Total, asymmetric synthesis of ethyl D-ido-4-heptulosuronate derivatives starting from diethyl 4-oxopimelate

Article abstract of DOI:10.1016/S0957-4166(99)00120-2

Bromination of diethyl 4-oxopimelate, followed by double elimination of HBr and ketalization provided diethyl (E,E)-4,4-(ethylidenedioxy)hepta-2,5- dienedioate 4. Sharpless asymmetric dihydroxylation of 4 produced diethyl (2S,3S)-4,4-(ethylidenedioxy)-2,3

Full text of DOI:10.1016/S0957-4166(99)00120-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1283–1293
Total, asymmetric synthesis of ethyl D-ido-4-heptulosuronate
derivatives starting from diethyl 4-oxopimelate
Sandrine Lemaire-Audoire ∗ and Pierre Vogel
Section de Chimie de l’Université de Lausanne, BCH, CH 1015 Lausanne-Dorigny, Switzerland
Received 24 February 1999; accepted 30 March 1999
Abstract
Bromination of diethyl 4-oxopimelate, followed by double elimination of HBr and ketalization provided diethyl
(E,E)-4,4-(ethylidenedioxy)hepta-2,5-dienedioate 4. Sharpless asymmetric dihydroxylation of 4 produced diethyl
(2S,3S)-4,4-(ethylidenedioxy)-2,3-dihydroxyhept-5-enedioate (+)-5, with 78% e.e. The corresponding tetrol could
not be obtained in one step. Silylation of (+)-5 and a second asymmetric dihydroxylation, followed by silyla-
tion led to 20% of meso-diester 9 and 60% of diethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis[(t-butyl)dimethylsilyloxy]-
4,4-(ethylidenedioxy)heptanedioate (−)-10. Reductive desymmetrization of (−)-10 with DIBAL-H furnished,
after selective oxidation, ethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis-[(t-butyl)dimethylsilyloxy]-4,4-(ethylidenedioxy)-7-
oxoheptanoate (+)-13 which was then converted into ethyl 1,2,3,6-O-tetraacetyl-4,4-ethylidenedioxy-α- and β-D-
ido-heptapyranuronate (−)-15α,β and into the corresponding 3-(α-D-pyranosyl)propene (−)-16. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Recently we disclosed1 our approach to the synthesis of the C37–C45-F-ring fragment of the
spongistatins2 starting from (R)-(+)-3-benzyloxy-2-methyl-propan-1-ol. The method generates a
4-deoxy-4-methyl-D-glycero-L-gluco-heptopyranose intermediate using two sequential Sharpless di-
hydroxylations as key-steps. With the goal to generate analogues of these rare and powerful antimitotic
agents we have explored a route to precursors of 40-nor-40-oxo derivatives. This requires the preparation
of D-ido-4-heptulosuronate esters which is presented in this report. To our knowledge these sugars have
never been described, although heptoses,3,4 have been derived from hexose,5 pentose,6 treose7 and
glyceraldehyde derivatives,8 or through total synthesis using achiral starting materials.9
∗
Corresponding author. Fax: +1-412-169-239-75; e-mail: pierre.vogel@ico.unil.ch
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00120-2

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2. Results and discussion
Our initial plan was to carry out a double asymmetric dihydroxylation10 of a derivative of (E,E)-4-
oxohepta-2,5-dien-1,7-dioic acid which would generate in one step a C2-symmetrical tetrol with the D-
or L-ido configuration, followed by desymmetrization of the dioic system through reduction11 into a
monoaldehyde or a primary mono-alcohol. Unfortunately, this plan failed as we found that the double
dihydroxylation of 3 or 4 could not be achieved in a one-pot operation.
The starting oxodienedioate 3 was readily obtained from diethyl 4-oxopimelate 1 through selective
dibromination with bromine in CH2Cl2 at 0°C. This gave a major dibromide 2 isolated in 93% yield
which was either a meso-3,5-dibromo or a racemic threo-3,5-dibromo derivative (Scheme 1). Treat-
ment of 2 with triethylamine led to double elimination of HBr (CH2Cl2, 0°C) with formation of the
desired diethyl (E,E)-4-oxohepta-2,5-diene-1,7-dioate 3 isolated in 80% yield. Attempts to carry out
dihydroxylation or double dihydroxylation of dienone 3 under standard conditions10 failed to furnish
the desired diols or tetrols in satisfactory yields because concurrent retroaldolizations led to decompo-
sition. We were forced to convert the ketone moiety into an acetal and we chose for that to generate
the corresponding dioxolane 4 on treating 3 with 1,2-bis(trimethylsilyloxy)ethane and trimethylsilyl
trifluoromethanesulfonate.12 Applying the Sharpless dihydroxylation protocol to 4 [(DHQD)2PHAL
1%, OsO4 0.2%, N-methylmorpholine N-oxide in excess, 5 h] gave diol (+)-5 which was isolated in
82% yield. Under forcing conditions (long reaction times, higher concentrations of catalyst and ligand)
expected tetrols were formed very slowly and could not be isolated in reasonable yield (<10%). We
thus protected the diol as the disilyl ether (−)-6 [(t-Bu)Me2SiOSO2CF3, 2,6-lutidine, CH2Cl2]. The
enantiomeric purity of (+)-5 was 78% (established as shown below) and could not be improved by varying
the concentration or temperature.
Dihydroxylation of alkene (−)-6 was a slow reaction that required some higher concentrations of
catalyst and ligand than for the dihydroxylation of diene 4. It led to a 25:75 mixture of two diastereomeric
diols 7 and 8 (93%) which was silylated under standard conditions giving a mixture of tetrasilyl ethers
9 and (−)-10 which was separated by flash chromatography on silica gel, in 20% and 60% yields,
respectively (based on (−)-6). Selective reduction of (−)-10 with diisobutylaluminum hydride13 (DIBAL-
H, 4 equivalents) was possible at low temperature and with slow addition of the reducing agent (−78°C,
CH2Cl2) producing a mixture of alcohol 11 and diol 12 which was not purified but directly oxidized with
pyridinium chlorochromate (PCC) to give a mixture of monoaldehyde (+)-13 and dialdehyde 14 which
was separated by flash chromatography on silica gel in 86% and 5% yield, respectively (based on (−)-10).
Desilylation of (+)-13 with Bu4NF led to the formation of a mixture of pyranoses which was acetylated
under standard conditions to give an 89:11 mixture of α- and β-acetyl pyranosides 15α and 15β (60%
yield). Treatment of (−)-15α,β with allyltrimethylsilane and BF3·Et2O14 generated the α-C-glycoside
(−)-16 in moderate yield (35%).
The enantiomeric excess of (−)-6 was evaluated in the following fashion (Scheme 2). Ozonolysis
of (−)-6 generated aldehyde 17 (80%) which was reacted with (1R,2R)-1,2-diphenylethylenediamine15
which produced a 89:11 mixture of aminals 18 and 19 (1H NMR of the crude) establishing an e.e. of
78%.
The absolute configuration of compounds 5–16 was established in the following way (Scheme 3).
Diol (+)-5 was protected with p-methoxybenzoyl chloride to give the corresponding diester 20 (72%).
Ozonolysis, followed by reduction in situ with NaBH4 afforded primary alcohol 21. Upon treatment
with DBU in THF, at 0°C, lactonization occurred to give lactone 22. Circular dichroism of this cyclic
compound (Fig. 1) gave the absolute configuration (2S,3S) of diol (+)-5 as it displayed a typical exciton
split type of spectrum.16

S. Lemaire-Audoire, P. Vogel / Tetrahedron: Asymmetry 10 (1999) 1283–1293
1285
Scheme 1.
Scheme 2.
Distinction between meso-diester 9 ([α]25 0) and its threo-stereomer (−)-10 ([α]25 −8.2) was given
D
D
1
by their optical rotations. The H NMR spectrum of 9 showed one quadruplet for the CH2 protons of
1
the ethyl esters whereas the H NMR spectrum of (−)-10 showed two quadruplet×doublet for these
protons (they are diastereotopic in 10 and enantiotopic in 9). 2D-1H NMR (COSY, NOESY) confirmed
the structures of (−)-15 and (−)-16. Monoaldehyde (+)-13 was reacted with (1S,2S)-diphenylethylene

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S. Lemaire-Audoire, P. Vogel / Tetrahedron: Asymmetry 10 (1999) 1283–1293
Scheme 3.
Figure 1.
diamine to give an 88:12 mixture of aminals corresponding to an enantiomeric excess of 76%, showing
that there is no modification of the optical purity during the second dihydroxylation and the other steps.
3. Conclusion
The as yet unknown D-ido-4-heptulosuronic acid derivatives can be obtained from diethyl 4-
oxopimelate with an enantiomeric excess of 76%. The L-ido enantiomers can also be obtained since
the method used relies upon the Sharpless asymmetric dihydroxylation.
4. Experimental
General, see literature.17 FC=flash chromatography on silica gel. All 1H NMR signal assignments were
confirmed by 2D-1H NMR (COSY, NOESY).

S. Lemaire-Audoire, P. Vogel / Tetrahedron: Asymmetry 10 (1999) 1283–1293
1287
4.1. Diethyl (3RS,5RS)- or (3RS,5SR)-3,5-dibromo-4-oxoheptadioate 2
Bromine (13.4 ml, 0.26 mol) in soln in anhydrous CH2Cl2 (30 ml) was added dropwise to a stirred
soln of diethyl 4-oxopimelate (30 g, 0.13 mol, Fluka) in anhydrous CH2Cl2 cooled to 0°C. After the
addition, the soln was stirred at 20°C for 5 min and CH2Cl2 (250 ml) was added. The soln was washed
with 1 M Na2S2O3 in H2O, then dried (MgSO4) and concentrated in vacuo. Recrystallization from light
petroleum at −18°C: 47 g (93%), white crystals, m.p. 48–49°C, Rf: 0.57 (2:1, light petroleum:Et2O). IR
1
(KBr): 2985, 2940, 1725, 1460, 1375, 1200, 1030, 960, 940, 865, 830, 785, 665. H NMR (400 MHz,
3
3
2
3
CDCl3): 5.34 (dd, J=6.9, H-3, H-5), 4.19 (q, J=7.2, 2 CH2(Et)), 3.27, 3.01 (2dd, J=17.1, J=6.9,
H2C(2), H2C(6)), 1.27 (t, 3J=7.2, 2 Me(Et)). 13C NMR (100.6 MHz, CDCl3): 194.3 (C-4), 169.3 (C-1,
C-7), 61.3 (CH2(Et)), 49.5 (C-3, C-5), 38.2 (C-2, C-6), 14.1 (Me). CI-MS (NH3): 389 (1, M+H+), 343
(17, M·+−OEt), 315 (7), 263, 261 (33, M·+−OEt−Br), 209, 207 (90), 183, 181 (28), 127 (100), 99 (63).
4.2. Diethyl (E,E)-4-oxohepta-2,5-dienedioate 3
Triethylamine (35 ml, 0.248 mol) was added dropwise to a stirred soln of 2 (47 g, 0.121 mol) in
anhydrous CH2Cl2 (400 ml) cooled to 0°C. After stirring at 0°C for 30 min, H2O (400 ml) and CH2Cl2
(300 ml) were added and the mixture was shaken vigorously. The organic phase was washed with H2O
(700 ml, twice). After drying (MgSO4), the solvent was evaporated and the residue crystallized from 96%
EtOH: 21.8 g (80%), yellow needles, m.p. 49–50°C, Rf: 0.47 (1:2, light petroleum:Et2O). UV (MeCN):
1
246 (15 000). IR (KBr): 3070, 2985, 1725, 1675, 1285, 1195, 1090, 1000, 865, 805, 775, 705, 635. H
3
3
3
NMR (400 MHz, CDCl3): 7.23 (d, J=15.9, H-3, H-5), 6.81 (d, J=15.9, H-2, H-6), 4.29 (q, J=7.2, 2
CH2), 1.34 (t, 3J=7.2, 2 Me). 13C NMR (100.6 MHz, CDCl3): 188.2 (s, C-4), 165.1 (s, C-1, C-7), 137.5
(d, J=163, C-3, C-5), 133.2 (d, J=167, C-2, C-6), 61.6 (t, J=148), 14.1 (q, J=127). CI-MS (NH3): 226
(34, M·+), 197 (16, M·+−Et), 181 (56, M·+−OEt), 153 (29, M·+−COOEt), 127 (70), 99 (100). Anal. calcd
for C11H14O5 (226.23): C 58.41, H 6.19; found: C 58.31, H 6.19.
4.3. Diethyl (E,E)-4,4-(ethylidenedioxy)hepta-2,5-dienedioate 4
Trimethylsilyl trifluoromethanesulfonate (0.8 ml, 4.43 mmol) was added dropwise to a stirred soln of 3
(10 g, 44.3 mmol) and 1,2-bis(trimethylsilyloxy)ethane (16.3 ml, 66.4 mmol) in anhydrous CH2Cl2 (100
ml) cooled to −78°C. After stirring at −78°C for 1 h, the mixture was stirred at 20°C for 18 h. Pyridine
(0.9 ml, 11.2 mmol) was added and the mixture poured into a sat. aq. soln of NaHCO3 (250 ml). The aq.
layer was extracted with CH2Cl2 (250 ml, three times). The combined organic extracts were washed with
brine (100 ml) and dried (1:1, MgSO4:K2CO3). The solvent was evaporated and the residue was purified
by FC (1:3, light petroleum:Et2O): 9.8 g (82%), pale yellow oil, Rf: 0.27 (2:1, light petroleum:Et2O). UV
(MeCN): 203 (10 000). IR (film): 3060, 2980, 2900, 1720, 1660, 1270, 1180, 1035, 980, 950, 865, 710,
1
3
3
665. H NMR (400 MHz, CDCl3): 6.78 (d, J=15.7, H-3, H-5), 6.17 (d, J=15.7, H-2, H-6), 4.21 (q,
3J=7.2, 2 CH2), 4.00 (s, 4H), 1.29 (t, 3J=7.2, 2 Me). 13C NMR (100.6 MHz, CDCl3): 165.8 (s, C-1, C-7),
143.0 (d, J=163, C-2, C-6), 123.0 (d, J=166, C-3, C-5), 105.1, (s, C-4), 65.3 (t, J=150), 60.8 (t, J=148),
14.1 (q, J=127). CI-MS (NH3): 217 (25, M+H+), 241 (2), 224 (52), 197 (100), 171 (86), 143 (13), 97
(24). Anal. calcd for C13H18O6 (270.28): C 57.78, H 6.67; found: C 57.88, H 6.66.

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4.4. Diethyl (2S,3S)-4,4-(ethylidenedioxy)-2,3-dihydroxyhept-5-enedioate (+)-5
A mixture of compound 4 (5 g, 18.5 mmol), tert-butanol (60 ml), (DHQD)2PHAL (145 mg, 0.185
mmol), 60% N-methylmorpholine-N-oxide (NMO) in H2O (7.14 ml, 27.8 mmol) and 0.1 M OsO4 in
CCl4 (0.37 ml) was stirred at 20°C for 5 h. Aqueous 1 N HCl (100 ml) was added and the mixture was
extracted with EtOAc (150 ml, three times). The combined organic extracts were washed with a sat. aq.
soln of NaHCO3, and then dried (MgSO4). The solvent was evaporated in vacuo and the residue purified
by FC (1:1, light petroleum:Et2O): 4.62 g (82%), colorless oil, Rf: 0.24 (1:1, light petroleum:EtOAc).
25
25
25
55
[α]25 +10.3, [α]
+8.4, [α]
+9.3, [α]
+10.7, [α]
+11.0 (c=1.0, CH2Cl2). UV (MeCN): 206
D
577
546
435
405
(9800). IR (film): 3470, 2985, 2900, 1720, 1660, 1470, 1445, 1270, 1075, 1030, 950, 865, 715, 665. 1H
3
3
3
NMR (400 MHz, CDCl3): 6.90, (d, J=15.6, H-5), 6.21 (d, J=15.6, H-6), 4.41 (d, J=1.3, H-2), 4.30
(q, 3J=7.0, CH2), 4.22 (q, 3J=7.1, CH2), 4.06 (d, 3J=1.3, H-3), 4.13–4.15 (2m, CH2–CH2 of dioxolane),
2.31 (br. s, HO–C(2), HO–C(30)), 1.32 (t, 3J=7.0, CH3), 1.31 (t, 3J=7.1, CH3). 13C NMR (100.6 MHz,
CDCl3): 172.7, 165.8 (2s, C-1, C-7), 143.0 (d, J=162, C-6), 123.6 (d, J=166, C-5), 107.9 (s, C-4), 74.2
(d, J=147, C-2), 69.9 (d, J=148, C-3), 65.9, 65.0 (2t, J=152, dioxolane), 60.7, 60.4 (2t, J=157, 2 CH2),
14.1 (q, J=126, 2 Me). CI-MS (NH3): 305 (5, M+H+), 241 (4, M·+−OEt−H2O), 205 (71), 171 (100), 157
(9), 143 (23), 99 (26). Anal. calcd for C13H20O8 (304.29): C 51.32, H 6.58; found: C 51.15, H 6.60.
4.5. Diethyl (2S,3S)-2,3-bis[(t-butyl)dimethylsilyloxy]-4,4-(ethylidenedioxy)hept-5-enedioate (−)-6
(t-Butyl)dimethylsilyl trifluoromethanesulfonate (15.1 ml, 65.8 mmol) was added dropwise to a stirred
soln of (+)-5 (4 g, 13.16 mmol) in 2,6-lutidine (9.17 ml) and anhydrous CH2Cl2 (70 ml) cooled to 0°C.
After stirring at 0°C for 30 min, the mixture was stirred at 20°C for 6 h. Aqueous 2 N NaOH (150 ml)
was added and the phases were separated. The aq. layer was extracted with EtOAc (150 ml, three times).
The combined organic extracts were washed with aq. 1 N HCl (100 ml), then with brine (100 ml) and
then dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by FC (15:1, light
25
petroleum:EtOAc): 5.6 g (80%), colorless oil, Rf: 0.58 (4:1, light petroleum:EtOAc). [α]25 −4.5, [α]
D
577
25
25
25
−8.1, [α]
−8.6, [α]
−13.9, [α]
−17.2 (c=1.2, CH2Cl2). UV (MeCN): 204 (9700). IR (film):
3080, 2950, 2930, 2885, 2845, 1720, 1460, 1355, 1265, 1160, 840, 740. H NMR (400 MHz, CDCl3):
546
435
405
1
3
3
3
7.05 (d, J=15.8, H-6), 6.03 (d, J=15.8, H-5), 4.45 (d, J=2.6, H-2), 4.20–4.14 (m, 2 CH2), 4.00 (d,
3J=2.6, H-3), 4.02–3.86 (m, CH2–CH2 of dioxolane), 1.31–1.25 (m, 2 Me), 0.92, 0.88 (2s, 2 t-Bu), 0.09,
0.04, 0.03, 0.00 (4s, 2 Me2Si). 13C NMR (100.6 MHz, CDCl3): 172.3, 166.3 (2s, C-1, C-7), 144.3 (d,
J=164, C-6), 121.6 (d, J=166, C-5), 108.0 (s, C-4), 78.1, 72.9 (2d, J=147, 144, C-2, C-3), 65.4, 64.8 (2t,
2 CH2, dioxolane), 60.8, 60.2 (2t, 2 CH2), 25.7, 25.6 (2q, 2 t-Bu), 18.1 (s, C(Me)3), 14.1, 14.0 (2q, 2 Me
(EtO)), −4.4, −4.8, −5.1, −5.4 (4q, 2 Me2Si). CI-MS (NH3): 551 (34, M+NH+4 ), 533 (24, M+H+), 475
(30, M·+−t-Bu), 401 (4), 373 (15), 343 (22), 286 (72). Anal. calcd for C25H48O8Si2 (532.82): C 56.39,
H 9.02, Si 10.53; found: C 56.49, H 9.12, Si 10.48.
4.6. Diethyl (2S,3S,5R,6R)-9 and (2S,3S,5S,6S)-2,3,5,6-tetrakis[(t-butyl)dimethylsilyloxy]-4,4-
(ethylidenedioxy)heptanedioate (−)-10
A mixture of (−)-6 (3 g, 5.64 mmol), tert-butanol (30 ml), (DHQD)2PHAL (440 mg, 0.564 mmol),
60% NMO in H2O (2.8 ml, 14.1 mmol) and 0.1 M OsO4 in CCl4 (2.8 ml, 0.28 mmol) was stirred at
20°C for 20 h. Aqueous 1 N HCl (60 ml) was added and the two phases were separated. The aq. layer
was extracted with EtOAc (80 ml, three times). The combined organic extracts were washed with sat.
aq. soln of NaHSO3 (100 ml), then with brine (100 ml) and dried (MgSO4). The solvent was evaporated

S. Lemaire-Audoire, P. Vogel / Tetrahedron: Asymmetry 10 (1999) 1283–1293
1289
in vacuo to afford 2.97 g (93%): 1:2 mixture of diols 7 and 8. The pale yellow oil was dissolved in
anhydrous CH2Cl2 (45 ml), and 2,6-lutidine (3.7 ml, 31.5 mmol) and (t-Bu)Me2SiOSO3CF3 (6.7 ml,
29.4 mmol) were added at 0°C. After stirring at 0°C for 30 min, the mixture was allowed to stay at
20°C for 6 h. Aqueous 2 N NaOH (150 ml) was added and the two phases were separated. The aq.
layer was extracted with EtOAc (150 ml, three times). The combined organic extracts were washed with
aqueous 1 N HCl (200 ml), then with brine (200 ml) and dried (MgSO4). The solvent was evaporated in
vacuo and the oily residue purified by FC (30:1, light petroleum:EtOAc): 895 mg (20%) of 9 and 2.69 g
(60%) of 10. Data for 9: Rf: 0.83 (15:1, light petroleum:EtOAc), colorless oil. [α]25=[α]42055=0 (c 1.3,
D
CH2Cl2). UV (MeCN): 192 (8600). IR (film): 2950, 2930, 2895, 2855, 1750, 1470, 1465, 1390, 1360,
1250, 1160, 1135, 1100, 1070, 1035, 1005, 995, 970, 940, 815, 680, 665. 1H NMR (400 MHz, CDCl3):
4.41 (d, 3J=2.0, H-2, H-6), 4.30 (d, 3J=2.0, H-3, H-5), 4.16 (q, 3J=7.1, 2 CH2(EtO)), 3.88 (m, CH2–CH2
3
(dioxolane)), 1.69 (t, J=7.1, 2 CH3), 0.93, 0.89 (2s, 2 t-Bu), 0.13, 0.07, 0.05, 0.03 (4s, 4 Me2Si). 13C
NMR (100.6 MHz, CDCl3): 172.4 (s, C-1, C-7), 110.0 (s, C-4), 75.5 (d, J=142, C-2, C-6), 73.6 (d, J=142,
C-3, C-5), 66.6 (t, J=149, CH2–CH2 (C2-symmetrical dioxolane)), 60.6 (t, J=145, CH2(EtO)), 25.8, 25.7
(2q, J=127, 2 t-Bu), 18.4, 18.1 (2s, 2 CMe2), 14.1 (q, CH3(EtO)), −4.1, −4.4, −5.0, −5.7 (4q, J=118, 4
Me2Si). CI-MS (NH3): 795 (100, M+H+), 737 (16, M·+−t-Bu), 606 (3), 531 (1), 491 (8), 433 (56), 303
(61). Anal. calcd for C37H78O10Si4 (795.36): C 55.92, H 9.82, Si 14.11; found: C 55.95, H 9.74, Si 14.05.
25
Data for (−)-10: Rf: 0.73 (15:1, light petroleum:EtOAc), colorless oil. [α]25 −08.2, [α]
−10.4,
D
577
[α]25546 −11.0, [α]52355 −14.5, [α] −20 (c 1.4, CH2Cl2). IR (film): 2950, 2930, 2895, 2860, 1745, 1470,
25
405
1465, 1390, 1360, 1110, 1030, 1005, 950, 940, 900, 815, 735, 665. 1H NMR (400 MHz, CDCl3): 4.37 (d,
3J=4.6, H-2, H-6), 4.28 (d, 3J=4.6, H-3, H-5), 4.16, 4.02 (2dq, 2J=10.8, 3J=7.1, 2 CH2(EtO)), 3.94, 3.78
(2m, AA0BB0, CH2–CH2 of dioxolane), 1.27 (t, 3J=7.1, 2 CH3(EtO)), 0.94, 0.91 (2s, 4 t-Bu), 0.16, 0.09,
0.07, 0.06 (4s, 4 Me2Si). 13C NMR (100.6 MHz, CDCl3): 172.6 (s, C-1, C-7), 110.3 (s, C-4), 75.9 (d,
J=146, C-2, C-6), 72.6 (d, J=143, C-3, C-5), 65.9, 64.5 (2t, J=151, 2 CH2 of C2-symmetrical dioxolane),
60.3 (t, J=144, 2 CH2(EtO)), 26.1, 25.9 (2q, J=126, 4 t-Bu), 18.3 (q, 4 CMe2), 14.0 (q, J=127, Me(OEt)),
−4.0, −4.2, −4.3, −4.8 (4q, J=117, 4 Me2Si). CI-MS (NH3): 812 (42, M+NH+4 ), 795 (87, M+H+), 738
(13), 491 (4), 433 (64), 303 (46), 229 (21), 90 (100). Anal. calcd for C37H78O10Si4 (795.36): C 55.92, H
9.82, Si 14.11; found: C 55.88, H 9.75, Si 13.88.
4.7. Ethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis[(t-butyl)dimethylsilyloxy]-4,4-ethylidenedioxy-7-oxoheptano-
ate (+)-13 and (2S,3S,5S,6S)-2,3,5,6-tetrakis[(t-butyl)dimethylsilyloxy-4,4-ethylidenedioxyheptadial 14
A solution of 1 M diisobutylaluminum hydride in CH2Cl2 (12.6 ml, 12.6 mmol) was added dropwise
(over 20 min) to a stirred soln of (−)-10 (2.5 g, 3.15 mmol) in anhydrous CH2Cl2 (40 ml) cooled to −78°C.
After stirring for 5 min at −78°C, MeOH (5 ml) was added, followed by aq. 1 N HCl (100 ml). The phases
were separated and the aq. layer was extracted with EtOAc (150 ml, three times). The combined organic
extracts were dried (MgSO4) and concentrated in vacuo. The residue was taken in anhydrous CH2Cl2
(40 ml). 4 Å molecular sieves (2 g) and pyridinium chlorochromate (1.7 g, 7.87 mmol) were added
whilst stirring the solution at 20°C. After 4 h at 20°C, the mixture was filtered through a pad of silica
gel (EtOAc) and the solvent was evaporated in vacuo. The pale brownish oil was purified by FC (40:1,
petroleum ether:EtOAc): 111 mg (5%) of 14 and 2.03 g (86%) of (+)-13.
25
Data for (+)-13: Rf: 0.52 (10:1, light petroleum:EtOAc), colorless oil. [α]25 +3.4, [α]52757 −1.6, [α]
D
546
25
25
−4.4, [α]
−9.1, [α]
−10.1 (c 1.2, CH2Cl2). UV (MeCN): 193 (13 200). IR (film): 3030, 2950,
435
405
1
2930, 2895, 2855, 1730, 1470, 1360, 1265, 1160, 1100, 1005, 915, 835, 780, 740, 705, 666. H NMR
(400 MHz, CDCl3): 9.77 (s, CHO), 4.51 (d, 3J=7.2, H-6), 4.50 (d, 3J=4.7, H-2), 4.10, 4.00 (2dq, 2J=10.1,
3J=7.2, CH2(EtO)), 4.02 (d, J=7.2, H-5), 3.90 (d, 3J=4.7, H-3), 3.85, 3.79 (2m, CH2–CH2 of dioxolane),

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S. Lemaire-Audoire, P. Vogel / Tetrahedron: Asymmetry 10 (1999) 1283–1293
3
1.25 (t, J=7.2, CH3(EtO)), 0.97, 0.93, 0.90, 0.89 (4s, 4 t-Bu), 0.26, 0.20, 0.15, 0.10, 0.07, 0.06, 0.03,
0.01 (8s, 4 Me2Si). 13C NMR (100.6 MHz, CDCl3): 198.7 (d, J=178, CNO), 172.7 (s, C-1), 110.6 (s,
C-4), 79.1 (d, J=139, C-6), 77.2 (d, J=146, C-5), 76.3 (d, J=145, C-2), 73.3 (d, J=150, C-3), 64.9, 63.6
(2t, J=150, CH2–CH2 of dioxolane), 60.3 (t, J=146, CH2(EtO)), 26.3, 25.9, 25.6 (4q, J=125, 4 t-Bu),
18.8, 18.1 (4s, 4 CMe3), 13.9 (q, J=126, CH3(EtO)), −3.3, −3.6, −3.8, −4.7, −4.8, −4.9, −5.7 (8q, J=118,
4 Me2Si). CI-MS (NH3): 752 (1, M+1+H+), 694 (1), 620 (2), 561 (3), 487 (2), 433 (71), 389 (73), 301
(34), 229 (33), 133 (10), 73 (100). Anal. calcd for C35H74O9Si4 (751.30): C 56.00, H 9.87, Si 14.93;
found: C 56.10, H 9.79, Si 14.96.
Data for 14: Rf 0.58 (10:1, light petroleum:EtOAc), colorless oil. UV (MeCN): 192 (11 700). IR (film):
3030, 2950, 2930, 2895, 2855, 1730, 1470, 1360, 1265, 1095, 1005, 910, 835, 780, 740. 1H NMR (400
3
3
MHz, CDCl3): 9.69 (s, H-1, H-7), 4.34 (d, J=4.9, H-2, H-6), 4.09 (d, J=4.9, H-3, H-5), 3.76, 3.71
(2m, CH2–CH2 of dioxolane), 0.93 (s, 4 t-Bu), 0.18, 0.15, 0.07, 0.05 (4s, 4 Me2Si). 13C NMR (100.6
MHz, CDCl3): 199.1 (d, C-1, C-7), 110.2 (s, C-4), 79.1 (d, C-2, C-6), 77.2 (d, C-3, C-5), 65.5, 64.6
(2t, CH2–CH2 of dioxolane), 25.90, 25.89 (2q, 4 t-Bu), 18.3, 18.1 (2s, 4 CMe4), −4.0, −4.5, −4.8 (4q,
4 Me2Si). CI-MS (NH3): 724 (1, M+NH+4 ), 649 (2), 576 (3), 517 (5), 389 (81), 303 (20), 229 (22), 73
(100).
4.8. Ethyl 1,2,3,6-O-tetraacetyl-4-deoxy-4,4-ethylidenedioxy-α- and β-D-ido-heptapyranuronate
(−)-15α,β
A 1 M soln of tetrabutylammonium fluoride in THF (9 ml, 9 mmol) was added dropwise to a stirred
soln of (+)-13 (1.5 g, 2 mmol) in anhydrous THF (20 ml) cooled to −20°C. After 5 min at −20°C, the
solvent was evaporated in vacuo and the residue dried in vacuo (20°C, 1 h). It was taken up in pyridine (10
ml), and acetic anhydride (10 ml) and 4-dimethylaminopyridine (2 mg) were added. After stirring at 20°C
for 6 h, the solvent was evaporated and the residue was purified by FC (3:2, light petroleum:EtOAc): 554
mg (60%), pale yellow oil that solidifies at −20°C, m.p. 112–113°C, 89:11 mixture of β- and α-anomers.
25
25
25
25
Rf: 0.39 (3:2, light petroleum:EtOAc). [α]25 −3.6, [α]
−1.0, [α]
−10.2, [α]
−22.0, [α]
D
577
546
435
405
−31.3 (c 1.0, CH2Cl2). IR (KBr): 2895, 2870, 1750, 1375, 1225, 1145, 1075, 1050, 940, 915, 730, 665.
3
3
1H NMR (400 MHz, CDCl3) of β-anomer 15β: 6.24 (d, J=3.6, H-1), 5.85 (d, J=9.6, H-3), 5.43 (d,
3J=4.5, H-5), 5.29 (dd, 3J=9.6, 3.6, H-2), 4.42 (d, 3J=4.5, H-6), 4.20 (q, 3J=7.2, CH2(EtO)), 4.14, 4.00
(2m, CH2–CH2 of dioxolane), 2.29, 2.18, 2.10, 2.05 (4s, 4 AcO), 1.26 (t, 3J=7.2, CH3(EtO)); α-anomer
3
3
3
3
15α: 6.15 (d, J=4.6, H-1), 5.50 (d, J=2.7, H-5), 5.49 (d, J=7.5, H-3), 5.13 (dd, J=7.5, 4.6, H-2),
4.52 (d, 3J=2.7, H-6), 4.20 (q, 3J=7.2, CH2(EtO)), 4.23, 3.92 (2m, 2 CH2(dioxolane)), 2.27, 2.10, 2.07,
2.05 (4s, 4 Ac), 1.27 (t, J=7.2, CH3(OEt)). 13C NMR (100.6 MHz, CDCl3) of α-anomer 15α: 169.7,
169.6, 169.4 (4s, 4 Ac), 166.9 (s, C-7), 105.6 (s, C-4), 88.8 (d, J=176, C-1), 77.2 (d, J=156, C-6), 70.9
(d, J=150, C-5), 68.7 (d, J=153, C-3), 67.9 (d, J=132, C-2), 66.8, 65.5 (2t, J=150, 2 CH2 of dioxolane),
61.9 (t, J=149, CH2(EtO)), 21.1, 20.8, 20.6 (4q, J=130, 4 Me(Ac)), 14.0 (q, Me(EtO)). CI-MS (NH3):
480 (0.3, M+NH+4 ), 462 (0.1, M·+), 403 (7), 360 (22), 301 (14), 241 (40), 143 (28), 115 (100), 87 (76).
Anal. calcd for C19H26O13 (462.40): C 49.35, H 5.63; found: C 49.23, H 5.74.
4.9. Ethyl 2,5,6-O-triacetyl-3,7-anhydro-4-deoxy-4,4-(ethylidenedioxy)-D-glycero-D-ido-dec-9-eno-
pyranuronate (−)-16
Pyranoside (−)-15 (100 mg, 0.216 mmol) was dissolved in 3 ml of 33% HBr in AcOH. After stirring
for 2 h at 0°C, evaporation of the solvent afforded the corresponding bromopyranoside as a pale brown
oil (81 mg, 78% yield). To a solution of this crude material (62 mg, 0.128 mmol) in 1 ml of anhydrous
CH2Cl2, ZnBr2 (2 equiv. 58 mg, 0.256 mmol) and allyltrimethylsilane (3 equiv. 61 µl, 0.384 mmol) were

S. Lemaire-Audoire, P. Vogel / Tetrahedron: Asymmetry 10 (1999) 1283–1293
1291
added. After stirring for 8 h at 20°C and 12 h at 30°C, the mixture was diluted with EtOAc (10 ml).
After washing with a sat. aq. soln of NaHCO3 (5 ml, three times) and with brine (5 ml), the organic
layer was dried (MgSO4). Evaporation of the solvent and purification of the residue by FC (3:2, light
petroleum:EtOAc) afforded a colorless oil: 34 mg (35%), Rf: 0.32 (1:2, light petroleum:EtOAc). [α]25
D
−4.7, (c 1.1, CH2Cl2). IR (film): 3100, 2980, 2945, 2915, 1755, 1645, 1430, 1375, 1225, 1130, 1075,
1
1035, 950, 915, 860. H NMR (400 MHz, CDCl3): 5.79 (d, 3J=9.8, H-5), 5.74 (m, CH(allyl)), 5.42 (d,
3
3J=3.6, H-3), 5.08, 5.02 (m, H-6, CH2(allyl)), 4.27, 4.18 (m, H-2, CH2(EtO)), 4.12 (td, J=8.7, 4.7, H-
7), 4.03, 3.89 (m, CH2 of dioxolane), 2.32, 2.08, 2.04 (3s, 3 AcO), 2.20, 2.00 (m, CH2(allyl)), 1.29 (t,
3J=7.2, CH3(EtO)). 13C NMR (100.6 MHz, CDCl3): 170.1, 169.1, 169.2 (3s, 3 Ac), 163.0 (s, C-1), 133.4
(d, CH(allyl)), 117.3 (t, CH2(allyl)), 105.7 (s, C-4), 77.5 (d, C-3), 73.9 (d, C-5), 72.8, 72.5, 72.2 (3 d,
C-3, C-6, C-7), 66.8, 65.8 (2t, 2 CH2 of dioxolane), 61.8 (t, CH2(EtO)), 36.6 (t, CH2(allyl)), 20.8 (q,
3 CH3(Ac)), 14.1 (q, CH3(EtO)). CI-MS (NH3): 462 (66, M+NH+4 ), 402 (18, M+Ac+1), 325 (11), 215
(12), 173 (16), 102 (100). Anal. calcd for C20H28O11 (444.43): C 54.05, H 6.35; found: C 54.16, H 6.32.
4.10. Ethyl 2,2-(ethylidenedioxy)-3,4-O-bis[(t-butyl)dimethylsilyl]-D-threo-penturonate (−)-17
Diol (−)-6 (80 mg, 0.150 mmol) was dissolved in 1:1, CH2Cl2:MeOH (1.2 ml) and cooled to −78°C.
Ozone was bubbled through the solution for 45 min. Three drops of Me2S were added and the mixture
was allowed to warm to 20°C over 1 h. After an additional hour at 20°C H2O (6 ml) was added.
The mixture was extracted with EtOAc (10 ml, three times). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. FC (15:1, light petroleum:EtOAc): 55 mg (80%) colorless oil, Rf:
0.71 (4:1, light petroleum:EtOAc). [α]20 −78 (c=0.9, CH2Cl2). 1H NMR (400 MHz, CDCl3): 9.68 (s, H-
D
5); 4.50 (d, 3J=2.2, H-2), 4.21 (dq, 2J=12.8, 3J=7.1, CH2(OEt)), 4.15 (dq, 2J=12.8, 3J=7.1, CH2(OEt)),
4.14 (d, 3J=2.2, H-3), 4.07, 3.99 (m, CH2 of dioxolane), 1.30 (t, 3J=7.1, CH3(OEt)), 0.92, 0.87 (2s, CH3(t-
Bu)), 0.12, 0.03, 0.02, 0.01 (4s, CH3(SiMe2)). 13C NMR (100.6 MHz, CDCl3): 195.5 (C-5), 171.6 (C-1),
105.4 (C-4), 77.9 (C-2), 72.8 (C-3), 66.5, 65.3 (CH2 of dioxolane), 61.0 (CH2(OEt)), 25.8, 25.4 (CH3(t-
Bu)), 18.1, 18.0 (C(CH3)3), 14.0 (CH3(OEt)), −4.5, −5.0, −5.2, −5.6 (CH3(SiMe2)). CI-MS (NH3): 480
(100, M+NH+4 ), 463 (34, M+H+), 433 (19), 405 (7), 303 (6), 90 (15). Anal. calcd for C21H42O7Si2
(462.73): C 54.51, H 9.15, Si 12.14; found: C 54.62, H 8.99, Si 12.02.
4.11. Aminals 18 and 19
Aldehyde 17 (26 mg, 0.056 mmol) was dissolved in C6D6 (0.5 ml) in an NMR tube. (1R,2R)-
Diphenylethylenediamine (13 mg, 0.062 mmol) was added. After 10 h at 20°C, transformation to the
diastereoisomeric aminals 18 and 19 was complete. 1H NMR (400 MHz, C6D6) of 18 (major): 7.43–7.03
(m, Har), 5.26 (s, H-5), 4.91 (d, 3J=5.1, H-2), 4.54 (d, 3J=5.1, H-3), 4.20, 3.96 (m, CH2(OEt) and CH2 of
dioxolane), 1.11 (t, 3J=8.1, CH3(OEt)), 1.10, 1.08 (2s, CH3(t-Bu)), 0.30, 0.28, 0.25, 0.21 (CH3(SiMe2)).
4.12. (2S,3S)-Diethyl 2,3-di[(p-methoxybenzoyl)oxy]-4,4-ethylenedioxyhept-5-ene-1,7-dioate (−)-20
Diol (+)-5 (1 g, 3.29 mmol) was dissolved in dry pyridine (16 ml) and the solution was cooled to
0°C. p-Methoxybenzoyl chloride (2.24 g, 13.2 mmol) and DMAP (50 mg) were added. After 30 min, the
mixture was allowed to warm to 20°C and stirred for 4 h. Pyridine was removed in vacuo (oil, pump).
The residue was diluted with AcOEt (70 ml), washed successively with aq. 1 N HCl (30 ml), sat. aq. soln
of NaHCO3 (30 ml) and brine (30 ml). Drying (MgSO4) and concentration in vacuo afforded a yellow
oil which was purified by FC (3:2, light petroleum:EtOAc): 1.35 g (72%), colorless oil, Rf: 0.41 (1:2,
25
25
25
25
EtOAc:light petroleum). [α]25 −15.1, [α]
−16.1, [α]
−18.2, [α]
−19.0, [α]
−22.0 (c 1.0,
D
577
546
435
405

1292
S. Lemaire-Audoire, P. Vogel / Tetrahedron: Asymmetry 10 (1999) 1283–1293
1
CH2Cl2). H NMR (400 MHz, CDCl3): 8.04 (m, 4 Har), 7.03 (d, 3J=15.7, H-6), 6.95 (d, 3J=9.0, Har),
6.92 (d, 3J=9.0, Har), 6.12 (d, 3J=15.7, H-5), 5.83 (d, 3J=2.6, H-2), 5.71 (d, 3J=2.6, H-3), 4.19 (q, 3J=7.2,
2
3
CH2(OEt)), 4.14–4.10 (m, CH2 dioxolane), 4.06 (dq, J=11.2, J=7.2, CH2(OEt)), 3.98–3.95 (m, CH2
of dioxolane), 3.87, 3.86 (2s, CH3(PMBz)), 1.23 (t, 3J=7.2, CH3(OEt)), 1.16 (t, 3J=7.2, CH3(OEt)). 13
C
NMR (100.6 MHz, CDCl3): 167.3, 165.7, 165.0, 164.7 (4s, C_O), 163.8, 163.7 (2s, Car), 142.0 (d, C-6),
132.2, 132.1 (2d, Car), 122.8 (d, C-5), 121.5, 121.3 (2s, Car), 113.8, 113.6 (2d, Car), 106.5 (C-4), 73.4
(d, C-2), 70.4 (d, C-3), 66.1, 65.1 (2t, CH2 of dioxolane), 61.9, 60.5 (2t, CH2(OEt)), 55.4 (q, CH3(OMe)),
14.0, 13.9 (2q, CH3(OEt)). IR (film): 2980, 2905, 2840, 1720, 1605, 1510, 1165, 1370, 1255, 1170, 1095,
1030, 850, 770, 615. Anal. calcd for C29H32O12 (572.56): C 60.84, H 5.63; found: C 60.64, H 5.60.
4.13. (2S,3S)-2,3-Di[(p-methoxybenzoyl)oxy]-4,4-ethylenedioxypentano-1,5-lactone (−)-22
Compound (−)-20 (200 mg, 0.35 mmol) was ozonolyzed for 10 min in 1:6, CH2Cl2:MeOH (14 ml) at
−78°C. Me2S (64 µl, 0.875 mmol) was added and the mixture was warmed to 0°C. After 15 min, NaBH4
(40 mg, 1.05 mmol) was introduced and the mixture was stirred at 0°C for 25 min, AcOH (100 µl) was
added and the solution was poured into a sat. aq. soln of NaHCO3 (20 ml). The aq. layer was extracted
with EtOAc (25 ml, three times). The combined organic layers were dried (MgSO4) and concentrated in
vacuo: 140 mg (80%) of 21. The oily alcohol 21 was dissolved in 3 ml of anhydrous THF (3 ml), and DBU
(125 µl, 0.833 mmol) was added at 0°C. After 2 h at 0°C, the solution was poured into water. The aq. layer
was extracted with EtOAc (20 ml, three times). The combined extracts were washed with aq. 1 N HCl (20
ml), then with brine, dried (MgSO4) and concentrated in vacuo. FC (3:1, light petroleum:EtOAc): 77 mg
25
(60%) of (−)-22, colorless oil, Rf: 0.57 (1:2, EtOAc:light petroleum). [α]25 −33.4, [α]52757 −36.0, [α]
D
546
25
25
−42.8, [α]
−70.9, [α]
−95.1 (c 1.1). CD (MeCN, 2.27×10−4 M): ∆ε=18.7 (246 nm), ∆ε=−18.4
435
405
1
(264 nm). IR (film): 2980, 2900, 2885, 1760, 1610, 1515, 1475, 1370, 1250, 1170, 1035, 850, 780. H
NMR (400 MHz, CDCl3): 8.05 (d, 3J=9.0, Har), 8.03 (d, 3J=9.0, Har), 6.94 (d, 3J=9.0, 2 Har), 6.87 (d,
3J=2.8, H-2), 6.55 (d, J=2.8, H-3), 4.20–4.05 (m, CH2 of dioxolane), 4.31 (d, J=11.5, H-5), 4.02 (d,
2J=11.5, H-5), 3.85, 3.83 (2s, CH3(OMe)). 13C NMR (100.6 MHz, CDCl3): 164.8, 164.1, 164.0 (4s, 4
C_O), 159.6, 158.9 (2s, 2 Car), 132.5, 131.6 (2d, J=163, Car), 120.6, 119.2 (2s, 2 Car), 113.8, 113.7 (2d,
J=162, Car), 105.9 (s, C-4), 72.2, 71.0 (2t, J=150, 148, C-2, C-3), 69.6 (t, C-5), 55.5, 55.2 (2q, J=144,
145, CH3(OMe)). CI-MS (NH3): 476 (51, M+NH+4 ), 459 (100, M+H+), 427 (26, M−OMe+). Anal. calcd
for C23H22O10 (458.42): C 60.26, H 4.84; found: C 59.98, H 4.86.
3
2
Acknowledgements
We thank the Swiss National Science Foundation and the Fonds Herbette for financial support, and the
COST-Chemistry D-2 program (Brussels) for a short mission grant.
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