Synthesis of (-)-agelastatin a by [3.3] sigmatropic rearrangement of allyl cyanate

Article abstract of DOI:10.1021/ol0709735

Total synthesis of (-)-agelastatin A has been achieved starting from L-arabitol. The highlights in our synthesis include the preparation of vicinal diamine moiety by [3.3] sigmatropic rearrangement of allyl cyanate and construction of central ring-C with

Full text of DOI:10.1021/ol0709735

ORGANIC
LETTERS
2007
Vol. 9, No. 16
2989-2992
Synthesis of (−)-Agelastatin A by [3.3]
Sigmatropic Rearrangement of Allyl
Cyanate
Yoshiyasu Ichikawa,* Tomonori Yamaoka, Keiji Nakano, and Hiyoshizo Kotsuki
Faculty of Science, Kochi UniVersity, Akebono-cho, Kochi 780-8520, Japan
ichikawa@kochi-u.ac.jp
Received April 26, 2007
ABSTRACT
Total synthesis of (
−)-agelastatin A has been achieved starting from L-arabitol. The highlights in our synthesis include the preparation of
vicinal diamine moiety by [3.3] sigmatropic rearrangement of allyl cyanate and construction of central ring-C with ring-closing metathesis.
In 1991, one of us reported that dehydration of allyl
carbamates generates allyl cyanates, which immediately
undergo isomerization to the allyl isocyanates.1 In an effort
to expand the scope and synthetic usefulness of this novel
reaction in the context of an allyl amine synthesis, we
performed mechanistic studies and confirmed that isomer-
ization of the allyl cyanate is a concerted process involving
a six-membered cyclic transition state with a high degree of
[1,3]-chirality transfer.2 As a consequence, the [3.3] sigma-
tropic rearrangement of allyl cyanates has been widely
accepted by the synthetic community as a useful tool for
allyl amine syntheses.3
novel alkaloids, (-)-agelastatin A (1) and its minor congener
agelastatin B (2) from the deep water marine sponge Agelas
dendromorpha collected in the Coral Sea near New Cale-
donia.6 A series of degradation and spectroscopic experiments
established the structure and relative stereochemistry of these
alkaloids, which feature an array of four nitrogen-substituted
stereogenic centers around a central cyclopentane ring. Two
closely related metabolites, agelastatin C (3) and D (4), were
later isolated by Molinski et al. from the sponge Cymbastela
sp. collected at Muiron Island in West Australia.7
To advance further the utility of this rearrangement, we
recently established a new protocol for stereoselective allyl
amine synthesis.4 We also developed a new approach to a
stereocontrolled synthesis of vicinal diamine.5 Further in-
vestigations to construct 1,2-diamino moieties led us to
explore the synthesis of marine alkaloid, (-)-agelastatin A.
In 1993 Pietra and co-workers reported their isolation of the
The architecturally unusual tetracyclic array, coupled with
significant biological activity and scarce availability from
(1) Ichikawa, Y. Synlett 1991, 238.
(2) (a) Ichikawa, Y.; Tsuboi, K.; Isobe, M. J. Chem. Soc., Perkin Trans.
1 1994, 2791. (b) Ichikawa, Y.; Yamauchi, E.; Isobe, M. Biosci. Biotechnol.
Biochem. 2005, 69 (5), 939.
(3) (a) Kapfere, P.; Sarabia, F.; Vassela, A. HelV. Chim. Acta 1999, 82,
645. (b) Roulland, E.; Monneret, C.; Florent, J.-C. J. Org. Chem. 2002, 67,
4399. (c) Roy, S.; Spino, C. Org. Lett. 2006, 8, 939.
(4) (a) Ichikawa, Y.; Ito, T.; Nishiyama, T.; Isobe, M. Synlett 2003, 1034.
(b) Ichikawa, Y.; Ito, T.; Isobe, M. Eur.sJ. Chem. 2005, 1949.
(5) Ichikawa, Y.; Egawa, H.; Ito, T.; Isobe, M.; Nakano, K.; Kotsuki,
H. Org. Lett. 2006, 8, 5737.
(6) 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, 1895.
(c) D’Ambrosio, M.; Guerriero, A.; Ripamonti, M.; Debitus, C.; Waikedre,
J.; Pietra, F. HelV. Chim. Acta 1996, 79, 727.
(7) Hong, T. W.; Jimenez, D. R.; Molinski, T. F. J. Nat. Prod. 1998,
61, 158.
10.1021/ol0709735 CCC: $37.00
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marine organisms, has already stimulated the synthetic
community, and several total synthesis of 1 have been
reported. The first total synthesis of (()-agelastatin A was
announced by a group of Weinreb, who employed a novel
hetero-Diels-Alder cycloaddition reaction and a Sharpless/
Kresze allylic amination sequence for assembly of the
cyclopentane core.8 Feldman and Saunders subsequently
reported an enantioselective route to (-)-agelastatin A and
B that exploited a unique vinylcarbene C-H insertion
sequence for the preparation of the cyclopentane ring.9 A
formal asymmetric synthesis of (-)-1 was accomplished by
Hale et al. in their enantioselective synthesis of Weinreb’s
intermediate using ring-closing metathesis (RCM) of 3,4-
diamino-1,5-diene as a substrate, which was prepared from
Hough-Richardson aziridine. This group later described the
total synthesis of (-)-agelastatin A (1) from a chiral bicyclic
cyclopentene oxazolidinone intermediate using a new strat-
egy.10 The synthesis of Davis and Deng is based upon the
sulfinimine-mediated enantioselective synthesis of syn-R,â-
diamino ester and RCM.11 Recently, a unique approach to
the synthesis of 1 was reported by Trost and Dong, who
employed palladium-catalyzed asymmetric allylic alkylation
using pyrroles as nucleophiles.12 In each of these syntheses,
construction of the array of nitrogen substituted stereogenic
centers around central cyclopentane core proved to be the
critical problem for the successful syntheses.
f 1), which draws on the Weinreb, Feldman, and Hale
syntheses. For an access to the 1,2-diamino moiety in R,â-
diaminocyclopentene 6, we reasoned that [1,3]-chirality
transfer using [3.3] sigmatropic rearrangement of an allyl
cyanate would be appropriate (7 f 6 and 9 f 8). RCM
reaction could be used to build up the cyclopentene C-ring
system (8 f 7), which would also set up the substrate for
the [1,3]-chirality transfer reaction to construct the vicinal
diamine moiety in 6. Allyl alcohol 9 would be derived from
L-arabitol (10) via a multistep pathway involving the selective
protection of hydroxy groups, carbon chain extension using
Wittig reaction, and enantioselective addition of diethylzinc.
In this paper we report the successful application of this
strategy to the total synthesis of agelastatin A.
We initiated the synthesis of agelastatin A (1) with the
preparation of allyl alcohol 9 starting from benzoate 11
derived from L-arabitol (10)13 (Scheme 2). Selective depro-
Scheme 2. Synthesis of Allyl Alcohol 9 from L-Arabitol
In our retrosynthetic route to 1 (Scheme 1), it was
Scheme 1. Synthesis Plan for (-)-Agelastatin A
tection of the terminal acetonide in 11 with aqueous acetic
acid followed by mesylation of the resultant diol14 gave the
dimesylate 12, which upon treatment with sodium iodide and
tetra-n-butylammonium iodide in 2-butanone at 75 °C
afforded the alkene 13: the overall yield for the three-step
sequence was 60%.15 Saponification of the benzoate 13 gave
the volatile alcohol, which was successively treated with a
mixture of o-iodoxybenzoic acid (IBX) and (carbethoxym-
ethylene)-triphenylphosphorane in DMSO.16 This one-pot,
two-step sequence furnished the R,â-unsaturated ester 14
predominantly in 77% yield. DIBAL reduction of the ester
envisioned that construction of ring-B could be accomplished
using intramolecular Michael addition of pyrrole ring-A (5
(12) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
(13) Benzoate 11 was readily prepared from commercially available
L-arabitol in 80% yield over two steps through acetonidation followed by
protection of the resultant primary alcohol as benzoate. See, Bukhari, M.
S.; Foster, A. B.; Lehmann, J.; Webber, J. M.; Westwood, J. H. J. Chem.
Soc. 1963, 2291.
(14) Yoshida, Y.; Shimonishi, K.; Sakakura, Y.; Okada, S.; Asao, N.;
Tanabe, Y. Synthesis 1999, 1633.
(15) Bladon, P.; Owen, L. N. J. Chem. Soc. 1950, 598.
(16) Crich, D.; Mo, X. Synlett 1999, 67.
(8) (a) Stien, D.; Anderson, G. T.; Chase, C. E.; Koh, Y.; Weinreb, S.
M. J. Am. Chem. Soc. 1999, 121, 9574. (b) Anderson, G. T.; Chase, C. E.;
Koh, Y-h.; Stien, D.; Weinreb, S. M. J. Org. Chem. 1998, 63, 7594.
(9) (a) Feldman, K. S.; Saunders, J. C. J. Am. Chem. Soc. 2002, 124,
9060. (b) Feldman, K. S.; Saunders, J. C. J. Org. Chem. 2002, 67, 7096.
(10) (a) Hale, K. J.; Domostoj, M. M.; Tocher, D. A.; Irving, E.;
Scheinmann, F. Org. Lett. 2003, 5, 2927. (b) Domostoj, M. M.; Irving, E.;
Scheinmann, F.; Hale, K. J. Org. Lett. 2004, 6, 2615.
(11) Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621.
2990
Org. Lett., Vol. 9, No. 16, 2007

14 and IBX oxidation of the resulting allyl alcohol gave the
aldehyde 15 in 91% yield in two steps.
of the acetonide in 19 with Dowex 50W × 8 in refluxing
methanol provided the diol 8 to set the stage for the next
RCM.
We next faced the task of constructing the cyclopentene
ring-C and the 2,3-diamino moiety (Scheme 4). The Grubbs
Enantioselective addition of diethylzinc to this R,â-
unsaturated aldehyde 15 was carried out in the presence of
the Soai catalyst (20 mol %) to provide allyl alcohol 9 in
good yield (92%) with 92:8 selectivity as an inseparable
diastereomeric mixture.17 The structure of 9, tentatively
assigned by the Soai empirical rule, and was confirmed by
Mosher-Kusumi MTPA ester analysis.18
Scheme 4. Construction of the Cyclopentene Ring-C and
2,3-Diamino Moiety
Our first introduction of the nitrogen-substituted stereo-
genic center by [3.3] sigmatropic rearrangement of an allyl
cyanate was achieved using allyl alcohol 9 as a substrate
(Scheme 3). Reaction of 9 with trichloroacetyl isocyanate
Scheme 3. [1,3]-Chirality Transfer of the Stereogenic Center
in Allyl Alcohol 9
catalyst is known to be tolerant of a wide range of
functionality;21 to our delight, RCM of the highly function-
alized 1,6-diene 8 using first-generation ruthenium catalyst
(5 mol %) took place smoothly at 60 °C over 15 h in benzene
(0.01 M solution) to furnish the requisite cyclopentene ring-C
7 as a crystalline intermediate in good yield (83%).22 The
synthesis continued with the protection of 7 with 2,2-
dimethoxypropane in the presence of p-TsOH to afford a
mixture of 20a and 1-methyl-1-methoxyethyl ether 20b; the
latter was hydrolyzed with wet silica gel, which set the stage
for a second [1.3]-chirality transfer. The allyl alcohol 20a
was transformed into allyl carbamate 21, and a one-pot, three-
stage sequence involving dehydration, sigmatropic rearrange-
ment (22 f 23), and trapping of the isocyanate with an
appropriate alcohol were carried out as described in Scheme
3, except 2,2,2-trichloroethanol was employed for the de-
followed by hydrolysis with aqueous potassium carbonate
gave the allyl carbamate 16. Dehydration of this carbamate
with triphenylphosphine, carbon tetrabromide, and triethyl-
amine in dichloromethane at -10 °C generated the allyl
cyanate 17,19 which instantaneously rearranged into the allyl
isocyanate 18 via a concerted cyclic transition state. To avoid
a partial hydrolysis of the isocyanate function during aqueous
workup, the reaction mixture was treated with tributyltin
benzyl alkoxide. After workup and purification, this one-
flask, three-step sequence furnished the Cbz-carbamate 19
in 85% overall yield from allyl alcohol 9.20 Finally, removal
(21) Our initial route focused on exploiting the fully protected 1,6-diene
i as a substrate for RCM, because oxazolidinone ring was expected to induce
turn-structure on the diene to facilitate the ring- closure process; in fact,
cyclopentene ii was obtained in good yields. Unfortunately, we encountered
difficulty associated with the manipulation of the carbamate group in ii,
which revised our protecting group strategy. As a result, 8 was chosen as
a substrate for RCM.
(17) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987,
109, 7111.
(18) Ohtani, I.; Kusumi, K.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(19) This dehydration condition was first reported as a synthetic method
for the preparation of isonitrile from formamide. See: Ichikawa, Y. J. Chem.
Soc., Perkin Trans. 1 1992, 2135.
(20) Addition of tributyltin alkoxide enhanced the yields of this in situ
transformation of isocyanate into the corresponding carbamate. See: (a)
Ichikawa, Y.; Osada, M.; Ohtani, I.; Isobe, M. J. Chem. Soc., Perkin Trans.
1 1997, 1449. (b) Bloodworth, A. J.; Davies, A. J. Chem. Soc. C 1965,
5238. (c) Davies, A. Synthesis 1969, 56.
(22) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 2039. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1988, 4413.
Org. Lett., Vol. 9, No. 16, 2007
2991

rivatization of isocyanate 23. As a result, the trichloroethoxy
(Troc) carbamate 24 was obtained in 95% yield.
With our C-ring intermediate available, we next attempted
B-ring construction (Scheme 5). At this stage, we planned
Deprotection of the acetonide group in 26 with Dowex 50W
× 8 in methanol at reflux furnished the allyl alcohol 27.
Although IBX oxidation of 27 was successful, the resultant
cyclopentanone 28 was found to be rather labile. Since tert-
amine was reported to be compatible with IBX oxidation,25
a one-flask two-sequence protocol was secured. Allyl alcohol
27 was thus initially treated with IBX in DMSO. After
checking the consumption of 27 by TLC, Hu¨nig base was
added to the reaction mixture. Pleasingly, an intramolecular
conjugate addition reaction occurred smoothly at ambient
temperature for 3.5 h to deliver the desired ABC-tricyclic
ring system 29 in 91% yield.
Scheme 5. Completion of the Total Synthesis of Agelastatin A
The final stage of D-ring construction started with depro-
tection of the Cbz group and concomitant hydrogenolysis
of the two bromine substituents in the pyrrole ring-A; thus,
29 was treated with hydrogen and a catalytic amount of 10%
palladium on carbon in the presence of triethylamine.
Without isolation of 30, the reaction mixture was treated with
methyl isocyanate26 to provide the cyclic hemiaminal;
debromoagelastatin A (31) was isolated in 78% yield for
these three steps.
Following the protocol of Feldman, regioselective bromi-
nation of 31 with NBS in a 1:2 mixture of MeOH/THF
1
furnished (-)-agelastatin A (1) in 77% yield. The H and
13C NMR spectra of our synthetic sample matched those
reported by the previous syntheses.
Thus the total synthesis of the marine alkaloid (-)-
agelastatin A (1) has been accomplished starting from
L-arabitol 10. The vicinal diamine moiety was successfully
installed within the intermediate 24 via [3.3] sigmatropic
rearrangements of allyl cyanates, and the central cyclopentane
ring-C was efficiently constructed by RCM using a highly
functionalized 1,5-diene 8 as a substrate.
Acknowledgment. We are grateful for the financial
supports from Grant-in-Aid for Scientific Research (Grants
16002007, 18032055, and 18037053) from MEXT. This
work was supported in part by a Special Research Grant for
Green Science from Kochi University.
to introduce two electron-withdrawing bromines onto the
pyrrole ring-A as in 25, analogously to Hale et al: this tactic
would lower the pKa of the pyrrole nitrogen and circumvent
the isomerization problem of a labile cyclopentenone such
as 28 during the base-catalyzed intramolecular Michael
addition.23 Annulation of ring-B onto the cyclopentene C-ring
intermediate 24 began with removal of the Troc-group with
zinc. The resultant amine was treated with bromopyrrole 25
and sodium carbonate in DMF to afford the amide 26.24
Supporting Information Available: Full experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0709735
(23) Similar strategy using bromopyrrole was noted in the previous
synthesis of Hale, which was rationalized and modified in our route. Hale,
K. J.; Domostoj, M. M.; El-Tanami, M.; Campbell, F. C.; Mason, C. K.
Total Synthesis and Mechanism of Action Studies on the Antitumor
Alkaloid, (-)-agelastatin A. In Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Elsevier: 2005; pp 352-394. See also ref 10b and
Supporting Information.
(25) (a) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J.
Org. Chem. 1995, 60, 7272. (b) Corey, E. J.; Palani, A. Tetrahedron Lett.
1995, 36, 3485.
(26) Commercially available methyl isocyanate was dissolved in THF
and then used as a THF-solution, which was titrated by the reaction with
excess benzylamine and isolation of the produced methyl benzyl urea. We
thank Prof. Weinreb, Dr. Stien, and Prof. Davis for informing us of the
source of methyl isocyanate (see ref 8a and 11).
(24) (a) Belanger, P. Tetrahedron Lett. 1979, 20, 2505. (b) Lindel, T.;
Hochgu¨rtel, M. J. Org. Chem. 2000, 65, 2806.
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Org. Lett., Vol. 9, No. 16, 2007