The spiro[pyrrolidine‐3,3′‐oxindole] ring system is found at the core of a number of alkaloids, which possess significant biological activity and are interesting, challenging targets for chemical synthesis. In the present review, we report on the different strategies for the synthesis of the spiro[pyrrolidine‐3,3′‐oxindole] ring system in the context of recent synthesis of coerulescine, horsfiline, elacomine, salacin, pteropodine, alstonisine, spirotryprostatin A and B, and strychnofoline. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The total synthesis of spirotryprostatin B, a cytostatic spiro[pyrrolidine-3,3'-oxindole] alkaloid, is described. The key step of the synthetic approach consists of the application of the MgI2-mediated ring-expansion reaction of a spiro[cyclopropane-1,3'-oxindole] with an aldimine, leading to rapid assembly of the spirotryprostatin core. The route documents the installation of the prenyl side chain by Julia-Kocieński olefination of a key aldehyde precursor, a transformation that ultimately allows for facile synthesis of analogues and facilitates structure-activity relationships studies.

The aldol addition reaction has become a strategically important, reliable transformation that is widely employed in the asymmetric synthesis of complex molecules. It can be counted on not only to provide access to polyketide fragments with their characteristic 1,3‐oxygenation pattern, but also to numerous other classes of compounds, such as oxo‐heterocycles, alpha and beta‐amino acids, and nucleosides. Two general approaches have emerged for aldol reaction: (1) diastereoselective additions, wherein stoichiometric quantities of a covalently bound, chiral controlling element shepherds the stereochemical course of the reaction and, alternatively, (2) enantioselective methods wherein a chiral catalyst functions as the stereochemical controlling element. Diastereoselective methods remain dominant. Enantioselective methods are new on the scene. However, explosive development has led to complex molecule assembly via catalytic asymmetric aldol transformations. Such reactions are described here.

Preparation of Useful Reagents and Buffers LHMDS, 0.330 M in THFTo a solution of HMDS (1.00 mL, 4.73 mmol, 1.00 equiv), in THF (10 mL) at −78°C was added nBuLi (1.42 M in hexanes, 3.33 mL, 4.73 mmol, 1.00 equiv). The solution was allowed to stir at 0°C for 30 min.A solution of KOH (500 mg, 8.77 mmol, 3.90 equiv) in H 2 O (500 µL), was cooled to 0 °C and Et 2 O (5.6 mL) was added. To the biphasic mixture at 0 °C was added N-methyl-N'-nitro-N-nitrosoguanidine (≈ 50% in H 2 O, 329 mg, 2.24 mmol, 1.00 equiv) in small portions. The yellow organic solution was decanted and used immediately. BocProCl (45), 0.140 M in CH 2 Cl 2To a solution of DMF (103 µL, 1.38 mmol, 1.00 equiv) in CH 2 Cl 2 (10 mL) at 0 °C was added oxalyl chloride (121 µL, 1.38 mmol, 1.00 equiv). A white precipitate was formed.Pyridine (111 µL, 1.38 mmol, 1.00 equiv) was added dropwise to the reaction mixture; the precipitate dissolved and the solution turned yellow. N-Boc-L-proline (297 mg, 1.38 mmol, 1.00 equiv) was then added to the solution. The reaction mixture was stirred at 0 °C for 30 min; this solution of N-Boc-L-proline chloride (45) solution was used for the subsequent peptide coupling. R f = 0.73 (EtOAc) Dimethyl-dioxirane, ≈ 0.09 M in acetoneIn a 2 L 2-neck flask (1 exit connected to 100 mL 2-neck receiving flask with dry ice condenser), a solution of NaHCO 3 (29 g) in acetone (96 mL) and H 2 O (127 mL) was cooled to 5-10 °C (ice-bath). Oxone (60 g) was added in 5 portions; in-between, the reaction mixture was stirred for 3 min. 3 min after the last addition, the condenser was filled with dry ice/acetone and the receiving flask was cooled with a −78 °C cooling bath.The ice-bath was removed and the solution of DMDO in acetone distilled at reduced S5 pressure (80-100 Torr). About 60 mL of solution were obtained. The solution is dried (K 2 CO 3 ) and stored over activated molecular sieves (3 Å) at −4 °C. pH 3.6 buffer Solution of citric acid monohydrate (1.43 g) and Na 2 HPO 4 •12H 2 O (2.31 g) in H 2 O (98.5 mL). S6 3. Synthesis of (-)-Spirotryprostatin B O S O Me O 4-methyl-[1,3,2]dioxathiolane 2-oxide1,2-Propane diol (10.0 g, 131 mmol, 1.00 equiv) was dissolved in CH 2 Cl 2 (30 mL) and the solution was cooled to 0 °C. A solution of SOCl 2 (11.8 mL, 162 mmol, 1.24 equiv) in CH 2 Cl 2 (20 mL) was added via addition funnel over 1 h. The reaction mixture was then heated to reflux for 1 h and allowed to cool to room temperature. H 2 O (50 mL) was added to the reaction mixture, the layers were separated and the organic layer was washed with H 2 O (2 × 50 mL) and brine (30 mL), dried (Na 2 SO 4 ), filtered, then the solvent was evaporated in vacuo and a colorless liquid was obtained. The unpurified sulfite was used for the next step.

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