A facile stereocontrolled synthesis of anti-alpha-(trifluoromethyl)-beta-amino alcohols.

Article abstract of DOI:10.1021/ol000195f

A short stereocontrolled preparation of anti-alpha-(trifluoromethyl)-beta-amino alcohols is described, involving an initial CF(3) transfer to cinnamaldehyde and a one-step, three-component condensation of 3,3,3-trifluorolactic aldehyde, an alkenyl (aryl)

Full text of DOI:10.1021/ol000195f

ORGANIC
LETTERS
2
000
Vol. 2, No. 20
173-3176
A Facile Stereocontrolled Synthesis of
anti-r-(Trifluoromethyl)-â-amino
Alcohols
3
G. K. Surya Prakash,* Mihirbaran Mandal, Stefan Schweizer,
Nicos A. Petasis,* and George A. Olah*
Donald P. and Katherine B. Loker Hydrocarbon Research Institute and
Department of Chemistry, UniVersity of Southern California, UniVersity Park,
Los Angeles, California 90089-1661
prakash@methyl.usc.edu
Received July 24, 2000
ABSTRACT
3
A short stereocontrolled preparation of anti-r-(trifluoromethyl)-â-amino alcohols is described, involving an initial CF transfer to cinnamaldehyde
and a one-step, three-component condensation of 3,3,3-trifluorolactic aldehyde, an alkenyl (aryl) boronic acid, and an amine. Applying this
methodology to chiral 3,3,3-trifluorolactic aldehyde allowed us to generate an amino alcohol enantioselectively in 92% ee.
Fluoroalkyl â-amino alcohols, like their nonfluorinated
analogues, are the focus of numerous studies. They are used
alcohols can be used as chiral auxiliaries or as ligands in
asymmetric synthesis. Reported preparations of these mol-
1
5
as peptidomimetics and transition state mimics in drug
ecules involved reduction of the trifluoromethylated ketone,
2
6
design, as well as novel precursors for the corresponding
Henry condensation between nitroalkane and hydrate of
3
fluoroalkyl peptidyl ketones. These ketones exist as stable
fluoral or the opening of epoxy ethers by nitrogen nucleo-
hydrates in aqueous medium because of their exceptionally
high electrophilicity. These hydrates serve as an ideal mimic
of the tetrahedral transition state of the amide bond, thus
(
4) (a) Imperiali, B. Synthetic Peptide in Biochemistry; A. R. Liss, Inc.:
New York, 1988; pp 97-129. (b) Gelb, H. H.; Svaren, J. P. Biochemistry
985, 24, 1813-1817. (c) Imperiali, B.; Abeles, R. H. Biochemistry 1986,
1
4
inhibiting proteolytic enzymes. Trifluoromethyl-â-amino
25, 3760-3767. (d) Brady, K.; Liang, T.-C.; Abeles, R. H. Biochemistry
1
2
989, 28, 9066-9070. (e) Liang, T.-C.; Abeles, R. H. Biochemistry 1987,
6, 7603-7608. (f) Brady, K.; Abeles, R. H. Biochemistry 1990, 29, 7608-
(1) (a) Asymmetric Fluoroorganic Chemistry; Abouabdellah, A.; Begue,
7617. (g) Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.;
Mehdi, S.; Bey, P.; Kolb, M.; Neises, B.; Schirlin, D. J. Med. Chem. 1990,
33, 394-397. (h) Skiles, J. W.; Fuchs, V.; Miao, C.; Sorcek, R.; Grozinger,
K. G.; Mauldin, S. C.; Vitous, J.; Mui, P. W.; Jacober, S.; Chow, G.; Matteo,
M.; Skoog, M.; Weldon, S. M.; Possanza, G.; Keirns, J.; Letts, G.; Rosenthal,
A. S. J. Med. Chem. 1992, 35, 641-662. (i) Angelastro, M. R.; Baugh, L.
E.; Bey, P.; Burkhart, J. P.; Chen, T.-M.; Durham, S. L.; Hare, C. M.; Huber,
E. W.; Janusz, M. J.; Koehl, J. R.; Marquart, A. L.; Mehdi, S.; Peet, N. P.
J. Med. Chem. 1994, 37, 4538-4554. (j) Ueda, T.; Kam, C.-M.; Powers, J.
C. Biochem. J. 1990, 265, 539-545. (k) Sham, H. L.; Stein, H.; Rempel,
C. A.; Cohen, J.; Platter, J. J. FEBS Lett. 1987, 220, 299-301. (l) Tarnus,
C.; Jung, M. J.; R e´ my, J. M.; Baltzer, S.; Schirlin, D. FEBS Lett. 1989,
249, 47-50. (m) Giordano, C.; Gallina, C.; Consalvi, V.; Scandurra, R.
Eur. J. Med, Chem. 1989, 24, 357-362. (n) Smith, R. A.; Copp, L. J.;
Donnelly, S. L.; Spencer, R. W.; Krantz, A. Biochemistry 1988, 27, 6568-
6573.
J.-P.; Bonnet-Delpon, D.; Kornilov, A.; Rodrigues, I.; Nga, T. T. T. ACS
Symposium Series 736; American Chemical Society: Washington, DC,
2
000; pp 84-97. (b) Biomedical Frontiers of Fluorine Chemistry; Ojima,
I., McGrath, J. R., Welch, J. T., Eds.; ACS Symposium Series 639, American
Chemical Society: Washington, DC, 1996.
(
2) (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett.
988, 29, 4665-4668. (b) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.;
Free, C. A.; Smith, S. A.; Pertillo, E. W., Jr. J. Med. Chem. 1993, 36, 2431-
447.
3) (a) Bernstein, P. R.; Gomes, B. C.; Kosmider, B. J.; Vacek, E. P.;
1
2
(
Williams, J. C. J. Med. Chem. 1995, 38, 212-215. (b) Warner, P.; Green,
R. C.; Gomes, B.; Strimpler, A. M. J. Med. Chem. 1994, 37, 3090-3099.
(
c) Brown, F. J.; Andisik, D. W.; Bernstein, P. B.; Bryant, C. B.; Ceccarelli,
C.; Damewood, J. R., Jr.; Edwards, P. D.; Earley, R. A.; Feeney, S.; Green,
R. C.; Gomes, B.; Kosminder, B. J.; Krell, R. D.; Shaw, A.; Steelman, G.
B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.;
Williams, J. C.; Wolanin, D, J.; Woolson, S. A. J. Med. Chem. 1994, 37,
(5) (a) B e´ gu e´ , J-P.; Bonnet-Delpon, D.; Sdassi, H. Tetrahedron Lett.
1992, 33, 1879-1882.
(6) Imperiali, B.; Abeles, R. H. Tetrahedron Lett. 1986, 27, 135-138.
1
259-1261.
1
0.1021/ol000195f CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/02/2000

7
philes, and subsequent reduction. These all require many
synthetic steps or suffer from lack of diastereoselectivity.
We report herein an astonishingly short route to R-tri-
fluoromethyl-â-amino alcohols via 3,3,3-trifluorolactic al-
dehyde. Following the initial report by one of us involving
a three-component condensation of boronic acids, amines,
Table 1. Synthesis of anti-R-(Trifluoromethyl)-â-amino
Alcohols
8
and R-hydroxy aldehydes to yield anti-â-amino alcohols,
we surmised that 3,3,3-trifluorolactic aldehyde under similar
conditions would give the corresponding fluorinated anti-
amino alcohols accordingly.
However, few reports exist on the preparation and proper-
9
10
ties of trifluorolactic aldehyde or its benzylated derivative.
Following our synthetic strategy, cinnamaldehyde was first
trifluoromethylated, using TMSCF and catalytic amounts
3
11
of CsF (Scheme 1). After acidic workup (E)-1,1,1-trifluoro-
Scheme 1
4
-phenyl-3-buten-2-ol (2) was obtained in 90% yield. The
allylic alcohol 2 was then quantitatively transformed to 3,3,3-
trifluorolactic aldehyde (5) by ozonolysis, using MeOH/CH
Cl (1:1). This aldehyde, which exists primarily in its
2
-
2
oligomeric form, was reacted with different boronic acids
and amines (Table 1). The remarkable feature of this
transformation is its diastereoselectivity, providing the anti-
8
(trifluoromethyl)-â-amino alcohol 6 in >99% de.
The reactions were carried out under mild conditions using
12
ethanol as a solvent at room temperature. Next we turned
our attention to the enantioselective synthesis of R-trifluo-
romethyl-â-amino alcohols. The preparation of (E)- or (Z)-
1
,1,1-trifluoro-4-phenyl-3-buten-2-ol enantioselectively has
been accomplished by means of a microbial reduction of the
corresponding ketone with Geotrichum candidum in 94% ee,
but the saturated alcohol was obtained along with the desired
allylic alcohol. Other synthetic approaches gave a lower
enantioselectivity. Starting from (E)-1,1,1-trifluoro-4-phen-
yl-3-buten-2-one (7), which was obtained from the alcohol
(
7) Abouabdellah, A.; B e´ gu e´ , J-P.; Bonnet-Delpon, D.; Kornilov, A.;
Rodrigues, I.; Richard, C. J. Org. Chem. 1998, 63, 6529-6534.
8) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798-
1799.
9) Coinciding with our studies, Fessner et al. reported a similar approach
1
3
(
14
1
(
to trifluorolactic aldehyde: Fessner, W.-D.; Go aˆ e, C.; Jaeschke, G.; Eyrisch,
2
by Swern oxidation, a variety of reagents are generally
O. Eur. J. Org. Chem. 2000, 125-132.
(10) (a) Bravo, P.; Frigerio, M.; Resnati, G. J. Org. Chem. 1990, 55,
4
216-4218. (b) Katagiri, T.; Kutose, K.; Shimokawa, N.; Kusunoki, N.;
Uneyama, K. Tetrahedron 1999, 55, 9163-9170.
11) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.
989, 111, 393-395.
12) Typical Reaction Procedure. To a solution of the aldehyde 5 in
(13) Arnone, A.; Bernardi, R.; Blasco, F.; Cardillo, R.; Resnati, G.; Gerus,
I. I.; Kukhar, V. P. Tetrahedron 1998, 54, 2809-2818.
(
(14) (a) Kubota, T.; Yamamoto, M. Tetrahedron Lett. 1992, 33, 2603-
2606. (b) Kitazume, T.; Lin, J. T.; Yamazaki, T. J. Fluorine Chem. 1989,
43, 177.
1
(
EtOH was added the amine 3a and 2-furylboronic acid (4a) successively.
The reaction mixture was sealed and stirred at room temperature for 24 h.
After concentration under vacuum, the residue was purified by chroma-
tography with hexanes/ethyl acetate (9:1) to yield 6a as colorless oil (560
mg, 85% yield, >99% de).
(15) (a) Singh, V. K. Synthesis 1992, 605-617. (b) Houben-Weyl,
Methods of Organic Chemistry, 4th ed.; G. Thieme, Stuttgart-New York,
1995; Vol. E21d, p 3945. (c) Brown, H. C.; Park, W. S.; Cho, B. T.;
Ramachandran, P. V. J. Org. Chem. 1987, 52, 5406-5412. (d) ApSimon,
J. W.; Collier, T. L. Tetrahedron 1986, 42, 5157-5254.
3174
Org. Lett., Vol. 2, No. 20, 2000

15
16
suitable for the enantioselective reduction. (S)-BINAL-H
reaction to be carried out at a lower temperature and is more
was selected first and applied to the reduction of ketone 7,
but it afforded (S)-1,1,1-trifluoro-4-phenyl-3-buten-2-ol [(S)-
compatible with olefinic ketones. The combination of (S)-
n
B- Bu-CBS and catecholborane allowed us to obtain the (R)-
17
19
2] in only 71% ee (Scheme 2). Chiral oxazaborolidines
carbinol (R)-2 in 85% yield and 85% ee (Table 2).
Scheme 2
Table 2. Asymmetric Reduction of
(E)-1,1,1-Trifluoro-4-phenyl-3-buten-2-one (7)
configuration yield ee
reagent
of 2
(%) (%)
(
(
(
S)-BINAL-H (3 equiv)
S
S
R
94
90
85
71
75
85
R)-B-Me-CBS (cat.) catecholborane
n
S)-B- Bu-CBS (cat.) catecholborane
In the subsequent ozonolysis of the double bond, the
solvent system employed turned out to have a major impact
on the outcome of the reaction. The 1:1 solvent mixture of
methanol and CH
allylic alcohol, results in a racemisation of the product (Table
). In pure methanol, the outcome was even worse. However,
2 2
Cl , which is compatible with the racemic
3
Table 3. Ozonolysis and Enantioselective Synthesis of the
Amino Alcohol 6h
configuration ee of 2
ratio of
chrom. sep.
ee of 6h
of 2
(%)
MeOH/CH2Cl2 after ozonolysis
(%)
R
R
R
R
S
82
77
77
85
96
1:1
yes
yes
no
no
no
55
8
30
85
92
MeOH
MeOH
1:4
1:4
represent an alternative catalyst system.18 The most com-
monly used reducing systems comprise the CBS-oxazaboro-
lidine catalyst, bearing a methyl- or n-butyl-group attached
2 2
a reduced amount of methanol (4:1 mixture of CH Cl /
MeOH) proved to be superior, and after treatment of the
crude aldehyde 5 (as oligomer) with bromostyrylboronic acid
3
to the boron, and BH or catecholborane as stoichiometric
reducing agent. The less reactive catecholborane allows the
4
d and dibenzylamine 3b the expected â-amino alcohol
17
(R,R)-6h was obtained in 85% ee and 71% yield. It should
(16) (a) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem.
be mentioned that column chromatographic purification of
the hydroxy aldehyde 5 after ozonolysis also caused race-
mization due to the highly acidic R proton adjacent to the
Soc. 1984, 106, 6717-6725. (b) Noyori, R.; Tomino, I.; Tanimoto, Y.;
Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6709-6716. (c) Hanzawa,
Y.; Kawagoe, K.; Kobayashi, Y. Chem. Pharm. Bull. 1987, 35, 2609. (d)
Chong, J. M.; Mar, E. K. J. Org. Chem. 1991, 56, 893-896.
19
3
CF group.
(
17) The % ee was established by HPLC and the F NMR of the Mosher
ester: Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
18) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998,
A detailed literature survey revealed that the reduction of
(
3
7, 1986-2012. (b) Corey, E. J.; Link, J. O.; Bakshi, R. K. Tetrahedron
the corresponding alkynyl ketone with (-)-DIP-chloride was
Lett. 1992, 33, 7107-7110. (c) Corey, E. J.; Link, J. O.; Sarshar, S.; Shao,
Y. Tetrahedron Lett. 1992, 33, 7103-7106. (d) Corey, E. J.; Cheng, X.-
M.; Cimprich, K. A.; Sarshar, S. Tetrahedron Lett. 1991, 32, 6835-6838.
20
reported in 98% ee. Following this procedure, the 1,1,1-
trifluoro-4-phenyl-3-butyn-2-one (8), which results from a
(e) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611-614.
21
coupling of ethyl phenylpropiolate and TMSCF
3
,
was
1
(
19) The absolute configuration was established by comparing the H
treated with (-)-DIP-chloride to yield (S)-1,1,1-trifluoro-4-
phenyl-3-butyn-2-ol [(S)-9] in 96% ee. (S)-9 was then
reduced to the alkenyl alcohol (S)-2, using Red-Al without
NMR spectra of the O-methylmandelate esters of the two enantiomers:
Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J.
M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer,
J. P. J. Org. Chem. 1986, 51, 2370-2374. This result is in agreement with
Corey’s mechanistic and structural analysis of the reduction of trifluoro-
methyl ketones by CBS, in which he attributes the product configuration
to a greater effective bulk of CF3 as compared to groups such as tert-butyl
2 2
any stereochemical loss. Ozonolysis (CH Cl /MeOH, 4:1),
1
8b
or 9-anthryl. Ramachandran and Brown come to the same conclusion,
claiming that each fluorine atom exerts a steric influence similar to those
of the CH3 group: Ramachandran, P. V.; Teodoroviæ, A. V.; Brown, H.
C. Tetrahedron 1993, 49, 1725-1738.
(20) Ramachandran, P. V.; Gong, B.; Teodorovic, A. V.; Brown, H. C.
Tetrahedron: Asymmetry 1994, 5, 1061-1074.
(21) Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J. M. J. Org.
Chem. 1999, 64, 2873-2876.
Org. Lett., Vol. 2, No. 20, 2000
3175

and immediate reaction of the crude product with boronic
acid 4d and amine 3b resulted in the formation of (S,S)-6h
in 79% yield and 92% ee.17
Acknowledgment. The support of our work by the Loker
Hydrocarbon Research Institute is gratefully acknowledged.
N.A.P. also thanks the National Institute of Health for its
support (GM 45970).
In conclusion, we have reported a facile multicomponent
synthesis of anti-R-(trifluoromethyl)-â-amino alcohols in
high diastereoselectivity. The method was extended to the
preparation of (S,S)-4-bromo-2-(N,N-dibenzylamino)-4-phen-
yl-1-trifluoromethyl-3-(Z)-butenol in 92% ee. The (R,R)-
isomer was also prepared in 85% ee. The evaluation of the
properties of this novel class of molecules is currently under
way.
Supporting Information Available: Full characterization
data for compounds 6a-h and some experimental proce-
dures. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL000195F
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Org. Lett., Vol. 2, No. 20, 2000