Communication
collective syntheses of more than 30 natural protoberberine al-
kaloids lacking a 13-methyl group and five aporhoeadane alka-
loids within four to eight steps.
by Yu). Next, we explored the exo-carbocyclization reaction of
4a to construct the tetracyclic framework, corresponding to
the protoberberine core. After unsuccessful attempts on the
radical cyclization using either AIBN/Bu3SnH or SmI2, we then
examined the possibility of Pd-catalyzed reductive carbocycli-
zation of 4a. Among all protocols examined, including
Pd(PPh3)4/Et3SiH, Pd(PPh3)4/Bu3SnH, Pd(PPh3)4/HCO2H/Et3N,
Pd(OAc)2/PPh3/HCO2Na, and Pd(PPh3)4 and HCO2Na, we fortu-
nately found that the combination of Pd(PPh3)4 and HCO2Na in
DMF at 1008C effected the reductive exo-carbocyclization to
provide the desired tetracyclic protoberberine framework 5a
in 79% yield. It was noted that longer reaction time (e.g., over-
night) caused a significant decomposition of the product 5a.
Next, we attempted the catalytic hydrogenation of the exo-
methylene of 5a for the synthesis of 13-methylprotoberberine.
After examination of many conditions, including Pd/C/H2 in
MeOH (EtOAc, or toluene), Pd(OH)2/C/H2 in MeOH, and PtO2/H2
in MeOH under various temperatures, PtO2/H2 (1 atm) in acetic
acid was found to be the only condition that could effectively
promote the hydrogenation, which furnished (Æ)-thalictrica-
vine[17] (6a) as the single diastereomer in a nearly quantitative
yield. The structure of our synthetic thalictricavine (6a) was
further confirmed by X-ray diffraction analysis and the NMR
data of our synthetic thalictricavine were in good agreement
with those reported for thalictricavine. To date, this constitutes
the most efficient and shortest synthesis (69.5% overall yield in
three steps). Oxidation of thalictricavine with iodine in ethanol
completed the synthesis of the quaternary 13-methylprotober-
berine salt dehydrothalictricavine[18] (7a, also known as 13-
methylberberine) in 99% yield, which is, to date, the first de
novo synthesis. We recognized that this two-step protocol
(5a!6a!7a) provides a reliable and high-yielding access to
the family of the quaternary 13-methylprotoberberines, but it
was not redox-economical[19] for employment of the reduction
and subsequent oxidation. Therefore, we were interested in
the idea of isomerization and concomitant oxidation (5a!
8a!7a) in a single operation. After some experimentation,
we found that the RhCl3-catalyzed isomerization[20] of 5a oc-
curred with concomitant oxidation under air atmosphere
(open flask) to produce the corresponding quaternary dehy-
drothalictricavine (7a) in a single step but with only 65% yield.
Notably, direct oxidation of 5a with iodine in ethanol resulted
in a 1:1 inseparable mixture of 7a and an unknown com-
pound.
Strategically inspired by recent work on redox-A3 reactions[10]
by the research groups of Seidel,[11] Yu,[12] and Ma,[13] we con-
ceived that a redox-A3 reaction of a tetrahydroisoquinoline
(THIQ), acetylene, and a 2-bromoaldehyde could be exploited
to construct the key tetracyclic protoberberine skeleton with
the C ring decorated with exo-alkene as the potential methyl
group if the subsequent Pd-catalyzed reductive exo-selective
carbocyclization[14] could be realized (Figure 1b). Furthermore,
if the exo-methylene at C13 could be cleaved by a method
such as NaIO4/RuCl3 or O3/Me2S and the oxidation state of the
C ring could be manipulated after cleavage, it would be possi-
ble for us to access other members of protoberberine alkaloids
lacking 13-methyl group. Optimistically, if this strategy is suc-
cessfully implemented, a rapid assembly of a large collection
of natural protoberberines and 13-methylprotoberberines and
their analogues could be achieved efficiently. Additionally, the
key redox-A3 reaction employs a one-pot transformation of al-
dehyde, amine, alkyne (A3)[15] and could be regarded as a multi-
component reaction, which will provide the most efficiency
and flexibility.[16]
We first concentrated on identification of redox-A3 reaction
conditions for THIQ (1a), aldehyde 2a, and acetylene (3a) be-
cause none of them has been employed in the previous exam-
ples of redox-A3 reaction. After preliminary examinations of the
redox-A3 reaction conditions reported previously,[11–13] we were
delighted to find that the redox-A3 reaction of 1a, 2a, and 3
under a slightly modified condition (addition of catalytic
amount of benzoic acid using CuI as the catalyst without the
phosphine ligand) gave an excellent yield of 4a on both milli-
gram and gram scales after subsequent desilylation with K2CO3
in methanol (Scheme 1). Remarkably, the addition of benzoic
acid (0.1 equiv) greatly accelerated the conversion, improved
the yield (from <5% to 81%) and reproducibility, and expand-
ed the THIQ scope for the redox-A3 reaction. This exciting
result was in sharp contrast to the observation by Yu and
Seidel. We speculated that the favorable steric effects of ortho-
substituents of 2-bromo-5,6,-dimethoxybenzaldehyde might
mitigate the unfavorable electronic effects of THIQ (observed
This extremely short and highly efficient route to 13-methyl-
protoberberines were further demonstrated in the collective
total synthesis of additional 20 natural 13-methylprotoberber-
ines[21] and four analogues in excellent overall yields with only
three or four steps (Table 1). In particular, we accomplished the
first de novo total synthesis of the following 15 natural prod-
ucts (names highlighted in bold in Table 1): 6i–l, 7a–c, 7 f, and
7h–n. When compared with previous total syntheses[22] of 6a,
6c, 6d, 6e, 6g, 7d, and 7e, our syntheses were shorter and
more efficient with a single flexible and catalytic strategy. It is
noteworthy that hydrogenation and debenzylation could be
accomplished by palladium catalysis in a single step with ex-
cellent yields to provide otherwise poorly accessible 2- or 3-de-
Scheme 1. Synthesis of thalictricavine and 13-methylprotoberberine through
redox-A3 reaction and Pd-catalyzed reductive carbocyclization.
Chem. Eur. J. 2016, 22, 7084 – 7089
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