Total synthesis of tryprostatins A and B

Article abstract of DOI:10.1016/j.tet.2011.05.112

Three distinct synthetic routes to the 2-prenyl tryptophan core skeleton of tryprostatins and their total syntheses are described. The strategies include a traditional gramine-mediated coupling reaction, Fuerstner indole synthesis, and our radical-mediated indole synthesis from o-alkenylphenyl isocyanide. The establishment of reliable conditions for the radical-mediated construction of indoles via a low-temperature radical initiator V-70 (2,2′-azobis(4- methoxy-2,4-dimethylvaleronitrile)) led to the highly efficient syntheses of tryprostatins A and B.

Full text of DOI:10.1016/j.tet.2011.05.112

Tetrahedron 67 (2011) 6547e6560
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of tryprostatins A and B
Takayuki Yamakawa a, Eiji Ideue a, Yuzo Iwaki a, Ayumu Sato a, Hidetoshi Tokuyama b, Jun Shimokawa a,
,
Tohru Fukuyama a
*
a Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
b Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 985-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2011
Received in revised form 26 May 2011
Accepted 26 May 2011
Available online 2 June 2011
Three distinct synthetic routes to the 2-prenyl tryptophan core skeleton of tryprostatins and their total
syntheses are described. The strategies include a traditional gramine-mediated coupling reaction,
€
Furstner indole synthesis, and our radical-mediated indole synthesis from o-alkenylphenyl isocyanide.
The establishment of reliable conditions for the radical-mediated construction of indoles via a low-
temperature radical initiator V-70 (2,20-azobis(4-methoxy-2,4-dimethylvaleronitrile)) led to the highly
efficient syntheses of tryprostatins A and B.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Total Synthesis
Natural product
Radical cyclization
Alkaloids
1. Introduction
O
O
O
O
H
H
N
H
N
H
In cancer chemotherapy, multiple drug resistance to cell cycle
inhibitors often becomes a serious obstacle. One strategy to cir-
cumvent this problem is to develop antimitotic agents that operate
by a new mode of action. Tryprostatins A (1) and B (2), which be-
long to this promising category, were isolated in 1995 from the
fermentation broth of Aspergillus fumigatus BM939 by Osada et al.
(Fig. 1).1 Tryprostatin A seems to have a greater potential because it
selectively arrests the cell cycle at the M phase in tsFT210 cells.2
Interesting biological activities along with seemingly simple
structures have stimulated the synthetic community, and several
total syntheses of 1 and 2 have already been reported to date.3,4
Due to our strong interest in the structural features of tryprosta-
tins as well as the therapeutic potential of their analogues recently
suggested in the SAR study4e by Cook et al., we launched a research
program towards the total synthesis of tryprostatins.
HN
HN
MeO
N
H
N
H
tryprostatin A (1)
tryprostatin B (2)
Fig. 1. Tryprostatins A and B.
synthesis of natural products containing a tryptophan substructure,
including sporidesmin and brevianamide, for example.5 Although
this strategy promises a highly convergent synthesis, one drawback
2. Results and discussion
Scheme 1 summarizes our plans for the synthesis of tryprosta-
tins. We initially envisioned that the introduction of diketopiper-
azine moiety 3 to 2-prenyl gramine intermediate 4 (strategy A). The
chemistry of gramine has been repeatedly applied to the total
* Corresponding author. Tel.: þ81 3 5841 4777; fax: þ81 3 5802 8694; e-mail
Scheme 1. Retrosynthetic analysis for tryprostatins A and B.
address: fukuyama@mol.f.u-tokyo.ac.jp (T. Fukuyama).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.112

6548
T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
may be the generation of a mixture of stereoisomers at the newly
generated stereocenter where the two units join.
Due to the uncertainty in the stereoselective transformation
using strategy A, we also planned two complementary strategies
that do not involve the stereochemical complications. In an attempt
to construct the unstable 2,3-disubstituted indole moiety in the late
6
€
stage of the synthesis, Furstner indole synthesis is to be employed
(strategy B). Intermediate 5 would be readily accessible by a Stille-
type coupling reaction between an arylstannane and an acid
€
chloride. Because the synthesis of 2-prenylindole via the Furstner
protocol is unprecedented, it is not clear whether or not the re-
ductive formation of the indole core would proceed with the prenyl
group intact. The other strategy involves a radical-mediated con-
struction of the indole core structure and a subsequent palladium-
mediated coupling reaction between the 2-stannyl intermediate
and the prenyl group donor to give intermediate 6, which is also
without precedent (strategy C).
2.1. Synthesis based on strategy A
The synthesis via the strategy A began with the construction of
diketopiperazine core unit 12. Following a reported procedure,5b,7
the nitrosation reaction of dimethyl malonate 7 with sodium ni-
trite under acidic conditions gave oxime 8 (Scheme 2). Primary
amine 9, obtained upon hydrogenation of the oxime, was coupled
Scheme 3. Coupling reaction via activated gramine.
short-lived product of the decarboxylation, the facial selectivity of
the protonation determines the product distribution. Table 1 shows
the ratio between 2 and 9-epi-tryprostatin B (21) under different
conditions. Conventional alkaline hydrolysis of the methyl ester and
the subsequent decarboxylation reaction in dioxane gave twice the
amount of 9-epimer 21 to desired product 2 in a combined yield of
66% (entry 1). In an effort to improve the ratio for the desired isomer,
decarbomethoxylation reactions under different conditions were
performed. Lithium iodide in 2,4,6-collidine did not give the desired
products (entry 2). On the other hand, Krapcho decarbomethox-
ylation9 and its modification gave better results. Treatment with
NaCN gave more of the 9-epimer (entry 3), and the ratio of the de-
sired isomer increased upon changing the salt to MgCl2 or NaCl
(entries 4 and 5). The ratio was reversed (2/21¼6:5) by employing
LiCl, and the yield improved to 86% combined yield (entry 6). Hence,
an efficient total synthesis of tryprostatin B (2) was achieved.
with N-Cbz- -proline 10 by treatment with EDCI to afford 11 in 86%
L
yield. Removal of the Cbz group was performed by hydrogenolysis
and subsequent heating in methanol caused cyclization to provide
diketopiperazine core structure 12 in 85% yield as a mixture of two
diastereomers.
Table 1
Total synthesis of tryprostatin B
Scheme 2. Synthesis of the diketopiperazine unit.
Synthesis of the gramine unit, a coupling partner of 12, began
with the introduction of the prenyl group on the C2 of indole
according to the report by Wenkert8 (Scheme 3). Thus, indole 13
was activated with a benzenesulfonyl group on its nitrogen atom
under phase transfer reaction conditions with benzenesulfonyl
chloride. Directed lithiation at C2 of 14 with LDA followed by ad-
dition of prenyl bromide 15 afforded the 2-prenylindole core
structure 16. Removal of the benzenesulfonyl group was effected
under the Birch reduction conditions to provide deprotected indole
17. Transformation to gramine was then carried out by the Mannich
reaction with formalin and dimethylamine in the presence of AcOH
to give 18. After rapid preparation of the two coupling units, con-
densation of these two units was carried out according to the well-
known chemistry of gramine.5 Highly reactive ammonium ion
intermediate 19 was generated in situ by treatment with dimethyl
sulfate, and was subsequently treated with the sodium enolate of
diketopiperazine 12, leading to the formation of a 1:2 mixture of
the two diastereomers 20.
Entry
Conditions
2/21
Yielda (%)
1
2
3
4
5
6
(1) NaOH, MeOH, rt, (2) dioxane, reflux
1:2
d
66
Decomp.
51
71
14
86
LiI, collidine, 90 ꢀC
NaCN, H2O, DMSO, 140 ꢀ
C
1:6
1:3
1:1
6:5
MgCl2$6H2O, DMSO, 140 ꢀ
NaCl, H2O, DMSO, 180 ꢀ
LiCl, H2O, DMSO, 140 ꢀ
C
C
C
a
Isolated yield.
Next, we embarked on the synthesis of tryprostatin A (1) fol-
lowing closely the strategy used for the total synthesis of 2. Since
6-methoxyindole is relatively expensive, we decided to synthesize
the prenylated indole 29 in a different way. The Sonogashira coupling
reaction between 1-bromo-4-methoxy-2-nitrobenzene 22 and
Since 20 possesses the entire carbon skeleton of tryprostatin B
(2), all that remained was to remove the carbomethoxy group to
complete the total synthesis. As either enolate or enol species is the

T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
6549
trimethylsilylacetylene 23 followed by methanolysis gave 24 in 90%
yield (Scheme 4). Introduction of the prenyl moiety failed with the
reaction between prenyl bromide and the lithium acetylide derived
from 24 due to the lability of the product under the reaction condi-
tions. Hence, a copper-mediated coupling reaction was employed.10
The reaction proceeded to afford the coupling product, albeit as an
inseparable 6.5:1 mixture of the regioisomers 25 and 26. The indole
structure was subsequently constructed according to the method we
reported previously.11 A mixture of adducts 25 and 26 was directly
dissolved in pyrrolidine and heated to 50 ꢀC. While the minor isomer
26 remained unchanged during the reaction, 25 was transformed
into enamine intermediate 27. The enamine 27 was subsequently
subjected to acid hydrolysis to afford the ketone 28.
Scheme 5. Total synthesis of tryprostatin A (1).
reaction using lithium chloride in aq DMSO gave a 4:3 mixture of 1
and 9-epimer 32 in 70% yield. The low selectivity of the last step
notwithstanding, the syntheses of tryprostatins A (1), and B (2)
constitute a convergent synthetic route to these natural products.
2.2. Synthesis based on strategy B
In pursuit of a more convergent synthetic route, we examined
6
€
the process involving Furstner indole synthesis as a key step.
Synthesis of 3-methyl-2-prenylindole 37 was initially examined to
explore the feasibility of this reaction to construct the
2-prenylindole structure. 4-Methyl-3-pentenoic acid (33) was
converted into the corresponding acid chloride 34,12 which was
coupled with 2-amino acetophenone 35 under biphasic reaction
Scheme 4. Construction of the indole precursor.
The remaining task was to reduce the nitro group in 28 without
affecting the olefin moiety in the prenyl group (Table 2). Reduction
with iron or tin(II) chloride led to the extensive decomposition of
the starting material (entries 1 and 2). Hydrogenation over Lindlar
catalyst gave a compound with the prenyl group reduced to satu-
ration (entry 3). Only a small quantity (1%) of the desired product
was obtained when sodium dithionite was used as a reductant
(entry 4). However, a zinc-mediated reduction, especially with TFA
as an acid, gave 29 in acceptable yield. With the desired 2-
prenylindole 29 in hand, transformation to 1 was carried out
along the lines developed in our earlier synthesis of 2 (Scheme 5).
Thus, 29 was converted into gramine intermediate 30 by the
Mannich reaction, and the product was coupled with the carbanion
derived from diketopiperazine 12 via an ammonium intermediate
to give 31 in 60% yield in two steps. A decarbomethoxylation
€
conditions to afford 36 in 51% yield (Scheme 6). Furstner indole
synthesis was then applied to this system to evaluate whether or
not the prenyl group survives. To our delight, the reductive cou-
pling reaction proceeded via a combination of TiCl4 and magnesium
metal, affording 37 without any sign of isomerization or de-
composition of the olefin moiety. Next, we examined the applica-
bility of this reaction to the synthesis of tryprostatin B.
Table 2
Construction of the 2-prenylindole moiety
€
Scheme 6. Furstner indole synthesis.
Aryl ketone 42 was synthesized according to Salituro’s pro-
cedure13 (Scheme 7).
L-Aspartic acid 38 was protected with a Cbz
group and the
a-amino acid moiety was protected as the methylene
Entry
Conditions
Yield (%)
acetal in 84% yield under DeaneStark conditions. The acid chloride
40 derived from 39 was coupled with stannyl aniline 41 under the
conditions of the Stille coupling to give aryl ketone 42. We decided
to assemble the diketopiperazine core before the formation of the
unstable 2,3-indole moiety. Since alkaline hydrolysis of the lactone
42 with LiOH led to decomposition, an alternative two-step pro-
cedure, involving triethylamine-mediated methanolysis and sub-
sequent hydrolysis of methyl ester 43, was employed. The
1
2
3
4
5
6
Fe, FeCl2, EtOH, reflux
SnCl2$2H2O, EtOH, rt
Lindlar cat., H2, MeOH, rt
Na2S2O4, K2CO3, H2O/DMF, rt
Zn, AcOH, rt
0a
0a
0b
1
29
59
Zn, TFA, CH2Cl2, rt
a
Starting material decomposed.
Olefin moiety was reduced.
b

6550
T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
2.3. Synthesis based on strategy C14
Our laboratory has long been engaged in the radical-mediated
construction of indoles and the application of our methods to total
synthesis of natural products.15,16 We thus envisioned that our method
could be applied to the synthesis of the 2,3-disubstituted indole
moiety of tryprostatins. As observed in our model studies, the
thioamide-basedindolesynthesiscannotbe appliedtothiscasesimply
because of the undesired intramolecular radical attack to the 2-prenyl
group of the intermediate indole. Accordingly, we decided to employ
our isocyanide-based indole synthesis (Scheme 9). Radical cyclization
and subsequent palladium-mediated coupling with a prenyl group
donor would enable the facile construction of 2,3-disubstituted indole
6. The requisite ortho-alkenyl isocyanide 50 would be prepared from
Garner’s aldehyde 51,17 which contains a latent amino acid unit to be
used for construction of the diketopiperazine at the late stage.
Scheme 9. Retrosynthesis.
Initially, we focused our efforts on the synthesis of isocyanide 57
as a radical cyclization precursor (Scheme 10). Alkyne 53 was
prepared from 51 via dibromo olefin 52 using a slight modification
of the known protocol.18 After Sonogashira coupling between 53
and 2-iodoformanilide 54, partial reduction of the triple bond in 55
was examined. While the use of Lindlar’s catalyst, Pd/C, nickel bo-
ride,19 or diimide20 resulted in no reaction or an overreduction,
treatment with Zn/LiCuBr2 in ethanol21 gave the desired olefin 56
along with the corresponding deformylated amine. Use of 2,2,2-
trifluoroethanol22 as a solvent could suppress the undesired sol-
volysis, resulted in improvement of the yield of 56 to as high as 99%.
Subsequent dehydration with triphosgene gave ortho-alkenyl iso-
cyanide 57, which set the stage for the radical-mediated cyclization.
When isocyanide 57 was subjected to the radical cyclization
conditions15a established in our laboratories, the desired 5-exo
adduct 58 was obtained in moderate yield along with a consider-
able amount of 6-endo cyclization-cleavage adduct, 59 and 60, after
acidic treatment with silica gel (Scheme 11). The imidoyl radical
cyclization tended to form a mixture of 5-exo and 6-endo products
Scheme 7. Construction of the 2-aminoaryl ketone.
carboxylic acid 44 thus obtained was then subjected to an HBTU-
mediated condensation with -proline methyl ester hydrochloride
L
45 to afford amide 46 in 65% yield in three steps from 42. Hydro-
genolysis of the Cbz group in 46 was accelerated by addition of
AcOH with a concomitant cyclization to give the diketopiperazine
47 in 76% yield.
With the diketopiperazine moiety assembled, we next pro-
€
ceeded to examine whether the Furstner indole synthesis would be
applicable to the total synthesis of tryprostatin B. Deprotection of
the aniline group followed by acylation gave amide 49 in moderate
yield due to the poor reactivity of aniline 48 (Scheme 8). When keto
amide 49 was subjected to the same conditions used for 36, try-
prostatin B 2 was obtained albeit in very low yield (20%). The poor
results might be attributable to the decomposition of the prenyl
group and the 2,3-disubstituted indole skeleton as well as the un-
desired participation of the diketopiperazine moiety. Because of the
difficulties in optimizing the reaction conditions, we decided to
pursue an alternative strategy.
O
Cl
O
O
O
34
H
H
TFA
pyridine
N
H
N
H
BocHN
O
HN
NH2
O
HN
CH2Cl2
rt
CH2Cl2, rt
O
57% (2 steps)
47
48
O
O
H
H
Mg (8.0 eq)
N
N
TiCl4 (2.0 eq)
O
NH
O
HN
HN
N
H
H
THF, rt
H
O
O
20%
49
tryprostatin B (2)
Scheme 8. Total synthesis of tryprostatin B.
Scheme 10. Synthesis of o-alkenyl isocyanide.

T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
6551
Pd(PPh3)4 as a catalyst, albeit in 29% yield (entry 2). Further in-
vestigations revealed that the combination of Pd2(dba)3, ligand,
and lithium chloride gave the best results (entries 3 and 4). Using
triphenylarsine as a ligand, the desired product 64 was obtained in
73% yield in a one-pot process from isocyanide 57.
Once construction of the indole moiety was complete, 64 was
converted into the corresponding amino acid 66 in a three-step se-
quence consisting of protection of the indole with a Boc group, hy-
drolysis of the acetonide, and TEMPO oxidation of the resulting
alcohol 65 into carboxylic acid 66 (Scheme 12). After condensation
with -proline methyl ester hydrotosylate 67, the remaining trans-
L
formation involved the removal of the two Boc groups in 68 and
cyclization to construct the diketopiperazine core. Unexpectedly,
the conventional method to remove the Boc groups under acidic
conditions caused substantial decomposition of the substrate. Thus,
thermal removal of the Boc groups was attempted.24 After optimi-
zation, this transformation was best accomplished by heating the
substrate under reflux in N-methyl pyrrolidinone. Under these
conditions, spontaneous cyclization gave 2 in 89% yield. Hence, we
have established a 11-step synthetic route for tryprostatin B from 51
with a 33% overall yield on a half gram scale.
Scheme 11. Attempted radical cyclization.
when the intermediate radical of 5-exo cyclization was not stabi-
lized by the neighboring substituents.16 Although our previous
studies showed that the 5-exo cyclization is dominant under ki-
netically controlled conditions,15e generally applicable conditions
for the formation of 2-stannylindole have yet to be established. In
an attempt to lower the reaction temperature, V-70 (2,20-azobis(4-
methoxy-2,4-dimethyl valeronitrile)) 6123 was employed as a radi-
cal initiator, which is known to decompose at lower temperature
than AIBN. Fortunately, the radical cyclization of isocyanide 57
initiated by V-70 virtually suppressed the formation of the 6-endo
adduct. Moreover, it showed complete selectivity for the cyclization
of the imidoyl radical, giving 2-stannylindole 62 as the sole product
(Table 3). Although we have already reported a one-pot Stille-type
coupling reaction between aromatic or vinylic halides and
2-stannylindole generated in situ to prepare 2,3-disubstituted
indoles,15a coupling reactions with allylic systems have yet to be
examined. Table 3 shows the results of the optimization of the
palladium-mediated coupling reaction. When 2-prenyl bromide
(15) was used as the prenyl source, the desired product was not
observed (entry 1). Whereas the coupling partner was changed to
2-prenyl acetate 63, the desired product was obtained with
Scheme 12. Total synthesis of tryprostatin B.
Table 3
Construction of 2-prenylindole
Entry
X (3.0 equiv)
Catalyst (10 mol %)
Ligand (40 mol %)
Additive
Yield (%)
1
2
3
4
Br (15)
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
d
Et3N (10 equiv)
LiCl (3.0 equiv)
LiCl (3.0 equiv)
LiCl (3.0 equiv)
Trace
29
45
OAc (63)
OAc (63)
OAc (63)
d
P(o-furyl)3
AsPh3
73

6552
T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
After establishing a generally applicable method to prepare 2-
an ensuing palladium-mediated coupling reaction at C2, a variety of
2,3-disubstituted indoles, such as tryprostatins A and B, can now be
prepared. Further investigations into the synthesis and biological
assay of tryprostatin analogues are currently underway.
stannylindoles using V-70, we initiated the total synthesis of try-
prostatin A (1) to showcase the synthetic utility of the protocol
(Scheme 13). The synthesis commenced by preparing 69 from 4-
methoxy-2-nitroaniline in a two step, slightly modified sequence,
including the Sandmeyer reaction, iron-mediated reduction.4c Fol-
lowing the route established for tryprostatin B, tryprostatin A (1)
was synthesized in 30% overall yield from 69 on a half gram scale.
4. Experimental section
4.1. General
All non-aqueous reactions were carried out under an inert at-
mosphere of argon in oven-dried glassware unless otherwise
noted. Dehydrated diethyl ether, tetrahydrofuran, methylene
chloride and toluene were obtained by passing commercially
available pre-dried, oxygen-free formulations through activated
alumina columns. Dehydrated N,N-dimethylformamide, 1,4-
dioxane, and dimethylsulfoxide were purchased from Kanto
Chemicals Co., Inc. and stored over activated MS4A. Dehydrated
methanol, ethanol and acetonitrile were also purchased from Kanto
Chemicals Co., Inc. and stored over activated MS3A. N-methyl
pyrrolidinone was purchased from Tokyo Chemical Industry Co.,
Ltd. and distilled before use. V-70 was purchased from Wako Pure
Chemical Industries, Ltd. All other reagents were commercially
available and used without further purification. Analytical thin
layer chromatography (TLC) was performed on Merck precoated
analytical plates, 0.25 mm thick, silica gel 60F254. Preparative flash
chromatography was performed using Silica Gel 60 (spherical,
40e100 mm) purchased from Kanto Chemical Co., Inc. Preparative
reverse-phase flash chromatography was performed using Cos-
mosil 75C18-PREP purchased from Nacalai Tesque Inc. 1H and 13C
NMR were recorded on a JEOL LA-400 spectrometer. All 1H NMR
spectra are reported in
d units, parts per million (ppm) downfield
from tetramethylsilane as the internal standard and coupling con-
stants are indicated in hertz (Hz).The following abbreviations are
used for spin multiplicity: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad. All 13C NMR spectra are
reported in ppm relative to the central line of the triplet for CDCl3 at
77.0 ppm. Infrared spectra (IR) were recorded on a JASCO FT/IR-410
Fourier Transform Infrared Spectrophotometer, and are reported in
wavenumbers (cmꢁ1). High resolution mass spectra (HRMS) were
obtained on a JEOL JMS-GCmate MS-DIP20 or on a JEOL JMS-T100LP
AccuTOF LC-plus either in positive electrospray ionization (ESI)
method or in positive direct analysis in real time (DART) ionization
method, using PEG as the internal standard. Optical rotations were
measured on a JASCO DIP-1000 Digital Polarimeter at room tem-
perature, using the sodium D line. Melting points, determined on
a Yanaco Micro Melting Point Apparatus, are uncorrected.
4.1.1. (8aS)-Methyl
3-((2-(3-methylbut-2-en-1-yl)-1H-indol-3-yl)
methyl)-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-3-carboxylate
Scheme 13. Total synthesis of tryprostatin A.
(20). To a solution of 2-prenylindole 17 (372 mg, 2.01 mmol) in
dioxane (8.0 mL) were added formalin (210
thylamine hydrochloride (245 mg, 3.02 mmol), and acetic acid
(950 L, 16.6 mmol). The reaction mixture was stirred for 1 h at
mL, 2.8 mmol), dime-
3. Conclusion
m
We have established three synthetic routes to the core structure
of tryprostatins. The first strategy confirmed the efficiency of
a gramine-mediated coupling reaction to construct a tryptophan
skeleton. However, the stereoselectivity was low in regard to the
junction between the diketopiperazine and the 2-substituted in-
room temperature before the reaction was quenched with satu-
rated aq NaHCO3. The aqueous layer was extracted with EtOAc, and
the combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure to give
18. The residue was used in the next reaction without further pu-
rification. To a stirred solution of 12 (405 mg, 1.91 mmol) in DMF
(4.0 mL) was added NaH (60% in mineral oil, 83 mg, 2.0 mmol)
followed by crude 18, which was pretreated with dimethyl sulfate
€
dole. In addition, we have shown that the Furstner indole synthesis
could be applied to the synthesis of 2-prenyl-3-substituted indole
system. Unfortunately, we were unable to improve the yield of
tryprostatin B through this route. Finally, we employed our radical-
mediated indole synthesis as the key reaction. Optimization of the
reaction conditions by means of V-70 allowed a facile synthesis of
2-stannyl-3-substituted indoles where the substituents at C3 could
not effectively stabilize the incipient radical. In combination with
(220 mL, 2.3 mmol) in DMF (4.0 mL) at room temperature for 5 min.
The mixture was stirred for 1 h at room temperature and then
heated for 1 h at 50 ꢀC under an argon before the reaction was
quenched with saturated aq NH4Cl. The aqueous layer was
extracted with EtOAc, and the combined organic extracts were

T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
6553
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (60% EtOAc in n-hexane) to afford 20
(691 mg, 88%) as a yellow foam. The ratio between less polar isomer
J¼8.4 Hz), 7.55 (1H, d, J¼2.8 Hz), 7.12 (1H, dd, J¼8.4, 2.8 Hz), 3.90
(3H, s), 3.40 (1H, s); 13C NMR (CDCl3, 100 MHz)
d 159.9, 136.4, 119.6,
109.4, 109.4, 83.2, 78.5, 56.0; HRMS (FAB) calcd for C9H7NO3 (Mþ)
177.0426, found 177.0425.
and more polar isomer was 1:2. Less polar isomer: [
a
]
D
24 ꢁ2.9 (c 0.54,
CHCl3); IR (film, cmꢁ1) 3350, 2956, 1741, 1678, 1433, 1213; 1H NMR
4.1.4. 1-(4-Methoxy-2-nitrophenyl)-5-methylhex-4-en-2-one
(CDCl3, 400 MHz)
d
8.04 (1H, br s), 7.41 (1H, d, J¼8.0 Hz), 7.30 (1H,
(28). To a solution of 24 (463 mg, 2.61 mmol) in DMF (10 mL) were
added 2-prenyl bromide (15) (520 mL, 4.4 mmol), K2CO3 (722 mg,
dd, J¼8.0, 6.4 Hz), 7.13e7.07 (2H, m), 6.02 (1H, s), 5.28 (1H, t,
J¼7.2 Hz), 4.03e3.99 (2H, m), 3.80 (3H, s), 3.68e3.58 (2H, m),
3.51e3.36 (3H, m), 2.40e2.33 (1H, m), 2.05e2.01 (2H, m), 1.91e1.87
5.22 mmol), CuI (498 mg, 2.61 mmol), and tetrabutylammonium
bromide (419 mg, 1.30 mmol) at room temperature. The reaction
mixture was stirred for 4 h at 50 ꢀC before it was partitioned be-
tween Et2O and saturated aq NH4Cl. The aqueous layer was
extracted with Et2O, and the combined organic extracts were
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (20% EtOAc in n-hexane) to afford
inseparable mixture of 4-methoxy-1-(5-methylhex-4-en-1-yn-1-
yl)-2-nitrobenzene (25) and 1-(3,3-dimethylpent-4-en-1-yn-1-
yl)-4-methoxy-2-nitrobenzene (26) as a yellow oil (484 mg, 75%,
25/26¼6.5:1). A solution of 25 and 26 (348 mg, 1.42 mmol) in
pyrrolidine (1.8 mL, 21 mmol) was stirred at 50 ꢀC for 1 h. After
removal of pyrrolidine on a rotary evaporator, 30% aq AcOH
(2.0 mL) was added to the reaction mixture. After stirring for
10 min at room temperature, the reaction was quenched by the
addition of saturated aq NaHCO3. The reaction mixture was diluted
with EtOAc and the organic phase was washed with brine. The
organic extracts were dried over MgSO4, filtered, and concentrated
to afford the crude product. The crude product was purified by flash
column chromatography on silica gel (5% EtOAc in n-hexane) to
afford 26 (52.0 mg, 15%). Further elution with 10% EtOAc in n-
(1H, m), 1.79 (3H, s), 1.75 (3H, s); 13C NMR (CDCl3, 100 MHz)
d 170.1,
169.3, 162.4, 137.3, 135.7, 135.4, 128.5, 121.9, 120.2, 119.5, 118.0, 110.7,
102.3, 66.5, 59.2, 53.7, 46.3, 29.4, 28.7, 25.7, 25.1, 22.6, 18.0; HRMS
(FAB) calcd for C23H27N3O4 (Mþ) 409.2002, found 409.1998. More
polar isomer: [
a]
24 ꢁ41 (c 0.92, CHCl3); IR (film, cmꢁ1) 3300, 2956,
D
1752, 1654, 1434, 1342, 1251; 1H NMR (CDCl3, 400 MHz)
d
8.02 (1H,
s), 7.51 (1H, d, J¼8.0 Hz), 7.25 (1H, m), 7.11e7.04 (2H, m), 6.48 (1H,
s), 5.29 (1H, t, J¼7.2 Hz), 3.96 (1H, d, J¼14.8), 3.92 (3H, s), 3.47e3.44
(3H, m), 3.23 (1H, d, J¼14.8 Hz), 2.97e2.92 (1H, m), 2.06e2.01 (1H,
m), 1.90e1.82 (1H, m), 1.78 (3H, s), 1.74e1.71 (1H, m), 1.73 (3H, s),
1.70e1.68 (1H, m), 1.11e1.07 (1H, m); 13C NMR (CDCl3, 100 MHz)
d
168.8, 168.1, 162.2, 137.5, 135.9, 134.8, 128.5, 121.6, 119.7, 119.3,
118.5, 110.4, 103.4, 69.3, 57.7, 53.7, 45.3, 32.9, 28.9, 25.8, 24.9, 21.2,
18.0; HRMS (FAB) calcd for C23H27N3O4 (Mþ) 409.2002, found
409.2008.
4.1.2. Tryprostatin B (2) and 9-epi-tryprostatin B (21). A mixture of
20 (31 mg, 0.074 mmol), lithium chloride (16 mg, 0.37 mmol), and
H2O (10 m
L) in DMSO (1.0 mL) was stirred for 30 min at 140 ꢀC
under an argon atmosphere. The resulting mixture was poured into
brine and extracted with CHCl3. The extract was evaporated to af-
ford a syrup, which was purified by preparative TLC (5% MeOH/
hexane afforded 28 (298 mg, 80%) as a yellow oil. IR (film, cmꢁ1
)
3423, 2970, 2916, 2063, 1720, 1626, 1572, 1533, 1504, 1444, 1404,
CH2Cl2) to give tryprostatin B (2) (12.3 mg, 47%) and 9-epi-try-
1352, 1286, 1254, 1188, 1109, 1066, 1036; 1H NMR (CDCl3, 400 MHz)
24
prostatin B (21) (10.2 mg, 39%). Compound 21: [
a
]
ꢁ19 (c 0.28,
d
7.64 (1H, d, J¼2.4 Hz), 7.17e7.11 (2H, m), 5.36 (1H, t, J¼7.2 Hz),
4.04 (2H, s), 3.87 (3H, s), 3.28 (2H, d, J¼7.2 Hz), 1.78 (3H, s), 1.67 (3H,
s); 13C NMR (CDCl3, 100 MHz)
204.9, 159.1, 136.4, 134.2, 122.5,
D
CHCl3); IR (film, cmꢁ1) 3280, 2971, 2923, 2885, 1652, 1456, 1340,
1305, 1117; 1H NMR (CDCl3, 400 MHz)
d
7.95 (1H, br), 7.51 (1H, d,
d
J¼8.4 Hz), 7.13e7.05 (2H, m), 6.02 (1H, br), 5.30 (1H, t, J¼7.2 Hz),
4.26e4.23 (1H, m), 3.54e3.49 (1H, m), 3.44e3.38 (3H, m),
3.18e3.11 (2H, m), 2.70e2.67 (1H, m), 2.04e2.00 (1H, m), 1.90e1.65
(2H, overlapped), 1.79 (3H, s), 1.75 (3H, s), 1.38e1.34 (1H, m); 13C
120.2, 115.5, 109.8, 55.8, 46.6, 42.5, 25.7, 18.1; HRMS (FAB) calcd for
C14H17NO4 (Mþ) 263.1158, found 263.1154.
4.1.5. 6-Methoxy-2-(3-methylbut-2-enyl)-indole (29). To a mixture
of 28 (735 mg, 2.80 mmol) and activated zinc dust (1.80 g,
27.5 mmol) in CH2Cl2 (14 mL) was added trifluoroacetic acid
(2.5 mL, 34 mmol) over a period of 15 min at 0 ꢀC. The reaction
mixture was stirred for 1 h at room temperature before the reaction
was quenched with saturated aqueous NaHCO3. The aqueous layer
was extracted with Et2O, and the combined organic extract was
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (20% EtOAc in n-hexane) to afford 6-
methoxy-2-(3-methylbut-2-enyl)-indole 29 (352 mg, 59%) as col-
orless crystals. Mp 87.0e90.2 ꢀC; IR (film, cmꢁ1) 3388, 2925, 1626,
NMR (CDCl3, 100 MHz)
d 170.0, 165.6, 136.7, 135.6, 135.0, 128.3,
121.6, 119.7, 119.5, 118.3, 110.4, 104.4, 58.7, 57.7, 45.1, 29.3, 25.8, 25.8,
24.9, 21.5, 17.9; HRMS (FAB) calcd for C21H25N3O2 (Mþ) 351.1947,
found 351.1944.
4.1.3. 1-Ethynyl-4-methoxy-2-nitrobenzene (24). To a solution of 1-
bromo-4-methoxy-2-nitrobenzene 22 (1.70 g, 7.3 mmol) in THF
(8.0 mL) and triethylamine (8.0 mL) were added Cul (140 mg,
0.735 mmol) and PdCl2(PPh3)2 (258 mg, 0.368 mmol) at room
temperature under an argon atmosphere. Trimethylsilylacetylene
(23) (1.50 mL, 11 mmol) was added slowly to the mixture, and the
resulting suspension was stirred at room temperature for 1 h. The
reaction was quenched with H2O and the resulting mixture was
partitioned between Et2O and H2O. The aqueous layer was extrac-
ted with Et2O, and the combined organic extracts were washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was dissolved in MeOH (10 mL), to
which was added K2CO3 at room temperature. The reaction mixture
was stirred for 10 min before it was partitioned between Et2O and
H2O. The aqueous layer was extracted with Et2O, and the combined
organic extracts were washed with brine, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (20% EtOAc
in n-hexane) to afford 24 (1.20 g, 90% in two steps) as a yellow
crystals. Mp 84.2e86.4 ꢀC; IR (film, cmꢁ1) 3284, 3079, 2987, 1617,
1549, 1454, 1309, 1159, 1028; 1H NMR (CDCl3, 400 MHz)
d 7.75 (1H,
s), 7.39 (1H, d, J¼8.8 Hz), 6.82 (1H, s), 6.74 (1H, dd, J¼8.8, 2.0 Hz),
6.15 (1H, d, J¼2.0 Hz), 5.38 (1H, t, J¼7.2 Hz), 3.83 (3H, s), 3.45 (2H, d,
J¼7.2 Hz), 1.74 (3H, s), 1.60 (3H, s); 13C NMR (CDCl3, 100 MHz)
d
155.7, 137.4, 136.6, 134.37, 123.1, 120.4, 120.3, 109.0, 99.1, 94.5, 55.7,
27.1, 25.8, 17.8; HRMS (FAB) calcd for C14H17NO (Mþ) 215.1310,
found 215.1310.
4.1.6. (8aS)-Methyl 3-((6-methoxy-2-(3-methylbut-2-en-1-yl)-1H-
indol-3-yl)methyl)-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-3-
carboxylate (31). To a solution of 6-methoxy-2-(3-methylbut-2-
enyl)-indole 29 (44.0 mg, 0.204 mmol) in dioxane (1.0 mL) were
added formalin (21
(25.0 mg, 0.307 mmol), and acetic acid (13
action was stirred for 1 h at room temperature before the reaction
m
L, 0.30 mmol), dimethylamine hydrochloride
mL, 0.21 mmol). The re-
1528, 1353, 1276, 1035; 1H NMR (CDCl3, 400 MHz)
d 7.60 (1H, d,

6554
T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
was quenched with saturated aq NaHCO3. The aqueous layer was
extracted with EtOAc, and the combined organic extracts were
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure to give 30. The residue was used in the next
reaction without further purification. To a stirred solution of 12
(51.0 mg, 0.240 mmol) in DMF (1.0 mL) was added NaH (60% in
mineral oil, 9.6 mg, 0.24 mmol) followed by crude 30, which was
added lithium hydroxide monohydrate (74.0 mg, 1.77 mmol) at 0 ꢀC
and the reaction mixture was stirred at room temperature for 1 h.
The reaction was quenched with 1 M aq HCl. After addition of
EtOAc, the aqueous phase was extracted with EtOAc twice and the
combined organic phase was washed with brine and dried over
anhydrous MgSO4. The solvent was removed under reduced pres-
sure and the crude product was used in the next reaction without
pretreated with dimethyl sulfate (21
mL, 0.22 mmol) in DMF
purification. To a solution of crude 44 and L-proline methyl ester
(1.0 mL) at room temperature for 5 min. The mixture was stirred for
1 h at room temperature and then heated for 1 h at 50 ꢀC under an
argon atmosphere before the reaction was quenched with satu-
rated aq NH4Cl. The aqueous layer was extracted with EtOAc, and
the combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by preparative TLC (5% MeOH in CH2Cl2) to
afford condensed product 31 (49 mg, 60%) as a yellow foam. The
hydrochloride 45 (221 mg, 1.70 mmol) in THF (8.0 mL) were added
HBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hex-
afluorophosphate) (644 mg, 1.70 mmol) and N,N-diisopropylethyl-
amine (560 m
L, 3.1 mmol) at 0 ꢀC. The resulting mixture was stirred
at 0 ꢀC for 2.5 h and was partitioned between EtOAc and saturated
aq NH4Cl. The aqueous phase was extracted with EtOAc and the
combined organic phase was washed with brine and dried over
anhydrous MgSO4. The solvent was removed under reduced pres-
sure and the residue was purified by column chromatography on
ratio between less polar isomer and more polar isomer was 1:2.2.
24
Less polar isomer: [
a]
ꢁ2.0 (c 0.28, CHCl3); IR (film, cmꢁ1) 3350,
silica gel (25% EtOAc in n-hexane) to afford 46 (250 mg, 65% in three
D
22
2954, 1741, 1677, 1409, 1214, 1159, 1030; 1H NMR (CDCl3, 400 MHz)
steps) as a pale yellow solid. [
a
]
ꢁ38 (c 1.00, CHCl3); IR (film,
D
d
7.91 (1H, br), 7.28 (1H, d, J¼6.4 Hz), 6.80 (1H, s), 6.75 (1H, t,
cmꢁ1) 3262, 2924, 1729, 1653, 1581, 1522, 1450, 1366, 1305, 1153,
J¼6.4 Hz), 6.02 (1H, s), 5.26 (1H, t, J¼7.2 Hz), 4.03e3.99 (2H, m),
3.82 (3H, s), 3.79 (3H, s), 3.76e3.59 (2H, m), 3.46e3.32 (3H, m),
2.39e2.33 (1H, m), 2.05e1.99 (2H, m), 1.97e1.86 (1H, m), 1.79 (3H,
1048, 1025, 754; 1H NMR (CDCl3, 400 MHz)
d
10.84 (1H, br s), 8.46
(1H, d, J¼8.5 Hz), 7.80 (1H, d, J¼7.8 Hz), 7.46 (1H, t, J¼7.6 Hz), 6.92
(1H, t, J¼7.4 Hz), 6.39 (1H, d, J¼8.5 Hz), 5.18e5.05 (3H, m), 4.47 (1H,
d, J¼6.2 Hz), 3.88e3.78 (2H, m), 3.66 (3H, s), 3.45 (2H, m),
2.30e2.15 (1H, m), 2.15e1.90 (3H, m), 1.52 (9H, s); 13C NMR (CDCl3,
s), 1.75 (3H, s); 13C NMR (CDCl3, 100 MHz)
d 170.1, 169.3, 162.4,
156.3, 136.2, 135.9, 135.5, 122.7, 119.8, 118.7, 109.6, 102.2, 94.6, 66.4,
59.2, 55.7, 53.7, 46.3, 31.6, 29.5, 28.7, 25.7, 25.1, 22.6, 18.0; HRMS
(FAB) calcd for C24H29N3O5 (Mþ) 439.2107, found 439.2110. More
100 MHz) d 200.5,172.6,170.7,156.3,153.4,142.2,136.5,135.5,131.3,
128.8, 128.5, 128.4, 126.9, 121.5, 119.5, 80.9, 67.4, 59.6, 52.5, 49.4,
47.5, 42.4, 29.3, 28.7, 25.1; HRMS (FAB) calcd for C29H36N3O8
(MþHþ) 554.2502, found 554.2484.
polar isomer: [
a
]
24 ꢁ26 (c 0.40, CHCl3); IR (film, cmꢁ1) 3298, 2954,
D
1755, 1655, 1437, 1250, 1159, 1032; 1H NMR (CDCl3, 400 MHz)
d
7.88
(1H, s), 7.39 (1H, d, J¼8.8 Hz), 6.76e6.72 (2H, m), 6.31 (1H, s), 5.28
(1H, t, J¼7.2 Hz), 3.96 (1H, d, J¼14.8 Hz), 3.90 (3H, s), 3.80 (3H, s),
3.55e3.41 (3H, m), 3.23 (1H, d, J¼14.8 Hz), 3.20e2.98 (1H, m),
2.18e2.06 (1H, m), 1.94e1.89 (1H, m), 1.75 (3H, s), 1.70e1.61 (2H,
m), 1.69 (3H, s), 1.27e1.19 (1H, m); 13C NMR (CDCl3, 100 MHz)
4.1.9. tert-Butyl (2-(2-((3S,8aS)-1,4-dioxooctahydropyrrolo[1,2-a]pyr-
azin-3-yl)acetyl)phenyl)carbamate (47). A mixture of 46 (143 mg,
0.258 mmol), 10% palladium on carbon (55.0 mg), and acetic acid
(15.0 mL, 0.26 mmol) in EtOH (1.5 mL) was stirred under 1 atm of
d
168.8, 168.0, 162.2, 156.0, 136.2, 135.7, 135.5, 122.8, 119.4, 119.2,
hydrogen for 13.5 h. The reaction mixture was filtered through
109.3, 103.1, 94.2, 69.3, 57.8, 55.6, 53.7, 45.3, 33.1, 28.8, 25.8, 24.8,
22.6, 18.0; HRMS (FAB) calcd for C24H29N3O5 (Mþ) 439.2107, found
439.2103.
a pad of Celite and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
22
(EtOAc) to afford 47 (69.9 mg, 76%) as a white solid. [
a
]
ꢁ188 (c
D
1.00, CHCl3); IR (film, cmꢁ1) 2923, 1728, 1651, 1580, 1520, 1449,
4.1.7. Tryprostatin A (1) and 9-epi-tryprostatin A (32). A mixture of
31 (12.9 mg, 0.0294 mmol), lithium chloride (3.2 mg, 0.075 mmol),
1366, 1305, 1152, 1025, 749; 1H NMR (CDCl3, 400 MHz)
d
10.76 (1H,
br s), 8.49 (1H, d, J¼8.0 Hz), 7.92 (1H, d, J¼8.3 Hz), 7.56 (1H,
t, J¼8.5 Hz), 7.05 (1H, t, J¼8.2 Hz), 6.54 (1H, br s), 4.62 (1H, d,
J¼9.8 Hz), 4.23e4.12 (2H, m), 3.70e3.55 (2H, m), 3.22 (1H, dd,
J¼18.6, 9.8 Hz), 2.44e2.36 (1H, m), 2.09e2.01 (2H, m), 1.96e1.92
and H2O (10 mL) in DMSO (500 m
L) was stirred for 30 min at 160 ꢀC
under an argon atmosphere. The resulting mixture was poured into
brine and extracted with CHCl3. The extract was evaporated to af-
ford a syrup, which was purified by preparative TLC (5% MeOH/
CH2Cl2) to give tryprostatin A (1) (4.5 mg, 40%) and 9-epi-trypros-
(1H, m), 1.54 (9H, s); 13C NMR (CDCl3, 100 MHz)
d 200.4, 169.4,
164.4, 152.5, 141.7, 135.2, 130.5, 120.8, 120.0, 118.9, 80.4, 58.6, 51.3,
45.3, 40.6, 28.0, 27.9, 22.1; HRMS (FAB) calcd for C20H25N3O5 (Mþ)
387.1794, found 387.1784.
tatin A (32) (3.3 mg, 30%). Compound 32: [
a]
23 ꢁ7.5 (c 0.24, CHCl3);
D
IR (film, cmꢁ1) 3284, 2929, 2927, 1653, 1461, 1402, 1250, 1159; 1H
NMR (CDCl3, 400 MHz)
d
7.79 (1H, br s), 7.37 (1H, d, J¼8.0 Hz),
6.78e6.73 (2H, m), 5.80 (1H, s), 5.28 (1H, t, J¼9.2 Hz), 4.23 (1H, m),
3.82 (3H, s), 3.56e3.49 (1H, m), 3.44e3.34 (3H, m), 3.19e3.07 (2H,
m), 2.74e2.70 (1H, m), 2.07e2.05 (1H, m), 1.90e1.66 (2H, over-
lapped), 1.79 (3H, s), 1.75 (3H, s), 1.43e1.38 (1H, m); 13C NMR
4.1.10. N-(2-(2-((3S,8aS)-1,4-Dioxooctahydropyrrolo[1,2-a]pyrazin-
3-yl)acetyl)phenyl)-4-methylpent-3-enamide (49). To a solution of
47 (64.0 mg, 0.170 mmol) in CH2Cl2 (0.75 mL) was added tri-
fluoroacetic acid (220 m
L, 2.9 mmol) at 0 ꢀC. After stirring at room
(CDCl3, 100 MHz)
d
169.4, 165.8, 156.1, 136.7, 135.4, 135.3, 122.6,
temperature for 2 h, the solvent was removed under reduced
pressure and the crude product was used in the next reaction
without purification. The crude aniline was dissolved in CH2Cl2
(0.80 mL) and the solution were added freshly prepared 3412
120.0, 119.0, 109.2, 104.2, 94.2, 58.7, 57.7, 55.6, 45.1, 29.4, 29.0, 25.8,
24.9, 21.5, 17.9; HRMS (FAB) calcd for C22H27N3O3 (Mþ) 381.2052,
found 381.2053.
(0.48 mmol) and pyridine (130 m
L, 1.4 mmol) at 0 ꢀC. The resulting
4.1.8. (S)-Methyl 1-((S)-2-(((benzyloxy)carbonyl)amino)-4-(2-((tert-
butoxycarbonyl)amino)phenyl)-4-oxobutanoyl)pyrrolidine-2-
carboxylate (46). To a solution of 42 (320 mg, 0.704 mmol) in
mixture was stirred at room temperature for 3 h, and quenched
with saturated aq NH4Cl. After addition of CH2Cl2, the aqueous
phase was extracted with CH2Cl2 and the combined organic phase
was washed with brine and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure and the residue was
purified by preparative TLC (5% MeOH in CH2Cl2) to afford 49
MeOH/CH2Cl2 (20:1, 5.0 mL) was added triethylamine (150 mL,
1.1 mmol) at room temperature. The reaction mixture was stirred
for 6.5 h. The solvent was evaporated to afford 43 as a pale yellow
foam. The crude product was used in the next reaction without
purification. To a solution of crude 43 in H2O/THF (1:1, 3.6 mL) was
(37.8 mg, 57% in two steps) as a pale yellow foam. [
a
]
D
22 ꢁ168 (c 1.00,
CHCl3); IR (film, cmꢁ1) 3259, 2926, 1683, 1652, 1582, 1520, 1448,

T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
6555
1303, 1259, 755; 1H NMR (CDCl3, 400 MHz)
d
11.39 (1H, br s), 8.70
(minor) d 4.62 (br s, 1H), 4.07e4.02 (m, 2H), 2.27 (br s, 1H), 1.65 (s,
(1H, d, J¼8.5 Hz), 7.90 (1H, d, J¼7.8 Hz), 7.52 (2H, m), 7.10 (1H, t,
J¼8.0 Hz), 5.40 (1H, t, J¼7.6 Hz), 4.62 (1H, d, J¼7.3 Hz), 4.13 (1H, t,
J¼7.1 Hz), 4.02 (1H, dd, J¼18.3, 3.2 Hz), 3.62e3.50 (2H, m), 3.29 (1H,
dd, J¼18.3, 8.7 Hz), 3.15 (2H, d, J¼7.4 Hz), 2.30e2.23 (1H, m),
2.00e1.87 (3H, m), 1.85 (3H, s), 1.71 (3H, s); 13C NMR (CDCl3,
3H), 1.50 (s, 12H); 13C NMR (CDCl3, 100 MHz) (major)
82.7, 80.3, 70.0, 68.6, 48.2, 28.3, 25.8, 24.2 (minor)
d
151.2, 94.4,
151.6, 93.9,
d
82.3, 80.8, 70.5, 68.5, 48.2, 28.3, 26.8, 25.1; HRMS (ESI) calcd for
C12H19NNaO3 ([MþNa]þ) 248.1263, found 248.1260.
100 MHz)
d
200.4,171.2,169.8,164.7,140.5, 138.0,135.1,130.3, 122.3,
4.1.14. N-(2-Iodophenyl)formamide (54). A mixture of formic acid
(3.46 mL, 91.6 mmol) and acetic anhydride (4.33 mL, 45.8 mmol)
was heated at 50 ꢀC for 1 h and then cooled to 0 ꢀC. This was added
to a stirred solution of 2-iodoaniline (5.01 g, 22.9 mmol) in CH2Cl2
(100 mL) at 0 ꢀC. After 1 h, the reaction mixture was quenched with
saturated aq NaHCO3 and the aqueous phase was extracted with
CH2Cl2 twice. The combined organic extract was washed three
times with saturated aq NaHCO3, brine, and dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was recrystallized
from EtOAc to afford 54 (5.19 g, 21.0 mmol, 92%) as a slightly purple
needle. Mp 113e114 ꢀC; IR (neat, cmꢁ1) 3223, 1658, 1583, 1572,
1526, 1393, 1281, 1152; 1H NMR (CDCl3, 400 MHz) (3:2 mixture of
121.6, 120.7, 115.7, 58.8, 51.4, 45.4, 40.6, 37.7, 28.0, 25.7, 22.3, 17.8;
HRMS (FAB) calcd for C21H25N3O4 (Mþ) 383.1845, found 383.1844.
4.1.11. Tryprostatin B (2). To a solution of magnesium (6.0 mg,
0.25 mmol) in degassed THF (150
chloride (14
L, 0.13 mmol) at 0 ꢀC. After stirring at room temper-
ature for 30 min, a solution of 49 (10 mg, 0.026 mmol) in degassed
THF (150
L) was added at 0 ꢀC. The reaction mixture was stirred for
mL) was added titanium tetra-
m
m
3 h at room temperature, and quenched with saturated aq NH4Cl.
After the addition of CH2Cl2 and H2O, the aqueous phase was
extracted with CH2Cl2 and the combined organic phase was dried
over anhydrous MgSO4. The solvent was removed under reduced
pressure and the residue was purified by preparative TLC (5% MeOH
in CH2Cl2) to afford 2 (1.8 mg, 20%) as a off-white solid.
two rotamers) (major)
J¼8.2 Hz, 1H), 7.48 (br s, 1H), 7.36 (dd, J¼7.8, 7.8 Hz, 1H), 6.89 (dd,
J¼7.8, 7.8 Hz, 1H) (minor) 8.66 (d, J¼11.0 Hz, 1H), 8.50 (s, 1H), 7.86
d
8.50 (s, 1H), 8.30 (d, J¼8.2 Hz, 1H), 7.80 (d,
d
(d, J¼7.8 Hz,1H), 7.48 (br s,1H), 6.23 (dd, J¼7.8, 7.8 Hz,1H), 6.89 (dd,
4.1.12. (S)-tert-Butyl 4-(2,2-dibromovinyl)-2,2-dimethyloxazolidine-
3-carboxylate (52). To a stirred solution of CBr4 (50.4 g, 152 mmol)
in CH2Cl2 (300 mL) was added a solution of PPh3 (80.0 g, 304 mmol)
in CH2Cl2 (500 mL) dropwise through the dropping funnel over
a period of 20 min at ꢁ30 ꢀC. After 20 min, the resulting orange-red
solution was cooled to ꢁ60 ꢀC, to which was added a solution of
5117 (17.4 g, 75.8 mmol) and triethylamine (10.6 mL, 75.8 mmol) in
CH2Cl2 (500 mL) dropwise through the dropping funnel over a pe-
riod of 30 min and warmed to 0 ꢀC. After 2 h, the reaction mixture
was quenched with saturated aq NaHCO3 and concentrated in
vacuo to half an amount. The resulting solution was partitioned
between H2O and CH2Cl2 and the aqueous layer was extracted with
CH2Cl2 twice. The combined organic extract was washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was dissolved in CH2Cl2 (500 mL) and Et2O (500 mL), and
stirred for 30 min at 0 ꢀC. The slurry was filtered through a pad of
Celite and concentrated in vacuo. The residue was purified with
flash column chromatography on silica gel (hexane/EtOAc¼17/3) to
J¼7.8, 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) (major)
d 158.9, 138.9,
d 161.9, 139.9, 137.7, 129.5,
137.2, 129.2, 126.3, 122.2, 89.3 (minor)
127.0, 119.3, 90.7; HRMS (ESI) calcd for C7H6INNaO ([MþNa]þ)
269.9392, found 269.9388.
4.1.15. (S)-tert-Butyl 4-((2-formamidophenyl)ethynyl)-2,2-
dimethyloxazolidine-3-carboxylate (55). To a stirred solution of 53
(4.28 g, 19.0 mmol) and 54 (3.98 g, 16.1 mmol) in triethylamine
(70 mL) were added CuI (280 mg, 1.46 mmol) and PdCl2(PPh3)2
(1.02 g, 1.46 mmol) at room temperature. After 2 h, the reaction
mixture was filtered through a pad of Celite. To the resulting so-
lution was added saturated aq NH4Cl and the mixture was extracted
with Et2O. The organic layer was washed three times with saturated
aq NH4Cl and the combined aqueous layer was reextracted with
Et2O. The combined organic extract was washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified with flash column chromatography on silica gel (hexane/
EtOAc¼4/1) to afford 55 (5.37 g,15.6 mmol, 97%) as a slightly yellow
22
afford 52 (25.8 g, 67.0 mmol, 88%) as a colorless solid. Mp 54e55 ꢀC;
oil. [a
]
þ15 (c 1.00, CHCl3); IR (neat, cmꢁ1) 3296, 2980, 2935,
D
22
[
a]
ꢁ19 (c 1.00, CHCl3); IR (neat, cmꢁ1) 2979, 2935, 2873, 1707,
2878, 1704, 1680, 1579, 1523, 1452, 1367; 1H NMR (CDCl3, 400 MHz)
D
1608, 1476, 1456, 1371, 1251, 1173, 1089, 1057; 1H NMR (CDCl3,
d
9.15 (br s, 1H), 8.57 (s, 1H), 8.51 (d, J¼8.7 Hz, 1H), 7.36e7.32 (m,
400 MHz) (2:1 mixture of two rotamers) (major)
1H), 4.51 (br s, 1H), 4.12e4.07 (m, 1H), 3.82e3.77 (m, 1H), 1.61e1.58
(m, 3H), 1.52 (s, 3H), 1.48 (s, 9H) (minor) 6.48 (br s, 1H), 4.61 (br s,
d
6.44 (d, J¼8.7 Hz,
2H), 7.03 (dd, J¼7.8, 7.3 Hz, 1H), 4.83 (dd, J¼6.4, 5.5 Hz, 1H), 4.23
(dd, J¼8.2, 6.4 Hz, 1H), 4.13e4.08 (m, 1H), 1.59 (s, 3H), 1.55 (s, 3H),
d
1.52 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 159.9, 152.4, 140.1, 130.3,
1H), 4.12e4.07 (m, 1H), 3.82e3.77 (m, 1H), 1.61e1.58 (m, 3H), 1.52
129.8, 123.2, 119.5, 111.1, 94.4, 94.1, 81.4, 79.6, 67.5, 49.0, 28.4, 26.1,
25.8; HRMS (ESI) calcd for C19H24N2NaO4 ([MþNa]þ) 367.1634,
found 367.1632.
(s, 3H), 1.48 (s, 9H); 13C NMR (CDCl3, 100 MHz) (major)
138.5, 94.5, 89.9, 80.4, 67.3, 59.5, 28.5, 26.2, 23.8 (minor)
d
151.6,
151.9,
d
138.5, 93.9, 90.5, 80.7, 67.3, 59.5, 28.5, 27.3, 24.7; HRMS (ESI) calcd
for C12H19Br2NNaO3 ([MþNa]þ) 405.9629, found 405.9638.
4.1.16. (S,Z)-tert-Butyl 4-(2-formamidostyryl)-2,2-dimethyloxazolidine-
3-carboxylate (56). To a stirred solution of zinc powder (11.4 g,
174 mmol) in 2,2,2-trifluoroethanol (43.6 mL) was added dibro-
moethane (1.18 mL, 13.1 mmol). The resulting solution was heated
up to 70 ꢀC. After 30 min, the stirred solution was cooled to room
temperature, to which was added an additional dibromoethane
(1.18 mL, 13.1 mmol) and heated up to 70 ꢀC for 30 min. After
cooling the stirred solution to room temperature, a mixture of CuBr
(3.75 g, 26.1 mmol) and LiBr (4.54 g, 52.3 mmol) in THF (40 mL) was
added and the reaction mixture turned black. The mixture was
heated at 70 ꢀC for 30 min and cooled to room temperature, to
which was added 55 (3.00 g, 8.71 mmol) in THF (10 mL) and stirred
at 70 ꢀC. After 3 h, the reaction mixture was filtered through a pad
of Celite. To the resulting solution was added saturated aq NH4Cl
and the aqueous layer was extracted with EtOAc twice. The com-
bined organic extract was washed with brine, dried over Na2SO4,
4.1.13. (S)-tert-Butyl 4-ethynyl-2,2-dimethyloxazolidine-3-
carboxylate (53). To a stirred solution of 52 (10.0 g, 26.0 mmol) in
THF (100 mL) at 0 ꢀC was added ethyl magnesium bromide (3.00 M
solution in Et2O, 17.3 mL, 52.0 mmol) dropwise through the drop-
ping funnel over a period of 20 min. After 2 h, the reaction mixture
was quenched with saturated aq NH4Cl and extracted with EtOAc
three times. The combined organic extract was washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified with flash column chromatography on silica gel
(hexane/EtOAc¼1/1) to afford 53 (5.74 g, 25.5 mmol, 98%) as a col-
22
orless oil. [
a
]
D
þ81 (c 1.00, CHCl3); IR (neat, cmꢁ1) 3293, 2981,
2936, 2878, 1701, 1477, 1457, 1379, 1264, 1246, 1173, 1097; 1H NMR
(CDCl3, 400 MHz) (3:2 mixture of two rotamers) (major)
d 4.51 (br s,
1H), 4.07e4.02 (m, 2H), 2.27 (br s, 1H), 1.65 (s, 3H), 1.50 (s, 12H)

6556
T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
filtered, and concentrated in vacuo. The residue was purified with
flash column chromatography on silica gel (hexane/EtOAc¼5/1 to
(dd, J¼7.3, 7.3 Hz,1H), 7.04 (s,1H), 4.26 (m,1H), 3.82 (s,1H), 3.75 (m,
1H), 3.35 (d, J¼12.8 Hz, 1H), 2.82 (m, 1H), 1.60 (s, 3H), 1.55 (s, 9H),
3/1) to afford 56 (3.01 g, 8.68 mmol, 99%) as a slightly yellow oil.
1.48 (s, 3H); 13C NMR (CDCl3, 100 MHz) (major)
d 151.9, 136.3, 127.4,
23
[
a]
ꢁ65 (c 1.00, CHCl3); IR (neat, cmꢁ1) 3277, 2979, 2934, 2871,
122.7,122.2,119.5,119.3,112.8,111.2, 94.2, 79.9, 66.4, 57.4, 29.4, 28.7,
27.1, 23.3 (minor) 152.3,136.1,127.7,122.4,122.1,119.5,119.0,112.9,
D
1696, 1673, 1581, 1529, 1452, 1391, 1366; 1H NMR (CDCl3, 400 MHz)
d
(3:1 mixture of two rotamers) (major)
d
9.58 (s, 1H), 8.41 (s, 1H),
110.9, 93.5, 80.0, 66.3, 58.2, 28.3, 28.5, 27.8, 24.5; HRMS (ESI) calcd
for C19H26N2NaO3 ([MþNa]þ) 353.1841, found 353.1827. Compound
60: IR (neat, cmꢁ1) 3383, 2979, 2935, 2883, 1698, 1478, 1456, 1393,
1366, 1260, 1174; 1H NMR (CDCl3, 400 MHz) (4:3 mixture of two
8.29 (d, J¼7.8 Hz, 1H), 7.29e7.15 (m, 1H), 7.08 (dd, J¼7.3, 7.3 Hz, 1H),
7.01 (d, J¼7.3 Hz, 1H), 6.52 (d, J¼11.0 Hz, 1H), 5.78 (dd, J¼11.0,
10.1 Hz, 1H), 4.25e4.20 (m, 1H), 3.89 (dd, J¼8.7, 8.7 Hz, 1H), 3.63
(dd, J¼8.7, 6.4 Hz, 1H), 1.56 (s, 3H), 1.49 (s, 9H), 1.47 (s, 3H) (minor)
rotamers) (major)
6H), 1.48 (br s, 9H) (minor)
1.51 (br s, 6H), 1.48 (br s, 9H); 13C NMR (CDCl3, 100 MHz) (major)
d
3.93 (t, J¼6.4 Hz, 1H), 3.55 (br s, 1H), 1.51 (br s,
d
8.84 (d, J¼10.1 Hz, 1H), 8.54 (d, J¼11.5 Hz, 1H), 8.41 (s, 1H),
d
3.93 (t, J¼6.4 Hz, 1H), 3.51 (br s, 1H),
7.29e7.15 (m, 1H), 7.08 (dd, J¼7.3, 7.3 Hz, 1H), 7.01 (d, J¼7.3 Hz, 1H),
6.52 (d, J¼11.0 Hz, 1H), 5.78 (dd, J¼11.0, 10.1 Hz, 1H), 4.29 (br s, 1H),
3.98e3.94 (m, 1H), 3.73 (br s, 1H), 1.56 (s, 3H), 1.49 (s, 9H), 1.47 (s,
d
152.4, 92.6, 80.0, 62.7, 45.7, 28.4, 25.7 (minor) d 152.0, 93.0, 79.4,
62.9, 45.7, 28.4, 24.7; HRMS (DART) calcd for C10H20NO3 ([MþH]þ)
3H); 13C NMR (CDCl3, 100 MHz) (major)
d
160.1, 152.6, 134.1, 134.0,
129.2, 128.0, 127.8, 126.5, 124.0, 121.9, 94.0, 81.1, 67.6, 56.0, 28.3,
26.2, 25.7 (minor) 162.7, 152.0, 134.9, 133.8, 130.3, 128.4, 128.0,
202.1443, found 202.1442.
d
4.1.19. (S)-tert-Butyl 2,2-dimethyl-4-((2-(3-methylbut-2-enyl)-1H-
indol-3-yl)methyl)oxazolidine-3-carboxylate (64). To a stirred solu-
tion of 57 (1.45 g, 4.42 mmol) and tributyltin hydride (3.51 mL,
13.3 mmol) in toluene (8.84 mL) was added 2,20-azobis(4-methoxy-
2,4-dimethylvaleronitrile) (61, V-70) (272 mg, 0.883 mmol) at 30 ꢀC.
After 1 h, the reaction mixture was added prenyl acetate (63)
(1.85 mL, 13.3 mmol), lithium chloride (562 mg, 13.3 mmol), triphe-
nylarsine (271 mg, 0.884 mmol), N,N-dimethylformamide (26.5 mL)
and Pd2(dba)3 (202 mg, 0.221 mmol), and the mixture was heated to
80 ꢀCfor1 h, beforehydroxylaminehydrochloride(1.23 g,17.7 mmol)
and sodium acetate (1.45 g, 17.7 mmol) was added. After 30 min, the
reaction mixturewasquenched with saturated aqKFand the aqueous
layer was extracted with Et2O three times. The combined extract was
washed with saturated aq KF twice, brine, and dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified with
125.3, 124.0, 121.2, 93.6, 80.9, 67.7, 55.4, 29.6, 26.9, 25.3; HRMS (ESI)
calcd for C19H26N2NaO4 ([MþNa]þ) 369.1790, found 369.1780.
4.1.17. (S,Z)-tert-Butyl 4-(2-isocyanostyryl)-2,2-dimethyloxazolidine-
3-carboxylate (57). To a stirred solution of 56 (1.96 g, 5.66 mmol)
and pyridine (4.58 mL, 56.6 mmol) in CH2Cl2 (28.3 mL) was added
triphosgene (672 mg, 2.26 mmol) at 0 ꢀC. After 20 min, the reaction
mixture was poured into ice-cold saturated aq NaHCO3. The organic
layer was washed with saturated aq NaHCO3 three times and brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified with flash column chromatography on silica gel
(hexane/EtOAc¼8/1) to afford 57 (1.61 g, 4.90 mmol, 87%) as
a slightly yellow oil. [
a]
21 ꢁ68 (c 1.00, CHCl3); IR (neat, cmꢁ1) 2980,
D
2935, 2871, 2119, 1697, 1480, 1449, 1384, 1366; 1H NMR (CDCl3,
400 MHz) (3:2 mixture of two rotamers) (major)
d
7.41e7.38 (m,
flash column chromatography on silica gel (hexane/EtOAc¼19/1 to
23
2H), 7.31e7.26 (m, 2H), 6.64 (d, J¼11.5 Hz, 1H), 5.94 (dd, J¼10.6,
13/1) to afford 64 (1.28 g, 3.21 mmol, 73%) asa slightlyyellowoil. [a]
D
10.6 Hz, 1H), 4.71 (br s, 1H), 4.18 (br s, 1H), 3.89 (br s, 1H), 1.67 (s,
ꢁ47 (c 1.00, CHCl3); IR (neat, cmꢁ1) 3345, 2979, 2933, 2876, 1692,
3H), 1.50 (s, 9H), 1.29 (s, 3H) (minor)
d
7.85 (br s, 1H), 7.41e7.38 (m,
1680,1462,1392,1366,1248; 1H NMR (CDCl3, 400 MHz) (4:3 mixture
1H), 7.31e7.26 (m, 2H), 6.64 (d, J¼11.5 Hz, 1H), 5.94 (dd, J¼10.6,
of two rotamers) (major)
d
7.83 (s, 1H), 7.63 (d, J¼7.1 Hz, 1H), 7.27 (m,
10.6 Hz, 1H), 4.77 (br s, 1H), 4.01 (br s, 1H), 3.76 (br s, 1H), 1.67 (s,
1H), 7.14e7.06 (m, 2H), 5.30 (t, J¼6.9 Hz, 2H), 4.19 (m, 1H), 3.71 (br s,
3H), 1.29 (s, 12H); 13C NMR (CDCl3, 100 MHz) (major)
d
167.0, 151.7,
135.8, 132.9, 129.7, 128.9, 128.1, 127.0, 125.6, 124.1, 94.6, 79.9, 68.6,
54.7, 28.1, 26.5, 23.9 (minor) 166.4, 151.9, 135.0, 133.0, 130.0, 129.1,
2H), 3.50 (d, J¼6.9 Hz, 1H), 3.17 (dd, J¼13.3, 3.2 Hz, 1H), 2.80 (m, 1H),
1.79 (s, 3H),1.77 (s, 3H),1.58 (s, 9H),1.55 (s, 6H) (minor) d 7.81 (s, 1H),
d
7.74 (d, J¼7.1 Hz,1H), 7.27 (m,1H), 7.14e7.06 (m, 2H), 5.30 (t, J¼6.9 Hz,
2H), 4.19 (m,1H), 3.71 (br s, 2H), 3.54 (d, J¼6.9 Hz,1H), 3.23 (d, J¼11.9,
1.2 Hz, 1H), 2.80 (m, 1H), 1.79 (s, 3H), 1.77 (s, 3H), 1.58 (s, 9H), 1.55 (s,
128.0, 126.7, 125.1, 124.1, 93.7, 80.1, 68.6, 55.0, 28.1, 27.3, 25.0; HRMS
(ESI) calcd for C19H24N2NaO3 ([MþNa]þ) 351.1685, found 351.1690.
6H); 13C NMR (CDCl3, 100 MHz) (major)
d
151.9, 135.4, 135.1, 135.0,
128.8, 121.2, 120.0, 119.2, 118.2,110.4,107.6, 94.1, 79.9, 66.3, 57.5, 28.7,
27.8, 27.2, 25.8, 25.1, 23.3, 17.9 (minor) 152.2, 135.3, 135.0, 134.7,
4.1.18. (S)-tert-Butyl 4-((1H-indol-3-yl)methyl)-2, 2-
dimethyloxazolidine-3-carboxylate (58). A solution of 57 (98.0 mg,
d
0.298 mmol), tributyltin hydride (160
m
L, 0.596 mmol) and 2,20-
129.0, 121.1, 120.3, 119.4, 118.7, 110.1, 107.8, 93.4, 79.9, 66.3, 58.3, 28.5,
27.9, 26.9, 25.8, 25.1, 24.5, 17.9; HRMS (ESI) calcd for C24H34N2NaO3
([MþNa]þ) 421.2467, found 421.2454.
azobis(2-methylpropionitrile) (AIBN) (7.3 mg, 0.0447 mmol) in dry
MeCN (1.50 mL) in a sealed tube was heated at 100 ꢀC for 1 h under
an argon atmosphere. The reaction mixture was cooled to room
temperature and silica gel (300 mg) was added. The resulting sus-
pension was stirred for an additional 2 h. After filtration through
a plug of cotton funnel, the resulting solution was added saturated
aq KF. The aqueous layer was extracted with Et2O twice. The
combined extract was washed with saturated aq KF and brine, and
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified with flash column chromatography on silica gel
(hexane/EtOAc¼9/1 to 4/1) to afford 58 (55.0 mg, 0.167 mmol, 56%),
59 (8.8 mg, 0.0619 mmol, 23%) and 60 (15 mg, 0.0745 mmol, 25%).
4.1.20. (S)-tert-Butyl 3-(2-(tert-butoxycarbonylamino)-3-
hydroxypropyl)-2-(3-methylbut-2-enyl)-indole-1-carboxylate
(65). To a stirred solution of 64 (1.10 g, 2.76 mmol) in MeCN
(13.8 mL) were added Boc2O (783 mg, 3.59 mmol) and 4-(dime-
thylamino)pyridine (DMAP) (101 mg, 0.828 mmol) at room tem-
perature. After 30 min, the reaction mixture was quenched with
saturated aq NH4Cl and extracted with EtOAc three times. The
combined organic extract was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied with flash column chromatography on silica gel (hexane/
EtOAc¼9/1) to afford the Boc intermediate (1.36 g, 2.72 mmol, 99%)
as a white solid. To a stirred solution of the Boc intermediate (1.36 g,
2.73 mmol) in THF (3.89 mL) and H2O (1.94 mL) at 0 ꢀC was added
ice-cold trifluoroacetic acid (7.77 mL). After 10 min, the reaction
mixture was poured into cooled saturated aq NaHCO3 and extracted
with EtOAc. The organic layer was washed with saturated aq
NaHCO3 three times, brine, and dried over Na2SO4, filtered, and
Compound 58: [
a
]
D
23 ꢁ41 (c 1.00, CHCl3); IR (neat, cmꢁ1) 3415, 3356,
2979, 2933, 2875, 1676, 1457, 1392, 1365, 1254, 1172; 1H NMR
(CDCl3, 400 MHz) (4:3 mixture of two rotamers) (major) d 8.10 (br s,
1H), 7.73 (d, J¼8.2 Hz 1H), 7.38 (d, J¼8.2 Hz, 1H), 7.21 (dd, J¼8.2,
7.4 Hz 1H), 7.12 (dd, J¼8.2, 7.4 Hz, 1H), 7.04 (s, 1H), 4.19 (m, 1H), 3.80
(s, 1H), 3.75 (m, 1H), 3.26 (d, J¼11.0 Hz, 1H), 2.82 (m, 1H), 1.70 (s,
3H), 1.58 (s, 9H), 1.52 (s, 3H) (minor)
d 8.06 (br s, 1H), 7.84 (d,
J¼7.3 Hz, 1H), 7.34 (d, J¼7.3 Hz 1H), 7.19 (dd, J¼7.3, 7.3 Hz, 1H), 7.12

T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
6557
concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/EtOAc¼7/3) to afford 65
room temperature. After 30 min, the reaction mixture was
quenched with saturated aq NH4Cl and the aqueous phase was
extracted with EtOAc three times. The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified with flash column chromatography
(1.10 g, 2.40 mmol, 88%) as a colorless oil. Boc intermediate: mp
23
110e111 ꢀC; [
a
]
ꢁ33 (c 1.00, CHCl3); IR (neat, cmꢁ1) 2979, 2933,
D
2874,1809, 1732, 1697, 1607, 1459, 1390,1366,1327; 1H NMR (CDCl3,
400 MHz) (1:1 mixture of two rotamers) (major)
d
8.08e8.06 (m,
on silica gel (hexane/EtOAc¼4/1) to afford 68 (1.10 g, 1.88 mmol,
21
1H), 7.61 (d, J¼7.3 Hz, 1H), 7.27e7.16 (m, 2H), 5.18 (t, J¼5.0 Hz, 1H),
4.22e4.14 (m, 1H), 3.90e3.72 (m, 2H), 3.69 (s, 2H), 3.23 (dd, J¼11.5,
1.0 Hz, 1H), 2.82e2.74 (m, 1H), 1.77 (s, 3H), 1.73 (s, 3H), 1.66 (s, 9H),
88%) as a colorless oil. [
a
]
þ3.3 (c 1.00, CHCl3); IR (neat, cmꢁ1
)
D
3307, 2977, 2930, 1733, 1647, 1457, 1365, 1326; 1H NMR (CDCl3,
400 MHz) (3:2 mixture of two rotamers) (major)
d
8.08 (d, J¼5.9 Hz,
1.57 (s, 9H), 1.55 (s, 3H), 1.53 (s, 3H) (minor)
d
8.08e8.06 (m, 1H),
1H), 7.56 (d, J¼7.4 Hz, 1H), 7.26e7.20 (m, 2H), 5.22 (br s, 1H), 5.14 (d,
J¼8.2 Hz, 1H), 4.78e4.72 (m, 1H), 4.55e4.52 (m, 1H), 3.74 (br s, 2H),
3.68 (s, 3H), 3.74e3.65 (m, 1H), 3.47e3.43 (m, 1H), 3.17e3.02 (m,
2H), 2.20e1.95 (m, 4H), 1.77 (s, 3H), 1.70 (s, 3H), 1.66 (s, 9H), 1.30 (s,
7.79e7.77 (m, 1H), 7.27e7.16 (m, 2H), 5.18 (t, J¼5.0 Hz, 1H),
4.22e4.14 (m, 1H), 3.90e3.72 (m, 2H), 3.69 (s, 2H), 3.12 (dd, J¼11.5,
1.4 Hz, 1H), 2.82e2.74 (m, 1H), 1.77 (s, 3H), 1.73 (s, 3H), 1.66 (s, 9H),
1.57 (s, 9H), 1.55 (s, 3H), 1.53 (s, 3H); 13C NMR (CDCl3, 100 MHz)
9H) (minor)
d
8.05 (m, 1H), 7.51 (d, J¼7.4 Hz, 1H), 7.26e7.20 (m, 2H),
(major)
118.2, 115.3, 114.7, 94.2, 83.7, 66.0, 80.0, 56.8, 28.7, 28.1, 27.4, 27.0,
25.8, 25.7, 23.2, 18.2 (minor) 151.4, 150.4, 137.6, 135.8, 132.2, 129.9,
d
151.8, 150.3, 137.8, 135.9, 132.4, 129.7, 123.6, 122.2, 121.6,
5.51 (d, J¼8.7 Hz, 1H), 5.16 (br s, 1H), 4.50e4.44 (m, 1H), 4.55e4.52
(m,1H), 3.74 (br s, 2H), 3.65 (s, 3H), 3.52 (d, J¼8.2 Hz,1H), 3.47e3.43
(m, 1H), 2.98e2.92 (m, 2H), 2.20e1.95 (m, 4H), 1.77 (s, 3H), 1.70 (s,
3H), 1.66 (s, 9H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz) (major)
d
123.5, 122.7, 121.8, 118.9, 115.1, 115.0, 93.4, 83.5, 66.0, 80.1, 57.6, 28.5,
28.0, 27.8, 27.2, 25.9, 25.7, 24.4, 18.0; HRMS (ESI) calcd for
d
172.3, 171.0, 155.1, 150.3, 138.1, 135.9, 132.1, 129.6, 123.4, 122.5,
122.1, 117.9, 115.3, 113.0, 83.5, 79.4, 58.7, 52.6, 52.1, 46.9, 29.6, 28.3,
27.5, 28.0, 25.7, 24.8, 22.0, 18.2 (minor) 171.7, 171.0, 154.5, 150.3,
C29H42N2NaO5 ([MþNa]þ) 521.2991, found 521.2981. Compound
24
65: [a
]
ꢁ3.1 (c 1.00, CHCl3); IR (neat, cmꢁ1) 3473, 2978, 2930,
d
D
1731, 1696, 1503, 1458, 1392, 1367, 1327; 1H NMR (CDCl3, 400 MHz)
138.4, 135.6, 132.6, 129.4, 123.8, 122.6, 121.2, 118.2, 115.0, 113.1, 83.9,
79.3, 58.7, 52.2, 51.5, 46.1, 30.0, 28.9, 27.6, 27.5, 25.8, 24.8, 22.0, 18.1;
HRMS (ESI) calcd for C32H45N3NaO7 ([MþNa]þ) 606.3155, found
606.3144.
d
8.08 (d, J¼8.2 Hz, 1H), 7.60 (d, J¼6.4 Hz, 1H), 7.27e7.20 (m, 2H),
5.23 (t, J¼5.0 Hz, 1H), 4.93 (br s, 1H), 3.93 (br s, 1H), 3.75 (d,
J¼5.0 Hz, 2H), 3.62 (br s, 1H), 3.55 (br s, 1H), 2.91e2.89 (m, 2H), 2.44
(br s, 1H), 1.76 (s, 3H), 1.71 (s, 3H), 1.66 (s, 9H), 1.43 (s, 9H); 13C NMR
(CDCl3, 100 MHz)
d
156.1, 150.3, 137.5, 135.9, 132.5, 129.7, 123.6,
4.1.23. Tryprostatin B (2). A solution of 68 (1.04 g, 1.78 mmol) in N-
methyl-2-pyrrolidinone (4.45 mL) was heated at reflux for 1.5 h.
After cooling to room temperature, the resulting solution was
purified with flash reverse-phase column chromatography (C-18,
50%e70% MeOH in H2O) to remove NMP. The residue was purified
with flash column chromatography on silica gel (hexane/EtOAc¼2/1)
122.6, 122.0, 118.4, 115.2, 114.5, 83.7, 79.5, 63.9, 52.4, 28.3, 28.1, 25.8,
25.6, 18.1, 18.1; HRMS (ESI) calcd for C26H38N2NaO5 ([MþNa]þ)
481.2678, found 481.2672.
4.1.21. (S)-3-(1-(tert-Butoxycarbonyl)-2-(3-methylbut-2-enyl)-in-
dol-3-yl)-2-(tert-butoxycarbonylamino)propanoic acid (66). To
a
to afford tryprostatin B (2) (559 mg, 1.59 mmol, 89%) as a yellow
24
stirred solution of 65 (1.08 g, 2.36 mmol) and iodobenzene diac-
etate (2.28 g, 7.08 mmol) in MeCN (5.9 mL) and phosphate buffer
(pH 6.8) (5.9 mL) was added 2,2,6,6-tetramethyl- piperidine-1-oxyl
(TEMPO) (36.8 mg, 0.236 mmol) at room temperature. After
30 min, saturated aq NaHCO3 was added to the reaction mixture
and the aqueous phase was extracted with EtOAc three times. The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified with
solid. Mp 100e102 ꢀC; [
a]
D
ꢁ71 (c 0.78, CHCl3); IR (neat, cmꢁ1
)
3283, 2926, 1668, 1657, 1459, 1438, 1422; 1H NMR (CDCl3, 400 MHz)
d
8.04 (br s,1H), 7.48 (d, J¼7.8 Hz, 1H), 7.32 (d, J¼7.8 Hz, 1H), 7.16 (dd,
J¼7.8, 6.9 Hz, 1H), 7.10 (dd, J¼7.8, 6.9 Hz, 1H), 5.63 (br s, 1H), 5.31 (t,
J¼7.4 Hz, 1H), 4.37 (dd, J¼11.4, 2.3 Hz, 1H), 4.07 (dd, J¼7.8, 7.4 Hz,
1H), 3.71e3.53 (m, 3H), 3.47 (m, 2H), 2.96 (dd, J¼14.6, 11.4 Hz, 1H),
2.37e2.31 (m, 1H), 2.10e1.99 (m, 2H), 1.95e1.89 (m, 1H), 1.79 (s, 3H),
1.75 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 169.3, 165.8, 136.4, 135.4,
flash column chromatography on silica gel (hexane/EtOAc¼7/3) to
135.3,127.9,121.7,119.8,119.7,117.7,110.7,104.5, 59.2, 54.5, 45.3, 28.3,
25.7, 25.5, 25.0, 22.6, 17.9; HRMS (ESI) calcd for C21H25N3NaO2
([MþNa]þ) 374.1845, found 374.1841.
24
afford 66 (1.01 g, 2.14 mmol, 91%) as a colorless oil. [
a]
þ25 (c
D
1.00, CHCl3); IR (neat, cmꢁ1) 3316, 2978, 2930, 2855, 1730, 1457,
1368, 1325, 1165, 1134; 1H NMR (CDCl3, 400 MHz) (3:1 mixture of
two rotamers) (major)
d
8.07 (d, J¼7.8 Hz, 1H), 7.50 (d, J¼6.9 Hz,
4.1.24. 2-Iodo-5-methoxyaniline (69). To a stirred solution of 4-
iodo-3-nitroanisole (6.33 g, 22.7 mmol) in acetic acid (3.78 mL)
and anhydrous EtOH (37.8 mL) were added Fe (7.60 g, 0.136 mol)
and FeCl3 (2.21 g, 13.6 mmol) portionwise at room temperature,
and then the mixture was heated to 80 ꢀC. After 40 min, the re-
action mixture was filtered through a pad of Celite. To the resulting
mixture was added H2O and the aqueous layer was extracted with
EtOAc three times. The combined organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified with flash column chromatography on silica
gel (hexane/EtOAc¼7/1) to afford 69 (4.77 g, 19.2 mmol, 84%) as
a slightly yellow solid. Mp 33e34 ꢀC; IR (neat, cmꢁ1) 3459, 3364,
1H), 7.27e7.19 (m, 2H), 5.22 (br s, 1H), 5.03 (d, J¼6.0 Hz, 1H), 4.52
(br s, 1H), 3.79e3.64 (m, 2H), 3.29 (dd, J¼14.6, 4.6 Hz, 1H),
3.13e3.08 (m, 1H), 1.76 (s, 3H), 1.71 (s, 3H), 1.66 (s, 9H), 1.38 (s, 9H)
(minor)
d
8.07 (d, J¼7.8 Hz, 1H), 7.50 (d, J¼6.9 Hz, 1H), 7.27e7.19 (m,
2H), 5.22 (br s, 1H), 5.03 (d, J¼6.0 Hz, 1H), 4.52 (br s, 1H), 3.79e3.64
(m, 2H), 3.29 (dd, J¼14.6, 4.6 Hz,1H), 2.96 (br s,1H),1.76 (s, 3H),1.71
(s, 3H), 1.66 (s, 9H), 1.38 (s, 9H); 13C NMR (CDCl3, 100 MHz) (major)
d
175.8, 155.5, 150.3, 138.3, 135.9, 132.7, 129.4, 123.7, 122.6, 121.8,
118.1, 115.3, 112.8, 83.8, 80.2, 54.6, 29.4, 28.2, 28.1, 27.4, 25.8, 18.1
(minor) 176.8, 156.5, 150.3, 137.9, 136.0, 132.1, 129.7, 123.6, 122.6,
d
122.0, 117.9, 115.3, 113.9, 83.6, 81.0, 53.7, 29.4, 28.2, 28.1, 26.8, 25.5,
18.2; HRMS (ESI) calcd for C26H36N2NaO6 ([MþNa]þ) 495.2458,
found 495.2457.
2936, 1613, 1569, 1486, 1428, 1332; 1H NMR (CDCl3, 400 MHz)
(d, J¼8.7 Hz, 1H), 6.32 (d, J¼2.8 Hz, 1H), 6.13 (dd, J¼8.7, 2.8 Hz, 1H),
4.06 (s, 2H), 3.74 (s, 3H); 13C NMR (CDCl3, 100 MHz)
161.1, 147.6,
d 7.47
d
4.1.22. tert-Butyl 3-((S)-2-(tert-butoxycarbonylamino)-3-((S)-2-(me-
thoxycarbonyl)pyrrolidin-1-yl)-3-oxopropyl)-2-(3-methylbut-2-enyl)-
139.2, 106.6, 100.5, 73.4, 55.3; HRMS (DART) calcd for C7H9INO
([MþH]þ) 249.9729, found 249.9738.
indole-1-carboxylate (68). To
2.14 mmol) and -proline methyl ester p-toluenesulfonate 67
(482 mg, 2.78 mmol) in CH2Cl2 (10.7 mL) were added HATU (1.06 g,
2.78 mmol) and N,N-diisopropylethylamine (932 L, 5.35 mmol) at
a stirred solution of 66 (1.01 g,
L
4.1.25. N-(2-Iodo-5-methoxyphenyl)formamide (70). A mixture of
formic acid (2.51 mL, 66.5 mmol) and acetic anhydride (3.39 mL,
33.2 mmol) was stirred at 50 ꢀC for 1 h and then cooled to 0 ꢀC. This
m

6558
T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
was added to a stirred solution of 2-iodo-5-methoxyaniline (69)
(4.14 g, 16.6 mmol) in CH2Cl2 (83 mL) at 0 ꢀC. After 2 h, the reaction
mixture was quenched with saturated aq NaHCO3 and the aqueous
phase was extracted with CH2Cl2 twice. The combined organic
extract was washed with saturated aq NaHCO3 three times, brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified with flash column chromatography on silica gel
(hexane/EtOAc¼4/1) to afford 70 (4.53 g, 16.4 mmol, 98%) as
a white solid. Mp 103e104 ꢀC; IR (neat, cmꢁ1) 3237, 2964, 2359,
1640, 1590, 1574, 1523, 1466; 1H NMR (CDCl3, 400 MHz) (2:1
1.56 (s, 3H), 1.49 (s, 9H), 1.47 (s, 3H); 13C NMR (CDCl3, 100 MHz)
160.4, 159.3, 152.7, 135.2, 134.3, 129.9, 127.6, 118.3, 110.7, 106.4,
d
94.1, 81.1, 67.8, 56.1, 55.4, 28.4, 26.3, 25.9; HRMS (ESI) calcd for
C20H28N2NaO5 ([MþNa]þ) 399.1896, found 399.1879.
4.1.28. (S,Z)-tert-Butyl 4-(2-isocyano-4-methoxystyryl)-2,2-
dimethyloxazolidine-3-carboxylate (73). To a stirred solution of 72
(5.09 g, 13.5 mmol) and pyridine (10.9 mL, 135 mmol) in CH2Cl2
(200 mL) was added triphosgene (1.60 g, 5.41 mmol) at 0 ꢀC. After
20 min, the reaction mixture was poured into ice-cold saturated aq
NaHCO3 The organic layer was washed with saturated aq NaHCO3
three times and brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified with flash column chromatog-
mixture of two rotamers) (major)
J¼2.8 Hz, 1H), 7.69 (d, J¼8.8 Hz, 1H), 7.51 (br s, 1H), 6.55 (dd, J¼8.8,
2.8 Hz, 1H), 3.81 (s, 3H) (minor)
8.66 (d, J¼11.2 Hz, 1H), 6.77 (d,
J¼2.8 Hz, 1H), 7.62 (d, J¼8.8 Hz, 1H), 7.51 (br s, 1H), 6.51 (dd, J¼8.8,
2.8 Hz, 1H), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz) (major)
158.9,
160.5, 138.7, 138.0, 113.2, 107.4, 78.8, 55.5 (minor) 161.7, 160.8,
d 8.49 (br s, 1H), 8.03 (d,
d
raphy on silica gel (hexane/EtOAc¼8/1 to 6/1) to afford 73 (4.13 g,
24
d
11.5 mmol, 85%) as a white solid. Mp 89e90 ꢀC; [
a
]
D
ꢁ83 (c 1.35,
d
CHCl3); IR (neat, cmꢁ1) 2979, 2935, 2871, 2120, 1697, 1610, 1503,
140.0, 138.4, 112.5, 105.8, 77.1, 55.6; HRMS (ESI) calcd for C8H8IN-
1385; 1H NMR (CDCl3, 400 MHz) (2:1 mixture of two rotamers)
NaO2 ([MþNa]þ) 299.9497, found 299.9488.
(major)
5.84 (dd, J¼11.9, 9.6 Hz, 1H), 4.70 (br s, 1H), 4.15 (br s, 1H), 3.85 (br s,
1H), 3.82 (s, 3H), 1.64 (s, 3H), 1.52 (s, 9H), 1.31 (s, 3H) (minor) 7.77
d
7.14 (s, 1H), 6.95e6.90 (m, 2H), 6.56 (d, J¼11.9 Hz, 1H),
4.1.26. (S)-tert-Butyl 4-((2-formamido-4-methoxyphenyl)ethynyl)-
2,2-dimethyloxazolidine-3-carboxylate (71). To a stirred solution of
53 (4.33 g, 19.2 mmol) and 70 (4.10 g, 14.8 mmol) in triethylamine
(37 mL) and THF (37 mL) were added CuI (141 mg, 0.74 mmol) and
PdCl2(PPh3)2 (519 mg, 0.74 mmol) at room temperature. After 2 h,
the reaction mixture was filtered through a pad of Celite. To the
resulting solution was added saturated aq NH4Cl and the aqueous
phase was extracted with EtOAc twice. The combined organic ex-
tract was washed with saturated aq NH4Cl twice, brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied with flash column chromatography on silica gel (hexane/
d
(s, 1H), 6.95e6.90 (m, 2H), 6.56 (d, J¼11.9 Hz, 1H), 5.84 (dd, J¼11.9,
9.6 Hz,1H), 4.70 (br s,1H), 4.02 (br s,1H), 3.76 (br s,1H), 3.82 (s, 3H),
1.64 (s, 3H), 1.52 (s, 9H), 1.31 (s, 3H); 13C NMR (CDCl3, 100 MHz)
(major)
d
167.0, 159.0, 151.9, 134.7, 130.7, 126.4, 125.5, 123.9, 115.5,
166.2,
112.1, 94.5, 80.1, 68.8, 55.7, 55.0, 28.4, 26.5, 24.1 (minor)
d
159.0, 151.9, 134.1, 130.7, 126.4, 125.5, 124.8, 115.5, 112.1, 93.8, 80.1,
68.8, 55.7, 55.0, 28.4, 27.4, 25.2; HRMS (ESI) calcd for C20H26N2NaO4
([MþNa]þ) 381.1790, found 381.1774.
4.1.29. (S)-tert-Butyl 4-((6-methoxy-2-(3-methylbut-2-enyl)-1H-indol-
3-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (74). To a stirred
solution of 73 (4.10 g, 11.4 mmol) and tributyltin hydride (9.07 mL,
34.2 mmol) in toluene (60 mL) was added 2,20-azobis(4-methoxy-
2,4-dimethylvaleronitrile) (61, V-70) (706 mg, 2.29 mmol) at 30 ꢀC.
After 1.5 h, the reaction mixture was added prenyl acetate (63)
(7.15 mL, 51.3 mmol), lithium chloride (2.17 g, 51.3 mmol), triphe-
nylarsine (998 mg, 3.26 mmol), N,N-dimethylformamide (170 mL),
and Pd2(dba)3 (722 mg, 0.788 mmol) and the mixture was heated
to 80 ꢀC. After 7 h, the reaction mixture was quenched with satu-
rated aq KF and the aqueous phase was extracted with Et2O three
times. The combined organic extract was washed with saturated aq
KF twice, brine, and dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified with flash column chromatography
on silica gel (hexane/EtOAc¼6/1 to 3/1) to afford 74 (3.89 g,
EtOAc¼6/1 to 4/1) to afford 71 (5.43 g, 14.5 mmol, 98%) as a slightly
20
yellow oil. [
a
]
D
þ10 (c 1.48, CHCl3); IR (neat, cmꢁ1) 3295, 2979,
2937, 1702, 1676, 1612, 1577, 1528, 1393; 1H NMR (CDCl3, 400 MHz)
d
9.15 (s, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.24 (d, J¼8.2 Hz, 1H), 6.59 (d,
J¼8.2 Hz, 1H), 4.81 (dd, J¼6.4, 5.0 Hz, 1H), 4.21 (dd, J¼8.7, 6.4 Hz,
1H), 4.08 (dd, 8.7, 5.0 Hz, 1H), 3.83 (s, 3H), 1.59 (s, 3H), 1.54 (s, 3H),
1.51 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 160.7, 160.1, 152.5, 141.6,
131.2, 110.1, 104.9, 103.3, 94.5, 92.8, 81.4, 79.9, 67.7, 55.5, 49.2, 28.5,
26.1, 26.0; HRMS (ESI) calcd for C20H26N2NaO5 ([MþNa]þ) 397.1739,
found 397.1722.
4.1.27. (S,Z)-tert-Butyl 4-(2-formamido-4-methoxystyryl)-2,2-
dimethyloxazolidine-3-carboxylate (72). To a stirred solution of
zinc powder (19.0 g, 290 mmol) in 2,2,2-trifluoroethanol (80 mL)
was added dibromoethane (1.88 mL, 2.18 mmol). The resulting so-
lution was heated up to 70 ꢀC. After 30 min, the stirred solution was
cooled to room temperature, to which was added an additional
dibromoethane (1.88 mL, 2.18 mmol) and heated up to 70 ꢀC for
30 min. After cooling the stirred solution to room temperature,
a mixture of CuBr (6.24 g, 43.5 mmol) and LiBr (7.56 g, 87.0 mmol)
in THF (45 mL) was added, and then the reaction mixture turned
black. The mixture was heated at 70 ꢀC for 30 min and cooled to
room temperature, to which was added 71 (5.43 g, 14.5 mmol) in
THF (10 mL), and stirred at 70 ꢀC. After 3 h, the reaction mixture
was filtered through a pad of Celite. To the resulting solution was
added saturated aq NH4Cl and the aqueous phase was extracted
with EtOAc twice. The combined organic extract was washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified with flash column chromatography on silica
9.08 mmol, 80%) as a slightly yellow oil. [
a]
24 ꢁ47 (c 1.02, CHCl3); IR
D
(neat, cmꢁ1) 3353, 2979, 2933, 1693, 1629, 1463, 1391, 1255; 1H
NMR (CDCl3, 400 MHz) (6:5 mixture of two rotamers) (major) d 7.72
(s, 1H), 7.48 (d, J¼8.4 Hz, 1H), 6.85e6.70 (m, 2H), 5.29 (t, J¼6.8 Hz,
1H), 4.24e4.09 (m, 1H), 3.82 (s, 3H), 3.71 (br s, 2H), 3.47 (d,
J¼6.8 Hz, 2H), 3.13 (br d, 13.2 Hz, 1H), 2.76 (t, J¼12.4 Hz, 1H),
1.84e1.60 (m, 9H), 1.60e1.43 (m, 12H) (minor) d 7.69 (s, 1H), 7.61 (d,
J¼8.0 Hz, 1H), 6.85e6.70 (m, 2H), 5.29 (t, J¼6.8 Hz, 1H), 4.24e4.09
(m,1H), 3.82 (s, 3H), 3.71 (br s, 2H), 3.47 (d, J¼6.8 Hz, 2H), 3.24 (br d,
13.6 Hz, 1H), 2.76 (t, J¼12.4 Hz, 1H), 1.84e1.60 (m, 9H), 1.60e1.43
(m, 12H); 13C NMR (CDCl3, 100 MHz) (major)
d 156.0, 152.0, 135.9,
134.7, 134.1, 123.3, 120.4, 118.8, 108.7, 107.4, 94.7, 94.2, 79.9, 66.4,
57.6, 55.8, 28.8, 27.9, 27.2, 25.8, 24.6, 23.3, 17.9 (minor) 156.0,
d
152.3, 135.8, 134.4, 133.9, 123.5, 120.6, 119.4, 108.9, 107.7, 94.4, 93.5,
79.9, 66.4, 58.3, 55.8, 28.6, 27.9, 27.1, 25.1, 24.6, 23.3, 17.9; HRMS
(ESI) calcd for C25H36N2NaO4 ([MþNa]þ) 451.2573, found 451.2568.
gel (hexane/EtOAc¼6/1 to 3/1) to afford 72 (5.15 g, 13.7 mmol, 94%)
20
as a slightly yellow oil. [
a
]
D
ꢁ114 (c 0.73, CHCl3); IR (neat, cmꢁ1
)
3286, 2979, 2871, 1697, 1673, 1580, 1531, 1399, 1215; 1H NMR
4.1.30. (S)-tert-Butyl 3-(2-(tert-butoxycarbonylamino)-3-
hydroxypropyl)-6-methoxy-2-(3-methylbut-2-enyl)-indole-1-
carboxylate (75). To a stirred solution of 74 (3.50 g, 8.17 mmol) in
MeCN (82 mL) were added Boc2O (2.32 g, 10.6 mmol) and 4-
(dimethylamino)pyridine (DMAP) (299 mg, 2.45 mmol) at room
(CDCl3, 400 MHz)
d
9.54 (s, 1H), 8.41 (s, 1H), 8.02 (d, J¼2.8 Hz, 1H),
6.90 (d, J¼8.2 Hz,1H), 6.64 (dd, J¼8.2, 2.8 Hz,1H), 6.45 (d, J¼11.0 Hz,
1H), 5.74 (dd, J¼11.0, 10.1 Hz, 1H), 4.26 (ddd, J¼10.1, 6.4, 6.4 Hz, 1H),
3.89 (dd, J¼8.7, 6.4 Hz, 1H), 3.61 (dd, J¼8.7, 6.4 Hz, 1H), 3.82 (s, 3H),

T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
6559
temperature. After 1 h, the reaction mixture was quenched with
saturated aq NH4Cl and extracted with EtOAc three times. The
combined organic extract was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied with flash column chromatography on silica gel (hexane/
EtOAc¼10/1) to afford the Boc intermediate (3.97 g, 7.51 mmol,
92%) as a white solid. To a stirred solution of the Boc intermediate
(3.97 g, 7.51 mmol) in THF (13.5 mL) and H2O (6.73 mL) at 0 ꢀC was
added cooled trifluoroacetic acid (26.9 mL). After 10 min, the re-
action mixture was poured into cooled saturated aq NaHCO3 and
extracted with EtOAc. The organic layer was washed with saturated
aq NaHCO3 three times, brine, and dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/EtOAc¼4/1 to 2/1) to afford
400 MHz) (3:1 mixture of two rotamers) (major)
d
7.70 (s,1H), 7.36 (d,
J¼8.2 Hz,1H), 6.85(dd, J¼8.2,1.8 Hz,1H), 5.21 (br s,1H), 5.01 (brs,1H),
4.50 (br s,1H), 3.85 (s, 3H), 3.78e3.58(m,1H), 3.22 (dd, J¼14.6, 4.6 Hz,
1H), 3.13e3.01 (m,1H),1.74 (s, 3H),1.70 (s, 3H),1.66 (s, 9H),1.38 (s, 9H)
(minor)
d
7.70(s,1H), 7.36(d, J¼8.2 Hz,1H), 6.85(dd,J¼8.2,1.8 Hz,1H),
5.21 (br s,1H), 5.01 (br s,1H), 4.50(br s,1H), 3.85(s, 3H), 3.78e3.58(m,
1H), 3.22 (dd, J¼14.6, 4.6 Hz, 1H), 2.96 (br s, 1H), 1.74 (s, 3H), 1.70 (s,
3H), 1.66 (s, 9H), 1.38 (s, 9H); 13C NMR (CDCl3, 100 MHz) (major)
d
176.5, 157.4, 155.7, 150.4, 136.8, 136.6, 132.5, 123.3, 122.1, 118.6, 112.7,
111.6, 100.1, 83.8, 80.3, 55.6, 53.7, 29.2, 28.3, 27.6, 25.9, 25.6, 18.1
(minor) 176.1, 157.4, 155.7, 150.4, 136.9, 136.6, 132.0, 123.6, 122.2,
d
118.3, 113.5, 111.6, 100.3, 83.6, 81.0, 55.6, 54.7, 29.2, 28.1, 26.7, 25.8,
25.6, 18.1; HRMS (ESI) calcd for C27H38N2NaO7 ([MþNa]þ) 525.2577,
24
found 525.2586. Compound 76: [
a
]
þ13 (c 1.01, CHCl3); IR (neat,
D
75 (3.31 g, 7.22 mmol, 96%) as a colorless solid. Boc intermediate:
cmꢁ1) 3437, 3308, 2977, 1726, 1646, 1579, 1491, 1442, 1365; 1H NMR
(CDCl3, 400 MHz) (10:7 mixture of two rotamers) (major) 7.73 (d,
24
mp 137e139 ꢀC; [
a
]
D
ꢁ36 (c 0.98, CHCl3); IR (neat, cmꢁ1) 2979,
d
1730, 1697, 1618, 1579, 1491, 1365; 1H NMR (CDCl3, 400 MHz) (1:1
J¼2.0 Hz, 1H), 7.43 (d, J¼8.0 Hz, 1H), 6.87 (dd, J¼8.0, 2.0 Hz, 1H), 5.15
(d, J¼8.4 Hz,1H), 5.21 (br s,1H), 4.76e4.70 (m,1H), 4.56e4.50(m,1H),
3.86 (s, 3H), 3.69 (s, 3H), 3.75e3.58 (m, 2H), 3.50e3.38 (m, 1H),
3.25e3.15 (m, 1H), 3.13e2.98 (m, 1H), 2.97e2.86 (m, 1H), 2.21e2.12
(m,1H), 2.01e1.89 (m, 3H),1.76 (s, 3H),1.70 (s, 3H),1.66 (s, 9H),1.32 (s,
mixture of two rotamers) (major)
d
7.70 (s, 1H), 7.65 (d, J¼8.7 Hz,
1H), 6.84 (d, J¼8.7 Hz, 1H), 5.17 (t, J¼5.0 Hz, 1H), 4.20e4.17 (m, 1H),
3.86 (s, 3H), 3.76 (d, J¼5.0 Hz, 1H), 3.69 (br s, 2H), 3.19 (br d,
J¼12.8 Hz, 1H), 2.80e2.68 (m, 1H), 1.78e1.44 (m, 30H) (minor)
d
7.70 (s, 1H), 7.46 (d, J¼8.7 Hz, 1H), 6.88 (d, J¼8.7 Hz, 1H), 5.17 (t,
9H) (minor)
d
7.68 (d, J¼2.4 Hz, 1H), 7.39 (d, J¼8.0 Hz, 1H), 6.85 (dd,
J¼5.0 Hz, 1H), 4.13e4.10 (m, 1H), 3.86 (s, 3H), 3.69 (d, J¼5.0 Hz, 1H),
3.69 (br s, 2H), 3.08 (dd, J¼13.7, 3.2 Hz, 1H), 2.80e2.68 (m, 1H),
J¼8.0, 2.4 Hz,1H), 5.49 (d, J¼8.8 Hz,1H), 5.14 (br s,1H), 4.49e4.43 (m,
1H), 4.56e4.50 (m, 1H), 3.86 (s, 3H), 3.65 (s, 3H), 3.75e3.58 (m, 2H),
3.50e3.38 (m, 1H), 3.13e2.98 (m, 1H), 3.13e2.98 (m, 1H), 2.97e2.86
(m,1H), 2.21e2.12 (m,1H), 2.01e1.89 (m, 3H),1.76 (s, 3H),1.70 (s, 3H),
1.78e1.44 (m, 30H); 13C NMR (CDCl3, 100 MHz) (major)
d 157.3,
151.9, 150.4, 136.8, 136.4, 132.2, 123.7, 122.1, 119.4, 115.0, 111.2, 100.2,
93.4, 83.6, 80.1, 66.1, 57.7, 55.7, 28.7, 28.1, 28.0, 27.2, 26.0, 25.7, 24.5,
1.66 (s, 9H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz) (major)
d 172.3,
18.2 (minor)
d
157.4, 152.2, 150.5, 136.9, 136.2, 132.0, 123.8, 122.0,
171.0, 157.2, 155.2, 150.5, 137.0, 136.7, 132.4, 123.6, 122.5, 118.3, 112.9,
111.5,100.2, 83.8, 79.4, 58.8, 55.8, 52.1, 51.6, 46.9, 30.1, 29.0, 28.2, 28.1,
118.7, 114.6, 111.6, 100.0, 94.2, 83.4, 80.0, 66.1, 56.9, 55.7, 28.5, 27.4,
27.9, 27.2, 26.0, 25.7, 23.3, 18.1; HRMS (ESI) calcd for C30H44N2NaO6
25.9, 25.7, 24.8, 18.2 (minor)
d 171.8, 171.0, 157.4, 154.6, 150.4, 136.9,
([MþNa]þ) 551.3097, found 551.3080. Compound 75: mp 43e44 ꢀC;
136.6,131.9, 123.4, 121.6, 118.7, 113.0,111.6, 99.9, 83.5, 79.3, 58.8, 55.8,
52.6, 52.2, 46.1, 29.8, 27.6, 28.3, 28.1, 25.8, 25.7, 22.1, 18.1; HRMS (ESI)
calcd for C33H47N3NaO8 ([MþNa]þ) 636.3261, found 636.3254.
25
[
a]
ꢁ5.4 (c 0.96, CHCl3); IR (neat, cmꢁ1) 3438, 2977, 2932, 1726,
D
1491, 1366, 1326; 1H NMR (CDCl3, 400 MHz)
d
7.71 (d, J¼2.3 Hz, 1H),
7.46 (d, J¼8.7 Hz, 1H), 6.86 (q, J¼8.7, 2.3 Hz, 1H), 5.22 (br s, 1H), 4.91
(br s, 1H), 3.95e3.84 (m, 1H), 3.86 (s, 3H), 3.70 (d, J¼5.2 Hz, 1H),
3.61 (br d, J¼9.2 Hz, 1H), 3.53 (br d, J¼9.2 Hz, 1H), 2.92e2.82 (m,
1H), 2.37 (br s, 1H), 1.75 (s, 3H), 1.71 (s, 3H), 1.66 (s, 9H), 1.43 (s, 9H);
4.1.32. Tryprostatin A (1). A solution of 76 (1.20 g, 1.96 mmol) in N-
methyl-2-pyrrolidinone (5.42 mL) was heated at reflux for 2 h. After
cooling to room temperature, the resulting solution was purified
with flash reverse-phase column chromatography (C-18, 50%e70%
MeOH in H2O) to remove NMP. The residue was purified with flash
column chromatography on silica gel (hexane/EtOAc¼2/1) to afford
13C NMR (CDCl3, 100 MHz)
d 157.4, 156.2, 150.5, 136.9, 136.1, 132.4,
123.7, 122.4, 118.9, 114.4, 111.5, 100.2, 83.6, 79.6, 64.0, 55.7, 52.5,
28.4, 28.1, 28.1, 25.9, 25.7, 18.1; HRMS (ESI) calcd for C27H40N2NaO6
([MþNa]þ) 511.2784, found 511.2762.
tryprostatin A (1) (580 mg, 1.52 mmol, 78%) as a yellow solid. Mp
23
119e120 ꢀC; [
a]
ꢁ70 (c 0.78, CHCl3); IR (neat, cmꢁ1) 3327, 2981,
D
4.1.31. tert-Butyl 3-((S)-2-(tert-butoxycarbonylamino)-3-((S)-2-(me-
thoxycarbonyl)pyrrolidin-1-yl)-3-oxopropyl)-6-methoxy-2-(3-
methylbut-2-enyl)-indole-1-carboxylate (76). To a stirred solution of
75 (1.58 g 3.23 mmol) and iodobenzene diacetate (5.20 g,16.2 mmol)
in MeCN (10 mL) and phosphate buffer (pH 6.8) (10 mL), was added
2,2,6,6-tetramethyl-piperidine-1-oxyl(TEMPO)(252 mg,1.62 mmol)
at 0 ꢀC. After 2 h, saturated aq NaHCO3 was added to the reaction
mixture andtheaqueous phasewasextractedwithEtOActhreetimes.
The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified
with flash column chromatography on silica gel (hexane/EtOAc¼3/1
to 1/1) to afford the carboxylic acid (1.47 g, 2.92 mmol, 91%) as a
colorless oil. To a stirred solution of the carboxylic acid (1.29 g,
2.57 mmol) and
(579 mg, 3.34 mmol) in CH2Cl2 (12.9 mL) were added HATU (1.95 g,
5.13 mmol) and N,N-diisopropylamine (895 L, 5.14 mmol) at room
temperature. After 1 h, the reaction mixture was quenched with
saturated aq NH4Cl and the aqueous phase was extracted with EtOAc
three times. The combined organic extract was washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purifiedwithflashcolumnchromatographyonsilicagel(hexane/
2929, 2884, 2838, 1668, 1657, 1458, 1422, 1159; 1H NMR (CDCl3,
400 MHz)
d
7.90 (br s,1H), 7.34 (d, J¼8.7 Hz,1H), 6.83 (d, 2.3 Hz,1H),
6.76 (dd, J¼8.7, 2.3 Hz, 1H), 5.65 (s, 1H), 5.32e5.26 (m, 1H), 4.33 (dd,
J¼11.2, 3.6 Hz, 1H), 4.06 (dd, J¼7.6, 7.6 Hz, 1H), 3.83 (s, 3H),
3.71e3.57 (m, 3H), 3.49e3.37 (m, 2H), 2.91 (dd, J¼15.1, 11.4 Hz, 1H),
2.38e2.29 (m, 1H), 2.09e2.02 (m, 2H), 1.98e1.86 (m, 1H), 1.77 (s,
3H), 1.74 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 169.3, 165.8, 156.3,
136.3, 135.2, 135.1, 122.2, 120.0, 118.3, 109.3, 104.4, 94.8, 59.3, 55.7,
54.5, 45.4, 28.4, 25.8, 25.7, 25.1, 22.6, 18.0; HRMS (ESI) calcd for
C22H27N3NaO3 ([MþNa]þ) 404.1950, found 404.1934.
Acknowledgements
L-proline methyl ester p-toluenesulfonate (67)
Financial support for this research was provided by Grants-in-
Aid (21790009 and 20002004) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
m
Supplementary data
EtOAc¼9/1 to 3/1) to afford 76 (1.21 g, 1.97 mmol, 77%) as a colorless
25
oil. Carboxylic acid: [
a
]
þ41 (c 1.06, CHCl3); IR (neat, cmꢁ1) 2978,
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.05.112.
D
2933, 1731, 1620, 1580, 1492, 1443, 1368, 1325; 1H NMR (CDCl3,

6560
T. Yamakawa et al. / Tetrahedron 67 (2011) 6547e6560
12. Spaltenstein, A.; Carpino, P. A.; Miyake, F.; Hopkins, P. B. J. Org. Chem. 1987, 52,
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