Organic Letters
Letter
ent-copalyl diphosphate (ent-CPP, 8, Scheme 1a), which upon
enzymatic cyclization delivers a common biosynthetic precursor
tertiary alcohol 14a (Scheme 1b) may serve as a possible
precursor. Although the C8 radical cyclization is disfavored with
C12−OH according to our previous calculations, we still hope
that the ent-atiserene skeleton may be formed under these
conditions. Finally, in order to fully map the substrate-based
dienyne radical cyclization, a small collection of dienyne
substrates, ketone 13 and alcohol 14 (Scheme 2), were derived
from a common intermediate dienone, (+)-12.2t
Scheme 1. Skeletal Diversity-Oriented Synthesis Guided by
Our Radical Cyclization Logic
Scheme 2. Unified Synthesis of Dienyne Precursors 13 and 14
ent-pimarenyl cation (9).6 Subsequent successive carbocation
rearrangement through presumably ent-beyeranyl cation (10) or
ent-kauranyl cation (11) generates all types of tetracyclic Isodon
diterpenoid skeletons. Indeed, this biogenetic rearrangement
pathway has served as a great inspiration to a lot of previous
synthetic endeavors, and based on this, many successful
interconversions of tetracyclic Isodon diterpenoid skeletons
have been reported.2
Our group has a continuous interest in diversity-oriented
synthesis of natural product scaffolds.7,8 Inspired by our
successful application of dienyne radical cyclization for the
synthesis of jungermannenone2i,p and ent-kaurene,2t we
considered the feasibility of a substrate-based approach rather
than a reagent-based approach which is generally found in
tetracyclic Isodon diterpenoid biosynthesis and previous
synthetic studies.4 The reagent-based approach affords diverse
scaffolds upon treatment of a common substrate with different
reagents, and the substrate-based approach involves the use of a
collection of different substrates and common reaction
conditions. We further envisaged that the C12 ketone precursor
with a quaternary carbon stereogenic center at C13 position
(13a, Scheme 1b) could deliver an ent-beyerene-type scaffold.
For the ent-atiserene-type skeleton, the C12 propargylated
Starting from the common intermediate (+)-12, we sought to
develop a unified route to rapidly generate all types of dienyne
precursors. As illustrated in Scheme 2, stereoselective α-
propargylation with 12 gave 17, which followed by sequential
methylation and TMS deprotection delivered 13a and 13b.
Ketone 13c was obtained through α-propargylation with 15, and
DBU induced C13 epimerization of 18. Toward dienyne 14,
direct 1,2-propargylation of dienone (+)-12 delivered a mixture
of dienynes 14a and 14b. Subsequent reduction of 13c formed
14c; nevertheless, further reduction of the ketone moiety of 13a
and 13b provided a mixture of inseparable isomers. Overall, a
small collection of new dienyne precursors including three
ketones and three alcohols were rapidly prepared within 1−3
steps starting from dienone (+)-12 with moderate to good
overall yields. Of note, the aforementioned well-defined
B
Org. Lett. XXXX, XXX, XXX−XXX