Synthesis and biological activity of some known and putative duloxetine metabolites

Article abstract of DOI:10.1016/j.bmcl.2004.04.066

Several putative phase I duloxetine metabolites, 4-hydroxy-, 5-hydroxy-, 6-hydroxy-, 5-hydroxy-6-methoxy-, 6-hydroxy-5-methoxy-, 5,6-dihydroxy-, and 4,6-dihydroxyduloxetine were synthesized, and their phase II metabolite as glucuronide or sulfate conjugates were also synthesized. Their in vitro binding activities were compared to that of parent compound duloxetine.

Full text of DOI:10.1016/j.bmcl.2004.04.066

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3481–3486
Synthesis and biological activity of some known and putative
duloxetine metabolites
F. Kuo,* T. A. Gillespie, P. Kulanthaivel, R. J. Lantz, T. W. Ma, D. L. Nelson,
P. G. Threlkeld, W. J. Wheeler, P. Yi and M. Zmijewski
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 USA
Received 20 March 2004; accepted 19 April 2004
Available online
Abstract—Several putative phase I duloxetine metabolites, 4-hydroxy-, 5-hydroxy-, 6-hydroxy-, 5-hydroxy-6-methoxy-, 6-hydroxy-
5-methoxy-, 5,6-dihydroxy-, and 4,6-dihydroxyduloxetine were synthesized, and their phase II metabolite as glucuronide or sulfate
conjugates were also synthesized. Their in vitro binding activities were compared to that of parent compound duloxetine.
Ó 2004 Elsevier Ltd. All rights reserved.
NHCH3
1. Introduction
CO2H
7
O
OH
8
Duloxetine HCl (1, (S)-N-methyl-3-(1-naphthalenyl-
oxy)-2-thiophenepropanamine hydrochloride) is
H
Glu =
R6
S
O
6
a
1
HO
2
5
potent and balanced dual reuptake inhibitor of norepi-
nephrine and serotonin1 that has been shown to be
effective for the treatment of depression2 and stress
urinary incontinence.3 Duloxetine undergoes substantial
oxidative metabolism followed by conjugation. During
the development of duloxetine, 1, several of the meta-
bolites (both primary and secondary) have been tenta-
tively identified (Fig. 1) by LC–MS.4 The major
biotransformation pathways involved oxidation of the
naphthyl ring at either 4-, 5-, or 6-positions followed by
further oxidation, methylation, and/or conjugation. The
proposed major metabolites found in plasma were
4-hydroxyduloxetine (2), 6-hydroxy-5-methoxyduloxe-
tine (7), 4,6-dihydroxyduloxetine (9) and the sulfate
conjugate of 5-hydroxy-6-methoxyduloxetine (12). In
order to confirm the structures of these and other
putative metabolites, it was necessary to prepare
authentic samples of each of them for use as compara-
tors. In the course of these studies, the metabolites were
also evaluated in vitro for their ability to inhibit radio-
ligand binding to the transporters of serotonin (5HT),
norepinephrine (NE), and dopamine (DA).
R5
OH
4
3
R4
1. R4 = R5 = R6 = H
10. R4 = OGlu; R5 = R6= H
11. R4 = R5= H; R6 = OGlu
12. R4 = H; R5= OSO3-, R6 = OCH3
13. R4 = H; R5 = OGlu; R6 = OCH3
14. R4 = H; R5 = OCH3; R6 = OGlu
15. R4 = H; R5 = OH; R6 = OGlu
or R5 = OGlu; R6 = OH
2. R4 = OH; R5 = R6 = H
3. R4 = R5 = H; R6 = OH
4. R4 = R6 = H; R5 = OH
5. R4 = H; R5 = R6 = OH
6. R4 = H; R5 = OH, R6 = OCH3
7. R4 = H; R5 = OCH3; R6 = OH
8. C5, C6 dihydro analog of 5
9. R4 = R6 = OH; R5 = H
16. R4 = OGlu; R5 = H; R6 = OH
or R4 = OH; R5 = H; R6 = OGlu
Figure 1.
2. Discussion
2.1. Chemistry
2.1.1. Synthesis of 1-fluoronaphthols, key intermediates
for the synthesis of phase I metabolites. Carbon-14
labeled duloxetine (R1 ¼ R2 ¼ R3 ¼ H) was synthesized
previously in this laboratory.5 The product was obtained
by condensing a carbon-14 labeled thiophene side chain
17 with 1-fluoronaphthalene. It was postulated that the
metabolites could be synthesized with the same man-
ner by reaction of the substituted 1-fluoronaphthols,
* Corresponding author. E-mail: kuo_fengjiun@lilly.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.066

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F. Kuo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3481–3486
18.2–18.9, with the thiophene side chain. The initial
object was to prepare these 1-fluoronapthols.
The hydroxy group on 1-fluoronaphth-6-ol, 18.3, was
protected as a methyl ether. The resulting 1-fluoro-6-
methoxynaphthalene 22 was then formylated as
described above. The formylation occurred exclusively
at the C-5 position.8 This aldehyde was then converted
to the corresponding 1-fluoro-6-methoxynaphth-5-ol,
18.6, by following the reactions shown in the previous
reaction scheme.
F
R6
NHCH3
NHCH3
R4 R5
S
H
S
O
H
18.2. R4 = OH, R5 = R6 = H
OH
Alternatively, the hydroxy group on 1-fluoronaphth-
6-ol was protected as an isopropyl ether, 23. Repeating
the steps shown above in the preparation of 18.2, yielded
1-fluoro-6-isopropyloxynaphth-5-ol (24). The 5-hydrox-
yl group was then protected as a methyl ether, and the
isopropyl ether was cleaved selectively with BCl3 at 0 °C
to give 1-fluoro-5-methoxynaphth-6-ol, 18.7, in good
overall yield.
18.3. R4 = R5 = H, R6 = OH
18.4. R4 = R6 = H, R5 = OH
18.5. R4 = H, R5 = R6 = OH
17
R6
18.6. R4 = H, R5 = OH, R6= OMe
18.7. R4= H, R5= OMe, R6= OH
R4 R5
18.8. C5,C6-dihydro analog of 18.5.
18.9. R4 = R6 = OH, R5 = H
2-9
The first two compounds, 1-fluoronaphth-6-ol, 18.3, and
1-fluoronaphth-5-ol, 18.4, were synthesized from com-
mercially available 1-aminonaphth-6-ol, 19a, and
1-aminonaphth-5-ol, 19b, using a modified Schiemann
reaction.6 The diazonium tetrafluoroborate intermedi-
ate, 20, was isolated and dried. The dried powder was
then heated in decahydronaphthalene at 160 °C to give
the desired fluoronaphthols, 18.3 and 18.4.
Treatment of 1-fluoronaphth-6-ol 18.3 with benzene-
seleninic anhydride9 in THF gave 5-fluoro-1,2-naphtho-
quinone 25 as a red-orange solid in 65% yield. The same
naphthoquinone was also obtained by reacting with
Fremy’s salt, (KSO3)2NO, but in a lower yield. The
-
N2+ BF4
F
NH2
heat
NaNO2
HBF4
R6
R6
R6
R5
R5
R5
18.3, R5 = H, R6 = OH
18.4 R5 = OH, R6= H
20
19a, R5 = H, R6 = OH
19b, R5 = OH, R6 = H
The 1-fluoronaphth-4-ol, 18.2, was synthesized from the
commercially available 1-fluoro-naphthalene, 18. Com-
pound 18 was formylated by stirring with 1,1-dichloro-
methyl methyl ether and SnCl4 at 0 °C in methylene
chloride to give 4-fluoro-1-naphthaldehyde, 21.7 Baeyer
Villiger rearrangement followed by saponification of the
corresponding formate gave the desired product 18.2 in
good overall yield.
naphthoquinone 25 was dissolved in ethanol and stirred
with sodium borohydride under an oxygen atmosphere
at room temperature to give the desired product, 18.8, in
35% isolated yield. 5,6-Dihydroxynaphthalene (18.5),
was a by-product of the reaction, but oxidized back to
naphthoquinone, which was subsequently reduced by
sodium borohydride. This cycle was repeated until the
naphthoquinone color was no longer detected.
Demethylation
of
1-fluoro-6-methoxynaphth-5-ol
(18.6), with BCl3 at room temperature yielded 1-fluoro-
5,6-dihydroxynaphthalene (18.5).
F
F
F
a. Cl2CHOCH3
SnCl4
b. m-CPBA
c. NaOH
The compound 1-fluoro-4-6-dihydroxynaphthalene
(18.9) was synthesized from the commercially available
1,7-dihydroxynaphthalene (26).10 The dihydroxy groups
were protected as methyl ethers by treatment with
methyl sulfate in aqueous KOH. Direct nitration with
OH
CHO
18
21
18.2
F
F
F
a,b,c
d. CH3I
OCH3
O-i-Pr
OCH3
F
base
OH
22
23
18.6
F
F
i-PrI
base
OH
d.
a,b,c
18.3
e. BCl3
CH2Cl2
0oC
OH
OCH3
O-i-Pr
OH
24
18.7

F. Kuo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3481–3486
3483
F
F
F
F
(KSO3)2NO
NaBH4
EtOH
+
or
OH
OH
O
OH
(PhSeO)2O
OH
18.8
O
OH
18.5
18.3
25
Oxygen
20% aqueous HNO3 in benzene at room temperature
gave C4 and C8-nitro isomers in 3:2 ratio as determined
by proton NMR. Recrystallization from hot methanol
gave pure 4,6-dimethoxy-1-nitronaphthalene. Alterna-
tively, chromatography (SiO2, 9:1 to 4:1 hexanes/meth-
ylene chloride) separated two isomers. The nitro group
was reduced by hydrogenation (5% Pd/C, EtOH/THF at
60 °C), and the resulting 1-amino-4,6-dimethoxy-naph-
thalene (27) was converted to 1-fluoro-4,6-dimethoxy-
naphthalene (28) by a modified Schiemann reaction in
low yield (17%). Presumably, as observed in the earlier
examples, the oxygen-containing electron-rich groups
on the naphthalene ring stabilized the cationic reaction
center, and made it less likely to accept an incoming
nucleophilic fluoride anion. Demethylation of 28 by
BBr3 at room temperature gave the desired 1-fluoro-4,6-
dihydroxynaphthalene (18.9) in good yield.
Without isolation, the reaction mixture was concen-
trated, and the crude naphthalene ketal condensed
directly with the thiophene side chain 33. The crude
reaction solution was then treated with an excess of 20%
acetic acid at room temperature to cleave the ketal
protective group. Chromatography gave the desired
product 4. The same process was then applied to the
synthesis of other metabolites. Compounds 2, 3, 4, 7,
and 9 were isolated in a reasonable yield. Low yield was
obtained when 18.6 was used, possibly due to steric
hindrance. When a less sterically demanding protecting
group (the acetal from ethyl vinyl ether) was employed,
the overall yield of 6 was greatly improved. Attempts to
prepare 8 from ketal protected 18.8 gave a mixture of
products in low yield. Fluoronaphthol 18.5 could not be
protected as a vicinal-ketal or a vicinal-acetal due to
steric hindrance. Treatment of 18.5 with trimethyl ortho-
F
NH2
a. (CH3)2SO4
d. NaNO2, HBF4
b. HNO3
OH
e. heat
OR
OCH3
c. H2, Pd/C
OH
OR
OCH3
26
27
28, R = CH3
18.9, R = H
f. BBr3
To improve the yield for the synthesis of 1-fluoro-4,6-
dimethoxy-naphthalene (28), a new approach using an
electrophilic fluorinating agent was designed. Bromina-
tion of 1,7-dimethoxynaphthalene (30) with NBS gave
mainly 4-bromo-dimethoxynaphthalene (31), with a
small amount of 8-bromo isomer. Bromo-lithium
exchange of the crude bromide followed by electrophilic
fluorination with N-fluorobenzenesulfonimide gave the
desired product 28 in 58% yield, together with formation
of 30 in 18% yield, presumably from an electron transfer
mechanism.11 Failure to degas the reaction system led to
formation of a reddish orange solid, presumably the
para-naphthoquinone.
formate gave a cyclic ortho-formate 35. After conden-
sation with 33, the desired product was isolated as a
cyclic ortho-formate and hydrolyzed to yield 5, which
was analyzed and identified by LC–MS.
Compound 5 was then stirred under oxygen atmosphere
in the presence of large excess of sodium borohydride in
ethanol to yield two diastereomers of compound 8. At-
tempted synthesis of 5 from 3 or 4 failed.
2.1.3. Synthesis of phase II metabolites: glucuronide
conjugates. Treatment of 2 (4-hydroxy-duloxetine) with
F
Br
a. NBS
b. n-BuLi
30 (18%)
+
c. (PhSO2)2NF
OR6
OCH3
OCH3
OCH3
OR4
OCH3
30
31
28 (58%)
2.1.2. Synthesis of phase I metabolites. To synthesize the
phase I metabolites by following the same manner as for
duloxetine, compound 18.4 was protected as a ketal
(32), which was partially hydrolyzed on the TLC plate.12
36 and LiOH in methanol at room temperature13 gave
the conjugate 37. Saponification with excess of LiOH in
aqueous methanol gave 10, which was identical to the
metabolite as confirmed by LC–MS. Conjugates 11, 13,

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F. Kuo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3481–3486
NHCH3
NHCH3
NHCH3
c. 20% aq.
HOAc
b.NaH, DMF
S
S
S
H
O
H
O
H
32
HO
33
R6
R4 R5
OC(CH3)2OCH3
21g
2, R4 = OH, R5 = R6 = H
3, R4 = R5 = H, R6 = OH
4, R4 = R6 = H, R5 = OH
5, R5 = R6 = OH, R4 = H
6, R4 = H, R5 = OH, R6 = OMe
7, R4 = H, R5 = OMe, R6 = OH
9, R4 = R6 = OH, R5 = H
F
OC(CH3)2OCH3
32
a. 2-methoxypropene
cat. PPTs, rt
R6 = H
F
F
NHCH3
b. NaH, DMF
d. ethyl vinyl ether
cat. PPTs, rt
S
H
O
33
R6
OCH3
c. 20% aq.
OCH(CH3)OEt HOAc
R6 = OCH3
OH
OCH3
18.4, R6 = H
18.6, R6 = OCH3
OH
6
F
F
NHCH3
a.HC(OCH3)3
cat PPTs
b. NaH, DMF, 33
S
H
O
c. 20% aq. HOAc
HCO2H
OH
O
O
OH
18.5
H OCH3
OH
OH
35
5
d. NaBH4, EOH
O2
F
e. bis-ketal formation
b. NaH, DMF, 33
NHCH3
S
H
O
c. 20% aq. HOAc,
HCO2H
OH
OH
18.8
OH
OH
8
and 14 were also synthesized by this method. Glucuro-
nide conjugate 15 was prepared from compound 5
(R4 ¼ H, R5 ¼ R6 ¼ OH) as above as a mixture, but
neither compound matched the LC–MS profiles of the
metabolite. Further evaluation of data suggested that it
may be a phase II glucuronide conjugate of 4,6-
dihydroxyduloxetine. 1-Fluoro-4,6-dihydroxynaphtha-
lene 18.9 was prepared as described in Section 2.1 of the
paper, and the phase I metabolite was synthesized as
above using a bis-acetal protecting group. As observed
for 5,6-dihydroxyduloxetine, 5, the free base 4,6-di-
hydroxyduloxetine, 9, was not very stable. To minimize
problems, bioconversion of 9 to the phase II glucuronide
conjugate 16 was conducted using Actinoplanes missou-
riensis. Two major products, presumably C4-OGlu and
C6-OGlu, were detected by LC–MS. One of the reaction

F. Kuo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3481–3486
3485
products matched with the metabolite. The material was
isolated by HPLC and its structure was confirmed by
proton NMR to be the 4-OH-glucuronide conjugate 16.
used), respectively, in membranes expressing the human
monoamine transporters. Membranes expressing human
5HT transporters (HST), human NE transporters
NHCH3
NHCH3
NHCH3
S
S
S
H
H
O
O
H
O
O
O
a. LiOH, CH3OH
b. aq. LiOH
CH3OH
36
CH3O2C
HO2C
R6
O
O
R4 R5
OH
OH
HO
HO
OH
2. R5 = R6 = H;
R4 = OH
OH
37
10
3. R4 = R5 = H, R6 = OH
11. R6 = OGlu, R4= R5 = H
CH3O2C
6. R4 = H, R5 = OH, R6 = OCH3
7. R4 = H, R5 = OCH3, R6 = OH
9. R4 = R6 = OH, R5 = H
13. R4 = H, R5 = OGlu, R6 = OCH3
14. R4 = H, R5 = OCH3, R6 = OGlu
16. R4 = OGlu, R5 = H, R6 = OH
O
OAc
AcO
Br
OAc
36
2.1.4. Synthesis of phase II metabolites: sulfate conju-
gates.14;15 The sulfate conjugate of 12 was prepared in
good yield with trimethylamine (or pyridine) sulfur tri-
oxide complex. The synthesis was accomplished by:
(a) protection of the amino group with allyl chloro
formate to yield 38, (b) conjugate formation using tri-
methylamine sulfur trioxide complex, (c) de-protection
by hydrogenolysis with palladium reagent.
(HNET), and human DA transporters (HDAT) were
obtained from Receptor Biology, Inc. (Beltsville, MD).
Using these membranes, the following radioligand
3
assays were performed: H-paroxetine (0.2 nM) for the
3
3
HST, H-nisoxetine (1.0 nM) for the HNET, and H-
3
mazindol (or H-WIN35,428) (1.0 nM) for the HDAT.
Assays for duloxetine (for the active metabolites,
duplicate assays were performed and for all others, a
NHAloc
OCH3
NHCH3
NHCH3
S
S
S
H
O
H
H
O
O
a.C3H5OCO2Cl
Et3N, CH2Cl2
b. NaH, DMF
(CH3)3N.SO3
c. Pdo, Et2NH
OCH3
OSO3- Na+
OCH3
OH
38
OH
12
6
2.2. In vitro pharmacology
single assay was performed) were performed in triplicate
in a final volume of 0.8 mL containing the following
components: 0.2 mL drug (0.1–10,000 nM), 0.2 mL
radioligand, 0.2 mL membrane suspension (10 mg/mL,
HST; 17 mg/mL, HNET; 7 mg/mL HDAT), and 0.2 mL
reaction media (50 mM TrisCl pH 7.4, 150 mM NaCl,
5 mM KCl for HST and HNET; 50 mM TrisCl pH 7.4,
Duloxetine and its putative metabolites were evaluated
for their ability to inhibit radioligand binding to the
transporters of serotonin (5HT), norepinephrine (NE),
and dopamine (DA) using 3H-paroxetine, 3H-nisoxetine,
and 3H-mazindol (for duloxetine, 3H-WIN35428 was
Table 1. [3H]-Radioligand binding to membranes expressing cloned human transporters
Compound
3H-Paroxetine 5HT, Ki, nM
3H-Nisoxetine NE, Ki, nM
3H-Mazindol DA, Ki, nM
1 (Duloxetine)
2 (4-Hydroxyduloxetine)
0.79 0.039
63.9 (57.3, 70.6)
1.06 (0.86, 1.25)
9.6 (10.1, 9.1)
266
7.45 0.32
97.1 (88.1, 106)
4.72 (4.67, 4.77)
18.4 (17.9, 18.9)
920
240 23.1a
130 (150, 110)
163.5 (124, 203)
240.5 (240, 241)
2814
3 (6-Hydroxyduloxetine)
4 (5-Hydroxyduloxetine)
6 (5-Hydroxy-6-methoxyduloxetine)
7 (6-Hydroxy-5-methoxyduloxetine)
8a (Duloxetine-5,6-diol I)
3.66 (3.48, 3.84)
120
31.7
235.5 (315, 156)
695
554
353 (503, 203)
7275
>10,000
8b (Duloxetine-5,6-diol II)
10 (4-Hydroxyduloxetine glucuronide)
11 (6-Hydroxyduloxetine glucuronide)
12 (5-Hydroxy-6-methoxyduloxetine sulfate)
13 (5-Hydroxy-6-methoxyduloxetine glucuronide)
15 (5,6-Dihydroxyduloxetine glucuronide)
>10,000
1459
>10,000
5454
3509
>10,000
3118
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
a Ki value obtained with another dopamine transporter (ligand WIN35428).

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F. Kuo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3481–3486
100 mM NaCl for HDAT). Incubations (40 min at 37 °C
for HST; 30 min at 25 °C for HNET and HDAT) were
terminated by rapid vacuum filtration over Whatman
GF/B filters (presoaked in 0.5% polyethylenimine) and
washed four times with cold Tris–HCl pH 7.4. Non-
specific binding was determined by including separate
samples of 1 lM duloxetine (HST), 10 lM desipramine
(HNET), and 10 lM nomifensin (HDAT).
References and notes
1. Bymaster, F. P.; Beedle, E. E.; Findlay, J.; Gallagher,
P. T.; Krushinski, J. H.; Mitchell, S.; Robertson, D. W.;
Thompson, D. C.; Wallace, L.; Wong, D. T. Bioorg. Med.
Chem. Lett. 2003, 13, 4477–4480.
2. Detke, M. J.; Lu, Y.; Goldstein, D. J.; Hayes, J. R.;
Demitrack, M. A. J. Clin. Psy. 2002, 63, 308–315.
3. Norton, P. A.; Zinner, N. R.; Yalein, I.; Bump, R. C. Am.
J. Obstet. Gynecol. 2002, 187, 40–80.
Inhibition curves were analyzed by nonlinear least
squares curve fitting to obtain IC50 values. The Ki values
were calculated from IC50 and Kd values according to
the method of Cheng and Prusoff.16
4. Lantz, R. J.; Gillespie, T. A.; Rash, T. J.; Kuo, F.;
Skinner, M.; Kuan, H.-Y.; Knadler, M. P. Drug Dispos.
Metab. 2003, 31, 1142–1150.
5. Wheeler, W. J.; Kuo, F. J. Labelled Compd. Radiopharm.
1995, 36, 213.
6. Adcock, W.; Alste, J.; Rizvi, S. Q. A.; Aurangzeb, M.
J. Am. Chem. Soc. 1976, 98, 1701; Adcock, W.; Dewar,
M. J. S. J. Am. Chem. Soc. 1967, 89, 386.
7. Boswell, G. E.; Licause, J. F. J. Org. Chem. 1995, 60,
6592.
8. Ishii, H.; Hanaoka, T.; Asaka, T.; Harada, Y.; Ikeda, N.
Tetrahedron 1976, 32, 2693; Harvey, R. G.; Pakaki, J.;
Lee, H. J. Org. Chem. 1986, 51, 1407.
9. Sukumaran, K. B.; Harvey, R. G. J. Am. Chem. Soc. 1979,
101, 1353; Barton, D. H. R. et al. J. C. S. Chem. Commun.
1976, 985.
10. 1,7-Dihydroxynaphthalene was purchased from Fluka,
catalog no. 37750.
11. Sankar, G.; Pez, G. P.; Syvert, R. G. Chem. Rev. 1996, 96,
1737–1755, and references cited therein.
12. For the selection of protective groups used in this study,
see: Greene, T. Protective Groups Org. Synth. and the
references therein.
13. Berrang, B.; Twine, C. E.; Hennessee, G. L.; Carroll, F. I.
Synth. Commun. 1975, 231.
The in vitro results are tabulated in Table 1. In HST and
HNET membranes, duloxetine potently inhibited the
binding of 3H-paroxetine and 3H-nisoxetine with Ki
values of 0.79 nM and 7.45 nM, respectively. In HDAT
membranes, duloxetine was a relatively weak inhibitor
of 3H-WIN 35,428 binding, yielding a Ki value of
240 nM. Compounds 3 and 4 were also potent inhibitors
at HST and HNET and had low affinity for HDAT.
3
Compound 7 inhibited H-paroxetine binding to HST
with a Ki value of 3.66 nM but showed low affinities for
HNET and HDAT. Compound 2 had moderate to weak
activity in all of the membranes. The secondary
metabolites tested (10, 11, 12, 13, 15) were devoid of any
significant binding to any of the three transporters.
Acknowledgements
The authors would like to thank Dr. Barry Peterson for
his suggestion to use ketal as the protective group, and
members of Dr. J. McGill’s group for providing the
naphthalenes 18.3, the formate ester of 18.6 and the side
chain 33 during the late stage of the studies.
14. Hardy, W. B.; Scalera, M. J. Am. Chem. Soc. 1952, 74,
5212.
15. Overman, L. E. et al. J. Am. Chem. Soc. 1999, 121, 12206.
16. Cheng, Y. C.; Prusoff, W. H. Biochem. Pharmacol. 1973,
22, 3099–3108.