Design and synthesis of a library of tetracyclic hydroazulenoisoindoles

Abstract

Forty-four tetracyclic hydroazulenoisoindoles were synthesized via a tandem cyclopropanation/Cope rearrangement, followed by a Diels-Alder sequence from easily available five-membered cyclic cross-conjugated trienones. These trienones were obtained from two different routes depending upon whether R(1) and R(2) are alkyl or amino acid derived functional groups, via a rhodium(I)-catalyzed cycloisomerization reaction. To increase diversity, four maleimides and two 1,2,4-triazoline-3,5-diones were used as dienophiles in the Diels-Alder step. Several Diels-Alder adducts were further reacted under palladium-catalyzed hydrogenation conditions, leading to a diastereoselective reduction of the trisubstituted double bond. This library has demonstrated rapid access to a variety of structurally complex natural product-like compounds via stereochemical diversity and building block diversity approaches.

Figure 1

A Reagent-Based Differentiating Pathway

Figure 2

Novel Chemotypes from Triene and Cyclopentenone Scaffolds

Scheme 1

Tandem Cyclopropanation/Cope Rearrangement of Trienone

Scheme 2

[Rh(OAc)₂]₂-Catalyzed Cyclopropanation/Cope Rearrangement

Scheme 3

Diels-Alder Reaction of Hydroazulenones 17 and 18

Figure 3

X-ray Structures of Diels-Alder Adducts 20 and 22

Scheme 4

Stereochemistry Determination via Hydrogenation Product 24

Figure 4

Trienone Building Blocks.

Figure 5

Dienophile Building Blocks in the Diels-Alder Reaction.

Scheme 5

Synthesis of Allene-ynones 10{1-11}

Scheme 6

Synthesis of Trienones 11{1-11}

Scheme 7

Synthesis of Hydroazulenoisoindoles 29{1-11,1-6}

Scheme 8

Palladium-Catalyzed Hydrogenation