Amphoteric Amino Aldehydes Enable Rapid Assembly of Unprotected Amino Alcohols

Hili, Ryan; Yudin, Andrei K.

doi:10.1002/anie.200705776

Cited by 38 publications

(9 citation statements)

References 29 publications

(23 reference statements)

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“…During this process, the aziridine nucleophile had attacked the intermediate iminium ion before the Wagner-Meerwein shift occurred. The high diastereoselectivity observed during indium-mediated allylation of aziridine aldehyde dimers has been attributed to a dimeric transition state mediated by the open dimer species (Scheme 3) [9]. Our DFT analysis of the transition state assembly is consistent with the high selectivity.…”

Section: Methodssupporting

confidence: 72%

“…In the past several years, we have demonstrated construction of complex alkaloid frameworks [8], diastereoselective allyl transfer reactions [9], and ''re-routed'' aza-Michael processes [10]. Thus, N-benzyl tryptamine was transformed into a complex pentacyclic alkaloid core through a single cascade transformation upon exposure to an aziridine aldehyde dimer (Scheme 2) [8].…”

Section: Methodsmentioning

confidence: 99%

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Synthesis of heterocycles using amphoteric molecules

Yudin

2012

Chem Heterocycl Comp

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Amphoteric molecules contain functional groups that are normally regarded as incompatible. We have shown that reagents of this class, particularly unprotected aziridine aldehydes and alpha-boryl aldehydes, enable rapid synthesis of complex heterocycles and facilitate the development of new synthetic processes that are characterized by high bond-forming efficiency.Due to their ability to interact with protein and nucleic acid targets, heterocycles constitute the core structure of a vast range of modern pharmaceuticals. Accordingly, chemoselective construction of heterocycles is one of the important challenges facing contemporary synthesis. Our efforts over the past several years have focused on designing small molecule reagents that allow efficient and chemoselective assembly of simple molecular fragments into complex skeletons. Chemoselective syntheses proceed with minimal reliance on protecting groups [1], enabling highly atom-[2] and step-economical processes [3]. Amphoteric molecules have served as the centerpiece of my lab's approaches to chemoselectivity. The term ''amphoteric'' is of Greek origin: amphoteros literally means ''both of two'' [4]. Although the term itself is not related to any particular chemical property, the word has been used in order to refer to a molecule that can act as both Brønsted acid and Brønsted base. Thus, amino acids are amphoteric, characterized by an isoelectric point at which the molecule exists in its zwitterionic state. Depending on pH and other factors, the position of proton, governed by thermodynamics, is subject to change. Figure 1 illustrates a comparison between amino acids and amino aldehydes. The former rely on thermodynamics for their stabilization, whereas the latter are transient species; their lability reflects Fig. 1. Amphoteric molecules and their stability: thermodynamic and kinetic factors.

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Section: Methodssupporting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Synthesis of heterocycles using amphoteric molecules

Yudin

2012

Chem Heterocycl Comp

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“…VAPOL was prepared according to literature procedures and was determined to be at least 99% optically pure. 27 The preparation of aziridine esters cis - 11a , b , 18 cis - 15a , b , 18 cis - 16a , b , 18 cis - 27a , 18 trans - 27a , 28 cis - 29a , b , 7a and 35 ( 20 ) has been previously reported.…”

Section: Methodsmentioning

confidence: 99%

“…To a flame-dried 25 mL round-bottomed flask filled with argon were added trans -2-carboxyethyl-3-phenylaziridine 27a ( 28 ) (150 mg, 0.784 mmol) and 5 mL of MeOH followed by the addition of NaHCO 3 (197 mg, 0.450 mmol, 3.00 equiv). The flask was put in an ultrasonic bath for 5 min, and then (Boc) 2 O (428 mg, 1.96 mmol, 2.50 equiv) was added.…”

Section: Methodsmentioning

confidence: 99%

β-Amino Esters from the Reductive Ring Opening of Aziridine-2-carboxylates

Zhao

Wulff

2014

J. Org. Chem.

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A general study is undertaken to examine the scope of the reductive ring opening of aziridine-2-carboxylates with samarium diiodide. The competition between C–C and C–N bond cleavage is examined as a function of the nature of the N-substituent of the aziridine, the nature of the substituent in the 3-position of the aziridine, and whether the substituent in the 3-position is in a cis or trans relationship with the carboxylate in the 2-position. The desired C–N bond cleavage leads to β-amino esters that are the predominant products for most aziridines with an N-activating group. However, C–C cleavage products are observed with an aryl group in the 3-position; this can be particularly pronounced with cis-aziridines where a nearly equal mixture of the two is observed. Exclusive formation of the C–N cleavage product is observed for all aziridines with the strongly N-activating p-toluene sulfonate group. Similarly high selectivity is observed for the 2-trimethylsilylethyl sulfonate group (SES), which is easier to remove. The utility of these methods is illustrated in the synthesis of protected forms of (R)-β3-DOPA and l-DOPA from the same aziridine, the former by SmI2-mediated reductive opening at C-2 and the latter by palladium-mediated reductive opening at C-3.

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“…Bench‐stable amphoteric α‐amino aldehydes mask their unstable functional groups through the formation of an intramolecular equilibrium, that is, hemiacetals, as observed with 2‐deoxy‐2‐amino sugars . Intermolecular masking with an excess amount of a nucleophile also enhances the stability of amino aldehydes, yielding again acetals, cyanohydrins, or amine derivatives .…”

Section: Introductionmentioning

confidence: 99%

Amino Aldehydes Revisited

2017

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The enzymatic oxidation of amino alcohols was studied to address the long‐standing problem of product stability. Amino aldehydes, highly sought and unstable compounds, can be generated under mild conditions if they are immediately protected. Utilizing a range of alcohol dehydrogenases (ADHs) and semicarbazide as a scavenger, the enantioselective synthesis of protected amino aldehydes is possible. Glycerol dehydrogenase from Gluconobacter oxydans (GoGDH) displayed excellent enantioselectivity but limited substrate scope, whereas horse liver ADH catalyzed a broad range of conversions with low enantioselectivities.

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Amphoteric Amino Aldehydes Enable Rapid Assembly of Unprotected Amino Alcohols

Cited by 38 publications

References 29 publications

Synthesis of heterocycles using amphoteric molecules

Synthesis of heterocycles using amphoteric molecules

β-Amino Esters from the Reductive Ring Opening of Aziridine-2-carboxylates

Amino Aldehydes Revisited

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