CHAPTER 4
Functionalization of the double bond of the carbaglycals
4.1. Introduction
The obtainment of the 1,4-addition products in the ring opening process of epoxides 1.17α and 1.17β1 (Chapter 1) and the corresponding N-nosyl aziridines 1.18α-Ns and 1.18β-Ns
(Chepter 2) by an appropriate O-nucleophile is a necessary condition for the utilization of these vinyl systems in the synthesis of carbaoligosaccharides and/or pseudodisaccharides, that is compounds in which a monosaccharide is linked to a carbasugar. In this framework, the amount of the 1,4-addition products, in each case obtained, can be taken as a measure of the
carbaglycosylating ability of these systems.
The results obtained with epoxides 1.17α and 1.17β and the corresponding N-nosyl aziridines 1.18α-Ns and 1.18β-Ns were, unfortunately, not completely satisfactory, because a complete 1,4-regioselective with consistent amount of syn- and/or anti-stereoselectivity was never observed and the 1,4-addition products (commonly obtained as a not stereoselective mixture of syn- and anti-adducts) were always accompanied by the corresponding regioisomeric 1,2-addition product. As a result the maximum obtained 1,4-regioselectivity value can be resumed for each epoxide and aziridine in this way: 47% from epoxide 1.17β, 80% from epoxide 1.17α, 62% from aziridine 1.18α-Ns and 60% from aziridine 1.18β-Ns. However, it should be noted that in both 1,2- and 1,4-addition products, an unsaturation in 3,4 or 2,3 is still present, respectively, and susceptible of further functionalizations. This means that fully functionalized carbasugars and aminocarbasugars could be obtained also by means of an appropriate functionalization of the residual 2,3-double bond present in 1,4-addition products or by elaboration of the 3,4-double bond present in 1,2-addition product derived from vinyl epoxides 1.17α and 1.17β and the corresponding vinyl N-nosyl aziridines 1.18α-Ns and 1.18β-Ns, with a regio- and stereodefined hydroxy or N-nosylamino functionality necessarily yet present on C(4), respectively (Scheme 4.1).
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Scheme 4.1. Generic functionalization of the double bond in 1,2- and 1,4-addition products from vinyl epoxides 1.17α and 1.17β and the corresponding N-nosyl aziridines 1.18α-Ns and 1.18β-Ns. In other words, the absence of a complete 1,4-regioselectivity necessary to make epoxides 1.17α and 1.17β and aziridines 1.18α-Ns and 1.18β-Ns act as “carbaglycosyl donors”, could be overcome by appropriate functionalization of the double bond present in 1,2- and 1,4-addition products in which the vinyl carbon C(1), that is the vinyl carbon closer to the methylene group which replaces the oxygen of the real monosaccharides, should be considered as the pseudo anomeric center of the carbamonosaccharide. This strategy appears particularly interesting when applied to 1,2-addition products which, as shown in the preceding parts of this thesis, are easy to synthesize in a completely regio- and stereoselective fashion.
4.2. Functionalization of 1,2-double bond in racemic carbaglucal systems As a preliminary study, some derivatives of triol 1.202 obtained by partial or complete protection of the hydroxy functionalities, triol 1.20 itself and some simple compounds easily available in our laboratory because obtained as anti-1,2-addition products in the ring opening of epoxides 1.17α and 1.17β,1 were prepared and examined in order to evaluate their stereoselectivity in epoxidation reactions of the residual C(1)-C(2) double bond. The interest toward the epoxidation reaction is due to the fact that an oxirane moiety inserted in that position, when subjected to nucleophilic ring opening, makes the entire molecule to act as a
carbaglycosylating agent, provided the nucleophilic attack occurs at C(1), the mimic
anomeric carbon. In the presence of such a favorable regioselectivity, the configuration α or β of the inserted oxirane ring, associated with a reasonable completely anti addition process by an O-nucleophile (ROH), as an example, determines, on the basis of the known configuration
of the initially present stereocenters, the configuration of the carba O-glycosides which in this way can be obtained. This important point is summarized in the following Scheme 4.2.
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Scheme 4.2. Synthesis of carba-O-glycosides by epoxidation of 1,2-double bond in derivatives of triol 1.20.
Two epoxidation protocols were considered: a) the direct oxidation of the double bond by a peracid, as the easily available MCPBA and b) the indirect, two steps procedure deriving by the initial reaction of the unsaturated system with NBS/H2O to give only one trans
bromohydrin or, more likely, a mixture of regioisomeric trans bromohydrins which are immediately cyclized under basic conditions (t-BuOK) to only one epoxide or a mixture of diastereoisomeric epoxides, respectively.
In this framework, these two epoxidation protocols (MCPBA and the sequence given by NBS/H2O followed by cyclization with t-BuOK of the mixture of the intermediate
bromohydrins) have the interesting property to lead, in some cases, to diastereoisomeric epoxides in a completely stereoselective way starting from the same unsaturated substrate. The following Scheme 4.3 summarizes this interesting point by means of an example derived from 2-cholestene (4.4). The reaction of 4.4 with MCPBA3 is governed by the steric effect of the axial β-directed –Me group: as a consequence, the attack of the electrophilic oxidant necessarily occurs on the opposite, not sterically hindered α-face and α-epoxide 4.7α is obtained, as practically the only reaction product.
When the same substrate is subjected to the reaction with NBS/H2O,3,4 the electrophile Br+,
associated to this protocol, is subjected to the same steric effect deriving from the presence of the axial –Me group. As a consequence, also in this case the electrophilic attack occurs
give trans bromohydrin 4.6 which on treatment with a base leads to the diastereoisomeric β-epoxide 4.7β, practically as the only reaction product.3,4
!" !#$%& !"! !" ' !#$%&'()$ !" ' "#$%&'()$ !" %( !"* )*'+ +,' )%-+,' !" !"+ %( +' !",! !"," Scheme 4.3. Diasteroselective epoxidation of 2-cholestene (4.4).
The completely different diastereoselective result obtained in the reported example by means of the two different protocols finds its rationalization by looking at the reaction step in which the “future oxirane oxygen” is inserted in the unsaturated substrate. With MCPBA, the “oxygen” is inserted in the unique step of the reaction corresponding to the electrophilic attack by the oxidant from the α-face whereas with the NBS/H2O/base protocol the insertion
of the “future oxirane oxygen” now occurs in the second step of the reaction, corresponding to the nucleophilic attack by water to the α-brominium ion 4.5 from the β-face: this is the difference between the two protocols.
This interesting aspect has indicated the possibility of directing the epoxidation in a stereoselective manner to the β− or α-face of the unsaturated systems derived from triol 1.20 by using these different procedures and different protecting groups of the hydroxy functionalities of the substrate. Clearly, the crude reaction product, derived from the reaction with NBS/H2O in THF, could be very complex (mixtures of bromohydrins). For this reason,
the crude product from NBS/H2O was never analyzed, but directly cyclized under basic
conditions (t-BuOK) in order to have a more simplified crude reaction product reasonably consisting of only one epoxide or a mixture of two diastereoisomeric epoxides.
In the following Scheme 4.4, it is reasumed what can occur by application of the two protocols to the systems of our present interest.
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Scheme 4.4. Generic application of the MCPBA and NBS/H2O/base protocols to triol 1.20 and derivatives.
A preliminary control of what present in literature on this argument showed that epoxidation reactions of triol 1.205 and its tri-O-benzyl derivative 4.16 by means MCPBA protocol were already described and indicated that, in these conditions, tri-O-benzyl olefin 4.1 afforded an 80:20 mixture of diasteroisomeric epoxides 4.2α and 4.2β, whereas triol 1.20 led to a mixture of the corresponding unprotected epoxides 4.3α and 4.3β which were obtained in an inverted 12:88 ratio (Scheme 4.5). Evidently, the observed partial stereoselectivity found in these two unsaturated systems, is governed by two different factors: steric and coordination effects. In tri-O-benzyl derivative 4.1, the direction of the oxidation process is determined by steric effects and in particular by the β-direction of the allyl –OBn group. As a consequence, the approach of the peracid occurs from the opposite face leading to a prevalent amount of α-epoxide 4.2α. In the unprotected unsaturated system of triol 1.20, the direction of the oxidation process is driven by the β-direction of the free allyl –OH group and by its directing ability by means of the formation of a hydrogen bond with the oxidant (MCPBA). As a consequence the approach of the oxidant (MCPBA) occurs selectively from the β-face and a diastereoisomeric excess of β-epoxide 4.3β is correspondingly found.
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Scheme 4.5. Stereoselecytivity of the MCPBA epoxidation of tri-O-benzyl derivative 4.1 and triol 1.20 (Ref. 6 and 5, respectively).
These results indicate that it is possible to have opposite diastereoselectivity in the epoxidation by means of the same oxidant (MCPBA) in strictly related unsaturated systems, provided appropriate simple differences are present in the comparing systems.
First of all, we have applied the NBS/H2O/base protocol to tri-O-benzyl derivative 4.1 and
repeated the already described reaction with MCPBA.
With MCPBA, the same α-stereoselectivity, as reported in the literature, was obtained, in accordance with the steric effect produced by the β-oriented allyl-OBn group (see Schemes 4.5 and 4.6 and related discussion). When the epoxidation reaction was repeated by
NBS/H2O/base protocol, a somewhat unexpected result was obtained, since α-epoxide 4.2α
was the only reaction product (Scheme 4.6).
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Scheme 4.6. Stereoselectivity of epoxidation of tri-O-benzyl derivative 4.1 by MCPBA and
NBS/H2O/base protocols (present results).
The completely α-stereoselective result obtained with NBS/H2O/base can be rationalized by
means of the following two possibilities:
1. The β-oriented allyl –OBn substituent acts as an efficient directing group: its coordination with the electrophile determines the attack of the Br+ on the β-face
and, as a consequence, the obtainment of the corresponding α-epoxide (route a, Scheme 4.7);
2. The attack of the Br+ species occurs on both α- and β-face of the unsaturated system
to give the corresponding α- and β-cyclic bromonium ions A and B (routes a and b, Scheme 4.7). The subsequent trans diaxial opening of these cyclic systems by nucleophilic attack of H2O should reasonably occur faster on C(1) of species A (α
attack) than on C(2) of B (β attack) because further from the unfavorable electron-withdrawing inductive effect of C(3)-OBn substituent. The preferential α-direction of the nucleophile H2O determines the preferential formation of epoxide 4.2α, as
found and shown in Scheme 4.7.
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Scheme 4.7. Stereoelectronic effects related to the epoxidation of 4.1 by NBS/H2O/base protocol.
The same considerations can be used in order to rationalize similar results obtained by means of MCPBA and NBS/H2O/base protocol with methoxy derivative 1.33 and allyl acetate 1.36,
which afforded, in both cases, mixtures of corresponding epoxides with a slight α-stereoselectivity, with only the exclusion of the reaction of monoacetyl derivative 1.36 with MCPBA, which turned out to be not stereoselective (Scheme 4.8).
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Scheme 4.8. Stereoselectivity of the epoxidation by MCPBA and NBS/H2O/base protocols of 1,2-addition products 1.33 and 1.36.
A completely different stereochemical profile was observed with derivatives of triol 1.20 in which the secondary allyl hydroxy functionality was not protected. In fact, application of MCPBA protocol to the homoallyl acetate 4.11 and trans diol 1.21 afforded, in a completely stereoselective fashion, only β-epoxides 4.12β and 4.13β, respectively. In this case, a particularly effective directing process in the form of a hydrogen bond is operative by the allyl β-oriented hydroxy functionality and the approaching peroxyacid, in accordance with results described in literature in structurally related compounds (Scheme 4.9).7
!"## !"#$! !"#$" !" #$! %&! !" #$! %&! !" #$! %&! ! ' ! ()*%#+)",)-,.../01...2331 04.5%67.8"9+",!.. ,4.!:%;!<7.%=&>=&= 2331 /01 !" "! %&! !" "! %&! !" "! %&! ! ' ! ()*%#+)",)-,.../01...2331 04.5%67.8"9+",!.. ,4.!:%;!<7.%=&>=&= 2331 /01 #"$# !"#%! !"#%"
Scheme 4.9. Stereoselectivity of the epoxidation by MCPBA and NBS/H2O/base protocols of acetyl
derivative 4.11 and trans diol 1.21.
On the other hand, the alternative NBS/H2O/base protocol led to a completely
α-stereoselectivity, which, in our opinion, is due to an effective coordination process between the Br+ species and the allyl−β-OH, and subsequent α-attack of H
2O affording α-epoxides
4.12α and 4.13α, respectively, after base-catalyzed intramolecular cyclization (Scheme 4.10).
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!"# $!%&! !"# ! %&! "'( $ )"* !"# "'( $!%&! $! $ $+! ,$( !"# ! $!%&! %&! !"# $! "' !$ !,"-!. "/#0/#/ ! !$ %&! "#! !"#$! !"##
Scheme 4.10. Allyl-OH directing effect in the epoxidation of homoallyl acetate 4.11 by MCPBA and
NBS/H2O/base protocols.
An interesting result was obtained with the tri-O-acetyl derivative 1.19, that is, with a substrate similar to the previously examined ones, but in which all the O-protecting groups, and in particular the allyl O-protecting group are electron-withdrawing groups stronger than ether groups (-OMe,-OBn), previously and exclusively considered. In this case, due to the inductive effect (-I) of the acetyl groups, no reaction at all was observed with MCPBA protocol. On the contrary, the NBS/H2O/base protocol proceedes with success, and a marked
β-stereoselectivity was obtained (70% of 4.14β, See Scheme 4.11).
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%&'(")&*+&,+---!"#$%&'()"! ./-0(12-3*4)*+
!--+/-(5(6!72-(89:898 ;<= ><= !"!# $"!$" $"!$!
Scheme 4.11. Stereoselectivity of MCPBA and NBS/H2O/base epoxidation protocols of tri-O-acetyl derivative 1.19.
In this case, due to the non-coordinating/directing ability of the allyl -OAc group (difference with the –OH group) the electrophilic attack by the Br+ largely occurs on the α-face, because
formation of α-brominium ion 4.15α with respect to the diastereoisomeric 4.15β. The subsequent trans diaxial opening of bromonium ions 4.15α and 4.15β occurs, by nucleophilic attack of H2O from the respectively opposite face, to the corresponding bromohydrines 4.16α
and 4.16β, which on treatment under alkaline conditions, cyclize to β-epoxide 4.14β and α-epoxide 4.14α, respectively (Scheme 4.12).
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4.3. Functionalization of the double bond in 1,2-addition products from N-nosyl aziridines 1.18α-Ns and 1.18β-Ns
The reactivity in electrophilic reactions of the double bond of model 1,2-addition products, as methyl ethers 2.10 and 2.13 and acetates 2.17 and 2.20 derived from aziridine 1.18α-Ns and 1.18β-Ns, respectively, was checked. These compounds were subjected to two typical electrophilic addition reactions such as catalytic dihydroxylation and epoxidation.
Catalytic dihydroxylation by OsO4/NMO protocol of methoxy derivatives 2.10 and 2.13
carried out at room temperature in a t-BuOH/acetone mixture turned out be completely stereoselective in both cases and cis diol 4.17 and cis diol 4.18 were obtained respectively, as the only reaction products (Schemes 4.13 and 4.14).
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Scheme 4.13. Dihydroxylation of 1,2-addition product 2.10 by OsO4/ NMO protocol.
In order to make the determination (1H NMR) of the structure and configuration of the addition products possible and easier, cis diols 4.17 and 4.18 were transformed into the corresponding diacetates 4.17-diAc and 4.18-diAc.
An accurate examination of the 1H NMR spectra of these compounds, togheter with
considerations based on the mechanism of the dihydroxylation reaction (complete syn-stereoselectivity) and on an appropriate conformational analysis, confirmed for 4.17-diAc and 4.18-diAc, and thus for the corresponding, direct, addition products, cis diols 4.17 and 4.18, the structure and configuration shown in Schemes 4.13 and 4.14.
In particular, in the case of 4.17-diAc, the signal of H3 proton at 3.28 (t, 1H, J2,3 = J3,4 = 9.7
Hz) shows a coupling constant value which is indicative of its axial disposition and of the presence of a trans diaxial relationship with both the vicinal H2 and H4 protons. Besides
indicating that 4.17-diAc largely (or exclusively) exists as the corresponding triequatorial conformer 4.17’-diAc, these data automatically assign the relative configuration to C(1) and
C(2) carbons with respect to C(3) and indicate the existence of a trans relationship between – OMe and the two α-directed -OAc groups in accordance with the assigned structure. The presence in the 1H NMR spectrum of cis diacetate 4.18-diAc of a signal for H
2 at δ 5.39
(t, 1H, J = 3.1 Hz), with a small coupling constant value, is indicative of the equatorial nature of this proton and of the presence of a trans diequatorial relationship with the vicinal H3
proton and an equatorial-axial relationship with the vicinal H1 proton. Futhermore, the high
coupling costant value of the signal of H1 at δ 5.07 (ddd, 1H, J1,5aax = 11.8, 4.7, 3.1 Hz)
indicates a trans diaxial realtionship between H1 and the axial H5a. Besides indicating that
4.18-diAc largely (or exclusively) exists as conformer 4.18’-diAc with –CH2OBn side chain
equatorial, these data clearly indicate that the two acetoxy groups on C(1) and C(2) are β-directed and, as a consequence, in a trans relationship with the C(3)–OMe group, in accornce with the assigned structure.
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Scheme 4.14. Dihydroxylation of 1,2-addition product 2.13 by OsO4/ NMO protocol.
The structures of 4.17-diAc and 4.18-diAc indicate that the dihydroxylation of 2.10 and 2.13 occurred in both cases with a completely anti facial selectivity with respect to the spatial direction of the corresponding allyl substituent (–OMe group). In other words, the facial selectivity of the dihydroxylation process appears to be determined only by the steric hindrance of the allyl substituent and not by any type of chelation-coordination process between the reagent (OsO4) and the ring substituents, as, for example, the homoallyl –NHNs
group. As for this bulky group, the different reaction time, found in olefins 2.10 (15 h) and 2.13 (90 h) for the dihydroxylation reaction be completed, suggests that, in the case of 2.13, the β-directed –NHNs group, axial in the more stable conformer 2.13’, could be responsible
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Scheme 4.15. Stereoselectivity of MCPBA epoxidation of 1,2-addition products 2.17 and 2.20.
The epoxidation of allyl acetates 2.17 and 2.20, obtained by acetolysis of N-nosyl aziridines 1.18α-Ns and 1.18β-Ns, respectively, was carried out by means of MCPBA/CH2Cl2 protocol.
In these conditions, the reaction of acetate 2.17 was not stereoselective affording a mixture of the two diastereoisomeric epoxides 4.19α (72%) and 4.19β (28%) which were separated, as pure compounds. The exact configuration of both epoxides was obtained by examination of
their 1H NMR spectra and by appropriate NOE experiments. In epoxides 4.19α and 4.19β,
largely or exclusively existing in the respective, reasonably more stable triequatorial conformers 4.19α’ and 4.19β’, the contemporary presence (epoxide 4.19α ) and absence (epoxide 4.19β) of NOE between the corresponding H4 (δ 3.72 and 3.82) and oxirane H1 (δ
3.27 and 3.30) and H2 (δ 3.04 and 3.35, respectively) is indicative of a cis (epoxide 4.19α)
and trans relationship (epoxide 4.19β) between the involved protons and, as a consequence, of the presence of an α- and β-directed oxirane ring, respectively, as shown in the assigned structures (Scheme 4.16). In the case of epoxide 4.19β, the assigned structure is furtherly confirmed by the presence of a strong NOE between oxirane H1 and pseudoequatorial H5a
proton (δ 2.25) and by the high, between H1 and pseudoaxial H5a (J1,5aax= 11.3 Hz), and small
coupling costant value between H1 and pseudoequatorial H5a (J1,5aeq = 5.5 Hz) in accordance
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Scheme 4.16. Preferred conformer in epoxides 4.19α and 4.19β and NOE experiments.
A mixture of the corresponding diasteroisomeric epoxides 4.20α (42%) and 4.20β (58%) was similary obtained when the same reaction was carried out on the diastereoisomeric acetate 2.20. The conformational analysis showed that epoxide 4.20α exists in an 1:1 equilibrium between 4.20α’ and 4.20α’’, due to the presence of NOEs in accordance with both conformers (Scheme 4.17). On the other hand, in the diastereoisomeric epoxide 4.20β the presence of small costant coupling value (J3,4 = 3.0 Hz) between corresponding H3 and H4
protons is indicative of a related trans diequatorial relationship between the substituents, -OAc and –NHNs, on C(3) and C(4). This means that, epoxide 4.20β exists as the only conformer 4.20β’ bearing the –CH2OBn side chain equatorial. On the basis of this
conformational analysis, the observation of a NOE between oxirane H1 (δ 3.25) and H5aax (δ
1.76) and between NH (δ 6.09) and H5aax (δ 1.76) protons in epoxide 4.20α confirmed the
assigned structure. Moreover, in epoxide 4.20β, the observed NOEs between oxirane H1 (δ
3.33) and H5aeq (δ 2.16) and between NH (δ 6.39) and H5aax (δ 1.77) protons are indicative of
the presence of an β-directed oxirane ring in 4.20β, in accordance with the structures assigned to this epoxide as shown in Scheme 4.17.
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Scheme 4.17. Conformational analysis in epoxides 4.20α and 4.20β and NOE experiments. The structural assignment to the epoxides obtained in the epoxidation of 1,2-addition products 2.17 and 2.20 makes some consideration possible on the stereoselectivity of these two reactions. The slight α-stereoselectivity (72%) found in the epoxidation of 2.17, a clear pseudoequatorial-diequatorial conformational system, can be rationalized on the basis of the steric effect due to the presence of the β-oriented allyl substituent (AcO-) which directs the electrophilic attack by the peracid, mostly from the opposite α-face (Scheme 4.18).
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Scheme 4.18. Conformational analysis in 1,2-addition products 2.17 and 2.20 and preferred direction of the epoxidation (MCPBA).
Conformational analysis of 1,2-addition product 2.20 suggests that two axial-pseudoaxial disposed substituents in conformer 2.20’ (homoallyl β-directed –NHNs and allyl α-directed –
OAc) and the two axial-pseudoequatorial substituents in conformer 2.20” (homoallyl β-directed –CH2OBn and allyl α-directed –OAc) make both the α- and β-face of the olefinic
system similarly hindered to the point that no selectivity is observed, accordingly. 4.4. Experimental
General Procedures. See Chapter 1.
Materials. t-BuOK, OsO4, anhydrous CH2Cl2 over molecular sieves, were purchased from
Aldrich and used without purification, MCPBA was purchased from Fluka and used without purification. NBS was purchased from Fluka and recrystallized by H2O. Benzene and THF
were distilled from sodium/benzophenone. Triol 1.20,2 tri-O-benzyl derivative 4.16, tri-O-acetyl derivative 1.19,2 trans diol 1.21 and methoxy derivative 1.33 were prepared as previously described.1
Instrumentation. See Chapter 1.
Functionalizations of 1,2-double bond present in derivatives of triol 1.20 Reaction of tri-O-benzyl-protected olefin 4.1 under NBS-THF/H2O/base protocol
Typical procedure: a solution of tri-O-benzyl-protected olefin 4.1 (0.010 g, 0.024 mmol) in a 3:1 distilled THF:H2O mixture (3.2 mL) was treated, at
0°C and in the dark, with NBS (0.005 g, 0.026 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature, for 4 h, and monitored by TLC analysis. After the disappearance of the starting material, reaction mixture was diluted with Et2O and evaporation of the washed (10% aqueous Na2S2O3, saturated aqueous NaHCO3
and brine) organic solution afforded a crude reaction product (0.009 g, 73% yield) consisting of a mixture of bromohydrins, which was dissolved in anhydrous benzene and treated with t-BuOK (0.002 g, 0.02 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 1 h, then filtered. Evaporation of the filtered organic solution afforded 3,4,6-tri-O-benzyl-1,2-anhydro-5a-carba-α-D,L-glucopyranose (4.2α) (0.007 g, 96% yield) as the only reaction product.6
Reaction of methoxy-substituted olefin 1.33 with MCPBA
Typical procedure: 70% MCPBA (0.021 g, 0.121 mmol, 1.0 equiv) was added to a solution of
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reaction by TLC analysis. After 12 h, dilution with CH2Cl2 and evaporation of the washed
(10% aqueous Na2S2O3, saturated aqueous NaHCO3 and brine) organic solution afforded a
crude reaction product (0.042 g) consisting of a 67:33 (1H NMR) mixture of
diastereoisomeric epoxides 4.8α and epoxide 4.8β, which was subjected to preparative TLC using 1:1 hexane/AcOEt mixture as the eluant. Extraction of the two most intense bands afforded epoxides 4.8α (0.021 g, 65% yield) and 4.8β (0.009 g, 28% yield).
6-O-Benzyl-3-O-methyl-1,2-anhydro-5a-carba-α-D,L-glucopyranose (4.9α): a liquid, Rf= 0.37 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.40 (m, 5H), 4.52 (s, 2H), 3.62 (dd, 1H, J= 9.5, 4.0 Hz), 3.58 (s, 3H), 3.49 (dd, 1H, J= 9.5, 5.3 Hz), 3.40 (d, 1H, J= 8.3 Hz), 3.32 (d, 1H, J= 8.3 Hz), 3.23 (d, 1H, J= 2.5 Hz), 3.10 (d, 1H, J= 3.7 Hz), 2.11-2.20 (m, 1H), 1.74-186 (m, 1H), 1.64-1.73 (m, 1H); 13C NMR (CDCl 3) δ 138.0, 133.8, 128.6, 127.9, 82.4, 74.1, 73.5, 72.1, 58.5, 53.2, 52.9, 32.9, 27.1. 6-O-Benzyl-3-O-methyl-1,2-anhydro-5a-carba-β-D,L-mannopyranose (4.9β): a liquid, Rf= 0.21 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.36 (m, 5H), 4.51 (s, 2H), 3.69 (t, 1H, J= 8.9 Hz), 3.59 (s, 3H), 3.55 (d, 1H, J= 5.0 Hz), 3.49 (bs, 1H), 3.47 (bs, 1H), 3.43 (bs, 1H), 3.29 (t, 1H, J= 5.0 Hz), 2.05-2.19 (m, 1H), 1.72-1.97 (m, 2H); 13C NMR (CDCl 3) δ 138.2, 133.8, 128.6, 127.8, 83.2, 73.5, 71.9, 70.4, 57.4, 53.6, 53.0, 29.9, 26.7.
Reaction of methoxy-substituted olefin 1.33 under NBS-THF/H2O/base protocol Following the typical procedure, a solution of methoxy-substituted olefin 1.331 (0.020 g,
0.081 mmol) in a 3:1 THF/H2O mixture (0.8 mL), was treated with NBS (0.017 g, 0.093
mmol, 1.1 equiv) and the reaction mixture was strirred for 4 h. Typical work up afforded a crude reaction product (0.022 g, 0.063 mmol, 79% yield) which was dissolved in anhydrous benzene (1.0 mL) and treated with t-BuOK (0.007 g, 0.06 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 1 h and evaporation of the filtered organic solution afforded a crude product consisting of a 64:36 mixture (1H NMR) of diastereoisomeric epoxides 4.9α and 4.9β (0.018 g, >99% yield).
Monoacetylation of trans diol 1.21
A solution of trans diol 1.211 (0.100 g, 0.427 mmol) in anhydrous CH
2Cl2 (3.0 mL) at -30°C
was treated at -30°C with Et3N (0.11 mL, 0.854 mmol, 2.0 equiv), Ac2O (40.2 µL, 0.427
mmol, 1.0 equiv) and DMAP (0.005 g, 0.043 mmol, 0.1 equiv). The resulting reaction mixture was stirred at the same temperature for 3 minutes. Dilution with Et2O and
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evaporation of the washed (brine) organic solution afforded a crude product (0.124 g) consisting of a 19:45:25:11 mixture of not reacted trans diol 1.21, allyl acetate 1.36, homonoallyl acetate 4.11 and the trans diacetate 1.21-diAc (1H NMR), which was subjected
to preparative TLC, using a 1:1 hexane/AcOEt mixture as the eluant. Extraction of the more intense bands afforded:
6-O-Benzyl-3-O-acetyl-5a-carba-D,L-glucal (1.36), pure as a liquid (0.025 g, 21% yield): Rf= 0.40 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.41 (m, 5H), 5.72-5.81 (m, 1H), 5.45-5.52 (m, 1H), 5.28-5.37 (m, 1H), 4.54 (s, 2H), 3.80 (dd, 1H, J= 10.2, 8.1 Hz), 3.87 (dd, 1H, J= 9.4, 4.8 Hz), 3.58-3.63 (m, 1H), 2.13-2.26 (m, 2H), 2.12 (s, 3H), 1.91-2.04 (m, 1H); 13C NMR (CDCl 3) δ 171.8, 137.9, 129.2, 128.6, 128.0, 127.8, 125.2, 77.0, 73.6, 72.8, 39.2, 28.0, 21.5.
6-O-Benzyl-4-O-acetyl-5a-carba-D,L-glucal (4.11), pure as a liquid (0.020 g, 17% yield): Rf= 0.30 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.41
(m, 5H), 5.71-5.79 (m, 1H), 5.56-5.64 (m, 1H), 4.90 (dd, 1H, J= 10.5, 7.6 Hz), 4.51 (d, 1H, J= 12.0 Hz), 4.41 (d, 1H, J= 12.0 Hz), 4.24 (d, 1H, J= 6.3 Hz), 3.45 (d, 2H, J= 4.7 Hz), 2.55 (bs, 1H), 2.08-2.36 (m, 3H), 2.03 (s, 3H); 13C NMR
(CDCl3) δ 172.2, 138.3, 128.6, 128.5, 127.9, 127.8, 73.5, 71.9, 70.5, 60.9, 38.0, 28.8, 21.2.
6-O-Benzyl-3,4-di-O-acetyl-5a-carba-D,L-glucal (1.21-diAc), pure as a liquid (0.006 g): Rf= 0.60 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.40 (m, 5H), 5.78-5.89 (m, 1H), 5.45-5.52 (m, 2H), 5.16 (dd, 1H, J= 10.5, 7.6 Hz), 4.49 (d, 1H, J= 11.9 Hz), 4.40 (d, 1H, J= 11.9 Hz), 3.46 (dd, 1H, J= 9.1, 3.9 Hz), 3.40 (dd, 1H, J= 9.1, 5.4 Hz), 2.08-2.41 (m, 1H), 2.03 (s, 3H), 1.97 (s, 3H); 13C NMR (CDCl3) δ 171.1, 170.6, 138.3, 129.8, 128.5, 127.9, 127.8, 124.8, 73.5, 73.3, 72.8, 70.4, 38.2, 28.6, 21.3, 21.1.
Reaction of allyl acetate 1.36 with MCPBA
Following the typical procedure, a solution of allyl acetate 1.36 (0.030 g, 0.108 mmol) in anhydrous CH2Cl2 (0.7 mL) was treated at 0°C with 70% MCPBA (0.024 g, 0.140 mmol, 1.3
equiv). ). After 18 h stirring at room temperature, typical workup afforded a crude product (0.023 g) consisting of an 1:1 mixture of the diastereoisomeric epoxides 4.10α and 4.10β (1H
NMR), which was subjected to preparative TLC with an 1:1 hexane/AcOEt mixture as the eluant. Extraction of the two most intense bands afforded:
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3.56-3.63 (m, 1H), 3.52-3.55 (m, 1H), 3.48 (dd, 1H, J= 9.4, 6.0 Hz), 3.24 (bs, 1H), 3.02 (d, 1H, J= 3.5 Hz), 2.15 (s, 3H), 2.11-2.21 (m, 1H), 1.55-1.97 (m, 1H), 1.60-1.81 (m, 1H); 13C NMR (CDCl3) δ 171.1, 137.8, 128.7, 128.1, 127.8, 75.1, 73.6, 73.1, 72.2, 54.0, 52.6, 32.9, 26.8, 21.3. 6-O-Benzyl-3-O-acetyl-1,2-anhydro-5a-carba-β-D,L-mannopyranose (4.10β): Rf= 0.40 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.40 (m, 5H), 5.06 (dd, 1H, J= 8.7, 1.8 Hz), 4.50 (s, 2H), 3.81 (t, 1H, J= 8.7 Hz), 3.52 (dd, 2H, J= 4.9, 3.9 Hz), 3.39 (dd, 1H, J= 4.0, 1.9 Hz), 3.28 (t, 1H, J= 4.7 Hz), 3.17 (s, 3H), 2.04-2.14 (m, 1H), 1.85-1.99 (m, 1H), 1.71-1.82 (m, 1H); 13C NMR (CDCl3) δ 171.6, 137.7, 128.7, 128.1, 127.9, 73.6, 72.1, 70.4, 73.2, 54.7, 53.3, 29.9, 26.1, 21.4.
Reaction of allyl acetate 1.36 under NBS/H2O-THF/base protocol
Following the typical procedure, a solution of allyl acetate 1.36 (0.045 g, 0.163 mmol) in a 3:1 THF/H2O mixture (1.6 mL), was treated with NBS (0.032 g, 0.179 mmol, 1.1 equiv) and
the reaction mixture was stirred for 4 h at room temperature. Typical workup afforded a crude reaction product (0.062 g, 0.167 mmol, >99% yield), which was dissolved in anhydrous benzene (2.4 mL) and treated with t-BuOK (0.022 g, 0.20 mmol, 1.2 equiv). After the reaction mixture was stirred at room temperature for 1 h, evaporation of the filtered organic solution afforded a crude product (0.043 g, 88% yield) consisting of a 65:35 mixture of epoxides 4.10α and 4.10β (1H NMR).
Reaction of homoallyl acetate 4.11with MCPBA
Following the typical procedure, a solution of homoallyl acetate 4.11 (0.030 g, 0.108 mmol) in anhydrous CH2Cl2 (0.7 mL) was treated with MCPBA (0.024 g, 0.140 mmol, 1.3 equiv).
After stirring for 18 h, typical workup afforded a crude product (0.027 g, 85% yield) consisting of epoxide 4.12β, as the only reaction product.
6-O-Benzyl-4-O-methyl-1,2-anhydro-5a-carba-β-D,L-mannopyranose (4.12β): Rf= 0.15 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.42 (m, 5H), 4.92 (dd, 1H, J= 10.5, 8.7 Hz), 4.47 (d, 1H, J= 11.9 Hz), 4.37 (d, 1H, J= 11.9 Hz), 3.91 (dd, 1H, J= 8.7, 1.9 Hz), 3.41 (dd, 1H, J= 4.0, 1.9 Hz), 3.26-3.37 (m, 3H), 2.03-2.26 (m, 2H), 1.99 (s, 3H), 1.90-1.98 (m, 1H); 13C NMR (CDCl 3) δ 171.8, 138.2, 128.5, 128.4, 127.9, 73.8, 73.4 73.0, 70.0, 57.6, 53.9, 38.5, 27.1, 21.1. !"# $%! &! ! !"#$! !" #$! %&! ! !"#$!
Reaction of homoallyl acetate 4.11 under NBS/H2O-THF/base protocol
Following the typical procedure, a solution of homoallyl acetate 4.11 (0.017 g, 0.063 mmol) in a 3:1 THF/H2O mixture (0.6 mL), was treated
with NBS (0.015 g, 0.08 mmol, 1.1 equiv) and the reaction mixture was stirred for 4 h at room temperature. Typical workup afforded a crude reaction product (0.021 g, 0.056 mmol, 89% yield), which was dissolved in anhydrous benzene (0.8 mL) and treated with t-BuOK (0.008 g, 0.067 mmol, 1.2 equiv). After the reaction mixture was stirred at room temperature for 1 h, evaporation of the filtered organic solution afforded a crude product (0.022 g) consisting of epoxy diol 4.13α, derived from the hydrolysis, under the basic cyclization reaction conditions, of the corresponding homoallyl group.
Reaction with MCPBA of trans diol 1.21
Following the typical procedure, a solution of trans diol 1.211 (0.030 g, 0.128 mmol) in
anhydrous CH2Cl2 (0.8 mL) was treated with 70% MCPBA (0.022 g, 0.128 mmol, 1.0 equiv).
After 18 h stirring, typical workup afforded a crude product (0.024 g, 75% yield) consisting of epoxide 4.13β, as the only reaction product.
6-O-Benzyl-1,2-anhydro-5a-carba-β-D,L-mannopyranose (4.13β): Rf= 0.13 (3:7 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.40 (m, 5H), 4.54 (d, 1H, J= 12.0 Hz), 4.48 (d, 1H, J= 12.0 Hz), 3.85 (dd, 1H, J= 8.3, 1.8 Hz), 3.62 (dd, 1H, J= 10.2, 8.3 Hz), 3.45-3.55 (m, 2H), 3.37 (dd, 1H, J= 3.8, 1.5 Hz), 3.28 (t, 1H, J= 4.4 Hz), 1.99-2.13 (m, 2H), 1.81-1.93 (m, 1H); 13C NMR (CDCl 3) δ 74.5, 73.5, 72.9, 72.1, 56.8, 53.4, 38.9, 26.4.
Reaction of trans diol 1.21 under NBS/H2O-THF/base protocol
Following the typical procedure, a solution of trans diol 1.211 (0.025 g, 0.107 mmol) in a 3:1
THF/H2O mixture (0.8 mL) was treated with NBS (0.021 g, 0.118 mmol, 1.1 equiv) and the
reaction mixture was stirred for 4 h at room temperature. Typical workup afforded a crude reaction product (0.023 g, 0.068 mmol, 65% yield), which was dissolved in anhydrous benzene (0.9 mL) and treated with t-BuOK (0.009 g, 0.082 mmol, 1.2 equiv). After the reaction mixture was stirred at room temperature for 1 h, evaporation of the filtered organic solution afforded a crude product (0.013 g, 76% yield) consisting of epoxide 4.13α, as the only reaction product.
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6-O-Benzyl-1,2-anhydro-5a-carba-α-D,L-glucopyranose (4.13α): Rf= 0.20 (3:7 hexane/AcOEt); 1H NMR (CDCl 3) δ 7.28-7.40 (m, 5H), 4.52 (s, 2H), 3.76 (d, 1H, J= 8.0 Hz), 3.63 (dd, 1H, J= 9.5, 3.7 Hz), 3.47 (dd, 1H, J= 9.5, 7.0 Hz), 3.36 (dd, 1H, J= 10.0, 8.0 Hz), 3.23 (bs, 1H), 2.01-2.22 (m, 1H), 1.71-1.88 (m, 2H); 13C NMR (CDCl 3) δ 137.4, 128.8, 128.2, 127.9, 74.1, 73.6, 73.1, 72.8, 55.6, 52.8, 32.7, 27.1.
Reaction of triacetate 1.19 under NBS/H2O-THF/base protocol
Following the typical procedure, a solution of triacetate 1.192 (0.500 g, 1.849 mmol) in a 3:1 THF/H2O mixture (16.0 mL), was treated with NBS (0.362 g, 2.035 mmol, 1.1 equiv) and the
reaction mixture was stirred for 4 h at room temperature. Typical workup afforded a crude reaction product (0.602 g, 1.633 mmol, 89% yield), which was dissolved in anhydrous benzene (40.0 mL) and treated with t-BuOK (0.275 g, 2.451 mmol, 1.2 equiv). After the reaction mixture was stirred at room temperature for 1 h, evaporation of the filtered organic solution afforded a crude product (0.459 g, 98% yield) consisting of a 30:70 mixture (1H
NMR) of diastereoisomeric epoxides 4.14α and 4.14β, which was subjected to flash chromatography. Elution with a 1:1 hexane/AcOEt mixture afforded epoxides 4.14α (0.069 g, 15% yield) and 4.14β (0.179 g, 38% yield).
3,4,6-Tri-O-acetyl-1,2-anhydro-5a-carba-α-D,L-glucopyranose (4.14α): Rf= 0.48 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 5.01 (d, 1H, J= 8.3 Hz), 4.94 (t, 1H, J= 10.4 Hz), 4.19 (dd, 1H, J= 11.4, 3.9 Hz), 3.83 (dd, 1H, J= 11.4, 2.1 Hz), 3.32 (bs, 1H), 3.07 (d, 1H, J= 3.4 Hz), 2.26-2.35 (m, 1H), 2.09-2.17 (m, 2H), 2.08 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H). 13C NMR (CDCl 3) δ 171.0, 170.5, 170.3, 72.0, 71.0, 62.9, 54.3, 52.6, 31.2, 27.3, 21.1, 21.0. 3,4,6-Tri-O-acetyl-1,2-anhydro-5a-carba-β-D,L-mannopyranose (4.14β): Rf= 0.33 (1:1 hexane/AcOEt); 1H NMR (CDCl3) δ 5.23 (dd, 1H, J= 8.7, 1.8 Hz), 5.14 (dd, 1H, J= 10.3, 8.7 Hz), 4.05 (dd, 1H, J= 11.2, 4.7 Hz), 3.85 (dd, 1H, J= 11.2, 3.2 Hz), 3.41 (dd, 1H, J= 4.2, 1.8 Hz), 3.33 (t, 1H, J= 4.2 Hz), 2.15-2.24 (m, 1H), 2.10 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 1.99-2.08 (m, 2H). 13C NMR (CDCl 3) δ 171.0, 170.0, 73.5, 69.5, 63.1, 54.8, 52.9, 37.5, 26.4, 21.1, 21.0. !"#$! !" #$! "! ! !"#!! !"# "#! "#! ! !"# "#! "#! ! !"#!!
Functionalization of 1,2-double bond present in derivatives of N-nosyl aziridines 1.18α-Ns and 1.18β-1.18α-Ns
Dihydroxylation of the methoxy derivative 2.10
A solution of methoxy derivative 2.10 (0.015 g, 0.034 mmol) in an 1:1 t-BuOH/acetone mixture (0.12 mL) was added, at 0°C under stirring and in the dark, to a 50% p/v aqueous solution of N-methyl morpholine-N-oxide (NMO) (0.03 mL) and the resulting reaction mixture was treated with 2.5% p/v OsO4 solution in t-BuOH (0.03 ml) and stirred for 15 h at
room temperature. Dilution with Et2O and evaporation of the filtered (Celite®) organic solution afforded cis diol 4.17 (0.018 g, >99% yield), practically pure as a liquid.
6-O-Benzyl-3-O-methyl-4-deoxy-4-(N-nosylamino)-5a-carba-α-D,L -glucopyranose (4.17): 1H NMR (CDCl3) δ 8.09-8.16 (m, 1H), 7.77-7.88 (m, 1H), 7.56-7.74 (m, 2H), 7.28-7.41 (m, 5H), 5.40 ( d, 1H, J = 9.4 Hz), 4.41 (d, 1H, J = 11.7 Hz), 4.36 (d, 1H, J = 11.7 Hz), 3.98-4.09 (m, 1H), 3.72 (t, 1H, J = 4.6 Hz), 3.52-3.57 (m, 2H), 3.47 (dd, 1H, J = 8.4, 2.4 Hz), 3.21 (t, 1H, J = 9.4 Hz), 2.97 (s, 3H), 2.37-2.44 (m, 1H), 1.94-2.12 (m, 2H). 13C NMR (CDCl 3) δ 147.9, 138.6, 136.3, 133.0, 132.8, 131.0, 128.7, 128.5, 128.0, 127.8, 125.0, 84.0, 76.1, 73.3, 70.4, 69.0, 60.5, 58.3, 55.6, 37.1, 30.5, 29.9.
A solution of cis diol 4.17 (0.018 g, 0.039 mmol) in anhydrous pyridine (1.0 mL) was treated with Ac2O (0.5 mL) at 0°C and the resulting reaction mixture was stirred at room temperature
overnight. Co-evaporation of the reaction mixture with toluene afforded a crude product (0.027 g) consisting of the diacetate 4.17-diAc, which was subjected to preparative TLC, using a 1:1 hexane/AcOEt mixture as the eluant. Extraction of the more intense band afforded derivative 4.17-diAc (0.008 g, 36% yield) pure as a pale yellow liquid.
1,2-Di-O-acetyl-6-O-benzyl-3-O-methyl-4-deoxy-4-(N-nosylamino)-5a-carba-α-D,L-glucopyranose (4.17-diAc): a liquid, Rf = 0.30 (1:1
hexane/AcOEt); 1H NMR (CDCl3) δ 8.07-8.15 (m, 1H), 7.81-7.88 (m, 1H), 7.63-7.75 (m, 2H), 7.27-7.40 (m, 5H), 5.38 (d, 1H, J = 8.7 Hz), 5.32-5.37 (m, 1H), 4.71 (dd, 1H, J = 9.7, 2.9 Hz), 4.54 (d, 1H, J = 11.7 Hz), 4.45 (d, 1H, J = 11.7 Hz), 3.59-3.69 (m, 2H), 3.53 (t, 1H, J = 9.7 Hz), 3.28 (t, 1H, J = 9.7 Hz), 2.72 (s, 3H), 2.09 (s, 3H), 1.66-1.77 (m, 1H), 1.55-1.65 (m, 2H). 13C NMR (CDCl 3) δ 170.1, 170.0, 147.8, 138.4, 136.2, 133.1, 132.8, 131.4, 128.5, 128.0, 127.8, 124.9, 81.4, 75.7, 73.5, 70.1, 68.9, 60.1, 58.5, 37.8, 29.9, 21.3, 21.1. !"# $%$& !& !& '(! !"#$ !"# $%$& !'( !'( )*! !"#$%&'()
Dihydroxylation of the methoxy derivative 2.13
Following the typical procedure, the treatment of a solution of methoxy derivative 2.13 (0.011 g, 0.024 mmol) in an 1:1 t-BuOH/acetone mixture (0.09 mL) with 50% p/v aqueous solution of N-methyl morpholine-N-oxide (NMO) (0.02 mL) and 2.5% p/v OsO4 solution in t-BuOH (0.02
ml) for 96 h at room temperature afforded cis diol (4.18) (0.019 g, >99% yield), practically pure as a liquid. Acetylation of cis diol 4.18 (0.019 g, 0.039 mmol) by anhydrous pyridine (1.0 mL)/Ac2O (0.5 mL) protocol at 0°C afforded a crude product (0.017 g) consisting of
diacetate 4.18-diAc, which was subjected to preparative TLC, using a 1:1 hexane/AcOEt mixture as the eluant. Extraction of the most intense band afforded diacetate 4.18-diAc (0.006 g, 25% yield), pure as a pale yellow liquid.
1,2-Di-O-acetyl-6-O-benzyl-3-O-methyl-4-deoxy-4-(N-nosylamino)-5a-carba-β-D,L-idopyranose (4.18-diAc): a liquid, Rf= 0.34 (1:1
hexane/AcOEt); 1H NMR (CDCl 3) δ 8.08 (dd, 1H, J = 7.7, 1.8 Hz), 7.85 (dd, 1H, J = 7.6, 1.5 Hz), 7.70 (dt, 1H, J = 7.6, 1.5 Hz), 7.62 (dt, 1H, J = 7.6, 1.8 Hz), 7.27-7.40 (m, 5H), 6.06 (d, 1H, J = 9.5 Hz), 5.39 (t, 1H, J = 3.1 Hz), 5.07 (ddd, 1H, J = 11.8, 4.7, 3.1 Hz), 4.33 (d, 1H, J = 12.0 Hz), 4.27 (d, 1H, J = 12.0 Hz), 3.92 (dt,1H, J = 9.6, 3.1 Hz), 3.46 (dd, 1H, J = 9.6, 7.6 Hz), 3.26-3.34 (m, 2H), 3.25 (s, 3H), 2.29-2.46 (m, 1H), 2.24 (s, 3H), 1.98 (s, 3H), 1.69-1.85 (m, 1H), 1.57-1.65 (m, 1H). 13C NMR (CDCl3) δ 170.2, 169.9, 147.8, 138.4, 134.7, 133.6, 133.0, 130.9, 128.6, 127.8, 127.6, 125.5, 79.1, 73.1, 70.9, 69.3, 68.6, 58.3, 51.9, 35.1, 29.9, 24.3, 21.1.
Reaction of the acetate 2.17 with MCPBA
70% dispersion of MCPBA (0.060 g, 0.243 mmol, 2.6 equiv) was added to a solution of acetate 2.17 (0.042 g, 0.094 mmol) in anhydrous CH2Cl2 (4.0 mL) at 0°C and the reaction
mixture was stirred at room temperature for 4 days. Dilution with CH2Cl2 and evaporation of
the washed (10% aqueous Na2S2O3, saturated aqueous NaHCO3 and brine) organic layer
afforded a crude reaction product (0.038 g) consisting of a 72:28 mixture of diastereoisomeric epoxides 4.19α and epoxide 4.19β (1H NMR), which was subjected to preparative TLC using
CH2Cl2/(i-Pr)2O mixture as the eluant. Extraction of the two most intense bands afforded
epoxides 4.19α (0.021 g, 48% yield) and 4.19β (0.009 g, 20% yield).
3-O-Acetyl-6-O-benzyl-4-deoxy-4-(N-nosylamino)-5a-carba-α-D,L -glucopyranose (4.19α): a liquid, Rf= 0.53 (6:4 CH2Cl2/(i-Pr)2O, 2 runs);
1H NMR (CDCl 3) δ 8.07 (dd, 1H, J = 7.7, 1.7 Hz), 7.85 (dd, 1H, J = 7.7, 1.4 Hz), 7.66 (dt, 1H, J = 7.7, 1.4 Hz), 7.57 (dt, 1H, J = 7.7, 1.7 Hz), 7.34 !"# $%$& !& !& '(! !"#$ !"# $%$& !'( !'( )*! !"#$%&'() !"#$! !"# $%$& '(! !
(t, 2H, J = 7.7 Hz), 7.29 (t, 1H, J = 7.7 Hz), 7.25 (d, 2H, J = 7.7 Hz), 5.60 (d, 1H, J = 8.3 Hz), 4.87 (d, 1H, J = 9.0 Hz), 4.24 (d, 1H, J = 12.1 Hz), 4.17 (d, 1H, J = 12.1 Hz), 3.72 (dd, 1H, J = 9.8, 9.0 Hz), 3.44 (dd, 1H, J = 9.8, 5.3 Hz), 3.38 (dd, 1H, J = 9.8, 4.6 Hz), 3.27 (bs, 1H), 3.04 (d, 1H, J = 3.7 Hz), 2.31 (dd, 1H, J = 14.8, 3.8 Hz), 2.00 (ddd, 1H, J = 14.8, 10.4, 1.5 Hz), 1.84-1.96 (m, 1H), 1.80 (s, 3H). 13C NMR (CDCl 3) δ 170.0, 147.8, 138.2, 136.0, 133.2, 133.1, 130.5, 128.5, 127.8, 127.5, 125.4, 73.0, 72.3, 70.2, 55.6, 54.3, 52.7, 33.3, 27.7, 28.8. 3-O-Acetyl-6-O-benzyl-4-deoxy-4-(N-nosylamino)-5a-carba-β-D,L -mannopyranose (4.19β): a liquid, Rf= 0.42 (6:4 CH2Cl2/(i-Pr)2O, 2 runs);
1H NMR (CDCl 3) δ 8.10 (dd, 1H, J = 7.3, 1.7 Hz), 7.83 (dd, 1H, J = 7.3, 1.7 Hz), 7.60-7.71 (m, 2H), 7.34 (t, 2H, J = 7.3 Hz), 7.28 (t, 1H, J = 7.3 Hz), 7.26 (d, 2H, J = 7.3 Hz), 5.39 (d, 1H, J = 9.4 Hz), 5.12 (dd, 1H, J = 9.7, 1.4 Hz), 4.33 (d, 1H, J = 11.9 Hz), 4.29 (d, 1H, J = 11.9 Hz), 3.82 (ddd, 1H, J = 11.4, 9.7, 9.4 Hz), 3.52 (dd, 1H, J = 9.3, 3.7 Hz), 3.35 (t, 1H, J = 4.6 Hz), 3.34 (dd, 1H, J = 9.3, 6.7 Hz), 3.30 (t, 1H, J = 4.6 Hz), 2.25 (ddd, 1H, J = 15.4, 5.5, 5.5 Hz), 1.98 (dd, 1H, J = 15.4, 11.3 Hz), 1.90-1.97 (m, 1H), 1.59 (s, 3H). 13C NMR (CDCl 3) δ 170.9, 147.8, 138.2, 136.0, 133.2, 130.7, 128.6, 127.8, 127.6, 125.3, 73.8, 73.2, 70.8, 54.8, 54.1, 53.3, 39.6, 27.3, 20.5. Reaction of the acetate 2.20 with MCPBA
70% dispersion of MCPBA (0.110 g, 0.446 mmol, 4.5 equiv) was added to a solution of acetate 2.20 (0.044 g, 0.099 mmol) in anhydrous CH2Cl2 (4.1 mL) at 0°C and the reaction
mixture was stirred at room temperature for 4 days. Dilution with CH2Cl2 and evaporation of
the washed (10% aqueous Na2S2O3, saturated aqueous NaHCO3 and brine) organic layer
afforded a crude reaction product (0.044 g) consisting of a 42:58 mixture of diastereisomeric epoxides 4.20α and 4.20β (1H NMR), which was subjected to preparative TLC using 1:1 hexane/AcOEt mixture as the eluant. Extraction of the two more intense bands afforded epoxides 4.20α (0.014 g, 31% yield) and 4.20β (0.024 g, 53% yield).
3-O-Acetyl-6-O-benzyl-4-deoxy-4-(N-nosylamino)-5a-carba-α-D,L -gulopyranose (4.20α): a liquid, Rf= 0.52 (1:1 hexane/AcOEt); 1HNMR
(CDCl3) δ 8.08-8.17 (m, 1H), 7.79-7.88 (m, 1H), 7.65-7.75 (m, 2H), 7.36 (t, 2H, J = 7.1 Hz), 7.32 (t, 1H, J = 7.1 Hz), 7.30 (t, 2H, J = 7.1 Hz), 6.09 (d, 1H, J = 7.4 Hz), 5.24 (dd, 1H, J = 8.3, 2.9 Hz), 4.49 (d, 1H, J = 12.0 Hz), 4.44 (d, 1H, J = 12.0 Hz), 3.79 (ddd, 1H, J = 8.3, 7.4, 2.9 Hz), 3.48 (dd, 1H, J = 9.7, 5.1 Hz), 3.40 (dd, 1H, J = 9.8, 8.2 Hz), 3.34 (dd, 1H, J = 3.7, 2.9 Hz), 3.25 (dd, 1H, J = 3.7, 3.7 Hz), 2.18-2.29 (m, 1H), !"#$! !"# $%$& '(! ! !"#$! !"# $%$& '(! !
(CDCl3) δ 170.7, 147.9, 137.5, 134.8, 133.5, 133.1, 130.9, 128.7, 128.1, 127.9, 125.3, 73.6,
70.1, 53.2, 53.1, 53.0, 35.7, 25.3, 20.8.
3-O-Acetyl-6-O-benzyl-4-deoxy-4-(N-nosylamino)-5a-carba-β-D,L -idopyranose (4.20β): a liquid, Rf= 0.42 (1:1 hexane/AcOEt); 1H NMR
(CDCl3) δ 8.12-8.23 (m, 1H), 7.83-7.92 (m, 1H), 7.66-7.80 (m, 2H), 7.27-7.49 (m, 5H), 6.39 (d, 1H, J = 9.7 Hz), 4.81 (dd, 1H, J = 3.0, 2.2 Hz), 4.57 (d, 1H, J = 11.8 Hz), 4.43 (d, 1H, J = 11.8 Hz), 3.85 (ddd, 1H, J = 9.7, 3.0, 3.0 Hz), 3.53 (dd, 1H, J = 9.4, 7.8 Hz), 3.36 (dd, 1H, J = 9.4, 6.2 Hz), 3.33 (dd, 1H, J = 5.1, 3.8 Hz), 3.09 (bs, 1H), 2.16 (ddd, 1H, J = 15.2, 6.3, 5.1 Hz), 2.06-2.24 (m, 1H), 2.02 (s, 3H), 1.77 (dd, 1H, J = 15.2, 11.4 Hz). 13C NMR (CDCl3) δ 169.5, 148.1, 138.4, 134.9, 133.7, 133.1, 131.4, 128.6, 128.1, 127.9, 125.4, 73.7, 71.1, 66.8, 52.6, 52.3, 51.9, 31.7, 22.6, 21.1. References
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Ohnishi, H. Bull. Chem. Soc. Jpn. 1984, 57, 3339; c) Ogawa, S.; Kasahara, I.; Suami, T. Bull.
Chem. Soc. Jpn. 1979, 52, 118; d) Ogawa, S.; Toyokuni, T.; Kondoh, T.; Hattori, Y.; Iwasaki,
S.; Suetsugu, M.; Suami, T. Bull. Chem. Soc. Jpn. 1981, 54, 2739.
3. Henbest, H.B.; Wilson, A.L. J. Chem. Soc. 1956, 3289.
4. a) Henbest, H.B.; Wilson, A.L. J. Chem. Soc. 1959, 4136; b) Beereboom, J. J.; Dejerassi, C.;
Ginsburg, D.; Fieser, F. L. J. Am. Chem. Soc.1953, 75, 3500.
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6. Tai, V. V.-F.; Fung, P.-H.; Wong, Y.-S.; Shing, K.M. Tetrahedron: Asymmetry 1994, 5, 1353.
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