Synthesis of phenyl 2-acryloyloxybornane-10-sulfonate diastereomers

Duggan, Andrew R.; Kaye, Perry T.; Caira, Mino R.

doi:10.3184/030823406779173307

Cited by 4 publications

(10 citation statements)

References 8 publications

(4 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The alcohol group reacts with cyclohexylisocyanate under copper(i) catalysis to make a carbamate linkage, which results in 3. [8] Subsequent treatment with 95 % TFA gives the unprotected peptidomimetic 4. The overall yield of the product was 5 % after HPLC purification.…”

mentioning

confidence: 99%

A Peptidomimetic HIV‐Entry Inhibitor Directed against the CD4 Binding Site of the Viral Glycoprotein gp120

Neffe

Meyer

2004

Angew Chem Int Ed

View full text Add to dashboard Cite

The first step in the infection of a human cell with HIV is interaction between the viral envelope glycoprotein gp120 and the human protein CD4. [1] We used this molecular interaction as a template to design and synthesize a new peptidomimetic compound that has the potential to block the interaction. In HIV infection, binding is followed by a conformational change [2] after which gp120 can interact with a co-receptor (CCR5 or CXCR4). This interaction finally leads to fusion of the membrane of the virus with that of a human T-cell. The fusion process is mediated by viral gp41 and leads to infection of the human cell. Compounds that inhibit this process are referred to as entry inhibitors.[3] We present a new way to inhibit the gp120/CD4 interaction through blocking the binding site on the CD4 protein with a peptidomimetic. Other research groups have targeted the same interaction and have developed gp120-or antibodyrelated peptides, [4] or gp120-binding molecules. [5] In our approach, which involves the development of CD4 ligands, interference with the human immune system or viral resistance are potential problems. However, resistance of the virus to inhibitors that bind to CD4 would require large changes in the viral glycoproteins to allow the virus to utilize a different entry mechanism. Such resistance is therefore not as likely as the evasion of inhibitors of viral proteins whose binding can be circumvented by one or two mutations of the viral amino acids.We started from the CD4-binding decapeptide NMWQKVGTPL, [6] which was derived from an X-ray structure of gp120.[2b] The peptide has a low binding affinity to CD4 (K D = 6 mm, determined by the surface plasmon resonance (SPR) and saturation transfer difference (STD) NMR spectroscopy protocols described herein) but has an antiviral activity that can be detected by a virus neutralization assay. The main targets of the design phase were to lower the molecular weight of the peptide, enhance its binding affinity, and incorporate nonnatural elements to increase proteolytic stability. The docking of peptides generated by molecular modeling studies by substituting each amino acid of the lead sequence in turn with alanine (see the Supporting Information) supported the results of saturation transfer difference (STD) NMR epitope mapping: [7] The docking study results suggest that the amino acids Asn, Met, and Gln do not contribute to the binding to CD4. Therefore, these inactive subunits were removed from the lead structure to reduce the molecular weight. Interactions of the aromatic ring of Trp and the hydrophobic side chain of Leu with CD4 could be replaced by the interaction of numerous other hydrophobic side chains without losing binding energy. Only the core peptide KVGTP was considered crucial for binding. The N and C termini were modified with various hydrophobic residues connected by nonpeptidic bonds. The candidate found from the molecular modeling studies to interact best with CD4 (Figure 1) was synthesized (Scheme 1).We synthesized the peptidomimetic from th...

show abstract

mentioning

confidence: 99%

A Peptidomimetic HIV‐Entry Inhibitor Directed against the CD4 Binding Site of the Viral Glycoprotein gp120

Neffe

Meyer

2004

Angew Chem Int Ed

View full text Add to dashboard Cite

show abstract

“…Firstly, the one-step esterification of (+)-camphor-10-sulfonic acid 6 to form 7 using trimethyl orthoacetate is superior to the literature synthesis of the analogous phenyl sulfonate ester, 17 which has to be carried out in two steps from 6 (ie: conversion of 6 into (+)-camphor-10-sulfonyl chloride using thionyl chloride, followed by treatment of the product with phenol in pyridine), and which employs toxic (phenol, pyridine) and corrosive (thionyl chloride) reagents. 18 Secondly, the optimized synthesis of 1 reported herein proceeds in higher overall yield (81 %) than previous syntheses of 1 from either (+)-camphor-10-sulfonyl chloride (76 %) 12 or from (+)-camphor-10-sulfonic acid 6 (44 % overall by Kaye's method, 12 75 % overall when thionyl chloride is used to convert 6 to (+)-camphor-10-sulfonyl chloride 19 ). Finally, our reduction of the sulfonate ester 7 to yield 8 requires a smaller excess of sodium borohydride (3 equivalents) than Kaye's reduction of the analogous phenyl sulfonate ester (which requires 10 equivalents of sodium borohydride).…”

Section: Methodsmentioning

confidence: 83%

“…Various reductions of 7 with excess (3-4 equivalents) sodium borohydride in methanol or in isopropanol, and subsequent additions of potassium tert-butoxide (1 equivalent) led at best to mixtures of 8 and sultone 1 (8:1 ratio ranging from 17:1 to 1:1.3) in overall yields no higher than 44 %. The reduced tendency of sulfonate ester 8 to cyclise to 1 under these conditions compared to Kaye's phenyl sulfonate ester (which cyclises smoothly to 1 in the absence of additional base) 12 can be attributed to the greater leaving group ability of the phenoxy-group in the latter compound.…”

Section: Nabh 4 Meohmentioning

confidence: 88%

“…2c,3,5,6a In a more recent report, Kaye obtained sultone 1 as a minor byproduct (4 % yield) during the reduction of phenyl (+)-camphor-10-sulfonate with sodium borohydride in H 2 O/EtOH at −8 o C, with the sultone 1 becoming the sole product (94 % yield) when the reduction was performed at 25 o C in absolute ethanol. 12 In this paper, we wish to report a modified and improved synthesis of sultone 1 13 which we have serendipitously discovered. …”

Section: Introductionmentioning

confidence: 99%

“…Evaporation of the aqueous phase from this reaction furnished an off-white solid whose 1 H NMR spectrum in D 2 O suggested the presence of the corresponding sodium isobornylsulfonate salt, 16 which was most likely obtained by simple methanolysis or hydrolysis of the sulfonate ester group of 8. Inspired by Kaye's synthesis of 1 via reduction of the analogous phenyl sulfonate ester followed by cyclisation, 12 we next sought to synthesize the sultone 1 from the ester 7 in a one-pot procedure via reduction of 7 and subsequent base-catalyzed cyclisation in situ. However, these attempts met with limited success.…”

Section: Nabh 4 Meohmentioning

confidence: 99%

See 2 more Smart Citations

An improved synthesis of 10-isobornylsultone

Lewis

Grayson

2014

Tetrahedron: Asymmetry

View full text Add to dashboard Cite

show abstract

Diversity Oriented Synthesis of Allocolchicinoids with Fluoro and/or Oxygen Substituent(s) on the C‐Ring from a Single Common Intermediate

et al. 2016

View full text Add to dashboard Cite

Allocolchicinoids, with a distinct polyoxygenated dibenzocycloheptane skeleton, attract much attention as potential candidate anticancer drugs. In this study, eight C‐ring fluorinated analogues of allocolchicinoids, seven C‐ring oxygen‐substituted analogues, and known compounds N‐acetylcolchinol and NSC 51046 were synthesized as racemates from a single common intermediate by using either the deoxyfluorination/migration domino reaction or acid‐promoted migration as the key step. Among the products obtained, some of the fluorinated derivatives strongly inhibited the growth of prostate DU145 and pancreas Panc 1 cancer cell lines with efficacy comparable to or better than those of N‐acetylcolchinol and NSC 51046. They were also less toxic against a non‐cancerous cell line than the known compounds were.

show abstract

Synthesis of phenyl 2-acryloyloxybornane-10-sulfonate diastereomers

Cited by 4 publications

References 8 publications

A Peptidomimetic HIV‐Entry Inhibitor Directed against the CD4 Binding Site of the Viral Glycoprotein gp120

A Peptidomimetic HIV‐Entry Inhibitor Directed against the CD4 Binding Site of the Viral Glycoprotein gp120

An improved synthesis of 10-isobornylsultone

Diversity Oriented Synthesis of Allocolchicinoids with Fluoro and/or Oxygen Substituent(s) on the C‐Ring from a Single Common Intermediate

Contact Info

Product

Resources

About