“…kcal.mol -1 , was in full agreement with the observed diastereoselectivity (dr > 99:1). 3,4 Chiral substitution on the three-membered ring of complex 1 by a methyl group, had likewise entailed the same extent of diastereoselectivity [D(TSE) = 4.8 kcal.mol -1 and de: 100%]. 5 The diastereomeric isoxazolidines exo-11a 14 and endo-12a 15 were readily separable by flash chromatography on silica gel.…”
Section: Methodsmentioning
confidence: 98%
“…Only fused cycloadducts were obtained because the strain caused by the propylidene chain joining the two reactive sites of the N-methylnitrone 10a, i.e., the strained alkylidene cyclopropane (SE = 40.9 kcal.mol) and the nitrone moiety prevented, as previously observed for the synthesis of 2, the formation of regioisomeric bridged adducts. [3][4][5]12 However, while diastereoselectively pure cycloadducts exo-2 could be obtained when the R substituent was sufficiently bulky (Scheme 1), 3,4 on the other hand the acetoxy group at the carbon C 3 of the N-methylnitrone 10a appeared unsuited to induce any diastereoselectivity.…”
Section: Methodsmentioning
confidence: 99%
“…Therefore, the geometries of the stereogenic centers 3'a, 5' and 6'a in the tricyclic isoxazolidine exo-11a were retained at the corresponding carbons 4a, 6 and 7a in the exo-octahydro pyrindin-4-ones 15a, since none of these chiral centers were involved in the thermal rearrangement exo-11a®exo-15a, which proceeded through homolysis of the N-O bond, ring opening of the resulting cyclopropyloxy radical 13a and intramolecular radical coupling of 14a (Scheme 4). [3][4][5] On the other hand, on heating in toluene in the presence of two equivalents of trifluoroacetic acid (TFA) at reflux for 1 h, the cycloadduct exo-11a underwent ring contraction to provide the 3-acetoxy-6-azabicyclo[3.2.0]heptan-7-one exo-18a in 76% yield, with elimination of one equivalent of ethylene; cleavage of the acetoxy protective group (K 2 CO 3 , MeOH) led to the exo-6-hydroxy derivative exo-18b (R = H). 18 Its structure was characterised from its spectroscopic data; 19 in particular the value of the coupling constant between the H 1 and H 5 (J cis = 3.9 Hz) was consistent with the depicted stereochemistry.…”
Section: Methodsmentioning
confidence: 99%
“…2 We have recently reported the ready asymmetric synthesis of cis-fused tricyclic isoxazolidines exo-2 involving regioselective nucleophilic substitution of p-1,1-ethyleneallylpalladium complex 1 by optically active a-amino acids, followed by diastereoselective 1,3-dipolar cycloaddition of the derived nitrones. Subsequently, the spirocyclopropane isoxazolidines exo-2 have been shown to undergo either thermally induced ring expansion into the pyrrolo [3,4-b]pyridin-4-ones 3, [3][4][5] or acid induced ring contraction into the b-lactams 4 with concomitant extrusion of ethylene (Scheme 1). 6 In order to widen the scope of this new approach towards these biologically important compounds, we have now investigated an alternative access to spirocyclopropane isoxazolidines such as 2 based on the electrophilic substitution of 1,1-ethyleneallylzinc complexes.…”
Electrophilic substitution of 1-ethenylcyclopropyl mesylate by 3,3-diethoxypropanal in the presence of palladium(0) (5%) and diethylzinc (2 equivalents) provided 5-cyclopropylidene-1,1-diethoxy-3-hydroxypentane; its nitrone derivatives underwent intramolecular cycloaddition to provide spirocyclopropane isoxazolidines, which then were transformed under thermal or acidic conditions, into octahydropyrindin-4-ones or bicyclic b-lactams with the ethylene phytohormone extrusion, respectively. Use of chiral auxiliaries, i.e, (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles.It is a matter of common knowledge now, that the cyclopropane ring, which can selectively undergo either ring opening, or ring enlargement or cycloaddition reactions, provides building blocks of unprecedented synthetic potential. 1 It is also known that, when substituted by simple functionalities, natural or synthetic three-membered rings are endowed with a large spectrum of biological activities, allowing consequently the design of new drugs. 2 We have recently reported the ready asymmetric synthesis of cis-fused tricyclic isoxazolidines exo-2 involving regioselective nucleophilic substitution of p-1,1-ethyleneallylpalladium complex 1 by optically active a-amino acids, followed by diastereoselective 1,3-dipolar cycloaddition of the derived nitrones. Subsequently, the spirocyclopropane isoxazolidines exo-2 have been shown to undergo either thermally induced ring expansion into the pyrrolo[3,4-b]pyridin-4-ones 3, 3-5 or acid induced ring contraction into the b-lactams 4 with concomitant extrusion of ethylene (Scheme 1). 6In order to widen the scope of this new approach towards these biologically important compounds, we have now investigated an alternative access to spirocyclopropane isoxazolidines such as 2 based on the electrophilic substitution of 1,1-ethyleneallylzinc complexes.We have observed that, in the presence of diethylzinc in THF, the p-1,1-ethyleneallylpalladium complex 1, arising from the readily available 1-ethenylcyclopropylsulfonates 5a,b and palladium(0), 7,8,10 underwent through the formation of s-or p-1,1-dimethyleneallylzinc complexes 6, chemo-and regioselective electrophilic addition of aldehydes and ketones. 9 Effectively, substitution of mesylate 5a by 3,3-diethoxypropionaldehyde 7 11 performed in the presence of 5% of palladium(0) [from Pd(OAc) 2 and 2 PPh 3 ] and two equivalents of diethylzinc in THF at room temperature for 3 h, provided 5-cyclopropylidene-1,1-diethoxy-3-hydroxypentane 8, in 63% yield after chromatography (Scheme 2).
Scheme 2O-protection (Ac 2 O, DMAP) of the secondary allylic alcohol 8 and subsequent deacetalisation under acidic conditions (0.2 M H 2 SO 4 , THF) led to the 3-acetoxy-5-cyclopropylidenepentanal 9a (R = Ac) in 72% overall yield. This aldehyde reacted at room temperature with N-methylhydroxylamine hydrochloride in the presence of one equivalent of pyridine in diethyl ether at 0°C to give the corresponding N-methylnitrone 10a which, spontaneously, evolved to a 1:1 mixture of ...
“…kcal.mol -1 , was in full agreement with the observed diastereoselectivity (dr > 99:1). 3,4 Chiral substitution on the three-membered ring of complex 1 by a methyl group, had likewise entailed the same extent of diastereoselectivity [D(TSE) = 4.8 kcal.mol -1 and de: 100%]. 5 The diastereomeric isoxazolidines exo-11a 14 and endo-12a 15 were readily separable by flash chromatography on silica gel.…”
Section: Methodsmentioning
confidence: 98%
“…Only fused cycloadducts were obtained because the strain caused by the propylidene chain joining the two reactive sites of the N-methylnitrone 10a, i.e., the strained alkylidene cyclopropane (SE = 40.9 kcal.mol) and the nitrone moiety prevented, as previously observed for the synthesis of 2, the formation of regioisomeric bridged adducts. [3][4][5]12 However, while diastereoselectively pure cycloadducts exo-2 could be obtained when the R substituent was sufficiently bulky (Scheme 1), 3,4 on the other hand the acetoxy group at the carbon C 3 of the N-methylnitrone 10a appeared unsuited to induce any diastereoselectivity.…”
Section: Methodsmentioning
confidence: 99%
“…Therefore, the geometries of the stereogenic centers 3'a, 5' and 6'a in the tricyclic isoxazolidine exo-11a were retained at the corresponding carbons 4a, 6 and 7a in the exo-octahydro pyrindin-4-ones 15a, since none of these chiral centers were involved in the thermal rearrangement exo-11a®exo-15a, which proceeded through homolysis of the N-O bond, ring opening of the resulting cyclopropyloxy radical 13a and intramolecular radical coupling of 14a (Scheme 4). [3][4][5] On the other hand, on heating in toluene in the presence of two equivalents of trifluoroacetic acid (TFA) at reflux for 1 h, the cycloadduct exo-11a underwent ring contraction to provide the 3-acetoxy-6-azabicyclo[3.2.0]heptan-7-one exo-18a in 76% yield, with elimination of one equivalent of ethylene; cleavage of the acetoxy protective group (K 2 CO 3 , MeOH) led to the exo-6-hydroxy derivative exo-18b (R = H). 18 Its structure was characterised from its spectroscopic data; 19 in particular the value of the coupling constant between the H 1 and H 5 (J cis = 3.9 Hz) was consistent with the depicted stereochemistry.…”
Section: Methodsmentioning
confidence: 99%
“…2 We have recently reported the ready asymmetric synthesis of cis-fused tricyclic isoxazolidines exo-2 involving regioselective nucleophilic substitution of p-1,1-ethyleneallylpalladium complex 1 by optically active a-amino acids, followed by diastereoselective 1,3-dipolar cycloaddition of the derived nitrones. Subsequently, the spirocyclopropane isoxazolidines exo-2 have been shown to undergo either thermally induced ring expansion into the pyrrolo [3,4-b]pyridin-4-ones 3, [3][4][5] or acid induced ring contraction into the b-lactams 4 with concomitant extrusion of ethylene (Scheme 1). 6 In order to widen the scope of this new approach towards these biologically important compounds, we have now investigated an alternative access to spirocyclopropane isoxazolidines such as 2 based on the electrophilic substitution of 1,1-ethyleneallylzinc complexes.…”
Electrophilic substitution of 1-ethenylcyclopropyl mesylate by 3,3-diethoxypropanal in the presence of palladium(0) (5%) and diethylzinc (2 equivalents) provided 5-cyclopropylidene-1,1-diethoxy-3-hydroxypentane; its nitrone derivatives underwent intramolecular cycloaddition to provide spirocyclopropane isoxazolidines, which then were transformed under thermal or acidic conditions, into octahydropyrindin-4-ones or bicyclic b-lactams with the ethylene phytohormone extrusion, respectively. Use of chiral auxiliaries, i.e, (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles.It is a matter of common knowledge now, that the cyclopropane ring, which can selectively undergo either ring opening, or ring enlargement or cycloaddition reactions, provides building blocks of unprecedented synthetic potential. 1 It is also known that, when substituted by simple functionalities, natural or synthetic three-membered rings are endowed with a large spectrum of biological activities, allowing consequently the design of new drugs. 2 We have recently reported the ready asymmetric synthesis of cis-fused tricyclic isoxazolidines exo-2 involving regioselective nucleophilic substitution of p-1,1-ethyleneallylpalladium complex 1 by optically active a-amino acids, followed by diastereoselective 1,3-dipolar cycloaddition of the derived nitrones. Subsequently, the spirocyclopropane isoxazolidines exo-2 have been shown to undergo either thermally induced ring expansion into the pyrrolo[3,4-b]pyridin-4-ones 3, 3-5 or acid induced ring contraction into the b-lactams 4 with concomitant extrusion of ethylene (Scheme 1). 6In order to widen the scope of this new approach towards these biologically important compounds, we have now investigated an alternative access to spirocyclopropane isoxazolidines such as 2 based on the electrophilic substitution of 1,1-ethyleneallylzinc complexes.We have observed that, in the presence of diethylzinc in THF, the p-1,1-ethyleneallylpalladium complex 1, arising from the readily available 1-ethenylcyclopropylsulfonates 5a,b and palladium(0), 7,8,10 underwent through the formation of s-or p-1,1-dimethyleneallylzinc complexes 6, chemo-and regioselective electrophilic addition of aldehydes and ketones. 9 Effectively, substitution of mesylate 5a by 3,3-diethoxypropionaldehyde 7 11 performed in the presence of 5% of palladium(0) [from Pd(OAc) 2 and 2 PPh 3 ] and two equivalents of diethylzinc in THF at room temperature for 3 h, provided 5-cyclopropylidene-1,1-diethoxy-3-hydroxypentane 8, in 63% yield after chromatography (Scheme 2).
Scheme 2O-protection (Ac 2 O, DMAP) of the secondary allylic alcohol 8 and subsequent deacetalisation under acidic conditions (0.2 M H 2 SO 4 , THF) led to the 3-acetoxy-5-cyclopropylidenepentanal 9a (R = Ac) in 72% overall yield. This aldehyde reacted at room temperature with N-methylhydroxylamine hydrochloride in the presence of one equivalent of pyridine in diethyl ether at 0°C to give the corresponding N-methylnitrone 10a which, spontaneously, evolved to a 1:1 mixture of ...
“…First of all, high level calculations (STO-3G, 6-31G, and 6-31G*) have indicated a higher positive charge on the primary carbon of the 1-ethenylcyclopropyl cation 120 , whereas MINDO/3, AM1, and 6-31G* have predicted a higher positive charge on the tertiary center of the 1,1-dimethylallyl cation 121 10c. However, calculations performed over both corresponding π-allylpalladium complexes 120 ‘ and 121 ‘ having two molecules of PH 3 as ligands, using the semi-emperical method PM3 (tm) and refining the results with ab initio calculations with 3-21G* basis, have suggested that in the complex 120 ‘ palladium is closer to the cyclopropyl carbon C 1 than to the other allylic terminus C 2 ‘ (2.14 and 2.29 Å, respectively), while in the complex 121 ‘ the trend is reversed with the transition metal being closer to the primary carbon C 3 than to the tertiary carbon C 1 (2.20 and 2.31 Å, respectively) (Scheme ). 10c,, 36 …”
Section: 1 Substitution By Soft Nucleophilesmentioning
The Brandi‐Guarna reaction is a group of reactions for forming tetrahydropyridone derivatives. It involves the initial 1,3‐dipolar cycloaddition of nitrones and alkylidenecyclopropanes to yield the mixtures of isoxazolidine regioisomers with spiro‐fused cyclopropane rings located on the C‐4 and C‐5, respectively, and the thermolysis of the 1,3‐dipolar cycloadducts via a unique hemolytic cleavage of the weak nitrogen‐oxygen bond accompanying by the subsequent opening of the adjacent cyclopropane ring and closure of the diradical to afford tetrahydropyridones;
N
‐bridgehead bicyclic ketones are ultimately formed from the cyclic nitrones. In addition, the analogous reactions involving the
1,3‐Dipolar
Cycloaddition
of alkylidenecyclopropanes and nitrile oxides followed by similar ring enlargement to form
aza
‐heterocycles are also referred to as the Brandi reaction.
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