Rhodium-catalyzed asymmetric conjugate additions of boronic acids to enones using DIPHONANE: A novel chiral bisphosphine ligand

Article abstract of DOI:10.1021/ol0522788

The synthesis of a novel enantiopure C₂-symmetric bisphosphine, DIPHONANE, was accomplished starting from 2,5-norbornadione, utilizing (R,R)- and/or (S,S)-(2,3-O-di[(phenylamino)carbonyl]tartaric acid for the resolution of an intermediate phosp

Full text of DOI:10.1021/ol0522788

ORGANIC
LETTERS
2006
Vol. 8, No. 3
363-366
Rhodium-Catalyzed Asymmetric
Conjugate Additions of Boronic Acids to
Enones Using DIPHONANE: A Novel
Chiral Bisphosphine Ligand
Koen Vandyck, Bavo Matthys, Mario Willen, Koen Robeyns,†
Luc Van Meervelt,† and Johan Van der Eycken*
Laboratory for Organic and Bioorganic Synthesis, Department of Organic Chemistry,
Ghent UniVersity, Krijgslaan 281 (S.4), B-9000 Gent, Belgium
johan.Vandereycken@ugent.be
Received September 20, 2005 (Revised Manuscript Received December 6, 2005)
ABSTRACT
The synthesis of a novel enantiopure C2-symmetric bisphosphine, DIPHONANE, was accomplished starting from 2,5-norbornadione, utilizing
(R,R)- and/or (S,S)-(2,3-O-di[(phenylamino)carbonyl]tartaric acid for the resolution of an intermediate phosphineoxide. The application of this
ligand in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to cyclic enones provides the 1,4-addition products in good
yields (69−98%) and high ee’s (78−95% ee). A byproduct arising from a consecutive 1,4-addition and 1,2-addition was also observed.
The 1,4-addition of aryl or alkenyl groups to electron-
deficient double bonds constitutes an interesting approach
for C-C bond formation.1 Therefore, the asymmetric
rhodium-catalyzed 1,4-addition to R,â-unsaturated enones has
recently received a lot of attention applying various ligands
such as biaryl bisphosphines,2 phosphoramidites,3a,b BINOL-
based diphosphonites,3c amidomonophosphines,3d N-hetero-
cyclic carbenes,3e ferrocenyl-based bisphosphines,2c a P-chiral
phosphine,3f and dienes.3g-k Some other bisphosphine ligands,
although efficient in the Rh(I)-catalyzed hydrogenation, fail
(3) (a) Boiteau, J.-G. Minnaard, A. J, Feringa, B. L. J. Org. Chem. 2003,
68, 9481-9484. (b) Iguchi, Y.; Itooka, R.; Miyaura, N. Synlett 2003, 1040-
1042. (c) Reetz, M. T.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083-
4085. (d) Kuriyama, M.; Nagai, K.; Yamada, K.-I.; Miwa, Y.; Taga, T.;
Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932-8939. (e) Ma, Y.; Song,
S.; Ma, C.; Sun, Z.; Chai, Q.; Andrus, M. B. Angew Chem., Int. Ed. 2003,
42, 5871-5874. (f) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem.
Soc. 2005, 127, 11934-11935. (g) Defieber, C.; Paquin, J.-F.; Serna, S.;
Carreira, E. M. Org. Lett. 2004, 6, 3873-3876. (h) Hayashi, T.; Ueyama,
K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508-11509.
(i) Otomaru, Y.; Kina, A.; Shintani, R.; Hayashi, T. Tetrahedron: Asym-
metry 2005, 16, 1673-1679. (j) Otomaru, Y.; Okamoto, K.; Shintani, R.;
Hayashi, T. J. Org. Chem. 2005, 70, 2503-2508. (k) Lang, F.; Breher, F.;
Stein, D.; Gru¨tzmacher, H. Organometallics 2005, 24, 2997-3007. For some
recent results on 1,4-additions to other R,â-unsaturated systems, see: (l)
Paquin, J. F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am.
Chem. Soc. 2005, 127, 10850-10851 for enals. (m) Paquin, J. F.;
Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005, 7, 3821-
3824 for acrylic esters. (n) Shintani, R.; Duan, W. L.; Nagano, T.; Okada,
A.; Hayashi, T. Angew. Chem., Int. Ed. 2005, 44, 4611-4614 for
maleimides. (o) Shintani, R.; Kimura, T.; Hayashi, T. Chem. Commun. 2005,
25, 3213-3214 for Weinreb amides. (p) Jagt, R. B. C.; de Vries, J. G.;
Feringa, B. L.; Minnaard, A. J. Org. Lett. 2005, 7, 2433-2435 for 2,3-
dihydro-4-pyridones. (q) Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett.
2005, 7, 2285-2288 and references therein for coumarins.
† Biomolecular Architecture, Department of Chemistry, K. U. Leuven,
Celestijnenlaan 200F, B-3001 Leuven (Heverlee), Belgium.
(1) For a review on rhodium-catalyzed asymmetric 1,4-addition and C-C
bond formation, respectively, see: (a) Hayashi, T.; Yamasaki, K. Chem.
ReV. 2003, 103, 2829-2844. (b) Fagnou, K.; Lautens, M. Chem. ReV. 2003,
103, 169-196.
(2) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579-5580. (b) Amengual, R.; Michelet,
V.; Geneˆt, J.-P. Synlett 2002, 1791-1794. (c) Pucheault, M.; Darses, S.;
Geneˆt, J.-P. Eur. J. Org. Chem. 2002, 3552-3557. (d) Shi, Q.; Xu, L.; Li,
X.; Jia, X.; Wang, R.; Au-Yeung, T. T.-L.; Chan, A. S. C.; Hayashi, T.;
Cao, R.; Hong, M. Tetrahedron Lett. 2003, 44, 6505-6508. (e) Madec, J.;
Michaud, G.; Geneˆt, J.-P.; Marinetti, A. Tetrahedron: Asymmetry 2004,
15, 2253-2261. (f) Yuan, W.-Y.; Cun, L.-F.; Gong, L.-Z. Mi, A.-Q.; Jiang,
Y.-Z. Tetrahedron Lett. 2005, 46, 509-512. (g) Ogasawara, M.; Ngo, H.
L.; Sakamoto, T.; Takahashi, T.; Lin, W. Org. Lett. 2005, 7, 2881-2884.
10.1021/ol0522788 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/31/2005

to induce high reactivity and/or selectivity in the rhodium-
catalyzed 1,4-addition to R,â-unsaturated enones.1,2a,c Within
our interest for the design of new ligand architectures4 and
stimulated by the synthesis of DIANANE5 (Figure 1), we
tion by applying the hydrogen bonding capacity of the
phosphineoxide and BH3-protected phosphines tend to act
as a catalyst poison for heterogeneous hydrogenation.10
Hydrogenation with Pd on charcoal (10 w/w %) resulted
stereoselectively in endo-bisphosphine-oxide (()-4.
The bis-endo configuration of (()-4 could be deduced
3
from the JPC coupling in the 31P NMR spectrum of P with
C7 being 15.2 Hz (expected endo ) 12-16.8 Hz, exo ≈ 0
Hz).11 Nevertheless, resolutions applying commercial (R,R)-
(-)-di-O,O-benzoyltartaric acid (DBTA) 7, R-(-)-mandelic
acid 9, or (1R)-(-)-camphorsulfonic acid (CSA) 10 (Figure
2) were unsuccessful. Fortunately, when (R,R)-(2,3-di-
Figure 1.
wish to present our results concerning the synthesis and
application of a novel C2-symmetric bisphosphine, DIPHO-
NANE.
Our approach started with the known 2,5-norbornadione
(()-16 (Scheme 1). Dienolization/alkylation of this interme-
Figure 2. Chiral acids tested for the resolution of (()-4.
Scheme 1. Synthesis and Resolution of DIPHONANE
[(phenylamino)carbonyl]tartaric acid 8 or its enantiomer was
applied (both obtained in three steps from the corresponding
tartaric acid12), bis-phosphineoxide (()-4 was resolved with
high enantiomeric excess (>98% ee), as determined by
HPLC analysis with a chiral stationary phase column
(Chiralpak AD-H). In this way, enantiomerically pure
(2S,5S)-4 could be obtained in 35% yield in two steps from
(()-3. Reduction of the phosphineoxide (HSi(OEt)3,
Ti(OiPr)4)13 was followed by reprotection with BH3 to ensure
easy purification of the phosphine precursor, resulting in the
isolation of 5. Again, the 3JPC coupling with C7 appeared to
be large (12.8 Hz), proving that no epimerization had
occurred. The absolute configuration of 5, being
(+)-(1S,2S,4S,5S) was established by single-crystal X-ray
diffraction (Figure 3).8 By refluxing the phosphine-borane
in EtOH, an efficient procedure recently applied in our group
for mild deprotection of phosphines,14 DIPHONANE 6 was
obtained.
diate is usually addressed in two separate steps,3h,j,7 but
nevertheless the dienolization with KHMDS followed by
treatment with PhNTf2 gave a satisfactory yield of the
bistriflate (()-2. Pd(0)-catalyzed coupling of 2 with HPPh2
and subsequent oxidation resulted in the racemic vinylic
bisphosphineoxide (()-3.8,9 This intermediate was preferred
over its phosphino-borane complex because it allows resolu-
The efficiency of our new ligand was tested in the
rhodium-catalyzed 1,4-addition of arylboronic acids to
enones (Table 1).1-3 We first examined the addition of
phenylboronic acid 12a to cyclohexenone 11A. In accordance
(9) Gilbertson, S. R.; Fu, Z.; Starkey, G. W. Tetrahedron Lett. 1999,
40, 8509-8512.
(10) (a) Boerner, A.; Ward, J.; Ruth, W.; Holz, J.; Kless, A.; Heller, D.;
Kagan, H. B. Tetrahedron 1994, 50, 10419-10430. (b) Vandyck, K.; Van
der Eycken, J. Unpublished results.
(11) Maffei, M.; Buono, G. New J. Chem. 1988, 12, 923-930.
(12) (a) Cereghetti, M.; Rageot, A. European Patent 511 558, 1992. (b)
Cereghetti, M.; Schmid, R.; Scho¨nholzer, P.; Rageot, A. Tetrahedron Lett.
1996, 37, 5343-5346. (c) Chen, Y.-X.; Li, Y.-M.; Lam, K.-H.; Chan, A.
S. C. Chin. J. Chem. 2001, 19, 794-799.
(13) Coumbe, T.; Lawrence, J. N.; Muhammad, F. Tetrahedron Lett.
1994, 35, 625-628.
(14) Although addition of DABCO accelerated the reaction, it was not
crucial to obtain full conversion. For deprotection with EtOH, see: (a)
Moulin, D.; Bago, S.; Bauduin, C.; Darcel, C.; Juge´, S. Tetrahedron:
Asymmetry 2000, 11, 3939-3956. (b) Vervecken, E.; Van der Eycken, J.
To be submitted.
(4) (a) Vandyck, K.; Matthys, B.; Van der Eycken, J. Tetrahedron. Lett.
2005, 46, 75-78. (b) Kuppens T.; Vandyck K.; Van der Eycken J.;
Herrebout W.; van der Veken, B. J.; Bultinck P. J. Org. Chem. 2005, 70,
9103-9114. (c) De Coster, G.; Vandyck, K.; Van der Eycken, E.; Van der
Eycken, J.; Elseviers, M.; Ro¨per, H. Tetrahedron: Asymmetry 2002, 13,
1673-1679.
(5) (a) Berkessel, A.; Schro¨der, M.; Sklorz, C. A.; Tabanella, S.; Vogl,
N.; Lex, J.; Neudo¨rfl, J. M. J. Org. Chem. 2004, 69, 3050-3056. (b)
Berkessel, A.; Menche, D.; Sklorz, C. A.; Schro¨der, M.; Paterson I. Angew.
Chem., Int. Ed. 2003, 42, 1032-1035.
(6) Hawkins, R. T.; Hsu, R. S.; Wood, S. G. J. Org. Chem. 1978, 43,
4648-4650.
(7) Smith, B. T.; Wendt, J. A.; Aube, J. Org. Lett. 2002, 4, 2577-2579.
(8) See Supporting Information for X-ray diffraction structure.
364
Org. Lett., Vol. 8, No. 3, 2006

perature to 50 °C (entries 5 and 6), affording the product
with an enantiomeric excess of 91%. Changing the base from
KOH to NEt3 (entry 7) or changing the solvent (entries 8-13)
did not lead to better results.
As a byproduct, resulting from the asymmetric 1,4-addition
and a consecutive 1,2-addition, (1R,3R)-1,3-diphenyl-cyclo-
hexanol 14Aa could be isolated.16 The Rh(I)-catalyzed 1,2-
arylation of ketones is usually limited to strained ketones as
acceptor or to intramolecular additions, whereas arylation
of aldehydes or aldimines has been described to a much
larger extent.1,17 The 1,2-addition showed a high level of
diastereoselectivity (95% de, entry 14), whereas the resulting
product 14Aa showed a comparable enantiomeric excess as
the initial 1,4-adduct 13Aa (entries 5, 6, and 14). At higher
concentration (0.91 M 11A) 14Aa was formed in up to 32%,
applying only 2 equiv 12a at 45 °C.
Figure 3. X-ray crystal structure of (2S,5S)-5.
Extending the Rh(I)/DIPHONANE-catalyzed addition to
a variety of boronic acids 12a-f and a range of acceptors
11A-E (Table 2) revealed high selectivity in the addition
of 4-CF3-Ph (12b) and 1-naphthyl boronic acid (12d) to
cyclohexenone (11A, 92% ee, entry 1, and 95% ee, entry 3,
respectively). The hindered o-tolyl boronic acid (12e) gave
with earlier findings,15 we observed that the generation of
the catalyst from [RhCl(C2H4)2]2 in the presence of KOH
and (S,S)-DIPHONANE (entry 1) resulted in a more active
catalyst than in the case of (S,S)-DIPHONANE with
Rh(acac)(C2H4)2 (entries 2 and 3), whereas the 1,4-addition
product was produced with comparable enantiomeric excess
(85% and 86% ee, respectively). The use of 3 mol % of
catalyst (entry 4) instead of 1 mol % (entry 1) resulted in an
equal enantiomeric excess (85%). The [RhCl(C2H4)2]2/KOH/
DIPHONANE system allowed lowering the reaction tem-
Table 2. Asymmetric 1,4-Addition of Arylboronic Acids
12a-f to R,â-Unsaturated Enones 11A-E
Table 1. Asymmetric 1,4-Addition of Phenylboronic Acid 12a
to Cyclohexenone 11Aa
temp
entry (°C)
time 13Aa ee 14Aa [%]
(h)
solvent
(%)b (%)c (ee [%])d
1
100 dioxane/H2O 10/1
100 dioxane/H2O 10/1
80 dioxane/H2O 10/1
100 dioxane/H2O 10/1
60 dioxane/H2O 10/1
50 dioxane/H2O 10/1
50 dioxane/H2O 10/1
50 DME/H2O 10/1
50 EtOH/H2O 10/1
50 toluene/H2O 10/1
50 dioxane/H2O 5/1
50 ethyleneglycol/
dioxane 3/1
2
5
21
3
4
4
16
16
16
21
4
66
43
50
72
83
78
65
69
76
9
85
86
87
85
90
91
87
90
91
nd
90
89
5
1
1
7
2e
3e
4f
5
entry
11
12
time (h) yield (%)a of 13 ee [%]b (config)
6 (88)
12 (89)
<1
<1
4
<1
3
6
6
7g
8
1
2
3
4
5
6
7
8
11A 12b
11A 12c
11A 12d
11A 12e
11A 12f
11B 12a
11C 12a
11C 12d
11D 12a
11E 12a
19
4
4
20
20
4
4
4
17
19
78 (13Ab)
73 (13Ac)
95 (13Ad)
69 (13Ae)
nc (13Af)
96 (13Ba)
98 (13Ca)
96 (13Cd)
nc (13Da)
96 (13Ea)
92 (R)
79 (R)
95 (R)
78 (R)
9
10
11
12
63
67
83 (R)
86 (R)
95 (+)
6
13
14h
50 2-ethoxyethanol
45 dioxane/H2O 10/1
21
19
74
50
90
91
10
32 (89)i
9c
10
31 (S)
a Standard conditions [RhCl(C2H4)2]2/DIPHONANE/cyclohexenone
0.5/1.1/100, ∼0.35 M 11A, 1.5 equiv KOH, 5 equiv PhB(OH)2. b Isolated
as a mixture with 14Aa. c Determined by HPLC analysis with a chiral
stationary phase column (Chiralcel AD-H). d Determined from 1H NMR
ratio with (R)-13Aa based on 11A, enantiomeric excess determined by
HPLC analysis with a chiral stationary phase column (Chiralcel OD-H).
e 1% Rh(acac)(C2H4)2 was used as catalyst precursor without the addition
of base. f 1.5% [RhCl(C2H4)2]2 was used. g 1.5 equiv NEt3 was applied as
a Isolated yield. nc ) no conversion. b Determined by HPLC analysis
with a chiral stationary phase column (Chiralpak AD-H or Chiralcel OD-
H). c 3% Rh(acac)(CH2CH2)2, 3.3% (2S,5S)-6, dioxane/H2O 10/1, 100 °C.
i
a base. h 0.91 M 11A, 2 equiv PhB(OH)2. ∼95% de.
Org. Lett., Vol. 8, No. 3, 2006
365

a lower selectivity and yield (69% yield, 78% ee, entry 4),
whereas no reaction was observed for 2,6-dimethylphenyl
boronic acid (12f, entry 5). A lower selectivity also was
observed with the electron-rich 4-MeO-Ph boronic acid (79%
ee, 73% yield, entry 2).
The Rh(I)/DIPHONANE-catalyzed addition was also ap-
plied to cyclopentenone 11B and cycloheptenone 11C as
acceptors. The addition to 11B resulted in the phenyl adduct
13Ba with good selectivity and excellent yield (entry 6, 83%
ee, 96% yield). Addition to 11C with both phenylboronic
acid (12a) and 1-naphthylboronic acid (12d) resulted in the
corresponding 1,4-adducts with high yield and good stereo-
selectivity (13Ca, entry 7, 98% yield, 86% ee and 13Cd,
entry 8, 96% yield and 95% ee, respectively.)
No reactivity was observed in the addition of 12a to
coumarin 11D (entry 9).3q Although the catalyst showed good
reactivity in the addition of 12a to the linear enone 11E (92%
yield, entry 10), the enantioselectivity dropped remarkably
(31% ee) Noteworthy is the fact that 1,2-addition was only
observed in minor amounts (<3%) in the case of 13Ad and
13Ab.
In conclusion, the Rh(I) complex derived from the new
bisdiphenylphosphine DIPHONANE catalyses the asym-
metric 1,4-addition of boronic acids to enones with ee’s up
to 95% ee. The intermediate 2 should allow elaboration of
a broader range of 2,5-norbornane bisphosphines, both C2-
and C1-symmetric.
Acknowledgment. The authors gratefully acknowledge
financial support by Ghent University. K.V. is a Research
Assistant of the Research Foundation-Flanders (F.W.O.-
Vlaanderen).
(15) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052-5058.
(16) For the assignment of the configuration, see Supporting Information.
(17) Intermolecular Rh-catalyzed 1,2-addition of arylboronic acids to
cyclobutanone: (a) Matsuda, T.; Makino, M.; Murakami, M. Org. Lett.
2004, 6, 1257-1259. (b) Matsuda, T.; Makino, M.; Murakami, M. Bull.
Chem. Soc. Jpn. 2005, 78, 1528-1533. Intramolecular Rh-catalyzed 1,2-
addition to ketones: (c) Takewasa, A.; Yamoguchi, K.; Ohmuna, T.;
Yamamoto, Y.; Miyaura, N. Synlett 2002, 1733-1735. (d) Miura, T.;
Shimada, M.; Murakami, M. Synlett 2005, 667-669. (e) Shintani, R.;
Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc.
2005, 127, 54-55. (f) Matsuda, T.; Makino, M.; Murakami, M. Angew.
Chem., Int. Ed. 2005, 44, 4608-4611. Rh-catalyzed trimethylphenylstannane
addition to cyclohexanone: (g) Oi, S.; Moro, M.; Fukuhara, H.; Kawanishi,
T.; Inoue, Y. Tetrahedron 2003, 59, 4351-4361.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 2-6, 14Aa and
its epimer 15Aa, and 13Cd. X-ray crystal structure of (()-3
and (1S,2S,4S,5S)-5 in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0522788
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