Synthetic strategies directed towards 5a-carbahexopyranoses and derivatives based on 6-endo-trig radical cyclizations

FULL PAPER

DOI: 10.1002/ejoc.201100956

Synthetic Strategies Directed Towards 5a-Carbahexopyranoses and Derivatives

Based on 6-endo-trig Radical Cyclizations

Ana M. Gómez,*^[a]Clara Uriel,^[a]Maria D. Company,^[a]and J. Cristóbal López*^[a]

Dedicated to Professor Dr. Benjamín Rodríguez on the occasion of his retirement

Keywords: Carbohydrates / Carbasugars / Radicals / Regioselectivity / Cyclization / Ozonation

Several synthetic strategies directed towards 5a-carbahexo-

and iii) the inclusion of ring strain in the system – have

pyranoses and based on 6-endo-trig radical cyclization of un- proved useful when used in combination. The simultaneous

saturated carbohydrate derivatives have been devised. Three

elements for regiocontrol to optimize the 6-endo/5-exo ratio

have been incorporated, and their efficiencies in directing

6-endo cyclizations have been evaluated. These elements –

namely: i) the incorporation of a substituent at C-5 (radical

numbering), ii) the use of a vinyl (rather than alkyl) radical,

presence of two of them also results in 6-endo selectivity. On

another topic, the ozonation of the ensuing alkenylstananes

to afford diols seems to be based on a tin-oxygen rearrange-

ment, similar to that reported for related vinylsilanes, rather

than on remarkable stabilities of tin-containing primary

ozonides as we had previously suggested.

through radical cyclization of the appropriate carbohydrate

precursors. At the onset of this work, only a very few exam-

ples of radical cyclizations of sugar derivatives leading to

carbapyranoses were known, and all of them were based on

6-exo-type cyclizations either of hept-6-enyl or of hept-6-

ynyl radicals (radical numbering).^[10,11,12]

On the other hand, six-membered rings could also be

accessible through 6-endo-type cyclizations of hex-5-enyl

radicals, and we were interested in evaluating the potential

of such transformations for the preparation of carbapyr-

anoses (Scheme 1, a, b). Radical cyclization of hex-5-enyl

Introduction

Carbasugars, carbohydrate derivatives in which the ring

oxygen has been replaced by a methylene group, were first

conceived by McCasland and co-workers in 1966,^[1]as

carbohydrate mimetics^[2]with enhanced chemical stabilities.

Soon after McCasland’s pioneering reports,^[1,3]5a-carba-α-

d-galactopyranose (2, Figure 1) was isolated as a natural

product from a fermentation broth of Streptomyces sp. MA-

4145.^[4]During the last four decades, and in parallel with

the recognition of the relevant role played by carbohydrate

derivatives in biological processes,^[5]the synthesis,^[6]biology

and conformational aspects of carbasugars have been the

subject of extensive studies.^[7]

Figure 1. α-d-Galactopyranose (1) and 5a-carba-α-d-galactopyr-

anose (2) as examples of a sugar and its carbasugar counterpart.

We are interested in the application of free radical pro-

cesses to carbohydrate chemistry.^[8]In this context we em-

barked some time ago on a project dealing with the synthe-

sis of carbapyranose derivatives (5a-carbahexopyranoses)^[9]

[a] Instituto de Química Orgánica General, CSIC,

Juan de la Cierva 3, 28006 Madrid, Spain

Fax: +34-915-644853

Scheme 1. a), b) 6-endo-trig versus 5-exo-trig, and c) 6-endo-dig

radical cyclizations of hex-5-enyl- (3, 6) and hex-5-ynyl-type (9)

radicals.

E-mail: ana.gomez@csic.es

jc.lopez@csic.es

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5a-Carbahexopyranoses by 6-endo-trig Radical Cyclizations

radicals usually gives rise to cyclopentane derivatives

through a predominant 5-exo ring-closure mode,^[13]how-

ever, in a process governed by stereoelectronic rather than

thermodynamic factors (Scheme 1, a).^[14]Nevertheless, we

were encouraged by the fact that the regiochemistry of the

process can be influenced, and even reversed, to favour the

formation of six-membered rings by factors other than

stereoelectronic control.^[15]

Scheme 2. Retrosynthesis of the carbahexopyranoses 11 by 6-endo-

trig radical cyclization of the carbohydrate-derived vinyl radicals

13.

In this context, three main strategies had previously been

used to induce 6-endo selectivity: i) the incorporation of a

substituent at C-5 (Scheme 1, a, R ϶ H), ii) the use of a

vinyl (rather than alkyl) radical (Scheme 1, b), and iii) the

introduction of ring strain in the system (Scheme 1, c). With

regard to issue i), the cyclization of 3a (R = H) yields a 49:1

mixture of 4 and 5, whereas the presence of a methyl group

at C-5, as in 3b, favours the formation of 5 over 4 (3:2

endo/exo ratio), a result that has been ascribed to an un-

favourable steric effect in the 5-exo mode of cyclization.^[16]

The use of vinyl radicals [issue ii); e.g., 6, Scheme 1, b] un-

der tin hydride reaction conditions was independently

studied by Beckwith’s^[17]and Stork’s^[18]groups. They found

that although 6a exclusively undergoes 5-exo cyclization,

the ensuing kinetic radical undergoes an isomerisation to

the thermodynamic methylenecyclohexane that is favoured

at low concentrations of stannane. On the other hand, we

have recently shown that 5-methyl-1-methylenehex-5-enyl

radicals (e.g., 6b) are able, unlike their demethyl analogues

6a, to undergo “direct” 6-endo-trig ring closure that adds to

the 6-endo regiochemistry of the transformation.^[19]Finally,

Hoffmann and co-workers found that five-membered rings

with two appendages, bearing the radical and the radical

acceptor in an anti disposition, undergo 6-endo ring closure

rather than the potentially faster 5-exo cyclization, which is

prevented by ring strain, as in issue iii) (Scheme 1, c).^[20]

Here we give a full account of our studies in the evalu-

ation of the regiodirecting factors favouring 6-endo-trig rad-

ical cyclization discussed above, as well as their application

to carbohydrate substrates for the preparation of carba-

hexopyranoses and derivatives.^[21]

These structural requirements were met by sugars in

which the OH groups at C-2 and C-3 displayed anti orienta-

tions, but with both configurations at C-4 being possible.

On the other hand, it was intended to generate the vinyl

radical by tributyltin hydride addition to a terminal alkyne

(Scheme 2, R = SnBu₃).^[22]The enynes 20a and 20b, based

on d-glucose and d-galactose diacetonides, were chosen as

our test candidates, and their preparation is outlined in

Scheme 3. The synthesis of the alkynes 17a and 17b was

carried out by the procedure of Toma and co-workers,^[23]

though with some modifications. We showed that hydro-

genolysis of the β-benzyl gluco- and β-benzyl galactosides

14a and 14b, respectively, is a more reliable and higher-

yielding process than the reported hydrogenolysis of mix-

tures of α- and β-benzyl glycosides.^[24]Accordingly, the

benzyl β-glycosides 14a and 14b were hydrogenolysed in the

presence of Pd/C in ethanol containing triethylamine to

give 15a and 15b in excellent yields. Next, Wittig treatment

of these hemiacetals with (chloromethylene)triphenylphos-

phorane in the presence of n-butyllithium (BuLi) and

DMPU in THF yielded 1:1 mixtures of the (E/Z)-chlorovi-

nyl derivatives 16a and 16b. Dehydrohalogenation of the

ethylenic derivatives with BuLi at –78 °C in THF, furnished

the desired heptynitols 17a and 17b in good yields.

Results and Discussion

6-endo-trig-Radical Cyclization of Vinyl Radicals in Ring-

Strained Systems

Our first approach to the preparation of carbapyranoses

(e.g., 11, Scheme 2) was based on the cyclization of the vinyl

radicals 13, incorporating the three regiodirecting factors

discussed above: substitution at C-5, the presence of a vinyl

radical, and fixing of the anti disposition of the carbon

chains bearing the radical and the radical acceptor with the

aid of an isopropylidene ring. The proposed strategy fea-

tured the generation of the stereogenic centre at C-5 (defin-

ing the d or l configuration) by reduction of the radicals

12 and the retrosynthetic correlation of the exocyclic vinyl

group with the OH at C-1 in the carbasugar (Scheme 2).

Scheme 3. Synthesis of the d-glucose- and d-galactose-derived en-

ynes 20a and 20b, respectively.

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FULL PAPER

Oxidation of 17a and 17b proved troublesome. Applica- enylstannanes 21a (18% yield). Application of similar reac-

tion of Swern oxidation conditions^[25]resulted in partial ep- tion conditions to the d-galactose isomer 20b furnished the

imerization at C-4 of the ensuing ketones, which thus both carbasugar derivative 22b in a regio- and stereoselective

gave mixtures of 18a and 18b. Dess–Martin reagent,^[26]manner and in 75% yield.

though, did allow the preparation of 18a (68% yield) with-

At high stannane concentrations (Scheme 4, a), hydrogen

out epimerization, and so did the PDC/Ac₂O combina- transfer from the tributyltin hydride takes place more

tion,^[27]which was preferred for its simplicity and was also rapidly than radical cyclization, to give the open-chain alk-

applied to the oxidation of 17b. Methylenation of the enylstannane^[31]21a (see also 20aǞ13aǞ21a in Scheme 5).

ketones 18a and 18b was first attempted by Wittig ole- At low stannane concentrations (syringe pump addition),

fination with methyltriphenylphosphonium bromide in the though, the vinyl radical 13 (R = SnBu₃) is able to undergo

presence of different bases (nBuLi, tBuOK, sodium hexa- the – slow – 6-endo-trig cyclization more rapidly than hy-

methyldisilazane) at several temperatures, but proved un- drogen transfer, thus leading to the tricyclic radical 24. This

successful. The use of Tebbe reagent^[28]furnished access to undergoes a hydrogen transfer from Bu₃SnH and, de-

the methylene derivatives 20 in small-scale reactions, but pending on the approach of the incoming tributyltin hy-

resulted in diminished reaction yields when the reaction was dride, gives the carbasugar derivatives 22 or 23 (only one

scaled up. The attempted use of Lombardo’s methylenating isomeric alkene was observed in each case, but the stereo-

reagent^[29]was also unsuccessful. Finally, we were able to chemistry has not been assigned). A completely stereoselec-

install the methylene group at C-4 by use of the two-step tive α-face hydrogen transfer was observed in the d-galact-

Peterson olefination procedure.^[30]Treatment of the ketones ose derivative 13b (leading to the 5a-carba-d-galactopyr-

18a or 18b with trimethylsilylmethylmagnesium chloride in anose derivative 22b), whereas in the d-glucose series (e.g.,

diethyl ether at 0 °C gave the silyl intermediates 19, isola- 13a) a highly selective α-approach, leading preferentially to

tion of which prior to the next elimination step proved to 22a, could also be observed. An alternative route involving

be beneficial (KH/THF). Attempts to carry out the elimi- 5-exo-trig cyclization to generate the methylenecyclopentyl-

nation without isolation of 19 resulted in the formation of type radical 25, and thence 24 via the cyclopropyl methyl-

desilylated methyl derivatives in a considerable extent.

type radical 26, is less likely to happen because of the strain

An attempted radical cyclization with the glucose-de- associated with the trans-2,3-O-isopropylidene ring.^[21b]

rived enyne 20a [Bu₃SnH (1.5 equiv.), toluene, 80 °C,

0.02 m] resulted in the formation of an open-chain alkenyl-

stannane (Scheme 4, a). However, it was gratifying to ob-

serve that slow (syringe pump) addition of Bu₃SnH

(1.5 equiv.) resulted in the formation of the tricyclic carba-

sugar derivatives 22a (56% yield) and 23a (5% yield) as

major products (Scheme 4, b), along with some bicyclic alk-

Scheme 5. Regio- and stereoselectivity in the formation of the car-

basugar derivatives 22 and 23 by radical cyclization of the diaceto-

nide-enynes 20.

The stereochemical outcomes of the reactions were con-

firmed by correlation of the resulting carbasugar derivatives

with the previously reported 5a-carba-β-d-glucopyranose

28a and 5a-carba-β-d-galactopyranose 28b, as outlined in

Scheme 6: acid treatment (AcOH/THF/H₂O) of the stannyl

diacetonides 22a and 22b furnished destannylated tetraols

that upon acetylation gave “carbasugar exo-glycals”^[32]27a

and 27b, and subsequent ozonolysis followed by stereo-

selective reduction and acetylation yielded the previously

Scheme 4. Radical cyclization of the enynes 20a and 20b.

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described

5a-carba-β-d-glucopyranose

pentaacetate

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5a-Carbahexopyranoses by 6-endo-trig Radical Cyclizations

{28a,^[33,34][α]²_D¹= +12.2 (c = 1.0, CHCl₃) [ref.^[34b]+13.8 (c

= 1.0, CHCl₃)]} and 5a-carba-β-d-galactopyranose penta-

acetate {28b,^[35][α]_D²¹= –3.4 (c = 0.4, CHCl₃)}.

Scheme 6. Preparation of 5a-carba-β-d-gluco- and 5a-carba-β-d-

galactopyranose pentaacetates (28a and 28b, respectively).

6-endo Radical Cyclization of Alkyl Radicals in Ring-

Strained Systems

The substrates 29–32 (Figure 2) were also of interest for

evaluation of the regiodirecting effect of the ring strain.

These substrates, incorporating 2,3-O-isopropylidene rings

(associated with ring strain), were precursors of alkyl radi-

cals and therefore devoid of the endo-directing properties

[21b]

associated with the vinyl radical.

Scheme 7. Synthesis of the xanthates 29 and 30 from the hemiacetal

15a.

Table 1. Radical cyclization of xanthates 29–32 by treatment with

Bu₃SnH (1.5 equiv.) and AIBN in toluene solution (0.02 m) at

85 °C under syringe pump addition conditions (6 h).

Figure 2. Precursors of alkyl radicals in ring-strained systems as

potential substrates for 6-endo radical cyclization leading to carba-

sugar derivatives.

The synthetic route to the xanthates 29 and 30 started

from the hemiacetal 15a (Scheme 7). Reduction of 15a (Li-

AlH₄) generated a diol^[36]that could be selectively silylated

at the primary position and subsequently oxidized (PDC/

Ac₂O) to afford the ketone 33. This was subjected to Pe-

terson olefination to give the alkene 34. Desilylation of 34

led to the primary alcohol 35, which was transformed into

the xanthates 29 and 30 (HNa, CS₂, MeI), the latter by an

oxidation (PDC/Ac₂O) and MeMgI addition sequence.

The phenyl thionocarbonates 31 and 32 were prepared

uneventfully by treatment of 16a and 17a, respectively, with

phenyl chlorothionoformate [PhOC(S)Cl].

The radical cyclization of derivatives 29–32 was per-

formed in toluene solution (0.02 m) at 85 °C by addition of

Bu₃SnH (1.5 equiv.) and AIBN under argon (Table 1).

For purposes of characterization, the tricyclic derivative 37

The cyclization of alkyl radicals arising from 29 and 30 was readily transformed into its tetraacetate 41, which dis-

took place in a 6-endo-trig manner to give the carbasugar played coupling constants consistent with a d-gluco deriva-

derivatives 37 and 38, respectively (Table 1, Entries i and ii). tive (e.g., 4-H, 4.96 ppm, t, J = 9.6 Hz), by acid hydrolysis

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(AcOH/THF/H₂O 2:4:1) followed by acetylation (Ac₂O/

pyridine) in 67% yield (Table 1, Entry i). Radical cycliza-

tion of the secondary alkyl radical arising from the xanthate

30 resulted in the stereoselective formation of the β-C-

methyl 5a-carba-d-glucopyranose 38, the stereochemistry

of which at C-1 was inferred from the 2-H coupling con-

stants J_1,2= 8.8 Hz and J_2,3= 9.0 Hz (Table 1, Entry ii).

In contrast, the cyclic secondary radicals arising from 31

and 32 (Table 1, Entries iii and iv, respectively) did not un-

dergo cyclization, and only the deoxygenated derivatives 39

and 40 could be isolated. In our opinion the cyclic natures

of the radicals complicate the approach from a steric stand-

point, thus making the hydrogen transfer process faster

than the cyclization step.

6-endo Radical Cyclization of Vinyl Radicals in Unstrained

Systems

To evaluate enynes devoid of ring strain we selected the

derivatives 42–44 (Figure 3). The d-mannose diacetonide

42, unlike the enyne diacetonides 20a and 20b, contains a

2,3-cis-O-isopropylidene ring rather than the 2,3-trans iso-

propylidene system responsible for ring strain. The d-mann-

ose- and d-glucose-derived enynes 43 and 44, respectively,

differ in the natures of their protecting groups, benzyl and

acetyl groups having been chosen to evaluate their compati-

bilities with the reaction process.

Scheme 8. Synthesis of the enynes 42–44.

Table 2. Radical cyclization of the enynes 42–44 by treatment with

Bu₃SnH (1.5 equiv.) and AIBN in toluene solution (0.02 m ) at

85 °C under syringe pump addition conditions (6 h).

Figure 3. Enynes 42–44, containing no trans-2,3-O-isopropylidene

groups.

The d-mannose enyne 42 was prepared from mannose

diacetonide (45^[37]) through a synthetic route similar to that

used for 20a and 20b (Scheme 8, a). A sequence consisting

of a Wittig reaction, Swern oxidation (no epimerization at

C-4 was observed), stepwise Peterson olefination and dehy-

drohalogenation then led to the enyne 42 in acceptable

overall yield.

2,3,4,6-Tetra-O-benzyl-d-mannose (50)^[38]was similarly

subjected to a related reaction sequence to provide the en-

yne 43 (Scheme 8, b). Finally, mild acid hydrolysis of the

isopropylidene groups in 20a and subsequent acetylation

paved the way to the tetraacetate 44 (Scheme 8, c).

Radical cyclization of the enynes 42–44, at low stannane

concentrations, in all cases furnished methylenecyclohexane

derivatives (Table 2). We have previously shown that at low

stannane concentrations the final “6-endo” regiochemistry

is the result both of a direct 6-endo-trig cyclization and of

a 5-exo-trig cyclization followed by rearrangement of the

ensuing methylenecyclopentyl radicals.^[21b]The tricyclic car-

basugar precursors 54 and 55 were obtained in a 15:1 ratio

[a] The radical cyclizations were followed by destannylation

through treatment with THF/H₂O/AcOH. The yields refer to the

(Table 2, Entry i), in favour of the d-carbasugar precursor two-step transformations.

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5a-Carbahexopyranoses by 6-endo-trig Radical Cyclizations

(i.e., 54), a result consistent with previous observations on ously determined by an observed nOe between the angular

the tricyclic derivatives 22a, 22b, 37 and 38. Benzyl and acyl methyl group and H-4. On the other hand, SmI₂-promoted

groups could be used as protecting groups in these radical carbonyl alkene cyclization^[39]of the aldehyde 64 yielded

cyclizations without any appreciable presence of intramo- the highly oxygenated cyclopentane derivative 66 along with

lecular hydrogen transfer from the former to the vinyl radi- the dimer 67 resulting from pinacol coupling.

cal (Table 2, Entries ii and iii). The destannylated methyl-

These results serve to illustrate that the presence of alkyl

enecyclohexane derivatives 57 and 59 were obtained from substitution at C-5 (radical numbering) as the only regiodi-

the corresponding alkenylstannanes on treatment with recting factor is not sufficient to induce 6-endo-trig cycliza-

THF/H₂O/AcOH.

tion [compare the radical cyclization of 63 (Scheme 9) with

Although from the examples in Table 2 it was clear that that of 29 (Table 1, Entry i), in which ring strain was also

the presence of the anti 2,3-O-isopropylidene group is not present].

a requirement for the cyclization to occur in a “6-endo

mode” the presence of isopropylidene groups is highly ad-

Synthesis of Carbasugar Derivatives – Formal Total

Synthesis of Penta-N,O-acetylvalidamine

visable in terms of stereoselectivity of the process. Enynes

43 and 44, without isopropylidene rings, afforded the meth-

ylenecyclohexanes 56/57 and 58/59, respectively, without

significant stereocontrol relative to the bicyclic enyne 42

(Table 2, compare Entry i with Entries ii and iii).

The methylenecyclohexane derivatives obtained by radi-

cal cyclization are useful precursors for the preparation of

different carbasugar derivatives. The 5a-carba-β-d-glucose

derivative 68 (Scheme 10), readily obtained by ozonolysis of

27a (O₃, MeOH, –78 °C) followed by reduction with

BH₃·SMe₂, for instance, yielded, after mesylation (MsCl,

NEt₃) and nucleophilic substitution (NaN₃), the azido de-

rivative 69. This had been previously transformed into the

penta-N,O-acetyl derivative of (+)-validamine (70) by treat-

ment with Raney nickel and acetylation.^[40]

5-exo Radical Cyclization of Alkyl Radicals in Unstrained

Systems

The phenylthionocarbonate 63 and the aldehyde 64

(Scheme 9), prepared by derivatization and oxidation,

respectively, of the hydroxy alkene 62, were used as precur-

sors for the generation of unstrained alkyl radicals to test

the regiochemistries in their radical cyclizations. Compound

62 was prepared uneventfully from the hemiacetal 45 by

the transformations outlined in Scheme 9. Its synthesis was

modelled after that of the alkene 35 (Scheme 7) and made

use of related transformations.

Scheme 10. Synthetic transformations of the azido carbasugar 69.

Treatment of the azide 69 with triphenylphosphane, in

order to achieve a Staudinger reaction,^[41]was very slug-

gish, which led us to use the more reactive nBu₃P. ^[42]In our

hands, however, only the olefin derivative 71 was obtained

upon treatment of 69 with nBu₃P. ^[43]The cyclohexene 71 is

an interesting synthetic intermediate, because related olefins

have been used by Plumet and co-workers in synthetic ap-

proaches to cyclophellitol.^[44]

Finally, hydrogenolysis of 69 led to the 1-deoxy carbasu-

gar derivative 72, rather than to the expected amino deriva-

tive.

Scheme 9. Synthesis and radical cyclization of the unstrained radi-

cal precursors 63 and 64.

Ozonation of Alkenylstannanes – Mechanistic

Considerations and Access to Carbasugar-Derived Ketoses.

The radical cyclization of 63, under the previously de-

scribed conditions, exclusively yielded the tricyclic cyclo-

The alkenylstannanes used for radical cyclizations of en-

pentane derivative 65, resulting from 5-exo-trig cyclization. ynes are useful substrates for further synthetic transforma-

The stereochemistry at the geminal carbon was unambigu- tions.

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In the route to C-1 ketones by ozonolysis of compounds The alkenylstannanes 75 [Z/E mixture, 1:1, prepared from

22a and 54 (Scheme 11), we observed that, rather than the corresponding alkyne by radical-mediated stannylation

double bond cleavage, these derivatives experienced a for- (HSnBu₃, Et₃B)]^[48]were used as model compounds. Ozon-

mal dihydroxylation process (without C–C bond cleavage) olysis of the stannanes 75 (O₃, –78 °C) followed by re-

leading to the carbasugar-derived ketoses 73 and 74, respec- duction (BH₃·SMe₂) and acetylation produced the diacet-

tively.^[45]

ates 77. This transformation was repeated several times with

similar results. One experiment was performed in CD₃OD,

1

with recording of H NMR and ¹³C NMR spectra of the

crude reaction mixture at –60 °C. The observed ¹³C NMR

chemical shifts – 97.5, 96.9, 91.0 and 84.7 ppm – seemed

more consistent with two isomeric dioxetanes (i.e., 76,

structure type C, R = SnBu₃, Scheme 12) than with a stan-

nylated primary ozonide (e.g., A, Scheme 12).

Scheme 11. Ozonation of the alkenylstannanes 22a and 54.

Although we had previously interpreted this behaviour

in terms of a remarkably stable tin-substituted primary

ozonide species [A, R = SnBu₃(Scheme 12),^[46]undergoing

reduction prior to cycloreversion and recombination

(AǞB, Scheme 12) to give a diol without cleavage of the

carbon-carbon bond (AǞD, Scheme 12)], re-examination

of our earlier proposal has led us to believe that a tin-oxy-

gen rearrangement (AǞC, R = SnBu₃, Scheme 12), similar

Scheme 13. Ozonation of the alkenylstannanes 75.

Conclusions

Several synthetic strategies directed towards carbapyr-

to that observed in related ozonolysis of vinylsilanes anoses and based on 6-endo-trig radical cyclizations of un-

(AǞC, Scheme 12, R = SiMe₃),^[47]is responsible for the saturated carbohydrate derivatives have been developed.

observed results. In this context, work by Büchi and Wüest The issue of 6-endo versus 5-exo radical cyclization has been

had shown that vinylsilanes, upon ozonization, evolved evaluated in different substrates. We considered three fac-

through dioxetane intermediates (AǞCǞD, Scheme 12) tors that might induce 6-endo radical cyclization over 5-exo

to give species D without C–C bond cleavage.

ring closure: i) substitution at C-5 (radical numbering),

ii) vinyl radical cyclization, and iii) ring strain. Substrates

incorporating all three elements (i.e., 20a and 20b) evolve to

give “6-endo” carbapyranose derivatives. 6-endo Cyclization

was also observed in vinyl radicals in C-5 substituted, non-

strained systems, as in 42–44. The presence of ring strain

and C-5 substitution is less clear-cut: 6-endo cyclizations

were only observed from a primary radical and from a

methyl-substituted secondary radical (i.e., those arising

from 29 and 30). Systems with C-5 substitution as the sole

regiodirecting effect furnished compounds resulting from 5-

exo radical cyclization (e.g., radical cyclizations of 62 and

64). The compounds resulting from these radical cycliza-

tions can be transformed into functionalized carbasugar de-

rivatives. The azido derivative 69, readily accessible by our

methodology, for instance, has previously been used in the

preparation of a peracetylated (+)-validamine derivative by

Ogawa and co-workers.^[40]Finally, we have re-examined our

initially proposed reaction pathway for the ozonation of al-

kenylstannanes leading to diols, and we now propose a tin-

Scheme 12. Proposed reaction pathway for the ozonation of alken-

ylstannanes (R = SnBu₃, e.g. 22a and 54) and its relationship to

that for alkenylsilanes (R = SiMe₃).

Our proposed revised reaction pathway is based on the oxygen rearrangement of the initially formed primary ozon-

above transformations of related alkenylsilanes and our ide to a substituted dioxetane that is subsequently reduced

own study of the transformations, as outlined in Scheme 13. to the diol, without C–C bond cleavage.

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5a-Carbahexopyranoses by 6-endo-trig Radical Cyclizations

3 H, Me), 1.43 (s, 3 H, Me), 1.42 (s, 3 H, Me), 1.37 (s, 3 H,

Me) ppm. For (Z)-16a: [α]²_D⁵= –3.2 (c = 3.0, CHCl₃). ¹H NMR

(200 MHz, CDCl₃): δ = 6.24 (d, J = 7.5 Hz, 1 H, 1Ј-H), 5.84 (dd,

J = 8.5, 7.5 Hz, 1 H, 1-H), 5.17 (t, J = 8.5 Hz, 1 H, 2-H), 4.06 (dd,

J = 8.5, 2.5 Hz, 1 H, 3-H), 3.92 (m, 2 H, 5-H, 6a-H), 3.68 (dd, J

= 8.5, 2.5 Hz, 1 H, 4-H), 3.62 (dd, J = 13.0, 10.5 Hz, 1 H, 6b-H),

2.0 (m, 1 H, OH), 1.46 (s, 3 H, Me), 1.44 (s, 6 H, 2ϫ Me), 1.40 (s,

3 H, Me) ppm.

Experimental Section

General Remarks: All reactions were performed in dry flasks fitted

with glass stoppers or rubber septa under a positive pressure of

Ar unless otherwise noted. Air- and moisture-sensitive liquids and

solutions were transferred by syringe or stainless steel cannula. Op-

tical rotations were determined for solutions in chloroform. Flash

column chromatography was performed with 230–400 mesh silica

gel. Thin-layer chromatography was conducted on Kieselgel

60 F254 (Merck). Spots were observed first under UV irradiation

(254 nm) and then by charring with a solution of aqueous H₂SO₄

(20%, 200 mL) in AcOH (800 mL). Anhydrous MgSO₄or Na₂SO₄

were used to dry organic solutions during workup, and evaporation

of the solvents was performed under vacuum with a rotary evapo-

rator. Solvents were dried and purified by standard methods. Un-

less otherwise noted ¹H and ¹³C NMR spectra were recorded in

CDCl₃at 300 MHz and 50 MHz, respectively. Chemical shifts are

expressed in parts per million (δ scale) downfield from tetramethyl-

silane and are referenced to residual protium in the NMR solvent

(CHCl₃: δ = 7.25 ppm). The numbering pattern used for the ¹H

NMR is illustrated below.

(E)- and (Z)-1-Chloro-1,2-dideoxy-3,4:5,7-di-O-isopropylidene-D-ga-

lacto-hept-1-enitol (16b):^[23]This compound was prepared from the

hemiketal 15b (3.58 g, 13.8 mmol) by the General Procedure. Purifi-

cation (hexane/EtOAc 7:3) afforded (E)-16b (1.14 g, 28%) followed

by (Z)-16b (1.10 g, 27%). For (E)-16b: [α]²_D⁵= –14.0 (c = 1.2,

CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 6.27 (dd, J = 13.5,

1.1 Hz, 1 H, 1Ј-H), 5.98 (dd, J = 13.5, 9.0 Hz, 1 H, 1-H), 4.31 (ddd,

J = 7.5, 5.5, 1.1 Hz, 1 H, 2-H), 4.07 (dd, J = 12.5, 1.5 Hz, 1 H, 6a-

H), 3.96 (dd, J = 8.5, 7.5 Hz, 1 H, 3-H), 3.84 (dd, J = 12.5, 2.0 Hz,

1 H, 6b-H), 3.80 (dd, J = 8.0, 1.5 Hz, 1 H, 4-H), 3.59 (m, 1 H, 5-

H), 2.6 (d, J = 11.0 Hz, 1 H, OH), 1.46 (s, 3 H, Me), 1.40 (s, 9 H,

3ϫ Me) ppm. For (Z)-16b: [α]²_D⁵= +38.2 (c = 1.8, CHCl₃). ¹H

NMR (200 MHz, CDCl₃): δ = 6.20 (dd, J = 7.5, 1.1 Hz, 1 H, 1Ј-

H), 5.81 (dd, J = 9.0, 7.5 Hz, 1 H, 1-H), 4.85 (ddd, J = 1.1, 7.5,

9.0 Hz, 2-H), 4.07 (dd, J = 12.5, 1.1 Hz, 1 H, 6a-H), 3.96 (dd, J =

8.5, 7.5 Hz, 1 H, 3-H), 3.86 (dd, J = 1.1, 8.5 Hz, 4-H), 3.84 (dd, J

= 2.0, 12.5 Hz, 1 H, 6b-H), 3.62 (m, 1 H, 5-H), 2.67 (d, J = 11.0 Hz,

1 H, OH), 1.46 (s, 3 H, Me), 1.42 (s, 6 H, 2ϫ Me), 1.40 (s, 3 H,

Me) ppm.

General Procedure C. Dehydrohalogenation of 1-Chloroenitols: A

solution of the appropriate 1-chloroenitol in dry THF

(10 mLmmol^–1) was cooled to –78 °C and then treated with nBuLi

(4 equiv.). After stirring for 2 h, and once TLC analyses showed

total disappearance of the starting material, the reaction mixture

was quenched with a saturated aqueous solution of NH₄Cl. After

partitioning between water and diethyl ether, the organic layer was

dried with MgSO₄and concentrated. The ensuing residue was then

purified by flash chromatography.

General Procedure A. Pd/C-Catalysed Hydrogenolysis of Benzyl

Glycosides in a Parr Apparatus: Argon was passed through a solu-

tion of the compound (ca. 50–75 μmol) in EtOH/Et₃N (7:1, v/v,

10 mL) for 5 min, after which a catalytic amount of Pd/C (20 mg,

10 wt.-% Pd on C) was added. The reaction vessel was placed under

vacuum and subsequently ventilated with hydrogen gas. This cycle

was repeated one more time, after which the vessel was placed un-

der hydrogen gas (25 psi) and mechanically shaken for 3 h. The Pd/

C was removed by filtration through a Celite path, followed by

thorough rinsing of the filter cake with EtOH. The filtrate was

concentrated under vacuum and the residue was used in the next

step without further purification.

1,2-Dideoxy-3,4:5,7-bis-O-(1-methylethylidene)-D-gluco-hept-1-

ynitol (17a):^[23]This compound was prepared from the 1-chloroeni-

tol 16a (4.5 g, 15.4 mmol) by the General Procedure. Purification

(hexane/EtOAc 7:3) afforded 17a (2.89 g, 73%). [α]²_D⁵= –49.1 (c =

General Procedure B. Wittig Treatment of Hemiketals with (Chloro-

methylene)triphenylphosphorane: A cooled (0 °C) solution of (chlo-

romethylene)triphenylphosphonium chloride (3 mmol) in anhy-

drous THF (10 mL) was treated with nBuLi (3 mmol, 1.6 m in hex-

anes). The resulting solution was stirred for 15 min and a solution

of the corresponding hemiketal (1 mmol) and DMPU (3 mmol) in

THF (5 mL) was added dropwise. The temperature was allowed to

rise slowly to room temp. and the reaction mixture was then stirred

for a further 2 h at room temp. The reaction mixture was then

poured into water (20 mL), extracted with CH₂Cl₂(3ϫ15 mL),

dried and concentrated under reduced pressure. Purification of the

residue by column chromatography gave the corresponding chlo-

roolefins as 1:1 mixtures of Z/E isomers.

1

1.6, CHCl₃). H NMR (200 MHz, CDCl₃): δ = 4.74 (dd, J = 7.5,

2.0 Hz, 1 H, 2-H), 4.36 (dd, J = 7.5, 2.0 Hz, 1 H, 3-H), 3.91 (dd,

J = 12.0, 5.5 Hz, 1 H, 5-H), 3.83 (ddd, J = 9.5, 9.0, 5.5 Hz, 1 H,

6a-H), 3.63 (dd, J = 12.0, 9.0 Hz, 1 H, 6b-H), 3.75 (dd, J = 9.5,

3.5 Hz, 1 H, 4-H), 2.52 (d, J = 2.0 Hz, 1 H, 1Ј-H), 2.30 (m, 1 H,

OH), 1.50 (s, 3 H, Me), 1.46 (s, 3 H, Me), 1.42 (s, 3 H, Me), 1.38

(s, 3 H, Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 110.9, 99.1,

81.2, 80.8, 74.6, 71.8, 64.3, 63.6, 27.9, 19.5 ppm. C₁₃H₂₀O₅

(256.29): calcd. C 60.92, H 7.87; found C 60.71, H 7.88.

1,2-Dideoxy-3,4:5,7-bis-O-(1-methylethylidene)-D-galacto-hept-1-

ynitol (17b):^[23]This compound was prepared from the 1-chloroen-

itol 16b (2.2 g, 7.6 mmol) by the General Procedure. Purification

(hexane/EtOAc 7:3) afforded 17b (1.45 g, 75%). [α]²_D⁵= –46.1 (c =

(E)- and (Z)-1-Chloro-1,2-dideoxy-3,4:5,7-di-O-isopropylidene-D-

1

gluco-hept-1-enitol (16a):^[23]This compound was prepared from the

hemiketal 15a (7.9 g, 30.4 mmol) by the General Procedure. Purifi-

cation (hexane/EtOAc 7:3) afforded (E)-16a (2.25 g, 25%) followed

by (Z)-16a (2.24 g, 25%). For (E)-16a: [α]²_D⁵= –55.1 (c = 1.0,

CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 6.30 (dd, J = 13.5,

1.0 Hz, 1 H, 1Ј-H), 5.95 (dd, J = 13.5, 6.5 Hz, 1 H, 1-H), 4.57 (ddd,

J = 8.1, 6.5, 1.0 Hz, 1 H, 2-H), 4.04 (dd, J = 8.1, 3.5 Hz, 1 H, 3-

H), 3.90 (m, 2 H, 5-H, 6a-H), 3.77 (dd, J = 9.0, 3.5 Hz, 1 H, 4-H),

3.61 (dd, J = 13.0, 10.5 Hz, 1 H, 6b-H), 2.5 (m, 1 H, OH), 1.45 (s,

1.6, CHCl₃). H NMR (200 MHz, CDCl₃): δ = 4.59 (dd, J = 4.5,

2.5 Hz, 1 H, 2-H), 4.34 (dd, J = 8.5, 2.5 Hz, 1 H, 3-H), 4.05 (dd,

J = 12.5, 2.5 Hz, 1 H, 6a-H), 3.60 (m, 1 H, 5-H), 3.84 (dd, J =

12.5, 2.5 Hz, 1 H, 6b-H), 3.70 (dd, J = 8.5, 1.5 Hz, 1 H, 4-H), 2.51

(d, J = 2.5 Hz, 1 H, 1Ј-H), 2.64 (d, J = 11 Hz, 1 H, OH), 1.54 (s,

3 H, Me), 1.44 (s, 3 H, Me), 1.42 (s, 3 H, Me), 1.41 (s, 3 H,

Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 111.4, 99.1, 82.5, 79.6,

74.0, 73.6, 68.5, 65.5, 62.9, 29.3, 27.4, 26.1, 18.5 ppm. C₁₃H₂₀O₅

(256.29): calcd. C 60.92, H 7.87; found C 60.81, H 7.79.

Eur. J. Org. Chem. 2011, 7116–7132

www.eurjoc.org

7123

A. M. Gómez, C. Uriel, M. D. Company, J. C. López

FULL PAPER

General Procedure D. PDC/Ac₂O (Oxidation): A solution of the

corresponding alcohol (1 mmol) in CH₂Cl₂(3 mL) was added to

a stirred, freshly prepared mixture of PDC (0.7 mmol) and acetic

anhydride (3 mmol) in CH₂Cl₂(3 mL). The mixture was stirred for

16 h at room temperature, after which Et₂O was added and the

crude reaction product was filtered though a short pad of celite.

The colourless eluate was concentrated to dryness under vacuum

and the residue was purified by flash chromatography.

69.2, 66.2, 64.2, 26.9, 26.3, 22.9 ppm. C₁₄H₂₀O₄(252.31): calcd. C

66.65, H 7.99; found C 66.38, H 7.75.

1,2-Dideoxy-3,4:5,7-bis-O-(1-methylethylidene)-6-methylene-D-

galacto-hept-1-ynitol (20b): This compound was prepared from the

ketone 19b (1.23 g, 4.85 mmol) by the General Procedure. Purifica-

tion (hexane/EtOAc 9:1) afforded the enyne 20b (831 mg, 68%).

1

[α]²_D⁵= +29.4 (c = 0.8, CHCl₃). H NMR (300 MHz, CDCl₃): δ =

5.18 (s, 1 H, 5Јa-H), 5.02 (s, 1 H, 5Јb-H), 4.76 (dd, J = 6.8, 2.1 Hz,

1 H, 2-H), 4.30 (m, 4 H), 2.54 (d, J = 2.1 Hz, 1 H, 1Ј-H), 1.54 (s,

3 H, Me), 1.47 (s, 3 H, Me), 1.44 (s, 3 H, Me), 1.39 (s, 3 H,

Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 141.6, 111.3, 109.7,

99.5, 82.4, 82.2, 73.9, 71.7, 67.6, 64.2, 27.3, 26.9, 26.2, 22.1 ppm.

C₁₄H₂₀O₄(252.31): calcd. C 66.65, H 7.99; found C 66.43, H 7.83.

1,2-Dideoxy-3,4:5,7-bis-O-(1-methylethylidene)-6-oxo-gluco-hept-

1-ynitol (18a): This compound was prepared from the hept-1-ynitol

17a (2.80 g, 10.9 mmol) by the General Procedure. Purification

(hexane/EtOAc 9:1) afforded the ketone 18a (2.19 g, 83%). [α]²_D⁵

=

–193.9 (c = 1.0, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 4.73

(dd, J = 2.1, 7.0 Hz, 1 H, 2-H), 4.50 (m, 1 H), 4.31 (m, 2 H), 4.05

(d, J = 16.8 Hz, 1 H, 6a-H), 2.54 (d, J = 2.1 Hz, 1 H, 1-H), 1.45

(s, 9 H, 3 ϫ Me), 1.40 (s, 3 H, Me) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 206.1, 111.3, 100.8, 80.4, 79.6, 75.0, 73.1, 66.9, 65.9,

26.4, 26.3, 24.1, 23.4 ppm. C₁₃H₁₈O₅(254.12): calcd. C 61.40, H

7.14; found C 61.26, H 7.16.

General Procedure F. Bu₃SnH-Induced Radical Cyclization: A thor-

oughly degassed solution of the appropriate acyclic derivative in

toluene (0.02 m) was heated at 80 °C under argon. A solution of

Bu₃SnH (1.5 equiv.) and AIBN (0.3 equiv.) in toluene (3 mL) was

then added by syringe-driven pump over 12 h. After cooling, the

reaction mixture was concentrated in vacuo and the residue was

purified by flash chromatography.

1,2-Dideoxy-3,4:5,7-bis-O-(1-methylethylidene)-6-oxo-D-gluco-hept-

1-ynitol (18b): This compound was prepared from the hept-1-ynitol

17b (1.45 g, 5.7 mmol) by the General Procedure. Purification (hex-

ane/EtOAc 9:1) afforded the ketone 18b (1.2 g, 72%). [α]²_D⁵= +114.1

2,3:4,6-Bis-O-(1-methylethylidene)-1-(tributylstannyl)methylene-

5a-carba-

D

-glucopyranose (22a) and 2,3:4,6-Bis-O-(1-methylethyl-

-glucopyranose (23a):

idene)-1-(tributylstannyl)methylene-5a-carba-

D

1

(c = 0.9, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 4.87 (dd, J =

These compounds were prepared from the enyne 20a (450 mg,

1.8 mmol) by the General Procedure for cyclization. Purification

(hexane/EtOAc 98:2) afforded the corresponding acyclic alkenyl-

stannanes 21a (176 mg, 18%), followed by 5a-carba-l-glucopyr-

anose and the 5a-carba-d-glucopyranose derivatives 23a (48 mg,

5%) and 22a (548 mg, 56%) respectively.

2.2, 6.8 Hz, 1 H, 2-H), 4.50 (dd, J = 3.5, 6.8 Hz, 1 H, 3-H), 4.44

(d, J = 3.5 Hz, 1 H, 4-H), 4.30 (dd, J = 16.9, 1.3 Hz, 1 H, 6a-H),

4.04 (d, J = 16.9 Hz, 1 H, 6b-H), 2.53 (d, J = 2.2 Hz, 1 H, 1Ј-H),

1.52 (s, 3 H, Me), 1.48 (s, 6 H, 2ϫ Me), 1.41 (s, 3 H, Me) ppm.

¹³C NMR (50 MHz, CDCl₃): δ = 206.0, 106.9, 96.6, 76.1, 75.4,

70.3, 69.2, 62.4, 61.5, 22.0, 21.8, 19.6, 18.9 ppm. C₁₃H₁₈O₅

(254.12): calcd. C 61.40, H 7.14; found C 61.31, H 7.09.

1

22a: [α]²_D⁵= +8.2 (c = 1.0, CHCl₃). H NMR (500 MHz, CDCl₃):

δ = 5.60 (t, J = 1.7 Hz, 1 H, 1Ј-H), 3.99 (dd, J = 9.2, 1.7 Hz, 1 H,

2-H), 3.87 (t, J = 9.2 Hz, 1 H, 4-H), 3.76 (dd, J = 11.2, 4.6 Hz, 1

H, 6a-H), 3.69 (t, J = 11.2 Hz, 1 H, 6b-H), 3.41 (t, J = 9.2 Hz, 1 H,

3-H), 2.15 (dd, J = 13.9, 4.1 Hz, 1 H, 5Јa-H), 1.95 (t, J = 13.9 Hz, 1

H, 5Јb-H), 1.75 (m, 1 H, 5-H), 1.52 (s, 3 H, Me), 1.47 (s, 3 H, Me),

1.45 (m, 6 H, CH₂), 1.44 (s, 6 H, 2ϫ Me), 1.29 (sext, J = 7.2 Hz,

6 H, CH₂Me), 0.88 (m, 6 H, CH₂Sn), 0.87 (t, J = 7.2 Hz, 9 H,

Me) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 147.8, 115.7, 110.6,

99.0, 81.6, 80.6, 73.8, 64.3, 39.5, 36.7, 29.6, 29.2, 27.3 (ϫ3), 27.0,

26.8, 19.2 (ϫ3), 13.7 (ϫ3), 11.8 (ϫ3) ppm. C₂₆H₄₆O₄Sn (543.37):

calcd. C 57.69, H 8.56; found C 57.43, H 8.37.

General Procedure E. Peterson Olefination: A solution of the appro-

priate ketone in anhydrous diethyl ether (10 mLmmol^–1) was co-

oled to 0 °C under argon. (Trimethylsilylmethyl)magnesium chlo-

ride (4 equiv., 1 m solution in diethyl ether) was added dropwise.

The resulting slightly yellow solution was then stirred at room

temp. for 6 h. The reaction mixture was quenched with ammonium

chloride and diluted with diethyl ether. The organic layer was sepa-

rated and the aqueous layer was extracted three times with diethyl

ether. The combined ethereal extracts were washed with saturated

aqueous sodium chloride solution, dried (MgSO₄) and concen-

trated under reduced pressure. The residue was then subjected to

flash chromatography (hexane/EtOAc 95:5).

23a: [α]²_D⁵= –72.4 (c = 0.16, CHCl₃). ¹H NMR (200 MHz, CDCl₃):

δ = 5.68 (s, 1 H, 1Ј-H), 4.13 (m, 2 H, 2-H, 4-H), 3.78 (m, 2 H, 3-

H, 6a-H), 3.47 (dd, J = 11.5, 8.7 Hz, 1 H, 6b-H), 2.57 (dt, J = 14.2,

2.0 Hz, 1 H, 5Јa-H), 2.35 (m, 1 H, 5-H), 2.02 (dd, J = 14.1, 3.6 Hz,

1 H, 5Јb-H), 1.35 (s, 3 H, Me), 1.33 (s, 3 H, Me), 1.29 (m, 6 H,

CH₂), 1.28 (s, 3 H, Me), 1.27 (s, 3 H, Me), 1.24 (m, 6 H, CH₂Me),

0.89 (m, 6 H, CH₂Sn), 0.87 (t, J = 7.2 Hz, 9 H, Me) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 148.0, 133.4, 109.3, 99.0, 81.3, 79.5,

75.1, 68.2, 36.4, 34.9, 29.6, 29.4, 28.9 (ϫ3), 27.0 (ϫ3), 26.5, 13.5

(ϫ3), 10.2 (ϫ3) ppm. C₂₆H₄₆O₄Sn (543.37): calcd. C 57.69, H 8.56;

found C 57.51, H 8.40.

The resulting silyl derivative, dissolved in dry THF

(10 mLmmol^–1), was treated at 0 °C with an excess of potassium

hydride (freed of the mineral oil by hexane washings) dispersed in

THF (2 mL). The mixture was stirred for 20 min and then carefully

quenched by addition of MeOH. Once the hydrogen evolution was

complete, diethyl ether was added and the resulting solution was

treated with water. The aqueous layer was extracted three times

with diethyl ether. The combined organic extracts were dried and

concentrated under reduced pressure. The residue was then purified

by flash chromatography.

1,2-Dideoxy-3,4:5,7-bis-O-(1-methylethylidene)-6-methylene-

D

-

2,3:4,6-Bis-O-(1-methylethylidene)-1-(tributylstannyl)methylene-

gluco-hept-1-ynitol (20a): This compound was prepared from the

ketone 18a (1.92 g, 7.6 mmol) by the General Procedure. Purifica-

tion (hexane/EtOAc 9:1) afforded the enyne 20a (1.34 g, 70 %).

5a-carba-D-galactopyranose (22b): This compound was prepared

from the enyne 20b (150 mg, 0.6 mmol) by the General Procedure.

Purification (hexane/EtOAc 98:2) afforded the carbagalacto deriva-

[α]²_D⁵= –142.7 (c = 1.0, CHCl₃). H NMR (300 MHz, CDCl₃): δ =

tive 22b (196 mg, 71%). [α]²_D⁵= +10.5 (c = 1.6, CHCl₃). H NMR

1

5.04 (s, 1 H, 5Јa-H), 5.02 (s, 1 H, 5Јb-H), 4.49 (dd, J = 7.3, 2.1 Hz,

1 H, 2-H), 4.30 (m, 4 H), 2.54 (d, J = 2.1 Hz, 1 H, 1Ј-H), 1.50 (s,

3 H, Me), 1.43 (s, 6 H, 2ϫ Me), 1.40 (s, 3 H, Me) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 142.3, 110.0, 108.5, 99.9, 82.1, 82.0, 74.5,

(400 MHz, CDCl₃): δ = 5.53 (br. s, 1 H, 1Ј-H), 4.51 (m, 2 H, 2-H,

4-H), 4.15 (dd, J = 16.2, 2.8 Hz, 1 H, 6a-H), 3.58 (d, J = 12.2 Hz,

1 H, 6b-H), 3.31 (dd, J = 9.9, 2.7 Hz, 1 H, 3-H), 2.95 (t, J =

14.3 Hz, 1 H, 5Јa-H), 2.15 (dd, J = 14.3, 5.3 Hz, 1 H, 5Јb-H), 1.49

7124

www.eurjoc.org

Eur. J. Org. Chem. 2011, 7116–7132

5a-Carbahexopyranoses by 6-endo-trig Radical Cyclizations

(s, 3 H, Me), 1.46 (m, 7 H, CH₂, 5-H), 1.45 (s, 6 H, 2ϫ Me), 1.42 2.01 (s, 3 H, Me), 1.99 (s, 3 H, Me), 1.56 (m, 1 H) ppm. C₁₇H₂₄O₁₀

(s, 3 H, Me), 1.27 (sext, J = 7.2 Hz, 6 H, CH₂Me), 0.88 (m, 6 H, (388.14): calcd. C 52.57, H 6.23; found C 52.18, H 6.17.

CH₂Sn), 0.87 (t, J = 7.2 Hz, 9 H, Me) ppm. ¹³C NMR (125 MHz,

1,2,3,4,6-Penta-O-acetyl-5a-carba-β-D-galactopyranose (28b): Com-

CDCl₃): δ = 151.0, 118.0, 110.0, 98.6, 82.8, 76.1, 66.5, 63.6, 37.1,

35.2, 29.6, 29.3, 27.4 (ϫ3), 27.2, 26.6 (ϫ3), 18.7, 13.7 (ϫ3), 11.8

(ϫ3) ppm. C₂₆H₄₆O₄Sn (543.37): calcd. C 57.69, H 8.56; found C

57.37, H 8.43.

pound 27b (20 mg, 0.05 mmol) was subjected to the General Pro-

cedure to give compound 28b (18 mg, 82%) after silica gel column

chromatography (hexane/EtOAc 7:3). [α]²_D⁵= –3.4 (c = 0.4, CHCl₃).

¹H NMR (300 MHz, CDCl₃): δ = 5.50 (t, J = 3.0 Hz, 1 H, 4-H),

5.40 (t, J = 10.0 Hz, 1 H, 2-H), 4.94 (ddd, J = 11.5, 10.0, 5.0 Hz,

1 H, 1-H), 4.87 (dd, J = 3.1, 10.0 Hz, 1 H, 3-H), 3.99 (dd, J = 8.7,

11.0 Hz, 1 H, 6a-H), 3.86 (dd, J = 6.1, 11.0 Hz, 1 H, 6b-H), 2.17

(m, 1 H, 5-H), 2.14 (s, 3 H, Me), 2.05 (s, 6 H, 2ϫ Me), 2.03 (s, 3

H, Me), 1.99 (s, 3 H, Me), 1.98 (m, 1 H, 5Јa-H), 1.67 (q, J =

12.8 Hz, 1 H, 5Јb-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 170.7,

170.1, 170.0, (ϫ2), 169.9, 72.0, 71.3, 70.7, 67.5, 62.7, 34.7, 27.0,

20.9 (ϫ 2), 20.7 (ϫ 2), 20.6 ppm. C₁₇H₂₄O₁₀(388.14): calcd. C

52.57, H 6.23; found C 52.41, H 6.08.

General Procedure G. Hydrolysis Under Acidic Conditions Followed

by Acetylation: A stirred solution of the appropriate vinyltrialkyltin

derivative (1 mmol) in THF/H₂O (15 mL, 2:1, v/v) was treated with

acetic acid (15 mL), heated in an oil bath for 5 h and then concen-

trated in vacuo. The residue was then taken up in pyridine and

treated with Ac₂O for 24 h. The solvent was removed in vacuo and

the residue was purified by flash chromatography.

2,3,4,6-Tetra-O-acetyl-1-deoxy-1-methylene-5a-carba-D-gluco-

pyranose (27a): This compound was prepared from the vinyltrialk-

yltin derivative 22a (300 mg, 0.55 mmol) by the General Procedure.

Purification (hexane/EtOAc 7:3) afforded 27a (118 mg, 63 %).

[α]²_D⁵= +3.2 (c = 0.9, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ =

5.37 (brd, J = 9.7 Hz, 1 H, 2-H), 5.14 (t, J = 9.7 Hz, 1 H, 4-H),

4.98 (m, 3 H, 3-H, 1Ј-H), 4.08 (dd, J = 11.3, 5.0 Hz, 1 H, 6a-H),

3.97 (dd, J = 11.3, 3.3 Hz, 1 H, 6b-H), 2.51 (dd, J = 11.5, 4.8 Hz,

1 H, 5Јa-H), 2.20 (m, 1 H, 5-H), 2.18 (t, J = 11.5 Hz, 1 H, 5Јb-H),

2.14 (s, 3 H, Me), 2.10 (s, 3 H, Me), 2.05 (s, 3 H, Me), 2.03 (s, 3

H, Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 170.8, 170.0, 169.9,

169.6, 139.3, 110.1, 75.0, 72.9, 71.5, 63.2, 40.2, 33.0, 20.7, 20.6

(ϫ3) ppm. C₁₆H₂₂O₈(342,13): calcd. C 56.14, H 6.48; found C

55.89, H 6.31.

General Procedure I. LiAlH₄Reduction Followed by Silylation: A

solution of the appropriate hemiketal (1 mmol) in anhydrous THF

(1 mLmmol^–1) was added under argon to a cooled (0 °C) suspen-

sion of LiAlH₄(3 mmol) in dry THF (1 mLmmol^–1). The resulting

mixture was stirred at room temp. for 2 h, diluted with diethyl ether

and quenched by dropwise addition of saturated aqueous sodium

sulfate (Na₂SO₄). After the mixture had been stirred for 20 min,

the resulting white solid was filtered through a pad of celite, and

the solvent was evaporated under reduced pressure. The residue

was then subjected to flash chromatography (hexane/EtOAc 7:3).

A solution of the thus-obtained diol in CH₂Cl₂(5 mLmmol^–1) was

treated with Et₃N (1.5 mmol), tert-butyldimethylchlorosilane

(3 equiv.) and 4-DMAP (0.1 mmol) and then stirred at room tem-

perature until all the starting material had been consumed (usually

10–12 h). The reaction mixture was quenched with aqueous sodium

hydrogencarbonate and diluted with CH₂Cl₂. The organic layer was

separated and the aqueous layer was extracted with CH₂Cl₂. The

combined organic extracts were washed with water and saturated

aqueous sodium chloride solution, dried (MgSO₄) and concen-

trated under reduced pressure. The residue was then subjected to

flash chromatography (hexane/EtOAc 8:2).

2,3,4,6-Tetra-O-acetyl-1-deoxy-1-methylene-5a-carba-D-galacto-

pyranose (27b): This compound was prepared from the vinyltrialk-

yltin derivative 22b (52 mg, 0.11 mmol) by the General Procedure.

Purification (hexane/EtOAc 7:3) afforded 27b (22 mg, 72%). [α]²_D⁵

= +1.6 (c = 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 5.58

(m, 2 H, 2-H, 4-H), 4.99 (s, 1 H, 1Јa-H), 4.88 (s, 1 H, 1Јb-H), 4.85

(dd, J = 10.6, 7.4 Hz, 1 H, 3-H), 3.94 (m, 2 H, 2ϫ6-H), 2.30 (m,

2 H), 2.13 (m, 1 H), 2.12 (s, 6 H, 2ϫ Me), 2.04 (s, 3 H, Me), 2.00

(s, 3 H, Me) ppm. ¹³CNMR (300 MHz, CDCl₃): δ = 170.8, 170.1,

170.0, 169.9, 140.0, 109.7, 73.3, 71.3, 68.5, 63.0, 38.4, 31.2, 29.7,

20.8, 20.7, 20.6 ppm. C₁₆H₂₂O₈(342,13): calcd. C 56.14, H 6.48;

found C 56.01, H 6.23.

1-(tert-Butyldimethylsilyl)-2,3:4,6-di-O-isopropylidene-5-oxo-D-gluc-

itol (33): This compound was prepared from the hemiketal 15a

(13.4 g, 38 mmol) by General Procedure I. Purification afforded the

glucitol derivative (7.8 g, 55% overall). [α]²_D⁵= –10.6 (c = 1.0,

CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 4.29 (m, 1 H, 6a-H),

4.13 (dd, J = 7.5, 4.8 Hz, 1 H, 4-H), 3.77 (m, 6 H), 3.27 (d, J =

1.6 Hz, 1 H, OH), 1.47 (s, 3 H, Me), 1.43 (s, 3 H, Me), 1.41 (s, 3

H, Me), 1.40 (s, 3 H, Me), 0.91 (s, 9 H, 3ϫ Me), 0.10 (s, 6 H, 2ϫ

Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 109.3, 98.9, 79.2, 76.6,

73.9, 65.0, 64.0, 63.8, 38.5, 27.1, 26.8, 26.0 (ϫ2), 25.7 (ϫ3), 19.4,

18.5 ppm. EI-MS: m/z = 376.0 [M]⁺. C₁₈H₃₆O₆Si (376.56): calcd.

C 57.41, H 9.64; found C 57.36, H 9.43.

General Procedure H. Ozonolysis Followed by Stereoselective Re-

duction and Acetylation: Ozone was bubbled through a cold

(–78 °C) solution of the appropriate “carbasugar exo-glycal” 27

(0.5 mmol) in MeOH (5 mL) until the solution appeared faintly

blue. A stream of argon was then bubbled through the reaction

mixture until the blue colour had disappeared. Dimethyl sulfide

(0.3 mL) was added dropwise to this solution and the reaction mix-

ture was allowed to warm to room temperature and stirred for 1 h.

Concentration in vacuo provided the crude ketone as a colourless

oil. This was dissolved in THF (3 mL) and cooled (0 °C), and

BH₃·SMe₂was added dropwise. The mixture was allowed to warm

to room temp. for 1 h and MeOH was added to destroy excess

hydride.

This material (7.5 g, 20.71 mmol) was subjected to the General Pro-

cedure for oxidation with PDC/Ac₂O (Procedure C) to give the

ketone 33 (6.2 g, 81%) after silica gel column chromatography (hex-

ane/EtOAc 8:2). [α]²_D⁵= –88.2 (c = 0.4, CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 4.47 (dd, J = 7.2, 2.3 Hz, 1 H, 3-H), 4.34

(d, J = 16.0 Hz, 1 H, 6a-H), 4.30 (br. s, 1 H, 4-H), 4.21 (dt, J =

7.2, 4.2 Hz, 1 H, 2-H), 4.02 (d, J = 16.0 Hz, 1 H, 6b-H), 3.91 (dd,

J = 10.4, 4.2 Hz, 1 H, 1a-H), 3.68 (dd, J = 10.4, 7.2 Hz, 1 H, 1b-

H), 1.52 (s, 3 H, Me), 1.50 (s, 3 H, Me), 1.45 (s, 3 H, Me), 1.41 (s,

3 H, Me), 0.90 (s, 9 H, 3ϫ Me), 0.10 (s, 6 H, 2ϫ Me) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 207.3, 110.0, 100.8, 77.6, 75.6, 74.3,

67.0, 64.3, 30.3, 27.3, 26.3, 25.9 (ϫ2), 25.6 (ϫ3), 24.0, 23.5 ppm.

1,2,3,4,6-Penta-O-acetyl-5a-carba-β-D-glucopyranose (28a): Com-

pound 27a (41 mg, 0.12 mmol) was subjected to General Procedure

G followed by standard acetylation to give compound 28a (27 mg,

58%) after silica gel column chromatography (hexane/EtOAc 7:3).

1

[α]²_D⁵= +12.2 (c = 1.0, CHCl₃). H NMR (300 MHz, CDCl₃): δ =

5.17 (t, J = 9.4 Hz, 1 H, 3-H), 5.11 (t, J = 9.4 Hz, 1 H, 2-H), 5.03

(dd, J = 10.6, 9.4 Hz, 1 H, 4-H), 4.93 (m, 1 H, 1-H), 4.08 (dd, J =

11.3, 5.0 Hz, 1 H, 6a-H), 3.95 (dd, J = 11.3, 3.2 Hz, 1 H, 6b-H),

2.20 (m, 1 H), 2.06 (m, 1 H), 2.05 (s, 3 H, Me), 2.02 (s, 3 H, Me),

Eur. J. Org. Chem. 2011, 7116–7132

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7125

A. M. Gómez, C. Uriel, M. D. Company, J. C. López

FULL PAPER

EI-MS: m/z = 374.0 [M]⁺. C₁₈H₃₄O₆Si (374.54): calcd. C 57.72, H

9.15; found C 57.59, H 9.03.

nitrile (50 mLmmol^–1) was treated with pyridine (3 mmol) and

phenyl chlorothionoformate (3 mmol). The reaction mixture was

heated at 85 °C for 1 h, after which it was cooled to room tempera-

ture and then quenched with water. The solution was diluted with

CH₂Cl₂and washed successively with HCl (10 %), saturated

NaHCO₃and brine. The organic phase was dried, filtered and con-

centrated under vacuum.

1-(tert-Butyldimethylsilyl)-5-deoxy-2,3:4,6-di-O-isopropylidene-5-

methylene-D-glucitol (34): This compound was prepared from the

ketone 33 (6.2 g, 16.5 mmol) by the General Procedure. Purification

(hexane/EtOAc 9:1) afforded 34 (3.7 g, 81%). [α]²_D⁵= –49.3 (c = 0.4,

CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 5.05 (dd, J = 12.5,

1.6 Hz, 2 H, 5Ј-H), 4.32 (m, 5 H), 3.84 (dd, J = 10.6, 4.0 Hz, 1 H,

6a-H), 3.76 (dd, J = 10.6, 4.0 Hz, 1 H, 6b-H), 1.45 (s, 3 H, Me),

1.44 (s, 6 H, 2ϫ Me), 1.42 (s, 3 H, Me), 0.92 (s, 9 H, 3ϫ Me), 0.10

(s, 6 H, 2 ϫ Me) ppm. ¹³CNMR (75 MHz, CDCl₃): δ = 143.3,

109.7, 108.3, 99.9, 79.2, 76.1, 69.8, 64.6, 64.3, 27.5, 26.9, 26.7, 26.0

(ϫ3), 23.0, 18.5 (ϫ2) ppm. C₁₉H₃₆O₅Si (372,57): calcd. C 61.25, H

9.74; found C 60.91, H 9.53.

1-Deoxy-2,3,4,6-tetra-O-acetyl-5a-carba-D-glucopyranose (41): This

compound was prepared from the xanthate 29 (97 mg, 0.29 mmol)

by the General Procedure for HBu₃Sn-induced radical cyclization

(Procedure F). Purification of the crude material by flash

chromatography (hexane/EtOAc 8:2) afforded the cyclohexane de-

1

rivative 37 (45 mg, 64%). [α]²_D⁵= –5.6 (c = 0.7, CHCl₃). H NMR

(CDCl₃, 300 MHz): δ = 3.65 (m, 5 H), 2.1 (m, 5 H), 1.44 (s, 6 H,

2ϫ Me), 1.43 (s, 6 H, 2ϫ Me) ppm. ¹³C NMR (CDCl₃, 75 MHz):

δ = 110.6, 99.0, 78.3, 75.4, 73.8, 64.4, 39.4, 30.6, 29.7, 27.4, 26.8,

22.3, 19.3 ppm. EI-MS: m/z = 243.0 [M + H]⁺.

General Procedure J. Unmasking of tert-Butyldimethylsilyl Ethers:

A stirred solution of the appropriate silyl derivative (1 mmol) in

THF (15 mL) was treated with TBAF (3 mmol) and then stirred

for 4 h, after which the reaction mixture was washed consecutively

with saturated aqueous sodium hydrogencarbonate solution and

water. The organic layer was then dried and concentrated, and the

residue was purified by flash chromatography (hexane/EtOAc 7:3).

For the purpose of correct characterization, the tricyclic derivative

37 (45 mg, 0.18 mmol) was uneventfully converted into its tetra-

acetate by General Procedure F (flash chromatography, hexane/

EtOAc 9:1) to give 41 (40 mg, 67%). [α]²_D⁵= +18.6 (c = 0.14,

1

CHCl₃). H NMR (CDCl₃, 300 MHz): δ = 5.07 (t, J = 9.6 Hz, 1

5-Deoxy-2,3:4,6-di-O-isopropylidene-5-methylene-D-glucitol (35):

H, 3-H), 4.96 (t, J = 9.6 Hz, 1 H, 4-H), 4.88 (m, 1 H, 2-H), 4.05

(dd, J = 9.0, 5.0 Hz, 1 H, 6a-H), 3.94 (dd, J = 9.0, 3.4 Hz, 1 H,

6b-H), 2.15 (m, 1 H, 5Ј-H), 2.02 (s, 3 H, Me), 2.01 (s, 3 H, Me),

2.00 (s, 6 H, 2ϫ Me), 1.96 (m, 1 H, 5-H), 1.92–1.87 (m, 3 H, 5Ј-

H, 1-H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ = 171.0, 170.2, 170.1,

170.0, 75.0, 72.2, 71.8, 63.6, 43.9, 40.2, 29.7, 28.4, 23.5, 20.7, 15.2.

API-ES (positive): m/z = 683 [2 M + Na]⁺, 353 [M + Na]⁺.

C₁₅H₂₂O₈(330.33): calcd. C 54.54, H 6.71; found C 54.47, H 6.62.

This compound was prepared from 34 (3.7 g, 9.9 mmol) by General

Procedure J. Purification afforded the derivative 35 (2.0 g, 79%).

1

[α]²_D⁵= –10.9 (c = 1.0, CHCl₃). H NMR (CDCl₃, 300 MHz): δ =

5.08 (dd, J = 12.6, 1.3 Hz, 2 H, 5Ј-H), 4.52 (br. s, 1 H, 4-H), 4.25

(m, 4 H), 3.82 (dd, J = 10.2, 4.0 Hz, 1 H, 1a-H), 3.66 (dd, J = 10.2,

4.0 Hz, 1 H, 1b-H), 2.61 (br. s, 1 H, OH), 1.44 (s, 6 H, 2ϫ Me), 1.43

(s, 3 H, Me), 1.40 (s, 3 H, Me) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ

= 142.5, 109.6, 109.3, 100.2, 78.3, 77.6, 69.5, 64.6, 62.8, 27.4, 26.9

(ϫ2), 23.2. API-ES (positive): m/z = 539 [2M + Na]⁺, 281 [M +

Na]⁺. C₁₃H₂₂O₅(258.31): calcd. C 60.45, H 8.58; found C 60.37,

H 8.59.

1-Deoxy-2,3:4,6-di-O-isopropylidene-1-methyl-5a-carba-β-D-gluco-

pyranoside (38): This compound was prepared from the xanthate

30 (150 mg, 0.37 mmol) by the General Procedure for HBu₃Sn-in-

duced radical cyclization (Procedure F). Purification of the crude

material by flash chromatography (hexane/EtOAc 98:2) afforded

the cyclohexane derivative 38 (59 mg, 64%). [α]²_D⁵= –8.4 (c = 0.2,

5-Deoxy-2,3:4,6-di-O-isopropylidene-1-methyl-5-methylene-D-gluc-

itol (36): This compound was prepared from the alcohol 35 (90 mg,

0.35 mmol) by General Procedure D. The resulting aldehyde was

immediately dissolved in dry Et₂O and then treated at 0 °C with

methylmagnesium iodide (0.90 mmol, 3.3 mL, 3.0 m solution in di-

ethyl ether). The reaction mixture was allowed to reach room tem-

perature and then stirred for 6 h. Diethyl ether was then added and

the resulting solution was treated with aqueous NH₄Cl. The aque-

ous layer was extracted three times with diethyl ether. The com-

bined organic extracts were dried and concentrated under reduced

pressure. The residue was then purified by flash chromatography

to provide the alcohol 36 as a 1:1 mixture of diastereomers. ¹³C

NMR (CDCl₃, 75 MHz): δ = 143.1, 142.6, 109.3, 109.2, 108.7,

108.6, 100.5, 100.2, 80.4, 80.1, 79.1, 77.9, 69.8, 68.3, 67.6, 64.7,

64.6, 64.5, 27.7, 27.4, 26.9, 23.3, 23.2, 20.3, 19.3 ppm. API-ES (pos-

itive): m/z = 295 [M + Na]⁺.

1

CHCl₃). H NMR (CDCl₃, 300 MHz): δ = 3.71 (m, 3 H), 3.44 (t,

J = 9.0 Hz, 1 H, 3-H), 3.04 (dd, J = 8.8, 9.0 Hz, 1 H, 2-H), 1.88

(m, 1 H, 1-H), 1.74 (m, 1 H, 5-H), 1.60 (m, 1 H, 5Јa-H), 1.53 (m,

1 H, 5Јb-H), 1.48 (s, 3 H, Me), 1.41 (s, 12 H, 3ϫ Me) ppm. ¹³C

NMR (CDCl₃, 50 MHz): δ = 110.9, 99.9, 83.7, 73.9, 64.4, 39.0,

34.2, 32.5, 27.8 (ϫ2), 26.8 (ϫ2), 17.5, 13.6 ppm. API-ES (positive):

m/z = 535 [2M + Na]⁺, 279 [M + Na]⁺. C₁₄H₂₄O₄(256.34): calcd.

C 65.60, H 9.44; found C 65.46, H 9.52.

(Z)-1-Chloro-1,2,6-trideoxy-3,4:5,7-di-O-isopropylidene-D-gluco-

hept-1-enitol (39): This compound was prepared from the thiocar-

bonate (Z)-31 (110 mg, 0.259 mmol) by General Procedure F. The

crude material was purified by flash chromatography (hexane/

EtOAc 8:2 to 7:3) to give 39 (47 mg, 65%) followed by the alcohol

(Z)-16 (24 mg, 31%). For 39: [α]²_D⁵= +8.7 (c = 0.25, CHCl₃). ¹H

NMR (CDCl₃, 300 MHz): δ = 6.26 (d, J = 7.3 Hz, 1 H, 1Ј-H), 5.84

(dd, J = 8.4, 7.3 Hz, 1 H, 1-H), 4.98 (t, J = 8.4 Hz, 1 H, 2-H),

3.95–4.02 (m, 2 H), 3.86 (ddd, J = 11.9, 5.7, 1.5 Hz, 1 H, 6a-H),

3.72 (dd, J = 8.4, 4.7 Hz, 1 H, 3-H), 1.80 (m, 1 H, 5a-H), 1.48 (s,

3 H), 1.45 (s, 3 H), 1.44 (s, 3 H), 1.42 (s, 3 H), 1.37 (m, 1 H, 5b-

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 129.7, 122.7, 110.2, 98.7,

83.1, 71.8, 68.5, 59.6, 29.9, 27.3, 27.0, 26.8, 19.3 ppm. API-ES (pos-

itive): m/z = 299.0 [M + Na]⁺. C₁₃H₂₁ClO₄(276.76): calcd. C 56.42,

H 7.65; found C 56.30, H 7.58.

General Procedure K. Preparation of the Methyl Xanthates 29–30:

NaH (1.5 mmol) was added under argon to a cooled (0 °C) solution

of the appropriate alcohol (1 mmol) in dry THF. The resulting sus-

pension was stirred for 15 min, after which CS₂(2 mmol) was

added. Stirring was continued for 15 min and the reaction mixture

was then treated with MeI (5 mmol) and stirred at room tempera-

ture for an additional 1 h. After the starting materials had been

consumed, the mixture was diluted with Et₂O and washed with

brine. The organic layer was then dried, concentrated in vacuo,

subjected to fast silica gel column chromatography and used with-

out further characterization.

1,2,6-Trideoxy-3,4:5,7-di-O-isopropylidene-D-gluco-hept-1-

General Procedure L. Preparation of the Phenyl Thiocarbonates 31, ynitol (40): This compound was prepared from the thiocarbonate

32 and 63: A solution of the appropriate alcohol (1 mmol) in aceto- 32 (100 mg, 0.25 mmol) by General Procedure F. The crude mate-

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Eur. J. Org. Chem. 2011, 7116–7132

5a-Carbahexopyranoses by 6-endo-trig Radical Cyclizations

rial was purified by flash chromatography (hexane/EtOAc 9:1 3) to

give compound 40 (20 mg, 33%) as a colourless oil. [α]²_D⁵= +14.5

(c = 0.15, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ = 4.52 (dd, J =

= 7.2 Hz, 1 H, 2-H), 4.90 (d, J = 7.2 Hz, 1 H, 3-H), 4.29 (d, J =

16 Hz, 1 H, 6a-H), 4.12 (s, 1 H, 4-H), 3.98 (d, J = 16 Hz, 1 H, 6b-

H), 1.50 (s, 3 H, Me), 1.48 (s, 3 H, Me), 1.43 (s, 3 H, Me), 1.38 (s,

7.3, 2.1 Hz, 1 H, 2-H), 4.08 (dd, J = 7.3, 5.4 Hz, 1 H, 3-H), 4.00 3 H, Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 207.8, 129.4,

(ddd, J = 11.9, 5.6, 2.7 Hz, 1 H, 4-H), 3.98 (ddd, J = 12.1, 6.3,

2.7 Hz, 1 H, 6a-H), 3.88 (ddd, J = 11.8, 5.6, 1.7 Hz, 1 H, 6b-H),

2.53 (d, J = 2.1 Hz, 1 H, 1Ј-H), 1.86 (ddt, J = 17.8, 12.1, 5.6 Hz, 1

H, 5a-H), 1.50 (s, 3 H, Me), 1.48 (s, 3 H, Me), 1.43 (s, 3 H, Me),

1.42 (s, 3 H, Me), 1.39 (m, 1 H, 5b-H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 113.3, 98.7, 83.8, 77.4, 74.8, 68.9, 66.2, 59.4, 29.6,

26.8, 26.7, 26.3, 19.3 ppm. API-ES (positive): m/z = 263.0 [M +

Na]⁺. C₁₃H₂₀O₄(240.30): calcd. C 64.98, H 8.39; found C 64.93,

H 8.33.

121.2, 109.9, 101.0, 75.5, 74.6, 73.3, 67.0, 26.5, 25.6, 24.1,

23.9 ppm. EI-MS: m/z = 290.0 [M]⁺. C₁₃H₁₉ClO₅(290.74): calcd.

C 53.70, H 6.59; found C 53.54, H 6.28.

(Z)- and (E)-1-Chloro-1,2-dideoxy-3,4:5,7-di-O-isopropylidene-6-

(trimethylsilyl)methyl-D-manno-hept-1-enitol (48): A solution of the

ketone 47 (520 mg, 1.79 mmol) in anhydrous diethyl ether (5 mL)

was cooled under argon to 0 °C. [(Trimethylsilyl)methyl]magnesium

chloride (7.16 mmol, 7.16 mL, 1 m solution in diethyl ether) was

added dropwise. The resulting slightly yellow solution was then

stirred at room temp. for 6 h. The reaction mixture was quenched

with ammonium chloride and diluted with diethyl ether. The or-

ganic layer was separated; the aqueous phase was extracted three

times with diethyl ether. The combined ethereal extracts were

washed with saturated aqueous sodium chloride solution, dried

(MgSO₄) and concentrated under reduced pressure. The residue

was then subjected to flash chromatography (hexane/EtOAc 95:5)

to afford (E)-48 (350 mg, 47%), followed by (Z)-48 (107 mg, 20%).

Although both isomers were uneventfully used as a mixture in the

synthetic route, they were separated for the purpose of correct char-

(E)- and (Z)-1-Chloro-1,2-dideoxy-3,4:5,7-di-O-isopropylidene-D-

manno-hept-1-enitol (46): This compound was prepared from the

hemiketal 45 (1.02 g, 3.92 mmol) by the General Procedure. Purifi-

cation (hexane/EtOAc 7:3) afforded (E)-46 (560 mg, 49%), followed

by (Z)-46 (556 mg, 48%). Although both isomers were uneventfully

used as a mixture in the synthetic route, they were separated for

the purpose of correct characterization. For (E)-46: [α]²_D⁵= –79.0

(c = 0.1, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 6.24 (d, J =

13.4 Hz, 1 H, 1Ј-H), 6.13 (dd, J = 13.4, 10.9 Hz, 1 H, 1-H), 4.67

(dd, J = 10.8, 8.7 Hz, 1 H, 2-H), 4.47 (dd, J = 8.7, 1.6 Hz, 1 H, 3-

H), 3.88 (m, 2 H, 5-H, 6a-H), 3.61 (m, 1 H, 4-H), 3.56 (dd, J =

8.7, 1.6 Hz, 1 H, 6b-H), 2.62 (br. s, 1 H, OH), 1.51 (s, 3 H, Me),

1.45 (s, 3 H, Me), 1.40 (s, 3 H, Me), 1.34 (s, 3 H, Me) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 124.7, 111.8, 105.1, 94.0, 70.3, 69.0,

68.3, 60.2, 58.0, 24.0, 21.8, 21.3, 14.5 ppm. EI-MS: m/z = 292.0

[M]⁺. C₁₃H₂₁ClO₅(292.11): calcd. C 53.33, H 7.23; found C 53.19,

H 7.18. For (Z)-46: [α]²_D⁵= –10.1 (c = 0.14, CHCl₃). ¹H NMR

(200 MHz, CDCl₃): δ = 6.19 (dd, J = 7.2 Hz, 1 H, 1Ј-H), 6.06 (t,

J = 7.2 Hz, 1 H, 1-H), 5.23 (dd, J = 7.1, 1.2 Hz, 1 H, 2-H), 4.62

(dd, J = 7.1, 1.2 Hz, 1 H, 3-H), 3.88 (m, 2 H, 5-H, 6a-H), 3.61 (m,

1 H, 4-H), 3.44 (dd, J = 8.7, 1.9 Hz, 1 H, 6b-H), 2.58 (d, J =

4.8 Hz, 1 H, OH), 1.52 (s, 3 H, Me), 1.40 (s, 3 H, Me), 1.39 (s, 3

H, Me), 1.38 (s, 3 H, Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ =

129.1, 120.2, 109.5, 98.4, 74.7, 73.4, 72.7, 64.7, 62.2, 28.4, 26.2,

25.7, 18.9 ppm. EI-MS: m/z = 292.0 [M]⁺. C₁₃H₂₁ClO₅(292.11):

calcd. C 53.33, H 7.23; found C 53.11, H 7.05.

1

acterization. For (E)-48: [α]²_D⁵= –79.1 (c = 0.1, CHCl₃). H NMR

(200 MHz, CDCl₃): δ = 6.22 (d, J = 13.4 Hz, 1 H, 1Ј-H), 6.12 (t, J

= 13.2 Hz, 1 H, 1-H), 4.78 (t, J = 13.2 Hz, 1 H, 2-H), 4.76 (d, J =

13.2 Hz, 1 H, 3-H), 3.92 (s, 1 H, 6a-H), 3.62 (s, 1 H, 6b-H), 1.58

(s, 3 H, Me), 1.47 (s, 3 H, Me), 1.41 (s, 3 H, Me), 1.39 (s, 3 H,

Me), 1.10 (d, J = 12.0 Hz, 1 H, CH₂Si), 0.68 (d, J = 12.0 Hz, 1 H,

CH₂Si), 0.03 (s, 9 H, SiMe₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

= 129.6, 122.9, 110.4, 98.5, 76.2, 75.4, 74.2, 73.2, 71.2, 29.4, 26.2,

25.7, 24.6, 18.5, 0.7 (ϫ3) ppm. EI-MS: m/z = 378.0 [M]⁺. For (Z)-

48: [α]²_D⁵= –77.0 (c = 0.34, CHCl₃). H NMR (200 MHz, CDCl₃):

1

δ = 6.18 (dd, J = 7.4 Hz, 1 H, 1Ј-H), 6.02 (t, J = 7.4 Hz, 1 H, 1-

H), 5.19 (t, J = 7.4 Hz, 1 H, 2-H), 4.78 (dd, J = 7.3 Hz, 1 H, 3-H),

4.16 (s, 1 H, 4-H), 3.62 (s, 1 H, 6a-H), 3.39 (s, 1 H, 6b-H), 1.55 (s,

3 H, Me), 1.43 (s, 3 H, Me), 1.37 (s, 3 H, Me), 1.36 (s, 3 H, Me),

1.01 (d, J = 12.8 Hz, 1 H, CH₂Si), 0.68 (d, J = 12.0 Hz, 1 H,

CH₂Si), 0.03 (s, 9 H, SiMe₃) ppm. ¹³C NMR (50 MHz, CDCl₃): δ

= 129.8, 120.0, 110.0, 98.4, 76.4, 75.4, 73.0, 70.4, 70.1, 29.3, 26.1,

25.6, 24.6, 18.4, 0.5 (ϫ 3) ppm. EI-MS (positive): m/z = 378.0

[M]⁺.

1,2-Dideoxy-3,4:5,7-bis-O-(1-methylethylidene)-6-oxo-D-manno-

hept-1-ynitol (47): Dry DMSO (0.54 mL, 7.66 mmol) was slowly

added under an inert atmosphere to a cold (–78 °C) stirred solution

of oxalyl chloride (965 μL, 5.75 mmol) in dry CH₂Cl₂(5 mL). After

the evolution of gas had ceased, the alcohol 46 (1.12 g, 3.83 mmol)

dissolved in dry CH₂Cl₂(10 mL) was slowly added. After 30 min

Et₃N was added and the reaction mixture was allowed to warm to

room temperature. After 45 min, the mixture was quenched by the

addition of water. The organic phase was separated and the aque-

ous phase was washed with CH₂Cl₂. The collected organic phases

were then washed with brine. The resulting organic solution was

dried, concentrated and purified by flash chromatography (hexane/

EtOAc 80:20) to give compound 47 (520 mg, 48%). For (E)-47:

1,2-Dideoxy-3,4:5,7-bis-O-(1-methylethylidene)-6-(trimethylsilyl)-

methyl-manno-hept-1-ynitol (49): This compound was prepared

from the 1-chloroenitol 48 (457 mg, 1.2 mmol) by General Pro-

cedure D. Purification (hexane/EtOAc 7:3) afforded 49 (280 mg,

68%). [α]²_D⁵= –25.5 (c = 0.9, CHCl₃). ¹H NMR (200 MHz, CDCl₃):

δ = 4.86 (dd, J = 6.7, 2.2 Hz, 1 H, 2-H), 4.52 (dd, J = 8.5, 2.5 Hz,

1 H, 3-H), 3.88 (d, J = 2.0 Hz, 1 H, 7a-H), 3.66 (m, 2 H, 2 6-H),

2.53 (d, J = 2.2 Hz, 1 H, 1Ј-H), 1.49 (s, 3 H, Me), 1.38 (s, 6 H, 2ϫ

Me), 1.25 (s, 3 H, Me), 0.98 (d, J = 12.0 Hz, 1 H, CH₂Si), 0.62 (d,

J = 12.0 Hz, 1 H, CH₂Si), 0.07 (s, 9 H, SiMe₃) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 111.5, 98.5, 78.3, 76.4, 74.8, 73.9, 69.9, 69.7,

67.5, 29.0, 25.9, 25.5, 23.7, 17.9, 0.3 (ϫ3) ppm.

1

[α]²_D⁵= –157.1 (c = 0.2, CHCl₃). H NMR (200 MHz, CDCl₃): δ =

6.22 (d, J = 13.2 Hz, 1 H, 1Ј-H), 6.12 (t, J = 13.2 Hz, 1 H, 1-H),

4.8 (t, J = 13.2 Hz, 1 H, 2-H), 4.62 (m, 1 H, 3-H), 4.28 (d, J =

15.0 Hz, 1 H, 6a-H), 4.21 (s, 1 H, 4-H), 3.96 (d, J = 15.0 Hz, 1 H,

6b-H), 1.49 (s, 3 H, Me), 1.48 (s, 3 H, Me), 1.46 (s, 3 H, Me), 1.35

1,2-Dideoxy-6-methylene-3,4:5,7-bis-O-(1-methylethylidene)-D-

manno-hept-1-ynitol (42): This compound was prepared from the

(s, 3 H, Me) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 207.9, 129.4, alkyne 49 (280 mg, 0.82 mmol) by the General Procedure. Purifica-

123.3, 110.0, 101.0, 76.8, 74.3, 73.3, 67.0, 26.5, 25.7, 24.1, tion (hexane/EtOAc 95:5) afforded the enyne 42 (132 mg, 63%).

23.9 ppm. EI-MS: m/z = 290.0 [M]⁺. C₁₃H₁₉ClO₅(290.74): calcd. [α]²_D⁵= –40.0 (c = 0.92, CHCl₃). H NMR (300 MHz, CDCl₃): δ =

1

C 53.70, H 6.59; found C 53.49, H 6.38. For (Z)-46: [α]²_D⁵= –197.2

4.97 (s, 2 H, 5Ј-H), 4.84 (dd, J = 6.0, 2.1 Hz, 1 H, 4-H), 4.70 (m,

1 H, 2-H), 4.37 (t, J = 6.0 Hz, 1 H, 3-H), 4.27 (dd, J = 14.2, 1.4 Hz,

(c = 0.18, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 6.24 (dd, J =

7.2, 1.0 Hz, 1 H, 1Ј-H), 6.09 (t, J = 7.2 Hz, 1 H, 1-H), 5.29 (dd, J 1 H), 2.54 (d, J = 2.2 Hz, 1 H), 1.56 (s, 3 H, Me), 1.46 (s, 3 H,

Eur. J. Org. Chem. 2011, 7116–7132

www.eurjoc.org

7127

A. M. Gómez, C. Uriel, M. D. Company, J. C. López

3,4:5,7-Tetra-O-benzyl-1,2-dideoxy-6-methylene- -manno-hept-1-yn-

FULL PAPER

Me), 1.42 (s, 3 H, Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ =

142.8, 110.8, 108.6, 100.1, 79.4, 78.0, 71.6, 67.4, 64.2, 53.4, 27.3,

27.0, 26.0, 23.0 ppm. C₁₄H₂₀O₄(252.31): calcd. C 66.65, H 7.99;

found C 66.38, H 7.75.

D

itol (43): This compound was prepared from the ketone 53 (520 mg,

0.97 mmol) by the General Procedure. Purification (hexane/EtOAc

8:2) afforded the enyne 43 (350 mg, 80%). [α]²_D⁵= –59.6 (c = 0.3,

CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.27 (m, 20 H, Ph), 5.30

(s, 2 H, 5Ј-H), 4.82 (d, J = 11.2 Hz, 1 H, CH₂Ph), 4.66 (d, J =

11.6 Hz, 1 H, CH₂Ph), 4.61 (d, J = 11.2 Hz, 1 H, CH₂Ph), 4.50 (d,

J = 12.0 Hz, 1 H, CH₂Ph), 4.36 (m, 3 H, CH₂Ph), 4.29 (dd, J =

5.6, J = 2.0 Hz, 1 H, 2-H), 4.19 (m, 2 H, 4-H, CH₂Ph), 3.94 (d, J

= 12.0 Hz, 1 H, 6a-H), 2.85 (d, J = 12.0 Hz, 1 H, 6b-H), 3.77 (t, J

= 5.6 Hz, 1 H, 3-H), 2.40 (d, J = 2.0 Hz, 1 H, 1Ј- H) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 142.5, 138.5, 138.3, 138.2, 137.8,

128.3 (ϫ4), 128.2 (ϫ4), 128.0 (ϫ2), 127.9 (ϫ2), 127.8 (ϫ2), 127.5

(ϫ4), 127.4 (ϫ2), 116.8, 81.8, 81.0, 75.3, 75.1, 72.7, 71.2, 70.6,

70.3, 69.8 ppm. API-ES (positive): m/z = 555.0 [M + Na]⁺.

C₁₃H₂₂O₅(258.31): calcd. C 60.45, H 8.58; found C 60.27, H 8.33.

(E)- and (Z)-3,4:5,7-tetra-O-benzyl-1-chloro-1,2-dideoxy-D-manno-

hept-1-enitol (51): This compound was prepared from the hemiketal

50 (5.4 g, 10 mmol) by the General Procedure. Purification (hexane/

EtOAc, 7:3) afforded (E)-51 (2.1 g, 35%), followed by (Z)-51 (1.6 g,

28%). Although both isomers were uneventfully used as a mixture

in the synthetic route, they were separated for the purpose of cor-

1

rect characterization. For (E)-51: H NMR (200 MHz, CDCl₃): δ

= 7.26 (m, 20 H, Ph), 6.31 (d, J = 13.4 Hz, 1 H, 1Ј-H), 6.00 (dd, J

= 13.4, 8.5 Hz, 1 H, 1-H), 4.58 (d, J = 11.5 Hz, 1 H, CH₂Ph), 4.56

(m, 6 H, 3 CH₂Ph), 4.22 (d, J = 11.5 Hz, 1 H, CH₂Ph), 4.12 (dd,

J = 13.4, 8.5 Hz, 1 H, 2-H), 4.00 (m, 1 H, 5-H), 3.86 (m, 2 H, 3-

H, 4-H), 3.66 (dd, J = 9.6, 3.3 Hz, 1 H, 6a-H), 3.58 (dd, J = 9.6,

5.4 Hz, 1 H, 6b-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 138.2,

137.9, 137.8, 137.7, 132.0, 128.5 (ϫ2), 128.4 (ϫ2), 128.3 (ϫ2),

128.2 (ϫ4), 127.8 (ϫ4), 127.7 (ϫ2), 127.6 (ϫ2), 127.5 (ϫ2), 122.3,

80.3, 78.3, 77.9, 74.6, 73.9, 73.2, 71.0, 70.2, 69.9 ppm. API-ES (pos-

itive): m/z = 595.0 [M + Na]⁺. For (Z)-51: ¹H NMR (200 MHz,

CDCl₃): δ = 7.21–7.05 (m, 20 H), 6.37 (dd, J = 7.3 Hz, 1 H, 1Ј-H),

5.96 (dd, J = 9.1, 7.3 Hz, 1 H, 1-H), 4.82 (dd, J = 9.3, 6.1 Hz, 1

H, 2-H), 4.62 (m, 7 H, CH₂Ph), 4.30 (d, J = 12.4 Hz, 1 H, CH₂Ph),

4.01 (m, 1 H, 5-H), 3.98 (dd, J = 6.5, 3.1 Hz, 1 H, 3-H), 3.82 (dd,

J = 7.7, 3.5 Hz, 1 H, 4-H), 3.63 (m, 2 H, 6-H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 138.2, 137.9, 137.8, 137.7, 132.0, 128.5 (ϫ2),

128.4 (ϫ3), 128.3 (ϫ4), 128.2 (ϫ5), 127.8 (ϫ5), 127.7 (ϫ4), 127.6

(ϫ3), 127.5 (ϫ2), 122.3, 80.4, 78.7, 74.2, 74.0, 73.9, 73.3, 71.1,

70.4, 70.2 ppm. EI-MS: m/z = 292.0 [M]⁺.

3,4:5,7-Tetra-O-acetyl-1,2-dideoxy-6-methylene-D-gluco-hept-1-

ynitol (44): This compound was prepared from the enyne 20a

(180 mg, 0.71 mmol) by General Procedure F. Purification (hexane/

EtOAc 9:1) afforded 44 (900 mg, 68%). [α]²_D⁵= +46.9 (c = 1.0,

1

CHCl₃). H NMR (200 MHz, CDCl₃): δ = 5.67 (d, J = 3.6 Hz, 1

H, 4-H), 5.57 (dd, J = 2.0, 7.0 Hz, 1 H, 2-H), 5.48 (dd, J = 3.6,

7.0 Hz, 1 H, 3-H), 5.31 (d, J = 14.0 Hz, 2 H, 5Ј-H), 4.71 (d, J =

13.2 Hz, 1 H, 6a-H), 4.57 (d, J = 13.2 Hz, 1 H, 6b-H), 2.56 (d, J

= 2.0 Hz, 1 H, 1Ј-H), 2.13 (s, 6 H, 2ϫ Ac), 2.12 (s, 3 H, Ac), 2.09

(s, 3 H, Ac) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 170.6, 169.5

(ϫ2), 139.11, 118.3, 111.7, 81.6, 80.9, 76.3, 72.1, 72.0, 64.4, 62.9,

29.0, 20.9, 20.8, 20.6 ppm. API-ES (positive): m/z = 363.2 [M +

Na]⁺. C₁₆H₂₀O₈(340,33): calcd. C 56.47, H 5.92; found C 56.33,

H 5.78.

2,3:4,6-Bis-O-(1-methylethylidene)-1-(tributylstannylmethylene)-

3,4:5,7-Tetra-O-benzyl-1,2-dideoxy-D-manno-hept-1-ynitol (52):

5a-carba-

D

-mannopyranose (54) and 2,3:4,6-Bis-O-(1-methylethyl-

-mannopyranose (55):

This compound was prepared from the 1-chloroenitol 51 (1.5 g,

2.6 mmol) by the General Procedure. Purification (hexane/EtOAc

7:3) afforded 52 (900 mg, 68%). [α]²_D⁵= –12.3 (c = 0.5, CHCl₃). ¹H

NMR (200 MHz, CDCl₃): δ = 7.20 (m, 20 H, Ph), 4.93 (d, J =

11.0 Hz, 1 H, CH₂Ph), 4.79 (d, J = 11.0 Hz, 1 H, CH₂Ph), 4.66 (d,

J = 11.0 Hz, 1 H, CH₂Ph), 4.40 (m, 4 H, CH₂Ph), 4.32 (d, J =

11.4 Hz, 1 H, CH₂Ph), 3.97 (dd, J = 7.0, 2.3 Hz, 1 H, 3-H), 3.94

(m, 1 H, 5-H), 3.75 (dd, J = 8.2, 2.8 Hz, 1 H, 4-H), 3.52 (m, 2 H,

6-H), 2.50 (d, J = 2.0 Hz, 1 H, 1Ј-H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 138.1 (ϫ2), 137.9, 137.4, 128.4 (ϫ 2), 128.3 (ϫ4),

128.2 (ϫ4), 128.1 (ϫ4), 127.9, 127.8, 127.7, 127.6, 127.5, 81.3, 80.1,

77.8, 75.7, 74.7, 73.9, 73.3, 71.0, 70.4, 69.8, 68.7 ppm. API-ES (pos-

itive): m/z = 559.0 [M + Na]⁺. C₃₅H₃₆O₅(536.26): calcd. C 78.33,

H 6.76; found C 78.19, H 6.53.

idene)-1-(tributylstannylmethylene)-5a-carba-

L

These compounds were prepared from the enyne 42 (450 mg,

1.8 mmol) by the General Procedure for cyclization. Purification

(hexane/EtOAc 98:2) afforded the methylenecyclohexanes 55

(39 mg, 4%) and 54 (587 mg, 60%).

1

Compound 55 (unassigned 4:1 Z/E mixture of stannanes): H NMR

(300 MHz, CDCl₃): δ = 6.12 (s, 1 H, 1Ј-H), 4.58 (d, J = 4.3 Hz, 1

H), 4.12 (dd, J = 4.3, 5.9 Hz, 1 H), 3.75 (m, 2 H), 3.62 (t, J =

8.5 Hz, 1 H), 2.12 (m, 2 H), 1.91 (dd, J = 10.4, 2.9 Hz, 1 H), 1.33

(s, 3 H), 1.31 (s, 3 H), 1.30 (m, 6 H), 1.29 (s, 3 H), 1.27 (s, 3 H),

1.24 (m, 6 H), 0.89 (m, 6 H), 0.87 (t, J = 7.2 Hz, 9 H) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 148.2, 133.4, 109.3, 98.9, 81.3, 79.2,

74.7, 64.0, 35.7, 32.3, 29.5, 28.9 (ϫ3) 28.2, 27.1 ( ϫ3), 27.0, 26.1,

13.5 (ϫ ·3), 10.0 (ϫ 3) ppm. API-ES (positive): m/z = 544

[M + H]⁺.

3,4:5,7-Tetra-O-benzyl-1,2-dideoxy-6-oxo-D-manno-hept-1-ynitol

(53): A stirred solution of hept-1-ynitol 52 (4 g, 7.48 mmol) in dry

CH₂Cl₂(50 mL) was treated with Dess–Martin periodinane (3.48 g,

8.23 mmol) and then stirred for 1 h, after which the reaction mix-

ture was washed consecutively with saturated aqueous sodium hy-

drogen carbonate solution and water. The organic layer was then

dried and concentrated, and the residue was purified by flash

chromatography (hexane/EtOAc 8:2) to afford the ketone 53 (3.4 g,

85%). [α]²_D⁵= –98.4 (c = 0.3, CHCl₃). ¹H NMR (200 MHz, CDCl₃):

δ = 7.27 (m, 20 H, Ph), 4.93 (d, J = 10.8 Hz, 1 H, CH₂Ph), 4.84

(d, J = 11.4 Hz, 1 H, CH₂Ph), 4.51–4.15 (m, 11 H), 4.14 (dd, J =

8.1, 2.7 Hz, 1 H), 2.59 (d, J = 2.1 Hz, 1 H, 1-H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 208.4, 137.5, 137.4, 137.1, 136.9, 128.5 (ϫ4),

128.4 (ϫ4), 128.3 (ϫ2), 128.2 (ϫ2), 128.1 (ϫ3), 127.9 (ϫ3), 127.8

(ϫ2), 83.4, 81.5, 81.0, 75.8, 75.3, 74.6, 74.4, 73.2, 70.5, 67.9 ppm.

Compound 54 (one unassigned isomer): ¹H NMR (CDC1₃,

300 MHz): δ = 5.91 (s, 1 H, 1Ј-H), 4.43 (d, J = 7.2 Hz, 1 H, 2-H);

4.00 (m, 3 H), 3.54 (dd, J = 2.2, 11.5 Hz, 1 H, 6b-H), 2.61 (m, 2

H, 5Јa-H, 5-H), 2.02 (m, 1 H, 5Јb-H), 1.35 (s, 3 H, Me), 1.33 (s, 3

H, Me), 1.29 (m, 6 H, CH₂), 1.28 (s, 3 H, Me), 1.27 (s, 3 H, Me),

1.24 (m, 6 H, CH₂CH₃), 0.89 (m, 6 H, CH₂Sn), 0.87 (m, 9 H,

CH₂CH₃) ppm. ¹³C NMR: δ = (50 MHz, CDCl₃): 148.0, 133.4,

109.3, 99.0, 81.3, 79.5, 75.1, 68.2, 36.4, 34.9, 29.6, 29.4, 28.9 (ϫ3),

27.0 (ϫ3), 26.5, 13.5 (ϫ3), 10.2 (ϫ3) ppm. API-ES (positive): m/z

= 544 [M + H]⁺. C₂₆H₄₆O₄Sn (543.37): calcd. C 57.69, H 8.56;

found C 57.39, H 8.23.

Methylene-2,3:4,6-tetra-O-benzyl-5a-carba-

D-mannopyranose (56)

and Methylene-2,3:4,6-tetra-O-benzyl-5a-carba-1-mannopyranose

API-ES (positive): m/z = 557.0 [M + Na]⁺. C₃₅H₃₄O₅(534.24): (57): These compounds were prepared from the enyne 43 (450 mg,

calcd. C 78.63, H 6.41; found C 78.51, H 6.38. 0.8 mmol) by the General Procedure for cyclization. Purification

7128

www.eurjoc.org

Eur. J. Org. Chem. 2011, 7116–7132

5a-Carbahexopyranoses by 6-endo-trig Radical Cyclizations

(hexane/EtOAc 98:2) afforded the corresponding stannylated meth-

ylenecyclohexanes, which were dissolved in THF/H₂O (5 mL,

2:1, v/v), treated with acetic acid (2 mL) and then heated in an oil

bath for 10 h. After concentration in vacuo, the residue was puri-

fied by flash chromatography (hexane/EtOAc 9:1) to give an in-

separable mixture (1.6:1, 341 mg, 80 %) of the stereoisomers 56

(major compound) and 57 (minor isomer). For the major isomer:

¹H NMR (300 MHz, CDCl₃): δ = 7.32 (m, 20 H, Ph), 5.03 (s, 1 H,

1Ј-H), 4.99 (d, 1 H, CH₂Ph), 4.85 (s, 1 H, 1Ј-H), 4.50 (m, 7 H,

CH₂Ph), 4.07 (d, J = 3.0 Hz, 1 H, 2-H), 3.99 (dd, J = 10.1, 9.4 Hz,

1 H, 4-H), 3.61 (m, 2 H, 6-H), 3.47 (dd, J = 9.4, 3.2 Hz, 1 H, 3-

H), 2.42 (t, J = 13.0 Hz, 1 H, 5Јa-H), 2.31 (dd, J = 13.4, 4.7 Hz, 1

H, 5Јb-H), 1.78 (m, 1 H, 5-H) ppm. For the minor isomer: ¹H

NMR (300 MHz, CDCl₃): δ = 7.15 (m, 20 H, Ph), 5.10 (s, 1 H, 1Ј-

H), 4.99 (s, 1 H, 1Ј-H), 4.58 (m, 8 H, CH₂-Ph), 4.16 (m, 1 H, 2-

H), 3.87 (dd, J = 3.2, 1.8 Hz, 1 H, 4-H), 3.73 (m, 1 H, 3-H), 3.54

(dd, J = 7.9, 9.9, 6a Hz, 1 H -H), 3.35 (dd, J = 7.9, 9.8 Hz, 1 H,

6b-H), 2.40 (m, 1 H, 5-H), 2.28 (dd, J = 13.8, 4.7 Hz, 1 H, 5Јa-H),

1.78 (m, 1 H, 5Јb-H) ppm. For the mixture: ¹³C NMR (75 MHz,

CDCl₃): δ = 143.8, 139.0, 138.9, 138.6, 138.3, 128.3, 128.2, 128.2,

128.1, 128.0, 127.9, 127.7, 127.7, 127.6, 127.5, 127.5, 127.4, 127.3,

114.3, 84.8 (ϫ2), 81.7, 80.8, 78.7, 78.1 (ϫ2), 77.9 (ϫ2), 77.2, 76.9,

75.2 (ϫ2), 73.0, 72.9, 72.6, 72.5, 71.7 (ϫ2), 70.9, 70.8, 70.6, 69.7,

68.8 (ϫ2), 43.1, 37.8, 31.8, 31.5 ppm. API-ES (positive): m/z =

557.0 [M + Na]⁺. C₃₆H₃₈O₄(534.68): calcd. C 80.87, H 7.16; found

C 80.61, H 7.33.

the reaction mixture was washed consecutively with saturated aque-

ous sodium hydrogencarbonate solution and water. The organic

layer was then dried and concentrated, and the residue was purified

by flash chromatography (hexane/EtOAc 95:5) to afford the ketone

61 (8.7 g, 82%). ¹H NMR (200 MHz, CDCl₃): δ = 4.66 (dd, J =

3.0, 6.0 Hz, 1 H), 4.60 (dd, J = 1.2, 3.0 Hz, 1 H), 4.36 (dd, J = 9.0,

15.0 Hz, 1 H), 4.30 (dd, J = 2.2, 17.2 Hz, 1 H), 3.85–4.02 (m, 3 H),

1.53 (s, 3 H), 1.50 (s, 6 H), 1.37 (s, 3 H), 0.92 (s, 9 H), 0.10 (s, 6

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 207.6, 109.2, 100.9, 76.5,

75.2, 73.9, 66.8, 61.8, 26.6 (ϫ2), 23.7 (ϫ3), 22.1 (ϫ2), 18.2, –5.4

(ϫ2) ppm. EI-MS: m/z = 374.0 [M]⁺. C₁₈H₃₄O₆Si (374.54): calcd.

C 57.72, H 9.15; found C 57.60, H 9.23.

2,3:4,6-Di-O-isopropylidene-5-methylene-D-mannitol (62): This com-

pound was prepared from 61 (2.51 g, 3.3 mmol) by General Pro-

cedure E for olefination followed by General Procedure J for desyl-

ilation. Purification (hexane/EtOAc 7:3) afforded the derivative 62

1

(827 mg, 48%). [α]²_D⁵= –93.6 (c = 1.2, CHCl₃). H NMR (CDCl₃,

300 MHz): δ = 5.02 (br. s, 1 H, 5Јa-H), 5.02 (br. s, 1 H, 5Јb-H),

4.39 (d, J = 13.5 Hz, 1 H, 6a-H), 4.34–4.54 (m, 3 H, 2-H, 3-H, 4-

H), 4.27 (d, J = 13.5 Hz, 1 H, 6b-H), 3.87 (dd, J = 5.0, 12.0 Hz, 1

H, 1a-H), 3.79 (dd, J = 4.1, 12.1 Hz, 1 H), 1.60 (s, 3 H, Me), 1.51

(s, 3 H, Me), 1.47 (s, 3 H, Me), 1.43 (s, 3 H, Me) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 142.7, 108.6, 107.6, 99.8, 77.5, 76.8, 66.8,

64.2, 61.1, 26.4, 26.3, 25.2, 22.3 ppm. API-ES (positive): m/z = 539

[2M + Na]⁺, 281 [M + Na]⁺. C₁₃H₂₂O₅(258.31): calcd. C 60.45,

H 8.58; found C 60.27, H 8.33.

Methylene-2,3:4,6-tetra-O-acetyl-5a-carba-D-glucopyranose (58)

1-O-Phenyl 2,3:4,6-Di-O-isopropylidene-5-methylene-D-mannitol

and Methylene-2,3:4,6-tetra-O-acetyl-5a-carba-1-glucopyranose

(59): These compounds were prepared from the enyne 44 (100 mg,

0.18 mmol) by the General Procedure for cyclization. Purification

(hexane/EtOAc 98:2) afforded the corresponding stannylated meth-

ylenecyclohexanes, which were dissolved in THF/H₂O (3 mL,

2:1, v/v), treated with acetic acid (1 mL) and then heated in an oil

bath for 10 h. After concentration in vacuo, the residue was puri-

fied by flash chromatography (hexane/EtOAc 9:1) to give an in-

separable mixture (1.4:1, 39 mg, 64 %) of the stereoisomers 58

(major compound) and 59 (minor isomer). For the mixture. ¹H

NMR (300 MHz, CDCl₃): δ = 5.91 (m, 2 H), 5.10 (m, 7 H), 4.24

(dd, J = 5.0, 10.6 Hz, 1 H), 4.09 (dd, J = 5.0, 11.6 Hz, 1 H), 4.02

(m, 3 H), 2.52 (m, 2 H), 2.16 (m, 2 H), 2.13 (s, 3 H), 2.11 (s, 3 H),

2.09 (s, 3 H), 2.08 (s, 3 H), 2.06 (s, 3 H), 2.04 (s, 3 H), 2.04 (s, 3

H), 2.03 (s, 3 H), 2.02 (m, 1 H), 1.68 (m, 2 H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 170.8, 170.6, 170.5 (ϫ2), 170.1, 170.0, 169.9,

169.8, 139.2, 137.7, 113.2, 110.1, 74.9, 73.1, 72.9, 71.5, 71.4, 71.2,

63.2, 61.6, 40.1, 36.3, 33.0, 31.0, 27.8, 26.7, 20.8 (ϫ2), 20.7, 20.6

(ϫ2), 20.5, 20.4 (ϫ2) ppm. API-ES: 365 [M + Na]⁺. C₁₆H₂₂O₈

(342.34): calcd. C 56.13, H 6.43; found C 55.94, H 6.31.

Carbonothioate (63): This compound was prepared from the

alcohol 62 (150 mg, 0.58 mmol) by General Procedure L. Purifica-

tion (hexane/EtOAc 9:1) afforded the derivative 63 (174 mg, 76%).

[α]²_D⁵= –2.6 (c = 1.0, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ =

7.38–6.98 (m, 5 H), 4.95 (s, 1 H, 5Јa-H), 4.92 (d, J = 2.0 Hz, 1 H,

5Јb-H), 4.58 (dd, J = 6.4, 4.6 Hz, 1 H, 1a-H), 4.50 (dd, J = 6.6 Hz,

1 H, 1b-H), 4.39 (m, 1 H), 4.25 (dd, J = 13.2, 1.2 Hz, 1 H, 6a-H),

4.10 (d, J = 13.4 Hz, 1 H, 6b-H), 1.48 (s, 3 H, Me), 1.40 (s, 3 H,

Me), 1.34 (s, 3 H, Me), 1.33 (s, 3 H, Me) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 195.4, 143.5, 129.8 (ϫ2), 126.9, 122.1 (ϫ2), 115.7,

110.1, 100.3, 108.4, 77.8, 74.7, 73.6, 69.4, 64.7, 27.0, 26.9, 25.7,

22.9 ppm.

5-Deoxy-2,3:4,6-di-O-isopropylidene-5-methylene-D-mannose (64):

A stirred solution of the alcohol 62 (200 mg, 0.77 mmol) in dry

CH₂Cl₂(10 mL) was treated with Dess–Martin periodinane

(358 mg, 0.85 mmol) and then stirred for 1 h, after which the reac-

tion mixture was washed consecutively with saturated aqueous so-

dium hydrogencarbonate solution and water. The organic layer was

then dried and concentrated, and the residue was purified by flash

chromatography (hexane/EtOAc 8:2) to afford the aldehyde 64

(170 mg, 86%). ¹H NMR (CDCl₃, 300 MHz): δ = 9.64 (s, 1 H),

5.03 (s, 1 H), 4.98 (s, 1 H), 4.78 (m, 1 H), 4.42 (m, 2 H), 4.27 (d, J

= 13.4 Hz, 1 H), 4.18 (d, J = 13.1 Hz, 1 H), 1.59 (s, 3 H), 1.31 (s,

3 H), 1.39 (s, 3 H), 1.37 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 201.3, 142.0, 108.5, 111.3 (ϫ2), 100.0, 80.2, 79.9, 67.9, 64.5,

27.0, 26.4, 25.3, 21.8 ppm. This compound proved to be not very

stable and was used in the next step directly after purification.

1-tert-Butyldimethylsilyl-2,3:4,6-di-O-isopropylidene-D-mannitol

(60): This compound was prepared from the hemiketal 45 (8.7 g,

38 mmol) by General Procedure I. Purification afforded the alcohol

1

60 (12.3 g, 86% overall). [α]²_D⁵= –40.6 (c = 1.0, CHCl₃). H NMR

(300 MHz, CDCl₃): δ = 4.41 (dd, J = 3.4, 6.7 Hz, 1 H), 4.35 (dd,

J = 7.8, 15.5 Hz, 1 H), 3.77–3.96 (m, 5 H), 3.58–3.68 (m, 1 H), 1.52

(s, 6 H, Me), 1.44 (s, 3 H, Me), 1.40 (s, 3 H, Me), 0.93 (s, 9 H,

Me), 0.14 (s, 6 H, Me) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

109.0, 98.5, 77.4, 75.3, 72.4, 64.9, 63.4, 61.9, 28.5, 26.7 (ϫ2), 25.2

(ϫ3), 19.3 (ϫ2), –5.4 ppm. EI-MS: m/z = 376.0 [M]⁺. C₁₈H₃₆O₆Si

(376.56): calcd. C 57.41, H 9.64; found C 57.36, H 9.43.

(1R,2S,3R,4R)-1,2:3,4-Di-O-isopropylidene-1-methylcyclopentane-

1,2,3,4-tetraol (65): This compound was prepared from the thiocar-

bonate 63 (174 mg, 0.44 mmol) by the General Procedure for cycli-

zation. Purification (hexane/EtOAc 8:2) afforded the derivative 65

1

1-tert-Butyldimethylsilyl-2,3:4,6-di-O-isopropylidene-5-oxo-

D

-

(72 mg, 68%). H NMR (CDCl₃, 300 MHz): δ = 4.77 (t, J = 6.3,

mannitol (61): A stirred solution of the alcohol 60 (10.5 g,

1 H, 6.0 Hz, 2-H), 4.37 (d, J = 6.0 Hz, 1 H, 3-H), 3.94 (s, 1 H, 4-

28.7 mmol) in dry CH₂Cl₂(50 mL) was treated with Dess–Martin H), 3.60 (d, J = 12.0 Hz, 1 H, 6a-H), 3.40 (d, J = 12.0 Hz, 1 H,

periodinane (17 g, 40 mmol) and then stirred for 4 h, after which 6b-H), 2.38 (dd, J = 14.4, 6.3 Hz, 1 H, 1-H), 1.59 (d, J = 14.4 Hz,

Eur. J. Org. Chem. 2011, 7116–7132

www.eurjoc.org

7129

A. M. Gómez, C. Uriel, M. D. Company, J. C. López

FULL PAPER

1 H, 1Ј-H), 1.48 (s, 3 H, Me), 1.38 (s, 3 H, Me), 1.32 (s, 3 H, Me),

1

(c = 1.035, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 5.43 (t, J =

1.27 (s, 3 H, Me), 1.07 (s, 3 H, Me) ppm. ¹³C NMR (75 MHz, 12.0 Hz, 1 H, 3-H), 5.01–4.92 (m, 2 H), 4.16 (m, 1 H), 4.09 (dd, J

CDCl₃): δ = 109.8, 97.4, 87.0, 80.7, 80.1, 66.7, 39.4, 38.9, 29.1,

25.5, 23.1, 21.7, 18.6 ppm. API-MS (positive): m/z = 265 [M +

Na]⁺. C₁₃H₂₂O₄(242.15): calcd. C 64.44, H 9.15; found C 64.36,

H 9.23.

= 11.6, 3.2 Hz, 1 H, 6a-H), 3.88 (dd, J = 11.6, 3.0 Hz, 1 H, 6b-H),

2.20 (m, 1 H, 5- H), 2.05 (s, 3 H, Ac), 2.04 (s, 3 H, Ac), 2.03 (s, 3

H, Ac), 2.02 (s, 3 H, Ac), 1.99 (t, J = 1.0 Hz, 1 H, 5a-H), 1.62–

1.68 (m, 1 H, 5a-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 166.2,

165.5 (ϫ2), 165.4, 69.1, 66.8, 66.6, 58.3, 54.3, 31.1, 24.5, 16.2, 16.1

(ϫ2), 16.0 (ϫ2 ppm.) API-MS (positive): m/z = 394 [M + Na]⁺.

C₁₅H₂₁N₃O₈(371.13): calcd. C 48.52, H 5.70; found C 48.39, H

5.57.

Alcohol 66: The aldehyde 64 (150 mg, 0.58 mmol) was dissolved in

THF (10 mL), HMPA (0.5 mL, 2.9 mmol) and tBuOH (121 μL,

1.8 mmol) in a dry flask flushed with argon. A solution of SmI₂in

THF (0.1 m, 128 μL, 1.8 mmol) was added to this solution at

–78 °C. After a few minutes of stirring the reaction mixture was

allowed to warm to room temperature and then stirred for an ad-

ditional 10 min. The mixture was then quenched with saturated

aqueous NaHCO₃and diluted with ethyl acetate, and the organic

phase was washed with water. The aqueous phase was extracted

three times with ethyl acetate and the combined organic layers were

washed with brine, dried with MgSO₄and concentrated in vacuo.

Further purification was achieved by flash chromatography on sil-

ica gel (hexane/EtOAc 80:20). This afforded the cyclization product

66 (66 mg. 44%), along with the dimer 67 (50 mg, 17%).

(1R,2R,3S,6R)-6-(Acetoxymethyl)cyclohex-4-ene-1,2,3-triyl Tri-

acetate (71): PBu₃(200 μL, 0.8 mmol) was added to a solution of

69 (150 mg, 0.4 mmol) in anhydrous CH₂Cl₂(10 mL) and the mix-

ture was stirred at room temp. for 1 h. The reaction mixture was

then cooled to –78 °C, Ac₂O (20 μL, 0.9 mmol) and Et₃N (40 μL,

0.9 mmol) were added, and after the mixture had been allowed to

warm to room temperature it was stirred overnight and then con-

centrated to dryness. The resulting residue was dissolved in pyr-

idine (3.0 mL), and Ac₂O (1.5 mL) was added dropwise at 0 °C.

The mixture was stirred for 4 h at room temp. and the solvent was

removed under vacuum. The residue was purified by column

chromatography on silica gel (hexane/EtOAc 7:3) to yield the title

compound 71 (93.1 mg, 71%): [α]²_D¹= +0.19 (c = 0.30, CHCl₃). ¹H

NMR (CDCl₃, 300 MHz): δ = 5.07 (t, J = 9.6 Hz, 1 H, 3-H), 4.96

(t, J = 9.6 Hz, 1 H, 4-H), 4.88 (m, 1 H, 2-H), 4.05 (dd, J = 9.0,

5.0 Hz, 1 H, 6a-H), 3.94 (dd, J = 9.0, 3.4 Hz, 1 H, 6b-H), 2.15 (m,

1 H, 5a-H), 2.1 (s, 3 H, Ac), 2.05 (s, 6 H, 2ϫ Ac), 2.0 (s, 3 H, Ac),

1.96 (m, 1 H, 5-H), 1.87 (m, 3 H, 1-H, 5a-H) ppm. ¹³C NMR

(CDCl₃, 75 MHz): δ = 166.0, 165.5 (ϫ2), 164.2, 75.0, 72.2, 71.8,

63.6, 43.9, 40.2, 29.7, 28.4, 23.5, 20.7, 15.2 ppm. API-MS (positive):

m/z = 353 [M + Na]⁺. C₁₅H₂₂O₈(330.13): calcd. C 54.54, H 6.71;

found C 54.65, H 6.83.

1

66: [α]²_D⁵= +50.4 (c = 0.62, CHCl₃). H NMR (CDCl₃, 300 MHz):

δ = 4.68 (t, J = 6.0 Hz, 1 H), 4.44 (d, J = 6.0 Hz, 1 H), 4.35 (d, J

= 6.0 Hz, 1 H), 4.03 (s, 1 H), 3.65 (d, J = 12.1 Hz, 1 H), 3.57 (d, J

= 12.1 Hz, 1 H), 1.53 (s, 3 H), 1.43 (s, 3 H), 1.34 (s, 3 H), 1.33 (s,

3 H), 0.93 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 110.8,

97.4, 83.5, 78.7, 77.3, 72.9, 64.9, 40.7, 29.1, 25.3, 23.3, 18.5,

15.1 ppm. API-ES (positive): m/z = 269 [M + Na]⁺. C₁₂H₂₂O₅

(246.15): calcd. C 58.52, H 9.00; found C 58.29, H 8.96.

1

67: H NMR (CDCl₃, 300 MHz): δ = 5.03 (br. s, 1 H), 4.99 (br. s,

1 H), 4.75 (br. s, 1 H), 4.54 (m, 1 H), 4.25–4.38 (m, 3 H), 4.19 (d,

J = 12.6 Hz, 1 H), 1.51 (s, 3 H), 1.49 (s, 3 H), 1.43 (s, 3 H), 1.35

(s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 143.3, 108.9, 107.7,

99.4, 78.3, 76.5, 69.6, 69.3, 64.8, 26.9, 26.5, 25.8, 22.9 ppm.

(1S,2R,3R,4R)-4-(Acetoxymethyl)cyclohexane-1,2,3-triyl Triacetate

(72): Argon was passed through a solution of 69 (10 mg,

0.03 mmol) in MeOH (2 mL) for 5 min, after which a catalytic

amount of Pd/C (50 mg, 10 wt.-% Pd on C) was added. The reac-

tion vessel was placed under vacuum and subsequently ventilated

with hydrogen gas. This cycle was repeated one more time, after

which the vessel was placed under hydrogen gas (25 psi) and me-

chanically shaken for 2 h. The Pd/C was removed by filtration

through celite, followed by thorough rinsing of the filter cake with

MeOH. The filtrate was concentrated under vacuum and the resi-

due was purified by silica gel flash chromatography (hexane/EtOAc

8:2) to afford compound 72 (5.1 mg, 58%): [α]²_D¹= +0.18 (c = 0.33,

2,3,4,6-Tetra-O-acetyl-5a-carba-β-D-glucopyranose (68): Com-

pound 27a (130 mg, 0.41 mmol) was subjected to General Pro-

cedure G to give compound 68 (81 mg, 56%) after silica gel column

chromatography (hexane/EtOAc 7:3). [α]²_D⁵= +18.6 (c = 0.86,

CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 4.94 (m, 3 H), 4.02 (dd,

J = 11.5, 5.0 Hz, 1 H, 6a-H), 3.97 (dd, J = 11.5, 3.3 Hz, 1 H, 6b-

H), 3.65 (m, 1 H, 1-H), 2.51 (dd, J = 11.5, 5.0 Hz, 1 H, 5a-H), 2.18

(t, J = 11.5 Hz, 1 H, 5a-H), 2.20 (m, 1 H), 2.05 (s, 3 H, Ac), 2.03

(s, 3 H, Ac), 2.01 (s, 3 H, Ac), 2.00 (s, 3 H, Ac), 1.62 (m, 1 H) ppm.

¹³C NMR (50 MHz, CDCl₃): δ = 170.6 (ϫ2), 170.2 (ϫ2), 71.9,

70.5, 66.8, 67.9, 62.8, 39.9, 38.1, 20.8, 20.7 (ϫ2), 20.2 ppm. API-

MS (positive): m/z = 369 [M + Na]⁺, 347 [M + 1]⁺(20). C₁₅H₂₂O₉

(346.13): calcd. C 52.02, H 6.40; found C 52.12, H 6.27.

1

CHCl₃). H NMR (CDCl₃, 300 MHz): δ = 5.72 (d, J = 15.3 Hz, 1

H, H_sp2), 5.64 (d, J = 15.3 Hz, 1 H, H_sp2), 5.57 (m, 1 H, 4-H), 5.31

(m, 2 H, 3-H, 2-H), 4.15 (dd, J = 11.6, 4.0 Hz, 1 H, 6a-H), 4.02

(dd, J = 11.6, 5.1 Hz, 1 H, 6b-H), 2.81 (m, 1 H, 5-H), 2.07 (s, 3 H,

Ac), 2.06 (s, 6 H, 2ϫ Ac), 2.05 (s, 3 H, Ac) ppm. ¹³C NMR =

(CDCl₃, 75 MHz): δ = 166.0, 165.5 (ϫ2), 165.3, 128.4, 126.5, 72.7,

72.1, 69.1, 63.0, 41.4, 21.0, 20.9, 20.8 (ϫ2) ppm. API-MS (posi-

tive): m/z = 351 [M + Na]⁺, 345 [M + NH₄]⁺. C₁₅H₂₀O₈(328.12):

calcd. C 54.87, H 6.14; found C 54.73, H 5.98.

2,3,4,6-Tetra-O-acetyl-1-azido-5a-carba-α-D-glucopyranose (69):

Methanesulfonyl chloride (21 μL, 0.27 mmol) was added at 0 °C to

a solution of the alcohol 68 (81 mg, 0.23 mmol) and triethylamine

(42 μL, 0.3 mmol), in dichloromethane (30 mL). The solution was

stirred at room temp. for 0.5 h and water was then added. The

aqueous phase was reextracted with CH₂Cl₂and the combined or-

ganic extracts were dried and concentrated in vacuo to give a resi-

due that was directly dissolved in dry DMF. Sodium azide (250 mg,

3.45 mmol) was added, and the resulting solution was heated at

85 °C for 48 h, during which considerable darkening occurred. The

reaction mixture was diluted with CH₂Cl₂(50 mL) and washed

General Procedure M. Ozonation of Vinylstannanes: A solution of

the appropriate olefin in MeOH (20 mLmmol^–1) at –78 °C was

bubbled through with ozone for 15 min, after which oxygen was

bubbled through the solution for 5 min. Next, the mixture

with water (20 mL). The aqueous layer was extracted with CH₂Cl₂was treated with borane-methyl sulfide complex (BMS)

and the combined organic solutions were washed with water. Con-

centration of the dried (magnesium sulfate) solution in vacuo

yielded a syrup, which was purified by flash chromatography (hex-

ane/EtOAc 70:30) to give the azide 69 (65 mg, 76%) [α]²_D⁵= +38.5

(2.5 mmolmmol^–1) and allowed to warm to room temperature over

2 h. After the mixture had been stirred for 1 h, the solvent was

removed and the residue was dissolved in a previously prepared

mixture of AcOH/THF/H₂O (4:2:1, 4 mL). The resulting solution

7130

www.eurjoc.org

Eur. J. Org. Chem. 2011, 7116–7132

5a-Carbahexopyranoses by 6-endo-trig Radical Cyclizations

Glycotechnol. 2004, 16, 33–53; c) T. Suami, Top. Curr. Chem.

1990, 154, 257–283; d) T. Suami, S. Ogawa, Adv. Carbohydr.

Chem. Biochem. 1990, 48, 21–90; e) T. Suami, Pure Appl. Chem.

1987, 59, 1509–1520; f) S. Ogawa, in: Studies in Natural Product

Chemistry (Ed.: Atta-ur-Rahman); Elsevier, New York, 1993,

p. 187; g) S. Ogawa, in: Carbohydrate and Drug Design (Eds.:

Z. J. Witczak, K. A. Nieforth), Marcel Dekker, New York,

1997, p. 433; h) Y. Kobayashi, in: Glycoscience (Eds.: B. Fraser-

Reid, K. Tatsuta, J. Thiem), Springer, Heidelberg, Germany,

2001, p. 2595.

was warmed to 85 °C and stirred at that temperature for 2 h. The

reaction mixture was then concentrated and the residue was sub-

jected to standard acetylation conditions by treatment with pyr-

idine and excess of acetic anhydride. The product was isolated by

flash chromatography with silica gel.

(1R,2R,4R,5R,6S)-5,6-Bis(acetoxy)-2,4-bis[(acetoxy)methyl]-2-

hydroxycyclohexyl Acetate (73): The olefin 22a (168 mg,

0.31 mmol) was subjected to ozonation by the General Procedure.

The residue was purified by column chromatography on silica gel

(hexane/EtOAc 1:1) to yield the title compound 73 (73 mg, 57%):

m.p. 61–63 °C. [α]²_D¹= +15.6 (c = 0.5, CHCl₃). ¹H NMR

(300 MHz): δ = 5.40 (t, J = 9.8 Hz, 1 H), 5.10 (d, J = 9.8 Hz, 1

H), 5.05 (t, J = 9.8 Hz, 1 H), 4.15 (m, 2 H), 3.98 (t, J = 11.2 Hz,

1 H), 3.90 (t, J = 11.2 Hz, 1 H), 2.45 (m, 1 H), 2.42 (br. s, 1 H),

2.09 (s, 3 H), 2.08 (s, 3 H), 2.07 (s, 3 H), 2.03 (s, 3 H), 1.98 (s, 3

H), 1.98 (s, 3 H), 1.91 (dd, J = 3.7, 14.4 Hz, 1 H), 1.67 (t, J =

14.4 Hz, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 170.8, 170.5,

170.1, 169.9, 169.3, 72.8, 72.4, 71.0, 66.9, 63.0, 60.4, 34.5, 33.0,

20.8, 20.7, 20.6, 20.5, 20.4 ppm. C₁₈H₂₆O₁₁(418.15): calcd. C 51.67,

H 6.26; found C 51.39, H 6.13.

[7]

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(1R,2S,3S,4R,6R)-2,3-Bis(acetoxy)-4,6-bis[(acetoxy)methyl]-4-

hydroxycyclohexyl Acetate (74): The olefin 54 (85 mg, 0.16 mmol)

was subjected to ozonation by the General Procedure. The residue

was purified by column chromatography on silica gel (hexane/

EtOAc, 1:1) to yield the title compound 73 (47 mg, 71% overall

yield). [α]²_D¹= –2.6 (c = 0.8, CHCl₃). ¹H NMR (300 MHz, CDCl₃):

δ = 5.27 (dd, J = 3.2, 10.1 Hz, 1 H), 5.23 (m, 1 H), 5.13 (t, J =

10.1 Hz, 1 H), 4.14 (d, J = 11.7 Hz, 1 H), 4.04 (dd, J = 5.6, 11.3 Hz,

1 H), 3.9 (dd, J = 3.7, 11.3 Hz, 1 H), 3.74 (d, J = 11.7 Hz, 1 H),

2.74 (br. s, 1 H), 2.36 (m, 1 H), 2.05 (s, 3 H), 2.01 (s, 3 H), 2.00 (s,

3 H), 1.97 (s, 3 H), 1.89 (s, 3 H), 1.64 (m, 2 H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 171.0, 170.8 (ϫ2), 170.2, 169.5, 72.3, 71.6,

69.8, 69.3, 67.4, 63.8, 35.0, 31.2, 20.8, 20.7 (ϫ2), 20.6 (ϫ2) ppm.

API-ES (positive): m/z = 441.2 [M + Na]⁺, 859.2 (2M+Na)⁺.

C₁₈H₂₆O₁₁(418.15): calcd. C 51.67, H 6.26; found C 51.43, H 6.04.

[11]

[12]

Acknowledgments

The authors are grateful to the Ministerio de Ciencia e Innovación

(MICINN) and the Comunidad de Madrid for financial support

through grants CTQ2009-10343 and S2009/PPQ-1752, respectively.

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Received: June 30, 2011

Published Online: October 14, 2011

7132

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Synthetic strategies directed towards 5a-carbahexopyranoses and derivatives based on 6-endo-trig radical cyclizations

DOI: 10.1002/ejoc.201100956

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