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. 2022 Jan 21;87(2):1398-1420.
doi: 10.1021/acs.joc.1c02700. Epub 2022 Jan 6.

Evolution of a Short and Stereocontrolled Synthesis of (+)-7,20-Diisocyanoadociane

Philipp C Roosen  1 , Alexander S Karns  1 , Bryan D Ellis  1 , Christopher D Vanderwal  1   2
Affiliations

Evolution of a Short and Stereocontrolled Synthesis of (+)-7,20-Diisocyanoadociane

Philipp C Roosen et al. J Org Chem. .

Abstract

A full account of the development of a concise and highly stereoselective synthesis of (+)-7,20-diisocyanoadociane (DICA)─a structurally complex isocyanoditerpene with potent antiplasmodial activity─is described. The strategy that evolved relies on the rapid construction of unsaturated tricyclic precursors designed to undergo stereocontrolled Birch reductions and a subsequent "bay ring" formation to generate the isocycloamphilectane core. This report is divided into three sections: (1) a description of the initial strategy and the results that focused our efforts on a single route to the DICA core, (2) a discussion of the precise choreography needed to enable a first-generation formal synthesis of (±)-DICA, and (3) the execution of a 13-step second-generation synthesis of (+)-DICA that builds on important lessons learned from the first-generation effort.

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Figures

Figure 1.
Figure 1.
Representative tetracyclic ICTs. Values in brackets are IC50 values against Plasmodium falciparum strain Dd2.
Scheme 1.
Scheme 1.
Synthetic approaches to the completion of DICA, including tactics for introduction of the key isonitrile functional groups and strategies for the synthesis of the tetracyclic architecture of DICA
Scheme 2.
Scheme 2.
Early strategies targeting tricyclic intermediates.
Scheme 3.
Scheme 3.
Honing in on an aromatic ring reduction strategy toward DICA.
Scheme 4.
Scheme 4.
The full reduction of a hydrophenanthrenone and two possible isomeric intermediates drawn from the near symmetry of DICA.
Scheme 5.
Scheme 5.
Hydrophenanthrenone synthesis and reduction attempts
Scheme 6.
Scheme 6.
New key aromatic intermediate with preinstalled trans-ring fusion.
Scheme 7.
Scheme 7.
Successful synthesis and Birch reduction of anisole 35
Scheme 8.
Scheme 8.
Fourth ring closure proves difficult, and some interesting configurational preferences in tricyclic intermediates. Note: although drawn in a three-dimensional perspective, the three-dimensional depictions of compounds do not necessarily represent their lowest energy conformations, as they likely exist largely in twist-boat conformations as shown in part B.
Scheme 9.
Scheme 9.
Change in strategy to permit early installation of two-carbon unit.
Scheme 10.
Scheme 10.
Dihydronaphthalene assembly and Birch reduction
Scheme 11.
Scheme 11.
First successful bay-ring cyclization en route to DICA
Scheme 12.
Scheme 12.
C─H oxidation as a means to process the 1,4-diol protected as a THF ring
Scheme 13.
Scheme 13.
Intercepting (±)-Corey’s dione completes a formal synthesis of racemic DICA
Scheme 14.
Scheme 14.
Formal synthesis analysis and redesign to an improved 2nd-generation approach to DICA.
Scheme 15.
Scheme 15.
Conception of a chiral pool approach to an asymmetric synthesis of DICA
Scheme 16.
Scheme 16.
Dehydrocryptone enables access to key intermediates in enantioenriched form
Scheme 17.
Scheme 17.
Synthesis of tetracyclic lactone 77 bearing the methyl group at C15, with optimization of a one-pot epoxidation/Meinwald rearrangement/cyclodehydration
Scheme 18.
Scheme 18.
Efficient Birch reduction with C15 methyl group and hydrogenation of the resulting cyclohexenone
Scheme 19.
Scheme 19.
Endgame features an unusual axial nucleophilic methylation of ketone 102
Scheme 20.
Scheme 20.
Summary of improvements that led to 2nd-generation total synthesis of DICA
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References

    1. Schnermann MJ; Shenvi RA Syntheses and biological studies of marine terpenoids derived from inorganic cyanide. Nat. Prod. Rep 2015, 32, 543–577. - PMC - PubMed
    1. Garson MJ; Simpson JS Marine isocyanides and related natural products—structure, biosynthesis and ecology. Nat. Prod. Rep 2004, 21, 164–179. - PubMed
    1. Baker JT; Wells JR; Oberhansli WE; Hawes GB A new diisocyanide of novel ring structure from a sponge. J. Am. Chem. Soc 1976, 98, 4010–4012.
    1. Aside from DICA, the only other perhydropyrene ICT that has succumbed to synthesis is 8-isocyanocycloamphilec-10-ene 4, the unnatural enantiomer of which was made by Schindeler and Piers: Schindeler TW Ph.D. Dissertation, University of British Columbia, 1998.
    1. Corey EJ; Magriotis PA Total synthesis and absolute configuration of 7,20-diisocyanoadociane. J. Am. Chem. Soc 1987, 109, 287–289.

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