A study on the diastereoselective synthesis of α-fluorinated β3-amino acids by α-fluorination

Article abstract of DOI:10.1002/hlca.201200520

The treatment of a β³-amino acid methyl ester with 2.2 equiv. of lithium diisopropylamide (LDA), followed by reaction with 5 equiv. of N-fluorobenzenesulfonimide (NFSI) at -78° for 2.5h and then 2h at 0°, gives syn-fluorination with high diastereoisomeric excess (de). The de and yield in these reactions are somewhat influenced by both the size of the amino acid side chain and the nature of the amine protecting group. In particular, fluorination of N-Boc-protected β³-homophenylalanine, β³-homoleucine, β³-homovaline, and β³-homoalanine methyl esters, 5 and 9-11, respectively, all proceeded with high de (>86% of the syn-isomer). However, fluorination of N-Boc-protected β³-homophenylglycine methyl ester (16) occurred with a significantly reduced de. The use of a Cbz or Bz amine-protecting group (see 3 and 15) did not improve the de of fluorination. However, an N-Ac protecting group (see 17) gave a reduced de of 26%. Thus, a large N-protecting group should be employed in order to maximize selectivity for the syn-isomer in these fluorination reactions. Copyright

Full text of DOI:10.1002/hlca.201200520

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Helvetica Chimica Acta – Vol. 95 (2012)
A Study on the Diastereoselective Synthesis of a-Fluorinated b3-Amino Acids
by a-Fluorination
by Victoria Peddiea)b), and Andrew D. Abell*a)
a) School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005, Australia
(phone: þ 61883135652; fax: þ 61883134358; e-mail: andrew.abell@adelaide.edu.au)
b) Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
Dedicated to Professor Dieter Seebach in celebration of his 75th birthday
The treatment of a b3-amino acid methyl ester with 2.2 equiv. of lithium diisopropylamide (LDA),
followed by reaction with 5 equiv. of N-fluorobenzenesulfonimide (NFSI) at ꢀ 788 for 2.5 h and then 2 h
at 08, gives syn-fluorination with high diastereoisomeric excess (de). The de and yield in these reactions
are somewhat influenced by both the size of the amino acid side chain and the nature of the amine
protecting group. In particular, fluorination of N-Boc-protected b3-homophenylalanine, b3-homoleucine,
b3-homovaline, and b3-homoalanine methyl esters, 5 and 9 – 11, respectively, all proceeded with high de
(> 86% of the syn-isomer). However, fluorination of N-Boc-protected b3-homophenylglycine methyl
ester (16) occurred with a significantly reduced de. The use of a Cbz or Bz amine-protecting group (see 3
and 15) did not improve the de of fluorination. However, an N-Ac protecting group (see 17) gave a
reduced de of 26%. Thus, a large N-protecting group should be employed in order to maximize
selectivity for the syn-isomer in these fluorination reactions.
1. Introduction. – b-Amino acids and their derivatives are found in both natural and
synthetic compounds that exhibit important biological activities. Naturally occurring
examples include microcystins, carnosine, pantothenic acid (vitamin B5), Paclitaxel,
and bestatin [1]. Paclitaxel is an important anti-neoplastic agent used in chemotherapy
for a variety of cancers [2], while bestatin is an immunological response modifier [3].
Both these agents contain a b-amino-a-hydroxy acid as a key structural feature.
Non-natural oligomers derived from b-amino acids (b-peptides) are also of
significant interest because of their ability to form well-defined and stable secondary
structures, such as 314-helices and hairpin turns [1][4], which can be further stabilized
with the appropriate incorporation of F in their backbone as discussed below [5]. b-
Peptides are reported to possess a range of biological activities, but unlike natural
peptides, they are stable to common proteases and peptidases [4a][6]. Interestingly,
simple fluorinated b-amino acids such as 1 and 2 (see Fig. 1) do in fact inhibit proteases
[7].
Fluorine is an important component of many existing pharmaceuticals, with an
ability to enhance metabolic stability, lipophilicity, and bioavailability, while also
influencing conformation [8]. Specifically, when a F-atom is positioned a to the CO
group in a b3-amino acid, the FꢀCꢀC¼O moiety adopts an antiperiplanar conformation,
and when the F-atom is positioned b to an amide N-atom, a conformation in which CꢀF
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
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Fig. 1. a-Fluoro b-amino acid protease inhibitors
and CꢀN(CO) bonds are gauche is favored [5c][9]. To more widely exploit these
observations in biomedical applications, we require efficient and well-defined stereo-
selective methods for the synthesis of a-fluoro b3-amino acids.
Two main strategies have been reported for the synthesis of a-fluoro b3-amino
acids: direct fluorination of b-amino enolates [10] and the conversion of the OH group
of an enantiomerically pure b-hydroxy a-amino acid to a F-atom [5a][6c][7b][11].
There are limited reports on this first method, with Davis and Reddy having reported
the direct fluorination of the dianion of the N-Bz-protected methyl ester of (R)-b3-
homophenylglycine, 3, to prepare the a-fluoro-b3-homophenylglycine derivatives 4a
and 4b as fluorinated analogues of the side chain of Paclitaxel (Scheme 1) [10]. The use
of N-fluorobenzenesulfonimide (NFSI), as the fluorinating agent in this reaction,
results in lower yields compared to N-fluoro-o-benzene-disulfonimide (NFOBS).
However, NFSI does give rise to improved diastereostereoselectivity, with the ratio
syn-4a/anti-4b being a respectable 81:19 in this case [10]. There is some debate as to
what controls the stereochemical outcome of this reaction, with some discussion on this
later on in the article.
Scheme 1. Fluorination of the Dianion of Methyl (ꢀ)-(3R)-3-(Benzoylamino)-3-phenylpropanoate (3)
with Electrophilic Fluorinating Reagents
The key starting b3-amino acids used in this sequence are either commercially
available, or readily prepared from the corresponding a-amino acid by ArndtꢀEistert
homologation [4a]. As such, this sequence provides a useful and direct route to a-
fluoro b3-amino acids from common a-amino acids. In this paper, we report an
investigation into the scope of this methodology as a means to prepare a-fluoro b3-
amino acids. Lithium diisopropylamide (LDA) was used to generate the intermediate
b-amino enolates and NFSI as the electrophilic source of F based on the earlier
literature reports mentioned above.

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2. Results. – 2.1. Synthesis of a-Fluoro-b3-homophenylalanine and Optimization of
Reaction Conditions. In the first instance, a study was carried out to define the optimum
conditions for the fluorination of a previously untested Boc-protected b3-amino acid
(b3-homophenylalanine methyl ester, see (S)-5 and (R)-6) with the results shown in
Table 1. The first attempt involved generating the required lithium enolate by reacting a
THF solution of (S)-5 with 2.2 equiv. of LDA (freshly prepared in THF) at ꢀ 788 (see
Entry 1 in Table 1). The solution was stirred for 1 h at ꢀ 788, 5 equiv. of NFSI were
added, and the resulting solution was stirred at ꢀ 788 for 2.5 h, and then for a further
2 h at 08. The a-fluoro b3-amino acid syn-7a (2S,3S) and its epimer anti-7b (2R,3S) were
produced in a ratio of 95 :5 (as determined from the corresponding 19F-NMR spectrum
of the crude product), and in a combined yield of 73% after purification by
chromatography (Entry 1 in Table 1).
Table 1. Results of the Fluorination of the Lithium Enolate of 5 and 6 with NFSI under Different
Conditions
Entry Starting equiv.
equiv.
Temp [8]/ Major
product
Minor
product
Yield dea) Ratio of
[%]
[%] isomersa)
material of LDA of NFSI time [h]
1
2
3
4
5 (3S)
6 (3R)
5 (3S)
6 (3R)
2.2
2.2
2.1
2.1
5
ꢀ 78/2.5
0/2
7a (2S,3S) 7b (2R,3S) 73
8a (2R,3R) 8b (2S,3R) 57
7a (2S,3S) 7b (2R,3S) 53
8a (2R,3R) 8b (2S,3R) 37
90
90
86
94
95 : 5
95 : 5
93 : 7
97: 3
2.5
2.5
1.1
ꢀ 78/2.5
0/2
ꢀ 78/3.5
ꢀ 40/1
ꢀ 78/2.5
ꢀ 40/1
a) Ratio of isomers and de were determined from the 19F-NMR spectra of the crude products.
A number of variations to the reaction conditions were investigated using both (S)-
5 and its enantiomer (R)-6. In particular, a reduction in number of equiv. of either LDA
or NFSI used in the reaction, or lowering the reaction temperature from 08 to ꢀ 408
gave reduced yields of the fluorinated product, with little effect on the observed de (see
Entries 2 – 4 in Table 1). Thus, 2.2 equiv. of LDA, 5 equiv. of NFSI, and a reaction
temperature kept at ꢀ 788 for 2.5 h, followed by 2 h at 08, were used as reaction

Helvetica Chimica Acta – Vol. 95 (2012)
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conditions for all subsequent fluorination reactions. Interestingly, the diastereoisomeric
excesses (de; 86 – 90%), obtained in the syntheses of 7 and 8, were higher than those
reported by Davis and Reddy for the fluorination of Bz-protected b3-homophenylgly-
cine using either NFSI or NFOBS as the fluorinating agent (de values of 4 to 62%
depending on the conditions). The relative configuration of the major isomer 8a,
(2R,3R), was assigned as syn based on our earlier published X-ray crystallographic
structure [7a]. The absolute configuration was then assigned on the basis of the known
absolute configuration of the starting b3-amino acid. The configuration of the other
isomers of 7 and 8 followed from this assignment.
Interestingly, the 19F-NMR spectra obtained for purified samples of 7a (2S,3S) and
8a (2R,3R) revealed pairs of resonances in both CDCl3 and (D6)DMSO. In all cases, the
pairs were evident in a ratio of ca. 9 :1 (e.g., see Fig. 2 for 8a). In the (D6)DMSO
spectrum of 8a, each resonance of the pair was resolved as a doublet of doublets at
ꢀ 199.9 (minor) and ꢀ 200.9 ppm (major), with both exhibiting very similar coupling
constants, J, of 48.8, 24.5, and 48.2, 23.3 Hz, respectively. A similar spectrum was
observed for 7a in (D6)DMSO. This doubling of resonances is likely due to 7a and 8a
existing as pairs of rotamers, presumably due to the presence of the N-Boc group as has
been noted in other systems [12]. The occurrence of rotamers was consistent with
variable-temperature 19F-NMR spectroscopy of 8a (in CDCl3) which showed the minor
and the major resonances coalescing at 558 to give a small shoulder (Fig. 2). The 9 :1
ratio of rotamers observed for 7a and 8a is typical for a pair of Boc rotamers [12].
2.2. The Effect of the Amino Acid and N-Protecting Group on the Diastereose-
lectivity of Fluorination. Given that there were some differences in the observed de
values for the fluorination of the N-Boc-b3-homophenylalanine and N-Bz b3-
homophenylglycine methyl esters as discussed above, we decided to investigate further
the influence of the amino acid containing a common N-Boc protecting group. A small
series of N-Boc-protected b3-amino acid methyl esters was used in this study, i.e. b3-
homoleucine, b3-homovaline, and b3-homoalanine, 9 – 11, respectively (see Scheme 2).
Fluorination of each of these b3-amino acids, 9 – 11, was performed under the optimum
conditions established earlier. The resulting de values for all three amino acids (see
Table 2) were similar and comparable to those obtained for N-Boc-protected (R)-
and (S)-b3-homophenylalanine (5 and 6; see Table 1). Based on these results the nature
of the component amino acid appears to have little effect on the diastereoselectivity
of the fluorination reaction, with the exception of the sterically more challenged
b3-homophenylglycine which appears to give a reduced de as discussed further
below.
Given the results of the previous section, we next investigated the influence of the
nature of the N-protecting group. Interestingly, all of the N-Boc-protected b3-amino
acid methyl esters used in our study to date, 5, 6, and 9 – 11, gave rise to a higher
diastereoselectivity (major isomer being syn) compared to the original study using N-
Bz-protected b3-homophenylglycine 3 [10]. Thus, a range of N-protected b3-homo-
phenylglycine derivatives was prepared (Bz, Cbz, Boc, and Ac, 3, 15 – 17, resp.), for
comparative analysis relative to the previous studies. Each of these amino acids was
separately fluorinated using our standard conditions, i.e., 2.2 equiv. of LDA, 5 equiv. of
NFSI, and a reaction temperature kept at ꢀ 788 for 2.5 h, followed by 2 h at 08 (see
Scheme 3 and Table 3).

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Helvetica Chimica Acta – Vol. 95 (2012)
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Scheme 2. Fluorination of N-Boc-Protected b3-Amino Acid Methyl Esters
i) 2.2 equiv. lithium diisopropylamide (LDA), THF, ꢀ 788, 1 h. ii) 5 equiv. N-fluorobenzenesulfonimide
(NFSI), THF, ꢀ 788, 2.5 h; 08, 2 h.
Table 2. Results of the Fluorination of the Lithium Enolates of 9 – 11 with NFSI
Starting Material
Products
Yield [%]
dea) [%]
Ratio of products (a/b)a)
9
10
11
12a/12b
13a/13b
14a/14b
60
57
45
86
91
92
93 : 7
96 : 4
96 : 4
a) Ratio of isomers and de were determined from the 19F-NMR spectra of the crude products.
Scheme 3. Fluorination of N-Protected b3-Homophenylglycine Methyl Esters
i) LDA, THF, ꢀ 788, 1 h. ii) NFSI, THF, ꢀ 788, 2.5 h; 08, 2 h.
Table 3. Results of the Fluorination of the Lithium Enolates of 3 and 15 – 17 with NFSI as Shown in
Scheme 3
Starting Material
Products
Yield [%]
dea) [%]
Ratio of products (a/b)a)
3
4a/4b
70
63
75
51
66
58
56
26
83 : 17
79 : 21
78 : 22
63 : 37
15
16
17
18a/18b
19a/19b
20a/20b
a) Ratio of isomers and de were determined from the 19F-NMR spectra of the crude products
Fluorination of the literature N-Bz-protected b3-homophenylglycine methyl ester 3,
under these conditions, gave 4a and 4b in a ratio of 83 :17 (de of 66%) and a combined
yield of 70% (Scheme 3). These values are very similar to those reported by Davis and
Reddy for their synthesis of 4 (see Scheme 1), who reported a de of 62% and a yield of

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Helvetica Chimica Acta – Vol. 95 (2012)
65% [10]. We obtained similar de values and yields for the fluorination of the N-CBz-
and N-Boc-protected b3-homophenylglycine derivatives 15 and 16 (de values of 58 and
56%, and combined yields of 63 and 75%, resp., as shown in Table 3). However, a
smaller N-Ac protecting group as in compound 17 gave rise to a considerably reduced
de (26%) and a lower yield (51%) for the fluorination reaction. In addition,
fluorination of N-Boc-protected b3-homophenylglycine methyl ester (16) occurred
with a reduced de (66%) compared to the fluorinations of the other N-Boc-protected
b3-amino acids, (S)-b3-hPhe (5), (R)-b3-hPhe (6), b3-hLeu (9), b3-hVla (10), and b3-
hAla (11), all of which proceeded with de values greater than 86%. The sterically
hindered Ph side-chain of b3-homophenylglycine is thus the least favored in these
reactions.
3. Discussion. – The related alkylation of b3-amino acids is also reported to give a
high syn diastereoselectivity [13]. These reactions have been proposed to proceed via a
dilithiated b-amino acid intermediate (e.g., 22), which is alkylated selectively from the
Re face to give 23 as shown in Scheme 4 [13a]. The fluorination of b3-amino acids shown
in Schemes 1 – 3 would be expected to proceed through a similar dilithiated
intermediate.
Scheme 4. Stereochemistry of the Alkylation of b-Aminobutanoic Acid Derivatives via a Dilithiated
Enolate [13a]
Intramolecular chelation of the Liþ cation with the enolate O-atom and the
deprotonated amino group in such an intermediate would give rise to the cyclic chelates
24 and 25 (see Scheme 5). A structure of this type has been proposed to explain the syn
selectivity in the alkylation reactions [13e][14]. Such a six-membered chelate ring has
been characterized by X-ray crystallography, with the enolate rings forming prismatic
hexamers [15]. The proposed chelated enolate intermediate preferentially adopts a
half-chair conformation in which the R group occupies a pseudo-axial position (see 25),
because of a steric clash in the alternative conformer 24 as indicated [13e][14].
Fluorination would then take place from the face opposite to the axial R group in 25 to
give the syn-product 27 as shown.
Scheme 5. Possible Lithium-Enolate Intermediate

Helvetica Chimica Acta – Vol. 95 (2012)
2467
Interestingly, we observed that fluorination of the b3-homophenylglycine methyl
ester (3) occurred with a reduced de value compared to those of the other amino acids
investigated (see 5, 6, 9 – 11). This is surprising given that the extra steric bulk1) of a Ph
group would be expected to enhance the facial selectivity in the halogenation of 25.
However, it may be the case that this sterically demanding axial group destabilizes
conformer 25 relative to 24, with an associated decrease in stereoselectivity. The Bz-,
Cbz-, and Boc-protected b3-homophenylglycines were all fluorinated with similar de
values, i.e., 56 – 66%. However, an N-Ac protecting group, as in derivative 17, gave rise
to a significantly reduced de of 26%. A smaller protecting group (P ¼ Ac in Scheme 5)
would be expected to diminish the steric clash in structure 24, such that the
thermodynamic preference for 25 relative to 24 is decreased (see Scheme 5). The net
result would again be decreased facial selectivity on fluorination.
4. Conclusions. – The method devised by Davis and Reddy (Scheme 1) [10] has been
shown to be suitable for the preparation of a number of a-fluoro-b3-amino acids. The
reactions occur in good yield and with high syn diastereoselectivity. This methodology
allows the stereoselective conversion of an a-amino acid to an a-fluoro-b3-amino acid
in two steps: ArndtꢀEistert homologation of the a-amino acid to generate the b3-amino
acid, which is fluorinated on treatment with LDA and NFSI (see Scheme 6).
Scheme 6. Stereoselective Conversion of an a-Amino Acid to an a-Fluoro-b3-amino Acid
It is important to note that the stereoselectivity of fluorination is influenced by both
the size of the amino acid side chain and the nature of the amine protecting group. In
particular, fluorination of N-Boc-protected b3-homophenylalanine, b3-homoleucine, b3-
homovaline, and b3-homoalanine methyl esters, 5 and 9 – 11, respectively, all proceeded
with high de values (> 86% de of the syn isomer). However, fluorination of the N-Boc-
protected b3-homophenylglycine (16) occurred with a reduced de of 66%. The use of a
N-Cbz or N-Bz protecting group (see 3 and 15) in place of Boc did not improve the de
value of fluorination reaction. However an Ac protecting group (see 17) gave rise to a
1
)
The WinsteinꢀHolness A values (or axial strain values) provide a measure of the conformational
preference of a substituent (R) in a monosubstituted cyclohexane to be equatorial rather than axial
[16]. It is defined as the Gibbs free energy between the equatorial and axial conformers. These
values provide a measure of steric bulk, with the literature values shown in Table 4 indicating that a
Ph substituent has the greatest steric bulk of these four substituents.
Table 4. WinsteinꢀHolness A Values for Selected Substituents
Substituent
A Value [kcal molꢀ1
]
Me
1.74 [17]
2.21 [17]
2.8 [18]
iPr
Ph
PhCH2
1.68 [19]

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Helvetica Chimica Acta – Vol. 95 (2012)
reduced de value of 26%. Thus, in order to maximize selectivity for the syn-isomer in
these fluorination reactions one should employ a large N-protecting group.
We gratefully acknowledge financial support from the Australian Research Council (ARC) and the
Tertiary Education Commission of New Zealand.
Experimental Part
1. General. N-Fluorobenzenesulfinimide (NFSI) was purchased from SigmaꢀAldrich. Dry THF was
distilled from Na and benzopheneone. All moisture-sensitive reactions were carried out under a positive
pressure of N2 or Ar in oven-dried glassware (1408). The b3-amino acids 3, 5, 6, 9 – 11, 15 – 17 were
synthesized according to published procedures [7a][20]. TLC: Plastic-backed Merck-Kieselgel
KG60F 254 or Polygram Sil G/UV254 plates. Flash chromatography (FC; positive pressure of anh.
N2): 230 – 400 mesh Merck silica gel 60. Radial chromatography (RC): ChromatotronTM apparatus with
silica plates (silica gel 60 PF254 with gypsum) of 5-, 2-, and 1-mm thickness. M.p.: electrothermal melting-
point apparatus, or a Reichert hot-stage melting-point apparatus; not corrected. Optical rotations:
PerkinꢀElmer 341 polarimeter or Polaar 2001 polarimeter, with a 1.0-dm cell length, at 21 – 238 in HPLC-
grade solvents at l ¼ 589 nm; [a]D values are given in deg ml gꢀ1 dmꢀ1; the sample concentration values
are in 10 mg mlꢀ1. IR Spectra: Shimadzu 9201PC series FT-IR spectrophotometer or a PerkinꢀElmer
1
1600 Series FT-IR spectrophotometer. H-spectra (300, 500, and 600 MHz) and 13C-NMR spectra (75,
126, and 151 MHz): Varian Unity 300, Varian Inova 500, or Varian Inova 600 spectrometers. 19F-NMR
spectra (282 MHz): Varian Unity 300 spectrometer, chemical shifts (d) in ppm and coupling constants J in
Hz. ESI-MS: Micromass/Waters LCT TOF mass spectrometer or an Agilent G1969A LC-TOF
spectrometer. Elemental analyses for C, N, H, and F: at the University of Otago Microanalytical
Laboratory.
2. General Procedure 1 (GP 1). Fluorination of b3-Amino Acids. A soln. of BuLi (1.6m in hexane, 2.2
equiv.) was added to a soln. of freshly distilled iPr2NH (2.2 equiv.) in anh. THF (0.5m) at ꢀ 788 under N2.
The reaction was stirred at ꢀ 788 for 1 h, and then a soln. of the amino acid (1 equiv.) in anh. THF (0.5m)
was added. The mixture was stirred for 1 h at ꢀ 788, NFSI (5 equiv.) in anh. THF (1m) was added
dropwise, and the resulting yellow mixture was stirred for 2.5 h at ꢀ 788 and for 2 h at 08. Sat. aq. NH4Cl
was added, and the aq. layer was extracted with CH2Cl2 (3ꢁ). The combined org. phases were dried
(MgSO4), and the solvent was removed in vacuo. Petroleum ether (PE)/AcOEt 4 :1 was added to give a
white precipitate that was removed by filtration. The filtrate was concentrated in vacuo, and the crude
mixture was purified as specified for each compound.
3. Synthesis of Methyl Esters of a-Fluoro-b3-homophenylalanine 7 and 8, and Optimization of
Reaction Conditions. 3.1. Methyl (2S,3S)- and (2R,3S)-3-[(tert-Butoxycarbonyl)amino]-2-fluoro-4-
phenylbutanoate ((2S,3S)-7a and (2R,3S)-7b, resp.). Table 1, Entry 1. Amino acid 5 (66 mg, 0.23 mmol)
i
was treated with BuLi (0.31 ml, 0.50 mmol, 1.6m in hexane), Pr2NH (70 ml, 0.50 mmol), and NFSI
(425 mg, 1.3 mmol) according to GP 1. The crude product was purified by RC (silica gel; 5-mm plate; PE/
AcOEt 1:9) to give a mixture (2S,3S)-7a/(2R,3S)-7b (51 mg, 73%). White solid. The diastereoisomeric
ratio (dr) 95 :5 (19F-NMR). Recrystallization (AcOEt/PE) gave the single diasteroisomer (2S,3S)-7a as
white needles.
Table 1 Entry 3. BuLi (0.56 ml, 0.89 mmol, 2.1 equiv, 1.6m in hexane) was added to a soln. of freshly
i
dist. Pr2NH (120 ml, 0.89 mmol, 2.1 equiv.) in anh. THF (2.75 ml) at ꢀ 788 under N2. The mixture was
stirred at ꢀ 788 for 1 h, then a soln. of (S)-5 (124 mg, 0.42 mmol) in anh. THF (1 ml) under N2 was added.
The mixture was stirred for 1 h at ꢀ 788 and then NFSI (333 mg, 1.1 mmol, 2.5 equiv.) in anh. THF
(1 ml), under N2, was added dropwise. The resulting yellow mixture was stirred for 3.5 h at ꢀ 788 then
allowed to slowly warm to ꢀ 408 over 1 h. Sat. aq. NH4Cl soln. was added to quench the reaction, and the
aq. layer was extracted with CH2Cl2 three times. The combined org. phases were dried (MgSO4), and the
solvent was removed in vacuo to give an orange oil. PE/AcOEt 4 :1 was added to give a white precipitate
that was removed by filtration. The filtrate was concentrated in vacuo to give an orange oil that was
purified by RC (silica gel, 1-mm plate; 1:9 AcOEt/PE) to give a mixture (2S,3S)-7a/(2R,3S)-7b (70 mg,
53%). White solid. The dr 93 :7 (19F-NMR).

Helvetica Chimica Acta – Vol. 95 (2012)
2469
Data of (2S,3S)-7a (isolated). M.p. 86 – 878. [a]2D2 ¼ þ13.1 (c ¼ 0.82 in CHCl3). IR (KBr): 3374, 1736,
1682, 1515, 1273, 1161, 1048, 1010, 740. 1H-NMR (500 MHz, CDCl3): 7.32 – 7.19 (m, 5 arom. H); 5.03 (dd,
J ¼ 48.5, 3.0, CHF); 4.73 (d, J ¼ 8.0, NH); 4.52 – 4.41 (m, NCH); 3.65 (s, MeO); 2.90 – 2.81 (m, PhCH2);
t
1.38 (s, Bu).13C-NMR (126 MHz, CDCl3): 167.9 (d, J ¼ 23.8); 154.9; 136.1; 129.4; 128.5; 126.8; 89.6 (d,
J ¼ 188.9); 80.0; 52.8 (d, J ¼ 20.2); 52.4; 35.2; 28.2. 19F-NMR (282 MHz, CDCl3): ꢀ 203.4 – ꢀ 203.9 (m,
minor rotamer); ꢀ 204.7 (dd, J ¼ 48.4, 24.9, major rotamer). HR-ESI-MS: 334.1425 ([M þ H]þ,
C16H22FNNaOþ4 ; calc. 334.1430). Anal. calc. for C16H22NO4F (311.35): C 61.72, H 7.12, F 6.10, N 4.50;
found C 61.61, H 7.07, F 6.01, N 4.44.
Selected Data for Minor Isomer (2S,3R)-7b from the Mixture. 19F-NMR (282 MHz, CDCl3: ꢀ 208.3
(dd, J ¼ 47.3, 28.8).
3.2. Methyl (2R,3R)- and (2S,3R)-3-[(tert-Butoxycarbonyl)amino]-2-fluoro-4-phenylbutanoate
((2R,3R)-8a and (2S,3R)-8b, resp.). Table 1, Entry 2. BuLi (1.23 ml, 2.0 mmol, 2.2 equiv, 1.6m in hexane)
i
was added to a soln. of freshly dist. Pr2NH (270 ml, 2.0 mmol, 2.2 equiv.) in anh. THF (6 ml) at ꢀ 788
under N2. The mixture was stirred at ꢀ 788 for 1 h, a soln. of (R)-6 (262 mg, 0.89 mmol) in anh. THF
(2 ml) was added, and the mixture was stirred under N2 for 1 h at ꢀ 788. NFSI (4.05 g, 2.2 mmol, 2.5
equiv.) in anh. THF (2 ml) was added dropwise, and the resulting yellow mixture was stirred for 2.5 h at
ꢀ 788 and then for 2 h at 08. Sat. aq. NH4Cl soln. was added to quench the reaction, and the aq. layer was
extracted with CH2Cl2 three times. The combined org. phases were dried (MgSO4), and the solvent was
removed in vacuo to give an orange oil. PE/AcOEt 4 :1 was added to give a white precipitate that was
removed by filtration. The filtrate was concentrated in vacuo to give an orange oil that was purified by
RC (silica gel, 1-mm plate; AcOEt/PE 1:9) to give a mixture (2R,3R)-8a/(2S,3R)-8b (158 mg, 57%).
White solid. The dr 95 :5 (19F-NMR). Recrystallization (PE/AcOEt) gave the single diasteroisomer 8a as
white needles.
Table 1, Entry 4. BuLi (0.59 ml, 0.94 mmol, 2.1 equiv, 1.6m in hexane) was added to a soln. of freshly
distilled iPr2NH (130 ml, 0.94 mmol, 2.1 equiv.) in anh. THF (2.75 ml) at ꢀ 788 under N2. The mixture was
stirred at ꢀ 788 for 1 h, a soln. of (R)-6 (131 mg, 0.45 mmol) in anh. THF (1 ml) was added, and the
mixture was stirred for 1 h at ꢀ 788. NFSI (155 mg, 0.49 mmol, 2.5 equiv.) in anh. THF (0.5 ml) was
added dropwise, and the resulting yellow mixture was stirred for 2.5 h at ꢀ 788. After slowly warming to
ꢀ 408 over 1 h, sat. aq. NH4Cl soln. was added to quench the reaction, and the aq. layer was extracted
with CH2Cl2 three times. The org. phases were combined, dried (MgSO4), and the solvent was removed in
vacuo to give an orange oil. PE/AcOEt 4 :1 was added to give a white precipitate that was removed by
filtration. The filtrate was concentrated in vacuo to give an orange oil that was purified by RC (silica gel,
1-mm plate; AcOEt/PE 1:9) to give a mixture (2R,3R)-8a/(2S,3R)-8b (38 mg, 37%). White solid. dr 97:3
(19F-NMR).
Data of (2R,3R)-8a (isolated). M.p. 88 – 898. [a]2D2 ¼ ꢀ10.0 (c ¼ 1.05 in CHCl3). IR (KBr): 3380,
1736, 1682, 1515, 1273, 1161, 1048, 1010, 740. 1H-NMR (500 MHz, CDCl3): 7.32 – 7.20 (m, 5 arom. H); 5.04
(dd, J ¼ 48.4, 2.6, CHF); 4.73 (d, J ¼ 7.7, NH); 4.52 – 4.40 (m, NCH); 3.65 (s, MeO); 2.88 – 2.82 (m,
CH2Ph); 1.38 (s, Me3C). 13C-NMR (126 MHz, CDCl3): 168.0 (d, J ¼ 23.8); 154.9; 136.2; 129.4; 128.5;
126.9; 89.6 (d, J ¼ 189.1); 80.1; 52.8 (d, J ¼ 21.0); 52.4; 35.2; 28.2. 19F-NMR (238, 282 MHz, (D6)DMSO):
ꢀ 199.9 (dd, J ¼ 48.8, 24.5, minor rotamer); ꢀ 200.9 (dd, J ¼ 48.2, 23.3, major rotamer). 19F-NMR (238,
282 MHz, CDCl3): ꢀ 203.4 to ꢀ 203.8 (m, minor rotamer); ꢀ 204.7 (dd, J ¼ 48.5, 24.8, major rotamer).
19F-NMR (308, 282 MHz, CDCl3): ꢀ 203.4 to ꢀ 203.8 (m, minor rotamer); ꢀ 204.6 (dd, J ¼ 48.5, 24.6,
major rotamer). 19F-NMR (358, 282 MHz, CDCl3): ꢀ 203.2 to ꢀ 203.7 (m, minor rotamer); ꢀ 204.5 (dd,
J ¼ 48.4, 24.4, major rotamer). 19F-NMR (408, 282 MHz, CDCl3): ꢀ 203.0 to ꢀ 203.7 (m, minor
rotamer); ꢀ 204.3 (dd, J ¼ 48.2, 24.0, major rotamer). 19F-NMR (458, 282 MHz, CDCl3): ꢀ 202.9 to
ꢀ 203.7 (m, minor rotamer); ꢀ 204.2 (dd, J ¼ 47.6, 23.9, major rotamer). 19F-NMR (508, 282 MHz,
CDCl3): ꢀ 202.8 to ꢀ 204.4 (m, majorþ minor rotamers). 19F-NMR (558, 282 MHz, CDCl3): ꢀ 202.8 to
ꢀ 204.1 (m, majorþ minor rotamers). HR-ESI-MS: 334.1425 ([M þ Na]þ, C16H22FNNaO4þ ; calc.
334.1431). Anal. calc. for C16H22FNO4 (311.35): C 61.72, H 7.12, F 6.10, N 4.50; found C 61.58, H 7.39,
F 5.90, N 5.37.
Selected Data for Minor Isomer (2S,3R)-8b from Mixture: 19F-NMR (282 MHz, CDCl3): ꢀ 208.3 (dd,
J ¼ 47.9, 28.6).

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Helvetica Chimica Acta – Vol. 95 (2012)
4. Synthesis of Methyl Esters of b3-Homoleucine, b3-Homovaline, and b3-Homoalanine 12, 13, and 14,
Respectively. (14). 4.1. Methyl (2S,3S)- and (2R,3S)-3-[(tert-Butoxycarbonyl)amino]-2-fluoro-5-methyl-
hexanoate (12a and 12b, resp.). The amino acid 9 (119 mg, 0.46 mmol) was treated with BuLi (0.63 ml,
1.0 mmol, 1.6m in hexane), iPr2NH (0.14 ml, 3.9 mmol), and NFSI (724 mg, 2.3 mmol) according to GP 1.
The crude product was purified by CC (SiO2; AcOEt/CH2Cl2 0 :1 ! 1:9) to give a mixture 12a/12b
(76 mg, 60%). White solid. dr 93 :7 (19F-NMR). Recrystallisation from PE gave the single diasteroisomer
12a as white block crystals.
Data for 12a (isolated). M.p. 65 – 668. [a]D22 ¼ ꢀ15.6 (c ¼ 0.22 in CHCl3). IR (KBr): 3473, 3411, 1762
1679, 1639, 1618, 1532, 1251, 1174, 1073. 1H-NMR (300 MHz, CDCl3): 5.04 (dd, J ¼ 49.2, 2.7, CHF); 4.63
(d, J ¼ 8.8, NH); 4.28 – 4.08 (m, NCH); 3.81 (s, MeO); 1.73 – 1.59 (m, Me2CH); 1.50 – 1.43 (m, 1 H,
CHCH2); 1.45 (s, tBu); 1.18 – 1.07 (m, 1 H, CHCH2); 0.93 (d, J ¼ 6.7, 1 Me of Me2CH); 0.90 (d, J ¼ 6.5,
1 Me of Me2CH). 13C-NMR (126 MHz, CDCl3): 168.2 (d, J ¼ 24.2); 155.2; 90.8 (d, J ¼ 187.5), 80.0; 52.4;
50.3 (d, J ¼ 20.0); 37.6; 28.3; 24.5; 23.4; 21.3. 19F-NMR (282 MHz, CDCl3): ꢀ 204.8 – ꢀ 205.2 (m, minor
rotamer); ꢀ 206.6 (dd, J ¼ 49.2, 27.0, major rotamer). HR-ESI-MS: 278.1761 ([M þ H]þ, C13H25FNO4þ ;
calc. 278.1768). Anal. calc. for C13H24FNO4 (277.33): C 56.30, H 8.72, F 6.85, N 5.05; found C 56.11, H
8.83, F 6.65, N 4.98.
Selected Data for Minor Diastereoisomer 12b from the Mixture. 19F-NMR (282 MHz, CDCl3):
ꢀ 206.2 (dd, J ¼ 48.1, 27.0).
4.2. Methyl (2S,3S)- and (2R,3S)-3-[(tert-Butoxycarbonyl)amino]-2-fluoro-4-methylpentanoate (13a
and 13b, resp.). Compound 10 (235 mg, 0.96 mmol) was treated with BuLi (1.32 ml, 2.1 mmol, 1.6m in
hexane), iPr2NH (0.29 ml, 2.1 mmol), and NFSI (1.51 g, 4.8 mmol) according to GP 1. The crude product
was purified by CC (SiO2; AcOEt/CH2Cl2, 0 :1 ! 1:19) to give a mixture 13a/13b (144 mg, 57%).
Colorless oil. dr 96 :4 (19F-NMR). [a]D22 (mixture) ¼ ꢀ7.6 (c ¼ 0.97 in CHCl3). IR (KBr) 3352, 2967, 1764,
1713, 1514, 1367, 1240, 1171.
1
Data of 13a from the Mixture. H-NMR (500 MHz, CDCl3): 4.95 (dd, J ¼ 48.4, 2.6, CHF); 4.75 (d,
J ¼ 9.2, NH); 4.08 – 3.97 (m, NCH); 3.81 (s, MeO); 1.97 – 1.89 (m, Me2CH); 1.46 (s, tBu), 0.99 – 0.94 (m,
Me2CH).13C-NMR (126 MHz, CDCl3: 168.6 (d, J ¼ 23.5); 155.5; 90.0 (d, J ¼ 189.3); 79.9; 56.0 (d, J ¼
20.5); 52.5; 28.6; 28.3; 20.1; 17.5. 19F-NMR (282 MHz, CDCl3): ꢀ 199.4 (dd, J ¼ 48.6, 22.0, minor
rotamer); ꢀ 201.0 (dd, J ¼ 48.4, 23.5, major rotamer). HR-ESI-MS: 286.1437 ([M þ Na]þ,
C12H22FNNaOþ4 ; calc. 286.1431).
Selected Data of Minor Diastereoisomer 13b from the Mixture. 19F-NMR (282 MHz, CDCl3): ꢀ 206.8
(dd, J ¼ 48.2, 30.9).
4.3. Methyl (2S,3S)- and (2R,3S)-3-[(tert-Butoxycarbonyl)amino]-2-fluorobutanoate (14a and 14b,
resp.). Compound 11 (302 mg, 1.4 mmol) was treated with BuLi (1.88 ml, 3.0 mmol, 1.6m in hexane),
iPr2NH (0.52 ml, 3.0 mmol), and NFSI (2.19 g, 7.0 mmol) according to GP 1. The crude product was
purified by CC (SiO2; AcOEt/CH2Cl2 0 :1 ! 1:19) to give a mixture 14a/14b (134 mg, 41%). Colorless
oil. dr 96 :4 (19F-NMR). M.p. 59 – 608. [a]D20 (mixture) ¼ ꢀ1.4 (c ¼ 0.91 in CHCl3). IR (KBr) 3370, 2981,
1766, 1713, 1519, 1367, 1247, 1168, 1061.
Data of 14a from the Mixture. 1H-NMR (300 MHz, CDCl3): 5.03 (dd, J ¼ 49.4, 2.0, CHF); 4.74 (d,
t
J ¼ 5.4, NH); 4.33 – 4.10 (m, NCH); 3.80 (s, MeO); 1.44 (s, Bu); 1.14 (d, J ¼ 7.0, MeCH). 13C-NMR
(126 MHz, CDCl3): 168.2 (d, J ¼ 23.9); 154.8; 90.2 (d, J ¼ 188.1); 80.0; 52.5; 47.8 (d, J ¼ 20.5); 28.3; 14.2.
19F-NMR (282 MHz, CDCl3): ꢀ 207.3 to ꢀ 207.9 (m, minor rotamer); ꢀ 208.2 (dd, J ¼ 49.3, 26.9, major
rotamer). HR-ESI-MS: 236.1298 ([M þ H]þ, C10H19FNO4þ ; calc. 236.1298). Anal. calc. for C10H18FNO4
(235.25): C 51.05, H 7.71, F 8.08, N 5.95; found C 51.11, H 7.71, F 7.96, N 5.86.
Selected Data of Minor Diastereoisomer 14b from the Mixture. 19F-NMR (282 MHz, CDCl3): ꢀ 205.9
(dd, J ¼ 48.0, 27.0).
5. Synthesis of the Fluorinated b-Homophenylglycine Methyl Esters 4 and 18 – 20. 5.1. Methyl (2S,3S)-
and (2R,3S)-3-(Benzoylamino)-2-fluoro-3-phenylpropanoate (4a and 4b, resp.). The ester 3 (196 mg,
0.69 mmol) was treated with BuLi (0.96 ml, 1.5 mmol, 1.6m in hexane), iPr2NH (0.21 ml, 1.5 mmol), and
NFSI (1.09 g, 3.5 mmol) according to GP 1. dr 83 :17 (19F-NMR). The mixture was purified by RC (silica
gel, 5-mm plate; AcOEt/CH2Cl2 0 :1 ! 1:9) to give a fraction containing a mixture 4a/4b (112 mg, 54%)
and a pure fraction of 4a (34 mg, 16%). Both fractions were an off-white solid and gave a total yield of
70%.

Helvetica Chimica Acta – Vol. 95 (2012)
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Data of 4a (isolated). M.p. 133 – 1358 ([10]: 138 – 1408). [a]2D0 ¼ ꢀ3.3 (c ¼ 1.14 in CHCl3). IR (KBr)
1
3412, 1764, 1713, 1521, 1456, 1289, 1231, 1107, 1048, 700. H-NMR (300 MHz, CDCl3): 7.84 – 7.78 (m, 2
arom. H); 7.58 – 7.33 (m, 8 arom. H); 6.86 (d, J ¼ 8.0, NH); 5.75 (ddd, J ¼ 26.7, 8.0, 3.7, NCH); 5.47 (dd,
J ¼ 48.8, 3.6, CHF); 3.67 (s, MeO). 13C-NMR (75 MHz, CDCl3): 167.4 (d, J ¼ 23.6); 166.8; 135.2; 133.7;
132.0; 129.0; 128.8; 128.7; 127.8; 127.1; 89.6 (d, J ¼ 191.4); 54.9 (d, J ¼ 18.6); 52.5. 19F-NMR (282 MHz,
CDCl3): ꢀ 202.45 (dd, J ¼ 48.8, 26.8). HR-ESI-MS: 302.1180 ([M þ H]þ, C17H17FNO3þ ; calc. 302.1192).
Selected Data of Minor Diastereoisomer 4b from the Mixture. 1H-NMR (300 MHz, CDCl3): 6.95 (d,
J ¼ 10.2, NH); 5.94 – 5.87 (m, NCH); 5.32 (dd, J ¼ 47.4, 1.8, CHF); 3.82 (s, MeO).13C-NMR (75 MHz,
CDCl3): 168.0 (d, J ¼ 25.1); 166.8; 90.0 (d, J ¼ 191.0); 54.0 (d, J ¼ 19.3); 52.7. 19F-NMR (282 MHz,
CDCl3): ꢀ 202.8 (dd, J ¼ 47.2, 27.8).
5.2. Methyl (2S,3S)- and (2R,3S)-3-{[(Benzyloxy)carbonyl]amino}-2-fluoro-3-phenylpropanoate
(18a and 18b, resp.). The ester 15 (226 mg, 0.72 mmol) was treated with BuLi (1.00 ml, 1.6 mmol, 1.6m
i
in hexane), Pr2NH (0.22 ml, 1.6 mmol), and NFSI (1.14 g, 3.6 mmol) according to GP 1. The crude
product was purified by RC (silica gel, 5-mm plate; AcOEt/CH2Cl2 0 :1 ! 1:9) to give a mixture 18a/18b
(150 mg, 63%). Off-white solid. dr 79 :2 (19F-NMR).
Data of the mixture 18a/18b. M.p. 53 – 558. [a]2D2 (mixture) ¼ þ19.5 (c ¼ 1.04 in CHCl3). IR (KBr)
3412, 1764, 1712, 1521, 1456, 1289, 1231,1107, 1048, 700. 1H-NMR (500 MHz, CDCl3): 7.47 – 7.20 (m, each
10 arom. H, majorþ minor); 5.68 – 5.55 (m, NH, majorþ minor), 5.44 – 5.06 (m, CHF, NCH, PhCH2O,
majorþ minor); 3.78 (s, MeO, minor); 3.64 (s, MeO, major). 13C-NMR (126 MHz, CDCl3): 167.7 (d, J ¼
25.0, minor); 167.1 (d, J ¼ 23.4, major); 155.5 (minor); 155.3 (major); 137.0 (minor); 135.9 (minor);
135.9 (major); 135.2 (major); 128.6; 128.6; 128.5;128.3; 128.3; 128.1; 128.1; 128.0; 127.9; 127.5; 126.8;
126.6; 90.2 (d, J ¼ 191.4, minor); 89.7 (d, J ¼ 192.1, major); 67.0 (major); 67.0 (minor); 56.1 (d, J ¼ 18.8,
major); 55.7 (d, J ¼ 19.3, minor); 52.5 (minor); 52.1 (major). 19F-NMR (282 MHz, CDCl3: ꢀ 203.2 (dd,
J ¼ 48.5, 27.4, major); ꢀ 203.5 (dd, J ¼ 47.4, 27.8, minor). HR-ESI-MS: 332.1284 ([M þ H]þ,
C18H19FNOþ4 ; calc. 332.1298).
5.3. Methyl (2S,3S)- and (2R,3S)-3-[(tert-Butoxycarbonyl)amino]-2-fluoro-3-phenylpropanoate (19a
and 19b, resp.). The ester 16 (214 mg, 0.77 mmol) was treated with BuLi (1.06 ml, 1.7 mmol, 1.6m in
i
hexane), Pr2NH (0.24 ml, 1.7 mmol), and NFSI (1.20 g, 3.8 mmol) according to GP 1. dr 78 :22 (19F-
NMR). The mixture was purified by RC (silica gel, 5-mm plate; AcOEt/CH2Cl2 0 :1 ! 1:9) to give a
fraction containing a mixture 19a/19b (157 mg, 68%) and a pure fraction of 19a (13 mg, 6%). Both
fractions were an off-white solid and gave a total yield of 74%.
Data of 19a (isolated). M.p. 82 – 848. [a]2D0 ¼ þ32.4(c ¼ 0.89 in CHCl3). IR (KBr) 3389, 2978, 1767,
1712, 1497, 1368, 1293, 1250, 1167, 702.1H-NMR (300 MHz, CDCl3): 7.38 – 7.27 (m, 5 arom. H); 5.43 – 5.13
(m, NH, CHF, NCH); 3.65 (s, MeO); 1.44 (s, Me3C). 13C-NMR (75 MHz, CDCl3): 167.4 (d, J ¼ 23.5);
154.7; 135.6; 128.8; 128.6; 127.6; 90.0 (d, J ¼ 192.0); 80.4; 55.9 (d, J ¼ 18.0); 52.3; 28.3.19F-NMR
(282 MHz, CDCl3): ꢀ 203.5 (dd, J ¼ 49.1, 26.4). HR-ESI-MS: 298.1443 ([M þ H]þ, C15H21FNO4þ ; calc.
298.1455).
Data of the Minor Diastereoisomer 19b from the Mixture. 1H-NMR (300 MHz, CDCl3): 7.52 – 7.17 (m,
5 arom. H); 5.49 – 5.05 (m, NH, CHF, NCH); 3.81 (s, MeO); 1.43 (s, Me3C).13C-NMR (75 MHz, CDCl3:
167.9 (d, J ¼ 25.1); 154.8; 137.4; 128.7; 128.1; 126.6; 90.4 (d, J ¼ 190.8); 80.2; 55.3 (d, J ¼ 18.3); 52.6; 28.1.
19F-NMR (282 MHz, CDCl3): ꢀ 204.0 (dd, J ¼ 47.3, 27.8).
5.4. Methyl (2S,3S)- and (2R,3S)-3-(Acetylamino)-2-fluoro-3-phenylpropanoate (20a and 20b resp.).
i
The ester 17 (200 mg, 0.90 mmol) was treated with BuLi (1.24 ml, 2.0 mmol, 1.6m in hexane), Pr2NH
(0.28 ml, 2.0 mmol), and NFSI (1.43 g, 4.5 mmol) according to GP 1. The crude product was purified by
RC (silica gel, 5-mm plate; AcOEt/CH2Cl2 0 :1 ! 1:9) to give a mixture 20a/20b (111 mg, 51%).
Colorless oil. dr 63 :37 (19F-NMR).
Data of the Mixture of 20a/20b. IR (KBr) 3289, 3065, 2957, 1763, 1659, 1536, 1295, 1222, 1101, 732,
1
711. H-NMR (500 MHz, CDCl3): 7.54 (d, J ¼ 8.3, NH, major); 7.47 (d, J ¼ 9.3, NH, minor); 7.38 – 7.25
(m, 10 arom. H); 5.64 (ddd, J ¼ 28.9, 9.3, 2.1, NCH, minor); 5.51 (ddd, J ¼ 28.1, 8.3, 3.7, NCH, major);
5.21 (dd, J ¼ 48.9, 3.7, CHF, major); 5.16 (dd, J ¼ 47.4, 2.3, CHF, minor); 3.72 (s, MeO, minor); 3.59 (s,
MeO, major); 2.02 (s, MeC, minor); 2.00 (s, MeC, major). 13C-NMR (126 MHz, CDCl3): 170.1 (majorþ
minor); 167.7 (d, J ¼ 25.3, minor); 167.2 (d, J ¼ 23.7, major); 136.8; 135.0; 128.4;128.3; 128.1; 127.8; 127.6;
126.6; 90.0 (d, J ¼ 190.3, minor); 89.4 (d, J ¼ 191.4, major); 54.1 (d, J ¼ 18.9, major); 53.5 (d, J ¼ 19.0,

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Helvetica Chimica Acta – Vol. 95 (2012)
minor); 52.3 (minor); 52.0 (major); 22.4 (major); 22.3 (minor).19F-NMR (282 MHz, CDCl3): ꢀ 203.0
(dd, J ¼ 47.4, 29.1, minor), ꢀ 203.1 (dd, J ¼ 48.9, 28.1, major). HR-ESI-MS: ([M þ H]þ, C12H15FNO3þ :
240.1036; found 240.1027.
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Received September 13, 2012