Title page for ETD etd-01302005-191303

Type of Document Master's Thesis
Author Tu, Sheng
Author's Email Address tsheng@vt.edu
URN etd-01302005-191303
Title Syntheses of Multi-headed, Two-tailed, Anionic Surfactants as Topical Microbicides
Degree Master of Science
Department Chemistry
Advisory Committee
Advisor Name Title
Gandour, Richard D. Committee Chair
Taylor, Larry T. Committee Member
Viers, Jimmy W. Committee Member
  • Microbicides
  • Anionic Surfactants
  • HIV
Date of Defense 2005-01-12
Availability restricted
The purpose of this research was to design and develop a facile synthesis of a series of multi-headed, two-tailed anionic surfactants (3CAm1(n)2) as anti-HIV microbicides, and to compare the biological activities of these compounds to the activities of their straight-acyl chain derivatives.

The synthesis requires coupling reaction of dialkylacetic acid (R2CHCOOH) (R2= n-C6H13, n-C7H15, n-C8H17, n-C9H19, n-C10H21) and Behera’s amine (H2NC(CH2CH2COOtBu)3).

Commercially available diethyl malonate and straight chain alkyl bromide were selected to produce dialkylacetic acid. Sodium methoxide (MeONa) was used as a base to deprotonate the acidic protons of diethyl malonate. The monoalkylmalonate (RCH(COOEt)2) was separated by vacuum distillation and then used as the starting material of the dialkylation step. This modification improved the yields of this reaction by about 10 percent from the routine procedure of introducing both alkyl groups in the same reaction.

The Behera's amine was prepared from the nitrotriester (O2NC(CH2CH2COOtBu)3) by Zn° reduction. The Behera's amine was then converted into an HCl salt by using a diluted HCl solution in 1:1 EtOH/H2O. By doing so, lactam impurity can be separated by solid-liquid extraction in hexane with sonication. The Behera's amine HCl salt was then separated and converted back into Behera's amine by Et3N in dry CH2Cl2.

Dialkylacetic acid was converted into its sodium salt by using aqueous NaOH solution; the sodium salt was then added to SOCl2 to yield the acyl chloride (R2CHCOCl). The coupling reaction of Behera's amine and acyl chloride was done in dry CH2Cl2 with 2.2 eq Et3N under sonication to give crude (R2CHCONHC(CH2CH2COOtBu)3), which was identified by 1H NMR.

The crude product from coupling reaction was treated with formic acid. The resulting product was the purified and isolated as a white solid by gravity column chromatography in 100:100:0.5 Hexane/EtOAc/AcOH. Five homologues (R2CHCONHC(CH2CH2COOH)3 R2= n-C6H13, n-C7H15, n-C8H17, n-C9H19, n-C10H21) were produced by this method; all were fully characterized by 1H and 13C NMR, IR, and HRMS.

Future improvements can be achieved by replacing the carboxylate groups with the other anionic groups, such as sulfate and phosphate, or add making tri-tailed surfactants, and by, exploring other possible way to improve the biological activities.

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