Enantioselective Polyene Cyclization Catalyzed by a Chiral Br?nsted Acid

Article abstract of DOI:10.1002/anie.201711603

The first enantioselective polyene cyclization initiated by a BINOL-derived chiral N-phosphoramide (NPA) catalyzed protonation of an imine is described. The ion-pair formed between the iminium ion and chiral counter anion of the NPA plays an important role for controlling the stereochemistry of the overall transformation. This strategy offers a highly efficient approach to fused tricyclic frameworks containing three contiguous stereocenters, which are widely found in natural products. In addition, the first catalytic asymmetric total synthesis of (?)-ferruginol was accomplished with an NPA catalyzed enantioselective polyene cyclization, as the key step for the construction of the tricyclic core, with excellent yield and enantioselectivity.

Full text of DOI:10.1002/anie.201711603

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Accepted Article
Title: Enantioselective Polyene Cyclization Catalyzed by Chiral
Brønsted Acid
Authors: Junfeng Zhao, Liwen Fan, Chunyu Han, Xuerong Li, Jiasheng
Yao, Zhenning Wang, Chaochao Yao, Weihao Chen, and Tao
Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711603
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Enantioselective Polyene Cyclization Catalyzed by a Chiral
Brønsted Acid
Liwen Fan†, Chunyu Han†, Xuerong Li†, Jiasheng Yao, Zhengning Wang, Chaochao Yao,Weihao
Chen, Tao Wang, and Junfeng Zhao*
Dedicated to Professor E. J. Corey on the occasion of his 90th birthday.
Abstract: The first enantioselective polyene cyclization initiated by a
BINOL-derived chiral N-phosphoramide (NPA)-catalyzed protonation
of imine is described. The ion pair formed between the iminium ion
and chiral counter anion of NPA plays an important role for controlling
the stereochemistry of the overall transformation. This strategy offers
a highly efficient approach to fused tricyclic frameworks containing
three contiguous stereocenters, which are widely found in natural
products. In addition, the first catalytic asymmetric total synthesis of
(−)−ferruginol was accomplished with the NPA 5g-catalyzed
enantioselective polyene cyclization as the key step for the
construction of the tricyclic core with excellent yield and enantio-
selectivity.
Scheme 1. Enantioselective polyene cyclization
Terpenes and steroids are ubiquitous natural products with a
broad range of interesting biological activities, which render them
and their derivatives valuable candidates for drug discovery.[1]
The breathtaking high selectivity and efficacy of enzyme-
However, the construction of their complex structures which
contain polycyclic frameworks and multiple contiguous chiral
centers, including all-carbon quaternary ones, is a great challenge
for synthetic chemists.[2] Their biosyntheses involve highly
efficient enzyme-catalyzed highly efficient domino cyclizations of
linear poly-alkenes (polyene cyclization).[3] One typical example is
the biosynthesis of optical pure hopene which involves a squalene
hopene cyclases (SHC) catalyzed polyene cyclization triggered
by enantioselective protonation of the terminal isoprene
functionality of squalene to initiate the polyene cyclization
(Scheme 1, Eq. 1).[4] Notably, up to five C-C bonds and nine chiral
carbon centers are formed in such bio-polyene cyclization.
Theoretically, thousands of isomers would be formed attributing
to the chemo-, regio-, and stereo-selectivity, and owing to
premature termination resulting from elimination and
rearrangement of the carbocation intermediates. Amazingly, only
one isomer among thousands of possibilities is produced in the
SHC-catalyzed polyene cyclization.
catalyzed polyene cyclization have drawn great interests of many
organic chemists, and enormous efforts have been made to
understand how nature works and to mimic such fantastic bio-
reactions in the laboratory. Stork[5] and Eschenmoser[6]
independently proposed that the ring-junction stereochemistry of
polyene cyclization is stereospecific with E-alkenes giving trans-
ring junctions while Z-alkenes giving cis-ring junctions. The Stork-
Eschenmoser postulate (SEP) offers a theoretical foundation for
biomimetic polyene cyclization, which has evolved into the most
powerful strategy for the total syntheses of terpene and steroid
natural products.[2] Despite this, almost all of the acid-catalyzed
polyene cyclizations reported in the last century were diastereo-
selective. Enantioselective polyene cyclization reaction remained
an unexplored challenge untill 1999, when Yamamoto and
Ishihara employed a stoichiometric Lewis acid-assisted Brønsted
acid (LBA) as a chiral proton promoter.[7] Later, several LBAs,[8]
Lewis base-assisted Brønsted acids[9] and other catalysts have
been developed to catalyze the enantioselective polyene
cyclization, in which the enantioselective protonation or
electrophilic halogenation[10] of terminal isoprene acted as the
initiating event. Aside from terminal isoprene, only few functional
groups that can produce carbocations[11] or radicals[12] upon
interacting with chiral catalysts have been used as initiators for
enantioselective polyene cyclization.[13] Thus, the development of
a superior catalytic enantioselective polyene cyclization is still of
great significance owing to the structural diversity of terpenes and
steroids. Herein, we report the first enantioselective polyene
cyclization initiated by a BINOL-derived chiral N-phosphoramide
(NPA)-catalyzed protonation.
†
†
†
]
[*]
L. Fan, [ ] C. Han,[ X. Li,[ ] J. Yao, Z. Wang, C. Yao, W. Chen,
Prof. Dr. T. Wang, Prof. Dr. J. Zhao
College of Chemistry & Chemical Engineering, Jiangxi Normal
University
Nanchang 330022 (China)
E-mail: Zhaojf@jxnu.edu.cn
Homepage: http://zhao.jxnu.edu.cn
Prof. Dr. J. Zhao
State Key Laboratory of Elemento-Organic Chemistry, Nankai
University
Tianjin 300071 (China)
Prof. Dr. T. Wang, Prof. Dr. J. Zhao
Key Laboratory of Chemical Biology of Jiangxi Province
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Owing to their rigid chiral backbones and adjustable acidities,
BINOL-derived chiral Brønsted acids, especially BINOL-derived
chiralphosphoric acids (CPA) with various acidities, provide a
platform for development of artificial protonases, which would be
effective for polyene cyclization.[14] However, enantioselective
[†]
[**]
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10.1002/anie.201711603
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Table 1. Optimization of reaction conditions[a]
would result in 4α/β-NH selectivity, which would complicate the
stereo-selectivity of the overall transformation.
The reaction conditions were evaluated extensively by
screening various amines and amides, solvents, BINOL-based
chiral Brønsted acids, and additives with aldehyde 1a as the
model substrate. The representative results are listed in Table 1
(see Supporting Information for details). Preliminary studies
revealed that our proposal is feasible. The reaction was sensitive
to solvent, and dichloromethane was identified to be optimal. As
expected, poor results with respect to the yield and
enantioselectivity were obtained when BINOL-derived CPA 5a
was used as the catalyst (Table 1). Meanwhile, a remarkable
improvement in enantioselectivity was observed with more acidic
NPA 5b (Table 1). Inspired by the cation–π interactions found in
enantioselective cationic polycyclization,[11d, 18] we evaluated the
BINOL-derived NPAs with different-sized aryl substituents at the
3,3′-positions. Interestingly, a significant improvement of the
reactivity and enantioselectivity was observed as the size of the
aryl substituents increased (Table 1, 5c, 5e, 5f, 5g).[19] The 2-
naphthyl (5d) and 4-pyrenyl (5h) groups were exceptions,
indicating that not only the cation–π interaction but also the steric
interaction related to the arrangement of the aryl substituents
plays an important role in asymmetric induction. Notably, the
additive significantly affected the reaction rate (Table 1, entries 1–
6). MgS2O3·6H2O was the best additive, which led to the fastest
reaction rate with good enantioselectivity and yield (Table 1, entry
5). Further optimization revealed that the enantioselectivity of the
polyene cyclization increased steadily with decreasing reaction
temperature (Table 1, entries 7–10). Enantioselective polyene
cyclization product 3a was obtained in 65% yield and with 91.7%
ee when the reaction was carried out at −60 ºC in the presence of
MgS2O3·6H2O with 20 mol% of NPA 5g as the catalyst. Control
experiment illustrated that magnesium salt of 5g is not effective
for this transformation (Table 1, entry 11). The π–π interaction
between the phenyl group of 4-methylbenzene sulfonamide and
the anthracenyl group of NPA 5g would also be involved in the
asymmetric induction event because other amides provided poor
results (see Supporting Information for details). Although a 1:1
ratio of 4α/β-NH diastereomers was produced when a nonchiral
Brønsted acid, such as TFA, was used as the catalyst for the
racemic version, only the enantioenriched α-NH diastereomer
was furnished for all of the chiral-NPA-catalyzed reactions.
Under the optimal reaction conditions, the substrate scope of
this highly efficient transformation was investigated. As shown in
Table 2, a broad range of substituted phenyl rings proved to be
efficient terminators for this enantioselective domino cyclization.
Both electron-donating and electron-withdrawing groups were
tolerated on the terminator phenyl ring. However, the position and
electronic effect of the substituents significantly influenced the
reaction efficiency. In general, the electron-rich substituents at the
para position benefitted the reaction remarkably with respect to
both reactivity and enantioselectivity (3b-3m). The electronic
properties of the terminator significantly affected the reaction yield
(3b-3e). Interestingly, meta Cl- and Br- were compatible; the
corresponding domino-cyclized products were generated in
moderate to high yields with excellent enantioselectivity (3d, 3e,
Time
(h)
Yield
(%)[b]
T (ºC)
Entry
Cat.
Additive
ee[c]
1
2
5g
-
50
50
50
50
50
50
25
0
72
72
18
18
1
51
50
42
25
58
32
55
57
58
65
0
70.0
61.0
69.2
74.8
79.3
72.8
80.9
82.4
88.9
91.7
n.d.
5g
4 Å MS
3
5g
Na2SO4
4
5g
Mg(OAc)2
MgS2O3·6H2O
TFA
5
5g
6
5g
1
7
5g
5g
MgS2O3·6H2O
MgS2O3·6H2O
MgS2O3·6H2O
MgS2O3·6H2O
-
2
8
6
9
5g
-40
-60
25
18
24
48
10
11
5g
Mg(5g-H)2
[a] Reaction conditions: 1 (0.1 mmol), 2 (0.4 mmol), additive (0.2 mmol), CPA
or NPA (0.02 mmol) in CH2Cl2 (4 mL). [b] Isolated yield. [c] Enantiomeric excess
(ee) determined by HPLC analysis using Chiralpak OJ-H column. TFA:
trifluoroacetic acid.
polyene cyclization initiated by CPA-catalyzed protonation
remains an unconquered challenge because of the low proton
affinity of π-bond of the isoprene initiator.[10b] According to the
SEP, the stereochemistry of the first formed chiral center is crucial
for controlling the overall enantioselectivity of the biomimetic
polyene cyclization. Successful pioneering works revealed that
the appropriate combination of a chiral catalyst and an initiating
functional group (initiator) is crucial for enantioselective polyene
cyclization. Imines have been proven to be efficient substrates in
organic transformations catalyzed by BINOL-based chiral
Brønsted acids.[15] We envisioned that the imine functionality
would be an ideal initiator because it could produce an iminium
upon protonation to initiate the polyene cyclization. Importantly,
the ion pair[16] formed between the iminium ion and the chiral
counter anion of the Brønsted acid would offer an opportunity for
controlling enantioselectivity (Scheme 1, Eq. 2). Although this
looks like a straight-forward strategy, it is indeed challenging
because of the potential competition from aldehyde-ene-reaction-
initiated polyene cyclization.[17] Furthermore, 6-exo-cyclization
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10.1002/anie.201711603
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strong electron-withdrawing substituents, such as nitro and cyano
groups, were present on the terminator phenyl ring (data not
shown). The relative configuration of the polyene cyclization
product was determined using NMR spectroscopy and X-ray
crystallographic analysis of racemic 3a. The absolute
configuration was established on the basis of the X-ray
crystallographic analysis of 3n, whereas the stereochemistries of
the other products were assigned by analogy (see Supporting
Information).[20]
This method provides an efficient strategy to enantioselectively
construct fused tricyclic frameworks with three contiguous
stereocenters, which are widely found in terpene and steroid
natural products. To further demonstrate the power of this method,
the first catalytic asymmetric total synthesis of (−)−ferruginol was
conducted with the 5g-catalyzed enantioselective polyene
cyclization as the key step. Ferruginol is isolated from Lamiaceae
plants and exhibits important bioactivities, such as antifungal,
antimicrobial, antitumor, and anti-inflammatory activities.[21] In
addition, it is an important intermediate in the syntheses of other
abietane diterpene natural products. The previous total syntheses
Scheme 2. Enantioselective polyene cyclization catalyzed by NPA 5g[a] [a]
Reaction conditions: Unless otherwise specified, the reactions were carried out
with 1 (0.1 mmol), 2 (0.4 mmol), MgS2O3·6H2O (0.2 mmol), NPA 5g (0.02 mmol)
and CH2Cl2 (4 mL) at -60 ºC. Isolated yields. ee determined by HPLC analysis
using Chiralpak OJ-H or AD-H column.
Scheme 3. First catalytic asymmetric total synthesis of (-)-ferruginol[a] [a]
Reagents and conditions: (a) 9-BBN, Pd(dppf)Cl2·CH2Cl2 (5 mol%), aq NaOH,
40%; (b) Bu4NF (1.5 equiv), THF, 92%; (c) DMP (1.5 equiv), CH2Cl2, 86%; (d)
NPA 5g (20 mol%), TsNH2 (4.0 equiv), MgS2O3·6H2O (2.0 equiv), CH2Cl2, -
60 °C, 18 h, 76%, 91.6% ee; (e) potassium isopropenyltrifluoroborate (1.5 equiv),
Pd(dppf)Cl2·CH2Cl2 (10 mol%), Cs2CO3 (3 equiv), THF:H2O = 10:1, reflux 12 h,
88%; (f) Pd/C, H2 balloon, CH3OH, 97%; (g) Li, naphthalene, THF, rt, 80%; (h)
TPAP, NMO,CH2Cl2, rt, 24 h, 78%; (i) Ph3P=CH2, THF, reflux, 8 h, 79%; (j) Et2Zn,
CH2I2, toluene, reflux 8 h, 68%; (k) H2 balloon, PtO2 (1 equiv), AcOH, 10 h, 78%;
(l) BBr3 (3.5 equiv), CH2Cl2, 0 °C, 83%. 9-BBN = 9-borabicyclo[3.3.1] nonane,
and 3n). These halogen substituents offer opportunities for further
functionalization via transition-metal-catalyzed cross-coupling
reactions. Although strong electron-donating groups, such as
MeO- and BnO-, were tolerated, no reaction occurred when
DMP
=
Dess Martin periodinane, TPAP
=
tetra-n-propylammo-
nium perruthenate, NMO = N-methylmorpholine N-oxide.
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10.1002/anie.201711603
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COMMUNICATION
of ferruginol either were racemic or started from optically pure
starting materials.[22] To the best of our knowledge, the catalytic
asymmetric total synthesis of ferruginol was unexplored. We
envisioned that 5g-catalyzed enantioselective polyene cyclization
product 3r would be a valid intermediate for the asymmetric total
synthesis of (−)−ferruginol. As shown in Scheme 3, the cyclization
precursor 7 can be synthesized easily in accordance with the
reported procedures from commercially available starting
materials.[17] Under the standard reaction conditions, tricyclic
product 3r was obtained in good yield and with excellent
enantioselectivity. Pd-catalyzed Suzuki coupling and Pd/C-
catalyzed hydrogenation introduced the isopropyl group to the
phenyl ring of the core structure. The deprotection of the tosyl
group was removed by means of Li/naphthalene, furnishing
compound 9, the oxidation of which provided ketone 10. The
carbonyl functionality of ketone 10 was transformed into a gem-
dimethyl group in good yield by employing a three-step strategy.
Finally, demethylation of 13 with boron tribromide afforded the
target (−)−ferruginol 14. The as-synthesized (−)−ferruginol has
the same NMR spectral data as those of (+)−ferruginol but an
opposite optical rotation.[23] It should be noted that the analogs of
ketone 10 are key intermediates for the total synthesis of natural
products (+)-triptolide[24] and steviol,[25] which means that this
method could also be used for the catalytic asymmetric total
synthesis of enantioenriched triptolide and steviol.
Acknowledgements ((optional))
This work is supported by the National Natural Science
Foundation of China (21462023, 21778025), the Natural Science
Foundation of Jiangxi Province (20143ACB20007) and the
Education Department of Jiangxi Province (150297). We thank
Prof. Shuanhu Gao (ECNU) for helpful discussion, Prof. Wenjun
Tang (SIOC) for donation of chemical, and Prof. Qingyan Liu
(JXNU) for the X-ray crystallographic analysis.
Keywords: enantioselective polyene cyclization • asymmetric
synthesis • chiral N-phosphoramide • total synthesis of ferruginol
• terpene
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In conclusion, we have developed the first BINOL-derived chiral
NPA-catalyzed protonation of imine initiated enantioselective
polyene cyclization. NPA 5g functioned as an artificial protonase,
which not only initiated but also controlled the stereochemistry of
the overall transformation, in which one C–N bond and two C–C
bonds were formed to furnish a tricyclic framework containing
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Experimental Section
To an oven-dried Schlenk tube equipped with a magnetic stir bar were
added TsNH2 (68.5 mg, 0.4 mmol, 4.0 equiv), BINOL-derived chiral N-
phosphoramide (NPA) 5g (16.6 mg, 0.02 mmol, 20 mol%), MgS2O3H2O
(0.2 mmol, 2.0 equiv) and CH2Cl2 (4 mL) at room temperature. Then the
reaction mixture was cooled to -60 ºC and aldehyde 1 (0.1 mmol, 1.0 equiv)
was added. The sealed Schlenk tube was stirred at -60 ºC for 15 ~ 28 h.
Upon the reaction completion (monitored by TLC), the solvent was
removed in vacuo and the residue was purified by silica gel
chromatography (eluent: petroleum ether/EtOAc = 20/1 to 4/1) to afford
the desired products 3a–3r.
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[20] CCDC 1577401 (racemic 3a), 1577402 (racemic β-NH diastereomer 3a’),
1577403 (enantioenriched 3r) contain the complete crystallographic data
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10.1002/anie.201711603
Angewandte Chemie International Edition
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Liwen Fan, Chunyu Han, Xuerong Li,
Jiasheng Yao, Zhengning Wang,
Chaochao Yao, Weihao Chen, Tao
Wang, Junfeng Zhao*
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Enantioselective Polyene Cyclization
Catalyzed by Chiral Brønsted Acid
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[a]
L. Fan, [ X. Li,[ ] C. Han,[ ] J. Yao, Z. Wang, C. Yao, X. W
You, W. Chen, Prof. Dr. T. Wang, Prof. Dr. J. Zhao
College of Chemistry & Chemical Engineering, Key Labora
Chemical Biology, Jiangxi Province
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