Pauson-Khand reaction of amino acid derived 3-pyrrolines: New enantiopure scaffolds for diversity-oriented synthesis

Article abstract of DOI:10.1055/s-2006-958408

Amino acid derived 3-pyrrolines can be readily prepared in a single step in enantiomerically pure form by cycloalkylation of the corresponding amino esters with (Z)-1,4-dichloro-2-butene. Enantiopure azabicyclo[3.3.0]octenones can be then easily obtained

Full text of DOI:10.1055/s-2006-958408

LETTER
119
Pauson–Khand Reaction of Amino Acid Derived 3-Pyrrolines:
New Enantiopure Scaffolds for Diversity-Oriented Synthesis
P
auson–Khand
é
R
eaction
l
A
min
i
oAcid
x
D
erived3-Pyrroli
C
ne
s
uevas,a Carmen García-Granda,a Helmut Buschmann,b Antoni Torrens,b Susana Yenes,b Miquel A. Pericàs*a,c
a
Institute of Chemical Research of Catalonia (ICIQ), Avda. Països Catalans, 16, 43007 Tarragona, Spain
Fax +34(977)920222; E-mail: mapericas@iciq.es
b
c
Laboratorios Dr. Esteve, S.A., Avda. Mare de Deu de Montserrat, 221, 08041 Barcelona, Spain
Departament de Química Orgànica, Universitat de Barcelona, 08028 Barcelona, Spain
Received 24 September 2006
O
O
Abstract: Amino acid derived 3-pyrrolines can be readily prepared
in a single step in enantiomerically pure form by cycloalkylation of
the corresponding amino esters with (Z)-1,4-dichloro-2-butene.
Enantiopure azabicyclo[3.3.0]octenones can be then easily obtained
through an unprecedented Pauson–Khand reaction followed by
diastereomer separation.
R2O
R2O
NH2
N
R1
R1
2
1
O
O
R2O
PKR
N
R3
Key words: Pauson–Khand reaction, pyrrolines, amino acids,
R1
cyclization, alkynes
3
Scheme 1
The Pauson–Khand reaction (PKR) is a powerful method
for the construction of cyclopentenones from alkynes,
alkenes, and carbon monoxide that receives continued
attention.1 Although not much-explored towards this end,
the PKR offers enormous possibilities for diversity orient-
ed synthesis, since both the alkyne and the olefin partner
tolerate a wide variety of substituents being in most cases
available from commercial sources.
Thus, our first aim was developing a short and efficient
synthesis of the enantiopure, amino acid derived 3-pyrro-
lines 2. We were pleased to find (Table 1) that treatment
of amino acid (ethyl or methyl) esters 1 with (Z)-1,4-
dichloro-2-butene in dichloromethane at room tempera-
ture directly affords 3-pyrrolines 2 in good yield.4
The best reaction conditions involved the use of an excess
(3.5 equiv) of the amino acid ester in the absence of any
added base, since the unreacted starting material can be
easily recovered and recycled.5,6
For medicinal chemistry purposes, Pauson–Khand ad-
ducts involving derivatives of the proteinogenic amino
acids are particularly interesting and, in fact, some syn-
thetic effort has been devoted to this goal.2 Up to now,
however, only the intramolecular PKR of unsaturated
amino acid derivatives has been exploited, so that diversi-
ty arising from the amino acid nature is strongly limited.
This direct procedure, while avoiding known intrinsic
problems associated to the key ring-closing-metathesis
step in the previous approach,3 takes place without the
need of nitrogen basicity deactivation by strong Lewis
acids. This should represent a clear advantage when race-
mization-prone substrates are involved in the reaction.
We reasoned that construction of a symmetrical hetero-
cycle on the free amino group of an amino acid derivative
could lead to a family of substrates incorporating all the
diversity of natural (or unnatural) amino acids, and allow-
ing this diversity to be transmitted and multiplied in the
corresponding adducts.
With pyrrolines 2 in hand, conditions for its PKR with ter-
minal alkynes were developed. Neither the classical ther-
mal conditions nor activation with amine N-oxides (NMO
or TMAO)7,8 led to practical yields in the reaction with the
dicobalt hexacarbonyl complex of phenylacetylene. On
the other hand, the activation with Lewis bases introduced
by Sugihara and co-workers proved to be much more
successful.9 Among the different Lewis bases tested (thio-
anisole, cyclohexylamine, and DMSO), the last one
provided the best results in the cycloaddition, and was
used in the PKR of 2a–f with the dicobalt hexacarbonyl
complexes of phenylacetylene and 1-hexyne. Results of
these cycloadditions have been summarized in Table 2.
Once the compromise between ring-strain and tendency to
intervene in PKR had been considered, amino acid de-
rived 3-pyrrolines appeared as the intermediates of choice
for our purpose (Scheme 1).
However, the use of heterocycles of this class in the PKR
has never been reported, and even the preparation of the
amino acid derived ones through a multistep sequence has
only been very recently disclosed.3
Although yields recorded in the cycloaddition are moder-
ate, the reactions are normally very clean and the adducts
are easily isolated by column chromatography. This fact,
together with the important increase in molecular com-
SYNLETT 2007, No. 1, pp 0119–0122
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-958408; Art ID: G25906ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
1.
2
0
0
7

120
F. Cuevas et al.
LETTER
Table 1 Direct Synthesis of 3-Pyrrolines 2 from Amino Acid Esters
Table 2 Pauson–Khand Reaction of 3-Pyrrolines 2
R3
O
O
O
O
O
R2O
R2O
R2O
Cl
Cl
R2O
Co2(CO)6
R3
NH2
N
N
N
CH2Cl2, r.t., 24 h
R1
R1
R1
R1
1,2-DCE, DMSO
83 °C, 24 h
2
3
Substrate
Product
Yield (%)
52
Substrate R1
R2
R3
Ph
Product
3ap
3ab
3bp
3bb
3cp
3cb
3dp
3db
3ep
3eb
3fp
Yield (%)
18
O
O
NH2
NH2
N
N
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
Me
Et
EtO
EtO
Me
Et
n-Bu
Ph
46
1a
2a
52
84
O
i-Pr
Et
20
O
EtO
i-Pr
Et
n-Bu
Ph
27
EtO
i-Bu
i-Bu
Bn
Me
Me
Me
Me
Me
Me
Me
Me
35
1b
2b
n-Bu
Ph
34
O
O
NH2
N
46
MeO
MeO
Bn
n-Bu
Ph
47
Ph
35
1c
2c
65
65
76
O
O
Ph
n-Bu
Ph
36
NH2
N
N
N
MeO
MeO
CH2Ind
CH2Ind
42
2f
n-Bu
3fb
29
1d
2d
O
O
Since the absolute configuration at the aminoacidyl resi-
due has been kept constant over the whole series of sub-
strates, the absolute configuration of the bicyclic system
in the whole series of products 3 has been assigned by
analogy.
NH2
MeO
MeO
1e
2e
O
O
NH2
MeO
MeO
N
N
H
H
1f
2f
plexity introduced by the PKR and the possibilities for
further elaboration offered by azabicyclooctenones 3
makes this approach particularly attractive.
As it could be anticipated from the distance (three bonds)
between the chiral center in the amino acid moiety and the
two newly created stereocenters in the Pauson–Khand ad-
ducts (Figure 1), the PKR takes place without stereocon-
trol, leading to ca. 1:1 mixtures of diastereomers. In any
case, the diastereomeric mixtures can be readily separated
Figure 1 Crystal structure of the slow-eluting diastereomer of 3cp
by preparative HPLC (Chiralcel® OD-H column), so that and configurational assignment of the diastereomers of 3
enantio- and diastereomerically pure adducts 3 are readily
available.10
Quite interestingly, azabicyclooctenones 3 are a conve-
nient starting point for further molecular complexity.
While the aminoacidyl residue could be used for growing
peptide chains, additions of different types can be per-
formed on the b-unsubstituted a,b-unsaturated moiety.
In the case of 3cp, the slow-eluting diastereomer could be
crystallized, and the obtained crystals submitted to X-ray
diffraction. In this manner, the absolute configuration at
the bicyclic system could be clarified (Figure 1).
Synlett 2007, No. 1, 119–122 © Thieme Stuttgart · New York

LETTER
Pauson–Khand Reaction of Amino Acid Derived 3-Pyrrolines
121
13C NMR (75 MHz, CDCl3): d = 172.67, 127.08, 70.72,
In summary, we have developed a convenient one-step
procedure for the cycloalkylation of the amino group in
amino esters leading to enantiomerically pure 3-pyrro-
lines, and have reported the first examples of Pauson–
Khand reaction of this class of heterocyclic olefins. The
corresponding adducts, which possess the characteristics
of dipeptide-like scaffolds, offer interesting structural
characteristics for further elaboration into more diverse
structures. Further research aimed at expanding the scope
of this synthetic strategy is underway in our laboratories
and will be reported in due course.
59.70, 55.79, 29.16, 19.94, 19.07, 14.45 ppm. MS (EI+):
m/z = 198.1 [M + H+].
Compound 2e: colorless oil. 1H NMR (400 MHz, CDCl3):
d = 7.48 (m, 2 H), 7.34 (m, 3 H), 5.75 (s, 2 H), 4.32 (s, 1 H),
3.69 (s, 3 H), 3.54 (m, 2 H), 3.52 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): d = 172.23, 137.31, 128.65, 128.52,
128.33, 127.20, 72.56, 58.09, 52.09 ppm. MS (EI+): m/z =
218.1 [M + H]+.
(7) (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
Tetrahedron Lett. 1990, 31, 5289. (b) Jeong, N.; Chung, Y.
K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991, 204.
(8) (a) Shen, J.-K.; Gao, Y.-C.; Shi, Q.-Z.; Basolo, F.
Organometallics 1989, 8, 2144. (b) Shen, J.-K.; Shi, Y.-L.;
Gao, Y.-C.; Shi, Q.-Z.; Basolo, F. J. Am. Chem. Soc. 1988,
110, 2414. (c) Shi, Y.-L.; Gao, Y.-C.; Shi, Q.-Z.; Kershner,
D. L.; Basolo, F. Organometallics 1987, 6, 1528.
Acknowledgment
F.C. and C.G. thank the Torres-Quevedo program for contracts.
(9) (a) Sugihara, T.; Yamaguchi, M.; Nishizawa, M. Chem. Eur.
J. 2001, 7, 1589. (b) Sugihara, T.; Yamada, M.; Yamaguchi,
M.; Nishizawa, M. Synlett 1999, 771. (c) Sugihara, T.;
Yamaguchi, M. Synlett 1998, 1384. (d) Sugihara, T.;
Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko, C. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2801.
References and Notes
(1) (a) Blanco-Urgoiti, J.; Anorbe, L.; Pérez-Serrano, L.;
Domínguez, G.; Pérez-Castells, J. Chem. Soc. Rev. 2004, 33,
32. (b) Pericàs, M. A.; Balsells, J.; Castro, J.; Marchueta, I.;
Moyano, A.; Riera, A.; Vázquez, J.; Verdaguer, X. Pure
Appl. Chem. 2002, 74, 167. (c) Brummond, K. M.; Kent, J.
L. Tetrahedron 2000, 3263. (d) Chung, Y. K. Coord. Chem.
Rev. 1999, 188, 297.
(2) (a) Brummond, K. M.; Curran, D. P.; Mitasev, B.; Fischer,
S. J. Org. Chem. 2005, 70, 1745. (b) Tanimori, S.; Sunami,
T.; Fukubayashi, K.; Kirihata, M. Tetrahedron 2005, 61,
2481. (c) Rh-mediated PKR: Manku, S.; Curran, D. P. J.
Comb. Chem. 2005, 7, 63. (d) Jiang, B.; Xu, M. Angew.
Chem. Int. Ed. 2004, 43, 2543. (e) Guenter, M.; Gais, H. J.
J. Org. Chem. 2003, 68, 8037. (f) Jiang, B.; Xu, M. Org.
Lett. 2002, 4, 4077. (g) Witulski, B.; Gössmann, M. Chem.
Commun. 1999, 1879. (h) Bolton, G. L.; Hodges, J. C.;
Rubin, J. R. Tetrahedron 1997, 53, 6611. (i) Bolton, G. L.
Tetrahedron Lett. 1996, 37, 3433.
(10) General Procedure for the Pauson–Khand Reaction of
Amino Acid Derived 3-Pyrrolines.
A mixture of alkyne (0.60 mmol) and Co2(CO)8 (0.65 mmol)
in 1,2-dichloroethane (2 mL) was stirred at r.t. for 2 h. A
solution of 2a–f (0.50 mmol) in 1,2-dichloroethane (1 mL)
and DMSO (1.75 mmol) was added and the mixture was
heated at 83 °C for 24 h. The reaction mixture was cooled at
r.t., filtrated through Celite® and washed with CH2Cl2. The
filtrate was concentrated and purified by flash chromatog-
raphy on silica gel, gradient with neat n-hexane to n-hexane–
EtOAc (1:2). Compounds 3 were obtained as mixture of two
diastereomers that were purified by HPLC: Chiralcel®
OD-H (1 cm × 25 cm), n-hexane–2-PrOH, 5 mL/min.
Spectral Data for Selected Compounds.
Compound 3cp: white solid.
Diastereomer 1: (2S)-methyl 4-methyl-2-[(3aR,6aS)-4-oxo-
5-phenyl-1,3a,4,6a-tetrahydrocyclo penta[c]pyrrol-2 (1H)-
yl]pentanoate.1H NMR (400 MHz, CDCl3): d = 7.67 (m, 2
H), 7.65 (d, J = 3.0 Hz, 1 H), 7.40–7.31 (m, 3 H), 3.68 (s, 3
H), 3.38 (m, 2 H), 3.16 (d, J = 9.0 Hz, 1 H), 2.89 (m, 1 H),
2.84 (m, 2 H), 2.77 (m, 1 H), 1.58–1.42 (m, 3 H), 0.85 (d,
J = 6.5 Hz, 3 H) 0.80 (d, J = 6.5 Hz, 3 H) ppm. HPLC
[Chiralcel® OD-H (0.46 cm × 25 cm), n-hexane–2-PrOH
(99:1), 0.5 mL/min, 254 nm]: r.t. 11.7 min. HRMS (ES+):
m/z calcd for C20H25NO3 + H+: 328.1913; found: 328.1923.
[a]D20 +46.1 (c 1, CHCl3).
Diastereomer 2: (2S)-methyl 4-methyl-2-[(3aS,6aR)-4-oxo-
5-phenyl-1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2 (1H)-
yl]pentanoate. 1H NMR (400 MHz, CDCl3): d = 7.70–7.65
(m, 3 H), 7.40–7.30 (m, 3 H), 3.68 (s, 3 H), 3.37 (m, 2 H),
3.18 (d, J = 9.0 Hz, 1 H), 2.92 (m, 2 H), 2.82 (m, 2 H), 1.59–
1.44 (m, 3 H), 0.86 (d, J = 6.5 Hz, 3 H), 0.80 (d, J = 6.5 Hz,
3 H) ppm. HPLC [Chiralcel® OD-H (0.46 cm × 25 cm), n-
hexane–2-PrOH (99:1), 0.5 mL/min, 254 nm]: r.t. 15.8 min.
HRMS (ES+): m/z calcd for C20H25NO3 + H+: 328.1913;
found: 328.1922. [a]D20 –79.2 (c 1, CHCl3).
(3) Yang, Q.; Xiao, W. J.; Yu, Z. Org. Lett. 2005, 7, 871.
(4) For the use of this reagent in the synthesis of simple 3-
pyrrolines, see: Mahboobi, S.; Fischer, E. C.; Eibler, E.;
Wiegrebe, W. Arch. Pharm. 1988, 321, 423.
(5) The preparation of 2a–f can also be performed, albeit in
somewhat decreased yield, by treating cis-1,4-dichloro-2-
butene with 1.1 equiv of amino ester hydrochloride and 3.5
equiv of diisopropylethylamine in CH2Cl2 at r.t. for 24 h. In
this way, 2d is obtained in 57% yield (vs. 65% yield with the
standard procedure).
(6) Representative Procedure for the Synthesis of 2a–f.
A mixture of cis-1,4-dichloro-2-butene (1 mmol) and amino
ester 1a–f (3.5 mmol) in CH2Cl2 (1 mL) was stirred at r.t. for
24 h. Then, CH2Cl2 was added and the precipitated was
filtered. The filtrate was washed with H2O and sat. solution
of NaCl, dried over Na2SO4, filtered and concentrated. The
crude was purified by flash chromatography on silica gel
with EtOAc and n-hexane, gradient 1:2 to 2:1.
Spectral Data for Selected Compounds.
Compound 2a: yellow oil. 1H NMR (400 MHz, CDCl3): d =
5.76 (s, 2 H), 4.17 (q, J = 7 Hz, 2 H), 3.63 (m, 4 H), 3.46 (q,
J = 7 Hz, 1 H), 1.36 (d, J = 7 Hz, 3 H), 1.26 (t, J = 7 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): d = 173.86, 127.13,
60.35, 60.28, 56.55, 17.22, 14.26 ppm. MS (EI+): m/z =
170.1 [M + H+].
Compound 3ab: yellow oil.
Diastereomer 1: (2S)-ethy l2-[(3aR,6aS)-5-butyl-4-oxo-
1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2 (1H)-
yl]propanoate.1H NMR (400 MHz, CDCl3): d = 7.12 (m, 1
H), 4.14 (q, J = 7 Hz, 2 H), 3.26 (m, 1 H), 3.22 (m, 1 H), 3.06
(d, J = 9 Hz, 1 H), 2.76 (m, 2 H), 2.66 (m, 2 H), 2.16 (m, 2
H), 1.45 (m, 2 H), 1.32 (m, 2 H), 1.26 (d, J = 7 Hz, 3 H), 1.25
(t, J = 7 Hz, 3 H), 0.89 (t, J = 7 Hz, 3 H) ppm. HPLC
Compound 2b: yellow oil. 1H NMR (400 MHz, CDCl3): d =
5.75 (s, 2 H), 4.10 (q, J = 7 Hz, 2 H), 3.70 (m, 2 H), 3.51 (m,
2 H), 2.98 (d, J = 7 Hz, 1 H), 1.95 (m, 1 H), 1.20 (t, J = 7 Hz,
3 H), 0.96 (d, J = 7 Hz, 3 H), 0.86 (d, J = 7 Hz, 3 H) ppm.
Synlett 2007, No. 1, 119–122 © Thieme Stuttgart · New York

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F. Cuevas et al.
LETTER
[Chiralcel® OD-H (0.46 cm × 25 cm), n-hexane–2-PrOH
(99.5:0.5), 0.5 mL/min, 254 nm]: r.t. 14.46 min. HRMS
(ES+): m/z calcd for C16H26NO3 + H+: 280.1913; found:
280.1906. [a]D20 +70.5 (c 1, CHCl3).
Diastereomer 2: (2S)-ethyl 2-[(3aS,6aR)-5-butyl-4-oxo-
1,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2 (1H)-
yl]propanoate. 1H NMR (400 MHz, CDCl3): d = 7.13 (m, 1
H), 4.14 (q, J = 7 Hz, 2 H), 3.26 (m, 2 H), 3.04 (m, 1 H), 2.78
(m, 2 H), 2.72 (m, 2 H), 2.16 (m, 2 H), 1.45 (m, 2 H), 1.33
(m, 2 H), 1.27 (d, J = 7 Hz, 3 H), 1.25 (t, J = 7 Hz, 3 H), 0.89
(t, J = 7 Hz, 3 H) ppm. HPLC [Chiralcel® OD-H (0.46 cm ×
25 cm), n-hexane–2-PrOH (99.5:0.5), 0.5 mL/min, 254 nm]:
r.t. 15.80 min. HRMS (ES+): m/z calcd for C16H26NO3 + H+:
280.1913; found: 280.1906. [a]D20 –83.6 (c 1, CHCl3).
Synlett 2007, No. 1, 119–122 © Thieme Stuttgart · New York

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