A chiral pool approach to the synthesis of optically active tetrahalo norbornyl building blocks

Article abstract of DOI:10.1021/ol800990m

(Chemical Equation Presented) Optical antipodes of the mono- and disubstituted polyhalo norbornyl derivatives were prepared in excellent yields. The monosubstituted derivatives 7 were obtained with good enantiopurities. A kaleidoscopic change in the product formation and distribution was observed by changing the chronology of reactions.

Full text of DOI:10.1021/ol800990m

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3029-3032
A Chiral Pool Approach to the
Synthesis of Optically Active Tetrahalo
Norbornyl Building Blocks
Faiz Ahmed Khan* and Ch. Sudheer
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
faiz@iitk.ac.in
Received April 30, 2008
ABSTRACT
Optical antipodes of the mono- and disubstituted polyhalo norbornyl derivatives were prepared in excellent yields. The monosubstituted
derivatives 7 were obtained with good enantiopurities. A kaleidoscopic change in the product formation and distribution was observed by
changing the chronology of reactions.
Chiral pool synthesis is one of the main approaches to
enantiopure organic compounds apart from asymmetric
synthesis and resolution of racemates. It involves the
synthesis of complex optically active compounds from a
stockpile of easily available enantiomerically pure com-
pounds. The built-in chirality present in the starting material
is then preserved or creatively used to generate more chiral
centers employing chosen methods in the run of reactions
toward the target molecule.1 Despite the presence of various
other methods to reach the optically active targets, the chiral
pool approach has carved a niche for itself and is widely
employed wherever it is viable. Unlike other resources, the
chiral pool is renewable and devoid of any strategic hold-
ings.2
which are exploited in the synthesis of complex multistereo
natural products, intermediates, and aesthetically pleasing
novel molecular entities.3 However, most of the applications
known with the tetrahalodimethoxy norbornyl derivatives
were with the racemic compounds.3 In the few reports
known, the optically active compounds were obtained by
kinetic resolution.4 Our interest in norbornyl derivatives as
building blocks in organic synthesis5 prompted us to check
for the reactions of 1a,b with dienophiles obtained from
renewable sources.
(3) Khan, F. A.; Das, B. P.; Dash, J. J. Prakt. Chem. 2000, 342, 512,
and references therein.
(4) (a) de Oliveira, L. F.; Costa, V. E. U. Tetrahedron Lett. 2006, 47,
3565. (b) Berger, B.; Rabiller, C. G.; Konigsberger, K.; Faber, K.; Griengl,
H. Tetrahedron: Asymmetry 1990, 1, 541, and references therein.
(5) For selected list of reports on the applications of norbornyl derivatives
from our group, see: (a) Khan, F. A.; Rout, B. J. Org. Chem. 2007, 72,
7011. (b) Khan, F. A.; Rout, B. Tetrahedron Lett. 2006, 47, 5251. (c) Khan,
F. A.; Rao, C. N. Tetrahedron Lett. 2006, 47, 7567. (d) Khan, F. A.; Dash,
J.; Sudheer, Ch.; Sahu, N.; Parasuraman, K. J. Org. Chem. 2005, 70, 7565.
(e) Khan, F. A.; Dash, J. Eur. J. Org. Chem. 2004, 2692. (f) Khan, F. A.;
Dash, J.; Sudheer, Ch. Chem. Eur. J. 2004, 10, 2507. (g) Khan, F. A.;
Satapathy, R.; Dash, J.; Savitha, G. J. Org. Chem. 2004, 69, 5295. (h) Khan,
F. A.; Dash, J.; Sahu, N.; Sudheer, Ch. J. Org. Chem. 2002, 67, 3783. (i)
Khan, F. A.; Sahu, N.; Dash, J.; Prabhudas, B. J. Indian Inst. Sci. 2001,
81, 325.
The tetrahalonorbornyl derivatives which are readily
accessible via a Diels-Alder reaction between diene 1a or1b
and a suitable dienophile have served as illustrious rigid
templates in organic synthesis. The importance can be
attributed to the high degree of regio- and stereocontrol,
(1) (a) Hanessian, S. Total Synthesis of Natural Products: The ‘Chiron’
Approach; Baldwin, J. E., Ed.; Pergamon: Oxford, UK, 1983. (b) Nugent,
W. A.; Rajanbabu, T. V.; Burk, M. J. Science 1993, 259, 479.
(2) Taylor, M. S.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5368.
10.1021/ol800990m CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

Scheme 1
Dienophile 2, which is easily accessible from d-mannitol6
following a protocol that was reported by us earlier.5h
γ-Lactone-fused cyclopentanoids are important substructures
found in umpteen number of natural products and are
important intermediates in organic synthesis.9 The present
method provides a simple route to the synthesis of one such
optically active intermediate.
After successfully preparing the monosubstituted nor-
bornyls 7, we turned our attention to the synthesis of optically
pure disubstituted polyhalo norbornyl derivatives. For this
purpose, we envisaged that 10 would be a good choice as
dienophile.10 Engrossed by the number of theoretically
possible products that can be obtained, we carried out the
Diels-Alder reaction of 1a,b with 10. Interestingly, out of
the two possible endo isomers, only 11 was formed in
excellent yields (Scheme 2).
was heated along with a benzene solution of the diene 1a in
a sealed tube to afford the inseparable diastereomers 3 and
4 in excellent yield (95%, Scheme 1). A catalytic amount of
hydroquinone plays the role of a radical scavenger while
epichlorohydrin helps in quenching any acidic impurities that
might be generated during the reaction. The diastereomeric
1
ratio (1:1) was determined from the H NMR analysis.
Removal of acetonide protection under acidic conditions
afforded the diastereomeric mixture of diols 5 and 6, which
were separated by column chromatography.
Scheme 2
Optically active tetrabromo adduct (+)-7 was obtained in
excellent yield by cleavage of diol 5 followed by reduction
of the resulting aldehyde (+)-8. The enantiomeric purity of
the alcohol (+)-7 was found to be >99%, which is much
higher than that reported in the literature.7 The aldehydes
(+)- and (-)-8, precursors for optical antipodes (+) and (-)-
7, are very useful compounds. The racemic aldehyde 8 was
utilized by us in the recent past for the synthesis of racemic
trans-hydrindan derivatives.5g The enantiopure aldehydes 8
were used for the synthesis of tetracyclic amines.8 Further,
(-)-7 was converted to γ-lactone fused cyclopentanoid (-)-9
(6) (a) Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6. (b)
Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999, 64, 2852.
(7) Mamedov, E. G. Russ. J. Org. Chem. 2002, 38, 15. In this report,
the Diels-Alder adduct of 1a and (-)-menthyl acrylate was transformed
to 7 without specifying if a single diastereomer was formed. Even the
authentic 7 obtained by repeated crystallization of acrylic acid adduct with
(-)-ephedrine, assumed to be optically pure, appears to have an ee of 66%.
We came to this conclusion by comparing the specific rotation values
obtained by us and Mamedov. We confirmed the enantiopurity of 7 obtained
by our method using chiral HPLC.
While the possibility of exo-adduct formation is ruled out
because of the intrinsic endo selectivity of the dienes 1a,b,
(8) Khan, F. A.; Upadhyaya, S. K. Unpublished results.
3030
Org. Lett., Vol. 10, No. 14, 2008

the transition states 15 and 17 provide a plausible explanation
for the formation of single endo-diastereomer. We presume
that the allylic 1,3-strain causes the dienophile to orient in a
way so as to accommodate the smallest group on the allylic
chiral center, present in the molecular plane, in the cavity
as depicted in Scheme 3.11 The TS 15 leading to 16 is
Scheme 4
Scheme 3
selectivity was in favor of the diastereomer formed via
alternate route (13b in Scheme 2). The minor diastereomer
19 was subjected to acetonide deprotection under acidic
condition to give diol 20 in 93% yield. The diastereomeric
diols 14b and 20 were separately subjected to NaIO4 cleavage
followed by NaBH4 reduction resulting in the formation of
antipodal monoprotected diol derivatives 21 and ent-21
(Scheme 5).
disfavored due to steric crowding, while TS 17 devoid of
such problem leads to products 11.
DIBAL-H reduction of 11a,b resulted in the alcohols
12a,b. Attempted benzylation of the free hydroxyl in 12a,b
with benzyl halides employing various bases (NaH, n-BuLi,
etc.) or Ag2O condition afforded a complex reaction mixture.
None of the components resulted were benzyl derivatives
as noted from 1H NMR spectra. However, benzylation could
be effected with benzyl trichloroacetimidate albeit with
modest yields. Another problem here was with the purifica-
tion of benzyl ethers from the trichloroacetamide impurities
generated. Acetonide deprotection of 13a,b under acidic
conditions yielded the diols 14a,b.
Scheme 5
To circumvent the problems associated with benzylation
of 12a,b, the chronology of reactions was changed. As per
the strategy, the benzyl protection was installed at the
dienophile stage and then the Diels-Alder reaction was
carried out with the diene 1b. DIBAL-H reduction of 10
followed by benzyl protection of the resulting alcohol with
n-BuLi and BnBr afforded the benzyl ether 18 in excellent
yield.12 Diels-Alder reaction of the dienophile 18 with diene
1b yielded an isomeric mixture of products (Scheme 4).
Although a mixture of diastereomers is obtained, the
Treating 11b with 10% HCl in MeOH afforded a mixture
of lactones 22 and 23 (Scheme 6). While the formation of
lactones was confirmed from NMR and IR spectra, it was
not possible to distinguish the two isomers with certainty.
With the intent of reconfirming the stereochemistry of the
lactone 22, we have carried out Diels-Alder reaction of the
cyclic dienophile 2413 with the dienes 1a,b. These reactions
resulted in intractable reaction mixtures, possibly due to the
presence of free hydroxyl group in 24. To circumvent this
problem, the hydroxyl was protected as TBS ether 25 which
was then subjected to Diels-Alder reactions with 1a,b.
Removal of TBS protection from the resulting compounds
gave the lactones 26a,b. The lactone 26b was found to be
different from that obtained by the hydrolysis of 11b. The
formation of the lactones 26a,b can be explained from the
(9) For selected examples, see references cited in ref 5h.
(10) (a) Haefele, B; Ja¨ger, V. Liebigs Ann. Chem. 1987, 85. For a
reaction of dienophile 10 with cyclopentadiene, see: (b) Mulzer, J.; Kappert,
M.; Huttner, G.; Jibril, I. Tetrahedron Lett. 1985, 26, 1631. (c) Casas, R.;
Parella, T.; Branchadell, V.; Oliva, A.; Ortun˜ o, R. M.; Guingant, A.
Tetrahedron 1992, 48, 2659.
(11) A distorted Felkin-Anh TS was invoked by Mulzer10b to explain
the observed diastereoselectivity for the reaction of 10 with cyclopentadiene
which furnished a mixture of endo/exo (85:15) isomers while Ortun˜o, who
obtained a mixture of endo/exo/endo (78:15:7) isomers for the same
reaction,10c proposed steric and electronic factors play a crucial role.
(12) (a) Sugisaki, C. H.; Ruland, Y.; Le Clezio, I.; Baltas, M. Synlett
2001, 1905. (b) Marshall, J. A.; Trometer, J. D.; Cleary, D. G. Tetrahedron
1989, 45, 391.
(13) Mann, J.; Weymouth-Wilson, A. C. Org. Synth. 1998, 75, 139.
Org. Lett., Vol. 10, No. 14, 2008
3031

this, the absolute configurations of 11a,b can be established,
which will eventually dodge out the uncertainties of absolute
configurations of all the compounds described here.
In conclusion, we have described efficient syntheses of
various optically active tetrahalo norbornyl derivatives from
abundantly available, cheap starting materials d-mannitol and
cyclopentadiene.15 The Diels-Alder reactions with the 1,2-
disubsituted optically active dienophiles are highly stereo-
selective and interesting changes in the product formation
and distribution were observed upon changing the chronology
of the reactions.
Scheme 6
Acknowledgment. We thank the Department of Science
and Technology (DST), New Delhi, for financial assistance.
F.A.K. acknowledges the DST for a Swarnajayanti Fellow-
ship. Ch.S. thanks DST for a fellowship.
Note Added after ASAP Publication. Due to a produc-
tion error structures 8 and 9 were added to the version
published June 17, 2008.
transition states involved. Further, a report by Ortun˜o and
Font14 which describes the Diels-Alder reaction of cyclo-
pentadiene with 24 substantiates the formation of 26a,b.
Finally, to rule out any ambiguity, single-crystal X-ray
analysis of the chloro derivatives 22 and 23 was carried out.
These studies have established that the minor isomer is
γ-lactone (22) and the major isomer is δ-lactone (23). From
Supporting Information Available: Experimental pro-
1
cedures, spectroscopic data, copies of H and 13C spectra,
and details on the X-ray structures. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL800990M
(14) Ortun˜o, R. M.; Corbera, J.; Font, J. Tetrahedron Lett. 1986, 27,
1081.
(15) Dienes 1a,b and and dienophiles 2, 10, 18, and 25 are prepared
from cyclopentadiene and d-mannitol, respectively.
3032
Org. Lett., Vol. 10, No. 14, 2008