A novel cyclisation strategy for the synthesis of lactonamycin: A new route to highly functionalised heterocyclic rings

Article abstract of DOI:10.1055/s-2006-951542

A novel thermal cascade reaction equivalent to the well-known [2+2+2] cycloaddition has been developed which is clean and reliable and does not involve the use of metal ions. This highly efficient method has been used to construct a model for the synthesi

Full text of DOI:10.1055/s-2006-951542

LETTER
3243
A Novel Cyclisation Strategy for the Synthesis of Lactonamycin: A New Route
to Highly Functionalised Heterocyclic Rings
Synthesisof
Lh
actonamycinilip J. Parsons,*a Johnathan Board,a Alexander J. Waters,a Peter B. Hitchcock,a Florian Wakenhut,b
Daryl S. Walterc
a
Department of Chemistry, School of LifeSciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK
Fax +44(1273)678861; E-mail: P.J.Parsons@sussex.ac.uk
b
Pfizer Ltd., Ramsgate Road, Sandwich, Kent CT13 9MJ, UK
c
GlaxoSmithKline Research & Development Ltd., New Frontiers Science Park, Third avenue, Harlow, Essex CM19 5AW, UK
Received 8 September 2006
Abstract: A novel thermal cascade reaction equivalent to the well-
O
Me
OH
Me
O
known [2+2+2] cycloaddition has been developed which is clean
and reliable and does not involve the use of metal ions. This highly
efficient method has been used to construct a model for the synthe-
sis of the antibiotic lactonamycin. The utility of this new sequence
for the formation of furans is also reported.
1 R =
OH
D
N
O
C
O
O
A
F
lactonamycin
MeO
O
OH
2 R = H lactonamycinone
B
E
O
RO
Key words: lactonamycin, furan, cascade, cyclisation, thermal
1, 2
Figure 1
Lactonamycin (1) was isolated from Streptomyces rishin-
iensis by Matsumoto et al. in 1996.1 Lactonamycin (1)
showed good antimicrobial activity against Gram-positive
bacteria including excellent efficacy against methicillin-
resistant Staphylococcus aureus (MRSA) and vancomy-
cin-resistant Enterococcus (VRE).2 Lactonamycin (1) was
also found to possess antitumour activity, and because of
its interesting biological profile2 and unusual structure it
has attracted significant interest from the chemical com-
munity. Hitherto four groups have published synthetic
work directed towards the construction of lactonamycin
(1).
In 2000 and 2001, Danishefsky and Cox reported two dif-
ferent approaches to the ABCD ring system of 1 and later
reported a synthetic route to lactonamycinone 2.3–6 Behar
and Deville reported a route to the CDEF ring system7
along with Kelly et al.8 who also reported a synthesis of
the chiral AB system.9 More recently, an approach to the
ABCD ring system has been reported by Barrett and co-
workers.10 Our approach to the CDEF ring system differs
from all the approaches hitherto reported and is reliant on
a cascade sequence.11 Retrosynthetic analysis of the lac-
tonamycin molecule revealed three new approaches.
Herein we report the first of these strategies (Scheme 1).
O
Me
N
Me
O
OH
N
OH
OMe
O
O
MeO
O
O
O
O
OH
OH
RO
MeO
O
1, 2
3
OH
OMe
O
OH
or
OMe
O
Me
N
Me
O
O
O
N
O
MeO
MeO
Br
SiMe3
Br
5
4
SiMe3
Scheme 1 Retrosynthesis of lactonamycin
SYNLETT 2006, No. 19, pp 3243–3246
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951542; Art ID: D26606ST
© Georg Thieme Verlag Stuttgart · New York

3244
P. J. Parsons et al.
LETTER
We elected to construct a model system in order to evalu- In his synthesis of gibberellic acid Corey used epoxy-
ate the palladium12 or radical-mediated (tin hydride)13 cy- propene as an acid trap.17 We employed the higher boiling
clisation reactions which would afford lactonamycin and less volatile 1-epoxyhexene as an acid trap and the
precursors (Scheme 2).
yield of 10 was thence improved to an isolated 76%. The
X-ray crystal structure of 10 is depicted in Figure 2.
O
N
H
N
d
a, b, c
Br
Br
6
7
OH
OH
Me
N
Me
e, f
O
N
O
O
Br
Br
8
9
SiMe3
Scheme 2 Reagents and conditions: (a) n-BuLi (1.05 equiv), THF,
–78 °C; (b) CuCN (1.05 equiv), –78 °C to –40 °C; (c) 2,3-dibromo-
propene (1.2 equiv), THF, –78 °C to r.t. then HCl, H2O (73% overall);
(d) HC≡C–CH2NMe(Boc), n-BuLi (1.05 equiv), THF, –90 °C then t-
BuBr (2 equiv), –90 °C to r.t. (83% overall); (e) HCl in Et2O (2 M);
(f) Et3N (2.5 equiv), CH2Cl2, trimethylsilylpropioloyl chloride (79%).
Figure 2 X-ray crystal structure of 10
In order to extend this finding to the synthesis of other het-
erocyclic systems we synthesised the ether 14
(Scheme 4).
Treatment of the aminal 6 with n-butyllithium in tetrahy-
drofuran at –78 °C, followed by the addition of an
equimolar amount of cuprous cyanide14 and then 2,3-di-
bromopropene, gave upon work-up the aldehyde 7 in
good (73%) yield. Careful addition of n-butyllithium to N-
Boc-N-methlypropargylamine at –90 °C followed by the
addition of aldehyde 7 afforded the alcohol 8 after work-
up with tert-butyl bromide. The addition of tert-butyl bro-
mide as a proton source proved to be essential to avoid
dimerisation and the formation of other unwanted impuri-
ties.
Me
N
Me
N
a
Boc
Boc
OH
c, d
11
12
Me
N
Me
O
O
O
N
b
Br
Br
Boc
13
14
SiMe3
Scheme 4 Reagents and conditions: (a) n-BuLi (1.05 equiv),
(CH2O)n, THF, –78 °C, (82%); (b) NaH (1.1 equiv), THF, 2,3-dibro-
mopropene (1.05 equiv), (81%); (c) TFA, CH2Cl2; (d) trimethylsilyl-
propioloyl chloride, CH2Cl2, Et3N (2.5 equiv), (82%, 2 steps).
Reaction of the alcohol 8 with ethereal hydrogen chloride
facilitated removal of the N-Boc15 protecting group and
addition of trimethylsilylpropioloyl chloride (generated
from trimethylsilyl-propiolic acid and oxalyl chloride) in
the presence of triethylamine gave the radical cyclisation
precursor 9 in 79% yield.16
When the ether 14 was heated in boiling toluene-contain-
ing 1-epoxyhexene as an acid scavenger, the furan 15 was
obtained in 90% yield (Scheme 5).18
We discovered, however, that when the cyclisation pre-
cursor 9 was heated alone in boiling toluene the tetracycle
10 was isolated in 50% yield (Scheme 3).
Me
N
a
O
14
OH
Me
O
Me
N
OH
SiMe3
N
O
15
O
a
Scheme 5 Reagents and conditions: (a) PhMe, reflux, 1 h, 1-epoxy-
hexene (90%).
Br
SiMe3
SiMe3
9
10
Diels–Alder cycloaddition of the furan 15 to maleic anhy-
dride gave the cycloadduct 16, which demonstrates the
utility of this novel strategy for an additional route to lac-
tonamycin (1) and its analogues (Scheme 6).
Scheme 3 Reagents and conditions: (a) PhMe, reflux, 2 h, (50%).
Synlett 2006, No. 19, 3243–3246 © Thieme Stuttgart · New York

LETTER
Synthesis of Lactonamycin
3245
Me
Me
The cyclisation could involve the formation of a diradical
intermediate as shown in Scheme 10. Trapping of the
diradical 19a with the pendent double bond would afford
the highly strained and unstable cyclohexadiene 19b,
which would undergo double-bond isomerisation to give
20.
N
N
O
O
O
H
H
O
O
a
O
O
O
SiMe3
SiMe3
O
O
15
16
Scheme 6 Reagents and conditions: (a) Et2O, r.t., 24 h, (50%).
Me
N
Me
O
O
N
Initially we wondered if an acid catalysed mechanistic
pathway was involved in the cyclisation process
(Scheme 7).
O
O
SiMe3
SiMe3
19
19a
Me
Me
N
Me
O
N
N
O
H
Br
O
O
O
20
O
SiMe3
SiMe3
19b
H
SiMe3
Br
14
17
Scheme 10 Suggested radical-based mechanism
Me
Me
N
N
We note that addition of tri-n-butyltin hydride to the reac-
tion mixture inhibits the formation of 20, which adds ad-
ditional support to a radical pathway. Examination of
molecular models also shows that the alkynes in 19 are in
very close proximity when invoking amide resonance.
Bergman et al.,19 have published extensively on enediyne
cyclisations which involve radical intermediates. We are
now investigating the scope and limitations of this inter-
esting new cyclisation which we feel will be of general in-
terest in natural product synthesis and will avoid the use
of metal catalysts.20,21
O
O
– HBr
O
O
SiMe3
SiMe3
Br
18
15
Scheme 7 Possible acid-catalysed mechanism
The mechanism outlined in Scheme 7 is less favoured be-
cause the ether 19 was also found to cyclise in boiling tol-
uene to afford the dihydrofuran 20 (Scheme 8).
In summary, we report a reliable and efficient novel cycli-
sation reaction for the formation of fused ring systems,
which is metal-free and hence environmentally friendly.
Me
N
Me
O
N
O
a
O
O
Acknowledgment
SiMe3
SiMe3
19
20
The authors would like to thank the EPSRC, Pfizer Ltd and Glaxo-
SmithKline for their generous financial support. Professor Jim
Hanson, Dr. Clive Penkett, Dr. Murray, Dr. Pennicott and Mr.
Graham Marsh (Sussex University) are gratefully acknowledged for
their useful discussions.
Scheme 8 Reagents and conditions: (a) PhMe, reflux, 1 h, (91%).
Of further interest is that when the ene-diyne 21 is heated
in boiling toluene the tricycle 22 is formed in 97% yield.
The longer reaction time of 13 hours is required to achieve
cyclisation in the absence of a trimethylsilyl group
(Scheme 9).
References and Notes
(1) Matsumoto, N.; Tsuchida, T.; Maruyama, M.; Sawa, R.;
Kinoshita, N.; Homma, Y.; Takahashi, Y.; Iinuma, H.;
Naganawa, H.; Sawa, T.; Hamada, M.; Takeuchi, T. J.
Antibiot. 1996, 49, 953.
Me
Me
(2) (a) Matsumoto, N.; Tsuchida, T.; Maruyama, M.; Kinoshita,
N.; Homma, Y.; Iinuma, H.; Sawa, T.; Hamada, M.;
Takeuchi, T.; Heida, N.; Yoshioka, T. J. Antibiot. 1999, 52,
269. (b) Matsumoto, N.; Tsuchida, T.; Nakamura, H.; Sawa,
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(3) Cox, C. D.; Danishefsky, S. J. Org. Lett. 2000, 2, 3493.
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(5) Cox, C. D.; Siu, T.; Danishefsky, S. J. Angew. Chem. Int. Ed.
2003, 42, 5625.
N
O
N
O
O
Br
a
O
H
21
22
H
Scheme 9 Reagents and conditions: (a) PhMe, reflux, 13 h, (97%).
Synlett 2006, No. 19, 3243–3246 © Thieme Stuttgart · New York

3246
P. J. Parsons et al.
LETTER
(6) Cox, C. D.; Siu, T.; Danishefsky, S. J. Angew. Chem. Int. Ed.
2003, 42, 5629.
(7) Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403.
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tetrahydrofuro[10,11-e]isoindol-7-one(15).
To 9-trimethylsilanyl-propynoic acid [4-(bromoallyl-
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toluene (10 mL) was added 1-epoxyhexene (1.00 g, 1.21 mL,
10.0 mmol). The solution was stirred at reflux for 1 h, after
which time TLC showed the reaction to be complete.
Toluene and 1-epoxyhexene were removed in vacuo and the
product purified by column chromatography (Et2O–hexane
7:3) to give the title compound as a bright yellow oil (0.235
g, 0.9 mmol, 90% yield). 1H NMR (CDCl3): d = 7.31 (s, 1 H,
C2), 7.14 (s, 1 H, C12), 4.15–4.24 (d, 1 H, J = 18.3 Hz, C5),
3.92–4.01 (m, 1 H, C5), 3.05 (s, 3 H, C13), 2.74–2.91 (m, 2
H, C9, C10), 2.32 (d, 1 H, J = 7.0 Hz, C10), –0.11 (s, 9 H,
C14, C15, C16). 13C NMR (CDCl3): d = 173.6 (C7), 139.8
(C2), 138.3 (C4), 138.0 (C12), 137.1 (C8), 123.3 (C3), 121.4
(C11), 54.4 (C5), 32.0 (C13), 24.6 (C9), 21.9 (C10), 0.0
(C14, C15, C16). IR (neat): 3104, 2953, 2235, 1673, 1562,
851 cm–1. MS (ES+): m/z = 284 [M + Na].
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Synlett 2006, No. 19, 3243–3246 © Thieme Stuttgart · New York