Organic Letters
Letter
Scheme 2. Pd-Catalyzed AAA of α-Aryl Cyclic Vinylogous
Esters
Scheme 3. Concise, Divergent, and Enantioselective Total
Syntheses of (+)-Oxomaritidine and (−)-Mesembrine
a
a
Reaction conditions: 4 (0.2 mmol, 1.0 equiv), allyl acetate (2.0
equiv), [(η3-C3H5)PdCl]2 (2.5 mol %), L2 (5 mol %) in THF (2.0
mL) at −78 °C to −20 °C. Yield of isolated product 5. Er determined
by chiral HPLC analysis. DME (1,2-dimethoxyethane) as the
b
c
solvent. DME as solvent, at −78 °C to −40 °C.
intermediate 7, a reductive amination/cyclization cascade
afforded (−)-mesembrine20,21 in one step. This catalytic
enantioselective total synthesis of mesembrine takes only five
steps from commercially available starting materials.
between the aryl group and the chiral ligand might also be
responsible for the high er in the allylation having the aryl group.
Having achieved the direct intermolecular Pd-AAA of α-aryl-
substituted cyclic vinylogous esters, we preliminarily explored its
utility in the enantioselective divergent natural product
synthesis. One crinine-type Amaryllidaceae alkaloid (+)-oxo-
maritidine12 and one Sceletium alkaloid (−)-mesembrine13 were
selected as our present synthetic targets. Crinine-type alkaloids,
a large subclass (over 80 members) of the Amaryllidaceae
alkaloid family, have attracted much attention from synthetic
chemists due to their interesting bioactivities and diverse
structures.14 However, catalytic enantioselective synthesis
remained rather limited,15 and the catalytic enantioselective
total synthesis of oxomaritidine, to the best of our knowledge, has yet
to be developed.16 One route for the enantioselective synthesis of
(+)-oxomaritidine was developed as in Scheme 3. (S)-5d,
obtained above, was treated with DIBAL-H to afford γ-allyl-γ-
aryl-substituted cyclohexenone 6 on aqueous acidic workup in
70% yield.17 Oxidative cleavage of the allyl group afforded the
aldehyde 7. 7 underwent intermolecular reductive amination to
afford the cis-aryl hydroindole 9 on N-Boc-protection. 9 was
transformed into the corresponding enone 10 via Saegusa
oxidation.18 The removal of the N-Boc group of 10 with
trifluoroacetic acid followed by the Pictet−Spengler-type
cyclization delivered (+)-oxomaritidine in 83% overall yield.
Since oxomaritidine has been previously transformed into
maritidine,19 this also constitutes an enantioselective formal
synthesis of (+)-maritidine. Divergently, from the common
In conclusion, a direct enantioselective synthesis of 6-allyl-6-
aryl-3-ethooxycyclohex-2-en-1-ones, an important structural
motif common in natural products chemistry, has been achieved
through the development of the first direct intermolecular Pd-
AAA of α-aryl-substituted cyclic vinylogous ester substrate class.
Unlike α-alkyl-substituted cyclic vinylogous esters, α-aryl-
substituted cyclic vinylogous esters underwent the direct
intermolecular Pd-AAA with good enantioselectivity. Based on
the preliminary exploration of this method, the first catalytic
enantioselective total synthesis of Amaryllidaceae alkaloid
(+)-oxomaritidine and a short, five-step catalytic enantioselec-
tive total synthesis of Sceletium alkaloid (−)-mesembrine were
achieved divergently. The synthetic utility conferred by the α-
aryl cyclic vinylogous ester substrate class is expected to find
further applications in the enantioselective synthesis of other
structurally diverse alkaloid natural products.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
Experimental procedures, analytical data, copies of NMR
spectra for all new compounds and HPLC spectra for all
922
Org. Lett. 2021, 23, 920−924