Titanium mediated asymmetric aldol reaction with α-fluoropropionimide enolates

Article abstract of DOI:10.1016/j.jfluchem.2007.05.012

Aldol reaction utilising Evans N-(α-fluoropropyl)-2-oxazolidinones with TiCl₄ have been explored. Reactions of N-(α-fluoropropyl)-2-oxazolidinones with aliphatic aldehydes generated α-fluoro-β-hydroxy-aldol products with high diastereoselectivi

Full text of DOI:10.1016/j.jfluchem.2007.05.012

Journal of Fluorine Chemistry 128 (2007) 1271–1279
www.elsevier.com/locate/fluor
Titanium mediated asymmetric aldol reaction with
a-fluoropropionimide enolates
*
Vincent A. Brunet, David O’Hagan , Alexandra M.Z. Slawin
School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, St Andrews KY16 9ST, UK
Received 12 April 2007; accepted 12 May 2007
Available online 17 May 2007
Dedicated to Professor Kenji Uneyama as recipient of the ACS Fluorine Chemistry Award for 2007.
Abstract
Aldol reaction utilising Evans N-(a-fluoropropyl)-2-oxazolidinones with TiCl4 have been explored. Reactions of N-(a-
fluoropropyl)-2-oxazolidinones with aliphatic aldehydes generated a-fluoro-b-hydroxy-aldol products with high diastereoselectivities.
When (aR)- and (aS)-N-(a-fluoropropyl)-2-(4S)-oxazolidinones were explored as substrates they gave rise to identical aldol diastereo-
isomer products. Examination of the enolates formed in each case by 19F NMR, after treatment with TiCl4, indicated that both preparations
gave the same predominant enolate. This was assumed to be the E-enolate. The a-fluoro-b-hydroxy-aldol products were removed
from the auxiliary either by alcoholysis or reduction and converted to the corresponding a,b-difluoro products by treatment with
DeoxofluorTM
.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Asymmetric synthesis; Evans auxiliary; a-Fluoroenolates; Asymmetric aldol reactions; Stereoselective fluorination; Vicinal difluoro compounds
1. Introduction
fluoroenolates they have never found a significant role in the
synthesis of organofluorine compounds [3]. In terms of
asymmetric aldol reactions, Pridgen et al. [4] have demon-
strated the most impressive methodology in this area exploring
asymmetric aldol reactions with fluoroacetamide 1, and using a
variety of base or Lewis acid catalysed enolate generation
processes for condensations to aromatic aldehydes.
We have a current interest in preparing vicinal difluoro
aliphatic compounds in a stereospecific manner. Although the
fluorine atom is the next smallest to hydrogen and has a limited
steric impact, the polar nature of the C–F bond induces
stereoelectronic influences which can differentially influence
the properties of erythro and threo diastereoisomers of
otherwise identical vicinal difluorine containing compounds
[1]. We have shown this for 9,10-difluorostearic acids and small
peptidic compounds derived from erythro- and threo-difluoro-
succinic acids [2]. In this regard, our attention was drawn to the
possibility of carrying our asymmetric aldol reaction with
chiral a-fluoroenolate equivalents and aliphatic aldehydes to
generate a-fluoro-b-hydroxy compounds, which could then be
manipulated by stereospecific fluorination of the product
alcohol to give vicinal difluoro compounds. Although there has
been some discussion on the nature and utility of a-
These reactions generated predominant syn aldol products
2a as major isomer when boron, titanium or tinII were employed
as Lewis acids, and anti aldol products 2b as major isomers in
the cases of tinIV and zinc (Scheme 1). In this paper, we report
our results on aldol reactions using (aR)- and (aS)-N-(a-
fluoropropyl)-2-(4S)-oxazolidinones 3 (Scheme 2). Unlike
aldol products such as 2, the aldol products 4 and 5 from
reaction of 3 are protected from epimerisation or elimination
due to the presence of the a-methyl group. In the subsequent
manipulations of these more stable products, this presents a
significant advantage. In this study, aldol reactions of the
diastereoisomers 3a and 3b were explored with hexanal and
benzaldehyde and these results are reported. This required a
suitable preparation of each of the diastereoisomers of 3
(Scheme 3).
* Corresponding author. Tel.: +44 1334 467176; fax: +44 1334 463808.
E-mail address: do1@st-and.ac.uk (D. O’Hagan).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.05.012

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Scheme 1.
revealed a diastereoisomeric ratio of 89:11. This ratio could be
improved to 95:5 after chromatography over silica gel.
The (S,R) diastereoisomer 3b was prepared by mesylation of
ethyl (S)-lactate 8 (Scheme 4). The mesylate 9 was treated with
potassium fluoride to generate a-fluoro ester 10 [6]. Direct
treatment of 10 with phthaloyl chloride and chlorosulfonic acid
gave the acid chloride as an intermediate [7], and the reaction
with oxazolidinone 6 gave 3b-(S,R) with a diastereoisomeric
ratio of 97:3 and in moderate yield (59%).
Scheme 2.
Aldol reactions with each of the diastereoisomers were then
carried out [8] (Scheme 5). Thus treatment of 3a-(S,S) with
TiCl4 (2 equivalents), DIEA (1 eq.) and hexanal (5 eq.) at
À78 8C generated 4a in 74% yield and as a predominant
diastereoistereoisomer (d.r. 97/3 by 19F NMR). A correspond-
ing reaction with benzaldehyde (2 eq.) generated aldol product
5 in 67% yield (d.r. 97.5/2.5 by 19F NMR).
Scheme 3. Reagents and conditions: (i) propionyl chloride, LDA, THF,
À78 8C, 80% (ii) LDA, NFSI, THF, À78 8C, 56%.
X-ray structure analysis of a suitable crystal of the major
aldol product 4a (Fig. 1) revealed that the absolute and relative
configuration of 4a as shown in Scheme 5 with an anti
relationship between the fluorine and the hydroxyl group [9]. It
is notable also that in the solid state the C–F bond and the amide
carbonyl are anti to each other, a stereoelectronic preference
found more generally in a-fluoroamides [10].
When the reaction was investigated with 3b-(S,R) the same
aldol diastereoisomer was observed as the major product (as
determined by 19F NMR). It is clear that the nature of the
starting diastereoisomer of 3a-(S,S) or 3b-(S,R) has no
influence on the stereochemical outcome of the aldol product,
2. Results and discussion
2.1. Oxazolidinone diastereoisomers (S,S)-3a and (S,R)-3b
In order to explore these aldol reactions, several methods
were investigated for the preparation of 3a and 3b. To this end
the (S,S) diastereoisomer 3a was prepared from the reaction of
propionyl chloride and oxazolidinone 6 to generate 7. An
electrophilic fluorination reaction was then explored with N-
fluorobenzene sulfonamide (NFSI) [5]. In the event, 3-(S,S) was
obtained in a moderate yield (56%) and 19F NMR analysis
Scheme 4. Reagents and conditions: (i) MsCl, DMAP, Et3N, THF, reflux, 91% (ii) KF, formamide, 70–90 8C, 87% (iii) phthaloyl chloride, HSO3Cl, 120 8C, 63% (iv)
oxazolidinone 6, BuLi, THF, À50 8C, 59%.
Scheme 5. Reagents and conditions: (i) TiCl4 (2 eq.), DIEA (1 eq.), hexanal (5 eq.) or benzaldehyde (2 eq.), DCM, À78 8C, 74% (4a) and 67% (5).

V.A. Brunet et al. / Journal of Fluorine Chemistry 128 (2007) 1271–1279
1273
around 4% of the overall enolate signal. When proton
decoupling was turned off both signals became quartets in
the 19F NMR spectrum, as expected (Fig. 3b). The 19F NMR
signals of the E- and Z-enolates derived from 3b after TiCl4
treatment at 0 8C are shown in Fig. 3a and b. Treatment of 3a
under the same conditions gave similar spectra with a similar E/
Z ratio.
Generation of the E-enolate is also consistent with the
stereochemical outcome as deduced by Zimmerman/Traxler
intermediates as illustrated in Scheme 7. Crimmins et al. [8],
have proposed that the second equivalent of TiCl4 abstracts ClÀ
from the complexed titanium allowing coordination of the
oxazolidinone carbonyl to Ti to generate a highly ordered
bicyclic enolate intermediate (Scheme 8).
Our attempts to prepare diastereoisomer 4b in a stereo-
selective manner were only partially successful. When only 1
equivalent of each of TiCl4 and DIEA was added, the reaction
proceeded with a poor conversion and only a low stereo-
selectivity was observed. When DIEA was replaced by (À)-
sparteine (1 eq. at 0 8C) a diastereoisomer ratio (80:20) in
favour of the assumed isomer 4b was observed. Although we
could reproduce the expected stereochemical tendancy, this did
not result in a satisfactory preparative method for the
fluorinated aldol product 4b.
Fig. 1. X-ray structure of 4a.
suggesting that the reactions proceed through a common
thermodynamically favoured enolate (Scheme 6).
Each of the two diastereoisomers of 3a and 3b were
separately treated with TiCl4 at À78 8C in deuteriated
dichloromethane (C2H2Cl2) and enolate formation was
monitored by 19F NMR. Only one enolate was apparent at
À150.1 ppm in 19F{1H} NMR (Fig. 2). The observation of a
common, enolate resulting from each of the diastereoisomers of
3 is consistent with the experimental outcome, where each
diastereoisomer gives the same product.
2.2. Strategies for vicinal difluoro preparation
The overall objective of this study was to develop a novel
stereoselective method for the introduction of the vicinal
difluoromotif into organic molecules. Having developed a
satisfactory stereoselective route to the anti-a-fluoro-b-
hydroxy products 4a and 5, we then investigated different
strategies for the introduction of the second fluorine substituent.
Direct deoxofluorination reactions of 4a were explored with
DeoxofluorTM however these were unsuccessful giving rise to
only uncharacterised products.
We assume that the E-enolate is the favoured enolate in
solution. The Z-enolate would necessarily result in a steric clash
of the methyl group of the propionimide moiety with the
isopropyl group of the auxiliary. Also the orientation of the C–F
bond anti to the enolate/amide C–O bond is anticipated to be
stereoelectronically favoured as it will result in a dipolar
relaxation.
The 19F{1H} NMR spectrum recorded at À78 8C in C2H2Cl2
showed only one enolate (Fig. 2) but when the solution was
warmed up to 0 8C a second signal appeared at À148.6 ppm
(Fig. 3a). This was assumed to be the Z-enolate, representing
An alternative strategy envisaged removal of the a-fluoro-
b-hydroxyacyl group from the auxiliary. This was achieved in
two ways. Firstly, reaction of lithium phenylmethanolate with
4a generated the benzyl ester 11 in 79% yield [11]. Separate
Scheme 6. Reagents and conditions: (i) TiCl4 (1 eq.), DIEA (1 eq.), C2H2Cl2, À78 8C (ii) TiCl4 (1 eq.) hexanal.

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V.A. Brunet et al. / Journal of Fluorine Chemistry 128 (2007) 1271–1279
Fig. 2. Comparison of the 19F{1H} NMR spectra of the enolates generated from 3a and 3b after treatment with TiCl4 (1 eq.) and DIEA in C2H2Cl2, À78 8C.
Fig. 3. (a) 19F{1H} NMR and (b) 19F NMR spectra of the E/Z enolate solution after treatment of 3b with TiCl4 and DIEA in DCM at 0 8C.

V.A. Brunet et al. / Journal of Fluorine Chemistry 128 (2007) 1271–1279
1275
Scheme 7. Zimmerman/Traxler intermediates showing the different intermediates after one and two equivalents of TiCl4, giving different stereochemical outcomes.
Scheme 8. Reagents and conditions: (i) benzyl alcohol, BuLi, THF, 0 8C, 79% (ii) NaBH4, THF, MeOH, 0 8C, 66% (iii) TsCl, collidine, 1,2-dichloroethane, 60 8C,
57%.
treatment with NaBH4, generated diol 12 in 66% yield. This
diol was selectively protected as its monotosyl derivative 13.
Our recent experience [12] has demonstrated that tosyl
groups are compatible with DeoxofluorTM deoxofluorination
reactions and in the event this proved a robust protecting
group.
Reaction of 11 with DeoxofluorTM in DCM resulted in
complete conversion to a mixture of 14 and olefin 15, but with
poor selectivity (35:65) in favour of 15 (Table 1, Entry 1).
Products 14 and 15 were purified in moderate yields, of 23%
and 40%, respectively. The selectivity was improved (72:28)
when the reaction was carried out at À30 8C also in favour of 14
(by 19F NMR), but now with a lower conversion (55%) (Table 1,
Entry 2).
When 13 was treated with DeoxofluorTM only the
elimination product 17 was generated (Entry 3), and when
the reaction was carried out at À30 8C no products formed at
this lower temperature (Entry 5). The vicinal difluoro product
Table 1
Entry
R
Temperature
Conversion
Selectivity
1
2
3
4
5
BnO(CO)
BnO(CO)
TsOCH2
TsOCH2
TsOCH2
Reflux
À30 8C
Reflux
r.t.
100%
14/15 = 35/65
14/15 = 72/28
16/17 = 0/100
16/17 = 11/85
55%
100%
96%
À30 8C
No reaction

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V.A. Brunet et al. / Journal of Fluorine Chemistry 128 (2007) 1271–1279
16 was generated after treatment with DeoxofluorTM at room
temperature but with a poor selectivity (85:11) in favour of 17
(Entry 4). Our attempts to purify 16 were unsuccessful due to
the small scale and poor selectivity of the reaction.
4.1.2. Preparation of the (S)-3-((S)-2-fluoropropanoyl)-4-
isopropyloxazolidin-2-one 3a
LDA (2 M in THF/n-heptane, 5.6 mL, 11.2 mmol) was
added to a solution of 7 (1.72 g, 9.29 mmol) in dry THF
(30 mL) at À78 8C. After 1.5 h N-fluorobenzene sulfonimide
97% (4.51 g, 13.93 mmol) was added and the solution was
stirred for 2 h at À78 8C. The reaction was then quenched with
a saturated solution of NH4Cl. The product was extracted into
Et2O, washed and dried over MgSO4. Solvents were removed
under reduced pressure. The product was purified over silica
(hexane/EtOAc from 90/10 to 70/30), and recovered as a brown
oil (1.05 g, 56%) with a diastereoisomeric ratio of 90:10. This
selectivity was improved to 95/5 after a second purification
over silica (hexane/EtOAc 95/5).
3. Conclusion
This study has explored enolate formation from the
diastereoisomers of 3a and 3b, and has demonstrated that
the common thermodynamic enolate results after treatment
with TiCl4. This was shown by 19F{1H} NMR analysis of the
intermediate titanium enolates and was also manifest in the
product outcome where the same a-fluoro-b-hydroxyl products
4a and 5 were generated with high diastereoselectivity from
each of 3a or 3b. Subsequent manipulation of 4a to generate
vicinal difluoroproducts such as 14 and 16 were only
moderately successful.
HRMS (CI) calculated for C9H15NO3F = 204.1036
found = 204.1029. nmax/cmÀ1 2962, 1777, 1713, 1388, 1201,
1133, 1044. 1H NMR (CDCl3, 300 MHz): d (ppm) = 6.01 (qd, 1
3
2
H, JH–H = 6.5 Hz, JF–H = 49.0 Hz, FCH); 4.42 (m, 1 H, N–
3
2
4. Experimental
CH); 4.34 (dd, 1 H, JH–H = 7.9 Hz, JH–H = 8.9 Hz, HCH);
4.27 (dd, 1 H, 3JH–H = 3.1 Hz, 2JH–H = 8.9 Hz, HCH); 2.47 (m,
3
3
1 H, (CH3)2CH); 1.58 (dd, 3 H, JH–H = 6.5 Hz, JF–
4.1. General
3
H = 23.9 Hz, FHC–CH3); 0.93 (d, 3 H, JH–H = 7.0 Hz, CH3);
All moisture sensitive reactions were carried out under a
positive pressure of nitrogen. Solvents were dried prior to use.
High-resolution mass spectrometry was performed on a Waters
LCT or GCT time-of-flight mass spectrometer.
0.88 (d, 3H, 3JH–H = 6.9 Hz, CH3). 13C NMR (CDCl3, 75 Mz): d
2
(ppm) = 170.7 (d, JF–C = 22.8 Hz, OC–CHF); 153.9, (CO);
1
86.2 (d, JF–C = 176.5 Hz, CHF); 64.5 (CH2); 59.0 (N–CH);
2
28.4 ((CH3)2CH); 18.6 (d, JF–C = 23.3 Hz, FHC–CH3); 18.3
NMR spectra were recorded on either Bruker AV-300 (1H at
300.06 MHz, 13C at 75.45 MHz, 19F at 282.34 MHz), or Bruker
AV-500 (1H at 499.90 MHz, 19F at 470.33 MHz). Chemical
shifts d are reported in parts per million (ppm) and quoted
(CH3); 14.8 (CH3). 19F NMR (CDCl3, 282 MHz):
d
(ppm) = À184.5 (qd, 3JF–H = 23.9 Hz, 2JF–H = 49.0 Hz).
19F{1H} NMR (CDCl3, 282 MHz): d (ppm) = À184.5. MS
(CI+) m/z (rel. int.): [MH+] 204 (100), 184 (100).
1
relative to internal standards (Me4Si, CFCl3). H, 13C and 19F
spectroscopic data were assigned by a combination of one- and
two-dimensional experiments (COSY, HSCQ, HMBC,
NOESY).
4.1.3. Preparation of the ethyl (S)-2-(methylsulfonyloxy)-
propanoate 9
(S)-(À)-Ethyl lactate 8 98% (10 mL, 85.78 mmol) was
added to a solution of triethylamine (15 mL, 107.62 mmol),
DMAP (0.2 g, 1.64 mmol) in dry THF (50 mL) at room
temperature. The solution was cooled to À20 8C and methyl
sulfonyl chloride (8 mL, 103.36 mmol) was added. The
reaction was then warmed to 60 8C and stirred for 6 h. The
solution was filtered through celite, washed with Et2O and
solvents were removed under reduced pressure. The product
was recovered as a brown oil (15.4 g, 91%) and used without
further purification.
4.1.1. Preparation of the (S)-4-isopropyl-3-
propionyloxazolidin-2-one 7
LDA (2 M in THF/n-heptane, 4.18 mL, 8.36 mmol) was
added to a solution of 4-(S)-4-isopropyl-2-oxazolidinone 6
98% (1 g, 7.59 mmol) in dry THF (15 mL) at À78 8C.
Propionyl chloride 97% (0.82 mL, 9.11 mmol) was added
after 35 min, and the solution was stirred for 1 h at À78 8C.
The reaction was then quenched with a saturated solution of
NH4Cl. The product was extracted into Et2O, washed, and
dried over MgSO4. Solvents were removed under reduced
pressure. The product 7 was purified over silica (cyclohexane/
EtOAc, 80/20) and recovered as a colourless oil (1.12 g,
80%).
[a]D = À44.48 (C = 1.05, DCM). 1H–NMR (CDCl3,
3
300 MHz): d (ppm) = 5.07 (q, 1 H, JH–H = 7.0 Hz); 4.21 (q,
3
2 H, JH–H = 7.1 Hz); 3.11 (s, 3 H); 1.57 (d, 3H, JH–
3
3
H = 7.0 Hz); 1.27 (t, 3 H, JH–H = 7.1 Hz). 13C–NMR (CDCl3,
75 Mz): d (ppm) = 169.81 (CO); 74.72 (SO2CH3); 62.46 (CH2);
39.49 (OCH); 18.75 (CH3); 14.44 (CH3). [14].
1H NMR (CDCl3, 300 MHz): d (ppm) = 4.39 (m, 1 H, N–
2
CH); 4.23 (dd, 1H, JH–H = 9.0 Hz, JH–H = 8.1 Hz, O–CHH);
3
2
3
4.16 (dd, 1 H, JH–H = 9.0 Hz JH–H = 3.2 Hz, O–CHH); 2.89
(m, 2 H, CH3–CH2); 2.33 (m, 1 H, (CH3)2CH); 1.12 (t, 3 H, 3JH–
H = 7.3 Hz, CH2–CH3); 0.87 (d, 3H, 3JH–H = 7.1 Hz, CH3); 0.83
4.1.4. Preparation of the ethyl 2-(R)-fluoropropanoate 10
(S)-Ethyl 2-(methylsulfonyloxy)-propanoate
9
(15 g,
76.44 mmol) was added to a solution of potassium fluoride
(17.7 g, 305 mmol) in formamide (60 mL). The solution was
heated at 90 8C for 4 h and then the product was distilled from
the reaction mixture under reduced pressure. The title
compound 10 was recovered as a colourless oil (8.1 g, 87%).
3
(d, 3 H, JH–H = 6.9 Hz, CH3). 13C NMR (CDCl3, 75 Mz): d
(ppm) = 174.4 (CO); 154.5 (CO); 63.8 (OC–CH2); 58.8 (N–
CH); 29.5 (O–CH2); 28.7 (CH3)2CH); 18.3 (CH2–CH3); 15.0
(CH3); 8.8 (CH3). [13]

V.A. Brunet et al. / Journal of Fluorine Chemistry 128 (2007) 1271–1279
1277
[a]D = + 3.9 8 (C = 1.045, DCM). 1H–NMR (CDCl3,
300 MHz): d (ppm) = 4.97 (qd, 1 H, JH–H = 6.9 Hz, JF–
dried over MgSO4. Solvents were removed under reduced
pressure and the product was purified over silica (hexane/ethyl
acetate, 80/20). The title compound 4a was recovered as a white
solid (0.332 g, 74%).
3
2
H = 48.7 Hz); 4.23 (q, 2 H, 3JH–H = 7.1 Hz); 1.55 (dd, 3H, 3JH–
H = 6.9 Hz, 3JF–H = 23.6 Hz); 1.28 (t, 3 H, 3JH–H = 7.1 Hz). 13
C
NMR (CDCl3, 100 MHz): d (ppm) = 170.4 (d, 2JC–F = 23.4 Hz,
CO); 85.6 (d, 1JC–F = 181.4 Hz, CF); 61.5 (CH2); 22.5 (d, 2JC–
F = 18.3 Hz, CH3); 14.11 (CH3). 19F NMR (CDCl3, 282 MHz):
HRMS (CI) calc for C15H27NO4F = 304.1924, found =
304.1929. mp = 122 8C. [a]D = +458 (C = 0.82, DCM). nmax
/
cmÀ1 3329, 2953, 1803, 1692, 1365, 1208, 1150, 1125. 1H NMR
(CDCl3, 300 MHz): d (ppm) = 4.46 (m, 1 H, N–CH); 4.32 (dd, 1
H, 2JH–H = 9.0 Hz 3JH–H = 8.0 Hz, O–CHH); 4.23 (dd, 1 H, 3JH–
H = 3.6 Hz, 2JH–H = 9.0 Hz, O–CHH); 4.1 (m, 1 H, HOCH); 3.26
(1H, 3JH–H = 5.3 Hz, HOCH); 2.38(m, 1 H, (CH3)2CH);1.7(d, 3
H, 3JF–H = 22.2 Hz, FC–CH3);1.47–1.29(m, 8 H, 4Â CH2);0.90
(m, 9 H, 3Â CH3). 13C NMR (CDCl3, 75 Mz): d (ppm) = 172.8
3
2
d (ppm) = À185.05 (dq, JF–H = 23.6 Hz, JF–H = 48.7 Hz).
[14].
4.1.5. Preparation of (S)-3-((R)-2-fluoropropanoyl)-4-
isopropyloxazolidin-2-one 3b
4.1.5.1. Preparation of (R)-2-fluoropropanoyl chloride.
Chlorosulfonic acid (3.3 mL, 50 mmol) was added to a solution
of phthaloyl dichloride (7.2 mL, 50 mmol) and ethyl-2-(R)-
fluoropropanoate 10 (3 g, 25 mmol) at room temperature. The
solution was heated at 120 8C for 4 h. 2-(R)-Fluoropropanoyl
chloride was distilled from the reaction mixture under reduced
pressure and recovered as a colour less oil (1.73 g, 63%).
1H NMR (CDCl3, 300 MHz): d (ppm) = 5.15 (dq, 1 H, 3JH–
2
1
(d, JC–F = 27.9 Hz, OC–CF); 153.0 (CO); 101.7 (d, JC–
F = 190.2 Hz, CF); 75.2 (d, 2JC–F = 23.5 Hz, HOCH); 64.1 (O–
CH2); 60.8 (N–CH); 32.0 (CH2); 31.5 (d, 3JC– = 4.5 Hz, CH2);
28.7 (CH3)2CH); 26.0 (CH2); 22.9 (CH2); 19.6 (d,
2JC,F = 23.6 Hz, FC–CH3); 18.4 (CH3); 15.1 (CH3); 14.4
(CH3). 19F NMR (CDCl3, 282 MHz): d (ppm) = À158.3 (qd,
3JH–F = 22.2 and 15.5 Hz). 19F{1H} NMR (CDCl3, 282 MHz): d
(ppm) = À158.3.
2
3
H = 6.9 Hz, JF–H = 48.6 Hz); 1.71 (dd, 3 H, JH–H = 6.9 Hz,
3JF–H = 22.8 Hz). 19F NMR (CDCl3, 282 MHz): d (ppm) =
3
2
À171.4 (dq, JF–H = 22.8 Hz, JF–H = 48.6 Hz).
4.1.7. Preparation of the aldol product 5
TiCl4 (1 M in DCM, 0.5 mL, 0.5 mmol) was added to a
solution of 3a (0.1 g, 0.45 mmol) in dry DCM (2 mL) at À78 8C.
After 5 min, diisopropylethylamine 99.5% (105 mL, 0.59 mmol)
wasaddedandthesolutionwasstirredfor2 hatÀ78 8C, andthen
TiCl4 (1 M in DCM, 0.5 mL, 0.5 mmol) was added. After 5 min,
benzaldehyde 99.5% (90 mL, 0.9 mmol) was added and the
solution was stirred for 4 h at À78 8C. Then the reaction was
quenched with a saturated solution of NH4Cl. The products were
extracted into Et2O, washed and dried over MgSO4. Solvents
were removed under reduced pressure and the product was
purified over silica (hexane/ethyl acetate, 70/30). The aldol
product 5 was recovered as a white solid (0.093 g, 67%).
HRMS (ES) calculated for C16H20NO4FNa = 332.1274,
found = 332.1280. mp = 102–104 8C. [a]D = +43.58 (C = 1,
DCM). nmax/cmÀ1 3490, 2965, 1787, 1701, 1454, 1387,
1366, 1305, 1201, 1112, 1054, 704. NMR (CDCl3, 300 MHz): d
(ppm) = 7.38 (m, 2 H, Ar); 7.30 (m, 3 H, Ar); 5.35 (d, 1 H, 3JF–
H = 15.9 Hz, HC–OH); 4.29 (m, 1 H, N–CH); 4.17 (m, 2 H, O–
CH2); 3.70 (br s, 1 H, OH); 2.16 (m, 1 H, (CH3)2CH); 1.67 (d,
4.1.5.2. Preparation of (S)-3-((R)-2-fluoropropanoyl)-4-iso-
propyloxazolidin-2-one 3b. n-Butyl lithium (2.5 M in hexane,
7.5 mL, 18.7 mmol) was added to a solution of 4-(S)-4-
isopropyl-2-oxazolidinone 6 (2.2 g, 1.7 mmol) in dry THF
(20 mL) at À50 8C. After 30 min (R)-2-fuoropropanoyl
chloride (1.7 mL, 1.5 mmol) was added, and the solution
was stirred for 4 h at À50 8C. The reaction was then quenched
with a saturated solution of NH4Cl. The organic compounds
were extracted into Et2O, washed and dried over MgSO4.
Solvents were removed under reduced pressure. The product 3b
was purified over silica (hexane/EtOAc, 80/20), and recovered
as a brown oil (1.85 g, 59%) with a diastereoisomeric ratio of
97:3 (in 19F NMR).
3
1H NMR (CDCl3, 300 MHz): d (ppm) = 6.0 (qd, 1 H, JH–
2
H = 6.7 Hz, JF–H = 49.5 Hz, FCH); 4.5 (m, 1 H, N–CH); 4.4
3
(dd, 1H, JH–H = 8.4 Hz, JH–H = 9.2 Hz, HCH); 4.3 (dd, 1 H,
2
2
3JH–H = 3.2 Hz, JH–H = 9.2 Hz, HCH); 2.35 (m,
1 H,
(CH3)2CH); 1.64 (dd, 3 H, JH–H = 6.7 Hz, JF–H = 23.6 Hz,
3
3
3
FHC–CH3); 0.92 (d, 3 H, JH–H = 7.0 Hz, CH3); 0.87 (d, 3 H,
3
3
3H, JF–H = 22.3 Hz, FC–CH3); 0.85 (d, 3 H, JH–H = 7.0 Hz,
(CH3)2CH); 0.75 (d, 3 H, JH–H = 6.9 Hz, (CH3)2CH). 13C
3
3JH–H = 6.9 Hz, CH3). 19F NMR (CDCl3, 282 MHz): d
3
2
2
NMR (CDCl3, 75 Mz): d (ppm) = 171.5 (d, JC–F = 27.5 Hz,
(ppm) = À186.2 (qd, JF–H = 23.6 Hz, JF–H = 49.5 Hz). MS
(CI+) m/z (rel. int.): [MH+] 204 (100), 184 (100).
OC–CF); 152.7 (CO); 138.1 (Ar); 128.5 (Ar); 128.2 (Ar); 127.8
(Ar); 99.4 (d, 1JC–F = 194.0 Hz, CF); 76.3 (d, 2JC–F = 23.1 Hz,
HOCH); 63.7 (O–CH2); 60.3 (N–CH); 28.4 (CH3)2CH); 19.6
4.1.6. Preparation of the aldol product 4a:
2
TiCl4 (1 M in DCM, 1.5 mL, 1.5 mmol) was added to a
solution of 3a (0.3 g, 1.48 mmol) in dry DCM (5 mL) at
À78 8C. After 5 min, diisopropylethyl amine 99.5% (310 mL,
1.77 mmol) was added and the solution was stirred for 2 h at
À78 8C. Then TiCl4 (1 M in DCM, 3 mL, 3 mmol) was added,
and then after 5 min hexanal 96% (0.9 mL, 7.5 mmol) was
added. The solution was stirred for 4 h at À78 8C and the
reaction was then quenched with a saturated solution of NH4Cl.
The organic products were extracted into Et2O, washed and
(d, JC,F = 23.3 Hz, FC–CH3); 17.9 (CH3); 14.5 (CH3). 19F
3
NMR (CDCl3, 282 MHz): d (ppm) = À159.2 (dq, JH–
F = 22.3 Hz and 15.9 Hz). 19F{1H} NMR (CDCl3, 282
MHz): d (ppm) = À159.2.
4.1.8. Preparation of (2S,3S)-benzyl 2-fluoro-3-hydroxy-2-
methyloctanoate 11
n-Butyl lithium (0.2 mL, 0.49 mmol) was added to benzyl
alcohol (70 mL, 0.66 mmol) in THF (2 mL) at 0 8C. After

1278
V.A. Brunet et al. / Journal of Fluorine Chemistry 128 (2007) 1271–1279
30 min, a solution of 4a (0.1 g, 0.33 mmol) in THF (2 mL)
(previously cooled down to 0 8C) was added and the solution
stirred at 0 8C for 2 h. The reaction was then quenched
with a saturated solution of NH4Cl. Organic residues were
extracted into Et2O and the organic layer was washed and
dried over MgSO4. Solvents were removed under reduced
pressure. The title compound 11 was purified over silica
(hexane/EtOAc, 80/20), and recovered as a white solid
(73 mg, 79%).
4.1.11. Elimination product 15
HRMS (ES) calculated for C16H21O2FNa = 287.1423,
found = 287.1426. [a]D = À15.7 8 (C = 1.1, CDCl3); nmax
/
cmÀ1 2958, 2930, 2873, 1761, 1740, 1456, 1378, 1269,
1
1118, 971, 696. H NMR (CDCl3, 300 MHz): d (ppm) = 7.35
3
3
(m, 5 H, Ar); 5.8 (ddt, 1 H, JH–H = 6.9 Hz, JH–H = 15.7 Hz
4
4JF–H = 1.7 Hz, FC–CH = CH); 5.6 (ddt, 1 H, JH–H = 1.4 Hz,
3
3JH–H = 15.7 Hz JF–H = 15.9 Hz, FC–CH = CH); 5.2 (s, 2 H,
3
PhCH2); 2.0 (m, 2 H, CH = CH–CH2); 1.6 (d, 3 H, JF–
3
HRMS (ES) calculated for C16H23O3FNa = 305.1529,
found = 305.1534. mp = 36–38 8C. [a]D = À25.4 8 (C = 1.1,
DCM); nmax/cmÀ1 3443, 2954, 2859, 1739, 1456, 1283, 1114,
H = 21.4 Hz, FCCH3); 1.3 (m, 4 H, CH2 Â2); 0.9 (t, 3 H, JH–
H = 7.1 Hz, CH3). 13C–NMR (CDCl3, 75 Mz): d (ppm) = 171.0
(d, 2JC–F = 27.1 Hz, CO); 135.3 (C ar); 133.4 (d, 3JC–F = 9.8 Hz
(FC–C = C); 128.6 (C ar); 128.4 (C ar); 128.1 (C ar); 127.1 (d,
1082, 956, 751, 6971H NMR (CDCl3, 300 MHz):
d
(ppm) = 7.36 (br s, 5 H); 5.23 (AB system, 2 H, PhCH2);
1
2JC–F = 21.1 Hz, (FC–C = C); 92.3 (d, JC–F = 183.9 Hz, CF);
3
H, JH–H = 2.3 Hz, JH–H = 10.0 Hz JF–
3
3
3.77 (ddd,
1
67.1 (phCH2); 31.8 (CH2); 30.8 (CH2); 26.0 (CH2); 23.9 (d,
2JC–F = 25.4 Hz, CH3CF); 22.1 (CH2); 13.9 (CH3). 19F NMR
H = 17.8 Hz, HOCH); 2.05 (br s, 1 H, OH), 1.60 (d, 3 H,
3JF–H = 22.1 Hz, FCCH3); 1.53–1.12 (br m, 8 H, 4Â CH2); 0.87
3
(CDCl3, 282MHz): d (ppm) = À150.6 (dq, JF–H = 15.9 Hz,
3
(t, 3 H, JH–H = 6.8 Hz, CH3). 13C NMR (CDCl3, 75 Mz): d
3JF–H = 21.4 Hz).
(ppm) = 171.2 (d, 2JC–F = 25.0 Hz, CO); 144.4 (C ar); 129.1 (C
ar); 129.0 (C ar); 128.8 (C ar); 97.3 (d, 1JC–F = 187.3 Hz, CF);
4.1.12. Preparation of (2R,3S)-2-fluoro-2-methyloctane-
1,3-diol 12
2
75.0 (d, JC–F = 22.7 Hz, COH); 67.7 (phCH2); 31.9 (CH2);
3
31.5 (d, JC–F = 3.4 Hz, CH2); 26.0 (CH2); 22.9 (CH2); 20.2
NaBH4 (70 mg, 1.84 mmol) was added portion wise to a
solution of 11 (138 mg, 0.455 mmol) in a mix of THF (4 mL)
and methanol (0.5 mL) at 0 8C. The solution was stirred for
2.5 h at that temperature and then HCl 2N was added till pH 3–
4. Water was added and the organic product was extracted into
EtOAc. Organic layers were dried over MgSO4 and the solvent
was removed under reduced pressure. The title compound 12
was purified over silica (cyclohexane/EtOAc, 60/40) and
recovered as a white solid (53 mg, 66%).
(2JC–F = 23.9 Hz, CH3CF); 14.4 (CH3). 19F NMR (CDCl3,
3
3
282 MHz): d (ppm) = À167.4 (dq, JF–H = 17.8 Hz, JF–
H = 22.1 Hz).
4.1.9. Preparation of vicinal difluoro compound 14
DeoxofluorTM (50% in THF, 200 mL, 0.53 mmol) was
added to 11 (30 mg, 0.11 mmol) in DCM (2 mL) at room
temperature. The solution was then heated under reflux for
2 h and then the reaction mixture was cooled to room
temperature and quenched by passing through a pad of silica.
19F NMR analysis indicated complete conversion of the
starting material to products 14 and 15 with a ratio 35/65.
These two products were purified over silica (hexane/ethyl
acetate, 95/5) and recovered as colour less oils (14, 7 mg,
23%) (15, 11 mg, 40%).
HRMS (ES) calc for C9H19O2FNa = 201.1267 found =
201.1276. [a]D = À28 8 (C = 0.98, DCM). nmax/cmÀ1 3320,
2923, 2853, 1463, 1378, 1057. mp = 58–59 8C. 1H NMR
(CDCl3, 300 MHz): d (ppm) = 3.83 (dd, 1 H,, 3JH–H = 12.4 Hz
3JF–H = 25.1 Hz, HaHb); 3.79 (m, 1 H, HCOH); 3.65 (dd, 1 H,,
3JH–H = 12.4 Hz 3JF–H = 17.5 Hz, HaHb); 2.96 (br s, 2 H, OH);
3
1.61–1.23 (m, 8 H, 4Â CH2); 1.24 (d, 3H, JF–H = 22.4 Hz,
3
CH3); 0.89 (t, 3H, JH–H = 6.6 Hz, CH3). 13C NMR (CDCl3,
4.1.10. Difluoro compound 14
75 Mz): d (ppm) = 97.6 (d, 1JC–F = 170.1 Hz, CF); 74.0 (d, 2JC–
2
F = 26.3 Hz, HCOH); 66.1 (d, JC–F = 23.6 Hz, H2COH); 31.7
HRMS (ES) calculated for C16H22O2F2Na = 307.1486,
found = 307.1479. [a]D = +5.08 (C = 0.7, CDCl3). nmax/cmÀ1
2958, 1768, 1652, 1456, 1381, 1282, 1136, 1104. H NMR
(CH2); 30.8 (d, 3JC–F = 2.8 Hz, CH2); 26.0 (CH2); 22.5 (CH2);
17.4 (d, 2JC–F = 23.2 Hz, CH3); 14.0 (CH3). 19F NMR (CDCl3,
1
3
(CDCl3, 300 MHz): d (ppm) = 7.4–7.3 (m, 5 H, Ar); 5.2 (2Â d,
2 H, 2JH–H = 12.2 Hz, PhCH2); 4.6 (dddd, 1 H, 3JH–H = 1.9 Hz,
3JH–H = 10.0 Hz 3JF–H = 19.8 Hz, 2JF–H = 46.5 Hz, FC–CFH);
1.7–1.8 (m, 1 H, FC–CHH); 1.6–1.5 (m, 1 H, FC–CHH); 1.5
(dd, 3 H, 3JF–H = 21.2 Hz, 4JF–H = 1.2 Hz, CH3–CF–CF); 1.4–
282 MHz): d (ppm) = À162.1 (dddq, JF–H = 25.1, 22.4, 17.5
and 7.7 Hz).
4.1.13. Preparation of (2R,3S)-2-fluoro-3-hydroxy-2-
methyloctyl 4-methylbenzenesulfonate 13
3
1.2 (m, 6 H, 3CH2); 7.0 (t, 3 H, JH–H = 7.0 Hz). 13C NMR
Tosyl chloride 98% (65 mg, 0.33 mmol) was added to a
solution of 12 (49 mg, 0.275 mmol) and 2,4,6-trimethyl
pyridine (73 mL, 0.55 mmol) in dichloroethane (3 mL). The
solution was heated at 60 8C for 3 days and then EtOAc was
added and the reaction mixture was washed with a saturated
solution of CuSO4 and thus water. The organic layers were
dried over MgSO4 and solvents were removed under reduced
pressure. The product 13 was purified over silica (cyclohex-
ane/EtOAc, 80/20) and recovered as a colour less oil (52 mg,
57%).
(CDCl3, 75 Mz): d (ppm) = 128.6 (Ar); 128.5 (Ar); 128.2 (Ar);
1
94.7 (dd, JC–F = 179.5 Hz, JC–F = 23.4 Hz, HCF); 67.5
2
2
3
(PhCH2); 31.4 (CH2); 28.2 (dd, JC–F = 21.5 Hz, JC–
2
F = 3.5 Hz, FCCH2); 24.8 (CH2); 22.4 (CH2); 19.5 (dd, JC–
3
F = 24.0 Hz, JC–F = 5.1 Hz, FCCH3); 14.0 (CH3). 19F NMR
(CDCl3, 282 MHz): d (ppm) = À170.2 (m, 1 F); À191.2 (m, 1
F). 19F{1H} NMR (CDCl3, 282 MHz): d (ppm) = À170.2 (d,
3
3JF–F = 11.1 Hz, CH3–CF); À191.2 (d, JF–F = 11.1 Hz,
HCF).

V.A. Brunet et al. / Journal of Fluorine Chemistry 128 (2007) 1271–1279
1279
(c) F.A. Davis, P.V.N. Kasu, G. Sundarababu, H.J. Qi, Org. Chem. 62
(1997) 7546–7547;
HRMS (CI) calc for C16H26O4SF = 333.1536 found =
333.1528. [a]D = À10.4 8 (C = 0.8, DCM). nmax/cmÀ1 2360,
117, 799, 668. 1H NMR (CDCl3, 300 MHz): d (ppm) = 7.80 (d,
2 H, 3JH–H = 8.3 Hz, H ar); 7.35 (d, 2 H, 3JH–H = 8.3 Hz, H ar);
(d) S.L. Less, S. Handa, K. Millburn, P.F. Leadlay, C.J. Dutton, J.
Staunton, Tetrahedron Lett. 37 (1996) 3515–3518.
[6] E.F. Langhals, G. Schutz, Tetrahedron Lett. 34 (1993) 293–296.
[7] (a) M. Wakselman, R. Labia, H. Molines, R. Joyeau, J. Med. Chem. 31
(1988) 370–374;
3
3
4.25 (dd, 1 H, JH–H = 11.1 Hz JF–H = 21.0 Hz, HaHb); 4.03
3
3
(dd, 1 H, JH–H = 11.1 Hz JF–H = 20.4 Hz, HaHb); 3.78–3.70
3
(m, 1 H, HOCH); 2.45 (s, 3 H, CH3 ar); 2.18 (d, 1 H, JH–
(b) W.J. Middleton, J. Org. Chem. 13 (1979) 2291–2292.
[8] M.T. Crimmins, B.W. King, E.A. Tabet, J. Am. Chem. Soc. 119 (1997)
7883–7884.
H = 5.04 Hz, OH); 1.56–1.23 (m, 8 H, 4Â CH2); 1.27 (d, 3 H,
3JF–H = 22.0 Hz, CH3); 0.88 (t, 3 H, 3JH–H = 6.7 Hz, CH3). 13
C
[9] Crystal structure data for 4a: X-ray diffraction studies on a colourless crystal
were performed at 93 K using a Rigaku MM007 high brilliance generator,
NMR (CDCl3, 75 Mz): d (ppm) = 145.6 (C ar); 132.9 (C ar);
130.3 (C ar); 128.4 (C ar); 96.5 (d, 1JC–F = 175.8 Hz, CF); 73.0
˚
confocal optics with Mo–Ka radiation (l = 0.71073 A) and a Mercury
CCD. The structure was solved by direct methods. C15H26FNO4,
2
2
(d, JC–F = 26.3 Hz, HOCHCF); 71.6 (d, JC–F = 24.1 Hz,
M = 303.37, crystallization from hexane/diethyl ether, monoclinic, space
˚
3
CH2CF); 32.1 (CH2); 30.7 (d, JC–F = 2.2 Hz, CH2); 26.4
group P2(1), a = 12.609(3), b = 5.1419(12), c = 13.677(4) A, b =
2
(CH2); 23.0 (CH2); 22.1 (CH3); 17.2 (d, JC–F = 23.2 Hz,
113.707(10)8, U = 811.9(4) A3, Z = 2, Dc = 1.241 mg mÀ3, m =
˚
CH3CF); 14.4 (CH3). 19F NMR (CDCl3, 282 MHz): d
0.096 mmÀ1, F000 = 328, crystal size = 0.28 Â 0.10 Â 0.01 mm3, The
absolute structure could not be determined, Flack parameter = 0.9(9). Of
4763 measured data, 2604 were unique (Rint = 0.0340) to give R1 = 0.0422
and wR2 = 0.0998 for 2406 observed reflections. Crystallographic data
(excluding structure factors) for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplemen-
tary publication nos. CCDC.
3
(ppm) = À160.7 (dddq, JF–H = (21.5 Hz) Â 3 and 7.8 Hz).
References
[1] M. Nicoletti, D. O’Hagan, A.M.Z. Slawin, J. Am. Chem. Soc. 127 (2005)
482–483.
[10] J.W. Banks, A.S. Batsanov, J.A.K. Howard, D. O’Hagan, H.S. Rzepa, S.
Martin-Santamaria, J. Chem. Soc., Perkin Trans. 2 (1999) 2409–2411.
[11] D.A. Evans, M.D. Ennis, D.J. Mathre, J. Am. Chem. Soc. 104 (1982)
1737–1739.
[2] M. Tavasli, M. Petty, C. Pearson, O. O’Hagan, Chem. Commun. (2002)
1226–1227.
[3] M. Schueler, D. O’Hagan, A.M.Z. Slawin, Chem. Commun. (2005) 4324–
4326.
[12] D. O’Hagan, L. Hunter, A.Z. Slawin, J. Am. Chem. Soc. 128 (51) (2006)
16422–16423.
[4] L.N. Pridgen, A.M. Ahmed, I. Lantos, S. Shilcrat, D.S.J. Eggleston, Org.
Chem. 58 (1993) 5107–51117.
[13] E.R. Thornton, M. Nerz-Stormes, J. Org. Chem. 56 (1991) 2489–2498.
[14] S. Colonna, A. Re, G. Gelbard, E. Cesarotti, J. Chem, Soc., Perkin Trans.
1, Org. Bio-Org. Chem. 9 (1979) 2248–2252.
[5] (a) F.A. Davis, W. Han, Tetrahedron Lett. 33 (1992) 1153–1156;
(b) F.A. Davis, P.V.N. Kasu, Tetrahedron Lett. 39 (1998) 6135–6138;