Efficient chemoenzymatic synthesis of chiral pincer ligands

Article abstract of DOI:10.1021/jo900271x

Chiral, nonracemic pincer ligands based on the 6-phenyl-2- aminomethylpyridine and 2-aminomethylbenzo[/z]quinoline scaffolds were obtained by a chemoenzymatic approach starting from 2-pyridyl and 2-benzoquinolyl ethanone. In the enantiodifferentiating ste

Full text of DOI:10.1021/jo900271x

Efficient Chemoenzymatic Synthesis of Chiral
Pincer Ligands
Fulvia Felluga,*,† Walter Baratta,‡ Lidia Fanfoni,†
Giuliana Pitacco,† Pierluigi Rigo,‡ and Fabio Benedetti†
Dipartimento di Scienze Chimiche, UniVersita` di Trieste, Via
Giorgieri 1, I-34127 Trieste, Italy, and Dipartimento di
Scienze e Tecnologie Chimiche, UniVersita` di Udine, Via
Cotonificio 108, I-33100 Udine, Italy
ffelluga@units.it
ReceiVed February 6, 2009
FIGURE 1. CNN pincer ligands and metal complexes.
(R)-4 gave high enantioselectivities (up to 98% ee of the alcohol
products) in the transfer hydrogenation of prochiral ketones.
The Os(II) derivatives are also excellent catalysts for the
asymmetric hydrogenation of ketones.1c More recently,1d com-
parably high enantioselectivities and productivities have been
obtained with Ru and Os complexes prepared from the racemic
tricyclic benzo[h]quinoline ligand 5 and chiral diphosphanes.
On account of their importance as scaffolds for chiral ligands
and as bioactive compounds,2 the synthesis of chiral aminoalkyl-
pyridines is of special interest. Common approaches based on
asymmetric synthesis include the addition of organometallics
to chiral imines,3 the enantioselective catalytic reduction of
imines4 and hydrazones,5 and the catalytic hydroamination of
alkenes.6
The synthesis of chiral ligands (R)-3 and (R)-4 via the
diastereoselective reduction of chiral N-p-toluenesulfinyl ketimines
was reported by Chelucci et al.7 However, replacement of the
bulky t-butyl group of (R)-3 with the methyl of (R)-4 dramati-
cally decreased the stereoselectivity. An alternative approach
to (R)-4 was also described,7c via mesylation of the correspond-
ing (S)-alcohol 8, obtained from a chiral precursor, and
displacement with azide; this method, however, suffered from
a significant loss of enantiopurity in the substitution step.
Biocatalysis with whole cell systems and isolated enzymes
provides a clean and ecological alternative for the synthesis of
a variety of chiral building blocks with high degree of selectivity
under mild reaction conditions.8
Chiral, nonracemic pincer ligands based on the 6-phenyl-2-
aminomethylpyridine and 2-aminomethylbenzo[h]quinoline
scaffolds were obtained by a chemoenzymatic approach
starting from 2-pyridyl and 2-benzoquinolyl ethanone. In the
enantiodifferentiating step, secondary alcohols of opposite
absolute configuration were obtained by a baker’s yeast
reduction of the ketones and by lipase-mediated dynamic
kinetic resolution of the racemic alcohols. Their transforma-
tion into homochiral 1-methyl-1-heteroarylethanamines oc-
curred without loss of optical purity, giving access to pincer
ligands used in enantioselective catalysis.
Metal complexes of general structure 1, in which ruthe-
nium(II) and osmium(II) are bound to a diphosphine and a bi-
or tricyclic, aminomethylpyridine-based, C,N,N-terdentate ligand
(CNN pincer), have recently been shown to be extremely
efficient catalysts for the catalytic reduction of aromatic ke-
tones.1 Ruthenium(II) complexes, in which the CNN pincer
ligand 2 (R ) Me) is present in combination with different
diphosphines, are the most active catalysts in the transfer
hydrogenation of alkyl aryl ketones in 2-propanol, displaying
turnover frequencies of up to 106 h-1 at remarkably low catalyst
loadings (0.005-0.001 mol %).1a Moreover, Ru(II)1b and
Os(II)1c complexes containing the chiral CNN ligands (R)-3 and
Enantiomerically pure secondary alcohols, in particular, can
be efficiently obtained by lipase-catalyzed resolution of the
(2) See for example: (a) Lawson, E. C.; Hoekstra, W. J.; Addo, M. F.;
Andrade-Gordon, P.; Damiano, B. P.; Kauffman, J. A.; Mitchell, J. A.; Maryanoff,
B. E. Bioorg. Med. Chem. Lett. 2001, 11, 2619–2622. (b) Lloyd, G. K.; Williams,
M. J. Pharmacol. Exp. Ther. 2000, 292, 461–467. (c) Wu, J. H.; Zamir, L. O.
Anti-Cancer Drug Des. 2000, 15, 73–78.
(3) Alvaro, G.; Pacioni, P.; Savoia, D. Chem.sEur. J. 1997, 3, 726–731.
(4) (a) Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006, 35, 226–236. (b)
Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029–3069. (c) Hansen, M. C.;
Buchwald, S. L. Org. Lett. 2000, 2, 713–715.
(5) Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron 1994,
50, 4399–4428.
† University of Trieste.
‡ University of Udine.
(6) (a) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347, 367–391. (b) Roesky,
P. W.; Mueller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708–2710.
(7) (a) Chelucci, G.; Baldino, S.; Chessa, S. Tetrahedron 2006, 62, 619–
636. (b) Chelucci, G. Tetrahedron: Asymmetry 2005, 16, 2353–2383. (c)
Chelucci, G.; Cabras, M. A.; Saba, A. Tetrahedron: Asymmetry 1994, 5, 1973–
1978.
(1) (a) Baratta, W.; Chelucci, G.; Gladiali, S.; Siega, K.; Toniutti, M.; Zanette,
M.; Zangrando, E.; Rigo, P. Angew. Chem., Int. Ed. 2005, 44, 6214–6219. (b)
Baratta, W.; Bosco, M.; Chelucci, G.; Del Zotto, A.; Siega, K.; Toniutti, M.;
Zangrando, E.; Rigo, P. Organometallics 2006, 25, 4611–4620. (c) Baratta, W.;
Ballico, M.; Chelucci, G.; Siega, K.; Rigo, P. Angew. Chem., Int. Ed. 2008, 47,
4362–4365. (d) Baratta, W.; Ballico, M.; Baldino, S.; Chelucci, G.; Herdtweck,
E.; Siega, K.; Magnolia, S.; Rigo, P. Chem.sEur. J. 2008, 14, 9148–9160.
(8) Faber, K. Biotransformations in Organic Chemistry, 5th ed.; Springer:
Berlin, 2004.
10.1021/jo900271x CCC: $40.75
Published on Web 03/30/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3547–3550 3547

TABLE 1. Kinetic and DKR of Alcohols 8 and 9 with Novozyme
435
SCHEME 1. General Strategy for the Synthesis of Chiral
Nonracemic Pincer Ligands 4 and 5
(R)-acetate ee % (S)-alcohol ee %
entry substrate
E
conv. (%)
(yield %)a
(yield %)a
f
(()-8b >500
(()-9b >500
(()-8h
46c
44c
93i
92i
10 >99.9d (45)
8
9
79e (50)
-
1
2
3
4
11 >99d g (40)
10 >99.9 (70)
11 >99 (70)
86g (47)
,
(()-9h
a Product isolated after chromatographic purification. b Kinetic
resolution. Conditions: vinyl acetate, t-butyl methyl ether, rt.
c Calculated conversion. d After hydrolysis. e By chiral high resolution
gas chromatography (HRGC; ꢀ-cyclodextrine). f Lit.18 98%. g From the
1H NMR analysis of the corresponding Mosher’s ester. h DKR.
corresponding racemic mixtures9 and by the asymmetric reduc-
tion of prochiral ketones with isolated dehydrogenases10 or with
baker’s yeast (Saccharomyces cereVisiae).11 Herein, we describe
the application of these stereocomplementary biotransformations
to the synthesis of both enantiomers of 1-(6-phenylpyridin-2-
yl)ethanamine 4 (Scheme 1). (S)-4 was obtained via the lipase-
mediated kinetic resolution of the secondary alcohol (()-8, while
the baker’s yeast (Saccharomyces cereVisiae) reduction of the
ketone 6 gave access to the enantiomeric ligand (R)-4. This
approach was then extended to the synthesis of the novel chiral
1-(benzo[h]quinolin-2-yl)ethanamine CNN pincer ligands (R)-5
and (S)-5.
Conditions:
p-chlorophenylacetate,
toluene,
70
°C,
2%
Ru2(CO)4(µ-H)(C4Ph4-COHOCC4Ph4). i By HRGC.
tiospecificity was unsatisfactory, and harsh conditions were
required for the recovery of amines from the resolved aceta-
mides. Therefore, we decided to use CAL-B immobilized on
polyacrylamide (Novozyme) for the kinetic resolution of the
racemic alcohols 8 and 9 (Scheme 1).The alcohols were obtained
by the NaBH4 reduction of the corresponding ketones 6 and 7.
2-Acetyl-6-phenylpyridine 6 was obtained by the Suzuki
coupling of phenylboronic acid and 2-acetyl-6-bromopyridine,17
while the 2-acetylbenzo[h]quinoline 7 was synthesized from
2-chlorobenzo[h]quinoline as reported.1d
Candida antarctica lipase B (CAL-B) shows a very high and
general specificity for the (R)-enantiomer in the acylation of
chiral secondary alcohols12 which has been fully explained at
the molecular level.13 The enantiospecific acylation of chiral
amines by CAL-B has also been reported;14 however, while the
dynamic kinetic resolution (DKR)15 of racemic sec-alcohols is
well established, few protocols have been reported for the DKR
of amines.16 When we applied these conditions to the resolution
of 6-substituted 2-(1-aminoethyl)pyridines, the resulting enan-
The lipase-catalyzed asymmetric acetylation of 8, with
Novozyme and vinyl acetate in t-butylmethylether gave the
corresponding (R)-acetate 10 with excellent enantioselectivity
(enantiomeric ratio E > 500) and with recovery of the unreacted
alcohol (S)-8 (Table 1, entry 1), in agreement with literature
data.18 Similarly, the tricyclic alcohol 9 gave the corresponding
(R)-acetate 11 in 40% yield (44% conversion) and ee > 99%
(E > 500; Table 1, entry 2), while the recovered alcohol (S)-9
had 86% ee.
Although the optical purity of the resolved acetates (R)-10
and (R)-11 was excellent (Table 1), their yield is intrinsically
limited by the 50% maximum attainable in a kinetic resolution
and by the need for a chromatographic separation of the
enantioresolved alcohol and ester products. Both limitations were
overcome by applying to the lipase-catalyzed transesterification
of (()-8 and (()-9 the conditions developed by Ba¨ckvall et al.
for the dinamic kinetic resolution of sec-alcohols.19 When the
acetylation, with p-chlorophenylacetate as the acyl donor, was
coupled to the in situ racemization of the slow reacting
enantiomer with the Ru based redox catalyst [Ru2(CO)4(µ-
H)(C4Ph4-COHOCC4Ph4)] (Shvo’s catalyst), the reaction reached
complete conversion, enantioconverging to the (R)-acetates as
unique products. These were isolated in 70% yield (not
optimized) after column chromatography (Table 1, entries 3,
4).
(9) (a) Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis:
Regio-and StereoselectiVe Biotransformations, 2nd ed.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Schmid, R. D.; Verger, R. Angew. Chem., Int. Ed. 1998,
37, 1608–1633.
(10) (a) Kroutil, W.; Mang, H.; Edegger, K.; Faber, K. Curr. Opin. Chem.
Biol. 2004, 8, 120–126. (b) Nakamura, K.; Yamanaka, R.; Matsuda, T.; Harada,
T. Tetrahedron: Asymmetry 2003, 14, 2659–2681. (c) Nakamura, K.; Matsuda,
T. Reduction of Ketones. In Enzyme Catalysis in Organic Synthesis; Drauz, K.,
Waldmann, H., Eds.; Wiley-VCH: Weinheim, 2002; Vol. 3, pp 991-1047.
(11) (a) Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem.
ReV. 1992, 92, 1071–1140. (b) Czuck, S.; Blanzer, B. I. Chem. ReV. 1991, 91,
49–97. (c) Servi, S. Synthesis 1990, 1–25.
(12) Rotticci, D.; Hæffner, F.; Orrenius, C.; Norin, T.; Hult, K. J. Mol. Catal.
B: Enzym. 1998, 5, 267–272. (b) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih,
C. J. J. Am. Chem. Soc. 1982, 104, 7294–7299.
(13) (a) Mccabe, R. W.; Rodger, A.; Taylor, A. Enzyme Microb. Technol.
2005, 36, 70–74. (b) Uppenberg, J.; Ohrner, N.; Norin, M.; Hult, K.; Kleywegt,
G. J.; Patkar, S.; Waagen, V.; Anthonsen, T.; Jones, T. A. Biochemistry 1995,
34, 16838–16851. (c) Uppenberg, J.; Hansen, M. T.; Patkar, S.; Jones, T. A.
Structure 1994, 2, 293–308.
(14) (a) Ismail, H.; Madeira Lau, R.; van Rantwijk, F.; Sheldon, R. A. AdV.
Synth. Catal. 2008, 350, 1511–1516. (b) van Rantwijk, F.; Sheldon, R. A.
Tetrahedron 2004, 60, 501–519. (c) Skupinska, K. A.; McEachern, E. J.; Baird,
I. R.; Skerlj, R. T.; Bridger, G. J. J. Org. Chem. 2003, 68, 3546–3551. (d) Torre,
O.; Busto, E.; Gotor-Ferna´ndez, V.; Gotor, V. AdV. Synth. Catal. 2007, 349,
1481–1488. (e) Gotor-Ferna´ndez, V.; Busto, E.; Gotor, V. AdV. Synth. Catal.
2006, 348, 797–812. (f) Iglesias, L. E.; Sa´nchez, V. M.; Rebolledo, F.; Gotor,
V. Tetrahedron: Asymmetry 1997, 8, 2675–2677.
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11, 226–232. (b) Pamies, O.; Ba¨ckvall, J.-E. Trends Biotechnol. 2004, 22, 130–
135. (c) Pamies, O.; Ba¨ckvall, J.-E. Chem. ReV. 2003, 103, 3247–3262. (d) Faber,
K. Chem.sEur. J. 2001, 7, 5005–5010.
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Chem. 1998, 63, 2481–2487.
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3548 J. Org. Chem. Vol. 74, No. 9, 2009

SCHEME 2. Synthesis of Chiral Ligands (S)-4 and (S)-5a
SCHEME 3. Synthesis of Chiral Ligands (R)-4 and (R)-(5)a
a (i) Baker’s yeast, 37 °C, glucose, phosphate buffer, pH 7.4, 70%. (ii)
See Table 1, entry 2. (iii) DPPA, DBU, 75%. (iv) Ph3P, THF/H2O, 95%.
a (i) K2CO3, MeOH/H2O, rt, 6 h, 100%. (ii) DPPA, DBU, toluene, 0 °C
then at rt, 75%. (iii) Ph3P, THF, H2O, rt, 95%.
the bioreduction of the tricyclic ketone 7 did not proceed beyond
5% conversion after 6 days. This lack of reactivity is a likely
consequence of the steric hindrance of the rigid tricyclic
aromatic structure that prevents the substrate from accessing
the active site of the alcohol dehydrogenase. However, the
desired alcohol (S)-9 could be obtained by the classical kinetic
resolution procedure (Table 1, entry 2); by stopping the acylation
at 44% conversion, unreacted (S)-9 was isolated in 47% yield
and 86% ee. Conversion of the alcohols (S)-8 and (S)-9 thus
obtained into the corresponding amines (R)-4 and (R)-5 was
carried out by the two-step procedure already described. Thus,
azides (R)-12 (>99.9% ee) and (R)-13 were obtained in 75%
yield from the alcohols and DPPA and reduced with triph-
enylphosphine to give the desired products (Scheme 3) with
>99.9% ee and 80% ee, respectively. The CD spectra of ligands
(R)-4 and (R)-5 confirm the structural assignments.20
In conclusion, three novel chiral, nonracemic CNN pincer
ligands (S)-4 (49%, 97% ee), (R)-5 (32%, 80% ee), and (S)-5
(50%, 95% ee) have been synthesized from the corresponding
ketones 6 and 7 by a combination of chemical and enzymatic
methods. The same chemoenzymatic approach also allowed
significant improvement in the synthesis of the known ligand
(R)-4, which has been now obtained in 50% yield (from the
ketone 6) and 99.9% ee. In particular, we have demonstrated
that the DKR of pyridyl ethanols is a superior method for the
synthesis of chiral CNN pincer ligands, on account of the high
enantioselectivity and wide substrate specificity of CAL-B.
Screening of the new ligands in the catalytic hydrogen transfer
reduction and hydrogenation of prochiral ketones is underway
and will be reported elsewhere.
Hydrolysis under mild basic conditions of the optically active
esters (R)-10 and (R)-11 gave the corresponding enantiopure
secondary alcohols (R)-818 and (R)-9, in 70% overall yield from
the racemic alcohols (Scheme 2). The (R) configuration of the
compounds thus obtained results from the well-known prefer-
ential recognition of (R) enantiomers by CAL-B.12 For the novel
alcohol (R)-9, this configurational assignment was further
supported by the CD spectra of the final amine products.20 To
obtain the target amines (S)-4 and (S)-5, the homochiral alcohols
(R)-8 and (R)-9 were first converted into the corresponding
azides (S)-12 and (S)-13 (Scheme 2). This transformation was
best carried out with diphenylphosphoroazidate (DPPA) in the
presence of DBU.21 These conditions led to a clean SN2
inversion, avoiding racemization and olefin formation, which
are commonly observed in the classical Mitsunobu reaction. By
this procedure, alcohols (R)-8 and (R)-9, having >99.9% ee and
>99% ee respectively, were converted into the corresponding
azides (S)-12 and (S)-13, with only a slight erosion of the
enantiomeric purity, which dropped to 95% in the case of (S)-
13. Finally, conversion of the azides into the corresponding
amines (S)-4 (97% ee) and (S)-5 (95% ee) was carried out by
treatment with Ph3P in refluxing THF/H2O22 (Scheme 2).
The CD spectra of chiral ligands (S)-4 and (S)-5 thus
obtained20 support the configurational assignments; in particular,
the sign of the Cotton effect for the band at around 280 nm is
the same for both ligands, suggesting that they have the same
configuration. The same, of course, must be true for all of their
precursors; as the (R) configuration had already been attributed
to the acetate 10 derived from the CAL-B catalyzed trans-
esterification of racemic alcohol 8,18 the same configuration can
also be attributed to the acetate 11 obtained from the kinetic
resolution of 9.
Experimental Section
DKR of Racemic Alcohols 8 and 9. Catalyst [Ru2(CO)4(µ-
H)(C4Ph4-COHOCC4Ph4)] (0.044 mg, 0.04 mmol) and Novozyme
435 (60 mg) were suspended in toluene, under argon. A degassed
solution of the racemic alcohol (2 mmol) and 4-chlorophenyl acetate
(1.02 g, 6 mmol) in toluene (5 mL) was transferred to this
suspension, and the mixture was stirred under argon, at 70 °C, for
46 h until complete conversion (GC). The enzyme was filtered off,
and the reaction mixture was separated on silica (petroleum ether:
ethyl acetate as eluant) to yield the acetates (R)-(+)-10 and (R)-
(+)-11.
(R)-(+)-2-(1-Acetoxyethyl)-6-phenylpyridine ((R)-10). (R)-10
was obtained in >99.9% ee and 71% yield (93% conversion) from
the DKR of alcohol 8. [R]D + 87.0 (c 0.25, CHCl3) [lit.:18 [R]D +
86.0 (c 1.00, CHCl3), ee 98%]. Spectroscopic data were in
agreement with those reported.18
Having succeeded in synthesizing the enantiopure (S) ligands
4 and 5, we then proceeded to the synthesis of the corresponding
(R) enantiomers by a complementary biocatalytic approach. We
anticipated from Prelog’s rule23 that the baker’s yeast reduction
of prochiral ketones 6 and 7 would proceed with delivery of
the hydride to the Re face of the carbonyl, affording the (S)
alcohols. Accordingly, when the reduction of 6 was carried out
under fermenting conditions (37 °C, glucose, phosphate buffer,
pH 7.4), 98% conversion was reached in 6 days, giving the
expected alcohol (S)-8 in >99.9% ee and 76% yield after
purification (Scheme 3). Surprisingly, under the same conditions,
(20) See Supporting Information.
(21) Thomson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.;
Grabowski, E. J. J. J. Org. Chem. 1993, 58, 5886–5888.
(22) Horner, L.; Gross, A. Liebigs Ann. Chem. 1955, 591, 117–134.
(23) Prelog, V. Pure Appl. Chem. 1964, 9, 119–122.
(R)-(+)-2-(1-Acetoxyethyl)benzo[h]quinoline ((R)-11). (R)-11
was obtained in >99% ee and 73% yield (92% conversion) from
the DKR of alcohol 9. [R]D + 119.0 (c 0.5, CHCl3).
J. Org. Chem. Vol. 74, No. 9, 2009 3549

(R)-(-)-2-(1-Hydroxyethyl)-6-phenylpyridine ((R)-8). The ac-
etate (R)-10 (1.4 mmol) was hydrolyzed with K2CO3 (193 mg, 1.4
mmol) in methanol/water (1:1) for 6 h at room temperature.
Methanol was evaporated under reduced pressure, and the aqueous
phase was extracted with CHCl3 (3 × 20 mL). The combined
organic phases were extracted with brine, dried over Na2SO4, and
concentrated in vacuo. Chromatography on silica gave the alcohol
(R)-(-)-8 (100%, >99.9% ee, by chiral HRGC); [R]D - 24.0 (c
0.30, CHCl3).
for 30 min at 37 °C, and the ketone 6 (0.7 g, 3.6 mmol) was added
at room temperature. The reaction was monitored by HRGC, and
after 6 days the broth was extracted with ether. The organic phase
was dried and evaporated to give a residue which was chromato-
graphed on an SiO2 column giving (S)-8. 76% yield at 98% conv.;
ee >99.9% (by HRGC). [R]D + 22.0 (c 0.55, CHCl3) [lit.:18 [R]D
+ 28.0 (c 1.00, CHCl3), 99% ee]. Spectroscopic data were in
agreement with those reported.18
Acknowledgment. This work was supported by Regione
Friuli Venezia Giulia.
(R)-(-)-2-(1-Hydroxyethyl)benzo[h]quinoline ((R)-9). (R)-9
was obtained quantitatively from the hydrolysis of acetate (R)-11,
1
as described for (R)-10; ee >99% (from the H NMR analysis of
Supporting Information Available: Full experimental pro-
cedures and spectral and analytical data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
the corresponding Mosher’s ester), [R]D - 85.3 (c 0.3, CHCl3).
Baker’s
Yeast
Reduction
of
6:
(S)-(+)-2-
(1-Hydroxyethyl)-6-phenylpyridine ((S)-8). Glucose (112 g) was
added to a stirred suspension of dry baker’s yeast (56 g) in
phosphate buffer (0.1 M, pH 7.4). The mixture was preincubated
JO900271X
3550 J. Org. Chem. Vol. 74, No. 9, 2009