Enantioselective total syntheses of ropivacaine and its analogues

Article abstract of DOI:10.1016/j.tetlet.2008.06.028

An alternative asymmetric synthesis of ropivacaine and analogues employing the 'cation pool' strategy and host/guest supramolecular co-catalysis approach is presented. In this study, chiral auxiliaries, several soft nucleophiles as well as one-pot conditions for anodic oxidation, followed by nucleophilic addition, have been applied.

Full text of DOI:10.1016/j.tetlet.2008.06.028

Tetrahedron Letters 49 (2008) 5098–5100
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective total syntheses of ropivacaine and its analogues
a,
Nagula Shankaraiah a, Ronaldo Aloise Pilli b, , Leonardo S. Santos
*
*
a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, Talca University, Talca, PO Box-747, Chile
b Instituto de Química, UNICAMP, PO Box 6154, 13083-970 Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An alternative asymmetric synthesis of ropivacaine and analogues employing the ‘cation pool’ strategy
and host/guest supramolecular co-catalysis approach is presented. In this study, chiral auxiliaries, several
soft nucleophiles as well as one-pot conditions for anodic oxidation, followed by nucleophilic addition,
have been applied.
Received 15 April 2008
Revised 3 June 2008
Accepted 5 June 2008
Available online 12 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Ropivacaine
Levobupivacaine
Anodic oxidation
Cation pool
Supramolecular complex
Bupivacaine is the most widely used drug in childbirth centers
as the anesthetic agent given to pregnant women. It has remained
the main drug for long-acting local anesthesia for many years.
Bupivacaine inhibits calcium channels of central nervous system
(CNS), but its systemic neurotoxic effects (e.g., convulsions, sei-
zures) affect infants and mothers in childbirth. Local anesthetics
bind to the ‘inner vestibule’ of the Na+ channel and an interesting
feature of their mechanism of action is that anesthetic drugs affin-
ity to the Na+ channel varies with the gating state of the channel.
Finally, the search for less cardiotoxic but equally long-acting local
anesthetic has led to the synthesis and development of levobupiva-
caine (1) and ropivacaine (2), which was recently introduced as a
new alternative for long-acting local anesthetic drug, being closely
related to mepivacaine (3) and levobupivacaine (1) that were first
synthesized by Ekenstam and co-workers in the mid-1950s (Fig.
1).1 After several experimental and clinical studies, it was con-
firmed that levobupivacaine (1) and ropivacaine (2) afforded lower
and different toxicity profile at least 70% less compared with
bupivacaine that are widely used in Europe and USA as anesthetics
in childbirth.2,3 Recently, Ramachandran and co-workers reported
an asymmetric synthesis of levobupivacaine.4 However, there are
few methods available for the enantioselective construction of pip-
ecolic moiety in high yields. Generally, the main process available
consists of resolution of racemic mixtures containing the pipecolic
ring. Thus, we disclose a novel alternative to reach this important
H
R = n-Bu, 1
R = n-Pr, 2
R = CH3, 3
N
N
R
O
Figure 1. Worldwide used anesthetics levobupivacaine (1), ropivacaine (2), and
mepivacaine (3).
class of compounds featuring an efficient and practical synthesis
of (L)-pipecolic acid derivatives. Our approach is based on the dia-
stereoselective addition of NCÀ to N-acyliminium ions bearing a
chiral auxiliary (a-phenylmenthyl) for the introduction of asym-
metry in 1–3.
Our strategy allowed the use of an interesting new approach to
obtain directly a N-acyliminium ion through anodic oxidation. The
advantages of this technique lie in its utility for selective oxidation
of cyclic N-carbamates generating highly reactive intermediates
under essentially neutral conditions.5 We also employed the ‘cat-
ion pool’ technique that is useful for N-acyliminium ion generation,
in which ions are accumulated in solution by low-temperature
electrolysis.6 In the next step, the reactive intermediates are
allowed to react in situ with nucleophiles. The idea has been suc-
cessfully applied to N-acyliminium ions.7,8 Initially, we set up some
model experiments to optimize the critical nucleophilic addition
step (TMSCN, NaCN, or n-Bu3SnCN) to chiral N-acyliminium ion
5a. According to Table 1, when using 8-phenylmenthyl as chiral
auxiliary (entry 1), isolation of the corresponding a-methoxy car-
* Corresponding authors. Tel: +56 71 201575; fax: +56 71 200448 (L.S.S.); tel.:
+55 19 3788 3114 (R.A.P).
E-mail addresses: pilli@iqm.unicamp.br (R. A. Pilli), lssantos@utalca.cl (L. S.
Santos).
bamate, followed by TMSCN addition catalyzed by TMSOTf in
CH2Cl2 at À78 °C, provided 6a in 85% yield and 76% ee. The
enantiomeric excess was determined after hydrolysis of 6a to
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.028

N. Shankaraiah et al. / Tetrahedron Letters 49 (2008) 5098–5100
5099
Table 1
Addition of cyanide to N-acyliminium ions 5
Entry
1
5
Conditions
Time (h)
5
Yielda (%)
85
ee (%)
76 (S)
5a
(a) Pt anode/W cathode MeOH, 100 mA, À2eÀ, 0 °C, 5 h
(b) TMSOTf, TMSCN, CH2Cl2, À78 °C, 5 min
(a) Pt anode/W cathode MeOH, 100 mA, À2eÀ, 0 °C, 5 h
(b) b-CD, TMSOTf, TMSCN, CH2Cl2, À40 °C, 5 min
2
5a
5
65
91 (S)
3
4
5
6
5a
5a
5a
5a
Pt anode/W cathode NaCN, MeOH/H2O (2:1), 100 mA, À2eÀ, 0 °C, 5 h
Pt anode/W cathode TMSCN, CH2Cl2, 70 mA, À2eÀ, À78 °C
Pt anode/W cathode Bu3SnCN, CH2Cl2, 70 mA, À2eÀ, À78 °C
5
2
3
5
—
—
18
40
35
80 (S)
85 (S)
90 (S)
(a) Pt anode/W cathode CH2Cl2, 60 mA, À2eÀ, À40 °C, b-CD, 5 h
(b) TMSOTf, TMSCN, À40 °C
7
5b
(a) Pt anode/W cathode CH2Cl2, 60 mA, À2eÀ, À40 °C, b-CD, 5 h
(b) TMSOTf, TMSCN, À40 °C
5
65
30 (S)
a
Isolated yields.
(S)-(À)-pipecolic acid, and the absolute configuration was deter-
mined to be (S), [
a]
À26 (c 1.0, H2O), mp 271–272 °C (lit. mp
D
+
272 °C).9 Our first attempt to use the ‘cation pool’ approach and
NCÀ as a nucleophile (entry 3) gave a complex mixture and no
product was observed in the crude reaction mixture when NaCN
was used.10 When TMSCN was used as nucleophile (entry 4), the
‘cation pool’ approach afforded (S)-6a in 18% yield and 80% ee.
Using Bu3SnCN as nucleophile (entry 5), the yield increased to
40% and the ee to 85%, respectively.
N
+
N
O
O
HO
HO
HO
HO
O
O
5a
β-CD/5a
HO
HO
HO
Next, we figured out to use b-CD as co-catalyst in the reaction.
The use of cyclodextrins as mild and efficient biomimetic catalysts
in promoting various transformations is well known.11,12 Cyclo-
dextrins (CDs) are cyclic oligosaccharides possessing hydrophobic
cavities, which bind substrates selectively and catalyze chemical
reactions with high selectivity. CDs catalyze reactions through a
supramolecular manner involving reversible formation of host/
guest complexes by non-covalent bonding. Complexation depends
on the size, shape, and hydrophobicity of the guest molecule. As
depicted in Table 1 (entry 6), the production of a ‘cation pool’ of
5a (Scheme 1) followed by the addition of TMSCN and TMSOTf at
À40 °C afforded (S)-6a in 35% yield and 90% ee. Then, using the
same protocol with N-Boc precursor 5b and b-CD as additive, the
yield of 6b was 65% but low enantiomeric excess was observed
(30% ee of S isomer).
Figure 2.
The absolute configuration at the newly generated stereogenic
center of 6a was established after acidic hydrolysis to give pipeco-
lic acid accompanied by recovery of the chiral auxiliary (95%), as
mentioned above. The Re-face selectivity displayed by the chiral
N-acyliminium ion 5a was rationalized based on our previous
results with 8-phenylmenthyl chiral auxiliaries13 and was assigned
to the kinetically preferred attack of the nucleophile to the s-cis
conformation of N-acyliminium ion 5a (Fig. 2)14 that might be
enforced by
p
-stacking interactions15 involving the low-lying
LUMO of the carbonyl group and HOMO of the phenyl substituent
Scheme 2.
Finally, as shown in Table 1 and entry 2, using b-CD as additive
and the two-step procedure afforded better % ee (90%) with mod-
erate yield (65%) when compared with entry 1 where b-CD was
not employed, under otherwise identical experimental conditions.
We rationalized the formation of a supramolecular arrangement
(b-CD/5a, Fig. 2), which might favor Re-face attack of the nucleo-
phile. The lower yield observed in entry 2 might be the result of
competition for Lewis acid by the hydroxyl groups in b-CD. In fact,
increasing the amount of TMSOTf and/or TMSCN to 4 equiv or
higher gave only poor selectivities. If nucleophilic solvent is em-
ployed, the N-acyl iminium ion is trapped and stabilized that is
not the case with aprotic solvents such as CH2Cl2. In this case,
decomposition of electrochemically generated N-iminium ion
might ensue.
The xylamide 7 was obtained from 6a in two steps by HCl
deprotection of chiral auxiliary (recovered in 95% yield), and con-
comitant production of pipecolic acid. Next, crude pipecolic acid
was treated with EDC/HOBt and 2,6-dimethylaniline affording 7
in 88% yield, [a]D 35 (c 2.0, HCl 1 M), mp 129–130 °C (lit. for R iso-
mer [
a
]
À46 (c 2.3, HCl 2.3 M), mp 130 °C).16,17 The introduction
D
of alkyl chains (R = n-Bu, n-Pr, and Me) was carried out using n-
butyl bromide, n-propyl bromide, and K2CO3 in MeCN, at reflux
for 12 h. Levobupivacaine 1 was obtained in 80% yield and no race-
mization was observed in the process (Scheme 3), [
a
]
À77 (c 5.0,
D
MeOH), mp 135–137 °C.16,17 Analogously, ropivacaine
2 was
obtained in 85% yield, [
a]
À78 (c 5.0, MeOH), mp 143–145 °C.17
D
Finally, mepivacaine 3 was achieved using reductive amination of
i) 6M HCl/CHCl3
48 h, reflux
NC-
Table 1
H
N
NH2
+
ii)
N
CN
OR
6a
N
"cation-pool"
N
N
N
CN
OR
6a,b
H
O
O
O
OR
5a
5b
O
R
O
EDC/HOBt
CH2Cl2, rt, 12 h
4a, R = 8-phenylmenthyl
4b, R = Boc
7
Scheme 1.
Scheme 2.

5100
N. Shankaraiah et al. / Tetrahedron Letters 49 (2008) 5098–5100
6. (a) Yoshida, J.; Suga, S. Chem. Eur. J. 2002, 8, 2650–2658; (b) Suga, S.; Okajima,
R
Br
M.; Fujiwara, K.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 7941–7942.
7. (a) Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.; Fujiwara, K. J.
Am. Chem. Soc. 1999, 121, 9546–9549; (b) Suga, S.; Okajima, M.; Yoshida, J.
Tetrahedron Lett. 2001, 42, 2173–2176; (c) Suga, S.; Suzuki, S.; Yoshida, J. J. Am.
Chem. Soc. 2002, 124, 30–31; (d) Suga, S.; Watanabe, M.; Yoshida, J. J. Am. Chem.
Soc. 2002, 124, 14824–14825; (e) Suga, S.; Nagaki, A.; Yoshida, J. Chem.
Commun. 2003, 354–355; (f) Suga, S.; Nagaki, A.; Tsutsui, Y.; Yoshida, J. Org.
Lett. 2003, 5, 945–947.
H
H
N
N
K2CO3/CH3CN
reflux, 12 h
N
R
N
H
O
O
7
R = Bu; Levobupivacaine, (1)
R = Prop; Ropivacaine, (2)
HCHO/MeCN
NaCNBH3/AcOH
8. Suga, S.; Suzuki, S.; Yamamoto, A.; Yoshida, J. J. Am. Chem. Soc. 2000, 122,
10244–10245.
H
N
9. Compared to the available data found in http://www.sigmaaldrich.com.
10. ‘Cation pool’ procedure: The anodic oxidation was carried out in an undivided
glass cell equipped with a platinum plate anode (4.0 cm2) and a tungsten wire
cathode. A solution of 4a,b (0.1 mmol) in 0.2 M Et4NOTs/CH2Cl2 (10.0 mL) was
placed in the cell and the substrate was electrolyzed at constant current (70–
100 mA). The substrate was electrolyzed at constant current (between 70 and
100 mA) under magnetic stirring and the reaction temperature was maintained
between À40 and À78 °C with external bath. After the passage of 3.0 F.molÀ1 of
electricity, the nucleophile (0.3 mmol) was added at À40 °C (or À78 °C, see
Table 1) to the ‘cation pool’ of 5, and the reaction mixture was stirred for
further 0.5 h. The solvent was removed under reduced pressure and the residue
purified by flash chromatography on silica gel.
11. Surendra, K.; Krishnaveni, S. N.; Sridhar, R.; Rao, K. R. J. Org. Chem. 2006, 71,
5819–5821.
12. Santos, L. S.; Fernandes, S. A.; Pilli, R. A.; Marsaioli, A. J. Tetrahedron: Asymmetry
2003, 17, 2515–2519.
13. (a) Wanner, K. T.; Kartner, A. Heterocycles 1987, 26, 921–924; (b) D’Oca, M. G.
M.; Pilli, R. A.; Vencato, I. Tetrahedron Lett. 2000, 41, 9709–9712.
14. (a) Seebach, D.; Lamatsch, B. Helv. Chim. Acta 1992, 75, 1095–1110; (b) Kupfer,
R.; Würthwein, E.-U.; Nagel, M.; Allmann, R. Chem. Ber. 1985, 118, 643–652.
15. Jones, G. B.; Chapman, B. J. Synthesis 1995, 475–497.
N
Me
O
Mepivacaine (3)
Scheme 3.
7 with formaldehyde (30% v/v) in MeCN and NaCNBH3 reduction
affording 3 in 85% yield, [
a]
À43 (c 5.0, MeOH), mp 148–
D
150 °C.16,18
In conclusion, an alternative asymmetric synthesis of ropiva-
caine and analogues employing the ‘cation pool’ strategy and
host/guest supramolecular co-catalysis approach is presented. In
this protocol, we applied anodic oxidation as well as soft nucleo-
philes to develop a short and high-yielding synthesis of pipecolic
derivatives 1–3.
16. Tullar, B. F. J. Med. Chem. 1971, 14, 891–892.
17. Ekenstam, T. A. B.; Christer, B. Int. Patent WO 85/00599, 1985.
Acknowledgments
18. Analytical data: Pipecolic acid: mp 271–272 °C. [
a
]
D À26 (c 1.0, H2O), 76% ee. 1
H
NMR (300 MHz, D2O), d 1.40–1.58 (m, 3H), 1.69–1.75 (m, 2H), 2.06 (d, 1H, J
12.8 Hz), 2.85 (t, 1H, J 12.5 Hz), 3.26 (d, 1H, J 12.5 Hz), 3.43 (d, 1H, J 7.7 Hz). 13
NMR (75 MHz, D2O), d 21.4 (CH2), 21.7 (CH2), 26.3 (CH2), 43.4 (CH2), 58.8 (CH),
C
L.S.S. thanks IFS (F/4195-1), Organisation for the Prohibition of
Chemical Weapons, and Programa de Investigación en Productos
Bioactivos-UTalca for support of research activity. S.N. is thankful
to PBCT (PSD-50) for financial support. FAPESP and CNPQ are also
acknowledged (R.A.P.).
174.1 (C). Levobupivacaine (1): mp 135–137 °C. [a]D À77 (c 1.0, MeOH), 76% ee.
1H NMR (300 MHz, CDCl3), d 0.94 (t, 3H, J 7.3 Hz), 1.29–1.41 (m, 3H), 1.42–1.81
(m, 7H), 2.04–2.19 (m, 2H), 2.26 (s, 6H), 2.80–2.96 (m, 2H), 3.24 (br d, 1H, J
9.5 Hz), 7.08 (s, 3H), 8.19 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3), d 14.2 (CH3),
18.8 (2Â CH3), 20.7 (CH2), 23.5 (CH2), 24.9 (CH2), 29.7 (CH2), 30.6 (CH2), 51.6
(CH2), 57.4 (CH2), 68.5 (CH), 126.8 (CH), 129.1 (2Â CH), 133.5 (C), 135.1 (2Â C),
172.6 (C). HRMS (EI) to
287.2123. Ropivacaine (2): [
C
18H28N2O m/z (M+ÅÀ1): calcd 287.2036, found
References and notes
a
]
D
À78 (c 5.0, MeOH), mp 143–145 °C (lit. mp
144–146 °C, [
a
]
À82 (c 2, MeOH)). 1H NMR (400 MHz, D2O), d 0.95 (t, 3H, J
D
1. Ekenstam, T. A. B.; Egner, B.; Petersson, G. Acta Chem. Scand. 1957, 11, 1183–
1190.
12.0 Hz), 1.68–2.10 (m, 7H), 2.19 (s, 6H), 2.40–2.46 (db, 1H), 3.10–3.19 (m, 3H),
3.70–3.75 (br d, 1H), 4.15–4.20 (br d, 1H), 4.78 (s, 3H), 7.17–7.28 (m, 3H). 13C
NMR (100 MHz, D2O), d 11.3 (CH3), 17.9 (CH2), 18.2 (2Â CH3), 21.9 (CH2), 23.3
(CH2), 29.9 (CH2), 53.1 (CH2), 58.9 (CH2), 66.8 (CH), 129.3 (2Â CH), 129.6 (CH),
132.8 (C), 137.0 (2Â C), 170.4 (C). HRMS (EI) to C17H26N2O m/z (M+Å): calcd
2. (a) Reiz, S.; Häggmark, S.; Johansson, G.; Nath, S. Acta Anaesthesiol. Scand. 1989,
33, 93–98; (b) Groban, L.; Deal, D. D.; Vernon, J. C.; James, R. L.; Butterworth, J.
Anesth. Analg. 2001, 97, 37–43; (c) Dony, P.; Dewinde, V.; Vanderick, B.;
Cuignet, O.; Gautier, P.; Legrand, E.; Lavand’homme, P.; De Kock, M. Anesth.
Analg. 2000, 91, 489–492; (d) Ohmura, S.; Kawada, M.; Ohta, T.; Yamamoto, K.;
Kobayashi, T. Anesth. Analg. 2001, 93, 743–748; (e) Knudsen, K.; Suurkula, B. S.;
Blomberg, S.; Sjovall, J.; Edvardsson, N. Br. J. Anaesth. 1997, 78, 507–514.
3. (a) Oda, Y.; Furuichi, K.; Tanaka, K. Anesthesiology 1995, 82, 214–220; (b)
Stienstra, R.; Jonker, T.; Bourdrez, P. Anesth. Analg. 1995, 80, 285–289.
4. (a) Kumar, S.; Ramachandran, U. Tetrahedron Lett. 2005, 46, 19–21; (b) Kumar,
S.; Ramachandran, U. Tetrahedron: Asymmetry 2003, 14, 2539–2545.
5. Moeller, K. Tetrahedron 2000, 56, 9527–9554.
274.2045, found 274.2006. Mepivacaine (3): mp 148–150 °C. [
a
]
D
À43 (c 1.0,
MeOH), 76% ee. 1H NMR (300 MHz, CDCl3), d 1.21 (ddt, 1H, J 12.8, 8.8, 3.7 Hz),
1.43–1.67 (m, 3H), 1.72 (dt, 1H, J 12.8, 2.9 Hz), 2.03 (ddd, 1H, J 11.7, 9.2, 2.9 Hz),
1.96–2.10 (m, 1H), 2.17 (s, 6H), 2.34 (s, 3H), 2.57 (dd, 1H, J 11.7, 3.7 Hz), 7.00 (s,
3H), 7.96 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3) d 18.9 (2Â CH3), 23.4 (CH2),
25.5 (CH2), 31.5 (CH2), 45.2 (CH3), 55.6 (CH2), 70.1 (CH), 126.9 (CH), 128.2 (2Â
CH), 133.4 (C), 135.1 (2Â C), 172.4 (C). HRMS (EI) to C15H22N2O m/z (M+Å): calcd
246.1732, found 246.1702.