Cyanohydrin Formation

Exploration of Methods for Functionalising the C-9 Ketone of Anthracycline Precursors

In some cases, ethynylcerium reagents showed incresed efficiency in their reaction with anthracycline precursors compared to their magnesium analogues; in other examples, the reagent is either unreactive or is still too basic. In fact, a common problem in using Grignard style reagents is elimination of tetra-acetyl glucose and induced aromatisation in the ring-A. 

Acyl Anion Equivalents under Acidic conditions

Trimethylsilyl cyanide (TMSCN) in the presence of certain catalysts [e.g. TiCl41, KCN/18-crown-62, ZnI22,3, Yb(CN)34, {HC(Py)3W(NO)2(CO)(SbF6)2}3 or Me3SiOTf5] reacts with ketones as shown in the scheme to afford, after aqueous work-up a cyanohydrin. The cynohydrin may be methylated [here Me(metal)], by the use of a Grignard reagent6 or alkylmetal7 to afford an imine which upon acidic hydrolysis affords α-hydroxyketones. Clearly, the C-9 carbonyl group would be a good contender in this process.

The optimum conditions for the formation of the cyanohydrin (2) involved the use of the dihydroxytrione (1)8 and ca. 30 mol equivalents of trimethylsilyl cyanide with 30 mol equiv. of titanium(IV) chloride in dry dichloromethane at room temperature under an atmosphere of argon. Thus, the cyanohydrin (2) was isolated in 17% yield after low temperature silica-gel chromatography and crystallisation. The cyanohydrin is considered to have the structure (2) on the basis of it's spectroscopic properties. However, a nitrile absorption expected around 2200 cm-1 was not detected in it's IR spectrum. The NMR assignments were helped with the aid of a 2D COSY spectrum, although the 10-Hβ and 10-Hα signals, which resonated at δ 1.98 and 3.58 were not found to be coupled. In addition, there was no 4J long-range coupling between the signals at δ 2.88 and 3.58 attributed to the 8-Hα and 10-Hβ signals. Reducing the amount of TMSCN and titanium(IV) chloride six-fold in dichloromethane decreased the rate of formation of compound (2), although increasing the temperature by ca. 20 oC i.e. to reflux compensated for this. tert-Butyldimethylsilyl triflate in dichloromethane prompted the formation of the cyanohydrin (2), with an unidentified component and the tetra-acetyl glucose (4).

Mechanistically, the role of the Lewis Acid catalyst is shown below; the driving force in the formation of the cyanohydrin is that the silicon-oxygen bond is considerably stronger than the silicon-carbon bond (dissociation energies are 530 and 320 KJmol-1 respectively), as seen in red.

In order to continue the sequence as shown in the scheme above, it was decided to oxidise compound (2) into compound (3) prior to conversion of the nitrile group into the ketone moiety. The cyanohydrin was oxidised by the action of lead(IV) acetate in acetic acid to afford the anthracycline (3) in 23% yield after crystallisation.

The cyano group in anthracycline systems can be methylated to acetyl group using methylmagnesium iodide9 and in general use, nickel(II) acetylacetonate has proven to be a useful catalyst for the methylation of nitriles by trimethylaluminium6. However, using the cyano-anthracycline (3), with MeMgI even in the presence of 5% of Ni(acac)2, was unsuccessful. Protection of the C-9 hydroxyl group was not examined.

Acyl Anion Equivalents under Basic Conditions

Sadly, the dihydroxytrione (1) failed to react with the lithiated 2-methyl-1,3-dithiane (5)10 to afford a dithiane of type (6) that could be deprotected (oxidised) to afford the anticipated α-hydroxytrione moiety. As expected in unsuccessful reaction, tetra-acetyl glucose (4) was detected.

Interestingly, TMSCN was used by Vilaivan12 in the asymmetric Strecker reaction.  In this example, the imine (7) in the presence of 10 mol% of the chiral N-salicyl-β-aminoalcohol (8) and the titanium catalyst was converted to the amine (9) in high yield with good enantiomeric excess.   The absolute configuration was determined by comparison of the [α]D and 1H NMR chemical shifts of the Cα-H proton in the presence of (s)-camphorsulfonic acid with the literature data.

References

1. D. A. Evans and L. K. Truesdale, Tetrahedron, 1973, 29, 4929.

2. D. A. Evans, L. C. Carroll and L. K. Truesdale, J. Org. Chem., 1974, 34, 914; K. Utimoto, Y. Wakabayashi, T. Horie, M. Inoue, Y. Shishiyama, M. Obayashi and H. Nozaki, Tetrahedron, 1983, 39, 967.

3. J. W. Faller and G. L. Gundersen, Tetrahedron Letters, 1993, 34, 2275.

4. S. Matsufama, T. Takai and K. Utimoto, Chemistry Letters, 1991, 1447.

5. S. Nurata, M. Suzuki and R. Noyori, J. Am. Chem. Soc., 1980, 102, 3248.

6. L. Bagnell, E. A. Jeffrey, A. Meisters and T. Mole, Aust. J. Chem., 1974, 27, 2577.

7. C. R. Hauser and J. Humphlett, J. Org. Chem., 1959, 15, 359.

8. R. C. Gupta, D. A. Jackson and R. J. Stoodley, Tetrahedron, 1984, 40, 4657.

9. Susan E. Thomas, "Organic Synthesis, the Roles of Boron and Silicon", p. 47, Oxford University Press, Oxford, 1991. ISBN 0 19 855662 4 (Pbk).

10. T. H. Smith, A. N. Fujiwara, W. W. Lee, H. Y. Wu and D. W. Henry, J. Org. Chem., 1977, 42, 3653.

11. D. Seebach and E. J. Corey, J. Org. Chem., 1975, 40, 231.

12. T. Vilaivan et al., Tetrahedron Letters, 2003, 44, 3805.

Some of this cyanohydrin chemistry from my PhD thesis has been briefly described in a recent publication; ISBN: 9781622579112 or here.

For experimental part, see experiments. 

University of Manchester. The online version of the PhD thesis can be found via the library link (ref. U070310).

Author: J. P. Miller. This article originally available from: “Cyanohydrin Formation” Main Page, www.jonathanpmiller.com/cyanohydrin/ [Accessed 08/05/2017].

Image on the left: laboratory (Lab H104, former Faraday Building, where PhD experiments were carried out) and right with supervisor Prof. Richard J. Stoodley a few months before the PhD work began. Contact: jonathan.miller[ at ]alumini.manchester.ac.uk.