Rhodium-Catalyzed Asymmetric 1,6-Addition of Aryltitanates to Enynones Giving Axially Chiral Allenes

Article abstract of DOI:10.1021/ol036309f

(Matrix presented) The addition of aryltitanate reagents ArTi(OPr-i) ₄Li to 3-alkynyl-2-en-1-ones in the presence of chlorotrimethylsilane and a rhodium-(R)-segphos as a catalyst proceeded in a 1,6-fashion to give a high yield of axially chiral

Full text of DOI:10.1021/ol036309f

ORGANIC
LETTERS
2004
Vol. 6, No. 2
305-307
Rhodium-Catalyzed Asymmetric
1,6-Addition of Aryltitanates to
Enynones Giving Axially Chiral Allenes
Tamio Hayashi,* Norihito Tokunaga, and Kazuya Inoue
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp
Received November 26, 2003
ABSTRACT
The addition of aryltitanate reagents ArTi(OPr-i)4Li to 3-alkynyl-2-en-1-ones in the presence of chlorotrimethylsilane and a rhodium-(R)-segphos
as a catalyst proceeded in a 1,6-fashion to give a high yield of axially chiral allenylalkenyl silyl enol ethers with up to 93% ee.
Enantiomerically enriched allenes whose chirality is due to
their allene axis are known to be useful as chiral building
blocks in synthetic organic chemistry.1 Although growing
attention has been paid to their asymmetric synthesis,2
synthesis by means of asymmetric catalysis has not been well
developed. To the best of our knowledge, there have been
reported only two types of catalytic methods: (1) palladium-
catalyzed asymmetric hydroboration3 and hydrosilylation4 of
but-1-en-3-ynes and rhodium- or nickel-catalyzed asymmetric
double hydrosilylation of butadiynes5 and (2) palladium-
catalyzed asymmetric substitution of 2-bromobuta-1,3-dienes
and allenylmethyl phosphonates.6 One of the reactions,
presumably applicable to the catalytic asymmetric synthesis
of axially chiral allenes, is the 1,6-addition of organometallic
reagents to 3-alkynyl-2-en-1-ones, which has been reported
by Hulce7 and Krause8 to proceed by means of organocopper
reagents; however, its catalytic asymmetric version has not
been reported. Here we wish to report that the catalytic
asymmetric 1,6-addition giving axially chiral allenes was
realized for the first time by rhodium-catalyzed addition of
aryltitanate reagents in the presence of chlorotrimethylsilane.
For the 1,6-addition to 3-(1-hexynyl)-2-cyclohexenone
(1a), which is readily accessible from 1,3-cyclohexanedione,9
we examined several reaction conditions, including those
(1) For reviews: (a) The Chemistry of the Allenes; Landor, S. R., Ed.;
Academic Press: London, 1982. (b) Schuster, H. F.; Coppola, G. M. Allenes
in Organic Synthesis; Wiley: New York, 1984. (c) Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2000, 39, 3590. (d) Krause, N.; Hoffmann-Ro¨der, A. In
Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
2002, p 145.
(2) For a relevant review on the enantioselective synthesis of allenes:
Hoffmann-Ro¨der, A.; Krause, N. Angew. Chem., Int. Ed. 2002, 41, 2933.
(3) Matsumoto, Y.; Naito, M.; Uozumi, Y.; Hayashi, T. J. Chem. Soc.,
Chem. Commun. 1993, 1468.
(4) Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123,
12915.
(5) (a) Tillack, A.; Michalik, D.; Koy, C.; Michalik, M. Tetrahedron
Lett. 1999, 40, 6567. (b) Tillack, A.; Koy, C.; Michalik, D.; Fischer, C. J.
Organomet. Chem. 2000, 603, 116.
(6) (a) Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem.
Soc. 2001, 123, 2089. (b) Ogasawara, M.; Ueyama, K.; Nagano, T.;
Mizuhata, Y.; Hayashi, T. Org. Lett. 2003, 5, 217. (c) Imada, Y.; Ueno,
K.; Kutsuwa, K.; Murahashi, S.-I. Chem. Lett. 2002, 140.
(7) (a) Fredrick, M. A.; Hulce, M. Tetrahedron 1997, 53, 10197 and
references therein. (b) Cheng, M.; Hulce, M. J. Org. Chem. 1990, 55, 964.
(c) Hulce, M. Tetrahedron Lett. 1988, 29, 5851.
(8) (a) For a relevant review: Krause, N.; Thorand, S. Inorg. Chim. Acta
1999, 296, 1. (b) Canisius, J.; Gerold, A.; Krause, N. Angew. Chem., Int.
Ed. 1999, 38, 1644 and references therein. (c) Krause, N. Chem. Ber. 1990,
123, 2173.
(9) Fu, X.; Zhang, S.; Yin, J.; Schumacher, D. P. Tetrahedron Lett. 2002,
43, 6673.
10.1021/ol036309f CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/18/2003

reported previously for the rhodium-catalyzed asymmetric
1,4-addition to electron-deficient olefins.10-13 It was found
that a new reaction system consisting of an aryltitanate
reagent, chlorotrimethylsilane, and a chiral phosphine-
rhodium catalyst gives a high yield of allenylalkenyl silyl
ether as a 1,6-addition product (Scheme 1). Thus, to a
through a short Celite/MgSO4 pad gave a crude 3-alk-
enylidene-1-(trimethylsilyloxy)cyclohexene 3am in a high
yield. Because the silyl ether 3am is not stable enough for
the determination of its enantiomeric purity by the HPLC
analysis with a chiral stationary phase column, it was
converted into the more stable pivalate ester 4am by
treatment with methyllithium in ether and then with pivaloyl
chloride. The pure ester 4am was isolated in 86% yield (from
1a) by a silica gel PTLC (hexane/ethyl acetate ) 20/1), and
its enantiomeric purity was determined to be 90% ee
(Chiralcel OD-H, hexane). Isolation of the allene as triflate
5am (82%) was also possible by treatment of the lithium
enolate with ArN(Tf)2 (Ar ) 2-pyridyl).7b On protonation
of the lithium enolate by treatment with pivalic acid, the
formation of allenyl ketone 6am was observed, but it readily
underwent isomerization into dienyl ketone 7am on silica
gel chromatography.
Scheme 1
The use of the titanate reagent (PhTi(OPr-i)4Li (2m)) and
chlorotrimethylsilane at the same time is important for the
present 1,6-addition reaction to proceed.15 The 1,6-addition
is not observed in the absence of chlorotrimethylsilane. The
rhodium-catalyzed reaction of 1a with titanium reagent PhTi-
11
(OPr-i)3 brought about 1,2-addition to carbonyl, giving
tertiary alcohol 8am as a major product (Scheme 2).
Scheme 2
solution of enynone 1a (0.30 mmol), chlorotrimethylsilane
(0.63 mmol), [RhCl(C2H4)2]2 (0.0045 mmol, 3 mol % Rh),
and (R)-segphos14 (0.014 mmol) in THF was added a THF
solution of titanate PhTi(OPr-i)4Li (2m) (0.45 mmol),
generated by the addition of Ti(OPr-i)4 to aryllithium or by
the addition of LiOPr-i to ArTi(OPr-i)3, and the mixture was
stirred at 20 °C for 0.5 h. Addition of a small amount of
water followed by removal of precipitates by filtration
As a chiral ligand, (R)-segphos was more enantioselective
than other phosphine ligands we examined. In the reaction
of 1a with 2m, (R)-binap, (S)-(R)-PPF-P(Bu-t)2, and (R)-
MeO-MOP gave 4am in 80, 14, and 0 % ee, respectively.
Because the 1,6-addition proceeds slowly in the absence of
the rhodium catalyst,16 the use of a larger amount (10 mol
% Rh) of the catalyst resulted in a slightly higher enanti-
oselectivity. The results obtained with the rhodium/(R)-
segphos catalyst for some other enynones 1 and titanates 2
(Scheme 1) are summarized in Table 1. The chemoselectivity
in giving allenes and the enantioselectivity were dependent
on the substituent at the alkyne terminus of 1. The yields of
allenes 3 were lower for the sterically more bulky substituents
1c and 1d, and the enantioselectivity was higher for the
sterically less bulky substituents, n-butyl 1a and cyclohexyl
1b, giving higher selectivity than tert-butyl 1c. Aryltitanate
reagents 2n and 2o, which contain fluoro and methoxy
groups at the 4-position of the phenyl, respectively, gave
essentially the same results as phenyltitanate 2m.
(10) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J. Am. Chem. Soc. 1998, 120, 5579. (b) Takaya, Y.; Ogasawara, M.;
Hayashi, T. Tetrahedron Lett. 1998, 39, 8479. (c) Takaya, Y.; Senda, T.;
Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999,
10, 4047. (d) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett.
1999, 40, 6957. (e) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J.
Am. Chem. Soc. 1999, 121, 11591. (f) Hayashi, T.; Senda, T.; Ogasawara,
M. J. Am. Chem. Soc. 2000, 122, 10716. (g) Senda, T.; Ogasawara, M.;
Hayashi, T. J. Org. Chem. 2001, 66, 6852. (h) Hayashi, T.; Takahashi, M.;
Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.
(11) (a) Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J. W. J. Am. Chem.
Soc. 2002, 124, 12102. (b) Yoshida, K.; Hayashi, T. J. Am. Chem. Soc.
2003, 125, 2872.
(12) (a) Kuriyama, M.; Nagai, K.; Yamada, K.-i.; Miwa, Y.; Taga, T.;
Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932. (b) Reetz, M. T.; Moulin,
D.; Gosberg, A. Org. Lett. 2001, 3, 4083. (c) Amengual, R.; Michelet, V.;
Geneˆt, J.-P. Synlett 2002, 1791. (d) Boiteau, J.-G.; Imbos, R.; Minnaard,
A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681.
(13) For reviews: (a) Hayashi, T. Synlett 2001, 879. (b) Fagnou, K.;
Lautens, M. Chem. ReV. 2003, 103, 169. (c) Hayashi, T.; Yamasaki, K.
Chem. ReV. 2003, 103, 2829.
(14) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(15) Reaction of 1a with phenylboronic acid under the conditions used
for the asymmetric 1,4-addition to enones (3 mol % Rh(acac)(C2H4)2/(R)-
binap in dioxane/H2O (10/1), 100 °C, 3 h) (see ref 10) gave only a small
amount (7%) of the dienyl ketone 7am.
(16) Reaction of 1a with 2m and ClSiMe3 in the absence of the rhodium
catalyst at 20 °C for 0.5 h gave ca. 70% yield of the silyl ether 3am.
306
Org. Lett., Vol. 6, No. 2, 2004

Table 1. Asymmetric 1,6-Addition of Aryltitanate Reagent 2 to Enynone 1 Catalyzed by [RhCl(C2H4)2]2/(R)-Segphos and Isolation as
Pivalate Ester 4a
entry
enynone 1 (R)
titanate 2 (Ar)
silyl ether 3 yield (%)b
pivalate 4 yield (%)c
% eed
1e
2
3
4
5
6
7
8
9e
1a (n-Bu)
1a (n-Bu)
1a (n-Bu)
1a (n-Bu)
1b (c-Hex)
1b (c-Hex)
1c (t-Bu)
2m (Ph)
2m (Ph)
3a m >99
3a m >99
3a n >99
3a o >99
3bm >99
3bo >99
3cm 61
4a m 86
4a m 85
4a n 85
4a o 83
4bm 91
4bo 80
4cm 44
4d m 56
4em 80f
90
92
91
93
70
80
26
75
70
2n (4-FC6H4)
2o (4-MeOC6H4)
2m (Ph)
2o (4-MeOC6H4)
2m (Ph)
1d (4-MeOC6H4)
1e (n-Bu)
2m (Ph)
2m (Ph)
3d m 60
3em >99
a To a solution of enynone 1 (0.30 mmol), chlorotrimethylsilane (0.63 mmol), [RhCl(C2H4)2]2 (0.015 mmol, 10 mol % Rh), and (R)-segphos (0.033
mmol) in THF was added a THF solution of titanate ArTi(OPr-i)4Li (2) (0.45 mmol), generated by the addition of Ti(OPr-i)4 to aryllithium or by the addition
of LiOPr-i to ArTi(OPr-i)3, and the mixture was stirred at 20 °C for 0.5 h. For the isolation of silyl enol ether 3 and pivalate ester 4, see the text and
Supporting Information. b Yield of 3 determined by NMR analysis of the crude product. c Isolated yield of 4 by silica gel chromatography. d Determined by
HPLC analysis of pivalate 4 with a chiral stationary phase column, Chiralcel OD-H. e With 3 mol % rhodium and 4.5 mol % (R)-segphos. f Contaminated
with ca. 20% dienyl ketone.
The present 1,6-addition giving the allenylalkenyl silyl
ethers 3 is considered to proceed through the catalytic cycle
shown in Scheme 3, which is analogous to the rhodium-
the asymmetric 1,6-addition should be determined. The final
step is the silylation and transmetalation of 10, giving
allenylalkenyl silyl ether 3 and the aryl-rhodium intermedi-
ate.18
In summary, catalytic asymmetric 1,6-addition to 3-alky-
nyl-2-en-1-ones giving enantiomerically enriched axially
chiral allenes (up to 93% ee) was realized for the first time
by use of a chiral bisphosphine-rhodium catalyst and
aryltitanate reagents and a chlorosilane. The axially chiral
allenes were produced as silyl enol ethers and can be
converted into enol pivalate esters or enol triflates. Studies
on the scope and limitation of this new catalytic asymmetric
transformation reaction are underway.
Scheme 3
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan. We thank
Professors Atsuhiro Osuka and Keiji Maruoka for high-
resolution mass spectra.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
catalyzed 1,4-addition.10h,11a Thus, insertion of the carbon-
carbon triple bond of enynone 1 into the rhodium-aryl bond
forms alkenylrhodium 9,17 which isomerizes into thermo-
dynamically more stable oxa-π-allylrhodium intermediate
10.10h At this isomerization, the stereochemical outcome of
OL036309F
(18) It was observed that treatment of an (oxa-π-allyl)rhodium complex
with chlorotrimethylsilane and titanate, PhTi(OPr-i)4Li (2m), gives silyl
enol ether and phenyl-rhodium species (see also ref 11a).
(17) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem.
Soc. 2001, 123, 9918.
Org. Lett., Vol. 6, No. 2, 2004
307