Catalytic asymmetric enyne addition to aldehdyes and Rh(I)-catalyzed stereoselective domino Pauson-Khand/[4 + 2] cycloaddition

Article abstract of DOI:10.1021/jo3026065

The 1,1′-bi-2-naphthol-ZnEt₂-Ti(OⁱPr) ₄-Cy₂NH system is found to catalyze the 1,3-enyne addition to aliphatic aldehydes as well as other aldehydes at room temperature with 75-96% yield and 82-97% ee. This system is also broadly applicable for the highly enantioselective reaction of other alkyl-, aryl-, and silylalkynes with structurally diverse aldehydes. The propargylic alcohols prepared from the catalytic asymmetric enyne addition to aliphatic aldehydes are used to prepare a series of optically active trienynes. In the presence of a catalytic amount of [RhCl(CO)₂]₂ and 1 atm of CO, the optically active trienynes undergo highly stereoselective domino Pauson-Khand/[4 + 2] cycloaddition to generate optically active multicyclic products. The Rh(I) catalyst is also found to catalyze the coupling of a diyne with CO followed by [4 + 2] cycloaddition to generate an optically active multicyclic product. These transformations are potentially useful for the asymmetric synthesis of polyquinanes containing a quaternary chiral carbon center.

Full text of DOI:10.1021/jo3026065

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Catalytic Asymmetric Enyne Addition to Aldehdyes and Rh(I)-
Catalyzed Stereoselective Domino Pauson−Khand/[4 + 2]
Cycloaddition
Wei Chen,†,‡ Jia-Hui Tay,‡ Jun Ying,‡ Xiao-Qi Yu,*,† and Lin Pu*,‡
†Department of Chemistry, Sichuan University, Chengdu 610064, China
‡Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319, United States
S
* Supporting Information
ABSTRACT: The 1,1′-bi-2-naphthol−ZnEt2−Ti(OiPr)4−Cy2NH sys-
tem is found to catalyze the 1,3-enyne addition to aliphatic aldehydes as
well as other aldehydes at room temperature with 75−96% yield and
82−97% ee. This system is also broadly applicable for the highly
enantioselective reaction of other alkyl-, aryl-, and silylalkynes with
structurally diverse aldehydes. The propargylic alcohols prepared from
the catalytic asymmetric enyne addition to aliphatic aldehydes are used
to prepare a series of optically active trienynes. In the presence of a
catalytic amount of [RhCl(CO)2]2 and 1 atm of CO, the optically active
trienynes undergo highly stereoselective domino Pauson−Khand/[4 +
2] cycloaddition to generate optically active multicyclic products. The Rh(I) catalyst is also found to catalyze the coupling of a
diyne with CO followed by [4 + 2] cycloaddition to generate an optically active multicyclic product. These transformations are
potentially useful for the asymmetric synthesis of polyquinanes containing a quaternary chiral carbon center.
INTRODUCTION
■
Terpenoid natural products have been extensively investigated
in both biology and organic synthesis. Polyquinanes represent a
class of terpenoids containing multiple fused five-membered
rings and some further fused with six-membered or other types
of rings.1−4 Figure 1 gives a few examples of the naturally
occurring polyquinanes that contain a quaternary chiral carbon
center shared by multiple rings. Efficient construction of these
interesting molecular structures has continuously challenged
the imagination of synthetic organic chemists.1−4
Chiral propargylic alcohols have found extensive applications
in organic synthesis.5−10 In the past few years, our laboratory
has worked on the development of chiral catalysts for the
asymmetric alkyne addition to aldehydes as well as the
application of the chiral propargylic alcohols in the synthesis
of cyclic organic compounds.11−13 In this paper, we report our
work on the first highly enantioselective addition of a
conjugated enyne to linear aliphatic aldehydes in the presence
of a chiral catalyst. The resulting chiral propargylic alcohols
Figure 1. Examples of polyquinanes containing rings jointed by a
have been converted to chiral trienyne ethers. In the presence
of a Rh(I) catalyst and CO, the chiral trienynes are discovered
to undergo highly stereoselective domino Pauson−Khand (PK)
and [4 + 2] cycloaddition to generate multicyclic organic
compounds with a quaternary chiral carbon core.14 These
products resemble the polyquinanes shown in Figure 1 and are
potentially useful for their synthesis.
quaternary chiral carbon.
Received: December 17, 2012
Published: January 17, 2013
© 2013 American Chemical Society
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Table 1. Catalytic Enantioselective Reactions of Structurally Diverse Aldehydes with 3-Methyl-3-buten-1-yne and Other Alkynes
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Table 1. continued
a
b
Aldehyde/alkyne/(S)-BINOL/ZnEt2/Ti(OiPr)4/Cy2NH = 1:3:0.4:3:1:0.05. Aldehyde/alkyne/(S)-BINOL/ZnEt2/Ti(OiPr)4/Cy2NH =
c
d
1:2.2:0.2:2:0.5:0.05. Aldehyde/alkyne/(S)-BINOL/ZnEt2/Ti(OiPr)4/Cy2NH = 1:2.2:0.4:2:1:0.05. Aldehyde/alkyne/(S)-BINOL/ZnEt2/Ti-
e
f
(OiPr)4/Cy2NH = 1:3:0.2:3:0.5:0.05. Aldehyde/alkyne/(S)-BINOL/ZnEt2/Ti(OiPr)4/Cy2NH = 1:3:0.2:3:0.5:0.2. Aldehyde/alkyne/(S)-
g
BINOL/ZnEt2/Ti(OiPr)4/Cy2NH = 1:3:0.2:3:0.5:1. 48 h for the first step.
enantioselectivities were also obtained for the enyne addition to
other aliphatic, aromatic, and α,β-unsaturated aldehydes.
Entries 15−65 show that besides the highly enantioselective
enyne additions, the reactions of other aryl-, alkyl-, and
silylalkynes with aromatic and aliphatic aldehydes can also be
conducted with high enantioselectivity. Entries 56−60 show
that increasing the amount of Cy2NH can increase the yield for
the reaction of trimethylsilylacetylene but has no influence on
the enantioselectivity. For the reactions shown in Table 1,
various stoichiometric amounts of the reagents were used as
indicated in the footnotes, in which the higher amount of (S)-
BINOL for certain substrates was used to improve the
enantioselectivity and the higher amounts of the alkyne and
ZnEt2 were used to improve the yield. The results of Table 1
together with our previously reported linear alkyl alkyne20 and
diyne additions13a demonstrate that the BINOL−ZnEt2−
Ti(OiPr)4−Cy2NH catalyst system has high generality in the
asymmetric alkyne addition to aldehydes for the synthesis of
structurally diverse propargylic alcohols under very mild
conditions.
2. Preparation of the Optically Active Trienynes. The
optically active propargylic alcohols (R)-1 were prepared
according to entries 2 and 4 of Table 1. As shown in Scheme
1, the optically active trienynes (R)-2a,b14 were obtained by
treatment of (R)-1 with KOH and then allyl bromide at room
temperature. The optically active compounds (R)-2c−f were
prepared by treatment of (R)-1 with NaH followed by reaction
with the corresponding allylic bromides. In the second step, the
preparation of (R)-2c required heating at 70 °C, but that of
(R)-2d−f proceeded at room temperature. Compound (R)-2d
contains one additional alkene unit in comparison with the
other trienynes.
RESULTS AND DISCUSSION
1. Catalytic Asymmetric Reactions of Aldehydes with
■
1,3-Enynes and Other Alkynes. In recent years, great
progress has been made in the development of chiral catalysts
for asymmetric alkyne addition to aldehydes and a number of
highly enantioselective catalysts have been obtained.5−10
Among these studies, several catalysts have shown high
enantioselectivity for the asymmetric 1,3-enyne addition to
aromatic aldehydes15−17 and an α-branched aliphatic alde-
hyde.17 The use of a stoichiometric amount of N-methylephe-
drine was reported to show high enantioselectivity for the
reaction of a 1,3-enyne with an α-branched aliphatic aldehyde,18
but the addition to a linear aliphatic aldehyde without an α-
substituent gave much lower enantioselectivity and low yield.19
There is no report on highly enantioselective catalysts for the
reaction of 1,3-enynes with linear aliphatic aldehydes.
Recently, we reported that 1,1′-bi-2-naphthol (BINOL) in
combination with ZnEt2, Ti(OiPr)4 and dicyclohexylamine
(Cy2NH) catalyzed the reaction of linear alkynes with linear
aliphatic aldehydes at room temperature with high enantiose-
lectivity.20 We further studied the use of this catalyst system for
the asymmetric reaction of structurally diverse aldehydes with
1,3-enynes as well as other alkynes, and the results are
summarized in Table 1. All these reactions were conducted in
diethyl ether at room temperature under nitrogen in a two-step,
one-pot process. In the first step, a terminal alkyne was treated
with ZnEt2 and Cy2NH, which presumably generated a
nucleophilic alkynylzinc reagent. In this step, it is proposed
that coordination of Cy2NH with ZnEt2 could increase the
basicity of the Et group on Zn to facilitate the deprotonation of
the terminal alkyne. (S)-BINOL (20−40 mol %) was also
added in the first step, which should be deprotonated by ZnEt2.
In the second step, Ti(OiPr)4 and an aldehyde were added. In
this step, the combination of the deprotonated (S)-BINOL
with Ti(OiPr)4 could generate a chiral Lewis acid complex to
catalyze the addition of the alkynylzinc reagent to the aldehyde.
After aqueous workup, a chiral propargylic alcohol product was
obtained.
3. Catalytic Conversions of (R)-2a−f in the Presence of
[RhCl(CO)2]2. The catalytic PK cycloaddition of an alkene and
an alkyne with CO has been extensively investigated, and a
number of catalysts have been developed.21−29 Previously, we
have studied the use of Rh(I) complexes to catalyze the
intramolecular PK reaction of the optically active propargylic
alcohol-based enynes to synthesize chiral bicyclic cyclo-
pentenones.13 We have also tested the PK reaction of (R)-2b
in the presence of a Rh(I) complex. When (R)-2b was treated
with [RhCl(CO)2]2 (10 mol %) under 1 atm of CO in refluxing
1,2-dichloroethane (DCE), a tetracyclic product 3b was
As shown in entries 1 and 2 of Table 1, the catalytic
asymmetric enyne additions to linear aliphatic aldehydes were
accomplished with high enantioselectivity. These were the first
examples for the enyne addition to this type of aldehydes in the
presence of a chiral catalyst. Entries 3−14 show that high
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converted to 3b smoothly in refluxing DCE.30 This
demonstrates that both the PK cycloaddition and the [4 + 2]
cyclization steps require the Rh catalyst.
Scheme 1. Preparation of the Optically Active Trienynes
(R)-2a−f
Similar to the conversion of (R)-2b to 3b, when (R)-2a was
treated with [RhCl(CO)2]2 and CO, compound 3a was
obtained as a single diastereomer in 75% yield and 90% ee
(Scheme 3).14 The stereochemistry of 3a was assigned on the
basis of the NMR analyses similar to those of 3b.
Scheme 3. Catalytic Conversion of (R)-2a To Generate 3a
obtained in 56% yield and 83% ee (Scheme 2).14 That is, an
apparent domino intramolecular PK and [4 + 2] cyclization
Scheme 2. Catalytic Conversion of (R)-2b To Generate 3b
Compound (R)-2c, in which the allylic ether double bond
was substituted with two additional methyl groups, was also
subjected to the same reaction conditions catalyzed by
[RhCl(CO)2]2 which generated 3c as a single diastereomer in
67% yield and 90% ee (Scheme 4). The formation of 3c
Scheme 4. Catalytic Conversions of (R)-2c−e
took place chemoselectively and stereoselectively to give 3b. In
3b, three new chiral carbon centers are generated whose
formation is controlled by the original chiral propargylic center
of (R)-2b. The two newly formed bridgehead hydrogens of 3b
have the syn configuration as shown (vide infra).
The structure of 3b was established by high-resolution mass
spectroscopic analysis and various 1H and 13C NMR
spectroscopic analyses including COSY, NOESY, HSQC 2D
NMR, and DEPT 135°. As shown in Figure 2, the observed
NOE effects between the proton signals have allowed the
determination of its structure. For detailed signal assignments,
see the Supporting Information.
When the conversion of (R)-2b to 3b was stopped early (in 5
h), the PK cyclization product 4b was isolated and its steric
structure was established by 2D COSY and NOESY NMR
analyses. When 4b was heated in DCE under reflux, no thermal
intramolecular Diels−Alder reaction was observed. However,
when [RhCl(CO)2]2 was added as the catalyst, 4b was
indicates that the PK reaction is sensitive to the substitution on
the allylic ether double bond. The two methyl groups on the
double bond a have inhibited its PK cycloaddition, which
allows the PK reaction of the less substituted double bond b to
take place first followed by the [4 + 2] cycloaddition of the
resulting conjugated diene with the double bond a to give 3c.
Similarly, when compounds (R)-2d and (R)-2e were treated
with [RhCl(CO)2]2 under CO, the corresponding products 3d
and 3e were isolated in 45% (93% ee) and 33% (89% ee)
yields, respectively.
The structure of 3e was determined by high-resolution mass
Figure 2. Observed NOE effects of 3b.
spectroscopic analysis and a variety of 1H and 13C NMR
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spectroscopic analyses including COSY, NOESY, HSQC 2D
NMR, and DEPT 135°. As shown in Figure 3, the observed
NOE effects between the proton signals have allowed the
determination of its structure. For detailed signal assignments,
see the Supporting Information.
to a 13.9:1 mixture of 3f with the α methyl group up as the
major diastereomer. The stereochemistry of 3f was determined
by NMR analyses similar to those of 3b and 3e. The
enantiomeric purities of both 3f and 3f′ were found to be
almost the same as that of the starting chiral propargylic
alcohol.
4. Proposed Mechanistic Explanation for the Chemo-
selectivity and Stereoselectivity of the Domino PK and
[4 + 2] Cycloadditions. On the basis of the previous studies
on the Rh-catalyzed PK reaction13,27 and [4 + 2] cyclization,30
mechanisms are proposed to illustrate the formation of the
products 3a−e. As shown in Scheme 6, coordination of (R)-2a
with the metal center of the catalyst could generate a chairlike
intermediate 5 in which the homoallylic substituent occupies a
more favorable equatorial position. Oxidative coupling of the
coordinated triple bond and double bond of 5 should give 6. In
this step, the anti configuration of Hα and Hβ is produced.
Migratory insertion of 6 with CO followed by reductive
elimination should give the PK cycloaddition product cis-7. In
the presence of the Rh catalyst, 7 could undergo a metal-
catalyzed [4 + 2] cycloaddition via the intermediate 8 to give
the product 3a with the observed exo-Diels−Alder reaction
stereochemistry.30 In this reaction, when (R)-2a is treated with
the Rh catalyst, 5′ is another possible chairlike intermediate in
which the double bond b is coordinated instead of the double
bond a. One of the possible factors that 5 is more favorable
than 5′ might be the greater 1,3-diaxial interaction in 5′ than in
5. The difference of the electronic effect in the formation of an
ether ring verses a carbocycle should also be important for the
observed chemoselectivity.
Figure 3. Observed NOE effects of 3e.
We have also studied the reaction of (R)-2f that contains
only one methyl group on the allylic ether double bond a
(Scheme 5). The result shows that the mono methyl
Scheme 5. Catalytic Conversion of (R)-2f
Previously, we reported that when a propargyl alcohol
derived dienediyne compound 9 was treated with the Rh
catalyst under CO, the PK cycloaddition product 10 was
obtained as a 1:2 mixture of the cis and trans stereoisomers with
the trans isomer being the major product (Scheme 7).13b This
is in sharp contrast to that observed for (R)-2a which should
only form the cis intermediate 7 in the production of 3a as
observed for the steric structure of 4b. The formation of the
trans product 10 from 9 was explained by proposing an
substitution led to the formation of both products 3f and 3f′.
The product 3f was found to contain a 1:2.3 mixture of two
diastereomers attributed to the two epimers of the α methyl
group. When a methanol solution of this 1:2.3 mixture of 3f
was stirred at room temperature with K2CO3, it was converted
Scheme 6. Proposed Mechanism for the Rh(I)-Catalyzed Domino Cycloaddition of (R)-2a
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cyclopentenone. The coupling of two alkyne units with CO
would generate a cyclopentadienone. Because of the anti-
aromatic character of a cyclopentadienone structure, it has
greatly reduced stability without metal coordination and its
catalytic formation was much more difficult. Pd complexes were
found to catalyze the diyne coupling with CO to generate
cyclopentadienones either as nonisolated intermediates31a,b or
double bond migrated products.31c Although Rh(I) catalysts
were developed by Ojima in 1996 to catalyze the intramolecular
coupling of diynes with CO, the reaction required the addition
of a silane molecule which probably reduced one of the alkyne
unit to an alkene to promote the coupling.32 Ir(I) complexes
were found to catalyze the intramolecular coupling of diynes
with CO to generate either the bistriarylsilyl stabilized
cyclopentadienones or the double bond migrated products,
but poor efficiency was observed when [Rh(COD)Cl]2 was
used.33 Since 1999, Chung has conducted an extensive study on
the Co-catalyzed diyne coupling with CO to generate
multicyclic products which might involve the formation of
the reactive cyclopentadienone intermediates.34
Scheme 7. Catalytic PK Reaction of the Dienediyne 9
intermediate 11 in which the homoallyl group occupies the
axial position encouraged by its coordination to the Rh center.
In order to explain the high cis selectivity in the PK reaction of
(R)-2a, we propose that in the intermediate 5, besides the
coordination of the triple bond and the allyl ether double bond
to the Rh center, the double bond of the conjugated enyne unit
can also coordinate to the Rh metal center. This coordination
discourages the coordination of the homoallyl double bond to
the Rh center and encourages it to occupy the equatorial
position as shown in 5, leading to the predominate formation of
cis-7 rather than its trans stereoisomer like 10.
When the substrate (R)-2c was used, because of the much
greater steric hindrance for the double bond a to coordinate to
the metal center, coordination of the less sterically hindered
double bond b to the Rh center becomes more favorable to
generate the chairlike intermediate 12 (Scheme 8). In 12, the
allyloxide group is placed at the equatorial position. The
intermediate 12 can then undergo oxidative coupling to give
13. In this step, the anti configuration of Hα and Hγ is
produced. Migratory insertion of 13 with CO followed by
reductive elimination should give the PK cycloaddition product
14. In the presence of the Rh catalyst, 14 could undergo a
metal-catalyzed [4 + 2] cycloaddition via the intermediate 15 to
give the product 3c with the observed exo-Diels−Alder reaction
stereochemistry.
We have prepared the optically active diyne (R)-16 according
to entry 5 of Table 1 by using the catalytic asymmetric alkyne
n
addition to aldehyde. Treatment of (R)-16 with BuLi at −78
°C followed by reaction with allyl bromide gave the chiral
dienediyne (R)-17 (Scheme 9). When (R)-17 was treated with
[RhCl(CO)2]2 under CO, the tetracyclic product 18 was
obtained in 36% yield as a single diastereomer.14 A single
crystal X-ray analysis of 18 has established its structure which is
consistent with the NMR analysis data.14 Formation of 18
demonstrates that in the first step the two alkyne units of (R)-
17 can couple with CO to presumably generate a cyclo-
pentadienone intermediate prior to the subsequent [4 + 2]
cyclization. Previously, Chung also reported that under 30 atm
of CO at 130 °C Co2(CO)8 catalyzed the domino cyclization of
racemic dienediynes to generate racemic multicyclic products
similar to 18.34g,h
For compound (R)-2f, its two double bonds a and b should
have similar activity with respect to the intramolecular PK
cycloaddition. Thus, in the catalytic conversion of (R)-2f shown
in Scheme 5, both mechanisms depicted in Schemes 6 and 8
might have been involved to give a mixture of products 3f and
3f′.
SUMMARY
■
We have found that the highly enantioselective enyne addition
to linear aliphatic aldehydes as well as other aldehydes can be
achieved at room temperature by using the BINOL−ZnEt2−
Ti(OiPr)4−Cy2NH catalyst system. We have further shown that
this system is broadly applicable for the asymmetric reaction of
other alkyl-, aryl-, and silylalkynes with structurally diverse
5. Catalytic Conversions of a Chiral Dienediyne (R)-17
in the Presence of [RhCl(CO)2]2. As shown in the above Rh-
catalyzed reactions, the PK cycloaddition normally involves the
coupling of one alkyne unit, one alkene unit, and CO to form a
Scheme 8. Proposed Mechanism for the Rh(I)-Catalyzed Domino Cycloaddition of (R)-2c
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Scheme 9. Preparation of a Chiral Dienediyne and Its Catalytic Conversion
CDCl3): δ 126.6, 122.2, 88.5, 87.0, 67.7, 44.4, 28.8, 28.4, 26.6, 26.1,
23.7. HRMS (ESI) for C12H19O (MH+): calcd 179.1436, found
179.1431.
aldehydes. Using the propargylic alcohols prepared from the
asymmetric enyne addition to linear aliphatic aldehydes we
have prepared a series of optically active trienynes. These
optically active trienynes are discovered to undergo highly
chemoselective and stereoselective domino PK and [4 + 2]
cycloaddition in the presence of a Rh catalyst to generate
optically active multicyclic products. The Rh(I) catalyst is also
found to catalyze the coupling of a diyne with CO followed by
[4 + 2] cycloaddition. This study could potentially provide an
efficient method for the asymmetric synthesis of polyquinanes
with a quaternary chiral carbon center.
4-Methyl-1-phenylpent-4-en-2-yn-1-ol (Entry 6). Colorless oil, 36
mg, 84% yield. 96% ee determined by HPLC analysis: Chiralcel OD-H
column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/min, λ = 254 nm,
retention time: tmajor = 7.7 tminor= 6.0. [α]24D = 6.3 (c = 1.80, CHCl3).
1H NMR (300 MHz, CDCl3): δ 7.57−7.54 (m, 2H), 7.42−7.34 (m,
3H), 5.57 (d, 1H, J = 6.0 Hz), 5.39−5.35 (m, 1H), 5.30−5.27 (m,
1H), 2.44 (d, 1H, J = 6.3 Hz), 1.95−1.92 (m, 3H). 13C NMR (75
MHz, CDCl3): δ 140.9, 128.9, 128.6, 126.9, 126.4, 122.9, 88.0, 87.9,
65.2, 23.6. HRMS (ESI) for C12H13O (MH+): calcd 137.0966, found
137.0968.
4-Methyl-1-(p-tolyl)pent-4-en-2-yn-1-ol (Entry 7). Colorless oil, 43
mg, 92% yield. 97% ee determined by HPLC analysis: Chiralpak AD-H
column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/min, λ = 254 nm,
retention time: tmajor =10.3, tminor = 8.4. [α]22D = 9.9 (c = 1.7, CHCl3).
1H NMR (300 MHz, CDCl3): δ 7.44 (d, 2H, J = 8.1 Hz), 7.19 (d, 2H,
J = 8.1 Hz), 5.54 (d, 1H, J = 5.1 Hz), 5.36 (s, 1H) 5.27 (s, 1H), 2.37
(s, 3H), 2.30 (d, 1H, J = 5.7 Hz), 1.93 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 138.4, 138.0, 129.5, 126.9, 126.4, 122.8, 88.1, 87.8, 65.0,
23.6, 21.4. HRMS (ESI): for C13H15O (MH+) calcd 187.1123, found
187.1120.
EXPERIMENTAL SECTION
■
General Procedure for Preparation of Racemic Propargylic
Alcohols from Alkyne Addition to Aldehydes. The racemic
propargylic alcohols are prepared according to the reported
procedure.13a An alkyne (1 mmol, 2 equiv) was weighed into a
tared flask and placed under nitrogen atmosphere. The alkyne was
n
dissolved in THF (5 mL) and cooled to −78 °C. BuLi (2.5 M in
hexane, 1.4 equiv) was added, and the reaction mixture was stirred for
30 min. An aldehyde (1 mmol) was then added. After 1 h, the reaction
was quenched with saturated aqueous ammonium chloride solution (5
mL) and extracted three times with CH2Cl2. The organic layer was
dried with sodium sulfate and concentrated by rotary evaporation. The
resultant oil was purified by flash column chromatography on silica gel.
General Procedure for the (S)-BINOL-Catalyzed Enantiose-
lective Alkyne Additions. The catalytic alkyne additions were
conducted according to the reported procedure.13a Under nitrogen
atmosphere, (S)-BINOL was weighed into a tared flask and dissolved
in Et2O (3 mL). An alkyne, Cy2NH, and Et2Zn were added, and the
mixture was stirred for 16 h (or 48 h). Then, Ti(OiPr)4 was added,
followed by an aldehyde (0.25 mmol), and the mixture was stirred for
another 4 h (for the stoichiometry of the catalyst and metal reagents in
the reactions of various alkynes, see Table 1). The reaction was
quenched with saturated aqueous ammonium chloride and extracted
three times with CH2Cl2. The organic layer was dried with anhydrous
sodium sulfate and concentrated by rotary evaporation. The resultant
oil was purified by flash column chromatography on silica gel eluted
with hexanes/ethyl acetate to give the product in 56−99% yield and 81
to >99% ee.
4-Methyl-1-(naphthalen-2-yl)pent-4-en-2-yn-1-ol (Entry 8).
White solid, 53 mg, 96% yield. 98% ee determined by HPLC analysis:
Chiralpak AD-H column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/
min, λ = 254 nm, retention time: tmajor = 16.8, tminor = 12.1. Mp = 45−
46 °C. [α]22 = −2.5 (c = 2.20, CHCl3). 1H NMR (300 MHz,
D
CDCl3): δ 7.98 (s, 1H), 7.90−7.82 (m, 3H), 7.67 (dd, 1H, J = 7.8, 1.8
Hz), 7.54−7.46 (m, 2H), 5.74 (d, 1H, J = 4.5 Hz), 5.39 (d, 1H, J = 0.9
Hz), 5.32 −5.27 (m, 1H), 2.39 (d, 1H, J = 8.1 Hz), 1.95 (t, 3H, J = 2.4
Hz). 13C NMR (75 MHz, CDCl3): δ 138.2, 133.5, 133.4, 128.8, 128.4,
127.9, 126.5, 126.4, 125.7, 124.9, 123.0, 88.3, 87.9, 23.6. HRMS (ESI)
for C16H15O (MH+) calcd 223.1123, found 223.1126.
4-Methyl-1-(naphthalen-1-yl)pent-4-en-2-yn-1-ol (Entry 9). Col-
orless oil, 43 mg, 78% yield. 97% ee determined by HPLC analysis:
Chiralpak AD-H column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/
min, λ = 254 nm, retention time: tmajor = 18.1, tminor = 11.0. [α]23
=
D
−7.4 (c = 0.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.31(d, 1H, J
= 8.7 Hz), 7.93−7.85 (m, 1H), 7.85 (d, 2H, J = 7.5 Hz), 7.61−7.46
(m, 3H), 6.22 (d, 1H, J = 4.8 Hz), 5.40 (s, 1H), 5.33−5.29 (m, 2H),
2.71 (d, 1H, J = 5.1 Hz), 1.96 (t, 3H, J = 1.2 Hz). 13C NMR (75 MHz,
CDCl3): δ 135.9, 134.3, 130.8, 129.6, 129.0, 126.7, 126.5, 126.1, 125.5,
124.9, 124.2, 122.9, 88.7, 87.9, 63.4, 23.6. HRMS (ESI): for C16H15O
(MH+) calcd 223.1123, found 223.1125.
Characterizations of the New Optical Active Propargylic
Alcohol Products Generated from the Alkyne Additions to
Aldehydes in Table 1. 2-Methyldodec-1-en-3-yn-5-ol (Entry 1).
Colorless oil, 41 mg, 85% yield. 90% ee determined by HPLC analysis:
Chiralpak AD-H column, 98:2 hexanes/iPrOH, flow rate = 1.0 mL/
1-(4-Chlorophenyl)-4-methylpent-4-en-2-yn-1-ol (Entry 10). Col-
orless oil, 48 mg, 93% yield. 91% ee determined by HPLC analysis:
Chiralpak AD-H column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/
min, λ = 254 nm, retention time: tmajor = 9.8, tminor = 8.2. [α]23D = 12.5
min, λ = 254 nm, retention time: tmajor = 12.9, tminor = 11.9. [α]22
=
D
−4.5 (c = 1.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ 5.27 (m, 1H),
5.21 (m, 1H), 4.46 (t, 1H, J = 6.6 Hz), 2.02 (s, 1H), 1.87 (dd, 3H, J =
1.1 Hz), 1.74−1.66 (m, 2H), 1.48−1.40 (m, 2H), 1.34−1.22 (m, 8H),
0.87 (t, 3H, J = 7.8 Hz). 13C NMR (75 MHz, CDCl3): δ 126.5, 122.3,
89.5, 86.2, 63.1, 38.1, 32.0, 29.4, 25.4, 23.7, 22.9, 14.3. HRMS (ESI)
for C13H23O (MH+): calcd 195.1749, found 195.1744.
1
(c = 1.84, CHCl3). H NMR (300 MHz, CDCl3): δ 7.48 (d, 2H, J =
8.7 Hz), 7.35 (d, 2H, J = 8.4 Hz), 5.55 (d, 1H, J = 6.0 Hz), 5.35 (s,
1H), 5.31−5.27 (m, 1H), 2.36 (d, 1H, J = 6.0 Hz), 1.91 (t, 3H, J = 1.2
Hz). 13C NMR (75 MHz, CDCl3): δ 139.3, 134.4, 129.0, 128.3, 126.2,
123.2, 88.3, 87.4, 64.5 23.5. HRMS (ESI): for C12H12ClO (MH+)
calcd 207.0577, found 207.0572.
1-(3-Chlorophenyl)-4-methylpent-4-en-2-yn-1-ol (Entry 11). Col-
orless oil, 43 mg, 83% yield. 97% ee determined by HPLC analysis:
Chiralpak AD-H column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/
min, λ = 254 nm, retention time: tmajor = 8.6, tminor = 7.5. [α]23D = 16.4
(c = 1.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.53 (d, 1H, J = 0.6
1-Cyclohexyl-4-methylpent-4-en-2-yn-1-ol (Entry 3). Colorless oil,
36 mg, 81% yield. 89% ee determined by HPLC analysis: Chiralpak
AD-H column, 98:2 hexanes/ iPrOH, flow rate = 1.0 mL/min, λ = 254
nm, retention time: tmajor = 16.0, tminor = 14.3. [α]23D = −11.4 (c = 1.14,
1
CHCl3). H NMR (300 MHz, CDCl3): δ 5.29−5.26 (m, 1H), 5.23−
5.19 (m, 1H), 4.24 (d, 1H, J = 6.0 Hz), 1.95 (s, 1H), 1.88−1.74 (m,
7H), 1.65−1.51 (m, 2H), 1.27−1.03 (m, 5H). 13C NMR (75 MHz,
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Hz), 7.45−7.37 (m, 1H), 7.33−7.27(m, 2H), 5.54 (s, 1H), 5.36 (s,
1H), 5.31−5.27 (m, 2H), 2.66 (s, 1H), 1.94−1.89 (m, 3H). 13C NMR
(75 MHz, CDCl3): δ 142.8, 134.7, 130.1, 128.7, 127.1, 126.1, 125.0,
123.3, 88.4, 87.2, 64.4, 23.5. HRMS (ESI) for C12H12ClO (MH+):
calcd 207.0577, found 207.0574.
(E)-2-Methyl-1,7-diphenylhept-1-en-4-yn-3-ol (Entry 40). Color-
less oil, 68 mg, 99% yield. 99% ee determined by HPLC analysis:
Chiralcel OD-H column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/
min, λ = 254 nm, retention time: tmajor = 12.0, tminor = 31.9. [α]23
=
D
1
−15.5 (c = 1.70, CHCl3). H NMR (300 MHz, CDCl3): δ 7.37−7.23
(m, 10H), 6.66 (s, 1H), 4.91 (s, 1H), 2.87 (t, 2H, J = 7.5 Hz), 2.58 (td,
2H, J = 7.5, 1.5 Hz), 2.03 (s, 1H), 1.96 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 140.7, 137.5, 129.3, 128.72, 128.66, 128.4, 127.0, 126.6,
86.6, 80.3, 68.8, 35.2, 21.3, 14.3. HRMS (ESI) for C20H21O (MH+):
calcd 277.1592, found 277.1589.
1-(2-Ethoxyphenyl)-4-methylpent-4-en-2-yn-1-ol (Entry 12). Col-
orless oil, 51 mg, 94% yield. 92% ee determined by HPLC analysis:
Chiralpak AD-H column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/
min, λ = 254 nm, retention time: tmajor =12.5, tminor = 11.7. [α]23
=
D
1
10.8 (c = 2.05, CHCl3). H NMR (300 MHz, CDCl3): δ 7.57−7.51
(m, 1H), 7.32−7.25 (m, 1H), 6.97 (td, 1H, J = 1.5, 0.9 Hz), 6.90 (d,
2H, J = 8.4 Hz), 5.80 (d, 1H, J = 6.0 Hz), 5.34 (s, 1H), 5.25 (t, 1H, J =
1.8 Hz), 4.18−4.06 (m, 2H), 3.24 (d, 1H, J = 6.3 Hz), 1.92 (t, 3H, J =
1.2 Hz), 1.45 (t, 3H, J=7.2 Hz). 13C NMR (75 MHz, CDCl3): δ 156.4,
129.8, 129.2, 128.2, 126.7, 122.4, 121.0, 112.0, 87.7, 87.3, 64.2, 62.0,
23.6, 15.1. HRMS (ESI) for C14H17O2 (MH+): calcd 217.1299, found
217.1298.
1-(m-Tolyl)hept-2-yn-1-ol (Entry 45). Colorless oil, 31 mg, 61%
yield. 98% ee determined by HPLC analysis: Chiralpak AD-H column,
90:10 hexanes/iPrOH, flow rate =1.0 mL/min, λ = 254 nm, retention
1
time: tmajor = 9.7, tminor = 8.6. [α]22 = 18.1 (c = 0.93, CHCl3). H
D
NMR (300 MHz, CDCl3): δ 7.39−7.32 (m, 2H), 7.27 (t, 1H, J = 7.5
Hz), 7.14 (d, 1H, J = 7.2 Hz), 5.41 (s, 1H), 2.38 (s, 3H), 2.35 (br,
1H), 2.29 (td, 2H, J = 6.9, 1.8 Hz), 1.57−1.41 (m, 4H), 0.94 (t, 3H, J
= 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ 141.5, 138.4, 129.2, 128.7,
127.6, 123.9, 87.7, 80.3, 65.0, 30.9, 22.2, 21.7, 18.8, 13.9.
(E)-6-Methyl-1-phenylhepta-1,6-dien-4-yn-3-ol (Entry 13). White
solid, 40 mg, 81% yield. 90% ee determined by HPLC analysis:
Chiralpak AD-H column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/
min. λ = 254 nm, retention time: tmajor = 15.0, tminor = 12.6. Mp = 48−
49 °C. [α]24D = 1.4 (c = 1.75, CHCl3). 1H NMR (300 MHz, CDCl3):
δ 7.43−7.40 (m, 2H), 7.36−7.25 (m, 3H), 6.77 (d, 1H, J = 15.9 Hz),
6.32 (dd, 1H, J = 12.6, 6.0 Hz), 5.37 (d, 1H, J = 0.3 Hz), 5.31−5.26
(m, 1H), 5.18 (t, 1H, J = 5.0 Hz), 2.35 (d, 1H, J = 4.8 Hz), 1.95−1.91
(m, 3H). 13C NMR (75 MHz, CDCl3): δ 136.3, 132.1, 128.8, 128.4,
128.3, 127.1, 126.4, 123.0, 87.8, 87.2, 53.5, 23.6. HRMS (ESI) for
C14H15O (MH+): calcd 119.1123, found 223.1124.
1-(4-Chlorophenyl)hept-2-yn-1-ol (Entry 48). Colorless oil, 38 mg,
68% yield. 97% ee determined by HPLC analysis: Chiralpak AD-H
column, 90:10 hexanes/iPrOH, flow rate =1.0 mL/min, λ = 254 nm,
retention time: tmajor = 11.0, tminor = 9.3. [α]22 = 19.4 (c = 1.54,
D
1
CHCl3). H NMR (300 MHz, CDCl3): δ 7.46 (d, 2H, J = 8.4 Hz),
7.33 (d, 2H, J = 8.4 Hz), 5.41 (s, 1H), 2.34−2.20 (m, 3H), 1.57−1.35
(m, 4H), 0.91 (t, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ
140.0, 134.2, 128.9, 128.3, 88.3, 79.8, 64.3, 30.8, 22.22, 18.7, 13.8.
1-(3-Chlorophenyl)hept-2-yn-1-ol (Entry 49). Colorless oil, 45 mg,
81% yield. 95% ee determined by HPLC analysis: Chiralpak AD-H
column, 90:10 hexanes/iPrOH, flow rate =1.0 mL/min, λ = 254 nm,
(E)-2,6-Dimethyl-1-phenylhepta-1,6-dien-4-yn-3-ol (Entry 14).
Colorless oil, 45 mg, 85% yield. 98% ee determined by HPLC
analysis: Chiralpak AD-H column, 90:10 hexanes/iPrOH, flow rate =
retention time: tmajor = 9.6, tminor = 8.7. [α]22 = 20.1 (c = 1.35,
D
1
1.0 mL/min, λ = 254 nm, retention time: tmajor =11.3, tminor = 8.9.
CHCl3). H NMR (300 MHz, CDCl3): δ 7.56−7.52 (m, 1H), 7.43−
1
[α]23 = −36.00 (c = 1.8, CHCl3). H NMR (300 MHz, CDCl3): δ
7.36 (m, 1H), 7.32−7.26 (m, 2H), 5.41 (s, 1H), 2.39 (br, 1H), 2.27
(td, 2H, J = 6.9, 2.1 Hz), 1.58−1.38 (m, 4H), 0.92 (t, 3H, J = 7.2 Hz).
13C NMR (75 MHz, CDCl3): δ 143.4, 134.6, 130.0, 128.5, 127.1,
125.0, 88.4, 79.6, 64.3, 30.8, 22.2, 18.7, 13.8. HRMS (ESI) for
C13H16ClO (MH+): calcd 223.0890, found 223.0888.
D
7.38−7.30 (m, 4H), 7.28−7.22 (m, 1H), 6.71 (s, 1H), 5.36 (s, 1H),
5.31−5.26 (m, 1H), 5.05 (d, 1H, J = 5.1 Hz), 2.30 (d, 1H, J = 5.7 Hz),
2.02 (d, 3H, J = 1.5 Hz), 1.93 (t, 3H, J = 1.2 Hz). 13C NMR (75 MHz,
CDCl3): δ 137.3, 137.0, 129.3, 128.4, 127.4, 127.0, 126.4, 122.8, 87.7,
87.3, 68.9, 23.6, 14.4. HRMS (ESI) for C15H17O (MH+): calcd
213.1279, found 213.1281.
1-(2-Ethoxyphenyl)hept-2-yn-1-ol (Entry 51). Colorless oil, 55 mg,
94% yield. 92% ee determined by HPLC analysis: Chiralpak AD-H
column, 90:10 hexanes/iPrOH, flow rate =1.0 mL/min, λ = 254 nm,
7-Phenylhept-4-yn-3-ol (Entry 28). Colorless oil, 47 mg, 99% yield.
retention time: tmajor = 12.3, tminor = 10.3. [α]22 = 7.48 (c = 1.90,
84% ee determined by HPLC analysis: Chiralcel OD-H column, 90:10
D
hexanes/iPrOH, flow rate = 1.0 mL/min, λ = 220 nm, retention time:
1
CHCl3). H NMR (300 MHz, CDCl3): δ 7.56 (dd, 1H, J = 7.5, 1.5
1
tmajor = 7.5, tminor = 13.3. [α]22 = 6.2 (c = 1.55, CHCl3). H NMR
Hz), 7.26 (td, 1H, J = 7.8, 1.5 Hz), 6.96 (td, 1H, J = 7.5, 0.9 Hz), 6.87
(d, 1H, J = 8.4 Hz), 5.71 (dt, 1H, J = 6.0, 1.8 Hz), 4.18−4.02 (m, 2H),
3.13 (d, 1H, J = 6.0 Hz), 2.28 (td, 2H, J = 6.9, 1.8 Hz), 1.59−1.37 (m,
7H), 0.92 (t, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ 156.4,
129.7, 129.6, 128.1, 120.9, 111.8, 87.2, 79.5, 64.1, 61.7, 30.9, 22.2, 18.8,
15.1, 13.9. HRMS (ESI) for C15H20O2 (MH+): calcd 232.1463, found
232.1460.
D
(300 MHz, CDCl3): δ 7.33−7.28 (m, 2H), 7.23−7.21 (m, 3H), 4.29
(s, 1H), 2.83 (t, 2H, J = 7.5 Hz), 2.51 (td, 2H, J = 7.5, 1.5 Hz), 1.80 (d,
1H, J = 3.6 Hz), 1.75−1.60 (m, 2H), 0.96 (t, 3H, J = 7.5 Hz). 13C
NMR (75 MHz, CDCl3): δ 140.8, 128.7, 128.6, 126.5, 85.0, 82.1, 64.2,
35.3, 31.3, 21.1, 9.7. HRMS (ESI) for C13H17O (MH+): calcd
189.1279, found 189.1280.
1-(2-Chlorophenyl)-5-phenylpent-2-yn-1-ol (Entry 37). Colorless
oil, 61 mg, 90% yield. 88% ee determined by HPLC analysis: Chiralpak
AD-H column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/min, λ =
225 nm, retention time: tmajor = 14.1, tminor = 11.7. [α]23D = −16.5 (c =
2-Methyldec-2-en-5-yn-4-ol (Entry 55). Colorless oil, 27 mg, 65%
yield. 87% ee determined by HPLC analysis: Chiralpak AD-H column,
95:5 hexanes/iPrOH, flow rate =0.5 mL/min, λ = 254 nm, retention
time: tmajor = 20.2, tminor = 18.6. [α]23D = −121.9 (c = 0.61, CHCl3). 1H
NMR (300 MHz, CDCl3): δ 5.65 (qd, 1H, J = 6.0, 0.9 Hz), 4.72 (s,
1H), 2.22 (t, 2H, J = 6.6 Hz), 1.90 (s, 1H), 1.72 (d, 3H, J = 0.9 Hz),
1.62 (d, 3H, J = 6.9 Hz), 1.51−1.35 (m, 4H), 0.89 (t, 3H, J = 7.2 Hz).
13C NMR (75 MHz, CDCl3): δ 135.7, 122.3, 86.9, 79.7, 68.5, 30.9,
1
2.72, CHCl3). H NMR (300 MHz, CDCl3): δ 7.67−7.63 (m, 1H),
7.39−7.36 (m, 1H), 7.33−7.20 (m, 7H), 5.82−5.77 (m, 1H), 2.87 (t,
2H, J = 7.5 Hz), 2.58 (td, 2H, J = 7.5, 2.1 Hz), 2.46 (d, 1H, J = 5.4
Hz). 13C NMR (75 MHz, CDCl3): δ 140.7, 138.5, 133.0, 129.9, 129.7,
128.8, 128.6, 127.4, 126.6, 87.2, 79.9, 62.3, 35.0, 21.2. HRMS (ESI) for
C17H16ClO (MH+): calcd 271.0890, found 271.0894.
22.2, 18.7, 13.8, 13.5, 12.0. HRMS (ESI) for C11H19O (MH+): calcd
167.1436, found 167.1433.
1-(2-Ethoxyphenyl)-5-phenylpent-2-yn-1-ol (Entry 38). Colorless
oil, 67 mg, 96% yield. 93% ee determined by HPLC analysis: Chiralcel
OD column, 90:10 hexanes/iPrOH, flow rate = 1.0 mL/min, λ = 254
nm, retention time: tmajor = 11.0, tminor = 16.9. [α]23D = 14.7 (c = 1.15,
Preparation and Characterization of the Optically Active
Trienynes (R)-2c−f. (R)-2-Methyl-5-((3-methylbut-2-en-1-yl)oxy)-
nona-1,8-dien-3-yne, (R)-2c. Under nitrogen, NaH (60% w/w) (102
mg, 2.55 mmol, 1.7 equiv) was weighed and dissolved in dry THF (5
mL) in a flame-dried, two-necked, round-bottom flask and cooled in
an ice bath. Then a dry THF solution (5 mL) of the optical active
propargylic alcohol 2-methylnona-1,8-dien-3-yn-5-ol (entry 2 in Table
1) (225 mg, 1.5 mmol) was injected into the flask, followed by 3,3-
dimethylallyl bromide (0.21 mL, 1.8 mmol, 1.2 equiv). The mixture
was heated at 70 °C for ∼12 h. After the reaction was complete, it was
quenched with ammonium chloride (10 mL saturated water) and
1
CHCl3). H NMR (300 MHz, CDCl3): δ 7.47 (dd, 1H, J = 7.5, 1.2
Hz), 7.33−7.21 (m, 6H), 6.95 (t, 1H, J = 7.5 Hz), 6.89 (d, 1H, J = 8.1
Hz), 4.19−4.02 (m, 2H), 3.12 (d, 1H, J = 5.4 Hz), 2.89 (t, 3H, J = 7.5
Hz), 2.60 (td, 2H, J = 7.5, 1.5 Hz), 1.45 (t, 3H, J = 6.9 Hz). 13C NMR
(75 MHz, CDCl3): δ 156.4, 140.9, 129.7, 129.5, 128.8, 128.6, 128.2,
126.5, 120.9, 111.8, 86.4, 80.2, 64.1, 61.8, 35.2, 21.4, 15.2. HRMS
(ESI) for C19H21O2 (MH+): calcd 281.1542, found 281.1540.
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extracted three times with CH2Cl2 (3 × 10 mL). The organic layer was
dried with sodium sulfate, concentrated with rotary evaporation and
Characterizations of the Pauson−Khand/[4 + 2] Cyclo-
addition Products 3c−f′. 3c. Colorless oil, 41 mg, 67% yield. 90%
ee determined by HPLC analysis: Chiralpak AD-H column, 95:5
purified by using column chromatography to give (R)-2c as a colorless
hexanes/iPrOH, flow rate = 1.0 mL/min, λ = 254 nm, retention time:
1
liquid in 76% yield (248 mg). [α]25 = 89.8 (c = 0.45, CHCl3). H
D
1
tmajor = 10.4, tminor = 8.3. [α]24 = 95.9 (c = 0.35, CHCl3). H NMR
NMR (300 MHz, CDCl3): δ 5.89−5.75 (m, 1H), 5.37−5.33 (m, 1H),
5.30−5.26 (m, 1H), 5.23−5.19 (m, 1H), 5.08−4.95 (m, 2H), 4.26−
4.12 (m, 2H), 4.03−3.91 (m, 1H), 2.22 (q, 2H, J = 7.5 Hz), 1.89 (s,
3H), 1.84−1.80 (m, 2H), 1.75 (s, 3H), 1.72−1.68 (m, 3H). 13C NMR
(75 MHz, CDCl3): δ 138.1, 137.9, 126.7, 122.0, 121.0, 115.2, 87.7,
87.2, 68.4, 65.3, 35.1, 29.8, 26.1, 23.7, 18.2. HRMS (ESI) for C15H23O
(MH+): calcd 219.1749, found 219.1752.
D
(600 MHz, CDCl3): δ 3.99 (dd, 1H, J = 9.0, 7.2 Hz), 3.77 (d, 1H, J =
4.8 Hz), 3.78 (dd, 1H, J = 10.8, 9.0 Hz,), 2.58 (dd, 1H, J = 19.8, 11.4
Hz), 2.42−2.37 (m, 1H), 2.27 (d, 1H, J = 16.8 Hz), 2.17 (d, 3H, J =
0.6 Hz), 2.11−2.05 (m, 1H), 1.99 (dd, 1H, J = 7.2, 1.8 Hz), 1.95 (dd,
1H, J = 19.8, 5.4 Hz), 1.88−1.85 (m, 1H), 1.68−1.59 (m, 3H), 0.93 (s,
3H), 0.80 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 206.6, 145.9,
134.9, 93.2, 70.3, 62.5, 55.7, 44.3, 43.3, 42.8, 33.0, 30.7, 30.5, 27.0,
26.9, 20.7. HRMS (ESI) for C16H23O2 (MH+): calcd 247.1698, found
247.1690.
(R,E)-5-((3,7-Dimethylocta-2,6-dien-1-yl)oxy)-2-methylnona-1,8-
dien-3-yne, (R)-2d. By following the procedure used to synthesize
(R)-2c, compound (R)-2d was prepared from the optical active
propargylic alcohol 2-methylnona-1,8-dien-3-yn-5-ol (entry 2 in Table
1) (165 mg, 1.1 mmol), NaH (60% w/w) (75 mg, 1.87 mmol, 1.7
equiv), and geranyl bromide (0.19 mL, 0.94 mmol, 0.85 equiv). The
reaction mixture was stirred at room temperature instead of heating to
give (R)-2d as a colorless liquid in 65% yield (204 mg). [α]24D = 83.1
3d. Colorless oil, 35 mg, 45% yield. 93% ee determined by HPLC
analysis: Chiralpak AD-H column, 95:5 hexanes/iPrOH, flow rate =
1.0 mL/min, λ = 254 nm, retention time: tmajor = 9.1, tminor = 7.1.
1
[α]24 = 63.1 (c = 0.60, CHCl3). H NMR (600 MHz, CDCl3): δ
D
5.00−4.96 (m, 1H), 3.98 (dd, 1H, J = 9.0, 7.8 Hz), 3.76 (d, 1H, J = 4.2
Hz), 3.87 (dd, 1H, J = 10.5, 9.3 Hz), 2.59 (dd, 1H, J = 19.8, 11.4 Hz),
2.42−2.37 (m, 1H), 2.21−2.16 (m, 4H), 2.12−2.06 (m, 2H), 1.95 (dd,
1H, J = 19.8, 6.0 Hz), 1.91−1.81 (m, 3H), 1.77−1.71 (m, 1H), 1.66 (s,
3H), 1.62−1.58 (m, 2H), 1.55 (s, 3H), 1.20−1.15 (m, 1H), 1.07−1.02
(m, 1H), 0.91 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 206.5, 145.3,
135.4, 131.7, 124.2, 93.3, 70.0, 62.5, 54.3, 44.4, 43.4, 40.6, 38.3, 35.9,
30.8, 30.4, 25.7, 23.3, 22.2, 20.6, 17.5. HRMS (ESI) for C21H31O2
(MH+): calcd 315.2324, found 315.2325.
1
(c = 0.50, CHCl3). H NMR (300 MHz, CDCl3): δ 5.87−3.71 (m,
1H), 5.36−5.30 (m, 1H), 5.29−5.25 (m, 1H), 5.22−5.18 (m,1H),
5.08−4.94 (m, 3H), 4.24−4.15 (m, 2H), 4.05−3.97 (m, 1H), 2.21 (q,
2H, J = 7.2 Hz), 2.10−2.05 (m, 4H), 1.90−1.86 (m, 3H), 1.85−1.81
(m, 2H), 1.69 (s, 3H), 1.66 (s, 3H), 1.59 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 141.0, 138.0, 131.7, 126.7, 124.2, 121.9, 120.1, 115.2, 87.7,
87.1, 68.2, 65.2, 39.9, 35.1, 29.8, 26.6, 25.9, 23.7, 17.9, 16.6. HRMS
(ESI) for C20H31O (MH+): calcd 287.2375, found 287.2384.
(R,E)-(3-((2-Methylnona-1,8-dien-3-yn-5-yl)oxy)prop-1-en-1-yl)-
benzene, (R)-2e. By following the procedure used to synthesize (R)-
2d, compound (R)-2e was obtained from the optical active propargylic
alcohol 2-methylnona-1,8-dien-3-yn-5-ol (entry 2 in Table 1) (195 mg,
1.3 mmol), NaH (60% w/w) (88 mg, 2.21 mmol, 1.7 equiv), and
cinnamyl bromide (205 mg, 1.04 mmol, 0.8 equiv) to give (R)-2e as a
3e. White solid, 24 mg, 33% yield. 89% ee determined by HPLC
analysis: Chiralpak AD-H column, 95:5 hexanes/iPrOH, flow rate =
1.0 mL/min, λ = 254 nm, retention time: tmajor = 13.1, tminor = 14.6.
1
[α]24 = 32.6 (c = 0.40, CHCl3). Mp: 151−152 °C. H NMR (600
D
MHz, CDCl3): δ 7.31 (t, 2H, J = 7.5 Hz), 7.23 (t, 1H, J = 7.2 Hz), 7.18
(d, 2H, J = 7.2 Hz), 4.99 (d, 1H, J = 3.0 Hz), 3.81 (dd, 1H, J = 8.7, 4.5
Hz), 3.62 (d, 1H, J = 8.4 Hz), 2.98 (td, 1H, J = 10.2, 6.0 Hz), 2.78 (dd,
1H, J = 19.8, 11.4 Hz), 2.63 (dd, 1H, J = 19.8, 6.0 Hz), 2.52−2.49 (m,
1H), 2.37 (dd,1H, J = 19.5, 10.5 Hz), 2.32 (dd, 1H, J = 10.8, 4.2 Hz),
2.08 (s, 3H), 2.05−1.97 (m, 3H), 1.72−1.68 (m, 1H), 1.64−1.61 (m,
1H). 13C NMR (150 MHz, CDCl3): δ 206.5, 146.5, 144.0, 133.4,
128.7, 127.9, 126.7, 89.9, 72.6, 61.9, 50.3, 45.4, 42.6, 42.1, 41.6, 34.0,
32.6, 19.2. HRMS (ESI) for C20H23O2 (MH+): calcd 295.1698, found
295.1695.
light yellow oil in 68% yield (235 mg). [α]23 = 87.2 (c = 1.65,
D
1
CHCl3). H NMR (300 MHz, CDCl3): δ 7.46−7.42 (m, 2H), 7.38−
7.34 (m. 2H), 7.30−7.26 (m, 1H), 6.69 (d, 1H, J = 15.9 Hz), 6.39−
6.31 (m, 1H), 5.92−5.86 (m, 1H), 5.84 (s, 1H), 5.30 (q, 1H, J = 1.5
Hz), 5.07−5.03 (m, 2H), 4.47 (ddt, 1H, J = 12.6, 5.7, 1.5 Hz), 4.32 (t,
1H, J = 6.6 Hz), 4.19 (ddt, 1H, J = 12.6, 6.6, 1.2 Hz), 2.34−2.29 (m,
2H), 2.03−1.89(m, 5H). 13C NMR (75 MHz, CDCl3): δ 138.0, 137.0,
132.9, 128.8, 127.4, 126.8, 126.7, 126.1, 122.3, 115.4, 87.6, 87.5, 69.6,
68.8, 35.2, 29.9, 23.8. HRMS (ESI) for C19H23O (MH+): calcd
267.1749, found 267.1748.
3f. Colorless oil, 20 mg, 34% yield. 88% ee determined by HPLC
analysis: Chiralpak AD-H column, 95:5 hexanes/iPrOH, flow rate =
(R,E)-5-(But-2-en-1-yloxy)-2-methylnona-1,8-dien-3-yne, (R)-2f.
By following the procedure used to synthesize (R)-2d, compound
(R)-2f was prepared from the optical active propargylic alcohol, entry
2 (150 mg, 1 mmol), NaH 60% w/w (68 mg, 1. Seven mmol, 1.7
equiv) and crotyl bromide (0.15 mL, 1.5 mmol, 1.5 equiv) to give (R)-
1.0 mL/min, λ = 254 nm, retention time: tmajor = 15.9, tminor = 12.1.
1
[α]24 = −39.5 (c = 0.65, CHCl3). H NMR (600 MHz, CDCl3): δ
D
4.15 (dd, 1H, J = 4.8 Hz), 4.05 (dd, 1H, J = 9.0, 4.8 Hz), 3.88 (d, 1H, J
= 9.0 Hz), 2.22 (s, 3H), 2.20−2.03 (m, 6H), 1.86−1.82 (m, 1H),
1.79−1.72 (m, 1H), 1.63−1.58 (m, 2H), 1.53−1.47 (m, 1H), 1.13 (d,
3H, J = 7.2 Hz). 13C NMR (150 MHz, CDCl3): δ 207.9, 150.6, 133.6,
90.9, 72.7, 61.0, 56.2, 48.4, 41.7, 34.2, 33.3, 31.5, 28.8, 20.1, 14.9.
HRMS (ESI) for C15H21O2 (MH+): calcd 233.1542, found 233.1537.
3f′. Colorless oil, 15 mg, 26% yield. 88% ee determined by HPLC
analysis: Chiralpak AD-H column, 95:5 hexanes/iPrOH, flow rate =
1.0 mL/min, λ = 254 nm, retention time: tmajor = 11.8, tminor = 10.2.
[α]24D = 36.9 (c = 0.44, CHCl3). 1H NMR (600 MHz, CDCl3): δ 3.98
(dd, 1H, J = 8.4, 4.8 Hz), 3.91 (d, 1H, J = 4.8 Hz), 3.76 (dd, 1H, J =
9.0, 3.6 Hz), 2.66 (dd, 1H, J =19.8, 11.4 Hz), 2.43−2.37 (m, 2H), 2.14
(s, 3H), 2.07−2.01 (m, 1H), 1.96−1.92 (m, 2H), 1.91−1.85 (m, 3H),
1.63−1.57 (m, 2H), 0.92 (d, 3H, J = 6.6 Hz). 13C NMR (150 MHz,
CDCl3): δ 206.8, 146.7, 133.5, 90.8, 72.4, 61.5, 52.1, 44.7, 43.6, 39.4,
32.8, 31.8, 29.5, 20.0, 19.5. HRMS (ESI) for C15H21O2 (MH+): calcd
233.1542, found 233.1542.
2f as a colorless oil in 78% yield (159 mg). [α]24 = 81.1 (c = 0.57,
D
CHCl3). 1H NMR (300 MHz, CDCl3): δ 5.89−5.54 (m, 3H), 5.28 (s,
1H), 5.24−5.20 (m, 1H), 5.07−4.95 (m, 2H), 4.20−4.14 (m, 2H),
3.41−3.85 (m, 1H), 2.22 (q, 2H, J = 7.2 Hz), 1.89 (d, 3H, J = 0.6 Hz),
1.85−1.77 (m, 2H), 1.71 (d, 3H, J = 6.0 Hz). 13C NMR (75 MHz,
CDCl3): δ 138.0, 130.1, 127.5, 126.6, 122.1, 115.2, 87.5, 87.2, 69.6,
68.4, 35.1, 29.7, 23.7, 18.0. HRMS (EI) for C14H20O (M): calcd
204.1514, found 204.1511.
General Procedure for the Rh(I)-Catalyzed Domino Pauson−
Khand/[4 + 2] Cycloaddition. Under nitrogen, a trienyne or
diendiyne (0.25 mmol) and [Rh(CO)2Cl]2 (9.8 mg, 0.10 equiv) were
weighed into a tared two-necked round-bottom flask and dissolved in
DCE (5 mL). The flask was fitted with reflux condenser fit with a
septum, and the side arm of the flask was also fitted with a septum.
The solution was bubbled with CO gas for 2 min through the side arm
fitted with septum and a vent needle in the septum of the reflux
condenser. Then, the solution was placed under CO atmosphere by
using a balloon. After the reaction mixture was heated at 65 °C to
reflux temperature for 26−72 h, it was cooled to room temperature
and the CO was released cautiously in the hood. The reaction mixture
was concentrated and the crude product was purified by column
chromatography on silica gel.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional data for synthesis and characterization of the
compounds, HPLC plots, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
2264
dx.doi.org/10.1021/jo3026065 | J. Org. Chem. 2013, 78, 2256−2265

The Journal of Organic Chemistry
Featured Article
L.; Lee, B. Y.; Chung, Y. K. Tetrahedron Lett. 1993, 34, 4027−4030.
(c) Kent, J. L.; Wan, H. H.; Brummond, K. M. Tetrahedron Lett. 1995,
36, 2407−2410. (d) Adrio, J.; Rivero, M. R.; Carretero, J. C. Org. Lett.
2005, 7, 431−434. (e) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc.
2007, 129, 778−779.
AUTHOR INFORMATION
Corresponding Author
*E-mail address: lp6n@virginia.edu, xqyu@scu.edu.cn.
Notes
■
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Partial support of this work from the US National Science
Foundation (CHE-1047104) is gratefully acknowledged.
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