Angewandte
Communications
Chemie
Scheme 2. Scalable synthesis of rac-Jungermannenones B (1) and C (2). AIBN=azobisisobutyronitrile, DABCO=1,4-diazabicyclo[2.2.2]octane,
DMAP=4-N,N-dimethylaminopyridine, DMF=N,N-dimethylformamide, HMPA=hexamethylphosphoramide, NaHMDS=sodium bis(trimethylsi-
lyl)amide, PPTS=pyridinium p-toluenesulfonate, Py=pyridine, TCDI=N,N’-thiocarbonyldiimidazole, Tf =trifluoromethanesulfonyl, THF=tetrahy-
drofuran.
plored, presumably because of the severe regioselectivity
concern in simple substrates. Nonetheless, we anticipated
that, if successful, the jungermannenone framework could be
installed in a straightforward manner from either the dienyne
were elucidated based on two-dimensional (2D) NMR
spectroscopic analyses.
[16]
With the dienynes 5 and 6 in hand, we conducted 1,6-
dienyne cyclizations with both substrates. Our initial attempts
for the development of a catalytic 1,6-dienyne cyclization
reaction led to failure using both 5 and 6, despite extensive
screening. Finally, upon treatment of 5 with tri-n-butyltin
hydride (2 equiv) and AIBN (50 mol%), reductive radical
cyclization occurred. Strikingly, we obtained the cyclization
product 16 exclusively in 64% yield, rather than the product
15, after in situ destannylation with PPTS. The structure of 16
was initially determined based on 2D NMR spectroscopy and
later unambiguously confirmed by X-ray crystallographic
5
or 6. The dienyne 6 can be derived through a reductive
cascade from the ketone 7, which in turn may be generated
from inexpensive geraniol (8) by a catalytic intramolecular
[
9]
hydroarylation reaction.
As shown in Scheme 2, our synthesis commenced with the
preparation of 1-geranyl-4-methoxybenzene (10). The desired
1
0 was obtained in 78% yield over two steps on a 100 gram
[
10]
scale. Subsequent intramolecular electrophilic hydroaryla-
tion of 10, using Samesꢀ protocol in the presence of 1 mol%
[16,17]
RuCl , proceeded smoothly to furnish the known tricyclic
analysis of its acetate derivative (17).
Thus, we managed
3
[9,11,12]
intermediate rac-11.
Finally, the ketone 7 was obtained
to install simultaneously the bicyclic[3,2,1]octene skeleton
and the endocyclic tetrasubstituted alkene moiety (the
jungermannenone framework) by a 1,6-dienyne reductive
radical cyclization using 5.
through a sequential hydroarylation/benzylic oxidation pro-
cess within 65% yield.
Treatment of 7 with Birch reduction conditions (Na/NH3,
EtOH) at À788C triggered a reductive cascade which
generated the dienone rac-14 in 54% yield upon isolation
after acidic workup. The reduction cascade is believed to
proceed through initial stereoselective reduction of the
ketone to the alcohol 12, with subsequent Birch reduction
Starting from 16 (Scheme 2), selective oxidative cleavage
of the exocyclic double bond proceeded smoothly and
[18]
provided the ketone 18 in 83% yield. Final installation of
exo-enone by a-methylenation using bis(dimethylamino)me-
thane and acetic anhydride enabled the first scalable synthesis
[13,14]
[4d]
and final acid-mediated hydrolysis of 13 to yield rac-14.
of rac-2 in nine steps (1.6 g prepared). Barton–McCombie
The sequence was easily performed on a decagram scale for
one run and more than 25 grams of rac-14 has been prepared.
Selective propargylation of rac-14 provided 6 in 75% yield
deoxygenation of 18 followed by a-methylenation delivered
rac-1, thus completing the first synthesis of rac-1 in 10 steps.
[19]
In both cases, the spectroscopic data fully matched that of the
[15]
[1b,16]
upon isolation (90% combined yield, d.r. 5:1).
Luche reduction of 6 yielded another dienyne substrate, 5, in
3% yield upon isolation (85% combined yield, d.r. 6:1). In
Further
natural isolate.
The current 1,6-dienyne reductive radical cyclization is
especially noteworthy for its scalability and regioselectivity
(Scheme 3a). Using other reaction conditions (reductive
7
both cases, the stereochemistry of the major stereoisomers
Angew. Chem. Int. Ed. 2016, 55, 3112 –3116
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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