One-Pot, Enantioselective Synthesis of 2,3-Dihydroazulen-6(1H)-one: A Concise Access to the Core Structure of Cephalotaxus Norditerpenes

Article abstract of DOI:10.1002/ejoc.201600321

A one-pot enantioselective synthesis of cis-substituted 2,3-dihydroazulen-6(1H)-one is described. In this cascade reaction, an organocatalyzed asymmetric Michael reaction furnishes a highly optically pure nitrobutylphenol intermediate, which is converted into an annulated tropone species by sequential oxidative dearomatization, conjugate addition, electrocyclic ring opening and nitrous acid elimination in the same reaction vessel. Both aliphatic and aromatic nitroalkenes are good substrates for the one-pot reaction, and this protocol appears to be general for various phenylpropionaldehydes as well. In the case of asymmetrically substituted phenylpropionaldehydes, the regioselectivity is likely determined by both the steric and electronic properties of the substituents. This methodology is successfully applied to the synthesis of the tricyclic core structure of Cephalotaxus norditerpenes.

Full text of DOI:10.1002/ejoc.201600321

DOI: 10.1002/ejoc.201600321
Communication
Norditerpenes
One-Pot, Enantioselective Synthesis of 2,3-Dihydroazulen-6(1H)-
one: A Concise Access to the Core Structure of Cephalotaxus
Norditerpenes
Yongsheng Zheng,[a] Ebrahim H. Ghazvini Zadeh,[a] and Yu Yuan*[a]
Abstract: A one-pot enantioselective synthesis of cis-substi- good substrates for the one-pot reaction, and this protocol ap-
tuted 2,3-dihydroazulen-6(1H)-one is described. In this cascade
reaction, an organocatalyzed asymmetric Michael reaction fur-
nishes a highly optically pure nitrobutylphenol intermediate,
which is converted into an annulated tropone species by se-
quential oxidative dearomatization, conjugate addition, electro-
cyclic ring opening and nitrous acid elimination in the same
reaction vessel. Both aliphatic and aromatic nitroalkenes are
pears to be general for various phenylpropionaldehydes as well.
In the case of asymmetrically substituted phenylpropionalde-
hydes, the regioselectivity is likely determined by both the
steric and electronic properties of the substituents. This meth-
odology is successfully applied to the synthesis of the tricyclic
core structure of Cephalotaxus norditerpenes.
Introduction
Harringtonolide was first isolated from Cephalotaxus harringto-
nia, and X-ray crystallography analysis of the natural product
revealed that it possesses a complex, polysubstituted 2,3-di-
hydroazulen-6(1H)-one moiety fused with a heavily decorated
cyclohexane motif (Scheme 1).[1] After the initial account, harring-
tonolide and related Cephalotaxus norditerpenes including hai-
nanolidol, fortunolide A and B were also extracted from other
Cephalotaxus species.[2] Harringtonolide was reported to have
interesting antineoplastic and antiviral properties,[3] and a more
recent study from Nay's group found that harringtonolide ex-
hibits potent cytotoxicity to KB cells with an IC50 of 43 nM.
[4] The
intriguing structural features, in conjunction with its anticancer
activity, have enticed significant synthetic efforts towards these
norditerpenes.[5] To date, two elegant racemic total syntheses
of the norditerpenes have been achieved by Mander's group
and Tang's group. Both teams employed reliable chemistry to
create the polysubstituted precursor at an early stage and used
novel methodologies to construct the tropone motif at the late
stage of the synthesis. Mander and co-workers utilized a rho-
dium-catalyzed arene cyclopropanation followed by a ring ex-
pansion reaction to create the fused tricyclic system;[6] and
Tang's group disclosed a [5+2] cycloaddition reaction as the key
step to form the core structure of harringtonolide.[7]
One promising strategy for accomplishing an enantioselect-
ive total synthesis of harringtonolide is to create the 2,3-di-
[a] Department of Chemistry, University of Central Florida
4111 Libra Drive, Orlando, FL 32816, USA
Scheme 1. Cephalotaxus norditerpenes and strategies to the core structure.
E-mail: yu.yuan@ucf.edu
http://pegasus.cc.ucf.edu/~yu451170/mysite/index.html
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600321.
hydroazulen-6(1H)-one skeleton, an annulated tropone with
two cis substituents, in optically pure form, and subsequently
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introduce other essential functional groups on the core struc- effectiveness to enable the oxidative dearomatization using
[16]
ture. There are many chemical methods to prepare tropones, KOH as a base. Mild reagents such as Mn(OAc)3[15] and CuCl2
and they have been thoroughly reviewed in the literature.[5h,8]
However, employing the known chemistry to synthesize chiral
dihydroazulenones will require multiple operations to assemble
the stereocenters and the tropone motif. In this regard, a direct
enantioselective cascade protocol[9] that allows access to chiral
dihydroazulenone in a one-pot operation is highly desirable.
Inspired by the methodology developed by Kende[10] and its
application to natural product total synthesis,[11] we envision
that a polysubstituted, enantiomerically pure nitroalkane with
a pendant para-hydroxyphenyl group can be converted into the
corresponding dihydroazulenone, the core structure of harring-
tonolide, by sequential oxidative cyclization and ring expansion.
One advantage of this approach is that optically pure nitroal-
kanes are easily prepared by enantioselective Michael reactions,
for instance, organocatalyzed conjugate additions.[12] To maxi-
mize the overall efficiency, it is appealing to carry out the conju-
gate addition and the subsequent oxidative dearomatization in
the same reaction vessel; thus we chose to convert the alde-
hyde group to the corresponding alcohol and to explore the
feasibility of accessing the enantiomerically pure dihydro-
azulenone in a one-pot process.
only gave a negligible amount of anticipated product or turned
out to be completely ineffective; in contrast, strong SET rea-
gents such as Ce(NH4)2(NO3)6 and Ag2O caused extensive de-
composition of the alcohol intermediate. To our delight,
K3[Fe(CN)6], which was used in Kende's initial report,[10] was
very effective in promoting the one-pot transformation and
gave the cis-disubstituted dihydroazulenone in 85 % yield. A
stabilized organic radical like TEMPO was also tested for the
one-pot reaction, but the desired dihydroazulenone was not
detected. KOH was the optimal base in our current investiga-
tion, and the attempts to replace it with organic bases, for ex-
ample iPr2NEt or DBU, were unsuccessful. In this one-pot proc-
ess, the stereoselectivity was determined by the organocata-
lyzed Michael reaction, and we were pleased to find out that
dihydroazulenone 4a was enantiomerically and diastereomeri-
cally highly pure (ee > 99 %, dr = 14:1). This protocol is very
reliable and can be extended to a gram-scale reaction, and di-
hydroazulenone 4a was obtained in comparable yield and ex-
cellent stereoselectivity.
With the optimized one-pot conditions in hand, we evalu-
ated the generality of this dihydroazulenone synthesis with dif-
ferent nitroalkenes as illustrated in Figure 1. Generally speaking,
substituted nitrostyrenes with either electron-donating or elec-
tron-withdrawing groups were well tolerated for this one-pot
protocol, and cis-dihydroazulenone 4b–4k were isolated in
good yields with excellent enantio- and diasteresoselectivity.
The mildly basic conditions can be adapted to more complex
aromatic groups with different electronic properties. For exam-
ple, nitro olefins derived from 1-naphthaldehyde, carbazole-3-
carbaldehyde and indole-3-carbaldehyde were successfully con-
verted into the optically highly pure dihydroazulenones in mod-
est to good yields. The modest yields of 4m and 4n were par-
tially attributed to the low solubility of the corresponding
nitronates in the mixed solvent. Aliphatic nitroalkenes also pro-
Results and Discussion
The Michael reaction between aldehyde 1a and nitrostyrene 2a
was effected by Jørgensen's catalyst[13] (S)-3 in the presence
of 4-nitrophenol in toluene.[14] Upon completion, the toluene
solution was diluted by an equal volume of MeOH followed by
the addition of 1.0 equiv. of NaBH4, which led to the clean
formation of an alcohol intermediate. Without any purification,
the reaction mixture was subjected to the oxidative conditions
to generate the optically pure dihydroazulenone, and the re-
sults are summarized in Table 1. First, inorganic metal salt based
single electron transfer (SET) reagents were evaluated for their
Table 1. Optimization for the one-pot reaction.[a]
Entry
Oxidant
Base
Yield [%][b]
1
2
3
4
5
6
7
8
9
Mn(OAc)3
CuCl2
Ce(NH4)2(NO3)6
Ag2O
K3[Fe(CN)6]
TEMPO
K3[Fe(CN)6]
K3[Fe(CN)6]
K3[Fe(CN)6]
KOH
KOH
KOH
KOH
KOH
KOH
DBU
< 2
0
decomposition
decomposition
85
0
0
iPr2NEt
KOH
0
83[c]
[a] All reactions were performed on a 0.4 mmol scale with 5 mol-% of (S)-3, 20 mol-% of 4-nitrophenol in toluene at room temp. [b] Isolated yield. [c] The
reaction was performed on a 1 g scale.
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Figure 1. Substrate scope for nitroalkenes.
ceeded smoothly under the optimized conditions and afforded protocol. In contrast, when a carboxylate group activated one
the desired dihydroazulenones 4o and 4p in enantiomerically of the enone systems in the spirocyclic intermediate, only proxi-
highly pure form. However, the Michael reactions with such ali- mal isomer 4x was detected in the crude reaction mixture.
phatic substrates had to be carefully monitored in order to These results suggested that the regioselectivity was likely con-
avoid prolonged reaction time, which would lead to very poor trolled by the steric and electronic properties of the spirocyclic
dr values in the final products. Finally, we tested whether the Michael acceptor, but not the substituents or the stereochemis-
one-pot transformation was applicable to the preparation of try on the cyclopentane. When the carboxylate group was re-
cyclohexane-fused tropones in an enantioselective manner. Un- placed by a mildly electron-donating methyl group, proximal
der the optimized conditions, when (hydroxyphenyl)butyralde- isomer 4y was also formed exclusively with excellent stereose-
hyde 1b was mixed with various nitrostyrenes, cyclohexane lectivity. However, when aldehyde 1c was used in the dihydro-
fused tropones 4q–4v were conveniently prepared in similar azulenone synthesis, a 1:1 mixture of the two regioisomers was
yields and selectivity to that of cyclopentane-fused counter- generated, albeit both 4z and 4z′ retained good optical purity.
parts.
Finally, we assessed whether the one-pot reaction was
applicable to hindered substrates. Thus, a dimethyl-substituted
aldehyde was treated with nitrostyrene 2a in the presence of
the organocatalyst, and the resulting product was subjected
to NaBH4 reduction and oxidative dearomatization; the desired
dihydroazulenone 5 was isolated in 54 % yield.
The tropone motif in Cephalotaxus norditerpene has an addi-
tional methyl group besides the fused cyclopentane, and this
asymmetric substitution pattern warrants a systematic study of
regioselectivity in the second conjugate addition step. As illus-
trated in Figure 2, if the phenyl ring is asymmetrically substi-
tuted, the intramolecular conjugate addition can potentially
To illustrate the practical utility of the dihydroazulenones,
generate a distal isomer (red-arrow pathway) and a proximal some of the one-pot products were used as substrates for dif-
isomer (black-arrow pathway). To better understand the regio- ferent derivatizations (Scheme 2). Amination of the tropone 4w
selectivity, we prepared an aldehyde that possesses a methyl was achieved by the treatment of hydrazine in EtOH,[17] and
group to increase the steric hindrance at the ꢀ-position in one aminodihydroazulenone 6 was obtained as a single isomer. Aro-
of the conjugated enones in the spirocyclic intermediate, and matization of 4w to polysubstituted azulene 7, a family of com-
only distal isomer 4w was obtained according to the one-pot pounds that have found broad applications in materials science
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Figure 2. Regioselectivity of asymmetrically substituted aldehydes.
and optics,[18] was accomplished in two steps: first, the free ide[19] followed by elimination and aerobic oxidation. In the
alcohol was protected as the corresponding acetate, and then third transformation, vinyl bromide 4z was proven to be a valid
the carbonyl group was converted into the geminal dichlor- substrate for the transition-metal-catalyzed cross-coupling reac-
tion. Under the effect of catalytic amounts of Pd(PPh3)4 and
CuI,[20] furylstannane was treated with 4z to smoothly afford
furyltropone 8 in 79 % yield.
Finally, we turned our attention to demonstrating the power
of the one-pot protocol by preparing the ABC ring skeleton of
Cephalotaxus norditerpenes. The synthesis commenced from
the union of aldehyde 1d and nitroalkene 2b (Scheme 3). Under
the optimized conditions, the readily available starting materi-
als underwent sequential Michael addition, NaBH4 reduction,
Scheme 2. Derivatization of dihydroazulenones.
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Scheme 3. Synthesis of the tricyclic ring skeleton of harringtonolide.
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Communication
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and oxidative dearomatization to afford dihydroazulenone 9 as
a single regioisomer in 70 % yield with 6:1 dr and 96 % ee. The
pedant alcohol group was oxidized by Dess–Martin periodinane
to give aldehyde 10 in 75 % yield, and the diastereomers were
separated at this stage. Conversion of the C=O bond into a C=
C bond was achieved by standard Wittig reaction using a stabi-
lized phosphorane, and the resulting enone was subjected to
ring-closing metathesis under the effect of Grubbs' first-genera-
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framework in 78 % yield.
Conclusions
We have developed a highly efficient, one-pot procedure to
prepare enantiomerically pure 2,3-dihydroazulen-6(1H)-ones by
organocatalyzed Michael reaction and selective oxidative dea-
romatization. This protocol has been extended to a diverse
range of nitroalkenes to give the desired tropone derivatives
with remarkable efficiency. When the methodology is applied
to various aldehydes bearing asymmetrically substituted aro-
matic rings, the distinctive regioselectivity pattern is likely an
outcome of both steric and electronic influences of the substit-
uent. Finally, we demonstrate the power of this methodology
by preparing the tricyclic framework of Cephalotaxus norditer-
penes, and we will continue our investigation on the enantiose-
lective total synthesis of harringtonolide by this one-pot proto-
col with more complex precursors.
Acknowledgments
Financial support from the University of Central Florida is great-
fully acknowledged. We thank Mr. Chance Reimer for the prepa-
ration of some racemic samples.
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Keywords: One-pot · Enantioselective · Organocatalysis ·
Dihydroazulenone · Norditerpene
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Received: March 15, 2016
Published Online: April 5, 2016
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