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Article

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

by
Bo Yin
,
Dong-Nai Ye
,
Kai-Hui Yu
and
Liang-Xian Liu
*
Department of Chemistry and Biology, Ganan Normal University, Ganzhou, Jiangxi 341000, China
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(4), 2771-2781; https://doi.org/10.3390/molecules15042771
Submission received: 18 December 2009 / Revised: 24 March 2010 / Accepted: 12 April 2010 / Published: 16 April 2010
(This article belongs to the Special Issue Asymmetric Synthesis)
Browse Figures
Versions Notes

Abstract

:
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.

1. Introduction

The (4,5)-dihydroxycarboxylate moiety is a critical framework shared by many bioactive compounds, such as Microcarpalide (1), which is a 10-membered lactone that was isolated from the fermentation broth of an unidentified endophytic fungus by Hemscheidt and co-workers in 2001 [1], and Kalanchosine dimalate (KMC, 2) [2], which is an anti-inflammatory salt from the fresh juice of the aerial parts of Kalanchoe brasiliensis, as well as natural gastroprotective 3,4-dihydroisocoumarins, such as amicoumacin C (3) [3,4] and AI-77B (4) [5,6]. Both the stereochemical variation at C-4, C-5 and the interesting biological activities exhibited by these compounds make them attractive synthetic targets [1,5,6,7]. A number of methods have been developed for the synthesis of these compounds [8,9,10,11,12,13], but few methods for the construction of the (4,5)-dihydroxycarboxylate moiety [14,15,16,17,18]. Generally, chiral pool starting materials or Sharpless asymmetric dihydroxylation was used in the construction of the (4,5)-dihydroxycarboxylate moiety.
Molecules 15 02771 g001 550
Figure 1. (4,5)-Dihydroxycarboxylate derivatives.
Figure 1. (4,5)-Dihydroxycarboxylate derivatives.
Molecules 15 02771 g001
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)-6-alkyl-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 BF3•OEt2 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].
Molecules 15 02771 sch001 550
Scheme 1. The synthesis of 6-alkyl-5-benzyloxy-2-piperidinones.
Scheme 1. The synthesis of 6-alkyl-5-benzyloxy-2-piperidinones.
Molecules 15 02771 sch001
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=CH2) 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).

2. Results and Discussion

The requisite 6-alkyl-5-benzyloxy-6-hydroxy-2-piperidinones 6, together with their ring-opened keto amide tautomers 7, were prepared via the addition of Grignard reagents to (S)-3-benzyloxy-glutarimide 5 under our recently improved conditions [23]. Treatment of the tautomeric mixture of 6a and 7a with 1.2 molar equiv of l-Selectride in THF (−20 °C - rt) yielded syn-10a and anti-10a in a ratio of 86:14 (combined yield: 93%). To explore the generality of the process, a series of hemi-azaketals 6 and their opened keto amide tautomers 7 were investigated using l-Selectride as reductive agent [26,27,28,29], and the results are reported in Table 1.
Molecules 15 02771 sch002 550
Scheme 2. The diastereoselective reduction by l-Selectride.
Scheme 2. The diastereoselective reduction by l-Selectride.
Molecules 15 02771 sch002
Table
Table 1. Results of reduction according to the procedure shown in Scheme 2.
Table 1. Results of reduction according to the procedure shown in Scheme 2.
EntryRYield [%] asyn/anti ratio
1CH3 (10a)936:1 b
2C2H5 (10b)977:1 c
3n-C4H9 (10c)977:1 c
4n-C5H11 (10d)9523:2 c
5n-C8H17 (10e)9823:2 b
6n-C12H25 (10f)859:1 b
7n-C16H33 (10g)837:1 b
8i-Bu (10h)923:1 c
9Ph (10i)813:1 b
10Bn (10j)9211:2 c
11PhCH2CH2 (10k)827:2 c
a Isolated yield of 10 starting from 6 and 7. b Ratio determined by 1H-NMR analysis. c Ratio based on HPLC analysis.
As can be seen from Table 1, high yields and modest to high syn-selectivities were obtained for all hemi-azaketals tested. It is interesting to note that modest syn-selectivities were obtained in the case where 6 and 7 bearing i-Bu or Ph (Table 1, entries 8 and 9) as well as PhCH2CH2 (Table 1, entry 11). The stereochemistry of the major diastereomer 10 was assigned to syn-conformer according to the observed vicinal coupling constants [24] (J4,5 = 5.1 Hz for syn-10a and J4,5 = 4.5 Hz for anti-10a; J4,5 = 5.2 Hz for syn-10b and J4,5 = 4.3 Hz for anti-10b; J4,5 = 5.1 Hz for syn-10c and J4,5 = 4.2 Hz for anti-10c; J4,5 = 5.1 Hz for syn-10e and J4,5 = 4.4 Hz for anti-10e; J4,5 = 5.1 Hz for syn-10g and J4,5 = 4.5 Hz for anti-10g; J4,5 = 6.1 Hz for syn-10i and J4,5 = 5.1 Hz for anti-10i). In addition, the stereochemistry of diastereomers syn-10 was confirmed by converting syn-10 to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidin-ones 8. For example, syn-10a can be converted to anti-8a in 78% yield by mesylation (MsCl, Et3N, CH2Cl2, −20 °C, 1 h) and t-BuOK-promoted cyclization (HMPA, THF, rt, 24 h) (Scheme 3).
Molecules 15 02771 sch003 550
Scheme 3. The synthesis of (5S,6R )-6-methyl-5-benzyloxy-2-piperidinones.
Scheme 3. The synthesis of (5S,6R )-6-methyl-5-benzyloxy-2-piperidinones.
Molecules 15 02771 sch003
Molecules 15 02771 g002 550
Figure 2. A plausible Cram chelation-controlled pathway for the syn-diastereoselective formation of syn-10.
Figure 2. A plausible Cram chelation-controlled pathway for the syn-diastereoselective formation of syn-10.
Molecules 15 02771 g002
The fact that starting from the tautomeric mixture of 6 and 7 syn-diastereomer 10 was obtained in modest to high diastereoselectivity is in accordance with a Cram model-based mechanism [30,31,32,33,34]. It was envisioned that the hydride to approach C-5 carbon from the same side of the chelate C-4 benzyloxy substituent led to the formation of syn-isomer because of the chelation between lithium ion and oxygen atom of the C-4 oxygen as well as C-5 carbonyl oxygen (Figure 2), which not only switches the equilibrium towards 7, but also allows the reduction to undergo with a Cram chelation-controlled manner.

3. 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.

4. Experimental

4.1. 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. 1H-NMR spectra were recorded in CDCl3 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 CH2Cl2 was distilled over P2O5 under N2.

4.2. 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 NH4Cl. After extraction with CH2Cl2, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)hexanoyl amide (syn-10a): White solid, mp: 74-75 °C; [α]25D: +4.75 (c 1.0, CHCl3); IR (film) νmax: 3407, 3305, 1649, 1513, 1248 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.33-7.25 (m, 5H, Ar-H), 7.15 (d, J = 8.6 Hz, 2H, Ar-H), 6.83 (d, J = 8.6 Hz, 2H, Ar-H), 5.60 (s, 1H, NH), 4.59 (d, J = 11.5 Hz, 1H, OCH2), 4.53 (d, J = 11.5 Hz, 1H, OCH2), 4.32 (dd, J = 14.5, 5.6 Hz, 1H, NCH2), 4.27 (dd, J = 14.5, 5.6 Hz, 1H, NCH2), 3.78 (s, 3H, OCH3), 3.70 (m, 1H, H-4), 3.35 (dd, J = 6.4, 5.1 Hz, 1H, H-5), 2.59 (d, J = 2.8 Hz, 1H, OH), 2.25 (t, J = 7.4 Hz, 2H, H-2), 2.04 (ddd, J = 14.0, 7.4, 4.9 Hz, 1H, H-6), 1.82 (ddd, J = 14.0, 7.4, 6.8 Hz, 1H, H-3), 1.17 (t, J = 6.4 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3): δ 172.4 (C=O), 158.9, 138.2, 130.3, 129.1 (2×C), 128.4 (2×C), 127.9 (2×C), 127.8, 114.0 (2×C), 82.1 (C-5), 71.9 (C-4), 68.6 (OCH2), 55.2 (OCH3), 43.0 (NCH2), 31.6, 25.6, 18.9; MS (ESI): 358 [M+H]+, 380 [M+Na]+; Anal calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found C, 70.31; H, 7.76; N, 4.25.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)heptanoyl amide (syn-10b): White solid, mp: 122-124 °C; [α]25D: +1.86 (c 1.2, CHCl3); IR (film) νmax: 3407, 3306, 1649, 1513, 1248 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.32-7.25 (m, 5H, Ar-H), 7.15 (d, J = 8.7 Hz, 2H, Ar-H), 6.83 (d, J = 8.7 Hz, 2H, Ar-H), 5.57 (s, 1H, NH), 4.59 (d, J = 11.5 Hz, 1H, OCH2), 4.53 (d, J = 11.5 Hz, 1H, OCH2), 4.32 (dd, J = 14.4, 5.5 Hz, 1H, NCH2), 4.28 (dd, J = 14.5, 5.5 Hz, 1H, NCH2), 3.78 (s, 3H, OCH3), 3.43 (m, 1H, H-4), 3.36 (ddd, J = 5.6, 5.6, 5.2 Hz, 1H, H-5), 2.42 (s, 1H, OH), 2.26 (t, J = 7.4 Hz, 2H, H-3), 2.03 (ddd, J = 13.8, 7.1, 5.2 Hz, 1H, H-2), 1.87 (ddd, J = 13.8, 7.5, 7.2 Hz, 1H, H-2), 1.55 (ddd, J = 13.8, 7.5, 4.1 Hz, 1H, H-6), 1.46 (ddd, J = 13.8, 7.2, 5.2 Hz, 1H, H-6), 0.95 (t, J = 7.5 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3): δ 172.4 (C=O), 158.9, 138.2, 130.4, 129.1 (2×C), 128.4 (2×C), 127.8 (2×C), 127.7, 114.0 (2×C), 80.8 (C-5), 74.0 (C-4), 72.5 (OCH2), 55.2 (OCH3), 43.0 (NCH2), 31.8, 26.2, 25.9, 10.2; MS (ESI): 371 [M+H]+, 394 [M+Na]+, 410 [M+K]+; Anal calcd for C22H29NO4: C, 71.13; H, 7.87; N, 3.77. Found C, 71.03; H, 7.55; N, 3.71.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)nonanoyl amide (syn-10c): Waxy solid; [α]25D: +1.90 (c 1.5, CHCl3); IR (film) νmax: 3407, 3305, 1650, 1513, 1248 cm-1; 1H-NMR (500 MHz, CDCl3): δ 7.35-7.25 (m, 5H, Ar-H), 7.16 (d, J = 8.7 Hz, 2H, Ar-H), 6.84 (d, J = 8.7 Hz, 2H, Ar-H), 5.55 (s, 1H, NH), 4.60 (d, J = 11.5 Hz, 1H, OCH2), 4.53 (d, J = 11.5 Hz, 1H, OCH2), 4.33 (dd, J = 14.4, 5.6 Hz, 1H, NCH2), 4.28 (dd, J = 14.4, 5.6 Hz, 1H, NCH2), 3.78 (s, 3H, OCH3), 3.52 (m, 1H, H-4), 3.36 (ddd, J = 6.2, 5.1, 5.1 Hz, 1H, H-5), 2.33 (s, 1H, OH), 2.26 (t, J = 7.4 Hz, 2H, H-2), 2.05 (ddd, J = 14.0, 7.4, 5.2 Hz, 1H, H-3), 1.87 (ddd, J = 14.0, 7.6, 7.4 Hz, 1H, H-3), 1.52-1.40 (m, 3H), 1.36-1.25 (m, 3H), 0.89 (t, J = 7.1 Hz, 3H, CH3); 13C-NMR (125 MHz, CDCl3): δ 172.4 (C=O), 159.0, 138.2, 130.3, 129.2 (2×C), 128.4 (2×C), 127.9 (2×C), 127.8, 114.0 (2×C), 81.1 (C-5), 72.6 (C-4), 72.5 (OCH2), 55.3 (OCH3), 43.1 (NCH2), 33.1, 31.8, 27.9, 23.9, 22.7, 14.0; MS (ESI): 400 [M+H]+, 422 [M+Na]+, 438 [M+K]+; Anal calcd for C24H33NO4: C, 72.15; H, 8.33; N, 3.51. Found C, 72.34; H, 8.36; N, 3.66.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)decanoyl amide (syn-10d): Waxy solid; [α]25D: ‑1.76 (c 2.3, CHCl3); IR (film) νmax: 3411, 3304, 2931, 1646, 1513, 1248 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.32-7.26 (m, 5H, Ar-H), 7.15 (d, J = 8.5 Hz, 2H, Ar-H), 6.82 (d, J = 8.5 Hz, 2H, Ar-H), 5.85 (s, 1H, NH), 4.59 (d, J = 11.5 Hz, 1H, OCH2), 4.52 (d, J = 11.5 Hz, 1H, OCH2), 4.32 (dd, J = 14.5, 5.6 Hz, 1H, NCH2), 4.28 (dd, J = 14.5, 5.6 Hz, 1H, NCH2), 3.78 (s, 3H, OCH3), 3.52 (m, 1H, H-4), 3.34 (ddd, J = 5.4, 5.4, 5.2 Hz, 1H, H-5), 2.38 (d, J = 4.3 Hz, 1H, OH), 2.25 (t, J = 7.3 Hz, 2H, H-2), 2.04 (ddd, J = 14.0, 7.7, 7.3 Hz, 1H, H-3), 1.87 (ddd, J = 14.0, 7.3, 7.1 Hz, 1H, H-3), 1.50-1.40 (m, 3H), 1.35-1.20 (m, 5H), 0.88 (t, J = 6.8 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3): δ 172.4 (C=O), 159.0, 138.2, 130.4, 129.1 (2×C), 128.4 (2×C), 127.9 (2×C), 127.8, 114.0 (2×C), 81.1 (C-5), 72.6 (C-4), 72.5 (OCH2), 55.2 (OCH3), 43.0 (NCH2), 33.3, 31.8, 26.0, 25.4 (2×C), 22.6, 14.0; MS (ESI): 414 [M+H]+, 436 [M+Na]+; Anal calcd for C25H35NO4: C, 72.61; H, 8.53; N, 3.39. Found C, 72.33; H, 8.52; N, 3.42.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)tridecanoyl amide (syn-10e): Waxy solid; [α]25D: ‑2.21 (c 2.3, CHCl3); IR (film) νmax: 3406, 3304, 2926, 2854, 1646, 1513, 1249 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.34-7.25 (m, 5H, Ar-H), 7.15 (m, 2H, Ar-H), 6.84 (m, 2H, Ar-H), 5.75 (s, 1H, NH), 4.60 (d, J = 11.5 Hz, 1H, OCH2), 4.53 (d, J = 11.5 Hz, 1H, OCH2), 4.33 (dd, J = 14.4, 5.6 Hz, 1H, NCH2), 4.29 (dd, J = 14.4, 5.6 Hz, 1H, NCH2), 3.78 (s, 3H, OCH3), 3.51 (m, 1H, H-4), 3.36 (ddd, J = 5.6, 5.6, 5.1 Hz, 1H, H-5), 2.32-2.23 (m, 2H), 2.26 (s, 1H, OH), 2.05 (m, 1H), 1.88 (ddd, J = 14.2, 6.7, 6.7 Hz, 1H), 1.52-1.40 (m, 3H), 1.34-1.20 (m, 11H), 0.88 (t, J = 6.9 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3): δ 172.4 (C=O), 159.0, 138.3, 130.4, 129.2 (2×C), 128.4 (2×C), 127.9 (2×C), 127.8, 114.0 (2×C), 81.2 (C-5), 72.7 (C-4), 72.6 (OCH2), 55.3 (OCH3), 43.1 (NCH2), 33.4, 31.8 (2×C), 29.7, 29.5, 29.3, 26.0, 25.8, 22.6, 14.1; MS (ESI): 456 [M+H]+; Anal calcd for C28H41NO4: C, 73.85; H, 9.01; N, 3.08. Found C, 73.59; H, 8.98; N, 3.06.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)heptadecanoyl amide (syn-10f): White solid, mp: 68-70 °C; [α]25D: -2.63 (c 1.1, CHCl3); IR (film) νmax: 3423, 3305, 2924, 2853, 1643, 1513, 1248 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.35-7.23 (m, 5H, Ar-H), 7.16 (d, J = 8.2 Hz, 2H, Ar-H), 6.85 (d, J = 8.2 Hz, 2H, Ar-H), 5.70 (s, 1H, NH), 4.61 (d, J = 11.5 Hz, 1H, OCH2), 4.54 (d, J = 11.5 Hz, 1H, OCH2), 4.34 (dd, J = 14.5, 5.5 Hz, 1H, NCH2), 4.30 (dd, J = 14.5, 5.5 Hz, 1H, NCH2), 3.79 (s, 3H, OCH3), 3.52 (m, 1H, H-4), 3.36 (ddd, J = 5.3, 5.3, 5.1 Hz, 1H, H-5), 2.30-2.23 (m, 2H), 2.26 (s, 1H, OH), 2.05 (ddd, J = 14.0, 7.3, 7.3 Hz, 1H, H-2), 1.88 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H, H-2), 1.52-1.40 (m, 3H), 1.35-1.20 (m, 19H), 0.88 (t, J = 6.6 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3): δ 172.4 (C=O), 159.1, 138.3, 130.4, 129.2 (2×C), 128.5 (2×C), 127.9 (2×C), 127.8, 114.1 (2×C), 81.2 (C-5), 72.7 (C-4), 72.6 (OCH2), 55.3 (OCH3), 43.1 (NCH2), 33.5, 31.9, 31.8, 29.7 (6×C), 29.4, 26.0, 25.8, 22.7, 14.1; MS (ESI): 512 [M+H]+, 534 [M+Na]+; Anal calcd for C32H49NO4: C, 75.11; H, 9.65; N, 2.74. Found C, 75.39; H, 9.91; N, 2.86.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)heneicosanoyl amide (syn-10g): White solid, mp: 62-64 °C; [α]25D: -1.93 (c 1.1, CHCl3); IR (film) νmax: 3419, 3302, 2923, 2852, 1655, 1513, 1249 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.33-7.27 (m, 5H, Ar-H), 7.17 (d, J = 8.6 Hz, 2H, Ar-H), 6.85 (d, J = 8.6 Hz, 2H, Ar-H), 5.65 (s, 1H, NH), 4.60 (d, J = 11.5 Hz, 1H, OCH2), 4.54 (d, J = 11.5 Hz, 1H, OCH2), 4.33 (dd, J = 14.4, 5.5 Hz, 1H, NCH2), 4.30 (dd, J = 14.4, 5.5 Hz, 1H, NCH2), 3.80 (s, 3H, OCH3), 3.52 (m, 1H, H-4), 3.35 (m, 1H, H-5), 2.30-2.22 (br s, 1H, OH), 2.26 (t, J = 7.4 Hz, 2H, H-2), 2.05 (ddd, J = 14.1, 7.4, 7.4 Hz, 1H, H-3), 1.88 (ddd, J = 14.1, 7.4, 6.8 Hz, 1H, H-3), 1.52-1.40 (m, 3H), 1.35-1.20 (m, 27H), 0.88 (t, J = 6.8 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3): δ 172.4 (C=O), 159.1, 138.3, 130.4, 129.2 (2×C), 128.5 (2×C), 127.9 (2×C), 127.8, 114.1 (2×C), 81.2 (C-5), 72.8 (C-4), 72.6 (OCH2), 55.3 (OCH3), 43.1 (NCH2), 33.5, 31.9, 31.8, 29.7 (8×C), 29.6 (2×C), 29.4, 26.0, 25.8, 22.7, 14.1; MS (ESI): 568 [M+H]+; Anal calcd for C36H57NO4: C, 76.15; H, 10.12; N, 2.47. Found C, 76.51; H, 9.74; N, 2.46.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-7-methyloctanoyl amide (syn-10h): Waxy solid; [α]25D: -7.34 (c 2.9, CHCl3); IR (film) νmax: 3410, 3303, 1644, 1513, 1248 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.35-7.23 (m, 5H, Ar-H), 7.15 (d, J = 8.5 Hz, 2H, Ar-H), 6.85 (d, J = 8.5 Hz, 2H, Ar-H), 5.85 (s, 1H, NH), 4.59 (d, J = 11.5 Hz, 1H, OCH2), 4.53 (d, J = 11.5 Hz, 1H, OCH2), 4.33 (dd, J = 14.4, 5.8 Hz, 1H, NCH2), 4.27 (dd, J = 14.4, 5.8 Hz, 1H, NCH2), 3.78 (s, 3H, OCH3), 3.65-3.57 (m, 1H, H-4), 3.32 (m, 1H, H-5), 2.37 (d, J = 4.9 Hz, 1H, OH), 2.25 (t, J = 7.2 Hz, 2H, H-2), 2.08-1.98 (m, 1H), 1.93-1.75 (m, 2H), 1.48-1.38 (m, 1H), 1.27-1.18 (m, 1H), 0.92 (d, J = 6.7 Hz, 3H, CH3), 0.88 (d, J = 6.7 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3): δ 172.4 (C=O), 158.9, 138.2, 130.3, 129.1 (2×C), 128.4 (2×C), 127.9 (2×C), 127.8, 114.0 (2×C), 81.6 (C-5), 72.6 (C-4), 70.6 (OCH2), 55.2 (OCH3), 43.0 (NCH2), 42.3, 31.8, 25.9, 24.5, 23.6, 21.7; MS (ESI): 400 [M+H]+, 422 [M+Na]+, 438 [M+K]+; Anal calcd for C24H33NO4: C, 72.15; H, 8.33; N, 3.51. Found C, 72.19; H, 8.16; N, 3.29.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-5-phenylpentanoyl amide (syn-10i): White solid, mp: 45-47 °C; [α]25D: +14.09 (c 2.7, CHCl3); IR (film) νmax: 3411, 3307, 1655, 1512, 1249 cm-1; 1H- NMR (400 MHz, CDCl3): δ 7.36-7.23 (m, 10H, Ar-H), 7.15 (d, J = 8.6 Hz, 2H, Ar-H), 6.86 (d, J = 8.6 Hz, 2H, Ar-H), 5.52 (s, 1H, NH), 4.83 (d, J = 6.1 Hz, 1H, H-5), 4.51 (d, J = 11.5 Hz, 1H, OCH2), 4.46 (d, J = 11.5 Hz, 1H, OCH2), 4.28 (dd, J = 14.4, 5.6 Hz, 1H, NCH2), 4.22 (dd, J = 14.4, 5.6 Hz, 1H, NCH2), 3.77 (s, 3H, OCH3), 3.63 (ddd, J = 6.3, 6.1, 5.2 Hz, 1H, H-4), 3.06 (d, J = 4.0 Hz, 1H, OH), 2.13 (t, J = 7.6 Hz, 2H, H-2), 1.90 (m, 1H, H-3), 1.78 (m, 1H, H-3); 13C-NMR (100 MHz, CDCl3): δ 172.3 (C=O), 159.0, 141.1, 138.0, 130.4, 129.2 (2×C), 128.5 (2×C), 128.3 (2×C), 128.1 (2×C), 127.9 (2×C), 126.8 (2×C), 114.1 (2×C), 82.6 (C-5), 75.8 (C-4), 72.0 (OCH2), 55.3 (OCH3), 43.1 (NCH2), 32.0, 26.5; MS (ESI): 420 [M+H]+, 442 [M+Na]+, 458 [M+K]+; Anal calcd for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found C, 74.49; H, 6.82; N, 3.59.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-6-phenylhexanoyl amide (syn-10j): Waxy solid; [α]25D: +2.01 (c 2.6, CHCl3); IR (film) νmax: 3403, 3305, 1644, 1513, 1248, 1030 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.35-7.23 (m, 8H, Ar-H), 7.17-7.12 (m, 4H, Ar-H), 6.83 (d, J = 8.7 Hz, 2H, Ar-H), 5.55 (s, 1H, NH), 4.61 (d, J = 11.5 Hz, 1H, OCH2), 4.54 (d, J = 11.5 Hz, 1H, OCH2), 4.30 (dd, J = 14.5, 5.6 Hz, 1H, NCH2), 4.25 (dd, J = 14.5, 5.6 Hz, 1H, NCH2), 3.82-3.75 (m, 1H, H-4), 3.75 (s, 3H, OCH3), 3.39 (ddd, J = 5.8, 5.8, 5.1 Hz, 1H, H-5), 2.85 (dd, J = 13.8, 4.8 Hz, 1H, H-6), 2.75 (dd, J = 13.8, 8.3 Hz, 1H, H-6), 2.45 (d, J = 5.8 Hz, 1H, OH), 2.23 (t, J = 7.3 Hz, 2H, H-2), 2.07 (ddd, J = 14.0, 7.3, 5.6 Hz, 1H, H-3), 1.93 (ddd, J = 14.0, 7.3, 7.0 Hz, 1H, H-3); 13C-NMR (100 MHz, CDCl3): δ 172.4 (C=O), 158.9, 138.6, 138.2, 130.3, 129.3 (2×C), 129.1 (2×C), 128.4 (4×C), 128.0 (2×C), 127.8, 126.3, 114.0 (2×C), 79.8 (C-5), 73.6 (C-4), 72.2 (OCH2), 55.2 (OCH3), 43.0 (NCH2), 39.7, 31.9, 25.7; MS (ESI): 434 [M+H]+, 456 [M+Na]+, 472 [M+K]+; Anal calcd for C27H31NO4: C, 74.80; H, 7.21; N, 3.23. Found C, 74.83; H, 7.55; N, 3.28.
(4S,5S)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-7-phenylheptanoyl amide (syn-10k): Waxy solid. [α]25D: -7.35 (c 1.9, CHCl3); IR (film) νmax: 3411, 3306 2932, 1645, 1513, 1248, 1030 cm-1; 1H-NMR (400 MHz, CDCl3): δ 7.40-7.20 (m, 10H, Ar-H), ,7.15 (d, J = 8.6 Hz, 2H, Ar-H), 6.85 (d, J = 8.6 Hz, ;2H, Ar-H), 5.63 (s, 1H, NH), 4.50 (d, J = 11.5 Hz, 1H, OCH2), 4.47 (d, J = 11.5 Hz, 1H, OCH2), 4.33 (dd, J = 14.5, 5.6 Hz, 1H, NCH2), 4.25 (dd, J = 14.5, 5.6 Hz, 1H, NCH2), 3.78 (s, 3H, OCH3), 3.71 (m, 1H, H-4), 3.37 (m, 1H, H-5), 2.90 (m, 2H), 2.67 (ddd, J = 13.8, 9.5, 7.0 Hz, 1H, H-3), 2.38 (d, J = 7.6 Hz, 2H, H-2), 2.52 (d, J = 5.6 Hz, 1H, OH), 2.08 (ddd, J = 13.8, 7.6, 5.2 Hz, 1H, H-3), 1.93-1.78 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ 172.9 (C=O), 159.0, 142.1, 138.0, 130.2, 129.4, 129.2 (2×C), 128.5, 128.1 (4×C), 128.0 (2×C), 127.8, 125.5, 114.0 (2×C), 81.2 (C-5), 72.5 (C-4), 70.3 (OCH2), 55.1 (OCH3), 43.1 (NCH2), 34.9, 32.1, 31.7, 23.3; MS (ESI): 448 [M+H]+, 470 [M+Na]+; Anal calcd for C28H33NO4: C, 75.14; H, 7.43; N, 3.13. Found C, 75.23; H, 7.75; N, 3.39.

4.3. 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 Et3N (0.14 mL, 1.00 mmol) in CH2Cl2 (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 CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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 NH4Cl at 0 °C. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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].

Acknowledgements

The authors are grateful to the NSF of China (No: 20772099) and Natural Science Foundation of Jiangxi Province (No: 2009GZH0013) for financial support.

References and Notes

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Sample Availability: Samples of the compounds 10a-10k are available from the authors.

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Yin, B.; Ye, D.-N.; Yu, K.-H.; Liu, L.-X. A General and Simple Diastereoselective Reduction by L-Selectride: Efficient Synthesis of Protected (4S,5S)-Dihydroxy Amides. Molecules 2010, 15, 2771-2781. https://doi.org/10.3390/molecules15042771

AMA Style

Yin B, Ye D-N, Yu K-H, Liu L-X. A General and Simple Diastereoselective Reduction by L-Selectride: Efficient Synthesis of Protected (4S,5S)-Dihydroxy Amides. Molecules. 2010; 15(4):2771-2781. https://doi.org/10.3390/molecules15042771

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Yin, Bo, Dong-Nai Ye, Kai-Hui Yu, and Liang-Xian Liu. 2010. "A General and Simple Diastereoselective Reduction by L-Selectride: Efficient Synthesis of Protected (4S,5S)-Dihydroxy Amides" Molecules 15, no. 4: 2771-2781. https://doi.org/10.3390/molecules15042771

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