(S)-Aceto(carbonyl)(cyclopentadienyl)-(triphenylphosphine)iron

[36548-60-4]  · C26H23FeO2P  · (S)-Aceto(carbonyl)(cyclopentadienyl)-(triphenylphosphine)iron  · (MW 454.29)

(chiral acetate enolate equivalent which can be deprotonated with BuLi or LDA in THF at -78 °C; the enolate reacts stereoselectively with a variety of achiral, prochiral, and chiral electrophiles to generate functionalized organoiron compounds from which the iron can subsequently be removed1)

Physical Data: mp 142 °C; [a]22 +288° (c 0.004, C6H6), [a]20 +160° (c 0.04, C6H6).

Solubility: insol H2O; sol THF, CHCl3, CH2Cl2, acetone.

Form Supplied in: orange solid.

Handling, Storage, and Precautions: can be stored in air for days with little decomposition. The solid is best stored under nitrogen for long periods of time. More air sensitive when in solution, especially chlorinated hydrocarbons. Like all metal carbonyls, it is best handled in a fume hood.

Preparation and Determination of Absolute Stereochemistry.

The preparation of racemic aceto(carbonyl)(cyclopentadienyl)(triphenylphosphine)iron (2) was first reported in 1966.2 Brunner subsequently recognized that the iron atom in the complex was a chiral center and first reported the preparation of the (+)- and (-)-enantiomers in 1972.3 Two groups4,5 recognized in the early 1980s that the enolate of this compound might serve as a chiral acetate enolate equivalent. The absolute configuration of the (+)-enantiomer was reported in 19866a and confirmed in 1988.7 Alternative preparations of (S)-(+)-(2) involving kinetic reductions were published in late 1993.6b,c The first reported preparation3a of (S)-(+)-(2) begins with treatment of [CpFe(CO)2(PPh3)]+PF6- with sodium mentholate to produce the menthol ester diastereomers which were separated by fractional crystalliza tion.3b The (-)-menthol ester (1) was then treated with MeLi (1.5 M in Et2O) (slow addition of the MeLi produces acetyl (2) of the highest optical purity)3c in THF at -30 °C (eq 1). Aqueous workup and alumina chromatography produced the (S)-(+)-acetyl (2). A resolution procedure for the separation of the related trimethyl- and triethylphosphine substituted acetyls has also been reported.8

Enolate Generation and Subsequent Alkylation or Oxidation.

The (S)-(+)-acetyl complex (2) is cleanly deprotonated to the configurationally stable enolate anion (3) upon treatment with n-Butyllithium or Lithium Diisopropylamide in THF at -78 °C.1 The enolate (3) is alkylated in an almost quantitative yield when treated with a variety of alkyl iodides (eq 2). Alkylation of (3) with (R)-chloromenthyl ether produced (5) which was used to establish the absolute stereochemistry of (2) (eq 3).6,1f Subsequent deprotonation of these alkylated products (4) is believed to produce (E)-enolates (6) which can be alkylated cleanly from the enolate face away from the triphenylphosphine ligand (eq 4).1

This sequential alkylation chemistry has been used to synthesize (-)-epicaptopril (9) (eq 5)1b,9 as well as (S)-(+)-2-methylhept-4-ynoate (10), a key intermediate for the side chain of prostacyclin ZK96480 (eq 6).10

Related alkylation chemistry of (2) has provided a route to chiral succinic acid derivatives (11) (eq 7).11 In this chemistry, acetyl complex (2) was used to produce a succinoyl complex which was subsequently deprotonated a to the ester and alkylated with primary and secondary alkyl halides. This sequence of reactions has been used to produce the succinate fragment of actinonin,11a as well as a variety of other succinic acid and amide derivatives.11b,c

a-Oxidation of the enolate (3) has also been reported. Deprotonation of (4) (R = Me) followed by treatment with Diphenyl Disulfide generated a thioether complex which was oxidized to the sulfoxide and used in an asymmetric synthesis of sulfoxides.12 Enolate (3) has also been trapped with MoOPH (Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide)) and benzylated to produce the a-benzyloxyacetyl complex.13 Enolate generation from the a-benzyloxyacetyl followed by alkylation with two equivalents of racemic 1-phenylethyl bromide provided almost exclusively the alkylation product derived from reaction with (S)-1-phenylethyl bromide. This sequence demonstrated the power of the CpFe(CO)(PPh3)R fragment as a chiral recognition element. Recently, treatment of (3) with Chlorodiphenylphosphine has been shown to produce chiral phosphine (12) which was subsequently used as a ligand in the preparation of several palladium complexes (eq 8).14

Aldol and Related Condensations.

The fact that the enolate of the racemic iron acetyl will participate in diastereoselective aldol condensations and that enolate counterions have a large effect on the diastereoselectivity of those reactions has been known for some time.1 More recently, an alkylation/aldol sequence involving (2) was used to prepare complex (13) of known absolute configuration. Complex (13) was used to assign, by chemical correlation, the absolute configuration to a series of marine cyclic epoxides (eq 9).15 Similar aldol chemistry followed by iron-carbon bond cleavage using Bromine has been used to prepare a series of optically active b-lactones (15)16 including tetrahydrolipstatin (eq 10).17

Examples of aldol condensations involving chiral aldehydes have also been reported. Condensation of the aluminum enolate derived from (2) with Boc-L-prolinal has been shown to proceed in a highly stereoselective manner and the iron chirality overpowered the latent stereoselectivity inherent in Boc-L-prolinal.18 Subsequent deprotection and demetalation of (16) produced (-)-(1R,8S)-1-hydroxypyrrolizidin-3-one (17) (eq 11). Aldol condensation between the tin(II) and aluminum enolates derived from (2) and 2,3-isopropylidene-D-glyceraldehyde also proceeded with high stereoselectivity and the iron once again had the overwhelming directing effect on the stereochemical outcome of these condensations (eq 12).19

Synthesis and Reaction Chemistry of a,b-Unsaturated Acyl Complexes Derived from (2).

Two methods for the preparation of optically active (E)- and (Z)-a,b-unsaturated iron acyls from (2) have been reported.1f One method involves aldol condensation of (2) with aldehydes followed by O-methylation to produce diastereomeric acyls (18). This mixture (18) is then treated with Sodium Hydride to produce predominantly (E)-a,b-unsaturated acyl complexes (19) (eq 13).20 Alternatively, (2) can be deprotonated and treated with Chlorotrimethylsilane to produce the C-silylated complex which is subsequently deprotonated and treated with an aldehyde.1f,21 This Peterson alkenation produced mixtures of the isomers (E)-(19) and (Z)-(20) which could be separated via chromatography (eq 14). The (Z) isomers (20) with g-protons are deprotonated when treated with strong bases and selectively alkylated a to the carbonyl.1f The (E) isomers and (Z) isomers without g protons participate in stereoselective Michael additions and Michael addition/alkylation sequences.1f,20-22 Most often this chemistry has been used to prepare optically active b-lactams and amides (21) and (22) (eqs 15 and 16).

The (E)- and (Z)-a,b-unsaturated acyls (19) and (20) have also been methylenated as part of an asymmetric route to cyclopropanecarboxylic acid derivatives.23 The acryloyl complex, which has been used in asymmetric Diels-Alder reactions24 as well as a verapamil precursor synthesis,25 has not been prepared in optically active form from (2), but can be prepared via an elimination reaction from (5).24,25


1. (a) Fatiadi, A. J. J. Res. Nat. Inst. Stand. Technol. 1991, 96, 1. (b) Davies, S. G. Aldrichim. Acta 1990, 23, 31. (c) Blackburn, B. K.; Davies, S. G.; Whittaker, M. Stereochemistry of Organometallic and Inorganic Compounds; Bernal, I., Ed.; Elsevier: Amsterdam, 1989; Vol. 3, pp 141-223. (d) Davies, S. G. PAC 1988, 60, 13. (e) Davies, S. G.; Bashiardes, G.; Beckett, R. P.; Coote, S. J.; Dordor-Hedgecock, I. M.; Goodfellow, C. L.; Gravatt, G. L.; McNally, J. P.; Whittaker, M. Philos. Trans. R. Soc. London, Ser. A 1988, 326, 619. (f) Davies, S. G.; Dordor-Hedgecock, I. M.; Easton, R. J. C.; Preston, S. C.; Sutton, K. H.; Walker, J. C. BSF 1987, 608.
2. Bibler, J. P.; Wojcicki, A. IC 1966, 5, 889.
3. (a) Brunner, H.; Schmidt, E. JOM 1972, 36, C18. (b) Brunner, H.; Schmidt, E. JOM 1973, 50, 219. (c) Brunner, H.; Strutz, J. ZN(B) 1974, 29, 446.
4. Aktogu, N.; Davies, S. G.; Felkin, H. CC 1982, 1303.
5. Liebeskind, L. S.; Welker, M. E. OM 1983, 2, 194.
6. (a) Davies, S. G.; Dordor-Hedgecock, I. M.; Sutton, K. H.; Walker, J. C.; Bourne, C.; Jones, R. H.; Prout, K. CC 1986, 607. (b) Baker, R. W.; Davies, S. G.; TA 1993, 4, 1479. (c) Case-Green, S. C.; Costello, J. F.; Davies, S. G.; Heaton, N.; Hedgecock, C. J. R.; Prime, J. C. CC 1993, 1621.
7. Bernal, I.; Brunner, H.; Muschiol, M. ICA 1988, 142, 235.
8. Brookhart, M.; Liu, Y.; Goldman, E. M.; Timmers, D. A.; Williams, G. D. JACS 1991, 113, 927.
9. Bashiardes, G.; Davies, S. G. TL 1987, 28, 5563.
10. Bodwell, G. J.; Davies, S. G. TA 1991, 2, 1075.
11. (a) Bashiardes, G.; Davies, S. G. TL 1988, 29, 6509. (b) Bashiardes, G.; Collingwood, S. P.; Davies, S. G.; Preston, S. C. JCS(P1) 1989, 1162. (c) Bashiardes, G.; Collingwood, S. P.; Davies, S. G.; Preston, S. C. JOM 1989, 364, C29.
12. Davies, S. G.; Gravatt, G. L. CC 1988, 780.
13. Davies, S. G.; Middlemiss, D.; Naylor, A.; Wills, M. CC 1990, 797.
14. Douce, L.; Matt, D. CR(2) 1990, 310, 721.
15. Capon, R. J.; MacLeod, J. K.; Coote, S. J.; Davies, S. G.; Gravatt, G. L.; Dordor-Hedgecock, I. M.; Whittaker, M. T 1988, 44, 1637.
16. Case-Green, S. C.; Davies, S. G.; Hedgecock, C. J. R. SL 1991, 779.
17. Case-Green, S. C.; Davies, S. G.; Hedgecock, C. J. R. SL 1991, 781.
18. (a) Beckett, R. P.; Davies, S. G. CC 1988, 160. (b) Beckett, R. P.; Davies, S. G.; Mortlock, A. A. TA 1992, 3, 123.
19. Bodwell, G. J.; Davies, S. G.; Mortlock, A. A. T 1991, 47, 10077.
20. Davies, S. G.; Dordor-Hedgecock, I. M.; Sutton, K. H.; Walker, J. C.; Jones, R. H.; Prout, K. T 1986, 42, 5123.
21. Davies, S. G.; Dupont, J.; Easton, R. J. C. TA 1990, 1, 279.
22. Davies, S. G.; Dordor-Hedgecock, I. M.; Sutton, K. H.; Walker, J. C. TL 1986, 27, 3787.
23. (a) Ambler, P. W.; Davies, S. G. TL 1988, 29, 6979. (b) Ambler, P. W.; Davies, S. G. TL 1988, 29, 6983.
24. Davies, S. G.; Walker, J. C. CC 1986, 609.
25. Brunner, H.; Forster, S.; Nuber, B. OM 1993, 12, 3819.

Mark E. Welker

Wake Forest University, Winston-Salem, NC, USA



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