Diastereocontrolled addition of organometallic reagents to S-chiral N-(tert-butanesulfinyl)-α-fluoroenimines

Article abstract of DOI:10.1016/j.tetlet.2008.10.140

Grignard and organolithium reagents efficiently react with (S)-N-(tert-butanesulfinyl)-α-fluoroenimines to provide chiral allylamines in excellent yields and with diastereomeric ratios of up to 96:4. Acidic removal of the sulfinyl group and simple functio

Full text of DOI:10.1016/j.tetlet.2008.10.140

Tetrahedron Letters 50 (2009) 264–266
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereocontrolled addition of organometallic reagents
to S-chiral N-(tert-butanesulfinyl)-a-fluoroenimines
Camille Pierry a, Ludivine Zoute a, Philippe Jubault a, Emmanuel Pfund b, Thierry Lequeux b,
Dominique Cahard a, Samuel Couve-Bonnaire a, Xavier Pannecoucke a,
*
a UMR 6014 CNRS, IRCOF, INSA et Université de Rouen, rue Tesnière, 76130 Mont Saint Aignan, France
b UMR 6507 CNRS, LCMT, ENSICAEN, Université de Caen Basse-Normandie, 6 Bd. Maréchal Juin, 14050 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Grignard and organolithium reagents efficiently react with (S)-N-(tert-butanesulfinyl)-a-fluoroenimines
Received 10 October 2008
Revised 28 October 2008
Accepted 29 October 2008
Available online 3 November 2008
to provide chiral allylamines in excellent yields and with diastereomeric ratios of up to 96:4. Acidic
removal of the sulfinyl group and simple functional group transformations allow to get enantiopure
fluoroolefin dipeptide mimics.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine compounds
Enimines
Diastereoselective synthesis
Grignard
Peptides mimics
Fluorine is certainly the element that has experienced the great-
est interest in the recent years as evidenced by the huge number of
fluorinated synthetic pharmaceuticals, agrochemicals, and materi-
als that had been synthesized.1 In the field of medicinal chemistry,
fluorinated molecules clearly have altered physicochemical prop-
erties when compared to non-fluorinated derivatives, and often
with an improved therapeutic profile.2 Among the very large vari-
ety of fluorine-containing compounds, functionalized fluoroolefins
represents a motif that is an effective amide bond mimic. Indeed,
the fluoroolefin moiety is both isosteric and isoelectronic to the
amide function and its stability to chemical or enzymatic hydro-
lysis is high.3 Relevant biologically active compounds that incor-
porate the fluoroolefin moiety include dipeptidyl peptidase
inhibitors,4 substance P analogues,5 and adenylate cyclase produc-
tion stimulators.6
O
O
NH2
R2
Ref. 8a
R2
R1
H
R1
R1
*
F
F
F
3
2
1
Scheme 1. Two synthetic pathways to chiral fluorinated allyl amines 1.
organolithium reagents to the C@N bond of chiral
mines 6 and 7 (Schemes 1 and 2).9
a-fluoroeni-
Both aliphatic and aromatic aldehydes 4 were considered in our
study. Ethyl dibromofluoroacetate reacted with aldehydes in the
presence of diethylzinc to afford pure (Z) a
-fluoroesters 5.10 Alter-
natively, (Z)-5 could be obtained by a modified Julia olefination
In our ongoing project devoted to the synthesis of new func-
O
S
tionalized fluoroolefins, we required the asymmetric access to
a-
O
N
O
substituted-b-fluorinated allyl amines 1 (Scheme 1). Few methods
have been described to produce enantioenriched molecules of type
1.5–7 Previously, we described an efficient access to compounds 1
a
b, c, d
R1
R1
R1
H
OEt
(Z)-5
H
F
F
4
via an asymmetric reductive amination of the corresponding
a-
6 : R1 = 4-MeOC6H4
fluoroenones 2 (Scheme 1).8
7 : R1 =
We herein report a complementary route to 1 from the more
easily accessible fluoroenals 3 via the addition of Grignard and
TBDPSO
Scheme 2. Synthesis of starting
a-fluoroenimines 6 and 7. Reagents and condi-
tions: (a) FBr2CCO2Et, Et2Zn, DCM, rt, 3h, 38–60%; (b) DIBAL-H, THF, À78 °C, 3 h,
quant.; (c) SO3Ápyridine, DMSO, Et3N, DCM, 0 °C, 82–89%; (d) (S)-(À)-t-butanesul-
finamide, Ti(OEt)4, THF, reflux, 1 h, 89–96%.
* Corresponding author.
E-mail address: xavier.pannecoucke@insa-rouen.fr (X. Pannecoucke).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.140

C. Pierry et al. / Tetrahedron Letters 50 (2009) 264–266
265
reaction from 4 and ethyl fluorobenzothiazolylsulfonyl acetate
for compounds 8c and 9c to 98% and 91%, respectively (entries
12 and 23). We explored a number of Lewis acids as additive to en-
hance the yield and the diastereomeric ratio of the reaction. Thus,
precomplexation of 6 or 7 with AlMe3 (1.1 equiv) and reaction with
PhMgBr did not allow the reaction to take place whereas the reac-
tion with PhLi happened albeit without improvement of yield and
dr (entries 2, 4, and 18). Interestingly, the diastereoselectivity was
dramatically reversed, changing from 10:90 with PhMgBr to 67:33
with PhLi for substrate 6 (entries 1 and 3), and from 14:86 to 65:35
for substrate 7 (entries 17 and 19). Reversals of diastereoselectivity
also applied to the reagents i-PrMgCl/i-PrLi (entries 11, 12, 22, and
23) and in a lower extend to MeMgBr/MeLi (entries 5–10). The
opposite induction is obviously due to different transition states.
Contrary to PhMgBr, the use of MeMgBr on the precomplexed sub-
strate with AlMe3 revealed that the reaction affords the desired
product 8b in high yield with higher dr, up to 6:94 (entry 7). The
addition of MeLi required low temperature (À78 °C) and longer
reaction time, but excellent yields are obtained although with poor
diastereoselectivity (entries 9 and 10). With the aliphatic substrate
7, in the presence of AlMe3, product 9b was also obtained in higher
dr (10:90, entry 21). Under similar conditions BF3ÁEt2O failed to
produce compound 8b (entry 8). The scope of the reaction was fur-
ther investigated in toluene, with or without AlMe3. Benzyl, allyl,
and vinyl Grignards were evaluated, all giving high product yields
in the range 82–98% with moderate to high drs. In particular,
allylMgBr provided the highest dr in our study in up to 4:96 for
compound 8f (entry 15).
with DBU in the presence of MgBr2.11 Next, a two-step sequence
of reduction and oxidation provided
a-fluoro-a,b-unsaturated
aldehydes 3. The straightforward preparation of b-fluoroenimines
6 and 7 was carried out according to the well-established Ellman
procedure with the aid of (S)-(À)-tert-butanesulfinamide (Scheme
2).9a
To determine suitable reaction conditions, we first carried out
the addition of phenylmagnesium bromide to
a-fluoroenimines 6
in various solvents (toluene, dichloromethane, and THF). Toluene
provided the best yield and diastereomeric ratio (95%, 10:90 dr)
while CH2Cl2 and THF gave lower yields (87% and 91%, respec-
tively) and lower dr were observed in THF (35:65). Consequently,
all experiments have been carried out in toluene. Representative
results are listed in Table 1.12 Importantly, all Grignard and organo-
lithium reagents were added regioselectively at the imino carbon
of a-fluoroenimines to give (SS,S) and (SS,R) diastereomers. Diaste-
reomeric ratios were determined by 19F NMR on the crude mix-
tures. It is worth noting that all diastereomeric mixtures could
be purified by silica gel column chromatography to afford each
product in a diastereomerically pure form. Attempts to react phe-
nylzinc bromide with substrate 6 at various temperatures failed to
get the addition product 8a; 6 was recovered unchanged. In most
cases, the yield of the desired addition product was high (>82%) ex-
cept for Grignard reagents possessing a b-hydrogen atom. For this
latter, reduction of the C@N bond occurred in quite high propor-
tion, thus lowering the yield of the desired product (entries 11,
13, 22, and 24). To circumvent this side reaction, i-PrLi at À78 °C
was used instead of i-PrMgCl at 0 °C allowing an increase in yield
The absolute configuration of the newly created stereogenic
center was established by X-ray crystallography of the minor
Table 1
Diastereoselective addition of Grignard and organolithium reagents to b-fluoroenimines 6 and 712
O
S
O
S
O
S
N
HN
HN
R2M, toluene
6 and 8 : R1 = 4-MeOC6H4
R2
R1
R1
R2
R1
+
H
7 and 9 : R1 =
F
F
F
TBDPSO
6, 7
(
SS, S)-8, 9
(
SS, R)-8, 9
Entry
Substrate
R2M (equiv)
T (°C)
Time (h)
Additive (1.1 equiv)
Product
Yield (%)
dra
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
PhMgBr (1.1)
PhMgBr (1.1)
PhLi (1.6)
À30
0
À78
À78
À30
0
0
0
À78
À78
0
2
12
3
0.75
30
0.5
0.75
48
5
5
0.7
1
0.7
1
1
—
AlMe3
—
AlMe3
—
—
AlMe3
8a
8a
8a
8a
8b
8b
8b
8b
8b
8b
8c
8c
8d
8e
8f
95
0
10:90
—
95
100b
45
93
82
0
96
96
60
98
27
94
82
95
67:33
65:35
25:75
11:89
6:94
PhLi (2)
MeMgBr (1.1)
MeMgBr (1.1)
MeMgBr (1.1)
MeMgBr (1.1)
MeLi (2)
MeLi (2)
i-PrMgCl (3)
i-PrLi (3)
i-BuMgBr (1.5)
BnMgCl (1.1)
AllylMgBr (3)
VinylMgBr (3)
BF3ÁEt2O
—
—
45:55
53:47
30:70
60:40
30:70
30:70
4:96
AlMe3
—
—
—
—
À78
0
0
0
0
—
—
0.5
8g
33:67
17
18
19
20
21
22
23
24
25
26
27
7
7
7
7
7
7
7
7
7
7
7
PhMgBr (1.1)
PhMgBr (1.6)
PhLi (2.6)
MeMgBr (2.6)
MeMgBr (2)
i-PrMgCl (3)
i-PrLi (3)
i-BuMgBr (1.1)
BnMgCl (1.1)
AllylMgBr (1.1)
VinylMgBr (1.5)
0
0
1.5
12
12
—
AlMe3
—
—
AlMe3
—
—
—
—
9a
9a
9a
9b
9b
9c
9c
9d
9e
9f
90
0
14:86
—
À78
83
90
84
41
91
36
90
91
98
65:35
21:79
10:90
49:51
67:33
30:70
43:57
8:92
0
4
0
0
2.5
0.75
1
0.5
1.5
0.75
0.75
À78
0
0
0
0
—
—
9g
35:65
a
Ratio determined by 19F NMR of the crude reaction mixture.
b
Conversion determined by 19F NMR of the crude reaction mixture.

266
C. Pierry et al. / Tetrahedron Letters 50 (2009) 264–266
4. (a) Edmondson, S. D.; Wei, L.; Xu, J.; Shang, J.; Xu, S.; Pang, J.; Chaudhary, A.;
three-step sequence
71% overall yield
NHFmoc
Me
Dean, D. C.; He, H.; Leiting, B.; Lyons, K. A.; Patel, R. A.; Patel, S. B.; Scapin, G.;
Wu, J. K.; Beconi, M. G.; Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett.
2008, 18, 2409–2413; (b) Van der Veken, P.; Senten, K.; Kertesz, I.; De Meester,
I.; Lambeir, A.-M.; Maes, M.-B.; Scharpé, S.; Haemers, A.; Augustyns, K. J. Med.
Chem. 2005, 48, 1768–1780; (c) Van der Veken, P.; Kertesz, I.; Senten, K.;
Haemers, A.; Augustyns, K. Tetrahedron Lett. 2003, 44, 6231–6234; (d) Lin, J.;
Toscano, P. J.; Welch, J. T. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 14020–14024; (e)
Zhao, K.; Lim, D. S.; Funaki, T.; Welch, J. T. Bioorg. Med. Chem. 2003, 11, 207–
215; (f) Welch, J. T.; Lin, J. Tetrahedron 1996, 52, 291–304.
(
SS, S)-9b
HO2C
see ref. 8a
F
10
Scheme 3. Synthesis of Fmoc-Ala-W[(Z)CF@CH]-Gly dipeptide analogue 10.
diastereomer of 8b, which was found to have the S-configuration.8a
This meant that addition of Grignard reagent MeMgBr to sulfini-
mine 6 proceeded on Re-face of the imine function. By analogy,
we assumed that all other Grignard reagents were added similarly
to b-fluoroenimines 6 and 7.
This methodology is quite general and should be amenable to
the synthesis of a large variety of chiral fluorinated allyl amines. In-
deed, the stereoselective addition of organometallic species served
as the key step in the construction of dipeptide analogues as exem-
5. Allmendinger, T.; Felder, E.; Hungerbühler, E. Tetrahedron Lett. 1990, 31, 7301–
7304.
6. Waelchli, R.; Gamse, R.; Bauer, W.; Meigel, H.; Lier, E.; Feyen, J. H. M. Bioorg.
Med. Chem. Lett. 1996, 6, 1151–1156.
7. (a) Lamy, C.; Hofmann, J.; Parrot-Lopez, H.; Goekjian, P. Tetrahedron Lett. 2007,
48, 6177–6180; (b) Narumi, T.; Tomita, K.; Inokuchi, E.; Kobayashi, K.; Oishi, S.;
Ohno, H.; Fujii, N. Tetrahedron 2008, 64, 4332–4346; (c) Tomita, K.; Narumi, T.;
Niida, A.; Oishi, S.; Ohno, H.; Fujii, N. Biopolymers 2007, 88, 272–278.
8. (a) Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X. Angew. Chem., Int. Ed.
2007, 46, 1290–1292; (b) Dutheuil, G.; Bailly, L.; Couve Bonnaire, S.;
Pannecoucke, X. J. Fluorine Chem. 2007, 128, 34–39.
9. For examples of addition of organometallics to chiral sulfinimides see: (a)
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995; (b)
Morton, D.; Storkman, R. A. Tetrahedron 2006, 62, 8869–8905.
plified by the transformation of (SS,S)-9b into Fmoc-Ala-
W[(Z)CF@
CH]-Gly 10 (Scheme 3).
10. (a) Zoute, L. Ph.D. Thesis, INSA of Rouen, 2007; (b) Lemonnier, G. Ph.D. Thesis,
INSA of Rouen, 2008.
11. Pfund, E.; Lebargy, C.; Rouden, J.; Lequeux, T. J. Org. Chem. 2007, 72, 7871–7877.
12. Typical procedure for synthesis of N-((Z)-1-allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-
In summary, an efficient synthetic method has been developed
whereby diastereoselective addition of Grignard and organolith-
ium reagents to N-(tert-butanesulfinyl)-b-fluoroenimines provided
chiral fluorinated sulfinamides in high yields with diastereomeric
ratios of up to 96:4. Separation of diastereomers on silica gel chro-
matography provided enantiopure versatile intermediates for the
synthesis of stable drug analogues. We have demonstrated that
further simple chemical transformations afforded fluoroolefin
dipeptide mimics.
2-fluoro-2-pentenyl)-2-methyl-2-propanesulfinamide 9f: b-Fluoroenimine
7
(70 mg, 0.152 mmol) was placed in a flask under argon and dissolved in
anhydrous toluene (1 mL). The solution was cooled to 0 °C and allylmagnesium
bromide (168
lL of a 1 M solution in diethyl ether, 0.168 mmol) was slowly
added. After stirring for 40 min, the solution was quenched with a saturated
solution of NH4Cl and extracted three times with EtOAc. The combined organic
layers were then washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was checked by 19F NMR
for determination of diastereomeric ratio (dr = 8:92) and purified by
chromatography on silica gel (eluent: cyclohexane/EtOAc 80/20 to 70/30)
affording the expected compound 9f as a colorless oil (70.2 mg, yield 91%).
Diastereomer (SS,R)-9f: 1H NMR (CDCl3, 300 MHz): d 1.04 (s, 9H), 1.19 (s, 9H),
2.32–2.39 (m, 2H), 2.43–2.57 (m, 2H), 3.35 (d, 3J = 4.35 Hz, 1H), 3.66 (t,
3J = 6.42 Hz, 2H), 3.92 (ddd, 3J = 4.35 Hz, 3J = 6.75 Hz, 3J = 17.50 Hz), 4.93 (dt,
3J = 7.53 Hz, 3J = 37.11 Hz, 1H), 5.15–5.20 (m, 2H), 5.73 (ddd, 3J = 6.97 Hz,
3J = 10.40 Hz, 3J = 17.52 Hz, 1H), 7.35–7.45 (m, 6H), 7.64–7.67 (m, 4H); 13C
NMR (CDCl3, 75.4 MHz): d 19.3, 22.5, 26.9, 27.2, 38.0, 55.4, 55.9, 63.1, 105.4 (d,
3J = 4.4 Hz), 119.8, 127.8, 128.9, 133.2, 133.8, 135.6, 157.7 (d, 1J = 257 Hz); 19F
NMR (CDCl3, 282.5 MHz): d 123.9 (dd, 3J = 17.5 Hz, 3J = 37.1 Hz); MS (EI+):
[M+H+] = 502.00; Anal. Calcd for C28H40FNO2SSi: C, 67.02; H, 8.04; N, 2.79.
Found: C, 66.99; H, 8.31; N, 2.75. Diastereomer (SS,S)-9f: 1H NMR (CDCl3,
300 MHz): d 1.04 (s, 9H), 1.20 (s, 9H), 2.33–2.52 (m, 4H), 3.41 (d, 3J = 4.53 Hz,
1H), 3.43 (t, 3J = 6.59 Hz, 2H), 3.79 (ddd, 3J = 4.53 Hz, 3J = 6.78 Hz,
3J = 18.50 Hz,), 4.95 (dt, 3J = 7.35 Hz, 3J = 38.20 Hz, 1H), 5.07–5.14 (m, 2H),
5.72 (ddd, 3J = 6.97 Hz, 3J = 10.00 Hz, 3J = 17.14 Hz, 1H), 7.34–7.45 (m, 6H),
7.65–7.67 (m, 4H); 13C NMR (CDCl3, 75.4 MHz): d 19.3, 22.7, 26.9, 27.2 (d,
3J = 4.4 Hz), 37.6, 56.4, 56.8 (d, 2J = 28.5 Hz), 63.1, 105.0 (d, 2J = 14.2 Hz), 118.6,
127.7, 129.7, 133.5, 133.9, 135.7, 158.5 (d, 1J = 257 Hz); 19F NMR (CDCl3,
Acknowledgment
We thank the ‘Région Haute-Normandie’ (CRUNCh programme)
for financial support (Ph.D. Grant to C.P.).
References and notes
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médicinale du fluor; CNRS Editions: Paris, 2005 or Bioorganic and Medicinal
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320–330; (b) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369; (c) Shah, P.;
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Fluorine Chem. 2006, 127, 1013–1029; (e) Special issue of J. Fluorine Chem.
2008, 129, 725–888.
282.5 MHz):
d
À122.8 (dd, 3J = 18.5 Hz, 3J = 38.2 Hz); MS (EI+):
[M+H+] = 502.00; Anal. Calcd for C28H40FNO2SSi: C, 67.02; H, 8.04; N, 2.79.
Found: C, 67.25; H, 8.11; N, 2.77.
3. (a) Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Org. Biomol. Chem. 2007, 5,
1151–1157; (b) Welch, J. T.; Lin, J.; Boros, L. G.; DeCorte, B.; Bergmann, K.; Gimi,
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J. T., Eds.; ACS Symp. Ser.: Washington, DC, 1996; pp 129–142.