Highly selective hydroformylation of the Cinchona alkaloids

Article abstract of DOI:10.1021/jo0255173

The four naturally occurring cinchona alkaloids were subjected to hydroformylation to create an extra functional group that allows immobilization. Cinchonidine, quinine, and quinidine, could be hydroformylated with virtually complete terminal selectivity, using a rhodium/tetraphosphite catalyst. The cinchonidine aldehyde was reduced to the alcohol and subjected to reductive amination with benzylamine.

Full text of DOI:10.1021/jo0255173

SCHEME 1. Hyd r ofor m yla tion of th e Cin ch on a
Alk a loid s
High ly Selective Hyd r ofor m yla tion of th e
Cin ch on a Alk a loid s
Marielle Lambers, Felix H. Beijer, J ose´ M. Padron,
Imre Toth, and J ohannes G. de Vries*
DSM Fine Chemicals-Advanced Synthesis & Catalysis,
P.O. box 18, 6160 MD Geleen, The Netherlands
Hans-J G.Vries-de@dsm.com
Received J anuary 11, 2002
Abstr a ct: The four naturally occurring cinchona alkaloids
were subjected to hydroformylation to create an extra
functional group that allows immobilization. Cinchonidine,
quinine, and quinidine, could be hydroformylated with
virtually complete terminal selectivity, using a rhodium/
tetraphosphite catalyst. The cinchonidine aldehyde was
reduced to the alcohol and subjected to reductive amination
with benzylamine.
The cinchona alkaloids take a central place in the
limited reservoir of naturally occurring chiral compounds.
Because of their interesting structure and architecture,
harboring a unique combination of polar and lipophilic
groups, they have found extensive use as catalysts1 and
as chiral host compounds.2 Further functionalization,
particularly at the aliphatic nitrogen and the alcohol
function, has created new families of highly enantio-
selective catalysts.3-5
The presence of these two functional groups make the
Cinchona alkaloids uniquely suited for a combinatorial
approach to catalysis6 and chiral recognition.7 Although
an obvious strategy for attachment of the alkaloids to a
solid support would be to link on either nitrogen or
oxygen; this would severely compromise the accessible
diversity.8 For this reason, we have explored methods to
convert the double bond that is available in all four
naturally occurring cinchona alkaloids into a functional
group that can be used as a linker, such as a carboxylic
acid or an aldehyde. In our hands, methods described in
the literature for the oxidation of the double bond to the
aldehyde9,10 or carboxylic acid11 either suffered from low
yields or led to epimerization at C-3. The latter problem
can best be resolved by moving the new carbonyl function
further away from the chiral center. Hence, we turned
to hydroformylation for the introduction of an aldehyde
functionality.12 As formation of the iso aldehyde intro-
duces another chiral center and thus raises the problem
of diastereomers, we required a method that leads to very
high terminal selectivity. Fearing that the strong basic
function present in the cinchonas might have a detri-
mental effect on catalyst activity, we first explored the
hydroformylation of an aqueous solution of cinchonidine
(1a ), brought to pH 6.0 with 2 N H2SO4. Surprisingly,
hydroformylation using the water-soluble catalyst
Rh(CO)2acac/TPPTS13 (2)12 at 90 °C and 20 bar CO/H2
(1:1) led to slow and unselective reactions. Hydroformyl-
ation with Rh(CO)2acac/TPP* (3)12 in toluene proceeded
much better and gave aldehyde 5a in 67% yield as a 3:1
mixture of n/iso isomers. Eventually, use of 4 (L/Rh 1.2-
1.5), one of the bulky polydentate phosphite ligands that
were developed by Mitsubishi Kasei,14 allowed the highly
(1) (a) Kacprzak, K.; Gawronsky, J . Synthesis 2001, 961-998. (b)
Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J ., III;
Lectka T. J . Am. Chem. Soc. 2000, 122, 7831-7832 and references
contained herein. (c) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A.
J . Org. Chem. 2000, 65, 6984-6991. (d) Wynberg, H. Top. Stereochem.
1986, 16, 87.
(2) (a) Kellner, K.-H.; Blasch, A.; Chmiel, H.; La¨mmerhofer, M.;
Lindner, W. Chirality 1997, 9, 268-273. (b) Lacour, J .; Ginglinger,
C.; Favarger, F.; Tetrahedron Lett. 1998, 39, 4825-4828. (c) Rowan,
S. J .; Sanders, J . K. M. J . Org. Chem. 1998, 63, 1536-1546.
(3) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp
357-398.
(4) O’Donnell, M. J . In ref 3, pp 727-755.
(5) Chen, Y.; Tian, S.-K.; and Deng, L. J . Am. Chem. Soc. 2000, 122,
9542-9543.
(6) J andeleit, B.; Schaefer, D. J .; Powers, T. S.; Turner, H. W.;
Weinberg, W. H. Angew. Chem., Int. Ed. 1999, 38, 2494-2532.
(7) (a) Maier, N. M.; Franco, P.; Lindner, W. J . Chromatogr. A 2001,
906, 3-33. (b) Braxmeier, T.; Demarcus, M.; Fessmann, T.; McAteer,
S.; Kilburn, J . D. Chem. Eur. J . 2001, 7, 1889-98. (c) Gennari, C.;
Nestler, H. P.; Piarulli, U.; Salom, B. Liebigs Ann./ Recl. 1997, 637-
47.
(8) For a review on the immobilization of cinchona derivatives that
are used as ligands in the Sharpless asymmetric dihydroxylation
reaction, see: Bolm, C.; Gerlach, A. Eur. J . Chem. 1998, 21-27.
(9) Viski, P.; Szevere´nyi, Z.; Sima´ndi, L. I. J . Org. Chem. 1986, 51,
3213.
(10) (a) Yanuka, Y.; Yosselson-Superstine, S.; Geryes, A.; Superstine,
E. J . Pharm. Sci. 1981, 70, 675. (b) Damas, M.; Vo-Quang, Y.; Vo-
Quang, L.; Le Goffic, F. Synthesis 1989, 65.
(11) (a) Skraup, Z. H. J ustus Liebigs Ann. Chem. 1879, 16, 374.
(12) Rhodium catalyzed hydroformylation; van Leeuwen, P. W. N.
M., Claver, C., Eds.; Kluwer Academic Publishers: Dordrecht, 2000.
(13) Abbreviations: TPPTS ) tris(m-sulfonatophenyl)phosphine tris
sodium salt, TPP ) triphenylphosphine, acac ) acetylacetonate.
10.1021/jo0255173 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/13/2002
5022
J . Org. Chem. 2002, 67, 5022-5024

150.0, 149.7, 148.0, 130.1, 129.0, 126.6, 125.6, 122.9, 118.2, 71.7,
60.1, 58.2, 43.1, 41.8, 34.9, 28.0, 26.7, 25.7, 20.9 ppm. IR: ν 3066,
2927, 2860, 2709, 1724 cm-1. Anal. Calcd for C20H24N2O2: C,
74.0; H, 7.5; N, 8.6. Found: C, 74.2; H, 7.4; N, 8.7.
SCHEME 2
10,11-Dih yd r oqu in in e-11-ca r ba ld eh yd e 5c. A similar pro-
cedure was used for the preparation of compound 5c with the
following alterations: hydroformylation of quinine 1c (1.0192
g, 3.14 mmol), Rh(CO)2acac (8.9 mg, 0.0379 mmol), and 4 (96.5
mg, 0.0509 mmol) resulted in a clear solution. After partial
concentration under reduced pressure and cooling of the result-
ing solution, aldehyde 5c (790.7 mg, 71%) crystallized as a white
solid. Mp: 104-107 °C. 1H NMR: δ 9.70 (t, 1H, J ) 1.5 Hz),
8.55 (d, 1H, J ) 4.4 Hz), 7.93 (ABd, 1H, J ) 8.9 Hz), 7.46 (d,
1H, 4.9 Hz), 7.35-7.10 (m, 2H), 5.49 (d, 1H, J ) 3.9 Hz), 4.25
(bs, 1H), 3.89 (s, 3H), 3.55-3.30 (m, 1H), 3.15-2.85 (m, 2H),
2.70-2.50 (m, 1H), 2.45-2.20 (m, 4H), 1.85-1.25 (m, 7H) ppm.
13C NMR: δ 202.1, 157.7, 147.8, 147.5, 144.2, 131.5, 126.6, 121.4,
118.4, 101.4, 72.0, 59.8, 58.3, 55.7, 43.1, 41.9, 35.1, 28.1, 26.8,
25.6, 21.3 ppm. IR: ν 3600-2500, 3074, 2930, 2860, 2714, 1720
cm-1. Anal. Calcd for C21H26N2O3: C, 71.2; H, 7.4; N, 7.9.
Found: C, 70.9; H, 7.3; N, 7.6.
10,11-Dih yd r oqu in id in e-11-ca r ba ld eh yd e 5d . A similar
procedure was used for the preparation of compound 5d with
the following alterations: hydroformylation of quinine 1d
(1.0039 g, 3.09 mmol), Rh(CO)2acac (11.2 mg, 0. 0433 mmol),
and 4 (97.4 mg, 0.0514 mmol) resulted in a clear solution. After
partial concentration under reduced pressure and cooling of the
resulting solution, aldehyde 5d (933.9 mg, 85%) crystallized as
a white solid. Mp: 110-112 °C. 1H NMR: δ 9.77 (s, 1H), 8.57
(d, 1H, J ) 4.4 Hz), 7.93 (ABd, 1H, J ) 8.9 Hz), 7.52 (d, 1H, J
) 4.4 Hz), 7.35-7.10 (m, 2H), 5.63 (bs, 1H), 5.12 (bs, 1H), 3.82
(s, 3H), 3.30-3.10 (m, 1H), 3.10-2.55 (m, 4H), 2.50-2.30 (m,
1H), 2.15-1.10 (m, 9H) ppm. 13C NMR: δ 202.5, 157.7, 148.0,
147.5, 144.0, 131.4, 126.5, 121.5, 118.4, 101.2, 71.8, 59.6, 55.6,
50.9, 50.1, 42.0, 35.1, 27.0, 26.4, 24.5, 20.3 ppm. IR: ν 3500-
2500, 2935, 2868, 1721 cm-1. Anal. Calcd for C21H26N2O3: C,
71.2; H, 7.4; N, 7.9. Found: C, 71.1; H, 7.4; N, 7.6.
selective hydroformylation of three out of the four
naturally occurring cinchona alkaloids (Scheme 1). In
fact, the reactions were performed on a slurry of the
starting material and gave slurries of pure terminal
aldehyde directly, or after concentration of the product
solution. The solids thus obtained in good yields did not
contain any of the unwanted iso isomers. We have
performed all three reactions successfully on a scale of
100 g. The low conversion (40%, product not isolated) of
cinchonine (5b) may be related to its poor solubility in
toluene.
With these three aldehydes in hand, the way is now
open to immobilization, for instance, via reductive ami-
nation of polymeric amines. The feasibility of this reac-
tion was proven by reductive amination of 5a with
benzylamine via NaBH4 reduction of the preformed imine
in ethanol in 83% isolated yield. Direct reduction of 5a
with NaBH4 gave the alcohol in 97% yield (Scheme 2).
The attachment of the Cinchona aldehydes to poly-
meric amines is currently under study as well as their
use in the construction of chiral host libraries.
11-N-Ben zyla m in om eth yl-10,11-d ih yd r ocin ch on id in e 6.
A suspension of aldehyde 5a (498.9 mg, 1.54 mmol) and
benzylamine (173.9 mg, 1.62 mmol) in toluene (50 mL) was
heated under reflux, while H2O was azeotropically distilled off.
After 3 h, the resulting clear and colorless reaction mixture was
cooled, resulting in the partial precipitation of the product. The
toluene was removed in vacuo affording the imine (625.1 mg,
1
98%) as a white solid. H NMR: δ 8.78 (d, 1H, J ) 4.5 Hz), 8.07
(ABd, 1H, J ) 8.3 Hz), 7.93 (ABd, 1H, J ) 8.4 Hz), 7.70-7.15
(m, 9H), 5.61 (bs, 1H), 4.82 (bs, 1H), 4.48 (s, 2H), 3.55-3.35 (m,
1H), 3.15-2.90 (m, 2H), 2.70-2.05 (m, 4H), 1.85-1.20 (m, 8H)
ppm.
Sodium borohydride (60.2 mg, 1.59 mmol) was added portion-
wise to a solution of the crude imine in EtOH (20 mL). The
mixture was stirred for 3 h at ambient temperature. Quenching
with H2O (20 mL) resulted in the precipitation of a white solid.
The mixture was extracted with chloroform (3 × 50 mL). The
precipitate dissolved in the organic phase. The combined organic
layers were dried over Na2SO4 and evaporated to dryness, giving
Exp er im en ta l Section
Gen er a l Rem a r k s. Chemicals were purchased from com-
mercial suppliers and used as received. Solvents were of analyti-
cal grade and used without further purification. All NMR spectra
were recorded in CDCl3.
1
amine 6 (519.7 mg, 83%) as a white solid. Mp: 128-131 °C. H
NMR: δ 8.71 (d, 1H, J ) 4.4 Hz), 8.04 (ABd, 1H, J ) 7.9 Hz),
7.90 (ABd, 1H, J ) 8.4 Hz), 7.65-7.45 (m, 2H), 7.30-7.05 (m,
6H), 6.43 (bs, 1H), 5.62 (s, 1H), 3.65 (s, 2H), 3.60-3.40 (m, 1H),
3.05-2.80 (m, 2H), 2.65-2.10 (m, 4H), 1.90-1.05 (m, 11 H) ppm.
13C NMR: δ 150.3, 150.0, 148.0, 140.1, 130.1, 128.9, 128.3, 128.1,
126.9, 126.5, 125.6, 123.0, 118.3, 71.4, 60.1, 58.6, 54.0, 49.4, 43.2,
35.4, 32.4, 28.1, 27.9, 25.8, 20.7 ppm. IR: ν 3500-2500, 3063,
2926, 2860 cm-1. HRMS (EI): calcd for C27H33N3O 415.2624,
found 415.2619.
10,11-Dih yd r ocin ch on id in e-11-ca r b a ld eh yd e 5a . A de-
oxygenated solution of Rh(CO)2acac (11.9 mg, 0.0416 mmol) and
4 (98 mg, 0.0516 mmol) in toluene (5 mL) was added via syringe
to a slurry of 1a (5.00 g, 17 mmol) in deoxygenated toluene (20
mL) in a Parr autoclave (125 mL). The reaction mixture was
stirred at 90 °C at 20 bar H2/CO 1:1 v/v pressure for 20 h. After
cooling, the white precipitate was filtered off and washed with
toluene (2 × 10 mL). Yield: 4.78 g, 87% of 5a . Mp: 200-201
°C. 1H NMR: δ 9.67(t, 1H, J ) 1.5 Hz), 8.72 (d, 1H, J ) 4.5 Hz),
8.04 (ABd, 1H, J ) 7.8 Hz), 7.92 (ABd, 1H, 8.3 Hz) 7.70-7.15
(m, 3H), 5.62 (d, 1H, J ) 3.0 Hz), 5.30 (s, 1H), 3.60-3.40 (m,
1H), 3.10-2.85 (m, 2H), 2.75-2.40 (m, 2H), 2.40-2.15 (m, 3H),
1.90-1.60 (m, 4H), 1.60-1.25 (m, 4H) ppm. 13C NMR: δ 202.1,
11-Hyd r oxym eth yl-10,11-d ih yd r ocin ch on id in e 7. Sodium
borohydride (60.2 mg, 1.59 mmol) was added portionwise to a
solution of aldehyde 5a (482.4 mg, 1.49 mmol) in EtOH (10 mL).
The mixture was stirred for 4 h at ambient temperature. The
reaction was quenched with H2O (20 mL), and the resulting
suspension was extracted with chloroform (3 × 25 mL). The
combined organic layers were dried over Na2SO4. After filtration
and removal of the solvent under reduced pressure, alcohol 7
(14) Keiichi, S.; Kawaragi, Y.; Takai, M.; Ookoshi, T. (Mitsubishi
Kasei Corp.) European Patent 0 518 241, Dec 16, 1992.
J . Org. Chem, Vol. 67, No. 14, 2002 5023

(470.5 mg, 97%) was obtained as a white solid. Mp: 104-107
Ack n ow led gm en t. This work was carried out as
part of a European TMR-network Chiral Separations
ERB FMRX-CT-98-233.
1
°C. H NMR: δ 8.67 (d, 1H, J ) 4.4 Hz), 8.02 (ABd, 1H, J ) 8.4
Hz), 7.91 (ABd, 1H, J ) 8.4 Hz), 7.65-7.45 (m, 2H), 7.40-7.20
(m, 1H), 5.80-5.40 (m, 2H), 3.65-3.40 (m, 3H), 3.23 (bs, 1H),
3.10-2.85 (m, 2H), 2.70-2.35 (m, 2H), 2.35-2.15 (m, 1H), 1.85-
1.10 (m, 9H) ppm. 13C NMR: δ 149.9, 147.9, 129.9, 129.0, 126.6,
125.6. 123.0, 118.3, 71.5, 62.5, 60.1, 58.6, 43.2, 35.3, 31.0, 30.7,
28.1, 25.9, 21.0 ppm. IR: ν 3500-3000, 2927, 2862 cm-1. HRMS
(EI): calcd for C20H26N2O2 326.1994, found 326.2004.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR of
compounds 6 and 7. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0255173
5024 J . Org. Chem., Vol. 67, No. 14, 2002