Chiral 2-(2-hydroxyaryl)alcohols (HAROLs) with a 1,4-diol scaffold as a new family of ligands and organocatalysts

Article abstract of DOI:10.1016/j.tet.2017.11.054

Efficient and modular syntheses of chiral 2-(2-hydroxyaryl)alcohols (HAROLs), novel 1,4-diols carrying one phenolic and one alcohol hydroxyl group, have been developed which led to generation of a small library of structurally diverse HAROLs in enantiomerically pure form. Of the different HAROLs examined, a HAROL based on the indan backbone exhibited the highest activity and enantioselectivity in the 1,2-addition of certain organometallic compounds to aldehydes in the presence of Ti(OⁱPr)₄ (up to 97% y, 88% ee) and performed as a hydrogen-bond donor organocatalyst in the Morita-Baylis-Hillman reaction, promoted by trialkylphosphines.

Full text of DOI:10.1016/j.tet.2017.11.054

Accepted Manuscript
Chiral 2-(2-hydroxyaryl)alcohols (HAROLs) with a 1,4-diol scaffold as a new family of
ligands and organocatalysts
Ömer Dilek, Mustafa A. Tezeren, Tahir Tilki, Erkan Ertürk
PII:
S0040-4020(17)31213-9
10.1016/j.tet.2017.11.054
TET 29134
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 June 2017
Revised Date: 10 November 2017
Accepted Date: 20 November 2017
Please cite this article as: Dilek Ö, Tezeren MA, Tilki T, Ertürk E, Chiral 2-(2-hydroxyaryl)alcohols
(HAROLs) with a 1,4-diol scaffold as a new family of ligands and organocatalysts, Tetrahedron (2017),
doi: 10.1016/j.tet.2017.11.054.
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ACCEPTED MANUSCRIPT
Chiral 2-(2-hydroxyaryl)alcohols (HAROLs) with a 1,4-
diol scaffold as a new family of ligands and
organocatalysts
Ömer Dileka,b, Mustafa A. Tezerena,b, Tahir Tilkib Erkan Ertürk*,a
,
a Institute of Chemical Technology, TÜBITAK Marmara Research Center, 41470 Gebze, Kocaeli, Turkey
b Department of Chemistry, Süleyman Demirel University, 32260 Isparta, Turkey
E-mail address of the corresponding author: erkan.erturk@tubitak.gov.tr (E. Ertürk)
Fax: +90-262-641 2309
Tel: +90-262-677 3893
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Graphical Abstract
Abstract
Efficient and modular syntheses of chiral 2-(2-hydroxyaryl)alcohols (HAROLs), novel
1,4-diols carrying one phenolic and one alcohol hydroxyl group, have been developed
which led to generation of a small library of structurally diverse HAROLs in
enantiomerically pure form. Of the different HAROLs examined, a HAROL based on the
indan backbone exhibited the highest activity and enantioselectivity in the 1,2-addition
of certain organometallic compounds to aldehydes in the presence of Ti(OiPr)4 (up to
97% y, 88% ee) and performed as a hydrogen-bond donor organocatalyst in the Morita-
Baylis-Hillman reaction, promoted by trialkylphosphines.
Key Words
Chiral 1,4-diols, Chiral ligands, Hydrogen-bond donor organocatalysts, Diethylzinc
addition, Morita-Baylis-Hillman reaction
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1. Introduction
Chiral compounds in enantiomerically pure form are intensely desired due to the fact
that not only biological systems, in most cases, recognize a pair of enantiomers as different
substances, but also enantiopure molecules offer new opportunities as functional materials.1,2
Over the last three decades, catalytic asymmetric synthesis has proven to be the most efficient
tool for providing pure enantiomers. Consequently, the development of novel chiral compounds,
especially for catalytic applications, continues to be a most vibrant field of research.1 In this
regard, enantiomerically pure diols, such as TADDOLs,3 hydrobenzoins4 as well as BINOLs5, have
played a significant role in enantioselective catalysis and materials science2c,4b,6 as chiral ligands,
organocatalysts, chiral luminophores etc. Whereas the majority of works with chiral diols have
dealt with their use as chiral ligands in combination with metals in asymmetric catalysis,3,4,5b-c,7
there have also been some reports in which chiral diols themselves serve as suitable hydrogen-
bond donor (HBD) organocatalysts for certain asymmetric transformations.8,9 For instance,
chiral diols have been reported to perform in some reactions with a high degree of activity and
enantioselectivity, such as the Morita-Baylis-Hillman reaction,9a,b epoxide ring-opening,9c,d
hetero Diels-Alder reactions,9e-i aldol-type reactions,9k,l as well as some other
transformations.9m,n As such, diols have become an appealing structural motif for
organocatalysis in recent years.10,11
Xu and his co-workers recently reported the synthesis of chiral Ar-BINMOLs (1,1′-
binaphthalene-2-α-arylmethan-2′-ols) possessing both axial and sp3 point chirality (Figure 1)12
which were shown to be efficient and highly enantioselective chiral ligands for the asymmetric
1,2-addition reactions of some organometallic compounds to aldehydes.13-18 In some cases, up to
>99% enantiomeric excesses were achieved for the 1,2-addition of organozinc,14
organolithium,15 organomagnesium,16 and organoaluminum17 reagents to aldehydes by
employing a catalytic amount of ArBINMOLs (e.g. 5 mol%) and a super-stoichiometric amount of
Ti(OiPr)4 (e.g. 2.50-6.00 equiv). Additionally, Xu and co-workers demonstrated that chiral
ArBINMOLs can also act as supramolecular HBD organocatalysts for the enantioselective
Michael addition of anthrone to (E)-β-nitrostyrene, furnishing the corresponding adduct in good
yields, albeit moderate enantiomeric excesses were detected.14 Despite their utility as catalysts,
ArBINMOL-type structures are rather limited to the 1,1′-binaphthalene-unit, due to the synthetic
approach developed. On the other hand, a modular synthesis of targets is regarded as a very
advantageous approach, because it leads to the generation of a library of compounds with
structural diversity, thereby enhancing the hit rate of the purpose.19 Encouraged by the
remarkable successes of ArBINMOLs as chiral ligands and by the potential catalytic applications
of diols in general, we set out to prepare new chiral 1,4-diols posessing one phenolic and one
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alcohol hydroxyl (-OH) group. Herein, we report efficient and modular syntheses of structurally-
diverse 2-(2-hydroxyaryl)alcohols (HAROLs) as well as their use as chiral ligands and
organocatalysts (Figure 1).
Figure 1. Structures of Ar-BINMOLs and hydroxyarylalcohols (HAROLs).
2. Results and discussion
In our previous work, we reported on the regioselective ring-opening of epoxides with
ortho-lithioanisoles in the presence of BF3·OEt2 as the Lewis acid catalyst (Scheme 1).20 This
method enabled us to prepare 2-(2-methoxyaryl)alcohols (5 and 6) in high yields and
regioselectivities. It was also shown that the enantiomerically pure 2-(2-methoxyaryl)alcohols
5a and 6a could be obtained by employing (R)-(+)-styrene oxide (4a). Thus, the protected form
of 2-(2-hydroxyaryl)alcohols (HAROLs) could be accessed in a one-pot fashion. However,
substrate scope of this methodology has found to be rather limited to monosubstituted terminal
epoxides and bicyclic epoxides, such as styrene oxide and cyclohexene oxide.
Scheme 1. Stereospecific ring-opening of (R)-(+)-styrene oxide (4a) with o-lithioanisoles (3) catalyzed
by BF3·OEt2.
Synthetic analysis suggested that precursors for 2-(2-hydroxyaryl)alcohols (HAROLs)
(5) could be effectively prepared via two ways as sketched in Scheme 2. Besides regioselective
ring-opening of epoxides with ortho-lithioanisoles (upper side of Scheme 2), palladium-
catalyzed α-arylation of ketones (10) with ortho-bromoanisoles (9) and enantioselective
reduction of the resulting ketones (11) stood out as an effective way to access the HAROL
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precursors 5 (lower side of Scheme 2). These two synthetic pathways were expected to provide
structurally diverse HAROLs in an efficient manner.
Scheme 2. Syntheses of hydroxyarylalcohols (HAROLs): (a) Methylation; (b) (1) Lithiation, (2)
BF3·OEt2; (c) Demethylation; (d) ortho-Bromination; (e) Methylation; (f) Pd-catalyzed α-arylation; (g)
Enantioselective reduction.
Unsubstituted anisole 2a was obtained from commercial sources. The anisoles 2b–d had
to be prepared from the corresponding phenols 7b-d through the usual methylation with
dimethyl sulfate (Scheme 3). The somewhat special anisole 2e (8-phenyl-1-
methoxynaphthalene) was synthesized starting from 1-naphthol (7e) by exploiting the Pd-
catalyzed arylation and subsequent methylation.21
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Scheme 3. Synthesis of anisoles. Reagents and conditions: (a) Me2SO4, K2CO3, acetone, reflux, 16 h,
N2; (b) PhI (1.20 equiv), Pd(OAc)2 (2.5 mol%), Cs2CO3 (1.20 equiv), DMF, 125 °C, 16 h, N 2.
With the anisole compounds 2a–e in hand, their ortho-lithiated derivatives were reacted
with (R)-(+)-styrene oxide (4a) to give the corresponding ring-opened products 5a–e (Table 1).
In this way, the enantiomerically pure (S)-2-(2-methoxyaryl)alcohols 5a–e were obtained in
satisfactory yields. As the ring-opening reaction of enantiopure 4a with the ortho-lithioanisoles
3 a–e is a stereospecific process proceeding via an SN2 mechanism, the absolute configurations
of 5 a-e were assigned as S. It should be noted that only the desired regioisomers of the ring-
opened products (such as 5a) are shown in Table 1. The other regioisomers (such as 6a) that are
formed by the attack of o-lithioanisoles at the more substituted carbon atom of (R)-(+)-styrene
oxide (4a) are not shown in Table 1.
Table 1. Synthesis of 2-(2-methoxyaryl)alcohols (5a–e) via the ring-opening of (R)-(+)-styrene oxide
(4a) with o-lithioanisoles in the presence of BF3·OEt2.
Yield
Entry
2
Product
(%)a
1b
2a
83
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2c
2b
2c
66
3c
68
4c
2d
2e
60
53
5b
a Yield of the isolated regioisomers 5a–e.
b Reaction conditions: (i) 2a or 2e (3.00 equiv), nBuLi (3.00 equiv), TMEDA (0.60 equiv), THF, 0 °C →
rt, 3 h; (ii) 4a (1.00 equiv), BF3·OEt2 (2.50 equiv), −78 °C, 1 h, N 2.
c Reaction conditions: (i) 2b–d (5.00 equiv), nBuLi (5.00 equiv), TMEDA (1.00 equiv), Et2O, 0 °C → rt,
16 h; (ii) 4a (1.00 equiv), BF3·OEt2 (5.00 equiv), −78 °C, 1 h, N 2.
Next, o-bromoanisoles that were needed for the Pd-catalyzed arylation of ketones were
prepared starting from the corresponding phenols (Scheme 4). Ortho-monobromination of the
phenols 7c–d with molecular bromine in dichloromethane and the subsequent methylation of
the ortho-bromophenols 8c–d as before, allowed access to the bromoanisoles 9c–d in high yields
as shown in Scheme 4.
Scheme 4. Synthesis of o-bromoanisoles 9c–d. Reagents and conditions: (a) Br2 (1.00 equiv), DCM,
0 °C, 2 h, N 2; (b) Me2SO4 (1.30 equiv), K2CO3 (1.40 equiv), acetone, reflux, 16 h, N2.
The o-bromoanisoles 9c–d were then subjected to the palladium-catalyzed Buchwald-
Hartwig α-arylation,22 with ketones 10a–e (Table 2). There have been several variants of the
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original Buchwald-Hartwig α-arylation conditions, reported in the literature over the last two
decades. Among them, considering the air stability and easy availability of the
triphenylphosphine ligand we first employed the Pd(OAc)2-triphenylphosphine couple as the
catalyst and cesium carbonate as the base in DMF at 150 °C (entry 1).22f The original Buchwald-
Hartwig procedure consisting of the Pd(OAc)2-tri-tert-butylphosphine couple and sodium tert-
butoxide in THF at room temperature was then tested for our substrates as well (entry 2).22a-d
The former was found to be effective in the coupling of the o-bromoanisole 9c with
acetophenone (10a) to some extent, giving the desired product 11a in 68% yield. Nonetheless,
the latter not only furnished the product 11a with higher yield (72%), but also allowed us to
purify the product more easily. So, 2-(2-methoxyaryl)ketones (11a–f) could be synthesized in
yields ranging from 72% to 93%, by employing the original Buchwald-Hartwig catalytic system.
Table 2. Synthesis of α-(2-methoxyaryl)ketones (11a–f) via Buchwald-Hartwig α-arylation.
Yield
Entry
9
Ketone
Product
(%)a
1b
9c
68
2c
9c
9c
10a
11a
72
75
3c
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4c
9c
86
5c
9c
83
6c
9d
9d
10d
76
93
7c
Method A: 9c (1.00 equiv), 10a (1.10 equiv), Cs2CO3 (2.50 equiv), Pd(OAc)2 (2 mol%), PPh3 (8 mol%),
DMF, 150 °C, 2 h, N 2. Method B: 9 (1.00 equiv), 10 (1.10 equiv), NaOtBu (2.50 equiv), Pd(OAc)2 (2
mol%), P(tBu)3 (2 mol%), THF, rt, 16 h, N2.
a Isolated yield.
b Method A was applied.
c Method B was applied.
Asymmetric reduction of ketones is a powerful tool for the synthesis of secondary
alcohols in enantiomerically enriched form. Asymmetric transfer hydrogenation (ATH) with the
Noyori-Ikariya RuCl(p-cymene)[(S,S)-TsDPEN] catalyst (13) in the presence of 5:2 HCO2H/Et3N
azeotropic mixture as the solvent and hydrogen source (Ru-ATH)23 as well as the asymmetric
reduction of ketones with proline-derived oxazoborolidine catalysts, e.g. (R)-(+)-2-methyl-CBS-
oxazoborolidine (14), in the presence of borane complexes as the hydrogen source (CBS-Red)24a
have played a pivotal role in the synthesis of chiral secondary alcohols. In numerous cases, both
methods have been proven to be effective and highly enantioselective for laboratory-scale
synthesis of chiral secondary alcohols from ketones. Moreover, the mechanisms of the both
techniques, Ru-ATH23c and CBS-Red24a, have been unequivocally provided. In case of ATH of
ketones by employing the ruthenium(II) complex 13 in the presence of formic acid-
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triethylamine mixture, 13 is first transformed to a 18e ruthenium hydride complex (RuH[(S,S)-
TsNCH(C6H5)CH(C6H5)NH2]−(η6-cymene)) through a triethylamine-promoted elimination and a
subsequent hydrogen abstraction from formic acid. This 18e ruthenium hydride complex then
effects the enantioselective reduction of ketones by the simultaneous delivery of the hydridic
RuH and protic NH to a C=O group through a six-membered pericyclic mechanism; i.e.
“bifunctional metal-ligand catalysis” takes place.23c As for CBS-Red, its established mechanism
evidenced by experimental findings as well as theoretical calculations in turn involves that the
oxazoborolidine 14 acts as a bifunctional organocatalyst, thereby activating the carbonyl oxygen
via Lewis acid catalysis as well as borane (hydride source) via Lewis base catalysis.24a Apart
from their efficiencies and enantioselectivities, reliable stereochemical models for
diastereomeric transition states have also been developed for both methods which allows us to
predict the absolute configurations of the alcohol products with a high degree of certainty. The
Noyori-Ikariya catalyst in Ru-ATH distinguishes the aryl and alkyl group attached to the
carbonyl functionality and preferentially forms a favored diastereomeric transition state with
the ketone substrate.23c On the other hand, oxazoborolidine catalyst 14 selectively forms a
diastereomorphic ternary transition state complex with ketones and boranes by recognizing the
organyl groups attached to the carbonyl functionality depending on their bulkiness.24a
Accordingly, Ru-ATH and CBS-Red were applied to our test substrate 11a by employing the
commercially available RuCl(p-cymene)[(S,S)-TsDPEN] (13) and (R)-(+)-2-methyl-CBS-
oxazoborolidine (14) as catalysts, respectively (Table 3). Although both Ru-ATH with 13 and
CBS-Red with 14 were found to give the alcohol 5c in excellent enantioselectivities (98% and
97% ee, respectively) they dramatically differed in their catalytic activities (Table 3, entries 1
and 2). Thus, CBS-Red gave the alcohol 5c in almost quantitative yield (95%, entry 2) whereas
Ru-ATH afforded it in modest yield (35%, entry 1). All attempts to increase the reduction yield of
Ru-ATH with 13 by increasing the amount of the catalyst, by changing the hydrogen source from
i
HCO2H/Et3N to HCO2H/DABCO as well as PrOH/KOH, and by employing solvents such as THF
and DMF did not lead to any improvement.23d Absolute configurations of the alcohol products
obtained from 11a through Ru-ATH with 13 and CBS-Red with 14 were examined by comparing
the sign of their optical rotations with the authentic sample 5c that was prepared by us through
the stereospecific ring-opening of (R)-(+)-styrene oxide (4a) with ortho-lithiated 2,4-di-tert-
butylanisole (2c) in the presence of BF3·OEt2 (Table 1, entry 3). Interestingly, it was determined
that both catalytic systems, Ru-ATH with 13 and CBS-Red with 14, gave the chiral secondary
alcohol 5c with the same absolute configuration (S) as depicted in Table 3 (entries 1 and 2).
These stereochemical outcomes from the reduction of 11a fit well with the mechanistic models
developed for Ru-ATH and CBS-Red explained above: In the Ru-ATH, the phenyl- and the benzyl
substituents attached to the C=O linkage of 11a were recognized as the aryl- and alkyl groups,
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respectively. On the other hand, the (R)-CBS catalyst 14 distinguishes the phenyl substituent as
the bulkier group than the benzyl group of the ketone 11a, thereby delivering the (S)-configured
product (5c) preferentially. This observation is also in good accordance with a literature report,
in which reduction of deoxybenzoin with borane dimethyl sulfide complex in the presence of
(R)-CBS catalyst 14 led to the (S)-configured product.24b Note that the ketone 11a might be
considered as a derivative of deoxybenzoin. Thereafter, we were able to prepare the chiral
alcohols 5f and 5g in almost enantiomerically pure form through the CBS-Red with 14 in
excellent yields (entries 3 and 4). Inspection of the stereochemical working model for CBS-Red
suggests that the absolute configurations of the secondary alcohols 5f and 5g are the same as for
5c.
Table 3. Synthesis of chiral 2-(2-methoxyaryl)alcohols (5) through enantioselective reduction.
Yield
(%)a
ee
(%)b
Entry
11
5
1c
11a
35
95
98
97
2d
11a
5c
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3d
11b
11c
96
97
4d
94
98
Ru-ATH: 13 (2 mol%), HCO2H/Et3N (5:2, 10.00 equiv HCO2H), 40 °C, 24 h, N 2. CBS-Red: 14 (5
mol%), BH3·SMe2 (1.00 equiv), THF, 0 °C →rt, 1 h, N2.
a Isolated yield.
b Enantiomeric excesses.
c Ru-ATH was applied.
d CBS-Red was applied.
We next turned our attention to the asymmetric reduction of racemic 2-(2-
methoxyaryl)indan-1-one and 2-(2-methoxyaryl)tetral-1-one derivatives (rac-11d–f) (Scheme
5). Ru-ATH was thought to be suitable for asymmetric reduction of these bicyclic α-aryl-
substituted racemic ketones, through a dynamic kinetic resolution (DKR) process, thus
facilitating the generation of the corresponding chiral alcohols in high yields. Note that ATH of
very similar substrates, such as (±)-2-methylindan-1-one and (±)-2-methyltetral-1-one, through
DKR process under the Ru-ATH conditions was recently demonstrated to be feasible.23d–f
Although the conversions of rac-11d–f into the cis-alcohols 5h–j via the Ru-ATH with 13 were
determined to be modest, the chiral secondary alcohols 5h–j could be obtained with excellent
enantiomeric excesses in this way (99–96% ee). Enantiomeric excesses of the remaining ketones
11d–f recovered after Ru-ATH were also checked by HPLC on a chiral column and determined to
be 0%. This observation clearly shows that the ketones 11d–f do racemize under Ru-ATH
conditions and that Ru-ATH via DKR process is possible. But, we were not able to isolate the
product in higher yields and enantiomeric excesses despite all efforts by doing some
modifications of the Ru-ATH conditions as reported in the literature.23d The structures and the
1
13
relative stereochemistries of the 5h–j were assigned from H and C NMR as well as NOE-DIFF
spectroscopic data which will be discussed below. We have not been able to grow single crystals
of 5h–j for X-ray analysis so far. Other chiroptical techniques, such as ORD, CD and the Octant
rule, for determining the absolute configurations of 5h–j were considered not to be applicable to
the remaining ketones 11d–f recovered after Ru-ATH, because they were determined to be
racemic. However, we could suggest the formation of (1S,2R)-configured 5h–j after careful
application of the stereochemical model for Ru-ATH that was discussed before. This is also in
good accordance with the sense of enantioselection in Ru-ATH of very similar compounds, such
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as racemic 2-substituted indan-1-ones and tetral-1-ones, under the very similar reaction
conditions.23d–e
Scheme 5. Synthesis of chiral cyclic 2-(2-methoxyaryl)alcohols via Ru-ATH with 13.
After the effective preparations of chiral 2-(2-methoxyaryl)alcohols 5a–j, we explored a
suitable demethylation procedure in order to synthesize our potential HAROL catalysts (Scheme
6). Boron tribromide (BBr3) was the first choice for demethylation of 5c, using different solvents
(e.g. DCM, THF, and toluene) at different temperatures. In most cases, unidentified products
formed except in one case, in which the corresponding dihydrobenzofuran was formed in almost
1
quantitative yield according to H NMR spectra, upon the treatment of 5c with BBr3 in DCM at
−78 °C. However, it was determined to be labile and decomposed rapidly during column
chromatographical purification on silica gel. On the other hand, treatment of 5c with
ethanethiol-sodium tert-butoxide couple in DMF afforded 12c in 65% isolated yield in a
practical way (Scheme 6). This demethylation technique was then applied to other 2-(2-
methoxyaryl)alcohols, thus providing HAROLs in good yields (97–65%). As such, the synthesis of
structurally different HAROLs with the 1,4-diol scaffold was accomplished by two different
synthetic pathways.
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Scheme 6. Preparation of the HAROLs 12a–j via demethylation. Conditions: 5 (1.00 equiv), EtSH
(8.00 equiv), NaOtBu (3.00 equiv), DMF (ca. 5 mL for 1.0 mmol of 5), 120 °C, 1.5 h, N 2.
After reduction of the cyclic ketones rac-11d–f by Ru-ATH (Scheme 5), two
diastereomers could be formed, i.e. it might theoretically have been expected that cis- and trans-
configured diastereomers could be obtained. As observed in numeorus cases in the literature,23d–
f
Ru-ATH of 2-substituted racemic ketones delivers cis-configured secondary alcohols
predominantly. Nonetheless, the relative stereochemistries of the 5h–j were determined on the
basis of 1H, 13C (APT), and NOE-DIFF NMR spectra as well as FT-IR spectral data. For conclusive
assignments of spectral data, conformation of the structure should be investigated carefully. As
is well known, substituted indanes are non-planar, usually assume envelope conformation, and
exhibit a much more restricted geometry compared to the isolated five-membered ring,
depending on the type of substituent. The racemic cis- and trans- 2-arylindanols rac-5h and rac-
18 were prepared through the reduction of rac–11d with NaBH4 and they were separated by
column chromatography (Table 4, see Supplementary Data). At this point, it should be noted that
conformational analysis of cis- and trans-2-phenyl-indan-1-ol, structurally very similar to rac-5h
1
13
and rac-18, was reported on the basis of their H and C NMR spectra.25a It was also reported
that FT-IR spectra of cis- and trans-2-phenyl-indan-1-ol are distinctive from each other and
shown to be suitable for their conformational analysis.25b Among the possible two extremes of
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rac-5h and rac-18 (C1 and C2 conformers), C2 conformers are expected to be predominant in
which the bulkier substituent (anisyl groups) is taking up the most staggered (equatorial)
position (Table 4). Distinctive NMR and FT-IR spectral data are summarized in Table 4. The
−
1
easily distinguishable strong peak at 3579 cm in the C2 conformer of rac-5h probably arises
from intramolecular OH···π bonding between OH and the anisyl group which is not the case for
25xb
the C2 conformer of rac-18.
This OH···π bonding also increases the population of the C2
13
conformer and thus accounts for the larger shielding for C signals of the C2 conformer of rac-
5h which is in good accordance with literature.25a Assignments of the important 1H NMR signals
of the alicyclic protons were made on the basis of the measured coupling constants and chemical
shift values as well as NOE-DIFF experiments. A larger coupling constant for H-1 in rac-18 than
rac-5h would be expected because the dihedral angle Φ for H1-C1-C2-H2 in rac-18 must
approximate 180°. However, the difference between the coupling constants for H-1 of rac-18
3
3
and rac-5h, J = 6.6 Hz and J = 5.4 Hz respectively, was not large enough to distinguish the
relative stereochemistry. NOESY and NOE-DIFF experiments revealed a strong correlation
between the proton resonances appearing at 5.31 (H-1) and 3.05 (H-3a) of rac-18. Such a
correlation was not observed between H-1 (δH 5.36) and H-3a (δH 3.30) or H-3e (δH 3.36)
protons of rac-5h, as illustrated in Table 4. It is noteworthy that the compounds 5d, rac-11e,
rac-11f, 5i, 5j, 12d, 12i, and 12j, having 2,4-bis(α,α-dimethylbenzyl)phenol (7d) as the building
block, exhibit interesting characteristics in their NMR spectra. In these chiral compounds, methyl
groups, which are adjacent to the methoxyl or phenolic hydroxyl groups, have different chemical
1
13
shifts in the H and C NMR spectra, i.e. they were determined to be diastereotopic. This might
be due to the hindered rotation about the C(aryl)-C(methyl) bond, which in turn causes two CH3
groups of the 2,4-bis(α,α-dimethylbenzyl)phenol or 2,4-bis(α,α-dimethylbenzyl)anisole moieties
to be diastereotopic.
Table 4. Conformers and spectral data of the cis-and trans-compounds rac-5h and rac-18.
1
νOH (cm− )
δC
3579
3599
3435
76.6 (C-1)
44.2 (C-2)
37.8 (C-3)
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δH (J in Hz)
1.68 (d, J = 5.1, 1H, OH)
3.30 (dd, J = 15.8, 7.8, 1H, H-3a)
3,36 (dd, J = 15.8, 7.8, 1H, H-3e)
3.86 (s, 3H, OCH3)
4.17 (td, J = 7.9, 6.2, 1H, H-2)
5.36 (t, J = 5.5, 1H, H-1)
7.19 (d, J = 2.4, 1H, H-5')
1
νOH (cm− )
3460
3430
δC
83.7 (C-1)
49.5 (C-2)
38.9 (C-3)
3394
δH (J in Hz)
2.56 (t, J = 11.4, 1H, OH)
3.05 (dd, J = 15.8, 9,4, 1H, H-3a)
3,43 (dd, J = 15.9, 8.3, 1H, H-3e)
3.86 (s, 3H, OCH3)
3.91 (dd, J = 16.9, 8.2, 1H, H-2)
5.31 (t, J = 6.6, 1H, H-1)
7.19 (d, J = 2.4, 1H, H-5')
With ten chiral HAROLs (12a–j) in hand, we started to assess their catalytic activities
and stereoselectivities in some asymmetric transformations. Analogous to ArBINMOLs as well as
to numerous other diol and aminoalcohol ligands, we first employed them as chiral ligands in
the addition of diethylzinc to benzaldehyde (13a), a benchmark reaction for testing the
performance of new chiral ligands.14,26,27 The initial setting for the Et2Zn addition to
benzaldehyde consisted of 1.80 equivs. of Et2Zn, 1.50 equivs. of Ti(OiPr)4 and 5 mol% of a
HAROL ligand compared to benzaldehyde in a solvent (Table 5). Our HAROLs were found to be
highly active in this reaction, providing (S)-1-phenyl-1-propanol (14a) in nearly quantitative
yield. Acyclic HAROLs carrying bulkier substituents appeared to be more enantioselective than
those carrying smaller substituents, 12c and 12e vs. 12a and 12b (entries 3, 17, 1, 2). Of the
solvents tested, hexane provided the optimum results (entries 4, 6, 7, 8). While the cyclic HAROL
ligands 12h–i with indane backbones exhibited superior enantioselectivity compared to their
acyclic counterparts (entries 12 and 13), the cyclic HAROL ligand 12j based on tetralin backbone
gave the addition product 14a in almost racemic form (entry 18). The reaction temperature was
determined to be an important factor that predominantly affects the enantioselectivity (entries
13, 14, 15, 16). As the reaction temperature was decreased, enantioselectivity increased.
However, the best compromise was to conduct reactions at −20 °C (entry 14). After all these
screening reactions, the most enantioselective ligand appeared to be 12i among the HAROLs
examined and the optimum reaction conditions were identified (entry 14).28
Table 5. Optimization of Et2Zn addition to benzaldehyde (13a) catalyzed by HAROLs.a
16

ACCEPTED MANUSCRIPT
T
(°C)
Yield
(%)b
ee
Entry HAROL
Solvent
(%)c
1
2
12a
12b
12c
12c
12c
12c
12c
12c
12d
12f
Toluene
0
0
95
95
95
95
95
95
70
70
98
96
97
97
97
97
97
97
97
97
10 (S)
30 (S)
50 (S)
58 (S)
58 (S)
54 (S)
50 (S)
50 (S)
64 (S)
58 (S)
8 (S)
Toluene
Toluene
Hexane
Hexane
Et2O
3
0
4
0
5
−40
0
6
7
THF
0
8
DCM
0
9
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
0
10
11
12
13
14
15
16
17
18
0
12g
12h
12i
0
0
68 (S)
74 (S)
83 (S)
83 (S)
58 (S)
80 (S)
2 (S)
0
12i
−20
−78
60
−20
−20
12i
12i
12e
12j
Reaction conditions: 13a (0.5 mmol, 1.00 equiv), Et2Zn (1.80 equiv), Ti(OiPr)4 (1.50 equiv), HAROL
a
ligand (5 mol%), solvent (2 mL), T (°C) for 2 h.
b Isolated yield of 14a.
c Determined by GC, using a chiral column (CP-Chirasil-Dex-CB, 25 m, 0.25 mm ID).
In order to examine the general applicability of the HAROL-Ti catalytic system, we next
subjected diverse aldehydes to the diethylzinc addition. The results using the HAROL 12i in
combination with Ti(OiPr)4 under the optimized conditions are shown in Table 6. While
electron-withdrawing substituents at the 4-position of benzaldehyde did not have a significant
influence on selectivity (entries 1-5), electron donating groups resulted in a decrease in
enantiomeric excesses (entries 1, 6 and 7). In the case of sterically more demanding aldehydes,
such as 2-methylbenzaldehyde (13g) and naphthalene-2-carbaldehyde (13o), somewhat lower
enantiomeric excesses were observed (entries 8 and 15). Pyridine-2-carbaldehyde (13i) gave
the addition product 14i in high yields but almost racemic form (entry 9). The addition product
of pyridine-4-carbaldehyde (14j) was obtained in modest ee (entry 10). Furfural (13k) could
17

ACCEPTED MANUSCRIPT
also be reacted with Et2Zn giving 14k in somewhat diminished yield (65%) with 85% ee (entry
11). The next heteroaromatic aldehyde 13l (thiophene-2-carbaldehyde) could be transformed
into the corresponding alcohol 14l in high yield and enantiomeric excess (90% y, 88% ee, entry
12). Aliphatic aldehydes such as n-heptanal (13m) and cyclohexanecarbaldehyde (13n) could be
converted into the corresponding propanol derivatives 14m and 14n in high yields as well
(entries 13 and 14). But, a lower enantiomeric excess for 14n was measured.
Table 6. Asymmetric addition of Et2Zn to aldehydes catalyzed by 12i.a
Product, Yield
(%)b
ee
Entry
R
(%)c
1
Ph
14a, 97
14b, 91
14c, 85
14d, 88
14e, 80
14f, 90
14g, 85
14h, 93
14i, 81
14j, 30
14k, 65
14l, 90
14m, 86
14n, 85
14o, 96
83 (S)
82 (S)
83 (S)
86 (S)
86 (S)
78 (S)
81 (S)
70 (S)
2 (S)
2
3
p-FC6H4
p-ClC6H4
p-BrC6H4
p-CF3C6H4
p-MeOC6H4
p-MeC6H4
o-MeC6H4
2-pyridyl
4-pyridyl
2-furyl
4
5
6
7
8
9
10
11
12
13
14
15
40 (S)
85 (S)
88 (S)
88 (S)
58 (S)
76 (S)
2-thiophenyl
hexyl
cyclohexyl
2-naphthyl
a Conditions: 13 (0.5 mmol, 1.00 equiv), Et2Zn (0.9 mmol, 1.80 equiv, 1.8 mL of 1.0 M Et2Zn solution in
hexane), 12i (11.5 mg, 25 ꢀmol, 5 mol%), Ti(OiPr)4 (0.75 mmol, 1.50 equiv), hexanes (2 mL), −20 °C,
2 h, N2. The aldehydes 13c and 13d were added to the reaction mixture by dissolving them in Et2O (2
mL).
b Isolated yield of the NMR-pure product.
c
Enantiomeric excesses determined by HPLC or GC on a chiral column. The absolute configurations
of the products (14a–o) were determined by comparing the sign of the rotation with literature data.
To further investigate the suitability of HAROLs for general use as ligands, the
enantioselective addition of some other organometallics to benzaldehyde was examined (Table
7). The HAROL ligand 12i which effected the diethylzinc addition to aldehydes with the highest
level of enantioselectivity was employed in the addition of methyllithium (MeLi),
18

ACCEPTED MANUSCRIPT
methylmagnesium bromide (MeMgBr) as well as trimethylaluminum (Me3Al) to benzaldehyde
(13a). Indeed, the additions of these common organometallic reagents to benzaldehyde took
place smoothly in the presence of Ti(OiPr)4 and a catalytic amount of 12i. However, the addition
of MeLi proceeded with the highest level of enantioselectivity affording (S)-1-phenylethanol
(15a) in 68% ee (entry 1), whereas (S)-1-phenylethanol was obtained in mediocre enantiomeric
excesses via the addition of MeMgBr and Me3Al, 46% and 24% ee (entries 2 and 3,
respectively).15-17
Table 7. Asymmetric addition of methyl-organometallics (RM) to benzaldehyde (13a) catalyzed by 12i.
Yield
(%)a
ee
Enrty
RM
(%)b
1c
MeLi
70
95
90
68 (S)
46 (S)
24 (S)
2d
3e
MeMgBr
Me3Al
a Isolated yield of the NMR-pure product.
b Enantiomeric excesses determined by HPLC or GC on a chiral column. The absolute configurations
of the products (15a) were determined by comparing the sign of the optical rotation with literature data.
c 13a (0.25 mmol, 1.00 equiv), MeLi (0.8 mmol, 3.20 equiv, 258 ꢀL of 3.1 M MeLi in diethoxymethane),
12i (23 mg, 50 ꢀmol, 20 mol%), Ti(OiPr)4 (1.5 mmol, 6.00 equiv), THF (1.5 mL), −78 °C, 2 h, N 2.
d
13a (0.5 mmol, 1.00 equiv), MeMgBr (1.5 mmol, 3.00 equiv, 0.5 mL of 3.0 M MeMgBr in Et2O), 12i
(11.5 mg, 25 ꢀmol, 5 mol%), Ti(OiPr)4 (2.5 mmol, 5.00 equiv), Diglyme (2 mL), 0 °C, 2 h, N2.
e 13a (0.5 mmol, 1.00 equiv), Me3Al (0.75 mmol, 1.50 equiv, 375 ꢀL of 2.0 M Me3Al in hexane), 12i (23
mg, 50 ꢀmol, 10 mol%), Ti(OiPr)4 (2.0 mmol, 4.00 equiv), Et2O (2 mL), 0 °C, 2 h, N 2.
We reasoned that our HAROL-type 1,4-diols, carrying a phenolic and an alcohol hydroxyl
(-OH) functionalities, could also be exploited as HBD organocatalysts due to their potential to
form intermolecular hydrogen bonds with electrophiles such as aldehydes and ketones (Figure
1). In order to demonstrate the feasibility of this idea, we explored the Morita-Baylis-Hillman
(MBH) reaction between 3-phenylpropanal (13p) and 2-cyclohexen-1-one (16) as the proof-of-
concept reaction, in the presence of 10 mol% of some selected HAROLs as well as 2.00 equivs. of
trialkylphosphines as Lewis base promoters (Table 8). All the HAROLs (12c, 12e, 12i) showed
similar catalytic activity, giving the MBH product 17 in 52–43% isolated yields in the presence
tributylphosphine (2.00 equiv) as the Lewis base promoter and THF as the solvent (entries 1–3).
Among our HAROLs, 12i turned out to be the best organocatalyst in terms of enantioselectivity,
affording the MBH adduct 17 in 52% yield and with 40% ee (entry 3). Using triethylphosphine
instead of tri-n-butylphosphine resulted in a decrease in enantioselectivity and activity (entry 4).
This observation is contrary to that reported by McDougal and Schaus, in which they reported
that Et3P promoted this MBH reaction with higher yield and enantioselectivity than nBu3P in the
19

ACCEPTED MANUSCRIPT
presence of a BINOL-derived organocatalyst.9a Changing the solvent from THF to acetonitrile
made some improvement in the catalytic activity of HAROL 12i (67% y), however, this resulted
in a dramatic decrease in enantioselectivity (16% ee, entry 5). It should be noted that other
nucleophilic promoters such as tri-cyclohexylphosphine, tri-tert-butylphosphine, DABCO, DBU,
and DMAP were found to be inactive in our catalytic system.
Table 8. Enantioselective Morita-Baylis-Hillman reaction catalyzed by HAROLs.a
Yield
(%)b
ee
Entry
HAROL
12c
(%)c
1
52
43
52
40
67
0
2
12e
12i
12i
12i
14 (R)
40 (R)
32 (R)
16 (R)
3
4d
5e
a Conditions: The reactions were carried out with 1.0 mmol (1.00 equiv) of 13p, 2.00 equiv of 17, 2.00
equiv of nBu3P, and 10 mol% HAROL (12) at −10 °C in THF (1 mL) for 48 h under N 2.
b Isolated yield of the NMR-pure product.
c Enantiomeric excesses determined by HPLC or GC on a chiral column. The absolute configuration of
the MBH product 17 was determined by comparing the sign of the optical rotation with literature data.
d Et3P (2.00 equiv) instead of nBu3P was employed.
e Acetonitrile as the solvent.
3. Conclusion
In summary, we have devised two efficient synthetic routes to chiral 2-(2-
hydroxyaryl)alcohols (HAROLs), new 1,4-diols carrying a phenolic and an alcohol hydroxyl
group: The first route is based on the regioselective ring-opening of enantiopure (R)-styrene
oxide with ortho-lithioanisoles as the key transformation, whereas the second route comprises
palladium-catalyzed α-arylation of ketones with ortho-bromoanisoles (Buchwald-Hartwig α-
arylation) and the enantioselective reduction of the resulting ketones through Ru-ATH or CBS
reduction, subsequently. Due to their modularity and complementarity, our synthetic routes
allow for the facile generation of structurally diverse HAROLs in enantiopure form. Furthermore,
the small library consisting of ten HAROLs was subjected to to screening as chiral ligands and
HBD organocatalysts, one of which with an indane backbone was found to catalyze the 1,2-
addition of some organometallic compounds (such as Et2Zn, MeLi, MeMgBr, and Me3Al) to
aldehydes with high yields and enantioselectivities (up to 97% yield and 88% ee). The same
20

ACCEPTED MANUSCRIPT
HAROL (12i) was also identified as a promising HBD organocatalyst for the enantioselective
Morita-Baylis-Hillman reaction, promoted by trialkylphosphines. We are optimistic that HAROLs
will find applications as catalysts in a broad range of asymmetric transformations. Consequently,
optimization of the synthetic routes to HAROLs, enlargement of HAROL library in terms of
structural diversity, as well as exploration of their use as catalysts are ongoing efforts in our
laboratory. Those results will be reported in due course.
4. Experimental section
4.1. General
All air-sensitive reactions were performed under an inert atmosphere of dry nitrogen (N2) using oven-
dried glassware. All reagents and solvents were transferred using gas-tight syringe and cannula
techniques under N2. Reactions were monitored by thin layer chromatography (TLC) on aluminum sheets
that were pre-coated with silica gel SIL G/UV254 from MN GmbH & Co., in which the spots were visualized
in UV-light (λ=254 nm) and/or by staining with phosphomolybdic acid solution in EtOH (10%, w/v).
Chromatographic separations were performed using silica gel (MN-silicagel 60, 230-400 mesh). All
melting points were determined in open glass capillary tube by means of a BÜCHI Melting Point B-540
apparatus and values are uncorrected. Infrared (FT-IR) spectra were recorded on a PerkinElmer Spectrum
One FT-IR spectrometer, νmax in cm-1. Bands are characterized as broad (br), strong (s), medium (m), and
weak (w). 1H and 13C NMR spectra were recorded on a 500 MHz or 600 MHz NMR spectrometer. Chemical
shifts δ are reported in parts per million (ppm) relative to the residual protons in the NMR solvent (CHCl3:
δ 7.26) and carbon resonance of the solvent (CDCl3: δ 77.00). NMR peak multiplicities were given as
follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Mass spectra were
recorded on a gas chromatography with mass sensitive detector from Agilent Technologies 6890N
Network GC System (EI, 70 eV) using Standard Method (column: HP-5MSI, 30 m, 0.25 mm ID, 0.25 μm film
tickness; inlet: 300 °C (split modus); det: 300 °C; He, 1 mL/min (constant flow modus); oven: 40 °C (5
min), 5 °C/min, 280 °C (5 min)). High resolution electrospray ionization mass spectra (HR-ESI-MS) were
obtained with MeOH on a Bruker micrOTOF-Q. The specific rotations ([α]) were measured on an Optical
Activity Ltd. AA-65 polarimeter using 1 mL cell with a 1.0 dm path length and the sample concentrations
are given in g/100 mL unit. Tetrahydrofuran (THF), diethyl ether (Et2O), toluene, hexane, and c-hexane
was freshly distilled under N2 from sodium/benzophenone prior to use under nitrogen atmosphere.
Diglyme, N,N-dimethylformamide (DMF), and anisole were distilled under reduced pressure from calcium
hydride (CaH2). Dichloromethane (DCM) and N,N,N′,N′-tetramethylethylenediamine (TMEDA) were dried
by distillation over CaH2 under N2. Some reagents, such as Et2Zn (1.0 M solution in hexane), MeLi (3.1 M
solution in diethoxymethane), MeMgBr (3.0 M solution in Et2O), Me3Al (2.0 M solution in hexane),
n
t
BF3·OEt2, BuLi (2.5 M or 1.7 M solution in hexane), Me2SO4, EtSH, Bu3P (1.0 M in toluene), BH3·SMe2,
nBu3P, Ph3P, Pd(OAc)2, the Noyori-Ikariya catalyst 13, and the CBS catalyst 14 were purchased from
commercial suppliers and used as received. All the aldehydes were filtered through a short plug of neutral
21

ACCEPTED MANUSCRIPT
alumina before use. Ti(OiPr)4 was distilled under reduced pressure and stored under nitrogen. The formic
acid-triethylamine azeotropic mixture (HCO2H/Et3N, 5:2) was prepared according to the literature
procedure and its quality was checked by 1H NMR spectroscopy.29 8-Phenyl-1-naphthol (7f) was prepared
according to the literature procedure.21 All experimental procedures for the synthesis of the anisoles 2b–
e, 9c–d and the bromophenols 8c–d are presented in the Supplementary Data part.
4.2. (S)-(−)-2-(2-Methoxyphenyl)-1-phenylethanol (5a)
An oven-dried 250 mL round-bottomed Schlenk flask, capped with a glass stopper and equipped with a
magnetic stirring bar, was evacuated under heating with a blow-drier for 15 min. After the flask was
cooled down to room temperature, dry nitrogen was back-filled and the glass stopper was replaced with a
rubber septum, under a positive pressure of nitrogen. The flask was charged with anisole (2a) (3.26 mL
3.24 g, 30.0 mmol, 3.00 equiv) and TMEDA (0.70 g, 0.90 mL, 6.0 mmol, 0.60 equiv), which was succeeded
by the addition of dry THF (60 mL) as the solvent. After the mixture was cooled in an ice-bath, 12 mL of a
2.50 M solution of nBuLi in hexanes (30.0 mmol, 3.00 equiv of nBuLi) were dropwise added to the mixture.
The mixture was then stirred for 3 h while the temperature was allowed to rise to room temperature.
After cooling the reaction mixture down to −78 °C in an acetone-dry ice bath, (R)-(+)-styrene oxide (4a)
(1.20 g, 1.15 mL, 10.0 mmol, 1.00 equiv) and BF3·OEt2 (3.60 g, 3.10 mL, 25.0 mmol, 2.50 equiv) were
added sequentially. The reaction mixture was stirred at −78 °C for 1 h and quenched with saturated
NaHCO3 solution (60 mL). THF was removed by rotary evaporation under reduced pressure and the
aqueous residue was extracted with Et2O (3×100 mL). The combined organic extracts were dried over
Na2SO4, filtered, and concentrated by rotary evaporation in vacuo. The residue was then purified by silica
gel column chromatography eluting with hexanes/EtOAc (9:1) to afford 5a (1.90 g, 8.3 mmol, 83%) as a
colorless solid. Mp: 75–76 °C. TLC: Rf = 0.24 (silica gel; hexane/EtOAc, 9:1). [α]ꢁꢀꢁ = −10 (c = 0.5, CH2Cl2).
HPLC: Chiralcel OD-H; n-hexane/iPrOH (90:10), 1.0 mL/min; 254 nm (UV−vis); tR = 8.1 min (ent-5a), tR =
−
1
9.7 min (5a). FTIR (KBr): νmax (cm ) = 3292 (m), 3064 (m), 3028 (s), 2836 (m), 2057 (w), 1928 (w), 1893
(m), 1798 (w), 1603 (m), 1587 (m), 1500 (s), 1454 (s), 1292 (s), 1245 (s), 1180 (m), 1162 (s), 765 (m),
1
745 (s), 699 (s). H NMR (500 MHz, CDCl3):
δ = 2.51 (s, 1H), 2.98 (dd, J = 13.6, 8.8 Hz, 1H), 3.12 (dd, J =
13.6, 4.0 Hz, 1H), 3.85 (s, 3H), 4.96 (dd, J = 8.8, 4.0 Hz, 1H), 6.88 (dd, J = 10.5, 4.2 Hz, 2H), 7.08 (dd, J = 7.6,
1.7 Hz, 1H), 7.20–7.28 (m, 2H), 7.35 (ddd, J = 15.1, 10.8, 4.6 Hz, 4H). 13C NMR (125 MHz, CDCl3):
= 41.1
δ
(CH2), 55.3 (CH3), 74.2 (CH), 110.4 (CH), 120.7 (CH), 125.7 (CH), 126.6 (C), 127.2 (CH), 128.0 (CH), 128.2
(CH), 131.4 (CH), 144.5 (C), 157.6 (C). GCMS: tR = 29.67 min, m/z (%) = 210 ([M-18]+, 10), 194 ([M-34]+, 1),
178 (2), 165 (6), 152 (3), 137 (1), 122 (100), 107 (29), 91 (24), 79 (22). HR MS (ESI): m/z [M+Na]+ calcd
for C15H16O2Na: 251.1043; found: 251.1055.
4.3. (S)-(−)-2-(2-Methoxy-3-phenylphenyl)-1-phenylethanol (5b)
An oven-dried 500 mL round-bottomed Schlenk flask, capped with a glass stopper and equipped with a
magnetic stirring bar, was evacuated under heating with a blow-drier for 15 min. The flask was cooled
down to room temperature, back-filled with dry nitrogen and the glass stopper was replaced with a
rubber septum, under a positive pressure of nitrogen. The flask was charged with 2-phenylanisole (2b)
22

ACCEPTED MANUSCRIPT
(9.21 g, 50.0 mmol, 5.00 equiv) and TMEDA (1.57 mL, 1.14 g, 10.0 mmol, 1.00 equiv), which was followed
by the addition of dry Et2O (150 mL) as the solvent. After the mixture was cooled in an ice-bath, 20 mL of
n
2.50 M n-butyllithium solution in hexanes (50.0 mmol, 5.00 equiv of BuLi) were dropwise added with a
syringe. The mixture was then stirred overnight (ca. 16 h) while the temperature was allowed to rise to
room temperature. After cooling the reaction mixture down to −78 °C in an acetone-dry ice bath, absolute
THF (43 mL) was added with a gas-tight syringe. (R)-(+)-Styrene oxide (4a) (1.20 g, 1.15 mL, 10.0 mmol,
1.00 equiv) and BF3·OEt2 (7.10 g, 6.17 mL, 50.0 mmol, 5.00 equiv) were added to the reaction mixture,
successively. After stirring the mixture at −78 °C for 1 h, the reaction was quenched by the addition of
saturated NaHCO3 solution (85 mL). After etheral solvents were removed by rotary evaporation under
reduced pressure, the aqueous residue was extracted with Et2O (3×100 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated by rotary evaporation in vacuo. The residue was
purified by silica gel column chromatography eluting with hexanes/EtOAc (9:1) to give 2.00 g (6.6 mmol,
66%) of the title compound (5b) as a colorless oil. TLC: Rf = 0.20 (silica gel; hexane/EtOAc, 9:1). [α]ꢀꢁꢁ
−22 (c = 0.5, CH2Cl2). HPLC: Chiralcel OD-H; n-hexane/iPrOH (98:2), 1.0 mL/min; 254 nm (UV−vis); tR =
16.2 min (ent-5b), tR = 19.8 min (5b). 1H NMR (500 MHz, CDCl3):
= 2.86 (s, 1H), 3.05 (dd, J = 13.8, 8.8 Hz,
1H), 3.14 (dd, J = 13.7, 3.9 Hz, 1H), 3.37 (s, 3H), 5.03 (dd, J = 8.8, 3.9 Hz, 1H), 7.06–7.16 (m, 2H), 7.21–7.30
(m, 2H), 7.36 (dd, J = 10.4, 4.5 Hz, 3H), 7.39–7.46 (m, 4H), 7.57–7.62 (m, 2H). 13C NMR (125 MHz, CDCl3):
=
δ
δ
= 41.3 (CH2), 60.4 (CH3), 75.0 (CH), 124.3 (CH), 125.8 (CH), 127.2 (CH), 127.4 (CH), 128.4 (CH), 129.1 (CH),
130.1 (CH), 130.8 (CH), 131.8 (C), 134.9 (C), 138.7 (C), 144.6 (C), 156.0 (C). GCMS: tR = 34.89 min, m/z (%)
= 286 ([M-18]+, 6), 270 ([M-34]+, 1), 252 (1), 239 (1), 215 (1), 209 (4), 198 (100), 183 (22), 165 (11), 152
(11), 128 (3), 107 (19), 79 (13). HRMS (ESI): m/z [M+Na]+ calcd for C21H20O2Na: 327.1356; found:
327.1373.
4.4. (S)-(−)-2-(3,5-Di-tert-butyl-2-methoxyphenyl)-1-phenylethanol (5c)
An oven-dried 500 mL round-bottomed Schlenk flask, capped with a glass stopper and equipped with a
magnetic stirring bar, was evacuated under heating with a blow-drier for 15 min. The flask was cooled
down to room temperature, back-filled with dry nitrogen and the glass stopper was replaced with a
rubber septum, under a positive pressure of nitrogen. 2,4-Di-tert-butylanisole (2c) (7.70 g, 35.0 mmol,
5.00 equiv) and TMEDA (1.10 mL, 0.80 g, 7.0 mmol, 1.00 equiv) were added into the flask, which was
followed by the addition of dry Et2O (105 mL) as the solvent. After the mixture was cooled in an ice-bath,
n
14.0 mL of 2.50 M n-butyllithium solution in hexanes (35.0 mmol, 5.00 equiv of BuLi) were dropwise
added with a syringe. The mixture was then stirred overnight (ca. 16 h) while the temperature was
allowed to rise to room temperature. After cooling the reaction mixture down to −78 °C in an acetone-dry
ice bath, absolute THF (30 mL) was added. (R)-(+)-Styrene oxide (4a) (0.84 g, 0.80 mL, 7.0 mmol, 1.00
equiv) and BF3·OEt2 (4.97 g, 4.32 mL, 35.0 mmol, 5.00 equiv) were added successively at −78 °C. After
stirring the mixture at −78 °C for 1 h, the reaction was quenched by the addition of saturated NaHCO3
solution (60 mL). After etheral solvents were removed by rotary evaporation under reduced pressure, the
aqueous residue was extracted with Et2O (3×100 mL). The combined organic extracts were dried over
Na2SO4, filtered, and concentrated by rotary evaporation in vacuo. Purification by flash column
23

ACCEPTED MANUSCRIPT
chromatography (hexanes/EtOAc, 8:2) gave 1.62 g (4.75 mmol, 68%) of the title compound (5c) as a
colorless solid. Mp: 87–88 °C. TLC: Rf = 0.51 (silica gel; hexane/EtOAc, 8:2). [α]ꢁꢀꢁ = −20 (c = 0.5, CH2Cl2).
−
1
FTIR (KBr): νmax (cm ) = 3307 (s), 2961(s), 1601 (w), 1477 (s), 1454 (s), 1427 (m), 1389 (m), 1323 (w),
1271 (m), 1231 (s), 1203 (m), 1156 (w), 1116 (s), 1077 (w), 1034 (s), 1010 (s), 950 (m), 907 (w), 878 (m),
1
772 (w), 754 (m), 697 (s), 652 (w), 541 (w). H NMR (500 MHz, CDCl3):
δ
= 1.23 (s, 9H), 1.41 (s, 9H), 2.91
(s, 1H), 3.09 (d, J = 6.0 Hz, 2H), 3.83 (s, 3H), 4.98 (t, J = 6.3 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 7.21–7.26 (m,
2H), 7.29–7.35 (m, 4H). 13C NMR (125 MHz, CDCl3):
= 31.3 (CH3), 31.5 (CH3), 34.4 (C), 35.3 (C), 42.1
δ
(CH2), 61.8 (CH3), 74.9 (CH), 123.2 (CH), 125.8 (CH), 126.9 (CH), 127.3 (CH), 128.3 (CH), 130.9 (C), 142.1
(C), 144.5 (C), 146.1 (C), 156.0 (C). GCMS: tR = 33.16 min, m/z (%) = 322 ([M-18]+, 7), 307 ([M-33]+, 10),
234 (65), 219 (100), 203 (5), 177 (10), 163 (9), 107 (10), 91 (6), 79 (7). HRMS (ESI): m/z [M+Na]+ calcd
for C23H32O2Na: 363.2295; found: 363.2295.
4.5. (S)-(−)-2-(2-Methoxy-3,5-bis(2-phenylpropan-2-yl)phenyl)-1-phenylethanol (5d)
An oven-dried 250 mL round-bottomed Schlenk flask, capped with a glass stopper and equipped with a
magnetic stirring bar, was evacuated under heating with a blow-drier for 15 min. The flask was cooled
down to room temperature, back-filled with dry nitrogen and the glass stopper was replaced with a
rubber septum, under a positive pressure of nitrogen. The flask was charged with 2,4-bis(α,α-
dimethylbenzyl)anisole (2d) (6.90 g, 20.0 mmol, 5.00 equiv) and TMEDA (0.63 mL, 0.46 g, 4.00 mmol, 1.00
equiv), which was succeeded by the addition of dry Et2O (60 mL) as the solvent. After the mixture was
cooled in an ice-bath, 8.0 mL of 2.50 M n-butyllithium solution in hexanes (20.0 mmol, 5.00 equiv of nBuLi)
were dropwise added to the mixture, by means of a gas-tight syringe. The mixture was then stirred
overnight (ca. 16 h) while the temperature was allowed to rise to room temperature. After the reaction
flask was cooled down to −78 °C in a acetone-dry ice bath, absolute THF (17 mL) was added. (R)-(+)-
Styrene oxide (4a) (457 µL, 481 mg, 4.0 mmol, 1.00 equiv) and BF3·OEt2 (2.84 g, 2.47 mL, 20.0 mmol, 5.00
equiv) were added to the reaction mixture at −78 °C sequentially. After stirring the mixture at −78 °C for 1
h, the reaction was quenched with saturated NaHCO3 solution (34 mL). After etheral solvents were
removed by rotary evaporation under reduced pressure, the aqueous residue was extracted with Et2O
(3×100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated by rotary
evaporation in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc, 9:1) to
afford 1.10 g (2.4 mmol, 60%) of the title compound (5d) as a colorless solid. Mp: 82 °C. TLC: Rf = 0.35
−
(silica gel; hexanes/EtOAc, 9:1). [α]ꢀꢁꢂ = −18 (c = 0.5, CHCl3). FTIR (KBr): νmax (cm ) = 3467 (m), 3082 (m),
1
3054 (m), 3024 (m), 2970 (m), 2931 (m), 2870 (m), 1951 (s), 1876 (m), 1808 (m), 1750 (m), 1598 (s),
1578 (s), 1491 (m), 1470 (m), 1444 (m), 1378 (s), 1425 (s), 1361 (s), 1321 (s), 1231 (s), 1204 (s), 1150
(s), 1133 (s), 1112 (s), 1075 (s), 1025 (m), 1006 (m), 914 (s), 891 (s), 874 (s), 799 (s), 770 (m), 755 (m),
603 (s), 578 (s), 549 (s), 535 (s). 1H NMR (500 MHz, CDCl3):
(d, J = 1.3 Hz, 3H), 2.94 (d, J = 5.4 Hz, 3H), 4.88 (t, J = 6.2 Hz, 1H), 7.12 (td, J = 7.1, 1.4 Hz, 1H), 7.31–7.15 (m,
15H). 13C NMR (125 MHz, CDCl3):
= 30.1 (CH3), 30.2 (CH3), 30.9 (CH3), 41.6 (C), 42.2 (CH3), 42.6 (C), 59.6
δ = 1.60 (s, 3H), 1.61 (s, 3H), 1.62 (s, 6H), 2.70
δ
(CH3), 74.7 (CH), 124.4 (CH), 125.2 (CH), 125.5 (CH), 125.7 (CH), 126.1 (CH), 126.7 (CH), 127.1 (CH), 127.9
(CH), 127.9 (CH), 128.1 (CH), 128.7 (CH), 130.9 (C), 142.4 (C), 144.2 (C), 145.4 (C), 150.7 (C), 151.8 (C),
24

ACCEPTED MANUSCRIPT
155.3 (C). GCMS: tR = 41.65 min; m/z (%) = 462 ([M-2]+, 3), 307 ([M-18]+, 100), 431 (74), 358 (67), 343
(66), 265 (21), 239 (10), 119 (40), 91 (51). HRMS (ESI): m/z [M+Na]+ calcd for C33H36O2Na: 487.2608;
found: 487.2613.
4.6. (S)-(−)-2-(1-Methoxy-8-phenylnaphthalen-2-yl)-1-phenylethanol (5e)
An oven-dried 50 mL dried round-bottomed Schlenk flask was charged with 1-methoxy-8-napthalene (2e)
(1.10 g, 4.5 mmol, 3.00 equiv), and the system was evacuated for 15 minutes and back-filled with nitrogen.
TMEDA (135 µL, 0.9 mmol, 0.60 equiv) and THF (12 mL) were added by means of syringes. The solution
was cooled in an ice-bath and 2.80 mL of 1.60 M n-butyllithium solution in hexanes (4.5 mmol, 3.00 equiv
n
of BuLi) were dropwise added to the mixture with a gas-tight syringe. The resulting solution was then
stirred for 3 h while the temperature was allowed to rise to room temperature. After the reaction flask
was cooled down to −78 °C in a acetone-dry ice bath, (R)-(+)-styrene oxide (4a) (170 µL, 180 mg, 1.5
mmol, 1.00 equiv) and BF3·OEt2 (460 µL, 532 mg, 3.75 mmol, 2.50 equiv) were successively added to the
reaction mixture. After stirring the mixture at −78 °C for 1 h, the reaction was quenched by the addition of
saturated NaHCO3 solution (6 mL). After THF was removed by rotary evaporation under reduced
pressure, the aqueous residue was extracted with Et2O (3×50 mL). The combined organic phases were
dried over Na2SO4, filtered, and concentrated by rotary evaporation in vacuo. The residue was purified by
flash column chromatography (hexanes/EtOAc, 9:1) to give 280 mg (0.78 mmol, 53%) of the title
compound (5e) as a colorless oil. TLC: Rf = 0.24 (silica gel; hexanes/EtOAc, 9:1). [α]ꢁꢀꢃ = −50 (c = 0.5,
CHCl3). HPLC: Chiralpak AS-H; n-hexane/iPrOH (95:5), 1.0 mL/min; 254 nm (UV−vis); tR = 9.6 min (ent-
−
1
5e), tR = 10.6 min (5e). FTIR (KBr): νmax (cm ) = 3428 (br), 3025 (s), 1945 (w), 1808 (w), 1743 (w), 1599
1
(m), 1570 (s), 1493 (s), 1363 (s), 1244 (s), 1082 (s), 833 (s), 756 (s). H NMR (500 MHz, CDCl3):
δ = 2.99
(s, 3H), 3.11 – 3.23 (m, 2H), 5.03 (dd, J = 7.6, 5.1 Hz, 1H), 7.18–7.40 (m, 11H), 7.41–7.49 (m, 3H), 7.62 (d, J
= 8.4 Hz, 1H), 7.81 (dd, J = 8.2, 1.1 Hz, 1H). 13C NMR (125 MHz, CDCl3):
= 40.8 (CH2), 60.9 (CH3), 75.1
δ
(CH), 125.0 (d), 125.0 (d), 125.5 (C), 125.8 (CH), 126.2 (CH), 126.8 (CH), 127.3 (CH), 128.1 (CH), 128.2 (C),
128.2 (CH), 129.0 (CH), 129.5 (CH), 130.3 (CH), 135.5 (C), 138.0 (C), 143.6 (C), 144.3 (C), 154.7 (C). HRMS:
m/z [M+Na]+ calcd for C25H22O2Na: 377.1512; found: 377.1536.
4.7. General Procedure I (Buchwald-Hartwig arylation of ketones with ortho-bromoanisoles): 2-(3,5-Di-tert-
butyl-2-methoxyphenyl)-1-phenylethanone (11a)
An oven-dried 50 mL Schlenk tube was charged with Pd(OAc)2 (22.5 mg, 0.1 mmol, 2 mol%) and NaOtBu
(1.10 g, 11.0 mmol, 2.20 equiv). The tube was then equipped with a magnetic stirring bar and capped with
a glass stopper. After evacuating the tube for 15 minutes, the system was back-filled with dry N2, the glass
stopper was replaced with a rubber septum under positive pressure of dry nitrogen. Anhydrous THF (5
mL) and 100 µL of 1.0 M tri-tert-butylphosphine solution in toluene (0.1 mmol, 2 mol% PtBu3) were added
sequentially by means of gas-tight syringes and the resulting heterogenous dark mixture was stirred for
30 minutes at ambient temperature. In a separate oven-dried 10 mL Schlenk tube, 1-bromo-3,5-di-tert-
butyl-2-methoxybenzene (9c) (1.30 mL, 1.50 g, 5.0 mmol, 1.00 equiv) was dissolved in 5 mL of anhydrous
THF under nitrogen and added dropwise to the reaction mixture via syringe. The mixture was stirred for
25

ACCEPTED MANUSCRIPT
30 minutes. In another oven-dried 10 mL Schlenk tube, acetophenone (10a) (642 µL, 661 mg, 5.5 mmol,
1.10 equiv) was dissolved in anhydrous THF (5 mL) and introduced into the reaction mixture dropwise,
using a syringe. The reaction mixture was stirred for 16 h at ambient temperatures under N2 during which
time the solution turned to dark green. It was then quenched with 1 M HCl solution (10 mL). After THF
was removed by rotary evaporation under reduced pressure, the aqueous residue was extracted with Et2O
(3×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated by rotary
evaporation in vacuo. Purification by flash column chromatography (hexanes/EtOAc, 98:2) gave 1.29 g
(3.8 mmol, 76%) of the title compound (11a) as a colorless solid. Mp: 120-122 °C. TLC: Rf = 0.40 (silica gel;
−
1
hexanes/EtOAc, 98:2). FTIR (KBr): νmax (cm ) = 3435 (w), 2956 (s), 1685 (s), 1597 (w), 1581 (w), 1479
1
(m), 1414 (m), 1338 (m), 1320 (s), 1233 (s), 1212 (s), 1116 (m), 999 (s), 881 (w), 754 (m), 691 (m). H
NMR (500 MHz, CDCl3):
(d, J = 2.5 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.57–7.49 (m, 1H), 8.01 (dd, J = 8.4, 1.3 Hz, 2H). 13C NMR (125
MHz, CDCl3): = 31.1 (CH3), 31.5 (CH3), 41.0 (CH2), 61.9 (CH3), 123.2 (CH), 126.6 (CH), 127.6 (C), 128.5
δ = 1.26 (s, 9H), 1.39 (s, 9H), 3.70 (s, 3H), 4.33 (s, 2H), 7.05 (d, J = 2.5 Hz, 1H), 7.25
δ
(CH), 128.5 (CH), 132.9 (CH), 136.7 (C), 142.0 (C), 145.8 (C), 155.6 (C), 198.4 (C=O). GCMS: tR = 33.53 min,
m/z (%) = 338 ([M]+, 86), 323 ([M-15]+, 100), 267 (13), 233 (19), 177 (20), 191 (8), 105 (98), 57 (36).
HRMS (ESI): m/z [M+H]+ calcd for C23H31O2: 339.2319; found: 339.2319.
4.8. 2-(3,5-Di-tert-butyl-2-methoxyphenyl)-1-(naphthalen-2-yl)ethanone (11b)
Following the general procedure I as described above, Pd(OAc)2 (22.5 mg, 0.1 mmol, 2 mol%), NaOtBu
(1.10 g, 11.0 mmol, 2.20 equiv), 100 µL of 1.0 M tri-tert-butylphosphine solution in toluene (0.1 mmol, 2
mol% PtBu3), 1-bromo-3,5-di-tert-butyl-2-methoxybenzene (9c) (1.30 mL, 1.50 g, 5.0 mmol, 1.00 equiv),
and 2-acethylnapthalene (10b) (851 mg, 5.0 mmol, 1.00 equiv) were employed. After stirring the reaction
mixture for 16 h at ambient temperatures under N2, it was quenched with 1 M HCl solution (10 mL) and
subsequently subjected to the usual work-up. Purification of the crude product by flash column
chromatography on silica gel (hexanes/EtOAc, 8:2) afforded 1.50 g (3.75 mmol, 75%) of the title
compound (11b) as a colorless solid. Mp: 127 °C. TLC: Rf = 0.20 (silica gel; hexanes/EtOAc, 8:2). FTIR
−
1
(KBr): νmax (cm ) = 3436 (w), 2954 (w), 2865 (s), 1691 (s), 1627 (s), 1597 (s), 1475 (s), 1429 (s), 1361
1
(s), 1333 (s), 1274 (s), 1229 (s), 1182 (s), 1120 (s), 1005 (s), 862 (s), 823 (s), 748 (s), 651 (s). H NMR
(500 MHz, CDCl3):
2.5 Hz, 1H), 7.53 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 7.58 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.86 (dd, J = 8.3, 4.6 Hz,
2H), 7.92 (d, J = 8.1 Hz, 1H), 8.08 (dd, J = 8.6, 1.8 Hz, 1H), 8.56 (s, 1H). 13C NMR (125 MHz, CDCl3):
= 31.0
δ = 1.27 (s, 9H), 1.42 (s, 9H), 3.77 (s, 3H), 4.46 (s, 2H), 7.13 (d, J = 2.5 Hz, 1H), 7.25 (d, J =
δ
(CH3), 31.4 (CH3), 34.4 (C), 35.3 (C), 41.1 (CH2), 62.0 (CH3), 123.2 (CH), 124.2 (CH), 126.4 (CH), 126.6 (CH),
127.7 (CH), 127.8 (C), 128.2 (CH), 128.3 (CH), 129.6 (CH), 130.4 (CH), 132.5 (C), 133.8 (C), 135.5 (C),
142.0 (C), 145.8 (C), 155.4 (C), 198.3 (C). GCMS: tR = 37.22 min, m/z (%) = 388 ([M]+, 23), 373 ([M-15]+, 7),
155 (100), 127 (21), 57 (7), 28 (36). HRMS (ESI): m/z [M+H]+ calcd for C27H33O2: 389.2475; found:
389.2477.
4.9. 1-(3,5-Di-tert-butyl-2-methoxyphenyl)-3,3-dimethylbutan-2-one (11c).
26

ACCEPTED MANUSCRIPT
Following the general procedure I as described above, Pd(OAc)2 (22.5 mg, 0.1 mmol, 2 mol%), NaOtBu
(1.10 g, 11.0 mmol, 2.20 equiv), 100 µL of 1.0 M tri-tert-butylphosphine solution in toluene (0.1 mmol, 2
mol% PtBu3), 1-bromo-3,5-di-tert-butyl-2-methoxybenzene (9c) (1.30 mL, 1.50 g, 5.0 mmol, 1.00 equiv),
and 3,3-dimethylbutan-2-one (10c) (625 µL, 501 mg, 5.0 mmol, 1.00 equiv) were employed. After stirring
the reaction mixture for 16 h at ambient temperatures under N2, it was quenched with 1 M HCl solution
(10 mL) and subsequently subjected to the usual work-up. Purification of the crude product by flash
column chromatography on silica gel (hexanes/EtOAc, 98:2) afforded 1.35 g (4.3 mmol, 86%) of the title
compound (11c) as a colorless solid. Mp: 67 °C. TLC: Rf = 0.40 (silica gel; hexanes/EtOAc, 98:2). FTIR
−
1
(KBr): νmax (cm ) = 3403 (w), 3013 (s), 2950 (s), 1984 (w), 1708 (s), 1599 (w), 1475 (s), 1410 (s), 1358
(s), 1320 (s), 1273 (m), 1230 (s), 1158 (m), 1114 (s), 1064 (s), 996 (s), 924 (m), 878 (s), 809 (m), 704 (m),
652 (m), 547 (w). 1H NMR (500 MHz, CDCl3):
2H), 6.92 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ
= 1.21 (s, 9H), 1.29 (s, 9H), 1.39 (s, 9H), 3.65 (s, 3H), 3.89 (s,
= 26.9 (q), 31.2 (q), 31.5
δ
(q), 34.4 (s), 35.3 (s), 30.0 (t), 44.6 (s), 61.7 (t), 123.0 (d), 126.6 (d), 127.7 (s), 141.7 (s), 145.5 (s), 155.8
(s), 213.8 (s). GCMS: tR = 29.49 min, m/z (%) = 318 ([M]+, 100), 303 ([M-15]+, 51), 233 ( 90), 219 (19), 203
(17), 191 (8), 177 (56), 161 (36), 105 (14), 57 (93). HRMS (ESI): m/z [M+H]+ calcd for C21H35O2: 319.2632;
found: 319.2627.
4.10. 2-(3,5-Di-tert-butyl-2-methoxyphenyl)indan-1-one (rac-11d)
Following the general procedure I as described above, Pd(OAc)2 (22.5 mg, 0.1 mmol, 2 mol%), NaOtBu
(1.10 g, 11.0 mmol, 2.20 equiv), 100 µL of 1.0 M tri-tert-butylphosphine solution in toluene (0.1 mmol, 2
mol% PtBu3), 1-bromo-3,5-di-tert-butyl-2-methoxybenzene (9c) (1.30 mL, 1.50 g, 5.0 mmol, 1.00 equiv),
and 1-indanone (10d) (661 mg, 5.0 mmol, 1.00 equiv) were employed. After stirring the reaction mixture
for 16 h at ambient temperatures under N2, it was quenched with 1 M HCl solution (10 mL) and
subsequently subjected to the usual work-up. Purification of the crude product by flash column
chromatography on silica gel (hexanes/EtOAc, 10:0.3) afforded 1.45 g (4.15 mmol, 83%) of the title
compound (rac-11d) as a colorless solid. Mp: 198 °C. TLC: Rf = 0.28 (silica gel; hexanes/EtOAc, 10:0.3).
−
1
FTIR (KBr): νmax (cm ) = 3416 (w), 2952 (w), 2862 (s), 1714 (s), 1608 (s), 1475 (s), 1428 (s), 1359 (s),
1
1327 (s), 1236 (s), 1205 (s), 1158 (s), 1113 (s), 1036 (s), 994 (s), 876 (s), 755 (s), 654 (s). H NMR (500
MHz, CDCl3):
(s, 3H), 4.37 (dd, J = 8.4, 4.7 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H),
7.53 (d, J = 7.7 Hz, 1H), 7.66 (td, J = 7.5, 1.2 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ = 1.20 (s, 9H), 1.44 (s, 9H), 3.17 (dd, J = 17.3, 4.7 Hz, 1H), 3.74 (dd, J = 17.4, 8.3 Hz, 1H), 3.89
δ
=
31.3 (CH3), 31.4 (CH3), 34.5 (C), 35.4 (C), 37.6 (CH2), 47.8 (CH), 63.4 (CH3), 123.00 (CH), 123.5 (CH), 124.3
(CH), 126.4 (CH), 127.6 (CH), 133.6 (C), 134.8 (CH), 136.8 (C), 142.0 (C), 146.3 (C), 153.9 (C), 156.5 (C),
207.4 (C). GCMS: tR = 34.48 min, m/z (%) = 350 ([M]+, 75), 335 ([M-15]+, 100), 279 ( 9), 160 (5), 57 (10),
28 (25). HRMS (ESI): m/z [M+Na]+ calcd for C24H30O2Na: 373.2138; found: 373.2135.
4.11. 2-(2-Methoxy-3,5-bis(2-phenylpropan-2-yl)phenyl)indan-1-one (rac-11e)
Following the general procedure I as described above, Pd(OAc)2 (22.5 mg, 0.1 mmol, 2 mol%), NaOtBu
(1.10 g, 11.0 mmol, 2.20 equiv), 100 µL of 1.0 M tri-tert-butylphosphine solution in toluene (0.1 mmol, 2
27

ACCEPTED MANUSCRIPT
mol% PtBu3), 6-bromo-2,4-bis(2-phenylpropan-2-yl)anisole (9d) (2.10 g, 5.0 mmol, 1.00 equiv), and 1-
indanone (10d) (727 mg, 5.5 mmol, 1.10 equiv) were employed. After stirring the reaction mixture for 16
h at ambient temperatures under N2, it was quenched with 1 M HCl solution (10 mL) and subsequently
subjected to the usual work-up. Purification of the crude product by flash column chromatography on
silica gel (hexanes/EtOAc, 9:1) afforded 1.80 g (3.8 mmol, 76%) of the title compound (rac-11e) as a
−
1
colorless solid. Mp: 59 °C. TLC: Rf = 0.33 (silica gel; hexanes/EtOAc, 9:1). FTIR (KBr): νmax (cm ) = 3415
(s), 3055 (m), 3022 (m), 2966 (m), 2871 (m), 1944 (m), 1871 (m), 1803 (m), 1714 (s), 1606 (s), 1493 (m),
1465 (m), 1443 (m), 1428 (m), 1382 (s), 1361 (s), 1273 (s), 1233 (s), 1203 (s), 11561 (m), 1110 (m), 1030
(s), 1000(s), 767 (m), 754 (m), 700 (s), 658 (s), 609 (s), 575 (s). 1H NMR (500 MHz, CDCl3):
δ = 1.56 (d, J =
2.2 Hz, 3H), 1.61 (dd, J = 4.8, 2.7 Hz, 6H), 1.65 (d, J = 2.3 Hz, 3H),), 2.75 (d, J = 2.7 Hz, 3H), 3.04 (d, J = 17.4
Hz, 1H), 3.62 (dd, J = 17.3, 8.3 Hz, 1H), 4.19–4.10 (m, 1H), 6.70 (t, J = 2.6 Hz, 1H), 7.12 (ddd, J = 8.2, 6.8, 1.4
Hz, 2H), 7.26–7.16 (m, 9H), 7.38 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.76 (d, J
= 7.7 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ = 29.3 (q), 30.8 (q, 30.9 (q), 31.1 (q), 37.3 (t), 42.3 (s), 42.8 (s),
47.7 (d), 61.5 (q), 124.2 (d), 124.6 (d), 125.0 (d), 125.2 (d), 125.5 (d), 126.15 (d), 126.3 (d), 126.7 (d),
127.5 (d), 127.9 (d), 128.0 (d), 133.7 (s), 134.7 (d), 136.7 (s), 142.3 (s), 145.6 (s), 150.6 (s), 151.6 (s),
153.6 (s), 155.97 (s), 206.8 (s). GCMS: tR = 43,55 min, m/z (%) = 326 ([M]+, (100)), 459 (70), 281 (7), 265
(4), 220 (9), 207 (8), 119 (31), 91 (27), 28 (60). HRMS (ESI ): m/z [M+Na]+ calcd for C34H34O2Na: 497.2451;
found: 497.2458.
4.12. 2-(2-Methoxy-3,5-bis(2-phenylpropan-2-yl)phenyl)-3,4-dihydro-2H-naphthalen-1-one (rac-11f)
Following the general procedure I as described above, Pd(OAc)2 (22.5 mg, 0.1 mmol, 2 mol%), NaOtBu
(1.10 g, 11.0 mmol, 2.20 equiv), 100 µL of 1.0 M tri-tert-butylphosphine solution in toluene (0.1 mmol, 2
mol% PtBu3), 6-bromo-2,4-bis(2-phenylpropan-2-yl)anisole (9d) (2.10 g, 5.0 mmol, 1.00 equiv), and α-
tetralone (10e) (731 µL, 804 mg, 5.5 mmol, 1.10 equiv) were employed. After stirring the reaction mixture
for 16 h at ambient temperatures under N2, it was quenched with 1 M HCl solution (10 mL) and
subsequently subjected to the usual work-up. Purification of the crude product by flash column
chromatography on silica gel (hexanes/EtOAc, 9:1) afforded 2.27 g (4.65 mmol, 93%) of the title
compound (rac-11f) as a colorless solid. Mp: 126 °C. TLC: Rf = 0.56 (silica gel; hexanes/EtOAc, 9:1). FTIR
−
1
(KBr): νmax (cm ) = 3445 (w), 3056 (w), 3022 (w), 2965 (s), 1685(s), 1599 (s), 1469 (m), 1360 (w), 1221
1
(s), 1002 (s), 767 (s). H NMR (500 MHz, CDCl3):
δ = 1.55 (s, 3H), 1.68 (d, J = 3.5 Hz, 9H), 2.23–2.15 (m,
1H), 2.34-2.23 (m, 1H), 2.63 (s, 3H), 2.96 (dt, J = 16.7, 3.6 Hz, 1H), 3.11 (ddd, J = 16.5, 11.9, 4.5 Hz, 1H), 4.04
(dd, J = 12.6, 4.5 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 7.5, 5.1 Hz, 1H), 7.15 (td, J = 6.1, 2.7 Hz, 1H),
7.33–7.19 (m, 11H), 7.46 (t, J = 7.5 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ = 28.9 (q),
29.7 (t), 31.0 (q), 31.6 (q), 31.9 (t), 42.3 (s), 42.9 (s), 48.8 (d), 60.8 (q), 124.6 (d), 125.2 (d), 125.5 (d),
126.0 (d), 126.2 (d), 126.6 (d), 126.8 (d), 127.6 (d), 127.9 (d), 128.0 (d), 128.8 (d), 133.1 (s), 133.2 (d),
133.7 (s), 141.9 (s), 144.0 (s), 145.1 (s), 150.9 (s), 151.7 (s), 155.3 (s), 198.9 (s). GCMS: tR = 45.34 min, m/z
(%) = 488 ([M]+, (100)), 473 ([M-15]+, (84)), 457 (7). HRMS (ESI): m/z [M+H]+ calcd for C35H37O2:
489.2788; found: 489.2794.
28

ACCEPTED MANUSCRIPT
4.13. General Procedure II (Enantioselective reduction of ketones with the CBS catalyst 14): (S)-(
tert-butyl-2-methoxyphenyl)-1-(naphthalen-2-yl)ethanol (5f)
−)-2-(3,5-Di-
An oven-dried and nitrogen-flushed 25 mL Schlenk tube was charged with the (R)-(+)-2-Methyl-CBS-
oxazaborolidine catalyst 14 (17.8 mg, 63 µmol, 5 mol%). The tube was equipped with a magnetic stirring
bar and capped with a glass stopper. After evacuating the tube for 15 minutes, the system was back-filled
with dry N2, the glass stopper was replaced with a rubber septum under positive pressure of dry nitrogen.
Then anhydrous THF (1.5 mL) was added by means of a gas-tight syringe. The mixture was cooled to 0 °C
in an ice-bath, BH3·SMe2 (119 µL, 95 mg, 1.25 mmol, 1.00 equiv) was added, and it was stirred for 30
minutes at 0 °C. In a separate oven-dried 10 mL Schlenk tube, 2-(3,5-di-tert-butyl-2-methoxyphenyl)-1-
(naphthalen-2-yl)ethan-1-one (11b) (486 mg, 1.25 mmol, 1.00 equiv) was dissolved in 1.5 mL of
anhydrous THF under nitrogen. The solution of ketone (11b) in THF was then transferred into the 25 mL
Schlenk tube containing the CBS catalyst 14 at 0 °C, via cannula technique and the reaction mixture were
stirred for 30 minutes at 0 °C. Conversion of the ketone 11b was followed by TLC and determined to be
completed within 1 h at 0 °C. The reaction mixture was quenched by the dropwise addition of MeOH (1
mL). Solvents were removed by rotary evaporation under reduced pressure, the residue was treated with
saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (3×30 mL). The combined organic
phases were dried over Na2SO4, filtered, and concentrated by rotary evaporation in vacuo. Purification of
the crude product by flash column chromatography on silica gel (hexanes/EtOAc, 9:1) gave 470 mg (1.2
mmol, 96%) of the title compound (5f) as a colorless solid, in 97% ee. Mp: 118 °C. TLC: Rf = 0,35 (silica gel;
−
hexanes/EtOAc, 9:1). [α]ꢁꢀꢂ = −22 (c = 0.5, CHCl3). FTIR (KBr): νmax (cm ) = 3340 (s), 3050 (s), 3247 (s),
1
2954 (m), 2865 (m), 1601(s), 1508 (s), 1478 (m), 1389 (s), 1360 (s), 1271 (s),1228 (s), 1124 (s), 1037
1
(m), 1013 (m) 903 (s), 882 (s), 857 (s), 820 (s), 752 (s), 705 (m),654 (m), 544 (s). H NMR (500 MHz,
CDCl3):
1H), 6.90 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.48–7.42 (m, 2H), 7.50 (dd, J = 8.5, 1.7 Hz, 1H), 7.85–
7.74 (m, 4H). 13C NMR (125 MHz, CDCl3):
= 31.3 (CH3), 31.4 (CH3), 34.4 (C), 35.3 (C), 42.0 (CH2), 61.8
δ = 1.18 (s, 9H), 1.43 (s, 9H), 3.08 (d, J = 2.4 Hz, 1H), 3.23–3.12 (m, 2H), 3.87 (s, 3H), 5.18–5.13 (m,
δ
(CH3), 75.0 (CH), 123.3 (CH), 124.1 (CH), 124.4 (CH), 125.6 (CH), 125.9 (CH), 126.9 (CH), 127.6 (CH), 127.9
(CH), 128.0 (CH), 130.8 (C), 132.9 (C), 133.3 (C), 141.8 (C), 142.2 (C), 146.1 (C), 156.0 (C). GCMS: tR =
37.22 min, m/z (%) = 372 ([M-18]+, (100)), 357 (57), 234 (42), 219 (49), 155 (23), 141 (24), 128 (13).
HRMS (ESI): m/z [M+Na]+ calcd for C27H34O2Na: 413.2451; found: 413.2459.
4.14 (S)-(−)-1-(3,5-Di-tert-butyl-2-methoxyphenyl)-3,3-dimethylbutan-2-ol (5g)
Following the general procedure II as described above, an oven-dried and nitrogen-flushed 50 mL Schlenk
tube was charged with the CBS catalyst 14 (87.3 mg, 0.32 mmol, 5 mol%). The tube was equipped with a
magnetic stirring bar and capped with a glass stopper. After evacuating the tube for 15 minutes, the
system was back-filled with dry N2, the glass stopper was replaced with a rubber septum, under positive
pressure of dry nitrogen. Then anhydrous THF (6 mL) was added by means of a gas-tight syringe. The
mixture was cooled to 0 °C in an ice-bath, BH3·SMe2 (600 µL, 479 mg, 6.3 mmol, 1.00 equiv) was added,
and it was stirred for 30 minutes at 0 °C. In a separate oven-dried 10 mL Schlenk tube, 1-(3,5-di-tert-
29