N-Tosyl-1,2,3-triazoles as Scaffolds for Morpholines: The Total Synthesis of (–)-Chelonin A

Abstract

Substituted morpholine derivatives appear frequently in biologically active compounds and thus novel routes towards such structures are of great synthetic interest. Herein, we report the total syntheses of chelonin A, a morpholine-derived marine natural product with reported antibacterial and anti-inflammatory activity. The key step in this process was a rhodium carbenoid 1,3-insertion into a bromohydrin O−H bond, followed by annulation, leading to a 2,6-disubstituted-3,4-dihydro-2H-1,4-oxazine core. This work was then extended to deliver the first asymmetric total synthesis of (−)-chelonin A using an enantioenriched bromohydrin prepared in-turn via asymmetric transfer hydrogenation of an -bromoketone.

Dirhodium-Catalyzed Transannulation ofN-Sulfonyl-1,2,3-triazoles to 2,3-Dehydropiperazines

“…Phenyl triazole 18a bearing a p -methoxy substituent performed well under our reaction conditions to afford 19a [91%, X-ray structure (see the Supporting Information)], as did the more sterically demanding o -methoxy isomer 18b , delivering 19b in 96% yield. We were pleased to observe successful incorporation of benzonitrile substrate 18d , given the nitrile functional group typically reacts with α-imino rhodium carbenoids to generate imidazoles, and had given very low yields in our analogous OH insertion procedure previously . Phenyl triazole substrates containing electron-withdrawing aryl substituents (-OBz, -CF 3 , and -COMe) also produced 2,3-dehydropiperizines ( 19c , 19e , and 19f , respectively) in excellent yields.…”

“…This constitutes a three-step, one-pot synthesis of deprotected dehydropiperazines, allowing the carbamate to act as a masked amine surrogate where typically weakly basic aliphatic amines fail to undergo 1,3-N-H insertion with α-imino rhodium carbenoids . During this investigation, we were able to isolate the intermediate enamine , from a reaction of methanesulfonyl-1 H -1,2,3-triazole 12 and 11a with Rh 2 ( S -NTTL) 4 (1 mol %) at 70 °C (see the Supporting Information).…”

“… It was anticipated that a dirhodium(II)-catalyzed synthesis of 2,3-dehydropiperazines 10 would also be possible through a reaction between 7 and alkyl halides 8 to afford Z -enamides 9 followed by an in situ cyclization. This synthetic approach is similar to our previous synthesis of 2,6-substituted 1,4-oxazines . A related triazole transannulation has previously enabled access to 1,2-dihydropyrazines from 2 H -azirines. , Notably, a rhodium-catalyzed methodology toward 2,3-dihydropiperazines was also attempted previously by treating carbamate-protected bicyclic aziridine derivatives with N -tosyl-1,2,3-triazoles. , Unfortunately, this work was ultimately unsuccessful, with the carbenoid instead reacting exclusively through the carbamate carbonyl oxygen.…”

Total Synthesis of (–)-Rauvomine B via a Strain-Promoted Intramolecular Cyclopropanation

“…With secondary amines 19 and 33 in hand, we screened a number of N-crotylation conditions on both substrates 42 using a chiral Ir catalyst 43 and palladium catalysts 44 with symmetrical and non-symmetrical p-allyl precursors, and even simple halide/pseudohalide electrophiles without success (see Table S1 for details). We attribute the failure of these N-allylations with secondary electrophiles to the steric hindrance around the amine in 19/33, with the flanking substituents likely oriented in a bis-equatorial fashion (35) Despite our failure to engage a secondary alkyl electrophile with hindered secondary amines 19 and 33, we were able to install a less hindered allyl unit using the N-Alloc group as a latent allyl source (Figure 2B). 46 In the event, decarboxylation of 32 under Pd(PPh3)4 catalysis in the absence of an allyl trap delivered N-allylamine 36 (61%, with 35% of 19).…”

“…A few aspects of the key cyclopropanation step warrant discussion. Although the Fokin-Gevorgyan transformation of N-sulfonyl-1,2,3-triazoles to a-imino carbenes has found some use in total synthesis, [32][33][34][35] to the best of our knowledge it is yet to be leveraged for cyclopropanation in natural product synthesis. Limited examples of intramolecular While these reports provided encouragement, our proposed indoloquinolizidine system 26 presents a number of conformational complications that are projected to affect the feasibility of this key transannular transformation (Figure 1D).…”