Asymmetric Syntheses of Potent Antitumor Macrolides Cryptophycin B and Arenastatin A

Abstract

Efficient and highly stereoselective syntheses of cryptophycin B and arenastatin A, potent cytotoxic agents, are described. An ester-derived titanium enolate mediated syn-aldol reaction was employed to generate the stereocenters C-5 and C-6. The route is convergent and provides a convenient

Solventless Mechanosynthesis of N-Protected Amino Esters

“…Except for β-amino esters (entries 14 and 15) yields were as high (80% to quantitative) as for the usual synthetic methods in solution. ,,− Final products were recovered by a very simple workup, based on a precipitation/filtration procedure without need of chromatographic purification for most of cases, contrary to synthesis in solution, resulting in more environmentally friendly conditions. Starting from our previous findings, equimolar amounts of glycine methyl ester hydrochloride and 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl) were ground without any special precaution in the presence of NaHCO 3 (Table , entry 1).…”

Capturing the Essence of Organic Synthesis: From Bioactive Natural Products to Designed Molecules in Today’s Medicine

“…This was converted to 71 and then to cryptophycin B (6) and arenastatin A (7). 14 We have also accomplished the synthesis of cryptophycin 52 (17, LY355703) utilizing an asymmetric nonaldol process for anti-aldol variants developed in our laboratory. 24 As shown in Figure 12, both stereogenic centers of the key epoxyoctenamide fragment in 17 were introduced by a diastereoselective alkylation of optically active 5-phenyl-γ-butyrolactone 72, prepared utilizing CBS-reduction as the key step.…”

“…Natural products display an incredible range of structural diversity and often possess intriguing biological properties. , In fact, many of today’s approved drugs are either natural product-derived or have been developed on the basis of natural product lead structures. , One of our main research objectives is to carry out the synthesis of rare and scarce natural products of biological relevance and then investigate their mode of action to obtain insight. Since our first synthesis of hapalosin ( 1 ) in 1996, my laboratory has carried out the synthesis of a range of medicinally important and structurally diverse natural products shown in Figures and . − …”

“…LAH reduction of 69 gave the corresponding alcohol, which was converted to methyl derivative 70 in a one-pot, two-step sequence involving tosylation with PhLi and p -TsCl followed by LAH reduction to provide 70 in 88% overall yield. This was converted to 71 and then to cryptophycin B ( 6 ) and arenastatin A ( 7 ) …”

Titanium Enolate Chemistry at the Beginning of the 21st Century

“…A titanium(IV) enolate of a (1 S ,2 R )‐arylsulfonamido‐2‐indanyl ester was applied in a total synthesis of microbial agent AI‐77‐B in which addition to monodentate trichlorobutyraldehyde led to the expected anti aldol 41. On the other hand, a bidentate 3‐(benzyloxy)propionaldehyde was applied in a highly stereoselective preparation of the desired syn aldol from a (1 R ,2 S )‐arylsulfonamido‐2‐indanyl ester in multi‐step syntheses of antitumor macrolides cryptophycin B and arenastatin A 42…”