A Concise, High Yield Synthesis of the Selective ECE-Inhibitor, CGS 35066

Article abstract of DOI:10.1081/SCC-120028350

A highly efficient synthesis of the selective endothelin-converting enzyme, CGS 35066 is described. The key steps involved a Pd-catalyzed coupling of the phenyl rings of a diphenyl ether, and the use of the Schoellkopf reagent, (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine as a chiral auxiliary furnishing a dibenzofuranylmethyl substituted amino ester in high (>98%) enantiomeric purity, which was then carried forward to complete the synthesis of the ECE inhibitor CGS 35066.

Full text of DOI:10.1081/SCC-120028350

This article was downloaded by: [Laurentian University]
On: 06 December 2014, At: 14:38
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
A Concise, High Yield Synthesis of the Selective
ECE‐Inhibitor, CGS 35066
Abdul H. Fauq a , Murad A. Khan a & Christopher Eckman a
a Birdsall Research Building , Mayo Clinic Jacksonville , 4500 San Pablo Rd., Jacksonville,
Florida, 32224, USA
Published online: 20 Aug 2006.
To cite this article: Abdul H. Fauq , Murad A. Khan & Christopher Eckman (2004) A Concise, High Yield Synthesis of the
Selective ECE‐Inhibitor, CGS 35066, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:5, 775-782, DOI: 10.1081/SCC-120028350
To link to this article: http://dx.doi.org/10.1081/SCC-120028350
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 775–782, 2004
A Concise, High Yield Synthesis of the
Selective ECE-Inhibitor, CGS 35066
*
Abdul H. Fauq, Murad A. Khan, and Christopher Eckman
Birdsall Research Building, Mayo Clinic Jacksonville, Jacksonville,
Florida, USA
ABSTRACT
A highly efficient synthesis of the selective endothelin-converting
enzyme, CGS 35066 is described. The key steps involved a Pd-catalyzed
coupling of the phenyl rings of a diphenyl ether, and the use of the
¨
Schollkopf reagent, (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyra-
zine as a chiral auxiliary furnishing a dibenzofuranylmethyl substituted
amino ester in high (.98%) enantiomeric purity, which was then carried
forward to complete the synthesis of the ECE inhibitor CGS 35066.
Key Words: ECE Inhibitor; Endotheline-1; CGS 35066; Dibenzofuran.
The highly potent vasoconstrictor peptide, Endotheline-1 (ET-1) has been
the subject of extensive studies with regard to its biological significance as
*
Correspondence: Abdul H. Fauq, Birdsall Research Building, Mayo Clinic
Jacksonville, 4500 San Pablo Rd., Jacksonville, FL 32224, USA; Fax: (904) 953-8034.
775
DOI: 10.1081/SCC-120028350
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
776
Fauq, Khan, and Eckman
well as its use as a pharmacological and therapeutic target.[1] Thus, its
implication in a variety of disease states, such as systemic and pulmonary
hypertension, asthma and cardiac, and renal failure, among others, has led to
the development of peptidic and nonpeptidic ET receptor antagonists, some of
which, such as SB 209670 are now in the final stages of clinical
development.[2]
Another therapeutic strategy to block the action of ET-1 appears to be to
develop inhibitors of its biogenesis. Specifically, a zinc metalloprotease,
endothelin-converting enzyme-1 (ECE-1) that is responsible for processing
the inactive big ET to mature ET-1 has emerged as a promising therapeutic
target for selective inhibition.[3] Recently several inhibitors of ECE-1 have
been developed, some of which show relatively non-selective action against
other metalloproteases such as the neutral endopeptidase 24.11 (NEP). While
a number of these inhibitors show dual ECE-1/NEP inhibitory activity,[4] the
compound CGS 35066 was developed as a nonpeptidic ECE-selective
inhibitor, which showed an IC50 of 22 nM against recombinant human ECE-1.
A report describing the synthesis of this compound using alcalase-mediated
chiral resolution of an advanced intermediate has appeared.[5] We now report,
herein, a new concise, high yield synthesis of enatiomerically pure CGS 35066
(VIII, Sch. 1).
The synthesis (Sch. 1) of CGS 35066 started with 3-phenoxybenzyl
alcohol 1 (Aldrich). Acetylation of 1 (Ac2O, pyridine, 08C), followed by Pd-
catalyzed ring closure[6] of the acetate II to a dibenzofuran nucleus proceeded
in 63.5% yield over two steps furnishing the dibenzofuran-3-ylmethyl acetic
acid ester III. The direct ring closure of 1 resulted unwanted oxidation at the
benzylic position. After removal of the acetyl group, the dibenzofuranyl-
methyl alcohol IV was readily converted to a benzylic bromide V (45%
HBr/AcOH, CHCl3, r.t., 1 hr) in quantitative yield. The bromide V was
[7]
¨
immediately coupled with the anion derived from the Schollkopf reagent,
(2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (n-butyllithium, THF,
2908C). This chiral auxiliary gave the product essentially in quantitative yield
of VI with .98% ee as indicated by a careful analysis of a multiply eluted
1
TLC (which indicated a single spot) as well as by analyzing H NMR of the
crude product. Comparison of the 1H NMR of the compound VI with those of
some other related materials[8] revealed the presence of clear, at least half a
ppm apart signals for the protons at the dihydropyrazine a-carbon atoms of
their corresponding diastereomeric mixtures. The unusually low temperature
(2908C) was found to be necessary for the observed outcome in enantiomeric
excess, as raising temperature to 2788C resulted in significant decrease in the
chiral induction.
The chiral auxiliary from the couple product VI was successfully cleaved
off, and the resulting aminoester product VII was isolated as a TFA-salt by

ORDER
REPRINTS
Synthesis of Selective ECE-Inhibitor
777
Scheme 1. a. Ac2O, DMAP, pyridine, overnight, 100%; b. Pd (OAc)2, AcOH, 1308C,
19 hr, 63.5%; c. IM LiOH, MeOH, r.t., 30 min. 94.1%; d. 45% HBr in AcOH, CHC13,
r.t., 1 hr, .99%; e. (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine, n-BuLi,
THF, 2908C, 1 hr, .99%; f. 0.15% TFA, acetonitrile, r.t. 5 hr, NaHCO3; g. (i)
Extraction from aq. NaHCO3. (ii) 37% formalin, H2O, EtOAc, NaHCO3, r.t., 18 hr; h.
(PhO)2POH, toluene, 708C, 2 hr, 87.7%; i. 9 N HCl, AcOH, 1008C, 2 hr, 95.5%.
extraction with dichloromethane (DCM). The extraction of the salt with DCM
conveniently and effectively removed the contaminating TFA-salt of the
valine methyl ester which remained behind in the aqueous phase during
extractive work-up. Such extractions seem to be general for relatively bulky
a-substituents of amino esters.[8] The free amine obtained from the methyl
ester amine salt VII was then reacted with the aqueous formalin (ethyl acetate,
NaHCO3, 18 hr) to form a hexahydrotriazine intermediate which, without
purification, was treated with diphenyl phosphite in toluene at 708C to form
the fully protected phosphonate VIII in 88% yield. The compound VIII has
been shown to serve as a bioavailable form of the CGS 35066. Finally, strong
acid hydrolytic deblocking of the diphenyl and methyl ester groups in VIII
furnished the target compound CGS 35066 IX as a crystalline solid. The
spectroscopic and optical activity data for IX was in complete agreement with
the published data.[5] The enantiomeric purity of the final compound was

ORDER
REPRINTS
778
Fauq, Khan, and Eckman
1
confirmed by analyzing the H NMR of the diastereomeric salt of IX with
þ(R)-1(1-naphthyl) ethylamine, and was found to be greater than 98%.
In summary, a concise and efficient synthesis of CGS 35066, a selective
inhibitor of ECE-1, was achieved in high overall yield and enantiomeric
purity.
EXPERIMENTAL SECTION
General
Unless otherwise stated, all reactions were carried out under argon or
nitrogen atmosphere. Commercially available materials were used without
purification. The dichloromethane was distilled over CaH2. Other solvents,
such as diethyl ether and tetrahydrofuran were dried by distillation over
sodium benzophenone ketyl. NMR spectra were recorded over a Bru¨ker
Avance-300 instrument at 300 MHz for 1H NMR, 75 MHz for 13C NMR, and
121 MHz for 31P NMR. Chemical shifts are given with tetramethylsilane as
internal standard set at zero ppm (1H, and 13C NMR). 31P NMR are measured
with 85% phosphoric acid taken as standard (31P NMR). The mass spectra
were measured by slow infusion electrospray ionization on a Sciex-365 Triple
Quadrupole mass spectrometer. The Flash chromatography was performed
using Kieselgel 60 (230–400 mesh) silica gel as described by Still.[9]
3-Phenoxybenzyl Acetate (II)
Pyridine (50 mL) was added to 3-phenoxybenzyl alcohol I (5.0 g,
25.0 mmol) and the resulting solution was stirred for 5 min under nitrogen.
4-N,N-dimethylaminopyridine (DMAP, 70 mg) was added and the mixture
was cooled to 08C. Gradual addition of acetic anhydride (7 mL, 75.0 mmol)
was followed by stirring at ambient temperatures for 4 hr. The reaction was
quenched by adding cold water (100 mL), and the excess acetic anhydride was
destroyed by stirring the reaction mixture for 1 hr. Extraction with CH2Cl2
(200 mL Â 3), was followed by washing the combined organic layers with
saturated aq. NaHCO3 and brine. Drying the organic phase with MgSO4, and
1
rotary evaporation gave II (6.01 g, 100%) which needed no purification. H
NMR (CDCl3) d 2.09 (3H, s), 5.06 (2H, s), 6.94 (1H, dd, J ¼ ) 7.02 (3H, dd),
7.1 (2H, m), 7.34 (2H, m).

ORDER
REPRINTS
Synthesis of Selective ECE-Inhibitor
779
Dibenzofuran-3-yl-methyl Acetic Acid Ester (III)
A mixture of the compound II (5.62 g, 23.22 mmol) and Pd(OAc)2
(7.82 g, 34.8 mmol) in 55 mL of AcOH was refluxed overnight. After cooling
to room temperature, the reaction mixture was filtered through Celite.
Concentration by rotary evaporation and removal of the traces of acetic acid
with toluene gave a residue from which the product isolated by Flash
chromatography using 3% EtAc/Hexane. The product containing fractions
were combined to give III as a white solid (3.54 g, 63.5%). 1H NMR
(CDCl3) d 2.13 (3H, s), 5.26 (2H, s), 7.35 (2H, m), 7.46 (1H, td, J ¼ 8.1,
1.4 Hz), 7.58 (2H, m) 7.93 (1H, d, J ¼ 7.8 Hz). 7.95 (1H, md, J ¼ 7.5 Hz),
ESI Mass 504 (2M þ 1)þ, 362 (M 2 OAc þ 1)þ, 263 (M þ Na)þ, 182
(M 2 OAc þ 1)þ.
Dibenzofuran-3-yl-methanol (IV)
The ester III (2.27 g, 9.46 mmol) was dissolved in 23 mL MeOH. To this
was added 23 mL of 1 N-LiOH solution at r.t. The mixture was left stirred for
30 min. The reaction was quenched with 1 N-HCl and the aqueous phase was
extracted twice with 100 mL of CH2Cl2. The organic phase was washed
sequentially with 50 mL of water, and brine, and dried over MgSO4, affording
IV as a white solid (1.76 g, 94.1%). 1H NMR (CDCl3) d 1.83 (1H, t,
J ¼ 5.7 Hz), 4.84 (2H, d, J ¼ 5.7 Hz), 7.35 (2H, m) 7.45 (1H, td, 8.0, 1.4 Hz),
7.58 (2H, m), 7.95 (2H, m); IR 3294, 1454, 1416 cm21
.
3-Bromomethyl Dibezofuran (V)
To a stirred solution of compound IV (1.6 g, 8.08 mmol) in 30 mL of
CHCl3 were added 2.18 mL of glacial acetic acid (12.12 mmol) and 45% HBr
(12.12 mmol). The acidic mixture was stirred under nitrogen at r.t for 1 hr,
and then quenched with 30 mL cold water. Extraction of the aqueous phase
with 50 mL of CHCl3, and washing of the chloroform layer sequentially with
25 mL of aq. NaHCO3, water, and brine was followed by drying it over
MgSO4. Evaporation of the organic solvent under vacuum furnished
1
essentially pure V (2.1 g, 100%) as a white solid. H NMR (CDCl3) d 4.66
(2H, s) 7.35 (2H, m), 7.46 (1H, td, J ¼ 8.0, 1.4 Hz), 7.59 (2H, m), 7.91
(2H, m).

ORDER
REPRINTS
780
Fauq, Khan, and Eckman
2-Dibenzofuran-3-ylmethyl-5-iisopropyl-3,6-dimethoxy-2,5-
dihydro-pyridine (VI)
A
solution of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine
(0.67 mL, 3.69 mmol) in 10 mL of dry THF was placed in an oven-dried
flask under argon, and cooled to 2788C. While stirring, 2.5 M BuLi (1.5 mL,
3.69 mmol) in hexane was added via syringe. After stirring for 10 min at
2788C, the reaction mixture was further cooled to 2908C. At this point,
compound V (803 mg, 3.08 mmol) dissolved in 5 mL of THF was added
dropwise via cannula. The mixture was stirred between 2908C to 2708C for
1 hr, and then quenched with saturated NH4Cl. After warming to r.t., the
volatiles were removed in vacuo, and the aqueous phase was extracted twice
with EtOAc. The EtOAc extracts were combined and washed with water, and
brine, and dried (MgSO4). Concentration in vacuo, and purification of the
residue by silica gel chromatography using 5% EtOAc/hexane as eluent
1
afforded pure VI as a solid (1.12 g, 100%). H NMR (CDCl3) d 0.61 (3H, d,
J ¼ 6.9 Hz), 0.75 (3H, d, J ¼ 6.9 Hz), 2.14 (1H, m), 3.21 (2H, d, J ¼ 4.8 Hz),
3.33 (1H, t, J ¼ 3.6 Hz), 3.70 (3H, s), 3.75 (3H, s), 4.39 (1H, q, J ¼ 7.8 Hz),
7.1 (1H, dd, J ¼ 7.8, 1.2 Hz), 7.28 (2H, m), 7.41 (1H, td, J ¼ 7.2, 1.2 Hz), 7.54
(2H, m), 7.78 (1H, m), 7.9 (1H, d, J ¼ 7.5 Hz); ESI-MS 366 (M þ 1)þ.
2-Amino-3-dibenzofuran-3-yl-propionic Acid Methyl
Ester (VII)
To a solution of the compound VI (1.12 g, 3.07 mmol) in 30 mL of
acetonitrile was added 8.0 mL (9.21 mmol) of aq. 0.15 N TFA solution. The
resulting clear solution was stirred under nitrogen for 5 hr. Water (50 mL) and
CH2Cl2 (100 mL) were added. The CH2Cl2-layer was separated. The aqueous
phase was back extracted with more CH2Cl2 (Â4), and the combined organic
layers were dried (Na2SO4). The 1H NMR of this TFA salt showed complete
absence of the contaminating valine methyl ester. The TFA-salt was then
neutralized with aqueous NaHCO3 and re-extracted with CH2Cl2 (Â3). The
combined organic extracts were washed with water and brine, and then dried
over Na2SO4. Concentration of the organic solvent yielded VII (776 mg,
94.0%) as a colorless oil which was used in the next step without purification.
1H NMR (CDCl3) d 3.03 (1H, dd, J ¼ 13.5, 7.8 Hz), 3.23 (1H, dd, J ¼ 13.5,
5.1 Hz), 3.73 (3H, s), 3.83 (1H, dd, J ¼ 7.8, 5.8 Hz), 7.16 (1H, dd, J ¼ 7.8,
1.2 Hz), 7.32 (2H, td, J ¼ 7.5, 1.0 Hz), 7.45 (2H, m), 7.55 (1H, d, J ¼ 8.1 Hz),
d 7.83 (1H, d, J ¼ 7.8 Hz), 7.92 (1H, din, J ¼ 7.2 Hz); ESI-MS 540
(2M þ 1)þ, 271 (M þ 1)þ.

ORDER
REPRINTS
Synthesis of Selective ECE-Inhibitor
781
(S)-3-Dibenzofuran-3-yl-2-[phosphonomethylamino]-
propionic Acid Methyl Ester (VIII)
Compound VII (211 mg, 0.756 mmol) was dissolved in 4 mL of a 1 : 1
mixture of EtOAc and H2O along with powdered NaHCO3 (7.6 mg,
0.10 mmol). After cooling this mixture to 128C, 37% of aqueous formalde-
hyde (76 ml, 1 mmol) was added. The reaction mixture was left stirred over-
night at ambient temperature. Addition of water was followed by extraction of
the aqueous phase with two 20 mL portions of CH2CL2. The organic phase
was washed with water and brine, dried over MgSO4, filtered, and
concentrated in vacuo to leave the intermediate hexahydrotriazine as a solid
residue which was characterized by NMR. 1H NMR (CDCl3) d 2.98 (2H, dd,
J ¼ 7.2, 3.3 Hz), 3.58 (3H, s), 3.75 (1H, m), 3.85 (2H, s), 6.91 (1H, dd,
J ¼ 8.1, 1.2 Hz), 7.25 (2H, m), 7.39 (1H, dt, J ¼ 7.5, 1.2 Hz), 7.49 (1H, m),
7.54 (1H, m), 7.72 (1H, m).
To a stirred solution of the hexahydrotriazine in toluene under nitrogen
was added diphenyl phosphite. The resulting solution was left stirred at 708C
for 2 hr, cooled to r.t., and partially concentrated to half of the initial volume.
Addition of hexane to this solution resulted in precipitation of the crude
product. After filtration and washing with ether and hexane, the solid residue
was dried under high vacuum. Yield 251 mg, 87.7%. 1H NMR (CDCl3) d 3.15
(3H, m), 3.41 (1H, dd, J ¼ 15.0, 10.5 Hz), 3.70 (3H, s), 3.79 (1H, t,
J ¼ 7.2 Hz), 7.08–7.17 (8H, m), 7.19–7.28 (4H, m), 7.35 (1H, td, J ¼ 7.3,
1.2 Hz), 7.45 (2H, m), 7.54 (1H, m), 7.87 (1H, d, J ¼ 7.8 Hz), 7.91 (1H, d,
J ¼ 7.5 Hz); ESJ-MS 538 (M þ Na)þ, 516 (M þ 1)þ.
(S)-3-Dibenzofuran-3-yl-2-[phosphonomethylamino]-
propionic Acid (IX)
Compound VIII (85 mg, 0.17 mmol) was suspended in a solution of
AcOH (1.0 mL) and 9 N HCl (3 mL) at r.t. The mixture was heated at 1008C
for 2 hr, then cooled by adding ice cold water (4 mL). The solid thus produced
was filtered and washed sequentially with water and ether. The residue
(57.12 mg, 0.68 mmol) was by neutralized with an aqueous solution of
NaHCO3, and the aqueous phase extracted with ethyl acetate. The aqueous
phase was neutralized with by dropwise addition of 2 N HCl. A white
precipitate formed which was washed with 3 Â 15 mL of water. The residue
was suspended in 10 mL of water and heated at 708C 1 hr, and then cooled and
filtered. After washing with cold water (10 mL), the white solid was dried
under high vacuum overnight. The crude IX was judged to be pure by optical
and spectroscopic analysis. Yield ¼ 55 mg, 95.5%. 1H NMR (DMSO-d6,

ORDER
REPRINTS
782
Fauq, Khan, and Eckman
TFA) d 3.35 (3H, m), 3.55 (1H, m), 4.46 (1H, m), 7.35 (1H, d, J ¼ 7.8 Hz),
7.43 (1H, t, J ¼ 7.5 Hz), 7.55 (1H, t, J ¼ 7.8 Hz), 7.70 (3H, m), 8.12 (2H, m);
ESI-MS (neg. mode) 360 (M 2 1); [a]2D5 (trisodium salt) þ20.48, c 2.35 mg/
mL, pH 12. The diastereomeric mixture with (R)(þ)1(1-naphthyl)ethylamine
in CD3OD showed a singlet at 3.72 ppm, indicating at least 98% ee; 31P NMR
(242.94 MHz, DMSO-d6 þ TFA, (1 : 1) d 11.30 (t, J ¼ 14 Hz).
ACKNOWLEDGMENT
Mayo Foundation’s research support is gratefully acknowledged.
REFERENCES
1. Yanagisawa, M.; Kurihara, S.; Kimura, S.; Tomobe, Y.; Kobayashi, M.;
Mitsui, Y.; Goto, K.; Masaki, T. Nature 1988, 322, 411–419.
2. Lago, M.A.; Luengo, J.I.; Peishoff, C.E.; Elliott, J.D. Annu. Rep. Med.
Chem. 1996, 31, 81–90.
3. Turner, A.J.; Murphy, L. Biochem. Pharmacol. 1996, 51, 91–102.
4. (a) Roques, B.P. Pathol. Biol. 1998, 46, 191–200; (b) Trapani, A.J.;
Beil, M.E.; Bruseo, C.W.; De Lombaert, S.; Jeng, A.Y. J. Cardiovasc.
Pharmacol. 2000, 36 (5 Suppl. 1), S40–3; (c) Battistini, B.; Ayach, B.;
Molez, S.; Blouin, A.; Jeng, A.Y. Clinical Science 2002, 103 (Suppl. 48),
363S–366S (printed in Great Britain).
5. Lombaert, S.D.; Blanchard, L.; Stamford, L.B.; Tan, J.; Wallace, E.M.;
Sato, Y.; Fit, J.; Hoyer, D.; Simonsbergen, B.; Moliterni, J.; Marco-
poulos, N.; Savage, P.; Chou, M.; Trapani, A.J.; Jeng, A.Y. J. Med. Chem.
2000, 43, 488–504.
6. Akermark, B.; Eberson, L.; Johnson, E.; Pettersson, E. J. Org. Chem. 1975,
40, 1365–1367.
7. Schollkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl. 1981, 20,
789–799.
8. (a) Fauq, A.H.; Hong, F.; Cusak, B.; Tyler, B.M.; Pang, Y.-P.; Richelson.
Teterahedron-Assymmetr 1998, 4127–4134; (b) Fauq, A.H.; Ziani-
Cherif, C.; Richelson, E. Teterahedron-Assymmetr 1998, 2333–4138.
9. Still, W.C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
Received in the USA August 28, 2003

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
Fair Use in the Classroom.
(AAP) website for guidelines on
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our
Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120028350