[132068-98-5]  · C36H33ClO4Ti  · Chloro(h5-cyclopentadienyl)[(4R,trans)-2,2-dimethyl-a,a,a“,a“-tetraphenyl-1,3-dioxolane-4,5-dimethanolato(2-)-Oa,Oa]titanium  · (MW 613.0)

(highly enantio- and diastereoselective addition of allyl and terminally monosubstituted allyl groups to achiral and chiral aldehydes;1 can also be used for enantioselective aldol reactions,2 especially of glycine ester enolates2a)

Physical Data: mp 214 °C (Mettler DSC); [a]D = -243.4° (c = 1, CHCl3); X-ray, 1H, 13C NMR.1a

Solubility: sol toluene (ca. 370 mg mL-1), THF (ca. 470 mg mL-1), diethyl ether (ca. 150 mg mL-1).

Form Supplied in: pale yellow powder or crystals.

Analysis of Reagent Purity: 1H NMR (CDCl3);1 may contain 1-5% of (4R,trans)-2,2-dimethyl-a,a,a“,a“-tetraphenyl-1,3-dioxolane-4,5-dimethanol (but does not affect its efficiency).

Preparative Method: see Trichloro(cyclopentadienyl)titanium.

Handling, Storage, and Precautions: the dry solid must be stored under exclusion of moisture and UV at rt (brown, tightly sealed bottle). It can, however, be handled quickly in the open, e.g. for weighing. Reactions should be carried out in dry equipment and with absolute solvents under argon or N2.

Allyltitanation of Aldehydes.

The two-stage, one-pot procedure involves first the generation of the allyltitanium reagents (R)-(2a-f) (eq 1) by transmetalation of allyl-Grignard or allyl-Li compounds with a slight excess (1.2 equiv) of (R,R)-(1). It is advisable to analyze the content of the allylmetal precursor solution. Optimal conditions (time and temperature) of these transmetalations are preferably determined by test reactions with a simple aldehyde, assessing for maximal diastereo- and enantioselectivity. For stable allylmetal compounds, 1-3 h at 0 °C is usually sufficient. The allyltitanates (2) can be analyzed by 1H and 13C NMR.1a Fast allylic rearrangements are responsible for the formation of the thermodynamically most stable allyltitanium isomer with terminal substitution and trans double bond, irrespective of the nature of the organometallic precursor.

The second step, performed in situ, is the addition of ca. 0.75 equiv (based on 1) of an aldehyde at -78 °C (eq 2). Most reactions are completed within 3 h and the resulting cyclopentadienyltitanium trialkoxides are hydrolyzed by stirring overnight with aqueous NH4F (45%) at rt. The precipitated cyclopentadienyltitanium oxide (3) is removed by filtration and can be recycled to CpTiCl3. The chiral ligand (4) and the product (5) are separated by crystallization or precipitation of (4) followed by distillation and/or chromatography.

The homoallylic alcohols (5) are isolated in fair to good yields. Their optical purity often exceeds 95% and the anti diastereomers are produced almost exclusively (&egt;98% ds). Exceptions with up to 33% syn epimer have, however, been obtained for (2f).1b The reagent controlled stereoselectivity of (R)-(2) and the enantiomers (S)-(2) is best documented by conversions with chiral aldehydes, examples being (6),1a (7),1a and (8).1b

The allylation of (2S)-2-phenylbutyraldehyde to give (6) allows a comparison with other similar reagents. Whereas the transformation to (6) with (S)-(2a) (mismatched pair) proceeds with 95% ds, lower selectivity is observed for the allyltitanium reagent prepared analogously from Chloro(cyclopentadienyl)bis[3-O-(1,2:5,6-di-O-isopropylidene-a-D-glucofuranosyl)]titanium (79% ds) or from B-Allyldiisopinocampheylborane (74% ds).3a Due to the fast E/Z isomerization of (2), the syn isomers of (5) cannot be obtained as the major product by using allyltitanium compounds, e.g. (R)-(2b), derived from chloride (1). Syn-crotyl adducts are efficiently obtained with chiral allylboron reagents,3 e.g. diisopinocampheyl-(Z)-crotylborane3a,b or diisopropyl tartrate (Z)-crotylboronate.3c Inferior stereoselectivity is also exhibited by 2-substituted and 1,3-disubstituted allyltitanium reagents derived from (1).1,2b The use of similar chiral titanium reagents4 and stereoselective additions with other allylmetal compounds5 have recently been reviewed. While all these methods rely on stoichiometric amounts of a chiral reagent, catalytic amounts of a chiral acyloxyborane complex mediate the enantioselective addition of allylsilanes6a and allylstannanes6b to aldehydes. Very recently, the addition of allyltributyltin was also found to be catalyzed by a complex formed from 1,1“-bi-2-naphthol and TiCl4 (see (R)-1,1“-Bi-2,2“-naphthotitanium Dichloride).7

Aldol Reaction.

In addition to the allyl derivatives (2) (eq 1), titanium ester enolates derived from chloride (1) react with aldehydes, affording aldol products after hydrolysis. Compared to the analogous reagents prepared from Chloro(cyclopentadienyl)bis[3-O-(1,2:5,6-di-O-isopropylidene-a-D-glucofuranosyl)]titanium the enantioselectivity of these enolates is only moderate, 78% ee for the enolate of t-butyl acetate2 and 26-78% ee in the case of 2,6-dimethylphenyl propionate.4 Better selectivity (81-94% ee) was, however, obtained for Ti enolates (9) derived from stabase-protected glycine esters (10) (eq 3).2a The primary N-bis-silyl-protected adduct (11) can easily be transformed to other N-derivatives, e.g. the t-butyl carbamate (12). This method thus gives access to L-threo-a-amino-b-hydroxy acids. Further details and references to other methods are provided in the entry for Chloro(cyclopentadienyl)bis[3-O-(1,2:5,6-di-O-isopropylidene-a-D-glucofuranosyl)]titanium, an analogous reagent affording the enantiomer of (12).

1. (a) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F. JACS 1992, 114, 2321. (b) Duthaler, R. O.; Hafner, A.; Alsters, P. L.; Rothe-Streit, P.; Rihs, G. PAC 1992, 64, 1897.
2. (a) Duthaler, R. O.; Hafner, A.; Riediker, M. PAC 1990, 62, 631. (b) Cambie, R. C.; Coddington, J. M.; Milbank, J. B. J.; Pausler, M. G.; Rustenhoven, J. J.; Rutledge, P. S.; Shaw, G. L.; Sinkovich, P. I. AJC 1993, 46, 583.
3. (a) Brown, H. C.; Bhat, K. S.; Randad, R. S. JOC 1989, 54, 1570. (b) Racherla, U. S.; Brown, H. C. JOC 1991, 56, 401. (c) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. JACS 1990, 112, 6339. (d) Short, R. P.; Masamune, S. JACS 1989, 111, 1892. (e) Corey, E. J.; Yu, Ch.-M.; Kim, S. S. JACS 1989, 111, 5495. (f) Stürmer, R. AG(E) 1990, 29, 59.
4. Duthaler, R. O.; Hafner, A. CRV 1992, 92, 807.
5. Yamamoto, Y.; Asao, N. CRV 1993, 93, 2207.
6. (a) Furuta, K.; Mouri, M.; Yamamoto, H. SL 1991, 561. (b) Marshall, J. A.; Tang, Y. SL 1992, 653.
7. (a) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. JACS 1993, 115, 7001. (b) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. JACS 1993, 115, 8467.

Andreas Hafner & Rudolf O. Duthaler

Ciba-Geigy AG, Marly, Switzerland

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