Direct access to furanosidic eight-membered ulosonic esters from cis-α,β-epoxy aldehydes

FULL PAPER

Direct Access to Furanosidic Eight-Membered Ulosonic Esters from

cis-α,β-Epoxy Aldehydes

Claudia H. Sugisaki,^[a]Yvan Ruland,^[b]and Michel Baltas*^[a]

Keywords: Aldol reactions / Cyclization / Epoxide / Regioselectivity / Ulosonic acids

Direct access to bicyclic precursors of octulosonic acids is

achieved by treatment of differentially (or not) protected γ,δ-

bis(silyloxy) cis-α,β-epoxy aldehydes with ethyl 2-(trimethyl-

dol reaction (syn) and the regioselectivity of the epoxide

ring-opening (C-6 atom). Functionalization and opening of

the bicyclic compound to afford octulosonic analogues in

their furanoside forms was studied. An octulosonic 8-phos-

phate analogue has been synthesized.

silyloxy)-2-propenoate

in

the

presence

of

boron

trifluoride−diethyl ether. An X-ray crystallographic structure

of a bicycle (compound 33a) was obtained and used to deter-

mine the absolute configurations of the different stereogenic

centers and thus the diastereoselective preference of the al-

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2003)

Introduction

fungi, and plants.^[1]KDO forms a vital and unique link

between the hydrophobic lipid A and the hydrophilic poly-

saccharide subunits in the outer membrane lipopolysac-

charide (LPS) of Gram-negative bacteria. This membrane is

an attractive target for the design of effective antimicrobial

agents against these bacteria.^[2]As incorporation of KDO

appears to be a vital step in the growth of bacteria, disrup-

tion of its synthesis or incorporation into LPS can be a

rational approach towards this goal.^[3]

The most representative members of the KDN family are

the sialic acids, usually found at the nonreducing ends of

oligosaccharides, glycoproteins, and glycolipids. They are

involved in the modulation of numerous biological pro-

cesses such as cellular recognition signal transduction, cell

adhesion, viral receptor recognition, etc.^[4]

3-Deoxy-2-ulosonic acids are widespread natural com-

pounds constituting a specific family of carbohydrates. The

anomeric carbon atom is quaternary, also possessing a

carboxylic functionality; in addition they are dehy-

droxylated in the C-3 position. Functionalized or not, these

compounds participate in various important biological pro-

cesses. The most important of the series (Figure 1) are 3-

deoxy--arabino-2-heptulosonic acid (DAH), 3-deoxy--

manno-2-octulosonic acid (KDO), 3-deoxy--glycero--gal-

acto-2-nonulosonic acid (KDN), and 3,5-dideoxy--glycero-

-galacto-5-acetylamino-2-nonulosonic acid (5-NANA or

sialic acid).

It is not surprising that these structures have evoked im-

mense interest from both the biological and synthetic stand-

points. Further study on the medicinal chemistry and bio-

chemistry of these compounds requires practical routes to

the natural and unnatural derivatives and to their ana-

logues. Work towards the elaboration of ulosonic acids and

analogues has thus accelerated and several such endeavors,

including chemical, enzymatic, and chemoenzymatic syn-

theses, both starting from carbohydrates and de novo, have

already appeared in the literature.^[5Ϫ8]

Figure 1. Most abundant natural 3-deoxy-2-ulosonic acids

DAH in its 7-phosphate form (DAH-7P) is an important

intermediate in the shikimic acid pathway, by which the

aromatic amino acids and a multitude of other aromatic

and alicyclic compounds are biosynthesized in bacteria,

Some years ago we reported a versatile synthesis of a pro-

tected DAH, starting from a non-carbohydrate precursor.

[a]

`

´

´ ˆ

Synthese et Physicochimie de Molecules d’Interet Biologique, The methodology was based on [4ϩ2ϩ1] carbon atom in-

´

UMR CNRS 5068, Universite Paul Sabatier,

corporation, starting from an α,β-epoxy aldehyde.^[9]This

synthesis began with a suitably chosen trans-α,β-epoxy al-

dehyde 1, obtained from cis-2-butene-1,4-diol after protec-

tion, double bond isomerization, Sharpless asymmetric

epoxidation, and oxidation of the alcohol. Compound 1

118 route de Narbonne, 31062 Toulouse Cedex 04, France

E-mail: baltas@chimie.ups-tlse.fr

NOVASEP, Site EIFEEL,

[b]

Boulevard de la Moselle, B. P. 50, 54340 Pompey, France

Supporting Information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

672

 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0204Ϫ0672 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 672Ϫ688

Direct Access to Furanosidic Eight-Membered Ulosonic Esters

FULL PAPER

was then condensed with lithium tert-butyl acetate and Results and Discussion

preferentially yielded the γ,δ-epoxy-β-hydroxy ester 2

Synthesis of α,β-Epoxy Aldehydes

(Scheme 1).

Epoxy aldehydes 13 were prepared in three steps (mono-

protection, epoxidation in the presence of mCPBA, and

Doering oxidation of the primary alcohol, Scheme 3) and

in 48% yield, starting from commercially available cis-2-but-

ene-1,4-diol.

Scheme 1

Treatment of 2 with a Lewis acid (ZnCl₂) quantitatively

yielded hydroxybutyrolactone 3, the result of regio- and ste-

reocontrolled opening of the epoxide at the C-4 atom.

Opening of the lactone 3 by the Weinreb method, trans-

formation into a thiazolyl ketone, acidic protection, and

benzylation of the free hydroxy groups gave compound 4,

which was then transformed into the protected heptulo-

sonic acid 5. Synthesis of protected DAH 5 was thus

achieved in six steps (19% yield) starting from epoxy ester 2.

Recently, while exploring a more direct route to heptulo-

sonic analogues, we have developed a new methodology

based on [4ϩ3] carbon atom incorporation. Mukaiyama

treatment of trans-α,β-epoxy aldehydes with ethyl 2-(trime-

thylsilyloxy)-2-propenoate (6), in the presence of the Lewis

acid BF₃Ϫdiethyl ether, resulted in the direct synthesis of a

separable mixture of 5- and 6-fluoroheptulosonic analogues

in their pyranosidic or furanosidic forms.^[10]On the other

hand, when cis-α,β-epoxy aldehydes were employed, bi-

cyclic precursors of ulosonic acids were obtained

(Scheme 2).^[11]

Scheme 3

Epoxy aldehydes 24 and 25 were prepared starting either

from -mannitol or from commercially available ethyl (S)-

cis-4,5-O-isopropylidene-4,5-dihydroxy-2-pentenoate.

-

Mannitol was first chosen as starting material for the pre-

paration of cis-allylic alcohols containing a stereogenic

center. (R)-Isopropylideneglyceraldehyde 15 could readily

be obtained from -mannitol in two steps (Scheme 4).^[12]

Treatment of -mannitol with 2-methoxypropene in anhyd-

rous DMF in the presence of Drierite and catalytic amounts

of pTSA under conditions described in the literature pro-

vided a mixture of five- and six-membered acetonides. Only

further treatment of this mixture in anhydrous DMF in the

presence of pTSA (6 mmol for 100 mmol of starting -man-

nitol) for 36 h at room temperature was capable of provid-

ing, through thermodynamic equilibration, 1,2:5,6-di-O-iso-

propylidene--mannitol (14) (65%, after recrystallization).

Glycol cleavage of 14 was then performed in the presence

of sodium periodate by an optimized procedure described

by Jackson.^[13]Treatment of -glyceraldehyde 15 with

methyl (triphenylphosphoranylidene)acetate in methanol at

0 °C provided a separable mixture of the corresponding

methyl esters 16Z and 16E in a 6:1 ratio in favor of the (Z)

isomer and in 70% yield (Scheme 4).^[14]

The cis-allylic alcohol 18 was synthesized either from 16Z

or from the commercially available ethyl ester of 16Z

Scheme 2

As a first step in our research concerning the potential

of the latter reaction, we present here a full account of the

synthesis of bicyclic compounds, an interpretation of the

results, functionalization, and the opening of these com-

pounds to provide the furanosidic analogues of ulosonic

acids.

Scheme 4

Eur. J. Org. Chem. 2003, 672Ϫ688

673

C. H. Sugisaki, Y. Ruland, M. Baltas

FULL PAPER

ative methods for the epoxidation of our compounds were

tried, by employment of TBHP (tert-butyl hydroperoxide)

in the presence of vanadium catalysts such as VO(OEt)₃

[(oxy)vanadium() triethoxide] or VO(acac)₂[vanadium()

acetylacetonate].^[17]After 18 h, no reaction was observed

when VO(acac)₂was employed, while treatment with

VO(OEt)₃resulted in cleavage of the TBDMS protective

group (after 96 h) and subsequent degradation of the

epoxy alcohol.

The epoxidation reaction was therefore conducted by em-

ploying mCPBA at 0 °C in CH₂Cl₂in the presence of so-

dium bicarbonate. After 16 h, the mixture was purified to

yield the two diastereoisomers in good total yield (75% for

22 and 87% for 23). Finally, Swern oxidation gave the de-

sired cis-α,β-epoxy aldehydes 24 and 25.

The erythro/threo diastereoselectivity in the epoxidation

reaction, affording epoxy alcohols 22 and 23, was 2:1 and

6:1, respectively, calculated by HPLC analysis. The absolute

configurations of the epoxy alcohols obtained were difficult

to establish at this stage. Nevertheless, characteristics of the

adducts were examined by NMR spectroscopy. While ¹³C

1

NMR did not reveal any particular trends, H NMR spec-

troscopy gave some helpful information. Epoxy alcohols,

either those obtained here or from literature data, pos-

sessing a chiral alkoxy or silyloxy center α to the epoxide

group have J_3/4vicinal coupling constants of higher value

Scheme 5

in the threo series than in the erythro one (Figure 2).^[18]

A

similar high value is also observed in the case of the threo-

(Scheme 5). Attempts to eliminate the acetonide protective γ,δ-epoxy-β-(silyloxy) ester 27, reported by us.^[19]

group first in order to introduce the silylated ones were un-

successful; a cyclization reaction occurred to afford the but-

enolide 17 exclusively. This reaction was observed under all

experimental conditions that might have allowed removal

of the acetonide group.

Synthesis of the target alcohols was thus achieved by the

following synthetic steps (Scheme 5). Reduction of the ester

group in the presence of DIBAL-H gave the cis-allylic alco-

hol 18 in good yield (80%). Acetate protection of the prim-

ary hydroxy group and acetonide removal afforded diol 19

in 84% yield. The hydroxy groups could then either be

identically protected (TBDPS group), furnishing compound

20, or they could be differentiated. In the latter case, the

primary hydroxy group was silylated first, by use of 1.2

equiv. of TBDMSCl in the presence of DMAP (1.8

equiv.).^[15]The monoprotected compound was exclusively

obtained in 87% yield. The secondary hydroxy group was

then protected as a tert-butyldiphenylsilyl ether group

(TBDPS), affording compound 21. The epoxidation step

was performed after removal of the acetate protective

group (Scheme 5).

Figure 2. J_3/4vicinal coupling constant of epoxy alcohols

Obtention of a chiral cis-epoxide by the Sharpless asym-

metric epoxidation reaction is difficult if not totally unfeas-

In addition, aldolization products 28Ϫ30 were also exam-

ible, because the presence of an α chiral center in the requis- ined by ¹H NMR spectroscopy. Compounds 28-anti and

ite starting (Z)-allylic alcohol slows the epoxidation reac- 28-syn were obtained from the aldol reaction between the

tion considerably. Sharpless et al. have reported the lack of epoxy aldehyde 25-erythro and the lithium enolate of 2-

any reaction of the acetonide equivalent of the allylic alco- acetylthiazole.^[20]Compounds 29-anti and 29-syn were ob-

hol 18 in the presence of (Ϫ)-DET, while with (ϩ)-DET the tained from epoxy aldehyde 25-erythro in aldol condensa-

reaction reaches only 55% completion after 14 d.^[16]Altern- tion with the lithium enolate of tert-butyl acetate. When the

674

Eur. J. Org. Chem. 2003, 672Ϫ688

Direct Access to Furanosidic Eight-Membered Ulosonic Esters

FULL PAPER

same conditions were applied to epoxy aldehyde 25-threo,

compounds 30-anti and 30-syn were synthesized

(Scheme 6).

Scheme 7

Scheme 8

Scheme 8). Gratifyingly, modification of the reaction condi-

tions (Method B, Scheme 8) gave an improved result, and

bicyclic products 32a and 32b were obtained in 78% yield.

This good result was also obtained when starting from

erythro-cis-α,β-epoxy aldehyde 25 and employing these

optimized conditions. Compounds 33a and 33b were thus

obtained in 78% yield. Compounds 34a and 34b, resulting

from removal of the TBDMS group, were also obtained, in

10% yield (total yield of 88%). If the reaction temperature

reached Ϫ10 °C, adducts 34a and 34b were obtained as ma-

jor compounds (Scheme 8).

The Mukaiyama reaction was also carried out with the

threo-cis-α,β-epoxy aldehyde diastereoisomers 24 and 25,

the corresponding bicyclic diastereoisomers of 32 and 33

also being obtained, in moderate yields (50% and 55%, re-

spectively).

Scheme 6

1

Study of the characteristics of the adducts 28Ϫ30 by H

NMR spectroscopy showed the same trends as before. The

values of the vicinal coupling constants J_3/4and J_5/6were

higher for an anti relationship between the hydroxy (or sily-

loxy) group and the epoxide ring than for the syn counter-

part (Scheme 6).

The stereochemistry and absolute configurations of the

epoxy alcohols were confirmed and established unambigu-

ously after the Mukaiyama aldolization reaction, inspection

of the products obtained, and an X-ray structure of one

of them.

The structural assignment of the bicyclic compounds was

established on the basis of NMR spectroscopy and data

Mukaiyama Aldol Reactions

A Mukaiyama aldol condensation of α,β-epoxy aldehyde from the literature.^[21]In fact there is only one example in

13 was achieved with ethyl 2-(trimethylsilyloxy)-2-propeno- the literature in which bicyclic compounds of this type were

ate (6) in the presence of different promoters (BiCl₃/ZnI₂or synthesized as masked octulosonic acids. Baasov’s group

NaI, Eu(fod)₃, LiClO₄, Sn(OTf)₂, TMSOTf, BF₃Ϫdiethyl has reported their multistep synthesis (13 steps) starting

ether). Only BF₃ϪEt₂O gave satisfactory results and so it from a differentially protected arabinose derivative into

was used for other aldol reactions. When epoxy aldehydes which an enolpyruvate moiety had been introduced, under-

13, 24, and 25 were employed, bicyclic products were ob- going Lewis acid intramolecular condensation. An X-ray

tained.^[11]From cis-α,β-epoxy aldehyde 13, anti and syn al- structure of one of the synthesized bicycles was available,

dolization products were formed, providing epimers 31a along with NMR spectroscopic data. According to these

and 31b in 45% yield (Scheme 7).

data there are similarities between the bicyclic frame 35 and

Initial aldol reactions employing erythro-cis-α,β-epoxy al- compound 33b: a) 3a-H resonates as a dd with J_3a/4a

ϭ

dehydes 24 afforded compounds 32a and 32b in 41% yield, 6.41 Hz; b) 5-H (δ ϭ 4.75 ppm) does not couple with 6-H,

together with 47% of recovered aldehyde (Method A, nor with 4-H; c) 6-H resonates at higher field (δ ϭ

Eur. J. Org. Chem. 2003, 672Ϫ688

675

C. H. Sugisaki, Y. Ruland, M. Baltas

FULL PAPER

3.71 ppm) than 6-H of the isomer 33a (δ ϭ 4.65 ppm), as the formation of an oxocarbenium ion, which may react in

in the case of Baasov’s compound. situ with the just formed alkoxide, forming the cyclic ketal

¹H NMR analysis of its isomer at C-4 (33a) shows that and thus the bicyclic compounds.

5-H (δ ϭ 4.75 ppm) does not couple with 6-H but does

Aldolization reactions with different chiral α,β-epoxy al-

couple with 4-H as a doublet with J_4/5ϭ 4.67 Hz.

dehydes have been extensively studied in our group. In the

The absolute configuration of the major bicycle adduct presence of lithium ester enolates the reaction proceeds with

33a was determined by its X-ray structure (Figure 3). If the anti-diastereofacial preference in all cases examined.^[19]This

absolute configuration (R) of the C-7 atom, originating was also the case when the α,β-epoxy aldehydes 25-erythro

from the starting material, is taken into account, the other and 25-threo of this study were allowed to react with

stereogenic centers are (S) (C-4), (R) (C-5), and (S) (C-6).

lithium tert-butyl acetate or lithiated acetylthiazole

(Scheme 6). We have also investigated and reported the

Mukaiyama aldolization reaction behavior of cis-α,β-epoxy

aldehydes and tert-butyl ketene silyl acetal in the presence

of various Lewis acids.^[22]Again, anti-diastereofacial prefer-

ence was observed except when an excess of LiClO₄(1.5

equiv.) was used, when the poorest selectivity (anti/syn ഠ

1:1) was obtained. In that study, use of SnCl₄or BF₃ϪEt₂O

as Lewis acid catalysts was found to be unsuccessful.

In the current case, considering the C-4 epimeric bicycles,

a syn-diastereofacial preference was observed for the Mu-

kaiyama aldolization reaction. Even though there is no un-

ambiguous explanation for the diastereofacial difference

observed, we can invoke some points:

The same aldolization reaction with the trans-α,β-epoxy

aldehyde analogues gave aldol compounds with syn-diaster-

eofacial preference.^[16]

Heathcock reported that treatment of chiral boron enol-

ates with prochiral aldehydes can result in inversion of dias-

tereoselectivity when catalytic or stoichiometric amounts of

SnCl₄are used as Lewis acid.^[23]Even though we cannot

compare results for catalytic and stoichiometric amounts of

BF₃ϪEt₂O (no reaction occurred in the first case), we have

also observed this effect when using LiClO₄, as mentioned

before.

Also, in order to understand the difference in the diaster-

eofacial preference of the Mukaiyama aldol reaction on em-

ployment of the erythro- and threo-α,β-epoxy aldehydes 25,

the energetically more favored conformers were calculated

by use of the Insight II program.^[24]Geometrical informa-

tion and relative energies calculated for some favored con-

formers are reported in Table 1.

Figure 3. X-ray structure of the major bicycle adduct 33a

Bicycle formation could be explained by the the mechan-

ism shown in Scheme 9; firstly, a Mukaiyama aldolization

reaction occurs with syn-diastereofacial preference to pro-

vide the intermediate γ,δ-epoxy-β-hydroxy oxo esters 36-

anti and 36-syn, which are diastereoisomers at C-4. The cyc-

lization process at the C-6 atom of these epoxy oxo esters

can be triggered by Lewis acid mediated intramolecular at-

tack of the carbonyl oxygen atom of the ketone on the ep-

oxide function. Such a cyclization process would result in

In both cases the energetically more favored conforma-

tion of the free epoxy aldehyde is the one in which the di-

hedral angle between the oxygen atom of the carbonyl

group and that of the epoxide is ca. 170°. If it is assumed

that the nucleophilic attack occurs from the face antiper-

iplanar to the epoxide bond, this should result in a si attack

in the case of the erythro compound and a re attack for the

threo aldehyde 25, preferentially producing syn adducts.

We can also note that the carbonyl group of the threo-

α,β-epoxy aldehyde is much more hindered than its coun-

terpart in the erythro one. This makes the aldolization reac-

tion more difficult and could explain the lower yield and the

lower diastereoselectivity observed during the aldolization

reaction of the threo-α,β-epoxy aldehyde 25 relative to 25-

erythro.

The intermediate aldol adducts 36-syn and 36-anti ob-

tained were cyclized to the corresponding bicycles. The ste-

Scheme 9

676

Eur. J. Org. Chem. 2003, 672Ϫ688

Direct Access to Furanosidic Eight-Membered Ulosonic Esters

Table 1. Geometrical information and relative energies for the different conformers of compounds 25-erythro and 25-threo

FULL PAPER

25e (I)

25e (II)

25e (III)

25t (I)

25t (II)

25t (III)

Energy [kcal/mol]

258.57

178

56

257.40

164

Ϫ57

256.31

177

Ϫ55

257.00

171

Ϫ32

256.72

171

Ϫ32

257.60

Ϫ159

Ϫ33

O_epϪC-2ϪC-1ϪO_ald[°]

O_epϪC-3ϪC-4ϪO_TBDPS[°]

O_epϪC-3ϪC-4ϪC5 [°]

Ϫ67

Ϫ178

Ϫ175

Ϫ157

Ϫ160

reochemistry of the products is the result of intramolecular

nucleophilic attack of the oxygen atom of the carbonyl

group at either C-5 or C-6 with inversion of configuration.

The X-ray structure of compound 33a unambiguously im-

plies a 6-endo-tet cyclization process. This preferential

opening of the epoxide ring reflects a more favorable tra-

jectory for C-6 opening, the result of a compromise between

conformational ring strain and stereochemical require-

ments.

Coxon et al. recently reported an ab initio study of the

intramolecular ring cyclization of protonated and BF₃-co-

ordinated cis-4,5-epoxyhexan-1-ol.^[25]The potential energy

surface for the rearrangement of protonated epoxy alcohols

shows activation barriers much more favorable to five-mem-

bered transition structures leading to furan. When BF₃is

coordinated to the epoxide, on the other hand, the five-

membered transition structure is marginally lower in energy

than the six-membered one, so in the latter case and with-

out consideration of any additional functional groups on

the molecule, opening of the epoxide ring both at C-5 and

at C-6 might occur.

For the major diastereoisomer 36-syn, originating from

the heavily substituted α,β-epoxy aldehyde 25-erythro, cy-

clization at C-6 could be preferential because it would allow

a better, almost antiperiplanar, stereochemical arrangement

of the oxygen atoms of the epoxide ring and the 4-hydroxy

group. Furthermore, in a six-membered transition state the

hydroxy group originating from the aldolization reaction is

almost equatorial. For the minor diastereoisomer 36-anti,

C-5 opening of the epoxide ring is also much less favorable

because of steric hindrance between the hydroxy group at

C-4 and the bulky alkylsilyloxy chain on the epoxide ring

(Figure 4).

Figure 4. Energetically favored rotamers around the C-4ϪC-5 bond

for the syn- and anti-aldol adducts

phosphate form in the outer membrane lipopolysaccharide

of Gram-negative bacteria.

Differentiation of the primary and the secondary hydroxy

group was successfully achieved in bicyclic compound 33a.

Compound 39 was synthesized by acetylation of the sec-

ondary alcohol of 33a, selective removal of the TBDMS

group, and protection of the primary alcohol as a phos-

phate group. In this case, all hydroxy groups have different

functions (Scheme 10).

Furthermore, protection of the hydroxy group of 33a as

a TBDPS ether and selective removal of the TBDMS group

gave compound 41. Phosphorylation of the primary hy-

droxy group and removal of TBDPS groups provided com-

pound 43.

Opening of Bicyclic Compounds

In a literature report, treatment of bicyclic compound 35

with para-toluenesulfonic acid (pTsOH) in methanol in-

Functionalization of Bicyclic Compounds

As the synthesized bicyclic compounds 31 and 33 are duced the formation of α- and β-methyl furanoside derivat-

masked heptulosonic and octulosonic acids, differential ives of KDO.^[21]

protection of hydroxy groups might result in different ana-

logues of ulosonic acids.

Starting from compound 33a, treatment with pTsOH in

methanol for 1 h and 45 min gave compound 44, resulting

Natural ulosonic carbohydrates are usually func- from acidolysis of the TBDMS group and replacement of

tionalized with phosphate or sulfate groups. In the shikimic the ethyl ester group by a methyl group. Compound 44 was

acid pathway, for example, the natural substrate of the en- then subjected to the same acidic conditions, and after 16

zyme DHQ synthase is 3-deoxy--arabino-heptulosonic 7- h the α- and β-methyl furanosidic compounds 45 (ana-

phosphate (DAH, 7-P). In addition, KDO is found in its 8- logues of the C-4 epimer of the natural compound) were

Eur. J. Org. Chem. 2003, 672Ϫ688

677

C. H. Sugisaki, Y. Ruland, M. Baltas

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Scheme 12

Scheme 10

consumption of starting material. After 17 h, only the ex-

change of ethyl and methyl ester groups had been observed,

giving compound 46. This, when treated under the same

conditions for 22 h, underwent removal of the acetate and

TBDPS groups, affording compound 47, which was de-

graded upon heating to 55 °C. Treatment of compound 39

in the presence of SnCl₄in methanol for 48 h at room tem-

perature also yielded transesterified compound 46.

The same result was observed when compound 41, pos-

sessing a primary hydroxy group instead of a C-4-protected

one, was treated with SnCl₄under conditions described be-

fore above.

obtained in 35% yield (56% based on recovered starting

material). When the reaction was conducted for a longer

period of time under the same conditions or the mixture

was heated at 60 °C, complete loss of protective groups was

observed, resulting in degradation products. Camphorsul-

fonic acid, a reagent with lower acidity, was then chosen.

Treatment of compound 33a for 41 h gave furanosidic com-

pound 45 in 31% yield (60% based on recovered starting

material).

The use of a Lewis acid (SnCl₄) in methanol was also

investigated, and better results were obtained. When com-

pound 44 was treated with SnCl₄in methanol for 49 h at

room temperature, the desired α- and β-methyl furanosidic

compounds 45 were obtained in 62% yield (94% based on

recovered starting material, Scheme 11). The TBDPS group

showed better stability with SnCl₄than with camphorsul-

fonic acid. In an attempt to reduce the reaction time, com-

pound 44 was treated under the same conditions but with

heating to 50 °C, for 15 h. Furanosidic compound 45 was

obtained in 50% yield (62% based on recovered starting

material).

Functionalization of the Primary Hydroxy Group of

Furanosidic Compound 45

As described above, bicyclic compounds functionalized

on the primary hydroxy group failed to react under the

acid-catalyzed opening reactions. Gratifyingly, differenti-

ation and functionalization of the hydroxy groups of

furanoside compound 45 was achieved by the following re-

action sequence. Selective phosphorylation at the primary

hydroxy position of compound 45 was observed when tri-

ethyl phosphite and carbon tetrabromide in pyridine were

used, resulting in the formation of the corresponding 8-di-

ethylphosphate ester 51 (Scheme 13).^[26]

Unfortunately, a significant decrease in reactivity was ob-

served when employing functionalized bicyclic compounds

in the acid-catalyzed opening reaction. Treatment of phos-

phorylated bicyclic compound 39 with pTsOH showed slow

Conclusion

In conclusion, a direct and efficient route to furanosidic

eight-membered ulosonic acids is described. The aldoliz-

ation reaction between the γ,δ-silyloxy cis-α,β-epoxy alde-

hydes and ethyl 2-(trimethylsilyloxy)-2-propenoate in the

presence of BF₃Ϫdiethyl ether preferentially gave syn-aldol

adducts that were cyclized in situ by an intramolecular pro-

Scheme 11

678

Eur. J. Org. Chem. 2003, 672Ϫ688

Direct Access to Furanosidic Eight-Membered Ulosonic Esters

FULL PAPER

butene-1,2-diol (6.65 g, 75.6 mmol) in dry DMF (400 mL). After

the mixture had been stirred for 20 h, water (100 mL) was added

and the aqueous phase was extracted with diethyl ether (800 mL).

The organic phase was dried with MgSO₄and filtered, and the

solvent was evaporated. The oil was purified by chromatography

on a silica gel column (petroleum ether/diethyl ether, 1:1, R_fϭ 0.3),

and alcohol 11 (19 g) was obtained as a colorless oil (77% yield).

¹H NMR (250 MHz, CDCl₃): δ ϭ 1.06 (s, 9 H, CH₃TBDPS), 4.01

(m, 2 H, 1-H), 4.27 (m, 2 H, 4-H), 5.69Ϫ5.77 (m, 1 H, 2-H, 1 H,

3-H), 7.36Ϫ7.46 (m, 6 H, phenyl), 7.69Ϫ7.72 (m, 4 H, phenyl) ppm.

¹³C NMR (50 MHz, CDCl₃): δ ϭ 19.1 (C_q, TBDPS), 26.8 (CH₃,

TBDPS), 58.8, 60.3 (CH₂, C1) (CH₂, C-4), 129.6, 129.8, 129.9,

134.8, 135.8 (CH, phenyl), 130.0, 131.0 (CH, C-2, C-3), 133.4 (C_q,

phenyl) ppm. C₂₀H₂₆O₂Si (326.5): calcd. C 73.57, H 8.03; found C

73.44, H 8.03. IR (film): ν˜ ϭ3355 cm^Ϫ1, 3073, 1589, 1111.

Epoxy Alcohol 12: A solution of mCPBA (70% tech., 17.15 g,

69.92 mmol) in dry CH₂Cl₂(30 mL) was added dropwise at 0 °C

to a suspension of allylic alcohol 11 (11.4 g, 34.96 mmol) and

NaHCO₃(6.76 g, 80.42 mmol) in dry CH₂Cl₂(250 mL). After the

mixture had been stirred for 30 min at 0 °C, the ice bath was re-

moved and the reaction mixture was stirred for a further 16 h at

room temperature. Aqueous sodium bisulfite (10%, 40 mL) was ad-

ded at 0 °C, and the mixture was stirred for 30 min. The organic

layer was separated and washed with saturated aqueous NaHCO₃,

dried with MgSO₄, and filtered, and the solvent was evaporated.

The residual oil was purified by chromatography on a silica gel

column (petroleum ether/ethyl acetate, 7:3, R_fϭ 0.33) and epoxy

Scheme 13

cess to provide bicycles in good to excellent yields. Func-

tionalization and discrimination of the hydroxy groups

could be achieved easily, and opening of the bicycle neces-

sitates the presence of free primary and 4-hydroxy groups.

Epimerization at the C-4 position, affording the configura-

tion of the natural KDO, along with further functionaliz-

ation will be presented in due course.

1

alcohol 12 was obtained (7.13 g, 87% yield). H NMR (250 MHz,

CDCl₃): δ ϭ 1.07 (s, 9 H, CH₃, TBDPS), 2.10 (s, 1 H, OH), 3.22

(m, 1 H, 2-H, 1 H, 3-H), 3.76 (dd, J_3/4aϭ 5.6, J_4a/4bϭ 11.7 Hz, 1

H, 4-H), 3.91 (dd, J_3/4bϭ 5.3, J_4a/4bϭ 11.7 Hz, 1 H, 4-H),

7.38Ϫ7.46 (m, 6 H, phenyl), 7.66Ϫ7.71 (m, 4 H, phenyl) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ ϭ 19.2 (C_q, TBDPS), 26.8 (CH₃,

TBDPS), 56.4, 56.2 (CH, C-2) (CH, C-3), 60.8, 62.3 (CH₂, C-4)

(CH₂, C-1), 127.9, 129.8, 130.0, 135.5, 135.6 (CH, phenyl), 132.9,

133.0 (C_q, phenyl) ppm. C₂₀H₂₆O₃Si (342.5): calcd. C 70.13, H

7.65; found C 69.88, H 7.60. IR (film): ν˜ ϭ3421 cm^Ϫ1, 3073, 2935,

2861, 1470, 1100.

Experimental Section

General: All reactions were carried out under nitrogen. The follow-

ing solvents were dried prior to use: dichloromethane (calcium hy-

dride), diethyl ether (sodium), methanol (Mg, iodine), pyridine and

triethylamine (calcium hydride and stored over potassium hydrox-

ide pellets), and THF (sodium). TLC was performed on ALUG-

RAM SIL G/UV₂₅₄(0.2 mm) plates. Column chromatography was

performed on Merck 60 silica gel (70Ϫ200 µm). Medium-pressure

Aldehyde 13: Anhydrous DMSO (6 mL) and Et₃N (2.05 mL,

14.7 mmol) were added to a solution of epoxy alcohol 12 (1.0 g,

2.94 mmol) in dry dichloromethane (4.5 mL). The mixture was co-

oled to 0 °C, and pyrSO₃complex (2.34 g, 14.7 mmol) was added

in four portions. The mixture was allowed to warm to room tem-

perature and stirred for a further 20 min. Diethyl ether (35 mL)

was added, and the organic phase was washed with water (3 ϫ

10 mL), dried with MgSO₄, and filtered, and the solvents were

evaporated. Aldehyde 13 (845 mg) was obtained (85% yield) and

liquid chromatography (MPLC) was performed with

a

JobinϪYvon apparatus on Merck silica (15Ϫ40 µm). High per-

formance liquid chromatography (HPLC) was performed with

PROCHROM apparatus on Merck silica (12 µm). NMR spectro-

scopic data were obtained with Bruker AC 200, AC 250, and AC

400 instruments operating at 200, 250, and 400 MHz (¹H spectra),

respectively, 50, 63, and 100 MHz (¹³C spectra), respectively, and

at 161 MHz (³¹P; AC 400). Chemical shifts are quoted in ppm

downfield from tetramethylsilane, and coupling constants J are in

Hz.^[27]Infrared spectra were recorded with a PerkinϪElmer FT-IR

1725X spectrometer. Mass spectrometry data were obtained with a

NERMAG R10Ϫ10 spectrometer. Elemental analyses were ob-

tained from the microanalysis laboratory of the ‘‘Ecole Nationale

1

employed without purification. H NMR (250 MHz, CDCl₃): δ ϭ

1.07 (s, 9 H, CH₃, TBDPS), 2.76 (m, 1 H, 3-H), 2.87 (t, J_2/1ϭ J_2/

ϭ 4.8 Hz, 1 H, 2-H), 3.53 (dd, J_3/4aϭ 4.3, J_4a/4bϭ 12.3 Hz, 1 H,

3

4-H), 3.49 (dd, J_3/4bϭ 3.2, J_4a/4bϭ 12.3 Hz, 1 H, 4-H), 7.18Ϫ7.23

(m, 6 H, phenyl), 7.64Ϫ7.74 (m, 4 H, phenyl) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ ϭ 19.2 (C_q, TBDPS), 26.8 (CH₃, TBDPS),

57.8, 59.8 (CH, C-2) (CH, C-3), 60.8 (CH₂, C-4), 128.0, 130.0,

135.6 (CH, phenyl), 132.4, 132.9 (C_q, phenyl), 198.1 (CϭO, CHO)

ppm. MS (DCI, NH₃): m/z ϭ 358 [M ϩ NH₄^ϩ]. IR (film): ν˜ ϭ

3074 cm^Ϫ1, 1724, 1111.

´

Superieure de Chimie’’, Toulouse, France. Optical rotations were

measured with a PerkinϪElmer model 141 polarimeter.

1,2,5,6-Diisopropylidene-

d

-mannitol

(14):

2-Methoxypropene

Ethyl 2-(Trimethylsilyloxy)-2-propenoate (6): This compound was

(14.4 g, 0.20 mol) and pTsOH (0.2 g) were successively added at 0

°C to a solution of -mannitol (18.2 g, 0.1 mol) in anhydrous DMF

(400 mL) and Drierite (1.0 g). After 2 h, further pTsOH (0.2 g) was

added and the mixture was stirred for 1 h. 2-Methoxypropene (4 g,

synthesized according to ref.^[28]

Alcohol 11: Imidazole (15.45 g, 227 mmol) and TBDPSCl (20.8 g,

75.6 mmol) were added at room temperature to a solution of cis-

Eur. J. Org. Chem. 2003, 672Ϫ688

679

C. H. Sugisaki, Y. Ruland, M. Baltas

0.05 mol) was then added in four portions over 2 h. Na₂CO₃(5 g) and 45 min, saturated aqueous NaHCO₃was added, and the aque-

FULL PAPER

was added and the stirring was continued for a further 1 h. The

mixture was filtered and DMF was distilled. The crude product

ous phase was extracted with CH₂Cl₂and ethyl acetate. The com-

bined organic phases were dried with MgSO₄, filtered, and concen-

was redissolved in DMF (300 mL), pTsOH (1.2 g) was added, and trated, to provide compound 17 (24 mg, 84% yield) (ethyl acetate/

the mixture was stirred at room temperature for 36 h. DMF was

distilled off, and the residue was dissolved in dichloromethane

(30 mL) and dibutyl ether (35 mL). After evaporation of dichloro-

methane, the desired product (11 g, 65% yield) was obtained as

methanol, 95:5, R_fϭ 0.54). ¹H NMR (250 MHz, CDCl₃): δ ϭ 3.52,

3.65 (2 dd, J_5a/4ϭ 4.0, J_5b/4ϭ 4.86, J_5a/5bϭ 12.1 Hz, 1 H, 5-H),

4.90 (t, J_3/4ϭ 1.50, J_4/2ϭ 2.04 Hz, 1 H, 4-H), 5.88 (dd, J_3/2

ϭ

5.76 Hz and J_4/2ϭ 2.04 Hz, 1 H, 2-H), 7.34 (dd, J_3/2ϭ 5.76,

1

crystals. H NMR (250 MHz, CDCl₃): δ ϭ 1.35 (s, 6 H, CH₃, ace-

J_3/4ϭ 1.50 Hz, 1 H, 3-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ

tonide), 1.41 (s, 6 H, CH₃, acetonide), 2.63Ϫ2.66 (m, 2 H, 2 OH), 61.6 (CH₂, C-5), 84.3 (CH, C-4), 122.0 (CH, C-3), 154.7 (CH, C-

3.71Ϫ3.76 (m, 2 H), 3.94Ϫ3.99 (m, 2 H), 4.08Ϫ4.21 (m, 4 H) ppm.

¹³C NMR (50 MHz, CDCl₃): δ ϭ 25.2, 26.7 (CH₃, acetonide), 66.8

(CH₂), 71.0, 75.8 (CH), 109.2 (C_q, acetonide) ppm.

2), 173.4 (CϭO) ppm. MS (DCI, NH₃): m/z ϭ 115 [M ϩ H^ϩ], 132

[M ϩ NH₄^ϩ]. C₅H₆O₃(114.1): calcd. C 52.63, H 5.30; found C

52.69, H 5.35. IR (film): ν˜ ϭ3416 cm^Ϫ1, 1737, 1602.

Aldehyde 15: Saturated aqueous NaHCO₃(2.7 mL) and a solution

of compound 14 (6.7 g, 25.54 mmol) in dichloromethane (60 mL)

were placed in a reaction vessel (250 mL) equipped with a mechan-

ical stirrer. NaIO₄(10.9 g, 51 mmol) was added, and the mixture

was stirred for 1.5 h at room temperature. After decantation,

dichloromethane was removed and the residue was extracted with

more dichloromethane (30 mL). The solvent was evaporated and

the residue was purified by distillation under reduced pressure

(30 mbar, 55 °C). Pure product 15 (6.5 g) was obtained in 98%

yield. ¹H NMR (250 MHz, CDCl₃): δ ϭ 1.40 (s, 3 H, CH₃, aceton-

Alcohol 18: DIBAL-H (1  in CH₂Cl₂, 28.0 mmol, 28.0 mL) was

slowly added at 0 °C to a solution of ethyl (2Z,3S)-(ϩ)-3-(2,2-di-

methyl-1,3-dioxolan-4-yl)-2-propenoate (3.04 g, 15.2 mmol) in dry

CH₂Cl₂(80 mL). The solution was stirred for 4 h at 0 °C. A satur-

ated aqueous ammonium chloride solution (10 mL) was then ad-

ded, and the mixture was stirred at room temperature for a further

30 min. After filtration, the organic phase was washed with water,

dried with MgSO₄, and filtered, and the solvent was evaporated.

The oil was purified by chromatography on a silica gel column

(petroleum ether/diethyl ether, 7:3 to 3:7) (petroleum ether/diethyl

ether, 3:7, R_fϭ 0.30) to give the desired product (1.92 g, 80% yield).

¹H NMR (250 MHz, CDCl₃): δ ϭ 1.39 (s, 3 H, CH₃, acetonide),

1.45 (s, 3 H, CH₃, acetonide), 3.56 (t, J ϭ 8.0 Hz, 1 H, 5-H), 4.09

(dd, J ϭ 6.2 Hz and J ϭ 8.1 Hz, 1 H, 5-H), 4.21Ϫ4.29 (m, 2 H, 1-

H), 4.87 (q, J ϭ 7.0 Hz, 1 H, 4-H), 5.56 (t, J ϭ 8.1 Hz, 1 H, 3-H),

5.79Ϫ5.86 (m, 1 H, 2-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ

25.9 (CH₃, acetonide), 26.7 (CH₃, acetonide), 58.7 (CH₂, C-1), 69.6

(CH₂, C-5), 71.9 (CH, C-4), 109.5 (C_q, acetonide), 129.6, 133.1

(CH, C-2 andC-3) ppm. MS (DCI, NH₃): m/z ϭ 159 [M ϩ H^ϩ],

176 [M ϩ NH₄^ϩ]. IR (film): ν˜ ϭ3412 cm^Ϫ1, 1651, 1059, 859.

C₈H₁₄O₃(158.1): calcd. C 60.74, H 8.92; found C 60.88, H 8.90.

ide), 1.45 (s, 3 H, CH₃, acetonide), 4.08 (dd, J_3/2ϭ 4.85, J_3a/3b

ϭ

8.73 Hz, 1 H, 3-H), 4.16 (dd, J_3/2ϭ 7.34, J_3a/3bϭ 8.68 Hz, 1 H, 3-

H), 4.37 (ddd, J_1/2ϭ 1.86, J_2/3ϭ 4.87, J_2/3ϭ 7.27 Hz, 1 H, 2-H),

9.70 (d, J_1/2ϭ 1.86 Hz, 1 H, CHO) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 24.9, 26.0 (CH₃, acetonide), 65.5 (C-2), 79.6 (C-3),

111.0 (C_q, acetonide), 201.5 (CϭO, CHO) ppm.

Compound 16: Methyl (trimethylphosphoranylidene)acetate (1.5 g,

4.61 mmol) was added at Ϫ10 °C to a solution of aldehyde 15

(500 mg, 3.84 mmol) in methanol (16 mL). After 20 h of stirring at

Ϫ10 °C, the solvent was evaporated and the residue was redissolved

in diethyl ether (10 mL). After filtration, the solvent was evapor-

ated. The residue was then purified by chromatography on a silica

gel column (petroleum ether/diethyl ether, 9:1), and compounds

16Z (430 mg) and 16E (70 mg) were obtained as colorless oils (70%

Acetate 19: Et₃N (3.0 mL), Ac₂O (1.5 mL), and DMAP (20 mg,

0.16 mmol) were added at room temperature to a solution of alco-

hol 18 (403 mg, 2.55 mmol) in dry CH₂Cl₂(20 mL). The mixture

was stirred for 1 h at room temperature and washed with saturated

aqueous NaHCO₃, and the organic phase was dried with MgSO₄,

filtered, and concentrated. The oil was purified by chromatography

on silica gel (petroleum ether/diethyl ether, 1:1, R_fϭ 0.46), and

the desired acetate (510 mg, 99% yield) was obtained. ¹H NMR

(250 MHz, CDCl₃): δ ϭ 1.36 (s, 3 H, acetonide), 1.40 (s, 3 H, ace-

tonide), 2.03 (s, 3 H, OAc), 3.54 (t, J_5a/5bϭ 7.9 Hz, 1 H, 5-H), 4.08

(dd, J_4/5ϭ 6.4, J_5a/5bϭ 7.9 Hz, 1 H, 5-H), 4.62Ϫ4.66 (m, 2 H, 1-

H), 4.84 (ddd, J ϭ 7.6, J ϭ 7.0, J ϭ 6.4 Hz, 1 H, 4-H), 5.58Ϫ5.72

(m, 1 H, 2-H, 1 H, 3-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ

20.9 (CH₃, OAc), 25.6 (CH₃, acetonide), 26.6 (CH₃, acetonide),

60.0 (CH₂, C-1), 69.3 (CH₂, C-5), 71.8 (CH, C-4), 109.5 (C_q, ace-

tonide), 127.6, 132.0 (CH, C-2 and C-3), 170.7 (CϭO, OAc) ppm.

MS (DCI, NH₃): m/z ϭ 201 [M ϩ H^ϩ], 218 [M ϩ NH₄^ϩ]. IR

(film): ν˜ ϭ2988 cm^Ϫ1, 2874, 1741, 1649, 1456, 1376, 1230, 1157,

1060, 1032, 966, 859. HCl (2 , 0.4 mL) was added dropwise at 0

°C to a solution of acetonide (64 mg, 0.32 mmol) in acetonitrile

(3.8 mL) and water (0.8 mL). After 2 h and 30 min, saturated aque-

1

total yield). 16Z: H NMR (250 MHz, CDCl₃): δ ϭ 1.34 (s, 3 H,

CH₃acetonide), 1.44 (s, 3 H, CH₃acetonide), 3.61 (dd, J_5/4ϭ 6.7,

J_5a/5bϭ 8.2 Hz, 1 H, 5-H), 3.70 (s, 3 H, CO₂Me), 4.37 (dd, J_5/4

6.9, J_5a/5bϭ 8.2 Hz, 1 H, 5-H), 5.48 (dq, J_4/2ϭ 1.7 Hz and J_4/5a

J_4/5bϭ J_4/3ϭ 6.6 Hz, 1 H, 4-H), 5.85 (dd, J_2/4ϭ 1.7, J_2/3

ϭ

11.6 Hz, 1 H, 2-H), 6.37 (dd, J_3/4ϭ 6.6, J_3/2ϭ 11.6 Hz, 1 H, 3-H)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 25.4 (CH₃, acetonide), 26.6

(CH₃, acetonide), 51.7 (CH₃, CO₂CH₃), 69.4 (CH₂, C-5), 73.6 (CH,

C-4), 109.7 (C_q, acetonide), 120.3, 149.6 (CH, C-2 andC-3), 166.1

(CϭO, CO₂CH₃) ppm. MS (DCI, NH₃): m/z ϭ 204 [M ϩ NH₄^ϩ].

C₉H₁₄O₄(186.1): calcd. C 58.05, H 7.58; found C 58.15, H 7.60. IR

1

(film): ν˜ ϭ1718 cm^Ϫ1, 1646, 1060, 860. 16E: H NMR (250 MHz,

CDCl₃): δ ϭ 1.38 (s, 3 H, CH₃, acetonide), 1.44 (s, 3 H, CH₃,

acetonide), 3.47 (s, 3 H, CO₂Me), 3.68 (dd, J_5/4ϭ 7.2, J_5a/5b

ϭ

15.4 Hz, 1 H, 5-H), 4.18 (m, 1 H, 5-H), 4.65 (dq, J_4/2ϭ 1.4 Hz and

J_4/5aϭ J_4/5bϭ J_4/3ϭ 7.0 Hz, 1 H, 4-H), 6.09 (dd, J_2/4ϭ 1.4,

J_2/3ϭ 15.6 Hz, 1 H, 2-H), 6.88 (dd, J_3/4ϭ 5.6, J_3/2ϭ 15.6 Hz, 1

H, 3-H). MS (DCI, NH₃): m/z ϭ 204 [M ϩ NH₄^ϩ].

5-(Hydroxymethyl)furan-2(5H)-one (17). Method A: Dowex ous NaHCO₃was added and the aqueous phase was extracted with

(350 mg) was added to a solution of acetonide 16Z (84 mg,

0.42 mmol) in ethanol (15 mL). After 8 h, the suspension was fil-

tered and the solvent was evaporated. Compound 17 (40 mg) was

CH₂Cl₂and ethyl acetate. The combined organic phases were dried

with MgSO₄, filtered, and concentrated. The residual oil was puri-

fied by chromatography on silica gel (petroleum ether/ethyl acet-

obtained (83% yield). Method B: A solution of HCl (2 , 0.2 mL) ate,10:90, R_fϭ 0.23), and diol 19 (44 mg, 85% yield) was obtained.

was added dropwise at 0 °C to a solution of acetonide (50 mg, ¹H NMR (250 MHz, CDCl₃): δ ϭ 2.05 (s, 3 H, OAc), 3.49 (dd,

0.25 mmol) in acetonitrile (3.8 mL) and water (0.8 mL). After 2 h

680

J_5/4ϭ 7.33, J_5a/5bϭ 11.29 Hz, 1 H, 5-H), 3.57 (dd, J_4/5ϭ 3.97,

Eur. J. Org. Chem. 2003, 672Ϫ688

Direct Access to Furanosidic Eight-Membered Ulosonic Esters

FULL PAPER

J_5a/5bϭ 11.29 Hz, 1 H, 5-H), 4.58 (dd, J ϭ 3.97, J ϭ 8.24 Hz, 2

H, 1-H), 4.78 (dd, J ϭ 6.41, J ϭ 13.13 Hz, 1 H, 4-H), 5.61Ϫ5.65

H, OAc), 3.43 (dd, J_5/4ϭ 7.01, J_5a/5bϭ 9.77 Hz, 1 H, 5-H), 3.59

(dd, J_5/4ϭ 5.19, J_5a/5bϭ 9.77 Hz, 1 H, 5-H), 4.10Ϫ4.30 (m, 2 H,

(m, 1 H, 2-H, 1 H, 3-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 1-H), 4.35Ϫ4.50 (m, 1 H, 4-H), 5.40Ϫ5.60 (m, 1 H, 2-H, 1 H, 3-

21.0 (CH₃, OAc), 58.5 (CH₂, C-1), 66.0 (CH₂, C-5), 68.6 (CH, C-

H), 7.34Ϫ7.42 (m, 4 H, CH C₆H₅), 7.62Ϫ7.70 (m, 6 H, CH, C₆H₅)

4), 127.0, 132.9 (CH, C-2 and C-3), 171.4 (CϭO, OAc) ppm. MS ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ Ϫ5.37 (CH₃, TBDMS),

(DCI, NH₃): m/z ϭ 143 [M ϩ H^ϩϪ H₂O], 161 [M ϩ H^ϩ], 178 [M

ϩ NH₄^ϩ]. IR (film): ν˜ ϭ3401 cm^Ϫ1, 3030, 2932, 2872, 1738, 1656,

1427, 1375, 1239, 1071, 1031, 958, 873.

18.40 (C_q, tBu), 19.29 (C_q, tBu), 20.95 (CH₃, OAc), 25.96 (CH₃,

tBu), 60.80 (CH₂, C-1), 67.21 (CH₂, C-5), 70.38 (CH, C-4), 125.23,

127.52, 127.63, 129.66, 129.71, 134.67, 135.97 (CH, C-2, CH, C-3,

CH aromatic), 133.85, 133.92 (C_q, aromatic), 170.65 (CϭO, OAc)

ppm. MS (DCI, NH₃): m/z ϭ 530 [M ϩ NH₄^ϩ].

Compound 20: A solution of TBDPSCl (2.71 g, 9.9 mmol) in

CH₂Cl₂(10 mL) was slowly added at room temperature to a solu-

tion of diol 19 (720 mg, 4.5 mmol) and imidazole (1.34 g,

19.8 mmol) in CH₂Cl₂(15 mL). The reaction mixture was stirred

Compounds 22-erythro and 22-threo: The same experimental pro-

cedure as described for the synthesis of compounds 23 was applied,

for 2 h at room temperature. Water (20 mL) was added, and the starting from the corresponding allylic alcohol (1.0 g, 1.68 mmol;

organic phase was washed with saturated aqueous NaHCO₃765 mg of products 22, 75% yield). The diastereoisomers (dr 66:34)

(10 mL), dried with MgSO₄, filtered, and concentrated. The resid- were separated by HPLC (silica, eluent petroleum ether/diethyl

ual oil was purified by chromatography on silica gel (petroleum

ether/diethyl ether, 90:10, R_fϭ 0.56), and the desired product

(2.0 g, 70% yield) was obtained. ¹H NMR (250 MHz, CDCl₃): δ ϭ

ether, 7:3). 22-erythro: ¹H NMR (400 MHz, CDCl₃): δ ϭ 1.05, 1.08

(s, 18 H, tBu, TBDPS), 2.90 (ddd, J_2/3ϭ 3.8, J ϭ 7.0 Hz, 1 H, 2-

H), 2.95Ϫ2.99 (m, 1 H, 1-H), 3.05Ϫ3.09 (m, 1 H, 1-H), 3.23 (dd,

0.99 (s, 9 H, tBu, OTBDMS), 1.03 (s, 9 H, tBu, OTBDMS), 1.95 J_3/4ϭ 7.5, J_2/3ϭ 3.9 Hz, 1 H, 3-H), 3.64 (ddd, J_4/5aϭ 4.4, J_4/5b

ϭ

(s, 3 H, OAc), 3.49 (dd, J_5/4ϭ 5.90, J_5a/5bϭ 10.00 Hz, 1 H, 5-H),

3.67 (dd, J_5/4ϭ 5.40, J_5a/5bϭ 10.00 Hz, 1 H, 5-H), 4.03Ϫ4.20 (m,

3.2, J_3/4ϭ 7.5 Hz, 1 H, 4-H), 3.74 (2dd, J_5a/5bϭ 10.7, J_5a/4ϭ 4.4,

J_5b/4ϭ 3.2 Hz, 2 H, 5-H), 7.26Ϫ7.68 (m, 20 H, C₆H₅) ppm. ¹³C

2 H, 1-H), 4.48Ϫ4.56 (m, 1 H, 4-H), 5.30Ϫ5.46 (m, 1 H, 3-H), NMR (100 MHz, CDCl₃): δ ϭ 19.3 (C_q, tBu), 26.90 (CH₃, tBu),

5.57Ϫ5.65 (m, 1 H, 2-H), 7.26Ϫ7.57 (m, 12 H, phenyl), 7.58Ϫ7.68 57.20 (CH, C-2), 57.40 (CH, C-3), 60.40 (CH₂, C-1), 66.90 (CH₂,

(m, 8 H, phenyl) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 19.10 C-5), 70.60 (CH, C-4), 127.80, 129.70, 135.90, 136.10 (CH, C₆H₅),

and 19.20 (C_q, tBu), 20.90 (CH₃, OAc), 26.70 and 26.90 (CH₃, 133.30, 133.60 (C_q, C₆H₅) ppm. [α]²_D⁵ϭ Ϫ5.1 (c ϭ 0.9, CHCl₃)

tBu), 60.60 (CH₂, C-1), 67.90 (CH₂, C-5), 70.30 (CH, C-4), 127.50 ppm. C₃₇H₄₆O₄Si₂(610.9): calcd. C 72.74, H 7.59; found C 72.62,

(CH, C-2), 129.60 (CH, C-3), 133.80 and 134.60 (C_q, TBDPS), H 7.51. IR (film): ν˜ ϭ3436 cm^Ϫ1, 3072, 3050, 2955, 2031, 2895,

135.60, 135.80, 136.00 (CH, phenyl), 170.80 (CϭO, OAc) ppm. MS

2858, 1590, 1473, 1463, 1428, 1391, 1362, 1335, 1257, 1217, 1189,

1047, 1005, 969, 922, 869, 837, 776, 760, 741, 703, 668. 22-threo:

(DCI, NH₃): m/z ϭ 654 [M ϩ NH₄^ϩ]. [α]²_D⁵ϭ Ϫ5.8 (c ϭ 0.7,

CHCl₃). IR (film): ν˜ ϭ3071 cm^Ϫ1(CϭCH aromatic), 1743 (CϭO), ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.99, 1.05 (s, 18 H, tBu,

1472 (CϭC aromatic), 1428, 1373.

TBDPS), 3.10 (dd, J_2/3ϭ 4.40, J_2/1ϭ 5.10 Hz, 1 H, 2-H), 3.16 (dd,

J_2/3ϭ 4.40, J_3/4ϭ 8.20 Hz, 1 H, 3-H), 3.30Ϫ3.31 (m, 2 H, 1-H),

3.57 (2 dd, J_5a/5bϭ 10.3, J_5a/4ϭ 4.70, J_5b/4ϭ 7.0 Hz, 2 H, 5-H),

3.63 (m, 1 H, 4-H), 7.26Ϫ7.69 (m, 20 H, C₆H₅) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ ϭ 19.20 (C_q, tBu), 19.40 (C_q, tBu), 26.90

(CH₃, tBu), 56.90 (CH, C-2), 59.80 (CH, C-3), 60.90 (CH₂, C-1),

66.40 (CH₂, C-5), 72.40 (CH, C-4), 127.50, 129.70, 135.70, 135.90,

136.10 (CH, C₆H₅), 133.20, 133.90 (C_q, C₆H₅) ppm. [α]²_D⁵ϭ Ϫ14.8

(c ϭ 0.9, CHCl₃).

Compound 21: A solution of TBDMSCl (420 mg, 2.80 mmol) in

dry CH₂Cl₂(5 mL) was slowly added at room temperature to a

solution of diol 19 (366 mg, 2.28 mmol) and DMAP (510 mg,

4.18 mmol) in dry CH₂Cl₂(13 mL). The solution was stirred for 5

h. The organic phase was washed with a saturated solution of

NaCl, dried with MgSO₄, filtered, and concentrated. The oil was

purified by chromatography on silica gel (petroleum ether/ethyl

acetate, 7:3, R_fϭ 0.56), and the TBDMS ether product (562 mg,

1

90% yield) was obtained. H NMR (400 MHz, CDCl₃): δ ϭ 0.09 Compounds 23-erythro and 23-threo: KOH (100 mg, 1.78 mmol)

(s, 6 H, CH₃, OTBDMS), 0.92 (s, 9 H, tBu, OTBDMS), 2.07 (s, 3

H, OAc), 3.49 (dd, J_5/4ϭ 7.55, J_5a/5bϭ 9.99 Hz, 1 H, 5-H), 3.61

was added at room temperature to a solution of acetate 21 (269 mg,

0.52 mmol) in dry methanol (15 mL). After 30 min of stirring, the

(dd, J_5/4ϭ 4.18, J_5a/5bϭ 9.99 Hz, 1 H, 5-H), 4.48Ϫ4.54 (m, 1 H, solvent was evaporated. The oil was dissolved in CH₂Cl₂(15 mL)

4-H), 4.64Ϫ4.70 (m, 1 H, 1-H), 4.72Ϫ4.77 (m, 1 H, 1-H), and washed with water (2 ϫ 5 mL), dried with MgSO₄, and filtered,

5.56Ϫ5.61 (m, 1 H, 3-H), 5.64Ϫ5.71 (m, 1 H, 2-H) ppm. ¹³C NMR and the solvent was evaporated. The desired product (225 mg, 92%

(100 MHz, CDCl₃): δ ϭ Ϫ5.20 (CH₃, TBDMS), Ϫ5.13 (CH₃, yield) was obtained and employed without purification (petroleum

1

TBDMS), 18.3 (C_q, tBu), 21.14 (CH₃, OAc), 26.06 (CH₃, tBu),

ether/ethyl acetate, 9:1, R_fϭ 0.44). H NMR (250 MHz, CDCl₃):

60.71 (CH₂, C-1), 66.79 (CH₂, C-5), 68.69 (CH, C-4), 127.27 (CH, δ ϭ Ϫ0.01 (s, 3 H, CH₃, OTBDMS), Ϫ0.00 (s, 3 H, CH₃,

C-2), 132.94 (CH, C-3), 170.90 (CϭO, OAc) ppm. MS (DCI, NH₃): OTBDMS), 0.85 and 1.07 (s, 9 H, tBu, OTBDPS, tBu, OTBDMS),

m/z ϭ 257 [M ϩ H^ϩϪ H₂O], 275 [M ϩ H^ϩ], 292 [M ϩ NH₄^ϩ]. 3.40 (dd, J_5/4ϭ 8.24, J_5a/5bϭ 9.46 Hz, 1 H, 5-H), 3.60Ϫ3.75 (m, 1

A solution of TBDPSCl (331 mg, 1.20 mmol) in CH₂Cl₂(3 mL)

was slowly added at room temperature to a solution of monopro-

H, 5-H, 2 H, 1-H), 4.51 (ddd, J ϭ 5.19, J ϭ 8.54, J ϭ 10.98 Hz, 1

H, 4-H), 5.45Ϫ5.65 (m, 1 H, 2-H, 1 H, 3-H), 7.34Ϫ7.42 (m, 4 H,

tected alcohol (166 mg, 0.60 mmol) and imidazole (100 mg, CH, C₆H₅), 7.62Ϫ7.70 (m, 6 H, CH, C₆H₅) ppm. ¹³C NMR

1.45 mmol) in CH₂Cl₂(2 mL). The reaction mixture was stirred for

(50 MHz, CDCl₃): δ ϭ Ϫ5.37 (CH₃, TBDMS), 18.56 and 19.26

2 h and 15 min at room temperature. Water (5 mL) was added, and (C_q, tBu, TBDMS, TBDPS), 26.01 and 26.97 (CH₃, tBu, TBDMS,

the organic phase was washed with saturated aqueous NaHCO₃

(5 mL), dried with MgSO₄, filtered, and concentrated. The residual

oil was purified by chromatography on silica gel (petroleum ether/

ethyl acetate, 95:5, R_fϭ 0.56), affording the desired product

TBDPS), 58.14 (CH₂, C-1), 66.75 (CH₂, C-5), 69.87 (CH, C-4),

125.23, 127.53, 127.67, 129.78, 129.82, 130.42, 134.15, 135.89,

136.04 (CH, C-2, CH, C-3, CH aromatic), 133.86 (C_q, aromatic)

ppm. A solution of mCPBA (165 mg, 0.67 mmol) in dry CH₂Cl₂

(7 mL) was added dropwise at 0 °C to a suspension of allylic alco-

1

(270 mg, 87% yield). H NMR (250 MHz, CDCl₃): δ ϭ Ϫ0.05 (s,

3 H, CH₃, OTBDMS), Ϫ0.04 (s, 3 H, CH₃, OTBDMS), 0.82 and hol (166 mg, 0.35 mmol) and NaHCO₃(140 mg, 1.65 mmol) in dry

1.07 (s, 9 H each singlet, tBu, OTBDMS, tBu, TBDPS), 2.04 (s, 3 CH₂Cl₂(5 mL). After the mixture had been stirred at 0 °C for 30

Eur. J. Org. Chem. 2003, 672Ϫ688

681

C. H. Sugisaki, Y. Ruland, M. Baltas

FULL PAPER

min, the ice bath was removed and the reaction mixture was stirred

for a further 16 h at room temperature. Aqueous sodium bisulfite

(10%, 10 mL) was added at 0 °C, and the mixture was stirred for

30 min. The organic layer was separated and washed with saturated

aqueous NaHCO₃, dried with MgSO₄, and filtered, and the solvent

was evaporated. The residual oil was purified by chromatography

on a silica gel column (petroleum ether/diethyl ether, 6:4) and the

epoxy alcohol (150 mg, 87% yield) was obtained. The diastereoiso-

mers (dr, 86:14) were separated by HPLC (silica, petroleum ether/

M0, 70:30, M0 ϭ CH₂Cl₂/ethyl acetate, 80:20, R_fof minor iso-

(CH₂, C-5), 71.5 (CH, C-4), 127.7, 129.9, 135.5, 136.0, 136.2 (CH,

C₆H₅), 132.8, 133.3 (C_q, C₆H₅), 197.0 (CHO) ppm.

Aldehyde 25-erythro: DMSO (4.23 mmol, 300 µL) was added at

Ϫ78 °C to a solution of oxalyl chloride (2.11 mmol, 183 µL) in

CH₂Cl₂(2 mL), and the mixture was stirred for 10 min. Epoxy

alcohol 23-erythro (0.52 mmol, 257 mg) in CH₂Cl₂(7 mL) was then

added, and the resulting solution was stirred for 1 h at the same

temperature. Et₃N (6.33 mmol, 0.88 mL) was then added at room

temperature, followed 15 min later by water (5 mL), and the mix-

ture was stirred for a further 10 min. The organic phase was washed

with a saturated solution of NaHCO₃, dried with MgSO₄, and fil-

tered, and the solvent was evaporated. The oil was purified by chro-

matography on silica gel (petroleum ether/ethyl acetate, 9:1, R_fϭ

0.55) and the aldehyde (231 mg, 90% yield) was obtained. ¹H NMR

(250 MHz, CDCl₃): δ ϭ Ϫ0.13, Ϫ0.07 (CH₃, TBDMS), 0.81, 1.05

(tBu, TBDMS, TBDPS), 3.31 (t, J ϭ 4.57 Hz, 1 H), 3.45Ϫ3.52 (m,

3 H), 4.01 (q, J ϭ 4.57 Hz, 1 H), 7.35Ϫ7.47 (m, 6 H, C₆H₅),

7.64Ϫ7.72 (m, 4 H, C₆H₅), 9.41 (d, J ϭ 4.61 Hz, 1 H, CHO) ppm.

¹³C NMR (50 MHz, CDCl₃): δ ϭ 18.2 (C_q, tBu), 19.2 (C_q, tBu),

25.8 (CH3, tBu), 26.9 (CH₃, tBu), 57.7 (CH), 60.6 (CH), 65.0 (CH₂,

C-5), 69.5 (CH, C-4), 127.8, 135.6, 135.9 (CH, C₆H₅), 130.1, 132.6

(C_q, C₆H₅), 198.3 (CHO) ppm. MS (DCI, NH₃): m/z ϭ 485 [M ϩ

H^ϩ], 502 [M ϩ NH₄^ϩ]. IR (film): ν˜ ϭ3073 cm^Ϫ1, 2930, 2858, 1722,

1590, 1472, 1391, 1362, 1257. 1112, 1005, 837.

1

mer ϭ 0.26 and R_fof major isomer ϭ 0.15). 23-erythro: H NMR

(400 MHz, CDCl₃): δ ϭ Ϫ0.04, Ϫ0.06 (CH₃, TBDMS), 0.92, 1.07

(tBu, TBDMS, TBDPS), 1.50Ϫ1.60 (m, 1 H, OH), 3.03 (dt, J_2/3

ϭ

4.18, J ϭ 6.9 Hz, 1 H, 2-H), 3.15 (dd, J_3/4ϭ 6.2, J_2/3ϭ 4.18 Hz, 1

H, 3-H), 3.18 Ϫ3.27 (m, 1 H, 1-H), 3.28 Ϫ3.38 (m, 1 H, 1-H),

3.64Ϫ3.66 (m, 2 H, 5-H, 1 H, 4-H), 7.34Ϫ7.42 (m, 6 H, C₆H₅),

7.67Ϫ7.71 (m, 4 H, C₆H₅) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ

Ϫ5.35 (CH₃, TBDMS), Ϫ5.23 (CH₃, TBDMS), 18.64 (C_q, tBu),

19.50 (C_q, tBu), 26.15 (CH₃, tBu), 27.00 (CH₃, tBu), 57.19 (CH,

C-2), 57.44 (CH, C-3), 60.77 (CH₂, C-1), 66.23 (CH₂, C-5), 71.11

(CH, C-4), 127.91, 127.94, 130.12, 130.21, 136.10, 136.14 (CH,

C₆H₅), 133.46, 133.70 (C_q, C₆H₅) ppm. MS (DCI, NH₃): m/z ϭ

487 [M ϩ H^ϩ], 504 [M ϩ NH₄^ϩ]. C₂₇H₄₂O₄Si₂(486.8): calcd. C

66.62, H 8.70; found C 66.85, H 8.63. IR (film): ν˜ ϭ 3436 cm^Ϫ1

,

3072, 3050, 2955, 2031, 2895, 2858, 1590, 1472, 1463, 1428, 1390,

1362, 1335, 1257, 1217, 1189, 1047, 1005, 969, 922, 871, 837, 778,

760, 741, 703, 668. [α]²_D⁵ϭ Ϫ22.02 (c ϭ 1.09, CHCl₃). 23-threo: ¹H

NMR (400 MHz, CDCl₃): δ ϭ Ϫ0.02, Ϫ0.00 (CH₃, TBDMS), 0.83,

1.12 (tBu, TBDMS, TBDPS), 2.68Ϫ2.71 (m, 1 H, OH), 3.11 (dd,

J_2/3ϭ 4.13, J_3/4ϭ 8.26 Hz, 1 H, 3-H), 3.18Ϫ3.27 (m, 1 H, 2-H, 1

H, 1-H), 3.49Ϫ3.71 (m, 2 H, 5-H, 1 H, 4-H, 1 H, 1-H), 7.34Ϫ7.42

(m, 6 H, C₆H₅), 7.67Ϫ7.71 (m, 4 H, C₆H₅) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ Ϫ5.49 (CH₃, TBDMS), Ϫ5.38 (CH₃,

TBDMS), 19.50 (C_q, tBu), 19.50 (C_q, tBu), 26.17 (CH₃, tBu), 27.12

(CH₃, tBu), 56.18 (CH, C-2), 59.97 (CH, C-3), 61.09 (CH₂, C-1),

65.55 (CH₂, C-5), 72.03 (CH, C-4), 127.74, 127.87, 129.85, 130.04,

130.08, 135.02, 136.09, 136.24 (CH, C₆H₅), 133.31, 134.02 (C_q,

C₆H₅). MS (DCI, NH₃): m/z ϭ 487 [M ϩ H^ϩ], 504 [M ϩ NH₄^ϩ].

IR (film): ν˜ ϭ3436 cm^Ϫ1, 3072, 3050, 2955, 2031, 2895, 2858, 1590,

1472, 1463, 1428, 1390, 1362, 1335, 1257, 1217, 1189, 1047, 1005,

969, 922, 871, 837, 778, 760, 741, 703, 668. [α]²_D⁵ϭ Ϫ15.24 (c ϭ

2.31, CHCl₃).

Aldehyde 25-threo: This compound was prepared in the same way

as isomer 25-erythro, starting from epoxy alcohol 23-threo (100 mg,

0.20 mmol; 95 mg of aldehyde 25-threo, 95% yield). ¹H NMR

(250 MHz, CDCl₃): δ ϭ Ϫ0.14, Ϫ0.12 (CH₃, TBDMS), 0.76, 1.10

(tBu, TBDMS, TBDPS), 3.32Ϫ3.57 (m, 4 H), 3.70Ϫ3.79 (m, 1 H),

7.38Ϫ7.44 (m, 6 H, C₆H₅), 7.67Ϫ7.74 (m, 4 H, C₆H₅), 8.88 (d, J ϭ

5.80 Hz, 1 H, CHO) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 19.3

(C_q, tBu), 25.9 (CH₃, tBu), 26.9 (CH₃, tBu), 58.1 (CH), 61.4 (CH),

64.5 (CH₂, C-5), 71.8 (CH, C-4), 127.7, 135.8, 135.9 (CH, C₆H₅),

132.6, 133.5 (C_q, C₆H₅), 196.7 (CHO) ppm. MS (DCI, NH₃):

m/z ϭ 485 [M ϩ H^ϩ], 502 [M ϩ NH₄^ϩ].

Compound 28: A solution of nBuLi (1.6  in hexane, 240 µL,

0.384 mmol) was added at room temperature to a solution of tert-

butyl alcohol (23 mg, 0.314 mmol) in dry THF (2 mL). After the

mixture had been stirred for 30 min, it was cooled to Ϫ78 °C and

a solution of aldehyde 25-erythro (160 mg, 0.314 mmol) and 2-

acetylthiazole (48 mg, 0.378 mmol) in dry THF (6 mL) was slowly

added. The mixture was stirred for 3 h at Ϫ78 °C and for 2 h at

Ϫ40 °C. Saturated aqueous NH₄Cl (2 mL) was added and the mix-

ture was stirred for a further 10 min at room temperature. The

aqueous phase was extracted with diethyl ether, the combined or-

ganic phases were dried with MgSO₄and filtered, and the solvents

were evaporated. The residual oil was purified by chromatography

on silica gel (petroleum ether/diethyl ether, 70:30 to 50:50) and

compound 28 (188 mg, 94% yield, ratio anti/syn ϭ 54:46) was ob-

tained. The diastereoisomers were then separated by chromato-

graphy on silica gel (petroleum ether/ethyl acetate, 70:30, R_fof 28-

anti ϭ 0.14 and R_fof 28-syn ϭ 0.06). 28-anti: ¹H NMR (400 MHz,

CDCl₃): δ ϭ 0.0 and 0.03 (2 s, 6 H, CH₃, OTBDMS), 0.88 and

1.07 (s, 9 H each singlet, tBu, OTBDPS, tBu, TBDMS), 2.64 (m,

1 H, OH), 3.04 (dd, J_3/4ϭ 8.10, J_4/5ϭ 3.80 Hz, 1 H, 4-H), 3.19

(dd, J_4/5ϭ 3.80, J_5/6ϭ 6.20 Hz, 1 H, 5-H), 3.35 (dd, J_2a/2bϭ 16.43,

J_2/3ϭ 3.76 Hz, 1 H, 2-H), 3.43 (dd, J_2a/2bϭ 16.43, J_2/3ϭ 8.49 Hz,

1 H, 2-H), 3.62Ϫ3.63 (m, 2 H, 7-H), 3.82Ϫ3.85 (m, 1 H, 6-H),

4.06Ϫ4.14 (m, 1 H, 3-H), 7.33Ϫ7.44 (m, C₆H₅), 7.67Ϫ7.97 (m,

C₆H₅, 2 H, thiazole) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ

Aldehydes 24-erythro and 24-threo: These compounds were pre-

pared in the same way as compound 25-erythro, starting from

epoxy alcohol 22-erythro (546 mg, 0.90 mmol) and 22-threo (44 mg,

0.07 mmol), respectively. Aldehydes 24-erythro (493 mg, 90% yield)

and aldehyde 24-threo (42 mg, 99% yield) were obtained. 24-er-

1

ythro: H NMR (250 MHz, CDCl₃): δ ϭ 1.00, 1.09 (s, 18 H, tBu,

TBDPS), 3.27 (t, J ϭ 5.60 Hz, 1 H, 2-H), 3.55Ϫ3.62 (m, 2 H, 5-

H, 1 H, 3-H), 3.99 (q, J ϭ 5.20 Hz, 1 H, 4-H), 7.25Ϫ7.44 (m, 12

H, C₆H₅), 7.50Ϫ7.66 (m, 8 H, C₆H₅), 9.17 (d, J ϭ 5.50 Hz, 1 H,

CHO) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 19.2 (C_q, tBu), 26.9

and 26.8 (CH₃, tBu), 57.7 (CH), 60.7 (CH), 66.1 (CH₂, C-5), 69.5

(CH, C-4), 127.7, 129.9, 135.5, 135.7, 135.9 (CH, C₆H₅), 132.7,

133.0 (C_q, C₆H₅), 197.7 (CHO) ppm. [α]²_D⁵ϭ Ϫ10.2 (c ϭ 0.5,

CHCl₃). IR (film): ν˜ ϭ3072 cm^Ϫ1, 2930, 2858, 1722, 1590, 1473,

1

1428, 1391, 1362, 1257. 1112, 1005, 837, 780. 24-threo: H NMR

(250 MHz, CDCl₃): δ ϭ 0.97, 1.07 (s, 18 H, tBu, TBDPS), 3.32 (t,

J ϭ 5.50 Hz, 1 H, 2-H), 3.50Ϫ3.70 (m, 2 H, 5-H, 1 H, 3-H),

3.75Ϫ3.90 (m, 1 H, 4-H), 7.28Ϫ7.71 (m, 20 H, C₆H₅), 8.85 (d, J ϭ

5.80 Hz, 1 H, CHO) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 19.0 Ϫ5.38 (CH₃, OTBDMS), Ϫ5.38 (CH₃, OTBDMS), 18.65, 19.43

(C_q, tBu), 26.7 and 26.9 (CH₃, tBu), 58.2 (CH), 61.4 (CH), 65.6 (C_q, tBu, TBDPS, tBu, TBDMS), 25.99, 27.05 (tBu, TBDPS,

682

Eur. J. Org. Chem. 2003, 672Ϫ688

Direct Access to Furanosidic Eight-Membered Ulosonic Esters

FULL PAPER

TBDMS), 44.04 (CH₂, C-2), 58.03 (CH, C-5), 59.09 (CH, C-4), J_2/3ϭ 8.12 Hz, 1 H, 2-H), 2.51 (dd, J_2a/2bϭ 14.89, J_2/3ϭ 3.69 Hz,

65.49 (CH, C-3), 65.89 (CH₂, C-7), 70.71 (CH, C-6), 126.51, 1 H, 2-H), 2.99 (dd, J_3/4ϭ 8.85, J_4/5ϭ 4.24 Hz, 1 H, 4-H), 3.11

127.80, 127.91, 135.82, 136.06, 136.12, 136.20, 144.97 (CH, C₆H₅,

(dd, J_4/5ϭ 4.24, J_5/6ϭ 7.93 Hz, 1 H, 5-H), 3.38Ϫ3.71 (m, 2 ϫ 7-

thiazole), 133.39, 133.79 (C_q, C₆H₅), 167.17 (CϭO) ppm. 28-syn: H, 1 ϫ 3-H, 1 ϫ 6-H), 7.38Ϫ7.45 (m, C₆H₅), 7.69Ϫ7.72 (m, C₆H₅)

¹H NMR (400 MHz, CDCl₃): δ ϭ 0.0 and 0.02 (2 s, 6 H, CH₃, ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ Ϫ5.47, Ϫ5.34 (CH₃,

OTBDMS), 0.89 and 1.05 (s, 9 H each singlet, tBu, OTBDPS, tBu, OTBDMS), 18.83, 19.58 (C_q, tBu, TBDPS, tBu, TBDMS), 26.23,

TBDMS), 2.98 (dd, J_2a/2bϭ 17.20, J_2/3ϭ 2.96 Hz, 1 H, 2-H), 3.02

27.11, 28.27 (tBu, TBDPS, TBDMS, CO₂tBu), 41.18 (CH₂, C-2),

(dd, J_4/5ϭ 4.06, J_3/4ϭ 6.77 Hz, 1 H, 4-H), 3.30 (dd, J_4/5ϭ 4.06, 58.82 (CH, C-4), 60.18 (CH, C-5), 65.75 (CH₂, C-7), 67.03, 72.24

J_5/6ϭ 7.02 Hz, 1 H, 5-H), 3.33 (dd, J_2a/2bϭ 17.20, J_2/3ϭ 9.20 Hz, (CH, C-3, C-6), 80.94 (C_q, tBu, CO₂tBu), 127.75, 127.86, 130.01,

1 H, 2-H), 3.66Ϫ3.75 (m, 2 H, 7-H), 3.82Ϫ3.92 (m, 1 H, 6-H, 1 H,

3-H), 7.33Ϫ7.44 (m, C₆H₅), 7.67Ϫ7.97 (m, C₆H₅, 2 H, thiazole) 170.41 (CϭO) ppm. 30-syn: ¹H NMR (400 MHz, CDCl₃): δ ϭ

ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ Ϫ5.38 (CH₃, OTBDMS),

Ϫ0.02 and Ϫ0.01 (2 s, 6 H, CH₃, OTBDMS), 0.83 and 1.10 (s, 9

Ϫ5.38 (CH₃, OTBDMS), 18.58, 19.47 (C_q, tBu, TBDPS, tBu, H each singlet, tBu, OTBDPS, tBu, TBDMS), 1.43 [s, 9 H,

TBDMS), 26.12, 27.04 (tBu, TBDPS, TBDMS), 43.23 (CH₂, C-2), CO₂C(CH₃)₃], 2.33Ϫ2.54 (m, 2 H, 2-H), 3.03 (dd, J_3/4ϭ 5.80,

130.06, 136.12, 136.22 (CH, C₆H₅), 133.30, 133.95 (C_q, C₆H₅),

58.16 (CH, C-5), 59.53 (CH, C-4), 65.56 (CH, C-3), 65.96 (CH₂, C- J_4/5ϭ 4.40 Hz, 1 H, 4-H), 3.17 (dd, J_4/5ϭ 4.40, J_5/6ϭ 8.54 Hz, 1

7), 70.72 (CH, C-6), 126.51, 127.80, 127.91, 135.82, 136.06, 136.12, H, 5-H), 3.37Ϫ3.71 (m, 2 ϫ 7-H, 1 ϫ 3-H, 1 ϫ 6-H), 7.37Ϫ7.46

136.20, 144.97 (CH, C₆H₅, thiazole), 133.39, 133.79 (C_q, C₆H₅),

(m, C₆H₅), 7.69Ϫ7.76 (m, C₆H₅) ppm.

167.17 (CϭO) ppm.

Bicyclic Compounds 31a and 31b: BF₃Ϫdiethyl ether (180 µL,

1.47 mmol) was added dropwise at Ϫ78 °C (bath of dry ice and

ethanol) to a solution of aldehyde 13 (500 mg, 1.45 mmol) and

ethyl 2-(trimethylsilyloxy)-2-propenoate (6, 415 mg, 2.20 mmol) in

Compound 29: The same experimental procedure as described for

the synthesis of compound 30 (see below) was applied, starting

from compound 25-erythro (80%). 29-anti: ¹H NMR (400 MHz,

CDCl₃): δ ϭ Ϫ0.01 and 0.02 (2 s, 6 H, CH₃, OTBDMS), 0.88 and dry dichloromethane (10 mL). The solution was stirred at Ϫ78 °C

1.09 (s, 9 H each singlet, tBu, OTBDPS, tBu, TBDMS), 1.45 [s, 9 for 3 h and was then allowed to warm to Ϫ40 °C and stirred at

H, CO₂C(CH₃)₃], 2.43Ϫ2.47 (m, 2 H, 2-H), 2.83 (d, J ϭ 3.2 Hz, 1 this temperature for a further 2 h. Saturated aqueous NaHCO₃

H, OH), 2.95 (dd, J_3/4ϭ 8.24, J_4/5ϭ 3.88 Hz, 1 H, 4-H), 3.16 (dd, (8 mL) was added and the mixture was stirred for a further 15

J_4/5ϭ 3.88, J_5/6ϭ 6.10 Hz, 1 H, 5-H), 3.57 (d, J ϭ 3.96 Hz, 2 H,

min at room temperature. The aqueous phase was extracted with

7-H), 3.81Ϫ3.86 (m, 1 H, 3-H, 1 H, 6-H), 7.38Ϫ7.45 (m, C₆H₅), dichloromethane (10 mL) and ethyl acetate (2 ϫ 15 mL). The com-

7.75Ϫ7.78 (m, C₆H₅) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ bined organic phases were dried with MgSO₄and filtered, and solv-

Ϫ5.45, Ϫ5.25 (CH₃, OTBDMS), 18.62, 19.47 (C_q, tBu, TBDPS, ents were evaporated. The residual oil was purified by chromato-

tBu, TBDMS), 26.13, 27.12, 28.28 (tBu, TBDPS, TBDMS, graphy on a silica gel column (petroleum ether/dichloromethane/

CO₂tBu), 40.88 (CH₂, C-2), 57.83 (CH, C-5), 58.89 (CH, C-4),

65.80 (CH₂, C-7), 65.85 (CH, C-3), 70.71 (CH, C-6), 81.21 (C_q,

tBu, CO₂tBu), 127.88, 127.97, 130.03, 130.16, 136.10, 136.26 (CH,

ethyl acetate, 4:4.8:1.2, R_fof isomer 31a ϭ 0.46, R_fof isomer 31b ϭ

0.37) and bicyclic compound 31a (152 mg, 32% yield) and bicyclic

compound 31b (48 mg, 13% yield) were obtained. 31a: ¹H NMR

C₆H₅), 133.33, 134.02 (C_q, C₆H₅), 171.25 (CϭO) ppm. MS (DCI, (250 MHz, CDCl₃): δ ϭ 1.07 (s, 9 H, tBu), 1.31 (t, J ϭ 7.15 Hz, 3

NH₃): m/z ϭ 601 [M ϩ H^ϩ], 618 [M ϩ NH₄^ϩ]. C₃₃H₅₂O₆Si₂H, CH₃, ethyl), 1.88 (dd, J_3b/3aϭ 12.8, J_3b/4ϭ 3.4 Hz, 1 H, 3-H),

1

(600.9): calcd. C 65.96, H 8.72; found C 65.71, H 8.81. 29-syn: H

NMR (400 MHz, CDCl₃): δ ϭ Ϫ0.01 and 0.01 (2 s, 6 H, CH₃,

2.40 (dd, J_3a/4ϭ 9.8, J_3a/3bϭ 12.8 Hz, 1 H, 3-H), 3.61 (dd, J_6/7

8.2, J_7a/7bϭ 10.0 Hz, 1 H, 7-H), 3.65 (dd, J_7a/6ϭ 5.6, J_7a/7b

ϭ

OTBDMS), 0.88 and 1.07 (s, 9 H each singlet, tBu, OTBDPS, tBu, 10.0 Hz, 1 H, 7-H), 4.27 (q, J ϭ 7.15 Hz, 2 H, CO₂Et), 4.60 (m, 1

TBDMS), 1.45 [s, 9 H, CO₂C(CH₃)₃], 2.24Ϫ2.25 (m, 2 H, 2-H), H, 4-H), 4.71 (d, J_5/4ϭ 4.6 Hz, 1 H, 5-H), 4.67 (dd, J_6/7aϭ 5.8,

2.90 (dd, J_3/4ϭ 7.02, J_4/5ϭ 4.27 Hz, 1 H, 4-H), 3.20 (dd, J_4/5

4.27, J_5/6ϭ 7.02 Hz, 1 H, 5-H), 3.57Ϫ3.81 (m, 2 ϫ 7-H, 1 ϫ 3-H,

ϭ

J_6/7bϭ 8.1 Hz, 1 H, 6-H), 4.76 (d, J_5/4ϭ 4.7 Hz, 1 H, 5-H),

7.36Ϫ7.64 (m, 10 H, CH, TBDPS) ppm. ¹³C NMR (50 MHz,

1 ϫ 6-H), 7.37Ϫ7.46 (m, C₆H₅), 7.69Ϫ7.76 (m, C₆H₅) ppm. MS CDCl₃): δ ϭ 14.0 (CH₃, ethyl), 19.2 (C_q, tBu), 26.8 (CH₃, tBu),

(DCI, NH₃): m/z ϭ 601 [M ϩ H^ϩ], 618 [M ϩ NH₄^ϩ].

43.3 (C-3), 62.3 (CH₂CO₂Et), 63.0 (C-7), 68.5 (C-4), 74.3 (C-6),

80.4 (C-5), 106.1 (C-2), 127.7, 129.8, 135.5 (CH, phenyl), 133.6,

134.1 (C_q, phenyl), 165.7 (C-1) ppm. MS (DCI, NH₃): m/z ϭ 474

[M ϩ NH₄^ϩ]. C₂₅H₃₂O₆Si (456.2): calcd. C 65.76, H 7.06; found C

66.08, H 6.95. IR (film): ν˜ ϭ 3506 cm^Ϫ1, 3072, 3050, 2932, 1752,

1114. 31b: ¹H NMR (250 MHz, CDCl₃): δ ϭ 1.05 (s, 9 H, tBu),

1.32 (t, J ϭ 7.15 Hz, 3 H, CH₃, ethyl), 1.88 (dd, J_3b/3aϭ 13.5,

J_3b/4ϭ 1.5 Hz, 1 H, 3-H), 2.56 (dd, J_3a/4ϭ 6.5, J_3a/3bϭ 13.5 Hz,

1 H, 3-H), 3.54 (t, J_6/7ϭ J_7a/7bϭ 9.5 Hz, 1 H, 7-H), 3.61 (dd,

J_7a/6ϭ 4.5, J_7a/7bϭ 9.9 Hz, 1 H, 7-H), 3.69 (dd, J_6/7aϭ 4.5,

J_6/7bϭ 9.1 Hz, 1 H, 6-H), 4.25 (dd, J_4/3aϭ 6.5, J_4/3bϭ 1.5 Hz, 1

H, 4-H), 4.31 (q, J ϭ 7.15 Hz, 2 H, CO₂Et), 4.76 (s, 1 H, 5-H),

7.34Ϫ7.66 (m, 10 H, CH, TBDPS) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 14.0 (CH₃, ethyl), 19.2 (C_q, tBu), 26.8 (CH₃, tBu),

47.3 (C-3), 62.4 (CH₂CO₂Et), 63.1 (C-7), 72.3 (C-4), 75.9 (C-6),

84.3 (C-5), 104.1 (C-2), 127.8, 129.9, 135.5 (CH, phenyl), 133.1,

133.2 (C_q, phenyl), 165.4 (C-1) ppm.

Compound 30: A solution of nBuLi (1.6  in hexane, 238 µL,

0.38 mmol) was added at Ϫ78 °C to a solution of diisopropylamine

(38 mg, 0.38 mmol) in diethyl ether (1 mL). After the mixture had

been stirred for 30 min, tert-butyl acetate (44 mg, 0.38 mmol) was

added. After

1 h, a solution of aldehyde 25-threo (74 mg,

0.152 mmol) in diethyl ether (2 mL) was slowly added. The mixture

was stirred for 1 h at Ϫ50 °C and for 1 h at Ϫ30 °C. Saturated

aqueous NH₄Cl (1 mL) was added and the mixture was stirred for

a further 10 min at room temperature. The aqueous phase was ex-

tracted with diethyl ether and the combined organic phases were

dried with MgSO₄and filtered, and the solvents were evaporated.

The residual oil was purified by chromatography on silica gel (pet-

roleum ether/diethyl ether, 70:30), affording compound 30 (79 mg,

87% yield, ratio anti/syn ϭ 94:6). The diastereoisomers were separ-

ated by chromatography on silica gel (petroleum ether/diethyl ether,

1

70:30, R_fof 30-anti ϭ 0.52 and R_fof 30-syn ϭ 0.28). 30-anti: H

NMR (400 MHz, CDCl₃): δ ϭ Ϫ0.03 and 0.01 (2s, 6 H, CH₃,

Bicyclic Compounds 32a and 32b. Method A: BF₃Ϫdiethyl ether (70

OTBDMS), 0.82 and 1.11 (s, 9 H each singlet, tBu, OTBDPS, tBu, µL, 0.56 mmol) was added dropwise at Ϫ78 °C (bath of dry ice

TBDMS), 1.45 [s, 9 H, CO₂C(CH₃)₃], 2.44 (dd, J_2a/2bϭ 14.89,

Eur. J. Org. Chem. 2003, 672Ϫ688

and ethanol) to a solution of aldehyde 24-erythro (340 mg,

683

C. H. Sugisaki, Y. Ruland, M. Baltas

FULL PAPER

0.56 mmol) and ethyl 2-(trimethylsilyloxy)-2-propenoate (6, (t, J ϭ 7.6 Hz, 3 H, CH₃, ethyl), 1.65 (d, J_3b/3aϭ 13.5 Hz, 1 H, 3-

157 mg, 0.84 mmol) in dry dichloromethane (5 mL). The temper- Hb), 2.46 (dd, J_3a/4ϭ 6.5 Hz and J_3a/3bϭ 13.5 Hz, 1 H, 3-Ha),

ature was allowed to warm to Ϫ40 °C over 3 h and the mixture 3.56 (d, J_6/7ϭ 6.4 Hz, 1 H, 6-H), 3.63 (dd, J_8b/7ϭ 5.16 Hz and

was stirred at this temperature for a further 1 h. Saturated aqueous J_8b/8aϭ 11.1 Hz, 1 H, 8-Hb), 3.68 (dd, J_8a/7ϭ 3.94 Hz and

NaHCO₃(2 mL) was added and the mixture was stirred for a fur- J_8a/8bϭ 11.1 Hz, 1 H, 8-Ha), 3.83Ϫ3.90 (m, 1 H, 4-H), 3.91Ϫ3.93

ther 15 min at room temperature. The aqueous phase was extracted

with dichloromethane (10 mL) and ethyl acetate (2 ϫ 15 mL). The

combined organic phases were dried with MgSO₄and filtered, and

solvents were evaporated. The residual oil was purified by chroma-

tography on a silica gel column (petroleum ether/diethyl ether, 6:

4). Starting material aldehyde 24-erythro (160 mg), bicyclic com-

pound 32a (105 mg) and bicyclic compound 32b (64 mg) were isol-

(m, 1 H, 7-H), 4.27 (q, J ϭ 7.6 Hz, 2 H, CH₂, ethyl), 4.62 (s, 1 H,

5-H), 7.26Ϫ7.70 (m, 20 H, CH, TBDPS) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 14.0 (CH₃, ethyl), 19.5, 19.3 (C_q, tBu), 26.9, 27.0

(CH₃, tBu), 47.1 (CH₂, C-3), 62.0 (CH₂CO₂Et), 65.1 (CH₂, C-8),

72.2 (CH, C-4), 73.8, 77.2 (CH, C-6 and CH, C-7), 83.5 (CH, C-

5), 104.3 (C_q, C-2), 127.6, 129.6, 135.6, 135.8, 136.0 (CH, phenyl),

133.2, 133.9 (C_q, phenyl), 165.4 (C_q, CO₂Et) ppm. MS (DCI, NH₃):

ated (41% yield). Method B: 78% yield (as described for the syn- m/z ϭ 725 [M ϩ H^ϩ], 742 [M ϩ NH₄^ϩ].

thesis of compounds 33a and 33b). 32a: ¹H NMR (250 MHz,

Bicyclic Compounds 33a and 33b. Method B: BF₃Ϫdiethyl ether

CDCl₃): δ ϭ 1.02 (s, 9 H, tBu), 1.07 (s, 9 H, tBu), 1.23 (t, J ϭ

7.2 Hz, 3 H, CH₃, ethyl), 1.81 (dd, J_3b/3aϭ 12.7, J_3b/4ϭ 3.6 Hz, 1

H, 3-H), 2.38 (dd, J_3a/4ϭ 9.9, J_3a/3bϭ 12.6 Hz, 1 H, 3-H), 3.56

(dd, J_8b/7ϭ 3.7, J_8a/8bϭ 10.9 Hz, 1 H, 8-H), 3.64 (dd, J_8a/7ϭ 3.7,

(390 µL, 3.10 mmol) was added, dropwise at Ϫ45 °C (bath of dry

ice and acetonitrile), to a solution of aldehyde 25-erythro (229 mg,

0.47 mmol) and ethyl 2-(trimethylsilyloxy)-2-propenoate (6)

(414 mg, 2.07 mmol) in dry dichloromethane (15 mL). After the

mixture had been stirred at Ϫ45 °C for 6 h, saturated aqueous

NaHCO₃(5 mL) was added and the mixture was stirred for a fur-

ther 15 min at room temperature. The aqueous phase was extracted

with dichloromethane (10 mL) and ethyl acetate (2 ϫ 15 mL). The

combined organic phases were dried with MgSO₄and filtered, and

solvents were evaporated. The residual oil was purified by chroma-

tography on a silica gel column (eluent petroleum ether/diethyl

ether, 6:4). Bicyclic compound 33 (217 mg, 77% yield) and depro-

tected bicyclic compound 31 (23 mg, 10% yield) were isolated. The

diastereoisomers 33a and 33b (dr 85:15) were separated by HPLC

{silica, eluent M6 [M6 ϭ hexane/M0 (60:40); M0 ϭ dichlorome-

thane/ethylacetate (80:20)], R_fof major isomer ϭ 0.28 and R_fof

minor isomer ϭ 0.16}. 33a: ¹H NMR (400 MHz, CDCl₃): δ ϭ

Ϫ0.06 (s, 6 H, CH₃, OTBDMS), 0.85 and 1.07 (s, 9 H each singlet,

tBu, OTBDPS, tBu, OTBDMS), 1.31 (t, J ϭ 7.14 Hz, 3 H,

CO₂CH₂CH₃), 1.75Ϫ1.80 (m, 1 H, OH), 1.82 (dd, J_3a/3bϭ 12.73,

J_3/4ϭ 3.57 Hz, 1 H, 3-H), 2.38 (dd, J_3a/3bϭ 12.73, J_3/4ϭ 9.85 Hz,

1 H, 3-H), 3.53Ϫ3.55 (m, 2 H, 8-H), 3.82Ϫ3.85 (m, 1 H, 7-H), 4.28

(q, J ϭ 7.14 Hz, 2 H, CO₂CH₂CH₃), 4.48Ϫ4.57 (m, 1 H, 4-H), 4.65

(d, J_6/7ϭ 6.77 Hz, 1 H, 6-H), 4.75 (d, J_4/5ϭ 4.67 Hz, 1 H, 5-

H), 7.33Ϫ7.43 (m, C₆H₅), 7.69Ϫ7.76 (m, C₆H₅) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ Ϫ5.38 (CH₃, OTBDMS), Ϫ5.38 (CH₃,

OTBDMS), 14.22 (CO₂CH₂CH₃), 18.56, 19.72 (C_q, tBu, TBDPS,

tBu, TBDMS), 25.98, 26.12 (tBu, TBDPS, TBDMS), 43.33 (CH₂,

C-3), 62.15 (CO₂CH₂CH₃), 64.04 (CH₂, C-8), 68.81 (CH, C-4),

74.18 (CH, C-7), 74.64 (CH, C-6), 80.21 (CH, C-5), 105.98 (C_q, C-

2), 127.70, 129.77, 136.13 (CH, C₆H₅), 134.11, 134.55 (C_q, C₆H₅),

165.96 (CϭO, CO₂CH₂CH₃) ppm. MS (DCI, NH₃): m/z ϭ 618 [M

ϩ NH₄^ϩ]. C₃₂H₄₈O₇Si₂(600.3): calcd. C 63.96, H 8.05; found C

J_8a/8bϭ 10.9 Hz, 1 H, 8-H), 3.94 (td, J_7/8aϭ J_7/8bϭ 3.7, J_7/6

ϭ

6.1 Hz, 1 H, 7-H), 4.23 (m, 2 H, CH₂, ethyl), 4.49Ϫ4.43 (m, 1 H,

4-H), 4.71 (d, J_5/4ϭ 4.6 Hz, 1 H, 5-H), 4.77 (d, J ϭ 6.1 Hz, 1 H,

6-H), 7.29Ϫ7.73 (m, 20 H, CH, TBDPS) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 14.0 (CH₃, ethyl), 19.3, 19.5 (C_q, tBu), 26.9, 27.0

(CH₃, tBu), 43.1 (CH₂, C-3), 61.9 (CH₂CO₂Et), 64.9 (CH₂, C-8),

68.5 (CH, C-4), 73.8, 74.4 (CH, C-6 and CH, C-7), 79.8 (CH, C-

5), 105.7 (C_q, C-2), 165.7 (C_q, CO₂Et), 127.5, 129.7, 135.7, 135.9,

136.1 (CH, phenyl), 133.6, 134.1 (C_q, phenyl) ppm. C₄₂H₅₂O₇Si₂

(725.04): calcd. C 69.58, H 7.23 found C 69.48, H 7.38. [α]²_D⁵

ϭ

ϩ2.3 (c ϭ 0.6, CHCl₃). 32b: ¹H NMR (250 MHz, CDCl₃): δ ϭ

1.03 (s, 9 H, tBu), 1.08 (s, 9 H, tBu), 1.29 (t, J ϭ 7.6 Hz, 3 H, CH₃

ethyl), 1.65 (d, J_3b/3aϭ 13.5 Hz, 1 H, 3-Hb), 2.50 (dd, J_3a/4

ϭ

6.5 Hz and J_3a/3bϭ 13.5 Hz, 1 H, 3-Ha), 3.50 (dd, J_8b/7ϭ 2.8 Hz

and J_8b/8aϭ 10.7 Hz, 1 H, 8-Hb), 3.59 (dd, J_8a/7ϭ 3.3 Hz and

J_8a/8bϭ 10.7 Hz, 1 H, 8-Ha), 3.76 (d, J_6/7ϭ 5.9 Hz, 1 H, 6-H),

3.81 (ddd, J_7/8aϭ 3.3, J_7/8bϭ 2.8, J_7/6ϭ 5.9 Hz, 1 H, 7-H), 4.06

(d, J_4/3aϭ 6.4 Hz, 1 H, 4-H), 4.27 (q, J ϭ 7.6 Hz, 2 H, CH₂, ethyl),

4.64 (s, 1 H, 5-H), 7.25Ϫ7.69 (m, 20 H, CH, TBDPS) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ ϭ 14.0 (CH₃, ethyl), 19.5, 19.3 (C_q,

tBu), 26.9, 27.0 (CH₃, tBu), 47.0 (CH₂, C-3), 62.0 (CH₂CO₂Et),

64.6 (CH₂, C-8), 72.0 (CH, C-4), 73.4, 76.1 (CH, C-6 and CH, C-

7), 83.6 (CH, C-5), 103.9 (C_q, C-2), 127.6, 129.6, 135.6, 135.8, 136.0

(CH, phenyl), 133.2, 133.9 (C_q, phenyl), 165.5 (C_q, CO₂Et) ppm.

C₄₂H₅₂O₇Si₂(725.04): calcd. C 69.58, H 7.23; found C 69.13, H

6.86. [α]²_D⁵ϭ ϩ5.6 (c ϭ 0.7, CHCl₃).

Diastereoisomers of Bicyclic Compounds 32a and 32b. Method B:

As described for the synthesis of compounds 33a and 33b, starting

from aldehyde 24-threo (40 mg, 0.06 mmol), 23 mg of diastereoiso-

mers of 32a and 32b were obtained (50% yield). Diastereoisomer of 63.74, H 7.96. IR (film, cm^Ϫ1): ν˜ ϭ 3510, 3072, 3050, 2955, 2931,

1

32a: H NMR (250 MHz, CDCl₃): δ ϭ 1.01 (s, 9 H, tBu), 1.08 (s,

2894, 2857, 1751, 1590, 1473, 1428, 1379, 1361, 1347, 1252, 1204,

1111, 1029, 975, 917, 837. [α]²_D⁵ϭ ϩ6.43 (c ϭ 2.49, CHCl₃). 33b:

¹H NMR (400 MHz, CDCl₃): δ ϭ Ϫ0.10 and Ϫ0.08 (s, 3 H each

singlet, CH₃, TBDMS), 0.84 and 1.08 (s, 9 H each singlet, tBu,

9 H, tBu), 1.21 (t, J ϭ 7.2 Hz, 3 H, CH₃, ethyl), 1.81 (dd, J_3b/3a

12.7, J_3b/4ϭ 3.5 Hz, 1 H, 3-H), 2.33 (dd, J_3a/4ϭ 9.9, J_3a/3b

ϭ

12.7 Hz, 1 H, 3-H), 3.65 (dd, J_8b/7ϭ 5.1, J_8a/8bϭ 11.0 Hz, 1 H, 8-

H), 3.75 (dd, J_8a/7ϭ 4.1, J_8a/8bϭ 11.0 Hz, 1 H, 8-H), 3.96Ϫ4.00 OTBDPS, tBu, TBDMS), 1.33 (t, J ϭ 7.12 Hz, 3 H, CO₂CH₂CH₃),

(m, 1 H, 7-H), 4.16Ϫ4.20 (m, 2 H, CH₂, ethyl), 4.36Ϫ4.42 (m, 1 1.86 (dt, J_3a/3bϭ 13.43, J_3/5ϭ 1.12 Hz,1 H, 3-H), 2.04 (d, J_OH/4ϭ

H, 4-H), 4.58 (d, J_5/4ϭ 4.7 Hz, 1 H, 5-H), 4.73 (d, J ϭ 6.5 Hz, 1 H, 9.16 Hz, 1 H, OH), 2.50 (dd, J_3a/3bϭ 13.43, J_3/4ϭ 6.41 Hz, 1 H,

6-H), 7.30Ϫ7.74 (m, 20 H, CH, TBDPS) ppm. ¹³C NMR (50 MHz, 3-H), 3.46 (d, J ϭ 3.68 Hz, 2 H, 8-H), 3.71 (d, J ϭ 6.08 Hz, 1 H,

CDCl₃): δ ϭ 14.0 (CH₃, ethyl), 19.3, 19.5 (C_q, tBu), 26.9, 27.0 6-H), 3.74Ϫ3.76 (m, 1 H, 7-H), 4.10Ϫ4.20 (m, 1 H, 4-H), 4.31 (q,

(CH₃, tBu), 43.4 (CH₂, C-3), 62.0 (CH₂CO₂Et), 65.4 (CH₂, C-8), J ϭ 7.12 Hz, 2 H, CO₂CH₂CH₃), 4.75 (d, J_5/3ϭ 1.12 Hz, 1 H, 5-

68.8 (CH, C-4), 73.9, 75.7 (CH, C-6 and CH, C-7), 79.6 (CH, C-

5), 106.1 (C_q, C-2), 165.7 (C_q, CO₂Et), 127.5, 129.7, 135.7, 135.9, (100 MHz, CDCl₃): δ ϭ Ϫ5.51 (CH₃, OTBDMS), Ϫ5.39 (CH₃,

136.1 (CH, phenyl), 133.6, 134.1 (C_q, phenyl) ppm. MS: (DCI, OTBDMS), 14.24 (CO₂CH₂CH₃), 18.56, 19.67 (C_q, tBu, TBDPS,

NH₃): m/z ϭ 742 [M ϩ NH₄^ϩ]. Diastereoisomer of 32b: H NMR tBu, TBDMS), 26.07, 27.15 (tBu, TBDPS, TBDMS), 47.34 (CH₂,

H), 7.38Ϫ7.44 (m, C₆H₅), 7.70Ϫ7.75 (m, C₆H₅) ppm. ¹³C NMR

1

(250 MHz, CDCl₃): δ ϭ 1.03 (s, 9 H, tBu), 1.04 (s, 9 H, tBu), 1.09

C-3), 62.31 (CO₂CH₂CH₃), 63.77 (CH₂, C-8), 72.27 (CH, C-4),

684

Eur. J. Org. Chem. 2003, 672Ϫ688

Direct Access to Furanosidic Eight-Membered Ulosonic Esters

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73.74 (CH, C-7), 76.31 (CH, C-6), 83.98 (CH, C-5), 104.05 (C_q, C-

2), 127.75, 127.87, 129.84, 129.96, 136.07, 136.19 (CH, C₆H₅),

CDCl₃): δ ϭ 14.12 (CO₂CH₂CH₃), 19.54 (C_q, TBDPS), 20.90

(CH₃, OAc), 27.17 (tBu, OTBDPS), 40.69 (CH₂, C-3), 62.62

133.72, 134.48 (C_q, C₆H₅), 165.80 (CϭO, CO₂CH₂CH₃) ppm. MS (CO₂CH₂CH₃), 63.75 (CH₂, C-8), 70.10 (CH, C-4), 72.82 (CH, C-

(DCI, NH₃): m/z ϭ 601 [M ϩ H^ϩ], 618 [M ϩ NH₄^ϩ]. IR (film, 7), 76.98 (CH, C-6), 79.41 (CH, C-5), 105.72 (C_q, C-2), 128.11,

cm^Ϫ1): ν˜ ϭ 3510, 3072, 3050, 2955, 2931, 2894, 2857, 1751, 1590,

128.13, 135.85, 136.02 (CH, C₆H₅), 133.22, 133.69 (C_q, C₆H₅),

1473, 1428, 1379, 1361, 1347, 1252, 1204, 1111, 1029, 975, 917, 164.86 (CϭO, OCOCH₃), 170.53 (CϭO, CO₂CH₂CH₃) ppm. MS

837. [α]²_D⁵ϭ ϩ8.65 (c ϭ 1.96, CHCl₃). 34a: H NMR (400 MHz,

CDCl₃): δ ϭ 1.06 (s, 9 H, tBu, OTBDPS), 1.28 (t, J ϭ 7.00 Hz, 3 3066, 2928, 2856, 1747, 1586, 1463, 1428, 1377, 1236, 1204, 1112,

(DCI, NH₃): m/z ϭ 546 [M ϩ NH₄^ϩ]. IR (film, cm^Ϫ1): ν˜ ϭ 3519,

1

H, CO₂CH₂CH₃), 1.80 (dd, J ϭ 12.82, J ϭ 3.05 Hz, 1 H, 3-H),

2.30Ϫ2.50 (m, 1 ϫ 3-H, 1 H, OH), 3.50Ϫ3.70 (m, 2 H, 8-H),

3.70Ϫ3.90 (m, 1 H, 7-H), 4.23 (q, J ϭ 7.00 Hz, 2 H, CO₂CH₂CH₃),

4.35Ϫ4.50 (m, 1 ϫ4-H, 1 ϫ 5-H), 4.65 (d, J ϭ 7.63 Hz, 1 H, 6-H),

7.36Ϫ7.70 (m, C₆H₅) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ

13.94 (CO₂CH₂CH₃), 19.41 (C_q, tBu, TBDPS), 27.00 (tBu,

TBDPS), 42.81 (CH₂, C-3), 62.35 (CO₂CH₂CH₃), 64.03 (CH₂, C8),

68.34 (CH-4), 72.75 (CH), 76.19 (CH), 80.87 (CH, C5), 105.98 (Cq,

C2), 127.87, 127.94, 135.71, 135.90 (CH, C₆H₅), 133.35, 133.44 (C_q,

C₆H₅), 165.51 (CϭO, CO₂CH₂CH₃) ppm. MS (DCI, NH₃): m/z ϭ

504 [M ϩ NH₄^ϩ].

1068, 971, 944, 822.

Compound 39: Phosphoramidite (120 mg, 0.348 mmol) was slowly

added at room temperature to a solution of alcohol 38 (46 mg,

0.087 mmol) and tetrazole (48 mg, 0.696 mmol) in dry CH₂Cl₂

(5 mL). After 65 min, a solution of mCPBA (180 mg, 0.696 mmol)

in dry CH₂Cl₂(5 mL) was added at Ϫ10 °C. The mixture was

stirred for a further 60 min at 0 °C. CH₂Cl₂(10 mL) was added

and the organic phase was washed with aqueous Na₂SO₃(10%),

saturated aqueous NaHCO₃, and brine, dried with MgSO₄, and

filtered, and the solvent was evaporated. The residual oil was puri-

fied by chromatography on silica gel (petroleum ether/CH₂Cl₂/ethyl

acetate, 5:4:1, R_fϭ 0.09) and the desired product (49 mg, 72%

Compound 37: Et₃N (0.50 mL) and acetic anhydride (0.25 mL) were

added at room temperature to a solution of alcohol 33a (56 mg,

1

yield) was obtained. H NMR (400 MHz, CDCl₃): δ ϭ 1.05 (s, 9

0.093 mmol) and DMAP (25 mg, 0.205 mmol) in dry CH₂Cl₂H, tBu, OTBDPS), 1.21 (t, J ϭ 7.33 Hz, 3 H, CO₂CH₂CH₃), 1.89

(3 mL). The solution was stirred for 5 h. The organic phase was

washed with saturated aqueous NaHCO₃and then brine, dried

with MgSO₄, filtered, and concentrated. The residual oil was puri-

fied by chromatography on silica gel (petroleum ether/diethyl ether,

(dd, J ϭ 3.66, J ϭ 13.13 Hz, 1 H, 3-H), 2.09 (s, 3 H, OCOCH₃),

2.46 (dd, J ϭ 10.07, J ϭ 13.13 Hz, 1 H, 3-H), 3.72Ϫ3.82 (m, 1

H, 7-H), 3.93Ϫ4.13 (m, 2 H, 8-H), 4.17 (q, J ϭ 7.33 Hz, 2 H,

CO₂CH₂CH₃), 4.47 (d, J_6/7ϭ 8.24 Hz, 1 H, 6-H), 4.80 (d, J_5/4

ϭ

6:4, R_fϭ 0.60) and the desired product (56 mg, 94% yield) was

4.88 Hz, 1 H, 5-H), 4.82Ϫ4.98 (m,4 H, OCH₂C₆H₅), 5.01Ϫ5.07 (m,

1

obtained. H NMR (250 MHz, CDCl₃): δ ϭ Ϫ0.13 (s, 3 H, CH₃, 1 H, 4-H), 7.31Ϫ7.69 (m, 20 H, C₆H₅) ppm. ¹³C NMR (100 MHz,

OTBDMS), 0.82 (s, 9 H, tBu, OTBDMS), 1.04 (s, 9 H, tBu,

OTBDPS), 1.29 (t, J ϭ 7.33 Hz, 3 H, CO₂CH₂CH₃), 1.95 (dd, J ϭ

CDCl₃): δ ϭ 13.96 (CO₂CH₂CH₃), 19.42 (C_q, TBDPS), 20.80

(CH₃, OAc), 26.92 (tBu, OTBDPS), 40.54 (CH₂, C-3), 62.27

12.82, J ϭ 3.06 Hz, 1 H, 3-H), 2.50 (dd, J ϭ 12.82, J ϭ 9.46 Hz, (CO₂CH₂CH₃), 67.58 (d, J ϭ 5.89 Hz, CH₂, C-8), 68.95 (d, J ϭ

1 H, 3-H), 3.41Ϫ3.43 (m, 2 H, 8-H), 3.71Ϫ3.77 (m, 1 H, 7-H), 4.26 5.23 Hz, CH₂, OBn), 69.85 (CH, C-4), 71.37 (d, J ϭ 9.16 Hz, CH,

(q, J ϭ 7.33 Hz, 2 H, CO₂CH₂CH₃), 4.50 (d, J ϭ 7.33 Hz, 1 H, 6- C-7), 74.70 (CH, C-6), 78.69 (CH, C-5), 105.64 (C_q, C-2), 127.80,

H), 5.05Ϫ5.12 (m, 1 H, 5-H, 1 H, 4-H), 7.32Ϫ7.72 (m, 10 H, C₆H₅) 127.85, 128.91, 128.43, 128.55, 135.95, 136.62 (CH, C₆H₅), 132.80,

ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ Ϫ5.73 (CH₃, OTBDMS), 133.09 (C_q, C₆H₅), 164.86 (CϭO, OCOCH₃), 170.50 (CϭO,

Ϫ5.58 (CH₃, OTBDMS), 14.01 (CO₂CH₂CH₃), 18.27, 19.44 (C_q,

tBu, TBDPS, tBu, TBDMS), 20.63 (CH₃, OAc), 25.84, 26.91 (tBu,

TBDPS, TBDMS), 40.94 (CH₂, C-3), 62.09 (CO₂CH₂CH₃), 63.06

(CH₂, C-8), 70.14 (CH, C-4), 73.38 (CH, C-7), 75.03 (CH, C-6),

78.15 (CH, C-5), 105.23 (C_q, C-2), 127.49, 127.64, 129.71 135.87,

135.97 (CH, C₆H₅), 133.41, 134.38 (C_q, C₆H₅), 165.96 (CϭO,

CO₂CH₂CH₃), 170.42 (CϭO, OAc) ppm. MS (DCI, NH₃): m/z ϭ

660 [M ϩ NH₄^ϩ]. IR (film, cm^Ϫ1): ν˜ ϭ 3072, 2995, 2931, 2857,

1748, 1590, 1473, 1428, 1376, 1235, 1206, 1111, 1039, 836, 779,

741, 704.

CO₂CH₂CH₃) ppm. MS (DCI, NH₃): m/z ϭ 806 [M ϩ NH₄^ϩ].

Compound 40: TBDPSCl (34 mg, 0.124 mmol) was added at room

temperature to a solution of alcohol 33a (50 mg, 0.083 mmol) and

imidazole (17 mg, 0.25 mmol) in dry DMF (0.33 mL). The solution

was heated at 70 °C for 21 h. Ethyl acetate (10 mL) was added, and

the organic phase was washed with water (5 mL), dried with

MgSO₄, filtered, and concentrated. The oil was purified by chroma-

tography on silica gel (petroleum ether/diethyl ether, 9:1, R_f

ϭ

0.37), affording the protected product (49 mg, 71% yield). ¹H NMR

(250 MHz, CDCl₃): δ ϭ Ϫ0.12 (s, 3 H, CH₃, OTBDMS), Ϫ0.09 (s,

3 H, CH₃, OTBDMS), 0.83 (s, 9 H, tBu, OTBDMS), 1.08, 1.10 (s,

Compound 38: BF₃ϪEt₂O (22 mg, 0.155 mmol) was slowly added

at Ϫ30 °C to a solution of silyl ether 37 (50 mg, 0.078 mmol) in 9 H, tBu, OTBDPS), 1.25 (t, J ϭ 7.33 Hz, 3 H, CO₂CH₂CH₃), 1.83

dry CH₂Cl₂(4 mL). The solution was allowed to warm to Ϫ3 °C (dd, J ϭ 3.35, J ϭ 12.52 Hz, 1 H, 3-H), 2.02 (dd, J ϭ 9.46, J ϭ

over 1 h. Saturated aqueous NaHCO₃was added, and the aqueous 12.52 Hz, 1 H, 3-H), 3.43 (dd, J ϭ 3.66, J ϭ 10.99 Hz, 1 H, 8-H),

phase was extracted with ethyl acetate. The combined organic

phases were dried with MgSO₄, filtered, and concentrated. The re-

sidual oil was purified by chromatography on silica gel (petroleum

ether/diethyl ether, 6:4 R_fϭ 0.14) and the desired product (43 mg,

quantitative) was obtained. ¹H NMR (400 MHz, CDCl₃): δ ϭ 1.06

3.54 (dd, J ϭ 3.05, J ϭ 10.99 Hz, 1 H, 8-H), 3.70Ϫ3.79 (m, 1 H,

7-H), 4.19 (q, J ϭ 7.33 Hz, 2 H, CO₂CH₂CH₃), 4.42Ϫ4.49 (m, 1

H, 4-H), 4.77 (d, J ϭ 4.88 Hz, 1 H, 5-H), 4.99 (d, J ϭ 7.63 Hz, 1

H, 6-H), 7.32Ϫ7.79 (m, C₆H₅) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ ϭ Ϫ5.63, Ϫ5.57 (CH₃, OTBDMS), 13.96 (CO₂CH₂CH₃), 18.38,

(s, 9 H, tBu, OTBDPS), 1.28 (t, J ϭ 7.14 Hz, 3 H, CO₂CH₂CH₃), 19.15, 19.58 (C_q, tBu, TBDPS, tBu, TBDMS), 25.97, 26.86, 27.05

1.93 (dd, J ϭ 3.36, J ϭ 13.12 Hz, 1 H, 3-H), 2.12 (s, 3 H, OC- (tBu, TBDPS, TBDMS), 43.40 (CH₂, C-3), 61.79 (CO₂CH₂CH₃),

OCH₃), 2.53 (dd, J ϭ 10.07, J ϭ 13.12 Hz, 1 H, 3-H), 3.58Ϫ3.65 62.69 (CH₂, C-8), 69.92 (CH, C-4), 73.70 (CH, C-7), 74.20 (CH,

(m, 2 H, 8-H), 3.73 (ddd, J_7/6ϭ 8.19, J_7/8ϭ 8.00, J_7/8ϭ 8.06 Hz, C-6), 79.97 (CH, C-5), 105.97 (C_q, C-2), 127.41, 127.80, 127.85,

1 H, 7-H), 4.25 (q, J ϭ 7.14 Hz, 2 H, CO₂CH₂CH₃), 4.43 (d, 129.46, 129.64, 130.14, 135.60, 135.65, 136.06 (CH, C₆H₅), 132.98,

J_6/7ϭ 8.19 Hz, 1 H, 6-H), 4.72 (d, J_5/4ϭ 4.74 Hz, 1 H, 5-H), 5.05 133.34, 133.67, 134.54 (C_q, C₆H₅), 170.53 (CϭO, CO₂CH₂CH₃)

(ddd, J_5/4ϭ 4.74, J ϭ 4.67, J ϭ 10.03 Hz, 1 H, 4-H), 7.33Ϫ7.43

ppm. MS(DCI, NH₃): m/z ϭ 856 [M ϩ NH₄^ϩ]. IR (film, cm^Ϫ1):

(m, C₆H₅), 7.69Ϫ7.76 (m, C₆H₅) ppm. ¹³C NMR (100 MHz, ν˜ ϭ 3072, 3050, 2957, 2893, 2858, 1764, 1590, 1472, 1428, 1391,

Eur. J. Org. Chem. 2003, 672Ϫ688

685

C. H. Sugisaki, Y. Ruland, M. Baltas

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1362, 1291, 1205, 1133, 1108, 1043, 1006, 978, 955, 890, 836, 778,

740, 702.

washed with brine, dried with MgSO₄, filtered, and concentrated.

The residue was purified by chromatography on silica gel (petro-

leum ether/ethyl acetate, 50:50 to 0:100), and the diol (11 mg, 50%

yield) was obtained. ¹H NMR (250 MHz, CDCl₃): δ ϭ 1.31 (t, J ϭ

7.12 Hz, 3 H, COCH₂CH₃), 1.87 (dd, J ϭ 12.86, J ϭ 3.36 Hz, 1

H, 3-H), 2.40 (dd, J ϭ 12.86, J ϭ 9.77 Hz, 1 H, 3-H), 3.70Ϫ3.80

(m, 1 H, 7-H), 4.04Ϫ4.18 (m, 2 H, 8-H, 2 H, CO₂CH₂CH₃),

4.50Ϫ4.60 (m, 1 H, 4-H), 4.54 (d, J ϭ 7.63 Hz, 1 H, 6-H), 4.84 (d,

J ϭ 4.58 Hz, 1 H, 5-H), 5.01Ϫ5.06 (m, 4 H, 2 ϫ OCH₂C₆H₅), 7.34

(br. s, 10 H, C₆H₅) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 14.05

(CO₂CH₂CH₃), 42.56 (CH₂, C-3), 62.30 (CO₂CH₂CH₃), 68.14

(CH), 68.65 (d, J ϭ 5.31 Hz, CH₂, C-8), 69.82 [2 d, J ϭ 5.32 Hz,

CH₂, P(O)(CH₂C₆H₅)], 73.50 (CH), 80.28 (CH), 106.33 (C_q, C-2),

128.11, 128.71, 128.78 (CH, C₆H₅), 165.36 (CϭO, CO₂CH₂CH₃)

ppm. ³¹P NMR (81 MHz, CDCl₃): δ ϭ 0.35 ppm.

Compound 41: BF₃ϪEt₂O (24 mg, 0.171 mmol) was added at Ϫ20

°C to a solution of silyl ether 40 (72 mg, 0.086 mmol) in dry

CH₂Cl₂(2 mL). The solution was stirred for 50 min at Ϫ20 to Ϫ5

°C. Dichloromethane (10 mL) was added, and the organic phase

was washed with saturated aqueous NaHCO₃, dried with MgSO₄,

filtered, and concentrated. The residual oil was purified by chroma-

tography on silica gel (petroleum ether/diethyl ether, 6:4) to give

the desired product (58 mg, 93% yield). ¹H NMR (250 MHz,

CDCl₃): δ ϭ 1.09 (s, 9 H, tBu, OTBDPS), 1.10 (s, 9 H, tBu,

OTBDPS), 1.26 (t, J ϭ 7.02 Hz, 3 H, CO₂CH₂CH₃), 1.82 (dd, J ϭ

3.36, J ϭ 12.51 Hz, 1 H, 3-H), 2.05 (dd, J ϭ 9.46, J ϭ 12.51 Hz,

1 H, 3-H), 2.18 (dd, J ϭ 4.88, J ϭ 8.55 Hz, 1 H, OH), 3.57Ϫ3.63

(m, 2 H, 8-H), 3.75Ϫ3.82 (m, 1 H, 7-H), 4.21 (q, J ϭ 7.02 Hz, 2

H, CO₂CH₂CH₃), 4.38Ϫ4.46 (m, 1 H, 4-H), 4.54 (d, J ϭ 4.58 Hz,

1 H, 5-H), 4.91 (d, J ϭ 7.32 Hz, 1 H, 6-H), 7.31Ϫ7.72 (m, 20 H,

Compound 45: A solution of SnCl₄in CH₂Cl₂(1 , 61 µL,

0.061 mmol) was added at room temperature to a solution of bicyc-

lic compound 33a (29 mg, 0.061 mmol) in methanol (1 mL). The

solution was stirred for 49 h at room temperature. The mixture was

cooled at 0 °C (ice bath), and ethyl acetate (5 mL) and aqueous

NaHCO₃(10%, 1 mL) were added. The organic phase was washed

with brine, dried with MgSO₄, and filtered, and the solvents were

evaporated. The residual oil was purified by chromatography on

silica gel [petroleum ether/ethyl acetate, 1:1, R_fϭ 0.19 (product)

and R_fϭ 0.33 (starting material)], and starting material (9.8 mg)

and an inseparable mixture of α- and β-methyl furanosidic com-

pounds 45 (19.2 mg) were obtained (62% yield, 94% yield based on

recovered starting material). ¹H NMR (400 MHz, CDCl₃): δ ϭ

1.10 (s, 9 H of α-methyl isomer and 9 H of β-methyl isomer, tBu,

OTBDPS), 2.36 (dd, J_3a/3bϭ 14.03, J_3/4ϭ 4.00 Hz, 1 H, 3-H of α-

methyl isomer and 1 H, 3-H of β-methyl isomer), 2.44 (dd, J_3a/3bϭ

14.03, J_3/4ϭ 5.96 Hz, 1 H, 3-H of α-methyl isomer and 1 H, 3-H

of β-methyl isomer), 3.22 and 3.39 (2 s, 3 H, OCH₃of α-methyl

isomer and 3 H, OCH₃of β-methyl isomer), 3.59Ϫ3.78 (m, 2 H, 8-

H of α-methyl isomer and 2 H, 8-H of β-methyl isomer), 3.79 and

3.83 (2 s, 3 H, CO₂CH₃of α-methyl isomer and 3 H, CO₂CH₃of

β-methyl isomer), 3.91Ϫ3.98 (m, 1 H, 7-H of α-methyl isomer and

1 H, 7-H of β-methyl isomer), 4.09Ϫ4.17 (m, 1 H, 6-H of α-methyl

isomer and 1 H, 6-H of β-methyl isomer), 4.40 (dd, J ϭ 2.58, J ϭ

4.19 Hz, 1 H, 5-H of one isomer), 4.42Ϫ4.49 (m, 1 H, 4-H of one

isomer), 4.52 (dd, J ϭ 1.29, J ϭ 5.29 Hz, 1 H, 5-H of one isomer),

4.54Ϫ4.60 (m, 1 H, 4-H of one isomer), 7.38Ϫ7.77 (m, C₆H₅of α-

and β-methyl isomers) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ

19.40 (C_q, tBu, TBDPS), 27.05 (tBu, TBDPS), 45.37 and 46.76

(CH₂, C-3 of α- and β-methyl isomers), 51.97, 52.69, 53.13

(CO₂CH₃of α- and β-methyl isomers and OCH₃of α- and β-methyl

isomers), 63.64 and 64.11 (CH₂, C-8 of α- and β-methyl isomers),

72.05 and 72.65 (CH, C-6 of α- and β-methyl isomers), 73.18 and

73.37 (CH, C-4 of α- and β-methyl isomers), 73.86 and 74.05 (CH,

C7 of α- and β-methyl isomers), 80.52 and 83.45 (CH, C-5 of α-

and β-methyl isomers), 105.69 (C_q, C-2 of α- and β-methyl iso-

mers), 127.88, 130.05, 135.87 (CH, C₆H₅), 133.72, 135.69 (C_q,

C₆H₅), 171.13 (CϭO, CO₂CH₃) ppm. MS (DCI, NH₃): m/z ϭ 505

[M ϩ H^ϩ], 522 [M ϩ NH₄^ϩ]. IR (film, cm^Ϫ1): ν˜ ϭ 3510, 3072,

3050, 2955, 2931, 2894, 2857, 1751, 1590, 1473, 1428, 1379, 1361,

1347, 1252, 1204, 1111, 1029, 975, 917, 837.

C₆H₅) ppm. ¹³C NMR (50 MHz, CDCl₃):

δ

ϭ

13.92

(CO₂CH₂CH₃), 19.14, 19.45 (C_q, tBu,TBDPS), 26.86, 27.07 (tBu,

TBDPS), 42.99 (CH₂, C-3), 62.22 (CO₂CH₂CH₃), 63.83 (CH₂, C-

8), 69.74 (CH, C-4), 72.84 (CH, C-7), 76.86 (CH, C-6), 80.69 (CH,

C-5), 106.13 (C_q, C-2), 127.88, 130.05, 135.53, 135.62, 135.66,

135.83 (CH, C₆H₅), 132.83, 133.08, 133.84 (C_q, C₆H₅), 165.43 (Cϭ

O, CO₂CH₂CH₃) ppm. MS (DCI, NH₃): m/z ϭ 742 [M ϩ NH₄^ϩ].

IR (film, cm^Ϫ1): ν˜ ϭ 3532, 3062, 2931, 2858, 1756, 1660, 1587,

1472, 1428, 1376, 1262, 1189, 1111, 1074, 1050, 968, 907, 823,

740, 703.

Compound 42: A solution of phosphoramidite (105 mg, 0.30 mmol)

in dry CH₂Cl₂(2 mL) was added at room temperature to a solution

of alcohol 41 (55 mg, 0.076 mmol) and tetrazole (43 mg,

0.60 mmol) in dry CH₂Cl₂(1 mL). After 1 h and 30 min, the reac-

tion mixture was cooled to Ϫ10 °C and a solution of mCPBA

(150 mg, 0.60 mmol) in dry CH₂Cl₂(2 mL) was added. The mixture

was stirred for a further 65 min at 0 °C. CH₂Cl₂(10 mL) was ad-

ded, and the organic phase was washed with aqueous Na₂SO₃

(10%), saturated aqueous NaHCO₃, and brine. The organic phase

was dried with MgSO₄, filtered, and concentrated. The residual

oil was purified by chromatography on silica gel (petroleum ether/

CH₂Cl₂/ethyl acetate, 5:4:1, R_fϭ 0.35) affording the desired com-

1

pound (66 mg, 88% yield). H NMR (250 MHz, CDCl₃): δ ϭ 1.06

(s, 9 H, tBu, OTBDPS), 1.10 (s, 9 H, tBu, OTBDPS), 1.20 (t, J ϭ

7.12 Hz, 3 H, CO₂CH₂CH₃), 1.78 (dd, J ϭ 3.36, J ϭ 12.51 Hz, 1

H, 3-H), 1.99 (dd, J ϭ 9.46, J ϭ 12.51 Hz, 1 H, 3-H), 3.78Ϫ3.90

(m, 1 H, 7-H), 3.93Ϫ4.05 (m, 2 H, 8-H), 4.11 (q, J ϭ 7.12 Hz, 2

H, CO₂CH₂CH₃), 4.37Ϫ4.45 (m, 1 H, 4-H), 4.61 (d, J ϭ 4.58 Hz,

1 H, 5-H), 4.80Ϫ5.03 [m, 1 H, 6-H, 4 H, P(O)(OCH₂C₆H₅)₂],

7.21Ϫ7.74 (m, 30 H, C₆H₅) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ

13.90 (CO₂CH₂CH₃), 19.14, 19.54 (C_q, tBu, TBDPS), 26.82, 27.02

(tBu, TBDPS), 43.02 (CH₂, C-3), 61.98 (CO₂CH₂CH₃), 67.45 (d,

J ϭ 5.31 Hz, CH₂, C-8), 68.82, 68.91 [2 d, J ϭ 5.32 Hz, CH₂,

P(O)(OCH₂C₆H₅)], 69.69 (CH, C4), 71.72 (d, J ϭ 9.01 Hz, CH, C-

7), 74.23 (CH, C-6), 80.04 (CH, C-5), 106.25 (C_q, C-2), 127.70

127.77, 128.24, 128.44, 129.82, 129.95, 130.02, 135.53, 135.58,

135.93, (CH, C₆H₅), 132.80, 132.96, 133.10, 133.34 (C_q, C₆H₅),

165.36 (CϭO, CO₂CH₂CH₃) ppm. ³¹P NMR (CDCl₃, 81 MHz):

δ ϭ Ϫ1.04 ppm. MS (DCI, NH₃): m/z ϭ 985 [M ϩ H^ϩ], 1002 [M

ϩ NH₄^ϩ]. IR (film, cm^Ϫ1): ν˜ ϭ 3060, 2931, 2858, 1752, 1589, 1456,

1428, 1379, 1266, 1207, 1106, 1040, 1021, 886, 823, 740.

Compound 51: Triethyl phosphite (17 µL, 0.098 mmol) was added

at 0 °C to a solution of α- and β-methyl furanoside compound

45 (40 mg, 0.079 mmol) and CBr₄(31 mg, 0.09 mmol) in pyridine

(0.5 mL). The ice bath was removed and the mixture was stirred

for 21 h. Diethyl ether (5 mL) was added, and the organic phase

was washed with saturated aqueous NH₄Cl (2 mL) and then with

Compound 43: A solution of TBAF (1 , 60 µL, 0.060 mmol) was

added at room temperature to a solution of silyl ether 42 (40 mg,

0.040 mmol) in dry THF (0.3 mL). The solution was stirred for 1

h. Diethyl ether (2 mL) was added, and the organic phase was

686

Eur. J. Org. Chem. 2003, 672Ϫ688

Direct Access to Furanosidic Eight-Membered Ulosonic Esters

FULL PAPER

´

brine (2 mL), dried with MgSO₄, filtered, and concentrated. The

residual oil was purified by chromatography on silica gel (petro-

leum ether/ethyl acetate, 1:1), affording compound 51 (40 mg, 80%

Rayons X sur monocristaux’’ and C. Andre for X-ray structure de-

termination.

1

yield). H NMR (250 MHz, CDCl₃): δ ϭ 1.06 (s, 9 H of α-methyl

B. Ganem, Tetrahedron 1978, 34, 3353. ^[1b]M. M. Cambell,

[1] [1a]

isomer and 9 H of β-methyl isomer, tBu, OTBDPS), 1.32 (t, J ϭ

7.02 Hz, OCH₂CH₃), 2.36 (dd, J_3a/3bϭ 14.03, J_3/4ϭ 4.00 Hz, 1 H,

3-H of α-methyl isomer and 1 H, 3-H of β-methyl isomer), 2.44

(dd, J_3a/3bϭ 14.03, J_3/4ϭ 5.96 Hz, 1 H, 3-H of α-methyl isomer

and 1 H, 3-H of β-methyl isomer), 3.18 and 3.35 (2s, 3 H, OCH₃

of α-methyl isomer and 3 H, OCH₃of β-methyl isomer), 3.58 (dd,

J ϭ 4.28, J ϭ 12.21 Hz, 1 H, 8-H of one isomer), 3.65 (dd, J ϭ

4.27, J ϭ 12.21 Hz, 1 H, 8-H of one isomer), 3.75 and 3.79 (2 s, 3

H, CO₂CH₃of α-methyl isomer and 3 H, CO₂CH₃of β-methyl

isomer), 3.91Ϫ3.93 (m, 1 H, 7-H of α-methyl isomer and 1 H, 7-H

of β-methyl isomer), 4.09 (q, J ϭ 7.02 Hz, OCH₂CH₃), 4.12Ϫ4.27

(m, 1 H, 6-H of α-methyl isomer and 1 H, 6-H of β-methyl isomer),

4.40 (br. s., 1 H, 5-H of one isomer), 4.49Ϫ4.54 (m, 1 H, 4-H of

both isomers, 1 H, 5-H of one isomer), 7.38Ϫ7.77 (m, C₆H₅of α-

and β-methyl isomers) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ

16.10 (CH₃, OCH₂CH₃), 19.48 (C_q, tBu, TBDPS), 27.04 (tBu,

TBDPS), 45.37 and 46.72 (CH₂, C-3 of α- and β-methyl isomers),

51.95, 52.68, 53.12 (CO₂CH₃of α- and β-methyl isomers and OCH₃

of α- and β-methyl isomers), 63.67, 64.10 and 65.30 (CH₂, C-8 of

α- and β-methyl isomers, OCH₂CH₃), 72.04 and 72.70 (CH, C-6 of

α- and β-methyl isomers), 73.12 and 73.32 (CH, C-4 of α- and β-

methyl isomers), 73.81 and 74.05 (CH, C-7 of α- and β-methyl iso-

mers), 80.50 and 83.36 (CH, C-5 of α- and β-methyl isomers),

105.66 (C_q, C-2 of α- and β-methyl isomers), 127.86, 130.03, 135.86

(CH, C₆H₅), 133.73, 135.69 (C_q, C₆H₅), 171.13 (CϭO, CO₂CH₃)

ppm. ³¹P NMR (161 MHz, CDCl₃): δ ϭ Ϫ0.15 ppm. MS (DCI,

NH₃): m/z ϭ 641 [M ϩ H^ϩ], 658 [M ϩ NH₄^ϩ]. C₃₀H₄₅O₁₁SiP

(640.7): calcd. C 56.24, H 7.08; found C 56.38, H 7.16.

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T. H. Chan, Y. C. Xin, J. Org. Chem. 1997, 62,

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[5f]

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˚

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70.727(3)°, V ϭ 1792.0(4) A , Z ϭ 2, ρ_calcd.ϭ 1.194 Mg·m^Ϫ3

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F(000) ϭ 695, λ ϭ 0.71073 A, T ϭ 193(2) K, µ(Mo-K_α) ϭ 0.145

mm^Ϫ1, crystal dimensions 0.2 ϫ 0.4 ϫ 0.5 mm, 1.87° Յ θ Յ 24.71°;

9224 reflections (7530 independent, R_intϭ 0.0617) were collected

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Bruker-AXS CCD 1000 diffractometer. The structure was solved

by direct methods (SHELXS-97), and 340 parameters were refined

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Ernst, U. Kragl, Biotechnol. Prog. 1997, 13, 810.

C. H. Lin,

3

˚

tron density: 0.504 e/A , R1 [for F Ͼ 2σ(F)] ϭ 0.0515 and wR2 (all

data) ϭ 0.1267 with R1 ϭ |F_o| Ϫ |F_c|/|F_o| and wR2 ϭ w[(F²_oϪ F_c²)²/

w(F²_o)²]^0.5. Refinement of an inversion twin parameter [x ϭ

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inverted structure] confirmed the absolute structure of 33a.^[31]

CCDC-187471 contains the supplementary crystallographic data

for this paper. These data can be obtained free of charge at

www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge

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C. Auge, B. Bouxom, B. Ca-

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N. J. Sugai, G. J. Shen, Y. Ichikawa, C. H. Wong, J.

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Acknowledgments

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`

We thank the CNRS and the ‘‘Ministere de l’Education Nationale

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the molecule. Molecular dynamics were carried out at constant

temperature (400 K) and for an overall duration of 10000 ps.

Six minima were chosen each time and minimized individually

as before. The same process was repeated for each minimum

until no variation in energy was observed. The program used

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µSI (now Accelrys), 9685 Scranton Road, San Diego, CA

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Received July 12, 2002

[O02389]

688

Eur. J. Org. Chem. 2003, 672Ϫ688

Article Doi

Direct access to furanosidic eight-membered ulosonic esters from cis-α,β-epoxy aldehydes

DOI: 10.1002/ejoc.200390108

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