Synthesis of some members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family

Abstract

The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family has been carried out. (+/-)-Lycoricidine and (+/-)-7-deoxypancratistatin were assembled through a one-pot Stille/intramolecular Diels-Alder cycloaddition cascade to construct the core skeleton. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further heating at 160 degrees C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used for the stereocontrolled installation of the remaining functionality present in the C-ring of the target molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/decarboxylation/elimination sequence to introduce the required pi-bond in the C-ring of (+/-)-lycoricidine, and (2) conversion of the initially formed Diels-Alder adduct into an aldehyde intermediate which then undergoes a stereospecific decarbonylation reaction mediated by Wilkinson's catalyst to set the trans-B-C ring junction of (+/-)-7-deoxypancratistatin.

Figure 1

Some Representative Lycorine-type Alkaloids

Scheme 1

Key Disconnections for the Synthesis of (±)-Lycoricidine

Scheme 2. Synthesis of a Model 2-Amidofuran

Reagents: (a) MeO₂CCH₂P(O)(OEt)₂, NaH, Cul, DMF, 100°C, 61%; (b) NaH, CH₂O, THF, 25 °C, 83%; (c) NaClO₂, H₂O₂, NaH₂PO₄, acetone, 10 °C, 93%; (d) (COCl)₂, CH₂Cl₂, n-BuLi, BocNHfuran, 65% (2 steps).

Scheme 3

Cycloaddition/Rearrangement Cascade

Scheme 4

An Unusual Acid-Catalyzed Rearrangement

Scheme 5

A Proposed Mechanism for the Rearrangement

Scheme 6

Dihydroxylation of the IMDAF Cycloadduct

Scheme 7

Decarboxylation/Elimination Sequence

Scheme 8

Intramolecular Diels-Alder Reaction

Scheme 9

Stereocontrolled Reduction of N-Acyliminium Ion Precursor

Scheme 10

Final Steps in the Synthesis of (±)-Lycoricidine

Scheme 11

Preference for the cis-Isomer

Scheme 12

Use of Wilkinson’s Catalyst to Control Stereochemistry

Scheme 13

Synthesis of (±)-7-Deoxypancratistatin