Chiral allylic cyanohydrins as versatile substrates for diastereoselective copper(I)-mediated SN2′ allylic substitutions

Article abstract of DOI:10.1055/s-2007-973881

2,6-Difluorobenzoated derivatives bearing a protected cyanohydrin function undergo highly stereoselective copper(I)-mediated S_N2′ allylic substitution reactions with diorganozinc reagents leading to chiral unsaturated nitriles. Georg Thieme Ver

Full text of DOI:10.1055/s-2007-973881

LETTER
1047
Chiral Allylic Cyanohydrins as Versatile Substrates for Diastereoselective
Copper(I)-mediated SN2¢ Allylic Substitutions
D
iastereoselec
y
tive
C
opper(
l
I)-med
v
iated
S
2
¢
A
l
N ilylic
S
e
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 17 January 2007
Cyanohydrin derivatives like 1 were synthesized in their
enantiomerically enriched form starting from the corre-
sponding carbaldehydes 3a and 3b (Scheme 2). The enan-
tioselective (S)-oxynitrilase-catalyzed addition of KCN (2
equiv) in a citrate buffer9 gave the chiral cyanohydrins
(S)-4a (58%, 96% ee) and (S)-4b (55%, 90% ee). Sub-
sequent esterification with 2,6-difluorobenzoyl chloride
afforded (S)-1a in 83% and (S)-1b in 73% yield without
racemization.
Abstract: 2,6-Difluorobenzoated derivatives bearing a protected
cyanohydrin function undergo highly stereoselective copper(I)-me-
diated SN2¢ allylic substitution reactions with diorganozinc reagents
leading to chiral unsaturated nitriles.
Key words: asymmetric synthesis, allylic substitution, cyano-
hydrins, copper, zinc, unsaturated nitriles
Cyanohydrins occupy a unique place at the interface be-
tween chemistry and biology.1 They are readily prepared
by a number of synthetic methods,2 and their stereoselec-
tive synthesis can be achieved either by chemical3 or en-
zymatic procedures.4 Herein, we wish to report a highly
stereoselective SN2¢ allylic substitution reaction5–8 on
chiral difluorobenzoated allylic cyanohydrins with dior-
ganozinc reagents in the presence of CuCN·2LiCl that
produces a,b-unsaturated nitriles bearing a new stereo-
genic center in the g-position.
The substitution of the allylic cyanohydrin derivative 1a
with Pent2Zn (2.4 equiv) in the presence of CuCN·2LiCl
[1.2 equiv, THF–NMP (2:1), –30 °C to 0 °C, 5 h) afforded
the g-substituted unsaturated nitrile 2a as a single regio-
isomer in 75% yield and 96% ee (entry 1 of Table 1). No
traces of the SN2 product was detected and the substitution
afforded only the E-isomer.10
The substitution with Et2Zn led to the expected product 2b
(65%, 96% ee, entry 2). Similarly, a functionalized zinc
reagent like [PivO(CH2)3]2Zn gave the chiral pivalate 5c
in 65% yield and 96% ee (entry 3). Although the substitu-
tion occurred in excellent diastereoselectivity, it was
limited to primary alkyl substituents. Indeed, reactions
with more sterically demanding groups like i-Pr2Zn or c-
Hex2Zn were not selective. However, the cyclopentyl
cyanobenzoate derivative 1b did not suffer from these
limitations and reacted with a wide range of diorgano-
zincs. Thus, the substitution of 1b with Pent2Zn as well as
with Et2Zn in the presence of CuCN·2LiCl afforded the
corresponding a,b-unsaturated nitriles 2d (91%, 90% ee,
entry 4) and 2e (80%, 90% ee, entry 5) with an optimum
transfer of chirality. The substitution proceeded with ex-
cellent diastereoselectivity with secondary diorganozincs
like i-Pr2Zn and c-Hex2Zn to furnish the sterically hin-
dered substituted cyclopentane derivatives 2f (75%, 90%
Tetrasubstituted allylic difluorobenzoated cyanohydrins
of type 1 bearing a methyl group in the g-position undergo
highly regio- and stereoselective SN2¢ substitutions and
afforded exclusively the SN2¢-substituted product of type
2 with perfect transfer of chirality (Scheme 1 and
Table 1).
2,6-F2C6H3
CN
O
O
R2Zn (2.4 equiv)
CuCN·2LiCl (1.2 equiv)
CN
R
THF–NMP (2:1)
–30 °C
Me
n
Me
n
1a: n = 1, 96% ee
1b: n = 0, 90% ee
2: up to 96% ee
40–91% yield
Scheme 1
C6F2H3
O
OH
Me
(S)-oxynitrilase
(400 U/mmol)
KCN (2 equiv)
2,6-difluorobenzoyl
chloride
DMAP, pyridine
O
O
H
CN
CN
citrate buffer (pH 5)
10–15 °C, 3–5 h
Et2O, 0 °C, 1 h
Me
Me
n
n
n
3a: n = 1
3b: n = 0
(S)-4a: 58%, 96% ee
(S)-4b: 55%, 90% ee
(S)-1a: 89%
(S)-1b: 73%
Scheme 2
SYNLETT 2007, No. 7, pp 1047–1050
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-973881; Art ID: G00907ST
© Georg Thieme Verlag Stuttgart · New York

1048
S. Perrone et al.
LETTER
Table 1 Copper(I)-Mediated SN2¢ Allylic Substitution of 2,6-Difluorobenzoated Allylic Cyanohydrins 1a,b
Entry
1
Allyl substrate (ee, %)a
R2Zn (R)
a,b-Unsaturated nitrile of type 1 Yield (%)b
ee (%)a
CN
OC(O)F2C6H3
CN
Pent
75
96
96
Pent
Me
Me
1a (96)
2a
CN
2
3
1a
Et
65
Et
Me
2b
CN
1a
PivO(CH2)3
65
96
Me
OPiv
2c
OC(O)F2C6H3
CN
CN
4
5
6
7
8
Pent
91
90
90
90
90
90
Pent
Me
Me
1b (90)
2d
CN
1b
1b
1b
1b
Et
80
Et
Me
2e
CN
i-Pr
75
60
40
iPr
Me
2f
2g
2h
2i
CN
c-Hex
Ph(CH2)2
cHex
Me
CN
Ph
Me
Me
CN
9
1b
PivO(CH2)3
71
90
OPiv
a The ee was determined by GC analysis of the pure product on Chirasil-Dex CB column. In each case the racemic product was used for
calibration.
b Isolated yield of analytically pure product.
ee, entry 6) and 2g (60%, 90% ee, entry 7). Diorganozincs Interestingly, we could demonstrate that in this sequence
like [Ph(CH2)2]2Zn (entry 8) or [PivO(CH2)3]2Zn (entry 9) the presence of the cyano group was essential. Indeed, any
reacted similarly with 1b and afforded, respectively, 2h in attempts to derivatize the cyclic allylic alcohol 5, in which
40% yield and 90% ee and 2i (71% and 90% ee).
the cyano group is replaced by a methyl group, into the
corresponding benzoated ester 6 provided only the elimi-
nation product 7 (Scheme 3).
Synlett 2007, No. 7, 1047–1050 © Thieme Stuttgart · New York

LETTER
Diastereoselective Copper(I)-mediated SN2¢ Allylic Substitutions
1049
OH
2,6-difluorobenzoyl
chloride
DMAP, pyridine
In addition, we explored the transformation of the result-
ing a,b-unsaturated nitriles of type 2. We found that 2c
and 2i underwent a diastereoselective cyclization when
treated with LiOH leading to the fused bicycles 8a and 8b
(Scheme 4).
OC(O)F2C6H3
Me
Me
Me
Et2O, 0 °C, 1 h
Me
Me
7
5
6 (not observed)
In summary, we have shown that enantiomerically en-
riched difluorobenzoated cyanohydrin derivatives con-
stituted substrates of choice for the copper(I)-mediated
SN2¢ allylic substitution. They reacted with diorganozinc
reagents in the presence of CuCN·2LiCl leading to a,b-
unsaturated nitriles bearing a new stereogenic center in
the g position with an excellent transfer of chirality.11
Scheme 3
NC
CN
CN
O
LiOH (10 equiv)
MeOH, r.t., 16 h
OPiv
OLi
n
n
Me
Me
n
Me
8a: n = 1, 58%
8b: n = 0, 65%
2c: n = 1
2i: n = 0
Scheme 4
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Acknowledgment
S.P. thanks the DFG for a fellowship. We thank the Fonds der
Chemischen Industrie, Chemetall GmbH (Frankfurt), Degussa AG
(Frankfurt), BASF AG (Ludwigshafen) for the generous gift of
chemicals.
References and Notes
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Synlett 2007, No. 7, 1047–1050 © Thieme Stuttgart · New York

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S. Perrone et al.
LETTER
(8) For copper-catalyzed reactions using chiral ligands, see:
(a) van Klaveren, M.; Persson, E. S. M.; del Villar, A.;
Grove, D. M.; Bäckvall, J.-E.; van Koten, G. Tetrahedron
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Meuzelaar, G. J.; Bäckvall, J.-E. Synlett 2001, 923.
(c) Meuzelaar, G. J.; Karlström, A. S. E.; van Klaveren, M.;
Persson, E. S. M.; del Villar, A.; van Koten, G.; Bäckvall, J.-
E. Tetrahedron 2000, 56, 2895. (d) Dübner, F.; Knochel, P.
Angew. Chem. Int. Ed. 1999, 38, 379. (e) Dübner, F.;
Knochel, P. Tetrahedron Lett. 2000, 41, 9233. (f) Alexakis,
A.; Malan, C.; Lea, L.; Benhaim, C.; Fournioux, X. Synlett
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mL) and stirred at 25 °C until the copper salts had dissolved
then extracted with Et2O (3 × 100 mL). The combined
extracts were washed with H2O, brine and dried over
Mg2SO4. Evaporation of the solvents and purification by
column chromatography (silica gel, pentane–Et2O, 9:1)
afforded the unsaturated nitrile 2d (382 mg, 2.0 mmol, 91%,
90% ee) as a pale yellow oil.
1H NMR (300 MHz, CDCl3): d = 5.02 (t, 3J = 2.55 Hz, 1 H),
2.81–2.56 (m, 2 H), 1.78–1.66 (m, 2 H), 1.66–1.53 (m, 2 H),
1.34–1.16 (m, 8 H), 1.04 (s, 3 H), 0.87 (t, 3J = 6.75 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 181.9, 117.9, 89.9, 47.6,
40.4, 38.9, 34.0, 32.6, 26.1, 24.4, 22.7, 22.1, 14.3. MS (EI,
70 eV): m/z (%) = 191 (8) [M+], 176 (11), 162 (8), 148 (12),
121 (89), 120 (100), 106 (12), 93 (23), 79 (25). HRMS: m/z
calcd: 191.1674; found: 191.1651. [a]D20 –15.9 (c 1.49,
CHCl3). GC (Chirasil-Dex CB), 100 °C (5 min), ramp of
2 °C/min to 140 °C; tR(min) = 23.45 (R), 23.93 (S).
(2R,E)-(-2-Methyl-2-phenethylcyclopentylidene)aceto-
nitrile (2h)
1H NMR (400 MHz, CDCl3): d = 7.31–7.14 (m, 5 H), 5.09
(t, 3J = 2.55 Hz, 1 H), 2.91–2.46 (m, 4 H), 1.88–1.58 (m, 6
H), 1.14 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 181.4,
142.2, 128.7, 128.4, 126.2, 117.8, 90.3, 47.7, 42.5, 38.9,
34.0, 31.3, 26.1, 22.2. MS (EI, 70 eV): m/z (%) = 225, 121
(16), 134 (9), 105 (100), 104 (63), 91 (64), 79 (18), 77 (18),
65 (15). HRMS: m/z calculated: 225.1517; found: 225.1487.
[a]D20 –5.8 (c 0.69, CHCl3). GC (Chirasil-Dex CB), 100 °C
(5 min), ramp of 2 °C/min to 160 °C; tR(min) = 49.21 (R),
50.24 (S).
(10) The stereochemistry of the double bond was confirmed by
2D 1H NMR spectroscopy.
(11) Typical Procedure for the SN2¢ Substitution: Preparation
of (2S,E)-2-(2-Methyl-2-pentylcyclopentylidene)aceto-
nitrile (2d)
A flame-dried flask equipped with a magnetic stirring bar, an
argon inlet, and a septum was charged with CuCN·2LiCl
solution (2.6 mL, 1.0 M in THF, 2.64 mmol, 1.2 equiv),
anhyd NMP (2.6 mL, overall ratio of solvents THF–
NMP = 2:1). The mixture was cooled at –30 °C. To this
solution was added dropwise dipentylzinc solution (1.1 mL,
4.8 M in THF, 5.28 mmol, 2.4 equiv). The resulting mixture
was stirred at –30 °C for 45 min, and then (2S)-cyano(2-
methylcyclopent-1-enyl)methyl 2,6-difluorobenzoate (1b,
610 mg, 2.2 mmol, 90% ee) was added dropwise as a
solution in THF (1.5 mL). The reaction mixture was stirred
at –30 °C to 0 °C for 2 h and sat. aq NH4Cl solution (5 mL)
was added. The quenched reaction mixture was poured into
25% aq NH3 (2 mL), aq sat. NH4Cl (100 mL) and Et2O (100
{4a-Methyl-hexahydro-cyclopenta[b]pyran-7a-yl}aceto-
nitrile (8b)
1H NMR (300 MHz, CDCl3): d = 3.81–3.74 (m, 1 H), 3.53–
3.43 (m, 1 H), 2.85 (d, 2J = 16.8 Hz, 1 H), 2.35 (d, 2J = 16.8
Hz, 1 H), 2.19–2.00 (m, 2 H), 1.94–1.58 (m, 5 H), 1.45–1.17
(m, 3 H), 0.85 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
117.8, 82.8, 61.8, 42.5, 36.5, 34.8, 30.2, 25.5, 21.3, 20.8,
18.9. MS (EI, 70 eV): m/z (%) = 180, 162 (2), 150 (2), 139
(100), 111 (15), 93 (15), 81 (12), 68 (36). HRMS: m/z calcd:
180.1388; found: 180.1390.
Synlett 2007, No. 7, 1047–1050 © Thieme Stuttgart · New York

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