Efficient Asymmetric Synthesis of β-Fluoro α-Amino Acids

Full text of DOI:10.1021/jo990947n

J . Org. Chem. 1999, 64, 6931-6934
6931
carbonyl building blocks12,13 and in the sulfinimine (N-
sulfinyl imine)-mediated asymmetric Strecker synthesis14
prompted studies aimed at the development of a general
protocol for the asymmetric synthesis of â-fluoro R-amino
acids.
Efficien t Asym m etr ic Syn th esis of â-F lu or o
r-Am in o Acid s
Franklin A. Davis,* Vaidyanathan Srirajan, and
Donald D. Titus
Our strategy for the synthesis of nonracemic â-fluoro
R-amino acids is outlined in Scheme 1. Hydrolysis of the
â-fluoro R-amino nitrile 2 will afford the amino acid 1.
The â-fluoro R-amino nitrile is obtained by “HCN” addi-
tion to R-fluoro sulfinimine 3, which in turn is prepared
from a nonracemic R-fluoro aldehyde 4 and a chiral
sulfinamide. We needed the N-sulfinyl group in the imine
to control the introduction of cyanide because our earlier
studies had indicated that fluorine is a poor stereodi-
recting group.13b Furthermore, not only is the N-sulfinyl
group a powerful stereodirecting group, but it is easily
deprotected in the product under mild conditions without
epimerization.15 This new protocol is illustrated for the
enantioselective synthesis of syn- and anti-3-fluorophe-
nylalanine (11a and 15) and syn-3-fluoroleucine (11b).
The R-fluoro aldehydes (S)-7 were prepared using the
oxazolidone R-fluoro amide building blocks 5a and 5b,
prepared by electrophilic fluorination of the correspond-
ing oxazolidone sodium enolates with N-fluorobenzene-
sulfonimide (NFSi).13a Reductive removal of the auxiliary
with LiBH4 afforded the 2-fluorohydrins (S)-6 in 79-84%
yield and recovery of the oxazolidone auxiliary in >90%
(Scheme 2).13d The fluorohydrins were isolated by flash
chromatography, and their enantiomeric purity was
determined by conversion into the Mosher esters.
Racemic R-fluoro aldehydes are characterized as un-
stable compounds that generally decompose on purifica-
tion.12,16 Previously, we prepared (R)-(-)-2-fluoropheny-
lacetaldehyde (7a) by Dess-Martin periodinane17 oxidation
of the (R)-6a in 95% yield and 90% ee.13b The enantio-
meric purity was very sensitive to the reaction conditions
with oxidation times longer than 10 min resulting in
significant epimerization. Addition of (S)-6 (typically 3.0
mmol) to 1.6 equiv of the Dess-Martin reagent at room
temperature in CH2Cl2 for 5-7 min produced (S)-(+)-7a
and (S)-(-)-7b in 90 and 98% crude yield. Workup
consisted of dilution with ether, addition of saturated
solutions of NaHCO3 and Na2S2O3, stirring until the
organic phase was colorless, and drying. The enantio-
meric purities of (S)-(+)-7a and (S)-(-)-7b were estimated
to be 80 and >95%, respectively, by forming the diaster-
Department of Chemistry, Temple University,
Philadelphia, Pennsylvania 19122
Received J une 11, 1999
The ability of a strategically placed fluorine to enhance
biological properties is well estabilizhed.1,2 In this regard
â-fluoro R-amino acids 1 are of particular significance
because they have been shown to exhibit diverse biologi-
cal properties including antibacterial, antihypertensive,
and antitumor activities.3 They act as metabolic antago-
nists to naturally occurring R-amino acids,4 as competi-
tive inhibitors of enzymes,5 and as suicide substrates.6
Consequently, a number of syntheses of â-fluoro R-amino
acids have been devised involving fluorodehydroxylation
of â-hydroxy R-amino acids,7 ring-opening of aziridines,8
reductive amination of â-fluoro-R-keto acids,9 and oth-
ers.10 Unfortunately, the majority of these procedures are
lengthy, racemic syntheses that usually result in mix-
tures of stereoisomers that are difficult to separate.
Furthermore, conversion of intermediates to the free
amino acids frequently results in defluorination. The one
asymmetric synthesis of 3-fluorophenylalanine, where
Schollkopf’s bis lactim ether strategy was employed,
resulted in low overall yields and mixtures of products.11
Our interest in the asymmetric synthesis of R-fluoro
(1) For reviews on biologically active organofluorine compounds,
see: (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; J ohn Wiley & Sons: New York, 1991. (b) Welch, J . T.
Tetrahedron 1987, 43, 3123. (c) Filler, R., Kobayashi, Y., Eds. Biome-
dicinal Aspects of Fluorine Chemistry; Kodanasha Ltd., Elsevier
Biomedical Press: Tokyo, New York, 1982. (d) Carbon-Fluorine
Compounds: Chemistry, Biochemistry and Biological Activities; Ciba
Foundation Symposium, Associated Scientific Publishers: Amsterdam,
1972.
(2) Welch, J . T., Ed. Selective Fluorination in Organic and Bioor-
ganic Chemistry; ACS Symposium Series, Vol. 456; American Chemical
Society: Washington, DC, 1991.
(3) For a review of â-fluoro R-amino acids, see: Sewald, N.; Burger,
K. In Fluorine Containing Amino Acids; Kukhar, V. P., Solshonok, V.
A., Eds.; J ohn Wiley & Sons: New York, 1995; Chapter 4, p 139.
(4) Klein, D. C.; Kirk, K. L.; Weller, J . L.; Oka, J .; Parfitt, A.; Owens,
I. S. Mol. Pharmacol. 1976, 12, 720.
(5) Hageman, J . J . M.; Wanner, M. J .; Koomen, G. J .; Pandit, U. K.
J . Med. Chem. 1977, 20, 1677.
(6) (a) Kollonitsch, J .; Barash, L.; Kahan, F. M.; Kropp, H. Nature
(London) 1973, 243, 346. (b) Maycock, A. L.; Aster, S. D.; Patchett, A.
A. J . Am. Chem. Soc. 1980, 102, 709. (c) Metcalf, B. W.; Bey, P.; Danzin,
C.; J ung, M. J .; Casara, P.; Ververt, J . P. J . Am. Chem. Soc. 1978,
100, 2551.
(7) (a) Kollonitsch, J .; Marburg, S.; Perkins, L. M. J . Org. Chem.
1979, 44, 771. (b) Pansare, S. V.; Vederas, J . C. J . Org. Chem. 1987,
52, 4804.
(12) For a review on R-fluoro carbonyl compounds, see: Davis, F.
A.; Kasu, P. V. N. Org. Prep. Proc. Int. 1999, 31, 125.
(13) (a) Davis, F. A.; Kasu, P. V. N. Tetrahedron Lett. 1998, 39, 6135.
(b) Davis, F. A.; Kasu, P. V. N.; Sundarababu, G.; Qi, H. J . Org. Chem.
1997, 62, 7546. (c) Davis, F. A.; Qi, H. Tetrahedron Lett. 1996, 37, 4345.
(d) Davis, F. A.; Han, W. Tetrahedron Lett. 1992, 33, 1153.
(14) (a) Davis, F. A.; Fanelli, D. L. J . Org. Chem. 1998, 63, 1981.
(b) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H. J . Org.
Chem. 1996, 61, 440.
(8) (a) Wade, T. N.; Gaymord, F.; Guedj, R. Tetrahedron Lett. 1979,
2681. (b) Wade, T. N. J . Org. Chem. 1980, 45, 5328. (c) Ayi, A. I.; Guedj,
R. J . Chem. Soc., Perkin Trans. 1 1983, 2045.
(15) For a review on the chemistry of sulfinimines, see: Davis, F.
A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13.
(9) (a) Tsushima, T.; Kawada, K.; Nishikawa, J .; Sato, T.; Tori, K.;
Tsuji, T.; Misaki, S. J . Org. Chem. 1984, 49, 1163. (b) Tsushima, T.;
Sato, T.; Tsuji, T. Tetrahedron Lett. 1980, 21, 3591.
(10) (a) O’Donnell, M. J .; Barney, C. L.; McCarthy, J . R. Tetrahedon
Lett. 1985, 26, 3067. (b) Kaneko, C.; Chiba, J .; Toyota, A.; Sato, M.
Chem. Pharm. Bull. 1995, 43, 760. (c) Vidal-Cros, A.; Gaundry, M.;
Marquet, A. J . Org. Chem. 1985, 50, 3163. (d) Anderson, W. K.; Halat,
J . J .; Rick, A. C. J . Med. Chem. 1980, 23, 87.
(16) For examples of racemic R-fluoro aldehydes, see: (a) Purrington,
S. T.; Lazaridis, N. V.; Bumgardner, C. L. Tetrahedron Lett. 1986, 27,
2715. (b) Suga, H.; Schlosser, M. Tetrahedron 1990, 46, 4261. (c)
Szarek, W. A.; Hay, G. W.; Perlmutter, M. M. J . Chem. Soc., Chem.
Commun. 1982, 1253. (d) Yamazaki, T.; Yamamoto, T.; Kitazume, T.
J . Org. Chem. 1989, 54, 83. (e) Patrick, T. B.; Hosseini, S.; Bains, S.
Tetrahedron Lett. 1990, 31, 179.
(17) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(11) Groth, U.; Schollkopf, U. Synthesis. 1983, 673.
10.1021/jo990947n CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/03/1999

6932 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
Sch em e 1
Sch em e 3
Sch em e 2
The sulfinimine-mediated asymmetric Strecker syn-
thesis involves the addition of ethylaluminum cyanoiso-
propoxide [EtAl(O-i-Pr)CN], generated in situ by addition
of i-PrOH to diethylaluminum cyanide (Et2AlCN), to the
sulfinimine.20 Treatment of sulfinimines 9 (1.0 mmol) at
-78 °C in THF with 1.5/1.0 equiv of Et2AlCN/i-PrOH
gave the â-fluoro R-amino nitriles 10a and 10b in 78 and
>96% de by 19F NMR (Scheme 3). Flash chromatography
gave the major diastereoisomers (RS,S,S)-(+)-10a and
(RS,S,S)-(+)-10b in 78 and 63% isolated yields. Refluxing
the amino nitriles with 6 N HCl for 3-5 h, removal of
the aqueous solvent, washing with ether, and treating
the residue with propylene oxide/i-PrOH afforded syn-
(2S,3S)-(+)-3-fluorophenylalanine (11a ) and syn-(2S,3S)-
(+)-3-fluoroleucine (11b) in 69 and 58% isolated yields,
respectively. When the hydrolysis of 10a was conducted
under biphasic conditions by stirring with 5 mL of 1 N
HCl and 5 mL of CH2Cl2 for 2 h at room temperature,
(2S,3S)-(+)-2-amino-3-fluoro-3-phenylpropionitrile (12)
was isolated in ca. 20% yield following washing with
ether and treatment with propylene oxide/i-PrOH.
eomeric imines with (R)-R-phenylethylamine and im-
1
mediately evaluating the H NMR spectrum. Within 2
h, these R-fluoro imines had racemized. Attempts to
purify 7 by chromatography resulted in decomposition,
and it was used in crude form to prepare the R-fluoro
sulfinimines. (R)-(-)-N-[2(S)-fluorophenylacetylidene]-p-
toluenesulfinamide (9a ) and (R)-(+)-N-[2(S)-fluoroisov-
alerylidene]-p-toluenesulfinamide (9b) were prepared by
stirring 7a and 7b in CH2Cl2 with 1 equiv of (R)-(-)-p-
toluenesulfinamide (8)18 and activated 4 Å molecular
sieves. Sulfinimines 9a and 9b were isolated in 70 and
62% yield by chromatography (Scheme 2).19 The diaster-
eomeric ratios were 80 and >95% for 9a and 9b, respec-
tively, which is in excellent agreement with the ratios
obtained using the more basic (R)-R-phenylethylamine.
The configurational assignments for syn and anti
â-fluoro R-amino acids have proven difficult and were
originally made based on reaction sequences for nonflu-
orinated compounds.3 More recently, X-ray analysis9a and
crown ether complexation studies of the ammonium
group have been utilized.20 The J HH and J HF proton
coupling constants of 6.6 and 14.3 Hz for 11a and 2.2
and 28.2 Hz for 11b agrees well with literature values
suggested for racemic syn-11a (3.3 and 16 Hz)9a and syn-
11b (2.2 and 25.6 Hz).10b Furthermore, the X-ray struc-
ture of R-amino nitrile (+)-12 firmly establishes the syn
nature of the fluorine and amino groups (Figure 1). As
expected, fluorine has little if any effect on the stereo-
selective introduction of “CN” and the primary stereo-
control element is the sulfinyl auxiliary.
3
3
(18) Davis, F. A.; Zhang, Y. Andemichael, Y. Fang, T. Fanelli, D.
L.; Zhang, H. J . Org. Chem. 1999, 64, 1403.
The fact that the sulfinyl group controls addition of CN
to 9 means that the corresponding anti â-fluoro R-amino
acids can be prepared simply by starting with the
opposite enantiomeric fluoro aldehyde or sulfinamide.
This is illustrated in Scheme 4 for the enantioselective
synthesis of anti-(2S,3R)-(-)-3-fluorophenylalanine (15).
The R-fluoro sulfinimine (RS,R)-13 was prepared in the
usual way from (R)-713b and (R)-8 in 80% yield, which
was converted into a diastereomeric mixture of amino
nitriles 14 (80% de). It is interesting to note that the
(19) An alternative route to 9 involving the resolution of racemic 7
with (RS)-8 was briefly explored. DIBAL-H reduction of 2-fluoroethyl
phenylacetate (i), prepared in 82% yield by electrophilic fluorination
of the sodium enolate of ethyl phenylacetate with NFSi, gave a nearly
quantitative yield of (()-7. Treatment of (()-7 with (RS)-8 afforded a
1:1 mixture of (RS,S)-9/(RS,R)-9 in 70% yield. A tedious chromatography
(EtOAc/n-hexane 2:98) produced a 48% yield of (RS,S)-(-)-9.
(20) Hamman, S.; Salon, M. C.; Beguin, C. Org. Magn. Reson. 1982,
20, 78.

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6933
EtOAc (3 × 50 mL) and brine (40 mL), dried (Na2SO4), and
concentrated. The solid was and crystallized from EtOAc\ hexane
to give 8.6 g (65%): mp 34 °C; [R]23 -32.46 (c 1.3, CH2Cl2); IR
D
1
(KBr) 1778, 1701, 1462 cm-1; H NMR (CDCl3, 500 MHz) δ 0.9
(d, J ) 6.6 Hz, 3H), 1.0 (2d, J ) 6.6 Hz, 6H), 2.2 (m, 1H), 2.9
(2dd, J ) 7, 16 Hz, 2H), 4.8 (q, J ) 7 Hz, 1H), 5.7 (d, J ) 7.3 Hz,
1H), 7.3-7.4 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 14.07, 22.2,
22.3, 24.9, 43.8, 54.4, 78.6, 125.3, 128.5, 128.6, 133.4, 152.8,
172.1. Anal. Calcd for C15H19NO3: C, 68.97; H, 7.32; N, 5.35.
Found: C, 69.60; H, 7.64; N, 5.18.
(4S,5R)-(-)-3-(1′-Oxo-2′(S)-flu or oisova ler yl)-4-m eth yl-5-
p h en yloxa zolid in -2-on e (5b). In an oven-dried 250 mL two-
neck round-bottom flask equipped with a rubber septum and
magnetic stir bar, and under an argon balloon was placed
(4S,5R)-(-)-3-(1′-oxoisovaleryl)-4-methyl-5-phenyloxazolidin-2-
one (4.95 g, 19 mmol) in THF (15 mL). The solution was cooled
to -78 °C, and NaHMDS (21.0 mL, 21.0 mmol THF solution) in
THF was added dropwise. After being stirred for 1.5 h, the
enolate was cannulated to a -78 °C of N-fluorobenzenesulfon-
imide (NFSi, 6.0 g, 19 mmol) in THF (30 mL) and stirred for 1
h. The reaction mixture was quenched with NH4Cl (25 mL),
extracted with EtOAc (3 × 15 mL) and brine (30 mL), dried (Na2-
SO4), and concentrated. Chromatography (EtOAc/hexane 8:92)
F igu r e 1. X-ray structure of (2S,3S)-(+)-12.
Sch em e 4
gave 4.0 g (76%) of (-)-5b as a thick gel: [R]23 -19.5 (c 0.63,
D
CHCl3); IR (NaCl) 1782, 1716 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 0.9 (d, J ) 6.6 Hz, 3H), 1.0 (d, J ) 6.6 Hz, 3H), 1.2 (d, J ) 6.5
Hz, 3H), 2.3 (m, 1H), 4.7 (q, J ) 7.0 Hz, 1H), 5.7 (d, J ) 7.3 Hz,
1H), 5.8 (dd, J ) 3.0, 49.5 Hz, 1H), 7.3 (d, J ) 7.3 Hz, 2H), 7.4
(m, 3H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 15.2, 18.9, 30.6 (d, J
) 22 Hz), 55.2, 79.8, 92.5 (d, J ) 183 Hz), 125.5, 128.7, 128.9,
132.6, 152.4, 169.1 (d, J ) 24.4 Hz); 19F NMR δ -206.7 (dd, J )
24.4, 48.8 Hz); HRMS calcd for C15H18NO3F (M + H) 280.134896,
found 280.134716.
P r ep a r a tion of (S)-(-)-2-F lu or oisova ler yl-1-ol (6b). In an
oven-dried, two-neck 250 mL round-bottom flask fitted with a
magnetic stir bar, rubber septum and argon balloon, was placed
(-)-5b (3.9 g, 14 mmol) in THF (30 mL). The reaction flask was
cooled to 0 °C and LiBH4 (2 M, 8.5 mL, 17 mmol) in THF was
added via syringe. The reaction mixture was stirred until TLC
indicated the reaction was complete (2-3 h) at which time the
reaction mixture was quenched with H2O (20 mL), extracted
with EtOAc (3 × 15 mL), dried (Mg2SO4), and concentrated.
Chromatography (EtOAc/hexane 15:85) followed by distillation
(bp 144 °C at 760 mm) gave 1.2 g (79%) of (-)-6b: [R]23D -35.04
(c 2.2, CHCl3); IR (NaCl) 3649-3061 cm-1; 1H NMR (CDCl3, 500
MHz) δ 0.95 (d, J ) 6.6 Hz, 3H), 1.0 (d, J ) 6.6 Hz, 3H), 1.9 (m,
2H), 3.75 (dd, J ) 4.4, 24.9 Hz, 2H), 4.6 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 17.4, 18.1, 29.2 (d, J ) 20 Hz), 63.1 (d, J )
22.4 Hz), 99 (d, J ) 170.9 Hz); 19F NMR (CFCl3 in CDCl3) δ
-194.0 (m); CIMS for Mosher amide calcd C15H18O3F4 322.0 (M
+ H), found 322.0.
diastereoselectivity for CN addition to (RS,S)-9a and
(RS,R)-14 are the same, suggesting the absence of any
cooperating or double diastereodifferentiating effect. The
major diastereoisomer was isolated by flash chromatog-
raphy in 80% yield and hydrolyzed to give anti-(2S,3R)-
(-)-15 in 55% yield. The J HH and J HF proton coupling
constants of 3.0 and 26.4 Hz are in good agreement with
literature values.9a
In summary, new methodology is presented for the
asymmetric synthesis of syn- and anti-â-fluoro R-amino
acids involving the sulfinimine mediated asymmetric
Strecker synthesis employing a new R-fluoro sulfinimine
building block.
3
3
Typ ica l P r oced u r e for t h e P r ep a r a t ion of r-F lu or o
Ald eh yd es. (S)-(+)-2-F lu or op h en yla ceta ld eh yd e (7a ). In an
oven-dried, one-neck 250 mL round-bottom flask fitted with a
magnetic stir bar, rubber septum, and an argon balloon was
placed 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one
(Dess-Martin periodine reagent)17 (2.0 g, 4.8 mmol) in CH2Cl2
(30 mL). After stirring at room temperature for 5 min a solution
6a (0.420 g, 3 mmol) in CH2Cl2 (5 mL) was added, and the
reaction mixture was stirred for 5-7 min. At this time, the
solution was diluted with ether (40 mL), saturated NaHCO3 (20
mL) and saturated Na2S2O3 (20 mL) were added, and the
reaction mixture was stirred until the ether phase became clear
(10 min). The organic phases were washed with saturated
NaHCO3 (30 mL) and brine (30 mL), dried (Mg2SO4), and
concentrated to give 0.41 g (90%) of 7a , which was used in the
next reaction without further purification due to its instability:
IR (NaCl) 1705 cm-1; [R]23D 42.8 (c 0.9, CHCl3); 1H NMR (CDCl3)
δ 5.7 (d, J ) 46 Hz, 1 H), 7.3-7.5 (m, 5 H), 9.78 (d, J ) 4 Hz).
Exp er im en ta l Section
Gen er a l P r oced u r e. Column chromatography was per-
formed on silica gel, Merck grade 60 (230-400 mesh). Analytical
and preparative thin-layer chromatography was performed on
precoated silica gel plates (250 and 1000 microns) purchased
from Analtech Inc. TLC plates were visualized with UV, in an
iodine chamber or with phosphomolybdic acid unless noted
otherwise. THF was freshly distilled under nitrogen from a
purple solution of sodium and benzophenone.
Unless stated otherwise, all reagents were purchased from
commercial sources and used without additional purification. (S)-
(+)-2-Fluoro-2-phenylethanol (6a ),13d (R)-(-)-2-fluorophenylac-
etaldehyde (7a ),13b and (R)-(+)-p-toluenesulfinamide (8)18 were
prepared as previously described.
P r ep a r a tion of (4S,5R)-(-)-3-(1′-Oxoisova ler yl)-4-m eth -
yl-5-p h en yloxa zolid in -2-on e. In an oven-dried, two-neck 500
mL round-bottom flask equipped with a rubber septum, mag-
netic stir bar, under argon, were placed (4S,5R)-(-)-4-methyl-
5-phenyloxazolidine-2-one (8.85 g, 50 mmol, Aldrich Chemical
Co.) in THF (120 mL). The solution was cooled to -78 °C, n-BuLi
(24 mL, 60 mmol, 2.5 M, 1.2 equiv) was added, and the mixture
was stirred for 1 h. A solution of isovaleryl chloride (6.6 mL, 55
mmol) in THF (10 mL) was added, and after 3 h, the reaction
mixture was quenched with NH4Cl (120 mL), extracted with
(S)-(-)-2-F lu or oisova ler yl a ld eh yd e (7b): 98% (crude);
1
[R]23 -23.6 (c 1.0, CHCl3); H NMR (CDCl3) δ 0.95 (d, J ) 6.3
D
Hz, 3 H), 1.0 (d, J ) 6.3 Hz, 3 H), 1.95 (m, 1H), 3.75 (dd, J ) 26
Hz, 4.1 Hz, 1H), 9.75 (d, J ) 4.3 Hz, 1H).
Meth od for Estim a ted th e En a n tiom er ic P u r ity of th e
r-F lu or o Ald eh yd es. To a dilute solution of the R-fluoro
aldehyde in CDCl3 (1 mL) in an NMR tube was added a few
drops of a dilute solution of (R)-R-phenyl ethylamine in CDCl3

6934 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
(1 mL). After 5 min the % de was determined by integration of
the Me proton in the 1H NMR spectra of the imine.
MHz) δ 17.3, 18.6, 21.4, 30.3 (d, J ) 19 Hz), 44.2 (d, J ) 20 Hz),
98.9 (d, J ) 183 Hz), 115.3, 126.1, 130.2, 139.0, 142.5; 19F NMR
(CFCl3 in CDCl3) δ -(193.14-193.34, m). Anal. Calcd for
Typ ica l P r oced u r e for th e P r ep a r a tion r-F lu or osu lfin -
im in es. (RS)-(-)-N-(2(S)-F lu or op h en yla cetylid en e)-p-tolu -
en esu lfin a m id e (9a ). In a 100 mL round-bottom flask, fitted
with a magnetic stir bar and calcium chloride tube, was placed
crude (S)-(+)-7a (0.276 g, 2 mmol) in CH2Cl2 (20 mL). Activated
(crushed) 4 Å molecular sieves (1.0 g) and (R)-(+)-p-toluene-
sulfinamide (8) (0.31 g, 2 mmol) in CH2Cl2 (5 mL) were added,
and the reaction mixture was stirred at room temperature for
6-8 h. The solution was filtered and concentrated. Chromatog-
raphy (EtOAc/hexane 10:90) afforded 0.380 g (69%) of (-)-9a :
C
13H17N2OSF: C, 58.18; H, 6.38; N, 10.43. Found: C, 57.99; H,
6. 27; N, 10.23.
(RS)-(-)-2-[N-(p-Tolu en esu lfin a m id o)]-3(R)-flu or o-3-p h e-
n ylp r op ion itr ile (14). Chromatography (EtOAc/hexane 15:85)
afforded 0.242 g (80%) of (-)-14: mp 121 °C; [R]23 -25.29 (c
D
0.85, CHCl3); IR (KBr) 3445-2874, 2249 cm-1; 1H NMR (CDCl3,
500 MHz) δ 2.43 (s, 3H), 4. 20-4.28 (m, 1H), 5.35 (d, J ) 9.73
Hz, 1H), 5.8 (dd, J ) 2.57, 45 8 Hz, 1H), 7.30-7.41 (m, 7H),
7.60 (d, J ) 8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.4, 48.5
(d, J ) 24.4 Hz), 94.3 (d, J ) 183.1 Hz), 114.5, 125.4, 126.2,
128.9, 129.8, 130.2, 133.5 (d, J ) 20.4 Hz), 139.0, 142.7. HRMS
calcd for C16H15N2OSF (M + H) 330.30967, found 303.0966 (M
+ H).
mp 91 °C; [R]23 -331.5 (c 0.38, CH2Cl2); IR (KBr) 1633 cm-1
;
D
1H NMR (CDCl3, 500 MHz) δ 1.68 (s, 3H), 5.50 (dd, J ) 4.0,
47.0 Hz, 1H), 6.56-6.67 (m, 7H), 6.78 (d, J ) 8.4 Hz, 2H), 7.60
(dd, J ) 4.0, 10.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 21.4,
92.8 (d, J ) 181 Hz), 124.6, 126.3, 126.4, 128.9, 129.5, 129.8,
134.3, 141.3, 162 (d, J ) 30.5 Hz); 19F NMR (CFCl3 in CDCl3) δ
-180.6 (dd, J ) 9, 45.7 Hz). Anal. Calcd for C15H14NOSF: C,
65.31; H, 5.11; N, 5.07. Found: C, 65.30; H, 4.94; N, 4.77.
(Rs)-(-)-N-(2(R)-F lu or op h en yla cet ylid en e)-p -t olu en e-
su lfin a m id e (13). Chromatography (EtOAc/hexane 10:90) af-
P r ep a r a tion of (2S,3S)-(+)-â-F lu or op h en ylp r op ion itr ile
(12). In a 50 mL round-bottom flask equipped with a magnetic
stir bar were placed 10a (0.150 g, 0.5 mmol) in CH2Cl2 (5 mL)
and 1 N HCl (5 mL). The solution was stirred at room temper-
ature for 2-3 h, the aqueous phase was separated and concen-
trated, and the resulting solid was treated with i-PrOH (2 mL)
and propylene oxide (0.058 g, 1 mmol). After being stirred for
5-6 h, the solution was concentrated to give 0.017 g (20%) of
forded 0.400 g (72%) of (-)-13: mp 64 °C; [R]23 -153.2 (c 2,
D
CHCl3); IR (KBr) 1628 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.39
(s, 3H), 6.11 (dd, J ) 4.0, 47.2 Hz, 1H), 7.26-7.39 (m, 7H), 7.48
(d, J ) 8 Hz, 2H), 8.31 (dd, J ) 4.0, 10.2 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 22.1, 93.5 (d, J ) 179 Hz), 125.3, 127.0,
127.1, 129.6, 130.2, 130.5, 134.8 (d, J ) 20 Hz), 142.8, 162.6 (d,
J ) 28.5 Hz); 19F NMR (CFCl3 in CDCl3) δ -183.40 (dd, J )
9.2, 45.8 Hz). Anal. Calcd for C15H14NOSF: C, 65.31; H, 5.10;
N, 5.07. Found: C, 65.29; H, 4.69; N, 4.86.
(+)-12: mp 118 °C; [R]23 34.4 (c 1.2, CHCl3); IR (KBr) 3750-
D
3000, 2347 cm -1; H NMR (CDCl3, 500 MHz) δ 1.58-1.61 (bs,
1
2H), 4.17 (dd, J ) 5.0, 12.5 Hz, 1H), 5.54 (dd, J ) 5.0, 45 Hz,
1H), 7.45 (s, 5H); 13C NMR (CDCl3, 75 MHz) δ 48.6 (d, J ) 29
Hz), 93.8 (d, J ) 179 Hz), 126.2, 126.3, 128.7, 129.8, 133.8 (d, J
) 19 Hz); 19F NMR (CFCl3 in CDCl3) δ -184.5 (dd, J ) 12.2,
45.8 Hz).
(RS)-(+)-N-(2(S)-F lu or oisova ler ylid en e)-p-tolu en esu lfi-
n a m id e (9b). Chromatography (EtOAc/hexane 3:97) afforded
0.570 g (62%) of (+)-12: oil; [R]23D 209.8 (c 0.8, CHCl3); IR (NaCl)
1632 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.0 (2d, J ) 7 Hz, 6H),
2.2 (m, 1H), 2.42 (s, 3H), 5.0 (ddd, J ) 3.6, 4.8, 49.8 Hz, 1H), 7.3
(d, J ) 8.4 Hz, 2H), 7.5 (d, J ) 8.4 Hz, 2H), 8.25 (dd, J ) 3.7,
11.0 Hz, 1H); 19F NMR (CFCl3 in CDCl3) δ -(197.35-197.55, m).
The compound was found to be unstable and attempts to obtain
a satisfactory elemental analysis or HRMS failed.
Gen er a l P r oced u r e for th e Hyd r olysis of th e r-Am in o
Nit r iles. (2S,3S)-(+)-3-F lu or op h en yla la n in e (11a ). In
a
single-neck 25 mL round-bottom flask were placed 10a (0.302
g, 1 mmol) and 6 N HCl (20 mL), and the solution was refluxed
for 3-5 h. The aqueous phase was washed with ether (2 × 10
mL), and the aqueous solution was concentrated. The solid was
treated with i-PrOH (5 mL) and propylene oxide (0.232 g, 4
mmol), and the solution was stirred for 5-6 h. At this time, the
reaction mixture was concentrated and the product was crystal-
lized from 2-propanol to give 0.125 g (68%) of 11a : mp 170 °C
Typ ica l P r oced u r e for th e Ad d ition of EtAlCN/i-P r OH
to th e r-F lu or osu lfin im in es. (RS)-(+)-2-[N-(p-Tolu en esu lfi-
n a m id o)]-3-(S)-flu or o-3-p h en ylp r op ion itr ile (10a ). In an
oven-dried 100 mL round-bottom flask equipped with a magnetic
stir bar and an argon balloon was placed the (RS,S)-(-)-9a (0.275
g, 1.0 mmol) in THF (10 mL) and cooled to -78 °C. In a separate
two-neck round-bottom flask equipped with a magnetic stir bar,
an argon balloon, was placed diethylaluminum cyanide (1.5 mL,
1.5 mmol) and i-PrOH (0.1 mL). The reaction mixture was
stirred for 15 min at 10 °C and was cannulated to the solution
of 9a . After being stirred at -78 °C for 15 min, the solution was
warmed to room temperature and stirred for 12 h. The reaction
mixture was quenched with aqueous NaHCO3 (5 mL) and
extracted with EtOAc (2 × 10 mL), and the combined organic
phases were washed with brine, dried (Na2SO4), concentrated.
Chromatography (EtOAc/hexane 12:88) afford 0.235 g (78%) of
(lit.9a 168-169 °C); [R]23 8.4 (c 0.5, H2O); IR (KBr) 3570-2350
D
1
(bs), 1650-1540 cm-1; H NMR (D2O, 500 MHz) δ 5.1 (dd, J )
6.6, 14.3 Hz), 6.1 (dd, J ) 6.9, 45.5 Hz, 1H), 7.5 (s, 5H); 19F NMR
(CFCl3 in D2O) -179.5 (dd, J ) 13.7, 45.8 Hz).
(2S,3R)-(-)-3-Flu or oph en ylalan in e (15): yield 0.06 g (55%);
mp 149-150 °C (lit.9a mp 150-152 °C); [R]23 -14.5 (c 0.4,
D
MeOH); IR (KBr) 3570-2350 (bs), 1650-1540 (3s) cm-1
;
1H
NMR (CD3OD, 500 MHz) δ 5.1 (dd, J ) 3.0, 26.4 Hz, 1H), 6.0
(dd, J ) 2.6, 46 Hz, 1H), 7.5 (s, 5H); 19F NMR (CFCl3 in CD3-
OD) δ -184.5 (dd, J ) 27.4, 48.5 Hz).
(2S,3R)-(+)-3-F lu or oleu cin e (11b): yield 0.055 g (58%); mp
160-161 °C (dec) (lit.10b 162-163 °C (dec)); [R]23D 10.4 (c 1, H2O);
IR (KBr) 3650-2600, 1639, 1508 cm -1; 1H NMR (D2O, 500 MHz)
δ 0.9 (d, J ) 6.9 Hz, 3H), 1.1 (d, J ) 6.6 Hz, 3H), 2.28 (m, 1H),
4.55 (ddd, J ) 1.8, 9.5, 47.6 Hz, 1H), 4.93 (dd, J ) 2.2, 28.2 Hz,
1H); 19F NMR (CFCl3 in CDCl3) δ -(189.58-189.76, m).
(+)-10 as an oil: [R]23 14.0 (c 0.5, CH2Cl2); IR (NaCl) 3445-
D
2733, 2249 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.4 (s, 3H), 4.5-
4.7 (m, 2H), 5.7 (dd, J ) 5.5, 44.7 Hz, 1H), 7.3-7.6 (m, 9H); 13
C
Ack n ow led gm en t. This work was supported by
grants from the National Institutes of Health (GM
57870) and the National Science Foundation. We thank
Dr. G. Sundarababu for preliminary studies and Allied-
Signal Corp. for a generous supply of N-fluorobenzene-
sulfonimide (NFSi).
NMR (CDCl3, 125 MHz) δ 22.1, 47.9 (d, J ) 34.0 Hz), 92.5 (d, J
) 193.6 Hz), 116.2, 126.6, 126.8, 127.6, 129.6, 130.8, 133.6 (d, J
) 21.3 Hz), 139.6, 143.3; 19F NMR (CFCl3 in CDCl3) δ -177.7
(dd, J ) 10, 43 Hz). Anal. Calcd for C16H15FN2OS: C, 63.55; H,
5.00; N, 9.26. Found: C, 63.48; H, 4.94; N, 9.05.
(RS)-(+)-2-[N-(p-Tolu en esu lfin a m id o)]-3(S)-flu or oisoh ex-
Su p p or tin g In for m a tion Ava ila ble: IR and 1H and 13C
NMR spectra of 5b, 6b, 7a ,b, 12, and 14 and X-ray crystal
data for (+)-12. This material is available free of charge via
the Internet at http://pubs.acs.org.
a n on itr ile (10b). Chromatography (EtOAc/hexane 10:90) af-
forded 0.170 g (63%) of (+)-10b: mp 126 °C; [R]23 67.0 (c 0.45,
D
CH2Cl2); IR (KBr) 3588-2870, 2167 cm-1; 1H NMR (CDCl3, 500
MHz) δ 0.87 (d, J ) 7.0 Hz, 3H), 1.0 (d, J ) 7.0 Hz, 3H), 2.0 (m,
1H), 2.4 (s, 3H), 4.2-4.4 (m, 2H), 5.25 (d, J ) 8.8 Hz, 1H), 7.3
(d, J ) 8 Hz, 2H), 7.6 (d, J ) 8 Hz, 2H); 13C NMR (CDCl3, 75
J O990947N