A new approach to cyclic hydroxamic acids: Intramolecular cyclization of N-benzyloxy carbamates with carbon nucleophiles

Abstract

N-Alkyl-N-benzyloxy carbamates, 2, undergo facile intramolecular cyclization with a variety of carbon nucleophiles to give functionalized 5- and 6-membered protected cyclic hydroxamic acids, 3, in good to excellent yields. This method can be extended to prepare seven-membered cyclic hydroxamic acids in moderate yields. The sulfone intermediates 3 from this study can be alkylated while the corresponding phosphonates have been shown to undergo HWE reaction. The α,β-unsaturated synthon, 8, prepared by thermal elimination of sulfoxide 3m, undergoes Michael addition with secondary amines. The usefulness of this approach to prepare polydentate chelators has been demonstrated by the synthesis of bis cyclic hydroxamic acids 12, 14, and 15.

Hydroxamic acids are a commonly found ligand in many siderophores and have received much attention due to their diverse biological activity that ranges from matrix metalloproteinase and histone deacetylase inhibition to therapeutic applications in the treatment of iron overload diseases.¹ On the other hand, the corresponding cyclic hydroxamic acids, have not been as widely studied. Although not as ubiquitous, cyclic hydroxamic acids are an interesting class of compounds that are present in a variety of natural products which exhibit varied biological activity.

Mycobacteria, such as mycobacterium tuberculosis which causes tuberculosis in humans, are the source of numerous infections worldwide.² Mycobacteria require iron for their growth and produce several classes of siderophores including mycobactins, exochelins, and carboxymycobactins for iron acquisition.^3,4 A common feature in these siderophores is a seven-membered cyclic hydroxamic acid although a few like exochelin MN⁵ have a six-membered hydroxamic acid. Many other natural products that are structurally related to the mycobactins have been isolated such as the amamistatins, nocardimicins, formobactin, nocobactin, and brasilibactin all of which also have 7-membered cyclic hydroxamic acids. Nocardimicins have been shown to inhibit the muscarinic M3 receptor.⁶ Amamistatins A⁷ and B⁸ as well as brasilibactin⁹ have shown an antiproliferative effect against several human tumor cell lines. Incorporation of a 7-membered cyclic hydroxamic acid into the benzodiazepine core structure has resulted in compounds with anticancer activity.¹⁰ Some cyclic hydroxamic acids have been shown to be inhibitors of matrix metalloproteinases.¹¹

Several approaches for the synthesis of cyclic non-conjugated hydroxamic acids, 1, have been reported. Probably the most commonly used method involves the formation of the amide bond, by reaction of a hydroxylamine with an acid derivative (bond a). Methods that have been reported include reduction of an oxime in the presence of an activated acid,¹² treatment of a nitrone with hydroxylamine hydrochloride followed by cyclization with EDC and HOAt,¹³ reductive cyclization of nitro alkylcarboxylic acids using Zn¹⁴ or hydrogenation of nitrolactones.¹⁵ An on-resin cyclization of a resin-supported hydroxylamine with an activated ester has also been reported.¹⁶ A less commonly used strategy for cyclic hydroxamate ring formation involves N-alkylation to form bond ‘b’. Alkylation of 4-chlorobutyro-O-benzylhydroxamate using sodium hydride followed by hydrogenation was used to prepare the 5-membered ring cyclic hydroxamic acid.¹⁷ Formation of bond ‘b’ has also been accomplished via an intramolecular acylnitroso ene reaction to form spirocyclic hydroxamic acids.¹⁸ The synthesis of 7-membered cyclic hydroxamic acids using Grubbs RCM (bond c) has been recently reported.¹⁹ Oxidation of a lactam to the corresponding cyclic hydroxamic acid (bond d) using a variety of oxidizing agents has been used.²⁰ Recently, cyclic hydroxamic acids have been prepared by NOH insertion into cyclic ketones.²¹ An alternate strategy to synthesize cyclic hydroxamic acids would involve the formation of bond ‘e’ in the key step. To our knowledge, there have been no reports on the synthesis of cyclic hydroxamic acids via formation of bond ‘e’.

Some recent discoveries in our laboratory led us to believe that formation of cyclic hydroxamic acids via intramolecular acylation reactions to form the C-C bond (bond e) may be feasible and provide an attractive alternate method to prepare cyclic hydroxamic acid derivatives. We recently discovered that stabilized carbanions react with N-benzyloxycarbamates to give the corresponding protected hydroxamic acids.²² It is also known that lactams can be prepared by intramolecular cyclization of α-sulfonyl carbanions with carbamates.²³ The question was whether these findings were applicable for the development of a new approach to prepare protected cyclic hydroxamic acids, 3, via intramolecular acylation of N-benzyloxycarbamates, 2 (Scheme 1). The goal was to prepare an array of cyclic hydroxamic acids (ring size 5 to 7) incorporating different electron withdrawing groups that would allow synthetic options for further manipulation.

Scheme 1.

The N-benzyloxy carbamate derivatives 2 required for this study were prepared in high yields by treating N-benzyloxy carbamic acid ethyl ester 4²² with a variety of alkylating reagents in the presence of K₂CO₃ in MeCN at reflux (Table 1). The alkylating reagents were either commercially available or easily prepared from commercially available reagents. The sulfoxide derivatives 2l and 2m were prepared by alkylation of 4 with bromopropyl phenyl sulfide or bromobutylphenyl sulfide, respectively, followed by oxidation of the sulfide using 1.1 equiv. of sodium metaperiodate in MeOH/H₂O (2:3).

Table 1.

Synthesis and Intramolecular Cyclization of N-Benzyloxy Carbamate Derivatives, 2

EWG	n	Carbamatea 2 (Yield %)	Temp. °C	3 (Yield %)	5 (Yield %)
SO2Ph	1	2a (90)	−78	3a (97)
SO2Ph	2	2b (95)	−78	3b (86)
SO2Ph	3	2c (94)	−78	3c (0)	5c (44)
SO2Ph	3	2c’ (89)b	rt	3c (35)
CO2Et	1	2d (94)	−78	3d (77)
CO2Et	2	2e (86)	−78	3e (81)
CO2Et	3	2f (86)	−78	3f (32)	5f (60)
CN	1	2g (93)	−78	3g (93)
CN	2	2h (90)	−78	3h (92)
CN	3	2i (88)	rt	3i (58)
PO(OEt)2	1	2j (94)	0	3j (89)
PO(OEt)2	2	2k (89)	0	3k (76)
SOPh	1	2l (42)c	rt	3l (74)d
SOPh	2	2m (57)c	0	3m (89)e

^a)R = Et

^b)R = tBu

^c)2 steps: i. alkylation with bromoalkyl phenyl sulfide ii. oxidation with 1.1 eq NaIO₄, MeOH/H₂O (2:3)

^d)Diastereomeric mixture in 2:1 ratio according to ¹H NMR.

^e)Diastereomeric mixture in 1:1 ratio according to ¹H NMR.

With the N-benzyloxy carbamate derivatives in hand, it was time to examine their intramolecular cyclization reactions. The N-benzyloxy carbamate 2a was treated with 2.1 equiv. of LHMDS at −78 °C in THF and the reaction progress monitored by TLC. After 5h, the reaction was quenched with 10% acetic acid. Chromatographic purification gave the benzyl protected five-membered cyclic hydroxamic acid 3a in 97% yield.

Our study showed that this intramolecular cyclization methodology could be readily extended to the formation of other five- and six-membered cyclic hydroxamic acids with a variety of electron withdrawing groups in the α position of the carbonyl group (Table 1). In the case of sulfoxide stabilized carbamates 2l and 2m, the cyclization proceeded better at a slightly higher temperature and gave a diastereomeric mixture of products (3l and 3m) in approximately 2:1 and 1:1 ratio, respectively, as evidenced by ¹H NMR spectra.

In contrast to the high yields observed in the formation of the five- and six-membered ring cyclic hydroxamic acids, the results with the corresponding 7 membered ring formation were less satisfactory. When sulfone 2c was treated with 2.1 equiv. of LHMDS in THF at −78°C, the major isolated product was 5c which is the result of intermolecular acylation. Variation of the experimental conditions, including dilution, changing the reaction temperature and using different equivalents of base, did not change the course of this reaction. To suppress the undesired intermolecular coupling reaction, we prepared the corresponding t-butyl carbamate, 2c’, for investigation. Interestingly, when t-butyl carbamate 2c’ was used in the cyclization and the reaction allowed to warm to room temperature, the desired cyclized product 3c was isolated in 35% yield, along with the recovered staring material (45%). Presumably, the presence of the bulky t-butyl ester moiety deters the intermolecular reaction and allows the intramolecular cyclization to proceed to some extent.

The intramolecular cyclization of ester 2f gave some of the desired cyclized 7-membered hydroxamate derivative 3f in 32% yield along with the corresponding dimeric product 5f (60%). In the case of nitrile 2i, only the cyclized product, 3i, was isolated in 58% yield after warming the reaction mixture to room temperature.

The known 1-hydroxy-2-pyrrolidone and 1-hydroxy-2-piperidone could be readily prepared from the corresponding intermediates 3a and 3b by desulfonylation followed by hydrogenolysis to remove the protecting group (Scheme 2). Treatment of 3a with 6% sodium amalgam in the presence of disodium hydrogen phosphate in MeOH at 0°C afforded the desulfonylation product 6a in 90% yield after chromatographic purification. The cleavage of the benzyl group of 6a was performed using 10% Pd on carbon in MeOH under a hydrogen balloon at room temperature, to give the five membered cyclic hydroxamic acid 7a^20c, in 83% yield. Using a similar synthetic sequence, the six-membered cyclic hydroxamic acid, 7b^20a,d, was synthesized in 86% overall yield from 3b. A tris complex of Ga(III) with cyclic hydroxamic acid 7b has been reported for the treatment of hypercalcemia of malignancy and related disorders of bone metabolism.²⁴

Scheme 2.

The availability of cyclic hydroxamic acid derivatives 3 functionalized with sulfone, sulfoxide and phosphonates in the α position, allows numerous options for further manipulation of the ligand moiety. For example, heating the sulfoxide 3m, in refluxing toluene gave the unsaturated N-benzyloxylactam 8 in 81% yield (Scheme 3). The conjugate addition reactions of 8 were of interest to us. Treatment of 8 with 1 equivalent of N,N’-dimethylethylenediamine in methanol at room temperature gave only starting materials. However, when 8 was treated with 10 equivalents of N,N’-dimethyl ethylenediamine in methanol at room temperature, the desired mono-adduct was obtained in 92% yield. Indeed, the Michael addition of 8 with a large excess of readily available diamines proceeded smoothly to give the corresponding mono-adducts in excellent yields. This is a useful result as the secondary amines in 9 provide handles for subsequent coupling of the cyclic hydroxamic unit onto acid chlorides and biomolecules of interest.

Scheme 3.

The intermediates 3 are also useful for the preparation of novel polydentate cyclic hydroxamic chelators, a class of ligands whose synthesis, chemistry and biological properties have not been studied. The sulfone derivative 3b appeared well-suited for alkylation reactions. Alkylation of 2.2 equivalents of 3b with 2-iodoethyl ether in the presence of excess potassium carbonate in refluxing acetonitrile gave the desired dialkylation product 10 in 51% yield (Scheme 4). Desulfonylation using 6% Na/Hg amalgam and disodium hydrogen phosphate in methanol gave 11 in 70% yield after purification. Finally, debenzylation using hydrogenolysis gave the bis cyclic hydroxamic acid 12.

Scheme 4.

The phosphonate 3k is ideally suited for coupling with aldehydes using the well-known Horner-Wittig-Emmons reaction. To demonstrate its synthetic utility, phosphonate 3k (3 eq.) was heated with 2,6-pyridine dicarboxaldehyde in the presence of potassium carbonate in THF/H₂O (1:1) at 80 °C for two days (Scheme 5).²⁵ The bisalkene, 13, with Z, Z-configuration, as evidenced by coupling constant analysis of the ¹H NMR spectra, was isolated as the major product in 64% yield after chromatographic purification. The benzyl protecting groups of 13 were removed using concentrated HBr/AcOH (1:1) at 55 °C to obtain the pyridine bis cyclic hydroxamic acid ligand 14. The ligand 14 was isolated as the hydrobromide salt in 85% yield. We also prepared the saturated analog, 15, for comparison purposes. Concurrent deprotection and reduction of the double bond of the bisalkene 13 were achieved using 10% Pd/C under hydrogen atmosphere to give the saturated pyridine bis cyclic hydroxamic acid 15 in 76% yield as a 1:1 mixture of diastereomers.

Scheme 5.

Given the increasing interest in the chemistry and biology of cyclic hydroxamic acids, methods for their preparation and derivatization are important. In this paper, we have shown that stabilized carbanions undergo intramolecular cyclization with internal N-benzyloxy carbamates to give functionalized cyclic hydroxamic acids. This provides a new and flexible approach to access this class of molecules. The usefulness of the intermediates obtained from this study has been clearly shown. The unsaturated N-benzyloxy lactam 8, is useful for conjugate addition reactions with amines. Both the sulfone and phosphonate derivatives 3b and 3k, permit the tethering of this ligand onto various host molecules. The synthetic value of intermediates 3b and 3k has been shown by the preparation of novel classes of bis cyclic hydroxamic acids whose properties remain to be explored.

Experimental

General Methods

Melting points were obtained on an Electrothermal^® melting point apparatus and are uncorrected. ¹H NMR (200 MHz) and ¹³C NMR (50 MHz) spectra were recorded on a Varian XL 200. ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded on a 300 MHz Varian NMR. ¹H NMR (400 MHz) spectra were recorded on a Varian Unity 400 spectrometer. NMR spectral samples were prepared in CDCl₃, CD₃OD, or D₂O as noted. Chemical shifts are given in parts per million (ppm) relative to tetramethylsilane (TMS) reference. For ¹H spectra obtained in D₂O, the HOD peak was set to 4.72 ppm and used as an internal reference. For ¹³C spectra obtained in D₂O, 1,4-dioxane (66.5 ppm) was used as an internal reference. Analytical and preparative thin layer chromatography were performed on silica 60/F254 plastic plates (EM Science). Column chromatography was performed on silica gel (Merck 60–200 mesh) or basic alumina (Aldrich 150 mesh). Radial chromatography was performed on a Harrison Research, Inc. Chromatotron^®. Chromatography solvents were reagent grade and were obtained from either Fisher Scientific or VWR Scientific. Reagents were obtained from Aldrich or Lancaster chemical companies and were used as received. tert-Butyl N-benzyloxycarbamate was obtained from SigmaAldrich. Anhydrous THF was collected from a GlassContour™ solvent purification system. Other dry solvents (CH₃CN, CH₂Cl₂, etc) were obtained from Acros. Desert Analytics, Tucson, Arizona performed elemental analyses. HRMS analyses were performed by the University of California Riverside Mass Spectrometry Facility.

Representative Procedure for the Preparation of Carbamates 2

(3-Benzenesulfonylpropyl)-N-benzyloxy-carbamic acid ethyl ester (2a)

Potassium carbonate (0.304 g, 2.2 mmol) was added to a solution of 4²² (0.086 g, 0.44 mmol) and 3-bromopropylphenyl sulfone (0.139 g, 0.53 mmol) in MeCN (4 mL) and the mixture was stirred at reflux overnight. The mixture was poured into water (60 mL), extracted with CH₂Cl₂ (4 × 15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na₂SO₄ and the solvent was removed in vacuo. The crude product was purified by radial chromatography (EtOAc:hexane=1:2~1:1) to give sulfone 2a as a colorless oil (0.15 g, 90.4%). IR(neat) 2982, 1699 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.97-7.77(m, 2H), 7.72-7.43(m, 3H), 7.41-7.28(m, 5H), 4.80(s, 2H), 4.19(q, J=7.0 Hz, 2H), 3.53(t, J=6.6 Hz, 2H), 3.15-3.07(m, 2H), 2.03-1.95(m, 2H), 1.30(t, J=7.0 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 157.2, 139.0, 135.1, 133.7, 129.4, 129.3, 128.7, 128.5, 128.0, 77.2, 62.3, 53.7, 48.1, 20.9, 14.5. Anal. Calcd for C₁₉H₂₃NO₅S: C, 60.46; H, 6.14; N, 3.71. Found: C, 60.68; H, 6.15; N, 3.58.

(4-Benzenesulfonylbutyl)-N-benzyloxy-carbamic acid ethyl ester (2b)

The representative procedure was followed using 3-bromobutylphenyl sulfone as the alkylating reagent to give 2b as a colorless oil; 94.9% yield; IR(neat) 2938, 1699 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.98-7.81(m, 2H), 7.74-7.47(m, 3H), 7.47-7.30(m, 5H), 4.81(s, 2H), 4.19(q, J=7.0 Hz, 2H), 3.40(t, J=6.6 Hz 2H), 3.06(t, J=7.3 Hz, 2H), 1.85-1.49(m, 4H), 1.30(t, J=7.0 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 157.3, 139.2, 135.4, 133.6, 129.3, 129.2, 128.6, 128.4, 128.0, 77.1, 62.1, 55.7, 48.7, 25.7, 20.0, 14.5. Anal. Calcd for C₂₀H₂₅NO₅S: C, 61.36; H, 6.44; N, 3.58. Found: C, 61.20; H, 6.17; N, 3.53.

(5-Benzenesulfonylpentyl)-N-benzyloxy-carbamic acid ethyl ester (2c)

The representative procedure was followed using 3-bromopentylphenyl sulfone as the alkylating reagent to give 2c as a colorless oil; 94.1% yield; IR (neat) 2941, 1704 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 8.00-7.81(m, 2H), 7.74-7.48(m, 3H), 7.46-7.29(m, 5H), 4.82(s, 2H), 4.19(q, J=7.0 Hz, 2H), 3.38(t, J=6.6 Hz, 2H), 3.09-3.01(m, 2H), 1.84-1.46(m, 4H), 1.46-1.25(m, 2H), 1.30(t, J=7.0 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 157.4, 139.2, 135.5, 133.6, 129.3, 129.2, 128.6, 128.4, 128.0, 77.0, 62.0, 56.1, 49.2, 26.5, 25.4, 22.4, 14.5. Anal. Calcd for C₂₁H₂₇NO₅S: C, 62.20; H, 6.71; N, 3.45. Found: C, 62.14; H, 6.73; N, 3.30.

(5-Benzenesulfonylpentyl)-N-benzyloxy-carbamic acid tert-butyl ester (2c’)

The representative procedure was followed using tert-butyl N-benzyloxy carbamate in place of 4 and 5-bromopentylphenyl sulfone as the alkylating reagent to give 2c’ as a colorless oil; 88.7% yield: IR (neat) 2976, 2938, 1699 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 8.02-7.81(m, 2H), 7.76-7.48(m, 3H), 7.47-7.30(m, 5H), 4.79(s, 2H), 3.35(t, J=7.0 Hz, 2H), 3.05(t, J=8.1 Hz, 2H), 1.82-1.60(m, 2H), 1.49(s, 9H), 1.44-1.19(m, 4H); ¹³C NMR (50 MHz, CDCl₃) δ 156.4, 139.3, 135.7, 133.6, 129.3, 129.2, 128.5, 128.4, 128.0, 81.2, 76.8, 56.1, 49.1, 28.3, 26.5, 25.4, 22.4. Anal. Calcd for C₂₃H₃₁NO₅S: C, 63.72; H, 7.21; N, 3.23. Found: C, 63.61; H, 7.22; N, 3.22.

4-(N-Benzyloxy-ethoxycarbonyl-amino)-butyric acid ethyl ester (2d)

The representative procedure was followed using ethyl 4-bromobutyrate as the alkylating reagent to give 2d as a colorless oil; 93.7% yield; IR(neat) 2982, 2940, 1733, 1703 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.34(m, 5H), 4.86(s, 2H), 4.22(q, J=7.3 Hz, 2H), 4.12(q, J=7.3 Hz, 2H), 3.50(t, J=7.0 Hz, 2H), 2.33(t, J=7.3 Hz, 2H), 1.92(quin, J=7.0 Hz, 2H), 1.31(t, J=7.3 Hz, 3H), 1.24(t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.9, 157.4, 135.4, 129.4, 128.6, 128.5, 77.1, 62.1, 60.4, 48.9, 31.4, 22.5, 14.6, 14.2. Anal. Calcd for C₁₆H₂₃NO₅: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.26; H, 7.39; N, 4.43.

5-(N-Benzyloxy-ethoxycarbonyl-amino)-pentanoic acid ethyl ester (2e)

The representative procedure was followed using ethyl 5-bromovalerate as the alkylating reagent to give 2e as a colorless oil: 85.6% yield; IR (neat) 2981, 2939, 1732, 1702 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.48-7.29(m, 5H), 4.86(s, 2H), 4.22(q, J=7.3 Hz, 2H), 4.11(q, J=7.0 Hz, 2H), 3.45(t, J=7.0 Hz, 2H), 2.30(t, J=7.3 Hz, 2H), 1.66-1.57(m, 4H), 1.31(t, J=7.3 Hz, 3H), 1.24(t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.2, 157.5, 135.6, 129.3, 128.5, 128.4, 77.1, 62.0, 60.2, 48.3, 33.8, 26.5, 22.1, 14.6, 14.2. Anal. Calcd for C₁₇H₂₅NO₅: C, 63.14; H, 7.79; N, 4.33. Found: C, 63.06; H, 7.69; N, 4.37.

6-(N-Benzyloxy-ethoxycarbonyl-amino)-hexanoic acid ethyl ester (2f)

The representative procedure was followed using ethyl 6-bromohexanoate as the alkylating reagent to give 2f as a colorless oil; 86.1% yield; IR (neat) 2981, 2938, 1733, 1705 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.47-7.30(m, 5H), 4.85(s, 2H), 4.21(q, J=7.2 Hz, 2H), 4.11(q, J=7.1 Hz, 2H), 3.43(t, J=7.0 Hz, 2H), 2.28(t, J=7.1 Hz, 2H), 1.66-1.55(m, 6H), 1.31(t, J=7.0 Hz, 3H), 1.25(t, J=7.1 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 173.5, 157.5, 135.6, 129.3, 128.5, 128.4, 77.1, 62.0, 60.1, 49.6, 34.2, 26.7, 26.2, 24.6, 14.6, 14.2. Anal. Calcd for C₁₈H₂₇NO₅: C, 64.07; H, 8.07; N, 4.15. Found: C, 64.16; H, 7.84; N, 4.20.

N-Benzyloxy-(3-cyanopropyl)-carbamic acid ethyl ester (2g)

The representative procedure was followed using 4-bromobutyronitrile as the alkylating reagent to give 2g as a colorless oil; 92.7% yield; IR (neat) 2982, 2943, 2247, 1702 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.51-7.30(m, 5H), 4.87(s, 2H), 4.24(q, J=7.3 Hz, 2H), 3.56(t, J=6.6 Hz, 2H), 2.34(t, J=7.0 Hz, 2H), 1.89(quin, J=7.0 Hz, 2H), 1.34(t, J=7.0 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 157.2, 135.2, 129.5, 128.8, 128.6, 119.1, 77.2, 62.4, 48.2, 23.4, 14.8, 14.5. Anal. Calcd for C₁₄H₁₈N₂O₃: C, 64.10; H, 6.92; N, 10.68. Found: C, 63.88; H, 7.07; N, 10.64.

N-Benzyloxy-(4-cyanobutyl)-carbamic acid ethyl ester (2h)

The representative procedure was followed using 5-chlorovaleronitrile as the alkylating reagent to give 2h as a colorless oil; 90.0% yield; IR (neat) 2917, 2247, 1699 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.51-7.29(m, 5H), 4.86(s, 2H), 4.23(q, J=7.3 Hz, 2H), 3.47(t, J=6.2 Hz, 2H), 2.33(t, J=7.0 Hz, 2H), 1.72-1.64(m, 4H), 1.33(t, J=7.0 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 157.4, 135.4, 129.4, 128.7, 128.5, 119.4, 77.1, 62.2, 48.5, 26.1, 22.6, 16.7, 14.5. Anal. Calcd for C₁₅H₂₀N₂O₃: C, 65.20; H, 7.30; N, 10.14. Found: C, 65.05; H, 7.34; N, 10.08.

N-Benzyloxy-(4-cyanopentyl)-carbamic acid ethyl ester (2i)

The representative procedure was followed using 6-bromohexanonitrile as the alkylating reagent to give 2i as a colorless oil; 88.2% yield; IR (neat) 2940, 2245, 1704 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.51-7.29(m, 5H), 4.85(s, 2H), 4.22(q, J=7.2 Hz, 2H), 3.44(t, J=6.8 Hz, 2H), 2.32(t, J=7.0 Hz, 2H), 1.68-1.58(m, 4H), 1.51-1.39(m, 2H), 1.32(t, J=7.1 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 157.4, 135.5, 129.3, 128.6, 128.5, 119.5, 77.1, 62.1, 48.2, 26.2, 25.7, 25.0, 17.0, 14.6. Anal. Calcd for C₁₆H₂₂N₂O₃: C, 66.18; H, 7.64; N, 9.65. Found: 66.21; H, 7.44; N, 9.71.

[3-(N-Benzyloxy-ethoxycarbonyl-amino)-propyl]-phosphonic acid diethyl ester (2j)

The representative procedure was followed using diethyl 3-bromopropyl phosphonate as the alkylating reagent to give 2j as a colorless oil; 93.5% yield; IR (neat) 2982, 1705 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.55-7.30(m, 5H), 4.86(s, 2H), 4.22(q, J=7.0 Hz, 2H), 4.11(quin, J=6.8 Hz, 4H), 3.52(t, J=6.6 Hz, 2H), 1.94-1.68(m, 4H), 1.35-1.27(m, 9H); ¹³C NMR (50 MHz, CDCl₃) δ 157.4, 135.4, 129.3, 128.6, 128.4, 77.2, 62.2, 61.6 (d, J=6.4 Hz), 50.0 (d, J=18.7 Hz), 23.1 (d, J=141.5 Hz), 20.4 (d, J=4.6 Hz), 16.5 (d, J=5.9 Hz), 14.6. Anal. Calcd for C₁₇H₂₈NO₆P: C, 54.68; H, 7.56; N, 3.75. Found: C, 54.60; H, 7.30; N, 3.91.

[3-(N-Benzyloxy-ethoxycarbonyl-amino)-butyl]-phosphonic acid diethyl ester (2k)

The representative procedure was followed using diethyl 4-bromobutyl phosphonate as the alkylating reagent to give 2k as a colorless oil; 89.4% yield; IR (neat) 2981, 1701 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.49-7.30(m, 5H), 4.85(s, 2H), 4.21(q, J=7.1 Hz, 2H), 4.07(quin, J=7.1 Hz, 4H), 3.44(t, J=6.4 Hz, 2H), 1.73-1.60(m, 6H), 1.35-1.25(m, 9H); ¹³C NMR (50 MHz, CDCl₃) δ 157.4, 135.5, 129.3, 128.6, 128.5, 77.2, 62.1, 61.4(d, J=6.8 Hz), 49.1, 27.9(d, J=15.9 Hz), 25.4(d, J=140.1 Hz), 19.8(d, J=5.3 Hz), 16.5(d, J=5.9 Hz), 14.6. Anal. Calcd for C₁₈H₃₀NO₆P: C, 55.80; H, 7.81; N, 3.62. Found: C, 56.14; H, 7.66; N, 3.91.

(3-Benzenesulfinylpropyl)-N-benzyloxy-carbamic acid ethyl ester (2l)

The representative procedure was followed using 3-bromopropylphenyl sulfide as the alkylating reagent to give the corresponding sulfide as a colorless oil; 57.4% yield; IR (neat) 2934, 1701 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.51-7.15(m, 10H), 4.83(s, 2H), 4.20(q, J=7.3 Hz, 2H), 3.57(t, J=7.0 Hz, 2H), 2.90(t, J=7.3 Hz, 2H), 1.91(quintet, J=7.0 Hz, 2H), 1.30(t, J=7.0 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 157.4, 136.2, 135.4, 129.5, 129.3, 128.9, 128.6, 128.4, 126.1, 77.1, 62.1, 48.6, 31.1, 26.7, 14.5. A solution of sodium metaperiodate (0.121 g, 0.56 mmol) in H₂O (3 mL) was added to a solution of the sulfide (0.184 g, 0.51 mmol) in MeOH (2 mL) at 0 °C and the mixture stirred at rt for 24 h. The reaction mixture was poured into water (50 mL) and the product extracted into chloroform (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄ and the solvent removed in vacuo. The crude product was purified by radial chromatography (EtOAc:hexane=1:2~1:1) to give sulfoxide 2l (0.140g, 73.3%) as colorless oil: IR (neat) 2981, 1705 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.67-7.44(m, 5H), 7.43-7.30(m, 5H), 4.82(s, 2H), 4.20(q, J=7.0 Hz, 2H), 3.61-3.54(m, 2H), 2.87-2.74(m, 2H), 2.23-1.76(m, 2H), 1.30(t, J=7.3 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 157.3, 143.7, 135.2, 130.9, 129.4, 129.2, 128.7, 128.5, 124.0, 77.1, 62.3, 54.4, 48.4, 20.2, 14.5.

(3-Benzenesulfinylbutyl)-N-benzyloxy-carbamic acid ethyl ester (2m)

The representative procedure was followed using 4-bromobutylphenyl sulfide as the alkylating reagent to give the corresponding sulfide as a colorless oil; 77.5% yield; IR(neat) 2935, 1699 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.48-7.07(m, 10H), 4.84(s, 2H), 4.21(q, J=7.1 Hz, 2H), 3.44(t, J=6.6 Hz, 2H), 2.90(t, J=7.0Hz, 2H), 1.71-1.63(m, 4H), 1.31(t, J=7.1Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.5, 136.5, 135.5, 129.3, 129.1, 128.8, 128.6, 128.4, 125.8, 77.1, 62.1, 49.2, 33.2, 26.3, 26.1, 14.6. A solution of sodium metaperiodate (0.786 g, 3.67 mmol) in H₂O (5 mL) was added to a solution of the sulfide (1.20 g, 3.34 mmol) in MeOH (5 mL) at 0 °C and the mixture stirred at rt for 14 h. The reaction mixture was poured into water (50 mL), and the product extracted into chloroform (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄ and the solvent removed in vacuo. The crude product was purified by radial chromatography (EtOAc:hexane=1:2~1:1) to give sulfoxide 2m (1.13 g, 90.1%) as colorless oil: IR (neat) 2937, 1695 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.69-7.44(m, 5H), 7.44-7.29(m, 5H), 4.82(s, 2H), 4.20(q, J=7.1 Hz, 2H), 3.43(t, J=6.4 Hz, 2H), 2.77(t, J=7.2 Hz, 2H), 1.73-1.66(m, 4H), 1.30(t, J=7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.4, 143.9, 135.5, 130.9, 129.4, 129.2, 128.6, 128.5, 124.0, 77.1, 62.2, 56.7, 49.0, 26.1, 19.4, 14.6. Anal. Calcd for C₂₀H₂₅NO₄S: C, 63.97; H, 6.71; N, 3.73. Found: C, 63.79; H, 6.78; N, 3.93.

Representative Procedure for the Intramolecular Cyclization Reactions of N-Benzyloxy Carbamate Derivatives 2

3-Benzenesulfonyl-1-benzyloxy-pyrrolidin-2-one (3a)

Lithium bis(trimethylsilyl) amide (0.92 mL, 0.9 mmol, 1 M solution in THF) was added to a solution of 2a (0.166 g, 0.44 mmol) in THF (4 mL) under N₂ at −78°C and the mixture was stirred at −78°C for 1 h. The reaction was quenched at −78°C with 10% AcOH aqueous solution (2 mL) and the solvent removed in vacuo. The residue was dissolved in EtOAc (50 mL), washed with brine (3×10mL), dried over Na₂SO₄ and the solvent removed in vacuo. The crude product was purified by radial chromatography (EtOAc:hexane = 1:3~1:1) to give 3a as colorless oil in 97.2% yield; IR (neat) 2918, 1721 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 8.09-7.86(m, 2H), 7.78-7.50(m, 3H), 7.45-7.30(m, 5H), 5.00-4.85 (m, 2H), 3.88(dd, J=10.3, 4.4 Hz, 1H), 3.39(q, J=8.8 Hz, 1H), 3.23(ddd, J=8.8, 8.8, 4.0 Hz, 1H), 2.79-2.52(m, 1H), 2.50-2.20(m, 1H); ¹³C NMR (50 MHz, CDCl₃) δ 161.6, 137.5, 134.7, 134.3, 129.5, 129.4, 129.1, 129.0, 128.6, 77.0, 62.8, 44.8, 17.5. Anal. Calcd for C₁₇H₁₇NO₄S: C, 61.62; H, 5.17; N, 4.23. Found: C, 61.50; H, 5.41; N, 4.49.

3-Benzenesulfonyl-1-benzyloxy-piperidin-2-one (3b)

The representative cyclization procedure was followed using 2b in place of 2a to give 3b as a colorless oil; 85.5 % yield; IR (neat) 2920, 1668 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 8.09-7.89(m, 2H), 7.81-7.54(m, 3H), 7.54-7.29(m, 5H), 5.02-4.89(m, 2H), 4.02(dd, J=5.5, 4.0 Hz, 1H), 3.47-3.28(m, 2H), 2.79-2.49(m, 1H), 2.48-2.21(m, 1H), 2.21-1.91(m, 1H), 1.91-1.66(m, 1H); ¹³C NMR (50 MHz, CDCl₃) δ 159.4, 139.4, 135.1, 133.9, 129.8, 129.1, 128.9, 128.8, 128.5, 76.1, 66.9, 50.9, 21.8, 20.7 Anal. Calcd for C₁₈H₁₉NO₄S: C, 62.59; H, 5.54; N, 4.06. Found: C, 62.76; H, 5.83; N, 4.33.

{5-Benzenesulfonyl-5-[(5-benzenesulfonyl-pentyl)-benzyloxy-carbamoyl]-pentyl}-benzyloxycarbamic acid ethyl ester (5c)

The representative cyclization procedure was followed using 2c in place of 2a to give dimer 5c as colorless oil; 44.3% yield; IR(neat) 3065, 3033, 2938, 2871, 1699, 1661 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.98-7.75(m, 4H), 7.72-7.44(m, 6H), 7.44-7.28(m, 10H), 5.01(d, J=10.3 Hz, 1H), 4.83(d, J=10.6 Hz, 1H), 4.77(s, 2H), 4.60(dd, J= 10.6, 4.0 Hz, 1H), 4.14(q, J=7.0 Hz, 2H), 3.76-3.38(m, 2H), 3.30(t, J=7.1 Hz, 2H), 3.10-3.02(m, 2H), 1.93-0.95(m, 12H), 1.26(t, J=7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.0, 157.3, 139.1, 137.0, 135.4, 134.0, 133.8, 133.6, 129.8, 129.3 (2 peaks), 129.2, 128.9, 128.7, 128.6, 128.4, 128.0, 77.0, 76.9, 65.5, 62.0, 55.9, 49.0, 45.4, 27.8, 26.6, 26.0, 25.4, 24.0, 22.2, 14.5. Anal. Calcd for C₄₀H₄₈N₂O₉S₂: C, 62.81; H, 6.32; N, 3.66. Found: C, 62.79; H, 6.29; N, 3.65.

3-Benzenesulfonyl-1-benzyloxy-azepan-2-one (3c)

The representative cyclization procedure was followed using 2c’ in place of 2a and the reaction was allowed to stir at rt for 18 h to give 3c as a white solid; 34.9% yield (43.8% recovered 2c’); mp 189–190 °C; IR (KBr) 2896, 2925, 1668 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 8.09-7.89(m, 2H), 7.81-7.54(m, 3H), 7.54-7.29(m, 5H), 4.95-4.81(m, 2H), 4.03(dd, J=9.9, 2.9 Hz, 1H), 3.85-3.57(m, 1H), 3.57-3.29(m, 1H), 2.52-2.21(m, 1H), 2.21-1.93(m, 1H), 1.93-1.67(m, 1H), 1.67-1.40(m, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 164.8, 138.5, 135.3, 133.9, 129.9, 129.7, 128.8, 128.7, 128.6, 76.8, 69.8, 52.5, 26.4, 26.1, 24.3. Anal. Calcd for C₁₉H₂₁NO₄S: C, 63.49; H, 5.89; N, 3.90. Found: C, 63.50; H, 5.61; N, 4.19.

1-Benzyloxy-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester (3d)

The representative cyclization procedure was followed using 2d in place of 2a to give 3d as a colorless oil; 76.5% yield; IR (neat) 2983, 2903, 1715 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.36(m, 5H), 5.00(d, J=10.8 Hz, 2H), 4.22(q, J=7.2 Hz, 2H), 3.38-3.27(m, 3H), 2.29-2.24(m, 1H), 2.19-2.12(m, 1H), 1.30(t, J=7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.6, 166.0, 135.0, 129.5, 128.9, 128.5, 76.8, 61.7, 45.5, 45.4, 19.9, 14.1. Anal. Calcd for C₁₄H₁₇NO₄: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.58; H, 6.58; N, 5.36.

1-Benzyloxy-2-oxo-piperidine-3-carboxylic acid ethyl ester (3e)

The representative cyclization procedure was followed using 2e in place of 2a to give 3e as a colorless oil; 80.8 % yield; IR (neat) 2949, 2879, 1737, 1667 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.56-7.30(m, 5H), 4.99(s, 2H), 4.24(q, J=7.3 Hz, 2H), 3.48(t, J=6.6 Hz, 1H), 3.38-3.29(m, 2H), 2.01-1.89(m, 4H), 1.32(t, J=7.0 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 170.1, 163.3, 135.3, 129.7, 128.7, 128.4, 75.8, 61.5, 50.9, 50.1, 24.8, 21.4, 14.1. Anal. Calcd for C₁₅H₁₉NO₄: C, 64.97; H, 6.91; N, 5.05. Found: C, 65.01; H, 7.02; N, 5.05.

6-(Benzyloxy-ethoxycarbonyl-amino)-2-[benzyloxy-(5-ethoxycarbonyl-pentyl)-carbamoyl]-hexanoic acid ethyl ester (3f) and 1-benzyloxy-2-oxo-azepane-3-carboxylic acid ethyl ester (5f)

The representative cyclization procedure was followed using 2f in place of 2a and stirring the reaction at 0 °C for 18h to give cyclized product 3f (31.9% yield, colorless oil) and dimer 5f (59.7% yield, colorless oil). 3f: IR (neat) 2936, 2870, 1743, 1668 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.53-7.29(m, 5H), 5.05-4.91(m, 2H), 4.25(q, J= 7.0 Hz, 2H), 3.57-3.45(m, 3H), 2.12-1.69(m, 3H), 1.66-1.39(m, 3H), 1.31(t, J= 7.1 Hz, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 169.7, 168.9, 135.6, 129.7, 128.7, 128.5, 76.4, 61.3, 53.2, 51.9, 27.3, 26.7, 25.8, 14.2. Anal. Calcd for C₁₆H₂₁NO₄: C, 65.96; H, 7.27; N, 4.81. Found: C, 66.00; H, 7.10; N, 5.14. 5f: IR (neat) 2981, 2938, 2869, 1713 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.28(m, 10H), 4.84(s, 2H), 4.83(s, 2H), 4.25-4.11(m, 6H), 3.46-3.34(m, 5H), 2.68-2.21(m, 2H), 1.95-1.71(m, 2H), 1.70-1.47(m, 6H), 1.39-1.10(m, 13H); ¹³C NMR (50 MHz, CDCl₃) δ 169.7, 157.5, 135.6, 129.3, 128.5, 128.4, 77.1, 62.0, 61.3, 59.0, 49.5, 49.4, 41.7, 27.8, 26.8, 24.6, 23.1, 14.6, 14.1. HRMS: calcd for C₃₄H₄₈N₂O₉Na (M + Na⁺) 651.3252, found 651.3254.

1-Benzyloxy-2-oxo-pyrrolidine-3-carbonitrile (3g)

The representative cyclization procedure was followed using 2g in place of 2a to give 3g as a pale yellow solid; 92.5 % yield; mp: 60–61 °C; IR (KBr) 2895, 2250, 1714 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.54-7.31(m, 5H), 5.03(s, 2H), 3.44(t, J=9.1 Hz, 1H), 3.31-3.24(m, 2H), 2.41-2.16(m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 162.4, 135.5, 129.5, 129.2, 128.7, 116.7, 77.1, 45.1, 30.7, 21.2. Anal. Calcd for C₁₂H₁₂N₂O₂: C, 66.65; H, 5 .59; N, 12.96. Found: C, 66.61; H, 5.69; N, 13.03.

1-Benzyloxy-2-oxo-piperidine-3-carbonitrile (3h)

The representative cyclization procedure was followed using 2h in place of 2a to give 3h as a colorless oil; 91.6 % yield; IR (neat) 2951, 2886, 2250, 1674 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.57-7.30(m, 5H), 5.06-4.94(m, 2H), 3.61(t, J=7.0 Hz, 1H), 3.37-3.32(m, 2H), 2.21-1.82(m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 159.4, 134.6, 129.7, 129.1, 128.6, 117.1, 76.0, 50.7, 36.0, 25.6, 21.5. Anal. Calcd for C₁₃H₁₄N₂O₂: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.45; H, 6.16; N, 12.15.

1-Benzyloxy-2-oxo-azepane-3-carbonitrile (3i)

The representative cyclization procedure was followed using 2i in place of 2a and stirring the reaction at rt for 3 hours to give 3i as a colorless oil; 57.7 % yield; IR (neat) 2937, 2252, 1674 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.53-7.31(m, 5H), 4.97(s, 2H), 3.84-3.70(m, 2H), 3.55-3.44(m, 1H), 2.05-1.98(m, 4H), 1.62-1.25(m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 164.1, 135.0, 129.8, 129.0, 128.6, 116.3, 76.7, 53.2, 38.7, 27.4, 26.7, 26.3. HRMS: calcd for C₁₄H₁₇N₂O₂ (M + H⁺) 245.1285, found 245.1284.

(1-Benzyloxy-2-oxo-pyrrolidin-3-yl)-phosphonic acid diethyl ester (3j)

The representative cyclization procedure was followed using 2j in place of 2a and stirring the reaction at 0 °C for 2 hours to give 3j as a colorless oil; 89.4% yield; IR (neat) 2984, 1714 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.53-7.30(m, 5H), 5.05-4.92(m, 2H), 4.28-4.11(m, 4H), 3.51-3.34(m, 1H), 3.27-3.23(m, 1H), 2.90-2.76(m, 1H), 2.33-2.19(m, 2H), 1.35(td, J=7.0, 1.5 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 166.1 (d, J=4.1 Hz), 135.2, 129.5, 128.9, 128.5, 76.9, 62.8 (d, J=6.6 Hz), 45.7 (d, J=4.5 Hz), 37.9 (d, J=143.8 Hz), 18.0(d, J=4.1 Hz), 16.5 (d, J=3.8 Hz). Anal. Calcd for C₁₅H₂₂NO₅P·0.5H₂O: C, 53.57; H, 6.89; N, 4.16. Found: C, 53.75; H, 6.56; N, 4.10.

(1-Benzyloxy-2-oxo-piperidin-3-yl)-phosphonic acid diethyl ester (3k)

The representative cyclization procedure was followed using 2k in place of 2a and stirring the reaction at 0 °C for 6 hours to give 3k as a colorless oil; 75.8% yield; IR (neat) 2980, 1655 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.57-7.32(m, 5H), 5.03-4.90(m, 2H), 4.26-4.15(m, 4H), 3.35(t, J=5.5 Hz, 2H), 3.04(dt, J=26.0, 6.2 Hz, 1H), 2.31-1.90(m, 3H), 1.88-1.59(m, 1H), 1.40-1.33(t, J=7.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 162.7(d, J=5.0 Hz), 135.5, 129.7, 128.7, 128.5, 75.9, 62.7(d, J=6.6 Hz), 50.9, 42.9(d, J=136.0 Hz), 22.8(d, J=4.6 Hz), 21.9(d, J=7.3 Hz), 16.5(d, J=5.9Hz). Anal. Calcd for C₁₃H₁₄N₂O₂·0.02H₂O: C, 56.24; H, 7.09; N, 4.10. Found: C, 55.86; H, 6.82; N, 4.49.

3-Benzenesulfinyl-1-benzyloxy-pyrrolidin-2-one (3l)

The representative cyclization procedure was followed using 2l in place of 2a and stirring the reaction at rt for 1 hour to give 3l as a 2:1 diastereomeric mixture in 74.1% yield as a pale yellow solid. IR (KBr) 2937, 1707 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 7.81-7.13 (m, 10H), 5.02 (dd, J=11.0, 10.6 Hz, 1.4H), 4.73(dd, J=32.0, 11.0 Hz, 0.7H), 4.20-4.00(dd, J=9.5, 3.7 Hz, 0.35H), 3.46(dd, J=9.9, 7.0 Hz, 0.7 H), 3.32-3.25(m, 1.4H), 2.95-2.90(m, 0.35H), 2.54-2.43(m, 1.4H), 2.35-2.08(m, 0.7H), 1.71-1.30(m, 0.35H); ¹³C NMR (100 MHz, CDCl₃): δ 164.5, 163.7, 141.7, 138.9, 134.8, 132.0, 131.2, 129.6, 129.3, 129.0, 128.6, 128.5, 125.2, 124.0, 77.3, 63.6, 61.5, 45.8, 45.4, 13.9, 11.9; Anal. Calcd for C₁₇H₁₇NO₃S: C, 64.74; H, 5.43; N, 4.44. Found: C, 64.62; H, 5.58; N, 4.72.

3-Benzenesulfinyl-1-benzyloxy-piperidin-2-one (3m)

The representative cyclization procedure was followed using 2m in place of 2a and stirring the reaction at 0°C for 0.5h to give 3m as a 1:1 mixture of diastereomers in 88.6% yield. colorless oil; IR(neat) 2947, 1652 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.84-7.21(m, 10H), 5.03(s, 1H), 4.82(dd, J=35.7, 10.8 Hz, 1H), 4.13(t, J=7.0 Hz, 0.5H), 4.46(dd, J=8.4, 6.6 Hz, 0.5H), 3.38-3.32(m, 1H), 3.21-3.13(m, 0.5H), 3.10-2.83(m, 0.5H), 2.43-1.86(m, 2H), 1.86-1.54(m, 1.5H), 1.54-1.34(m, 0.5H); ¹³C NMR (100 MHz, CDCl₃) δ 162.2, 161.4, 142.5, 140.1, 135.1, 131.5, 131.0, 129.8, 129.5, 129.2, 128.9, 128.7, 128.5, 125.9, 124.4, 76.4, 76.2, 67.1, 64.5, 50.8, 50.3, 21.5, 21.3, 18.1, 17.5. Anal. Calcd for C₁₈H₁₉NO₃S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.58; H, 5.85; N, 4.37.

Representative Procedure for Desulfonylation

N-Benzyloxy-pyrrolidin-2-one (6a)

Disodium hydrogen phosphate (0.240 g, 1.68 mmol) and 6% Na/Hg amalgam (1.97 g, 5.04 mmol) were added to a solution of 3a (0.140 g, 0.42 mmol) in MeOH (15 mL) at 0°C and the mixture was stirred at 0°C for 3h. The reaction mixture was vacuum filtered through a short silica gel column and rinsed with EtOAc (50 mL). The filtrate was washed with saturated NaHCO₃ (3 × 10mL), dried (Na₂SO₄) and the solvent was removed in vacuo. The product 6a was obtained as a colorless oil (0.072 g, 90.0%), which was homogeneous by TLC. IR (neat) 2953, 2882, 1710 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.51-7.30(m, 5H), 4.99(s, 2H), 3.26(t, J=7.0 Hz, 2H), 2.32(t, J=8.1 Hz, 2H), 1.91(quin, J=7.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 171.6, 135.4, 129.3, 128.8, 128.5, 76.8, 47.0, 27.8, 15.4. Anal. Calcd for C₁₁H₁₃NO₂: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.38; H, 7.20; N, 6.98.

N-Benzyloxy-piperidin-2-one (6b)

The representative desulfonylation procedure was followed using 3b in place of 3a to give 6b as a colorless oil; 92.0% yield; IR (neat) 2948, 2876, 1667 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.53-7.31(m, 5H), 4.97(s, 2H), 3.34(t, J=6.0 Hz, 2H), 2.32(t, J=6.0 Hz, 2H), 1.87-1.57(m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 167.2, 135.5, 129.5, 128.7, 128.4, 75.7, 50.8, 33.3, 23.8, 21.0. Anal. Calcd for C₁₂H₁₅NO₂: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.17; H, 7.23; N, 6.88.

Representative Procedure for Hydrogenolysis

N-Hydroxy-pyrrolidin-2-one (7a)

Palladium on carbon (10%, 17 mg) was added to a solution of 6a (35 mg, 0.18 mmol) in MeOH (2 mL) and the mixture was stirred at rt under hydrogen balloon for 18 hours. The catalyst was removed by centrifugation followed by filtration. The solvent was removed in vacuo to give the known cyclic hydroxamic acid 7a^20c (0.015 g, 83.3%) as a colorless oil. ¹H NMR (200 MHz, CDCl₃) δ 10.40(br s, 1H), 3.67(t, J=7.0 Hz, 2H), 2.41(t, J=7.7 Hz, 2H), 2.06(quin, J=7.1 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 170.4, 48.5, 28.0, 15.1.

N-Hydroxy-piperidin-2-one (7b)

The representative hydrogenolysis procedure was followed using 6b in place of 6a to give the known cyclic hydroxamic acid 7b^20a,d as a colorless oil; 94.2% yield, ¹H NMR (400 MHz, CDCl₃) δ 8.14(br s, 1H), 3.63(t, J=6.0 Hz, 2H), 2.44(t, J=6.4 Hz, 2H), 1.96-1.88(m, 2H), 1.82-1.74(m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 49.7, 31.2, 23.2, 20.7.

N-Benzyloxy-5,6-dihydro-1H-pyridin-2-one (8)

A solution of 3m (0.437 g, 1.33 mmol) in toluene (10 mL) was stirred at reflux for 3 days. The reaction mixture was diluted with EtOAc (150 mL), washed with saturated NaHCO₃ (3 × 25 mL), brine (25 mL), dried (Na₂SO₄) and the solvent removed in vacuo. The crude product was purified by radial chromatography (EtOAc:hexane=1:3~1:1) to give 8 (0.212 g, 80.5%) as pale yellow oil: IR (neat) 2940, 2875, 1685, 1618 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.54-7.29(m, 5H), 6.52(dt, J=9.9, 4.0 Hz, 1H), 5.89(dt, J=9.9, 1.5 Hz, 1H), 4.99(s, 2H), 3.41(t, J=7.0 Hz, 2H), 2.50-2.25(m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 165.7, 140.4, 135.8, 129.6, 128.6, 128.4, 124.8, 77.0, 49.2, 25.8. Anal. Calcd. for C₁₂H₁₃NO₂: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.70; H, 6.64; N, 6.59.

Representative Procedure for the Michael Addition Reactions of 8 with Diamines

1-Benzyloxy-4-[methyl-(2-methylamino-ethyl)-amino]-piperidin-2-one (9a)

N,N’-Dimethyl ethylenediamine (0.32 mL, 3 mmol) was added to a solution of 8 (60 mg, 0.30 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 2 days. The solvent was removed in vacuo. The crude product was purified by column chromatography on alumina (5% MeOH/DCM) to give 9a (80 mg, 92.0%) as yellowish oil: IR (neat) 3317, 2940, 2791, 1667 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.31(m, 5H), 4.99(d, J=10.5 Hz, 1H), 4.93(d, J=10.6 Hz, 1H), 3.46-3.14(m, 2H), 2.85-2.67(m, 1H), 2.67-2.34(m, 6H), 2.43(s, 3H), 2.21(s, 3H), 2.06-1.85(m, 1H), 1.84-1.62(m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 166.7, 135.4, 129.5, 128.7, 128.4, 75.8, 57.3, 52.8, 49.3, 48.2, 37.3, 36.5, 35.1, 26.7. HRMS: calcd for C₁₆H₂₆N₃O₂ (M + H⁺) 292.2020, found 292.2022.

1-Benzyloxy-4-piperazin-1-yl-piperidin-2-one (9b)

The representative procedure for Michael addition was followed using piperazine in place of N,N’-dimethyl ethylenediamine to give 9b as a pale yellow solid; mp 131–132 °C; 96.9% yield; IR (KBr) 3436, 2939, 2800, 1651 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.52-7.30(m, 5H), 4.99(d, J=10.8 Hz, 1H), 4.94(d, J=10.5 Hz, 1H), 3.47-3.20(m, 2H), 2.90(s, 4H), 2.71-2.36(m, 8H), 2.06-1.89(m, 1H), 1.85-1.63(m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 166.4, 135.4, 129.5, 128.7, 128.4, 75.8, 57.8, 50.4, 47.9, 46.2, 35.7, 26.5. HRMS: calcd for C₁₆H₂₄N₃O₂ (M + H⁺) 290.1863, found 290.1869.

1-Benzyloxy-4-(2-dimethylamino-ethylamino)-piperidin-2-one (9c)

The representative procedure for Michael addition was followed using N,N-dimethyl ethylenediamine in place of N,N’-dimethyl ethylenediamine to give 9c as a pale yellow oil; 96.6% yield; IR (neat) 3301, 2944, 2819, 1668 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 7.48-7.28(m, 5H), 4.98(d, J=10.6 Hz, 1H), 4.95(d, J=10.8 Hz, 1H), 3.46-3.36(m, 1H), 3.36-3.24(m, 1H), 2.99-2.86(m, 1H), 2.69-2.59(m, 2H), 2.43-2.17(m, 4H), 2.20(s, 6H), 2.00-1.89(m, 1H), 1.74-1.61(m, 1H); ¹³C NMR(75 MHz, CDCl₃) δ 166.3, 135.5, 129.5, 128.6, 128.4, 75.7, 58.9, 51.3, 47.5, 45.4, 44.4, 39.9, 29.4. HRMS: calcd for C₁₆H₂₆N₃O₂ (M + H⁺) 292.2020, found 292.2025.

3-Benzenesulfonyl-1-benzyloxy-3-{2-[2-(3’-benzenesulfonyl-1’-benzyloxy-2’-oxo-piperidin-3’-yl) ethoxy]-ethyl}-piperidin-2-one (10)

Potassium carbonate (304 mg, 2.2 mmol) was added to a solution of 3b (76 mg, 0.22 mmol) and 2-iodoethyl ether (33 mg, 0.1 mmol) in MeCN (5 mL) and the mixture was stirred at reflux for 3 days. The reaction mixture was cooled, poured into water (50 mL) and the product extracted into CH₂Cl₂ (3 × 20mL). The combined organic layer was washed with brine (15 mL), dried (Na₂SO₄) and the solvent removed in vacuo. The crude product was purified by radial chromatography (EtOAc:hexane= 1:4~1:1) to give 10 (0.039 g, 51.3%) as a 1:1 mixture of diastereomers; white solid; IR (KBr) 2930, 2876, 1663 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 7.96-7.76(m, 4H), 7.72-7.29(m, 16H), 5.07-4.83(m, 4H), 3.55-3.19(m, 8H), 2.72-2.48(m, 2H), 2.48-2.27(m, 2H), 2.26-1.94(m, 4H), 1.94-1.66(m, 4H); ¹³C NMR (50 MHz, CDCl₃) δ 162.0, 136.3, 135.1, 134.0, 131.0, 129.7, 128.8, 128.7, 128.5, 76.7, 75.9, 72.0, 71.7, 66.4, 66.3, 50.6, 33.9, 25.9, 20.3. Anal. Calcd for C₄₀H₄₄N₂O₉S₂·H₂O: C, 61.68; H, 5.95; N, 3.60. Found: C, 61.47; H, 5.90; N, 3.31.

1-Benzyloxy-3-{2-[2-(1’-benzyloxy-2’-oxo-piperidin-3’-yl)ethoxy]-ethyl}-piperidin-2-one (11)

Disodium hydrogen phosphate (30 mg, 0.21 mmol) and 6% Na/Hg amalgam (200 mg, 0.84 mmol) was added to a solution of 10 (32 mg, 0.042 mmol) in MeOH (1 mL) at −78 °C and the mixture was stirred at −78 °C for 2h and then at rt for 12h. The reaction mixture was vacuum filtered through a short column of silica gel and washed with MeOH (30 mL). The solvent was removed in vacuo. The residue was dissolved in EtOAc (50 mL), washed with saturated NaHCO₃ (2 × 10 mL), brine (10 mL), dried (Na₂SO₄) and the solvent was removed in vacuo. The product 11 (14 mg, 70.0%) was obtained as colorless oil. IR (neat) 2942, 2870, 1660 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.29(m, 10H), 5.05-4.80 (m, 4H), 3.66-3.45 (m, 4H), 3.45-3.25 (m, 4H), 2.60-2.40 (m, 2H), 2.39-2.13(m, 2H), 1.98-1.80(m, 4H), 1.80-1.55(m, 4H), 1.55-1.39(m, 2H); ¹³C NMR (50 MHz, CDCl₃) δ 170.2, 135.6, 129.6, 128.6, 128.4, 75.6, 68.8, 68.6, 51.0, 40.1, 40.0, 31.5, 26.8, 26.7, 22.2. Anal. Calcd for C₂₈H₃₆N₂O₅: C, 69.98; H, 7.55; N, 5.83. Found: C, 70.29; H, 7.49; N, 5.77.

1-Hydroxy-3-{2-[2-(1’-hydroxy-2’-oxo-piperidin-3’-yl)ethoxy]-ethyl}-piperidin-2-one (12)

Palladium on carbon (10%, 8 mg) was added to a solution of 11 (40 mg, 0.08 mmol) in MeOH (1 mL) and the mixture was stirred at rt under hydrogen balloon for 20 h. The catalyst was removed by centrifugation followed by filtration. The product was lyophilized from deionized water to give bis cyclic hydroxamic acid 12 (22mg, 88.0%) as pale yellow oil: IR (neat) 3233, 2920, 2861, 1634 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 3.58-3.59(m, 4H), 3.59-3.50(m, 4H), 3.46-3.38(m, 2H), 2.64-2.45(m, 4H), 2.27-2.21(m, 2H), 2.07-1.81(m, 6H), 1.75-1.53(m, 4H); ¹³C NMR (50 MHz, D₂O) δ 175.5, 72.6, 56.1, 46.3, 43.0, 41.8, 34.9, 29.5, 29.3, 25.2, 24.5. Anal. Calcd for C₁₄H₂₄N₂O₅: C, 55.98; H, 8.05; N, 9.33. Found: C, 56.17; H, 8.15; N, 8.91.

(Z,Z)-1-Benzyloxy-3-(6-(1'-benzyloxy-2'-oxo-piperidin-3'-ylmethylene)-pyridin-2-ylmethylene)-piperidin-2-one (13)

A solution of potassium carbonate (0.497 g, 3.6 mmol) in H₂O (3 mL) was added to a solution of 3k (0.612 g, 1.8 mmol) and 2,6-pyridine dicarboxaldehyde (81 mg, 0.6 mmol) in THF (3 mL) and the mixture was stirred at 80 °C for 2 days. The reaction mixture was cooled, poured into water (50 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried (Na₂SO₄) and the solvent removed in vacuo. The crude product was purified by radial chromatography (EtOAc:hexane 33~100%) to give 13 (0.194 g, 63.6%) as white solid: mp 145–147 °C; IR (KBr) 3049, 2942, 2871, 1660, 1619 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.78-7.67(m, 3H), 7.53-7.33(m, 10H), 7.29(s, 2H), 5.28(s, 4H), 3.50(t, J=6.0 Hz, 4H), 3.08(td, J=7.1, 1.9 Hz, 4H), 1.82(quin, J=6.2 Hz, 4H); ¹³C NMR (50 MHz, CDCl₃) δ 162.7, 154.8, 136.6, 135.5, 134.1, 132.8, 129.7, 128.5, 125.2, 75.9, 50.8, 25.6, 22.7. Anal. Calcd for C₃₁H₃₁N₃O₄: C, 73.06; H, 6.13; N, 8.25. Found: C, 72.66; H, 6.05; N, 8.24.

(Z,Z)-1-Hydroxy-3-(6-(1'-hydroxy-2'-oxo-piperidin-3'-ylmethylene)-pyridin-2-ylmethylene)-piperidin-2-one hydrobromide (14)

Concentrated HBr (1 mL) and glacial acetic acid (1 mL) was added to 13 (51 mg, 0.1 mmol) and the mixture was stirred at 55 °C for 4 d. The solvent was removed in vacuo. The bis cyclic hydroxamic acid 13 (35 mg, 85.4%) was obtained as brownish solid, which was homogeneous by TLC: mp 121–123 °C; IR (KBr) 3401, 2945, 1710, 1629 cm⁻¹; ¹H NMR (300 MHz, D₂O) δ 8.51 (t, J=8.0 Hz, 1H), 7.89(d, J=8.2 Hz, 2H), 7.59(s, 2H), 7.42(s, 1H), 3.18(t, J=7.5 Hz, 4H), 2.51(t, J=7.9 Hz, 4H), 2.01-1.72(m, 4H); ¹³C NMR (75 MHz, D₂O) δ 168.9, 148.2, 142.0, 141.9, 128.8, 126.8, 50.0, 24.8, 22.1. Anal. Calcd for C₁₇H₂₂N₃O₄S₂Br₃·2H₂O: C, 33.58; H, 4.31; N, 6.91. Found: C, 33.87; H, 4.05; N, 6.82.

1-Hydroxy-3-(6-(1'-hydroxy-2'-oxo-piperidin-3'-ylmethyl)-pyridin-2-ylmethyl)-piperidin-2-one (15)

Palladium on carbon (10%, 10 mg) was added to a solution of 13 (50 mg, 0.1 mmol) in MeOH (2 mL) and the mixture was stirred at rt under hydrogen balloon for 2 d. The catalyst was removed by centrifugation followed by filtration. The solvent was removed in vacuo. The residue was purified by washing with CH₂Cl₂ to give 15 (25 mg, 75.8%) as pale yellow solid: mp 95–98 °C; IR (KBr) 3095, 2943, 2864, 1635 cm⁻¹; ¹H NMR (300 MHz, D₂O) δ 8.35 (t, J=7.9 Hz, 1H), 7.75(d, J=8.2 Hz, 2H), 3.67-3.56(m, 4H), 3.51-3.38(m, 2H), 3.30-3.13(m, 2H), 3.08-2.94(m, 2H), 2.18-1.76(m, 6H), 1.76-1.53(m, 2H); ¹³C NMR (50 MHz, CD₃OD) δ 170.6, 170.2, 160.2, 138.3, 138.1, 122.9, 122.6, 52.6, 50.3, 47.7, 43.0, 42.6, 40.0, 39.8, 26.7, 26.3, 22.7, 22.6. HRMS: calcd for C₁₇H₂₄N₃O₄ (M + H⁺) 334.1761, found 334.1765.