Diastereoselective Pauson-Khand reactions on aromatic substrates

Article abstract of DOI:10.1016/S0040-4039(01)00446-4

The synthesis of several natural products' frameworks is carried out by means of a diastereoselective intramolecular Pauson-Khand reaction promoted by molecular sieves. Diastereoselectivity is achieved only if a coordinating group is present at a convenie

Full text of DOI:10.1016/S0040-4039(01)00446-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3315–3317
Diastereoselective Pauson–Khand reactions on
aromatic substrates
Jaime Blanco-Urgoiti, Luis Casarrubios, Gema Dom´ınguez and Javier Pe´rez-Castells*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de CC. Experimentales y Te´cnicas, Universidad San Pablo-CEU,
Urb. Montepr´ıncipe, Boadilla del Monte, 28668 Madrid, Spain
Received 19 March 2001
Abstract—The synthesis of several natural products’ frameworks is carried out by means of a diastereoselective intramolecular
Pauson–Khand reaction promoted by molecular sieves. Diastereoselectivity is achieved only if a coordinating group is present at
a convenient distance from the alkene moiety. Naphthalenes can be obtained directly under refluxing toluene conditions. © 2001
Elsevier Science Ltd. All rights reserved.
The use of the Pauson–Khand reaction as key step for
obtaining natural products’ skeletons is becoming one
of the most useful applications of this cocyclization.1,2
Several new ways of promotion have allowed an
increase in the scope of this reaction, traditionally
limited to a few aliphatic systems.3 In particular, we
have recently introduced zeolites as new promoters for
Pauson–Khand reactions.4 Following our ongoing pro-
gram to extend the intramolecular Pauson–Khand reac-
tion to aromatic substrates, we have already reported
the use of aryl propargyl ethers5 and enynoindoles6 as
new substrates for this cocyclization. Nevertheless, sev-
eral natural products have tricyclic aromatic hydrocar-
bon structures and, thus, we herein apply our
methodology to the synthesis of indenes and tetralines.
We have found an interesting influence of coordinating
groups in the diastereoselectivity of this process.
reaction with an appropriate Grignard reagent, gave
alcohols 3a and 4a. These alcohols were submitted to
the Pauson–Khand reaction and were also converted
into the other starting materials. Thus, protection of
the hydroxyl with different groups gave compounds
3b–d and 4b,c. Phthalimido derivatives 3e and 4d were
also obtained by Mitsunobu reactions.
The Pauson–Khand reactions were carried out in all
cases under two different experimental conditions:
combining trimethylamine N-oxide (TMANO) with
molecular sieves in toluene at room temperature
(method A) and only with molecular sieves as pro-
moters in refluxing toluene (method B).8 The results are
summarized in Table 1.
All reactions gave good yields under both experimental
conditions except for substrates containing phthalimido
groups, which decomposed in refluxing toluene, and, in
the case of substrate 3e, did not react at room tempera-
ture. All the mixtures of diastereoisomers were sepa-
The starting materials were readily obtained from 2-
iodobenzyl alcohol 1, following Scheme 1. Shono-
gashira coupling,7 followed by MnO2 oxidation and
TMS
H
1) Pd(PPh3)2Cl2
CuI, nBuNH2
I
( )n
1)
BrMg
( )n
OH
TMS
H
CHO
2) TBAF
CH2OH
2) MnO2
2
n=0, 3a
n=1, 4a
1
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00446-4

3316
J. Blanco-Urgoiti et al. / Tetrahedron Letters 42 (2001) 3315–3317
Table 1. Synthesis of indenes 5 and tetralines 6
O
O
H
1) Co2(CO)8
4Å, Mol. Sieves
or
( )n
R
( )n
2) TMANO, r.t.
or
∆
R
n=0, 3
n=1, 4
n=0, 5
n=1, 6
7
Entry
Substrate
R
Method
Product
Trans/cisa
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
4a
4b
4c
4d
OH
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
5a
1:1
–
60b
–
Dec.c
5b
OTBS
OTBDPS
OAc
Phth
OH
2:1
4:1
2:1
4:1
1:1
1:1
–
80b
82b
52b
50b
87b
57b
–
5b
5c
5c
5d
5d
N.R.
Dec.c
6a
7
6b
6b
6c
6c+7
6d
N.R.
–
–
\19:1
–
77d,e
75d
64b
64b
75d,e
53d,e+15d
86d,e
–
OTBS
OAc
Phth
1:1
2:1
\19:1
\19:1
\19:1
–
a The trans/cis ratio was calculated by integration of well-resolved signals in the 1H NMR spectra of crude reaction mixtures. The major isomer
was identified by NOE experiments.
b Pure mixture of isomers.
c Total decomposition of starting material was observed.
d Pure material with correct spectroscopic data (1H, 13C NMR, IR).
e Only the trans isomer was detected by NMR
rated by column chromatography and the compounds
characterized. The relative stereochemistry of the
stereogenic carbons was assigned by NOE experiments
and were found to be trans for all the major products.
Compound 4a gave different products depending on the
reaction conditions. Thus, the hydroxy tetraline 6a was
obtained at room temperature, while in refluxing tolu-
ene, dehydration and isomerization lead to naphthalene
7 in good yields.9 Stereoselectivity of the process
deserves a mention. None of the reactions, in which
five-membered rings were formed, gave important
diastereoselectivities, the trans/cis ratio being slightly
better when raising the reaction temperature. On the
contrary, compounds 4, where the inducing stereogenic
center is further away, gave surprising results. When
reacting compound 4a, we only observed one product
in the NMR spectrum of the crude material. This was
also the case with compounds 4c and 4d, but not with
O
1) Ph3P=CHOMe
TMS
H
1) Co2(CO)8
4Å, Mol. Sieves
2) HCl, 1N
OH
H
2) TMANO, r.t.
3) CH2=CHMgBr
CHO
OH
4) TBAF
2
8
9, 75% (1:1)
1) Co2(CO)8
4Å, Mol. Sieves
2) ∆
O
7, 80%
Scheme 2.

J. Blanco-Urgoiti et al. / Tetrahedron Letters 42 (2001) 3315–3317
3317
the TBS-protected compound 4b, which reacted with
low diastereoselectivity. We can explain these results by
assuming that the electron pairs of the oxygen present
in all the substituents coordinate with the cobalt in a
similar fashion to that for the directed Pauson–Khand
reaction described by Kraft.10 This coordination may
neither occur in the case of compound 4b, due to the
bulky substituent, nor in compounds 3, due to the
proximity of the coordinating group to the double bond
that avoids complexation. We are currently investigat-
ing the structure of the cobalt complexes of these
starting materials and extending this methodology to
substrates bearing other coordinating groups.
Ingate, S. T.; Marco-Contelles, J. Org. Proc. Prep. Int.
1998, 123; (d) Shore, N. E. In Comprehensive Organo-
metallic Chemistry II; Hegedus, L. S., Ed.; Pergamon
Press: Oxford, 1995; Vol. 12, p. 703.
2. For some recent examples of natural products syntheses
using Pauson–Khand reactions, see: (a) Brummond, K.
M.; Lu, J.; Petersen, J. J. Am. Chem. Soc. 2000, 122,
4915; (b) Brummond, K. M.; Lu, J. J. Am. Chem. Soc.
1999, 121, 5087; (c) Kowalczyk, B. A.; Shmith, T. C.;
Dauben, W. G. J. Org. Chem. 1998, 63, 1379.
3. (a) Sugihara, T.; Yamada, M.; Yamaguchi, M.;
Nishizawa, M. Synlett 1999, 771; (b) Sugihara, T.;
Yamaguchi, M. Synlett 1998, 1384; (c) Sugihara, T.;
Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko, C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2801.
4. Pe´rez-Serrano, L.; Casarrubios, L.; Dom´ınguez, G.;
Pe´rez-Castells, J. Org. Lett. 1999, 1, 1187.
5. Pe´rez-Serrano, L.; Blanco-Urgoiti, J.; Casarrubios, L.;
Dom´ınguez, G.; Pe´rez-Castells, J. J. Org. Chem. 2000, 65,
3513.
In an attempt to verify that the distance of the coordi-
nating group to the double bond is crucial to achieve
diastereoselectivity, we prepared compound 8 following
the method of Scheme 2 and submitted it to the exper-
imental conditions described before. The results showed
no diastereoselectivity at room temperature, and the
formation of the naphthalene 7 under refluxing condi-
tions. Again, the hydroxy group seems to be too close
to the alkene to allow coordination to the cobalt.
6. Pe´rez-Serrano, L.; Gonza´lez-Pe´rez, P.; Casarrubios, L.;
Dom´ınguez, G.; Pe´rez-Castells, J. Synlett 2000, 1303.
7. Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495.
8. For experimental conditions, see Ref. 5.
In conclusion, indenes, tetralines and a naphthalene can
be prepared by diastereoselective Pauson–Khand reac-
tion of aromatic enynes. The reactions are achieved if
appropriate coordinating groups are situated at a suit-
able distance from the alkene moiety.
9. Spectroscopic data for 6a and 7. Compound 6a: Yellow
oil; 1H NMR (CDCl3) l 1.79 (td, 1H, J1=13.7 Hz,
J2=3.3 Hz), 2.16 (dd, 1H, J1=18.1 Hz, J2=3.3 Hz),
2.38–2.44 (m, 1H), 2.73 (dd, 1H, J1=18.1 Hz, J2=6.6
Hz), 3.17 (bs, 1H), 3.52–3.58 (m, 1H), 4.92–4.93 (m, 1H),
6.36 (d, 1H, J=2.2 Hz), 7.36–7.40 (m, 1H), 7.44–7.46 (m,
2H), 7.64 (d, 1H, J=7.7 Hz); 13C NMR (CDCl3) l 208.5,
174.9, 139.1, 131.6, 130.5, 129.1, 128.5, 126.6, 124.0, 66.9,
41.9, 37.1, 33.7; IR (neat) w 3390, 2910, 1690, 1665, 1595
cm−1. Compound 7: Colorless oil; 1H NMR (CDCl3) l
2.47 (s, 2H), 2.58 (s, 2H), 7.28 (d, 1H, J=8.2 Hz), 7.39 (t,
1H, J=6.6 Hz), 7.47 (dt, 1H, J1=6.6 Hz, J2=1.1 Hz),
7.60 (d, 1H, J=8.8 Hz), 7.78 (d, 1H, J=7.7 Hz), 8.01 (d,
1H, J=8.8 Hz); 13C NMR (CDCl3) l 205.2, 133.0, 132.7,
132.2, 131.1, 128.9, 128.3, 125.7, 125.6, 124.4, 123.6, 20.7,
Acknowledgements
This work was supported by grants from the DGES
(MEC-Spain, grant PB98-0053) and the Universidad
San Pablo-CEU (grant 2/99).
References
14.4; IR (neat) w 3050, 2920, 1690, 1600 cm−1
.
10. Krafft, M. E.; Scott, I. L.; Romero, R. H.; Feibelmann,
S.; Van Pelt, C. E. J. Am. Chem. Soc. 1993, 115, 7199 and
references cited therein.
1. For recent reviews, see: (a) Brummond, K. M.; Kent, J.
L. Tetrahedron 2000, 56, 3263; (b) Geis, O.; Schmalz,
H.-G. Angew. Chem., Int. Ed. Engl. 1998, 37, 911; (c)
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.