Camphor-based Schiff base ligand SBAIB: An enantioselective catalyst for addition of phenylacetylene to aldehydes

Article abstract of DOI:10.1039/c1ob06683h

A series of Schiff base ligands were synthesized from (1R)-camphor. Under the optimal conditions, (+)-SBAIB-a, 10 was found to be an excellent catalyst for the enantioselective addition of phenylacetylene to various aldehydes without utilizing either achiral additives or Ti(OⁱPr)₄. This approach yielded (R)-propargylic alcohols in extremely high yields (up to 99%) and excellent enantioselectivities (up to 92%). The corresponding (S)-propargylic alcohols were synthesized in good to high enantioselectivities (up to 91%) and excellent yields (up to 99%) using (-)-SBAIB-a, 41.

Full text of DOI:10.1039/c1ob06683h

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PAPER
Camphor-based Schiff base ligand SBAIB: an enantioselective catalyst for
addition of phenylacetylene to aldehydes†
Ramalingam Boobalan,a Chinpiao Chen*a and Gene-Hsian Leeb
Received 4th October 2011, Accepted 11th November 2011
DOI: 10.1039/c1ob06683h
A series of Schiff base ligands were synthesized from (1R)-camphor. Under the optimal conditions,
(+)-SBAIB-a, 10 was found to be an excellent catalyst for the enantioselective addition of
phenylacetylene to various aldehydes without utilizing either achiral additives or Ti(OiPr)4. This approach
yielded (R)-propargylic alcohols in extremely high yields (up to 99%) and excellent enantioselectivities
(up to 92%). The corresponding (S)-propargylic alcohols were synthesized in good to high
enantioselectivities (up to 91%) and excellent yields (up to 99%) using (−)-SBAIB-a, 41.
Camphor derivatives are one of the most efficient chiral cata-
Introduction
lysts in asymmetric synthesis.7,8 To date, four camphor-based
ligands 1,7a 2,7b 37c and 47d are used as catalysts for the enantio-
The synthesis of enantioenriched propargylic alcohols is an area
of intense research in asymmetric synthesis due to the usefulness
of propargylic alcohol as versatile building blocks for a large
number of pharmaceutically significant molecules and natural
products.1 This synthesis generates a new C–C bond and a
stereogenic alcoholic center simultaneously. In the last two
decades, considerable development has surfaced for the enantio-
selective nucleophilic addition of alkyne to carbonyl compounds
to construct chiral propargylic alcohols.2–6 Among them, an
addition of alkynylzinc, which has been generated in situ from
alkyne and either zinc salt or dialkylzinc to prochiral
aldehyde,3–5 is a widely preferred method due to its mildness for
the wide range of functional groups and easy preparation of alky-
nylzinc. Despite there being numerous catalytic systems for the
enantioselective addition of phenylacetylene to aldehyde, many
require a long reaction time of up to 1–2 days, high catalyst
loading, an extra addition of achiral additives5,6 and elevated
temperature to generate alkynylzinc. Therefore, the search for an
ideal catalyst, which is either readily available in both enantio-
pure forms or easily synthesizable in a few steps in high yields,
capable of providing very high enantiomeric excesses (ees) and
yields for a wide range of substrates without the requirement of
any extra additives, is still an ongoing process for enantioselec-
tive phenylalkynylation reactions.
selective alkynylation of aldehydes (Fig. 1). Among the four
ligands, however, camphorsulfonamide 1, reported by Wang
et al., was the only ligand that catalyzed this reaction success-
fully to achieve various propargylic alcohols in excellent ees and
yields. Nevertheless, this catalytic system also has limitations,
such as the need for an additional Lewis acid, Ti(OiPr)4,
excesses of diethylzinc and phenylacetylene and yielding only
moderate ees for aliphatic aldehydes.
This study hypothesized that camphor-based tridentate Schiff
base ligands of 3-exo-aminoisoborneol [SBAIB] (Scheme 1)
would generate a bifunctional catalytic system with dialkylzinc
and phenylacetylene (Fig. 3), which would also circumvent the
necessity of additional Lewis acids and achiral additives that are
commonly required for many catalytic systems of this reaction.5,6
Herein, this study reports the synthesis of a series of SBAIB
ligands and their catalytic efficiency toward the enantioselective
addition of phenylacetylene to various aldehydes.
aDepartment of Chemistry, National Dong Hwa University, Soufeng,
Hualien 974, Taiwan, Republic of China. E-mail: chinpiao@mail.ndhu.
edu.tw; Fax: 886 3 863 0475; Tel: 886 3 863 3597
bInstrumentation Center, College of Science, National Taiwan
University, Taipei 106, Taiwan, Republic of China
†Electronic supplementary information (ESI) available: Crystallographic
data of (+)-SBAIB-a, 10, NMR, MASS, IR, HPLC spectra for all
SBAIB and propargylic alcohols. CCDC reference number 823886.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1ob06683h
Fig. 1 Camphor-based ligands for enantioselective alkynylation to
aldehydes.
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Scheme 1 The synthesis of SBAIB Ligands. Reagents and conditions: (a) SeO2, Ac2O, reflux, 17 h, 98%; (b) H2NOH.HCl, NaOAc, EtOH/H2O,
reflux, 15 min, 98%; (c) LiAlH4, THF, reflux, 20 h, 91%; (d) (Cl3CO)2CO, 6 M NaOH, DCM, −5 °C, 1 h then rt, 2.5 h, 78%; (e) 3 M NaOH, EtOH/
H2O, reflux, 6h, 96%; (f) Anhy. Na2SO4, EtOH/DCM, reflux, 12 h.
Results and discussion
Synthesis of tridentate Schiff base ligands from (1R)-camphor
Eight tridentate Schiff base ligands, (+)-SBAIB-a–h, 10–17,
were synthesized from commercially available and inexpensive
(1R)-camphor 5 in six steps (Scheme 1).9 Each ligand varies at
aromatic rings by substituents and their positions. Firstly, the
Riley oxidation of (1R)-camphor 5 produced camphorquinone
6,9a which was subsequently converted to (1R,2S,3R,4S)-
(−)-3-aminoisoborneol ((−)-AIB), 9, according to Zaidelwicz’s
procedure.9b The (−)-AIB successively underwent a conden-
sation reaction with 2-hydroxybenzaldehydes in MeOH/CH2Cl2
(1 : 3) in the presence of anhydrous Na2SO4 at reflux temperature
to produce (+)-SBAIB-a–g, 10–1610 in extremely high yields
(up to 99%, overall yields: up to 65% from (1R)-camphor). The
(1R,2S,3R,4S)-(−)-AIB, 9, also reacted with 2-hydroxynaphthal-
dehyde to yield (+)-SBAIB-h, 17. An X-ray crystallographic
analysis of (+)-SBAIB-a, 10 (Fig. 2) verified the general struc-
ture of these tridentate (N, O, O) Schiff base ligands.
Fig. 2 X-ray crystallographic structures of (+)-SBAIB-a, 10 (CCDC
823886†).
(Table 1, entry 7). To further increase the ee and yields, the reac-
tion was carried out with dimethylzinc (Table 1, entry 8) and
tried with various additives, such as alcohols, polyethylene gly-
colic ethers and even Ti(OiPr)4 in various equivalents (not
shown in Table 1). However, none of them improved the ees and
yields. In an effort to enhance the enantioselectivity of this reac-
tion, Protocol A was modified into protocols B, C and D, in
which 10 (10 mol%), diethylzinc (2 eq., 1 M in hexane) and
phenylacetylene (2 eq.) were mixed and stirred for 1 h, 3 h and
5 h, respectively, before the addition of benzaldehyde 18.
Despite a lack of high enrichment in ees compared to Protocol
A, a regular increment was present in the ees of the products of
66%, 72% and 78% (Table 1, entries 9–11) in reduced reaction
time (15 h, 13 h and 11 h, respectively). When the solvent of
diethylzinc was changed from hexane to toluene, the ee was
Optimization of reaction conditions using (+)-SBAIB-a, 10
In the optimization of the reaction conditions, benzaldehyde 18
was utilized as a benchmark aldehyde and 10 was employed as a
chiral promoter. Using Protocol A, toluene was the optimal
solvent (Table 1, entries 1–4). A superior enantioselectivity
(82% ee) of (R)-1,3-diphenylprop-2-yn-1-ol 18a was found
when 20 mol% 10, phenylacetylene (2 eq), diethylzinc (1 M in
hexane) (2 eq) reacted at room temperature in 2 mL of toluene
1626 | Org. Biomol. Chem., 2012, 10, 1625–1638
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Fig. 3 The proposed mechanism.
Table 1 Optimization for catalytic enantioselective addition of phenylacetylene to benzaldehydea,d
Entry
Ligand (mol %)
Solvent
Alkyl zinc/solvent (eq)b
Protocolc
T/°C
Time (h)
Yield (%)
ee (%)e
1
2
3
4
5
6
7
8
10
10
10
10
10
10
20
10
10
10
10
10
10
20
25
30
20
20
THF
toluene
Et2O
Et2Zn/hexane (2)
Et2Zn/hexane (2)
Et2Zn/hexane (2)
Et2Zn/hexane (2)
Et2Zn/hexane (2)
Et2Zn/hexane (2)
Et2Zn/hexane (2)
Me2Zn/heptane (2)
Et2Zn/hexane (2)
Et2Zn/hexane (2)
Et2Zn/hexane (2)
Et2Zn/toluene (2)
Et2Zn/toluene (2)
Et2Zn/toluene (2)
Et2Zn/toluene (2)
Et2Zn/toluene (2)
Et2Zn/toluene (1.2)
Et2Zn/toluene (3)
A
A
A
A
A
A
A
A
B
C
D
C
E
0–rt
0–rt
0–rt
0–rt
0
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
34
20
20
20
30
18
17
20
15
13
11
9
7
6
6
6
20
4
92
99
97
98
54
88
88
93
94
90
82
96
>99
97
96
98
90
97
11
74
70
69
78
79
82
78
66
72
78
84
86
91
89
90
85
90
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15
16
17
18
E
E
E
F
G
a For all of the reactions benzaldehyde (50 mg, 1 eq.). b Phenylacetylene/R2Zn ratio = 1 : 1 unless mentioned. c Protocol A: phenylacetylene (2 eq.),
solvent (2 mL), dialkylzinc (2 eq.), stir 1 h, ligand/solvent (2 mL), stir 1 h then benzaldehyde (1 eq.) at mentioned temperature; Protocol B: ligand,
phenylacetylene (2 eq.), solvent (2 mL), dialkylzinc (2 eq.), stir 1 h then benzaldehyde (1 eq.); Protocol C: same as Protocol B except stir 3 h before
benzaldehyde (1 eq) addition; Protocol D: same as Protocol B except stir 5 h before benzaldehyde (1 eq.) addition; Protocol E: same as Protocol B
except stir 4 h before benzaldehyde (1 eq.) addition; Protocols F and G: Same as Protocol B except equivalents of diethylzinc 1.2 and 3, respectively.
d The absolute configuration was based on determination of specific rotation and its comparison with the literature. e The enantiomeric excess was
determined by HPLC analysis (Chiralcel OD-H column).
amplified to 84%, with a high yield of 96% in a short time
period of 9 h (Table 1, entry 12). The homo solvent (the reaction
solvent and the solvent of dialkylzinc are same) played a signifi-
cant role compared to the homogeneous mixture of hetero sol-
vents in the proposed asymmetric catalytic system. A slight
enhancement in ee (86%) with a quantitative yield in 7 h was
present with the addition of benzaldehyde after 4 h (Table 1,
entry 13). The optimal ee of 91% with a high yield (97%) was
achieved in a short time (6 h) (Table 1, entry 14) when the
amount of 10 increased from 10 to 20 mol%. This study also
examined the reaction with a higher molar ratio of ligands
(Table 1, entries 15 and 16), as well with a molar ratio lower
than 10 mol%, though no significant increments emerged in the
ee. Upon decreasing the amounts of diethylzinc and phenylace-
tylene (Table 1, entry 17), the ee decreased while the amounts of
diethylzinc were increased and the ee remained constant, with no
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change in yield (Table 1, entry 18). Thus, entry 14 in Table 1
was chosen as the optimal condition for phenylacetynylation of
benzaldehyde using 10.
To find out the optimal Schiff base ligand and study the sub-
stituent effects on the aromatic ring of the ligand, this study
applied all other SBAIB ligands to this reaction. It was obvious
from the results (Table 2, entries 2–8) that the substitution,
mainly ortho-substitution, in the aromatic ring decreases the
enantioselectivity. This is possibly due to the resulting steric hin-
drance for the aromatic hydroxy group that would be participat-
ing in the transition state of the reaction. Thus, among all of the
catalysts, the simple salicylaldehyde derivative 10 was found to
be an optimal catalyst for this reaction.
Catalytic enantioselective addition of phenylacetylene to various
aldehydes
Table 2 Screening of ligandsa
The scope of this catalytic system was studied for various
aromatic and aliphatic aldehydes (Table 3). Both the electron-
donating and electron-withdrawing groups that substituted
benzaldehydes (Table 3, entries 2–14) produced propargylic
alcohols (19a–31a) with excellent enantioselectivities (up to
92%) in excellent yields (up to 98%) within a short reaction time
(4 h).
The ees were slightly lower for meta-halo-benzaldehydes;
for instance, 3-chloro- and 3-fluorobenzaldehyde (entries 10 and
13) yielded 27a and 30a with slightly lower ees (85% and 83%,
respectively). The best enantioselectivity (92%) was obtained
for 2-anisaldehyde 23. For the heteroaromatic aldehydes, high
ees of 34a (88%) and 35a (91%) were achieved (entries17
and 18).
Entry
Ligand
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
(+)-SBAIB-a, 10
(+)-SBAIB-b, 11
(+)-SBAIB-c, 12
(+)-SBAIB-d, 13
(+)-SBAIB-e, 14
(+)-SBAIB-f, 15
(+)-SBAIB-g, 16
(+)-SBAIB-h, 17
6
4
4
4
5
5
5
4
97
90
93
90
93
99
87
81
91
14
53
49
86
17
84
52
a Reaction conditions: ligand (20 mol%), phenylacetylene (2 eq), solvent
(2 mL), dialkylzinc (2 eq), stir for 4 h then benzaldehyde (1 eq).
Aliphatic aldehydes also offered propargylic alcohols with
moderate to good ees in excellent yields under the same optimal
Table 3 Enantioselective addition of phenylacetylene to aldehydes catalyzed by (+)-SBAIB-a, 10
Entry
Aldehydea
Product
Time (h)
Yield (%)
ee (%)b
Sign/config.c
1
2
3
4
5
6
7
8
benzaldehyde 18
2-tolualdehyde 19
3-tolualdehyde 20
4-tolualdehyde 21
4-tert-butylbenzaldehyde 22
2-anisaldehyde 23
3-anisaldehyde 24
18a
19a
20a
21a
22a
23a
24a
25a
26a
27a
28a
29a
30a
31a
32a
33a
34a
35a
36a
37a
38a
39a
40a
6
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
97
98
98
96
95
98
93
94
91
92
97
93
88
92
99
98
91
90
87
86
89
92
91
91
91
85
88
88
83
88
84
85
+/R
−/R
+/R
+/R
+/R
−/R
+/R
+/R
−/R
+/R
+/R
−/R
+/R
+/R
−/R
−/R
+/Re
+/Re
+/R
−/R
−/R
−/Re
−/Re
4-anisaldehyde 25
9
2-chlorobenzaldehyde 26
3-chlorobenzaldehyde 27
4-chlorobenzaldehyde 28
2-bromobenzaldehyde 29
3-fluorobenzaldehyde 30
4-fluorobenzaldehyde 31
1-naphthaldehyde 32
2-naphthaldehyde 33
2-furfural 34
2-thiophen-carboxaldehyde 35
(2E)-cinnamaldehyde 36
(2E)-2-methyl-cinnamaldehyde 37
cyclohexanecarboxaldehyde 38
isobutyraldehyde 39
10
11
12
13
14
15
16
17
18
19
20
21
22
23
98
95
94
99
88
91
64
88
93
66
84(86)d
83(87d
73(72)d
87(86)d
pivaldehyde 40
a Phenylacetylene : Et2Zn in toluene : ligand : aldehyde ratio = 2 : 2 : 0.2 : 1, all of the reactions were done with 50 mg aldehydes. b The enantiomeric
excess was determined by HPLC analysis on a Chiralcel OD-H column. c The absolute configuration was based on determination of specific rotation
and its comparison with the literature. d The reactions were carried out on a 250 mg scale and the obtained ees and yields are in parentheses. e The
confusion that exists in the literature about the relationship between the absolute configuration and sign of specific rotation for these propargylic
alcohols was addressed and clarified.
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conditions. Entries 19 and 20 apparently indicate that α-
substituted α,β-unsaturated aldehydes would yield significantly
superior ees compared to simple α, β-unsaturated aldehydes. The
aliphatic aldehyde with a higher substitution at the α-carbon
yielded higher ees than the less substituted. For example, one
additional methyl substitution of pivaldehyde 40 (entry 23) in
comparison to isobutyraldehyde 39 (entry 22) causes an
increased steric hindrance and, thus, the ee of propargylic
alcohol, 40a, rose to 87%.
The clarification of the absolute configuration of propargylic
alcohols
All of the propargylic alcohols produced by the 10 catalyzed
reaction (Table 3) possess R configuration compared with their
specific rotation in the relevant literature. The propargylic alco-
hols 39a and 40a misled us initially to state that their configur-
ation is S, based on their sign of specific rotation. However, this
became controversial due to chiral HPLC data. Hence, the mag-
nitude of the specific rotations of 39a and 40a are small and con-
fusion is present in the literature regarding the relationship
between their absolute configuration and sign of specific rotation.
This study conducted a thorough analysis of all of the literature
related to these alcohols, clarified the misunderstandings and
proved that their absolute configuration is R, as shown below.
Scheme 2 The synthesis of 39ac to confirm the absolute configuration
of 39a. Reagents and conditions: (a) BzCl, Et3N, DCM; (b) OsO4,
NaIO4, HMTA, THF/H2O; (c) catalytic conc. H2SO4, MeOH.
[α]2D3.2 = +26.2 (c 1.91, benzene), proving that 39a has an R
configuration.
In addition, this study synthesized 39a on a larger scale and
tested the specific rotation at high concentration, which was [α]D22
= +1.3 (c 6.4, CHCl3, 73% ee) [S enantiomer: lit.13a [α]D23
=
−1.6 (c 6.3, CHCl3, 99% ee)]. This proves that the magnitude
and even sign of the specific rotation could change with concen-
tration, which was possibly the chief reason for the confusion in
the literature. Thereafter, this study checked the HPLC of 39a on
the Chiralcel OD column, which showed that tr (major):
13.6 min and tr (minor): 22.97 min. The R enantiomer of 4-
methyl-1-phenyl-pent-1-yn-1-ol is derived earlier, followed by
the S enantiomer in both Chiralcel OD-H and Chiralcel OD
columns. Therefore, to state the configuration of a molecule, not
only does the sign of specific rotation require analysis, but the
order of the major and minor peaks in the chiral HPLC also
needs to be checked. Therefore, this study tabulated (Table 4) the
confusions in existing literature for 4-methyl-1-phenyl-pent-1-
yn-1-ol and their corrections.
4-Methyl-1-phenyl-pent-1-yn-1-ol 39a
The specific rotation of 39a was found to be [α]2D2 = −2.4 (c
0.69, CHCl3, 73% ee) (lit.7a [α]D15 = −2 (c 0.69, CHCl3, 75%
ee)) and its peak retention times in chiral HPLC were tr (major):
5.83 min and tr (minor): 10.11 min (column: Chiralcel OD-H).
The absolute configuration of the title compound was first
confirmed by Noyori et al.13a for S enantiomer ([α]2D3 = −1.6 (c
6.26, CHCl3), 99% ee)) and the retention times of peaks in
chiral HPLC were R-isomer: 12.8 min, S-isomer: 21.3 min.
Therefore, 39a should have an S configuration as per the specific
rotation and an R configuration as per the order of the peaks
in the chiral HPLC. To find the absolute configuration, this
study synthesized 1-methoxy-3-methyl-1-oxobutan-2-yl-benzo-
ate 39ac from 39a (Scheme 2), which has a specific rotation
of [α]2D3 = −17.4 (c 2.00, benzene). The reported specific rota-
tion for (S)-1-methoxy-3-methyl-1-oxobutan-2-yl-benzoate13a is
4,4-Dimethyl-1-phenyl-pent-1-yn-1-ol 40a
This study came to a conclusion with this molecule as well, that
initially the compound 40a (87% ee) has an S configuration
since the specific rotation was checked in a low concentration
[α]2D2 = −2.2 (c 1.0, CHCl3). However, this was not true with
Table 4 The corrections of 4-methyl-1-phenyl-pent-1-yn-1-ol’s absolute configuration
Entry
Literature
Column
tr major
tr minor
[α]
ee
Reported configuration
Re-assigned configuration
1
2
3
4
5
6
7
ref. 13a
ref. 3a
ref. 7a
ref. 5c
Chiralcel OD
Chiralcel OD
Chiralcel OD
Chiralcel OD
Chiralcel OD
Chiralcel OD
Chiralcel OD-H
21.3
7.9
6.1
12.6
5.5
5.8
12.8
16.0
10.7
6.8
9.2
4.3
−1.6 (c 6.3, CHCl3)
+3.2 (c 6.8, CHCl3)
−2.0 (c 0.7, CHCl3)
+1.5 (c 0.6, CHCl3)
+3.1 (c 1.1, CHCl3)
+2.7 (c 2.9, CHCl3)
−2.4 (c 0.7, CHCl3)
+1.3 (c 6.4, CHCl3)
99
90
75
47
95
88
73
73
S
R
proved as S
R
R
S
NA/Sa
NA/Ra
R
ref. 3e
R
S
ref. 6fb
this study
Sb
5.8
10.1
Sa
Rc
Rc
Ra
a These are the expected configurations from the sign of rotation. b Like us, ref. 6f also had the same problem with the sign of specific rotation,
however they haven’t clarified this; instead they simply state that it possess S configuration. c This is also confirmed by HPLC analysis on Chiralcel
OD (tr (major): 13.6 min and tr (minor): 22.97 min).
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Scheme 3 Syntheses of 40ad and 40ai to confirm the absolute configuration of 40a. Reagents and conditions: (a) BzCl, Et3N, DCM; (b) OsO4,
NaIO4, HMTA, THF/H2O; (c) catalytic conc. H2SO4 MeOH; (d) 2 M NaNO2, 2 N H2SO4; (e) catalytic conc. H2SO4; (f) BzCl, Et3N, DMAP, DCM.
high concentrations; the specific rotation was [α]2D4 = +1.4 (c 4.0,
CHCl3). The absolute configuration of 4,4-dimethyl-1-phenyl-
pent-1-yn-1-ol was first reported by E. J. Corey et al.14b
However, their back reference is ref. 14a, which failed to report
the absolute configuration of the titled compound, instead men-
tioning only the specific rotation. Therefore, we wanted to have
solid proof to state the absolute configuration of this molecule.
This study thus synthesized 1-methoxy-3,3-methyl-1-oxobutan-
2-yl benzoate 40ad from 40a (Scheme 3, A), and compared its
specific rotation with (S)-1-methoxy-3,3-methyl-1-oxobutan-2-yl
benzoate 40ai, which was synthesized from L-tert-leucine14c
(Scheme 3, B). This revealed that 40a has an R configuration.
The R enantiomer of 4,4-dimethyl-1-phenyl-pent-1-yn-1-ol was
revealed to come first, followed by S enantiomers in all chiral
columns (Chiralcel OD,3a,3e,13a,14b our result and Chiralcel
OD-H column our result), with the eluent isopropanol/hexane.
By thorough literature analysis of propargylic alcohols 34a11 and
35a,12 their configuration was confirmed as R.
of various aldehydes would be possible if the aforementioned
proposed model is true. Thus, this study synthesized another
Schiff base ligand, 41 (Scheme 4), and applied it to this asym-
metric reaction.
Synthesis and application of (−)-SBAIB-a, 41
The 41 was synthesized from (1S)-camphor 42, (Scheme 4) in
an overall 65% yield by implementing the same procedure of
(+)-SBAIB-a, 10. (−)-SBAIB-a, 41 is catalyzed in this asym-
metric reaction to produce various (S)-propargylic alcohols in
good to excellent yields and ees. The experimental conditions
and the results are shown in Table 5. The maximum enantios-
electivity (91%) was obtained for pivaldehyde.
Conclusions
In summation, this study demonstrated the efficient synthesis of
camphor-based Schiff base ligands, including (+)- and
(−)-SBAIBs in very high yield. Among the Schiff base ligands,
the (+)-SBAIB-a, under mild conditions, promotes the enantiose-
lective addition of phenylacetylene to various aldehydes in a
short reaction time (4 h). Various (R)-propargylic alcohols are
consequently obtained in excellent enantiomeric excess (up to
92%) and in extremely high yields (up to 99%). This process
also circumvents the requirements for either metallic additives/
Lewis acids, such as titanium alkoxide and copper triflate, or
nonmetallic/achiral additives, including DiMPEG, amine bases
Proposed mechanism for asymmetric induction
The absolute configuration of the newly generated stereogenic
centre regarding benzaldehyde and 10 is predicted by the pro-
posed model (Fig. 3). For this bifunctional catalyst system, TS-1
is favorable due to less steric hindrance between the phenyl rings
of the aldehyde and ligand. The alcoholic oxygen and imine’s
nitrogen can coordinate to zinc, which would act as a Lewis acid
to activate the electrophilicity of the carbonyl group. Alcoholic
oxygen and phenolic oxygen can coordinate to alkynylzinc; the
alkynyl group can thus become activated nucleophiles. The
addition of phenylacetylide to the si-face of carbonyl carbon
consequently leads to the generation of (R)-propargylic alcohol,
18a. The addition of phenylacetylide to the re-face of carbonyl
carbon is unfavored (Fig. 3, TS-2) due to the steric hindrance
between the phenyl rings of the aldehyde and the ligand. If this
reaction is done with levo isomer (−)-SBAIB-a, 41 instead of
dextro isomer (+)-SBAIB-1, the steric hindrance and face of the
addition of the carbonyl group would seemingly experience
an exact reversal. Therefore, regarding benzaldehyde, (S)-
propargylic alcohol, 18b, would be the enantioenriched alcohol,
as shown in Fig. 3 (TS-3). Synthesizing (S)-propargylic alcohols
Scheme 4 The synthesis of (−)-SBAIB-a, 41 from (1S)-camphor.
1630 | Org. Biomol. Chem., 2012, 10, 1625–1638
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Table 5 (−)-SBAIB-a, 41-catalyzed asymmetric addition of
were recorded using a FT/IR spectrometer. Mass spectra
(EI-MS) and high resolution mass spectra (HRMS-EI) were
determined on a Thermo Quest MAT 95XL mass spectrometer.
Melting points are checked by the use of melting point instru-
ment. Melting point of the compounds might not be correct.
Enantiomeric excesses were determined using high performance
liquid chromatography (HPLC) with a Chiralcel OD-H chiral
column and also with Chiralcel OD. Optical rotations were
measured using a polarimeter at the indicated temperature using
a sodium lamp (D line, 589 nm).
phenylacetylene to aldehydesa,b
Entry Aldehyde Product Yield (%) ee (%)c Sign/config.d
1
2
3
4
5
6
7
8
9
18
19
21
23
25
26
29
35
37
40
18b
19b
21b
23b
25b
26b
29b
35b
37b
40b
99
99
95
99
98
95
91
91
97
99
89
90
88
90
88
87
86
89
82
91
−/S
+/S
−/S
+/S
−/S
+/S
+/S
−/S
+/S
+/S
(1R,2S,3R,4S)-(−)-3-Aminoisoborneol, 9
This was prepared by the literature procedures from (1R)-
Camphor.9 mp 199–201 °C; [α]2D5 = −14.3 (c 1.20, MeOH);
lit.9b [α]D22 = −8.2 (c 1.15, MeOH); 1H NMR (CDCl3, 400 MHz)
δ 3.37–3.35 (d, J = 7.4 Hz, 2H), 3.05–3.03 (d, J = 7.4 Hz, 2H),
2.40 (br, s, 3H), 1.73–1.65 (m, 1H), 1.54–1.53 (d, J = 4.5 Hz,
1H), 1.43–1.37 (m, 1H), 1.06–0.95 (m, 2H), 1.05 (s, 3H), 0.94
(s, 3H), 0.77 (s, 3H); 13C NMR (CDCl3, 100.6 MHz) δ 79.0,
57.3, 53.4, 48.7, 46.6, 33.1, 26.9, 21.9, 21.2, 11.3.
10
a The reaction conditions were the same as in Table 3.
b Phenylacetylene : Et2Zn in toluene : ligand : benzaldehyde ratio
=
2 : 2 : 0.2 : 1. c The enantiomeric excess was determined by HPLC
analysis of the products (Chiralcel OD-H column). d The absolute
configuration was based on a comparison of the retention time HPLC
peaks and sign of specific rotation with the literature.
(1S,2R,3S,4R)-(+)-3-Aminoisoborneol, 43
This was synthesized from (1S)-camphor using same literature
procedures as for compound 9. mp 201–203 °C; [α]2D0 = +5.9 (c
1.15, MeOH).
and alcohols. In addition, under the same reaction conditions,
this study synthesized good to highly enantioenriched various
(S)-propargylic alcohols (up to 91%) by employing 41 as a cata-
lyst. This method represents the use of first camphor-based
ligands for the enantioselective phenylacetylene addition reac-
tion without use of any other extra additive. As a part of this
work, we clarified the confusion in the scientific literature related
to the absolute configuration of the propargylic alcohols 34a,
35a, 39a and 40a by thorough literature analysis. The appli-
cations of these ligands to other asymmetric reactions are in
progress.
General procedure for Schiff base ligands synthesis
Under an argon atmosphere, 2-hydroxy-1-aromaticaldehydes and
3-aminoisoborneol were mixed together in MeOH/CH2Cl2 (1 : 3)
in the presence of anhydrous Na2SO4 at room temperature and
refluxed for 12 h to complete either of one starting material.
Then, it was filtered through an anhydrous Na2SO4 plug and the
filtrate was evaporated to offer a yellow solid. The Schiff base
ligands were purified by a proper solvent wash; washed with
pentane to remove traces of 2-hydroxy-1-aromatic aldehyde and
dissolved with hexane, cooled and filtered to remove traces of
insoluble 3-aminoborneol.
Experimental section
General remarks
All reactions were carried out in anhydrous solvents. THF and
diethyl ether were distilled from sodium–benzophenone under
argon. Toluene, CH2Cl2 and hexane were distilled from CaH2.
The aldehydes, dialkylzinc and phenylacetylene were used as
purchased. All asymmetric reactions were carried out in dry
glassware under nitrogen using a standard glovebox. Reactions
were monitored by thin-layer chromatography using pre-coated
silica gel 60 glass plates with F254 indicator. Visualization was
accomplished by UV light (254 nm) in combination with iodine,
potassium permanganate staining solutions. The products were
purified by neutral column chromatography on 70–230 mesh
silica gels. Yields refer to chromatographically and spectrogra-
(1R,2S,3R,4S)-(+)-3-[(2-Hydroxybenzylidene)amino]-isoborneol,
(+)-SBAIB-a, 1010
The condensation of salicylaldehyde (390 mg, 3.19 mmol) and
(1R,2S,3R,4S)-3-aminoisoborneol 9 (450 mg, 2.65 mmol) was
done in 18 mL of MeOH/CH2Cl2 (1 : 3) in the presence of anhy-
drous Na2SO4 (900 mg). Yield: 720 mg (99%); yellow solid, mp
135–137 °C; [α]2D4.5 = +157.7 (c 1.00, MeOH);1H NMR (CDCl3,
400 MHz) δ 13.28 (br, 1H), 8.36 (s, 1H), 7.33 − 7.24 (m, 2H),
6.96–6.94 (d, J = 8.1 Hz, 1H), 6.89–6.85 (m, 1H), 3.83–3.81 (d,
J = 7.6 Hz, 1H), 3.59–3.57 (d, J = 7.6 Hz, 1H), 1.85–1.77 (m,
3H), 1.60–1.54 (m, 1H), 1.27 (s, 3H), 1.20–1.08 (m, 2H), 1.10
(s, 3H), 0.87 (s, 3H);13C NMR (CDCl3, 100.6 MHz) δ 165.7,
161.7, 132.6, 131.6, 118.7, 118.4, 117.3, 81.7, 76.5, 53.3, 49.3,
47.2, 33.5, 26.4, 21.6, 21.5, 11.4; IR (KBr) 3400, 2951, 2879,
1631, 1526, 1480, 1389, 1281, 1218, 1149, 1092, 1052, 755,
735 cm−1; LRMS-EI (m/z) 273 (M+, 100), 244 (22), 230 (34),
202 (25), 18 (26), 161 (55), 133 (36), 122 (72), 107 (37), 77
phically pure material, unless otherwise noted. 1H NMR and 13
C
NMR spectra were obtained from 400 and 100.6 MHz NMR
spectrometers, respectively. Chemical shifts (δ) are reported in
parts per million (ppm) relative to CDCl3 (7.26 and 77.0 ppm),
the coupling constants are reported in Hertz (Hz) and the multi-
plicities are indicated as br = broad, s = singlet, d = doublet, dd
= doublet of doublet, t = triplet, m = multiplet. Infrared spectra
This journal is © The Royal Society of Chemistry 2012
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(21); HRMS-EI (m/z) [M]+ calcd for C17H23NO2 273.1729,
found 273.1723.
2.04–1.98 (br, 1H), 1.81–1.76 (m, 2H), 1.60–1.53 (m, 1H), 1.29
(s, 3H), 1.15–1.07 (m, 2H), 1.01 (s, 3H), 0.87 (s, 3H);13C NMR
(CDCl3, 100.6 MHz) δ 166.0, 159.9, 133.5, 129.3, 126.1, 118.0,
81.7, 76.6, 53.2, 49.3, 47.2, 33.5, 26.5, 21.6, 15.6, 11.4; IR
(KBr) 3436, 2951, 1628, 1541, 1457, 1271, 1235, 1093, 1052,
850, 774, 747, 617 cm−1; LRMS-EI (m/z) 287 (M+, 100), 258
(19), 244 (32), 216 (26), 202 (29), 175 (52), 147 (34), 136 (75),
121 (44), 91 (59), 77 (32); HRMS-EI (m/z) [M]+ calcd for
C18H25NO2 287.1885, found 287.1891.
(1R,2S,3R,4S)-(+)-3-[(3,5-Di-tert-butyl-2-hydroxybenzy-lidene)
amino]isoborneol, (+)-SBAIB-b, 11
The condensation of 3,5-di-tert-butylsalicylaldehyde (200 mg,
0.85 mmol) and (1R,2S,3R,4S)-(−)-3-aminoisoborneol
9
(173 mg, 1.02 mmol) was done in 8 mL of MeOH/CH2Cl2
(1 : 3) in the presence of anhydrous Na2SO4 (400 mg). Yield:
330 mg (quantitative); yellow solid, mp 66–68 °C; [α]D17.3
=
(1R,2S,3R,4S)-(+)-3-[(2-Hydroxy-5-methylbenzylidene)-amino]
+59.6 (c 1.00, CHCl3);1H NMR (CDCl3, 400 MHz) δ 13.15 (br,
1H), 8.41 (s, 1H), 7.39–7.38 (d, J = 2.4 Hz, 1H), 7.11–7.10 (d, J
= 2.4 Hz, 1H), 3.82 − 3.79 (m, 1H), 3.59–3.57 (d, J = 7.6 Hz,
1H), 3.48 (s, 3H), 1.95–1.93 (d, J = 4.9 Hz, 1H), 1.83–1.75 (m,
2H), 1.62–1.53 (m, 1H), 1.43 (s, 9H), 1.30 (s, 9H), 1.27 (s, 3H),
1.14–1.13 (m, 2H), 1.02 (s, 3H), 0.87 (s, 3H);13C NMR (CDCl3,
100.6 MHz) δ 167.4, 157.8, 140.2, 136.7, 127.2, 126.2, 118.0,
81.7, 53.3, 50.9, 49.3, 47.1, 35.0, 34.1, 33.5, 31.5, 29.4, 26.5,
21.7; IR (KBr) 3418, 2954, 1626, 1478, 1440, 1390, 1361,
1273, 1250, 1203, 1173, 1093, 1055, 876 cm−1; LRMS-EI (m/
z): 385 (M+, 83), 370 (100), 342 (49), 203 (33), 131 (36), 105
(71), 91 (57), 77 (53); HRMS-EI (m/z): [M]+ calcd for
C25H39NO2 385.2981, found 385.2974.
isoborneol, (+)-SBAIB-e, 14
The condensation of 5-methylsalicylaldehyde (45 mg,
0.32 mmol) and (1R,2S,3R,4S)-(−)-3-aminoisoborneol 9 (50 mg,
0.29 mmol) was done in 2 mL of MeOH/CH2Cl2 (1 : 3) in the
presence of anhydrous Na2SO4 (100 mg). Yield: 82 mg (96%);
Yellow solid, mp 145–147 °C; [α]2D4.5 = +90.9 (c 1.00,
CHCl3);1H NMR (CDCl3, 400 MHz) δ 13.02 (br, 1H), 8.25 (s,
1H), 7.11–7.09 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.85–6.83 (d, J
= 8.4 Hz, 1H), 3.81–3.80 (d, J = 7.5 Hz, 1H), 3.54–3.52 (d, J =
7.5 Hz, 1H), 2.28 (s, 3H) 2.06 (br, 1H), 1.82–1.76 (m, 2H),
1.59–1.53 (m, 1H), 1.25 (s, 3H), 1.17–1.07 (m, 2H), 1.00 (s,
3H), 0.85 (s, 3H);13C NMR (CDCl3, 100.6 MHz) δ 165.8,
159.3, 133.5, 131.5, 127.4, 118.4, 116.9, 81.7, 76.6, 53.2, 49.2,
47.2, 33.5, 26.5, 21.6, 21.5, 20.3, 11.4; IR (KBr) 3436, 2952,
1634, 1590, 1494, 1389, 1281, 1225, 1093, 1053, 820,
757 cm−1; LRMS-EI (m/z): 287 (M+, 100), 244 (29), 216 (24),
200 (21), 175 (44), 136 (68), 121 (37), 91 (28), 77 (15).
HRMS-EI (m/z) [M]+ calcd for C18H25NO2 287.1885, found
287.1892.
(1R,2S,3R,4S)-(+)-3-[(3,5-Dimethyl-2-hydroxybenzylidene)-
amino]isoborneol, (+)-SBAIB-c, 12
The condensation of 3,5-dimethylsalicylaldehyde (50 mg,
0.33 mmol) and (1R,2S,3R,4S)-(−)-3-aminoisoborneol
9
(173 mg, 0.38 mmol) was done in 2 mL of MeOH/CH2Cl2
(1 : 3) in the presence of anhydrous Na2SO4 (100 mg). Yield:
99 mg (99%); yellow solid, mp 117–119 °C; [α]2D3 = +89.2 (c
1.00, CHCl3);1H NMR (CDCl3, 400 MHz) δ 13.03 (br, 1H),
8.31–8.30 (d, J = 3.6 Hz, 1H), 7.01 (s, 1H), 6.89 (s, 1H),
3.81–3.79 (d, J = 5.4 Hz, 1H), 3.56–3.55 (d, J = 7.2 Hz, 1H),
2.26 (s, 3H) 2.24 (s, 3H), 1.87–1.86 (br, 1H), 1.81–1.77 (m,
2H), 1.59–1.53 (m, 1H), 1.29 (s, 3H), 1.19–1.07 (m, 2H), 1.01
(s, 3H), 0.86 (s, 3H);13C NMR (CDCl3, 100.6 MHz) δ 166.3,
157.1, 134.6, 129.2, 127.1, 125.7, 117.8, 81.8, 77.0, 53.2, 49.2,
47.2, 33.6, 26.5, 21.7, 20.3, 15.5, 11.3; IR (KBr) 3468, 2952,
1630, 1540, 1477, 1389, 1337, 1268, 1093, 1046, 858,
786 cm−1; LRMS-EI (m/z) 301 (M+, 100), 258 (19), 189 (29),
150 (28); HRMS-EI (m/z) [M]+ calcd for C19H27NO2 301.2042,
found 301.2052.
(1R,2S,3R,4S)-(+)-3-[(2-Hydroxy-3-tert-butyllbenzylidene)-
amino]isoborneol, (+)-SBAIB-f, 15
The condensation of 3-tert-butylsalicylaldehyde (58 mg,
0.32 mmol) and (1R,2S,3R,4S)-(−)-3-aminoisoborneol 9 (50 mg,
0.29 mmol) was done in 2 mL of MeOH/CH2Cl2 (1 : 3) in the
presence of anhydrous Na2SO4 (100 mg). Yield: 95 mg (98%);
yellow solid, mp 126–128 °C; [α]2D4.5 = +65.17 (c 1.00,
CHCl3);1H NMR (CDCl3, 400 MHz) δ 13.52 (br, 1H), 8.38 (s,
1H), 7.34–7.33 (d, J = 6.4 Hz, 1H), 7.12–7.11 (d, J = 6.2 Hz,
1H), 6.84–6.80 (t, J = 7.6 Hz, 1H), 3.82–3.81 (d, J = 7.5 Hz,
1H), 3.58–3.56 (d, J = 7.5 Hz, 1H)) 2.46 (br, 1H), 1.85–1.80 (m,
2H), 1.61–1.53 (m, 1H), 1.44 (s, 3H), 1.30 (s, 3H), 1.17–1.07
(m, 2H), 1.00 (s, 3H), 0.88 (s, 3H); 13C NMR (CDCl3,
100.6 MHz) δ 166.8, 160.4, 137.4, 130.0, 129.6, 118.8, 117.9,
81.6, 76.9, 53.3, 49.3, 47.2, 34.9, 33.5, 29.3, 26.5, 21.7, 21.6,
11.4; IR (KBr) 3435, 2953, 1736, 1628, 1434, 1388, 1362,
1265, 1202, 1111, 1052, 855, 796, 751, 618 cm−1; LRMS-EI
(m/z) 329 (M+, 100), 286 (88), 178 (38), 91 (40), 77 (22);
HRMS-EI (m/z) [M]+ calcd for C21H31NO2 329.2355, found
329.2348.
(1R,2S,3R,4S)-(+)-3-[(2-Hydroxy-3-methylbenzylidene)-amino]
isoborneol, (+)-SBAIB-d, 13
The condensation of 3-methylsalicylaldehyde (49 mg,
0.35 mmol) and (1R,2S,3R,4S)-(−)-3-aminoisoborneol 9 (50 mg,
0.29 mmol) was done in 2 mL of MeOH/CH2Cl2 (1 : 3) in the
presence of anhydrous Na2SO4 (100 mg). Yield: 85 mg (quanti-
tative); yellow solid, mp 153–155 °C; [α]2D3.6 = +94.3 (c 1.00,
CHCl3);1H NMR (CDCl3, 400 MHz) δ 13.40–13.38 (br, 1H),
8.32 − 8.30 (d, J = 8.0 Hz, 1H), 7.19–7.17 (d, J = 7.3 Hz,
1H), 7.10–7.08 (d, J = 7.4 Hz, 1H), 6.79– 6.76 (t, J = 7.4 Hz,
1H), 3.80 (br, 1H), 3.55–3.53 (d, J = 7.2 Hz, 1H), 2.27 (s, 3H)
(1R,2S,3R,4S)-(+)-3-[(2-Hydroxy-5-tert-butyllbenzylidene)-
amino]isoborneol, (+)-SBAIB-g, 16
The condensation of 5-tert-butylsalicylaldehyde (58 mg,
0.32 mmol) and (1R,2S,3R,4S)-(−)-3-aminoisoborneol 9 (50 mg,
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0.29 mmol) was done in 2 mL of MeOH/CH2Cl2 (1 : 3 ratio) in
the presence of anhydrous Na2SO4 (100 mg). Yield: 93 mg
(96%); yellow solid, mp 133–135 °C; [α]2D4.5 = +76.2 (c 1.00,
CHCl3);1H NMR (CDCl3, 400 MHz) δ 12.97 (br, 1H), 8.37 (s,
1H), 7.37–7.34 (m, 1H), 7.24–7.23 (d, J = 2.4 Hz, 1H),
6.90–6.88 (d, J = 8.7 Hz, 1H), 3.82–3.80 (d, J = 7.6 Hz, 1H),
3.57–3.55 (d, J = 7.6 Hz, 1H), 2.08 (br, 1H), 1.84–1.74 (m, 2H),
1.62–1.53 (m, 1H), 1.31 (s, 9H), 1.26 (s, 3H), 1.18–1.07 (m,
2H), 1.00 (s, 3H), 0.86 (s, 3H);13C NMR (CDCl3, 100.6 MHz) δ
166.3, 159.1, 141.2, 130.0, 127.9, 118.0, 116.7, 81.7, 76.7, 53.3,
49.2, 47.2, 33.9, 33.5, 31.4, 26.5, 21.7, 21.5, 11.3; IR (KBr)
3435, 2954, 1634, 1494, 1390, 1362, 1289, 1266, 1210, 1093,
1054, 827, 620 cm−1; LRMS-EI (m/z) 329 (M+, 100), 314 (76),
286 (29), 178 (58), 147 (27); HRMS-EI (m/z) [M]+ calcd for
C21H31NO2 329.2355, found 329.2350.
122 (72), 107 (35), 77 (25); HRMS-EI (m/z) [M]+ calcd for
C17H23NO2 273.1729, found 273.1726.
General procedure of enantioselective addition of
phenylacetylene to aldehydes (Table 3 and 4)
THF (2 mL) was added to a vial containing (+)-SBAIB-a, 10 or
(−)-SBAIB-1 (20 mol %) in an inert atmosphere box. To this
solution, Et2Zn (2 equiv., 1.1 M in toluene) and phenylacetylene
(2 equiv.) were added successively. After stirring for 4 h to gen-
erate the alkynylzinc–ligand complex aldehyde (50 mg, 1 equiv.)
was added, then it was stirred till reaction finish, as checked by
TLC. Saturated NH4Cl was added (CAUSION! Gas evolution)
and it was extracted with Et2O (3 × 25 mL). The combined Et2O
layer washed with brine, dried (Na2SO4), filtered and concen-
trated. This was then purified by column chromatography (silica
gel 70–230 mesh, eluent: 12 to 15% EtOAc/hexane). The enan-
tiomeric excess of all propargylic alcohols were determined by
Chiral HPLC (condition for all propargylic alcohols: Chiralcel
OD-H, 10% 2-propanol/hexane, 1 mL min−1, 254 nm; except
the flow rate for compounds 29a and 29b: 0.25 mL min−1).
(1R,2S,3R,4S)-(+)-3-[(2-Hydroxynaphthen-1-yl)methylene-
amino]isoborneol, (+)-SBAIB-h, 17
The condensation of 2-hydroxyl-1-naphthaldehyde (56 mg,
0.32 mmol) and (1R,2S,3R,4S)-(−)-3-aminoisoborneol 9 (50 mg,
0.29 mmol) was done in 2 mL of MeOH/CH2Cl2 (1 : 3) in the
presence of anhydrous Na2SO4 (100 mg). Yield: 85 mg (89%);
yellow solid, mp 247–249 °C (decomposed); [α]2D4.8 = +139.5 (c
1.00, MeOH);1H NMR (CDCl3, 400 MHz) δ 8.44–8.42 (d, J =
10.7 Hz, 1H), 7.64–7.60 (t, J = 9.5 Hz, 2H), 7.56–7.54 (d, J =
7.7 Hz, 1H), 7.32–7.28 (m, 1H), 7.18–7.15 (t, J = 7.5 Hz, 1H),
6.86–6.84 (d, J = 9.3 Hz, 1H), 3.94–3.92 (d, J = 7.3 Hz, 1H),
3.58–3.55 (t, J = 6.9 Hz, 1H)) 3.07 (br, 1H), 1.92–1.90 (d, J =
4.5 Hz, 1H), 1.85–1.80 (m, 1H), 1.63–1.55 (m, 1H), 1.27 (s,
3H), 1.18–1.11 (m, 2H), 1.02 (s, 3H), 0.85 (s, 3H);13C NMR
(CDCl3, 100.6 MHz) δ 156.4, 137.7, 134.1, 129.1, 127.9, 125.7,
122.4, 119.9, 117.5, 106.5, 79.9, 69.3, 52.8, 49.2, 47.3, 33.2,
26.5, 21.4, 21.1, 11.3; IR (KBr) 3151, 2920, 2865, 2756, 1741,
1631, 1617, 1516, 1491, 1341, 1309, 1189, 1163, 1105, 1079,
994, 862, 832, 750, 617, 493 cm−1; LRMS-EI (m/z) 323 (M+,
100), 280 (25), 182 (43), 170 (43), 128 (28); HRMS-EI (m/z)
[M]+ calcd for C21H25NO2 323.1885, found 323.1880.
(R)-1,3-Diphenylprop-2-yn-1-ol, 18a,2f,4h,5a,5d,7a
Yield: 95 mg (97%), oil; ee: 91%; Retention time: tr(major)
:
11.25 min, tr(minor): 20.54 min; [α]2D6 = +1.72 (c 1.67, CHCl3);
1
lit.5d [α]2D7 = +2.4 (c 1.67, CHCl3, 96% ee); H NMR (CDCl3,
400 MHz) δ 7.64–7.62 (d, J = 7.2 Hz, 2H), 7.49–7.26 (m, 8H),
5.71–5.69 (d, J = 6.2 Hz, 1H), 2.29–2.27 (d, J = 6.2 Hz, 1H);
13C NMR (CDCl3, 100.6 MHz) δ 140.7, 131.8, 128.7, 128.6,
128.4, 128.3, 126.8, 122.4, 88.8, 86.6, 65.1; IR (KBr) 3338,
3063, 2925, 2872, 2229, 1598, 1489, 1279, 1189, 1030, 961,
916, 757, 619 cm−1; LRMS-EI (m/z) 208 (M+, 100), 191 (25),
145 (65), 129 (38), 102 (29), 77 (37); HRMS-EI (m/z): [M]+
calcd for C15H12O 208.0888, found 208.0884.
(R)-1-(2-Methylphenyl)-3-phenylprop-2-yn-1-ol, 19a4h,5a
Yield: 91 mg (98%), white solid; mp 57–59 °C; ee: 90%; reten-
tion time: tr(major): 9.32 min, tr(minor): 21.13 min; [α]2D6 = −7.9 (c
1
1.13, CHCl3); lit.5a [α]D27 = −10.0 (c 1.13, CHCl3, 96% ee); H
(1S,2R,3S,4R)-(−)-3-[(2-Hydroxybenzylidene)amino]-isoborneol,
(−)-SBAIB-a, 41
NMR (CDCl3, 400 MHz) δ 7.76–7.74 (m, 1H), 7.49–7.44 (m,
2H), 7.34–7.21 (m, 6H), 5.84 (s, 1H), 2.61 (s, 1H), 2.51 (s, 3H);
13C NMR (CDCl3, 100.6 MHz) δ 138.4, 136.0, 131.7, 130.8,
128.5, 128.4, 128.3, 126.6, 126.3, 122.6, 88.7, 86.4, 62.9, 19.0;
IR (KBr) 3337, 3262, 3056, 2969, 2862, 2224, 2602, 1448,
The condensation of salicylaldehyde (173 mg, 1.41 mmol) and
(1S,2R,3S,4R)-(+)-3-aminoisoborneol 43 (200 mg, 1.18 mmol)
was done in 8 mL of MeOH/CH2Cl2 (1 : 3) in the presence of
anhydrous Na2SO4 (400 mg). Yield: 320 mg (99%); yellow
solid, mp 133–135 °C; [α]2D0.2 = −129.2 (c 1.00, MeOH);1H
NMR (400 MHz, CDCl3) δ 13.23 (br, 1H), 8.36 (s, 1H),
7.33–7.24 (m, 2H), 6.96–6.94 (d, J = 8.1 Hz, 1H), 6.89–6.85
(m, 1H), 3.83–3.81 (d, J = 7.6 Hz, 1H), 3.59–3.57 (d, J = 7.6
Hz, 1H), 1.85–1.77 (m, 3H), 1.60–1.54 (m, 1H), 1.27 (s, 3H),
1.20–1.08 (m, 2H), 1.10 (s, 3H), 0.87 (s, 3H);13C NMR
(100.6 MHz, CDCl3) δ 165.7, 161.7, 132.6, 131.6, 118.7, 118.4,
117.3, 81.7, 76.5, 53.3, 49.3, 47.2, 33.5, 26.4, 21.6, 21.5, 11.4;
IR (KBr) 3391, 2951, 1630, 1526, 1480, 1389, 1281, 1209,
1149, 1052, 917, 755, 562 cm−1; LRMS-EI (m/z) 273 (M+,
100), 244 (29), 230 (34), 202 (27), 18 (26), 161 (55), 133 (40),
1460, 1445, 1279, 1174, 1109, 1029, 259, 754, 690 cm−1
;
LRMS-EI (m/z) 222 (M+, 12), 207 (100), 190 (3.8), 145 (17),
129 (21), 115 (23), 91 (33), 77 (19); HRMS-EI (m/z): [M]+
calcd for C16H14O 222.1045, found 222.1085.
(R)-1-(3-Methylphenyl)-3-phenyl-prop-2-yn-1-ol, 20a4h,5a
Yield: 91 mg (98%), oil; ee: 87%; retention time: tr(major)
:
10.89 min and tr(minor): 27.23 min; [α]2D2.7 = +5.1 (c 1.6, CHCl3);
1
lit.5d [α]2D7 = +6.0 (c 1.6, CHCl3, 94% ee); H NMR (CDCl3,
400 MHz) δ 7.52–7.49 (m, 2H), 7.45–7.43 (d, J = 6.5 Hz, 2H),
7.34–7.29 (m, 4H), 7.19–7.17 (d, J = 7.5 Hz, 1H), 5.67 (s, 1H),
This journal is © The Royal Society of Chemistry 2012
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1
2.71 (s, 1H), 2.41 (s, 3H); 13C NMR (CDCl3, 100.6 MHz) δ
140.6, 138.4, 131.8, 129.2, 128.6, 128.6, 128.4, 127.4, 123.8,
122.5, 89.0, 86.5, 65.1, 21.1; IR (KBr) 3350, 3054, 3024, 2971,
2923, 2865, 2232, 1598, 1489, 1442, 1375, 1313, 1260, 1151,
1032, 910, 794, 756, 690 cm−1; LRMS-EI (m/z) 222 (M+, 72),
207 (100), 189 (13), 145 (13), 129 (38), 91 (27), 77 (24);
HRMS-EI (m/z): [M]+ calcd for C16H14O 222.1045, found
222.1041.
lit.5d [α]2D8 = +15.7 (c 1.03, CHCl3, 96% ee); H NMR (CDCl3,
400 MHz) δ 7.49–7.46 (m, 2H), 7.33–7.29 (m, 4H), 7.21–7.19
(d, J = 8.1 Hz, 2H), 6.90–6.88 (m, 1H, 5.66 (s, 1H), 3.82 (s,
3H), 2.88 (br, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 159.8,
142.3, 131.8, 129.7, 128.6, 128.3, 122.4, 119.0, 114.1, 112.2,
88.8, 86.5, 5.0, 55.3; IR (KBr) 3392, 3056, 2938, 2835, 2228,
1599, 1489, 1454, 1435, 1318, 1258, 1156, 1037, 997, 972, 870,
790, 756, 691 cm−1; LRMS-EI (m/z) 238 (M+, 100), 223 (21),
207 (29), 179 (22), 137 (28), 109 (52), 86 (28), 77 (36);
HRMS-EI (m/z) [M]+ calcd for C16H14O2 238.0994, found
238.0990.
(R)-1-(4-Methylphenyl)-3-phenyl-prop-2-yn-1-ol, 21a2f,4h,5d
Yield: 89 mg (96%), pale yellow solid; mp 68–70 °C; ee: 86%;
retention time: tr(major): 9.58 min, tr(minor): 20.52 min; [α]D22.7
=
+3.7 (c 1.0, CHCl3); lit.5d [α]D27 = +4.8 (c 1.0, CHCl3, 92% ee);
1H NMR (CDCl3, 400 MHz) δ 7.53–7.48 (m, 4H), 7.34–7.32
(m, 3H), 7.23–7.21 (d, J = 7.9 Hz, 2H), 5.67 (s, 1H), 2.68 (s,
1H), 2.39 (s, 3H); 13C NMR (CDCl3, 100.6 MHz) δ 138.2,
137.8, 131.8, 129.3, 128.5, 128.3, 126.8, 122.5, 89.0, 86.4,
64.9, 21.2; IR (KBr) 3351, 3054, 2921, 2865, 2228, 1597, 1513,
(R)-1-(4-Methoxyphenyl)-3-phenyl-prop-2-yn-1-ol, 25a4h,5d,7a
Yield: 82 mg (94%), white solid; mp 91–93 °C; ee: 91%; Reten-
tion time: tr(major): 13.56 min, tr(minor): 30.01 min; [α]2D1.3 = +3.6
(c 0.90, CHCl3); lit.7a [α]D15 = +3 (c 0.93, CHCl3, 92% ee); H
1
NMR (CDCl3, 400 MHz) δ 7.55–7.53 (d, J = 8.7 Hz, 2H),
7.49–7.47 (m, 2H), 7.33–7.30 (m, 3H), 6.94–6.92 (d, J = 8.6 Hz
2H), 5.64 (s, 1H), 3.82 (s, 3H), 2.41 (br, 1H); 13C NMR (CDCl3,
100.6 MHz) δ 159.7, 133.0, 131.7, 128.5, 128.3, 128.2, 122.5,
114.0, 88.9, 86.5, 64.7, 55.3; IR (KBr) 3368, 3063, 2958, 2839,
2228, 1612, 1514, 1488, 1414, 1278, 1255, 1172, 1107, 1028,
960, 828, 754, 689 cm−1; LRMS-EI (m/z) 238 (M+, 100), 223
(23), 207 (51), 178 (38), 135 (25), 91 (8), 77 (24); HRMS-EI
(m/z) [M]+ calcd for C16H14O2 238.0994, found 238.0989.
1489, 1442, 1414, 1305, 1261, 1177, 1031, 819, 756, 691 cm−1
;
LRMS-EI (m/z): 222 (M+, 60), 207 (100), 178 (33), 129 (25), 91
(13), 77 (8); HRMS-EI (m/z) [M]+ calcd for C16H14O 222.1045,
found 222.1038.
(R)-1-(4-tert-Butylphenyl)-3-phenylprop-2-yn-1-ol, 22a15
Yield: 77 mg (95%), oil; ee: 89%; retention time: tr(major)
:
7.54 min, tr(minor): 25.63 min; [α]2D0.7 = +2.0 (c 1.15, CHCl3); 1H
NMR (CDCl3, 400 MHz) δ 7.59–7.57 (d, J = 8.3 Hz, 2H),
7.52–7.44 (m, 4H), 7.34–7.32 (m, 3H), 5.69–5.68 (d, J = 5.0
Hz, 1H), 2.57–2.56 (d, J = 5.5 Hz, 1H), 1.36 (s, 1H); 13C NMR
(CDCl3, 100.6 MHz) δ 151.5, 137.7, 131.8, 128.6, 128.3, 126.6,
125.6, 122.5, 88.9, 86.5, 64.9, 34.6, 31.4; IR (KBr) 3368, 3056,
2962, 2867, 2228, 2197, 1738, 1599, 1509, 1489, 1409, 1363,
(R)-1-(2-Chlorophenyl)-3-phenyl-prop-2-yn-1-ol, 26a4h
Yield: 78 mg (91%), white solid; mp 65–67 °C; ee: 91%; Reten-
tion time: tr(major): 9.07 min, tr(minor): 10.74 min; [α]2D2 = −49.3 (c
0.50, CHCl3); lit.4h [α]D25 = −37.9 (c 0.51, CHCl3, 64% ee); H
1
1268, 1203, 1108, 1017, 963, 839, 756, 690, 578 cm−1
;
NMR (CDCl3, 400 MHz) δ 7.85–7.83 (m, 1H), 7.49–7.47 (m,
2H), 7.41–7.39 (m, 1H), 7.35–7.26 (m, 5H), 6.05 (s, 1H), 2.81
(br, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 138.0, 132.8, 131.8
129.8, 129.7, 128.7, 128.5, 128.3, 127.3, 122.3, 87.7, 86.7,
62.4; IR (KBr) 3368, 3063, 2914, 2228, 1739, 1596, 1572,
LRMS-EI (m/z) 264 (M+, 8), 249 (30), 207 (100), 179 (16), 129
(42), 91 (14) 77 (12); HRMS-EI (m/z) [M]+ calcd for C19H20O
264.1514, found 264.1505.
1497, 1469, 1441, 1373, 1267, 1121, 1031, 964, 755, 690 cm−1
;
(R)-1-(2-Methoxyphenyl)-3-phenyl-prop-2-yn-1-ol, 23a4h,5a,5d,7a
Yield: 86 mg (98%), pale yellow solid; mp 55–57 °C; ee: 92%;
LRMS-EI (m/z) 242 (M+, 12), 207 (100), 179 (20), 139 (8), 129
(11), 77 (11); HRMS-EI (m/z) [M]+ calcd for C15H11ClO
242.0498, found 242.0494.
retention time: tr(major): 13.54 min, tr(minor): 17.12 min; [α]D20.7
=
−10.5 (c 1.20, CHCl3); lit.5d [α]D27 = −11.8 (c 1.22, CHCl3, 92%
1
ee); H NMR (CDCl3, 400 MHz) δ 7.68–7.66 (d, J = 7.4 Hz,
(R)-1-(3-Chlorophenyl)-3-phenyl-prop-2-yn-1-ol, 27a4h,5a
1H), 7.50–7.48 (m, 2H), 7.35–7.32 (m, 4H), 7.03–7.00 (t, J =
7.4 Hz, 1H), 6.95–6.93 (d, J = 8.2 Hz, 1H), 5.96 (br, 1H), 3.91
(s, 3H), 3.21 (br, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 156.8,
131.8, 129.7, 128.8, 128.4, 128.2, 128.0, 122.8, 120.9, 110.9,
88.5, 86.1, 61.6, 55.6; IR (KBr) 3400, 3059, 2935, 2835, 2232,
1600, 1490, 1463, 1439, 1286, 1109, 1029, 962, 823, 754,
691 cm−1; LRMS-EI (m/z) 238 (M+, 23), 223 (100), 207 (29),
178 (20), 135 (12), 115 (21), 91 (12), 77 (24); HRMS-EI (m/z)
[M]+ calcd for C16H14O2 238.0994, found 238.0993.
Yield: 79 mg (92%), oil; ee: 85%; retention time: tr(major)
:
9.45 min, tr(minor): 27.71 min; [α]2D2.3 = +11.6 (c 0.60, CHCl3);
1
lit.5a [α]2D7 = +12 (c 0.61, CHCl3, 92% ee); H NMR (CDCl3,
400 MHz) δ 7.49–7.39 (m, 2H), 7.37–7.30 (m, 6H), 7.06–7.01
(m, 1H), 5.68 (s, 1H), 2.88 (br, 1H); 13C NMR (CDCl3,
100.6 MHz) δ 143.1, 143.0, 131.8, 130.2, 130.1, 128.8, 128.4,
122.4, 122.3, 122.1, 88.1, 86.9, 64.3; IR (KBr) 3338, 3063,
2874, 2227, 1614, 1593, 1489, 1443, 1316, 1247, 1133, 1033,
916, 897, 875, 792, 756, 690 cm−1; LRMS-EI (m/z) 244 (12),
242 (M+, 35), 207 (100), 189 (17), 179 (40), 178 (60), 139 (11),
129 (35), 89 (11), 77 (21); HRMS-EI (m/z) [M]+ calcd for
C15H11ClO 242.0498, found 242.0505.
(R)-1-(3-Methoxyphenyl)-3-phenyl-prop-2-yn-1-ol, 24a4h,5a,5d,7a
Yield: 81 mg (93%), oil; ee: 91%; retention time: tr(major)
:
16.21 min, tr(minor): 28.93 min; [α]2D1.3 = +13.0 (c 1.03, CHCl3);
1634 | Org. Biomol. Chem., 2012, 10, 1625–1638
This journal is © The Royal Society of Chemistry 2012

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(R)-1-(4-Chlorophenyl)-3-phenyl-prop-2-yn-1-ol, 28a,2f,4h,5a,5d,7a
(45), 102 (22), 77 (20); HRMS-EI (m/z) [M]+ calcd for
C15H11FO 226.0794, found 226.0790.
Yield: 83 mg (97%), white solid; mp 61–63 °C; ee: 88%; reten-
tion time: tr(major): 9.38 min and tr(minor): 29.49 min; [α]2D2 = +7.2
(R)-1-(Naphthalen-1-yl)-3-phenyl-prop-2-yn-1-ol, 32a4h,7a,13c
1
(c 1.25, CHCl3); lit.5d [α]D28 = +7.2 (c 1.25, CHCl3, 94% ee); H
NMR (CDCl3, 400 MHz) δ 7.54–7.52 (d, J = 8.4 Hz, 2H),
7.48–7.45 (m, 2H), 7.36–7.29 (m, 5H), 5.65 (s, 1H), 2.92 (br,
1H); 13C NMR (CDCl3, 100.6 MHz) δ 139.1, 134.2, 131.8,
128.8, 128.8, 128.4, 128.1, 122.1, 88.3, 87.0, 64.3; IR (KBr)
3350, 3054, 2918, 2861, 2227, 1734, 1597, 1579, 2489, 1442,
1407, 1294, 1238, 1179, 1090, 1014, 960, 847, 801, 749,
688 cm−1; LRMS-EI (m/z) 244 (8), 242 (M+, 24), 207 (100),
178 (48), 129 (30), 77 (15); HRMS-EI (m/z) [M]+ calcd for
C15H11ClO 242.0498, found 242.0503.
Yield: 83 mg (99%), white solid; mp 82–84 °C; ee: 84%; reten-
tion time: tr(major): 16.91 min, tr(minor): 36.97 min; [α]2D3.1 = −23.4
1
(c 1.84, CHCl3); lit.7a [α]D19 = −26 (c 1.84, CHCl3, 91% ee); H
NMR (CDCl3, 400 MHz) δ 8.39–8.37 (d, J = 8.4 Hz, 1H),
7.95–7.86 (m, 3H), 7.61–7.49 (m, 5H), 7.35–7.30 (m, 3H), 6.34
(s, 1H), 2.79 (br, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 135.7,
134.0, 131.8, 130.6, 129.4, 128.8, 128.3, 126.5, 125.9, 125.3,
124.7, 124.0, 122.5, 88.6, 87.3, 63.3; IR (KBr) 3367, 3051,
2918, 2852, 2228, 1738, 1597, 1509, 1489, 1366, 1228, 1162,
1008, 954, 912, 802, 779, 756, 690 cm−1; LRMS-EI (m/z) 258
(M+, 100), 257 (92), 241 (47), 229 (85), 228 (51), 181 (47), 129
(64), 77 (36); HRMS (m/z) [M]+ calcd for C19H14O 258.1045,
found 258.1037.
(R)-1-(2-Bromophenyl)-3-phenyl-prop-2-yn-1-ol, 29a13c,16
Yield: 73 mg (93%), white solid; mp 65–67 °C; ee: 88%; Reten-
tion time: tr(major): 41.27 min, tr(minor): 44.53 min; [α]2D2.1 = −53.9
(c 1.05, CHCl3); lit.13c [α]D23 = −55.7 (c 1.475, CHCl3, 77% ee);
1H NMR (CDCl3, 400 MHz) δ 7.86–7.84 (d, J = 7.7 Hz, 1H),
7.59–7.58 (d, J = 7.9 Hz, 1H), 7.49–7.47 (m, 2H), 7.40–7.36
(m, 1H), 7.34–7.29 (m, 3H), 7.23–7.18 (m, 1H), 6.02 (s, 1H),
2.82 (br, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 139.5, 133.0,
131.8, 131.8, 130.0, 128.7, 128.3, 127.9, 122.8, 122.3, 87.7,
86.7, 64.6; IR (KBr) 3351, 3062, 2923, 2857, 2230, 1738, 1597,
1569, 1489, 1467, 1440, 1375, 1313, 1190, 1120, 1027, 965,
815, 755, 690, 630 cm−1; LRMS-EI (m/z) 287 (6), 285 (M+, 6),
207 (100), 129 (11), 77 (13); HRMS-EI (m/z) [M]+ calcd for
C15H11BrO 285.9993, found 285.9998.
(R)-1-(Naphthalen-2-yl)-3-phenyl-prop-2-yn-1-ol,
33a,2f,4h,5d,7a,13c
Yield: 81 mg (98%), white solid; mp 111–113 °C; ee: 85%;
retention time: tr(major): 15.25 min, tr(minor): 56.14 min; [α]D24.3
=
−11.2 (c 1.30, CHCl3); lit.5d [α]D28 = −7.8 (c 1.30, CHCl3, 96%
1
ee); H NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.89–7.86 (m,
3H), 7.75–7.73 (m, 1H), 7.54–7.51 (m, 4H), 7.36–7.32 (m, 3H),
5.87 (s, 1H), 2.86 (br, 1H); 13C NMR (CDCl3, 100.6 MHz) δ
138.0, 133.3, 133.2, 131.8, 128.7, 128.6, 128.4, 128.3, 127.7,
126.3, 125.6, 124.7, 122.4, 88.8, 86.9, 65.2; IR (KBr) 3245,
3054, 2918, 2852, 2668, 2224, 1737, 1598, 1488, 1366, 1282,
1-(3-Fluorophenyl)-3-phenyl-prop-2-yn-1-ol, 30a13b
1168, 1123, 1012, 997, 960, 944, 862, 830, 754, 690 cm−1
;
LRMS-EI (m/z) 258 (M+, 100), 257 (44), 241 (31), 229 (71),
127 (34), 77 (17); HRMS (m/z): [M]+ calcd for C19H14O
258.1045, found 258.1036.
Yield: 81 mg (88%), oil; ee: 83%; retention time: tr(major)
:
9.76 min, tr(minor): 35.24 min; [α]2D2.3 = +11.3 (c 1.0, CHCl3);
1
lit.13b [α]D25 = +10 (c 1.0, EtOH, 85% ee); H NMR (CDCl3,
400 MHz) δ 7.61 (s, 1H), 7.49–7.47 (m, 3H), 7.37–7.30 (m,
5H), 5.66 (s, 1H), 2.82 (br, 1H); 13C NMR (CDCl3, 100.6 MHz)
δ 142.5, 134.5, 131.8, 129.9, 128.8, 128.5, 128.4, 126.9, 124.9,
122.1, 88.1, 87.0, 64.3; IR (KBr) 3338, 3059, 2923, 2870, 2230,
1596, 1576, 1473, 1489, 1427, 1313, 1278, 1188, 1095, 1033,
998, 969, 789, 756, 711, 690 cm−1; LRMS-EI (m/z): 226 (M+,
100), 225 (79), 209 (31), 207 (24), 196 (48), 77 (23); HRMS-EI
(m/z) [M]+ calcd for C15H11FO 226.0794, found 226.0790.
(R)-1-(Furan-2-yl)-3-phenyl-prop-2-yn-1-ol, 34a,11,2f,4e,4h,5d
Yield: 101 mg (98%), brown semi-solid; ee: 88%; retention
time: tr(major): 10.30 min, tr(minor): 19.18 min; [α]2D6 = +18.4 (c
1.12, CHCl3); lit.5d [α]D28 = +10.4 (c 1.12, CHCl3, 96% ee); H
1
NMR (CDCl3, 400 MHz) δ 7.50–7.48 (m, 2H), 7.44–7.43 (d, J
= 0.7 Hz, 1H), 7.34–7.30 (m, 3H), 6.53–6.52 (d, J = 3.2 Hz,
1H), 6.38–6.37 (m, 1H), 5.71–5.70 (d, J = 4.0 Hz, 1H),
3.01–3.00 (d, J = 5.2 Hz, 1H); 13C NMR (CDCl3, 100.6 MHz) δ
152.9, 143.1, 131.8, 128.8, 128.3, 122.1, 110.5, 107.9, 86.3,
85.7, 58.6; IR (KBr) 3379, 3054, 2918, 2861, 2280, 1631, 1598,
1489, 1443, 1384, 1308, 1223, 1180, 1142, 1071, 1009, 969,
916, 816, 756, 690 cm−1; LRMS-EI (m/z) 198 (M+, 46), 197
(44), 196 (66), 181(80), 168 (53), 152 (46), 129 (84), 115 (100),
105 (58), 77 (42); HRMS-EI (m/z) [M]+ calcd for C13H10O2
198.0681, found 198.0688.
(R)-1-(4-Fluorophenyl)-3-phenyl-prop-2-yn-1-ol, 31a4h,5a,7a
Yield: 84 mg (92%), yellow solid; mp 40–42 °C; ee: 88%; reten-
tion time: tr(major): 8.92 min, tr(minor): 24.97 min; [α]2D2.3 = +4.8 (c
1
1.0, CHCl3); lit.7a [α]D15 = +3 (c 0.94, CHCl3, 93%ee); H NMR
(CDCl3, 400 MHz) δ 7.60–7.57 (m, 2H), 7.49–7.46 (m, 2H),
7.37–7.30 (m, 3H), 7.10–7.05 (t, J = 8.7 Hz, 2H), 5.67 (s, 1H),
2.69 (br, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 164.0–161.5 (d,
JC,F = 246.5 Hz), 136.5–136.5 (d, JC,F = 3.0 Hz), 131.8, 128.8,
128.7–128.6 (d, JC,F = 9.1 Hz), 128.4, 122.3, 115.6–155.4 (d,
JC,F = 22.1 Hz), 88.5, 86.9, 64.4; IR (KBr) 3350, 3065, 2874,
2228, 1893, 1738, 1605, 1508, 1489, 1413, 1295, 1225, 1096,
1031, 1015, 963, 837, 856, 691 cm−1; LRMS-EI (m/z): 226
(M+, 100), 225 (97), 209 (43), 197 (66), 183 (32), 148 (37), 129
(R)-3-Phenyl-1-(thiophen-2-yl)prop-2-yn-1-ol, 35a12,4e,5d
Yield: 91 mg (95%), pale brown solid; mp 79–81 °C; ee: 91%;
Retention time: tr(major): 11.06 min, tr(minor): 21.20 min; [α]D25
=
+18.7 (c 1.07, CHCl3); lit.5d [α]D28 = +20.7 (c 1.07, CHCl3, 96%
This journal is © The Royal Society of Chemistry 2012
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(R)-4-Methyl-1-phenyl-pent-1-yn-1-ol, 39a,3a,3e,5c,6f,7a,13a
Yield: 102 mg (84%), oil; ee: 73%; retention time: tr(major)
ee); 1H NMR (CDCl3, 400 MHz) δ 7.51–7.49 (m, 2H),
7.36–7.31 (m, 4H), 7.26–7.25 (m, 1H), 7.01–7.00 (m, 1H),
5.90–5.88 (d, J = 6 Hz, 1H), 2.95–2.93 (d, J = 6.5 Hz, 1H); 13C
NMR (CDCl3, 100.6 MHz) δ 144.7, 131.8, 128.8, 128.4, 126.8,
126.2, 125.7, 122.1, 88.1, 86.0, 60.7; IR (KBr) 3400, 3063,
2918, 2861, 2224, 1738, 1596, 1489, 1441, 1383, 1225, 1121,
1028, 942, 851, 838, 757, 689, 570 cm−1; LRMS-EI (m/z) 214
(M+, 84), 213 (79), 197 (75), 185 (100), 152 (51), 129 (64), 111
(46), 102 (49), 97 (41), 77 (28); HRMS-EI (m/z) [M]+ calcd for
C13H10OS 214.0452, found 214.0444.
:
5.83 min, tr(minor): 10.11 min; [α]2D2 = +1.3 (c 6.30, CHCl3); lit.3a
[α]2D3 = +3.2 (c 6.8, CHCl3, 98% ee); 1H NMR (CDCl3,
400 MHz) δ 7.45–7.43 (m, 2H), 7.31–7.29 (m, 3H), 4.41 (s,
1H), 2.34 (s, 1H), 2.02–1.94 (m, 1H), 1.09–1.05 (m, 6H); 13C
NMR (CDCl3, 100.6 MHz) δ 131.7, 128.4, 128.3, 122.7, 89.0,
85.5, 68.3, 34.7, 18.2, 17.5; IR (KBr) 3367, 2962, 2929, 2872,
2224, 1738, 1598, 1489, 1468, 1443, 1383, 1252, 1069, 1028,
987, 755, 690 cm−1; LRMS-EI (m/z) 174 (M+, 8), 173 (2), 145
(3), 131 (100), 103 (18), 77 (14); HRMS-EI (m/z) [M]+ calcd for
C12H14O 174.1045, found 174.1041.
(R,E)-1,5-Diphenylpent-1-en-4-yn-3-ol, 36a3d,5d,7a
Yield: 84 mg (94%), white solid; mp 77–79 °C; ee: 64%; Reten-
tion time: tr(major): 16.64 min, tr(minor): 56.07 min; [α]2D2 = +1.7 (c
(R)-4,4-Dimethyl-1-phenyl-pent-1-yn-1-ol, 40a,3a,3e,13a,14a,14b
1
1.25, CHCl3); lit.5d [α]D26 = +0.5 (c 1.25, CHCl3, 92% ee); H
Yield: 91 mg (83%), oil; ee: 87%; retention time: tr(major)
:
5.63 min, tr(minor): 7.18 min; [α]2D4 = +1.4 (c 4.0, CHCl3); lit.14b
[α]2D3 = +1.56 (c 4.0, CHCl3, 97% ee); 1H NMR (CDCl3,
400 MHz) δ 7.45–7.43 (m, 2H), 7.31–7.30 (m, 3H), 4.25–4.24
(d, J = 2.5 Hz, 1H), 2.11 (s, 1H), 1.07 (s, 9H); 13C NMR
(CDCl3, 100.6 MHz) δ 131.7, 128.3, 128.3, 122.8, 89.0, 85.6,
71.8, 36.2, 25.4; IR (KBr) 3399, 3059, 2964, 2869, 2219, 1738,
1598, 1489, 1443, 1364, 1322, 1238, 1254, 1206, 979, 755,
690 cm−1; LRMS-EI (m/z) 188 (M+, 11), 173 (10), 145 (5), 131
(100), 115 (5), 103 (15), 77 (16); HRMS-EI (m/z) [M]+ calcd for
C13H16O 188.1201, found 188.1196.
NMR (CDCl3, 400 MHz) δ 7.53–7.51 (m, 2H), 7.45–7.42 (m,
2H), 7.38–7.27 (m, 6H), 6.87–6.83 (d, J = 15.8 Hz, 1H),
6.45–6.39 (dd, J = 15.8, 6.0 Hz, 1H), 5.33–5.32 (d, J = 5.6 Hz,
1H), 2.70 (br, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 136.1,
132.0, 131.8, 128.6, 128.4, 128.2, 128.1, 126.9, 122.4, 88.1,
86.4, 63.4; IR (KBr) 3350, 3026, 2857, 2224, 1738, 1594, 1489,
1442, 1375, 1088, 1066, 1011, 963, 754, 690 cm−1; LRMS-EI
(m/z) 234 (M+, 47), 233 (61), 215 (55), 205 (47), 129 (100), 115
(39), 102 (67), 91 (52), 77 (46); HRMS-EI (m/z): [M] + calcd for
C17H14O 234.1045, found 234.1051.
(S)-1,3-Diphenylprop-2-yn-1-ol, 18b3d
(R,E)-2-Methyl-1,5-diphenylpent-1-en-4-yn-3-ol, 37a2f,5b
Yield: 97 mg (99%), oil; ee: 89%; retention time: tr(minor)
:
Yield: 84 mg (99%), low melting solid; ee: 88%; retention time:
13.28 min, tr(major): 24.89 min; [α]2D0.7 = −1.4 (c 0.9, CHCl3);
lit.3d [α]2D5 = −1.6 (c 0.88, CHCl3, 94% ee).
t
r(major): 9.62 min, tr(minor): 41.74 min; [α]2D2.4 = −25.3 (c 1.02,
1
CHCl3); lit.5b [α]2D7 = −23.2 (c 1.02, acetone, 99%ee); H NMR
(CDCl3, 400 MHz) δ 7.50–7.48 (t, J = 4.3 Hz, 2H), 7.39–7.33
(m, 7H), 7.28–7.26 (m, 1H), 6.79 (s, 1H), 5.18 (s, 1H), 2.46 (br,
1H), 2.09 (s, 3H); 13C NMR (CDCl3, 100.6 MHz) δ 137.1,
136.8, 131.8, 129.1, 128.6, 128.3, 128.2, 127.3, 126.8, 122.5,
88.1, 86.3, 68.8, 14.2; IR (KBr) 3339, 3056, 2918, 2852, 2224,
1737, 1598, 1489, 1442, 1364, 1280, 1176, 1070, 1007, 919,
755, 691 cm−1; LRMS-EI (m/z) 248 (M+, 11), 247 (23), 231
(91), 215 (88), 191 (12), 129 (44), 115 (47), 105 (100), 91 (28),
77 (38); HRMS-EI (m/z) [M]+ calcd for C18H16O 248.1201,
found 248.1205.
(S)-1-(2-Methylphenyl)-3-phenylprop-2-yn-1-ol, 19b2f,7c
Yield: 91 mg (99%), white solid; ee: 90%; retention time:
t
r(minor): 10.14 min and tr(major): 23.49 min; [α]2D2 = +12.5 (c 1.2,
CHCl3); lit.7c [α]D27 = +12.2 (c 1.2, CHCl3, 86% ee).
(S)-1-(4-Methylphenyl)-3-phenyl-prop-2-yn-1-ol, 21b7c
Yield: 89 mg (95%), pale yellow solid; ee: 88%; retention time:
t
r(minor): 10.21 min, tr(major): 22.47 min; [α]2D2 = −5.0 (c 1.2,
CHCl3); lit.7c [α]D27 = −5.2 (c 1.2, CHCl3, 86%ee).
(R)-1-Cyclohexyl-3-phenyl-prop-2-yn-1-ol, 38a5d,13c,13d
Yield: 88 mg (93%), oil; ee: 66%; retention time: tr(major)
:
(S)-1-(2-Methoxyphenyl)-3-phenyl-prop-2-yn-1-ol, 23b6f
6.04 min, tr(minor): 11.98 min; [α]2D2.3 = −7.6 (c 1.29, CHCl3);
1
lit.5d [α]2D7 = −8.8 (c 1.29, CHCl3, 86%ee); H NMR (CDCl3,
Yield: 87 mg (99%), pale yellow solid; ee: 90%; Retention time:
tr(minor): 15.67 min, tr(major): 19.72 min; [α]2D2 = +11.1 (c 0.53,
CHCl3); lit.6f [α]D25 = +12.7 (c 0.53, CHCl3, 95% ee).
400 MHz) δ 7.45–7.43 (m, 2H), 7.31–7.29 (m, 3H), 4.38 (s,
1H), 2.23 (s, 1H), 1.94–1.91 (d, J = 11.5 Hz, 2H), 1.81–1.78 (d,
J = 12.0 Hz, 2H), 1.71–1.62 (m, 2H), 1.33–1.26 (m, 5H); 13C
NMR (CDCl3, 100.6 MHz) δ 131.7, 128.3, 128.2, 122.8, 89.3,
85.6, 67.6, 44.3, 28.7, 28.2, 26.4, 26.0, 25.9; IR (KBr) 3350,
2935, 2852, 2228, 1738, 1598, 1489, 1449, 1375, 1082, 1028,
983, 755, 690 cm−1; LRMS-EI (m/z) 214 (M+, 60), 213 (3), 131
(100), 103 (15), 77 (14), 55 (15); HRMS-EI (m/z) [M]+ calcd for
C15H18O 214.1358, found 214.1360.
(S)-1-(4-Methoxyphenyl)-3-phenyl-prop-2-yn-1-ol, 25b7c
Yield: 86 mg (98%), white solid;. ee: 88%; retention time:
t
r(minor): 15.40 min, tr(major): 35.43 min; [α]2D3 = −4.8 (c 1.7,
CHCl3); lit.7c [α]D27 = −4.2 (c 1.7, CHCl3, 80%ee).
1636 | Org. Biomol. Chem., 2012, 10, 1625–1638
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(S)-1-(2-Chlorophenyl)-3-phenyl-prop-2-yn-1-ol, 26b2f,7c
2-(Benzoyloxy)-3-methylbutanoic acid, 39ab
Yield: 82 mg (95%), white solid; ee: 87%; Retention time:
The above 39aa (750 mg, 2.69 mmol), NaIO4 (5.75 g,
26.94 mmol), HMTA (1.88 g, 13.47 mmol) in THF/H2O
(30 mL, 1 : 1) was stirred for 15 min, after which time OsO4
(1.3 mL, 0.13 mmol of a 2.5 wt. % solution in t-BuOH) was
added. This was stirred for 15 h at room temperature then for
10 h at 50 °C. The reaction mixture was cooled to room tempera-
ture and quenched slowly with saturated NaHSO3 solution. This
was extracted with DCM (3 × 100 mL). The combined DCM
layer was extracted with saturated NaHCO3 solution (3 ×
100 mL), then this aqueous layer was acidified and extracted
with DCM (3 × 100 mL). The combined DCM layer was
washed with brine, dried over anhydrous Na2SO4 and concen-
trated to give solid 39ab (500 mg) with benzoic acid as a by-
product. This was carried to the next step without further
purification.
t
r(minor): 10.29 min, tr(major): 12.29 min; [α]2D4 = +47.1 (c 1.4,
CHCl3); lit.7c [α]D25 = +46.2 (c 1.4, CHCl3, 83%ee).
(S)-1-(2-Bromophenyl)-3-phenyl-prop-2-yn-1-ol, 29b16,13c
Yield: 71 mg (91%), white solid; ee: 86%; retention time:
t
r(minor): 44.86 min, tr(major): 48.18 min; [α]2D2.5 = +54.2 (c 1.0,
CHCl3), lit.13c,16 for R enantiomer [α]D23 = −55.7 (c 1.48, CHCl3,
77%ee).
(S)-3-Phenyl-1-(thiophen-2-yl)prop-2-yn-1-ol, 35b12,4e,5d
Yield: 87 mg (91%), pale brown solid; ee: 89%; Retention time:
t
r(minor): 12.06 min, tr(major): 24.14 min; [α]2D2.5 = −20.2 (c 1.00,
1-Methoxy-3-methyl-1-oxobutan-2-yl-benzoate, 39ac
CHCl3); lit.5d [α]D28 = +20.4 (c 1.07, CHCl3, 96% ee); For R
isomer see ref. 12.
The above solid mixture (39ab) was taken into methanol
(20 mL) followed by the addition of catalytic amount of conc.
H2SO4. The resulting mixture was refluxed for 20 h then cooled
to room temperature and basified with saturated NaHCO3. This
was extracted with DCM (3 × 100 mL) and the combined
organic layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated to get the crude product. This was
purified by column chromatography (silica gel 70–230 mesh,
ethyl acetate/hexane (1 : 9)) to get colorless oil 39ac. Yield:
300 mg (47%, for 2nd step); [α]2D3 = −17.4 (c 2.00, benzene);
(S,E)-2-Methyl-1,5-diphenylpent-1-en-4-yn-3-ol, 37b7c
Yield: 82 mg (97%), low melting solid; ee: 82%; retention time:
tr(minor): 10.62 min, tr(major): 51.71 min; [α]2D2.5 = +32.0 (c 1.00,
CHCl3); lit.7c [α]D27 = +31.6 (c 1.02, CHCl3, 71% ee).
1
lit.13a for S isomer [α]2D3.2 = +26.2 (c 1.91, benzene); H NMR
(S)-4,4-Dimethyl-1-phenyl-pent-1-yn-1-ol, 40b13a
(CDCl3, 400 MHz) δ 8.10–8.07 (m, 2H), 7.60–7.56 (m, 1H),
7.47–7.43 (t, J = 7.9 Hz, 2H), 5.08–5.07 (d, J = 4.6 Hz, 1H),
3.76 (s, 1H), 2.41–2.33 (m, 1H), 1.10–1.08 (m, 6H); 13C NMR
(CDCl3, 100.6 MHz) δ 170.2, 166.1, 133.3, 129.8, 129.6, 128.4,
77.2, 52.1, 30.3, 18.9, 17.4.
Yield: 108 mg (99%), oil; ee: 91%; retention time: tr(minor)
:
5.94 min, tr(major): 7.75 min; [α]1D7 = −2.1 (c 5.20, CHCl3); lit.13a
[α]2D3 = −2.5 (c 5.13, CHCl3, 97%ee).
Synthesis of 39ac from 39a for the confirmation of the absolute
configuration of 39a
Synthesis of 40ad and 40ai to confirm the absolute configuration
of 32a
4-Methyl-1-phenylpent-1-yn-3-yl benzoate 39aa
1-Methoxy-3,3-methyl-1-oxobutan-2-yl benzoate, 40ad. The
synthesis of 40ad followed the same procedure as for 39ac. [α]D23
= −6.2 (c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz) δ
8.09–8.07 (t, J = 7.1 Hz, 2H), 7.60–7.56 (t, J = 6.0 Hz, 1H),
7.47–7.44 (t, J = 7.8 Hz, 2H), 4.82 (s, 1H), 3.75 (s, 3H), 1.13 (s,
9H); 13C NMR (CDCl3, 100.6 MHz) δ 169.6, 166.2, 133.3,
129.8, 129.5, 128.4, 80.4, 51.8, 33.9, 26.3.
39a (600 mg, 3.44 mmol) was dissolved in dry CH2Cl2
(12 mL), followed by the addition of Et3N (522 mg, 5.17 mmol)
and benzoyl chloride (0.16 g, 1.2 mmol) at 0 °C. The reaction
mixture was warmed to room temperature over two hours, then
quenched with saturated NaHCO3 at room temperature and
stirred for a further 30 min. The aqueous phase was extracted
with CH2Cl2 (3 × 75 mL) and the combined organic layer was
dried over anhydrous Na2SO4. The organic solvent was concen-
trated under vacuum to afford crude product, which was purified
by flash column chromatography (silica gel 60–230 mesh, 10%
ethyl acetate/hexane) to give products 39aa as a colorless oil.
(S)-2-Hydroxy-3,3-dimethylbutanoic acid, 40af. The prep-
aration of 40af followed the literature procedure.14c [α]D19.3
=
1
+4.2 (c 1.00, CH3OH); lit.14c [α]D = +3.9 (c 1.00, CH3OH); H
NMR (CDCl3, 400 MHz) δ 7.26 (br, 2H), 3.89 (s, 1H), 1.00 (s,
9H); 13C NMR (CDCl3, 100.6 MHz) δ 178.5, 78.3, 35.1, 25.7.
1
Yield: 927 mg (97%); H NMR (CDCl3, 400 MHz) δ 8.12–8.10
(d, J = 8.2 Hz, 2H), 7.59–7.56 (t, J = 7.3 Hz, 1H), 7.48–7.44
(m, 4H), 7.33–7.27 (m, 3H), 5.72–5.71 (d, 1H), 2.29–2.21 (m,
1H), 1.19–1.15 (m, 6H); 13C NMR (CDCl3, 100.6 MHz) δ
165.6, 133.1, 131.9, 130.1, 129.8, 128.5, 128.4, 128.2, 122.4,
85.9, 85.3, 69.9, 32.9, 18.3, 17.8.
(S)-1-Methoxy-3,3-methyl-1-oxobutan-2-yl benzoate, 40ai.
Esterification of 40af and benzoyl protection of 40ag were done
according to the same procedures as for the preparation of 39ac
1
and 39aa, respectively. [α]2D2 = +6.9 (c 1.00,CHCl3). H and 13C
NMR were the same as those of 40ad.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1625–1638 | 1637

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Lett., 2004, 6, 1193–1195; (b) J. Sun, X. Pan, Z. Dai and C. Zhu, Tetrahe-
dron: Asymmetry, 2008, 19, 2451–2457; (c) P. Y. Wu, H. L. Wu,
Y. Y. Shen and B. J. Uang, Tetrahedron: Asymmetry, 2009, 20, 1837–
1841; (d) S. Gou, Z. Ye, Z. Huang and X. Ma, Appl. Organomet. Chem.,
2010, 24, 374–379.
8 References for camphor-derived ligands in enantioselective alkynylation
of ketones: (a) T. F. Briggs, M. D. Winemiller, B. Xiang and
D. B. Collum, J. Org. Chem., 2001, 66, 6291–6298; (b) G. Li, X. Li,
X. Jia, L. Chan and A. S. C. Chan, Angew. Chem., Int. Ed., 2003, 42,
5057–5058; (c) G. Lu, X. Li, Y. M. Li, F. Y. Kwong and A. S. C. Chan,
Adv. Synth. Catal., 2006, 348, 1926–1933.
9 (a) P. F. Xu, Y. S. Chen, S. I. Lin and T. J. Lu, J. Org. Chem., 2002, 67,
2309–2314; (b) M. J. Bosiak, M. P. Krzeminski, P. Jaisankar and
M. Zaidlewicz, Tetrahedron: Asymmetry, 2008, 19, 956–963.
Selected other references of synthesis of AIB: (c) Organic Syntheses,
Wiley & Sons, New York, 2004; Coll. Vol.10, p 305; (d) Organic Synth-
eses, Wiley & Sons, New York, 2009; Coll. Vol. 11, p 702–707;
(e) M. P. Bonner and E. R. Thornton, J. Am. Chem. Soc., 1991, 113,
1299–1308.
Acknowledgements
The authors thank Ms. L. M. Hsu at the Instruments Center,
National Chung Hsing University, for her help in obtaining
HRMS, and the National Science Council of the Republic of
China for financially supporting this research under Contract
NSC 97-2113-M-259-002-MY3.
Notes and references
1 (a) B. M. Trost and A. H. Weiss, Org. Lett., 2006, 8, 4461–4464;
(b) B. M. Trost and A. H. Weiss, Angew. Chem., Int. Ed., 2007, 46,
7664–7666; (c) L. Lin, Q. Zhao, A. N. Li, F. Ren, F. Yang and R. Wang,
Org. Biomol. Chem., 2009, 7, 3663–3665; (d) J. Wu and J. S. Panek,
Angew. Chem., Int. Ed., 2010, 49, 6165–6168; (e) S. Archambaud,
F. Legrand, K. A. Julienne, S. Collet, A. Guingant and M. Evain,
Eur. J. Org. Chem., 2010, 1364–1380.
2 Reviews: (a) D. E. Frantz, R. Fassler, C. S. Tomooka and E. M. Carreira,
Acc. Chem. Res., 2000, 33, 373–381; (b) L. Pu, Tetrahedron, 2003, 59,
9873–9886; (c) P. G. Cozzi, R. Hilgraf and N. Zimmermann, Eur. J. Org.
Chem., 2004, 4095–4105; (d) G. Lu, Y. M. Li, S. S. Li and
A. S. C. Chan, Coord. Chem. Rev., 2005, 249, 1736–1744;
(e) B. M. Trost and A. H. Weiss, Adv. Synth. Catal., 2009, 351, 963–983;
(f) D. L. Usanov and H. Yamamoto, J. Am. Chem. Soc., 2011, 133,
1286–1289 and reference therein.
3 Selected examples for zinc triflate, base and chiral inducer mediated alky-
nylation: (a) D. E. Frantz, R. Fassler and E. M. Carreira, J. Am. Chem.
Soc., 2000, 122, 1806–1807; (b) Z. Chen, W. Xiong and B. Jiang, Chem.
Commun., 2002, 2098–2099; (c) D. Boyall, D. E. Frantz and
E. M. Carreira, Org. Lett., 2002, 4, 2605–2606; (d) M. Yamshita,
K. I. Yamada and K. Tomioka, Adv. Synth. Catal., 2005, 347, 1649–
1652; (e) D. P. G. Emmerson, W. P. Hems and B. G. Davis, Org. Lett.,
2006, 8, 207–210.
4 Selected examples for dialkylzinc and chiral inducer mediated alkynyla-
tion of aldehydes: (a) Z. B. Li and L. Pu, Org. Lett., 2004, 6, 1065–1068;
(b) S. Dahmen, Org. Lett., 2004, 6, 2113–2116; (c) Y. F. Kang, L. Liu,
R. Wang, W. J. Yan and Y. F. Zhou, Tetrahedron: Asymmetry, 2004, 15,
3155–3159; (d) C. Wolf and S. Liu, J. Am. Chem. Soc., 2006, 128,
10996–10997; (e) G. Blay, I. Fernandez, A. M. Aleixandre and J.
R. Pedro, J. Org. Chem., 2006, 71, 6674–6677; (f) Z. B. Li, T. D. Liu
and L. Pu, J. Org. Chem., 2007, 72, 4340–4343; (g) J. Ruan, G. Lu,
L. Xu, Y. M. Li and A. S. C. Chan, Adv. Synth. Catal., 2008, 350, 76–84;
(h) G. Blay, L. Cardona, I. A. M. Fernandez Aleixandre, M. C. Munoz
and J. R. Pedro, Org. Biomol. Chem., 2009, 7, 4301–4308;
(i) M. Rachwalski, S. Lesniak and P. Kielbansinki, Tetrahedron: Asymme-
try, 2010, 21, 2687–2689.
10 J. Hartung, S. Drees, M. Greb, P. Schmidt, I. Svoboda, H. Fuess,
A. Murso and D. Stalke, Eur. J. Org. Chem., 2003, 2388–2408 has
reported 61% yield for the synthesis of (+)-SBAIB-a, 10 from
(−)-AIB, which was improved to 99% yield for (+)-SBAIB-a, 10, by
our method.
11 (a) R. Takita, K. Yakura, T. Ohshima and M. Shibasaki, J. Am. Chem.
Soc., 2005, 127, 13760–13761. Till today, there were only four reports
(refs 2f, 4e, 4h and 5d), of which ref. 4e is the first report to specify the
configuration of 1-(furan-2-yl)-3-phenyl-prop-2-yn-1-ol as the S enantio-
mer, which has [α]2D5 = +34 (c 0.58, CHCl3, 83% ee). To assign the
configuration of the same molecule, ref. 4e cited ref. 4a in which neither
the absolute configuration nor specific rotation of this compound was
mentioned. Thereafter, the reports ref. 2f and ref. 4h cited ref. 4e to
specify the configuration of this compound. As all of the propargylic
alcohols that we have got by (+)-SBAIB-a, 10, catalyzed reaction were in
the R configuration, we had a doubt about the earlier report. As a proof,
the ref. 4e wrongly assigned the configuration of 1-(3-furyl)-3-phenyl-2-
propyn-1-ol as the S enantiomer, which has [α]2D5 = +3.0 (c 0.53, CHCl3,
89% ee). This is revealed from their back reference, ref. 11a, which
reported that the same compound with R configuration, specific rotation
[α]2D4 = +1.8 (c = 2.10, CHCl3) (99% ee) and with same order of major
and minor peaks in the HPLC. This confirms to us that the configuration
of 1-(furan-2-yl)-3-phenyl-prop-2-yn-1-ol in ref. 4e would have
been wrongly assigned. Therefore, compound 34a should have
configuration.
R
12 The ref. 4e also has the same controversy, as that above, for 1-(2-thiophe-
nyl)-3-phenyl-2-propyn-1-ol. It mentioned that the S isomer has [α]D25
=
+20 (c 0.53, CHCl3, 90% ee), however, it doesn’t have any back refer-
ence for this compound. As all of our propargylic alcohols possess R
configuration, we suspected that our compound 35a should also have R
configuration.
5 Selected examples for dialkylzinc, Ti(OiPr)4 and chiral inducer mediated
alkynylation of aldehydes: (a) D. Moore and L. Pu, Org. Lett., 2002, 4,
1855–1857; (b) G. Gao, D. Moore, R.-G. Xie and L. Pu, Org. Lett.,
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wrongly written as compared to their HPLC data.
6 Examples for the influence of achiral additives on alkynylation reaction:
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15 1-(4-Tert-butylphenyl)-3-phenylprop-2-yn-1-ol 22a has the first peak in
HPLC as a major peak like all other propargylic alcohols, which are R in
configuration, generated by (+)-SBAIB-1-catalyzed reactions. With the
support of our proposed mechanism, we are proposingthat compound 5a
should possess R configuration.
16 The similarities of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-ol 29a with
all other ortho-substituted propargyl alcohols ((R)-1-(2-methylphenyl)-3-
phenylprop-2-yn-1-ol 19a, (R)-1-(2-methoxyphenyl)-3-phenyl-prop-2-yn-
1-ol 23a, (R)-1-(2-chlorophenyl)-3-phenyl-prop-2-yn-1-ol 26a) are as
follows; 1) The first peak is the major peak in HPLC data; 2) It has (−)
sign of specific rotation like all other ortho-substituted propargylic alco-
hols. Hence as there is no report for the configuration of this compound,
we are proposing that 1-(2-bromophenyl)-3-phenylprop-2-yn-1-ol 29a
could have R configuration.
7 Camphor-derived ligands used in enantioselective alkynylation of alde-
hydes: (a) Z. Xu, C. Chen, J. Xu, M. Miao, W. Yan and R. Wang, Org.
1638 | Org. Biomol. Chem., 2012, 10, 1625–1638
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