A General and Simple Diastereoselective Reduction by l-Selectride: Efficient Synthesis of Protected (4S,5S)-Dihydroxy Amides

A general approach to (4S,5S)-4-benzyloxy-5-hydroxy-N-(4-methoxybenzyl) amides 10 based on a diastereoselective reduction of (5S,6RS)-6-alkyl-5-benzyloxy-6-hydroxy-2-piperidinones 6 and their tautomeric ring-opened keto amides 7 is described. The reduction with l-Selectride at -20 °C to room temperature afforded the products 10 in excellent yields and moderate to high syn-diastereoselectivities.


OPEN ACCESS
Generally, chiral pool starting materials or Sharpless asymmetric dihydroxylation was used in the construction of the (4,5)-dihydroxycarboxylate moiety.  Previously, we have shown that the protected (S)-3-hydroxyglutarimide 5 may serve as a versatile building block for the asymmetric synthesis of a variety of 2,6-disubstituted 3-hydroxypiperidines [19][20][21][22][23]. A flexible regio-and diastereoselective reductive alkylation method was developed for the conversion of 5 to trans-6-alkyl-5-benzyloxy-2-piperidinone derivatives 8 [20]. Recently, we also developed a chemo-and diastereoselective transformation of the N,O-acetals 6 and their chain tautomers 7, readily derived from protected 3-hydroxyglutarimide 5, into cyclic products (5S,6S/R)-6alkyl-5-benzyloxy-2-piperidinones 9/8, and anti-10/syn-10 with a combination of boron trifluoride etherate/zinc borohydride in modest chemo-and diastereoselectivities (Scheme 1) [24]. Moreover, the reduction with zinc borohydride in the absence of BF 3 •OEt 2 leading exclusively to the formation of the ring-opening products anti-10 in excellent anti-diastereoselectivities was exploited. In addition, we reported the application of this new variation to the asymmetric synthesis of (+)-azimic acid [25]. In the continuation of our interest in the amino acid chiral template-assisted synthesis of natural and unnatural bioactive compounds, as a part of our research program aimed at developing enantioselective syntheses of naturally occurring bioactive compounds, such as Microcarpalide (1), we decided to explore the construction of the (4,5)-dihydroxycarboxylate moiety in order to develop a simple and feasible approach to syn-10, a key intermediate (R = CH=CH 2 ) for the synthesis of 1. Herein we report a diastereoselective reduction of 6 and 7 employing L-Selectride as the reductive agent to obtain syn-10 (Scheme 2).

Conclusions
In summary, a simple and efficient route to protected (4S,5S)-dihydroxy amides via the reduction of the tautomeric mixture of 6 and 7 with L-Selectride has been developed. This strategy offers a concise platform for the construction of (4S,5S)-dihydroxycarboxylate moieties under mild conditions. As such, this method is complementary, in part, to our previously established anti-diastereoselective method.

General methods
Melting points were determined on a Yanaco MP-500 micro melting point apparatus and are uncorrected. Infrared spectra were measured with a Nicolet Avatar 360 FT-IR spectrometer using film KBr pellet technique. 1 H-NMR spectra were recorded in CDCl 3 on a Bruker 400 or a Varian unity +500 spectrometer with tetramethylsilane as an internal standard. Chemical shifts are expressed in δ (ppm) units downfield from TMS. Mass spectra were recorded with Bruker Dalton Esquire 3000 plus LC-MS apparatus. Optical rotations were measured with a Perkin-Elmer 341 automatic polarimeter. Elemental analysis was carried out on a Perkin-Elmer 240B instrument. Flash column chromatography was carried out with silica gel (300-400 mesh). THF was distilled over sodium and CH 2 Cl 2 was distilled over P 2 O 5 under N 2 .

General procedure for preparation of syn-10
To a cooled (−20 °C) solution of tautomeric mixture 6/7 [20] (1.0 mol equiv) in THF (0.1 M) was added dropwise a solution of L-Selectride (1.2 mol equiv) under argon atmosphere and the mixture was stirred at −20 ~ −10 °C for 1 h. Then, the mixture was allowed to slowly warm to room temperature and was stirred at room temperature overnight. The reaction was quenched with a saturated aqueous NH 4 Cl. After extraction with CH 2 Cl 2 , the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/Petroleum ether = 1:2), some pure syn-10 and the mixture of syn-10 and anti-10 were obtained.

The synthesis of (5S,6R)-2-Piperidinone 8a via the cyclization of 10a
To a cooled (−20 °C) solution of a mixture of 10a (182 mg, 0.51 mmol) and Et 3 N (0.14 mL, 1.00 mmol) in CH 2 Cl 2 (5 mL) was added dropwise MsCl (0.047 mL, 0.61 mmol) under a nitrogen atmosphere. The mixture was stirred at −20 ~ −10 °C for 1 h. Water was added and the aqueous layer was separated and extracted with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/P.E. = 1:2) to yield the mesylate 11 (202 mg), which is unstable and was used immediately in the next step. To a solution of mesylate 11 (202 mg, 0.43 mmol) in THF (3 mL) and HMPA (0.15 mL, 0.86 mmol) was added dropwise a solution of potassium tert-butoxide (58 mg, 0.52 mmol) in THF (2 mL) at 0 °C under nitrogen atmosphere. The mixture was allowed slowly warming to room temperature and was stirred for 24 h. The reaction was quenched with saturated NH 4 Cl at 0 °C. The aqueous layer was separated and extracted with CH 2 Cl 2 . The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent EtOAc/P.E. = 1:2) to yield (5S,6R)-8a (135 mg, 78% yield). For the data of (5S,6R)-8a see [20].