De novo synthesis of teleocidin B analogs

Article abstract of DOI:10.1016/j.tet.2010.01.048

Teleocidin B analogs have been synthesized in 24 steps and 1.9% overall yield. The key steps include aromatic Claisen rearrangement, intramolecular Heck reaction of a tetra-substituted alkene, and ruthenium (II) catalyzed indole cyclization. Teleocidin an

Full text of DOI:10.1016/j.tet.2010.01.048

Tetrahedron 66 (2010) 1963–1972
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
De novo synthesis of teleocidin B analogs
Jun Pu a, Kangwen Deng b, John Butera a, Michael Chlenov a, Adam Gilbert a, Mike Kagan a,
,
James Mattes a, Lynn Resnick a
*
a Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
b Neuroscience Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Teleocidin B analogs have been synthesized in 24 steps and 1.9% overall yield. The key steps include
aromatic Claisen rearrangement, intramolecular Heck reaction of a tetra-substituted alkene, and ru-
thenium (II) catalyzed indole cyclization. Teleocidin and the new analogs promote cell spreading on fi-
broblast cells that were treated with amino-Nogo, an inhibitor of cell spreading.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 October 2009
Received in revised form
22 December 2009
Accepted 8 January 2010
Available online 18 January 2010
Keywords:
Teleocidin B
Intramolecular Heck reaction
Claisen rearrangement
Ruthenium catalyzed indole cyclization
O
H
1. Introduction
O
H
N
N
OH
12
19
N
9
N
OH
Teleocidins B 1–4 (1a–d), natural products that were isolated
from the Mycelia of Streptomyces mediocidicus,1 are potent tumor
promoters.2 They belong to a family of tumor promoters, repre-
sented by 12-O-teteadecanoylphorbol 13 acetate (TPA), that bind to
and activate a group of kinase receptors, including protein kinase C
and D (PKC and PKD).3 Recently, we have found that teleocidin B and
TPA reverse the inhibitory cell spreading effect of the myelin-asso-
ciated inhibitor, NogoA, and do so through activation of PKD.4
Additionally, teleocidin B stimulates neurite outgrowth of cerebellar
neurons that were treated with Nogo. The newly discovered
biological activities of teleocidin B sparked our interest in the
synthesis of teleocidin B analogs.
N
25
H
N
H
1a teleocidin B-1 (19 R, 25 S)
1b teleocidin B-2 (19 S, 25 R)
1c teleocidin B-3 (19 S, 25 S)
1d teleocidin B-4 (19 R, 25 R)
2 indolactam V (IL-V)
Figure 1. Structures of teleocidins B (1–4) and indolactam V (IL-V).
Teleocidin B is a mixture of four stereoisomers, teleocidin B-1
(1a), teleocidin B-2 (1b), teleocidin B-3 (1c), and teleocidin B-4 (1d)
(Fig. 1).5 It is an indolactam-based alkaloid that possesses the nine-
membered ring lactam, (ꢀ)-indolactam V (IL-V, 2) fused to a six-
membered cyclic monoterpenoid with quaternary carbon centers
at positions C-25 and C-19.
Friedel–Crafts type of cyclization to form the C-25 quaternary
center of the six-membered ring. However, the strong acidic con-
ditions caused undesired side reactions and low yields. Alterna-
tively, Tanner et al.7 envisioned the utilization of an intramolecular
Heck reaction (IHR) to form the C-25 quaternary carbon. However,
Several groups have pursued the synthesis of teleocidin B.6 Total
syntheses of (ꢁ)-teleocidins B-3 and B-4 have been accomplished
by Nakatsuka et al. in 19876d and Okabe et al. in 1991.6j A key re-
action that was used in both of these syntheses is an acid-mediated
CO2Et
CO2Et
N
H
N
H
TfO
IHR
3
4
* Corresponding author.
E-mail address: resnicl@wyeth.com (L. Resnick).
Scheme 1. Tanner’s model study of intramolecular Heck reaction (IHR).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.048

1964
J. Pu et al. / Tetrahedron 66 (2010) 1963–1972
in the model study, it was found that cyclization with triflate 3
provided cyclopentadieno-indole 4 (Scheme 1), the result of the
reaction proceeding in a 5-endo-trig manner with the less sterically
hindered terminal alkene.
We rationalized that the intramolecular Heck reaction would
providethedesiredsix-memberedringproductbyreplacementofthe
terminal alkene with a methyl group. Such a change in functionality
would lead, eventually, to dimethyl teleocidin analog 5 (Fig. 2).
Since there are few examples of an intramolecular Heck reaction
with
highly sterically hindered tetra-substituted alkene,13
a
a model study was initiated to explore and optimize cyclization
conditions. In this regard, compound 18 was prepared as a simpli-
fied cyclization substrate compared to intermediate 11. Thus,
treatment of commercially available 2-allylphenol (15) with tert-
butyldimethylsilyl chloride (TBSCl) afforded compound 16 in good
yield (Scheme 3). A hydroboration–Suzuki protocol11 provided side
chain extension and desilylation to give phenol 17, which was
subsequently converted to triflate 18 in excellent yield.
O
H
N
N
OH
TfO
IHR
b
a
TBSO
HO
RO
N
24
H
19
17 R=H
18 R=Tf
c
5
15
16
Figure 2. Structure of target teleocidin B analog 5.
Scheme 3. Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2, rt, 16 h, 90%. (b) i. 9-
BBN, THF, 0 ꢂC to rt, 4 h. ii. PdCl2(dppf)2, 3 M NaOH (3 equiv), 2-bromo-3-methyl-but-
2-ene, 60 ꢂC, 16 h, 70% for two steps. (c) Tf2O, triethylamine, CH2Cl2, 0 ꢂC to rt, 2 h, 90%.
We predicted that analog 5 would possess similar biological
activity to teleocidin B based on the activities of reported analogs.8
In particular, tetramethyl 8,9 a teleocidin analog without the ter-
minal alkene has been shown to possess comparable PKC binding
activity to teleocidin B. The core structure, IL-V (2) is essential for
PKC binding and alkyl substituents at either the C-6 (6) or C-7 (7)
positions of the indole nucleus have increased potency compared to
the unsubstituted IL-V (2) (Fig. 3).
We then examined the IHR cyclization to convert triflate 18 to
tetrahydronaphthalene 20 (Table 1). In our first attempt at the cy-
clization, substrate 18, with 10% Pd(OAc)2, 20% rac-BINAP, and
K2CO3 was heated in THF at 70 ꢂC. However, no reaction took place
(entry 1). It was realized that a higher temperature may be required
to initiate the reaction. Therefore, the solvent was changed to DMF
and the reaction was heated to 90 ꢂC. In this case, compound 19, the
product of reduction of the triflate, was isolated as the single
product in 72% yield (entry 2). Fortunately, when N,N-dimethyl-
acetamide (DMA) was used as the solvent and the reaction mixture
was heated to 120 ꢂC, cyclization product 20 was obtained in 82%
yield (entry 3). These results demonstrate that solvent and tem-
perature play a pivotal role in the cyclization reaction. Next, the
reaction conditions were optimized by lowering catalyst loading
from 10% to 5% Pd(OAc)2 (entry 4), which gave comparable yields.
O
O
H
N
H
N
N
OH
N
OH
R1
N
N
H
H
R2
6 R1 = alkyl, R2 = H
7 R1 = H, R2 = alkyl
8
Figure 3. Structures of teleocidin B analogs 6, 7, and 8.
Table 1
Reaction conditions for intramolecular Heck reaction of compound 18
2. Chemistry
Pd(OAc)2 (x mol%),
BINAPa, K2CO3,
We envisioned a synthetic route to make analog 5 that utilizes
tricyclic indole intermediate 9 whereby, the transformation to the
teleocidin scaffold can be prepared by methods described in the
literature.6,8 The 4-amino indole 9 could be synthesized from dihy-
dronaphthalene 10 in an analogous manner to that which was used
by Webb et al.9 Intermediate 10 could be made by the intramolecular
Heck reaction (IHR)10 from tetra-substituted alkene 11. Compound 11
could be made with a hydroboration–Suzuki protocol11 from 12,
which, in turn could be prepared from an aromatic Claisen rear-
rangement of ether 1312 (Scheme 2).
TfO
solvent
18
19
20
Entry
xa
Solvent
T (ꢂC)
Resultsb
1
2
3
4
10
10
10
5
THF
70
90
120
120
No reaction
19 (72%)c
20 (82%)c
20 (80%)c
DMF
DMA
DMA
a
NHR1
Pd(OAc)2/rac-BINAP, 1:2.
Isolated yield.
Only product detected.
b
c
TfO
5
N
H
With confidence that the integral IHR step will be successful, the
synthesis of analog 5 was initiated, starting with the preparation of
intermediate 26. Alkylation of 4-methylphenol (14) with 1-bromo-
3-methyl-but-2-ene afforded compound 1314 in excellent yield
(Scheme 4). Compound 13 underwent an aromatic Claisen rear-
rangement15 in N,N-dimethylaniline in the presence of acetic an-
hydride at 200 ꢂC, and crude acetate 21 was converted to phenol 22
by basic hydrolysis in 30–40% yield for two steps. Protection of
phenol 22 as the tert-butyldimethylsilyl (TBS) ether gave com-
pound 23. Alternatively, the thermally stable 1,1,1,3,3,3-hexa-
methyl-disilazane (HMDS)16 was used as the trapping reagent in
9
10
11
O
R2O
HO
12
13
14
Scheme 2. Retrosynthetic analysis of teleocidin B analog 5.

J. Pu et al. / Tetrahedron 66 (2010) 1963–1972
1965
d
TBSO
RO
b
23
21 R=Ac
c
O
a
f
22 R=H
HO
e
14
13
HO
f
TMSO
25
24
TfO
g
h
i
11
10
26
Scheme 4. Reagents and conditions: (a) 1-bromo-3-methyl-but-2-ene, K2CO3, acetone, 60 ꢂC, 16 h, 90%. (b) Ac2O, N,N-dimethylaniline, 200 ꢂC, 24 h. (c) KOH/MeOH, 40 ꢂC, 2 h; 30–
40% for two steps. (d) TBSCl, imidazole, CH2Cl2, rt, 16 h, 66%. (e) HMDS, N,N-dimethylaniline, 200 ꢂC, 24 h, 78%. (f) i. 9-BBN, THF, 0 ꢂC to rt, 4 h; ii. 2-bromo-3-methyl-but-2-ene,
PdCl2(dppf)2 (5 mol %), 3 M NaOH, 60 ꢂC, 16 h, 88% for two steps. (g) NaH, PhN(Tf)2, 0 ꢂC to rt, 2 h, 87%. (h) Pd(OAc)2 (5 mol %), BINAP, N,N-dimethylacetamide, K2CO3, 120 ꢂC, 16 h,
85%. (i) H2 (1 atm), Pd/C (10%), EtOH, 16 h, 90%.
the Claisen rearrangement instead of the thermally unstable acetic
anhydride. In this case, silyl ether 24 was obtained in one-step from
alkene 13 in 78% yield. Hydroboration of compounds 23 and 24
with 9-BBN followed by Suzuki coupling with 2-bromo-3-methyl-
but-2-ene afforded tetra-substituted alkene 25, whereby the silyl
group was also removed. Compound 25 was converted to triflate 11
in good yield. Cyclization of intermediate 11, under the optimized
intramolecular Heck reaction conditions, afforded tetrahydro-
naphthalene 10 as a single product in 90% yield. Catalytic hydro-
genation of alkene 10 provided intermediate 26 in good yield.
With key intermediate 26 in hand, a strategy analogous to that
which was developed by Webb et al.9 was used to convert this
compound to 4-amino indole 9. Thus, nitro groups were introduced
at the C-5 and C-7 positions of 26 by treatment with concentrated
nitric acid and sulfuric acid to provide dinitro 27 in excellent yield
(Scheme 5). Compound 27 was then treated with Triton-B and
paraformaldehyde to give 2-arylethanol 28 in 90% yield. The less
sterically hindered C-7 nitro group of 28 was reduced by transfer
hydrogenation17 (10% Pd/C, cyclohexene/ethanol, reflux) to provide
amine 29 in quantitative yield. Protection of 29 with benzyl car-
bamate (CBz) afforded compound 30. The C-5 nitro group was then
reduced to amine 31 with iron in acetic acid/ethanol18 in 95% yield.
Cyclization of intermediate 31 with a catalytic amount of tris
(triphenylphosphine) ruthenium (II) dichloride9,19 in refluxing
toluene furnished indole 9 in 90% yield.
The remaining steps of the synthesis required formation of the
lactam ring. Thus, reaction of indole 9 with ethyl (3-bromo-2-oxi-
mido)pyruvate (32; Gilchrist’s reagent20) gave oxime 33 in quan-
titative yield (Scheme 6). Reduction of oxime 33 with aluminum
amalgam in wet THF afforded an amine intermediate, which was
subsequently protected with Boc anhydride to provide compound
34. Removal of the CBz group in 34 by hydrogenation followed by
treatment of the resulting 4-aminoindole with triflate 35, a reagent
that was synthesized from D
-valine in three steps,6i provided (S)-N-
valylindole 36. The S-configuration at the C-12 stereocenter is
presumed due to the SN2 mechanism of the reaction with triflate
35, which would lead to inversion of stereochemistry. Following
removal of the benzyl group, the resulting carboxylic acid was
converted to the succinimide.21 Removal of the Boc group with TFA
followed by cyclization formed the nine-membered lactam in-
termediate 37, which was then N-methylated by reductive amina-
tion to afford compound 38 (21% yield in five steps). Reduction of
ester 38 with LiBH4 in THF provided the corresponding alcohol.
Flash chromatographic separation of diastereomers at this step
NH2
NO2
7
NO2
OH
OH
5
a
b
e
c
NO2
NO2
26
NO2
28
29
27
NHCBz
NHCBz
NHCBz
OH
OH
d
f
N
H
NH2
NO2
9
31
30
Scheme 5. Reagents and conditions: (a) HNO3, H2SO4, 1,2-dichloroethane, 0 ꢂC, 3 h, 92%. (b) Triton-B, HCHO, DMSO, rt, 16 h, 90%. (c) H2, Pd/C, cyclohexene, EtOH, 80 ꢂC, 4 h, 99%. (d)
CBzCl, aqueous NaHCO3, THF, rt, 16 h, 90%. (e) Fe/AcOH, EtOH, 80 ꢂC, 3 h, 95%. (f) RuCl2(PPh3)2 (5 mol %), toluene, 120 ꢂC, 16 h, 90%.

1966
J. Pu et al. / Tetrahedron 66 (2010) 1963–1972
CO2Et
CO2Et
NOH
(12S)
NH
CO2Et
O
a
CBzHN
CBzHN
b,c
d,e
9
NHBoc
NHBoc
BnO
NOH
(R)
N
H
N
H
Br
OEt
OBn
N
H
TfO
O
O
32
35
33
34
36
O
O
H
N
O
H
N
O
H
N
(9R)
H
N
(9S)
CO2Et
j
CO2Et
HN
N
N
N
OH
OH
f-i
k
+
N
N
H
N
N
H
H
H
37
38
5
39
Scheme 6. Reagents and conditions: (a) 32, Na2CO3, CH2Cl2, rt, 1 h, 97%. (b) Al(Hg), THF/H2O, rt, 16 h. (c) (Boc)2O, aqueous NaHCO3, THF, 16 h, 81% for two steps. (d) H2 (45 psi), Pd/C
(10%), EtOH, 4 h. (e) 35, 2,6-lutidine, 1,2-dichloroethane, 83 ꢂC, 12 h, 85% for two steps. (f) H2 (45 psi), Pd/C (10%), EtOH, 2 h. (g) HOSu, DCC, MeCN, 0 ꢂC to rt, 2 h. (h) TFA, CH2Cl2, 0 ꢂ
to rt, 2 h. (i) aqueous NaHCO3, EtOAc, 70 ꢂC, 3 h. (j) HCHO, NaBH(OAc)3, AcOH, 1,2-dichloroethane, rt, 12 h, 21% for five steps. (k) LiBH4, THF, 0 ꢂC to rt, 4 h, 56%.
C
gave two fractions in equal amount. We tentatively assigned one
fraction as compound 5, which possesses natural 9S stereocenter
and the other fraction as compound 39 with the epimeric 9R ster-
eocenter. Further separation of compound 5 by HPLC gave com-
pounds 40 and 41 in a ratio of 1:1.
Elucidation of the C-9 stereochemistry by NMR analysis proved
to be inconclusive. Therefore, our assignment of stereochemistry at
the C-9 position is made by comparison to literature examples. The
1H NMR spectra of diastereomers 40 and 41 indicate the presence of
two conformers in a 3:1 ratio, a feature typical of teleocidin systems
with 9S, 12S stereochemistry. It has been reported that the con-
formers are due to the cis (twist) and trans (sofa) configurations of
the amide, with the cis-amide being the predominant form. 6a,9,22 In
NOESY experiments with compounds 5, 40, and 41, a correlation
between the predominant H-8 and the predominant H-12 is ob-
served, a typical feature found in teleocidin systems. Alternatively,
the 1H NMR of compound 39 and its diastereomeic components
(data not shown) indicates a single conformer. A similar observa-
tion was made by Webb et al. with a 9R,12S analog of teleocidin.
From these observations, we postulated the stereochemical as-
signments of 5 and 39.9
The assignment of the stereochemistry at C-24 was postulated
from the NOE interaction between isopropyls at the C-12 and C-24
positions in compound 40, a correlation that clearly demonstrates
their syn relationship. Thus, the configuration at position 24 in 40
was defined as 24R and the configuration in 41 was determined to
be 24S (Fig. 4).
Figure 5. Cell spreading activity of compounds 5, 39, 40, and 41. NIH/3T3 cells were
seeded on Nogo substrate. (A) Fibroblast spreading assay was performed on Nogo
substrate with different concentrations of compounds
5 and 39; (B) fibroblast
spreading was performed on Nogo substrate without treatment (NT, white bar), with
teleocidin (tele, black bar), compound 5 (trellis bar), and three concentrations of
compounds 40 (striped bars) and 41 (confetti bars). Cells were fixed and stained for F-
actin. Cell area of each Hoechst positive cell was measured. Triplicate wells per
treatment in each experiment. Relative mean cell area combined from at least three
independent experiments is shown.
3. Biological activity
In a previous study, it was found that teleocidin B promotes cell
spreading on NIH/3T3 fibroblast cells that were treated with the
O
O
H
H
O
nOe
H
N
N
N
N
N
N
OH
OH
OH
H12
H12
H12
HPLC Separation
H8
+
H8
H8
N
N
N
nOe
nOe
24
nOe
H
H
H
5
40
41
Figure 4. Isolation and characterization of compounds 40 and 41.

J. Pu et al. / Tetrahedron 66 (2010) 1963–1972
1967
cell spreading inhibitor, Nogo.4 The EC50 value of this effect is
was added
a
solution of 9-BBN (0.5 M in THF, 31.2 mL,
4.3 nM. Compound 5 demonstrated comparable cell spreading ac-
tivity, with an EC50 value of 1.2 nM, whereas, diastereomer 39 was
much less potent (EC50¼2037 nM) (Fig. 5a). The activity of com-
pounds 40 and 41 is similar to their parent compound 5 and tele-
ocidin B extract (Fig. 5b). These results are in accordance with
literature reports that demonstrate that the 9S and 12S configura-
tions are crucial for the biological activity of teleocidin B (1a–d) and
its derivatives.8 Similarly, our analogs with 9S and 12S configura-
tion, mixture 5, and its components 40 and 41, are active, while
compound 39 with 9R, 12S stereocenters, shows significantly re-
duced activity. Additionally, it was found that the stereochemistry
at C-24 is irrelevant to its biological activity as is evident by the
similar activities of 40 and 41.
15.6 mmol) dropwise. The mixture was stirred at 0 ꢂC for
30 min. The ice-water bath was removed and the mixture was
stirred at room temperature for 5 h. Aqueous NaOH solution
(3 M, 12.0 mL, 36.0 mmol) was then added dropwise followed by
addition of 2-bromo-3-methyl-but-2-ene (2.2 mL, 18.0 mmol)
and PdCl2 (dppf)2 (0.47 g, 0.6 mmol). The mixture was stirred at
60 ꢂC under N2 for 16 h. The reaction mixture was cooled to
room temperature, diluted with ethyl acetate (100 mL), and
washed with water (100 mL). The aqueous layer was extracted
with ethyl acetate (2ꢃ80 mL). The combined organic layers were
washed with brine (60 mL), dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography eluting with ethyl
acetate/hexane (0–20%) to provide compound 17 (1.7 g, 90%) as
4. Conclusions
a colorless oil. 1H NMR (400 MHz, CDCl3)
d
7.12 (d, J¼7.5 Hz, 1H),
7.08 (t, J¼7.7 Hz, 1H), 6.87 (t, J¼7.4 Hz, 1H), 6.74 (d, J¼7.4 Hz, 1H),
4.69 (s, 1H), 2.58 (t, J¼7.8 Hz, 2H), 2.12 (t, J¼7.5 Hz, 2H), 1.70 (m,
In summary, teleocidin B analogs have been synthesized in 24
linear steps with an overall yield of 1.9%. The key steps include an
aromatic Claisen rearrangement, an intramolecular Heck reaction
2H), 1.65 (s, 9H). 13C NMR
d 153.3, 130.1, 130.0, 128.4, 127.4,
127.0, 124.4, 120.8, 115.2, 34.2, 29.7, 28.2, 20.6, 20.2, 18.2. MS:
(þESI) (MþH)þ m/z 205.2. HRMS: calcd 204.1515 for C14H20O,
found 204.1515.
of
a tetra-substituted alkene, and a tris(triphenylphosphine)
ruthenium (II) dichloride catalyzed indole cyclization of an ortho-
amino arylethanol. Analogs with 9S and 12S stereochemistry
(diastereomeric mixture 5 and its components 40 and 41) dem-
onstrated comparable cell spreading activity with teleocidin B.
5.3. 2-(4,5-Dimethylhex-4-enyl)phenyl trifluoromethane-
sulfonate 18
5. Experimental section
5.1. General
To a solution of compound 17 (1.6 g, 7.9 mmol) in anhydrous
methylene chloride (20 mL) under N2 at 0 ꢂC were added triethyl-
amine (3.3 mL, 23.4 mmol) and triflic anhydride (2.0 mL,
11.9 mmol) dropwise. The mixture was then stirred at room tem-
perature for 2 h. The reaction was quenched with water (30 mL)
and diluted with methylene chloride (50 mL). The mixture was
separated and the aqueous layer was extracted with methylene
chloride (3ꢃ50 mL). The combined organic layers were washed
with satd aqueous NaHCO3 (50 mL) and brine (50 mL), then dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
eluting with ethyl acetate/hexane (0–20%) to provide compound 18
All reagents and solvents were purchased from commercial
sources and used as received. 1H and 13C NMR spectra were
determined on a 400 MHz Varian Unity Plus, using Me4Si as the
internal standard. Chemical shifts are reported in parts per million
downfield from zero and coupling constants are reported in hertz
(Hz). Mass spectra were recorded on a Micromass LCT mass
spectrometer. HRMS were recorded in FAB mode on an Agilent
mass spectrometer. Optical rotation was recorded with a Jasco
P-1020 polarimeter with a 30 mm cell. Melting points were taken
on a Mel-Temp 3.0 capillary melting point apparatus and were
uncorrected.
(2.4 g, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
(m, 4H), 2.70 (t, J¼7.9 Hz, 2H), 2.14 (t, J¼7.5 Hz, 2H), 1.76–1.70 (m,
2H), 1.66 (s, 9H). 13C NMR
148.1, 135.4, 131.1, 128.3, 127.6, 126.8,
d 7.36–7.34
d
Cell spreading assay-NIH/3T3 cells were obtained from ATCC
(CRL-1658). Cells were grown in Dulbecco’s modified Eagle’s me-
dium (DMEM) supplemented with 10% bovine calf serum (BCS)
(Invitrogen), 100 U/mL penicillin/streptomycin (Invitrogen), and
124.8, 121.2, 117.6, 34.1, 29.8, 28.4, 20.5, 20.0, 18.2. MS: (þESI)
(MþH)þ m/z 337.1.
200 mM
L
-glutamine in an incubator maintained at 37 ꢂC with 5%
5.4. 1-Methyl-1-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-
naphthalene 20
CO2. NIH/3T3 cells were cultured to 70–80% confluence before
trypsinized and plated at a sub-confluent density (2.67ꢃ104/cm2)
24 h before the cell spreading assay. Nogo (2–4
mg/mL in H2O,
To a solution of compound 18 (1.0 g, 3.0 mmol) in anhydrous
N,N-dimethylacetamide (10 mL) were added potassium carbonate
(1.3 g, 8.9 mmol) and 2,20-bis(diphenylphosphino)-1,10-binaphthyl
(0.065 g, 0.3 mmol). The mixture was degassed with N2 for 15 min.
Palladium acetate (0.042 g, 0.15 mmol) was added and the mixture
was degassed with N2 for an additional 15 min. The mixture was
heated in an oil bath at 120 ꢂC under N2 for 16 h. The dark solution
was cooled to room temperature and the solvent was removed
under reduced pressure. The mixture was diluted with ethyl acetate
(50 mL) and washed with water (20 mL). The aqueous layer was
extracted with ethyl acetate (2ꢃ30 mL). The combined organic
layers were washed with brine (20 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography eluting with
ethyl acetate/hexane (0–10%) to provide compound 20 (0.44 g, 80%)
50 mL/well) or control (50 mL H2O) was air-dried on poly-D-lysine
coated 96-well plate overnight in a tissue culture hood. Cells were
removed by 0.05% trypsin/EDTA (Invitrogen). The reaction was
neutralized with DMEM/10% BCS. Then, NIH/3T3 cells were added
to wells at 2500 cell/well and grow for 1 h at 37 ꢂC in a 5% CO2
incubator. Cells were fixed with 4% paraformaldehyde, per-
meablized with 0.3% Triton X-100 in PBS for 5 min and then stained
with Hoechst 33342 (Invitrogen) and AlexaFluor 488 conjugated
phalloidin (Invitrogen) in PBS for 20 min. Cell images were scanned
and cell spreading was quantified by MetaXpress cell scoring
module (Molecular Device). All data is presented as percentage
mean cell area compared with cell area on control substrate ꢁSEM.
5.2. 2-(4,5-Dimethylhex-4-enyl)phenol 17
as a colorless oil. 1H NMR (400 MHz, DMSO-d6)
d 7.07–7.01 (m, 4H),
To a solution of (2-allylphenoxy)(tert-butyl)dimethylsilane 16
(3.0 g, 12.0 mmol) in anhydrous THF (40 mL) at 0 ꢂC under N2
4.87 (d, J¼1.3 Hz, 1H), 4.62 (d, J¼1.3 Hz, 1H), 2.70 (t, J¼6.4 Hz, 2H),
1.92 (m, 1H), 1.71 (m, 2H), 1.55 (s, 3H), 1.45 (m, 1H), 1.34 (s, 3H). 13C

1968
J. Pu et al. / Tetrahedron 66 (2010) 1963–1972
NMR
d
152.2, 142.5, 136.2, 128.7, 127.6, 125.6, 125.4, 112.0, 43.3, 34.9,
(0–20%) to provide compound 24 (12.1 g, 78%) as a colorless oil. 1H
NMR (400 MHz, CDCl3)
7.10 (d, J¼1.9 Hz, 1H), 6.92 (m, 1H), 6.68 (d,
J¼8.2 Hz, 1H), 6.17 (dd, J¼10.1, 17.8 Hz, 1H), 4.95 (m, 2H), 2.30 (s,
29.6, 28.6, 19.1. MS: (þESI) (MþH)þ m/z 187.2.
d
5.5. 4-Methyl-2-(2-methyl-but-3-en-2-yl) phenol 22
3H), 1.46 (s, 6H), 0.32 (s, 9H). 13C NMR
d 151.7, 148.2, 137.5, 129.4,
128.2, 127.4, 118.3, 109.8, 40.3, 27.2, 20.8, 0.7. MS: (MþH)þ m/z
A solution of 1-methyl-4-(3-methyl-but-2-enyloxy) benzene
1314 (0.60 g, 3.41 mmol), acetic anhydride (10 mL), and N,N-dime-
thylaniline (10 mL) was added to a thick-walled tube (125 mL). The
solution was purged with N2 for 5 min. The sealed tube was then
inserted into an oil bath at 200 ꢂC. The mixture was stirred for 24 h.
The reaction mixture was cooled to room temperature and diluted
with ethyl acetate (60 mL). The mixture was washed with 3 M
aqueous HCl (3ꢃ30 mL). The organic layer was further washed with
satd aqueous NaHCO3 (1ꢃ100 mL) and brine (30 mL), then dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The obtained crude dark oil 21 (1.0 g) was dissolved in
anhydrous MeOH (10 mL). KOH (0.50 g, 9.2 mmol) was added. The
dark solution was stirred at 40 ꢂC until TLC indicated completion of
reaction. The reaction mixture was cooled to room temperature and
the solvent was removed under reduced pressure. The mixture was
diluted with water (50 mL) and extracted with ethyl acetate
(2ꢃ60 mL). The combined organic layers were washed with brine
(50 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography eluting with ethyl acetate/hexane (20%) to provide
compound 22 (0.18 g, 30% yield for two steps) as a colorless oil. 1H
249.4. HRMS: calcd 249.1666 for C15H24OSi, found 249.1667.
5.8. 4-Methyl-2-(2,5,6-trimethylhept-5-en-2-yl) phenol 25
To a solution of 24 (2.5 g, 10.3 mmol) in anhydrous THF (60 mL)
at 0 ꢂC under N2 was added a solution of 9-BBN (0.5 M in THF,
27.8 mL, 13.4 mmol) dropwise. The mixture was stirred at 0 ꢂC for
30 min. The ice-water bath was removed and the mixture was
stirred at room temperature for 5 h. Aqueous NaOH solution (3 M,
11.0 mL, 32.0 mmol) was added dropwise followed by addition of 2-
bromo-3-methyl-but-2-ene (1.9 mL, 16.0 mmol) and PdCl2 (dppf)2
(0.39 g, 0.5 mmol). The mixture was stirred at 60 ꢂC under N2 for
16 h. The reaction mixture was cooled to room temperature, diluted
with ethyl acetate (100 mL), and washed with water (100 mL). The
aqueous layer was extracted with ethyl acetate (2ꢃ80 mL). The
combined organic layers were washed with brine (60 mL), dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
eluting with ethyl acetate/hexane (0–20%) to provide compound 25
(2.4 g, 90%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6)
d 8.96 (s,
1H), 6.85 (s, 1H), 6.76 (d, J¼8.1 Hz,1H), 6.63 (d, J¼8.1 Hz,1H), 2.16 (s,
3H), 1.81 (m, 2H), 1.62 (m, 2H), 1.53 (s, 3H), 1.51 (s, 3H), 1.48 (s, 3H),
1.28 (s, 6H). 13C NMR (DMSO-d6) 153.4, 132.9, 128.0, 127.9, 126.9,
126.5, 122.2, 115.6, 38.3, 37.4, 30.1, 27.8, 20.4, 20.3, 19.5, 18.3. MS
(MꢀH)ꢀ m/z 245.1. HRMS [MꢀH]: calcd 245.1911 for C17H26O, found
245.1910.
NMR (400 MHz, CDCl3)
d
7.03 (d, J¼2.0 Hz,1H), 6.94 (m,1H), 6.71 (d,
J¼8.1 Hz, 1H), 6.16 (dd, J¼10.7, 17.6 Hz, 1H), 5.55 (br, 1H) 5.25 (m,
2H), 2.27 (s, 3H), 1.42 (s, 6H). 13C NMR
d 152.4, 147.9, 131.7, 129.7,
128.6, 126.8, 117.5,113.4, 40.2, 26.9, 20.2. MS: (þESI) (MþH)þ m/z
177.9.
5.6. tert-Butyldimethyl(4-methyl-2-(2-methyl-but-3-en-2-
yl)phenoxy)silane 23
5.9. 4-Methyl-2-(2,5,6-trimethylhept-5-en-2-yl)phenyl
trifluoromethanesulfonate 11
To a solution of compound 22 (0.55 g, 3.12 mmol) in anhydrous
methylene chloride (5 mL) was added imidazole (0.64 g,
9.40 mmol) and TBSCl (0.72 g, 4.71 mmol). The mixture was stirred
at room temperature under N2 atmosphere overnight. The reaction
mixture was diluted with methylene chloride (50 mL) and washed
with water (30 mL). The organic layer was washed with brine
(50 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography eluting with ethyl acetate/hexane (10%) to provide
compound 23 (0.60 g, 66% yield) as a colorless oil. 1H NMR
To a solution of compound 25 (3.0 g, 12.2 mmol) in anhydrous
THF (40 mL) was added sodium hydride (0.73 g, 18.3 mmol, 60% in
mineral oil) in three portions at 0 ꢂC under N2. The mixture was
stirred at 0 ꢂC for 1 h. N-phenyltrifluoromethane sulfonamide
(6.5 g, 18.3 mmol) was added. The mixture was stirred at room
temperature for 1 h. The reaction mixture was quenched by slow
addition of water (60 mL) and extracted with ethyl acetate
(3ꢃ80 mL). The combined organic layers were washed with brine
(60 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography eluting with ethyl acetate/hexane (5–20%) to
provide compound 11 (4.0 g, 87%) as a colorless oil. 1H NMR
(400 MHz, DMSO-d6)
J¼8.1 Hz,1H), 6.11 (dd, J¼10.7,17.4 Hz,1H), 4.83 (m, 2H), 2.16 (s, 3H),
1.35 (s, 6H), 0.93 (s, 9H), 0.21 (s, 6H). 13C NMR (DMSO-d6)
152.0,
d
6.96 (d, J¼2.2 Hz, 1H), 6.84 (m, 1H), 6.68 (d,
d
(400 MHz, CDCl3)
d 7.16 (m, 2H), 7.02 (m, 1H), 2.33 (s, 3H), 1.73 (m,
148.7, 131.1, 129.4, 128.8, 128.1, 118.8,110.8, 40.6, 28.0, 26.8, 21.1, 18.9,
2H), 1.68 (m, 2H), 1.56 (s, 3H), 1.54 (s, 3H), 1.50 (s, 3H), 1.39 (s, 6H).
ꢀ3.2. MS: (þESI) (MþH)þ m/z 291.4.
13C NMR
d 147.3, 139.6, 137.5, 130.5, 128.4, 127.6, 123.9, 120.9,
120.2, 40.3, 38.3, 30.4, 29.0, 21.3, 20.7, 19.9, 18.4. MS: (MþH)þ m/z
5.7. Trimethyl(4-methyl-2-(2-methyl-but-3-en-2-yl)
phenoxy)silane 24
378.9.
5.10. 1,4,4,6-Tetramethyl-1-(prop-1-en-2-yl)-1,2,3,4-
tetrahydronaphthalene 10
1-Methyl-4-(3-methyl-but-2-enyloxy) benzene 13 (10.0 g,
55.8 mmol) was dissolved in a solution of N,N-dimethylaniline
(50 mL), and 1,1,1,3,3,3-hexamethyl-disilazane (HMDS, 50 mL) in
a thick-walled flask (350 mL). The solution was purged with N2 for
5 min. The sealed flask was then inserted into an oil bath at 200 ꢂC.
The mixture was stirred for 16 h. The mixture was cooled to room
temperature and diluted with ethyl acetate (300 mL). The mixture
was extracted with aqueous HCl (3 M, 3ꢃ100 mL). The organic layer
was further washed with satd aqueous NaHCO3 (2ꢃ100 mL) and
brine (100 mL), then dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was pu-
rified by flash chromatography eluting with ethyl acetate/hexane
To a solution of compound 11 (3.9 g, 10.3 mmol) in anhydrous
N,N-dimethylacetamide (40 mL) was added potassium carbonate
(4.3 g,
30.9 mmol)
and
2,20-bis(diphenylphosphino)-1,10-
binaphthyl (0.65 g, 1.03 mmol). The mixture was degassed with N2
for 15 min. Palladium acetate (0.16 g, 0.57 mmol) was added and
the mixture was degassed with N2 for an additional 15 min. The
mixture was heated in an oil bath at 120 ꢂC under N2 for 16 h. The
dark solution was cooled to room temperature and the solvent was
removed under reduced pressure. The mixture was diluted with
ethyl acetate (100 mL) and washed with water (100 mL). The

J. Pu et al. / Tetrahedron 66 (2010) 1963–1972
1969
aqueous layer was extracted with ethyl acetate (2ꢃ100 mL). The
combined organic layers were washed with brine (100 mL), dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
eluting with ethyl acetate/hexane (0–10%) to provide compound 10
purified by flash chromatography eluting with ethyl acetate/hexane
(10–20%) to provide compound 28 (3.0 g, 90%) as white solid. Mp
110–112 ꢂC. 1H NMR (400 MHz, CDCl3)
d 7.89 (s, 1H), 3.79 (m, 2H),
3.16 (m, 1H), 2.77 (m, 1H), 2.13 (m, 1H), 1.85 (m, 2H), 1.64 (m, 1H,
OH), 1.53 (m, 1H), 1.38 (m, 1H), 1.31 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H),
(2.0 g, 85%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
7.12 (s,
0.99 (d, J¼6.7 Hz, 3H), 0.62 (d, J¼6.8 Hz, 3H). 13C NMR
d 152.1, 148.2,
1H), 6.99 (d, J¼8.0 Hz, 1H), 6.92 (m, 1H), 4.90 (s, 1H), 4.64 (d,
J¼0.4 Hz, 1H), 2.31 (s, 3H), 2.03 (m, 1H), 1.73 (m, 1H), 1.64 (s, 3H),
1.62 (m, 1H), 1.47 (m, 1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.23 (s, 3H). 13C
147.9, 141.3, 124.5, 122.4, 61.9, 41.2, 37.5, 37.1, 34.4, 30.2, 29.9, 28.2,
27.8, 23.8, 17.9, 16.2. MS: (þESI) (MþNa)þ m/z 373.1. HRMS
[MþNH4]: calcd 368.2180 for C18H26N2O5,, found 368.2197.
NMR d 152.9, 145.2, 139.0, 135.0, 128.0, 126.8, 126.4, 112.1, 44.1, 35.1,
33.9, 31.9, 31.7, 31.4, 28.8, 21.2, 19.9. MS: (MþH)þ m/z 229.2.
5.14. Benzyl 3-(2-hydroxyethyl)-8-isopropyl-5,5,8-trimethyl-
4-nitro-5,6,7,8-tetrahydronaphthalen-2-ylcarbamate 30
5.11. 1-Isopropyl-1,4,4,6-tetramethyl-1,2,3,4-
tetrahydronaphthalene 26
To a stirred solution of compound 28 (8.3 g, 24.7 mmol) in
ethanol (100 mL) under N2 at room temperature were added
cyclohexene (3.5 mL, 34.2 mmol) and 10% Pd/C (0.9 g). The mixture
was heated at 83 ꢂC under N2 overnight. The mixture was cooled to
room temperature and was filtered through a pad of Celite. The pad
was washed with ethyl acetate (200 mL). The filtrate was concen-
trated under reduced pressure to afford the crude amine in-
termediate 29 (7.4 g, 99%) as a yellow oil, which was used in the
next step without further purification.
To a solution of the crude amine 29 in THF (100 mL) were added
satd aqueous NaHCO3 (30 mL) and benzyl chloroformate (6.6 mL,
46.2 mmol) at 0 ꢂC. The mixture was stirred at room temperature
overnight. The mixture was diluted with water (100 mL) and
extracted with ethyl acetate (2ꢃ100 mL). The combined organic
layers were washed with brine (100 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography eluting with
methylene chloride/ethyl acetate (0–20%) to provide compound 30
(10.3 g, 92% for two steps) as yellow solid. Mp 167–169 ꢂC. 1H NMR
To a solution of compound 10 (2.7 g, 11.7 mmol) in ethanol (98%,
30 mL) under N2 was added 10% Pd/C (0.2 g). The system was
vacuumed and purged with H2 three times. The mixture was stirred
under H2 atmosphere (1 atm) overnight. The solution was filtered
through a pad of Celite and the pad was washed with ethyl acetate
(100 mL). The solvent was removed under reduced pressure. The
crude product was purified by flash chromatography eluting with
ethyl acetate/hexane (0–10%) to provide compound 26 (2.4 g, 90%)
as colorless oil. 1H NMR (400 MHz, CDCl3)
d 7.22 (m, 2H), 7.01 (m,
1H), 2.39 (s, 3H), 2.26 (m, 1H),1.87 (m, 2H),1.61 (m, 2H),1.39 (s, 3H),
1.34 (s, 3H),1.31 (s, 3H),1.08 (d, J¼6.8 Hz, 3H), 0.71 (d, J¼6.8 Hz, 3H).
13C NMR
d 145.0, 140.6, 133.8, 126.1, 125.9, 39.1, 36.6, 34.4, 33.2, 31.5,
30.8, 28.6, 25.2, 20.7, 17.9, 16.6. MS: (EI) (MþH)þ m/z 231.2.
5.12. 1-Isopropyl-1,4,4,6-tetramethyl-5,7-dinitro-1,2,3,4-
tetrahydronaphthalene 27
To a stirred solution of fuming nitric acid (98%, 15 mL) and
concentrated sulfuric acid (95–98%, 20 mL) in anhydrous di-
chloroethane (15 mL) at 0 ꢂC under N2 was added a solution of
compound 26 (2.3 g, 1.0 mmol) in anhydrous dichloroethane
(10 mL) dropwise through a dropping funnel over 15 min. After
completion of addition, the reaction mixture was stirred at 0 ꢂC for
3 h. The mixture was slowly poured into ice-water (approximately
200 mL). The mixture was extracted with methylene chloride
(3ꢃ100 mL). The combined organic layers were washed with water
(1ꢃ100 mL), satd aqueous NaHCO3 (2ꢃ100 mL) and brine (60 mL),
then dried over anhydrous Na2SO4, filtered, and concentrated un-
der reduced pressure. The crude product was purified by flash
chromatography eluting with ethyl acetate/hexane (10–20%) to
provide compound 27 (2.9 g, 92%) as pale yellow solid. Mp 124–
(400 MHz, CDCl3) d 8.52 (br s, 1H, ArH), 7.95 (br, 1H, ArNHCO2),
7.41–7.33 (m, 5H, Ph), 5.20 (m, 2H, PhCH2), 3.96–3.91 (m, 2H,
OCH2), 2.85 (m, 1H), 2.41 (m, 1H), 2.23 (br, 1H, OH), 1.94 (m, 2H),
1.81 (m, 1H), 1.48 (m, 1H), 1.36 (m, 1H), 1.32 (s, 3H), 1.28 (s, 3H), 1.25
(s, 3H), 0.98 (d, J¼5.0 Hz, 3H), 0.64 (br, 3H). 13C NMR
d 149.6, 147.5,
142.1, 131.6, 131.5, 127.3, 124.0, 123.7, 118.9, 115.8, 62.4, 59.7, 36.6,
33.5, 33.3, 29.4, 25.7, 25.2, 25.1, 24.4, 24.0, 20.1, 13.7, 12.2. MS: (ESI)
(MꢀH)ꢀ m/z 453.2. HRMS: calcd 454.2468 for C26H34N2O5, found
454.2469.
5.15. Benzyl 6-isopropyl-6,9,9-trimethyl-6,7,8,9-tetrahydro-
1H-benzo[g]indol-4-ylcarbamate 9
To a solution of compound 30 (10.3 g, 22.7 mmol) in ethanol
(100 mL) were added iron powder (12.9 g, 0.27 mol) and acetic acid
(30 mL). The mixture was stirred at 80 ꢂC for 3 h and was cooled to
room temperature. The solution was filtered through a pad of Celite
and the pad was washed with ethyl acetate. The filtrate was con-
centrated under reduced pressure. The residue was dissolved in ethyl
acetate (200 mL) and washed with satd aqueous NaHCO3
(2ꢃ200 mL). The organic layer was washed with brine (100 mL),
dried over anhydrous Na2SO4, filtered, and concentrated. The crude
product was dissolved in anhydrous toluene (100 mL) and the sol-
vent was removed under reduced pressure. The crude amine in-
termediate was placed under high vacuum pump for 2 h. The amine
intermediate 31 (9.5 g) was dissolved in anhydrous toluene (150 mL)
and the solution was degassed with N2 for 15 min. After addition of
tris(triphenylphosphine)ruthenium dichloride (2.2 g, 2.3 mmol), the
mixture was stirred at 120 ꢂC under N2 overnight. The mixture was
cooled to room temperature and the solvent was removed under
reduced pressure. The crude product was purified by flash chroma-
tography eluting with ethyl acetate/hexane (10–30%) to provide
compound 9 (7.9 g, 86% for two steps) as yellow solid. Mp 107–
127 ꢂC. 1H NMR (400 MHz, CDCl3)
d 7.92 (s,1H), 2.32 (s, 3H), 2.18 (m,
1H), 1.95 (m, 1H), 1.84 (m, 1H), 1.56 (m, 1H), 1.53 (s, 3H), 1.41 (m, 1H),
1.35 (s, 3H),1.30 (s, 3H),1.02 (d, J¼6.6 Hz, 3H), 0.65 (d, J¼6.8 Hz, 3H).
13C NMR
d 152.7, 148.2, 147.4, 141.6, 124.4, 122.4, 41.5, 37.9, 37.5,
34.8, 30.4, 28.7, 28.3, 24.3, 18.3, 16.7, 13.9. MS: (EI) (MþH)þ m/z
321.1.
5.13. 2-(5-Isopropyl-5,8,8-trimethyl-1,3-dinitro-5,6,7,8-
tetrahydronaphthalen-2-yl)ethanol 28
To a solution of compound 27 (3.1 g, 9.7 mmol) in anhydrous
DMSO (20 mL) were added paraformaldehyde (0.43 g, 14.5 mmol)
and a Triton-B solution (40% in methanol, 0.5 mL) at room tem-
perature. The resulting purple solution was stirred at room tem-
perature overnight. The solvent was removed under reduced
pressure. The mixture was diluted with ethyl acetate (100 mL) and
washed with water (100 mL). The aqueous layer was extracted with
ethyl acetate (2ꢃ60 mL). The combined organic layers were washed
with brine (50 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was
109 ꢂC. 1H NMR (DMSO-d6)
d 9.20 (br s, 1H), 7.44–7.31 (m, 6H), 7.08

1970
J. Pu et al. / Tetrahedron 66 (2010) 1963–1972
(t, J¼2.9 Hz,1H), 6.6 (d, J¼1.0 Hz,1H), 5.14 (s, 2H, PhCH2), 2.05 (m,1H,
CH(CH3)2), 1.72 (m, 2H, CH2CH2), 1.58 (m, 1H, CH2), 1.39 (s, 3H), 1.35
(s, 3H), 1.28 (m, 1H, CH2), 1.22 (s, 3H), 0.90 (d, J¼6.7 Hz, 3H), 0.42 (d,
5.18. (2S)-Benzyl 2-(3-(2-(tert-butoxycarbonylamino)-3-
ethoxy-3-oxopropyl)-6-isopropyl-6,9,9-trimethyl-6,7,8,9-
tetrahydro-1H-benzo[g]indol-4-ylamino)-3-methyl-
butanoate 36
J¼6.6 Hz, 3H). 13C NMR
d 153.9, 136.9, 136.8, 133.6, 128.4, 128.2, 128.0,
127.9, 124.3, 123.1, 119.2, 98.6, 65.5, 54.9, 37.1, 36.9, 32.6, 29.9, 28.6,
26.9, 25.0, 18.0, 17.1. MS: (ESI) (MꢀH)ꢀ m/z 403.2. HRMS: calcd
404.2464 for C26H32N2O2, found 404.2465.
A mixture of compound 34 (5.20 g, 8.4 mmol) and 10% Pd/C
(0.5 g) in methanol (100 mL) was hydrogenated at 45 psi on a Parr
shaker apparatus. After 4 h, the suspension was filtered through
a pad of Celite and the pad was washed with methanol. The filtrate
was concentrated under reduced pressure to afford the crude
amine intermediate (4.2 g) as a green solid, which was used in the
next step without further purification.
5.16. Ethyl 3-(4-(benzyloxycarbonylamino)-6-isopropyl-6,9,9-
trimethyl-6,7,8,9-tetrahydro-1H-benzo[g]indol-3-yl)-2-
(hydroxyimino)propanoate 33
To a solution of compound 9 (7.4 g, 18.3 mmol) in anhydrous
methylene chloride (100 mL) were added sodium carbonate (3.0 g,
36.5 mmol) and ethyl 4-bromo-2-(hydroxyimino)butanoate 32
(3.8 g, 18.3 mmol) at room temperature under N2. The reaction
mixture was stirred overnight. The mixture was filtered through
a pad of Celite and the pad was washed with ethyl acetate. The
filtrate was concentrated and the crude product was purified by
flash chromatography eluting with ethyl acetate/hexane (30–80%)
to provide compound 33 (9.4 g, 97% yield) as yellow solid. Mp
To a solution of the amine (4.2 g, 8.4 mmol) in anhydrous 1,2-
dichloroethane (100 mL) was added 2,4-lutidine (1.5 mL, 12.6 mmol)
and (S)-benzyl 4-methyl-2-(trifluoromethylsulfonyloxy)pentanoate
35 (3.87 g, 10.9 mmol). The mixture was stirred under N2 at 83 ꢂC for
12 h. The mixture was cooled to room temperature and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography eluting with ethyl acetate/hexane
(10–30%) to give compound 36 (4.8 g, 82% for two steps) as a brown
solid. Mp 82–85 ꢂC. 1H NMR (DMSO-d6)
d 10.10 (br s, 1H, NH), 7.33–
118.2–120.8 ꢂC. 1H NMR (DMSO-d6)
d
12.35 (br s, 1H, NOH), 10.23 (s,
7.31 (m, 5H, Ph), 6.92 (m, 1H), 6.03 (m, 1H, Ph-H), 5.13–4.97 (m, 2H,
OCH2Ph), 4.55–4.52 (m, 1H, PhNH), 4.24 (m, 1H, CHCO2Et), 4.19–4.01
(m, 2H, OCH2), 3.28–3.22 (m, 1H, 1H of CH2), 3.14–3.11 (m, 1H, 1H of
CH2), 2.18–2.16 (m, 1H, NCHCO2Et), 2.13–1.99 (m, 1H, PhNH–CH),
1.72–1.63 (m, 2H), 1.56–1.51 (m, 1H), 1.41–1.26 (m, 12H, C(CH3)3 and
CH3), 1.22–1.16 (m, 6H, CH3), 1.11 (m, 1H, CH), 1.09–1.01 (m, 6H, CH3),
0.92 (m, 3H, CH3), 0.89–0.77 (two sets of doublets, 3H, CH3), 0.48–
1H), 9.0 (br s, 1H), 7.37–7.26 (m, 5H), 6.83 (br s, 1H), 6.58 (m, 1H),
5.12 (s, 2H), 4.18 (q, J¼7.1 Hz, 2H), 3.98 (s, 2H), 2.08 (m, 1H), 1.78 (m,
2H), 1.61 (9m, 1H), 1.39 (s, 3H), 1.36 (s, 3H), 1.31 (m, 1H), 1.22 (s, 3H),
1.17 (t, J¼7.1 Hz, 3H), 0.91 (d, J¼6.8 Hz, 3H), 0.41 (d, J¼6.7 Hz, 3H).
13C NMR
d 164.6, 164.2, 155.0, 150.5, 150.3, 137.1, 137.0, 134.5, 128.3,
127.8, 127.7, 127.6, 126.3, 121.6, 121.5, 120.5, 107.2, 65.4, 60.9, 52.2,
36.9, 32.7, 29.6, 24.9, 21.3, 21.2, 17.9, 17.1, 14.0. MS: (ESI) (MꢀH)ꢀ m/z
533.2. HRMS: calcd 533.2897 for C31H39N3O5, found 533.2892.
0.32 (m, 3H, CH3). 13C NMR
d (mixture of diastereomers) 173.9,173.8,
172.5, 155.5, 155.4, 138.8, 137.2, 135.6, 128.3, 128.2, 128.1, 128.0, 127.9,
122.4, 120.1, 120.0, 119.8, 114.8, 108.3, 78.2, 78.1, 78.1, 65.9, 65.8, 62.2,
60.4, 60.2, 56.2, 56.0, 37.3, 37.2, 36.9, 36.8, 36.8, 32.2, 31.2, 31.1, 31.0,
30.0, 29.9, 29.9, 29.8, 28.4, 28.4, 28.1, 27.7, 27.6, 27.0, 26.8, 26.7, 24.9,
19.4, 19.3, 19.2, 19.1, 19.1, 19.0, 18.9, 18.2, 18.0, 17.9, 17.8, 17.1, 17.0, 16.9,
14.0,13.9,13.9. MS: (þESI) (MþH)þ m/z 676.3. HRMS: calcd 675.4247
for C40H57N3O6, found 675.4250.
5.17. Ethyl 3-(4-(benzyloxycarbonylamino)-6-isopropyl-6,9,9-
trimethyl-6,7,8,9-tetrahydro-1H-benzo[g]indol-3-yl)-2-(tert-
butoxycarbonylamino)propanoate 34
To a solution of compound 33 (9.4 g, 18.3 mmol) in THF/H2O
(100 mL/10 mL) were added mercury chloride solution (2% HgCl2 in
H2O solution, 10 mL) and aluminum foil (5.0 g, 0.18 mol, which has
been cut into small pieces). The green solution was stirred at room
temperature overnight. The mixture was filtered through a pad of
Celite and the pad was washed with ethyl acetate (100 mL). The
filtrate was diluted with water (60 mL) and extracted with ethyl
acetate (3ꢃ80 mL). The combined organic layers were washed with
brine (60 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated to afford the amine intermediate (9.0 g, 94% yield), which
was used in the next step without further purification.
5.19. (7S)-Ethyl 7,10-diisopropyl-8,10,13,13-tetramethyl-6-oxo-
3,4,5,6,7,8,10,11,12,13-decahydro-1H-benzo[g][1,4]diazonino-
[7,6,5-cd]indole-4-carboxylate 38
A mixture of 10% Pd/C (0.1 g) and compound 36 (0.62 g,
0.92 mmol) in methanol (20 mL) was hydrogenated at 45 psi on
a Parr shaker apparatus. After 2 h, the reaction was complete as
determined by TLC. The suspension was filtered through a pad of
Celite and the pad was washed with methanol. The filtrate was
concentrated under reduced pressure to afford the crude acid in-
termediate (0.54 g) as a green solid, which was used in the next
step without further purification.
To a solution of the crude acid (0.54 g, 0.92 mmol) in anhydrous
acetonitrile (10 mL) at 0 ꢂC was added N,N0-dicyclohex-
ylcarbodiimide (0.31 g, 1.47 mmol) and N-hydroxysuccinimide
(0.21 g, 1.79 mmol). The mixture was stirred at 0 ꢂC for 1 h and at
room temperature for 2 h. The solvent was removed under reduced
pressure. The solid was dissolved in ethyl ether and filtered through
a pad of Celite. The pad was washed with ethyl ether. The filtrate
was concentrated. The crude product was purified by flash
chromatography eluting with ethyl acetate/hexane (50–80%) to
give the activated ester intermediate (0.57 g) as white solid.
To a solution of the activated ester (0.57 g, 0.83 mmol) in
anhydrous methylene chloride (5 mL) at 0 ꢂC under N2 was
added trifluoroacetic acid (5 mL) dropwise. The mixture was
then stirred at room temperature for 2 h. The solvent was re-
moved under reduced pressure (the temperature should be kept
under 30 ꢂC).
To a solution of the crude amine (9.0 g, 17.3 mmol) in THF
(100 mL) was added satd aqueous NaHCO3 (20 mL) and di-tert-
butyl dicarbonate (7.6 g, 34.6 mmol). The mixture was stirred at
room temperature overnight. The reaction mixture was extracted
with ethyl acetate (3ꢃ80 mL). The combined organic layers were
washed with brine (60 mL), dried over anhydrous Na2SO4, filtered,
and concentrated. The crude product was purified by flash chro-
matography eluting with ethyl acetate/hexane (30–50%) to give
compound 34 (8.7 g, 81% for two steps) as yellow solid. Mp 91–
95 ꢂC. 1H NMR (DMSO-d6)
d 10.43 (br s, 1H), 8.83 (br s, 1H), 7.42–
7.24 (m, 5H), 7.16 (m, 1H), 7.01 (m, 1H), 6.76 (br s, 1H), 5.03 (s, 2H),
4.19 (m, 1H), 4.06–3.97 (m, 2H), 3.21 (m, 1H), 2.98 (m, 1H), 2.02 (m,
1H), 1.71 (m, 2H), 1.58 (m, 1H), 1.41–1.39 (m, 4H), 1.33 (two sets of
singlet, 3H from CH3), 1.30 (s, 9H), 1.22 (s, 3H), 1.06 (m, 3H), 0.91 (m,
3H), 0.42 (m, 3H). 13C NMR
d (mixture of diastereomers) 172.8,
155.5,155.5,155.3,137.0,136.6,134.6,134.6,128.3,128.2,127.7,127.6,
127.6,127.5,126.6,123.5,121.4,108.9, 78.0, 78.0, 65.6, 60.1, 55.1, 54.9,
37.0, 36.9, 36.8, 32.7, 29.6, 28.5, 28.5, 28.1, 28.1, 27.8, 27.3, 27.2, 26.7,
26.6, 25.0, 25.0, 18.0, 17.1, 17.1, 14.0, 14.0. MS: (ESI) (MþH)þ m/z
620.4. HRMS: calcd 619.3621 for C36H49N3O6, found 619.3624.

J. Pu et al. / Tetrahedron 66 (2010) 1963–1972
1971
To a solution of the crude amine in ethyl acetate (10 mL) was
added satd aqueous NaHCO3 (6 mL). The mixture was stirred at
70 ꢂC for 16 h. The mixture was cooled to room temperature, di-
luted with ethyl acetate (50 mL), and washed with water (50 mL).
The aqueous layer was extracted with ethyl acetate (2ꢃ50 mL). The
combined organic layers were washed with brine (50 mL), dried
over anhydrous Na2SO4, filtered, and concentrated. The crude
product was purified by flash chromatography eluting with ethyl
acetate/hexane (10–50%) to give lactam 37 (0.18 g, 41% yield over
four steps) as a mixture of diastereomers.
28.5, 27.8, 27.8, 25.7, 25.6, 21.9, 19.7, 19.2, 18.2, 18.1, 17.2, 17.1. MS:
(ESI) (MþH)þ m/z 440.3. HRMS: calcd 439.3201 for C27H41N3O2,
found 439.3197.
Teleocidin B analog 39 (mixture of two diastereomers): mp 137–
141 ꢂC.1H NMR (500 MHz, CDCl3)
d 8.06 (br,1H, NH), 7.99 (br,1H, NH),
6.86 (s, 1H), 6.83 (s, 1H), 6.80 (s, 1H), 6.73 (s, 1H), 3.84 (m, 5H, H-9, H-
12, H-14 and H-19), 3.26 (m,1H, H-8), 3.09–3.06 (two sets of singlets,
6H, N–CH3), 2.89 (m, 1H, H-8), 2.62 (m, 1H, H-15), 2.19 (m, 1H), 1.86
(m, 2H),1.62 (m, 2H),1.49 (m, 3H),1.45 (s, 3H),1.36 (s, 3H),1.29 (s, 3H),
1.27 (s, 3H), 1.25 (s, 3H), 1.01 (m, 3H), 0.96 (m, 3H), 0.83 (m, 6H), 0.74
To a solution of lactam 37 (0.18 g, 0.39 mmol) in anhydrous
methylene chloride (10 mL) was added paraformaldehyde (0.058 g,
1.93 mmol) and acetic acid (0.11 mL, 1.93 mmol). The mixture was
stirred at room temperature for 1 h. Sodium triacetoxyborohydride
(0.36 g, 1.93 mmol) was added in one portion. The mixture was
stirred at room temperature under N2 for 16 h. The reaction was
quenched by addition of water (20 mL). The mixture was diluted
with methylene chloride (50 mL) and the layers were separated.
The aqueous layer was extracted with methylene chloride
(2ꢃ30 mL). The combined organic layers were washed with brine
(30 mL), dried over anhydrous Na2SO4, filtered, and concentrated.
The crude product was purified by flash chromatography eluting
with ethyl acetate/hexane (0–30%) to give lactam 38 (0.16 g, 21%
yield over five steps) as a mixture of diastereomers. Mp 102–106 ꢂC.
(m, 6H), 0.58 (m, 3H), 0.52 (m, 3H). 13C NMR
d 174.9, 174.8, 145.8,
145.6, 138.8, 138.6, 136.4, 136.4, 122.8, 121.3, 120.6, 118.8, 118.7, 113.6,
110.1, 110.0, 68.5, 65.4, 57.6, 57.5, 40.3, 39.9, 38.2, 37.6, 37.2, 37.1, 33.1,
32.8, 32.5, 32.3, 31.1, 30.8, 29.7, 29.3, 29.0, 28.2, 28.1, 27.8, 27.3, 25.3,
20.5, 20.4, 20.3,19.7,18.8,18.2,17.2,17.1. MS: (ESI) (MþH)þ m/z 440.3.
HRMS: calcd 439.3201 for C27H41N3O2, found 439.3271.
5.21. Teleocidin B analogs 40 and 41
HPLC separation of alcohol 5: chiralcel AD-H column, 2ꢃ25 cm;
detection at 280 nm; temperature: 25 ꢂC; sample was dissolved in
EtOH, sample concentration: 0.035 g/mL; mobile phase: 5% iso-
propanol in hexane; flow rate: 20 mL/min.; injection volume: 5
in EtOH.
mL
1H NMR (500 MHz, CDCl3)
d (mixture of four diastereomers) 8.25
25
Teleocidin B analog 40: 18 mg, white solid: mp 197–199 ꢂC. [
a]
D
ꢀ353.8 (c, 0.5, CHCl3).1H NMR (500 MHz, CDCl3)
d 8.13 (br s,1H, NH),
(br s, 1H), 7.01 (s, 1H), 6.99 (s, 1H), 5.12 (m, 1H), 4.22 (m, 3H), 3.58
(m,1H), 3.18 (m,1H), 2.75 (s, 3H), 2.61 (m,1H), 2.39 (m,1H),1.85 (m,
2H), 1.66 (m, 2H), 1.47 (m, 3H), 1.39 (m, 3H), 1.26 (m, 6H, 3H each
overlapping), 0.99 (m, 3H), 0.92 (m, 3H), 0.58 (m, 6H). 13C NMR
6.88 (s,1H), 6.52 (s,1H), 4.36 (br,1H), 4.32 (d, J¼12 Hz,1H, H-12), 3.72
(m, 1H), 3.56 (m, 2H), 3.18 (q, J¼15 Hz, 1H, H-8), 3.05 (qd, J¼4, 15 Hz,
1H, H-8), 2.91 (s, 3H), 2.86 (br s, 1H, OH), 2.62 (m, 1H), 2.18 (m, 1H),
1.82 (m, 2H),1.64 (m, 2H),1.48 (s, 3H),1.41 (s, 3H),1.31 (s, 3H),1.01 (d,
J¼9.0 Hz, 3H), 0.96 (d, J¼6.8 Hz, 3H), 0.72 (d, J¼6.7 Hz, 3H), 0.51 (d,
d
(mixture of four diastereomers) 172.2, 172.1, 171.9, 171.2, 171.1,
171.0,170.9,145.3,145.1,142.7,139.6,139.5,139.3,139.2,137.2,136.9,
127.3, 126.8, 126.2, 126.1, 123.1, 123.0, 122.8, 122.3, 121.8, 121.5,
120.8, 120.2, 117.4, 117.1, 113.9, 113.7, 107.6, 107.5, 107.3, 71.2, 71.2,
62.0, 61.8, 61.0, 58.0, 57.8, 55.6, 55.6, 40.2, 39.8, 39.7, 38.0, 37.6, 37.5,
37.4, 37.3, 37.1, 36.1, 35.9,35.9, 35.4, 33.2, 33.1, 33.1, 32.9, 31.1, 31.0,
30.8, 30.0, 29.9, 29.7, 29.0, 28.6, 28.5, 28.4, 28.4, 27.8, 27.7, 27.6, 27.5,
25.6, 25.5, 24.5, 24.4, 21.9, 21.8, 20.4, 19.8, 19.7, 19.5, 19.4, 19.3, 18.3,
18.2, 18.1, 17.3, 17.2, 17.1, 17.1, 14.4, 14.3, 14.2, 14.1. MS: (ESI) (MþH)þ
m/z 482.3. HRMS: calcd 481.3304 for C29H43N3O3, found 481.3308.
J¼9.0 Hz, 3H). 13C NMR
d 174.3, 145.3, 139.2, 137.3, 121.1, 120.6, 117.2,
113.9,106.9, 70.9, 65.1, 55.8, 40.2, 38.0, 37.6, 33.8, 33.1, 32.9, 31.0, 29.7,
28.5, 27.8, 25.7, 21.7, 19.7, 18.1, 17.2. MS: (ESI) (MþH)þ m/z 440.3.
HRMS: calcd 439.3201 for C27H41N3O2, found 439.3201.
25
Teleocidin B analog 41: 13 mg, white solid: mp 173–175 ꢂC. [
a]
D
ꢀ153.8 (c, 0.5, CHCl3). 1H NMR (500 MHz, CDCl3)
d 8.08 (br s, 1H,
NH), 6.81 (s, 1H), 6.42 (s, 1H), 4.38 (br s, 1H), 4.30 (d, J¼12 Hz, 1H, H-
12), 3.76 (m, 1H), 3.59 (m, 1H), 3.53 (br, 1H, OH), 3.16 (q, J¼15 Hz,
1H, H-8), 3.06 (qd, J¼4.2, 15 Hz, 1H, H-8), 2.88 (s, 3H), 2.58 (m, 1H),
2.17 (m, 1H), 1.86 (m, 2H), 1.66 (m, 2H), 1.49 (s, 3H), 1.38 (s, 3H), 1.31
(s, 3H), 0.98 (d, J¼9.1 Hz, 3H), 0.91 (d, J¼6.8 Hz, 3H), 0.62 (d,
5.20. Teleocidin B analogs 5 and 39
J¼6.8 Hz, 3H), 0.56 (d, J¼9.1 Hz, 3H). 13C NMR
d 174.6, 145.7, 138.8,
To a solution of ester 38 (0.15 g, 0.31 mmol) in anhydrous THF
(5 mL) at 0 ꢂC under N2 was added a solution of LiBH4 (0.93 mL,
0.93 mmol, 1 M solution in THF) dropwise. The mixture was stirred
at 0 ꢂC for 3 h until TLC revealed completion of reaction. The mix-
ture was quenched with H2O (10 mL). The mixture was extracted
with ethyl acetate (3ꢃ20 mL). The combined organic layers were
washed with brine (10 mL), dried over anhydrous Na2SO4, filtered,
and concentrated to provide a white solid. The crude product was
purified by flash chromatography eluting with ethyl acetate/hexane
(80–100%) to give alcohol 5 (43 mg, 29% yield) as the first fraction
and alcohol 39 (38 mg, 27% yield) as the second fraction.
137.2, 121.1, 120.6, 116.6, 113.6, 106.8, 70.8, 65.6, 55.7, 39.8, 37.8, 37.7,
33.9, 33.2, 32.6, 31.2, 28.9, 28.4, 27.7, 25.6, 21.9, 19.2, 18.1, 17.1. MS:
(ESI) (MþH)þ m/z 440.3. HRMS: calcd 439.3201 for C27H41N3O2,
found 439.3109.
Acknowledgements
The authors wish to thank Wyeth Research post-doctoral pro-
gram for financial support, colleagues in Discovery Analytical
Chemistry at Wyeth Research for analytical support, Dr. Heedong
Yun and Dr. Yike Ni for their helpful discussions.
Teleocidin B analog 5 (mixture of two diastereomers): mp 165–
169 ꢂC. 1H NMR (500 MHz, CDCl3)
d 8.32 (br, 1H, NH), 8.12 (br, 1H,
NH), 8.06 (br,1H, NH), 7.01 (m,1H), 6.82 (m,1H), 6.57 (s,1H), 6.44 (s,
1H), 4.42 (m, 1H), 4.38 (br, 1H), 4.31 (d, J¼12 Hz, 1H), 4.28 (d,
J¼12 Hz, 1H), 3.74 (m, 2H), 3.56 (m, 2H), 3.18 (m, 2H), 3.06 (m, 1H),
2.98 (m,1H), 2.89 (two sets of singlets, 3H, N–CH3), 2.72 (two sets of
singlets, 3H, N–CH3), 2.62 (m, 2H), 2.18 (m, 2H), 1.83 (m, 4H), 1.62
(m, 4H), 1.49 (m, 3H), 1.47 (s, 3H), 1.42 (m, 3H), 1.41 (m, 3H), 1.32 (m,
3H), 1.31 (m, 3H), 1.01 (m, 6H), 0.96 (m, 6H), 0.72 (m, 3H), 0.62 (m,
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