4986
Organometallics 1995, 14, 4986-4988
Highly Efficient Enantioselective Pauson-Khand Reactions? Alistair M. Hay, William J. Kerr,* George G. Kirk, and David Middlemisst Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, Glasgow GI lXL, Scotland, U.K. Received September 1, 1995@ Summary: Diastereomeric (a1kyne)pentacarbonyldicobalt complexes containing the chiral phosphine ligand (R)-(+)-Glyphos have been synthesized and separated chromatographically. The isolated, optically pure diastereomeric complexes have been employed in intermolecular Pauson-Khand reactions, using anhydrous Nmethylmorpholine N-oxide as the reaction promoter under mild conditions, to give high yields of cyclopentenone products in good to excellent enantiomeric excesses. The cobalt-mediated Pauson-Khand cyclization has been shown to be a powerful synthetic tool in organic synthesis.l More recently, this annulation has been improved by utilizing dry-state adsorption techniques2 and tertiary amine N - ~ x i d e s . In ~ particular, amine N-oxides have been used to accelerate the rate of cyclopentenone formation in both inter- and intramolecular examples at low temperatures (0-40 "C). To date, examples of asymmetric versions of the Pauson-Khand reaction have been few in number and have been utilized with a limited range of substrate^.^-^ Diastereoselectiveapproaches to intramolecular cyclizations using chiral auxiliaries are known4 and have been extended to the intermolecular version of the cyclizat i ~ n However, .~ these auxiliary-controlledexamples are either restricted to the use of specific substrates or show poor stereocontrol and, in some cases, involve the use +This paper is dedicated with warmth and the utmost respect to Professor Peter L. Pauson on the occasion of his 70th birthday. t Present address: Glaxo Wellcome, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, England, U.K. Abstract published in Advance ACS Abstracts, October 1, 1995. (1)For reviews on the Pauson-Khand reaction see: Pauson, P. L.; Khand, I. U. Ann. N.Y. Acad. Sci. 1977, 295, 2. Pauson, P. L. Tetrahedron 1985, 41, 5855. Schore, N. E. Org. React. 1991, 40, 1. Schore, N. E. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U.K., 1991; Vol. 5, pp 1037-1064. (2)Smit, W. A.; Gybin, A. S.; Simonyan, S. 0.; Shashkov, A. S.; Tarasov, V. A.; Ibragimov, I. I. Izv. h a d . Nauk SSSR,Ser. Khim. 1985, 2650. Smit, W. A.; Gybin, A. S.; Shashkov, A. S.; Strychkov, Y. T.; Kyz'mina, L. G.; Mikaelian, G. S.; Caple, R.; Swanson, E. D. Tetrahedron Lett. 1986,27, 1241. Simonyan, S. 0.;Smit, W. A.; Gybin, A. S.; Shashkov, A. S.; Mikaelian, G. S.; Tarasov, V. A.; Ibragimov, I. I.; Caple, R.; Froen, D. E. Tetrahedron Lett. 1986,27, 1245. Smit, W. A.; Simonyan, S. 0.; Tarasov, V. A.; Mikaelian, G. S.; Ibragimov, I. I.; Caple, R.; Froen, D. E.; Kreager, A. Synthesis 1989,472, Smit, W. A,; Kireev, S. L.; Nefedov, 0. M.; Tarasov, V. A. Tetrahedron Lett. 1989, 30, 4021. (3) Shambayati, S.;Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett. 1990, 31, 5289. Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991,204. Chung, Y. K.; Lee, B. Y.; Jeong, N.; Hudeck, M.; Pauson, P. L. Organometallics 1993,12,220. Krafft, M. E.; Scott, I. L.; Romero, R. H.; Feibelmann, S.; Van Pelt, C. E. J . Am. Chem. SOC.1993, 115, 7199. (4) Castro, J.; Moyano, A.; Pericas, M. A.; Riera, A.; Greene, A. E. Tetrahedron: Asymmetry 1994, 5, 307 and references cited therein. ( 5 )Bernardes, V.; Verdaguer, X.; Kardos, N.; Riera, A,; Moyano, A,; PericBs, M. A.; Greene, A. E. Tetrahedron Lett. 1994, 35, 575. Verdaguer, X.; Moyano, A.; Pericls, M. A.; Riera, A. J . Am. Chem. SOC. 1994,116,2153. Fonquerna, S.; Moyano, A,; Pericas, M. A,; Riera, A. Tetrahedron 1995, 51, 4239. Park, H. P.; Lee, B. Y.; Kang, Y. K.; Chung, Y. K. Organometallics 1995, 14, 3104. @
of tediously prepared starting materials. I n this communication we disclose the first series of efficient asymmetric intermolecular Pauson-Khand reactions which result i n the formation of cyclopentenone products, containing no residual chiral auxiliary, in high yields and good to excellent enantiomeric excesses. Alkyne complexes of the type 1 are chiral around the C2C02 cluster, provided R1 f R2 and L t CO. Examples where the ligand L is a phosphine such as triphenylphosphine and trimethyl phosphite are k n o ~ nand, ,~ if the optically active phosphine (R)-(+I-Glyphos(2) is used, the two diastereoisomers la and lb are f ~ r m e d . ~ ~ ~ Previous studies on the phenylacetylene complex (la,b: R' = Ph, R2 = H, L = (R)-(+)-Glyphos(2))) by Pauson R'
R'
R2
o c , H L, oc"..~-co" \"co oc co
L
,
Y
R2 ,co
,..co-co,, \"CO oc co
^P ;,P ,lt
oc I
2
I&
and co-workers, have shown that after the separation of the diastereomeric complexes, by fractional recrystallization, reaction of one diastereoisomer with norbornene gave only a 31% yield of the Pauson-Khand product, but with excellent enantioselectivity.6 Despite the high stereochemical control in this isolated example, the reaction yields were consistently poor. Furthermore, separation of the diastereoisomers was not trivial and the elevated temperatures required for reaction led to the interconversion of the two diastereomeric forms of the starting complex. The initial aims of this study were to show that a range of homochiral complexes containing the Glyphos ligand were readily accessible and, in turn, that the diastereomeric mixtures could be more routinely separated. The chiral ligand (R)-(+)-Glyphos (2) was prepared in four steps from D-mannitd(3) by a modification of the known procedure.1° The final step involved addition of potassium diphenylphosphide as a THF (6) As well as the techniques described in the publications of refs 4 and 5, methods which simply involve complexation of homochiral enynes and their subsequent cyclizations (often with high degrees of stereoselectivity) have also been described: Magnus, P.; Becker, D. P. J . Am. Chem. SOC. 1987, 109, 7495. Roush, W. R.; Park, J. C. Tetrahedron Lett. 1991,32,6285. Takano, S.; Inomato, IC;Ogasawana, K. J . Chem. SOC.,Chem. Commun. 1992, 169. Takano, S.; Inomato, K.; Ogasawana, K. Chem. Lett. 1992, 443. Stolle, A,; Becker, H.; Salaun, J.; de Meijere, A. Tetrahedron Lett. 1994, 35, 3517. Stolle, A.;~Becker, H.; Salaun, J.; de Meijere, A. Tetrahedron Lett. 1994, 35, 3521. (7) Dunn, J. A.; Pauson, P. L. J.Organomet. Chem. 1991,419, 383. DAgostino, M. F.; Frampton, C. S.;McGlinchey, M. J. Organometallics 1990, 9, 2972. (8) Bladon, P.; Pauson, P. L.; Brunner, H.; Eder, R. J . Organomet. Chem. 1988,355,449. (9) Brunner, H.; Niederhuber, A. Tetrahedron: Asymmetry 1990, 1, 711.
0276-7333/95/2314-4986$09.00/00 1995 American Chemical Society
Organometallics, Vol. 14, No. 11, 1995 4987
Communications
Table 2. Enantioselective Pauson-Khand Reactions of Complexes 5-7"
Scheme 1" HOi
complex
4
R'
3 Conditions: KPPhJl'HF; toluene; room temperature; 20
min.
Reactions with Norbornene* 10a,b 76 Ph 10a,b 79 CMezOH lla,b 77 CMezOH lla,b 83 73d CMezOH lla,b lla,b 65d CMezOH 12a,b 90 CHzOH CHzOH 12a,b 69
Scheme 2" RICTCRz CO*(C0)6
+
"-
xoJ"PPh2
a
R1C,CR2
-I-boz(CO)5PPhzR'
5ah
2
a) Toluene, 60-70 'C, 3-4h.
- Qam
PPhZR' = R-(+)-Glyphos
a Conditions and definitions: toluene; 60-70 "C; 3-4 h; PPhZR* = (R)-(+)-Glyphos.
Reactions CMezOH CMezOH CHzOH CHzOH
6a 6b 7a
W
7b
R1
R2
product
H H H H CH3
Sa,b 6a,b 7a,b 8a,b 9a,b
with Norbornadieneb 13a,b 77 13a,b 75 14a,b 75 14a,b 77
ee (%Y >99 of 10a >99 of lob 64 of l l a 75 of l l b
80 of l l a 75 of l l b 93 of 12a 83 of 12b 75 of 13a 74 of 13b 90 of 14a
84 of 14b
a 6 equiv of anhydrous NMO added to a CHzClz solution of the complex and alkene (6-8 h). 1.1 equiv of alkene was used in every reaction. c All enantiomerie excesses were calculated using a CHIRALCEL-OD-HHPLC column and 2%EtOH in heptane as the mobile phase. Reaction temperature of 0 "C; reaction time of 18 h.
*
Table 1. Formation of Cobalt-Alkyne Complexes Containing (R)-(+)-Glyphos Ph CMezOH CHzOH TMS TMS
yield (%)
Ph
5a 5b 6a 6b 6a 6b 7a 7b
2
product
Scheme 3
yield (%) 78"
100 83b 68 57c
a Bis-(R)-(+)-Glyphosproduct also isolated in 13% yield. Bis(R)-(+)-Glyphos product also isolated in 12%yield. e Yield based on recovered starting material.
solution" to the tosylate (4), giving an improved overall yield of 34% (Scheme 1). In turn, the diastereomeric complexes 5a,b-9a,b were readily formed under thermal conditions in good t o high yields (Scheme 2, Table 1). Furthermore, it was found that the diastereomeric mixtures of complexes 5a,b-7a,b could be efficiently separated by preparative HPLC.12J3 With a range of optically pure complexes now readily available in good yields, our attention was turned to their use as substrates in cyclopentenone synthesis. The strained alkenes norbornene and norbornadiene are recognized as efficient olefins when used in the PausonKhand annulation. The first of these, norbornene, was used in the initial reactions with diastereomeric mixtures of our complexes. These studies showed that the complexes containing the chiral phosphine ligand reacted less readily than the parent hexacarbonyl complexes and generally gave lower yields and low enantiomeric excesses (ee;0-13%) of cyclopentenoneproduds. As an example, a 1:l mixture of the diastereoisomers 5a and 5b gave a 52% yield of product 10a,b in only 12%ee following reaction in toluene a t 70 "C for 18 h, whereas reaction of the parent hexacarbonyl complex (1: R1 = Ph, R2 = H, L = CO) gave a 75% yield of the same product after heating at the same temperature for (10)Schmidt, U.; Talbiersky, J.; Bartkowiak, F.; Wild, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 198. Baldwin, J. J.; Raab, A. W. 8.; Mender, K.;Arison, B. H.; McLure, D. E. J.Org. Chem. 1978,43,4876. Brunner, H.; Leyerer, H. J. Orgunomet. Chem. 1987,334, 369. (11) Available commercially from Aldrich Chemical Co. (12) Separation was achieved by use of a SPHERISORBm Si-SB39961 HPLC column with varying percentages of tert-butyl methyl ether in heptane as the mobile phase. (13)Complexes Sa,b-Sa,b could not be separated on a preparative scale, although they could be separated on an analytical column.
only 4 h. Additionally, the complexes 7a,b failed to give any cyclopentenone products under the same thermal conditions. Furthermore, even when the single diastereoisomers 6a and 6b were reacted with norbornene in toluene at 70 "C, enantiomeric excesses of only 14%and 21% were obtained. At the elevated temperatures employed in these reactions, we believe that interconversion of the diastereomeric complexes was occurring, leading to the low enantiomeric excesses achieved. Despite this and the lowered reactivity of the Glyphos complexes, we then endeavored to develop conditions which would provide cyclopentenones in enhanced rates and yields with good enantioselectivity. As previously mentioned, amine N-oxides, as additive in the Pauson-Khand reaction, have been shown to readily promote annulations in a wide range of examples both in our laboratories14 and e l ~ e w h e r e .Following ~ studies with suitable oxidants and careful optimization of conditions, anhydrous N-methylmorpholine N-oxide (NMO) was found to be the most efficient promoter in our reactions with the Glyphos-containing complexes. More specifically, when NMO is utilized in dichloromethane, reactions between single diastereomeric complexes 5a,b-7a,b and norbornene or norbornadiene proceed relatively quickly (6-8 h) a t room temperature (Scheme 3, Table 2). More importantly, we have found that the reactions with both alkenes proceed to give only the exo-cyclopentenone products in good yields (65-90%) and, to our delight, in consistently high and, in some cases, excellent enantiomeric excesses (64- > 99%). Additionally, reactions have also been shown t o proceed a t lower temperatures (0 "C), albeit over a longer period of 18 h, to give comparable yields and ee's (eg., Table 2,6a,b). ~~~~
~
(14) Johnstone, C.; Kerr, W. J.; Lange, U. J. Chem. SOC.,Chem. Commun. 1995,457.
4988 Organometallics, Vol. 14, No. 11, 1995
Communications
It is also important to note that, despite the I&(+)form of Glyphos having been used in every complex, each single diastereomeric complex yields one of the two possible enantiomeric forms of the cyclopentenone product in excess (eg.Sa >99%ee of loa, and 6b '99% ee of 10b).15This observation leads us to conclude that the enantioselection does not arise from the influence of the chiral Glyphos ligand but from the chiral C2C02 core. Therefore, the chiral (R)-(+)-Glyphoscomplexes, in principle, can provide routes to cyclopentenone products enriched with the enantiomer of choice. In summary, we have shown that a range of cobaltalkyne complexes containing the chiral ligand @)-(+)Glyphos can be readily synthesized and the diastereomers routinely separated by preparative HPLC. In turn, we have formulated enantioselective intermolecular Pauson-Khand cyclization techniques which are more flexible and applicable than the diastereoselective
-
-
(15) At the present time the absolute configurations of the diastereomeric complexes or the enantiomeric products are unknown. However, these issues are currently being addressed by the combination of derivatization and crystallographic studies. It should also be stated that optical rotation studies show consistency in that one form of the starting complex gives predominantly the cyclopentenone product of the same sign; e g . , at room temperature 6a ( [ u I D ~ O = -168") gives lla,b in 64% ee of l l a ([u]D~O = -38.0") and 6b ([uID~O = +172") gives lla,b in 75% ee of I l b ([uID~O = +45.1").
processes previously reported. Using anhydrous NmethylmorpholineN-oxide under mild conditions, which prevent racemization of the cobalt compounds, techniques have been developed to give the cyclopentenone products in good to high yields and with powerful asymmetric control. Studies on a range of alkenes in this asymmetric version of the Pauson-Khand reaction are currently underway. The physical properties of the pure diastereomeric complexes, their diastereoselective formation, and a range of further reactions are currently being investigated in our laboratory and will be reported in due course.
Acknowledgment. We thank Glaxo Research and Development Ltd. for funding this research. Supporting Information Available: Text giving all experimental procedures and relevant spectroscopic characterizations for the organometallic complexes and cyclopentenone products listed in Tables 1and 2 (6 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, can be ordered from the ACS, and can be downloaded from the Internet; see any current masthead page for ordering information and Internet access instructions.
OM950689U
