Quaternary Carbon Stereogenic Centers through Copper‐Catalyzed Enantioselective Allylic Substitutions with Readily Accessible Aryl‐ or Heteroaryllithium Reagents and Aluminum Chlorides

Gao, Fang; Lee, Yun-Mi; Mandai, Kyoko; Hoveyda, Amir H.

doi:10.1002/ange.201005124

Cited by 47 publications

(24 citation statements)

References 42 publications

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“…Once the addition was complete, the mixture was stirred for another 2 h at À80 8C. The reaction was quenched with a saturated aqueous NH 4 Cl solution (2 mL) and the mixture was warmed up to room temperature, diluted with dichloromethane and the layers were separated. The aqueous layer was extracted with dichloromethane (3 5 mL) and the combined organic layers were dried with anhydrous Na 2 SO 4 , filtered, and the solvent was evaporated in vacuo.…”

Section: Methodsmentioning

confidence: 99%

“…when the phenyl derivative 9 a (entries 1 and 2) and p-chloro-and pmethyl-substituted allyl bromides 9 b,c were used (entries [3][4][5][6]. An alkyl-substituted allyl bromide, such as the cyclohexyl derivative 9 d, could also be used in this transformation to afford the desired product 10 g with excellent regioselectivity and good enantioselectivity (entry 7).…”

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confidence: 99%

“…[1] Recently, this C À C bond-forming reaction has also been successfully applied to the challenging enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. [2] Organozinc, [3] aluminium, [4] and Grignard [5] reagents have been shown to be highly effective in the AAA reaction. However, the cheap and readily available organolithium reagents have not been successfully used in the catalytic asymmetric C À C bond formation of quaternary centers until now.…”

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confidence: 99%

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Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents

et al. 2012

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confidence: 99%

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Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents

et al. 2012

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“…To illustrate its utility, the methodology of homologation and vinylation of chiral tertiary boronic esters has been applied to the synthesis of the natural product (+)-sporochnol [17] and the serotonin antagonist (S)-1,2-diphenyl-4-[4-(2methoxyphenyl)-1-piperazinyl]-2-methyl-1-butanone. [18] (+)-Sporochnol (19) is a monoterpene-substituted phenol that is known to be a chemical defense compound and to exhibit feeding deterrence activity towards reef fish.…”

Section: Methodsmentioning

confidence: 99%

“…[18] (+)-Sporochnol (19) is a monoterpene-substituted phenol that is known to be a chemical defense compound and to exhibit feeding deterrence activity towards reef fish. [19] Of the syntheses reported, [17] the shortest is attributed to Hoveyda and co-workers, and involves a copper-catalyzed allylic substitution that furnished the target concisely, albeit with low enantioselectivity. [17a] Our synthesis is presented in Scheme 6.…”

Section: Methodsmentioning

confidence: 99%

Enantioselective Construction of Quaternary Stereogenic Centers from Tertiary Boronic Esters: Methodology and Applications

et al. 2011

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The creation of quaternary stereogenic centers with high enantioselectivity is challenging, in part, because of the high steric repulsion between the substituents on the carbon center that is generated during construction. Nevertheless, significant progress has been made towards this goal in recent years, even in conformationally flexible acyclic systems.[1] However, whilst in many cases high e.r. values have been achieved, the selectivities are invariably substrate-dependent.We have approached this problem from a different perspective and considered the possibility of employing stereospecific homologations of tertiary boronic esters 1. Such boronic esters can be easily prepared from the corresponding secondary alcohols with very high e.r. values by using the methodology developed by our group, [2] or alternatively, by borylation of allylic carbonates/Michael acceptors reported by Hoveyda and co-workers (Scheme 1).[3] However, whilst the homologation reaction may seemingly appear to be a straight forward extension of the literature it should be noted that hindered tertiary boranes (e.g., thexyl) have often been employed as nonmigrating groups in homologations of boranes, [4] and examples of related transformations of tertiary boronic esters are rare. [5,6] Furthermore, extending methodology from secondary to tertiary substrates is rarely straightforward as the extra steric demand often results in lower selectivity or alternative reaction pathways being followed.[7] Herein we describe our success in creating quaternary stereogenic centers with very high e.r. values and with a range of versatile functional groups; the subsequent application of the methodology in synthesis is also presented.We began our studies using the tertiary boronic ester 2 a which was subjected to standard Matteson homologation conditions [6] using chloromethyl lithium [6b] at low temperature. However, whilst the homologated alcohol product was obtained after oxidation in reasonable yield, almost 20 % of the oxidation product 4, seemingly derived from the starting material 2 a, was also isolated even when a large excess (4.0 equiv) of LiCH 2 Cl was employed (Scheme 2).Analysis of the reaction by 11 B NMR spectroscopy prior to oxidation revealed that in addition to the signal of desired boronic ester 5 at d = 32 ppm, a new peak at d = 49 ppm was observed, which is indicative of the presence of borinic ester 6.[8] This ester must have formed from the unexpected migration of the oxygen substituent [9] instead of the normally favored carbon migration, presumably as a consequence of the very hindered nature of the boronic ester. We reasoned that using a bulkier and less polar leaving group (smaller dipole moment) would favor the conformation required for C migration and therefore explored LiCH 2 Br as an alternative reagent.[10] Making this simple modification resulted in an improved yield of the desired homologated product (83 % yield) with only about 5 % of the product derived from O migration (Scheme 2).This reagent was applied to a series of ...

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Organocatalytic Enantioselective Sulfenylation of β‐Keto Phosphonates: A Convenient Approach to Construct Hetero‐ Quaternary Stereocenters

et al. 2011

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Abstract:The highly effective and enantioselective sulfenylation of b-keto phosphonates catalyzed by a,a-diaryl-l-prolinols has been developed. The optically active a-sulfenylated b-keto phosphonates could be obtained under mild reaction conditions in good yields (up to 92%) and with excellent enantioselectivities (up to 92% ee).Keywords: hetero-quaternary stereocenters; b-keto phosphonates; organocatalysis; sulfenylation A quaternary stereocenter is an essential structural motif in numerous biologically active natural molecules and pharmaceuticals, and the construction of such a framework in an asymmetric catalytic manner is one of the most challenging tasks for organic chemists. In the past few years, a lot of effort has been made on it and many powerful catalysts were developed.[1] The introduction of an electrophilic hetero atom to b-dicarbonyl compounds, such as b-keto esters has been successfully established as a simple and powerful method to construct hetero-quaternary stereocenters [2][3][4][5] due to the activated C À H bond in bketo esters.Optically active sulfur-containing compounds constitute an important class of chiral ligands, auxiliaries and synthetic intermediates in organic chemistry. [6] Benzenethiol and thioacetic acid as nucleophiles used in the direct asymmetric sulfenylation reaction have been reported in the literature. [7] Recently, as a complementary procedure, several groups have successfully reported the asymmetric sulfenylation of aldehydes, [8] ketones, [9] and substituted piperazine-2,5-diones [10] with different electrophilic sulfur reagents. Jørgensen [4a] described the first enantioselective a-sulfenylation of b-keto esters using the Cinchona alkaloid derivatives as the catalysts, which gave the products in up to 91% ee. Moreover, Togni also successfully reported the analogous transformation with chiral Ti complexes. [4b-d] As a result of the increasing applications of chiral phosphonic acids and derivatives in peptide, pharmaceutical and medicinal chemistry, the development of efficient methods for the synthesis of these compounds is of particular significance.[11] On the basis of the feature of bond-forming reactions, a few reports on enantioselective a-amination (C À N bond formation, path a), [12,13b] a-halogenation (C À Cl or C À F bond formation, path b), [13] and Mannich-type reaction (C À C bond formation, paths c and d) [14] of b-keto phosphonates catalyzed by chiral metal complexes have been reported (Scheme 1).Due to their inexpensive nature and ready availability, a,a-diarylprolinols as organocatalysts have attracted considerable interest and proved to be effective in many asymmetric reactions.[15] Recently, our group successfully reported the sulfenylation of bketo esters under the catalysis of a,a-diaryl-l-prolinols with excellent enantioselectivities and satisfactory yields (92-97% ee with 70-82% yield).[4e] In this paper, we present the asymmetric a-sulfenylation of b-keto phosphonates based on a,a-diaryl-l-prolinols catalysis [Eq. (1)].

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Quaternary Carbon Stereogenic Centers through Copper‐Catalyzed Enantioselective Allylic Substitutions with Readily Accessible Aryl‐ or Heteroaryllithium Reagents and Aluminum Chlorides

Cited by 47 publications

References 42 publications

Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents

Enantioselective Synthesis of Tertiary and Quaternary Stereogenic Centers: Copper/Phosphoramidite‐Catalyzed Allylic Alkylation with Organolithium Reagents

Enantioselective Construction of Quaternary Stereogenic Centers from Tertiary Boronic Esters: Methodology and Applications

Organocatalytic Enantioselective Sulfenylation of β‐Keto Phosphonates: A Convenient Approach to Construct Hetero‐ Quaternary Stereocenters

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