- Stereocontrolled Total Synthesis of (?)-Stemaphylline
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Homologation of readily available α-boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (Cl?) are employed. By performing a solvent switch from Et2O to CHCl3, efficient 1,2-metalate rearrangement of the intermediate boronate occurs with both halide and ester leaving groups. The methodology was used in the total synthesis of the Stemona alkaloid (?)-stemaphylline in just 11 steps (longest linear sequence), with high stereocontrol (>20:1 d.r.) and 11 % overall yield. The synthesis also features a late-stage lithiation–borylation reaction with a tertiary amine containing carbenoid.
- Varela, Ana,Garve, Lennart K. B.,Leonori, Daniele,Aggarwal, Varinder K.
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- A convenient entry to indolizidine alkaloids using Kharasch type reactions
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A convenient entry to indolizidine alkaloids based on a free-radical atom transfer reaction (ATRA or Kharasch reaction) as the key step is reported. The strategy is based on the free radical reaction between ethyl iodoacetate and an l-proline derivative serving as a radical acceptor. The key intermediate obtained after the radical reaction is used for the synthesis of indolizidine (-)-167B and of an advanced intermediate for the synthesis of (+)-dendroprimine.
- Morales-Chamorro, Maricela,Meza-González, Jorge,Cordero-Vargas, Alejandro
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- A highly efficient conversion of a simple derivative of the amino acid proline into a nearly enantiomerically pure n-protected allyl amine: Use of thionyl chloride to promote the Peterson olefination
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A novel two-step conversion of an N-Boc methyl ester of the natural amino acid proline into highly enantioenriched N-Boc 2-vinylpyrrolidine is described. Key steps include (1) an SNi displacement of a methoxy group of the DIBAL-H adduct of the starting ester by the TMSCH2 group of the corresponding Grignard reagent, and (2) the use of thionyl chloride to promote the Peterson olefination of the resulting -hydroxysilane bearing a stereocenter adjacent to the alcohol function. The overall transformation occurs with remarkable facility and virtually without loss of stereochemical integrity under mild conditions. The use of thionyl chloride in the elimination step is necessary because both basic and acidic conditions are incompatible with the Boc protecting group. In stark contrast to the standard Wittig olefination of the corresponding N-protected amino aldehyde, where 8-10% racemization (80-84% ee) occurs, only about 1% racemization (98% ee) was observed in this novel process. Georg Thieme Verlag Stuttgart · New York.
- Wei, Guoqing,Cohen, Theodore
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- Construction of chiral 1,2-cycloalkanopyrrolidines from L-proline using ring closing metathesis (RCM)
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An efficient synthetic method for the preparation of optically active pyrroloazocine, pyrroloazepine, quinolizidine, indolizidine using ring closing olefin metathesis (RCM) is described.
- Arisawa,Takahashi,Takezawa,Yamaguchi,Torisawa,Nishida,Nakagawa
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- A metallocarbenoid approach to the formation of spirocyclic ammonium ylides leading to the preparation of medium-sized azacane rings
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A novel approach to azacyclooctene and azacyclononene containing substrates has been achieved via the intermediacy of a spirocyclic ammonium ylide derived from the diazodecomposition of a tethered α-diazoester moiety.
- Wright, Dennis L.,Weekly, R. Matt,Groff, Royce,McMills, Mark C.
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Read Online
- Chiron approach to (-)-deoxocuscohygrine
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A facile chiron approach to C2-symmetrical (-)-deoxocuscohygrine is described by using cross metathesis as the key step.
- Jagadeesh, Yerri,Reddy, Kotha Kapu Sridhar,Rao, Batchu Venkateswara
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Read Online
- BIARYL DERIVATIVES AS YAP/TAZ-TEAD PROTEIN-PROTEIN INTERACTION INHIBITORS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; (I) a method for manufacturing said compound, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition comprising said compound.
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(2021/09/26)
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- A One-Pot Iodo-Cyclization/Transition Metal-Catalyzed Cross-Coupling Sequence: Synthesis of Substituted Oxazolidin-2-ones from N-Boc-allylamines
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A one-pot iodo-cyclization/transition metal-catalyzed cross-coupling sequence is reported to access various C5-functionalized oxazolidin-2-ones from unsaturated N-Boc-allylamines. Depending on the Grignard reagents used for the cross-coupling, e.g., aryl- or cyclopropylmagnesium bromide, a cobalt or copper catalyst has to be used to obtain the functionalized oxazolidin-2-ones in good yields.
- Chaumont-Olive, Pauline,Cossy, Janine
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supporting information
(2020/05/14)
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- Enantioselective Aza-Heck Cyclizations of N-(Tosyloxy)carbamates: Synthesis of Pyrrolidines and Piperidines
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Pd(0)-systems modified with SPINOL-derived phosphoramidate ligands promote highly enantioselective aza-Heck cyclizations of alkenyl N-(tosyloxy)carbamates. The method provides versatile access to challenging N-heterocycles and represents the broadest scope enantioselective aza-Heck protocol developed to date.
- Ma, Xiaofeng,Hazelden, Ian R.,Langer, Thomas,Munday, Rachel H.,Bower, John F.
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p. 3356 - 3360
(2019/03/07)
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- Synthesis of γ-Lactams by Mild, o-Benzoquinone-Induced Oxidation of Pyrrolidines Containing Oxidation-Sensitive Functional Groups
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The late-stage oxidation of substituted pyrrolidines offers good flexibility for the construction of γ-lactam libraries, and especially in recent years the methods for functionalization of pyrrolidine have been available. We reported a new strategy for oxidation of pyrrolidines to γ-lactams: reaction of pyrrolidine with an o-benzoquinone gives an N,O-acetal by direct oxidation of the α-C-H bond of the pyrrolidine ring, and then the N,O-acetal is further oxidized by the o-benzoquinone to the γ-lactam. Because the first oxidation occurs selectively at the α-C-H of the pyrrolidine ring, oxidation-sensitive functional groups (allyl-, vinyl-, hydroxyl-, and amino groups) on pyrrolidine ring are unaffected. The synthetic utility of this novel method was demonstrated by the facile syntheses of (S)-vigabatrin and two analogues.
- Rong, Hao-Jie,Cheng, Yong-Feng,Liu, Fan-Fan,Ren, Shu-Jian,Qu, Jin
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p. 532 - 540
(2017/04/26)
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- Synthesis of chiral, enantiopure allylic amines by the Julia olefination of α-amino esters
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The four-step conversion of a series of N-Boc-protected L-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the reductive elimination of related α-acetoxysulfones. The overall transformation takes place under mild conditions, with good yields, and without loss of stereochemical integrity, being in this respect superior to the conventional Julia reaction of α-amino aldehydes.
- Benedetti, Fabio,Berti, Federico,Fanfoni, Lidia,Garbo, Michele,Regini, Giorgia,Felluga, Fulvia
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- Enantioselective synthesis of pyrrolidine-, Piperidine-, and azepane-type N -heterocycles with α-alkenyl substitution: The CpRu-catalyzed dehydrative intramolecular N -allylation approach
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A cationic CpRu complex of chiral picolinic acid derivatives [(R)- or (S)-Cl-Naph-PyCOOCH2CH=CH2] catalyzes asymmetric intramolecular dehydrative N-allylation of N-substituted ω-amino- and -aminocarbonyl allylic alcohols with a substrate/catalyst ratio of up to 2000 to give α-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1. The wide range of applicable N-substitutions, including Boc, Cbz, Ac, Bz, acryloyl, crotonoyl, formyl, and Ts, significantly facilitates further manipulation toward natural product synthesis.
- Seki, Tomoaki,Tanaka, Shinji,Kitamura, Masato
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supporting information; experimental part
p. 608 - 611
(2012/03/10)
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- A common approach to pyrrolizidine and indolizidine alkaloids; Formal synthesis of (-)-isoretronecanol, (-)-trachelanthamidine and an approach to the synthesis of (-)-5-epitashiromine and (-)-tashiromine
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A common and short stereoselective route is described for the formal synthesis of pyrrolizidine alkaloids, (-)-isoretronecanol and (-)-trachelanthamidine. An approach to the synthesis of indolizidine alkaloids (-)-5-epitashiromine and (-)-tashiromine utilizing ring closing metathesis is also described starting from commercially available and inexpensive l-proline.
- Reddy, Kotha Kapu Sridhar,Rao, Batchu Venkateswara,Raju, Sagi Satyanarayana
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experimental part
p. 662 - 668
(2011/07/08)
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- Delayed fibril formation of amylin(20-29) by incorporation of alkene dipeptidosulfonamide isosteres obtained by solid phase olefin cross metathesis
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The synthesis of a new peptidomimetic structure, the alkene dipeptidosulfonamide isostere, is described. The synthesis is based on a cross metathesis reaction between two allylic building blocks, both in solution and on the solid phase. This method was also applicable to the solid phase synthesis of alkene dipeptide isosteres. Derivatives of amylin(20-29) containing the alkene dipeptidosulfonamide isostere as well as the alkene dipeptide isostere were successfully synthesized using the solid phase cross metathesis method. Investigation of relations between structure and fibril formation of these amylin(20-29) derivatives showed retardation of fibril formation and altered secondary structures, compared to native amylin(20-29).
- Brouwer, Arwin J.,Elgersma, Ronald C.,Jagodzinska, Monika,Rijkers, Dirk T.S.,Liskamp, Rob M.J.
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- Copper mediated scalemic organolithium reagents in alkaloid syntheses
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Scalemic 2-pyrrolidinylcuprates generated via asymmetric deprotonation of N-Boc-pyrrolidine followed by treatment with THF soluble CuCN·2LiCl react with ω-functionalized vinyl halides to afford 2-alkenyl-N-Boc- pyrrolidines. N-Boc deprotection and cyclization via intramolecular N-alkylation generates the pyrrolizidine or indolizidine skeletons. Subsequent functional group manipulation affords enantioenriched (+)-heliotridane, (+)-isoretronecanol, a formal synthesis of (+)-laburnine, (+)-(R)-2,3,5,7a- tetrahydro-1H-pyrrolizine, (R)-1,2,3,5,6,8a-hexahydroindolizine, (+)-ent-δ-coniceine, (+)-tashiromine and (+)-5-epitashiromine.
- Dieter, R. Karl,Chen, Ningyi,Watson, Rhett T.
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p. 3221 - 3230
(2007/10/03)
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- FUSED BENZENE DERIVATIVE AND USE
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The present invention provides a compound represented by the general formula: [wherein Ring A represents an optionally substituted 5- to 8-membered ring, Ring B represents a further optionally substituted 4- to 10-membered ring, Ring C represents a further optionally substituted benzene ring, X1 represents carbon atom, X2 represents a carbon atom, an oxygen atom, etc., W represents a nitrogen atom, etc., Y11 represents a group represented by the formula CR2R3' (wherein R2 represents a hydrogen atom, a cyano group, a nitro group, etc., and R3' represents a hydrogen atom, a cyano group, a nitro group, etc., respectively), Y21 represents a group represented by the formula CR4R5' (wherein R4 represents a hydrogen atom, a cyano group, a nitro group, etc., and R5' represents a hydrogen atom, a cyano group, a nitro group, etc., respectively), etc., and R1 represents an electron-withdrawing group, respectively. The formula represents a single bond or a double bond] or a salt thereof, which is useful as an androgen receptor modulator.
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- Pharmaceutical compositions and methods for use
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The present invention relates to aryl olefinic azacyclic compounds and aryl acetylenic azacyclic compounds, including pyridyl olefinic cycloalkylamines and pyridyl acetylenic cycloalkylamines. The present invention also relates to prodrug derivatives of the compounds of the present invention.
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- Reactivity and Enantioselectivity in the Reactions of Scalemic Stereogenic α-(N-Carbamoyl)alkylcuprates
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Stereogenic 2-(N-carbamoyl)pyrrolidinylcuprates prepared from scalemic (i.e., enantioenriched) N-Boc-2-lithiopyrrolidine and THF soluble CuCN·2LiCl react with vinyl iodides, vinyl triflates, β-iodo-α,β-enoates, propargyl mesylates, and allyl bromide to afford the substitution products with excellent enantioselectivity. Excellent enantiomeric ratios are obtained in the conjugate addition reactions with methyl vinyl ketone while low enantiomeric ratios can be achieved with acrylate esters using HMPA/TMSCl activation. Enantiomeric ratios vary with substrate substitution patterns and the observed enantioselectivities appear to be more a function of cuprate-electrophile reactivities than of the reaction type (e.g., substitution, conjugate addition). Low enantiomeric ratios are obtained with the α-(N-carbamoyl)benzylcuprates. The lithium-copper transmetalation and cuprate vinylation reactions proceed with retention of configuration.
- Dieter, R. Karl,Oba, Gabriel,Chandupatla, Kishan R.,Topping, Chris M.,Lu, Kai,Watson, Rhett T.
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p. 3076 - 3086
(2007/10/03)
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- Pharmaceutical compositions and methods for use
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The present invention relates to aryl olefinic azacyclic compounds and aryl acetylenic azacyclic compounds, including pyridyl olefinic cycloalkylamines and pyridyl acetylenic cycloalkylamines. The present invention also relates to prodrug derivatives of the compounds of the present invention.
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- Asymmetric syntheses of N-Boc 2-substituted pyrrolidines and piperidines by intramolecular cyclization
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Asymmetric lithiation-substitutions by n-BuLi/(-)-sparteine with the N- Boc-N-(3-halopropyl)allylamines 1-4 provide the N-Boc-2-alkenylpyrrolidines (S)-5, (S)-6, and (S)-7 in yields of 3193% with enantiomeric ratios (ers) from 65:35 to 90:10. These reactions are shown to involve an initial asymmetric deprotonation, but the enantiodetermining step is a subsequent asymmetric cyclization under the influence of the chiral ligand. Extension to formation of a piperidine is illustrated by reaction of N-Boc-(4- chlorobutyl)cinnamylamine (9) to afford (S)-N-Boc-2-(trans-β- styryl)piperidine ((S)-10) in 68% yield with an enantiomeric ratio (er) of 84:16. Analogous reactions with epoxide ring openings of N-Boc-N- (oxaalkenyl)benzylamines 11 and 12 afford the corresponding N-Boc-2-phenyl- 3-(hydroxymethyl)pyrrolidine (13) in 67% yield with a diastereomeric ratio (dr) of 50:50 and ers of 97:3 and 95:5 and the corresponding N-Boc-2-phenyl- 3-(hydroxymethyl)piperidine (14) in 29% yield with a dr of 86:14 and ers of 81:19 and 86:14.
- Serino,Stehle,Yong Sun Park,Florio,Beak
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p. 1160 - 1165
(2007/10/03)
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- Synthesis of Chiral Bicyclic Lactams Using Ring Closure Metathesis: Synthesis of (-)-Coniceine and (S)-Pyrrolam A
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Chiral (-)-coniceine and (S)-pyrrolam A were synthesized from dienes prepared from L-proline by ring closure metathesis.
- Arisawa, Mitsuhiro,Takezawa, Emiko,Nishida, Atsushi,Mori, Miwako,Nakagawa, Masako
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p. 1179 - 1180
(2007/10/03)
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- Synthesis of tricyclic nitrogen-containing heterocycles by palladium-catalyzed cyclization of 2-alkenyl-N-(o-iodobenzoyl)-and 2-alkenyl-N-(o-iodophenylacetyl)-pyrrolidines
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The palladium-catalyzed cyclization of the 2-alkenyl-N-(o-iodobenzoyl)-and 2-alkenyl-N-(o-iodophenylacetyl)pyrrolidines gave the tricyclic nitrogen-containing heterocycles.
- Ikeda, Masazumi,Akamatsu, Susumu,Kugo, Yasuhiro,Sato, Tatsunori
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p. 155 - 158
(2007/10/02)
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- Synthetic studies towards proline amide isosteres, potentially useful molecules for biological investigations
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2-Ethenylpyrrolidine derivative 8b was prepared from N-protected proline ethyl ester 6b. Bromofluorination of 8b wth NBS-Bu4NF/2HF gave a 1:1 regioisomeric mixture, 9b and 10b (X = Br). Dehydrobromination of 9b and 10b with t-BuOK produced a fluoroolefin 11 and a proline amide isostere model 12, respectively. Deprotection of the Z group in 12 was attempted by treatment with CF3COOH. Although formation of the useful molecule is pseudopeptide synthesis, 13, was observed as checked by NMR spectra, it seemed to decompose slowly during purification procedure to give a mixture of fluorine-free compounds.
- Takeuchi,Yamada,Suzuki,Koizumi
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p. 225 - 232
(2007/10/02)
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