SYNTHETIC STUDIES ON TULEARIN MACROLIDES

In this communication we present our initial synthetic studies to the natural product tulearin A. The total synthesis relies on the assembly of two chiral building blocks through regioselective nucleophilic epoxide opening and macrolactonization for the construction of 18-membered lactone skeleton. In this initial contribution we report the partial synthesis of the fragment C1-C7 containing three stereogenic centers where the key step is an asymmetric aldol condensation.


Scheme 1. Retrosynthetic analysis for Tulearins.
The fragment A (C 13 -C 26 ) possessing two stereogenic centers and a E,E-diene was envisaged by palladium-catalyzed cross-coupling reaction using the alkenylindium organometallic 1 and vinyl iodide 2 (Scheme 2). 5 The enantioselective synthesis vinyl iodide 2 was devised using commercial (R)-methyl glutarate as chiral building block. The versatility of the strategy should allow the synthesis of the four possible stereoisomers. To construct the fragment B (C 1 -C 10 ) with five stereogenic centers we planned an asymmetric aldol reaction starting from available (S)-citronellal using a chiral oxazolidinone for generation of the stereocenters at C 2 and C 3 (Scheme 3). A stereoselective olefination followed by reduction should lead the allylic alcohol 5. Finally, the stereocenters at C 8 and C 9 of fragment B would come from an asymmetric epoxidation followed by a Payne rearrangement starting from allylic acohol 5.

■ RESULTS AND DISCUSSION
The synthesis of fragment B began with an asymmetric aldol reaction using the readily available (S)-citronellal and N-acyloxazolidinone. Initially, we explored the reactivity of different oxazolidinones with (S)-citrollenal (8) to obtain the anti-aldol product 7b. Unfortunately, under several reactions conditions the anti-aldol product 7b was obtained only in very low yields (entries 1-3, table 1) and isopulegone (byproduct from a acid-catalyzed rearrangement) was obtained as major reaction product. For this reason we decided to optimize the synthesis of 7a-syn to later convert it into 7b-anti. In this research, the reaction of chiral oxazolidinone furnished with a benzyl group with 8 using TiCl 4 , ()sparteine and N-methylpyrrolidine (table 1, entry 7) afforded the syn-aldol product 7a in 97% yield as the only diastereoisomer detected by 1 H NMR (97% yield, dr = 95:5). 6 Table 1. Synthesis of compound 7 by asymmetric aldol reaction.
According to our synthetic plan, the reduction of oxazolidinone moiety with NaH and protection of primary alcohol as TBSether gave 10 in good yield (97%, two steps). The inversion of configuration under Mitsunobu conditition's using of DIAD, PH 3 P and 4-NBA in THF at room temperature provided 11 in 76% yield. After hydrolysis with NaOH, the p-nitrobenzoate ester 11 was converted to alcohol 12 (57% yield). Protection of 12 as TBSether (13) and reductive ozonolysis gave alcohol 14 in 66% overall yield. Then, careful oxidation of alcohol 14 by using IBX in DMSO led the aldehyde 15 in good yield. Finally, the stereoselective olefination of 15 under Still-Gennari conditions (NaH in THF at 10 ºC followed by addition of CF 3 CH 2 O) 2 P(O)CO 2 Et) provided -unsaturated ester 16 in 62% as a separable mixture of olefins (Z/E 87:13). In this way the C1-C7 piece of tulearin containing three stereogenic centers of tulearin was synthetized. Now, for the synthesis of fragment B only remains: (i) reduction of -unsaturated ester (ii) asymmetric epoxidation followed by Payne rearrangement to generate the chiral centers at C 8 and C 9 (iii) protection of secundary alcohol (iv) deprotection of primary alcohol followed by oxidation and esterification to the corresponding ester.

■ EXPERIMENTAL PROCEDURE
Synthesis of 7a-syn. A solution of the N-acyloxazolidinone (1.0 g, 4.29 mmol) in 30 mL of CH 2 Cl 2 was cooled to 0ºC. TiCl 4 (4.5 mL, 4.5 mmol) was added, and the mixture was stirred for 5 minutes. ()-Sparteine (0.98 mL, 4.28 mmol) was added dropwise slowly. After complete addition, the mixture was stirred at 0 ºC for 20 minutes. The mixture was cooled to 78ºC and N-methyl-2-pyrrolidinone (0.42 mL, 4.28 mmol) was added. The mixture was stirred for 10 minutes followed by addition of (S)-citronellal (0.85 mL, 4.71 mmol) in 5 mL of CH 2 Cl 2 dropwise. The mixture was stirred 1h at 78ºC, gradually warmed to 0ºC, and stirred for 1h. The reaction was quenched with half-saturated NH 4 Cl and warmed to 25ºC. The layers were separated, and the aqueous layer was extracted twice with CH 2 Cl 2 . The combined extracts were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuum. Purification by flash chromatography (1:1 Hexanes/Et 2 O) afforded, after concentration and high-vacuum drying, 1.60 g (97%) of 7a-syn product. 1

Synthesis of 16.
A suspension of HNa (43 mg, 1.03 mmol) in 5 mL of dry THF was cooled to 10ºC. A solution of (CF 3 CH 2 O) 2 P(O)CO 2 Et (330 L, 1.0 mmol) was added dropwise and the mixture was stirred for 30 minutes at the same temperature. Aldehyde 15 (36 mg, 0.86 mmol) in 2 mL of THF was added dropwise and the reaction was warmed to 25ºC slowly. The reaction was quenched with saturated NH 4 Cl. The layers were separated and the aqueous layer was extracted twice with CH 2 Cl 2 (20 mL). The combined extracts were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuum. Purification by flash chromatography (Hexanes) afforded, after concentration and high-vacuum drying, 260 mg (62%) of 16.