The synthesis of some C-4 and C-9 substituted derivatives of KDN2en methyl ester

Article abstract of DOI:10.1081/CAR-100108270

The synthesis of a number of C-4 and C-9 substituted derivatives of KDN2en methyl ester 2 is reported. 9-Deoxy-9-iodo, 9-azido-9-deoxy and 9-O-methyl derivatives of 2 (compounds 5, 7 and 9) were prepared from the corresponding 9-O-tosylate, methyl 2,6-anh

Full text of DOI:10.1081/CAR-100108270

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THE SYNTHESIS OF SOME C-4 AND C-9 SUBSTITUTED
DERIVATIVES OF KDN2EN METHYL ESTER
Adele K. Norton a , Gaik B. Kok a & Mark von Itzstein b
a Department of Medicinal Chemistry , Monash University , 381 Royal Parade, Parkville,
Victoria, 3052, Australia
b Department of Medicinal Chemistry , Monash University , 381 Royal Parade, Parkville,
Victoria, 3052, Australia
Published online: 16 Aug 2006.
To cite this article: Adele K. Norton , Gaik B. Kok & Mark von Itzstein (2001) THE SYNTHESIS OF SOME C-4 AND C-9
SUBSTITUTED DERIVATIVES OF KDN2EN METHYL ESTER, Journal of Carbohydrate Chemistry, 20:7-8, 507-517
To link to this article: http://dx.doi.org/10.1081/CAR-100108270
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J. CARBOHYDRATE CHEMISTRY, 20(7&8), 507–517 (2001)
THE SYNTHESIS OF SOME C-4 AND C-9
SUBSTITUTED DERIVATIVES OF KDN2EN
METHYL ESTER
Adele K. Norton,1 Gaik B. Kok,1 and Mark von Itzstein1,2,*
1Department of Medicinal Chemistry, Monash University,
381 Royal Parade, Parkville 3052, Victoria, Australia
2Centre for Biomolecular Science and Drug Discovery,
Griffith University (Gold Coast Campus), PMB 50 Gold
Coast Mail Centre, Queensland 9726, Australia
Dedicated to Dr. Joachim Thiem on the occasion of his 60th birthday.
ABSTRACT
The synthesis of a number of C-4 and C-9 substituted derivatives of KDN2en
methyl ester 2 is reported. 9-Deoxy-9-iodo, 9-azido-9-deoxy and 9-O-methyl
derivatives of 2 (compounds 5, 7 and 9) were prepared from the corresponding
9-O-tosylate, methyl 2,6-anhydro-3-deoxy-9-O-p-toluenesulfonyl-D-glycero-
D-galacto-non-2-enonate (3). These compounds have been fully characterised
as the peracetates 6, 8 and 10. Treatment of 3 with KSAc gave the 9-thioacetyl
derivative which was isolated as the peracetate 11. 4-C-Ethenyl-4-deoxy (14),
4-C-phenyl-4-deoxy (15) and 4-C-[1-(methoxycarbonyl)ethenyl]-4-deoxy (16)
derivatives of 2 were prepared via the palladium-catalysed coupling of the 4-
epi-chloride, methyl 5,7,8,9-tetra-O-acetyl-2,6-anhydro-4-chloro-3,4-dideoxy-
D-glycero-D-talo-non-2-enonate (12) with the appropriate organostannanes.
INTRODUCTION
Prior to its discovery in nature some 15 years ago from the membrane
polysialoglycoproteins (PSGP) of fish eggs,1 KDN (3-deoxy-D-glycero-
D-galacto-non-2-ulosonic acid) was considered to be the result of C-5 deamination
*Corresponding author. E-mail: m.vonitzstein@mailbox.gu.edu.au
507
Copyright © 2001 by Marcel Dekker, Inc.
www.dekker.com

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NORTON, KOK, AND VON ITZSTEIN
of Neu5Ac, the more ubiquitously distributed member of the ulosonic acid family.
As terminal constituents of glycoproteins and glycolipids, these carbohydrates have
been implicated in a diverse array of biological processes such as cell adhesion and
differentiation.2 In particular, as a terminal unit of PSGP chains, KDN plays a
unique role by protecting the membrane from bacterial degradation since only sialic
acid residues with an acylamino group at C-5 are cleaved by bacterial sialidases.3 In
recent years, Li and coworkers have found new sialidases that have unique KDN
metabolism. For example, the sialidase, KDNase, first isolated from the liver of the
loach, specifically hydrolyses KDN-bearing glycoconjugates and not N-acylneu-
raminyl linkages.4 More recent studies have found the coexistence of two different
sialidases in the starfish Asterina pectinifera; namely, a regular sialidase (RS) which
cleaves sialic acid from sialoglycoconjugates, and a KDN-sialidase (KS) which hy-
drolyses KDN from KDN-containing glycoconjugates.5 A KDN-specific sialidase
has also been isolated from Sphingobacterium multivorum.6,7
The 2,3-unsaturated analogues of the ulosonic acids have received much
interest in recent years as inhibitors of sialidases. For example, the C-4 nitrogen-
containing Neu5Ac2en derivative, 5-acetamido-2,6-anhydro-3,4,5-trideoxy-4-
guanidino-D-glycero-D-galacto-non-2-enonic acid, is a potent inhibitor of a viral
sialidase.8 Neu5Ac2en itself, but not KDN2en, is still one of the most potent in-
hibitors of bacterial sialidase.5,9 However, both Neu5Ac2en and KDN2en are mod-
erate inhibitors of KS.5 Therefore, the synthesis of more complex derivatives and
analogues of KDN is required, both for further study of the functional role of KDN-
containing glycoconjugates, and for probing the role played by the unique enzymes
involved in their metabolism. The synthesis of KDN has been achieved by various
chemistries.2,10,11
We report here the synthesis of several C-4 and C-9 derivatives of the per-
acetylated methyl ester of KDN2en, methyl 4,5,7,8,9-penta-O-acetyl-2,6-anhydro-
3-deoxy-D-glycero-D-galacto-non-2-enonate (1).
RESULTS AND DISCUSSION
Our initial approach towards the synthesis of C-9 functionalised KDN2en
derivatives was based on some of our earlier work on the preparation of
12,13
Neu5Ac2en derivatives.
In that study we reported a facile approach into
functionalised Neu5Ac2en derivatives via acetolysis of the corresponding substi-
tuted glycosides of Neu5Ac methyl ester.12,13 Very recently we have reported the
synthesis of a range of C-9 substituted derivatives of the methyl glycoside of
KDN methyl ester.14 Based on our earlier study,12,13 we thought it reasonable

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KDN2EN METHYL ESTER DERIVATIVES
509
that this series of compounds may be directly converted into the corresponding
C-9 substituted KDN2en via the same acetolysis conditions. Indeed, an initial
investigation was carried out using the ꢀ-methyl glycoside of KDN methyl ester,
methyl (methyl 3-deoxy-D-glycero-ꢀ-D-galacto-non-2-ulopyranosid)onate, as a
1
template. A cursory examination of the H NMR spectrum of the crude product
showed an insignificant amount of the desired KDN2en derivative; namely,
methyl 4,5,7,8,9-penta-O-acetyl-2,6-anhydro-3-deoxy-D-glycero-D-galacto-non-
2-enonate. Interestingly, a compound consistent with the known furanosonate,15
methyl 5-[{D-erythro-(1,2,3,4-tetra-O-acetyl-1,2,3,4-tetrahydroxy)butyl}-2-
furanosid]onate was obtained as the major product (data not shown).
The failure of the acetolysis chemistry to provide us direct entry into
KDN2en derivatives prompted us to search for an alternative approach to these
valuable probes. As part of an investigation of the chemistry of KDN derivatives,
Sun and coworkers reported that, not unlike the Neu5Ac system, the 2-ꢁ-chloride
of peracetylated KDN methyl ester, methyl 4,5,7,8,9-penta-O-acetyl-2-chloro-3-
deoxy-D-glycero-ꢁ-D-glycero-non-2-ulopyranosonate, readily undergoes base-
promoted dehydrochlorination. This chemistry readily provides the 2,3-unsatu-
rated analogue of KDN methyl ester 1 in high yield.16 Subsequent de-O-acetylation
of 1 under standard Zemplén conditions gave 2. The 2,3-unsaturated analogue of
KDN methyl ester 2 makes an ideal starting template for elaboration into a range
of functionalised KDN2en derivatives.
Our approach to the introduction of new functionalities at C-9 of the KDN2en
template required activation of the C-9 hydroxyl group. This was readily achieved
by the use of well-established sulfonate ester chemistry. Accordingly, compound 2
was treated with p-toluenesulfonyl chloride in pyridine which resulted in selective
tosylation at C-9 to provide methyl 2,6-anhydro-3,9-dideoxy-9-p-toluenesulfonyl-
D-glycero-D-galacto-non-2-enonate (3), in 92% yield. The 9-O-tosylate 3 was fur-
ther characterised as the peracetate 4.
The readily available 9-O-tosylate 3 provides a common starting material for
the synthesis of all of the C-9 derivatives of KDN2en in this study. Thus, nucle-
ophilic displacement of the sulfonate ester 3 with azide at 50°C proceeded
smoothly giving the corresponding 9-azide 5 which was characterised as the
peracetate 6 (76%, 2 steps). Similarly, treatment of the 9-O-tosylate 3 with NaI in
acetone under reflux gave the corresponding 9-iodide 7 which was also fully char-
acterised as the peracetate 8 (65%, 2 steps). An attempt to displace the sulfonate
ester 3 with methoxide (unoptimised) resulted in partial conversion to the desired
9-O-methyl derivative 9. Compound 9 was isolated from the unreacted starting
material 3 (62%) in 38% yield after column chromatography and was further char-
acterised as the peracetate 10.
To achieve introduction of sulfur at C-9, the 9-O-tosylate 3 was treated with
KSAc in acetone for 2 days at rt. This resulted in the isolation of the 9-thioacetyl
peracetate 11 after chromatography in high yield (95%). It was found that a pro-
longed reaction time gave an appreciable amount of the corresponding disulfide as
a by-product (data not shown).

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NORTON, KOK, AND VON ITZSTEIN
With a selection of C-9 derivatives of KDN2en in hand, our focus turned to
the preparation of C-4 modified KDN2en derivatives. Recently, we have reported
the facile synthesis of C-4 halogen-substituted derivatives of Neu5Ac and
KDN2en.17 We have also shown that the 4-chloride, methyl 5-acetamido-7,8,9-tri-
O-acetyl-2,6-anhydro-4-chloro-5,7,8-trideoxy-D-glycero-D-talo-non-2-enonate
can be elaborated into a range of C-4 C-branched 2,3-unsaturated Neu5Ac deriva-
tives by using a palladium(0)-mediated coupling with different organostannanes.18
In analogous reactions, using the readily accessible 4-epi-chloride of KDN2en,
methyl 5,7,8,9-tetra-O-acetyl-2,6-anhydro-4-chloro-3,4-dideoxy-D-glycero-D-
talo-non-2-enonate (12) as a coupling partner, we have successfully prepared
several C-4 C-branched derivatives of KDN2en. Not unexpectedly, this reaction
results in inversion of stereochemistry at C-4, as is evident from the smaller 3J3,4
coupling constant for the D-glycero-D-galacto configuration. As representative
examples of this reaction we selected the readily available organnostannanes, trib-
utylvinyltin, tributylphenyltin and methyl ꢀ-(tributylstannyl)propenoate.18,19
Accordingly, 4-C-ethenyl-4-deoxy, 4-C-phenyl-4-deoxy and 4-C-[1-(methoxycar-
bonyl)ethenyl]-4-deoxy derivatives, 14–16, have been prepared in modest yields.
Interestingly, while the reaction with either tributylvinyltin and methyl ꢀ-(trib-
utylstannyl)propenoate gave only the coupled products, the same reaction with
tributylphenyltin also gave 20% of the reduced product, methyl 5,7,8,9-tetra-O-
acetyl-2,6-anhydro-3,4-dideoxy-D-glycero-D-galacto-non-2-enonate (17), which
was shown to be identical to known material.16

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511
In conclusion, a range of C-9 and C-4 modified KDN2en derivatives have
been prepared from the 2,3-unsaturated analogue of KDN methyl ester. These
compounds, upon deprotection, may provide useful probes for KDN-recognising
proteins.
EXPERIMENTAL
General Methods. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra
(in ꢂ ppm) were recorded on a Bruker AMX300 spectrometer at 303 K and were
referenced using solvent residues. J-Values are in hertz (Hz). Both low resolution
(LR) and high resolution (HR) fast atom bombardment (FAB) mass spectra were
obtained on a JEOL JMS-DX 300 spectrometer. Specific optical rotations [ꢀ]D,
quoted in 10ꢃ1 deg cm2 gꢃ1, were measured at room temperature using a JASCO
DIP-370 polarimeter with a path length 50 mm. Concentrations are quoted in
10ꢃ2 g cmꢃ3. Elemental analyses were performed by the Chemical and Microana-
lytical Service, Essendon, Victoria. IR spectra were recorded using a Hitachi 270-
30 spectrophotometer. Column chromatography was performed on Merck silica
gel 60 (0.040–0.063 mm). Reactions were monitored by TLC on Kieselgel 60 F254
plates (Merck 5554) and the spots were detected under ultraviolet (UV) irradiation
and by spraying with 95% aq ethanol containing 5% H2SO4 and charring for sev-
eral minutes at 180°C. Triphenylphosphine (Aldrich) and bis(dibenzylideneace-
tone)palladium(0) (Lancaster Synthesis) were used as received. Chloroform was
put through a short plug of basic alumina just prior to use. All reactions were per-
formed under anhydrous conditions in flame-dried glassware under an atmosphere
of nitrogen or argon.
Preparation of the Organostannanes. Methyl ꢀ-(tributylstannyl)
propenoate was prepared from methyl propynoate according to the literature.18,19
Tributylphenyltin (Fluka) and tributylvinyltin (Aldrich) were used as supplied,
without prior purification.
Preparation of the Starting Materials. KDN was prepared by aldolase
(EC 4.1.3.3) condensation of D-mannose and pyruvate according to the literature,20
with slight modification. Rather than using an immobilised system, the enzyme
was contained within a dialysis bag. Methanolysis of KDN and subsequent treat-
ment of the resulting methyl ester with neat AcCl gave the 2-ꢁ-chloride, methyl
4,5,7,8,9-penta-O-acetyl-2-chloro-3-deoxy-D-glycero-ꢁ-D-glycero-non-2-ulopy-

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NORTON, KOK, AND VON ITZSTEIN
ranosonate. DBU-promoted dehydrochlorination of the latter compound according
to the literature,16 followed by chromatography (EtOAc/hexane, 1:1) gave the p
eracetylated KDN2en methyl ester, methyl 4,5,7,8,9-penta-O-acetyl-2,6-anhydro-
3-deoxy-D-glycero-D-galacto-non-2-enonate (1). Standard Zemplén de-O-acetyla-
tion (NaOMe/MeOH) of 1 afforded 2 in 97% yield. The 4-epi-chloride, methyl
5,7,8,9-tetra-O-acetyl-2,6-anhydro-4-chloro-3,4-dideoxy-D-glycero-D-talo-non-2-
enonate (12) was prepared from a 1:1 epimeric mixture of the peracetylated methyl
esters of KDN2en, methyl 4,5,7,8,9-penta-O-acetyl-2,6-anhydro-3-deoxy-D-glyc-
ero-D-galacto-non-2-enonate (1) and methyl 4,5,7,8,9-penta-O-acetyl-2,6-anhy-
dro-3-deoxy-D-glycero-D-talo-non-2-enonate (13) in 56% yield, according to the
method as previously described.16
General Procedure for Acetylation. Ac2O (0.5 mL) and DMAP (ca.
5 mg) were added to a sample of the compound (amount as specified) to be acety-
lated in pyridine (1 mL). After stirring at rt for 16 h, the mixture was concentrated
and the residue purified by column chromatography on silica using the solvent(s)
specified.
General Procedure for Palladium-Catalysed Cross-Coupling Reactions
of the Chloride 12 and Organostannanes. To a solution of 12 (100 mg, 0.022
mmol) in chloroform (5 mL) was added triphenylphosphine (3.5 mg, approx.
6 mol%) and bis(dibenzylideneacetone)palladium(0) (4 mg, approx. 3 mol%). The
tin reagent (0.34 mmol, 1.5 mol equiv) was then added and the resulting solution
heated under reflux for 18 h. The reaction mixture was cooled; saturated aq KF
(5 mL) was added and the mixture stirred for 24 h. The solids were filtered off and
concentrated. The residue was extracted with ether (20 mL ꢄ 3), the ethereal ex-
tracts combined and washed successively with H2O and brine, and dried (MgSO4).
After removal of the volatiles, the residue obtained was purified by chromatogra-
phy on silica. The product was eluted using a combination of EtOAc and hexane
(1:1).
Methyl 2,6-anhydro-3-deoxy-9-O-p-toluenesulfonyl-D-glycero-D-galacto-
non-2-enonate (3). A mixture of 1 (1.20 g; 4.53 mmol) and p-TsCl (1.34 g; 7.03
mmol) in pyridine (20 mL) was stirred at 0 °C for 2 h. More p-TsCl (0.25 g; 1.36
mmol) was added and the mixture left to stir at 5 °C for a further 10 h. MeOH
(20 mL) was added and the mixture concentrated. The residue was purified by col-
umn chromatography (EtOAc/i-PrOH/H2O, 6:2:1) which gave the 9-O-tosylate 3 as
a colourless amorphous mass (1.74 g; 92%): [ꢀ]D ꢃ11.6° (c 5.63, MeOH); 1H NMR
(D2O) ꢂ 2.47 (3 H, s, Ph-CH3), 3.76 (1 H, dd, J9,8 7.9, J9,9ꢅ 10.4, H-9), 3.82 (3 H, s,
COOCH3), 3.85 (1 H, dd, J6,5 9.5, J6,7 2.1, H-6), 3.99 (1 H, dd, J9ꢅ,8 1.0, H-9ꢅ), 4.10
(1 H, dd, J4,5 10.4, H-5), 4.30 (1 H, dd, J8,7 5.3, H-8), 4.41 (1 H, dd, H-7), 4.44 (1
H, dd, J4,3 2.6, H-4), 5.97 (1 H, d, H-3), 7.50–7.88 (4 H, m, Ph); 13C NMR (D2O) ꢂ
21.8 (Ph-CH3), 52.9 (COOCH3), 68.3, 68.5, 69.3, 69.8, 77.6 (C-4, C-5, C-6, C-7,
C-8), 72.6 (C-9), 112.6 (C-3), 128.3, 130.3, 132.9, 143.5 (aromatic carbons), 145.3

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513
(C-2), 163.5 (carbonyl); IR (vmax, KBr): 3448, 1731, 1653, 1446, 1356, 1257, 1173,
1092, 972, 903, 972, 903, 810 cmꢃ1; LRMS m/z: 419 (MHꢆ, 6%), 383 (31), 365
(37), 351 (51), 257 (53), 227 (39), 211 (100).
Methyl 4,5,7,8-tetra-O-acetyl-2,6-anhydro-3-deoxy-9-O-p-toluenesul-
fonyl-D-glycero-D-galacto-non-2-enonate (4). Acetylation of 3 (151 mg, 0.36
mmol) according to the general acetylation conditions gave, after chromatography
(EtOAc/hexane, 1:1), 4 as a colourless amorphous mass (202 mg; 99%): [ꢀ]D
ꢆ21.2° (c 6.00, CHCl3); 1H NMR (CDCl3) ꢂ 2.00, 2.02, 2.04, 2.05 (each 3 H, s,
OCOCH3 ꢄ 4), 2.45 (3 h, s, Ph-CH3), 3.82 (3 H, s, COOCH3), 4.15 (1 H, dd, J9,8
6.6, J9,9ꢅ 11.4, H-9), 4.29 (1 H, dd, J6,5 9.9, J6,7 2.7, H-6), 4.69 (1 H, dd, J9ꢅ,8 2.7, H-
9ꢅ), 5.17 (1 H, dd, J5,4 7.2, H-5), 5.29 (1 H, dd, J8,7 5.1, H-8), 5.49 (1 H, dd, H-7),
5.58 (1 H, dd, J4,3 2.8, H-4), 5.95 (1 H, d, H-3); 13C NMR (CDCl3) ꢂ 20.7, 20.9, 21.0
(OCOCH3 ꢄ 4), 21.9 (Ph-CH3), 52.9 (COOCH3), 65.8, 67.1, 69.3, 70.5 (C-5, C-6,
C-7, C-8), 67.4 (C-9), 108.3 (C-3), 128.3, 130.1, 132.5, 145.2 (aromatic carbons),
145.6 (C-2), 169.9, 170.7 (carbonyls); IR (vmax, KBr): 2998, 1740, 1660, 1440,
1378, 1268, 1178, 1110, 1048, 1024, 984, 821, 786, 660 cmꢃ1; LRMS: m/z, 587
(MHꢆ, 5%), 527 (100), 485 (21), 453 (26), 425 (31), 371 (21), 365 (100);
Anal. Calcd for C25H30O14S: C, 51.19; H, 5.16. Found: C, 51.11; H, 5.21.
Methyl 4,5,7,8-tetra-O-acetyl-2,6-anhydro-9-azido-3,9-dideoxy-D-glyc-
ero-D-galacto-non-2-enonate (5). To a solution of the 9-O-tosylate 3 (133 mg,
0.32 mmol) in DMF (10 mL) was added LiN3 (93 mg, 1.91 mmol) and the result-
ing solution heated at 50°C for 3.5 days. The reaction mixture was concentrated to
dryness and the residue acetylated according to the general conditions. After col-
umn chromatography (EtOAc/hexane, 1:1), the title compound 5 was obtained as
1
a colourless amorphous mass (110 mg; 76%): [ꢀ]D ꢆ30.4° (c 3.17, CHCl3); H
NMR (CDCl3) ꢂ 2.01, 2.04, 2.07, 2.09 (each 3 H, s, OCOCH3 ꢄ 4), 3.46 (1 H, dd,
J9,8 7.4, J9,9ꢅ 13.5, H-9), 3.82 (3 H, s, COOCH3), 3.87 (1 H, dd, J9ꢅ,8 2.9, H-9ꢅ), 4.34
(1 H, dd, J6,5 9.8, J6,7 2.8, H-6), 5.23 (2 H, m, H-5, H-8), 5.49 (1 H, dd, J7,8 4.5, H-
7), 5.59 (1 H, dd, J4,3 2.8, J4,5 7.2, H-4), 5.97 (1 H, d, H-3); 13C NMR (CDCl3) ꢂ
20.8, 20.9, 21.0 (OCOCH3 ꢄ 4), 50.6 (C-9), 52.9 (COOCH3), 65.9, 67.8, 69.4,
72.2 (C-5, C-6, C-7, C-8), 108.3 (C-3), 145.6 (C-2), 170.0, 170.1 (carbonyls); IR
(v max, KBr): 2104, 1752, 1660, 1438, 1370, 1234, 1146, 1110, 1062, 1022, 972,
936 cmꢃ1; LRMS: m/z, 475 (MNHꢆ4, 100%), 415 (8), 398 (6);
Anal. Calcd for C18H23N3O11: C, 47.27; H, 5.07; N, 9.19. Found: C, 47.19;
H, 4.95; N, 8.97.
Methyl 4,5,7,8-tetra-O-acetyl-2,6-anhydro-3,9-dideoxy-9-O-iodo-D-glyc-
ero-D-galacto-non-2-enonate (8). A mixture of the 9-O-tosylate 3 (108 mg, 0.26
mmol), NaI (154 mg, 1.03 mmol) and acetone (20 mL) was heated under reflux for
3.5 days. The mixture was cooled and the solids filtered off. The resulting solution
was concentrated to dryness which gave crude methyl 2,6-anhydro-3,9-dideoxy-9-
O-iodo-D-glycero-D-galacto-non-2-enonate (7) (96 mg; 99%).

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NORTON, KOK, AND VON ITZSTEIN
The 9-iodide 7 (96 mg, 0.26 mmol) was acetylated under the general acetyla-
tion conditions which, after chromatography (EtOAc/hexane, 1:1), afforded the ti-
tle compound 8 (93 mg; 66%).
7: 1H NMR (D2O) ꢂ 3.63 (1 H, dd, J9,9ꢅ 10.9, J9,8 5.4, H-9), 3.76 (1 H, dd, J9ꢅ,8
2.3, H-9ꢅ), 3.83 (1 H, dd, J6,5 8.9, J6,7 2.2, H-6), 3.92 (1 H, m, H-8), 3.92 (3 H, s,
COOCH3), 4.00 (1 H, pseudo t, J7.9, H-5), 4.34 (1 H, m, H-7), 4.61 (1 H, dd, J4,3
2.2, H-4), 6.09 (1 H, d, H-3); IR (vmax, KBr): 3440, 1722, 1650, 1438, 1272, 1136,
1076 cmꢃ1
.
1
8: [ꢀ]D ꢆ42.1° (c 1.76, CHCl3); H NMR (CDCl3) ꢂ 2.04, 2.06, 2.10, 2.11
(each 3 H, s, OCOCH3 ꢄ 4), 3.25 (1 H, dd, J9,8 8.5, J9,9ꢅ 11.2, H-9), 3.82 (3 H, s,
COOCH3), 3.89 (1 H, dd, J9ꢅ,8 3.0, H-9ꢅ), 4.33 (1 H, dd, J6,5 9.6, J6,7 2.9, H-6), 5.14
(1 H, m, H-8), 5.20 (1 H, dd, J5,4 7.1, H-5), 5.43 (1 H, dd, J7,8 4.3, H-7), 5.58 (1 H,
dd, J4,3 3.0, H-4), 5.96 (1 H, d, H-3); 13C NMR (CDCl3) ꢂ 2.7 (C-9), 20.8, 20.9,
21.0 (OCOCH3 ꢄ 4), 52.9 (COOCH3), 66.0, 68.9, 69.3, 72.9, 76.3 (C-4, C-5, C-6,
C-7, C-8), 108.2 (C-3), 145.6 (C-2), 170.0, 170.6 (carbonyls); IR (vmax, KBr):
1746, 1662, 1438, 1370, 1236, 1148, 1110, 1062, 1022, 970, 934, 910, 590 cmꢃ1
;
LRMS: m/z, 560 (MNHꢆ4 , 100%), 531 (18), 423 (10), 374 (20), 321 (11), 297 (16);
Anal. Calcd for C18H23O11I: C, 39.87; H, 4.28. Found: C, 40.02; H, 4.38.
Methyl 4,5,7,8-tetra-O-acetyl-2,6-anhydro-3,9-dideoxy-9-O-methyl-D-
glycero-D-galacto-non-2-enonate (10). NaOMe (2 mL of a 0.04 M solution in
MeOH, 0.8 mmol) was added to a stirring solution of the 9-O-tosylate 3 (108 mg,
0.26 mmol) in MeOH (6 mL). After 30 min, a further 2 mL of the NaOMe solution
was added and the solution stirred for a further 30 min. Dowex 50W (Hꢆ) resin was
added to pH 2 and the mixture stirred for 1 h. After filtration, all volatiles were re-
moved in vacuo and the residue purified by chromatography (EtOAc/hexane, 1:15)
to give methyl 2,6-anhydro-3,9-dideoxy-9-O-methyl-D-glycero-D-galacto-non-2-
enonate (9) as a colourless amorphous mass (27 mg; 38%) and unreacted starting
material (68 mg; 62%).
Acetylation of 9 (27 mg, 0.1 mmol) according to the general procedure gave,
after chromatography (EtOAc/hexane, 1:1), the title compound 10 as a colourless
amorphous mass (22 mg; 50%): [ꢀ]D ꢆ23.8° (c 1.73, CHCl3); 1H NMR (CDCl3)
ꢂ 2.03, 2.05, 2.06, 2.08 (each 3 H, s, OCOCH3 ꢄ 4), 3.35 (3 H, s, OCH3), 3.48 (1
H, dd, J9,8 6.0, J9,9ꢅ 10.9, H-9), 3.80 (3 H, s, COOCH3), 3.82 (1 H, dd, J9ꢅ,8 5.9,
H-9ꢅ), 4.36 (1 H, dd, J6,5 9.0, J6,7 3.5, H-6), 5.22 (1 H, dd, J5,4 6.5, H-5), 5.30 (2 H,
m, J7,8 5.7, H-7, H-8), 5.52 (1 H, dd, J4,3 3.1, H-4), 5.96 (1 H, d, H-3); 13C NMR
(CDCl3) ꢂ 21.0 (OCOCH3 ꢄ 4), 52.7, 59.4 (OCH3, COOCH3), 66.2, 67.7, 68.9,
70.6, 70.9 (C-4, C-5, C-6, C-7, C-8), 107.8 (C-3); IR (v max, KBr): 3550, 1756,
1742, 1656, 1458, 1438, 1372, 1310, 1252, 1144, 1110, 1062, 1046, 1034, 972
cmꢃ1; LRMS: m/z, 469 (MNaꢆ, 30%), 391 (8), 257 (11), 240 (62)
Anal. Calcd for C19H26O12: C, 51.12; H, 5.87. Found: C, 51.07; H, 5.78.
Methyl 4,5,7,8-tetra-O-acetyl-9-S-acetyl-2,6-anhydro-3,9-dideoxy-9-
thio-D-glycero-D-galacto-non-2-enonate (11). KSAc (20 mg, 0.45 mmol) was
added to a stirred mixture of the 9-O-tosylate 3 (64 mg, 0.15 mmol) and acetone

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KDN2EN METHYL ESTER DERIVATIVES
515
(5 mL). After 2 days at rt, the solids were filtered off and the resulting solution con-
centrated. The residue was acetylated according to the general conditions which
gave, after chromatography (hexane/acetone, 1:1), the title compound 11 as a
colourless amorphous mass (71 mg; 95%): [ꢀ]D ꢆ33.3° (c 4.45, CHCl3); 1H NMR
(CDCl3) ꢂ 2.00, 2.03, 2.04, 2.10 (each 3 H, s, OCOCH3 ꢄ 4), 2.31 (1 H, dd, J9,8
8.2, J9,9ꢅ 14.5, H-9), 3.67 (1 H, dd, J9ꢅ,8 3.2, H-9ꢅ), 3.81 (3 H, s, COOCH3), 4.35 (1
H, dd, J6,5 8.7, J6,7 3.6, H-6), 5.28 (2 H, m, H-5, H-8), 5.43 (1 H, dd, J7,8 5.1, H-7),
5.52 (1 H, dd, J4,3 3.2, J4,5 6.4, H-4), 5.96 (1 H, d, H-3); 13C NMR (CDCl3) ꢂ 20.9
(OCOCH3 ꢄ 4), 29.3 (C-9), 52.8 (COOCH3), 66.3, 66.5, 68.3, 70.8, 76.0 (C-4,
C-5, C-6, C-7, C-8), 107.8 (C-3), 169.8 (carbonyls); IR (v max, KBr): 1750, 1698,
1436, 1370, 1226, 1108, 1038, 1024, 974, 944, 622 cmꢃ1
Anal. Calcd for C20H26O12S.0.25CHCl3: C, 46.75; H, 5.09. Found: C, 46.93;
H, 5.10.
;
Methyl 5,7,8,9-tetra-O-acetyl-2,6-anhydro-3,4-dideoxy-4-C-ethenyl-D-
glycero-D-galacto-non-2-enonate (14). According to the general coupling con-
ditions, 12 and tributylvinyltin gave 14 in 29% yield; [ꢀ]D ꢆ16.9° (c 0.90,
CHCl3); 1H NMR (CDCl3) ꢂ 2.03, 2.07, 2.08, 2.09 (each 3 H, s, OCOCH3 ꢄ 4),
3.09 (1 H, ddd, J3,4 2.5, J4,5 9.4, J4,10 9.4, H-4), 3.80 (3 H, s, COOCH3), 4.15 (1
H, dd, J6,5 9.6, J6,7 2.0, H-6), 4.20 (1 H, dd, J9,8 6.8, J9,9ꢅ 12.5, H-9), 4.68 (1 H,
dd, J9ꢅ,8 2.6, H-9ꢅ), 4.98 (1 H, dd, H-5), 5.14 (1 H, d, J11,11ꢅ 9.5, H-11), 5.19 (1
H, d, J10,11 16.6, H-10), 5.37 (1 H, dd, J8,7 5.5, H-8), 5.50 (1 H, dd, H-7), 5.62
(1 H, m, H-11ꢅ), 5.93 (1 H, d, H-3); 13C NMR (CDCl3) ꢂ 20.6, 20.8 (OCOCH3
ꢄ 4), 44.8 (C-4), 52.3 (COOCH3), 62.1 (C-9), 66.5, 67.1, 70.8, 76.1 (C-5, C-6,
C-7, C-8), 111.8 (C-3), 118.4 (C-10), 135.7 (C-11), 143.4 (C-2), 169.7, 169.9,
170.1, 170.6 (carbonyls); IR (v max, KBr): 1746, 1700, 1258 cmꢃ1; LRMS: m/z,
443 (MHꢆ, 8%), 383 (28), 291 (100);
HRMS: Calcd for C20H27O11:[Mꢆ ꢆ 1], 443.1553. Found: m/z, 443.1527.
Anal. Calcd for C20H26O11.1.5H2O: C, 51.17; H, 6.23. Found: C, 51.27; H,
6.01.
Methyl 5,7,8,9-tetra-O-acetyl-2,6-anhydro-3,4-dideoxy-4-C-phenyl-D-
glycero-D-galacto-non-2-enonate (15). According to the general coupling con-
ditions, 12 and phenyltributyltin gave 15 in 32% yield; [ꢀ]D ꢆ19.3° (c 4.46,
CHCl3); 1H NMR (CDCl3) ꢂ 1.88, 2.02, 2.05, 2.07 (each 3 H, s, OCOCH3 ꢄ 4),
3.65 (1 H, dd, J4,3 2.5, J4,5 9.3, H-4), 3.80 (3 H, s, COOCH3), 4.19 (1 H, dd, J9,8
6.9, J9,9ꢅ 12.5, H-9), 4.30 (1 H, dd, J6,5 9.8, J6,7 2.1, H-6), 4.68 (1 H, dd, J9ꢅ,8 2.6,
H-9ꢅ), 5.13 (1 H, dd, H-5), 5.38 (1 H, dd, J8,7 5.4, H-8), 5.48 (1 H, dd, H-7), 6.10
(1 H, d, H-3); 13C NMR (CDCl3) ꢂ 20.4, 20.6, 20.7, 20.8 (OCOCH3 ꢄ 4), 46.2
(C-4), 52.3 (COOCH3), 62.2 (C-9), 67.2, 68.3, 70.9, 76.9 (C-5, C-6, C-7, C-8),
112.9 (C-3), 127.8, 127.9, 128.8, 138.8 (aromatic carbons), 144.0 (C-2), 162.0,
168.8, 169.9, 170.1, 170.5 (carbonyls); IR (vmax, KBr): 2968, 1854, 1438, 1136,
1098, 964, 946, 760, 698 cmꢃ1; LRMS: m/z, 493 (MHꢆ, 11%), 433 (28), 357 (46),
271 (45), 253 (21), 215 (96), 185 (100);
HRMS: Calcd for C24H29O11:[Mꢆ ꢆ 1], 493.1710. Found: m/z, 493.1719.

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516
NORTON, KOK, AND VON ITZSTEIN
Methyl 5,7,8,9-tetra-O-acetyl-2,6-anhydro-3,4-dideoxy-4-C-[1-(methoxy-
carbonyl)ethenyl]-D-glycero-D-galacto-non-2-enonate (16). The reaction of 12
with (Z)-methyl 1-(tributylstannyl)propenoate, according to the general coupling
conditions, gave 49% 16 and 20% of the 4-deoxy compound, methyl 5,7,8,9-tetra-
O-acetyl-2,6-anhydro-3,4-dideoxy-D-glycero-D-galacto-non-2-enonate (17).
16: [ꢀ]D ꢆ53.9° (c 2.17, CHCl3); 1H NMR (CDCl3) ꢂ 2.00, 2.06, 2.07, 2.08
(each 3 H, s, OCOCH3 ꢄ 4), 3.69 (1 H, dd, J4,3 2.6, J4,5 9.0, H-4), 3.76, 3.80 (each
3 H, s, COOCH3 ꢄ 2), 4.21 (1 H, dd, J9,8 6.4, J9,9ꢅ 12.5, H-9), 4.21 (1 H, dd, J6,5
9.2, J6,7 2.2, H-6), 4.66 (1 H, dd, J9ꢅ,8 2.5, H-9ꢅ), 5.14 (1 H, dd, H-5), 5.39 (1 H, dd,
J8,7 5.8, H-8), 5.51 (1 H, dd, H-7), 5.78 (1 H, s, H-11), 5.93 (1 H, d, H-3), 6.32 (1
H, s, H-11ꢅ); 13C NMR (CDCl3) ꢂ 20.5, 20.7, 20.8 (OCOCH3 ꢄ 4), 42.4 (C-4),
52.1, 52.3 (COOCH3 ꢄ 2), 62.1 (C-9), 66.8, 67.1, 70.6, 76.4 (C-5, C-6, C-7, C-8),
112.3 (C-3), 128.0 (C-11), 138.7 (C-10), 143.4 (C-2), 161.9, 166.1, 169.8, 170.0,
170.5 (carbonyls); IR (v max, KBr): 2964, 1658, 1628, 1438, 1310, 1092, 988, 952
cmꢃ1; LRMS: m/z, 501 (MHꢆ, 16%), 441 (75), 279 (51), 265 (26), 223 (100);
HRMS: Calcd for C22H29O13:[Mꢆ ꢆ 1], 501.1608. Found: m/z, 501.1631.
17: physical and spectral data were consistent with the literature.16
ACKNOWLEDGMENTS
This work was supported by an Australian Postgraduate Award to AKN and
the Australian Research Council.
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Received January 22, 2001
Accepted May 2, 2001

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