Next Article in Journal
Theoretical Investigation of Geometries and Bonding of Indium Hydrides in the In2Hx and In3Hy (x = 0–4,6; y = 0–5) Series
Next Article in Special Issue
Cancer Vaccines Based on Fluorine-Modified KH-1 Elicit Robust Immune Response
Previous Article in Journal
A Highly Efficient Fluorescent Sensor Based on AIEgen for Detection of Nitrophenolic Explosives
Previous Article in Special Issue
Impact of N-Linked Glycosylation on Therapeutic Proteins
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 1
10.3390/molecules28010182
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Kukhtin–Ramirez-Reaction-Inspired Deprotection of Sulfamidates for the Synthesis of Amino Sugars

by
Ting Li
1,†,
Bingbing Xu
1,†,
Dengxian Fu
1,
Qian Wan
1 and
Jing Zeng
1,2,*
1
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
2
Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Qingdao 266237, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(1), 182; https://doi.org/10.3390/molecules28010182
Submission received: 30 November 2022 / Revised: 14 December 2022 / Accepted: 21 December 2022 / Published: 25 December 2022
(This article belongs to the Special Issue Carbohydrate-Based Drugs Discovery)
Browse Figures
Versions Notes

Abstract

:
Herein, we present a mild strategy for deprotecting cyclic sulfamidates via the Kukhtin–Ramirez reaction to access amino sugars. The method features the removal of the sulfonic group of cyclic sulfamidates, which occurs through an N-H insertion reaction that implicates the Kukhtin–Ramirez adducts, followed by a base-promoted reductive N-S bond cleavage. The mild reaction conditions of the protocol enable the formation of amino alcohols including analogs that bear multiple functional groups.

1. Introduction

Amino alcohols are important skeletons which are widely distributed in pharmaceuticals and biologically active natural products (Figure 1a) [1,2,3]. Amino alcohols also play important roles in organic synthesis as synthons, ligands, auxiliaries, and chiral catalysts [4,5,6,7,8]. This significance has inspired tremendous efforts to devise elegant synthetic methods for the construction of amino alcohols [9,10,11,12,13,14,15]. Among them, the utility of sulfamate esters [16,17,18,19,20,21] as precursors of amino groups to form cyclic sulfamidate [22,23,24,25] via substitution [26,27], condensation [28,29,30], C-H amination [31,32,33,34], C-H aziridination [35], etc. [36,37,38], has been well established. This has emerged as one of the most prominent methods to produce amino alcohols, due to the ready availability of the materials, the high efficiency of transformations, as well as the well-controlled regioselectivity and stereoselectivity (Figure 1b).
3-Amino deoxy sugars represent a special type of amino alcohols found in many carbohydrate-based antibiotics [39,40]. This strategy has also been incorporated into our study to prepare various 3-amino deoxy sugars (Figure 1c) [41,42,43]. However, the subsequent removal of the SO2 group of the cyclic sulfamidate to deliver free amino alcohols presented a notable challenge. Conventional deprotection methods employ strong reducing reagents such as LiAlH4, AlH3, and so on [30,44]. Apparently, the functional group tolerance is largely hampered by these conditions, wherein esters, ketones, aldehydes, and so on must be avoided altogether. Another common deprotection method is hydrolysis under acidic or alkaline conditions, but epimerization is always encountered for secondary alcohols [26,45]. To address these limitations and, more importantly, to gain expedite access to diversified 3-amino sugars, we have developed a new deprotection method for the SO2 group of sulfamidates under mild conditions.

2. Results and Discussion

Our reaction design was inspired by a three-decade-old reaction known as the Kukhtin–Ramirez reaction, which was independently discovered by Kukhtin [46] and Ramirez [47,48]. In this reaction, the redox condensation of a 1,2-dicarbonyl compound with a trivalent phosphorus derivative produces a pentacoordinate dioxaphospholene Ia, which exists in equilibrium with a tetracoordinate oxyphosphonium enolate Ib (Scheme 1a). Due to their unique properties, these species that are known as the Kukhtin–Ramirez adducts have been well explored in X-H insertion [49,50,51,52], reductive addition [53], cycloaddition [54,55,56], etc. [57,58,59,60]. Very recently, Fier et al. described an ingenious solution to degrade secondary sulfonamides into the corresponding sulfinates by virtue of the Kukhtin–Ramirez adducts [61]. This chemistry involves the addition of sulfonamides onto the Kukhtin–Ramirez adducts to form an N-H insertion intermediate II, which undergoes further degradation through a base-promoted reductive cleavage of the N-S bond (Scheme 1b). This unprecedented example of the cleavage of a strong sulfonamide S-N bond led us to envision a similar protocol that might be amenable to cleave the sulfamidate S-N bond to deliver an intermediate (V) containing both sulfinate and imine functionalities. The corresponding amino alcohol would be revealed upon hydrolysis (Scheme 1c).
With this idea in mind, our investigation commenced with the deprotection of disaccharide 1a as the model reaction. The requisite cyclic sulfamidate 1a used in this study was prepared with the application of the corresponding glycals as starting materials [43]. Initially, disaccharide 1a was subjected to the Kukhtin–Ramirez intermediate formed from ethyl benzoylformate and tris(dimethylamino)phosphorus (Table 1, entry 1). To our delight, the N-H insertion reaction proceeded smoothly to generate N-sulfonyl phenylglycine ester 3a in 95% yield, which set the stage for the deprotection reaction. Subsequently, BTMG was added into the system as a base to facilitate the S-N bond cleavage (Table 1, entry 2). As expected, the S-N bond was efficiently cleaved with the removal of the SO2 group, but imino ester 4a was obtained in 79% yield instead of the target free amino alcohols 2a. This indicated the occurrence of intramolecular esterification prior to the hydrolysis. To avoid this competing reaction, the second step was carried out in an aqueous solution of THF (THF:H2O, 1:1). Following this modification, the desired free amino sugar 2a was obtained in 88% yield. Other than BTMG, DBU and KOH could also yield the target product in 86% and 80% yields, respectively. However, weak bases such as K2CO3 and Et3N lead to dramatic decreases in yield. Interestingly, the basic anion exchange resin Ambersep® 900 (OH) could cleave the S-N bond effectively. This could simplify the product isolation, although the yield of 2a would be slightly compromised. Considering the product isolation convenience and the price of the reagent (especially in large-scale preparations), DBU was selected as the base. In principle, the 1,2-dicarbonyl entity could be fully recovered, but the ethyl benzoylformate used in this reaction was hydrolyzed under the strong basic conditions. Several other 1,2-dicarbonyl reagents [62,63,64] were subsequently examined to circumvent this process. Unfortunately, none of the examined reagents could promote the preceding N-H insertion reaction (see the SI for the screening of 1,2-dicarbonyl compounds).
With the optimized conditions in place, we then surveyed the scope and limitations of the method, especially in attaining our ultimate goal to prepare 3-aminosugars (Scheme 2). After examining a series of 3-aminosugars, it could be concluded that: (1) The glycosidic bonds (including both O- and C-analogs) were left intact and the optical purities of the α- and β-glycosidic bonds were not eroded at all. (2) All d- and l-sugars of the 3,5-cis or 3,5-trans configuration could undertake the transformation smoothly to produce the cis amino sugars in good yields. (3) Acid-labile groups such as benzylidine acetals (2b, 2i), isopropylidene ketals (2c, 2d), and other ketals (2f) as well as alkenes (2e) were well tolerated. (4) Functional groups that are generally sensitive to reductive conditions such as esters (2e), ketones (2m), and iodine (2i) endured the established conditions. However, it is worth mentioning that the ester group was hydrolyzed under the strong basic conditions, with the exception of an α,β-unsaturated ester that could furnish 2e in good yield. (5) The latent glycosyl donors SPTB ((S-2-(2-propylthio)benzyl, 2b) and OPTB (O-2-(2-propylthio)benzyl, 2c) featured in the interrupted Pummer reaction mediated (IPRm) glycosylations were well compatible [65,66,67,68,69], and could be transformed into the corresponding active SPSB/OPSB glycosyl donors via oxidation, indicating the potential for the further elongation of the sugar chain.
To verify the general synthetic utility of this protocol, we sought to merge the well-defined alcohol-induced amination reactions [31,32,33,34] with this deprotection protocol to modify naturally occurring or biologically important alcohols by introducing amino groups at nearby positions (Scheme 3). As an example, cholesterol was subjected to in-situ-generated sulfamoyl chloride [16,18], followed by Rh-catalyzed C-H amination conditions [32]. This sequence produced the five-membered cyclic sulfamidate 6a in 38% yield. Subsequently, the application of the optimized deprotection conditions gave rise to the β-amino alcohol analog of cholesterol 7a in 70% yield. The implementation of a similar protocol for the synthetic modification of indole-3-propanol also successfully introduced the amino group at the γ-position. To further showcase the applicability, a 1 mmol scale reaction of 6b was performed under the optimized conditions. The desired amino alcohol 7b was obtained in a comparable yield (82%).

3. Experimental Section

3.1. General

All the commercially available chemicals were purchased from Alfa, Innochem, and Adamas and used without further purification. The solvents for the reactions were dried on an Innovative Technologies Pure Solv400 solvent purifier. All the reactions were monitored using thin-layer chromatography over silica-gel-coated TLC plates (Yantai Chemical Industry Research Institute). The spots on the TLC were visualized by warming 10% H2SO4-(10% H2SO4 in ethanol) or 10% phosphomolybdic-acid (10% phosphomolybdic acid in ethanol) -sprayed plates on a hot plate. Column chromatography was performed using silica gel (Qingdao Marine Chemical Inc., Qingdao, China). NMR spectra were recorded with a Bruker AM-400 spectrometer (400 MHz) or Bruker Ascend TM-600 spectrometer (600 MHz). The 1H and 13C NMR chemical shifts were referenced against the solvent or solvent impurity peaks for CDCl3 at δH 7.24 and δC 77.23, for CD2Cl2 at δH 5.32 and δC 53.80, and for DMSO-d6 at δH 2.50 and δC 39.52 ppm, respectively. Optical rotations were measured at 25 °C with a Rudolph Autopol IV automatic polarimeter using a quartz cell with a 2 mL capacity and a 1 dm path length. Concentrations (c) are given in g/100 mL. High-resolution mass spectra were recorded with a Bruker micrOTOF II spectrometer using electrospray ionization (ESI). The copies of 1H and 13C NMR spectra of the new compounds are provided in the Supplementary Material.

3.2. Procedures for Compound 3a and 4a

3.2.1. Procedures for Compound 3a

Ethyl 2-((3aS,4S,6R,7aS)-4-methyl-2,2-dioxido-6-(((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methoxy)tetrahydropyrano [4,3-d][1,2,3]oxathiazol-1(4H)-yl)-2-phenylacsetate (3a).
To a solution of 1a (20.0 mg, 0.031 mmol) in THF (0.31 mL, C = 0.1 M), Ph(CO)CO2Et(5.3 μL, 0.034 mmol) and P(NMe2)3 (6.7 μL, 0.037 mmol) were added sequentially. After stirring for 45 min at room temperature, the mixture was concentrated and purified using silica gel chromatography to obtain 3a (23.8 mg, 95%) as a colorless syrup. The major isomer: Rf = 0.71 (petroleum ether-EtOAc 2:1). [α ] D 25 −19.6 (c, 1.34 in CHCl3). The readings for 1H NMR spectra (400 MHz, CDCl3) were δ 7.37–7.25 (m, 18H, Ar-H), 7.14 (dd, J = 7.6, 2.8 Hz, 2H, Ar-H), 5.28 (s, 1H, CH), 4.98–4.95 (m, 2H, PhCH2, H-4′), 4.78 (d, J = 11.2 Hz, 3H, PhCH2), 4.66 (d, J = 12.0 Hz, 1H, PhCH2), 4.53 (d, J = 3.6 Hz, 2H, H-1, H-1′), 4.36–4.21 (m, 4H, CH2, PhCH2, H-3′), 4.02 (dq, J = 6.4, 1.6 Hz, 1H, H-5′), 3.93 (t, J = 9.2 Hz, 1H, H-3), 3.66 (d, J = 11.6 Hz, 1H, H-6a), 3.61 (dd, J = 10.4, 5.2 Hz, 1H, H-5), 3.46 (dd, J = 9.6, 3.6 Hz, 1H, H-2), 3.30 (dd, J = 10.8, 5.6 Hz, 1H, H-6b), 3.26–3.21 (m, 4H, H-4, OMe), 1.77–1.69 (m, 1H, H-2′a), 1.29–1.25 (m, 6H, H-6′, Me), and 1.05 (dd, J = 13.2, 6.4 Hz, 1H, H-2′b). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 170.8, 138.9, 138.3, 133.6, 129.4, 129.3, 128.7, 128.6, 128.3, 128.2, 128.2, 128.0, 127.9, 127.9, 98.0, 96.8, 82.3, 81.5, 80.3, 78.1, 76.0, 75.2, 73.6, 70.1, 66.8, 62.7, 62.2, 61.2, 55.1, 53.0, 32.4, 16.8, and 14.2. The HRMS calculation for C44H51NO12S was [M + Na]+: 840.3024, found: 840.3041. The minor isomer: Rf = 0.58 (petroleum ether-EtOAc 2:1). [α ] D 25 −43.8 (c, 1.17 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.44–7.42 (m, 2H, Ar-H), 7.36–7.26 (m, 16H, Ar-H), 7.21–7.18 (m, 2H, Ar-H), 5.15 (s, 1H, CH), 4.97 (d, J = 10.8 Hz, 1H, PhCH2), 4.82 (d, J = 10.8 Hz, 1H, PhCH2), 4.80–4.75 (m, 3H, PhCH2, H-1′), 4.65 (d, J = 12.4 Hz, 1H, PhCH2), 4.51 (d, J = 3.6 Hz, 1H, H-1), 4.41 (d, J = 11.2 Hz, PhCH2), 4.26 (dd, J = 4.0, 1.2 Hz, 1H, H-4′), 4.23–4.12 (m, 2H, CH2), 3.92 (t, J = 9.2 Hz, 1H, H-3), 3.86 (qd, J = 6.4, 1.6 Hz, 1H, H-5′), 3.76 (ddd, J = 11.2, 6.4, 4.4 Hz, 1H, H-3′), 3.68 (dd, J = 10.4, 0.8 Hz, 1H, H-6a), 3.61 (dd, J = 10.4, 5.6 Hz, 1H, H-5), 3.41 (dd, J = 9.6, 3.2 Hz, 1H, H-2), 3.38 (dd, J = 10.8, 6.0 Hz, 1H, H-6b), 3.26 (t, J = 9.2 Hz, 1H, H-4), 3.23 (s, 3H, OMe), 2.23–2.16 (m, 1H, H-2′a), 1.98 (dd, J = 14.0, 6.4 Hz, 1H, H-2′b), and 1.22–1.18 (m, 6H, H-6′, Me). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 168.9, 138.9, 138.3, 138.2, 133.3, 129.9, 129.3, 129.1, 128.7, 128.7, 128.6, 128.3, 128.2, 128.1, 128.0, 127.9, 98.0, 96.8, 82.3, 80.3, 80.2, 78.0, 76.0, 75.3, 73.5, 70.1, 66.6, 64.0, 62.6, 62.3, 55.2, 54.3, 30.8, 16.8, and 14.1. The HRMS calculation for C44H51NO12S was [M + Na]+: 840.3024, found: 840.3051.

3.2.2. Procedures for Compound 4a

(4aS,5S,7R,8aS)-5-methyl-2-phenyl-7-(((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methoxy)-4a,7,8,8a-tetrahydropyrano [3,4-b][1,4]oxazin-3(5H)-one (4a).
To a solution of 1a (20.0 mg, 0.031 mmol) in THF (0.31 mL, C = 0.1 M), Ph(CO)CO2Et(5.3 μL, 0.034 mmol) and P(NMe2)3 (6.7 μL, 0.037 mmol) were added sequentially. After stirring for 45 min at room temperature, BTMG was added, and the mixture was stirred for 4 h at 65 °C. The mixture was concentrated and purified using silica gel chromatography to obtain 4a (17.0 mg, 79%) as a white solid. Rf = 0.61 (petroleum ether-EtOAc 2:1), m.p. 159–160 °C. [α ] D 25 −128.3 (c, 1.36 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.95–7.82 (m, 2H, Ar-H), 7.47–7.26 (m, 18H, Ar-H), 5.00 (d, J = 11.2 Hz, 1H, PhCH2), 4.90 (d, J = 11.2 Hz, 1H, PhCH2), 4.84–4.77 (m, 3H, PhCH2, H-1), 4.66 (d, J = 12.0 Hz, 1H, PhCH2), 4.58 (d, J = 3.6 Hz, 1H, H-1′), 4.56 (d, J = 11.2 Hz, PhCH2), 4.52 (ddd, J = 10.8, 4.8, 3.2 Hz, 1H, H-3′), 4.29 (d, J = 1.6 Hz, 1H, H-4′), 4.07 (q, J = 6.4 Hz, 1H, H-5′), 4.01 (t, J = 9.2 Hz, 1H, H-3), 3.85 (dd, J = 10.8, 1.6 Hz, 1H, H-6a), 3.76 (ddd, J = 10.0, 4.8, 1.2 Hz, 1H, H-5), 3.55 (dd, J = 10.8, 5.2 Hz, 1H, H-6b), 3.52–3.46 (m, 2H, H-2, H-4), 3.38 (s, 3H, OMe), 2.15 (dd, J = 13.2, 4.8 Hz, 1H, H-2′a), 1.42 (td, J = 12.8, 3.2 Hz, 1H, H-2′b), and 1.33 (d, J = 6.4 Hz, 3H, H-6′). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 158.8, 155.9, 138.9, 138.4, 138.4, 134.3, 131.4, 129.0, 128.7, 128.6, 128.5, 128.3, 128.2, 128.1, 127.8, 98.2, 96.7, 82.4, 80.3, 78.0, 75.9, 75.3, 75.0, 73.6, 70.2, 66.6, 63.6, 55.3, 51.5, 30.7, and 15.9. The HRMS calculation for C42H45NO9 [M + Na]+: 730.2987, found: 730.2989.

3.3. General Procedure for Deprotection and Characterization of the Products

To a solution of the substrate (1.0 equiv) in THF (C = 0.1 M), Ph(CO)CO2Et(1.1 equiv) and P(NMe2)3 (1.2 equiv) were added sequentially. After stirring for 45 min at room temperature, DBU (3.0 equiv relative to the starting substrate) and H2O (the amount of water was equal to that of the THF) were added sequentially, and the mixture was stirred for 4 h at 65 °C. The mixture was extracted with CH2Cl2 after removing the THF by concentration. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified with column chromatography on silica gel (dichloromethane-methanol gradient elution, with 0.5% or 1% NH3·H2O) to obtain the desired product.
(2S,3S,4S,6R)-4-amino-2-methyl-6-(((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methoxy)tetrahydro-2H-pyran-3-ol (2a).
According to the General Procedure, 1a (20.0 mg, 0.031 mmol) was used to obtain 2a as a white solid in 86% yield. Rf = 0.43 (CH2Cl2-MeOH 10:1), m.p. 181–182 °C. [α ] D 25 −29.6 (c, 0.45 in CHCl3).The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.27–7.24 (m, 4H, Ar-H), 7.23–7.14 (m, 11H, Ar-H), 4.89 (d, J = 10.8 Hz, 1H, PhCH2), 4.78 (d, J = 11.2 Hz, 1H, PhCH2), 4.71 (d, J = 10.8 Hz, 1H, PhCH2), 4.69 (d, J = 12.0 Hz, 1H, PhCH2), 4.64 (br s, 1H, H-1′), 4.56 (d, J = 12.0 Hz, PhCH2), 4.48 (d, J = 3.6 Hz, 1H, H-1), 4.44 (d, J = 11.2 Hz, 1H, PhCH2), 3.89 (t, J = 9.2 Hz, 1H, H-3), 3.77 (q, J = 6.4 Hz, 1H, H-5′), 3.72 (dd, J = 10.8, 1.6 Hz, 1H, H-6a), 3.65 (ddd, J = 10.0, 4.8, 1.2 Hz, 1H, H-5), 3.42–3.37 (m, 3H, H-2, H-4, H-6b), 3.28–3.25 (m, 4H, H-4′, OMe), 3.15–3.08 (m, 1H, H-3′), 1.52 (dd, J = 9.2, 2.4 Hz, 2H, H-2′a, H-2′b), and 1.11 (d, J = 6.8 Hz, 3H, H-6′). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 138.9, 138.4, 138.4, 128.7, 128.6, 128.3, 128.2, 128.1, 128.0, 127.9, 98.1, 97.6, 82.3, 80.2, 78.1, 76.0, 75.2, 73.5, 71.1, 70.2, 66.3, 66.0, 55.3, 46.4, 32.8, and 17.1. The HRMS calculation for C36H45NO9 was [M + Na]+: 658.2987, found: 658.3006.
(2S,3S,4S,6S)-4-amino-6-(((2R,4aR,6S,7R,8S,8aR)-8-(benzyloxy)-6-((2-(isopropylthio)benzyl)thio)-2-phenylhexahydropyrano [3,2-d][1,3]dioxin-7-yl)oxy)-2-methyltetrahydro-2H-pyran-3-ol (2b).
According to the General Procedure, 1b (20.0 mg, 0.027 mmol) was used to obtain 2b as a white solid in 87% yield. Rf = 0.13 (CH2Cl2-MeOH 15:1), m.p. 57–58 °C. [α ] D 25 −121.5 (c, 0.61 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.46–7.41 (m, 3H, Ar-H), 7.36–7.34 (m, 3H, Ar-H), 7.30–7.25 (m, 6H, Ar-H), 7.21–7.14 (m, 2H, Ar-H), 5.54 (s, 1H, PhCHO2), 5.35 (d, J = 3.2 Hz, 1H, H-1′), 4.93 (d, J = 11.2 Hz, 1H, PhCH2), 4.60 (d, J = 11.2 Hz, 1H, PhCH2), 4.36–4.31 (m, 3H, H-1), 4.14 (d, J = 13.2 Hz, 1H, PhCH2S), 4.01 (d, J = 13.2 Hz, PhCH2S), 3.78–3.66 (m, 4H), 3.40–3.33 (m, 3H), 3.03 (d, J = 10.8 Hz, 1H), 1.61 (dd, J = 13.2, 4.0 Hz, 1H, H-2′a), 1.46–1.40 (m, 1H, H-2′b), 1.28–1.23 (m, 6H, (CH3)2CH), and 1.18 (d, J = 6.8 Hz, 3H, H-6′). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 139.7, 138.1, 137.3, 135.5, 132.8, 130.0, 129.0, 128.5, 128.3, 128.0, 127.8, 127.7, 126.8, 126.0, 101.2, 98.4, 84.1, 84.0, 81.8, 75.1, 71.2, 70.0, 68.8, 66.9, 46.3, 38.8, 33.1, 29.8, 23.3, 23.1, and 16.8. The HRMS calculation for C36H45NO7S2 was [M + H]+: 668.2710, found: 668.2688.
(2S,3S,4S,6S)-4-amino-6-(((3aR,4R,6S,7S,7aR)-4-((2-(isopropylthio)benzyl)oxy)-2,2,6-trimethyltetrahydro-4H-[1,3]dioxolo [4,5-c]pyran-7-yl)oxy)-2-methyltetrahydro-2H-pyran-3-ol (2c).
According to the General Procedure, 1c (20.0 mg, 0.036 mmol) was used to obtain 2c as a colorless syrup in 86% yield. Rf = 0.30 (CH2Cl2-MeOH 10:1). [α ] D 25 −93.9 (c, 1.20 in CHCl3).The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.43 (dd, J = 8.0, 1.6 Hz, 1H, Ar-H), 7.39 (dd, J = 7.2, 1.6 Hz, 1H, Ar-H), 7.27–7.24 (m, 1H, Ar-H), 7.23–7.19 (m, 1H, Ar-H), 5.45 (d, J = 2.4 Hz, 1H, H-1′), 5.07 (s, 1H, H-1), 4.85 (d, J = 12.0 Hz, 1H, PhCH2), 4.62 (d, J = 11.6 Hz, 1H, PhCH2), 4.19–4.15 (m, 1H), 4.12 (d, J = 5.2 Hz, 1H), 3.88 (q, J = 6.8 Hz, H-5′), 3.78–3.71 (m, 1H), 3.52 (dd, J = 10.0, 7.2 Hz, 1H, H-4), 3.40 (br s, 1H), 3.38–3.31 (m, 1H), 3.16 (br s, 1H), 1.73–1.61 (m, 4H, H-2′a, H-2′b, NH2), 1.52 (s, 3H, Me), 1.31 (s, 3H, Me), and 1.28–1.19 (m, 12H, H-6, H-6′, (CH3)2CH),. The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 138.8, 135.4, 132.8, 129.5, 128.5, 127.1, 109.5, 96.8, 95.6, 79.2, 76.5, 76.4, 71.4, 67.8, 66.5, 64.7, 46.5, 38.9, 33.1, 28.1, 26.7, 23.4, 23.3, 18.7, 18.2, and 17.2. The HRMS calculation for C25H39NO7S was [M + H]+: 498.2520, found: 498.2541.
(2S,3S,4S,6R)-4-amino-2-methyl-6-(((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4′,5’-d]pyran-5-yl)methoxy)tetrahydro-2H-pyran-3-ol (2d).
According to the General Procedure, 1d (15.5 mg, 0.034 mmol) was used to obtain 2d as a colorless syrup in 92% yield. Rf = 0.33 (CH2Cl2-MeOH 10:1). [α ] D 25 −99.5 (c, 1.17 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 5.51 (d, J = 5.2 Hz, 1H, H-1), 4.88 (d, J = 2.8 Hz, 1H, H-1′), 4.58 (dd, J = 7.6, 2.4 Hz, 1H), 4.29 (dd, J = 5.2, 2.4 Hz, 1H), 4.21 (dd, J = 8.0, 1.6 Hz, 1H), 3.97–3.90 (m, 2H), 3.79 (dd, J = 10.0, 6.0 Hz, 1H), 3.54 (dd, J = 10.0, 6.8 Hz, 1H), 3.38 (d, J = 2.4 Hz, 1H), 3.21 (d, J = 8.8 Hz, 1H), 1.72–1.59 (m, 4H, H-2′a, H-2′b, NH2), 1.51 (s, 3H, Me), 1.42 (s, 3H, Me), 1.31 (s, 3H, Me), 1.30 (s, 3H, Me), and 1.23 (d, J = 6.4 Hz, 3H, H-6′). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 109.5, 108.7, 97.3, 96.5, 71.5, 71.4, 70.9, 70.8, 67.0, 66.1, 65.6, 46.6, 33.0, 26.3, 26.2, 25.2, 24.8, and 17.2. The HRMS calculation for C18H31NO8 was [M + H]+: 390.2122, found: 390.2138.
Ethyl (E)-3-(3-(((2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)phenyl)acrylate (2e).
According to the General Procedure, 1e (12.0 mg, 0.031 mmol) was used to obtain 2e as a colorless syrup in 74% yield. Rf= 0.23 (CH2Cl2-MeOH 10:1). [α ] D 25 −110.9 (c, 0.60 in CHCl3).The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.62 (d, J = 16.0 Hz, 1H, CH = CH), 7.27 (t, J = 7.6 Hz, 1H, Ar-H), 7.20 (br s, 1H, Ar-H), 7.14 (d, J = 7.6 Hz, 1H, Ar-H), 7.07 (dd, J = 8.4, 1.6 Hz, 1H, Ar-H), 6.39 (d, J = 16.0 Hz, 1H, CH = CH), 5.60 (br s, 1H, H-1), 4.24 (q, J = 7.2 Hz, 2H, CH2), 3.96 (q, J = 6.4 Hz, 1H, H-5), 3.48–3.44 (m, 2H, H-3, H-4), 1.86 (dd, J = 8.8, 2.4 Hz, 2H, H-2a, H-2b), 1.32 (t, J = 7.2 Hz, 3H, Me), and 1.22 (d, J = 6.8 Hz, 3H, H-6). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 167.2, 157.5, 144.6, 136.1, 130.1, 121.9, 118.9, 118.4, 115.8, 96.1, 71.0, 67.2, 60.7, 46.4, 32.8, 17.2, and 14.5. The HRMS calculation for C17H23NO5 was [M + H]+: 322.1649, found: 322.1676.
(2S,3S,4S,6R)-4-amino-2-methyl-6-(((4S,5’R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-5’,6a,8a,9-tetramethyl-1,3,3’,4,4’,5,5’,6,6a,6b,6’,7,8,8a,8b,9,11a,12,12a,12b-icosahydrospiro[naphtho [2’,1’:4,5]indeno [2,1-b]furan-10,2’-pyran]-4-yl)oxy)tetrahydro-2H-pyran-3-ol (2f).
According to the General Procedure, 1f (20.0 mg, 0.033 mmol) was used to obtain 2f as a white solid in 76% yield. Rf= 0.32 (CH2Cl2-MeOH 10:1), m.p. 243–244 °C. [α ] D 25 −154.8 (c, 1.09 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 5.31 (d, J = 5.2 Hz, 1H, C = CH), 5.00 (d, J = 3.2 Hz, 1H, H-1), 4.38 (q, J = 7.2 Hz, 1H), 3.94 (q, J = 6.4 Hz, 1H, H-5), 3.47–3.32 (m, 4H), 3.24 (d, J = 10.4 Hz, 1H), 2.32 (ddd, J = 13.2, 4.4, 1.6 Hz, 1H), 2.15 (td, J = 12.4, 2.4 Hz, 1H), 2.02–1.92 (m, 2H), 1.85–1.48 (m, 18H), 1.46–1.38 (m, 2H), 1.30–1.25 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H, H-6), 1.17 (dd, J = 12.4, 4.4 Hz, 1H), 1.13–1.05 (m, 2H), 1.00 (s, 3H, Me), 0.96–0.89 (m, 4H), and 0.78–0.75 (m, 6H, Me). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 140.9, 121.7, 109.5, 95.4, 81.0, 76.3, 71.5, 67.1, 66.1, 62.4, 56.7, 50.3, 46.6, 41.8, 40.5, 40.0, 38.9, 37.6, 37.1, 33.6, 32.3, 32.1, 31.7, 31.6, 30.5, 29.7, 29.0, 21.1, 19.6, 17.3, 17.2, 16.5, and 14.7. The HRMS calculation for C33H53NO5 was [M + H]+: 544.3997, found: 544.4011.
(2S,3S,4S,6S)-4-amino-2-methyl-6-(((2R,3R,5R,6S)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)methoxy)tetrahydro-2H-pyran-3-ol (2g).
According to the General Procedure, 1g (20.0 mg, 0.031 mmol) was used to obtain 2g as a white solid in 72% yield. Rf = 0.13 (CH2Cl2-MeOH 15:1). The readings for the 1H NMR spectra (600 MHz, CDCl3) were δ 7.31–7.18 (m, 15H, Ar-H), 4.91 (d, J = 11.4 Hz, 1H, PhCH2), 4.79 (d, J =10.8 Hz, 1H, PhCH2), 4.78 (d, J = 10.8 Hz, 1H, PhCH2), 4.73 (d, J = 12.0 Hz, 1H, PhCH2), 4.66 (d, J = 10.8 Hz, 1H, PhCH2), 4.60 (d, J = 12.6 Hz, 1H, PhCH2), 4.56 (d, J = 3.6 Hz, 1H, H-1), 4.40 (dd, J = 9.6, 1.8 Hz, 1H, H-1’), 4.10 (dd, J = 11.4, 3.6 Hz, 1H, H-6a), 3.92 (t, J = 9.6 Hz, 1H, H-3), 3.68–3.61 (m, 2H, H-5, H-6b), 3.54 (t, J = 9.6 Hz, 1H, H-4), 3.47 (dd, J = 9.6, 3.6 Hz, 1H, H-2), 3.42 (q, J = 6.6 Hz, 1H, H-5’), 3.33 (d, J = 1.8 Hz, 1H, H-4’), 3.30 (s, 3H, OMe), 2.97 (brs, 3H, NH2, OH), 2.92–2.87 (m, 1H, H-3’), 1.85–1.78 (m, 1H, H-2’a), 1.51–1.43 (m, 1H, H-2’b), and 1.19 (d, J = 6.6 Hz, 3H, H-6’). The readings for the 13C NMR spectra (150 MHz, CDCl3) were δ 139.0, 138.6, 138.4, 128.6, 128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 100.4, 98.3, 82.2, 80.1, 77.8, 75.9, 75.2, 73.6, 71.9, 70.1, 70.1, 66.9, 55.3, 50.6, 34.4, and 17.1.
(2S,3R,4R,6S)-4-amino-6-(((2R,3R,4S,5R,6S)-4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pran-3-yl)oxy)-2-methyltetrahydro-2H-pyran-3-ol (2h).
According to the General Procedure, 1h (21.0 mg, 0.032 mmol) was used to obtain 2h as a colorless syrup in 62% yield. Rf = 0.58 (CH2Cl2-MeOH 10:1). [α ] D 25 −15.0 (c, 0.56 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.35–7.25 (m, 15H, Ar-H), 5.25 (d, J = 3.2 Hz, 1H, H-1’), 4.77 (d, J = 11.6 Hz, 2H, PhCH2), 4.69 (m, 2H, PhCH2, H-1), 4.65 (d, J = 11.6 Hz, 1H, PhCH2), 4.56 (d, J = 11.6 Hz, 1H, PhCH2), 4.65 (d, J = 11.6 Hz, 1H, PhCH2), 4.06 (d, J = 1.2 Hz, 1H, H-4), 3.92 (t, J = 10.0 Hz, 1H), 3.84 (qd, J = 10.0, 2.8 Hz, 2H), 3.61–3.56 (m, 3H), 3.38 (s, 3H, OMe), 3.06 (dd, J = 9.2, 4.4 Hz, 1H), 3.00 (m, 1H), 2.06–2.03 (m, 1H, H-2’a), 1.79 (dt, J = 14.4, 4.4 Hz, 1H, H-2’b), and 1.18 (d, J = 6.0 Hz, 3H, H-6’). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 138.6, 138.5, 138.1, 128.7, 128.6, 128.6, 128.4, 128.0, 128.0, 127.8, 127.7, 99.0, 98.7, 78.9, 75.8, 74.8, 73.8, 73.5, 73.4, 71.0, 70.1, 69.6, 65.2, 55.6, 47.5, 36.4, and 18.2. The HRMS calculation for C34H43NO8 was [M + H]+: 594.3061, found: 594.3078.
(2R,3R,4R,6R)-4-amino-6-(((2S,6S,7R,8R,8aS)-7-iodo-6-methoxy-2-phenylhexahydropyrano [3,2-d][1,3]dioxin-8-yl)oxy)-2-methyltetrahydro-2-pyran-3-ol (2i).
According to the General Procedure, 1i (19.0 mg, 0.033 mmol) was used to obtain 2i as a white solid in 79% yield. Rf = 0.36 (CH2Cl2-MeOH 10:1), m.p. 89–90 °C. [α ] D 25 +22.8 (c, 1.48 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.43–7.39 (m, 2H, Ar-H), 7.37–7.30 (m, 3H, Ar-H), 5.57 (s, 1H, PhCHO2), 5.18 (d, J = 3.2 Hz, 1H, H-1’), 5.05 (s, 1H, H-1), 4.36 (d, J = 4.4 Hz, 1H, H-2), 4.25 (dd, J = 9.6, 4.0 Hz, 1H, H-6a), 4.02–3.95 (m, 2H, H-4, H-5′), 3.90 (td, J = 10.0, 4.0 Hz, 1H, H-5), 3.84 (t, J = 10.0 Hz, 1H, H-6b), 3.48 (dd, J = 9.6, 4.4 Hz, 1H, H-3), 3.45 (br s, 1H, H-4’), 3.36 (s, 3H, OMe), 3.30 (ddd, J = 12.0, 4.8, 2.8 Hz, 1H, H-3’), 1.74 (dd, J = 13.2, 4.8 Hz, 1H, H-2’a), 1.65 (td, J = 12.4, 3.6 Hz, 1H, H-2’b), and 1.25 (d, J = 6.8 Hz, 3H, H-6’). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 137.5, 129.2, 128.4, 126.2, 104.0, 101.8, 99.3, 80.8, 71.6, 70.9, 68.9, 67.4, 64.8, 55.3, 46.5, 35.2, 32.6, and 17.2. The HRMS calculation for C20H28INO7 was [M + H]+: 522.0983, found: 522.0996.
(2R,3R,4R,6S)-4-amino-6-(((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-2-methyltetrahydro-2H-pyran-3-ol (2j).
According to the General Procedure, 1j (24.0 mg, 0.042 mmol) was used to obtain 2j as a white solid in 81% yield. Rf = 0.26 (CH2Cl2-MeOH 10:1), m.p. 185–186 °C. [α ] D 25 +54.0 (c, 1.62 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 5.32 (d, J = 4.8 Hz, 1H, C = CH), 4.99 (d, J = 3.2 Hz, 1H, H-1), 3.96 (q, J = 6.4 Hz, 1H, H-5), 3.44 (m, 1H,), 3.39 (d, J = 2.4 Hz, 1H, H-4), 3.25 (ddd, J = 11.6, 4.4, 2.8 Hz, 1H, H-3), 2.32–2.21 (m, 2H), 2.00–1.92 (m, 2H), 1.84–1.77 (m, 4H), 1.71–1.63 (m, 2H), 1.61–1.37 (m, 4H), 1.51–1.36 (m, 5H), 1.36–1.28 (m, 3H), 1.23 (d, J = 6.4 Hz, 4H, H-6), 1.20–0.99 (m, 8H), 0.98–0.92 (m, 5H), 0.89 (d, J = 6.4 Hz, 3H, Me), 0.85 (d, J = 1.6 Hz, 3H, Me), 0.83 (d, J =1.6 Hz, 3H, Me), and 0.65 (s, 3H, Me). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 141.2, 121.9, 95.2, 76.3, 71.4, 66.1, 57.0, 56.4, 50.4, 46.6, 42.6, 40.4, 40.0, 39.7, 37.3, 37.0, 36.4, 36.0, 33.6, 32.2, 32.1, 28.4, 28.2, 28.1, 24.5, 24.1, 23.0, 22.8, 21.3, 19.6, 18.9, 17.2, and 12.1. The HRMS calculation for C33H57NO3 was [M + H]+: 516.4411, found: 516.4422.
(2S,3S,4S,6S)-4-amino-6-(4-methoxynaphthalen-1-yl)-2-methyltetrahydro-2H-pyran-3-ol (2k).
According to the General Procedure, 1k (20.0 mg, 0.057 mmol) was used to obtain 2k as a white solid in 78% yield. Rf = 0.29 (CH2Cl2-MeOH 10:1), m.p. 112–113 °C. [α ] D 25 −86.6 (c, 0.56 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 8.28 (d, J = 8.0 Hz, 1H, Ar-H), 7.98 (d, J = 8.4 Hz, 1H, Ar-H), 7.53–7.43 (m, 3H, Ar-H), 6.76 (d, J = 8.0 Hz, 1H, Ar-H), 5.00 (d, J = 10.4 Hz, 1H, H-1), 3.97 (s, 3H, OMe), 3.82 (q, J = 6.4 Hz, 1H, H-5), 3.52 (br s, 1H, H-4), 3.18 (d, J = 10.4 Hz, 1H, H-3), 1.96–1.84 (m, 2H, H-2a, H-2b), and 1.39 (d, J = 6.4 Hz, 3H, H-6). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 155.5, 131.8, 129.3, 126.8, 126.0, 125.1, 123.6, 123.3, 122.8, 103.3, 75.7, 75.6, 71.5, 55.7, 52.2, 35.7, and 17.9. The HRMS calculation for C17H21NO3 was [M + H]+: 288.1594, found: 288.1597.
(2S,3S,4S,6S)-4-amino-6-(6-hydroxy-2,3,4-trimethoxyphenyl)-2-methyltetrahydro-2H-pyran-3-ol (2l).
According to the General Procedure, 1l (20.0 mg, 0.053 mmol) was used to obtain 2l as a white solid in 77% yield. Rf = 0.24 (CH2Cl2-MeOH 10:1), m.p. 178–179 °C. [α ] D 25 −71.0 (c, 0.67 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 6.23 (s, 1H, Ar-H), 4.90 (dd, J = 11.6, 2.8 Hz, 1H, H-1), 3.86 (s, 3H, OMe), 3.78 (s, 3H, OMe), 3.74 (s, 3H, OMe), 3.65 (q, J = 6.4 Hz, 1H, H-5), 3.45 (d, J = 2.4 Hz, 1H, H-4), 3.16 (d, J = 10.4 Hz, 1H, H-3), 1.89 (q, J = 12.0 Hz, 1H, H-2a), 1.61 (dq, J = 13.2, 3.2 Hz, 1H, H-2b), and 1.36 (d, J = 6.4 Hz, 3H, H-6). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 153.7, 152.4, 150.1, 135.1, 111.5, 97.3, 75.3, 73.6, 69.8, 61.5, 61.1, 56.1, 50.7, 33.9, and 17.8. The HRMS calculation for C15H23NO6 was [M + H]+: 314.1598, found: 314.1625.
5-((2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)-9-hydroxy-8-methoxy-3,4-dihydroanthracen-1(2H)-one (2m).
According to the General Procedure, 1m (15.0 mg, 0.035 mmol) was used to obtain 2m as a yellow solid in 91% yield. Rf = 0.27 (CH2Cl2-MeOH 10:1), m.p. 166–167 °C. [α ] D 25 −154.0 (c, 0.82 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 7.66 (d, J = 8.4 Hz, 1H, Ar-H), 7.11 (s, 1H, Ar-H), 6.77 (d, J = 8.4 Hz, 1H, Ar-H), 4.87 (d, J = 10.4 Hz, 1H, H-1), 3.98 (s, 3H, OMe), 3.80 (q, J = 6.4 Hz, 1H, H-5), 3.52 (d, J = 2.0 Hz, 1H, H-4), 3.18 (dt, J = 11.6, 3.6 Hz, 1H, H-3), 2.99 (t, J = 6.0 Hz, 2H, CH2), 2.74 (t, J = 6.4 Hz, 2H, CH2), 2.13–2.06 (m, 2H, CH2), 1.91 (dd, J = 13.2, 2.4 Hz, 1H, H-2a), 1.81–1.72 (m, 3H, H-2b, NH2), and 1.39 (d, J = 6.8 Hz, 3H, H-6). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 204.8, 166.5, 159.9, 139.5, 137.3, 129.1, 128.6, 115.5, 112.0, 111.8, 105.3, 75.7, 75.4, 71.4, 56.4, 52.1, 39.2, 35.6, 31.0, 23.0, and 17.9. The HRMS calculation for C21H25NO5 was [M + H]+: 372.1805, found: 372.1790.
(3S,4R,8S,9S,10R,13R,14S,17R)-4-amino-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol (7a).
To a solution of 6a (23.0 mg, 0.050 mmol, 1.0 equiv) in THF (0.5 mL), Ph(CO)CO2Et(0.055 mmol, 1.1 equiv) and P(NMe2)3 (0.060 mmol, 1.2 equiv) were added sequentially. After stirring for 45 min at room temperature, DBU (0.200 mmol, 4.0 equiv) and H2O (0.5 mL) were added sequentially, and the mixture was stirred for 4 h at 65 °C. The mixture was extracted with CH2Cl2 after removing the THF by concentration. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified using column chromatography on silica gel (dichloromethane-methanol gradient elution, with 1% NH3·H2O) to obtain 7a as a white solid in 70% yield. Rf = 0.40 (CH2Cl2-MeOH 10:1), m.p. 158–159℃. [α ] D 25 −41.3 (c, 0.76 in CHCl3). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 5.54 (s, 1H, C = CH), 3.52–3.46 (m, 2H), 2.42 (br s, 3H, OH, NH2), 2.06–1.96 (m, 2H), 1.84–1.72 (m, 3H), 1.65–1.50 (m, 4H), 1.42–1.23 (m, 8H), 1.13–1.03 (m, 12H), 0.89 (d, J = 6.4 Hz, 3H, Me), 0.85 (d, J = 1.6 Hz, 3H, Me), 0.83 (d, J = 1.6 Hz, 3H, Me), and 0.65 (s, 3H, Me). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 127.2, 71.5, 57.3, 56.3, 50.5, 42.5, 39.9, 39.7, 36.8, 36.4, 36.3, 36.0, 32.4, 32.1, 28.4, 28.2, 25.9, 24.5, 24.1, 23.0, 22.8, 21.9, 20.7, 18.9, and 12.1. The HRMS calculation for C27H47NO was [M + H]+: 402.3730, found: 402.3717.
tert-butyl 3-(1-amino-3-hydroxypropyl)-1H-indole-1-carboxylate (7b).
To a solution of 6b (20.0 mg, 0.079 mmol, 1.0 equiv) in THF (0.79 mL), Ph(CO)CO2Et(0.158 mmol, 2.0 equiv) and P(NMe2)3 (0.166 mmol, 2.1 equiv) were added sequentially. After stirring for 45 min at room temperature, DBU (0.474 mmol, 6.0 equiv) and H2O (0.79 mL) were added sequentially, and the mixture was stirred for 4 h at 65 °C. The mixture was extracted with CH2Cl2 after removing the THF by concentration. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified using column chromatography on silica gel (dichloromethane-methanol gradient elution, with 1% NH3·H2O) to obtain 7b as a yellow oil in 87% yield. According to the above procedure, 6b (352.4 mg, 1.0 mmol) was used to obtain 7b as a yellow oil in 82% yield. Rf = 0.25 (CH2Cl2-MeOH 10:1). The readings for the 1H NMR spectra (400 MHz, CDCl3) were δ 8.12 (d, J = 7.2 Hz, 1H, Ar-H), 7.54 (d, J = 8.4 Hz, 2H, Ar-H, C = CH), 7.30 (t, J = 7.2 Hz, 1H, Ar-H), 7.21 (t, J = 7.2 Hz, 1H, Ar-H), 4.47 (dd, J = 7.6, 4.0 Hz, 1H), 3.84 (t, J = 5.2 Hz, 2H), 3.18 (s, 3H, OH, NH2), 2.10–1.98 (m, 2H), and 1.64 (s, 9H, (CH3)3C). The readings for the 13C NMR spectra (100 MHz, CDCl3) were δ 149.9, 136.0, 128.7, 124.9, 122.8, 122.0, 119.2, 115.8, 84.1, 62.2, 48.9, 37.8, and 28.4. The HRMS calculation for C16H22N2O3 was [M + H]+: 291.1703, found: 291.1691.

4. Conclusions

In conclusion, the investigation described above has led to the development of a practical method to smoothly convert cyclic sulfamidates into amino alcohols under mild conditions. This highly efficient deprotection method is initiated with the Kukhtin–Ramirez reaction. It exhibited operational simplicity, which provided a solution to the deprotection problem encountered in our synthesis of rare amino sugar. In addition, this approach allows the construction of valuable building blocks and structurally complex compounds containing amino alcohol motifs.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules28010182/s1: synthesis of compounds 1a–1m, 6a–6b, and 1,2-dicarbonyl reagents (S3–S5) [70,71]; Table S1: screening of 1,2-dicarbonyl compounds; 1H NMR spectra for 6a–6b and S3–S5; 1H and 13C NMR spectra for compounds 2a–2m, 3a, and 4a; 2D HSQC and COSY NMR spectra for compounds 2a, 3a, and 4a.

Author Contributions

Conceptualization, J.Z.; methodology, J.Z. and Q.W.; investigation, T.L. and B.X.; writing—original draft preparation, T.L.; writing—review and editing, J.Z., Q.W. and D.F.; supervision and funding acquisition, J.Z. and Q.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (22077039, 22277033, 21772050, 21761132014), the National Science and Technology Innovation 2030—Major program of “Brain Science and Brain-Like Research” (2022ZD0211800), and the Open Projects Fund of the Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University (2021CCG02).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are included within the manuscript or the Supplementary Data File.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Heravi, M.M.; Lashaki, T.B.; Fattahi, B.; Zadsirjan, V. Application of asymmetric Sharpless aminohydroxylation in total synthesis of natural products and some synthetic complex bio-active molecules. RSC Adv. 2018, 8, 6634–6659. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Dimarco, A.; Gaetani, M.; Orezzi, P.; Scarpinato, B.M.; Silvestrini, R.; Soldati, M.; Dasdia, T.; Valentini, L. ‘Daunomycin’, a new antibiotic of the rhodomycin group. Nature 1964, 201, 706–707. [Google Scholar] [CrossRef] [PubMed]
  3. Bergmeier, S.C.; Stanchina, D.M. Acylnitrene route to vicinal amino alcohols. Application to the synthesis of (-)-Bestatin and analogues. J. Org. Chem. 1999, 64, 2852–2859. [Google Scholar] [CrossRef] [PubMed]
  4. Ager, D.J.; Prakash, I.; Schaad, D.R. 1,2-Amino alcohols and their heterocyclic derivatives as chiral auxiliaries in asymmetric synthesis. Chem. Rev. 1996, 96, 835–876. [Google Scholar] [CrossRef] [PubMed]
  5. Fache, F.; Schulz, E.; Tommasino, M.L.; Lemaire, M. Nitrogen-containing ligands for asymmetric homogeneous and heterogeneous catalysis. Chem. Rev. 2000, 100, 2159–2231. [Google Scholar] [CrossRef] [PubMed]
  6. Shrestha, B.; Rose, B.T.; Olen, C.L.; Roth, A.; Kwong, A.C.; Wang, Y.; Denmark, S.E. A unified strategy for the asymmetric synthesis of highly substituted 1,2-amino alcohols leading to highly substituted bisoxazoline ligands. J. Org. Chem. 2021, 86, 3490–3534. [Google Scholar] [CrossRef] [PubMed]
  7. Malkov, A.V.; Kabeshov, M.A.; Bella, M.; Kysilka, O.; Malyshev, D.A.; Pluháčková, K.; Kočovský, P. Vicinal amino alcohols as organocatalysts in asymmetric cross-aldol reaction of ketones: Application in the synthesis of convolutamydine A. Org. Lett. 2007, 9, 5473–5476. [Google Scholar] [CrossRef]
  8. Heravi, M.M.; Zadsirjan, V.; Farajpour, B. Applications of oxazolidinones as chiral auxiliaries in the asymmetric alkylation reaction applied to total synthesis. RSC Adv. 2016, 6, 30498–30551. [Google Scholar] [CrossRef]
  9. Lait, S.M.; Rankic, D.A.; Keay, B.A. 1,3-Aminoalcohols and their derivatives in asymmetric organic synthesis. Chem. Rev. 2007, 107, 767–796. [Google Scholar] [CrossRef]
  10. Donohoe, T.J.; Callens, C.K.; Flores, A.; Lacy, A.R.; Rathi, A.H. Recent developments in methodology for the direct oxyamination of olefins. Chemistry 2011, 17, 58–76. [Google Scholar] [CrossRef]
  11. Palomo, C.; Oiarbide, M.; Laso, A. Recent advances in the catalytic asymmetric nitroaldol (Henry) reaction. Eur. J. Org. Chem. 2007, 2007, 2561–2574. [Google Scholar] [CrossRef]
  12. Gupta, P.; Mahajan, N. Biocatalytic approaches towards the stereoselective synthesis of vicinal amino alcohols. New J. Chem. 2018, 42, 12296–12327. [Google Scholar] [CrossRef]
  13. Karjalainen, O.K.; Koskinen, A.M. Diastereoselective synthesis of vicinal amino alcohols. Org. Biomol. Chem. 2012, 10, 4311–4326. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Bergmeier, S.C. The synthesis of vicinal amino alcohols. Tetrahedron 2000, 56, 2561–2576. [Google Scholar] [CrossRef]
  15. Burchak, O.N.; Py, S. Reductive cross-coupling reactions (RCCR) between C=N and C=O for β-amino alcohol synthesis. Tetrahedron 2009, 65, 7333–7356. [Google Scholar] [CrossRef]
  16. Appel, R.; Berger, G. Hydrazinsulfonsäure-amide, I. Über das Hydrazodisulfamid. Chem. Ber. 1958, 91, 1339–1341. [Google Scholar] [CrossRef]
  17. Armitage, I.; Berne, A.M.; Elliott, E.L.; Fu, M.; Hicks, F.; McCubbin, Q.; Zhu, L. N-(tert-butoxycarbonyl)-N-[(triethylenediammonium)sulfonyl] azanide: A convenient sulfamoylation reagent for alcohols. Org. Lett. 2012, 14, 2626–2629. [Google Scholar] [CrossRef]
  18. Okada, M.; Iwashita, S.; Koizumi, N. Efficient general method for sulfamoylation of a hydroxyl group. Tetrahedron Lett. 2000, 41, 7047–7051. [Google Scholar] [CrossRef]
  19. Rapp, P.B.; Murai, K.; Ichiishi, N.; Leahy, D.K.; Miller, S.J. Catalytic sulfamoylation of alcohols with activated aryl sulfamates. Org. Lett. 2020, 22, 168–174. [Google Scholar] [CrossRef]
  20. Sguazzin, M.A.; Johnson, J.W.; Magolan, J. Hexafluoroisopropyl sulfamate: A useful reagent for the synthesis of sulfamates and sulfamides. Org. Lett. 2021, 23, 3373–3378. [Google Scholar] [CrossRef]
  21. Wang, H.M.; Xiong, C.D.; Chen, X.Q.; Hu, C.; Wang, D.Y. Preparation of sulfamates and sulfamides using a selective sulfamoylation agent. Org. Lett. 2021, 23, 2595–2599. [Google Scholar] [CrossRef] [PubMed]
  22. Collet, F.; Dodd, R.H.; Dauban, P. Catalytic C-H amination: Recent progress and future directions. Chem. Commun. 2009, 5061–5074. [Google Scholar] [CrossRef] [PubMed]
  23. Bower, J.F.; Rujirawanich, J.; Gallagher, T. N-heterocycle construction via cyclic sulfamidates. Applications in synthesis. Org. Biomol. Chem. 2010, 8, 1505–1519. [Google Scholar] [CrossRef] [PubMed]
  24. Pham, Q.H.; Hyland, C.J.T.; Pyne, S.G. Five-membered cyclic sulfamidate imines: Versatile scaffolds for organic synthesis. Org. Biomol. Chem. 2020, 18, 7467–7484. [Google Scholar] [CrossRef]
  25. Meléndez, R.E.; Lubell, W.D. Synthesis and reactivity of cyclic sulfamidites and sulfamidates. Tetrahedron 2003, 59, 2581–2616. [Google Scholar] [CrossRef]
  26. Nicolaou, K.C.; Huang, X.; Snyder, S.A.; Bheema Rao, P.; Bella, M.; Reddy, M.V. A novel regio- and stereoselective synthesis of sulfamidates from 1,2-diols using Burgess and related reagents: A facile entry into β-amino alcohols. Angew. Chem. Int. Ed. 2002, 41, 834–838. [Google Scholar] [CrossRef]
  27. Nicolaou, K.C.; Snyder, S.A.; Longbottom, D.A.; Nalbandian, A.Z.; Huang, X. New uses for the Burgess reagent in chemical synthesis: Methods for the facile and stereoselective formation of sulfamidates, glycosylamines, and sulfamides. Chemistry 2004, 10, 5581–5606. [Google Scholar] [CrossRef]
  28. Lee, H.K.; Kang, S.; Choi, E.B. Stereoselective synthesis of norephedrine and norpseudoephedrine by using asymmetric transfer hydrogenation accompanied by dynamic kinetic resolution. J. Org. Chem. 2012, 77, 5454–5460. [Google Scholar] [CrossRef]
  29. Kang, S.; Han, J.; Lee, E.S.; Choi, E.B.; Lee, H.K. Enantioselective synthesis of cyclic sulfamidates by using chiral Rhodium-catalyzed asymmetric transfer hydrogenation. Org. Lett. 2010, 12, 4184–4187. [Google Scholar] [CrossRef]
  30. Wang, Y.Q.; Yu, C.B.; Wang, D.W.; Wang, X.B.; Zhou, Y.G. Enantioselective synthesis of cyclic sulfamidates via Pd-catalyzed hydrogenation. Org. Lett. 2008, 10, 2071–2074. [Google Scholar] [CrossRef]
  31. Alderson, J.M.; Phelps, A.M.; Scamp, R.J.; Dolan, N.S.; Schomaker, J.M. Ligand-controlled, tunable silver-catalyzed C-H amination. J. Am. Chem. Soc. 2014, 136, 16720–16723. [Google Scholar] [CrossRef] [PubMed]
  32. Espino, C.G.; Wehn, P.M.; Chow, J.; Du Bois, J. Synthesis of 1,3-difunctionalized amine derivatives through selective C−H bond oxidation. J. Am. Chem. Soc. 2001, 123, 6935–6936. [Google Scholar] [CrossRef]
  33. Paradine, S.M.; Griffin, J.R.; Zhao, J.; Petronico, A.L.; Miller, S.M.; Christina White, M. A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp3)-H amination. Nat Chem. 2015, 7, 987–994. [Google Scholar] [CrossRef] [PubMed]
  34. Hazelard, D.; Nocquet, P.A.; Compain, P. Catalytic C–H amination at its limits: Challenges and solutions. Org. Chem. Front. 2017, 4, 2500–2521. [Google Scholar] [CrossRef]
  35. Ruppel, J.V.; Kamble, R.M.; Zhang, X.P. Cobalt-catalyzed intramolecular C−H amination with arylsulfonyl azides. Org. Lett. 2007, 9, 4889–4892. [Google Scholar] [CrossRef] [PubMed]
  36. Jiang, C.; Lu, Y.; Hayashi, T. High performance of a palladium phosphinooxazoline catalyst in the asymmetric arylation of cyclic N-sulfonyl ketimines. Angew. Chem. Int.Ed. 2014, 53, 9936–9939. [Google Scholar] [CrossRef]
  37. Higginbotham, M.C.; Bebbington, M.W. Gold(I)-catalysed synthesis of cyclic sulfamidates by intramolecular allene hydroamination. Chem. Commun. 2012, 48, 7565–7567. [Google Scholar] [CrossRef]
  38. Chen, Y.J.; Chen, Y.H.; Feng, C.G.; Lin, G.Q. Enantioselective Rhodium-catalyzed arylation of cyclic N-sulfamidate alkylketimines: A new access to chiral β-alkyl-β-aryl amino alcohols. Org. Lett. 2014, 16, 3400–3403. [Google Scholar] [CrossRef]
  39. Weymouth-Wilson, A.C. The role of carbohydrates in biologically active natural products. Nat. Prod. Rep. 1997, 14, 99–110. [Google Scholar] [CrossRef]
  40. William Lown, J. Anthracycline and anthraquinone anticancer agents: Current status and recent developments. Pharmacol. Ther. 1993, 60, 185–214. [Google Scholar] [CrossRef]
  41. Zeng, J.; Sun, G.; Yao, W.; Zhu, Y.; Wang, R.; Cai, L.; Liu, K.; Zhang, Q.; Liu, X.W.; Wan, Q. 3-Aminodeoxypyranoses in glycosylation: Diversity-oriented synthesis and assembly in oligosaccharides. Angew. Chem. Int.Ed. 2017, 56, 5227–5231. [Google Scholar] [CrossRef] [PubMed]
  42. Zeng, J.; Wang, R.; Yao, W.; Zhang, S.; Sun, G.; Liao, Z.; Meng, L.; Wan, Q. Diversified synthesis and α-selective glycosylation of 3-amino-2,3,6-trideoxy sugars. Org. Chem. Front. 2018, 5, 3391–3395. [Google Scholar] [CrossRef]
  43. Fu, D.; Zhang, S.; Xu, B.; Peng, P.; Wan, Q.; Zeng, J. Selective reduction leading to 3,5-cis-3-aminosugars: Synthesis and stereoselective glycosylation. J. Org. Chem. 2022. [Google Scholar] [CrossRef] [PubMed]
  44. Yamashita, S.; Himuro, M.; Hayashi, Y.; Hirama, M. Remote C–H bond functionalization of androstane C-ring: C12-amination. Tetrahedron Lett. 2013, 54, 1307–1308. [Google Scholar] [CrossRef]
  45. Liu, M.-Q.; Jiang, T.; Chen, W.-W.; Xu, M.-H. Highly enantioselective Rh/chiral sulfur-olefin-catalyzed arylation of alkyl-substituted non-benzofused cyclic N-sulfonyl ketimines. Org. Chem. Front. 2017, 4, 2159–2162. [Google Scholar] [CrossRef]
  46. Kukhtin, V.A. Some new types of Arbuzov’s regrouping. Dokl. Akad. Nauk SSSR 1958, 121, 466–469. [Google Scholar]
  47. Ramirez, F. Condensations of carbonyl compounds with phosphite esters. Pure Appl. Chem. 1964, 9, 337–370. [Google Scholar] [CrossRef]
  48. Ramirez, F. Oxyphosphoranes. Acc. Chem. Res. 1968, 1, 168–174. [Google Scholar] [CrossRef]
  49. Miller, E.J.; Zhao, W.; Herr, J.D.; Radosevich, A.T. A nonmetal approach to α-heterofunctionalized carbonyl derivatives by formal reductive X-H insertion. Angew. Chem. Int. Ed. 2012, 51, 10605–10609. [Google Scholar] [CrossRef]
  50. Harpp, D.N.; Mathiaparanam, P. 1,3,2-Dioxaphospholene-sulfenyl chloride condensation. Scope and mechanism. J. Org. Chem. 1972, 37, 1367–1374. [Google Scholar] [CrossRef]
  51. Zhao, W.; Yan, P.K.; Radosevich, A.T. A phosphetane catalyzes deoxygenative condensation of α-keto esters and carboxylic acids via PIII/PV=O redox cycling. J. Am. Chem. Soc. 2015, 137, 616–619. [Google Scholar] [CrossRef] [PubMed]
  52. Zhao, W.; Fink, D.M.; Labutta, C.A.; Radosevich, A.T. A Csp3-Csp3 bond forming reductive condensation of α-keto esters and enolizable carbon pronucleophiles. Org. Lett. 2013, 15, 3090–3093. [Google Scholar] [CrossRef] [PubMed]
  53. Haugen, K.C.; Rodriguez, K.X.; Chavannavar, A.P.; Oliver, A.G.; Ashfeld, B.L. Phosphine-mediated addition of 1,2-dicarbonyls to diazenes: An umpolung approach toward N-acyl hydrazone synthesis. Tetrahedron Lett. 2015, 56, 3527–3530. [Google Scholar] [CrossRef] [Green Version]
  54. Zhang, L.; Lu, H.; Xu, G.Q.; Wang, Z.Y.; Xu, P.F. PPh3 mediated reductive annulation reaction between isatins and electron deficient dienes to construct spirooxindole compounds. J. Org. Chem. 2017, 82, 5782–5789. [Google Scholar] [CrossRef] [PubMed]
  55. Zhou, R.; Yang, C.; Liu, Y.; Li, R.; He, Z. Diastereoselective synthesis of functionalized spirocyclopropyl oxindoles via P(NMe2)3-mediated reductive cyclopropanation. J. Org. Chem. 2014, 79, 10709–10715. [Google Scholar] [CrossRef]
  56. Rodriguez, K.X.; Vail, J.D.; Ashfeld, B.L. Phosphorus(III)-mediated stereoconvergent formal [4+1]-cycloannulation of 1,2-dicarbonyls and o-quinone methides: A multicomponent assembly of 2,3-dihydrobenzofurans. Org. Lett. 2016, 18, 4514–4517. [Google Scholar] [CrossRef]
  57. Corre, E.; Foucaud, A. Synthesis of 2-acetyl-3-aryl-1,1-dicyano-2-methyl-cyclopropanes. J. Chem. Soc. D 1971, 570a. [Google Scholar] [CrossRef]
  58. Choi, G.; Kim, H.E.; Hwang, S.; Jang, H.; Chung, W.J. Phosphorus(III)-mediated, tandem deoxygenative geminal chlorofluorination of 1,2-diketones. Org. Lett. 2020, 22, 4190–4195. [Google Scholar] [CrossRef]
  59. Wang, S.R.; Radosevich, A.T. P(NMe2)3-mediated umpolung alkylation and nonylidic olefination of α-keto esters. Org. Lett. 2015, 17, 3810–3813. [Google Scholar] [CrossRef] [Green Version]
  60. Calcatelli, A.; Denton, R.M.; Ball, L.T. Modular synthesis of α,α-diaryl α-amino esters via Bi(V)-mediated arylation/SN2-displacement of Kukhtin–Ramirez intermediates. Org. Lett. 2022, 24, 8002–8007. [Google Scholar] [CrossRef]
  61. Fier, P.S.; Kim, S.; Maloney, K.M. Reductive cleavage of secondary sulfonamides: Converting terminal functional groups into versatile synthetic handles. J. Am. Chem. Soc. 2019, 141, 18416–18420. [Google Scholar] [CrossRef] [PubMed]
  62. Zhang, J.-R.; Liao, Y.-Y.; Deng, J.-C.; Tang, Z.-L.; Xu, Y.-L.; Xu, L.; Tang, R.-Y. DABCO-promoted decarboxylative acylation: Synthesis of α-keto and α,β-unsaturated amides or esters. Asian J. Org. Chem. 2017, 6, 305–312. [Google Scholar] [CrossRef]
  63. Yu, T.T.; Nizalapur, S.; Ho, K.K.K.; Yee, E.; Berry, T.; Cranfield, C.G.; Willcox, M.; Black, D.S.; Kumar, N. Design, Synthesis and biological evaluation of N-sulfonylphenyl glyoxamide-based antimicrobial peptide mimics as novel antimicrobial agents. ChemistrySelect 2017, 2, 3452–3461. [Google Scholar] [CrossRef] [Green Version]
  64. Ryu, H.; Seo, J.; Ko, H.M. Synthesis of spiro[oxindole-3,2’-pyrrolidine] derivatives from benzynes and azomethine ylides through 1,3-dipolar cycloaddition reactions. J. Org. Chem. 2018, 83, 14102–14109. [Google Scholar] [CrossRef] [PubMed]
  65. Shu, P.; Xiao, X.; Zhao, Y.; Xu, Y.; Yao, W.; Tao, J.; Wang, H.; Yao, G.; Lu, Z.; Zeng, J.; et al. Interrupted Pummerer reaction in latent-active glycosylation: Glycosyl donors with a recyclable and regenerative leaving group. Angew. Chem. Int. Ed. 2015, 54, 14432–14436. [Google Scholar] [CrossRef]
  66. Xiao, X.; Zhao, Y.; Shu, P.; Zhao, X.; Liu, Y.; Sun, J.; Zhang, Q.; Zeng, J.; Wan, Q. Remote activation of disarmed thioglycosides in latent-active glycosylation via interrupted Pummerer reaction. J. Am. Chem. Soc. 2016, 138, 13402–13407. [Google Scholar] [CrossRef]
  67. Zhao, X.; Zeng, J.; Meng, L.; Wan, Q. Application of interrupted Pummerer reaction mediated (IPRm) glycosylation in natural product synthesis. Chem. Rec. 2020, 20, 743–751. [Google Scholar] [CrossRef]
  68. Xiao, X.; Zeng, J.; Fang, J.; Sun, J.; Li, T.; Song, Z.; Cai, L.; Wan, Q. One-pot relay glycosylation. J. Am. Chem. Soc. 2020, 142, 5498–5503. [Google Scholar] [CrossRef]
  69. Cai, L.; Chen, Q.; Liang, Z.; Fu, D.; Meng, L.; Zeng, J.; Wan, Q. Recyclable fluorous-tag assisted two-directional oligosaccharide synthesis enabled by interrupted Pummerer reaction mediated glycosylation. Chem. Sci. 2022, 13, 8759–8765. [Google Scholar] [CrossRef]
  70. Paradine, S.M.; White, M.C. Iron-catalyzed intramolecular allylic C-H amination. J. Am. Chem.Soc. 2012, 134, 2036–2039. [Google Scholar] [CrossRef]
  71. Zhang, X.; Wang, L. TBHP/I2-promoted oxidative coupling of acetophenones with amines at room temperature under metal-free and solvent-free conditions for the synthesis of α-ketoamides. Green Chem. 2012, 14, 2141–2145. [Google Scholar] [CrossRef]
Molecules 28 00182 g001 550
Figure 1. Representative drugs containing amino alcohol motifs and established approaches to synthesizing amino alcohols.
Figure 1. Representative drugs containing amino alcohol motifs and established approaches to synthesizing amino alcohols.
Molecules 28 00182 g001
Molecules 28 00182 sch001 550
Scheme 1. Application of Kukhtin–Ramirez reaction [61].
Scheme 1. Application of Kukhtin–Ramirez reaction [61].
Molecules 28 00182 sch001
Molecules 28 00182 sch002 550
Scheme 2. Substrate scope a. a Yield of isolated product. b c = 0.05 M.
Scheme 2. Substrate scope a. a Yield of isolated product. b c = 0.05 M.
Molecules 28 00182 sch002
Molecules 28 00182 sch003 550
Scheme 3. Amino alcohol synthesis through cyclic sulfamidate.
Scheme 3. Amino alcohol synthesis through cyclic sulfamidate.
Molecules 28 00182 sch003
Table
Table 1. Reaction development.
Table 1. Reaction development.
Molecules 28 00182 i001
EntryVariation from Standard ConditionsYield a
1Step 1 only3a, 95%
2Without H2O4a, 79%
3Standard conditions2a, 88%
4DBU instead of BTMG2a, 86%
5KOH instead of BTMG2a, 80%
6K2CO3 instead of BTMG2a, 16%
7Et3N instead of BTMG2a, trace
8Ambersep® 900 (OH) instead of BTMG2a, 80%
a Yield of isolated product.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Li, T.; Xu, B.; Fu, D.; Wan, Q.; Zeng, J. Kukhtin–Ramirez-Reaction-Inspired Deprotection of Sulfamidates for the Synthesis of Amino Sugars. Molecules 2023, 28, 182. https://doi.org/10.3390/molecules28010182

AMA Style

Li T, Xu B, Fu D, Wan Q, Zeng J. Kukhtin–Ramirez-Reaction-Inspired Deprotection of Sulfamidates for the Synthesis of Amino Sugars. Molecules. 2023; 28(1):182. https://doi.org/10.3390/molecules28010182

Chicago/Turabian Style

Li, Ting, Bingbing Xu, Dengxian Fu, Qian Wan, and Jing Zeng. 2023. "Kukhtin–Ramirez-Reaction-Inspired Deprotection of Sulfamidates for the Synthesis of Amino Sugars" Molecules 28, no. 1: 182. https://doi.org/10.3390/molecules28010182

Article Metrics

Back to TopTop