CN107722106A

CN107722106A - Hiv inhibitor

Info

Publication number: CN107722106A
Application number: CN201610661992.1A
Authority: CN
Inventors: 贺耘; 戚娜; 王占龙
Original assignee: Chongqing University
Current assignee: Chongqing University
Priority date: 2016-08-11
Filing date: 2016-08-11
Publication date: 2018-02-23

Abstract

The present invention provides compound of formula I：

Description

HIV inhibitors

Technical Field

The present invention relates to novel compounds useful for anti-HIV activity, and more particularly, to compounds derived from the natural product Aetheramide a and other structurally related compounds, and their preparation methods, and to pharmaceutical compositions containing these compounds.

Background

Since the discovery of the HIV virus in 1981 to date, over 3000 million people have died from HIV virus infection, and over 3000 million people are still afflicted with the HIV virus, and the majority of patients are from low-to-medium-income countries. The HIV virus has a very rapid mutation rate unlike other viruses. About 10 per day^9-12Production of individual novel virions, on average 10 per replication cycle^-4～-3Secondary mutation, accompanied by about 34 recombinations.This rapid variation results in a large number of variant strains that are increasingly resistant to existing drugs¹. The wide spread and rapid variation of the HIV virus put higher demands on the medical and academic circles, and the development of antiviral drugs with new targets and new mechanisms is not easy.

The importance of natural products is becoming increasingly prominent in the development of new drugs. In 1981-2010, 1073 small molecule drugs were approved. Of these, although 66% of drugs are all synthetically derived, 16% contain pharmacophores derived from natural products, and 14% are mimics from natural products, so that only 36% of drugs are unrelated to natural products. In addition to 66% of the synthetic drugs, another 34% of the drugs are derived entirely from natural products or modified natural products²。

Myxobacteria are gram-negative proteobacteria, widely found in soil, bark, decaying vegetation, herbivore faeces and in the sea. This interesting microorganism behaves very strangely and is rich in secondary metabolites, a well-known natural product manufacturing plant in nature³. Up to now, 7500 species of myxobacteria have been identified, at least 100 structurally defined compounds have been obtained, and more than 500 analogues have been derivatized⁴Mainly comprising polyketide, non-ribosomal polypeptide and hybrid of the two, and other structural types such as terpenes, alkaloids and the like⁵. The activities of these compounds mainly include antibacterial and antiviral activities, which make it possible to play a role in the treatment of cancer. More importantly, most of the compounds have unique or even completely new action mechanisms, so that the compounds become excellent lead compounds in drug development. However, it is difficult to obtain sufficient amounts for physiological and toxicological experiments by means of natural purification alone, and thus chemical total synthesis of important compounds is required.

In 2010, a new genus of myxobacteria, Aetherobacter, was reported, and a. rufus (SBSr003) was the first strain of this new genus. A cyclic depsipeptide, named Aethene, was obtained from an ethyl acetate extract of A.rufus (SBSr003)Amides, which include a unique polyketone structure and two amino acid residues (including one unnatural amino acid), are a class of structurally novel natural products. By screening for antibacterial, antifungal, cytotoxic and anti-HIV activity: the compounds Aetheramide A and Aetheramide B can effectively inhibit HIV-1 virus infection, IC₅₀Values were 15nM and 18nM, respectively; the two also have obvious inhibitory effect on human colon cancer cell HCT-116, IC₅₀Are all 110 nM; meanwhile, the two have stronger inhibitory activity on the fungus Candida Albicans⁶。

Structures of aetheramides a and B

Natural products reported to have anti-HIV activity mainly include alkaloid, phenol, terpene, protein, polysaccharide, etc., some of which have been in clinical (pre) research, such as Calanolide A, Bevirimat, DCK, DCQA, curcumin, etc., but these compounds have structures completely different from Aetheramides, such as Calanolide A⁷、Bevirimat⁸、DCK⁹、DCQA¹⁰Dextran sulfate (9.1. mu.g/mL IC50 inhibiting HIV-1 replication, first stage of the clinic)¹¹Curcumin, pharmaceutical compositions containing the same and pharmaceutical compositions containing the same¹²Cyanovirin A (a protein comprising 101 amino acid residues, which inhibits HIV-1 and HIV-2 at the nanomolar level, preclinical)¹³And the like. Meanwhile, some cyclic depsipeptides having anti-HIV activity have been reported, such as Echinomycin, Neoamphetamine A, etc., for example, Echinomycin found in metabolites of microorganisms¹⁴Neamphamide A found in the ocean¹⁵And the like. However, the cyclic depsipeptides are complex in structure, have large molecular weights, are more similar to a micro-protein, and have great differences from the structures of the Aetheramides.

anti-HIV natural products for clinical (pre) studies

Therefore, the Aetheramides are natural products with unique structures and excellent anti-HIV activity, and may have novel action mechanisms. The research on the anti-HIV activity of the structure type is of great significance to the discovery of new targets and the research on new action mechanisms. Meanwhile, the further modification of the structure of the analogue can possibly become a lead compound of a new anti-HIV drug, the structure of the analogue is optimized by means of chemical and biological means, an excellent analogue with stable structure and good activity is obtained, and a new thought is provided for the research and development of the anti-HIV drug.

Reference to the literature

1.Kumari,G.,Curr.Pharm.Design,2013,19,1767-1783.

2.Cragg,G.M.,Biochimica et BiophysicaActa,2013,1830,3670-3695.

3.Wenzel,S.C.,Curr.Opin.Drug Discov.Devel.,2009,12,220-230.

4.Garcia,R.O.,Methods Enzymol.,2009,458,59-91.

5.Weissmana,K.J.,Nat.Prod.Rep.,2010,27,1276-1295.

6.Plaza,A.,Org.Lett.,2012,14,2854-2857.

7.Kashman,Y.,J.Med.Chem.,1992,35,2735-2743.

8.Kashiwada,Y.,J.Med.Chem.,1996,39,1016-1017.

9.Xie,L.,J.Med.Chem.,1999,42,2662-2672.

10.Robinson,W.E,Jr.,Mol.Pharmacol.,1996,50,846-855.

11.Baba,M.,Proc.Natl.Acad.Sci.U.S.A.,1988,85,6132-6136.

12.Mazumder,A.,Biochem.Pharmacol.,1995,49,1165-1170.

13.Boyd,M.R.,Antimicrob.AgentsandChemother.,1997,41,1521-1530.

14.Jayasuriya,H.,Chem.Biodivers.,2005,2,112-122.

15.Oku,N.,Neamphiushuxleyi.J.Nat.Prod.,2004,67,1407-1411.。

Disclosure of Invention

The invention relates to compounds derived from the natural product Aetheramide A and other structurally related compounds, in particular to compounds shown in a formula I,also relates to pharmaceutically acceptable salts or esters of the compounds of formula I and stereochemically isomeric forms thereof.

Wherein,

x, Y and Z are independently: -O-, -NH-, -NMe-;

R₁，R₃independently, the following components: c_1-6Alkyl, -O-C_1-6Alkyl, H, halogen, C_3-6Cycloalkyl, aryl or heteroaryl, halo C_1-6Alkyl, halo C_3-6Cycloalkyl, heteroalicyclic;

R₂，R₄，R₇independently, the following components: c_1-6Alkyl, -O-C_1-6Alkyl, H, halogen, C_3-6Cycloalkyl, halo C_1-6Alkyl, halo C_3-7A cycloalkyl group;

R₅the method comprises the following steps: -OH, -O (C)_1-6Alkyl) -, -O (C)_3-6Cycloalkyl) -, -O (halo C)_1-6Alkyl) -,-O (halo C)_3-6Cycloalkyl) -;

R₆the method comprises the following steps: c_1-6Alkyl, H, halogen, C_3-6Cycloalkyl radical, C_2-8An alkynyl group;

R₈the method comprises the following steps: -OH, -O-C_1-6An alkyl group;

R₁-R₈can be mono-substituted or di-substituted, when R is di-substituted₁-R₈May be the same or different groups;

when X is: -O-, and R₈When it is-OH, the ester group may migrate between the two;

m＝1-6；n＝1-5；o＝0-6；

R₉，R₁₀independently, the following components: h, C_1-6Alkyl radical, C_3-6Cycloalkyl, aryl or heteroaryl, halo C_1-6Alkyl, halo C_3-6A cycloalkyl group.

Definitions of terms, unless explicitly stated otherwise elsewhere in this application, one or more of the following terms may be used in this application and shall have the following meanings:

"H" refers to hydrogen, including isotopes thereof such as deuterium.

The term "C1-6 alkyl" as used in the present application and claims (unless otherwise specified) means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

"halogen" means chlorine, bromine, iodine or fluorine.

An "aryl" or "Ar" group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a fully conjugated pi-electron system. Examples of aryl groups are, but are not limited to, phenyl, naphthyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituent groups are preferably selected from one or more of the following: alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicyclic oxy, mercapto, arylthio (thioaryloxy), heteroarylthio (thioheteroaryloxy), heteroalicyclic thio (thioheteroalicyloxy), cyano, halo, nitro, carbonyl, O-carbamoyl, N-carbamoyl, C-acylamino, N-acylamino, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino, and-NRxRy, wherein Rx and R y are independently selected from the following: hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, if combined, a five or six membered heterocycloaliphatic ring.

As used herein, "heteroaryl" refers to a monocyclic or fused ring (i.e., rings that share adjacent pairs of atoms) group having one or more atoms in the ring selected from nitrogen, oxygen, and sulfur, and further having a fully conjugated pi-electron system. Unless otherwise indicated, a heteroaryl group may be attached at a carbon or nitrogen atom within the heteroaryl group. It should be noted that the term heteroaryl is intended to encompass N-oxides of the parent heteroaryl, if such N-oxides are known in the art to be chemically feasible. Examples of heteroaryl groups are (but are not limited to) furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, pyrazinyl, diazinyl, triazinyl, tetrazinyl, and tetrazolyl. When substituted, the substituent groups are preferably selected from one or more of the following: alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicyclyloxy, alkylthio, mercapto, arylthio, heteroarylthio, heteroalicyclylthio, cyano, halogen, nitro, carbonyl, O-carbamoyl, N-carbamoyl, C-acylamino, N-acylamino, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino and-NRxRy, wherein Rx and R y are as defined above.

As used herein, a "heteroalicyclic" group refers to a monocyclic or fused ring group having one or more atoms in the ring selected from nitrogen, oxygen, and sulfur. These rings are selected from those that provide a stable bonding arrangement and are not intended to encompass absent systems. These rings may also have one or more double bonds. However, these rings do not have a fully conjugated pi-electron system. Examples of heteroalicyclic groups are, but are not limited to, azetidinyl, piperidinyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl, and tetrahydropyranyl. When substituted, the substituent groups are preferably selected from one or more of the following: alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicyclyloxy, mercapto, alkylthio, arylthio, heteroarylthio, heteroalicyclylthio, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, C-thioamido, N-acylamino, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, amidino, guanidino, ureido, phosphonyl, amino and-NRxRy, where Rx and R y are as defined above.

"cycloalkyl" refers to all carbon monocyclic or fused ring (i.e., rings that share an adjacent pair of carbon atoms) groups in which one or more rings do not have a fully conjugated pi-electron system. Examples of cycloalkyl groups are, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, and adamantane. Cycloalkyl groups may be substituted or unsubstituted. When substituted, the substituent groups are preferably independently selected from one or more of the following: alkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicyclyloxy, mercapto, alkylthio, arylthio, heteroarylthio, heteroalicyclylthio, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, C-thioamido, N-acylamino, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl sulfonyl, silyl, amidino, guanidino, ureido, phosphonyl, amino and-NRxRy, and Rx and Ry are as defined above.

"alkynyl" refers to an alkyl group as defined herein having at least two carbon atoms and at least one carbon-carbon triple bond.

More specifically, the present invention provides compounds selected from the group consisting of:

in general, the invention includes all tautomeric and isomeric forms of a chemical structure or compound, and mixtures thereof, e.g., individual tautomers, geometric isomers, stereoisomers, atropisomers, enantiomers, diastereomers, racemates, racemic or non-racemic mixtures of stereoisomers, mixtures of diastereomers, or mixtures of any of the foregoing, unless a specific stereochemistry or isomeric form is specified in the compound name or structure.

It is known in the art that the biological and pharmaceutical activity of a compound is quite sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit significantly different biological activities, including pharmacokinetic differences, including metabolism, protein binding, and the like, as well as pharmacological property differences, including differences in the type of activity exhibited, the degree of activity, toxicity, and the like. Thus, one skilled in the art will recognize that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other or when separated from the other. Furthermore, those skilled in the art will know from the present disclosure and the knowledge of the prior art how to isolate, enrich or selectively prepare enantiomers of the compounds of the invention.

The preparation of pure stereoisomers (e.g. enantiomers and diastereomers), or mixtures of the desired enantiomeric excesses (ee) or enantiomeric purities can be achieved by one or more of the following methods: (a) separation or resolution of enantiomers; or (b) enantioselective synthesis well known to those skilled in the art, or combinations thereof. These resolution methods typically rely on the identification of chirality and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliary agents, enantioselective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are generally described in the Chiral Separation Techniques: APractcal Approach (2ndEd.), G.Subramanian (ed.), Wiley-VCH, 2000; satinder Ahuja, Chiral Separations by chromatography, am. chem. soc., 2000, et al, prior art documents or books, which are incorporated herein by reference. Furthermore, the quantitative methods for enantiomeric excess or purity are known methods, such as GC, HPLC, CE or NMR, and confirmation of absolute configuration and conformation, such as CD, ORD, X-ray crystallography or NMR.

The present invention also provides pharmaceutical compositions, which compounds of the present invention can be administered to a mammal in need of treatment for HIV infection as a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or ester thereof; and one or more conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. The specific formulation of the composition will be determined by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice. The pharmaceutical composition of the present invention may be administered orally or systemically.

When one enantiomer of a chiral active ingredient has different biological activity compared to another, it will be understood that the pharmaceutical composition according to the invention may comprise a racemic mixture of the active ingredients, a mixture enriched in one enantiomer of the active ingredient or a pure enantiomer of the active ingredient. A mixture enriched in one enantiomer of the active ingredient may contain from greater than 50% to about 100% of one enantiomer of the active ingredient, and from about 0% to less than 50% of the other enantiomer of the active ingredient. Preferably, when the composition comprises a mixture of enantiomers enriched in the active ingredient or a pure enantiomer of the active ingredient, the composition comprises from greater than 50% to about 100% or only the more physiologically active enantiomer and/or the less toxic enantiomer. It is known that one enantiomer of an active ingredient may be more physiologically active for one therapeutic indication, while another enantiomer of the active ingredient may be more physiologically active for a different therapeutic indication; thus, the preferred enantiomeric composition of the pharmaceutical composition may vary with the use of the composition in the treatment of different therapeutic indications.

For oral administration, the compound or a pharmaceutically acceptable salt or ester thereof may be formulated into any orally acceptable dosage form, including but not limited to aqueous suspensions and solutions, capsules, powders, syrups, elixirs, or tablets. For systemic administration, including but not limited to subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal and intrapalpebral (intradivision) injection or infusion techniques, it is preferred to use solutions of the compounds or pharmaceutically acceptable salts thereof in pharmaceutically acceptable sterile aqueous carriers.

Pharmaceutically acceptable carriers, adjuvants, vehicles, diluents, excipients and additives, and methods of formulating pharmaceutical compositions for various modes of administration are well known to those skilled in the art and are described in the pharmaceutical literature, such as Remington: the science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005; and l.v. allen, n.g. popovish and h.c. ansel, Pharmaceutical Dosage Forms and drug delivery Systems, 8th edition, Lippincott Williams & Wilkins, 2004, which are incorporated herein by reference.

The dosage administered depends on known factors including, but not limited to, the activity and pharmacokinetic properties of the particular compound used, as well as the mode, time and route of administration; age, diet, sex, weight, and general health of the recipient; the nature and extent of the symptoms; severity and course of infection; the kind of concurrent treatment; the frequency of treatment; the desired effect; and the judgment of the treating physician. In general, it is most desirable to administer the drug at a dosage that generally achieves an antiviral effective result without causing any harmful or adverse side effects.

The daily dose of the active ingredient may be from about 0.001 to about 100 mg per kg of body weight, with a preferred dose being from about 0.01 to about 50 mg/kg. Typically, the pharmaceutical compositions of the present invention are administered from about 1 to about 5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute treatment. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular route of administration. Typical formulations contain from about 5% to about 95% active compound (w/w). Preferably, the formulation contains from about 20% to about 80% of the active compound.

The present invention also provides combination therapies (combination therapies) involving a compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, co-administered with at least one other antiviral agent. Other drugs may be combined with the compounds of the present invention to form a single dosage form. Or these other drugs may be administered separately, simultaneously or sequentially as part of a multiple dosage form.

When the pharmaceutical compositions of the present invention comprise a compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, in combination with one or more other antiviral agents, both the compound and the other agent should be present in a dosage amount of from about 10 to 100%, and preferably from about 10 to 80%, of the normal dosage administered in a single course of treatment. In the case of synergy between the compounds of the present invention and other antiviral agents or agents, the dose of any or all of the active agents in the combination may be reduced as compared to the dose normally administered in a single course of treatment.

Antiviral agents for use in such combination therapies include drugs (compounds or biologicals) effective to inhibit virus formation and/or replication in a mammal, including but not limited to drugs that interfere with host or viral mechanisms required for virus formation and/or replication in a mammal. Such a drug may be selected from:

NRTIs (nucleoside or nucleotide reverse transcriptase inhibitors) include, but are not limited to: zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), emtricitabine, abacavir succinate, jejuncitabine (elvucitabine), adefovir dipivoxil, lobbucavir (BMS-180194), lodenosine (FddA), and tenofovir, including tenofovir dipivoxil and tenofovir dipivoxil fumarate, COMBIVIRTM (containing 3TC and AZT), TRIZIVIRTM (containing abacavir, 3TC, and AZT), TRUVADATM (containing tenofovir and emtricitabine), epzicomcmos (containing abacavir and 3 TC);

NNRTIs (non-nucleoside reverse transcriptase inhibitors) include, but are not limited to: nevirapine, delavirdine, efavirenz, etavirenz (etravirine), and rilpivirine;

protease inhibitors include, but are not limited to: ritonavir, tipranavir, saquinavir, nelfinavir, indinavir, amprenavir, fosamprenavir, atazanavir (atazanavir), lopinavir, darunavir (darunavir) (TMC-114), lacinavir and brecanavir (brecanavir) (VX-385);

CCR5 antagonists: including but not limited to maraviroc (maraviroc), viliviroc (vicriviroc), INCB9471 and TAK-652;

CXCR4 antagonists: including but not limited to AMD-11070;

fusion inhibitor: including but not limited to Enfuvirtide (T-20), TR1-1144 and TR 1-999;

integrase inhibitors: including but not limited to Raltegravir (MK-0518), BMS-707035, and also Wittigerbera (elvitegravir) (GS 9137);

immune modulating agent: including but not limited to levotetramisole;

other antiviral agents: including hydroxyurea, ribavirin, IL-2, IL-12, and flaxsaposide.

In addition, the compounds of the present invention may be used with at least one other compound of the present invention or with one or more antifungal or antibacterial agents, including but not limited to fluconazole (fluconazole).

The compounds according to the invention can also be used as laboratory or research reagents. For example, the compounds of the invention may be used as a positive control group to confirm tests, including but not limited to, alternative cell-based tests, and in vitro or in vivo viral replication tests.

In addition, the compounds of the present invention may be used to treat or prevent viral contamination of substances, thereby reducing the risk of viral infection in laboratories or medical personnel or patients coming into contact with such substances (e.g., blood, tissue, surgical instruments and clothing, laboratory instruments and clothing, and blood collection devices and substances).

The invention also provides a preparation method of the compound shown in the formula I, and relates to two synthetic routes, namely a synthetic route I and a synthetic route II. If desired, the starting materials and intermediates in the synthetic reaction schemes can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. Unless indicated to the contrary, the reactions described herein are preferably carried out under an inert atmosphere, at atmospheric pressure, at a reaction temperature range of about-78 ℃ to about 180 ℃, and most preferably and conveniently at room (or ambient) temperature, e.g., about 20 ℃. The compounds of the invention were prepared according to the scheme shown below and by employing the procedures described in the examples. In the following schemes, some possible synthetic routes leading to the compound objects of the present invention are described. The groups X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, are as defined above unless otherwise indicated.

Synthetic routes of Aetheramide a and Aetheramide B are one:

the synthesis is carried out on three fragments i-1, i-2 and i-3, and a simple and easily obtained compound is used as a raw material, so that the organic total synthesis of the natural product Aetheramides A is simply and efficiently realized.

The fragment i-1 is synthesized by taking iodoserine as a starting material and carrying out seven steps of reactions such as Nigishi reaction, hydroxyl protection, deprotection, N-methylation and the like to obtain a target compound i-1.

The fragment i-2 takes 2-methyl-2-cyclohexene-1-ketone as a raw material, and chiral reduction is carried out by using a Bu-CBS catalyst to obtain a compound i-2 b; then carrying out hydroxyl methylation, ozone oxidation and selective Wittig reaction to obtain a compound i-2 e; converting methyl ketone groups into methyl-substituted iodo double bonds by utilizing a Takai reaction to obtain a compound i-2 f; and then converting the ester group of the compound i-2f into an aldehyde group, carrying out Evans aldol condensation and removing a protecting group to obtain a compound i-2.

The fragment i-3 is subjected to Sharpless asymmetric dihydroxylation to obtain a compound i-3 b; then, obtaining a compound i-3d through hydroxyl protection and reduction; then converting aldehyde group into alkyne by using Ohira-Bestman reagent, and then carrying out deprotection and selective TBS protection to obtain a compound i-3 g; and converting alkynyl into tributyltin substituted double bond to obtain the compound i-3.

The fragments i-10 and iv-10 obtained are subjected to condensation and deprotection processes to obtain the fragment iv-12.

And (3) condensing and coupling the fragment iv-12 and the fragment iii-10 to obtain an important ring-closing product v-2, and then carrying out oxidation, deprotection and other steps to obtain a natural product Aetheramides A.

Scheme two for the synthesis of Aetheramide a and Aetheramide B:

the synthesis of the i-1, i-3, ii-1 and ii-2 fragments is carried out, and the organic total synthesis of the natural product Aetheramide A is simply and efficiently realized by taking a simple and easily obtained compound as a raw material.

The fragment ii-1 takes methyl propionylacetate as a starting material, and the target compound is obtained by hydrolysis, cyclization of acetone and reaction with diethyl phosphorochloridite.

The segment ii-2 is obtained by performing Aldol reaction between ii-2a serving as a raw material and ii-2b, wherein a reaction product of i-5 and diphenyl boron chloride serving as a chiral catalyst is subjected to oxidation reaction by using newly prepared silver oxide as an oxidant, and reduction reaction by reducing lithium aluminum hydride to obtain ii-2.

ii-2 is oxidized into corresponding aldehyde, then is subjected to HWE olefination reaction with ii-1 and then subjected to Stille reaction, and a series of coupling and deprotection reactions to obtain a key intermediate ii-mou, ii-mou is subjected to intramolecular reaction for cyclization, and finally the Aetheramide A is obtained through methylation reaction and deprotection reaction.

Detailed Description

The first embodiment is as follows:

synthesis of Compound i-1:

to a solution of compound i-1a (1.5g,0.01mol,1eq.) in acetonitrile (5ml) at 0 ℃ were added triethylamine (4ml,0.03mol,3eq.) and di-tert-butyl dicarbonate (2.1g,0.01mol,1eq.) and reacted at room temperature for 5 hours, and after water extraction and concentration of the organic phase, the target compound i-1b was obtained by silica gel column chromatography (yield 95%). Rf 0.20 (petroleum ether/ethyl acetate 5/1);¹H NMR(400MHz,CDCl3)δ5.42(m,1H),4.38(m,1H),3.92(m,2H),3.78(s,3H),2.21(s,1H),1.44(s,9H)。

synthesis of Compounds i-1 c:

triphenylphosphine (9.0g,0.03mol,1.5eq.) and imidazole (2.3g,0.03mol,1.5eq.) were dissolved in a dry dichloromethane (100ml) solution, iodine (8.7g,0.03mol,2eq.) was added to the reaction solution at 0 ℃, after stirring for 45min, compound i-1b (5g,0.02mol,1eq.) was added to the reaction solution in portions, after stirring for 2h at room temperature, acetic acid (0.2ml) and an aqueous solution of sodium thiosulfate were added to quench the reaction, the organic phase was extracted and concentrated, and the target compound i-1c was obtained by silica gel column chromatography (yield 90%). Rf 0.20 (petroleum ether/ethyl acetate 30/1);¹H NMR(400MHz,CDCl3)δ5.34(m,1H),4.50(m,1H),3.78(s,3H),3.55(m,2H),1.44(s,9H)；¹³C NMR(150MHz,CDCl3)δ170.02,154.80,80.47,53.65,52.98,28.25,7.81。

synthesis of Compounds i-1 e:

to a solution of compound i-1d (5.0g,0.04mol,1eq.) in methanol (200ml) at-78 ℃, sodium iodide (9g,0.06mol,1.5eq.) and sodium hydroxide (2.4g,0.06mol,1.5eq.) and sodium hypochlorite (4.5g,0.06mol,1.5eq.) were added, the reaction was quenched with sodium thiosulfate after stirring at-78 ℃ for 10h, neutralized to pH 5 with HCl (1M), water was added to extract and concentrate the organic phase, and the target compound ii-2 was obtained by silica gel column chromatography (yield 60%). Rf 0.20 (petroleum ether/ethyl acetate 10/1);¹H NMR(400MHz,CDCl3)δ7.17(m,1H),7.10(m,1H),6.67(m,1H),5.55(s,1H),3.87(s,3H)。

synthesis of Compounds i-1 f:

imidazole (1.6g,0.02mol,2eq.) and tert-butyldimethylchlorosilane (3.0g,0.02mol,2eq.) were added to a solution of compound i-1e (3.0g,0.01mol,1eq.) in dry dichloromethane (30ml) at 0 ℃, stirred at room temperature for 2h, extracted with water and the organic phase was concentrated to give the desired compound i-1f (100% yield) by silica gel column chromatography. Rf 0.90 (petroleum ether/ethyl acetate 500/1);¹H NMR(400MHz,CDCl3)δ7.10(m,2H),6.58(m,1H),3.77(s,3H),0.97(s,9H),0.13(s,6H)；¹³C NMR(100MHz,CDCl3)δ151.93,145.22,129.93,122.76,121.18,83.27,55.61,25.63,18.40,-4.70。

synthesis of Compound i-1 g:

zinc powder (15.6g,0.24mol,6eq.) and iodine (1.1g,0.004mol,0.1eq.) were added to a dry solution of N, N-dimethylformamide (100ml) in sequence at room temperature, then a solution of compound i-1c (14.0g,0.04mol,1eq.) in dry N, N-dimethylformamide (50ml) was slowly added dropwise to the reaction solution, and the reaction was completed after stirring at room temperature for 4h to obtain the desired zinc reagent. Adding tris (dibenzylideneacetone) dipalladium (2.1g,0.002mol,0.05eq.) and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (2g,0.004mol,0.1eq.) into a dried N, N-dimethylformamide (50ml) solution of the compound i-1f (8.0g,0.02mol,0.5eq.), subsequently adding the aforementioned zinc reagent into the reaction solution in three portions, stirring at room temperature for 5 hours, removing the N, N-dimethylformamide solvent, extracting and concentrating the organic phase, and separating by silica gel column chromatography to obtain the target compound i-1g (product yield)The rate is 90%). Rf 0.20 (petroleum ether/ethyl acetate 20/1);¹H NMR(400MHz,CDCl3)δ6.74(d,J＝7.9Hz,1H),6.55(m,2H),4.97(m,1H),4.52(m,1H),3.75(s,3H),3.66(s,3H),2.98(m,2H),1.40(s,9H),0.96(s,9H),0.12(s,6H)；¹³C NMR(100MHz,CDCl3)δ172.43,155.02,150.78,143.99,129.30,121.48,120.78,113.03,79.78,55.37,54.49,52.07,38.01,28.28,25.67,18.38,-4.68。

synthesis of Compounds i-1 h:

to a solution of compound i-1g (9g,0.02mol,1eq.) in tetrahydrofuran (50ml) was slowly added dropwise a solution of tetrabutylammonium fluoride (12.0g,0.04mol,2eq.) in tetrahydrofuran (50ml), stirred at room temperature for 1h, extracted with water, the organic phase was concentrated, and the target compound i-1h was isolated by silica gel column chromatography (yield 90%). Rf 0.20 (petroleum ether/ethyl acetate 5/1);¹H NMR(400MHz,CDCl3)δ6.70(d,J＝8.0Hz,1H),6.65(s,1H),6.52(d,J＝8.1Hz,1H),5.67(s,1H),4.98(m,1H),4.52(m,1H),3.88(s,3H),3.75(s,3H),2.98(m,2H),1.42(s,9H)；¹³C NMR(100MHz,CDCl3)δ172.35,155.11,145.62,128.81,120.71,115.43,110.60,79.80,55.88,54.42,52.21,37.58,28.29。

synthesis of Compound i-1 i:

dissolving a compound i-1h (3.3g,0.01mol,1eq.) in a mixed solvent of methanol (12ml) and tetrahydrofuran (36ml), dropwise adding an aqueous solution (12ml) of lithium hydroxide (1.3g,0.03mol,3eq.) to the reaction solution at 0 ℃, stirring for 4h, adding 2N hydrochloric acid to neutralize the reaction solution to pH 4, adding water to extract and concentrating the organic phase to obtain a crude product (crude yield 101%) of the compound i-1i, and directly using the crude product in the next reaction without further purification. Rf is 0.10 (dichloromethane/methanol 5/1).

Synthesis of Compounds i-1 j:

imidazole (2.1g,0.03mol,2eq.) and tert-butyldimethylchlorosilane (3.5g,0.02mol,1.5eq.) are sequentially added to a solution of a compound i-1i (4.8g,0.015mol,1eq.) in dry dichloromethane (100ml) at 0 ℃, stirred at room temperature for 3 hours, added with water for extraction, the organic phase is concentrated, and subjected to silica gel column chromatography to obtain the targeted compoundCompound i-1j (yield 95%). Rf 0.20 (dichloromethane/methanol 20/1);¹H NMR(400MHz,CDCl3)δ6.75(d,J＝7.9Hz,1H),6.63(m,2H),4.95(m,1H),4.55(m,1H),3.75(s,3H),3.12(m,2H),1.37(s,9H),0.97(s,8H),0.10(s,6H)；¹³C NMR(100MHz,CDCl3)δ176.55,155.36,150.82,144.08,129.14,121.60,120.79,113.17,80.17,55.41,54.32,37.44,28.47,28.17,25.63,18.38,-4.66。

synthesis of Compound i-1 k:

sodium hydride (2.1g,0.084mol,6eq.) and methyl iodide (7.15ml,0.112mol,8eq.) were added sequentially to a solution of compound i-1j (6.1g,0.014mol,1eq.) in dry tetrahydrofuran (60ml) at 0 ℃, stirred at room temperature for 6 hours, then 3M hydrochloric acid was added to neutralize the reaction solution to pH 4, water was added to extract and concentrate the organic phase, and the target compound i-1k was isolated by silica gel column chromatography (yield 90%). Rf 0.20 (dichloromethane/methanol 25/1);¹H NMR(400MHz,CDCl3)δ6.75(m,1H),6.65(m,2H),4.65(m,1H),4.45(m,1H),3.77(s,3H),3.21(m,1H),3.04(m,1H),2.67(m,3H),1.38(m,9H),0.97(s,8H),0.12(s,6H)；¹³C NMR(150MHz,CDCl3)δ176.04,175.32,156.52,154.90,150.85,143.77,130.84,130.48,121.17,120.84,112.95,112.67,80.68,61.95,61.57,55.46,34.93,34.32,33.66,33.12,28.27,25.69,18.41,-4.70。

synthesis of Compound i-1:

trifluoroacetic acid (5ml) was added to a solution of compound i-1k (5.5g,0.01mol,1eq.) in dichloromethane (50ml) at 0 ℃ and after stirring at room temperature for 2h, dichloromethane and trifluoroacetic acid were removed using a rotary evaporator to give compound i-1l as a crude product (crude yield 110%). The crude product is dissolved in 1, 4-dioxane (20ml) solution, saturated sodium bicarbonate aqueous solution is added into the reaction solution under the condition of 0 ℃, the pH value is adjusted to 7, sodium bicarbonate (2.5g,0.03mol,3eq.) aqueous solution (10ml) and fluorenylmethoxycarbonyl chloride (6.7g,0.02mol,2eq.) are added continuously, the mixture is stirred for 5 hours at room temperature, 3M hydrochloric acid is added to adjust the pH value to 4, water is added for extraction, the organic phase is concentrated, and the target compound i-1 is obtained by silica gel column chromatography (yield 90%). Rf 0.20 (dichloromethane/methanol 30/1);¹HNMR(400MHz,CDCl3)δ7.75(m,2H),7.50(m,2H),7.37(m,2H),7.29(m,2H),6.70(m,3H),6.47(m,1H),4.86(m,1H),4.55(m,1H),4.32(m,2H),4.17(m,1H),3.79(m,3H),3.32(dd,J＝14.6,4.8Hz,1H),3.08(dd,J＝14.5,11.2Hz,1H),2.79(s,3H),0.94(m,9H),0.10(m,6H)；¹³C NMR(100MHz,CDCl3)δ175.70,156.75,155.96,150.93,143.77,141.25,130.27,127.68,127.08,125.00,124.73,121.31,119.96,112.59,72.73,67.93,67.50,61.18,60.89,55.48,47.12,34.42,32.77,25.70,18.41,-4.70。

example two:

synthesis of Compounds i-2 l:

compound i-2j (4.8g,0.05mol,1.2eq.) was added to a solution of compound i-2k (10g,0.04mol,1eq.) in toluene (750ml), and after refluxing at 115 ℃ for 4 days, it was cooled to room temperature and toluene was removed using a rotary evaporator to give a crude product of compound i-2j (crude yield 120%).

Synthesis of Compound i-2 b:

compound i-2a (10g,0.09mol,1eq.) was added to a solution of compound i-2j (12.6g,0.05mol,0.5eq.) in toluene (50ml) at-78 ℃, followed by slow addition of a solution of catecholborane (10.7ml,0.10mol,1.1eq.) in toluene (100ml) to the reaction mixture, after 5h at-78 ℃, quenching was performed by addition of 1M sodium hydroxide, extraction with water and concentration of the organic phase, and isolation by silica gel column chromatography gave the desired compound i-2b (90% yield). Rf 0.20 (petroleum ether/ethyl acetate 20/1);¹HNMR(400MHz,CDCl3)δ5.52(s,1H),3.97(m,1H),1.95(m,2H),1.73(m,5H),1.55(m,2H)；¹³C NMR(100MHz,CDCl3)δ135.41,125.63,68.61,32.34,25.57,20.76,18.29。

synthesis of Compounds i-2 c:

to a di-compound of i-2b (20g,0.18mol,1eq.) at 0 deg.CTo a solution of methyl chloride (100ml), sodium hydride (14g,0.36mol,2eq.) and methyl iodide (50g,0.36mol,2eq.) were added in this order, and after stirring at room temperature for 5 hours, the reaction was quenched by addition of water, extracted with dichloromethane and the organic phase was concentrated, and the objective compound i-2c was isolated by silica gel column chromatography (92% yield). Rf 0.20 (petroleum ether/ethyl acetate 40/1);¹HNMR(400MHz,CDCl3)δ5.56(s,1H),3.50(s,1H),3.36(s,3H),1.91(m,3H),1.74(s,3H),1.52(m,3H)；¹³C NMR(100MHz,CDCl3)δ135.41,125.63,68.61,32.34,25.57,20.76,18.29。

synthesis of Compounds i-2 d:

continuously introducing ozone into a dichloromethane solution of the compound i-2c (16g,0.13mol,1eq.) at the temperature of minus 78 ℃ for 2h, subsequently introducing oxygen for 1h to exhaust the ozone in a reaction device, slowly adding dimethyl sulfide (38g,0.65mol,5eq.) into the reaction solution, reacting for one hour at room temperature, and removing partial dichloromethane by using a rotary evaporator to obtain a crude product of the compound i-.

Synthesis of Compounds i-2 n:

after the compound i-2M (5g,0.029mol,1.1eq.) and triphenylphosphine (7g,0.026mol,1eq.) were dissolved in water (20ml), stirred at 70 ℃ for 16 hours, the reaction solution was cooled to room temperature, an aqueous solution of sodium hydroxide (0.85M,70ml,2.2eq.) was added and stirred at room temperature for 5 minutes, a yellow solid was formed, dichloromethane was added to the reaction solution to dissolve the yellow solid, and the organic phase was extracted and concentrated to obtain a crude product of the compound i-2n (yield 96%).

Synthesis of Compounds i-2 e:

after the compound i-2n (26.1g,0.075mol,0.6eq.) was added to a dichloromethane (300ml) solution of the compound i-2d (19.8g,0.125mol,1eq.) and stirred at 40 ℃ for 6 hours, the organic phase was extracted with water and concentrated, and the target compound i-2e was isolated by silica gel column chromatography (93% yield). Rf 0.20 (petroleum ether/ethyl acetate 8/1);¹H NMR(400MHz,CDCl3)δ6.72(m,1H),3.72(s,3H),3.54(m,1H),3.35(s,3H),2.18(m,5H),1.81(s,3H),1.57(m,4H)；¹³C NMR(100MHz,CDCl3)δ211.25,168.47,141.44,128.02,87.13,58.11,51.63,31.35,28.23,25.09,24.13,12.35。

synthesis of Compounds i-2 f:

iodoform (13g,0.032mol,8eq.) and chromium dichloride (3.2g,0.024mol,6eq.) were added sequentially to a solution of compound i-2e (1g,0.004mol,1eq.) in tetrahydrofuran (50ml) at 0 ℃ under oxygen-free conditions, after stirring at room temperature for 6 hours, sodium thiosulfate was added to quench the reaction, water and ethyl acetate were added to extract, the organic phase was concentrated, and the target compound i-2f was isolated by silica gel column chromatography (yield 33%). Rf 0.20 (petroleum ether/ethyl acetate 30/1);¹H NMR(400MHz,CDCl3)δ6.71(t,J＝7.0Hz,1H),6.14(m,1H),3.72(s,3H),3.60(m,1H),3.19(d,J＝16.0Hz,3H),2.17(m,2H),1.82(m,3H),1.74(m,3H),1.37(m,4H)；¹³C NMR(100MHz,CDCl3)δ168.58,147.81,145.99,142.07,141.86,127.84,85.99,84.21,56.38,51.69,33.25,32.69,28.55,28.38,24.69,24.44,18.60,18.28,12.46,12.40。

synthesis of Compounds i-2 g:

adding diisobutylaluminum hydride (8.5ml,1.5M,3eq.) to a dichloromethane (25ml) solution of the compound i-2f (1.5g,0.004mol,1eq.) at-78 ℃, stirring the reaction solution at-78 ℃ for 2 hours, adding a saturated aqueous solution of sodium potassium tartrate, quenching, adding dichloromethane for extraction, concentrating the organic phase, and removing the solvent by using a rotary evaporator to obtain a crude product of the compound iii-7 (crude yield: 110%); rf is 0.20 (petroleum ether/ethyl acetate 10/1).

Synthesis of Compounds i-2 h:

adding dess-martin oxidant (3.6g,0.008mol,2eq.) to a dichloromethane (15ml) solution of compound i-2g (1.3g,0.004mol,1eq.) at 0 ℃, stirring at room temperature for 5h, adding saturated aqueous sodium thiosulfate and aqueous sodium bicarbonate to quench the reaction, adding water to extract, concentrating the organic phase, and separating by silica gel column chromatography to obtain the target compound i-2h (85% yield). Rf 0.30 (petroleum ether/ethyl acetate 15/1);¹H NMR(400MHz,CDCl3)δ9.38(s,1H),6.44(t,J＝7.2Hz,1H),6.20(s,1H),3.62(t,J＝6.0Hz,1H),3.20(s,3H),2.34(m,2H),1.75(m,6H),1.53(m,4H)；¹³CNMR(100MHz,CDCl3)δ195.34,154.12,147.83,139.73,86.00,79.12,56.55,33.41,28.84,24.71,18.78,9.37。

synthesis of Compound i-2 p:

to compound i-2o (25g,0.15mol,1eq.) were added diethyl carbonate (36ml,0.30mol,2eq.) and potassium carbonate (2g,0.015mol,0.1eq.), respectively, and after refluxing at 135 ℃ for 5h, it was cooled to room temperature, the solvent was removed using a rotary evaporator, extraction was performed with water and dichloromethane, the organic phases were combined, and the objective compound i-2p was isolated by silica gel column chromatography (yield 95%). Rf 0.20 (petroleum ether/ethyl acetate 1/1);¹H NMR(400MHz,CDCl3)δ7.32(t,J＝7.1Hz,2H),7.28(m,1H),7.16(d,J＝7.9Hz,2H),4.44(t,J＝8.2Hz,1H),4.09(m,2H),2.86(d,J＝6.7Hz,2H)。

synthesis of Compounds i-2 q:

4-dimethylaminopyridine (0.4g,0.004mol,0.1eq.) and triethylamine (8.3ml,0.090mol,2eq.) were added sequentially to a tetrahydrofuran (50ml) solution of the compound i-2p (5.5g,0.045mol,1eq.) at 0 ℃, reacted at room temperature for 5 hours, then extracted with water and dichloromethane, the organic phase was concentrated, and the target compound i-2q was obtained by silica gel column chromatography (yield 95%). Rf 0.20 (petroleum ether/ethyl acetate 10/1);¹H NMR(600MHz,CDCl3)δ7.43(m,2H),7.37(m,2H),7.31(m,2H),4.77(s,1H),4.29(d,J＝15.0Hz,2H),3.40(m,1H),3.06(m,2H),2.87(m,1H),1.33(m,3H)。

synthesis of Compounds i-2 i:

at the temperature of 0 ℃, adding dibutylboron trifluoromethanesulfonate (5.6ml,1M,3.6eq.) into a dichloromethane (50ml) solution of a compound i-2q (1g,0.005mol,3eq.), stirring for 30min, adding triethylamine (1ml,7.2M,3.9eq.) into a reaction solution, continuing stirring for 1h, placing the reaction at the temperature of-78 ℃, adding i-2h (0.5g,0.002mol,1eq.) into the reaction solution, stirring for 30min, transferring the reaction to the temperature of 0 ℃, and continuing stirring for 3h to complete the reaction. To the reaction solution were added sodium phosphate buffer (pH 4) and 30% hydrogen peroxide/methanol (1/2) solution in this order to quench the reactionThen, water and methylene chloride were added for extraction, and the organic phases were combined and separated by silica gel column chromatography to obtain the objective compound i-2i (yield 85%). Rf 0.20 (petroleum ether/ethyl acetate 3/1);¹H NMR(400MHz,CDCl3)δ7.33(m,2H),7.27(m,1H),7.19(m,2H),6.16(s,1H),5.51(t,J＝6.8Hz,1H),4.68(m,1H),4.34(s,1H),4.19(m,2H),3.97(m,1H),3.59(t,J＝6.6Hz,1H),3.25(m,1H),3.15(s,3H),2.78(m,1H),2.68(m,1H),2.04(m,2H),1.72(s,3H),1.60(s,3H),1.43(m,4H),1.18(m,3H)；¹³C NMR(100MHz,CDCl3)δ177.20,153.13,148.10,135.21,133.94,129.58,129.12,127.57,126.14,86.343,78.92,75.40,66.32,56.47,55.42,40.52,37.91,33.38,27.51,25.69,18.73,13.57,10.76。

compound i-2:

adding lithium hydroxide (0.2g,5.4mmol,5eq.) in water (3ml) to a tetrahydrofuran (9ml) solution of a compound i-2i (0.6g,1.1mol,1eq.) at 0 ℃, then adding 30% hydrogen peroxide (2ml), stirring at room temperature for 5h, adding sodium thiosulfate in water to quench the reaction, then adding hydrochloric acid (1N) to adjust the solution pH to 4, adding dichloromethane to extract, concentrating the organic phase, and separating by silica gel column chromatography to obtain the target compound i-2 (yield 87%). Rf 0.20 (dichloromethane/methanol 40/1);¹H NMR(400MHz,CDCl3)δ6.17(s,1H),5.45(t,J＝6.4Hz,1H),4.28(d,J＝4.8Hz,1H),3.60(t,J＝6.4Hz,1H),3.17(s,3H),2.70(m,1H),2.02(m,2H),1.71(s,3H),1.58(s,3H),1.42(m,4H),1.12(m,3H)；¹³C NMR(100MHz,CDCl3)δ179.97,147.88,134.37,126.97,86.48,79.12,56.47,42.90,33.13,27.33,25.57,18.72,12.82,11.11。

example three:

synthesis of Compounds i-3 b:

potassium ferricyanide (280.0g,0.85mol,3eq.) was dissolved in tert-butanol (80ml) and water (80 m.) at 0 deg.Cl), then potassium carbonate (117.6g,0.85mol,3eq.) and methanesulfonamide (27.0g,0.28mol,1eq.), after stirring for 10min, hydrogenated quinidine 1,4- (2, 3-naphthyridine) diether (2.2g,2.84mmol, 1% eq.) and osmium tetroxide (10ml, 4% aqueous solution, 0.5% eq.), after stirring for 20min at 0 ℃, compound i-3a (50g,0.28mol,1eq.) is slowly added, after reaction for 16h at room temperature, sodium thiosulfate aqueous solution is added to quench the reaction, then ethyl acetate is added to extract and concentrate the organic phase, and the target compound i-3b is obtained by silica gel column chromatography (yield 90%). Rf 0.20 (petroleum ether/ethyl acetate 3/1);¹H NMR(400MHz,CDCl3)δ7.31(m,5H),4.96(dd,J＝6.8,3.2Hz,1H),4.31(dd,J＝6.0,3.2Hz,1H),4.20(q,J＝7.2Hz,2H),3.32(d,J＝6.0Hz,1H),3.04(d,J＝6.8Hz,1H),1.25(t,J＝6.8Hz,3H)；¹³C NMR(100MHz,CDCl3)δ172.69,139.94,128.35,127.97,126.28,74.82,74.80,74.78,74.76,74.59,62.05,14.01。

synthesis of Compounds i-3 c:

to a solution of the compound i-3b (0.5g,2.38mmol,1eq.) in acetone (10ml) at 0 ℃, p-toluenesulfonic acid (0.02g,0.12mmol,0.05eq.) and 2, 2-dimethoxypropane (1.5ml,11.9mmol,5eq.) were added in sequence, the mixture was stirred at room temperature for 6 hours, an aqueous solution of sodium bicarbonate was added to quench the reaction, ethyl acetate was added to extract and concentrate the organic phase, and the target compound i-3c was isolated by silica gel column chromatography (yield 90%). Rf 0.20 (petroleum ether/ethyl acetate 30/1);¹H NMR(400MHz,CDCl3)δ7.38(m,5H),5.16(d,J＝7.6Hz,1H),4.35(d,J＝7.6Hz,1H),3.78(s,3H),1.60(s,3H),1.55(s,3H)；¹³C NMR(100MHz,CDCl3)δ170.68,137.59,128.58,128.53,126.49,111.60,81.23,80.69,52.40,26.89,25.77。

synthesis of Compounds i-3 d:

adding diisobutylaluminum hydride (0.6ml,1.5M,1.2eq.) to a solution of compound i-3c (0.2g,0.8mmol,1eq.) in dry dichloromethane (10ml) at-78 deg.C, stirring for 2h at-78 deg.C, adding aqueous ammonium chloride to quench the reaction, extracting and concentrating the organic phase, and removing the solvent using a rotary evaporator to obtain a crude product of compound i-3d (crude yield: 110%); rf is 0.20 (petroleum ether/ethyl acetate 5/1).

Synthesis of Compounds i-3 e:

to a solution of the compound i-3d (1g,4.85mmol,1eq.) in dry methanol (5ml) was added sequentially dimethyl (1-diazo-2-oxopropyl) phosphonate (1.5g,7.76mmol,1.6eq.) and anhydrous potassium carbonate (1.4g,9.70mmol,2eq.) at 0 ℃, stirred at room temperature for 16h, quenched by addition of aqueous ammonium chloride, followed by extraction with ethyl acetate and concentration of the organic phase, and isolation by silica gel column chromatography gave the target compound i-3e (50% yield). Rf 0.20 (petroleum ether/ethyl acetate 100/1);¹H NMR(400MHz,CDCl3)δ7.38(m,5H),5.01(d,J＝7.6Hz,1H),4.36(d,J＝7.6Hz,1H),2.58(s,1H),1.59(s,3H),1.57(s,3H)；¹³C NMR(100MHz,CDCl3)δ136.61,128.58,128.55,126.13,110.62,83.09,79.70,75.53,75.48,72.67,26.84,26.40。

synthesis of Compounds i-3 f:

to a solution of the compound i-3e (5g,0.03mol,1eq.) in methanol (20ml) was added a cation exchange resin, and after stirring at room temperature for 12 hours, the reaction was completed, the organic phase was filtered and concentrated, and the objective compound i-3f was isolated by silica gel column chromatography (yield 70%). Rf 0.20 (petroleum ether/ethyl acetate 5/1);¹H NMR(400MHz,CDCl3)δ7.35(m,5H),4.71(d,J＝6.9Hz,1H),4.39(d,J＝6.3Hz,1H),2.92(m,1H),2.70(m,1H),2.44(d,J＝2.0Hz,1H)；¹³C NMR(100MHz,CDCl3)δ138.72,128.39,127.01,75.22,67.12,10.64。

synthesis of Compounds i-3 g:

imidazole (0.3g,3.7mmol,3eq.) and tert-butyldimethylchlorosilane (0.4g, mmol,2eq.) were added sequentially to a solution of compounds i to 3f (0.2g,1.2mmol,1eq.) in dry dichloromethane (20ml) at 0 ℃, the reaction was completed after stirring for 2h at 0 ℃, water was added for extraction, the organic phase was concentrated, and the target compound i to 3g (50% yield) was obtained by silica gel column chromatography. Rf 0.20 (petroleum ether/ethyl acetate 15/1);¹H NMR(400MHz,CDCl₃)δ7.53-7.43(m,2H),7.42-7.30(m,3H),4.69(dd,J＝7.2,2.0Hz,1H),4.41-4.28(m,1H),3.38-3.26(m,1H),2.46-2.39(m,1H),1.13-0.91(m,9H),0.84-0.63(m,6H)；¹³C NMR(100MHz,CDCl₃)δ139.0,128.1,128.0,127.2,82.0,77.4,74.9,68.0,6.7,4.7¹。

synthesis of Compound i-3:

to a solution of the compound i-3g (1.5g,3.6mmol,1eq.) in dry tetrahydrofuran (20ml) was added successively bis (triphenylphosphine) palladium dichloride (0.05g,0.07mmol,0.02eq.) and tributyltin hydride (1.6g,5.4mmol,1.5eq.) at 0 ℃, stirred at room temperature for 30min, quenched with water, extracted with ethyl acetate, the organic phase was concentrated, and the desired compound i-3 was isolated by silica gel column chromatography (50% yield). Rf 0.20 (petroleum ether/ethyl acetate 20/1);¹HNMR(400MHz,CDCl₃)δ7.34-7.20(m,5H),5.96(dd,J＝19.2,0.8Hz,1H),5.86(dd,J＝19.2,5.6Hz,1H),4.45-4.37(m,1H),4.11-3.98(m,1H),3.24-3.10(m,1H),1.55-1.36(m,6H),1.33-1.19(m,6H),1.08-0.70(m,24H),0.65-0.49(m,6H)；¹³C NMR(100MHz,CDCl₃)δ147.2,140.6,132.0,127.9,127.6,127.4,82.2,77.8,29.2,27.4,13.8,9.5,6.9,5.1。

compound i-3h synthesis:

dissolving the compound i-3(20mg,0.035mmol,1eq.) and fluorenylmethoxycarbonyl-L-valine (18mg,0.052mmol,1.5eq.) in a dry dichloromethane (2ml) solution, adding dicyclohexylcarbodiimide (15mg,0.070mmol,2eq.) and 4-dimethylaminopyridine (0.5mg,0.003mmol,0.1eq.) to the reaction solution at 0 ℃, stirring at room temperature for 12h, adding water to quench, extracting and concentrating the organic phase, and separating by silica gel column chromatography to obtain the target compound i-3h with 55% yield. Rf 0.20 (petroleum ether/ethyl acetate 20/1);¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝7.2Hz,2H),7.59(d,J＝7.2Hz,2H),7.44-7.34(m,2H),7.34-7.23(m,7H),6.03(d,J＝19.2Hz,1H),5.71-5.61(m,2H),5.35(d,J＝9.2Hz,1H),4.41(dd,J＝9.2,4.4Hz,1H),4.39-4.31(m,3H),4.21(t,J＝6.8Hz,1H),2.25-2.15(m,1H),1.38-1.18(m,12H),1.03-0.62(m,30H),0.61-0.47(m,6H)；¹³C NMR(100MHz,CDCl₃)δ171.4,156.2,145.9,144.1,143.9,141.4,137.0,132.2,128.3,128.1,127.9,127.8,127.2,125.2,120.0,80.6,78.3,67.1,58.9,47.3,31.7,29.1,27.4,19.1,17.2,13.8,9.5,6.9,5.0。

synthesis of Compounds i-3 i:

piperidine (0.5ml) was added to a solution of compound i-3h0.4g,0.45mmol,1eq.) in dry dichloromethane (10ml) at 0 ℃ to react at room temperature for 3 hours, water was added to extract, the organic phase was concentrated, and the target compound i-3i was isolated by silica gel column chromatography (85% yield). Rf 0.20 (petroleum ether/ethyl acetate 5/1);¹H NMR(400MHz,CDCl₃)δ7.32-7.22(m,5H),6.04(d,J＝19.2Hz,1H),5.70(dd,J＝18.8,6.0Hz,1H),5.64(d,J＝7.2Hz,1H),4.40-4.32(m,1H),3.36(d,J＝4.4Hz,1H),2.15-2.03(m,1H),1.42-1.18(m,12H),1.03-0.67(m,30H),0.65-0.52(m,6H)；¹³C NMR(100MHz,CDCl₃)δ175.1,146.2,137.5,131.7,128.1,128.0,127.9,79.7,78.3,59.8,31.9,29.1,27.4,19.7,16.8,13.8,9.5,7.0,5.0。

synthesis of Compound i-4 a:

compounds i-3(0.35g,0.52mmol,1eq.) and i-1(0.35g,0.63mmol,1.2eq.) were dissolved in dry N, N-dimethylformamide (5ml), then N, N-diisopropylethylamine (0.2ml,1.05mmol,2eq.) and benzotriazole-N, N' -tetramethyluronium hexafluorophosphate (0.24g,0.63mmol,1.2eq.) were added to the reaction solution, after stirring for 12h at room temperature, water was added to extract and concentrate the organic phase, which was separated by silica gel column chromatography to give the target compound i-4a (yield 80%). Rf 0.20 (petroleum ether/ethyl acetate 5/1);¹H NMR(400MHz,CDCl₃)δ7.75(d,J＝7.6Hz,2H),7.53(d,J＝7.2Hz,1H),7.46(d,J＝7.2Hz,1H),7.40-7.33(m,2H),7.26-7.16(m,7H),6.75-6.60(m,4H),6.04(d,J＝18.8Hz,1H),5.65(dd,J＝18.8,6.0Hz,1H),5.58(d,J＝7.2Hz,1H),5.07-5.00(m,1H),4.66(dd,J＝8.8,4.0Hz,1H),4.39-4.33(m,1H),4.29(d,J＝7.6Hz,2H),4.21-4.15(m,1H),3.73(s,3H),3.33(dd,J＝14.4,6.8Hz,1H),2.92-2.83(m,4H),2.22-2.15(m,1H),1.41-1.32(m,6H),1.26-1.20(m,6H),1.04-0.67(m,39H),0.61-0.57(m,6H),0.07(s,6H)；¹³C NMR(100MHz,CDCl₃)δ171.1,170.2,157.3,150.9,145.9,144.0,143.7,141.4,137.1,132.2,130.7,128.3,128.1,127.9,127.8,127.2,125.2,125.0,121.4,120.9,120.0,112.9,80.7,78.2,68.2,60.4,56.8,55.5,47.2,33.9,31.4,30.6,29.1,27.4,25.8,19.3,18.5,17.2,13.8,9.5,7.0,5.0,-4.6。

synthesis of Compound i-4:

piperidine (0.4ml) was added to a solution of compound i-4a (0.4g,0.29mmol,1eq.) in dry dichloromethane (10ml) at 0 ℃ to react at room temperature for 4 hours, water was added to extract, the organic phase was concentrated, and the target compound i-4 was isolated by silica gel column chromatography (56% yield). Rf 0.20 (dichloromethane/methanol 20/1);¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝9.2Hz,1H),7.35-7.25(m,5H),6.78(d,J＝7.6Hz,1H),6.73(d,J＝1.6Hz,1H),6.65(dd,J＝8.0,1.6Hz,1H),6.06(dd,J＝19.2,0.8Hz,1H),5.69(dd,J＝19.2,6.0Hz,1H),5.64(d,J＝7.2Hz,1H),4.69(dd,J＝9.6,4.0Hz,1H),4.43-4.35(m,1H),3.78(s,3H),3.21-3.12(m,2H),2.50(dd,J＝14.4,11.6Hz,1H),2.33-2.22(m,4H),1.42-1.20(m,12H),1.07-0.67(m,39H),0.65-0.55(m,6H),0.15(s,6H)；¹³C NMR(100MHz,CDCl₃)δ173.6,171.2,151.2,146.0,143.9,137.2,132.1,131.3,128.3,128.1,127.9,121.2,121.0,112.6,80.5,78.2,66.9,56.4,55.6,39.4,35.9,31.5,29.1,27.4,25.8,19.4,18.5,17.4,13.8,9.5,7.0,5.0,-4.5。

example four:

synthesis of Compound i-5:

dissolving the compounds i-4(0.10g,0.25mmol,1eq.) and i-2(0.43g,0.50mmol,2eq.) in N, N-dimethylformamide (2ml) at 0 ℃, adding N, N-diisopropylethylamine (0.21ml,1.25mmol,5eq.) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.29g,0.75mmol,3eq.) in turn into the reaction solution, reacting at room temperature for 12h, adding water, extracting and concentrating the organic phase, and separating by silica gel column chromatography to obtain the target compound v-1 (product)Rate 74%). Rf 0.20 (petroleum ether/ethyl acetate 10/1);¹H NMR(400MHz,CDCl₃)δ7.36-7.23(m,5H),6.77-6.67(m,2H),6.63(d,J＝7.6Hz,1H),6.55(d,J＝9.2Hz,1H),6.16(s,1H),6.05(d,J＝18.8Hz,1H),5.64(dd,J＝19.2,6.0Hz,1H),5.60-5.48(m,3H),4.61(dd,J＝8.8,3.6Hz,1H),4.43-4.33(m,2H),4.22(s,1H),3.76(s,3H),3.60(t,J＝6.4Hz,1H),3.26(dd,J＝14.8,6.4Hz,1H),3.17(s,3H),2.98-2.83(m,4H),2.75-2.68(m,1H),2.27-2.19(m,1H),2.06-1.98(m,2H),1.72(s,3H),1.60-1.21(m,19H),1.07-0.69(m,39H),0.67-0.53(m,9H),0.17-0.05(m,6H)；¹³C NMR(100MHz,CDCl₃)δ179.4,171.1,170.3,150.9,148.1,145.8,143.8,136.9,133.0,132.1,130.1,128.3,128.0,127.9,125.6,121.2,120.8,112.4,86.3,80.6,78.8,78.1,74.2,56.8,56.4,55.5,37.5,33.4,33.1,31.3,30.8,29.1,27.5,27.3,25.8,25.7,19.3,18.7,18.5,16.9,14.1,13.8,9.4,7.0,5.0,-4.6；HRMS(ESI):calcd for C₆₅H₁₁₁IN₂NaO₉Si₂Sn⁺[M+Na⁺]1389.5787,found 1389.5742。

synthesis of Compound i-6:

to a solution of the compound i-5(0.26g,0.19mmol,1eq.) in N, N-dimethylformamide (10ml) were added N, N-diisopropylethylamine (0.28ml,1.71mmol,9eq.) in this order, triphenylarsenic (0.35g,1.14mmol,6eq.) and tris (dibenzylideneacetone) dipalladium (0.01g,0.11mmol,0.6eq.) in sequence, and after reacting for 2 hours at room temperature, the organic phase was extracted and concentrated with water, and the target compound v-2 was isolated by silica gel column chromatography (yield 84%). Rf 0.20 (petroleum ether/ethyl acetate 3/1);¹H NMR(400MHz,CDCl₃)δ7.33-7.24(m,5H),6.77-6.67(m,3H),6.63(d,J＝7.6Hz,1H),6.50(dd,J＝14.8,11.6Hz,1H),5.99(d,J＝11.2Hz,1H),5.86(d,J＝2.8Hz,1H),5.67(dd,J＝14.8,4.8Hz,1H),5.57-5.45(m,2H),4.57(dd,J＝8.4,4.8Hz,1H),4.52-4.46(m,1H),4.20(d,J＝3.2Hz,1H),3.76(s,3H),3.63-3.54(m,2H),3.27(dd,J＝14.8,6.8Hz,1H),3.16(s,3H),2.93(dd,J＝14.8,10.0Hz,1H),2.88(s,3H),2.80-2.72(m,1H),2.29-2.21(m,1H),2.11-1.99(m,2H),1.67-1.57(m,4H),1.49-1.39(m,4H),1.38-1.29(m,2H),0.97(s,9H),0.94-0.73(m,18H),0.54-0.41(m,6H),0.10(s,6H)；¹³C NMR(100MHz,CDCl₃)δ178.5,170.4,169.8,151.1,143.9,137.6,137.2,134.5,130.8,129.9,127.9,127.5,127.3,126.8,121.2,121.0,112.5,87.0,78.4,75.7,74.2,57.5,56.7,56.1,55.6,39.6,33.8,33.7,31.6,31.3,28.1,25.8,24.7,19.2,18.6,17.6,13.6,11.7,11.1,6.9,4.8,-4.6；HRMS(ESI):calcd for C₅₃H₈₄N₂NaO₉Si₂ ⁺[M+Na⁺]971.5608,found 971.5576。

synthesis of Compound i-7:

to a solution of compound i-6(0.32g,0.34mmol,1eq.) in dichloromethane (5ml) was added dess-martin oxidant (1.44g,3.4mmol,10eq.), stirred at room temperature for 2h, quenched and extracted by the addition of aqueous sodium bicarbonate and aqueous sodium thiosulfate, the organic phase was concentrated and the desired compound v-3 was isolated by silica gel column chromatography (95% yield). Rf 0.20 (petroleum ether/ethyl acetate 3/1);¹H NMR(400MHz,CDCl₃)δ7.32-7.26(m,5H),6.75-6.68(m,3H),6.59(dd,J＝8.0,1.6Hz,1H),6.52(t,J＝6.8Hz,1H),6.46(dd,J＝15.2,11.2Hz,1H),5.85(d,J＝10.8Hz,1H),5.82-5.75(m,2H),5.68(dd,J＝15.2,5.2Hz,1H),4.53-4.46(m,2H),4.02(q,J＝7.2Hz,1H),3.75(s,3H),3.52-3.42(m,2H),3.19(s,3H),2.79(dd,J＝15.2,11.2Hz,1H),2.70(s,3H),2.41-2.31(m,2H),2.27-2.19(m,1H),1.87(s,3H),1.77-1.70(m,1H),1.65-1.54(m,5H),1.37-1.29(m,1H),1.12(d,J＝7.2Hz,3H),1.05-0.90(m,15H),0.80(t,J＝8.0Hz,9H),0.45-0.29(m,6H),0.11(s,3H),0.10(s,3H)；¹³C NMR(100MHz,CDCl₃)δ199.6,172.2,170.7,170.6,151.0,143.7,143.2,137.4,137.2,136.0,131.7,130.3,127.9,127.8,127.7,127.5,127.2,120.9,120.8,112.2,85.5,78.5,73.8,58.0,56.4,56.2,55.5,45.1,34.6,32.8,31.5,30.7,28.3,25.8,23.5,19.2,18.6,18.0,14.2,12.3,11.1,6.9,4.7,-4.6,-4.6；HRMS(ESI):calcd for C₅₃H₈₂N₂NaO₉Si₂ ⁺[M+Na⁺]969.5451,found969.5480。

synthesis of the Compound Aetheramide A:

to a solution of compound v-3(20mg) in methanol (2ml) was added camphorsulfonic acid (0.1ml,6mg/ml methanol)Solution), stirred at room temperature for 24h and then reacted completely, the solvent was removed, and the objective compound, Aetheramide a (yield 75%) was obtained by silica gel column chromatography. Rf 0.20 (dichloromethane/methanol 50/1);¹H NMR(400Hz,CD3CN)δ7.39(d,J＝7.2,2H),7.37(t,J＝7.8,2H),7.32(t,J＝7.2,1H),6.81(s,1H),6.69(d,J＝7.8,1H),6.69(d,J＝7.8,1H),6.65(m,1H),6.62(dd,J＝15.0,10.8,1H),6.51(m,1H),5.97(d,J＝11.4,1H),5.87(brs,J＝1.2,1H),5.82(dd,J＝15.0,4.2,1H),5.56(dd,J＝12.0,4.8,1H),4.51(dd,J＝8.4,4.8,1H),4.44(br s,1H),4.23(q,J＝6.6,1H),3.80(s,3H),3.51(t,J＝7.2,1H),3.31(dd,J＝15.0,5.4,1H),3.12(s,3H),2.88(s,3H),2.87(dd,J＝14.5,11.9,1H),2.39(m,2H),2.14(m,1H),1.76(s,3H),1.66(s,3H),1.58(m,2H),1.45(m,1H),1.35(m,1H),0.95(d,J＝6.6,3H),0.82(d,J＝7.2,3H),0.80(d,J＝7.2,3H)；¹³C NMR(100Hz,CD3CN)δ199.6,173.8,172.0,171.8,148.1,145.7,144.4,139.2,138.5,137.3,130.0,129.1,128.8,128.1,128.0,127.5,122.3,115.4,113.1,86.3,78.4,74.1,57.9,57.3,56.7,56.2,45.0,35.7,33.6,32.5,31.5,29.1,24.5,19.7,17.6,12.1,11.4。

synthesis of the Compound Aetheramide B:

after the compound Aetheramide A is placed in a methanol solution and stirred for 12 hours, the compound Aetheramide A can be partially converted into Aetheramide B.¹H NMR(400Hz,CD3CN)δ7.39(d,J＝6.8,2H),7.34(t,J＝6.8,2H),7.28(t,J＝7.2,1H),6.82(s,1H),6.69(d,J＝8.0,1H),6.64(dd,J＝8.0,1.2,1H),6.50(m,1H),6.49(br,1H),6.41(dd,J＝15.2,11.2,1H),6.36(br,1H),5.82(d,J＝11.2,1H),5.53(dd,J＝10.8,5.6,1H),5.45(dd,J＝15.2,8.8,1H),5.26(dd,J＝8.8,6.8,1H),4.82(t,J＝6.0,1H),4.34(dd,J＝8.8,5.6,1H),4.18(q,J＝6.8,1H),3.80(s,3H),3.71(d,J＝4.4,1H),3.50(dd,J＝8.8,5.2,1H),3.24(dd,J＝14.8,5.2,1H),3.06(s,3H),2.81(s,3H),2.80(m,1H),2.26(m,1H),2.24(m,1H),2.04(m,1H),1.72(s,3H),1.60(m,1H),1.53(s,3H),1.44(m,1H),1.19(m,2H),0.87(d,J＝7.2,3H),0.85(d,J＝6.8,3H),0.82(d,J＝6.8,3H)；¹³CNMR(100Hz,CD3CN)δ200.3,173.4,171.7,171.2,147.9,145.6,143.5,141.7,140.8,136.3,133.0,130.2,129.1,128.8,128.2,128.1,128.0,122.5,115.3,113.4,86.8,81.5,75.4,58.9,57.6,56.6,56.2,45.8,34.6,32.8,31.8,30.4,28.4,25.1,19.7,17.8,13.9,12.5,10.7。

Example five:

synthesis of Compound i-1 b:

potassium hydroxide (1.0g,17.86mmol) was slowly dissolved in a mixed solution of i-1(1.2g,9.22mmol) in methanol and water (5mL, 20mL) under a zero-temperature condition, followed by dropwise addition of hydrogen peroxide (30%, 0.2mL). The reaction was diluted with water and ethyl acetate, and the aqueous phase was adjusted to pH 2-3 with 1M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product of propionylacetic acid. The crude product was dissolved in acetone (10mL), acetic anhydride (2.16mL,23mmol) was added to the solution, and concentrated sulfuric acid (0.05mL) was slowly added dropwise under a sub-five temperature environment. The mixed solution was stirred for 10 hours under an environment of-five degrees, water was added to quench the reaction, and then extraction was performed with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of i-2, which was subjected to silica gel column chromatography to obtain the objective compound i-1b (yield 68%), Rf 0.20 (petroleum ether/ethyl acetate 20/1);¹H NMR(400MHz,CDCl₃)δ5.17(s,1H),2.19(q,J＝7.5Hz,2H),1.62(s,6H),1.07(t,J＝7.5Hz,3H)ppm；¹³C NMR(100MHz,CDCl₃)δ173.38,161.71,106.44,92.48,27.01,25.16,10.15ppm；HRMS(ESI):calcd for C₈H₁₂NaO₃[M+Na]⁺179.0679；found 179.0679。

synthesis of Compound i-1:

compound i-1b (120mg,0.769mmol) was dissolved in 1mL of tetrahydrofuran, and this solution was slowly added dropwise to a solution of lithium bistrimethylsilylamide (1.15mL,1.15 mmol). After the resulting solution was stirred at-78 ℃ for 2 hours, diethylphosphorous was added to the reaction solutionAcid chloride (180mg,1.154mmol), and the reaction mixture was stirred at-78 ℃ for 20 minutes, then slowly warmed to room temperature, and stirred at room temperature for 30 minutes. The reaction was quenched with saturated sodium chloride solution and extracted with ether. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain the objective compound i-1 (yield 64%) with Rf 0.25 (petroleum ether/ethyl acetate 1: 1);¹H NMR(400MHz,CDCl₃)δ5.38(d,J＝3.2Hz1H),4.20–4.09(m,4H),2.79(dq,J＝24Hz,7.2Hz,1H),1.70(s,6H),1.42(dd,J＝17.6Hz,7.2Hz,3H),1.33,(td,J＝4.4Hz,2Hz,6H)；¹³C NMR(101MHz,CDCl₃)δ168.14,160.99,106.93,94.91(d,J＝7.6Hz),62.69(t,J＝6.5Hz),38.11,36.74,25.38,24.40,16.44(d,J＝5.9Hz),12.13(d,J＝5.7Hz)；HRMS(ESI)[M+Na⁺]m/z 315.0961(calcd for C₁₂H₂₁NaO₆P⁺,315.0968)。

example six:

synthesis of Compound ii-2 b:

ii-2d (1.0g,2.79mmol) was dissolved in tetrahydrofuran (15mL), phenylboron dichloride (0.36mL,2.79mmol) was added dropwise to this solution, the reaction was allowed to react at room temperature under nitrogen for one hour, concentrated, redissolved in tetrahydrofuran (5mL) as a catalyst, the catalyst solution was cooled to-78 ℃, ii-2a, ii-2e and dry isopropanol (0.23mL,3.05mmol) were dissolved in tetrahydrofuran (3mL), slowly added dropwise to the above catalyst solution, the reaction solution was stirred at-78 ℃ for 8 hours, extracted with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried and concentrated, and separated by silica gel column chromatography to give the desired compound ii-2b (yield 98%), Rf 0.25 (petroleum ether/ethyl acetate: α:1) [ α ]]_D ²⁸+1.8(c 0.3,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ＝6.89(dt,J＝15.2,7.6Hz,1H),6.35(s,1H),5.90(d,J＝15.2Hz,1H),4.30(t,J＝6.4Hz,1H),3.72(s,3H),2.53-2.38(m,2H),1.82(s,3H)；¹³CNMR(100MHz,CDCl₃)δ166.8,148.9,144.5,123.7,79.4,75.1,51.8,38.1,20.1；HRMS(ESI)[M+Na⁺]m/z 318.9800(calcd forC₉H₁₃INaO₃ ⁺,318.9802)。

Synthesis of Compounds ii-2 c:

ii-2b (5.0g,16.9mmol) was dissolved in dry ether (80mL), and to this solution was added freshly prepared silver oxide (19.6g,84.5mmol) and iodomethane (21.1mL,338 mmol). after stirring the reaction at room temperature for 12 hours, the reaction solution was filtered, the filtrate was concentrated by drying, and the target compound ii-2c (yield 97%) was isolated by silica gel column chromatography with Rf of 0.2 (petroleum ether/ethyl acetate of 20:1) [ α ]]_D ²⁸-14.4(c 0.3,CHCl₃)；IR(film)ν_max2930,1725,1659,1436,1276,1103cm^-1；¹H NMR(400MHz,CDCl₃)δ6.86(dt,J＝15.2,7.2Hz,1H),6.26(s,1H),5.86(d,J＝16.0Hz,1H),3.81-3.66(m,4H),3.19(s,3H),2.58-2.42(m,1H),2.42-2.25(m,1H),1.75(s,3H)；¹³C NMR(100MHz,CDCl₃)δ166.8,146.9,144.7,123.2,84.6,80.1,56.6,51.7,36.9,18.9；HRMS(ESI)[M+Na⁺]m/z 332.9950(calcd forC₁₀H₁₅INaO₃ ⁺,332.9958)。

Synthesis of Compound ii-2:

adding lithium aluminum hydride (614mg,16.1mmol) to a solution of ii-2c (1.0g,3.23mmol) in dichloromethane/tetrahydrofuran (200mL/200mL) at 0 ℃, stirring the reaction solution for 5 hours, quenching with water, extracting with dichloromethane, concentrating the organic phase by drying, and separating by silica gel column chromatography to obtain the target compound ii-2 (yield 87%), Rf 0.25 (petroleum ether/ethyl acetate 6:1) [ α ]]_D ³¹+19.5(c 0.2,CHCl₃)；IR(film)ν_max2933,2863,1619,1266,1092,748cm^-1；¹H NMR(400MHz,CDCl₃)δ6.16(s,1H),3.60(t,J＝6.8Hz,3H),3.16(s,3H),1.71(s,3H),1.63-1.23(m,6H)；¹³C NMR(100MHz,CDCl₃)δ148.0,86.3,79.0,62.7,56.5,33.4,32.5,22.0,18.7；HRMS(ESI)[M+Na⁺]m/z 307.0170(calcd forC₉H₁₇INaO₂ ⁺,307.0165)。

Example seven:

synthesis of Compound ii-3 a:

adding dess-martin reagent (2.4g,5.7mmol) into a solution of ii-2(800mg,2.85mmol) in dichloromethane/tetrahydrofuran (200mL/200mL) at 0 ℃, stirring the reaction solution at room temperature for 3 hours, extracting with saturated sodium bicarbonate/saturated sodium thiosulfate solution, extracting with dichloromethane, concentrating by organic phase drying to obtain the crude product of the corresponding aldehyde, adding lithium diisopropylamide (2.9mL,5.8mol) into a solution of ii-1(970mg,3.42mmol) in tetrahydrofuran (10mL) at minus 78 ℃, stirring the reaction solution at room temperature for 20 minutes, cooling to minus 78 ℃, adding hexamethylphosphoric triamide, stirring for 30 minutes, adding the crude product of the aldehyde, stirring the reaction solution at minus 78 ℃ for 30 minutes, heating to room temperature, stirring for 2 hours, extracting with saturated ammonium chloride solution, quenching, extracting with ethyl acetate, concentrating by organic phase drying, and separating the crude product by silica gel column chromatography to obtain the target compound (ii-martin yield of 0.25 ═ 25.32%) petroleum ether (0.72%: α%: petroleum ether)]_D ³¹+19.5(c 0.2,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ6.35(t,J＝7.5Hz,1H),6.19(s,1H),5.40(s,1H),3.61(t,J＝6.4Hz,1H),3.18(s,3H),2.19(q,J＝7.3Hz,2H),1.78(s,3H),1.72(s,3H),1.69(s,6H),1.67-1.55(m,2H),1.51-1.44(m,2H)；¹³C NMR(101MHz,CDCl₃)δ165.86,162.74,148.06,137.46,127.77,106.30,91.80,86.27,79.37,56.74,33.65,28.83,25.30,18.92,12.54；HRMS(ESI)[M+Na⁺]m/z 443.0682(calcd for C₁₇H₂₅INaO₄ ⁺,443.0690)。

Synthesis of Compounds ii-3 b:

bis (dibenzylideneacetone) palladium (300mg,0.33mmol), cuprous iodide (250mg,1.31mmol) and triphenylarsine (400mg,1.31mmol) were added to a solution of ii-3a and a known compound i-3 in N, N-dimethylformamide (20mL), the reaction mixture was stirred at 50 ℃ for 8 hours, concentrated, and subjected to silica gel column chromatography to obtain the objective compound ii-3b (yield 81%), Rf 0.2 (petroleum ether/ethyl acetate 6:1) [ α ]]_D ³¹+19.5(c 0.2,CHCl₃)_x；¹H NMR(400MHz,CDCl₃)δ7.37-7.23(m,5H),6.37(t,J＝7.4Hz,1H),6.27(dd,J＝15.2,11.2Hz,1H),5.89(d,J＝11.2Hz,1H),5.58(dd,J＝15.2,6.5Hz,1H),5.39(s,1H),4.47(dd,J＝6.0,3.8Hz,1H),4.24-4.18(m,J＝6.0Hz,1H),3.43(t,J＝6.3Hz,1H),3.19-3.09(m,4H),2.19(q,J＝7.2Hz,2H),1.77(s,3H),1.68(s,6H),1.56(s,3H),1.53-1.41(m,2H),0.91(t,J＝7.9Hz,9H),0.55(q,7.9Hz,6H)；¹³C NMR(101MHz,CDCl₃)δ165.63(s),140.55(s),137.53(s),132.35(s),127.97(s),127.62,127.43,127.28,126.95,126.82,105.92,91.38,86.80,78.36,77.58,77.34(s),77.02(s),76.70(s),55.99(s),33.32(s),28.61(s),25.24–24.83(m),12.15(s),10.96(s),6.71(s),4.88(s)；HRMS(ESI)[M+Na⁺]m/z 593.3274(calcd forC₃₃H₅₀NaO₆Si,593.3269)。

Synthesis of Compounds ii-3 c:

ii-2b and 9-fluorenylmethyl chloroformate-L-valine were dissolved in methylene chloride (30mL), dicyclohexylcarbodiimide (530mg,2.57mmol) and 4-dimethylaminopyridine (11mg,0.09mmol) were added at 0 ℃ and the reaction mixture was stirred at room temperature for 10 hours, concentrated and subjected to silica gel column chromatography to obtain the objective compound ii-3c (yield 64%), Rf 0.2 (petroleum ether/ethyl acetate 6:1) [ α ]]_D ³¹+19.5(c 0.2,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.76(d,J＝7.4Hz,2H),7.60(d,J＝7.2Hz,2H),7.39(t,J＝7.4Hz,2H),7.35–7.26(m,7H),6.42–6.31(m,2H),5.84(d,J＝10.9Hz,1H),5.69(d,J＝6.6Hz,1H),5.45–5.34(m,3H),4.52(t,J＝6.2Hz,1H),4.44(dd,J＝9.1,4.2Hz,1H),4.41–4.34(m,2H),4.24(t,J＝7.0Hz,1H),3.41(t,J＝5.6Hz,1H),3.12(s,3H),2.26-2.13(m,3H),1.77(s,3H),1.69(s,6H),1.58(s,3H),1.48–1.41(m,2H),1.36-1.26(m,2H),0.98–0.86(m,12H),0.73(d,J＝6.8Hz,3H),0.58(q,J＝7.9Hz,6H)；¹³C NMR(101MHz,CDCl₃)δ171.61,165.94,162.71,156.43,144.22,144.10,141.58,137.95,137.76,137.10,131.51,128.60,128.37,128.06,127.99,127.36,127.11,125.39,120.26,106.23,91.70,87.08,80.58,75.10,67.37,59.11,56.30,47.49,33.62,31.84,28.91,25.45,25.28,25.25,19.33,17.40,12.45,11.26,7.08,5.20；(ESI)[M+Na⁺]m/z 914.4644(calcd for C₅₃H₆₉NNaO₉Si,914.4634)。

Synthesis of Compounds ii-3 d:

ii-3c (400mg,0.45mmol) was dissolved in N, N-dimethylformamide (10mL), and 1-hydroxybenzotriazole (80mg,0.59mmol) and 1, 8-diazabicyclo [5.4.0 ] were added to the solution]Undecyl-7-ene (94 μ L,0.67mmol) was reacted and stirred at room temperature for 40 minutes, the reaction solution was filtered, the filtrate was dried and concentrated, and the target compound i-13 (yield 96%) was isolated by silica gel column chromatography with Rf ═ 0.2 (petroleum ether/ethyl acetate ═ 4:1) [ α ]]_D ³¹+19.5(c 0.2,CHCl₃)；¹HNMR(400MHz,CDCl₃)δ＝7.32–7.26(m,5H),6.41–6.28(m,2H),5.83(d,J＝11.0Hz,1H),5.65(d,J＝6.7Hz,1H),5.44–5.37(m,2H),4.50(t,J＝6.1Hz,1H),3.41(t,J＝6.4Hz,1H),3.36(d,J＝4.5Hz,1H),3.12(s,3H),2.18(q,J＝7.2Hz,2H),1.77(s,3H),1.69(s,6H),1.57(s,3H),0.96–0.89(m,12H),0.72(d,J＝6.8Hz,3H),0.58(q,J＝8.0Hz,6H)；¹³C NMR(101MHz,CDCl₃)δ＝174.20,164.98,161.76,136.78,136.60,130.87,127.43,137.33 127.03,126.71,126.62,126.18,105.27,90.72,86.13,78.81,74.23,59.09,55.32,32.66,31.18,27.95,24.48,24.30,24.27,18.79,16.01,11.49,10.28,6.11,4.22ppm；(ESI)[M+H⁺]m/z670.41113(calcd forC₃₈H₆₀NO₇Si+,670.4134)。

Synthesis of Compounds ii-3 e:

ii-3d (250mg,0.37mmol) and i-1(315mg,0.56mmol) were dissolved in N, N-dimethylformamide (10mL), N-diisopropylethylamine (125 μ L,0.77mmol) and 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate (280mg,0.74mmol) were added to the solution, stirred at room temperature for 8 hours, extracted with ethyl acetate, the organic phase was dried, concentrated, and separated by silica gel column chromatography to give the objective compound ii-3e (yield 76%), Rf ═ 0.3 (petroleum ether/ethyl acetate ═ 5:1) [ α ]]_D ³¹+19.5(c 0.2,CHCl₃)；¹H NMR(400MHz,CDCl₃)δ7.75(d,J＝7.4Hz,2H),7.52(d,J＝7.4Hz,1H),7.46(d,J＝7.6Hz,1H),7.37(t,J＝7.4Hz,2H),7.30-7.21(m,7H),6.75–6.61(m,4H),6.39–6.31(m,2H),5.84(d,J＝11.0Hz,1H),5.60(d,J＝6.7Hz,1H),5.40–5.34(m,2H),5.01(t,J＝7.6Hz,1H),4.65(dd,J＝8.7,3.8Hz,1H),4.50(t,J＝6.2Hz,1H),4.32-4.15(m,3H),3.77–3.64(m,4H),3.41(t,J＝6.4Hz,1H),3.32(dd,J＝14,6.8Hz 1H),3.12(s,3H),2.89(s,3H),2.23–2.14(m,3H),1.77(s,3H),1.69(s,6H),1.63(s,3H),1.48–1.41(m,2H),1.38–1.26(m,2H),1.03–0.86(m,18H),0.80(d,J＝6.8Hz,3H),0.67–0.49(m,9H),0.12–0.03(m,6H)；¹³C NMR(101MHz,CDCl₃)δ171.18,170.46,165.93,162.70,157.51,151.11,144.15,141.53,137.74,137.15,130.78,128.34,127.98,127.59,127.37,127.13,125.35,121.56,121.06,120.22,113.08,106.22,91.70,87.09,80.63,75.09,68.40,60.64,57.09,56.30,55.70,47.34,34.09,33.62,31.46,30.79,28.91,25.99,25.46,25.27,25.24,19.44,18.69,17.34,12.46,11.26,7.09,5.19,-4.43；(ESI)[M+Na⁺]m/z 1235.6381(calcd for C₇₀H₉₆N₂NaO₁₂Si₂ ⁺,1235.6394)。

Synthesis of Compound ii-3:

piperidine (0.41mL,4.23mmol) was added to a dichloromethane solution of ii-3e (290mg,0.29mmol) at room temperature, and the resulting solution was stirred at room temperature for 2 hours, concentrated, and subjected to silica gel column chromatography to obtain the objective compound ii-3 (yield 76%), Rf 0.25 (petroleum ether/ethyl acetate 2:1) [ α ]]_D ³¹+19.5(c 0.2,CHCl₃)；IR(film)ν_max；¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝9.5Hz,1H),7.33–7.26(s,5H),6.77(d,J＝8.0Hz,1H),6.72(d,J＝1.5Hz,1H),6.64(d,J＝7.9Hz,1H),6.41-6.31(m,2H),5.85(d,J＝10.9Hz,1H),5.66(d,J＝6.5Hz,1H),5.47–5.38(m,2H),4.69(dd,J＝9.4,4.1Hz,1H),4.52(t,J＝6.3Hz,1H),3.77s,3H),3.41(t,J＝6Hz,1H),3.20–3.07(m,5H),2.53–2.45(m,1H),2.24(s,3H),2.23–2.13(m,3H),1.77(s,3H),1.69(s,6H),1.58(s,3H),1.48–1.42(m,2H),1.37–1.26(m,2H),0.99(s,9H),0.97–0.85(m,12H),0.72(d,J＝6.9Hz,3H),0.58(q,J＝8Hz,6H),0.14(s,6H)；¹³C NMR(101MHz,CDCl₃)δ＝173.99,172.43,166.00,162.78,151.47,144.22,137.92,137.81,131.75,128.58,128.38,128.11,127.92,127.64,127.23,121.46,121.28,112.90,106.29,91.74,87.16,80.57,77.56,75.13,67.04,56.67,56.35,55.80,39.55,36.06,33.69,31.67,28.97,26.05,25.52,25.33,19.66,18.76,17.61,12.51,11.30,7.16,5.25,-4.28；(ESI)[M+Na⁺]m/z 1013.5703(calcd for C₅₅H₈₆N₂NaO₁₀Si₂ ⁺,1013.5713)。

Example eight:

synthesis of Compound ii-4:

dissolving the compound ii-3 in toluene, sealing, stirring at 110 deg.C for 7 hr, concentrating, separating by silica gel column chromatography to obtain the target compound ii-4 (yield 72%), Rf 0.35 (petroleum ether/ethyl acetate 5:1), and nuclear magnetic hydrogen spectrum and carbon spectrum of the compound i-16 are not single set of nuclear magnetic peaks [ α ] due to conformational isomer]_D ³¹+19.5(c 0.2,CHCl₃)；IR(film)ν_max；(ESI)[M+Na⁺]m/z 955.5294(calcd for C₅₂H₈₀N₂O₉Si₂,955.5295)。

Synthesis of Compound ii-5 a:

cesium carbonate (21mg, 64.4. mu. mol) and iodomethane (30mg, 211.3. mu. mol) were added to a solution of ii-4(20mg, 21.4. mu. mol) in N, N-dimethylformamide (2mL), and the resulting solution was stirred at room temperature for 8 hours, concentrated and then subjected to silica gel column chromatography to obtain the objective compound ii-5a (yield 69%); rf 0.25 (5: 1 petroleum ether/ethyl acetate) and isomer ii-5b (19% yield), Rf 0.2 (5: 1 petroleum ether/ethyl acetate).

¹H NMR(400MHz,CDCl₃)δ7.32-7.26(m,5H),6.75-6.68(m,3H),6.59(dd,J＝8.0,1.6Hz,1H),6.52(t,J＝6.8Hz,1H),6.46(dd,J＝15.2,11.2Hz,1H),5.85(d,J＝10.8Hz,1H),5.82-5.75(m,2H),5.68(dd,J＝15.2,5.2Hz,1H),4.53-4.46(m,2H),4.02(q,J＝7.2Hz,1H),3.75(s,3H),3.52-3.42(m,2H),3.19(s,3H),2.79(dd,J＝15.2,11.2Hz,1H),2.70(s,3H),2.41-2.31(m,2H),2.27-2.19(m,1H),1.87(s,3H),1.77-1.70(m,1H),1.65-1.54(m,5H),1.37-1.29(m,1H),1.12(d,J＝7.2Hz,3H),1.05-0.90(m,15H),0.80(t,J＝8.0Hz,9H),0.45-0.29(m,6H),0.11(s,3H),0.10(s,3H)；¹³C NMR(100MHz,CDCl₃)δ199.6,172.2,170.7,170.6,151.0,143.7,143.2,137.4,137.2,136.0,131.7,130.3,127.9,127.8,127.7,127.5,127.2,120.9,120.8,112.2,85.5,78.5,73.8,58.0,56.4,56.2,55.5,45.1,34.6,32.8,31.5,30.7,28.3,25.8,23.5,19.2,18.6,18.0,14.2,12.3,11.1,6.9,4.7,-4.6,-4.6；HRMS(ESI):calcd for C₅₃H₈₂N₂NaO₉Si₂ ⁺[M+Na⁺]969.5451,found969.5480。

Synthesis of the Compound Aetheramide A:

10mg/mL of a methanol solution of D (+) -10-camphorsulfonic acid was prepared, ii-5a (14mg, 14.8. mu. mol) was dissolved in 1mL of the above solution, stirred at room temperature for 8 hours, concentrated, and then separated by a silica gel thick plate to obtain the desired compound Aetheramide A (yield 93%), Rf 0.3 (petroleum ether/ethyl acetate 2:1) [ α ]]_D ²⁹+78.6(c 0.1,CH₃CN)；¹H NMR(400MHz,CD₃CN)δ7.44-7.28(m,5H),6.86(d,J＝7.6Hz,1H),6.80(s,1H),6.77-6.67(m,2H),6.64(d,J＝8.0Hz,1H),6.44(dd,J＝15.2,10.8Hz,1H),6.41(s,1H),5.83-5.69(m,3H),5.56(dd,J＝11.2,4.8Hz,1H),4.41-4.30(m,2H),4.19-4.12(m,1H),3.79(s,3H),3.50(t,J＝6.0Hz,1H),3.35(dd,J＝15.2,4.8Hz,1H),3.29(d,J＝5.2Hz,1H),3.11(s,3H),2.79(dd,J＝15.2,11.6Hz,1H),2.73(s,3H),2.47-2.32(m,2H),2.27-2.22(m,1H),1.84(s,3H),1.67-1.53(m,4H),1.51-1.36(m,3H),1.04(d,J＝6.8Hz,3H),0.96(d,J＝6.8Hz,3H),0.90(d,J＝6.8Hz,3H)；¹³C NMR(100MHz,CD₃CN)δ201.8,173.6,171.8,171.4,148.0,145.7,145.6,139.6,139.1,136.3,132.1,130.4,129.4,129.2,128.9,127.9,127.2,122.3,115.5,113.2,85.5,80.1,74.1,60.4,58.0,56.7,56.5,45.9,33.6,33.3,32.1,30.6,28.3,24.5,19.8,18.9,14.8,12.4,11.9；HRMS(ESI):calcd for C₄₁H₅₄N₂NaO₉ ⁺[M+Na⁺]741.3722,found 741.371。

Example nine:

synthesis of Compound D-1:

referring to scheme one, i-1b is replaced by D-1-1 to give derivative D-1.

Example ten:

synthesis of Compound D-2:

referring to scheme one, i-3 is replaced with D-2-2. The synthesis method of D-2-2 comprises the following steps:

dissolving i-3 and triethylamine in a dry dichloromethane solution, dropwise adding a dichloromethane solution of methylsulfonyl chloride into a reaction solution, stirring at room temperature for 2 hours, adding water to perform extraction and quenching reaction, extracting dichloromethane, concentrating an organic phase, and performing column chromatography to obtain D-2-1; dissolving D-2-1 in tetrahydrofuran solution, slowly dropping sodium azide solution to react, stirring at room temperature for two hours, adding triphenylphosphine, stirring at room temperature for 2 hours, adding water to react, stirring for 1 hour, extracting, concentrating, and performing column chromatography to obtain D-2-2.

Example eleven:

synthesis of Compound D-3:

referring to scheme one, i-3i is replaced with D-3-1. The synthesis method of D-3-1 is as follows:

dissolving i-3i in dry ether, adding newly prepared silver oxide and methyl iodide into the solution, reacting at room temperature, stirring for 10h, filtering, drying the organic phase solution, and purifying by column chromatography to obtain D-3-1.

Example twelve:

synthesis of Compound D-4:

referring to scheme one, i-1 is replaced with D-4-1. To obtain the derivative D-4.

Example thirteen:

synthesis of Compound D-5:

referring to scheme one, i-1 is replaced with D-5-1.

Example fourteen:

synthesis of Compound D-6:

referring to scheme one, i-3 is replaced with D-6-1. D-6-1 referring to example three, i-3a was replaced with D-6-2.

Example fifteen:

synthesis of Compound D-7:

referring to scheme one, i-1 was replaced with D-7-1. D-7-1 referring to example one, i-1f was replaced with D-7-2.

Example sixteen:

synthesis of Compound D-8:

referring to scheme one, i-1 is replaced with D-8-1. h-1 was obtained by substituting i-1f with D-8-2, according to example one.

Example seventeen:

synthesis of Compound D-9:

referring to the actual synthetic scheme I, i-1 is replaced by D-9-1.

Example eighteen:

synthesis of Compound D-10:

referring to the actual synthetic scheme one, i-3 is replaced by D-10-1. D-10-1 referring to example three, i-3a was replaced with D-10-2.

Example nineteenth:

synthesis of Compound D-11:

referring to scheme one, i-1 was replaced with D-11-1. D-11-1 referring to example one, i-1f was replaced with D-11-2.

Example twenty:

synthesis of Compound D-12:

referring to scheme one, i-3 is replaced with D-12-1. D-12-1 referring to example three, i-3a was replaced with D-12-2.

Example twenty one:

synthesis of Compound D-13:

referring to scheme one, i-1 is replaced with D-13-1. D-13-1 referring to example one, i-1f was replaced with D-13-2.

Example twenty two:

synthesis of Compound D-14:

referring to scheme one, i-3 is replaced with D-14-1. D-14-1 referring to example three, i-3a was replaced with D-14-2.

Example twenty three:

synthesis of Compound D-15:

referring to scheme one, i-1 was replaced with D-15-1. D-15-1 referring to example one, i-1f was replaced with D-15-2.

Example twenty-four:

synthesis of Compound D-16:

referring to scheme one, i-3 is replaced with D-16-1. D-16-1 referring to example three, i-3a was replaced with D-16-2.

Example twenty-five:

synthesis of Compound D-17:

referring to scheme one, i-3 is replaced with D-17-1. D-17-1 referring to example three, i-3a was replaced with D-17-2.

Example twenty-six:

synthesis of Compound D-18:

referring to scheme one, i-1 was replaced with D-18-1. D-18-1 referring to example one, i-1f was replaced with D-18-2.

Example twenty-seven:

synthesis of Compound D-19:

referring to scheme one, i-1 was replaced with D-19-1. D-19-1 referring to example one, i-1f was replaced with D-19-2.

Example twenty-eight:

synthesis of Compound D-20:

referring to scheme one, i-3 is replaced with D-20-1. D-20-1 referring to example three, i-3a was replaced with D-20-2.

Example twenty-nine:

synthesis of Compound D-21:

referring to scheme one, i-3 is replaced with D-21-1. D-21-1 was obtained by substituting i-3a with D-21-2, according to example three.

Example thirty:

synthesis of Compound D-22:

referring to scheme one, i-1 was replaced with D-22-1. D-22-1 referring to example one, i-1f was replaced with D-22-2.

Example thirty one:

synthesis of Compound D-23:

referring to scheme II, D-23 was obtained from ii-4.

A10 mg/mL solution of D (+) -10-camphorsulfonic acid in methanol was prepared, ii-4(20mg,25.0mol) was dissolved in 1mL of the above solution, stirred at room temperature for 8 hours, concentrated, and then isolated by silica gel thick plates to give the desired compound D-23 (yield 81%).

Example thirty-two:

synthesis of Compound D-24:

referring to scheme one, i-2 is replaced with D-24-1. D-24-1 referring to example II, i-2q was replaced with D-24-2.

4-dimethylaminopyridine (0.4g,0.004mol,0.1eq.) and triethylamine (8.3ml,0.090mol,2eq.) were added sequentially to a tetrahydrofuran (50ml) solution of a compound i-2p (5.5g,0.045mol,1eq.) at 0 ℃, and after 5 hours of reaction at room temperature, water and dichloromethane were added to extract the organic phase, and the target compound D-24-2 was obtained by silica gel column chromatography.

Example thirty-three:

synthesis of Compound D-25:

referring to scheme one, i-3h is replaced with D-25-1. D-25-1 was obtained by reacting i-3 with D-25-2, according to example three.

Example thirty-four:

synthesis of Compound D-26:

referring to scheme one, wherein ii-2c is replaced with D-26-1. D-26-1 was obtained by reacting ii-2b with D-26-2, according to example six.

Example thirty-five:

synthesis of Compound D-27:

referring to scheme one, i-3h is replaced with D-27-1. D-27-1 was obtained by reacting i-3 with D-27-2, according to example three.

Example thirty-six:

synthesis of Compound D-28:

referring to scheme one, i-2 is replaced with D-28-1. D-28-1 referring to example II, i-2q was replaced with D-28-2.

Example thirty-seven:

synthesis of Compound D-29:

referring to scheme one, i-3h was replaced with D-29-1. D-29-1 was obtained by reacting i-3 with D-29-2, according to example three.

Example thirty-eight:

synthesis of Compound D-30:

referring to scheme one, where i-3h is replaced by D-30-1, D-30-1 is obtained by reacting i-3 with D-30-2, see example three.

Example thirty-nine:

synthesis of Compound D-31:

referring to scheme II, wherein ii-5a is replaced by D-31-1, D-31-1 is obtained by reacting ii-4 with D-31-2.

Example forty:

synthesis of Compound D-32:

referring to scheme one, where i-3h is replaced by D-32-1, D-32-1 is obtained by reacting i-3 with D-32-2, see example three.

Example forty one:

synthesis of Compound D-33:

referring to scheme one, where i-3h was replaced with D-33-1, D-33-1 was obtained by reacting i-3 with D-33-2, see example three.

Example forty two:

synthesis of Compound D-34:

referring to scheme one, ah was deprotected from i-6.

10mg/mL of a methanol solution of D (+) -10-camphorsulfonic acid was prepared, i-6(20mg) was dissolved in 1mL of the above solution, stirred at room temperature for 8 hours, concentrated, and then isolated by silica gel thick plate preparation to obtain the objective compound D-34 (yield: 81%).

Example forty-three:

synthesis of Compound D-35:

referring to scheme one, where i-7 is replaced by D-35-1, D-35-1 is obtained by reaction of i-3, see example three.

Dissolving i-6 in dry ether solution, adding newly prepared silver oxide and iodomethane into the reaction solution, reacting at room temperature for 10h, filtering, concentrating the organic phase, and purifying by column chromatography to obtain D-35-1.

Example forty-four:

synthesis of Compound D-36:

referring to scheme one, where i-7 is replaced by D-36-1, D-36-1 is obtained by reaction of i-3, see example three.

Dissolving i-6 in dry ether solution, adding newly prepared silver oxide and iodon-hexane into the reaction solution, reacting at room temperature for 10h, filtering, concentrating the organic phase, and purifying by column chromatography to obtain D-36-1.

Example forty-five:

synthesis of Compound D-37:

referring to scheme one, where i-7 is replaced by D-37-1, D-37-1 is obtained by reacting i-3 with D-37-2, see example three.

Example forty-six:

synthesis of Compound D-38:

referring to scheme one, where i-7 is replaced by D-38-1, D-38-1 is obtained by reacting i-3 with D-38-2, see example three.

Example forty-seven:

synthesis of Compound D-39:

referring to scheme one, i-2a is replaced with D-39-1.

Example forty-eight:

synthesis of Compound D-40:

referring to scheme one, i-2a is replaced with D-40-1.

Example forty-nine:

synthesis of Compound D-41:

referring to scheme one, i-2a is replaced with D-41-1.

Example fifty:

synthesis of Compound D-42:

referring to the actual synthetic scheme one, i-2a is replaced by D-42-1.

Example fifty one:

synthesis of Compound D-43:

referring to scheme one, i-2a is replaced with D-43-1.

Example fifty two:

synthesis of Compound D-44:

referring to scheme one, i-2a is replaced with D-44-1.

Example fifty three:

synthesis of Compound D-45:

referring to scheme one, i-2a is replaced with D-45-1.

Example fifty-four:

synthesis of Compound D-46:

referring to scheme one, i-2a is replaced with D-46-1.

Example fifty-five:

synthesis of Compound D-47:

referring to scheme one, i-2a is replaced with D-47-1.

Example fifty-six:

synthesis of Compound D-48:

referring to scheme one, i-2a is replaced with D-48-1.

Example fifty-seven:

synthesis of Compound D-49:

referring to scheme one, where i-3h was replaced with D-49-1, D-49-1 was obtained by reacting i-3 with D-49-2, according to example three.

Example fifty-eight:

synthesis of Compound D-50:

referring to the practical scheme one, wherein i-2f is replaced by D-50-1, wherein D-50-1 is obtained from ii-2 through a series of reactions.

Example fifty-nine:

synthesis of Compound D-51:

referring to the actual synthetic scheme one, wherein i-3e is replaced by D-51-1, wherein D-51-1 is obtained from i-3D through a series of reactions.

Example sixty:

synthesis of Compound D-52:

referring to the practical synthetic scheme one, i-2f is replaced by D-52-1, wherein D-52-1 is obtained from D-52-2 through a series of reactions.

Example sixty one:

synthesis of Compound D-53:

referring to the actual synthetic scheme one, i-2a is replaced by D-53-1.

Example sixty two:

synthesis of Compound D-54:

referring to the actual scheme one, wherein i-2e is replaced by D-54-1, wherein D-54-1 is obtained by reacting D-54-2 with i-2D.

Example sixty-three:

synthesis of Compound D-55:

referring to the actual synthetic scheme I, i-2a is replaced by D-55-1.

Example sixty-four:

synthesis of Compound D-56:

referring to the actual synthetic scheme one, i-2e was replaced with D-56-1. Wherein D-56-1 is obtained by reacting D-56-2 with i-2D.

Example sixty-five:

synthesis of Compound D-57:

referring to the actual scheme one, i-2a is replaced by D-57-1.

Example sixty-six:

synthesis of Compound D-58:

referring to the actual synthetic scheme one, i-2e was replaced with D-58-1. Wherein D-58-1 is obtained by reacting D-58-2 with i-2D.

Example sixty-seven:

synthesis of Compound D-59:

referring to the actual synthetic scheme one, i-2a is replaced by D-59-1.

Example sixty-eight:

synthesis of Compound D-60:

referring to the actual synthetic scheme one, i-2e was replaced with D-60-1. Wherein D-60-1 is obtained by reacting D-60-2 with i-2D.

Example sixty-nine: biological activity assay

In vitro evaluation of anti-HIV drugs was performed using rapid, sensitive and automated assay methods. T4-cell line, MT-4, was transformed with the existing HIV-1 strain (Koyanagi et al, INT. J. cancer, 36, 445-Bufonic 451, 1985), which showed high susceptibility to HIV infection and susceptibility to infection, as a target cell line. The inhibition of HIV-induced cytopathic effects was used as the end point. Viability of HIV-infected and mock-infected cells was assessed spectrophotometrically by reducing 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT). The percent protection by compound in HIV-infected cells was calculated by the following formula: (OD)_{HIV test compounds})-(OD_Control)/(OD_{Mock infected cell})-(OD_Control) Wherein (OD)_{HIV test compounds}) Is the optical density measured for a particular amount of test compound in HIV-infected cells; (OD)_Control) Is the optical density measured in untreated HIV-infected control cells; (OD)_{Mock infected cell}) Is the optical density measured on untreated mock-infected control cells. Optical density values are typically measured at 540 nm. The dose of anti-HIV test compound that provides 50% protection according to the above formula is defined as the 50% Inhibitory Concentration (IC)₅₀，μM)。

It is noted herein that the above-mentioned embodiments illustrate rather than limit the technical solution of the present invention, and although the present invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention.

Claims

1. A compound of formula I, pharmaceutically acceptable salts or esters and stereochemically isomeric forms thereof,

wherein,

x, Y, Z are independently: -O-, -NH-, -NMe-;

R₅the method comprises the following steps: -OH, -O (C)_1-6Alkyl) -, -O (C)_3-6Cycloalkyl) -, -O (halo C)_1-6Alkyl) -, -O (halo C)_3-6Cycloalkyl) -;

R₈the method comprises the following steps: -OH, -O-C_1-6An alkyl group;

m＝1-6；n＝1-5；o＝0-6；

2. The compound according to claim 1, selected from:

3. a compound according to any one of claims 1-2 for use in the manufacture of a medicament for the treatment or prevention of HIV infection.

4. A pharmaceutical composition comprising a compound of any one of claims 1-2 and at least one pharmaceutically acceptable carrier, excipient or diluent.

5. The pharmaceutical composition of claim 4, further comprising one or more additional antiviral agents.