Synthesis and exploration of electronically modified (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX in palladium-catalyzed enantio- and diastereoselective allylic alkylation: a practical alternative to (R)-(p-CF3)3-t-BuPHOX

Craig, Robert A.; Stoltz, Brian M.

doi:10.1016/j.tetlet.2015.06.039

Cited by 16 publications

(12 citation statements)

References 45 publications

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“…27 This gem-disubstitution effect 28 was further applied in many other areas of research, 29,30 including chiral auxiliaries, 31−35 phosphinooxazoline (PHOX) ligands, 36,37 and recently by Paquin, 38,39 who explored the gem-disubstituent effect, again with the PHOX type ligands, 40,41 as did Stoltz in a very recent report on an electronically modified PHOX ligand. 42 We have recently exploited this effect in the design of oxazoline-containing N,O ligands 4 and P,N ligands 5 and 6, which were applied with success in the diethylzinc and ethylphenylzinc addition to aldehydes and the asymmetric intermolecular Heck reaction, respectively ( Figure 2). 43,44 In general, metal complexes of C-5 gem-disubstituted ligands afforded higher levels of enantioselectivity than those with just an isopropyl group at C-4 and approached that of their tertbutyl counterpart.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis of Bis(oxazoline) Ligands Possessing C-5 gem-Disubstitution and Their Application in Asymmetric Friedel–Crafts Alkylations

et al. 2015

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A series of eight novel bis(oxazoline) ligands incorporating gem-disubstitution on one of the oxazoline rings were prepared from (S)-valine. These ligands are designed as a cost-effective alternative to similar ligands possessing an oxazolinyl C(5)-tert-butyl group derived from expensive (S)-tert-leucine. Four of the ligands possess a C(4)-gem-dimethyl group and four a C(4)-gem-diphenyl group adjacent to the C(5)-isopropyl substituent. Zinc complexes of ligands 11a-h, along with non-C(4)-gem-disubstituted analogues 1a-g, were effective in the Friedel-Crafts alkylation of both indole (up to 74% ee) and 2-methoxyfuran (up to 95% ee) with a series of nitroalkenes. Three of the ligands (11a-c), an iron dichloride complex of ligand 11d and two zinc dichloride complexes, were characterized by X-ray crystallography, one with ligand 11d and the second a bis-tert-butyl-substituted N-methylamine ligand. A direct comparison of the latter structures clearly illustrates the gem-dimethyl effect.

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Section: ■ Introductionmentioning

confidence: 99%

Synthesis of Bis(oxazoline) Ligands Possessing C-5 gem-Disubstitution and Their Application in Asymmetric Friedel–Crafts Alkylations

et al. 2015

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“…For the purposes of synthetic development, chloroallyl ketone ( S )-25 was used as an intermediate in the opposite enantiomeric series from the naturally occurring furanobutenolide-derived norcembranoid diterpenes. The synthesis of the enantiomerically matched norcembranoid diterpenes may be subsequently achieved using either ( R )- t -BuPHOX ( ( R )-24 ) or PHOX ligands derived from ( R )-valine, which have been shown to be comparably effective for the enantioselective formation of ketone ( R )-25 …”

Section: Resultsmentioning

confidence: 99%

Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade

et al. 2018

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An enantioselective and diastereoselective approach toward the synthesis of the tetracyclic scaffold of the furanobutenolide-derived polycyclic norditerpenoids is described. Focusing on synthetic efforts toward ineleganolide, the synthetic approach utilizes a palladium-catalyzed enantioselective allylic alkylation for the construction of the requisite chiral tertiary ether. A diastereoselective cyclopropanation-Cope rearrangement cascade enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold. Investigation of substrates for this critical tandem annulation process is discussed along with synthetic manipulations of the [6,7,5,5]-tetracyclic scaffold and the attempted interconversion of the [6,7,5,5]-tetracyclic scaffold of ineleganolide to the isomeric [7,6,5,5]-core of scabrolide A and its naturally occurring isomers. Computational evaluation of ground-state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures.

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“…The purification of enol ether 369 was complicated by the presence of this impurity, however, limiting the isolated yield of the desired product ( 369 ) to 40% over three steps from ketodioxanone 368 . Nevertheless, access to enol ether 369 enabled the development of the first pivotal reaction en route to ineleganolide, a palladium-catalyzed asymmetric allylic alkylation from the requisite chiral tetrasubstituted center. − Under optimized conditions, employing mesylate 370 as the allyl electrophile and ( S )- t -BuPHOX [( S )- 371 ] as the chiral ligand, ketone ( S )- 372 was formed in 82% yield with 92% ee. For the purpose of synthetic development, choice of ( S )- t -BuPHOX [( S )- 371 ] as the most readily available and cost-effective enantiomer of the ligand dictated formation of the antipode necessary for the synthesis of ineleganolide ( 9 ).…”

Section: Synthetic Studies Toward Polycyclic Furanobutenolide-derived...mentioning

confidence: 99%

Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts

Craig

Stoltz

2017

Chem. Rev.

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The polycyclic furanobutenolide-derived cembranoid and norcembranoid natural products are a family of congested, stereochemically complex, and extensively oxygenated polycyclic diterpenes and norditerpenes. Although the elegant architectures and biological activity profiles of these natural products have captured the attention of chemists since the isolation of the first members of the family in the 1990s, the de novo synthesis of only a single polycyclic furanobutenolide-derived cembranoid and norcembranoid has been accomplished. This article will begin with a brief discussion of the proposed biosyntheses and biosynthetic connections among the polycyclic furanobutenolide-derived cembranoids and norcembranoids followed by a comprehensive review of the synthetic efforts toward each member of the natural product family, including biomimetic, semisynthetic, and de novo synthetic strategies. This body of knowledge has been gathered in order to provide insight into the reactivity and constraints of these compact and highly oxygenated polycyclic structures, as well as to offer guidance for future synthetic endeavors.

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Synthesis and exploration of electronically modified (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX in palladium-catalyzed enantio- and diastereoselective allylic alkylation: a practical alternative to (R)-(p-CF3)3-t-BuPHOX

Cited by 16 publications

References 45 publications

Synthesis of Bis(oxazoline) Ligands Possessing C-5 gem-Disubstitution and Their Application in Asymmetric Friedel–Crafts Alkylations

Synthesis of Bis(oxazoline) Ligands Possessing C-5 gem-Disubstitution and Their Application in Asymmetric Friedel–Crafts Alkylations

Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade

Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts

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