New class of nucleophiles for palladium-catalyzed asymmetric allylic alkylation. Total synthesis of agelastatin A

Article abstract of DOI:10.1021/ja061105q

New classes of nucleophiles, pyrroles, and N-methoxyamides were developed for Pd-catalyzed AAA reactions. By varying the functional groups at the 2-position of pyrroles, either regioisomer of the piperazinone is available. Using one regioisomer, the total

Full text of DOI:10.1021/ja061105q

Published on Web 04/15/2006
New Class of Nucleophiles for Palladium-Catalyzed Asymmetric Allylic
Alkylation. Total Synthesis of Agelastatin A
Barry M. Trost* and Guangbin Dong
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received February 15, 2006; E-mail: bmtrost@stanford.edu
Metal-catalyzed allylic alkylations increase in importance as a
synthetic method as the ability to expand their scope increases. A
major feature of this method is its applicability for formation of a
broad array of bond types, including carbon-carbon and carbon-
heteroatom bonds. The importance of nitrogen-containing bioactive
molecules1 directs special attention to the formation of carbon-
nitrogen bonds.2 The recent revelation of bromopyrroles as a
growing family of bioactive natural products represented by the
manzacidines, axinellamine A, dibromophakellstatin, and palau’amine,
typically derived from marine organisms,3 led us to consider the
Figure 1. Agelastatins.
Table 1. Selected Optimization Studies
use of pyrroles as nucleophiles in AAA (asymmetric allylic
alkylation) reactions. The agelastatins (1), a family of four
tetracyclic compounds (see Figure 1), possess nanomolar activity
against several cancer cell lines.4 Furthermore, agelastatin A inhibits
glycogen synthase kinase-3â (GSK-3â), a behavior that may provide
an approach for the treatment of Alzheimer’s disease.4a In this paper,
we report the use of pyrroles as nucleophiles in the Pd AAA and
the use of such a process for a facile asymmetric synthesis of
agelastatin A.
Cs2CO3
(equiv)
concentrated
(M)
yield
(%)a
ee
entry
Pd source (mol %)
(%)b
1
2
3
4
5
6
Pd2(dba)3CHCl3 (5)
Pd2(dba)3CHCl3 (5)
Pd2(dba)3CHCl3 (2.5)
Pd2(dba)3CHCl3 (1.25)
[Pd(C3H5)Cl]2 (2)
1.0
0.7
1.0
1.0
1.0
1.0
0.02
0.02
0.02
0.08
0.17
0.08
90
75
89
75
88-93
83
84
92
66
85
87
92
[Pd(C3H5)Cl]2 (1.25)
a Isolated yield. b Enantioselectivities were determined by chiral HPLC.
Initial studies examined the reaction between the Boc-activated
cyclopentene-1,4-diol 2 and methyl 5-bromopyrrole-2-carboxylate
3 (eq 1). After a general screening, Cs2CO3 and DCM proved to
be the base and best solvent combination.
Scheme 1 . Piperazinone Synthesisa
a Conditions: (a) LiOH (1 N), THF/water ) 3/1, 48 h, rt; (b) oxalyl
chloride, cat. DMF in THF, then NH2OMe‚HCl, K2CO3, and H2O, rt.
Table 2. Synthesis of Piperazinone 9a
ligand
additive
(mol %)
temp
C)
yield
(%)b
ee
(%)c
entry
Pd source (mol %)
(mol %)
(
°
1
2
3
4
5
6
7
8
9
[Pd(C3H5)Cl]2 (2) (R,R)-4 (6)
[Pd(C3H5)Cl]2 (2) (R,R)-4 (6) Cs2CO3 (100)
[Pd(C3H5)Cl]2 (5) (R,R)-4 (15)
Pd2(dba)2CHCl3 (5) (R,R)-4 (15)
Pd2(dba)3CHCl3 (5) (R,R)-4 (15)
Pd2(dba)3CHCl3 (5) (R,R)-4 (15)
none
rt trace NA
rt NA
rt traced NA
0
The yield and enantioselectivity were optimized by varying the
palladium source and loading, base loading, and concentration
(Table 1). From these studies emerged the most practical set of
conditions, as shown in entry 6, which gives the N-alkyl pyrrole 5
in 83% yield and 92% ee. Direct transformation of the carboxylate
ester 5 to the N-methoxyamide 6 failed,5 but a two-step process
(hydrolysis, condensation) gave a high yield (Scheme 1). Although
the chiral ligand was not necessary for cyclization to piperazinone
7, the intramolecular Pd-catalyzed AAA with the N-methoxyamide
as the nucleophile gave a higher yield when (R,R)-4 was used as a
ligand (91%) compared to dppp (70%). At this point, the absolute
configuration was assigned by analogy to other reactions of substrate
2.
HOAc (10)
HOAc (10)
BSA (100)
HOAc (10) 0 to rt
HOAc (10) rt
HOAc (10) 0 to rt 80e,f 96
HOAc (10) 0 to rt 82e,g 97.5
rt
rt
51 NA
50 NA
65e 89
88e NA
Pd2(dba)2CHCl3 (5)
rac-4 (15)
Pd2(dba)2CHCl3 (5) (R,R)-4 (15)
Pd2(dba)2CHCl3 (5) (R,R)-4 (15)
a Unless otherwise indicated, all reactions were performed with 1.0 equiv
of 2 and 1.0 equiv of 8 at 0.2 M in DCM. b Isolated yield. c Enantioselec-
tivities were determined by chiral HPLC. d Single alkylation product was
the main product. e The reaction was performed with 1.5 equiv of 2 and
1.0 equiv of 8. f Another portion of Pd2(dba)3CHCl3 (5 mol %), (R,R)-4
(15 mol %) was added after 1 h. g Another portion of Pd2(dba)3CHCl3 (5
mol %), rac-4 (15 mol %) was added after 3.5 h.
With success of both the pyrrole and the N-methoxyamide as
nucleophiles, respectively, and considering that the nitrogen on the
N-methoxyamide is more nucleophilic than the one on the pyrrole,
we designed a cascade reaction to further extend this methodology.
Theoretically, piperazinone 9 could be synthesized in one pot from
successive alkylations with the N-methoxyamide 86 as nucleophile.
Surprisingly, almost no reaction occurred when base was present
(see Table 2). We hypothesized that after deprotonation, 8 could
act as a good bidentate ligand for palladium, and the first ionization
might be inhibited. On the basis of this hypothesis, 10 mol % of
9
6054
J. AM. CHEM. SOC. 2006, 128, 6054-6055
10.1021/ja061105q CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Total Synthesis of (+)-Agelastatin Aa
In conclusion, we have developed new classes of nucleophiles,
pyrroles and N-alkoxyamides, for palladium-catalyzed AAA reac-
tions. By varying the functional groups at the 2-position of pyrroles,
we can efficiently and enantioselectively access either regioisomer
of the piperazinones. Using one regioisomer, we completed the total
synthesis of (+)-agelastatin A in a short and concise way (10 steps
total), during the course of which we developed a new copper
catalyst for aziridination, and an In(OTf)3-DMSO system to
oxidatively open an N-tosyl aziridine. We further show the prospect
to access (-)-agelastatin A using the same enantiomer of the chiral
catalyst in the Pd AAA by using the other piperazinone regioisomer.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM13598) for their generous
support of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center for the University of Californias
San Francisco, supported by the NIH Division of Research
Resources. We are indebted to Johnson-Matthey who generously
provided palladium salts.
a Conditions: (a) catalyst 14 (0.5 equiv), PhIdNTs (5 equiv), 4 Å M.S.,
benzene, 0 °C to rt; (b) TFA (10 equiv), microwave, dioxane/water ) 3/2,
150 °C, 2.5 h; (c) DMP, DCM, rt; (d) In(OTf)3 (0.7 equiv), DMSO, 80 °C,
6 h; (e) CH3NCO (1.2 equiv), Cs2CO3 (0.2 equiv), DCM, 0 °C to rt; (f)
SmI2 (10 equiv), THF, 0 °C to rt.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
HOAc was added to the reaction. To our delight, piperazinone 9
was obtained in 51% yield when Pd2(dba)3CHCl3 was used as the
palladium source. After optimization, piperazinone 9 could be
obtained in up to 82% yield, 97.5% ee (entry 9). Thus, by proper
choice of pyrrole nucleophiles in the Pd-catalyzed AAA, access to
either piperazinone regioisomer is possible.
References
(1) (a) Cordell, G. A., Ed. The Alkaloids. Chemistry and Biology; Academic
Press: San Diego, 2005, Vol. 62 and earlier volumes in the series. (b)
Hesse, M. Alkaloids: Nature’s Curse or Blessing; Wiley-VCH: New
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(2) For a recent review: (a) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003,
103, 2921. (b) Trost, B. M. Chem. Pharm. Bull. 2004, 50, 1.
(3) (a) Gribble, G. W. J. Nat. Prod. 1992, 55, 1353. Also see: (b) Faulkner,
D. J. Nat. Prod. Rep. 2002, 19, 1. (c) Berlinck, R. G. S.; Kosuga, M. H.
Nat. Prod. Rep. 2005, 22, 516 and references therein.
(4) For the isolation and biological activities of (-)-agelastatin A: (a)
D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Ribes, O.; Pusset, J.; Leroy,
S.; Pietra, F. J. Chem. Soc., Chem. Commun. 1993, 1305. (b) D’Ambrosio,
M.; Guerriero, A.; Chiasera, G.; Pietra, F. HelV. Chim. Acta 1994, 77,
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Mandelkov, E. M.; Kim, S. H.; Pettit, G. R. Chem. Biol. 2000, 2, 51.
(5) Reagents that have been tried: AlMe3, ClMgiPr, KCN, MgCl2, Zr(OBut)4,
an N-heterocyclic carbene, Sn[N(TMS)2]2, etc.
For agelastatin A4,7 (Scheme 2) starting with piperazinone 7, we
envisioned aziridination of the double bond followed by transfor-
mation to the required urea. The aziridination which we anticipated
to be difficult led us to explore the N-heterocyclic carbene complex
148 which, to our knowledge, has not previously been explored for
aziridination. Indeed, this catalyst performed well for this difficult
rather electron-deficient cyclopentene. Hydrolytic ring opening of
10 occurs best upon heating in a microwave. Dess-Martin oxidation
then gives R-amino ketone 12. A more efficient direct oxidative
opening with DMSO, for which few cases previously existed,9 was
explored. While following the previously reported thermal protocol
proved inefficient, heating N-tosyl aziridine 10 in the presence of
(6) See Supporting Information for the synthesis of 8.
(7) For previous total syntheses: (a) Stien, D.; Anderson, G. T.; Chase, C.
E.; Koh, Y.; Weinreb, S. M. J. Am. Chem. Soc. 1999, 121, 9574. (b)
Feldman, K. S.; Saunders, J. C. J. Am. Chem. Soc. 2002, 124, 9060. (c)
Domostoj, M. M.; Irving, E.; Scheinmann, F.; Hale, K. J. Org. Lett. 2004,
6, 2615. (d) Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621.
(8) (a) Fructos, M. R.; Belderrain, T. R.; Nicasio, M. C.; Nolan, S. P.; Kaur,
H.; D´ıaz-Requejo, M. M.; Pe´rez P. J. J. Am. Chem. Soc. 2004, 126, 10846.
(b) Fructos, M. R.; Belderrain, T. R.; de Fre´ment, P.; Scott, N. M.; Nolan,
S. P.; Kaur, H.; D´ıaz-Requejo, M. M.; Pe´rez P. J. Angew. Chem., Int. Ed.
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40, 5109.
(9) For N-aroylaziridines: (a) Heine, H. W.; Newton, T. Tetrahedron Lett.
1967, 8, 1859. For N-alkoxycarbonylaziridines: (b) Fujita, S.; Hiyama,
T.; Nozaki, H. Tetrahedron Lett. 1969, 10, 1677. (c) Fujita, S.; Hiyama,
T.; Nozaki, H. Tetrahedron 1970, 26, 4347. We thank J. Du Bois and K.
Guthikonda for drawing our attention to application of this thermal method
for opening trichloroethoxysulfamoylaziridines.
(10) Yadav, J. S.; Subba Reddy, B. V.; Mahesh Kumar, G.; Murthy, Ch. V. S.
R. Synth. Commun. 2002, 32, 1797 and earlier references therein.
(11) The spectroscopic data are identical to the reported data except for [R]20
+53.2° (c ) 0.13, MeOH), while [R]20D for (-)-agelastatin A is -59.3D°
(c ) 0.13, MeOH) given by Hong, T. W.; Jimenez, D. R.; Molinski, T.
F. J. Nat. Prod. 1998, 61, 158.
10
0.7 equiv of In(OTf)3 in DMSO at 80 °C provides the R-amino
ketone 12 in excellent yield. Finally, addition of methyl isocyanate
to 12, followed by SmI2-mediated cleavage of N-OMe and N-Ts,
completed the total synthesis of (+)-agelastatin A (1).11 This
completion also established the absolute configuration of the Pd
AAA, as shown in Scheme 1.
Access to the natural (-)-enantiomer simply requires use of the
S,S-ligand in eq 1. Alternatively, the product of the one-pot
annulation 9 could also provide access to the (-)-enantiomer based
upon the work of Weinreb.7a To explore this prospect, piperazinone
9 was subjected to allylic amination,12 as shown in eq 3. A single
regio- and diastereomer was obtained which, by analogy to other
reactions of this reagent, is assigned as 15. Given Weinreb’s
synthesis, it is reasonable to propose that (-)-1 could be accessed
from 15.
(12) (a) Sharpless, K. B.; Hori, T. J. Org. Chem. 1976, 41, 176. (b) Bussas,
R.; Kresze, G. Liebigs Ann. Chem. 1980, 629.
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