procedure, cis-1-acetoxy-2-ethoxyethene 2d (100 mg,
0.75 mmol) was reacted with 1b (86 mg, 0.5 mmol) in Et2O (2
mL) at room temperature in 16 h with 20 mol % catalyst.
Purification by FC on silica gel (pentane:EtOAc 7:1) gave the
product as a pale yellow oil isolated in 70% yield with 99.5%
81.5% ee according to chiral GC-MS: [R]rt ) +55.95° (c )
D
0.0042 g/mL, CHCl3); 1H NMR δ 6.17 (dd, 1H, J ) 4.9, 1.6
Hz), 5.55 (d, 1H, J ) 2.7 Hz), 4.27 (q, 2H, J ) 7.1 Hz), 4.23
(m, 1H), 4.06 (dd, 1H, J ) 4.9, 1.6 Hz), 3.72-3.54 (m, 2H),
1.46 (s, 3H), 1.41 (s, 3H), 1.30 (t, 3H, J ) 7.1 Hz), 1.21 (t, 3H,
J ) 7.1 Hz); 13C NMR δ 162.1, 142.5, 111.3, 106.0, 95.5, 76.7,
68.5, 64.6, 61.6, 27.8, 25.9, 15.4, 14.2; mass (EI): m/z 272 (M+•);
HRMS (TOF ES+) calcd for C13H20O6Na 295.1158, found
295.1155. Endo-3l was isolated as a colorless oil in 62.5% yield
with >99% ee detected by HPLC using a Chiralcel OD column
ee according to chiral GC-MS: [R]rt ) -0.31° (CHCl3, c )
D
1
0.019 g/mL); H NMR δ 6.02 (d, 1H, J ) 2.7 Hz), 5.33 (d, 1H,
J ) 3.9 Hz), 5.08 (bs, 1H), 4.29-4.18 (m, 3H), 3.96 (dq, 1H, J
) 9.9, 7.2 Hz), 3.70-3.56 (m, 2H), 3.51 (dq, 1H, J ) 8.8, 7.2
Hz), 2.14 (s, 3H), 1.29 (t, 3H, J ) 7.2 Hz), 1.23 (t, 3H, J ) 7.2
Hz), 1.16 (t, 3H, J ) 7.2 Hz); 13C NMR δ 170.6, 161.8, 142.1,
109.6, 97.9, 69.9, 65.8, 65.6, 61.5, 20.9, 15.2, 14.9, 14.1; mass
(EI): m/z 302 (M+•), 257 (M - OEt), 243 (M - AcO), 173.

4496 J . Org. Chem., Vol. 65, No. 15, 2000
Audrain et al.
(hexane:i-PrOH 99.5:0.5), 0.2 mL/min: [R]rt ) -22.93 (c )
H2O2 (35% in H2O) were added. The solution was then heated
at 60 °C for 1 h. After the addition of H2O, the product was
extracted with EtOAc (10 mL × 3). The aqueous layer was
then saturated with NaCl and extracted with 25% i-PrOH/
CH2Cl2. The combined organic extracts were dried over MgSO4,
and the solvent was evaporated. The crude mixture was
separated by FC (3% MeOH in CH2Cl2) to afford 30 mg of diol
5 (40% yield for two steps) as a colorless oil which crystallized
D
0.015 g/mL, CHCl3); 1H NMR δ 6.25 (dd, 1H, J ) 2.2, 1.7 Hz),
5.80 (d, 1H, J ) 3.9 Hz), 4.58 (m, 1H), 4.29 (dd, 1H, J ) 2.2,
2.2 Hz), 4.24 (q, 2H, J ) 7.2 Hz), 3.78-3.58 (m, 2H), 1.42 (s,
3H), 1.37 (s, 3H), 1.27 (t, 3H, J ) 7.1 Hz), 1.28 (t, 3H, J ) 7.1
Hz); 13C NMR δ 161.6, 141.5, 113.2, 112.5, 98.5, 76.1, 71.4,
65.2, 61.3, 27.1, 26.0, 15.2, 14.1; mass (EI): m/z 272 (M+•), 227
(M+• - OEt), 199 (M+• - CO2Et); HRMS (TOF ES+) calcd for
1
C
13H20O6Na 295.1158, found 295.1152.
upon standing. H NMR δ 3.95-3.84 (m, 2H), 3.83-3.76 (m,
5-P h en yl-4a ,8a -d ih yd r o-4H ,5H -p yr a n o[2,3-d ][1,3]d i-
2H), 3.69-3.59 (m, 3H), 3.53-3.39 (m, 2H), 2.91 (bs, 1H), 2.29
(m, 1H), 2.15 (dd, 1H, J ) 12.7, 5.0 Hz), 2.10-1.77 (m, 3H),
1.73 (dd, 1H, J ) 9.3, 3.8 Hz), 1.67 (dd, 1H, J ) 12.6, 11.5
Hz), 1.20 (t, 3H, J ) 7.1 Hz); 13C NMR δ 106.6, 78.1, 72.0,
71.4, 67.4, 64.4, 62.9, 37.6, 37.2, 23.3, 15.6.
oxin e-7-ca r boxylic Acid Meth yl Ester (en d o-3m ). Accord-
ing to the general procedure 4H-1,3-dioxine 2g (91 mg, 1.0
mmol) was reacted with 1a (95 mg, 0.5 mmol) in Et2O (2 mL)
at room temperature in 36 h with 20 mol % catalyst. Purifica-
tion by FC on silica gel (pentane:EtOAc 10:1) gave the product
as a pale yellow oil in 66% yield with 93% ee detected by HPLC
using a Chiralcel OJ column (hexane:i-PrOH 92:8), 0.7 mL/
Acetic Acid 5-Acetoxy-4-(ben zyloxy)-6-eth oxy-5,6-d i-
h yd r o-4H-p yr a n -2-ylm eth yl Ester (6). To the compound
endo-3i (510 mg, 1.4 mmol) in THF (45 mL) at 0 °C was added
3.5 equiv of LAH (190 mg). The reaction mixture was strirred
at 0 °C for 30 min and 1 h at room temperature. Quenching of
the reaction was done by careful addition of 0.3 mL of H2O
and then 0.6 mL of NaOH (30% in H2O) and finally 0.6 mL of
H2O. The resulting mixture was filtered through Celite, and
the organic phase was dried over MgSO4. After evaporation
of the solvent, the diol was used immediately in the next step
without further purification. To the solution of the crude diol
(1.4 mmol) in dry pyridine (10 mL) was added Ac2O (2 mL).
The solution was stirred overnight and then quenched by
addition of ice-water. The solution was extracted with CH2-
Cl2 (10 mL × 5); the combined organic phases were washed
successively with AcOH 1 N (10 mL × 3), NaHCO3 aq (sat.)
(20 mL × 2) and a satd brine solution. The organic phase was
dried over MgSO4 and concentrated in a vacuum. The crude
was used immediately without further purification: 1H NMR
δ 7.35-7.23 (m, 5H), 5.37 (d, 1H, J ) 4.9 Hz), 5.01 (bs, 1H),
4.92 (d, 1H, J ) 2.7 Hz), 4.65 (d, 1H, J ) 12.1 Hz), 4.50 (d,
1H, J ) 12.1 Hz), 4.47 (s, 2H), 4.24 (m, 1H), 3.92 (dq, 1H, J )
9.9, 7.2 Hz), 3.63 (dq, 1H, J ) 9.9, 7.2 Hz), 2.14 (s, 3H), 2.05
(s, 3H), 1.23 (t, 3H, J ) 7.1 Hz); 13C NMR δ 170.5, 170.2, 148.0,
137.7, 128.2, 127.6, 127.6, 99.8, 97.4, 71.3, 68.9, 65.9, 65.3, 62.6,
20.9, 20.7, 14.8.
Acetic Acid 3,5-Dia cetoxy-4-(ben zyloxy)-6-eth oxytet-
r a h yd r op yr a n -2-ylm eth yl Ester (7). A solution of the crude
6 (1.29 mmol) in dry THF (35 mL) was cooled to 0 °C and was
treated with a 2 M solution of BH3‚SMe2 in THF (1.6 mL, 3.20
mmol). The resulting solution was stirred 1 h at 0 °C and
overnight at room temperature, and then 2.3 mL of a solution
of NaOH (30% in H2O) and 2.3 mL of H2O2 (35% in H2O) were
added. The solution was then warmed to 60 °C for 1 h. After
the addition of H2O (5 mL), the product was extracted with
EtOAc (10 mL × 3). The aqueous layer was then saturated
with NaCl and was extracted with 25% i-PrOH/CH2Cl2. The
combined organic extracts were dried over MgSO4, and the
solvent was evaporated. The crude product was used im-
mediately in the next step. To the solution of the crude diol
(1.29 mmol) in dry pyridine (9 mL) was added Ac2O (2 mL).
The solution was stirred overnight and quenched by addition
of ice-water. Then the solution was extracted with CH2Cl2
(10 mL × 5); the combined organic phases were washed
successively with AcOH 1 N (10 mL × 3), NaHCO3 aq (satd)
(20 mL × 2), and a satd brine solution (20 mL). The organic
phase was dried over MgSO4 and concentrated under vacuum.
The crude was purified by FC (pentane:Et2O 8:1) to afford 166
mg of compound 7 (35% yield for two steps): 1H NMR δ 7.38-
7.23 (m, 5H), 5.61 (d, 1H, J ) 3.3 Hz), 5.18 (dd, 1H, J ) 9.9
Hz), 4.70 (d, 1H, J ) 12.1 Hz), 4.54 (s, 1H), 4.41 (d, 1H, J )
12.1 Hz), 4.27 (dd, 1H, J ) 12.1, 6.0 Hz), 4.12 (dd, 1H, J )
12.1, 2.2 Hz), 3.93 (dq, 1H, J ) 9.9, 7.2 Hz), 3.63-3.49 (m,
3H), 2.20 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.22 (t, 3H, J ) 7.2
Hz); 13C NMR δ 170.7, 170.5, 169.5, 137.2, 128.3, 127.8, 127.7,
98.7, 76.3, 72.2, 70.8, 67.4, 67.4, 65.5, 62.7, 21.0, 20.7, 20.7,
14.8.
min: [R]rt ) -5.46° (c ) 0.0162 g/mL; CH2Cl2); 1H NMR δ
D
7.42-7.06 (m, 5H), 6.19 (dd, 1H, J ) 2.8, 1.1 Hz), 5.63 (bs,
1H), 5.16 (d, 1H, J ) 5.5 Hz), 4.79 (d, 1H, J ) 6.1 Hz), 4.01
(dd, 1H, J ) 7.1, 2.7 Hz), 3.86 (s, 3H), 3.55 (dd, 1H, J ) 12.1,
12.1 Hz), 3.14 (dd, 1H, J ) 11.6, 4.9 Hz), 2.72-2.60 (m, 1H);
13C NMR δ 162.4, 142.7, 137.9, 128.8, 127.5, 127.4, 111.1, 95.9,
87.2, 63.5, 52.5, 39.4, 36.0; mass (TOF ES+): m/z 299 (M +
Na)+; HRMS calcd for C15H16O5Na 299.0895, found 299.0849.
5-E t h oxy-4a ,8a -d ih yd r o-4H ,5H -p yr a n o[2,3-d ][1,3]d i-
oxin e-7-ca r boxylic Acid Eth yl Ester (en d o-3n ). According
to the general procedure 4H-1,3-dioxine 2g (91 mg, 1.0 mmol)
was reacted with 1b (86 mg, 0.5 mmol) in Et2O (2 mL) at room
temperature in 36 h with 20 mol % catalyst. Purification by
FC on silica gel (pentane:EtOAc 10:1) gave the product as a
pale yellow oil in 65% yield with 96% ee detected by HPLC
using a Chiralcel OJ column (hexane:i-PrOH 95:5), 0.4 mL/
1
min: [R]rtD) -10.93° (c ) 0.0151 g/mL; CH2Cl2); H NMR δ
5.96 (dd, 1H, J ) 1.6, 1.6 Hz), 5.49 (d, 1H, J ) 1.7 Hz), 5.19
(d, 1H, J ) 6.1 Hz), 4.83 (d, 1H, J ) 6.1 Hz), 4.32 (dd, 1H, J
) 6.6, 2.2 Hz), 4.27 (q, 2H, J ) 7.2 Hz), 3.98 (dd, 1H, J ) 11.5,
4.9 Hz), 3.73 (dd, 1H, J ) 12.1, 12.1 Hz), 3.55 (q, 2H, J ) 7.2
Hz), 2.78 (m, 1H), 1.31 (t, 3H, J ) 7.2 Hz), 1.20 (t, 3H, J ) 7.2
Hz); 13C NMR δ 161.7, 141.6, 109.2, 95.5, 87.4, 70.8, 64.8, 62.7,
61.6, 34.6, 15.2, 14.2; mass (TOF ES+): m/z 281 (M + Na)+;
HRMS calcd for C12H18O6Na 281.1001, found 281.0984.
5-(Ben zyloxy)-4a ,8a -d ih yd r o-4H,5H-p yr a n o[2,3-d ][1,3]-
d ioxin e-7-ca r boxylic Acid Eth yl Ester (en d o-3o). Accord-
ing to the general procedure 4H-1,3-dioxine 2g (91 mg, 1.0
mmol) was reacted with 1d (117 mg, 0.5 mmol) in Et2O (2 mL)
at room temperature in 36 h with 20 mol % catalyst. Purifica-
tion by FC on silica gel (pentane:EtOAC, 10:1 then 7:1) gave
the product as a pale yellow oil in 81% yield with 91% ee
detected by HPLC using a Chiralcel OJ column (hexane:i-
PrOH 99:1), 0.4 mL/min: [R]rt ) +7.31° (c ) 0.0112 g/mL;
D
CH2Cl2); 1H NMR δ 7.42-7.28 (m, 5H), 6.01 (dd, 1H, J ) 1.6,
1.6 Hz), 5.48 (d, 1H, J ) 1.1 Hz), 5.21 (d, 1H, J ) 6.0 Hz),
4.85 (d, 1H, J ) 6.0 Hz), 4.59 (s, 2H), 4.42 (dd, 1H, J ) 6.6,
2.2 Hz), 4.29 (q, 2H, J ) 7.2 Hz), 4.09 (dd, 1H, J ) 12.1, 5.0
Hz), 3.80 (dd, 1H, J ) 12.1, 12.1 Hz), 2.82 (m, 1H), 1.33 (t,
3H, J ) 7.2 Hz); 13C NMR δ 161.7, 141.8, 137.2, 128.6, 128.4,
128.1, 127.6, 108.9, 95.5, 87.4, 71.0, 70.0, 62.7, 61.7, 34.5, 14.2;
mass (TOF ES+): m/z 343 (M + Na)+; HRMS calcd for
C
17H20O6Na 343.1157, found 343.1158.
9-Eth oxy-7-(h yd r oxym eth yl)-1,6-d ioxa sp ir o[4.5]d eca n -
8-ol (5). To the compound endo-3f (84 mg, 0.33 mmol) in THF
(10 mL) at 0 °C was added 2 equiv of LAH (40 mg). The
reaction mixture was strirred at 0 °C for 30 min and 1 h at
room temperature. Quenching of the reaction was done by
careful addition of 0.05 mL of H2O and then 0.1 mL of NaOH
(15% in H2O) and finally 0.1 mL of H2O. The resulting mixture
was filtered through Celite, and the organic phase was dried
over MgSO4. After evaporation of the solvent, the alcohol was
used immediately without further purification. A solution of
the crude alcohol (0.33 mmol) in dry THF (10 mL) was cooled
to 0 °C and was treated with a 2 M solution of BH3‚SMe2 in
THF (0.41 mL, 0.82 mmol). The resulting solution was stirred
for 1 h at 0 °C and overnight at room temperature, after which
0.6 mL of a solution of NaOH (30% in H2O) and 0.6 mL of
Syn th esis of Eth yl â-D-Ma n n osid e Tetr a a ceta te (8).
Compound 7 (188 mg, 0.44 mmol) was dissolved in EtOH (5
mL) and was set under vacuum and flushed with N2. This
procedure was repeated (3×), and Pd(OAc)2 (40 mg, 0.18 mmol)

Synthesis of Optically Active Carbohydrate Derivatives
J . Org. Chem., Vol. 65, No. 15, 2000 4497
1
was added. The reaction mixture was set under vacuum and
flushed with H2. The reaction mixture was stirred overnight
and then filtered through Celite, and the residual Pd(OAc)2
was washed thoroughly with EtOH and pyridine. The filtrate
was concentrated in vacuo and coevaporated with toluene (5
mL × 3). The residue was then taken into the next step
without further purification. To the solution of the crude
alcohol (0.44 mmol) in dry pyridine (4 mL) was added Ac2O
(0.7 mL). The solution was stirred overnight, quenched by
addition of ice-water. Next the solution was extracted with
CH2Cl2 (10 mL × 5); the combined organic phases were washed
successively with AcOH 1 N (10 mL × 3), NaHCO3 aq (satd)
(20 mL × 2), and a satd brine solution (20 mL). The organic
phase was dried over MgSO4 and concentrated under vacuum.
The crude was purified by FC (pentane:Et2O 2.5:1) to afford
standing. H NMR δ 7.50-7.30 (m, 5H), 5.32 (d, 1H, J ) 2.2
Hz), 4.21 (ddd, 1H, J ) 10.9, 9.3, 3.2 Hz), 4.19 (dd, 1H, J )
2.7, 2.7 Hz), 3.91-3.81 (m, 2H), 3.49 (ddd, 1H, J ) 9.3, 3.9,
3.9 Hz), 2.99 (dd, 1H, J ) 11.0, 3.3 Hz), 2.27 (dd, 1H, J ) 6.6,
6.6 Hz), 1.84 (d, 1H, J ) 3.3 Hz), 1.58 (s, 3H), 1.28 (s, 3H); 13
C
NMR δ 137.0, 129.7, 128.7, 127.8, 111.8, 97.6, 84.4, 78.7, 77.1,
66.6, 63.0, 50.9, 28.3, 25.8.
X-r a y Str u ctu r e Deter m in a tion of en d o-3c, en d o-3g, 9,
a n d th e Com p lex of Ca ta lyst w ith Hyd r olyzed En on e 11.
In all cases at least a hemisphere of data was collected at 120
K on
a SIEMENS SMART diffractometer using Mo KR
radiation (λ ) 0.71073 Å). The structures were solved by direct
methods (SIR97)31 and refined by full matrix least-squares
methods.
en d o-3c: Tetragonal, P41212, a ) 14.2997(6) Å, c ) 12.0909-
(7) Å; 16880 reflections measured, 3210 unique, 2883 with I
>3σ(I) used in refinement of 227 parameters; final R ) 0.029,
Rw ) 0.034.
en d o-3g: orthorhombic, Pca21, a ) 10.2673(7) Å, b ) 18.519-
(1) Å, c ) 8.7856(6) Å, 23936 reflections measured, 4039
unique, 1932 with I > 3σ(I) used in refinement of 208
parameters, final R ) 0.051, Rw ) 0.055.
Compound 9: monoclinic, P21/c, a ) 14.420(6) Å, b ) 5.944-
(3) Å, c ) 17.858(8) Å, â ) 113.813(6)°; 12548 reflections
measured, 4250 unique, 2645 with I >3σ(I) used in the
refinement of 262 parameters, final R ) 0.037, Rw ) 0.043.
Com p lex of Ca ta lyst w ith Hyd r olyzed En on e 11: ortho-
rhombic, P212121, a ) 9.6416(6) Å, b ) 14.9091(9) Å, c )
20.504(1) Å; 64800 reflections measured, 8639 unique, 7402
with I > 3σ(I) used in refinement of 511 parameters; final R
) 0.023, Rw ) 0.028.
In all structures the distances and angles fit the formulas
given in the text. All crystallographic data have been deposited
with the Cambridge Structural Database 12 Union Road,
Cambridge CB2 1EZ, UK (fax: (+44) 1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
153 mg of compound 8 (92% yield for two steps): [R]rt
)
D
1
-48.8° (c ) 0.015 g/mL; CHCl3); H NMR δ 5.41 (d, 1H, J )
2.7 Hz), 5.20 (dd, 1H, J ) 9.9 Hz), 5.00 (dd, 1H, J ) 9.9, 3.3
Hz), 4.61 (d, 1H, J ) 1.1 Hz), 4.26 (dd, 1H, J ) 12.1, 5.5 Hz),
4.09 (dd, 1H, J ) 12.1, 2.2 Hz), 3.87 (dq, 1H, J ) 9.9, 7.2 Hz),
3.65-3.60 (m, 1H), 3.55 (dq, 1H, J ) 9.9, 7.2 Hz), 2.14 (s, 3H),
2.04 (s, 3H), 1.99 (s, 3H), 1.94 (s, 3H), 1.16 (t, 3H); 13C NMR
δ 170.6, 170.4, 169.9, 169.5, 98.4, 72.3, 71.1, 68.9, 66.0, 65.8,
62.5, 20.8, 20.7, 20.6, 20.5, 14.8; mass (EI): m/z 361 (M - CH3),
317 (M - CO2Me).
5-(Hyd r oxym eth yl)-2,2-d im eth yl-7-p h en yltetr a h yd r o-
[1,3]d ioxolo[4,5-b]p yr a n -6-ol (9). To endo-3k (100 mg, 0.34
mmol) in THF (10 mL) at 0 °C was added 2 equiv of LAH (40
mg). The reaction mixture was strirred at 0 °C for 30 min and
1 h at room temperature. Quenching of the reaction was done
by careful addition of 0.05 mL of H2O and then 0.1 mL of
NaOH (30% in H2O) and finally 0.1 mL of H2O. The resulting
mixture was filtered through Celite, and the organic phase
was dried over MgSO4. After evaporation of the solvent, the
alcohol was used immediately without further purification. A
solution of the crude alcohol (0.34 mmol) in dry THF (10 mL)
was cooled at 0 °C and treated with a 2 M solution of BH3‚
SMe2 in THF (0.4 mL, 0.80 mmol). The resulting solution was
stirred for 1 h at 0 °C and overnight at room temperature,
and then 0.6 mL of a solution of NaOH (30% in H2O) and 0.6
mL of H2O2 (35% in H2O) were added. The solution was heated
at 60 °C for 1 h. After the addition of H2O, the product was
extracted with EtOAc (10 mL × 3). The aqueous layer was
saturated with NaCl and extracted with 25% i-PrOH/CH2Cl2.
The combined organic extracts were dried over MgSO4, and
the solvent was evaporated. The crude mixture was separated
by FC (2% MeOH in CH2Cl2) to afford 60 mg of diol 9 (63%
yield for two steps) as a colorless oil which crystallized upon
Ack n ow led gm en t. We are indebted to The Danish
National Science Foundation for financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for products 1a ,d , endo-3a -o, exo-3e-g,k ,l,5-7,9 and
X-ray data for endo-3c, endo-3g, 9, and complex of catalyst
with hydrolyzed enone 11. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O9918596