Facile synthesis of lipophilic δ-amino acid conjugates from 4-alkoxy-dithionaphthoic acids

Article abstract of DOI:10.1080/00397911.2011.565142

(Chemical Equation Presented) Novel 4-alkoxy-dithionaphthoic acids were prepared and shown to be valuable synthons for δ-amino acid conjugates. These dithioacids are efficiently synthesized and purified, stable to storage, and easily derivatized to facilitate thioacylation chemistry. To this end, we have demonstrated dithionaphthoic acids (6) to successfully undergo coupling with both protected and unprotected amino acids, giving rise to stable thioamide conjugates (8 and 9). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.565142

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Facile Synthesis of Lipophilic δ-Amino
Acid Conjugates from 4-Alkoxy-
dithionaphthoic Acids
Anna C. Worth a , Catherine E. Needham a b , Donald B. Franklin a
Andrew J. Lampkins a b
&
a Department of Chemistry and Biochemistry, Samford University,
Birmingham, Alabama, USA
b McWhorter School of Pharmacy, Department of Pharmaceutical,
Social, and Administrative Sciences, Samford University,
Birmingham, Alabama, USA
Accepted author version posted online: 09 Nov 2011.Published
online: 29 May 2012.
To cite this article: Anna C. Worth , Catherine E. Needham , Donald B. Franklin & Andrew
J. Lampkins (2012): Facile Synthesis of Lipophilic δ-Amino Acid Conjugates from 4-Alkoxy-
dithionaphthoic Acids, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 42:18, 2694-2706
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Synthetic Communications1, 42: 2694–2706, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.565142
FACILE SYNTHESIS OF LIPOPHILIC d-AMINO ACID
CONJUGATES FROM 4-ALKOXY-DITHIONAPHTHOIC
ACIDS
Anna C. Worth,1 Catherine E. Needham,1,2
Donald B. Franklin,1 and Andrew J. Lampkins1,2
1Department of Chemistry and Biochemistry, Samford University,
Birmingham, Alabama, USA
2McWhorter School of Pharmacy, Department of Pharmaceutical, Social,
and Administrative Sciences, Samford University, Birmingham, Alabama,
USA
GRAPHICAL ABSTRACT
Abstract Novel 4-alkoxy-dithionaphthoic acids were prepared and shown to be valuable
synthons for d-amino acid conjugates. These dithioacids are efficiently synthesized and
purified, stable to storage, and easily derivatized to facilitate thioacylation chemistry. To
this end, we have demonstrated dithionaphthoic acids (6) to successfully undergo coupling
with both protected and unprotected amino acids, giving rise to stable thioamide conjugates
(8 and 9).
Keywords Bioconjugates; dithioacid; naphthalene; thioacylation; thioamide coupling
INTRODUCTION
The design of drug molecules and medicinal peptides whose biological target(s)
lie within the central nervous system (CNS) poses a unique set of bioavailability
challenges.[1] Unless directly administered (i.e., intracranial or epidural injection)
into the CNS, these compounds must not only contend with normal metabolic pro-
cesses but also penetrate the blood–brain barrier (BBB), a semipermeable barrier
evolved to keep xenobiotics and toxins from reaching the brain. As such, many
CNS disorders have either no or inadequate treatment modalities, including disor-
ders whose pathology has been elucidated and biological targets identified [i.e.,
matrix metalloproteinase (MMP) -2, -9, and -12 in the progression of cerebral aneur-
ysms,[2] prolyl oligopeptidase (POP) in schizophrenia and bipolar disorder,[3]
Received January 24, 2011.
Address correspondence to Andrew J. Lampkins, Department of Chemistry and Biochemistry,
Samford University, 800 Lakeshore Drive, Birmingham, AL 35229, USA. E-mail: alampkin@samford.edu
2694

LIPOPHILIC AMINO ACID CONJUGATES
2695
b-secretase in Alzheimer’s disease,[4] and calpain in multiple sclerosis,[5] to name a
few]. A focus area within our research is the directed synthesis of broadly applicable,
metabolically stable scaffolds onto which precise customization would lead to novel
families of druggable, biologically active peptide mimics that penetrate the CNS.
The two fundamental chemical moieties utilized to begin carrying out this task
are a donor–acceptor 1,4-disubstutited naphthalene and a thioamide. To the former,
a flat, rigid naphthalene system of this nature provides a lipophilic core with fluor-
escent properties that facilitate in vitro detection and assay development.[6] In
addition, this core is synthetically accessible and readily amenable to further manipu-
lation toward targeted derivatives. To the latter, a thioamide is isosteric to a tra-
ditional oxygenated amide (or peptide) group, more lipophilic, and potentially
more stable to in vivo hydrolysis and protease-mediated cleavage.[7] Taken together,
these two chemical accessories can dramatically influence the bioavailability and=or
pharmacodynamics of any conjugate or agent containing this scaffold. Medicinal
peptides, for instance, are ideal for this technology because their polar (oftentimes
zwitterionic) nature and susceptibility to rapid in vivo degradation often limits their
utility as pharmaceuticals.[8] As such, we envision amino acid conjugates of 4-alkoxy-
naphthalene-1-thioamides to display (1) improved metabolic stability and (2)
enhanced lipophilicity for preferential distribution into the CNS.
In this article, we describe a practical synthesis of new 4-alkoxy-dithio-
naphthoic acids, featuring a scalable and chromatography-free Grignard acylation
using carbon disulfide. Further, we demonstrate the utility of this synthon by prepar-
ing thioamide-derived d-peptide conjugates as scaffolds for drug discovery applica-
tions. The described preparations are user-friendly, amenable to scale-up, ideal for
combinatorial synthesis, and broadly applicable to a wide variety of practitioners.
RESULTS AND DISCUSSION
Our initial attempt at preparing suitably functionalized naphthalenes reactive
toward aminolysis focused upon 4-alkoxy-dithiomethylnaphthylates. We envisioned
these scaffolds as suitable for thioamide ligation reactions and constructed a small
family of derivatives in four to six efficient steps, depending upon the phenoxy sub-
stituent. A representative synthesis illustrating the preparation of methoxy derivative
3 is shown in Scheme 1. 4-Methoxy-naphthonitrile (1) was first saponified and
converted to the acid chloride before nucleophilic acyl substitution with sodium
methane thiolate afforded thiomethylester 2 in good yield. Lawesson’s reagent was
then employed to prepare the corresponding dithioester (3). While this reaction
was oftentimes sluggish (typically taking 2–3 days in refluxing toluene), it provided
consistently good yields of dithiomethylester product for every alkoxy substrate
we prepared. However, in all cases, we were unable to observe any thioamide
product—reactions were monitored via thin layer chromatography (TLC) and gas
chromatography=mass spectrometry (GC=MS), and only starting material spots=
peaks were observed even when reactions were allowed to stir for up to 14 days—
when these dithiomethylnaphthylates were treated with primary or secondary
aliphatic amines, even in the presence of standard acylation catalysts (e.g., dimethyl-
aminopyridine, triethylamine, etc.). These results were surprising because thioacyla-
tions of amines using electron-rich benzoyl dithiomethylates are known to occur,

2696
A. C. WORTH ET AL.
Scheme 1. Reagents and conditions: (i) NaOH, aqueous EtOH, reflux; (ii) SOCl2, reflux; (iii) CH3SNa,
DMAP, THF=DMF; (iv) Lawesson’s reagent, toluene, reflux; (v) 1ꢀ or 2ꢀ aliphatic amines, DMAP,
THF=DMF.
albeit slowly (up to 10 days in some cases) and in moderate yields.[9] Thus,
4-alkoxy-dithiomethylnaphthylates such as 3 likely undergo aminolysis at even
slower rates, rendering them essentially unreactive for practical synthetic purposes.
To generate more reactive thioacylating agents, we utilized dithionaphthoic
acid groups and customized them for this chemistry. This functional group can be
easily modified to esters that rapidly undergo aminolysis and similar nucleophilic
acylation reactions. We envision this coupling reaction to be ideal for generating
large families of thioamide peptide mimics combinatorially because it can be per-
formed using the amino terminus of functionalized amino acids or polypeptide
chains under extremely mild conditions. While a variety of methods exist for creating
thioamides, the vast majority are not suitable for preparing bioconjugates of
this nature. Perhaps the most widely utilized method is treatment of traditional
oxygenated amides with thionating reagents such as phosphorus pentasulfide or
Lawesson’s reagent.[10] However, a selective conversion is oftentimes difficult in
polyfunctionalized molecules with multiple carbonyl-containing functional groups.
Other commonly employed methods (such as the Willgerodt–Kindler reaction[11]
or alkylation of isothiocyanates[12]) typically employ harsh conditions (e.g., sustained
elevated temperatures, acid catalysis, highly reactive reagents or intermediates, etc.)
unsuitable for conjugating potentially labile biomolecules to a fixed scaffold. Thus,
we believe 4-alkoxy-dithionaphthoic acids to be key synthons in preparing novel,
functionalized thionaphthalene conjugates of this type.
We began our synthesis of 4-alkoxy-dithionaphthoic acids by bromination and
subsequent etherification of 1-napthol (Scheme 2).[13] These alkyl ethers (5) were
prepared to determine the optimal combination of pharmacodynamic properties
(e.g., absorption, half-life, etc.) and CNS penetration of the resulting naphthalene
conjugates. Factors affecting these key parameters, including molecular weight,
ClogP, molecular volume and flexibility, and polar surface area, can be carefully
modulated by variance of this alkyl group.
Bromo-ethers 5 were then converted to Grignard reagents and quenched with
carbon disulfide to afford dithionaphthoic acids 6. This protocol was found superior
to others attempted (in situ thioacylation of organolithium or Gilman cuprate

LIPOPHILIC AMINO ACID CONJUGATES
2697
Scheme 2. Reagents and conditions: (i) NBS, CH3CN; (ii) RI, K2CO3, CH3CN; (iii) (1) Mg turnings, I2,
THF=ether (2); CS2.
nucleophiles instead of Grignard reagents), and gave consistent, scalable (50 mg to
5 g) yields in our hands. Furthermore, this reaction does not require chromato-
graphic purification, as a series of simple acid=base extractions efficiently separate
the (blood-red) dithioacid products from the neutral organic starting materials
and by-products.
These 4-alkoxy-dithionaphthoic acids (6) were then treated with mercaptoben-
zothiazole disulfide to give dithiazoyl esters (7, Scheme 3). These esters are extremely
reactive thioacylating agents, in contrast to dithiomethylates 3 (vide supra), yet are
stable for months in ambient conditions[14]
.
We have shown that dithioesters 7 readily undergo aminolysis with amino acid
derivatives. When these dithioesters (7) are treated with protected amino acids (such
as 5-amino methylvalerate, shown) the resulting thioamides (8) are generated in
reasonable (54–76%) yield. The methyl esters within 8 can be selectively hydrolyzed
in the presence of thioamides to generate thioacylated amino acids 9 in excellent
yields. In addition, treatment of 7 with unprotected amino acids also resulted in
thioamide coupling in moderate, albeit reproducible, yields. This functional group
specificity allows for direct thioacylation of the amino terminus within highly func-
tionalized polypeptides or mimics thereof, facilitating expedited syntheses and
diminished usage of protecting groups.
Scheme 3. Reagents and conditions: (i) MBTS, PPh3, toluene=THF; (ii) 5-amino-methylvalerate HCl,
DMAP, CH2Cl2=DMF; (iii) 5-aminovaleric acid, ultrasonication, DMF; (iv) NaOH, H2O=THF.

2698
A. C. WORTH ET AL.
CONCLUSION
In conclusion, we have developed a short, scalable synthesis for 4-alkoxy-
dithionaphthoic acids which can be readily coupled to the amino terminus of (both
protected and unprotected) d-amino acids by way of a thioamide bond. We are cur-
rently evaluating the bioavailability and CNS permeability of this novel class of
molecules and are investigating functionalized derivatives designed as selective
agents toward Alzheimer’s disease and other neurodegenerative disorders. The
results of these investigations will be presented in due course.
EXPERIMENTAL
Reagents and solvents were purchased from commercial sources and used with-
out further purification unless otherwise specified. Tetrahydrafuran (THF), toluene,
CH2Cl2, and dimethylformamide (DMF) were degassed in 16 L drums and passed
through two sequential purification columns (activated alumina; molecular sieves
for DMF) under a positive argon atmosphere. Thin-layer chromatography (TLC)
was performed on aluminum sheets with visualization with ultraviolet (UV) light
1
or staining. H (300 MHz) and 13C (75 MHz) NMR spectra were recorded on a
Bruker (ARX series) spectrometer. Chemical shifts (d) are given in parts per million
¨
(ppm) relative to tetramethylsilane (TMS; 0.00 ppm). Abbreviations used are s (sing-
let), d (doublet), t (triplet), q (quartet), sext (sextet), sept (septet), b (broad), and m
(multiplet). Mass (MS) spectra were recorded on a ThermoElectron LCQ Deca XP
MAX LC-MS.
S-Methyl-4-methoxynaphthalene-1-carbothioate, 2
To a solution of nitrile 1 (1.00 g, 5.46 mmol) and ethanol (95%, 40 mL) in a
thick-walled pressure tube was added 6 N sodium hydroxide (20 mL). The reaction
vessel was then sealed and heated to 100–120 ꢀC, and the mixture was stirred rapidly
overnight. After cooling to rt, the ethanol was removed in vacuo, and the remaining
aqueous residue was acidified with concentrated HCl to pH < 3 and extracted with
EtOAc (50 mL ꢁ 3). The combined organic extracts were washed with water and
brine, dried with MgSO4, and concentrated to afford the crude naphthoic acid
(1.10 g, 5.44 mmol), which was dissolved in SOCl2 (25 mL) and heated to reflux for
2 h. The solvent was then removed in vacuo. The remaining crude brown residue
was then dissolved in dry THF (25 mL) and slowly added to a solution of sodium
methane thiolate (0.57 g, 8.16 mmol), triethylamine (2 mL), dry THF (25 mL), and
dry DMF (5 mL) in a round-bottomed flask. The resulting solution was allowed
to stir under a blanket of argon overnight. The reaction mixture was then diluted
with methylene chloride and washed with 10% aqueous. HCl, water, and brine. After
drying over MgSO4, the organic layer was evaporated and purified using flash chro-
matography (2:1 hexanes=methylene chloride eluent system) to afford 2 (1.027 g,
1
81% from 1) as a colorless solid: H NMR (CDCl3) d2.52 (s, 3H), 4.04 (s, 3H),
6.78 (d, J ¼ 8.4 Hz, 1H), 7.50–7.64 (m, 2H), 8.13 (d, J ¼ 8.4 Hz, 1H), 8.31 (d,
J ¼ 8.1 Hz, 1H), 8.68 (d, J ¼ 8.7 Hz, 1H). 13C NMR (CDCl3) d12.4, 55.6, 102.0,

LIPOPHILIC AMINO ACID CONJUGATES
2699
121.9, 125.0, 125.4, 125.7, 127.5, 128.3, 129.8, 130.5, 158.9, 193.2. MS (ESI) calcd.
for C13H12O2S (M)- 232.06, found 232.22.
S-Methyl-4-methoxynaphthalene-1-carbodithioate, 3
Lawesson’s reagent (2.61 g, 6.47 mmol) was added to a solution of 2 (500 mg,
2.15 mmol) in dry toluene (80 mL), and the resulting mixture was heated to reflux
for 2 days under argon. Upon cooling to rt, the solid was removed via filtration
and rinsed with toluene. The filtrate was concentrated, and the remaining residue
was purified using flash chromatography (5:3 hexanes=methylene chloride eluent sys-
1
tem) to afford 3 (404 mg, 76%) as a red solid: H NMR (CDCl3) d2.83 (s, 3H), 4.03
(s, 3H), 6.77 (d, J ¼ 7.8 Hz, 1H), 7.46–7.55 (m, 3H), 8.26 (d, J ¼ 8.4 Hz, 1H), 8.29 (d,
J ¼ 8.7 Hz, 1H). 13C NMR (CDCl3) d20.9, 55.4, 102.1, 121.8, 124.7, 125.0, 125.4,
127.1, 130.4, 137.9, 156.7, 231.2. MS (ESI) calcd. for C13H12OS2 (M)- 248.03, found
248.28.
General Procedure for Alkylating 4-Bromo-1-naphthol
An alkyl halide (24.1 mmol) was added to a stirring suspension of 4-bromo-
naphthol (5.68 mmol) and K2CO3 (17.1 mmol) in acetonitrile (40 mL). After stirring
at room temperature for 30 min, the reaction was warmed to 60 ꢀC overnight. Upon
cooling to rt, the reaction was quenched with water and the acetonitrile evaporated.
The crude residue was dissolved in dichloromethane and sequentially washed with
water, 0.5 M NaOH, and brine. The organic layer was then dried over MgSO4,
filtered, evaporated, and purified using flash chromatography (hexanes=dicholoro-
methane 15:1).
1
4-Bromo-1-methoxynaphthalene, 5a. Colorless oil, yield ¼ 91%. H NMR
(CDCl3) d3.95 (3H, s), 6.60 (1H, d, J ¼ 8.4 Hz), 7.60 (2H, m), 7.70 (1H, d,
J ¼ 8.4 Hz), 8.30 (2H, m). 13C NMR (CDCl3) d55.9, 104.9, 113.6, 122.5, 126.2,
127.1, 127.2, 128.3, 129.8, 132.8, 155.5.
1
4-Bromo-1-ethoxynaphthalene, 5b. Colorless solid, yield ¼ 88%. H NMR
(CDCl3) d1.44 (t, J ¼ 6.9 Hz, 3H), 3.98 (q, J ¼ 6.9 Hz, 2H), 6.46 (d, J ¼ 8.4 Hz, 1H),
7.42–7.55 (m, 3H), 8.12 (d, J ¼ 8.1 Hz, 1H), 8.25 (d, J ¼ 8.4 Hz, 1H). 13C NMR
(CDCl3) d14.3, 63.4, 104.8, 112.5, 122.1, 125.4, 126.3, 126.5, 127.2, 129.1, 132.0,
154.1
4-Bromo-1-propoxynaphthalene, 5c. Colorless solid, yield ¼ 91%. 1H
NMR (CDCl3) d1.05 (t, J ¼ 7.5 Hz, 3H), 1.83 (sext, J ¼ 7.5 Hz, 2H), 3.89 (t,
J ¼ 6.3 Hz, 2H), 6.47 (d, J ¼ 8.4 Hz, 1H), 7.41–7.54 (m, 3H), 8.11 (d, J ¼ 8.4 Hz,
1H), 8.26 (d, J ¼ 8.4 Hz, 1H). 13C NMR (CDCl3) d10.7, 22.5, 69.7, 105.1, 112.8,
122.5, 125.7, 126.7, 126.9, 127.6, 129.5, 132.4, 154.6.
4-Bromo-1-isopropoxynaphthalene, 5d. Colorless solid, yield ¼ 69%. 1H
NMR (CDCl3) d1.40 (d, J ¼ 6.0 Hz, 6H), 4.65 (sept, 6.0 Hz, 1H), 6.63 (d, J ¼ 8.4 Hz,
Hz, 1H), 7.43–7.61 (m, 3H), 8.12 (d, J ¼ 8.4 Hz, 1H), 8.27 (d, J ¼ 8.4 Hz, 1H). 13C
NMR (CDCl3) d21.6, 70.2, 106.5, 112.4, 122.4, 125.3, 126.4, 127.2, 127.4, 129.1,
132.3, 153.1.

2700
A. C. WORTH ET AL.
4-Bromo-1-isobutoxynaphthalene, 5e. Colorless oil, yield ¼ 71%. 1H
NMR (CDCl3) d 1.09 (d, J ¼ 6.9 Hz, 6H), 2.20 (m, J ¼ 6.6 Hz, 1H), 3.81 (d,
J ¼ 6.6 Hz, 2H), 6.58 (d, J ¼ 8.1 Hz, 1H), 7.48–7.7.60 (m, 3H), 8.14 (d, J ¼ 9.0 Hz,
1H), 8.30 (d, J ¼ 8.1 Hz, 1H). 13C NMR (CDCl3)d 18.9, 27.9, 74.1, 104.7, 112.4,
122.0, 125.3, 126.3, 126.5, 127.2, 129.0, 132.0, 154.2. MS (ESI) calcd. for C14H15BrO
(M)þ 278.03, found 278.12.
4-Bromo-1-benzyloxynaphthalene, 5f. Colorless solid, yield ¼ 79%. 1H
NMR (CDCl3) d 5.22 (s, 2H), 6.75 (d, J ¼ 8.4 Hz, 1H), 7.41–7.78 (m, 8H), 8.20 (d,
J ¼ 8.4 Hz, 1H), 8.37 (d, J ¼ 8.4 Hz, 1H). 13C NMR (CDCl3)d 70.3, 106.0, 113.5,
122.7, 126.3, 129.8, 126.9, 127.4, 127.9, 128.0, 128.8, 129.5, 132.5, 136.8, 154.2.
General Procedure for Grignard Reaction of 5 with CS2
A solution of 5 (4.12 mmol) dissolved in THF (3 mL) under argon was added to
magnesium turnings (7.38 mmol) in flame-dried glassware covered with dry ether
(1 mL). A crystal of iodine was then added, and the suspension warmed to reflux
with stirring for 3 h to facilitate Grignard initiation=formation. Upon cooling to
room temperature, carbon disulfide (13 mmol) was added dropwise, and the resulting
mixture was allowed to stir overnight. The reaction was then poured onto ice (30 g)
and diluted with hexanes (20 mL). The (red) aqueous layer was separated, acidified
with 3 M HCl, and extracted with ether. The organic extracts were pooled, dried over
MgSO4, and concentrated to dryness. No further purification was necessary.
4-Methoxy-dithionaphthoic acid, 6a. Red oil that solidified upon standing,
yield ¼ 64%. 1H NMR (CDCl3)d 3.96 (s, 3H), 6.66 (br, 1H), 6.67 (d, J ¼ 8.1 Hz, 1H),
7.44–7.56 (m, 2H), 7.69 (d, J ¼ 8.4 Hz, 1H), 8.25 (d, J ¼ 8.1 Hz, 1H), 8.46 (d,
J ¼ 7.5 Hz, 1H). 13C NMR (CDCl3) d 55.7, 102.2, 122.1, 125.2, 125.5, 125.8, 127.7,
129.7, 138.7, 157.7, 229.1. MS (ESI) calcd. for C12H9OS2 (M ꢂ H)ꢂ 233.02, found
233.27.
4-Ethoxy-dithionaphthoic acid, 6b. Red oil that solidified upon standing,
1
yield ¼ 64%. H NMR (CDCl3)d 1.56 (t, J ¼ 6.9 Hz, 3H), 4.23 (q, J ¼ 6.9 Hz, 2H),
6.70 (br, 1H), 6.72 (d, J ¼ 8.4 Hz, 1H), 7.48–7.60 (m, 2H), 7.73 (d, J ¼ 8.1 Hz, 1H),
8.33 (d, J ¼ 8.1 Hz, 1H), 8.50 (d, J ¼ 9.0 Hz, 1H). 13C NMR (CDCl3)d 14.7, 64.1,
103.0, 122.4, 125.3, 125.7, 125.8, 126.1, 127.8, 129.9, 138.6, 157.3, 229.2. MS (ESI)
calcd. for C13H13OS2 (M þ H)þ 249.03, found 249.21.
4-Propoxy-dithionaphthoic acid, 6c. Red oil that solidified upon standing,
yield ¼ 62%. 1H NMR (CDCl3) d 1.14 (t, J ¼ 7.5 Hz, 3H), 1.96 (sext, J ¼ 7.5 Hz, 2H),
4.13 (t, J ¼ 6.3 Hz, 2H), 6.70 (br, 1H), 6.72 (d, J ¼ 8.1 Hz, 1H), 7.48–7.61 (m, 2H),
7.73 (d, J ¼ 8.4 Hz, 1H), 8.34 (d, J ¼ 8.1 Hz, 1H), 8.51 (d, J ¼ 8.4 Hz, 1H). 13C
NMR (CDCl3)d 10.8, 22.6, 70.1, 103.0, 122.4, 125.4, 125.8, 125.9, 126.2, 127.8,
130.0, 138.7, 157.5, 229.2. MS (ESI) calcd. for C14H13OS2 (M ꢂ H)ꢂ 261.05, found
261.20.
4-Isopropoxy-dithionaphthoic acid, 6d. Red oil that solidified upon stand-
ing, yield ¼ 72%. 1H NMR (CDCl3) d 1.48 (d, J ¼ 6.0 Hz, 6H), 4.82 (sept, J ¼ 6.0 Hz,
1H), 6.71 (br, 1H), 6.76 (d, J ¼ 8.1 Hz, 1H), 7.48–7.62 (m, 2H), 7.76 (d, J ¼ 8.4 Hz,

LIPOPHILIC AMINO ACID CONJUGATES
2701
1H), 8.34 (d, J ¼ 8.4 Hz, 1H), 8.52 (d, J ¼ 8.4 Hz, 1H). 13C NMR (CDCl3) d 22.0,
70.7, 104.1, 122.7, 125.3, 125.7, 126.2, 126.4, 127.8, 130.1, 138.4, 156.3, 229.1. MS
(ESI) calcd. for C14H13OS2 (M ꢂ H)ꢂ 261.05, found 261.14.
4-Isobutoxy-dithionaphthoic acid, 6e. Red oil that solidified upon stand-
1
ing, yield ¼ 79%. H NMR (CDCl3) d 1.13 (d, J ¼ 6.6 Hz, 6H), 2.27 (m, J ¼ 6.6 Hz,
1H), 3.94 (d, J ¼ 6.3 Hz, 2H), 6.70 (br, 1H), 6.72 (d, J ¼ 8.1 Hz, 1H), 7.46–7.61 (m,
2H), 7.74 (d, J ¼ 8.1 Hz, 1H), 8.34 (d, J ¼ 8.4 Hz, 1H), 8.51 (d, J ¼ 8.4 Hz, 1H).
13C NMR (CDCl3)d 19.4, 28.3, 74.7, 102.9, 122.3, 125.3, 125.8, 125.8, 126.1,
127.7, 129.9, 138.6, 157.4, 229.1. MS (ESI) calcd. for C15H15OS2 (M ꢂ H)ꢂ 275.06,
found 275.24.
4-Benzyloxy-dithionaphthoic acid, 6f. Red oil that solidified upon stand-
ing, yield ¼ 68%. 1H NMR (CDCl3) d 5.27 (s, 2H), 6.69 (br, 1H), 6.79 (d, J ¼ 8.1 Hz,
Hz, 1H), 7.35–7.60 (m, 7H), 7.79 (d, J ¼ 8.1 Hz, 1H), 8.37 (d, J ¼ 8.4 Hz, 1H), 8.48 (d,
J ¼ 7.8 Hz, 1H). 13C NMR (CDCl3) d 70.2, 103.5, 122.2, 125.1, 125.5, 125.6, 125.8,
127.1, 127.6, 128.0, 128.5, 129.7, 136.1, 138.9, 156.6, 229.0. MS (ESI) calcd. for
C18H15OS2 (M þ H)þ 311.05, found 311.21.
General Procedure for Dithiazoyl Ester Synthesis from Dithioacids 6
A THF (5 mL) solution of 6 (0.262 mmol) was added dropwise to a stirring
suspension of 2,20-dithiobis[benzothiazole] (0.210 mmol) and triphenylphosphine
(0.210 mmol) in toluene (5 mL). After being heated to reflux for 2 h, the reaction
was cooled to room temperature. The reaction mixture was then washed with dilute
HCl solution and water and evaporated under reduced pressure. The crude residue
was purified using flash chromatography (hexanes=dichloromethane 1:1). Trace
amounts of PPh3 were removed by dissolving the resulting orange solid in a minimal
amount of CH2Cl2 and precipitating with cold hexanes. The red filtrate was concen-
trated to afford pure dithiazoyl ester.
1-(2-Benzothiazolyl)-4-methoxy-dithionaphthylate,
7a. Red
solid,
1
yield ¼ 68%. H NMR (CDCl3) d 4.07 (s, 3H), 6.83 (d, J ¼ 8.1 Hz, 1H), 7.42–7.61
(m, 2H), 7.70-7.77 (m, 2H), 7.83 (d, J ¼ 8.1 Hz, 1H), 7.97 (d, J ¼ 7.8 Hz, 1H), 8.16
(d, J ¼ 8.1 Hz, 1H), 8.33 (d, J ¼ 9.3 Hz, 1H), 8.47 (d, J ¼ 7.5 Hz, 1H). 13C NMR
(CDCl3)d 55.9, 102.4, 121.6, 122.3, 123.7, 124.9, 126.1, 126.6, 128.0, 128.4, 128.6,
131.5, 132.2, 132.3, 136.5, 152.3, 158.1, 160.1, 224.2. MS (ESI) calcd. for
C19H14NOS3 (M þ H)þ 368.02, found 367.91.
1-(2-Benzothiazolyl)-4-ethoxy-dithionaphthylate,
7b. Red
solid,
1
yield ¼ 57%. H NMR (CDCl3) d 1.58 (t, J ¼ 6.9 Hz, 3H), 4.27 (q, J ¼ 6.9 Hz, 2H),
6.79 (d, J ¼ 8.4 Hz, 1H), 7.44–7.47 (m, 2H), 7.69–7.75 (m, 2H), 7.81 (d, J ¼ 8.1 Hz,
1H), 7.95 (d, J ¼ 8.7 Hz, 1H), 8.14 (d, J ¼ 7.2 Hz, 1H), 8.35 (d, J ¼ 7.8 Hz, 1H),
8.46 (d, J ¼ 8.1 Hz, 1H). 13C NMR (CDCl3)d 14.7, 64.2, 103.0, 121.6, 122.4, 123.7,
124.9, 126.0, 126.2, 126.6, 126.9, 128.0, 130.8, 131.5, 133.5, 136.3, 136.5, 152.3,
157.6, 224.2. MS (ESI) calcd. for C20H16NOS3 (M þ H)þ 382.03, found 382.11.
1-(2-Benzothiazolyl)-4-propoxy-dithionaphthylate,
1
7c. Red
solid,
yield ¼ 70%. H NMR (CDCl3) d 1.15 (t, J ¼ 7.5 Hz, 3H), 1.99 (sext, J ¼ 7.5 Hz,

2702
A. C. WORTH ET AL.
2H), 4.17 (t, J ¼ 6.3 Hz, 2H), 6.80 (d, J ¼ 8.4 Hz, 1H), 7.47–7.55 (m, 2H), 7.69–7.76
(m, 2H), 7.82 (d, J ¼ 8.1 Hz, 1H), 7.97 (d, J ¼ 7.5 Hz, 1H), 8.15 (d, J ¼ 7.2 Hz, 1H),
8.35 (d, J ¼ 7.8 Hz, 1H), 8.47 (d, J ¼ 8.1 Hz, 1H). 13C NMR (CDCl3)d 10.7, 22.5,
70.1, 103.0, 121.6, 122.3, 123.7, 124.9, 126.0, 126.2, 126.6, 126.9, 128.4, 128.6,
131.5, 132.2, 132.3, 152.3, 157.7, 160.0, 224.2. MS (ESI) calcd. for C21H18NOS3
(M þ H)þ 396.05, found 396.21.
1-(2-Benzothiazolyl)-4-isopropoxy-dithionaphthylate, 7d. Red solid,
1
yield ¼ 77%. H NMR (CDCl3) d 1.45 (d, J ¼ 6.0 Hz, 6H), 4.79 (sept, J ¼ 6.0 Hz,
1H), 6.77 (d, J ¼ 8.1 Hz, 1H), 7.42–7.48 (m, 2H), 7.69–7.79 (m, 2H), 7.80 (d, J ¼ 8.1 Hz,
Hz, 1H), 7.91 (d, J ¼ 8.1 Hz, 1H), 8.14 (d, J ¼ 7.8 Hz, 1H), 8.33 (d, J ¼ 8.4 Hz, 1H),
8.47 (d, J ¼ 7.5 Hz, 1H). 13C NMR (CDCl3)d 22.0, 70.8, 104.1, 121.3, 121.7, 122.7,
123.7, 124.9, 126.0, 126.3, 127.1, 128.0, 128.5, 128.7, 131.6, 132.2, 132.4, 152.3,
156.7, 224.1. MS (ESI) calcd. for C21H18NOS3 (M þ H)þ 396.05, found 396.33.
1-(2-Benzothiazolyl)-4-isobutoxy-dithionaphthylate,
7e. Red
solid,
yield ¼ 58%. 1H NMR (CDCl3) d 1.15 (d, J ¼ 6.6 Hz, 6H), 2.30 (m, J ¼ 6.6 Hz,
1H), 3.98 (d, J ¼ 6.3 Hz, 2H), 6.80 (d, J ¼ 8.1 Hz, 1H), 7.40–7.61 (m, 2H),
7.70–7.78 (m, 2H), 7.82 (d, J ¼ 8.1 Hz, 1H), 7.97 (d, J ¼ 7.8 Hz, 1H), 8.16 (d,
J ¼ 8.1 Hz, 1H), 8.37 (d, J ¼ 7.5 Hz, 1H), 8.48 (d, J ¼ 7.5 Hz, 1H). 13C NMR (CDCl3)
d 19.4, 28.4, 74.8, 103.0, 121.6, 122.3, 123.7, 124.9, 126.0, 126.2, 126.6, 128.0, 128.4,
128.6, 130.9, 131.5, 132.3, 136.5, 152.3, 157.7, 224.1. MS (ESI) calcd. for
C22H20NOS3 (M þ H)þ 410.06, found 410.32.
1-(2-Benzothiazolyl)-4-benzyloxy-dithionaphthylate,
7f. Red
solid,
1
yield ¼ 62%. H NMR (CDCl3)d 5.33 (s, 2H), 6.90 (d, J ¼ 8.4 Hz, 1H), 7.40–7.63
(m, 9H), 7.81 (d, J ¼ 8.1 Hz, 1H), 7.98 (d, J ¼ 8.1 Hz, 1H), 8.17 (d, J ¼ 7.8 Hz,
1H), 8.41 (d, J ¼ 8.4 Hz, 1H), 8.47 (d, J ¼ 8.1 Hz, 1H). 13C NMR (CDCl3) d 70.5,
103.7, 121.7, 122.5, 123.8, 124.9, 126.0, 126.2, 126.6, 127.4, 128.1, 128.3, 128.4,
128.8, 130.9, 132.2, 136.3, 136.6, 136.7, 152.3, 157.1, 160.1, 224.2. MS (ESI) calcd.
for C25H18NOS3 (M þ H)þ 443.05, found 443.22.
General Procedure for Coupling Dithiazoyl Esters 7 with
5-Amino-methylvalerate
A mixture of 7 (0.545mmol), 5-amino-methylvalerate HCl (0.599 mmol) and
DMAP (0.654 mmol) was added DMF (3mL) and dichloromethane (3mL). The result-
ing solution was allowed to stir overnight. The solvent was then evaporated, and the
crude residue was dissolved in dichloromethane (50 mL) and washed with dilute HCl
and water. The organic layer was then concentrated to dryness, and the product purified
using flash chromatography (hexanes=ethyl acetate 3:1) to afford pure thioamide 8.
Methyl-5-(4-methoxynaphthalene-1-thioamido)pentanoate, 8a. Color-
1
less oil, yield ¼ 73%. H NMR (CDCl3) d 1.74–1.85 (m, 4H), 2.40 (t, J ¼ 6.6 Hz,
2H), 3.65 (s, 3H), 3.90 (q, J ¼ 6.9 Hz, 2H), 4.01 (s, 3H), 6.76 (d, J ¼ 7.8 Hz, 1H),
7.45–7.55 (m, 3H), 7.70 (br, 1H), 8.11 (d, J ¼ 7.8 Hz, 1H), 8.28 (d, J ¼ 7.5 Hz, 1H).
13C NMR (CDCl3) d 22.2, 27.5, 33.4, 45.8, 51.6, 55.7, 102.9, 122.4, 124.6, 125.4,
125.6, 125.6, 127.4, 130.1, 134.5, 156.5, 173.8, 200.5. MS (ESI) calcd. for
C18H22NOS3 (M þ H)þ 332.12, found 332.28.

LIPOPHILIC AMINO ACID CONJUGATES
2703
Methyl-5-(4-ethoxynaphthalene-1-thioamido)pentanoate, 8b. Colorless
1
solid, yield ¼ 55%. H NMR (CDCl3) d1.56 (t, J ¼ 6.9 Hz, 3H), 1.78 (m 4H), 2.40
(t, J ¼ 6.9 Hz, 2H), 3.66 (s, 3H), 3.89 (q, J ¼ 6.9 Hz, 2H), 4.22 (q, J ¼ 6.9 Hz, 2H),
6.74 (d, J ¼ 8.1 Hz, 1H), 7.47–7.55 (m, 3H), 7.70 (br, 1H), 8.11 (d, J ¼ 7.2 Hz, 1H),
8.32 (d, J ¼ 7.8 Hz, 1H). 13C NMR (CDCl3) d 14.7, 22.2, 27.5, 33.4, 45.8, 51.6,
64.0, 103.6, 122.5, 124.5, 125.5, 125.5, 125.7, 127.4, 130.1, 134.2, 155.8, 173.8,
200.6. MS (ESI) calcd. for C19H24NO3S (M þ H)þ 346.14, found 346.26.
Methyl-5-(4-propoxynaphthalene-1-thioamido)pentanoate, 8c. Color-
1
less oil, yield ¼ 76%. H NMR (CDCl3) d 1.13 (t, J ¼ 7.5 Hz, 3H), 1.77 (m, 4H),
1.95 (sext, 7.5 Hz, 2H), 2.38 (t, J ¼ 6.9 Hz, 2H), 3.64 (s, 3H), 3.87 (q, J ¼ 6.9 Hz,
2H), 4.10 (t, J ¼ 6.6 Hz, 2H), 6.73 (d, J ¼ 8.1 Hz, 1H), 7.44–7.54 (m, 3H), 7.73 (br,
1H), 8.10 (d, J ¼ 7.2 Hz, 1H), 8.32 (d, J ¼ 7.8 Hz, 1H). 13C NMR (CDCl3) d 10.8,
22.3, 22.6, 27.5, 33.4, 45.9, 51.7, 69.9, 103.6, 122.5, 124.6, 125.5, 125.6, 125.7,
127.4, 130.2, 134.2, 155.9, 173.8, 200.6. MS (ESI) calcd. for C20H26NO3S
(M þ H)þ 360.16, found 360.32.
Methyl-5-(4-isopropoxynaphthalene-1-thioamido)pentanoate, 8d. Col-
1
orless oil, yield ¼ 54%. H NMR (CDCl3) 1.45 (d, J ¼ 6.0 Hz, 6H), 1.79 (m, 4H),
2.40 (t, J ¼ 6.6 Hz, 2H), 3.65 (s, 3H), 3.90 (q, J ¼ 6.6 Hz, 2H), 4.77 (sept, J ¼ 6.0 Hz,
Hz, 1H), 6.77 (d, J ¼ 8.1 Hz, 1H), 7.43–7.54 (m, 3H), 7.68 (br, 1H), 8.09 (d,
J ¼ 7.5 Hz, 1H), 8.30 (d, J ¼ 9.0 Hz, 1H). 13C NMR (CDCl3) d 22.0, 27.5, 29.7,
33.4, 45.8, 51.6, 70.5, 105.1, 122.8, 124.5, 125.4, 125.6, 126.4, 127.3, 130.3, 134.0,
154.8, 173.8, 200.7. MS (ESI) calcd. for C20H26NO3S (M þ H)þ 360.16, found
360.41.
Methyl-5-(4-isobutoxynaphthalene-1-thioamido)pentanoate, 8e. Col-
1
orless solid, yield ¼ 76%. H NMR (CDCl3) d 1.12 (d, J ¼ 6.9 Hz, 6H), 1.78 (m,
4H), 2.29 (m, J ¼ 6.9 Hz, 1H), 2.39 (t, J ¼ 6.9 Hz, 2H), 3.64 (s, 3H), 3.88 (q,
J ¼ 6.6 Hz, 2H), 3.90 (d, J ¼ 6.3 Hz, 2H), 6.72 (d, J ¼ 8.1 Hz, 1H), 7.44–7.54 (m,
3H), 7.71 (br, 1H), 8.11 (d, J ¼ 7.8 Hz, 1H), 8.33 (d, J ¼ 7.8 Hz, 1H).13C NMR
(CDCl3) d19.2, 22.1, 27.3, 28.2, 33.2, 45.7, 51.5, 74.5, 103.4, 122.3, 124.4, 125.3,
125.4, 125.6, 127.2, 130.0, 134.0, 155.8, 173.6, 200.4. MS (ESI) calcd. for
C21H28NO3S (M þ H)þ 374.17, found 374.31.
Methyl-5-(4-benzyloxynaphthalene-1-thioamido)pentanoate, 8f. Color-
less oil, yield ¼ 61%. 1H NMR (CDCl3) d 1.77 (m, 4H), 2.38 (t, J ¼ 6.6 Hz, 2H), 3.64
(s, 3H), 3.87 (q, J ¼ 6.6 Hz, 2H), 5.26 (s, 2H), 6.80 (d, J ¼ 8.1 Hz, 1H), 7.35–7.56 (m,
8H), 7.71 (br, 1H), 8.12 (d, J ¼ 8.1 Hz, 1H), 8.37 (d, J ¼ 6.9 Hz, 1H). 13C NMR
(CDCl3) d 22.2, 27.4, 33.3, 45.8, 51.6, 70.2, 104.2, 122.4, 124.6, 125.2, 125.6, 127.2,
127.4, 128.0, 128.6, 130.2, 134.6, 136.6, 155.3, 173.7, 200.3. MS (ESI) calcd. for
C24H26NO3S (M þ H)þ 408.16, found 408.18.
General Procedure for Preparing Thioamide-Derived Amino Acids 9
Method A. A suspension of 7 (0.27 mmol), 5-amniovaleric acid (0.30 mmol),
and DMF (5 mL) in a sealed vial was allowed to sonicate for 3 h. The solvent was
then evaporated, and the crude residue was dissolved in dichloromethane (50 mL)
and washed with dilute HCl and water. The organic layer was then concentrated

2704
A. C. WORTH ET AL.
to dryness, and the product was purified via flash chromatography (0–3% MeOH in
CH2Cl2) to afford pure 9.
Method B. A solution of 8 (0.27 mmol) in THF (3 mL) and 1 M NaOH (2 mL)
was allowed to stir at 50 ꢀC for 3 h. The organic solvent was then removed in vacuo
and the aqueous residue was acidified with concentrated. HCl and extracted with
EtOAc. The combined organic extracts were washed with brine, dried over MgSO4,
concentrated, and purified using flash chromatography (0–3% MeOH in CH2Cl2) to
afford pure 9.
5-(4-Methoxynaphthalene-1-thioamido)pentanoic acid, 9a. Colorless
1
solid, yield ¼ 63% (Method A), 96% (Method B). H NMR (DMSO-d6) d1.58–1.73
(m, 4H), 2.29 (br, 2H), 3.31 (br, 2H), 3.99 (s, 3H), 6.98 (m, 1H), 7.55 (m, 3H),
8.02–8.41 (m, 2H), 10.48 (br, 1H), 12.14 (br, 1H). 13C NMR (DMSO-d6) d 21.8,
28.3, 33.0, 44.9, 55.5, 102.8, 121.2, 124.2, 125.2, 125.9, 126.7, 129.6, 130.7, 134.2,
155.6, 174.1, 197.7. MS (ESI) calcd. for C17H20NO3S (M þ H)þ 318.11, found
318.40.
5-(4-Ethoxynaphthalene-1-thioamido)pentanoic acid, 9b. Colorless
1
solid, yield ¼ 68% (Method A), 98% (Method B). H NMR (20:1 CDCl3=DMSO-
d6)
d
1.52 (t, J ¼ 6.9 Hz, 3H), 1.73–1.82 (m, 4H), 2.34 (t, J ¼ 8.1 Hz,
2H), 3.82 (t, J ¼ 6.3 Hz, 2H), 4.19 (q, J ¼ 6.9 Hz, 2H), 6.75 (d, J ¼ 8.1 Hz, 1H),
7.38–7.49 (m, 3H), 8.05 (d, J ¼ 8.4 Hz, 1H), 8.25, (d, J ¼ 8.1 Hz, 1H), 9.60 (br,
1H).13C NMR (20:1 CDCl3=DMSO-d6) d 14.5, 22.2, 27.0, 33.5, 45.7, 63.7, 103.5,
122.0, 124.8, 124.8, 125.1, 125.2, 126.8, 130.1, 134.5, 154.9, 175.2, 199.2. MS (ESI)
calcd. for C18H22NO3S (M þ H)þ 332.12, found 332.38.
5-(4-Propoxynaphthalene-1-thioamido)pentanoic acid, 9c. Colorless
1
solid, yield ¼ 64% (Method A), 96% (Method B). H NMR (20:1 CDCl3=DMSO-
d6) d 1.13 (t, J ¼ 7.5 Hz, 3H), 1.76–1.81 (m, 4H), 1.95 (sext, J ¼ 6.3 Hz, 2H), 2.37
(t, J ¼ 6.9 Hz, 2H), 3.85 (br, 2H), 4.12 (br, 2H), 6.78 (d, J ¼ 8.1 Hz, 1H), 7.41–7.54
(m, 3H), 8.07 (d, J ¼ 7.8 Hz, 1H), 8.29 (d, J ¼ 8.1 Hz, 1H), 9.70 (br, 1H).13C NMR
(20:1 CDCl3=DMSO-d6)d 10.7, 22.4, 22.4, 27.1, 33.7, 45.9, 69.8, 103.6, 122.1,
125.0, 125.3, 125.4, 127.0, 130.3, 134.6, 155.2, 175.3, 199.3. MS (ESI) calcd. for
C19H24NO3S (M þ H)þ 346.14, found 346.22.
5-(4-Isopropoxynaphthalene-1-thioamido)pentanoic acid, 9d. Colorless
solid, yield ¼ 57% (Method A), 97% (Method B). 1H NMR (CDCl3) d1.45 (d,
J ¼ 6.0 Hz, 6H), 1.85 (m, 4H), 2.49 (t, J ¼ 6.3 Hz, 2H), 3.95 (q, J ¼ 6.3 Hz, 2H),
4.76 (sept, J ¼ 6.0 Hz, 1H), 6.76 (d, J ¼ 8.4 Hz, 1H), 7.27–7.53 (m, 3H), 7.78 (br,
13
1H), 8.12 (d, J ¼ 7.8 Hz, 1H), 8.29 (d, J ¼ 7.5 Hz, 1H), 12.01 (br, 1H).n C NMR
(CDCl3) d 22.0, 27.5, 29.7, 33.5, 45.9, 70.5, 105.0, 112.3, 121.3, 122.7, 124.6, 125.6,
127.2, 130.0, 140.3, 154.7, 179.2, 190.9. MS (ESI) calcd. for C19H24NO3S (M þ H)þ
346.14, found 346.28.
5-(4-Isobutoxynaphthalene-1-thioamido)pentanoic acid, 9e. Colorless
1
solid, yield ¼ 55% (Method A), 95% (Method B). H NMR (20:1 CDCl3=DMSO-
d6)
d
1.09 (d, J ¼ 6.6 Hz, 6H), 1.73–1.81 (m, 4H), 2.23 (m, J ¼ 6.6 Hz,
1H), 2.33 (t, J ¼ 9.3 Hz, 2H), 3.82–3.89 (m, 4H), 6.73 (d, J ¼ 6.0 Hz, 1H),
7.37–7.49 (m, 3H), 8.05 (d, J ¼ 7.2 Hz, 1H), 8.26 (d, J ¼ 8.1 Hz, 1H), 9.60 (br, 1H).

LIPOPHILIC AMINO ACID CONJUGATES
2705
13C NMR (20:1 CDCl3=DMSO-d6) d 19.3, 22.4, 27.1, 28.2, 33.7, 45.9, 74.6, 103.6,
122.0, 125.0, 125.3, 125.4, 125.4, 127.0, 130.3, 134.6, 155.2, 175.4, 199.3. MS (ESI)
calcd. for C20H26NO3S (M þ H)þ 360.16, found 360.34.
5-(4-Benzyloxynaphthalene-1-thioamido)pentanoic acid, 9f. Colorless
solid, yield ¼ 69% (Method A), 97% (Method B). 1H NMR (DMSO-d6) d
1.56–1.77 (m, 4H), 2.29 (t, J ¼ 7.5 Hz, 2H), 3.74 (q, J ¼ 6.9 Hz, 2H), 5.36 (s, 2H),
7.05 (d, J ¼ 8.1 Hz, 1H), 7.30–7.7.45 (m, 4H), 7.52–7.56 (m, 4H), 7.98–8.01 (m,
1H), 8.25–8.28 (m, 1H), 10.48 (t, J ¼ 5.4 Hz, 1H). 13C NMR (DMSO-d6) d 22.1,
26.7, 33.3, 45.1, 69.5, 104.8, 121.6, 124.3, 124.7, 125.0, 125.6, 126.9, 127.3, 127.8,
128.5, 130.0, 134.7, 136.9, 153.7, 174.3, 197.9. MS (ESI) calcd. for C23H24NO3S
(M þ H)þ 394.14, found 394.28.
ACKNOWLEDGMENTS
This research was supported by an award from the Research Corporation for
Science Advancement and Samford University. A. C. W. was supported by an
Alabama Power Fellowship. The authors also thank Mike Jablonsky (University
of Alabama, Birmingham) and Brian Gregory (Samford University) for use of their
spectroscopic equipment facilities.
REFERENCES
1. Su, Y.; Sinko, P. J. Drug delivery across the blood–brain barrier: Why is it difficult? How
to measure and improve it? Expert Opin. Drug Deliv. 2006, 3, 419–435.
2. Aoki, T.; Kataoka, H.; Ishibashi, R.; Nozaki, K.; Hashimoto, N. Cathepsin, B. K, and S
are expressed in cerebral aneurysms and promote the progression of cerebral aneurysms.
Stroke 2008, 39, 2603–2610
3. Tarrago, T.; Sabido, E.; Kogan, M.; De Oliveira, E.; Giralt, E. Primary structure, recom-
binant expression, and homology modeling of human brain prolyl oligopeptidase, an
important therapeutic target in the treatment of neuropsychiatric diseases. J. Pept. Sci.
2005, 11, 283–287.
4. Citron, M. b-secretase as a target for the treatment of Alzheimer’s disease. J. Neurosci.
Res. 2002, 70, 373–379.
5. Imam, S. A.; Guyton, M. K.; Haque, A.; Vandenbark, A.; Tyor, W. R.; Ray, S. K.; Banik,
N. L. Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients.
J. Neuroimmunol. 2007, 190, 139–145.
6. (a) Chakraborty, C.; Hsu, C. H.; Wen, Z. H.; Lin, C. S. Recent advances of fluorescent
technologies for drug discovery and development. Curr. Pharm. Des. 2009, 15, 3552–
3570; (b) Sapsford, K. E.; Berti, L.; Medintz, I. L. Materials for fluorescence resonance
energy transfer analysis: Beyond traditional donor–acceptor combinations. Angew. Chem.
Int. Ed. 2006, 45, 4562–4588.
7. Bardi, R.; Piazzesi, A. M.; Toniolo, C.; Jensen, O. E.; Omar, R. S.; Senning, A. Molecular
and crystal structures of three monothiated analogues of the terminally blocked
ala-aib-ala sequence of peptaibol antibiotics. Biopolymers 1988, 27, 747–761.
8. Gentilucci, L.; De Marco, R.; Cerisoli, L. Chemical modifications designed to improve
peptide stability: Incorporation of non-natural amino acids, pseudo-peptide bonds, and
cyclization. Curr. Pharm. Des. 2010, 16, 3185–3203.

2706
A. C. WORTH ET AL.
9. (a) Farina, C.; Pellegata, R.; Pinza, M.; Pifferi, G. Research on alkoxythiobenzamides, III:
Synthesis of new 3,4,5-trimethoxythiobenzamides and related thiomorpholides with
potential antisecretory and antiulcer activity. Arch. Pharm. 1981, 314, 108–117; (b)
Csomos, P.; Fodor, L.; Sohar, P.; Bernath, G. Synthesis of thiazino[6,5-b]indole deriva-
´ ´ ´
tives, analogues of the phytoalexin cyclobrassinin: A new method for preparation of
3-aminomethylindole. Tetrahedron 2005, 61, 9257–9262
10. Ozturk, T.; Ertas, E.; Mert, O. Use of Lawesson’s reagent in organic synthesis. Chem. Rev.
2007, 107, 5210–5278.
11. Brown, E. V. The Willgerodt reaction. Synthesis 1975, 358–375.
12. Dell, C. P. Thionoamides and their selenium and tellurium analogues. In Comprehensive
Organic Functional Group Transformations; A. R. Katritzky, O. Meth-Cohn, C. W. Rees
(Eds.); Pergamon: Oxford, 1995, vol. 5, pp. 565–628.
13. (a) Suzuki, Y.; Takeuchi, K.; Kodomari, M. Regioselective halogenation and dimerization
of alkoxynaphthalenes with alumina- or Kieselguhr-supported copper(II) halides. J. Chem.
Res., Synop. 1997, 11, 426–427; (b) Lorz, E.; Baltzly, R. N,N-Disubstituted amidines, III:
4-Alkoxy-a -naphthamidines. J. Am. Chem. Soc. 1951, 73, 93–5; (c) Bringmann, G.;
Goetz, R.; Harmsen, S.; Holenz, J.; Walter, R. Acetogenic isoquinoline alkaloids,
LXXXII: Biomimetic total synthesis of michellamines A–C. Liebigs Ann. Chem. 1996,
12, 2045–2058; (d) Imanzadeh, G. K.; Zamanloo, M. R.; Eskandari, H.; Shayesteh, K.
A new ring bromination method for aromatic compounds under solvent-free conditions
with NBS=Al2O3. J. Chem. Res. 2006, 3, 151–153.
14. Yeo, S. K.; Choi, B. G.; Kim, J. D.; Lee, J. H. A convenient method for the synthesis of
thiobenzamide derivatives and O-thiobenzoates by use of 2-benzothiazolyl dithiobenzoate
as effective thiobenzoylation reagent. Bull. Korean Chem. Soc. 2002, 23, 1029–1030.