Development of Zn-prophenol-catalyzed asymmetric alkyne addition: Synthesis of chiral propargylic alcohols

Article abstract of DOI:10.1002/chem.201202085

The development of a general and practical zinc-catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand (1) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and α,β-unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. The enantioenriched propargylic alcohols from this reaction serve as versatile synthetic intermediates and have enabled efficient syntheses of several complex natural products. A precious few: A general and practical zinc-catalyzed enantioselective alkyne addition methodology is reported (see scheme). New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. This methodology has enabled the efficient synthesis of several complex natural products.

Full text of DOI:10.1002/chem.201202085

DOI: 10.1002/chem.201202085
Development of Zn–ProPhenol-Catalyzed Asymmetric Alkyne Addition:
Synthesis of Chiral Propargylic Alcohols
Barry M. Trost,* Mark J. Bartlett, Andrew H. Weiss, Axel Jacobi von Wangelin, and
Vincent S. Chan[a]
Abstract: The development of a gener-
al and practical zinc-catalyzed enantio-
selective alkyne addition methodology
is reported. The commercially available
ProPhenol ligand (1) has facilitated the
addition of a wide range of zinc al-
enantioselectivity. New insights into
the mechanism of this reaction have re-
sulted in a significant reduction in re-
agent stoichiometry, enabling the use
of precious alkynes and avoiding the
use of excess dimethylzinc. The enan-
tioenriched propargylic alcohols from
this reaction serve as versatile synthetic
intermediates and have enabled effi-
cient syntheses of several complex nat-
ural products.
Keywords: alkynes · alkynylide ·
asymmetric catalysis · nucleophilic
addition · total synthesis
ACHTUNGTRENNUNGkynylides to aryl, aliphatic, and a,b-un-
saturated aldehydes in high yield and
Introduction
Propargyl alcohols serve as robust and versatile inter-
mediates in the synthesis of fine chemicals, natural products,
and therapeutic agents (Figure 1).[8] The broad synthetic util-
ity of this motif lies in the bifunctional reactivity of alkynes.
The terminal alkyne can act as a nucleophile through depro-
The design and development of the ProPhenol ligand, 1,[1]
as an enantioselective catalyst for base-mediated nucleophil-
ic addition reactions has led to the discovery of a number of
highly efficient transformations.[2] The combination of the
ProPhenol ligand and a dialkylzinc reagent has been shown
to catalyze asymmetric Mannich and Henry reactions,[3,4] the
desymmetrization of meso-1,3-diols,[5] and the direct aldol
reaction.[6] The success of this catalyst system with stabilized
nucleophiles, such as enolates and nitronates, prompted us
to investigate zinc alkynylides and their addition to alde-
hydes (Scheme 1). Herein, we provide a full account of the
development of a practical and general methodology for
zinc-catalyzed enantioselective alkynylation of aldehydes by
using the commercially available ProPhenol ligand, 1.[7]
Figure 1. Formation and reactivity of propargylic alcohols.[12]
tonation and subsequent alkylation or metal-catalyzed cross-
coupling. Conversely, the latent electrophilicity of alkynes
can be chemoselectively activated by complexation with a
transition metal. Furthermore, the reactivity of propargyl al-
cohols toward SN2 displacement extends the activation to
the propargylic position as well. This synthetic versatility
makes the catalytic enantioselective preparation of propar-
gylic alcohols especially valuable. Three general approaches
have been utilized for the synthesis of secondary propargyl
alcohols: enantioselective ynone reduction (A),[9] asymmet-
ric alkyne addition to aldehydes (B),[10] and ynal alkylation
(C).[11] Although a number of catalysts have been developed
to facilitate both ynone reduction and ynal alkylation, the
application of these methods is limited by the propensity of
these alkynes to decompose, isomerize, and act as Michael
acceptors. The addition of a terminal acetylene to an alde-
Scheme 1. ProPhenol-catalyzed alkyne addition.
[a] Prof. B. M. Trost, M. J. Bartlett, Dr. A. H. Weiss,
Dr. A. J. von Wangelin, Dr. V. S. Chan
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (+1)650-725-0002
E-mail: bmtrost@stanford.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202085. It contains full ex-
perimental details.
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Chem. Eur. J. 2012, 18, 16498 – 16509

FULL PAPER
Table 1. Initial optimization.[a]
hyde avoids these problems and provides a convergent ap-
proach to the desired propargyl alcohol.
The mild reactivity of organozinc reagents has enabled
the enantioselective addition of alkyl, vinyl, and alkynyl
groups to a variety of carbonyl compounds with excellent
functional group tolerance.[13] The asymmetric addition of al-
kynylzinc nucleophiles to aldehydes has recently generated
a large amount of interest in the chemical community.[14]
Early reports by Carreira et al. demonstrated that stoichio-
metric (+)-N-methyl ephedrine, ZnCAHTUNGTERN(NUNG OTf)2, and triethyl-
ACHTUNGTRENNUNG
tion to aliphatic aldehydes under particularly mild condi-
tions.[15] High enantioselectivity and yield were obtained
with a variety of alkynes, although aryl and a,b-unsaturated
aldehydes typically gave lower yields. The initial conditions
requiring stoichiometric zinc and ephedrine were ultimately
rendered catalytic by increasing the reaction temperature to
608C.[15f] The groups of Pu and Chan independently report-
ed the use of (S)-1,1’-bi-2-naphthol ((S)-BINOL), in con-
R
Conc.
T
[8C]
t
X
Yield
[%]
ee
[m][b]
[h]
A
[%][c]
ligand screening
1
2
3
Ph
Ph
Ph
0.18
0.18
0.18
RT
0
22
16
16
20 (1)
20 (L2)
20 (L3)
78
26
36
80
35
À66
0
junction with TiACHTUNGTRENNUNG(OiPr)4 and either Et2Zn or Me2Zn to facili-
time, temperature and catalyst loading, X=(S,S)-1
tate nucleophilic addition of alkynes to aldehydes.[16,17]
These conditions require an excess of alkyne and dialkylzinc
but ultimately provide good yield and enantioselectivity
with a range of substrates. A number of other chiral zinc
catalysts have also been reported to enable the enantioselec-
tive addition of alkynes to aldehydes.[18] Efficient asymmet-
ric alkyne addition often requires the use of relatively high
catalyst loadings and an excess of alkyne and dialkylzinc re-
agents.[19] Our aim was to develop an efficient chiral catalyst
system capable of adding functionalized alkynes to a wide
range of aldehydes while minimizing the use of excess re-
agents and stoichiometric additives, improving the atom
economy of this transformation.[20] This would ultimately
enable facile access to chiral propargyl alcohols and entry
into alkyne-based strategies in the synthesis of natural prod-
ucts.
4
5
6
7
Ph
Ph
Ph
Ph
0.18
0.18
0.18
0.18
RT
RT
72
48
45
45
20
10
10
5
95
77
60
32
79
83
77
72
À20
À20
reaction concentration, X=(S,S)-1
8
9
10
11
TMS
TMS
TMS
TMS
0.18
0.26
0.38
0.69
3
3
3
3
21
21
24
21
10
10
10
10
35
50
74
87
85
85
85
75
catalyst loading at higher concentration, X=(S,S)-1
12
13
14
Ph
Ph
Ph
0.38
0.38
0.38
3
3
3
24
24
21
10
5
2.5
86
73
68
74
58
46
[a] Reactions run on a 0.325 mmol scale with 2.7 or 2.8 equivalents of an
alkyne and 2.6 or 2.95 equivalents of dimethylzinc, respectively. Yields of
the isolated product are reported. [b] Reaction concentration (in molari-
ty) is reported with respect to the alkyne and includes the toluene added
as part of the dimethylzinc solution. [c] Enantiomeric excess determined
by chiral HPLC analysis. TMS=trimethylsilyl.
Results and Discussion
(Table 1, entries 2 and 3). These results contrast with Cozziꢁs
asymmetric alkyne addition reaction to ketones, which uti-
lizes a similar Salen ligand to obtain excellent results.[21]
Enantiomeric induction from (S,S)-1 was found to be a
robust process and provided excellent selectivity for the
(R)-propargylic alcohol 3a, at a range of temperatures and
catalyst loadings (Table 1, entries 4–7).[22] Consequently, the
majority of optimization experiments focused primarily on
improving reactivity and catalyst turnover. Reducing the
catalyst loading to 10 mol% and increasing the reaction
time to 48 h produced the desired product in 77% yield and
83% ee (Table 1, entry 5). These results are similar to those
given in Table 1, entry 1 with 20 mol% of (S,S)-1. In an at-
tempt to obtain even better enantioselectivity, the alkyne
addition was performed at À208C with both 5 and 10 mol%
of (S,S)-1 (Table 1, entries 6 and 7). These reactions provid-
ed similar levels of enantioselectivity, but resulted in a sub-
stantial decrease in reactivity.
Initial optimization: Optimization of the enantioselective
addition of phenyl- and TMS-acetylene to para-anisaldehyde
(2) commenced with the screening of several C2-symmetric
ligands, (S,S)-1, L2, and L3, designed in our group (Table 1).
Stoichiometric zinc alkynylide was required for adequate
enantioselectivity, and all optimization was initially carried
out by using nearly three equivalents of the dialkylzinc and
alkyne. Further experiments to improve the atom economy
of this alkynylation methodology will be discussed below.
Ligand screening revealed that the ProPhenol ligand, (S,S)-
1, provided the best results in terms of both yield and enan-
tioselectivity, with the desired propargyl alcohol being iso-
lated in 78% yield and 80% ee (Table 1, entry 1). Ligands
L2 and L3, resembling a Salen ligand and the backbone of
our phosphine ligands for Pd-catalyzed asymmetric allylic
alkylation, also provided the desired product, albeit with a
lower enantioselectivity of 35 and À66% ee, respectively
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B. M. Trost et al.
Table 2. Alkynylation of aryl aldehydes.
TMS-acetylene was found to be significantly less reactive
in ProPhenol-catalyzed alkyne addition reactions than phe-
nylacetylene. However, by increasing the reaction concen-
tration, improved reactivity could be obtained with TMS-
acetylene to ultimately provide the desired product in 74%
yield and 85% ee (Table 1, entry 10). The optimal alkyne
concentration was found to be 0.38m and a further increase
in concentration, to 0.69m, resulted in decreased enantiose-
lectivity (Table 1, entry 11). At higher reaction concentra-
tions (ca. 2m) the ligand-free background reaction proceeds
readily, and is presumably the cause of the slight decrease in
enantioselectivity.[23] Unfortunately, decreasing the catalyst
loading further (<10 mol%) provided a lower yield and sig-
nificantly lower ee (Table 1, entries 13 and 14).
R1
R2
Yield
[%][a]
ee
[%][b]
1
H
Ph
95
84
91
78
77
98
trace
81
90
89
100
86
86
74
86
87
79
90
82
27
87
81
92
68
83
85
83
–
84
85
75
86
84
76
85
74
99
97
82
87
35
92
2
2-NO2
Ph
3
3-NO2
Ph
4
4-NO2
4-F
4-Cl
4-NHAc
2-furyl
Ph
Ph
Ph
Ph
TMS
Ph
5[c,d]
6[c,d]
7
8
9[c]
2-furyl
The optimization of reaction temperature, time, concen-
tration, and catalyst loading has enabled the addition of
either TMS-acetylene or phenylacetylene to para-anisalde-
hyde in good yield (>70%) and ee (>70%) with just
10 mol% catalyst loading. Interestingly, similar results were
generally observed for dimethyl- and diethylzinc; however,
others have noted that alkyl transfer from dimethylzinc is
significantly slower than from diethylzinc, and therefore, di-
methylzinc was chosen to avoid the formation of potential
alkyl addition side products.[24] Utilizing the optimized con-
ditions outlined in Table 1, entries 10 and 12, we set out to
investigate the scope of this reaction.
10
C4H4 (2-naphth)
2-MeO
2-MeO
3-MeO
4-MeO
Ph
Ph
CH2OMe
Ph
TMS
Ph
Ph
TMS
CH2CHACTHUNGRETNNU(G OEt)2
CH2CH2OTBS
11[c,d]
12
13[c,d]
14
15[c]
16
4-MeO
2,6-(MeO)2
2,6-(MeO)2
3,5-(MeO)2
3,5-(MeO)2
2,6-(Me)2
2,4-(MeO2)-3-Me
17
18
19
20[c]
21
Ph
Ph
[a] Yield of the isolated product. Reactions performed on a 0.325 mmol
scale. [b] Enantiomeric excess determined by chiral HPLC analysis.
[c] Reaction performed with 2.5 equivalents of the alkyne and 2.5 equiva-
lents of Me2Zn. [d] Reaction run at a concentration of 0.2m with respect
to alkyne. Naphth=naphthyl.
Alkynylation of aryl aldehydes: A variety of aryl aldehydes
underwent efficient alkyne addition by using the previously
optimized conditions (Table 2). High yields and enantiose-
lectivities were obtained in addition reactions to benzalde-
hydes containing both electron-donating and electron-with-
drawing substituents. Substitution on each aromatic carbon
atom was tolerated and particularly good results were ob-
tained with ortho-substituted benzaldehydes. However, the
steric encumbrance of 2,6-dimethylbenzaldehyde resulted in
a decreased yield and ee (Table 2, entry 20) although 2,6-di-
methoxybenzaldehyde performed very well (Table 2,
entry 16). Good functional group tolerance was observed,
with only N-(4-formylphenyl)acetamide providing poor re-
sults (Table 2, entry 7). Good results were obtained with a
variety of alkynes and only small variations in yield and
enantioselectivity were observed.
Table 3. Alkynylation of a,b-unsaturated aldehydes.
R1
R2
R3
R4
Yield
[%][a]
ee
[%][b]
1
H
H
H
H
Ph
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
TMS
TMS
TMS
TMS
TMS
TMS
TMS
89
89
90
100
74
67
91
39
36
94
91
87
90
90
76
91
95
86
73
82
87
77
2[c]
3
Me
C6H13
iPr
H
4
5
6
7
8
9
10
11
12
13
14
15
16
Me
Me
Et
Alkynylation of a,b-unsaturated aldehydes: Alkyne addition
to a,b-unsaturated aldehydes provides a particularly valua-
ble extension of the substrate scope. The resulting alkenyl
alkynyl carbinols contain three orthogonal functional groups
primed for further synthetic manipulation. ProPhenol-cata-
lyzed addition of TMS-acetylene to a range of a,b-unsatu-
rated aldehydes proceeded in excellent yield and enantiose-
lectivity (Table 3) although the substitution pattern of the
a,b-unsaturated aldehyde has a significant effect on the
enantioselectivity of alkyne addition. (E)-Cinnamaldehyde
provides the desired propargyl alcohol in 91% ee (Table 3,
entry 1). However, replacement of the phenyl substituent
with a methyl or hexyl group produces the desired product
À
G
À
81
55
H
H
A
Ph
TMS
TMS
TMS
TMS
BDMS
CH
CH
C6H13
80
Br
Br
Me
H
C6H13
Ph
CO2Et
Ph
66[d]
68
75
100
85
85
100
H
H
H
Ph
iPr
Ph
ACHTUNGTRENNUNG
A
[a] Yield of the isolated product. Reactions performed on a 0.325 mmol
scale. [b] Enantiomeric excess determined by chiral HPLC analysis.
[c] Reaction performed with 2.7 equivalents of alkyne and 2.6 equivalents
of Me2Zn. [d] A 14% yield of the methyl addition side product was also
isolated. TBS=tert-butyldimethylsilyl, BDMS=benzyldimethylsilyl.
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Zn–ProPhenol-Catalyzed Asymmetric Alkyne Addition
FULL PAPER
Table 4. Addition of methyl propiolate to a,b-unsaturated aldehydes.
in less than 40% ee (Table 3, entries 2 and 3, but also see
Table 6, entry 2 below), which was, however, restored to
over 90% by addition of an a-bromo group (see below).
The difference in results between these b-substituents seems
to result primarily from steric interactions. Following this
notion, the incorporation of an isopropyl group at the b-po-
sition restored the excellent enantioselectivity (Table 3,
entry 4). Interestingly, the absence of substitution at the b-
position also led to high enantioselectivity (Table 3, entry 5
and 8). A number of functionalized substrates gave good re-
sults, including a-bromoenals (Table 3, entries 10 and 11), b-
formyl propionates (Table 3, entry 12), propiolaldehyde di-
ethyl acetals (Table 3, entries 14 and 15), and aliphatic al-
kynes (Table 3, entry 16).
Methyl propiolate represents a particularly attractive class
of nucleophiles for alkyne addition.[25] The resulting g-hy-
droxy-a,b-acetylenic esters are extremely versatile synthetic
intermediates and have been used in a number of total syn-
theses.[26] Propiolate donors have traditionally been difficult
substrates for asymmetric alkynylation due to their propen-
sity to decompose in the presence of Lewis acids and nucle-
ophiles.[27] Methyl propiolate ultimately proved to be one of
the most effective alkynes under Zn–ProPhenol alkynylation
conditions (Table 4). Excellent results were obtained with a
range of a,b-unsaturated aldehydes, including (E)-non-2-
Aldehyde
Product
Yield ee
[%][a] [%][b]
1
2
3
4
4a
4b
4c
4d
5a
5b
5c
5d
5e
5 f
94
86
97
92
71
86
90
97
97
95
90
96
5[c] 4e
6[d] 4 f
enal, which provided a 97% ee with methyl propiolate 7[e] 4g
(Table 3, entry 2), a major improvement on the 36% ee ob-
tained with TMS-acetylene. The superior results are pre-
5g
5h
95
97
82
72
sumed to be a consequence of the stabilization of the al-
ACHTUNGTRENNUNGkynylide of this alkyne along with potential coordination of
8
4h
the propiolate ester with the bimetallic catalyst.
[a] Yield of the isolated product. [b] Enantiomeric excess determined by
chiral HPLC. [c] Reaction performed by using 3 equivalents of alkyne and
3 equivalents of Me2Zn. [d] Reaction performed by using (R,R)-1. [e] Reac-
tion performed by using ethyl propiolate.
Aliphatic aldehydes: While the initial communication dis-
closed[7] only the use of unsaturated aldehydes, a variety of
aliphatic aldehydes are suitable electrophiles for asymmetric
alkynylation with the ProPhenol ligand, (S,S)-1 (Table 5).
The addition of methyl propiolate to a- and b-substituted
aliphatic aldehydes proceeded in good yield and enantiose-
lectivity. The addition of methyl propiolate to cyclopropane-
carboxaldehyde gave the desired propargylic alcohol in
88% yield and 94% ee. n-Aliphatic aldehydes are particular-
ly challenging substrates for alkynylation due to their pro-
pensity to enolize and undergo cross-aldol side reactions.[28]
Modest yields and excellent enantioselectivities were ulti-
mately achieved when utilizing the more acidic alkyne,
methyl propiolate (Table 5). Aliphatic aldehydes with an in-
creased propensity to enolize, such as cyclopentanecarboxal-
dehyde and 3-methylbut-3-enal, did not produce the desired
products. On the other hand, the less easily enolized alde-
hyde cyclohexanecarboxaldehyde performed exemplarily.
The increased steric hindrance of 2,2-dimethyl-substituted
aldehydes often results in decreased enantioselectivity al-
though addition of methyl propiolate to pivaldehyde provid-
ed the desired product in 88% ee. However, the analogous
3-chloro- and 3-oxopropanoate substrates provided signifi-
cantly lower enantioselectivity. Extension of this methodolo-
gy to aliphatic aldehydes further demonstrates the generality
of the ProPhenol-catalyzed alkynylation with respect to
both nucleophile and electrophile.
Proposed mechanism: The proposed mechanism for ProPhe-
nol-catalyzed alkyne addition involves the formation of the
dinuclear zinc species A (Scheme 2). This complex contains
both Brønsted basic and Lewis acidic sites, and can there-
fore act as a bifunctional catalyst, activating two reagents si-
multaneously. The relative acidity of a terminal alkyne (pKa
[29]
ꢀ
(DMSO) PhC CH=28.7) enables the formation of an al-
kynylzinc nucleophile, which undergoes nucleophilic addi-
tion to the Si face of an aldehyde. Product dissociation
through metal exchange liberates a propargylic zinc alkox-
ide and regenerates the active catalyst. Turnover of the cata-
lyst in this way necessitates the use of a stoichiometric
amount of the organozinc reagent. In contrast, the ProPhe-
nol-catalyzed direct aldol reaction requires only a catalytic
amount of the dialkylzinc reagent and dissociation of the
product alkoxide is postulated to occur through proton ex-
change.[6]
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B. M. Trost et al.
Table 5. Enantioselective alkynylation of aliphatic aldehydes.[a,b]
ported by the X-ray crystal structure of the ProPhenol dinu-
clear zinc complex reported by Ding and co-workers
(Figure 2).[31] The crystal structure contains a molecule of
60%, 90%ee
60%, 88%ee
44%, 91%ee
62%, 92%ee
92%, 88%ee
72%, 74%ee
Figure 2. Zn-ProPhenol crystal structure and proposed interaction with
Lewis basic additives.
62%, 93%ee
88%, 94%ee
65%, 95%ee
52%, 95%ee
48%, 70%ee
75%, 21%ee
THF (dashed circle) coordinated to each of the zinc atoms,
analogous to the postulated interaction with a Lewis base.
Screening a variety of substoichiometric Lewis basic addi-
tives revealed that the addition of TPPO (20 mol%) provid-
ed optimal results. The largest improvements were observed
in cases for which the substrates lacked potential Lewis
basic sites (Table 6). A large improvement in enantioselec-
tivity was observed for the addition of TMS-acetylene to
(E)-nonenal (Table 6, entry 2). Methyl propiolate, an alkyne
containing a Lewis basic ester, often shows little or no im-
provement with the addition of TPPO (Table 6, entry 4).
The addition of TPPO to the reaction has enabled the suc-
cessful addition of a silylated enyne to both unsaturated
(Table 6, entry 5) and saturated aldehydes (Table 6, entries 6
and 7).
94%, 69%ee[c]
71%, 90%ee
[a] Yield of the isolated product. [b] Enantiomeric excess determined by
chiral HPLC analysis. [c] Enantiomeric excess determined by chiral
HPLC analysis of the corresponding benzoate.
Additive effects and triphenylphosphine oxide (TPPO):
During research into the ProPhenol-catalyzed addition of
diynes, it was discovered that the presence of acetate groups
in the substrate, far from the reacting alkyne terminus, re-
sulted in significantly higher enantioselectivity.[30] It was hy-
pothesized that this Lewis basic group interacts with the di-
nuclear zinc catalyst and reinforces the chiral pocket created
by the ProPhenol ligand. The proposed coordination is sup-
Reagent stoichiometry: To maximize the practicality and
synthetic efficiency of this methodology, we sought to
reduce reagent stoichiometry to a minimum. Ideally, the
alkyne addition could be catalytic in metal with the resultant
zinc alkoxide serving as a base for subsequent alkyne depro-
Scheme 2. Proposed mechanism for ProPhenol-catalyzed alkynylation of aldehydes.
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Zn–ProPhenol-Catalyzed Asymmetric Alkyne Addition
Table 6. Alkynylation with TPPO.[a,b]
FULL PAPER
Zinc alkoxides are known to form aggregates,[32] and it
was hypothesized that the aggregation state of the reactive
zinc species plays an important role in enantioselectivity.
Since the aggregation state is likely to be concentration de-
pendent, a number of experiments were performed with the
concentration of the alkyne and dimethylzinc held constant,
while reducing the stoichiometry of each. Consequently, the
ProPhenol-catalyzed addition of methyl propiolate was
found to give the same high enantioselectivity with less than
half the amount of alkyne (Table 7, entry 3). 1-Octyne addi-
tion by using 1.5 equivalents of the alkyne also provided
good enantioselectivity, although a drop in yield was ob-
served. The lower yield is presumably a consequence of de-
creased reactivity and to counter this, the reaction concen-
tration was increased to 0.5m (Table 7, entry 6). When this
adjustment was used in conjunction with TPPO (20 mol%),
the desired product was obtained in 80% yield and 93% ee
by using just 1.2 equivalents of alkyne. TMS-acetylene also
Aldehyde
R2
No TPPO
With TPPO
Yield [%] (ee [%]) Yield [%] (ee [%])
1
2
C6H13
TMS
100 (77)
90 (36)
79 (93)
79 (94)
3
4
CO2Me
TMS
71 (90)
74 (85)
85 (95)
83 (81)
5
6
7
–
–
–
85 (91)
56 (66)
58 (74)
required
a higher reaction concentration and TPPO
(20 mol%) to provide a high yield and enantioselectivity.
The concentration dependence of this reaction led us to
investigate the possibility of a dimeric active catalyst.[33]
A
[a] Yield of the isolated product. [b] Enantiomeric excess determined by
chiral HPLC analysis. PMB=para-methoxybenzyl.
number of dimeric zinc amino alcohol catalysts have been
reported previously and display characteristic nonlinear
asymmetric induction in alkyl addition to aldehydes.[34] To
evaluate potential nonlinear effects in ProPhenol-catalyzed
alkyne addition reactions, the addition of methyl propiolate
to (E)-nonenal was performed under the original superstoi-
chiometric conditions with (S,S)-1 of varying optical purity
(Figure 3, see the Supporting Information for full experi-
tonation reactions. Carreira and co-workers were able to
achieve alkynylation that was catalytic in zinc triflate in
some cases by increasing the reaction temperature to
608C.[15f] Attempts to use a catalytic amount of dimethylzinc
and elevated reaction temperatures in the ProPhenol-cata-
lyzed alkynylation resulted only in recovered starting mate-
rial (Table 7, entry 4). Previous attempts to use just a slight
excess of the alkyne and dimethylzinc have resulted in a sig-
nificant drop in enantioselectivity.
Table 7. Alkynylation with reduced stoichiometry.
R1
R2 X/Y
Comments[a]
Yield ee
[%][b] [%][c]
Figure 3. The absence of nonlinear effects in the addition of methyl pro-
piolate to (E)-nonenal with (S,S)-1.
1
2
3
4
5
6
7
8
9
CO2Me
CO2Me
CO2Me
CO2Me
iPr 3.0:3.0
iPr 1.5:1.5
Ph 1.2:1.5 0.48 m
–
–
97
79
97
97
81[d] 94
Ph 1.2:0.2 608C, 24 h
–
83
60
80
100
71
–
A
–
–
81
75
93
94
50
90
mental details). The enantiomeric excess of the product dis-
played a linear correlation (R2 =0.99) with the enantiopurity
of the ProPhenol ligand used to catalyze the reaction. When
the ligand is not enantiomerically pure a dimeric active cata-
lyst could potentially form three different association com-
plexes: Zn–[(S,S)-1+(S,S)-1], Zn–[(S,S)-1+(R,R)-1], and
Zn-[(R,R)-1+(R,R)-1]. It is likely that the homo- and heter-
ochiral complexes would display significantly different cata-
lytic activities and, therefore, display nonlinear asymmetric
induction. The results shown in Figure 3 suggest that a
N
A
TMS
TMS
iPr 3.0:3.0
iPr 1.2:1.2
Ph 3.0:3.0
Ph 1.2:1.2
–
–
–
–
10 TMS
11 TMS
12 TMS
75
52[e] 50
Ph 1.2:1.5 TPPO (20mol%), 0.48 m
83
88
[a] Reaction concentration is reported with respect to the alkyne.
[b] Yield of the isolated product. [c] Enantiomeric excess determined by
chiral HPLC analysis. [d] Isolated along with a 16% yield of the methyl
addition side product. [e] 17% of the starting material was recovered.
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16503

B. M. Trost et al.
single ProPhenol ligand is present in the enantiodetermining
step.
turated aldehydes.[38] Minor quantities of methyl addition
side products, such as compound 21, have been isolated in
only a small number of cases (Scheme 3). ProPhenol-cata-
lyzed methyl addition is a relatively slow process and re-
quired 3 days to react with approximately half of the starting
aryl aldehyde (Scheme 4).
Alkynylzinc formation and analysis of the alkyne premix:
Reducing the number of equivalents of alkyne used in addi-
tion reactions to enolizable aldehydes represents a much
more challenging prospect. These reactions produce unde-
sired cross-aldol side products and reducing the number of
equivalents of alkyne exacerbates the problem (Table 8, en-
tries 1–3). We hypothesized that this side reaction occurs as
a result of incomplete alkynylzinc formation and the pres-
ence of unreacted dimethylzinc in the reaction mixture. For-
mation of the alkynylzinc species is driven, in part, by the
entropically favored release of methane gas. However, a
number of additional factors also contribute to the overall
composition of the alkyne premix. Nonpolar solvents have
been shown to disfavor formation of the alkynylzinc species.
In the case of phenylacetylene in heptane, no formation of
the methylalkynylzinc species is observed.[35] A number of
other Zn–alkyne addition methodologies rely on the use of
additives to aid in the formation of the alkynylzinc nucleo-
phile.[36]
Scheme 3. ProPhenol-catalyzed methyl addition.
A stepwise 1H NMR analysis of the methyl propiolate/
Scheme 4. Competing methyl addition.
Me2Zn/
alkyne deprotonation. By using a 1.2:1.5:0.1 ratio of methyl
propiolate/Me2Zn/(S,S)-1, integration of the peaks at d=
ACHTUNGTRENNUNG(S,S)-1 premix in [D8]toluene was used to evaluate
A
These observations prompted the investigation of meth-
ods to facilitate the formation of the alkynylzinc nucleophile
and, therefore, reduce the amount of dimethylzinc present
(Table 8). The addition of aliphatic alkyne 22 to the enoliz-
ꢀ
0.17 (s, 3H; CH3ZnC C) and À0.69 ppm (s, 6H; (CH3)2Zn)
revealed that approximately 30% of the desired alkynylzinc
species was being formed during the standard 1 hour pre-
mixing reaction at room temperature (Figure 4, see the Sup-
AHCTUNGTREGaNNNU ble aldehyde 23a provided the desired propargylic alcohol
24a in low yield under the original superstoichiometric con-
ditions (Table 8, entry 1). The low yield is a consequence of
competing aldol side reactions, which provide a complex
mixture of oligomers including
compound 25, which was isolat-
ed in 19% yield as a mixture of
diastereomers from the reaction
in Table 8, entry 1. The use of
Lewis basic additives, such as
N-methyl imidazole (NMI),
DMSO, and DMF, to aid the
formation of the desired alkynylzinc nucleophile provided a
low yield of the desired product 24a (Table 8, entries 4–
6).[37] However, extending the alkyne premixing time from
1 hour to 24 h provided a 19% increase in the yield
(Table 8, entry 7). Combining this discovery with a higher
catalyst loading (20 mol%) led to an optimized result of
69% yield and 67% ee for this challenging alkyne–aldehyde
pairing (Table 8, entry 8). Thus, applying our mechanistic
understanding of the reaction led to a modest improvement
in the addition of a nonstabilized alkyne nucleophile (22) to
an enolizable aliphatic aldehyde (23), the most challenging
combination for this methodology.
Figure 4. 1H NMR analysis of the alkyne premix.
porting Information for full experimental details).[37] Depro-
tonation of the terminal alkyne was not observed in the ab-
sence of the ProPhenol ligand. Analysis of the alkyne
premix by volumetric gas titration of methane revealed that
the initial rate of deprotonation is rapid but tapers off after
about 15 min. The volume of methane obtained over the
standard premixing time was in good agreement with the re-
sults of the 1H NMR spectroscopy.
In contrast to the previous example, enolizable aliphatic
aldehydes were shown to be excellent electrophiles in the
ProPhenol-catalyzed alkynylation when more stabilized nu-
cleophilic alkynes were employed. For example, the higher
In contrast to enolizable aldehydes, the presence of signif-
icant amounts of dimethylzinc has little effect on the out-
come of the alkyne addition reactions to aryl and a,b-unsa-
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Chem. Eur. J. 2012, 18, 16498 – 16509

Zn–ProPhenol-Catalyzed Asymmetric Alkyne Addition
FULL PAPER
Table 8. Optimization of alkyne addition with an enolizable substrate.
Alkynylation scope with reduced alkynylide stoichiometry:
The use of a stoichiometric amount of the alkyne would
enable the use of precious alkynes to access complex syn-
thetic targets in a highly efficient manner. Thus, we were
pleased to observe that the newly developed reaction condi-
tions allowed for the use of only 1.2 equivalents of the
alkyne (Table 10). In line with our previous results, the
CHO X/Y
Conditions
Yield ee
[%][a] [%][b]
Table 10. Scope and evaluation of the alkynylation with reduced stoi-
chiometry.[a]
1
2
3
4
5
6
7
8
23a
23a
23a
23a
23a
23a
23b
23b
2.8:2.95
–
35[c]
39
22
11
4
45
62
54
72
2.8:2.95 TPPO (20 mol%)
1.2:1.5 TPPO (20 mol%)
1.2:1.3 NMI (30 mol%)
1.2:1.4 DMSO (4 equiv)
1.2:1.4 DMF (4 equiv)
2.8:2.95 TPPO (20mol%), 24 h alkyne premix 58
2.8:2.95 (S,S)-1 (20 mol%), TPPO (40 mol%), 69
24 h alkyne premix
14
10
17
50[d]
67[d]
ACHTUNGTRENNUNG
[a] Yield of the isolated product. All reactions were run on
a
0.1625 mmol scale. [b] Enantiomeric excess determined by chiral HPLC
analysis. [c] Isolated along with a 19% yield of the cross-aldol side prod-
uct 25. [d] Enantiomeric excess determined by 1H NMR analysis of the
corresponding (S)-methyl mandelate. Bz=benzoyl.
acidity of methyl propiolate provides improved results with
enolizable aldehydes relative to other alkynes (Table 9). Ad-
dition of methyl propiolate to octanal under the initial con-
Table 9. Optimization of methyl propiolate addition to octanal.
X/Y
Conditions
Yield
[%][a]
ee
[a] Conditions A: alkyne (2.8 equiv), Me2Zn (2.95 equiv), ProPhenol
(10 mol%), 0.34 m in toluene. Conditions B: alkyne (1.2 equiv), Me2Zn
(1.5 equiv), ProPhenol (20 mol%), 0.48 m in toluene. [b] (S,S)-1
(10 mol%) was used in the reaction. [c] (S,S)-1 (20 mol%) and TPPO
[%][b]
1
2
3
4
5
6
7
2.8:2.95
1.5:1.5
1.5:1.5
1.2:1.5
2.8:2.95 (Et2Zn)
1.2:1.5
–
–
62
37
35
42
60
57
72
92
86
90
91
70
90
87
TPPO (20 mol%)
–
4 h alkyne premix
(40 mol%) were used in conjunction with a 24 h premixing time.
[d] (S,S)-1 (20 mol%) was used in the reaction. [e] TPPO (20 mol%) was
used in this reaction. [f] 3.0 equivalents of Me2Zn were used in the reac-
tion. [g] Reaction performed with (R,R)-1.
AHCTUNGTRENNUNG
2.8:2.95
ACHTUNGTRENNUNG
[a] Yield of the isolated product. All reactions were run on a 0.325 mmol
scale. [b] Enantiomeric excess determined by chiral HPLC analysis.
nature of the alkyne affected the results of the alkynylation.
When methyl propiolate was used, good enantioselectivity
and yield were observed with each class of aldehydes: ali-
phatic, a,b-unsaturated and aryl. However, when only
1.2 equivalents of a nonstabilized aliphatic alkyne, such as
22, is added to an a,b-unsaturated aldehyde, TPPO is re-
quired as an additive to provide a high yield and ee. The ad-
dition of 22 to enolizable aldehydes is particularly challeng-
ing and gives only a moderate yield and enantioselectivity
when an excess of the alkyne is used in conjunction with
TPPO, increased catalyst loading, and a 24 hours of alkyne
premixing. The synthesis of propargyl alcohol 27 in 88%
yield and 90% ee was achieved by using a single equivalent
of both the alkyne and aldehyde.
ditions provides propargylic alcohol 26 in 62% yield. Lower-
ing the reaction stoichiometry from 2.8 to 1.2 equivalents of
alkyne results in a significantly decreased yield (Table 9,
entry 4). Longer alkyne premixing times result in visible de-
composition of methyl propiolate (Table 9, entry 5). There-
fore, a higher catalyst loading was used to aid the consump-
tion of dimethylzinc through alkynylzinc formation (Table 9,
entries 6 and 7). Ultimately, a 57% yield and 90% ee of the
desired propargyl alcohol were obtained by using 1.2 equiva-
lents of the alkyne.
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16505

B. M. Trost et al.
Synthetic Applications: The Zn–ProPhenol-catalyzed alkyne
addition methodology has enabled the total synthesis of a
wide range of complex natural products.[39] The synthetic
utility of this transformation is a direct consequence of the
mild reaction conditions and broad substrate scope that has
become a focal point of this methodology. The propargylic
alcohol moiety is present in a number of biologically and
structurally interesting polyacetylenic natural products. The
ProPhenol ligand enables the direct and convergent installa-
tion of this functionality, as shown in the total synthesis of
adociacetylene B, 28 (Scheme 5).[40] The key intermediate,
Scheme 6. Alkyne additions in the total synthesis of spirolaxine methyl
ether.
The orthogonal reactivity of alkynes was utilized to great
effect in the total synthesis of (+)-spirolaxine methyl ether
(Scheme 6).[42] ProPhenol-catalyzed addition of the aliphatic
alkyne 33 to 3,5-dimethoxybenzaldehyde provided propar-
gylic alcohol 34 in high ee and yield. Mild and selective
alkyne reduction was subsequently achieved by using
Adamꢁs catalyst, providing access to the chiral benzyl alco-
hol 35. An additional asymmetric alkynylation/hydrogena-
tion sequence was used to install a second chiral alcohol in
the presence of a relatively sensitive phthalide group. This
alkyne strategy ultimately led to the total synthesis of spiro-
laxine methyl ether in 13 linear steps. This work highlights
the utility of asymmetric alkyne addition as a surrogate for
a saturated alkyl group addition in the preparation of chiral
alcohols.
Scheme 5. Total synthesis of adociacetylene B. Tf=triflyl, CSA=cam-
phorsulfonic acid.
bisACHTUNGTRENNUNG(enal) 30, was prepared from the symmetric propargylic
alcohol 29 by using a Ru-catalyzed redox/isomerization.[41]
This atom-economic transformation avoids the use of pro-
tecting groups and multiple redox operations often used
with conventional olefination chemistry. Bis(alkynylation) of
30 with TMS-acetylene provided the desired product 31 in
excellent enantioselectivity and a 9:1 mixture of dl- and
meso-diastereomers. Alkynylation with the conditions from
the original optimization [Me2Zn (3 equiv), alkyne
(3 equiv), and (S,S)-1 (10 mol%)] resulted in significant
amounts of the monoalkynylation product and the starting
material, even after an extended reaction time of 3 days.
The superior performance of methyl propiolate as an al-
The formal total synthesis of aspergillide B (36) was en-
AHCTUNGTREGaNNNU bled by an alkyne addition linchpin strategy, whereby (S)-
hept-6-yn-2-yl benzoate (22) and methyl propiolate were
added to each end of a butane dialdehyde equivalent 37
(Scheme 7).[43] Substrate and reaction optimization enabled
alkynylation by using just 1 equivalent of the precious
alkyne 22 (see Table 8). Subsequent Ru-catalyzed hydrosil-
AHCTUNGTREGyNNNU lation was used to achieve an E-selective reduction while
also differentiating the two alkenes present in the product
and enabling selective hydrogenation.[44] The late-stage addi-
tion of methyl propiolate to aliphatic aldehyde 38 proceeded
in good yield. Chemoselective reduction of 39 was then ach-
ieved by using our hydrosilylation/protodesilylation protocol
for the formation of (E)-alkenes. The basic reaction condi-
tions used for this transformation triggered spontaneous
oxy-Michael addition to produce the desired tetrahydrofur-
an ring and complete the formal total synthesis of aspergilli-
ACHTUNGTRENNUNGkynylzinc nucleophile was once again illustrated by the in-
creased yield and d.r. obtained relative to reaction with
TMS-acetylene. The resulting g-hydroxy-a,b-acetylenic ester
32 was saponified and decarboxylated to provide (À)-ado-
ciacetylene B (28) in a highly efficient manner. Ligand
(R,R)-1 was also used to facilitate this reaction, providing
access to both enantiomers of the natural product.
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Chem. Eur. J. 2012, 18, 16498 – 16509

Zn–ProPhenol-Catalyzed Asymmetric Alkyne Addition
FULL PAPER
ed three times with Et2O and the combined organic layers were concen-
trated in vacuo. The crude product was purified by flash column chroma-
tography. 1-Phenyl-5-trimethylsilanylpent-1-en-4-yn-3-ol was isolated as a
white solid (67 mg, 83% yield). M.p. 57–588C; [a]2D5 =+2.16 (c=1.05,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.40–7.43 (m, 2H), 7.32–7.36
(m, 2H), 7.25–7.29 (m, 1H), 6.77 (dd, J=16, 1.2 Hz, 1H), 6.29 (dd, J=
16, 6 Hz, 1H), 5.05 (dt, J=6, 1.2 Hz, 1H), 1.96 (t, J=6 Hz, 1H),
0.21 ppm (s, 9H); 13C NMR (101 MHz, CDCl3): d=136.0, 132.0, 128.6,
128.1, 127.8, 126.8, 104.1, 91.3, 66.3, À0.2 ppm; IR (film): n˜ =3300 (br,
OH), 2960, 2172, 1654, 1496, 1449, 1407, 1251 cmÀ1; HRMS (EI): m/z
calcd for C14H18OSi: 230.1127; found: 230.1126, Æ0.6 ppm; Chiral
HPLC: Chiralcel AD column, heptane/iPrOH=90:10, 1.0 mLminÀ1, l=
254 nm: 6.97/8.79 min (88% ee); this characterization data matches the
literature data.[45]
Acknowledgements
We thank the National Science Foundation (CHE-0846427) and the Na-
tional Institutes of Health (GM-33049) for their generous support of our
programs. M.J.B. is grateful to Victoria University of Wellington for a
Ph.D. scholarship. A.H.W. thanks GlaxoSmithKline (ACS Division of Or-
ganic Chemistry Fellowship) and Bristol–Myers Squibb (for a graduate
fellowship). A.J.v.W. thanks the DAAD for a postdoctoral fellowship. We
also thank Sigma–Aldrich for donating the ProPhenol ligand.
Scheme 7. Alkyne addition in the synthesis of aspergillide B. [a] The d.r.
was determined by chiral HPLC analysis. Cp*=pentamethylcyclopenta-
dienyl, BDMS-H=benzyldimethylsilane, DCE=1,2-dichloroethene.
[1] B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003–12004.
[2] For subsequent applications of this ligand, see: a) B. M. Trost, S.
Malhotra, P. Koschker, P. Ellerbrock, J. Am. Chem. Soc. 2012, 134,
2075–2084; b) B. M. Trost, J. Hitce, J. Am. Chem. Soc. 2009, 131,
4572–4573, and references cited therein.
de B. In this case, the asymmetric alkynylation served as a
surrogate for a vinylation.
[3] a) B. M. Trost, L. R. Terrell, J. Am. Chem. Soc. 2003, 125, 338–339;
b) B. M. Trost, J. Jaratjaroonphong, V. Reutrakul, J. Am. Chem. Soc.
2006, 128, 2778–2779.
[4] a) B. M. Trost, V. S. C. Yeh, Angew. Chem. 2002, 114, 889–891;
Angew. Chem. Int. Ed. 2002, 41, 861–863; b) B. M. Trost, V. S. C.
Yeh, H. Ito, N. Bremeyer, Org. Lett. 2002, 4, 2621–2623; c) B. M.
Trost, D. W. Lupton, Org. Lett. 2007, 9, 2023–2026.
[5] a) B. M. Trost, T. Mino, J. Am. Chem. Soc. 2003, 125, 2410–2411;
b) B. M. Trost, S. Malhotra, T. Mino, N. S. Rajapaksa, Chem. Eur. J.
2008, 14, 7648–7657.
[6] a) B. M. Trost, H. Ito, E. R. Silcoff, J. Am. Chem. Soc. 2001, 123,
3367–3368; b) B. M. Trost, A. Fettes, B. T. Shireman, J. Am. Chem.
Soc. 2004, 126, 2660–2661; c) B. M. Trost, S. Shin, J. A. Sclafani, J.
Am. Chem. Soc. 2005, 127, 8602–8603.
Conclusion
Continued optimization of the Zn–ProPhenol-catalyzed
alkyne addition has led to the development of practical and
general conditions for the asymmetric alkynylation of alde-
hydes. This synthetically efficient methodology operates
with relatively low catalyst loading and can avoid the use of
excess alkyne and dialkylzinc reagents. The chiral propargyl-
ic alcohols produced in this reaction are versatile synthetic
intermediates and have enabled the synthesis of various nat-
ural products. Further research into the asymmetric al-
[7] For the initial communication of this methodology, see: B. M. Trost,
A. H. Weiss, A. J. von Wangelin, J. Am. Chem. Soc. 2006, 128, 8–9.
[8] Modern Acetylene Chemistry (Eds.: P. J. Stang, F. Diederich), Wiley-
VCH, Weinheim, 2008.
ACHTUNGTRENNUNGkynylation of enolizable aldehydes is currently underway.
[9] For selected examples of catalytic enantioselective ynone reduction,
see: a) C. J. Helal, P. A. Magriotis, E. J. Corey, J. Am. Chem. Soc.
1996, 118, 10938–10939; b) K. Matsumura, S. Hashiguchi, T. Ikariya,
R. Noyori, J. Am. Chem. Soc. 1997, 119, 8738–8739; c) K. A.
Parker, M. W. Ledeboer, J. Org. Chem. 1996, 61, 3214–3217.
[10] For a recent review on asymmetric alkyne addition to carbonyls,
see: B. M. Trost, A. H. Weiss, Adv. Synth. Catal. 2009, 351, 963–983.
[11] For selected examples of asymmetric ynal alkylation, see: a) D. See-
bach, A. K. Beck, B. Schmidt, Y. M. Wang, Tetrahedron 1994, 50,
4363–4384; b) M. Fontes, X. Verdaguer, L. Sola, A. Vidal-Ferran,
K. S. Reddy, A. Riera, M. A. Pericas, Org. Lett. 2002, 4, 2381–2383;
c) S. BouzBouz, F. Pradaux, J. Cossy, C. Ferroud, A. Falguieres, Tet-
rahedron Lett. 2000, 41, 8877–8880; d) D. Uraguchi, S. Nakamura,
T. Ooi, Angew. Chem. 2010, 122, 7724–7727; Angew. Chem. Int. Ed.
2010, 49, 7562–7565; e) S. Belot, A. Quintard, A. Alexakis, N.
Krause, Adv. Synth. Catal. 2010, 352, 667–695.
Experimental Section
Representative alkynylation procedure with reduced reagent stoichiome-
try: Preparation of 1-phenyl-5-trimethylsilanylpent-1-en-4-yn-3-ol:Dime-
thylzinc (406 mL, 1.2m solution in tol-
uene, 0.488 mmol, 1.5 equiv) was
added to a solution of the (S,S)-ProPh-
enol ligand (20.8 mg, 0.0325 mmol,
10 mol%), triphenylphosphine oxide
(18 mg, 0.065 mmol, 20 mol%), and
TMS-acetylene (56 mL, 0.39 mmol, 1.2 equiv) in anhydrous toluene
(0.44 mL) at 08C (0.813 mL total toluene, 0.48m alkyne concentration).
The reaction mixture was warmed to room temperature and stirred for
60 min before addition of trans-cinammaldehyde (43 mg, 0.325 mmol,
1 equiv) at 08C. The reaction was stirred for 48 h at 48C before it was
quenched with saturated, aqueous NH4Cl. The organic phase was extract-
[12] For 1,2-dialkylidenecyclopentane formation, see: a) ref. [6]; for syn
a,b-dihydroxy ketone formation, see: b) B. M. Trost, Z. T. Ball,
Chem. Eur. J. 2012, 18, 16498 – 16509
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B. M. Trost et al.
K. M. Laemmehold, J. Am. Chem. Soc. 2005, 127, 10028–10038; for
b-arylation of propargylic alcohols, se : c) B. M. Trost, M. R. Macha-
cek, Z. T. Ball, Org. Lett. 2003, 5, 1895–1898; for [2+2+2] cycload-
dition, see: d) B. Witulski, A. Zimmermann, N. D. Gowans, Chem.
Commun. 2002, 2984–2985; for chiral allene formation, see:
e) W. H. Pirkle, C. W. Boeder, J. Org. Chem. 1978, 43, 1950–1952.
[13] For reviews on asymmetric addition of organozinc nucleophiles, see:
a) K. Soai, S. Niwa, Chem. Rev. 1992, 92, 833–856; b) L. Pu, H.-B.
Yu, Chem. Rev. 2001, 101, 757–824; c) R. Noyori, M. Kitamura,
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[14] For reviews on zinc-mediated alkyne addition, see: a) L. Pu, Tetra-
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mann, Eur. J. Org. Chem. 2004, 4095–4105; c) G. Lu, Y.-M. Li, X.-S.
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16508
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Chem. Eur. J. 2012, 18, 16498 – 16509

Zn–ProPhenol-Catalyzed Asymmetric Alkyne Addition
FULL PAPER
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Received: June 13, 2012
Revised: August 29, 2012
Published online: October 23, 2012
Chem. Eur. J. 2012, 18, 16498 – 16509
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www.chemeurj.org
16509