Synthetic studies on the key component of the new generation of quinolonecarboxylic acid, DU-6859. 1. Synthesis of (1R,2S)-2-fluorocyclopropylamine by the use of optical resolution
“…The 2-trimethylsilylethyloxycarbonyl (Teoc)-protected enamine 1g was available from carbamoyl chloride 3 , which in turn was synthesized by the reaction of aldimine 2b with diphosgene (Cl 3 COCOCl) according to a published procedure (Scheme ) …”
The regio-and stereoselective synthesis of the protected cis-3-aminooxetanes cis-5 and cis-7 is reported. The oxetanes were obtained by the photocycloaddition of aliphatic (6c-e) and aromatic (4, 6a) aldehydes to the corresponding enamides (1a-d,h) or enecarbamates (1e-g). The enamine derivatives used in the Paterno `-Bu ¨chi reaction were either commercially available or prepared from the corresponding acetaldehyde imines 2 by acylation. The oxetane formation proceeded with good-to-excellent simple diastereoselectivity for aromatic aldehydes (56-82% yield) and moderate selectivity for aliphatic aldehydes (46-55% yield). The cis-3-aminooxetanes are precursors for synand anti-1,2-amino alcohols. The relative configuration established in the photochemical step was retained upon nucleophilic ring opening between the oxygen atom and carbon atom C-4. By this means, syn-1,2-amino alcohols such as 8 and 10 were available in good yields. In contrast, the N-Boc-protected cis-3-aminooxetanes cis-5e and cis-5f were transformed into anti-1,2-amino alcohols. Upon treatment with trifluoroacetic acid, they underwent an intramolecular nucleophilic substitution at the carbon atom C-2 of the oxetane and the oxazolidinones 11 and 12 were formed. Because the substitution occurs with inversion of configuration, anti-1,2-amino alcohols, e.g., ephedrine (15), are accessible.
“…The 2-trimethylsilylethyloxycarbonyl (Teoc)-protected enamine 1g was available from carbamoyl chloride 3 , which in turn was synthesized by the reaction of aldimine 2b with diphosgene (Cl 3 COCOCl) according to a published procedure (Scheme ) …”
The regio-and stereoselective synthesis of the protected cis-3-aminooxetanes cis-5 and cis-7 is reported. The oxetanes were obtained by the photocycloaddition of aliphatic (6c-e) and aromatic (4, 6a) aldehydes to the corresponding enamides (1a-d,h) or enecarbamates (1e-g). The enamine derivatives used in the Paterno `-Bu ¨chi reaction were either commercially available or prepared from the corresponding acetaldehyde imines 2 by acylation. The oxetane formation proceeded with good-to-excellent simple diastereoselectivity for aromatic aldehydes (56-82% yield) and moderate selectivity for aliphatic aldehydes (46-55% yield). The cis-3-aminooxetanes are precursors for synand anti-1,2-amino alcohols. The relative configuration established in the photochemical step was retained upon nucleophilic ring opening between the oxygen atom and carbon atom C-4. By this means, syn-1,2-amino alcohols such as 8 and 10 were available in good yields. In contrast, the N-Boc-protected cis-3-aminooxetanes cis-5e and cis-5f were transformed into anti-1,2-amino alcohols. Upon treatment with trifluoroacetic acid, they underwent an intramolecular nucleophilic substitution at the carbon atom C-2 of the oxetane and the oxazolidinones 11 and 12 were formed. Because the substitution occurs with inversion of configuration, anti-1,2-amino alcohols, e.g., ephedrine (15), are accessible.
“…The reaction was postulated to proceed through an organozinc carbenoid intermediate ( 5 ). While the use of the pyrophoric diethylzinc reagent makes this procedure less attractive on a large scale, it has been used to prepare fluorocyclopropylamines in fair to good yield and moderate to excellent cis-selectivity. , Copper has been used in place of diethylzinc to accomplish the same transformation, but much longer reaction times were required. …”
“…Commercially available solvents and starting materials were used as received. Starting materials, i.e., diacetyl monoxime ( 3a ), 21 benzil monoxime ( 3b ), 22 formaldimine 4a ( 23 ) (in the form of a trimer, i.e., 1,3,5-tribenzylhexahydro-1,3,5-triazine), and acetimine 4c ( 24 ) (monomeric) were prepared following the general literature procedures.…”
A straightforward
access to 2-unsubstituted imidazole
N
-oxides with
subsequent deoxygenation by treatment with Raney-nickel
followed by
N
-benzylation opens up a convenient route
to lepidilines A and C. Both imidazolium salts were used to generate
in situ the corresponding imidazol-2-ylidenes, which smoothly reacted
with elemental sulfur, yielding imidazole-2-thiones. These reactions
were performed either under classical conditions in pyridine solutions
or mechanochemically using solid Cs
2
CO
3
as a
base. The structure of lepidiline C was unambiguously confirmed by
X-ray analysis of its hexafluorophosphate. An analogous protocol toward
lepidilines B and D and their 4,5-diphenyl analogues is less efficient
due to observed instability of the key precursors, i.e., the respective
2-methylimidazole
N
-oxides. Comparison of cytotoxic
activity against HL-60 and MCF-7 cell lines of all lepidilines, as
well as their selected structural analogues (e.g., 4,5-diphenyl derivatives
and PF
6
salts), revealed slightly more potent activity
of the 2-methylated series, irrespectively of the type of counterion
present in the imidazolium salt. Remarkably, the well-known 1,3-diadamantylimidazolium
bromide (the “Arduengo salt”), known as the precursor
of the first, shelf-stable NHC representative, and its adamantyloxy
analogue displayed the most significant cytotoxic activity in the
studied series.
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