An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan® piperazine intermediate

Rossen, Kai; Pye, Philip J.; DiMichele, Lisa; Volante, R. P.; Reider, Paul J.

doi:10.1016/s0040-4039(98)01484-1

Cited by 103 publications

(66 citation statements)

References 7 publications

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“…[190] The iminodicarboxylic acid derivatives formed with aldehydes can also cyclize to 2,6-piperazine diones in THF/tBuOK in good yields. In an interesting variant, aamino acids like 216 react with a-haloaldehydes such as 217 and isocyanides to form aziridine derivatives (218). [191] The one-step formation of the b-lactam ring starting from b-amino acids, oxo compounds, and isocyanides is a very early and interesting application of the U-4CR.…”

Section: Cyclic Variants Of the U-mcrs With Bifunctional Parent Compomentioning

confidence: 99%

“…After the Ugi reaction of 262, base-supported cyclization of 263, racemization, and enantioselective hydrogenation, the crixivan precursor 264 was isolated with good overall yield and excellent enantioselectivity. [218] The described synthesis is an advantageous alternative to the classic route. [219] The phenol moiety of salicylaldehydes can serve as the acidic function in the U-4CR.…”

Section: Multicomponent Reactions With Isocyanidesmentioning

confidence: 99%

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Multicomponent Reactions with Isocyanides

Dömling

Ugi

2000

Angew. Chem. Int. Ed.

3,969

1,635

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Multicomponent reactions (MCRs) are fundamentally different from two‐component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic‐chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low‐molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.

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Section: Cyclic Variants Of the U-mcrs With Bifunctional Parent Compomentioning

confidence: 99%

Section: Multicomponent Reactions With Isocyanidesmentioning

confidence: 99%

Multicomponent Reactions with Isocyanides

Dömling

Ugi

2000

Angew. Chem. Int. Ed.

3,969

1,635

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“…Using Ugi-4CR the important piperazine-pharmacophor 8 could be used as a component in the large scale synthesis of Crixivan 7 by the Merck Company and so the number of steps was reduced by 6 steps from 18 down to 12 (33 %)! Scheme 12 [162,163].…”

Section: Nifedipine and Xylocain Synthesesmentioning

confidence: 99%

Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)—The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules

Eckert

2017

Preprint

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Synergistic effects between reactions, reagents and catalysts can lead to minor heats of reaction and occur as an inherent result of multi-component reactions (MCRs) and their extensions. They enable syntheses to be performed at a low energy level and the number of synthesis steps to be drastically reduced in comparison with 'classical' two-component reactions. The very high potential for variability, diversity and complexity of MCRs additionally generates an extremely diverse range of products, thus bringing us closer to the aim of being able to produce tailor-made and extremely low-priced materials, drugs and libraries.Keywords: multicomponent reaction; MCR; post condensation modification PCM; post condensation cyclisation PCC; MFCR; multifunction catalysis; variability; diversity; complexity; efficiency of synthesis. PrologueThe high discrepancy between traditional feasibility mania and rational efficiency assessment in chemical synthesis became immediately apparent to the author while working on his thesis and during everyday laboratory life. On the one hand, classic peptide synthesis with an inefficient, extremely high number of synthesis steps and on the other hand, elegant multicomponent reactions that can make such efforts unnecessary. This double strategy in chemical synthesis has given the author cause to reflect (Picture 2) on how to close this gap using a consistent procedure. Picture 2. Problem in chemical syntheses relating to terms of producibility, ecology and economy.

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“…48 Initially the HIV protease inhibitor Crixivan TM (MK 639) 29 (Scheme 1.10) could not be prepared very well by a complicated conventional multistep synthesis, but 29 became available when it was prepared by an easier synthesis, whose essential step was accomplished by a U-4CR.…”

Section: The Modern Chemistry Of the Isocyanidesmentioning

confidence: 99%

The Four‐Component Reaction and Other Multicomponent Reactions of the Isocyanides

Ugi¹,

Werner²

2007

Methods and Reagents for Green Chemistry

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An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan® piperazine intermediate

Cited by 103 publications

References 7 publications

Multicomponent Reactions with Isocyanides

Multicomponent Reactions with Isocyanides

Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)—The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules

The Four‐Component Reaction and Other Multicomponent Reactions of the Isocyanides

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An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan® piperazine intermediate

Cited by 103 publications

References 7 publications

Multicomponent Reactions with Isocyanides

Multicomponent Reactions with Isocyanides

Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)&mdash;The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules

The Four‐Component Reaction and Other Multicomponent Reactions of the Isocyanides

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Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)—The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules