Sequential hydrozirconation/cyclization of dienes, a new route toward trans 2-substituted vinylcyclopentanes

Article abstract of DOI:10.1021/ol500400s

The diastereoselective synthesis of trans-2-substituted vinylcyclopentanes is described. The method is based on the intramolecular coupling of 7-methoxy-1,5-dienes involving a sequential activation of the C=C double bonds via hydrozirconation and TMSOTf-promoted allylation.

Full text of DOI:10.1021/ol500400s

Letter
pubs.acs.org/OrgLett
Sequential Hydrozirconation/Cyclization of Dienes, a New Route
toward Trans 2‑Substituted Vinylcyclopentanes
Sebastien Clergue and Jean-Luc Vasse*
́
́ ́
Institut de Chimie Moleculaire de Reims, CNRS (UMR 7312) and Universite de Reims, 51687 Reims Cedex 2, France
S
* Supporting Information
ABSTRACT: The diastereoselective synthesis of trans-2-
substituted vinylcyclopentanes is described. The method is
based on the intramolecular coupling of 7-methoxy-1,5-dienes
involving a sequential activation of the CC double bonds via
hydrozirconation and TMSOTf-promoted allylation.
wing to the ubiquity of the cyclopentane skeleton in a
Onumber of biologically active and naturally occurring
molecules, the development of methodologies allowing access to
functionalized cyclopentanes remains important. In this context,
2-substituted vinylcyclopentanes, which are amenable to a wide
range of synthetic transformations, may constitute valuable
building blocks.
Several methodologies leading to vinylcyclopentanes are
reported in the literature. Among them, Ti(III)-,1 Ti(II)-,
Zr(II)-,2 Pd-,3 and Au4-mediated coupling of dienes and a Ti/Ni
multimetallic intramolecular Heck-type5 and SmI2-promoted6
coupling of iodoalkane/alkene are emerging. Alternatively,
vinylcyclopentanes could be prepared via an intramolecular
allylic substitution.7 This strategy relies on the generation of a
C−metal bond onto substrates containing a reactive allylic
fragment and could also be applied to vinylpyrrolidine synthesis.8
The hydrozirconation of alkenes is a powerful method for
generating functionalized zirconocenes. Moreover, the hydro-
zirconation of alkenes is highly sensitive to steric hindrance,
rendering possible the chemoselective hydrometalation of
substrates containing two CC double bonds with a different
degree of substitution. This high chemoselectivity allows the
development of intramolecular processes from dienes through a
sequential activation of the two CC double bonds.9
Figure 1. Approach toward vinylcyclopentanes.
Table 1. Optimization of the Cyclization
a
entry
1
additive
convertion
1
2
3
4
5
1a
1a
1b
1b
CuBr·SMe2
CuI
56%
20%
−
BF3·OEt2
TMSOTf
TMSOTf
b
78% (52%)
c
1c
47%
According to this approach, access to vinylcarbocycles from
dienes could be envisioned by combining a chemoselective
hydrozirconation to an intramolecular allylic addition. Such a
strategy could be developed from dienes combining a terminal
alkene to an internal allylic fragment.
a
Determined from the 1H NMR spectrum of the crude reaction
b
c
mixture. Isolated yield. 2 equiv of Cp2Zr(H)Cl were used.
equiv) until complete dissolution. Hydrolytic treatment gave the
expected allylbromide, exclusively.11 The cyclization conditions
under Cu catalysis were first investigated (Table 1, entries 1 and
2). Whereas a low conversion was observed with CuI, the use of
CuBr·Me2S gave an encouraging result. In parallel, the
electrophilic activation strategy was also tested, with the
analogous methyl ether 1b. This approach was proven to be
more efficient.12 However, the choice of the Lewis acid is crucial
Two activation modes could be considered to promote the
cyclization: (i) by a Zr → Cu transmetalation, zirconocenes
being known for acting as alkyl or vinyl promotors in Cu-
catalyzed allyllic addition10 or (ii) by a Lewis acid activation of
the residual allylic fragment (Figure 1).
In this paper, we disclose a new access to 2-substituted
vinylcyclopentanes from dienes via a sequential activation of the
two CC double bonds.
The present study began by checking the chemoselectivity of
the hydrozirconation reaction toward dienes. Thus, model
substrate 1a was put in a reaction with the Schwartz reagent (1.2
Received: February 7, 2014
Published: February 26, 2014
© 2014 American Chemical Society
1506
dx.doi.org/10.1021/ol500400s | Org. Lett. 2014, 16, 1506−1509

Organic Letters
Letter
Scheme 1. Diene vs Vinylcyclopentane Formation
Table 2. Substrate Scope
a
entry
n
R
X
additive
4 (yield)
dr
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2
Ph
Ph
OMe
Br
TMSOTf
CuBr·SMe2
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
4a (72%)
4a (36%)
4b (60%)
4c (68%)
4d (25%)
4e (51%)
4f (61%)
−
4:1
4:1
2-Br-C6H4
PMP
OMe
OMe
OMe
OMe
OMe
OMe
3.8:1
4:1
b
2-thiophenyl
CH2Ph
4:1
2.8:1
2.9:1
−
BnO-(CH2)3
Ph
to promote the cyclization. While the use of a stoichiometric
amount of TMSOTf gave the expected product, polymerization
was observed when using BF3·OEt2. Finally, the allylic alcohol 1c
was also tested but did not give satisfactory results.
These optimal conditions were next applied to analogous
substrates bearing one or two phenyl groups. In these cases, a
diene was obtained along with the desired cyclopentane (Scheme
1). By using 1d as the substrate, a 1:1.3 mixture of cyclopentane
and diene, which could not be separated, was obtained.13 In the
case of 1e, the proportion of diene increased to 7.6:1.
a
b
Isolated product. Obtained after 12 h of stirring.
Scheme 2. Diastereoselective Synthesis of 2-Substituted
Vinylcyclopentanes
Interestingly, cyclopentane 2d was obtained as a 13:1 mixture
of diastereomers in favor of the trans-isomer.14
The competitive diene formation may be due to steric
congestion located at the proximity of the cyclization site. The
diene is assumed to result from a [1,2]-phenyl shift onto the
activated allylic ether, concerted with domino metallo-
abstraction and ethylene exclusion. Similar metallo-abstraction
and ethylene exclusion leading to alkenes have been previously
observed from 4-trimethylstannylbutan-1-ol upon Lewis acid
treatment.15
The possibility of performing a diastereoselective cyclization,
from substrates incorporating a single substituant closely located
with respect to the ring-closure site, was next examined. For that
purpose, a series of dienes 316 were prepared from known
aldehydes17 and tested. In a typical experiment, the Schwartz
reagent (1.2 equiv) was added to a solution of 3 in CH2Cl2 and
stirred until complete dissolution, and then TMSOTf (1 equiv)
was added. The mixture was stirred for 1 h at rt and quenched
with water.
From this series of substrates, vinylcyclopentanes 4 were the
only identified products (Table 2). The method could be applied
to the synthesis of vinylcyclopentanes bearing, at the 2-position,
an aromatic (Table 2, entries 1−4), an alkyl substituent (entry 6),
or a chain including a protected alcohol (Table 2, entry 7).
Compound 4d, bearing a thiophene group (Table 2, entry 5),
was also obtained, however in low yield, even after a prolonged
reaction time. Identical diastereoselectivities were observed
independently of the cyclization strategy employed (Table 2,
entries 1 and 2) and remained poor (Table 2). Extension of this
methodology to vinylcyclohexanes was initiated; however, a
complex mixture of vinylcyclopentanes and vinylcyclohexanes
was obtained (Table 2, entry 8).
In order to improve the stereoselectivity of the cyclization, we
decided to modify the allylether fragment.
The incorporation of a methyl group onto the allylic fragment
afforded cyclopentene 4′g by applying the above conditions.
Nevertheless, it was pleasantly found that the addition of
TMSOTf at 0 °C prevents the CC migration and ensures a
Figure 2. Diastereoselectivity rationale.
totally diastereoselective process, affording the trans-isomer.18
Thus, trans-2-substituted vinylcyclopentanes with an aromatic or
an alcohol protected chain could be obtained (Scheme 2).
Considering that the cyclization might proceed through a
pseudochair-like transition state, the high diastereoselectivity
observed in the case of 4g−i would originate from a marked
difference in the relative rates of cyclization of the two possible
reactive rotameric forms A and B (Curtin−Hammett principle)
(Figure 2). Assuming that the R substituent adopts a quasi-
equatorial orientation, A would suffer from severe steric
1507
dx.doi.org/10.1021/ol500400s | Org. Lett. 2014, 16, 1506−1509

Organic Letters
Letter
repulsions. The cyclization would thus favorably occur from B to
give the trans isomer. In contrast, it is likely that the relative rates
of cyclization of C and D, precursors of 4a−f, are less contrasted,
leading to a cis/trans mixture of isomers.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jean-luc.vasse@univ-reims.fr.
The synthetic interest of this approach relies on the possibility
of functionalizing the CC double bond to generate valuable
building blocks. It was exemplified by converting cyclopentane
4g into the allylic alcohol 5 in a two step sequence involving the
formation of an epoxide,19 followed by treatment with a base20
(Scheme 3).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The CNRS, for financial support, and Anthony Robert, Carine
Machado, Sylvie Lanthony, and Dr. Dominique Harakat of the
́
Institut de Chimie Moleculaire de Reims, for technical assistance,
are gratefully acknowledged.
Scheme 3. Synthetic Applications
REFERENCES
■
(1) Campana, A. G.; Bazdi, B.; Fuentes, N.; Robles, R.; Cuerva, J. M.;
̃
Oltra, J. E.; Porcel, S.; Echavarren, A. M. Angew. Chem., Int. Ed. 2008, 47,
7515−7519.
(2) (a) Knight, K. S.; Waymouth, R. M. Organometallics 1994, 13,
2575−2577. (b) Takahashi, T.; Kondakov, D. Y.; Suzuki, N.
̌
Organometallics 1994, 13, 3411−3412. (c) Korotvicka, A.;
Hybelbauerova,
́
S.; Kotora, M. Synlett 2009, 2445−2448. (d) Betík,
R.; Herrmann, P.; Kotora, M. Eur. J. Org. Chem. 2010, 646−655.
̌
́
̆ ̌ ̌ ́
(e) Herrmann, P.; Kotora, M.; Budesínsky, M.; Saman, D.; Císaro I.
va,
̆ ̌
Org. Lett. 2006, 8, 1315−1318. (f) Herrmann, P.; Budesínsky, M.;
́
Kotora, M. J. Org. Chem. 2008, 73, 6202−6206. (g) Herrmann, P.;
Kotora, M. Tetrahedron Lett. 2007, 48, 3209−3212.
(3) (a) Doi, T.; Iijima, Y.; Takasaki, M.; Takahashi, T. J. Org. Chem.
2007, 72, 3667−3671. (b) Oppolzer, W.; Kuo, D. L.; Hutzinger, M. W.;
Leg
6216.
(4) Porcel, S.; Lop
Angew. Chem., Int. Ed. 2008, 47, 1883−1886.
(5) Millan, A.; Alvarez de Cienfuegos, L.; Miguel, D.; Campana, A. G.;
́
er, R.; Durand, J.-O.; Leslie, C. Tetrahedron Lett. 1997, 38, 6213−
́
ez-Carrillo, V.; García-Yebra, C.; Echavarren, A. M.
́
̃
Cuerva, J. M. Org. Lett. 2012, 14, 5984−5987.
Additionally, access to polycyclic skeletons could be
envisioned by coupling together the two branches of the
cyclopentane. As an example, a seven-membered ring could be
annulated to the cyclopentane through an ene reaction. The
required aldehyde 6 was prepared from 4i.21 Subsequent
Et2AlCl-promoted cyclization22 provided 7 as a single diaster-
eoisomer (Scheme 3). This tricyclic skeleton constitutes the
framework of naturally occurring presphaerene, isolated from the
red alga sphaerococcus coronopifolius.23
In summary, an efficient diastereoselective method for the
construction of 2-substituted vinylcyclopentanes is described.
The method involves the successive activation of the two CC
double bonds of dienes via chemoselective hydrozirconation,
followed by the electrophilic activation of an allylic ether which
was preserved during the hydrozirconation stage.
Trans 2-substituted vinylcyclopentanes could be obtained in a
highly diastereoselective manner by adequately substituting the
allylic ether fragment. The synthetic potential of the method was
illustrated by the preparation of 1,2-substituted cyclopentane
bearing two functional groups and by the diastereoselective
synthesis of an original tricyclic skeleton which opens the way to
the synthesis of a presphaerene analogue.
(6) Ferjani, M. B. S.; Zhou, Z.; Bennett, S. M. Tetrahedron 2004, 60,
8113−8130.
(7) (a) Rychnovsky, S. C.; Takaoka, L. R. Angew. Chem., Int. Ed. 2003,
42, 818−820. (b) Christoph, G.; Hoppe, D. Org. Lett. 2002, 4, 2189−
2192. (c) La Cruz, T. E.; Rychnovsky, S. D. Chem. Commun. 2004, 168−
169. (d) Kriek, A.; Remacle, B.; Mercier, J. Synlett 2000, 1443−1446.
(e) Cooke, M. P., Jr.; Huang, J.-J. Synlett 1997, 535−536. (f) Harms, A.
E.; Stille, J. R.; Taylor, S. K. Organometallics 1994, 13, 1456−1464.
(g) Bailey, W. F.; Aspris, P. H. J. Org. Chem. 1995, 60, 754−757.
(h) Broka, C. A.; Shen, T. J. Am. Chem. Soc. 1989, 111, 2981−2984.
(8) Coldham, I.; Price, K. N.; Rathmell, R. E. Org. Biomol. Chem. 2003,
1, 2111−2119.
(9) Azemi, T.; Kitamura, M.; Narasaka, K. Tetrahedron 2003, 60,
1339−1344.
(10) (a) Wipf, P. Synthesis 1993, 537−557. (b) Wipf, P.; Takahashi, H.
J. Chem. Soc., Chem. Commun. 1996, 2675−2676. (c) Yoshifuji, M.;
Loots, M.; Schwartz, J. Tetrahedron Lett. 1997, 15, 1303−1306. (d) Sato,
A.; Ito, H.; Yamaguchi, Y.; Taguchi, T. Tetrahedron Lett. 2000, 41,
10239−10243. (e) Doherty, S.; Knight, J. G.; Robins, E. G.; Scanlan, T.
H.; Champkin, P. A.; Clegg, W. J. Am. Chem. Soc. 2001, 123, 5110−5111.
(f) Sato, A.; Ito, H.; Okada, M.; Nakamura, Y.; Taguchi, T. Tetrahedron
Lett. 2005, 46, 8381−8383.
(11) Hydrolytic reaction providing an allylbromide:
ASSOCIATED CONTENT
■
(12) For a related hydrozirconation/cyclization sequence, see: Harada,
S.; Kowase, N.; Tabuchi, N.; Taguchi, T.; Dobashi, Y.; Dobashi, A.;
Hanzawa, Y. Tetrahedron 1998, 54, 753−766.
(13) Performing the addition of TMSOTf at different temperatures did
not signifcantly affect the ratio of products.
S
* Supporting Information
Experimental procedures and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1508
dx.doi.org/10.1021/ol500400s | Org. Lett. 2014, 16, 1506−1509

Organic Letters
Letter
(14) The relative configuration of 2d was deduced from alcohol 2′′d
obtained by OsO4-catalyzed oxidation of the mixture of 2d and 2′d
followed by NaBH4 reduction. The trans configuration in 2′′d was
determined by NOESY experiments.
(15) Fleming, I.; Rowley, M. Tetrahedron 1986, 42, 3181−3198.
(16) For detailed preparation of 3, see Supporting Information.
(17) Joosten, A.; Lambert, E.; Vasse, J.-L.; Szymoniak, J. Org. Lett.
2010, 12, 5128−5131.
(18) The trans configuration was determined by NOESY experiments.
(19) Ferraz, H. M. C.; Muzzi, R. M.; de O. Vieira, T.; Viertler, H.
Tetrahedron Lett. 2000, 41, 5021−5023.
(20) Mander, L. M.; Thomson, R. J. J. Org. Chem. 2005, 70, 1654−
1670.
(21) Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009,
131, 2056−2057.
(22) Kato, M.; Kosugi, H.; Ichiyanagi, T.; Hagiwara, H.; Kodaira, A.;
Kusakari, T.; Suzuki, T.; Ando, M.; Lee, J.; Drechsel, P.; Vogler, B.
Tetrahedron 2001, 57, 8243−8256.
(23) (a) Cafieri, F.; Ciminiello, P.; Santacroce, C.; Fattorusso, E.
Phytochemistry 1983, 22, 1824−1825. (b) Cafieri, F.; Napoli, L. D.;
Fattorusso, E.; Santacroce, C. Phytochemistry 1987, 26, 471−473.
(c) Lee, J.; Hong, J. J. Org. Chem. 2004, 69, 6433−6440.
1509
dx.doi.org/10.1021/ol500400s | Org. Lett. 2014, 16, 1506−1509