Enantioselective palladium-catalyzed dearomative cyclization for the efficient synthesis of terpenes and steroids

Article abstract of DOI:10.1002/anie.201411817

A novel enantioselective palladium-catalyzed dearomative cyclization has been developed for the efficient construction of a series of chiral phenanthrenone derivatives bearing an all-carbon quaternary center. The effectiveness of this method in the synthe

Full text of DOI:10.1002/anie.201411817

Angewandte
Chemie
DOI: 10.1002/anie.201411817
Asymmetric Cyclization
Hot Paper
Enantioselective Palladium-Catalyzed Dearomative Cyclization for the
Efficient Synthesis of Terpenes and Steroids**
Kang Du, Pan Guo, Yuan Chen, Zhen Cao, Zheng Wang, and Wenjun Tang*
Abstract: A novel enantioselective palladium-catalyzed dear-
omative cyclization has been developed for the efficient
construction of a series of chiral phenanthrenone derivatives
bearing an all-carbon quaternary center. The effectiveness of
this method in the synthesis of terpenes and steroids was
demonstrated by a highly efficient synthesis of a kaurene
intermediate, the facile construction of the skeleton of the
anabolic steroid boldenone, and the enantioselective total
synthesis of the antimicrobial diterpene natural product
(À)-totaradiol.
Figure 2. Novel asymmetric dearomative cyclization for the synthesis
of terpenes and steroids.
T
ricyclic skeletons bearing chiral all-carbon quaternary
centers, such as chiral phenanthrenone derivatives, exist in
numerous complex terpenes and steroids with interesting
biological activities (Figure 1).[1] For example, kaurene[2] is the
olefin moiety necessary for the Heck cyclization or for the
post-modification of the Heck product to the target molecule.
Alternatively, asymmetric intramolecular dearomative cycli-
zations[7,8] between two aryl systems can offer better synthetic
efficiency owing to the availability of aryl systems as well as
the convenience in the post-modification of the cyclization
product. Herein, we present a powerful asymmetric palla-
dium-catalyzed dearomative cyclization that has led to
a series of chiral phenanthrenone derivatives bearing an all-
carbon quaternary center in excellent enantioselectivities.
The new method has been successfully applied in the highly
efficient synthesis of a chiral kaurene intermediate, the facile
construction of the skeleton of the anabolic steroid bolde-
none, and an enantioselective total synthesis of the diterpene
natural product (À)-totaradiol.
Figure 1. Terpenes and steroids bearing chiral all-carbon quaternary
centers.
biosynthetic precursor of the plant hormones gibberellins,
boldenone[3] is an anabolic steroid, totaradiol[4a–d] is a diter-
pene natural product that exhibits good antimicrobial proper-
ties, and triptoquinone B exhibits a remarkable inhibitory
activity against interleukin-1 release.[4e–f] Their syntheses have
attracted a great deal of attention with the emergence of
various excellent methods.[5] Among them, the asymmetric
intramolecular Heck reaction[6] has become a powerful
method for constructing chiral polycyclic skeletons bearing
all-carbon quaternary centers (Figure 2). However, a number
of synthetic steps are often required either in constructing the
Although dearomative cyclizations have been frequently
applied in natural product synthesis, the asymmetric transi-
tion-metal-catalyzed dearomative cyclization has remained
underdeveloped, and only a few examples of efficient intra-
molecular dearomative arylations have been reported thanks
to the pioneering work from the Buchwald,[9] Bedford,[10] and
You[11] groups. Buchwald[9] and co-workers developed effi-
cient dearomative cyclizations to form chiral benzocarbazole
derivatives and spirocyclohexadienones bearing all-carbon
quaternary centers. You[11e] et al. recently reported an inter-
esting dearomative cyclization to form a tetracyclic spiro-
amine framework. However, to the best of our knowledge,
enantioselective dearomative arylations have not been
applied in the synthesis of complex natural products. Asym-
metric dearomative cyclizations for the efficient construction
of chiral terpenes and steroids remain to be uncovered. We
believed that bromine-substituted phenol 1a could undergo
an asymmetric dearomative cyclization in the presence of
a chiral palladium catalyst to form chiral phenanthrenone
compound 2a as well as the achiral regioisomeric cyclization
product 3a (Figure 3). Mechanistically, after oxidative addi-
tion, compound 1a would yield PdII complex II. In the
presence of a base, nucleophilic substitution could take place
[*] K. Du, P. Guo, Y. Chen, Z. Cao, Prof. Dr. W. Tang
State Key Laboratory of Bio-organic and Natural Products Chemis-
try, Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Ling Ling Rd, Shanghai 200032 (China)
E-mail: tangwenjun@sioc.ac.cn
Dr. Z. Wang
Innovation Center China, AstraZeneca Global R&D (China)
[**] We thank the NSFC (21432007, 21272254), STCSM (13J1410900),
and the “Thousand Plan” Youth program for financial support and
Mettler Toledo for a ReactIR Instrument.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411817.
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Table 1: Palladium-catalyzed asymmetric cyclization of compound 1a.[a]
Entry Ligand
Solvent
Yield [%] 2a/3a ee of 2a [%][b]
1
2
(S)-BINAP
(S,S)-DuPhos toluene
toluene
0
0
–
–
–
–
3
4
5
6
7
8
9
(S)-L1
(S,S)-L2
(S)-L3
(S)-L4
(S)-L5
(S)-L6
(S)-L6
(S)-L6
(S)-L6
(S)-L6
(S)-L6
toluene
toluene
toluene
toluene
toluene
toluene
toluene/H2O
dioxane
cyclohexane
CF3C6F5
toluene
68
92
88
86
91
94
90
94
95
64
94
95
87:13
94:6
91:9
91:9
97:3
96:4
96:4
96:4
96:4
88:12
96:4
96:4
81
54
78
86
84
92
82
88
87
86
90
88
10
11
12
13[c]
14[d] (S)-L6
toluene
[a] Unless otherwise specified, the reactions were performed under
nitrogen atmosphere at 908C for 16 hours with 1a (0.1 mmol), K2CO3
(0.15 mmol), [{Pd(cinnamyl)Cl}2] (1 mol%), and the specified ligand
(2 mol%). Isolated yields are given. The absolute configuration of 2a
was assigned by comparing the sign of the optical rotation to that of
product 2e. [b] Determined by HPLC analysis on a chiral stationary phase
(Chiralcel AD-H). [c] Pd(OAc)2 (2 mol%). [d] [{Pd(allyl)Cl}2] (1 mol%).
Figure 3. Competitive cyclization pathways of 1a.
at the 4-position of the phenol moiety (path a) to form IIIa,
which, after reductive elimination, leads to the formation of
chiral phenanthrenone 2a. In parallel, the cyclization could
also occur at the 2-position of the phenol moiety (path b),
providing the achiral product 3a. Although 2a is thermody-
namically less stable than 3a, the formation of 2a could be
kinetically more favorable. The task is to achieve high
reactivity, chemoselectivity, and enantioselectivity for this
unprecedented challenging dearomative cyclization.
We first studied the intramolecular cyclization of com-
pound 1a by employing a chiral palladium catalyst (Table 1).
The reactions were performed in toluene at 908C for 16 hours
with K2CO3 as the base at a palladium loading of 2 mol%. A
series of chiral bis- or monophosphine ligands were
employed. Although cyclization did not occur with BINAP
or DuPhos (entries 1 and 2), the reactions with P-chiral biaryl
monophosphine ligands L1–L6[12] all proceeded smoothly.
Excitingly, good to excellent yields of 2a were isolated along
with 3a as the minor product. A good ee (81%) was obtained
when BI-DIME was employed as the ligand (entry 3). The
enantioselectivity (54% ee) decreased when L2 was
employed, which bears a methyl substituent on the upper
ring (entry 4). We then modified the ligand structure by
changing the second aryl moiety. Ligand L4, with two ortho
aryloxy substituents on the second aryl ring, gave the product
with 86% ee (entry 6). AntPhos (L5) also gave a similar
selectivity (84% ee, entry 7). Gratifyingly, when a new ligand
L6[13] bearing a 2,5-diphenylpyrrole moiety was employed, the
cyclization product was formed in 94% yield and 92% ee
(entry 8). Further studies on the solvents and catalyst
precursors showed that toluene and [{Pd(cinnamyl)Cl}2]
were most suitable for this cyclization (entries 9–14).
Table 2: Substrate scope of the asymmetric cyclization.[a]
[a] The reactions were performed in toluene under nitrogen atmosphere
at 908C for 16 hours with 1b–1m (0.1 mmol), K2CO3 (0.15 mmol),
[{Pd(cinnamyl)Cl}2] (1 mol%), and (S)-L6 (2 mol%). Yields of isolated
products are given. The absolute configurations were determined or
assigned by analogy on the basis of the X-ray structure of 2e, the
enantioselectivities were determined by HPLC analysis on a chiral
stationary phase (Chiralcel AD-H or OJ-H column). [b] Prepared from
vinyl triflate 1h. [c] Cyclization exclusively occurred at the 2-position of
the phenol moiety.
We then studied the substrate scope of this asymmetric
cyclization. A series of tricyclic phenanthrenone derivatives
(2a–2l; Table 2, see also Figure 4) bearing an all-carbon
quaternary center were efficiently synthesized in moderate to
high yields and in excellent enantioselectivities (83–99% ee).
Functional groups, such as fluoro, chloro, and methoxy
substituents, were well tolerated (2b–2d). Substrates with
2
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Figure 4. X-ray structure of cyclization product 2e.[14] Ellipsoids set at
30% probability. The absolute configuration at the C10 position is R.
Scheme 1. Efficient synthesis of kaurene intermediate 8. TBS=tert-
butyldimethylsilyl, Ts=para-toluenesulfonyl.
naphthalene, quinone, and furan rings were also compatible
with the reaction conditions (2e–2g). A vinyl triflate 1h was
also successfully employed to provide the desired product 2h
in 99% yield and 99% ee. Aside from six-membered rings,
five- and seven-membered rings were also constructed
efficiently (2i–2j). The alkyl substituent at the 4a-position
was not limited to a methyl group, as longer aliphatic
substituents, such as ethyl and butyl groups, were also
tolerated (2k and 2l). However, the cyclization failed to
form compound 2m, which bears a phenyl substituent at the
4a-position.
to provide tricyclic compound 7 in 98% yield and 92% ee.
Hydrogenation of 7 using a reported procedure[16a] led to the
formation of 8 in four steps from aldehyde 5. This synthetic
route by a palladium-catalyzed dearomative cyclization
provides significant advantages over a reported fourteen-
step synthesis featuring an asymmetric Heck reaction.[16a]
The method was also applied to the construction of the
skeleton of the anabolic steroid boldenone (Scheme 2).[3]
The high rigidity of (S)-L6 allowed us to propose
a stereochemical model for this cyclization, where the
enantioselectivity should be determined during the reductive
elimination. As shown in Figure 5, the 2,5-diphenylpyrrole
Scheme 2. Efficient synthesis of boldenone skeleton 13. brsm=based
on recovered starting material, Tf=trifluoromethylsulfonyl.
Figure 5. Proposed stereochemical model for the reductive elimination
step of the cyclization of 1a with Pd/(S)-L6 as the catalyst.
Thus, ketal 9,[18] which was readily prepared from the
Hajos–Parrish ketone, was reacted with bromide 10 in the
presence of NaH to form 11 in an unoptimized yield of 17%.
Conversion of 11 into the vinyl triflate with Tf2O as the
reagent followed by treatment with BBr3 provided 12 in 70%
overall yield. Cyclization of triflate 12 in the presence of the
Pd/(R)-L6 catalyst led to boldenone skeleton 13 in 90% yield
and a diastereomeric ratio of > 99:1. Notably, its diastereo-
isomer 13b could also be prepared efficiently by cyclization
with a Pd/(S)-L6 catalyst in 90% yield and 98:2 d.r. The
catalyst-controlled preparation of both 13 and 13b demon-
strates the high compatibility of this asymmetric cyclization
with other chiral elements that might be present in the
substrate and its potential synthetic utilities in steroid syn-
thesis.
moiety of (S)-L6 blocks the backside of the complex, and its
bulky tert-butyl group can well dictate the orientation of
substrate coordination. We believe that substrate 1a, after
oxidative addition and nucleophilic substitution, could adopt
two major conformers, A and B, when coordinated to the Pd/
(S)-L6 complex.[15] Conformer B appears to be more strained
whereas the more favorable conformer A undergoes reduc-
tive elimination to provide the cyclization product 2a with the
observed R configuration.
The cyclization was applied in the efficient synthesis of
enone 8, a key chiral intermediate[16] for the synthesis of
kaurene, abietic acid, and a bruceantin analogue (Scheme 1).
Horner–Wadsworth–Emmons reaction between phosphonate
4 and aldehyde 5[17] followed by reduction of the double bond
with TsNHNH2 provided bromide 6 in 67% overall yield. The
cyclization of 6 with Pd/(S)-L4 (2 mol%) proceeded smoothly
Finally, this asymmetric cyclization was applied to the
total synthesis of (À)-totaradiol (Scheme 3). Thus, a Wittig
reaction with compound 14 and the known aldehyde[4d] 15
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Scheme 3. Total synthesis of (À)-totaradiol (21). LAH=lithium alumi-
num hydride, NBS=N-bromosuccinimide, TBAF=tetrabutylammo-
nium fluoride.
followed by hydrogenation provided the saturated coupling
product 16 in 91% overall yield. Bromination with NBS and
subsequent treatment with TBAF provided phenol 17 in 68%
overall yield. Asymmetric cyclization of 17 with Pd/(S)-L6 as
the catalyst provided the desired product 18 in 78% yield and
89% ee. A simple crystallization of 18 from hexane elevated
its optical purity to > 99% ee. Hydrogenation and methyl-
ation[19] of 18 provided ketone 19 in 82% overall yield.
Reduction of 19 with LAH followed by hydrogenation
formed compound 20 in 83% overall yield. Methoxy depro-
tection of 20 with AlBr3/nPrSH[4d] completed the enantiose-
lective synthesis of (À)-totaradiol (21) in 23% overall yield
over ten steps from the known aldehyde 15 by using our newly
developed cyclization method. We believe that this asym-
metric cyclization can offer rapid access to various other
diterpenoids, such as triptoquinone B.
In summary, we have developed a novel and efficient
palladium-catalyzed dearomative cyclization, which enabled
the synthesis of a series of chiral tricyclic phenanthrenone
derivatives bearing all-carbon quaternary centers in excellent
enantioselectivities. This method, which is complementary to
the traditional Heck reaction, has provided a new strategy for
the efficient synthesis of terpenes and steroids. The effective-
ness of this method has been demonstrated by the efficient
syntheses of a chiral kaurene intermediate, the boldenone
skeleton, and of the antimicrobial diterpene totaradiol.
Received: December 8, 2014
Published online: && &&, &&&&
Keywords: asymmetric cyclization · palladium ·
.
phosphine ligands · total synthesis · transition-metal catalysis
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
Angewandte
Communications
Communications
Asymmetric Cyclization
K. Du, P. Guo, Y. Chen, Z. Cao, Z. Wang,
W. Tang*
&&& — &&&
Enantioselective Palladium-Catalyzed
Dearomative Cyclization for the Efficient
Synthesis of Terpenes and Steroids
One, two, three: An enantioselective
palladium-catalyzed dearomative cycliza-
tion was developed for the efficient con-
struction of a series of chiral tricyclic
phenanthrenone derivatives bearing all-
carbon quaternary centers. This method
was applied in highly efficient syntheses
of a kaurene intermediate, the skeleton of
the anabolic steroid boldenone, and the
antimicrobial diterpene (À)-totaradiol.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!