Diasteroselective conjugate addition of diethylaluminum cyanide to a conjugated N -enoyl system: An alternative synthesis of (S)-pregabalin

Article abstract of DOI:10.1139/cjc-2013-0397

We have explored in this work the conjugate addition of diethylaluminum cyanide (Nagata's reagent) to an N-enoyl system bearing the (R)-4-phenyl-2- oxazolidinone chiral auxiliary. Since this method provided a practical synthesis of γ-amino acids, we report the conjugate addition of diethylaluminum cyanide as the key step in the synthesis of (S)-pregabalin 1 in a five-step sequence of reactions from commercially available starting materials.

Full text of DOI:10.1139/cjc-2013-0397

45
ARTICLE
Diasteroselective conjugate addition of diethylaluminum
cyanide to a conjugated N-enoyl system: an alternative
synthesis of (S)-pregabalin
Erika Tovar-Gudiño, Rosmarbel Morales-Nava, and Mario Fernández-Zertuche
Abstract: We have explored in this work the conjugate addition of diethylaluminum cyanide (Nagata’s reagent) to an N-enoyl
system bearing the (R)-4-phenyl-2-oxazolidinone chiral auxiliary. Since this method provided a practical synthesis of ␥-amino
acids, we report the conjugate addition of diethylaluminum cyanide as the key step in the synthesis of (S)-pregabalin 1 in a
five-step sequence of reactions from commercially available starting materials.
Key words: diethylaluminum cyanide, conjugate addition, chiral auxiliary, pregabalin.
Résumé : Dans les présents travaux, nous étudions l’addition conjuguée de cyanure de diéthylaluminum (réactif de Nagata) a` un
système N-énoyl portant l’auxiliaire chiral (R)-4-phényl-2-oxazolidinone. Comme cette méthode donne une synthèse pratique des
acides aminés ␥, nous présentons l’addition conjuguée du cyanure de diéthylaluminum en tant qu’étape clé de la synthèse de la
(S)-prégabaline 1 selon une séquence de réactions en cinq étapes, a` partir de matières disponibles dans le commerce. [Traduit par
la Rédaction]
Mots-clés : cyanure de diéthylaluminum, addition conjuguée, auxiliaire chiral, (S)-prégabaline.
Introduction
Results and discussions
Our synthetic strategy is outlined in Scheme 1. We envisioned a
strategy in which compound 1 could be prepared from 7a after
removal of the 1,3-oxazolidine chiral auxiliary and reduction of
the nitrile group. In turn, 7a could be obtained from 6 via the
conjugate addition of cyanide. The conjugate addition of diethyl-
aluminum cyanide to the ␣,␤-unsaturated N-enoyl systems 6 ap-
pealed to us as suitable to secure the ␤-sterogenic center of 1. In
this regard, it was expected that addition of diethylaluminum
cyanide (Nagata’s reagent) as the cyanide source to 6, bearing the
known D-phenylglycine-derived (R)-4-phenyl-1,3-oxazolidine-2-one
chiral auxiliary 5,6 would take place from the less hindered Si face
affording 7a with the required (S)-configuration at the ␤-stereogenic
center. Diethylaluminum cyanide has been shown to be not only
an efficient cyanating agent but also a Lewis acid10 with the pos-
sibility of coordinating to the oxygens of 6 and then delivering the
cyanide group from the Si face. With 7a at hand, 1 could be ob-
tained after removal of the chiral auxiliary and reduction of the
cyano group.
Therefore, our approach for the synthesis of (S)-pregabalin 1
began with the Horner−Wadsworth−Emmons olefination of alde-
hyde 2 (Scheme 2) to produce ester 3 in 86% yield. In a subsequent
step, ester 3 was subjected to a basic hydrolysis with lithium
hydroxide in aqueous methanol to afford acid 4 in 89% yield.
Preparation of the ␣,␤-unsaturated substrate 6 was then accom-
plished by the N-acylation of the known D-phenylglycine-derived
oxazolidinone 5 with acid 4 under an adaptation of Merck condi-
tions (trimethylacetyl chloride, Et3N, THF)11 to afford 6 in 62%
yield for the two steps.
The asymmetric conjugate addition of cyanide to ␣,␤-unsaturated
carbonyl substrates has great potential in organic synthesis, since
the resulting cyano adducts can be transformed to ␥-amino acids
such as ␥-aminobutyric acid (GABA) or its derivatives.1 Although
the enantioselective 1,4-conjugate addition of cyanide from a va-
riety of nucleophilic cyanide sources under catalytic methods is
very well documented,2 the conjugate addition of diethylaluminum
cyanide (Nagata’s reagent)3 to these type of substrates bearing
1,3-oxazolidinones chiral auxiliaries, to the best of our knowl-
edge, has not been previously reported in the literature. Only the
research group of Armstrong4 has reported the conjugate addi-
tion of acetone cyanohydrins, catalyzed by samarium (III) iso-
propoxide, to a series of substrates attached to the Evans chiral
auxiliary.5
As part of our ongoing program directed toward the design and
synthesis of chiral ␤-substituted ␥-amino acids, we have ex-
plored the conjugate addition of diethylaluminum cyanide to
some N-enoyl systems bearing both the L- and D-phenylglycine-
derived 4-phenyl-1,3-oxazolidine-2-one chiral auxiliaries.6 Encour-
aged by our results, we report in this work a practical synthesis of
(S)-(+)-3-aminomethyl-5-methylhexenoic acid 1 (pregabalin) (Fig. 1),
a structural analog of GABA, in a five-step sequence of reactions
from commercially available starting materials, a synthetic route
adaptable to the synthesis of analogues of this important pharma-
ceutical agent. Due to its wide spectrum of biological activities as
a clinical agent on the treatment of neurological disorders,7 sev-
eral approaches to the synthesis of 1 have been reported in the
literature8 including some industrial procedures.9
With the ␣,␤-unsaturated substrate 6 at hand, our effort was
then oriented toward the crucial conjugate addition of Et2AlCN to
Received 3 September 2013. Accepted 5 November 2013.
E. Tovar-Gudiño, R. Morales-Nava, and M. Fernández-Zertuche. Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos.
Av. Universidad 1001, Col. Chamilpa, Cuernavaca, Morelos, México 62209.
Corresponding author: Mario Fernández-Zertuche (e-mail: mfz@uaem.mx).
Can. J. Chem. 92: 45–48 (2014) dx.doi.org/10.1139/cjc-2013-0397
Published at www.nrcresearchpress.com/cjc on 7 November 2013.

46
Can. J. Chem. Vol. 92, 2014
Fig. 1. (S)-Pregabalin.
Synthesis of (E)-5-methylhex-2-enoic acid (4)
Light yellow oil, 2.94 g (89%). HRMS (FAB+) calcd. for C7H12O2:
128.0750; found (M+1): 129.0915. IR (ATR, cm−1): 2958, 2872, 1691,
1
1648, 1418, 984, 687. H NMR (CDCl3, 200 MHz) ␦: 11.25 (br s, 1H),
7.07 (dt, J = 16.0, 8.0 Hz, 1H), 5.82 (dt, J = 14.0, 2.0 Hz, 1H), 2.13 (td, J =
7.0, 2.0 Hz, 2H), 1.79 (hept, J = 8.0 Hz, 1H), 1.28 (t, J = 6.8 Hz, 3H), 0.93
(d, J = 6.0 Hz, 6H). 13C NMR (CDCl3, 50 MHz) ␦: 172.49, 151.52, 121.90,
41.71, 27.96, 22.53.
Synthesis of (R,E)-3-(5-methylhex-2-enoyl)-4-phenyl-1,3-oxazolidine-2-
one (6)
this substrate (Scheme 3). Conjugate addition of Et2AlCN to 6 was
carried out in toluene at 0 °C to produce a mixture of the 1,4-
adducts 7a and 7b in 66% yield and in an 87:13 ratio as determined
by gas chromatography.
White solid, 0.36 g (62%), mp = 66–68 °C. IR (ATR, cm−1): 2955,
1
2920, 2870, 1773, 1684, 1634, 1324, 1205, 756, 712, 695. H NMR
(CDCl3, 200 MHz) ␦: 7.44–7.30 (m, 5H), 7.26 (dt, J = 16.0, 2.0 Hz, 1H),
7.08 (dt, J = 14.0, 8.0 Hz, 1H), 5.49 (dd, J = 8.0, 4.8 Hz, 1H), 4.70 (t, J =
8.0 Hz, 1H), 4.28 (dd, J = 8.0, 4.0 Hz, 1H), 2.16 (td, J = 8.0, 2.0 Hz, 2H),
1.76 (hept, J = 6.0 Hz, 1H), 0.92 (d, J = 6.0 Hz, 6H). 13C NMR (CDCl3,
50 MHz) ␦: 164.78, 158.75, 151.38, 139.27, 129.37, 128.85, 126.17,
121.30, 70.14, 57.94, 42.03, 28.09, 22.58.
The mixture was easily separated in column chromatography
(silica gel) to afford 7a and 7b in a pure form. The diastereomeric
ratio observed in this reaction shows the well-established effec-
tiveness of the phenyl substituent of the chiral auxiliary12 in this
case to shield the Re face of the diastereotopic double bond of the
␣,␤-unsaturated substrate 6. Determination of the absolute con-
figuration of the newly formed ␤-stereogenic center was accom-
plished at the end of our procedure by correlating the optical
rotation of the final product with the optical rotations of 1 re-
ported in the literature.
After securing the ␤-stereogenic center, our next goal was to
remove the chiral auxiliary and then reduce the cyano group to
the corresponding amino group. Removal of the chiral auxiliary
was accomplished by treatment of 7a with lithium peroxide in
aqueous THF according to the protocol reported by Evans.13 In the
final step, (S)-(+)-pregabalin 1 was obtained when reduction of the
cyano group was performed by hydrogenolysis under Raney
nickel7f with a 95% yield for the last two steps (Scheme 4). Both
1H and 13C NMR spectral data are identical to those reported pre-
viously. In addition, the optical rotation of 1 is within the range
of those optical rotations reported in previous synthesis,8g,8i,9b
assessing the correct (S)-configuration at the ␤-stereogenic cen-
ter of 1.
Synthesis of (S)-4-methyl-2-(2-oxo-2-((R)-2-oxo-4-phenyloxazolidin-
3-yl)ethyl)pentanenitrile (7a) and (R)-4-methyl-2-(2-oxo-2-((R)-2-
oxo-4-phenyloxazolidin-3- yl)ethyl)pentanenitrile (7b)
In a 50 mL round bottomed flask, compound 6 (1.56 g,
5.69 mmol) was dissolved in anhydrous toluene (5.0 mL) under a
nitrogen atmosphere and the resulting solution cooled to 0 °C. To
this mixture, a 1.0 mol/L solution of Et2AlCN in toluene (11.39 mL,
11.39 mmol) was added slowly. The resulting mixture was stirred
for 3 h at 0 °C and then for 12 h at room temperature. When the
reaction was over, methanol (15.0 mL) was added and the resulting
solution acidified to pH = 1 with 10.0 mol/L HCl. The solvents were
evaporated and the resulting crude product was redissolved in
dichloromethane (15.0 mL). The organic layer was separated, dried
over Na2SO4, and evaporated to give the mixture of diastereoiso-
mers 7a−7b in an 87:13 ratio (GC-MS). The diastereoisomers were
separated by column chromatography (silica gel hexanes − ethyl
acetate 1:3) yielding 7a as a light yellow oil, 0.98 g (57%). [␣]D −76.6
(c 1.0, THF). HRMS (FAB+) calcd. for C17H20N203: 300.1474; found
(M+1): 301.1462. IR (ATR, cm−1): 2946, 2916, 2848, 2240, 1778, 1702,
1385, 1201, 759, 708. 1H NMR (CDCl3, 200 MHz) ␦: 7.45–7.29 (m, 5H),
5.46 (dd, J = 8.0, 4.0 Hz, 1H), 4.75 (t, J = 8.0 Hz, 1H), 4.35 (dd, J = 10.0,
4.0 Hz, 1H), 3.41(dd, J = 19.0, 12.0 Hz, 1H), 3.07 (dd, J = 19.0, 4.0 Hz,
1H), 3.03 (m, 1H), 1.85 (m, 1H), 1.64 (m, 1H), 1.26 (m, 1H), 0.93 (d, J =
6.0 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H). 13C NMR (CDCl3, 50 MHz) ␦:
169.09, 153.863, 138.80, 129.46, 129.19, 126.31, 121.54, 70.63, 57.67,
40.82, 38.96, 26.12, 25.21, 23.04, 21.39. 7b, light yellow oil, 0.15 g
(9%). [␣]D −78.3 (c 1.0, THF). HRMS (FAB+) calcd. for C17H20N203:
300.1474; found (M+1): 301.1562. IR (ATR, cm−1): 2946, 2916, 2848,
2240, 1778, 1702, 1385, 1201, 759, 708. 1H NMR (CDCl3, 200 MHz) ␦:
7.41–7.27 (m, 5H), 5.44 (dd, J = 8.0, 4.0 Hz, 1H), 4.73 (t, J = 8.0 Hz, 1H),
4.32 (dd, J = 10.0, 4.0 Hz, 1H), 3.31(m, 2H), 3.09 (m, 1H), 1.85 (m, 1H),
1.64 (m, 1H), 1.30 (m, 1H), 0.95 (d, J = 4.0 Hz, 3H), 0.92 (d, J = 6.0 Hz,
3H). 13C NMR (CDCl3, 50 MHz) ␦: 169.224, 153.121, 138.72, 129.78,
129.46, 126.30, 121.53, 70.75, 58.07, 41.14, 38.94, 26.54, 25.36, 23.28,
21.61.
Conclusions
In summary, we have accomplished a short and efficient syn-
thesis of (S)-pregabalin 1 in a five-step sequence of reactions and a
26% overall yield in a process suitable for a large-scale synthesis.
The key step in this synthesis is a diastereoselective 1,4-conjugate
addition of cyanide from Et2AlCN to an ␣,␤-unsaturated system
bearing the (R)-4-phenyl-1,3-oxazolidine-2-one chiral auxiliary. To
the best of our knowledge, the conjugate addition of Nagata’s
reagent to these type of substrates has not been previously re-
ported in the literature. This work provides an alternative syn-
thetic route toward an efficient preparation of 1.
Experimental
General
1H NMR spectra were recorded at 200 MHz with CDCl3 as solvent
and tetramethylsilane as internal standard. 13C NMR spectra were
recorded at 50 MHz with CDCl3 as solvent. THF and toluene were
dried by distillation over sodium benzophenone ketyl. All other
solvents were used after distillation at normal pressure.
Synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (1)
In a round-bottomed flask, lithium hydroxide (126.30 mg,
5.28 mmol) was suspended in distilled water (16.40 mL) and 35%
H2O2 (2.06 mL, 21.12 mmol). The resulting solution was stirred at
0 °C for 20 min and then 7a (0.79 g, 2.64 mmol) dissolved in THF
(20.0 mL) was added. The resulting mixture was stirred for 30 min
at 0 °C and then for 24 h at room temperature. When the reaction
was over, the solvents were evaporated and the remaining aque-
ous solution washed with dichloromethane (2 × 30.0 mL). The
aqueous layer was acidified to pH = 1 with a 10.0 mol/L solution of
HCl and was extracted with ethyl acetate (3 × 30.0 mL). The organic
layers were combined, dried over Na2SO4, and evaporated to give
Synthesis of (E)-ethyl-5-methylhex-2-enoate (3)
Light yellow oil, 12.2 g (86%). IR (ATR, cm−1): 2958, 2872, 1719,
1654, 1178, 1046, 983. 1H NMR (CDCl3, 200 MHz) ␦: 6.94 (dt, J = 15.4,
7.4, Hz, 1H), 5.80 (dt, J = 15.8, 1.2 Hz, 1H), 4.18 (quart, J = 6.8 Hz, 2H),
2.08 (td, J = 6.6, 1.2 Hz, 2H), 1.76 (hept, J = 6.6 Hz, 1H), 1.28 (t, J =
6.8 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3, 50 MHz) ␦:
166.26, 147.80, 122.27, 59.92, 41.40, 27.82, 22.30, 14.24.
Published by NRC Research Press

Tovar-Gudiño et al.
47
Scheme 1. Synthetic strategy toward (S)-pregabalin.
Scheme 2. Synthesis of substrate 6.
Scheme 3. Conjugate addition of Et2AlCN.
Scheme 4. Preparation of (S)-pregabalin 1.
a residue that was immediately treated with ammonium hydrox-
ide (27.6 mL), ethanol (100.0 mL), and Raney nickel (274.0 mg)
under a hydrogen atmosphere for 24 h. The resulting mixture was
filtered through a bed of celite, concentrated, and acidified by the
addition of 10.0 mol/L solution of HCl affording 0.38 g (95%) of 1 as
its hydrochloride salt. A portion of the resulting hydrochloride
salt of 1 was subjected to an ion-exchange chromatography
(Dowex 50WX8-200) to characterize the product by NMR spectros-
copy. [␣]D + 11.3 (c 1.0, H2O) (lit.9i [␣]D + 10.1 (c 1.0, H2O). IR (ATR,
cm−1): 2955, 2895, 2687, 2602, 2206, 1644, 1546, 1387, 1334, 1278,
700. 1H NMR (D2O, 400 MHz) ␦: 2.87 (dd, J = 13.0, 5.6 Hz, 1H), 2.80
(dd, J = 13.0, 6.8 Hz, 1H), 2.15 (dd, J = 14.8, 6.0 Hz, 1H), 2.01 (m, 1H),
1.51 (m, J = 6.8 Hz, 1H), 1.07 (dd, J = 7.2 Hz, 2H), 0.75 (d, J = 4.8 Hz, 3H),
0.73 (d, J = 4.8 Hz, 3H). 13C NMR (D2O, 100 MHz) ␦: 181.17, 43.74,
40.75, 40.62, 31.68, 24.39, 21.98, 21.50.
Supplementary material
Supplementary material is available with the article through
the journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/cjc-2013-0397.
Published by NRC Research Press

48
Can. J. Chem. Vol. 92, 2014
Ekhato, V.; Kinsora, J. J.; Field, M. J.; Heffner, T. G.; Meltzer, L. T.;
Schwarz, J. B.; Taylor, C. P.; Thorpe, A. J.; Vortanian, M. G.; Wise, L. D.;
Zhi-Su, T.; Weber, M. L.; Wustrow, D. J. J. Med. Chem. 2005, 48, 2294. doi:10.
1021/jm049762l.
Acknowledgements
The authors wish to thank CONACyT of México (82129) for fi-
nancial support for this work and a graduate student scholarship
awarded (226849) to Erika Tovar-Gudiño.
(8) (a) Bobade, V. D.; Mhaske, P. C.; Vadgaonkar, K. S.; Shelke, S. H. Monatsh.
Chem. 2012, 143, 847. doi:10.1007/s00706-011-0654-8; (b) Yu, H. J.; Shao, C.;
Cui, Z.; Feng, C. G.; Lin, G. Q. Chem Eur. J. 2012, 18, 13274. doi:10.1002/chem.
201202660; (c) Liu, J.; Wang, X.; Ge, Z. M.; Sun, Q.; Cheng, T. M.;
Li, R. T. Tetrahedron 2011, 67, 636. doi:10.1016/j.tet.2010.11.053; (d) Bassas, O.;
Huuskonen, J.; Rissanen, K.; Koskinen, A. M. P. Eur. J. Org. Chem. 2009, 1340.
doi:10.1002/ejoc.200801220; (e) Felluga, F.; Pitacco, G.; Valentin, E.;
Venneri, C. D. Tetrahedron: Asymmetry. 2008, 19, 945. doi:10.1016/j.tetasy.2008.
03.014; (f) Izquierdo, S.; Aguilera, J.; Bushmann, H. H.; García, M.;
Torrens, A.; Ortuño, R. M. Tetrahedron: Asymmetry. 2008, 19, 651. doi:10.1016/
j.tetasy.2008.03.005; (g) Hammersak, Z.; Stipetie, I.; Advagie, A. Tetrahedron:
Asymmetry. 2007, 18, 1481. doi:10.1016/j.tetasy.2007.06.014; (h) Ok, T.; Jean, A.;
Lee, J.; Lim, J. H.; Hong, C. S.; Lee, H. S. J Org. Chem. 2007, 72, 7390. doi:10.
1021/jo0709605; (i) Rodríguez, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron
Lett. 2007, 48, 4305. doi:10.1016/j.tetlet.2007.04.054; (j) Chen, Z.; Chen, Y.;
Hu, J. W. Synlett 2004, 1763. doi:10.1055/s-2004-829568; (k) Sammis, G. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442. doi:10.1021/ja034635k;
(l) Burk, M. J.; de Koning, P. D.; Grote, T. M.; Hoekstra, M. S.; Huge, G.;
Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.; Mulhern, T. A.;
Ramsden, J.; Wade, R. A. J. Org. Chem. 2003, 68, 5731. doi:10.1021/jo034397b.
(9) (a) Martínez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L. Org.
Process Res. Dev. 2008, 12, 392. doi:10.1021/op7002248; (b) Hoekstra, M. S.;
Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.;
Huckabee, B. K.; Hendrikson, V. S.; Franklin, L. C.; Granger, E. J.;
Karric, G. L. Org. Process Res. Dev. 1997, 1, 26. doi:10.1021/op9600320.
(10) Merino, P.; Tejero, T.; Revuelta, J.; Romero, P.; Cicchi, S.; Mannucci, V.;
Brandi, A.; Goti, A. Tetrahedron: Asymmetry 2003, 14, 367. doi:10.1016/S0957-
4166(02)00832-7.
References
(1) Ordoñez, M.; Cativiela, C. Tetrahedron:Asymmetry 2007, 18, 3. doi:10.1016/j.
tetasy.2006.12.001.
(2) (a) Provencher, B. A.; Bartelson, K. J.; Liu, Y.; Foxman, B. M.; Deng, L. Angew.
Chem. Int. Ed. 2011, 50, 10565. doi:10.1002/anie.201105536; (b) Bernal, P.;
Fernández, R.; Lassaletta, J. M. Chem. Europ. J. 2010, 16, 7714. doi:10.1002/
chem.201001107; (c) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2010, 132, 8862. doi:10.1021/ja1035286; (d) Tanaka, Y.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072. doi:10.1021/ja801201r;
(e) Tanaka, Y.; Kanai, M.; Shibasali, M. Synlett 2008, 2295. doi:10.1055/s-2008-
1078264; (f) Madhaven, N.; Weck, M. Adv. Synth and Cat. 2008, 350, 419.
doi:10.1002/adsc.200700491; (g) Bernardi, L.; Fini, F.; Fochi, M.;
Ricci, A. Synlett 2008, 1857. doi:10.1055/s-2008-1078496; (h) Iida, H.;
Moromizato, T.; Hamana, H.; Matsumoto, K. Tetrahedron Lett. 2007, 48, 2037.
doi:10.1016/j.tetlet.2006.12.145; (i) Mita, T.; Sasaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514. doi:10.1021/ja043424s.
(3) Nagata, W.; Yoshioka, M. Org. React. 1977, 25, 255. doi:10.1002/0471264180.
or025.03.
(4) Armstrong, A.; Convine, N. J.; Popkin, M. E. Synlett 2006, 1589. doi:10.1055/
s-2006-941584.
(5) Evans, D. A. Aldrichimica Acta 1982, 15, 23.
(6) Nicolás, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766. doi:10.1021/
jo00055a039.
(7) (a) Reinares, M.; Rosa, A. R.; Franco, C.; Goikolea, J. M.; Fountoulakis, K.;
Siamouli, M.; Gonda, X.; Frangou, S.; Vieta, E. Int. J. Neuropsychop. 2013, 16,
485. doi:10.1017/S1461145712000491; (b) Wensel, T. M.; Powe, K. W.;
Cates, M. E. Ann. Pharmacother. 2012, 46, 424. doi:10.1345/aph.1Q405;
(c) Ogawa, S.; Satoh, J.; Arakawa, A.; Yoshiyama, T.; Suzuki, M. Drug Safety
2012, 35, 793. doi:10.1007/BF03261976; (d) Bockbroder, H. N.; Radulovic, L. L.;
Posvar, E. L.; Strand, J. C.; Alvey, C. W.; Busch, J. A.; Randinitis, E. J.;
Corrigan, B. W.; Haig, G. M.; Boyd, R. A.; Wesche, D. L. J. Clin Pharmcol. 2010,
50, 941. doi:10.1177/0091270009352087; (e) Silverman, R. B. Angew. Chem. Int.
Ed. 2008, 47, 3500. doi:10.1002/anie.200704280; (f) Bellioti, T. R.; Capiris, T.;
(11) (a) Prashad, M.; Kim, H. Y.; Har, D.; Repic, O.; Blacklock, T. J. Tetrahedron Lett.
1998, 39, 9369. doi:10.1016/S0040-4039(98)02112-1; (b) Ho, G.-J.; Mathre, D. J.
J. Org. Chem. 1995, 60, 2271. doi:10.1021/jo00112a060.
(12) Lou, B.-S.; Li, G.; Lung, F.-D.; Hruby, V.J. J. Org. Chem. 1995, 60, 5509. doi:10.
1021/jo00122a033.
(13) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83. (b) Evans, D. A.;
Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141. doi:10.1016/S0040-
4039(00)61830-0.
Published by NRC Research Press