Enantioselective copper-catalysed propargylic substitution: Synthetic scope study and application in formal total syntheses of (+)-anisomycin and (-)-cytoxazone

Article abstract of DOI:10.1002/chem.201003727

A copper catalyst with a chiral pyridine-2,6-bisoxazoline (pybox) ligand was used to convert a variety of propargylic esters with different side chains (R=Ar, Bn, alkyl) into their amine counterparts in very high yields and with good enantioselectivities (up to 90% enantiomeric excess (ee)). Different amine nucleophiles were applied in the reactions and the highest enantioselectivities were obtained for aniline and its analogues. Interestingly, some carbon nucleophiles could also be used and with indoles excellent ee values were obtained (up to 98% ee). The versatility of the propargylic amines obtained was demonstrated by their further elaboration to formal total syntheses of the antibiotic (+)-anisomycin and the cytokine modulator (-)-cytoxazone. Copyright

Full text of DOI:10.1002/chem.201003727

FULL PAPER
DOI: 10.1002/chem.201003727
Enantioselective Copper-Catalysed Propargylic Substitution:
Synthetic Scope Study and Application in Formal Total Syntheses of
(+)-Anisomycin and (À)-Cytoxazone
Remko J. Detz, Zohar Abiri, Remi le Griel, Henk Hiemstra, and
Jan H. van Maarseveen*[a]
Abstract: A copper catalyst with a
chiral pyridine-2,6-bisoxazoline
were applied in the reactions and the
highest enantioselectivities were ob-
tained for aniline and its analogues. In-
terestingly, some carbon nucleophiles
could also be used and with indoles ex-
cellent ee values were obtained (up to
98% ee). The versatility of the propar-
gylic amines obtained was demonstrat-
ed by their further elaboration to
formal total syntheses of the antibiotic
(+)-anisomycin and the cytokine mod-
ulator (À)-cytoxazone.
(pybox) ligand was used to convert a
variety of propargylic esters with differ-
ent side chains (R=Ar, Bn, alkyl) into
their amine counterparts in very high
yields and with good enantioselectivi-
ties (up to 90% enantiomeric excess
(ee)). Different amine nucleophiles
Keywords: asymmetric catalysis
·
copper · homogeneous catalysis ·
propargylic substitution · synthetic
methods
Introduction
The propargylic moiety is a popular functionality in organic
synthesis. The electron-rich triple bond, in combination with
the fairly acidic character of the terminal acetylenic hydro-
gen atom, makes it a versatile entity for further chemical
transformations.[1] In addition, various natural products, fine
chemicals and pharmaceuticals containing propargylic subu-
nits as components of their structures have been reported.[2]
Unlike allylic substitution, which is one of the most reliable
methods in organic synthesis, asymmetric transition-metal-
catalysed propargylic substitution is a poorly developed re-
action.[3,4] Several palladium-catalysed reactions with propar-
gylic compounds are known, but these usually yield the cor-
responding allenic systems.[5]
Scheme 1. Enantioselective transition-metal-catalysed propargylic substi-
tution.
However, propargylic substitution reactions with heteroa-
tom-centred nucleophiles, such as alcohols, amines, thiols
and diphenylphosphine oxide, did not proceed enantioselec-
tively in the presence of this diruthenium complex.[7c]
Although some diastereoselective methods have been de-
scribed,[6] only one example of an enantioselective propar-
gylic substitution reaction (Scheme 1) is known. This
method, developed in the group of Uemura, Hidai and
Nishibayashi, uses a chiral diruthenium complex (1) to
À
induce asymmetry in the C C bond formation during the
propargylation of aromatic compounds or acetone with
Recently, the first example of an enantioselective copper-
catalysed propargylic amination, starting from the propar-
gylic acetates 2 (Scheme 2), was discovered both by our
group and by the group of Nishibayashi.[8] This new method,
an enantioselective version of the propargylic substitution
reaction originally reported by Murahashi et al.,[9] provides
the propargylic amines 3 in very high yields and optical puri-
ties. The major difference between Nishibayashiꢀs method
and ours is the structure of the chiral ligand. Whereas Nishi-
bayashi used a diphosphine ligand ((R)-Cl-OMe-biphep, 4),
we focussed on chiral 2,6-bis(oxazolinyl)pyridine-type
(pybox, 5) ligands.
propargylic alcohols (up to 95% enantiomeric excess (ee)).[7]
[a] Dr. R. J. Detz, Z. Abiri, R. le Griel, Prof. Dr. H. Hiemstra,
Dr. J. H. van Maarseveen
Biomolecular Synthesis Group
Van ꢀt Hoff Institute for Molecular Sciences
P.O. Box 94157, 1090GD Amsterdam (The Netherlands)
Fax : (+31)20–5255604
E-mail: j.h.vanmaarseveen@uva.nl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003727.
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Table 1. Screening of several pybox ligands.[a]
Entry
1
Ligand
ee[b] [%]
13
Scheme 2. Enantioselective copper-catalysed propargylic amination.
2
21
1
Whereas our system showed high yields and ee values
with primary amines such as o-anisidine (Scheme 2, R=H),
Nishibayashiꢀs method gave the best results if secondary
3[c]
amines such as N-methylaniline (R=Me) were used.[8b,c]
A
4
23
disadvantage of both Nishibayashiꢀs and our method is the
incompatibility with substrates bearing non-aromatic side
chains. However, in a recent paper, Nishibayashi et al. de-
scribe enantioselective copper-catalysed ring-opening reac-
tions of racemic ethynyl epoxides with amines containing
non-aromatic side chains.[8d]
5
21
Herein, we disclose the results of our synthetic scope
study starting from propargylic substrates bearing non-aro-
matic side chains in combination with the introduction of
several nucleophiles such as anilines, but also aliphatic pri-
mary and secondary amines and some C-centred nucleo-
philes. The versatility of the obtained enantiomerically en-
riched propargylic amines is demonstrated by their further
elaboration, leading to a formal total synthesis of the biolog-
ically active compound (+)-anisomycin.
6[c]
64
66
52
22
7
8
9[c]
Results and Discussion
Our previous study found that diPh-pybox (5) is the optimal
ligand for propargylic substrates bearing aromatic side
chains. With the propargylic acetate 6a, bearing an n-pentyl
group, diPh-pybox (5) gave poor stereoselectivity, affording
the propargylic amine 7a in only 13% ee under the opti-
mised reaction conditions (Table 1, entry 1). After examina-
tion of ligands 8–11 it became apparent that aromatic sub-
stituents next to the oxazoline N atom are detrimental for
the enantioselectivity (Table 1, entries 2–5). We speculated
that substitution of the two phenyl groups in ligand 5 for
two methyl groups to give diMe-pybox (12) might increase
the enantioselectivity for aliphatic propargylic acetates. The
synthesis of this ligand (see the Supporting Information)
proved challenging because the required (2R,3S)-3-amino-
butan-2-ol had to be synthesised. Gratifyingly, though, the
reaction catalysed by the pybox ligand 12 afforded the prop-
argylic amine 7a in good yield and with 64% ee at room
temperature. Removal of the methyl group adjoining the ox-
azoline O atom to give the ligand 13 gave a slightly further
improved ee value of 66% (Table 1, entry 7). Replacement
[a] Reaction conditions: 6 (0.20 mmol), o-anisidine (0.40 mmol), DIPEA
(0.80 mmol), CuI (0.02 mmol) and ligand (0.024 mmol) were stirred in
methanol (2 mL) at room temperature, unless noted otherwise. [b] The ee
value is determined by chiral HPLC of the isolated product. [c] Reaction
is performed at 408C.
of the methyl groups in 13 by sterically more demanding
groups gave lower enantioselectivities (Table 1, entries 8, 9).
Apparently, the pybox ligand 13, bearing the small methyl
group, is the most selective ligand for this transformation.
With this finding observed, we explored the scope of
enantioselective propargylic aminations of substrates with
more hindered aliphatic side chains (Table 2). In some cases
we have also shown the results when diMe-pybox (12) was
used. The phenethyl-substituted propargylic amine 7b was
obtained with yield and selectivity comparable to those seen
with the phenyl-substituted 7a (Table 2, entry 1).
We were pleased to see that branching near the propar-
gylic C atom caused an increase in the asymmetric induction
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Enantioselective Copper-Catalysed Propargylic Substitution
Table 2. Propargylic aminations with several propargylic esters.[a]
FULL PAPER
is limited to a few methods, thus giving access only to a
narrow set of structural motifs.[10] In particular, products
such as 22, containing an aromatic ring and a methyl group
as the substituents, are of importance. Known routes to
products of this type are few and provide the products, al-
though with high optical purities (78 and 98% de), in low
yields (11 and 31%, respectively).[10e,h] The ability of the cat-
alyst to discriminate between a methyl and a propyl moiety
appeared to be limited, as was shown for substrate 17
(Scheme 3), which gave the amine 18 in good yield (79%)
but in low optical purity (21% ee), in the presence of Me-
pybox 13 as the optimal ligand. Replacement of the propyl
group by a cyclohexyl moiety gave the product 20 with
higher selectivity in the presence of either Me- or diMe-
pybox (13 or 12, 54% ee). For substrates containing aromat-
ic rings as substituents the diPh-pybox ligand 5 gave the
best results and afforded the propargylic amine 22 in very
high yield and with good selectivity (78% ee).
Entry
R
R1
Ligand Product Yield[b]
[%]
ee[c]
[%]
Ac
(6b)
1
2
13
13
7b
7c
84
80
67
82
Ac
(6c)
Ac
(6d)
Bz
3
4
13
13
7d
7d
77
89
82
79
(6d2)
5
6
13
12
7e
7e
96
63
85
86
Ac
(6e)
7
8
9
Ac (6 f) 13
Ac (6 f) 12
7 f
7 f
7 f
66
88
89
88
60
66[d]
Nitrogen nucleophiles: After the study of several propargyl-
ic acetates in the enantioselective propargylic amination re-
action (see above), the scope, with regards to the nitrogen
nucleophile, was investigated (Table 3). p-Methoxyphenyl
(PMP) is a commonly used protecting group for amines, so
p-anisidine was included in our series under the optimal re-
action conditions and with diPh-pybox (5) as the ligand
(Table 2, entry 2). The observed enantioselectivity was
slightly lower than seen with o-anisidine. Moreover, 2,4-di-
methoxyaniline (Table 2, entry 3) also gave lower ee values
than o-anisidine, so the latter system was chosen as the
masked primary amine in our protocol. Results similar to
those obtained with o-anisidine were also obtained both
with aniline and with 4-(trifluoromethyl)aniline (Table 2, en-
tries 4 and 5). Nitroanilines did not react properly and gave
only small amounts of product among many side products
(data not shown). In analogy with the Nishibayashi meth-
od,[8b] we applied N-methylaniline as the nucleophile: an ee
value significantly lower than those obtained with the pri-
mary anilines was observed (Table 2, entry 6), underscoring
the complementarity of the two methods.
Carreira et al. recently reported the use of 4-piperidone
hydrate hydrochloride as an interesting masked primary
amine in copper-catalysed three-component reactions of al-
dehydes, alkynes and amines.[11] Once the 4-piperidone is at-
tached at the propargylic moiety, double dealkylation by use
of an excess of a primary amine affords the unprotected
propargylic amine. However, when 4-piperidone hydrate hy-
drochloride was applied in our reaction, the product was ob-
tained in good yield but in almost racemic form (Table 2,
entry 7). N-Benzylhydroxylamine, which also serves as a
masked primary amine, gave the anticipated product in
good yield. Although product 23h showed an optical rota-
tion, demonstrating an enantioselective reaction, all at-
tempts to separate the enantiomers by chiral HPLC failed
and no ee value could be determined. With O-benzylhydrox-
ylamine, the product was obtained in good yield (74%), but
with a low ee value (36% ee, Table 2, entry 9). On the other
Piv
13
(6 f2)
Piv
(6g)
10
13
7g
59[d]
90
[a] Reaction conditions: the propargylic ester 6 (0.20 mmol), o-anisidine
(0.40 mmol), DIPEA (0.80 mmol), CuI (0.02 mmol) and the pybox ligand
(0.024 mmol) were stirred in methanol (2 mL) at room temperature typi-
cally for 24–48 h. [b] Isolated yield after chromatographic purification.
[c] Enantioselectivity was determined by chiral HPLC of the isolated
product. [d] No full conversion was observed and starting material (23–
24%) was recovered. Bz=benzoyl, Piv=pivaloyl.
to the 79–90% ee range, as was shown for products 7c–g
(Table 2, entries 2–10). The acetate group proved sensitive
to base-catalysed transesterification by the methanol sol-
vent, thus giving the propargylic alcohol as a side product
and lowering the yield. Use of the sterically more demand-
ing benzoate or pivaloate esters gave the products in higher
yields without sacrificing enantioselectivity and no transes-
terification was observed (Table 2, entries 4, 9 and 10).
Gratifyingly, the procedure also allows amination of qua-
ternary propargylic acetates (Scheme 3). Currently, asym-
metric synthesis of these a,a-dibranched propargylic amines
Scheme 3. Propargylic amination with quaternary propargylic acetates:
the reactions were performed with the propargylic acetate (0.2 mmol), o-
anisidine (H2N OMP, 0.4 mmol), DIPEA (0.8 mmol) and the indicated
catalyst (10 mol%) in methanol.
À
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5923

J. H. van Maarseveen et al.
Table 3. Propargylic amination with various nitrogen nucleophiles.[a]
same observation was made with several other nitrogen nu-
cleophiles, such as phthalimide, 4-nitrophenylsulfonamide,
tritylsulfenylamide and P,P-diphenylphosphinic amide.
Carbon nucleophiles: As is illustrated above, the copper-cat-
alysed propargylic substitution reaction is rather sensitive
with regard to the nitrogen nucleophile. The question arose
of whether carbon nucleophiles could also be applied. If
possible, this would lead to a novel and promising carbon–
carbon bond-formation process, which is always the utmost
challenge for organic chemists. During the course of this
work Fang and Hou reported the first example of Cu-cata-
lysed asymmetric propargylic substitution in which enamines
were used as carbon nucleophiles. With Nishibayashiꢀs
ligand 4 the substitution of several propargylic acetates
bearing aromatic side chains with different aryl-substituted
enamines resulted in the propargylic substituted products in
high yields (40–95%) and with good enantioselectivities
(67–91%).[12] Other examples of asymmetric substitutions at
the propargylic moiety with carbon nucleophiles, reported
by Nishibayshi et al., rely on a chiral thiolate-bridged diru-
thenium complex.[7] With its success in Nishibayashiꢀs ruthe-
nium-catalysed substitution in mind,[7c] the special p-nucleo-
philicity and biological relevance of indole prompted us to
subject it to our reaction conditions. The first attempt at this
novel copper-catalysed asymmetric Friedel–Crafts propargy-
lation of indole gave very promising results. Treatment of 1-
phenylprop-2-ynyl acetate (2a) with indole in the presence
of diPh-pybox (5) gave the propargylated indole 24a in high
yield and with excellent selectivity (94% ee, Table 4,
entry 1). Very delighted with this result, we subjected N-
methylindole to the same conditions and obtained the prod-
uct 24b in high yield and with even higher selectivity
(98% ee, Table 4, entry 2). N-Triisopropylsilylindole, which
had given the best results in the ruthenium-catalysed propar-
gylation, gave no product at all, which may be ascribed to
steric hindrance (Table 4, entry 3).
Entry NuH
1
t [h] T [8C] Product Yield[b] [%] ee[c] [%]
24
19
À20
À20
23a
23b
23c
23d
23e
97
93
90
94
87
85
78
64
87
86
2
3
4
5
1.5 RT
42
À20
À20
43
1
6
RT
23 f
90
60
7
8
3
2
RT
0
23g
23h
66
77
3
n.d.
9
1.5
0
23i
23j
74
94
36
68
10
24
À20
[a] Reaction conditions: the propargylic acetate 2a (0.20 mmol), the
NuH (0.40 mmol), DIPEA (0.80 mmol), CuI (0.02 mmol) and
(0.024 mmol) were stirred in methanol (2 mL). [b] Isolated yield after
chromatographic purification. [c] Enantioselectivity is determined by
chiral HPLC of the isolated product. N.d.=could not be determined by
chiral HPLC, PMB=p-methoxybenzyl.
5
With the propargylic acetate 6 f, containing an aliphatic
side chain (R=Bn), and with indole as the nucleophile, no
desired product was formed with either ligand 5 or 11
(Table 4, entry 4), even with a longer reaction time (144 h)
and elevated temperatures (up to 508C).
hand, with N-benzyl-N-p-methoxybenzylamine, the desired
product was obtained in high yield and with a moderate se-
lectivity (Table 2, entry 10). This suggests that more hin-
dered secondary aliphatic amines might provide products in
even higher enantiopurity.
After the establishment of enantioselective copper-cata-
lysed propargylic substitution with indoles, we envisaged
that other carbon p-nucleophiles might also be applicable
(Table 4, entries 5, 6). Unfortunately, the enol ester tert-
butyl(1-methoxyvinyloxy)dimethylsilane gave a disappoint-
ing result and only a small amount of product was isolated
(Table 4, entry 5). Interestingly, though, with 2,2,5-trimethyl-
1,3-dioxane-4,6-dione the propargylic acetate was fully con-
verted (Table 4, entry 6). Besides the anticipated product
24 f, compounds 25 and 26 (Scheme 4) were also identified
Removal of the o-anisidyl group was achieved in reasona-
ble to high yields for most substrates, as is described later. It
was nevertheless interesting to know whether other types of
nitrogen nucleophiles would also lead to the desired prod-
ucts. In single-attempt experiments (not shown) a set of dif-
ferent nitrogen nucleophiles was tested under the optimal
reaction conditions. tert-Butyl carbamate and di-tert-butyl
iminodicarbonate were applied in the substitution reactions,
but without success. In both cases the starting material de-
composed into unidentified compounds. The nucleophilicity
of the nitrogen atom is probably too low in these cases. Ap-
parently the desired reaction is unable to compete with an
unknown decomposition pathway, which we also observed if
only base was added in the absence of nucleophile. The
1
in the H NMR spectrum of a crude sample, indicating that
an intriguing cascade of reactions had occurred. Probably,
after the formation of 24 f, small amounts of methoxide,
present in the basic reaction medium, could have attacked
one of the ester functionalities (Scheme 4).
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Enantioselective Copper-Catalysed Propargylic Substitution
Table 4. Propargylic amination with various carbon nucleophiles.[a]
FULL PAPER
This could have liberated, after loss of acetone, a carbox-
ylate anion, which in turn could have attacked the copper-
activated alkyne moiety. After proteolysis, product 25,
1
which was identified by H NMR analysis, would have been
obtained. Another methanolysis step could have formed the
dimethyl ester enolate, which could have isomerised to the
ketone 26. After a prolonged reaction time at higher tem-
perature (708C), NMR analysis indicated total conversion to
this product, which was isolated in moderate yield (40%). If
the temperature was kept low, the product 24 f could be iso-
lated in good yield (64%), although as a near racemate.
Entry NuH
R
T [8C] Product
Yield[b] ee[c]
[%]
[%]
1
Ph
À20
71
94
2
3
Ph
Ph
À20
À20
91
98
–
Applications
The establishment of the enantioselective copper-catalysed
propargylic amination protocol motivated us to find new ap-
plications for the resulting optically active propargylic
amines. Alkyne moieties are amenable to further functional-
isation and conversion into natural products and biologically
interesting molecules. This virtue, in combination with the
ease of variation of the side chains (R), makes the new pro-
tocol a simple and versatile synthetic procedure. Optically
active propargylic amines have been used before as starting
materials, and compounds of this type are usually prepared
by starting from a-amino acids (Scheme 5).[13] However,
multiple steps are required and the procedures are prone to
racemisation.[14] With our protocol a large array of substitu-
ents (R) is available. Because the absolute configuration of
the product is determined by the pybox ligand, both enan-
tiomers of which are available, complete stereocontrol of
the product is possible.
n.r.
up to
50
4[d]
Bn
Ph
n.r.
–
5
RT
ꢀ10
n.d.
6[e]
Ph
À20
64
6
[a] Reaction conditions: propargylic acetate (2a, 0.20 mmol), NuH
(0.40 mmol), DIPEA (0.80 mmol), CuI (0.02 mmol) and 5 (0.024 mmol)
were stirred in methanol (2 mL) for 24 h. [b] Isolated yield after chroma-
tographic purification. [c] Enantioselectivity is determined by chiral
HPLC of the isolated product. [d] In this entry ligand 11 was also used,
as well as the pivaloate ester 6 f2. [e] In this reaction only 0.22 mmol of
the nucleophile was used, and after completion the reaction mixture was
first quenched with sat. NH4Cl (aq) and extracted, before chromato-
graphic purification. n.r.=no product formation observed, n.d.=could
not be determined by chiral HPLC, Bn=benzyl, TBDMS=tert-butyldi-
methylsilyl.
Scheme 5. Synthesis of chiral propargylic amines.
When the substrate 6d was converted into the propargylic
amine 7d (Table 2), a valine analogue was obtained. Oxida-
tive removal of the anisidyl moiety with iodobenzene diace-
tate, as reported by Snapper et al.,[15] and subsequent N-pro-
tection with a tert-butoxycarbonyl (Boc) group gave the
propargylic amine 27 in good yield (Scheme 6). The absolute
configuration was determined by comparison of the optical
rotation with a literature value ([a]2D0 =À59.9, 96% ee).[12b]
The (S)-Me-pybox ligand 13 gave the (S)-valine analogue
27, which is similar to the natural amino acid derived config-
uration.
Anisomycin: Elaboration of the optically enriched products
obtained by the copper-catalysed enantioselective propargyl-
ic amination into Boc-protected amines opens pathways for
Scheme 4. Unexpected reaction cascade.
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J. H. van Maarseveen et al.
by the Crabbꢂ reaction. Crabbꢂ and co-workers found that
terminal alkynes react with paraformaldehyde and diisopro-
pylamine in the presence of copper(I) to form allenes.[22]
The enantioselective copper-catalysed propargylic amina-
tion reaction provided the benzyl-substituted propargylic
amines 7 f and 7g (Scheme 8) in good yields and with high
Scheme 6. Synthesis of an alkyne-containing amino acid (valine) ana-
logue.
further transformations. Pyrrolidine rings are important
structural motifs in many alkaloids, such as hygrine, nicotine
and cocaine. Their biological activities make these alkaloids
attractive synthetic targets. A formal total synthesis of aniso-
mycin, which also contains a pyrrolidine system, is detailed
below.
The antibiotic anisomycin was isolated from culture fil-
trates of two Streptomyces species (S. griseolus and S. roseo-
chromogenes) in the early 1950s.[16] In the 1960s the struc-
ture was elucidated after a joint effort by several groups.[17]
The natural product, (À)-anisomycin (29a), was found to
block peptide bond formation specifically in eukaryotic ribo-
somes, and this made it a valuable tool in molecular biol-
ogy.[18] In addition to its fungicidal activity,[15,18] anisomycin
and some of its derivatives display high in vitro antitumor
activity.[19] This diverse biological activity of anisomycin has
stimulated many scientists to develop new routes for its syn-
thesis, both in racemic and in enantiopure form.[20]
Scheme 8. Synthesis of N-Boc-protected 3,4-dehydropyrrolidines.
ee values. Even after prolonged reaction times no full con-
version of the starting material was observed, which may be
ascribed to catalyst deactivation. We were able to recover
the starting materials together with the desired products.
Oxidative removal of the anisidyl moiety of 7 f with iodo-
benzene diacetate followed by treatment with di-tert-butyl
dicarbonate gave the Boc-protected propargylic amine 30 in
good overall yield. Surprisingly, application of the same pro-
cedure to 7g gave 31 in only 29% yield. This is probably
due to partial oxidation of the electron-rich p-methoxyben-
zyl moiety, lowering the yield of the desired product. Subse-
quent subjection to Crabbꢂ reaction conditions provided the
allenic amines 32 and 33 in reasonable yields. The optical ro-
tation of the allene 32 ([a]2D4 =+16, c=1.3, CHCl3) was in
good agreement with the literature value[28] ([a]D26 =+20.0,
c=0.274, CHCl3) for the enantiopure compound. In a first
cyclisation attempt with 32, catalysed by a cationic gold
complex prepared in situ, compound 34 was obtained in
high yield (86%). In another attempt the starting material
was totally recovered, indicating that the reaction was diffi-
cult to reproduce. It seems that on small scales the reaction
is sensitive to traces of water and/or air oxygen, probably
due to the very hygroscopic AgOTf. Altogether, the two N-
Boc-protected 3,4-dehydropyrrolidines 34 and 28 were ob-
Retrosynthetically, anisomycin could be prepared from
the 3,4-dehydropyrrolidine 28, as described by Jegham and
Das.[19d,k] To produce 28 from a starting propargylic amine
would afford a formal synthesis of (+)-anisomycin (29b)
now based on the enantioselective copper-catalysed propar-
gylic amination. During the last five years the use of gold
complexes in catalytic chemical transformations has under-
gone extensive growth.[21] Gold catalysis provides a new syn-
thetic pathway by which to construct otherwise difficult to
achieve complex chemical architectures in a mild manner.
We envisaged that the 3,4-dehydropyrrolidine ring could be
accessible through gold-catalysed ring closure of an aminoal-
lene derived from an N-Boc-protected propargylic amine
(Scheme 7). Access to this aminoallene could be provided
Scheme 7. Retrosynthetic scheme for the synthesis of 3,4-dehydropyrroli-
dines.
5926
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Chem. Eur. J. 2011, 17, 5921 – 5930

Enantioselective Copper-Catalysed Propargylic Substitution
FULL PAPER
tained in satisfactory yields (72%), although higher conver-
sions should be feasible.
With the synthesis of 28 we accomplished the formal syn-
thesis of (+)-anisomycin 29b in only seven steps. It is also
noteworthy that the substituent at the 2-position can be
varied easily, as is illustrated by the synthesis of 34, allowing
facile synthesis of anisomycin analogues.
Cytoxazone: Since the isolation and structural elucidation of
(À)-cytoxazone (35) by Osada and co-workers in 1998,[23]
several groups have published
total syntheses of this novel cy-
tokine modulator.[24] The com-
pound was isolated from cul-
tures of Streptomyces species
and interferes with the produc-
tion of cytokines IL4 and IL10
and IgG through selective in-
hibition of the signalling path-
way in Th2 cells.
We envisioned a short synthetic route to oxazolidinones
such as (À)-cytoxazone (35) by gold-catalysed cyclisation, as
described by Shin et al.,[24d] of N-Boc-protected propargylic
amines, prepared by enantioselective copper-catalysed prop-
argylic amination (Scheme 9). Hydroboration would afford
(À)-cytoxazone (35), or other interesting oxazolidinones.
As shown in Scheme 10, our new amination methodology
was applied for a short synthesis of (À)-cytoxazone. Com-
mercially available p-anisaldehyde was converted into the
Scheme 10. Formal total synthesis of (À)-cytoxazone.
Conclusion
Several propargylic amines with non-aromatic side chains
were prepared in reasonable to high yields (59–96%) and
optical purities (64–90% ee) from a variety of readily avail-
able propargylic esters through the enantioselective copper-
catalysed propargylic amination reaction. In addition, a
series of primary and secondary amines were tested as nu-
cleophiles. Aniline and its derivatives gave the best results,
affording the corresponding propargylic amines in high
yields and with high optical purities. With other nitrogen nu-
cleophiles the results were less promising, although reasona-
ble enantioselectivity (68% ee) was obtained with the steri-
cally hindered secondary amine N-benzyl-N-p-methoxyben-
zylamine. Carbon nucleophiles were also evaluated in the
propargylic substitution reaction. Indole and N-methylindole
especially stand out in this series, giving high yields (up to
91%) and enantioselectivities (up to 98% ee). Some of the
propargylic amines synthesised by our new protocol were
converted into a-amino acid derivatives and further elabo-
rated to provide formal total syntheses of the biologically
active compounds (+)-anisomycin and (À)-cytoxazone.
Scheme 9. Retrosynthetic scheme for the synthesis of oxazolidinones.
propargylic acetate 36 upon treatment with ethynylmagnesi-
um bromide and subsequent acetylation. The enantioselec-
tive copper-catalysed propargylic amination gave the propar-
gylic amine 37 in high yield and enantioselectivity. After re-
moval of the anisidyl moiety with iodobenzene diacetate,
the primary amine was treated with di-tert-butyl dicarbonate
to afford the Boc-protected propargylic amine 38 in good
overall yield. At this point the cyclisation, catalysed by a
cationic gold(I) complex prepared in situ from [AuACTHNUTRGNEUNG(PPh3)Cl]
and AgOTf in toluene as reported by Shin et al.,[24d] provid-
ed us with the oxazolidinone 39 in excellent yield. The hy-
droboration of the double bond of 39, although successful
according to Shin et al., did not afford (À)-cytoxazone (35)
in good yield in our hands and only traces of the desired
compound were observed by NMR spectroscopy and LC-
MS analysis of the crude product. Thus, although the total
synthesis of (À)-cytoxazone (35) regrettably ended before
the intended last step of the sequence, we had accomplished
a short synthesis of enantioenriched oxazolidinones, such as
39, in high overall yields (six steps to 39 in 55% yield).
Experimental Section
The Experimental Section gives general procedures and some examples.
Further procedures and spectroscopic data for the new compounds de-
scribed are collected in the Supporting Information, together with the
general remarks and equipment used.
Synthesis of the ligand 12: The ligand 12 was prepared as shown in
Scheme 11.
Chem. Eur. J. 2011, 17, 5921 – 5930
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www.chemeurj.org
5927

J. H. van Maarseveen et al.
CHCl3); 1H NMR (400 MHz): d=8.14 (d, J=7.8 Hz, 2H), 7.84 (d, J=
7.8 Hz, 1H), 4.96 (dq, J=6.6 Hz, 9.3 Hz, 2H), 4.38 (dq, J=7.0 Hz,
9.3 Hz, 2H), 1.40 (d, J=6.6 Hz, 6H), 1.25 ppm (d, J=7.0 Hz, 6H);
13C NMR (101 MHz): d=162.0, 147.5, 137.3, 125.6, 80.0, 63.9, 15.7,
15.0 ppm; HRMS (FAB+) m/z calcd: 274.1556 [M+H]+; found:
274.1557.
General method for the synthesis of propargylic acetates
The aldehyde (or ketone) (7.3 mmol) was dissolved in dry THF (20 mL)
and added at 08C to a solution of ethynylmagnesium bromide in THF
(0.5m in THF, 22.0 mL, 11.0 mmol). After 3 h the reaction mixture was
quenched in a mixture of saturated NH4Cl solution (50 mL) and ice
(50 mL). After the evaporation of THF, diethyl ether (50 mL) was added.
The organic and water layer were separated and the organic layer was
washed with saturated NaCl solution (50 mL). After separation of phases
the organic layer was dried over anhydrous Na2SO4 and concentrated to
dryness. The crude product was used without further purification in the
next step.
Scheme 11. Preparation of the ligand 12.
ACHTUNGTRENNUNG(4R,5R)-2-Methoxy-2,4,5-trimethyl-1,3-dioxolane (29): 1,1,1-Trimethoxy-
ethane (5.6 mL, 44 mmol) and a catalytic amount of H2SO4 (60 mL,
1.1 mmol) were added at 08C to a solution of commercially available
(2R,3R)-butane-2,3-diol (2.0 mL, 22 mmol) in freshly distilled Et2O
(30 mL). The mixture was stirred for 24 h, being allowed to warm to
room temperature. After addition of Et3N (2 mL), the reaction mixture
was poured into saturated aqueous NaHCO3 (100 mL) and extracted
three times with Et2O (50 mL). After evaporation of the solvent, the
crude product 29 was obtained and used in the next step without further
purification (contains 1,1,1-trimethoxyethane and triethylamine).
1H NMR (400 MHz): d=3.88–3.85 (m, 1H), 3.77–3.72 (m, 1H), 3.31 (s,
3H; OCH3), 1.56 (s, 3H; CH3), 1.33 (d, J=6.0 Hz, 3H), 1.27 ppm (d, J=
6.0 Hz, 3H).
A solution of the propargylic alcohol (max. 7.3 mmol), acetic anhydride
(0.9 mL, 9.5 mmol) and triethylamine (1.3 mL, 9.5 mmol) in dry CH2Cl2
(20 mL) was stirred overnight at room temperature. If necessary a cata-
lytic amount of N-dimethylaminopyridine (DMAP) was added to achieve
total conversion. CH2Cl2 was evaporated with a laboratory evaporator.
The mixture was purified by silica gel column chromatography.
1-Phenylprop-2-ynyl acetate (2a):[29] Acetic anhydride (1.0 mL, 11 mmol)
was added under nitrogen to a solution of commercially available 1-phe-
nylprop-2-ynyl alcohol (1.0 mL, 8.2 mmol) in dry CH2Cl2 (20 mL). After
addition of Et3N (1.5 mL, 11 mmol) the solution was stirred at ambient
temperature for 21 h. The reaction mixture was concentrated under
vacuum and the product 2a was obtained after column chromatography
ACHTUNGTRENNUNG
(2R,3S)-3-Azidobutan-2-yl acetate (30):[25] Trimethylsilyl azide (10 mL)
was added to the crude product 29 (5.5 g, ꢀ50% w/w pure, max.
19.4 mmol). The mixture was warmed for 7 h at 608C. After full conver-
sion of the starting material (monitoring by NMR spectroscopy), the mix-
ture was heated for 13 h at 1308C, turning red. NMR analysis indicated
the formation of 30 and the evaporation of most other reagents. Flash
chromatography (petroleum ether (PE)/EtOAc 3:1) gave a clear yellow-
ish liquid (2.01 g, 66%). 1H NMR (400 MHz): d=4.95–4.90 (m, 1H),
3.67–3.60 (m, 1H), 2.10 (s, 3H; OAc), 1.26 (d, J=6.8 Hz, 3H), 1.25 ppm
(d, J=6.8 Hz, 3H); 13C NMR (101 MHz): d=170.3, 72.8, 60.0, 20.1, 15.1,
14.9 ppm; FTIR (film): n˜ =2109 (s, azide), 1736 cmÀ1 (s).
(CH2Cl2/PE 5:1) as
a
colourless liquid (1.37 g, 96%). 1H NMR
(400 MHz): d=7.55–7.52 (m, 2H; m-Ar), 7.42–7.37 (m, 3H; o,p-Ar), 6.45
ꢁ
(d, J=2.2 Hz, 1H; CH), 2.66 (d, J=2.3 Hz, 1H; C CH), 2.12 ppm (s,
3H; OAc).
General Procedure A—propargylic amination in the presence of the
ligand 5
Copper iodide (3.8 mg, 0.020 mmol) and 2,6-bisACTHNUTRGNEU[GN (4R,5S)-4,5-diphenyl-4,5-
dihydrooxazol-2-yl]pyridine (5, 12.5 mg, 0.024 mmol) were suspended in
methanol (1.4 mL). The mixture was stirred for 20 min before addition of
a solution of the propargylic acetate (0.20 mmol) in methanol (0.3 mL).
The suspension was cooled to À208C. After 10 min of stirring at À208C,
ACHTUNGTRENNUNG
(2R,3S)-3-Aminobutan-2-ol (31):[25] K2CO3 (excess, 8.3 g, 60 mmol) was
added to a solution of 30 (2.00 g, 12 mmol) in MeOH (120 mL). After
the system had been stirred for 2 h at room temperature, the MeOH was
evaporated. The residue was extracted with Et2O (3ꢃ25 mL). Evapora-
tion of the Et2O fractions gave a clear yellowish liquid (1.23 g, 89%),
which was further purified by flash chromatography (PE/EtOAc 4:1) to
afford the azido alcohol (1.22 g, 88%): [a]2D0 =+59 (c=1.0, CHCl3);
1H NMR (400 MHz): d=3.86–3.79 (m, 1H), 3.60–3.54 (m, 1H), 1.67 (brs,
1H; OH), 1.27 (d, J=6.8 Hz, 3H), 1.21 ppm (d, J=6.4 Hz, 3H);
13C NMR (101 MHz): d=70.2, 62.8, 18.4, 13.9 ppm; FTIR (film): n˜ =3371
(brs, OH), 2097 cmÀ1 (s, azide).
a
cooled solution of nucleophile (0.40 mmol) and DIPEA (139 mL,
0.80 mmol) in methanol (0.3 mL) was added. The suspension was stirred
until TLC analysis indicated total conversion of the propargylic acetate.
When the reaction was complete the mixture was allowed to warm to
room temperature and concentrated in vacuo. Silica gel chromatography
gave the pure propargylic amine.
General Procedure B—propargylic amination in the presence of ligands
8 or 12
See General Procedure A. In this procedure, the pybox ligands 8 or 12
were used instead of ligand 5. The reaction mixture was stirred at ambi-
ent temperature (18–258C) and the ligand dissolved in methanol, togeth-
er with the CuI, to form a clear red solution.
Pd/C (10%, w/w, 0.14 g) was added to a solution of the azido alcohol
(300 mg, 2.7 mmol) in MeOH (3 mL). After stirring for 5 h at room tem-
perature under H2 (balloon), the reaction mixture was filtrated over
celite and the celite was rinsed with some fresh MeOH. Subsequent
evaporation of the MeOH gave the amino alcohol 31 as a colourless oil
(0.18 g, 75%). 1H NMR (400 MHz): d=3.73–3.67 (m, 1H), 3.02–2.95 (m,
1H), 1.95 (brs, 3H; NH2/OH), 1.13 (d, J=6.4 Hz, 3H), 1.05 ppm (d, J=
6.6 Hz, 3H); 13C NMR (101 MHz): d=70.3, 62.8, 18.4, 13.9 ppm; FTIR
(film): n˜ =3400 cmÀ1 (brs, NH2/OH).
(S)-2-Methoxy-N-(oct-1-yn-3-yl)aniline (7a): General Procedure B was
followed. Compound 6a (34 mg, 0.20 mmol) was added to the catalyst so-
lution before addition of the o-anisidine/DIPEA mixture. After the mix-
ture had been stirred for 24 h, concentration and silica gel chromatogra-
phy (CH2Cl2/PE 1:1) afforded the product 7a as a colourless oil (35 mg,
76% yield, 66% ee): [a]2D0 =À85 (c=0.5, CHCl3). HPLC conditions: Chir-
alcel AD (4.6ꢃ250 mm), heptane/iPrOH 98:2, 1.0 mLminÀ1, l=254 nm:
General method for the synthesis of the non-commercially available
pybox ligands from amino alcohols[26,27]
1
5.7 min (major isomer) and 6.8 min (minor isomer). H NMR (400 MHz):
2,6-BisACHTUNGTRENNUNG[(4S,5R)-4,5-dimethyl-4,5-dihydrooxazol-2-yl]pyridine (12): The
d=6.93–6.89 (m, 1H), 6.82–6.72 (m, 3H), 4.34 (brs, 1H; NH), 4.10 (br,
amino alcohol 31 (180 mg, 2.0 mmol) was added to a suspension of di-
methyl pyridine-2,6-bis(carbimidate)[28] (32, 193 mg, 1.0 mmol) in CH2Cl2
(4 mL). The mixture was stirred at reflux for 18 h. After evaporation of
solvent, the residue was purified by flash chromatography (CH2Cl2 with
1% Et3N to CH2Cl2 with 1% Et3N and 1% MeOH) to afford the DiMe-
pybox (12) ligand as a white powder (196 mg, 72%): [a]2D0 =À172 (c=0.5,
ꢁ
1H; CH), 3.86 (s, 3H; OMe), 2.22 (d, J=2.0 Hz, 1H; C CH), 1.87–1.81
(m, 2H), 1.60–1.56 (m, 2H), 1.39–1.34 (m, 4H), 0.95–0.91 ppm (m, 3H;
CH3); 13C NMR (101 MHz): d =147.2, 136.5, 121.2, 117.6, 111.4, 109.7,
85.0, 70.6, 55.5, 45.2, 35.8, 31.6, 25.8, 22.7, 14.2 ppm; FTIR (film): n˜ =
3408 (w), 3290 (m), 2934 (s), 2860 (m), 1603 (m), 1513 (s), 1456 (m), 1428
5928
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Enantioselective Copper-Catalysed Propargylic Substitution
FULL PAPER
(m), 1248 (s), 1222 (s), 1030 cmÀ1 (m); HRMS (FAB+): m/z calcd:
232.1701 [M+H]+; found: 232.1697.
[7] a) Y. Nishibayashi, G. Onodera, Y. Inada, M. Hidai, S. Uemura, Or-
ganometallics 2003, 22, 873–876; b) Y. Inada, Y. Nishibayashi, S.
Uemura, Angew. Chem. 2005, 117, 7893–7895; Angew. Chem. Int.
Ed. 2005, 44, 7715–7717; c) H. Matsuzawa, Y. Miyake, Y. Nishibaya-
shi, Angew. Chem. 2007, 119, 6608–6611; Angew. Chem. Int. Ed.
2007, 46, 6488–6491; d) H. Matsuzawa, K. Kanao, Y. Miyake, Y.
Nishibayashi, Org. Lett. 2007, 9, 5561–5564.
General method for the oxidative removal of the anisidyl moiety
(S)-tert-Butyl 4-methylpent-1-yn-3-ylcarbamate (27): A solution of 7d
(197 mg, 0.97 mmol) in acetonitrile (2.5 mL) was added by syringe pump
over 30 min at room temperature to a solution of PhIACTHNUGTRENUNG(OAc)2 (1.25 g,
3.88 mmol) in methanol (10 mL). After the addition, the reaction mixture
was stirred for another 2 h, followed by addition of aqueous HCl (1.0m,
10 mL). The mixture was stirred for 1.5 h. Afterwards, the mixture was
extracted four times with CH2Cl2 (8 mL). The organic layers were back-
washed once with aqueous HCl (0.1m, 10 mL). The combined water
layers were neutralised by addition of solid K2CO3 and a solution of
Boc2O (635 mg, 2.9 mmol) in CH2Cl2 (10 mL) was added. The biphasic
mixture was basified to pH 11 by K2CO3 (s) addition and stirred for 17 h.
The layers were separated and the water layer was extracted once with
CH2Cl2 (10 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated to dryness. Silica gel column chromatography
(CH2Cl2) gave 27 in good yield (145 mg, 76% yield, 82% ee): [a]2D0 =À52
(c=0.5, CHCl3); lit.[13] ([a]D20 =À59.9, 96% ee); 1H NMR (400 MHz): d=
[8] a) R. J. Detz, M. M. E. Delville, H. Hiemstra, J. H. van Maarseveen,
Angew. Chem. 2008, 120, 3837–3840; Angew. Chem. Int. Ed. 2008,
47, 3777-3780; b) G. Hattori, H. Matsuzawa, Y. Miyake, Y. Nishi-
bayashi, Angew. Chem. 2008, 120, 3841–3843; Angew. Chem. Int.
Ed. 2008, 47, 3781–3783; c) G. Hattori, K. Sakata, H. Matsuzawa, Y.
Tanabe, Y. Miyake, Y. Nishibayashi, J. Am. Chem. Soc. 2010, 132,
10592–10608; d) G. Hattori, A. Yoshida, Y. Miyake, Y. Nishibaya-
shi, J. Org. Chem. 2009, 74, 7603–7607; e) G. Hattori, Y. Miyake, Y.
Nishibayashi, ChemCatChem 2010, 2, 155–158.
[9] Y. Imada, M. Yuasa, I. Nakamura, S. I. Murahashi, J. Org. Chem.
1994, 59, 2282–2284.
[10] a) M. Crucianelli, F. De Angelis, F. Lazzaro, L. Malpezzi, A. Volon-
terio, M. Zanda, J. Fluorine Chem. 2004, 125, 573–577; b) B. Jiang,
Y. G. Si, Angew. Chem. 2004, 116, 218–220; Angew. Chem. Int. Ed.
2004, 43, 216–218; c) G. S. Kauffman, G. D. Harris, R. L. Dorow,
B. R. P. Stone, R. L. Parsons, Jr., J. A. Pesti, N. A. Magnus, J. M. For-
tunak, P. N. Confalone, W. A. Nugent, Org. Lett. 2000, 2, 3119–3121;
d) M. A. Huffman, N. Yasuda, E. A. DeCamp, E. J. J. Grabowski, J.
Org. Chem. 1995, 60, 1590–1594; e) A. W. Patterson, J. A. Ellman,
J. Org. Chem. 2006, 71, 7110–7112; f) A. W. Shaw, J. S. de Solms,
Tetrahedron Lett. 2001, 42, 7173–7176; g) X. Y. Chen, X. L. Qiu,
F. L. Qing, Tetrahedron 2008, 64, 2301–2306.
ꢁ
4.71 (brs, 1H), 4.31 (brs, 1H), 2.24 (d, J=2.4 Hz, 1H; C CH), 1.94–1.85
(m, 1H), 1.45 (s, 9H; tBu), 0.98 ppm (d, J=6.8 Hz, 6H). Data correspond
with the literature.[13c]
Acknowledgements
[11] P. Aschwanden, C. R. J. Stephenson, E. M. Carreira, Org. Lett. 2006,
8, 2437–2440.
[12] P. Fang, X. L. Hou, Org. Lett. 2009, 11, 4612–4615.
[13] a) J. Jurczak, A. Golebiowski, Chem. Rev. 1989, 89, 149–164;
b) J. R. Hauske, P. Dorff, S. Julin, G. Martinelli, J. Bussolari, Tetrahe-
dron Lett. 1992, 33, 3715–3716; c) G. Reginato, A. Mordini, F. Mes-
sina, A. DeglꢀInnocenti, G. Poli, Tetrahedron 1996, 52, 10985–10996.
[14] A. Ito, R. Takahashi, Y. Baba, Chem. Pharm. Bull. 1975, 23, 3081–
3087.
[15] J. F. Traverse, A. H. Hoveyda, M. L. Snapper, Org. Lett. 2003, 5,
3273–3275.
[16] a) B. A. Sobin, F. W. Tanner, Jr., J. Am. Chem. Soc. 1954, 76, 4053;
b) S. Ishida, O. Yamada, F. Futatsuya, K. Ito, H. Yamamoto, K. Mu-
nakata, Proc. Int. Congr. IAMS 1st 1974, 3, 641–648.
The National Research School Combination-Catalysis (NRSC-C) is
gratefully acknowledged for financial support of this project. J. A. J. Gee-
nevasenꢀs help with NMR characterisation is greatly appreciated. J. W. H.
Peeters is gratefully acknowledged for mass spectroscopy analysis.
[1] For two illustrative examples of chemical transformations with al-
kynes, see: (Sonogashira reaction) a) K. Sonogashira, Y. Tohda, N.
Hagihara, Tetrahedron Lett. 1975, 16, 4467–4470; b) R. Chinchilla,
C. Nꢄjera, Chem. Rev. 2007, 107, 874–922; (copper-catalysed azide–
alkyne “click” reaction) c) V. V. Rostovtsev, L. G. Green, V. V.
Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708–2711; Angew.
Chem. Int. Ed. 2002, 41, 2596–2599; d) C. W. Tornøe, C. Christen-
sen, M. Meldal, J. Org. Chem. 2002, 67, 3057–3062.
[17] a) J. J. Beereboom, K. Butler, F. C. Pennington, I. A. Solomons, J.
Org. Chem. 1965, 30, 2334–2342; b) K. Butler, J. Org. Chem. 1968,
33, 2136–2141; c) M. Salmon, E. Diaz, F. Walls, F. Bol, Inst. Quim.
Univ. Nac. Auton Mex. 1969, 21, 7–65; d) J. P. Schaefer, P. F. Wheat-
ley, Chem. Commun. (London) 1967, 578–579; e) J. P. Schaefer, P. F.
Wheatley, J. Org. Chem. 1968, 33, 166–169; f) C. M. Wong, Can. J.
Chem. 1968, 46, 1101–1104.
[18] a) E. Battaner, D. Vasquez, Biochim. Biophys. Acta Nucleic Acids
Protein Synth. 1971, 254, 316–330; b) A. P. Grollman, J. Biol. Chem.
1967, 242, 3226–3233.
[2] a) N. Fusetani, M. Sugano, S. Matsunaga, K. Hashimoto, Tetrahe-
dron Lett. 1987, 28, 4311–4312; b) A. S. Thompson, E. G. Corley,
M. F. Huntington, E. J. J. Grabowski, Tetrahedron Lett. 1995, 36,
8937; c) J. L. Wright, T. F. Gregory, S. P. Kesten, P. A. Boxer, K. A.
Serpa, L. T. Meltzer, L. D. Wise, S. A. Espitia, C. S. Konkoy, E. R.
Whittemore, R. M. Woodward, J. Med. Chem. 2000, 43, 3408–3419.
[3] For recent reviews about the propargylic substitution, see: a) R. J.
Detz, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem. 2009,
6263–6276; b) Y. Miyake, S. Uemura, Y. Nishibayashi, ChemCatCh-
em 2009, 1, 342–356; c) N. Ljungdahl, N. Kann, Angew. Chem. 2009,
121, 652–654; Angew. Chem. Int. Ed. 2009, 48, 642–644; d) Kabalka
and Yao: G. W. Kabalka, M. Yao, Curr. Org. Synth. 2008, 5, 28–32.
[4] For reviews, see: a) B. M. Trost, D. L. Van Vrancken, Chem. Rev.
1996, 96, 395–422; b) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
103, 2921–2943; c) J. Tsuji, Palladium Reagents and Catalyst: Inno-
vations in Organic Synthesis, Wiley, Chichester, 1997, pp. 290–340.
[5] a) E. Keinan, E. Bosch, J. Org. Chem. 1986, 51, 4006–4016; b) J.
Tsuji, T. Mandai, Angew. Chem. 1995, 107, 2830–2854; Angew.
Chem. Int. Ed. Engl. 1996, 34, 2589–2612.
[19] a) Y. Hosoya, T. Kameyama, H. Naganawa, Y. Okami, T. Takeuchi,
J. Antibiot. 1993, 46, 1300–1302; b) O. Schwardt, U. Veith, C. Gas-
pard, V. Jꢆger, Synthesis 1999, 1473–1490.
[20] Racemic synthesis: a) C. M. Wong, J. Buccini, J. Te Raa, Can. J.
Chem. 1968, 46, 3091–3094; b) S. Oida, E. Ohki, Chem. Pharm.
Bull. 1968, 16, 2086–2087; c) C. M. Wong, J. Buccini, I. Chang, J. Te
Raa, R. Schwenk, Can. J. Chem. 1969, 47, 2421–2424; d) D. P. Schu-
macher, S. S. Hall, J. Am. Chem. Soc. 1982, 104, 6076–6080. Chiral
pool approach: e) I. Felner, K. Schenker, Helv. Chim. Acta 1970, 53,
754–763; f) J. P. H. Verheyden, A. C. Richardson, R. S. Bhatt, B. D.
Grant, W. L. Fitch, J. G. Moffat, Pure Appl. Chem. 1978, 50, 1363–
1383; g) J. G. Buchanan, K. A. MacLean, R. H. Wightman, J. Chem.
Soc. Perkin Trans. 1 1985, 1463–1470; h) H. Iida, N. Yamazaki, C.
Kibayashi, J. Org. Chem. 1986, 51, 1069–1073; i) T. Shono, N. Kise,
Chem. Lett. 1987, 697–700; j) H. H. Baer, M. Zamkanei, J. Org.
Chem. 1988, 53, 4786–4792; k) S. Jegham, B. C. Das, Tetrahedron
[6] a) A. J. M. Caffyn, K. M. Nicholas, J. Am. Chem. Soc. 1993, 115,
6438–6439; b) Y. Nishibayashi, H. Imajima, G. Onodera, S.
Uemura, Organometallics 2005, 24, 4106–4109; c) T. J. J. Mꢅller,
Eur. J. Org. Chem. 2001, 2021–2033; d) A. Netz, K. Polborn, T. J. J.
Mꢅller, J. Am. Chem. Soc. 2001, 123, 3441–3453; e) T. J. J. Mꢅller,
A. Netz, Tetrahedron Lett. 1999, 40, 3145–3148; f) M. R. Luzung,
F. D. Toste, J. Am. Chem. Soc. 2003, 125, 15760–15761.
Chem. Eur. J. 2011, 17, 5921 – 5930
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5929

J. H. van Maarseveen et al.
Lett. 1988, 29, 4419–4422; l) S. Takano, Y. Iwabuchi, K. Ogasawara,
Heterocycles 1989, 29, 1861–1864; m) R. Ballini, E. Marcantoni, M.
Petrini, J. Org. Chem. 1992, 57, 1316–1318; n) S. H. Kang, H. W.
Choi, Chem. Commun. 1996, 1521–1522; o) A. N. Hulme, E. M.
Rosser, Org. Lett. 2002, 4, 265–267; p) M. Y. Chang, S. T. Chen,
N. C. Chang, Heterocycles 2003, 60, 1203–1209; q) P. Q. Huang, X.
Zheng, ARKIVOC 2003, ii, 7–14; r) H. Gruza, D. Gryko, J. Jurczak,
ARKIVOC 2004, iii, 112–119; s) J. H. Kim, M. J. Curtius-Long,
W. D. Seo, Y. B. Ryu, M. S. Yang, K. H. Park, J. Org. Chem. 2005,
70, 4082–4087; with chiral auxiliaries or catalysts: t) A. I. Meyers, B.
Dupre, Heterocycles 1987, 25, 113–116; u) H. Takahata, Y. Banba,
M. Tajima, T. Momose, J. Org. Chem. 1991, 56, 240–245; v) Z. C.
Shi, G. Q. Lin, Tetrahedron Asymmetry 1995, 6, 2907–2910; w) P.
Delair, E. Brot, A. Kanazawa, A. E. Greene, J. Org. Chem. 1999,
64, 1383–1386; x) M. Ono, S. Tanikawa, K. Suzuki, H. Akita, Tetra-
hedron 2004, 60, 10187–10195; y) S. Kaden, M. Brockmann, H. U.
Reissig, Helv. Chim. Acta 2005, 88, 1826–1838.
[22] a) P. Crabbꢂ, H. Fillion, D. Andrꢂ, J. L. Luche, J. Chem. Soc. Chem.
Commun. 1979, 859–860; b) S. Searles, Y. Li, B. Nassim, M. T. R.
Lopes, P. T. Tran, P. Crabbꢂ, J. Chem. Soc. Perkin Trans. 1 1984,
747–751.
[23] a) H. Kakeya, M. Morishita, K. Kobinata, M. Osono, M. Ishizuka,
H. Osada, J. Antibiot. 1998, 51, 1126–1128; b) H. Kakeya, M. Mor-
ishita, H. Koshino, T. Morita, K. Kobayashi, H. Osada, J. Org.
Chem. 1999, 64, 1052–1053.
[24] a) J. D. Kim, I. S. Kim, C. H. Jin, O. P. Zee, Y. H. Jung, Org. Lett.
2005, 7, 4025–4028 and references cited therein; b) Review: A. Gra-
jewska, M. D. Rozwadowska, Tetrahedron: Asymmetry 2007, 18,
803–813; c) O. V. Singh, H. Han, Tetrahedron Lett. 2007, 48, 7094–
7098; d) E.-S. Lee, H. S. Yeom, J. H. Hwang, S. Shin, Eur. J. Org.
Chem. 2007, 3503–3507.
[25] W. Hartmann, H. G. Heine, Tetrahedron Lett. 1979, 20, 513–516.
[26] G. Desimoni, G. Faita, M. Guala, C. Pratelli, Tetrahedron: Asymme-
try 2002, 13, 1651–1654.
[27] M. K. Tse, S. Bhor, M. Klawonn, G. Anilkumar, H. Jiao, C. Dçbler,
A. Spannenberg, W. Mꢆgerlein, H. Hugl, M. Beller, Chem. Eur. J.
2006, 12, 1855–1874.
[28] P. Mꢅller, C. Bolꢇa, Helv. Chim. Acta 2001, 84, 1093–1111.
[29] B. I. Glꢆnzer, K. Faber, H. Griengl, Tetrahedron 1987, 43, 5791–
5796.
[21] A selection of recent papers: a) D. J. Gorin, F. D. Toste, Nature
2007, 446, 395–403; b) A. S. K. Hashmi, Angew. Chem. 2005, 117,
7150–7154; Angew. Chem. Int. Ed. 2005, 44, 6990–6993; c) A. Hoff-
mann-Rçder, N. Krause, Org. Biomol. Chem. 2005, 3, 387–391;
d) R. A. Widenhoefer, Chem. Eur. J. 2008, 14, 5382–5391; e) Special
Issue: “Gold—Chemistry, Materials and Catalysis,” Chem. Soc. Rev.
2008, 37, Issue 9.
Received: December 24, 2010
Published online: April 15, 2011
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