Enantioselective synthesis of the ester side chain of homoharringtonine

From D -Malic acid as chiral starting material, an efficient synthesis of the ester side chain of homoharringtonine has been developed. A cross-metathesis reaction leads to the formation of the key intermediate, which can be converted later by selective hydrogenation to the methyl ester side chain of homoharringtonine and deoxy-homoharringtoine in a total of six steps with 24.5% and 23.5% in yields, respectively


Introduction
5] In 2012, omacetaxine mepesuccinate (Synribo), a semisynthetic HHT compound (99.7% purity) was used in studies of chronic myeloid leukemia (CML) and approved by the FDA for the treatment of CML.Later approval from the FDA in 2013 for this drug to be self-administered by patients further demonstrated its efficacy and safety. 6

Results and Discussion
Our methodology started with the application of Seebach's concept of "self-reproduction of chirality" as a means to introduce the stereocenter of the ester side chain.Starting with D-Malic acid as a readily available chiral starting material, dioxolanone 2 was synthesized as previously reported. 15The cis-product was predominant due to its being favored thermodynamically.The allylation of the dioxolanone 2 with allyl bromide in the presence of two equivalents of LiHMDS in THF at -78 o C gave the desired compound in 75% yield.Due to the strong steric hinderance by the t-butyl group, the allyl electrophile attacks from the opposite face, thereby securing the required R-configuration.
The cross metathesis of the acid 3 with 2-methylbut-3-en-2-ol was next undertaken using Grubbs's 2 catalyst 16 in DCM with a large excess of the tertiary alcohol.Unfortunately, only starting materials together with the dimerization product of the alcohol were observed.However, the transformation of acid 3 into its methyl ester 4 by DCC/DMAP 17 in the presence of catalytic amount of PTSA, permitted the cross metathesis to succeed in high yield. 1 H NMR analysis showed that the product 5 exists mainly as the trans-isomer.
With the key intermediate 5 in hand, hydrogenation of the double bond with H 2 -Pd/C in methanol gave surprisingly a quantitative dehydroxy product 7.This result can be explained by the fact that the allylic alcohol position in 5 is slightly acidic, thus making it more favourable to be removed under the reaction conditions.Addition of an amine, to neutralize the alcohol and afford a selective hydrogenation, was then applied.After several trials, we found that one equivalent of triethylamine in ethanol permitted a complete conversion of 5 into the desired product 6.The final transformations of the protected dioxalanes 6 and 7 were performed smoothly using MeOH/MeONa affording the methyl ester side chains of homoharringtonine 8 and deoxy-homoharringtonine 9 in very high yields.The NMR and optical rotation data obtained were identical with the reported data.

Conclusions
An enantioselective synthesis of homoharringtonine ester side chain and its deoxy-derivative have been completed in six steps with 24.5% and 23.5% overall yields, respectively.The key tactical elements of this synthesis include the use of chiral malic acid as starting material and the cross metathesis with available methylbut-3-en-2-ol.These enabled an efficient access to the protected intermediate 5, which can be converted easily into methyl ester of the side chain.This strategy can be considered as a potential pathway to the semi-synthesis of homoharringtonine and its derivatives by the coupling of cephalotaxine and the ester side chain.Studies directed towards the esterification of the α-hydroxy acid with cephalotaxin to produce enantiopure HHT are currently under investigation.

Experimental Section
General.All the reactions were carried out under a nitrogen atmosphere.Unless otherwise noted, all the reagents obtained from commercial sources were used without further purification.All solvents were dried by standard methods.THF were dried with sodium and benzophenone and used immediately after distillation.DCM was dried with diphosphorus pentoxide (P 2 O 5 ).Pentane was distilled and then dried with sodium.Analytical thin-layer chromatography (TLC) was performed on 0.25 mm Merck precoated silica gel plates (60-F254).Column chromatography was carried out with silica gel (60-F254).The TLC plates were visualized with a UV lamp (254 nm and 366 nm) and/or with TLC visualizing solutions activated with heat, including: p-anisaldehyde solution and potassium permanganate solution.Mass spectral analyses were performed with a VARIAN 920-MS at VAST.The specific optical rotation data were measured with a JASCO P-2000 Polarimeter instrument (wavelength of the light used was 589 nm). 1 H NMR and 13 C NMR were recorded on BRUKER 300 and 500 MHz instruments using TMS as the internal standard and CDCl 3 as the solvent.
The solid cake was dissolved in CH 2 Cl 2 , and washed with 8% aqueous H 3 PO 4 (2×40 mL).The combined organic phases were dried with Na 2 SO 4 .The solvent was removed under vacuum, giving 9.554 g of the product as a white solid (yield 64%).

Scheme 2 .
Scheme 2. Synthesis of the methyl ester side chains.