CHAPTER 7
Synthesis of enantiomerically pure cis-2,5-disubstituted-2,5-dihydropyrroles
7.1. IntroductionMultisubstitued 2,5-dihydropyrroles are encountered in significantly important pharmaceuticals, bioactive natural products and building blocks in organic and diversely oriented synthesis, because scaffolds of molecules characterized by important biological activity, such as NK1 antagonist, protein geranylgeranyltransferase type I inhibitor, thrombin inhibitor or potent drug with antimigratory activity (Figure 7.1).
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Figure 7.1. Biologically active compounds containing the 2,5-dihydropyrrole moiety.
As a consequence, the construction of 2,5-dihydropyrrole rings bearing different substitution patterns has received much attention.
1) Ring Close Methatesis (RCM) of Aza-Baylis-Hillman adducts-derived α-mathylene-β-amino esters easily available from α,β-unsaturated esters and imines.1
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2) RCM of typical products derived from allyl substituted Morita-Baylis-Hillman carbonates with allylamines;2 ! "#$% &""! ' ( )* ! + ,#(-%./0$1.23 .4454.6713 ! ' )* ! &""! !8.44548!8.671$8"8632954313-3*23/ !&, ' &""! )* ! :;<8=795=/$>5//$43
3) Phosphine-catalyzed [3+2] cycloaddition of electron deficient allenoates with imines.3, or alkynyl ketones with N-tosylimines.4
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4) Cascade Iminium/Enamine-Metal cooperative catalysis by using cheap and readily available α,β-unsaturated aldehydes and N-tosyl propargyl amines as starting materials.5
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Despite great efforts that have been made, the asymmetric synthesis is still limited to the phosphine-catalyzed [3+2] cycloaddition of electron-deficient allenoates with imines. However, in this case, both the catalyst and the allenoate substrates are not easily prepared. Another drawback is their limited substrate scope and the difficulty of synthesizing multisubstituted pyrroles.
Given the importance of these valuable 2,5-dihydropyrroles and their potential biological properties, as well the lack of effective asymmetric methods for the preparation of these important agents, the development of alternative methodologies leading to enantiopure compounds is of great importance for organic and medicinal chemistry.
7.2. Reactions of vinyl aziridines 1.2α-Ms and 1.2β-Ms
As a natural extension of our interest in heterocyclic compounds and in the synthesis of compounds with potential biological activity, we saw the possibility of the construction of an enantiomerically pure 2,5-disubstituted-2,5-dihydropyrrole system starting from D-allal 1.2α-Ms6 and D -galactal-derived N-mesyl aziridine 1.2β-Ms.7 After having refined some experimental results and submitted and finally published the corresponding paper on the regio- and stereoselectivity of the nucleophilic addition reactions to N-mesyl aziridines 1.2α-Ms and 1.2β-Ms,8 we realized that the use of a particular type of C-nuclophile, as a metal enolate, never tried before with these glycal-derived systems, in the reaction with 1.2α-Ms and 1.2β-Ms, could determine the occurrence of an opening-closing process with ring contraction and the formation of a 2,5-dihydropyrrole system. Two points were necessary for such a rearrangement process could occur: a) the use of a C-nucleophile characterized by the presence of a C-H bond with a consistent acidity, as a β-dicarbonyl compound (active methylene dicarbonyl compounds), b) the formation of a corresponding syn- and/or anti-1,4-addition product and c) the presence in the reaction intermediate of a sufficiently acid N-H as MsN-H bond.
N-mesyl aziridines 1.2α-Ms and 1.2β-Ms were prepared as previously described, starting from the
corresponding epoxide with opposite configuration 1.1β and 1.1α, respectively. Epoxide 1.1α was prepared starting from epoxide 1.1β, on its own prepared starting from tri-O-acetyl-D-glucal
! !" #$! %&! %&! ! ! !"#! !"!! !'%(!) ! !" "! %&! %(*+#,-./! 0"1 ! !0%. "! %&! 0%.23 45/67893,: ;#1 ! !0%. #$! %&! ! !" #$! %&! !"#" #$23 <= ! + -"! %&! 0%>1 0"1 ! + -"! %&! ! +"? "! %&! ! +"#$ #$:! %&! @AB'!"$" ! %&! ! !"!" %(*+#,-./! 0"1 #$23 <= 0#C> <.'<<D -0#C> ! +"? "! %&! ! +"#$ #$:! %&! @AB'!"$! ! %&! + !"%"&'( #$ #$23 <= ! %&! + !"%!&'( )?2! -)?2! -#$ <.'<<D -! !>E >E! >E! @AB'#")
Scheme 7.1. Synthesis of N-mesyl aziridines 1.2α-Ms and 1.2β-Ms.
As reported briefly in the first part of this thesis, N-mesyl aziridines 1.2α-Ms and 1.2β-Ms, as well the corresponding N-nosyl derivatives, are not stable and can be prepared only in situ by cyclization of the corresponding stable precursors, the trans N-mesyl-O-mesyltates (+)-1.4α and (+)-1.4β, respectively.6,7
In order to check the validity of the new approach to 2,5-dihydropyrroles, initially we took into consideration N-mesyl aziridine 1.2α-Ms as the substrate, because more easily accessible, and dibenzoyl methane as the β-dicarbonyl compound. Under necessarily protocol B reaction
conditions, dibenzoyl methane, in anhydous toluene, was transformed into the corresponding potassium enolate (3 equivalents) by means of t-BuOK and added to a solution, in the same solvent, of N-mesyl aziridine 1.2α-Ms, generated in situ by cyclization under basic conditions (t-BuOK) of the stable precursor, the trans O-mesyl-N-mesylate (+)-1.4α. A clean reaction occurred leading to a crude reaction product which showed the presence of
(2R,5S,6S)-2-(dibenzoylmethyl)-5-(2-benzyloxy-1-hydroxyethy)-2,5-dihydropyrrole (+)-7.2 (42%), as expected, in a mixture with
the corresponding anti-1,2-addition product, the trans 4-N-mesylamino-3-dibenzoylmethyl derivative (-)-7.1 (42%) and only a lower amount of the anti-1,4-addition product, the β-C-glycoside 7.3β (16%) which were separated pure by flash chromatography (Scheme 7.2). The regioisomeric structure of (-)-7.1 and 7.3β was easily determined by simple examination of their 1H and 13C NMR spectra, whereas for the assignment of the relative configuration to C(3) of (-)-7.1 and C(1) carbon of 7.3β, NOE experiments were necessary. Even if the 1H and 13C NMR data of 2,5-dihydropyrrole derivative (+)-7.2 were in accordance with the expetactions and thus with the structure given to these compounds (Scheme 7.2), the relative configuration at C(2) and C(5) carbons of the heterocyclic system were firmly established by NOE experiments. The configuration of C(6) carbon of (+)-7.2 necessarily corresponds to that of C(5) carbon of the starting aziridine
1.2α-Ms (vide infra). ! "#! $ !"#!$%& %& '( '( ! ! )*"+!, )-.+/#/ ! 0120!'(34 %&1$ "#! $ %& 0120!'(34 "#! !1 ! ! " ! %&1$ "#! 0120!'(343 5 5 ! ! 6 2*3*'"! 253*'"# '"(" 647 647 897 8 4 : 9 ; 6 8 4 : 9 ; 6 4 : 9 ; 6 48 : 9 ;
Scheme 7.2. Reaction of N-mesyl aziridine 1.2α-Ms with potassium enolate of dibenzoylmethane. If the formation of anti-1,2-addition product (-)-7.1 can be easily rationalized by a commonly observed direct attack of the nucleophile to the allyl C(3) aziridine carbon, typically in a complete
anti fashion,8 the apparently exclusive formation of the corresponding β-C-glycoside 7.3β with opposite configuration with respect to that (α) of the starting aziridine, is somewhat unusual. Actually in these glycal-derived systems (aziridine and epoxides) when protocol B reaction conditions are used and the nucleophile can coordinate with the oxirane oxygen or the aziridine nitrogen of the substrate, the only addition product or most of the diastereoisomeric 1,4-addition products eventually obtained, has the same configuration as the starting aziridine or epoxide in the concept of coordination product, as adeguately discussed in other parts of this thesis. In the present case, β-C-glycoside 7.3β, the anti-1,2-addition product, is not a coordination
ring, and thus, as the anti-1,2-addition product (-)-7.1, corresponds to a non-coordination product.8 In this framework, the complete absence in the crude reaction mixture of the syn-1,4-addition product 7.3α, the coordination product, with the contemporary exclusive presence of the corresponding anti-1,4-addition product 7.3β (the non-coordination product) was even more unusual. However, the consistent presence in the crude product of the 2,5-dihydropyrrole (+)-7.2 could justify the result obtained. Actually, we think that syn-1,4-addition product 7.3α (the
coordination product) is formed, even if in a not determinable amount, and corresponds to a
primary reaction product, as 7.1 and 7.3β similarly are. However, α-C-glycoside 7.3α cannot be recovered from the reaction because it is rapidly subjected to a base-catalyzed rearrangement process which selectively transforms 7.3α into 2,5-dihydropyrrole derivative (+)-7.2, as shown in the following Scheme 7.3.
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Scheme 7.3. Mechanism of the formation of the cis-2,5-disubstituted-2,5-dihydropyrrole (+)-7.2.
In this rationalization, once formed, the syn-1,4-addition product 7.3α is deprotonated by the base (a small excess of t-BuOK is present in the reaction mixture) along the residual acid C-H bond of the dibenzoyl methine group, generating the corresponding enolate species 7.4. Subsequent E1cb-type elimination leads to the formation of the vinylogous conjugated system present in 7.5, with an intramolecular alcoholate species acting as the leaving group. Acid-base equilibration between the base alcoholate and the acid -NHMs present in 7.5 leads to the formation of the new species 7.6 bearing the weaker acid (the alcoholic functionality) and weaker base (the MsN- anion). The MsN- behaves as the internal nucleophile by attacking, in a conjugate fashion, the α,β-unsaturated system
with the formation of the cis-2,5-disubstituted-2,5-dihydropyrrole (+)-7.2. As for the unexpected complete stereoselectivity toward the cis-2,5-diastereoisomer, we think that it derives from the fact that in the unfolded, more stable conformer of the nucleophilic species 7.7, in which the conjugate system assumes a s-cis conformation in order to form a hydrogen bond between a carbonyl group and the newly formed secondary hydroxy funtionality, the nucleophilic terminal MsN- is appropriately disposed for a favored, completely selective attack on the Re face of the conjugated system, leading to the observed regioselective results.
In order to have a direct confirmation of the proposed mechanism, the residual anti-1,4-addition product 7.3β still present in the reaction mixture was treated with t-BuOK. After 24 h, β-C-glycoside 7.3β was completely transformed into the same cis-2,5-disubstituted-2,5-dihydropyrrole (+)-7.2 which we have previously supposed deriving from the not isolated α-C-glycoside 7.3α
(Scheme 7.3). This result is due to the fact that the only difference existing between the two starting material, the diastereoisomeric 1,4-addition products 7.3α and 7.3β, is the configuration of the anomeric C(1) carbon, which is lost in the E1cb step of the rearrangement process.
In the course of this control reaction, we found that if the 2,5-dihydropyrrole (+)-7.2 was left in
contact with the base (t-BuOK, only in a low molar excess, 1.2 equiv) for a sufficiently long time (2 days), at room temperature, a haloform-like reaction occurred with the formation of the corresponding 2,5-dihydropyrrole (+)-7.8, in which the 2-dibenzoylmethyl substituting chain of
(+)-7.2 was transformed into the simpler 2-benzoylmethyl group of (+)-7.8, accompanied by an
equivalent amount of t-butyl benzoate (1H NMR) (Scheme 7.3). ! "# $%&$'()*+ ,-' '% ! ! " &.*/!"# ! "# ,-' '% ! ! " &.*/!"$ ' () /' '/#/,0 () ! "# $%+$'()* ,-' '% ! ! " #/,0'1 23405-5 .6()$''/#/,0*
Scheme 7.4. Haloform-like reaction of the cis-2,5-disubstituted-2,5-dihydropyrrole (+)-7.2.
This last simple transformation is a property of the dibenzoyl methyl group. In fact, the same type of transformation is obtained also with the regioisomeric anti-1,2-addition product, the dibenzoylmethyl glycal derivative (-)-7.1, with the obtainment of the corresponding 3-benzoylmethyl derivative (-)-7.9 (Scheme 7.5).
! "#$"!%&'( )*#+ ,-! $.'.!"# !.,/!0 123/4-4 ! "#("!%&' )*#+ ,-! $.'.!"$
Scheme 7.5. Haloform-like reaction of the anti-1,2-addition product (-)-7.1.
The reaction of aziridine 1.2α-Ms with dibenzoylmethane (t-BuOK as the base) was repeated in a solvent different from the originally used toluene. When DMF was used, a complex reaction mixture was obtained from which only the anti-1,2-addition product (-)-7.1 was recovered by flash chromatography. On the contrary, when THF was used as the solvent, a satisfactory increased amount of the rearranged product (+)-7.2 was obtained (60%), accompanied only by the anti-1,2-addition product (-)-7.1 (40%).
The reaction was repeated under the typical reaction conditions (t-BuOK/toluene) with the diastereoisomeric N-mesyl aziridine 1.2β-Ms. Unexpectedly, the corresponding anti-1,2-addition product, the trans 4-N-mesylamino-3-dibenzoylmethyl derivative (+)-7.10 turned out to be the only reaction product (Scheme 7.6).
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Scheme 7.6. Reaction of N-mesyl aziridine 1.2β-Ms with potassium enolate of dibenzoylmethane. In order to check the more general validity of this new protocol found for the construction of highly functionalized 2,5-disubstituted-2,5-dihydropyrroles, enolates derived from other active methylene dicarbonyl compounds were tried as C-nucleophiles, necessary for the reaction to occur. Dimethyl malonate potassium enolate was the second C-nucleophile we tried.
The reaction of N-mesylaziridine 1.2α-Ms with the potassium enolate obtained from dimethyl malonate and t-BuOK in anhydrous toluene, afforded a crude reaction product consisting of a 68:32 mixture of the corresponding anti-1.2-addition product, the trans 4-N-mesylamino-3-dimethoxycarbonylmethyl glycal derivative (-)-7.11, and the expected rearranged product, the corresponding (2R,5S,6S)-2,5-disubstituted-2,5-dihydropyrrole (+)-7.12. In this case, a dimethoxycarbonylmethyl chain is present on C(2) with the 2-(benzyloxy)-1-hydroxyethyl chain, common to all these dihydropyrrole derivatives, on C(5) (Scheme 7.7).
! "#! $ !"#!$%& %& %'! !%' ! ! ()*+'#' ! ,-.,!/%'0/ %&-$ "#! ! ! 1 .202'"!! $ %& ,-.,!/%'0/0 "#! !-! ! " .302'"!# #2"+!4555555555555678555555555555555555555555555555555555555555559/8 5555:;-5555555555555559<855555555555555555555555555555555555555555555=<8 3
Scheme 7.7. Reaction of N-mesyl aziridine 1.2α-Ms with potassium and lithium enolate of dimethylmalonate.
The use of a different solvent (THF) did not modify substantially the result (anti-1,2-addition product (-)-7.11: rearranged product (+)-7.12 ratio = 75:25).
As the 2,5-dihydropyrrole product derives from the corresponding syn- and/or anti-1,4-addition product, we thought that if the amount of these primary addition products could be increased, also the amount of the rearranged product would be reasonably and correspondently increased. We had previously demonstrated, in the reaction of glycal-derived aziridines (and epoxides) with other nucleophiles, that the corresponding syn-1,4-addition product (coordination product)/anti-1,2-addition product (non-coordination product) ratio could be increased or decreased depending on the occurence or less of a coordination between the nucleophile and the aziridine nitrogen (or oxirane oxygen).8,9 For these reasons, we thought interesting to repeat the reaction of aziridine
1.2α-Ms with the lithium enolate of dimethyl malonate (generated by means of LiH) in order to
have in the reaction mixture a cation, as Li+ more coordinating than the previously used K+ (from t-BuOK). Actually, under these modified reaction conditions (LiH/toluene as the solvent), the 2,5-dihydropyrrole (+)-7.12 turned out to be the main reaction product (70%) accompanied, as usual, by the anti-1,2-addition product (+)-7.11 (30%), as expected (Scheme 7.7).
When the same reaction was repeated with the diastereoisomeric aziridine 1.2β-Ms under standard conditions (dimethylmalonate/t-BuOK/toluene), the corresponding anti-1,2-addition product, the
trans 4-N-mesylamino-3-(dimethoxycarbonyl)methyl glycal derivative (+)-7.13 was practically the
only reaction product accompanied by only a small amount (7%) of a rearranged product which turned out to be
(2S,5R,6S)-2-(dimethoxycarbonylmethyl)-5-(2-benzyloxy-1-hydroxyethyl)-2,5-dihydropyrrole (+)-7.14. By changing the base from t-BuOK to LiH and finally to t-BuOLi, the
amount of the 2,5-dihydropyrrole (+)-7.14 increased to 15 and 38%, respectively (Scheme 7.8). Also in this case the rearranged product derives from both the corresponding syn- and/or anti-1,4-addition products which were not found in the crude product, due to their, evidently rapid, rearrangement process. The diastereoisomeric nature of 2,5-dihydropyrrole (+)-7.12 from 1.2α-Ms with respect to 2,5-dihydropyrrole (+)-7.14 from aziridine 1.2β-Ms, is due to the opposite
configuration of C(4) carbon in the starting aziridine, and as the consequence, for the opposite configuration of C(5) carbon in the corresponding 1,4-addition product which determines the opposite configuration at the dihydropyrrole C(5) and C(2) carbons of the corresponding rearranged product. ! "#! $ !"#!$%& %& %'! !%' ! ! ()*+'#' ! ,-.,!/%'0/ %&-$ "#! ! " 1 .203'"!( $ %& ,-.,!/%'0/0 "#! -! 4 " ! .203'"!) #3"+!56666666666678966666666666666666666666666666666666666666666:;9 6666<=-6666666666666>?9666666666666666666666666666666666666666666666:?9 #3"+!<=6666666666@/96666666666666666666666666666666666666666666668>9 2 -
-Scheme 7.8. Reaction of N-mesyl aziridine 1.2β-Ms with potassium and lithium enolate of dimethylmalonate.
The mechanism associated with the formation of 2,5-dihydropyrrole (+)-7.14 from the reaction of aziridine 1.2β-Ms with the potassium enolate of dimethyl malonate is analogous to that previously described for aziridine 1.2α-Ms in the reaction with potassium enolate of dibenzoylmethane. The only difference is given by the internal nucleophilic attack which in this case occurs on the Si face of the conjugated system (Scheme 7.9, where, being indifferent, a not defined anomeric 1,4-addition product 7.15 is taken as the reactive species).
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Scheme 7.9. Mechanism of the formation of the cis-2,5-disubstituted-2,5-dihydropyrrole (+)-7.14.
The use of the potassium enolate of ethyl acetoacetate afforded a crude reaction product consisting of a 38:32:30 mixture of corresponding trans 4-N-mesylamino-3-(1-acetyl-1-ethoxycarbonyl)-methyl glycal derivative 7.20 (anti-1,2-addition product),
7.22, a kind of O-alkylation product never observed with the other C-nucleophiles previously used.
Due to the presence of the new chiral centre deriving from the enolate, both the anti 1,2-addition product 7.20 and the rearranged product 7.21 were obtained as an unseparable mixture of the two corresponding diastereoisomers. The cis relationship between the side chains and, as a consequence, the absolute configuration at C(2) and C(5) found in the rearranged product 7.21, are in accordance with the regio- and stereochemical behavior of N-mesyl aziridine 1.2α-Ms in this transformation (see the following Scheme 7.10, and the previous Schemes 7.2 and 7.7). At this moment the exact stereochemistry of the only O-glycoside 7.22 has not yet been determined.
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Scheme 7.10. Reaction of N-mesyl aziridine 1.2α-Ms with potassium enolate of ethyl acetoacetate. Potassium enolates derived from other active methylene dicarbonyl compounds, as ethyl cyanoacetate and malononitrile were examined in their reactions with N-mesyl aziridine 1.2α-Ms. Unfortunately and unexpectedly, the reactions were completely 1,2-regioselective with the exclusive formation of the corresponding anti-1,2-addition product 7.23 (from malononitrile) and
7.24 (from ethyl cyano acetate). As a consequence, no corresponding 2,5-dihydropyrrole systems
were obtained with these C-nucleophiles (Scheme 7.11).
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Scheme 7.11. Reactions of N-mesyl aziridine 1.2α-Ms with potassium enolate of malononitrile and ethyl cyanoacetate.
In conclusion, we have found a simple, completely regio- and stereoselective procedure for the construction of enantiomerically pure 2,5-dihydropyrrole systems bearing a cis 2,5-disubstitution constituted by two highly functionalized allyl chains, starting from an easily available vinyl N-mesyl aziridine. The source of the chirality present in the obtained heterocyclic system derives from the easily available, and sufficiently not expensive, tri-O-acetyl-D-glucal (+)-3.6. To note that,
in addition to the 3,4-double bond, the presence in the 2,5-dihydropyrroles of the two highly functionalized chains allows easy further functionalizations for the construction of derivatives, also complex.
7.3. Experimental
General Procedures. See Experimental Chapter 1.
Materials. Toluene, Et2O and THF were distilled from sodium/benzophenone. Trans N,O-dimesylate (+)-1.4α and trans N,O-N,O-dimesylate (+)-1.4β were prepared as previously described.6,7
Instrumentation. See Experimental Chapter 1.
Reaction of aziridine 1.2α-Ms with potassium enolate of dibenzoylmethane by t-BuOK, as the base
Typical procedure. A solution of trans N,O-dimesylate (+)-1.4α (0.034 g, 0.090 mmol) in
anhydrous toluene (1 mL) was treated with t-BuOK (0.020 g, 0.18 mmol, 2 equiv) in the presence of dibenzoylmethane (0.061 g, 0.27 mmol, 3 equiv) and the reaction mixture was stirred 3 h at room temperature. The solution was partitioned between Et2O (15 mL) and brine (5 mL), and the aqueous layer was further extracted with Et2O (2 x 10 mL). Evaporation of the combined organic extracts afforded a crude product consisting of a 48:48:4 mixture of 3-(dibenzoylmethyl)-D-glucal derivative 7.1 (anti-1,2-addition product), 2,5-dihydropyrrole derivative 7.2 (rearraged product) and β-C-glycoside 7.3β (anti-1,4-addition product) (1H NMR), which was subjected to preparative TLC using a 4:3:3 hexane/CH2Cl2/(i-Pr)2O mixture, as the eluant (6 runs). Extraction of the two most intense bands (the faster moving band contained 7.2) afforded pure 3-(dibenzoylmethyl)-D -glucal derivative 7.1 (0.011 g, 29% yield), 2,5-dihydropyrrole derivative 7.2 (0.011 g, 23% yield) and β-C-glycoside 7.3 (0.0015 g, 4% yield).
6-O-Benzyl-4-deoxy-4-N-(mesylamino)-3-(dibenzoylmethyl)-D-glucal
(-)-(7.1): a liquid, Rf = 0.30 [3:4:3 hexane/CH2Cl2/(i-Pr)2O]; [α]20D −37.4 (c 0.85, CHCl3). 1H NMR (CDCl3) δ 7.86-7.96 (m, 4H), 7.18-7.62 (m, 11H), 6.34 (dd, 1H, J = 6.3, 2.3 Hz), 5.90 (d, 1H, J = 6.9 Hz), 4.87 (d, 1H, J = 8.7 Hz), 4.48-4.65 (m, 1H), 4.55 (s, 2H), 3.94-4.19 (m, 2H), 3.86 (dd, 1H, J = 11.1 Hz, 4.3 Hz), 3.78 (dd, 1H, J = 11.1, 5.0 Hz), 3.30-3.44 (m, 1H), 3.06 (s, 3H). 13C NMR (CDCl3) δ 195.8, 195.4, 143.7, 137.4, 133.8, 133.6, 129.0, 128.8, 128.6, 128.1, 128.0, 100.1, 77.3, 74.0, 68.7, 57.0, 51.7, 41.4, 39.1. Anal. Calcd for C29H29NO6S: C, 67.03; H, 5.63; N, 2.70. Found: C, 67.16; H, 5.34; N, 2.87. ! "#$"!%&'(' )*#+ ,-! $.'.!"#
(2R,5S,6S)-5-[2-(benzyloxy)-1-hydroxy-ethyl]-2-(dibenzoylmethyl)-1-mesyl-2,5-dihydro-1H-pyrrole (+)-(7.2): a
liquid Rf = 0.37 [3:4:3 hexane/CH2Cl2/(i-Pr)2O]; [α]20D +79.2 (c 1.37, CHCl3). 1H NMR (CDCl3) δ 8.08-8.18 (m, 2H) 7.88-7.98 (m, 2H), 7.21-7.66 (m, 11H), 6.32 (dt, 1H, J = 6.3, 1.8 Hz), 6.15 (d, 1H, J = 5.1 Hz), 5.90 (dt, 1H, J = 6.3 Hz), 5.17-5.28 (m, 1H), 4.42 (d, 1H, J = 11.7 Hz), 4.34 (d, 1H, J = 11.7 Hz), 4.28-4.35 (m, 2H), 3.45-3.59 (m, 1H), 3.40 (dd, 1H, J = 9.7, 5.8 Hz), 3.30 (dd, 1H, J = 9.7, 4.5 Hz), 2.81 (s, 3H). 13C NMR (CDCl3) δ 194.6, 137.9, 136.9, 136.3, 134.2, 133.8, 130.7, 129.6, 129.3, 128.9, 128.6, 127.9, 127.2, 73.6, 73.0, 71.5, 70.6, 69.2, 61.0, 32.5. Anal. Calcd for C29H29NO6S: C, 67.03; H, 5.63; N, 2.70. Found: C, 67.31; H, 5.78; N, 2.65.
(2R,5S,6R)-6-(Benzyloxymethyl)-5-N-(mesylamino)-2-(dibenzoylmethyl)-2H-5,6-dihydropyran (7.3β), a liquid: Rf = 0.21 [3:4:3 hexane/CH2Cl2/(i-Pr)2O]. 1H NMR (CDCl3) δ 7.87-8.03 (m, 4H), 7.12-7.61 (m, 11H), 6.05 (dt, 1H, J = 10.4, 1.7 Hz), 5.85 (dt, 1H,
J = 10.4, 1.9 Hz), 5.56 (d, 1H, J = 8.2 Hz), 5.15-5.26 (m, 1H), 4.37 (d, 1H, J = 12.0 Hz), 4.30 (d,
1H, J = 12.0 Hz), 4.25-4.42 (m, 1H), 4.02-4.20 (m, 1H), 3.61 (d, 2H, J = 4.0 Hz), 3.41-3.52 (m, 1H), 2.93 (s, 3H). 13C NMR (CDCl
3) δ 193.1, 137.0, 133.7, 133.3, 130.5, 129.1, 128.9, 128.5, 127.8, 75.6, 73.4, 69.4, 60.6, 48.0, 41.5, 33.8. Anal. Calcd for C29H29NO6S: C, 67.03; H, 5.63; N, 2.70. Found: C, 66.89; H, 5.56; N, 2.48.
Reaction of debenzoylation of 3-(dibenzoylmethyl)-D-glucal derivative (-)-7.1
Typical procedure. A solution of 3-(dibenzoylmethyl)-D-glucal derivative (-)-7.1 (0.011 g, 0.021 mmol) in anhydrous toluene (0.1 mL) was treated with t-BuOK (0.003 g, 0.025 mmol, 1.2 equiv) and the reaction mixture was stirred 48 h at room temperature. Evaporation of the filtered organic solution afforded 3-(benzoylmethyl)-D-glucal derivative (-)-7.9 (0.009 g, 82% yield), pure as a liquid. 6-O-Benzyl-4-deoxy-4-N-(mesylamino)-3-(benzoylmethyl)-D-glucal (-)-(7.9): Rf = 0.42 (1:1 hexane/AcOEt); [α]20 D -14.0 (c 0.14, CHCl3). 1H NMR (CDCl3) δ 7.92-8.02 (m, 2H), 7.41-7.59 (m, 3H), 7.28-7.38 (m, 5H), 6.36 (dd, 1H, J = 6.4, 1.9 Hz), 4.66 (d, 1H, J = 11.8 Hz), 4.59 (d, 1H, J = 11.8 Hz), 4.60-4.71 (m, 2H), 4.49 (d, 1H, J = 8.4 Hz), 3.86-3.96 (m, 2H), 3.78-3.84 (m, 1H), 3.62-3.75 (m, 1H), 3.48-3.60 (m, 1H), 2.98-3.06 (m, 1H), 2.98 (s, 3H). 13C NMR (CDCl 3) δ 189.1, 143.5, 139.2, 138.7, 128.9, 128.7, 128.3, 127.9, 104.7, 74.3, 69.2, 53.6, 42.0, 41.9, 36.1, 30.0. ! "# $%&'$()*+&+ ,-( (% '.+/!"# ! "#$% &'! ($)(!*+,-, !"#! ! "#$"!%&' ()#* +,! -.'.!"#
Reaction of debenzoylation of 2-(dibenzoylmethyl)-2,5-dihydropyrrole derivative (+)-7.2
Following the typical procedure, a solution of 2-(dibenzoylmethyl)-2,5-dihydropyrrole derivative (+)-7.2 (0.011 g, 0.021 mmol) in anhydrous toluene (0.1 mL) was treated with t-BuOK (0.003 g, 0.025 mmol, 1.2 equiv) and the reaction mixture was stirred 48 h at room temperature. Evaporation of the filtered organic solution afforded the 2-(benzoylmethyl)-2,5-dihydropyrrole derivative
(+)-7.8 (0.007 g, 64% yield), pure as a liquid.
(2R,5S,6S)-5-[2-(benzyloxy)-1-hydroxy-ethyl]-2-(benzoylmethyl)-1-mesyl-2,5-dihydro-1H-pyrrole (+)-(7.8): Rf = 0.37 (1:1 hexane/AcOEt); [α]20 D +12.4 (c 0.14, CHCl3). 1H NMR (CDCl3) δ 7.88-7.94 (m, 2H), 7.49-7.57 (m, 1H), 7.38-7.47 (m, 2H), 7.24-7.37 (m, 5H), 6.06-6.11 (m, 1H), 5.77-5.83 (m, 1H), 4.82-4.91 (m, 1H), 4.56 (d, 1H, J = 12.0 Hz), 4.52 (d, 1H, J = 12.0 Hz), 4.41-4.46 (m, 1H), 3.96-4.04 (m, 1H), 3.53-3.68 (m, 2H), 3.22-3.39 (m, 2H), 2.78 (s, 3H), 2.54 (d, 1H, J = 6.3 Hz). 13C NMR (CDCl 3) δ 196.2, 138.1, 136.8, 133.7, 132.0, 128.9, 128.3, 128.0, 126.3, 73.8, 72.8, 71.6, 70.5, 64.7, 46.8, 33.6.
Reaction of aziridine 1.2β-Ms with potassium enolate of dibenzoylmethane by t-BuOK, as the base
Following the above described typical procedure, the treatment of a solution of N,O-dimesylate (+)-1.4β (0.093 g, 0.092 mmol) in anhydrous toluene (1.0 mL) with t-BuOK (0.021 g, 0.186 mmol, 2.0 equiv) in the presence of dibenzoylmethane (0.062 g, 0.276 mmol, 3.0 equiv) afforded a crude product consisting of 3-(dibenzoylmethyl)-D-gulal derivative (+)-7.10 (anti-1,2-addition product) (0.041 g, 85% yield), pure as a liquid.
6-O-Benzyl-4-deoxy-4-N-(mesylamino)-3-(dibenzoylmethyl)-D-gulal (+)-(7.10): a liquid: Rf = 0.30 (1:1 hexane/AcOEt); [α]20 D +2.2 (c 1.84, CHCl3). 1H NMR (CDCl3) δ 7.90-8.03 (m, 2H), 7.77-7.87 (m, 2H), 7.56-7.67 (m, 1H), 7.44-7.55 (m, 5H), 7.27-7.39 (m, 5H), 6.47 (d, 1H, J = 6.2 Hz), 5.30 (d, 1H J = 10.6 Hz), 4.75 (d, 1H, J = 9.9 Hz), 4.57 (d, 1H, J = 11.7 Hz), 4.52 (d, 1H, J = 11.7 Hz), 4.43-4.50 (m, 1H), 4.10-4.17 (m, 1H), 3.81 (dd, 1H, J = 10.2, 6.6 Hz), 3.71 (dd, 1H, J = 10.2, 4.5 Hz), 3.60-3.65 (m, 1H), 3.32-3.44 (m, 1H), 3.36 (s, 3H). 13C NMR (CDCl 3) δ 194.2, 193.3, 146.0, 137.8, 136.5, 136.1, 134.3, 129.3, 129.1, 128.8, 128.6, 128.3, 128.0, 99.0, 74.1, 73.4, 70.5, 61.6, 60.6, 50.2, 42.2, 39.6. ! "#$"!%&'(' )*#+ ,-! $.'/!"#$ ! "# $%&$'()* +,' '% -.*/!"#
Reaction of aziridine 1.2α-Ms with potassium enolate of dimethylmalonate by t-BuOK, as the base
Following the typical procedure, a solution of trans N,O-dimesylate (+)-1.4α (0.034 g, 0.09 mmol) in anhydrous toluene (1.0 mL) was treated with t-BuOK (0.020 g, 0.18 mmol, 2.0 equiv) in the presence of dimethylmalonate (0.030 mL, 0.27 mmol, 3.0 equiv) and the reaction mixture was stirred 3 h at room temperature. Evaporation of the washed (brine) organic solution afforded a crude reaction product consisting of a 68:32 mixture of 3-(dimethoxycarbonylmethyl)-D-glucal derivative (-)-7.11 (anti-1,2-addition product) and 2,5-dihydropyrrole derivative (+)-7.12 (rearranged product) (1H NMR), which was subjected to preparative TLC using a 6:4 hexane/AcOEt mixture as the eluant (4 runs). Extraction of the two most intense bands [the faster moving band contained (-)-7.11] afforded pure 3-(dimethoxycarbonylmethyl)-D-glucal derivative (-)-7.11 (0.014 g, 38% yield) and 2,5-dihydropyrrole derivative (+)-7.12 (0.008 g, 22% yield).
6-O-Benzyl-4-deoxy-4-N-(mesylamino)-3-(dimethoxycarbonylmethyl) -D-glucal (-)-(7.11): a liquid: Rf = 0.45 (3:7 hexane/AcOEt); [α]20D −6.4 (c 0.26, CHCl3). 1H NMR (CDCl3) δ 7.25-7.38 (m, 5H), 6.40 (dd, 1H, J = 6.2, 2.2 Hz), 4.75 (d, 1H, J = 9.1 Hz), 4.68 (dd, 1H, J = 6.2, 2.8 Hz), 4.62 (d, 1H, J = 11.8 Hz), 4.54 (d, 1H, J = 11.8 Hz), 3.87-4.13 (m, 2H), 3.84 (d, 1H, J = 5.8 Hz), 3.78 (dd, 2H, J = 4.6, 2.0 Hz), 3.73 (s, 3H), 3.70 (s, 3H), 3.05 (s, 3H), 2.88-3.00 (m, 1H). 13C NMR (CDCl3) δ 169.1, 167.9, 144.4, 137.6, 128.7, 128.0, 99.5, 77.6, 73.9, 68.9, 53.0, 52.8, 52.2, 51.1, 42.1, 39.1. Anal. Calcd for C19H25NO8S: C, 53.39; H, 5.89; N, 3.28. Found: C, 53.51; H, 5.65; N, 3.39. (2R,5S,6S)-5-[2-(benzyloxy)-1-hydroxy-ethyl]-2-(dimethoxycarbonylmethyl)-1-mesyl-2,5-dihydro-1H-pyrrole (+)-(7.12): a liquid, Rf = 0.37 (3:7 hexane/AcOEt); [α]20 D +5.4 (c 0.30, CHCl3). 1H NMR (CDCl3) d 7.24-7.38 (m, 5H), 6.03 (dt, 1H, J = 6.3, 1.9 Hz), 5.91 (dt, 1H, J = 6.3, 1.8 Hz), 4.93 (dq, 1H, J = 7.1, 1.7 Hz), 4.56 (d, 2H, J = 3.0 Hz), 4.48-4.54 (m, 1H), 4.00-4.15 (m, 1H), 3.91 (d, 1H, J = 7.0 Hz), 3.76 (s, 3H), 3.73 (s, 3H), 3.62 (dd, 1H, J = 10.0, 5.5 Hz), 3.55 (dd, 1H, J = 10.0, 5.7 Hz), 3.01-3.12 (m, 1H), 2.79 (s, 3H). 13C NMR (CDCl 3) δ 168.1, 137.8, 129.7, 128.6, 128.1, 128.0, 73.7, 71.5, 70.9, 66.3, 57.2, 53.2, 52.8, 34.2, 29.9. Anal. Calcd for C19H25NO8S: C, 53.39; H, 5.89; N, 3.28. Found: C, 53.12; H, 5.95; N, 3.46. ! "#$"!%&'(%( &)#* +,! $-(-!"## ! "# $%&$'(")*(* +,' '% &-*.!"#$
Reaction of aziridine 1.2α-Ms with lithium enolate of dimethylmalonate by LiH, as the base Typical procedure. A solution of trans N,O-dimesylate (+)-1.4α (0.034 g, 0.09 mmol) in
anhydrous toluene (1 mL) was treated with LiH (0.003 g, 0.36 mmol, 4 equiv) in the presence of dimethylmalonate (0.030 mL, 0.27 mmol, 3 equiv) and the reaction mixture was stirred 2 h at room temperature. Dilution with Et2O and evaporation of the washed (brine) organic solution afforded a crude product (0.070 g) consisting of a 30:70 mixture of 3-(dimethoxycarbonylmethyl)-D-glucal derivative (-)-7.11 and 2,5-dihydropyrrole derivative (+)-7.12 (1H NMR).
Reaction of aziridine 1.2β-Ms with lithium enolate of dimethylmalonate by t-BuOLi, as the base
Following the above described typical procedure, the treatment of a solution of N,O-dimesylate (+)-1.4β (0.018 g, 0.047 mmol) in anhydrous toluene (0.5 mL) with t-BuOLi (0.015 g, 0.189 mmol, 4.0 equiv) in the presence of dimethylmalonate (0.020 mL, 0.14 mmol, 3.0 equiv) afforded a crude product consisting of a 62:38 mixture of 3-(dimethoxycarbonylmethyl)-D-gulal derivative (+)-7.13 (anti-1,2-addition product) and 2,5-dihydropyrrole derivative (+)-7.14 (rearranged product) (1H NMR) which was subjected to preparative TLC using an 1:1 CH
2Cl2/i-Pr2O mixture, as the eluant (2 runs). Extraction of the two most intense bands (the faster moving band contained (+)-7.13) afforded pure 3-(dimethoxycarbonylmethyl)-D-gulal derivative (+)-7.13 (0.010 g, 50% yield) and 2,5-dihydropyrrole derivative (+)-7.14 (0.004 g, 19% yield).
6-O-Benzyl-4-deoxy-4-N-(mesylamino)-3-(dimethoxycarbonylmethyl) -D-gulal (+)-(7.13): a liquid: Rf = 0.39 [1:1 CH2Cl2/(i-Pr)2O]; [α]20D +75.7 (c 0.94, CHCl3). 1H NMR (CDCl3) δ 7.25-7.40 (m, 5H), 6.50 (dd, 1H, J = 6.2, 1.2 Hz), 4.75 (d, 1H, J = 9.9 Hz, NH), 4.65 (ddd, 1H, J = 6.2, 4.7, 1.7 Hz), 4.57 (s, 2H), 3.88-3.99 (m, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.73 (s, 3H), 3.68-3.79 (m, 4H), 3.13 (s, 3H), 2.82-2.95 (m, 1H). 13C NMR (CDCl
3) δ 168.1, 167.6, 146.1, 137.8, 128.6, 128.2, 128.0, 98.2, 73.9, 72.4, 69.5, 56.7, 53.2, 53.0, 49.6, 42.0, 38.0. Anal. Calcd for C19H25NO8S: C, 53.39; H, 5.89; N, 3.28. Found: C, 53.67; H, 5.73; N, 3.15.
(2S,5R,6S)-5-[2-(benzyloxy)-1-hydroxy-ethyl]-2-(dimethoxycarbonylmethyl)-1-mesyl-2,5-dihydro-1H-pyrrole
(+)-(7.14): a liquid: Rf = 0.31 [1:1 CH2Cl2/(i-Pr)2O]; [α]20D +27.4 (c 0.13, CHCl3). 1H NMR (CDCl3) δ 7.27-7.41 (m, 5H), 6.05 (dt, 1H, J = 6.2, 1.9 Hz), 5.82 (dt, 1H, J = 6.2, 1.8 Hz), 5.02 (dq, 1H, J = 7.5, 1.2 Hz), 4.64 (d, 1H, J = 11.7 Hz), 4.52 (d, 1H, J = 11.7 Hz), 4.46-4.64 (m, 1H), 3.91 (d, 1H, J = 7.5 Hz), 3.76 (s, 3H), 3.72 (s, 3H), 3.52-3.77 (m, 3H), 3.21-3.30 (m, 1H), 2.83 (s, 3H). 13C NMR (CDCl 3) δ 167.7, 167.6, ! "# $%&$'(")*(* +,' %' &-*.!"#$ % % ! "#$"!%&'(%( &)#* +,! $-(.!"#$
138.1, 129.5, 128.9, 128.7, 128.2, 128.0, 73.8, 73.2, 71.5, 70.6, 67.1, 57.4, 53.2, 52.7, 34.8. Anal. Calcd for C19H25NO8S: C, 53.39; H, 5.89; N, 3.28. Found: C, 53.44; H, 5.68; N, 3.33.
Reaction of aziridine 1.2β-Ms with dimethylmalonate and LiH, as the base
Following the above described typical procedure, the treatment of a solution of N,O-dimesylate (+)-1.4β (0.018 g, 0.047 mmol) in anhydrous toluene (0.5 mL) with LiH (0.0015 g, 0.189 mmol, 4.0 equiv) in the presence of dimethylmalonate (0.020 mL, 0.14 mmol, 3.0 equiv) afforded a crude product consisting of a 85:15 mixture of (+)-7.13 and (+)-7.14 (1H NMR).
Reaction of aziridine 1.2β-Ms with potassium enolate of dimethylmalonate by t-BuOK, as the base
Following the above described typical procedure, the treatment of a solution of N,O-dimesylate (+)-1.4β (0.024 g, 0.06 mmol) in anhydrous toluene (1.0 mL) with t-BuOK (0.014 g, 0.12 mmol, 2.0 equiv) in the presence of dimethylmalonate (0.020 mL, 0.18 mmol, 3.0 equiv) afforded a crude product consisting of a 97:3 mixture of 3-(dimethoxycarbonylmethyl)-D-gulal derivative (+)-7.13 (anti-1,2-addition product) and 2,5-dihydropyrrole derivative (+)-7.14 (rearranged product) (1H NMR).
Reaction of aziridine 1.2α-Ms with potassium enolate of ethyl acetoacetate by t-BuOK, as the base
Following the above described typical procedure, the treatment of a solution of N,O-dimesylate (+)-1.4α (0.004 g, 0.102 mmol) in anhydrous THF (1.0 mL) with t-BuOK (0.023 g, 0.204 mmol, 2.0 equiv) in the presence of ethyl acetoacetate (0.004 mL, 0.307 mmol, 3.0 equiv) afforded a crude product (0.065 g) consisting of a 38:32:30 mixture of 3-(1-acetyl-1-ethoxycarbonyl-methyl)-D -glucal derivative 7.20 (anti-1,2-addition product), 2,5-dihydropyrrole derivative 7.21 (rearranged product) and O-alkylation product 7.22 (1H NMR) which was subjected to preparative TLC using an 6:4 hexane/AcOEt mixture, as the eluant. Extraction of the three most intense bands (the faster and the slower moving band contained 7.20 and 7.22, respectively) afforded pure 3-(1-acetyl-1-ethoxycarbonyl-methyl)-D-glucal derivative 7.20 (0.015 g, 34% yield), 2,5-dihydropyrrole derivative 7.21 (0.012 g, 28% yield) and O-glycoside 7.22 (0.012 g, 23% yield).
6-O-benzyl-4-deoxy-4-N-(mesylamino)-3-(1-acetyl-1-ethoxycarbonyl-methyl)-D-glucal (7.20): a liquid: Rf = 0.27 (6:4 hexane/AcOEt); 1H NMR (CDCl3) δ 7.28-7.41 (m, 5H), 6.37(dd, 1H, J = 6.2, 1.9 Hz), 4.53-4.73 (m, 2H), 4.58 (s, 2H), 4.58 (s, 2H), 4.10-4.27 (m, 2H), 3.97-4.08 (m, 1H), 3.66-3.96 (m, 5H), 3.07 and 3.04 (two singlets corresponding to two !
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diastereoisomers, 3H), 2.23 and 2.19 (two singlets corresponding to two diastereoisomers, 3H), 1.26 and 1.24 (two triplet corresponding to two diastereoisomers, 3H, J = 6.7 Hz). 13C NMR (CDCl3) δ 202.6, 202.5, 169.2, 168.2, 144.2, 143.9, 137.6, 137.5, 128.7, 128.2, 128.1, 99.8, 99.6, 77.5, 77.3, 74.0, 73.9, 68.6, 62.1, 61.9, 60.0, 59.3, 50.9, 50.7, 41.8, 41.7, 38.8, 37.6, 31.3, 30.0, 29.9, 14.6, 14.1. (2R,5S,6S)-5-[2-(benzyloxy)-1-hydroxy-ethyl]-2-(1-acetyl-1-ethoxycarbonyl-methyl)-1-mesyl-2,5-dihydro-1H-pyrrole (7.21): a liquid: Rf = 0.17 (6:4 hexane/AcOEt); 1H NMR (CDCl3) δ 7.27-7.41 (m, 5H), 5.96-6.04 (m, 1H), 5.85.5.90 (m, 1H), 4.88-4.95 (m, 1H), 4.59 (d, 1H, J = 11.8 Hz), 4.53 (d, 1H, J = 11.8 Hz), 4.45-4.49 (m, 1H), 4.14-4.27 (m, 2H), 4.04-4.11 (m, 1H), 4.02 and 3.93 (two doublet corresponding to two diastereoisomers, 1H, J = 6.3 Hz), 3.55-3.63 (m, 2H), 2.78 and 2.76 (two singlet corresponding to two diastereoisomers, 3H), 2.35 (bs, 1H), 2.27 and 2.23 (two singlet corresponding to two diastereoisomers, 3H), 1.28 and 1.26 (two triplet corresponding to two diastereoisomers, 3H, J = 7.2 Hz). 13C NMR (CDCl 3) δ 197.7, 195.8, 168.3, 167.6, 138.0, 130.9, 129.9, 128.7, 128.0, 127.5, 73.7, 72.3, 71.3, 71.2, 71.1, 70.9, 66.2, 64.9, 64.6, 62.5, 62.1, 34.1, 33.7, 31.3, 29.9, 14.2, 14.1. (7.22): a liquid: Rf = 0.10 (6:4 hexane/AcOEt); 1H NMR (CDCl 3) δ 7.27-7.39 (m, 5H), 6.10 (dd, 1H, J =10.0, 1.6 Hz), 5.99 (ddd, 1H, J = 10.0, 3.0, 2.2 Hz), 5.71 (d, 1H, J =3.0 Hz), 5.12 (d, 1H, J =10.2 Hz), 5.08 (d, 1H, J =0.7 Hz), 5.62 (d, 1H, J =11.9 Hz), 4.53 (d, 1H, J =11.9 Hz), 4.21-4.34 (m, 1H), 4.00-4.15 (m, 3H), 3.78 (dd, 1H, J = 10.8, 3.6 Hz), 3.66 (dd, 1H, J = 10.8, 2.2 Hz), 2.88 (s, 3H), 2.08 (s, 3H), 1.22 (t, 3H, J = 7.0 Hz). 13C NMR (CDCl 3) δ 165.9, 165.1, 137.9, 133.1, 128.6, 128.1, 128.0, 126.2, 101.1, 92.0, 73.8, 70.7, 68.7, 59.6, 47.7, 41.7, 29.9, 19.7, 14.5.
Reaction of aziridine 1.2α-Ms with potassium enolate of malononitrile by t-BuOK, as the base
Following the above described typical procedure, the treatment of a solution of N,O-dimesylate (+)-1.4α (0.034 g, 0.09 mmol) in anhydrous toluene (1.0 mL) with t-BuOK (0.020 g, 0.18 mmol, 2.0 equiv) in the presence of malononitrile (0.017 g, 0.27 mmol, 3.0 equiv) afforded a crude product consisting of pratically pure 3-(dicyanomethyl)-D-glucal derivative 7.23 (anti-1,2-addition product) (1H NMR) which was subjected to flash chromatography. Elution with a 4:6 hexane/AcOEt mixture afforded pure 3-(dicyanomethyl)-D-glucal derivative 7.23 (0.020 g, 62% yield), as a liquid.
6-O-Benzyl-4-deoxy-4-N-(mesylamino)-3-(dicyanomethyl)-D-glucal (7.23) (0.020 g, 62% yield), pure as a liquid: Rf = 0.43 (3:7 hexane/AcOEt). 1H NMR (CDCl3) δ 7.23-7.43 (m, 5H), 6.65 (dd, 1H, J = 6.0, 2.1 Hz), 5.03 (dd, 1H, J = ! "#$% &'! %( (% ! "# $%& &' !"#$ ' ' (&") (&*+, ! "#$% &'! ! !"## (!)*+
8.7, 2.1 Hz), 7.96 (dd, 1H, J = 6.0, 1.9 Hz), 4.52-4.71 (m, 1H), 4.66 (d, 1H, J = 11.9 Hz), 4.57 (d, 1H, J = 11.9 Hz), 3.53-4.18 (m, 5H), 2.97 (s, 3H). 13C NMR (CDCl
3) δ 147.5, 136.9, 128.9, 128.4, 128.1, 110.9, 96.8, 74.5, 71.2, 68.6, 51.2, 43.6, 40.7, 26.3. Anal. Calcd for C17H19N3O4S: C, 56.50; H, 5.30; N, 11.63. Found: C, 56.75; H, 5.47; N, 11.43.
Reaction of aziridine 1.2α-Ms with potassium enolate of ethyl cyanoacetate, by t-BuOK, as the base
Following the above described typical procedure, the treatment of a solution of N,O-dimesylate (+)-1.4α (0.032 g, 0.081 mmol) in anhydrous THF (1.0 mL) with t-BuOK (0.018 g, 0.16 mmol, 2.0 equiv) in the presence of ethyl cyanoacetate (0.026 mL, 0.24 mmol, 3.0 equiv) afforded a crude product consisting of pratically pure 3-(1-cyano-1-ethoxycarbonyl-methyl)-D-glucal derivative 7.24 (anti-1,2-addition product) (1H NMR), which was subjected to flash chromatography. Elution with an 1:1 hexane/AcOEt mixture afforded pure 3-(1-cyano-1-ethoxycarbonyl-methyl)-D-glucal derivative 7.24 (0.022 g, 70% yield), as a liquid.
6-O-Benzyl-4-deoxy-4-N-(mesylamino)-3-(cyanoetoxycarbonylmethyl)- -D-glucal (7.24) (0.022 g, 70% yield), pure as a liquid: Rf = 0.26 (1:1 hexane/AcOEt). 1H NMR (CDCl
3) δ 7.24-7.40 (m, 5H), 6.53 (dd, 1H, J = 6.1, 2.1 Hz), 4.90 (d, 1H, J = 9.0 Hz), 4.52-4.70 (m, 1H), 4.66 (d, 1H, J = 11.9 Hz), 4.56 (d, 1H, J = 11.9 Hz), 4.58 (dd, 1H, J = 6.0, 1.9 Hz), 4.22-4.36 (m, 2H), 3.61-3.95 (m, 4H), 2.95-3.05 (m, 1H), 2.99 (s, 3H), 1.23 (t, 3H, J = 7.1 Hz). 13C NMR (CDCl3) δ 165.9, 146.4, 137.3, 128.8, 128.1, 114.7, 97.9, 74.2, 68.8, 63.4, 51.2, 41.6, 41.2, 40.3. Anal. Calcd for C19H24N2O6S: C, 55.87; H, 5.92; N, 6.86. Found: C, 55.68; H, 5.56; N, 6.95.
Reaction of aziridine 1.2α-Ms with lithium enolate of ethyl cyanoacetate by LiH, as the base
Following the above described typical procedure, the treatment of a solution of N,O-dimesylate (+)-1.4α (0.026 g, 0.066 mmol) in anhydrous toluene (1.0 mL) with LiH (0.002 g, 0.264 mmol, 4.0 equiv) in the presence of ethyl cyanoacetate (0.021 mL, 0.20 mmol, 3.0 equiv) afforded a crude product (0.050 g) consisting of practically pure 3-(1-cyano-1-ethoxycarbonyl-methyl)-D-glucal derivative 7.24 (1H NMR).
References
1. Ishikawa, A.; Noguchi, F.; Kammura, A. J. Org. Chem. 2010, 75, 3578. 2. Sun, W.; Ma, X.; Hong, L.; Wang, R. J. Org. Chem. 2011, 76, 7826. 3. Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031.
4. Meng, L-G.; Cai, P.; Guo, Q.; Xue, S. J. Org. Chem. 2008, 73, 8491. 5. Sun, W.; Zhu, G.; Hong, L.; Wang, R. Chem. Eur. J. 2011, 17, 13958.
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6. Di Bussolo, V.; Romano, M. R.; Pineschi, M.; Crotti, P. Org. Lett. 2005, 7, 1299.
7. Di Bussolo, V.; Romano, M. R.; Favero, L.; Pineschi, M.; Crotti, P. J. Org. Chem. 2006, 71, 1696. 8. Di Bussolo, V.; Frau, I.; Pineschi, M.; Crotti, P. Synthesis 2012, 44, 2863.
9. a) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett. 2003, 5, 2173. b) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett. 2002, 4, 3695. c) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi, M.; Crotti, P. J. Org. Chem. 2004, 69, 7383 and 8702.
