Tải bản đầy đủ - 0 (trang)
Synthesis of Isopropylidene, Benzylidene and Related Acetals

Synthesis of Isopropylidene, Benzylidene and Related Acetals

Tải bản đầy đủ - 0trang

4



C8l1naud and Gelas



only acyclic and cyclic acetals, but also analogues in which the oxygen atoms have been

replaced by other heteroatoms, the sulfut atom being of particular importance (thio- and

dithio-acetals). This chapter will consider only the most popular and useful acetals, with

some comments concerning related acetals and extension to oligosaccharides. The case

where the acetal involves the anomeric center (glycosides) falls outside the scope of this

chapter.A later chapter deals with acyclic dithioacetals, and these can be found elsewhere

in this monograph.

Several reviewshave already been published on the subject,for example, the acetalation of alditols [4], of aldoses and aldosides [5,6], and of ketoses [7]. Some aspects of the

stereochemistry of cyclic acetals have been discussed in a review dealing with cyclic

derivativesof carbohydrates [8], also in a general article [9] and, morerecently, in a chapter

of a monograph devoted to the stereochemistry and the conformationalanalysis of sugars

[10].Aspects on predicting reactions patterns of alditol-aldehyde reactions are reviewed

within a general series of books on carbohydrates [11]. The formation and migration of

cyclic acetals of carbohydrates have also been reviewed [12,13].

The evident success of the transformation of polyols into cyclic acetals as a method

for temporary protection, is mainly due to the following features: (1) accessibility and

cheapnessof the reagents; (2) ease of the procedure leading quickly and in high yield to the

protected derivatives; (3) inertness of the protecting group to a large variety of reagents

used in the structural modifications of the substrate; (4) ease and high-yielding step for

deprotection.Usually, reagents for acetalation are quite common chemicals that are essentially nontoxic; their uses are well established and straightforward. Some representative

procedures of the various methods will be presented here, especiallyfor the most important

derivatives; namely, O-isopropylidene and O-benzylidene sugars. For example, 1,2:5,6di-O-isopropylidene-o-glucofuranose 1,1,2:3,4-di-O-isopropylidene-o-galactopyranose 2,

and methyI4,6-0-benzylidene-a-o-glucopyranoside 3, continue to be used extensively by

sugar chemists.



3



Only short comments will be given for other acetal derivatives that are less popular.'

Chart 1 presents a list of formulae of cyclic acetals, mainly, those with five- and sixmemberedrings (1,3-dioxolanes and 1,3-dioxanes).Seven-membered ring acetals are omitted because they are scarcely represented in carbohydrate chemistry. The special case of

spiroacetals and cyclohexane-1,2-diacetal-protecting groups, which have been reported

recently, will be presented in Part Il.

The essential justifications for the choice of one type of acetal among the various

possibilities are probably (1)the structure of the acetal obtained (i.e., dioxolane or dioxane

type; with or without involvement of the anomerichydroxyl group; obtention of a furanoid

or a pyranoid protected form of the sugar, especially when one starts from a free one);

(2) the respective reactivity of these acetals as far as the deprotecting step is concerned. A

brief discussion of the point (1)will be given in the next paragraph. Relative to the deprotection of cyclic acetals, generallytheir cleavage,regeneratinga diol, is obtainedusing very

similaracidic aqueous conditions [4-7]. However, a selective removal of one acetal in the

presence of the same (or different) functions, at distinct positions in the same molecule,



lsopropylldene, Benzylidene, and Related Acetals



j



5



- 0 " /R

__ o/c",,-~,



R



R'



O-methylene



H



H



O-ethylidene



Me



H



O-cycloalkylidenes

0=4 cyclopcnt,ylidene

o=S cyclohexylidene

O-isopropylidene



Me



Me



O-benzylidene



Ph



H



Y-C6H4

O-benzylidene substituted

y~ o-N0 2, p -OMe, P- NMe 2



H



Chart 1 Most common cyclic acetaIs used in carbohydrate chemistry



is possible and has been quite often observed. As examples, one can recall that generally a

1,2-0-isopropylidene group is more resistant to acid hydrolysis than the same group at any

other position. trans-Fused 4,6-0-benzylidene acetals of hexopyranosides are hydrolyzed

faster than the corresponding cis-fused acetals and a para-anisylidene group can be

removed without loss of a benzylidenegroup in the same molecule by graded acid hydrolysis. A list of representative examples of this kind of selective removal within a multifunctional carbohydrate derivative can be found in a review partly devoted to acetals [14].

Finally, it should be emphasized, even if it is paradoxical, that this excellent protecting group can, under special conditions, behave as a real functional group with its own

reactivity. During these last 20 years, reactions have opened the way for the developmentof

strategies for structural modifications, thereby amplifying the interest for acetals. Among

these reactions one can briefly recall: (1) oxidation (ozonolysis, action of potassium

permanganate); (2) photolysis; (3) halogenation (N-bromosuccinimide, triphenylmethylfluoroborate, and halide ions; hydrogen bromide in acetic acid; dibromomethylmethylether; miscellaneous reagents); (4) hydrogenolysis (mixed hydride reagents); (5) action of

strong bases (ring opening with butyllithium, other strong bases); (6) formation of esters

induced by peroxides and (7) cleavage with Grignard reagents. This reactivity has been the

subject of a review [15] that demonstrated the versatility of acetals

Chart2 shows some protective groups closely related to cyclic acetals, and it may be

useful to comment briefly about them as they will not be discussed further here. The first

example corresponds to the O-cyanoalkylidene group, especially the O-eyanoethylidene

group, which actually has been introduced in carbohydrate chemistry as a method for

activation of the anomericcenter in oligosaccharidesynthesis [16].Other examples are less

closely related to acetals and result from the substitution of the acetal carbon atom by an

heteroatom (Si, So, or B) or correspond to the presence of three heteroatoms (0 or N) on

this center. Thus, use of 1,3-dichloro-l,1,3,3-tetraisopropyldisiloxane in basic medium has

been introduced for the simultaneous protection of the 3'- and the 5'- OH groups in

nucleosides [17];this strategy has been extended to the monosaccharides and the migration



C8l1naud and Gelu



6



l80propylldene, Benzylidene, and Related Acetale



7



Acetalation in Acidic or Neutral Conditions

O-cyanoalkylidene



--0

--0



Ph



"8/

/1



O-silylene



\.ph



O-alkylboron



DIred Condensation of a Carbonyl Derivative. Historically, this is the first

procedure and generally the sugar and an aldehyde (or a ketone) are simply mixed either

directly (the reagent,for instance propanone,used in a large excess, also being the solvent)

or in solution in a solvent (~N-dimethylformamide is the most frequently used, dimethylsulfoxidebeing encounteredfar less) and eventually in the presenceof a catalyst.The latter

can be either a soluble acid (practicallyall kinds of organic and inorganic acids have been

tested, and the most frequently used are sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, or hydrogen chloride)or an insoluble one (Amberlystresins, Montmorillonite KIO). An idealizedrepresentationof the mechanismof the reactionis given in SchemeI,

but it does not necessarilygive the exact nature of all possibleintermediates(see Sec. II.B).



O-(dimethylaminoalkylidene)



Chart 2



Derivatives related to acetals used in carbohydrate chemistry



of the silyl-protectinggroup hasbeen studied [18]. A slightly different silyl group has also

been suggestedfor the selective protection of sucrose, even if the interosidic acetals (1',2silylene and 1',2:6,6'-disilylene derivatives), resulting from the action of dimethoxydiphenylsilanein the presence of acid, are obtained in low yield [19].More interesting from

the preparativepoint of viewis the introductionin carbohydratechemistryof the reactionof

dibutyltinoxide giving dibutylstannylenederivatives(or stannoxane)[20]. Their reactivity

with electrophiles gives predominantly monosubstituted products, usually with a high

regioselectivity[21],as exemplifiedby a monoalkylation [22]. Anotherexample is offered

by cyclic boronates,whichhave been used to a limitedextent owingto their high sensitivity

to hydrolyticconditions [23]. However,the O-ethylboronderivativeshave been especially

developed to give special assistance in various controlled reactions of monosaccharides

[24]. The last example is concerned with protecting groups closer to ortho-esters than to

aceta1s. The selectiveformationof ortho-esters at nonanomericpositions hasbeen recently

described[25]. Amide acetalshave been used particularlyin carbohydratechemistryin the

a-(dimethylarnino)-ethylidene and -benzylideneacetal series [26].Their general properties

have been considered,especiallythe acid hydrolysisto monoesters,which is of valuein the

ribofuranoside series for oligonucleotide synthesis.

II.



METHODS FOR PREPARATION OF ACETALS IN CARBOHYDRATE

CHEMISTRY



A. General Methods

Fundamentally,we can classifythe differentmethodsinto two categories,dependingon the

experimentalconditions: (1) acid or neutral medium; (2) basic conditions. Less common

procedures will be presented in a third section.



The use of a Lewis acid (e.g., triethyl1luoroborate, zinc chloride, stannous chloride,

titanium chloride, iron(ITI)chloride) and other reagents (e.g., iodine, trimethylsilane,

triftuoromethane-sulfonylsilane) have also been recommended. Exhaustive lists of catalysts and conditionscan be found in reviews devoted to carbohydrates[5-7], or to general

organic chemistry [27,28]. However, one can add the new catalyst, which has been

introduced for the smooth formation of p-methoxybenzylidene acetals and p-methoxyphenylmethyl methyl ether [29], namely 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ),

andhas been applied very recently [30] to the synthesis of isopropylidenemixed acetals.

Obviously,the condensationof a carbonyl group with a diol produces 1 mol of water

and because of the reversibilityof the reaction(hydrolysisof the acetal),yields are lowered

if this by-productis not removed.For such a purpose,there are essentiallytwo possibilities:

(1) the continuous removal of water by an azeotropic distillation with a solvent mainly

chosen for its boilingyoint (petroleumether,benzene,toluene,xylene, for instance);(2) the

presence of a desiccant (the most commonly taken is copper(Il)sulfate,but sodium sulfate

or molecular sieveshave been also used); moleculesknown to be water scavengers,such as

ortha-esters or dialkylsulfites, have also been suggested, even if they are seldom used in

carbohydrate chemistry.

Important in this quite general strategy is that, for practically all instances, the

reaction is underthermodynamiccontrol, and the control of the stoichiometryis extremely

difficolt.lt follows that only the more stableacetals are produced(see Sec. II.B) and usually

multiacetals are obtained if several hydroxyl groups are available within the same molecule. This has been a major concern in acetalation reactions in neutral conditions. For

instance, use of copper(II)sulfate either in acetone alone or in ~N-dimethylformamide

without any additional catalyst, leads to acetals with structures that differ from those

resultingfromreactionsin the presenceof an acid; The reactiondependson the temperature

[31];however, the strict neutrality of a medium in which copper(Il)sulfateand polyols are

interacting can be questioned.



Callnaud and GeIa8



8



Tnmsacetalation. This strategy, based on an acetal exchange in acid conditions,

has been introduced more recently in carbohydrate chemistry [32-34]. It offers several

advantages over the direct condensation of the corresponding free carbonyl group: (1)

anhydrous conditions can be strictly followed, as the only by-product is 2 mol of the alcohol

(e.g., MeOH) used to prepare the reagent (Scheme 2); this alcohol can even be removed by



9



l80propylldene, Benzylidene, and Related Acetal.



molecular addition of an hydroxyl group on monovinylethers of 1,2-diols [48]; and its

application to the synthesis of 1,2-0-isopropylidene-a-n-galactose [49], this strategy was

underestimated until it was shown that the use of 2-aIkoxypropene in N,N-dimethylformamide was a simple and efficient method of acetonation under exclusive kinetically

controlled conditions. In many instances, the products differed from those prepared under

thermodynanrlc control [50]. The reaction (Scheme 3) is characterized mainly by the

.c----....~c ....--....

,\I\,__ ~, H+

OH

+

C-OR+

~



COH



,0....

/

,r:.. /

"o,.C, ~ '0""-H+



I



c< -w



H



SCheme 2

diminished pressure to displace the equilibrium if necessary; (2) the stoichiometric of the

reaction can be controlled; (3) in some instances, it is possible to obtain acetal(s) under

kinetically controlled conditions, even if many sugars (especially free sugars) still react to

give the more stable structures (see Sec. II.B); (4) also th~ is a possibility .of obtaining

strained acetals, such as those resulting from the acetalation of 2,3-trans-diols of pyranosides, although yields are generally low.

Thus, the formation of O-isopropylidene derivatives using 2,2-dimethoxy-propane~N-dimethylformamide-p"toluenesulfonicacid has become one of the .most pop~ar w~ys

to protect diols. This strategy has been applied to many sugars and IS ~~~tible With

aminosugars [35] and oligosaccharides such as sucrose [36], maltose,laminanbiose, cellobiose, and gentobiose [37]. It has been extended to O-benzylidene derivatives for which the

use of a a-dimethoxytoluene can advantageously replace benzaldehyde [38,39]. Its application to oligosaccharides is also .possible and has been described, for instance, for ~~

oligosaccharides [40]. A slight modification of the classic procedure (the ~tion 1S

followed by a partial hydrolysis of the crude mixture to remove unstabl~ acyclic acetals)

offers a convenient route to an interosidic, eight-membered. cyclic benzylidene acetals [41].

can ~~ the

Once again, efforts have been made to find neutral conditions

course of the reaction. For instance, use of 2,2-dimethoxypropane m solution in 1,2,dimethoxyethane (which probably plays a role through its interaction with polyols) ~

been suggested as a reagent for acetalation in neutral conditions (no catalyst) of n-mannitol

[42] and n-glucitol [43].

.

For transacetalation reactions, it is worth noting here the recent strategy mtroduced

for selective protection of vicinal diols (and especially with. a trans confi~tion) in

carbohydrates: a double exchange involving the acetal functio~ of l,1,2,~~ethoxy­

cyclohexane gave a dispiroacetal, structurally related to a 1,4-dioxane, stab~zed by ~e

axial position of the methoxyl groups [44]. This method completes th~ preced;ing one usmg

enol ethers, leading to an analogue of 1,4-dioxane [45] (see followmg section).

Acetalation with Enol Ethen Under KlneticaDy Controlled Conditions. The

first mentio~ of the use of an enol ether to protect the hydroxyl group of an alcohol was

developed by Paul [46], who introduced the reaction ~th lIibydrop~ to give tetrahydroyranyl ethers, which is still used 60 years later. In spite of some no~ceable developmen~,

~uch as the preparation of2',3'-O-alk.ylidene derivatives ofnucl~S1des [33]; the syn~es1s

of 4,6-0-ethylidene-a-n-glucopyranoside with use of methylvmylether [47]; the mtra-



th:tt



q;<~

H



+



C;tr<



SCheme 3

following considerations. (1) The favored site for initial attack by the reagent is at a primary

hydroxyl group, even with free sugars in solution; thus, n-glucose [51], n-mannose [52],

n-allose, and n-talose [53] give the 4,6-0-isopropylidene derivative exclusively, and

n-galactose gives essentially the same type of acetal [53]. (2) Ifthe favored tautomeric form

of the sugar in solution does not have a primary hydroxyl group, the attack of the most

reactive secondary group leads to 1,3-dioxolanes without tautomerization: for example, one

observes exclusive formation of 3,4-0-isopropylidene-n-arabinopyranose, and formation

of 3,4-0-isopropylidene-n-ribopyranose as major products [54]; on the other hand, a

tautomerization leads to theformation of the more stable 2,3-0-isopropylidene-n-lyxofuranose [55] (also compare the acetonation products ofn-fucose and n-rhamnose [56]). (3) In

the initial.process, 'the anomeric hydroxyl group does not take part in the reaction. (4)

Access to either mono- or diacetals is permitted by careful stoichiometric control, as in the

preparation of mono- and di-o-isopropylidene-n-mannopyranoses [52]. (5) The method

can be applied to the acetonation of oligosaccharides with the same characteristics and

without cleavage of the glycosidic bond. For example, it is possible to effect a selective

monoacetonation of a,a-trehalose [57] and to obtain acetonides of sucrose [58], lactose

[59], and maltose [60]. (6) The method permits an efficient access to a strained ring, as in

the acetonation of trans vicinal diols [61], the formation of medium-sized acetals (interosidic acetals of oligosaccharides [58-60], and to obtain 1,s-o-isopropylidene-n-ribofuranose [54]. The reaction has been used in a variety of contexts covering a large assortment of sugars. For instance, it has been applied to the selective acetonation of alditols,

such as n-mannitol [62] and 1,4-anhydropolyols [63], ketoses [64], di,ethyldithioacetals of

monosaccharides [65], as well as thiosugars (5-thio-n-xylopyranoside [66]). It can also be

nsedto obtain aldelrydo derivatives of monosaccharides, exemplified by aldelrydo-2,3:4,5di-O-isopropylidene-n-xylose [55,67].

Extension of this strategy to other vinyl ethers using essentially 2-methoxypropene

has been described. Minor structural variations in the reagent used are. possible. Thus,

entirely comparable results giving cyclohexylidene acetals ate observed using l-alkoxycyclohexene [68]. 2-1iimethylsilyloxypropene has been nsed for the acetalation of 1,2cyclohexanediol [69]. On the other hand, acycl!ic acetals (6-substituted mixed acetals) are

obtained when methyl 2,3-0-benzyl-a-n-glucopyranoside is allowed to react with

2-benzyloxypropene or 2-benzyloxy-3-tluoropropene [70]. More important structural vari-



Callnaud and Gelas



10



ations are concerned with (1) the smooth preparation of ethylenic acetals (monomers for

polymerization) with ethylenic enol ethers [71]; (2) the selective reaction of the vinyl ether

unit in ketonic enol ethers,leading to an acetal substituted with a ketonic chain [72]; (3) the

introduction of a bis-dihydropyran (namely 3,3',4,4'-tetrahydro-6,6'-bi-2H-pyran) as a

reagent useful for the selective protection of trans (diequatorial) vicinal diols in monosaccharides for which there is an evident competition between the acetalation of 1,2-cis,

1,2-trans, and l,3-diols; the formation of an unique dispiroacetal (a tetraoxadispiro[5.0.5.4]hexadecane) is explained by the anomeric effect, which stabilized the structure ofa

l,4-dioxane substituted by two axial C-O bonds originating from this bis-dihydropyran

[45].

Finally, all these reactions are catalyzed by p-toluenesulfonic acid, or camphorsulfonic acid, or pyridinium salts. Use of pyridinium p-toluenesulfonate is now well

established as a mild catalyst. We have already noted the recent use of DDQ which has

recently proved to be effective with 2-methoxypropene [30].



Acetalation in Basic Conditions

The search for kinetically controlled conditions has stimulated the study of basic media for

acetalation. Essentially, methylene and benzylidene acetals have been prepared according

to reactions corresponding to Scheme 4:

Ott

( Ott



+



X



'c//



+ [8"+ HX)



1"-



X



SCheme 4

Thus, dichloro- or dibromomethane in the presence of sodium hydride in solution

in N,N-dimethylformamide gives O-methylene derivatives [73,74]. Other conditions are

also possible, for instance; use of potassium hydroxide and dimethylsulfoxyde [75), but an

interesting development is the application of the phase-transfer catalysis technique, by

which dibromomethane and sodium hydroxide in water, in the presence of an appropriate

ammonium salt, leads to a cis-2,3-0-methylenation of methyl-4,6-0-benzylidene-a-omannopyrsnoside, [76] and similar conditions afford the trans-2,3-0-methylenation of

methyl-4,6-0-benzylidene-o-hexopyranosides [77]. Other examples have been published

[78].

Concerning the O-benzylidene derivatives, the main objective is to obtain stereoisomeric control of the chirality introduced at the acetal carbon atom. Classic methods of

benzylidenation (using benzaldehyde or a,a-dimethoxytoluene) are based on acidic catalysis and give the more stable compound, with a thermodynamically controlled acetalic

configuration. For instance, the known [79] free-energy for the equatorial preference of a

phenyl substituent at position 2 on a l,3-dioxane (structurally comparable with a 4,6-0benzylidene derivative) is such that no diastereoisomer corresponding to the axial position

can be isolated in acidic medium. In contrast both diastereoisomers of 4,6-0-benzylidene

acetals are actually obtained [80] using a,a-dimethoxytoluene and potassium tertbutoxide. Even if the reaction has not yet found practical applications owing to its rather

low yield, benzaldehyde itself can react in the presence of potassium tert-butoxide with

methyl-2,3-di-0-(toly-p-sulfonyl)-a-o-glucopyranoside to give 4,6-0-benzylidene acetals

[81]. In fact, it has been demonstrated that a strong basic medium is unnecessary. Thus, an

alternative method of benzylidenation is the reaction of a, a-dihalotoluenes simply in



lsopropylldene, Benzylidene, and. Related Acetals



11



pyridine at reflux. When l,3-dioxoIanes are obtained, the formation of both exo- and endophenyl-substituted derivatives is observed, but for a l,3-dioxane, only the most stable

isomer (equatorial phenyl) is obtained [82]. However, in noncarbohydrates, pyridinium

chloride can catalyze acetalations [83). It has recently been shown that4,6-0-isopropylidenesucrose can be conveniently obtained using 2-methoxypropene in solution in pyridine and,

in the presence of pyridinium, p-toluenesulfonate [84]; thus, it is not surprising to observe

the formation of the more stable compound in the preceding examples of benzylidenation.



Miscellaneous Methods

Several less general methods of aceta1ation are known [28], and a few of them have found

some application in carbohydrate chemistry. Because they can represent exceptional alternatives to classic procedures, they will be briefly presented here.

.

Hydrogenolysis of orlho-Esters. A two-stage procedure for converting methoxyethylidene derivatives by using boron trifluoride, followed by reduction with lithium

aluminium hydride, has been used to prepare exo- and endo-diastereoisomers of methyl

3,4-0-ethylidene-~-L-arabinopyranoside[85]. A similar approach has been described

using diborane [86]. Other reducing agents, such as "mixed hydrides", prepared by mixing

lithium aluminium hydride and aluminium chloride (see ref. [15] imd references cited

therein), have been useful to directly reduce ortho-esters (methoxyethylidene derivatives)

to methylene, ethylidene, and benzylidene acetals [74].

Ortho-esters at position 1,2- of sugars are more easily prepared than the corresponding aceta1s; as an exchange of both functional groups is possible, 1,2-0-alkylidene derivatives can be prepared by the reaction of these ortho-esters with the appropriate carbonyl

reagent in strictly anhydrous conditons and in the presence of an acid [87].

In fact, these reactions likely involve l,3-dioxocarbenium ions, which can also be

prepared from pyranosyl chloride and reduced to acetals; thus endo- and exo-l,2-0ethylidene-a-o-allopyranoses have been prepared from penta-O-acetyl-~-o-allopyranosyl

chloride (reaction with sodium borohydride) [88]. These types of l,2-acetoxonium ions are

also known to react with dialkylcadmium to give 1,3-diacetals [89].

Action ofN-Bromosucdnbnide in Dimethylsulfoxide. An alternative to the classic methylenation of diols has been offered by the simple procedure using N-bromosuccinimide in dimethylsulfoxide and has been applied, for instance, to the aceta1ation of

n-mannitol and o-ribofuranosides [90].



B. Mechanistic and Structural



AsR8dS



The formation and the hydrolysis of acyclic and cyclic acetals have been studied in rather

great detail [91]. Several reviews on this topic are available [92) and some comments have

beenmade [13] concerning the carbohydrate series. We have shown in Schemes 1, 2, and 3

that a common feature of this reaction seems to be the intermediacy of an oxocarbenium

ion. However, the cyclization of suchan intermediate has been questioned more recently

[93] in the light of the Baldwin's rules for ring closure [94]. At least for the five-membered

ring, an SN2-type displacement mechanism for the protonated (orm (8) of the hemiacetal

(A) (favorable 5-exo-tet cyclization) has been proposed; rather than the unfavorable

5-endo-trig cyclization of the oxocarbenium ion (C); (Scheme 5). Except when the formation of the enol ether (D) is structurally impossible, the intermediacy of such a compound

remains feasible.



Callnaud and Gelas



12



lsopropylldene, Benzylld8ne, and Related Acetals



13



Me:zc(CX(~



Q



1



OC



0-.1



"'MIl2



~

~

~(OMe12

\/~

,,--or

OH

OH



-f'"



OMe



o



4



OH



Scheme 7



Kinetic Control Versus Thermodynamic Control

The major mechanistic and structural aspect of the acetalation process is its orientation

toward derivatives obtained either under thermodynamically controlled conditions or under

kinetically controlled conditions. We will not discuss here all structural factors concerning

the relative stabilities of acyclic and cyclic acetals of polyols and monosaccharides,

because such a discussion has been extensively reviewed and adequately commented on

[8,10,12 -14]. However, it is important to focus here on the main consequences of these

relative stabilities in relation to the various experimental conditions to orientate the choice

of specific conditions, particularly for the most important monosaccharides (n-glucose,

o-mannose, and o-galaetose).

Concerning the most popular derivatives, one can say (Scheme 6) that a better kinetic

control is obtained using successively acetone, or 2,2-di~oxypropanes, or 2-alkoxypropenes.

Me'>.-



MIl2CO



~



c/



OR



K1netlc

control



Thermodynamlc



control



.



SCheme 6

Practically all examples iiI the literature show that the use of acetone leads to the

more stable acetalsand, conversely, that 2-methoxypropene generally allows an access to

structurally quite different products (kinetic compounds). An intermediate behavior is

observed for the transacetalation process involving, 2,2~methoxypropane. which gives

results either similar to those obtained with acetone or similar to those obtained with enol

ethers. A good choice for the elucidation of whether a reaction is under thermodynamic or

kinetic control is the study of the acetonation of free monosaccharides, which are subject to

the tantomerization phenomena. Two examples of the "mixed behavior" of 2,2-dimethoxypropane are given in Schemes 7 and 8. The reaction of o-glucose with acetone and

acid [95] gives the classic diacetone glucose 1 (see Scheme 7). On the other hand, use of

2,2-dimethoxypropane [96], or 2-methoxypropene [51], gives a high yield of the less stable

pyranoid monoacetal4 (kinetic and stoichiometric controls). It is possible to confirm the



SChemeS



relative stabilities of acetals 1 and 4 by the easy transformation of the latter into 1 by

treatment in acidic acetone [51].

The second example concerns the study of acetonation of o-mannose (see Scheme 8)

and allows a clear distinction between the use of 2,2-dimethoxypropane and 2-methoxypropene. Thus, whereas o-mannose gives 2,3:5,6-di-0-isopropylidene-o-mannofuranose 5

by reaction of the free sugar with acetone [5,6] as well as with 2,2-dimethoxypropane [96],

the major compound (more than 85%) obtained with 2-methoxypropene is 4,6-0isopropylidene-o-mannopyranose 6 [52]. Onceagain, a confirmation of the better stability

of furanoid acetals in this series is given by the selective hydrolysis of the 2,3:4,6-di-0isopropylidene-o-mannopyranose 7 (by-product of the preceding reaction or quantitatively

obtained by action of2-methoxypropene on acetal 6), wllch gives the furanoid monoacetal

8. Actually, the pyranoid monoacetal 9 can be easily prepared as soon as the anomeric

hydroxyl group is protected by acetylation [52].

The main characteristics of the use of 2-methoxypropene for the acetonation of

sugars have already been summarized (see Sec. n.A), and one of them is the initial attack

on the primary hydroxyl group, if any, in the preferred tautomeric form. Although this is

confirmed by easily obtaining 4,6-isopropylidene-o-ga1actopyranose 10 (Scheme 9) in 67%

yield, the 3,4-cis-diol, as 3,4-0-isopropylidene-o-galactopyranose 11 is also isolated (14%

yield) along with traces of 5,6-0-isopropylidene-o-galaetofutanose [53]. This result is still

in clear contrast with the classic acetonation of o-galactose, which gives [95] the well

known l,2:3,4-di-0-isopropylidene-o-galaetopyranose 11 exclusively.

The difficulty in obtaining pyranoid 4,6-0-isopropylidene derivatives is due to the



C8l1naud and·Gelas



14



CHPi



M....CO



">"

o-galaclose



J~ J-:o

~~-.>J

MeI!--- I

6



12



oc~



Mll2C?~O~



~._H



./~~



:~OH

OH



11



Scheme 9



presence of an axial methyl group at position 2 of the 1,3-dioxane system. A strong synaxial interaction[98] results, which has been confirmedby the evaluationof the free energy

of such an axial methyl group and is estimated to more than 3 kcallmol [99]. Obviously,

using aldehydes(benzaldehydemost frequently) instead of acetone, suppresses this interaction, and pyranoid derivatives are thus easily obtained.

The acetonationunder kinetically controlledconditionsis also useful for the protection of vicinal trans-diols, which are quite reluctant to cycllzation into five-membered

rings. Althoughuse of2-methoxypropene has been successfulin this objective [61,66], one

should recommend the recently discovered uses of reagents that minimized the ring strain

by obtainingsix-memberedrings from vicinal trans-diols, which are protected(Scheme10)

as l,4-dioxanes (dispiroacetals, trans-decalinic system) stabilized by an anomeric effect



or



~'?-?~



+ HO~}



~~Me



/

----...



~OMe

OMe



Usually 2,2-disubstituted, 1,3-dioxanes(for instance, acetonides) are hydrolyzed

more easily than corresponding 1,3-dioxolanes(essentially owing to the strong

syn-axial interaction operative in the six-membered ring [79,98).

2. Most of 1,2:5,6-di-O-isopropylidene acetals of the aldohexoses may be selectively (or partially) hydrolyzed to 1,2-0-isopropylidene derivatives.

3. For sugars in which the acetal function does not involve the anomericcenter, a

1,3-dioxolanecis-fused to a furanose or a pyranose is more stable than the 1,3dioxo1ane which involves a side chain.

4. trans-Fused 4,6-0-benzylidene acetals of hexopyranosides(trans-deca1inic system) are generally hydrolyzed faster than the corresponding cis-fused acetals

(cis-decalinic system).

1.



OH

10



~



15



have already been reviewed and discussed [see Refs. 5,6,14]. Thus, one can briefly

summarize some well-establishedobservations:



o-bMll2



}-ou~



l80propylldene, Benzylidene, and Related Acetals



~J

.



~~~

OM~~}



Scheme 10



Selective Hydrolysis of Diacetals



Ome of theinterestingpropertiesof sugarsprotectedby more than one cyclic acetal groupis

the possibility for them to experience a selective hydrolysis, which may be of great

potential for practical applications in synthesis. The regioselectivity of hydrolysis of

multiacetals(mainly diacetals) is governed particularly by the eventual implication of the

anomericcenter and the structure of the bicyclic ring system that essentially can be either

(1) a 1,3-dioxolane or a l,3-dioxane, or (2) fused to a furanose or a pyranose, or (3) covalently independent from the sugar ring. Ml)st of these factors and their consequences



Twospecificexamplesof selectedhydrolysisof diacetals are givenin the experimental section in the o-gluco-furanose and the o-mannopyranose series.



III. EXPERIMENTAL PROCEDURES



The following procedures have been arbitrarily chosen as representativeof classic acetals

extensivelyused as versatile starting materials for synthesis [102]. It covers aspects of the

chemistryof acyclic and cyclic monosaccharidesand some disaceharides.Proceduresfrom

other Iaboratorieshave been reproducedfrom the original publication and their authors are

acknowledged.



A. Acyclic Sugars

Aldehydo-2,3:4,5-di.Q-isopropyfidene-o-xylose [67]



~

~



HO



H



)-OMe

H







CHO

I



H(f9



M82C=::::::OCH

I



13



CHO~



H:zCQ/CM82



p-Toluenesulfonic acid hydrate (40 mg) was added with stirring to a solution ofo-xylose

(lOg, 0.067 mol) and 2-methoxypropene (14.4 g, 0.2 mol) in DMF (130 mL) at O°C. After

8 h at 0-5°C, the xylose has reacted (thin-layerchromatography [TLC], 3:2 ethyl acetateJ

hexane), and three spots were evident by TLC (Rr 0.61,0.30, and 0.28). The acid was

neutralized by stirring with dried Amberlite 1RA-400 resin (OH- form). The resin was

removed, washed with ~OH, and the extracts and reaction mixture were evaporated

under vacuum (1 mm, < 40°C) to give a syrup (14.4 g) that was thoroughlyextracted with

dry hexane. The insoluble residue (5.9 g, TLC) 3:2 ethyl acetatelhexane, Rf 0.28, major;

0.30, minor; 0.61, trace) has inappreciable amounts of 3,5-0-isopropylidene-o-xylofuranose or 1,2-0-isopropylidene-o-xylopyranoseand may been been madeup of acyclic

monoisopropylidenation products. Vacuum evaporation of the hexane-soluble fraction

gave 8.5 g (51% yield, Rf 0.61) of the free aldehyde 13.



C8l1naudand Gelas



16

Acetonation of Diethyl Dithioacetals of Monosaccharides



As the well-known transformation of free monosaccharides to diethyl dithioacetals is

probably the best access to open-chain sugar derivatives, the preparation of acetals [65] of

such compounds has been studied using either conventionalmethods [for instance see Ref.

101 and references cited therein, for the cupric sulfate catalyzed isopropylidenation with

acetone] or kineticallycontrolled conditions.Thus the synthesisof cyclohexylideneacetals

(using 1-ethoxycyclohexene)or isopropylidene acetals (using 2-methoxypropene) of diethyl dithioacetalsofo-arabinose, o-xylose, n-glucose, and o-galactose has been described

[65]. As a specific example we reproduce here only the reaction involving o-glucose

diethyl dithioacetal.



yH(SEIh

HOyH

HCOH



HtoH



Isopropylldene, Benzylidene, and Related Acetals



17



2,a.Q-lsopropyildene-a-o-Iyxofuranose [55}



D-Lyxose



~M: Hqc~



11



~H



To a solution ofo-lyxose (1.5 g; 10 mmol) in anhydrousDMF (30 mL) at ooe was added 2

Eq of 2-methoxypropene and a catalytic amount of p-toluenesulfonic acid. After 3 h at

ooe, the mixture was made neutral. The filtrate was evaporated under diminished pressure

at 40°C to afford2.0 g of crude product (yield 80-85%), which was purifiedon a column of

silica gel (EtOAc)to afford 1.3 g (68%) oft6 mp 80-82°e, [a]e + 23 ~ +18° (final,H20).

Pyranoses



14



~::::CMB:z



a,4.Q-lsopropylidene-p-o-ribopyranose [54}



~



A solution of the dry o-glucose diethyldithioacetal (10.725 g; 37.5 mmol) 2-methoxypropene (3.245 g; 45 mmol) in anhydrous DMF (130 mL) and p-toluenesulfonic acid

(375 mg) was kept for 68 h at oDe. The homogeneous mixture was kept with exclusion

moisture until TLC indicated that all the starting material had reacted, and it was then

poured into a solution of sodium hydrogenocarbonate(2% w/v, 60 mL). This mixture was

extracted with ether (4 x 30 mL). The combined ether extracts were washed with water

(2 x 30 mL), dried (magnesiumsulfate),and evaporated,giving yellowishcrystals (8.275g,

68%) that wererecrystallizedtwice from dichloromethanepetroleumether to give colorless

crystals of 14: yield 5.735 g (47%), mp 73.5-74.5°e, [al e - 11° (c 2.027, methanol).



B. Penta...

Furanoses



D-Rlbose



.>-oMe





Q



0 OH



17



Mll2c"-O OH

To a solution of o-ribose (7.5 g, 50 mmol) in dry DMF (30 mL) containing 1 g of Drierite

and maintained below 5°C with an ice bath, 2-methoxypropene(100 mmol) andp-toluenesulfonic acid (20 mg) were added. The mixture was stirred magnetically at 0-5°e until

monitoringby TLC indicated that all starting material had disappeared (3-4 h), whereupon

anhydrous sodium carbonate (5 g) was added and the cooling mixture was stirred vigorously for 1 h more. In subsequent experiments, 3,4-0-isopropylidene-o-ribopyranose 17

was obtained directly by evaporating the neutralized reaction mixture to remove DMF,

extracting the residue with ethyl acetate, adding ether to the extract and nucleating; yields

were in the range 40-50%.

3,4-0-Isopropylidene-o-ribopyranose 17 obtained by this procedure had an mp of

115-117°e (from ethyl acetate), [ale -85° initial ~ -82° (final 24 h; c 1.1, water).



Methyl 2,a-o-isopropylldene-f>-o-ribofuranoslde [1DO}

a,4.Q-isopropylidene-p-o-arabinopyranose'[54}



A solution of 50g (330 mmol) of dry o-ribose in 1.0L of acetone, 100 mL of 2,2dimethoxypropane, and 200 mL of methaiJ.ol containing20 mL of methanol saturated with

hydrogen chloride at ooe was stirred at 25°C overnight. The resulting orange solution was

neutralized with pyridine and evaporated to a yellow oil. This oil was partitioned between

500 mL of water and 200 mL of ether. The water layer was extracted twice with 200-mL

portions of ether, and the combined ether extracts were dried. Evaporation yielded a pale

yellow oil, whiclt was distilled at 0.3 mm and 75°C to give 47 g (70%) of the colorless,

protected glycoside: "n 1.4507, [a]D -82.2° (c 2, chloroform).



To a solution of o-arabinose (7.5 g, 50 mmol) in dry DMF (150 mL; the slightly turbid

mixture became clear after 1 min of reaction) containing 1 g of Drierite, and maintained

below 5°C with an ice-bath,2-methoxypropene (100 mmol) and p-toluenesulfonic acid

(20 mg) were added. The mixture was stirred magnetically at 0-5°e until monitoring by

TLe indicated that all starting material had disappeared (3-4 h), whereupon anhydrous

sodium carbonate (5 g) was added, and the cooling mixture was stirred vigorously for 1 h

more. The mixture was filtered, poured into ice water (50 mL), and extracted with



Calln aud and Gelas



18

wash ed with wate r

the com bine d organic extracts were

dichloromethane (3 x 30 mL) , and

were freeze-dried.

and the com bine d aque ous extra cts

(3 x 20 mL). The aque ous phas e

gave pure 2; yield

iol)

ethaJ

telm

150 g; 4:1 ethy l aceta

Colu mn chromatography (silic a gel

ixture was evap orate d

ion-m

react

ed

raliz

neut

nal

origi

the

4.8 g (63%). In a direc t procedure,

ition of ethe r and a

syru p disso lved in ethy l acetate. Add

directly in vacu o and the resu ltant

.

yield

0%

60-7

crystal nucleus affored solid 2 in

. of 75-7 6°C.

yran ose 18 thus obta ined had am.p

3,4-0 -Isop ropy liden e-a-o -arab inop

e crystals, mp 82whit

gave

nol

etha

ate-m

acet

l

1:1 ethy

Slow evaporation of a solu tion in

(final, 24 h;

ted) 4 -128 ° (10- 12 min) 4 -IW

84°C, [aID -156 ° (initial. extrapola

e i.i, water).



C. Hexosea



Furanoses

furanose [95J

1,2:5,6-Di'()-isopropy}idene-o-gluco



D-GhJcose



Related Acet als

Isop ropy flden e, Benzytldene, and

oc~



?~H



M~ ,I



~~HOa<~

0,,,\



se [95J

1.2-o-lsopropylidene-o-gJucofurano

the acetone

is followed until evap orati on of

oing

foreg

the

in

ribed

The proc edur e desc

r redu ced

unde

is disti lled

is adde d, and the mixt ure

solu tion to a syru p. Water (2.5 L)

ensa tion products.

remo ve acetone and aceto ne cond

to

mL

1600

to

pres sure at 6O-70OC

hydrochloric acid

ted

entra

conc

with

2

pH

to

sted

is adju

The final alkal ine aque ous mist ure

ed to pH 8 with

raliz

neut

is

te

stirring. The hydrolysa

and heat ed 4 h at 4O"C with cons tant



0 \



CMez



'c~



.

e'

ed from 1.7 g ofin sol ubl

te ISconcentrated

sodi um hydr oxid e and filter

material. The filtralide

. .

"

to'

sure

pres

.

0

ced

under redu

ation of 1,2 - -ISOpropyI ne-a -o-g luco mClplent cryst alliz

luran

ti

ose. The prod uct is remo ved by filtra

ed with cold ethanol, and air-d ried''

-120 ( 83 on, washConc

entratio f th e moth er liquo r

yield 81.2 g, mp 1610C' raj

r)

wate

.,

c

0

n 0

.

d

) E'

.

55%

yield

l

(tota

g

33.6

yield

;

crop

grves a seco n

of ~e ~ moth er liquo r to

~

ti°hi

1~~ra

148'_

mp

uct,

prod

e

purif y and

near dry n~ give s 83 g of crud

. ' w ch 18 difficult to.

'

the hydr ol sate 0 f a SUcceedin

g run.

therefore, IS adde d to

y

,



Pyranoses



-gJucopyranoside [3B]

Methyl 4,6'()-benzylidene-a_ and J3-o



H~~

OMe



d vigo rous ly with

dere d in a Waring blender, is stirre

Anh ydro us a-D- gluc ose (200 g), pow

L porti ons at

20-m

in

d

adde

is

mL)

160

uric acid (96%,

4 L of aceto ne in an ice bath . Sulf

addition of

the

r

Afte

ng the temp eratu re at 5-10 °C.

10-1 5-m in intervals, whil e main taini

re to rise

eratu

temp

the

ing

allow

h,

5

ng is cont inue d for

the sulfuric acid, the vigorous stirri

oxid e

hydr

um

sodi

is cool ed again (ice bath), and 50%

gradually to 2O-2 5°C. The solution

. The

ality

neutr

near

to

ng

stirri

with

of water) is adde d

solution (245 g of NaO H in 300 mL

ogen carb onat e is

hydr

um

sodi

of

unt

amo

l

smal

A

ng.

addi tion is mad e slow ly to avoi d heati

t, the salts are

neutrality. Afte r standing overnigh

adde d to main tain the solu tion near

ced pres sure to a

redu

r

unde

ted

entra

conc

is

ion

ne solut

remo ved by filtration. and the aceto

rofo rm on a wate r

ing. The mixt ure is disso lved in chlo

thick syrup that solidifies on stand

then wash ed with

is

tion

solu

rm

rofo

chlo

The

r.

with wate

bath, and the solu tion is extra cted

ions are com solut

rm

rofo

respe ctive wate r and chlo

chlo rofo rm or dichloromethane. The

and the wate r

ative

deriv

e

liden

ropy

-isop

di-O

ains the

bined. The chlo rofo rm solu tion cont

r redu ced

unde

ted

entra

conc

ative. The solu tions are

the mono-O-isopropylidene deriv

ethyl acefrom

ed

alliz

cryst

is

ative

deriv

e

ropy liden

pres sure to syrups. The mon o-O- isop

zed from

stalli

recry

is

di-O-isopropylidene deriv ative

tate; yield 37 g, mp 160°C. The

C.

cyclo hexa ne; yield 121 g, mp llO°



19



«.a-dlmethoxytoluen:.



Ph~~

OMe



-dim

)

Meth yl-a- O-gl ucop yran osid e (97 a~ . etho xyto luen e (7.6 g), DMF (40 mL), and

p-tol uene sulfo nic acid (0.025 g) 'w:~

ed flask; this was

Ptated, m a 250- mL, roun d-bo ttom

then attac hed to a Bllcbi evap orate

a wate r bath at

into

red

lowe

ev:;: uate d, and

~:

60 ± 5°C, so that DMF refluxed

h evap orati on

t-pat

shor

a

h,

1

r

Afte

uct

~~

adaptor(descriptionofwbichiSgivenine

flask and the

the

een

betw

orated th re=n ce) was fitted

vapo r duet, and the DMF was evap

g raise d to

bein

bath

r

wate

the

of

ture

pera

,e

led

100°C. Whe n no more DMF di stilled over, the flask

from the

ved

and remo

was ~oo

dro en c

adde d to

evaporator. A solution of sodi um h

was

mL)

(50

r

wate

m

g)

(1

he:t ed; lOO ~na ~

The

rsed

th~ residue, and the mixture0wasand

dispe

y

finel

was

until the prod uct

th prod

.

mIXture was cool ed to 2Q C, e

was filtered off' washe d th orou ghly with

uct

d dri

rni '

te

ed for 4 h at 30°C and then ove

wa r, an

pentaOJude

m 1 : ~ v~o over phos phor us

)'

824%

g

(11.6

19

give

to

wax

and paraffin

prop yl

from

ion

lizat

ystal

63.5 %)' ~~67 5- 1~ C~ Recr

alco hol (28 mL) gave 19 (8.95 g,

8.5 C, [aID + 105° (c 1.1, chIoro.

,

..

form).



Ph""\
~OMe



ZO



OH



.

liden an

g) was be

in the foreribed

. Methyl-J3-o-glucopyranoside (9.7 cake f my

desc

as

d

nate

the

uct

gom g. After remo val of thesolvents

la, and

spatu

a

with

up

en

brok

ogen c::.,:naoc:e w~

disso lved in a solu tion of sodi um h;dr

mL) and etha nol

(150

w~r

~

g)

(l

bath

ng-w ater

(150 mL) by heat ing on a boili

.' The solution was cooled to 4°C and

ashed

com poun d 20 was filtered ot!

30 h at 30°: The

of :w; '': ~~ water, lIlId dried for

prod uct (8.2 g, 58% ) had an ~.;

stallization from

recry

by

ed

methanoi). C (unc hang

ethyl alcoh ol) and [aJo -760 (c 1.0,



C8l1naud and Gelas



Related Acet als

l8op ropy llden e, Benz ylide ne, and



21



20



Met hyI2 .3-0 -ace tyJ 4.6-Q-benzyl



J



Me



idene-a.-o-glucopyranoside {82}



_ r -...A~ ..



(Ii)



\.

H~CtizO

H



.(1)

PhCHCb

pyridine



nv---~

OMe



Ptf'b~q



AozO



~



P~~

OMe



21



11



chloride (7.6 g),

in drypyridine (100 mL) and benzyl

Methyl a-o-g luco pyra nosi de (7.6 g),

r for 9 h. After

ense

cond

the

of

top

tube fitted to the

was refluxed with a calcium chloride

tion allowed

solu

anhydride (20 mL) was added, and the

cooling to room temperature, acetic

benzene.

with

cted

extra

was

ure

adde d, and the mixt

to stand overnight. Excess water was

saturated aqueous

acid,

ric

sulfu

M

1

cold

ice

tum,

, in

The benzene layer was washed with

over magnesium

r. The benzene solution was dried

sodium bicarbonate, and finally wate

stallized to yield

recry

was

ue

resid

red

-colo

dark

The

sulfate, filtered and concentrated..

101- 104° C, [alo

lidene-a-D-glucopYraDoside 21: mp

methyI2,3-di-0-acetyl-4,5-0-benzy

% amm onia in

1.67

with

ted

etyla

deac

was

rial

mate

+75° (c 1.0, chlorofonn). Part of the

161- 163° C

mp

19:

ide

anos

zylidene-a.-o-glucopyr

methanol to yield methyl 4,6-0-ben

le.

samp

entic

auth

undepressed on admixture with an

Methy/2,6-di-Q-acety/-3,4-Q-ben



H~C



~



PhC~



(1)

ine

H~ OM e Pyrid

(2)AezO

HO



22



{82}

zylldene-f3-o-galactopyranoside

PhC H,/ Oa .



~



HO



0



r;ld



.



4,6-Q-lsopropylidene-o-galaeto



~o



>"'"-



pyranose [53}



0000 .



.



~ . -(~

OH



e



22 (obtained from ~-o­

acetyl-~-D-galactopyranoside

A solution of 1.77 g of methyl 6-0(2) benzylation at 0-3,

;

ation

trltyl

6-0

(1) selective

galactopyranoside by a sequence of

olysis) and 1.61 g of

ogen

tion; and (5) catalytic hydr

4, and 5; (3) detrltylation; (4) O-ae etyla

re for 5 h. Mor e

eratu

temp

x

reflu

the

at

d

ine is heate

a,a-d ichlo roto luen e in 25 mL of pyrid

an additional 3

for

x

reflu

d and the solution is heated to

a,a-d icblo rotol uene (1.61 g) is adde

allowed to

then

is

h

whic

ion,

solut

warm

d to the still

h. Acetic anhydride (5 mL) is adde

solution is

ne

tolue

the

tion is diluted with toluene, and

stand at 20-2 5°C over nigh t The solu

g with

dryin

r

Afte

r.

wate

then

and

te,

hydrogenocarbona

shaked with water, aqueous sodium

presced

redu

r

unde

tion is concentrated. to dryness

ure.

sodium sulfate and filtration, the solu

press

ced

redu

r

unde

ne

tolue

with

codistillation

ss

sure. Pyridine is remo ved by repe ated

exce

ve

remo

to

)

ed with light petroleum (6O-80°C

The crude crystalline product is wash

colu mn

gel

silica

by

ied

purif

is

g)

prod uct (2.74

a,a-dichlorotoluene. The remaining

chloroform/ethyl

em, diameter 5 em) using 9:1 v/v

SO

th

leng

mn

(colu

hy

grap

mato

chro

C.

117°

g (58%), mp 113ether as elue nt to give 23, yield 1.60



4.6-Q-ls

over Drierite) kept

30 mn\.ol) in DMF (100 mL, dried

Toa solution of o-glu cose (5.4 g,

l) and p-toluenemmo

d 2-methoxypropene (5.2 g, 60

below 5°C in an ice bath was adde

TI.C monitoruntil

C

0-5°

at

ally

netic

mag

was stiJred

sulfonic acid (-10 mg). The mixture

n sodium.

eupo

wher

h),

had disappeared (about 5-6

ing indicated that all starting material



0



OH



minor

21



major



26

OM



23



[51J

opropy/idene-o-gJucopyranose



"

'

carbonate (-5 g) was added, with ene ~::mgdo~the cold mixture for I h. The mixture

r::

was refrigerated overnight and then

ed into ice water

extracted ~ ~~trate was. pour

(50 mL). The resultant solution was

x SO mL), and the

(3

nde

chlo

ene

y

ed 'th· WI me

combined organic extracts were wash

phas e and the

ous

aque

WI • wate r (4 x 20.mL). The

combined aqueous extracts were free

(6.25 g,

solid

e

whit

a

as

~

=(~:

95%) that was homogeneous by 'TI..C

ed no appreciable

show

on,

ylatt

Ys

Q

d

th

."

peak s for components othe r than e a-. an ....-anomers of 24 . R ecrystall

izatton could be

small hi

0.5° C [a] +240

effected from etha nol- hexa ne to give

5-17

169.

mp

ules;

gran

te

w

:

° r 059

0

h; 21

48c

(initial, extrapolated) ~ +85

., water).

. ,c. min) ~ -7.3 ° (final ,



laeto se ( hi h

To a slightly turbid mixture of o-ga

-5. ~ of reaction);

kon;~dbecehy:e.cIear after

Sik

of

g

I

g

0C

ainin

cont

l)

mmo

(?O g, 50

agent) ll18lntained at 0-5

ting

acid

nic

(Ice bath) are added 2-methox

sulfo

uene

p-tol

and

l)

::rn e (7.2. g, 100 mmo

(30- 50 mg). The mixture is sYJ

itoring by TLc

s ; : : ; : : a la:;-~OC until mon

the

of

aU

indicates that practically

whereupon

(-4

~

~

cold

is added, andthe

rouslyfor I

anhydrous sodiumcarbonate (-5 g)

VIgo

rred

ISsti

re

. ~tu

the filtrate

h more. The mixture is filtered, and

water (SO mL). The resultant

lee

mto

ed

pour

(

th

d th

solution is extracted with dichl orome ane 3 x 30 mL)

e extracts are combined,

' an

and dried. (sod i

extracted with wate r (3 x 30 mL)

The aqueous phase is

ate).

.sulf

~

.

en

the

combined lVith the water extracts ~

ed. The freeze-dried

e-dri

freez

18

ton

sol~t

am

aqueous extract gave 9.8 g of ~

ed a majo r

ethan~ as. solid, TI.C of which shOw

of a third

component (Rr 0.30; 3:1 benzene/

s

trace

and

),

0.37

(R

r

one

r

were ~ nnno

component (Rr0.45). Theseproducts

hY(440g0f

ive su~bycolumn.Chromatograp

silica gel, 3:1 benzene/ethanol) to

galacto_

e-D_

iden

oPYl

SOpr

ac~tal26 (~slve.l~ii~-O-l

furanose (0.10 g, yield 1-2% ) and

yield 67%).

g,

(75

25

and

%)

m

g':

e'

es thes

Directly on evaporation of the eluat

obta!ned pure.

o~ 25 crys . e products were

4,6-0-Isopropylidene-o-galacto

an mp of 141- 1420C

~

)

67%

d

YIel

g,

(7.4

I

0

[alo +92 ° (3 min) ~ +118 °

ylidene_o-gaIacto0C fa]

;1~5; w~)r) and 3,4-0-18oprop

pyranose 26: [mp 99-I 03

c OJ, water).

h;

(~

°

+44

~

mm

0

,



.?),



h:



r:::



(3



ctopyranose [9S}

1,2:3,4-0i-Q-isopropylfdene-o-gaia

pped .

90 g

In a 4- to 6-L, wide-necked bottle, equi

a ground-glass stopper, are plac ed

s 0drou

anhy

d

dere

pow

d

dere

pow

of

(0.5 mol) of finely

mol)

1.25

g,

g actose (200



w:



Callnaud and Gel. .



23



lsopropylldene, Benzylidene, and Related Acetals



2



D-Galactose



Met?0 •



eus0 4. ~04



M~~OO~~~

"-



o-Mennose



'eMil:!



HOH;zC



H~

CMIl:!



OAe



Me



>-OMe. ~~t?27

HO~OH



1)' dry DMF (20 mL) containing Orierite (1 g)

A soluti?n ~f o-mannose ~c4g~Ob=oan~ 2-methoxypropene (4.3 g, 60 ~ol) and

was mamtamed below 5

added Tb mixture was stirred magnetically at

p-toluenes~oni~ ac~d (-20 mg~ :ereted that S~g material had disappeared (-~ h),

0_5°C until momtonng by:U: in ca

added, and the cold mixture was stirred

whereafter anhydroUS sodium c~natew:S~ltered,and the filtrate poured into ice water

vigorously for 1 more hour. The ~~th dichloromethane (4 x 20 mL),and the ex~ts

(SO mL). ~e product was ex~ Wl(4 x 20 mL). The aqueous phase and the com~med,

were combined. and washed WltJ:" water . Id 8Il amorphous solid (mono-O-isopropylidene

aqueous extracts were freeze-dried, to ~e f the dried (sodium sulfate) dichloromethane

derivatives; fraction A, 6.0 g). Evaporationderi°. ti es fraction B' 07 g). Fraction A was

di 0 .

pylidene

va v ,

' .

7

extract gave a syrup ( - -ieopro

f the 4 6-0_isopropylidene-o-mannOpyranose 2;

essentially a mixture of the an~~rant. The amorphous solid (yield 91%? was ~­

with the a-anomer strongly prepo

. the a anomer as a microcrystalline, white

~stallized twice fi:om ethyl ac~1~7~;~a]

(3 min) -+ -16° (5 min) -+ -24°

powder; yield 5.4 g (-.i2%),mp

D

(final, 48 h; c 1.2, water).



'mI



_10



ylidene-o-mannopyranose and Its Selective



1-0-Acetr'-2,3:4,6-d/~:~~isopropylidfJne-D-mannopyranose {52]



01 ill

DMF (20 mL). containing Orierite (1 ~)

A solutionofo-mannose (5.4 g, 30 mm) dry (43 g 6Oromol)andp-toluenesulfoJllC

was maintained at _-lo°C, and 2:methoxyp:-:=:tma~eticallY for -3 h, and then a further

acid (-20 mg) were added. The unxture was



OAe



2.



28



4.6-0_ISOpropylidene-o-mannopyranose (52]



HydrolYSIS to 1-Q-ace.



~~~

.



form).



.'







(2) Aozo



Jp

CMe:z



trated sulfuric acid and 2 L (27.4 mol) of

anhydroUS cupric sulfate, 10 mL of concen

'-__leal shaker The cupric sulfate

.

ture is shaken 24 h on a mec"......·

ed

. anh dro acetone' the washings are combin

anhydrous acetone. Tbe unx

fi1 ti

d washed Wlth

Y us,

shak.in

is removed.~ tra on an

combined washings and filtrate are neutralized by

g

.

xide until the solution is neutral to Congo

with the onginal filtrate. The

with 94 g (1.27 mol) of powdered ~clumd~!.~ sulfate are filtered and washed with dry

ted eal ium hydroXide an .....Clum

b .

red. The unreac

c

ted b distillation of the acetone at atmosp enc

acetone, and the J:iltrate is co:;ntr:tainJ. the major portion of the remaining acetone is

no

tel aspirator). The last traces of acetone are

pressure. After a thin syrup has

removed by distillation at 50°C and 15 rom ~w:

The residua1light yellow oil is crude

finally removed by distillation at ~~o~ ~OO-;;:~, (76-92%), [a]D -55° (c 3.5"chloro\

l,2:3,4-di-O-a-o-galactopyranose. yie



o-Mannose



(1~OMe



amount of ether (4.3 g, 60 mmol) was addeddropwise over -2 h, the temperature being kept

at --lo°C. The lLC (ethyl acetate) indicated that slow-migrating components (Rf < 0.5)

were absent. The mixture was then treated exactly as described for the foregoing procedure.

In the present experiment, the aqueous phase contained only traces of the monoacetals.

Evaporation of the dichloromethane extract gave an amorphous solid the properties of

which in 1LC (1:2, ethyl acetate/petroleum ether) were very similar to those of the syrup

(fraction B) described for structure 27 for the preparation of the monoacetal, except for the

presence of very minor, fast-migrating contaminants. The mixture was acetylated conventionally with acetic anhydride and pyridine. Evaporation of the solvents, and nucleation

(nucleation was not needed in subsequent preparations) gave a solid. One recystallization

from methanol-water gave reasonably pure compound; a second recystallization afforded

analytically pure 1-O-acetyl-2,3:4,6-di-O-isopropylidene-a-o-mannopyranose 28: yield

5.9 g (65% from o-mannose); mp 145-147°C (methanol-water), [a]D +3° (c 1.0, chloroform). If necessary the acetate could be deacetylated conventionally to the free sugar [52].

A suspension of diacetal28 (0.5 g) in 1:3 acetic acid/water (20 mL) was stirred at room

temperature until dissolution was complete (-1 h). The solution was then refrigerated (-0°)

overnight. Use of TLCthen indicated the presence of a major component (Rf 0.43, ethyl

acetate). The solution was freeze-dried to give 1-0-acetyl-2,3-0-isopropylidene-a-omannopyranose 29 as a microcrystalline powder that could be effectively purified by

recrystallization from ethyl acetate; yield 0.32 g (74%), mp 130-131°C, [a]D -24.5° (cO.9,

chloroform),

Note that if the anomeric hydroxyl group was not acetylated as it is in the acetal 28, a

transformation of the monoacetal to its isomer 2,3-0-isopropylidene-o-mannofuranose

could be observed



D. Amlnosugars

Acetonation of 2cacetamido-2-deoxy-o-glucose {35]



C~OH



H~q



.



Me~o



M8:zC(OM~h



H~H



O~~



HO~H



30



It had been demonstrated that the result of the reaction was dependent on the temperature at

which it was conducted.

1.



At 80-85°C during 15 min, a stirred solution of2-acetamido-2-deoxy-o-glucose

(9.5 g. 43 mmol) andp-toluenesulfonic acid monohydrate (100 mg) in dry DMF

(130 mL) was heated to SO-85°C, and then 2,2-dimethoxyprop8llC (20 mL) was

added; stirring was continued for 15 min at 80-85° (the starting material was

then no longer detectable by 1LC). The mixture was cooled and treated with



C8l1naUd and Gela.



24



filtraAmberlite IRA-410 (OH-) ion-exchange resin to remove the acid After

ous,

spontane

was

zation

Crystalli

tion, the filtrate was evaporated at 60° (bath).

chlorowith

stirred

cooled,

was

mass

the

,

complete

was

ion

evaporat

and when

g, 54%)

form, and the product removed by filtration. The crystalline product (6

pyranose

-o-gluco

pylidene

0-isopro

oxy-4,6ido-2-de

2-acetam

as

was identified

30: mp 189-190 °C [«]0 +57S (c 0.99, methanol).

9.5 g of

2. At room temperature during 2 h, the reaction was conducted with

in

2-acetamido-2-deoity-o-glucose by the same method lind procedure [reported

was

filtrate

final

the

90%),

(lOg,

product

the

of

lization

Ref. 96]. After recrystal

rm!

chromatographed on a column of silicic acid (30 g) with 30: 1 chlorofo

methanol.



lsopropy lldene, Benzylidene, and Related Acetal.



evaporatin fro

24 h, c 0.1

g m the chromatography solvent; mp 90-91 "C, [«:I., + 10° (equil.,

water).



F. Ollg088CCharides

Benzylidenation of Sucrose [97]



Ph,""\~O0



.

H2~.

H~C



.



H.



o



HOC~H:z0



E. Deoxysugars



HO



(2) Ac:zO



2,3-G-lsopropylidene-L-rhamnopyranose



..



CH:zOH



ACOCH:z



~o



CH:zOAc



.

be

Asolutio nofsucro se (2.5 g) in dry pyridine (50 mL) was treated ith

e bromide

~liden

li:

benz

of

addition

further

a

After

h.

1.5

for

850C

at

(2.8 mL)

mL), the

(1

~rmde

ne

y.

ith

treated

h

0.5

for

reaction mixture was heated at 95°C

1~ acetic anI;lydride (5 mL) at O°C,

and then stored at room temperature for 5 h.' Th

. e so ution was poured into ice water and

extracted with dichloromethane and

with water and dried

The 1LC (4:1 ethermgh t

four products. The

of

rmxture

a

thas:t

with

identical

was

Rf of the slow-moving spot

ate, and the second,

fast-moving spot was the major product The 1 ~ sucrose acta-acet

so ution was concentrated andfractionated on

.'

a column of silica el (200

g), usmg 1:I etherllight petroleum. 1'2 3 3' 4' 6'-Hexa-O.

ligde

be

6-0

l-4

acety

staUize d:'"

ne-sucrose 33 (1.7 g, 35%) which

- nzy

. '

0.82, c:O:o~~s of the

c

+44.3~

[«]:

°C,

ISS-157

of

fraction collector, had an m.p.



~=c ~aY:7as ~ashed



Acetonatlon of Sucrose [58J



~e



..



Q

~

~

~

tK>~r~

+



PCH,OH



OH

34



g, 30 mmol) except

The procedure used for L-fucose was applied with t-rhamno se (4.22

mmol) was added

60

g.

(4.32

that twice the stoichiometric amount of 2-methoxypropene

us residue (that

amorpho

crude

the

of

1LC

The

reaction.

the

of

g

beginnin

directly at the

95% by

(purity>

spot

one

only

ly

remained after removal of the solvent) showed essential

rapid

by

ion

Purificat

85%).

g,

5.2

(yield

acetal

g

attemptin

the

to

NMR) corresponding

2,3-0syrupy

pure,

gave

ether)

column chromatography (1:1 ethyl acetate/petroleum

crystallized by slow

isopropylidene-L-mamnopyranose 32 (4.9 g. 80%) that eventually



33



AcO



Ace



(N~S0.J.



was stirred with a

A solution of L-fucose (4.92 g, 30 mmol) in anhydrous DMF (50 mL)

(2.16 g, 30

ypropene

2-methox

and

bath),

(ice

O°C

at

desiccant (Drierite or Sikkon, 1 g)

1 hat O°C, an

After

mg).

(-20

acid

esulfonic

p-toluen

by

followed

added

was

mmol)

was continued

additional stoichiometric amount of reagent (2.16 g) was added, and stirring

further 1 hat

stirred

was

mixture

the

and

added,

was

g)

(-5

e

carbonat

ium

for 2 h at O°C.Sod

ed under

evaporat

was

filtrate

the

and

room temperature. The solids were filtered off,

major

one

acetate)

ethyl

(TLC,

d

containe

that

syrup

a

to

40°C

at

diminished pressure

on a

product

the

of

graphy

chromato

product plus minor, fast-migrating components. Rapid

yield

31;

se

copyrano

ene-L-fu

propylid

3,4-0-iso

e

crystallin

pure,

gave

column of silica gel

0.2, water).

3.7 g (-60%); rnp 1l0-1l10 C, [«]0 -90° -+ -70° (24 h, equil.; c



0



OA



(1)PhCH;z8r/pyridine



HO



Acetonation of L-fucose and L-rhamnose [56J

3,4-G-lsopropylldene-L-fucopyranose:



25



M



\



J-wsH, OH



oc~;;r

35



..

A solution of sucrose (34.2 g, 0.1 mol) in dry DMF 400

mL) containing molecular sieve

pellets (YJ6 in., type 3 A) was stirred with 2 eth (

0.13 mol) in the

presence of dry p-toluenesulfonic acid (25-: ) o::;p:en~ (12.1 mL,

mID at 70OC, cooled to room

temperature, and made neutral with anh dro g .

to us sodium ~nate. The inorganic residue

was filtered offand the filtrate eva

of

a

of

silica gel with 1:I ethyl acetate la::e

2,1 .4,6-di-O-ls0pr0pylidene_

sucrose 35 as a syrup: 3 g (7%)' [«] +25 50

~~ 1, methanol). F~erelution gave themajor

product 4,6-o-isopropyliden;suc~

ld 23 g (60%); white powder; [«]0 +45.40

yt

.

l).

(c 1.0, methano



tel



aff~~'d?:= ~ sy~p~ m col~



34'



Tài liệu bạn tìm kiếm đã sẵn sàng tải về

Synthesis of Isopropylidene, Benzylidene and Related Acetals

Tải bản đầy đủ ngay(0 tr)

×