Highly diastereoselective synthesis of enantiopure β-trifluoromethyl β-amino alcohols from chiral trifluoromethyl oxazolidines (Fox)

Article abstract of DOI:10.1021/ol2032174

The organolithium species addition to 2-hydroxymethyl fluorinated oxazolidines (Fox) provides a highly diastereoselective and straightforward route for the synthesis of enantiopure trifluoromethyl β-amino alcohols quaternarized at the β-position.

Full text of DOI:10.1021/ol2032174

ORGANIC
LETTERS
2012
Vol. 14, No. 2
604–607
Highly Diastereoselective Synthesis of
Enantiopure β-Trifluoromethyl β-Amino
Alcohols from Chiral Trifluoromethyl
Oxazolidines (Fox)
Julien Simon, Evelyne Chelain,* and Thierry Brigaud*
ꢀ
Laboratoire “Synthese Organique Selective et Chimie bioOrganique” (SOSCO),
Universite de Cergy-Pontoise, 5 Mail Gay-Lussac 95000 Cergy-Pontoise cedex, France
ꢁ
ꢁ
thierry.brigaud@u-cergy.fr; evelyne.chelain@u-cergy.fr
Received December 2, 2011
ABSTRACT
The organolithium species addition to 2-hydroxymethyl fluorinated oxazolidines (Fox) provides a highly diastereoselective and straightforward
route for the synthesis of enantiopure trifluoromethyl β-amino alcohols quaternarized at the β-position.
Enantiopure β-amino alcohols are very interesting com-
pounds for biological use1 and for the design of chiral
ligands or auxiliaries.2 Because of the great impact of the
incorporation of a trifluoromethyl group on the chemical
and the biological properties of molecules,3 β-trifluoromethyl
β-amino alcohols are very attractive compounds mainly as
biologically active compounds such as peptidomimetic units.4
Although several methodologies have been reported for the
asymmetric synthesis of β-trifluoromethyl β-amino alcohols
monosubstituted in the β-position,5 to our knowledge very
few reports exist on the synthesis of their analogues quater-
narized at the β-position.6 The limitations of these methods
are their low diastereoselectivity6a,b or the numerous steps
required to obtain the enantiopure target compound.6c
In order to provide a straight forward and highly
stereoselective access to these challenging quaternarized
(1) (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576. (b) Klingler,
F. D. Acc. Chem. Res. 2007, 40, 1367–1376. (c) Lee, H.-S.; Kang, S. H.
Synlett 2004, 1673–1685.
(2) (a) Fache, F.;Schulz, E.;Tommasino, M.L.;Lemaire, M.Chem. Rev.
2000, 100, 2159–2231. (b) Senanayake, C. H. Aldrichimica Acta 1998, 31, 3–
15. (c) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–875.
(d) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151–4202. (e)
Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry 1998,
9, 1–45. (f) Rechavi, D.; Lemaire, M. Chem. Rev. 2002, 102, 3467–3494. (g) de
Parrodi, C. A; Juaristi, E. Synlett 2006, 2699–2715. (h) Vicario, J. L.; Badia,
D.; Carrillo, L.; Reyes, E.; Etxebarria, J. Curr. Org. Chem. 2005, 9, 219–235.
(3) (a) Bioorganic and Medicinal Chemistry of Fluorine; Begue, J.-P.,
Bonnet-Delpon, D., Eds.; Wiley: Hoboken, NJ, 2008. (b) Fluorine In Medicinal
Chemistry And Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell: 2009. (c)
Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Kirsch,
P., Ed.; Wiley-VCH: Weinheim, 2004. (d) Organofluorine chemistry; Uneyama,
K., Ed.; Blackwell Publishing: Oxford, 2006. (e) Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; American Chemical Society: Washington, DC, 2005. (f)
Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–996. (g) Ma, J.-A.;
Cahard, D. Chem. Rev. 2004, 104, 6119–6146. (h) Ma, J.-A.; Cahard, D.
Chem. Rev. 2008, 108, PR1–PR43. (i) Nie, J.; Guo, H.-C.; Cahard, D.; Ma,
J.-A. Chem. Rev. 2011, 111, 455–529.
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Chem. 1999, 97, 27–49. (b) Kuznetsova, L. V.; Pepe, A.; Ungureanu,
I. M.; Pera, P.; Bernacki, R. J.; Ojima, I. J. Fluorine Chem. 2008, 129,
817–828. (c) Binkert, C.; Frigerio, M.; Jones, A.; Meyer, S.; Pesenti, C.;
Prade, L.; Viani, F.; Zanda, M. ChemBioChem 2006, 7, 181–186. (d)
Pesenti, C.; Arnone, A.; Bellosta, S.; Bravo, P.; Canavesi, M.; Corradi,
E.; Frigerio, M.; Meille, S. V.; Monetti, M.; Panzeri, W.; Viani, F.;
Venturini, R.; Zanda, M. Tetrahedron 2001, 57, 6511–6522. (e) Molteni,
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r
10.1021/ol2032174
Published on Web 12/22/2011
2011 American Chemical Society

β-trifluoromethyl β-amino alcohols, we decided to investigate
the addition reactions of organometallic species to a chiral
2-trifluoromethyl-2-hydroxymethyl-1,3-oxazolidine. The ad-
dition of organometallics to unfunctionalized chiral trifluoro-
methyloxazolidines (Fox) has been reported to provide
a convenient access to chiral R-trifluoromethylamines.7À12
However the stereoselectivity of the organolithium reagent
addition to (R)-phenylglycinol based fluorinated oxazolidines
was reported to proceed with retention of configuration.8 As a
consequence, this strategy requires a tedious separation of the
starting oxazolidine diastereomers before the reaction with
the organometallics (Scheme 1). Other procedures involve the
stereoselective addition of organolithium reagents on a hy-
droxylated imine which is difficult to isolate or on silylated
imine intermediates (Scheme 1).8,9
We recently reported that the LAH reduction of
(R)-phenylglycinol and ethyl trifluoropyruvate based oxazo-
lidines provided a straightforward access to enantiopure
(S)- and (R)-trifluoroalaninols (Scheme 2).5k
Scheme 2. LAH Reduction of Chiral Ethyl Trifluoropyruvate-
Based CF3-Oxazolidines Leading to Enantiopure (S)- and
(R)-Trifluoroalaninolsa
Scheme 1. Stereoselective Synthesis of Chiral Trifluoromethylated
Amines from Trifluoromethylated Oxazolidines and Imines
a See ref 5k.
In order to extend this approach to the synthesis of
chiral β-trifluoromethyl β-amino alcohols quaternarized at
the β-position, we report herein the stereoselective addition
of various organolithium compounds to fluorinated
2-hydroxymethyl oxazolidines 2. The oxazolidines 2 were
conveniently obtained as a 71:29 diastereomeric mixture
through the chemoselective NaBH4 reduction of the tri-
fluoropyruvate-based oxazolidine 1 (Scheme 3).13 Each
diastereomer of oxazolidines 2 could be easily isolated by
silica gel chromatography14 or by precipitation of the major
diastereomer in pentane.
Scheme 3. NaBH4 Reduction of the Chiral Ethyl Trifluoropyru-
vate-Based CF3-Oxazolidine 1a
a See ref 8. bSee ref 9.
a See ref 13.
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215. (b) Sakai, T.; Yan, F.; Kashino, S.; Uneyama, K. Tetrahedron 1996, 52,
233–244. (c) Uneyama, K.; Hao, J.; Amii, H. Tetrahedron Lett. 1998, 39,
4079–4082. (d) Abouabdellah, A.; Begue, J.-P.; Bonnet-Delpon, D.; Nga,
T. T. T. J. Org. Chem. 1997,62, 8826–8833. (e) Arnone, A.; Bravo, P.; Capelli,
S.; Fronza, G.; Meille, S. V.; Zanda, M.; Cavicchio, G.; Crucianelli, M. J.
Org. Chem. 1996, 61, 3375–3387. (f) Volonterio, A.; Bravo, P.; Stefano, S. C.;
Meille, S. V.; Zanda, M. Tetrahedron Lett. 1997,38, 1847–1850. (g) Bravo, P.;
Farina, A.; Kukhar, V. P.; Markovsky, A. L.; Meille, S. V.; Soloshonok,
V. A.; Sorochinsky, A. E.; Viani, F.; Zanda, M.; Zappala, C. J. Org. Chem.
1997, 62, 3424–3425. (h) Volonterio, A.; Vergani, B.; Crucianelli, M.; Zanda,
M.; Bravo, P. J. Org. Chem. 1998, 63, 7236–7243. (i) Bravo, P.; Guidetti, M.;
Viani, F.; Zanda, M.; Markovsky, A. L.; Sorochinsky, A. E.; Soloshonok,
I. V.; Soloshonok, V. A. Tetrahedron 1998, 54, 12789–12806. (j) Pesenti, C.;
Arnone, A.; Aubertin, A. M.; Bravo, P.; Frigerio, M.; Panzeri, W.; Schmidt,
S.; Viani, F.; Zanda, M. Tetrahedron Lett. 2000, 41, 7239–7243. (k) Pytkowicz,
J.; Stephany, O.; Marinkovic, S.; Inagaki, S.; Brigaud, T. Org. Biomol. Chem.
2010, 8, 4540–4542.
(6) (a) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71, 7075–7078.
(b) Chaume, G.; Van Severen, M.-C.; Marinkovic, S.; Brigaud, T. Org.
Lett. 2006, 8, 6123–6126. (c) Grellepois, F.; Nonnenmacher, J.;
Lachaud, F.; Portella, C. Org. Biomol. Chem 2011, 9, 1160–1168.
(7) Ishii, A.; Higashiyama, K.; Mikami, K. Synlett 1997, 1381–1382.
(8) Ishii, A.; Miyamoto, F.; Higashiyama, K.; Mikami, K. Tetrahe-
dron Lett. 1998, 39, 1199–1202.
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Org. Lett. 2004, 6, 641–644.
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Med. Chem. Lett. 2005, 154741–4744.
Org. Lett., Vol. 14, No. 2, 2012
605

iso-butyllithium and phenylthiomethyllithium to 2maj and
min proceeded with lower diastereoselectivity (66% to 82%
2
Table 1. Diastereoselective Organolithium Reagents Addition
to 2-Hydroxymethyloxazolidines 2
de) although the yields of diastereomerically pure com-
pounds were acceptable after silica gel purification (54%
to 73%) (Table 1, entries 8À11). As a preliminary study, the
addition of a Grignard reagent (EtMgBr) was investigated
but the expected addition product was obtained in a low
yield (28%) and an average diastereoselectivity (74% de).
Scheme 4. Removal of the Phenylethanol Side Chain of (R)-3,
(R)-4, and (R)-5
a Measured by 1H and 19F NMR spectroscopy analysis of the crude
reaction mixture. >98% means that one single diastereomer was de-
tected. b Yields of pure isolated compounds. c 71:29 mixture of 2maj/2min
.
d Reaction performed at À40 °C. e Reaction performed at À20 °C.
In order to obtain the enantiopure targeted amino
alcohols, the phenylethanol side chains of (R)-3, (R)-4,
and (R)-5 were cleanly removed by hydrogenolysis. The
enantiopure fluorinated amino alcohol hydrochlorides
(R)-9, (R)-10, and (R)-11 were then obtained in 94%,
89%, and 99% yields respectively (Scheme 4).
f 88:12 mixture of 2maj/2min
The major diastereomer 2maj was treated with an excess
amount of methyllithium (4 equiv) at À78 °C in THF to
give the amino diol (R)-3 in 93% yield with complete
diastereoselectivity (Table 1, entry 1). Intriguingly the
addition of methyllithium to the minor diastereomer 2min
gave the same amino diol (R)-3 in 80% yield and 90% de
(Table 1, entry 2). These results strongly contrast with the
organolithium reagent additions on diastereomerically
pure (S) or (R) non-hydroxylated oxazolines giving differ-
ent diastereoisomers (Scheme 1).8 This result suggests that
the same transition state should be involved in the methyl-
lithium addition reaction on both oxazolidines diastereo-
mers 2maj and 2min. This was confirmed by the fact that the
addition of methyllithium to a 71:29 diastereomeric mixture
of oxazolidines 2 also gave the unique (R)-3 diastereomer
with an excellent diastereoselectivity (Table 1, entry 3).
The addition of n-butyllithium and phenyllithium to
2maj occurred also with complete diastereoselectivity
(>98% de) to give (R)-4 and (R)-5 in 77% and 67% yields
respectively (Table 1, entries 4 and 5). The addition of
lithium trimethylsilyl acetylidetoisolated oxazolidines2maj
and 2min was also completely diastereoselective (>98% de)
giving the same (R)-6 aminodiol in 59% and 77% yields
respectively (Table 1, entries 6 and 7). The addition of
Scheme 5. Structure Correlation for the Assignment of (R)-3
Absolute Configuration
The (R) configuration of the amino alcohols obtained
was assigned by structure correlation with known com-
pounds. We previously reported that the enantiopure
(R)-trifluoromethylalanine was efficiently obtained in a
few steps from the (R)-amino nitrile (R)-12 (Scheme 5).6a
Thus the amino nitrile (R)-12 and its corresponding dia-
mino alcohol (R)-13 were resynthesized according to our
reported procedure6a and (R)-13 was converted into the
(11) Legros, J.; Meyer, F.; Coliboeuf, M.; Crousse, B.; Bonnet-
Delpon, D.; Begue, J.-P. J. Org. Chem. 2003, 68, 6444–6446.
(12) Harper, S.; Ferrara, M.; Crescenzi, B.; Pompei, M.; Palumbi,
M. C.; Di Muzio, J. M.; Donghi, M.; Fiore, F.; Koch, U.; Liverton, N. J.;
Pesci, S.; Petrocchi, A.; Rowley, M.; Summa, V.; Gardelli, C. J. Med.
Chem. 2009, 52, 4820–4837.
(13) Simon, J.; Nguyen, T. T.; Chelain, E.; Lensen, N.; Pytkowicz, J.;
Chaume, G.; Brigaud, T. Tetrahedron: Asymmetry 2011, 22, 309–314.
(14) Although each diastereomer was obtained in enantiopure form,
their configurations at the C-2 could not be assigned.
606
Org. Lett., Vol. 14, No. 2, 2012

sulting from the organometallic mediated ring opening of
the hydroxymethyloxazolidines 2maj and 2min. To rational-
ize the diastereoselectivity of this reaction we propose a
transition state inspired by both Iwao’s model15 based on
the N,O (phenylglycinol) metal chelation and Spero’s
model16 involving a N,O (oxymethyl) chelation. The N,
O,O-tridentate chelation model we propose is consistent
with an si-face attack of the chelated Z metallo-imine by a
dimeric organolithium compound (Figure 1).
Figure 1. Postulated transition state: si-face attack of a chelated
Z metallo-imine.
In summary, the organolithium species addition on
chiral hydroxymethyl trifluoromethyl oxazolidines is highly
diastereoselective. This provides a convenientand straight-
forward access to enantiopure β-trifluoromethyl β-amino
alcohols quaternarized at the β-position.
corresponding diastereomerically pure amino diol (R)-3
through a diazotization reaction (Scheme 5). The optical
rotation and the spectral data of this compound perfectly
matched the compound (R)-3 synthesized in this work
(Table 1, entry 1). Because of similar postulated reaction
mechanisms the configurations of compounds 4 to 8 were
also anticipated to be (R).
Acknowledgment. We thank the Central Glass Company
for financial support and the gift of ethyl trifluoropyruvate.
In order to explain these results we suggest that the
reaction proceeds through the same Z-metallo-imine re-
Supporting Information Available. Complete experi-
mental procedures, and characterization data for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Fukuda, T.; Takehara, A.; Haniu, N.; Iwao, M. Tetrahedron:
Asymmetry 2000, 11, 4083–4091.
(16) Steinig, A. G.; Spero, D. M. J. Org. Chem. 1999, 64, 2406–2410.
Org. Lett., Vol. 14, No. 2, 2012
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