Organic Letters
Letter
reaction partners, cyclopentenones with a quaternary carbon
can be formed.
We then tested different conditions for the first IMPKR.
Treatment of enyne 6 with stoichiometric Co (CO) and
2
8
Herein we report a synthetic study toward (−)-retigeranic
acid A, in which two IMPKRs were used as the key steps to
forge the complex pentacyclic core structure and the bridged
quaternary carbons in a diastereoselective manner.
Our study commenced with known chiral ketone compound
NMO under a CO atmosphere resulted in the formation of
fused tricyclic compound 7 in 72% yield as a single
diastereomer. However, Co (CO) is expensive, and this
2
8
reaction required high-quality NMO. The use of hygroscopic
NMO dramatically decreased the efficiency of the reaction.
We therefore explored alternative ways to prepare this key
intermediate. Initially, we tested the annulation reaction using
a catalytic amount of Co (CO) and TMTU under a CO
1
2
2
(Scheme 1). Cyclic epoxy ketone hydrazone 3, which was
a
Scheme 1. Evaluation of the First IMPKR
2
8
11a
atmosphere,
but the product yield was affected by the
quality of the Co (CO) , and the yield of 7 was inconsistent,
2
8
ranging from 55 to 73%. We finally found out that product 7
could be obtained in 80% yield by treatment of air- and
moisture-stable CoBr with zinc dust (2.0 equiv) in the
2
11b
presence of TMTU.
It is noteworthy that the stereo-
chemistry at the C11a position matched that of (−)-retigeranic
acid A. A conformational analysis I → IV showed that the
enyne−cobalt complex got close to the alkene moiety from
below and eventually forged the C −C bond with excellent
3
a
11a
diastereoselectivity.
,4-Reduction of conjugated carbonyl compound 7 with
copper hydride using lithium tri-tert-butoxyaluminum hydride
1
16
(
LTBA) as the hydrogen source followed by trapping of the
resultant enolate anion with iodomethane afforded ketone 8 in
0% yield with excellent diastereoselectivity (Scheme 2).
9
Reduction of the ketone into an alcohol and subsequent
removal of the hydroxyl group through a Barton−McCombie
17
radical deoxygenation delivered silyl ether 10.
18
The subsequent desilylation/oxidation sequence trans-
formed 10 into ketone compound 11. Conversion of the
ketone into an enol silyl ether followed by a visible-light-
promoted organocatalytic aerobic oxidation developed by our
19
group generated cyclopentenone 12 in 70% yield over two
steps. A Grignard reaction of 12 using 2-methylallylmagnesium
chloride gave allylic alcohol 13, and its structure was
established by X-ray crystallographic analysis. Pyridinium
2
0
dichromate (PDC)-mediated oxidative rearrangement of
allylic alcohol 13 afforded enone 14 in 86% yield over two
steps. The next step was a selective reduction of the enone into
a ketone in the presence of the terminal alkene moiety, which
proved to be difficult because the terminal alkene was easily
reduced under many reductive conditions. Eventually, this was
a
Reagents and conditions: (a) entry 1: p-TsNHNH (1.05 equiv),
2
EtOH, 50 °C, 1 h, 20−30%; entry 2: p-NsNHNH (1.1 equiv),
2
pyridine (1.3 equiv), THF/EtOH, −78 to 0 °C to rt, 4 h, 42%; entry
3
0
: 2,4-DNsNHNH (1.05 equiv), pyridine (1.3 equiv), THF, −78 to
2
realized by treatment of enone 14 with Li/NH (l) at −78 °C,
3
°C, then rt, 18 h, 48−85%; entry 4: o-NsNHNH (1.0 equiv),
2
and ketone 15 was obtained as an inseparable mixture of
diastereoisomers in a ratio of 4:1 and a combined yield of 80%.
Subsequent installation of the alkyne moiety at the α-position
of the ketone was achieved through a three-step reaction
sequence, specifically, aldol addition, activation of the resultant
alcohol with methanesulfonyl chloride, and base-promoted β-
elimination of the newly generated mesylate, delivering enyne
16 in 78% yield.
NaHCO (3 equiv), THF, −15 to 50 °C, 36 h, 86%; (b) MePPh Br
3
3
(
1.3 equiv), t-BuOK (1.3 equiv), THF, 0 °C to rt, 24 h, 86%; (c)
conditions 1: Co (CO) (1.2 equiv), NMO (4.0 equiv), CO, toluene,
2
8
9
0 °C, 8 h, 72%; conditions 2: Co (CO) (10 mol %), TMTU (60
2 8
mol %), CO, toluene, 90 °C, 48 h, 55−73%; conditions 3: CoBr (10
mol %), TMTU (60 mol %), Zn (2 equiv), 4 Å MS, CO, toluene, 90
2
°C, 18 h, 80%. TBS = tert-butyldimethylsilyl, p-Ts = p-toluenesulfonyl,
p-Ns = p-nitrobenzenesulfonyl, 2,4-DNs = 2,4-dinitrobenzenesulfonyl,
o-Ns = o-nitrobenzenesulfonyl, NMO = 4-methylmorpholine N-oxide,
TMTU = tetramethylthiourea, MS = molecular sieves.
Enyne compound 16 was an inseparable mixture of
diastereoisomers. After a Luche reduction, allylic alcohol 17
was isolated as the major isomer in 70% yield, but the
stereochemistry at C5b could not be identified (Scheme 3).
Subjecting 17 to IMPKR conditions successfully produced a
fused pentacyclic compound in a highly diastereoselective
manner. However, this proved to be C ,C -bis-epi-1 after a
prepared in situ from the condensation of ketone 2 and the
aromatic sulfonylhydrazide, could undergo an Eschenmoser−
Tanabe fragmentation to deliver acyclic alkynone 5.
Preliminary investigation by variation of the sulfonylhydra-
zide, solvent, and base showed that a yield of 86% could be
obtained when the reaction was carried out with o-nitro-
benzenesulfonylhydrazide and sodium bicarbonate in THF.
A Wittig olefination of ynone 5 produced enyne compound 6.
1
3
5
b
6a
1
4
1
1
careful analysis of the H− H NOESY spectra, meaning that
the stereochemistry at C of the major diastereoisomer in the
5
b
15
mixed enyne 16 was the opposite of that in (−)-retigeranic
acid A.
5
093
Org. Lett. 2021, 23, 5092−5097
Wang, Xiao
