Meerwein-Ponndorf-Verley alkynylation of aldehydes: Essential modification of aluminium alkoxides for rate acceleration and asymmetric synthesis

Article abstract of DOI:10.1039/b411090k

A novel carbonyl alkynylation has been accomplished based on utilization of the Meerwein-Ponndorf-Verley (MPV) reaction system. The success of the MPV alkynylation crucially depends on the discovery of the remarkable ligand acceleration effect of 2,2′-biphenol. For example, the alkynylation of chloral (2c) with the aluminium alkoxide 6 (R = Ph), prepared in situ from Me₃Al, 2,2′-biphenol and 2-methyl-4-phenyl-3-butyn-2-ol (1a) as an alkynyl source, proceeded smoothly in CH₂Cl₂ at room temperature to give the desired propargyl alcohol 3ca in almost quantitative yield after 5 h stirring. The characteristic feature of this new transformation involving no metal alkynides can be visualized by the fact that the alkynyl group bearing keto carbonyl was transferred successfully to aldehyde carbonyl without any side reactions on keto carbonyl. Although the use of (S)-1,1′-bi-2-naphthol and its simple analogues was found to be unsuitable for inducing asymmetry in this reaction, design of new chiral biphenols bearing a certain flexibility of the biphenyl axis led to satisfactory results in terms of enantioselectivity as well as reactivity.

Full text of DOI:10.1039/b411090k

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A R T I C L E
Meerwein–Ponndorf–Verley alkynylation of aldehydes: Essential
modification of aluminium alkoxides for rate acceleration and
asymmetric synthesis†
Takashi Ooi, Tomoya Miura, Kohsuke Ohmatsu, Akira Saito and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo,
Kyoto 606-8502, Japan. E-mail: maruoka@kuchem.kyoto-u.ac.jp
Received 22nd July 2004, Accepted 15th September 2004
First published as an Advance Article on the web 7th October 2004
A novel carbonyl alkynylation has been accomplished based on utilization of the Meerwein–Ponndorf–Verley
(MPV) reaction system. The success of the MPV alkynylation crucially depends on the discovery of the remarkable
ligand acceleration effect of 2,2-biphenol. For example, the alkynylation of chloral (2c) with the aluminium
alkoxide 6 (R = Ph), prepared in situ from Me3Al, 2,2-biphenol and 2-methyl-4-phenyl-3-butyn-2-ol (1a) as an
alkynyl source, proceeded smoothly in CH2Cl2 at room temperature to give the desired propargyl alcohol 3ca in
almost quantitative yield after 5 h stirring. The characteristic feature of this new transformation involving no metal
alkynides can be visualized by the fact that the alkynyl group bearing keto carbonyl was transferred successfully to
aldehyde carbonyl without any side reactions on keto carbonyl. Although the use of (S)-1,1-bi-2-naphthol and its
simple analogues was found to be unsuitable for inducing asymmetry in this reaction, design of new chiral biphenols
bearing a certain flexibility of the biphenyl axis led to satisfactory results in terms of enantioselectivity as well as
reactivity.
Introduction
In 1925 Meerwein1 and Verley2 independently reported
the reduction of aldehydes with primary alcohols in the
presence of aluminium ethoxide, and in the next year Ponndorf3
extended the scope to the reduction of ketones using second-
ary alcohols and their aluminium alkoxides, particularly
aluminium isopropoxide (Al(OPri )3). This type of reaction,
i.e., Meerwein–Ponndorf–Verley (MPV) reduction is believed
to proceed via a six-membered transition state [A] and can be
performed under mild conditions both in the laboratory and
on a large scale without sophisticated experimental technique,
generally exhibiting high chemoselectivity (Scheme 1).4
Accordingly, numerous studies have been carried out to expand
Scheme 1
the inherent potential of this classical yet important organic
transformation as exemplified by the recent elaborations of
lanthanides and transition metal catalysts as well as modified
aluminium alkoxides.5,6 During our continuous effort toward
the development of new MPV reduction systems, we have been
interested for some time in the possibility of alkyl transfer
through the MPV process, which should provide a practical,
nonorganometallic way for carbonyl alkylation.7–9 However,
developing the MPV alkylation seemed to be a great challenge
because of the inertness of alkyl transfer [B] compared to the
facile hydride transfer [A] in the MPV reduction. In pursuing this
project, we chose 1,1-dimethyl-3-alkyl-2-propyn-1-ol (1) as an
alkynyl source in view of the susceptibility of generating the
corresponding carbanion through the formation of acetone,
and envisioned that employment of appropriate aluminium
ligand would lead to stabilization of the desired transition state,
facilitating the expected alkynyl transfer. Herein we wish to
describe details of the development of the MPV alkynylation
of various reactive aldehydes.10 The reaction was further lifted
to the enantioselective stage for the first time by designing a
new, axially chiral aluminium alkoxide with conformational
flexibility.
Results and discussion
1. Development of the Meerwein–Ponndorf–Verley (MPV)
alkynylations
First, we prepared Al(OC(CH3)2CCPh)3 as
a typical
aluminium alkoxide for the MPV alkynylation by treatment of
propargylic alcohol 1a (3 equiv) in CH2Cl2 with a 1 M hexane
solution of Me3Al (1 equiv) at room temperature for 30 min, and
evaluated its intrinsic reactivity with 2,2-dichlorodecanal (2a)11,12
as a representative substrate (Scheme 2). Upon stirring an
equimolar mixture of the aldehyde 2a and the in situ generated
Al(OC(CH3)2CCPh)3 at room temperature for 5 h, the desired
secondary propargyl alcohol 3aa was obtained in only a trace
amount and most of the starting aldehyde was recovered. This
result led us to investigate the effect of aluminium ligands on the
reaction and several commercially available phenol derivatives
were examined. Although the use of (PhCCC(CH3)2O)2AlOPh
[derived from 1a and Me2AlOPh] brought no appreciable
rate acceleration, aluminium alkoxide with two phenoxy
ligands, PhCCC(CH3)2OAl(OPh)2, on reaction with 2a
under otherwise identical conditions gave 3aa in higher yield
(16%) (Scheme 2). Employment of o-phenylenedioxy and o,o-
biphenylenedioxy ligands further enhanced the rate of alkynyl-
ation and 3aa was obtained in 20% and 53% yields, respectively.
Eventually, a synthetically useful level of chemical yield was
attained with (o,o-biphenylenedioxy)methylaluminium (4) in
† Electronic supplementary information (ESI) available: Preparation
and spectroscopic characterization of tertiary alkynyl alcohols 1,
aldehydes 2 and chiral ligands 10. See http://www.rsc.org/suppdata/ob/
b4/b411090k/
3 3 1 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 1 2 – 3 3 1 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1 MPV alkynylation of various aldehydesa
Entry
Aldehyde, 2 R1
Alkyl source 1 R (equiv)
Al reagent
Reaction time/h
Product 3 (% yield)b
Product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CH(Cl)(CH2) 7CH3 (2b)
Ph (3)
4
2
1
5
5
5
5
2
2
5
5
5
12
2
5
5
5
2.5
2.5
5
40 (78:32)c
3ba
3bb
3bb
3aa
3aa
3aa
3ab
3ab
3ca
3ca
3ca
3ca
3cb
3cb
3da
3da
3db
3db
3ea
3ea
3ea
3ea
3eb
3eb
3fa
CHCHPh (3)
CHCHPh (3)
Ph (1)
Ph (3)
Ph (3)
CHCHPh (1)
CHCHPh (3)
Ph (1)
Ph (3)
Ph (3)
4
80 (75:25)c
4 (10 mol%)
72 (76:24)c
53
70
61
42
66
81
97
84
63
85
99
52
81
58
89
67
C(Cl2)(CH2) 7CH3 (2a)
4
4
5
4
4
CCl3 (2c)
4
4
5
Ph (3)
4 (20 mol%)
CHCHPh (1)
CHCHPh (2)
Ph (1)
4
4
CBr3 (2d)
C6F5 (2e)
4
Ph (3)
4
CHCHPh (1)
CHCHPh (3)
Ph (1)
Ph (3)
Ph (3)
4
4
4
4
5
5
12
1.5
1.5
1
85
75
51
79
5
Ph (3)
4 (10 mol%)
CHCHPh (1)
CHCHPh (3)
Ph (5)
4
4
99
CCPh (2f)
4d
54e
a Unless otherwise noted, alcohol 1 was reacted with Al reagent 4 or 5 (1 equiv) in CH2Cl2 at room temperature for 10 min, and then treated with
1
aldehyde 2 under the given reaction conditions. b Isolated yield. c Erythro/threo ratio of 3 (R = Ph or CHCHPh) was determined by H NMR
analysis. The relative configuration of these isomers was correlated, after hydrogenation to the corresponding saturated chlorohydrins, with that
of alkylation products of 2-chlorodecanal by the corresponding Grignard reagents.19 d Use of 5 equiv of Al reagent. e The alkynylation product 3fa
(R = Ph, R1 = PhCC) works as a hydride source for the MPV reduction of the starting aldehyde to furnish 1,5-diphenyl-1,4-pentadiyn-3-one (17%)
as a side-reaction product.
However, the alkynylation proceeds catalytically in certain cases
(entries 3, 12 and 22). Acetylenic aldehyde 2f can also be trans-
formed to the corresponding secondary propargylic alcohol
3fa under the MPV alkynylation conditions using 6 (R = Ph),
albeit the product can function as a good hydride donor to
the starting aldehyde through the MPV process, producing the
corresponding ketone and alcohol as side products.16 Since
the MPV reaction is reversible, the overall efficiency is
subtly influenced by the steric and electronic properties of the
aldehydic substrates 2 and alkynyl donors 1 as well as reaction
conditions as shown in Table 1.
Scheme 2
the presence of excess propargylic alcohol 1a (3 equiv) (entry 5
in Table 1).13
A
variety of reactive aldehydes14 were examined as
Scheme 3
substrates for this MPV alkynylation system with 1a and
1b, and the results are summarized in Table 1. The requisite
(propargyloxy)aluminium reagents 6 are also readily accessible
from (o,o-biphenylenedioxy)(t-butoxy)aluminium (5) and 1 by
the ligand exchange and the effectiveness of the preparative
method was also demonstrated (Scheme 3 and entries 6, 11 and
21).15 The reaction generally requires a stoichiometric amount
of aluminium alkoxides, probably because of the difficulty
of ligand exchange between the in situ formed aluminium
alkoxide of the product and the tertiary propargyl alcohol 1.
One characteristic feature of the MPV alkynylation is the
chemoselective transfer of functionalized alkynyl groups to
aldehyde carbonyls. For instance, functionalized aluminium
reagent 7 can be readily prepared from the corresponding
tertiary alcohol 1c and 4, and the subsequent reaction with
chloral (2c) was found to proceed smoothly at room temperature
to furnish alcohol 3cc in 85% yield without suffering from any
undesired reactions on keto carbonyl (Scheme 4).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 1 2 – 3 3 1 9
3 3 1 3

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Table 2 Asymmetric MPV alkynylation of various reactive aldehydesa
Entry
Aldehyde (R1)
Alkyl source (R)
Time/h
Yield (%)b
ee (%)c (config)d
Product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C(Br2)(CH2)7CH3 (2g)
Ph
Ph
1.5
1.5
1.5
1
1.5
1
78
88
82
84
81
70
72
85
99
73
87
94
71
30fg
64e
81
74
78 (R)
80
82
67
83 (R)
85
71
3ga
3ga
3gb
3ha
3hb
3ia
CHCHPh
Ph
CHCHPh
Ph
CHCHPh
Ph
CHCHPh
CCPh
Ph
C(Br2)(CH2)3CH3 (2h)
C(Br2)CH2Ph (2i)
CCl3 (2c)
5
3ib
18
1.5
1.5
18
1.5
5
3ca
3cb
3cd
3da
3db
3dd
3ja
CBr3 (2d)
90 (R)
83
86
CHCHPh
CCPh
Ph
CClCHPh (2j)
1.5
96
a Unless otherwise noted, aldehyde 2 was treated with in situ generated aluminium alkoxide 9b (1 equiv) in the presence of 1 (1 equiv) in distilled
toluene at 0 °C. b Isolated yield. c Enantiopurity was determined by HPLC analysis using a following chiral column with hexane/i-PrOH as solvent:
Daicel Chiralcel OJ for entries 1, 2, 12 and 13; Daicel Chiralcel OD for entries 3, 4, 6, 8, 10 and 11; Daicel Chiralpak AD for entries 5, 7, 9 and
14. d Absolute configuration was established, after conversion to the known products, by comparing the optical rotation with the literature values.
f
See the Experimental Section. e With aluminium alkoxide 9a. Use of each 2 equiv of Al reagent and 1. g The alkynylation product 3ja (R = Ph,
R1 = PhCHCCl) works as a hydride source for the MPV reduction of the starting aldehyde to furnish 2-chloro-1,5-diphenyl-1-penten-4-yn-3-one
and 2-chloro-3-phenyl-2-propen-1-ol as side-reaction products.
Scheme 4
Scheme 5
2. Development of new chiral aluminium alkoxides for the
asymmetric Meerwein–Ponndorf–Verley (MPV) alkynylations
With this information, we assumed that certain flexibility
of the biphenyl axis would be prerequisite to attain an ample
ligand acceleration effect, and undertook the design of a new,
axially chiral aluminium alkoxide 9 (Scheme 5). The requisite
optically pure biphenol, (S)-10, can be readily prepared from
(S)-1,1-bi-2-naphthol in six-step sequences as illustrated in
Scheme 6. Sequential treatment of (S)-10a (1 equiv) in toluene
with Me3Al in hexane and 1a (1 equiv) at room temperature
for 1 h generated a conformationally flexible chiral aluminium
alkoxide 9a (R = Ph). This subsequently reacted with 2,2-
dibromodecanal (2g) in the presence of an additional 1 equiv of
1a (R = Ph) at 0 °C for 1.5 h to furnish 3ga in 78% yield, whose
enantiomeric excess was determined to be 64% ee as included in
Scheme 5 (entry 1 in Table 2).
In light of the remarkable ligand acceleration effect exerted by
o,o-biphenyldioxy moiety of 6, we further envisaged that the
employment of chiral C2-symmetric biphenyl type compounds
as an aluminium ligand would lead to the asymmetric version
of this unprecedented transformation: this, if successful, could
provide a new yet practical method for the asymmetric synthesis
of optically active propargylic alcohols,17,21 versatile and useful
chiral building blocks in organic synthesis.
On the basis of this hypothesis, we first used commercially
available (S)-1,1-bi-2-naphthol as a chiral ligand and examined
the asymmertic Meerwein–Ponndorf–Verley type alkynyl transfer
reaction of 2,2-dibromodecanal (2g) as a representative system.
Thus, the chiral aluminium alkoxide 8a (R = Ph) was prepared
by the simple treatment of (S)-1,1-bi-2-naphthol (1 equiv) with
Me3Al (1 equiv) in toluene at room temperature for 0.5 h and
followed by 2-methyl-4-phenyl-3-butyn-2-ol (1a, 1 equiv) for an
additional 0.5 h. Subsequent reaction with the aldehyde 2g in the
presence of an additional 1 equiv of 1a at 0 °C for 18 h gave rise to
the corresponding secondary propargyl alcohol 3ga in 23% yield
with moderate enantioselectivity (50% ee).18 Encouraged by the
initial result, we attempted the use of (S)-3,3-diphenyl-1,1-bi-2-
naphthol-derived aluminium alkoxide 8b (R = Ph), which turned
out to diminish both reactivity and selectivity (5% yield, 15% ee
at 0 °C for 11 h and at room temperature for 3 h) (Scheme 5).
Scheme 6 (a) Tf2O, i-Pr2NEt, CH2Cl2. (b) MeMgI, then ArMgBr,
NiCl2(dppe), ether. (c) NaH, MOMCl, THF. (d) BuLi, THF, then dry
Br2. (e) o-MOMO-PhB(OH)2, Pd(PPh3)4, Ba(OH)2·8H2O, DME, H2O.
(f) conc. HCl, dioxane.
3 3 1 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 1 2 – 3 3 1 9

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according to literature procedures.11,14 Other simple chemicals
were purchased and used as such.
Fortunately, switching the aryl moiety (Ar) to b-naphthyl
(9b) further increased both the chemical yield and the
enantioselectivity (88%, 81% ee) (Scheme 5 and entry 2).
Other selected examples summarized in Table 2 demons-
trated the effectiveness of the present system in the
asymmetric MPV alkynylation of various reactive aldehydes. It
should be particularly emphasized that facile enantioselective
transfer of enyne and diyne moieties appeared feasible to
produce the corresponding optically active, more conjugated
secondary propargylic alcohols (entries 3, 5, 7, 9, 10, 12 and
13), indicating the distinct advantage of this method. Although
the highest enantioselectivity was observed in the reaction
with a-chlorocinnamaldehyde, the chemical yield was not
synthetically satisfactory mainly due to the intervention of the
MPV hydride transfer process (entry 14).
General procedure for Meerwein–Ponndorf–Verley (MPV)
alkynylation of 2,2-dichlorodecanal (2a) with aluminium
alkoxides drived from various ligands
To a degassed solution of a ligand (0.5 mmol) in freshly dis-
tilled CH2Cl2 (5 mL) was added a 1 M hexane solution of
Me3Al (0.5 mL, 0.5 mmol) dropwise at room temperature
and the mixture was stirred for 0.5 h. After the addition of a
solution of alkynyl alcohol 1a (80.1 mg, 0.5 mmol) in freshly
distilled CH2Cl2 (1 mL), the resulting mixture was stirred for an
additional 0.5 h. 2,2-Dichlorodecanal (2a; 112.6 mg, 0.5 mmol)
was then introduced and the reaction mixture was stirred for
5 h at room temperature. The resulting solution was poured
into 1 M HCl and extractive workup was performed with ether.
The combined extracts were washed with brine and dried over
Na2SO4. Removal of volatiles and purification of the residue by
column chromatography on silica gel (EtOAc–hexane = 1:12 as
eluant) gave the corresponding alcohol 3aa: 1H NMR (CDCl3)
d 7.47–7.50 (2H, m, Ph), 7.30–7.36 (3H, m, Ph), 4.83 (11H,
d, J = 8.8 Hz, CHOH), 2.77 (1H, dd, J = 8.8, 1.2 Hz, OH),
2.29–2.38 (2H, m, CH2CCl2), 1.74 (2H, quint, J = 6.8 Hz,
CH2CCCl2), 1.20–1.44 (10H, m, 5CH2), 0.88 (3H, t, J = 6.8 Hz,
CH3); IR (liquid film) 3423, 2955, 2926, 2855, 2237, 1599, 1491,
1466, 1445, 1379, 1236, 1069, 951, 756, 691 cm−1. Anal. calcd
for C18H24Cl2O: C, 66.06; H, 7.39; Cl, 21.66. Found: C, 65.87;
H, 7.58; Cl, 21.45.
Summary
We have successfully developed
a
MPV alkynylation
procedure which is highly effective for the selective alkynyl-
ation of aldehydes under mild conditions. The alkynylation
can be performed without using alkynyl metal reagents by
taking advantage of the ligand-acceleration effect of modified
aluminium reagents. The asymmetric version of this reaction
has also been achieved by the employment of newly designed
axially chiral biphenol ligands bearing conformational flexibility.
Thus far, successful MPV alkynylation has been limited to reac-
tive aldehydes. Nevertheless, the present study sheds light on an
entirelynewaspectof MPVreactionsystem, which, togetherwith
the inherent advantage of MPV reactions, makes it an attractive
tool for chemo- and stereoselective carbonyl alkylations.
General procedure for MPV alkynylation of various reactive
aldehydes with aluminium alkoxide 6
Experimental
General
2,2-Biphenol (93.1 mg, 0.5 mmol) was placed in a dry two-neck
flask with a stirring bar, and freshly distilled CH2Cl2 (5 mL)
was introduced. After the suspension was carefully degassed, a
1 M hexane solution of Me3Al (0.5 mL, 0.5 mmol) was added
dropwise at room temperature and the mixture was stirred for
0.5 h. The subsequent treatment with a solution of alkynyl
alcohol 1 (0.5–1.5 mmol) in freshly distilled CH2Cl2 (1.0 mL)
was followed by the continuous stirring for 0.5 h to generate 6
[6 can also be generated by the treatment of a stock solution
of 5 with 1 (1:1 molar ratio) at room temperature for 0.5 h].
Then, a reactive aldehyde (0.5 mmol) was added and the result-
ing mixture was stirred for 1–12 h at room temperature. The
reaction was quenched with 1 N HCl and extractive workup
was performed with ether. The organic extracts were washed
with brine and dried over Na2SO4. Evaporation of solvents and
purification of the residual oil by column chromatography on
silica gel (CH2Cl2–hexane or EtOAc–hexane as eluant) gave the
corresponding alkynyl alcohol.
Infrared (IR) spectra were recorded on a Shimadzu FT-IR
8200A spectrometer. H NMR spectra were measured on a
1
Varian Gemini-300 spectrometer and a JEOL JNM-FX400
spectrometer. Analytical gas–liquid phase chromatography
(GLC) was performed on Shimadzu GC-14B instruments
equipped with a flame ionization detector and a capillary
column of PEG-HT (0.25 × 25 000 mm) using nitrogen as
carrier gas. High performance liquid chromatography (HPLC)
was done with Shimadzu 10A instruments using 4.6 mm × 25 cm
Daicel Chiralcel OD, OJ and Chiralpak AD. Optical rotations
were measured on a JASCO DIP-1000 digital polarimeter.
All experiments were carried out under an atmosphere of dry
argon. For thin layer chromatography (TLC) analysis through-
out this work, Merck precoated TLC plates (silica gel 60 GF254
,
0.25 mm) were used. The products were purified by preparative
column chromatography on silica gel (E. Merck 9385). The
high-resolution mass spectra (HRMS) were conducted at the
School of Agriculture, Hokkaido University and at the School
of Engineering, Kyoto University, and also performed on
Applied Biosystems Mariner API-TOF workstation and JEOL
JMS-HX100. Microanalyses were accomplished at the School
of Pharmaceutical Sciences, Kyoto University.
In experiments requiring dry solvents, ether and tetra-
hydrofuran (THF) were purchased from Kanto Chemical Co.
Inc.as“Dehydrated”.Benzeneandhexaneweredriedoversodium
metal. N,N-Dimethylformamide (DMF) was stored over
4 Å molecular sieve pellets. Dichloromethane (CH2Cl2) was
freshly distilled from calcium hydride, and toluene was freshly
distilled from sodium metal. Pyridine and triethylamine
(Et3N) were stored over potassium hydroxide (KOH) pellets.
Trimethylaluminium (Me3Al) was kindly supplied from Toso-
Finechem. Co. Ltd., Japan. A stock solution of 5 was prepared
by sequential treatment of 2,2-biphenol with 1 equiv each
of Me3Al and freshly distilled t-BuOH in CH2Cl2 at room
temperature. 2,2-Dihalogenated and 2-halogenated aldehydes
were prepared from the corresponding aliphatic aldehydes
Alkynyl alcohol 3ba
1H NMR (CDCl3) d 7.43–7.49 (2H, m, Ph, erythro and threo
isomers), 7.29–7.37 (3H, m, Ph, erythro and threo isomers),
4.75 (0.78H, dd, J = 8.4, 3.6 Hz, CHOH, erythro isomer), 4.66
(0.22H, dd, J = 6.4, 5.6 Hz, CHOH, threo isomer), 4.13 (0.78H,
ddd, J = 9.6, 4.4, 3.6 Hz, CHCl, erythro isomer), 4.07 (0.22H,
ddd, J = 9.6, 5.6, 4.0 Hz, CHCl, threo isomer), 2.53 (0.78H, d,
J = 8.4 Hz, OH, erythro isomer), 2.48 (0.22H, d, J = 6.4 Hz, OH,
threo isomer), 1.74–2.12 (2H, m, CH2CCl, erythro and threo
isomers), 1.16–1.73 (12H, m, 6CH2, erythro and threo isomers),
0.88 (3H, t, J = 6.8 Hz, CH3, erythro and threo isomers); IR
(liquid film) 3382, 2928, 2855, 2233, 1599, 1491, 1466, 1443,
1379, 1124, 1032, 756, 691 cm−1. Anal. calcd for C18H25ClO: C,
73.83; H, 8.60; Cl, 12.11. Found: C, 73.74; H, 8.77; Cl, 11.65.
Determination of the relative configuration of the product 3ba
The relative configuration of these isomers were correlated,
after hydrogenation to the corresponding saturated
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 1 2 – 3 3 1 9
3 3 1 5

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chlorohydrins with 10% Pd/C and hydrogen gas in MeOH, with
that of alkylation products of 2b by the corresponding Grignard
reagent.19 4-Chloro-1-phenyl-3-dodecanol: 1H NMR (CDCl3) d
7.25–7.34 (2H, m, Ph, erythro and threo isomers), 7.16–7.25 (3H,
m, Ph, erythro and threo isomers), 3.96–4.05 (0.78H, m, CHOH,
erythro isomer), 3.87–3.94 (0.22H, m, CHOH, threo isomer),
3.70–3.78 (0.78H, m, CHCl, erythro isomer), 3.59–3.66 (0.22H,
m, CHCl, threo isomer), 2.86–2.96 (0.78H, m, PhCH, erythro
isomer), 2.78–2.86 (0.22H, m, PhCH, threo isomer), 2.61–2.78
(1H, m, PhCH, erythro and threo isomers), 1.98 (0.78H, d,
J = 6.4 Hz, OH, erythro isomer), 1.93 (0.22H, d, J = 7.2 Hz,
OH, threo isomer), 1.75–1.94 (2H, m, CH2CCl, erythro and threo
isomers), 1.64–1.75 (2H, m, CH2CPh, erythro and threo isomers),
1.42–1.62 (2H, m, CH2CCCl, erythro and threo isomers), 1.18–
1.42 (10H, br s, 5CH2, erythro and threo isomers), 0.88 (3H, t,
J = 6.4 Hz, CH3, erythro and threo isomers); IR (liquid film)
3412, 3028, 2926, 2855, 1603, 1497, 1454, 1377, 1307, 1047, 748,
700 cm−1. Anal. calcd for C18H29ClO: C, 72.82; H, 9.85; Cl, 11.94.
Found: C, 73.09; H, 10.09; Cl, 11.69.
915, 756, 693 cm−1. Anal. calcd for C15H17F5O: C, 60.41; H, 2.37.
Found: C, 60.43; H, 2.58.
Alkynyl alcohol 3eb
1H NMR (CDCl3) d 7.26–7.40 (5H, m, Ph), 7.00 (1H, d,
J = 16.5 Hz, PhCH), 6.16 (1H, dd, J = 16.5, 1.8 Hz, PhCCH),
5.93 (1H, d, J = 7.5 Hz, CHOH), 2.65 (1H, d, J = 7.5 Hz, OH);
IR (KBr) 3394, 2212, 1659, 1527, 1506, 1281, 1020, 990, 753,
690 cm−1. Anal. calcd for C17H9F5O: C, 62.97; H, 2.80. Found:
C, 63.16; H, 2.81.
Alkynyl alcohol 3fa20
1H NMR (CDCl3) d 7.45–7.53 (4H, m, Ph), 7.29–7.39 (6H, m,
Ph), 5.59 (1H, d, J = 7.6 Hz, CHOH), 2.41 (1H, d, J = 7.6 Hz,
OH); IR (liquid film) 3298, 3229, 2232, 1597, 1489, 1443, 1300,
1032, 1015, 995, 914, 754, 689 cm−1.
MPV alkynylation of chloral with aluminium alkoxide 7
To a degassed solution of 2,2-biphenol (93.1 mg, 0.5 mmol) in
freshly distilled CH2Cl2 (5 mL) was added a 1 M hexane solution
of Me3Al (0.5 mL, 0.5 mmol) dropwise at room temperature and
the mixture was stirred for 0.5 h. A solution of alkynyl alcohol
1c (244.3 mg, 1 mmol) in freshly distilled CH2Cl2 (1 mL) was
added to the reaction mixture, and the stirring was continued for
an additional 0.5 h. Freshly distilled chloral (73.7 mg, 0.5 mmol)
was added to the solution, and the resulting mixture was stirred
for 8 h at room temperature. The reaction solution was poured
into 1 N HCl and extracted with ether. The ethereal extracts were
washed with brine and dried over Na2SO4. Removal of volatiles
and purification of the residual oil by column chromatography
on silica gel (CH2Cl2–hexane = 6:1 as eluant) gave the desired
alkynyl alcohol 3cc (143.5 mg, 0.43 mmol, 85%): 1H NMR
(CDCl3) d 7.66 (2H, m, Ph), 7.52 (2H, m, Ph), 5.06 (1H, d, J =
9.0 Hz, CHOH), 3.31 (1H, br d, J = 9.0 Hz, OH), 1.34 (9H, s,
t-Bu); IR (liquid film) 3302, 2972, 2367, 2242, 1674, 1603, 1477,
1396, 1367, 1279, 1194, 1175, 1082, 964, 827, 768, 746 cm−1.
Anal. calcd for C15H15Cl3O2: C, 54.00; H, 4.53; Cl, 31.88. Found:
C, 54.09; H, 4.69; Cl, 31.60.
Alkynyl alcohol 3bb
1H NMR (CDCl3) d 7.25–7.42 (5H, m, Ph, erythro and threo
isomers), 7.00 (1H, d, J = 16.5 Hz, PhCH, erythro and threo
isomers), 6.19 (1H, dt, J = 16.5, 2.1 Hz, PhCCH, erythro and
threo isomers), 4.67–4.75 (0.75H, m, CHOH, erythro isomer),
4.58–4.65 (0.25H, m, CHOH, threo isomer), 4.09 (0.75H,
ddd, J = 8.7, 4.8, 3.3 Hz, CHCl, erythro isomer), 4.03 (0.25H,
ddd, J = 9.6, 5.4, 4.2 Hz, CHCl, threo isomer), 2.49 (0.75H, d,
J = 8.4 Hz, OH, erythro isomer), 2.45 (0.25H, d, J = 6.6 Hz,
OH, threo isomer), 1.74–2.05 (2H, m, CH2CCl, erythro and
threo isomers), 1.51–1.70 (2H, m, CH2CCCl, erythro and threo
isomers), 1.18–1.51 (10H, m, 5CH2, erythro and threo isomers),
0.88 (3H, t, J = 6.9 Hz, CH3, erythro and threo isomers); IR
(liquid film) 3381, 3032, 2953, 2855, 2212, 1465, 1448, 1379,
1155, 1030, 955, 748, 691 cm−1. Anal. calcd for C20H27ClO: C,
75.33; H, 8.53; Cl, 11.12. Found: C, 75.27; H, 8.53; Cl, 11.18.
Confirmation of the relative configuration of the product 3bb
The relative configuration of these isomers was determined by
the same procedure as described above.19 6-Chloro-1-phenyl-
5-tetradecanol: 1H NMR (CDCl3) d 7.22–7.34 (2H, m, Ph,
erythro and threo isomers), 7.14–7.22 (3H, m, Ph, erythro and
threo isomers), 3.95–4.02 (0.75H, m, CHOH, erythro isomer),
3.85–3.92 (0.25H, m, CHOH, threo isomer), 3.68–3.76 (0.75H,
m, CHCl, erythro isomer), 3.56–3.65 (0.25H, m, CHCl, threo
isomer), 2.63 (2H, t, J = 7.2 Hz, PhCH2, erythro and threo
isomers), 1.90 (0.75H, d, J = 6.8 Hz, OH, erythro isomer), 1.83
(0.25H, d, J = 7.6 Hz, OH, threo isomer), 1.11–1.83 (20H, m,
10CH2, erythro and threo isomers), 0.88 (3H, t, J = 7.2 Hz, CH3,
erythro and threo isomers); IR (liquid film) 3429, 3026, 2926,
2856, 2367, 2338, 1719, 1605, 1497, 1454, 1377, 1290, 1070, 746,
698 cm−1. Anal. calcd for C20H33ClO: C, 73.93; H, 10.24; Cl,
10.91. Found: C, 74.21; H, 10.17; Cl, 10.68.
Enantioselective MPV alkynylation of 2,2-dibromodecanal (2g)
with various chiral aluminium alkoxides
To a carefully degassed solution of a chiral binaphthyl ligand
(0.3 mmol) in freshly distilled toluene (3 mL) was added a 1 M
hexane solution of Me3Al (0.3 mL, 0.3 mmol) dropwise at room
temperature and the mixture was stirred for 0.5 h. A solution
of 2-methyl-4-phenyl-3-butyn-2-ol (1a; 96.1 mg, 0.6 mmol) in
freshly distilled toluene (1 mL) was introduced and the resulting
mixture was stirred for an additional 0.5 h. Then, a solution of
2,2-dibromodecanal (2g; 94.2 mg, 0.3 mmol) in distilled toluene
(0.5 mL) was carefully added at 0 °C and the reaction mixture
was stirred for 1–18 h at 0 °C. The reaction was quenched with
1 M HCl and extracted with ether. The ethereal extracts were
washed with brine, dried over Na2SO4 and concentrated. The
residual oil was purified by column chromatography on silica
gel (CH2Cl2–hexane or EtOAc–hexane as eluant) to afford the
desired alkynyl alcohol 3ga in an enantioselective manner.
Enantiomeric excess was determined by chiral HPLC analysis.
Alkynyl alcohol 3ab
1H NMR (CDCl3) d 7.24–7.43 (5H, m, Ph), 7.04 (1H, d,
J = 16.2 Hz, PhCH), 6.20 (1H, dd, J = 16.2, 1.8 Hz, PhCCH),
4.79 (1H, dd, J = 8.1, 1.8 Hz, CHOH), 2.74 (1H, d, J = 8.1 Hz,
OH), 2.27–2.35 (2H, m, CH2CCl2), 1.72 (2H, quint, J = 7.2 Hz,
CH2CCCl2), 1.18–1.45 (10H, m, 5CH2), 0.89 (3H, d, J =
7.2 Hz, CH3); IR (liquid film) 3395, 2926, 2856, 2216, 1448,
1377, 1043, 955, 746, 691 cm−1. Anal. calcd for C20H26Cl2O: C,
67.99; H, 7.42; Cl, 20.07. Found: C, 67.88; H, 7.45; Cl, 20.03.
Alkynyl alcohol 3ga
1H NMR (CDCl3) d 7.46–7.51 (2H, m, Ph), 7.29–7.40 (3H, m,
Ph), 4.77 (1H, d, J = 8.8 Hz, CHOH), 2.86 (1H, d, J = 8.8 Hz,
OH), 2.41–2.56 (2H, m, CH2CBr2), 1.77 (2H, quint, J = 7.2 Hz,
CH2CCBr2), 1.18–1.47 (10H, m, 5CH2), 0.88 (3H, t, J =
7.2 Hz, CH3); IR (liquid film) 3537, 3423, 2926, 2855, 2233,
1491, 1466, 1443, 1379, 1296, 1234, 1057, 756, 691 cm−1. Anal.
calcd for C18H24Br2O: C, 51.95; H, 5.81; Br, 38.40. Found:
C, 52.19; H, 5.93; Br, 38.46. HPLC (Daicel Chiralcel OJ,
hexane–i-PrOH = 10:1, flow rate = 0.5 mL min−1, k = 254 nm)
Alkynyl alcohol 3ea
1H NMR (CDCl3) d 7.39–7.51 (2H, m, Ph), 7.28–7.39 (3H, m,
Ph), 5.97 (1H, d, J = 8.0 Hz, CHOH), 2.80 (1H, d, J = 8.0 Hz,
OH); IR (KBr) 3172, 2242, 1656, 1506, 1290, 1122, 1053, 984,
3 3 1 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 1 2 – 3 3 1 9

View Article Online
tr = 12.2 min (major) and 14.5 min (minor); [a]2D8 +6.61° (c 1.06,
CHCl3); 81% ee.
m, CH2CBr2), 1.67–1.84 (2H, m, CH2CCBr2), 1.43 (2H, sext,
J = 7.6 Hz, CH2CCCBr2), 0.98 (3H, t, J = 7.6 Hz, CH3), 0.28
(9H, s, (CH3)3Si).
To a solution of the silyl ether (102.4 mg, 0.237 mmol) and
Bu3SnH (128 lL, 0.474 mmol) in toluene (2 mL) was added a
1 M hexane solution of Et3B (240 lL, 0.237 mmol) at −78 °C
and the mixture was stirred for 2 h at the same temperature.
The solution was poured into a mixture of 1 M HCl (2 mL)
and THF (2 mL), and the resulting mixture was stirred for 1 h
at room temperature. After extractive workup with ether, the
combined extracts were washed with saturated NaHCO3 and
dried over Na2SO4. Removal of solvents and purification by
column chromatography on silica gel (ether–hexane = 1:5 as
eluant) afforded 1-phenyl-1-octyn-3-ol (40.3 mg, 0.199 mmol,
84%, 78% ee (S)): 1H NMR (CDCl3) d 7.39–7.47 (2H, m,
Ph), 7.28–7.34 (3H, m, Ph), 4.60 (1H, q, J = 6.4 Hz, CHOH),
1.83 (1H, d, J = 6.4 Hz, OH), 1.72–1.86 (2H, m, CH2COH),
1.46–1.61 (2H, m, CH2CCOH), 1.29–1.42 (4H, m, 2CH2), 0.91
(3H, t, J = 6.8 Hz, CH3); IR (liquid film) 3333, 2955, 2932, 2860,
2361, 1599, 1491, 1466, 1443, 1379, 1339, 1123, 1030, 914, 756,
691 cm−1. HPLC (Daicel Chiralcel OD, hexane–i-PrOH = 9:1,
flow rate = 0.5 mL min−1, k = 254 nm) tr = 12.6 min (R) and
31.5 min (S); [a]2D1 +4.46° (c 1.02, CHCl3); 78% ee (S).
General procedure for asymmetric MPV alkynylation of various
reactive aldehydes with aluminium alkoxide 9b
Chiral ligand (S)-10b (146.6 mg, 0.3 mmol) was placed in a dry
two-neck flask with a stirring bar, and freshly distilled toluene
(3 mL) was introduced. After the suspension was carefully
degassed, a 1 M hexane solution of Me3Al (0.3 mL, 0.3 mmol)
was added dropwise at room temperature and the mixture was
stirred for 0.5 h. After the subsequent treatment with a solu-
tion of alkynyl alcohol 1 (0.6 mmol) in freshly distilled toluene
(1 mL), the stirring was continued for an additional 0.5 h.
Then, a toluene (0.5 mL) solution of freshly distilled aldehyde
(0.3 mmol) was added slowly at 0 °C and the resulting mixture
was maintained at 0 °C for 1–18 h with stirring. The reaction
was quenched with 1 M HCl and extracted with ether. The ethe-
real extracts were washed with brine and dried over Na2SO4.
Removal of solvents and purification of the residue by column
chromatography on silica gel (CH2Cl2–hexane or EtOAc–hexane
as eluant) gave the corresponding alkynyl alcohol. Enantio-
meric excess was determined by chiral HPLC analysis (Daicel
Chiralpak AD, Chiralcel OD and OJ as chiral columns).
Alkynyl alcohol 3hb
Alkynyl alcohol 3gb
1H NMR (CDCl3) d 7.29–7.42 (5H, m, Ph), 7.04 (1H, d,
J = 16.4 Hz, PhCH), 6.19 (1H, dd, J = 16.4, 2.0 Hz, PhCCH),
4.73 (1H, dd, J = 8.4, 2.0 Hz, CHOH), 2.83 (1H, d, J = 8.4 Hz,
OH), 2.39–2.52 (2H, m, CH2CBr2), 1.75 (2H, quint, J = 7.2 Hz,
CH2CCBr2), 1.44 (2H, sext, J = 7.2 Hz, CH2CCCBr2), 0.98
(3H, t, J = 7.2 Hz, CH3); IR (liquid film) 3528, 3398, 3030,
2957, 2932, 2872, 2212, 1448, 1379, 1298, 1211, 1119, 1038,
955, 748, 691 cm−1. Anal. calcd for C16H18Br2O: C, 49.77; H,
4.70; Br, 41.39. Found: C, 49.79; H, 4.65; Br, 41.52. HPLC
(Daicel Chiralpak AD, hexane–i-PrOH = 9:1, flow rate =
0.5 mL min−1, k = 254 nm) tr = 21.6 min (major) and 26.1 min
(minor); [a]2D7 +8.04° (c 0.99, CHCl3); 80% ee.
1H NMR (CDCl3) d 7.25–7.42 (5H, m, Ph), 7.04 (1H, d,
J = 16.4 Hz, PhCH), 6.19 (1H, dd, J = 16.4, 2.0 Hz, PhCCH),
4.73 (1H, dd, J = 8.4, 2.0 Hz, CHOH), 2.81 (1H, d, J = 8.4 Hz,
OH), 2.40–2.51 (2H, m, CH2CBr2), 1.76 (2H, quint, J = 7.2 Hz,
CH2CCBr2), 1.20–1.42 (10H, m, 5CH2), 0.89 (3H, t, J =
6.8 Hz, CH3); IR (liquid film) 3533, 3423, 3030, 2928, 2855,
2214, 1491, 1466, 1448, 1377, 1298, 1038, 955, 748, 691 cm−1.
Anal. calcd for C20H26Br2O: C, 54.32; H, 5.93; Br, 36.14. Found:
C, 54.25; H, 5.87; Br, 35.47. HPLC (Daicel Chiralcel OD,
hexane–i-PrOH = 4:1, flow rate = 0.5 mL min−1, k = 254 nm)
tr = 12.4 min (minor) and 16.0 min (major); [a]2D6 +23.93° (c 0.91,
CHCl3); 74% ee.
Alkynyl alcohol 3ia
Alkynyl alcohol 3ha
1H NMR (CDCl3) d 7.47–7.54 (4H, m, Ph), 7.31–7.40 (6H, m,
Ph), 4.63 (1H, d, J = 9.2 Hz, CHOH), 3.97 (1H, d, J = 14.0 Hz,
PhCH), 3.87(1H, d, J = 14.0Hz, PhCH), 2.89(1H, d, J = 9.2 Hz,
OH); IR (liquid film) 3530, 3445, 3063, 3032, 2928, 2232, 1599,
1491, 1454, 1427, 1377, 1298, 1234, 1078, 1051, 955, 756, 700,
691 cm−1. MS (ESI) m/z 431, 429 (100%), 427 ([M + Cl]−). HRMS
(ESI-TOF) calcd for C17H14ClBr2O: 426.9094 ([M + Cl]−).
Found: 426.9091 ([M + Cl]−). HPLC (Daicel Chiralcel OD,
hexane–i-PrOH = 20:1, flow rate = 0.5 mL min−1, k = 254 nm)
tr = 26.5 min (minor) and 34.2 min (major); [a]2D7 +46.18° (c 1.00,
CHCl3); 82% ee.
1H NMR (CDCl3) d 7.46–7.52 (2H, m, Ph), 7.30–7.40 (3H, m,
Ph), 4.77 (1H, d, J = 8.4 Hz, CHOH), 2.88 (1H, d, J = 8.4 Hz,
OH), 2.42–2.55 (2H, m, CH2CBr2), 1.76 (2H, quint, J = 7.2 Hz,
CH2CCBr2), 1.44 (2H, sext, J = 7.2 Hz, CH2CCCBr2), 0.98
(3H, t, J = 7.2 Hz, CH3); IR (liquid film) 3535, 3429, 2959,
2872, 2233, 1599, 1491, 1466, 1443, 1381, 1288, 1234, 1047,
945, 918, 808, 756, 691 cm−1. Anal. calcd for C14H16Br2O: C,
46.70; H, 4.48; Br, 44.38. Found: C, 46.91; H, 4.53; Br, 44.23.
HPLC (Daicel Chiralcel OD, hexane–i-PrOH = 10:1, flow
rate = 0.5 mL min−1, k = 254 nm) tr = 15.9 min (R) and 17.8 min
(S); [a]3D0 +6.77° (c 1.00, CHCl3); 78% ee (R).
Alkynyl alcohol 3ib
Assignment of the absolute configuration of 3ha
1H NMR (CDCl3) d 7.27–7.48 (10H, m, Ph), 7.05 (1H, d,
J = 16.0 Hz, PhCHC), 6.21 (1H, dd, J = 16.0, 1.6 Hz,
PhCCH), 4.69 (1H, dd, J = 8.8, 1.6 Hz, CHOH), 3.71 (1H,
d, J = 14.4 Hz, PhCH), 3.64 (1H, d, J = 14.4 Hz, PhCH), 2.75
(1H, d, J = 8.8 Hz, OH); IR (liquid film) 3533, 3433, 3061, 3032,
2928, 2212, 1603, 1495, 1454, 1427, 1375, 1296, 1265, 1234, 1211,
1157, 1067, 1032, 957, 748, 700 cm−1. Anal. calcd for C19H16Br2O:
C, 54.32; H, 3.84; Br, 38.04. Found: C, 54.05; H, 3.95; Br, 38.00.
HPLC (Daicel Chiralpak AD, hexane–i-PrOH = 2:1, flow
rate = 0.5 mL min−1, k = 254 nm) tr = 12.9 min (minor) and
15.0 min (major); [a]D26 +51.11° (c 1.16, CHCl3); 67% ee.
The absolute configuration of 3ha was determined, after the
reductive debromination of the trimethylsilyl ether of 3ha with
Bu3SnH in the presence of Et3B and the successive deprotection
with diluted HCl, by comparison with the optical rotation of
the known (S)-1-phenyl-1-octyn-3-ol.21 To a solution of 3ha
(90.7 mg, 0.252 mmol, 78% ee), imidazole(25.7mg, 0.378 mmol)
and 4-(dimethylamino)pyridine (3.1 mg, 0.025 mmol) in DMF
(1 mL) was added chlorotrimethylsilane (48 lL, 0.378 mmol)
at 0 °C, and the resulting mixture was stirred for 5 h at room
temperature. The solution was poured into saturated NaHCO3
and extracted with ether. The organic extracts were washed
with brine and dried over Na2SO4. Evaporation of solvents and
purification by column chromatography on silica gel (ether–
hexane = 1:50 as eluant) gave the silyl ether of 3ha (102.4 mg,
0.237 mmol, 94%): 1H NMR (CDCl3) d 7.44–7.49 (2H, m, Ph),
7.29–7.37 (3H, m, Ph), 4.90 (1H, s, CHOSi), 2.35–2.48 (2H,
Alkynyl alcohol 3ca22
1H NMR (CDCl3) d 7.47–7.54 (2H, m, Ph), 7.31–7.43 (3H, m,
Ph), 5.04 (1H, d, J = 9.3 Hz, CHOH), 3.11 (1H, d, J = 9.3 Hz,
OH); IR (liquid film) 3542, 3393, 3082, 2362, 2243, 1599, 1491,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 1 2 – 3 3 1 9
3 3 1 7

View Article Online
1445, 1385, 1298, 1072, 1043, 937, 824, 756, 727, 691 cm−1.
HPLC (Daicel Chiralcel OD, hexane–i-PrOH = 30:1, flow
rate = 0.5 mL min−1, k = 254 nm) tr = 44.9 min (S) and 52.1 min
(R); [a]2D6 −2.50° (c 1.13, CHCl3); 83% ee (R).
4.98 (1H, dd, J = 8.7, 1.8 Hz, CHOH), 3.24 (1H, d, J = 8.7 Hz,
OH); IR (KBr) 3401, 2218, 1489, 1447, 1385, 1274, 1211,
1163, 1072, 1040, 955, 754, 723, 692 cm−1. MS (EI) m/z 410,
408, 406 (M+), 158, 157 (100%), 152, 141, 139, 129, 128,
127, 115, 70. HRMS (EI) calcd for C12H9Br3O: 405.8203
(M+). Found: 405.8231 (M+). HPLC (Daicel Chiralcel OJ,
hexane–i-PrOH = 4:1, flow rate = 0.5 mL min−1, k = 254 nm)
tr = 30.0 min (minor) and 37.0 min (major); [a]2D6 −2.72° (c 1.00,
CHCl3); 83% ee.
Determination of the absolute configuration of 3ca
The absolute configuration of 3ca was determined, after hydro-
genation of the triple bond with 10% Pd/C under hydrogen gas
in MeOH, by comparison with the optical rotation of the known
(R)-4-phenyl-1,1,1-trichloro-2-butanol:23 1H NMR (CDCl3)
d 7.18–7.38 (5H, m, Ph), 3.99 (1H, ddd, J = 10.0, 5.2, 2.0 Hz,
CHOH), 3.00 (1H, ddd, J = 13.6, 9.2, 4.8 Hz, PhCH), 2.73–2.83
(2H, m, PhCH and OH), 2.33–2.44 (1H, m, PhCCH), 1.93–2.06
(1H, m, PhCCH); IR (liquid film) 3558, 2964, 2939, 1601, 1497,
1456, 1244, 1096, 1070, 1053, 997, 812, 785, 754, 702 cm−1.
HPLC (Daicel Chiralpak AD, hexane–i-PrOH = 30:1, flow
rate = 0.5 mL min−1, k = 254 nm) tr = 19.6 min (S) and 21.6 min
(R); [a]2D7 +42.13° (c 1.00, CHCl3); 83% ee (R).
Alkynyl alcohol 3dd
1H NMR (CDCl3) d 7.50–7.55 (2H, m, Ph), 7.30–7.44 (3H, m,
Ph), 4.97 (1H, d, J = 9.2 Hz, CHOH), 3.27 (1H, d, J = 9.2 Hz,
OH); IR (CHCl3) 3522, 3298, 2243, 1489, 1441, 1408, 1379,
1317, 1267, 1113, 1047, 754, 689, 660 cm−1. MS (ESI) m/z 445,
443, 441 (100%), 439 ([M + Cl]−). HRMS (ESI-TOF) calcd
for C12H7ClBr3O: 438.7730 ([M + Cl]−). Found: 438.7727
([M + Cl]−). HPLC (Daicel Chiralcel OJ, hexane–i-PrOH = 4:1,
flow rate = 0.5 mL min−1, k = 254 nm) tr = 25.0 min (minor) and
30.7 min (major); [a]D30 −2.06° (c 1.00, CHCl3); 86% ee.
Alkynyl alcohol 3cb
1H NMR (CDCl3) d 7.25–7.50 (5H, m, Ph), 7.08 (1H, d,
J = 16.5 Hz, PhCH), 6.19 (1H, dd, J = 16.5, 1.8 Hz, PhCCH),
5.00 (1H, d, J = 8.7 Hz, CHOH), 3.08 (1H, d, J = 8.7 Hz, OH);
IR (KBr) 3482, 3022, 2922, 2220, 1489, 1447, 1396, 1292, 1259,
1211, 1165, 1055, 957, 827, 779, 746, 689 cm−1. Anal. calcd for
C12H9Cl3O: C, 52.30; H, 3.29; Cl, 38.60. Found: C, 52.55; H, 3.41;
Cl, 38.72. HPLC(DaicelChiralpakAD, hexane–i-PrOH = 20:1,
flow rate = 0.5 mL min−1, k = 254 nm) tr = 46.7 min (minor) and
54.8 min (major); [a]D26 +1.09° (c 1.00, CHCl3); 85% ee.
Alkynyl alcohol 3ja
1H NMR (CDCl3) d 7.66–7.71 (2H, m, Ph), 7.46–7.53 (2H, m,
Ph), 7.29–7.42 (6H, m, Ph), 7.05 (1H, s, PhCH), 5.30 (1H, d,
J = 7.6 Hz, CHOH), 2.59 (1H, d, J = 7.6 Hz, OH); IR (KBr)
3504, 3053, 2230, 1638, 1597, 1491, 1448, 1389, 1296, 1223,
1096, 1072, 1018, 964, 926, 880, 754, 691, 650 cm−1. Anal.
calcd for C17H13ClO: C, 75.98; H, 4.88; Cl, 13.19. Found:
C, 75.96; H, 4.81; Cl, 13.11. HPLC (Daicel Chiralpak AD,
hexane–i-PrOH = 10:1, flow rate = 0.5 mL min−1, k = 254 nm)
tr = 30.0 min (minor) and 37.1 min (major); [a]2D1 −12.78° (c 0.32,
CHCl3); 96% ee.
Alkynyl alcohol 3cd
1H NMR (CDCl3) d 7.48–7.56 (2H, m, Ph), 7.30–7.43 (3H, m,
Ph), 4.96 (1H, d, J = 9.2 Hz, CHOH), 3.16 (1H, d, J = 9.2 Hz,
OH); IR (KBr) 3522, 2936, 2359, 2341, 2243, 1489, 1441, 1379,
1317, 1256, 1117, 1057, 1027, 860, 829, 795, 756, 687 cm−1.
MS (ESI) m/z 311, 309 (100%), 307 ([M + Cl]−), 237, 235.
HRMS (ESI-TOF) calcd for C12H7Cl4O: 306.9246 ([M + Cl]−).
Found: 306.9237 ([M + Cl]−). HPLC (Daicel Chiralcel OD,
hexane–i-PrOH = 4:1, flow rate = 0.5 mL min−1, k = 254 nm)
tr = 16.4 min (minor) and 23.9 min (major); [a]2D7 −0.72° (c 1.00,
CHCl3); 71% ee.
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. T.M. is grateful to the
Japan Society for the Promotion of Science for Young Scientists
for a research fellowship.
References
1 H. Meerwein and R. Schmidt, Liebigs Ann. Chem., 1925, 444, 221.
2 A. Verley, Bull. Soc. Chim. Fr., 1925, 37, 537.
Alkynyl alcohol 3da
1H NMR (CDCl3) d 7.50–7.54 (2H, m, Ph), 7.32–7.43 (3H, m,
Ph), 5.02 (1H, d, J = 9.0 Hz, CHOH), 3.26 (1H, d, J = 9.0 Hz,
OH); IR (liquid film) 3503, 3443, 2361, 2237, 1489, 1443, 1387,
1293, 1225, 1069, 1028, 920, 779, 756, 691 cm−1. Anal. calcd for
C10H7Br3O: C, 31.37; H, 1.84; Br, 62.61. Found: C, 31.38; H, 1.94;
Br, 62.29. HPLC (Daicel Chiralcel OD, hexane–i-PrOH = 10:1,
flow rate = 0.5 mL min−1, k = 254 nm) tr = 24.5 min (R) and
29.2 min (S); [a]2D6 −3.69° (c 1.10, CHCl3); 90% ee (R).
3 W. Ponndorf, Angew. Chem., 1926, 39, 138.
4 Reviews: A. L. Wilds, Org. React., 1944, 2, 178; R. M. Kellogg,
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Determination of the absolute configuration of 3da
The absolute configuration of 3da was determined, after
reductive debromination according to the same procedure as
described in the case of 3ha, by comparison with the optical
rotation of the known (S)-4-phenyl-3-butyn-2-ol:24 1H NMR
(CDCl3) d 7.38–7.45 (2H, m, Ph), 7.27–7.34 (3H, m, Ph), 4.76
(1H, dq, J = 6.4, 5.6 Hz, CHOH), 1.87 (1H, d, J = 5.6 Hz, OH),
1.56 (3H, d, J = 6.4 Hz, CH3); IR (liquid film) 3335, 2982, 2932,
2361, 1599, 1491, 1443, 1371, 1331, 1278, 1107, 1072, 1038, 934,
853, 756, 691 cm−1. HPLC (Daicel Chiralcel OD, hexane–i-
PrOH = 10:1, flow rate = 1.0 mL min−1, k = 254 nm) tr = 8.3 min
(R) and 18.9 min (S); [a]D25 −28.36° (c 0.65, CHCl3); 90% ee (S).
Alkynyl alcohol 3db
1H NMR (CDCl3) d 7.30–7.45 (5H, m, Ph), 7.09 (1H, d,
J = 16.2 Hz, PhCH), 6.19 (1H, dd, J = 16.2, 1.8 Hz, PhCCH),
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L. D. Buyck and N. Schamp, Synthesis, 1975, 455.
3 3 1 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 1 2 – 3 3 1 9

View Article Online
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13 Attempted allylation of aldehyde 2a with 2-methyl-4-penten-2-ol
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 1 2 – 3 3 1 9
3 3 1 9