CHAPTER 1
Synthesis and regio- and stereochemical behavior in nucleophilic addition
reactions of carba-glycal derived vinyl epoxides
1.1. Introduction
Carbohydrate chemistry constitutes today a “multifaceted” discipline strongly connected with organic and medicinal chemistry.1 Carbohydrates are important biomolecules whose role is not only limited to energy storage, since they are constituents of glycoproteins, glycolipids, and other conjugates. They are therefore key elements in a variety of processes such as signaling, cell-cell communication, and molecular and cellular targeting. Many biological processes, ranging from blood clotting to fertilization, all involve carbohydrates, and the biological implications of these compounds are strongly related with diseases such as cancer, diabetes, or inflammatory processes. On the basis of these considerations, the search for new derivatives with analogous or even improved biological properties compared to those of the parent structures (the carbohydrate
mimetics) appears to be a logical matter of research. The term “carbohydrate mimetic” is frequently
used to refer to any carbohydrate derivative or other compound that has multiple hydroxy groups and thus resembles a sugar or a saccharide. On the other hand, the structural substitution of the endocyclic oxygen atom with a methylene group leads to compounds more stable toward endogenous degradative enzyme.1
1.2. State of the art
The addition reactions of nucleophiles to glycal-derived vinl epoxides 1.1α,2 1.1β3 and aziridines
1.2α-Ms,4 1.2β-Ms,5 1.2α-Ns, 1.2β-Ns6 had indicated that when the reactions were carried out in the presence of a small amount of the nucleophile (3 equiv), the anomeric C(1) carbon of the glycoside (1,4-addition product) in each case obtained either as the only addition product, or in a mixture with the corresponding anti-1,2-addition product, had the same configuration as the starting epoxide or aziridine and thus it corresponds to a syn-1,4-addition product (Schemes 1.1 and 1.2). This behaviour was particularly interesting and marked with O-nucleophiles (alcohols, phenol and partially protected monosaccharides) and, only in the case of epoxides 1.1α and 1.1β, with C-nucleophiles (alkyl lithium reagents),3c where the corresponding O- and C-glycosides were obtained by means of a completely 1,4-regio- and stereoselective process, with exclusive formation of the corresponding α- and β-glycosides from epoxide 1.1α and aziridines 1.2α-Ms,
directly substrate-dependent, stereospecific O-glycosylation and C-glycosylation process (Schemes 1.1 and 1.2). These results and, in particular, the close correspondence between the configuration of the glycosides obtained (syn-1,4-addition products) and that of the starting epoxide were rationalized by supposing the occurrence of a coordination between the nucleophile and the oxirane oxygen in the form of a hydrogen bond, in the case of O-nucleophiles, or through the metal (lithium cation), in the case of alkyl lithium reagents, as shown in structures 1.1α’ and
1.1β’, 1.2α’ and 1.2β’ (Schemes 1.1 and 1.2). In this way, the nucleophile is appropriately
disposed for an entropically favored attack on C(1) from the same side as the heterocyclic functionality (route a in 1.1α’ and 1.2α’ and route b in 1.1β’ and 1.2β’), thus accounting for the complete facial selectivity observed.2,3 As they are supposed to arise from a coordination process, the 1,4-addition products (glycosides) with the same configuration as the starting glycal-derived epoxide or aziridine were often indicated as coordination products and in this way easily distinguished from the other reaction products. In this framework, products, as 1,2- and anti-1,4-addition products, which have been supposed to derive from attack of a free, non-coordinated nucleophile have been simply named non-coordination products.
! ! !" #$! !" #$! %&! %&! !"#! !"#" ! ! %&! ! ! %&! !"!" !"!! !'%(!) *"+*, ! ! %&! ! ! !%& ! ! !%& -./ 0+123(456 *"+*, !'%(!) *"+*, -./ 0+123(456 *"+*, !"!!$ !"!!$$ !"!"$ / -. . . #+ #+ / -. ! " ! " ! !-.10-.6 "! %&! !#$%&'%(#)*+,&-./0 ! !-.10-.6 "! %&! "#$%&'%(#)*+,&-./0 "'&(7829:;482$10<879;98$6=1/1>1!" #'&(7829:;482$1084?;4(@1<8AB8$6=1/1>1C4 -.1>1#2=1D?=1$'EF=1!'%(=1E;=1@9&9$<77;<F4G2$ ! " -+1#234#"//.5.&1%6'&/7,5-8,&&'/.1"5.&1%6'&/7,5-6 %&'!()" %&'!()!
Scheme 1.1. 1,4-regio- and syn-stereoselective addition of O- (alcohols) and C-nucleophiles (lithium alkyl
! ! "#$ %&! "#$ %&! '(! '(! $)*)%&+)!"#$! $)*)"&+!"#%! ! " '(! ! " '(! "#&!'() "#&!'*) ,-.!/ .#/." ! " '(! ! " !'( ! " !'( $0!# 1/)234567 .#/." ,-.!/ .#/." $0!# 1/)234567 .#/." "#&!++'() "#&!++'*) 8 $0 0 0 "+ "+ 8 $0 ! " ! !$0 $#" '(! "#$%#&'&"()*+,#-.*%#"/0*.& !&12&3#%4.+05) ! !$0 $#" '(! $!#)*)!9(4:;2<=>5;2&)1?;:<><;&7 $0)*)%2+)@A+)"9BC+)#9'4+)B>+)D<(<&?::>?C5E2& ! # +%*&67'&"55080.*29(.5,48+ :4..(50*"80.*29(.5,48+7 $ $)*)%&+)%& "#&!+'() "#&!+'*) $%&#'(" $%&#'(! $)*)%&+)!"#$#
$)*)"&+!"#%# "#&#'()"#&#'*)
"#&#+'() "#&#+'*) "#$%#&'&"()*+,#-.*%#"/0*.& #&12&3#%4.+05) $ $ $ $
Scheme 1.2. 1,4-regio- and syn-stereoselective addition of O-nucleophiles (alcohols) to N-mesyl- 1.2α-Ms
and 1.2β-Ms and N-nosyl-vinyl aziridines 1.2α-Ns and 1.2β-Ns.
Epoxides 1.1α and 1.1β and corresponding N-mesyl aziridines 1.2α-Ms and 1.2β-Ms and N-nosyl aziridines 1.2α-Ns and 1.2β-Ns were not stable and could be prepared only in situ by cyclization under basic conditions of the corresponding stable precursor, the trans hydroxy mesylates 1.3α and
1.3β for epoxides 1.1α and 1.1β, respectively and trans N,O-dimesylates 1.4α-Ms and 1.4β-Ms
for aziridine 1.2α-Ms and 1.2β-Ms and trans N-nosyl-O-mesylates 1.5α-Ns and 1.5β-Ns for aziridines 1.2α-Ns and 1.2β-Ns, respectively, and left to react immediately with the appropriate nucleophile.
As for the comformational populations, theoretical conformational studies have indicated that epoxide 1.1β and aziridines 1.2β-Ms and 1.2β-Ns exist as the only corresponding conformer
1.1β’, 1.2β’-Ms and 1.2β’-Ns with the side chain equatorial, whereas epoxide 1.1α and aziridines 1.2α-Ms and 1.2α-Ns exist as an almost 60:40 equilibrium between the two corresponding
conformers 1.1α’ and 1.1α’’, 1.2α’-Ms and 1.2α’’-Ms, 1.2α’-Ns and 1.2α’’-Ns with the side chain axial and equatorial, respectively (Schemes 1.1 and 1.2).5a,7
As for the activating group present in aziridines 1.2α-Ns and 1.2β-Ns, the choice for the N-nosyl group was determined by the necessity to have a N-protecting group sufficiently stable to the action of different nucleophiles, but at the same time susceptible to be removed by a simple protocol in order to have a free amino group in the final products.
! ! !" #$#% &'! &'! !" #$#% ()*% +,-!./-%.-# ()*% +,-!./-%.-# ! !" %,# &'! ! &'! !" %,# !"!"#$%&'()*#$" !"" "+'&,$%*-. !"!"#$%&'()*#$" """ "+'&,$%*-. !"()*#$"!"""+'&,$%*-. !"()*#$"""""+'&,$%*-. /01 /02! /02" /03
Scheme 1.3. Deprotection of NH-nosyl group in 4-N-nosylamino-O-glycosides 1.6α and 1.6β.
The N-nosyl group turned out to have the desired characteristics, since it is stable to most nucleophiles and can be easily removed by treatment with the simple PhSH/K2CO3 protocol at room temperature to give corresponding 4-amino-substituted derivatives. This possibility was demonstrated in the case of the obtained α-(1.6α) and β-2,3-unsaturated-O-glycoside (1.6β) (where the –NHNs group initially transferred regio- and stereoselectively to carbon C(4) is easily deprotected to a free amino group, with the formation of corresponding 4-amino-α- (1.7) or β-O-glycoside (1.8) giving in this way an additional value to the new glycosylation protocol (Scheme 1.3).6
The versatility and the efficiency of the new glycosylation process made its application in a reiterative version possible on epoxide 1.1β and aziridine 1.2α-Ns for the synthesis of 2,3-unsaturated-1,6-di- (1.9,1.12) and trisaccharides (1.10,1.13), also bearing a 4-amino group (1.12,1.13) when aziridine 1.2α is used.8 A mixed version of the original protocol made the synthesis of the mixed disaccharide 1.15 possible. Subsequently, disaccharides 1.9, 1.12 and 1.15 were dihydroxylated to the corresponding fully substituted disaccharides 1.11, 1.14, and 1.16 by a completely facial selective process (Scheme 1.4).8
! ! "#! ! $! ! "#! ! $! !%!%"& ! $! ! ! $! !%!%"& ! $! "#! ! '(! ! "#! ! '(! !%!%"& !'( !'( !'( !'( !"!! !"# !"!$ !"!! ! ) "#! ! $*) ! "#! ! $*) !%"%+, ! $*) ! ! $*) !%"%+, ! $*) "#! ! '($) ! "#! ! '($) !%!%"& !'( !'( !'( !'( !"%" !"!% !"!& !"!' )-! ! "#! ! $*) ! "#! ! $! !%!%"& !"!! !"!( ! '($) ! "#! ! '(! !%!%"& !"!) !'( !'( !'( !'( ! ) "#! !"%"
)-Scheme 1.4. 2,3-Unsaturated and 2,3-dihydroxy-1,6-di- and -trisaccharides from epoxide 1.1β and
N-nosyl aziridine 1.2α-Ns.
On the basis of these results, we thought interesting to examine, initially, the regio- and stereoselective behavior of the new distereoisomeric vinyl epoxides 1.17α and 1.17β, the carba analogs of glycal-derived epoxides 1.1α and 1.1β and, now, of the corresponding N-nosyl aziridines 1.18α and 1.18β (Scheme 5), in their reactions with nucleophiles and in particular with
O-nucleophiles, in view of a possible use of these systems as carbaglycosylating agents,
particularly toward O-nucleophiles, for the synthesis of carba mono- and/or disaccharides as mimics of the corresponding “true sugars” (See Chapter 2).
! ! "#! "#! !"!#! !"!#" $ $ "#! "#! !"!$! !"!$" $% $%
Scheme 1.5. Vinyl epoxides 1.17α and 1.17β and corresponding vinyl N-nosyl aziridines 1.18α-Ns and 1.18β-Ns.
The examination of the chemical behavior of epoxides 1.17α and 1.17β had started before the beginning of my PhD course. As a consequence, my initial project in the field of carbasugars was limited to complete some results previously obtained with O-nucleophiles by epoxides 1.17α and
1.17β in view of their pubblication.9
Subsequently, my project was directed toward the synthesis of epoxides 1.17α and 1.17β as pure enantiomers, with particulr attention to improve the quality of the process as the number and the yield of the reaction steps are concerned with respect to the corresponding racemic version. At the same time, I proceeded to the synthesis of the not previously described, racemic N-nosyl vinyl aziridines 1.18α-Ns and 1.18β-Ns, the aza analogues of vinyl epoxides 1.17α and 1.17β. The behavior of the new aziridines 1.18α-Ns and 1.18β-Ns was examined in nucleophilic addition reactions and compared with that of the corresponding epoxides. Finally, in view of a possible use of these aziridine systems for the construction of amino analogue of carbohydrate mimetics, I prepared enatiopure aziridines 1.18α-Ac and 1.18β-Ac, the chiral N-acetyl analogues of the racemic N-nosyl aziridines 1.18α-Ns and 1.18β-Ns, by an enatioselective version of the racemic synthetic protocol (See Chapter 3).
1.3. Synthesis of racemic epoxides 1.17α and 1.17β
The original synthesis of racemic epoxides 1.17α and 1.17β starts from triol 1.20 having the same relative configuration as D-glucal. Triol 1.20 and its immediate precursor tri-acetate 1.19, were prepared by the procedure of Ogawa, in which the first step is a Diels-Alder reaction between furane and methyl acrilate (Scheme 1.6).
! ! ! "!!#$ "!!#$ ! ! %& ! !'( %& !'( "!!#$ )* %+,-./0! 1 ! )*2345"!, 0*2%&0 0*2)67248234!5 ,*2,9724825": )*2;5'<2=5+ 0*2'(0!<>? %& %& %& !'( '(! %& !'( '(! '(! !'( '(! !5 5! 5! )@725%&<'(!5 A9B" CD<'(!5 E6B" '(!34 0672482F#+ )66B" #$!34 #$!5 !"!# !"$%
Scheme 1.6. Synthesis of triacetate 1.19 and triol 1.20 by Ogawa’s procedure.
A typical protection-deprotection-cyclization procedure transforms triol 1.20 into epoxide 1.17β, which is obtained in 66% overall yield (4 steps from trans diol 1.21, Scheme 1.7).10
!" "! "! !" "! #$! %&'(")*+ ,&'#$#-!.#+ "! #$! .#+/01*)2 34567809 ):/01;< =>/ !.#+ ):! #$! !" ):! #$! .#?21."2 #$! ! !@#A!B /"C/D !"#$ !"#! !"!%! !"## !"#& !"#' CEF GHF GIF E%F GGF =>/
Scheme 1.7. Synthesis of vinyl epoxide 1.17β.
Epoxide 1.17β is the starting compound for the synthesis of the diasteroisomeric epoxide 1.17α, which is obtained in 41% overall yield (7 steps from trans diol 1.21, Scheme 1.8).9
! "#! $! "#! !%& %&!$'()'*+,-./ 0$1021 34567)'8 99: ;<02=>? 6@0 ;<! "#! !%& !7",!A 0$)08 ! "#! !"!#$ !"%' BB: !"%& C1: !"!#!
Epoxides 1.17α and 1.17β turned out to be sufficiently stable also at room temperature. However they were commonly stored, safely, also for long times at –15 °C.
Hereafter, in order to make easier the discussion of the new results obtained by me with epoxides
1.17α and 1.17β and the discussion and comparison of the results obtained with aziridines 1.18α-Ns and 1.18β-Ns, the regio- and stereoselective behavior of epoxides 1.17α and 1.17β in
their reaction with O-nucleophiles (MeOH and AcOH), yet discussed in a previous PhD thesis11 and published,9 will be briefly reasumed.
1.4. Addition reactions of O-nucleophiles to epoxides 1.17α and 1.17β
Simple MeOH and AcOH were taken as appropriate O-nucleophiles models in order to check the regio- and stereoselective behavior of diastereoisomeric epoxides 1.17α and 1.17β.8 For the sake of simplification, the addition products obtained both by epoxides 1.17α and 1.17β and N-nosyl aziridines 1.18α-Ns and 1.18β-Ns (see Chapter 2) were usually indicated as 1,2-addition products or 1,4-addition products when the nucleophile attacks the allyl C(3) oxirane carbon or C(1) vinyl carbon of the unsaturated system in a conjugate fashion, respectively.
!" #$ %&' %&' $ !"#"$!%!&!'!( !"#")!*+,%!&!'!+*+, !" #$ %&' !" !"#$%&'(% !))$#$*"+,-*)./#0 !" #$ %&' #$ %&' 01"%&'2% !))$#$*"+,-*)./#0 !" !" #$ %&' #$ %&' !"#$%&'2% !))$#$*"+,-*)./#0 !" !" ( ( !"#"$"%!&!'!( !"#")"*+,%!&!'!+*+, )!* )!*+ ,-. , / 0 1 * %&' $ ,-. , / 0 1 * !" #$ %&' !" #$ %&' 01"%&'(% !))$#$*"+,-*)./#0 ( ( / / 0 0 / / 0 0 / / 1 1 / 1 / 1 !" )!*+ !" )!*
Scheme 1.9. Syn- and anti-1,2 and syn- and anti-1,4-addition products from epoxides 1.17α and 1.17β and
aziridines 1.18α-Ns and 1.18β-Ns.
The additional prefix syn- or anti- indicates that the nucleophilic attack occurred with retention (cis-3,4- or -1,4-derivatives) or inversion of configuration (trans-3,4- or -1,4-derivatives), respectively, with respect to the C(3)-X bond configuration of the starting heterocyclic system (epoxide and aziridine). As a consequence, only for the reason of maintaining the useful resemblance of these carbasystems with the corresponding real monosacchariders, an independently, arbitrary numbering is given to the cyclic carbasystems as shown in Scheme 1.9. In
this way, the C(1) carbon of the carbasugar corresponds to the anomeric center of the real monosaccharide.
Protocol A (O-nucleophile as the solvent) and/or protocol B reaction conditions (O-nucleophile,
3-6 equiv, in a non-nucleophilic solvent as CH2Cl2) were commonly used.
The regio- and stereoselective behavior of epoxides 1.17α and 1.17β with O-nucleophiles was examined by means of simple and synthetically significant MeOH and AcOH, used under different reaction conditions (acid or basic conditions with different epoxide:nucleophile ratio). The results obtained are collected in Tables 1.1 and 1.2.
The methanolysis of epoxide 1.17β carried out under alkaline conditions (MeONa/MeOH, protocol
A) is completely 1,2-regioselective and anti-stereoselective, with the exclusive obtainment of trans
methoxy alcohol 1.27 (entry 1, Table 1).
When the methanolysis reaction is carried out under acid conditions (MeOH/H2SO4 0.2 N, protocol
A), the reaction is not regioselective, and leads to an 80:20 mixture of the corresponding 1,2- and
1,4-addition products. Inside this mixture, while the 1,2-addition process is completely anti stereoselective and leads to the trans-3,4-methoxy alcohol 1.27, the 1,4-addition process is not stereoselective, leading to a 1:2 mixture of the corresponding syn- (the cis-1,4-methoxy alcohol
1.28) and anti-1,4-addition product (the trans-1,4-methoxy alcohol 1.29) (entry 2, Table 1.1 and
Scheme 1.10).
Table 1.1. Regio- and stereoselectivity of solvolysis reactions of epoxide 1.17β with
O-nucleophiles.
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$% $% $% "#! "#! "#! ' ' !"#$%&'(%!))$#$*"+ ,-*)./# 01"%&'2%!))$#$*"+ ,-*)./# !"#$%&'2%!))$#$*"+,-*)./# !"$#(%$%)*)!+, !"$&()$%)*)!-. !"'$()$%)*)!& !"$((%$%)*)!+, !"')()$%)*)!-. !"$*(%$%)*)!+,!"'!()$%)*)!-. $%&)*)+,!&()-.!&()&/! Entry Reagents T (°C) anti- 1,2-addition product syn- 1,4-addition product anti- 1,4-addition product 1 2 N MeONa/MeOH 80 >99 - - 2 MeOH/0.2N H2SO4 rt 80 5 15 3 MeOH/CH2Cl2/0.01N TsOHa rt >99 - - 4 AcOH/0.2 N TsOH rt 77 - 23 5 AcOH/CH2Cl2/5.10-3N TsOHb rt >99 - - 6 AcONa/DMF-H2O 90 >99d - -
Considering that the 1,4-addition of an appropriate O-nucleophile to epoxide 1.17β is necessary for the synthesis of “carba” oligosaccharides or, in general, carba O-glycosides, different reaction conditions were tried in order to increase the desired 1,4-regioselectivity. Unfortunately, also the application of protocol B reaction conditions (MeOH/CH2Cl2/0.01 N TsOH, epoxide : MeOH ratio 1:6) was unexpectedly unsuccessful, leading to a completely 1,2-regioselective process with the exclusive formation of the corresponding anti-1,2-addition product, the trans-1,2-methoxy alcohol
1.27 (entry 3, Table 1.1).
The completely or highly 1,2-regioselective behavior found in the methanolysis of epoxide 1.17β was also found in the corresponding acetolysis reaction (Table 1.1). To note that also in this case, the use of protocol B reaction conditions led to a completely anti-1,2-addition process giving the
anti-1,2-addition product, the trans-3,4-hydroxy acetate 1.25, as the only reaction product (entry 5,
Table 1.1).
The methanolysis of the diastereoisomeric carba-epoxide 1.17α indicated that the behavior of this epoxide is similar to that of epoxide 1.17β, but significant and synthetically useful differences are present (Table 1.2).
Table 1.2. Regio- and stereoselectivity of solvolysis reactions of epoxide 1.17α with
O-nucleophiles.
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$% $% $% "#! "#! "#! ' ' !"#$%&'(%!))$#$*"+ ,-*)./# 01"%&'2%!))$#$*"+,-*)./# !"#$%&'2%!))$#$*"+,-*)./# &! $% "#! ' 01"%&'(%!))$#$*"+ ,-*)./# !"$$(%$%)*)!+, !"$&()$%)*)!-. !"$#()$%)*)!-. !"$'(%$%)*)!+,!"$(()$%)*)!-. !"$)(%$%)*)!+, $%&)*)+,!&()-.!& Entry Reagents T (°C) syn- 1,2-addition product anti- 1,2-addition product syn- 1,4-addition product anti- 1,4-addition product 1 2 N MeONa/MeOH 80 - >99 - - 2 MeOH/0.2N H2SO4 rt - 32 44 24 3 MeOH/CH2Cl2/10-2N TsOHa rt - 43 47 10 4 AcOH/0.2 N TsOH rt 28 56 16 - 5 AcOH/CH2Cl2/ 5.10-3N TsOHb rt 30 38 32 -
a Epoxide : MeOH ratio 1:6. b Epoxide : AcOH ratio = 1: 3.
As with 1.17β, the alkaline methanolysis (MeONa/MeOH) of epoxide 1.17α is completely 1,2-regio- and anti-stereoselective and the acid methanolysis (MeOH/0.2 N H2SO4) is not
regioselective, leading to a mixture of the corresponding anti-1,2-addition product (trans-3,4-methoxy alcohol 1.33, 32%) and 1,4-addition products (a 2:1 mixture of syn- and anti-1,4-addition products, the cis- 1.34 and trans-1,4-methoxy alcohol 1.35), but the significant difference is that the 1,4-addition is now the main addition process (68%). In this case, the application of protocol B reaction conditions is not dramatic toward 1,4-addition, as in 1.17β, and determines only a slight decrease in the overall 1,4-regioselectivity (57%), which is accompanied by an increase in the
syn-1,4- /anti-syn-1,4-addition product stereoselectivity (from 2:1 to 4.7:1, entry 4, Table 1.2).
Decidedly different is the behavior of epoxide 1.17α in acetolysis. Actually, under these conditions a substantial amount of syn-1,2-addition product, the cis-3,4-acetoxy alcohol 1.37, was obtained to the point that an almost 1:1:1 mixture of 1.37, trans-3,4-acetoxy alcohol 1.36 and cis-1,4-acetoxy alcohol 1.38 was obtained under protocol B reaction conditions. To note that corresponding syn-1,2-addition products were never observed in the opening reactions of epoxide 1.17β with O-nucleophiles (Tables 1 and 1.2).
The sufficiently satisfactory 1,4-regioselective result observed in the methanolysis, under protocol
B reaction conditions, indicated epoxide 1.17α as a potentially useful candidate for the
construction of carba O-glycosides and O-linked carba oligosaccharides.
Because considered useful to the rationalization of the results, a theoretical conformational study was carried out on epoxides 1.17α and 1.17β. The results obtained, confirmed by a corresponding 1H NMR conformational analysis, indicated that epoxides 1.17α and 1.17β exist almost exclusively (96% in the case of 1.17α and >99% in the case of 1.17β) as the corresponding conformer 1.17α’ and 1.17β’ with the side chain axial and equatorial, respectively (Schemes 1.11 and 1.12).
An important general feature of epoxide opening in 6-membered rings (A) is the tendency for trans diaxial ring opening (route a).12 The existing substituent on the cyclohexane ring favour one of the two possible half-chair conformations. In Scheme 1.10 a typical half-chair conformation A is subjected to nucleophilic attack of a generic nucleophile (Nu). In the chair-like transition state corresponding to a trans diaxial ring opening (route a), the principle of microscopic reversibility requires an antiperiplanar relationship (B) between the nucleophile and the epoxide oxygen which is found in the product after reaction (C’), rapidly equilibrates to the more stable conformer bearing all the substituents in a trans diequatorial relationship (C’’).
On the other hand, the trans diequatorial ring opening (route b) evolves to a more energetic twist-like transition state, which at the end of the addition diaxial product (E’) equilibrates to give diequatorial product (E’’). As the twist is a higher energy conformation, this situation is disfavored from a stereoelectronic point of view.
! ! "# $ % & ' ( ) $ % & ' ( ) "# ! " !* "# $ % & ' ( ) & ' % $ ) ( ! "# ! $ % & ' ( ) "# % $ & ' ( ) !* "# !"#$%+! !"#$%+" $ %## "## & "# &'()*+&',! +&',!*(,-%.$!'/0,$,"/.0$'$% $1,0$*(,-%.$!'/0,$,"/.0$'$% $!'/0.2,'3,'(.!,/4."5%/,/4 $!'/0.2,%6#'$"!,'(.!,/4."5%/,/4 "# *! $ % & ' ( ) "# !* %#
Scheme 1.10. Rationalization of trans diaxial ring opening and trans diequatorial ring opening of epoxide
in 6-membered rings.
Considering that stereoelectronic factors associated with the opening processes of three-membered rings make trans diaxial opening of a cycloaliphatic oxirane the favored opening process, the conformational population inside 1.17α and 1.17β is responsible, in our opinion, for the opposite regioselective behavior found for these epoxides in methanolysis reactions. Actually, in epoxide
1.17β, nucleophilic attack on C(3) allyl oxirane carbon, from the α-side, of the only existing
protonated conformer 1.17β’-H (route a) corresponds to the requirement for a trans diaxial opening process, and does not show any particular steric hindrance. Accordingly, the anti-1,2-addition process is correctly the main opening process with this epoxide (Scheme 1.11 and Table 1), whereas the 1,4-addition process (routes b and c) is decidedly less important.
! !"# ! !"# $ %&!$ %&!$ !"!#! !"!#!$%& !"#$%&! " ! # !"#$%&" !"#$%&# '$( '$( '$( %&!$ $( $! $! $! !%& !%& !%& "#! "#! "#! $%&'()*'!++,-,.&/01.+2#- !&-,'()3'!++,-,.&/01.+2#- !&-,'()*'!++,-,.&/01.+2#-!"'( !"'# !"')
Scheme 1.11. Methanolysis of epoxide 1.17β: possible addition pathways.
In the diastereoisomeric epoxide 1.17α, the corresponding trans diaxial opening of the oxirane ring can occur only by nucleophilic attack from the β-side of the corresponding, largely existing, protonated conformer 1.17α’-H, but in this case the attack is subjected to an unfavorable 1,3-diaxial interaction (torsional strain) with the C(6)-C(7) bond of the axial side chain (route a, Scheme 1.12). As a consequence, the anti-1,2-addition process is sufficiently slowed down to make the 1,4-addition process [routes b and c from more stable protonated conformer 1.17α’-H and d and e from less stable protonated conformer 1.17α”-H] competitive to the point of becoming the main addition process. Inside the 1,4-addition pathway, in agreement with the experimental results, the syn-1,4-addition process (routes b and e), which is not subjected to any particular strain (route
b) or corresponds to a pseudoaxial attack (route e), prevails over the alternative anti-1,4-addition
process (routes c and d) for which a 1,3-diaxial interaction with the axial side chain is present (route c) or it corresponds to a less favored pseudoequatorial attack (route d) (Scheme 1.12). In this framework, considering that the 1,2-addition process with retention of configuration is favored by the axial opening of the oxirane ring and formation of a discrete (not free) allyl carbocationic species (possible only in protonated conformer 1.17α’-H), the slowing steric effect of the side chain toward nucleophilic attack from the β-face of 1.17α’-H, could be responsible of the formation of a substantial amount (27%) of the corresponding syn-1,2-addition product with the less nucleophilic AcOH. Evidently, in these conditions, a syn-1,2-addition process, which
necessarily develops entirely on the less hindered α-face, can become competitive (route f, Scheme 1.12). ! !"# !"!#!$$%& $ %&$ %&$ %&$ $' ! !"# !"!#! ! !"# !"!#!$ ! !"!#!$%& !"# %&$ $' $ %&$ %&$ ! " # $ % !"#$%&" ($' ($' !"#$%&! !"# $! %& "#! $! %& "#! &'()*+,)%""-.-/(012/"3#.& !"#$%&$ ($' !"#$%04 ($' ! $ )* ! $ " + " + $! !)* "#! &'()*+5)%""-.-/(012/"3#. $! %& "#! !"#$%0% ($' %&$+,+-.!$/+)*!$ !"'# !"''/(%&+,+!-. !"')/+%&+,+!)* !"'*/(%&+,+!-. !"'+/+%&+,+!)* %(.-)*+,)%""-.-/(012/"3#.& %(.-)*+5)%""-.-/(012/"3#.& !"',/(%&+,+!-.
Scheme 1.12. Reaction of epoxide 1.17α with MeOH and AcOH under acid conditions: possible addition
pathways.
1.5. Methanolysis of epoxides 1.17α and 1.17β in the presence of an ionic liquid
On the basis of above described results, I tried to find some different conditions able to influence positively the regioselectivity of the methanolysis reactions of epoxides 1.17α and 1.17β toward 1,4-addition products. Clearly, only acid-catalyzed or at least neutral reaction conditions could be advantageously explored considering that an increase of 1,4-addition process could reasonably derived only from an opening process characterized by a more diffused carbocation-like intermediate as shown in 1.17β-D, Scheme 1.13. For his reason we thought that the use of an ionic liquid as a solvent, or a cosolvent, could be beneficial to the development of a more carbocationic character of the intermediate and as a consequence usefull to our scope.
! "#! ! "#! ! "#! $ $ !% !% $% &'!$ &'!$ !"#$%&' !"#$%&( ' ( $! !&' "#! $! !&' "#! !"#$%&'(%!))$#$*"+ ,-*)./# &'0%!))$#$*"+ ,-*)./#1 !"!#" !"!#"$% !"!#"$&
Scheme 1.13. Possible intermediate species in the acid methanolisis of epoxide 1.17β.
Two different ILs, as butylmethylimidazolium tetrafluoroborate ([bmin][BF4]) and benzylbutylimidazolium tetrafluoroborate ([bzbim][BF4]), soluble in organic solvents, were used in order to check the validity of our assumption (Scheme 1.13).
! !" #$%& '()*)*+'#$%+ ! !" #$%& '(,()*+'#$%+
These ILs have been used as solvent or cosolvent in different reaction conditions, steadily acid for H2SO4 or TsOH. The nucleophile (MeOH) could be present in a large amount, when cosolvent with IL of the reaction, or only in a controlled amount (3 equiv) with respect to the epoxide, when IL was the solvent of the reaction. The result obtained with epoxides 1.17α and 1.17β in the different reaction conditions are reported in the following Tables 1.3 and 1.4, respectively.
Table 1.3. Regio- and stereoselectivity of acid methanolysis reactions of epoxide 1.17β in the
presence of an IL. ! "#! !"!#! $! $! $! !%& !%& !%& "#! "#! "#! ' ' !"#$%&'(%!))$#$*"+ ,-*)./# 01"%&'2%!))$#$*"+,-*)./# !"#$%&'2%!))$#$*"+,-*)./# !"$# !"$% !"$& %&!$ $' ()#*+,-*./*0
Entry Reaction conditions anti-1,2-addition
product syn-1,4-addition product anti-1,4-addition product 1 MeOH/H2SO4 0.2 N 80 5 15 20
2 MeOH/TsOH/CH2Cl2 10-2 Na >99 - - -
3 MeOH/[bmim][BF4] (1:1) H2SO4
5.10-2 N 67 23 10
33
4 MeOH (3 eq)/CHTsOH 2.10-3 N,[bmim][BF2Cl2
4] 55 27 18 45 5 MeOH/[bmim][BF4] (1:1) 64 26 10 36 6 MeOH (3 eq)/TsOH 9 .10-3 N [bmim][BF4] 53 27 20 47 7 MeOH/ H2SO4 5.10-2 N [bzbim][BF4] (1:1) 84 - 16 16
Table 1.4. Regio- and stereoselectivity of acid methanolysis reactions of epoxide 1.17α in the
presence of an ILs. ! "#! !"!#! $! $! $! !%& !%& !%& "#! "#! "#! ' ' !"#$%&'(%!))$#$*"+ ,-*)./# 01"%&'2%!))$#$*"+ ,-*)./# !"#$%&'2%!))$#$*"+,-*)./# !"$$ !"$% !"$& %&!$ $' ()#*+,-*./*0
Entry Reaction conditions anti-1,2-addition
product anti-1,2-addition product anti-1,2-addition product 1 MeOH/H2SO4 0.2 N 32 44 24 68 2 MeOH/TsOH/CH2Cl2 10-2 Na 43 47 10 57 3 MeOH/[bmim][BF4] (1:1) H2SO4 5.10-2 N 31 33 36 69 4 MeOH (3 eq)/CH2Cl2 TsOH 2.10-3 N,[bmim][BF 4] 20 76 4 80 5 MeOH (3 eq)/TsOH 9 .10-3 N [bmim][BF4] 25 45 30 75 6 MeOH/ H2SO4 5.10-2 N [bzbim][BF4] (1:1) 50 30 20 50
able to increase the 1,4-regioselectivity in both the epoxides and particularly in epoxide 1.17β. In fact, if numerically speaking the increase is 1,4 times in epoxide 1.17α (from 57 to 80%, entries 2 and 3, Table 1.4) and 2.4 times in epoxide 1.17β (from 20 to 47%, entries 1 and 6, Table 1.3), the percent of increasing is 40% in epoxide 1.17α and 140% in epoxide 1.17β.
The supposed ability of the IL, present in consistent amount in the reaction medium, to delocalize the partial positive charge deriving from the protonation of the oxirane oxygen in the transition state of the opening process, favors a greater development of partial positive charge on C(1) further from the inductive electron-withdrawing effect of the protonated oxirane oxygen. Subsequent more favorable attack of the nucleophile (MeOH) on that carbon occurs with corresponding increase of 1,4-addition product, even if as a mixture of corresponding cis- and trans-diastereoisomers. In both epoxides the best result is obtained when the nucleophile is present only in a limited amount (3 equiv, protocol B reaction conditions) and IL is the solvent with TsOH as the acid (0.002-0.009 N). Remarkable is that the best result obtained with epoxide 1.17α (80% 1,4-addition) is accompanied, for the first time, with a consistent level of syn-stereoselectivity (76% yield with syn-/anti-adduct ratio 19:1). The remaining is constituted by the usual anti-1,2-addition product which, in this way, reaches its lowest result (4%).
These last results confirm, once again, epoxide 1.17α as an efficient candidate as carbaglycosyl donor in the reaction with O-nucleophiles. At the same time, epoxide 1.17β presents 1,4-addition values which become to make also this system interesting for a corresponding synthetic application.
1.6. Experimental
General Procedures. All reactions were performed in flame-dried modified Schlenk (Kjeldahl
shape) flasks fitted with a glass stopper or rubber septa under a positive pressure of argon. Air/and moisture-sensitive liquids and solutions were transferred via a syringe. Organic solutions were dried on MgSO4 and concentrated by a rotary evaporator below 40°C at ca. 25 Torr. Flash chromatography was performed employing 230-400 mesh silica gel. Analytical TLC was performed on Alugram SIL G/UV254 silica gel sheets (Macherey-Nagel) with detection by 0.5% phosphomolybdic acid solution in 95% EtOH.
Materials. MeOH and CH2Cl2 over molecular sieves were purchased from Aldrich and used without purification. Vinyl epoxides 1.17α and 1.17β were prepared as previously described.8
trans-1,2-methoxy alcohol 1.33, cis-1,4-methoxy alcohol 1.34 and trans-1,4-methoxy alcohol 1.35
were previously described.9
Instrumentation. Infrared (IR) spectra were obtained using a FTIR spectrophotometer. Data are
presented as frequency of absorption (cm-1). Proton and carbon-13 nuclear magnetic resonance (1H NMR and 13C NMR) spectra were recorded at 250 and 62.5 MHz, respectively; chemical shifts are expressed in parts per million (δ scale) downfield from tetramethylsilane and refer to residual protium in the NMR solvent [CHCl3: δ 7.26; CD3CN: δ 1.94, CD3OD: δ 3.31, (CD3)2CO: δ 2.05, D2O: δ 4.79]. Data are presented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, m=multiplet and/or multiple resonances), integration, coupling constant in Hertz (Hz).
Acid methanolysis of vinyl epoxide 1.17β in the presence of an ionic liquid
Reaction of epoxide 1.17β with 1:1 MeOH/[bmim][BF4] in the presence of 0.05 N H2SO4
Typical procedure: A solution of epoxide 1.17β (0.010 g, 0.046 mmol) in a 0.05 N H
2SO4-MeOH/[bmim][BF4] mixture (1:1) (1.0 mL) was stirred at room temperature for 18 h. Dilution with Et2O and evaporation of the washed (saturated aqueous of NaHCO3 and brine) afforded a crude reaction product (0.012 g, 99% yield) consisting of a 67:23:10 mixture of trans-1,2-methoxy alcohol 1.27, cis-1,4-methoxy alcohol 1.28 and trans-1,4-methoxy alcohol 1.29 (1H NMR).
Reaction of epoxide 1.17β with MeOH (3 equiv) in 1:1 CH2Cl2/[bmim][BF4] in the presence of 2.10-3N TsOH
Following the typical procedure, epoxide 1.17β (0.010 g, 0.046 mmol) was added to a 2.10-3 N TsOH-CH2Cl2/[bmim][BF4] (1:1) mixture (1.0 mL) containing MeOH (5.6 µL, 0.138 mmol, 3.0 equiv) and the reaction mixture was stirred at room temperature for 18 h. Usual workup afforded a crude reaction product (0.013 g, 99% yield) consisting of a 55:27:18 mixture of trans-1,2-methoxy alcohol 1.27, cis-1,4-methoxy alcohol 1.28 and trans-1,4-methoxy alcohol 1.29 (1H NMR).
Reaction of epoxide 1.17β with a 1:1 MeOH/[bmim][BF4] mixture
Following the typical procedure, epoxide 1.17β (0.010 g, 0.046 mmol) was dissolved in a 1:1 MeOH/[bmim][BF4] mixture (1.0 mL) and the reaction mixture was stirred at room temperature for 18 h. Usual workup afforded a crude reaction product (0.012 g, 99% yield) consisting of a 64:26:10 mixture of trans-1,2-methoxy alcohol 1.27, cis-1,4-methoxy alcohol 1.28 and trans-1,4-methoxy alcohol 1.29 (1H NMR).
Reaction of epoxide 1.17β with MeOH (3 equiv) in [bmim][BF4] in the presence of 9.10-3 N TsOH
Following the typical procedure, epoxide 1.17β (0.010 g, 0.046 mmol) was added to a 9.10-3 N TsOH in [bmim][BF4] (0.2 mL) containing MeOH (5.6 µL, 0.138 mmol, 3 equiv) and the reaction mixture was stirred 18 h at room temperature. Typical workup afforded a crude reaction product (0.012 g, 99% yield) consisting of a 53:27:20 mixture of trans-1,2-methoxy alcohol 1.27, cis-1,4-methoxy alcohol 1.28 and trans-1,4-cis-1,4-methoxy alcohol 1.29 (1H NMR).
Reaction of epoxide 1.17β with 1:1 MeOH/[bzmim][BF4] in the presence of 0.05 N H2SO4
Following the typical procedure, a solution of epoxide 1.17β (0.010 g, 0.046 mmol) in a 0.05 N H2SO4-MeOH/[bzmim][BF4] mixture (1:1) (1.0 mL) was stirred at room temperature for 18 h. Typical workup afforded a crude reaction product (0.012 g, >99% yield) consisting of an 84:16 mixture of trans-1,2-methoxy alcohol 1.27 and trans-1,4-methoxy alcohol 1.29 (1H NMR).
Acid methanolysis of vinyl epoxide 1.17α in the presence of an ionic liquid
Reaction of epoxide 1.17α 1:1 MeOH/[bmim][BF4] in the presence of 0.05 N H2SO4
Following the typical procedure previuosly decribed for vinyl epoxide 1.17β, a solution of epoxide
1.17α (0.010 g, 0.046 mmol) in a 0.05 N H2SO4-MeOH/[bmim][BF4] mixture (1:1) (1.0 mL) was
stirred at room temperature for 18 h. Typical workup afforded a crude reaction product (0.012 g, 99% yield) consisting of a 31:33:36 mixture of trans-1,2-methoxy alcohol 1.33, cis-1,4-methoxy alcohol 1.34 and trans-1,4-methoxy alcohol 1.35 (1H NMR).
Reaction of epoxide 1.17α with MeOH (3 equiv) in 1:1 CH2Cl2/[bmim][BF4] in the presence of 2.10-3N TsOH
Following the typical procedure, epoxide 1.17α (0.010 g, 0.046 mmol) in a 2.10-3 TsOH-CH2Cl2/[bmim][BF4] mixture (1:1) (1.0 mL) was treated with MeOH (5.6 µL, 0.138 mmol, 3.0 equiv) and the reaction mixture was stirred at room temperature for 18 h. Typical workup afforded a crude reaction product (0.013 g, 99% yield) consisting of a 23:73:4 mixture of trans-1,2-methoxy alcohol 1.33, cis-1,4-methoxy alcohol 1.34 and trans-1,4-methoxy alcohol 1.35 (1H NMR).
Reaction of epoxide 1.17α with MeOH (3 equiv) in [bmim][BF4] in the presence of 9.10-3 N TsOH
reaction mixture was stirred 18 h at room temperature. Typical workup afforded a crude reaction product (0.012 g, 99% yield) consisting of a 25:45:30 mixture of trans-1,2-methoxy alcohol 1.33,
cis-1,4-methoxy alcohol 1.34 and trans-1,4-methoxy alcohol 1.35 (1H NMR).
Reaction of epoxide 1.17α with 1:1 MeOH/[bzmim][BF4] in the presence of 0.05 N H2SO4 Following the typical procedure, a solution of epoxide 1.17α (0.010 g, 0.046 mmol) in 0.05 N H2SO4-MeOH/[bzmim][BF4] mixture (1:1) (1.0 mL) was stirred at room temperature for 18 h. Typical workup afforded a crude reaction product (0.012 g, 99% yield) consisting of 50:30:20 mixture of trans-1,2-methoxy alcohol 1.33, cis-1,4-methoxy alcohol 1.34 and trans-1,4-methoxy alcohol 1.35 (1H NMR).
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