Asymmetric homogeneous hydrogenation of 2,5-disubstituted furans

Article abstract of DOI:10.1021/ol061681r

A homogeneous catalyst system for the asymmetric cis-hydrogenation of 2,5-disubstituted furans leading to 2′,3′-dideoxynucleoside analogues is described. Best enantioselectivities (ee values of up to 72%) were obtained with cationic rhodium complexes ligated by diphospholanes of the butiphane family. The selectivity of the hydrogenation was reversed by the addition of a base or a polar protic solvent in certain cases. Ferrocene- and proline-based systems gave significant, but lower, ee values.

Full text of DOI:10.1021/ol061681r

ORGANIC
LETTERS
2
006
Vol. 8, No. 18
133-4135
Asymmetric Homogeneous
Hydrogenation of 2,5-Disubstituted
Furans
4
Petra Feiertag,†,‡ Martin Albert,*,†,‡ Ulrike Nettekoven, and Felix Spindler§
§
Institut f u¨ r Organische Chemie, Technische UniVersit a¨ t Graz, A-8010 Graz, Austria,
and SolVias AG, Klybeckstrasse 191, Postfach, CH-4002 Basel, Switzerland
martin.albert@sandoz.com
Received July 8, 2006
ABSTRACT
A homogeneous catalyst system for the asymmetric cis-hydrogenation of 2,5-disubstituted furans leading to 2′,3′-dideoxynucleoside analogues
is described. Best enantioselectivities (ee values of up to 72%) were obtained with cationic rhodium complexes ligated by diphospholanes of
the butiphane family. The selectivity of the hydrogenation was reversed by the addition of a base or a polar protic solvent in certain cases.
Ferrocene- and proline-based systems gave significant, but lower, ee values.
For olefins with suitable substitution patterns, such as
enolacetates, enamides, allylic alcohols, or enones, a plethora
of powerful catalysts, which allow for an enantioselective
the stereoselective reduction of asymmetrically substituted
aromatic rings still represents a particular challenge, which
is reflected by the small number of successful reports.
Although the hydrogenation of aromatic compounds is
considered to be rather a domain of heterogeneous catalysis,
enantiodifferentiation upon reduction of appropriately sub-
stituted (hetero)arenes is more often achieved using structur-
ally diverse homogeneous catalysts. Cinchona-modified
1
hydrogenation, have been developed. Though the asym-
metric reduction of alkenes devoid of such a directing polar
anchor group is more demanding, some efficient catalytic
2
systems have been described in the literature. In contrast,
3
†
Technische Universit a¨ t Graz.
Current adress: Sandoz GmbH, A-6262 Kundl, Austria.
Solvias AG, Basel.
heterogeneous Pt or Pd catalysts have been used for the
‡
4
5
reduction of ethyl nipecotinate, a series of 2-pyrons, and
§
6
furan carboxylic acids with varying ee values. Recently, an
(1) (a) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.;
Studer, M. AdV. Synth. Catal. 2003, 345, 103-151. (b) Brown, J. M. In
ComprehensiVe Asymmetric Synthesis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: Berlin, 1999; Vol. I, Chapter 5.1, pp 121-182.
efficient diastereoselective hydrogenation of chiral oxazo-
(
c) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008-2022. (d) Knowles,
(3) Studer, M.; Blaser, H.-U.; Exner, C. AdV. Synth. Catal. 2003, 345,
45-65.
(4) Blaser, H.-U.; H o¨ nig, H.; Studer, M.; Wedemeyer-Exl, C. J. Mol.
Catal. A 1999, 139, 253-257.
(5) (a) Huck, W.-R.; Mallat, T.; Baiker, A. New J. Chem. 2002, 26, 6-8.
(b) Huck, W.-R.; B u¨ rgi, T.; Mallat, T.; Baiker, A. J. Catal. 2003, 219,
41-51. (c) Huck, W.-R.; Mallat, T.; Baiker, A. AdV. Synth. Catal. 2003,
345, 255-260.
(6) (a) Maris, M.; Huck, W.-R.; Mallat, T.; Baiker, A. J. Catal. 2003,
219, 52-58. (b) Maris, M.; Mallat, T.; Orglmeister, E.; Baiker, A. J. Mol.
Catal. A 2004, 219, 371-376.
W. S. Angew. Chem., Int. Ed. 2002, 41, 1998-2007.
(
2) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed.
1
998, 37, 2987-2989. (b) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; H o¨ rmann,
E.; McIntyre, S.; Menges, F.; Sch o¨ nleber, M.; Smidt, S. P.; W u¨ stenberg,
B.; Zimmermann, N. AdV. Synth. Catal. 2003, 345, 33-43. (c) Troutman,
M. V.; Appella, D. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4916-
4
917. (d) Forman, G. S.; Ohkuma, T.; Hems, W. P.; Noyori, R. Tetrahedron
Lett. 2000, 41, 9471-9475. (e) Conticello, V. P.; Brard, L.; Giardello, M.
A.; Tsuji, Y.; Sabat, M.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992,
1
14, 2761-2762.
1
0.1021/ol061681r CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/09/2006

lidinone-substituted pyridines with Pd(OH)
been reported.
A ferrocene-based homogeneous diphosphinerhodium
complex was applied by Fuchs for the reduction of a
2
/C as catalyst has
trivial task, an enantioselective hydrogenation of the furan
ring is highly desirable. In this paper, we want to com-
municate our results for the asymmetric hydrogenation of a
selected furan derivative, leading to enantiomerically en-
riched 2′,3′-dideoxynucleosides.
7
2-substituted pyrazine derivative yielding the corresponding
8
16
piperazine with enantiomeric purities up to 78%. Studer et
al. employed Rh(nbd) BF /(S,S)-DIOP for the reduction of
Furan 1 (Table 1) appeared to be a promising substrate
for an asymmetric homogeneous hydrogenation for the
2
4
a series of pyridines and furans with enantioselectivities up
9
to 27%. 2-Methylquinoxaline was reduced to (-)-(2S)-2-
methyl-1,2,3,4-tetrahydroquinoxaline with ee’s up to 90%
by Bianchini and his group using an ortho-metalated di-
Table 1. Asymmetric Hydrogenation of 1 with Chiral Rh and
Ru Catalysts
hydride Ir complex (fac-exo-(R)-[IrH
CH CH PPh
}]).10 Kuwano and co-workers reported on
the efficient reduction of N-protected indoles catalyzed by
2 6 4
{C H C*H(Me)N-
(
2
2
2 2
)
1
1
[
Rh(nbd)
2 6
]SbF /(S,S)-(R,R)-PhTRAP with very good enantio-
12
selectivities. Substituted-quinolines were hydrogenated by
13
[
Ir(cod)Cl]
ligand with good to excellent ee values.
Recently, we published a new diastereoselective route to
2
with (R)-MeO-Biphep or with (R)-P-PHOS as
yieldb,c/
ee (%)
14
d
catalyst (equiv)
conditionsa
1
2
3
4
5
6
7
8
9
0
1
2
3
4
[Rh(nbd)2]BF4/6e
THF/MeOH, H2 (80 bar),
80 °C
THF, H2 (50 bar), rt
<5/0
15
16
2
′,3′-dideoxynucleoside analogues from 2-substituted furans.
(
0.3)
[Rh(nbd)Cl]2/7
0.3)
[Rh(nbd)Cl]2/7
0.3)
[Rh(nbd)(8)]ClO4
0.3)
[Ru(p-cymene)Cl2]2/9
0.2)
[Ru(p-cymene)Cl2]2/9
0.2)
[Rh(cod)(10)]BF4
0.2)
[Rh(cod)(10)]BF4
0.2)
[Rh(cod)(11)]BF4
0.3)
[Rh(cod)(11)]BF4
0.3)
[Rh(cod)(11)]BF4
0.1)
[Rh(cod)(12)]BF4
0.1)
[Rh(cod)(12)]BF4
0.2)
In this short reaction sequence (Figure 1), planar, prochiral
e
75/0
(
e
THF, Et3N (0.1 equiv),
H2 (50 bar), rt
THF, H2 (50 bar), rt
73/10
(â-L-2)
65/0
(
(
e
e
THF, H2 (50 bar), rt
56/0
(
THF, Et3N (0.1 equiv),
H2 (50 bar), rt
THF, H2 (80 bar), 80 °C
77/26
(â-L-2)
10/0
(
(
f
THF, Et3N (0.1 equiv),
H2 (80 bar), 80 °C
THF, H2 (80 bar), 80 °C
10 /0
(
f
68 /23
(
(â-D-2)
Figure 1. Reaction sequence for the synthesis of 2′,3′-dideoxy-
nucleosides.
f
1
1
1
1
1
MeOH, H2 (80 bar), 80 °C
THF, H2 (80 bar), 80 °C
THF, H2 (80 bar), 80 °C
10 /23
(
(â-L-2)
f
60 /32
(
(â-D-2)
98/72
furylnucleosides (C) served as key intermediates, which were
subsequently transformed into the target compounds by a
chemo- and diastereoselective heterogeneous hydrogenation
(
(â-D-2)
f
THF, NEt3 (0.2 equiv),
H2 (80 bar), 80 °C
THF, Cs2CO3 (0.25 equiv), 10 /29
30 /49
2 3
using Pd/C or Rh/Al O as catalysts. The required â-con-
(
(â-L-2)
figuration is thereby established, and only two out of four
possible diastereoisomers are formed. Since the separation
of the enantiomers (the â-D- and â-L-nucleoside) is not a
f
[Rh(cod)(12)]BF4
(0.1)
[Rh(cod)(12)]BF4
H (80 bar), 80 °C
2
(â-L-2)
67/58
15
THF, H2 (80 bar), 80 °C
(
0.01)
(â-D-2)
(
7) (a) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.; Lehmann, C.
a
Reaction time 22-24 h. b Isolated yield of 2. c Compound 3 was
W. Angew. Chem., Int. Ed. 2004, 43, 2850-2852. (b) Glorius, F. Org.
d
e
detected in each run in low amounts. Determined by HPLC. Prepared
in situ. Compound 4 was detected as a side product.
Biomol. Chem. 2005, 3, 4171-4175.
f
(8) Fuchs, R. EP 0 803 502 A2, 1997.
(9) Studer, M.; Wedemeyer-Exl, C.; Spindler, F.; Blaser, H.-U. Monatsh.
Chem. 2000, 131, 1335-1343.
10) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M.
Organometallics 1998, 17, 3308-3310.
11) S,S)-(R,R)-PhTRAP ) (R,R)-2,2′′-bis[(S)-(diphenylphosphino)ethyl]-
,1′′-biferrocene: (a) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron:
(
following reasons: (i) furan as an electron-rich heterocycle
with low aromatic character is reduced under mild conditions
and (ii) the presence of anchor groups (methyl carboxylate
(
1
Asymmetry 1991, 2, 593-596. (b) Sawamura, M.; Hamashima, H.;
Sugawara, M.; Kuwano, R.; Ito, Y. Organometallics 1995, 14, 4549-4558.
(12) (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am.
(14) (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han X.-W.; Zhou, Y.-G.
J. Am. Chem. Soc. 2003, 125, 10536-10537. (b) Yang, P.-Y.; Zhou, Y.-G.
Tetrahedron: Asymmetry 2004, 15, 1145-1149. (c) Lu, S.-M.; Han, X.-
W.; Zhou, Y.-G. AdV. Synth. Catal. 2004, 346, 909-912. (d) Xu, L.; Lam,
K. H.; Ji, J.; Wu, J.; Fan, Q.-H.; Lo, W.-H.; Chan, A. S. C. Chem. Commun.
2005, 1390-1392.
Chem. Soc. 2000, 122, 7614-7615. (b) Kuwano, R.; Kaneda, K.; Ito, T.;
Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213-2215.
(
13) R)-MeO-Biphep ) (R)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(di-
phenylphosphine): Schmid, R.; Foricher, J.; Cereghetti, M.; Sch o¨ nholzer,
P. HelV. Chim. Acta 1991, 74, 370-389.
4134
Org. Lett., Vol. 8, No. 18, 2006

and/or thymine) in the substrate might enable a precoordi-
nation with the catalyst, which should enhance the selectivity.
The fully hydrogenated tetrahydrofuran derivative 5, the
selectively base-hydrogenated furan 4, and nucleobase 3
formed upon hydrogenolytic C-N bond cleavage were
expected as possible byproducts in the hydrogenation of 1.
Table 1 summarizes our results obtained for the asym-
metric hydrogenation of furan 1. Emphasis in this catalyst
screening study was put on commercially available ligands
and recently published diphosphines. Depending on catalyst
precursor, additives, solvent, and reaction conditions, marked
differences within the individual systems have been observed.
In this paper, only systems leading to hydrogenated products
are disclosed. The yield always refers to isolated product 2.
The amount and distribution of side products thymine (3)
3
(NEt ) led to some enantioselectivity (10% ee; entry 3). The
selectivity-enhancing effect of an admixed base has already
been observed by Kuwano and co-workers, but to a much
1
2
larger extent. As expected, by using the mirror-imaged
ligand (S)-(R)-7 the â-D-nucleoside (65% yield, 8% ee)
predominated.
The catalyst [Rh(nbd)(8)]ClO
4
was unselective re-
garding enantiocontrol but exhibited a good reactivity
2
0
(entry 4). L-Hydroxyproline-derived ligand 9 with [Ru(p-
cymene)Cl provided racemic tetrahydrofuran 2 in 56%
yield (entry 5). Again, addition of a base (0.1 equiv of NEt
2 2
]
3
,
entry 6) significantly enhanced both yield and ee (77%
and 26%, respectively). The benzothiophene-based catalyst
2
1
[Rh(cod)((R,R)-10)]BF
4
performed rather disappointingly,
giving 2 in only 10% yield without any detectable selectivity
(entry 7). The addition of base only influenced the chemo-
selectivity of the hydrogenation, yielding side product 4 to
a larger extent.
1
7
and 4 (Figure 2) was not accurately determined for each
However, the increase of the steric bulk in the ligand
sphere by switching from bis(dimethylphospholane) (R,R)-
1
0 to the bis(diethylphospholane) derivative (S,S)-1121
improved not only the activity but also the selectivity of the
catalyst (68% yield and 23% ee (â-D-2), entry 9). MeOH
instead of THF as solvent reVersed the enantioselectivity of
the hydrogenation. Though in low yield, â-L-2 was prefer-
entially obtained (23% ee; entry 10). A lower catalyst loading
(from 0.3 to 0.1 equiv) led to a slightly decreased yield but
increased the ee (32%; entry 11). By further increasing the
steric demands of the catalyst, yields and enantioselectivities
could be improved. Addition of 0.1 equiv of butiphane-type
2
1
catalyst [Rh(cod)((R,R)-12)]BF
of 1 in 98% yield together with 72% enantiomeric purity
entry 12). The addition of a base (NEt or Cs CO ) reversed
4
allowed for the reduction
Figure 2. Ligands 6-12.
(
3
2
3
the stereoselectivity of the hydrogenation (entries 13 and 14),
yielding predominantly â-L-2 with 49% and 29% ee,
respectively. The performance of [Rh(cod)((R,R)-12)]BF at
4
a catalyst loading of 1% still gave â-D-2 with 67% yield
and 58% ee.
In the present paper, one of the highest enantioselectivities
for a homogeneous hydrogenation of a furan derivative is
reported.
run. Surprisingly, the fully hydrogenated tetrahydrofuran 517
was not detected under conditions described in this paper.
Products arising from trans-hydrogenations (de values >99%)
were not observed in any of these experiments.
The reactivity of the cationic catalyst generated in situ from
[
2 4
Rh(nbd) ]BF and the bulky electron-rich ligand of the
18
Josiphos family (R)-(S)-6 was significantly lower than the
one of the neutral Rh catalyst with the structurally similar
19
ligand (R)-(S)-7. The latter afforded the desired product in
good yields (73-75%, entries 1-3). The addition of a base
Acknowledgment. Kerstin Waich (Technical University
of Graz) is thanked for the preparation of compound 1.
Supporting Information Available: Experimental pro-
cedures and selected spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
15) For the biological significance of nucleoside analogues, see:
Mansour, T. S.; Storer, R. Curr. Pharm. Des. 1997, 3, 227-264.
16) Albert, M.; De Souza, D.; Feiertag, P.; H o¨ nig. H. Org. Lett. 2002,
(
4
, 3251-3254.
(17)
OL061681R
(
19) Fryzuk, M. D.; Bosnich, B J. Am. Chem. Soc. 1977, 99, 6262-
6
267.
(
(
20) Achiwa, K. J. Am. Chem. Soc. 1976, 98, 8265-8266.
21) (a) Berens, U. WO 2003031456 A2, 2003. (b) Berens, U.; Englert,
U.; Geyser, S.; Runsink, J.; Salzer, A. Eur. J. Org. Chem. 2006, 9, 2100-
2109.
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