Synthesis of new monodentate spiro phosphoramidite ligand and its application in Rh-catalyzed asymmetric hydrogenation reactions

Article abstract of DOI:10.1021/ol048528m

(Chemical Equation Presented) A new spirocyclic diol, 9,9′- spirobixanthene-1,1′-diol, was synthesized in two steps from readily available starting material m-phenoxyanisole. Resolution of the racemic diol was achieved by cocrystallization with N-benzylcinchondimium chloride and N-benzylquininium chloride in acetonitrile. The corresponding spiro monodentate phosphoramidite ligand has been prepared for Rh-catalyzed asymmetric hydrogenation of α-dehydroamino acid derivatives and itaconic acid with excellent enantioselectivities (up to >99% ee).

Full text of DOI:10.1021/ol048528m

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3565-3567
Synthesis of New Monodentate Spiro
Phosphoramidite Ligand and Its
Application in Rh-Catalyzed Asymmetric
Hydrogenation Reactions
Shulin Wu, Weicheng Zhang, Zhaoguo Zhang, and Xumu Zhang*
Department of Chemistry, 104 Chemistry Research Building, The PennsylVania State
UniVersity, UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received July 27, 2004
ABSTRACT
A new spirocyclic diol, 9,9′-spirobixanthene-1,1′-diol, was synthesized in two steps from readily available starting material m-phenoxyanisole.
Resolution of the racemic diol was achieved by cocrystallization with N-benzylcinchonidinium chloride and N-benzylquininium chloride in
acetonitrile. The corresponding spiro monodentate phosphoramidite ligand has been prepared for Rh-catalyzed asymmetric hydrogenation of
r
-dehydroamino acid derivatives and itaconic acid with excellent enantioselectivities (up to >99% ee).
Transition-metal-catalyzed enantioselective hydrogenation is
a powerful strategy to synthesize chiral substances from
unsaturated starting materials.1 Since DIOP ligand was
discovered by Kagan in 1971,2 a large number of bidentate
ligands, especially those diphosphine ligands with C2 sym-
metry, have been developed for highly efficient asymmetric
hydrogenation of various olefins, ketones, and imines.3 In
comparison, monodentate ligands had been much less
successful due to the conformational flexibility of their metal/
ligand complexes. However, recent advances4-6 indicated that
monodentate ligands can be effective for asymmetric hy-
drogenation. For example, MonoPhos has been prepared from
BINOL5a and led to excellent enantioselectivities in Rh-
catalyzed asymmetric hydrogenation of R- and â-dehy-
(4) (a) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.;
Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961. (b)
Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889. (c)
Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2001, 40, 1197. (d)
Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831. (e) Hoen, R.;
Berg, v d M.; Bernsmann, H.; Minnaard, A. J.; Vries, J. G. d.; Feringa, B.
L. Org. Lett. 2004, 6, 1433.
(5) (a) Hulst, R.; de Vries, K.; Feringa, B. L. Tetrahedron: Asymmetry
1994, 5, 699. (b) Berg, M. v. d.; Minnaard, A. J.; Schudde, E. P.; Esch, J.
v.; Vries, A. H. M. d.; Vries, J. G. d.; Feringa, B. L. J. Am. Chem. Soc.
2000, 122, 11539. (c) Pen, D.; Minnaard, A. J.; Vries, J. G. d.; Feringa, B.
L. J. Am. Chem. Soc. 2002, 124, 14552. (d) Berg, M. v. d.; Haak, R. M.;
Minnaard, A. J.; Vries, A. H. M. d.; Vries, J. G. d.; Feringaa, B. L. AdV.
Synth. Catal. 2002, 344, 1003. (e) Berg, M. v. d.; Minnaard, A. J.; Haak,
R. M.; Leeman, M.; Schedde, E. P.; Meetsma, A.; Feringa, B. L.; Vries, A.
H. M. d.; Maljaars, C. E. P.; Williams, C. E.; Hyett, D.; Boogers, J. A. F.;
Henderickx, H. J. W.; Vries, J. G. d. AdV. Synth. Catal. 2003, 345, 308.
(1) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe
Asymmetric Catalysis I-III; Springer: Berlin, New York, 1999. (b) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994.
(c) Ojima, I., Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New
York, 2000.
(2) (a) Kagan, H. B.; Dang, T.-P. Chem. Commun. 1971, 481. (b) Kagan,
H. B.; Dang, T.-P. J. Am. Chem. Soc. 1972, 94, 6429.
(3) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
10.1021/ol048528m CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/10/2004

Scheme 1. Retrosynthetic Analysis of 3
Figure 1. 9,9′-Spirobixanthene-1,1′-diol (3).
droamino acid derivatives,5b,c itaconic acid derivatives,5b and
enamides.5d Using 1,1-spirobiindane-7,7-diol,6a Zhou et al.
have prepared a series of spiro monodentate phosphoramidite
ligands (SIPHOS), and good to excellent results6b-e have
been achieved in asymmetric hydrogenation reactions. During
the past few years, our group has examined a variety of
readily available ligands with conformational rigidity.7 In
searching for new structural motifs, we found that 9,9′-
spirobixanthene was first synthesized in the 1930s,8a and no
further attempts had been made to assemble functional groups
onto its aromatic rings.8b,c We therefore modified this
spirocyclic framework into a new C2-symmetric 9,9′-spiro-
bixanthene-1,1′-diol (3, Figure 1), which possesses a larger
biting angle and more rigid coordinating structure than
BINOL.9 This new spirocyclic diol 3 is among the most
accessible (two-step synthesis) diols reported to date and can
be practical for many applications. Herein we report the facile
synthesis and resolution of 3. To demonstrate its potential
role in asymmetric catalysis, spiro monodentate phosphor-
amidite ligand 4 was prepared, which exhibited excellent
enantioselectivity (up to 99% ee) in Rh-catalyzed asymmetric
hydrogenation of R-dehydroamino acid derivatives and
itaconic acid.
protection with removable substituents on the positions para
to the methoxy groups in the aromatic ring before cyclization
occurs.6a On the other hand, there is no competing cyclization
in method b. Therefore, it is a preferred strategy to construct
the designed spirocyclic molecule.
Starting from 3-phenoxyanisole (1),11 the symmetric ketone
2 was prepared in a moderate yield by linking 2 equiv of
lithiated 1 with methyl chloroformate (Scheme 2). Further
Scheme 2. Synthesis of Chiral Monodentate Spiro Ligand via
9,9′-Spirobixanthene-1,1′-diola
The original synthesis of 9,9′-spirobixanthene8a involved
the reaction of a Grignard reagent with xanthenone to form
a tertiary alcohol. Subsequent cyclization in the presence of
acetic acid produced the spiran molecule. Considering the
C2-symmetric structure of 3, we envisioned double cycliza-
tion of ketone10 would be a more efficient approach. Among
the two possible ways (Scheme 1) to disconnect the spiro-
cyclic backbone into its ketone precursor, method a requires
a Reagents and conditions: (a) (i) n-BuLi, THF, -78 °C, (ii)
ClCO2CH3, THF, -78 °C; (b) (i) AlCl3, toluene, reflux, (ii) concd
HCl, reflux; (c) (i) N-benzylcinchonidinium chloride, acetonitrile,
(ii) N-benzylquininium chloride, acetonitrile; (d) hexamethylphos-
phorus triamide, toluene, reflux.
(6) (a) Birman, V. B.; Rheingold, A. L.; Lam, K.-C. Tetrahedron:
Asymmetry 1999, 10, 125. (b) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang,
L.-X.; Zhou, Q.-L. Chem. Commun. 2002, 480. (c) Hu, A.-G.; Fu, Y.; Xie,
J.-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2002,
41, 2348. (d) Zhu, S.-F.; Fu, Y.; Xie, J.-H.; Liu, B.; Xing, L.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2003, 14, 3219. (e) Fu, Y.; Guo, X.-X.; Zhu, S.-
F.; Hu, A.-G.; Xie, J.-H.; Zhou, Q.-L. J. Org. Chem. 2004, 69, 4648.
(7) (a) Zhang, X. Enantiomer 1999, 4, 541. (b) Zhu, G.; Cao, P.; Jiang,
Q.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 1799. (c) Zhang, Z.; Qian, H.;
Longmire, J.; Zhang, X. J. Org. Chem. 2000, 65, 6223. (d) Tang, W.; Zhang,
X. Angew. Chem., Int. Ed. 2002, 41, 1612. (e) Tang, W.; Wang, W.; Chi,
Y.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3509.
(8) (a) Clarkson, R. G.; Gomberg, M. J. Am. Chem. Soc. 1930, 52, 2881.
(b) Gilman, H.; Weipert, E. A.; Dietrich, J. J.; Hayes, F. N. J. Org. Chem.
1958, 23, 361. (c) Aleksiuk, O.; Biali, S. E. Tetrahedron Lett. 1993, 34,
4857.
(9) During the course of our work, synthesis and resolution of 9,9′-
spirobifluorene-1,1′-diol was reported by Zhou et al. in a six-step
synthesis: Cheng, X.; Hou, G.-H.; Xie, J.-H.; Zhou, Q.-L. Org. Lett. 2004,
6, 2381.
treatment of 2 with an acid was expected to produce the
spiran precursor 5. However, several acidic reagents (H2-
SO4, HCl, polyphosphoric acid, acetic acid, and trifluoro-
acetic acid) have been tested, and none of them can lead to
the desired product. Interestingly, when we tried AlCl3, target
molecule 3 was formed directly.12 As a Lewis acid, AlCl3
can promote not only Frediel-Crafts alkylation but also
deprotection of methyl ether. That accounts for the direct
formation of 3 from 2 in one pot.
To obtain enantiomerically pure 3, cocrystallization13 of
racemic 3 with chiral resolving reagents has been extensively
(11) Oliveira, A. M. A. G.; Raposo, M. M. M.; Oliveira-Campos, A. M.
(10) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 1980, 45, 2930.
E.; Griffiths, J. Machado, A. E. H. HelV. Chim. Acta 2003, 86, 2900.
3566
Org. Lett., Vol. 6, No. 20, 2004

Table 1. Rh(I)/(R)-4-Catalyzed Asymmetric Hydrogenation of
R-Dehydroamino Acid Derivatives and Itaconic Acida
Figure 2. ORTEP representation of molecular complex crystal of
(R)-3 and 6.
studied. The most efficient reagent was found to be N-
benzylcinchonidinium chloride (6), which can precipitate as
cocrystals with one enantiomer of 3 in acetonitrile. X-ray
diffraction of a single crystal grown from the precipitate
revealed a regularly packed molecular complex of 3 and 6
in 1:1 molar ratio (Figure 2). Based on the crystal structure
of 6, the absolute configuration of 3 is assigned as (R). The
other (S) enantiomer of 3 can be obtained from the mother
solution by cocrystallization with N-benzylquininium chlo-
ride.
To demonstrate the utilities of the spirocyclic diol, we have
prepared monodentate phosphoramidite derivative 4 for
asymmetric hydrogenation reactions. Following the procedure
of Monophos synthesis,5a (R)-4 was prepared by reacting
(R)-3 with hexamethylphosphorus triamide (HMPT) in
refluxing toluene. Then a series of R-dehydroamino acid
derivatives 7 were explored as substrates in hydrogenation
reactions. The results (Table 1, entries 1-7) confirm excel-
lent enantioselectivities of 4 as a monodentate phosphor-
amidite ligand in Rh-catalyzed asymmetric hydrogenation
reactions of dehydroamino acid derivatives (up to >99% ee).
Itaconic acid 9 was also used for hydrogenation, and 97.9%
ee was achieved (Table 1, entry 8). This result compares
a Refer to the Experimental Section for details. All hydrogenation
reactions were performed with 0.1 mmol substrate and 0.001 mmol in situ
prepared [Rh(nbd)2]BF4/(R)-4 in CH2Cl2 at room temperature, PH2 ) 25psi.
100% conversion was observed within 12 h. b Determined by chiral GC
(Chirasil-VAL III FSOT). c The S absolute configuration was assigned by
comparison of optical rotation with reported data. d THF/CH2Cl2 (5:1) was
used as solvent. e The ee was measured through its corresponding methyl
ester (chiral GC, Gamma Dex-225).
favorably to those obtained with other monodentate phos-
phorus ligands (e.g., Monophos, 97% ee;5e SIPHOS, 94.7%
ee5b).
In conclusion, we have developed a new C2-symmetric
spirocyclic diol as a rigid motif for asymmetric catalysis.
Initial studies on its corresponding monodentate phosphor-
amidite ligand showed excellent enantioselectivities in Rh-
catalyzed asymmetric hydrogenation of R-dehydroamino acid
derivatives and itaconic acid. With this distinct and readily
accessible structural motif, various transition-metal-catalyzed
asymmetric reactions can be realized.
Acknowledgment. Financial support from NIH-GM is
appreciated. X-ray diffraction experiments (financially sup-
ported by NSF CHE-0131112) were carried out by Dr.
Yennawar. We thank Duan Liu for helpful suggestions.
(12) Other Lewis acids such as BBr3 and ZnCl2 are unsuccessful for the
desired transformation.
(13) (a) Toda, F.; Tanaka, K. J. Org. Chem. 1994, 59, 5748. (b) Cai,
D.-W.; Huges, D. L.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett.
1995, 36, 7991. (c) Pu, L.; Hu, Q.-S.; Vitharana, D. Tetrahedron:
Asymmetry 1995, 6, 2123. (d) Ding, K.; Wang, Y.; Yun, H.; Liu, J.; Wu,
Y.; Terada, M.; Okubo, Y.; Mikami, K. Chem. Eur. J. 1999, 5, 1734. (e)
Zhang, J.-H.; Liao, J.; Cui, X.; Yu, K.-B.; Zhu, J.; Deng, J.-G.; Zhu, S.-F.;
Wang, L.-X.; Zhou, Q.-L.; Chung, L. W.; Ye, T. Tetrahedron: Asymmetry
2002, 13, 1363.
Supporting Information Available: Experimental details
and spectroscopic data for all the new compounds and a
general hydrogenation procedure. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL048528M
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