Synthesis of β-Hydroxy O-Alkyl Hydroxylamines from Epoxides Using a Convenient and Versatile Two-Step Procedure

Abstract

A simple and convenient synthetic method was developed to prepare β-hydroxy O-alkyl hydroxylamines in which base-mediated ring opening of epoxides with acetophenone oxime followed by cleavage of the oxime with 2,4-dinitrophenylhydrazine in acidic media furnished the hydroxylamine, which can be protected in situ with various N-protecting groups.

Key words

hydroxylamines - epoxides - ring opening - oxime cleavage - protecting groups

O-Alkyl hydroxylamines (or aminooxy compounds), which are non-basic substitutes for amines,[ ¹ ] are found in various natural products such as l-canaline[ ² ] and in various synthetic products displaying interesting biological activities.[2] [3] Along with their β-hydroxy congeners,[ ⁴ ] these compounds predominantly show enzyme inhibition activities whereby the aminooxy moiety forms a stable oxime with an aldehyde group present on the cofactor. In preparative chemistry these reactive species usually serve as starting material for the preparation of functionalized O-alkyl oximes by simple condensation with aldehydes or ketones, often with quantitative yields and with almost complete functional group compatibility. This classical reaction has undergone a renaissance as a chemoselective ligation strategy and has emerged as a powerful means for the assembly of bioconjugates.[ ⁵ ]

Scheme 1

In connection with ongoing projects in our laboratory,[ ⁶ ] we required a variety of β-hydroxy O-alkyl hydroxylamines 2 and conceived that these might be accessed by the opening of epoxides 1 by N-protected hydroxylamines followed by deprotection of the nitrogen atom (Scheme [1]). Toward this end, the most efficient approach leading to 2 seemed to be a direct opening of epoxide 1 with an N-protected hydroxylamine (i.e., N-Fmoc-hydroxylamine[ ⁷ ] or commercially available N-Boc-hydroxylamine). Surprisingly, such protocols are scarcely documented in the literature. In most reports, N-Boc-hydroxylamine is used under basic conditions, which leads to the expected β-hydroxy O-alkyl hydroxylamines in low to modest yields.[4b] [c] [8] The successful employment of N-hydroxyphthalimide in this context was also described by Porco and co-workers[ ⁹ ] with promotion by a Co-oligosalen catalyst.[ ¹⁰ ] In pursuit of our goal, we initially looked for viable conditions on commercially available cyclopentene oxide (3h; see Table [1]). Because the use of potassium carbonate with N-Fmoc-hydroxylamine under Plenkiewicz’s conditions[ ^8b ] showed no discernible conversion (Table [1], entry 1), we decided to leave basic conditions aside and investigate the ring opening of epoxide 3h under Lewis acid catalysis conditions (Table [1], entries 2–15), which is a method usually used for the insertion of alcohols and/or amines but not yet employed with hydroxylamines as the nucleophile component. The ring opening of epoxide 3h with N-Fmoc-hydroxylamine was first investigated with BF₃·Et₂O in dichloromethane (Table [1], entry 2), conditions that are known to be efficient for the reaction of benzyl alcohol with a similar epoxide,[ ^6a ] but this approach was unsuccessful in this case. The use of lanthanide-based Lewis acids [i.e., Sc(OTf)₃ and Yb(OTf)₃] also failed (Table­ [1], entries 3–6). Changing the nucleophile to N-Boc hydroxylamine or N-hydroxypiperidine, presumably more nucleophilic species, was also unproductive with numerous types of Lewis acid [LiBr, InCl₃, ZrCl₄, Cu(OTf)₂, or Ti(OiPr)₄; Table [1], entries 7–15]. Finally, we envisaged an alternative two-step procedure based on the intermediate introduction of an oxime under basic conditions as a hydroxylamine precursor, followed by its acid-mediated cleavage to give the expected β-hydroxy O-alkyl hydroxylamine. Oximes are more nucleophilic than hydroxylamines under basic conditions and their high-yield ring-opening of epoxides has been described.[ ¹¹ ] Thus, the group of Soltani Rad recently described the aqueous-mediated ring opening of various epoxides with a range of oximes.[ ^11a ] Their protocol involved the use of a slight excess of potassium hydroxide (1.3 equiv) to deprotonate the oxime (1 equiv) in a mixture of water–dimethyl sulfoxide (DMSO) (7:3) at room temperature, followed by the addition of an excess of epoxide (1.5 equiv). Similar conditions were evaluated on cyclopentene oxide (3h) but with a slight excess of acetophenone oxime, as it would ultimately represent the least precious component in reactions employing more complex epoxides (Table [1], entry 16). Surprisingly, the solvent system used by Soltani Rad et al. was not efficient for our model epoxide and only traces of the expected compound were obtained. Heating to 90 °C led to formation of the desired oxime 4h in low yield (23%; Table [1], entry 17). Switching from DMSO to N,N-dimethylformamide (DMF) did not increase the yield at room temperature (Table [1], entry 18) but compound 4h was obtained in a good yield at 90 °C (73%; Table [1], entry 19).

Table 1 Ring Opening of Cyclopentene Oxide with Hydroxylamine-Derived Nucleophiles

Entry	Nucleophile	LA (cat.) orbase	Solvent	Temp (°C)	Yield (%)a,b
1	HONHFmoc	K2CO3	EtOH	60	NR
2	HONHFmoc	BF3Et2O	CH2Cl2	r.t.	NR
3		Sc(OTf)3	CH2Cl2	r.t.	NR
4		Sc(OTf)3	MeCN	r.t.	NR
5		Sc(OTf)3	THF	r.t.	NR
6		Yb(OTf)3	THF	r.t.	NR
7	HONHBoc	Sc(OTf)3	CH2Cl2	r.t.	NR
8		Yb(OTf)3	CH2Cl2	r.t.	NR
9		Sc(OTf)3	CH2Cl2	r.t.	NR
10		Yb(OTf)3	CH2Cl2	r.t.	NR
11		LiBr	CH2Cl2	r.t.	NR
12		InCl3	CH2Cl2	r.t.	NR
13		Ti(OiPr)4	CH2Cl2	r.t.	NR
14		Cu(OTf)2	CH2Cl2	r.t.	NR
15		ZrCl4	CH2Cl2	r.t.	NR
16		KOH	H2O–DMSOc	r.t.	trace
17		KOH	H2O–DMSOc	90	23
18		KOH	DMF	r.t.	trace
19		KOH	DMF	90	73

^a Isolated yield.

^b NR = no reaction.

^c In a 7:3 ratio.

With conditions established for the ring-opening of cyclopentene oxide by acetophenone oxime, we next focused on the cleavage of the oxime functionality to liberate the O-alkyl hydroxylamine. After many unfruitful assays under acidic conditions, we found that 2,4-dinitrophenylhydrazine was efficient for the liberation of O-alkyl hydroxylamine from oximes with generation of 2,4-dinitrophenylhydrazone as a by-product. We also established that protection of the hydroxylamine product in situ was possible by reaction with FmocCl, CbzCl, or AllocCl, which provides a means to isolate the target compound in the form of a carbamate, cleavable under basic, acidic, or metal-catalyzed conditions. To evaluate the scope of the process, we tested its versatility towards various epoxides 3, so as to obtain the corresponding β-hydroxy O-alkyl hydroxylamines 5. The results, presented in Table [2], show regioselective ring-opening of terminal epoxides with preferential attack at the less hindered position (Table [2], entries 1–6). The presence of a double bond or an aromatic core did not affect the yield (Table [2], entries 1 and 3). The PMP-protected glycidol epoxide furnished α-hydroxyoxime 4a in 83% yield. Hydrolysis of the oxime furnished free hydroxylamine 5a in 77% yield or 6a–8a in a range of 80–89%, depending on the carbamate used (Table [2], entry 1). A free hydroxyl group was found to be compatible with the ring opening but decreased the yield to 46% (Table [2], entry 4). In the case of epichlorohydrin (Table [2], entry 5), the epoxide, which is known to be the more reactive site,[ ¹² ] was opened smoothly to afford 4e with acetophenone oxime in 73% yield. Unfortunately, the presence of an epoxide was not compatible with 2,4-dinitrophenylhydrazine-mediated cleavage of the oxime (Table [2], entry 5). Thus, epoxide 4e was opened with a second equivalent of acetophenone oxime to give 4f in good yield (Table [2], entry 6). Highly functionalized Cerny’s epoxide 3j was converted into its β-hydroxy O-alkyl hydroxylamine derivative 5j in 76% over two steps (Table [2], entry 9). Protection as carbamates in situ was also successful, and 5–8j were obtained in high yields (Table [2], entry 9). Finally, the cyclopentene-derived epoxide 1a was opened with acetophenone oxime at 90 °C and converted into the Fmoc-protected targeted skeleton 2a in good yield (73%) over two steps (Table [2], entry 10).

Table 2 Scope of the Two-Step Procedure; Synthesis of β-Hydroxy O-Alkyl Hydroxylamines

Entry	Epoxide 3	O-Alkyl oxime 4	Product	Yield (%)a	O-Alkyl hydroxylamine 5–8	R3	Product	Yield (%)a
1			4a b	83		H Fmoc Cbz Alloc	5a 6a 7a 8a	77 81c 80 89
2			4b	74d		Fmoc	6b	95
3			4c	84d		Fmoc	6c	69
4			4d	46e		Fmoc	6d	93
5			4e	73		H Fmoc	5e 6e	0f 0f
6			4f	86		Fmoc Alloc	6f 8f	–h 61
7			4h	73e		H Fmoc	5h 6h	–g 99
8			4i	89e		Fmoc Alloc	6i 8i	–h 81
9			4j	89e		H Fmoc Cbz Alloc	5j 6j 7j 8j	76 76 88 74
10	1a		4k	84e		Fmoc	2a	87

^a Isolated yield.

^b PMP = p-methoxyphenyl.

^c The yield dropped to 54% when only 2 equiv of H₂SO₄ were used.

^d Reaction performed at 50 °C.

^e Reaction performed at 90 °C

^f Formation of the expected product was not observed.

^g Formation of the expected product was observed by ¹H NMR spectroscopic analysis, but its isolation was troublesome.

^h The expected product was obtained as an inseparable mixture with Fmoc-protected 2,4-dinitrophenylhydrazine.

In conclusion, we have established a convenient two-step procedure for the synthesis of β-hydroxy O-alkyl hydroxylamines by oxime-mediated regioselective opening of epoxides under basic conditions, followed by cleavage of the resulting oxime by 2,4-dinitrophenylhydrazine. We showed that various protecting groups could be introduced for protection of the highly polar resulting O-alkyl hydroxylamines in situ. The scope of the reaction revealed its good tolerance for alkenes, halogens, and alcohols.

Reactions were performed under an atmosphere of argon and monitored by thin-layer chromatography on Merck silica gel plates (60 F₂₅₄ aluminum sheets). All separations were carried out under flash-chromatographic conditions on silica gel (Redi Sep prepacked column, 230–400 mesh) with the use of a CombiFlash Companion. N,N-Dimethylformamide (DMF) was purified by filtration through an activated alumina column under argon. MeOH was purchased from Acros Organics at the highest commercial quality and used without further purification. Reagent-grade chemicals were obtained from Sigma–Aldrich or Acros Organics chemical companies and were used as received. Optical rotations were measured with an Anton Paar MCP 300 polarimeter at 589 nm and are expressed in deg·cm³·g^–1·dm^–1 and c is expressed in g/100 cm³. IR spectra were recorded with a Perkin–Elmer FT-IR system using a diamond window Dura SamplIR II and the data are reported in reciprocal centimeters (cm^–1). ¹H (500 or 300 MHz) and ¹³C (125 or 75 MHz) NMR spectra were recorded with Brüker Avance spectrometers. Chemical shifts are given in ppm (δ) and are referenced to the internal solvent signal or to TMS used as an internal standard. High-resolution mass spectra (HRMS) were recorded with a Micromass LCT Premier XE instrument (Waters) and were determined by electrospray ionization (ESI).

Epoxide Opening; General Procedure A

Acetophenone oxime (1.5 equiv) and KOH (3 equiv) were dissolved in anhydrous DMF (0.15 M in epoxide) and the solution was stirred at r.t. for 30 min. A solution of epoxide (1 equiv) in anhydrous DMF (0.3 M in epoxide) was then added and the mixture was stirred at the indicated temperature for 16 h. After addition of H₂O, aq HCl (1 M) was added dropwise until pH 1–2. The mixture was extracted with MTBE (3×) and the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Purification by column chromatography with the indicated eluent afforded β-hydroxy oxime O-ethers.

(E)-Acetophenone O-[2-Hydroxy-3-(4-methoxyphenoxy)propyl]oxime (4a)

The reaction was carried out according to General Procedure A with glycidyl 4-methoxyphenyl ether (90 mg, 0.5 mmol), acetophenone oxime (101 mg, 0.75 mmol) and KOH (84 mg, 1.5 mmol) in DMF (5 mL). The mixture was stirred at r.t. for 16 h and worked up as described. The crude product was purified by column chromatography (heptane–EtOAc, 95:5→9:1) to give 4a.

Yield: 131 mg (0.415 mmol, 83%); colorless oil; R_f = 0.19 (heptane–EtOAc, 4:1).

IR (neat): 3461, 2953, 2926, 1739, 1507, 1228, 1113, 1034, 826, 766, 742, 696 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 2.25 (s, 3 H, Me), 3.75 (s, 3 H, OMe), 3.98–4.06 (m, 2 H, H-3), 4.31–4.44 (m, 3 H, H-1, H-2), 6.82 (d, J = 8.9 Hz, 2 H, ArH), 6.87 (d, J = 8.9 Hz, 2 H, ArH), 7.32–7.39 (m, 3 H, Ph-H), 7.58–7.64 (m, 2 H, Ph-H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.7 (CH₃), 55.6 (OCH₃), 69.5 (C-3), 70.0 (C-2), 74.6 (C-1), 114.6 (CH-Ar), 115.5 (CH-Ar), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.3 (CH-Ph), 136.0 (C_q-Ph), 152.7 (C_q-O), 154.0 (C_q=N), 155.8 (C_q-OMe).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₂₂NO₄: 316.1549; found: 316.1556.

(E)-Acetophenone O-(2-Hydroxyoctyl) Oxime (4b)

The reaction was carried out according to General Procedure A with 1,2-epoxyoctane (128 mg, 1 mmol), acetophenone oxime (203 mg, 1.5 mmol), and KOH (168 mg, 3 mmol) in DMF (10 mL). The mixture was stirred at 50 °C for 16 h and worked up as described. The crude product was purified by preparative HPLC (NW50 column, Merck; heptane–EtOAc, 10:0→7:3 over 35 min; 100 mL/min; UV detection at 254 nm) to give 4b.

Yield: 97 mg (0.368 mmol, 74%); colorless oil; R_f = 0.39 (heptane–EtOAc, 4:1).

IR (neat): 3411, 2954, 2927, 2857, 1444, 1369, 1313, 1036, 927, 912, 901, 758, 691 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.85–0.93 (m, 3 H, H-8), 1.24–1.56 (m, 10 H, H3–H7), 2.26 (s, 3 H, Me), 2.93 (br s, 1 H, OH), 3.94–4.04 (m, 1 H, H-2), 4.08 and 4.22 (ABX, J _AB = 11.6 Hz, J _AX = 1.2 Hz, J _BX = 8.0 Hz, 2 H, H-1), 7.33–7.40 (m, 3 H, Ph-H), 7.58–7.66 (m, 2 H, Ph-H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.7 (CH₃), 14.1 (C-8), 22.6 (C-7), 25.4 (C-4 or C-5), 29.3 (C-4 or C-5), 31.8 (C-6), 33.2 (C-3), 71.4 (C-2), 77.9 (C-1), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.3 (CH-Ph), 136.2 (C_q-Ph), 155.6 (C_q=N).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₆H₂₆NO₂: 264.1964; found: 264.1965.

(E)-Acetophenone O-(2-Hydroxy-2-methylbut-3-en-1-yl) Oxime (4c)

The reaction was carried out according to General Procedure A with 2-methyl-2-vinyloxirane (84 mg, 1 mmol), acetophenone oxime (203 mg, 1.5 mmol) and KOH (168 mg, 3 mmol) in DMF (10 mL). The mixture was stirred at 50 °C for 16 h and worked up as described. The crude product was purified by preparative HPLC (NW50 column, Merck; heptane–EtOAc, 10:0→8:2 over 35 min; 100 mL/min; UV detection at 254 nm) to give 4c.

Yield: 92 mg (0.420 mmol, 84%); colorless oil; R_f = 0.24 (heptane–MTBE, 4:1).

IR (neat): 3425, 2976, 2930, 2873, 1445, 1370, 1307, 1044, 994, 914, 758, 691 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.31 (s, 3 H, H-5), 2.25 (s, 3 H, Me), 3.41 (br s, 1 H, OH), 4.14 (s, 2 H, H-1), 5.14 (dd, J = 1.5, 10.7 Hz, 1 H, H-4), 5.37 (dd, J = 1.5, 17.1 Hz, 1 H, H-4), 5.96 (dd, J = 10.7, 17.1 Hz, 1 H, H-3), 7.32–7.39 (m, 3 H, Ph-H), 7.57–7.65 (m, 2 H, Ph-H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.8 (CH₃), 72.5 (C-2), 77.2 (C-1), 116.3 (C-4), 115.5 (CH-Ar), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.4 (CH-Ph), 136.1 (C_q-Ph), 136.4 (C-3), 155.9 (C_q=N).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₈NO₂: 220.1338; found: 220.1336.

(S,E)-Acetophenone O-(2,3-Dihydroxypropyl) Oxime (4d)

The reaction was carried out according to General Procedure A with (S)-glycidol (74 mg, 1 mmol), acetophenone oxime (203 mg, 1.5 mmol) and KOH (168 mg, 3 mmol) in DMF (10 mL). The mixture was stirred at 90 °C for 16 h and worked up as described. The crude product was purified by column chromatography (heptane–EtOAc, 1:1) to give 4d.

Yield: 97 mg (0.464 mmol, 46%); pale-yellow oil; [α]_D ²⁴ –12.6 (c 0.89, CHCl₃); R_f = 0.22 (heptane–EtOAc, 3:7).

IR (neat): 3277, 2927, 2872, 1467, 1441, 1058, 1046, 914, 754, 690 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 2.24 (s, 3 H, Me), 3.26 (br s, 2 H, 2 × OH), 3.66 and 3.74 (ABX, J _AB = 11.6 Hz, J _AX = 3.9 Hz, J _BX = 5.9 Hz, 2 H, H-3), 4.01–4.12 (m, 1 H, H-2), 4.25 (d, J = 5.3 Hz, 2 H, H-1), 7.32–7.39 (m, 3 H, Ph-H), 7.55–7.63 (m, 2 H, Ph-H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.8 (CH₃), 63.6 (C-3), 71.6 (C-2), 74.6 (C-1), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.3 (CH-Ph), 136.0 (C_q-Ph), 156.0 (C_q=N).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₆NO₃: 210.1130; found: 210.1133.

(E)-Acetophenone O-Oxiran-2-ylmethyl Oxime (4e)

The reaction was carried out according to General Procedure A with epichlorohydrin (234 μL, 3 mmol), acetophenone oxime (405 mg, 3 mmol) and KOH (336 mg, 6 mmol) in DMF (20 mL). The mixture was stirred at r.t. for 16 h and worked up as described. The crude product was purified by column chromatography (heptane–EtOAc, 4:1) to give 4e.

Yield: 420 mg (2.2 mmol, 73%); colorless oil; R_f = 0.48 (heptane–EtOAc, 7:3).

IR (neat): 3056, 3001, 2926, 2876, 1497, 1445, 1370, 1311, 1038, 992, 909, 885, 759, 693 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 2.28 (s, 3 H, Me), 2.69 (dd, J = 2.8, 5.1 Hz, 1 H, H-3), 2.87 (d, J = 4.5 Hz, 1 H, H-3), 3.30–3.37 (m, 1 H, H-2), 4.16 and 4.42 (ABX, J _AB = 12.2 Hz, J _AX = 3.4 Hz, J _BX = 6.0 Hz, 2 H, H-1), 7.33–7.41 (m, 3 H, Ph-H), 7.61–7.69 (m, 2 H, Ph-H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.7 (CH₃), 44.8 (C-3), 50.2 (C-2), 74.8 (C-1), 126.0 (CH-Ph), 128.3 (CH-Ph), 129.1 (CH-Ph), 136.3 (C_q-Ph), 155.3 (C_q=N).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₄NO₂: 192.1025; found: 192.1034.

(1E,1′E)-Acetophenone O-(2-Hydroxy-3-{[(E)-(1-phenylethylidene)amino]oxy}propyl) Oxime (4f)

The reaction was carried out according to General Procedure A with 4e (100 mg, 0.52 mmol), acetophenone oxime (106.1 mg, 0.78 mmol) and KOH (88 mg, 1.6 mmol) in DMF (5 mL). The mixture was stirred at r.t. for 16 h and worked up as described. The crude product was purified by column chromatography (heptane–EtOAc, 7:3) to give 4f.

Yield: 147.5 mg (0.45 mmol, 86%); colorless oil; R_f = 0.63 (heptane–EtOAc, 3:2).

IR (neat): 3423, 3059, 2931, 2877, 1497, 1444, 1369, 1311, 1042, 998, 935, 919, 889, 759 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 2.28 (s, 6 H, Me), 4.26–4.42 (m, 5 H, H-1, H-2), 7.32–7.41 (m, 6 H, Ph-H), 7.59–7.69 (m, 4 H, Ph-H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.8 (CH₃), 70.8 (C-2), 74.8 (C-1), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.3 (CH-Ph), 136.2 (C_q-Ph), 155.6 (C_q=N).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₂₃N₂O₃: 327.1709; found: 327.1714.

(E)-Acetophenone O-[(trans)-2-Hydroxycyclopentyl] Oxime (4h)

The reaction was carried out according to General Procedure A with cyclopentene oxide (50 mg, 0.6 mmol), acetophenone oxime (121 mg, 0.9 mmol) and KOH (100 mg, 1.8 mmol) in DMF (6 mL). The mixture was stirred at 90 °C for 16 h and worked up as described. The crude product was purified by column chromatography (heptane–EtOAc, 80:20) to give 4h.

Yield: 96 mg (0.44 mmol, 73%); colorless oil; R_f = 0.31 (heptane–EtOAc, 4:1).

IR (neat): 3358, 3056, 2961, 1496, 1445, 1369, 1316, 1083, 1037, 995, 973, 914, 760, 693 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.56–1.83 (m, 4 H, H-3, H-4, H-5), 1.93–2.18 (m, 2 H, H-3, H-5), 2.21 (s, 3 H, Me), 2.87 (br s, 1 H, OH), 4.28 (td, J = 4.1, 6.2 Hz, 1 H, H-2), 4.53 (ddd, J = 3.8, 4.8, 7.3 Hz, 1 H, H-1), 7.31–7.38 (m, 3 H, Ph-H), 7.57–7.65 (m, 2 H, Ph-H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.7 (CH₃), 20.8 (C-4), 28.5 (C-5), 31.6 (C-3), 77.8 (C-2), 89.7 (C-1), 126.0 (CH-Ph), 128.3 (CH-Ph), 129.1 (CH-Ph), 136.5 (C_q-Ph), 155.1 (C_q=N).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₈NO₂: 220.1338; found: 220.1339.

(E)-Acetophenone O-[(trans)-2-Hydroxycyclohexyl] Oxime (4i)

The reaction was carried out according to General Procedure A with cyclohexene oxide (46.1 mg, 0.5 mmol), acetophenone oxime (101.3 mg, 0.75 mmol) and KOH (84 mg, 1.5 mmol) in DMF (5 mL). The mixture was stirred at r.t. for 16 h and worked up as described. The crude product was purified by preparative HPLC (Eurospher­ 100–5 Si column, Knauer; 250 × 20 mm; heptane–EtOAc­, 10:0→7:3 over 40 min; 12 mL/min; UV detection at 254 nm) to give 4i.

Yield: 104.4 mg (0.45 mmol, 89%); colorless oil; R_f = 0.32 (heptane–EtOAc, 7:3).

IR (neat): 3429, 2933, 2862, 1497, 1447, 1371, 1074, 1039, 1007, 998, 936, 920, 760, 693 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.22–1.43 (m, 4 H, H-3, H-4, H-5, H-6), 1.68–1.80 (m, 2 H, H-3, H-4), 2.02–2.15 (m, 2 H, H-6, H-5), 2.27 (s, 3 H, Me), 3.69–3.76 (m, 1 H, H-2), 3.97–4.07 (m, 1 H, H-1), 7.32–7.41 (m, 3 H, Ph-H), 7.58–7.66 (m, 2 H, Ph-H).

¹³C NMR (75 MHz, CDCl₃): δ = 12.7 (CH₃), 23.7 (C-3 or C-4), 24.2 (C-3 or C-4), 29.6 (C-5), 32.6 (C-6), 74.6 (C-2), 85.8 (C-1), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.2 (CH-Ph), 136.2 (C_q-Ph), 155.2 (C_q=N).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₂₀NO₂: 234.1494; found: 234.1487.

Compound 4j

The reaction was carried out according to General Procedure A with NAP-protected Cerny’s epoxide[ ^6a ] (142 mg, 0.5 mmol), acetophenone oxime (101 mg, 0.75 mmol) and KOH (84 mg, 1.5 mmol) in DMF (5 mL). The mixture was stirred at 90 °C for 16 h and worked up as described. The crude product was purified by column chromatography (heptane–EtOAc, 8:2→7:3) to give 4j.

Yield: 187 mg (0.446 mmol, 89%); pale-yellow foam; [α]_D ²⁴ –7.6 (c 1.09, CHCl₃); R_f = 0.47 (heptane–EtOAc, 1:1).

IR (neat): 3411, 2925, 2905, 1445, 1359, 1318, 1304, 1039, 972, 918, 905, 886, 760, 690 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 2.23 (s, 3 H, Me), 3.23 (br s, 1 H, OH), 3.43 (s, 1 H, H-2), 3.64 (dd, J = 6.4 Hz, 1 H, H-6), 3.84 (d, J = 7.3 Hz, 1 H, H-6), 4.07–4.14 (m, 2 H, H-3, H-4), 4.60 (d, J = 4.9 Hz, 1 H, H-5), 4.77 and 4.84 (AB, J _AB = 12.2 Hz, 2 H, CH₂-NAP), 5.63 (s, 1 H, H-1), 7.28–7.36 (m, 3 H, ArH), 7.39–7.51 (m, 3 H, ArH), 7.56–7.63 (m, 2 H, ArH), 7.73–7.82 (m, 4 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 13.0 (CH₃), 66.5 (C-6), 71.0 (C-3), 71.8 (CH₂-NAP), 75.6 (C-5), 79.9 (C-2), 83.3 (C-4), 100.6 (C-1), 125.7 (CH-Ar), 125.9 (CH-Ar), 126.1 (CH-Ar), 126.1 (CH-Ar), 126.5 (CH-Ar), 127.6 (CH-Ar), 127.8 (CH-Ar), 128.2 (CH-Ar), 128.4 (CH-Ar), 129.4 (CH-Ar), 132.9 (C_q-NAP), 133.1 (C_q-NAP), 135.3 (C_q-NAP), 136.0 (C_q-Ph), 156.8 (C_q=N).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₅H₂₅NNaO₅: 442.1630; found: 442.1631.

(1R,2S,3R,5S)-2-[(Benzyloxy)methyl]-3-(naphthalen-2-yl­methoxy)-6-oxabicyclo[3.1.0]hexane (1a)

To a solution of (1R,2S,3R,5S)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexan-3-ol[ ^6a ] (205 mg, 0.931 mmol, 1 equiv) in anhydrous DMF (10 mL) were added NaH (60% in mineral oil, 67 mg, 1.68 mmol, 1.8 equiv) and 2-bromomethylnaphthalene (309 mg, 1.40 mmol, 1.5 equiv) and the mixture was stirred at r.t. for 4 h. After addition of crushed ice, the mixture was extracted with MTBE (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated in vacuo. Purification by column chromatography (heptane–EtOAc, 7:3) gave 1a.

Yield: 322 mg (0.893 mmol, 96%); pale-yellow oil; [α]_D ²⁴ –48.0 (c 0.89, CHCl₃); R_f = 0.43 (heptane–EtOAc, 3:2).

IR (neat): 2925, 2856, 1362, 1121, 1084, 1027, 839, 815, 737, 697 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 2.04 (ddd, J = 0.9, 7.6, 15.3 Hz, 1 H, H-5), 2.18 (d, J = 15.3 Hz, 1 H, H-5), 2.65 (t, J = 5.8 Hz, 1 H, H-2), 3.37 and 3.40 (ABX, J _AB = 9.5 Hz, J _AX = 6.1 Hz, J _BX = 6.1 Hz, 2 H, CH₂-OBn), 3.46 (d, J = 2.1 Hz, 1 H, H-4), 3.54 (br s, 1 H, H-3), 3.93 (d, J = 7.6 Hz, 1 H, H-1), 4.45 (s, 2 H, CH₂-Bn), 4.61 and 4.68 (AB, J _AB = 12.8 Hz, 2 H, CH₂-NAP), 7.20–7.33 (m, 5 H, ArH), 7.40–7.50 (m, 3 H, ArH), 7.69–7.84 (m, 4 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 34.8 (C-5), 47.4 (C-2), 57.9 (C-3), 59.7 (C-4), 69.2 (CH₂-OBn), 70.9 (CH₂-NAP), 73.2 (CH₂-Bn), 80.9 (C-1), 125.7 (CH-Ar), 125.9 (CH-Ar), 126.0 (CH-Ar), 126.4 (CH-Ar), 127.4 (CH-Ar), 127.6 (CH-Ar), 127.8 (CH-Ar), 128.0 (CH-Ar), 128.3 (CH-Ar), 132.9 (C_q-NAP), 133.2 (C_q-NAP), 135.9 (C_q-NAP), 138.0 (C_q-Bn).

HRMS (ESI-TOF): m/z [M + NH₄]⁺ calcd for C₂₄H₂₈NO₃: 378.2069; found: 378.2070.

(E)-Acetophenone O-{(1R,2R,3R,4R)-3-[(Benzyloxy)methyl]-2-hydroxy-4-(naphthalen-2-ylmethoxy)cyclopentyl} Oxime (4k)

The reaction was carried out according to General Procedure A with 1a (23 mg, 0.064 mmol), acetophenone oxime (13 mg, 0.096 mmol) and KOH (11 mg, 0.192 mmol) in DMF (850 μL). The mixture was stirred at 90 °C for 16 h and worked up as described. The crude product was purified by column chromatography (heptane–MTBE, 4:1) to give 4k.

Yield: 27 mg (0.054 mmol, 84%); colorless oil; [α]_D ²⁴ +3.6 (c 0.72, CHCl₃); R_f = 0.41 (heptane–MTBE, 1:1).

IR (neat): 3441, 3058, 3027, 2924, 2858, 1366, 1065, 1028, 995, 913, 855, 815, 756, 736, 693 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 2.03–2.15 (m, 1 H, H-5), 2.20 (s, 3 H, Me), 2.23–2.39 (m, 2 H, H-2, H-5), 3.63 and 3.67 (ABX, J _AB = 9.3 Hz, J _AX = 5.3 Hz, J _BX = 5.7 Hz, 2 H, CH₂-OBn), 3.95–4.03 (m, 1 H, H-1), 4.11 (dd, J = 6.2, 8.3 Hz, 1 H, H-3), 4.49 and 4.53 (AB, J _AB = 12.0 Hz, 2 H, CH₂-Bn), 4.62 and 4.70 (AB, J _AB = 12.1 Hz, 2 H, CH₂-NAP), 4.71–4.85 (m, 1 H, H-4), 7.20–7.50 (m, 11 H, ArH), 7.55–7.64 (m, 2 H, ArH), 7.72–7.86 (m, 4 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 12.8 (CH₃), 34.7 (C-5), 51.7 (C-2), 69.4 (CH₂-OBn), 71.2 (CH₂-NAP), 73.2 (CH₂-Bn), 77.1 (C-1), 78.1 (C-3), 86.9 (C-4), 125.8 (CH-Ar), 126.0 (CH-Ar), 126.0 (CH-Ar), 126.3 (CH-Ar), 127.5 (CH-Ar), 127.6 (CH-Ar), 127.7 (CH-Ar), 127.9 (CH-Ar), 128.1 (CH-Ar), 128.3 (CH-Ar), 128.4 (CH-Ar), 128.4 (CH-Ar), 129.2 (CH-Ar), 132.9 (C_q-NAP), 133.3 (C_q-NAP), 135.9 (C_q-Ph), 136.4 (C_q-NAP), 138.3 (C_q-Bn), 155.4 (C_q=N).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₃₂H₃₃NNaO₄: 518.2307; found: 518.2313.

Synthesis of N-Protected O-Alkyl Hydroxylamine; General Procedure B

To a solution of β-hydroxy oxime O-ether (1 equiv) in anhydrous MeOH (0.13 M) were added H₂SO₄ (10 equiv) and 2,4-dinitrophenylhydrazine (2 equiv) and the mixture was stirred at r.t. for 16 h. After dilution with MeOH (4 × initial volume), powdered NaHCO₃ (20 equiv) was added slowly at 0 °C, followed by protecting reagent (5 equiv). The reaction mixture was stirred for 3 h at r.t. and diluted with EtOAc (2 × volume of MeOH). The organic layer was washed with H₂O (×2), brine, dried over Na₂SO₄ and concentrated in vacuo. Purification by column chromatography with the indicated eluent gave the expected N-protected β-hydroxy O-alkyl hydroxylamine.

1-(Aminooxy)-3-(4-methoxyphenoxy)propan-2-ol (5a)

To a solution of 4a (79 mg, 0.25 mmol, 1 equiv) in anhydrous MeOH (2 mL) were added H₂SO₄ (135 μL, 2.5 mmol, 10 equiv) and 2,4-dinitrophenylhydrazine (99 mg, 0.5 mmol, 2 equiv) and the mixture was stirred at r.t. for 16 h. Powdered NaHCO₃ (420 mg, 5 mmol, 20 equiv) was then added slowly and the reaction mixture was diluted with H₂O (20 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic layers were washed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄ and concentrated in vacuo. Purification by column chromatography (heptane–EtOAc, 1:1→3:7) gave 5a.

Yield: 41 mg (0.192 mmol, 77%); pale-yellow amorphous solid; R_f  = 0.10 (heptane–EtOAc, 1:4).

IR (neat): 3301, 3249, 2935, 1513, 1240, 1046, 1033, 825 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 3.76 (s, 3 H, OMe), 3.83 and 3.90 (ABX, J _AB = 11.7 Hz, J _AX = 3.1 Hz, J _BX = 6.5 Hz, 2 H, H-1), 3.96 (d, J = 5.6 Hz, 2 H, H-3), 4.22–4.30 (m, 1 H, H-2), 6.79–6.89 (m, 4 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 55.7 (OCH₃), 69.5 (C-3), 70.0 (C-2), 75.8 (C-1), 114.6 (CH-Ar), 115.5 (CH-Ar), 152.7 (C_q-O), 154.0 (C_q-OMe).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₁₆NO₄: 214.1079; found: 214.1076.

(9H-Fluoren-9-yl)methyl 2-Hydroxy-3-(4-methoxyphen­oxy)propoxycarbamate (6a)

The reaction was carried out according to General Procedure B with 4a (79 mg, 0.25 mmol), 2,4-dinitrophenylhydrazine (99 mg, 0.5 mmol), H₂SO₄ (135 μL, 2.5 mmol) in MeOH (2 mL), and then with NaHCO₃ (420 mg, 5 mmol) and FmocCl (323 mg, 1.25 mmol) in MeOH (10 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→7:3) to give 6a.

Yield: 88 mg (0.202 mmol, 81%); pale-yellow amorphous solid; R_f  = 0.22 (heptane–EtOAc, 3:2).

IR (neat): 3238, 1707, 1508, 1269, 1230, 1124, 1107, 1042, 822, 755, 737 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 3.76 (s, 3 H, OMe), 3.91–4.07 (m, 4 H, H-1, H-3), 4.16–4.21 (m, 1 H, H-2), 4.23 (t, J = 7.0 Hz, 1 H, CH-Fmoc), 4.52 and 4.56 (ABX, J _AB = 10.7 Hz, J _AX = 6.7 Hz, J _BX = 6.7 Hz, 2 H, CH₂-Fmoc), 6.79–6.87 (m, 4 H, ArH), 7.31 (t, J = 7.6 Hz, 2 H, ArH), 7.40 (t, J = 7.3 Hz, 2 H, ArH), 7.56 (d, J = 7.6 Hz, 2 H, ArH), 7.64 (s, 1 H, NH), 7.76 (d, J = 7.3 Hz, 2 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 47.0 (CH-Fmoc), 55.7 (OCH₃), 67.5 (C-2), 67.7 (CH₂-Fmoc), 69.1 (C-3), 78.9 (C-1), 114.7 (CH-Ar), 115.5 (CH-Ar), 120.1 (CH-Ar), 124.9 (CH-Ar), 124.9 (CH-Ar), 127.2 (CH-Ar), 127.9 (CH-Ar), 141.3 (C_q-Fmoc), 143.2 (C_q-Fmoc), 143.3 (C_q-Fmoc), 152.6 (C_q-O), 154.1 (C_q-OMe), 158.6 (C=O).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₅H₂₅NNaO₆: 458.1580; found: 458.1573.

Benzyl 2-Hydroxy-3-(4-methoxyphenoxy)propoxycarbamate (7a)

The reaction was carried out according to General Procedure B with 4a (79 mg, 0.25 mmol), 2,4-dinitrophenylhydrazine (99 mg, 0.5 mmol), H₂SO₄ (135 μL, 2.5 mmol) in MeOH (2 mL), and then with NaHCO₃ (420 mg, 5 mmol) and CbzCl (188 µL, 1.25 mmol) in MeOH (10 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→7:3) to give 7a.

Yield: 69 mg (0.199 mmol, 80%); yellow amorphous solid; R_f = 0.24 (heptane–EtOAc, 3:2).

IR (neat): 3406, 3160, 2954, 1724, 1506, 1266, 1232, 1129, 1109, 1041, 823, 739, 696 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 3.76 (s, 3 H, OMe), 3.92–4.12 (m, 4 H, H-1, H-3), 4.20–4.29 (m, 1 H, H-2), 5.19 (s, 2 H, CH₂-Bn), 6.78–6.87 (m, 4 H, ArH), 7.33–7.40 (m, 5 H, H-Bn), 7.63 (s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 55.7 (OCH₃), 67.5 (C-2), 68.1 (CH₂-Bn), 69.1 (C-3), 79.0 (C-1), 114.7 (CH-Ar), 115.5 (CH-Ar), 128.4 (CH-Ar), 128.7 (CH-Ar), 135.1 (C_q-Bn), 152.6 (C_q-O), 154.1 (C_q-OMe), 158.7 (C=O).

HRMS (ESI-TOF): m/z [M – H]^– calcd for C₁₈H₂₀NO₆: 346.1291; found: 346.1306.

Allyl 2-Hydroxy-3-(4-methoxyphenoxy)propoxycarbamate (8a)

The reaction was carried out according to General Procedure B with 4a (79 mg, 0.25 mmol), 2,4-dinitrophenylhydrazine (99 mg, 0.5 mmol), H₂SO₄ (135 μL, 2.5 mmol) in MeOH (2 mL), and then with NaHCO₃ (420 mg, 5 mmol) and AllocCl (133 μL, 1.25 mmol) in MeOH (10 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→7:3) to give 8a.

Yield: 66 mg (0.222 mmol, 89%); yellow amorphous solid; R_f = 0.18 (heptane–EtOAc, 3:2).

IR (neat): 3351, 3177, 2933, 2913, 1708, 1507, 1267, 1220, 1104, 994, 827, 756 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 3.76 (s, 3 H, OMe), 3.92–4.12 (m, 4 H, H-1, H-3), 4.21–4.29 (m, 1 H, H-2), 4.64 (t, J = 1.3 Hz, 1 H, CH ₂-CH=CH₂), 4.66 (t, J = 1.3 Hz, 1 H, CH ₂-CH=CH₂), 5.23–5.38 (m, 2 H, CH₂-CH=CH ₂), 5.83–5.98 (m, 1 H, CH₂-CH=CH₂), 6.78–6.87 (m, 4 H, ArH), 7.89 (s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 55.7 (OCH₃), 66.8 (CH₂-CH=CH₂), 67.5 (C-2), 69.1 (C-3), 78.8 (C-1), 114.6 (CH-Ar), 115.5 (CH-Ar), 119.0 (CH₂-CH=CH₂), 131.5 (CH₂-CH=CH₂), 152.6 (C_q-O), 154.0 (C_q-OMe), 158.5 (C=O).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₄H₁₉NNaO₆: 320.1110; found: 320.1106.

(9H-Fluoren-9-yl)methyl (2-Hydroxyoctyl)oxycarbamate (6b)

The reaction was carried out according to General Procedure B with 4b (70 mg, 0.266 mmol), 2,4-dinitrophenylhydrazine (105 mg, 0.532 mmol), and H₂SO₄ (143 μL, 2.66 mmol) in MeOH (2 mL), and then with NaHCO₃ (447 mg, 5.32 mmol) and FmocCl (344 mg, 1.33 mmol) in MeOH (10 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→7:3) to give 6b.

Yield: 97 mg (0.253 mmol, 95%); pale-rose crystals; R_f = 0.27 (heptane–EtOAc, 7:3).

IR (neat): 3319, 3271, 2954, 2925, 2855, 1698, 1495, 1479, 1465, 1447, 1268, 1127, 755, 736, 725 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 0.78–0.94 (m, 3 H, H-8), 1.18–1.54 (m, 10 H, H3–H7), 3.62 (dd, J = 9.8, 11.3 Hz, 1 H, H-1), 3.75 (br s, 1 H, OH), 3.78–3.85 (m, 2 H, H-1, H-2), 4.22 (t, J = 6.7 Hz, 1 H, CH-Fmoc), 4.50 and 4.54 (ABX, J _AB = 10.5 Hz, J _AX = 6.4 Hz, J _BX = 7.1 Hz, 2 H, CH₂-Fmoc), 7.30 (t, J = 7.3 Hz, 2 H, ArH), 7.40 (t, J = 7.3 Hz, 2 H, ArH), 7.55 (d, J = 7.3 Hz, 2 H, ArH), 7.67 (s, 1 H, NH), 7.75 (d, J = 7.3 Hz, 2 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 14.1 (C-8), 22.6 (C-7), 25.5 (C-4 or C-5), 29.3 (C-4 or C-5), 31.7 (C-6), 32.1 (C-3), 46.9 (CH-Fmoc), 67.6 (CH₂-Fmoc), 68.1 (C-2), 81.8 (C-1), 120.0 (CH-Ar), 124.9 (CH-Ar), 124.9 (CH-Ar), 127.1 (CH-Ar), 127.8 (CH-Ar), 141.3 (C_q-Fmoc), 143.3 (C_q-Fmoc), 143.3 (C_q-Fmoc), 158.7 (C=O).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₃H₂₉NNaO₄: 406.1994; found: 406.1999.

(9H-Fluoren-9-yl)methyl (2-Hydroxy-2-methylbut-3-en-1-yl)oxycarbamate (6c)

The reaction was carried out according to General Procedure B with 4c (96 mg, 0.438 mmol), 2,4-dinitrophenylhydrazine (173 mg, 0.876 mmol), and H₂SO₄ (235 μL, 4.38 mmol) in MeOH (3 mL), and then with NaHCO₃ (736 mg, 8.76 mmol) and FmocCl (567 mg, 2.19 mmol) in MeOH (12 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→7:3) to give a mixture of 6c and Fmoc-protected 2,4-dinitrophenylhydrazine (304 mg) as an orange solid. This mixture was purified by preparative HPLC (NW50 column, Merck; heptane–EtOAc, 10:0→6:4 over 35 min; 100 mL/min; UV detection at 254 nm) to give 6c.

Yield: 102 mg (0.301 mmol, 69%); pale-yellow oil; R_f = 0.31 (heptane–EtOAc, 3:2).

IR (neat): 3262, 2975, 1716, 1449, 1252, 1115, 757, 737 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.25 (s, 3 H, H-5), 3.10 (br s, 1 H, OH), 3.77 and 3.83 (AB, J _AB = 10.5 Hz, 2 H, H-1), 4.21 (t, J = 6.6 Hz, 1 H, CH-Fmoc), 4.49 (d, J = 6.6 Hz, 2 H, CH₂-Fmoc), 5.12 (d, J = 10.7 Hz, 1 H, H-4), 5.36 (dd, J = 1.1, 17.1 Hz, 1 H, H-4), 5.87 (dd, J = 10.7, 17.3 Hz, 1 H, H-3), 7.30 (t, J = 7.3 Hz, 2 H, ArH), 7.39 (t, J = 7.3 Hz, 2 H, ArH), 7.55 (d, J = 7.3 Hz, 2 H, ArH), 7.75 (d, J = 7.3 Hz, 2 H, ArH), 7.85 (br s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 24.4 (C-5), 46.9 (CH-Fmoc), 67.6 (CH₂-Fmoc), 72.6 (C-2), 84.4 (C-1), 113.8 (C-4), 120.0 (CH-Ar), 124.9 (CH-Ar), 127.1 (CH-Ar), 127.8 (CH-Ar), 141.3 (C_q-Fmoc), 141.6 (C-3), 143.3 (C_q-Fmoc), 143.3 (C_q-Fmoc), 158.0 (C=O).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₀H₂₁NNaO₄: 362.1368; found: 362.1371.

(S)-(9H-Fluoren-9-yl)methyl 2,3-Dihydroxypropoxycarbamate (6d)

The reaction was carried out according to General Procedure B with 4d (80 mg, 0.382 mmol), 2,4-dinitrophenylhydrazine (152 mg, 0.765 mmol), and H₂SO₄ (205 μL, 3.82 mmol) in MeOH (3 mL), and then with NaHCO₃ (642 mg, 7.64 mmol) and FmocCl (494 mg, 1.91 mmol) in MeOH (15 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 1:1→0:1) to give 6d.

Yield: 117 mg (0.355 mmol, 93%); pale-yellow amorphous solid; [α]_D ²⁴ +7.9 (c 1.11, MeOH); R_f = 0.13 (heptane–EtOAc, 3:7).

IR (neat): 3496, 3336, 3149, 2959, 2934, 2905, 2874, 1699, 1510, 1447, 1261, 1118, 1103, 1071, 755, 733 cm^–1.

¹H NMR (300 MHz, CD₃OD): δ = 3.49–3.63 (m, 2 H, H-3), 3.73–3.91 (m, 3 H, H-1, H-2), 4.14 (t, J = 6.6 Hz, 1 H, CH-Fmoc), 4.40 (d, J = 6.6 Hz, 2 H, CH₂-Fmoc), 7.27 (dt, J = 1.1, 7.3 Hz, 2 H, ArH), 7.35 (t, J = 7.3 Hz, 2 H, ArH), 7.58 (d, J = 7.3 Hz, 2 H, ArH), 7.73 (d, J = 7.3 Hz, 2 H, ArH).

¹³C NMR (75 MHz, CD₃OD): δ = 48.2 (CH-Fmoc), 64.1 (C-3), 68.2 (CH₂-Fmoc), 70.6 (C-2), 79.2 (C-1), 120.9 (CH-Ar), 126.0 (CH-Ar), 128.1 (CH-Ar), 128.8 (CH-Ar), 142.5 (C_q-Fmoc), 144.9 (C_q-Fmoc), 159.8 (C=O).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₈H₁₉NNaO₅: 352.1161; found: 352.1157.

Diallyl [(2-Hydroxypropane-1,3-diyl)bis(oxy)]dicarbamate (8f)

The reaction was carried out according to General Procedure B with 4f (74 mg, 0.227 mmol), 2,4-dinitrophenylhydrazine (90 mg, 0.453 mmol), and H₂SO₄ (122 μL, 2.27 mmol) in MeOH (1.75 mL), and then with NaHCO₃ (381 mg, 4.54 mmol) and AllocCl (120 μL, 1.14 mmol) in MeOH (7 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 4:1→1:1) to give 8f.

Yield: 40 mg (0.138 mmol, 61%); pale-yellow oil; R_f = 0.19 (heptane–EtOAc, 1:1).

IR (neat): 3262, 2924, 2851, 1714, 1249, 1109, 1042, 992, 930, 768 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 3.92 and 3.98 (ABX, J _AB = 11.3 Hz, J _AX = 2.9 Hz, J _BX = 7.8 Hz, 4 H, H-1), 4.14–4.20 (m, 1 H, H-2), 4.65 (d, J = 5.2 Hz, 4 H, CH ₂-CH=CH₂), 5.26 (d, J = 10.7 Hz, 2 H, CH₂-CH=CH ₂), 5.34 (d, J = 17.4 Hz, 2 H, CH₂-CH=CH ₂), 5.86–5.97 (m, 2 H, CH₂-CH=CH₂), 7.99 (br s, 2 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 66.7 (CH₂-CH=CH₂), 67.0 (C-2), 77.7 (C-1), 118.9 (CH₂-CH=CH₂), 131.7 (CH₂-CH=CH₂), 158.1 (C=O).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₈N₂NaO₇: 313.1012; found: 313.1004.

(9H-Fluoren-9-yl)methyl (2-Hydroxycyclopentyl) Oxycarbamate (6h)

The reaction was carried out according to General Procedure B with 4h (100 mg, 0.457 mmol), 2,4-dinitrophenylhydrazine (175 mg, 0.914 mmol), and H₂SO₄ (244 μL, 4.57 mmol) in MeOH (3 mL), and then with NaHCO₃ (1.47 g, 18.28 mmol) and FmocCl (1.13 g, 5.48 mmol) in MeOH (15 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 9:1→8:2) to give 6h.

Yield: 152.8 mg (0.451 mmol, 99%); pale-yellow oil; R_f = 0.13 (heptane–EtOAc, 7:3).

IR (neat): 3270, 2957, 1723, 1450, 1251, 1115, 908, 758, 728 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.49–1.58 (m, 1 H, H-3), 1.59–1.73 (m, 3 H, H-4, H-5), 1.89–2.00 (m, 2 H, H-3, H-5), 2.36 (br s, 1 H, OH), 4.04–4.09 (m, 1 H, H-1), 4.13–4.18 (m, 1 H, H-2), 4.20 (t, J = 6.7 Hz, 1 H, CH-Fmoc), 4.50 (d, J = 6.7 Hz, 2 H, CH₂-Fmoc), 7.29 (td, J = 0.9, 7.6 Hz, 2 H, ArH), 7.38 (t, J = 7.3 Hz, 2 H, ArH), 7.55 (br s, 1 H, NH), 7.56 (d, J = 7.3 Hz, 2 H, ArH), 7.74 (d, J = 7.6 Hz, 2 H, ArH).

¹³C NMR (75 MHz, CD₃OD): δ = 20.5 (C-4), 27.9 (C-5), 31.7 (C-3), 47.3 (CH-Fmoc), 67.6 (CH₂-Fmoc), 75.8 (C-2), 93.5 (C-1), 120.2 (CH-Ar), 125.1 (CH-Ar), 127.3 (CH-Ar), 128.0 (CH-Ar), 141.5 (C_q-Fmoc), 143.6 (C_q-Fmoc), 158.3 (C=O).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₂₂NO₄: 340.1549; found: 340.1561.

Allyl [(1S,2S)-2-Hydroxycyclohexyl]oxycarbamate (8i)

The reaction was carried out according to General Procedure B with 4i (63 mg, 0.27 mmol), 2,4-dinitrophenylhydrazine (107 mg, 0.54 mmol), and H₂SO₄ (145 μL, 2.70 mmol) in MeOH (2 mL), and then with NaHCO₃ (454 mg, 5.40 mmol) and AllocCl (145 μL, 1.35 mmol) in MeOH (8 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→6:4) to give an inseparable mixture of 8i and Alloc-protected 2,4-dinitrophenylhydrazine (117 mg) as an orange solid. This mixture was purified by preparative HPLC (NW50 column, Merck; heptane–EtOAc, 10:0→6:4 over 40 min; 100 mL/min; UV detection at 254 nm) to give 8i.

Yield: 47 mg (0.218 mmol, 81%); pale-yellow oil; R_f = 0.44 (heptane–EtOAc, 1:1; visualized by KMnO₄ only).

IR (neat): 3223, 2938, 2863, 1718, 1453, 1256, 1111, 1084, 993, 920, 770 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 1.13–1.51 (m, 4 H, CH₂-cyclohexane), 1.64–1.84 (m, 2 H, CH₂-cyclohexane), 1.92–2.13 (m, 2 H, CH₂-cyclohexane), 3.47–3.62 (m, 2 H, H-1, H-2), 4.50 (br s, 1 H, OH), 4.65 (d, J = 5.5 Hz, 2 H, CH ₂-CH=CH₂), 5.27 (d, J = 10.4 Hz, 1 H, CH₂-CH=CH ₂), 5.34 (d, J = 17.1 Hz, 1 H, CH₂-CH=CH ₂), 5.87–5.97 (m, 1 H, CH₂-CH=CH₂), 7.86 (br s, 2 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 23.7, 24.3 (C-4, C-5), 28.8, 32.3 (C-3, C-6), 66.7 (CH₂-CH=CH₂), 71.0 (C-2), 90.4 (C-1), 118.8 (CH₂-CH=CH₂), 131.6 (CH₂-CH=CH₂), 158.8 (C=O).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₁₈NO₄: 216.1236; found: 216.1219.

(1R,2R,3S,4R,5R)-4-(Aminooxy)-2-(naphthalen-2-ylmethoxy)-6,8-dioxabicyclo[3.2.1]octan-3-ol (5j)

To a solution of 4j (100 mg, 0.238 mmol, 1 equiv) in anhydrous MeOH (2 mL) and THF (100 μL) were added H₂SO₄ (128 μL, 2.38 mmol, 10 equiv) and 2,4-dinitrophenylhydrazine (94 mg, 0.477 mmol, 2 equiv) and the mixture was stirred at r.t. for 16 h. 2,4-Dinitrophenylhydrazine (47 mg, 0.238 mmol, 1 equiv) was then added to complete the reaction and the mixture was stirred for 1 h before being neutralized with powdered NaHCO₃ (400 mg, 4.76 mmol, 20 equiv). After addition of H₂O (20 mL), the aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic layers were washed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, and concentrated in vacuo. Purification by column chromatography (heptane–EtOAc, 1:1→3:7) gave 5j.

Yield: 57 mg (0.180 mmol, 76%); pale-yellow oil; [α]_D ²⁴ –22.4 (c 0.86, MeOH); R_f = 0.15 (heptane–EtOAc, 3:7).

IR (neat): 3524, 3327, 2912, 1102, 1029, 1016, 896, 860, 813 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 3.39 (d, J = 3.4 Hz, 1 H, H-4), 3.49 (d, J = 3.4 Hz, 1 H, H-2), 3.64 (dd, J = 5.5, 7.0 Hz, 1 H, H-6), 3.80 (d, J = 7.0 Hz, 1 H, H-6), 3.95 (t, J = 3.7 Hz, 1 H, H-3), 4.57 (d, J = 5.5 Hz, 1 H, H-5), 4.83 and 4.91 (AB, J _AB = 12.2 Hz, 2 H, CH₂-NAP), 5.52 (s, 1 H, H-1), 7.44–7.55 (m, 3 H, ArH), 7.79–7.88 (m, 4 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 66.5 (C-6), 70.7 (C-3), 72.0 (CH₂-NAP), 75.5 (C-5), 79.6 (C-4), 84.0 (C-2), 100.1 (C-1), 125.8 (CH-Ar), 126.0 (CH-Ar), 126.2 (CH-Ar), 126.8 (CH-Ar), 127.7 (CH-Ar), 127.9 (CH-Ar), 128.4 (CH-Ar), 133.0 (C_q-NAP), 133.2 (C_q-NAP), 135.3 (C_q-NAP).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₂₀NO₅: 318.1341; found: 318.1350.

Fluorenylmethyl {(1R,2R,3S,4R,5R)-3-Hydroxy-2-(naphthalen-2-ylmethoxy)-6,8-dioxabicyclo[3.2.1]octan-4-yl}oxycarbamate (6j)

The reaction was carried out according to General Procedure B with 4j (100 mg, 0.238 mmol), 2,4-dinitrophenylhydrazine (94 mg, 0.477 mmol), and H₂SO₄ (128 μL, 2.38 mmol) in MeOH (2 mL). THF (100 μL) was added to improve the solubility of the starting material. After 16 h at r.t., 2,4-dinitrophenylhydrazine (47 mg, 0.238 mmol, 1 equiv) was added to complete the reaction and the mixture was stirred for 2 h before being diluted with MeOH (8 mL). NaHCO₃ (400 mg, 4.76 mmol) and FmocCl (308 mg, 1.19 mmol) were added and the reaction mixture was stirred at r.t. for 4 h. Addition of NaHCO₃ (200 mg, 2.38 mmol) and FmocCl (154 mg, 0.595 mmol) were necessary to complete the reaction. The mixture was then stirred overnight and worked up as described. Purification by column chromatography (heptane–EtOAc, 4:1→3:2) afforded 6j.

Yield: 98 mg (0.182 mmol, 76%); pale-yellow amorphous solid; [α]_D ²⁴ –2.6 (c 0.94, CHCl₃); R_f = 0.21 (heptane–EtOAc, 1:1).

IR (neat): 3264, 1725, 1450, 1249, 1102, 1073, 1009, 757, 739 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 3.36 (dd, J = 0.8, 4.5 Hz, 1 H, H-4), 3.56–3.63 (m, 2 H, H-2, H-6), 3.74 (d, J = 7.5 Hz, 1 H, H-6), 3.95 (t, J = 4.5 Hz, 1 H, H-3), 4.18 (t, J = 6.6 Hz, 1 H, CH-Fmoc), 4.42–4.56 (m, 3 H, H-5, CH₂-Fmoc), 4.76 and 4.87 (AB, J _AB = 12.4 Hz, 2 H, CH₂-NAP), 5.55 (s, 1 H, H-1), 7.22–7.57 (m, 9 H, ArH), 7.68–7.84 (m, 6 H, ArH), 7.91 (s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 46.9 (CH-Fmoc), 66.5 (C-6), 67.7 (CH₂-Fmoc), 69.4 (C-3), 72.0 (CH₂-NAP), 75.7 (C-5), 79.4 (C-4), 86.4 (C-2), 100.1 (C-1), 120.0 (CH-Ar), 124.9 (CH-Ar), 125.8 (CH-Ar), 126.0 (CH-Ar), 126.2 (CH-Ar), 126.8 (CH-Ar), 127.2 (CH-Ar), 127.7 (CH-Ar), 127.9 (CH-Ar), 128.3 (CH-Ar), 133.0 (C_q-NAP), 133.2 (C_q-NAP), 135.1 (C_q-NAP), 141.3 (C_q-Fmoc), 143.2 (C_q-Fmoc), 143.3 (C_q-Fmoc), 158.3 (C=O).

HRMS (ESI-TOF): m/z [M+NH₄]⁺ calcd for C₃₂H₃₃N₂O₇: 557.2288; found: 557.2264.

Benzyl {(1R,2R,3S,4R,5R)-3-Hydroxy-2-(naphthalen-2-yl­methoxy)-6,8-dioxabicyclo[3.2.1]octan-4-yl}oxycarbamate (7j)

The reaction was carried out according to General Procedure B with 4j (100 mg, 0.238 mmol), 2,4-dinitrophenylhydrazine (141 mg, 0.714 mmol, 3 equiv), and H₂SO₄ (128 μL, 2.38 mmol) in MeOH (2 mL) and THF (100 μL, added to improve the solubility of the starting material) and then with NaHCO₃ (400 mg, 4.76 mmol) and CbzCl (179 μL, 1.19 mmol) in MeOH (8 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→6:4) to give 7j.

Yield: 95 mg (0.210 mmol, 88%); pale-yellow oil; [α]_D ²⁴ –0.3 (c 1.02, CHCl₃); R_f = 0.15 (heptane–EtOAc, 3:2).

IR (neat): 3384, 3209, 1721, 1511, 1269, 1116, 1101, 1076, 1011, 993, 973, 877, 826, 751, 735 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 3.36 (dd, J = 0.8, 4.5 Hz, 1 H, H-4), 3.57 (dd, J = 5.7, 7.5 Hz, 1 H, H-6), 3.66–3.75 (m, 2 H, H-2, H-6), 3.99 (d, J = 4.7 Hz, 1 H, H-3), 4.51 (d, J = 5.3 Hz, 1 H, H-5), 4.75 and 4.87 (AB, J _AB = 12.3 Hz, 2 H, CH₂-NAP), 5.10 and 5.11 (AB, J _AB = 12.2 Hz, 2 H, CH₂-Cbz), 5.60 (s, 1 H, H-1), 7.26–7.31 (m, 5 H, ArH), 7.41–7.49 (m, 3 H, ArH), 7.74–7.82 (m, 6 H, ArH), 8.13 (s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 66.4 (C-6), 67.9 (CH₂-Cbz), 69.4 (C-3), 71.9 (CH₂-NAP), 75.6 (C-5), 79.5 (C-4), 86.6 (C-2), 100.1 (C-1), 125.7 (CH-Ar), 126.0 (CH-Ar), 126.1 (CH-Ar), 126.7 (CH-Ar), 127.6 (CH-Ar), 127.8 (CH-Ar), 128.2 (CH-Ar), 128.5 (CH-Ar), 128.5 (CH-Ar), 133.0 (C_q-NAP), 133.1 (C_q-NAP), 135.1 (C_q-NAP), 135.2 (C_q-Cbz), 158.3 (C=O).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₅H₂₅NNaO₇: 474.1529; found: 474.1534.

Allyl {(1R,2R,3S,4R,5R)-3-Hydroxy-2-(naphthalen-2-ylmeth­oxy)-6,8-dioxabicyclo[3.2.1]octan-4-yl}oxycarbamate (8j)

The reaction was carried out according to General Procedure B with 4j (100 mg, 0.238 mmol), 2,4-dinitrophenylhydrazine (141 mg, 0.714 mmol, 3 equiv), and H₂SO₄ (128 μL, 2.38 mmol) in MeOH (2 mL) and THF (100 μL, added to improve the solubility of the starting material) and then, with NaHCO₃ (400 mg, 4.76 mmol) and AllocCl (126 μL, 1.19 mmol) in MeOH (8 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→6:4) to give 8j.

Yield: 71 mg (0.177 mmol, 74%); pale-yellow solid; [α]_D ²⁴ –1.1 (c 0.92, CHCl₃); R_f = 0.15 (heptane–EtOAc, 3:2).

IR (neat): 3381, 3217, 1714, 1507, 1258, 1099, 1076, 996, 819, 749 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 3.38 (d, J = 4.5 Hz, 1 H, H-4), 3.60 (dd, J = 5.7, 7.5 Hz, 1 H, H-6), 3.67–3.77 (m, 2 H, H-2, H-6), 4.00 (t, J = 4.7 Hz, 1 H, H-3), 4.54 (d, J = 5.3 Hz, 1 H, H-5), 4.59 (d, J = 5.7 Hz, 2 H, CH ₂-CH=CH₂), 4.78 and 4.90 (AB, J _AB = 12.4 Hz, 2 H, CH₂-NAP), 5.18–5.34 (m, 2 H, CH₂-CH=CH ₂), 5.63 (s, 1 H, H-1), 5.79–5.94 (m, 1 H, CH₂-CH=CH₂), 7.42–7.51 (m, 3 H, ArH), 7.75–7.84 (m, 4 H, ArH), 8.18 (s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 66.5 (C-6), 66.7 (CH₂-CH=CH₂), 69.4 (C-3), 71.9 (CH₂-NAP), 75.7 (C-5), 79.5 (C-4), 86.6 (C-2), 100.1 (C-1), 118.8 (CH₂-CH=CH₂), 125.8 (CH-Ar), 126.0 (CH-Ar), 126.1 (CH-Ar), 126.7 (CH-Ar), 127.6 (CH-Ar), 127.8 (CH-Ar), 128.3 (CH-Ar), 131.5 (CH₂-CH=CH₂), 133.0 (C_q-NAP), 133.1 (C_q-NAP), 135.2 (C_q-NAP), 158.2 (C=O).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₁H₂₃NNaO₇: 424.1372; found: 424.1355.

(9H-Fluoren-9-yl)methyl {(1R,2R,3R,4R)-3-[(Benzyloxy)methyl]-2-hydroxy-4-(naphthalen-2-ylmethoxy)cyclopentyl}oxycarbamate (2a)

The reaction was carried out according to General Procedure B with 4k (37 mg, 0.075 mmol), 2,4-dinitrophenylhydrazine (30 mg, 0.150 mmol), and H₂SO₄ (40 μL, 0.750 mmol) in MeOH (600 μL), and then with NaHCO₃ (126 mg, 1.5 mmol) and FmocCl (97 mg, 0.375 mmol) in MeOH (2.5 mL). The mixture was worked up as described and the crude product was purified by column chromatography (heptane–EtOAc, 8:2→6:4) to give 2a.

Yield: 40 mg (0.065 mmol, 87%); pale-yellow foam; [α]_D ²⁴ –36.6 (c 1.63, CHCl₃); R_f = 0.12 (heptane–EtOAc, 3:2).

IR (neat): 3256, 3061, 2887, 2863, 1723, 1451, 1250, 1114, 1096, 1074, 755, 741 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.90–2.04 (m, 1 H, H-5), 2.07–2.30 (m, 2 H, H-2, H-5), 3.18 (br s, 1 H, OH), 3.56 and 3.63 (ABX, J _AB = 9.3 Hz, J _AX = 5.2 Hz, J _BX = 6.2 Hz, 2 H, CH₂-OBn), 3.80–3.88 (m, 1 H, H-1), 3.97 (dd, J = 6.4, 8.3 Hz, 1 H, H-3), 4.20 (t, J = 6.8 Hz, 1 H, CH-Fmoc), 4.34 (dt, J = 6.3, 7.8 Hz, 1 H, H-4), 4.46 and 4.50 (AB, J _AB = 11.9 Hz, 2 H, CH₂-Bn), 4.47 (s, 2 H, CH₂-Fmoc), 4.56 and 4.63 (AB, J _AB = 12.1 Hz, 2 H, CH₂-NAP), 7.20–7.50 (m, 12 H, ArH), 7.52–7.58 (m, 2 H, ArH), 7.59 (s, 1 H, NH), 7.69–7.84 (m, 4 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 33.6 (C-5), 46.9 (CH-Fmoc), 51.1 (C-2), 67.5 (CH₂-Fmoc), 69.7 (CH₂-OBn), 71.2 (CH₂-NAP), 73.2 (C-3), 76.3 (CH₂-Bn), 76.5 (C-1), 90.4 (C-4), 120.0 (CH-Ar), 125.0 (CH-Ar), 125.7 (CH-Ar), 125.8 (CH-Ar), 126.1 (CH-Ar), 126.4 (CH-Ar), 127.1 (CH-Ar), 127.6 (CH-Ar), 127.6 (CH-Ar), 127.6 (CH-Ar), 127.8 (CH-Ar), 128.1 (CH-Ar), 128.4 (CH-Ar), 132.9 (C_q-NAP), 133.2 (C_q-NAP), 135.6 (C_q-NAP), 138.1 (C_q-Bn), 141.3 (C_q-Fmoc), 143.3 (C_q-Fmoc), 143.4 (C_q-Fmoc), 158.1 (C=O).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₃₉H₃₇NNaO₆: 638.2519; found: 638.2529.

Acknowledgment

A.F. and G.M. thank the ICSN for financial support.

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