Synthesis of the asperparaline core by a radical cascade

Article abstract of DOI:10.1021/ol202769f

A concise access to the pentacyclic core structure of the asperparalines is described. The key step is a radical cascade sequence comprised of a 1,6-hydrogen atom transfer followed by 6exo-trig and 5exo-trig cyclizations.

Full text of DOI:10.1021/ol202769f

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6472–6475
Synthesis of the Asperparaline Core by a
Radical Cascade
Peter J. Crick,† Nigel S. Simpkins,*,† and Adrian Highton‡,§
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, B15 2TT,
U.K., and AstraZeneca R&D Charnwood, Loughborough, LE11 5RH, U.K.
n.simpkins@bham.ac.uk
Received October 14, 2011
ABSTRACT
A concise access to the pentacyclic core structure of the asperparalines is described. The key step is a radical cascade sequence comprised of a
1,6-hydrogen atom transfer followed by 6-exo-trig and 5-exo-trig cyclizations.
The asperparalines (1ꢀ3) are members of the prenylated
alkaloid family of fungal-derived natural products, which
were isolated from Aspergillus japonicus JV-23.1 Related
members of this family include brevianamide (4), para-
herquamide B (5), and malbrancheamide B (6) (Figure 1).
These compounds possess a bicyclo[2.2.2]diazaoctane
core, present as a keto- or diketopiperazine (DKP), which
is usually combined with a fused indole or spiro-oxindole
motif. The asperparalines are known to paralyze silk-
worms, and very recentlyasperparaline A has beendemon-
strated to strongly and selectively block insect nicotinic
acetylcholine receptors.2
total syntheses of several family members by a number of
research groups,3 most notably that of Williams.4
The synthetically challenging structures of these alka-
loids along with their interesting biological profiles have
provoked significant synthetic activity, culminating in the
† The University of Birmingham.
‡ AstraZeneca R&D Charnwood.
§ Current address: Selcia Limited, Fyfield Business & Research Park,
Fyfield Road, Ongar, Essex, CM50GS, U.K.
(1) (a) Hayashi, H.; Nishimoto, Y.; Nozaki, H. Tetrahedron Lett.
1997, 38, 5655. (b) Banks, R. M.; Blanchflower, S. E.; Everett, J. R.;
Manger, B. R.; Reading, C. J. Antibiot. 1997, 50, 840. (c) Hayashi, H.;
Nishimoto, Y.; Akiyama, K.; Nozaki, H. Biosci., Biotechnol., Biochem.
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(2) Hirata, K.; Kataoka, S.; Furutani, S.; Hayashi, H.; Matsuda, K.
PLoS ONE 2011, 6, doi:10.1371/journal.pone.0018354.
(3) Lead references: (a) Miller, K. A.; Williams, R. M. Chem. Soc.
Rev. 2009, 38, 3160. (b) Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc.
2005, 127, 5342. (c) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.;
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129, 3086.
Figure 1
The asperparalines are unique in incorporating a spiro
succinimide motif, and while Williams5 and Tanimori6
(4) Finefield, J. M.; Williams, R. M. J. Org. Chem. 2010, 75, 2785 and
references therein.
(5) (a) Gonzalez, F.; Sanz-Cervera, J. F.; Williams, R. M. Tetrahe-
dron Lett. 1999, 40, 4519. (b) Adams, L. A.; Gray, C. R.; Williams, R. M.
Tetrahedron Lett. 2004, 45, 4489.
r
10.1021/ol202769f
Published on Web 11/14/2011
2011 American Chemical Society

have published approaches to individual components
of the asperparalines, no total synthesis has been forth-
coming.
bromide to afford acetylene 12 in 71% yield.10 Acid-
mediated ring opening yielded modified proline O-methyl
ester 13 as a single enantiomer which could be used in
subsequent steps without purification (Scheme 2).11
We have recently published a concise access to the
bicyclo[2.2.2]diazaoctane core structure of these com-
pounds via a cationic cascade, culminating in the total
syntheses of (ꢀ)-brevianamide B and (ꢀ)-malbranchea-
mide B.7 Here, we report our initial investigations of a
complementary, strategically related, radical cascade for
the construction of the asperparaline core structure.
Our approach is outlined in Scheme 1 (for the L-proline
series). Initial formation of an alkenyl radical by cleavage
ofa suitablevinylhalide precursor7 (e.g., X =Br, I) would
be followed by 1,6-hydrogen atom transfer to form the
more stabilized captodative DKP radical 8.8 Subsequent
stereocontrolled 6-exo-trig and 5-exo-trig ring closures
would furnish 8-oxa-asperparaline 10.
Scheme 2
Scheme 1
Next, N-acylation by treatment with bromoacetyl bro-
mide in the presence of triethylamine gave bromide 14 in
65% yield. Formation of proline-glycine DKPs 15aꢀc was
then accomplished smoothly by exposure to a methanolic
solution of methylamine, para-methoxybenzylamine, or
ammonia respectively.12 Secondary amide 15c was Boc
protected under standard conditions to afford carbamate
15d in 82% yield over two steps.
To generate more complex systems, modified proline 13
was coupled with suitably protected alanine, leucine, or
aspartic acid under standard conditions (Scheme 3).13
Removal of the Boc group by treatment with neat formic
acid was followed by thermal ring closure by refluxing in a
mixture of toluene and 2-butanol to give the correspond-
ing DKPs which were Boc protected in the presence of
4-DMAP to give 17aꢀc.14
To test the viability of this type of approach we decided
to focus on the initial 1,6-hydrogen atom abstraction in
tandem with the first (6-exo) cyclization. The use of a
simple acetylene to generate the initial alkenyl radical, in
place of a vinyl halide, was also preferred so as to facilitate
the synthesis of a series of simple model compounds to
probe our strategy (vide infra).
With a variety of acetylene substituted DKPs in hand,
the stage was set for our 1,6-hydrogen transfer 6-exo-trig
sequence. Using conditions described by Renaud,15 we
found that slow addition of thiophenol and AIBN to a
refluxing solution of DKP in tert-butanol afforded the
desired bridged system in good to excellent yield (Table 1).
Stereocontrol is modest but favors the desired C-6 stereo-
chemistry required for the asperparalines. The nitrogen
Starting from L-proline, the enolate of (commercially
available) oxazolidinone 119 was treated with propargyl
(6) (a) Tanimori, S.; Fukubayashi, K.; Kirihata, M. Biosci., Biotech-
nol., Biochem. 2000, 64, 1758. (b) Tanimori, S.; Fukubayashi, K.;
Kirihata, M. Tetrahedron Lett. 2001, 42, 4013.
(7) (a) Frebault, F.; Simpkins, N. S.; Fenwick, A. J. Am. Chem. Soc.
2009, 131, 4214. (b) Frebault, F. C.; Simpkins, N. S. Tetrahedron 2010,
66, 6585.
(8) For a review of radical translocations, see: Robertson, J.; Pillai, J.;
Lush, R. K. Chem. Soc. Rev. 2001, 30, 94.
(11) Harris, P. W. R.; Brimble, M. A.; Muir, V. J.; Lai, M. Y. H.;
Trotter, N. S.; Callis, D. J. Tetrahedron 2005, 61, 10018.
(12) Maw, G. N.; Allerton, C. M. N.; Gbekor, E.; Million, W. A.
Bioorg. Med. Chem. Lett. 2003, 13, 1425.
(13) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
(14) Pichowicz, M.; Simpkins, N. S.; Blake, A. J.; Wilson, C. Tetra-
hedron 2008, 64, 3713.
(9) 11 can be purchased from Sigma Aldrich or synthesized by
condensation of chloral with L-proline; see: Amedjkouh, M.; Ahlberg,
P. Tetrahedron: Asymmetry 2002, 13, 2229. Based on Seebach’s seminal
work on the self-reproduction of chirality:Seebach, D.; Boes, M.; Naef,
R.; Schweizer, W. B. J. Am. Chem. Soc. 1983, 105, 5390.
(10) Compound 12 has been prepared before in 24% yield; see:
Pisaneschi, F.; Cordero, F. M.; Lumini, M.; Brandi, A. Synlett 2007,
2882.
(15) (a) Beaufils, F.; Denes, F.; Renaud, P. Org. Lett. 2004, 6, 2563.
(b) Denes, F.; Beaufils, F.; Renaud, P. Org. Lett. 2007, 9, 4375.
Org. Lett., Vol. 13, No. 24, 2011
6473

Scheme 3
Scheme 4
protecting group seems to have only a small effect on the
stereochemical outcome of the reaction with the best ratio
achieved using PMB protected DKP 15b (entry 2).
Scheme 5
Table 1. Initial Radical Cyclizationsa
entry
R
R0
% yield
dr
1
2
3
4
5
6
Me
H
62
53
55
98
96
73
5:4
2:1
5:4
2:1
4:1
2:1
Thus, 20 and 22 were treated with thiophenol and AIBN
PMB
Boc
Boc
Boc
Boc
H
under our established conditions. These cyclizations are
considerably more complex than those shown above, as
two new carbonꢀcarbon bonds and three stereocenters are
formed. Although both examples gave complex mixtures
of products, in each case only one major product was
formed. Pleasingly, we were able to isolate tetracycle 21
and the asperaparaline core stucture 23, albeit each in
modest yield. In each case the isolated, single diastereomer
product has the desired configuration for the majority of
known natural products.17
In summary, we have developed a novel synthesis of
the bridged bicyclic core common to a variety of alka-
loids. We have applied this to a radical cascade for the
synthesis of the asperparaline core structure 23 in just six
steps from commercially available starting materials.
Efforts in our laboratory are now focused on completing
the total syntheses of the asperparalines, along with
probing the activities of readily available spiro succini-
mides such as 23.
H
Me
i-Bu
CH2CO2Bn
a Reaction conditions: AIBN (2.0 equiv) in toluene and thiophenol
(2.0 equiv) in toluene added to a refluxing solution of DKP in tert-
butanol via syringe pump over 20 h. The major isomer is the C-6 epimer
shown.
The sequence appears to be more efficient when R0 is
not H (Table 1, entries 4ꢀ6 vs 1ꢀ3). The reason for this
is not immediately clear, although conformational
and/or radical stabilization effects are presumably
responsible.
In principle, heteroatoms other than sulfur can be used
for radical addition to a triple bond. For example, treat-
ment of a solution of N-methyl DKP 15a in benzene with
AIBN and tributyltin hydride afforded bridged bicyclic
stannane 19, albeit in poor yield (Scheme 4).16
Turning our attention to more faithful mimics of the
asperparaline core structure, we synthesized DKPs 20 and
22 incorporating an allyl and maleimide group respectively
(Scheme 5; full details in Supporting Information). As we
encountered unforeseen difficulties in the introduction
of a nitrogen protecting group, we attempted the radical
cascade with a free secondary amide.
Acknowledgment. We acknowledge AZ, Charnwood,
U.K. and the University of Birmingham for support of
P.C. The NMR instruments used in this research were
obtained through Birmingham Science City: Innova-
tive Uses for Advanced Materials in the Modern
(17) The stereochemistry was assigned by NOE experiments; see
Supporting Information for full details.
(16) Bosch, E.; Bachi, M. D. J. Org. Chem. 1993, 58, 5581.
6474
Org. Lett., Vol. 13, No. 24, 2011

World (West Midlands Centre for Advanced Materials
Project 2), with support from Advantage West Midlands
(AWM) and partial funding by the European Regional
Development Fund (ERDF).
Supporting Information Available. Complete experi-
mental details and characterization data for the synthesis
of compounds 12ꢀ23. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
6475