Additional Stereogenic Center Research Articles

Highly Diastereo‐ and Enantioselective Aldol Reactions in Common Organic Solvents Using N‐Arylprolinamides as Organocatalysts with Enhanced Acidity

AbstractA broad set of N‐arylprolinamides 1–8 with increasing NH acidity and steric crowding has been synthesized and its catalytic activity explored for enantioselective aldol reactions. In DMF containing 10 mol‐% of TFA, all arylamides are found to catalyze the reaction between cyclohexanone and a variety of electrophilic aldehydes leading to aldols in excess of 90 % yield and >95 % enantioselectivity. The perfluorophenyl catalyst 8 is found to perform best with a broad substrate scope as compared to all other N‐arylamides 1–7. It is shown that 8 can indeed be employed in highly nonpolar as well as polar solvents including brine to afford high yields of aldols with excellent diastereo‐ as well as enantioselectivity. The results observed for 8 are amongst the best reported so far for prolinamides that do not contain additional stereogenic center(s) and hydrogen‐bonding site(s). The molecular structures of 7 and 8, determined by X‐ray crystallography and presumed to reflect the most stable conformations, reveal a notable difference in the conformations of the N‐aryl rings; the aryl ring exhibits tendency to lie coplanar with the amide functionality in the case of 7, while the perfluorophenyl ring twists almost orthogonally with respect to the plane of the amide of functionality in 8. The superior performance of the latter is attributed to, in addition to the enhanced NH acidity, the tendency of the perfluorophenyl ring to lie orthogonally to the amide group, which may facilitate a stronger binding of the electrophilic aldehyde via hydrogen bonding in the transition state.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Cyclochiral conformers of resorcin[4]arenes stabilized by hydrogen bonds

Cyclochiral resorcinarenes, that maintain their cyclochirality by means of hydrogen bonds, were synthesized by a sequence of reactions involving the Mannich reaction, removal of the N,O-acetal bridge and subsequent N-substitution with an RCO group. During this study it was found that ethyl nitroacetate is a mild and very efficient agent for N,O-acetal bridge removal. The resulting resorcinarenes 4a-j exist in cyclochiral/inherently chiral kite conformations (resembling 4-bladed propellers) that are stabilized by eight hydrogen bonds (in both solid state and solution). It is shown that the cycloisomerization process is characterized by the relatively high racemization barrier (14.6-18.5 kcal mol(-1) as determined by 2D EXSY) and thus it can be concluded that the transformation of one cycloconformer into the other requires the simultaneous rupture of all eight hydrogen bonds. For derivatives with additional stereogenic centers two cyclodiastereoisomeric conformations were detected (diastereomeric excess in the range of 72% up to >95%). The experimental results are additionally supported by AM1 semi-empirical calculations.

Synthesis of Nonracemic 3-Deoxyschweinfurthin B

Synthesis of nonracemic 3-deoxyschweinfurthin B has been accomplished through a synthetic sequence including a key cascade cyclization of an epoxy olefin. The intermediate epoxide could be prepared as a single enantiomer through an AD-mix-alpha (or AD-mix-beta) oxidation, and the stereochemistry of the epoxide has been shown to control formation of the two additional stereogenic centers created through the cyclization. Synthetic 3-deoxyschweinfurthin B was found to have potent differential activity in the National Cancer Institute's 60 cell line anticancer assay. This represents the first synthesis of the tetracyclic schweinfurthin skeleton, validating our overall synthetic strategy and providing the first schweinfurthin analogue with activity slightly greater than those of the natural products.

Synthesis and Cardiovascular Activity of Metoprolol Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and cardiovascular activity of metoprolol analogues

The synthesis of four novel analogues of metoprolol, a well-known β 1-blocker used to reduce arterial blood pressure, is described. The preparation of (2 S,2′ S)- 7, (2 R,2′ S)- 7, (2 R,2′ R)- 8, and (2 S,2′ R)- 8 was based on the reaction of racemic 2-[4-(2′-methoxyethyl)-phenoxymethyl]-oxirane ( 4) with ( R)- or ( S)-2-amino-1-butanol. Salient characteristics of analogues 7 and 8 relative to metoprolol are the incorporation of an additional stereogenic center, as well as a methyl group and a hydroxyl function on the nitrogen-containing chain. These novel derivatives present significant hypotensive and bradycardiac activity, although no blocking action toward β 1 and β 2 adrenergic receptor.

Regioselective and Enantiospecific Rhodium‐Catalyzed Allylic Alkylation Reactions Using Copper(I) Enolates: Synthesis of (‐)‐Sugiresinol Dimethyl Ether.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regioselective and enantiospecific rhodium-catalyzed allylic alkylation reactions using copper(I) enolates: synthesis of (-)-sugiresinol dimethyl ether.

The transition metal-catalyzed allylic alkylation represents a fundamentally important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a regioselective and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical allylic alcohol derivatives using copper(I) enolates to prepare beta-substituted ketones. This protocol represents a convenient asymmetric Claisen rearrangement surrogate in which alpha-substituted enolates permit the introduction of an additional stereogenic center. The synthetic utility of this transformation was highlighted in the construction of a trans-1,2-disubstituted cyclohexene and the total synthesis of (-)-sugiresinol dimethyl ether. Finally, we anticipate that copper(I) enolates may prove useful nucleophiles in related metal-catalyzed reactions.

Photochemical and thermal isomerization processes of a chiral auxiliary based donor-acceptor substituted chiroptical molecular switch: convergent synthesis, improved resolution and switching properties.

A new type of chiroptical molecular switch is presented where irradiation employing different wavelengths of light induces a reversible helix inversion of a sterically overcrowded alkene bearing a second chiral entity in the form of a stereogenic center present in a pyrrolidine unit. The additional stereogenic center in the chiral auxiliary group has a distinct influence on the switching selectivity of this system and greatly facilitates the resolution of the different diastereoisomers, which is a considerable improvement compared with previously reported systems. In addition, the pyrrolidine stereogenic center causes small energetic differences between the various states of the switch system resulting in a small but significant directional preference in the helix inversion steps.

New Results on the Stereoselective Alkylations of Malic Acid Derivatives Supported by Molecular Modeling

AbstractThe stereoselectivity of the alkylation of dialkyl malates is dependent on steric hindrance of both ester alkyl groups. It was found that the two alkyl groups have opposite effects on diastereoselectivity. Increased steric hindrance at the C(1) carboxy group increases the anti‐selectivity, whereas increased steric hindrance at the C(4) carboxy group decreases it. The results are explained by comparing the structures of the enolates, which were obtained by molecular modeling. Alkylation at C(4′) of dioxolanones, derived from benzyl‐substituted malic acids, with an additional stereogenic center on the side chain is dependent on the stereogenic centers of the ring acetal and of the side chain. Alkylation at low temperatures occurs only with cis‐dioxolanones having an (R)‐configured side‐chain stereogenic center. The corresponding trans‐dioxolanone and the cis‐dioxolanone with a (S)‐configured side‐chain stereogenic center were recovered unchanged. A rationale is presented with models of monolithiated dioxolanones obtained by ab initio calculations.

Synthesis of enantiomerically pure 2,2,3,4,5-pentasubstituted pyrrolidines by phenylsulfanyl migration.

[reaction: see text] Enantiomerically pure 2,2,3,4,5-pentasubstituted pyrrolidines can be prepared, in high overall yield, from alpha,beta-unsaturated esters. Asymmetry is introduced via a Michael addition, and additional stereogenic centers are introduced by an aldol reaction. A novel stereospecific ring-forming reaction, proceeding via a thiiranium (episulfonium) ion, yields pyrrolidines from beta-hydroxy sulfides. In this manner, 2,2,3,4,5-pentasubstituted pyrrolidines, containing three contiguous stereogenic centers around the ring, can be prepared in 44% overall yield from ethyl crotonate.

1,1′-Binaphthylazepine-based ligands for asymmetric catalysis. Part 1: Preparation and characterization of some new aminoalcohols and diamines

Starting from ( S)-1,1′-binaphthol, a series of ten novel enantiopure 1,1′-binaphthylazepine-based aminoalcohols and diamines 1a– 1j were efficiently prepared and fully characterized. These derivatives, having either only an atropisomeric bridged-binaphthyl backbone or an additional stereogenic carbon center, can be interesting ligands for asymmetric catalysis.

The role of the alpha-stereogenic center in the control of stereoselection in the reduction of alpha-alkyl-beta-hydroxy ketones: a highly diastereoselective protocol for the synthesis of 1,2-syn-2-alkyl-1,3-diols

Accurate investigations on the role played by an alpha-stereogenic center in controlling the reduction of various classes of beta-hydroxy ketones allowed us to set up a general and highly diastereoselective protocol for the synthesis of 2-alkyl-1,3-diols with 1,2-syn relationship. This methodology is based on the conversion of a beta-hydroxy ketone into the corresponding titanium alcoholate that permits us to organize the substrate in a stable and rigid structure, which stereofacially favors attacking hydride ions. The use of THF as solvent makes available a variety of hydride donors that cover a large spectrum of steric demand: the choice of the more appropriate one depends on the conformational stability of the cyclic intermediate. Excellent results are obtained also in the presence of an additional stereogenic center in the beta-position, even if it exerts a concordant or an opposite steric effect with respect to the alpha-substituent.

Studies Toward an Asymmetric Synthesis of CP-263,114 and CP-225,917

An enantioselective approach to construction of the complex framework of the CP compounds is presented. The synthesis relies on initial elaboration of the two sidechains. The "upper" appendage was asymmetrically dihydroxylated with both AD-mix reagents in order to lend flexibility to the scheme and provide the necessary handle for evolving the additional stereogenic centers. These fragments were linked to benzoic acidviaBirch reduction-alkylation and subsequent cuprate addition. A series of functionalization reactions including dissolving metal reduction, Claisen rearrangement, iodolactonization, regioselective epoxide cleavage-oxidation, and intramolecular Wadsworth-Emmons cyclization took advantage of highly efficient stereocontrol. However, this flexibility was thwarted when deprotonation of a penultimate intermediate failed to be regioselective in the proper direction.

Enantiomerically pure cyclopropylboronic esters: auxiliary- versus substrate-control

Stable, enantiomerically pure cyclopropylboronic esters are synthesized from alkynes by a hydroboration–cyclopropanation sequence. The direct hydroboration—utilizing 1,3,2-dioxaborolane 4—is most convenient, however, with more functionalized side-chains it failed to give the desired intermediates. Using the more reactive dicyclohexylborane, followed by oxidation and transesterification, is a good alternative one-pot conversion. Cyclopropanations were performed either following a Simmons–Smith protocol or with diazomethane–palladium(II) acetate. The influence on the diastereoselectivity of the auxiliary 1 is compared with the influence of an additional stereogenic center in the side-chain.

Chiral nitrogen-stabilized Fischer carbene complexes: an efficient tool in the stereocontrolled elaboration of additional stereogenic centers

Article Chiral nitrogen-stabilized Fischer carbene complexes: an efficient tool in the stereocontrolled elaboration of additional stereogenic centers was published on August 1, 1999 in the journal Pure and Applied Chemistry (volume 71, issue 8).

Selective Intermolecular Photo-[4 + 4]-cycloaddition with 2-Pyridone Mixtures. 3. Synthetic Transformations of the Trans Cross-Product (1α,2β,5β,6α)-3-Butyl-9- methoxy-3,7-diazatricyclo[4.2.2.22,5]dodeca-9,11-diene-4,8-dione

Transformations of the tricyclic product 3 derived from [4 + 4] photocycloaddition of N-butyl-2-pyridone with 4-methoxy-2-pyridone has demonstrated, for the first time, facile opening of the secondary lactam after activation of the amide nitrogen with a tert-butyl carboxylate (Boc) group. Methanolysis and lithium borohydride reduction both result in opening of the amide group under very mild conditions to give 21 and 24, respectively. Concomitant reduction of a ketone derived from hydrolysis of the enol ether sets an additional stereogenic center in 24 with complete stereogenic control. These reactions illustrate the synthetic potential of the 2-pyridone photocycloaddition products, generating a cyclooctene as a single isomer, with functionality at seven carbons and five stereogenic centers.

Total Synthesis of Spinosyn A. 1. Enantioselective Construction of a Key Tricyclic Intermediate by a Multiple Configurational Inversion Scheme

The condensation of (+)-7,7-dimethoxynorbornen-2-one with the cerium reagent derived from enantiopure bromide (+)-11 gives rise to an exo carbinol, which readily undergoes highly stereocontrolled anionic oxy-Cope rearrangement. Conversion of the resulting ketone into 20 proceeds with clean epimerization at C-11 (spinosyn numbering) to properly set the absolute configuration at that site. Reduction of 20 with lithium in liquid ammonia serves to introduce two additional stereogenic centers of the perhydro-as-indacene core. In addition, the protocol makes possible the convenient incorporation of a functionalized two-carbon appendage at C-3 and ultimate generation of a cyclohexene double bond after stereochemical inversion at C-7. This scheme leads to 34, a tricyclic compound subsequently shown to be an advanced precursor to the powerful insecticide spinosyn A.

Diastereoselective Protonation of Chiral Enolates with Chelating Proton Donors under Reagent Control: Scope, Mechanism, and Applications

AbstractEndocyclic keto‐enolates of type 2 can be protonated under reagent control with high diastereoselectivities when chelating proton donors with a salicylate structure are used. The stereochemical course of these protonations is hardly affected by the ring size, the substitution pattern, and the presence of additional stereogenic centers in the enolate. The substrates can be prepared by conjugate cuprate addition as well as deprotonation; in the latter case, good diastereoselectivities are obtained by removal of competing proton sources and the inclusion of transmetalation steps. The chelate complex A serves as a mechanistic model that makes the usual trial and error search for stereoselective protonating agents unnecessary. The method is applied to stereoselective syntheses of a precursor for methyl epijasmonate and of the insect pheromone (2S,3S)‐diprionyl acetate.

ChemInform Abstract: Stereochemical Aspects in the Asymmetric Michael Addition of Chiral Imines to Substituted Electrophilic Alkenes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Asymmetric radical cyclization leading to β-lactams: Stereoselective synthesis of chiral key intermediates for carbapenem antibiotics PS-5 and thienamycin

A stereoselective synthesis of β-lactams by 4- exo-trig radical cyclizations of N-[2,2-bis(phenylthio)ethenyl]-α-bromo amides bearing a chiral inductor on the nitrogen atom has been examined. Bromide 8, upon treatment with Bu 3SnH in the presence of AIBN in boiling benzene, gave a mixture of (4 S)-2-azetidinone 12a and its (4 R)-isomer 12b in a ratio of 71:29 and 69% combined yield. Similar treatment of α-bromobutanamide 11 with Bu 3SnH afforded trans-(4 S)-2-azetidinone 17a as the major product along with its (4 R)-isomer 17b (70:30, 77% combined yield). Compound 17a was converted into 24, a chiral key intermediate in the synthesis of (+)-PS-5 (25). The cyclization of bromide 28 bearing an additional stereogenic center [( S)-oxygen functionality] at the side chain proceeded with much higher (4 S)-stereoselectivity to give azetidinone 29a as the major product together with its (4 R)-isomer 29b in a ratio of 78:22 and 40% combined yield. Compound 29a was converted, via an inversion of the oxygen functionality, into 37, a chiral key intermediate in the synthesis of (+)-thienamycin (38). A possible explanation for the observed diastereoselectivity in radical cyclizations is presented.