Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino Acids

Article abstract of DOI:10.1002/1615-4169(200201)344:1<70::AID-ADSC70>3.0.CO;2-1

Enantiomerically pure acetylene-containing α-amino acids were used as versatile starting materials for the synthesis of a variety of heterocycles via Pd-mediated cyclization reactions. Depending on the protecting group strategy, both the carboxylate and the amine function of the amino acids could participate in the cyclizations, thus giving rise to oxygen heterocycles (α-aminolactones) and nitrogen heterocycles (cyclic α-amino acid derivatives), respectively. Beside the straightforward cyclization, cyclization/cross-coupling reactions were also successfully carried out to provide the corresponding substituted cyclic amino acid derivatives.

Full text of DOI:10.1002/1615-4169(200201)344:1<70::AID-ADSC70>3.0.CO;2-1

FULL PAPERS
Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino
Acids
Larissa B. Wolf,a Kim C. M. F. Tjen,a Hefziba T. ten Brink,a Richard H. Blaauw,b
Henk Hiemstra,a Hans E. Schoemaker,a, c Floris P. J. T. Rutjesa, d,*
a
Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
SynBio B.V., P.O. Box 31070, 6503 CB Nijmegen, The Netherlands
b
Fax: ( ‡ 31)-24-365-3393, e-mail: info@synbio.com
c
DSM Research, Life Science Products, Department of Chemistry and Catalysis, P.O. Box 18, 6160 MD Geleen, The Netherlands
d
NSR Center, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax: ( ‡ 31)-24-265-3393, e-mail: rutjes@sci.kun.nl
Received September 29, 2001; Accepted November 8, 2001
Abstract: Enantiomerically pure acetylene-containing a-
amino acids were used as versatile starting materials for the
synthesis of a variety of heterocycles via Pd-mediated
cyclization reactions. Depending on the protecting group
strategy, both the carboxylate and the amine function of the
amino acids could participate in the cyclizations, thus giving
rise to oxygen heterocycles (a-aminolactones) and nitrogen
heterocycles (cyclic a-amino acid derivatives), respectively.
Beside the straightforward cyclization, cyclization/cross-
coupling reactions were also successfully carried out to
provide the corresponding substituted cyclic amino acid
derivatives.
Keywords: cross-coupling reactions; cyclic amino acids;
palladium catalysis; unsaturated amino acids.
Introduction
acetylenes. Representative for these types of reactions is the
intramolecular aminopalladation of alkyne 4, which upon
treatment with a Pd(II)-catalyst leads to the five-membered
cyclic imine 5 in good yield (Scheme 2).[5] In a similar fashion,
the corresponding six-membered imines can also be obtained.
Small functionalized heterocycles are important intermediates
in the synthesis of pharmaceuticals and natural products[1] and
may serve as ideal scaffolds for further functionalization via
combinatorial techniques.[2] Amongst a wide variety of existing
approaches, intramolecular palladium-catalyzed cyclizations
of heteronucleophiles onto alkynes provide a convenient
method for preparing such heterocycles.[3] Successful examples
of the latter include oxygen nucleophiles in the form of
carboxylic acids or alcohols which cyclize onto the triple bond
to give five- or six-membered lactones or cyclic ethers,
respectively, when treated with palladium catalysts.[4] As an
example, 4-pentynoic acid (1) cyclized to the unsaturated
lactone 3 upon exposure to PdCl2(MeCN)2 in the presence of a
catalytic amount of base (Scheme 1).[4d] The catalytic cycle
presumably involves electrophilic activation of the triple bond
by Pd(II), followed by nucleophilic attack of the carboxylate
function. The resulting vinylpalladium(II) intermediate 2
cannot in contrast with analogous cyclizations of olefins
undergo b-hydride elimination, but instead undergoes proton-
olysis of the Pd-C bond which leads to the formation of lactone
3 and regeneration of the Pd(II)-catalyst.
Me
H2N
PdCl2(MeCN)2
n-C7H15
H2O, MeCN
reflux
Me
N
n-C7H15
Scheme 2.
5 (70%)
4
In the presence of vinyl or aryl halides it is possible to
perform Pd(0)-catalyzed cyclization/cross-coupling reactions
in a single step.[6] Under these circumstances, the first step
involves the in situ formation of an organopalladium(II)
species [oxidative addition of the aryl halide onto the Pd(0)
species], which then activates the triple bond towards nucle-
ophilic attack. After ring closure (viz. 1), the resulting vinyl-
palladium(II) species 2 (X ˆ Ph) can undergo a reductive
elimination to form a newC-C bond
the aryl group is
Nitrogen nucleophiles such as amines and amides have also
been successfully applied in Pd-catalyzed cyclizations of
transferred trans with respect to the oxygen nucleophile giving
rise to 6 and regenerate the Pd(0)-catalyst (Scheme 3).[6e] In
Pd(OAc)2/2 PPh3
X
−Pd(0)
PdCl2(MeCN)2
−PdX2
−L2
2
PdL2
Ph
CO2H
CO2H
Et3N, TBAC, PhI
MeCN, 60 °C
−L2
O
O
(X = Ph)
O
O
O
O
Et3N, MeCN
reflux
1
2
3 (100%)
6 (82%)
1
Scheme 1.
Scheme 3.
70
¹ VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1615-4150/02/34401070 083 $ 17.50-.50/0
Adv. Synth. Catal. 2002, 344, No. 1

Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino Acids
FULL PAPERS
the literature, several other successful examples of this type of
reaction involving oxygen nucleophiles are known.[6]
( )n
CO2Me
a or b or c
d, e
( )n
CO2H
( )n
Analogously, these types of Pd-catalyzed coupling/cycliza-
tion reactions can also be carried out with nitrogen nucleo-
philes.[7] For example, tosylated carbamates,[8] tosylated
amides[9] and sulfonamides[10] are known to react with aryl
halides and vinyl triflates to give the corresponding cross-
coupled tosylated oxazolidinones, tosylated lactams and
sulfonylated piperidines, respectively, all containing an (E)-
configured double bond.
HN
P
P1
H2N
N
P
CO2H
(R)-13: (83%)
(S/R)-11: n = 1
(S/R)-12: n = 2
(S)-18: (94%)
n = 1, P = Ts
(R)-19: (72%)
n = 2, P = Ts
(R)-20: (59%)
n = 2, P = Ns
n = 1, P = Ts, P1 = H
(S)-14: (73%)
n = 2, P = Ts, P1 = H
(R)-15: (83%)
n = 1, P = Boc, P1 =
H
Inversely, in the group of Hiemstra acetylene-substituted
lactams and oxazolidinones (viz. 7) were cyclized under similar
conditions to afford the corresponding bicyclic (Z)-substituted
enamides (Scheme 4).[11] A plausible reaction mechanism that
explains these contradictary results involves the intermediate
8, in which palladium(II) coordinates to the carbamate nitro-
gen atom before the nitrogen-carbon bond is formed. This
intramolecular activation of the triple bond is then followed by
nucleophilic attack of the nitrogen from within the coordina-
tion sphere of palladium to initially give the bicyclic species 9.
Reductive elimination of Pd(0) finally gives rise to the (Z)-
configured olefin 10.
(S)-16: (91%)
n = 1, P = P1 = Phth
rac-17: (91%)
n = 2, P = P1 = Phth
Scheme 5. Reagents and conditions: 13, 14 ! 15, 16 (a) TsCl
(1.4 equiv), 1 M NaOH (1.1 equiv), rt, 16 h; 13 ! 17 (b) di-tert-
butyl dicarbonate (1.1 equiv), NaHCO3 (2 equiv), dioxane/H2O,
reflux, 4 h; 13, 14 ! 18, 19 (c) phthalic anhydride (1 equiv), H2O,
microwave (600 W, 5 min); (d) SOCl2 (2 equiv), MeOH, reflux;
(e) TsCl or NsCl (2 equiv), Et3N (5 equiv), CH2Cl2, rt, 16 h.
enantiopurity according to chiral HPLC analysis (Scheme 5).
Additionally, rac-12 was converted to racemic phthalimide 17.
Conversely, the enantiomerically pure amidopalladation
precursors 18 20 were obtained by esterification using thionyl
chloride (2 equiv) in MeOH at reflux temperature and
subjection of the crude residue to Et3N (5 equiv) and p-
toluenesulfonyl chloride (TsCl, 2 equiv) or p-nitrobenzenesul-
fonyl chloride (NsCl, 2 equiv) in CH2Cl2. Alternatively, the
crude esterified residue was dissolved in pyridine and treated
with TsCl or NsCl to give the same products in similar yields.
The palladium-catalyzed cyclizations with the carboxylic
acid as the nucleophile are shown in Table 1. Subjection of the
N-protected amino acids 13 17 to a mixture of 10 mol % of a
Pd(II) catalyst and 15 mol % of Et3N in various solvents at
different temperatures led to five- and six-membered lactones.
The tosylamide (R)-13 was cyclized in a satisfactory yield of
66% at 708C (entry 1). Changing the catalyst to Pd(OAc)2 led
to amuch faster reaction at room temperature in the same yield
(66%, entry 2). A single attempt to use an inorganic base
(K2CO3) appeared fatal to the reaction (entry 3). Subjection of
Pd(PPh3)4,
O
O
NH
TBAC, PhI
K2CO3, MeCN
reflux, 3 h
N
O
O
H
Ph
10 (60%)
7
−Pd(0)
O
O
N
L
N
H
Pd
Pd
Ph
O
O
L
L
Ph
9
8
Scheme 4.
The precedence of these literature examples, combined with
the relatively facile biocatalytic access to enantiomerically
pure acetylene-containing amino acids developed in our group
in collaboration with DSM (Geleen, The Netherlands)[12]
inspired us to use these trifunctional amino acids[13] in similar
Pd-catalyzed reactions. Logically, these amino acids contain-
ing both an oxygen and a nitrogen nucleophile might upon
suitable protection give access to a variety of enantiomerically
pure substituted lactones, as well as to the corresponding
nitrogen heterocycles.[14]
Table 1.
( )n
CO2H
10% of catalyst
base, solvent , T
( )n
P1
P1
O
N
P
N
P
O
13-17
21-25
T
time
yield
(%)[a]
Results and Discussion
entry
catalyst
base
substrate
solvent
product
(°C) (h)
Et3N
Et3N
THF
THF
70 16
(R)-21
(R)-21
66
66[b]
1
2
3
4
5
6
7
(R)-13 Pd(MeCN)2Cl2
(R)-13 Pd(OAc)2
(R)-13 Pd(MeCN)2Cl2
In order to obtain the cyclization precursors, the enantiomeri-
cally pure amino acids 11 and 12[12] were protected with
different protecting groups. In case of the oxypalladation
precursors, the nitrogen atom was protected according to
literature procedures[15] involving either tosylation or acylation
in an aqueous medium or irradiation in a microwave in the
presence of phthalic anhydride.[16] In all cases, the N-protected
amino acids 13 16 were obtained in good yields without loss of
rt
80
rt
1
6
K2CO3 DMF
0
Et3N
Et3N
THF
THF
2
(R)-22
(S)-23
rac-24
rac-25
63
42[b]
(R)-15
(S)-16
Pd(OAc)2
Pd(OAc)2
rt
1.5
Et3N MeCN 60 16
Et3N THF
60
32
rac-14 Pd(MeCN)2Cl2
rac-17 Pd(OAc)2
5
24
[a] Isolated yields after column chromatography.
[b] ee >97% according to 1H NMR using Eu(hfc)3 as the shift reagent in CDCl3.
Adv. Synth. Catal. 2002, 344, 70 83
71

Larissa B. Wolf et al.
FULL PAPERS
the Boc-protected acid 15 to similar conditions resulted at
room temperature in 22 in 63% (entry 4). Likewise, the
phthalimide-protected amino acid 16 cyclized in a lower yield.
In contrast with the five-membered rings, the six-membered
lactones 24 and 25 were obtained in somewhat disappointing
yields (entries 6 and 7), which is probably due to the lower
tendency of Pd to react in a 6-exo-fashion.[4d,6f] The ee of 21 and
formation of a six-membered lactone appeared difficult as
indicated by the relatively lowyield of 31 (31%, entry 9).
In summary, the yields of the cross-coupling reactions turned
out to be somewhat disappointing; this could either be due to a
lower reactivity of the amino acids towards oxypalladation
reactions compared to −regular× carboxylic acids, but on the
other hand also to the relative instability of the enol esters that
are formed. The fact that analysis by TLC always showed
complete conversion and no starting material was recovered in
these reactions seems to support the latter hypothesis.
1
23 was determined via H NMR experiments using a chiral
shift reagent [Eu(hfc)3 in CDCl3] showing an ee higher than
97%, which led us to conclude that virtually no racemization
occurred in these cyclization reactions.
The Pd-catalyzed cyclizations with the enantiopure prop-
argylglycine-derived precursor (S)-18 are shown in Table 3.
The anticipated five-membered endocyclic enamide (S)-32
was formed in 76% yield using 10 mol % of Pd(PPh3)4 and
5 equiv of K2CO3 in DMF at 808C (entry 1). Unfortunately,
partial racemization occurred under these conditions leading
to an enantiopurity of the product of only 33%. To circumvent
the undesired racemization, catalyst, solvent, reaction temper-
ature and the base were varied. By changing the solvent from
DMF to THF and the catalyst from Pd(PPh3)4 to Pd(OAc)2/
2PPh3, the ee increasedfrom 91% at 608C (entry 2)to >99% at
408C (entry 3), albeit that the yield dropped to 48%. Adding a
smaller amount of base, i.e., one equiv instead of five equiv,
resulted in a dramatic lowering of the yield (18%), while still
partialracemization was observed (entry 5). Changing the base
to the less basic salt NaHCO3 did not improve the yield either
(entry 6). When using the organic base Et3N, no cyclization
product was observed at all (entry 7). In addition, the influence
of different ligands was studied. Several combinations of
catalysts and ligands with different bite angles[18] were
screened, but none of these combinations had a dramatic
influence on the yield or the reaction time. The chloride
sources were also varied to study their effect on the yield and
the reaction rate at 408C. The use of TBAC led to an
In addition to these reactions, other cyclization reactions
were carried out in the presence of various aryl halides or a
vinyl triflate to introduce an organic substituent in the
cyclization step, which are summarized in Table 2. The general
reaction conditions involved 10 mol % of a Pd(0) catalyst,
Et3N (5 equiv), tetrabutylammonium chloride (TBAC,
2 equiv) and the aryl halide (2 equiv) in MeCN at 608C.
When tosylamide (R)-13 was reacted under these conditions
neither cyclization nor introduction of the aryl group was
observed. Although the starting material had disappeared,
amidopalladation could be excluded on the basis of NMR
analysis. More gratifyingly, the Boc-protected amino acid (R)-
15 reacted under similar conditions to the cross-coupled
lactone (R)-27 in a moderate yield of 44%, without detectable
racemization. The phthalimide-protected amino acid (S)-16
was treated with iodobenzene and p-iodoanisole to afford the
lactams 28 and 29, respectively, in similar yields (entries 3 6).
Unfortunately, in all these cases complete racemization
occurred at the temperature required for cyclization. Appa-
rently, the phthalimide protecting group renders the a-proton
of the amino acid sufficiently acidic to beprone to racemization
under the slightly basic reaction conditions. No cyclization
occurred with p-nitroiodobenzene (entry 7), which was prob-
ably due to the decreased reactivity of the organopalladium
intermediate. Treatment of (S)-16 with vinyl triflate 26[17]
afforded 30, albeit in only 23% (entry 8). Furthermore, in
analogy with the aforementioned oxypalladation reactions,
Table 3.
10% of catalyst
CO2Me
HN
Ts
CO2Me
N
base (5 equiv)
solvent, T
O
PPh2
PPh2
Table 2.
Ts
xantphos
R
(S)-18
(S)-32
10% of catalyst
RX, Et3N
( )n
yield
ee
T
time
(h)
( )n
entry
catalyst
base
solvent
(%)[a] (%)[b]
(°C)
P1
P1
O
TBAC
MeCN, 60 °C
N
P
CO2H
N
P
1
2
Pd(PPh3)4
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(PPh3)4
K2CO3
K2CO3
K2CO3
K2CO3
DMF
THF
THF
THF
THF
80
60
40
40
60
60
60
60
60
60
60
40
40
60
80
3.5
4
76
65
33
91
O
13, 15-17
27-31
3
48
48
24
24
24
3
48 >99
36
4
yield
RX
PhI
entry
catalyst
substrate
time (h) product
(%)[a]
c
5
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/xantphos
Pd2(dba)3/xantphos
Pd(OAc)2/dppe
Pd(OAc)2/dppb
K2CO3
18
18
0
84
61
6
NaHCO3 THF
1
2
3
4
5
6
7
8
(R)-13
(R)-15
(S)-16
(S)-16
(S)-16
(S)-16
(S)-16
(S)-16
Pd(PPh3)4
2
0
44[b]
43
41
18
41
0
7
Et3N
THF
THF
THF
THF
THF
THF
THF
DMF
THF
Pd(OAc)2/2PPh3
Pd(PPh3)4
PhI
PhI
(R)-27
28
6
5
8
K2CO3
K2CO3
K2CO3
K2CO3
66
64
44
40
64
26
12
25
9
25
4
Pd(OAc)2/2PPh3
Pd(PPh3)2Cl2
Pd(PPh3)4
PhI
28
5
10
11
PhI
5
28
21
24
48
5
p-MeOC6H4I
p-NO2C6H4I
24
16
16
29
12 Pd(OAc)2/2PPh3/TBAC K2CO3
89
Pd(PPh3)4
13
14
15
Pd(OAc)2/2PPh3/LiCl
Pd(OAc)2
K2CO3
K2CO3
K2CO3
Pd(PPh3)4
30
31
23
tBu
OTf
26
5.5
9
rac-17
Pd(OAc)2/2PPh3
PhI
5
31
[a] Isolated yields after column chromatography.
[a] Isolated yields after column chromatography.
[b] The geometry of the (E)-double bond was proven via 1H NMR NOE experiments.
[b] The ee was determined by chiral HPLC (Chiralpak OD; eluent: 20% IPA/heptane).
[c] One instead of five equiv of base was added.
72
Adv. Synth. Catal. 2002, 344, 70 83

Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino Acids
FULL PAPERS
improvement of the yield to 64%, but again significant
racemization occurred (entry 12). Inversely, the use of LiCl
did not result in any improvement (entry 13). Conducting the
reaction under ligandless conditions with only Pd(OAc)2
present resulted in a disappointing yield of only 12%.
reaction, the products were shown to have completely retained
their enantiopurity with the aid of chiral HPLC. When 5 equiv
of iodobenzene were added during the reaction, the yield
improved to 90% (entry 3). A possible explanation is that the
iodobenzene reacts with the Pd(0)-catalyst to in situ generate
an organopalladium(II) catalyst that is more reactive towards
the triple bond. As long as there is no TBAC present, reductive
elimination to form the corresponding phenyl-substituted
cross-coupled product does not occur (see also the mechanistic
discussion).
By changing the catalyst or the ligands, comparable yields
were obtained; remarkably, when dppb, xantphos and P(o-tol)3
were used as the ligands, the isomerized enamide (R)-34 was
obtained after column chromatography (entries 5 7). How-
ever, from 1H NMR data of the crude product it was apparent
that the isomerization took place during column chromatog-
raphy.
Analogous to previous examples, the combination of a
Pd(II) catalyst with Et3N as a base did not give any product
(entry 9). With Cs2CO3 as the base, (R)-33 was formed in a
small amount (entry 11). Without a metal catalyst, the cyclized
product was found in 12% (entry 12), which is in line with the
results described in Table 3. Finally, the homopropargylglycine
derivative (R)-20 containing the more easily removable Ns-
protecting group cyclized in satisfactory yields to (R)-35
(entries 13 and 14). As before, the addition of iodobenzene
resulted in an improved yield (difference between entries 13
and 14).
Similar Pd-catalyzed cyclizations were also carried out in the
presence of aryl halides and vinyl triflates to introduce an
organic substituent in the cyclization step (Table 5). The
enantiomerically pure Ts- and Ns-protected amino acids (R)-
19 and (R)-20, respectively, were subjected to 10 mol % of a
Pd(0) catalyst, TBAC (1 equiv), an aryl halide or a vinyl triflate
(5 equiv) and K2CO3 (5 equiv). When the reaction was carried
out in DMF and iodobenzene was added as the aryl halide,
beside (R)-37, a small amount of the undesired non-arylated
cyclized product (R)-33 was found. In MeCN, however, the
cross-coupled product (R)-37 was selectively formed in 74%
(entry 2) without detectable racemization. Coupling with p-
nitroiodobenzene and p-iodoanisole resulted in the cross-
coupled products (R)-38 and (R)-39 in reasonable yields.
Reaction with the less reactive p-bromoanisole resulted in the
same product albeit in a significantly lower yield of 22%
(entry 5). The range of coupling reagents was extended to vinyl
triflates (viz. 26 and 36),[22] which resulted in the coupled
products (R)-40 and (R)-41 (entries 6 and 7). Changing from
the Ts to the Ns-protecting/activating group resulted in a high
yield and excellent selectivity using standard conditions in
MeCN at a lower temperature (entry 8). On the other hand,
poor selectivity was observed when the solvent or the ligands
were changed. Apparently, the CC-bond formation through
reductive elimination is slower with these ligands.
Finally, without a Pd-catalyst present, the cyclization also
proceeded to afford product 32 in a yield of 25% (entry 15). In
the literature, several examples of such types of cyclizations
without using a transition metal catalyst have been published.
Examples include the cyclization of acetylenic amines (neat at
180 2008C),[19] the cyclization of acetylenic amides using
TBAFas the base at 808C[20] and the cyclization of amides using
NaOEt in refluxing EtOH[21] to provide the corresponding
cyclic enamides. Presumably, the base acts to generate a more
nucleophilic nitrogen anion, and then gives rise to a cyclo-
isomerization. However, in order to obtain acceptable yields in
our reactions the cyclizations have to be enhanced through
palladium(II) activation of the triple bond.
Not shown in Table 3 are cyclizations that were carried out
with several other protecting groups at the nitrogen atom
under the standard conditions. Precursors activated as an
amide (e.g., acetyl) or a carbamate (Boc, CO2Me) were
subjected to these conditions, but all of them failed to give
the desired cyclized product. Apart from the tosyl group, only a
nosyl-protected compound gave cyclized material under the
optimized conditions albeit in the very lowyield of 8%.
A similar set of reactions was carried out using the
enantiopure homologous precursors (R)-19 and (R)-20 of
which the results are summarized in Table 4. A satisfactory
yield of the five-membered ring (R)-33 containing an exocyclic
double bond was obtained upon subjection of (R)-19 to the
standard conditions in THF at 608C (entries 1 and 2). In both
cases, no (partial) racemization was observed during the
Table 4.
10% of
catalyst
CO2Me
CO2Me
HN
P
CO2Me
N
N
P
base
THF, 60 °C
Ts
(R)-19
(R)-20
(R)-33: P = Ts
(R)-35: P = Ns
(R)-34: P = Ts
time
(h)
yield
(%)[a]
reactant
entry
catalyst
base
product
K2CO3
K2CO3
33
33
33
33
34
34
34
33
64[c]
74[c]
90
1
2
19
19
19
19
19
19
19
19
19
19
19
19
20
20
Pd(PPh3)4
1
1
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3/5PhI
Pd(OAc)2/dppe
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N[b]
Et3N[b]
Cs2CO3
K2CO3
K2CO3
K2CO3
3
1
74
4
1
70[d]
60[d]
43
5
Pd(OAc)2/dppb
1
6
Pd(OAc)2/xantphos
Pd(OAc)2/2P(o-tol)3
Pd2(dba)3/2PPh3
PdCl2(MeCN)2
1.5
1
7
54
8
1
0
9
5
33
34
33
35
35
<5
10
11
12
13
14
Pd(PPh3)4
7
4
Pd(OAc)2/2PPh3
1
12
5
The double bond geometry of (R)-37 was unambiguously
48
Pd(OAc)2/2PPh3
1
1
proven by H NMR NOE studies which clearly showed the
75
Pd(OAc)2/2PPh3/5PhI
0.5
(E)-configuration. Figure 1 summarizes the NOE-enhance-
ments of the different protons. Especially the enhancement of
the aromatic protons upon irradiation of the vinylic proton was
diagnostic for proving the (E)-geometry.
[a] Isolated yield after column chromatography.
[b] One instead of five equiv of base was added.
[c] The enantiopurity (>98%) was determined by chiral HPLC (Chiralpak OD; eluent:
20% IPA/heptane).
[d] Isolated as a mixture of 33:34; 1:8 (entry 5), 33:34; 1:10 (entry 6).
Adv. Synth. Catal. 2002, 344, 70 83
73

Larissa B. Wolf et al.
FULL PAPERS
Table 5.
Both the TBS-protected and the unprotected amino alcohols
were subjected to the aforementioned amidopalladation con-
ditions of which the results are summarized in Table 6. Amino
alcohol (R)-43 cyclized in a 5-endo fashion to the five-
membered enamide in a lowyield (entry 1). When the
homologous alcohol (S)-44 was subjected to similar conditions,
the yield of the cyclized product improved to 55% (entry 2). A
possible explanation for the increase of yield is the stability of
the product; the endocyclic enamide readily decomposed
under the reaction conditions and during work-up. Under
ligandless conditions [Pd2(dba)3] even higher yields were
obtained (entry 3). Furthermore, using the TBS-protected
amino alcohols (R)-45 and (S)-46 (entries 4 and 5) somewhat
higher yields were obtained. Surprisingly, the best result was
obtained at room temperature (entry 6); although the reaction
was rather slow, the yield (90%) was excellent. This might be a
result of the fact that the formed enamide is more stable at
room temperature than at 608C.
The cyclization/coupling reaction of the unprotected alcohol
(S)-44 with iodobenzene did only result in trace amounts of the
cyclized product. In contrast, the TBS-protected alcohol (S)-46
reacted in high yield (82%) to the desired product (S)-52
(entry 8). When this reaction was carried out at room temper-
ature under the same conditions, cyclization did occur, but no
CC-coupling took place and the only product that was isolated
was the cyclic product (S)-50 (entry 9). Apparently, at this
temperature protonolysis of the intermediate organopalladi-
um intermediate is faster than reductive elimination.
10% of
catalyst
+
R
CO2Me
CO2Me
RX, TBAC
N
N
HN
P
CO2Me
K2CO3
P
P
MeCN, T
A
B
(R)-37-41: P = Ts
(R)-42: P = Ns
(R)-19
(R)-20
(R)-33: P = Ts
(R)-35: P = Ns
T
time ratio[a] prod- yield[b] ee[c]
entry
reactant
RX
catalyst
(°C) (h)
A:B uct (%) (%)
[d]
1
2
3
4
5
6
7
8
9
19
19
PhI
PhI
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
80
1
83:17
>99
37
37
38
39
39
40
41
42
42
42
42
42
42
53
74
59
58
22
55
13
80
62
57
17
59
19
82 2.5 100:0
82 0.6 100:0
19 p-NO2C6H4I
95
97
19 p-MeOC6H4I Pd(PPh3)4
19 p-MeOC6H4Br Pd(PPh3)4
82
82
82
82
2
2
1
1
100:0
100:0
100:0
100:0
19
19
20
20
26
Pd(PPh3)4
Pd(PPh3)4
>99
>99
36
OTf
Bu
PhI
PhI
PhI
PhI
PhI
PhI
Pd(PPh3)4
60 1.5 100:0
100:0
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/dppe
Pd(OAc)2/dppb
60
1
[e]
10 20
11 20
12 20
13 20
60 3.5 91:9
[e]
60 0.5 66:33
60
4
2
93:7
Pd(OAc)2/xantphos 60
25:75
[a] In entries 1 and 10-13, the products were isolated as mixtures of which the
ratio was determined on the basis of 1H NMR spectra of the crude mixtures.
[b] Isolated yield after column chromatography.
[c] The ee was determined by chiral HPLC (Chiralpak OD; eluent: 20%
IPA/heptane)
[d] The reaction was carried out in DMF.
At first sight, there is no significant difference between the
cyclizations of the amino esters and the amino alcohols. It is
clear that the reactions with the protected alcohols proceed in
higher yields than the unprotected ones. Furthermore, from the
latter cyclizations it is apparent that the alcohol itself is not
sufficiently nucleophilic to effect cyclization. This might be due
to the fact that the alcohol is not deprotonated under the mildly
basic conditions, which is the case for the corresponding
carboxylic acids.
[e] The reaction was carried out in THF.
7.6%
H
3.1%
H
7.8%
H
Ph
CO2Me
N
H
9.3%
Ts
6.5%
(R)-37
Figure 1. 1H NMR NOE data of enamide (R)-37.
The mechanism of the oxypalladation reactions follows what
is known from literature experiments and is already mentioned
Table 6.
In order to study the influence of the ester group on the
amidopalladation reactions, the enantiopure amino acids were
converted into the corresponding (protected) amino alcohols
(Scheme 6). The Ts-protected amino acids (R)-13 and (S)-14
were reduced with LiAlH4 (4 equiv) following a literature
procedure.[23] The resulting alcohols (R)-43 and (S)-44 were
without further purification protected using TBSCl (1.2 equiv)
and imidazole (2.5 equiv) in DMF[24] to give (R)-45 and (S)-46
in good overall yields without loss of enantiopurity.
10 mol%
of catalyst
( )n
Ph
RX, base
THF, T
N
N
N
HN
Ts
43-46
OR
Ts
OR
OR
Ts
Ts
OR
47: R = H
48: R = TBS 50: R = TBS
49: R = H
51: R = H
52: R = TBS
T
time prod- yield
(h)
entry
reactant
RX
catalyst
Pd2(dba)3
base
(°C)
uct (%)[a]
60
60[b]
60
7
1
2
3
4
5
6
7
8
9
(R)-43
(S)-44
(S)-44
(R)-45
(S)-46
(S)-46
(S)-44
(S)-46
(S)-46
K2CO3
K2CO3
(R)-47 16
(S)-49 55
(S)-49 78
(R)-48 28
(S)-50 74
(S)-50 90
(S)-51 <5
(S)-52 82
(S)-50 67
Pd(OAc)2/2PPh3
Pd2(dba)3
3.5
1.5
4.5
25
48
16
5.5
48
K2CO3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
80[b]
K2CO3
TBSCl
( )n
CO2H
( )n
CH2OH
( )n
HN CH2OTBS
LiAlH4
60
imidazole
K2CO3
rt
K2CO3
HN
HN
Ts
THF, rt
DMF, 35 °C
60
K2CO3/TBAC
K2CO3/TBAC
K2CO3/TBAC
PhI
2.5 h
Ts
Ts
PhI
PhI
Pd(PPh3)4
Pd(PPh3)4
60
rt
(R)-13: n = 1
(S)-14: n = 2
(R)-43: n = 1
(S)-44: n = 2
(R)-45: n = 1 (80%)
(S)-46: n = 2 (90%)
[a] Isolated yield after column chromatography.
[b] The reaction was carried out in DMF.
Scheme 6.
74
Adv. Synth. Catal. 2002, 344, 70 83

Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino Acids
FULL PAPERS
Pd(PPh3)4, PhI
CO2Me
Ph
CO2Me
N
N
CO2Me
HN
Ts
CO2Me
N
Ts
Ts
TBAC, K2CO3
MeCN, reflux
Ts
33
32
19
38
H
Pd
L2
H
CO2Me
Pd
L2
CO2Me
N
N
Ph
Ts
XL
Ts
+L2
+L2
Pd
Ph
Pd
56
54
−HX
L2
CO2Me
N
HN
CO2Me
+L
PdL4
Ts
Ts
57
58
−L2
−L2
Scheme 8.
Pd
N
CO2Me
H
Pd
N
CO2Me
H
L2 Ts
L2 Ts
55
53
In case of the coupling/cyclization reactions, the latter
mechanism also operates and is shown in Scheme 8. Again,
phenylpalladium(II) is generated in situ via oxidative addition
of palladium(0) into the aryl halide bond and complexes to the
triple bond to give the p-complex (57). The acetylene is now
electrophilic enough for nucleophilic attack of the (deproto-
nated) nitrogen atom to give the corresponding vinylpalladium
intermediate (58). This intermediate undergoes reductive
elimination to regenerate Pd(0) and give the cross-coupled
products.
The addition of TBAC to the reaction mixture appeared
essential to effect the reductive elimination process. Without
TBAC no cross-coupled product was observed, but instead
only the cyclized product 33. The beneficial influence of
quaternary ammonium chlorides on Pd-catalyzed reactions
has been investigated by Arcadi[6e] and Jeffery.[28] A possible
effect is a halogen exchange between the in situ formed
PhPdI(PPh3)2 species and TBAC to generate the more reactive
intermediate PhPdCl(PPh3)2. On the other hand, it cannot be
ruled out that TBAC simply might serve as a phase-transfer
catalyst, increasing the amount of base in the reaction.
In order to further explore the possibilities of the cyclic
enamides, different methods to functionalize the double bond
were investigated. A first method involved reduction of the
enamide (R)-35 to the saturated proline derivative 60 via the
intermediate N-sulfonyliminium ion 59 (Scheme 9).[29] This
was achieved using a mixture of trifluoroacetic acid and
triethylsilane to give the proline derivative 60 in 32% as a 2:1
mixture of diastereoisomers. Unfortunately, we were unable to
identify the relative configuration of the major isomer.
The enamides (R)-37 and (R)-42 were subjected to identical
conditions affording (R)-61 in good yield (88%, 10:1 mixture
of diastereoisomers) and (R)-62 in a somewhat lower yield
(35%, 10:1 mixture of isomers). The increased selectivity
HN
Ts
CO2Me
HN
Ts
CO2Me
19
18
Scheme 7.
in the introduction. Therefore, we will mainly focus on the
mechanism of the amidopalladation reactions, which showed
some remarkable features. The most striking observation was
that the use of Pd(0) catalysts resulted in the formation of the
cyclization products, while Pd(II) is required as an intermedi-
ate. It is our hypothesis that the reaction starts with oxidative
addition of Pd(0) into the NH-bond to form a Pd-H species
(viz. structures 53 and 55 in Scheme 7). Then, intramolecular
insertion of the triple bond can take place, which depending on
the chain length can result in a vinylpalladium species that
either contains an endocyclic (54) or an exocyclic (56) double
bond. Eventually, reductive elimination of the Pd-H inter-
mediate will provide the unsubstituted enamides. To the best of
our knowledge, the activation of Pd(0) via oxidative addition
into the sulfonamide NH has not been reported previously in
the literature. On the other hand, weak acids have been used to
react in such a manner with Pd(0) (e.g., HCO2H and
CH3CO2H),[25] and more recently even malonitriles have
been reported to undergo oxidative addition of Pd(0) into
the acidic CH-bond.[26] We assume that a similar reaction is also
possible with the relatively acidic NH bond, which then also
explains that the reaction does not proceed with the less acidic
carbamates and amides. Furthermore, we believe that the
latter observation favors the proposed mechanism over the
previously reported mechanism,[27] involving insertion in the
acetylenic CH-bond, which does not account satisfactorily for
the difference in reactivity between the carbamates and the
sulfonamides.
It is possible, however, that more than one mechanism is
operating at the same time. For instance, the reaction also
proceeds in the presence of Pd(II) salts, although in lower
yields. This might be due to the difference in reactivity between
the Pd-H intermediate (53 and 55) and an intermediate that
contains an acetate as the counterion.
Similarly, in the presence of an in situ generated phenyl-
palladium(II) species, the reaction results in a higher yield
which might be due to the presence of the aryl group on the
palladium.
H
TFA
Et3SiH
CO2Me
CO2Me
CO2Me
N
N
N
CH2Cl2
0 °C → rt
1 h
Ns
Ns
Ns
60 (32%)
2:1 mixture of isomers
(R)-35
59
Scheme 9.
Adv. Synth. Catal. 2002, 344, 70 83
75

Larissa B. Wolf et al.
FULL PAPERS
compared to the reduction of 35 was probably a result of the
steric bulk of the larger phenyl group. The reaction with the Ns-
protecting group took significantly longer due to its stronger
electron-withdrawing properties and therefore more difficult
formation of the N-sulfonyliminium ion. The long reaction
time was probably also the main reason for the lower yield.
Despite the fact that extensive NOE-experiments were carried
out with product (R)-62, the configuration of the major isomer
could not be unambiguously determined (Scheme 10).
Conclusions
In this article, several types of palladium-catalyzed cyclization
reactions with different acetylene-containing amino acids are
detailed. Depending on the protection of the amine or the
carboxylic acid function, either the nitrogen or the oxygen
could act as a nucleophile to form nitrogen- or oxygen-
heterocycles, respectively. In most cases, the yield of the
cyclization(/coupling) reactions was satisfactory and the enan-
tiopurity of the starting material was retained in the product.
The nitrogen appeared a more useful and efficient nucleophile
than the oxygen atom, leading to a larger variety of cyclization
products. The cyclic enamides and enol ethers that were
formed in these reactions were generally not very stable and
therefore partially responsible for the moderate yields. A few
methods to derivatize these products were investigated, but
were abandoned due to the reluctance of the resulting cations
to undergo further substitution.
TFA
Et3SiH
Ph
Ph
CO2Me
CO2Me
N
P
N
P
CH2Cl2
0 °C → rt
(R)-37: P = Ts
(R)-42: P = Ns
61: P = Ts (88%, 10:1)
62: P = Ns (35%, 10:1)
Scheme 10.
Straightforward hydrogenation of the enamide function
using Pd on carbon under a hydrogen atmosphere in the
presence of a catalytic amount of base led to 61 (major isomer
appeared identical to the major isomer in the previous
reactions on the basis of NMR data), albeit in a lower yield
and significantly lower selectivity (Scheme 11). In this reaction
a small amount of ketone 63 was also isolated, but the yield was
not determined. Without the base, the hydrolysis product 63
was the only isolated product.
Experimental Section
General Information
All reactions were carried out under an inert atmosphere of dry nitrogen,
unless stated otherwise. Standard syringe techniques were applied for
transfer of Lewis acids and dry solvents. Infrared (IR) spectra were obtained
from KBr pellets or neat, using a Bruker IFS 28FT spectrometer and
wavelengths (n) are reported in cmÀ1. Proton nuclear magnetic resonance
(1H NMR) spectra were determined in CDCl3 (unless stated otherwise)
using a Bruker AC 200 (200 MHz) and a Bruker ARX 400 (400 MHz)
spectrometer. The machines were also used for 13C NMR (APT) spectra
(50 MHz and 100 MHz) in CDCl3 (unless stated otherwise). Chemical shifts
(d) are given in ppm downfield from tetramethylsilane. Mass spectra and
accurate mass measurements were carried out using a JEOL JMS-SX/SX
102A Tandem Mass Spectrometer, a Varian NIAT 711 or a VG Micromass
ZAB-HFQQ instrument. Elemental analysis were performed by Dornis u.
Kolbe Mikroanalytisches Laboratorium, M¸lheim an der Ruhr, Germany.
Rf values were obtained by using thin layer chromatography (TLC) on silica
gel-coated plastic sheets (Merck silica gel 60 F254) with the indicated solvent
(mixture). Chromatographic purification refers to flash column chromatog-
raphy[31] using the indicated solvent (mixture) and Acros Organics silica gel
(0.035 0.070 mm). Melting and boiling points are uncorrected. Melting
points were determined with B¸chi melting point B-545. Dry THFand Et2O
were distilled from sodium benzophenone ketyl prior to use. Dry DMF,
CH2Cl2 and MeCN were distilled from CaH2 and stored over MS 4 ä under a
dry nitrogen atmosphere. Triethylamine was dried from KOH pellets. Et2O,
EtOAc, PE (60 808C) were distilled prior to use. All commercially
available reagents were used as received, unless indicated otherwise.
O
Ph
Pd/C, H2
Ph
61
+
EtOAc
base, rt
16 h
CO2Me
N
HN
Ts
CO2Me
Ts
(R)-37
Scheme 11.
(50%, 4.5:1)
63
Instead of the small hydride nucleophile, it was also
attempted to introduce a larger nucleophile via the tertiary
N-sulfonyliminium ion using a cocktail of allyltrimethylsilane
(10 equiv), trifluoroacetic acid (TFA, 5 equiv) and trifluoro-
acetic anhydride (TFAA, 5 equiv). The latter compound was
added to trap traces of water that might be present in the
reaction mixture. The allylated product 64 was obtained in a
moderate yield and slightly contaminated with the hydrolysis
product and the isomerized product 34. The formation of side
products is understandable, considering the difficulty of
nucleophilic attack on the tertiary iminium ion.[30] Unfortu-
nately, the stereochemistry of both isomers could not be
assigned.
(R)-2-(Toluene-4-sulfonylamino)pent-4-ynoic Acid (13)
TFA, TFAA
SiMe3
To a solution of (R)-11 (200 mg, 1.77 mmol) in H2O (15.0 mL), 1 M NaOH
(1.80 mL, 1.80 mmol) and p-toluenesulfonyl chloride (47.2 mg, 2.47 mmol)
were added. The reaction mixture was stirred at ambient temperature for
16 h. The reaction mixture was kept at a basic pH by slowly adding 1 M
aqueous NaOH. After the conversion was complete, the reaction mixture
was extracted with ether (3 Â 10 mL), acidified with 1 M aqueous HCl and
extracted with EtOAc (3 Â 15 mL). The combined EtOAc layers were dried
(MgSO4) and concentrated. Purification of the crude product by flash
chromatography (EtOAc, 5% AcOH) afforded (R)-13 as an amorphous
solid; yield: 390 mg (1.46 mmol, 83%); (R)-13: [a]D: ˆ À36.0 (c 1, CH2Cl2);
1H NMR (400 MHz, CDCl3): d ˆ 10.27 (s, 1H), 7.73 (d, J ˆ 8.3 Hz, 2H), 7.27
(d, J ˆ 8.1 Hz, 2H), 5.75 (d, J ˆ 8.8 Hz, 1H), 4.16 4.11 (m, 1H), 2.69 2.63
CO2Me
CO2Me
N
N
CH2Cl2
0 °C → rt, 3 h
Ts
Ts
(R)-33
64 (21%, 1.6:1)
Scheme 12.
The enamide (R)-37 was subjected to the same conditions,
but in this case only the product resulting from hydrolysis was
found. Due to the lability of the enamides and the reluctancy of
the tertiary iminium ions to undergo nucleophilic attack,
further investigations were not carried out.
76
Adv. Synth. Catal. 2002, 344, 70 83

Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino Acids
FULL PAPERS
(m, 2H), 2.39 (s, 3H), 1.23 (t, J ˆ 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d ˆ 173.8, 143.9, 136.5, 129.6, 127.0, 80.0, 72.5, 53.7, 23.5, 21.4; IR (film): n ˆ
3500 2750, 3288, 2125, 1732, 1598, 1335, 1161, 1092 cmÀ1; HRMS (FAB):
17: 1H NMR (400 MHz, CD3OD): d ˆ 7.90 7.81 (m, 4H), 4.98 4.94 (m,
1H), 2.46 2.40 (m, 2H), 2.32 2.22 (m, 2H), 2.10 (t, J ˆ 2.6 Hz, 1H);
13C NMR (100 MHz, CD3OD): d ˆ 169.4, 135.5, 133.2, 132.0, 131.7, 124.3,
83.5, 70.4, 53.0, 28.8, 16.6; IR (film): n ˆ 3288 2750, 1715, 1393 cmÀ1; HRMS
(EI): calcd. for C14H11NO4 257.0688, found 257.0671.
‡
calcd. for C12H14NO4S (MH ) 268.0644, found 268.0654.
(S)-2-(Toluene-4-sulfonylamino)hex-5-ynoic Acid (14)
(S)-2-(4-Toluenesulfonylamino)pent-4-ynoic Acid Methyl
To a solution of (S)-12 (100 mg, 0.79 mmol) in H2O (2.0 mL), 1 M NaOH
(0.90 mL, 0.90 mmol) and p-toluenesulfonyl chloride (180 mg, 0.95 mmol)
were added and the reaction mixture was stirred for 16 h at ambient
temperature. The reaction mixture was kept basic during the reaction time.
The reaction mixture was washed with ether (3Â50 mL), acidified with 1 M
HCl and extracted with EtOAc (3 Â 50 mL). The combined EtOAc layers
were dried (MgSO4) and concentrated. After purification of the crude
product by flash chromatography (ether, 5% AcOH), (S)-14 was obtained as
an amorphous solid; yield: 162 mg (0.58 mmol, 73%). (R)-14: 1H NMR
(400 MHz, CDCl3): d ˆ 7.74 (d, J ˆ 8.3 Hz, 2H), 7.29 (d, J ˆ 7.7 Hz, 2H), 5.35
(d, J ˆ 8.8 Hz, 1H), 4.07 4.02 (m, 1H), 2.41 (s, 3H), 2.30 2.26 (m, 2H),
2.09 2.00 (m, 1H), 1.94 (t, J ˆ 2.6 Hz, 1H), 1.87 1.81 (m, 1H); 13C NMR
(100 MHz, CDCl3); d ˆ 175.6, 143.9, 136.2, 129.6, 127.1, 81.8, 69.8, 54.2, 31.6,
21.4, 14.5; IR (film): n ˆ 3292, 3250-2750, 1750, 1410, 1334 cmÀ1; HRMS (EI):
calcd. for C13H15NO4S 281.0722, found 281.0707.
Ester (18)
To a solution of (S)-11 (3.00 g, 0.020 mol) in MeOH (100 mL) thionyl
chloride (2.9 mL, 0.040 mol) was added. After refluxing at 708C for 3 h, the
reaction mixture was concentrated under vacuum. The crude reaction
mixture was dissolved in pyridine (50 mL), p-toluenesulfonyl chloride
(4.60 g, 0.020 mol) was added and the reaction mixture was stirred for 16 h at
ambient temperature. The pyridine was evaporated and aqueous saturated
CuSO4 (50 mL) was added. The mixture was extracted with CH2Cl2 (3 Â
50 mL) and the combined organic layers were washed with aqueous
saturated sodium bicarbonate (25 mL), then with brine, dried (MgSO4)
and concentrated. After purification by flash chromatography (70% ether/
petroleum ether) and crystallization (EtOAc/petroleum ether), (S)-18 was
obtained as a white solid; 5.30 g (18.0 mmol, 94%). (S)-18: mp 82 848C; [a]D:
1
‡ 19.4 (c 1, CH2Cl2); H NMR (400 MHz, CDCl3) d ˆ 7.73 (d, J ˆ 1.5 Hz,
2H), 7.71 (d, J ˆ 7.7 Hz, 2H), 5.71 (d, J ˆ 8.8 Hz, 1H), 4.12 4.07 (m, 1H),
3.59 (s, 3H), 2.67 2.63 (m, 2H), 2..39 (s, 3H), 2.01 (t, J ˆ 2.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): d ˆ 169.9, 143.7, 136.7, 126.6, 127.1, 77.4, 72.2,
53.9, 52.7, 23.9, 21.4; IR (film): n ˆ 3273, 2953, 1712 cmÀ1; HRMS: (FAB)
(R)-2-tert-Butoxycarbonylaminopent-4-ynoic Acid (15)
‡
calcd. for C13H16NO4S (MH ) 282.0800, found 282.0791.
To a solution of (R)-11 (100 mg, 0.88 mmol) in dioxane/water (2.0 mL/
2.0 mL), sodium bicarbonate (148 mg, 1.76 mmol) and di-tert-butyl dicar-
bonate (203 mg, 0.92 mmol) were added. After refluxing for 4 h, the dioxane
was evaporated and aqueous saturated sodium bicarbonate (5 mL) was
added to the reaction mixture. The reaction mixture was washed with ether
(3 Â 10 mL), acidified with 1 M HCl and extracted with EtOAc (3 Â 10 mL).
The combined EtOAc layers were dried (MgSO4) and concentrated.
Purification of the crude product by flash chromatography (ether, 5%
AcOH) afforded (R)-15 as a colorless oil; yield: 114 mg (0.73 mmol, 83%).
(R)-15: [a]D: À33.6 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d ˆ 5.34 (d,
J ˆ 7.8 Hz, 1H), 4.52 4.51 (m, 1H), 2.80 2.74 (m, 2H), 2.08 (t, J ˆ 2.6 Hz,
1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3): d ˆ 174.5, 155.2, 80.4, 78.1,
71.6, 51.5, 28.0, 22.3; IR (film): n ˆ 3500 2800, 3298, 2980, 1716, 1668, 1514,
1161 cmÀ1; HRMS (EI): calcd. for C10H15NO4 213.1001, found 213.0994.
(R)-2-(4-Toluenesulfonylamino)hex-5-ynoic Acid Methyl
Ester (19)
To a solution of (R)-12 (1.00 g, 7.87 mmol) in MeOH (250 mL) thionyl
chloride (1.12 mL, 15.7 mmol) was added. After refluxing at 708C for 5 h the
reaction mixture was concentrated under vacuum. The crude reaction
mixture was dissolved in CH2Cl2 (50 mL), Et3N (5.46 mL, 29.4 mmol) and p-
toluenesulfonyl chloride (3.0 g, 15.7 mmol) were added and the reaction
mixture was stirred for 16 h at ambient temperature. An aqueous solution of
NH4Cl (50 mL) was added to the reaction mixture. After separation, the
aqueous layer was extracted with CH2Cl2 (3 Â 50 mL). The combined
organic layers were stirred with aqueous saturated sodium bicarbonate
(25 mL) for 1 h. After separation the organic layer was dried (MgSO4) and
concentrated. Purification of the crude product by flash chromatography
(70% ether/petroleum ether) and crystallization (EtOAc/petroleum ether)
afforded (R)-19 as a white solid; yield: 1.68 g (5.69 mmol, 72%). (R)-19: mp
75 778C; [a]D: À 35.7 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3) d ˆ 7.73
(dd, J ˆ 1.6 Hz, 6.6 Hz, 2H), 7.29 (d, J ˆ 7.9 Hz, 2H), 5.22 (d, J ˆ 8.9 Hz, 1H),
4.02 3.99 (m, 1H), 3.52 (s, 3H), 2.41 (s, 3H) 2.32 2.27 (m, 2H), 1.98 1.94
(m, 2H), 1.86 1.81 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 171.6, 143.6,
136.4, 129.5, 127.1, 82.1, 69.4, 54.6, 52.4, 31.9, 21.3, 14.4; IR (film): n ˆ 3280,
2954, 2119, 1922, 1732, 1598 cmÀ1; HRMS (EI): calcd. for C14H17NO4S
295.0878, found 295.0858.
(S)-2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)pent-4-ynoic Acid
(16)
To a solution of (S)-11 (500 mg, 3.76 mmol) in H2O (10 mL) phthalic
anhydride (560 mg, 3.76 mmol) was added. The reaction mixture was
irradiated in a microwave until the water was evaporated. Then, again H2O
(10 mL) was added and this procedure was repeated three times. After
purification of the crude product by flash chromatography (ether, 5%
AcOH), (S)-16 was obtained as a colorless oil; yield: 830 mg (3.42 mmol,
91%). (S)-16: [a]D: À40.4 (c 0.5, MeOH); 1H NMR (400 MHz, CDCl3): d ˆ
9.20 8.80 (bs, 1H), 7.92 7.85 (m, 2H), 7.78 7.72 (m, 2H), 5.14 (dd, J ˆ
4.8 Hz, 11.3 Hz), 3.30 3.22 (m, 1H), 3.12 3.06 (m, 1H), 1.90 (t, J ˆ 2.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): d ˆ 171.3, 168.8, 135.7, 134.1, 132.9,
132.0, 130.0, 124.4, 80.3, 71.7, 51.9, 20.04; IR (film): n ˆ 3290, 1775, 1713,
1393 cmÀ1; HRMS (EI): calcd. for C13H9NO4 243.0532, found 243.0537.
(R)-2-(4-Nitrobenzenesulfonylamino)hex-5-ynoic Acid
Methyl Ester (20)
To a solution of (R)-12 (400 mg, 3.15 mmol) in MeOH (250 mL) thionyl
chloride (0.45 mL, 6.30 mmol) was added. After refluxing at 708C for 5 h the
reaction mixture was concentrated under vacuum. The crude residue was
dissolved in CH2Cl2 (25 mL), Et3N (2.15 mL, 15.7 mmol) and p-nitro-
phenylsulfonyl chloride (1.05 g, 4.72 mmol) was added and the reaction
mixture was stirred for 16 h at ambient temperature. An aqueous solution of
NH4Cl (50 mL) was added to the reaction mixture. After separation the
aqueous layer was extracted with CH2Cl2 (3 Â 50 mL). The combined
organic layers were stirred with aqueous saturated sodium bicarbonate
(25 mL) for 1 h. After separation the organic layer was dried (MgSO4) and
2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)hex-5-ynoic Acid (17)
To a solution of rac-12 (200 mg, 1.57 mmol) in H2O (10 mL) phthalic
anhydride (233 mg, 1.57 mmol) was added. The reaction mixture was
irradiated in a microwave until the water was evaporated. Then, again H2O
(10 mL) was added and the procedure was repeated three times. After
purification of the crude product by flash chromatography (ether, 5%
AcOH), 17 was obtained as a colorless oil; yield: 369 mg (1.44 mmol, 91%).
Adv. Synth. Catal. 2002, 344, 70 83
77

Larissa B. Wolf et al.
FULL PAPERS
concentrated. Purification by flash chromatography (70% ether/petroleum
ether) and crystallization (EtOAc/petroleum ether) afforded (R)-20 as a
yellowsolid; yield: 604 mg (1.85 mmol, 59%). ( R)-20: mp 87 898C; [a]D:
4-Methyl-N-(6-methylene-2-oxotetrahydropyran-3-
yl)benzenesulfonamide (24)
1
À33.9 (c 1, CH2Cl2); H NMR (400 MHz, CDCl3): d ˆ 8.35 (d, J ˆ 8.6 Hz,
Following the general procedure A, to a solution of rac-14 (50 mg,
0.18 mmol) in MeCN (2.0 mL), Et3N (4.0 mL, 0.03 mmol) and PdCl2
(MeCN)2 (2.3 mg, 0.01 mmol) were added. The reaction mixture was stirred
for 16 h at reflux temperature. Purification afforded 24 as a white amorphous
solid; yield: 16.0 mg (0.06 mmol, 32%). 24: 1H NMR (400 MHz, CDCl3): d ˆ
7.76 (d, J ˆ 8.2 Hz, 2H), 7.32 (d, J ˆ 8.1 Hz, 2H), 5.10 (d, J ˆ 4.1 Hz, 1H), 4.72
(s, 1H), 4.41 (d, J ˆ 1.5 Hz, 1H), 3.84 3.78 (m, 1H), 3.05 2.98 (m, 1H),
2.73 2.66 (m, 1H), 2.63 2.57 (m, 1H), 2.55-2.44 (m, 1H), 2.43 (s, 3H).
2H), 8.05 (d, J ˆ 8.6 Hz, 2H), 5.40 (d, J ˆ 8.8 Hz, 1H), 4.13 4.11 (m, 1H),
3.60 (s, 3H), 2.34 2.29 (m, 2H), 2.05 2.01 (m, 1H), 1.98 (t, J ˆ 2.6 Hz, 1H),
1.90 1.84 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 171.1, 149.9, 145.2,
128.2, 124.0, 81.6, 69.7, 54.6, 52.6, 31.6, 14.3; IR (film): n ˆ 3284, 1742, 1532,
1351, 1166 cmÀ1; HRMS (EI): calcd. for C13H14N2O6S 326.0573, found
326.0583.
General Procedure A for the Oxypalladation Reactions
1-(6-Methylene-2-oxotetrahydropyran-3-yl)isosindole-1,3-
dione (25)
To a solution of the cyclization precursor in THF, Et3N and the Pd-catalyst
were added. The reaction mixture was stirred at ambient temperature or at
608C. After the reaction was finished (TLC), the solvent was evaporated and
the product was purified by flash chromatography (gradient: 20 ! 70%
ether/petroleum ether, 1% Et3N).
Following the general procedure A, to a solution of 17 (50 mg, 0.19 mmol) in
THF (2.0 mL) Et3N (4.0 mL, 0.03 mmol) and Pd(OAc)2 (4.0 mg, 0.02 mmol)
were added. The reaction mixture was refluxed for 6 h. Purification afforded
25 as a colorless oil; yield: 12 mg (0.05 mmol, 24%). 25: 1H NMR (400 MHz,
CDCl3): d ˆ 7.90 7.86 (m, 2H), 7.77 7.73 (m, 2H), 5.00 4.95 (m, 1H), 4.79
(t, J ˆ 1.5 Hz, 1H), 4.43 (t, J ˆ 1.4 Hz, 1H), 2.86 2.80 (m, 1H) 2.72-2.52 (m,
2H), 2.16 2.09 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 166.8, 164.5,
153.8, 134.5, 131.4, 123.7, 95.2, 48.0, 26.5, 23.6; IR (film): n ˆ 2923, 1759, 1716,
(R)-4-Methyl-N-(5-methylene-2-oxotetrahydrofuran-3-
yl)benzenesulfonamide (21)
1666, 1392 cmÀ1
.
Following the general procedure A, to a solution of (R)-13 (100 mg,
0.37 mmol) in THF (3.0 mL), Et3N (8.0 mL, 0.06 mmol) and Pd(OAc)2
(8.0 mg, 0.04 mmol) were added. The reaction mixture was stirred for 1 h
at ambient temperature. Purification afforded (R)-21 as a colorless oil; yield:
66.0 mg (0.25 mmol, 66%). (R)-21: [a]D: À 27.2 (c 1, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d ˆ 7.78 (d, J ˆ 8.3 Hz, 2H), 7.74 (d, J ˆ 8.1 Hz, 2H), 5.19
(d, J ˆ 3.4 Hz, 1H), 4.82 4.81 (m, 1H), 4.46 4.45 (m, 1H), 4.12 4.06 (m,
1H), 3.27 (dd, J ˆ 15.9 Hz, 9.1 Hz, 1H), 2.92 2.85 (m, 1H), 2.44 (s, 3H);
13C NMR (100 MHz, CDCl3): d ˆ 171.9, 151.6, 144.1, 136.1, 129.8, 127.1, 90.9,
General Procedure B for the Oxypalladation Reactions
To a solution of the cyclization precursor in MeCN, Et3N, TBAC, the aryl
halide and finally the Pd(0) catalyst were added. The reaction was heated at
reflux and monitored with TLC. Upon completion, the reaction mixture was
poured into saturated aqueous ammonium chloride, extracted with EtOAc
(3 Â ), dried (MgSO4) and concentrated. The product was purified by flash
chromatography (gradient: 20 ! 70% ether/petroleum ether, 1% Et3N).
51.9, 33.8, 21.4; IR (film): n ˆ 3270, 2922, 2258, 1811, 1681, 1598, 1340 cmÀ1
;
‡
HRMS (FAB): calcd. for C12H13NO4S (MH ) 267.0565, found 267.0554.
(R)-(5-Benzylidene-2-oxotetrahydrofuran-3-yl)-carbamic
Acid tert-Butyl Ester (27)
(R)-(5-Methylene-2-oxotetrahydrofuran-3-yl)carbamic Acid
tert-Butyl Ester (22)
Following the general procedure B, to a solution of (R)-15 (52 mg,
0.27 mmol) in MeCN (2.0 mL), Et3N (186 mL, 1.34 mmol), TBAC (148 mg,
0.53 mmol), PhI (60 ml, 0.53 mmol), PPh3 (15 mg, 0.05 mmol) and Pd(OAc)2
(6.0 mg, 0.03 mmol) were added. Work-up and purification afforded (R)-27
as a yellowamorphous solid; yield: 34 mg (0.12 mmol, 44%). ( R)-27:
1H NMR (400 MHz, CDCl3): d ˆ 7.48 7.20 (m, 5H), 6.37 (s, 1H), 5.22 (d,
J ˆ 6.2 Hz, 1H), 4.44 (m, 1H), 3.63 3.57 (m, 1H), 3.17 3.12 (m, 1H), 1.46 (s,
9H); 13C NMR (100 MHz, CDCl3): d ˆ 172.0, 147.5, 133.6, 128.5, 127.7,
126.8, 108.4, 82.3, 50.2, 33.1, 28.1, (the quaternary olefinic carbon was not
Following the general procedure A, to a solution of (R)-15 (40 mg,
0.19 mmol) in THF (2.0 mL) Et3N (4.0 mL, 0.03 mmol) and Pd(OAc)2
(4.0 mg, 0.02 mmol) were added. Work-up and purification afforded (R)-
22 as an amorphous solid; yield: 25 mg (0.12 mmol, 63%). (R)-22: [a]D:
‡64.1 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d ˆ 5.13 (s, 1H), 4.80 (d,
J ˆ 1.8 Hz, 1H), 4.41 4.40 (m, 2H), 3.29 3.23 (m, 1H), 2.89-2.83 (m, 1H),
1.45 (s, 9H); 13C NMR (100 MHz, CDCl3): d ˆ 172.0, 152.11, 90.26, 80.1, 50.4,
33.3, 28.0 (the quaternary olefinic carbon was not observed); IR (film): n ˆ
3360, 2980, 1816, 1682, 1520, 1255, 1138 cmÀ1; HRMS (EI): calcd. for C10H15
NO4 213.1001, found 213.1003.
observed); IR (film): n ˆ 2978, 1810, 1681, 1507, 1156 cmÀ1
.
2-(5-Benzylidene-2-oxotetrahydrofuran-3-yl)-isoindole-1,3-
dione (28)
(S)-2-(5-Methylene-2-oxotetrahydrofuran-3-yl)isoindole-1,3-
dione (23)
Following the general procedure A, to a solution of (S)-16 (50 mg,
0.21 mmol) in THF (2.0 mL), Et3N (4.0 mL, 0.03 mmol) and Pd(OAc)2
(4.0 mg, 0.02 mmol) were added. The reaction mixture was stirred for 24 h
at ambient temperature. Purification afforded (S)-23 as a white amorphous
solid; yield: 21 mg (0.09 mmol, 42%). (S)-23: [a]D : À 58.4 (c 0.5, CH2Cl2);
1H NMR (400 MHz, CDCl3): d ˆ 7.91 7.86 (m, 2H), 7.80 7.76 (m, 2H),
5.24 (t, J ˆ 10.1 Hz, 1H), 4.91 (d, J ˆ 1.2 Hz, 1H), 4.47 (s, 1H), 3.32 3.18 (m,
2H); 13C NMR (100 MHz, CDCl3): d ˆ 168.0, 166.5, 151.5, 134.5, 131.4,
Following the general procedure B, to a solution of (S)-16 (50 mg,
0.21 mmol) in MeCN (2.0 mL), Et3N (142 mL, 1.03 mmol), TBAC (114 mg,
0.41 mmol), PhI (46 mg, 0.41 mmol) and Pd(PPh3)4 (24 mg, 0.03 mmol) were
added. Purification afforded 28 as a white amorphous solid; yield: 28 mg
(0.09 mmol, 43%). 28: 1H NMR (400 MHz, CDCl3): d ˆ 7.91 7.88 (m, 2H),
7.80 7.76 (m, 2H), 7.36 7.32 (m, 2H), 7.24 7.21 (m, 3H), 6.49 (t, J ˆ
2.0 Hz, 1H), 5.28 (t, J ˆ 9.9 Hz, 1H), 3.55 3.52 (m, 2H); 13C NMR (100
MHz, CDCl3): d ˆ 169.3, 166.5, 146.9, 134.5, 133.5, 131.4, 128.5, 127.8, 126.9,
123.7, 90.7, 47.0, 30.3; IR (film): n ˆ 2900, 1809, 1775, 1716, 1676, 1397 cmÀ1
;
123.8, 108.7, 46.8, 30.4; IR (film): n ˆ 2926, 1815, 1778, 1721, 1682, 1397 cmÀ1
;
HRMS (EI): calcd. for C13H9NO4 243.0532, found 243.0531.
HRMS (EI): calcd. for C19H13NO4 319.0845, found 319.0840.
78
Adv. Synth. Catal. 2002, 344, 70 83

Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino Acids
FULL PAPERS
2-[5-(4-Methoxybenzylidene)-2-oxo-tetrahydrofuran-3-
yl]isoindole-1,3-dione (29)
(R)-5-Methylene-1-(4-toluenesulfonyl)pyrrolidine-2-
carboxylic Acid Methyl Ester (33)
Following the general procedure B, to a solution of (S)-16 (50 mg,
0.21 mmol) in MeCN (2.0 mL), Et3N (142 mL, 1.03 mmol), TBAC (114 mg,
0.41 mmol), 4-iodoanisole (96 mg, 0.41 mmol) and Pd(PPh3)4 (24 mg,
0.03 mmol) were added. Work-up and purification afforded 29 as a yellow
oil; yield: 29 mg (0.08 mmol, 45%). 29: 1H NMR (400 MHz, CDCl3): d ˆ
7.90 7.87 (m, 2H), 7.80 7.76 (m, 2H), 7.16 7.12 (m, 2H), 6.88 6.85 (m,
2H), 6.41 (t, J ˆ 1.9 Hz, 1H), 5.27 (t, J ˆ 9.9 Hz, 1H), 3.70 (s, 3H), 3.51 3.47
(m, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 169.5, 166.5, 158.5, 145.4, 134.5,
131.4, 128.9, 125.9, 123.7, 114.0, 114.0, 55.1, 46.9, 30.3; IR (film): n ˆ 1807,
1778, 1716, 1683, 1397 cmÀ1; HRMS (EI): calcd. for C20H15NO5 349.0950,
found 349.0924.
Following the general procedure C, to a solution of (R)-19 (50 mg,
0.17 mmol) in THF (2.0 mL) were added K2CO3 (117 mg, 0.85 mmol),
Pd(OAc)2 (4.0 mg, 0.02 mmol) and PPh3 (19 mg, 0.07 mmol). Work-up and
purification afforded (R)-33 as a yellowoil; yield: 37 mg (0.125 mmol, 74%).
(R)-33: [a]D: À 50.5 (c 1, CH2Cl2); 1H NMR (400 MHz, C6D6): d ˆ 7.93 (d,
J ˆ 8.3 Hz, 2H), 6.79 (d, J ˆ 8.1 Hz, 2H), 5.52 (d, J ˆ 1.2 Hz, 1H), 4.71 (dd,
J ˆ 4.7 Hz, 8.2 Hz, 1H), 4.23 (d, J ˆ 1.3 Hz, 1H), 3.39 (s, 3H), 2.22 2.13 (m,
1H), 1.88 (s, 3H), 1.80 1.69 (m, 1H), 1.51 1.41 (m, 2H); 13C NMR
(100 MHz, CDCl3): d ˆ 172.6, 145.2, 144.4, 137.2, 130.2, 128.9, 91.0, 64.5,
52.6, 32.0, 30.8, 21.7; IR (film): n ˆ 2921, 2849, 1734, 1162 cmÀ1; HRMS (EI):
calcd. for C14H19NO4S 295.0878, found 295.0881.
2-[5-(4-tert-Butylcyclohex-1-enylmethylene)-2-
(R)-5-Methyl-1-(4-toluenesulfonyl)-2,3-dihydro-1H-pyrrole-
oxotetrahydrofuran-3-yl]isoindole-1,3-dione (30)
2-carboxylic Acid Methyl Ester (34)
Following the general procedure B, to a solution of (S)-16 (50 mg,
0.21 mmol) in THF (2.0 mL) were added Et3N (142 ml, 1.03 mmol), TBAC
(114 mg, 0.41 mmol), 26 (46 mg, 0.41 mmol) and Pd(PPh3)4 (24 mg,
0.03 mmol). Purification afforded 30 as a white amorphous solid; yield:
18 mg (0.05 mmol, 23%). 30: 1H NMR (200 MHz, CDCl3): d ˆ 7.89 7.84
(m, 2H), 7.77 7.74 (m, 2H), 5.92 (d, J ˆ 12.7 Hz, 1H) 5.68 5.66 (m, 1H),
5.37 5.16 (m, 1H), 3.96 3.21 (m, 2H), 2.71 2.09 (m, 2H), 1.84 1.52 (m,
2H), 1.40 1.09 (m, 3H), 0.85 (s, 9H).
Following the general procedure C, to a solution of (R)-19 (50 mg,
0.17 mmol) in THF (2.0 mL) were added K2CO3 (117 mg, 0.85 mmol),
Pd(OAc)2 (4.0 mg, 0.02 mmol) and dppb (7.2 mg, 0.02 mmol). Work-up and
purification afforded a 1:8 mixture of (R)-33 and (R)-34 as a yellowoil; yield:
35 mg (0.12 mmol, 70%). (R)-34: 1H NMR (400 MHz, CDCl3): d ˆ 7.75 (d,
J ˆ 8.3 Hz, 2H), 7.31 (d, J ˆ 8.2 Hz, 2H), 4.82 (s, 1H), 4.69 (dd, J ˆ 4.9 Hz,
10.9 Hz, 1H), 3.79 (s, 3H), 2.63 2.58 (m, 1H), 2.56 2.55 (m, 1H), 2.43 (s,
3H), 2.02 (m, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 171.7, 143.8, 139.5,
138.2, 129.6, 127.5, 108.9, 62.1, 52.5, 32.1, 21.7, 15.0; IR (film): n ˆ 2953, 1743,
1346, 1163 cmÀ1
.
2-(6-Benzylidene-2-oxotetrahydropyran-3-yl)isoindole-1,3-
dione (31)
(R)-5-Methylene-1-(4-nitrobenzenesulfonyl)pyrrolidine-2-
carboxylic Acid Methyl Ester (35)
Following the general procedure B, to a solution of 17 (50 mg, 0.19 mmol) in
MeCN (2.0 mL) were added Et3N (135 mL, 0.94 mmol), TBAC (107 mg,
0.39 mmol), PhI (43 mL, 0.39 mmol) PPh3 (10 mg, 0.04 mmol) and Pd(OAc)2
(4.3 mg, 0.02 mmol). Purification afforded 31 as a white amorphous solid;
yield: 20 mg (0.06 mmol, 31%). 31: 1H NMR (400 MHz, CDCl3): d ˆ 7.90
7.85 (m, 2H), 7.77 7.74 (m, 2H), 7.56 7.53 (m, 2H), 7.39 7.35 (m, 2H),
7.28 7.26 (m, 1H), 6.45 (s, 1H), 5.04 (dd, J ˆ 6.4 Hz, 12.3 Hz, 1H), 3.23 3.17
(dt, J ˆ 15.8 Hz, 4.4 Hz, 1H), 2.88 2.79 (m, 1H), 2.69 2.58 (dt, J ˆ 12.4 Hz,
4.4 Hz, 1H), 2.15 2.08 (m, 1H).
Following the general procedure C, to a solution of (R)-20 (48 mg,
0.15 mmol) in THF (2.0 mL) were added K2CO3 (104 mg, 0.74 mmol),
Pd(OAc)2 (4.0 mg, 0.015 mmol) and PPh3 (8.0 mg, 0.03 mmol). Work-up and
purification afforded (R)-35 as a yellowoil; yield: 23 mg (0.07 mmol, 48%).
(R)-35: [a]D: À 41.9 (c 1, CH2Cl2); 1H NMR (400 MHz, C6D6): d ˆ 8.36 (d,
J ˆ 8.9 Hz, 2H), 8.15 (d, J ˆ 8.9 Hz, 2H), 5.52 (d, J ˆ 1.2 Hz, 1H), 4.75 4.72
(m, 1H), 4.39 (dd, J ˆ 1.6 Hz, 3.2 Hz, 1H), 3.79 (s, 3H), 2.67 2.59 (m, 1H),
2.44 2.40 (m, 1H), 2.40 2.36 (m, 1H), 2.21 1.97 (m, 1H); 13C NMR
(100 MHz, CDCl3): d ˆ 171.4, 150.3, 143.8, 143.3, 128.9, 123.9, 91.2, 63.4,
52.6, 31.0, 26.9; IR (film): n ˆ 2956, 1747, 1531, 1351 cmÀ1; HRMS (EI): calcd.
for C13H14N2O6S 326.0573, found 326.0579.
General Procedure C for the Amidopalladation Reactions
To a solution of the cyclization precursor in DMFor THF were added K2CO3
(5 equiv) and the Pd catalyst (10 mol %). The solution was refluxed and
monitored with TLC. Upon completion, the reaction mixture was poured
into saturated aqueous NaHCO3 and extracted with ether (3 Â ). The
combined organic layers were dried (MgSO4), concentrated and purified by
flash chromatography (70% ether/petroleum ether, 1% Et3N) to afford the
pure product.
General Procedure D for the Amidopalladation Reac-
tions
To a solution of the cyclization precursor in MeCN were added K2CO3
(5 equiv), anhydrous TBAC (1 equiv), an aryl halide (5 equiv) and finally a
Pd(0) catalyst (10 mol %). The solution was heated at reflux and monitored
by TLC. Upon completion, the reaction mixture was poured into saturated
aqueous NaHCO3 and extracted with ether (3 Â ). The combined organic
layers were dried (MgSO4), concentrated and purified by flash chromatog-
raphy (gradient: 20 ! 70% ether/petroleum ether, 1% Et3N) to afford the
pure product.
(S)-1-(4-Toluenesulfonyl)pyrrolidine-2-carboxylic Acid
Methyl Ester (32)
Following the general procedure C, to a solution of (S)-18 (50 mg,
0.18 mmol) in THF (2.0 mL) were added K2CO3 (123 mg, 0.90 mmol) and
Pd(PPh3)4 (21 mg, 0.02 mmol). Work-up and purification afforded (S)-32 as
a colorless oil; yield: 38 mg (0.14 mmol, 76%). (S)-32: [a]D: À 102.9 (c 1,
CH2Cl2); 1H NMR (400 MHz, CDCl3); d ˆ 7.69 (d, J ˆ 8.3 Hz, 2H), 7.32 (d,
J ˆ 8.1 Hz, 2H), 6.38 6.36 (m, 1H), 5.08 5.06 (m, 1H), 4.25 (dd, J ˆ 7.2 Hz,
11 Hz, 1H), 3.79 (s, 3H), 2.80 2.63 (m, 2H), 2.44 (s, 3H); 13C NMR
(100 MHz, CDCl3): d ˆ 171.4, 144.21, 133.3, 133.0, 130.3, 129.7, 127.7, 109.6,
60.0, 52.7, 35.2, 21.5; IR (film): n ˆ 1742, 1355, 1167 cmÀ1; HRMS (EI): calcd.
for C13H15NO4S 281.0722, found 281.0722.
(R)-5-Benzylidene-1-(4-toluenesulfonyl)pyrrolidine-2-
carboxylic Acid Methyl Ester (37)
Following the general procedure D, to a solution of (R)-19 (80 mg,
0.27 mmol) in MeCN (2.0 mL) were added K2CO3 (187 mg, 1.36 mmol),
TBAC (79 mg, 0.27 mmol), PhI (84 mL, 1.36 mmol) and Pd(PPh3)4 (31 mg,
0.03 mmol). Work-up and purification afforded (R)-37 as an amorphous
solid; yield: 74 mg (0.20 mmol, 74%). (R)-37: [a]D: À73.6 (c 0.5, CH2Cl2);
Adv. Synth. Catal. 2002, 344, 70 83
79

Larissa B. Wolf et al.
FULL PAPERS
1H NMR (400 MHz, CDCl3): d ˆ 7.80 (d, J ˆ 8.3 Hz, 2H), 7.32 7.26 (m,
5H), 7.18 7.12 (m, 3H), 6.74 (s, 1H), 4.57 (dd, J ˆ 6.6 Hz, 7.8 Hz, 1H), 3.82 (s,
3H), 2.79 2.75 (m, 1H), 2.42 (s, 3H), 2.35-2.30 (m, 1H), 2.15 2.10 (m, 1H),
1.94 1.89 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 171.9, 144.2, 139.8,
136.9, 134.7, 129.5, 128.1, 128.0, 126.0, 111.3, 62.4, 52.5, 28.8, 27.3, 21.4; IR
(film): n ˆ 2951, 1750, 1653, 1349, 1163 cmÀ1; HRMS (EI): calcd. for
C20H21NO4S 371.1191, found 371.1178.
(R)-5-(2-Butylallylidene)-1-(4-toluenesulfonyl)pyrrolidine-2-
carboxylic Acid Methyl Ester (41)
Following the general procedure D, to a solution of (R)-19 (50 mg,
0.17 mmol) in MeCN (2.0 mL) were added K2CO3 (117 mg, 0.85 mmol),
TBAC (49 mg, 0.17 mmol), 36 (196 mg, 0.85 mmol) and Pd(PPh3)4 (20 mg,
0.02 mmol). Work-up and purification afforded (R)-41 as an amorphous
1
solid; yield: 9 mg (0.02 mmol, 13%). (R)-41: H NMR (400 MHz, CDCl3):
d ˆ 7.72 (d, J ˆ 8.3 Hz, 2H), 7.28 (d, J ˆ 8.0 Hz, 2H), 6.00 (d, J ˆ 15.8 Hz,
1H), 5.57 (td, J ˆ 7.0 Hz, 15.8 Hz, 1H), 5.10 (d, J ˆ 9.2 Hz, 1H), 3.94 3.88
(m, 1H), 3.50 (s, 3H), 2.41 (s, 3H), 2.17-2.13 (m, 4H), 1.87 1.68 (m, 2H),
1.47 1.40 (m, 2H), 1.37 1.28 (m, 2H), 0.93 091 (m, 3H).
(R)-5-(4-Nitrobenzylidene)-1-(4-toluenesulfonyl)pyrrolidine-
2-carboxylic Acid Methyl Ester (38)
Following the general procedure D, to a solution of (R)-19 (50 mg,
0.17 mmol) in MeCN (2.0 mL) were added K2CO3 (117 mg, 0.85 mmol),
TBAC (49 mg, 0.17 mmol), 1-iodo-4-nitrobenzene (210 mg, 0.85 mmol) and
Pd(PPh3)4 (20 mg, 0.02 mmol). Work-up and purification afforded (R)-38 as
a yellowoil; yield: 42 mg (0.10 mmol, 59%). ( R)-38: [a]D: À 152.2 (c 1,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d ˆ 8.13 8.09 (m, 3H), 7.83 7.80
(m, 3H), 7.60 7.22 (m, 4H), 6.68 (s, 1H), 4.71 (dd, J ˆ 5.2 Hz, 8.2 Hz, 1H),
3.82 (s, 3H), 2.87 2.83 (m, 1H), 2.52-2.51 (m, 1H), 2.42 (s, 3H), 2.22 2.14 (m,
1H), 2.04 1.97 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 171.5, 144.7,
144.0, 143.1, 141.1, 134.7, 129.6, 129.2, 128.1, 127.1, 123.5, 123.1, 107.7, 62.6,
52.6, 29.4, 27.0, 22.1; IR (film): n ˆ 2953, 2925, 2851, 1748, 1641, 1593, 1513,
1340 cmÀ1; HRMS (EI): calcd. for C20H20N2O6S 416.1042, found 416.1037.
(R)-5-Benzylidene-1-(4-nitrobenzenesulfonyl)pyrrolidine-2-
carboxylic Acid Methyl Ester (42)
Following the general procedure D, to a solution of (R)-20 (50 mg,
0.15 mmol) in MeCN (2.0 mL) were added K2CO3 (106 mg, 0.77 mmol),
TBAC (43 mg, 0.15 mmol), PhI (34 mL, 0.31 mmol) and Pd(PPh3)4 (18 mg,
0.015 mmol). Work-up and purification afforded (R)-42 as a yellowsolid;
yield: 50 mg (0.12 mmol, 80%). (R)-42: mp 149 1508C; [a]D: À 129.3 (c 1,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d ˆ 8.35 (d, J ˆ 8.9 Hz, 2H), 8.16 (d,
J ˆ 8.9 Hz, 2H), 7.32 7.12 (m, 5H), 6.69 (s, 1H), 4.67 (dd, J ˆ 5.6 Hz, 8.2 Hz,
1H), 3.83 (s, 3H), 2.85 2.77 (m, 1H), 2.49 2.41 (m, 1H), 2.25 2.15 (m, 1H),
2.04 1.96 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 171.4, 150.4, 143.5,
138.5, 136.1, 128.9, 128.3, 128.1, 126.5, 124.0, 111.4, 62.4, 52.7, 28.7, 27.3; IR
(film): n ˆ 1717, 1652, 1532, 1350 cmÀ1; HRMS (EI): calcd. for C19H18N2O6S
402.0886, found 402.0894.
(R)-5-(4-Methoxybenzylidene)-1-(4-toluenesulfonyl)-
pyrrolidine-2-carboxylic Acid Methyl Ester (39)
Following the general procedure D, to a solution of (R)-19 (50 mg,
0.17 mmol) in MeCN (2.0 mL) were added K2CO3 (117 mg, 0.85 mmol),
TBAC (49 mg, 0.17 mmol), 4-iodoanisole (198 mg, 0.85 mmol) and Pd(PPh3
(R)-N-(1-Hydroxymethylbut-3-ynyl)-4-methylbenzene-
sulfonamide (43)
)
(20 mg, 0.02 mmol). Work-up and purification afforded (R)-39 as an
4
amorphous solid; yield: 39 mg (0.10 mmol, 58%). (R)-39: [a]D: À 78.2 (c 1,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d ˆ 7.78 (d, J ˆ 8.3 Hz, 2H), 7.28 (d,
J ˆ 8.0 Hz, 2H), 7.06 (d, J ˆ 8.6 Hz, 2H), 6.83 (dd, J ˆ 2.0 Hz, 6.8 Hz, 2H),
6.72 (s, 1H), 4.54 (dd, J ˆ 7.0 Hz, 7.6 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 2.80
2.65 (m, 1H), 2.42 (s, 3H) 2.33 2.26 (m, 1H), 2.23 2.05 (m, 1H), 1.95 1.82
(m, 1H); 13C NMR (400 MHz, CDCl3): d ˆ 171.9, 157.9, 144.1, 137.6, 134.7,
129.4, 129.2, 127.6, 113.6, 111.5, 62.3, 55.1, 52.5, 28.6, 27.3, 21.4; IR (film): n ˆ
2952, 2838, 1740, 1654, 1606, 1511, 1163 cmÀ1; HRMS (EI): calcd. for C21H23
NO5S 401.1297, found 401.1303.
To a solution of LiAlH4 (531 mg, 3.76 mmol) in dry THF (20 mL) (R)-13
(250 mg, 0.94 mmol) was added in portions. After stirring for 16 h, the
LiAlH4 was carefully quenched by dropwise adding 1 M HCl at 08C. The
reaction mixture was extracted with ether (3 Â 20 mL) and the combined
organic layers were dried (MgSO4) and concentrated. Without further
purification (R)-43 was obtained as white solid; yield: 249 mg (0.98 mmol,
1
100%). (R)-43: [a]D: ‡ 51.0 (c 1.6, CH2Cl2); H NMR (400 MHz, CDCl3):
d ˆ 7.78 (d, J ˆ 8.3 Hz, 2H), 7.31 (d, J ˆ 8.0 Hz, 2H), 4.94 (d, J ˆ 7.9 Hz, 1H),
3.72 3.86 (m, 1H), 3.64 3.59 (m, 1H), 3.45 3.40 (m, 1H), 2.46 2.39 (m,
1H), 2.44 (s, 3H), 2.36 2.33 (dd, J ˆ 2.7 Hz, 6.8 Hz, 1H), 1.98 (t, J ˆ 2.7 Hz,
1H), 1.81 (bs, 1H); IR (film): n ˆ 3503, 3280, 2925, 1328 cmÀ1; HRMS (FAB):
‡
calcd. for C12H16NO3S (MH ) 254.0851, found 254.0845.
(R)-5-(4-tert-Butylcyclohex-1-enylmethylene)-1-(4-
toluenesulfonyl)pyrrolidine-2-carboxylic Acid Methyl Ester
(40)
(S)-N-(1-Hydroxymethylpent-4-ynyl)-4-methylbenzene-
sulfonamide (44)
Following the general procedure D, to a solution of (R)-19 (50 mg,
0.17 mmol) in MeCN (2.0 mL) were added K2CO3 (117 mg, 0.85 mmol),
TBAC (49 mg, 0.17 mmol), 26 (242 mg, 0.85 mmol) and Pd(PPh3)4 (20 mg,
0.02 mmol). Work-up and purification afforded (R)-40 as an amorphous
solid; yield: 40 mg (0.09 mmol, 55%). (R)-40: [a]D: À 30.4 (c 1, CH2Cl2);
1H NMR [400 MHz, CDCl3, several signals are double due to the s(cis, trans)
rotamers]: d ˆ 7.73 (d, J ˆ 8.0 Hz, 2H), 7.28 (d, J ˆ 8.1 Hz, 2H), 6.17 (s, 0.5H),
6.15 (s, 0.5H), 5.52 (s, 0.5H), 5.41 (s, 0.5H), 4.46 4.42 (m, 1H), 3.79 (s, 3H),
2.52 2.41 (m, 1H), 2.15 2.02 (m, 5H), 1.88 1.80 (m, 3H), 1.22 1.13 (m,
2H), 0.86 (s, 9H); 13C NMR (100 MHz, CDCl3): d ˆ 171.8, 143.6, 136.3, 133.8,
131.1, 129.3, 127.2, 115.4, 115.0, 62.1, 52.4, 43.5, 36.4, 30.3, 30.0, 28.8, 27.2,
27.0, 27.0, 21.4; IR (film): n ˆ 2950, 2390, 2380, 1745, 1700 cmÀ1; HRMS (EI):
calcd. for C24H33NO4S 431.2130, found 431.2119.
To a solution of LiAlH4 (750 mg, 19.8 mmol) in dry THF (25 mL) (S)-14
(1.40 g, 4.90 mmol) was added in portions. After stirring for 16 h, the LiAlH4
was carefully quenched by dropwise adding 1 M HCl at 08C. The reaction
mixture was extracted with ether (3 Â 20 mL) and the combined organic
layers were dried (MgSO4) and concentrated. Without further purification
(S)-44 was obtained as white solid; yield: 1.41 mg (5.26 mmol, 100%). (S)-44:
[a]D: À 19.5 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d ˆ 7.78 (d, J ˆ
8.3 Hz, 2H), 7.31 (d, J ˆ 8.0 Hz, 2H), 4.92 (d, J ˆ 8.2 Hz, 1H), 3.61 3.39 (m,
3H), 2.43 (s, 3H), 2.17 2.09 (m, 2H), 1.92 (t, J ˆ 2.6 Hz, 1H), 1.73 1.60 (m,
2H); 13C NMR (400 MHz, CDCl3): d ˆ 143.5, 137.3, 129.6, 127.0, 81.9, 69.2,
64.2, 54.5, 30.3, 21.4, 14.8; IR (film): n ˆ 3470, 3283, 1433, 1308, 1155 cmÀ1
;
‡
HRMS (FAB): calcd. for C13H18NO3S (MH ) 268.1007, found 268.1004.
80
Adv. Synth. Catal. 2002, 344, 70 83

Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino Acids
FULL PAPERS
(R)-N-[1-(tert-Butyldimethylsiloxymethyl)but-3-ynyl]-4-
(S)-[5-Methyl-1-(4-toluenesulfonyl)pyrrolidin-2-yl]methanol
methylbenzenesulfonamide (45)
(49)
To a solution of (R)-43 (255 mg, 1.01 mmol) in DMF (1.0 mL), imidazole
(172 mg, 2.53 mmol) and tert-butyldimethylsilyl chloride (181 mg,
1.21 mmol) were added. After stirring for 2.5 h at 358C aqueous saturated
NaHCO3 was added and the organic layer was extracted with CH2Cl2 (3 Â
10 mL). The combined organic layers were dried (MgSO4) and concen-
trated. The crude product was purified by flash chromatography (20 ! 70%
ether/petroleum ether, 5% Et3N) to afford (R)-45 as a colorless oil; yield:
298 mg (0.81 mmol, 80%). (R)-45: [a]D: À 12.6 (c 1, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d ˆ 7.76 (d, J ˆ 8.3 Hz, 2H), 7.30 (d, J ˆ 8.0 Hz, 2H), 4.88
(d, J ˆ 8.2 Hz, 1H), 3.66 (dd, J ˆ 3.8 Hz, 9.9 Hz, 1H), 3.48 3.44 (m, 1H),
3.40 3.37 (m, 1H), 2.51 2.44 (m, 1H), 2.43 (s, 3H), 2.35 2.28 (ddd, J ˆ
2.7 Hz, 7.9 Hz, 16.8 Hz, 1H), 1.93 (t, J ˆ 2.6 Hz, 1H), 0.84 (s, 9H), 0.01 (s, 3H),
À 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 143.3, 137.3, 129.6, 126.9,
79.5, 70.8, 62.6, 53.0, 25.6, 21.3, 20.8, 18.0, À 5.7; IR (film): n ˆ 3280, 2954,
Following the general procedure C, to a solution of (S)-44 (37 mg,
0.14 mmol) in THF (2.0 mL) were added K2CO3 (96 mg, 0.70 mmol) and
Pd2(dba)3 (2 mg). After work-up and purification (S)-49 was obtained as a
yellowoil; yield: 29 mg (0.11 mmol, 78%). ( S)-49: [a]D: À 19.3 (c 0.9, CH2Cl2);
1H NMR (400 MHz, CD3OD): d ˆ 7.74 (d, J ˆ 8.3 Hz, 2H), 7.37 (d, J ˆ
8.0 Hz, 2H), 5.01 (s, 1H), 4.36 (s, 1H), 4.11 4.08 (m, 1H), 3.80 (dd, J ˆ
3.9 Hz, 11.0 Hz, 1H), 3.65 3.60 (m, 1H), 2.56 2.50 (m, 1H), 2.49 (s, 3H)
2.16 2.09 (m, 1H), 1.82 1.76 (m, 1H), 1.67 1.60 (m, 1H); 13C NMR
(100 MHz, CD3OD): d ˆ 146.9, 145.4, 137.2, 130.3, 128.3, 92.7, 65.9, 65.2,
31.4, 25.5, 21.2; IR (film): n ˆ 3560 3250, 2923, 1312, 1163 cmÀ1; HRMS
(EI): calcd. for C13H17NO3S 267.0929, found 267.0930.
‡
2928, 2857, 1333, 1163 cmÀ1; HRMS (FAB): calcd. for C18H30NO3Si (MH )
(S)-(2-tert-Butyldimethylsiloxymethyl)-5-methylene-1-(4-
368.1716, found 368.1706.
toluenesulfonyl)pyrrolidine (50)
Following the general procedure C, to a solution of (S)-46 (49 mg,
0.13 mmol) in THF (3.0 mL) were added K2CO3 (91 mg, 0.70 mmol) and
Pd(PPh3)4 (2 mg). After work-up and purification (R)-50 was obtained as a
colorless oil; yield: 37 mg (0.10 mmol, 74%). (S)-50: [a]D: ‡ 73.2 (c 0.25,
(S)-(N-[1-(tert-Butyldimethylsiloxymethyl)pent-4-ynyl]-4-
methylbenzenesulfonamide) (46)
1
CH2Cl2); H NMR (400 MHz, C6D6): d ˆ 7.77 (d, J ˆ 8.2 Hz, 2H), 6.73 (d,
To a solution of (S)-44 (934 mg, 3.50 mmol) in DMF (7.5 mL), imidazole
(595 mg, 8.75 mmol) and tert-butyldimethylsilyl chloride (633 mg,
4.20 mmol) were added. After stirring for 2.5 h at 358C, aqueous saturated
NaHCO3 was added and the organic layer was extracted with CH2Cl2 (3 Â
10 mL). The combined organic layers were dried (MgSO4) and concen-
trated. The crude product was purified by flash chromatography with (20 !
70% ether/petroleum ether, 5% Et3N) to afford (R)-46 as a colorless oil;
yield: 1.20 g (3.16 mmol, 90%). (S)-46: ee 96.5% (HPLC); [a]D: ‡ 10.9 (c 1,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d ˆ 7.76 (d, J ˆ 8.3 Hz, 2H), 7.29 (d,
J ˆ 8.0 Hz, 2H), 4.81 (d, J ˆ 8.2 Hz, 1H), 3.49 3.37 (m, 3H), 2.42 (s, 3H),
2.20 2.15 (m, 1H), 1.91 (t, J ˆ 2.6 Hz, 1H), 1.72 1.65 (m, 1H), 0.84 (s, 9H),
À 0.02 (s, 3H), À 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 143.2, 129.5,
126.9, 73.3, 68.8, 63.9, 53.9, 30.9, 25.6, 21.3, 18.0, 14.9, À 5.7; IR (film): n ˆ
3280, 2957, 2927, 2855, 2119, 1327, 1259 cmÀ1; HRMS (FAB): calcd. for
J ˆ 8.0 Hz, 2H), 5.47 (s, 1H), 4.29 (s, 1H), 4.18 4.14 (m, 1H), 4.00 (dd, J ˆ
3.5 Hz, 10.1 Hz, 1H), 3.75 3.71 (m, 1H), 2.32 2.28 (m, 1H), 1.85 (s, 3H),
1.83 1.77 (m, 1H), 1.65 1.61 (m, 1H), 1.38 1.27 (m, 1H), 0.96 (s, 9H), 0.10
(s, 3H), 0.09 (s, 3H); 13C NMR (100 MHz, C6D6): d ˆ 143.5, 91.0, 65.6, 64.4,
30.5, 25.6, 24.5, 20.5, À 5.8; IR (film): n ˆ 2954, 2928, 2856, 1352, 1166 cmÀ1
;
‡
HRMS (FAB): calcd. for C19H32SNO3Si (MH ) 382.1872, found 382.1878.
(S)-2-Benzylidene-5-(tert-butyldimethylsiloxymethyl)-1-(4-
toluenesulfonyl)pyrrolidine (52)
‡
C19H32NO3Si (MH ) 382.1872, found 382.1875.
Following the general procedure D, to a solution of (S)-46 (35 mg,
0.09 mmol) in THF (2.0 mL) were added K2CO3 (60 mg, 0.43 mmol),
TBAC (10 mg), PhI (48 mL, 0.43 mmol) and Pd(PPh3)4 (2 mg). After work-
up and purification (S)-52 was obtained as a colorless oil; yield: 34 mg
(0.07 mmol, 82%). (S)-52: [a]D: ‡ 17.4 (c 1.5, CH2Cl2); 1H NMR (400 MHz,
C6D6): d ˆ 7.76 (d, J ˆ 8.3 Hz, 2H), 7.28 (s, 1H), 7.16 7.05 (m, 5H), 6.69 (d,
J ˆ 8.0 Hz, 2H), 4.16 4.10 (m, 2H), 3.79 3.75 (m, 1H), 2.46 2.38 (m, 1H),
1.89 1.78 (m, 1H), 1.84 (s, 3H), 1.62 1.54 (m, 1H), 1.45 1.36 (m, 1H), 0.96
(s, 9H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (100 MHz, C6D6): d ˆ 144.1,
142.0, 136.3, 137.2, 130.2, 129.3, 129.2, 126.9, 114.0, 67.4, 64.2, 29.7, 26.7, 26.4,
21.7, 19.1, À 4.53, À 4.56; IR (film): n ˆ 2954, 2929, 2857, 1651, 1350,
(R)-[1-(4-Toluenesulfonyl)-3,4-dihydro-2H-pyrrol-2-
yl]methanol (47)
Following the general procedure C, to a solution of (R)-43 (44 mg,
0.12 mmol) in THF (3.0 mL) were added K2CO3 (83 mg, 0.66 mmol) and
Pd2(dba)3. After work-up and purification (R)-47 was obtained as a colorless
oil; yield: 7 mg (0.02 mmol, 16%). (R)-47: 1H NMR (400 MHz, CDCl3): d ˆ
7.60 (d, J ˆ 8.2 Hz, 2H), 6.72 (d, J ˆ 8.0 Hz, 2H), 6.26 6.24 (m, 1H), 4.54
4.52 (m, 1H), 3.63 3.55 (m, 3H), 1.88-1.83 (m, 2H), 1.83 (s, 3H).
‡
1165 cmÀ1; HRMS (FAB): calcd. for C25H36SNO3Si (MH ) 458.2185, found
458.2191.
5-Methyl-1-(4-nitrobenzenesulfonyl)pyrrolidine-2-carboxylic
Acid Methyl Ester (60)
(R)-2-(tert-Butyldimethylsiloxymethyl)-1-(4-
toluenesulfonyl)-3,4-dihydro-2H-pyrrole (48)
Following the general procedure C, to a solution of (R)-45 (90 mg,
0.25 mmol) in DMF (2.0 mL) were added K2CO3 (173 mg, 1.25 mmol) and
Pd(PPh3)4 (33 mg, 0.03 mmol). After work-up and purification (R)-48 was
obtained as a colorless oil; yield: 24 mg (0.07 mmol, 28%). (R)-48: [a]D:
À39.9 (c 0.3, CH2Cl2); 1H NMR (400 MHz, CDCl3) d ˆ 7.66 (d, J ˆ 8.3 Hz,
2H), 7.30 (d, J ˆ 7.9 Hz, 2H), 6.29 6.27 (m, 1H), 5.10 5.08 (m, 1H), 3.86
(dd, J ˆ 3.9 Hz, 9.7 Hz, 1H), 3.77 3.72 (m, 1H), 3.64 (dd, J ˆ 9.7 Hz, 7.9 Hz,
1H), 2.49 2.35 (m, 2H), 2.43 (s, 3H), 0.88 (s, 9H), 0.08 (s, 3H); 13C NMR
(100 MHz, C6D6): d ˆ 143.9, 131.6, 130.3, 128.9, 128.70, 112.2, 66.6, 61.6, 34.1,
To a solution of (R)-35 (37 mg, 0.11 mmol) in CH2Cl2 (3.0 mL) was added
triethylsilane (90 mL, 0.56 mmol). At 08C trifluoroacetic acid (43 mL,
0.11 mmol) was added to the reaction mixture. It was allowed to reach
ambient temperature, stirred for 1 h and concentrated under vacuum.
Purification of the crude product by flash chromatography (20 ! 70% ether/
petroleum ether) afforded 60 (2:1 mixture of cis/trans-isomers) as a yellow
oil; yield: 12 mg (0.04 mmol, 32%). 60 (data of both isomers): 1H NMR
(400 MHz, CDCl3): d ˆ 8.36 (d, J ˆ 8.8 Hz, 2H), 8.11 (d, J ˆ 8.9 Hz, 1.3H),
8.07 (d, J ˆ 8.9 Hz, 0.67H), 4.53 4.51 (m, 0.33H), 4.21 4.39 (m, 0.67H),
4.09 4.07 (m, 0.33H), 3.98 3.93 (m, 0.67H), 3.75 (s, 2H), 3.67 (s, 1H), 2.08
2.01 (m, 2H), 1.99 1.89 (m, 1H), 1.70 1.61 (m, 1H), 1.30 (d, J ˆ 6.4 Hz, 3H).
26.7, 21.7, 19.1, À 4.52; IR (film): n ˆ 2951, 2929, 2857, 1345, 1161 cmÀ1
;
HRMS (EI): calcd. for C19H29SNO3Si 379.1637, found 367.1636.
Adv. Synth. Catal. 2002, 344, 70 83
81

Larissa B. Wolf et al.
FULL PAPERS
5-Benzyl-1-(4-toluenesulfonyl)pyrrolidine-2-carboxylic Acid
Methyl Ester (61)
Acknowledgements
DSM Research is kindly acknowledged for providing research grants to L. B.
Wolf and K. C. M. F. Tjen.
Method 1: To a solution of (R)-37 (78 mg, 0.23 mmol) and triethylsilane
(179 mL, 1.12 mmol) in CH2Cl2 (4.0 mL) was added trifluoroacetic acid
(86 mL, 1.12 mmol) at 08C. It was allowed to reach ambient temperature,
stirred for 16 h and concentrated. Purification of the crude product by flash
chromatography(20 ! 70%ether/petroleumether)afforded61(10:1mixture
of trans/cis-isomers) as a yellowoil; yield: 69 mg (0.20 mmol, 88%). 61 (data
of the major isomer): 1H NMR (400 MHz, CDCl3): d ˆ 7.78 (d, J ˆ 8.2 Hz,
2H), 7.33 7.22 (m, 5H), 7.20 7.18 (m, 2H), 4.28 4.25 (m, 1H), 3.94 3.87
(m, 1H), 3.77 (s, 3H), 3.33 (dd, J ˆ 4.0 Hz, 13.4 Hz, 1H), 2.75 (dd, J ˆ 10.5 Hz,
13.4 Hz, 1H), 2.42 (s, 3H), 2.03 1.90 (m, 1H), 1.89 1.82 (m, 1H), 1.74 1.66
(m, 1H), 1.53 1.42 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 172.4, 143.6,
138.2, 135.0, 129.6, 129.5, 129.2, 128.3, 127.4, 127.3, 126.3, 63.0, 61.8, 52.3, 42.1,
29.4, 29.0, 21.4; IR (film): n ˆ 3027, 2952, 1754, 1454, 1349, 1161 cmÀ1; HRMS
(EI): calcd for C20H23NO4S 373.1348, found 373.1332.
Method 2: To a suspension of 10% Pd/C (5 mg) in EtOAc (3.0 mL) were
added K2CO3 (5 mg) and (R)-37 (28 mg, 0.11 mmol). The flask was
evaporated with a water aspirator and filled with H2 gas (3 Â ). After
stirring for 16 h under an H2 atmosphere, the reaction mixture was filtered
over Celite. The filtrate was concentrated and the residue was purified by
flash chromatography (20 ! 70% ether/petroleum ether) to afford 61 (4.5:1
,mixture of trans/cis-isomers) as a yellowoil; yield: 19 mg (0.05 mmol, 50%).
References
[1] See e.g.: Progress in heterocyclic chemistry, Vol. 12, (Eds.: G. W.
Gribble, T. L. Gilchrist), Pergamon: Oxford, 2000.
[2] See e. g.: A. Nefzi, J. H. Ostresh, R. A. Houghten, Chem. Rev. 1997,
97, 449; Combinatorial Chemistry, (Ed.: G. Jung), Wiley-VCH,
Weinheim, 1999.
[3] For reviews, see e. g.: S. Cacchi, J. Organomet. Chem. 1999, 576, 42; J.
Tsuji, Palladium Reagents and Catalysis, Wiley: NewYork, 1995.
[4] M. Kotora, E. Negishi, Synthesis 1996, 121; Y. Fukuda, H. Shiragami,
K. Utimoto, H. Nozaki, J. Org. Chem. 1991, 56, 56816; T. Hosokawa,
S.-I. Murahashi, Heterocycles 1992, 33, 1079; C. Lambert, K. Utimoto,
H. Nozaki, Tetrahedron Lett. 1984, 25, 5323; K. Utimoto, Pure Appl.
Chem. 1983, 55, 1845.
[5] M. Kimura, Y. Wakamiya, Y. Horino, Y. Tamura, Tetrahedron Lett.
1997, 38, 3963; S. Cacchi, V. Carnicelli, F. Marinelli, J. Organomet.
Chem. 1994, 475, 289; Y. Fukuda, S. Matsubara, K. Utimoto, J. Org.
Chem. 1991, 56, 5812; D. E. Rudisill, J. K. Stille, J. Org. Chem. 1989,
54, 5856.
5-Benzyl-1-(4-nitrobenzenesulfonyl)pyrrolidine-2-carboxylic
Acid Methyl Ester (62)
[6] For carboxylic acids, see e.g.: R. Rossi, F. Bellina, M. Biagetti, L.
Mannina, Tetrahedron Lett. 1998, 39, 7599; Z. Wang, X. Lu, J. Org.
Chem. 1996, 61, 2254; M. Cavicchioli, S. Decortiat, D. Bouyssi, J.
¬
Gore, G. Balme, Tetrahedron 1996, 52, 11463; M. Cavicchioli, D.
To a solution of (R)-42 (34 mg, 0.10 mmol) and triethylsilane (78 mL,
0.48 mmol) in CH2Cl2 (4.0 mL) was added trifluoroacetic acid (37 mL,
0.48 mmol) at 08C. It was allowed to reach ambient temperature, stirred for
24 h and concentrated. Purification by flash chromatography (20 ! 70%
ether/petroleum ether) afforded 62 (10:1 mixture of trans/cis-isomers) as a
yellowoil; yield: 13 mg (0.03 mmol, 35%). 62 (data of the major isomer):
1H NMR (400 MHz, CDCl3): d ˆ 8.33 (d, J ˆ 8.8 Hz, 2H), 8.06 (d, J ˆ 8.9 Hz,
2H), 7.28 7.20 (m, 3H), 7.18 7.14 (m, 2H), 4.42 (t, J ˆ 7.2 Hz, 1H), 4.11
4.07 (m, 1H), 3.77 (s, 3H), 3.20 (dd, J ˆ 4.8 Hz, 13.4 Hz, 1H), 2.71 (dd, J ˆ
9.9 Hz, 13.4 Hz, 1H), 2.10 2.04(m, 2H), 1.77 175 (m, 1H), 1.66 1.62(m, 1H).
¬
Bouyssi, J. Gore, G. Balme, Tetrahedron Lett. 1996, 37, 1429; A.
Arcadi, A. Burini, S. Cacchi, M. Delmastro, F. Marinelli, B. Pietroni,
J. Org. Chem. 1992, 57, 976; N. Yanagihara, C. Lambert, K. Iritani, K.
Utimoto, H. Nozaki, J. Am. Chem. Soc. 1986, 108, 2753; for alcohols,
see: F. Luo, I. Schreuder, R.-T. Wang, J. Org. Chem. 1992, 57, 2213.
¬
[7] H. D. Doan, J. Gore, J.-M. Vatele, Tetrahedron Lett. 1999, 40, 6765; S.
Cacchi, G. Fabrizi, P. Pace, J. Org. Chem. 1998, 63, 1001; A. Arcadi,
R. Anacardio, G. d×Anniballe, M. Gentile, Synlett 1997, 1315.
[8] A. Arcadi, Synlett 1997, 941; D. Bouyssi, M. Caviccioli, G. Balme,
Synlett 1997, 944.
[9] A. Lei, X. Lu, Org. Lett. 2000, 2, 2699.
[10] F. T. Luo, R. T. Wang, Tetrahedron Lett. 1992, 33, 6835.
[11] W. F. J. Karstens, M. Stol, F. P. J. T. Rutjes, H. Kooijman, A. L. Spek,
H. Hiemstra, J. Organomet. Chem. 2001, 624, 244.
5-Oxo-6-phenyl-2-(4-toluenesulfonylamino)hexanoic Acid
Methyl Ester (63)
[12] L. B. Wolf, T. Sonke, K. C. M. F. Tjen, B. Kaptein, Q. B. Broxterman,
H. E. Schoemaker, F. P. J. T. Rutjes, Adv. Synth. Catal. 2001, 343, 662;
T. Sonke, B. Kaptein, W. H. J. Boesten, Q. B. Broxterman, J.
Kamphuis, F. Formaggio, C. Toniolo, F. P. J. T. Rutjes, H. E. Schoe-
maker, in Stereoselective Biocatalysis, (Ed.: R. N. Patel), Marcel
Dekker: NewYork, 2000, pp. 23 À 58.
1H NMR (400 MHz, CDCl3): d ˆ 7.67 (d, J ˆ 8.3 Hz, 2H), 7.36 7.20 (m,
7H), 5.16 (d, J ˆ 9.1 Hz, 1H), 3.91 3.85 (m, 1H), 3.72 (s, 2H), 3.46 (s, 3H),
2.76 2.69 (m, 1H), 2.61 2.55 (m, 1H), 2.41 (s, 3H), 2.08 2.05 (m, 1H),
1.77 1.71 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 206.9, 171.6, 143.5,
136.1, 133.8, 129.4, 129.3, 128.5, 127.0, 126.8, 54.5, 52.3, 49.8, 36.9, 26.7, 21.3;
IR (film): n ˆ 3265, 1742, 1716, 1339, 1162 cmÀ1
.
[13] For a reviewon applications of unsaturated amino acids, see: F. P. J. T.
Rutjes, L. B. Wolf, H. E. Schoemaker, J. Chem. Soc. Perkin Trans. 1
2000, 4197.
[14] Part of this work has been published: L. B. Wolf, K. C. M. F. Tjen,
F. P. J. T. Rutjes, H. Hiemstra, H. E. Schoemaker, Tetrahedron Lett.
1998, 39, 5081.
5-Allyl-5-methyl-1-(4-toluenesulfonyl)pyrrolidine-2-
carboxylic Acid Methyl Ester (64)
[15] For the Boc-protection, see e.g.: A. Afzali-Ardakani, H. Rapoport, J.
Org. Chem. 1980, 45, 4817; for other protecting groups, see: T. W.
Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley,
NewYork, 1999.
[16] A. G. Griesbeck, J. Hirt, K. Peters, E.-M. Peters, H. G. Von
Schnering, Chem. Eur. J. 1996, 2, 1388.
[17] J. E. McMurry, W. J. Scott, Tetrahedron Lett. 1983, 24, 979; D. L.
Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299; for reviews
on triflate chemistry, see: Ritter, K. Synthesis 1993, 735; P. J. Stang, M.
Hanack, L. R. Subramanian, Synthesis 1982, 85.
[18] For a recent overviewon bite angles, see: P. W. N. M. Van Leeuwen,
P. C. J. Kamer, J. N. H. Reek, P. Dierkes, Chem. Rev. 2000, 100,
2741.
To a solution of (R)-33 (40 mg, 0.14 mmol) and allyltrimethylsilane (217 mL,
1.37 mmol) in CH2Cl2 (2.0 mL) was added trifluoroacetic acid anhydride
(96.5 mL, 0.68 mmol) at 08C. After stirring for 15 min at 08C, trifluoroacetic
acid (53 mL, 0.68 mmol) was added. After stirring for 3 h at 08C, the reaction
mixture was concentrated and purified by flash chromatography (20 ! 70%
ether/petroleum ether) to afford 64 (1.6:1 mixture of isomers) as a yellowoil;
1
yield: 10 mg (0.03 mmol, 21%). 64 (data of mixture of isomers): H NMR
(400 MHz, CDCl3): d ˆ 7.76 (d, J ˆ 8.3 Hz, 2H), 7.26 (d, J ˆ 7.0 Hz, 2H),
5.87 5.83 (m, 1H), 5.14 4.99 (m, 2H), 4.41 4.39 (m, 1H), 3.57 (s, 3H), 2.47
(d, J ˆ 8.9 Hz, 2H), 2.41 (s, 3H), 2.18 2.11 (m, 2H), 1.96 1.85 (m, 2H), 1.39
(s, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 172.7, 145.56, 143.0, 134.5, 129.2,
127.7, 117.9, 69.5, 61.8, 51.9, 45.8, 37.5, 27.5, 24.7, 21.3; IR (film): n ˆ 2951,
‡
1753, 1344, 1156 cmÀ1; HRMS (FAB): calcd. for C17H24NO4S (MH )
[19] J. Cossy, D. Belotti, V. Bellosta, C. Boggio, Tetrahedron Lett. 1997, 38,
2677.
338.1426, found 338.1428.
82
Adv. Synth. Catal. 2002, 344, 70 83

Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino Acids
FULL PAPERS
[20] For recent examples, see e.g.: P. A. Jacobi, H. Liu, J. Org. Chem. 2000,
65, 7676; P. A. Jacobi, J. Guo, S. Rajeswari, W. J. Zheng, J. Org. Chem.
1997, 62, 2907; P. A. Jacobi, H. L. Brielamn, S. I. Hauck, J. Org.
Chem. 1996, 61, 5013.
[21] M. W. Kahn, N. G. Kundu, Synlett 1997, 1435.
[22] R. H. Summerville, P. Von Rague Schleyer, J. Am. Chem. Soc. 1974,
96, 1110.
[28] T. Jeffery, Tetrahedron Lett. 1999, 40, 1673; T. Jeffery, M. David,
Tetrahedron Lett. 1998, 39, 5751; T. Jeffery, Tetrahedron Lett. 1996, 52,
10113.
[29] For a recent reviewon N-acyliminium ions and related intermediates,
see: W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56,
3817.
[30] For some recent publications on tertiary N-acyliminium ions, see e.g.:
L. Ollero, G. Mentink, F. P. J. T. Rutjes, W. N. Speckamp, H.
Hiemstra, Org. Lett. 1999, 1, 1331; M. A. Brodney, A. Padwa, J.
Org. Chem. 1999, 64, 556; N. Langlois, P. K. Choudhury, Tetrahedron
Lett. 1999, 40, 2525; S. F. Martin, S. K. Bur, Tetrahedron Lett. 1997, 38,
7641.
[23] G. Kokotos, Synthesis 1990, 4, 299.
[24] D. F. Ewingand, D. G. Neilson, J. Org. Chem. 1966, 31, 390.
[25] Ref.[3b], pp. 510-511.
[26] N. Tsukada, Y. Yamamoto, Angew. Chem. Int. Ed. 1997, 36, 2477; Y.
Yamamoto, U. Radhakrishnan, Chem. Soc. Rev. 1999, 28, 199.
[27] D. Bouyssi, J. Gore, G. Balme, Tetrahedron 1992, 48, 10103.
[31] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.
Adv. Synth. Catal. 2002, 344, 70 83
83