Diastero- and enantioselective intramolecular carbometalation reaction

Article abstract of DOI:10.1016/j.tet.2010.04.038

The zinc-catalyzed addition of various alkynes to acylsilanes followed by a Zn-Brook rearrangement and either the Zn-ene-allene or Zn-yne-allene cyclization led to the enantio- and diastereoselective formation of carbocycles in a single-pot operation.

Full text of DOI:10.1016/j.tet.2010.04.038

Tetrahedron 66 (2010) 4874e4881
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastero- and enantioselective intramolecular carbometalation reaction
,
Rozalia Ungera, Theodore Cohen b, Ilan Marek a
*
a Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry,
Technion-Israel Institute of Technology, 32000 Haifa, Israel
b Department of Chemistry, University of Pittsburgh, PA 15260, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The zinc-catalyzed addition of various alkynes to acylsilanes followed by a Zn-Brook rearrangement and
either the Zn-ene-allene or Zn-yne-allene cyclization led to the enantio- and diastereoselective forma-
tion of carbocycles in a single-pot operation.
Received 17 January 2010
Received in revised form 6 April 2010
Accepted 7 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 13 April 2010
This paper is dedicated to Professor Brian
Stoltz in honor of his Tetrahedron Award
Keywords:
Brook rearrangement
Zn-ene-allene cyclization
Enantioselective alkynylation
Carbometalation
Asymmetric catalysis
1. Introduction
Addition of a carbonemetal bond of an organometallic 1 across
a carbonecarbon double bond 2, leading to a new organometallic 3
in which the newly formed carbonemetal bond of 3 can be used for
further synthetic transformations to give 4 are called carbometa-
lation reactions1 (Scheme 1). To be synthetically useful, the new
organometallic 3 must have a reactivity different from that of 1 to
avoid oligomerization of the carbometalated substrate. So, the
carbometalation ability of 1 must be higher than that of 3, except in
the case of an intramolecular carbometalation reaction, where
entropy factors favor the mono-addition even if the starting orga-
nometallic and the product has similar reactivities. If an efficient
method would be available to render such a method asymmetric, it
would acquire significant utility as a method for the creation of
asymmetric stereocenters. Although the enantioselective carbo-
metalation reaction of double carbonecarbon bonds has a huge
potential in synthesis, it has not yet reached its promise due to the
difficulty of enantiofacial differentiation of unactivated alkenes.2
Even more challenging would be to render such approach enan-
tioselective through asymmetric catalysis.3
Scheme 1.
In the last fewyears, it has become abundantlyclear that zinc-ene
cyclizations have a great potential in organic synthesis,4 and in this
context, we have initially developed the zinc-ene-allene carbo-
cyclization through a metalation of propargylic hydrogens followed
by a transmetalation into an allenylzinc species and subsequent
cyclization.5 This strategy was extended to the stereoselective
syntheses of polysubstituted tetrahydrofurans,6 pyrrolidines,7 and
to an efficient approach to angular and linear triquinane skeletons,8
as well as to the zinc-yne-allene9 carbocyclization reactions. This
initial approach was further improved when it was found that
a
tandem Zn-promoted Brook rearrangement/carbocyclization
reaction also leads to cyclic product in similar yields (70e80%) with
complete diastereoselectivity (Scheme 2).10
Various alkynylmagnesium bromide derivatives 5 were added
to acylsilane 6 over a period of 30 min to lead to the corresponding
* Corresponding author. Tel./fax: þ972 4 829 3709; e-mail address: chilanm@tx.
technion.ac.il (I. Marek).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.038

R. Unger et al. / Tetrahedron 66 (2010) 4874e4881
4875
In the former case, and following our previously described
‘metalationetransmetalation’ procedure, the allenyl organozinc
bromide reagent 10 undergoes a highly diastereoselective cycliza-
tion reaction to lead to three contiguous stereogenic center on
a cyclopentane ring 11 with total diastereoselection (Scheme 3,
path A).5 In contrast, when 12 was treated with alkynylmagnesium
bromide derivatives 5, two diastereoisomers 13 were first obtained
in a 1:1 ratio (as determined by crude NMR on hydrolyzed aliquots).
The addition of zinc salt promotes the tandem Zn-Brook rear-
rangement and Zn-ene-allene cyclization, to give the cyclic isomers
16a,b in good yields, but in a 1:1 ratio (Scheme 3, path B).10b
Therefore, we suggest that each diastereoisomer of the alleny-
lzinc bromide 14a and 14b (with regard to the allylic stereogenic
center), generated through our tandem reaction, leads to its own
cyclic product 15a,b, since allenylzinc species are known to be
configurationally stable.11 If indeed each diastereoisomer of 14a,
b leads to its own cyclic product, one may assume that the prepa-
ration of enantiomerically enriched allenylzinc derivatives would
lead to enantiomerically enriched product as described in Scheme 4.
Thus, a few important questions were immediately raised:
Scheme 2.
a
-metallooxypropargylsilanes 7. Then, by addition of one equi-
valent of zinc bromide, a Zn-Brook rearrangement proceeds to
give the corresponding propargyl 8a/allenylzinc 8b derivatives,
that is, immediately followed by a diastereoselective Zn-ene-
allene cyclization reaction leading to the cyclic product 9 as
a unique diastereoisomer (Scheme 2).10 The reaction proceeds
smoothly for all tested metalated alkynes (R¼SiMe3, R¼Ph, and
R¼Hex) and the formation of an organometallic species was
checked by reaction with electrophiles. The unique cis-configu-
ration could be rationalized by a zinc-ene-allene transition state
8b as illustrated in Scheme 2. However, we were intrigued by the
stereochemistry obtained when an alkyl substituent was in-
troduced in the allylic position for the reaction performed
through metalation (Scheme 3, path A) versus alkynylation of
acylsilane (Scheme 3, path B).
(1) How to prepare enantioenriched propargylsilanol?
(2) Will the Brook rearrangement proceeds with complete transfer
of chirality?
(3) What will be the stereochemistry of the stereocenter generated
in the reaction?
(4) Will the allenylzinc species remain configurationally stable in
these experimental conditions?
(5) Will the carbocyclization always be diastereoselective?
If all these questions could be answered, the diastereo- and
enantioselective intramolecular carbometalation through the
Zn-ene-allene reaction would now become possible.
Scheme 4.
2. Results and discussion
Although the preparation of enantioenriched propargylic alco-
hols represents a stimulating and dynamic area in organic syn-
thesis,12 the addition of alkynes to acylsilanes is much less
documented and therefore remains a challenging goal. Fortunately,
Scheidt has recently reported the preparation of moderately
enantioenriched propargylsilane 17 through the catalytic asym-
metric alkyne addition to acylsilane using chiral ligand L1 with 74%
enantiomeric excess.13 This substrate undergoes the Brook rear-
rangement with a catalytic amount of n-BuLi to provide the cor-
responding enantioenriched allene 18 with minimal erosion of the
stereochemical information (Scheme 5).
Scheme 3.
Scheme 5.

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R. Unger et al. / Tetrahedron 66 (2010) 4874e4881
If the reaction described by Scheidt would also be applicable to
various -ene acylsilanes, a powerful new entry, through asym-
metric catalysis, would be opened for the formation of enantioen-
riched metalated carbocycles. Therefore, we investigated the
As can be seen from the results summarized in Table 2, the re-
u
action proceeds efficiently in all cases (except THF) and 20c is
obtained in similar yields and enantioselectivity. Toluene showed
slightly better results, and therefore, was used for further optimi-
zation. The nature of the dialkylzinc used for the deprotonation of
the alkyne has also an effect on the enantioselectivity of the re-
action as shown in Table 3.
enantioselectivity of the alkynylation of various u-ene acylsilanes as
described inTable 1, and we found that the nature of the substituents
on the silicon atom has a dramatic effect on the enantioselectivity of
the reaction. When acylsilane 19a, possessing three methyl groups,
was alkynylated (Table 1, entry 1), the enantiomeric ratio of the
corresponding propargylsilanol is only 76:24. A even lower selec-
tivity was obtained when triethylsilane was used (Table 1, entry 2).
However, replacement of one methyl by one phenyl group increases
the enantiomeric ratio substantially (er 86:14, Table 1, entry 3). The
presence of this aromatic ring is essential for good selectivity since
its saturated analog (R3¼c-C6H11) or a bulkier group (R3¼t-C4H9)
lead to either lower enantiomeric ratio or almost racemic species in
low yield (Table 1, entries 4 and 5, respectively). Interestingly, when
two phenyl rings are present, the best selectivity was achieved
(Table 1, entry 6) whereas the use of triphenylacylsilane (Table 1,
entry 7) leads again to lower selectivity.
Table 3
Nature of R2Zn on the enantioselectivity of alkynylation of the acylsilane 19c
Entry
R2Zn
Yielda (%)
erb
1
2
3
4
5
Et2Zn
Me2Zn
Bu2Zn
Ph2Zn
96
53
62
23
7
86:14
65:35
75:25
68:32
57:43
t-BuMe2Si2Zn
Table 1
a
Yield determined after purification by column chromatography.
Enantiomeric ratio determined by chiral HPLC (Chiracel AD-H, 5% IPA/hexanes).
Effect of substituents on silicon on the enantioselectivity of the alkynylation of
acylsilanes 19
b
Diethylzinc (Table 3, entry 1) is by far the best R2Zn in term of
yield and enantiomeric ratio of the desired product. An additional
factor that we briefly investigated was the presence of additional
metallic salts. For instance, addition of 1 equiv of ZnBr2 should lead,
via a Schlenk equilibrium to the alkynyl zinc bromide instead of
alkyl alkynyl zinc species and as expected the reaction still proceed
in good yield (87%) but racemic adduct was obtained (54:46 er). An
additional attempt was to add a lithium salt to form the more re-
active zincate species or to use a cocatalyst such as Ti(O-iPr)4; here
again the reaction afforded the expected product in good yields but
in racemic forms. Finally, we screened a number of chiral ligands
(L1eL20) for the transformation of 19c into 20c (Et2Zn, toluene) and
yields and as well as enantiomeric ratios as summarized in Chart 1.
As shown in Chart 1, while keeping constant indenol as the
amino alcohol residue, decent enantioselectivity was only observed
when two tert-butyl groups were present on the aromatic ring
(compare L1 with L2e4). Keeping now constant the aryl group,
various amino alcohols were examined and the best result found so
far was with the ligand L7 resulting from the condensation of tert-
leucinol with 3,5-di-tert-butyl-2-hydroxybenzaldehyde (compare
L7 with L5,6 and L8,9). The nature of the aryl group was also briefly
checked with tert-leucinol and again, the best enantiomeric ratio
was obtained when the two tert-butyl groups are present (ligand L7
vs L10e12). All other variations (L13eL20) did not improve the en-
antiomeric ratio.
Entry
R1
R2
R3
Pdts
Yielda (%)
erb
1 (19a)
2 (19b)
3 (19c)
4 (19d)
5 (19e)
6 (19f)
7 (19g)
Me
Et
Me
Et
Me
Me
Me
Ph
Me
Et
Ph
c-C6H11
t-Bu
Ph
20a
20b
20c
20d
20e
20f
96
89
93
95
55
83
51
76:24
63:37
86:14
73:27
53:47
88:12
63:37
Me
Me
Me
Me
Ph
Ph
Ph
20g
a
Yield determined after purification by column chromatography.
Enantiomeric ratio determined by chiral HPLC (Chiracel AD-H, 5% IPA/hexanes).
b
Although additional studies are needed to fully understand the
effect of substituents on acylsilanes, symmetric (R1¼R2¼R3) as well
as asymmetric with a bulky substituent (R3¼c-C6H11 or t-Bu)
acylsilane lead to low enantiomeric ratios. Good ratios can only be
obtained when an aryl group is present on the acylsilane (R3¼Ph).
The absolute configuration of 20c was determined by comparison
of the experimental and calculated circular dichroism spectra.14,15
Aiming to further improve the enantioselectivity of the reaction,
several solvents were tested in the alkynylation reaction of acylsi-
lane 19c as shown in Table 2.
Although the best enantiomeric ratio obtained is only 90:10
with L7, we did not pursue a deeper investigation of chiral ligands
since we were more interested to investigate the stereochemistry of
the Zn-Brook rearrangement followed by its Zn-ene-allene carbo-
cyclization. The Brook rearrangement usually proceeds only when
a catalytic amount of base is utilized and the typically rapid and
essentially irreversible reaction is by protonation of the carbanion
by the starting alcohol.16 Therefore, transfer of chirality into
a metalated allenyl species through a stoichiometric amount of
base for the Brook rearrangement17 had no precedent and also
drove our curiosity. Indeed, having in hand propargylsilanol 20c,
we then investigated the transfer of chirality in the tandem Zn-
Brook rearrangement followed by the Zn-ene-allene carbocycliza-
tion reaction as described in Scheme 6.14
Table 2
Solvent effects on the enantioselectivity of the alkynylation of acylsilane 19c
Entry
Solvent
Yielda (%)
erb
1
2
3
4
5
Toluene
Hexane
Et2O
CH2Cl2
THF
96
85
91
89
<7
86:14
80:20
81:19
82:18
c
We were pleased to see that when a solution of Et2Zn was added
to enantioenriched 20c (er 76:24) in THF and heated at 40 ꢀC for
24 h,18 the corresponding cyclic product 21 was obtained, after
a
Yield determined after purification by column chromatography.
Enantiomeric ratio determined by chiral HPLC (Chiracel AD-H, 5% IPA/hexanes).
Not determined.
b
c

R. Unger et al. / Tetrahedron 66 (2010) 4874e4881
4877
R1
L1: R1 = t-Bu; R2 = t-Bu, 96%, 86:14 er
L2: R1 = H; R2 = t-Bu, 82%, 63:37 er
L3: R1 = t-Bu; R2 = H, 89%, 59:41 er
L4: R1 = H; R2 = H, 84%, 68:32 er
Although more mechanistic investigations are needed to fully
explore this rearrangement, the absolute configuration of the starting
propargylsilanol 20c and the final cyclic product 21 (also determined
by comparing experimental and theoretical CD spectra)14 led us to
postulate the following mechanistic hypothesis: the oxygen atom of
the zinc alcoholate 20cZn first interacts with the silicon atom to form
through the transition state 22,21 the Brook product 23. The zinc
countercation occupies the less sterically hindered face, adjacent to
the alkyne (Scheme 7). Thus, the zinc-Brook rearrangement leads to
the corresponding propargylzinc derivative 23 (possibly only as
a transient species), with pure retention of configuration. The second
rearrangement in our process, the metalotropic equilibrium with its
allenic counterpart 24 occurs via a suprafacial migration leading to
the corresponding configurationally stable allenylzinc derivative 24
with pure retention of configuration.11 The latter then undergoes the
last step, a diastereoselective Zn-ene-allene cyclization reaction in
which the allenyl metal moiety plays the role of the ene moiety and
fixes the cis relationship of the two substituents as described in 25 to
give the corresponding alkynyl cyclopentyl methylzinc derivative 26
(Scheme 7). Clearly, this whole sequence (three consecutive steps)
proceeds with virtually complete transfer of chirality from 20c to 26
with the creation of two new stereocenters, including the formation
of a quaternary stereocenter.22
HO
OH
N
R2
L5: R3 = Bu, 87%, 73:27 er
L6: R3 = i-Pr, 90%, 76:24 er
L7: R1 = t-Bu, 93%, 90:10 er
L8: R1 = Bn, 88%, 69:31 er
L9: R1 = Ph, 79%, 58:42 er
t-Bu
OH
HO
R3
N
t-Bu
R1
L10: R1 = H; R2 = H, 89%, 83:17 er
L11: R1 = H; R2 = t-Bu, 85%, 71:29 er
L12: R1 = t-Bu; R2 = H, 89%, 59:41 er
OH
HO
N
R2
t-Bu
t-Bu
t-Bu
t-Bu
OH
OH
OH
O
HO
O
Ph
OH
t-Bu
N
N
OMe
N
t-Bu
t-Bu
Ph
L14
t-Bu
L13
t-Bu
L15
87%
54:46 er
t-Bu
85%
88%
52:48 er
49:51 er
Bu-t
OH
t-Bu
t-Bu
HO
OH
OH
HO
HO
t-Bu
Bu-t
H
N
N
t-Bu
N
N
L17
L18
86%
55:45 er
L16
77%
77:23 er
t-Bu
t-Bu
71%
73:27 er
H
N
CH3
H
H
O
N
HO
Ph
L20
NH
O
L19
75%
53:47 er
93%
52:48 er
Chart 1.
Scheme 7.
As the alkynylation of the acylsilane, the Brook rearrangement
and the carbocyclization involve only zinc species, we were there-
fore able to perform the entire sequence in a single-pot operation as
described in Scheme 8, via asymmetric catalysis. When acylsilane
Scheme 6.
hydrolysis, in excellent yield with a similar enantiomeric ratio (er
74:26) over three consecutive steps (Zn-Brook rearrangement, Zn
suprafacial migration, and Zn-ene-allene cyclization, Scheme 6,
path A).19 On the other hand, when racemic 20c was treated with
Et2Zn in the presence of chiral ligand L1, only racemic 21 was
formed, excluding a possible equilibration of racemic propargyl/
allenylzinc into enantiomerically enriched species via interactions
with chiral ligand (Scheme 6, path B). The stereochemical outcome
of the first rearrangement, namely the 1,2-silyl migration, has been
occasionally investigated in the chemistry of organolithium species
and occurs with partial inversion of configuration for secondary
and tertiary
configuration for saturated
a
-silyl benzyl alcohols but with retention (>97%) of
a
-silyl alcohols.20 However, silylalkyl
anions were always intercepted rapidly and irreversibly in-situ by
using solvents containing water or a protic source.17 No report on
the stereochemistry of the 1,2-Brook rearrangement is available
particularly for the formation of a propargylzinc species.
Scheme 8.

4878
R. Unger et al. / Tetrahedron 66 (2010) 4874e4881
19c was added to phenylacetylene in the presence of Et2Zn and
20 mol % ofchiral ligand L1, as shownin Scheme 8, thecorresponding
cyclopentanol 21 was obtained in excellent isolated yield as a unique
diastereoisomer with an almost complete transfer of chirality after
hydrolysis. The formation of a discrete organometallic species after
carbocyclization was checked by iodinolysis (formation of 27).
The same behavior was found when acylsilane 19f was treated
with phenylacetylene. The enantiomeric ratio determined after the
alkynylation reaction is practically the same as the one obtained for
the cyclic product 21 (88:12 for propargylsilanol 20f versus 86:14 er
for 21, Scheme 8). Similarly, when acylsilane 19c was treated with
1-octyne, the enantiomeric ratio of the cyclic products 31 and 32,
after hydrolysis and iodinolysis, respectively, are in the same range
as those of the hydrolyzed addition product 29 (Scheme 9).23
product during the Zn-Brook rearrangement. Currently, our efforts
are directed toward expanding this concept to various different and
challenging substrates.
4. Experimental section
4.1. General
Experiments involving organometallics were carried out under
a positive pressure of argon. All glassware were oven dried at 150 ꢀC
overnight and assembled quickly while hot under a stream of ar-
gon. Liquid nitrogen was used as a cryogenic fluid and all indicated
temperatures, unless otherwise stated, refer to internal ones. Ether
and THF were distilled from sodium benzophenone ketyl. NMR
spectra were recorded in CDCl3. Chemical shifts are reported in part
per million (ppm) relative to tetramethylsilane (TMS) as an internal
standard (0.1%) in 1H NMR spectra. In 13C NMR spectra, CDCl3
Hex
Hex
Hex
H
O
OH
Et Zn, 20 mol% L , Toluene
OZnEt
H O
PhMe Si
PhMe Si
PhMe Si
19c
(
d
¼77 ppm) was used as a reference.
29
28
80%
84:16 er
Starting materials were prepared by standard procedure from
THF
literature.24
40 C, 24 h
EtZn
Hex
I
Hex
Hex
Me
4.1.1. 1-Trimethylsilyl-hex-5-en-1-one14 19a. Compound 19a was
prepared according to the standard procedure.24 After purification
by column chromatography, 1.08 g (80%) of 19a was obtained as
H
O
I
then n-Bu NF
then n-Bu NF
OH
OH
OSiPhMe
32
30
31
65%
81%
>99:1 dr
a colorless liquid. 1H NMR (CDCl3, 500 MHz)
d (ppm): 0.16 (s, 9H),
>99:1 dr
>80/20 er
>80:20 er
1.59 (quint, J¼7.5 Hz, 2H), 1.99 (q, J¼7.0 Hz, 2H), 2.57 (t, J¼7.2 Hz,
Scheme 9.
2H), 4.91e4.98 (m, 2H), 5.69e5.74 (m, 1H); 13C NMR (CDCl3,
125 MHz)
(thin film): 912, 997, 1079, 1091, 1162, 1249, 1351, 1411, 1443, 1642,
2856, 2927, 2956 cmꢁ1
d
(ppm): ꢁ3.2, 21.1, 33.2, 47.5, 115.0, 138.1, 248.3; FTIR
The same principle could be extended to the enantioselective
Zn-yne-allene cyclization as described in Scheme 10. The addition
of phenylacetylene to the new acylsilane 33 possessing an elec-
trophilic alkynylsilane moiety led to the corresponding prop-
argylsilanol 34, after hydrolysis, in excellent yield with an
enantiomeric ratio of 77:23 (path A, Scheme 10). By heating the
reaction mixture at 40 ꢀC in THF for 24 h before hydrolysis, the
cyclic product 35, resulting from the Brook rearrangement followed
by suprafacial migration of the zinc along the carbon chain of the
alkyne and then the Zn-yne-allene carbocyclization, was obtained
in 79% yield with a complete transfer of chirality (77:23 er) and as
a unique E-geometrical isomer.
.
4.1.2. 1-Triethylsilyl-hex-5-en-1-one14 19b. Compound 19b was
prepared according to the standard procedure.24 After purification
by column chromatography, the expected acylsilane 19b was
obtained in 91% yield as a colorless liquid. 1H NMR (CDCl3,
500 MHz)
d
(ppm): 0.73 (q, J¼14 Hz, 6H), 0.95 (t, J¼14.5 Hz, 9H),
1.63 (quint, J¼7.5 Hz, 2H), 2.02 (q, J¼7.0 Hz, 2H), 2.56 (t, J¼7.2 Hz,
2H), 4.93e5.02 (m, 2H), 5.69e5.79 (m, 1H); 13C NMR (CDCl3,
125 MHz)
(thin film): 912, 997, 1079, 1091, 1162, 1249, 1351, 1411, 1443, 1642,
2856, 2927, 2956 cmꢁ1
d (ppm): 5.8, 7.2, 22.1, 33.1, 47.5, 115.0, 138.1, 248.5; FTIR
.
4.1.3. 1-Dimethyl(phenyl)silyl-hex-5-en-1-one14 19c. Compound 19c
was prepared according to the standard procedure.24 After purifi-
cation by column chromatography, the expected acylsilane 19c was
obtained in 81% yield as an yellow liquid. 1H NMR (CDCl3, 300 MHz)
d
(ppm): 0.52 (s, 6H),1.60 (dquint, J1¼7.2 Hz, J2¼1.2 Hz, 2H),1.97 (dq,
J1¼7.4 Hz, J2¼0.9 Hz, 2H), 2.61 (dt, J1¼0.9 Hz, J2¼7.2 Hz, 2H),
4.91e4.97 (m, 2H), 5.65e5.75 (m, 1H), 7.35e7.42 (m, 3H), 7.57e7.59
(m, 2H); 13C NMR (CDCl3, 125 MHz)
d
(ppm): ꢁ4.9, 21.0, 32.9, 47.7,
114.8, 128.0, 129.7, 132.8, 133.8, 137.9, 245.8; FTIR (thin film): 912,
998, 1026, 1062, 1114, 1253, 1428, 1642, 2939, 2958, 3071 cmꢁ1
.
4.1.4. 1-Dimethyl(cyclohexyl)silyl-hex-5-en-1-one14 19d. Compound
19d was prepared according to the standard procedure.24 After
purification by column chromatography, the expected acylsilane
19d was obtained in 75% yield as a colorless liquid. 1H NMR (CDCl3,
Scheme 10.
3. Conclusions
In summary, the catalytic enantioselective alkynylation of an
acylsilane followed by a zinc-promoted Brook rearrangement and
finally the Zn-ene-allene or Zn-yne-allene cyclization represents
a very efficient and powerful entry to enantiomerically enriched
carbocycles with formation of synthetically challenging quaternary
stereocenters. Three new bonds are generated in a single-pot
operation. One of the most remarkable features of this enantiose-
lective intramolecular carbometalation reaction are the highly
efficient transfer of chirality in the formation of the organometallic
500 MHz)
6H), 1.58e1.71 (m, 5H), 2.01 (q, J¼7.0 Hz, 2H), 2.57 (t, J¼7.2 Hz, 2H),
4.93e5.02 (m, 2H), 5.70e5.79 (m, 1H); 13C NMR (CDCl3,125 MHz)
d (ppm): 0.13 (s, 6H), 0.87e0.88 (m, 2H), 1.07e1.24 (m,
d
(ppm): ꢁ3.2, 19.4, 21.1, 25.5, 27.2, 28.6, 33.2, 47.5, 115.0, 138.1, 248.3;
FTIR (thin film): 910, 999, 1079, 1089, 1162, 1249, 1351, 1411, 1443,
1642, 2854, 2925, 2956 cmꢁ1
.
4.1.5. 1-Dimethyl(tert-butyl)silyl-hex-5-en-1-one14 19e. Compound
19e was prepared according to the standard procedure.24 After

R. Unger et al. / Tetrahedron 66 (2010) 4874e4881
4879
25
purification by column chromatography, the expected acylsilane
19e was obtained in 49% yield as a colorless liquid. 1H NMR (CDCl3,
[a
]
þ13.6 (CH2Cl2, c 0.9, er¼76:24). The enantiomeric ratio was
D
measured by chiral HPLC (Chiracel AD-H, 3% IPA/hexanes, Rt1¼8.12,
500 MHz)
2H), 1.93 (q, J¼5.1 Hz, 2H), 2.51 (t, J¼7.7 Hz, 2H), 4.84e4.91 (m, 2H),
5.62e5.68 (m, 1H); 13C NMR (CDCl3, 75 MHz)
(ppm): ꢁ7.2, 16.3,
20.7, 26.2, 33.0, 49, 114.8, 138.0, 246.7; FTIR (thin film): 912, 998,
1251, 1363, 1405, 1467, 1641, 2859, 2887, 2898, 2931, 2952 cmꢁ1
d
(ppm): 0.09 (s, 9H), 0.84 (s, 9H), 1.52 (quint, J¼7.5 Hz,
Rt2¼14.02).
d
4.2.2. (R)-3-Triethylsilyl-1-phenyl-oct-7-en-1-yn-3-ol
20b. Com-
pound 20b was prepared according to the general procedure using
19b (106 mg, 0.50 mmol), phenylacetylene (0.11 mL, 1.0 mmol),
ZnEt2 (0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg, 0.100 mmol) to
afford 139.8 mg of 20b (89%) as a colorless oil. 1H NMR (CDCl3,
.
4.1.6. 1-Methyl(diphenyl)silyl-hex-5-en-1-one14 19f. Compound 19f
was prepared according to the standard procedure.24 After purifi-
cation by column chromatography, the expected acylsilane 19f was
obtained in 79% yield as a yellow liquid. 1H NMR (CDCl3, 300 MHz)
300 MHz)
d
(ppm): 0.75 (q, J¼7.5 Hz, 6H), 1.03 (t, J¼6.9 Hz, 9H), 1.69
(br s, 1H), 1.73e1.75 (m, 4H), 2.11e2.14 (m, 2H), 4.94e5.00 (m, 2H),
5.79e5.86 (m, 1H), 7.24e7.29 (m, 3H), 7.35e7.36 (m, 2H); 13C NMR
d
(ppm): 0.69 (s, 3H), 1.52 (quint, J¼7.2 Hz, 2H), 1.84 (q, J1¼1.2 Hz,
(CDCl3, 125 MHz)
115.6, 123.1, 128.3, 128.4, 131.4, 139.1; [
er¼63:37). The enantiomeric ratio was measured by chiral HPLC
(Chiracel AD-H, 5% IPA/hexanes, Rt1¼6.82, Rt2¼16.72).
d (ppm): 2.6, 8.1, 22.7, 33.8, 37.0, 65.2, 89.2, 91.7,
25
J2¼7.2 Hz, 2H), 2.60 (dt, J1¼3.4 Hz, J2¼7.1 Hz, 2H), 4.78e4.84 (m,
a
]
D
þ18.6 (CH2Cl2, c 1.1,
2H), 5.52e5.57 (m, 1H), 7.26e7.29 (m, 6H), 7.51e7.54 (m, 4H); 13C
NMR (CDCl3, 125 MHz)
129.8, 129.8, 134.7, 137.7, 243.6; FTIR (thin film): 913, 997, 1112,
1253, 1429, 1642, 2931, 3050, 3071 cmꢁ1
d
(ppm): ꢁ5.6, 20.9, 32.7, 48.5, 114.7, 127.9,
.
4.2.3. (R)-3-Dimethyl(phenyl)silyl-1-phenyl-oct-7-en-1-yn-3-ol
20c. Compound 20c was prepared according to the general pro-
cedure using 19c (116 mg, 0.50 mmol), phenylacetylene (0.11 mL,
1.0 mmol), ZnEt2 (0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg,
0.100 mmol) to afford 157.8 mg (94%) of 20c as a colorless oil. 1H
4.1.7. 1-Triphenylsilyl-hex-5-en-1-one14 19g. Compound 19g was
prepared according to the standard procedure.24 After purification
by column chromatography, the expected acylsilane 19g was
obtained in 43% yield as yellow liquid. 1H NMR (CDCl3, 300 MHz)
d
NMR (CDCl3, 300 MHz) d (ppm): 0.52 (s, 6H), 1.67e1.75 (m, 4H),
(ppm): 1.55 (quint, J¼7.2 Hz, 2H), 1.89 (q, J1¼1.2 Hz, J2¼7.2 Hz, 2H),
2.60 (dt, J1¼3.4 Hz, J2¼7.1 Hz, 2H), 4.78e4.84 (m, 2H), 5.52e5.57 (m,
1H), 7.23e7.38 (m, 10H), 7.51e7.54 (m, 5H); 13C NMR (CDCl3,
1.99 (br s, 1H), 2.08e2.10 (m, 2H), 4.93e5.05 (m, 2H), 5.81e5.83 (m,
1H), 7.30e7.32 (m, 3H), 7.38e7.41 (m, 5H), 7.69e7.71 (m, 2H); 13C
NMR (CDCl3, 75 MHz)
d
(ppm): ꢁ5.9, ꢁ5.6, 23.1, 33.8, 36.9, 64.8,
125 MHz)
137.7, 243.6; FTIR (thin film): 918, 997, 1112, 1253, 1427, 1642, 2935,
3050, 3071 cmꢁ1
d
(ppm): 20.5, 32.7, 48.5, 114.7, 127.9, 129.8, 129.8, 134.7,
88.1, 91.8, 114.5, 123.3, 127.7, 127.9, 128.2, 129.6, 131.4, 134.7, 135.2,
138.6; [
a]
25 þ23.1 (CH2Cl2, c 0.9, er¼86:14). The enantiomeric ratio
D
.
was measured by chiral HPLC (Chiracel AD-H, 5% IPA/hexanes,
Rt1¼5.70, Rt2¼14.40).
4.1.8. 1-Trimethylsilyl-hex-(6-trimethylsilyl)-5-yn-1-one14 33. Com-
pound 33 was prepared according to the standard procedure.24
After purification by column chromatography, 33 was obtained in
4.2.4. (R)-3-Dimethyl(cyclohexyl)silyl-1-phenyl-oct-7-en-1-yn-3-ol
20d. Compound 20d was prepared according to the general pro-
cedure using 19d (108 mg, 0.50 mmol), phenylacetylene (0.11 mL,
1.0 mmol), ZnEt2 (0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg,
0.100 mmol) to afford 187.1 mg of 20d (95%) as a colorless oil. 1H
77% yield as a colorless liquid. 1H NMR (CDCl3, 300 MHz)
d (ppm):
0.03 (s, 9H), 0.09 (s, 9H), 1.60 (quint, J¼6.0 Hz, 2H), 2.11 (t, J¼6.1 Hz,
2H), 2.64 (t, J¼5.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
(ppm): ꢁ3.4,
d
ꢁ3.3, 0.0, 19.0, 20.7, 46.4, 85.0, 106.4, 247.2; FTIR (thin film): 911,
NMR (CDCl3, 300 MHz) d (ppm): 0.10 (s, 6H), 0.81 (m, 4H), 0.94 (m,
1044, 1248, 1351, 1407, 1430, 1645, 2173, 2900, 2957 cmꢁ1
.
4H), 1.21 (m, 4H), 1.72e1.75 (m, 4H), 2.11e2.13 (m, 2H), 4.93e5.06
(m, 2H), 5.79e5.85 (m, 1H), 7.23e7.29 (m, 3H), 7.35e7.38 (m, 2H);
4.2. Preparation of enantiomerically enriched
propargylsilanol derivatives
13C NMR (CDCl3, 125 MHz)
d
(ppm): ꢁ4.2, 18.5, 23.1, 25.5, 27.6, 28.6,
33.8, 36.8, 63.2, 89.2, 91.0, 114.6, 123.1, 128.3, 128.4, 131.0, 139.1;
25
[a
]
þ19.1 (CH2Cl2, c 1.1, er¼73:27). The enantiomeric ratio was
D
To a flame-dried round bottom flask charged with alkyne
(1.0 mmol) in toluene (2 mL) was added diethylzinc (1.0 mmol,
1.5 M in toluene). The solution was first stirred at rt for 1 h, and
then chiral ligand (0.100 mmol) was added in toluene (1 mL). After
the solution had been stirred for an additional 1 h, acylsilane
(0.50 mmol) dissolved in toluene (1 mL) was added at room
temperature. The yellow solution was stirred until complete con-
sumption of acylsilane (8e12 h, followed by TLC analysis with a 10%
EtOAc/hexane eluent) at room temperature. The reaction was then
quenched at room temperature with a saturated aqueous solution
of NH4Cl and extracted with Et2O (3ꢂ10 mL). The organic solution
was washed with brine (10 mL), dried over anhydrous MgSO4, fil-
tered, and concentrated to give the unpurified propargylsilane. The
product was purified by flash chromatography (5% EtOAc/hexanes).
measured by chiral HPLC (Chiracel AD-H, 5% IPA/hexanes, Rt1¼6.87,
Rt2¼15.62).
4.2.5. (R)-3-Dimethyl(tert-butyl)silyl-1-pheny-loct-7-en-1-yn-3-ol
20e. Compound 20e was prepared according to the general pro-
cedure using 19e (106 mg, 0.50 mmol), phenylacetylene (0.11 mL,
1.0 mmol), ZnEt2 (0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg,
0.100 mmol) to afford 86.4 mg (55%) of 20e as a colorless oil. 1H
NMR (CDCl3, 300 MHz)
d (ppm): 0.13 (s, 3H), 0.14 (s, 3H), 1.05 (s,
9H),1.63 (s,1H),1.71e1.81 (m, 4H), 2.11e2.14 (m, 2H), 4.94e5.06 (m,
2H), 5.79e5.88 (m, 1H), 7.27e7.29 (m, 3H), 7.36e7.37 (m, 2H); 13C
NMR (CDCl3,125 MHz)
65.4, 87.9, 92.7, 114.6, 123.5, 127.9, 128.3, 131.3, 138.7; [
d
(ppm): ꢁ7.6, ꢁ7.3,1.0, 22.7, 27.8, 33.9, 38.0,
25
a]
0.0
D
(CH2Cl2, c 1.1, er¼53:47). The enantiomeric ratio was measured by
chiral HPLC (Chiracel AD-H, 5% IPA/hexanes, Rt1¼6.64, Rt2¼8.81).
4.2.1. (R)-3-Trimethylsilyl-1-phenyl-oct-7-en-1-yn-3-ol 20a. Com-
pound 20a was prepared according to the general procedure using
19a (85 mg, 0.50 mmol), phenylacetylene (0.11 mL, 1.0 mmol),
ZnEt2 (0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg, 0.100 mmol) to
afford 130.2 mg of 20a (96%) as a colorless oil. 1H NMR (CDCl3,
4.2.6. (R)-3-Methyl(diphenyl)silyl-1-phenyl-oct-7-en-1-yn-3-ol
20f. Compound 20f was prepared according to the general pro-
cedure using 19f (146 mg, 0.50 mmol), phenylacetylene (0.11 mL,
1.0 mmol), ZnEt2 (0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg,
0.100 mmol) to afford 154.5 mg (78%) of 20f as a yellow oil. 1H NMR
300 MHz)
2H), 4.94e5.06 (m, 2H), 5.79e5.88 (m, 1H), 7.27e7.29 (m, 3H),
7.37e7.40 (m, 2H); 13C NMR (CDCl3, 75 MHz)
(ppm): ꢁ4.2, 23.1,
33.9, 36.8, 64.9, 87.6, 91.8, 114.6, 123.4, 127.9, 128.2, 131.5, 138.6;
d (ppm): 0.17 (s, 9H), 1.67e1.75 (m, 4H), 2.12e2.14 (m,
(CDCl3, 300 MHz)
4H), 2.00e2.05 (m, 2H), 4.88e4.99 (m, 2H), 5.72e5.81 (m, 1H),
7.28e7.40 (m, 11H), 7.76e7.77 (m, 4H); 13C NMR (CDCl3,125 MHz)
d (ppm): 0.75 (s, 3H), 1.54 (br s, 1H), 1.71e1.82 (m,
d
d

4880
R. Unger et al. / Tetrahedron 66 (2010) 4874e4881
(ppm): ꢁ6.2, 23.0, 33.8, 37.3, 64.9, 88.9, 92.0, 114.5, 123.2, 127.8,
times with Et2O. Next, the combined organic phases were washed
once with brine and dried over MgSO4.
127.8, 128.1, 128.2, 129.7, 129.8, 131.4, 133.6, 133.9, 135.6, 135.6,
25
138.6; [
a]
þ28.0 (CH2Cl2, c 1, er¼88:12). The enantiomeric ratio
D
was measured by chiral HPLC (Chiracel AD-H, 5% IPA/hexanes,
4.3.1. (1R,2R)-2-Methyl-1-(phenylethynyl)-cyclopentanol 21. Com-
pound 21 was prepared according to the general procedure using
19c and compared with literature data:14 (116 mg, 0.50 mmol),
phenylacetylene (0.11 mL, 1.0 mmol), ZnEt2 (0.7 mL, 1.0 mmol), li-
gand L1 (36.5 mg, 0.100 mmol). After purification by column chro-
matography, 92.1 mg (92%) of product (R,R)-21 was obtained as
Rt1¼7.78, Rt2¼28.41).
4.2.7. (R)-3-Triphenylsilyl-1-pheny-loct-7-en-1-yn-3-ol 20g. Com-
pound 20g was prepared according to the general procedure using
19g (165 mg, 0.50 mmol), phenylacetylene (0.11 mL, 1.0 mmol),
ZnEt2 (0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg, 0.100 mmol) to
afford 114.5 mg of 20g (51%) as a yellow oil. 1H NMR (CDCl3,
a colorless liquid. 1H NMR (CDCl3, 300 MHz)
J¼6.6 Hz, 3H), 1.40e1.43 (m, 1H), 1.56 (br s, 1H), 1.73e1.78 (m, 2H),
1.96e2.16 (m, 4H), 7.27e7.43 (m, 5H); 13C NMR (CDCl3, 100 MHz)
(ppm): 16.5, 20.6, 31.2, 40.9, 46.1, 78.9, 85.9, 90.6, 122.9, 128.2,
d (ppm): 1.10 (d,
300 MHz)
4.83e4.96 (m, 2H), 5.71e5.81 (m, 1H), 7.18e7.56 (m, 20H); 13C NMR
(CDCl3, 125 MHz) (ppm): 23.0, 33.9, 37.2, 65.2, 89.2, 91.9, 114.6,
123.1,127.7,127.8,128.2,128.3,128.4,129.7,129.9,131.0,133.5,133.8,
d
(ppm): 1.71e1.75 (m, 4H), 2.01e2.04 (m, 2H),
d
25
d
128.2, 131.6. [
a]
þ8.4 (CH2Cl2, c 1, er¼81:19). The enantiomeric
D
ratio was measured by chiral HPLC (Chiracel AD-H, 5% IPA/hexanes,
25
136.0, 136.3, 139.1; [
a
]
þ29.4 (CH2Cl2, c 1.1, er¼63:37). The en-
Rt1¼13.35, Rt2¼14.04).
D
antiomeric ratio was measured by chiral HPLC (Chiracel AD-H, 5%
IPA/hexanes, Rt1¼7.91, Rt2¼17.18).
4.3.2. (1R,2R)-2-Iodomethyl-1-(phenylethynyl)-cyclopentanol 27.
Compound 27 was prepared according to the general procedure
using 19c and compared with literature data:14 (116 mg,
0.50 mmol), phenylacetylene (0.11 mL, 1.0 mmol), ZnEt2 (0.7 mL,
1.0 mmol), ligand L1 (36.5 mg, 0.100 mmol), and I2 (6 equiv) was
added at ꢁ30 ꢀC in 10 ml of THF. The reaction was warmed to room
temperature, stirred for an additional 2 h before the hydrolysis and
further treatment are done as usual to afford 81.7 mg (50%) of 27 as
4.2.8. (R)-3-Dimethyl(phenyl)silyl-1-phenyl-oct-7-en-1-yn-3-ol 29.
Compound 29 was prepared according to the general procedure
using 19c (116 mg, 0.50 mmol), 1-octyne (0.13 mL, 1.0 mmol), ZnEt2
(0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg, 0.100 mmol) to afford
136.9 mg (80%) of 29 as a colorless oil. 1H NMR (CDCl3, 300 MHz)
d
(ppm): 0.40 (s, 6H), 0.88 (t, J¼7.1 Hz, 3H), 1.23e1.83 (m, 10H),
2.00e2.19 (m, 4H), 2.21 (t, J¼6.9 Hz, 2H), 4.88e4.99 (m, 2H),
a yellow liquid. 1H NMR (CDCl3, 300 MHz)
d (ppm): 1.65e1.71 (m,
5.70e5.81 (m, 1H), 7.34e7.67 (m, 5H); 13C NMR (CDCl3, 75 MHz)
d
2H), 1.92e1.96 (m, 1H), 2.08e2.12 (m, 2H), 2.20 (t, J¼7.1 Hz, 2H),
(ppm): ꢁ5.8, ꢁ5.6, 14.1, 19.0, 22.6, 28.6, 28.9, 29.7, 31.4, 33.9, 37.1,
2.28e2.30 (m, 1H), 3.08 (t, J¼9.3 Hz, 1H), 3.47 (dd, J1¼9.5 Hz,
25
60.1, 82.3, 88.7, 114.4, 127.6, 129.4, 130.9, 134.7, 138.8; [
a
]
þ23.1
J2¼5.9 Hz, 1H), 7.29e7.43 (m, 5H); 13C NMR (CDCl3, 100 MHz)
d
D
(CH2Cl2, c 0.9, er¼86:14). Enantiomeric ratio was measured by
(ppm): 7.7, 20.6, 31.2, 40.6, 52.3, 75.9, 83.9, 92.6, 122.9, 128.2, 128.4.
chiral HPLC (Chiracel AD-H, 5% IPA/hexanes, Rt1¼5.70, Rt2¼14.40).
4.3.3. (1R,2R)-2-Methyl-1-(2-octynyl)-cyclopentanol 31. Compound
31 was prepared according to the general procedure using 19c and
compared with literature data:14 (116 mg, 0.50 mmol), 1-octyne
(0.15 mL, 1.0 mmol), ZnEt2 (0.7 mL, 1.0 mmol), ligand L1 (36.5 mg,
0.100 mmol). After purification by column chromatography, 94.8 mg
(91%) of product (R,R)-31 was obtained as a colorless liquid. 1H NMR
4.2.9. (R)-3-Trimethylsilyl-1-phenyl-oct-7-yn-8-trimethylsilyl-1-yn-
3-ol 34. Compound 34 was prepared according to general pro-
cedure using 33 (120 mg, 0.50 mmol), phenylacetylene (0.11 mL,
1.0 mmol), ZnEt2 (0.7 mL, 1.0 mmol), and ligand L1 (36.5 mg,
0.100 mmol) to afford 161.7 mg (80%) of 34 as a colorless oil. 1H
NMR (CDCl3, 500 MHz)
1H),1.80e1.88 (m, 4H), 2.32 (dt, J1¼6.6 Hz, J2¼1.5 Hz, 2H), 7.27e7.29
(m, 3H), 7.37e7.39 (m, 2H); 13C NMR (CDCl3, 125 MHz)
(ppm):
ꢁ4.2, 0.1, 20.0, 23.2, 36.4, 64.7, 85.0, 87.7, 91.6, 107.2, 123.3, 127.9,
d
(ppm): 0.13 (s, 9H), 0.14 (s, 9H), 1.66 (br s,
(CDCl3, 300 MHz)
d
(ppm): 0.83e0.88 (d, J¼6.8 Hz, 3H), 1.00 (d,
J¼6.6 Hz, 3H), 1.23e1.45 (m, 8H), 1.45e1.48 (m, 2H), 1.66e1.69 (m,
d
2H), 1.85e2.05 (m, 4H), 2.21 (t, J¼6.9 Hz, 2H); 13C NMR (CDCl3,
75 MHz)
d (ppm): 14.0,16.4,18.7, 20.4, 22.5, 28.5, 28.8, 31.0, 31.3, 41.0,
25
25
128.2, 131.5; [
a]
ꢁ21.0 (CH2Cl2, c 1, er¼23:77). The enantiomeric
45.7, 78.6, 81.5, 114.5. [
were not fullyseparated bychiralHPLC on Chiracel AD-H column. The
enantiomeric ratio was deduced from the reaction with iodine.
a]
þ4.2 (CH2Cl2, c 0.8). Both enantiomers
D
D
ratio was measured by chiral HPLC (Chiracel AD-H, 5% IPA/hexanes,
Rt1¼4.49, Rt2¼5.21).
4.3. General procedure for the enantioselective tandem Zn-
Brook rearrangement/Zn-ene-allene carbocyclization reaction
4.3.4. (1R,2R)-2-Iodomethyl-1-(2-octynyl)-cyclopentanol 32. Com-
pound 32 was prepared according to the general procedure using
19c and compared with literature data:14 (116 mg, 0.50 mmol),
1-octyne (0.15 mL, 1.0 mmol), ZnEt2 (0.7 mL, 1.0 mmol), ligand L1
(36.5 mg, 0.100 mmol), and I2 (6 equiv) was added at ꢁ30 ꢀC in
10 ml of THF. The reaction was warmed to room temperature,
stirred for an additional 2 h before the hydrolysis and further
treatment were done as usual to afford 108.6 mg (65%) of 32 as
To a flame-dried round bottom flask charged with alkyne
(1.0 mmol) in toluene (2 mL) was added diethylzinc (1.0 mmol,
1.5 M in toluene). The solution was first stirred at rt for 1 h, and
then ligand L1 (0.100 mmol) was added in toluene (1 mL). After the
solution had been stirred for an additional 1 h, acylsilane
(0.50 mmol) dissolved in toluene (1 mL) was added at room tem-
perature. The yellow solution was stirred until complete con-
sumption of acylsilane (8e12 h, followed by TLC analysis with a 10%
EtOAc/hexane eluent) at room temperature. Then, THF (five times
the volume of toluene) was added and the reaction mixture was
stirred at 40 ꢀC for 24 h. The reaction was then quenched with an
aqueous saturated solution of NH4Cl and extracted with Et2O
(3ꢂ10 mL). The solution was concentrated to give the unpurified
cyclic product, which was further desilylated. To a solution of the
corresponding silylether in THF (10 mL) at room temperature was
added a 1 M solution of n-Bu4NF (1.05 equiv). When the reaction
was over the crude was concentrated under reduced pressure.
Then, brine was added and the aqueous phase was extracted five
a yellow liquid. 1H NMR (CDCl3, 300 MHz)
d (ppm): 0.88 (t,
J¼6.8 Hz, 3H), 1.23e1.31 (m, 5H), 1.34e1.40 (m, 3H), 1.47e1.55 (m,
2H), 1.65e1.70 (m, 2H), 1.92e1.96 (m, 1H), 2.08e2.12 (m, 2H), 2.20
(t, J¼7.1 Hz, 2H), 2.28e2.30 (m, 1H), 3.08 (t, J¼9.3 Hz, 1H), 3.45 (dd,
J1¼9.5 Hz, J2¼5.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
d (ppm): 7.6,
14.1, 18.7, 19.7, 22.6, 28.5, 28.6, 31.2, 31.3, 42.5, 53.1, 77.6, 80.0, 87.0;
25
[a
]
þ8.0 (CH2Cl2, c 0.8, er>77:23). The enantiomeric ratio was
D
measured by chiral HPLC (Chiracel AD-H, 4% IPA/hexanes,
Rt1¼14.90, Rt2¼15.37). In this case, the two enantiomers were only
partially separated.
4.3.5. (1R,2E)-2-(Trimethylsilylmethylidene)-1-(phenylethynyl)-cy-
clopentanol 35. Compound 35 is prepared according to general

R. Unger et al. / Tetrahedron 66 (2010) 4874e4881
4881
procedure 33 and compared with literature data:14 (120 mg,
0.50 mmol), phenylacetylene (0.11 mL, 1.0 mmol), ZnEt2 (0.7 mL,
1.0 mmol), ligand L1 (36.5 mg, 0.100 mmol). After purification by
column chromatography, 105.0 mg (79%) of product (R)-35 was
127, 2838 and references cited therein; (o) Chinkov, N.; Majumdar, S.; Marek, I.
J. Am. Chem. Soc. 2002, 124, 10282.
4. (a) Denk, K.; Chalker, J.; Yang, A.; Cohen, T. Org. Lett. 2005, 7, 3637; (b) Chalker,
J. M.; Yang, A.; Deng, K.; Cohen, T. Org. Lett. 2007, 9, 3825.
5. Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J. F. J. Org. Chem. 1995, 60, 863.
6. (a) Lorthiois, E.; Marek, I.; Meyer, C.; Normant, J. F. Tetrahedron Lett. 1995, 36,
1263; (b) Lorthiois, E.; Marek, I.; Normant, J. F. Bull. Soc. Chim. Fr. 1997, 134, 333.
7. Lorthiois, E.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1997, 38, 89.
8. Meyer, C.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1996, 37, 857.
9. Meyer, C.; Marek, I.; Normant, J. F.; Platzer, N. Tetrahedron Lett. 1994, 31, 5645.
10. (a) Unger, R.; Cohen, T.; Marek, I. Org. Lett. 2005, 7, 5313; (b) Unger, R.; Cohen,
T.; Marek, I. Eur. J. Org. Chem. 2009, 1749.
11. (a) Poisson, J.-F.; Chemla, F.; Normant, J. F. Synlett 2001, 305; (b) Poisson, J.-F.;
Normant, J. F. J. Am. Chem. Soc. 2001, 123, 4639; (c) Marshall, J. A.; Adams, N. D. J.
Org. Chem. 1998, 63, 3812; (d) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64,
5201; (e) Marshall, J. A.; Schaaf, G. M. J. Org. Chem. 2001, 66, 782; (f) Marshall, J.
A. J. Org. Chem. 2007, 72, 8153.
obtained as a colorless liquid. 1H NMR (CDCl3, 300 MHz)
d
(ppm):
1.56 (s, 1H), 1.70e1.78 (m, 2H), 1.91e2.21 (m, 4H), 5.96 (t, J¼2.6 Hz,
1H), 7.27e7.42 (m, 5H); 13C NMR (CDCl3, 75 MHz)
(ppm): ꢁ0.7,
20.6, 29.7, 40.9, 78.9, 85.9, 90.6,122.3,122.9,128.2,128.2,163.0. [
d
25
a
]
D
ꢁ24.7 (CH2Cl2, c 1, er¼23:77). Enantiomeric ratio was measured by
chiral HPLC (Chiracel AD-H, 3% IPA/hexanes, Rt1¼12.73, Rt2¼14.44).
Acknowledgements
12. For recent reviews see: (a) Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351,
963; (b) Aschwanden, P.; Carreira, E. M. In Acetylene Chemistry; Diederich, F.,
Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2005; p 101; (c) Pu, L.;
Yu, H. B. Chem. Rev. 2001, 101, 757.
13. (a) Reynolds, T. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128,
15382; (b) Nicewicz, D. A.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 6170; (c) Li,
F.-Q.; Zhong, S.; Lu, G.; Chan, A. S. C. Adv. Synth. Catal. 2009, 351, 2541.
14. Unger, R.; Weisser, F.; Chinkov, N.; Stanger, A.; Cohen, T.; Marek, I. Org. Lett.
2009, 11, 1853.
This research was supported by the Grant No. 20088078 from
the United States-Israel Binational Science Foundation (BSF), Jer-
usalem, Israel and by a grant from the Israel Science Foundation
administrated by the Israel Academy of Sciences and Humanities
(Grant No. 70/08). IM is holder of the Sir Michael and Lady Sobell
Academic Chair.
15. (a) Masarwa, A.; Stanger, A.; Marek, I. Angew. Chem., Int. Ed. 2007, 46, 8039; (b)
Simaan, S.; Masarwa, A.; Bertus, P.; Marek, I. Angew. Chem., Int. Ed. 2006, 45, 3963;
(c) Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46, 7364.
16. For representative examples, see: (a) Reich, H. J.; Eisenhart, E. K.; Olson, R. E.;
Kelly, M. J. J. Am. Chem. Soc. 1986, 108, 7791; (b) Reich, H. J.; Holtan, R. C.; Bolm,
C. J. Am. Chem. Soc. 1990, 112, 5609.
17. For recent reports on the Brook rearrangements, see: (a) Smith, A. B., III; Wuest,
W. M. Chem. Commun. 2008, 5883; (b) Smith, A. B., III; Kim, W.-S.; Wuest, W. M.
Angew. Chem., Int. Ed. 2008, 47, 7082; (c) Smith, A. B., III; Kim, D. S. J. Org. Chem.
2006, 71, 2547; (d) Smith, A. B., III; Kim, D. S. Org. Lett. 2005, 7, 3247; (e) Smith,
A. B., III; Kim, D. S. Org. Lett. 2004, 6, 1493; (f) Reynolds, T. E.; Stern, C. A.;
Scheidt, K. A. Org. Lett. 2007, 9, 2581; (g) Tsubouchi, A.; Onishi, K.; Takeda, T.
J. Am. Chem. Soc. 2006, 128, 14268; (h) Linghu, X.; Potnick, J. R.; Johnson, J. S.
J. Am. Chem. Soc. 2004, 126, 3070; (i) Nicewicz, D. A.; Yates, C. M.; Johnson, J. S.
Angew. Chem., Int. Ed. 2004, 43, 2652; (j) Linghu, X.; Johnson, J. S. Angew. Chem.,
Int. Ed. 2003, 42, 2534; (k) Linghu, X.; Nicewicz, D. A.; Johnson, J. S. Org. Lett. 2002,
4, 2957.
References and notes
1. For reviews, see. (a) Marek, I.; Normant, J. F. In Metal-catalyzed Cross Coupling
Reactions; Stang, P. J., Diederich, F., Eds.; Wiley-VCH: Weinheim, 1998; p 271; (b)
Marek, I.; Normant, J. F. In Transition Metals for Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; p 514; (c) Marek, I.; Chinkov, N.;
Banon-Tenne, D. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Mei-
jere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; p 395; (d) Marek, I.;
Banon-Tenne, D. In Transition Metals for Organic Synthesis, 2nd ed.; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; p 563; (e) Knochel, P. In Com-
prehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Per-
gamon: New York, NY, 1993; Vol. 4, p 865; (f) Hogan, A.-M. L.; O’Shea, D. F.
Chem. Commun. 2008, 3839; (g) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57,
5899; (h) Negishi, E. Pure Appl. Chem. 1981, 53, 2333.
2. For relevant recent examples, see: (a) Coldham, I.; Hufton, R.; Snowden, D. J.
J. Am. Chem. Soc. 1996, 118, 5322; (b) Woltering, M. J.; Frohlich, R.; Hoppe, D.
€
18. When the reaction mixture is warmed at a higher temperature, the diaster-
eoselectivity of the reaction decreases. In pure toluene, no significant Brook
rearrangement product could be detected (<5%).
Angew. Chem., Int. Ed. 1997, 36, 1764; (c) Hoppe, D.; Woltering, M. J.; Oestreich,
€
M.; Frohlich, R. Helv. Chim. Acta 1999, 82, 1860; (d) Oestreich, M.; Hoppe, D.
€
Tetrahedron Lett. 1999, 40, 1881; (e) Laqua, H.; Frohlich, R.; Wibbeling, B.;
19. For an easier determination of enantiomeric ratio by chiral HPLC, silylether is
transformed into the free alcohol by treatment of the crude reaction mixture
with a solution of tetra-n-butylammonium fluoride.
Hoppe, D. J. Organomet. Chem. 2001, 624, 96; (f) Bailey, W. F.; Mealy, M. J. J. Am.
Chem. Soc. 2000, 122, 6787; (g) Gil, G. S.; Groth, U. M. J. Am. Chem. Soc. 2000,
122, 6789; (h) Barluenga, J.; Fañanás, F. J.; Sanz, R.; Marcos, C. Chem.dEur. J.
2005, 11, 5397; (i) Hogan, A.-M.; O’Shea, D. F. J. Org. Chem. 2007, 72, 9557; (j)
Hogan, A.-M.; O’Shea, D. F. J. Am. Chem. Soc. 2006, 128, 10360; (k) Hogan, A.-M.;
O’Shea, D. F. Org. Lett. 2006, 8, 3769; (l) Brasseur, D.; Marek, I.; Normant, J. F. C.R.
Acad. Sci. Paris, Ser. II C 1998, 621; (m) Lorthiois, E.; Marek, I.; Normant, J. F.
J. Org. Chem. 1998, 63, 2442; (n) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed.
1997, 36, 2491; (o) Nakamura, M.; Hatakeyama, T.; Hara, K.; Nakamura, E. J. Am.
Chem. Soc. 2003, 125, 6362; (p) Nakamura, M.; Hatakeyama, T.; Nakamura, E.
J. Am. Chem. Soc. 2004, 126, 11820; (q) Denes, F.; Chemla, F.; Normant, J.-F.
Synlett 2002, 919; (r) Denes, F.; Perez-Luna, A.; Chemla, F. J. Org. Chem. 2007, 72,
398; (s) Denes, F.; Perez-Luna, A.; Cutri, S.; Chemla, F. Chem.dEur. J. 2006, 12,
6506; (t) Perez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. New J. Chem. 2008,
32, 594; (u) Lorthiois, E.; Marek, I.; Normant, J. F. J. Org. Chem. 1998, 63, 566; (v)
Brasseur, D.; Marek, I.; Normant, J. F. Tetrahedron 1996, 52, 7235.
3. (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J. F. J. Am. Chem. Soc.1995,117, 8853;
(b) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J.-F.; Normant, J. F. Chem.dEur. J.
1999, 5, 2055; (c) Norsikian, S.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1997, 43,
7523; (d) Norsikian, S.; Marek, I.; Poisson, J.-F.; Normant, J. F. J. Org. Chem.1997, 62,
4898; (e) Majumdar, S.; de Meijere, A.; Marek, I. Synlett 2002, 423; (f) Marek, I.
J. Chem. Soc., Perkin Trans. 11999, 535; (g) Bell, L.; Brookings, D. C.; Dawson, G. J.;
Whitby, R. J.; Jones, R. V. H.; Standen, M. C. H. Tetrahedron 1998, 54, 14617; (h)
Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6997; (i)
Visser, S. M.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda, A. H. J. Am. Chem. Soc.
1996, 118, 4291; (J) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000,
122, 978; (k) Liang, B.; Negishi, E. Org. Lett. 2008, 10, 193; (l) Zhu, G. G.; Negishi, E.
Org. Lett. 2007, 9, 2771; (m) Liang, B.; Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc.
2006,128, 2770; (n) Novak, T.; Tan, Z.; Liang, B.; Negishi, E. J. Am. Chem. Soc. 2005,
20. For 1,2-silyl migration with retention of configuration, see: (a) Simov, B. J.;
Wuggenig, F.; Mereiter, K.; Andres, H.; France, J.; Schnelli, P.; Hammerschmidt,
F. J. Am. Chem. Soc. 2005, 127, 13934; (b) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni,
A. K. J. Am. Chem. Soc. 1982, 104, 6809; (c) Hoffmann, R.; Brückner, R. Chem. Ber.
1992, 125, 2731; (d) Kapeller, D. C.; Brecker, L.; Hammerschmidt, F. Chem.dEur. J.
2007, 13, 9582; For 1,2-silyl migration with inversion of configuration, see: (e)
Brook, A. G.; Pascoe, J. D. J. Am. Chem. Soc. 1971, 93, 6224; (f) Biernbaum, M. S.;
Mosher, H. S. J. Am. Chem. Soc. 1971, 93, 6221.
21. For theoretical investigations, see: (a) Antoniotti, P.; Tonachini, G. J. Org. Chem.
1993, 58, 3622; (b) Wang, Y.; Dolg, M. Tetrahedron 1999, 55, 12751; (c) Yu, Y.;
Feng, S. J. Phys. Chem. A 2004, 108, 7468.
22. For examples for the creation of several carbonecarbon bonds in a single-pot
operation including the formation of quaternary stereocenters from our group,
see: (a) Simaan, S.; Marek, I. J. Am. Chem. Soc. 2010, 132, 4066; (b) Simaan, S.;
Goldberg, A. F. G.; Rosset, S.; Marek, I. Chem.dEur. J. 2010, 16, 774; (c) Das, J. P.;
Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128; (d) Marek, I. Chem.dEur. J.
2008, 14, 7460; (e) Marek, I.; Sklute, G. Chem. Commun. 2007, 1683; (f) Ko-
lodney, G.; Sklute, G.; Perrone, S.; Knochel, P.; Marek, I. Angew. Chem., Int. Ed.
2007, 119, 9451; (g) Sklute, G.; Marek, I. J. Am. Chem. Soc. 2006, 128, 4642; (h)
Sklute, G.; Amsallem, D.; Shibli, A.; Varghese, J. P.; Marek, I. J. Am. Chem. Soc.
2003, 125, 11776.
23. The exact enantiomeric ratio of 31 and 32 could not be more precise since
peaks are not fully separated by chiral HPLC.
24. (a) Hammaecher, C.; Ouzzane, I.; Portella, C.; Bouillon, J.-P. Tetrahedron 2005, 61,
657; (b) Janlowski, P.; Plesniak, K.; Wicha, J. Org. Lett. 2003, 5, 2789; (c) Reich,
H. J.; Olson, R. E.; Clark, M. C. J. Am. Chem. Soc. 1980, 102, 1423.