Stereoselective nucleophilic additions to the carbon-nitrogen double bond. 3. Chiral acyliminium ions

Polniaszek, Richard P.; Belmont, Stephen E.; Alvarez, R. Michael

doi:10.1021/jo00288a036

Cited by 87 publications

(17 citation statements)

References 3 publications

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“…2.3.1). Attempts to form the corresponding acyliminium ion with a Lewis acid (BF 3´O Et 2 [37], SnCl 4 [38], or CF 3 COOH [39]) and to add allyl trimethylsilane to give the allyl-substituted lactam were unsuccessful. Similarly, transformation of (AE)-47 into the methanesulfonate and subsequent reaction with MeLi did not provide the methylated lactam.…”

Section: Preparation Of Inhibitors With Lipophilicmentioning

confidence: 99%

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Obst¹,

Betschmann²,

Lerner³

et al. 2000

HCA

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A novel class of nonpeptidic, active, and selective thrombin inhibitors has resulted from X‐ray‐structure‐based design and subsequent improvement of the initial lead molecules. These inhibitors possess a bi‐ or tricyclic central core structure with attached side chains to reach the three binding pockets (selectivity S1 pocket, distal D pocket, and proximal P pocket) present in the active site of the enzyme. The key step in the preparation of these compounds is the 1,3‐dipolar cycloaddition between an azomethine ylide, prepared in situ by the decarboxylative method from an aromatic aldehyde and an α‐amino acid, with an N‐substituted maleimide (e.g., see Schemes 1 and 2). All potent inhibitors contain an amidinium residue in the side chain for incorporation into the S1 pocket, which was introduced in the last step of the synthesis by a Pinner reaction. The compounds were tested in biological assays for activity against thrombin and the related serine protease trypsin. The first‐generation lead compounds (±)‐11 and (±)‐19 (Scheme 1) with a bicyclic central scaffold showed Ki values for thrombin inhibition of 18 μM and 0.67 μM, respectively. Conformationally more restricted second‐generation analogs (Scheme 2) were more active ((±)‐22i: Ki=90 nM (Table 1)); yet the selectivity for thrombin over trypsin remained weak. In the third‐generation compounds, a small lipophilic side chain for incorporation into the hydrophobic P pocket was introduced (Schemes 7 and 8). Since this pocket is present in thrombin but not in trypsin, an increase in binding affinity was accompanied by an increase in selectivity for thrombin over trypsin. The most selective inhibitor (Ki=13 nM, 760‐fold selectivity for thrombin over trypsin; Table 2) was (±)‐1 with an i‐Pr group for incorporation into the P pocket. Optical resolution of (±)‐1 (Scheme 9) provided (+)‐1 with a Ki value of 7 nM and a 740‐fold selectivity, whereas (−)‐1 was 800‐fold less active (Ki=5.6 μM, 21‐fold selectivity). The absolute configuration of the stronger‐binding enantiomer was assigned based on the X‐ray crystal structure of the complex formed between thrombin and this inhibitor. Compound (+)‐1 mimics the natural thrombin substrate, fibrinogen, which binds to the enzyme with the Ph group of a phenylalanine (piperonyl in (+)‐1) in the distal D pocket, with the i‐Pr group of a valine (i‐Pr in (+)‐1) in the proximal P pocket, and with a guanidinium side chain of an arginine residue (phenylamidinium group in (+)‐1) in the selectivity S1 pocket of thrombin. A series of analogs of (±)‐1 with the phenylamidinium group replaced by aromatic and aliphatic rings bearing OH or NH2 groups (Schemes 10 – 14) were not effectively bound by thrombin. A number of X‐ray crystal‐structure analyses of free inhibitors confirmed the high degree of preorganization of these compounds in the unbound state. Since all inhibitors prefer similar modes of association with thrombin, detailed information on the strength of individual intermolecular bonding interactions and their incremental con...

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Section: Preparation Of Inhibitors With Lipophilicmentioning

confidence: 99%

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Obst¹,

Betschmann²,

Lerner³

et al. 2000

HCA

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“…Furthermore, the use of TBSOTf as a Lewis acid resulted in significant enhancement of the reaction rate to give almost the same stereochemical outcome (98 and 92% de) with slightly and moderately higher yields (29 and 41%) for the periods of 2 and 3 h (Table 2, entries 4 and 5), respectively. In spite of its increased susceptibility, which should be discriminated from those of unsubstituted structural systems [45–50], it became apparent that this multiply functionalized hemiaminal 4 is well tolerated to undergo direct allylation with the silyl reagents. The results of the above investigations provide one particularly successful route that has the potential to allow direct asymmetric access to the advanced-stage intermediate 7 under precise stereochemical control as well as for circumventing the purification problems related to the diastereomeric impurity in this product.…”

Section: Resultsmentioning

confidence: 99%

A new approach toward the total synthesis of (+)-batzellaside B

Wierzejska¹,

Motogoe²,

Makino³

et al. 2012

Beilstein J. Org. Chem.

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SummaryA new synthetic approach to (+)-batzellaside B from naturally abundant L-pyroglutamic acid is presented in this article. The key synthetic step involves Sharpless asymmetric dihydroxylation of an olefinic substrate functionalized with an acetoxy group to introduce two chiral centres diastereoselectively into the structure. Heterocyclic hemiaminal 4, which could be converted from the resulting product, was found to provide stereospecific access to enantiomerically enriched allylated intermediate, offering better prospects for the total synthesis of this natural product.

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“…A one-pot reduction-methylation procedure using lithium triethylborohydride as the reductant 6 and then acidic methanol gave the 5-methoxy-2-pyrrolidinone 6a in 61% yield after chromatography. The reaction of Nacyliminium ions with vinyl magnesium bromide is well precedented.…”

Section: Resultsmentioning

confidence: 99%