Total Synthesis of (−)‐Spirotryprostatin B

Abstract

Spirotryprostatin A (1) and B (2), two powerfully bioactive indole alkaloids, were isolated in 1996 by Osada et al. from the fermentation broth of Aspergillus fumigatus BM939. [1] Only miniscule amounts of 1 and 2 (11 and 1 mg, respectively) were isolated from 400 L of fermentation medium. Both compounds inhibit the cell cycle in the G2/M phase, and 2 shows cytotoxic activity on the growth of human leukemia cell lines. In this communication, we report a novel strategy towards the synthesis of spirotryprostatin B that is characterized by the MgI 2 -catalyzed annulation reaction of a spiro[oxindole-3,1'-vinylcyclopropane] and an alkynyl imine. It is notable that in the context of our investigations we have developed the functionalization of an advanced aldehyde intermediate which enables the generation of biologically active congeners. The synthetic chemistry of the spirotryprostatins has recently been the subject of intense investigations by several groups. The various creative, distinct strategies have been devised to provide access to the spiro[oxindole-3,3'-pyrrolidine] core. [2±6] We have recently developed a novel approach to spiro[oxindole-3,3'-pyrrolidines] by the MgI 2 -catalyzed ringexpansion reaction of spiro[cyclopropane-1,3'-oxindoles] and aldimines. [7] The methodological studies we have carried out to date have left unaddressed a pertinent issue, which impacts the general applicability of the method to provide access to a wide range of related alkaloids. In particular, in none of the earlier studies had we or others examined the use of 1,2disubstituted cyclopropanes, which would give access to 2,5substituted pyrrolidines. [8] At the outset, there were two key questions we wished to address: the use of vinyl cyclopropane 3 in the ring-expansion reaction to yield 7 and the relative stereochemical outcome of the annulation. With respect to the former, it was not at all clear whether the intermediate allylic iodide/enolate 5 would be stable, as it could collapse by intramolecular cyclization to form a dihydrofuroindole 6 (Scheme 1). [9] An additional problem we wished to explore was whether an aldehyde at C18 (spirotryprostatin B numbering) would serve as a useful precursor to the requisite prenyl side chain through an olefination reaction. Because earlier work in this area had concluded that olefination of a related aldehyde was unfeasible, revisting this strategic challenge was not without risk.Our synthesis commenced with known diazoketone 8, accessible in two steps and 79 % yield from isatin (Scheme 2). [10] Rhodium-catalyzed cyclopropanation of [*] Prof.

The Three‐Component Reaction between Isatin, α‐Amino Acids, and Dipolarophiles

“…The pyrrolidino-2-spiro-3Ј-oxindole ring system can be found in several pharmacologically active alkaloids, such as horsfiline (1) [1] and spirotryprostatin B (2) [2,3] (Figure 1). Various strategies have been used to obtain these spiro compounds, such as oxidative rearrangement of β-carbolines and 1,3-dipolar addition.…”

Diastereoselective Synthesis of β‐Lactam–Oxindole Hybrids Through a Three‐Component Reaction of Azetidine‐2,3‐diones, α‐Diazo‐oxindoles, and Alcohols Catalyzed by [Rh2(OAc)4]

“…Enantiopure azetidine-2,3-diones (+)-1a and (-)-1b were obtained as single cis-enantiomers from imines of (R)-2,3-O-isopropylideneglyceraldehyde, through Staudinger reaction with acetoxyacetyl chloride in the presence of Et 3 N, followed by sequential transesterification and Swern oxidation, as previously reported. [14] Figure 2. [13] Diazo-isatin 2c was synthesized by N-acylation of compound 2a with p-nitrobenzoyl chloride, [14] and N-methyl diazocarbonyl compounds 2b and 2d-f were prepared from the corresponding NH-isatin through N-alkylation under standard conditions (MeI, NaH, in DMF) followed by diazotization using a modification of Carreira's procedure ( Figure 2).…”

Design and synthesis of spiro derivatives containing a thiophene ring and evaluation of their Anti-microbial activity

“…11 1,3-dipolar cycloaddition reactions of azomethineylides has been well developed, and also the reactions proceed with high regio-and stereoselectivity 12,13 . Thiophene and its derivatives are the significant class of heterocyclic compounds possessing broad biological activities, such as antiinflammatory 14 , analgesic 14 , antioxidant 15 , antitubercular, 16 antidepressant, 17 sedative, 18 antiamoebic, 19 oral analgesic, 20 anti-metabolite, 21 and antineoplastic properties. 22 For a extended analysis of the regiochemistry in 1,3-dipolar cycloaddition reaction and also the bioactivity of spiro [pyrrolidine-2,3'-oxindoline] compounds, three varieties of trapping agents like dipolarophiles, diketone, -amino acid, were introduced during this reaction to synthesis a series of spiro [pyrrolidine-2,3'-oxindole] derivatives, with that the bioactivity on anti-microbial activity was evaluated.…”