Formal synthesis of (-)-agelastatin A: An iron(II)-mediated cyclization strategy

Article abstract of DOI:10.3762/bjoc.9.99

An iron(II)-mediated aminohalogenation of a cyclopentenyl N-tosyloxycarbamate provided new access to the key intermediate for the synthesis of (-)-agelastatin A (AA, 1), a potent antiproliferative alkaloid. The present synthetic endeavour offered an insight into the mechanism underlying the iron(II)-mediated aminohalogenation of N-tosyloxycarbamate, in which the radical properties of the N-iron intermediates in the redox states were operative.

Full text of DOI:10.3762/bjoc.9.99

Formal synthesis of (−)-agelastatin A:
an iron(II)-mediated cyclization strategy
Daisuke Shigeoka, Takuma Kamon and Takehiko Yoshimitsu*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 860–865.
Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
doi:10.3762/bjoc.9.99
Received: 23 February 2013
Accepted: 10 April 2013
Published: 03 May 2013
Email:
Takehiko Yoshimitsu* - yoshimit@phs.osaka-u.ac.jp
* Corresponding author
This article is part of the Thematic Series "Organic free radical chemistry".
Guest Editor: C. Stephenson
Keywords:
agelastatin; aminohalogenation; iron(II); free radical; natural product
synthesis
© 2013 Shigeoka et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
An iron(II)-mediated aminohalogenation of a cyclopentenyl N-tosyloxycarbamate provided new access to the key intermediate for
the synthesis of (−)-agelastatin A (AA, 1), a potent antiproliferative alkaloid. The present synthetic endeavour offered an insight
into the mechanism underlying the iron(II)-mediated aminohalogenation of N-tosyloxycarbamate, in which the radical properties of
the N–iron intermediates in the redox states were operative.
Introduction
Marine organisms often produce bioactive substances that The first-generation strategy employed a stereoselective thermal
potentially serve as attractive resources for drug discovery. aziridination of azidoformate 2 and a subsequent aziridine-
(−)-Agelastatin A (AA, 1), a cytotoxic alkaloid isolated from opening reaction to establish the vicinal trans nitrogen motif 4
marine sponges Agelas dendromorpha and Cymbastela sp., is [26]. The second-generation strategy involved the radical
one such substance, which has drawn considerable attention due aminobromination of azidoformate 3 followed by lactamization
to its potential applicability in the development of anticancer of the resultant bromide 5a to furnish a tetracyclic compound
agents [1-5]. The intriguing biological activity of 1 has stimu- (structure not shown), which was transformed into the natural
lated interest in developing various chemical accesses to the product [27]. In the present study, we disclose a new approach
natural product [6-25]. Our previous synthetic endeavours have to the key intermediate for AA synthesis in which N-tosyloxy-
established two approaches to 1, in which cyclopentenyl azido- carbamate 8, a nonhazardous azidoformate surrogate, is trans-
formates 2 and 3 were utilized as the pivotal intermediates formed into aminohalogenated compounds 5a and 5b by FeBr2/
(Scheme 1).
Bu4NBr [28,29], FeCl2/Bu4NCl, or FeCl2/TMSCl [30-35]
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Beilstein J. Org. Chem. 2013, 9, 860–865.
Scheme 1: Our first- [26] and second-generation [27] approaches to (−)-agelastatin A (1).
(Scheme 2). Moreover, a plausible mechanism of the present With this carbamate 8, we examined the iron(II)-mediated
iron(II)-mediated aminohalogenation, which is inferred from cyclization under various conditions (Table 1).
the unique reactivity of N-tosyloxycarbamate 8 with the
reagents, is discussed.
The application of FeBr2 (0.5 equiv)/Bu4NBr (1.5 equiv) in
EtOH effected cyclization, but the yield of 5a was poor due to
the concomitant formation of carbamate 9 (39%) and enone 10
(30%) (Table 1, entry 1). This was in marked contrast to
the observation that the same reagent system, i.e., FeBr2
(0.5 equiv)/Bu4NBr (1.2 equiv), allowed the efficient conver-
sion of azidoformate 3 (2 g scale) in EtOH to afford 5a in 70%
yield (Scheme 3). The distinct yields of the cyclized materials
obtained from N-tosyloxycarbamate 8 and azidoformate 3
suggested the unique reactivity of each substrate towards the
iron(II) halide (see below). An aminochlorination reagent
system, i.e., FeCl2 (0.5 equiv)/Bu4NCl (1.2 equiv) in EtOH, in
turn, furnished the corresponding chloride 5b in 39% yield as
the major product (Table 1, entry 2). Our recent studies on the
iron(II)-mediated aminobromination reactions of structurally
simple N-tosyloxycarbamates with FeBr2/Bu4NBr revealed
significant solvent effects on the product yields [28]. This was
also the case in the present study: FeBr2 (0.5 equiv)/Bu4NBr
(1.2 equiv) in t-BuOH successfully improved the yield of 5a
relative to the reaction in EtOH (Table 1, entry 3). FeCl2
(0.5 equiv)/Bu4NCl (1.2 equiv) in t-BuOH culminated in the
highest yield of 5b among the examined conditions (Table 1,
entry 4) However, a reduction of FeX2 loading even in t-BuOH
led to erosion of the yields of halides 5a and 5b with recovery
of the substrate (Table 1, entries 5 and 6). With the FeCl2/
TMSCl reagent system [30-35], chloride 5b was accessible
from N-tosyloxycarbamate 8 in 29% yield, along with 9 in 12%
Scheme 2: The present iron(II)-mediated aminohalogenation of
N-tosyloxycarbamate 8 providing key intermediates 5a/5b for
(−)-agelastatin A synthesis.
Results and Discussion
N-Tosyloxycarbamate 8 was prepared from alcohol 6, which yield (Table 1, entry 7). In this particular case, cyclopentanone
was obtained by a previously reported protocol (Scheme 2) derivative 11 (16%) and diethyl ketal 12 (14%) were produced
[26,27]. Alcohol 6 was first treated with CDI (N,N’-carbonyldi- as well (Figure 1). An additional experiment to elucidate the
imidazole) and then with hydroxylamine hydrochloric acid salt origin of their formation provided evidence that these byprod-
to afford N-hydroxycarbamate 7 in 67% yield [36]. Thereafter, ucts were generated by the intramolecular cyclization of enone
N-hydroxycarbamate 7 was reacted with TsCl and triethyl- 10 with TMSCl in EtOH, suggesting that the FeCl2/TMSCl
amine in THF to furnish N-tosyloxycarbamate 8 in 92% yield. system also gave enone 10 in ca. 30% yield [37].
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Beilstein J. Org. Chem. 2013, 9, 860–865.
Table 1: Aminohalogenation of N-tosyloxycarbamate 8 by iron(II) catalysis.
entry
conditionsa
products (%)
1
2
3
4
5
6
7
FeBr2 (0.5 equiv), Bu4NBr (1.5 equiv), EtOH, rt, 1.75 h
FeCl2 (0.5 equiv), Bu4NCl (1.2 equiv), EtOH, rt, 0.75 h
FeBr2 (0.5 equiv), Bu4NBr (1.2 equiv), t-BuOH, rt, 0.5 h
FeCl2 (0.5 equiv), Bu4NCl (1.2 equiv), t-BuOH, rt, 2.5 h
FeBr2 (0.2 equiv), Bu4NBr (1.2 equiv), t-BuOH, rt, 3.3 h
FeCl2 (0.2 equiv), Bu4NCl (1.2 equiv), t-BuOH, rt, 3.3 h
FeCl2 (0.5 equiv), TMSCl (1.5 equiv), EtOH, 0 °C to rt, 16 h
5a (13), 9 (39), 10 (30)
5b (39), 9 (20), 10 (19)
5a (38), 9 (22), 10 (19)
5b (48), 9 (9), 10 (9)
5a (25)b, 9 (16), 10 (5)
5b (31)c, 9 (9), 10 (14)
5b (29), 9 (12)d
aAll reactions were conducted using 20 mg of substrate 8. b22% of 8 was recovered. c35% of 8 was recovered. dCompounds 11 (16%) and 12 (14%)
were obtained.
Scheme 3: Aminohalogenation of azidoformate 3 (2 g scale) under FeBr2/Bu4NBr conditions.
complex (i) that has free-radical character, as previously
proposed in the catalytic cyclization of azidoformates [30,38-
40]. The contrasting yields obtained from N-tosyloxycarbamate
8 and azidoformate 3 under FeBr2/Bu4NBr in EtOH conditions
(see Table 1, entry 1 versus Scheme 3) likely originate from the
distinct chemical property of the N–iron species (i) generated
from each substrate. The possible coordination of tosylate anion
to the N–iron after the N–O bond cleavage with FeX2 may have
Figure 1: Byproducts formed by aminohalogenation of N-tosyloxycar-
bamate 8 with FeCl2/TMSCl in EtOH (see Table 1; entry 7).
affected the electronic and steric characters of intermediate (i),
leading to retardation of the subsequent cyclization. Because of
the low cyclization rate, the production of reduced carbamate 9
The present study on the aminohalogenation reaction of carba- and enone 10 became pronounced. This is consistent with the
mate 8 has inspired mechanistic insights that deserve discus- observation that the relatively efficient production of cyclized
sion (Scheme 4). We hypothesize that cyclized material 5a/5b, material 5a was observed for azidoformate 3, where N–iron
reduced material 9, and enone 10 are generated from an N–iron intermediate (i) was free from such interactions. One of the
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Beilstein J. Org. Chem. 2013, 9, 860–865.
other characteristics found in the present transformations was ates two equivalents of iron(III) species per one equivalent of
the incomplete consumption of substrate 8 by lowering FeBr2/ vii. Given the observation that FeCl3/Bu4NCl gave none of the
Bu4NBr loading (e.g., Table 1, entry 5), which, in turn, enabled products shown in Table 1, an iron(III) species possibly gener-
the efficient conversion of structurally simple N-tosyloxycarba- ated via the halogen exchange of vii with Bu4NX, if any, no
mates into the corresponding cyclic aminobromides [28]. This longer has catalytic activity and thus the catalytic cycle is termi-
poor conversion under conditions of less FeX2/Bu4NX loading nated. Therefore, active FeX2 species should somehow be
may be attributable to the decrease of the concentration of regenerated to maintain the catalysis. One possible pathway that
reactive FeX2 through capture with the polar amide function- may account for the production of carbamate 9 through the
ality of 8.
regeneration of FeX2 species is the intermolecular hydrogen
abstraction from substrate 8 by N–iron species (i) (Scheme 5).
The intermediacy of the intermolecular hydrogen abstraction of
N–iron species (i) is supported by the fact that the production of
9 was more pronounced in EtOH having a C–H bond α to the
oxygen, which likely served as a hydrogen donor (Table 1,
entries 1 and 2). It should be mentioned that reduced material 9
may also be produced by Bu4NBr alone as observed in our
previous study [28]. To elucidate the contribution of this
pathway, compound 8 was treated with Bu4NX in t-BuOH.
However, no reduced material was obtained within the reaction
times depicted in Table 1 [for instance, 0.5 h stirring for
Bu4NBr (Table 1, entry 3) and 2.5 h stirring for Bu4NCl
(Table 1, entry 4)], indicating that the non-iron-mediated
process is not significant [42]. Various yields of 9 obtained by
loading consistent amounts (1.2–1.5 equiv) of Bu4NX salts also
indicated the poor contribution of the pathway. Chan and
co-workers demonstrated that an iron–imido complex gener-
ated from FeCl2/PhI=NTs underwent radical hydrogen abstrac-
tion from a formyl group, and combined the resultant radicals
(hydrogen atom abstraction/radical rebound pathway) to
provide amides [43,44]. The involvement of such an iron com-
plex (shown in brackets in Scheme 4) that features radical/
metal–nitrenoid properties can be considered in our reactions. A
recent study by Betley and co-workers on high-spin iron–imido
complexes generated by the reactions of alkyl azides with FeCl2
bearing dipyrromethene ligands revealed the radical character of
the complex [39,40], harmonizing well with our result, which
implies the intermediacy of the nitrogen radical species.
Scheme 4: Plausible reaction pathways in the aminohalogenation of
N-tosyloxycarbamate 8 with FeX2/Bu4NX.
It is speculated that product 9 may be produced by trapping
N–iron complex (i) with another FeX2 (i→vii→9), whereas
enone 10 is likely to be generated via intramolecular allylic
hydrogen abstraction followed by halogen transfer to regen-
erate iron(II) species (i→iv→v→10) and/or by directly
releasing FeX2 (i→iv→vi→10) [41]. However, it is worth
discussing the process for yielding 9, which theoretically gener-
Scheme 5: Plausible reaction pathway to produce compounds 9 and
10.
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Beilstein J. Org. Chem. 2013, 9, 860–865.
11.Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
Conclusion
doi:10.1021/ja061105q
We have developed a new approach to key compounds 5a/5b
for (−)-agelastatin A (1) synthesis, which features the iron(II)-
mediated radical cyclization of N-tosyloxycarbamate, a safe
azidoformate surrogate. Although somewhat moderate chemi-
cal yields of the compounds were obtained in this study, the
elimination of hazardous synthetic processes enables the estab-
lishment of more robust strategies to access 1. Furthermore, the
present study has allowed us to obtain mechanistic insights
suggesting that N–iron species (i) has a metal-radical character.
Much work is currently being undertaken to comprehend fully
the unique properties of the present reactions.
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Supporting Information
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Supporting Information File 1
Experimental procedures, characterization data of new
compounds, and 1H/13C NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-99-S1.pdf]
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The authors are deeply indebted to Professor Tetsuaki Tanaka
for his encouragement. This work was supported by a Special
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