Iodocyclization of chiral cf3-allylmorpholinones: A versatile strategy for the synthesis of enantiopure α-Tfm-prolines and α-Tfm-dihydroxyprolines

Article abstract of DOI:10.1021/ol8024567

An efficient iodocyclization reaction of a chiral Tfm-allylmorpholinone provides a straightforward route to α-Tfm-prolines and α-Tfmdihydroxyprolines. The methodologies developed are particularly well adapted for gram-scale synthesis of enantiopure compou

Full text of DOI:10.1021/ol8024567

ORGANIC
LETTERS
2009
Vol. 11, No. 1
209-212
Iodocyclization of Chiral
CF3-Allylmorpholinones: A Versatile
Strategy for the Synthesis of
Enantiopure r-Tfm-Prolines and
r-Tfm-Dihydroxyprolines
Caroline Caupe`ne,† Gre´gory Chaume,† Louis Ricard,‡ and Thierry Brigaud*,†
Laboratoire SOSCO (Synthe`se Organique Se´lectiVe et Chimie Organome´tallique),
UniVersite´ de Cergy-Pontoise, UMR CNRS 8123, F-95000 Cergy-Pontoise, France,
and Laboratoire He´te´roe´le´ments et Coordination, Ecole Polytechnique, UMR CNRS
7653, 91128 Palaiseau, France
thierry.brigaud@u-cergy.fr
Received October 24, 2008
ABSTRACT
An efficient iodocyclization reaction of a chiral Tfm-allylmorpholinone provides a straightforward route to r-Tfm-prolines and r-Tfm-
dihydroxyprolines. The methodologies developed are particularly well adapted for gram-scale synthesis of enantiopure compounds.
It is well known that proline and proline derivatives play
a unique and important role in the conformation of peptides
and proteins. In this context, ring-substituted and quaternary
proline analogues are of special interest.1 Because of the
unique effects due to the incorporation of fluorine atoms into
molecules, fluorinated amino acids are very attractive target
molecules for the design of biologically active compounds,
and several methods have been reported for their stereose-
lective synthesis.2 Among them, enantiopure ꢀ-fluorinated
proline derivatives are interesting, but their stereoselective
synthesis constitutes a challenge. To our knowledge only (R)-
ꢀ,ꢀ-difluoroproline3 and (R)- and (S)-R-trifluoromethylpro-
lines4 have been synthesized in enantiopure form. As part
of our research program related to the stereoselective
(2) For review, see: (a) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch,
B. Chem. Soc. ReV. 2008, 37, 1727–1739. (b) Brigaud, T.; Chaume, G.;
Pytkowicz, J.; Huguenot, F. Chim. Oggi 2007, 25, 8–10. (c) Qiu, X.-L.;
Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60, 6711–6745. (d) Sutherland,
A.; Wilis, C. L. Nat. Prod. Rep. 2000, 17, 621–631. (e) Kukhar, V. P.;
Soloshonok, V. A. Fluorine Containing Amino Acids: Synthesis and
Properties; Wiley: New York, 1995. (f) Zanda, M. New J. Chem. 2004,
28, 1401–1411. (g) Molteni, M.; Pesenti, C.; Sani, M.; Volonterio, A.;
Zanda, M. J. Fluorine Chem. 2004, 125, 1335–1743. (h) Qing, F.-L.; Qiu,
X.-L. Synthesis of fluorinated prolines and pyroglutamic acids. In Fluorine-
Containing Synthons; Soloshonok, V. A., Ed.; American Chemical Society:
Washington, DC, 2005; pp 562-571.
† Universite´ de Cergy-Pontoise.
‡ Ecole Polytechnique.
(1) For recent reviews, see: (a) Karoyan, P.; Sagan, S.; Lequin, O.;
Quancard, J.; Lavielle, S.; Chassaing, G. Targets Heterocycl. Syst. 2004,
8, 216–273. (b) Calaza, M. I.; Cativiela, C. Eur. J. Org. Chem. 2008, 3427–
3448.
(3) Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K. J. Org. Chem. 2004,
69, 5132–5134.
10.1021/ol8024567 CCC: $40.75
Published on Web 12/02/2008
2009 American Chemical Society

Scheme 1
.
Synthesis of Enantiopure R-Tfm-Amino Acids from
Allylmorpholinone 1
Scheme 2. Multigram-Scale Synthesis of Allylmorpholinone 1
According to our previously reported three-step proce-
dure,4,6 an improved efficient multigram-scale synthesis of
a 75:25 diastereomeric mixture of (R,S)-1 and (R,R)-1 was
achieved (Scheme 2). The (R,S) configuration of the major
1 diastereomer was assigned according to our previous
communication.4
synthesis of ring-substituted R-Tfm-prolines, we are now
interested in the synthesis of enantiopure 3,4-dihydroxy-R-
Tfm-prolines. Because of their potential as azasugar ana-
logues and in peptide synthesis, numerous syntheses of 3,4-
dihydroxyprolines are reported in the literature5 but none in
the fluorinated series. We report here an efficient stereose-
lective synthesis of 3,4-dihydroxy-R-Tfm-proline, as well as
an improved synthesis of enantiopure R-Tfm-prolines using
the same chiral Tfm-allylmorpholinones intermediate.
We recently reported that the allylic lactone 1 (Scheme
1) obtained from (R)-phenylglycinol and ethyl trifluoropy-
ruvate was a multipotent intermediate for the synthesis of
various R-Tfm amino acids such as R-Tfm-allylglycine,
R-Tfm-norvaline, R-Tfm-proline,4 and R-Tfm-pyroglutamic
acids.6 Both enantiomers of the cyclic R-Tfm-proline were
obtained from 9-BBN hydroboration reaction of 1 followed
by H2O2 oxidation and cyclization of the corresponding
alcohols. However, this pathway is not suitable for the
multigram-scale synthesis of R-Tfm-proline. As we are
interested in the development of scalable methods for the
synthesis of enantiopure cyclic R-Tfm amino acids, we
decided to explore the scope of the iodocyclization7 reaction
of the allylic lactone 1.
Table 1. Iodocylization of 1
I2
product
(yield %)a
entry
conditions
(equiv)
1
2
3
4
5
6
THF/Et2O/satd NaHCO3
CH3CN (wet)/ K2CO3
CH2Cl2/Na2CO3·5H2O
CH2Cl2/K2CO3
CH2Cl2
toluene
2.5
3.3
3.3
2.8
2.6
1.5
low conversion
low conversion
2 (40),b 3 (22),c 4 (38)d
2 (32),b 3 (40),c 4 (5)d
2 (87)b
2 (71)b
a Isolated yield. b Four diastereomers. c One diastereomer. d Two
diastereomers.
(4) Chaume, G.; Van Severen, M.-C.; Marinkovic, S.; Brigaud, T. Org.
Lett. 2006, 8, 6123–6126.
(5) (a) Angle, S. R.; Bensa, D.; Belanger, D. S. J. Org. Chem. 2007,
72, 5592–5597. (b) Davis, F. A.; Ramachandar, T.; Chai, J.; Skucas, E.
Tetrahedron Lett. 2006, 47, 2743–2746. (c) Taylor, C. M.; Jones, C. E.;
Bopp, K. Tetrahedron 2005, 61, 9611–9617. (d) Taylor, C. M.; Hardre´,
R.; Edwards, P. J. B. J. Org. Chem. 2005, 70, 1306–1315. (e) Taylor, C. M.;
Barker, W. D.; Weir, C. A.; Park, J. H. J. Org. Chem. 2002, 67, 4466–
4474. (f) Mart´ın, R.; Alco´n, M.; Perica`s, M. A.; Riera, A. J. Org. Chem.
2002, 67, 6896–6901. (g) Weir, C. A.; Taylor, C. M. J. Org. Chem. 1999,
64, 1554–1558. (h) Zanardi, F.; Battistini, L.; Nespi, M.; Rassu, G.; Spanu,
P.; Cornia, M.; Casiraghi, G. Tetrahedron: Asymmetry 1996, 7, 1167–1180.
(i) Schumacher, K. K.; Jiang, J.; Joullie´, M. M. Tetrahedron: Asymmetry
1998, 9, 47–53.
The iodocyclization reaction was first attempted in basic
conditions following known procedures reported in the
literature for similar substrates (Table 1). The reaction in
THF/Et2O/H2O mixture with NaHCO3 as the base8 or in wet
9
CH3CN in the presence of K2CO3 afforded only very low
conversion of the starting allylic compound (entries 1 and
2). The conversion of 1 was complete with Na2CO3·5H2O
in refluxing CH2Cl2,10 but 5 days reaction time was required
and a mixture of five-membered ring compounds 2 (40%),
four-membered ring compounds 3 (22%), and five-membered
(6) Chaume, G.; Van Severen, M.-C.; Ricard, L.; Brigaud, T. J. Fluorine
Chem. 2008, 129, 1104–1109.
(7) For reviews and recent examples of iodocyclization reactions, see:
(a) Togo, H.; Iida, S. Synlett 2006, 2159–2175. (b) Amjad, M.; Knight, D.
Tetrahedron Lett. 2006, 47, 2825–2828. (c) Diaba, F.; Puigbo´, G.; Bonjoch,
J. Eur. J. Org. Chem. 2007, 3038–3044. (d) Bonjoch, J.; Diaba, F.; Puigbo´,
G.; Peidro´, E.; Sole´, D. Tetrahedron Lett. 2003, 44, 8387–8390. (e)
Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 70,
7297–7304. (f) Kim, J. H.; Curtis-Long, M. J.; Seo, W. D.; Lee, J. H.; Lee,
B. W.; Yoon, Y. J.; Kang, K. Y.; Park, K. H. Bioorg. Med. Chem. Lett.
2005, 15, 4282–4285.
(8) Kim, J. H.; Curtis-Long, M. J.; Seo, W. D.; Ryu, Y. B.; Yang, M. S.;
Park, K. H. J. Org. Chem. 2005, 70, 4082–4087.
(9) Davis, F. A.; Song, M.; Augustine, A. J. Org. Chem. 2006, 71, 2779–
2786.
(10) Be´gue´, J.-P.; Bonnet-Delpon, D.; Dogbeavou, R.; Oure´vitch, M.
J. Chem. Soc., Perkin Trans. 1993, 2787–2791.
210
Org. Lett., Vol. 11, No. 1, 2009

Scheme 3
.
Synthesis of (S)- and (R)-R-Tfm-Prolines in
Scheme 4
.
Synthesis of 3,4-Dihydroxy-2-trifluoromethylprolines
in Enantiopure Form
Enantiopure Form
hydroxylated compound 4 (38%) was obtained (entry 3). The
formation of 4 (5%) was reduced by the use of anhydrous
CH2Cl2 and K2CO3, but a mixture of five- and four-
membered ring iodocompounds 2 (32%) and 3 (40%) was
still obtained (entry 4). It should be noted that there are very
few reports in the literature of the formation of such four-
membered rings through electrophilic cyclization of homoal-
lylamine derivatives.11 We suppose that this uncommon
cyclization is due to the cyclic nature of our substrate.
Fortunately, when the reaction was performed without
neutralization of the medium with a base, the formation of
both four-membered ring 3 and hydroxylated compound 4
was avoided. We assume that the use of a base is not
necessary in our case because of the strong deactivation of
the nitrogen atom in R-position of the trifluoromethyl group.
When the reaction was carried out in refluxing CH2Cl2 or
refluxing toluene, the expected five-membered ring products
2 were highly selectively obtained in 87% and 71% yield
(entries 5 and 6). The advantage of the use of toluene as the
solvent was that the amount of iodine required to achieve a
good yield was reduced to 1.5 equiv. The iodocompounds 2
were obtained as a mixture of diastereomers.12 At this stage,
the separation of the diastereomers was not necessary because
this separation was very conveniently achieved at the next
step of the synthesis.
silicagel chromatography because of their very large Rf
difference.14 The corresponding enantiopure (S)- and (R)-
R-Tfm-prolines were then very conveniently obtained from
each bicyclic compound after removal of the phenylglycinol
side chain by hydrogenolysis.15 As a result, the iodocycliza-
tion-hydrogenolysis sequence from lactone 1 constitutes an
improved alternative method to the hydroboration-cycliza-
tion4 of 1 for the gram-scale synthesis of R-Tfm-prolines.
We surmised that the bicyclic iodinated compounds 2
would also be very valuable intermediates for the synthesis
of highly substituted R-Tfm-prolines. Because of the biologi-
cal importance of hydroxyproline derivatives, we considered
that 3,4-dihydroxylated R-Tfm-prolines would be relevant
challenging target molecules. We envisaged their straight-
forward stereoselective synthesis from 2 through an elimina-
tion-dihydroxylation sequence, provided that the elimination
was regioselective and that the dihydroxylation was stereo-
selective. Thus, the isolated iodinated bicyclic compounds
(R,S)-2 and (R,R)-2 were submitted to DBU-mediated
dehydroiodination (Scheme 4). In opposition to the unflu-
orinated series with similar substrates,5i the elimination
reaction was completely regioselective to give exclusively
the C7-C8 elimination products (R,S)-7 and (R,R)-7. We
assume that the enamimes are not formed because of the
increased acidity of the protons on C8 caused by the electron-
The 75:25 diastereomeric mixture of (R,S)-213 and (R,R)-
213 was then submitted to a reductive deiodination reaction
to give a diastereomeric mixture of (R,S)-5 and (R,R)-5
bicyclic compounds (Scheme 3). At this stage, the (R,S)-5
and (R,R)-5 compounds were very easily separated by
(11) (a) Minakata, S.; Morino, Y.; Oderaotoshi, Y.; Komatsu, M. Org.
Lett. 2006, 8, 3335–3337. (b) Morino, Y.; Hidaka, I.; Oderaotoshi, Y.;
Komatsu, M.; Minakata, S. Tetrahedron 2006, 62, 12247–12251. (c) Knapp,
S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006–4014.
(12) The 75:25 ratio of (S) and (R) compounds at the C8a carbon was
reflecting the initial 75:25 diastereomeric ratio of the allylmorpholinones
1. Each (S) and (R) diastereomer at the C8a cabone gave two diastereomers
because of the non-stereoselective introduction of the iodine atom at the
C7 carbon. A pure analytical samples of each diastereomers was isolated
for the determination of their analytical data.
(14) With petroleum ether/ethyl acetate (90:10) system: Rf of (R,R)-5
) 0.43 and Rf of (R,S)-5 ) 0.13.
(15) Harwood, L. M.; Hamblett, G.; Jimenez-Dias, A. I.; Watkin, D. J.
Synlett 1997, 935–938.
(13) Two diastereomers because of the iodinated C7 stereogenic center.
Org. Lett., Vol. 11, No. 1, 2009
211

stereodirecting group, and the configuration of the phenyl-
glycinol moiety has no influence on the diastereoselectivity
of the dihydroxylation reaction. The absolute configurations
of the newly generated centers were assigned by X-ray
crystallographic analysis of (S)-8 (Figure 1).17 The target
enantiopure 3,4-dihydroxy-2-trifluoromethylproline (S)-9 was
obtained in 92% yield after hydrogenolysis of (S)-8. In a
similar manner, an analytical sample of the bicyclic dihy-
droxylated compound (R)-8 was submitted to the same
hydrogenolysis conditions to give the (R)-9 enantiomer.18
This result confirms that the dihydroxylation reaction takes
place in trans position of the trifluoromethyl group.
Thus, in this work, we have demonstrated that the
iodocyclization reaction of a chiral CF3-allylmorpholinone
constitutes an efficient scalable pathway for the synthesis of
enantiopure R-Tfm-prolines and dihydroxyprolines. Further
development in the synthesis and the applications of cyclic
enantiopure Tfm-aminoacids is currently in progress.
Figure 1. ORTEP diagram of (S)-8.
Acknowledgment. We thank Central Glass Company for
their financial support and the gift of ethyl trifluoropyruvate.
Supporting Information Available: General experimental
methods, complete experimental procedures and character-
ization data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
withdrawing effect of the trifluoromethyl group in R position.
The dihydroxylation reaction of alkenes (R,S)-7 and (R,R)-7
was then performed with the osmium tetroxide/ NMO
system.5i,16 The dihydroxylation reaction occurred with a
complete diastereoselectivity in relative trans position of the
trifluoromethyl group to give the compounds (S)-8 and (R)-8
in good yields. The trifluoromethyl group is thus the
OL8024567
(17) Crystallographic data for compound (S)-8 have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 710191. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+ 44 1223 336033 or email: deposit@ccdc.cam.ac.uk.
(16) Murray, A. J.; Parsons, P. J.; Hitchcock, P. Tetrahedron 2007, 63,
6485–6492
.
(18) Spectral data of (R)-9 were identical to those of (S)-9.
212
Org. Lett., Vol. 11, No. 1, 2009