Catalytic Cyclotrimerization Pathway for Synthesis of Selaginpulvilins C and D: Scope and Limitations

Article abstract of DOI:10.1021/acs.orglett.1c00519

A facile and unified approach to the main selaginpulvilin's framework was achieved by catalytic [2 + 2 + 2]-cyclotrimerization of a triyne with monosubtituted alkynes. The reaction proceeded with high "ortho"selectivity by using Wilkinson's catalyst (RhCl

Full text of DOI:10.1021/acs.orglett.1c00519

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Letter
Catalytic Cyclotrimerization Pathway for Synthesis of
Selaginpulvilins C and D: Scope and Limitations
Lukas Rycek, Miguel Mateus,‡ Nela Beytlerová,‡ and Martin Kotora*
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ABSTRACT: A facile and unified approach to the main selaginpulvilin’s framework was achieved by catalytic [2 + 2 + 2]-
cyclotrimerization of a triyne with monosubtituted alkynes. The reaction proceeded with high “ortho” selectivity by using Wilkinson’s
catalyst (RhCl(PPh3)3) under ambient conditions with reasonable yields. The scope of the reaction with respect to the alkyne as well
as the catalytic system was evaluated. The formal total modular syntheses of selaginpulvilin C and D were accomplished by
transformation of the cyclotrimerization’s products.
atural compounds possess a diverse spectrum of
Nintriguing polycyclic carbon skeletons. Some of them
seem to be somewhat unexpected and surprising. One such
class of compounds are substances containing the fluorene
scaffold. The presence of methylated fluorenes (namely
1,2,3,4-tetraalkylated fluorenes) has been confirmed in
naturethey were detected in aromatic fractions of Athabasca
oil sand bitumens.1 However, until recently, there have not
been any reports on the existence of more complex compounds
possessing the fluorene skeleton (excluding those with the
fluorenone moiety2). In 2014, Yin and co-workers reported
isolation and characterization of four selaginpulvilins A−D (1)
(Figure 1), new phenols with an unprecedented 9,9-diphenyl-
1-(phenylethynyl)-9H-fluorene skeleton, from a plant used in
traditional Chinese medicine Selaginella pulvinata.3 Interest-
ingly, selaginpulvilins A−D showed high inhibitory activity
against PDE4D2 with IC50 values in the range 0.11−0.26 μM.
The high activity values might explain the anti-inflammatory
activity of the previously mentioned usage of Selaginella
pulvinata plants. Later, the same plant’s content reinvestigation
led to the identification and isolation of other selaginpulvilins
(E−J).4,5 The densely substituted fluorene scaffold of
selaginpulvilins has sparked great interest as a challenging
target for synthesis. Since their isolation, total or formal
syntheses of selaginpulvilins A−F based on various synthetic
strategies have been disclosed. The reported synthetic strategy
relied on (i) a hexadehydro Diels−Alder reaction of a tetrayne
(selaginpulvilins A and C)6 and (ii) a tetradehydro Diels−
Alder reaction of an enyne−diyne (selaginpulvilins A, B and
D),7,8 and sequences comprising of cross-coupling reactions
and an intramolecular SEAr reaction.9
Figure 1. Selaginpulvilins A−D (1a−1d) and their retrosynthetic
analysis.
Herein we would like to present a different synthetic
approach toward selaginpulvilins based on a modular strategy.
The approach relies on two key operations (Figure 1). The
Received: February 12, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00519
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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first one is the crucial assembly of the aromatic ring on the
right-hand side of the fluorenol’s molecular scaffold 2 by using
catalytic [2 + 2 + 2] cyclotrimerization of a substituted 1,3-
diyne-yne 3 with alkynes 4. The second one is synthesizing 3
from a 2-halo-5-methoxybenzaldehyde and trimethylsilyle-
thyne by using standard methods of alkyne chemistry such
as Sonogashira and Cadiot−Chodkiewicz couplings.
The reactivity of 1,3-diynes or their higher congeners in
catalytic cycloaddition reactions has not been extensively
studied, and only a few examples exist. For instance,
homocyclotrimerization of 1,3-diynes to benzenes catalyzed
by Pd,10 Co,11 Ni, and Rh11c complexes have been reported.
Catalytic cocyclotrimerization (Co, Rh, Ir, and Ni complexes)
of compounds having the 1,3-diyne moieties with alkynes and
nitriles was explored as a route to various substituted biaryl or
heterobiaryl compounds.12−19
Information (SI) for details). Mixtures of 2a (ortho) and 2a′
(meta) regioisomers were obtained in all cases. The best
selectivity for the desired ortho (2a:2a′ = 9.5:1) and the
moderate overall yield of 48% were obtained by using
Wilkinson’s catalysts in dichloroethane. Unlike previously
reported,21 catalytic systems prepared by mixing [Rh(COD)2]-
BF4 and various bidentate phosphine22 led to a considerable
decrease in regioselectivity, albeit the overall product yields
increased. Besides 2a and 2a′ were also detected intractable
aromatic side products (vide infra). Catalysis by Cp*Ru(cod)
Cl provided 2a and 2a′ in only 10% yield (1:4).
Then the scope of the reaction of 3 with terminal alkynes
bearing various functionalities was assessed (Table 1). A
Table 1. Scope of Cyclotrimerization of 3 with Various
Alkynes 4
On the other hand, cyclotrimerization of a 1,3-diyne-yne
with alkynes to construct a single benzene ring is a relatively
rare and unexplored field. Cramer’s synthesis of fijiolide
utilizing Ru-catalyzed cyclotrimerization of diyne-yne (con-
nected by the B−O spacer) with an alkyne is the only
example.20 The lack of data in this field provides a sufficient
impetus to explore the scope and synthetic applications of
these reactions. In this respect, selaginpulvilins with their
unique structure constitutes challenging synthetic objects to
apply this methodology.
At the outset, we focused on the synthesis of the key
intermediate 3. It began with a Sonogashira coupling of 2-
bromo-5-methoxybenzaldehyde and trimethylsilyl ethyne to
furnish aldehyde 5 in 91% yield. Then NBS mediated
bromination of 4-methoxyphenylethyne followed by Cadiot−
Chodkiewicz coupling with trimethylsilyl ethyne provided
TMS protected dialkyne (30% after two steps). Its desilylation
furnished diyne 6 in 90% yield. Finally, alkynylation of
aldehyde 5 with diyne 6 followed by desilylation gave rise to
the desired triyne 3 in 58% yield after two steps (Scheme 1).
With a competent substrate in hand, we turned our attention
to the key [2 + 2 + 2] cyclotrimerization step. Cyclo-
trimerization of 3 with propargyl alcohol (4a) catalyzed by Rh
and Ru-complexes under various reaction conditions was
chosen as the standard reaction (see Table S1 the Supporting
a
entry
alkyne 4
R
2a:2′a ratio
yield (%)
b
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH2OH
9.5:1
1.4:1
5.6:1
1.5:1
>99:1
>99:1
48
15
52
26
49
39
0
64
0
12 (36)
CH2OTBS
CH2OBz
C(Me)2OH
CH2CH2OH
CH2CH2CH2OH
CH2NH2
c
c
n.d.
13.1:1.
n.d.
CH2NHBz
COOEt
d
4j
SiMe3
6.8:1
a
b
c
Isolated yields. Reaction carried out at 1.58 mmol scale. “meta
isomer” 2′ was not detected. The overall yield could be improved by
d
using 20 eq. of 4j, at 25 °C and 20 h.
reaction with the TBS-protected propargyl alcohol 4b gave the
product in just 15% yield and poor regioselectivity (entry 2).
The use of other catalytic systems did not improve the
situation (see Table S2 in the SI for details). A reaction with
propargyl benzoate (4c) gave desired products in 52% yield
and a good 2c:2c′ ratio of 5.6:1 (entry 3). Using 2-methylbut-
3-yn-2-ol (4d) resulted in a decrease in the yield of the desired
product (26%) along with regioselectivity (2d:2′d = 1.5:1),
presumably due to the steric hindrance of the alkyne (entry 4).
When but-3-yn-1-ol 4e and pent-4-ynol 4f were engaged, the
desired products were isolated as single regioisomers 2e and 2f
in 49% and 39% yields, respectively (entries 5 and 6). A
reaction with propargyl amine (2g) did not lead to any
consumption of the starting material, probably due to the
poisoning of the catalyst (entry 2). On the other hand, the use
of N-propargyl benzamide (2h) led to a formation of desired
product 2h in 64% yield with very high selectivity for the
“ortho isomer” (2h:2′h = 13.1:1) (entry 8). A reaction with
ethyl propionate (2i) did not provide the expected product
(entry 9). A reaction with trimethylsilyl ethyne (4j) yielded
12% of the desired cycloaddition products 2j and 2j′ as the
6.8:1 mixture (entry 10). We also tested internal alkynes such
Scheme 1. Synthesis of Triyne 3
B
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as 3-hexyne, 4-octyne, diphenylethyne, and but-2-yn-1-ol, but
the reactions did not provide the desired products.
two cases, intermediate III contains a thermodynamically
stable five- or six-membered chelation ring, respectively. In
contrast, alcohols 2a−2c and 2d form less stable four-
membered chelation rings.
In all cases, except the reaction with propargyl amine (4g),
the full consumption of 3 was observed, which led us to an
assumption that 3 can undergo [2 + 2 + 2]-homocyclotrime-
rization. Thus, subjecting triyne 3 to the standard reaction
conditions in the absence of the external alkyne led to full
consumption of the starting material. Analyses (MS and NMR)
of crude reaction mixtures as well as isolated material revealed
the presence of inseparable mixtures of compounds corre-
sponding to the dimers of 3. The formation of similar species
was also observed in cyclotrimerizations with internal alkynes.
For the sake of accuracy, it cannot be excluded that some
aromatic side products could be formed by dehydro-Diels−
Alder reaction of triyne 3.23
In accordance with the recently proposed mechanism
involving coordination of Lewis basic functionalities by
Tanaka24 and Dudley25 as the means of regiocontrol, we
offer the following rationalization of the observed regioselec-
tivity. After the initial formation of rhodacyclopentadiene I
(Scheme 2), two competing reaction pathways can take place:
Moreover, steric hindrance in the case of 2-methylbut-3-yn-
2-ol (2d) can lead to further destabilization of the intermediate
and loss of the regioselectivity and the desired reactivity as
well. The higher Lewis basicity of amides increases the ability
to coordinate to the metal center compared to that of esters
and can account for the higher regioselectivity: compare the
reaction with N-propargyl benzamide (2h) and propargyl
benzoate (2c) (entries 8 and 3). On the other hand, for
sterically hindered terminal alkynes or the terminal alkynes
without the polar moiety the homodimerization (pathway B) is
mostly observed. Internal alkynes proved to be not suitable
alkynes for the desired transformation regardless of the polar
moiety’s presence or absence, perhaps due to the steric
hindrance.
Then, we turned our attention to the synthesis of
selaginpulvilins to demonstrate the versatility of the method
(Scheme 3). We chose as synthetic targets selaginpulvilin C
Scheme 2. Mechanistic Rational of the Observed Reactivity
and Selectivity
Scheme 3. Formal Synthesis of Selaginpulvilin C
(1c), bearing the methyl group at C2 position, and
selaginpulvilin D (1d), which does not bear any substitution
at the C2 position. We commenced with the selaginpulvilin C
(1c) synthesis by using compound 2a bearing the hydrox-
ymethyl group (Scheme 3). The initial attempts to directly
reduce the hydroxymethyl moiety to the methyl group under
various conditions failed. Pd-catalyzed reduction with
triethylsilane26 gave rise to a mixture of products that consisted
of species with the reduced benzyl alcohol moiety and the
reduced triple bond. Also, the use of a nickel chloride/sodium
borohydride27 system gave a complex reaction mixture. An
attempt to employ Kursanov−Parnes reduction (triethylsilane/
formic acid) gave rise to an intractable reaction mixture.28
Finally, the reduction was brought about in the two-step
process. First, the benzyl alcohol 2a was converted to bromide
7 in 43% yield via the Appel reaction29 (bromide 7 was not
stable and underwent partially unspecified decomposition
upon the chromatographic purification). Its immediate
reduction with the zinc powder in a water/THF solution of
NH4Cl and subjecting the crude product to oxidation with
PCC provided ketone 8 in 36% yield (after two steps). Ketone
8 is the known advanced intermediate in the synthesis of
the desired pathway A leading to regioisomers 2 and pathway
B giving rise to homodimers. It seems that the nature of the
external alkyne 4 strongly influences the course of the reaction.
The terminal alkynes containing in their structure a Lewis basic
functionality bearing lone electron pairs undergo preferably the
desired pathway A. Two aspects can rationalize the high
preference of the formation of the “ortho” regioisomers 2. First,
the insertion of the external alkyne takes place in a less
sterically demanded C4−Rh vs C1−Rh bond (the fluorenol
numbering, intermediate II, Scheme 2). Second, precoordina-
tion of the alkyne causes the correct orientation of the alkyne
II and leads to the formation of the intermediate III, which
upon the reductive elimination furnishes the desired product.
This model reasonably explains exclusive “ortho” regioselectiv-
ity in the cyclotrimerization of homopropargyl alcohol (2e)
and pent-4-ynol (2f) (entries 5 and 6) in comparison with
propargyl alcohol (2a), its protected derivatives 2b and 2c, and
2-methylbut-3-yn-2-ol (2d) (entries 1−3 and 4). In the former
C
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selaginpulvilin C (1c). Therefore, the formal synthesis of 1c
was accomplished.8
A mixture of regioisomeric trimethylsilylated fluorenols
consisting of 2j and 2′j was used for the formal synthesis of
selaginpulvilin D (1d), because the removal of the TMS group
from both components would result in a single compound
(Scheme 4). However, the low yield of the cyclotrimerization
FAIR data, including the primary NMR FID files, for
compounds 2a, 2′a, 2b, 2′b, 2c, 2d, 2′d, 2e, 2f′, 2h, 2j,
8, 9, and 10 (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Martin Kotora − Department of Organic Chemistry, Faculty of
Science, Charles University, 128 43 Praha 2, Czech
Republic; orcid.org/0000-0003-4491-7091;
Email: kotora@natur.cuni.cz
Scheme 4. Formal Synthesis of Selaginpulvilins D
Authors
Lukas Rycek − Department of Organic Chemistry, Faculty of
Science, Charles University, 128 43 Praha 2, Czech Republic
Miguel Mateus − Department of Organic Chemistry, Faculty
of Science, Charles University, 128 43 Praha 2, Czech
Republic
Nela Beytlerová − Department of Organic Chemistry, Faculty
of Science, Charles University, 128 43 Praha 2, Czech
Republic
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00519
Author Contributions
‡M.M. and N.B. contributed equally.
Notes
product 2j and 2′j prompted us to reinvestigate the reaction
conditions (see Table S3 in the SI for details). Eventually,
increasing the amount of trimethylsilyl ethyne from a 5- to 20-
fold excess (with respect to 3), lowering the reaction
temperature to 25 °C, and prolonging the reaction time to
20 h gave a mixture of fluorenols 2j and 2′j in an improved
yield of 36%. Subsequent oxidation of the fluorenol mixture
with PCC furnished a mixture of fluorenones 9 and 9′ in 82%
isolated yield. The formal synthesis of the selaginpulvilin D
(1d) was concluded by desilylation of 9 and 9′ by TBAF at 20
°C to ketone 10 in 78% yield. Ketone 10 is the known
advanced intermediate for the synthesis of selaginpulvilin D
(1d).6
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Czech Science Foundation
(Grant No. 18-17823S).
■
REFERENCES
■
(1) (a) Mojelsky, T. W.; Strausz, O. P. Detection of methyl
fluorenones in Athabasca oil sand bitumens. Org. Geochem. 1986, 9,
31−37. (b) Mojelsky, T. W.; Strausz, O. P. Detection of alkylated
fluorenes in Athabasca oil sand bitumens. Org. Geochem. 1986, 9, 39−
45.
(2) For a recent review on fluorenones, see: Patel, S.; Rathod, B.;
Regu, S.; Chak, S.; Shard, A. A Perspective on Synthesis and
Applications of Fluorenones. ChemistrySelect 2020, 5, 10673−1069.
(3) Liu, X.; Luo, H.-B.; Huang, Y.-Y.; Bao, J.-M.; Tang, G.-H.; Chen,
Y.-Y.; Wang, J.; Yin, S. Selaginpulvilins A−D, New Phosphodiesterase-
4 Inhibitors with an Unprecedented Skeleton from Selaginella
pulvinate. Org. Lett. 2014, 16, 282−285.
(4) Zhang, J.-S.; Liu, X.; Weng, J.; Guo, Y.-Q.; Li, Q.-J.; Ahmed, A.;
Tang, G.-H.; Yin, S. Natural diarylfluorene derivatives: isolation, total
synthesis, and phosphodiesterase-4 inhibition. Org. Chem. Front. 2017,
4, 170−177.
In summary, we have demonstrated that catalytic [2 + 2 + 2]
cyclotrimerization of triyne 3 (1-(2-ethynyl-5-methoxyphenyl)-
5-(4-methoxyphenyl)penta-2,4-diyn-1-ol) with selected termi-
nal alkynes (propargyl alcohol and trimethylsilylethyne) is a
suitable method for synthesis of intermediates 2a and 2j
possessing the 1-alkynylfluorenol core of selaginpulvilins. Both
intermediates were converted to the known advanced
intermediates in selaginpulvilins C and D syntheses. The
synthesis showcases the power of Rh-catalyzed intermolecular
cyclotrimerizations to construct heavily substituted arenes
selectively. Besides, it brings new information on the scope of
catalytic [2 + 2 + 2] cyclotrimerization of diyne-ynes with
terminal alkynes and ligand effect affecting its regioselectivity.
The modular synthetic strategy allows accessing selaginpulvi-
line analogues and further exploring the biological activities of
this substance class.
(5) Woo, S.; Kang, K. B.; Kim, J.; Sung, S. H. Molecular Networking
Reveals the Chemical Diversity of Selaginellin Derivatives, Natural
Phosphodiesterase-4 Inhibitors from Selaginella tamariscina. J. Nat.
Prod. 2019, 82, 1820−1830.
(6) Karmakar, R.; Lee, D. Total Synthesis of Selaginpulvilin C and D
Relying on in Situ Formation of Arynes and Their Hydrogenation.
Org. Lett. 2016, 18, 6105−6102.
(7) Chinta, B. S.; Baire, B. Formal Total Synthesis of Selaginpulvilins
D. Org. Biomol. Chem. 2017, 15, 5908−5911.
ASSOCIATED CONTENT
* Supporting Information
■
sı
(8) Chinta, B. S.; Baire, B. Total Synthesis of Selaginpulvilins A and
C. Org. Biomol. Chem. 2018, 16, 262−265.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00519.
(9) Sowden, M. J.; Sherburn, M. S. Four-Step Total Synthesis of
Selaginpulvilin D. Org. Lett. 2017, 19, 636−637.
All experimental procedures, compound characterization
data, and copies of spectra (PDF)
(10) Takeda, A.; Ohno, A.; Kadota, I.; Gevorgyan, V.; Yamamoto, Y.
Regioselective Synthesis of 1,3,5-Unsymmetrically Substituted
D
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Letter
Benzenes via the Palladium-Catalyzed Cyclotrimerization of 1,3-
Diynes. J. Am. Chem. Soc. 1997, 119, 4547−4548.
2000, 100, 2741−2770. (c) Birkholz, M.-N.; Freixa, Z.; van Leeuwen,
P. W. N. M. Bite angle effects of diphosphines in C−C and C−X
bond forming cross coupling reactions. Chem. Soc. Rev. 2009, 38,
1099−1118.
(11) (a) Sugihara, T.; Wakabayashi, A.; Nagai, Y.; Takao, H.;
Imagawa, H.; Nishizawa, M. Methylidynetricobalt nonacarbonyl
catalyzed cyclotrimerization of alkynes. Chem. Commun. 2002, 576−
577. (b) Traber, B.; Wolff, J. J.; Rominger, F.; Oeser, T.; Gleiter, R.;
Goebel, M.; Wortmann, R. Hexasubstituted Donor−Acceptor
Benzenes as Nonlinear Optically Active Molecules with Multiple
Charge-Transfer Transitions. Chem. - Eur. J. 2004, 10, 1227−1238.
(c) Weber, S. M.; Hilt, G. Chemoselective Cobalt(I)-Catalyzed
Cyclotrimerization of (Un)Symmetrical 1,3-Butadiynes for the
Synthesis of 1,2,4-Regioisomers. Org. Lett. 2019, 21, 4106−4110.
(12) Nishida, G.; Ogaki, S.; Yusa, Y.; Yokozawa, T.; Noguchi, K.;
Tanaka, K. Practical Enantioselective Synthesis of Axially Chiral Biaryl
Diphosphonates and Dicarboxylates by Cationic Rhodium(I)/
Segphos-Catalyzed Double [2 + 2 + 2] Cycloaddition. Org. Lett.
2008, 10, 2849−2852.
(23) (a) Kimura, H.; Torikai, K.; Miyawaki, K.; Ueda, I. Scope of the
Thermal Cyclization of Nonconjugated Ene−Yne−Nitrile System: A
Facile Synthesis of Cyanofluorenol Derivatives. Chem. Lett. 2008, 37,
662−663. (b) Wessig, P.; Muller, G. The Dehydro-Diels-Alder
̈
Reaction. Chem. Rev. 2008, 108, 2051−2063.
(24) For the suggested coordination of oxygen atoms during
cyclotrimerization, see: (a) Tanaka, K.; Nishida, G.; Ogino, M.;
Hirano, M.; Noguchi, K. Enantioselective Synthesis of Axially Chiral
Biaryls through Rhodium-Catalyzed Complete Intermolecular Cross-
Cyclotrimerization of Internal Alkynes. Org. Lett. 2005, 7, 3119−
3121. (b) Tanaka, K.; Suda, T.; Noguchi, K.; Hirano, M. Catalytic [2
+ 2 + 2] and Thermal [4 + 2] Cycloaddition of 1,2-Bis(arylpropiolyl)-
benzenes. J. Org. Chem. 2007, 72, 2243−2246. (c) Otake, Y.; Tanaka,
R.; Tanaka, K. Cationic Rhodium(I)/H8-binap Complex Catalyzed
[2 + 2 + 2] Cycloadditions of 1,6- and 1,7-Diynes with Carbonyl
Compounds. Eur. J. Org. Chem. 2009, 2009, 2737−2747. (d) Aida, Y.;
Tooriyama, S.; Kimura, Y.; Hara, H.; Shibata, Y.; Tanaka, K.
Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition−Aromatization of
1,6-Diynes with Cyclic Enol Ethers at Room Temperature. Eur. J. Org.
Chem. 2016, 2016, 132−138. (e) Yamano, R.; Kinoshita, S.; Shibata,
Y.; Tanaka, K. Substituent-Controlled and Rhodium-Catalyzed
Intramolecular [2 + 2 + 2] and [2 + 1+2 + 1] Cycloadditions of
Electron-Deficient Triynes. Eur. J. Org. Chem. 2018, 2018, 5916−
5920.
(13) (a) Doherty, S.; Knight, J. G.; Smyth, C. H.; Harrington, R. W.;
Clegg, W. Rhodium-Catalyzed Double [2 + 2 + 2] Cycloaddition of
1,4-Bis(diphenylphosphinoyl)buta-1,3-diyne with Tethered Diynes: A
Modular, Highly Versatile Single-Pot Synthesis of NU-BIPHEP Biaryl
Diphosphines. Org. Lett. 2007, 9, 4925−4928. (b) Doherty, S.; Smyth,
C. H.; Harrington, R. W.; Clegg, W. Highly Enantioselective Synthesis
of Pseudo-C2-Symmetric Axially Chiral Biaryl Diphosphines via
Rhodium-Catalyzed Double [2 + 2 + 2] Cycloaddition. Organo-
metallics 2008, 27, 4837−4840.
(14) Sato, Y.; Ohashi, K.; Mori, M. Synthesis of biaryls using nickel-
catalyzed [2 + 2 + 2] cocyclization. Tetrahedron Lett. 1999, 40, 5231−
5234.
(25) Tavakoli, A.; Dudley, G. B. Synthesis of 4,4-Dimethyl-1,6-
heptadiyne and Alcyopterosin O. Org. Lett. 2020, 22, 8947−8951.
(26) Mirza-Aghayan, M.; Boukherroub, R.; Rahimifard, M. A simple
and efficient hydrogenation of benzyl alcohols to methylene
compounds using triethylsilane and a palladium catalyst. Tetrahedron
Lett. 2009, 50, 5930−5932.
(27) (a) Khurana, J. M.; Kumar, S.; Nand, B. Facile reductive
dehalogenation of organic halides with nickel boride at ambient
temperature. Can. J. Chem. 2008, 86, 1052−1054. (b) Thiem, J.;
Meyer, B. Chem. Ber. 1980, 113, 3058−3066.
(28) Ciszek, B.; Fleischer, I. Homogeneous Palladium-Catalyzed
Transfer Hydrogenolysis of Benzylic Alcohols Using Formic Acid as
Reductant. Chem. - Eur. J. 2018, 24, 12259−12263.
(15) Sawada, Y.; Furumi, S.; Takai, T.; Takeuchi, M.; Noguchi, K.;
Tanaka, K. Rhodium-Catalyzed Enantioselective Synthesis, Crystal
Structures, and Photophysical Properties of Helically Chiral 1,1′-
Bitriphenylenes. J. Am. Chem. Soc. 2012, 134, 4080−4083.
(16) (a) Shibata, T.; Yoshida, S.; Arai, Y.; Otsuka, M.; Endo, K.
Iridium-catalyzed consecutive and enantioselective [2 + 2 + 2]
cycloaddition of tetraynes and hexaynes for the construction of an
axially chiral biaryl system. Tetrahedron 2008, 64, 821−830.
(b) Shibata, T.; Uchiyama, T.; Yoshinami, Y.; Takayasu, S.;
Tsuchikama, K.; Endo, K. Highly enantioselective synthesis of
silahelicenes using Ir-catalyzed [2 + 2 + 2] cycloaddition. Chem.
Commun. 2012, 48, 1311−1313.
(17) Mori, F.; Fukawa, N.; Noguchi, K.; Tanaka, K. Asymmetric
Synthesis of Axially Chiral Biaryl Diphosphine Ligands by Rhodium-
Catalyzed Enantioselective Intramolecular Double [2 + 2 + 2]
Cycloaddition. Org. Lett. 2011, 13, 362−365.
(18) (a) Varela, J. A.; Castedo, L.; Saá, C. J. Am. Chem. Soc. 1998,
120, 12147−12148. (b) Varela, J. A.; Castedo, L.; Maestro, M.;
Mahía, J.; Saá, C. Regiocontrolled One-Step Synthesis of 3,3′-
Disubstituted 2,2′-Bipyridine Ligands by Cobalt(I)-Catalyzed Cyclo-
trimerization. Chem. - Eur. J. 2001, 7, 5203−5213.
(29) (a) Appel, R. Tertiary Phosphane/Tetrachloromethane, a
Versatile Reagent for Chlorination, Dehydration, and P-N Linkage.
Angew. Chem., Int. Ed. Engl. 1975, 14, 801−811. This reaction was
first reported: (b) Downie, I.; Holmes, J.; Lee, J. Preparation of Alkyl
Chlorides Under Mild Conditions. Chem. Ind. 1966, 22, 900−901.
̌
́
̌
(19) (a) Hrdina, R.; Dracínsky, M.; Valterová, I.; Hodacová, J.;
̌
Císarová, I.; Kotora, M. New Pathway to C2-Symmetric Atropoiso-
meric Bipyridine N,N′-Dioxides and Solvent Effect in Enantioselec-
tive Allylation of Aldehydes. Adv. Synth. Catal. 2008, 350, 1449−
̌
1456. (b) Kadlcíková, A.; Hrdina, R.; Valterová, I.; Kotora, M. Simple
and Fast Synthesis of New Axially Chiral Bipyridine N,N′-Dioxides
for Highly Enantioselective Allylation of Aldehydes. Adv. Synth. Catal.
2009, 351, 1279−1283.
(20) Heinz, C.; Cramer, N. Synthesis of Fijiolide A via an
Atropselective Paracyclophane Formation. J. Am. Chem. Soc. 2015,
137, 11278−11281.
̌
̌
(21) Matousová, E.; Gyepes, R.; Císarová, I.; Kotora, M. [2 + 2 + 2]-
Cyclotrimerization of 1-Cyclopropyl-1,6-diynes with Alkynes: For-
mation of Cyclopropylarynes. Adv. Synth. Catal. 2016, 358, 254−267.
(22) For reviews on ligand effect, see: (a) Mansell, S. M. Catalytic
applications of small bite-angle diphosphorus ligands with single-atom
linkers. Dalton Trans. 2017, 46, 15157−15174. (b) van Leeuwen, P.
W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Ligand Bite
Angle Effects in Metal-catalyzed C−C Bond Formation. Chem. Rev.
E
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