One of the most common procedures for the synthesis of pseudoglycals is the Ferrier allylic rearrangement of glycals.

CHAPTER II

2,3-UNSATURATED-O-GLYCOSIDES FROM

GLYCAL-DERIVED VINYL EPOXIDES AND N-MESYL AND N-NOSYL AZIRIDINES

2.1. D -Galactal- and D -allal-derived vinyl epoxides and vinyl aziridines

One of the most common procedures for the synthesis of pseudoglycals is the Ferrier allylic rearrangement of glycals.

Recently, in the laboratory where I have carried out this thesis, new glycal-derived vinyl heterocyclic systems were synthesized and studied: the D -galactal- 2.1,

and D -allal-derived vinyl epoxide 2.1

and the corresponding vinyl N-mesyl- 2.2

and 2.2

and N-nosyl-aziridines 2.3 and 2.3

(Figure 2.1).

Epoxides 2.1-2.1, and aziridines 2.2-2.2 and 2.3-2.3possess an intrinsic synthetic interest, due to the fact that they are simultaneously glycals and vinyl oxiranes or vinyl aziridines (Scheme 2.1, for the sake of simplicity only epoxides 2.1 and aziridines 2.2 and 2.3 are shown). As vinyl oxiranes and vinyl aziridines, they are characterized by a double reactivity when subjected to a nucleophilic addition reaction:

the nucleophile can attack (i) at the C(1) vinyl terminus of the “conjugate system”

through a typical 1,4-addition pathway (conjugate addition or S

2’ process, route a) to yield 2,3-unsaturated-- and/or -glycosides (pseudoglycals), hereafter generically called

- and -1,4-addition products, and (ii) at the allylic C(3) oxirane or aziridine carbon to give substituted glycals through a direct, commonly completely anti-1,2-addition process (S

2 process, route b) to give substituted glycals, hereafter generically called anti-1,2-

Figure 2.1. Epoxides 2.1-2.1, and aziridines 2.2-2.2 and 2.3-2.3.

BnO O

O 2.1

BnO O

O 2.1

BnO O

N

2.2, R = Ms 2.3, R = Ns

BnO O

R R N

2.2, R = Ms 2.3, R = Ns

addition products. The 1,4-addition products having the same configuration ( or ) of the starting heterocycle ( or ) can be also called syn-1,4-addition products or coordination products, because supposed to derive from an heterocycle-nucleophile coordination process, whereas 1,4-addition products having a configuration ( or ) opposite to that of the starting heterocycle ( or ) can be also called anti-1,4-addition products or non-coordination products, because supposed to derive from a free, non- coordinated attack by the nucleophile. Under this respect, also anti-1,2-addition products are clearly non-coordination products, whereas eventually present syn-1,2-addition products, derived from a syn addition of the nucleophile, could be also called coordination products if demonstrated to derive from an isomerization of the corresponding, initially formed, syn-1,4-addition products (the primary reaction product).

The C(1) of the vinyl oxirane and vinyl aziridine system also corresponds to the classic reactive site of any glycal system, as epoxides 2.1-2.1 and aziridines 2.2-2.2 and 2.3-2.3 actually are (Scheme 2.1).

Scheme 2.1. Regioselectivity of nucleophilic addition in glycal-derived vinyl oxirane 2.1 and  aziridines 2.2 and  2.3 . 

BnO O

X

BnO O

HX

Nu

BnO O

HX Nu a

1 4

3 2 Nu

Nu

b

2.1, X = O 2.2, X = NMs

2.3, X = NNs 2,3-unsatur ated-





3-substituted glycals

anti-1,2-addition pr oduct



BnO O

HX

Nu and/or



syn- and anti-1,4-addition (conjugated or S_N2'addition)

BnO O

HX and/or

Nu syn-1,2-addition product

syn- and anti-1,2-addition ( S_N2 addition) r oute a

Nu

r oute b Nu

Epoxides 2.1, and 2.1 and the N-mesyl 2.2-2.2 and N-nosyl aziridines 2.3-2.3 turned out to be not sufficiently stable to be isolated, but they could be only prepared in situ by cyclization under alkaline conditions (t-BuOK) of the corresponding ultimate precursor, the trans hydroxy mesylates 2.4, (Scheme 2.3) and 2.4 (Scheme 2.8) for epoxides 2.1, and 2.1 and the trans N,O-dimesylates 2.32 and 2.32

(Schemes 2.14and 2.20) and trans N-nosyl-O-mesylates 2.47 and 2.47 (Scheme 2.24) for aziridines 2.2-2.2 and 2.3-2.3respectively, and then left to react immediately with a nucleophile (O-, C-, N-, and S-nucleophiles).

The addition reactions of nucleophiles to these vinyl heterocyclic systems were carried out by making use of two different protocols:

- protocol A: the base (t-BuOK, 1 equiv) is added to a solution of the corresponding ultimate precursor of the epoxide or aziridine in the nucleophile (e.g.

alcohols) used as the solvent, that is under reaction conditions characterized by a large excess of the nucleophile;

– protocol B: the base (t-BuOK, 1 equiv) is added to a solution of the corresponding ultimate precursor of the epoxide or aziridine in an anhydrous, non- nucleophilic solvent (benzene, toluene, THF, MeCN, Et

O) and the nucleophile is then added (3-4 equiv), that is under reaction conditions characterized by the presence of only a small excess of the nucleophile.

Calculations indicated that D -galactal-derived epoxides 2.1 and aziridines 2.2

and 2.3 exist as the only corresponding conformer ’, whereas D -allal-derived epoxide 2.1 and aziridines 2.2 and 2.3 exist as an almost 35:65 (in the case of epoxide 2.1) and 1:1 (in the case of aziridines 2.2 and 2.3) equilibrium mixture of the two possible corresponding conformers, ’ and ’’, as shown in Scheme 2.2.

Scheme 2.2. Conformers of vinyl epoxides 2.1 and 2.1and vinyl aziridines 2.2, 2.2, 2.3and 2.3.

O X

O OBn X

BnO

2.1', 2.2', 2.3' 2.1", 2.2", 2.3"

X = O, N-Ms, N-Ns

O X

OBn

O X BnO

2.1', 2.2', 2.3' 2.1", 2.2", 2.3"

The unique conformer ’  has the side chain pseudoequatorial, whereas the slightly more stable conformer ”  has the side chain pseudoaxial.

2.2. Synthesis and regio- and stereoselectivity of the addition of O-, C-, and S-nucleophiles to D -galactal-derived vinyl epoxides 2.1

Trans hydroxy mesylate 2.4, the precursor of epoxide 2.1, was prepared from the commercially available tri-O-acetyl- D -glucal (2.5) through a simple protection- deprotection protocol (Scheme 2.3).

2.2.1. O-Nucleophiles

The addition reaction of alcohols (MeOH, EtOH, i-PrOH, t-BuOH) to epoxide 2.1 (protocol A) afforded the corresponding O-glycosides (1,4-addition products) in a completely 1,4-regioselective way, but with a stereoselectivity depending on the type of alcohol used.

In fact, if in the reaction carried out in MeOH an almost 1:1 mixture of anomeric 2,3-unsaturated methyl - and -O-glycosides 2.6 and 2.6 was obtained, the use of more hindered alcohols such as EtOH and i-PrOH led to an increased -selectivity with an / ratio 25:75 and 5:95, respectively. Only when a reduced amount of alcohol (3 equiv) was added to the epoxide preformed in a benzene solution (protocol B), there is a completely 1,4-regio- and -stereoselective process obtained with the exclusive formation of corresponding -O-glycosides 2.6 (syn-1,4-addition products). Under these conditions, also not simple O-nucleophiles such as PhOH, BnOH and diacetone- D - glucose could be used as glycosyl acceptors affording the corresponding -O-glycosides and a -linked disaccharide as the only reaction product, in a new, uncatalyzed,

Scheme 2.3. Synthesis of trans hydroxy mesylate 2.4 and epoxide 2.1 . 

OAc AcO

AcO

O

OH BnO

MsO

2.5 2.4

benzene, Et₂O, MeCN,

or THF 2.1

t-BuOK O

BnO

O

completely stereoselective, directly substrate-dependent glycosylation procedure (Scheme 2.4).

Contrary to expectations, the same completely 1,4-regio- and -stereoselective behavior was observed also with an alcoholate such as MeONa (protocol B) (Scheme 2.5)

The complete 1,4-regio- and -stereoselective result obtained in the addition reaction of O-nucleophiles (alcohols and alcoholates) to epoxide 2.1, with the exclusive formation of corresponding syn-1,4-addition products (protocol B) was rationalized by a coordination between the oxirane oxygen and the nucleophile through a hydrogen bond (alcohols) or the metal (alcoholate), as shown in structures 2.8 and 2.9, respectively (Schemes 2.4 and 2.5). In this way, the nucleophile is efficiently transported on the -face of the vinyl oxirane system and appropriately disposed for an entropically favored - directed conjugate addition, as experimentally found. Due to the unexpected rigidity of this vinyl oxirane system, the attack of the coordinated nucleophile on C(1) necessarily proceedes in a pseudoequatorial fashion (route a, Scheme 2.4).

Confirmation of this rationalization was obtained in the reaction of epoxide 2.1

with MeONa in the presence of 15-crown-5, the crown ether specific for Na

. In these modified reaction conditions, the corresponding sin-1,4-addition product 2.6 was still present in the crude reaction mixture (nearly 60%), but a substantial amount of the corresponding anti-1,2-addition product, the trans methoxy alcohol 2.11 was also obtained. Evidently, as a consequence of the sequestering ability of the crown ether, under these conditions the epoxide is not entirely coordinated with the nucleophile and an

Scheme 2.4. Regio- and stereoselectivity of the addition reactions of O-Nucleophiles to the in situ prepared epoxide 2.1.

O OR

BnO HO BnO O

O t-BuOK

(1 equiv) O

BnO alcohol, HO

benzene,

or THF 2.1 OR

2.4

2.7 +

2.6

O OR

BnO HO

2.6

ROH +

R = Me, Et, i-Pr, t-Bu, Ph, Bn, diacetone-D-glucose

O O OBnH O R

2.8

 

1

coor dination products non-coordination pr oducts

r oute a

a

equilibrium exists between coordinated and non-coordinated epoxide molecules 2.9 and 2.10 (Scheme 2.5). While in the former (2.9), the nucleophilic attack can effectively occur from the coordinated nucleophile to give the -1,4-addition product (route a, the coordination product), as stated above, the latter (2.10) can react only with the free, non- coordinated nucleophile. In this case, the nucleophilic attack occurs necessarily at the C(3) allylic oxirane carbon (route b), which, in the absence of any other factors, is the most reactive position in these vinyl oxirane system, and the corresponding anti-1,2- addition product (a non-coordination product) (2.11) was obtained in a completely anti fashion in accordance with a classic S

2-type oxirane ring-opening process (Scheme 2.5).

These results indicated that in order to have a complete 1,2-addition process with O-nucleophiles, and probably also with other types of nucleophiles, in oxirane systems such as epoxide 2.1, it is necessary to use a nucleophile which is not able to coordinate with the oxirane oxygen through a hydrogen bond or by a metal, or with a counterion with no Lewis acid (LA) character.

In this framework, it was thought that tetrabutylammonium methoxide (Bu

N

MeO

), simply prepared by evaporation of commercially available 1M tetrabutylammonium hydroxide (TBAOH) in MeOH, might be an appropriate reagent in order to have a complete 1,2-addition by MeO

species, because not able to give a hydrogen bond and characterized by the presence of a counterion (Bu

N

) with no LA

Scheme 2.5. Regio and stereoselectivity of the addition reaction of MeONa and Bu

N

MeO

to epoxide 2.1.

BnO O

O OMe

BnO

OH

HO

MsO

BnO O

O

BnO O

HO OMe Bu₄N⁺MeO^-

(4 equiv) benzene THF

(or THF) 15-Crown-5

rt t-BuOK

(1 equiv) benzene

rt

MeONa (4 equiv)

 -1,4-addition

product anti-1,2-addition

pr oduct r oute b

r oute a

2.1

2.6

2.4

Me

b 2.11

O 3 O

O OBn O Me

2.9

O O OBn

2.10

 

1 a Na

Na⁺ O O

O O O

properties. Actually the reaction of epoxide 2.1 with Bu

N

OMe

(3 equiv, protocol B) in anhydrous THF resulted in a very clean reaction affording the corresponding anti-1,2 addition product, the trans hydroxy ether 2.11, practically pure, in a completely 1,2-regio- and anti stereoselective fashion (Scheme 2.5). To date, this is the only protocol available in order to obtain this class of addition products.

2.2.2. C-Nucleophiles

As for the reaction of epoxide 2.1 with C-nucleophiles, different results were obtained depending on the type of reagent. Grignard reagents such as MeMgBr and PhMgBr did not react with epoxide 2.1, generated in situ from trans hydroxy mesylate 2.4 in the presence of t-BuOK (protocol B).

However, when MeMgBr or PhMgBr were added directly to trans hydroxy mesylate 2.4 , a clear ring contraction reaction occurred with the formation of an almost  1:1 mixture of the diastereoisomeric 4,5-dihydrofurane-derived alcohols 2.12 and 2.13 (R

= Me or Ph), as the only reaction products. Alcohols 2.12 and 2.13 derived from a highly

Scheme 2.6. Regio- and stereoselectivity of the addition reaction of Grignard reagents, cuprates and alkyllithium reagents to trans hydroxy mesylate 2.4 and epoxide 2.1.

BnO O

MsO OH

BnO O

R HO BnO O

O

O BnO

R HOH

O BnO

R HOH

or EtMgBr/CuCN (3 equiv) 2.4

2.1

H BnO O O

H

2.16, R = Me,Et no reaction

RMgBr (3 equiv)

O R

BnO HO

2.12 2.13 +

2.15

R = Ph, Me 4

R = Me, Bu, i-Pr, t-Bu, Ph Et₂O

0ºC

2.18

RLi (3 equiv)

5 4 5

4 O

OBn

2.14

O O OBnLi R

2.17 H

H MsOO

 

1 a

RMgBr Et₂O Et₂O

t-BuOK Et₂O

anti-1,2-addition product

-1,4-addition product 1) RMgBr

2) H⁺

r oute a Me₂CuLi

stereocontrolled Grob fragmentation process on trans hydroxy mesylate 2.4 , as shown in  2.14, by the basic Grignard reagent (RMgBr), initially leading to aldehyde 2.15, then unstereoselectively attacked by the excess of RMgBr (Scheme 2.6). On their own, cuprates such as Me

CuLi and EtMgBr in the presence of stoichiometric CuCN afforded only the corresponding anti-1,2-addition product, the trans alcohol 2.16 (R = Me, Et, Scheme 2.6).

Only lithium alkyls such as MeLi, BuLi, i-PrLi, t-BuLi and PhLi gave a completely 1,4-regio and -stereoselective result affording the corresponding -C- glycosides 2.18 (-1,4-addition products, the coordination products) as the only reaction products. As previously, a coordination of the reagent (RLi) with the oxirane oxygen through the metal, as shown in 2.17, was considered responsible for the observed regio- and stereoselectivity (Scheme 2.6).

2.2.3. S-Nucleophiles

Thiols such as PhSH and EtSH were taken as typical S-nucleophiles. The addition reaction of PhSH and EtSH to epoxide 2.1 (protocol B) led to the obtainment of the corresponding anti-1,2-addition product 2.19 (non-coordination product) (Scheme 2.7), as largely the main (in the case of PhSH) or the only reaction product (in the case of EtSH).

Only in the case of PhSH, a slight, even if significant, amount (15%) of the

corresponding -1,4-addition product 2.20, the -phenyl thioglycoside, was observed. In

the framework of the rationalization previously used for the corresponding reaction with

alcohols, the reduced ability of thiols, with respect to alcohols, to coordinate with the

oxirane oxygen, considerably reduces the amount, in the reaction medium, of a

coordinated species such as 2.22, the only one which can lead to the -1,4-addition

products 2.20 (route a, Scheme 2.7), to the point that this type of addition is not

experimentally observed with the less acidic EtSH (pK

= 10.78) or observed only at a

slight extent with the more acidic PhSH (pK

= 6.61). As a consequence, under these

conditions, most of the epoxide is not coordinated with the nucleophile (structure 2.21),

and the reaction with the free thiol can occur only at the C(3) allylic oxirane carbon

(route b, Scheme 2.7), to yield the corresponding anti-1,2-addition product 2.19, as experimentally observed.

2.3. Synthesis and regio- and stereoselectivity of the addition of O-, C-, and S-nucleophiles to D -allal derived vinyl epoxide 2.1

The synthesis of trans hydroxy mesylate 2.4, the stable precursor of epoxide 2.1, started from epoxide 2.1 and proceeded through a simple protection-deprotection protocol applied to trans diol 2.23 (Scheme 2.8).

To enable a direct comparison with the diastereoisomeric epoxide 2.1 under the same conditions, the regio- and stereoselectivity of epoxide 2.1 in opening reactions with nucleophiles was examined in the addition reaction of the simple O-, C-, and S-

Scheme 2.7. Regio- and stereoselectivity of the addition reaction of thiols to epoxide 2.1.

BnO O

O SR

BnO OH

HO MsO

BnO O

O

benzene

2.20, R = Ph (15%) R = Et (not observed) benzene

BnO O

HO SR

2.4 2.1

route a r oute b

2.19, R =Ph (85%) R =Et (>99%)

t-BuOK (1 equiv)

b 2.21 R

(3 equiv)

3 O O OBn

O O OBnH S R

2.22 1

a

S

RSH

 

 -1,4-addition product (coordination products) anti-1,2-addition product

H

Scheme 2.8. Synthesis of trans hydroxy mesylate 2.4 and epoxide 2.1.

2.1

THF O

O

BnO O

OH BnO

HO

O

OH BnO

MsO

BnO O

O 2.4

2.1

2.23

benzene or Et2O t-BuOK Bu₄N⁺Me₃SiO^-

nucleophiles, previously used with epoxide 2.1b.

2.3.1. O-Nucleophiles

The results obtained in the reaction of epoxide 2.1 with alcohols (O- nucleophiles) under protocol A indicated that the addition reaction is completely 1,4- regioselective, but with an / stereoselectivity which depends on the type of alcohol used: with MeOH and EtOH an 81:19 and a 97:3 mixture of the corresponding - and - glycosides, 2.24 and 2.24, was obtained, respectively, whereas with i-PrOH and t- BuOH the corresponding -glycosides 2.24 were practically the only reaction products (Scheme 2.9).

In the alternative protocol B, a completely 1,4-regio- and -stereoselective result was observed with the obtainment of the corresponding -glycosides 2.24 as the only addition products (syn-1,4-addition products, the coordination products), with all the alcohols and partially protected monosaccharide used, in a corresponding completely and directly substrate-dependent glycosylation process.

A coordination between the oxirane oxygen and the nucleophile through a hydrogen bond, as shown in structure 2.25 in

Scheme 2.9. Glycosylation of alcohols by epoxide 2.1

O OR BnO

HO 2.24

H O

R 2.25

ROH = MeOH, EtOH, i-PrOH, t-BuOH,

di-O-isopropylidene--D-monosaccharide O

O

OBn

O O

BnO

a

route a

coor dination pr oduct

-1,4-addition product

2.1' 2.1"

BnO O O OR

BnO O HO

t-BuOK (1 equiv)

+

2.1

2.4

ROH, C₆H₆,

or Et₂O 2.24

ROH

route a = pseudoaxial attack

Scheme 2.9 was admitted in order to rationalize the completely 1,4-regio- and syn-1,4- stereoselective result. In this addition process, epoxide 2.1 should reasonably react through conformer 2.1’, in which the conjugate pathway proceeds by a more favorable pseudoaxial nucleophilic attack on C(1) carbon (route a, Scheme 2.9).

A corresponding complete 1,4-regio- and syn-1,4-stereoselectivity was found also with an alcoholate as MeONa, whereas the use of tetrabutylammonium methoxide (Bu

N

MeO

) afforded the trans methoxy alcohol 2.26 (the anti-1,2-addition product, the non-coordination product) as the only reaction product, in a completely regio- and stereoselective fashion (Scheme 2.10).

2.3.2. C-Nucleophiles

As previously observed with epoxide 2.1, the addition of lithium alkyls such as MeLi, BuLi, s-BuLi, t-BuLi and PhLi (C-nucleophiles, 3 equiv, protocol B) to epoxide 2.1, occurred with the exclusive formation of the corresponding syn-1,4-addition products, the -C-glycosides 2.27 (coordination-products). The occurrence of a coordination between the oxirane oxygen and the nucleophile through the metal, as shown in structure 2.28 was admitted on order to rationalize the result (Scheme 2.11).

Scheme 2.10. Reaction of epoxide 2.1 with MeONa and Bu

N

MeO

.

O OMe

BnO OH

2.24

Na O Me O O

OBn

 

coor dination pr oduct

2.1'' 2.1'

BnO O

O t-BuOK

(1 equiv)

2.1 2.4

benzene

MeONa Bu4N⁺MeO^-

BnO O

HO

2.26 OMe non-coor dination

product

O O BnO

The reaction of epoxide 2.1 with Me

CuLi was not regio- and stereoselective and an almost 1:1:1 mixture of all the reasonable addition products (coordination and non-coordination products) was obtained: anti 1,2-addition product (the trans methyl alcohol 2.29, 30%), -1,4-addition product (the -glycoside 2.27, 38%) and -1,4- addition product (the -glycoside 2.27, 32%) (Scheme 2.12).

2.3.3. S-Nucleophiles

The reaction of epoxide 2.1 with EtSH and PhSH led to a 74:26 and 47:43 mixture of the corresponding anti-1,2 addition product 2.30 and syn-1,4-addition product 2.31 (coordination product, Scheme 2.13).

In the case of PhSH, a certain amount of anti-1,4-addition product 2.31 (10%) was also found. As in the case of epoxide 2.1, the regio- and stereoselective results are in accordance with the reduced ability of thiols to coordination (hydrogen bond), compared with alcohols. Actually, as a consequence of the

Scheme 2.11. Rationalization of the 1,4-regio- and -stereoselectivity in the addition of lithium alkyls to epoxide 2.1.

Scheme 2.12. Regio- and stereoselectivity of the addition reaction of Me

CuLi to epoxide 2.1.

BnO O

O 2.1

2.4

O Me BnO

OH

2.27(38%) BnO O

HO Me 2.29 (30%)

+

O Me BnO

OH

2.27 (32%) Me₂CuLi +

non-coor dination

product coor dination

product t-BuOK

r oute a BnO O

O

O R

BnO

 HO

2.1 

 2.28 Li R

2.27

RLi= MeLi, BuLi, s-BuLi, t-BuLi, PhLi Et₂O

RLi O

O

OBn

O O

BnO

a

coordination product

-1,4-addition product

increased acidity of the PhSH and related ability to hydrogen bonding, an increased amount of the corresponding syn-1,4-addition product 2.31 (43%, coordination product) was interestingly observed with this S-nucleophile.

2.4. Comparison of the results obtained with epoxides 2.1 and 2.1

The comparison of the results obtained with -epoxide 2.1

and -epoxide 2.1

in their reactions with O- and C-nucleophiles indicated that, in these glycal-derived vinyl oxirane systems, the configuration  or  of the oxirane ring and the related coordination or chelation effects could be responsible for the complete, substrate- dependent, syn-stereoselectivity (- from 2.1 and -1,4-selectivity from 2.1) observed in the completely regioselective conjugate addition. In this way, - (from 2.1) and -O- and C-glycosides (from 2.1) can be stereospecifically obtained by a simple and efficient protocol which does not need a catalyst, but only smoothly basic conditions in order to generate epoxides 2.1 and 2.1 from the corresponding hydroxy mesylates 2.4 and 2.4, respectively, in a new, uncatalyzed, directly substrate-dependent, stereoselective, glycosylation process.

Scheme 2.13. Addition reactions of EtSH and PhSH to epoxide 2.1.

BnO O

O 2.1

2.4

O SR BnO

HO

2.31 (26%) (43%)

BnO O

HO SR EtSH

PhSHor

R= Et

R= Ph 2.30 (74%)

(47%) +

coordination pr oduct non-coordination product

BnO O

HO

2.31 (10%) +

SPh t-BuOK

2.5. D -Allal- and D -galactal-derived vinyl N-(mesyl)- and N-(nosyl)-aziridines

Alkyl O-glycosides having differently functionalized amino groups in different positions (aminosugars) are an important category of modified carbohydrate units present in several oligosaccharides and glycoconjugates.

Furthermore, aminosugars are important as essential components of bacterial capsular polysaccharides and as structural elements of aminoglycoside antibiotics with antiviral and antitumor activity.

In consideration of the biological importance of natural products containing aminosugars,

the development of efficient synthetic routes to these carbohydrates is an attractive goal.

In this framework, the interest of our group was directed towards the stereoselective introduction of a nitrogen functionality at the C(4) carbon of a glycal system with simultaneous glycosylation to give 2,3,4-trideoxy-4-N-(substituted-amino)- hex-2-enopyranosides as valuable, nitrogen-containing, synthetic intermediates since the unsaturation allows further functionalizations.

Few methods were reported to date for the synthesis of these synthetically useful compounds: the most convenient of these involves an allyl cyanate-to-isocyanate rearrangement of hex-3-enopyranosides and a palladium-catalyzed allylic substitution by secondary amines of suitable hex-2-enopyranosides.

2.5.1. Stereoselective synthesis of 4-(N-mesylamino)-2,3-unsaturated--O-glycosides via the new D -allal-derived N-(mesyl)-aziridine 2.2a

The observation that in the stereospecific - and -O-glycosylation of alcohols and phenol and C-glycosylation of lithium alkyls by epoxides 2.1 and 2.1,

the C(4)- OH group present in the 1.4-addition products (Schemes 2.4-2.6 and 2.9-2.11) comes from the epoxide led our group to pursue the prospect of achieving an analogous nitrogen transfer to C(4) position via a corresponding activated aziridine intermediate.

As a first preliminary approach to the chemistry of glycal-derived aziridines, the

readily available D -allal-derived vinyl N-mesyl-aziridine 2.2 (Scheme 2.14) turned out

to be appropriate in order to check the chemical behavior of this new class of activated

aziridines.

The synthesis of trans N,O-dimesylate 2.32, the stable precursor of N-mesyl- aziridine 2.2, was achieved starting from epoxide 2.1 of inverted configuration (Scheme 2.14).

Actually, vinyl N-acetyl aziridine 2.2-Ac (obtained by base-catalyzed cyclization of N-acetyl-O-mesylate 2.32-Ac, Scheme 2.15), corresponding to N-mesyl- aziridine 2.2, was initially prepared and examined in addition reaction with alcohols.

Unfortunately, N-acetyl aziridine 2.2-Ac turned out to be completely unreactive with alcohols under protocol A reaction conditions and corresponding 1,4-addition products were obtained, even if in an unsatisfactory yield, only when 2.2-Ac was left to react under protocol B only with MeOH and EtOH.

2.5.2. O-Nucleophiles

Under protocol B, MeOH, EtOH, i-PrOH, phenol as well as more hindered O- nucleophiles such as t-BuOH, (+)-dihydrocholesterol, diacetone D -glucose and 1,2:3,4-di- O-isopropylidene-- D -galactopyranose were glycosylated by N-nosyl aziridine 2.2a with good yields and the corresponding 4-N-(mesylamino)-2,3-unsaturated--glycosides and

Scheme 2.14. Synthesis of vinyl N-mesyl aziridine 2.2.

BnO O

MsO

NHMs 2.32

BnO O

O 2.1

BnO O

MsN t-BuOK

(1 equiv)

2.2

benzene or MeCN

Scheme 2.15. Vinyl N-acetyl aziridine 2.2-Ac.

BnO O

MsO

NHAc

BnO O

Ac N t-BuOK

(1 equiv)

2.2-Ac 2.32-Ac

-linked disaccharides 2.33 (syn-1,4-addition products) were obtained with complete 1,4-regio- and high (93-95%), in the case of MeOH, EtOH and i-PrOH, or complete - stereoselectivity, in the case of t-BuOH and monosaccharide (Scheme 2.16).

The great tendency of aziridine 2.2, to give syn-1,4-addition products with O- nucleophiles was furtherly demonstrated by its reaction with AcONa in DMF, that is to say, under conditions which should reasonably favor a typical S

2 process on the allylic C(3) carbon. Actually, the corresponding -acetyl glycoside, acetate 2.34 (the coordination product) turned out to be clearly the main addition reaction product (91%) with only a small amount of the expected anti-1,2 addition product, the trans mesylamino acetate 2.35 (the non-coordination product, 9%) (Scheme 2.17).

A selective 1,2-regio- and anti-stereoselective addition process with O- nucleophiles was obtained only by reagents in which the appropriate O-nucleophile is the counter ion of the non-coordinating tetrabutylammonium cation (Bu

N

), as the previously used tetrabutylammonium methoxide (TBAOMe) and the new tetrabutylammonium trimethylsilanolate (TBAOSiMe

). Under these non-coordinating conditions, the corresponding trans methoxy- and trans hydroxymesylamino derivatives 2.36 and 2.37, respectively, were found to be the only reaction products (Scheme 2.17).

Scheme 2.16. Regio- and stereoselectivity of the addition reaction of O- nucleophiles to the in situ formed N-mesyl-aziridine 2.2under protocol B.

BnO O

MsO

NHMs 2.32

BnO O

Ms N

BnO O

MsHN t-BuOK OR

(1 equiv) ROH (4 equiv)

2.2 2.33

C₆H₆

ROH = MeOH, EtOH, i-PrOH, t-BuOH, PhOH, (+)-dihydrocholesterol, diacetone-D-glucose, 1,2:3,4-di-isopropylidene--D-galactopyranose

In the case of MeOH, EtOH, i-PrOH and t-BuOH, the addition reactions were repeated by using the alcohol itself as the solvent (protocol A). Under these conditions, the glycosylation reactions were still completely 1,4-regioselective, but the / anomeric ratio turned out to depend on the alcohol used (Scheme 2.18).

The results obtained indicated that in the case of aziridine 2.2 there is a close

Scheme 2.17. Regio- and stereoselectivity of the addition reaction of alcoholates and acetate to N- mesyl aziridine 2.2.

BnO O

N

O OAc BnO

MsHN BnO O

NHMs MsO

2.32 2.2

Ms

+ BnO O

MsHN OAc

2.34 (91%) 2.35 (9%)

[2.2]

BnO O

MsHN OH DMF

AcONa

Ac₂O t-BuOK

TBAOSiMe₃

2.37 BnO O

MsHN

OMe [2.2]

t-BuOK TBAOMe

2.36

anti-1,2-addition pr oduct

anti-1,2-addition

product -1,4-addition pr oduct

anti-1,2-addition pr oduct

Scheme 2.18. Regio- and stereoselectivity of addition of alcohols to N-mesyl aziridine 2.2

(protocol A).

BnO O

MsN

2.2

O OR

MsHN t-BuOK

(1 equiv)

+

MeOH EtOH i-PrOH t-BuOH

R= Me R= Et R= i-Pr R= t-Bu (60)

(75) (93) (>99)

(40) (25) (7) (<1)

O OR BnO

MsHN

ROH (solvent/nucleophile)

2.33 2.33

BnO O

MsO

NHMs 2.32

coor dination pr oduct BnO

non-coor dination pr oduct

ROH

relationship between the configuration () of the three-membered heterocycle (the aziridine ring) and the largely predominant or exclusive direction () of the O- glycosylation process. As previously admitted with the corresponding epoxide 2.1, the occurrence of an effective coordination (hydrogen bond) between the aziridine nitrogen and the O-nucleophile (ROH), as shown in structure 2.38 (Scheme 2.19) with the aziridine, reacting through conformer 2.2’, can reasonably rationalize the results and justify the observed complete and direct substrate-dependent stereoselctivity observed.

In this framework, the reactivity of aziridine 2.2 through conformer 2.2’ as shown in Scheme 2.19 (route a) allows a more favorable pseudoaxial nucleophilic attack on C(1).

2.5.3. Stereoselective synthesis of 4-(N-mesylamino)-2,3-unsaturated--O-glycosides via the new D -galactal-derived N-(mesyl)-aziridine 2.2b

In order to evaluate the synthetic utility of this new class of activated vinylic aziridines, and to confirm whether the stereoselectivity observed in the glycosylation of alcohols and monosaccharides by aziridine 2.2 was substrate-dependent, the diastereoisomeric activated D -galactal-derived vinyl N-mesyl aziridine 2.2 was synthesized and its regio- and stereochemical behavior in nucleophilic addition reactions with O-nucleophiles was examined.

The stereoselective synthesis of aziridine 2.2 starts from the previously described glycal-derived vinyl epoxide 2.1 of opposite configuration and leads to the

Scheme 2.19. Rationalization of the regio- and -stereoselective addition of alcohols to aziridine 2.2.

1 O OBn

Ms N

O 2.2' R

a b

route b

route a O OR

BnO MsHN

O OR

BnO MsHN

-1,4-addition pr oduct

-1,4-addition pr oduct ( coordination pr oduct) H

O R

-H⁺ -H⁺

H ROH

benzene BnO O

MsN

2.2

O N

BnO

Ms

1 b

H O R

2.2''

2.38

r oute a = pseudoaxial attack

trans-N,O-dimesylate 2.32, the stable precursor of vinyl aziridine 2.2 (Scheme 2.20).

The glycosylation of simple alcohols (MeOH, EtOH, i-PrOH, t-BuOH) by the in situ-formed vinyl aziridine 2.2, carried out in the alcohol itself as the solvent (protocol A), turned out to be completely 1,4-regioselective, with a stereochemical behavior (the

/ anomeric ratio) not only largely dependent on the alcohol used, but also decidedly different from that previously observed with aziridine 2.2 and related vinyl oxiranes 2.1 and 2.1 in the same experimental conditions. In fact, both with MeOH and EtOH, a practically identical 31:69 / selectivity was observed, indicating, for the first time, the same stereochemical behavior for these two alcohols and, more notably, a stereoselectivity () opposite to the configuration () of the starting heterocycle, the aziridine 2.2 (an anti-1,4-stereoselectivity) (Scheme 2.21). Only in the case of the more sterically demanding i-PrOH was the usual syn-1,4-stereoselectivity observed, even if inferior to expectations (60%), favoring the -anomer 2.39 configurationally homogeneous with the -configuration of the aziridine intermediate, to the point that with t-BuOH a complete -stereoselectivity was observed (Scheme 2.21).

Scheme 2.20. Synthesis of vinyl N-mesyl aziridine 2.2 . 

O 2.1

O

NHMs BnO

MsO

2.32

BnO O

2.2

Ms N t-BuOK

benzene or MeCN

Scheme 2.21. Regio-and stereoselectivity of the addition reaction of alcohols to aziridine 2.2

(protocol A).

BnO O

N

O OR BnO

MsHN BnO O

NHMs MsO

2.32 2.2

t-BuOK

(1 equiv) Ms

+

O OR BnO

MsHN

(69%) (69%) (40%) (<1%)

(31%) (31%) (60%) (>99%) R= Me

R= Et R= i-Pr R= t-Bu

coordination product

ROH= MeOH, EtOH, i-PrOH, t-BuOH ROH

2.39 2.39

non coordination pr oduct

When the addition reactions were repeated by treating a benzene solution of aziridine 2.2 with only a small amount of nucleophile (3-4 equiv) (protocol B), with the only exclusion of phenol, the addition reactions were completely 1,4-regioselective and showed a stereoselectivity drastically driven toward that anomer () having the same configuration () as the starting aziridine to give the corresponding coordination products (syn-1,4-addition products) 2.39 as the only (>99% with i-PrOH, t-BuOH, dihydrocholesterol, diacetone- D -glucose, and 1,2;3,4-diisopropyliden- D -galactopyranose) or the main product (85-95% with MeOH and EtOH) (Scheme 2.21).

As previously observed with aziridine 2.2, the reaction of aziridine 2.2 with AcONa in DMF, that is under typical S

2 conditions, does not lead to the expected anti- 1,2-addition product 2.41, but the corresponding -acetyl glycoside 2.40 was the main addition reaction product (92%). The expected anti-1,2-addition product, the trans mesylamino acetate 2.41 was present only in a small amount (8%) (Scheme 2.22).

In the same way, the reaction of aziridine 2.2 with a nucleophile such as MeONa afforded a crude reaction mixture containing the corresponding anti-1,2 and - 1,4-addition products in a 60:40 ratio. A selective 1,2-addition process was obtained only

Scheme 2.22. Regio- and stereoselectivity of the addition reaction of alcoholates and acetate to aziridine 2.2.

BnO O

N

O OAc BnO

MsHN BnO O

NHMs MsO

2.2 2.32

Ms

+ BnO O

MsHN

anti-1,2-addition product

OAc

-1,4-addition pr oduct

2.40 (92%) 2.41 (8%)

BnO O

MsHN OMe 2.42 [2.2b]

[2.2]

BnO O

MsHN OH 2.43 DMF

AcONa

Ac₂O t-BuOK

t-BuOK TBAOMe

TBAOSiMe₃

2.41 [2.2]

TBAOAc t-BuOK

anti-1,2-addition pr oduct

anti-1,2-addition pr oduct anti-1,2-addition

product

by treatment of aziridine 2.2 with tetrabutylammonium methoxide (TBAOMe), tetrabutylammonium trimethylsilanolate (TBAOSiMe

) and tetrabutylammonium acetate (TBAOAc), which afforded exclusively the corresponding trans methoxy- 2.42, trans hydroxy- 2.43 and trans acetoxy-mesylamino derivative 2.41 in a complete 1,2-regio- and anti-stereoselective fashion (Scheme 2.22).

With the only exception of these three last reactions, which are completely 1,2- regio- and anti-stereoselective, the addition reactions of O-nucleophiles to aziridine 2.2, at least in conditions of a reduced amount of nucleophile present (protocol B), showed a complete 1,4-regioselectivity and a stereoselectivity (), which appeared to be driven by the configuration of the aziridine. As in the case of the other previously examined aziridines and epoxides derived from the glycal system, the occurence of a suitable coordination, in the form of a hydrogen bond between the reactive substrate, the aziridine 2.2, reacting in the only stable conformation 2.2’, and the O-nucleophile, as shown in 2.44, appears to be adequate in order to rationalize the observed results (Scheme 2.23).

Also in this case, the conjugate addition on C(1) of the coordinated nucleophile necessarily occurs through a less favored pseudoequatorial pathway.

Scheme 2.23. Rationalization of the 1,4- regio- and b-stereoselective addition of alcohols to aziridine 2.2.

OBnO

N H O R

Ms

O H

O MsBnON

2.44

2.2"

1



b

a r oute b

-1,4-addition pr oduct ( coordination pr oduct)

-1,4-addition pr oduct



R r oute a

route b = pseudoequatorial attack 2.2'

2.5.4. Comparison of the results obtained with vinyl N-mesyl aziridines 2.2 and 2.2

A comparison of the results obtained with the D -galactal-derived aziridine 2.2

with the previously studied D -allal-derived aziridine 2.2 in their reactions with O- nucleophiles, under protocol B, indicated that, in these glycal-derived vinyl aziridine systems, the configuration  or  of the aziridine ring and the related coordination effects are responsible for the complete or almost complete - or -stereoselectivity, respectively observed in the completely regioselective conjugate addition of O-nucleophiles. The syn- 1,4-stereoselectivity (-1,4-stereoselectivity) observed with aziridine 2.2 under protocol A is larger than the correspondly syn-1,4-stereoselectivity (-1,4-stereoselectivity) obtained with aziridine 2.2, under the same conditions in accordance with the more favored pseudoaxial nature of the coordination-driven nucleophilic attack on C(1) in aziridine 2.2Scheme 2.19)  with respect to the less favored pseudoequatorial nature of the corresponding attack in aziridine 2.2 (Scheme 2.23).

2.6. D -Galactal- and D -allal-derived vinyl N-(nosyl)-aziridines 2.3 and 2.3

The use of vinyl N-mesyl aziridines 2.2 and 2.2 in the glycosylation process made the regio- and stereoselective insertion of a N-mesylamino functionality at C(4) of a pseudoglycal system possible.

Actually, limited to this application, the N-mesylamino group is not the best choice to have a free amino group by deprotection procedures. As a consequence, it appeared necessary to introduce on the starting aziridine a different N- activating group, which could easily be removed after the glycosylation process had taken place. Considering that the simple N-acetyl group could not be used because the corresponding vinyl N-acetyl aziridine 2.2-Ac had proved to be not sufficiently reactive (Scheme 2.15), the choice fell on aziridines 2.3 and 2.3 which bear the N-(o- nitrobenzenesulfonyl) [N-(nosyl)] protecting/activating group.

Actually, the N-nosyl group could easily be removed from the addition products by the simple PhSH/K

CO

protocol, in accordance with a S

Ar reaction mechanism,

in order to have free amino

group-containing products.

The synthesis of vinyl N-nosyl aziridines starts from trans 3-amino alcohols 2.45 and 2.45 obtained from epoxides 2.1 and 2.1, respectively, leading to trans N- nosyl-O-mesylates 2.47 and 2.47 respectively, the stable ultimate precursors of aziridines 2.3and 2.3, through trans N-nosylamino alcohols 2.46a e 2.46b. Base- catalyzed cyclization (K

CO

/MeCN) of 2.47 and 2.47 afforded the desired aziridines 2.3 and 2.3, respectively (Scheme 2.24).

To check the efficiency of aziridines 2.3 and 2.3 as glycosyl donors, the possible influence of the N-nosyl group on the regio- and stereoselectivity and the applicability of the deprotection procedure to the N-(nosylamino)-substituted products deriving from the glycosylation process, the regio- and stereochemical behavior of aziridines 2.3 and 2.3 in the reaction with alcohols, partially protected monosaccharides and phenol (O-nucleophiles) was examined.

The results obtained indicated that the regio- (only the corresponding 1,4- addition products were observed in each case) and stereoselectivity (-1,4-addition product/-1,4-addition product ratio) of N-nosyl aziridines 2.3 and 2.3 under protocols A and B substantially resembled that of the corresponding N-mesyl aziridines 2.2 and 2.2, respectively. The only slight difference is found under protocol B in the sense that the glycosylation reactions of aziridines 2.3 and 2.3 are completely stereoselective toward that anomer (2.48 and 2.48, respectively) having the same configuration of the starting aziridine (a or b, respectively) also in those cases in which N-mesyl aziridines

Scheme 2.24. Synthesis of vinyl N-nosyl aziridines 2.3 and 2.3.

O

NH₂ BnO

HO

2.45

BnO O

2.3

Ns N O

NHNs BnO

MsO

2.47

O

NH₂ BnO

HO

2.45

BnO O

2.3

Ns N O

NHNs BnO

MsO

2.47

BnO O

2.1

O BnO O

2.1

O

K₂CO₃

K₂CO₃ MeCN

MeCN O

NHNs BnO

HO

2.46

O

NHNs BnO

HO

2.46

MsCl

MsCl Py

Py NsCl

NsCl Et₃N

Et₃N

2.2 and 2.2 were not (Scheme 2.25).

The complete 1,4-regioselectivity and aziridine ring configuration-related stereoselectivity, observed in all the reactions of the N-nosyl aziridines 2.3 and 2.3

with O-nucleophiles, could be rationalized, as previously admitted for 2.2 and 2.2, by the occurrence of an effective coordination (hydrogen bond) of the O-nucleophile with the aziridine nitrogen of 2.3 and 2.3, followed by a nucleophilic attack on the nearby C(1) carbon of the vinyl aziridine system (routes a and b for 2.3 and 2.3, respectively, as shown in structures 2.49’ and 2.49’ in Scheme 2.25). In the present case, the metal ion (K

from K

CO

used in the cyclization process) and/or an intrinsically higher ability to coordination by the aziridine nitrogen of the N-nosyl group probably plays a role in determining the complete stereoselectivity observed.

The 4-N-(nosylamino)-O-glycosides 2.48 (R=Me, Et, i-Pr, Bn, menthyl and 2.48 (R= t-Bu, allyl, diacetone- D -glucopyranosyl) were chosen in order to check the applicability of these pseudoglycals to the deprotection procedure which makes use of the PhSH/K

CO

protocol. In this way, solutions of alkyl 4-N-(nosylamino)-4-deoxy--O- glycosides 2.48 in MeCN were treated with PhSH (3 equiv) in the presence of K

CO

(4 equiv) (solution phase conditions). The deprotection reaction was very fast and completed in 3h (conversion >99%, TLC and

H NMR) and the corresponding alkyl 4- amino-4-deoxy--O-glycosides 2.50 were obtained in pure form (65% yield) after simple preparative TLC or flash chromatography (Scheme 2.26). Application of the same protocol to alkyl 4-N-(nosylamino)-4-deoxy--O-glycosides 2.48 afforded the

Scheme 2.25. Rationalization of the regio- and stereoselective addition of alcohols (ROH) to N-nosyl aziridines 2.3 and 2.3.

OBnO N H O R Ns

2.49' 1



b route a

-1,4-addition pr oduct 

1 OBnO

Ns N

H O R

a

route b BnO O OR

NsNH

-1,4-addition pr oduct



2.49' O OR

BnO NsNH

2.48  2.48

coor dination pr oduct coor dination pr oduct

R= Me, Et, i -Pr, Bn, t-Bu, allyl, menthyl, diacetone-D-glucopyranosyl

corresponding free-amino group containing -O-glicosydes 2.50 with good yield. An alternative procedure carried out by means of a PhSH-supported resin (PS-thiophenol) (solid phase conditions) turned out to be unsatisfactory, as for yield and reaction time.

In conclusion, the original glycosylation protocol of alcohols, partially protected monosaccharides and phenol by the diastereoisomeric D -allal and D -galactal-derived vinyl N-mesyl aziridines 2.2 and 2.2 was substantially improved by the use of the corresponding N-nosyl aziridines 2.3 and 2.3. On passing from the N-mesyl to the N- nosyl protecting/activating group, the stereoselectivity of all the O-glycosylation reactions increases, and the N-(nosylamino) functionality, regio- and stereoselectively introduced at C(4) carbon of O-glycosides 2.48 and 2.48, could be easily deprotected by the simple PhSH/K

CO

protocol and transformed into corresponding O-glycosides bearing a free amino group in the same position.

All these results indicated that the use of our O-glycosylation process by means of N-nosyl aziridines 2.3 and 2.3, followed by the deprotection protocol, may constitute a simple and valid tool for the completely C(4)-regioselective and stereospecific synthesis of 2,3-unsaturated-4-deoxy-4-amino-O-glycosides as 2.50 and 2.50, bearing a free amino group at C(4) carbon, with an added value to the final product and the glycosylation process itself.

Scheme 2.26. Deprotection reaction of 4-N-(nosylamino)-O-glycosides 2.48 and 2.48.

O OR

BnO NsHN

2.48

PhSH K₂CO₃/MeCN

O OR

BnO NsHN

2.50

O OR

BnO NH₂ 2.48

PhSH K₂CO₃/MeCN

O OR

BnO NH₂

2.50