Biomimetic synthetic studies on lactonamycin: An expedient synthesis of dihydroxy-isoindolinone-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2011.08.173

The synthesis of dihydroxy-isoindolinone-carboxylates from a dioxinone keto-ester and N-protected sarcosine without the use of phenolic protection is described. Base-induced aromatization of the dioxinone diketo-ester followed by lactamization furnished the desired dihydroxy-isoindolinone moiety, which could be used as an EF-ring precursor toward the synthesis of lactonamycin.

Full text of DOI:10.1016/j.tetlet.2011.08.173

Tetrahedron Letters 52 (2011) 6072–6075
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Biomimetic synthetic studies on lactonamycin: an expedient synthesis
of dihydroxy-isoindolinone-carboxylates
⇑
Sylvain A. Jacques, Bhavesh H. Patel, Anthony G. M. Barrett
Department of Chemistry, Imperial College, London SW7 2AZ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2011
Revised 16 August 2011
Accepted 30 August 2011
Available online 10 September 2011
The synthesis of dihydroxy-isoindolinone-carboxylates from a dioxinone keto-ester and N-protected
sarcosine without the use of phenolic protection is described. Base-induced aromatization of the dioxi-
none diketo-ester followed by lactamization furnished the desired dihydroxy-isoindolinone moiety,
which could be used as an EF-ring precursor toward the synthesis of lactonamycin.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lactonamycin
C-Acylation
Aromatization
Lactamization
Dioxinones
Introduction
condensation of isobenzofuran-1(3H)-one derivatives7 or o-phthal-
aldehyde derivatives8 with a primary amine; nitrile reduction of 2-
Lactonamycin (1) possesses several intriguing structural fea-
tures (Fig. 1).1 The novel, highly functionalized hexacyclic aglycone
core, contains, in the western half, a highly-oxygenated fused per-
hydrofuran-furanone ring with a labile tertiary methoxy group,
and in the eastern half, a naphtha[e]isoindole ring system. In addi-
tion to its interesting structure, the biological evaluation of lacton-
amycin (1) against Gram-positive bacteria showed significant
levels of antimicrobial activity.2 It was especially active against
clinically isolated methicillin-resistant Staphylococcus aureus
(MRSA) and vancomycin-resistant Enterococcus (VRE) with mini-
cyanobenzoyl ester derivatives and subsequent lactamization;9
palladium-catalyzed reactions,10 and finally the reduction of
phthalimide derivatives.11 Albeit usually high yielding, many of
these conditions are often not suitable for phthalimidine deriva-
tives bearing sensitive substituents on the aromatic ring.
We recently published the biomimetic synthesis of several res-
orcylate natural products by late-stage aromatization reactions
from triketo-ester derivatives.12 Based on this methodology,13 we
sought a second-generation biomimetic approach toward the syn-
thesis of triflate 5. Herein, we report the synthesis of an advanced
intermediate toward triflate 5 using a late-stage base-induced aro-
matization of dioxinone diketo-ester.
mum inhibitory concentration levels of 0.39 and 0.20 lg/mL,
respectively. Lactonamycin (1) also showed significant levels of
cytotoxicity against various tumor cell lines.2
We3 and others4 have reported studies on the syntheses of the
ABCD and CDEF ring systems of 1. Our approach was based on the
use of an intramolecular Friedel–Crafts acylation of acid 3, which
was synthesized from bromide 4 and triflate 5 via a Suzuki cou-
pling reaction (Scheme 1).3b Although the original route provided
sufficient quantities of triflate 5, the synthesis was insufficiently
concise and, therefore, we have investigated alternative routes to-
ward the synthesis of triflate 5.
O
NMe
O
OH
O
A
F
O
MeO
OH
B
C
D
E
O
Simple phthalimidines 65(Fig. 2) are typically synthesized from
2-methylbenzoyl ester derivatives via radical benzylic bromination
followed by condensation with a primary amine and cyclization;6
OH
O
O
O
1
⇑
Corresponding author.
E-mail address: agm.barrett@imperial.ac.uk (Anthony G. M. Barrett).
Figure 1. Structure of lactonamycin (1).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.173

S. A. Jacques et al. / Tetrahedron Letters 52 (2011) 6072–6075
6073
NMe
NMe
O
O
OH
OMe
HO2C
O
O
RO
RO
OH
OMe
OMe
2
3
OMe
OMe
NMe
MeO2C
TfO
O
Br
RO
OMe
5
4,
R = PMB, Me
Scheme 1. Retrosynthetic analysis of model CDEF tetracyclic target 2.
keto-ester dioxinone 10b was prepared from acid chloride 14b15
in a lower yield of 35%.
O
R1
R2
R3
N Me
The next step involved the key C-acylation of keto-ester dioxi-
nones via Mg-enolate formation (Scheme 4). Sarcosine (16) was
protected by sequential reaction with trimethylsilyl chloride16
and 2-Me3SiCH2CH2SO2Cl (SESCl) followed by de-trimethylsilyla-
tion upon acid work-up to give 17.17 Upon treatment with oxalyl
chloride, SES-protected sarcosine 17 was converted into the corre-
sponding acid chloride 11a, which was directly allowed to react
with the Mg-enolates 18a and 18b of 10a and 10b to form dioxi-
none diketo-esters 9a and 9b.12 These crude adducts were unstable
and, therefore, were directly cyclized using triethylamine18 to give
resorcylates 8a and 8b in moderate yields of 49% and 30% over
three steps, respectively.
6
Figure 2. Generic structure of phthalimidine derivatives 6.
Results and discussion
Our retrosynthesis is illustrated in Scheme 2. Dihydroxy-isoind-
olinone-carboxylates 7 should be available by deprotection fol-
lowed
by
lactamization
from
isopropylidene-protected
Methanolysis of 8a and 8b in the presence of cesium carbonate
gave methyl esters 19a and 19b in good yields (Scheme 5).18 The
deprotection of the SES group with Bu4NF was followed by subse-
quent lactamization to give dihydroxy-lactams 7a and 7b in 78%
and 65% yields, respectively.19
In summary, we have developed a concise five-step synthesis to
dihydroxy-isoindolinone-carboxylates 8a and 8b in good yield.
Both could serve as potential precursors toward the synthesis of
the EF-ring system of lactonamycin (1). This methodology could
be further applied for the synthesis of a wider range of dihy-
droxy-isoindolinone derivatives starting from different amino
acids or dioxinone keto-esters.
resorcylates 8, which in turn could be prepared from dioxinone
diketo-esters 9 by base-induced aromatization. Finally, C-acylation
between keto-ester dioxinones 10 and acid chloride 11 derived
from N-protected sarcosine could generate dioxinone diketo-esters
9.
Reaction of Meldrüm’s acid 12 with tert-butanol at 100 °C gave
the half malonate ester 13 in 52% yield (Scheme 3).14 The corre-
sponding acid chloride 14a, synthesized with oxalyl chloride, was
allowed to react with the lithium enolate 15a derived from dioxi-
none 15 by treatment with lithium hexamethyldisilazide to afford
keto-ester dioxinone 10a in 76% yield. In a similar manner,
PG(Me)N
O
NMe
Lactamization
RO2C
HO
O
RO2C
O
OH
HO
O
7
8
Aromatization
O
PG
N
Cl
Me
O
O
O
O
PG
N
11
O
O
O
O
O
Me
O
OR
C-acylation
CO2R
10
9
Scheme 2. Retrosynthetic analysis.

6074
S. A. Jacques et al. / Tetrahedron Letters 52 (2011) 6072–6075
tBuOH
100 °C
O
O
O
O
HO
OtBu
O
O
12
13 (52%)
(COCl)2, DMF,
CH2Cl2, 0 °C to 23 °C
O
O
LiO
O
O
15a
O
O
O
O
Cl
OR1
−
THF, 78 °C
O
OR1
1
R
R
= tBu (76%)
14a, R1 = tBu
14b, R1 = Me
10a,
10b,
1 = Me (35%)
Scheme 3. Synthesis of dioxinone keto-esters 10a and 10b.
Scheme 4. Synthesis of resorcylates 8a and 8b.
SES(Me)N
N(Me)SES
O
O
Cs2CO3,
Acknowledgments
R1O2C
R1O2C
HO
CO2Me
OH
O
MeOH
60 °C
We thank the Engineering and Physical Sciences Research
Council (EPSRC) and GlaxoSmithKline for grant support, and P. R.
Haycock and R. N. Sheppard (Imperial College) for high-resolution
NMR spectroscopy.
HO
1
, R1 = tBu
, R = Me
, R = tBu (77%)
8a
8b
19a
19b
, R1 = Me (60%)
1
Supplementary data
Δ
Bu4NF,
NMe
Supplementary data (experimental procedures, characteriza-
tion data and copies of 1H and 13C NMR spectra for all new com-
pounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.08.173.
R1O2C
HO
O
References and notes
OH
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, R1 = tBu (78%)
, R = Me (65%)
7a
7b
1
Scheme 5. Synthesis of dihydroxy-isoindolinone-carboxylates 7a and 7b.

S. A. Jacques et al. / Tetrahedron Letters 52 (2011) 6072–6075
6075
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