Stereoselective synthesis of anti-α-(difluoromethyl)-β-amino alcohols by boronic acid based three-component condensation. Stereoselective preparation of (2S,3R)-difluorothreonine

Article abstract of DOI:10.1021/jo011116w

Starting from optically active 3,3-difluorolactaldehyde, an alkenyl or aryl boronic acid, and an amine, a one-step three-component methodology was developed for the stereoselective preparation of anti-α-(difluoromethyl)-β-amino alcohols. β-Furyl-substituted anti-α-(difiuoromethyl)-β-amino alcohol was further elaborated to form (2S,3R)-difluorothreonine in high yield and ee.

Full text of DOI:10.1021/jo011116w

3718
J . Org. Chem. 2002, 67, 3718-3723
Ster eoselective Syn th esis of a n ti-r-(Diflu or om eth yl)-â-a m in o
Alcoh ols by Bor on ic Acid Ba sed Th r ee-Com p on en t Con d en sa tion .
Ster eoselective P r ep a r a tion of (2S,3R)-Diflu or oth r eon in e
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
gprakash@.usc.edu
Received December 3, 2001
Starting from optically active 3,3-difluorolactaldehyde, an alkenyl or aryl boronic acid, and an amine,
a one-step three-component methodology was developed for the stereoselective preparation of anti-
R-(difluoromethyl)-â-amino alcohols. â-Furyl-substituted anti-R-(difluoromethyl)-â-amino alcohol
was further elaborated to form (2S,3R)-difluorothreonine in high yield and ee.
In tr od u ction
The scarcity of fluorinated molecules in nature together
with their increasing use in new materials and new
pharmaceuticals has inspired chemists to develop ef-
ficient methodologies for their synthesis. Among the most
important applications of organofluorine compounds is
in medicinal chemistry.1 A noteworthy example is the use
of fluoroalkyl groups in peptidyl fluoroalkyl ketones,
which can serve as protease inhibitors2 and are charac-
terized by high oral activity and bioavailability.
In recent years, we have developed several nucleophilic
trifluoromethylation methods,3 which allow the efficient
incorporation of fluorine into organic molecules. These
processes have found wide use in the preparation of
various types of bioactive compounds. Our most recent
advances in this area include direct preparation of
F igu r e 1.
trifluoromethylated amines4 and amino alcohols.5 Unlike
trifluoromethylated compounds, their difluoromethylat-
ed6 congeners provide further opportunity for interaction
with the solvent and biological molecules7 due to their
ability to serve as hydrogen bond donors. Also the -CF2H
group is isosteric with an -OH group. Difluoromethy-
lated amino alcohols, therefore, are significant synthetic
targets because they feature important functional handles
(Figure 1) that allow diverse interaction within biologi-
cally active molecules.
In this paper we disclose a new convenient methodol-
ogy for the preparation of difluoromethylated amino
alcohols using a novel three-component reaction strategy
(Scheme 1).8 This approach is based on our recently
reported chemistry involving the one-step three-compo-
(1) Human neutrophil elastase: (a) Edwards, P. D.; Andisik, D. W.;
Bryant, C. A.; Ewing, B.; Gomes, B.; Lewis, J . J .; Rakiewicz, D.;
Steelman, G.; Strimpler, A.; Trainor, D. A.; Tuthill, P. A.; Mauger, R.
C.; Veale, C. A.; Wildonger, R. A.; Williams, J . C.; Wolanin, D. J .;
Zottola, M. J . Med. Chem. 1997, 40, 1876-1885. (b) Cregge, R. J .;
Durham, S. L.; Farr, R. A.; Gallion, S. L.; Hare, C. M.; Hoffman, R. V.;
J anusz, M. J .; Kim, H.-O.; Koehl, J . R.; Mehdi, S.; Metz, W. A.; Peet,
N. P.; Pelton, J . T.; Schreuder, H. A.; Sunder, S.; Tardif, C. J . Med.
Chem. 1998, 41, 2461-2480. (c) Veale, C. A.; Bernstein, P. R.; Bohnert,
C. M.; Brown, F. J .; Bryant, C.; Damewood, J . R. J r.; Earley, R.; Feeney,
S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J . M.; Kosmider, B. J .;
Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.;
Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E.
P.; Williams, J . C.; Wolanin, D. J .; Woolson, S. J . Med. Chem. 1997,
40, 3173-3181.
(2) (a) Inhibitors of recombinant human calpain I: Chatterjee, S.;
Ator, M. A.; Bozyczko-Coyne, D.; J osef, K.; Wells, G.; Tripathy, R.;
Iqbal, M.; Bihovsky, R.; Senadhi, S. E.; Mallya, S.; O’Kane, T. M.;
McKenna, B. A.; Siman, R.; Mallamo, J . P. J . Med. Chem. 1997, 40,
3820-3828. (b) Inhibitors of the human cytomegalovirus protease:
Ogilvie, W.; Bailey, M.; Poupart, M.-C.; Abraham, A.; Bhavsar, A.;
Bonneau, P.; Bordeleau, J .; Bousquet, Y.; Chabot, C.; Duceppe, J .-S.;
Fazal, G.; Goulet, S.; Grand-Maˆıtre, C.; Guse, I.; Halmos, T.; Lavalle´e,
P.; Leach, M.; Malenfant, E.; O’Meara, J .; Plante, R.; Plouffe, C.;
Poirrier, M.; Soucy, F.; Yoakin, C.; De´ziel, R. J . Med. Chem. 1997, 40,
4113-4135.
(4) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 77-
78. (b) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2000, 40, 589-590. (c) Prakash, G. K. S.; Mandal, M.; Olah, G. A.
Org. Lett. 2001, 3, 2847-2850. (d) Prakash, G. K. S.; Mandal, M. J .
Fluorine Chem. 2001, 112; 123-131.
(5) Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis, N. A.;
Olah, G. A. Org. Lett. 2000, 2, 3173-3176.
(6) (a) Wolfe, M. S.; Citron, M.; Diehl, T. S.; Xia, W.; Donkor, I. O.;
Selkoe, D. J . J . Med. Chem. 1998, 41, 6-9. (b) Schirlin, D.; Baltzer,
S.; Altenburger, J . M.; Tarnus, C.; Remy, J . M. Tetrahedron 1996, 52,
305-318. (c) Van Dorsselaer, V.; Schirlin, D.; Tarnus, C.; Taylor, D.
L.; Tyms, A. S.; Weber, F.; Baltzer, S.; Remy, J . M.; Brennan, T.;
J anowick, D. Bioorg. Med. Chem. Lett. 1994, 4, 1213-1218. (d) Shirlin,
D.; Tarnus, C.; Galtzer, S.; Remy, J . M. Bioorg. Med. Chem. Lett. 1992,
2, 651. (e) Kirk, K. L.; Filler, R. In Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J . R., Welch, J . T., Eds.; American
Chemical Society: Washinton, DC, 1996; Chapter 1. (f) R,R-Difluoro-
alkyl phosphonate mimics: Burke, T. R., J r.; Kole, H. K.; Roller, P. P.
Biochem. Biophys. Res. Commun. 1994, 204, 129-134.
(3) (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J . Am. Chem.
Soc. 1989, 111, 393-395. (b) Krishnamurti, R.; Bellew, A. D. R.;
Prakash, G. K. S. J . Org. Chem. 1991, 56, 984-989. (c) Prakash, G.
K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757-786. (d) Prakash, G. K.
S.; Ramaiah, R. Synlett 1991, 643-644. (e) Wiedemann, J .; Heiner,
T.; Mloston, G.; Prakash, G. K. S.; Olah, G. A. Angew. Chem., Int. Ed.
1998, 37, 820-821.
(7) (a) Kaneko, S.; Yamazaki, T.; Kitazume, T. J . Org. Chem. 1993,
58, 2302-2312. (b) Imperiali, B.; Abeles, R. H. Biochemistry 1986, 25,
3760-3767. (c) Imperiali, B.; Abeles, R. H. Tetrahedron Lett. 1986,
27, 135-138.
10.1021/jo011116w CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/27/2002

Synthesis of anti-R-(Difluoromethyl)-â-amino Alcohols
J . Org. Chem., Vol. 67, No. 11, 2002 3719
Sch em e 1
Sch em e 3a
a
Reagents and conditions: (a) D(PPh3)4/CH2Cl2, dimethylbar-
Sch em e 2
bituric acid, ∆, or Rh(PPh3)3Cl, H2O, CH3CN, ∆.
alkylnyl alcohol (R)-7 thus obtained was converted to
alkenyl alcohol (R)-8 using Red-Al without any stereo-
chemical loss. Ozonolysis of (R)-8 in a 4:1dichloromethane/
methanol mixture provided quantitatively the hydroxy-
aldehyde (R)-1 in an oligomeric form.12 The corresponding
(S)-1 was prepared similarly.
Hydroxyaldehyde 1 (in its oligomeric form12) was used
directly in the coupling reaction, without further purifi-
cation. Alkenyl, aryl, and heteroaryl boronic acids par-
ticipated very well in this process. In general, the
coupling products were obtained in good yields in the
presence of secondary amines (Table 1). Under these
reaction conditions, however, the primary amine 2c
afforded the coupling product 4h in only moderate yield,
albeit in a high de (>99%) and ee as well. It should be
mentioned that the commercially available boronic acids
gave higher yields of the coupling products only upon
purification by recrystallization.
The overall enantiomeric excess (% ee) was similar to
the one observed during the ketone reduction step
(Scheme 2), and no loss of enantiomeric purity was
observed during the ozonolysis (Scheme 2) and coupling
reaction, as confirmed by comparing the ee values of the
amino alcohols with that of the alcohol precursor. The
ee values of the amino alcohols were determined by 19F
NMR using Mosher’s chloride and compared with the
corresponding Mosher’s derivatives of the racemic com-
pounds.
The unprotected amino alcohol derivatives can also be
prepared by the present method, using diallylamine as
the amine component, followed by catalytic deallylation,
as we have previously reported.8f This is exemplified with
the efficient synthesis of compound 9 from the dially-
lamino alcohol 4g via deallylation in the presence of a
catalytic amount of Pd(Ph3)4 using dimethylbarbituric
acid as the allyl group scavenger (Scheme 3).13
nent reaction among a carbonyl compound, an amine, and
an organoboronic acid. We have previously reported the
use of this novel process for the synthesis of amino
acids8a,b and amino alcohols8c,d including trifluoromethy-
lated derivatives5 as well as the synthesis of aminopoly-
ols.8f The application described herein involves the one-
step reaction among difluorolactaldehyde (1), an amine
(2), and an alkenyl or aryl organoboronic acid (3) to form
directly anti-R-(difluoromethyl)-â-amino alcohols 4.9
Resu lts a n d Discu ssion
No literature precedence exists for the preparation and
properties of 1, the envisioned precursor for our three-
component condensation reaction. We have now achieved
its convenient preparation as outlined in Scheme 2
starting from ethyl difluoroacetate (5). The acetylenic
alcohol 7 was synthesized according to a literature
procedure.10 However, instead of using the chloroborane
protocol for its asymmetric reduction, we relied on Corey’s
CBS reduction using (R)- as well as (S)-methyloxazaboro-
lidine.11 This resulted in a significantly increased ee. The
En a n tioselective P r ep a r a tion of (2S,3R)-Diflu o-
r oth r eon in e (13). Having developed a general method
for the preparation of difluoromethylated amino alcohols,
we subsequently investigated their possible conversion
to biologically important compounds, such as fluorinated
amino acids.1,14 In addition to being employed as chemo-
therapeutic agents, these molecules are also used in the
(11) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. 1998, 37, 1986-
2012.
(12) NMR spectra of the hydroxyaldehyde were found to be compli-
cated because of its oligomeric form.
(13) Garro-Helion, F.; Merzouk, A.; Guibe, F. J . Org. Chem. 1993,
58, 6109-6113.
(14) (a) Sting, A. R.; Seebach, D. Tetrahedron 1996, 52, 279-290.
(b) Kitazume, T.; Lin, J . T.; Yamazaki, T. Tetrahedron: Asymmetry
1991, 2, 235-238. (c) Bussche-Huennefeld, C.; Seebach, D. Chem. Ber.
1992, 125, 1273-1281. (d) Soloshonok, V. A.; Kacharov, A. D.; Avilov,
D. V.; Ishikawa, K.; Nagashima, N.; Hayashi, T. J . Org. Chem. 1997,
62, 3470-3479. (e) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron
1988, 44, 5553-5562. (f) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V.
P. Tetrahedron 1996, 52, 12433-12442. (g) Scolastico, C.; Conca, E.;
Prati, L. Synthesis 1985, 850-855.
(8) (a) Petasis, N. A.; Zavialov, I. A. J . Am. Chem. Soc. 1997, 119,
445-446. (b) Petasis, N. A.; Good-man, Zavialov, I. A. Tetrahedron
1997, 53, 16463-16470. (c) Petasis, N. A.; Zavialov, I. A. J . Am. Chem.
Soc. 1998, 120, 11798-11799. (d) Petasis, N. A.; Boral, S. Tetrahedron
Lett. 2001, 42, 539-542. (e) Petasis, N. A.; Patel, Z. D. Tetrahedron
Lett. 2000, 41, 9607-9611. (f) Petasis, N. A.; Patel, Z. D.; Raber, J . C.
Unpublished results.
(9) The anti stereochemical assignment was made on the basis of
the analogy with our previous finding (see ref 8c) as well as comparison
of the coupling constant of the proton H4 of the oxazolidinone 11 and
with that of a similar system. Begue, J .-P.; Bonnet-Delpon, D.; Fischer-
Durand, N. Tetrahedron: Asymmetry 1994, 5, 1099-1110.
(10) Ramachandran, P. V.; Gong, B.; Teodoroviæ, A. V.; Brown, H.
C. Tetrahedron: Asymmetry 1994, 5, 1061-1.74.

3720 J . Org. Chem., Vol. 67, No. 11, 2002
Ta ble 1. Syn th esis of a n ti-r-(Diflu or om eth yl)-â-a m in o Alcoh ols
Prakash et al.
a
All the amino alcohols were obtained in >99% de.
study of biosynthetic pathways and as conformational
modifiers in physiologically active enzymes.14a Conse-
quently, several studies have been directed for their
synthesis.14 The reports on difluoromethylated amino
acids are, however, fewer, since feasible enantioselective
synthetic strategies for these compounds have been
limited.7,15 Although some enzymatic routes have been
described15 for the synthesis of (2S,3S)- as well as (2R,
3R)-difluorothreonine, there have been no reports on the
asymmetric synthesis of anti-difluorothreonine. To em-
ploy the synthetic concept described herein to the syn-
thesis of anti-difluorothreonine, the group incorporated
via the boronic acid component had to be an appropriate
precursor for a carboxyl or carbonyl group. Thus, furyl
derivative 4f was investigated (Scheme 4). Compound 4f
was first deallylated and subsequently converted to the
oxazolidinone8f,17 11 using Boc2O in 90% yield. Although
oxidation of the furyl group of the oxazolidinone 11 was
successful with the RuCl3/NaIO4 system,16 the extreme
water solubility of 12 led us to search for an alternative
nonaquatic methodology. Thus, ozonolytic oxidation18 of
the furyl moiety of 11 gave the acid 12 in 75% isolated
yield, which was hydrolyzed using 6 N HCl to the anti-
difluorothreonine (2S,3R)-13.
In summary, we have developed a facile and efficient
multicomponent methodology for the stereoselective syn-
thesis of anti-R-(difluoromethyl)-â-amino alcohols 4. The
method was extended to the enantioselective preparation
of 13 in high yield and high ee.
(16) Nunez, M. T.; Martin, V. S. J . Org. Chem. 1990, 55, 1928-
1932.
(17) Begue, J .-P.; Bonnet-Delpon, D.; Fischer-Durand, N. Tetrahe-
dron: Asymmetry 1994, 5, 1099-1110.
(18) Demir, A. S. Pure Appl. Chem. 1997, 69, 105-108.
(15) For the synthesis of difluorothreonine see: (a) Shimizu, M.;
Yokota, T.; Fujimori, K.; Fujisawa, T. Tetrahedron: Asymmetry 1993,
4, 835-838. (b) Yamazaki, T.; Haga, J .; Kitazume, T. Bioorg. Med.
Chem. Lett. 1991, 1, 271-276.

Synthesis of anti-R-(Difluoromethyl)-â-amino Alcohols
J . Org. Chem., Vol. 67, No. 11, 2002 3721
aqueous phase was separated and extracted twice with ether.
The combined ether extract was washed with saturated
NaHCO3, dried (MgSO4), filtered, and concentrated to afford
Sch em e 4
0.670 g (99%) of (R)-4. [R]20 +14.5 (c 1.0 CHCl3); 1H NMR
D
(CDCl3) δ 2.41 (1H, d, J ) 4.76 Hz), 4.44 (1H, m), 5.70 (1H,
dt, J ) 60.4, 4.76 Hz), 6.19 (1H, d, J ) 14.6 Hz), 6.2 (1H, dd,
J ) 16.1 Hz), 7.24-7.41 (5H, m); 13C NMR (CDCl3) δ 72.2 (t,
1
1
2J C-F ) 25.3 Hz), 115.7 (t, J C-F ) 245 Hz), 122.5(t, J C-F
)
3.97 Hz), 126.7,128.4, 128.7, 134.8, 135.7; 19F NMR (CDCl3) δ
-128.4 (1F, ddd, J ) 285, 57.1, 11.0), -129.8 (1F, ddd, J )
285, 57, 10.5 Hz).
P r epar ation of Diflu or om eth ylactaldeh yde (1). A flame-
dried tube containing (R)-8 (152 mg, 0.75 mmol) in 31 mL of
a
dichloromethane/methanol mixture (25 mL of dichlo-
romethane and 6 mL of methanol) was cooled to -78 °C and
a stream of ozone bubbled through the solution until the blue
color of ozone persisted. Oxygen was passed to remove the
excess ozone from the solution. At this point polymer-bound
triphenylphosphine (280 mg, 0.85 mmol) was added, and the
reaction mixture was stirred for 10 min at -78 °C. Subse-
quently, the solution was warmed to 0 °C and stirred for 10
min. Then the reaction mixture was warmed to room temper-
ature and stirred for an additional 10 min. The reaction
mixture was filtered through a plug of Celite and concentrated.
This crude difluoromethylactaldehyde (in its oligomeric form12
was taken directly for the coupling reaction.
)
Typ ica l P r oced u r e for th e Syn th esis of Am in o Alco-
h ol. To a 25 mL round-bottom flask containing 0.5 mmol of
difluoromethylactaldehyde and 0.5 mmol of amine in 5 mL of
ethanol was added boronic acid. The reaction mixture was
stirred for 24-48 h at room temperature. Evaporation of
solvent gave a crude oil that was purified by flash chroma-
tography (5-10% ethyl acetate in hexanes) to afford 60-90%
amino alcohols.
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise mentioned, all the
reagents were purchased from commercial sources. THF was
distilled under nitrogen from sodium/benzophenone ketyl prior
to use. Flash chromatography was carried out using Merck
60 230-400 mesh silica gel. Diastereoselectivities were de-
termined directly from a crude reaction mixture by 19F NMR.
Chemical shifts are reported relative to those of internal
chloroform (δ 7.24), methanol (δ 4.78), or tetramethylsilane
Da ta for (2R,3R)-3-Diben zyla m in o-1,1-d iflu or o-5-p h en -
1
yl-4-p en ten -2-ol (4a ): [R]20 -166.7 (c 1.1 CHCl3); H NMR
D
(CDCl3) δ 3.43 (1H, m), 3.49 (2H, d, J ) 13.7 Hz), 3.92 (2H, d,
J ) 13.7 Hz), 4.02 (1H, m), 5.94 (1H, t, J ) 52.9 Hz), 6.30
(1H, dd, J ) 15.8, 6.6 Hz), 6.55 (1H, d, J ) 16.0 Hz), 7.22-
7.44 (15H, m); 13C NMR (CDCl3) δ 55.2, 62.1, 71.6 (t, J C-F
)
2
22.7 Hz), 115.0 (t, 1J C-F ) 243 Hz), 122.5, 126.6, 127.3, 128.1,
128.5, 128.6, 128.7, 136.3, 136.9, 139.0; 19F NMR (CDCl3) δ
-129.8 (1F, ddd, J ) 284, 55, 6.7 Hz), -135.2 (1F, ddd, J )
285, 57.2, 17.4 Hz); HRMS (DCI, NH3) m/z 394.1971 [M+], calcd
for C25H26F2NO 394.1982.
(δ 0.0) for H, chloroform (δ 77.0) or methanol (δ 49.0) for 13C,
1
and CFCl3 (δ 0.0) for 19F. The 1H NMR shifts of the -OH
groups are not shown because of their dependence on concen-
tration. Optical rotations were measured at ambient temper-
ature. Enantioselectivities were determined from 19F NMR of
the corresponding (S)-MTPA derivatives.
Data for (2R,3R)-5-Br om o-3-diben zylam in o-1,1-diflu or o-
5-p h en yl-4-p en ten -2-ol (4b): obtained as a colorless oil by
flash chromatography (5% ethyl acetate in hexanes); 1H NMR
(CDCl3) δ 3.62 (2H, d, J ) 13.5 Hz), 3.96 (2H, d, J ) 13.5 Hz),
4.0-4.11 (2H, m), 5.86 (1H, td, J ) 55.5, 3.2 Hz), 6.47 (1H, d,
J ) 9.3 Hz), 7.25-7.59 (15H, m); 13C NMR (CDCl3) δ 55.7,
61.9, 72.2 (t, 2J C-F ) 21.7 Hz), 114.8 (t, 1J C-F ) 243 Hz), 125.1,
127.3, 127.9, 128.4, 128.5, 128.8, 129.2, 131.2, 138.9, 139.4;
19F NMR (CDCl3) δ -128.5 (1F, ddd, J ) 281, 57.0, 6.5 Hz),
-133.9 (1F, ddd, J ) 289, 57, 19.9 Hz); HRMS (DCI, NH3)
m/z 472.1070 [M+], calcd for C25H25BrF2NO 472.1087.
Red u ction of 2 to 3: (R)-(+)-1,1-Diflu or o-4-p h en yl-3-
bu tyn -2-ol (7). In a flame-dried flask containing 2 (0.962 g,
5.34 mmol, azeotropically dried with toluene) in 5 mL of
toluene was placed (R)-methyl-CBS-oxazaborolidine (0.534
mmol). The reaction mixture was cooled to -78 °C, 0.768 g
(6.4 mmol) of catecholborane in 4.4 mL of toluene was added
slowly down the side of the flask over 30 min, and the reaction
mixture was stirred for 20 h. Methanol was added at the end
of the reaction, and the solution was warmed to room tem-
perature, diluted with ether, and washed with buffer (pH 13,
1 N NaOH/saturated NaHCO3, 2:1) until the aqueous phase
became colorless. The aqueous phase was extracted twice with
ether. The combined organic phase was washed with brine,
dried (MgSO4), filtered, and concentrated in vacuo. Purification
by flash chromatography (10% ethyl acetate in hexanes)
Da ta for (1R,2R)-1-Diben zyla m in o-3,3-d iflu or o-1-(4-
m eth oxyph en yl)pr opan -2-ol (4c): [R]20D -81.3 (c 0.3 CHCl3);
1H NMR (CDCl3) δ 3.49 (2H, d, J ) 13.5 Hz), 3.92 (6H, m),
4.40 (1H, m), 6.20 (1H, dt, J ) 55.0, 2.0 Hz), 6.80-7.52 (14H,
2
m); 13C NMR (CDCl3) δ 54.8, 55.3, 62.7, 70.3 (t, J C-F ) 22
Hz), 113.8, 115.3 (t, 1J C-F ) 240 Hz), 125.0, 127.3, 128.5, 131.0,
138.8, 159.4; 19F NMR (CDCl3) δ -129.6 (1F, ddd, J ) 283,
58, 9.0 Hz), -136.6 (1F, ddd, J ) 280, 54.9, 15.5 Hz); HRMS
(DCI, NH3) m/z 398.1922 [M+], calcd for C24H26F2NO2 398.1931.
provided 0.850 g (87%) of (R)-3 in 90% ee: [R]20 + 17.2 (c
D
0.96 CHCl3); 1H NMR (CDCl3) δ 2.54 (1H, d, J ) 6.7 Hz), 4.75
(1H, m), 5.83 (1H, dt, J ) 55.5, 3.16 Hz), 7.30-7.39 (3H, m),
7.46-7.48 (2H, m); 13C NMR (CDCl3) δ 63.5 (t, 2J C-F ) 27 Hz),
82.1, 87.9, 113.8 (t, 1J C-F ) 247 Hz), 121.3,128.4, 129.3, 131.9;
19F NMR (CDCl3) δ -128.5 (1F, dd, J ) 51.9, 5.4 Hz).
Da ta for (1R,2S)-1-Diben zyla m in o-3,3-d iflu or o-1-th io-
p h en -2-ylp r op a n -2-ol (4d ): [R]20D -117.7 (c 1.26 CHCl3); 1H
NMR (CDCl3) δ 3.27 (2H, d, J ) 13.6 Hz), 3.87 (2H, d, J )
13.7 Hz), 4.20 (1H, d, J ) 8.2 Hz), 4.29 (1H, m), 6.04 (1H. dt,
P r ep a r a tion of (R)-4: (R)-(+)-1,1-Diflu or o-4-p h en yl-3-
bu ten -2-ol (8). To a solution of 0.664 g (3.65 mmol) of (R)-3
in 25 mL of ether under an argon atmosphere was added 1.63
mL (5.47 mmol) of Red-Al at 0 °C. The resulting solution was
warmed to room temperature and stirred for 20 h. Subse-
quently, the solution was cooled in an ice bath and cautiously
decomposed by adding dilute aqueous H2SO4 dropwise. The
J ) 55.6, 2.43 Hz), 7.0 (1H, d, J ) 3.0 Hz), 7.10 (1H, m), 7.21-
2
7.37 (11H, m); 13C NMR (CDCl3) δ 55.2, 58.9, 71.7 (t, J C-F
)
21.3 Hz), 114.8 (t, 1J C-F ) 243 Hz), 125.7, 126.7, 127.4, 128. 3,
128.5, 128.8, 135.9, 138.7; 19F NMR (CDCl3) δ -129.7 (1F, ddd,
J ) 284, 57.5, 6.4 Hz), -136.5 (1F, ddd, J ) 284, 54.8, 17.0

3722 J . Org. Chem., Vol. 67, No. 11, 2002
Prakash et al.
Hz); HRMS (DCI, NH3) m/z 374.1384 [M+], calcd for C21H22F2-
NOS 374.1390.
argon atmosphere. The reaction mixture was stirred for 3 h
at 35 °C. The orange-red heterogeneous reaction mixture was
cooled to room temperature and evaporated to dryness. The
crude reaction mixture was redissolved in 100 mL of ether and
extracted twice with 20 mL of saturated aqueous Na2CO3. This
amine-containing ethereal solution was washed with 20 mL
of water and dried with MgSO4. Evaporation of ether followed
by column chromatography with 1:10 methanol/dichloromethane
Da ta for (1R,2S)-1-Ben zofu r a n -2-yl-1-d iben zyla m in o-
3,3-d iflu or op r op a n -2-ol (4e): [R]20 -184.6 (c 1.26 CHCl3);
D
1H NMR (CDCl3) δ 3.29 (2H, d, J ) 13.6 Hz), 3.97 (2H, d, J )
13.6 Hz), 4.08 (1H, d, J ) 9.6 Hz), 4.49 (1H, m), 6.22 (1H, t, J
) 55.0 Hz), 6.70 (1H, s), 7.21-7.36 (12H, m), 7.53 (1H, d, J )
8.0 Hz), 7.61 (1H, d, J ) 7.4 Hz); 13C NMR (CDCl3) δ 55.7,
provided 0.388 g (82%) of the deallylated amine: [R]20 -8.4
2
1
D
57.7, 69.7 (t, J C-F ) 21 Hz), 107.8, 111.4, 114.7 (t, J C-F
)
1
(c 0.95 CHCl3); H NMR (CDCl3) δ 3.99 (1H, m), 4.20 (1H, d,
243 Hz), 121.1, 123.0, 124.4, 127.4, 127.9, 128.5, 128.9, 138.6,
152.5, 154.9; 19F NMR (CDCl3) δ -130.4 (1F, ddd, J ) 281,
54, 5.2 Hz), -137.8 (1F, ddd, J ) 281, 54, 18.7 Hz); HRMS
(DCI, NH3) m/z 408.1767 [M+], calcd for C25H24F2NO2 408.1775.
J ) 4.4 Hz), 5.66 (1H, dt, J ) 55.7, 4.0 Hz), 6.29 (1H, d, J )
2.7 Hz), 6.36 (1H, dd, J ) 3.8, 2.0 Hz), 7.40 (1H, m); 13C NMR
2
(CDCl3) δ 50.2, 72.7 (t, J C-F ) 20.3 Hz), 107.0, 110.4, 115.0
(t, J C-F ) 243 Hz), 142.3, 154.0; 19F NMR (CDCl3) δ -128.8
1
Da ta for (1S,2R)-1-Dia llyla m in o-3,3-d iflu or o-1-fu r yl-
p r op a n -2-ol (4f): [R]20 -104.9 (c 1.05 CHCl3); 1H NMR
(1F, ddd, J ) 290, 54.5, 5.7 Hz), -131.2 (1F, ddd, J ) 289,
D
54.6, 15.0 Hz).
(CDCl3) δ 2.74 (2H, dd, J ) 14.9, 8.6 Hz), 3.32 (2H, m), 4.05
(1H, d, J ) 1.2 Hz), 4.31 (1H, m), 5.15 (3H, m), 5.20 (1H, m),
5.73 (2H, m), 6.10 (1H, dt, J ) 55.0, 2.0 Hz), 6.27 (1H, d, J )
3.2 Hz), 6.38 (1H, dd, J ) 3.6, 2.0 Hz), 7.43 (1H, m); 13C NMR
(4S ,5R )-5-Diflu or om e t h yl-4-fu r a n -2-yloxa zolid in -2-
on e (11). A mixture of 0.384 g (2.17 mmol) of 10 and 0.568 g
(1.2 equiv) of di-tert-butyl dicarbonate in dry dioxane was
stirred for 24 h at room temperature. Dioxane was evaporated,
and the residue was dissolved in ethyl acetate and washed
with brine. The organic layer was dried over MgSO4. Evapora-
tion under reduced pressure followed by column chromatog-
2
(CDCl3) δ 54.1, 57.3, 69.7 (t, J C-F ) 20.9 Hz), 110.1, 110.4,
1
115.0 (t, J C-F ) 239 Hz), 117.8, 135.7, 142.4, 150.1; 19F NMR
(CDCl3) δ -131.6 (1F, ddd, J ) 290, 56.4, 6.9 Hz), -138.8 (1F,
ddd, J ) 280, 51.5, 17.5 Hz).
raphy using 20% ethyl acetate/hexanes yielded N-Boc-protect-
Da ta for (2R,3R)-3-Dia llyla m in o-1,1-d iflu or o-5-p h en yl-
4-p en ten -2-ol (4g): 1H NMR (CDCl3) δ 3.05 (2H, dd, J ) 14.0,
7.9 Hz), 3.35 (dd, 2H, J ) 14.9, 5.7 Hz), 3.51 (1H, m), 3.99
(1H, m), 5.19 (4H, m), 5.74-6.07 (3 H, m), 6.20 (1H, dd, J )
15.4, 9.7 Hz), 6.57 (1H, d, J ) 15.4 Hz), 7.25-7.42 (5H, m);
1
ed 10 as a white solid: [R]20 -38.0 (c 0.94 CHCl3); H NMR
D
(CDCl3) δ 1.44 (9H, s), 3.33 (1H, m), 4.08 (1H, m), 5.06 (1H,
m), 5.39 (1H, m), 5.60 (1H, t, J ) 55.2 Hz), 6.34 (2H, d, J )
9.8 Hz), 7.39 (1H, s); 13C NMR (CDCl3) δ 28.2, 49.4, 72.9 (t,
2J C-F ) 22.5 Hz), 80.7, 108.4, 110.5, 114.8 (t, 1J C-F ) 244 Hz),
142.6, 150,2, 155.5; 19F NMR (CDCl3) δ -128.0 (1F, ddd, J )
295, 54.4, 4.0 Hz), -131.0 (1F, ddd, J ) 293, 55.8, 13.2 Hz);
HRMS (DCI, NH3) m/z 278.1202 [M+], calcd for C12H18F2NO4
278.1203. A flame-dried flask containing sodium hydride (1.1
equiv, 0.079 g, 60% dispersion in mineral oil) in 5 mL of DMF
was cooled to -78 °C under an inert atmosphere, and a
solution of 0.497 g of N-Boc-protected 10 in 3 mL of DMF was
added quickly. The heterogeneous mixture was warmed to
room temperature and stirred for 7 h. The clear homogeneous
solution thus obtained was diluted with ethyl acetate and
washed several times with water. The organic phase was dried
over MgSO4 and concentrated to give an oil that was purified
2
13C NMR (CDCl3) δ 53.5, 62.7, 70.8 (t, J C-F ) 20 Hz), 115.5
1
(t, J C-F ) 241 Hz), 117.8, 123.0, 126.5, 128.0, 128.6, 135.5,
136.2, 136.3; 19F NMR (CDCl3) δ -130.8 (1F, ddd, J ) 277,
54, 9.5 Hz), -134.2 (1F, ddd, J ) 285, 52.4, 13.9 Hz).
Da ta for (2R,3R)-1,1-Diflu or o-3-(4-m eth oxyben zyla m i-
n o)-5-p h en ylp en t-4-en -2-ol (4h ): [R]20D -73.7 (c 1.0 CHCl3);
1H NMR (CDCl3) δ 3.5 (1H, m), 3.65 (1H, d, J ) 12.2 Hz), 3.80-
3.95 (5H, m), 5.74 (1H, dt, J ) 55.5, 4.34 Hz), 6.15 (1H, dd, J
) 16.0, 8.68 Hz), 6.56 (1H, d, J ) 16.4 Hz), 6.80 (2H, d, J )
8.67 Hz), 7.20-7.41 (7H, m); 13C NMR (CDCl3) δ 50.2, 55.3,
2
1
60.3, 71.6 (t, J C-F ) 22 Hz), 113.9, 116.0 (t, J C-F ) 244 Hz),
125.5, 126.5, 128.1, 128.6, 129.4, 131.4, 134.5, 136.0; 19F NMR
(CDCl3) δ -128.46 (1F, ddd, J ) 289, 54.7, 12.1 Hz), -130.3
(1F, ddd, J ) 292, 54.7, 9.0 Hz); HRMS (DCI, NH3) m/z
334.1617 [M+], calcd for C19H22F2NO2 334.1617.
by column chromatography using 35% ethyl acetate/hexanes
1
to afford 0.273 g (75%) of 11: [R]20 -16.6 (c 1.06 MeOH); H
D
NMR (CDCl3) δ 4.82 (1H, m), 5.12 (1H, d, J ) 8.5 Hz), 5.57
(R ,R )-2-Am i n o -1-d i flu o r o m e t h y l-4-p h e n y l-3-(E )-
bu ten ol (9). 4g (147 mg, 0.501 mmol) was dissolved in 13 mL
of acetonitrile and water (84:16). A Claisen adapter fitted with
a reflux condenser and addition funnel on one arm and with
a short-path distillation head on the other was then attached
to the reaction flask. The addition funnel was charged with
excess acetonitrile/water (84:16), the system flushed with
argon, and 27 mg of (PPh3)3RhCl added at room temperature.
The orange mixture was brought to vigorous boiling, and fresh
solvent was added to replace the volume of liquid swept out
the distillation head and into a cooled trap (-78 °C) by a slow
stream of argon. After 1.5 h the reaction was judged complete
according to TLC and the solvent removed in a vacuum. The
residue was purified by flash chromatography (CH2Cl2/MeOH,
(1H, dd, J ) 55.7, 5.6 Hz), 6.43 (2H, m), 7.47 (1H, m); 13C NMR
2
(CD3OD) δ 52.0, 77.8 (t, J C-F ) 23.6 Hz), 110.5, 111.8, 114.2
(t, J C-F ) 240 Hz), 144.9, 149.9, 159.9; 19F NMR (CDCl3) δ
1
-126.5 (1F, ddd, J ) 309, 54.0, 9.6 Hz), -128.9 (1F, ddd, J )
309, 55.4, 6.7 Hz); HRMS (DCI, NH3) m/z 221.0735 [M+], calcd
for C8H11F2N2O3 221.0737.
(4S,5R)-5-Diflu or om eth yl-2-oxooxa zolid in e-4-ca r boxy-
lic Acid (12). In a 100 mL tube 0.05 g (0.245 mmol) of 11 in
20 mL of methanol was cooled to -78 °C, and ozone was passed
until the blue color persisted. The reaction was stopped and
N2 gas bubbled to remove the excess ozone. Evaporation of
solvent gave the crude product as a white solid that was
purified by flash chromatography (7:2.5:0.5 ethyl acetate/
methanol/ammonium hydroxide) to afford 0.032 g (72%) of
12: [R]20D -34.4 (c 1.07 MeOH); 1H NMR (CD3OD) δ 4.45 (1H,
d, J ) 9.2 Hz), 6.18 (1H, dt, J ) 54.9, 2.9 Hz); 13C NMR (CD3-
10:1; Rf ) 0.15), yielding 66 mg (62%) of 9: [R]20 -17.3 (c 1.0
D
CHCl3); 1H NMR (CD3OD) δ 3.58 (dd, J ) 8.1, 3.6 Hz, 1H),
3.77 (m, 1H), 5.68 (ddd, J ) 56.4, 55.2, 5.4 Hz, 1H), 6.30 (dd,
J ) 15.9, 8.1 Hz, 1H), 6.57 (d, J ) 15.9 Hz, 1H), 7.18-7.48
(m, 5H); 13C NMR (CD3OD) δ 55.38 (dd, J ) 6.0, 2.4 Hz), 74.74
(dd, J ) 24.5, 20.6 Hz), 117.44 (t, J ) 242 Hz), 127.51 (2C),
128.73, 129.13, 129.60 (2C), 133.38, 138.19; 19F NMR (CDCl3)
δ -127.99 (ddd, J ) 310, 55.4, 6.6 Hz), -129.9 (ddd, J ) 310,
56.6, 15.0 Hz); HRMS (DCI, NH3) m/z 214.1046 [M+], calcd
for C11H14F2NO 214.1043.
2
1
OD) δ 58.1, 76.7 (t, J C-F ) 21.1 Hz), 114.4 (t, J C-F ) 245
Hz), 160.7, 173.7; 19F NMR (CD3OD) δ -127.0 (1F, ddd, J )
294, 53.3, 6.5 Hz), -132.4 (1F, ddd, J ) 295, 55.4, 18.6 Hz);
HRMS (DCI, NH3) m/z 182.0267 [M+], calcd for C5H6F2NO4-
182.0264.
(2S,3R)-2-Am in o-4,4-d iflu or o-3-h yd r oxyb u t yr ic Acid
(13). In a 25 mL single-neck, round-bottom flask equipped with
a magnetic stirring bar and a reflux condenser were placed
0.032 g of 12 and 10 mL of 6 N HCl, and the mixture was
refluxed at 100 °C for 8 h. Evaporation of the reaction mixture
gave a brown solid that was purified by flash chromatography
(6:3.5:0.05 ethyl acetate/methanol/ammonium hydroxide) to
(1S,2R)-1-Am in o-3,3-d iflu or o-1-fu r a n -2-ylp r op a n -2-ol
(10). 8f was deallylated according to the reported procedure.
Thus, a solution of 0.681 g (2.63 mmol) of 8f in 7 mL of dry
degassed dichloromethane was added to a flask containing 0.06
g (0.051 mmol, 10-2 mmol/allylic group) of the catalyst (tet-
rakis(triphenylphosphino)palladium and 1.23 g (7.89 mmol, 3
mmol/allylic group) of N,N′-dimethylbarbituric acid under an
afford 0.025 g (92%) of 13 as a white solid: [R]20 +7.0 (c 1.0
D
1
MeOH); H NMR (CD3OD) δ 4.15 (1H, m), 4.22 (1H, m), 6.05

Synthesis of anti-R-(Difluoromethyl)-â-amino Alcohols
(1H, dt, J ) 56.2, 6.07 Hz); 13C NMR (CD3OD) δ 54.8, 70.8 (t,
J . Org. Chem., Vol. 67, No. 11, 2002 3723
acknowledged. N.A.P. also thanks the National Insti-
tutes of Health (Grant GM 45970) for its support.
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and 19F
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
2J C-F ) 28.0 Hz), 116.3 (t, J C-F ) 241 Hz), 168.1; 19F NMR
(CD3OD) δ -127.1 (2F, ddd, J ) 56.1, 21.9, 11.0 Hz); HRMS
(DCI, NH3) m/z 156.0471 [M+], calcd for C4H8F2NO3 156.0472.
Ack n ow led gm en t. The support of our work by the
Loker Hydrocarbon Research Institute is gratefully
J O011116W