Nickel-Catalyzed Construction of Chiral 1-[6]Helicenols and Application in the Synthesis of [6]Helicene-Based Phosphinite Ligands

Article abstract of DOI:10.1002/ejoc.201600677

Two 1-[6]helicenol derivatives were synthesized by Ni-catalyzed [2+2+2] cycloaddition on a multigram scale. Both enantiomers of the 1-[6]helicenols could be efficiently prepared by simple optical resolution. As a synthetic application of helically chiral 1-[6]helicenols, a novel class of [6]helicene-based phosphinites was developed; these compounds represent the first examples of helically chiral phosphinite ligands. Up to 90 % ee was obtained for the Pd-catalyzed asymmetric allylic alkylation reaction.

Full text of DOI:10.1002/ejoc.201600677

A Journal of
Accepted Article
Title: Ni-Catalyzed Construction of Chiral 1-[6]Helicenols and Application in the
Synthesis of [6]Helicene-Based Phosphinite Ligands
Authors: Tetsuya TSUJIHARA; Nao INADA-NOZAKI; Tsunayoshi TAKEHARA;
Da-Yang Zhou; Takeyuki SUZUKI; Tomikazu KAWANO
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600677
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COMMUNICATION
Ni-Catalyzed Construction of Chiral 1-[6]Helicenols and
Application in the Synthesis of [6]Helicene-Based Phosphinite
Ligands
Tetsuya Tsujihara,[a] Nao Inada-Nozaki,[a] Tsunayoshi Takehara,[b] Da-Yang Zhou,[b] Takeyuki
Suzuki,[b] and Tomikazu Kawano[a]
Abstract: Two 1-[6]Helicenol derivatives have been synthesized via
Ni-catalyzed [2+2+2] cycloaddition on a multigram-scale. Both
enantiomers of 1-[6]helicenols can be efficiently prepared by the
simple optical resolution. As a synthetic application of helically chiral
1-[6]helicenols, a novel class of [6]helicene-based phosphinites has
been developed, representing the first example of helically chiral
phosphinite ligands. Up to 90% ee was obtained for the Pd-
catalyzed asymmetric allylic alkylation (AAA).
Introduction
Helicenes and helicene-like molecules are attractive nonplanar
helical compounds. Due to their unique screw-shaped structure
and chiroptical properties, these compounds have been applied
Scheme 1. Synthetic Approach to 1-[6]Helicenols (P)-1a and (P)-1b and
in chiral functional materials prototypes, chiral reagents, chiral
recognition of biomolecules, and asymmetric catalysis.[1]
[6]Helicene-based Phosphinites (P)-4a and (P)-4b.
So far, several helicene-based phosphorus ligands were
studied.[2] The pioneering Reetz’s and Brunner’s [6]helicene-
based phosphine[2a-2c] has the diphenylphosphino groups at 2-
and 15-position which are situated at the outer positions of the
helical backbone. The other recently reported helicene-based
phosphites[2d] and phospholes[2e,2f] include not only helical
chirality but also central chirality in their structure. To explore
the chiral recognition ability of helicenes, chiral 1-functionalized
helicenes are ideal synthetic targets because the active catalytic
sites or coordinating groups are located at the inner screw of the
helical skeleton.[3]
Results and Discussion
For the construction of helical structure, many synthetic routes to
helicenes have been reported including photochemical
cyclization,[6] Diels-Alder cycloaddition,[7] olefin metathesis,[8]
Friedel-Crafts
cyclization,[9]
[2+2+2]
cycloaddition,[10]
cycloisomerization,[11] and organocatalytic approach based on
Fischer Indolization.[12] From these methods, we focused on the
transition metal catalyzed [2+2+2] cycloaddition, because of its
broad scope and operational simplicity.[10,13] Although this key
[2+2+2] cycloaddition has already proven effective for the
construction of [6]helicene scaffolds as reported by Stará, Starý,
and co-workers,[10a-10c] multigram-scale [2+2+2] cycloaddition for
the synthesis of 1-functionalized helicene derivatives remains a
challenge.[14] Thus, our approach to chiral 1-[6]helicenols 1 is
based on Ni-catalyzed [2+2+2] cycloaddition of methoxy-
substituted triyne 3, followed by optical resolution of rac-1.
Initially, methoxy-substituted triyne 3, the precursor of 1-
methoxy-5,6,9,10-tetrahydro[6]helicene rac-2, was synthesized
via the route shown in Scheme 2. Sonogashira–Hagihara cross
coupling of o-vanillin triflate 5 with trimethylsilylacetylene, and
subsequent reduction of the formyl group furnished the alcohol 6
in 83% yield over two steps. After mesylation of 6, the addition
of a THF solution of LiBr afforded the bromide 7 in 90% yield.
On treatment with LiCH2C≡CTIPS (TIPS = triisopropylsilyl) and
subsequent selective removal of the trimethylsilyl (TMS) group,
diyne 8 was obtained in 83% yield. Sonogashira–Hagihara
cross coupling of 8 and the iodide 9[15] afforded the silylated
triyne 10 in 95% yield. Removal of the TIPS groups by
tetrabutylammonium fluoride (TBAF) gave desired triyne 3 in
97% yield. Throughout the synthesis of 3, all the steps were
performed on a large scale (>18 g) and good to high yields were
achieved (57% overall yield in 6 steps).
Herein, we report the multigram-scale Ni-catalyzed
construction of 1-[6]helicenols 1a and 1b bearing a hydroxy
group at the 1-position of the [6]helicene skeleton (Scheme 1).
The reason we focused on the synthesis of 1-[6]helicenol is as
follows.[4] The scaffold larger than [5]helicene is reliable as a
chiral unit because [5]helicene is known to undergo racemization
at room temperature but [6]helicene is stable at room
temperature.[5a,5b] We also envisioned the introduction of a
substituent in the 1-position of the helicene will cause a further
increase in the energy barrier of racemization.[4,5c]
application of (P)-1a and (P)-1b to the synthesis of the novel
An
[6]helicene-based phosphinites (P)-4a and (P)-4b and
a
preliminary investigation as an asymmetric ligand is described.
[a]
[b]
Department of Medicinal and Organic Chemistry, School of
Pharmacy, Iwate Medical University
Yahaba, Iwate 028-3694, Japan
E-mail: ttsujiha@iwate-med.ac.jp (T. T.)
tkawano@iwate-med.ac.jp (T. K.)
http://www.iwate-med.ac.jp
The Institute of Scientific and Industrial Research, Osaka University
Mihogaoka, Ibaraki, Osaka 567-0047, Japan
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ejoc.201600677.

European Journal of Organic Chemistry
10.1002/ejoc.201600677
COMMUNICATION
Entry
Ligand (X mol-%)
none
Ni : L
1 : 0
1 : 2
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 4
Yield[b] [%]
85 (0)
1
2
PPh3 (20 mol-%)
dppe (10 mol-%)
dppp (10 mol-%)
tmeda (10 mol-%)
bpy (10 mol-%)
cod (10 mol-%)
cod (40 mol-%)
cod (200 mol-%)
nbd (200 mol-%)
15 (44)
86 (2)
3
4
69 (19)
75 (8)
5
6
28 (62)
90 (0)
7
8
91 (0)
9
1 : 20
95 (0)
10
1 : 20
9 (70)
[a] All reactions were carried out in the presence of 10 mol-% of Ni(cod)2
and X mol-% of ligand at 30 °C in THF (0.033 M) under an argon
atmosphere. [b] NMR yield based on benzyl 4-hydroxybenzoate as an
internal standard. The values in parentheses are the amounts of the
unreacted 3. dppe
=
1,2-bis(diphenylphosphino)ethane, dppp
= 1,3-
bis(diphenylphosphino)propane,
tmeda N,N,N’,N’-
=
Scheme 2. Synthesis of the Triyne 3. TIPS = triisopropylsilyl, TBAF =
tetramethylethylenediamine, bpy = 2,2’-bipyridyl, cod = 1,5-cyclooctadiene.
tetrabutylammonium fluoride.
Having prepared the precursor 3 for rac-2, we examined the
Ni-catalyzed [2+2+2] cycloaddition using various ligands (Table
1). The reaction of 3 in the presence of 10 mol-% of Ni(cod)2 in
THF at 30 °C afforded the desired rac-2 in 85% yield (entry 1).
In this reaction, oligomeric byproducts arising from the
intermolecular side reactions of 3 were also observed. When
the reaction was conducted with 20 mol-% of PPh3 under
otherwise identical conditions, the yield of rac-2 was diminished
to 15% and 44% of 3 remained unreacted (entry 2). Addition of
phosphorus or nitrogen bidentate ligands showed no
improvement (entry 1 and entries 3-6). To our delight, the
desired reaction of 3 proceeded smoothly in the presence of 10
mol-% of 1,5-cyclooctadiene (cod) to furnish rac-2 in 90% yield
(entry 7). Increasing the amount of cod (40 and 200 mol-%)
suppressed the formation of oligomeric byproduct and the yield
of rac-2 was further improved (entries 8-9). Thus, rac-2 was
obtained in 95% yield when the reaction was performed at 30 °C
for 2 h with 200 mol-% of cod. In this reaction, the addition of
cod was essential to keep the catalyst active and to suppress
the undesired intermolecular reaction of 3. Interestingly, 2,5-
norbornadiene (nbd) inhibited the formation of rac-2 (entry 10).
Presumably, Ni(nbd)2 formed in situ did not work as the catalyst
in this [2+2+2] cycloaddition. Moreover, attempt at the catalytic
asymmetric [2+2+2] cycloaddition using chiral diene ligand,
(1S,4S)-2,5-diphenylbicyclo[2,2,2]octa-2,5-diene ((S,S)-Ph-bod*),
gave rac-2 in 86% yield (Scheme S1).[16]
Being encouraged by the results in Table 1, we next carried
out a multigram-scale Ni-catalyzed [2+2+2] cycloaddition of 3
(Scheme 3). After attempts at reducing the catalytic amount and
loosening the high dilution conditions, the synthesis of rac-2 was
successfully achieved on a 10 g scale in 97% yield in the
presence of 5 mol-% of Ni(cod)2 and 100 mol-% of cod.[17]
Scheme 3. Synthesis of the rac-2 on a 10 g Scale.
After demethylation of rac-2 by BBr3, we next performed the
optical resolution of 5,6,9,10-tetrahydro-1-[6]helicenol rac-1a
using (1S)-camphanic chloride as the chiral resolving agent
(Scheme 4).[18]
Treatment of rac-1a with (1S)-camphanic
chloride in the presence of 4-(N,N-dimethylamino)pyridine
(DMAP) and Et3N afforded the diastereomeric mixture of
camphanate esters 11a, which were separated by flash column
chromatography over silica gel to give (P,S)-11a (49%) and
(M,S)-11a (49%). Subsequent alkaline saponification of (P,S)-
11a and (M,S)-11a afforded enantiomerically pure (P)-1a (99%)
and (M)-1a (98%). Furthermore, the transformations of the
tetrahydro[6]helicene skeleton of 11a to the fully aromatic
[6]helicene skeleton were achieved with triphenylmethylium
tetrafluoroborate (Ph3CBF4)[9,15] in DCE to give (P,S)-11b (92%)
and (M,S)-11b (89%). Similarly, alkaline saponification of (P,S)-
11b and (M,S)-11b afforded the enantiomerically pure 1-
Table 1. Effect of Ligands on the Ni-Catalyzed [2+2+2] Cycloaddition of 3.[a]

European Journal of Organic Chemistry
10.1002/ejoc.201600677
COMMUNICATION
[6]helicenols (P)-1b (quantitative yield) and (M)-1b (94%). Thus,
the optical resolution via common synthetic intermediate 11
afforded two types of 1-[6]helicenols 1a and 1b in non-racemic
forms, efficiently. The prepared compounds 1a and 1b were
identified by NMR and mass spectrometry. X-ray diffraction
analysis unequivocally established the relative and absolute
configurations of (P,S)-11b and (M,S)-11b (Figures S6 and
S7).[19] Furthermore, the X-ray analysis of (P)-1b revealed an
intramolecular OH··· interaction (Figure 1).[19,20] The distance
between H(28) and the midpoint of the bond C(15)–C(19) is
2.307 Å. Thus, it is evident that an intramolecular OH··· bond
is formed between H(28) and the  electrons around C(15) and
C(19).
(P)-4b from (P)-1a and (P)-1b, respectively (Scheme 5).[2,21] (P)-
4a and (P)-4b were easily prepared from the respective (P)-1a
and (P)-1b by the reaction with chlorodiphenylphosphine in the
presence of sodium hydride. Filtration of the reaction mixture
through
a
short plug of silica gel and subsequent
recrystallization from hexane and CH2Cl2 at −20 °C afforded
pure crystals of (P)-4a and (P)-4b in 72% and 74% yields,
respectively.
The structures of (P)-4a and (P)-4b were
characterized by NMR and mass spectrometry. Furthermore,
the X-ray analysis of (P)-4a confirmed its structure assigned by
NMR data and the selected bond distances and bond angles of
(P)-4a are listed in Figure 2.[19]
Scheme 5. Synthesis of Helicene-based Phosphinites (P)-4a and (P)-4b.
Scheme 4. Optical resolution and transformations of rac-1a.
Figure 1. POV-Ray drawing of (P)-1b with 50% ellipsoid probability. Hydrogen
atoms except for hydroxyl group are omitted for clarity. Selected bond length
(Å), angle (deg), and atomic distances (Å) are as follows: C(15)–C(19)
1.456(2), C(2)–O–H(28) 112.0(11), C(15)–H(28) 2.230(17), C(19)–H(28)
2.094(19).
Figure 2. Crystal structure of (P)-4a. Hydrogen atoms are omitted for clarity.
a) POV-Ray drawing with 50% ellipsoid probability. b) Top and c) side views in
a stick style except for phosphorus atom depicted in ball style. Selected bond
lengths (Å), angles (deg), and torsion angles (deg) are as follows: P–O
1.6650(19), P–C(2) 1.817(3), P-C(5) 1.837(3), O–C(8) 1.389(3), O–P–C(2)
101.73(12), O–P–C(5) 97.51(11), C(2)–P–C(5) 100.44(13), P–O–C(8)
117.06(16), C(2)–P–O–C(8) 116.85(15), C(5)–P–O–C(8) –140.80(15).
To pursue application of the title helicenols, we next
synthesized novel [6]helicene-based phosphinites (P)-4a and

European Journal of Organic Chemistry
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COMMUNICATION
As a preliminary experiment to investigate the utility of novel
chiral phosphinite ligands (P)-4a and (P)-4b, we performed a
Pd-catalyzed AAA[22] of 1,3-diphenyl-2-propenyl acetate rac-12
with dimethyl malonate (13) (Scheme 6). The reactions were
carried out at 0 °C for 24 h in the presence of 2.5 mol-% of
[Pd(3-C3H5)Cl]2, 10 mol-% of (P)-4 and a mixture of 3.0 equiv.
of N,O-bis(trimethylsilyl)acetamide (BSA) and 10 mol-% of
LiOAc.[23] A Pd catalyst prepared from (P)-4a afforded the
desired alkylation product 14 of R configuration in 96% yield with
90% ee, while that prepared from (P)-4b proved less effective
regarding stereoselectivity, giving (R)-14 in 97% yield with 84%
ee.
This work was financially supported by a Takasago Award in
Synthetic Organic Chemistry, Japan (2012), and performed
under the Cooperative Research Program of “Network Joint
Research Center for Materials and Devices” (Osaka University).
We are also grateful to the technical staff of the Comprehensive
Analysis Center of ISIR for their assistance.
Keywords: Helical structures • Nickel • Cycloaddition • P ligands
• Asymmetric catalysis
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Scheme 6. Pd-Catalyzed AAA using (P)-4a and (P)-4b.
Conclusions
We have established efficient synthetic method toward 1-
[6]helicenols 1a and 1b, where multigram-scale Ni-catalyzed
[2+2+2] cycloaddition is included as the key step. To the best of
our knowledge, 10 g scale in the synthesis of helicene
derivatives by [2+2+2] cycloaddition was the largest scale in this
field. Moreover, novel [6]helicene-based phosphinite ligands
(P)-4a and (P)-4b derived from helicenols (P)-1a and (P)-1b,
respectively, have been developed. The present study is the
first example of helically chiral phosphinites. Our early-stage
[3]
resolution
intermediate 11 afforded two
strategy
via
the
types
common
of
synthetic
compounds
[4]
[5]
1a, 4a and 1b, 4b in non-racemic forms. This approach might
be significant from the view points of the resolution efficiency
and step economy. For the construction of more effective
asymmetric environments, introduction of alkyl and/or aryl
substituent to the 2-position of [6]helicene skeleton is in
progress. Further studies on the utility of [6]helicene-based
phosphinite ligands toward other catalytic asymmetric reactions
and the synthetic applicability of (P)-1 as a versatile precursor
for truly [6]helicene-based asymmetric catalysts are also in
progress.
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General experimental procedures and characterization data.
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COMMUNICATION
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[22] For reviews of catalytic asymmetric allylic alkylation, see: a) B. M. Trost,
D. L. Van Vranken, Chem. Rev. 1996, 96, 395-422; b) Z. Lu, S. Ma,
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[14] 5.4 g scale (87%) synthesis of [5]helquat via Rh-catalyzed [2+2+2]
cycloaddition of the corresponding triyne has been reported. To the
best of our knowledge, this is the largest scale [2+2+2] cycloaddition for
the construction of helical framework except for this paper. J. Vávra, L.
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[16] See Supporting Information for details (Scheme S1). N. Tokunaga, Y.
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[17] For the scale up synthesis of rac-2, see Supporting Information for
details (Table S1).
[23] For the optimization of reaction conditions, see Supporting Information
for details (Table S2).

European Journal of Organic Chemistry
10.1002/ejoc.201600677
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Helical Phosphinites
Tetsuya Tsujihara,* Nao Inada-Nozaki,
Tsunayoshi Takehara, Da-Yang Zhou,
Takeyuki Suzuki, and Tomikazu
Kawano,*
Page No. – Page No.
Multigram scale synthesis of 1-[6]helicenols has been realized via Ni-catalyzed
[2+2+2] cycloaddition of triyne. As a synthetic application of chiral 1-[6]helicenols,
the synthesis of novel [6]helicene-based phosphinite ligands and their preliminary
investigation in Pd-catalyzed asymmetric allylic alkylation (AAA) are described.
Ni-Catalyzed Construction of Chiral 1-
[6]Helicenols and Application in the
Synthesis of [6]Helicene-Based
Phosphinite Ligands