Exploiting the ring strain in bicyclo[2.2.1]heptane systems for the stereoselective preparation of highly functionalized cyclopentene, dihydrofuran, pyrroline, and pyrrolidine scaffolds

Article abstract of DOI:10.1021/ol2027009

The high strain of bicyclic systems drives retro-condensation reactions on bridgehead substituted bicyclo[2.2.1]hept-2-enes giving rise to orthogonally functionalized cyclopentene, 2,5-dihydrofuran, and 3-pyrroline scaffolds. Retro-Dieckman reactions were

Full text of DOI:10.1021/ol2027009

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6244–6247
Exploiting the Ring Strain in
Bicyclo[2.2.1]heptane Systems for the
Stereoselective Preparation of Highly
Functionalized Cyclopentene, Dihydrofuran,
Pyrroline, and Pyrrolidine Scaffolds
€
Elena Moreno-Clavijo, Antonio J. Moreno-Vargas,* Raphaelle Kieffer,
Therese Sigstam, Ana T. Carmona, and Inmaculada Robina*
ꢀ ꢁ
Department of Organic Chemistry, Faculty of Chemistry, University of Seville,
´ ꢀ
Prof. Garcıa Gonzalez, 1, 41012-Seville, Spain
ajmoreno@us.es; robina@us.es
Received October 7, 2011
ABSTRACT
The high strain of bicyclic systems drives retro-condensation reactions on bridgehead substituted bicyclo[2.2.1]hept-2-enes giving rise to
orthogonally functionalized cyclopentene, 2,5-dihydrofuran, and 3-pyrroline scaffolds. Retro-Dieckman reactions were easily carried out on
3-tosyl-(7-carba/7-oxa/7-aza)bicyclo[2.2.1]hept-5-en-2-ones. Retro-aldol reactions of N-Boc-3-tosyl-7-azabicyclo[2.2.1]hept-5-en-2-ol and func-
tionalized N-Boc-3-tosyl-7-azabicyclo[2.2.1]heptan-2-ols yield functionalized pyrrolidine scaffolds stereoselectively. The same reaction does not
work with corresponding norbornene and 7-oxanorbornene derivatives.
Five-membered rings, such as cyclopentane, tetrahydro-
furan, and pyrrolidine derivatives, are widely found in
natural products. In contrast to the situation with six-
memberedrings, five-membered ringsusuallydonotadopt
a single well-defined conformation. They exist as a rapidly
interconverting mixture of envelope and twist conforma-
tions, which makes the stereoselective synthesis of functio-
nalized cyclopentane, tetrahydrofuran, and pyrrolidine
derivatives more difficult compared with the synthesis of
corresponding six-membered analogues.
A common approach for the synthesis of diastereomeri-
cally pure substituted cyclopentanes is the use of confor-
mationally rigid norbornene derivatives ([2.2.1]bicyclic
systems) as precursors. The substituents can be introduced
stereoselectively onto the rigid norbornene ring in an easy
manner, so the cleavage of a suitable bond in the bicyclic
skeleton should lead to cyclopentane derivatives with well-
defined configurations. Important examples of this meth-
odology are reported for cyclopentane derivatives.1One of
them is the classical Corey’s synthesis of prostaglandins.2
On the other hand, a strategy based on the preparation
of functionalized tetrahydrofurans (as rare carbohydrate
analogues) from 7-oxabicyclo[2.2.1]hept-5-ene-2-yl deri-
vatives was developed by Vogel’s group with the so-called
“naked sugar” methodology3 and further extended to the
preparation of hydroxylated pyrrolidine derivatives from
(1) For recent review, see: Heasley, B. Eur. J. Org. Chem. 2009, 1477.
(2) (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W.
J. Am. Chem. Soc. 1969, 91, 5675. (b) Corey, E. J.; Schaaf, T. K.; Huber;
Koelliker, W. U.; Weinshenker, N. M. J. Am. Chem. Soc. 1970, 92, 397.
r
10.1021/ol2027009
Published on Web 11/08/2011
2011 American Chemical Society

7-azabicyclo[2.2.1]heptanes by the same research group
(“aza-naked sugars”).4 Other transformations of azabicyc-
lic systems into pyrrolidine and aminocyclohexene deriva-
tives have also been recently reported,5 including the
interesting synthesis of cis-2,5-disubstituted pyrrolidine
building blocks from 2-tropinone derivatives.6
All these strategies require the opening of the functio-
nalized bicyclic skeleton through well established reaction
sequences, such as ozonolysis and metathesis of double
bonds, BaeyerꢀVilliger oxidation of bicyclic ketones, and
subsequent lactone alcoholysis, among others. Norbor-
nene is more strained (ca. 100 kJ/mol) than the sum of
cyclopentene (23.4 kJ/mol) and cyclopentane (26.4 kJ/mol)
which is comparable with those of cyclobutane and cyclo-
propane (111 and 115 kJ/mol, respectively).7 The relatively
high ring strain of bicyclo[2.2.1]hept-2-ene systems has
been scarcely exploited for the construction of functiona-
lized cyclopentene derivatives.8
In this paper we present a novel synthesis of functiona-
lized cyclopentene, 2,5-dihydrofuran, 3-pyrroline, and pyr-
rolidine by ring opening on the appropriate strained
bicyclic β-keto- and β-hydroxysulfone through reverse
Dieckman and aldol reactions. In the case of 7-oxa- and
7-azanorbornenes withan electronegative atom bridge, the
ring strain increases due to a shorter carbonꢀheteroatom
bond. The highly functionalized five-membered ring sys-
tems constitute convenient scaffolds for organic and bioor-
ganic chemistry.
We have previously reported that when crude racemic
7-azanorbornenone 1 was passed through a chromatogra-
phy column (SiO2, CH2Cl2ꢀMeOH) for purification, the
pyrroline byproduct 2 could be isolated (Figure 1).9 Pyrro-
line 2 can be seen as a versatile scaffold for the preparation
of unsymmetric 2,5-cis-disubstituted pyrrolidines, of which
few synthetic routes have been reported.6,10 The formation
of 2 can be explained through a retro-Dieckman reaction
on the β-ketosulfone induced by the high ring strain of the
unsaturated bicyclic skeleton, increased in this case by the
presence of the sp2 carbon atom of the ketone group. How-
ever, the reproducibility of this opening reaction was dif-
ficult and strongly depended on the chromatographic
conditions.
Figure 1. Previously described pyrroline 2 and 7-azanorborn-5-
en-2-one 1.
To accurately define the ring-opening experimental con-
ditions and study the scope of this reaction, we have explored
the methanolysis (formal retro-Claisen type reaction) of
7-azanorbornenone 1 and of its oxa- and carba-analogues,
7 and 8, whose general synthesis is outlined in Scheme 1. We
have also explored the ring opening of strained norborn-
5-en-2-ol derivatives 9ꢀ11 through a retro-aldol reaction.
Thus, 7-azanorbornadiene 4, 7-oxanorbornadiene 5, and
norbornadiene 6 were prepared through a DielsꢀAlder
reaction between p-tolyl-2-bromoethynylsulfone 311 and
the corresponding diene according to the procedure de-
scribed by Trudell and co-workers,12 including some experi-
mental modifications in the case of 5 and 6.13 Treatment of 4,
5, and 6 with a mixture of triethylamine/diethylamine in
acetonitrile followed by addition of 10% HCl afforded the
known bicyclic ketone 1,9,12 and the new bicyclic ketones 7
and 8, respectively, as mixtures of epimers. This step implies
a three-reaction sequence: (i) conjugate addition of diethyl-
amine to the vinyl sulfone, (ii) elimination of HBr promoted
by the triethylamine to afford the enamine intermediate,
(iii) acidic hydrolysis of the resulting enamine to give the
ketone. In the case of norbornadiene 6, the initial conjugate
addition of diethylamine to the double bond was clearly
slower than in the case of 7-aza and 7-oxa analogues 4 and 5,
respectively, requiring a higher temperature (50 °C) and a
longer reaction time.
(3) For example, see: (a) Warm, A.; Vogel, P. J. Org. Chem. 1986, 51,
5348. (b) Vogel, P.; Fattori, D.; Gasparini, F.; Le Drian, C. Synlett 1990,
173. (c) Vogel, P.; Sevin, A.-F.; Kernen, P.; Bialecki, M. Pure Appl.
Chem. 1996, 68, 719. (d) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O.
Tetrahedron 1999, 55, 13521. (e) Vogel, P. Curr. Org. Chem. 2000, 4, 455.
(f) Robina, I.; Vogel, P. Synthesis 2005, 675. (g) Vogel, P. In Organic
Chemistry of Sugars; Levy, D. E., Fu€gedi, P., Eds.; CRC LLC: Boca Raton,
FL, 2006; p 629.
(4) For recent examples on the synthesis of functionalized pyrroli-
dines from 7-azanorbornanes, see: (a) Moreno-Vargas, A. J.; Vogel, P.
Tetrahedron Lett. 2003, 44, 5069. (b) Moreno-Vargas, A. J.; Robina, I.;
Petricci, E.; Vogel, P. J. Org. Chem. 2004, 69, 4487. (c) Ruggiu, A. A.;
Lysek, R.; Moreno-Clavijo, E.; Moreno-Vargas, A. J.; Robina, I.;
Vogel, P. Tetrahedron 2010, 66, 7309.
(5) (a) Kamimura, A.; Nakano, T. J. Org. Chem. 2010, 75, 3133. (b)
Pandey, G.; Tiwari, K. N.; Puranik, V. G. Org. Lett. 2008, 10, 3611. (c)
Bu1chert, M.; Meinke, S.; Prenzel, A. H. G. P.; Deppermann, N.;
Maison, W. Org. Lett. 2006, 8, 5553.
(6) (a) Zhang, S.; Xu, L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org.
Chem. 2007, 72, 3133. (b) Shu, H.; Noble, A. R.; Zhang, S.; Miao, L.;
Trudell, M. L. Tetrahedron 2010, 66, 4428.
The stereoselective synthesis of azabicyclic alcohol 9
from ketone 1 was previously reported by us using LiBH4
in THF at low temperature.9 When the same reducing
(7) (a) North, M. In Advances in Strained and Interesting Organic
Molecules; Halton, B., Ed.; JAI Press: Stamford, CN, 2000; Vol. 8, pp
145ꢀ185. (b) NIST Chemistry WebBook.
(11) Alkyne 3 can be easily obtained by bromination of commercially
available p-tolyl 2-(trimethylsilyl)ethynyl sulfone, according to ref 12.
(12) Zhang, C.; Ballay, C. J., II; Trudell, M. L. J. Chem. Soc., Perkin
Trans. 1 1999, 675.
(13) The syntheses of 7-oxanorbornadiene and norbornadiene sys-
tems 5 and 6 were previously reported in ref 12. However, the experi-
mental procedure was slightly modified with different temperatures and
times for the cycloaddition reaction. Detailed experimental procedures
and characterization data for 5 and 6 are given in this paper for the first
time (see Supporting Information). The synthesis of the aza-analogue 4
was also previously described by us; see ref 9.
(8) For some recent examples, see: (a) Avenoza, A.; Barriobero, J. I.;
Busto, J. H.; Peregrina, J. M. J. Org. Chem. 2003, 68, 2889. (b)
Pellegrino, S.; Clerici, F.; Gelmi, M. L. Tetrahedron 2008, 64, 5657.
€
(9) Moreno-Vargas, A. J.; Schutz, C.; Scopelliti, R.; Vogel, P. J. Org.
Chem. 2003, 68, 5632.
(10) For recent examples, see: (a) Wang, P.-A.; Xu, Z.-S.; Chen, C.-
F.; Gao, X.-G.; Sun, X.-L.; Zhang, S.-Y. Chirality 2007, 19, 581. (b)
Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 70,
7297. (c) Donohoe, T. J.; Headley, C. E.; Cousins, R. P. C; Cowley, A.
Org. Lett. 2003, 5, 999.
Org. Lett., Vol. 13, No. 23, 2011
6245

Table 1. Retro-Dieckman Reaction on (7-Hetero)norborn-5-
en-2-ones
Scheme 1. General Synthesis of (7-Hetero)norborn-5-en-2-ones
and (7-Hetero)norborn-5-en-2-ols
reaction
entry
1
X
conditions
product
yield (%)
quant
NBoc
AcOH (cat.),
rt, 1 h
2
2
3
4
5
6
7
8
9
NBoc
O
NaOMe (cat.),
rt, 1 h
2
82
AcOH (cat.),
rt, 1 h
12
12
13a
13
ꢀ
quant
quant
quanta
quant
O
NaOMe (cat.),
rt, 1 h
CH2
CH2
CH2
CH2
CH2
NaOMe (cat.),
rt, 1 h
Py (1 equiv),
rt, 1 h
b
AcOH (cat.),
rt, 1 h
ꢀ
b
AcOH (1 equiv),
rt, 24 h
ꢀ
ꢀ
b
TfOH (1 equiv),
60 °C, 72 h
ꢀ
ꢀ
a Epimerization of C-2 in compound 13 was detected (1:1 ratio).
b Starting material was recovered.
The formyl pyrroline 14 was obtained by treatment of
the azabicyclic alcohol 9 with NaOMe (cat.) in MeOH
(2 h, rt). As racemic alcohol 9 can be easily resolved,9
both enantiomerically pure aldehydes (ꢀ)-14 and (þ)-14
were also prepared readily. The retro-aldol reaction was
unsuccessful in the case of oxa- and carba-analogues 10
and 11. None of these alcohols reacted when treated with
NaOMe (cat.) in MeOH at room temperature. Attempts
to increase the amount of NaOMe and/or the tempera-
ture of reaction led to complex mixtures of compounds
together with unreacted starting materials. Probably,
norbornenol derivatives 10 and 11 do not have enough
strain to induce the retro-aldol reaction, in spite of the
fact that norbornenes are more strained than cyclopen-
tenes and cyclopentanes (the gas phase isomerization
of cyclopentanol into pentanal is endothermic by only
10 kJ/mol). The high reactivity observed for the azabi-
cyclic systems toward both reverse reactions could be
explained by the presence of the Boc protecting group
which induces an extra strain due to gauche effects in the
bicyclic systems that is released upon ring opening and to
the partially sp2 hybridized 7-aza moiety of the carba-
mate group (7-methylidenenorbornane is more strained
than 2-methylidenenorbornane by 8 kJ/mol).15
conditions were applied to the oxa- and carba-analogues,
the reaction was not totally stereoselective and mixtures of
stereoisomers were obtained: 10a and 10b, for the oxa-
analogue, and 11a, 11b and 11c, for the carba-analogue.
For azanorbornenone 1, the retro-Dieckman reaction could
be induced by a catalytic amount of AcOH in MeOH (Table 1,
entry 1), affording the desired pyrroline 2 in a quantitative
manner. Additionally, the treatment of 1 with a catalytic
amount of NaOMe in MeOH afforded the same pyrroline
(Table 1, entry 2) in excellent yield. These results were also
obtained when the same reaction conditions were applied to
the oxabicyclic ketone 7to afford the new 2,5-dihydrofuran 12
in a very clean process (Table 1, entries 3 and 4). However, in
the case of norbornenone 8, the retro-Dieckman reaction only
worked successfully when applying pyridine as a basic pro-
moter. This led to the new cyclopentene 13 in quantitative
yield.14 The use of NaOMe in MeOH induced the ring open-
ing of 8but simultaneously provoked the epimerization of C-2
in 13, even when a catalytic amount of the base was used.
Under acidic conditions (AcOH or TfOH in a catalytic or
stoichometric amount) no ring opening was observed.
As the β-hydroxysulfone functionality is present in
alcohols 9ꢀ11, attempts to open these bicyclic systems
through a retro-aldol reaction were carried out (Scheme 2).
(15) Vogel, P. Science of Synthesis, Houben-Weyl Methods of Mole-
cular Transformations; Georg Thieme Verlag: Stuttgart-New York, 2005;
Vol. 26, p 13.
(14) Purification of compounds 2, 12, and 13 was not required after
the opening reaction.
6246
Org. Lett., Vol. 13, No. 23, 2011

highly functionalized system such as the hydroxylated
bicycle 17, previously obtained from 9 with total and
unambiguous control of the stereoselectivity.9 Treatment
of 17 with NaOMe (cat.) in MeOH afforded the formyl
pyrrolidine 18 after 1 h in a clean reaction. The rate of this
reaction is comparable to the opening of the unsaturated
derivative 9 and much faster than the opening of satu-
rated azabicycle 15, which indicates that the exo-5,6-(2,2-
dimethyldioxolane) moiety induces a similar strain to the
polycyclic system as does the endocyclic double bond. This
might be attributed to extra gauche effects between the
methyl group and the BocN moiety of 17. Both enantio-
mers of pyrrolidine 18 can be easily prepared starting from
enantiomerically pure alcohols 9 and ent-9.
Scheme 2. Retro-Aldol Reactions on 7-Azanorborn-5-en-2-ol
and 7-Azanorbornan-2-ol Derivatives
To conclude, retro-Dieckman reactions of bicyclo[2.2.1]-
hept-5-en-2-ones and retro-aldol reactions of bicyclo-
[2.2.1]hept-5-en-2-ols permit the stereoselective synthesis
of polyfunctional cyclopentene-, 2,5-dihydrofuran-, and
3-pyrroline-based scaffolds. The methodology has been
extended to the functionalization of the double bond in
7-azabicyclo[2.2.1]hept-2-ene systems, allowing the addi-
tional installation of two functional groups in a stereo-
selective manner taking advantage of the high facial stereo-
selectivity and regioselectivity of the reactions of the
norbornene double bond.3 Ring opening of the polyfunc-
tionalized azabicycles affords new pyrrolidine based scaf-
folds ideally suited for the construction of iminosugars
(polyhydroxylated-pyrrolidines, indolizidines, and pyrro-
lizidines). The presence of aldehyde and ꢀCH2Ts func-
tions in pyrroline 14 and pyrrolidine 18 makes these
compounds interesting precursors for further Wittig and
Julia olefination reactions.
In order to study the influence of the double bond in the
retro-aldol opening reaction of the azabicyclic system, the
preparation of the saturated azabicycle 15 was achieved by
catalytic hydrogenation of 9 (Scheme2). Retro-aldol open-
ing of the saturated bicycle, under usual conditions, af-
forded the formyl pyrrolidine 16 in excellent yield. In this
case, as expected, the ring-opening reaction was slower
than in the case of the unsaturated analogue. Nevertheless,
after 10 h all the starting material was transformed into the
pyrrolidine derivative at room temperature. This observa-
tion showed that the presence of the double bond in this
bicyclic system favors the ring opening due to a higher ring
strain (by about 33 kJ/mol, between norbornene and
norbornane)7b but is not critical for the reaction outcome.
This result led us to attempt the retro-aldol opening on a
Acknowledgment. We thank Ministerio de Ciencia e
ꢀ
Innovacion of Spain (CTQ2008-01565/BQU) and Junta
de Andalucıa (FQM 345) for financial support. We also
´
thank Erasmus (Lausanne-Seville) for fellowships to R.K.
and T.S., and Prof. P. Vogel (EPFL, Switzerland) for
helpful discussions.
Supporting Information Available. Experimental de-
1
tails and H and 13C NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 23, 2011
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