On the lipase-catalyzed resolution of functionalized biaryls

The implementation of lipase catalysis as a tool for the preparation of optically active biaryls is discussed. While attempts toward dynamic kinetic resolution based on the catalytic ring opening of configurationally unstable biaryl lactones were fruitless, kinetic resolution via transesterification of hydroxymethyl-decorated substrates was successfully employed in the generation of optically enriched, axially chiral biaryls.     

Catalytic atropo-enantioselective reduction of biaryl lactones to axially chiral biaryl compounds

The atropo-enantioselective borohydride reduction with dynamic kinetic resolution of biaryl lactones was catalyzed by an optically active beta-ketoiminatocobalt(II) complex to afford optically active biaryl compounds. Chiral HPLC analysis of the starting biaryl lactones was performed at various temperatures to determine suitable reaction conditions for dynamic kinetic resolution. Various types of axially chiral biaryl compounds were obtained with high enantioselectivity.     

On the verge of axial chirality: atroposelective synthesis of the AB-biaryl fragment of vancomycin

[structure: see text] Using the "lactone concept", differently substituted AB-biaryl fragments (P)-2 (R = Me, t-Bu) of vancomycin have been synthesized atroposelectively. Their otherwise configurational instability was remedied by inclusion of two chlorine atoms in the B ring to give (M)-29. Starting from a still configurationally unstable lactone-bridged precursor, we obtained this biaryl with high atroposelectivity (dr 94:6) by ring cleavage with dynamic kinetic diastereomeric resolution.     

Nondynamic kinetic resolution of configurationally stable biaryl lactones by reduction with oxazaborolidine-activated borane: AM1 studies and experimental verification

The complete mechanistic course of the atroposelective ring opening of a lactone-bridged biaryl, dinaphth[2,1-c:1',2'-e]oxepin-3-(5H)-one (3), with a chiral oxazaborolidine-BH3 complex was calculated using the semiempirical AM1 method. The first hydride transfer to the activated carbonyl function of the adduct complexes was elaborated to be the selectivity-determining step in the postulated five-step mechanism. The calculated enantioselectivity is in good accordance with the experimental results, so that related calculations were performed on the atroposelective ring opening of a sterically strongly hindered and therefore also configurationally stable six-membered biaryl lactone, 1,3-di-tert-butyl-6H-benzo[b]naphtho[1,2-d]pyran-6-one (6f). These calculations predicted a highly (M)-selective reduction of 6f (kM/kP = 358 at -78 degrees C), which, after the smooth preparation of 6f by intramolecular biaryl coupling in high yields, was fully confirmed experimentally (kM/kP > 200 at -78 degrees C). Isolation of the intermediate hydroxy aldehyde (M)-14 at the beginning of the reaction with the same enantiomeric excess as found for the corresponding alcohol (M)-7f conclusively showed the first hydride transfer step to determine the selectivity of this process. The good agreement of computationally predicted and experimentally confirmed values proves the suitability of the AM1 method for mechanistic studies on even such complex reactions and opens a most efficient overall synthesis of sterically highly hindered biaryls, in excellent chemical (for the ring closure) and optical (for the ring cleavage) yields and for any desired axial configuration.     

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

Atropisomeric biaryl pyridine and isoquinoline N‐oxides were synthesized enantioselectively by dynamic kinetic resolution (DKR) of rapidly racemizing precursors exhibiting free bond rotation. The DKR was achieved by ketoreductase (KRED) catalyzed reduction of an aldehyde to form a configurationally stable atropisomeric alcohol, with the substantial increase in rotational barrier arising from the loss of a bonding interaction between the N‐oxide and the aldehyde. Use of different KREDs allowed either the M or P enantiomer to be synthesized in excellent enantiopurity. The enantioenriched biaryl N‐oxide compounds catalyze the asymmetric allylation of benzaldehyde derivatives with allyltrichlorosilane.     

Asymmetric synthesis of antimicrotubule biaryl hybrids of allocolchicine and steganacin

The asymmetric synthesis of novel axially chiral biaryl compounds 5 a-f containing a seven- or eight-membered heterocyclic medium ring is described. These molecules can be considered to be structural hybrids of allocolchicine- and steganacin-type natural products. The synthesis featured an atropo-diastereoselective biaryl Suzuki coupling in which a benzylic stereocenter efficiently transferred its stereochemical information to the biaryl axis. The coupling conditions were optimized, and two biphenylphosphane ligands (DavePhos and S-Phos) were found to give the highest yields and diastereoselectivities. A three-element stereochemical model was proposed to explain the observed diastereoselectivities. In a second key step, the medium ring of the target molecules was formed by a stereoselective S(N)1-type cyclodehydration that probably involved a configurationally stable carbocationic intermediate, as supported by calculations. Alternatively, S(N)2-type cyclizations were employed on the same Suzuki coupling products to give the target molecules in a stereodivergent or stereoconvergent manner. These cyclization methods furnished the target hybrid analogues 5 a-f with ee values above 94 %. All analogues were evaluated as antimicrotubule agents and against a panel of cancer-cell lines using colchicine (1) and N-acetylcolchinol (3) as references. Promising activities were found for R,aR-configured compounds 5 a, b and 5 f; in particular, ethyl analogue 5 b showed a twofold antimicrotubule activity relative to colchicine.     

Helically chiral poly(quinoxalin‐2,3‐diyl)s: Toward the synthesis of stereoregular polymeric organocatalysts

The synthesis of seven new aromatic diisocyanide monomers is described and a rationale for their stability is given, as well as their behavior in the palladium‐mediated aromatizing polymerization yielding helically chiral poly(quinoxalin‐2,3‐diyl)s (PQs). Acceleration of the otherwise slow polymerization by microwave heating was observed. The polymers are designed to display potential organocatalytically active functionalities (e.g., phenols, pyridines) nearby stereolabile biaryl axes, which are asymmetrically governed by the configurationally stable helical backbone. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4830–4839, 2009     

Atroposelective Heck Macrocyclization: Enantioselective Synthesis of Bis(bibenzylic) Natural Products

The Heck protocol was applied for the first time to the atroposelective synthesis of macrocyclic natural products. As ring closure to bis(bibenzyls) of the isoplagiochin type leads to a configurationally stable biaryl axis in the molecule, cyclization could be conducted atroposelectively in the presence of a chiral BINAP ligand.     

Atroposelective synthesis of axially chiral biaryl compounds

A rotationally hindered and thus stereogenic biaryl axis is the structurally and stereochemically decisive element of a steadily growing number of natural products, chiral auxiliaries, and catalysts. Thus, it is not surprising that significant advances have been made in the asymmetric synthesis of axially chiral biaryl compounds over the past decade. In addition to the classic approach (direct stereoselective aryl-aryl coupling), innovative concepts have been developed in which the asymmetric information is introduced into a preformed, but achiral-that is, symmetric or configurationally labile-biaryl compound, or in which an aryl--C single bond is stereoselectively transformed into an axis. This Review classifies these strategies according to their underlying concepts and critically evaluates their scope and limitations with reference to selected model reactions and applications. Furthermore, the preconditions required for the existence of axial chirality in biaryl compounds are discussed.     

Applications of vinylogous Mannich reactions. Total syntheses of the Ergot alkaloids rugulovasines A and B and setoclavine.

Concise syntheses of the Ergot alkaloids rugulovasine A (3a), rugulovasine B (3b), and setoclavine (2) have been completed by strategies that feature inter- and intramolecular vinylogous Mannich reactions as the key steps. Thus, the first synthesis of 3a,b commenced with the conversion of the known indole 17 into 24 via the addition of the furan 22 to the iminium ion 21, which was generated in situ from the aldehyde 19. Cyclization of 24 by a novel S(RN)1 reaction followed by removal of the N-benzyl group furnished a mixture (1:2) of 3a and 3b. In an alternative approach to these alkaloids, the biaryl 35 was reduced with DIBAL-H to give an intermediate imine that underwent spontaneous cyclization via an intramolecular vinylogous Mannich addition to provide 36a,b. N-Methylation of the derived benzyl carbamates 37a,b followed by global deprotection gave a mixture (2:1) of rugulovasines A and B (3a,b). Setoclavine (2) was then prepared from the biaryl 41 using a closely related intramolecular vinylogous Mannich reaction to furnish the spirocyclic lactones 42a,b. These lactones were subsequently transformed by hydride reduction and reductive methylation into the ergoline derivatives 43a,b, which were in turn converted into 2 by deprotection and solvolytic 1,3-rearrangement of the allylic hydroxyl group.     

Lipase‐Catalyzed Dynamic Kinetic Resolution of C1‐ and C2‐Symmetric Racemic Axially Chiral 2,2′‐Dihydroxy‐1,1′‐biaryls

We have discovered that the racemization of configurationally stable, axially chiral 2,2′‐dihydroxy‐1,1′‐biaryls proceeds with a catalytic amount of a cyclopentadienylruthenium(II) complex at 35–50 °C. Combining this racemization procedure with lipase‐catalyzed kinetic resolution led to the first lipase/metal‐integrated dynamic kinetic resolution of racemic axially chiral biaryl compounds. The method was applied to the synthesis of various enantio‐enriched C₁‐ and C₂‐symmetric biaryl diols in yields of up to 98 % and enantiomeric excesses of up to 98 %, which paves the way for new developments in the field of asymmetric synthesis.     

Remote Central‐to‐Axial Chirality Conversion: Direct Atroposelective Ester to Biaryl Transformation

A strategy for the remote central‐to‐axial chirality conversion by simultaneous planarization of an encoding and a transient stereocenter is presented. Based on a diastereoselective double addition of a chiral 1,5‐bifunctional organomagnesium alkoxide reagent to a broad range of aryl ester substrates, axially chiral biaryls are directly obtained upon in situ reduction. Various structurally distinct atropisomeric biaryl silanes that serve as valuable chiral biaryl anion surrogates are accessible in one step with e.r. values of up to 98:2.     

Intramolecular biaryl coupling reaction of benzyl benzoate and phenyl benzoate derivatives, and its application to the formal synthesis of (−)-steganone

Construction of the biaryl moiety of stegane and related compounds through an intramolecular biaryl coupling reaction is described. Undesired products were obtained by the intramolecular coupling reaction of benzyl benzoates (8, 13, and 14) because of their steric and electrostatic properties, and only that of phenyl benzoates (26b and 26c) afforded the desired biaryl lactones in good yields. An asymmetric formal synthesis of the title compound has been achieved using an enantioselective lactone-opening reaction followed by a four-step conversion to the known compound.     

First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method"

The stereoselective total synthesis of the antimalarial korupensamines A (1a) and B (1b) by application of the "lactone method" is described. Key steps of this first atropo-selective access to 5,8'-coupled naphthylisoquinoline alkaloids were the regioselective intramolecular coupling of ester 8 to give the configurationally labile lactone-bridged biaryl 9 and its atropisomer-selective cleavage with a variety of chiral and achiral H-nucleophiles, yielding the configurationally stable P-diol 10a or, optionally, the M-product 10b. From the axially chiral phenylisoquinolines thus obtained atropo-diastereodivergently, the authentic natural naphthylisoquinolines with the respective axial configurations, korupensamines A (1a) and B (1b), were obtained by completion of the second naphthalene ring, starting from the previous "bridgehead" C1 unit.     

Ring-closure reactions through intramolecular substitution of thiophenoxide by oxygen and nitrogen nucleophiles: simple stereospecific synthesis of 4,5-dihydroisoxazoles and 4,5-dihydropyrazoles

A new and simple method for the stereospecific synthesis of 3,5-disubstituted-4,5-dihydro-isoxazoles (chiral isoxazolines) from readily available oximes of chiral Michael adducts of thiophenol to chalcones is reported. An analogous reaction with the N-arylhydrazones of the Michael adduct gave nonracemic 1-(aryl)-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (chiral pyrazolines), but these products are configurationally unstable. The key step of the synthesis is the ring-closure reaction, which occurs by a stereospecific intramoleculer nucleophilic substitution of thiophenoxide.     

Non‐biaryl atropisomers. part 1. configurationally stable 1,2‐diaryl‐3‐methyl‐1,4,5,6‐tetrahydropyrimidinium salts

In the present communication we describe two examples of a new kind of configurationally stable non‐biaryl atropisomers in which the Ar‐N bond is the chiral axis, namely 1‐(o‐nitrophenyl)‐2‐aryl‐3‐methyl‐1,4,5,6‐tetrahydropyrimidinium iodides 1. Stereochemical features of such compounds are analyzed on the basis of their ¹H and ¹³C one‐ and two‐dimensional nmr spectra. A comparison is made with the corresponding amidines 2 .     

Ancistrocladinium A and B, the first N,C-coupled naphthyldihydroisoquinoline alkaloids, from a Congolese ancistrocladus species

The isolation and structural elucidation of three novel-type naphthylisoquinoline alkaloids, ancistrocladinium A and B (the latter along with its atropisomer), from a Congolese Ancistrocladus species collected in the habitat Yeteto is reported. Their structures, including all stereochemical features, were elucidated by spectroscopic, chemical, and chiroptical methods. Ancistrocladinium A and B are the first N,C-coupled naphthyldihydroisoquinoline alkaloids found in nature, i.e., with an iminium-aryl axis. Although ancistrocladinium A, which is N,8'-coupled, is configurationally stable at this axis, ancistrocladinum B and its rotational isomer are based on a hitherto unprecedented N,6'-coupling type, with a slow rotation about the hetero biaryl axis at room temperature; they thus occur as a 46:54 mixture of two configurationally semistable atropo-diastereomers. For the isomerization of (P)-ancistrocladinium B to its (M)-diastereomer and for the opposite direction, the Gibbs free energies of activation were determined to be DeltaG double dagger1 = 105.8 kJ mol-1 and DeltaG double dagger2 = 105.7 kJ mol-1, respectively. In addition, the compounds were shown to have promising antileishmanial activities.     

Quinine‐Catalyzed Asymmetric Synthesis of 2,2′‐Binaphthol‐Type Biaryls under Mild Reaction Conditions

Simple quinine as an organocatalyst mediates the addition of various naphthols to halogenated quinones to afford non‐C₂‐symmetrical, axially chiral biaryl products, which are promising compounds as chiral ligands and organocatalysts. The rotational barrier required to have two distinct atropisomers has been evaluated in the products generated from the addition of naphthols to various quinones by means of DFT calculations and HPLC. The use of halogenated quinones as reagents was necessary to have configurationally stable enantiomeric products which can be obtained in good yield and stereoselectivity. These compounds have also been prepared in gram quantities and recrystallized to near enantiopurity.     

Stereochemistry of isoplagiochin C, a macrocyclic bisbibenzyl from liverworts

Cyclic bisbibenzyls, like isoplagiochins C (1) and D (2), are stereochemically intriguing molecules: Although not equipped with any of the traditional stereogenic elements that render molecules conformationally stable per se, they are sometimes isolated in an optically active form and are thus chiral at room temperature. The paper describes quantum chemical calculations, in particular investigations of the conformational space and molecular dynamics simulations, showing that the helicity is a property of the entire molecule, whose ring strain makes the molecule configurationally stable overall, with (formally) three stereogenic elements (two biaryl axes and one helical stilbene unit). Only one of the biaryl axes (the 'upper' one, joining C-12' and C-14) has a stable configuration, leading to a population of four interconverting diastereomers, yet without racemization at room temperature. On the basis of these conformational and dynamic calculations, the circular dichroism spectrum of isoplagiochin C (1) was calculated, leading to the first assignment of the absolute configuration of a cyclic bisbibenzyl. Accordingly, 1 has the P-configuration at the stereochemically stable biaryl axis and constitutes a mixture of diastereomers with respect to the other biaryl axis and the helical stilbene unit. From the temperature dependence of the racemization rates, an enantiomerization barrier of 101.6 kJ/mol was determined. Likewise, for the first time for cyclic bisbibenzyls, the enantiomeric ratio of this natural product was determined, by chromatography on a chiral phase with CD-coupling. Accordingly, 1 from Plagiochila deflexa is not enantiomerically pure, but occurs in a 85:15 ratio in favor of the enantiomer that has the P-configuration at the stereochemically stable axis.     

A borderline case between meso and stable C1: an axially chiral, yet configurationally semi-stable biphenyl with two oppositely configured [10]paracyclophane portions

The synthesis of the bi[10]paracyclophanes 2 and 4 from the meso-configured bioxepine 3 is described. These compounds are stereochemically remarkable: the biaryl axis that connects the constitutionally identical, but oppositely configured planar-chiral paracyclophane portions, is configurationally semi-stable. Thus, 2 is an unprecedented borderline case of a (planar-chiral)-(axially chiral)-(planar-chiral) molecule that is right in between a meso-compound (as a macroscopical result of the—albeit slow—rotation about the central C,C-bond) and C₁-symmetry (with respect to the existence of separable—even though configurationally unstable—discrete atropo-enantiomers). Despite their restricted configurational stability, these atropo-enantiomers were resolved on a chiral phase at 5 °C and were stereochemically assigned by LC-CD coupling, in combination with quantum chemical CD calculations.