Total synthesis of (-)-agelastatin A: The application of a sequential sigmatropic rearrangement

Article abstract of DOI:10.1021/ol900799e

An enantioselective total synthesis of (-)-agelastatin A from (-)-2,3-O-isopropylidene-D-threitol is described. The sequential Overman/Mislow-Evans rearrangement of the allylic bistrichloroimidate is the key step, which efficiently installed a diaminohydr

Full text of DOI:10.1021/ol900799e

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2687-2690
Total Synthesis of (-)-Agelastatin A:
The Application of a Sequential
Sigmatropic Rearrangement
Naoto Hama, Tomoki Matsuda, Takaaki Sato, and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology,
Keio UniVersity, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
chida@applc.keio.ac.jp
Received April 13, 2009
ABSTRACT
An enantioselective total synthesis of (-)-agelastatin A from (-)-2,3-O-isopropylidene-D-threitol is described. The sequential Overman/
Mislow-Evans rearrangement of the allylic bistrichloroimidate is the key step, which efficiently installed a diaminohydroxy group.
Chirality transfer through the sigmatropic rearrangement of
optically active allylic alcohols has been recognized as a
useful approach to enantiomerically pure synthetic targets.1
We have been especially attracted to the utilization of
hydroxy groups embedded in naturally occurring organic
compounds, such as carbohydrates and tartaric acid, since
these compounds are readily available and operationally
versatile enantiopure starting materials. In order to render
this approach more efficient and practical, our laboratory has
been exploring strategies using the cascade sigmatropic
rearrangement2 of allylic vicinal diols for the synthesis of
biologically active natural products and their derivatives. To
date, we have reported a formal total synthesis of (-)-
morphine by a cascade Claisen rearrangement starting from
D-glucal3,4 and a total synthesis of A-315675 by a cascade
Overman rearrangement using diisopropyl D-tartrate as a
chiral starting material.5,6
As part of our ongoing studies aimed at developing
chemistry involving sequential sigmatropic rearrange-
ments, our group took an interest in the oroidin alkaloid,
(-)-agelastatin A (1). Isolated by Pietra in 1994 from the
deep water marine sponge Agelas dendromorpha,7 (-)-1
inhibits a number of human tumor cell lines.7a,8 The recent
excellent report by El-Tanani and Hale has revealed that
(-)-1 acts as an antimetastatic agent through the inhibition
(3) For selected reviews on Claisen rearrangement, see: (a) Castro,
A. M. M. Chem. ReV. 2004, 104, 2939–3002. (b) Majumdar, K. C.; Alam,
S.; Chattopadhyay, B. Tetrahedron 2008, 64, 597–643
.
(4) Tanimoto, H.; Saito, R.; Chida, N. Tetrahedron Lett. 2008, 49, 358–
362. For selected examples on cascade Claisen rearrangement except for
an aromatic version, see: (a) Curran, D. P.; Suh, Y.-G. Carbohydr. Res.
1987, 171, 161–191. (b) Wallace, G. A.; Scott, R. W.; Heathcock, C. H. J.
Org. Chem. 2000, 65, 4145–4152. (c) Kotha, S.; Sreenivasachary, N.;
Brahmachary, E. Tetrahedron 2001, 57, 6261–6265. (d) Majumdar, K. C.;
Kundu, U. K.; Ghosh, S. K. Org. Lett. 2002, 4, 2629–2631. (e) Warrington,
J. M.; Barriault, L. Org. Lett. 2005, 7, 4589–4592. (f) Cle´ment, R.; Grise´,
C. M.; Barriault, L. Chem. Commun. 2008, 3004–3006. For an selected
example on stepwise double-Claisen rearrangement of an allylic diol, see:
(1) For selected reviews on chirality transfer through sigmatropic
rearrangemetnt, see: (a) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron:
Asymmetry 1996, 7, 1847–1882. (b) Nubbemeyer, U. Synthesis 2003, 961–
1008.
(2) For selected reviews on cascade, tandem, and domino reactions
including sigmatropic rearrangement, see: (a) Tietze, L. F. Chem. ReV. 1996,
96, 115–136. (b) Paquette, L. A. Eur. J. Org. Chem. 1998, 1709–1728. (c)
Neuschu¨tz, K.; Velker, J.; Neier, R. Synthesis 1998, 227–255. (d) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134–7186. (e) Pellissier, H. Tetrahedron 2006, 62, 1619–1665. (f) Padwa,
A.; Bur, S. K. Tetrahedron 2007, 63, 5341–5378. (g) Arns, S.; Barriault,
L. Chem. Commun. 2007, 2211–2221.
Marchart, S.; Mulzer, J.; Enev, V. S. Org. Lett. 2007, 9, 813–816
.
(5) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599. (b)
Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910. For reviews on
Overman rearrangement, see: (c) Overman, L. E. Acc. Chem. Res. 1980,
13, 218–224. (d) Overman, L. E.; Carpenter, N. E. In Organic Reactions;
Overman, L. E., Ed.; Wiley: New York, 2005; Vol 66, pp 1-107.
10.1021/ol900799e CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

of osteopontin-mediated malignant transformation and the
arrest of the cell cycle.8c (-)-Agelastatin A (1) has also been
reported to show insecticidal properties7c and to selectively
inhibit glycogen synthase kinase-3ꢀ (GSK-3ꢀ).9 In addition
to the intriguing biological properties of (-)-1, its unique
architecture including a tetraamino carbocyclic ring and a
bromopyrrole unit has inspired a number of synthetic
chemists.10,11 Initially, Weinreb,10a,b Feldman,10c,d Hale,10e,f
Davis,10g,k Trost,10h and Ichikawa10i all accomplished the
elegant total synthesis of 1 by different strategies. Recently,
three more novel total syntheses have been reported.10j,l,m
In designing a synthetic route toward (-)-agelastatin A
(1), we envisioned that cyclopentene 6 possessing a diami-
nohydroxy group would be a promising intermediate, and
cyclopentene 6 was itself expected to be derived from acyclic
compound 5 through RCM12 (Scheme 1). Our major chal-
Scheme 2. Synthesis of Allylic Vicinal Diol 11
Overman rearrangement, Z-diene 9 was isomerized to
E-diene 10 with thiophenol and AIBN under radical condi-
tions.19 Removal of the acetonide followed by recrystalli-
zation furnished allylic diol 11 as a single isomer.
Scheme 1. Synthetic Strategy toward (-)-Agelastatin A (1)
With allylic diol 11 in the (E)-arrangement, the stage was
now set for the crucial sequential sigmatropic rearrangement.
Treatment of 11 with trichloroacetonitrile and DBU in
CH2Cl2 gave allylic bistrichloroacetimidate 3 (Scheme 3).
Scheme 3. Sequential Overman/Mislow-Evans Rearrangement
lenge in the synthesis of (-)-1 would be the efficient
installation of the diaminohydroxy group [C8, C4, and C5
(agelastatin numbering)] through the sequential Overman/
Mislow-Evans rearrangement of bistrichloroimidate 3.13-15
The two nitrogen-substituted stereocenters16 (C4, C8) could
be established by the cascade Overman rearrangement of 3
in a single operation. The subsequent Mislow-Evans rear-
rangement of allylic sulfide 4 could introduce a hydroxy
group at the C5 carbon center. Bistrichloroimidate 3, with
its two chiral stereocenters, was expected to be readily
prepared from D-tartaric acid 2.
The synthesis of (-)-agelastatin A (1) commenced with
the monotosylation of commercially available (-)-2,3-O-
isopropylidene-D-threitol 7,17 which is derived from D-tartaric
acid, followed by thiophenol installation to produce alcohol
8 (Scheme 2). After Swern oxidation18 of the primary
alcohol, the Wittig reaction with allylphosphorous ylide
provided diene 9 in a Z-selective manner. To set the
appropriate stereochemical configuration in the cascade
To our delight, the cascade Overman rearrangement of 3
under thermal conditions at 140 °C in o-xylene in a sealed
2688
Org. Lett., Vol. 11, No. 12, 2009

tube in the presence of Na2CO320 provided desired bistrichlo-
roacetamide 4 in 58% yield from allylic diol 11. The reaction
proceeded in a stereoselective manner probably through the
known chair transition state,5 and 4 was isolated as the sole
product. The allylic sulfide in 4 was subsequently oxidized
to sulfoxide 13, which underwent the Mislow-Evans rear-
rangement with P(OMe)3 in refluxing MeOH to give a 1:1
mixture of two diastereomers 5.21 Although the stereoselec-
tivity of the Mislow-Evans rearrangement was poor, both
isomers could be used in the synthesis without separation.
The ring-closing metathesis of 5 provided a 1:1 mixture of
cyclopentene 6. Then, the treatment of 6 with methane-
sulfonic anhydride and pyridine generated the oxazoline 14
in 58% yield (three steps from 13).22 It is noteworthy that
two isomers derived from the Mislow-Evans rearrangement
converged to a single oxazoline, and the two trichloroaceta-
mides on the carbocyclic ring were successfully differentiated
in this reaction.
Michael reaction of the pyrrole was envisaged. Originally
developed by Weinreb,10b the reaction has been extensively
investigated by several groups,10c,d,f,g,i,k with Hale10f and
Ichikawa10i revealing that lowering pKa of the pyrrole
nitrogen is often highly beneficial and sometimes necessary
in the aza-Michael addition. Ichikawa employed the dibro-
mopyrrole and Hale employed a number of bromopyrroles
to effect cyclization, and in both cases, the adducts were
transformed into the monobromopyrrole in the final step. We
took into account their critical findings and explored a more
direct and efficient procedure that used the monobromopy-
rrole unit and a 2,4-dimethoxybenzyl (DMB) group as a
protecting group for the N-methylurea. The one-pot formation
of the urea from trichloroacetamide 16 with 2,4-dimethoxy-
benzylmethyl amine and Na2CO3 in DMSO at 100 °C
efficiently furnished protected N-methylurea 17 in 70%
yield.26 Removal of the THP group on the secondary alcohol
followed by IBX oxidation27 gave R,ꢀ-unsaturated ketone
With oxazoline 14 now available by the sequential
Overman/Mislow-Evans rearrangement, we turned our
attention to the installation of the piperazinone ring with the
sensitive bromopyrrole (Scheme 4). Removal of the trichlo-
(6) Momose, T.; Hama, N.; Higashino, C.; Sato, H.; Chida, N.
Tetrahedron Lett. 2008, 49, 1376–1379. For selected examples on cascade
Overman rearrrangement of allylic or propalgylic diols, see: (a) Banert,
K.; Fendel, W.; Schlott, J. Angew. Chem., Int. Ed. 1998, 37, 3289–3292.
(b) Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863–866. For
selected examples on cascade reactions including Overman rearrangement,
see: (c) Villemin, D.; Hachemi, M. Synth. Commun. 1996, 26, 1329–1334.
(d) Singh, O. V.; Han, H. Org. Lett. 2004, 6, 3067–3070. For construction
of 1,2-diamines from allylic 1,2-diols by stepwise sigmatropic rearrange-
ment, see: (e) Ichikawa, Y.; Egawa, H.; Ito, T.; Isobe, M.; Nakano, K.;
Kotsuki, H. Org. Lett. 2006, 8, 5737–5740. (f) Ichikawa, Y.; Yamaoka, T.;
Nakano, K.; Kotsuki, H. Org. Lett. 2007, 9, 2989–2992.
Scheme 4. Total Synthesis of (-)-Agelastatin A (1)
(7) (a) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Ribes, O.; Pusset,
J.; Leroy, S.; Pietra, F. J. Chem. Soc., Chem. Commun. 1993, 1305–1306.
(b) D’Ambrosio, M.; Guerriero, A.; Chiasera, G.; Pietra, F. HelV. Chim.
Acta 1994, 77, 1895–1902. (c) Hong, T. W.; J´ımenez, D. R.; Molinski,
T. F. J. Nat. Prod. 1998, 61, 158–161.
(8) For studies on the biological activities of (-)-(1), see : (a)
D’Ambrosio, M.; Guerriero, A.; Ripamonti, M.; Debitus, C.; Waikedre, J.;
Pietra, F. HelV. Chim. Acta 1996, 79, 727–735. (b) Pettit, G. R.; Ducki, S.;
Herald, D. L.; Doubek, D. L.; Schmidt, J. M.; Chapuis, J.-C. Oncol. Res.
2005, 15, 11–20. (c) Mason, C. K.; McFarlane, S.; Johnston, P. G.; Crowe,
P.; Erwin, P. J.; Domostoj, M. M.; Campbell, F. C.; Manaviazar, S.; Hale,
K. J.; El-Tanani, M. Mol. Cancer Ther. 2008, 7, 548–558.
(9) Meijer, L.; Thunnissen, A.-M. W. H.; White, A. W.; Garnier, M.;
Nikolic, M.; Tsai, L.-H.; Walter, J.; Cleverley, K. E.; Salinas, P. C.; Wu,
Y.-Z.; Biernat, J.; Mandelkow, E.-M.; Kim, S.-H.; Pettit, G. R. Chem. Biol.
2000, 7, 51–63.
(10) Total synthesis of 1: (a) Anderson, G. T.; Chase, C. E.; Koh, Y.-
H.; Stien, D.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1998, 63, 7594–
7595. (b) Stien, D.; Anderson, G. T.; Chase, C. E.; Koh, Y.-H.; Weinreb,
S. M. J. Am. Chem. Soc. 1999, 121, 9574–9579. (c) Feldman, K. S.;
Saunders, J. C. J. Am. Chem. Soc. 2002, 124, 9060–9061. (d) Feldman,
K. S.; Saunders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096–
7109. (e) Hale, K. J.; Domostoj, M. M.; Tocher, D. A.; Irving, E.;
Scheinmann, F. Org. Lett. 2003, 5, 2927–2930. (f) Domostoj, M. M.; Irving,
E.; Scheinmann, F.; Hale, K. J. Org. Lett. 2004, 6, 2615–2618. (g) Davis,
F. A.; Deng, J. Org. Lett. 2005, 7, 621–623. (h) Trost, B. M.; Dong, G.
J. Am. Chem. Soc. 2006, 128, 6054–6055. (i) Ichikawa, Y.; Yamaoka, T.;
Nakano, K.; Kotsuki, H. Org. Lett. 2007, 9, 2989–2992. (j) Yoshimitsu,
T.; Ino, T.; Tanaka, T. Org. Lett. 2008, 10, 5457–5460. (k) Davis, F. A.;
Zhang, J.; Zhang, Y.; Qiu, H. Synth. Commun. 2009, 39, 1914–1919. (l)
Dickson, D. P.; Wardrop, D. J. Org. Lett. 2009, 11, 1341–1344. (m) Wehn,
P. M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 3802–3805. For selected
reviews on total synthesis of agelastatin A, see: (n) Hale, K. J.; Domostoj,
M. M.; El-Tanani, M.; Campbell, F. C.; Mason, C. K. In Strategies and
Tactics in Organic Synthesis; Harmata, M., Ed.; Elsevier Academic Press:
London, 2005; Vol. 6, pp 352-394. (o) Weinreb, S. M. Nat. Prod. Rep.
2007, 24, 931–948.
roacetyl group in 14 with DIBAL23 and condensation of the
resulting amine with 2-bromopyrrole carboxylic acid24
afforded amide 15. After hydrolysis of the oxazoline of 15
with p-TsOH·H2O in pyridine/H2O,10k,25 the resulting sec-
ondary alcohol was protected as the THP acetal. In order to
construct the piperazinone ring, an intramolecular aza-
(11) Synthetic studies of 1 : (a) Baron, E.; O’Brien, P.; Towers, T. D.
Tetrahedron Lett. 2002, 43, 723–726. (b) Chen, Y.; Dias, H. V. R.; Lovely,
C. J. Tetrahedron Lett. 2003, 44, 1379–1382. (c) Porter, M. J.; White, N. J.;
Howells, G. E.; Laffan, D. D. P. Tetrahedron Lett. 2004, 45, 6541–6543.
(d) Endeshaw, M. M.; Bayer, A.; Hansen, L. K.; Gautun, O. R. Eur. J.
Org. Chem. 2006, 5249–5259. (e) Li, S.-W.; Batey, R. A. Chem. Commun.
2007, 3759–3761.
Org. Lett., Vol. 11, No. 12, 2009
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18, which was exposed to Et3N in MeCN to induce the
crucial aza-Michael addition. Due to the instability of the
aza-Michael product, the next deprotection was immediately
performed. The 2,4-dimethoxybenzyl group was successfully
cleaved with CAN in MeCN/H2O at 10 °C without affecting
the bromopyrrole group, thus affording (-)-agelastatin A (1)
in 54% over two steps from 18. Our synthetic sample was
found to be indistinguishable from a natural sample based
on 1H NMR, 13C NMR, HRMS, and IR, as well as its optical
rotation.7a,c
In summary, we have achieved a total synthesis of (-)-
agelastatin A (1), using a sequential Overman/Mislow-
Evans rearrangement as the key step. The cascade Overman
rearrangement has thus been shown to be a powerful tool
for the stereoselective one-step construction of diamino
moieties in complex natural products. Progress toward the
development of a new series of sequential sigmatropic
rearrangements and their applications are ongoing.
(12) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856–9857. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1996, 118, 100–110. For reviews on RCM in synthesis of
alkaloids, see: (c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371–388. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
(e) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712. (f)
Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199–2238. (g) Nicolaou,
K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–
4527. (h) Brown, R. C. D.; Satcharoen, V. Heterocycles 2006, 70, 705–
736. Ring-closing metathesis was successfully employed in the total
synthesis of 1; see: ref 10e, g, i.
(13) Recently, Wardrop and co-workers reported the practical total
synthesis of (()-1 using the Overman rearrangement; see ref 10l.
(14) (a) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow,
K. J. Am. Chem. Soc. 1968, 90, 4869–4876. (b) Evans, D. A.; Andrews,
G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956–4957. For reviews on
Mislow-Evans rearrangement, see: (c) Evans, D. A.; Andrews, G. C. Acc.
Chem. Res. 1974, 7, 147–155. (d) Hoffmann, R. W. Angew. Chem., Int.
Ed. 1979, 18, 563–572. (e) Weinreb and co-workers reported the first total
synthesis of (()-1 using the N-sulfinyl dienophile Diels-Alder methodology
including the Mislow-Evans rearrangement; see ref 10a, b.
Acknowledgment. Support from a Grant-in-Aid for
Scientific Research, B20350021, from the Ministry of
Education, Culture, Sports, Science and Technology, Japan,
is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures; copies of H NMR and 13C NMR spectra of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) The cascade Claisen/Mislow-Evans rearrangement was reported:
(a) Posner, G. H.; Carry, J. C.; Crouch, R. D.; Johnson, N. J. Org. Chem.
1991, 56, 6987–6993. (b) Pelc, M. J.; Zakarian, A. Org. Lett. 2005, 7, 1629–
1631. (c) Pelc, M. J.; Zakarian, A. Tetrahedron Lett. 2006, 47, 7519–7523.
(16) For selected reviews on the chemistry on 1,2-diamines, see: (a)
Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97, 3161–3196. (b) Lucet,
D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580–
2627. (c) Viso, A.; de la Pradilla, R. F.; Garc´ıa, A.; Flores, A. Chem. ReV.
2005, 105, 3167–3196. (d) Parrodi, C. A. d.; Juaristi, E. Synlett 2006, 2699–
2715. (e) Kizirian, J.-C. Chem. ReV. 2008, 108, 140–205.
OL900799E
(22) For conversion of the R-hydroxy trichloroacetamides into the
oxazolines by Mitsunobu reaction, see: Roush, D. M.; Patel, M. M. Synth.
Commun. 1985, 15, 675–679.
(23) Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N.
Org. Lett. 2002, 4, 151–154.
(24) For synthesis of the bromopyrrole carboxylic acid, see: (a) Reference
10h. (b) Fringuelli, F.; Marino, G.; Savelli, G. Tetrahedron 1969, 25, 5815–
5818.
(17) Valverde, S.; Herradon, B.; Rabanal, R. M.; Martin-Lomas, M. Can.
J. Chem. 1987, 65, 332–338.
(25) (a) Pauls, H. W.; Fraser-Reid, B. Carbohydr. Res. 1986, 150, 111–
119. (b) Asai, M.; Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, M.
Tetrahedron 2001, 57, 4543–4558.
(18) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
(19) Schwarz, M.; Graminski, G. F.; Waters, R. M. J. Org. Chem. 1986,
51, 260–263.
(26) (a) Yamamoto, N.; Isobe, M. Chem. Lett. 1994, 2299–2302. (b)
Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, M. Tetrahedron 1999,
55, 4325–4340. (c) Wardrop and co-workers modified the original procedure
in the total synthesis of (()-1; see ref 10l.
(20) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem.
1998, 63, 188–192.
(21) The two diastereomers of the sulfoxides were separated, and each
diastereomer was independently subjected to the Mislow-Evans rearrange-
ment. Rearrengements of both sulfoxides were found to be non-selective,
giving a 1:1 diastereomeric mixture of the allylic alcohols.
(27) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–
8022. (b) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org.
Chem. 1995, 60, 7272–7276.
2690
Org. Lett., Vol. 11, No. 12, 2009