Enantiodivergent Synthesis of Benzoquinolizidinones from L-Glutamic Acid.

Benzoquinolizidinone systems were synthesized in both enantiomeric forms from L-glutamic acid. The key chiral arylethylglutarimide intermediate was synthesized from dibenzylamino-glutamate and homoveratrylamine. Aldol reaction of the glutarimide afforded a mixture of syn and anti-aldol adducts. Subsequent regioselective hydride reduction of the glutarimide carbonyl followed by N-acyliminium ion cyclization afforded a product with opposite absolute configurations at C3 and C11b. Cope elimination of the dibenzylamino group then converted the two diastereomers into enantiomers.

Total synthesis of the marine toxin phorboxazole A using palladium(II)-mediated intramolecular alkoxycarbonylation for tetrahydropyran synthesis.

The potent antitumor agent phorboxazole A was synthesized from six subunits comprising C1-C2 (115), C3-C8 (98), C9-C19 (74), C20-C32 (52), C33-C41 (84) and C42-C46 (85). Tetrahydropyrans B and C containing cis-2,6-disubstitution were fabricated via palladium(II)-mediated intramolecular alkoxycarbonylation which, in the case of tetrahydropyran C, was carried out with catalytic palladium(II) and p-benzoquinone as the stoichiometric re-oxidant. Tetrahydropyran D was obtained by a stereoselective tin(IV)-catalyzed coupling of a C9 aldehyde with an allylsilane, and the C19-C20 connection was made using a completely stereoselective Wittig-Schlosser (E) olefination. Coupling of the oxazole C32 methyl substituent with the intact C33-C46 δ-lactone 3was accompanied by elimination of the vinyl bromide to a terminal alkyne, but the C32-C33 linkage was implemented successfully with 83 and C33-C41 lactone 84. The C42-C46 segment of the side chain was then appended via Julia-Kocienski olefination. The macrolide portion of phorboxazole A was completed by means of an Ando-Still-Gennari intramolecular (Z)-selective olefination at C2-C3 which required placement of a (dimethoxyphosphinyl)acetate moiety at C24. Final deprotection led to phorboxazole A via a route in which the longest linear sequence is 37 steps and the overall yield is 0.36%.

N-(9,11-Dimeth-oxy-4-oxo-2,3,4,6,7,11b-hexa-hydro-1H-pyrido[2,1-a]isoquinolin-3-yl)benzamide.

The title schulzeine derivative, C(22)H(24)N(2)O(4), crystallizes with two crystallographically independent mol-ecules of almost identical conformation in the asymmetric unit. The tricyclic core of schulzeine has a fused-three-ring system comprising the tetra-hydro-isoquinoline and δ-lactam moieties. In both mol-ecules, the pyridine ring adopts a twisted-boat conformation, whereas the lactam ring is in a boat conformation. The two meth-oxy groups are slightly twisted from the attached benzene ring [C-O-C-C torsion angles = -21.3 (2) and -20.5 (2)° in mol-ecule A, and -6.3 (2) and -16.2 (2)° in mol-ecule B] and the benzamide moiety is in a (-)-synclinal conformation with respect to the lactam ring. In the crystal, mol-ecules are linked into V-shaped dimers by inter-molecular N-H⋯O hydrogen bonds and weak C-H⋯O inter-actions. These dimers are stacked into V-shaped columns along the a axis. Adjacent columns are further linked in an anti-parallel manner. C-H⋯π inter-actions are also observed.

Total synthesis of phorboxazole a. 1. Preparation of four subunits.

[Structure: see text] Four subunits of the potent antitumor agent phorboxazole A were constructed; fragments C20-C32 and C9-C19 containing tetrahydropyrans A and B, respectively, were assembled using palladium-catalyzed intramolecular alkoxycarbonylation.

Total synthesis of phorboxazole A. 2. Assembly of subunits and completion of the synthesis.

[Structure: see text] Subunits of phorboxazole A containing C1-C2, C3-C8, C9-C19, C20-C32, C33-C41, and C42-C46 were connected in a sequence that first linked C32 with C33 and then C41 with C42. A C3-C8 fragment was joined to C9-C19, and the assembled unit was then joined with the left half of 1. Closure of the macrolide was accomplished by esterification of the C24 alcohol followed by intramolecular Horner-Wadsworth-Emmons condensation to set the (E)-C2-C3 alkene.