The asymmetric hydrogenation of 2-phenethylacrylic acid as the key step for the enantioselective synthesis of Citralis Nitrile

Article abstract of DOI:10.1016/j.tetlet.2006.10.129

A catalytic approach to the enantioselective synthesis of Citralis Nitrile (3-methyl-5-phenyl-pentanenitrile, a citrus-type odorant) is described. The key step is the transition-metal catalyzed asymmetric hydrogenation of 2-phenethylacrylic aci

Full text of DOI:10.1016/j.tetlet.2006.10.129

Tetrahedron Letters 47 (2006) 9261–9265
The asymmetric hydrogenation of 2-phenethylacrylic acid as the
key step for the enantioselective synthesis of Citralis Nitrileꢀ
Alberto Scrivanti,* Sara Bovo, Alessandra Ciappa and Ugo Matteoli
`
Dipartimento di Chimica, Universita di Venezia, Dorsoduro, 2137, 30123 Venice, Italy
Received 3 August 2006; revised 25 October 2006; accepted 25 October 2006
Abstract—A catalytic approach to the enantioselective synthesis of Citralis Nitrileꢀ (3-methyl-5-phenyl-pentanenitrile, a citrus-type
odorant) is described. The key step is the transition-metal catalyzed asymmetric hydrogenation of 2-phenethylacrylic acid. Among
the different catalysts tested, the most efficient appears to be the one formed by combining in situ [Ru(benzene)Cl2]2 with the atrop-
isomeric diphosphine MeOBIPHEP and triethylamine, which allows us to obtain enantiomeric excesses up to 98% under mild con-
ditions. Very good results (ees >80%) have also been obtained using iridium cationic complexes in combination with a
phosphinooxazoline ligand.
ꢁ 2006 Elsevier Ltd. All rights reserved.
Citralis Nitrileꢀ (3-methyl-5-phenyl-pentanenitrile)
(Scheme 1) is a citrus-type odorant marketed as race-
mate by Aroma and Fine Chemicals (AFC).1
merically enriched fragrances arises from economical
and environmental concerns.
Spurred by our interest in developing practical synthetic
routes to enantiomerically enriched fragrances,5,6 we
wish to report here a catalytic process (Scheme 1) for
the enantioselective synthesis of Citralis Nitrileꢀ. In this
connection, it is worth mentioning that the enantiomers
of Citralis Nitrileꢀ were prepared with ee up to 70% by
Pfaltz through a cobalt catalyzed asymmetric reduction
of (E)- or (Z)-3-methyl-5-phenyl-pent-2-enenitrile with
NaBH4.7
Even if today many synthetic fragrances are traded as
racemates, it often occurs that the opposite enantiomers
of a fragrance may induce quite different sensorial reac-
tions, that is, have a different scent.2 Accordingly, there
is practical interest in developing preparative routes
which selectively lead to the single stereomers of a fra-
grance.3,4 In fact, if the two enantiomers have different
olfactory activity, the use of the enantiomerically pure
or of an enantiomerically enriched fragrance will pro-
vide unique odour properties, different from those of
the racemate; further motivation in the use of enantio-
Carbonylation of but-3-ynyl-benzene 1 (Aldrich) in the
presence of the Pd(OAc)2/2-pyridyldiphenylphosphine/
Scheme 1. Asymmetric synthesis of Citralis Nitrileꢀ.
Keywords: Acrylic acids; Enantioselective hydrogenation; Atropisomeric diphosphine; Ruthenium; Iridium; Fragrance chemistry; Citralis Nitrileꢀ.
*
Corresponding author. Tel.: +39 041 2348903; fax: +39 041 2348967; e-mail: scrivanti@unive.it
0040-4039/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.129

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A. Scrivanti et al. / Tetrahedron Letters 47 (2006) 9261–9265
methanesulfonic acid catalytic system8,9 gives phenethyl-
acrylic acid 2 in a 92% yield.10 Asymmetric hydrogena-
tion of 2 in the presence of a chiral transition-metal
catalyst leads to enantiomerically enriched acid 3. Then,
the reduction of 3 to the corresponding alcohol 4 fol-
lowed by a Mitsunobu type reaction11 affords Citralis
Nitrileꢀ.
Table 1. Hydrogenation of 2 with of Ir-PHOX: influence of the
temperaturea
Entry
T (ꢂC)
t (h)
eeb (%)
1
2
3
4
5
6
100
60
30
2
2
2
2
2
66c
66c
64c
46c
27c
66c
0
ꢀ20
30
24
The above synthesis of acrylic acid 2 is particularly con-
venient because it does not only afford the olefin in a
high yield, but also with a complete regioselectivity. This
is of paramount importance because it is known that the
metal catalyzed asymmetric hydrogen addition on iso-
meric olefins often gives opposite enantiomers.6,12
a Reaction conditions. Substrate: 0.57 mmol; cat.: 2.27 · 10ꢀ2 mmol;
solvent: dichloromethane (15 mL); P(H2): 50 atm; in all the experi-
ments the substrate conversion is complete.
b The ees were determined by chiral GLC (on the methyl ester using
Chiraldex G-TA column).
c Configuration of the prevailing enantiomer: (R) by polarimetry see
Ref. 22.
The most challenging step is the asymmetric hydro-
genation of acrylic acid 2. As a matter of fact, inspection
of the literature reveals that while the asymmetric
hydrogenation of a-arylacrylic acids and of disubsti-
tuted or trisubstituted acrylic acids has received much
attention,13–17 there are few studies dealing with the
hydrogenation of acrylic acids bearing as the only sub-
stituent an aliphatic chain in a position, such as 2.18,19
thus, it appears that the hydrogen pressure is the most
important parameter in determining the asymmetric
induction (e.g., compare entries 4, 7 and 10 in Table 2).
This behaviour is in keeping with the Pfaltz’s observa-
tion that terminal olefins react with a higher enantio-
selectivity at lower hydrogen pressures.24
The asymmetric hydrogenation of olefin 2 was first car-
ried out in the presence of an iridium-based catalyst (Ir-
PHOX, Fig. 1) containing the chiral ligand 2-(o-diphen-
ylphosphinophenyl)-3-tert-butyloxazoline, which has
been shown by Pfaltz to be able to provide very high
asymmetric inductions in the hydrogenation of a wide
variety of unfunctionalized olefins.20
Aiming at broadening our investigations with other
transition-metal catalysts some experiments were carried
out in the presence of the commercially available
[Rh(COD)(S)-BINAP]+ClO4ꢀÆTHF (Aldrich).
Unfortunately, preliminary tests carried out in CH2Cl2
at 23 ꢂC under 20 atm of hydrogen showed that while
the hydrogenation proceeds with acceptable rates, no
asymmetric induction is obtained.
Preliminary experiments carried out at 100 ꢂC under
50 atm of hydrogen showed that under these conditions
the carbon–carbon double bond is quantitatively hydro-
genated furnishing acid 3 with a fairly good enantio-
selectivity (66% ee, see Table 1).21
The best results were obtained with a ruthenium cata-
lytic system prepared in situ25 by reacting [Ru(benz-
ene)Cl2]2 with a chiral atropisomeric diphosphine
(ligand:complex = 2:1 molar ratio) (see Table 3).
On lowering the reaction temperature at 60 or 30 ꢂC, the
substrate conversion remains complete, but the enantio-
selectivity does not increase. More adversely, when the
reaction temperature is further lowered, the asymmetric
induction drops dramatically. A decrease of the enantio-
selectivity on lowering the reaction temperature is quite
unusual; however, it seems to be somewhat peculiar
when using catalysts such as Ir-PHOX since an alike
behaviour has been reported by Pfaltz.23 No product
racemization occurs as shown by an experiment carried
out over 24 h (entry 6 of Table 1).
Indeed, the hydrogenation of 2 in the presence of the
[Ru(benzene)Cl2]2/(S)-BINAP catalyst at 0 ꢂC and
Table 2. Hydrogenation of 2 with Ir-PHOX: effect of the hydrogen
pressurea
Entry
T (ꢂC)
P(H2) (atm)
eeb (%)
1
2
3
4
5
6
7
8
9
60
60
60
60
30
30
30
0
100
50
10
2
50
10
2
50
10
2
61c
66c
76c
81c
64c
79c
80c
46c
75c
80c
On decreasing the hydrogen pressure the asymmetric
induction increases (Table 2) whatever the reaction tem-
perature; the effect is stronger at lower temperatures;
0
0
10
a Reaction conditions. Substrate: 0.57 mmol; cat.: 2.27 · 10ꢀ2 mmol;
solvent: dichloromethane (15 mL); time: 2 h; in all the experiments
the substrate conversion is complete.
b The ees were determined by chiral GLC (on the methyl ester using
Chiraldex G-TA column).
c Configuration of the prevailing enantiomer: (R) by polarimetry see
Ref. 22.
Figure 1. Ir-PHOX.

A. Scrivanti et al. / Tetrahedron Letters 47 (2006) 9261–9265
9263
Table 3. Hydrogenation of 2 in the presence of the Ru/atropisomeric diphosphine systema
Entry
Ligand
Promoter
T (ꢂC)
t (h)
P(H2) (atm)
Conv. (%)
ee (%)b
1
2
3
4
5
6
7
8
(S)-BINAP
(S)-BINAP
(S)-BINAP
(R)-MeOBIPHEP
(R)-MeOBIPHEP
(R)-MeOBIPHEP
(R)-MeOBIPHEP
(R)-MeOBIPHEP
—
0
0
24
24
24
24
24
24
24
24
100
100
100
100
80
100
130
80
26
100
100
27
100
100
100
100
35c
85c
88c
63d
88d
96d
98d
96d
Et3N
Et3N
—
Et3N
Et3N
Et3N
Et3N
ꢀ20
0
0
0
0
ꢀ20
a Reaction conditions. Substrate: 2.84 mmol; [Ru(benzene)Cl2]2: 0.018 mmol; ligand: 0.036 mmol; solvent: methanol (10 mL).
b The ees were determined by chiral GLC (on the methyl ester using Chiraldex G-TA column).
c Configuration of the prevailing enantiomer: (S).
d Configuration of the prevailing enantiomer: (R).
under 100 atm of hydrogen proceeds quite slowly fur-
nishing 3 with only a moderate enantioselectivity
(35%, entry 1 of Table 3); however, when the same
experiment is performed using triethylamine (1 equiv
with respect to the substrate)26 as the promoter, a
remarkable increase of both the rate and the enantio-
selectivity (ee 85%) of the reaction is observed (entry 2
of Table 3). A further small improvement on the enantio-
selectivity (ee 88%) can be obtained working at ꢀ20 ꢂC.
both the hydrogen pressure and the reaction tempera-
ture influence the enantioselectivity. Indeed, at 0 ꢂC on
increasing the hydrogen pressure from 80 to 130 atm
the enantioselectivity increases from 88% to 98% (entries
5–7 of Table 3) and keeping the hydrogen pressure con-
stant at 80 atm on decreasing the reaction temperature
from 0 ꢂC to ꢀ20 ꢂC, the enantioselectivity increases
from 88% up to 96%.
31
Upon treatment with LiAlH4 a sample of (R)-322 (ee
25
At present, we have no rationalization for the promot-
ing effect played by triethylamine. As far as the increase
in the rate is concerned, likely the base promotes the
reaction by removing the HCl which forms owing to
the heterolytic hydrogen activation on ruthenium.27 As
far as the increase in enantioselectivity is concerned, a
simple explanation is that the amine transforms the acid
substrate in the conjugated base allowing a stronger
interaction with the metal centre; however, such hypoth-
esis should be supported by a larger body of experimen-
tal evidences. It is worth to note that the promoting
effect of bases in olefin hydrogenation in the presence
of chiral ruthenium catalysts has been already described.
In particular, Chan claims a useful promoting effect of
amines in the asymmetric hydrogenation of a-arylprop-
enoic acids,28 instead Noyori reports that t-C4H9OK
strongly enhances the catalytic activity of certain
ruthenium complexes in the asymmetric hydrogenation
of a-ethylstyrene derivatives.29 The promoting effect of
triethylamine is observed also when the atropisomeric
diphosphine (R)-MeOBIPHEP (Fig. 2)30 is employed
instead of (S)-BINAP (compare entries 4 and 6 in Table
3).
96%, ½aꢁD ꢀ28.0 (neat)) afforded (R)-2-methyl-4-phen-
ylbutan-1-ol 4 (81% yield) having the same enantiomeric
25
purity (ee 96% by chiral GC,32 ½aꢁD +19.1 (c, 5.0,
CHCl3)33); the so obtained alcohol was reacted with
acetone cyanohydrin in the presence of diethyl azo-
dicarboxylate and PPh3 (Mitsunobu conditions)11 to
afford Citralis Nitrileꢀ 5 (73% yield, (R)-3-methyl-5-
25
phenylpentanenitrile,34 ee 96% by chiral GC,35 ½aꢁD
ꢀ2.35 (c, 2.2, EtOH)) without the loss of enantiopurity.
In conclusion, we have found a highly enantioselective
and convenient catalytic system for the asymmetric
hydrogenation of acrylic acid 2. Using this catalytic sys-
tem we have been able to synthesize almost enantio-
merically pure Citralis Nitrileꢀ. A practical application
of this process would require the development of a con-
venient synthesis of alkyne 1. Otherwise, an alternative
route to the key acid 2, such as a Mannich reaction on
2-phenylethylmalonic acid,36,37 could be employed.
More economically feasible and environmentally
friendly processes, such as the catalytic hydrogenation38
of 3 to give 4 and the direct conversion of alcohol 4 to
the nitrile,39 are also to be adopted for an industrial
application.
In the hydrogenation of 2, (R)-MeOBIPHEP appears as
a ligand distinctly more efficient than BINAP affording
under the same conditions higher asymmetric induc-
tions. As usual in the presence of ruthenium catalysts,
Further studies aimed at improving the asymmetric
hydrogenation rate and gathering more information
on the catalytic cycle are in progress.
Acknowledgements
We are indebted to the reviewers for helpful comments
and suggestions. Rhodia UK Ltd—Phosphorus Special-
ties and Derivatives is acknowledged for generously sup-
plying the BINAP ligand. The work has been performed
with the Financial Support of the MIUR (Cofin 2004).
Figure 2. (R)-MeOBIPHEP.

9264
A. Scrivanti et al. / Tetrahedron Letters 47 (2006) 9261–9265
150 mL stainless steel autoclave was charged, under
References and notes
an inert atmosphere, with 15 mL of CH2Cl2, 100 mg
(0.57 mmol) of 2-phenethylacrylic acid, 35 mg (0.023
mmol) of Ir-PHOX, then pressurized with H2 (50 atm)
and heated to 60 ꢂC. After 2 h, the crude product was
concentrated and the residue filtered on a short silica
column (eluent: diethyl ether/pentane 1:1) to give (R)-2-
methyl-4-phenylbutyric acid as a colourless liquid (ee
66%). 1H NMR (300 MHz, CDCl3): d = 1.29 (d,
J = 7.0 Hz, 3H, CH3), 1.79 (m, 1H, CH2), 2.07 (m, 1H,
CH2), 2.60 (m, 1H, CH), 2.72 (t, J = 8.0 Hz, 2H, CH2),
7.19–7.48 (m, 5H, arom), 11.61 (br s, 1H, COOH). 13C
NMR (75 MHz, CDCl3): d = 17.0, 33.4, 35.2, 38.9, 126.0,
128.5, 141.5, 183.1. After conversion of the acid to the
methyl ester, the ee was determined by Chiral GLC
(Chiraldex GTA column (0.25 mm · 50 m); nitrogen flow
3.5 mL/min; T = 93 ꢂC; tR = 81.26 min (R), 82.65 (S)).
22. Potapov, V. M.; Dem’yanovich, V. M.; Vendrova, O. E.;
Strel’tsova, E. S. J. Org. Chem. USSR (Engl. Transl.)
1981, 17, 2080.
1. Bauer, K.; Harder, U.; Sturm, W. (to Haarmann and
Reimer), DE 2308735, 1974.
2. Abate, A.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S.
In Perspectives in Flavor and Fragrance Research; Kraft,
P., Swift, K. A. D., Eds.; VHCA-Wiley-VCH: Zurich,
¨
2005; pp 55–65.
3. Sell, C. S. In Perspectives in Flavor and Fragrance
Research; Kraft, P., Swift, K. A. D., Eds.; VHCA-Wiley-
VCH: Zurich, 2005; pp 67–88.
¨
4. Chapuis, C.; Jacoby, D. Appl. Catal. A: Gen. 2001, 221,
93.
5. Ciappa, A.; Matteoli, U.; Scrivanti, A. Tetrahedron:
Asymmetry 2002, 13, 2193.
6. Ciappa, A.; Scrivanti, A.; Matteoli, U. J. Mol. Catal. A:
Chem. 2004, 219, 217.
7. Misun, M.; Pfaltz, A. Helv. Chim. Acta 1996, 79,
961.
8. Drent, E.; Arnoldy, P.; Budzelaar, P. H. M. J. Organomet.
Chem. 1993, 455, 247.
23. McIntyre, S.; Ho¨rmann, E.; Menges, F.; Smidt, S. P.;
Pfaltz, A. Adv. Synth. Catal. 2005, 347, 282.
24. Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; Ho¨rmann, E.;
McIntyre, S.; Menges, F.; Scho¨nleber, M.; Smidt, S. P.;
9. Scrivanti, A.; Matteoli, U. Tetrahedron Lett. 1995, 36,
9015.
10. Synthesis of 2-phenethylacrylic acid, 2: A magnetically
stirred stainless steel autoclave (total volume 150 mL) was
charged with 35 mL of THF, 2.57 g (19.8 mmol) of
but-3-ynyl-benzene, 11.2 mg (0.05 mmol) of Pd(OAc)2,
0.53 g (2.0 mmol) of 2-pyridyldiphenylphosphine, 0.26 mL
(4.0 mmol) of methanesulfonic acid, and 5.6 mL
(310 mmol) of H2O, then it was pressurized with CO
(30 atm) and heated at 50 ꢂC. After 24 h, the crude was
taken to dryness and the residue dissolved in diethyl ether.
The ethereal phase was extracted with satd aq NaHCO3.
The aq phase was washed with diethyl ether, then acidified
until pH = 1 and extracted with dichloromethane. After
filtration on a short silica gel column (eluent: diethyl
ether), removal of the solvent afforded 2 as a white solid
(3.21 g, 92% yield); 1H NMR (300 MHz, CDCl3): d = 2.68
(m, 2H, CH2), 2.88 (m, 2H, CH2), 5.66 (d, J = 1.2 Hz, 1H,
CH), 6.36 (d, J = 1.2 Hz, 1H, CH), 7.18–7.39 (m, 5H,
arom), 11.51 (br s, 1H, COOH). 13C NMR (75 MHz,
CDCl3): d = 33.9, 35.2, 126.4, 128.3, 128.8, 128.9, 139.7,
141.6, 173.0.
Wustenberg, B.; Zimmermann, N. Adv. Synth. Catal.
2003, 345, 33.
25. Matteoli, U.; Beghetto, V.; Scrivanti, A. J. Mol. Catal. A:
Chem. 1999, 140, 131.
¨
26. Ru/atropisomeric diphosphine hydrogenation of 2: In a
typical experiment (entry 2 of Table 3), a Schlenk flask was
charged with 10 mL of methanol, 500 mg (2.84 mmol) of
2-phenethylacrylic acid, 9.0 mg (0.018 mmol) of [Ru(benz-
ene)Cl2]2, 22.0 mg (0.036 mmol) of (S)-BINAP and
0.363 mL (2.84 mmol) of triethylamine. The solution was
kept under stirring until an orange solution was obtained,
and then, transferred via cannula into a magnetically
stirred stainless steel autoclave (total volume: 150 mL)
which was pressurized with H2 (100 atm). The reactor
temperature was kept at 0 ꢂC for 24 h. The crude product
was taken to dryness and the residue taken in CH2Cl2
(20 mL). The suspension was treated with 10% aq Na2CO3
until the aq phase is at pH = 11 and washed with diethyl
ether. The aqueous phase was acidified until pH = 1 and
extracted with CH2Cl2. Removal of the solvent afforded
(S)-2-methyl-4-phenylbutyric acid as a colourless liquid in
an 80% yield (ee 85%).
11. Zhang, W.; Carter, R. G. Org. Lett. 2005, 7, 4209.
12. Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R. J.
Am. Chem. Soc. 1987, 109, 1596.
13. Otha, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori,
R. J. Org. Chem. 1987, 52, 3176.
27. Oro, L. A.; Carmona, D.; Fraile, J. M. In Metal-Catalysis
in Industrial Organic Processes; Chiusoli, G. P., Maitlis,
P. M., Eds.; RSC Publishing: Cambridge, 2006; p 80.
28. Chan, A. S. C.; Laneman, S. A. (to Monsanto), U.S.
5,198,561, 1993.
14. Ito, Y.; Hayashi, T.; Kawamura, N.; Takemoto, I. (to
Sumitomo), U.S. 4,762,948, 1988.
29. Forman, G. S.; Ohkuma, T.; Hems, W. P.; Noyori, R.
Tetrahedron Lett. 2000, 41, 9471.
30. Schmid, R.; Foricher, J.; Cereghetti, M.; Heiser, B.;
Schonholzer, P. Helv. Chim. Acta 1991, 74, 370.
31. Brenna, E.; Dei Negri, C.; Fuganti, C.; Gatti, F. G.; Serra,
S. Tetrahedron: Asymmetry 2004, 15, 335.
32. The ee of alcohol 4 was determined as follows: A solution
of 4 in CH2Cl2 was treated with a solution of pyridinium
chlorochromate; after standard work-up the resulting
2-methyl-4-phenyl-butyraldehyde was analyzed by chiral
GC (Chiraldex GTA column (0.25 mm · 50 m); nitrogen
flow 3.8 mL/min; T = 82 ꢂC; tR = 149.04 (R), 152.61
(S).
15. Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.;
Kumobayashi, H.; Otha, T.; Takaya, H. J. Org. Chem.
1996, 61, 5510.
16. Deng, G.-J.; Yi, B.; Huang, Y.-Y.; Tang, W.-J.; He,
Y.-M.; Fan, Q.-H. Adv. Synth. Catal. 2004, 346, 1440.
17. Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard,
A. J.; Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries,
A. H. M.; de Vries, J. G.; Feringa, B. L. Angew. Chem.,
Int. Ed. 2005, 44, 4209, and references cited therein.
18. Takaya, H.; Otha, T.; Noyori, R.; Sayo, N.; Kumoba-
yashi, H.; Akutagawa, S. (to Takasago), U.S. 4,962,230,
1990.
19. Knochel, P.; Almena Perea, J. J.; Drauz, K.; Klement, I.
(to Degussa–Huls), U.S. 6,348,620, 2002.
20. Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int.
Ed. 1998, 37, 2897.
33. Hoffmann, R. W.; Haeberlin, E.; Rohde, T. Synthesis
2002, 2, 207.
34. Citralis Nitrileꢀ (3-methyl-5-phenyl-pentanenitrile) 5. 1H
NMR (300 MHz, CDCl3): d = 1.13 (d, J = 6.6 Hz, 3H,
CH3), 1.58–1.95 (m, 3H, CH2+CH), 2.31 (m, 2H, CH2),
21. Ir-PHOX catalyzed hydrogenation of 2: In a typical
experiment (entry 2 of Table 1), a magnetically stirred

A. Scrivanti et al. / Tetrahedron Letters 47 (2006) 9261–9265
9265
2.65 (m, 2H, CH2), 7.14–7.35 (m, 5H, arom). 13C NMR
(75 MHz, CDCl3): d = 19.3, 24.4, 29.8, 33.0, 37.4, 118.6,
126.0, 128.2, 128.4, 141.3.
37. Jackson, P. L.; Tays, K. L.; Maclin, K. M.; Ko, Y.-S.;
Vitharana, D.; Tsukamoto, T.; Stoermer, D.; Lu, X.-C.
M.; Wozniak, K.; Slusher, B. S. J. Med. Chem. 2001, 44,
4170.
38. Bianchi, M.; Menchi, G.; Francalanci, F.; Piacenti, F.;
Matteoli, U.; Frediani, P. J. Organomet. Chem. 1980, 188,
109.
35. The ee of nitrile 5 was determined by chiral GC: Chiraldex
GTA column (0.25 mm · 50 m); nitrogen flow 3.5 mL/
min; T = 120 ꢂC; tR = 64.30 (S), 65.25 (R).
36. Gilpin, M. L.; Payne, D. J.; Hargreaves Bateson, J. (to
SmithKline Beecham), U.S. 6,022,885, 2000.
39. Davis, R.; Untch, K. G. J. Org. Chem. 1981, 46, 2985.