The first total syntheses of (±)-Preussomerins K and L using 2-arylacetal anion technology

Article abstract of DOI:10.1016/j.tetlet.2004.04.143

The first syntheses of newly isolated members of the Preussomerin family, Preussomerins K and L, are reported. Key steps include the functionalisation of a 2-arylacetal anion, one-pot Friedel-Crafts cyclisation-deprotection and reductive opening of epoxides.

Full text of DOI:10.1016/j.tetlet.2004.04.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4877–4881
The first total syntheses of (± ±)-reꢀssoꢁerꢂns K and L ꢀsꢂng
)arylacetal anꢂon technology
2
Ernesto Quesada, Martin Stockley and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, United Kingdom
Received 17 March 2004; revised 14 April 2004; accepted 22 April 2004
Abstract—The first syntheses of newly isolated members of the Preussomerin family, Preussomerins K and L, are reported. Key
steps include the functionalisation of a 2-arylacetal anion, one-pot Friedel–Crafts cyclisation–deprotection and reductive opening of
epoxides.
Ó 2004 Published by Elsevier Ltd.
In recent years, a large number of novel bioactive
metabolites have been isolated from fungi, which con-
tain two naphthalene units linked together. Biosyn-
O
OH
O
O
OH
O
1
O
O
thetically, they all have a common origin, being
generated by oxidative coupling via the 1,8-dihydroxy-
naphthalene (DHN) pathway and late introduction of
O
O
O O
OMe
2
their individual oxygenation patterns. Most of these
metabolites exhibit significant antifungal and antibac-
terial properties, presumably arising because of inter-
species competition among dung-inhabiting fungi.
However, the main biological interest concerns their
ability to inhibit farnesyl-protein transferase (FTPase) in
a highly selective fashion. This enzyme plays a critical
role in the post-translational modification of a range of
different intracellular proteins. As a result, FTPase
O
O
Preussomerin G
Preussomerin I
O
OH
O
OH
O
HO
O
O
O
O O
O
3
inhibitors have great potential in cancer chemotherapy.
Among the main representatives of this large group of
OH
OH
4
5
natural products are the Diepoxins, Palmarumycins,
7
Spiroxins and Preussomerins.
6
O
O
Preussomerin K
Preussomerin L
The Preussomerin family of natural products currently
consists of 13 members (representative examples are
Fꢂgꢀre 1. Representative members of the Preussomerin natural
products.
7
shown in Fig. 1). Preussomerins A–F were the first
members of the family to be reported and Preus-
7a
7b
somerins G–L are the most recent additions. From a
structural viewpoint, all the Preussomerins possess
two naphthalene units linked by three oxygen atoms,
generating a bis-spiroacetal system. This remarkable
head-to-tail trioxabicyclo[3.3.1]nonane nucleus repre-
sents a unique natural product unit and a challenging
target for total synthesis.
The first synthesis of a Preussomerin was carried out by
Chi and Heathcock, who reported an elegant total
synthesis of (±)-Preussomerins G and I. This approach
followed a putative biomimetic pathway based on the
Keywords: Total synthesis; Natural products; Preussomerins; Aryl-
acetal anion.
8
*
Corresponding author. Tel.: +44-1904-432606; fax: +44-1904-4345-
3; e-mail: rjkt1@york.ac.uk
2
0
040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.04.143

4878
E. Quesada et al. / Tetrahedron Letters 45 (2004) 4877–4881
spontaneous oxidative dimerisation of naphthalenediol
monoacetals. Further work by Barrett et al., using an
oxidative spirocyclisation again as the key step, allowing
was achieved by direct Jones oxidation, which provided
the diacid 6 in high yield. This sequence represents a
considerable improvement of the route originally pub-
9
12
them to access ())-Preussomerin G.
lished by our group.
Our interest in the Preussomerins began as part of a
programme involving the synthesis of FTPase inhibitors
The next key step of the synthesis involved Friedel–
Crafts cyclisation of the diacid 6. After activating the
diacid as the acid chloride, treatment with a homogenous
solution of AlCl in nitromethane produced the Friedel–
3
Crafts adduct 7. However, if the reaction was allowed to
10
for biological screening (e.g., Manumycin A and Pal-
11
marumycin CP1 ). In this letter we describe the total
syntheses of Preussomerin K and L based on a novel
non-biomimetic strategy. The route involves formation
of the bis-acetal in a single step at the start of the syn-
thesis, with the elaboration of the outer fringes of the
molecule at the end. One key step involves the previ-
ously reported 2-aryl acetal anion alkylation chemis-
3
stand for longer in the presence of excess AlCl , two new
compounds, characterised as 8 and 9, began to appear,
indicating that after a rapid cyclisation (less than 1 h to
completion), the remaining Lewis acid slowly catalysed
the cleavage of the phenolic methoxy groups. All com-
pounds 7–9 contain the full Preussomerin skeleton but,
additionally, in compound 9 the symmetry has been
broken. This one-pot cyclisation–deprotection reaction
has been optimised to give a 44% yield of compound 9
(Scheme 2), thereby providing an ideal advanced inter-
mediate for the assault on Preussomerins K and L. It
should be noted that compounds 7 and 8 can be recycled
to provide additional amounts of 9.
12
try, which has now been successfully applied to
construct the newer members of the family, Preusso-
merin K and L, for the first time.
The synthesis started with the inexpensive methoxy-
phenol 1. Magnesium methoxide-mediated ortho-
13
formylation gave access to large amounts of 5-meth-
oxysalicylaldehyde 2, which was smoothly dimerised to
12
provide the key bis-acetal 3 in high yield (Scheme 1).
Deprotonation of bis-acetal 3 with n-BuLi, followed by
alkylation with oxetane, provided the unsymmetrical
compound 4. The second alkylation was found to be
more difficult, due in part for the need of a stronger base
than n-BuLi. Under the optimised conditions, both
alkylations were conducted in a one-pot manner and the
diol 5 could be isolated in 52% yield. Oxidation of diol 5
The deoxygenation of the free phenolic group in 9 was
carried out by formation of triflate 10, which was cleanly
reduced by catalytic hydrogenation to provide 11 in
good overall yield.
14
Having established an easily scalable route to 11, our
attention was focused on the introduction of the two
OH
OH
Mg(OMe)2
(t-BuCO) O
2
CHO
H2SO4 (cat)
(CH2O)n
rt, 30 min
Toluene, 90 ºC
(>90%)
(96%)
OMe
OMe
1
2
OMe
OH
OMe
O
OMe
i) n-BuLi, THF
ii) oxetane
.
BF3 Et2O
-100 to -40 ºC
O
O
O
O
O
O
O
O
+
iii) s-BuLi, THF
iv) oxetane
.
BF3 Et2O
OMe
OMe
OH
OMe
-100 to -40 ºC
OH
3
4 (32%)
5 (52%)
OMe
HO2C
Jones' reagent
acetone, rt
O
O
O
5
1
(
0 min
95%)
CO2H
OMe
6
Scheꢁe 1. Early steps of the synthesis.

E. Quesada et al. / Tetrahedron Letters 45 (2004) 4877–4881
4879
OMe
O
OMe
O
OR
O
i) (COCl)2
DMF (cat)
CH2Cl2
HO2C
0
1
ºC to rt,
h
+
O
O
O
O
O O
O
O
ii) AlCl3
7.2 equiv)
(
MeNO2
CH2Cl2
rt, 20 h
CO2H
OMe
OMe O
7 (10%)
OH
O
6
R = H; 8 (33%)
R = Me; 9 (44%)
O
OMe
O
O
OMe
O
H2
Pd(OH)2
Et N
3
Tf2O
Py
9
O
O
CH2Cl2
AcOEt/MeOH
rt, 24 h
O O
-10 ºC to rt
(
85%, two steps)
OTf
O
O
1
0
11
Scheꢁe 2. Friedel–Crafts acylation–desymmetrisation of the bis-acetal.
1
1
15
conjugated double bonds (Scheme 3). Attempts to
carry out the direct conversion of 11 into dienone 13
(benzeneseleninic anhydride, DDQ, IBX, etc.) were
unsuccessful. This problem was circumvented by pro-
ceeding via the bis-silyl enol ether 12. Conversion of 12
into dienone 13 was first attempted using IBX com-
O
OMe
O
TMSO
O
OMe
O
16
plexes. The complex IBX-MPO generated the dienone
13 in 41% yield but the best results were found using
Saegusa conditions, giving dienone 13 in 91% yield on
treatment with stoichiometric Pd(OAc)
catalytic Pd was not successful.
TMSOTf
Pd(OAc)2
17
2
,6-lutidine
CH CN
3
2
. The use of
O
O
O
CH2Cl2
rt, 16 h
(91%)
0
ºC to rt, 1 h
Epoxidation of dienone 13 was carried out using tert-
butyl hydroperoxide in presence of 1,3,4,6,7,8-hexa-
hydro-2H-pyrimido[1,2-a]pyrimidine (TBD) following
O
OTMS
1
1
12
18
our own methodology to yield the bis-a,b-epoxyketone
1
4 in excellent yield (Scheme 3). It should be noted that
O
OMe
O
O
OMe
O
(PhSe)2
the epoxidation proceeded with complete stereoselec-
tivity for the less hindered faces of the dienone 13 giving
a single diepoxide. In the next step, selective opening of
the diepoxide 14 proved straightforward and the bis-b-
hydroxyketone 15 was formed easily in good yields by a
regio- and stereoselective organoselenium-mediated
NaBH4
2.5 equiv)
AcOH
(
O
t-BuOOH
TBD
EtOH
O
O
O
O
Toluene
0
ºC to rt, 1h
0
ºC to rt
(67%)
O
19
1
h
process. The X-ray crystallographic analysis of 15
20
(91%)
confirmed the structure (Fig. 2), showing it to be
exactly in accordance with that of the natural products,
with the two aromatic rings almost perpendicular to
O
O
1
3
14
7b
each other.
O
OMe
O
OH
O
Removal of the methyl of the phenolic ether in 15 was
achieved successfully using 9-I-BBN affording the first
of the natural products, Preussomerin L 16.
9
-I-BBN
HO
CH2Cl2
HO
O
O
O
O O
0
ºC to rt
OH
OH
1
h
This route could also be modified to prepare Preus-
somerin K (Scheme 4). The use of sub-stoichiometric
amounts of organoselenium reagent during the reduc-
tion of diepoxide 14 generated a mixture of four com-
pounds––the starting material 14, diol 15 and two new
compounds namely 17 and 18. The most interesting was
(
50%)
O
O
1
5
Preussomerin L 16
Scheꢁe 3. Synthesis of Preussomerin L 16.

4880
E. Quesada et al. / Tetrahedron Letters 45 (2004) 4877–4881
synthesis. Further studies towards the total synthesis of
more members of the Preussomerin family as well as
asymmetric approaches are currently under investiga-
tion and will be reported in due course.
Acknowledgeꢁents
The authors thank Professor K. Krohn (University of
Paderborn) for providing authentic comparison samples
of Preussomerins K and L. Dr. A. C. Whitwood is
acknowledged for assistance with the X-ray study.
Fꢂgꢀre 2. ORTEP drawing of compound 15 (50% probability thermal
ellipsoids).
20
References and notes
1
2
3
. For a recent review, see Krohn, K. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Falk,
H., Kirby, G. W., Eds.; Springer: Wien, 2003; Vol. 85, p 1.
. (a) Bode, H. B.; Wegner, B.; Zeeck, A. J. Antibiot. 2000,
compound 18, which was easily separated and isolated
in 54% yield under the optimised conditions. Unfortu-
nately, attempted deprotection of 18 (9-I-BBN,
bromochatecolborane, etc.) resulted in extensive de-
gradation. We circumvented this limitation by using
excess boron tribromide, which provided the interme-
diate bromohydrin 19. The epoxide was regenerated by
basic treatment of 19 affording Preussomerin K 20
5
5
3, 153; (b) Bode, H. B.; Zeeck, A. Phytochemistry 2000,
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(
Scheme 4). The data from the synthetic samples of
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5
. (a) Krohn, K.; Michel, A.; Florke, U.; Aust, H. J.;
Draeger, S.; Schulz, B. Liebigs Ann. Chem. 1994, 1099; (b)
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In summary, we have successfully synthesised the race-
mic natural products Preussomerin K and L (4% overall
yields in both cases) from inexpensive building blocks
through the application of a novel non-biomimetic
strategy with the functionalisation of a 2-arylacetal
anion, one-pot Friedel–Crafts cyclisation–deprotection
and reductive opening of epoxides as the key steps of the
1
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OMe
O
O
OMe
O
O
OMe
O
(
PhSe)2
O
NaBH4
0.9 equiv)
O
(
HO
O
O
O
O
+
O
O
+
14
+
15
AcOH
EtOH
(
18%) (17%)
OH
O
0 ºC to rt, 1 h
O
O
O
O
1
4
17 (11%)
18 (54%)
O
OH
O
OH
O
Br
t-BuOK
EtOH
O
BBr3
DCM
HO
1
8
O
O
O
O O
rt, 45 min
-
78 ºC
OH
OH
(50%)
then, rt
O
O
1
9
Preussomerin K 20
Scheꢁe 4. Synthesis of Preussomerin K 20.

E. Quesada et al. / Tetrahedron Letters 45 (2004) 4877–4881
4881
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