(3aR,7aR)-2-Ethyloctahydro-1H-1,3-dineopentyl-1,3,2-benzodiazaphosphole Oxide

(1; R1 = neopentyl, R2 = Et)

[146397-34-4]  · C18H37N2OP  · (3aR,7aR)-2-Ethyloctahydro-1H-1,3-dineopentyl-1,3,2-benzodiazaphosphole Oxide  · (MW 328.54) (2; R1 = Me, R2 = allyl)

[146098-95-5]  · C11H21N2OP  · (3aR,7aR)-2-Allyloctahydro-1H-1,3-dimethyl-1,3,2-benzodiazaphosphole Oxide  · (MW 228.31) (3; R1 = Me, R2 = Et)

[91633-73-7]  · C10H21N2OP  · (3aR,7aR)-2-Ethyloctahydro-1H-1,3-dimethyl-1,3,2-benzodiazaphosphole Oxide  · (MW 216.30) (4; R1 = Me, R2 = Bn)

[146098-94-4]  · C15H23N2OP  · (3aR,7aR)-2-Benzyloctahydro-1H-1,3-dimethyl-1,3,2-benzodiazaphosphole Oxide  · (MW 278.37) (5; R1 = Me, R2 = CH2CH=CHMe)

[-]  · C12H23N2OP  · (3aR,7aR)-2-(2-Butenyl)octahydro-1H-1,3-dimethyl-1,3,2-benzodiazaphosphole Oxide  · (MW 242.34) (6; R1 = Bn, R2 = Et)

[-]  · C22H29N2OP  · (3aR,7aR)-2-Ethyloctahydro-1H-1,3-dibenzyl-1,3,2-benzodiazaphosphole Oxide  · (MW 368.50) (7; R1 = Bn, R2 = Pr)

[-]  · C23H31N2OP  · (3aR,7aR)-2-Propyloctahydro-1H-1,3-dibenzyl-1,3,2-benzodiazaphosphole Oxide  · (MW 382.53) (8; R1 = Me, R2 = CH2Cl)

[146983-74-6]  · C9H18ClN2OP  · (3aR,7aR)-2-(Chloromethyl)octahydro-1H-1,3-dimethyl-1,3,2-benzodiazaphosphole Oxide  · (MW 236.71)

(chiral a-alkyl bicyclophosphonamides useful for the asymmetric synthesis of alkenes,1-3 of a,a-substituted phosphonic acids,4 and of a-amino-a-substituted phosphonic acids,5,6 and for asymmetric conjugate additions of C-allyl and C-crotyl groups to a,b-unsaturated carbonyl compounds7)

Physical Data: (1) mp 110-111 °C; [a]25D -98.8° (c 1.10, CHCl3). (2) mp 45-46 °C; [a]25D -51.1° (c 1.85, CHCl3). (3) mp 55-56 °C; [a]25D -98.9° (c 1.48, CHCl3). (4) mp 104-105 °C; [a]25D -109.6° (c 1.17, CHCl3). (6) mp 153-154 °C; [a]25D -68.2° (c 1.18, CHCl3). (7) mp 117 °C; [a]25D -66.0° (c 1.02, CHCl3). (8) mp 84 °C; [a]25D -109.8° (c 1.0, CHCl3).

Solubility: sol chlorinated and dipolar aprotic solvents, and hydrocarbon solvents in some cases. Gradual hydrolysis in protic media.

Form Supplied in: colorless crystalline or waxy solids.

Preparative Methods: 3 to a solution of (1R,2R)-N,N-dineopentyl-1,2-diaminocyclohexane (1.37 g, 5.40 mmol) and triethylamine (2.3 mL, 48.5 mmol) in 25 mL of benzene is added ethylphosphoryl dichloride (0.89 g, 6.06 mmol). The suspension is heated to reflux for 80 h, the salts are filtered, and the filtrate is washed successively with 10% aq HCl (2 × 10 mL), aq saturated NaHCO3, and water. Drying, evaporation, and chromatographic separation (EtOAc) gives the title compound (1.1 g, 62%) as a crystalline solid, mp 110-111 °C (hexanes). Single crystal X-ray analysis confirmed the structure. For an alternative synthesis of related compounds, see Kueller and Spilling.8 Other 2-alkyl derivatives can be similarly prepared.1-4

Handling, Storage, and Precautions: crystalline reagents are stable when stored under argon at 0 °C for several months.

Asymmetric Alkenation of Alkylcyclohexanones.1-3

Anions of the reagents (1), (4), (6), and (7) add to alkylcyclohexanones in THF solution at -78 °C to give intermediate b-hydroxyphosphonamide adducts, which can be isolated and purified by chromatography. Treatment of the adducts with aq acetic acid leads to the corresponding alkylidene alkylcyclohexanes in good to excellent enantiomeric or diastereomeric excesses. The alkenes can also be obtained directly from the original reaction mixtures (aq AcOH quench), without isolation of intermediates. Except in the case of reagent (1), using the reagents prepared from (R,R)-1,2-diaminocyclohexane gives the (aR)-alkenes with 4-substituted alkylcyclohexanones and the (E)-alkenes with other analogs, based on a transition state that favors equatorial attack of the least encumbered face of the anion on the cyclohexanone derivative. For steric reasons, the reverse is observed with reagent (1).3 Eq 1 illustrates a typical reaction and other examples of products are listed in Table 1 (enantiomeric excesses >99:1).2,3

Kinetic Resolution.2

When the reacting partners allow for a high degree of stereodifferentiation in the transition state, it is possible to achieve asymmetric alkenation by kinetic resolution (eq 2). This is best done with a-alkyl substituted cyclohexanones and bulky anions such as that derived from (4). In a typical procedure, (±)-2-methylcyclohexanone (1 mmol) is treated with the anion of (3) (0.5 mmol, -78 °C, THF, 1 h; then AcOH, -> 25 °C, and workup), to give (E,2S)-(2-methylcyclohexylidene)benzene; [a]25D -86.4° (c 1, CHCl3), and the (Z)-isomer (>98:2 by capillary GC; 63% based on the reagent).

Sequential Asymmetric Alkenation and Ene Reactions.3

Treatment of a number of (alkylcyclohexylidene)ethane derivatives with chiral nonracemic a-benzyloxy aldehydes results in the formation of branched alkylcyclohexene derivatives via a highly stereocontrolled ene reaction. Based on a chelated transition state, it is possible to predict the disposition of the double bond and the chirality of two new stereogenic centers, as illustrated in eq 3. The newly created stereogenic center bearing a C-methyl group from the ene reaction leads to interesting substitution patterns in relation to the existing C-methyl group. Oxidative cleavage of the double bond leads to acyclic counterparts with predictable disposition and chirality (e.g. 1,6-dimethyl, 1,5-dimethyl, etc.).3

a-Substituted a-Alkylphosphonic Acids.4

In general, a-substituted phosphonamides can be transformed into the corresponding a-alkyl derivatives of very high diastereomeric purity by alkylation of the anions at -78 °C or lower (eq 4, Table 2). In most cases the approach of the electrophile is favored from the least hindered side of the anion, leading to highly enriched diastereomers. These products can be subsequently hydrolyzed to the corresponding phosphonic acids. A typical procedure is as follows. To a solution of (3) (1 mmol) in THF, is added n-Butyllithium (1.40 mmol at -78 °C), the temperature is lowered to -100 °C, and Allyl Bromide (1.15 mmol) is added. After stirring for 15 min, the reaction mixture is quenched with MeOH, and the solution processed as usual. Chromatographic purification gives the expected product as a crystalline solid (X-ray), mp 87-88 °C, [a]25D -91.5° (c 1.0, CHCl3).

a-Chloro-a-alkylphosphonic Acids.4

The reagent is prepared from a-chloromethylphosphonyl dichloride and (R,R)- or (S,S)-N,N-dimethyl-1,2-diaminocyclohexane as described above. Alkylation is done as described above (BuLi, THF, -100 °C, followed by isolation, then hydrolysis, 0.1N HCl, 25 °C). Eq 5 and Table 3 illustrate some examples.4

a-Amino-a-alkylphosphonic Acids.5

Treatment of iminodithiolane derivatives (eq 6) with Potassium Hexamethyldisilazide in THF (-78 °C) generates the corresponding anions which, when treated with various alkyl halides, give the corresponding a-alkyl derivatives in high diastereomeric excess. Unlike other a-substituted phosphonamides discussed above, the alkylation of the (R,R)-a-iminodithiolane derivative gives products with the opposite orientation of the new alkyl chain, which are normally expected from the enantiomeric (S,S) series. This has been rationalized based on the intermediacy of a potassium chelate involving the phosphoryl oxygen and the imino nitrogen atoms, thus exposing the other face of the anion.5 Eq 6 illustrates a typical sequence and Table 4 lists some examples of a-amino-a-alkylphosphonic acids prepared using this sequence.

a-Amino-b-aryl phosphonic acids are accessible from the addition of the anion of chloromethylphosphonamide (8) to N-arylimines, followed by hydrogenolysis of the aziridine derivative.6

Asymmetric Conjugate Addition of Allyl- and Crotylphosphonamides.7

The asymmetric C-allylation of a,b-unsaturated carbonyl compounds is a powerful tool for the functionalization of a carbonyl compound in the b-position. Since such a process normally leads to the corresponding enolate derivative when anionic reagents are used, there exists the possibility of trapping with an electrophile. Thus sequential addition and trapping can lead to vicinally substituted carbonyl compounds. Asymmetric allylation has been achieved previously with simple cycloalkenones using phosphorus9 and sulfur10 based reagents that must be prepared in diastereomerically pure form.

The anions of allyl- and crotylphosphonamides, (2) and (5) respectively, show excellent selectivity toward a variety of a,b-unsaturated compounds, affording the diastereomerically pure or enriched products. Quenching the enolates with various electrophiles gives vicinally substituted carbon centers. Oxidative cleavage of the phosphonamide moiety affords the equivalent of an acetaldehyde (a-methylacetaldehyde) anion 1,4-adduct to the original a,b-unsaturated carbonyl compound. Pertinent examples are shown in eq 7 and Table 5.

Conclusion.

The C2 symmetry of (R,R)- and (S,S)-1,2-diaminocyclohexane, readily available from the racemic compound by resolution,11 has served as a versatile chiral motif in the design of topologically unique stereodifferentiating reagents such as the phosphonamide anions described here. Several other applications of these reagents via anion chemistry, or simply based on the exploitation of other effects offered by their structures and heteroatom functionality, can be explored (catalytic processes, chiral ligands, etc.). The N,N-disubstituted 1,2-diaminocyclohexane motif has also been remarkably versatile in other asymmetric processes such as the dihydroxylation of alkenes,12 and a variety of other C-C bond-forming reactions.13


1. Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. JACS 1984, 106, 5754; CS 1985, 88, 1419.
2. Hanessian, S.; Beaudoin, S. TL 1992, 33, 7655.
3. Hanessian, S.; Beaudoin, S. TL 1992, 33, 7659.
4. Hanessian, S.; Bennani, Y.; Delorme, D. TL 1990, 31, 6461.
5. Hanessian, S.; Bennani, Y. TL 1990, 31, 6465.
6. Hanessian, S.; Bennani, Y.; Hervé, Y. S 1993, 35.
7. Hanessian, S.; Gomtsyan, A.; Payne, A.; Hervé, Y.; Beaudoin, S. JOC 1993, 58, 5032.
8. Koeller, K.; Spilling, C. D. TL 1991, 32, 6297.
9. Haynes, R. K.; Vonwiller, S. C.; Hambley, T. W. JOC 1989, 54, 5162.
10. Hua, D. H.; Chan-Yu-King, R.; McKie, J.-A.; Myer, L. JACS 1987, 109, 5026.
11. (a) Gasbol, F.; Seenbol, P.; Sorensen, B. S. ACS 1972, 26, 3605; (b) Asperger, R. G.; Liu, C. F. IC 1965, 4, 1492.
12. Hanessian, S.; Meffre, P.; Girard, M.; Beaudoin, S.; Sancéau, J.-Y.; Bennani, Y. JOC 1993, 58, 1991.
13. (a) Rozema, M. J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P. TL 1993, 34, 3115. (b) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. JACS 1991, 113, 7063. (c) Denmark, S. E.; Stadler, H.; Dorw, R. L.; Kim, J.-H. JOC 1991, 56, 5063. (d) Alexakis, A.; Mutti, S.; Normant, J. F. JACS 1991, 113, 6332. (e) Bertz, S. H.; Dabbagh, G.; Sundararajan, G. JOC 1986, 51, 4953. (f) Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M. TL 1989, 30, 7095.

Stephen Hanessian

University of Montreal, Quebec, Canada



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