Expedient Construction of Multiple Stereogenic Centers in an Acyclic System via the Addition of Aldehydes, Ketones, and Chiral Imines to an Enyne−Titanium Alkoxide Complex

Hamada, Takeshi; Mizojiri, Ryo; Urabe, and Hirokazu; Sato, Fumie

doi:10.1021/ja001334r

Cited by 50 publications

(20 citation statements)

References 7 publications

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“…A variety of aromatic aldehydes undergo reductive coupling with 2-methyl-1-hexen-3-yne under these conditions in excellent regioselectivity and modest enantioselectivity. Both electron-donating (entries 4 -6, 11 -12) and electron-withdrawing [19] (entries 7 -10) substituents are tolerated, and aromatic ketones and esters are also compatible (entries 9 and 10).In our previously reported investigations, [11] we found that related coupling reactions of 1,3-enynes proceeded in excellent regioselectivity, regardless of the substitution pattern on the alkene or the size or nature of the other alkyne substituent. The same was found to be true in reactions promoted by ferrocenylphosphine 1b, and a variety of vinyl-substituted enynes provided a single dienol regioisomer with moderate enantioselectivity (Table 2, entries 1 -5), even when this required C À C bond formation to occur adjacent to sterically-demanding tert-butyl [20] (entry 4) and trimethylsilyl (entry 5) groups.…”

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confidence: 65%

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Asymmetric Catalytic Reductive Coupling of 1,3‐Enynes and Aromatic Aldehydes

et al. 2005

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Nickel-catalyzed reductive coupling reactions of 1,3-enynes and aromatic aldehydes efficiently afford conjugated dienols in excellent regioselectivity and modest enantioselectivity when conducted in the presence of catalytic amounts of a monodentate, P-chiral ferrocenyl phosphine ligand. 1-(Trimethylsilyl)-substituted enynes are shown to be effective coupling partners in these reactions, and the dienol products thus formed readily undergo protiodesilylation under mild conditions. Keywords: allylic alcohols; asymmetric catalysis; C À C bond formation; nickel; reductive coupling 1,3-Dienes are important and versatile intermediates in organic synthesis. They are able participants in an array of cycloaddition reactions, most notably the Diels-Alder reaction, [1 -3] and there are a variety of efficient methods for preparing them.[4] Many of these, such as olefination reactions, [5,6] cross-couplings, [7,8] alkene/ enyne metathesis, [9] and other transformations, [10] facilitate convergent synthesis because they simultaneously construct a new carbon-carbon bond. Recently, our laboratory [11] and others [12] reported a new strategy for the synthesis of 1,3-dienes via transition metal-catalyzed reductive coupling reactions of 1,3-enynes and aldehydes. In addition to forming a new carbon-carbon bond, these methods also generate a stereogenic center, [13] allowing for efficient construction of chiral 1,3-dienes that have been widely employed in diastereoselective Diels-Alder reactions. [14,15] We now report the first enantioselective examples of catalytic reductive coupling reactions of 1,3-enynes, promoted by sub-stoichiometric amounts of a monodentate, P-chiral ferrocenyl phosphine ligand.Previous work from our laboratory has shown that nickel-catalyzed reductive couplings of aryl-substituted alkynes (Ar À C C À R) and aldehydes are highly enantioselective when ( þ )-neomenthyldiphenylphosphine (NMDPP) is employed as a chiral ligand (Scheme 1).[16]We have also described a class of P-chiral, monodentate ferrocenyl phosphines (e.g., 1a, 1b; Figure 1) that are efficient promoters of related couplings of aliphatic internal alkynes (Alkyl À C C À Alkyl') and aldehydes, [17] and of multi-component coupling reactions of alkynes, imines, and organoboron reagents. [18] Reductive coupling reactions of 2-methyl-1-hexen-3-yne and benzaldehyde in the presence of catalytic amounts of Ni(cod) 2 and ( þ )-NMDPP, and a stoichiometric quantity of triethylborane (Et 3 B), afforded dienol 2a in low yield and low enantioselectivity, but with high regioselectivity (Table 1, entry 1). Ferrocenylphosphine 1a maintained this high regioselectivity but enhanced both the efficacy and enantioselectivity of the transformation (entry 2). ortho-Isopropylphenyl-substiScheme 1. Asymmetric, nickel-catalyzed reductive coupling of arylalkynes and aldehydes. tuted-ferrocenylphosphine 1b provided even higher levels of both reactivity and enantioselectivity (entry 3). A variety of aromatic aldehydes undergo reductive coupling with 2-methyl-1-hexen-3...

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“…[f] Reaction was conducted at 65 8C. [19] [g] Reaction was conducted at 38 8C. [19] [h] Absolute configuration of the major enantiomer determined to be ( R ) via Moshers ester analysis.…”

Section: Standard Procedures For the Protiodesilylation Of Dienyl Alcomentioning

confidence: 99%

Asymmetric Catalytic Reductive Coupling of 1,3‐Enynes and Aromatic Aldehydes

et al. 2005

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“…Transfer epititanation occurs selectively at an internal alkyne with enyne substrates bearing disubstituted alkenes (Scheme 64D) -interestingly, this example also demonstrates selective reactions of conjugated Ti-alkyne complexes, where protonation delivers a 1,3-diene but reaction with an aldehyde engages the alkene of the conjugated complex such that bond formation occurs in a manner typical of allylic metal reagents. 145 Hydroxyl-directed early transition metal metallacycle-mediated coupling chemistry has also been explored in contexts that illustrate a great degree of chemoselectivity in functionalization reactions of polyunsaturated substrates. Scheme 50A and B have already presented some interesting observations with respect to chemoselectivity in a complex setting, and recent explorations have defined additional processes that enable site-and stereoselective functionalization of polyenes by metallacycle-mediated bond construction.…”

Section: Chemoselective Coupling Reactions Of Polyenesmentioning

confidence: 99%

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

Micalizio¹

2014

Comprehensive Organic Synthesis II

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“…The synthetic utility of the reaction was further demonstrated by an efficient synthesis of azasugars [63] and allopumiliotoxin 267A, [62] which is one component of the toxic skin secretion of certain neotropical frogs and displays significant cardiotoxic activity. Using the Ti(II)-mediated INAS reaction as a key step, optically active 5-[(t-butyl)dimethylsilyl]oxy-2-cyclohexenone was prepared efficiently from readily available 4-chloro-3-hydroxybutanoate or epichlorohydrin as shown in Equation 26. [64±66] While the enone thus synthesized reacted with R 2 Cu(CN)Li 2 with excellent diastereoselectivity to afford an anti-1,4-addition product, the reaction with RCu(CN)Li gave a syn-1,4-addition product almost exclusively as shown in Equation 27.…”

Section: Synthetic Applications Of the Inas Reactionmentioning

confidence: 99%

“…and 11; thus, an expedient method for the construction of multiple stereogenic centers from readily available enynes has been opened up. [26] Table 2 summarizes the results for asymmetric construction of three stereogenic centers using optically active imines derived from phenylethylamine as the first electrophile.…”

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The Divalent Titanium Complex Ti(O-i-Pr)4/2i-PrMgX as an Efficient and Practical Reagent for Fine Chemical Synthesis

Sato

Okamoto

2001

Adv. Synth. Catal.

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This account describes synthetic transformations of unsaturated hydrocarbons, such as alkynes, alkenes, and dienes, mediated by the divalent titanium reagent Ti(O‐i‐Pr)4/2 i‐PrMgX, which proceed via (ν 2‐alkene)‐ or (ν 2‐alkyne)‐titanium intermediates. Many of these transformations are otherwise difficult or require multi‐step reaction sequences. Since Ti(O‐i‐Pr)4 and i‐PrMgX are non‐toxic and available in bulk at low price, the reagent satisfies the qualifications for use in large‐scale synthesis. 1 Introduction 2 A General View of the Ti(O‐i‐Pr)4/2 i‐PrMgX Reagent 3 Generation of an (ν 2‐Alkyne)Ti(O‐i‐Pr)2 and its Utilization as a Vicinal Vinylic Dianion 4 Preparation of Allyl‐ and Allenyltitanium Reagents and their Synthetic Utility 4.1 Allylic Titanium Reagents 4.2 Allenylic Titanium Reagents 5 Intramolecular Nucleophilic Acyl Substitution (INAS) Reactions Mediated by Ti(O‐i‐Pr)4/2 i‐PrMgX 5.1 Scope of the Reaction 5.2 Synthetic Applications of the INAS Reaction 6 Intra‐ and Intermolecular Coupling of Olefins and Acetylenes 6.1 Intramolecular Reactions 6.2 Intermolecular Reactions 6.3 Tandem Inter‐ and Intramolecular Reactions 7 Summary and Outlook

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Expedient Construction of Multiple Stereogenic Centers in an Acyclic System via the Addition of Aldehydes, Ketones, and Chiral Imines to an Enyne−Titanium Alkoxide Complex

Cited by 50 publications

References 7 publications

Asymmetric Catalytic Reductive Coupling of 1,3‐Enynes and Aromatic Aldehydes

Asymmetric Catalytic Reductive Coupling of 1,3‐Enynes and Aromatic Aldehydes

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

The Divalent Titanium Complex Ti(O-i-Pr)4/2i-PrMgX as an Efficient and Practical Reagent for Fine Chemical Synthesis

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