Asymmetric transfer hydrogenation of unsaturated ketones; factors influencing 1,4- vs 1,2- regio- and enantioselectivity, and alkene vs alkyne directing effects

Article abstract of DOI:10.1016/j.tet.2020.131771

A detailed study has been completed on the asymmetric transfer hydrogenation (ATH) of a series of enones using Ru(II) catalysts. Electron-rich rings adjacent to the C[dbnd]O group reduce the level of C[dbnd]O reduction compared to C[dbnd]C. The ATH reaction can readily discriminate between double and triple bonds adjacent to ketones, reducing the double bond but leaving a triple bond intact in the major product.

Full text of DOI:10.1016/j.tet.2020.131771

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric transfer hydrogenation of unsaturated ketones; factors
influencing 1,4- vs 1,2- regio- and enantioselectivity, and alkene vs
alkyne directing effects
Thomas H. Hall, Hannah Adams, Vijyesh K. Vyas, K.L. Michael Chu, Martin Wills*
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A detailed study has been completed on the asymmetric transfer hydrogenation (ATH) of a series of
enones using Ru(II) catalysts. Electron-rich rings adjacent to the C]O group reduce the level of C]O
reduction compared to C]C. The ATH reaction can readily discriminate between double and triple bonds
adjacent to ketones, reducing the double bond but leaving a triple bond intact in the major product.
© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Received 4 October 2020
Received in revised form
8 November 2020
Accepted 10 November 2020
Available online xxx
Dedicated to the memory of Professor
Jonathan M. J. Williams, a brilliant scientist
and a friend since our PhD years. Jon once
said to me at a conference some time ago
that he was trying to introduce the term
“hydrogen borrowing” to synthetic chemis-
try, and hoped it would catch on. It certainly
did.
Keywords:
Asymmetric
Catalysis
Ruthenium
Reduction
Enone
Alkyne
Enantioselective
Regioselective
1. Introduction
Related complexes, 3 [4], 4 [5], 5 [5], 6 [4] and 7 [4] have been re-
ported and widely studied in ATH applications [6].
Asymmetric transfer hydrogenation (ATH) of ketones using
Ru(II)/arene/TsDPEN complexes such as 1e7 (Fig. 1) is a well-
established process that generates alcohols in high enantiose-
lectivities [1-6]. The catalysts are well-suited to the reductions of
acetophenone derivatives and alkynyl(acetylenic) ketones, which
are reduced in high ee through relatively well-understood transi-
tion states (Fig. 2) [2]. Complex 1 was first reported by Noyori et al.
in 1995 [3] and in 2005, we reported tethered complexes of type 2
[4], which have subsequently seen widespread application [5].
ATH, using the Ru(II) catalysts 1e5, of a,b-unsaturated ketones
reveals a rather more complex pattern of selectivities. Deng et al.
[7] described the reductions of ketones with catalyst 1 to the cor-
responding allylic alcohols, using a combination of formic acid and
trimethylamine (FA/TEA) as solvent and reducing agent, in high
yield; enantioselectivities depended on the substitution pattern on
the alkene (Fig. 3a). Using chalcone as the substrate for TH with the
achiral ligand N-tosylethyenediamine (TsEN), the reduction prod-
uct was a ca. 3:1 mixture of saturated ketone and saturated alcohol
[7].
Increasing the steric bulk of the alkyl substituent on benzylidi-
neacetones has a complicated effect on the reduction selectivity
using catalyst 1 (Fig. 3b) [8]. The ethyl substituent increased the 1,2
* Corresponding author.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
https://doi.org/10.1016/j.tet.2020.131771
0040-4020/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Please cite this article as: T.H. Hall, H. Adams, V.K. Vyas et al., Asymmetric transfer hydrogenation of unsaturated ketones; factors influencing
1,4- vs 1,2- regio- and enantioselectivity, and alkene vs alkyne directing effects, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131771

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
reduced. Adolfsson’s
a
-amino acid hydroxyamide ligand 12 has
been applied to ATH of allylic alcohols by oxidation to the corre-
sponding enone, followed by complete reduction of alkene and
carbonyl functionalities (Fig. 5) [11]. Use of the stronger base po-
tassium tert-butoxide was important for the success of this
reduction.
Kosmalski applied the Noyori catalyst 1 to the reduction of b-
dimethylamino-acetophenone and found that the main product
was the partially reduced elimination product [12]. Therefore there
is still scope for increased understanding of the subtle effects of
substrate structure on the regioselectivity of enone ATH. In this
paper, we report our results from our investigation into this area.
2. Results and discussion
We first examined the ATH of b-chloropropiophenone 13 [13].
Reduction using catalyst (S,S)-2 in FA/TEA at 60 ꢀC gave complete
conversion to 1-phenylpropan-1-ol 14, in high enantioselectivity
(Fig. 6).
Fig. 1. Ru(II)/arene/TsDPEN complexes reported for the ATH of ketones and imines.
Subjecting 15 to the same ATH conditions gave 14, in identical ee
as obtained previously, as did the reduction of 16, indicating that
both were likely to be common intermediates in the formation of
14. Vinyl alcohol 17 was inert under the same conditions in contrast
to the result in Fig. 5 [11] and no 17 was observed in the reduction of
15 or 16. Initial 1,4-reduction of 15 is expected to be favourable due
to the high reactivity of the unhindered mono-substituted vinyl
group. trans-Benzylideneacetophenone 18 (chalcone) was reduced
using both catalyst (S,S)-2 and the methoxy analogue 3 under a
variety of conditions (Table 1).
selectivity whilst the larger isopropyl group gave equal proportions
of 1,2- and 1,4-reduction products in lower conversion. The tert-
butyl substituent strongly disfavoured all ketone reduction. Noyori
catalyst 1 was applied to the ATH of b-alkyl b-trifluoromethyl a,b-
unsaturated ketones to yield 1,2-reduction products selectively [9].
Aryl-ketone substrates were reduced in high ee as expected, while
a methyl ketone gave a product in poor enantioselectivity (Fig. 3c).
The (non-asymmetric) TH of C]C bonds in enones, using TsEN
as a ligand in the Ru(II) complex, can be promoted by incorporating
an electron withdrawing groups into the substrate [7], including
nitro, ester, nitrile and carboxylic acids. Some asymmetric exam-
With both catalysts, 1,4-reduction was favoured. The substrate
was fully consumed but some saturated ketone 20 was observed.
Alcohol 19 was produced with consistently good ee of ca. 95e98% in
FA/TEA for both catalysts. Compound 21 was formed with a lower
ples of C]C reduction have been reported [7]. A series of
a-
substituted cyclic -unsaturated ketones were reduced selec-
a,b
ee (73e85%), which is consistent with the presence of two
p sys-
tively with the Noyori-Ikariya complex 1 to the corresponding
cycloalkenols 8e10, although the carbamate substrate also yielded
a small amount of the 1,4-reduction product 11 (Fig. 4) [10]. The
acyclic analogue of 10 in contrast was reduced with complete 1,4-
alkene selectivity, yielding a mixture of 33% saturated ketone and
67% saturated alcohol.
tems that could compete as directing groups for reduction (Fig. 2).
Catalyst (R,R)-3 delivered products in slightly higher ee than (S,S)-2
under the same conditions. Racemic standards were prepared using
sodium borohydride; alcohol 21 was prepared by Luche reduction
[12], while a sample of 20 was produced by a one pot reduction in
the presence of palladium on carbon, acetic acid, isopropanol, and
sodium borohydride [13]. The products ees were measured by
In some cases an enone can be formed in situ and directly
Fig. 2. Control of asymmetric reduction of various types of ketones using complex 2 (representative of 1e7).
2

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
Fig. 3. a. ATH of
a,
b-unsaturated ketones by Deng et al. [7] b, Variation between 1,2- and 1,4-reduction of alkyl-benzylidineacetone derivatives (the ee of C was not determined) [8].
c . Products of selective 1,2- reduction of
b-trifluoromethyl enones using catalyst 1 [9].
reduction was slower, with incomplete conversion after 45 h at
60 ꢀC and the ee of alcohol 19 reduced to 86%. Increasing the FA/
TEA/MeOH reaction temperature to 60 ꢀC or decreasing it to 25 ꢀ
C
had a marginal effect on the selectivities (entries 7 and 8).
Screening of alternative co-solvents in the reduction of 18 was
undertaken (Supporting Information). Aprotic solvents tested per-
formed similarly, giving similar or slightly improved 1,4-selectivity
and ee compared to reactions with MeOH. Water was also tested as
a co-solvent with FA/TEA, however the solubility of 18 in the
aqueous FA/TEA mixture was poor, and the enantioselectivty of
both products lower than for the other solvents tested.
Fig. 4. Product of ATH of
a
ꢁsubstituted cyclic enones (using catalyst 1).
It was expected that the configurations of both 19 and 21 were
the same and this was confirmed by hydrogenating the product
mixture from Table 1 entry 4 using Pt2O as a catalyst. Given the
ratio of alcohols 19 and 21, the predicted ee of 19 after alkene hy-
drogenation is 97% if the configuration of both alcohols is the same,
and 91% if it is different (Supporting Information). The experi-
mental measurement of ee after hydrogenation was 97%, confirm-
ing that 19 and 21 must have the same configuration. The electronic
nature of the aromatic ring adjacent to the ketone could influence
the 1,4- vs 1,2-selectivity of reduction [15]. To test this, chalcone
chiral HPLC, and the product ratio was determined by NMR spec-
troscopy to ensure that the measurement was quantitative.
Cerium trichloride [12] was tested as an additive (Table 1, entry
5), but it had only a marginal effect. However the additional
methanol co-solvent was advantageous, as substrate 18 was poorly
soluble in FA/TEA. Further reactions using equal quantities of FA/
TEA and MeOH at lower concentration (0.5 M instead of 2 M) gave
full conversion to product (Table 1, entries 3 and 4). Using H2O/
MeOH as the solvent system and sodium formate as hydrogen
donor (Table 1, entry 6) [14], with (R,R)-3 as the catalyst, the
Fig. 5. Isomerisation and reduction of benzyl-vinyl alcohol [11].
Fig. 6. Reduction of
b-chloropropiophenone 13, 14 and 15.
3

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
Table 1
In order to establish the importance of each aromatic ring in the
chalcone derivatives, the corresponding cyclohexyl substituted
substrates were reduced by ATH (Fig. 7). The ketone with a cyclo-
hexyl adjacent to the alkene reacted with similar selectivity to
chalcone, to give 25 with a slight increase in 1,4-selectivity (97% ee).
Reduction of the ketone with the cyclohexyl adjacent to the ketone,
in contrast, gave different products 26 depending on which catalyst
was used. In general it gave a much higher proportion of 1,2-
reduction product, although 1,4-selectivity was highest under
aqueous conditions using sodium formate as the hydrogen source
(Fig. 7). The ee of reduction was also poor. This demonstrates the
importance of the aromatic ring adjacent to the ketone for the
control of enantioselectivity, but that the aromatic ring on the
ATH of chalcone 18 and its reduction products.
Entry Catalyst t/h Conv/% 20/% 1,4e19: 19 ee/% 21 ee/% R/S
1,2-21
1a
(S,S)-2
(R,R)-3
(S,S)-2
(R,R)-3
(S,S)-2
(R,R)-3
(R,R)-3
(R,R)-3
1.5 98
2
2
0
0
2
6
4
1
91 : 7
96 : 2
89 : 11
96 : 4
88 : 10
94 : 0
91 : 5
96 : 3
96
98
95
98
95
86
98
96
73
84
79
85
78
e
S
R
S
R
S
R
R
R
2a
4
98
3b
20
22
100
100
4b
5c
5.5 98
alkene is of secondary importance. ATH of a substrate with a b,b-
6d
7b,e
8b,f
45
25
18
94
96
99
disubstitution gave a product in high 1,4-selectivity, with pre-
dominant formation of the saturated alcohol 27 over the equivalent
allylic alcohol although in only 55% ee.
It is known in the literature that alkynes are generally inert
under ATH conditions, and are capable of acting as directing groups
(Fig. 2) [3d,4,6]. It was therefore of interest to establish the outcome
of the ATH of substrates containing both an alkyne and an alkene
flanking the central ketone (Fig. 8).
83
77
Conditions.
a
2 M in FA/TEA, 100:1 S/C, 40 ꢀC.
b
c
d
e
f
0.5 M in 5:2 FA/TEA: MeOH (1:1), 100:1 S/C, 40 ꢀC.
as b) with CeCl3 additive (0.5 eq).
0.5 M in 1:1H2O/MeOH, NaHCO2, 100:1 S/C, 60 ꢀC.
at 25 ꢀC.
at 60 ꢀC.
The precursor ketones were prepared by reaction of the
required lithiated acetylene with the Weinreb amide of cinnamic
acid. Racemic standards were obtained for all the products and
HPLC was used to directly assess the regio- and stereoselectivity of
the reactions. Product ratios were also determined by 1H NMR data.
In the ATH of the diphenyl substrate, using (R,R)-2, the saturated
and unsaturated products 28 and 29 respectively were formed in an
83:17 ratio (Fig. 8). The ee of 28 was highest, presumably because
derivatives containing p-Cl, p-OMe and p-NMe2 were reduced with
catalyst (R,R)-3 to products 22e24 (Fig. 7). Electron donating sub-
stituents slow down the rate of reduction, and increase the 1,4-
selectivity. The proportion of 1,2-product was so low for the p-
methoxy and p-dimethylamino products 23 and 24 respectively,
that the ee of the unsaturated product could not be determined.
Fig. 7. Products of ATH of chalcone derivatives. Conditions: 22e24: [S] ¼ 0.5 M in 5:2 FA/TEA, MeOH (1:1), 24 h, 40 ꢀC, 100:1 S/C, (R,R)-3. Assumed R product is formed by analogy
with chalcone. 25: as for 22e24, catalyst (S,S)-2. 26: run 1 and 2: as for 22e24, catalyst (S,S)-2. run 3: [S] ¼ 0.5 M in 1:1H2O:MeOH, NaHCO2, 100:1 S/C, (R,R)-2. 27: as for 22e24.
4

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
Fig. 8. Products of ATH of alkene/alkyne substrates. The illustrated configuration is that for the assumption that the alkyne dominates the selectivity as in Fig. 2. Conditions: FA:TEA
5:2 (0.5 mL), solvent (0.5 mL), 1 mol% catalyst and 40 ꢀC unless otherwise stated.
the alkene is reduced first and the resulting propargylic ketone is
selectively reduced following existing precedent [1,3d,4c]. The 1,2-
reduction product 29 was formed in lower ee likely due to
cases different solvents have been demonstrated to reverse the
enantioselectivity [16]. However the results, whilst similar to those
in Fig. 8, were inferior with respect to product selectivity, enan-
tioselectivity and conversion. Four further ATH catalysts, 1, 3, ‘4C-
tethered’ 6 and the ‘benzyl-bridged’ 7 were also used (Fig. 8). Time
studies were also conducted to track the formation of products and
intermediates in each case (Supporting Information). Catalyst 6
produced similar ratios of alcohols and ee values as seen with 2,
however, it gave lower conversion. Catalyst 3 gave a similar result
to that of 6. ATH with 3 at the lower temperature of 25 ꢀC gave a
more selective product ratio (79:21 28:29) with high ee’s of 98%
and 87% for the saturated OH and unsaturated OH respectively.
However the conversion was slightly lower at 85%. Catalyst 7 gave
approximately a 1:1 ratio between the saturated and unsaturated
products which could be due to the hindered nature of the catalyst.
The ATH (1 mol% catalyst (R,R)-2, MeOH co-solvent at 40 ꢀC) was
tested with other substrates and in all cases, standards of the
reduction products were prepared for HPLC analysis. Attempts
were made at ATH of the TMS-substituted alkyne but decomposi-
tion was observed. However the ATH of the TIPS-enynone was
successful. Products 30 and 31 were isolated as a mixture, in a ratio
competing electron-rich unstaturated bonds in the CH/
p of the
reduction transition state (Fig. 2). The absolute configuration of the
products was not unambiguously determined. However it is likely
that the R-configuration products will be formed using the (R,R)-
configuration catalyst, based on the precedent for this class of
reductions.
A reaction/time study was completed to investigate the ATH
using HPLC (Supporting Information). From an early stage in the
reaction, the formation of the intermediate saturated ketone was
essentially instantaneous, and a small amount of unsaturated
product was also observed. As time increases, starting material and
intermediate ketone disappear and the two alcohol products are
formed. The effect of solvent on the reaction was also investigated
and a time study for each solvent was undertaken to explore the
relative rate of formation of each of the intermediate and product
species over time (Supporting Information). DFT studies have
indicated that using MeOH engages in hydrogen bonding in-
teractions to the ketone during the reduction [2a,2e] and in some
5

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
of 69:31 and in a conversion of just 81%. The ATH was less selective
for the 1,4-reduction pathway and hence, produced more of un-
saturated alcohol 31. The enantioselectivity was high for both
alcoholic products however. The products of ATH of the p-
methoxyphenyl derivative were obtained as an 86:14 mixture of 32
and 33. Hence the electron-donating group does not appear to
significantly affect the reaction mechanism or product distribution.
The p-chlorobenzene (PCB) derivative gave a product as a mixture
of 34 and 35, with slightly lower enantioselectivity. An impurity
was found in the 1H NMR spectrum and it was hypothesised that
this was the alkyne reduction production 36, based on the obser-
vation of a further ABX system in the 1H NMR spectrum (see the
Supporting Information).
4.1.1. rac-1-Phenylpropan-1-ol 14
This compound is known [17]. To a solution of propiophenone
16 (66 mg, 0.49 mmol, 1 eq) in methanol (0.9 mL) and water
(0.1 mL) was added sodium borohydride (41 mg,1.08 mmol, 2 eq) as
a solid in one portion. The reaction was monitored by TLC. After
stirring for 6 h, the reaction mixture was concentrated under vac-
uum, the residue suspended in water (1 mL) and extracted with
Et2O (3 mL total). The organic layer was dried (Na2SO4) and
concentrated to give the product 35 as a clear oil (35 mg,
0.26 mmol, 52%). The spectroscopic data were consistent with
those observed for the asymmetric product below.
4.1.2. (S)-1-Phenylpropan-1-ol 14
This compound is known [17]. From 3-chloropropiophenone 13:
A degassed solution of 3-chloropropiophenone (170 mg, 1.01 mmol,
1.0 eq) and (S,S)-2 (3.1 mg, 0.005 mmol, 0.5%) in FA/TEA (5:2,
0.5 mL) was stirred at 60 ꢀC for 1.5 h. The mixture was diluted with
ethyl acetate (5 mL) and quenched with NaHCO3 (sat., 5 mL), the
aqueous layer was extracted further with ethyl acetate (2 ꢂ 5 mL)
and the organic extracts dried over Na2SO4 and concentrated to
give a brown oil. The crude was dissolved in diethyl ether and
passed through a silica plug to yield the product 14 as a red oil
(123 mg, 0.97 mmol, 96%) in 100% conv and 95% ee as measured by
3. Conclusions
Investigation of the ATH of a range of enones showed that
predominant 1,4- reactivity is favoured and the majority of
aromatic-ketone substrates were reduced to their saturated alco-
hols with high ee. Electron-donating para substituents on the ke-
tone favoured 1,4-reduction further. The ATH of alkene/alkyne
ketones leads to a mixture of chiral alcohols via 1,4 and 1,2-
reduction pathways, the 1,4-pathway being predominant in the
reaction. A time study of the reaction confirmed that the C]C bond
is rapidly reduced early in the reduction process, and the saturated
products were formed in higher ee than the unsaturated ones.
22
22
GC. [
a
]
D
-43.5 (c 0.35 in CHCl3); lit [17] [
a
]
D
-43.6 (S) (c 1.0 in
CHCl3); dH (300 MHz, CDCl3) 7.29e7.15 (5H, m, Ph), 4.49 (1H, dt,
J ¼ 3.2, 6.6 Hz, CHOH), 1.85 (1H, brs, OH), 1.78e1.57 (2H, m, CH2),
0.82 (3H, t, J ¼ 7.4 Hz, CH3); dC (75 MHz, CDCl3) 143.9, 127.8, 126.9,
4. Experimental section
125.4, 75.4, 31.3, 9.5; Chiral GC; (CP-Chirasil-Dex-Cb,
25 m ꢂ 0.25 mm x 0.25
m
m column, oven: hold 12 min at 125 ꢀC,
ꢀ
4.1. General experimental
then ramp 1 C/min, final temp 145 ꢀC, inj.: split 220 ꢀC, det.: FID
250 ꢀC, 18 Psi He), retention times: 11.2 (R) and 11.4 (S) minutes.
From phenyl vinyl ketone 15: Compound 14 could also be pre-
pared with 100% conversion and 95% ee with the same method,
starting from 15 (prepared by elimination of HCl from 3-
chloropropriophenone [18], 126 mg, 0.95 mmol, 1 eq), (S,S)-2
catalyst (3.5 mg, 0.006 mmol, 0.5%) and FA/TEA (5:2, 0.5 mL). The
product was isolated as a clear oil (103 mg, 0.76 mmol, 79%).
Attempted reduction of 1-phenylprop-2-en-1-ol 17. Application
All reagents and solvents were used as purchased and without
further purification, with the exception of cyclohexane carbox-
aldehyde which was redistilled for storage.
All reactions were carried out under a nitrogen atmosphere
unless otherwise specified. Reactions at elevated temperature were
maintained by thermostatically controlled oil-baths or aluminium
heating blocks. A temperature of 0 ꢀC refers to an ice slush
bath, ꢁ78 ꢀC to a dry ice acetone bath.
of the same method to commercially available
a-vinylbenzyl
NMR spectra were recorded on a Bruker AV (250 MHz), Bruker
DPX (300 or 400 MHz), Bruker DRX (500 MHz) or Bruker AV-II.
(700 MHz). All chemical shifts are rounded to the nearest
0.01 ppm for 1H spectra and the nearest 0.1 ppm for 13C spectra, and
are referenced to the solvent chemical shift. Coupling constants are
rounded to the nearest 0.1 Hz. Mass spectra were recorded on an
Esquire 2000 and high resolution mass spectra were recorded on a
Bruker Micro ToF or MaXis. IR spectra were recorded on a Perki-
nElmer spectrum 100 and peaks are reported in wavenumbers.
Optical rotations were measured on an Optical Activity Ltd. AA-
alcohol 17 (134 mg) and (S,S)-2 catalyst (3.3 mg, 5 mmol, 0.5%) in FA/
TEA (5:2. 0.5 mL) gave no reaction in 1.5 h at 60 ꢀC.
4.1.3. rac-1,3-Diphenylpropan-1-ol 19
This compound is known [19]. To a suspension of chalcone 18
(212 mg, 1.02 mmol, 1 eq) and Pd/C (5% w/w, 52 mg, 24 mmol, 2.5%
Pd) in isopropanol (5 mL) was added acetic acid (124 mg,
2.06 mmol, 2 eq) followed by sodium borohydride (160 mg,
4.23 mmol, 4 eq), with vigorous effervescence. The reaction
mixture was stirred at rt for 2 h and quenched slowly with HCl
(0.2 M, 2.5 mL). The resulting suspension was neutralised with
NaOH (2 M, ~1.5 mL) and filtered through Celite with isopropanol to
remove Pd/C. The mixture was concentrated to remove excess
isopropanol and then the aqueous layer was extracted with diethyl
ether (3 ꢂ 20 mL), dried over Na2SO4 and concentrated to give the
saturated alcohol 19 as a clear oil that solidifies on standing.
(183 mg, 0.86 mmol, 85%). dH (400 MHz, CDCl3) 7.34 (4H, br. s., Ph),
7.30e7.23 (3H, m, Ph), 7.22e7.14 (3H, m, Ph), 4.67 (1H, br. s., CHOH),
2.82e2.55 (2H, m, PhCH2), 2.20e1.96 (2H, m, CHCH2), 1.92 (1H, br.
s., OH); dC (101 MHz, CDCl3) 144.6, 141.8, 128.6, 128.5, 128.4, 127.7,
126.0, 125.9, 73.9, 40.5, 32.1; Chiral HPLC (CHIRALPAK IB column:
(0.46 ꢂ 25 cm), 1 mL/min, 7% IPA: 93% Hexane; 256 nm UV, 30 ꢀC):
retention times: 9.4 (S) and 10.4 (R) minutes.
1000 Polarimeter and are reported in deg dmꢁ1 cm3 gꢁ1
.
The chiral GC measurements were performed using a Perki-
nElmer 8500 or Hewlett-Packard 1050 instrument linked to a PC
running DataApex Clarity software. HPLC measurements were
performed out using a Hewlett Packard 1050 Series with a qua-
ternary pump, autosampler and variable wavelength detector
linked to a PC running DataApex Clarity software.
Melting points were determined on a Stuart scientific melting
point apparatus and are uncorrected. Flash column chromatog-
raphy was performed using silica gel of mesh size 230e400, Thin
layer chromatography was carried out on aluminium backed silica
gel 60(F254) plates, visualised using 254 nm UV light, potassium
permanganate, iodine stains or cerium ammonium molybdate
(CAM) as appropriate. Column chromatography was performed
either by gradient elution (reported as a range, eg EtOAc/Petroleum
ether (2e12%), or by isocratic elution.
4.1.4. rac-(E)-1,3-Diphenylprop-2-en-1-ol 21
This compound is known [20,21]. To a suspension of chalcone 18
6

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
(625 mg, 3.0 mmol, 1 eq) and cerium trichloride heptahydrate
(1.12 g, 3.0 mmol, 1 eq) in methanol (6 mL) was added sodium
borohydride (113 mg, 3.0 mmol, 1 eq) at 0 ꢀC. The reaction was
stirred for 1 h, quenched with NH4Cl (sat., 10 mL) and extracted
with diethyl ether (3 ꢂ 10 mL). The organic layers were dried over
Na2SO4 and concentrated to give the unsaturated alcohol 21 as a
clear oil that solidifies on standing (532 mg, 2.53 mmol, 84%). dH
(400 MHz, CDCl3) 7.48e7.19 (10H, m, Ph), 6.69 (1H, d,
J ¼ 15.8 Hz, ¼CHPh), 6.38 (1H, dd, J ¼ 6.4, 15.8 Hz CHCH ¼ ), 5.39
(1H, d, J ¼ 6.4 Hz, CHOH), 2.08 (1H, br. s., OH); dC (101 MHz, CDCl3)
142.9, 136.6, 131.6, 130.6, 128.7, 128.7, 127.9, 127.2, 126.7, 126.5, 75.1;
Chiral HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1 mL/min, 7%
IPA: 93% Hexane; 256 nm UV, 30 ꢀC): retention times: 13.4 (S) and
16.9 (R) minutes.
concentrated to give the product 22 as a pale yellow oil. Purification
by column chromatography (5 g silica, 30% Et2O:Petroleum ether)
gave the pure product as a white solid (192 mg, 0.78 mmol, 78%). dH
(400 MHz, CDCl3) 7.35e7.24 (6H, m, Ph), 7.23e7.14 (3H, m, Ph),
4.74e4.57 (1H, m, CHOH), 2.81e2.54 (2H, m, PhCH2), 2.15e1.93 (2H,
m, CHCH2), 1.91e1.84 (1H, m, OH); dC (101 MHz, CDCl3) 143.0 (C),
141.5 (C), 133.2 (C), 128.6 (CH), 128.4 (CH), 128.4 (CH), 127.3 (CH),
125.9 (CH), 73.1 (CH), 40.5 (CH2), 31.9 (CH2); Chiral HPLC (CHIR-
ALPAK IB column: (0.46 ꢂ 25 cm), 1 mL/min, 7% IPA: 93% Hexane;
210 nm UV, 30 ꢀC) retention times: 9.3 (S) and 10.6 (R) minutes.
4.1.8. rac-(E)-1-(4-Chlorophenyl)-3-phenylprop-2-en-1-ol
This compound is known [20,24,25]. To a suspension of (E)-1-(4-
chlorophenyl)-3-phenylprop-2-en-1-one (242 mg, 1.0 mmol, 1 eq)
and cerium trichloride heptahydrate (392 mg, 1.1 mmol, 1 eq) in
methanol (2 mL) was added sodium borohydride (43 mg, 1.1 mmol,
1 eq) at 0 ꢀC. The reaction was stirred for 1 h and quenched with sat.
NH4Cl (5 mL) and extracted with diethyl ether (3 ꢂ 5 mL) and
passed through a plug of activated carbon/Celite. The filtrate was
concentrated to give the unsaturated alcohol as a clear oil that
solidified on standing in the freezer for 3 days (239 mg). Trituation
from water gave a sticky white solid that was dried under vacuum
to yield pure compound as a grey solid. (174 mg, 0.71 mmol, 71%).
dH (400 MHz, CDCl3) 7.59e7.06 (9H, m, ArH), 6.68 (1H, d,
J ¼ 15.8 Hz, ¼CHPh), 6.32 (1H, dd, J ¼ 15.8, 6.7 Hz, CHCH ¼ ), 5.36
(1H, d, J ¼ 6.3 Hz, CHOH), 2.09 (1H, br. s., OH); dC (101 MHz, CDCl3)
141.2, 136.3, 133.5, 131.1, 131.0, 128.8, 128.7, 128.0, 127.7, 126.7, 74.5;
Chiral HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1 mL/min, 7%
IPA: 93% Hexane; 210 nm UV, 30 ꢀC) retention times: 12.5 (S) and
17.9 (R) minutes.
4.1.5. (S)-1,3-Diphenylpropan-1-ol 19 and (S,E)-1,3-diphenylprop-
2-en-1-ol 21
These compounds are known [19e21]. A degassed suspension of
trans-chalcone 18 (208 mg, 1.0 mmol, 1 eq) and (S,S)-2 (6.2 mg,
0.01 mmol, 1%) in FA/TEA (5:2, 0.5 mL) was stirred at 40 ꢀC for 1.5 h.
On completion the reaction mixture was homogenous. The mixture
was diluted with diethyl ether (2 mL) and quenched with NaHCO3
(sat., 2 mL), the aqueous layer was extracted further with ether
(2 ꢂ 2 mL) and the organic extracts dried over Na2SO4 and passed
through a silica plug to yield the product as an off white solid
(203 mg, 0.96 mmol, 96%). The product was obtained as a mixture
of saturated and unsaturated alcohols in 98% conversion, ratio 91:7
by 1H NMR, major product 96% ee, minor product 73% ee. The
opposite enantiomer was obtained using (R,R)-3 (3.3 mg, 1%), trans-
chalcone (104 mg, 0.5 mmol), FA/TEA (0.5 mL) and methanol
(0.5 mL), to give the product (102 mg, 0.48 mmol, 96%). The product
was obtained as a mixture of saturated and unsaturated alcohols in
100% conversion, ratio 96:2 by 1H NMR, major product 98% ee,
minor product 84% ee. Spectroscopic data for asymmetric product
4.1.9. (R)-1-(4-Chlorophenyl)-3-phenylpropan-1-ol 22 and (R,E)-1-
(4-chlorophenyl)-3-phenylprop-2-en-1-ol
The major compound is known in racemic form [23]. The
asymmetric form has not been reported. The minor compound is
is consistent with the prepared standards. Mp 52 ꢀC; [
a]
27 þ 29.4, R
D
22
98% ee (c 0.425 in CHCl3); lit [19] [
a
]
þ27.3, R 93% ee (c 0.51 in
D
known [20,24,25].
A
degassed suspension of (E)-1-(4-
CHCl3); Chiral HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1 mL/
min, 7% IPA: 93% Hexane; 256 nm UV, 30 ꢀC): retention times: 10.0
(S)-saturated, 11.0 (R)-saturated, 13.4 (S)-unsaturated and 16.8 (R)-
unsaturated minutes.
chlorophenyl)-3-phenylprop-2-en-1-one (120 mg, 0.49 mmol, 1
eq) and (R,R)-3 catalyst (3.3 mg, 0.005 mmol, 1%) in FA/TEA (5:2,
0.5 mL) and methanol (0.5 mL) was stirred at 40 ꢀC for 22 h. The
mixture was quenched with NaHCO3 (sat., 2 mL), extracted into
diethyl ether (2 mL) and dry loaded onto silica (~200 mg). Filtration
with 40% Et2O/Hexane through a silica plug (~200 mg) gave the
crude product as a sticky red film (114 mg). Purification by column
chromatography (15% EtOAc in petroleum ether) gave the pure
mixture of alcohols as a clear oil. (98 mg, 0.40 mmol, 80%). The
product was obtained as a mixture of saturated 22 and unsaturated
alcohols, ratio 96:4 by 1H NMR. Total conv 100%, major product 94%
ee as determined by HPLC, minor product was 69% ee as deter-
4.1.6. (E)-1-(4-Chlorophenyl)-3-phenylprop-2-en-1-one
This compound is known [22]. 40-Chloroacetophenone (1.54 g,
10.0 mmol, 1 eq) was dissolved in a solution of sodium methoxide
(25 wt% in MeOH, 1.11 g, 5.1 mmol, 0.5 eq) and MeOH (20 mL) and
cooled to 0 ꢀC. Benzaldehyde (1.59 g, 15.0 mmol, 1.5 eq) in MeOH
(5 mL) was added and the suspension was warmed to 40 ꢀC. The
resulting solution was stirred for 18 h, THF (10 mL) was added to
dissolve solids and the reaction was then quenched by dropwise
addition of HCl (0.25 M, 20 mL). The resulting yellow crystalline
precipitate was isolated by filtration and purified by recrystalliza-
tion from hot ethanol and water. The pure product was isolated as
an off white crystalline solid (2.08 g, 8.6 mmol, 86%). Mp 93e96 ꢀC;
dH (400 MHz, CDCl3) 7.98 (2H, d, J ¼ 8.3 Hz, ArH), 7.83 (1H, d,
J ¼ 15.8 Hz, CH ¼ ), 7.71e7.61 (2H, m, ArH), 7.49 (2H, d, J ¼ 8.8 Hz, o-
Cl ArH), 7.50 (1H, d, J ¼ 15.8 Hz, CH ¼ ), 7.45e7.41 (3H, m, Ph).
mined by HPLC. [
a
]
27 þ12.8 R 94% ee (c 0.375 in CHCl3); Chiral HPLC
D
(CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1 mL/min, 7% IPA: 93%
Hexane; 210 nm UV, 30 ꢀC) retention times: 9.6 (S)-saturated, 10.8
(R)-saturated, 13.0 (S)-unsaturated and 16.1 (R)-unsaturated
minutes.
4.1.10. (E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1-one
This compound is known [22] 40-Methoxyacetophenone (1.51 g,
10.1 mmol, 1 eq) was dissolved in a solution of sodium methoxide
(25 wt% in MeOH, 0.43 g, 2.0 mmol, 0.2 eq) and MeOH (20 mL) and
cooled to 0 ꢀC. Benzaldehyde (1.50 g, 14.1 mmol, 1.4 eq) in MeOH
(5 mL) was added and the suspension was warmed to 40 ꢀC. The
resulting solution was stirred for 48 h, then quenched by dropwise
addition of HCl (0.25 M, 20 mL). The resulting white crystalline
solid was isolated by filtration (2.20 g, 9.2 mmol, 92%). dH (500 MHz,
CDCl3) 8.09e8.02 (2H, m, ArH), 7.81 (1H, d, J ¼ 15.7 Hz, ¼CH), 7.65
4.1.7. rac-1-(4-Chlorophenyl)-3-phenylpropan-1-ol 22
This compound is known [23]. To
a
solution of 4-
chlorobenzaldehyde (141 mg, 1.0 mmol, 1 eq) in THF (1 mL)
at ꢁ78 ꢀC was added phenethyl magnesium chloride (1 M in THF,
1 mL, 1 eq). The reaction was allowed to warm to rt over 2.5 h,
quenched with sat. NH4Cl (2 mL) and extracted with Et2O
(2 ꢂ 2.5 mL). The organic extract was dried over MgSO4 and
7

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
(2H, dd, J ¼ 7.2, 2.1 Hz, ArH), 7.55 (1H, d, J ¼ 15.7 Hz, ¼CH),
7.45e7.36 (3H, m, ArH), 7.02e6.96 (2H, m, ArH), 3.89 (3H, s, OCH3);
dC (126 MHz, CDCl3) 188.7, 163.5, 144.0, 135.1, 131.1, 130.8, 130.4,
129.0, 128.4, 121.9, 113.9, 55.5.
(126 MHz, CDCl3) 187.8, 153.4, 142.5, 135.5, 130.8, 129.9, 128.9,
128.2, 126.0, 122.2, 110.9, 40.1.
4.1.14. rac-1-(4-(Dimethylamino)phenyl)-3-phenylpropan-1-ol 24
This compound is known but not fully characterised [29]. To a
solution of 4-(dimethylamino)benzaldehyde (152 mg, 1.02 mmol, 1
eq) in THF (1 mL) at ꢁ78 ꢀC was added phenethyl magnesium
chloride (1 M in THF, 1 mL, 1 eq). The reaction was allowed to warm
to rt over 5.5 h and quenched with sat. NH4Cl (1 mL), diluted with
water (1 mL) and extracted with Et2O (3 ꢂ 3 mL). The organic
extract was dried over MgSO4 and concentrated to give the product
24 as a white solid (260 mg,1.02 mmol,100%). Mp 67e68 ꢀC; HRMS:
found (ESI) [M þ H]þ, 256.1692. (C17H22NO requires 256.1696); dH
(300 MHz, CDCl3) 7.46e6.99 (8H, m, Ph), 6.73 (2H, d, J ¼ 7.5 Hz, o-N
Ph), 4.59 (1H, t, J ¼ 6.5 Hz, CHOH), 2.95 (6H, s, NMe2), 2.79e2.56
(2H, m, PhCH2), 2.21e1.93 (2H, m, CHCH2), 1.69 (1H, br. s., OH); dC
(75 MHz, CDCl3) 150.3, 142.1, 132.3, 128.5, 128.3, 127.0, 125.7, 112.6,
73.7, 40.7, 40.04, 32.3; m/z (ESI): 256.2 ([M þ H]þ)); Chiral HPLC
(CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1 mL/min, 10% IPA: 90%
Hexane; 210 nm UV, 30 ꢀC) retention times: 10.6 (S) and 11.3 (R)
minutes.
4.1.11. rac-1-(4-Methoxyphenyl)-3-phenylpropan-1-ol 23
This compound is known [26] To a suspension of (E)-1-(4-
Methoxyphenyl)-3-phenylprop-2-en-1-one (240 mg, 1.0 mmol, 1
eq) and Pd/C (5% w/w, 54 mg, 25 mmol, 2.5% Pd) in isopropanol
(5 mL) was added acetic acid (120 mg, 2.0 mmol, 2 eq) followed by
sodium borohydride (152 mg, 4.0 mmol, 4 eq), with vigorous
effervescence. The reaction mixture was stirred at rt for 2.5 h, then
additional sodium borohydride was added (76 mg, 2.0 mmol, 2 eq).
The suspension was stirred for another hour, then filtered through
Celite with isopropanol (40 mL) and water (10 mL). The filtrate was
partially concentrated under vacuum but continued to evolve gas,
so was quenched with NH4Cl (sat. soln, 10 mL) and concentrated at
50 ꢀC. The concentrated residue was partitioned between diethyl
ether (10 mL) and NaOH (2 M soln, 5 mL). The aqueous layer was
extracted with further portions of ether (2 ꢂ 5 mL), and the com-
bined organic layers were dried (Na2SO4) and concentrated under
vacuum to give the crude product as a clear oil that solidifies into a
sticky solid on standing (218 mg). This material was dissolved in a
minimum quantity of methanol and water was added until a white
emulsion formed. Concentrating the emulsion gave a the pure
product as a white crystalline solid (206 mg, 0.84 mmol, 84%). Mp
52e53 ꢀC; dH (400 MHz, CDCl3) 7.32e7.23 (4H, m, Ph), 7.22e7.13
(3H, m, Ph), 6.88 (2H, d, J ¼ 8.3 Hz, o-O Ph), 4.78e4.53 (1H, m,
CHOH), 3.80 (3H, s, OCH3), 2.79e2.58 (2H, m, PhCH2), 2.20e1.94
(2H, m, CHCH2), 1.83 (1H, br. s., OH); dC (101 MHz, CDCl3) 159.1,
141.9, 136.7, 128.5, 128.4, 127.3, 125.9, 113.9, 73.5, 55.3, 40.4, 32.1;
Chiral HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1 mL/min, 7%
IPA: 93% Hexane; 210 nm UV, 30 ꢀC) retention times: 11.9 (S) and
13.1 (R) minutes.
4.1.15. rac-(R)-1-(4-(Dimethylamino)phenyl)-3-phenylpropan-1-ol
24
The asymmetric form of this compound has not been reported. A
degassed suspension of (E)-1-(4-(dimethylamino)phenyl)-3-
phenylprop-2-en-1-one. (129 mg, 0.51 mmol, 1 eq) and catalyst
(R,R)-3 (3.3 mg, 0.005 mmol, 1%) in FA/TEA (5:2, 0.5 mL) and
methanol (0.5 mL) was stirred at 40 ꢀC for 24 h. The mixture was
quenched with NaHCO3 (sat., 2 mL), extracted into diethyl ether
(2 mL) and dry loaded onto silica (~200 mg). Filtration with 20%
EtOAc/petroleum ether (10 mL) through a silica plug (~0.75 g) gave
the crude product.in 91% conversion, with the remainder being the
saturated ketone. (121 mg). Purification by column chromatog-
raphy (20% EtOAc in petroleum ether) gave the pure product 24 as a
white solid (98 mg, 0.38 mmol, 75%). in 97% ee as determined by
HPLC. Spectral data matched those of the racemic compound. TLC:
30% EtOAc in petroleum ether, silica, Rf ¼ 0.22 (SM 0.28);
4.1.12. (R)-1-(4-Methoxyphenyl)-3-phenylpropan-1-ol 23
This compound is known [27]. A degassed suspension of (E)-1-
(4-methoxyphenyl)-3-phenylprop-2-en-1-one
(121
mg,
0.51 mmol, 1 eq) and catalyst (R,R)-3 (3.3 mg, 0.005 mmol, 1%) in
FA/TEA (5:2, 0.5 mL) and methanol (0.5 mL) was stirred at 40 ꢀC for
22 h. The mixture was quenched with NaHCO3 (sat., 2 mL),
extracted into diethyl ether (2 mL) and dry loaded onto silica
(~200 mg). Filtration with 20% Et2O/Hexane (10 mL) through a silica
plug (~0.2 g) gave the pure product 23 as a white solid (110 mg,
0.45 mmol, 89%). Total conv 100%, major product 98% ee. The ee of
[
a
]
24 þ18.8 (c 0.295 in CHCl3); Chiral HPLC (CHIRALPAK IB column:
D
(0.46 ꢂ 25 cm), 1 mL/min, 10% IPA: 90% Hexane; 210 nm UV, 30 ꢀC):
retention times: 10.6 (S) and 11.2 (R) minutes.
4.1.16. (E)-3-Cyclohexyl-1-phenylprop-2-en-1-one
the unsaturated product was not determined. [
CHCl3); lit [27] [
a
]
D
22 þ19.4 (c 0.24 in
This compound is known [31]. To a suspension of sodium hy-
dride (60 wt% dispersion in mineral oil, 0.20 g, 5.0 mmol, 1.0 eq) in
THF (5 mL) at 0 ꢀC was added dropwise a solution of the diethyl (2-
oxo-2-phenylethyl)phosphonate [30] (1.25 g, 4.9 mmol, 1.0 eq) in
THF (5 mL) and the resulting clear solution was stirred for 30 min at
room temperature. Cyclohexanecarboxaldehyde (0.57 g, 5.1 mmol,
1.0 eq) was added neat and the reaction mixture stirred at room
temperature overnight. The reaction was quenched with NH4Cl
(half saturated, 30 mL) and extracted with ethyl acetate (3 ꢂ 15 mL),
the organic extracts washed with brine (25 mL), dried over Na2SO4
and concentrated to give the crude product as a clear oil (1.13 g).
The crude was taken up in methanol (50 mL) and cooled to ꢁ72 ꢀC.
The resulting white precipitate was filtered and dried to give the
pure product as a white solid (492 mg, 2.30 mmol, 45%). Mp
46e48 ꢀC; dH (400 MHz, CDCl3) 7.92 (2H, d, J ¼ 7.5 Hz, o-Ph),
7.57e7.51 (1H, m, p-Ph), 7.49e7.42 (2H, m, m-Ph), 7.01 (1H, dd,
J ¼ 6.8, 15.6 Hz, ¼CHCH), 6.83 (1H, d, J ¼ 15.6 Hz, COCH ¼ ),
2.32e2.18 (1H, m, Cy), 1.88e1.74 (4H, m, Cy), 1.70 (1H, d, J ¼ 12.0 Hz,
Cy), 1.34e1.15 (6H, m, Cy); dC (101 MHz, CDCl3) 191.4, 154.9, 138.2,
132.6, 128.5, 128.5, 123.4, 41.1, 31.8, 25.9, 25.8.
a
]
D
22 10.3 (c 0.86 in CHCl3); Chiral HPLC (CHIRALPAK
IB column: (0.46 ꢂ 25 cm), 1 mL/min, 7% IPA: 93% Hexane; 210 nm
UV, 30 ꢀC) retention times: 11.7 (S) and 13.1 (R) minutes.
4.1.13. (E)-1-(4-(Dimethylamino)phenyl)-3-phenylprop-2-en-1-
one
This compound is known [22]. 1-(4-(Dimethylamino)phenyl)
ethan-1-one [28] (1.63 g, 10 mmol, 1 eq) was dissolved in a solution
of sodium methoxide (25 wt% in MeOH, 1.08 g, 5 mmol, 0.5 eq) and
MeOH (20 mL) and cooled to 0 ꢀC. Benzaldehyde (1.59 g, 15 mmol,
1.5 eq) in MeOH (5 mL) was added and the suspension was warmed
to 40 ꢀC. The resulting yellow solution was stirred for 48 h, then
quenched with HCl (0.25 M, 20 mL). The resulting yellow precipi-
tate was filtered and washed with aqueous methanol. The crude
solid was purified by recrystallization from hot ethanol, to give the
pure chalcone as a fluffy yellow solid, (884 mg, 3.52 mmol, 35%). Mp
168e170 ꢀC; dH (500 MHz, CDCl3) 8.05e7.96 (2H, m, ArH), 7.78 (1H,
d, J ¼ 15.6 Hz, ArH), 7.66e7.55 (3H, m, ArH), 7.43e7.35 (3H, m, ArH),
6.74e6.66 (2H, m, ArH), 3.07 (s, 6H)., 3.07 (6H, s, N(CH3)2); dC
8

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
4.1.17. rac-3-Cyclohexyl-1-phenylpropan-1-ol 25
This compound is known [32]. To a suspension of (E)-3-
cyclohexyl-1-phenylprop-2-en-1-one (215 mg, 1.0 mmol, 1 eq)
water (1 mL). The suspension was extracted with Et2O (2 ꢂ 2.5 mL),
the organic layers dried over MgSO4 and concentrated to give the
crude product as a white solid. The crude was purified by column
chromatography (10% EtOAc in petroleum ether) to give the pure
product as a white powder (110 mg, 0.51 mmol, 45%). TLC: 10%
EtOAc in petroleum ether, silica, Rf 0.16, KMnO4; Mp 68e70 ꢀC; dH
(300 MHz, CDCl3) 7.31e7.18 (5H, m, ArH), 3.45e3.31 (1H, m, CHOH),
2.91e2.78 (1H, m, CHCHH), 2.72e2.58 (1H, m, CHCHH), 1.89e1.60
(7H, m, CH2 and Cy), 1.37e0.97 (7H, m, OH and Cy); dC (75 MHz,
CDCl3) 142.4, 128.4, 128.4, 125.8, 75.6, 43.8, 36.0, 32.4, 29.2, 27.8,
26.5, 26.3, 26.2; Chiral HPLC (CHIRALPAK IB column:
(0.46 ꢂ 25 cm), 1 mL/min, 4% IPA: 96% Hexane; 210 nm UV, 30 ꢀC):
retention times: 8.3 and 13.3 min.
and Pd/C (5% w/w, 55 mg, 26 mmol, 2.5% Pd) in isopropanol (5 mL)
was added acetic acid (121 mg, 2.0 mmol, 2 eq) followed by sodium
borohydride (153 mg, 4.0 mmol, 4 eq), with vigorous effervescence.
The reaction mixture was stirred at rt for 2.5 h, then additional
sodium borohydride was added (75 mg, 2.0 mmol, 2 eq). The re-
action was stirred for an additional 2 h and then quenched slowly
with HCl (0.2 M, 2.5 mL). The resulting suspension was neutralised
with NaOH (2 M, ~1.5 mL) and filtered through Celite with iso-
propanol to remove Pd/C. The mixture was concentrated to remove
excess isopropanol and then the aqueous layer was extracted with
diethyl ether (3 ꢂ 10 mL), dried over Na2SO4 and concentrated to
give the product 25 as a white solid (214 mg, 0.98 mmol, 98%). dH
(300 MHz, CDCl3) 7.39e7.31 (4H, m, ArH), 7.31e7.26 (1H, m, ArH),
4.68e4.58 (1H, m, CHOH), 1.88e1.57 (8H, m, alkylH), 1.39e1.06 (6H,
m, alkylH), 0.93e0.79 (2H, m, AlkylH); dC (75 MHz, CDCl3) 162.3,
128.4, 127.5, 125.9, 75.07, 37.7, 36.5, 33.5, 33.36, 26.7, 26.3; Chiral
HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm),1 mL/min, 4% IPA: 96%
Hexane; 210 nm UV, 30 ꢀC): retention times: 7.4 (S) and 7.9 (R)
minutes.
4.1.21. rac-(E)-1-Cyclohexyl-3-phenylprop-2-en-1-ol
This compound is known [34]. To a suspension of (E)-1-
cyclohexyl-3-phenylprop-2-en-1-one (211 mg, 1.0 mmol, 1 eq)
and cerium trichloride heptahydrate (372 mg, 1.0 mmol, 1 eq) in
methanol (2 mL) was added sodium borohydride (43 mg, 1.1 mmol,
1 eq) at 0 ꢀC. The reaction was stirred for 1.5 h, quenched with
NH4Cl (sat., 5 mL), diluted with water (3 mL), and extracted with
diethyl ether (3 ꢂ 5 mL). The organic layers were dried over Na2SO4
and concentrated to give the unsaturated alcohol as a white solid
(168 mg, 0.78 mmol, 78%). dH (400 MHz, CDCl3) 7.40e7.22 (5H, m,
ArH), 6.55 (1H, d, J ¼ 15.9 Hz, ¼CHPh), 6.23 (1H, dd, J ¼ 7.2,
15.9 Hz, ¼CHCH), 4.02 (1H, br. s., CHOH), 1.92 (1H, d, J ¼ 12.0 Hz,
OH), 1.83e1.61 (4H, m, Cy), 1.60e1.42 (2H, m, Cy), 1.35e0.90 (5H, m,
Cy); dC (101 MHz, CDCl3) 136.8, 131.2, 131.1, 128.6, 127., 126.5, 77.6,
44.0, 28.9, 28.7, 26.5, 26.2, 26.1); Chiral HPLC (CHIRALPAK IB col-
umn: (0.46 ꢂ 25 cm), 1 mL/min, 4% IPA: 96% Hexane; 210 nm UV,
30 ꢀC): retention times: 9.9 and 14.4 min.
4.1.18. rac-(S)-3-Cyclohexyl-1-phenylpropan-1-ol 25
The asymmetric form of this compound has not been reported. A
degassed suspension of (E)-3-cyclohexyl-1-phenylprop-2-en-1-
one (107 mg, 0.5 mmol, 1 eq) and catalyst (S,S)-2 (5
mmol,
100:1 S/C) in FA/TEA (5:2, 0.5 mL) and methanol (0.5 mL) was
stirred at 40 ꢀC for 3 h. On completion the reaction mixture was
homogenous. The mixture was diluted with diethyl ether (2 mL)
and quenched with NaHCO3 (sat., 2 mL), the aqueous layer was
extracted further with ether (2 ꢂ 2 mL) and the organic extracts
dried over Na2SO4 and passed through a silica plug to yield the
product. Total conversion 100%. Product obtained as a grey solid
(55 mg, 0.25 mmol, 50%) containing a mixture of saturated and
unsaturated alcohols, ratio 98 : 2 by 1H NMR. Major product ee 97%.
4.1.22. (E)-1-Cyclohexyl-3-phenylprop-2-en-1-ol and 1-cyclohexyl-
3-phenylpropan-1-ol 26
The asymmetric form of these compound have not been re-
ported. A degassed suspension of (E)-1-cyclohexyl-3-phenylprop-
[a]
24 -10.9 (c 0.245 in CHCl3); Chiral HPLC (CHIRALPAK IB column:
D
(0.46 ꢂ 25 cm), 1 mL/min, 4% IPA: 96% Hexane; 210 nm UV, 30 ꢀC):
retention times: 7.5 (S)-saturated and 7.9 (R)-saturated minutes.
2-en-1-one (97 mg, 0.45 mmol, 1 eq) and catalyst (S,S)-2 (5 mmol,
100:1 S/C) in FA/TEA (5:2, 0.5 mL) and methanol (0.5 mL) was
stirred at 40 ꢀC for 2.5 h. On completion the reaction mixture was
homogenous. The mixture was diluted with diethyl ether (2 mL)
and quenched with NaHCO3 (sat., 2 mL), the aqueous layer was
extracted further with ether (2 ꢂ 2 mL) and the organic extracts
dried over Na2SO4 and passed through a silica plug to yield the
product. Conversion 82%. Product obtained as a clear oil (78 mg,
0.36 mmol, 80%) containing a mixture of saturated and unsaturated
alcohols, ratio 10 : 90 by 1H NMR. Major (1,2-) product ee 59%,
minor (1,4-) product ee 36%. With (E)-1-cyclohexyl-3-phenylprop-
2-en-1-one (108 mg, 0.50 mmol) and catalyst (R,R)-3; 23 h reaction
time, conversion 100%. Product obtained as a white solid (111 mg,
0.51 mmol, 100%) containing a mixture of saturated and unsatu-
rated alcohols, ratio 59 : 41 by 1H NMR. Major product ee 21%,
minor product ee 76%. Aqueous reduction: Sodium formate
(170 mg, 2.5 mmol, 5 eq), (E)-1-cyclohexyl-3-phenylprop-2-en-1-
4.1.19. (E)-1-Cyclohexyl-3-phenylprop-2-en-1-one
This compound is known [33]. Sodium methoxide solution (25%
w/w, 5.96 g, 27.6 mmol, 1 eq) was diluted to 50 mL with methanol
and added to cyclohexylmethyl ketone (3.33 g, 26.4 mmol, 1 eq).
The mixture was cooled to 0 ꢀC and a solution of benzaldehyde
(2.81 g, 26,5 mmol, 1 eq) in methanol (15 mL) was added. The re-
action mixture was warmed to 40 ꢀC and stirred for 3 days. The
reaction was quenched with 0.25 M HCl (100 mL) and extracted
with diethyl ether (4 ꢂ 100 mL), the organic layers were dried and
concentrated to give the crude product as a yellow oil that solidifies
slowly on standing. The oil was dissolved in ~150 mL of methanol
and cooled to ꢁ78 ꢀC, the resulting precipitate was filtered and
washed once with cold methanol and dried to give the purified
product as a white solid (2.78 g, 13.0 mmol, 49%). Mp 54e58 ꢀC; dH
(250 MHz, CDCl3) 7.60 (1H, d, J ¼ 15.9 Hz, PhCH ¼ ), 7.60e7.52 (2H,
m, o-Ph), 7.45e7.30 (3H, m, m,p-Ph), 6.82 (1H, d, J ¼ 15.9 Hz,
COCH ¼ ), 2.73e2.59 (1H, m, CHCO), 2.01e1.77 (4H, m, alkylH),
1.77e1.65 (1H, m, alkylH), 1.55e1.14 (5H, m, alkylH).
one (110 mg, 0.51 mmol, 1 eq) and (R,R)-3 (3.3 mg, 5 mmol, 1%)
were suspended in water (1 mL) and methanol (0.5 mL) and heated
to 60 ꢀC. The solids melt and form a brown oil on top of the aqueous
phase. The mixture was stirred vigorously for 19 h before being
cooled to rt and diluted with diethyl ether (2 mL). The organic layer
was separated, then concentrated directly onto silica. Elution
through a short silica plug with 40% diethyl ether in petroleum
ether gave the product in 98% conversion as a clear oil (103 mg,
0.47 mmol, 92%) containing a mixture of saturated and unsaturated
alcohols, ratio 68 : 32 by 1H NMR. Major product ee 49%, minor
product ee 82%.
4.1.20. rac-1-Cyclohexyl-3-phenylpropan-1-ol 26
This compound is known [32]. To a solution of cyclohexane
carboxaldehyde (128 mg, 1.14 mmol, 1 eq) in THF (1 mL) was added
phenethyl magnesium chloride (1 M in THF, 1 mL, 1.0 mmol, 1 eq)
at ꢁ78 ꢀC. The reaction was stirred for 2.75 h while gradually
warming to ~0 ꢀC, then quenched with NH4Cl (sat. soln, 2 mL) and
9

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
4.1.23. 2-(1-Hydroxycyclohexyl)-1-phenylethan-1-one
Chiralpak IA column with 97% Hexane, 3% IPA, 0.5 mL/min, 22.8 and
26.9 min.
This compound is known [35]. TiCl4 (1 M in DCM, 12 mL,
12 mmol, 1.2 eq) was added dropwise at 0 ꢀC to a solution of
cyclohexanone (1.23 g, 12.5 mmol, 1.25 eq) in DCM (20 mL) and
stirred for 25 min. To the resulting yellow suspension was added
dropwise 1-phenyl-1-(trimethylsiloxy)ethylene (1.94 g, 10 mmol,
1.0 eq). The resulting orange suspension was allowed to warm to rt
and stirred for 24 h before being quenched with water (35 mL). The
mixture was extracted with DCM (2 ꢂ 20 mL), washed with brine
(10 mL) and filtered through a plug of silica gel (~4 g) with DCM to
give the crude product as a thick yellow oil that crystallises on
standing (2.69 g).The crude was dissolved in hot methanol,
concentrated to a thick oil and then crystallised by addition of
hexane (~10 mL) to give the pure product as a white crystalline
solid (0.95 g, 4.3 mmol, 43%). A second crop was isolated by con-
centration of the mother liquors and addition of hexane to give
white plates (0.20 g, 0.91 mmol, 9%). Combined yield (1.15 g,
5.2 mmol, 52%). TLC: 20% EtOAc in petroleum ether, silica, Rf ¼ 0.2,
UV; Mp 78e79 ꢀC; dH (400 MHz, CDCl3) 8.00e7.91 (2H, m, o-Ph),
7.63e7.56 (1H, m, p-Ph), 7.52e7.45 (2H, m, m-Ph), 3.97 (1H, s, OH),
3.12 (2H, s, COCH2), 1.83e1.65 (5H, m, Cy), 1.58 (1H, dd, J ¼ 2.9,
6.2 Hz, Cy), 1.52e1.38 (4H, m, Cy), 1.36e1.23 (1H, m, Cy); dC
(101 MHz, CDCl3) 202.0, 137.5, 133.6, 128.7, 128.11, 71.0, 47.7, 37.8,
25.8, 22.0.
4.1.26. rac-2-Cyclohexylidene-1-phenylethan-1-ol
This compound has been reported as part of a mixture of iso-
mers but has not been fully characterised [38]. To a suspension of 2-
cyclohexylidene-1-phenylethan-1-one (101 mg, 0.5 mmol, 1 eq)
and cerium trichloride heptahydrate (185 mg, 0.5 mmol, 1 eq) in
methanol (1 mL) was added sodium borohydride (29 mg, 0.8 mmol,
1.5 eq) at 0 ꢀC. The reaction was stirred for 2 h and quenched with
NH4Cl (sat., 0.5 mL), diluted with water (0.5 mL) and extracted with
diethyl ether (3 ꢂ 2 mL). The organic extracts were dried over
Na2SO4 and concentrated to give the product as a clear oil (103 mg,
0.50 mmol, 100%). The crude product was purified by column
chromatography on silica gel (2.6 g) with 10% diethyl ether in pe-
troleum ether as eluent, to yield the pure product as a clear oil
(65 mg, 0.32 mmol, 64%). The pure product decomposes at room
temperature within a few days. HRMS: found (ESI): [M þ H]þ,
225.1251. (C14H18NaO requires 225.1250); nmax: 3374 (OH), 2928
(CH), 2854 (CH), 1447 (CO), cmꢁ1
; dH (400 MHz, CDCl3) 7.42e7.29
(4H, m, Ph), 7.27e7.19 (1H, m, Ph), 5.54e5.45 (1H, m, CHOH), 5.33
(1H, d, J ¼ 8.8 Hz, ¼CH), 2.41e2.21 (2H, m, Cy), 2.14e2.04 (2H, m,
Cy), 1.95 (1H, br. s., OH), 1.63e1.50 (6H, m, Cy); dC (101 MHz, CDCl3)
144.5, 143.1, 128.5, 127.2, 125.8, 124.5, 69.8, 37.1, 29.4, 28.4, 27.9,
26.7; m/z (ESI): 225.1 ([M þ Na]þ), 185.1 (30%, [M ꢁ OH]þ). Chiral
HPLC/GC not obtained, suitable conditions for separation were not
found before the compound decomposed.
4.1.24. 2-Cyclohexylidene-1-phenylethan-1-one
This compound is known [36]. 2-(1-Hydroxycyclohexyl)-1-
phenylethan-1-one (868 mg, 3.9 mmol, 1 eq) and p-toluene-
sulfonic acid monohydrate (613 mg, 3.2 mmol, 0.8 eq) were sus-
pended in toluene (8 mL) and stirred at 40 ꢀC for 4.5 h, as monitored
by TLC. Na2SO4 (~0.5 g) and petroleum ether (5 mL) were added,
and the resulting suspension filtered through a silica plug (~1 g)
with 10% EtOAc in petroleum ether to give the crude product as a
yellow oil. The crude product was purified by column chromatog-
raphy (6% Et2O in pentane) to give the pure product as a pale yellow
oil (616 mg, 2.93 mmol, 77%). TLC: 10% EtOAc/Pet ether, silica, Rf
0.38, UV; dH (300 MHz, CDCl3) 8.00e7.89 (2H, m, o-Ph), 7.57e7.48
(1H, m, p-Ph), 7.48e7.40 (2H, m, m-Ph), 6.60 (1H, s, ¼CH),
2.81e2.72 (2H, m, Cy), 2.35e2.28 (2H, m, Cy),1.77e1.61 (6H, m, Cy);
dC (75 MHz, CDCl3) 192.4, 162.8, 132.3, 128.5, 128.4, 128.4, 118.8,
38.4, 30.7, 28.9, 28.0, 26.3.
4.1.27. (S)-2-Cyclohexyl-1-phenylethan-1-ol 27 and (S)-2-
cyclohexylidene-1-phenylethan-1-ol
A
suspension of 2-cyclohexylidene-1-phenylethan-1-one
(95 mg, 0.47 mmol, eq) and catalyst (S,S)-2 (3.1 mg,
1
0.005 mmol, 1%) in FA/TEA (5:2, 0.5 mL) and MeOH (0.5 mL) was
stirred at 40 ꢀC for 22.5 h. The mixture was diluted with diethyl
ether (2 mL) and quenched with NaHCO3 (sat., 2 mL), the aqueous
layer was extracted further with ether (2 ꢂ 2 mL) and the organic
extracts dried over Na2SO4 and passed through a silica plug to yield
the crude product as an off white solid (86 mg, 0.42 mmol, 89%).
The product was obtained in full conversion as a mixture of satu-
rated and unsaturated alcohols, ratio 94:6 by 1H NMR. Major
product 55% ee as calculated by HPLC. Purification by chromatog-
raphy on silica (8% Et2O/Petroleum ether) separated the unsatu-
rated alcohol and gave the purified product as a white solid (60 mg,
0.29 mmol, 62%). Spectroscopic data for asymmetric product is
4.1.25. rac-2-Cyclohexyl-1-phenylethan-1-ol 27
This compound is known [37]. To
cyclohexylidene-1-phenylethan-1-one (215 mg, 1.08 mmol, 1 eq)
and Pd/C (5% w/w, 55 mg, 26 mol, 2.5% Pd) in isopropanol (5 mL)
a suspension of 2-
consistent with the prepared standards. Mp 52 ꢀC; [
0.245 in CHCl3); Chiral HPLC: Chiralpak IA column with 97% Hex-
a]
26 þ50.4, R (c
D
m
was added acetic acid (121 mg, 2.0 mmol, 2 eq) followed by sodium
borohydride (153 mg, 4.0 mmol, 4 eq), with vigorous effervescence.
The reaction mixture was stirred at rt for 2.5 h, then additional
sodium borohydride was added (75 mg, 2.0 mmol, 2 eq). The re-
action was stirred for an additional 2 h and then quenched slowly
with HCl (0.2 M, 2.5 mL). The resulting suspension was neutralised
with NaOH (2 M, ~1.5 mL) and filtered through Celite with iso-
propanol to remove Pd/C. The mixture was concentrated to remove
excess isopropanol and then the aqueous layer was extracted with
diethyl ether (3 ꢂ 10 mL), dried over Na2SO4 and concentrated to
give the product 27 as a white solid (214 mg, 1.0 mmol, 93%). Mp
57e59 ꢀC; HRMS: found (ESI): [M þ Na]þ, 227.1406 (C14H20NaO
requires 227.1411); nmax: 3240 (OH), 2920 (CH), 2847 (CH), 1446
ane, 3% IPA, 0.5 mL/min, 22.8 and 26.9 min. 55% ee (27).
4.1.28. Section on ATH alkene/alkynes.The results on the reduction
of the TMS-containing substrates are in the supporting information
4.1.28.1. General procedure for asymmetric transfer hydrogenation
(procedure 1). To a degassed solution of substrate and catalyst was
added 5:2 FA:TEA. The concentration of the reaction was set at
1.0 M. The reaction mixture was heated to 40 ꢀC for 26 h. The re-
action was monitored by TLC and/or HPLC. Once completed, the
mixture was quenched with NaHCO3 (sat. soln.) and extracted with
EtOAc. The organic layers were combined, dried with MgSO4 and
concentrated in vacuo to give the crude product. Where appropriate
further purified was undertaken.
(CeO), 1003, 697 (monosubsituted Ph) cmꢁ1
; dH (400 MHz, CDCl3)
7.38e7.31 (4H, m, Ph), 7.31e7.24 (1H, m, Ph), 4.85 4.73 (1H, m,
CHOH), 1.91e1.59 (6H, m, CHH þ Cy), 1.58e1.48 (2H, m, OH þ CHH),
1.48e1.36 (1H, m, CH), 1.31e1.08 (3H, m), 1.04e0.88 (2H, m); dC
(126 MHz, CDCl3) 145.4, 128.5, 127.5, 125.8, 72.1, 47.1, 34.3, 34.0,
32.9, 26.6, 26.3, 26.2; m/z (ESI): 227.1 ([M þ Na]þ); Chiral HPLC;
4.1.28.2. General n-BuLi procedure for racemic alcohol synthesis
(procedure 2). A degassed solution of acetylene in THF (anhyd.) was
cooled to ꢁ78 ꢀC. Once cooled, n-butylithium was added dropwise,
the reaction mixture was left to stir at ꢁ78 ꢀC for 30 min. Aldehyde
was added dropwise and the reaction mixture was left to stir
10

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
at ꢁ78 ꢀC. After 1 h, the reaction mixture was allowed to warm to
r.t. The reaction was monitored by TLC. Once completed, the reac-
tion was quenched with NH4Cl (sat. soln) and extracted with EtOAc.
The organic layers were combined, dried with MgSO4 and
concentrated in vacuo to give the crude product. The crude product
was further purified using column chromatography to give the
desired product.
Compound 29 was prepared using General Procedure 2. Phenyl-
acetylene (0.2247 g, 2.63 mmol, 1.20 eq.) was dissolved in THF
(anhyd., 5 mL) and n-butyllithium (1.6 M in hexanes, 1.71 mL,
2.75 mmol, 1.25 eq.) was added dropwise. After 30 min, E-cinna-
maldehyde (0.290 g, 2.20 mmol, 1.00 eq.) was added. The crude was
purified using column chromatography (SiO2; Rf: 0.30; (9.1) pe-
troleum/EtOAc) to give the desired product 29 as a yellow oil
(0.426 g, 1.83 mmol, 83%). dH (400 MHz, CDCl3) 7.43e7.34 (4H m,
ArH), 7.30e7.16 (6H, m, ArH), 6.84 (1H, d, J ¼ 15.9 Hz, CH]
CHCHOH), 6.39 (1H, dd, J ¼ 15.8, 6.0 Hz, CH]CHCHOH), 5.28 (1H, d,
J ¼ 6.0 Hz, CHOH), 2.15 (1H, s, OH); dC (101 MHz, CDCl3) 136.1, 133.0,
132.1, 131.8, 129.1, 128.7, 128.4, 128.2, 128.1, 126.9, 122.4, 87.9, 86.5;
LCMS (ESI) m/z: [MþNa]þ 255.10, 257.10; IR (v): 3400, 3073, 3023,
2212, 1596, 1489, 1254, 1091, 1014, 966, 753, 687 cmꢁ1; Chiral HPLC
(CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1.0 mL/min, IPA:Hexane
(20:80); 250 nm UV, 30 ꢀC): retention times: 6.31 (R)-unsaturated
and 12.81 (S)-unsaturated mins. Data matched that reported.
4.1.28.3. General procedure for MnO2 oxidation for ketone synthesis
(procedure 3). Alcohol and activated MnO2 were dissolved in DCM
(anhyd.) and stirred at r.t. The reaction was monitored using TLC.
When completed, the reaction mixture was diluted with DCM and
filtered through a Celite pad and concentrated in vacuo to give the
crude product.
4.1.29. (E)-1,5-Diphenylpent-1-en-4-yn-3-one
N-Methoxy-N-methylcinnamide was prepared following the
published procedure [39]. This compound is known and has been
fully characterised [40]. Phenylacetylene (1.34 g, 13.1 mmol, 1.20
eq.) was dissolved in THF (anhyd., 25.0 mL) and cooled to ꢁ78 ꢀC. n-
butyllithium (1.6 M in hexanes, 8.19 mL, 13.1 mmol, 1.20 eq.) was
added dropwise and the mixture was left to stir for 30 min
at ꢁ78 ꢀC. Pre-cooled to ꢁ78 ꢀC, N,O-methyoxy-N-methyl-
cinnamide (2.092 g, 10.9 mmol 1.00 eq.) in THF (anhyd. 8 mL) was
added to the reaction via cannula transfer. The reaction mixture
was stirred for 1 h at ꢁ78 ꢀC before being warmed to r.t. The re-
action was monitored using TLC until starting material had dis-
appeared. The reaction mixture was quenched with NH4Cl (sat.
soln, 10 mL) and extracted with EtOAc (3 ꢂ 10 mL). The organic
layers were combined, dried with MgSO4, filtered and concentrated
in vacuo. The crude product was purified by column chromatog-
raphy (SiO2, Rf: 0.60 (9:1) hexanes/EtOAc) to give the desired
product as a yellow solid (2.125 g, 9.12 mmol, 84%). dH (400 MHz,
CDCl3) 7.92 (1H, d, J ¼ 16.1 Hz, CH]CHCO), 7.70e7.57 (4H, m, ArH),
7.53e7.37 (6H, m, ArH), 6.88 (1H, d, J ¼ 16.1 Hz, CH]CHCO); dC
(101 MHz, CDCl3) 178.3, 148.3, 135.0, 132.9, 131.2, 130.6, 129.1, 128.7,
128.7, 128.6, 120.2, 91.1, 86.6; LCMS (ESI) m/z: [MþNa]þ 255.09; IR
(v): 3061, 3053, 2922, 2854, 2212,1627,1609,1488,1445,1288,1173,
971, 909, 757, 673, 579, 533, 502, 482 cmꢁ1; Mp: 67.4e69.0 ꢀC;
Chiral HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm); 1.0 mL/min,
IPA:Hexane (20:80); 250 nm UV, 30 ꢀC): retention times: 5.76
(ketone) mins. Data matched that reported.
4.1.32. 1,5-Diphenylpent-1-yn-3-one
This compound is known and has been fully characterised [43].
This compound was prepared using General Procedure 3 from
compound 28 (0.200 g, 0.85 mmol, 1.00 eq.) and activated MnO2
(1.10 g, 12.7 mmol, 15.0 eq.) to yield the desired product as a yellow
solid (0.068 g, 0.30 mmol, 35%). Also contains side product impurity
(25% NMR integration). dH (400 MHz, CDCl3) 7.51e7.46 (2H, m, ArH),
7.41e7.36 (1H, m, ArH), 7.31 (2H, dd, J ¼ 8.2, 6.7 Hz, ArH), 7.26e7.19
(2H, m, ArH), 7.19e7.11 (3H, m, ArH), 3.03e2.91 (4H, m, CH2); dC
(101 MHz, CDCl3) 188.1, 140.3, 133.1, 130.8, 129.8, 128.7, 128.6, 128.0,
125.8, 91.1, 87.6, 47.0, 30.0; LCMS (ESI) m/z: [MþNa]þ 257.20; IR (v):
3062, 2924, 2202, 1700, 1604, 1490, 1214, 1092, 1020, 756, 689,
617 cmꢁ1; Chiral HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm),
1.0 mL/min, IPA:Hexane (20:80); 250 nm UV, 30 ꢀC): retention
times: 5.00 (ketone) mins. Data matched that reported.
4.1.33. (R)-1,5-Diphenylpent-1-yn-3-ol 28 and (R,E)-1,5-
diphenylpent-1-en-4-yn-3-ol 29
Both compounds are known and have been fully characterised
[44,45]. The ATH was conducted using General Procedure 1. (E)-1,5-
Diphenylpent-1-en-4-yn-3-one (0.1164 g, 0.50 mmol, 1.00 eq.),
(R,R)-2 (3.10 mg, 5.0
mmol, 0.01 eq.) and MeOH (0.5 mL) were
reacted for 25 h at 40 ꢀC. The crude product was purified using
column chromatography (SiO2; (9:1) petroleum/EtOAc) to give a
mixture of both alcohol products 28 and 29 (0.114 g, 0.23 mmol,
46%). The product was obtained as a colourless oil with an NMR
ratio of 83:17 of the major (Sat. OH) 28 and minor (Unsat. OH) 29.
Enantiomeric excess and conversion were determined by Chiral
HPLC analysis (CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1.0 mL/min,
IPA:Hexane (10:90); 250 nm UV, 30 ꢀC): retention times: retention
times: 7.66 (R)-saturated, 12.94 (S)-saturated, 9.70 (R)-unsaturated
and 24.26 (S)-unsaturated mins. Conversion was determined to be
100% and the major and minor products was determined to be 98%
ee (28) and 86% ee (29) respectively.
4.1.30. rac-1,5-Diphenylpent-1-yn-3-ol 28
This compound is known and has been fully characterised [41].
Compound 28 was prepared using General Procedure 2. Phenyl-
acetylene (0.457 g, 4.48 mmol, 1.20 eq.) was dissolved in THF
(anhyd., 5.00 mL) and n-butyllithium (1.6 M in hexanes, 2.91 mL,
4.66 mmol, 1.25 eq.) was added dropwise. After 30 min, 3-
phenylpropanal (0.500 g, 3.73 mmol, 1.00 eq.) was added. The
crude product was purified using column chromatography (SiO2;
Rf: 0.60; (4.1) hexanes/EtOAc) to give the desired product 28 as a
yellow oil (0.6083 g, 2.57 mmol, 69%). dH (300 MHz, CDCl3)
7.42e7.35 (2H, m, ArH), 7.29e7.11 (8H, m, ArH), 4.60 (1H, t,
J ¼ 6.6 Hz, CHOH), 2.86e2.77 (2H, m, CH2CH2Ph), 2.17e2.00 (2H, m,
CH2CH2Ph), 1.89 (1H, s, OH); dC (75 MHz, CDCl3) 141.3, 131.7, 128.6,
128.5, 128.4, 128.3, 126.0, 122.6, 89.8, 85.3, 62.3, 39.3, 31.5; LCMS
(ESI) m/z: [MþNa]þ 259.20; IR (v): 3321, 3026, 2927, 2862, 1602,
1490, 1454, 1041, 1009, 755, 692 cmꢁ1; Chiral HPLC (CHIRALPAK IB
column (0.46 ꢂ 25 cm); 1.0 mL/min IPA:Hexane (20:80), UV
250 nm, 25 ꢀC). Retention times 5.52 (R)-unsaturated and 7.84 (S)-
unsaturated mins. Data matched that reported.
4.1.34. (E)-1-Phenyl-5-(triisopropylsilyl)pent-1-en-4-yn-3-one
This compound is known and fully characterised [46]. (E)-1-
Phenyl-5-(triisopropylsilyl)pent-1-en-4-yn-3-one was prepared
using General Procedure 3 from racemic 31 (0.501 g, 1.60 mmol,
1.00 eq.) and MnO2 (0.970 g, 11.2 mmol, 7.00 eq.). The crude was
further purified using column chromatography (SiO2; Rf: 0.75
(95:5) petroleum/EtOAc) to yield the desired product as a yellow oil
(0.4103 g, 1.31 mmol, 82%). dH (400 MHz, CDCl3) 7.96 (1H, d,
J ¼ 16.1 Hz, CH]CHCO), 7.59e7.54 (2H, m, ArH), 7.50e7.41 (3H, m,
ArH), 6.82 (1H, d, J ¼ 16.1 Hz, CH]CHCO), 1.17 (21H, m, Si(iPr)3); dC
(101 MHz, CDCl3) 178.1, 149.0, 134.1, 131.2, 129.1, 128.7, 128.6, 102.6,
96.2, 18.6, 11.1; HRMS (ESI) m/z: [MþNa]þ calcd for C20H28NaOSi
4.1.31. rac-(E)-1,5-Diphenylpent-1-en-4-yn-3-ol 29
This compound is known and has been fully characterised [42].
11

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
335.1802, found 335.1805; IR (v): 3060, 3012, 2891, 2154, 1628,
1449, 1228, 1196, 1120, 1070, 975, 869, 761, 676, 574 cmꢁ1; Chiral
HPLC (CHIRALPAK ODH column: (0.46 ꢂ 25 cm), 0.5 mL/min,
IPA:Hexane (5:95); 254 nm UV, 30 ꢀC): retention times: 8.44 (ke-
tone) mins. Data matched that reported.
4.1.38. (R)-5-Phenyl-1-(triisopropylsilyl)pent-1-yn-3-ol 30 and
(R,E)-1-phenyl-5-(triisopropylsilyl)pent-1-en-4-yn-3-ol 31
Compound 30 is known and fully characterised [49]. The ATH
was conducted using General Procedure 1. Substrate (0.119 g,
0.38 mmol, 1.00 eq.), (R,R)-2 (2.4 mg, 3.8 mmol, 0.01 eq.) and MeOH
(0.5 mL) were reacted for 26 h at 40 ꢀC. The crude product was
purified using column chromatography (SiO2; (9:1) petroleum/
EtOAc) to give a mixture of both alcohol products 30 and 31 (0.115 g,
0.36 mmol, 95%). The product was obtained as a pale-yellow oil
with an NMR ratio of 69:31 of the major (Sat. OH) 30 and minor
(Unsat. OH) 31 product respectively. Enantiomeric excess and
conversion determined by (CHIRALPAK ODH column:
(0.46 ꢂ 25 cm), 0.5 mL/min, IPA:Hexane (5:95); 254 nm UV, 30 ꢀC):
retention times: 15.3 (S)-unsaturated, 23.5 (R)-unsaturated and
30.2 (R)-saturated mins. Conversion was determined to be ca. 81%
(HPLC) and the ee of the major and minor product was determined
to be >99% (30) and 95% (31) respectively.
4.1.35. rac-5-Phenyl-1-(triisopropylsilyl)pent-1-yn-3-ol 30
This compound is known and fully characterised [47]. Com-
pound 30 was prepared using General Procedure 2. (Triisopro-
pylsilyl)acetylene (0.300 g, 1.64 mmol, 1.00 eq.) was dissolved in
THF (anhyd. 3.00 mL) and n-butyllithium (2.5 M in hexanes,
0.656 mL,1.64 mmol,1.00 eq.) was added dropwise. After 30 min, 3-
phenylpropanal (0.221 g, 1.64 mmol, 1.00 eq.) was added. The crude
product was purified using column chromatography (SiO2; Rf: 0.70
(20:1) petroleum/EtOAc) to give the desired product 30 as a col-
ourless oil (0.4422 g, 1.41 mmol, 86%). dH (400 MHz, CDCl3)
7.25e7.11 (5H, m, ArH), 4.38e4.30 (1H, m, CH(OH)), 2.75 (2H, t,
J ¼ 7.9 Hz, CH2CH2Ph), 2.02e1.89 (2H, m, CH2CH2Ph), 1.71 (1H, d,
J ¼ 5.1 Hz, OH), 1.04e0.96 (21H, m, Si(iPr)3); dC (101 MHz, CDCl3)
141.4, 128.5, 128.5, 126.0, 108.5, 86.9, 62.4, 39.6, 31.5, 18.6, 11.2;
HRMS (ESI) m/z: [MþNa]þ calcd for C20H32NaOSi 339.2115, found
339.2110; IR (v): 3325, 3085, 2941, 2864, 2329, 2170, 1604, 1495,
4.1.39. (E)-5-(4-Methoxyphenyl)-1-phenylpent-1-en-4-yn-3-one
Synthetic route 1: This compound is novel. Ethynyl-4-
methoxybenzene (0.153 g, 1.15 mmol, 1.10 eq.) was dissolved in
THF (anhyd. 6.0 mL) and cooled to ꢁ78 ꢀC. n-butyllithium (1.6 M in
hexanes, 2.60 mL, 4.16 mmol, 1.10 eq.) was added dropwise and the
mixture was left to stir for 30 min at ꢁ78 ꢀC. Pre-cooled to ꢁ78 ꢀC,
N,O-methyoxy-N-methylcinnamide (0.200 g, 1.05 mmol 1.00 eq.) in
THF (anhyd. 5 mL) was added to the reaction via cannula transfer.
The reaction mixture was stirred for 1 h at ꢁ78 ꢀC before being
warmed to r.t. The reaction was monitored using TLC until starting
material had disappeared. The reaction mixture was quenched with
NH4Cl (sat. soln, 3 mL) and extracted with EtOAc (3 ꢂ 3 mL). The
1457, 1383, 1366, 1212, 1045, 997, 882, 810, 746, 698, 665 cmꢁ1
;
Chiral HPLC (CHIRALPAK ODH column: (0.46 ꢂ 25 cm), 0.5 mL/min,
IPA:Hexane (5:95); 254 nm UV, 30 ꢀC): retention times: 14.2 (S)-
saturated and 28.0 (R)-saturated mins. Data matched that reported.
4.1.36. rac-(E)-1-Phenyl-5-(triisopropylsilyl)pent-1-en-4-yn-3-ol
31
organic layers were combined, dried with MgSO4,
and
filtered
This compound is known and fully characterised [48]. Com-
pound 31 was prepared using General Procedure 2. (Triisopro-
pylsilyl)acetylene (1.06 g, 5.30 mmol, 1.10 eq.) was dissolved in THF
(anhyd. 6.0 mL) and n-butyllithium (2.5 M in hexanes, 2.32 mL,
5.67 mmol, 1.10 eq.) was added dropwise. After 30 min E-cinna-
maldehyde (0.70 g, 5.30 mmol, 1.00 eq.) was added. The crude
product was purified using column chromatography (SiO2; Rf: 0.45
(9:1) petroleum/EtOAc) to give the desired product 31 as a pale-
yellow oil (0.591 g, 2.04 mmol, 35%); dH (300 MHz, CDCl3)
7.33e7.14 (5H, m, ArH), 6.77 (1H, dd, J ¼ 15.8, 1.5 Hz, CH]
CHCH(OH)), 6.22 (1H, dd, J ¼ 15.8, 5.6 Hz, CH]CHCH(OH)),
5.04e4.91 (1H, m, CHCO), 1.85 (1H, d, J ¼ 6.7 Hz, OH), 1.01e0.98
(21H, m, Si(iPr)3). dC (75 MHz, CDCl3) 162.3, 132.1, 128.6, 128.1, 12.1,
126.8, 106.1, 87.9, 63.4, 18.6, 11.2. HRMS (ESI) m/z: [MþNa]þ calcd
for C20H30NaOSi 337.1958, found 337.1957. IR (v): 3303, 3062, 3027,
2864, 2164, 2045, 1669, 1462, 1244, 965, 882, 673, 459 cmꢁ1 Chiral
HPLC (CHIRALPAK ODH column: (0.46 ꢂ 25 cm), 0.5 mL/min,
IPA:Hexane (5:95); 254 nm UV, 30 ꢀC): retention times: 14.7 (S)-
unsaturated and 22.1 (R)-unsaturated mins. Data matched that
reported.
concentrated in vacuo. The crude product was purified by column
chromatography (SiO2; Rf: 0.60 (9:1) hexanes/EtOAc) to give the
desired product as a yellow oil (0.1261 g, 0.48 mmol, 48%).
Synthetic route 2: (E)-5-(4-Methoxyphenyl)-1-phenylpent-1-
en-4-yn-3-one was prepared using General Procedure 3 from
compound 33 (0.6088 g, 2.31 mmol, 1.00 eq.) and MnO2 (1.403 g,
16.1 mmol, 7.00 eq.). The crude product was further purified using
column chromatography (SiO2; Rf: 0.55 (9:1) petroleum/EtOAc) to
yield the desired product as a yellow solid (0.6052 g, 1.80 mmol,
78%). dH (400 MHz, CDCl3) 7.89 (1H, d, J ¼ 16.1 Hz, CH¼CHPh), 7.60
(4H, dt, J ¼ 7.4, 4.0 Hz, ArH), 7.48e7.38 (3H, m, ArH), 6.96e6.90 (2H,
m, ArH), 6.86 (1H, d, J ¼ 16.1 Hz, CH¼CHPh), 3.85 (3H, s, OMe); dC
(101 MHz, CDCl3) 178.3, 161.6, 147.7, 135.0, 134.2, 131.1, 129.1, 128.7,
114.4, 112.0, 92.7, 86.6, 55.5; HRMS (ESI) m/z: [MþNa]þ calcd for
C
18H14NaO2 285.0886, found 285.0885; IR 3073, 3024, 2847, 2176,
1645, 1591, 1507, 1447, 1253, 1163, 1095, 1018, 972, 828, 755, 690,
537 cmꢁ1; Mp 142.2 ꢀC; Chiral HPLC (CHIRALPAK IB column:
(0.46 ꢂ 25 cm),1.0 mL/min, IPA:Hexane (10:90); 250 nm UV, 30 ꢀC):
retention times: 9.83 (ketone) mins.
4.1.40. rac-1-(4-Methoxyphenyl)-5-phenylpent-1-yn-3-ol 32
4.1.37. 5-Phenyl-1-(triisopropylsilyl)pent-1-yn-3-one
This compound is known and fully characterised [50]. Com-
pound 32 was prepared using General Procedure 2. 1-Ethynyl-4-
methoxybenzene (0.216 g, 1.64 mmol, 1.10 eq.) was dissolved in
THF (anhyd. 5.0 mL) and n-butyllithium (1.6 M in hexanes, 1.03 mL,
1.64 mmol, 1.10 eq.) was added dropwise. After 30 min 3-
phenylpropanal (0.200 g, 1.49 mmol, 1.00 eq.) was added. The
crude was purified using column chromatography (SiO2; Rf: 0.75
(4:1) petroleum/EtOAc) to give the desired product 32 as a yellow
oil (0.3122 g, 1.18 mmol, 79%). dH (400 MHz, CDCl3) 7.43e7.34 (2H,
m, ArH), 7.34e7.15 (5H, m, ArH), 6.89e6.79 (2H, m, ArH), 4.58 (1H, t,
J ¼ 6.5 Hz, CHOH), 3.81 (3H, s, OMe), 2.86 (2H, t, J ¼ 7.8 Hz,
CH2CH2Ph), 2.17e2.06 (2H, m, CH2CH2Ph), 1.91 (1H, s, OH); dC
(101 MHz, CDCl3) 159.8, 141.4, 133.2, 128.6, 128.5, 126.0, 114.7, 114.0,
This compound is known and fully characterised [46]. This
compound was prepared using General Procedure 3 from com-
pound 31 (0.182 g, 0.57 mmol, 1.00 eq.) and MnO2 (0.353 g,
4.06 mmol, 7.00 eq.) to yield the desired product as a yellow oil
(0.1691 g, 0.52 mmol, 92%). dH (300 MHz, CDCl3) 7.33e7.26 (2H, m,
ArH), 7.24e7.17 (3H, m, ArH), 3.05e2.87 (4H, m, CH2CH2Ph),
1.11e1.08 (21H, m, Si(iPr)3); HRMS (ESI) m/z: [MþNa]þ calcd for
C
20H30NaOSi 337.1958, found 337.1957; IR (v): 3028, 2943, 2865,
2171, 1675, 1632, 1496, 1461, 1281, 1104, 1071, 997, 920, 882, 804,
749, 665, 585 cmꢁ1; Chiral HPLC (CHIRALPAK ODH column:
(0.46 ꢂ 25 cm), 0.5 mL/min, IPA:Hexane (5:95); 254 nm UV, 30 ꢀC):
retention times: 6.99 (ketone) mins. Data matched that reported.
12

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
88.4, 85.3, 62.4, 55.3, 39.4, 31.5; HRMS (ESI) m/z: [MþNa]þ calcd for
was prepared using General Procedure 3 from compound 35
(0.2407 g, 0.896 mmol, 1.00 eq.) and MnO2 (0.5390 g, 6.27 mmol,
7.00 eq.) to yield the desired product as a yellow solid (0.2146 g,
0.806 mmol, 90%).dH (400 MHz, CDCl3) 7.88 (1H, d, J ¼ 16.0 Hz,
COCH]CH), 7.68e7.56 (4H, m, ArH), 7.49e7.30 (5H, m, ArH), 6.86
(1H, d, J ¼ 16.2 Hz, COCH]CH); dC (101 MHz, CDCl3) 177.9, 148.5,
C
18H18NaO2 289.1196 found 289.1199; IR (v): 3346, 2911, 2216,1890,
1605, 1569, 1507, 1302, 1244, 1032, 825, 751, 697 cmꢁ1; Chiral HPLC
(CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1.0 mL/min, IPA:Hexane
(10:90); 250 nm UV, 30 ꢀC): retention times: 10.47 (R)-unsaturated
and 15.20 (S)-unsaturated mins. Data matched that reported.
137.0, 134.2, 134.0, 131.3, 129.2, 129.1, 128.8, 128.4, 118.7, 90.1, 87.4;
35
4.1.41. rac-(E)-5-(4-Methoxyphenyl)-1-phenylpent-1-en-4-yn-3-ol
33
HRMS (ESI) m/z: [MþNa]þ calcd for C17
H ClNaO 289.0391, found
11
289.0392; IR (v): 3029, 2894, 2883, 2210, 1672, 1627, 1485, 1447,
1342, 1176, 1085, 970, 862, 815, 690, 582 cmꢁ1; Mp 145.9 ꢀC; Chiral
HPLC (CHIRALPAK ADH column: (0.46 ꢂ 25 cm), 0.7 mL/min,
IPA:Hexane (10:90); 250 nm UV, 30 ꢀC): retention time: 15.48
(ketone) mins. Data matched that reported.
This compound is known and has been partially characterised
[51]. Compound 33 was prepared using General Procedure 2. 1-
Ethynyl-4-methoxybenzene (0.5497 g, 4.16 mmol, 1.10 eq.) was
dissolved in THF (anhyd. 7.0 mL) and n-butyllithium (1.6 M in
hexanes, 2.60 mL, 4.16 mmol, 1.10 eq.) was added dropwise. After
30 min E-cinnamaldehyde (0.500 g, 3.78 mmol, 1.00 eq.) was
added. The crude was purified using column chromatography
(SiO2; Rf: 0.50 (4:1) petroleum/EtOAc) to give the desired product
33 as a yellow oil (0.7203 g, 2.72 mmol, 72%). dH (400 MHz, CDCl3)
7.46e7.31 (4H, m, ArH), 7.31e7.26 (3H, m, ArH), 6.89e6.77 (3H, m,
ArH and CH¼CHPh), 6.38 (1H, dd, J ¼ 15.8, 6.0 Hz, CH¼CHPh), 5.27
(1H, d, J ¼ 5.2 Hz, CHOH), 3.74 (3H, s, OMe), 2.08 (1H, s, OH); dC
(101 MHz, CDCl3) 159.9, 138.1, 136.2, 133.3, 131.9, 128.6, 128.3, 128.1,
126.8, 114.0, 86.6, 86.5, 63.6, 55.3; HRMS (ESI) m/z: [MþNa]þ calcd
for C18H16NaO2 287.1040, found 287.1044; IR (v): 3327, 2835, 2209,
4.1.45. rac-1-(4-Chlorophenyl)-5-phenylpent-1-yn-3-ol 34
This compound is novel. Compound 34 was prepared using
General Procedure 2. 1-Chloro-4-ethynylbenzene (0.407 g,
2.98 mmol, 1.00 eq.) was dissolved in THF (anhyd. 5.00 mL) and n-
butyllithium (2.5 M in hexanes, 1.19 mL, 2.98 mmol, 1.00 eq.) was
added dropwise. 3-phenylpropanal (0.400 g, 2.98 mmol, 1.00 eq.)
was added after 30 min. The crude was purified using column
chromatography (SiO2; Rf:0.3 (9:1) petroleum/EtOAc) to give the
desired product 34 as an orange solid (0.386 g, 1.43 mmol, 48%). dH
(400 MHz, CDCl3) 7.37e7.19 (9H, m, ArH), 4.59 (1H, q, J ¼ 6.1 Hz,
CHOH), 2.86 (2H, t, J ¼ 7.8 Hz, CH2CH2Ph), 2.18e2.07 (2H, m,
CH2CH2Ph), 1.87 (1H, d, J ¼ 5.4 Hz, OH); dC (101 MHz, CDCl3) 141.2,
1603, 1507, 1290, 1246, 1173, 1029, 967, 833, 750, 693, 534 cmꢁ1
;
Chiral HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1.0 mL/min,
IPA:Hexane (10:90); 250 nm UV, 30 ꢀC): retention times: 11.28 (R)-
unsaturated and 20.72 (S)-unsaturated mins. Data matched that
reported.
138.2, 136.6, 134.6, 132.9, 128.7, 128.5, 128.5, 126.1, 121.0, 90.8, 84.2,
35
62.2, 39.2, 31.5; HRMS (ESI) m/z: [MþNa]þ calcd for C17
H ClNaO
15
293.0704, found 293.0707; IR (v): 3209, 3060, 3025, 2952, 2919,
2858, 2229,1902, 1801, 1719, 1648, 1487,1453, 1395, 1087, 1012, 826,
756, 699, 522 cmꢁ1; Mp: 48.5e50.7 ꢀC; Chiral HPLC (CHIRALPAK
ADH column: (0.46 ꢂ 25 cm), 0.7 mL/min, IPA:Hexane (10:90);
250 nm UV, 30 ꢀC): retention times: 14.52 (R)-saturated and 15.54
(S)-saturated mins.
4.1.42. 1-(4-Methoxyphenyl)-5-phenylpent-1-yn-3-one
This compound is novel. This compound was prepared using
General Procedure 3 from compound 32 (0.3122 g, 1.17 mmol, 1.00
eq.) and MnO2 (0.714 g, 8.22 mmol, 7.00 eq.) to yield the desired
product as a yellow solid (0.1521 g, 0.57 mmol, 49%). dH (400 MHz,
CDCl3) 7.54e7.48 (2H, m, ArH), 7.33e7.17 (5H, m, ArH), 6.91e6.87
(2H, m, ArH), 3.84 (3H, s, OMe), 3.10e3.04 (2H, m, CH2CH2Ph),
3.08e2.95 (2H, m, CH2CH2Ph). dC (101 MHz, CDCl3) 186.9, 161.7,
140.4, 135.2, 128.6, 128.4, 126.3, 114.4, 111.7, 92.4, 87.7, 55.4, 46.9,
30.1; HRMS (ESI) m/z: [MþNa]þ calcd for C18H16NaO2 287.12 found
287.20; Chiral HPLC (CHIRALPAK IB column: (0.46 ꢂ 25 cm), 1.0 mL/
min, IPA:Hexane (10:90); 250 nm UV, 30 ꢀC): retention times: 6.81
(ketone) mins.
4.1.46. rac-(E)-5-(4-Chlorophenyl)-1-phenylpent-1-en-4-yn-3-ol
35
This compound is novel. Compound 35 was prepared using
General Procedure 2. 1-Chloro-4-ethynylbenzene (0.73 g,
5.67 mmol, 1.00 eq.) was dissolved in THF (anhyd. 8 mL) and n-
butyllithium (2.5 M in hexanes, 2.27 mL, 5.67 mmol, 1.00 eq.) was
added dropwise. After 30 min, E-cinnamaldehyde (0.75 g,
5.67 mmol, 1 eq.) was added. The crude product was purified using
column chromatography (SiO2; Rf: 15:1 (9:1) petroleum/EtOAc) to
give the desired product 35 as a yellow oil (0.2327 g, 0.85 mmol,
15%). dH (400 MHz, CDCl3) 7.40e7.19 (9H, m, ArH), 6.75 (1H, dd,
J ¼ 15.8,1.4 Hz, CH¼CHPh), 6.30 (1H, dd, J ¼ 15.8, 6.1 Hz, CH¼CHPh),
5.20 (1H, d, J ¼ 5.9 Hz, CHOH), 2.07 (1H, s, OH); dC (101 MHz, CDCl3)
4.1.43. (R)-1-(4-Methoxyphenyl)-5-phenylpent-1-yn-3-ol 32 and
(R,E)-5-(4-methoxyphenyl)-1-phenylpent-1-en-4-yn-3-ol 33
The ATH was conducted using General Procedure 1. (E)-5-(4-
Methoxyphenyl)-1-phenylpent-1-en-4-yn-3-one
(150
mg,
0.57 mmol,1.00 eq.), (R,R)-2 (3.6 mg, 5.72 mol, 0.01 eq.) and MeOH
m
136.0, 134.7, 133.0,132.2, 128.7, 128.7, 128.3, 127.8, 126.9, 120.9, 88.9,
85.3, 63.5; HRMS (ESI) m/z: [MþNa]þ calcd for C17
H ClNaO
13
35
(0.5 mL) was reacted for 26 h at 40 ꢀC. The crude product was
purified using column chromatography (SiO2; Rf: 0.10 (9:1) petro-
leum/EtOAc) to give a mixture of both alcohol products 32 and 33
(0.1375 g, 0.51 mmol, 90%). The product obtained was a pale-yellow
oil with an NMR ratio of 86:14 of the major 32 and minor 33
product. Enantiomeric excess and conversion were determined by
Chiral HPLC analysis (CHIRALPAK IB column: (0.46 ꢂ 25 cm),1.0 mL/
min, IPA:Hexane (10:90); 250 nm UV, 30 ꢀC): retention times: 9.52
(R)-saturated, 11.40 (R)-unsaturated, 12.66 (S)-saturated and 21.04
(S)-unsaturated mins. Conversion was determined to be 98% and
the ee of the major and minor product was determined to be 95%
(32) and 78% (33) respectively.
291.0546, found 293.0547; IR (v): 3298, 3028, 2852, 2661, 2228,
1648, 1475, 1447, 1398, 1248, 1202, 1090, 1060, 1020, 967, 828,
760 cmꢁ1; Chiral HPLC (CHIRALPAK ADH column: (0.46 ꢂ 25 cm),
0.7 mL/min, IPA:Hexane (10:90); 250 nm UV, 30 ꢀC): retention
times: 23.68 (R)-unsaturated and 27.11 (S)-unsaturated mins.
4.1.47. 1-(4-Chlorophenyl)-5-phenylpent-1-yn-3-one
This compound is novel. This compound was prepared using
General Procedure 3 from compound 34 (0.285 g, 1.42 mmol, 1 eq.)
and MnO2 (0.855 g, 9.95 mmol, 7 eq.) to yield the desired product as
a yellow solid (0.246 g, 0.91 mmol, 64%). dH (300 MHz, CDCl3)
7.52e7.44 (2H, m, ArH), 7.38e7.21 (7H, m, ArH), 3.09e2.96 (4H, m,
CH2CH2Ph); dC (75 MHz, CDCl3) 162.3, 161.6, 140.5, 134.6, 129.1,
4.1.44. (E)-5-(4-Chlorophenyl)-1-phenylpent-1-en-4-yn-3-one
This compound is known and fully characterised [53]. 1-Chloro-
4-ethynylbenzene was prepared as reported [52]. This compound
128.6, 128.4, 126.4, 116.9, 89.6, 88.5, 46.9, 29.9; HRMS (ESI) m/z:
35
[MþNa]þ calcd for C17
H ClNaO 291.0547, found 291.0552; IR (v):
13
13

T.H. Hall, H. Adams, V.K. Vyas et al.
Tetrahedron xxx (xxxx) xxx
b) P.A. Dub, J.C. Gordon, The mechanism of enantioselective ketone reduction
with Noyori and NoyorieIkariya bifunctional catalysts, Dalton Trans. 45
(2016) 6756e6781;
c) P.A. Dub, J.C. Gordon, Metaleligand bifunctional catalysis: the “accepted”
mechanism, the issue of concertedness, and the function of the ligand in
catalytic cycles involving hydrogen atoms, ACS Catal. 7 (2017) 6635e6655;
d) X. Wu, J. Liu, D. Di Tommaso, J. Iggo, C.R. Catlow, J. Bacsa, J. Xiao,
A multilateral mechanistic study into asymmetric transfer hydrogenation in
water, Chem. Eur. J. 14 (2008) 7699e7715;
3085, 3059, 2954, 2898, 2201, 1806, 1667, 1588, 1485, 1399, 1296,
1173, 1083, 1012, 823, 744, 697, 529 cmꢁ1; Mp 62.6 ꢀC; Chiral HPLC
(CHIRALPAK ADH column: (0.46 ꢂ 25 cm), 0.7 mL/min, IPA:Hexane
(10:90); 250 nm UV, 30 ꢀC): retention times: 9.90 (ketone) mins.
4.1.48. (R)-1-(4-Chlorophenyl)-5-phenylpent-1-yn-3-ol 34 and
(R,E)-5-(4-chlorophenyl)-1-phenylpent-1-en-4-yn-3-ol 35
Both compounds 34 and 35 are novel. The ATH was conducted
using General Procedure 1. (E)-5-(4-Chlorophenyl)-1-phenylpent-
1-en-4-yn-3-one (60.4 mg, 0.27 mmol, 1 eq.), (R,R)-2 (approxi-
e) J.W. Handgraaf, E.J. Meijer, Realistic modeling of ruthenium-catalyzed
transfer hydrogenation, J. Am. Chem. Soc. 129 (2007) 3099e3103.
[3] a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, Asymmetric transfer
hydrogenation of aromatic ketones catalyzed by chiral ruthenium (II) com-
plexes, J. Am. Chem. Soc. 117 (1995) 7562e7563;
mately 1.4 mg, 2.27 mmol, 0.01 eq.) and DCM (0.5 mL) were reacted
b) J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya, R. Noyori, Amino
alcohol effects on the ruthenium (II)-catalysed asymmetric transfer hydro-
genation of ketones in propan-2-ol, Chem. Commun. (1996) 233e234;
c) A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, Ruthenium (II)-
catalyzed asymmetric transfer hydrogenation of ketones using a formic acidꢁ
triethylamine mixture, J. Am. Chem. Soc. 118 (1996) 2521e2522;
d) K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, Asymmetric transfer
for 26 h at 40 ꢀC. The crude product was purified using column
chromatography (SiO2; Rf: 0.20 (9:1) petroleum/EtOAc) to give a
mixture of both Sat OH and Unsat OH product (0.043 g, 0.16 mmol,
70%) The product was obtained as a yellow oil with an NMR ratio of
72:21 of the major (Sat. OH) and minor (Unsat. OH) product. There
was also a small side product with 0.1 integration (NMR ratio
approx. 7%) in relation to the major and minor products. Enantio-
meric excess and conversion determined by Chiral HPLC analysis
(CHIRALPAK ADH column: (0.46 ꢂ 25 cm), 0.7 mL/min, IPA:Hexane
(10:90); 250 nm UV, 30 ꢀC): retention times: 14.65 (R)-saturated,
23.90 (R)-unsaturated, 15.66 (S)-saturated and 27.38 (S)-unsatu-
rated mins. Conversion was determined to be 100% and the major
and minor product was determined to be 96% ee (34) and 71% ee
(35) respectively. The 1H NMR of the crude mixture contain an
additional alkene peak which was tentatively assigned to 36; dH
(400 MHz, CDCl3) 6.81 (d, J ¼ 15.8 Hz, 0.29H; 35), 6.55 (d,
J ¼ 16.0 Hz, 0.10H; 36), 6.36 (dd, J ¼ 15.8, 6.1 Hz, 0.29H; 35),
6.26e6.16 (m, 0.10H; 36), 5.26 (d, J ¼ 5.8 Hz, 0.28H; 35), 4.58 (t,
J ¼ 6.5 Hz, 1H, 34), 4.27 (q, J ¼ 6.5 Hz, 0.1H; 36), 2.84 (t, J ¼ 7.8 Hz,
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Declaration of competing interest
The authors declare no conflicting interests.
Acknowledgements
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b) F. Foubelo, C. Najera, M. Yus, Catalytic asymmetric transfer hydrogenation
of ketones: recent advances, Tetrahedron: Asymmetry 26 (2015) 769e790;
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We thank The Royal Society (UK) and the Science and Engi-
neering Research Board (SERB, India) for funding VKV through an
SERB-Newton International Fellowship (Grant no, NIF/R1/180142).
The EPSRC are thanked for supporting THH through a DTP PhD
studentship (Grant no EP/L505110/1).
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ylum alkaloids, J. Org. Chem. 84 (2019) 15294e15308;
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Efficient synthesis of differentiated syn-1,2-diol derivatives by asymmetric
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131771.
transfer hydrogenationedynamic kinetic resolution of
ketoesters, Chem. Eur. J. 21 (2015) 11799e11806;
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