Asymmetric synthesis of polycyclic 3-fluoroalkylproline derivatives by intramolecular azomethine ylide cycloaddition

Rabasa‐Alcañiz, Fernando; Hammerl, Daniel; Sánchez-Merino, Anabel; Tejero, Tomás; Merino, Pedro; Fustero, Santos; Pozo, Carlos del

doi:10.1039/c9qo00525k

Cited by 5 publications

(7 citation statements)

References 69 publications

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“…[1,2] A vast number of publications have been published since several years ago dealing with the insights of this cycloaddition due to the versatile organic molecules obtained through this methodology. [3][4][5][6][7][8][9][10][11][12] More interesting is the asymmetric version of this reaction, which allows to obtain up to 4 stereogenic centers in one reaction step in a selective manner, classically achieved by the use of metal-or organocatalysis. [13][14][15][16][17][18][19][20][21] The origin of the exo/endo selectivity in the catalytic asymmetric synthesis of pyrrolidines by 1,3-dipolar cycloaddition of azomethine ylides has been brilliantly rationalized and reported recently.…”

Section: Introductionmentioning

confidence: 99%

The Crucial Role of S‐oxidation State on the Selectivity and Reaction Rate of the 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Homochiral Thiazolines

2021

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The novel enantiopure synthesis of protected proline-cysteine analogs by means of 1,3-dipolar cycloaddition of homochiral thiazolines and azomethine ylides is described. The important role of the oxidation state of the sulfur atom of the dipolarophile in such reaction is demonstrated affecting strongly the regioselectivity and reactivity of the 1,3-dipolar cycloaddition. Mono-oxidized sulfur atom (sulfoxide group) and di-oxidized (sulfone group) led to 2,3 regio-addition whereas reactions starting from non-oxidized sulfur atom resulted in the 2,4 addition. Besides, sulfur oxidized thiazolines reacted smoothly upon heating in an organic solvent media but the non-oxidized sulfur thiazoline required metal catalysis. Diastereofacial selectivity was observed to be independent of the oxidation state of the sulfur atom but controlled by the bulky tert-butyl group at the thiazoline ring. The highly substituted and functionalized enantiopure pyrrolidine-thiazolidine bicyclic compounds are considered as novel (homo)cysteine-proline analogs with important properties to discover.

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Section: Introductionmentioning

confidence: 99%

The Crucial Role of S‐oxidation State on the Selectivity and Reaction Rate of the 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Homochiral Thiazolines

2021

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“…There is a rich portfolio of fluorine-containing proline analogues that have been developed to date (Figure 1B): fluorinated [6][7][8][9][10][11][12], trifluoromethylated [13][14][15][16][17][18][19][20][21][22][23], chimeric [16,19,[24][25][26][27][28][29], conformationally restricted [30][31][32][33] having variations in the ring size [34][35][36][37][38][39], non-α [40][41][42][43][44], and other analogues [45][46][47][48]. The fluorine-containing functional groups are usually chemically inert under most biologically relevant conditions.…”

Section: Introductionmentioning

confidence: 99%

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Kubyshkin¹

2020

Beilstein J. Org. Chem.

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Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of the interplay between the substituents and the main chain groups of the amino acid residue. This study aims to showcase the polarity-related effects that arise from the interaction between the functional groups in molecular models. Properties such as conformation, acid–base transition, and amide-bond isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pK a values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors C4-exo conformation of the pyrrolidine ring.

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“…The third employs a fluorinated dipolarophile, difluorinated allylic alcohol that reacted with the AMY generated from sarcosine . The last one, recently described by our research group, involved the reaction of benzaldehydes bearing a trifluoromethyl alkene in ortho position with an azomethine ylide precursor derived from chiral 2‐amino indanol, giving rise to fluorinated proline derivatives with excellent levels of diastereoselectivity …”

Section: Introductionmentioning

confidence: 99%

Intramolecular Cycloaddition Azomethine Ylides and α‐(Trifluoromethyl)styrenes as Dipolarophiles

et al. 2019

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The synthesis of polycyclic fluorinated tertiary amines has been accomplished by means of an intramolecular azomethine ylide cycloaddition with fluorinated dipolarophiles. Thus, tri‐ and tetracyclic fused pyrrolidines bearing a quaternary trifluoromethyl group were obtained in moderated yields in a stereoselective manner. This is one of the few examples reported in the literature of intramolecular 1,3‐dipolar cycloaddition of azomethine ylides with fluorinated dipolarophiles. Initial attempts of the asymmetric version of the process have been performed, but low levels of diastereoselectivity were achieved.

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Asymmetric synthesis of polycyclic 3-fluoroalkylproline derivatives by intramolecular azomethine ylide cycloaddition

Abstract: The asymmetric intramolecular dipolar cycloaddition of azomethine ylides was developed for fluorinated dipolarophiles, being the RF group crucial for selectivity.

Cited by 5 publications

References 69 publications

The Crucial Role of S‐oxidation State on the Selectivity and Reaction Rate of the 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Homochiral Thiazolines

The Crucial Role of S‐oxidation State on the Selectivity and Reaction Rate of the 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Homochiral Thiazolines

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

Intramolecular Cycloaddition Azomethine Ylides and α‐(Trifluoromethyl)styrenes as Dipolarophiles

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