An intramolecular titanium-catalyzed asymmetric Pauson - Khand type reaction

Article abstract of DOI:10.1021/ja990683m

The development of the first catalytic asymmetric Pauson - Khand type cyclization of enynes is described. The active catalyst, (S,S)-(EBTHI)Ti(CO)₂ (1), is generated in situ from (S,S)-(EBTHI)TiMe₂ (2). A variety of 1,6-enynes can be

Full text of DOI:10.1021/ja990683m

7026
J. Am. Chem. Soc. 1999, 121, 7026-7033
An Intramolecular Titanium-Catalyzed Asymmetric Pauson-Khand
Type Reaction1
Frederick A. Hicks† and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed March 3, 1999
Abstract: The development of the first catalytic asymmetric Pauson-Khand type cyclization of enynes is
described. The active catalyst, (S,S)-(EBTHI)Ti(CO)2 (1), is generated in situ from (S,S)-(EBTHI)TiMe2 (2).
A variety of 1,6-enynes can be converted to the corresponding cyclopentenones in high yield (70-94%) with
excellent ee’s (87-96%). Limitations of the catalyst with respect to substrate structure are discussed. The
absolute configurations of several of the enone products have been ascertained, and these assignments represent
a reversal with respect to an assignment in the initial report. A rationale for the sense and levels of
enantioselectivity for this catalyst is proposed.
Introduction
of Pauson-Khand type reactions6 requiring only catalytic
amounts of Co7 and other metals such as Ti,8,9 Ru,10,11 and
Rh.12,13
The application of transition metals to the field of organic
synthesis has led to a plethora of new transformations which
allow for the rapid and elegant assembly of complex carbocyclic
systems.2 A powerful and much studied example that falls in
this category is the Pauson-Khand reaction,3 which involves a
cobalt-mediated formal [2 + 2 + 1] cycloaddition of an alkyne,
an alkene, and CO to produce a cyclopentenone (Scheme 1a).
Although much work has been devoted to investigating inter-
molecular variants of this transformation, it is the intramolecular
Pauson-Khand cyclization of enynes (Scheme 1b) which has
received the most attention in terms of synthetic application.4
There is a high degree of efficiency embodied in this transfor-
mation, with the formation of three new C-C bonds, two rings,
and a new chiral center; this reaction has been utilized as the
key step in a variety of efforts in total synthesis.5 The practicality
of this process has also been improved recently with the advent
Based on the frequent application of the intramolecular
Pauson-Khand reaction in the total synthesis of natural products
in racemic form, the availability of an asymmetric variant would
be a useful tool for the organic chemist. Much effort has been
devoted toward this end in the past decade, and the approaches
toward a stoichiometric intramolecular version fall into two basic
categories: the diastereoselective cyclization of optically active
enynes and that of enynes equipped with chiral auxiliaries; this
field has been the subject of a recent review.14
The first attempts at effecting asymmetric Pauson-Khand
type cyclizations evolved from the diastereoselective cyclization
of chiral enynes. Magnus conducted studies in the 1980s
designed to assess the diastereoselectivity of the Pauson-Khand
cyclization of a variety of chiral enynes.15 This work culminated
in the stereoselective total syntheses of coriolin, hirsutic acid,
and quadrone.5 He later applied this approach to an enantio-
selective synthesis of a carbocyclin analogue via an enyne
derived from D-(+)-ribolactone (Scheme 2).16 A similar route
† Current address: Department of Chemistry, University of North
Carolina at Chapel Hill, CB 3290, Chapel Hill, NC 27599.
(1) This paper has been adapted, in part, from the following thesis: Hicks,
F. A. Ph.D. Dissertation, Massachusetts Institute of Technology, 1999.
(2) For recent reviews on the use of transition metal-mediated carbocy-
clizations, see: (a) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96,
49. (b) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV.
1996, 96, 635. (c) Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523.
(7) (a) Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J. Am. Chem.
Soc. 1994, 116, 3159. (b) Lee, B. Y.; Chung, Y. K.; Jeong, N.; Lee, Y.;
Hwang, S. H. J. Am. Chem. Soc. 1994, 116, 8793. (c) Pagenkopf, B. L.;
Livinghouse, T. J. Am. Chem. Soc. 1996, 118, 2285. (d) Lee, N. Y.; Chung,
Y. K. Tetrahedron Lett. 1996, 37, 3145. (e) Jeong, N.; Hwang, S. H.; Lee,
Y. K.; Lim, J. S. J. Am. Chem. Soc. 1997, 119, 10549. (f) Kim, J. W.;
Chung, Y. K. Synthesis 1998, 142. (g) Belanger, D. B.; O’Mahony, D. J.
R.; Livinghouse, T. Tetrahedron Lett. 1998, 39, 7637. (h) Belanger, D. B.;
Livinghouse, T. Tetrahedron Lett. 1998, 39, 7641. (i) Sugihara, T.;
Yamaguchi, M. J. Am. Chem. Soc. 1998, 120, 10782.
(8) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 9450.
(9) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 5881.
(10) Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. J. Org. Chem.
1997, 62, 3762.
(11) Kondo, T.; Suzuki, N.; Okada, T.; Mitsudo, T.-a. J. Am. Chem. Soc.
1997, 119, 6187.
(12) Koga, Y.; Kobayashi, T.; Narasaka, K. Chem. Lett. 1998, 249.
(13) Jeong, N.; Lee, S.; Sung, B. S. Organometallics 1998, 17, 3642.
(14) Ingate, S. T.; Marco-Contelles, J. Org. Prep. Proced. Int. 1998, 30,
121.
(3) Schore, N. E. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Ed.; Pergamon: Kidlington, 1995; Vol. 12, p 703.
(4) For the first report of an intramolecular Pauson-Khand reaction,
see: Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436.
(5) dl-Coriolin and hirsutic acid: Exon, C.; Magnus, P. J. Am. Chem.
Soc. 1983, 105, 2477. Magnus, P.; Exon, C.; Albaugh-Robertson, P.
Tetrahedron 1985, 41, 5861. Tetrahydroanhyroaucubigenone: Billington,
D. C.; Willison, D. Tetrahedron Lett. 1984, 25, 4041. Pentalene: Hua, D.
H. J. Am. Chem. Soc. 1986, 108, 3835. Schore, N. E.; Rowley, E. G. J.
Am. Chem. Soc. 1988, 110, 5224. Quadrone: Magnus, P.; Principe, L. M.;
Slater, M. J. J. Org. Chem. 1987, 52, 1483. Methyl deoxynorpentaleno-
lactone H: Magnus, P.; Slater, M. J.; Principe, L. M. J. Org. Chem. 1989,
54, 5148. Pentalenic acid: Rowley, E. G.; Schore, N. E. J. Organomet.
Chem. 1991, 413, C5. Rowley, E. G.; Schore, N. E. J. Org. Chem. 1992,
57, 6853. Logamine: Jeong, N.; Lee, B. Y.; Lee, S. M.; Chung, Y. K.,
Lee, S.-G. Tetrahedron Lett. 1993, 34, 4023.
(6) While the term “Pauson-Khand reaction” applies, strictly speaking,
only to Co-mediated process, the term “Pauson-Khand type reaction” refers
to any analogous reaction mediated or catalyzed by a transition metal.
(15) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851.
(16) Magnus, P.; Becker, D. P. J. Am. Chem. Soc. 1987, 109, 7495.
10.1021/ja990683m CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/20/1999

Ti-Catalyzed Asymmetric Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7027
Scheme 1
Scheme 2
Scheme 3
to carbocyclin analogues was also reported by Mulzer.17
Approaches toward (-)-dendrobine18 and xestobergsterol19 and
total syntheses of (-)-R-kainic acid20 and (+)-epoxydictymene21
have since been reported utilizing this concept. However, this
general tack to an asymmetric Pauson-Khand reaction is limited
by the necessity to prepare an optically active enyne.
Another approach which has been developed by Perica`s,
Moyano, Greene, and co-workers involves the use of enynes
with pendant chiral auxiliaries. Enynes with trans-2-phenylcy-
clohexanol attached to the terminus of the alkene undergo
Pauson-Khand cyclization to provide products with high
diastereomer ratios (7:1 for a 1,6-enyne and 10:1 for a 1,7-
enyne).22 A 1,6-enyne possessing an alkyne substituted with a
camphor-derived chiral auxiliary could also be cyclized dias-
tereoselectively (∼9:1, Scheme 3).23 This methodology has been
applied to the formal total synthesis of (+)-hirsutene22 and the
total synthesis of (+)-â-cuparenone24 and (+)-15-norpentalene.25
These chiral auxiliaries can be cleaved from the product with
SmI2 and recovered for reuse. This methodology suffers from
the need to contrive an enyne synthesis around the auxiliary,
much in the same manner as for the optically active enynes
(vide supra).
Both of these synthetic methods require a stoichiometric
amount of an optically active agent. A more efficient method
would involve a catalytic, asymmetric Pauson-Khand reaction
where the asymmetry is derived from an optically active catalyst.
In the past 20 years, the field of asymmetric catalysis has
experienced a developmental explosion.26 In the area of asym-
metric transition metal-catalyzed cycloadditions, progress has
been made on the cyclization of unfunctionalized substrates.
Lautens has reported good levels of enantioselectivity for both
a cocatalyzed [2 + 2 + 2] homo Diels-Alder reaction27 (55-
91% ee, five examples) and an analogous cocatalyzed [4 + 2
+ 2] process28 (71-79% ee, six examples) employing norbor-
nadiene and the chiral ligands S,S-chiraphos and R-prophos,
respectively. A detailed investigation of a series of (+)-DIOP-
related ligands was undertaken by Livinghouse for the Rh-
catalyzed intramolecular Diels-Alder reaction with good results
(62-87% ee, four examples).29 When a derivative of the trans-
chelating (S,S)-(R,R)-TRAP ligand was utilized for the Pd-
catalyzed Alder-ene reaction of a series of substituted sulfona-
mido enynes, excellent (95% ee, one example) to good (53-
76% ee, eight examples) levels of selectivity were obtained.30,31
(17) Mulzer, J.; Graske, K.-D.; Kirste, B. Liebigs Ann. Chem. 1988, 891.
(18) Takano, S.; Inomata, K.; Ogasawara, K. Chem. Lett. 1992, 443.
(19) (a) Krafft, M. E.; Chirico, X. Tetrahedron Lett. 1994, 35, 4511. (b)
Krafft, M. E.; Dasse, O. A.; Shao, B. Tetrahedron 1998, 54, 7033.
(20) (a) Takano, S.; Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1992, 169. (b) Yoo, S.-e.; Lee, S.-H.; Jeong, N.; Cho, I.
Tetrahedron Lett. 1993, 34, 3435. (c) Yoo, S.-e.; Lee, S. H. J. Org. Chem.
1994, 59, 6968.
(21) (a) Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
J. Am. Chem. Soc. 1994, 116, 5505. (b) Jamison, T. F.; Shambayati, S.;
Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
(22) Castro, J.; So¨rensen, H.; Riera, A.; Morin, C.; Moyano, A.; Perica`s,
M. A.; Greene, A. E. J. Am. Chem. Soc. 1990, 112, 9388.
(23) Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A.; Greene, A.
E.; Piniella, J. F.; Alvarez-Larena, A. J. Organomet. Chem. 1992, 433, 305.
(24) Castro, J.; Moyano, A.; Perica`s, M. A.; Riera, A.; Greene, A. E.;
Alvarez-Larena, A.; Piniella, J. F. J. Org. Chem. 1996, 61, 9016.
(25) Tormo, J.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem.
1997, 62, 4851.
(27) Lautens, M.; Lautens, J. C.; Smith, A. C. J. Am. Chem. Soc. 1990,
112, 5627.
(28) Lautens, M.; Tam, W.; Sood, C. J. Org. Chem. 1993, 58, 4513.
(29) McKinstry, L.; Livinghouse, T. Tetrahedron 1994, 50, 6145.
(30) Goeke, A.; Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem., Int.
Ed. Engl. 1996, 35, 662.
(31) For the use of a chiral ligand to effect double asymmetric induction
in an optically active enyne via the Pd-catalyzed cycloisomerization, see:
Trost, B. M.; Czeskis, B. A. Tetrahedron Lett. 1994, 35, 211.
(26) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons: New York, 1994.

7028 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Hicks and Buchwald
Scheme 4
Scheme 5
circumvent these problems. Because the cyclopentadienyl
ligands are covalently bound to the titanium center, it should
be possible to design a chirally modified catalyst which will be
stable under the conditions required for cyclocarbonylation
chemistry. We elected to start our investigations with the
ethylene-1,2-bis(η5-4,5,6,7-tetrahydro-1-indenyl) (EBTHI) ligand,
which was first introduced into group 4 chemistry by Brint-
zinger.37 Its titanium complexes have found a number of
applications in catalytic asymmetric hydrogenations of imines,38
olefins,39 and enamines40 and hydrosilylations of ketones41 and
imines.42 Additionally, zirconium complexes have been utilized
to effect a number of enantioselective carbon-carbon bond-
forming processes,43 including several elegant applications by
Hoveyda to natural product synthesis.44
Finally, Wender has reported a single example of the Rh-
catalyzed [5 + 2] cycloaddition of a cyclopropyl diene with
S,S-chiraphos to provide a 5,7-fused carbocycle with 63% ee.32
Results and Discussion
Development of Reaction Conditions. Our initial investiga-
tions centered around the development of a synthesis of the
requisite catalyst (S,S)-(EBTHI)Ti(CO)2 (1). The conversion of
However, besides the work presented herein,33 only one
catalytic asymmetric cyclocarbonylation reaction has been
described. Ito recently reported utilizing (R,R)-Me-DuPHOS as
a chiral ligand for the Rh-catalyzed cyclocarbonylation of
vinylallenes. Several examples with moderate to good enanti-
oselectivity (64.5-78.0% ee) were reported, while one class of
substrates was cyclocarbonylated with excellent enantioselec-
tivity (Scheme 4).34 The large number of catalytic cyclocarbo-
nylation reactions and the paucity of asymmetric variants
emphasizes the difficulty of this transformation. There are
several factors which may contribute to the problems of
developing catalytic asymmetric cyclocarbonylations employing
later transition metal complexes. The ligands typically employed
for effecting asymmetry, such as polydentate phosphines,
amines, imines, oxazolines, and hybrids thereof, may not be
stable with regard to CO substitution under the forcing reaction
conditions often employed in cyclocarbonylation reactions.
Additionally, even if there is a highly unfavorable equilibrium
with the ligand dissociated complex, it is often more reactive
than the ligand-substituted one.35 Such a situation would lead
to product formation with low levels of enantioselectivty.
Additionally, there are a limited number of available coordina-
tion sites for late transition metal complexes of these polydentate
ligands, often necessitating the use of cationic complexes.36
The recently reported titanocene-catalyzed enyne cyclocar-
bonylation (vide supra, Scheme 5) represents an opportunity to
titanocene dialkyl derivatives to the corresponding dicarbonyl
complexes under a CO atmosphere is a well-documented
process.45 Presumably, initial CO coordination and migratory
insertion generates a transient alkyl acyl derivative, which
undergoes reductive elimination to generate the η2-ketone
complex.46 Subsequent ligand exchange with CO produces the
dicarbonyl. In particular, dimethyl ethylene-1,2-biscyclopenta-
dienyltitanium, which contains a ligand framework closely
related to EBTHI, was converted to the dicarbonyl in high yield
(37) Wild, F. R. W. P.; Zsolnai, L.; Huttner, G.; Brintzinger, H. H. J.
Organomet. Chem. 1982, 232, 233.
(38) (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1992,
114, 7562. (b) Willoughby, C. A.; Buchwald, S. L. J. Org. Chem. 1993,
58, 7627. (c) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994,
116, 8952. (d) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994,
116, 11703.
(39) (a) Broene, R. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115,
12569. (b) Troutman, M. V.; Appella, D. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 4916.
(40) Lee, N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5985.
(41) Carter, M. B.; Schiøtt, B.; Gutie´rrez, A.; Buchwald, S. L. J. Am.
Chem. Soc. 1994, 116, 11667.
(32) Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.; Pleuss,
N. Tetrahedron 1998, 54, 7203.
(33) Initial communication: Hicks, F. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 11688.
(34) Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc. 1997, 119,
2950.
(42) (a) Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S.
L. J. Am. Chem. Soc. 1996, 118, 6784. (b) Verdaguer, X.; Lange, U. E.
W.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1998, 37, 1103.
(43) For a review on the work in this field, see: Hoveyda, A. H.; Morken,
J. P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1262.
(35) (a) Billington, D. C.; Helps, I. M.; Pauson, P. L.; Thomson, W.;
Willison, D. J. Organomet. Chem. 1988, 354, 233. (b) Bladon, P.; Pauson,
P. L.; Brunner, H.; Eder, R. J. Organomet. Chem. 1988, 355, 449. (c) Park,
H.-J.; Lee, B. Y.; Kang, Y. K.; Chung, Y. K. Organometallics 1995, 14,
3104.
(36) For examples in late transition metal-catalyzed asymmetric reduc-
tions, see: (a) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114,
6266. (b) Buriak, J. M.; Osborn, J. A. Organometallics 1996, 15, 3161. (c)
Schnider, P.; Koch, G.; Pre´toˆt, R.; Wang, G.; Bohnen, F. M.; Kru¨ger, C.;
Pfaltz, A. Chem. Eur. J. 1997, 3, 887.
(44) (a) Johannes, C. W.; Visser, M. S.; Weatherhead, G. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 1998, 120, 8340. (b) Xu, Z.; Johannes, C. W.;
Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.; Hoveyda, A. H. J.
Am. Chem. Soc. 1997, 119, 10302. (c) Xu, Z.; Johannes, C. W.; Salman, S.
S.; Hoveyda, A. H. J. Am. Chem. Soc. 1996, 118, 10926. (d) Houri, A. F.;
Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117, 2943.
(45) Sikora, D. J.; Macomber, D. W.; Rausch, M. D. In AdVances in
Organometallic Chemistry; Stone, F. G. A., West, R., Eds.; Academic
Press: New York, 1986; Vol. 25, p 317.
(46) Erker, G.; Rosenfeldt, F. J. Organomet. Chem. 1982, 224, 29.

Ti-Catalyzed Asymmetric Pauson-Khand Type Reaction
Table 1. Catalytic Asymmetric Cyclocarbonylation of Enynes
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7029
Scheme 6
using this methodology.47 Initial NMR tube experiments re-
vealed that heating (S,S)-(EBTHI)TiMe2 (2)48 under 12 psig CO
at 90 °C did, indeed, produce the corresponding dicarbonyl
complex 1 and acetone. Addition of 1 equiv of an enyne (Table
1, entry 1) to the NMR tube followed by heating at 90 °C led
to the formation of the desired cyclopentenone in >95% ee.
For the purposes of catalytic cyclizations, dicarbonyl 1 was
formed in situ from 2 under the reaction conditions.
several sets of reaction conditions revealed that there was no
significant advantage to the use of isolated 1 as the precatalyst.
Due to the greater stability and ease of synthesis of 2, it was
utilized as the precatalyst for the synthetic work described
herein.
Synthetic Scope. Under the appropriate reaction conditions
(Scheme 6), a variety of simple 1,6-enynes (Table 1, entries
1-10) can be converted to the corresponding cyclopentenones
with excellent levels of enantioselectivity. The functional group
tolerance displayed by this catalyst system appears to be similar
to that seen for the titanocene-catalyzed Pauson-Khand type
reaction. Aliphatic and aromatic ethers (entries 1 and 3),
aliphatic and aromatic ethyl esters (entry 5), an aromatic chloride
and trifluoromethyl group (entries 4 and 6), and a terminally
unsubstituted alkyne (entry 12) are all compatible with this
methodology. A few discrepancies have been found with regard
to the aromatic functional groups, however, in that enynes
A direct route to 1 involving reductive carbonylation of (S,S)-
(EBTHI)TiCl2 was later developed (eq 1).49 It was thought that
Mg, cat. HgCl2,
18 psig CO
(S,S)-(EBTHI)TiCl2
8
(S,S)-(EBTHI)Ti(CO)2
THF, 50 °C, 1.5 h
1
(1)
55% yield
the isolated dicarbonyl complex might serve as a more effective
precatalyst than 2. However, a survey of several enynes under
(47) Smith, J. A.; Brintzinger, H. H. J. Organomet. Chem. 1981, 218,
159.
(48) Xin, S.; Harrod, J. F. J. Organomet. Chem. 1995, 499, 181.
(49) The procedure for this reaction was adapted from the corresponding
reductive carbonylation of Cp2TiCl2: Sikora, D. J.; Moriarty, K. J.; Rausch,
M. D. In Inorganic Syntheses; Angelici, R. J., Ed.; John Wiley and Sons:
New York, 1990; Vol. 28, p 248.

7030 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Hicks and Buchwald
containing aryl bromides or nitriles (3 and 4) provided only
poor levels of conversion to the corresponding enones under
catalytic conditions.
the X-ray crystal structure of the (S)-camphorsulfonate salt of
enone 14, which was synthesized via the catalytic asymmetric
Pauson-Khand type cyclization of enyne 15.50 This assignment
has been confirmed by another approach based upon 1H NMR
analyses. Stereoselective Luche reduction of the initially
obtained cyclopentenone leads to the formation of the allylic
alcohol as a single or highly predominant compound. Conversion
of the allylic alcohol into both diastereomeric R-methoxy-R-
(trifluoromethyl)phenylacetic acid (MTPA) esters and compari-
son of the resulting 1H NMR spectra in CDCl3 using the
modified Mosher protocol51 clearly revealed the absolute
configuration of the new chiral centers to be as shown in Table
1 (see Experimental Procedures for details). The technique has
been applied to four enones (entries 3-6 in Table 1), all of
which corroborate the absolute configuration assignment de-
termined by X-ray crystalography. This method was previously
used by Ito to assign the absolute configuration of the related
dieneones obtained in the asymmetric cyclocarbonylation
mentioned earlier.34,52
The most significant differences observed between in situ
generated 1 and titanocene dicarbonyl, in terms of synthetic
scope, arise from the increased steric hindrance of the EBTHI
ligand in comparison to that of Cp2. While enynes containing
substituted alkynes, e.g., phenyl, methyl, or n-alkyl (entries 2,
7, and 10), can be cyclized with both catalysts, substrates
containing the larger i-Pr and c-pentyl groups (5 and 6) produced
no cyclopentenone with 1. Additionally, enynes possessing 1,2-
disubstituted olefins (7 and 8) were not substrates for 1, and an
enyne containing a 1,1-disubstituted olefin (entry 11) required
much higher quantities of catalyst (20 mol % for 1 vs 5 mol %
for Cp2Ti(CO)2) to attain complete conversion. While a 1,7-
enyne (entry 13) can be cyclized with the asymmetric catalyst
at elevated catalyst levels (20 mol % for 1 vs 10 mol % for
Cp2Ti(CO)2), other 1,7-enynes (9 and 10) which can be cyclized
by titanocene dicarbonyl produced no enone upon exposure to
1 under the reaction conditons. Attempts to cyclize 1,6-enynes
substituted in either the propargylic or allylic position (11-13)
also met with failure. Even the simple 1,6-enynes, which can
be cyclized with (S,S)-(EBTHI)Ti(CO)2, reveal the influence
of this phenomenon. While the enynes in entries 1 and 9 can
be converted to product with 5 mol % Cp2Ti(CO)2, the
cyclization of these substrates, which lack geminal diester
substitution and the corresponding benefit provided by the
Thorpe-Ingold effect, proved more difficult for 1, requiring
20 mol % precatalyst. All these discrepancies can be explained
on the basis of the increased steric hindrance at the titanium
center of 1 relative to that in Cp2Ti(CO)2.
The mechanism for this transformation is believed to be
analogous to the one proposed for the titanocene-catalyzed enyne
cyclocarbonylation (Scheme 7),9 leaving the question of which
Scheme 7
step in this mechanism is stereochemistry determining. If the
formation of metallacyclopentene 16 is kinetically controlled,
then the selectivity of olefin insertion into the titanacyclopropene
is the key step. However, the formation of group 4 metallacy-
clopentenes is documented to be a reversible process.53 The
selectivity of metallacycle formation could, therefore, represent
the relative thermodynamic stabilities of the diastereomers of
16. Finally, a kinetic partitioning at the point of CO insertion
or an equilibration between diastereomeric acyl complexes 17
cannot be ruled out a priori as possible enantiodetermining steps.
Absolute Configuration, Mechanism, and Mode of
Stereoinduction. We have previously reported a tentative
assignment of the absolute configuration of the enone from
Table 1, entry 9, based on an X-ray crystal structure.33 However,
the level of uncertainty in the configuration of the chiral center
prevented us from making a definitive assignment. Subsequently
we have found that the enone products are actually of the
opposite absolute configuration. This has been determined from
(53) (a) Agnel, G.; Owczarczyk, Z.; Negishi, E.-i. Tetrahedron Lett. 1992,
33, 1543. (b) Reference 59.
(54) The compound was prepared according to the literature procedure,
with the modification that a catalytic amount of HgCl2 was added: Lefeber,
C.; Baumann, W.; Tillack, A.; Kempe, R.; Go¨rls, H.; Rosenthal, U.
Organometallics 1996, 15, 3486.
(50) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. In press.
(51) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(52) For the application of this method of absolute configuration
determination to transition metal mediated carbocyclizations, see: (a) Urabe,
H.; Takeda, T.; Hideura, D.; Sato, F. J. Am. Chem. Soc. 1997, 119, 11295.
(b) Reference 27. (c) Reference 28.
(55) The metallacyclopentene derived from the enyne in entry 10 was
prepared and identified in an NMR tube reaction. The use of excess enyne
was necessary to ensure clean and efficient metallacycle formation.
Therefore, it is difficult to assign all the peaks for the metallacycle, but its
presence and diastereomeric purity are clearly indicated by a single set of
four indenyl doublets: δ 6.78 (J ) 2.75 Hz, 1 H); 6.55 (J ) 2.75 Hz, 1 H);
4.79 (J ) 1.83 Hz, 1 H); 4.61 (J ) 1.83 Hz, 1 H).

Ti-Catalyzed Asymmetric Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7031
Scheme 8a
Scheme 9a
+
+
a Ethylene bridges omitted for clarity.
a Ethylene bridges omitted for clarity.
In an attempt to determine whether the formation of metal-
lacyclopentenes 16 proceeded diastereoselectively, a route to
their synthesis was developed. Heating the bis trimethylsilyl
acetylene complex of rac(EBTHI)Ti (18)54 in the presence of
an enyne (Table 1, entry 10) led to the formation of the desired
Scheme 10a
1
metallacyclopentene 16a as indicated by H NMR (eq 2).55
Additionally, this complex was formed as essentially one
diastereomer.56 This suggests that the enantioselectivity of the
cyclocarbonylation reaction utilizing optically pure EBTHI
complexes probably arises from either a highly selective olefin
insertion into the titanacyclopropene intermediate or the dif-
ferences in thermodynamic stability of the diastereomers of 16.
However, this result does not rule out the possibility that
enantioselectivity is derived from the relative rates of CO
insertion into the diastereomeric metallacycles 16 or an equi-
librium between the resulting acyl species 17, as was mentioned
earlier. In a related zirconium-catalyzed diene cyclization which
proceeds with high levels of enantioselectivity, the formation
of the intermediate zirconacyclopentane occurs with essentially
no selectivity, indicating the stereochemistry-determining step
happens later in the catalytic cycle.57
Examination of the literature on (EBTHI)MX2-promoted
carbon-carbon bond-forming reactions reveals that Jordan’s
work on the synthesis of diastereomerically enriched azazir-
conacycles from cationic (EBI)zirconium pyridyl complexes
bears a number of similarities to the cyclocarbonylation reac-
tion.58 The reaction involves the insertion of a monosubstituted
olefin into an η2-bound pyridyl, a process which mimics the
intramolecular olefin insertion into the η2-alkyne (Scheme 8).
The relative thermodynamic stability of the resulting diastereo-
meric azazirconacycles, obtained from experimental studies and
consistent with molecular modeling calculations, has a large
dependence on the presence of an ortho substituent on the
pyridine ring (R in Schemes 8 and 9), which interacts strongly
with the cyclohexadienyl moiety of the EBI ligand. This
interaction leads to a severe tilting of the pyridyl moiety to
alleviate the strain, forcing the alkene substituent (R′ in Schemes
8 and 9) into close contact with the cyclopentadienyl portion
of the EBI ligand in 19b. The combination of these destabilizing
a Ethylene bridges omitted for clarity.
interactions dictates the selective formation of 19a (Scheme 9).
While this rationale was derived from the thermodynamic
stability of the azazirconacycles, a kinetic analysis of olefin
insertion predicts the same diastereomeric product.58
A similar argument can explain both the sense of enantio-
selection for the enyne cyclocarbonylation and the fact that
certain substrates were cyclized with moderate levels of
selectivity. The tilting of the η2-alkyne would lead to the
preferential formation of metallacyclopentene 14b, where the
unfavorable steric interaction between the enyne tether and the
cyclopentadienyl portion of the EBTHI ligand is avoided
(Scheme 10). As with Jordan’s work, an analysis based upon
kinetically controlled olefin insertion into the metallacyclopro-
pene predicts the same isomer. The interaction between the
terminal alkyne substituent appears to play the same role as
the ortho substituent on the pyridine ring; without this crucial
steric interaction, as in the case of a terminally unsubstituted
enyne (Table 1, entry 12), low levels of enantioselectivity are
observed. When the olefinic moiety of the enyne is 1,1-
disubstituted (Table 1, entry 11), destabilizing interactions are
now present in both diastereomeric intermediates, leading to
decreased ee’s in the cyclopentenone products. It should be
noted that this substrate still gives enone with a noticeably higher
ee than the enyne with a terminally unsubstituted alkyne,
emphasizing the relative importance of the two key interactions
(the positioning of R is more important than R′) to the overall
asymmetric induction. The cyclization of a 1,7-enyne also
proceeded with low levels of enantioselectivity (Table 1, entry
13), presumably due to the increased levels of conformational
flexibility in the metallacycle, which allows for the alleviation
of the strain generated by the key interactions in both diaster-
eomeric metallacycles.
(56) The diastereoselective cyclization of an enyne by the rac-(EBTHI)
moiety serves as an accurate model for the enantioselective cyclization of
an enyne by the (S,S)-(EBTHI) moiety.
(57) Yamaura, Y.; Hyakutake, M.; Mori, M. J. Am. Chem. Soc. 1997,
119, 7615.
Conclusion
(58) (a) Rodewald, S.; Jordan, R. F. J. Am. Chem. Soc. 1994, 116, 4491.
(b) Dagorne, S.; Rodewald, S.; Jordan, R. F. Organometallics 1997, 16,
5541.
The development of the first catalytic asymmetric Pauson-
Khand type enyne cyclocarbonylation has been described. The

7032 J. Am. Chem. Soc., Vol. 121, No. 30, 1999
Hicks and Buchwald
mmol), HgCl2 (127 mg, 0.47 mmol), and THF (5 mL). The Schlenk
flask was removed from the glovebox and evacuated and backfilled
with 18 psig CO on a vacuum line in a hood. The sealed Schlenk flask
was placed in a 45 °C oil bath for 1 h until the solution changed color
to a dark brown-yellow. The Schlenk flask was allowed to cool to room
temperature, and the THF was removed in vacuo. The Schlenk flask
was transferred into the glovebox, and the insoluble impurities were
removed via filtration of a pentane solution of the crude product through
a pad of Celite. The pentane was removed in vacuo to afford 120 mg
(46%) of a light brown powder. Mp: 150-153 °C. 1H NMR (300 MHz,
C6D6): δ 4.76 (d, J ) 2.9 Hz, 2 H); 4.31 (d, J ) 2.9 Hz, 2 H); 2.32-
catalytic species (S,S)-(EBTHI)Ti(CO)2 (1) was generated in
situ from (S,S)-(EBTHI)TiMe2 (2). A variety of 1,6-enynes were
converted to the corresponding cyclopentenones with excellent
levels of enantioselectivity (87-96% ee). The methodology has
limitations in terms of substrate scope due to the sterically
hindered nature of the EBTHI ligand; 1,6-enynes substituted in
the allylic and propargylic positions, some 1,7-enynes, and
enynes containing 1,2-disubstituted olefins could not be cyclized
with 1. The absolute configuration of the enone products has
been established by comparison to the X-ray structure of a
related enone and by the modified Mosher analysis of the allylic
MPTA esters derived from several of the enones. These
assignments represent a reversal of an assignment from our
initial report. A rationale for the observed absolute configuration
and levels of asymmetric induction has been proposed which
involves diastereoselective formation of a titanacyclopentene
intermediate.
2.22 (m, 10 H); 1.84-1.77 (m, 4 H); 1.63 (m, 2 H); 1.44 (m, 2 H). 13
C
NMR (75 MHz, C6D6): δ 268.6, 128.7, 128.4, 128.1, 120.9, 113.9,
108.4, 92.4, 90.1, 30.0, 25.0, 24.9, 24.1, 23.4. IR (pentane solution,
cm-1): 1962, 1881. Anal. Calcd for C22H24O2Ti: C, 71.71; H, 6.08.
Found: C, 71.68; H, 6.57.
(S,S)-Ethylene-1,2-bis(η5-4,5,6,7-tetrahydro-1-indenyl)titanium Di-
carbonyl (1). The same procedure mentioned above for the racemic
dichloride was employed with (S,S)-(EBTHI)TiCl2 (100 mg, 0.26
mmol), Mg powder (21 mg, 0.875 mmol), HgCl2 (47 mg, 0.173 mmol),
and THF (3 mL) for 1.5 h to afford 52 mg (55%) of a light brown
Experimental Procedures
powder. Mp: 134-136 °C. [R]23 ) -145 (c ) 0.60, toluene). The
D
General Considerations. All manipulations involving air-sensitive
materials were conducted in a Vacuum Atmospheres glovebox under
an atmosphere of argon or using standard Schlenk techniques under
argon. Toluene was distilled under argon from molten sodium. CO was
scientific grade (minimum purity 99.997%) from MG Industries.
Note: It is important to take appropriate safety precautions when
dealing with CO under eleVated pressures; all reactions should be
conducted in an efficient fume hood behind a blast shield. Enynes were
prepared as previously reported.9,59,60 All other reagents were available
from commercial sources and were used without further purification,
unless otherwise noted. Except for entry 1 of Table 1, all substrates
were filtered through a plug of alumina in a glovebox to remove
adventitious moisture. The substrate for entry 1 was distilled under
vacuum and stored in the glovebox.
1H NMR spectrum matched that of the racemic complex. Anal. Calcd
for C22H24O2Ti: C, 71.71; H, 6.08. Found: C, 71.39; H, 5.66.
Dimethyl (S,S)-Ethylene-1,2-bis(η5-4,5,6,7-tetrahydro-1-indenyl)-
titanium (2). To a Schlenk flask under argon were added (S,S)-
(EBTHI)TiCl2 (700 mg, 1.83 mmol) and Et2O (50 mL), and the flask
was placed in a water bath. A solution of MeLi in pentane (1.4 M, 7
mL, 5.0 mmol) was added slowly, and the reaction was allowed to stir
at room temperature for 4 h. The solvent was removed in vacuo, and
the crude product was taken into the glovebox. The product was
dissolved in hexane (50 mL), and insoluble impurities were removed
by filtration through a plug of Celite, followed by rinsing with hexane.
The solvent was removed in vacuo to yield 520 mg (83% yield) of the
desired product as yellow-orange crystals. Mp: 78-80 °C. [R]23
)
D
+28.0 (c ) 1.0 toluene). The 1H NMR spectrum matched the published
Flash chromatography was performed on E. M. Science Kieselgel
60 (230-400 mesh). Yields refer to isolated yields of compounds of
spectrum.48
General Procedure for the Asymmetric Conversion of Enynes
to Cyclopentenones. In an argon-filled glovebox, a dry sealable Schlenk
flask was charged with (S,S)-(EBTHI)TiMe2 (8 mg, 0.025 mmol),
toluene (3 mL), and the substrate (0.50 mmol). The Schlenk flask was
removed from the glovebox, evacuated, and backfilled with 14 psig
CO. Caution: Appropriate precautions should be taken when perform-
ing reactions under eleVated CO pressure. The reaction mixture was
heated to 90 °C for 12-16 h. After the reaction mixture was cooled to
room temperature, the CO was cautiously released in the hood. In the
air, the crude reaction mixture was filtered through a plug of silica gel
with the aid of diethyl ether and purified by flash chromatography.
2-Phenyl-7-oxabicyclo[3.3.0]oct-1-en-3-one (Entry 1). The general
procedure employing (S,S)-(EBTHI)TiMe2 (16 mg, 0.05 mmol) was
used to convert 3-(allyloxy)-1-phenyl-1-propyne59 (43 µL, 0.25 mmol)
to the desired product in 12 h. Purification by flash chromatography
(hexane:ether ) 4:6) afforded 44 mg (88% yield) of a clear oil. The ee
was determined to be 96%. [R]26D ) -7.69 (c ) 0.52, CHCl3). The 1H
NMR spectrum matched the published spectrum.59
1
greater than 95% purity, as estimated by capillary GC and H NMR
analyses and, in the case of unknown compounds, elemental analysis.
In general, yields and ee’s indicated in this section refer to a single
experiment, while those reported in the tables are an aVerage of two
or more runs, so the numbers may differ slightly. Nuclear magnetic
resonance (NMR) spectra were recorded on a Varian XL-300, a Varian
XL-500, or a Varian Unity 300 instrument. Gas chromatography (GC)
analyses were performed on a Hewlet-Packard 5890 gas chromatograph
with a 3392A integrator and FID detector using a 25-m capillary column
with cross-linked SE-30 as a stationary phase. Optical rotations were
measured with a Perkin-Elmer model 241 polarimeter. High-perfor-
mance liquid chromatography (HPLC) was conducted using a Hewlett-
Packard model 1050 pumping system with a Hewlett-Packard model
1040A ultraviolet detector. Chiral GC analyses were conducted using
a 5890 Hewlett-Packard Series II gas chromatograph with an FID
detector. Elemental analyses were performed by E + R Analytical
Laboratory, Inc.
Determination of Enantiomeric Purity. The enantiomeric excesses
(% ee) were primarily determined by chiral GC. For entries 1, 9, 12,
and 13 of Table 1, a Chiraldex B-PH 20-m × 0.25-mm (ASTEC)
capillary column was used. For entries 7, 8, 10, and 11, a Chiraldex
G-TA 20-m × 0.25-mm (ASTEC) capillary column was used. For entry
2, the ee was determined by chiral HPLC on a Chiralcel OD 25-cm ×
0.46-cm column (Daicel Chemical Ind., Ltd.). For entries 3-6, the ee
was determined from the 19F NMR analyses of the MTPA esters derived
from the allylic alcohol obtained from selective Luche reduction of
the corresponding enone.
Diethyl 2-Phenyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate
(Entry 2). The general procedure employing (S,S)-(EBTHI)TiMe2 (12
mg, 0.0375 mmol) was used to convert diethyl 1-phenyl-6-hepten-1-
yne-4,4-dicarboxylate60 (157 mg, 0.50 mmol) to the desired product in
12 h. Purification by flash chromatography (hexane:ether ) 2:1)
afforded 157 mg (92% yield) of a clear oil. The ee was determined to
1
be 94%. [R]26 ) +20.4 (c ) 2.1, CHCl3). The H NMR spectrum
D
matched the published spectrum.60
Diethyl 2-(p-Methoxyphenyl)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-di-
carboxylate (Entry 3). The general procedure employing (S,S)-
(EBTHI)TiMe2 (6 mg, 0.0175 mmol) was used to convert diethyl 1-(p-
methoxyphenyl)-6-hepten-1-yne-4,4-dicarboxylate9 (81 mg, 0.234 mmol)
to the desired product in 16 h. Purification by flash chromatography
(hexane:ether ) 3:2) afforded 77 mg (88% yield) of a white solid.
Mp: 61-63 °C. The ee was determined to be 93% on the basis of the
19F NMR spectrum of the corresponding (R)-MTPA ester of the
rac-Ethylene-1,2-bis(η5-4,5,6,7-tetrahydro-1-indenyl)titanium Di-
carbonyl (1). To a Schlenk flask in an Ar-filled glovebox were added
rac-(EBTHI)TiCl2 (272 mg, 0.71 mmol), Mg powder (57 mg, 2.38
(59) Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc.
1994, 116, 8593.
(60) Zhang, M.; Buchwald, S. L. J. Org. Chem. 1996, 61, 4498.

Ti-Catalyzed Asymmetric Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 30, 1999 7033
corresponding allylic alcohol. [R]23D ) +34.3 (c ) 0.67, CHCl3). The
1H NMR spectrum matched the published spectrum.9
The ee was determined to be 87%. [R]26D ) -19.6 (c ) 0.46, CHCl3).
1
The H NMR spectrum matched the published spectrum.59
Diethyl 2-(p-Chlorophenyl)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-di-
carboxylate (Entry 4). The general procedure employing (S,S)-
(EBTHI)TiMe2 (6 mg, 0.0175 mmol) was used to convert diethyl 1-(p-
chlorophenyl)-6-hepten-1-yne-4,4-dicarboxylate9 (61 mg, 0.175 mmol)
to the desired product in 20 h. Purification by flash chromatography
(hexane:ether ) 2:1) afforded 53 mg (81% yield) of a clear liquid.
The ee was determined to be 93% on the basis of the 19F NMR spectra
Diethyl 2-Methyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate
(Entry 10). The general procedure was used to convert diethyl 7-octen-
2-yne-5,5-dicarboxylate59 (126 mg, 0.50 mmol) to the desired product
in 12 h. Purification by flash chromatography (hexane:ether ) 3:2)
afforded 130 mg (93% yield) of a clear liquid. The ee was determined
to be 87%. [R]26D ) +86.4 (c ) 1.3, CHCl3). The 1H NMR spectrum
matched the published spectrum.59
Di-tert-butyl 2,5-Dimethylbicyclo[3.3.0]oct-1-ene-7,7-dicarboxy-
late (Entry 11). The general procedure employing (S,S)-(EBTHI)TiMe2
(16 mg, 0.05 mmol) was used to convert di-tert-butyl 7-methyl-7-octen-
2-yne-5,5-dicarboxylate9 (81 mg, 0.25 mmol) to the desired product in
12 h. Purification by flash chromatography (hexane:ether ) 4:1)
afforded 80 mg (91% yield) of a clear liquid. The ee was determined
to be 72%. [R]26D ) +86.8 (c ) 0.38, CHCl3). The 1H NMR spectrum
matched the published spectrum.9
of the (R)-MTPA ester of the corresponding allylic alcohol. [R]23
)
D
+44.6 (c ) 0.56, CHCl3). The 1H NMR spectrum matched the published
spectrum.9
Diethyl 2-(p-Ethyl benzoate)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-
dicarboxylate (Entry 5). The general procedure employing (S,S)-
(EBTHI)TiMe2 (6 mg, 0.0175 mmol) was used to convert diethyl 1-(p-
ethyl benzoate)-6-hepten-1-yne-4,4-dicarboxylate9 (61 mg, 0.175 mmol)
to the desired product in 20 h. Purification by flash chromatography
(hexane:ether ) 2:1) afforded 53 mg (81% yield) of a clear liquid.
The ee was determined to be 91% on the basis of the19F NMR spectrum
Di-tert-butyl 3-Oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate (En-
try 12). The general procedure employing (S,S)-(EBTHI)TiMe2 (16
mg, 0.05 mmol) was used to convert di-tert-butyl 6-hepten-1-yne-4,4-
dicarboxylate9 (73 mg, 0.25 mmol) to the desired product in 13 h.
Purification by flash chromatography (hexane:ether ) 1:1) afforded
of the (S)-MTPA ester of the corresponding alcohol. [R]23 ) +44.7
D
(c ) 0.85, CHCl3). The 1H NMR spectrum matched the published
spectrum.9
Diethyl 2-(p-Trifluoromethylphenyl)-3-oxobicyclo[3.3.0]oct-1-ene-
7,7-dicarboxylate (Entry 6). The general procedure employing (S,S)-
(EBTHI)TiMe2 (6 mg, 0.0175 mmol) was used to convert diethyl 1-(p-
trifluoromethylphenyl)-6-hepten-1-yne-4,4-dicarboxylate9 (67 mg, 0.175
mmol) to the desired product in 14 h. Purification by flash chroma-
tography (hexane:ether ) 3:1) afforded 65 mg (90% yield) of a clear
liquid. The ee was determined to be 94% on the basis of the 19F NMR
68 mg (85% yield) of a clear liquid. The ee was determined to be 50%.
1
[R]26 ) -95.0 (c ) 0.20, CHCl3). The H NMR spectrum matched
D
the published spectrum.9
Di-tert-butyl 2-Methyl-3-oxobicyclo[3.4.0]non-1-en-8,8-dicarboxy-
late (Entry 13). The general procedure employing (S,S)-(EBTHI)TiMe2
(16 mg, 0.05 mmol) was used to convert di-tert-butyl 8-nonen-2-yne-
4,4-dicarboxylate59 (81 mg, 0.25 mmol) to the desired product in 14 h.
Purification by flash chromatography (hexane:ether ) 7:3) afforded
of the (S)-MTPA ester of the corresponding allylic alcohol. [R]23
)
D
+35.0 (c ) 0.80, CHCl3). The 1H NMR spectrum matched the published
66 mg (76% yield) of a clear liquid. The ee was determined to be 47%.
spectrum.9
1
[R]26 ) -52.3 (c ) 0.44, CHCl3). The H NMR spectrum matched
D
the published spectrum.59
Diethyl 2-n-Propyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate
(Entry 7). The general procedure was used to convert diethyl 1-n-
propyl-6-hepten-1-yne-4,4-dicarboxylate60 (140 mg, 0.50 mmol) to the
desired product in 12 h. Purification by flash chromatography (hexane:
Acknowledgment. We thank the NIH (GM 34917), Pfizer,
Novartis, and Merck for their support of this work. F.A.H.
thanks the National Science Foundation for a predoctoral
fellowship. We also thank Bain Chin, Dr. Matthew Reding,
Marcus Hansen, Shana Sturla, and Jaesook Yun for providing
(S,S)-(EBTHI)TiCl2 and Dr. Natasha Kablaoui for the initial
synthesis of (S,S)-(EBTHI)Ti(CO)2 (1). We are also indebted
to Shana Sturla for preparing 14 and Dr. William Davis for
obtaining its X-ray crystal structure.
ether ) 2:1) afforded 142 mg (92% yield) of a clear oil. The ee was
1
determined to be 89%. [R]26 ) +117.1 (c ) 0.70, CHCl3). The H
D
NMR spectrum matched the published spectrum.60
Di-tert-butyl 2-Methyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarbox-
ylate (Entry 8). The general procedure was used to convert di-tert-
butyl 7-octen-2-yne-5,5-dicarboxylate59 (154 mg, 0.50 mmol) to the
desired product in 12 h. Purification by flash chromatography (hexane:
ether ) 4:1) afforded 151 mg (90% yield) of a white solid. Mp: 76-
78 °C. The ee was determined to be 89%. [R]26 ) +86.5 (c ) 1.3
D
1
CHCl3). The H NMR spectrum matched the published spectrum.59
Supporting Information Available: Details on the absolute
configuration assignments for Table 1, entries 3-6 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
2-Phenylbicyclo[3.3.0]oct-1-en-3-one (Entry 9). The general pro-
cedure employing (S,S)-(EBTHI)TiMe2 (16 mg, 0.05 mmol) was used
to convert 1-phenyl-6-hepten-1-yne59 (43 mg, 0.25 mmol) to the desired
product in 12 h. Purification by flash chromatography (hexane:ether
) 7:3) afforded 36 mg (73% yield) of a white solid. Mp: 78-80 °C.
JA990683M