A stereodivergent strategy to both product enantiomers from the same enantiomer of a stereoinducing catalyst: agelastatin

Article abstract of DOI:10.1002/chem.200900794

In this article, we report a full account of our recent development of pyrroles and N-alkoxyamides as new classes of nucleophiles for palladiumcatalyzed AAA reactions, along with application of these methodologies in the total synthesis of agelastatin A,

Full text of DOI:10.1002/chem.200900794

DOI: 10.1002/chem.200900794
A Stereodivergent Strategy to Both Product Enantiomers from the Same
Enantiomer of a Stereoinducing Catalyst: Agelastatin A
Barry M. Trost* and Guangbin Dong[a]
Abstract: In this article, we report a
full account of our recent development
of pyrroles and N-alkoxyamides as new
classes of nucleophiles for palladium-
catalyzed AAA reactions, along with
application of these methodologies in
the total synthesis of agelastatin A, a
marine natural product with exception-
al anticancer activity and other biologi-
cal properties. Our method allows for
access to either regioisomer of the pyr-
rolopiperazinones (6 and 19) with high
efficiency and enantioselectivity. Note
that isomer 19 was obtained via a cas-
cade reaction through a double allylic
alkylation pathway. From regioisomer
6, the total synthesis of (+)-agelastati-
n A was completed in a very short fash-
ion (four steps from 6), during the
course of which we developed a new
copper catalyst for aziridination and an
InACTHNGURETNNU(G OTf)3/DMSO system to oxidatively
open an N-tosyl aziridine. Starting with
the other pyrrolopiperazinone 19, a
five-step sequence has been developed
to furnish a formal total synthesis of
(À)-agelastatin A. A unique feature of
our syntheses is the use of two rather
different strategies for the total synthe-
ses of both enantiomers of agelasta-
tin A using the same enantiomer of a
chiral palladium catalyst.
Keywords: alkaloids
agents asymmetric catalysis
pyrrole · total synthesis
·
antitumor
·
·
and N-alkoxyamide-based AAA reactions, along with a de-
tailed description of our enantioselective total synthesis of
both (+) and (À) agelastatin A via two rather different
strategies that rely on the use of the same enantiomer of a
chiral palladium catalyst.
Introduction
During the last several decades, asymmetric catalysis has
dramatically improved the synthetic efficiency of producing
biologically important molecules. Among various catalytic
asymmetric methods, metal-catalyzed asymmetric allylic al-
kylation (AAA) constitutes an incredibly feasible reaction,
largely attributed to its broad substrate scope and its capa-
bility to asymmetrically form different bonds, including
À
À
À
carbon carbon, carbon oxygen, carbon nitrogen, and
[1]
À
carbon sulfur bonds. For those AAA reactions, however,
the scope of the potential nucleophiles is still unknown. Re-
cently, due to the increased medicinal significance of nitro-
gen containing bioactive molecules,[2] especially those with a
bromopyrrole moiety[3] such as the agelastatins (Figure 1),
we began to explore pyrroles and N-alkoxyamides as nucle-
ophiles in AAA reactions. In this article, we report a full ac-
count of our recent development of Pd-catalyzed pyrrole-
Figure 1. Agelastatin A–D.
Agelastatins A–D, which possess a highly fused tetracyclic
ring structure, comprise a family of oroidin alkaloids. Age-
lastatin A (1) along with agelastatin B (2), were first isolated
in 1993 by Pietra et al. from a deep water marine sponge
Agelas dendromorpha collected in the Coral Sea near New
Caledonia.[4] Later in 1998, agelastatin C (3) and D (4) were
isolated from the West Australia sponge Cymbastela sp. by
Molinski and co-workers.[5] The agelastatins exhibit excep-
tional biological activities; most notable of these is their
nanomolar activity against a broad range of cancer cell lines
[a] Prof. B. M. Trost, G. Dong
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Fax : (+1)650-725-0002
E-mail: bmtrost@stanford.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900794.
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that include human KB nasopharyngeal cancer cells (IC50 =
0.075 mgmLÀ1), L1210 murine tumor cell line, RT112/84
bladder carcinoma cells, SK-MEL-5 melanoma cells, HCT-
116 colon carcinoma cells, and MDA-MB-435s breast cancer
cells.[6] In many cases, agelastatin A was shown to be 1.5 to
16 times more potent than the frontline chemotherapeutic
agent cisplatin at inhibiting cell growth.[6c] Very recently,
agelastatin A has been found to inhibit osteopontin-mediat-
ed adhesion, invasion, and colony formation.[7] It also inhib-
its glycogen synthase kinase-3 b (GSK-3b) at low concentra-
tion, suggesting a potential approach for the treatment of
Alzheimerꢁs disease.[4] Hale et al. has also suggested that
agelastatin A might also function as a novel insulin mimet-
ic.[8] In addition, agelastin A has been reported to possess
potent activity against brine shrimp (LC50 =1.7 ppm), larvae
of beet army worm and corn rootworm.[5]
Besides these appealing biological activities, the structure
of agelastain A has also been attractive to the synthetic
community. First, this natural product contains an unusual
5-6-5-5 fused tetracylic system, including a bromo-pyrrole
motif. Second, it contains four contiguous stereocenters, all
of which are located in a five-membered ring. In addition,
each of these stereogenic centers bears a nitrogen atom. All
of these features constitute significant challenges for the
total synthesis of agelastatin A. To date, several elegant
total syntheses of this natural product have been reported.[9]
In 1999, Weinreb et al. completed the first total synthesis of
racemic agelastatin A, highlighted by a novel N-sulfinyl di-
Results and Discussion
Synthesis plan: From a retrosynthetic viewpoint (Scheme 1),
agelastatin A (1) could be accessed from tricyclic amino
ketone 5 that in turn could be derived from tricyclic olefin
6. An intramolecular Pd-catalyzed allylic alkylation of
amide 7 was envisioned to provide pyrrolopiperazinone 6.
Amide 7 could be ultimately synthesized from an intermo-
lecular Pd-catalyzed desymmetrization AAA between bisal-
lylic carbonate 8 and pyrrole 9. The most attractive feature
of this sequence was that a complex tricyclic structure such
as 6 could be efficiently and enantioselectively obtained
from two consecutive AAA reactions.
À
enophile Diels–Alder reaction followed by a tandem N S
bond cleavage, [2,3]-sigmatropic rearrangement, and oxazo-
lidinone formation to efficiently construct a [3.3.0] bicycle
from cyclopentadiene.[10] Feldman and Saunders in 2002 re-
ported the first enantioselective synthesis of (À)-agelastati-
n A and B, in which a unique approach using alkynyliodoni-
um salts was described.[11] Starting from the Hough–Ri-
chardson aziridine, Hale and co-workers completed a formal
total synthesis of (À)-agelastatin A in 2003 along with a new
total synthesis in 2004.[12] The Davis group then published
an asymmetric synthesis of 1 in 2005 using a chiral sulfini-
mine.[13] Shortly after, Wehn and Du Bois completed a total
synthesis of (À)-agelastatin A by application of a Rh-cata-
lyzed intramolecular aziridination reaction.[14] A recent syn-
thesis by the Ichikawa group in 2007 featured the double
usage of a [3,3]-sigmatropic rearrangement of allyl cya-
nate.[15] In 2008, Yoshimitsu–Tanaka disclosed a new asym-
metric synthesis of agelastatin A using an azidoformate-
mediated aziridination reaction.[16] Most recently, a racemic
synthesis was reported by Dickson and Wardrop, employing
a strategy based on multiple usage of the trichloroacetamide
functionality.[17] While most previous total syntheses relied
on an intramolecular Michael addition to provide the ABC-
ring system of 1 [Eq. (1)], we devised a new strategy to con-
struct this key tricycle by dual usage of Pd-AAA reactions.
Herein, we provide a full report of our work directed to-
wards the total synthesis of agelastatin A.[18]
Scheme 1. Retrosynthetic analysis.
Pd-catalyzed AAA reactions with pyrroles and N-methoxy-
amides as nucleophiles leading to the formation of tricycle
pyrrolopiperazinone 6: Throughout the initial studies for the
Pd-catalyzed AAA between 8 and 9, Cs2CO3 and CH2Cl2
were found to be the best base and solvent combination
[Eq. (2)]. The use of other solvents, such as THF or DMF,
or other bases, such as NaH, Hꢂnigꢁs base or DBU, gave
either low conversion or decomposition of the starting mate-
rials. The yield and enantioselectivity of this desymmetriza-
tion reaction were further optimized by varying the palladi-
um source, catalyst loading, base loading, and concentration
(Table 1). Lowering the amount of base increased the enan-
tioselectivity from 84 to 92% ee, but reduced the yield (en-
tries 1 and 2). Entry 3 indicated that lowering the catalyst
loading at the same substrate concentration afforded the
same yield for this transformation, but a reduction in ee
value (66%) was obtained. When the catalyst loading was
decreased while keeping the catalyst concentration the same
as in entry 1, almost the same enantioselectivity was ob-
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B. M. Trost and G. Dong
tained but with lower yield (entry 4). Upon changing the
palladium source from [Pd2A(dba)3]·CHCl3 to [Pd(p-
The intramolecular Pd-catalyzed AAA with N-methoxy-
amide as the nucleophile proceeded successfully [Eq. (3)].
Although a chiral ligand is not necessary for this cyclization,
when (R,R)-LST (LST: standard Trost ligand) was used as
ligand,[20] piperazinone 6 was obtained in 91% yield. Use of
achiral dppp proved to be less efficient and gave 6 in 70%
yield. Cs2CO3 was not required for this cyclization, but in
the absence of base, tricycle 6 was obtained in only 77%
yield.
G
ACHTUNGTRENNUNG
C3H5)Cl]2, both the yield and the enantioselectivity were sig-
nificantly enhanced. From these studies emerged the most
practical set of conditions, as shown in entry 6, which pro-
vided the N-alkyl pyrrole 10 in 83% yield and 92% ee. At
this point, the absolute configuration was tentatively as-
signed by analogy to other AAA reactions of substrate 8.[1]
Table 1. Selected optimization studies.
Alkene elaboration: Elaboration of intermediate 6 to the
natural product required dual functionalization of the cyclo-
pentene olefin (Scheme 3). Hydroxybromination and hy-
droxyiodination of 6 only yielded the pyrrole-brominated or
iodinated products, while the alkene functionality remained
intact.
Entry Pd source
(mol%)
Cs2CO3
(equiv)
Substrate
conc. [m]
Yield
[%][a]
ee
[%][b]
1
2
3
4
5
6
A
C
0.02
0.02
0.02
0.08
0.17
0.08
90
84
92
66
85
87
92
E
75
N
89
U
75
[{Pd
(2)
[{PdACHTUNGTRENNUNG
88-93
83
(1.25)
Scheme 3. Advancement of compound 6.
[a] Isolated yield. [b] Enantioselectivities were determined by chiral
HPLC.
Thus, an aziridination route to transform pyrrolopiperazi-
none 6 was eventually sought. Although no reaction oc-
curred either using either Sharplessꢁ method[21] with bromine
as catalyst or using tosyl azide under thermal or photochem-
ical conditions,[22] a copper-catalyzed aziridination with PhI=
N-Ts as the nitrene source[23] proved to be more promising
[Eq. (4), Table 2]. Due to the rather electron-deficient char-
acter of the olefin moiety in 6, a number of different copper
catalysts, solvents, and other conditions were examined. Se-
lected optimization results are summarized in Table 2. Mo-
lecular sieves have been found to be a critical additive to
secure consistent results. Among the various catalyst sys-
tems employed, copper(I) thiophene-2-carboxylate (CuTc,
entry 2) in acetonitrile and cop-
Direct transformation of the carboxylate ester 10 to N-
methoxyamide 7 was next attempted, however, treatment
with a variety of reagents[19] resulted in either no product or
cleavage of the tert-butyl carbonate (Boc) group. A two-step
process was then developed involving careful hydrolysis of
the methyl ester with lithium hydroxide, followed by amide
formation via the acyl chloride to give N-methoxyamide 7 in
high yield (Scheme 2). Notably, the N-methoxyamide was
chosen because of the increased nucleophilicity relative to a
simple amide, which should facilitate the subsequent cycliza-
tion.
per(I) triflate (CuOTf) in ben-
zene (entries 6 and 7) exhibited
good reactivity. A more effec-
tive catalyst was found when
using complex 13 or 14, and the
desired aziridine product 12
was obtained in 51 and 52%
Scheme 2. Synthesis of compound 7.
yield, respectively (entries 10
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Agelastatin A
FULL PAPER
and 11). Although N-heterocyclic carbene (NHC) metal
complexes have been known to enable carbene transfer to
olefins,[24] to our knowledge, these examples represent the
first NHC-copper catalyzed aziridination reactions.[25]
then secured in 70–80% yield by treatment of 15 with Dess–
Martin periodinane.[28]
With access to 5, a direct oxidative ring opening of aziri-
dine 12 was then pursued [Eq. (5)], and the explored condi-
tions are summarized in Table 3. When using o-iodoxyben-
zoic acid (IBX) as oxidant in combination with b-cyclodex-
trin[29] in aqueous acetone at room temperature (entry 1),
only the starting material 12 was isolated. Higher reaction
temperatures (50–608C) using aqueous dioxane as solvent
led to decomposition of the substrate (entry 2). DMSO has
been known to be able to oxidatively open epoxides to give
a-hydroxy ketones,[30] however, few cases existed using
DMSO in oxidative aziridine ring opening.[31] Heating 12 in
dry DMSO at 808C did provide the desired a-amino ketone
5 but in only 42% yield (entry 3). A substantial amount of
the direct hydrolytic ring-opening product 15 was observed
as the major product. As shown in entry 4, addition of mo-
lecular sieves did not help minimize the formation of hy-
drolysis byproducts. On the contrary, it seemed to be detri-
mental for this reaction, and no desired product could be
isolated. Although microwave conditions were demonstrated
to be efficient in the hydrolytic ring opening of aziridine 12,
significant decomposition was detected after heating 12 in
DMSO for 1 h at 1508C in a microwave apparatus (entry 5).
A broad range of additives were also surveyed to improve
the reaction yield. For example, addition of a stoichiometric
amount of Hꢂnigꢁs base or sodium chloride generated a
complex mixture of products, and addition of water yielded
more hydrolytic product 15. On the other hand, addition of
Table 2. Selected optimization of aziridination reaction.
Entry Catalyst
(mol%)
PhI=NTs
(equiv)
Solvent
T [8C] Yield
[%][a]
1
Cu
CuTc (20)
Cu(OTf)2 (20)
CuOTf (10)
CuOTf (30)
CuOTf (10)
N
2
CH3CN
CH3CN
0 to
RT
0 to
RT
RT
RT
RT
0 to
RT
RT
RT
RT
28
2
2
29–40
3
4
5
6
2
2
3
2
CH3CN
DME
CH3CN
benzene
trace
0
16
30
7
8
9
CuOTf (50)
CuOTf (100)
Cu(py)2Cl2
(100)
2
2
2
benzene
benzene
CH2Cl2
41
47
<30
10
11
catalyst 13 (50)
5
5
benzene[b] 0 to
RT
benzene
52
51
catalyst 14 (50)
0 to
RT
[a] Isolated yield. [b] Decomposition was observed when CH3CN was
used as solvent.
a Lewis acid, In
ACHTUNGRTEN(NUNG OTf)3, was found to be most effective for
this transformation. Treatment of 12 with 0.7 equiv In-
[32]
AHCTUNGRTEN(NGUN OTf)3 in dry DMSO at 808C for 6 h cleanly produced a-
amino ketone 5 in 91% yield (entry 6), and the direct hy-
drolytic ring opening only occurred to a very limited
amount (ca. 5%). This observation can be plausibly ex-
Hydrolytic ring opening of
the un-activated tosyl aziridine
functionality in 12 proved non-
trivial. When treating aziridine
12 either with ceric ammomium
nitrate (CAN; 10 mol% up
to 1 equiv)[26] or BF3·Et2O
(0.2 equiv) in aqueous acetoni-
Scheme 4. Synthesis of compound 5.
trile,[27] or with
a
catalytic
amount of TFA in aqueous ace-
tone at room temperature, only
plained by the mild Lewis acidity of InACTHNUTRGENUG(N OTf)3 to chemose-
recovered starting material was provided. Reaction of 12
with excess TFA upon conventional heating (978C) in aque-
ous dioxane ultimately delivered the desired a-amino alco-
hol 15 in 97% yield. However, this result is difficult to re-
produce. Moreover, this reaction required a long reaction
time (ca. 48 h) with continuous refilling of TFA every 8 h.
To increase the rate of this transformation, the effect of mi-
crowave heating was investigated. To our delight, the micro-
wave-assisted hydrolytic ring opening was completed in only
2.5 h at 1508C, and amino alcohol 15 was obtained reprodu-
cibly in 84% yield (Scheme 4). The a-amino ketone 5 was
lectively activate the aziridine functionality,[33] thus allowing
facile attack by DMSO (A plausible mechanism is shown in
Scheme 5). To the best of our knowledge, this reaction rep-
resents the first InIII-catalyzed oxidative ring opening of a
tosyl aziridine with DMSO.
End game: Advancement of a-amino ketone 5 to agelasta-
tin A required installation of the d-ring urea. After an ex-
tensive study, Cs2CO3 was found to most efficiently catalyze
the N-acylation of sulfonamide with methyl isocyanate
(Scheme 6). Treatment of 5 with 20 mol% Cs2CO3 in meth-
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B. M. Trost and G. Dong
Table 3. Oxidative ring-opening of aziridine 12.
debrominated products (entry 1). Attempts to remove the
N-Ts group either with magnesium metal in methanol[35] or
with TBAF[36] also failed (entries 2, 3 and 4). Photochemical
À
conditions have been demonstrated to cleave nitrogen sul-
fone bonds,[37] however, irradiation of 16 with UV light
(254 nm) in several solvents (entries 5–7) did not afford any
useful amount of product. In the end, we turned to the
SmI2-mediated radical reduction method.[38] Gratifyingly,
treatment of 16 with freshly prepared SmI2/THF solution se-
lectively removed both the N-Ts and N-OMe groups with-
out reduction of the pyrrolyl bromide, which ultimately pro-
vided (+)-agelastatin A (1) in 88% yield. Synthetic (+)-
agelastatin A displayed identical spectroscopic data
(1H NMR, 13C NMR, IR, MS, and Rf value) to those report-
ed for the natural product. The optical rotation of synthetic
Entry Conditions
Results
1
2
IBX, b-cyclodextrin, aqueous acetone, RT
IBX, b-cyclodextrin, aqueous dioxane, 50–
608C
recovered 12 only
decomposition of
12
3
4
DMSO, 808C
DMSO, molecular sieves, 808C
5 (42% yield[a]
)
decomposition of
12
decomposition of
5
6
DMSO, microwave, 1508C
12
DMSO, In
A
5 (91% yield[a]
)
(+)-agelastatin A was [a]D20
= + 53.2 (c=0.13, MeOH),
[a] Isolated yield.
which compared well to the rotation of naturally isolated
(À)-agelastatin A [a]D20 = À59.3 (c=0.13, MeOH)[5] report-
ed under identical conditions. This also established the abso-
lute configuration of the Pd AAA as shown in Equation (2).
Table 4. Removal of the N-Ts and N-OMe groups.
Entry Conditions
Results
1
2
3
4
5
Li, cat. naphthalene, À788C
debrominated products
no reaction
debrominated products
decomposition of 16
1 (trace) + decomposition of
16
Mg, MeOH, sonication
Mg, MeOH, reflux
TBAF, THF
hv (254 nm), CH3CN
6
7
8
hv (254 nm), dry THF
hv (254 nm), THF/H2O
SmI2 (8 equiv), THF, 08C to
RT
decomposition of 16
decomposition of 16
1 (88% yield[a]
)
Scheme 5. Plausible mechanism for the oxidative ring-opening of aziri-
dine 12.
[a] Isolated yield.
ylene chloride at 08C followed by slow addition of a ben-
zene solution of methyl isocyanate at room temperature suc-
cessfully provided tetracycle 16 in 53% yield. Using a
weaker base such as K2CO3 or using CuCl as catalyst[34]
proved less effective.
Development of Pd-catalyzed one-pot cascade AAA to
enable a more efficient tricyclic pyrrolopiperazinone forma-
tion: With successful application of both the pyrrole and the
N-methoxyamide as nucleophiles respectively in the Pd-cat-
alyzed AAA, a cascade cyclization reaction was next de-
signed to streamline the synthesis (Scheme 7). For a nucleo-
phile containing both pyrrole and N-methoxyamide (17), a
one-pot double AAA could be envisioned, in which a tricy-
clic pyrrolopiperazinone (6 or 19) could be obtained with
high efficiency. A further intriguing question arises—which
nitrogen will serve as the kinetically faster nucleophile?
Toward this end, the bifunctional nucleophile 17 was syn-
thesized in two steps from commercially available 2-(tri-
chloroacetyl)pyrrole 20 (Scheme 8). To effect the Pd-cata-
lyzed cascade AAA transformation, one challenge was to
chemoselectively differentiate the two nitrogen nucleophiles
in substrate 17, enabling one to react at a much faster rate
than the other. Attempts to promote initial attack by the
pyrrole nitrogen were unsuccessful.[39] Given that the nitro-
gen of the N-methoxyamide should be more nucleophilic
relative to the pyrrole, extensive effort was then conducted
Scheme 6. End game.
It is not totally unexpected that removal of the N-Ts
group of 16 needed a great extent of experimentation. A
summary of attempted conditions is summarized in Table 4.
Dissolving metal reduction of 16 with lithium in the pres-
ence of a catalytic amount of naphthalene only yielded the
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Agelastatin A
FULL PAPER
Table 5. Cascade AAA for the synthesis of piperazinone 19.[a]
Entry Pd source
(mol%)
Ligand
(mol%)
Additive
(mol%)
T
Yield
ee
[8C] [%][b]
[%][c]
1
[{Pd
(2)
[{Pd
(2)
[{Pd
(2)
[{Pd
(2)
N
G
RT
RT
RT
RT
RT
RT
0
NA
NA
NA
NA
2
0
3
trace
0
4
trace[d] NA
Scheme 7. A cascade Pd-catalyzed AAA.
5
[{Pd
(5)
6
A
U
51
50
NA
NA
89
7
A
U
8
A
U
0 to 65[e]
RT
RT
(15)
(dba)3]·CHCl3 rac-LST
(15)
9
G
E
88[e]
NA
96
Scheme 8. Synthesis of compound 17.
10
11
R
C
0 to 80[e,f]
RT
to allow a tandem cyclization to access pyrrolopiperazinone
19 (Table 5). Surprisingly, almost no reaction occurred in the
presence of a base (entries 1, 2 and 4). We hypothesized
that after deprotonation, 17 could act as a bidentate ligand
for palladium (Figure 2), thereby preventing the first ioniza-
tion. On the basis of this hypothesis, 10 mol% of acetic acid
was added to the reaction. To our delight, piperazinone 19
was obtained in 51% yield when (R,R)-LST and [Pd2-
A
H
0 to 82[e,g]
RT
97.5
[a] Unless otherwise indicated, all reactions were performed with
1.0 equiv of 8 and 1.0 equiv of 17 at 0.2m in CH2Cl2. [b] Isolated yield.
[c] Enantioselectivities were determined by chiral HPLC. [d] Single alky-
lation product was the main product. [e] The reaction was performed
with 1.5 equiv of 8 and 1.0 equiv of 17. [f] Another portion of [Pd2-
AHCTNUGTERNNG(UN dba)3]·CHCl3 (5 mol%), (R,R)-LST (15 mol%) was added after 1 h.
[g] Another portion of [Pd
was added after 3.5 h.
2ACTHUGNTREN(NUGN dba)3]·CHCl3 (5 mol%), rac- LST (15 mol%)
ACHTUNGTRENNUNG(dba)3]·CHCl3 were used as catalyst (entry 6). As shown in
entry 7, one equivalent of N,O-bis(trimethylsilyl) acetamide
(BSA) also proved to be effective (50% yield), but given
the higher cost and moisture sensitivity of BSA, further op-
timization was pursued on employing a catalytic amount of
acetic acid. Higher yield (88%) was obtained when using
racemic standard Trost lignad (LST), presumably because the
rate of the second allylic alkylation (from 18 to 19) could
likely be accelerated by using the other enantiomer of the
Pd catalyst as in a matched case. Based on this hypothesis,
the identified optimum conditions involved addition of a
portion of racemic catalyst after the completion of the first
AAA, and piperazinone 19 could be obtained in up to 82%
yield and 97.5% ee (entry 11). Thus, using the same ligand
[(R,R) standard Trost ligand] as in Equation (2) and (3), but
with a different pyrrole nucleophile (17), the other pyrrolo-
piperazinone regioisomer (19) could be efficiently accessed.
Another way to look at the tri-
Formal total synthesis of (À)-agelastatin A: With tricycle 19
in hand, we turned to examine the feasibility of transform-
ing this advanced intermediate to the natural (À)-enantio-
mer of agelastatin A. Inspired by the work of Weinreb,[10,40]
pyrrolopiperazinone 19 was subjected to allylic amination
conditions.[41] As shown in Equation (6) (Table 6), several
modifications were attempted in order to improve the yield
for this Kresze reaction,[41b] but the original thermal condi-
tions gave the best results (43–47% yield). Microwave con-
ditions or Lewis acid additives [20 mol% InACTHNURGTNEUNG(OTf)3] caused
increased decomposition, and addition of NHC-copper com-
plex 13 neither harmed nor benefited this transformation.
Although the yield of this allylic amination is moderate, we
were pleased to find that a single regio- and diastereomer
was obtained given the complexity of substrate 19, which
was assigned as tricycle 22 by analogy.
cycle 19 is that it can be consid-
ered as a pseudoenantiomer of
tricycle 6, for example, they
would be enantiomers if the lo-
cation of the double bond was
the same.
Based on the precedent from Weinrebꢁs synthesis, it
seemed to be straightforward to advance 22 to the natural
product 1. However, any attempts to functionalize the cyclo-
pentene olefin in 22 remained unfruitful (Scheme 9). For ex-
ample, under several hydroboration conditions (BH3, 9-
BBN-H, Rh-catalyzed hydroboration, etc.) and epoxidation
Figure 2. Plausible structure of
Pd-17 complex.
Chem. Eur. J. 2009, 15, 6910 – 6919
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www.chemeurj.org
6915

B. M. Trost and G. Dong
Table 6. Allylic amination conditions for piperazinone 19.[a]
completed the formal total synthesis of (À)-agelastatin A
starting from pyrrolopiperazinone 19 in five steps.
Conditions
Yield [%]
MW 1508C, 1 h
1008C, 30 h
36
43–47
19
1008C, InACHTUNGTRENNUNG(OTf)3 (20 mol%)
1008C, 13 (20 mol%)
47
conditions (mCPBA with or without a buffer, MTO-UHP,
[Mo(CO)6]-catalyzed epoxidation, DMDO, etc.), either a
complicated reaction mixture was obtained, or no reaction
occurred.
Scheme 10. Formal total synthesis of (À)-agelastatin A.
Scheme 9. Unsuccessful advancement of compound 22.
Conclusions
After extensive experimentation, we eventually found
that the presence of the acidic sulfonamide N-H hydrogen
seemed to be detrimental for the subsequent functionaliza-
tion of the adjacent olefin. The problem was solved by alter-
ing the reaction sequence between hydroboration of the
olefin and acylation of the sulfonamide (Scheme 10). Reac-
tion of 22 with methyl isocyanate and 0.2 equiv Cs2CO3 in
CH2Cl2 provided urea 23 in 90% yield. When treating 23
with BH3 in THF followed by oxidative treatment with hy-
drogen peroxide and sodium hydroxide, secondary alcohol
(À)-15 was isolated as the major product, however, surpris-
ingly, the urea group was cleaved, presumably by the basic
oxidative workup. Alcohol (À)-15 is spectroscopically identi-
cal to compound (+)-15, an intermediate in our synthesis of
Two new classes of nucleophiles, pyrroles and N-alkoxya-
mides (hydroxamic esters), have been employed in palladi-
um-catalyzed AAA reactions. By varying the functional
groups at the 2-position of pyrroles, we were able to effi-
ciently and enantioselectively access either regioisomer of
the pyrrolopiperazinones 6 and 19 (Scheme 11), among
which 19 was obtained via a cascade reaction through a
double allylic alkylation pathway. Using regioisomer 6, we
completed the total synthesis of (+)-agelastatin A in eight
steps from pyrrole 9, during the course of which, we devel-
oped a new copper catalyst for aziridination, and an In-
AHCTUNGRTEG(NNUN OTf)3/DMSO system to oxidatively open an N-tosylaziri-
dine. Starting from the other pyrrolopiperazinone (19), a
five-step sequence has been developed to furnish a formal
total synthesis of (À)-agelastatin A, requiring just the reduc-
tive cleavage of the N-Ts and N-OMe bonds as performed
on the enantiomer. In either of the two syntheses, although
we use reagents that require substituents for the appropriate
reactivity, which need to be removed, it is worth noting that
no protecting groups have been employed in the sense of
putting on such a group to impart chemoselectivity that then
must be removed. For example, the O-Boc and N-OMe
groups were used as activating groups, and the N-Ts groups
(+)-agelastatin A. The optical rotation of (À)-15 was [a]D20
=
À35.6 (c = 0.34, CH2Cl2), which compared well to the rota-
tion of (+)-15 [a]2D0 = +36.2 (c=0.90, CH2Cl2). This hydrol-
ysis problem could be overcome by changing to a less-basic
workup. Indeed, upon working up the hydroboration reac-
tion with aqueous sodium perborate, alcohol 24 was ob-
tained as the major regio- and diastereomer, and the relative
stereochemistry of 24 was tentatively assigned by analogy to
(À)-15. Subsequent Dess–Martin oxidation of 24 provided
tetracycle (À)-16 in 84% yield, which displayed identical
spectroscopic data (1H NMR, 13C NMR, IR and Rf value) to
À
were inherent from the C N bond-forming reactions.
Therefore, we have developed two distinctive strategies
for the enantioselective total synthesis of marine alkaloid
agelastatin A. As a rather unique feature of our syntheses,
two complementary routes differing only in the choice of
nucleophile in the Pd-AAA reactions provide either enan-
tiomer of this natural product.
those of (+)-16. The optical rotation of (À)-16 was [a]D20
=
À11.1 (c=0.17, CHCl3), which compared well to the rota-
tion of (+)-16 [a]2D0 = +9.7 (c=0.73, CHCl3). Given that
the final N-Ts and N-OMe cleavage of (À)-16 has been
demonstrated on its enantiomer (Scheme 6), therefore, we
6916
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Chem. Eur. J. 2009, 15, 6910 – 6919

Agelastatin A
FULL PAPER
Compound 12: Benzene (1 mL) was
added to a mixture of 4 ꢃ molecular
sieve (75 mg), compound
0.071 mmol), PhI=NTs
6
(20 mg,
(132 mg,
0.355 mmol) and catalyst 13 (17.3 mg,
0.0355 mmol) under N2. The resulting
mixture was stirred at RT for 4 h,
before it was filtered through a silica
gel cake and rinsed with ethyl acetate.
The solvent was removed under vacuum, and compound 12 was purified
via alumina (neutral, activity 3) flash column chromatography (petroleum
ether/ethyl acetate 8:1, 4:1, then 3:1) to give a colorless foam (16.6 mg,
52%). Rf = 0.5 (petroleum ether/ethyl acetate 3:2); [a]2D0 = +21.8 (c
0.85, CHCl3); 1H NMR (CDCl3, 500 MHz): d = 7.86 (dd, J=1.5, 6.5 Hz,
2H), 7.40 (dd, J=0.5, 8.5 Hz, 2H), 6.94 (d, J=4.0 Hz, 1H), 6.26 (d, J=
4.5 Hz, 1H), 4.50–4.44 (m, 2H), 3.97 (s, 3H), 3.88 (d, J=5 Hz, 1H), 3.61
(dd, J=2.5, 5.0 Hz, 1H), 2.77 (dd, J=7.0, 14 Hz, 1H), 2.48 (s, 3H),
1.93 ppm (ddd, J=14.5, 9.0, 2.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz):
d = 158.2, 145.5, 134.8, 130.3, 128.2, 122.8, 116.2, 114.1, 106.2, 64.5, 61.3,
53.3, 44.7, 44.1, 32.9, 22.0 ppm; IR (film): n˜ = 2925, 2855, 1682, 1543,
1433, 1416, 1325, 1163 cmÀ1; HRMS (C18H18N3O4SBr): m/z: calcd for:
451.020139 [M+]; found 451.020921.
Scheme 11. Total synthesis of (+) and (À)-agelastatin A with two differ-
ent routes.
Experimental Section
Compound 5
Selected experimental procedures for the preparation of 9, 6, 12, 5, 19,
and 1 (agelastatin A) appear below. Full experimental details for all new
compounds are given in the Supporting Information.
From Compound 15: To a solution of
compound 15 (10 mg, 0.0213 mmol)
and NaHCO3 (5.4 mg, 0.0639 mmol) in
CH2Cl2 (0.25 mL) was added Dess–
Compound 9: To a solution of pyrrole-
2-carboxylate methyl ester (2.0 g,
Martin
periodinane
(13.5 mg,
16 mmol) in THF (160 mL) and
0.032 mmol). The resulting mixture
was stirred at RT for 30 min before
quenched with sat. aq. Na2S2O3. Com-
MeOH (80 mL) was added NBS (re-
crystallized, 0.49 g, 2.8 mmol) at 08C.
The reaction was stirred at 08C for
30 min, before another portion of NBS
pound
5 was purified via silica gel
flash column chromatography (petro-
leum ether/ethyl acetate 3:1, then 3:2)
as a white solid (ca. 7 mg 70–80%).
(recrystallized, 0.63 g, 3.5 mmol) was
added. After 40 min, more NBS (re-
crystallized, 0.51 g, 2.9 mmol) was added to the reaction mixture. After
another 30 min, another portion of NBS (recrystallized, 1.27 g, 7.1 mmol)
was added. The resulting solution was then stirred for another 2 h, before
the solvent was removed under vacuum. Compound 9 was purified via
silica gel flash column chromatography (petroleum ether/diethyl ether
20:1, then 8:1) to give a white floppy solid (1.63 g, 50%). M.p. 101–
From Compound 12: DMSO (1 mL) was added to a mixture of com-
pound 12 (30 mg, 0.0665 mmol) and InACHTUNRGTNEUNG(OTf)3 (26 mg, 0.0462 mmol) at
RT under N2. The resulting solution was heated at 808C for 6 h, before
diluted with ethyl acetate (30 mL). The solution was washed with brine.
The aqueous phases were combined, and extracted with ethyl acetate
three times. The combined the organic phase was dried over MgSO4, and
compound 5 was purified via silica gel flash column chromatography (pe-
troleum ether/ethyl acetate 3:1, then 3:2) to give a white solid (28.3 mg,
91%). M.p. 100–1028C; Rf = 0.3 (petroleum ether/ethyl acetate 1:1);
[a]2D0 = +57.8 (c = 0.97, CH2Cl2); 1H NMR (CDCl3, 500 MHz): d =
7.82 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.03 (d, J=4.0 Hz, 1H),
6.35 (d, J=4.0 Hz, 1H), 5.63 (d, J=7.5 Hz, 1H), 5.23–5.18 (m, 1H), 5.00
(d, J=2.5 Hz, 1H), 4.98 (d, J=5.5 Hz, 1H), 4.00 (br, 1H), 3.84 (s, 3H),
3.02 (dd, J=7.5, 18 Hz, 1H), 2.68 (dd, J=11, 18 Hz, 1H), 2.46 ppm (s,
3H); 13C NMR (CDCl3, 125 MHz): d = 206.3, 157.9, 144.7, 134.7, 130.0,
127.7, 122.6, 116.7, 114.3, 106.4, 64.1, 61.1, 51.9, 41.2, 29.7, 21.6 ppm; IR
(film): n˜ = 3252, 2924, 2854, 1768, 1652, 1548, 1416, 1338, 1162, 1093,
1025 cmÀ1; HRMS (C18H18N3O5SBr): m/z: calcd for: 469.013008 [M+];
found 469.013016.
1038C; Rf
=
0.35 (petroleum ether/ether 4:1); 1H NMR (CDCl3,
400 MHz): d = 9.1 (brs, 1H), 6.82 (dd, J=3.0, 3.5 Hz, 1H), 6.21 (dd, J=
3.0, 3.5 Hz, 1H), 3.86 ppm (s, 3H); 13C NMR (CDCl3, 100 MHz): d =
160.8, 123.7, 116.8, 112.7, 105.2, 51.8 ppm; IR (film): n˜ = 3250, 2924,
2853, 1702, 1552, 1449, 1415, 1389,
1327,
(C6H6NO2Br):
1207 cmÀ1
m/z:
;
HRMS
for:
calcd
202.958190 [M+]; found 202.958096.
Compound 6:
(dba)3]·CHCl3
0.00025 mmol)
A
solution of [Pd2-
(2.29 mg,
AHCTUNGTRENNUNG
and
(R,R)-LST
(5.18 mg, 0.00075 mmol) in CH2Cl2
(1 mL), which had been stirred at RT
for 10 min, was added to a mixture of
Compound 19 (e.g., Table 5, entry 11):
compound 7 (20 mg, 0.05 mmol) and Cs2CO3 (16.3 mg, 0.05 mmol) under
Ar. The mixture was stirred at RT for 12 h, and then filtered through a
celite cake. The solvent was removed under vacuum, and compound 6
was purified via silica gel flash column chromatography (petroleum
ether/ether 8:1, then CH2Cl2/MeOH 40:1) to give a white solid (12.9 mg,
91.5%). M.p. 107–1098C; Rf = 0.6 (CH2Cl2/MeOH 9:1); [a]2D0 = +164.7
(c = 0.34, CH2Cl2); 1H NMR (CDCl3, 500 MHz): d = 6.94 (dd, J=1,
4 Hz, 1H), 6.30 (dd, J=1, 4 Hz, 1H), 6.22–6.20 (m, 1H), 6.13–6.12 (m,
1H), 4.84–4.79 (m, 2H), 3.85 (s, 3H), 3.13–3.07 (m, 1H), 2.63–2.58 ppm
(m, 1H); 13C NMR (CDCl3, 125 MHz): d = 156.3, 135.5, 128.6, 123.7,
116.1, 106.8, 101.6, 64.1, 64.0, 57.2, 38.2 ppm; IR (film): n˜ = 2927, 2853,
1668, 1545, 1418, 1358, 1334, 1310, 1027 cmÀ1; HRMS (C11H11N2O2Br):
m/z: calcd for: 282.000389 [M+]; found 281.999714.
A
solution of [Pd2ACHTUGNTERN(NUG dba)3]·CHCl3
(5.2 mg, 0.005 mmol) and (R,R)-LST
(10.4 mg, 0.015 mmol) in degassed
CH2Cl2 (0.5 mL), which had been
stirred for 10 min at 08C, was added to
a mixture of compound 17 (21.9 mg,
0.1 mmol), compound
0.15 mmol) and HOAc (10 mL, 1m so-
lution in CH2Cl2) under Ar. The mix-
ture was stirred at RT for 3.5 h, and then was added a solution of [Pd2-
8
(45 mg,
AHCTNUGTERN(GNUN dba)3]·CHCl3 (5.2 mg, 0.005 mmol) and rac-LST (10.4 mg, 0.015 mmol) in
degassed CH2Cl2 (0.5 mL), which had been stirred for 10 min at RT. The
resulting solution was stirred at RT for 3 h. Compound 19 was purified
Chem. Eur. J. 2009, 15, 6910 – 6919
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6917

B. M. Trost and G. Dong
via silica gel flash column chromatography (petroleum ether/ethyl acetate
4:1, then 3:1) as a colorless solid (23.0 mg, 82%, 97.5% ee by HPLC OD
[5] T. W. Hong, D. R. Jimenez, T. F. Molinski, J. Nat. Prod. 1998, 61,
158–161.
column, 90:10 heptane/isopropanol, 0.8 mLminÀ1): m.p. 111–1138C; Rf
=
[6] a) L. Meijer, A. M. Thunnissen, A. W. White, M. Garnier, M. Nikol-
ic, L. H. Tsai, J. Walter, K. E. Cleverley, P. C. Salinas, Y. Z. Wu, J.
Biernat, E. M. Mandelkov, S. H. Kim, G. R. Pettit, Chem. Biol. 2000,
7, 51–63; b) G. R. Pettit, S. Ducki, D. L. Herald, D. L. Doubek,
J. M. Schmidt, J. C. Chapuis, Oncol. Res. 2005, 15, 11–20; c) Total
synthesis and mechanism of action studies on the antitumour alka-
loid, (À)-agelastatin A: K. J. Hale, M. M. Domostoj, M. El-Tanani,
F. C. Campbell, C. K. Mason in Strategies and tactics in organic syn-
thesis (Ed.: M. Harmata), Academic Press, London, 2005, pp. 352–
394.
0.2 (petroleum ether/ethyl acetate 4:1); [a]D20
=
À120.2 (c
= 1.0,
CH2Cl2); 1H NMR (CDCl3, 500 MHz): d = 6.91 (d, J=5.0 Hz, 1H), 6.28
(d, J=5.0 Hz, 1H), 6.02 (m, 1H), 5.95 (m, 1H), 5.29 (d, J=8.0 Hz, 1H),
4.65 (ddd, J=8.0, 6.5, 2.5 Hz, 1H), 3.85 (s, 3H), 2.92 (d, J=21.5 Hz, 1H),
2.71 ppm (ddd, J=21.5, 6.5, 2.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d
= 157.3, 132.0, 129.0, 123.8, 114.7, 113.6, 104.8, 63.0, 61.6, 60.7, 36.4 ppm;
IR (film): n˜ = 2925, 2854, 1667, 1545, 1417, 1320, 1028 cmÀ1; HRMS
(C11H11N2O2Br): m/z: calcd for 282.000389 [M+]; found 281.999491.
(+)-Agelastatin A (1): Freshly made
SmI2 (1.6 mL, 0.1m in THF) was
added to compound 16 (10.0 mg,
[7] C. K. Mason, S. McFarlane, P. G. Johnston, P. Crowe, P. J. Erwin,
M. M. Domostoj, F. C. Campbell, S. Manaviazar, K. J. Hale, M. El-
Tanai, Mol. Cancer Ther. 2008, 7, 548–558.
0.019 mmol) under argon at 08C. The
[8] K. J. Hale, M. M. Domostoj, D. A. Tocher, E. Irving, F. Scheinmann,
Org. Lett. 2003, 5, 2927–2930.
resulting blue solution was allowed to
gradually warm to RT and stirred for
[9] For a review, see: S. M. Weinreb, Nat. Prod. Rep. 2007, 24, 931–948.
[10] D. Stien, G. T. Anderson, C. E. Chase, Y.-H. Koh, S. M. Weinreb, J.
Am. Chem. Soc. 1999, 121, 9574–9579.
2 h before another 0.5 mL SmI2 (0.1m
in THF) was added. After the solution
was stirred at RT for 15 min, THF was
[11] a) K. S. Feldman, J. C. Saunders, J. Am. Chem. Soc. 2002, 124, 9060–
9061; b) K. S. Feldman, J. C. Saunders, M. L. Wrobleski, J. Org.
Chem. 2002, 67, 7096–7109.
removed under vacuum. The residue
was first purified by silica gel chroma-
tography (10% to 15% MeOH in
[12] a) K. J. Hale, M. M. Domostoj, D. A. Tocher, E. Irving, F. Schein-
mann, Org. Lett. 2003, 5, 2927–2930; b) M. M. Domostoj, E. Irving,
F. Scheinmann, K. J. Hale, Org. Lett. 2004, 6, 2615–2618.
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[14] P. A. Wehn, PhD Thesis, Stanford University CA (USA), 2005.
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2989–2992.
[16] T. Yoshimitsu, T. Ino, T. Tanaka, Org. Lett. 2008, 10, 5457–5460.
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[18] For a preliminary report of a portion of our work, see: B. M. Trost,
G. Dong, J. Am. Chem. Soc. 2006, 128, 6054–6055.
CH2Cl2). A yellow solid was obtained,
which was then dissolved in 15% MeOH in CH2Cl2 and filtered through
charcoal. The (+)-agelastatin A was further purified by another silica gel
chromatography (10% to 15% MeOH in CH2Cl2) to give an off-white
solid (6.0 mg, 88%). M.p. 1958C (decomposed); Rf = 0.25 (10% MeOH
in CH2Cl2); [a]2D0
= +53.2 (c =
0.13, MeOH); 1H NMR (CD3OD,
500 MHz): d = 6.91 (d, J=4.0 Hz, 1H), 6.33 (d, J=4.0 Hz, 1H), 4.60 (m,
1H), 4.09 (d, J=5.5 Hz, 1H), 3.89 (s, 1H), 2.81 (s, 3H), 2.65 (dd, J=6.5,
13 Hz, 1H), 2.10 ppm (dd, J=13, 13 Hz, 1H); 13C NMR (CD3OD,
150 MHz): d = 161.4, 161.1, 124.1, 116.0, 113.8, 107.2, 95.7, 67.4, 62.2,
54.4, 40.0, 24.2 ppm; IR (film): n˜ = 3346 (br), 2923, 1685, 1644, 1555,
1424, 1380 cmÀ1
;
ESI (C12H13N4O3Br): m/z: 341.0 [M+H]+, 363.0
[19] Reagents that have been tried: AlMe3, ClMgiPr, KCN, MgCl2, Zr-
[M+Na]+.
ACHUNTGERNN(UG OtBu)4, N-heterocyclic carbene, Sn[NCAHTUNGTRNE(NUNG TMS)2]2, etc.
[20] The reason of using (R,R) ligand in this cyclization was initially to
examine the possibility of cascading two AAA reactions in one reac-
tion vessel, although here is a mismatched situation.
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Acknowledgements
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We thank the National Science Foundation and the National Institutes of
Health (GM33049) for their generous support of our programs. Mass
spectra were provided by the Mass Spectrometry Regional Center for the
University of California-San Francisco, supported by the NIH Division of
Research Resources. G.D. is a Stanford graduate fellow. Palladium salts
were generously supplied by Johnson-Matthey. We thank Prof. Du Bois
and Dr. Wehn for a TLC sample of agelastatin A. We also thank Prof.
Weinreb for providing an experimental procedure of the allylic amination
reaction.
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6918
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6910 – 6919

Agelastatin A
FULL PAPER
thank J. Du Bois and K. Guthikonda for drawing our attention to
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Received: March 26, 2009
Published online: June 16, 2009
Chem. Eur. J. 2009, 15, 6910 – 6919
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6919