Unusual nonchelation controlled allylation of a N-monoprotected α-amino aldehyde: Stereoselective entry to nonracemic trifluoromethyl dipeptide isosteres

Article abstract of DOI:10.1016/S0022-1139(01)00363-3

An efficient synthesis of the non-racemic (66-68% e.e.) homoallylic β-trifluoromethyl β-amino alcohol (2S,3R)-9, a key intermediate in the synthesis of trifluoromethylated dipeptide isosteres and oligopeptides, was developed starting from N-Cbz-trifluoropyruvaldehyde-N,S-ketal (R)-1a. The correct syn-stereochemistry was achieved by combining two moderately stereoselective steps: (1) addition of allylmagnesium chloride to (R)-1a, occurring with unusual nonchelation control; (2) reductive desulfenylation of the phenylacetate 6 with NaBH₄/pyridine.

Full text of DOI:10.1016/S0022-1139(01)00363-3

Journal of Fluorine Chemistry 108 /2001) 245±252
Unusual nonchelation controlled allylation of a N-monoprotected
a-amino aldehyde: stereoselective entry to nonracemic
tri¯uoromethyl dipeptide isosteres
Alessandro Volonterioa,*, Pierfrancesco Bravoa,b, Eleonora Corradia, Giovanni Fronzab,
Stefano V. Meillea, Barbara Vergania, Matteo Zandaa,1
aDipartimento di Chimica del Politecnico, via Mancinelli 7, I-20131 Milano, Italy
bC.N.R. Ð Centro di Studio sulle Sostanze Organiche Naturali, via Mancinelli 7, I-20131 Milano, Italy
Received 22 December 2000; accepted 10 February 2001
Abstract
An ef®cient synthesis of the non-racemic /66±68% e.e.) homoallylic b-tri¯uoromethyl b-amino alcohol /2S,3R)-9, a key intermediate in
the synthesis of tri¯uoromethylated dipeptide isosteres and oligopeptides, was developed starting from N-Cbz-tri¯uoropyruvaldehyde-N,S-
ketal /R)-1a. The correct syn-stereochemistry was achieved by combining two moderately stereoselective steps: /1) addition of
allylmagnesium chloride to /R)-1a, occurring with unusual nonchelation control; /2) reductive desulfenylation of the phenylacetate 6 with
NaBH4/pyridine. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: Tri¯uoromethyl group; Asymmetric synthesis; Grignard reactions; Aldehydes; Peptide isosteres
1. Introduction
novel hydroxymethylene peptide isosteres having the same
stereochemistry as natural statine, and characterised by the
presence of b-tri¯uoromethyl b-amino-alcohol units [13].
Next, we described their incorporation into complex peptide
sequences [14]. This success prompted us to investigate
further stereoselective routes to the same family of ¯uori-
nated peptide mimetics.
An extremely direct protocol to synthesise non-¯uori-
nated hydroxymethylene dipeptide isosteres /Scheme 1)
relies on the addition of nucleophiles to chiral a-amino
aldehydes [15±19]. Owing to their ready availability,
Grignard reagents and amino acid-derived aldehydes have
been widely used for this purpose. Unfortunately, nonrace-
mic b-¯uoro a-amino aldehydes have been hitherto unavail-
able, precluding the exploitation of this strategy for the
synthesis of the ¯uorinated analogues.
We now report in detail a novel stereoselective approach
to syn-homoallylic b-tri¯uoromethyl b-amino alcohol tem-
plates A /Scheme 1), which are valuable intermediates for
the preparation of tri¯uoromethylated hydroxymethylene
/statine) peptide isosteres [13], as we demonstrated in
our synthesis of the enantiomeric products. In this work
N-tri¯uoropyruvaldehyde N,S-ketal /R)-1 /Scheme 1)
[20,21], and allylmagnesium chloride were used as starting
materials.
Replacement of natural peptide bonds with surrogates
incapable of hydrolytic cleavage gives rise to the so-called
``peptide isosteres''. This strategy proved to be extremely
effective for producing molecules having a number of
biomedicinal and pharmaceutical applications, such as in
the regulation of blood pressure /renin inhibitors) and anti-
HIV activity /HIV-protease inhibitors) /[1±4], and [5] and
references therein). Stereochemically de®ned b-¯uoroalkyl
b-aminoalcohol peptide isosteres show a great potential for
the preparation of new peptide mimics having hydrophobic
and strongly polar sites, which might have improved proper-
ties as drugs. Unfortunately, the overwhelming dif®culties
connected with the preparation of such units have strongly
limited the research in this ®eld [6±12]. Recently, we started
a research program aimed at the investigation of the beha-
viour of ¯uoroalkyl functionalities in enzyme active sites. In
our initial studies, we used innovative asymmetric sulfoxide
chemistry for accomplishing a very effective synthesis of
* Corresponding authors. Fax: ‡39-02-23993080.
E-mail addresses: alessandro.volonterio@dept.chem.polimi.it
/A. Volonterio), zanda@dept.chem.polimi.it /M. Zanda).
1 Co-corresponding author.
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 / 0 1 ) 0 0 3 6 3 - 3

246
A. Volonterio et al. / Journal of Fluorine Chemistry 108 22001) 245±252
Scheme 1.
2. Results and discussion
2.1. Reaction of fluoropyruvaldehyde N,S-ketals with
allylmagnesium chloride
Scheme 2.
Slow addition of a THF solution of tri¯uoromethyl alde-
hyde /R)-1a to allylmagnesium chloride in THF /3 equiv.,
À788C, 1 min) produced the corresponding homoallylic
alcohols syn-/2R,3R)-2a/anti-/2R,3S)-3a in 9:2 diastereo-
meric ratio /85%) /Scheme 2, eq. 1).2 Samples of starting
material /R)-1a having 66±68% e.e., which can be prepared
in high yields according to a published procedure [20,21],
were used for this purpose. 1H and 19F NMR analyses using
the chiral shift reagent Eu/hfc)3 showed that no loss of
enantiomeric purity occurs during the synthesis of 2a. The
stereochemical outcome of this reaction is quite surprising,
considering that reactions of /R)-1a with alkyl, vinyl and
phenyl Grignard reagents /Scheme 2, eq. 2) have been
shown to produce the corresponding anti-products 5a, pos-
sibly originated by a highly effective ``chelation control''
[22,23]. Moreover, the same ``chelation control'' mechan-
ism was proposed for a wide range of reactions between N-
monoprotected a-amino aldehydes and Grignard reagents,
including allylic ones [24±30].
Thus, we decided to investigate more in depth the stereo-
chemical course of the process. Addition of 1 equiv. of
allylmagnesium chloride to /R)-1a produced a 50% conver-
sion,3 which necessarily means that 1,2-addition of the
allylic Grignard to the carbonyl is at least kinetically com-
petitive with the proton abstraction from nitrogen. In con-
trast, the other tested Grignard reagents /Scheme 2, eq. 2) led
to almost only proton abstraction from /R)-1a under the
same conditions, providing very low yields of the corre-
sponding products 4 and 5a [22,23]. This behaviour is in line
with other examples in the literature, which describe the use
of large excesses of Grignard reagents with N-monopro-
tected a-amino aldehydes, to obtain good conversions into
the corresponding b-amino alcohols [24±27]. According to
the arguments above, allylmagnesium chloride might pre-
ferentially react with /R)-1a via the syn-selective chair-like
transition state /TS) A /Fig. 1), involving sterically con-
trolled approach of the allylic nucleophile to the Re face of
the carbonyl /Felkin-Anh) [31,32], rather than via the anti-
selective TS B, involving attack to the Si carbonyl face of the
intramolecularly chelated halomagnesium salt of /R)-1a
[33]. Thus, the observed stereochemical outcome might
be ascribed to the proclivity of /R)-1a to undergo 1,2-
addition at the carbonyl rather than deprotonation of the
NHCbz moiety, by action of allylmagnesium chloride. As a
possible explanation, a synergistic action of several con-
comitant factors can be envisaged: /1) the strong electro-
philic character of the carbonyl group of /R)-1a, due to the
presence of both a strongly electron-withdrawing tri¯uor-
omethyl and an activating p-tolylthio group [34]; /2) the
high steric congestion and surrounding electronic density
experienced by the NHCbz group; /3) the extremely high
reactivity of allylmagnesium chloride in 1,2-addition reac-
tions /for an excellent review on organomagnesium halides
see [35]); /4) the SE20 mechanism of addition of allylmag-
nesium chloride, a unique feature within the range of
Grignard reagents reacted with /R)-1a /Allylmagnesium
chloride was purchased from Sigma/Aldrich. The Schlenk
equilibrium:
MgCl2 ‡ ꢀC3H5†2Mg , 2C3H5MgCl
in THF solution at À788C should be shifted toward the
monohapto covalent species Mg/Z1±C3H5)Cl, which under-
goes rapid 1,3-shift of magnesium atom even at that tem-
perature, see [35±37]).
For sake of comparison, addition of allylmagnesium
chloride to the di¯uoromethyl aldehyde /R)-1b was also
investigated /Scheme 2, Eq. 1). The reaction afforded an
equimolar mixture of the corresponding diastereomeric
2 Syn and anti descriptors refer to the relative position of the amino and
the hydroxy groups with respect to the molecular carbon backbone.
3 2 Equiv. of allylmagnesium chloride, under the same conditions,
improved the conversion to ca. 60%. In both cases /1 and 2 equiv. of allylic
Grignard) a 9:2 mixture of 2/3a was obtained.
Fig. 1. Stereochemical models for the formation of 2A and 3A.

A. Volonterio et al. / Journal of Fluorine Chemistry 108 22001) 245±252
247
Table 1
Selected bond lengths and angles of 2a
Ê
Bond lengths /A)
C/3)±C/8)
C/3)±S
1.531/7)
1.841/3)
1.212/4)
1.342/4)
1.443/4)
C/3)±N
1.466/5)
C/3)±C/4)
C/4)±C/5)
C/4)±O/3)
C/2)±N
1.574/1)
1.521/6)
1.420/5)
1.339/5)
C/2)±O/2)
C/2)±O/1)
C/1)±O/1)
Bond angles /8)
C/2)±N±C/3)
126.7/4)
105.5/2)
122.7/3)
C/3)±C/4)±C/5)
C/5)±C/6)±C/7)
C/1)±O/1)±C/2)
112.7/2)
125.7/7)
116.7/3)
C/1S)±S±C/3)
O/1)±C/2)±O/2)
Torsion angles /8)
C/8)±C/3)±C/4)±C/5)
C/2)±N±C/3)±S
À169.2/4)
À159.2/4)
À166.2/3)
À166.3/2)
67.3/2)
C/3)±C/4)±C/5)±C/6)
C/4)±C/5)±C/6)±C/7)
S±C/3)±C/4)±O/3)
À162.9/4)
À113.8/8)
À164.3/2)
177.9/4)
67.2/4)
C/4)±C/3)±C/8)±F/3)
C/1S)±S±C/3)±N
C/1)±O/1)±C/2)±N
N±C/3)±C/8)±F/3)
S±C/3)±C/4)±C/5)
C/3)±S±C/1S)±C/2S)
À82.1/5)
O/1)±C/1)±C/11)±C/12)
31.9/2)
n-hexane. An ORTEP view of 2a is shown in Fig. 2 and
selected molecular dimensions are reported in Table 1. Bond
lengths and angles fall in the expected range [39]. The N
atom is planar, as expected for carbamic compounds. Hydro-
gen bonding is both intermolecular and intramolecular
involving respectively the amidic hydrogen with the O3
Ê
atom of another ꢁ molecule /H Á Á Á O3 ˆ 1:99ꢀ1† A;
O3ÁÁÁHÀN ˆ 159:7ꢀ2† ) and the hydroxyl hydrogen with
Ê
the O2 ꢁ atom /H Á Á Á O2 ˆ 1:96ꢀ1† A; O2 Á Á Á HÀO3 ˆ
148:3ꢀ1† ). One of the hydrogen atoms on C5 is nearly
eclipsed with C7, which is consistent with the sp2 hybridisa-
tion on C6. The orientations of the two aromatic rings with
respect to the carbamic plane differ substantially, probably
because of the relative steric requirements of O1 and of
quaternary C3. In the crystal, the molecules of 2a tend to
pack so that the aromatic rings of distinct molecules are
locally in a herring-bone arrangement, with interplanar
angles of about 608 /Fig. 3).
Fig. 2. ORTEP view of 2a showing the atomic labelling scheme. 30%
thermal ellipsoid for non-hydrogen atoms are shown.
homoallylic b-di¯uoromethyl b-amino alcohols 2 and 3b in
83% yield. It should be noted that, in analogy with the
tri¯uoromethyl counterpart /R)-1a /vide supra), the reaction
between /R)-1b and Grignard reagents other than allylic was
shown to provide the corresponding di¯uoromethyl deriva-
tives 5b with high levels of stereoselectivity /chelation
control) /Scheme 2, Eq. 2) [22,23]. This result indicates
that the unusual ``nonchelation control'' observed for the
reaction of the tri¯uoromethyl aldehyde /R)-1a with allyl-
magnesium chloride is mainly due to the unique stereoelec-
tronic features of the tri¯uoromethyl group /Bondi volumes
for CHF2 and CF3 groups are respectively 16.0 and
21.3 cm3 molÀ1, see [38]), whereas the presence of the
di¯uoromethyl group, both less sterically demanding and
electron-withdrawing, is unable to produce the same out-
come.
2.3. Synthesis of the trifluoromethyl peptide isosteres
templates
To obtain the targeted b-tri¯uoromethyl b-amino alcohols
with the correct syn-stereochemistry, /2R,3R)-2a was trans-
formed into the corresponding phenylacetic ester /2R,3R)-6
/Scheme 3),4 which was submitted to reductive desulfenyla-
tion with the NaBH4/pyridine system /08C, 60 min), afford-
ing the desired syn-derivative /2S,3R)-7 with good
diastereoselectivity /9:2). This reaction involves two steps
[23]: /1) the generation of the transient imine 11b by pyri-
dine promoted elimination of p-thiocresol; /2) reduction of
11b by NaBH4. In contrast, direct reductive desulfenylation
2.2. X-Ray diffraction of homoallylic b-trifluoro-
methyl b-amino alcohol 2a
4 Analytical samples of enantiopure 2a could be obtained via
crystallization ꢀsee the X-ray section), however the low yields of this
process led us to use 2a in 66±68% e.e., as obtained from ꢀR)-1a.
The absolute stereochemistry of 2a was determined by
X-ray diffraction of a chiral single crystal obtained from

248
A. Volonterio et al. / Journal of Fluorine Chemistry 108 22001) 245±252
Fig. 3. Packing of 2a viewed down a-axis.
of the secondary alcohol /2R,3R)-2a /Scheme 3), according
to the same procedure, afforded the diastereomeric b-amino
alcohols 9 and 10 as an equimolar mixture, without stereo-
control.
The stereocontrol of the hydride promoted reduction of
the imine 11b can be explained by the Felkin-Anh model C
/Fig. 4) [31,32], in which the phenylacetoxy group plays the
role of electronegative, ``large'' substituent.
Finally, the b-amino alcohol /2S,3R)-9 was obtained by
methanolysis of the ester function. Syn-stereochemistry was
con®dently assigned to 9, since its JH-2,H-3 value is lower
/1 Hz) than that of the minor anti isomer 10 /4.5 Hz), in line
with previously described b-tri¯uoromethyl b-amino alco-
hols [11,12,22,23]. To con®rm the syn-stereochemistry of
/2S,3R)-7 and -9, the N-Cbz 2,4-dihydroxy-5-Tfm-pyrroli-
dine 12 /Scheme 3) was prepared by oxidative cleavage of
the double bond of /2S,3R)-9 with OsO4 /cat.)/NaIO4 fol-
lowed by spontaneous intramolecular cyclisation [40] /for
other examples of 2,4-dihydroxy-pyrrolidines see [41], and
the following references [42,43]). After ¯ash chromato-
graphic puri®cation, 12 was obtained as a 1:1 mixture of
a- and b-anomers, which were submitted to detailed NMR
analysis. For the anomer 12-a, the coupling constants
JH-1;H -2 and JH -2;H-3 are 0.0 and 12.5 Hz, respectively,
b
a
indicating that the hydrogens H-1 and Hb-2 are trans-pseu-
doequatorially oriented, whereas Ha-2 and H-3 are trans-
pseudoaxially oriented. Thus, for the anomer 12-a the
hydroxyls are also trans. Changing from the anomer 12-a
Scheme 3.
Fig. 4. Stereochemical models for the formation of 7.

A. Volonterio et al. / Journal of Fluorine Chemistry 108 22001) 245±252
249
to the anomer 12-b, the resonances of the protons H-3 and H-
4 are shifted up®eld by 0.37 and 0.07 ppm, respectively. This
up®eld effect, called the 1,3- /or g-) effect [44], is char-
acteristic of hydrogens belonging to ®ve-membered rings
whenag-substituentchangesfromthesyn-totheanti-position.
The observed effects clearly indicate that the hydrogens H-3
and H-4 are both syn to OH-1 for the anomer 12-a, and
therefore are cis-oriented with respect to each other.
All steps summarised in Scheme 3 feature almost quan-
titative yields. It is worth noting that the synthesis of
compounds 7 and 9 can be equally applied to the synthesis
of their enantiomers by simply switching the starting pyr-
uvaldehyde /R)-1a to its enantiomer. Therefore, both enan-
tiomers of the ¯uorinated statine analogue A can be prepared
in good e.e. and yields from 9, and eventually incorporated
into peptidic sequences, following the recently described
methodology [13,14].
/5 ml) a solution of aldehyde /R)-1a /210 mg, 0.55 mmol) in
dry THF /2 ml) was added dropwise under a nitrogen atmo-
sphere. After 1 min the reaction was quenched with a
saturated aqueous solution of NH4Cl, heated at room tem-
perature and extracted with AcOEt. The collected organic
phases were dried over anhydrous sodium sulfate, ®ltered
and the solvent removed in vacuo. The crude was puri®ed
by FC /9:1 n-hexane/AcOEt) affording 198 mg /85%) of
2a and 3a /9:2), both obtained in diastereomerically pure
form.
20
/2R,3R)-2a: Rf /85:15 n-hexane/AcOEt) 0.5; ‰aŠD À126:0
/c 0.76, CHCl3), e:e: > 95% /after crystallisation); mp 938C
1
/n-hexane); H NMR /CDCl3) d 7.47 /2H, d, J ˆ 7:9 Hz),
7.40 À 7.28 /5H, m), 7.18 /2H, d, J ˆ 7:9 Hz), 5.98 /1H,
ddt, J ˆ 17:3, 10.3 and 6.9 Hz), 5.18 /1H, dq, J ˆ 17:3 and
1.5 Hz), 5.14 /1H, d, J ˆ 10:3 Hz), 5.09 /1H, d, J ˆ
12:3 Hz), 5.05 /1H, d, J ˆ 12:3 Hz), 4.95 /1H, br s), 4.52
/1H, d, J ˆ 9:8 Hz), 4.22 /1H, dt, J ˆ 9:8 and 2.0 Hz), 2.88
/1H, ddq, J ˆ 14:3, 6.9 and 1.5 Hz), 2.38 /1H, m), 2.37 /3H,
s); 19F NMR /CDCl3) d À 72.3 /s); 13C NMR /CDCl3) d
155.1, 141.8, 138.5, 135.4, 135.1, 130.4, 128.7, 128.6,
128.2, 125.3 /q, J ˆ 289:8 Hz), 123.0, 117.3, 72.8, 71.5
/q, J ˆ 26:7 Hz), 67.9, 36.6, 21.3; MS /EI, 70 eV) m/z /%)
3. Experimental section
3.1. General
1H /400 or 250 MHz), 19F /235 MHz) and 13C /100.6 or
62.8 MHz) nuclear magnetic resonance samples were pre-
pared as dilute solutions in CDCl3 or acetone-d6. The NMR
spectra were recorded using Bruker spectrometers. Chemi-
cal shifts /d) are reported in parts per million /ppm) of the
applied ®eld. The Me4Si was used as internal standard /dH
and dC ˆ 0:00) for 1H and 13C nuclei, while C6F6 was used
as external standard /dF ˆ À162:90) for 19F nuclei. The e.e.s
have been determined by 1H and 19F NMR analysis of pure
samples of the appropriate compounds, by using the chiral
shift reagent /‡)-[Eu/hfc)3] in CDCl3 solution. The FT-IR
spectra were taken on a Perkin-Elmer 2000 spectrometer.
Anhydrous THF was distilled from sodium and benzophe-
none. Anhydrous CH2Cl2 was distilled from calcium hydride.
In all other cases commercially available reagent-grade sol-
vents were employed without puri®cation. Allylmagnesium
chloride was purchased from Sigma/Aldrich Co. Reactions
performed in dry solvents were carried out in nitrogen atmo-
spheres. Melting points are uncorrected and were obtained
on a capillary apparatus. Analytical thin-layer chromatogra-
phy /TLC) was routinely used to monitor reactions. Plates
precoated with E. Merck silica gel 60 F254 of 0.25 mm thick-
ness were used. Merck silica gel 60 /230±400 ASTM mesh)
was employed as a reagent /for the preparation of /R)-1) and
for ¯ash column chromatography /FC). Fluoropyruvalde-
hyde N,S-ketals /R)-1a and b /having ca. 70% e.e.) were
prepared according to the procedure described in [20,21].
‡
426 /M ‡ 1, 9), 302 /5), 258 /11), 124 /49), 91 /100); FT-
IR /cmÀ1) 3369, 3044, 1703, 1557, 1278, 1239, 1193, 1154,
1070. Anal. Calculated /%) for C21H22F3NO3S: C, 59.28; H,
5.21; N, 3.29. Found: C, 59.27; H, 5.21; N, 3.27.
/2R,3S)-3a: Rf /85:15 n-hexane/AcOEt) 0.4; 1H NMR
/CDCl3) d 7:50 À 7:29 /7H, m), 7.04 /2H, d, J ˆ 7:9 Hz),
5.95 /1H, ddt, J ˆ 17:1, 10.4 and 6.6 Hz), 5.28 /1H, br s),
5.16 /1H, dq, J ˆ 17:1 and 1.6 Hz), 5.12 /1H, d,
J ˆ 11:7 Hz), 5.09 /1H, d, J ˆ 10:4 Hz), 4.99 /1H, d,
J ˆ 11:7 Hz), 4.38 /1H, d, J ˆ 13:9 Hz), 3.95 /1H, br s),
2.61 /1H, dd, J ˆ 13:9 and 6.6 Hz), 2.35 /1H, m), 2.32 /3H,
s); 19F NMR /CDCl3) d À 71.1 /s); 13C NMR /CDCl3) d
154.7, 140.7, 138.1, 135.2, 134.9, 129.8, 128.67, 128.61,
124.6 /q, J ˆ 286:7 Hz), 124.1, 117.5, 75.3 /q,
J ˆ 25:9 Hz), 72.1, 67.8, 36.8, 21.3.
3.3. Reaction of difluoromethyl pyruvaldehyde
2R)-1b with allylmagnesium chloride
To a cooled solution /À788C) of allylmagnesium chloride
/168 ml of a 2 M solution in THF, 0.33 mmol) in dry THF
/1 ml) a solution of aldehyde /R)-1b /41 mg, 0.11 mmol) in
dry THF /500 ml) was added dropwise under nitrogen atmo-
sphere. After 1 min the reaction was quenched with a
saturated aqueous solution of NH4Cl, heated at room tem-
perature and extracted with CHCl3. The collected organic
phases were dried over anhydrous sodium sulfate, ®ltered
and the solvent removed in vacuo. The crude was puri®ed by
FC /9:1 n-hexane/Et2O) affording 37 mg /83%) of 2b and
3b, obtained as an equimolar mixture.
3.2. Reaction of trifluoromethyl pyruvaldehyde 2R)-
1a with allylmagnesium chloride
1
/2R,3R)-2b: Rf /85:15 n-hexane/AcOEt) 0.37; H NMR
/CDCl3) d 7.45 À 7.24 /7H, m), 7.07 /2H, d, J ˆ 7:8 Hz),
To a cooled solution /À788C) of allylmagnesium chloride
/830 ml of a 2 M solution in THF, 1.64 mmol) in dry THF
6.66 /1H, t, J ˆ 55:9 Hz), 5.99 À 5.78 /1H, m), 5.57 /1H, br

250
A. Volonterio et al. / Journal of Fluorine Chemistry 108 22001) 245±252
s), 5.22 À 5.08 /2H, m), 5.02 /1H, d, J ˆ 12:4 Hz), 4.86
/1H, d, J ˆ 12:4 Hz), 4.09 /1H, d, J ˆ 10:5 Hz), 3.14 /1H,
br s), 2.76 À 2.54 /1H, m), 2.33 /3H, s), 2.42 À 2.21 /1H,
m); 19F NMR /CDCl3) d À 132.2 /1F, dd, J ˆ 277:2 and
55.9 Hz), À119.7 /1F, dd, J ˆ 277:2 and 55.9 Hz); 13C
NMR /CDCl3) /1:1 mixture of the two diastereoisomers)
d 140.6, 140.4, 138.3, 138.0, 135.4, 134.7, 134.5, 129.8,
128.6, 128.5, 128.3, 124.5, 124.1, 118.1, 117.9, 115.0 /dd,
J ˆ 257:1 and 247.8 Hz), 114.4 /t, J ˆ 247:0 Hz), 73.9 /dd,
J ˆ 24:0 and 18.5 Hz), 73.5, 72.2 /t, J ˆ 20:4), 71.5, 67.6,
was removed in vacuo. The FC of the crude /9:1 n-hexane/
AcOEt) afforded 74 mg /quantit.) of the two diastereoi-
somers syn-7 and anti-8, obtained as a 9:2 mixture.
The same procedure, applied on the b-p-tolylthio b-amino
alcohol syn-2a provided an equimolar mixture of the corre-
sponding desulfenylated b-amino alcohols syn-9 and anti-
10, in quantitative yield.
Syn-/2S,3R)-7: Rf /85:15 n-hexane/AcOEt) 0.5; 1H NMR
/CDCl3) d 7.42 À 7.18 /10H, m), 5.65 /1H, ddt, J ˆ 18:1,
10.8 and 7.1 Hz), 5.35 /1H, t, J ˆ 7:3 Hz), 5.15 /2H, s),
5.21 À 5.04 /2H, m), 4.52 À 4.36 /1H, m), 3.60 /2H, s),
2.42 À 2.23 /2H, m); 19F NMR /CDCl3) d À 75.7 /d,
J ˆ 7:7 Hz); 13C NMR /CDCl3) d 169.6, 155.7, 135.6,
131.0, 129.3, 129.2, 128.63, 128.57, 128.48, 128.2, 127.3,
124.1 /q, J ˆ 283:9 Hz), 120.2, 68.7, 67.8, 53.4 /q,
J ˆ 30:5 Hz), 41.1, 35.9; FT-IR /cmÀ1) 3336, 3035,
1736, 1516, 1455, 1281, 1185, 1146.
‡
36.9, 36.1, 21.3; MS /EI, 70 eV) m/z /%) 408 /M ‡ 1, 16),
284 /9), 240 /4), 123 /10), 91 /100); FT IR /cmÀ1) 3394,
3069, 1698, 1493, 1266, 1061.
1
/2R,3S)-3b: Rf /85:15 n-hexane/AcOEt) 0.37; H NMR
/CDCl3) d 7.45 À 7.24 /7H, m), 7.07 /2H, d, J ˆ 7:8 Hz),
6.54 /1H, t, J ˆ 55:1 Hz), 5.99 À 5.78 /1H, m), 5.29 /1H, br
s), 5.20 À 5.09 /2H, m), 4.94 /2H, s), 3.52 /1H, m), 3.14 /1H,
br s), 2.76 À 2.54 /1H, m), 2.42 À 2.21 /1H, m), 2.33 /3H,
m); 19F NMR /CDCl3) d À 129.9 /1F, dd, J ˆ 274:6 and
55.1 Hz), À125.2 /1F, dd, J ˆ 274:6 and 55.1 Hz).
Anti-/2R,3R)-8: Rf /85:15 n-hexane/AcOEt) 0.5; 1H NMR
/CDCl3) d 7.42 À 7.18 /10H, m), 5.56 À 5.75 /1H, m),
5.40 À 5.32 /1H, m), 5.21 À 5.04 /4H, m), 4.70 À 4.57
/1H, m), 3.6 /2H, s), 2.51 À 2.40 /2H, m); 19F NMR /CDCl3)
d À 72.8 /d, J ˆ 7:7 Hz).
3.4. Esterification of 2a with phenylacetic acid
To a solution of 2a /143 mg, 0.33 mmol) in dry CH2Cl2
/8.5 ml) were added solid phenylacetic acid /46 mg,
0.33 mmol), then DCC /68 mg, 0.33 mmol) and ®nally a
catalytic amount of 4-DMAP. The mixture was kept at room
temperature for 1 h. The solution was diluted with diethyl
ether, ®ltered and the solvent was removed in vacuo. The
residue was puri®ed by FC /9:1 n-hexane/AcOEt) affording
182 mg /quantit.) of 6.
3.6. Synthesis of the b-amino alcohols 9 and 10
To a solution of syn-7 and anti-8 /9:2 mixture) /123 mg,
0.30 mmol) in MeOH /5 ml) a 0.5 M solution of K2CO3
/0.6 mmol, 1.2 ml) was added at room temperature. After
30 min the reaction was quenched with a saturated aqueous
solution of NH4Cl, the organic solvent evaporated under
reduced pressure and the aqueous layer extracted with
AcOEt. The collected organic phases were dried over
anhydrous sodium sulfate, ®ltered and the solvent was
removed in vacuo. The FC of the crude /85:15 n-hexane/
AcOEt) afforded 90 mg /quantit.) of the two diastereoi-
somers syn-9 and anti-10, both isolated in diastereomeri-
20
/2R,3R)-6: Rf /85:15 n-hexane/AcOEt) 0.52; ‰aŠD À120:6
/c 0.86, CHCl3), e.e. 66%; 1H NMR /CDCl3) d 7.36 /2H, d,
J ˆ 8:0 Hz), 7.34 À 7.15 /10H, m), 6.97 /2H, d, J ˆ
8:0 Hz), 6.54 /1H, d, J ˆ 10:1 Hz), 5.71 À 5.58 /1H, m),
4.96 /1H, d, J ˆ 12 Hz), 4.93 À 4.87 /2H, m), 4.87 /1H, d,
J ˆ 12 Hz), 3.62 /2H, s), 2.69 À 2.62 /1H, m), 2.41 À 2.30
/1H, m), 2.25 /3H, s); 19F NMR /CDCl3) d À 70.3 /s); 13C
NMR /CDCl3) d 169.6, 153.0, 140.5, 138.3, 135.2, 133.4,
129.6, 129.4, 128.42, 128.39, 128.33, 128.2, 126.8, 124.6
/q, J ˆ 286:4 Hz), 123.8, 117.9, 72.9 /q, J ˆ 26:9 Hz), 72.6,
cally pure form.
20
D
Syn-/2S,3R)-9: Rf /8:2 n-hexane/AcOEt) 0.28; ‰aŠ ‡16:6
/c 0.92, CHCl3), e.e. 68%; 1H NMR /CDCl3) d 7.41 À 7.33
/5H, m), 5.77 /1H, ddt, J ˆ 17:0, 10.4 and 6.6 Hz), 5.54 /1H,
br d, J ˆ 9:3 Hz), 5.20 /1H, d, J ˆ 10:4 Hz), 5.17 /1H, dd,
J ˆ 17:0 and 1.5 Hz), 4.27 /1H, dq, J ˆ 9:3 and 8.2 Hz),
4.15 /1H, t, J ˆ 6:6 Hz), 2.28 /2H, t, J ˆ 6:6 Hz); 19F NMR
/CDCl3) d À 75.3 /d, J ˆ 8:2 Hz); 13C NMR /CDCl3) d
156.3, 135.9, 132.5, 128.3, 128.1, 127.6, 124.9 /q,
J ˆ 282:8 Hz), 119.7, 67.6, 67.0, 54.8 /q, J ˆ 29:1 Hz),
‡
67.3, 41.1, 35.7, 21.0; MS /EI, 70 eV) m/z /%) 544 /M ‡ 1,
6), 420 /100), 376 /19), 284 /6), 91 /9); FT-IR /cmÀ1) 3320,
3034, 1752, 1516, 1455, 1244, 1133. Anal. Calculated /%)
for C28H26F3NO4S: C, 63.50; H, 4.95; N, 2.64. Found: C,
63.31; H, 5.24; N, 3.04.
‡
38.5; MS /EI, 70 eV) m/z /%) 303 /M ‡ 1, 7), 264 /10),
3.5. Reductive desulfenylation of 6
224 /46), 172 /41), 91 /100); FT-IR /cmÀ1) 3295, 2924,
2855, 1697, 1555, 1459, 1250, 1189. Anal. Calculated /%)
for C14H16F3NO3: C, 55.44; H, 5.32; N, 4.62. Found: C,
55.21; H, 5.44; N, 4.40.
To a cooled solution /08C) of 6 /110 mg, 0.18 mmol) in
pyridine /2.6 ml) NaBH4 /35 mg, 0.92 mmol) was added
portionwise and the mixture was kept 1 h under stirring at
the same temperature. Then the reaction was quenched with
1 N aqueous solution of HCl heated at room temperature and
extracted with AcOEt. The collected organic phases were
dried over anhydrous sodium sulfate, ®ltered and the solvent
Anti-/2R,3R)-10: Rf /8:2 n-hexane/AcOEt) 0.20;
20
1
‰aŠ À 3:3 /c 0.81, CHCl3), e.e. 68%; H NMR /Acetone-
D
d6) d 7.42±7.29 /5H, m), 6.99 /1H, br d, J ˆ 9:6 Hz), 5.92
/1H, ddt, J ˆ 17:6, 10.3 and 7.3 Hz), 5.13 /2H, s), 5.09 /1H,
d, J ˆ 10:3 Hz), 5.07 /1H, d, J ˆ 17:6 Hz), 4.40 /1H, d,

A. Volonterio et al. / Journal of Fluorine Chemistry 108 22001) 245±252
251
J ˆ 6:6 Hz), 4.31 /1H, m), 4.01 /1H, m), 2.52 À 2.24 /2H,
m); 19F NMR /CDCl3) d À 71.8 /d, J ˆ 7:3 Hz).
three standard re¯ections, measured every 100 re¯ections,
showed no signi®cant decay. Data were corrected for Lor-
entz and polarisation effects and an empirical absorption
correction was applied.
3.7. Synthesis of the pyrrolidine 12
The structure was solved by direct methods using
SIR92 [45], and re®ned by full-matrix least squares on
F2 using SHELXL97 [46]. Non-hydrogen atoms were
re®ned anisotropically and the two aromatic rings were
inserted as rigid groups. The amide and hydroxyl hydro-
gens were located by difference-Fourier technique and
re®ned, while the others have been included at calculated
positions and re®ned with group temperature factors. Final
value of the residual R1 and wR2 /for re¯ections with
I > 2sI) were, respectively, 6.20 and 16.91. The highest
peak and hole in ®nal difference-Fourier map were 0.242
To a solution of syn-9 /43 mg, 0.14 mmol) in a 3:1
mixture of THF/H2O /1.4 ml) a 4% /in weight) aqueous
solution of OsO4 /0.014 mmol, 10 ml) was added at room
temperature /RT) under nitrogen. After 5 min the solution
became dark and NaIO4 /100 mg, 0.47 mmol) was added.
After 4 h the mixture was ®ltered and the residue washed
with diethyl ether. The organic solution was washed with
water twice and dried over anhydrous sodium sulfate,
®ltered, then concentred in vacuo. The FC of the crude
afforded 43 mg /quantit.) of the two anomers 12-a and -b, as
Ê 3
a 1:1 mixture.
and À0.316 eA . The re®ned value of Flack's parameter [47]
20
D
12-a: Rf /6:4 n-hexane/AcOEt) 0.28; ‰aŠ ‡ 7:3 /c 1.4,
was À0.04/4).
CHCl3) as a 1:1 mixture with 12-b, with e.e. 68%; 1H NMR
/Acetone-d6) d 7.30 À 7.43 /5H, m, C6H5), 5.56 /1H, t,
JH-1;H -2 ˆ 5:9 and JH-1;H -2 ˆ 0:0 Hz, H-1), 5.15 /2H, s,
Crystallographic data /excluding structure factors) for the
structure 2a reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC-149431. Copies of the data can
be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK /fax: international
code ‡ 44/1223)336-033; e-mail: deposit@ccdc.cam.ac.uk).
a
b
OCH2), 5.11 /1H, br, OH-3), 4.96 /1H, m, H-3), 4.76 /1H,
d, JH-1;OH ˆ 5:6 Hz, OH-1), 4.50 /1H, dq, JH-3;H-4
ˆ
JH-4;CF ˆ 8:0 Hz, H-4), 2.25 /1H, td, JH-1;H -2 ˆ 5:9 and
3
a
JH -2;H -2 ˆ JH -2;H-3 ˆ 12:5 Hz, Ha-2), 2.11 /1H, dd,
a
b
a
JH -2;H -2 ˆ 12:5; JH -2;H-3 ˆ 7:0 and JH-1;H -2 ˆ 0:0 Hz,
a
b
b
b
Hb-2); 19F NMR /CDCl3) d À 69.7 /d, J ˆ 8:0 Hz); MS
‡
/EI, 70 eV) m/z /%) 306 /M ‡ 1, 4), 288 /11), 244 /10), 181
Acknowledgements
/4), 153 /13), 108 /28), 91 /100); FT-IR /cmÀ1) 3295, 2954,
2924, 2855, 1702, 1545, 1460, 1377, 1251, 1139.
The authors gratefully acknowledge C.N.R.
Ð
12-b: Rf /6:4 n-hexane/AcOEt) 0.14; 1H NMR /Acetone-
C.S.S.O.N. for ®nancial support. Eleonora Corradi and
Barbara Vergani thank Politecnico di Milano for a scholar-
ship.
d6) d 7.30 À 7.43 /5H, m, C6H5), 5.56 /1H, td, JH-1;H -2
ˆ
a
JH-1;H -2 ˆ 6:5 and JH-1;OH ˆ 4:6 Hz, H-1), 5.22 /1H, d,
b
J ˆ 12:6 Hz, OHCHPh), 5.12 /1H, d, J ˆ 12:6 Hz,
OHCHPh), 4.84 /1H, d, JH-1;OH ˆ 4:6 Hz, OH-1), 4.59
/1H, m, H-3), 4.55 /1H, d, JH-3;OH ˆ 5:6 Hz, OH-3), 4.43
References
/1H, dq, JH-3;H-4 ˆ JH-4;CF ˆ 7:7 Hz, H-4), 2.57 /1H, ddd,
3
JH-1;H -2 ˆ 6:5, JH -2;H -2 ˆ 13:1 and JH -2;H-3 ˆ 7:5 Hz,
b
a
b
b
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