Efficient Total Synthesis of (+)-Dihydropinidine, (−)-Epidihydropinidine, and (−)-Pinidinone

Kavala, Miroslav; Mathia, František; Kožı́šek, Jozef; Szolcsányi, Peter

doi:10.1021/np100852p

Cited by 41 publications

(17 citation statements)

References 39 publications

(23 reference statements)

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“…Under mild hydrogenation conditions,compound 6a was readily converted into the 2,5-disubstituted piperidine 9 in good yield [Eq. [13] In summary,w eh ave described an ovel, efficient, and metal-free approach for the elusive azidocyanation of unactivated alkenes.Avariety of synthetically useful alkyl nitriles are readily prepared in good yields,a nd, most importantly, Angewandte Chemie with exquisite regio-and stereo-selectivities.T he intramolecular cyano migration strategy is combined with alkene difunctionalization for the first time,o pening up new vistas for this area. (1), left].…”

Section: Angewandte Chemiementioning

confidence: 99%

Combination of a Cyano Migration Strategy and Alkene Difunctionalization: The Elusive Selective Azidocyanation of Unactivated Olefins

2016

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Section: Angewandte Chemiementioning

confidence: 99%

Combination of a Cyano Migration Strategy and Alkene Difunctionalization: The Elusive Selective Azidocyanation of Unactivated Olefins

2016

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“…The required diketone 1 a was obtained in one step, starting from commercially available diyhdropyrane-2-one 7 (Scheme 2). [15] Although some syntheses are highly sophisticated, long reaction sequences (up to 14 steps), [15f,h] the use of protecting groups or stoichiometric amount of auxiliaries [15c,g] hampered their overall efficiency. to obtain (R)-4 a, as described above.…”

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confidence: 99%

“…Piperidine (2S,6R)-6 a has already been the object of numerous synthetic efforts, which have resulted in a variety of asymmetric syntheses based on, for example, chiral auxiliaries and chiral precursors. [15] Although some syntheses are highly sophisticated, long reaction sequences (up to 14 steps), [15f,h] the use of protecting groups or stoichiometric amount of auxiliaries [15c,g] hampered their overall efficiency. Thus, the chemoenzymatic [16] synthesis of 2,6-disubsituted chiral piperidines based on the regioselective amination of diketones presented herein represents the shortest route by far, with an excellent overall yield.…”

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confidence: 99%

Regio‐ and Stereoselective Monoamination of Diketones without Protecting Groups

et al. 2012

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Regioselective transformations are highly desirable in organic synthesis, since they allow for the differentiation between two or more (chemically identical) reactive centers, [1] which is otherwise only possible by employing sophisticated and laborious protection strategies. [2] However, protectinggroup-free strategies are superior and have received outstanding merits for their successes. [3,4] Although the regioselective amination of, for example, alkanes, [5] allylic systems, [6] or indoles, [7] has been recently described, the regioselective asymmetric bioamination of diketones has not yet been reported, to the best of our knowledge. For example, diketones, such as 1,5-diketo compounds, may serve as possible precursors for a chiral piperidine scaffold. [8] Consequently, we chose 2,6-diketones 1 as model substrates to investigate the possible asymmetric regioselective amination employing w-transaminases (w-TAs; Scheme 1). [9,10] Various (S)-and (R)-stereoselective w-transaminases were tested initially for the transformation of diketone 1 a at a substrate concentration of 50 mm (Table 1). Five w-TAs (Chromobacterium violaceum, [10i, 11] Bacillus megaterium, [10i, 12] (R)-Arthrobacter, [10b] Aspergillus terreus, and Hyphomonas neptunium [10b,h] ) out of six showed perfect regioselectivity for the differentiation between the two keto groups. Hence, the amination occurred exclusively at the sterically less demanding w-1 ketone moiety, leading to the amino ketone 2 a, while the w-3 position remained untouched. The intermediate amino ketone 2 a spontaneously cyclized, finally giving D1piperideine 4 a. Only the w-TA from Vibrio fluvialis [9h, 13] (entry 3) showed diminished regioselectivity, since regioisomer 5 a was formed in minor quantities (5-7 %) along with regioisomer 4 a at high conversion. Notably, the corresponding diamine was never detected in any experiment.Using alanine as amine donor led to the formation of pyruvate as a by-product, which was removed/recycled to alanine through the use of an alanine dehydrogenase (AlaDH) system. In all cases, perfect conversions were achieved for this system. When removing pyruvate by reduction to lactate through the use of a lactate dehydrogenase (LDH) system, the conversions varied from 56-98 %. The Scheme 1. Regioselective amination of various 1,5-diketones. Table 1: Asymmetric reductive amination of diketone 1 a. [a] AlaDH system LDH system Entry w-TA conv [%] 4 a [%] ee 4 a [%] 5 a [%] conv [%] 4 a [%] ee 4 a [%] 5 a [%] 1 C. violaceum > 99 > 99 > 99 (S) < 0.1 93 93 > 99 (S) < 0.1 2 B. megaterium > 99 83 [b] > 99 (S) < 0.1 98 98 > 99 (S) < 0.1 3 V. fluvialis > 99 93 > 99 (S) 7 98 92 > 99 (S) 6 4 (R)-Arthrobacter > 99 87 [b] > 99 (R) < 0.1 63 63 > 99 (R) < 0.1 5 A. terreus > 99 > 99 > 99 (R) < 0.1 56 56 > 99 (R) < 0.1 6 H. neptunium > 99 89 [b] > 99 (R) < 0.1 78 78 > 99 (R) < 0.1 [a] Conversions/compositions and ee values were determined by GC-FID analysis. Reaction conditions: diketone 1 a (50 mm), lyophilized E. coli cells containing the overexpressed w-T...

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“…Furthermore, compound 6 a could be selectively transformed into the cyclic imine 10 by means of the Staudinger ligation [Eq. (1), left] …”

Section: Methodsmentioning

confidence: 99%

Combination of a Cyano Migration Strategy and Alkene Difunctionalization: The Elusive Selective Azidocyanation of Unactivated Olefins

Ren

Zhu

2016

Angewandte Chemie

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A conceptually new, efficient, and metal‐free approach for the challenging azidocyanation of unactivated alkenes is presented. The strategy of intramolecular distal cyano migration is combined with alkene difunctionalization for the first time. A variety of useful azido‐substituted alkyl nitriles are prepared in good yields and, most importantly, with exquisite regio‐ and stereo‐selectivities.

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Efficient Total Synthesis of (+)-Dihydropinidine, (−)-Epidihydropinidine, and (−)-Pinidinone

Cited by 41 publications

References 39 publications

Combination of a Cyano Migration Strategy and Alkene Difunctionalization: The Elusive Selective Azidocyanation of Unactivated Olefins

Combination of a Cyano Migration Strategy and Alkene Difunctionalization: The Elusive Selective Azidocyanation of Unactivated Olefins

Regio‐ and Stereoselective Monoamination of Diketones without Protecting Groups

Combination of a Cyano Migration Strategy and Alkene Difunctionalization: The Elusive Selective Azidocyanation of Unactivated Olefins

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