Chiral Propargylic Alcohols Research Articles

Asymmetric Alkyne Addition to Aldehydes Catalyzed by BINOL and Its Derivatives

This Account describes our research over the past decade in theasymmetric alkyne addition to aldehydes to generate optically activepropargylic alcohols. Our methods employ a dialkylzinc reagent toreact with a terminal alkyne to form an alkynylzinc nucleophile,and can be grouped into the BINOL-catalyzed reactions and the functionalizedBINOL catalyzed reactions. We first describe the development ofthe BINOL-ZnEt 2 -Ti(O I-Pr) 4 catalystsystem, and its modification through the use of Lewis base additivesto form the alkynylzinc at room temperature. The substrate scopecompatible with these methods and the enantioselectivities achievedare discussed. We then describe the functionalized BINOL and H 8 BINOL catalystsystems, which can be further divided into classes based on themanner in which the BINOL framework has been modified. Generally,these functionalized BINOL and H 8 BINOL derivatives containinternal Lewis basic sites which can both promote the formationof the nucleophilic alkynylzinc reagents at reduced temperatureand modify the catalytic properties of the chiral biaryl unit. In afew cases, these catalysts also show good efficiency even without theuse of the Ti(IV) reagent. The catalytic methods in this Account havedemonstrated that a wide range of alkyne and aldehyde substratescan be subjected to the asymmetric addition reactions to generatestructurally diverse chiral propargylic alcohols with high enantioselectivity.Some of these methods have exhibited high practicality in synthesis. 1 Introduction 2 BINOL-Based Catalytic Systems 2.1 Catalysis by BINOL-ZnEt 2 -Ti(O I-Pr) 4 2.2 Catalysis by BINOL-ZnEt 2 -Ti(O I-Pr) 4 -HMPA 2.3 Catalysis by BINOL-ZnEt 2 -Ti(O I-Pr) 4 -NMI 2.4 Catalysis by BINOL-ZnEt 2 -Ti(O I-Pr) 4 -Cy 2 NH 3 Functionalized BINOL-Based Catalytic Systems 3.1 Catalysis by 3,3′-Dianisyl-BINOLs and -H 8 BINOLs 3.2 Catalysis by 3,3′-Bis(diphenylmethoxy)methyl Substituted BINOLs 3.3 Catalysis by Acyclic and Macrocyclic Binaphthyl Salens 3.4 Catalysis by 3,3′-Bismorpholinomethyl H 8 BINOL 3.5 Catalysis by C 1 -SymmetricBINOL-Terpyridine 4 Summary

Stereoselective total synthesis of dinemasone A by double intramolecular hetero-Michael addition (DIHMA)

The first total synthesis of dinemasone A, a bioactive metabolite with a spiroketal moiety, is described. The main strategy for the construction of the spiroketal unit involves a double intramolecular hetero-Michael addition (DIHMA) of an ynone moiety. The thus obtained axial-equatorial mono anomeric spiroketal, on spiroepimerization with ZnBr(2), was converted into the requisite axial-axial double anomeric spiroketal. The ynone moiety with four stereocentres, was prepared from a chiral propargylic alcohol (C5-C11 fragment) and a dihydroxy aldehyde (C1-C4 fragment), which in turn were obtained from D-mannitol and crotyl alcohol respectively.

Hydrogen‐Bond‐Assisted Helical Folding of Propeller‐Shaped Molecules: Effects of Extended π‐Conjugation on Chiral Selection, Conformational Stability, and Exciton Coupling

AbstractCooperative interaction between multiple chiral centers dictates the absolute handedness of structural folding. We have designed and prepared a series of chiral C3‐symmetric tris(N‐salicylidenamine) derivatives that adopt three‐blade propeller‐like conformations. Synthetic access to an expanded family of such constructs was aided by enzymatic resolution and C–C cross‐coupling reactions of aryl‐substituted chiral propargylic alcohol derivatives. These key structural components were integrated into molecular propellers of predetermined helical screw sense. Through comparative studies on a homologous set of molecules, we found that installation of phenylene‐ethynylene‐derived π‐conjugation profoundly affected the stabilities of the helically folded structures, as evidenced by UV/Vis and circular dichroism (CD) studies. Increasing the number of hydrogen bonds through additional substitution also enhanced the populations of the folded conformations in solution. In addition to introducing steric bias to control structural folding, linearly π‐conjugated groups function as spatially well‐defined chromophores that give rise to characteristic exciton‐coupled circular dichroism. Absolute configurations of chiral centers could thus be further confirmed by comparing the torsional relationships between pairs of chromophores on adjacent subunits, which are fully consistent with the computationally predicted structural models.

ChemInform Abstract: Chiral Propargyl Alcohols via the Enantioselective Addition of Terminal Di‐ and Triynes to Aldehydes.

AbstractThe products are useful synthons for triazoles such as (IX).

Synthesis of N,4-diaryl substituted β-lactams via Kinugasa cycloaddition/rearrangement reaction

The methodology of construction of N,4-diaryl substituted β-lactam framework, based on the Kinugasa cycloaddition/rearrangement sequence is presented. The series of protected chiral propargyl alcohols was treated with diaryl nitrones to afford mainly the cis-I adduct, providing direct access to the highly-functionalized azetitidin-2-one derivatives with a well-defined stereochemistry. Under the optimized reaction conditions, the unprotected chiral propargylic alcohols were also found to be suitable precursors of β-lactams. The absolute configuration of adducts was determined by CD or HPLC-CD technique, which was shown to be reliable method of determination of the configuration at C-4 of 4-aryl-substituted azetidin-2-ones. Epimerization of the cis adduct to the respective trans isomer could be easily done by the oxidation of hydroxyl group next to the four-membered β-lactam ring to the ketone, followed by a base-mediated epimerization of the malonyl fragment.

Enantioselective Synthesis of Chiral Propargylic Alcohols Catalyzed by Bifunctional Zinc-Based Complexes

This work demonstrates an efficient way to prepare chiral propargylic alcohols by asymmetric addition of terminal Zn-acetylide to aldehydes catalyzed by bifunctional zinc-based complexes. The corresponding products with moderate to good yields and enantioselectivities were obtained in the absence of moisture-sensitive Ti(O i Pr)4.

Formal synthesis of (+)-didemniserinolipid B

The formal synthesis of (+)-didemniserinolipid B is achieved using Weinreb reaction, Yadav’s chiral propargyl alcohol protocol and hydrolytic ketal formation as the key steps.

Chiral Propargyl Alcohols via the Enantioselective Addition of Terminal Di- and Triynes to Aldehydes

The enantioselective addition of di- and triynes to aldehydes is presented, including the first examples of an asymmetric triyne addition. Modification of the Carreira alkynylation protocol shows that addition of diynes and triynes to α-branched aldehydes can be complete in as little as 4 h, and these reactions give good yields and enantioselectivities (up to 98% ee) for di- and triynes tested (aryl, alkyl, and silyl). It is shown for two cases (20 and 24) that products of this asymmetric addition reaction can undergo further manipulation (desilylation and triazole formation) without affecting the enantiopurity.

A Powerful New Construction of Complex Chiral Polycycles by an Indium(III)-Catalyzed Cationic Cascade

InI(3) and InBr(3) have been found to be effective catalysts for the π activation of C≡C bonds to initiate the conversion of chiral propargylic alcohols or silyl ethers to polycyclic products in excellent yields and with high stereoselectivity. The method has been applied to the synthesis of chiral fused hexacyclic ring systems with the creation of multiple new stereocenters. The power and scope of the method are illustrated by a variety of examples.

C1‐Symmetric Rh/Phebox‐Catalyzed Asymmetric Alkynylation of α‐Ketoesters

Thinking outside the box: A newly developed C1-symmetric Rh/Phebox complex efficiently catalyzed the asymmetric alkynylation of α-ketoester 1 with various aryl and alkyl substituted terminal alkynes to provide the corresponding chiral tertiary propargylic alcohols with up to 99 % ee (see scheme; TMS=trimethylsilyl).

Stereoselective total synthesis of (+)-sapinofuranone B

Two approaches for the total synthesis of (+)-sapinofuranone B have been described. The first strategy utilizes the methodology developed earlier in our group to get the chiral propargyl alcohol and the second strategy involves generation of threo-1,2-diol derivative by diastereoselective and enantioselective addition of [( Z)-γ-methoxymethoxyallyl]diisopinocampheylborane onto aldehyde and cross metathesis as the key steps.

Resolution of Carboxylic Acids Using Copper(I)-Promoted Removal of Propargylic Esters under Neutral Conditions

A method for the optical resolution of carboxylic acids is described. Condensation of racemic carboxylic acids with chiral terminal propargyl alcohols gave separable diastereomeric esters. Chromatographic separation followed by heating the individual diastereomers in methanol with catalytic copper(I) halide regenerated the carboxylic acids in good yields and in enantiomeric ratios of ≥94%. This method is particularly useful for the resolution of carboxylic acids that are incompatible with conventional ester hydrolysis.

Synthesis of Stereoisomers of Cryptofolione 6′‐Mono‐ and 4′,6′‐Di‐O‐benzyl Ethers

AbstractSynthesis of stereoisomers of 6′‐mono‐ and 4′,6′‐di‐O‐benzyl cryptofolione is described through a key intermediate 6, which was prepared by coupling of iodobenzene 8 with chiral propargyl alcohol 9 under Cosford protocol conditions. Monobenzyl ether 4 is obtained via epoxide 6 opening with vinyl Grignard, followed by cross‐metathesis reaction with a vinyl lactone 11. Whereas, dibenzyl ether 5 is prepared by epoxide 6 opening with chiral propargyl alcohol 7 followed by simple transformations and finally cis‐Wittig olefination.

Mild and Expedient Asymmetric Reductions of α,β-Unsaturated Alkenyl and Alkynyl Ketones by TarB-NO2 and Mechanistic Investigations of Ketone Reduction

A facile and mild reduction procedure is reported for the preparation of chiral allylic and propargyl alcohols in high enantiomeric purity. Under optimized conditions, alkynyl and alkenyl ketones were reduced by TarB-NO2 and NaBH4 at 25 °C in 1 h to produce chiral propargyl and allylic alcohols with enantiomeric excesses and yields up to 99%. In the case of α,β-unsaturated alkenyl ketones, α-substituted cycloalkenones were reduced with up to 99% ee, while more substituted and acyclic derivatives exhibited lower induction. For α,β-ynones, it was found that highly branched aliphatic ynones were reduced with optimal induction up to 90% ee, while reduction of aromatic and linear aliphatic derivatives resulted in more modest enantioselectivity. Using the (L)-TarB-NO2 reagent derived from (L)-tartaric acid, we routinely obtained highly enantioenriched chiral allylic and propargyl alcohols with (R) configuration. Since previous models and a reduction of a saturated analogue predicted propargyl products of (S) configuration, a series of new mechanistic studies were conducted to determine the likely orientation of aromatic, alkenyl, and alkynyl ketones in the transition state.

Catalytic Asymmetric Synthesis of Chiral Propargylic Alcohols for the Intramolecular Pauson−Khand Cycloaddition

Several methods for the catalytic asymmetric alkyne addition to aldehydes are used to prepare the propargylic alcohol-based chiral en-ynes. Protection of the propargylic alcohols with either an acetyl or a methyl group allows the resulting en-ynes to undergo the intramolecular Pauson-Khand reaction to form the corresponding optically active 5,5- and 5,6-fused bicyclic products with high diastereoselectivity and high enantiomeric purity. In the major product, the propargylic substituent and the bridgehead hydrogen are cis with respect to each other on the fused bicyclic rings. The enantiomeric purity of the propargylic alcohols generated from the asymmetric alkyne addition is maintained in the cycloaddition products. The allylic ethers of the chiral propargylic alcohols are prepared which can also undergo the highly diastereoselective Pauson-Khand cycloaddition with retention of the high enantiomeric purity. This study has shown that the size of the substituents at the propargylic position as well as on the alkyne is important for the diastereoselectivity with the greater bulkiness of the substituents giving higher diastereoselectivity.

Enantioselective alkynylation of ketones with trimethoxysilylalkynes using lithium binaphtholate as a catalyst

Abstract Chiral lithium 3,3′-diphenylbinaphtholate successfully catalyzed the alkynylation of ketone with trimethoxysilylalkyne, affording chiral tertiary propargylic alcohols in high chemical yields and high enantioselectivities. The present reaction could be extended to the alkynylation of acetylpyridine, which afforded a biologically active pyridyl propargylic alcohol in good enantioselectivity.

Methylsulfonyl-Based Sulfamide-Amine Alcohol as a Ligand for Enantioselective Alkynylation of Aldehydes

Chiral methylsulfonyl-based sulfamide-amine alcohol (SAA) ligands were synthesized from commercially available starting materials in two simple steps. Methylsulfonyl-based SAA ligands catalyzed the asymmetric alkynylation of various aldehydes using alkynylzinc to provide chiral propargyl alcohols with moderate to good enantioselectivity up to 83% ee. ： 以商业易得的 (–)-麻黄碱、(+)-伪麻黄碱和各种手性氨醇为主要原料, 经过简单的两步反应, 合成了一系列基于甲磺酰基的磺酰胺-氨醇 (SAA) 配体, 并将其用于催化苯乙炔基锌对醛的不对称加成反应. 在没有 Ti(O i Pr) 4 等金属试剂的条件下, 配体表现出较好的不对称诱导能力, 取得了高达 83% ee. Newly developed methylsulfonyl-based sulfamide-amine alcohol ligands, which were conveniently synthesized from commercially available starting materials in two simple steps, have been found to be effective ligands for the asymmetric alkynylation of aromatic aldehydes with up to 83% ee.

A Striking Exception to the Chelate Model for Acyclic Diastereocontrol: Efficient Access to a Versatile Propargyl Alcohol for Chemical Synthesis

The four-step, asymmetric synthesis of a chiral propargyl alcohol 1 from (R)-pantolactone is described. A key feature of the synthesis is a diastereoselective acetylide addition to a chiral α-alkoxy-aldehyde 7, in which unusual Felkin selectivity is observed, despite the potential for chelation control. Crystalline propargyl alcohol 1 is valuable for complex molecule synthesis, and is easy to prepare in multi-gram quantities and high diastereomeric purity.

3,3′-Anisyl-Substituted BINOL, H4BINOL, and H8BINOL Ligands: Asymmetric Synthesis of Diverse Propargylic Alcohols and Their Ring-Closing Metathesis to Chiral Cycloalkenes

A series of optically active BINOL, H(4)BINOL, and H(8)BINOL derivatives were prepared. These compounds in combination with ZnEt(2) and Ti(O(i)Pr)(4) were used to catalyze the asymmetric reaction of alkynes with aldehydes to generate chiral propargylic alcohols at room temperature. Through this comparative study, a 3,3'-bisanisyl-substituted H(8)BINOL (S)-7 was found to be a generally enantioselective catalyst for the reaction of structurally diverse terminal alkynes with a variety of aldehydes. It catalyzed the reactions of alkyl propiolates with 88-99% ee; the reactions of phenylacetylene with 81-87% ee; the reactions of 4-phenyl-1-butyne, an alkyl alkyne, with 77-89% ee; and the reactions of trimethylsilylacetylene with 92-97% ee. The optically active propargylic alcohols generated from this catalytic asymmetric alkyne addition were observed to undergo efficient ring-closing-metathesis (RCM) reaction in the presence of the Grubbs II catalyst to produce chiral cycloalkenes. It was further found that some of the chiral propargylic alcohols underwent a highly chemoselective tandem RCM hydrogenation reaction with retention of the enantiomeric purity.

A Concise Asymmetric Route to Chiral α-Aminoxy Acids

An efficient three-step method has been developed for enantioselective synthesis ot chiral α-aminoxy acids trom aldehydes. In this method, chiral propargylic alcohols are obtained by asymmetric addition of terminal alkynes to aldehydes. The hydroxyl group then converted to aminoxy group via Mitsunobu reaction and oxidative cleavage of the internal carbon-carbon triple bond produce the carboxylic acid group. This represents a convenient approach to the general asymmetric synthesis of α-aminoxy acids with the advantages of substantial overall yields (37-73%) and high enantioselectivities (81-99% ee).