Letter
Total Syntheses of Paraconic Acids and 1,10-seco-Guaianolides via a
Barbier Allylation/Translactonization Cascade of 3‑(Bromomethyl)-
ACCESS
*
ABSTRACT: A palladium-catalyzed Barbier allylation/translactoniza-
tion cascade reaction was established for the rapid construction of β,γ-
disubstituted α-exo-methylene-γ-butyrolactone, an important motif in
sesquiterpenes. Dimethyl zinc played significant roles in both steps for
the umpolung of π-allylpalladium as a nucleophile and promoting a
Lewis acid-mediated translactonization. This sequence showed a broad
substrate scope and was further harnessed for the synthesis of two
paraconic acids as well as the first protecting-group-free total synthesis
of two 1,10-seco-guaianolides.
esquiterpene lactones are a rich source of bioactive
afforded the trans-configuration, and the use of an excess of
dimethyl zinc promoted a further translactonization to give
11 (Figure 1c).
S
natural products, and an α-exo-methylene-γ-butyrolactone
1
moiety is often central to their biological activity. Well-
2
studied and recent examples include helenalin (1),
We initiated our work using hexanal (8a) and bromo-
3
4
5
parthenolide (2), arglabin (3), deoxyelephantopin (4),
lactone 7, a reported substrate pair for the palladium-
6
15
and tagitinin F (5) (Figure 1a). This framework is also
found in paraconic acids (6), and the synthesis of α-exo-
catalyzed reaction, and compared the results of this reaction
7
with the results of the CrCl -mediated allylation, which
2
methylene-γ-butyrolactones has attracted significant interest
affords the trans-configuration (10a, Scheme 1). Indeed, the
products were spectroscopically different. However, perform-
ing the palladium-catalyzed reaction under the same
conditions but with 1.2 equiv of dimethyl zinc afforded the
8
over the years. The biosynthetic pathways leading to
sesquiterpene lactones intrinsically produce a combinatorial
output of natural products; accordingly, different diastereo-
meric relationships in the butyrolactones are found across the
family of natural products (Figure 1a).
The presence of a hydroxyl group two carbons away from
the methylene unit of the γ-butyrolactone in many
sesquiterpenes offers the opportunity for a strategic
disconnection to an aldehyde (8) and an allylic bromide 3-
same product as that obtained with the CrCl -mediated
2
allylation (10a). Puzzled by these results, we next treated the
trans-configuration product (10a) obtained in the CrCl2-
mediated allylation with dimethyl zinc and observed a clean
conversion to the same product as that obtained in the
palladium-catalyzed reaction with an excess of dimethyl zinc
(
bromomethyl)-2(5H)-furanone (7, Figure 1b). This reaction
(
11a). Collectively, these results suggest that the palladium-
0
0
2+
9
is well-precedented using a variety of metals (Zn , In , Cr )
catalyzed reaction yields the trans-configuration, likely
proceeding through a Zimmerman−Taxler transition state
and affords the desired allylation product (10) in a good
yield and diastereoisomeric purity based on a Zimmerman−
(
Scheme 1, I) as with other metals. However, the excess of
10
Traxler transition state. This methodology has been widely
dimethyl zinc used for the umpolung of π-allylpalladium as a
1
1
used in the total syntheses of butyrolactone antibiotics,
15
nucleophile can promote a Lewis acid-mediated trans-
5
,12
9
9,13
sesquiterpene lactones,
paraconic acids, and lignans.
lactonization. The complexation of a Lewis acid to the
secondary alcohol and carbonyl results in unfavorable steric
While this strategy reliably affords an anti-relationship
between the substituents, examples of a syn-relationship (9)
among the natural products beg for alternative method-
ologies. Our interest in the synthesis and biological
Received: December 16, 2020
Published: January 27, 2021
5
,14
investigation of sesquiterpene lactones
led us to revisit a
report of a palladium-catalyzed diastereoselective allylation
using dimethyl zinc as a stoichiometric reducing agent to
1
5
afford a syn-configuration. We found that the trans-
formation with 1 equiv, or a slight excess, of dimethyl zinc
©
2021 American Chemical Society
9
69
Org. Lett. 2021, 23, 969−973