Diasteroselective Cyclizations with Enantiopure Malonaldehyde Monocycloacetals (original) (raw)
The Journal of Organic Chemistry, 1997
The factors which effect the stereoselective formation of trans-1-alkyl-2-benzyl-3-(alkoxycarbonyl)-1,2,3,4-tetrahydro-carbolines and trans-3-(alkoxycarbonyl)-1-alkyl-2-(diphenylmethyl)-1,2,3,4tetrahydro-carbolines by the Pictet-Spengler cyclization were examined by heating tryptophan derivatives with aldehydes of varied steric bulk under aprotic and acidic conditions, followed by determination of the ratio of cis to trans diastereomers so formed. The presence of a benzyl group at the N b-nitrogen atom alters the diastereochemical outcome of this condensation to provide 100% trans stereoselectivity when the cyclization is carried out with cyclohexanecarboxaldehyde. Furthermore, when N b-(diphenylmethyl)tryptophan isopropyl ester was condensed with aldehydes of any size, trans diastereomers are formed with 100% stereoselectively. The trans N b-substituted diastereomers are thermodynamically more stable than their cis congeners as shown by equilibration experiments in TFA. Conversion of the cis diastereomers into the more stable trans diastereomers is believed to occur under acidic conditions by cleavage of the carbon (C-1)-nitrogen (N-2) bond with complete retention of configuration at the C-3 stereocenter. Evidence from deuterium exchange experiments as well as optical rotations support this model for epimerization. In addition, when cis diastereomer 66a was allowed to stir in CF 3 COOD, the trans isomer 66b was isolated in 90% yield, while treatment of cis 66a with CF 3 COOH/NaBH 4 provided a mixture of the ring cleaved [scission across C(1)-N(2) bond] product 67 and the trans isomer 66b. Treatment of 66b (control experiment) with NaBH 4 /CF 3 COOH under the same conditions returned only starting trans 66b in excellent yield. The Pictet-Spengler reaction of substrates with sufficiently large substituents, followed by treatment with acid, permits the 100% enantiospecific formation of trans-1,3disubstituted-1,2,3,4-tetrahydro-carbolines for alkaloid total synthesis.
ChemInform Abstract: Enantioselective Synthesis of the Four Catechin Diastereomer Derivatives
Cheminform, 2010
An enantioselective total synthesis of (+)-cassiol is reported. The complex derived from Pd 2 (pmdba) 3 and enantiopure t-BuPHOX ligand catalyzes enantioconvergent decarboxylative alkylation to generate the quaternary carbon stereocenter at an early stage. The overall synthetic strategy involves a convergent late-stage coupling of two fragments. The synthesis features a longest linear sequence of eight steps. In 1988, Fukaya reported the isolation of (-)-cassioside (2) (Figure ) from the stem bark of Cinnamonum cassia Blume. 1 This glycosylated sesquiterpenoid exhibited potent antiulcerogenic activity in rats. The aglycon of (-)-cassioside, (+)-cassiol (1), demonstrated even stronger antiulcerogenic activity than observed with the glycosylated precursor. Given this useful biological property, (+)-cassiol (1) has attracted a great deal of attention from synthetic laboratories. 2 Herein, we report an expedient enantioselective synthesis of (+)-cassiol with a longest linear sequence of eight steps. A principal challenge to the synthesis of (+)-cassiol (1) is the presence of an all-carbon quaternary stereocenter. 3 Several total syntheses of cassiol have been reported; however, most have relied on chiral pool starting materials, or chiral auxiliaries. 4,5 Few of these syntheses addressed the challenge of catalytic enantioselective quaternary carbon stereocenter generation. For example, successful catalytic enantioselective approaches have utilized Diels-Alder, 6 intramolecular alkylidine insertion, 7 and enzymatic 8 reactions to form the quaternary carbon. We envisioned a different strategy 9 wherein the key quaternary stereocenter would be installed through an enantioselective Pd-catalyzed allylic alkylation method recently developed in our laboratories. 10 Our plan consisted of coupling two complex pieces (3 and 5 , Scheme 1) in the final step of the synthesis through a Stork-Danheiser-type addition/ rearrangement reaction. 11 Precursors 3 and 5 would in turn be available from known vinylogous thioester 4 12 and primary alcohol 6 ,13 respectively.
Diastereocontrolled multicomponent pathway to 3,4-heterocycle-annulated tetrahydro-β-carbolines
Tetrahedron: Asymmetry, 2005
A diastereoselective synthesis, using the Yonemitsu-type trimolecular condensation as the key step, has been used for the preparation of 3,4-heterocycle(furanone-, pyrrolidinone-and pyranone-) annulated tetrahydro-b-carbolines. The chirality of D D-glyceraldehyde or that of the GarnerÕs aldehyde ensured a high and predictable diastereocontrol of the additional newly created stereocentres.
Journal of the Brazilian Chemical Society, 2013
Uma nova síntese dos enantiômeros (-)-(R)-e (+)-(S)-angustureina, assim como do racemato (±)-angustureina, a partir de um b-amino éster racêmico controlado por resolução cinética enzimática, é descrita. Esta estratégia permitiu, incorporar tanto o esqueleto básico como controlar o único estereocentro no carbono 2 de ambos enantiômeros. A sequência em cinco etapas a partir dos b-amino éster e o carboxilato de sódio quirais para a síntese de ambos os alcalóides foi feita com um rendimento global de 80 e 44%, respectivamente, e excelentes excessos enantiomericos (95 e 96%, respectivamente) e sem nenhuma proteção de grupos funcionais em todas as etapas. The present study describes a new synthesis of (-)-(R)-and (+)-(S)-angustureine enantiomers, as well as of racemate (±)-angustureine, from a racemic b-amino ester controlled by kinetic enzymatic resolution. This strategy allowed to incorporate the basic skeleton, as well as to control the single stereocenter at carbon 2 in both enantiomers. The sequence of five steps starting from the chiral b-amino ester and sodium carboxylate for the synthesis of both alkaloids achieved overall yields of 80 and 44%, respectively, and produced excellent enantiomeric excesses (95 and 96%, respectively) with no protection of functional groups in any of the steps.
A Highly Diastereoselective Synthesis of New Polyhydroxy 2-Aminonorbornanecarboxylic Acids
The Journal of Organic Chemistry, 2001
Our recent research is directed toward the synthesis of -heterosubstituted carbocyclic amino acids [1][2][3][4] in which the skeleton of natural amino acid is included. For this reason and for their rigidity, they appear to be interesting compounds as biological targets. In particular, the 2-aminonorbornanecarboxylic acid derivatives, because of the bulkiness and apolarity of the ring and the metabolic stability, are characterized by different biological activities. As evidenced by recent literature, a new and very promising research field is related to the preparation of hydroxy-and polyhydroxycarbocyclic amino acids, which are considered mimetic of carbohydrates but are characterized by a greater metabolic stability. 4,6 In continuing our research in this area, we now report on the highly diastereoselective synthesis of 2-amino-3,6-dihydroxynorbornanecarboxylic acid 14 and of 2-amino-3,5,6-trihydroxynorbornanecarboxylic acids 15-18. Our purpose in the synthesis of the polyhydroxylated norbornanecarboxylic acid derivatives is related to the possibility to change the polarity of this nucleus and their biological properties. As known, in many cases, polar substituents are responsible for the interactions between the substrate and the enzymatic receptor and their spatial arrangement is determinant to realize those interactions. So, the preparation of compounds 14-18 having several hydroxy groups in a specific position and in a controlled spatial arrangement represents an important goal. The key starting materials for the preparation of these compounds are the exo-and endo-2-amino-3-hydroxynorbornenecarboxylic acid derivatives 3 and 4, including the serine skeleton, which were synthesized recently in our laboratory. 3 The cycloaddition reaction between oxazolone (Z)-1 and cyclopentadiene (2) was carried out using litium perchlorate as the catalyst, giving a mixture of cycloadducts exo-3 and endo-4. After the addition of anhydrous ethanol to the crude reaction mixture, cycloadducts 3 and 4 were transformed into the corresponding esters exo-5 and endo-6 (70:30 ratio), which were isolated in a 70% overall yield (Scheme 1). Esters 5 and 6 were the key starting materials for the preparation of the 5,6-dihydroxy derivatives in which the cis or trans relationship between the two hydroxy groups exists (Scheme 1). Treatment of ester exo-5 with a catalytic amount of osmium tetraoxide in the presence of an excess of N-methylmorpholine N-oxide in a mixture of acetone/water allowed the formation of the cis-dihydroxy derivative exo-7, as a single diastereoisomer, in 74% yield. The derivative endo-8 was isolated in 80% yield when starting from endo-6 and operating under the same conditions.
Angewandte Chemie International Edition, 2013
Domino and cascade reactions that give access to multiple CÀ C bonds and multiple contiguous stereocenters with high chemo-and stereoselectivity are important for chemical synthesis and are performed in nature by multi-enzymatic pathways. [1] Cascade reactions enable the synthesis of complex molecules in a minimal number of synthetic steps and with lower amounts of waste and solvents (green chemistry). [2] Catalytic asymmetric cascade transformations are most commonly catalyzed by single metal complexes. However, recently the use of organic catalysts has resulted in important advances in this research field. The concept of using a transition metal catalyst together with a metal-free catalyst in one flask ("organo/metal cooperative catalysis") is gaining increasing interest. [6][7] The reactivity and advantages of both metal and organic catalyst systems are combined and thereby can result in unique reactivity. However, this research field is still in its infancy with challenges such as incompatibility between the transition metal and organocatalyst (e.g. catalyst inhibition and different optimal reaction conditions). In 2006, we disclosed the merging of transition metal and aminocatalysis for the aallylic alkylation of aldehydes. [6a] Since disclosure of this synergistic catalysis strategy there has been increasing number of reports on the development of the concept of organo/metal cooperative catalysis. [6][7] The construction of quaternary carbon stereocenters with high enantioselectivity is important and challenging goal in organic synthesis. In this context, new methods for the catalytic construction of polysubstituted carbocycles with contiguous stereocenters, including an all-carbon stereocen-ter, are desirable but difficult to achieve. Based on our previous research on organo/metal cooperative catalysis, [6] we envisioned a novel dynamic catalytic asymmetric Michael/aallylic alkylation cascade reaction between compounds 1 and enals 2 mediated by a combination of Pd and chiral amine 5 catalysts (Scheme 1). Thus, initial reversible conjugate addition via an iminium intermediate I would give the corresponding enamine intermediate II, which upon hydrolysis would provide Michael adduct 3. This process is reversible, however, oxidative addition of the Pd catalyst to intermediate II would generate p-allyl intermediate III, ready for intramolecular nucleophilic stereoselective attack by its enamine moiety. Subsequent CÀC bond formation, hydrolysis, and protonation would deliver polysubstituted carbocycles 4 as well as regenerate the amine and Pd catalysts. However, there are a few main challenges to address. For example, chemoselectivity issues, as substrates 1 could undergo a Pd-catalyzed intermolecular Tsuji-Trost reaction, polymerization, or Nalkylation with amine 5 instead of the desired pathway. We also know from our previous research that the Pd/amine cocatalyzed conjugate additions can deliver racemic Michael products. [6g-i] Thus, the reaction via enamine intermediate II has to occur at a higher rate compared to the that via IIa. Moreover, the equilibration between ent-3 and 3 (racemization) must be faster than the carbocyclization for this reaction to become a dynamic kinetic transformation (DYKAT). If no racemization occurred, the overall process would have a maximum theoretical yield of 50 % (kinetic resolution). With respect to the construction of carbocycles 4 (E ¼ 6 E 1 ), the cascade transformation is also complex and difficult to control as Michael adducts (3 having 2 stereocenters) are formed as four stereoisomers. Herein, we disclose a novel highly enantioselective dynamic Michael/a-allylic alkylation cascade transformation that gives polysubstituted cyclopentanes and cyclohexanes, which have a quaternary carbon stereocenter, in high yields with excellent enantiomeric ratios (99.5:0.5! 99:0.5 e.r.).
Easy preparation of enantiopure C2-symmetrical aminoalcohols derived from m-xylylene diamine
Tetrahedron: Asymmetry, 1994
WE prepared by coadmsahon of i.wphlhahlehyde with chiral amino alcohols of a-amino esters in three differem ways depending on the substihltion pa~tem. These methti are: for N-rubstibted amino alcohols. by reduction of the cpimeric mixtures of 1,3.oxazolidines formed in the condensation proxss; for unsubstituted ones, by reduction of the cm~~spwdiig hydmxy imillcs, follwcd by N-alkylatiin; and for the imiics cbtaincd in the condcnsstion with amino esters, by sequential reduction and reaction with methylmagnesium iodide. Chill aminoalcohols have been extensively used as modifiers of organometallic reagents for asymmetric reactions,'.3 and as important materials in the preparation of azacrown derivatives for chiral recognition.4vS Cue of the best rational approaches to the conuol of the stereoselectivity and the prediction of enamioselectivity is ba3et-l on the use as ligands molecules possessing only symmetry elements of pure rotation, and the most popular class of such a structures are those having ~~-syrnme~~y.6-7 We present here a facile synthesis of polydentate Cz-symmeaioal amino alcohols @A-J) that can be wed as modifiers of organometallics in catalytic additions and in other type of reactions.8 Our general method of synthesis is based on the transformation of the condensation products of isophthaldehyde with, readily available, amino alcohols or a-amino esterS from chiral pool,9 and is summarized in the scheme I. We have explored three different ways for the synthesis, depending on the substitution type on the nitrogen m the starting materials, and on the nvailabiity of the amino derivative used in the initial condensation. The most direct access tc compounds 6 is represented by the two-step synthesis of 6A-C from isophthaldehyde in 72.86% total chemical yield. It has been previously described that the condensation of aldehydes with N-alkyl substituted ohiral aminoalcohols leads to epimeric mixtores of oxazoliincs.l0 Following this methodology, the reaction of isophthaldehyde with the commercially available (+)-(lS,2R)-ephedrine, or Ihe easily prepared (t)-(lSIR)-N-ethyl-UC knzylnorephedrine yields an epimeric (cn 9O:lO) mixture of bh-1,3-oxazolidmes IA-C. The diastereomeric constitution at carbon-2 in the heterocycle of these compounds does not constitute a major problem because they are uansfomwd into enantiomerically pure 6A-C by reduction with lithium aluminium hydride in THF. In the same way, the compound ent-6C was prepared sting from (-)-(lR,2S)-N-benzylnorh~ne. 3. M. ANDRESS et al. HO NH, I R1R.f p;3
Journal of the American Chemical Society, 2014
Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C−C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Brønsted base (BB) catalysis and the use of α′-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/ donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α′-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo-and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α′-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,βunsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.