Scalable Total Synthesis and Biological Evaluation of Haouamine A and Its Atropisomer

Abstract

Haouamine A 1 (1, Figure 1) is a biologically active and architecturally unique alkaloid whose striking feature is a [7]-azaparacyclophane macrocycle containing a highly deformed nonplanar aromatic ring. Somewhat mysteriously, 1 was discovered to exist as a mixture of two rapidly interconverting isomers in solution, a quality attributed to either atropisomerism of the bent arene or slowed pyramidal inversion at nitrogen. Recent computational work 2 supported a theory coupling the latter process with conformational reorganization of the tetrahydropyridine ring but could not rule out atropisomerism. 3 The total synthesis of 1 from this laboratory 4 also did not answer this question unequivocally due to an inability to control the atropisomer formed in the low-yielding cyclophaneforming step, which fortuitously favored the natural planar stereochemistry. 5,6 Here, we report a scalable and controllable route to 1 and its atropisomer (2) that features point-to-planar chirality transfer 7 via a one-step, chemoselective cyclohexenone to phenol oxidation to introduce strain within the macrocycle, a reaction that may find future use in strained chiral cyclophane synthesis. We also demonstrate that the strained cyclophane in 1 is crucial for anticancer activity in PC3 cells.To program planar chirality within the cyclophane macrocycle a reduced compound (3, Figure 1) was selected as the bent phenol precursor. Molecular models suggested that hybridization change of one of the para carbons of the cyclophane from sp 2 to sp 3 should significantly reduce the strain present within the macrocycle and thus make for an accessible intermediate 5c (numerous attempts to form the macrocycle with a preinstalled phenol in this 4 and other 5,6 laboratories have all failed). Furthermore, it was surmised that the point chirality introduced by such a change in hybridization could be used to select for the planar chirality present in 1 and 2. Saturated cyclophane 3 could then be traced † The Scripps Research Institute. ‡ Genentech Inc. 3 equiv), -78°C (for 7) or -95°C (for 8), 1 min, 60% of 9 + 23% 7, or 61% of 10; (e) BBr 3 (7.0 equiv), CH 2 Cl 2 , -78 to 5°C, 20 h, 63% for 1, or 60% for 2.

Regioselectivity in Tether‐Directed Remote Functionalization – The Addition of a Cyclotriveratrylene‐Based Trimalonate to C60 Revisited

“…[39] Cleavage of the iodoethyl groups with zinc in acetic acid yielded cyclotriguaiacylene (-)-5, [34] which, according to Collet and co-workers, has the absolute configuration (P). [38] By assuming a retention of configuration in all steps (Scheme 3) and by taking into account a change in the Cahn-Ingold-Prelog (CIP) priorities [40,41] of the substituents on transition from (+)-6 to (-)-(P)-5, the absolute configuration of the starting material (+)-1 could be assigned as (M) and, accordingly, (-)-1 has the absolute configuration (P).…”

A twist of nature – the significance of atropisomers in biological systems

“…The originally isolated molecule was observed to contain two rapidly-interconverting isomers; the cause for this was thought to be the result of either a slowed pyramidal inversion of the sp 3 nitrogen, or the presence of an atropisomer (Figure 14, compound 19). 104 Computational modelling studies indicated a pyrimidal nitrogen inversion to be the more likely cause of this interconversion, however to confirm the configurational stability of the biaryl axis, an atropselective total synthesis had to be devised, which was eventually realised by Baran et al 106 Figure 13: The structure of Haouamine A (64) and its atropisomer (65), with the highly uncommon distorted benzene ring shown in blue.…”

Stereospecific ring expansion from orthocyclophanes with central chirality to metacyclophanes with planar chirality

“…This result assured the stereochemical integrity during the transfer of central chirality of 5a to planar chirality of 4a (ref. 50), letting us examine the stereospecificity of chiral transfer in more detail. Thus, the twostep ring expansion of orthocyclophane 1b to metacyclophane (±)-4b was carried out (Fig.…”