Organic Letters
Letter
constitutes a formal synthesis of trichoderone A (3). Above all,
it provides the preliminary “cyclase” phase for future prospects
on the second “oxidase” phase toward functionalized
derivatives.
Scheme 2. Synthesis of Ireland−Claisen Substrate 10
Retrosynthetically, compound 5 could be obtained by an
intramolecular Diels−Alder reaction (IMDA), expectedly
favoring the endo cycloadduct. The dienophile in IMDA
substrate 7 can be installed in a two-stage manner involving the
α-acylation of lactam 8 with carboxylic acid 9 after activation
as a mixed anhydride, followed by a selenide-mediated
oxidation of the α-position. Lactam 8 is accessible on a
26
decagram scale from L-leucine. Compound 9 could be
stereoselectively delivered by an Ireland−Claisen rearrange-
2
7
ment of allylic acetate 10, enabling the transfer of
28
stereochemistry from the chiral acetate. In fact, this allylic
acetate is also a sensitive triene, and as far as we know, the
Ireland−Claisen rearrangement has never been applied to such
highly unsaturated substrate. This reaction would however
allow an asymmetric access to acid 9, foreseeing an
enantioselective synthesis of acetate precursor 10. The triene
moiety could be installed on enol triflate 12 by a Suzuki−
2
2
29
Miyaura sp −sp cross-coupling with dienyl boronate 11.
Finally, intermediate 12 could be synthesized from enantioen-
riched syn-diol 13, which was envisioned to be obtained from
thraquinone-1,4-diyl diether], also proposed for trisubstituted
olefins, was evaluated giving a better NMR yield (88%) but a
lower er (86:14). Finally, increasing the loadings of K OsO
2
4
1
-methylcycloheptene 14 through a Sharpless asymmetric
(0.7 mol %) and of (DHQD) PHAL (1.75 mol %) resulted in
2
3
0
dihydroxylation. This reaction was expected to provide a
reliable entry to secure an asymmetric synthesis of compound
good yields (81%) and er (90:10) after 4 days. The reaction
was easily reproducible and scalable (5 g batches).
5
(Scheme 1).
Diol 13 was then engaged in functional group manipulation
toward enol triflate 16 (Scheme 2). The oxidation of the
secondary alcohol was achieved by a Swern protocol, directly
Scheme 1. Retrosynthetic Strategy toward Intermediate 5
35
followed by the protection of the tertiary alcohol in the
presence of 1-(trimethylsilyl)imidazole (TMSImid), affording
1
5 in 84% yield over two steps (11 g scale). The enol triflation
of 15 was performed by deprotonation with LiHMDS in the
presence of PhNTf . The tertiary alcohol was regenerated
2
upon acidic treatment (HCl) at the end of the reaction, giving
unprotected enol triflate 12 in 86% (5 g scale). Significant
difficulties were observed with the acetylation of the tertiary
alcohol, in view of the Ireland−Claisen rearrangement. The
reaction was ineffective in most classical conditions, but finally
succeeded in the presence of isopropenyl acetate under acid
catalysis (pTsOH), to give acetate 16 in 95% (1.4 g scale).
Unfortunately, these conditions were hardly scalable, as the
yields dropped gradually from 95% to 52% when scaling up
from 1.4 to 10 g (this problem was solved by running the
reaction in multiple flasks).
1
-Methylcycloheptene 14 was available from a two-step
The final step to Ireland−Claisen substrate 10 involved a
Suzuki−Miyaura cross coupling between triflate 16 and
dienylboronate 17 (easily available from tiglic aldehyde
see Scheme S1). It was submitted to a Sharpless asymmetric
dihydroxylation to access diol 13 (Scheme 2). Since this
reaction had not been described on alkene 14, we relied on
ligand guidelines to choose the most appropriate conditions
3
1
(
36
Morken; see Scheme S2). The cross coupling performed
well in the presence of Pd(OAc) (10 mol %) and K PO in a
32
2
3
4
and on the reported dihydroxylation of 1-methylcyclohexene
7:3 dioxane/water mixture at 0 °C without ligand, providing
triene 10 in 71% yield after 1 h. In fact, the absence of ligand
allowed us to perform the reaction on a 1.6 g scale, providing
10 as a 4:1 mixture of E and Z isomers, respectively,
supposedly formed through triene isomerization under the
reaction conditions (the undesired Z isomer was eliminated
during the next step, possibly due to lower reactivity attributed
to a steric clash during the Ireland−Claisen rearrangement).
Although electron-rich ligands like PCy , P(2-furyl) , or
or 1-phenylcycloheptene using the ligand (DHQD) PHAL
2
33
[
dihydroquinidine-1,4-phthalazinediyl diether]. In the pres-
ence of commercially available AD-mix-β (involving 1 mol %
of (DHQD) PHAL and 0.4 mol % of K OsO ) combined with
2
2
4
1
1
equiv of CH SO NH in a 1:1 mixture of tBuOH/H O, diol
3 2 2 2
3 was promisingly obtained in 65% yield and an er of 84:16 at
34
room temperature (after 3 days), which were respectively
improved to 69% and 90:10 at 0 °C (after 7 days as the
reaction was slowed down at this temperature). The
3
3
bis(diphenylphosphino)ferrocene (dppf) allowed the reaction
anthraquinone ligand (DHQD) AQN [dihydroquinidine an-
to proceed in good yields (75−80%) and selectivities, these
2
5
756
Org. Lett. 2021, 23, 5755−5760