Birch-Cope project

Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments. However, their complexity creates synthetic challenges in devising efficient methods to make analogs and to make quantities necessary for biological testing (Figure 1). One particular challenge is the enantioselective synthesis of carbocyclic quaternary stereogenic centers.  Synthetic chemistry tools are being developed in our lab which will allow the efficient, enantioselective construction of carbocyclic quaternary stereocenters.

Figure 1: Examples of complex biologically active natural products

platensimycinwebpage_000platensimycin
(S. Singh et al. Nature 2006, 441, 358-361.)

Guanacastepene_A_000guanacastepene
(J. Clardy et al. JACS 2000, 122, 2116-7)

retapumulinwebpage_000retapamulin
(J. Ross et al. Antimicrob Agents Chemother 2006, 50 (7): 2583–6)

The methods combine the previously reported asymmetric Birch reduction-alkylation with the stereospecific Cope rearrangement (Scheme 1).  In sequence, the two reactions permit the efficient transfer of chiral information to enantioselectively create a new carbocyclic quaternary stereogenic center.  Modifications of the o-anisic acid Birch reduction substrate or the alkylation group will allow access to a range of carbocyclic quaternary centers with high levels of stereocontrol. The C-4 disubstituted cyclohexenone structure can serve as valuable intermediates (Tetrahedron Lett. 2004, 45(44), 8183-8185 and J. Org. Chem. 2007, 72(3), 930-937).

Scheme 1. Birch-Cope sequence
BC sequenceIn fact, we have applied the Birchreduction-allylation/Cope rearrangement sequence to the enantioselective synthesis of (+)-mesembrine (Org. Lett. 20068(18), 4007-4010) and (+)-lycoramine ( J. Org. Chem. 2007, 72(18), 6792-6796) (Figure 2).  (+)-Lycoramine is the C-3,4-dihydro derivative of (-)-galanthamine, a drug that is used for the treatment of Alzheimer’s disease.

Figure 2: Natural products synthesized with the Birch-Cope sequence

mesembrine

(+)-mesembrine

mesembrine plant sourceSceletium tortuosum, a succulent plant and a natural source of (-)-mesembrine

lycoramine

(+)-lycoramine

Red_spider_lily_October_2007_Osaka_Japan
The red spider lily plant, a natural source of Amaryllidaceae alkaloids

Our current focus is to further explore the use of the Birch-Cope sequence products (Tetrahedron Lett. 2010, 51(19), 2636-2638). In particular, we are developing inter- and intramolecular carbon nucleophile additions to the cyclohexenone core. One application for an intermolecular carbon nucleophile addition that we are exploring is the synthesis of trigonochinene D (Scheme 2), a recently reported diterpene natural product which, with its unique chemical architecture and antibiotic activity, is representative of the riches found in natural product chemistry. An intramolecular carbon nucleophile conjugate addition has revealed a potential pathway to the gibberillin and ent-kaurene skeleton (Scheme 3). The Birch-Cope sequence and the subsequent transformations of the cyclohexenone intermediate provide new tools and pathways for the synthesis of complex bioactive natural products that can address modern challenges like the burgeoning crisis in antibiotic resistance.

Scheme 2. Proposed trigonochinene D path

TrigonoSynforwebpage_000Scheme 3. Proposed paths to gibberillin and ent-kaurene skeletons
kaurenegibberilwebpage2_000We gratefully acknowledge support of this work from the National Institutes of Health (1-R15-GM087291-01A1).
NIH
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