An efficient entry to optically active anti- and syn-β-amino-α- trifluoromethyl alcohols

Article abstract of DOI:10.1021/ol702947n

The reaction of chiral 5,6-dihydro-2H-1,4-oxazin-2-ones with TMSCF ₃ in the presence of a suitable activator leads to trifluoromethyl lactols, which can be selectively reduced to anti-β-amino-α- trifluoromethyl alcohols. The corresponding syn d

Full text of DOI:10.1021/ol702947n

ORGANIC
LETTERS
2008
Vol. 10, No. 4
605-608
An Efficient Entry to Optically Active
anti- and syn-â-Amino-r-trifluoromethyl
Alcohols
Santos Fustero,*,†,‡ Laia Albert,†,‡ Jose´ Luis Acen˜a,‡ Juan F. Sanz-Cervera,†,‡ and
Amparo Asensio†
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot,
Spain, and Laboratorio de Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe
Felipe, E-46013 Valencia, Spain
santos.fustero@uV.es
Received December 5, 2007
ABSTRACT
The reaction of chiral 5,6-dihydro-2H-1,4-oxazin-2-ones with TMSCF3 in the presence of a suitable activator leads to trifluoromethyl lactols,
which can be selectively reduced to anti- -amino- -trifluoromethyl alcohols. The corresponding syn diastereoisomers are obtained when the
â
r
starting imines are reduced and the nitrogen atom is conveniently protected. In addition, a novel rearrangement of the CF3 group in the lactol
intermediates has been observed. This represents a formal CF3 addition to the imine function in the starting substrates.
Nucleophilic trifluoromethylation reactions1 constitute one
of the simplest ways of introducing the valuable trifluorom-
ethyl group into organic molecules.2 The most common
method for achieving this involves the use of the Ruppert-
Prakash reagent (TMSCF3)3 in combination with a variety
of activators/catalysts to facilitate the addition of CF3 groups
to electrophilic substrates such as aldehydes, ketones, esters,
and imines. Fluoride sources such as TBAF or CsF are
commonly employed as activators in this process, although
other reagents such as Lewis bases4 and acids5 can also be
used in catalytic amounts. The reaction can even work in
the absence of a catalyst with DMSO as solvent.6 Although
asymmetric trifluoromethylations with chiral activators have
been reported,7 they more often entail the diastereoselective
addition of TMSCF3 to chiral substrates.
In connection with our interest in the preparation of
enantiopure fluorine-containing synthons of biologically
interesting molecules,8 we have now developed an efficient
method for preparing both anti- and syn-â-amino-R-trifluo-
(4) (a) Prakash, G. K. S.; Panja, C.; Vaghoo, H.; Surampudi, V.;
Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.; Olah, G. A. J. Org.
Chem. 2006, 71, 6806-6813. (b) Kawano, Y.; Kaneko, N.; Mukaiyama,
T. Bull. Chem. Soc. Jpn. 2006, 79, 1133-1145.
(5) Mizuta, S.; Shibata, N.; Ogawa, S.; Fujimoto, H.; Nakamura, S.; Toru,
T. Chem. Commun. 2006, 2575-2577.
(6) Iwanami, K.; Oriyama, T. Synlett 2006, 112-114.
(7) (a) Kuroki, Y.; Iseki, K. Tetrahedron Lett. 1999, 40, 8231-8234.
(b) Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 666-
667. (c) Zhao, H.; Qin, B.; Liu, X.; Feng, X. Tetrahedron 2007, 63, 6822-
6826.
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) For reviews, see: (a) Prakash, G. K. S.; Yudin, A. K. Chem. ReV.
1997, 97, 757-786. (b) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000,
56, 7613-7632. (c) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001,
112, 123-131. (d) Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104, 6119-
6146. (e) Langlois, B. R.; Billard, T.; Roussel, S. J. Fluorine Chem. 2005,
126, 173-179. (f) Billard, T.; Langlois, B. R. Eur. J. Org. Chem. 2007,
891-897. (g) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975-
996.
(2) Organofluorine Chemistry: Principles and Commercial Applications;
Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New York,
1994.
(3) (a) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984,
25, 2195-2198. (b) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J.
Am. Chem. Soc. 1989, 111, 393-395.
(8) (a) Fustero, S.; Sa´nchez-Rosello´, M.; Rodrigo, V.; del Pozo, C.; Sanz-
Cervera, J. F.; Simo´n, A. Org. Lett. 2006, 8, 4129-4132. (b) Fustero, S.;
Sa´nchez-Rosello´, M.; Sanz-Cervera, J. F.; Acen˜a, J. L.; del Pozo, C.;
Ferna´ndez, B.; Bartolome´, A.; Asensio, A. Org. Lett. 2006, 8, 4633-4636.
(c) Fustero, S.; Ferna´ndez, B.; Bello, P.; del Pozo, C.; Arimitsu, S.;
Hammond, G. B. Org. Lett. 2007, 9, 4251-4253.
10.1021/ol702947n CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/23/2008

romethyl alcohols. These fluorinated amino alcohols are a
useful class of compounds because they serve as precursors
of more elaborate molecules such as peptidyl fluoroalkyl
ketones, which are thought to act as protease inhibitors.9 In
addition, fluorinated amino alcohols have been used as chiral
ligands/auxiliaries in asymmetric processes in much the same
way as their nonfluorinated counterparts.10 Several synthetic
approaches to these compounds have been reported,11 but
the direct addition of TMSCF3 to chiral R-amino aldehydes
usually affords only low to moderate diastereoselectivities.11e,12
In contrast, our method involves the addition of TMSCF3 to
optically pure 5,6-dihydro-2H-1,4-oxazin-2-ones 1 (Scheme
1). Since the lactone moiety should be more reactive13 than
We first tested the addition of TMSCF3 to the known imino
lactone 1a (R ) Me), available from the condensation of
methyl pyruvate with (R)-2-phenylglycinol.16 Several activa-
tors and reaction conditions were tested (see Table 1). The
Table 1. Addition of TMSCF3 to Imino Lactones 1
entry
1
R
activator (equiv)
2
yield (%)
Scheme 1. Synthetic Plan
1
2
3
4
5
6
7
8
9
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1b Ph(CH2)2
1c MeO2C(CH2)2
1d t-Bu
TBAF (0.5)
TBAT (0.5)
CsF (1.0)
KOt-Bu (0.5)
K2CO3 (0.1)b
TASF (0.5)
TASF (0.5)
TASF (0.5)
TASF (0.5)
TASF (0.5)
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
56
54
55
38a
65
72
75
74
65
32
69
10
11
1e Ph
1f CH2dCH(CH2)3 TASF (0.5)
a 12% of silyl ether 2a′ was also isolated. b The reaction was performed
in DMF at rt.
the imino functionality,14 this reaction should afford the
corresponding trifluoromethyl lactols 2 rather than R-trif-
luoromethyl amines 4. Stereoselective reduction of both the
lactol and imino functionalities in 2 and subsequent removal
of the chiral auxiliary should then yield the target compounds
3. Because we have found that suitably substituted com-
pounds 2 can undergo a migration of the CF3 group toward
the imino carbon, this particular procedure may also provide
an indirect access to trifluoromethyl amino acids 5.15
use of a catalytic amount of TBAF produced a mixture of
imino lactol 2a and its silyl ether 2a′ (TLC analysis), which
upon aqueous workup (satd NH4Cl, 3 h) afforded compound
2a isolated as a single isomer in moderate yield17 (entry 1).
However, since the quality of TBAF severely affected the
reproducibility of the reaction, other fluoride sources were
evaluated. The non-hygroscopic tetrabutylammonium triph-
enyldifluorosilicate (TBAT) was found to be effective, but
the difficulty in removing TBAT byproducts had a negative
effect on the yield of 2a (entry 2). CsF also led to modest
yields, probably due to its low solubility in THF (entry 3).
Reagents other than fluorides were also used with similar
results (entries 4 and 5). In the end, good yields of 2a were
finally achieved with tris(dimethylamino)sulfonium difluo-
rotrimethylsilicate (TASF), which, although it is barely
soluble in THF, efficiently promoted the addition of TMSCF3
to 1 (entry 6).
(9) (a) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985, 24,
1813-1817. (b) Veale, C. A.; Damewood, J. R., Jr.; Steelman, G. B.; Bryant,
C.; Gomes, B.; Williams, J. J. Med. Chem. 1995, 38, 86-97.
(10) Katagiri, T.; Iguchi, N.; Kawate, T.; Takahashi, S.; Uneyama, K.
Tetrahedron: Asymmetry 2006, 17, 1157-1160 and references cited therein.
(11) (a) Tomoyasu, T.; Tomooka, K.; Nakai, T. Synlett 1998, 1147-
1149. (b) Abouabdellah, A.; Be´gue´, J.-P.; Bonnet-Delpon, D.; Kornilov,
A.; Rodrigues, I.; Richard, C. J. Org. Chem. 1998, 63, 6529-6534. (c)
Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A.
Org. Lett. 2000, 2, 3173-3176. (d) Jiang, Z.-X.; Qin, Y.-Y.; Qing, F.-L. J.
Org. Chem. 2003, 68, 7544-7547. (e) Andre´s, J. M.; Pedrosa, R.; Pe´rez-
Encabo, A. Eur. J. Org. Chem. 2004, 1558-1566. (f) Huguenot, F.; Brigaud,
T. J. Org. Chem. 2006, 71, 7075-7078. (g) Tur, F.; Saa´, J. M. Org. Lett.
2007, 9, 5079-5082.
(12) For additional examples of nonselective additions of TMSCF3 to
Garner’s aldehyde, see: (a) Qing, F.-L.; Peng, S.; Hu, C.-M. J. Fluorine
Chem. 1998, 88, 79-81. (b) See also ref 4b.
(13) For examples of additions of TMSCF3 to lactones, see: (a) Walter,
M. W.; Adlington, R. M.; Baldwin, J. E.; Schofield, C. J. J. Org. Chem.
1998, 63, 5179-5192. (b) Walter, M. W.; Thaker, N.; Baldwin, J. E.; Mu¨ller,
M.; Schofield, C. J. J. Chem. Res., Synop. 2000, 310-311. (c) Sydnes, M.
O.; Hayashi, Y.; Sharma, V. K.; Hamada, T.; Bacha, U.; Barrila, J.; Freire,
E.; Kiso, Y. Tetrahedron 2006, 62, 8601-8609.
Following a procedure reported by Harwood and co-
workers,16,18 we then proceeded to prepare other imino
lactones by varying the R groups (Scheme 2). This method
(15) For a review, see: Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron
2004, 60, 6711-6745.
(16) Harwood, L. M.; Vines, K. J.; Drew, M. G. B. Synlett 1996, 1051-
1053.
(17) The stereochemistry of lactols 2 was deduced as depicted after the
further transformations carried out in Scheme 6.
(14) Only a few examples of additions of TMSCF3 to highly activated
ketimines have been reported: (a) Fe´lix, C. P.; Khatimi, N.; Laurent, A. J.
Tetrahedron Lett. 1994, 35, 3303-3304. (b) Blazejewski, J.-C.; Anselmi,
E.; Wilmshurst, M. P. Tetrahedron Lett. 1999, 40, 5475-5478. (c) Petrov,
V. A. Tetrahedron Lett. 2000, 41, 6959-6963.
(18) A slight modification was made in that the condensation of R-keto
esters with (R)-phenylglycinol occurred under microwave irradiation in order
to reduce the reaction times. R-Keto esters were commercially available or
prepared by Grignard additions to diethyl oxalate; see: Macritchie, J. A.;
Silcock, A.; Willis, C. L. Tetrahedron: Asymmetry 1997, 8, 3895-3902.
606
Org. Lett., Vol. 10, No. 4, 2008

â-amino lactols could reverse the reduction selectivity.22
Thus, the starting substrates 1a-d were hydrogenated as
described (H2, PtO2)23 to afford 7a-d, after which the amino
group was protected with BnBr to yield 8a-d (Scheme 3).
Scheme 2. Preparation of Imino Lactones 1a-f
Scheme 3. Syn Reduction of Benzyl-Protected Amino Lactols
was not suitable in the case of compounds 1d,e, which
contain R-branched R groups; thus, a SeO2-promoted rear-
rangement of oxazolines as described by Schafer and
Molinski19 was carried out instead.
We then undertook the trifluoromethylation of the different
imino lactones and obtained similar results (Table 1, entries
7-11); indeed, the yield was lower solely in the case of 1e,
probably due to undesired imine isomerization16 (entry 10).
In the case of compound 1c (entry 8), the addition of CF3
only affected the lactone, leaving the methyl ester moiety
unaltered.
The second key step was the stereoselective reduction of
imino lactols 2, which was carried out under a variety of
conditions.20 The best results were achieved with LiBH4,
which produced anti-amino diols 6 as the major isomers with
good selectivity21 (Table 2, entries 1, 3, and 6). However,
The addition of TMSCF3 to these amino lactones was more
effective when using TBAT as activator;24 further reduction
with NaBH4 produced syn-diols 9a-c with excellent dias-
tereoselectivity (>97:3).25
From 6a-d, removal of phenylglycinol through hydro-
genation was best carried out in the presence of Boc2O in
order to facilitate the isolation of N-Boc-protected amino
alcohols anti-10a-d, which were then deprotected to afford
the target compounds anti-3a-d, isolated as their hydro-
chloride salts (Scheme 4). In addition, hydrogenolysis and
Scheme 4. Preparation of Amino Alcohols 3
Table 2. Anti Reduction of Imino Lactols 2
entry
2
R
6
yielda (%)
drb
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Me
6a
6b
6cc
6d
6e
6f
74
88
68
75
55
74
96:2:2:0
76:15:5:4
91:5:4:0
73:18:6:3
55:34:9:2
89:5:3:3
Ph(CH2)2
MeO2C(CH2)2
t-Bu
Ph
CH2dCH(CH2)3
a Overall yield of pure products. b Determined by integration in the 19F
NMR crude spectra. c The ester group was also reduced to the corresponding
primary alcohol (R ) HO(CH2)3).
in situ N-Boc protection of 9a-c provided syn-10a-c, which
were subsequently transformed into syn-3a-c. The relative
stereochemistry of these amino alcohols was confirmed
through coupling constant analysis in the corresponding cis
the selectivity decreased somewhat when R ) Ph(CH2)2 or
t-Bu (entries 2 and 4), affording only a 55:34:9:2 mixture
of unseparable diols when R ) Ph (entry 5).
For the preparation of the corresponding syn diastereo-
isomers, we reasoned that the use of appropriately protected
(22) Reetz, M. T. Chem. ReV. 1999, 99, 1121-1162.
(23) Cox, G. C.; Harwood, L. M. Tetrahedron: Asymmetry 1994, 5,
1669-1672.
(19) Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1996, 61, 2044-2050.
(20) Other reducing agents tested (LiAlH4, NaBH4, NaCNBH3, DIBAL-
H, Red-Al) led to lower selectivities and/or partial reductions.
(21) The anti diastereoselectivity could be attributed to the initial
reduction of the latent trifluoromethyl ketone prior to the imino group under
these conditions.
(24) The corresponding benzylated lactols were obtained as mixtures of
unseparable epimers. Compound 8d failed to react with TMSCF3 under all
conditions tested.
(25) In contrast, TMSCF3 addition to unprotected 7a, and subsequent
reduction with LiBH4 afforded the anti-amino alcohol with (2S,3S)
configuration as the major diastereoisomer (dr 80:20).
Org. Lett., Vol. 10, No. 4, 2008
607

and trans oxazolidinones 11.26 Finally, comparison of
compounds cis-11a and trans-11a with those previously
reported by Pedrosa and co-workers confirmed their absolute
configuration.11e
Scheme 6. Synthesis of Bicyclic Diiodide 19
We next embarked on the synthesis of amino alcohols
containing a quaternary center in â-position. Thus, addition
of TMSCF3 to the known amino lactone 1216 gave lactol 13
(Scheme 5). Further reduction with LiBH4 and hydrogenation
Scheme 5. Synthesis of Quaternary Amino Alcohol 15
applied to 2f to yield 19 in a one-pot reaction. Overall, this
process constitutes a formal addition of CF3 to the starting
ketimine, which cannot be carried out directly (see Scheme
1).
In summary, we have developed a simple methodology
for the preparation of either anti- or syn-â-amino-R-trifluo-
romethyl alcohols. Both enantiomeric series can be obtained
by simply changing the chiral auxiliary. In addition, we
observed a novel rearrangement of the CF3 group which
allowed for the preparation of chiral quaternary R-trifluo-
romethyl amines. Further investigations are currently un-
derway.
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2007-61462 and CTQ2006-01317) and the
Generalitat Valenciana (GR03/193) for financial support and
Prof. G. K. S. Prakash (University of Southern California)
for helpful discussions. L.A. thanks the Universidad de
Valencia for a predoctoral fellowship, and J.L.A. thanks the
MEC for a Ramo´n y Cajal research contract.
produced a separable mixture of 14 and its epimer (84:16
diastereoselectivity). Finally, Boc removal with HCl afforded
amino alcohol 15 as its hydrochloride salt; subsequent
cyclization to oxazolidinone 16 again provided the config-
uration of the newly formed stereocenter with the aid of NOE
correlations (see the Supporting Information).
Compound 2f containing an unsaturated side chain was
found to be a substrate suitable for further cyclization
reactions. For instance, when treated with I2 in order to
promote an iodoamination reaction, iodide 17 was obtained
as a single isomer (Scheme 6). However, under harsher
conditions (I2, NaH, microwave), a second iodine atom was
introduced, presumably through a iodonium cation interme-
diate 18 which evolves to compound 19 by means of the
rearrangement of the CF3 group27 with concomitant regenera-
tion of the lactone functionality.28 These conditions were also
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702947N
(27) To the best of our knowlegde, only two examples of migrations of
CF3 groups have been reported. See: (a) Hein, F.; Burger, K.; Firl, J. J.
Chem. Soc., Chem. Commun. 1979, 792-793. (b) Chambers, R. D.;
Cheburkov, Y. A.; Tanabe, T.; Vaughan, J. F. S. J. Fluorine Chem. 1995,
74, 227-228.
(28) The stereochemistry in 19 was assigned with the aid of various 2D
NMR experiments (COSY, NOESY, and 1H-19F HOESY); see the
Supporting Information.
(26) The coupling constant between vicinal protons in the oxazolidinone
ring was significantly larger in the cis isomers.
608
Org. Lett., Vol. 10, No. 4, 2008