An enantioselective synthesis of the bicyclic core of the marine natural product awajanomycin

Article abstract of DOI:10.1016/j.tetlet.2010.01.123

A concise stereoselective synthesis of the N-benzylated bicyclic core of the marine natural product awajanomycin is described starting with naturally occurring l-alanine. Key steps in the synthesis include a ring-closing metathesis to establish a δ-lactam ring followed by a stereoselective hydroxylation to instal the quaternary centre.

Full text of DOI:10.1016/j.tetlet.2010.01.123

Tetrahedron Letters 51 (2010) 1819–1821
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An enantioselective synthesis of the bicyclic core of the marine natural product
awajanomycin
*
Deiniol R. Pritchard, Jonathan D. Wilden
Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise stereoselective synthesis of the N-benzylated bicyclic core of the marine natural product awaj-
Received 19 November 2009
Revised 4 January 2010
Accepted 29 January 2010
Available online 4 February 2010
anomycin is described starting with naturally occurring L-alanine. Key steps in the synthesis include a
ring-closing metathesis to establish a d-lactam ring followed by a stereoselective hydroxylation to instal
the quaternary centre.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ring-closing metathesis
d-Lactam
Acremonium sp.
Diastereoselective hydroxylation
Awajanomycin (1) is a highly functionalised secondary metabo-
lite from the marine-derived fungus Acremonium sp.1 It was iso-
lated and characterised in 2006 during a programme designed to
isolate new structures with novel biological activity. It has at-
tracted interest due to its cytotoxic activity, inhibiting the growth
of human lung adenocarcinoma cells (A549 cells) with an IC50 va-
O
O
O
O
OH
4
2
HO
NH
3
HO
NH
1
O
10
H3C(H2C)6
11
H3C(H2C)6
7
8
6
5
9
OH
1
OH
2
OH
lue of 27.5 l
g mLÀ1.1 At present, only one full total synthesis of the
Figure 1.
enantiomer of this molecule is present in the literature, which has
helped to establish the complete stereochemical profile of the mol-
ecule as 3R,5R,6S,8S,11S.2 Additionally, one racemic approach to
the core skeleton has been reported.3 In addition to awajanomycin,
the ring-opened product 2 has also been isolated (Fig. 1).1
O
O
O
O
O
O
A number of structural features of these molecules make them
OH
HO
worthy of further investigation. Firstly, the bicyclic
c-lactone-d-
HO
NH
NH
HO
NH
O
lactam core of 1 is rare in natural products and few reports are gi-
ven in the literature for the synthesis of this type of structure. It
has been noted that 2 is rather less active than 1 and this suggests
that the rigid core of the molecule is responsible, at least in part, for
its biological activity.1
At the outset of our programme, only the relative stereochemis-
try of the awajanomycin core had been elucidated and the stereo-
chemistry of the C11 hydroxy group was unknown. Our first
thoughts directed towards an enantioselective total synthesis of
awajanomycin involved the disconnection outlined in Scheme 1
which would employ the union of aldehyde 4 derived from com-
R
1
OPiv
OH
O
O
OEt
NHBoc
NHBoc
O
O
HO
+
O
EtO
OEt
3
OPiv 4
OPiv
NHBoc
mercially available D- or L-alanine with diethyl malonate (3). In this
L-alanine
way we believed that we would be able to control the absolute ste-
OPiv
* Corresponding author. Tel.: +44 02076795813.
E-mail address: j.wilden@ucl.ac.uk (J.D. Wilden).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.123

1820
D. R. Pritchard, J. D. Wilden / Tetrahedron Letters 51 (2010) 1819–1821
NHBoc
O
O
O
NHBoc
NHBoc
MgBr
81%
EDCI, CH2Cl2, Et3N
Br
N
HO
(i) Br2, NEt3, 81%
(ii) NaH, BnBr, 61%
G-H II, 54%
CH2Cl2, 40 o
NH
NH
NBn
O
H2
Cl
N
75%
C
O
O
O
O
7 OPiv
6 OPiv
8
OPiv
EtO2C
CO2Et
NHBoc
NHBoc
O
NHBoc
NaBH4
Scheme 5.
(i) PivCl, 86%
(ii) O3, 56%
CeCl3, 74%
dr = 2.5:1
OH
5
OPiv
4
OPiv
At this stage our intention was to introduce a halogen atom al-
pha to the amide carbonyl group in order that we could introduce
the ester functionality at this position. Disappointingly however,
despite the initial bromination proceeding smoothly, all our at-
tempts to convert compound 8 into the ester failed. Attempts to
form reactive organometallic species (lithium, zinc and magne-
sium)6 at low temperatures by metal–halogen exchange followed
by quenching with methyl chloroformate generally resulted in
only the reduced non-halogenated compounds on work up. Simi-
larly, attempts at introducing the ester via palladium-catalysed
carbonylation protocols also met with failure.7 Various other
methods from the literature for introducing this group were also
attempted, however, none were successful in our hands.
Given the difficulties with utilising the bromine functional
group we decided to seek an alternative route. Removal of the al-
kene of 7 by hydrogenation followed by benzyl protection of the
nitrogen atom was effected in order that we might be able to func-
tionalise the 3-position via standard enolate chemistry.8 Indeed,
we were pleased to observe that deprotonation of the saturated
species with LDA followed by treatment with diethyl carbonate
yielded the ester 10 in good yield as a 6:1 mixture of diastereoiso-
Scheme 2.
reochemistry of each newly created centre via stereorelay from the
C6 centre derived from the amino acid. In this way both enantio-
mers of the natural product core would be available to us to com-
pare the analytical data to ascertain the absolute stereochemistry
of the naturally occurring material.
Preparation of the chiral aldehyde 4 was achieved without inci-
dent by the method outlined in Scheme 2 to yield an inseparable
2.5:1 mixture of diastereoisomers in favour of the alkene 5. The
yields and diastereoselectivity of this sequence are comparable to
those of similar reactions found in the literature.4
The diastereoselectivity of the reduction can be explained by an
internal hydrogen bond that restricts the rotation of the C5–C6
bond resulting in hydride delivery from the opposite face to the
methyl substituent (Scheme 3).
Treatment of 5 with ozone gave the aldehyde 4 in good yield.
Disappointingly, however, exposure of this aldehyde to diethyl
malonate under classic Knoevenagel conditions yielded none of
the desired unsaturated diester and only the starting materials
were isolated. It seems that the aldehyde is unstable to the reaction
conditions, and consequently only polymeric material was ob-
tained from the reaction.
r-
O
O
O
O
Despite this setback, we were keen to use the intermediate 5
since two of the stereogenic centres are correctly installed. We
therefore decided to modify our strategy to include a ring-closing
metathesis step which would allow us to construct the six-mem-
bered ring of awajanomycin while still utilising the intermediate
5.5 The modified disconnection is shown in Scheme 4.
Pivaloyl protection of 5 followed by TFA-mediated Boc depro-
tection and then treatment with acryloyl chloride yielded the
unsaturated amide 6 in good yield. Dropwise addition of the Grub-
bs–Hoveyda 2nd generation catalyst (G–H II) to a dichloromethane
solution of 6 at reflux then yielded the cyclised product 7 in 54%
yield. We were pleased to observe however that the 2.5:1 diaste-
reoisomeric mixture was easily separable by column chromatogra-
phy, and as such, the major (S,R) diastereoisomer was readily
isolated in pure form (Scheme 5).
(i) H2, PtO, 80%
LDA, THF, -78 ºC
(EtO)2CO, 90%
dr = 6:1
NH
NBn
EtO
NBn
(ii) BnBr, NaH, 85%
7
9
10
OPiv
OPiv
O
OPiv
O
O
O
O
LDA, THF, -78 ºC
PhSeCl, then H2O2
EtO
NBn
EtO
NBn
+
51%
34%
11a OPiv
tBuOOH, nBuLi, THF, 85%
Scheme 6.
11b
OPiv
O
O
O
O
OH
LDA, THF, 83%
EtO
NBn
EtO
NBn
NHBoc
H
H
NBoc
O
NBoc
HO
O
NaBH4
CeCl3
N
Ph
SO2Ph
10 OPiv
13 OPiv
5
12
OH
Scheme 3.
Scheme 7.
O
O
O
O
NHBoc
OPiv
EtO
NH
NH
NH
OPiv
OPiv
6
OPiv
Scheme 4.

D. R. Pritchard, J. D. Wilden / Tetrahedron Letters 51 (2010) 1819–1821
1821
O
O
O
O
O
OH
OH
O
O
(i) NaOEt, EtOH
(ii) HCl, EtOH
NBn
EtO
NBn
HO
48%
HO
NBn
13
14
OH
OPiv
Scheme 8.
ment of the axial proton resonance at C8 (Fig. 2) confirming the
(3R,5R,6S) stereochemistry of the core. A number of attempts have
been made to remove the benzyl-protecting group (H2/Pd/C,
NH4HCO2/Pd/C, Pearlman’s Catalyst, H2/PtO),10,11 however, these
have so far been proved unsuccessful.
1.7%
OH
H
O
Me
Bn
N
O
In conclusion, we have described a concise enantioselective
synthesis of the N-benzylated core of the marine natural product
O
Figure 2.
awajanomycin starting with
the synthesis is the capacity to prepare either enantiomer of the fi-
nal product simply by starting with either - or -alanine since ste-
L-alanine. One of the key features of
D
L
reocontrol is achieved by stereorelay in the order C6?C5?C3. We
have also demonstrated a potential strategy for the inclusion of the
side chain at C8 with stereochemical control. Work is underway in
our laboratory to refine the synthesis in order to complete the full
total synthesis of awajanomycin.
mers. Interestingly, further enolate formation followed by treat-
ment with phenyl selenyl chloride and aqueous hydrogen peroxide
work-up led not only to the expected alkene 11a, but also to the
epoxide 11b directly. Presumably selenide elimination is followed
by rapid nucleophilic oxidation of the extremely electron-deficient
alkene. The product was also obtained as a single diastereoisomer,
presumably due to the steric bulk of the pivaloyl group shielding
the lower face of the alkene. The remainder of the material was
easily converted into the epoxide, again as a single diastereoiso-
mer, by treatment with the lithium salt of tert-butyl hydroperoxide
generated in situ from n-butyllithium and the peroxide. This result
was particularly welcome as all but one of the stereogenic centres
were now installed with the appropriate stereochemistry for the
awajanomycin core. The centres at C4, C5 and C6 have the correct
relative stereochemistry and the centre at C8 has the appropriate
inverted stereochemistry which will allow us to instal the side
chain via SN2 inversion with an organocopper reagent (Scheme
6). Unfortunately, as yet, our attempts to achieve the epoxide ring
opening with a variety of organometallic reagents have resulted in
only trace amounts of products being obtained.
At this stage we decided to modify our procedure and focus on
the synthesis of the bicyclic core of the molecule in order to vali-
date our strategy and include the side chain (C9–18) at a later
stage. Starting with compound 10, sequential enolate formation
followed by treatment with the oxaziridine reagent9 12 gave the
alcohol 13 as a single diastereoisomer with the desired stereo-
chemistry for the awajanomycin core (Scheme 7).
With the compound 13 in hand all that was required to com-
plete the synthesis of the core of the natural product was the re-
moval of the ethyl ester and pivaloyl groups. We reasoned that
these would be simultaneously removed under basic conditions
and that under these conditions the molecule would spontane-
ously form the second five-membered ring of the awajanomycin
core. We were pleased to observe that this occurred smoothly, al-
beit in moderate yield at this stage, to yield the bicyclic molecule
14 in good yield (Scheme 8).
Acknowledgements
The authors would like to acknowledge the Engineering and
Physical Sciences Research Council and University College London
for financial support of this work. They would also like to thank Dr.
A. Aliev for his help with NMR analysis and John Hill and Lisa Har-
ris for mass spectrometry support.
Supplementary data
Supplementary data (spectroscopic assignments and experi-
mental procedures) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.123.
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Stereochemical confirmations have been made on the basis of
NOE experiments which revealed that in the bicyclic structure,
irradiation of the methyl group at C7 resulted in a 1.7% enhance-