Application of a dual fries-Claisen protocol to access pyranonaphthoquinone natural products

Article abstract of DOI:10.1055/s-0032-1317943

In this paper we describe the application of a recently developed dual Fries-Claisen protocol as a novel synthetic approach to the pyranonaphthoquinone natural products eleutherin and isoeleutherin. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317943

LETTER
▌185
lAettper plication of a Dual Fries–Claisen Protocol to Access Pyranonaphtho-
quinone Natural Products
Fries–Claisen Protocol for Pyranonaphthoquinone Natural Products
Liam J. Duffy,a Jason Garcia-Torres,b Raymond C. F. Jones,b Mark R. J. Elsegood,b Steven M. Allin*c
a
Research Institute for the Environment, Physical Sciences and Mathematics, Keele University, Keele ST5 5BG, UK
b
Chemistry Department, Loughborough University, Loughborough, Leics LE11 3TU, UK
c
School of Science & Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, UK
E-mail: steve.allin@ntu.ac.uk
Received: 23.11.2012; Accepted: 02.12.2012
annelation involving a dual Fries–Claisen rearrangement
strategy10 and we now wish to report the first application
of this methodology in the synthesis of the pyranonaph-
thoquinone natural products eleutherin (3a) and isoeleu-
therin (3b).
Abstract: In this paper we describe the application of a recently de-
veloped dual Fries–Claisen protocol as a novel synthetic approach
to the pyranonaphthoquinone natural products eleutherin and isoe-
leutherin.
Key words: annelation, pericyclic reaction, rearrangement, Fries,
Claisen, cyclisation
The rearrangement precursor 4, required for this study,
was prepared following our reported route and subjected
to the recently developed sequential anionic ortho-Fries–
Claisen protocol, followed by O-methylation to yield ad-
vanced intermediate 5.10 The O-methylation [step (iv)]
following the Claisen step [step (iii)] was carried out in or-
der to prevent unwanted competitive cyclisation onto the
pendant allyl substituent at a later stage of our synthesis
(Scheme 1).
The pyranonaphthoquinones (Figure 1) are an interesting
class of naturally occurring antibiotic compound that also
display a wide range of other biological activities, such as
antifungal, antiviral and anticancer activity. In addition to
the antibiotic activity shown by frenolicin A (1), and
nanaomycin A, (2),1 eleutherin (3a) has been shown to be
a reversible inhibitor of the anticancer target topoisomer-
ase II2 and isoeleutherin (3b) has shown activity as a se-
lective modulator of Th cell-mediated immune
responses.3 Isoeleutherin (3b) has also recently been
shown to suppress nitric oxide synthase (NOS), responsi-
ble for the production of the important signalling mole-
cule nitric oxide (NO).4
O
OMe
O
OMe
O
NMe2
i–iv
OMe
NMe2
OMe
5
O
4
OH
O
Pr
O
OH
O
Me
Scheme 1 Reagents and conditions: (i) s-BuLi, TMEDA, THF,
–78 °C (92%); (ii) NaH, MeI, THF, 20 °C, 4 h (80%); (iii) mesitylene,
reflux, 3 h (92%); (iv) K2CO3, MeI, acetone, reflux, 24 h, 83%.
O
O
O
CO2H
O
CO2H
1
2
In our recent paper highlighting the development of this
methodology, compound 5 was subsequently subjected to
acid-mediated lactonisation10 to yield a pyranonaphtho-
quinone, with concomitant demethylation–oxidation of
the aromatic ring to furnish quinone functionality. In this
current paper we describe an alternative, and complemen-
tary, functionalisation of our rearrangement products.
OMe
O
Me
OMe
O
Me
O
O
Me
Me
O
O
3a
3b
Figure 1 Pyranonaphthoquinone natural products
Using the related rearrangement product 6 as a model sub-
strate, cyclisation was investigated and achieved through
iodolactonisation, affording the potentially useful iodol-
actone 7, as outlined in Scheme 2, and an X-ray crystal
structure was obtained to confirm the identity of the prod-
uct.11 It is noteworthy that this alternative sequence does
not lead to formation of a quinone product as in our initial
work,10 but rather leaves the fused naphthalene unit intact.
The ability to control the oxidation state of the product
aromatic system in this manner will prove to be an impor-
Previously reported annelation routes to compounds such
as eleutherin have included application of Hauser–Kraus,5
oxa-Pictet–Spengler,6 Dötz,7 Diels–Alder8 and tandem
enamine conjugate addition–cyclisation methodologies.9
We have recently reported a novel protocol for benz-
SYNLETT 2013, 24, 0185–0188
Advanced online publication: 18.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317943; Art ID: ST-2012-D1001-L
© Georg Thieme Verlag Stuttgart · New York

186
L. J. Duffy et al.
LETTER
Isolation of the major isomer, cis-pyran 11a,12 could be
achieved at this point by column chromatography, and
this pure compound was subjected to CAN oxidation to
access racemic eleutherin (3a) in 93% yield (Scheme 5).13
Unfortunately separation of trans-isomer 11b from the
original 11a,b mixture proved to be impossible by column
chromatography, however an analytical sample of isoe-
leutherin (3b) was isolated following direct CAN oxida-
tion of the 11a,b mixture.14
OMe OH
OMe
O
OMe
OMe
Me
O
i
O
Me
Me
OMe
10
OMe
9
ii
Scheme 2 Reagents and conditions: (i) I2, NaHCO3, THF–Et2O, heat,
48 h, (77%).
OMe Me
O
OMe Me
OMe
OMe
O
tant asset as we seek to apply this chemistry to a range of
targets.
Me
Me
OMe
OMe
Our route to the target natural products in this study re-
quired the application of the Fries–Claisen rearrangement
product, 5, to this sequence. Thus, amide 5 was subjected
to iodolactonisation to yield lactone 8 in 83% yield, fol-
lowed by dehalogenation using tributyltin hydride to give
the key eleutherin precursor, methyl lactone 9, in 80%
yield (Scheme 3).
11b
11a
Scheme 4 Reagents and conditions: (i) MeLi, THF–Et2O (1:1), 0 °C,
12 h; (ii) TES, BF3·OEt2, CH2Cl2, –78 °C, 8 h, (85% for both steps).
OMe Me
O
Me
OMe
OMe
i
O
O
OMe
O
OMe
Me
Me
OMe
O
OMe
OMe
11a
O
O
NMe2
i
3a
Scheme 5 Reagents and conditions: (i) CAN, MeCN–H2O (2:1),
2 h, (93%).
OMe
8
I
OMe
5
ii
In conclusion, we have successfully applied our recently
reported dual Fries–Claisen protocol10 to a racemic syn-
thesis of the topoisomerase II inhibitor, eleutherin (3a)
and its biologically active isomer isoeleutherin (3b). Fur-
ther applications of the dual Fries–Claisen rearrangement
strategy to the synthesis of more complex pyranonaphtho-
quinone natural product targets will be reported in due
course.
OMe
O
OMe
O
Me
OMe
9
Scheme 3 Reagents and conditions: (i) I2, NaHCO3, THF–Et2O,
heat, 48 h, (83%); (ii) Bu3SnH, AIBN, toluene, heat, 2 h, (80%).
Acknowledgment
Access to the natural product targets in this study from
intermediate 9 was achieved by a two-step procedure in-
volving addition of methyllithium to the lactone carbonyl
group to form a diastereoisomeric mixture of lactols, 10.
This compound was not isolated but instead subjected to
a Lewis acid mediated reduction using triethylsilane to
yield a 5:1 mixture of racemic cis- and trans-pyrans,
11a,b respectively, in a combined overall yield of 85% for
the two steps (Scheme 4).
We thank EPSRC for financial support of this project
(EP/F026552/1), Keele and Loughborough Universities for faci-
lities and financial support, and the EPSRC Mass Spectrometry
Service Centre (Swansea) for some HRMS data.
References and Notes
(1) (a) Uno, H. J. Org. Chem. 1986, 51, 350. (b) Kraus, G. A.;
Molina, M. T.; Walling, J. A. J. Org. Chem. 1987, 52, 1273.
(c) Brimble, M. A.; Lynds, S. M. J. Chem. Soc., Perkin
Trans. 1 1994, 493. (d) Salaski, E. J.; Krishnamurthy, G.;
Synlett 2013, 24, 185–188
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fries–Claisen Protocol for Pyranonaphthoquinone Natural Products
187
Ding, W.-D.; Yu, K.; Insaf, S. S.; Eid, C.; Shim, J.; Levin, J.
vigorously for 1 h at −78 °C before being allowed to warm
to r.t. over 2 h. The reaction was carefully quenched with the
addition of H2O (50 mL) and then partitioned between brine
(50 mL) and CH2Cl2 (50 mL). The organic layer was
separated and the aqueous phase was extracted twice more
with CH2Cl2 (2 × 30 mL). The combined organics were dried
over anhyd MgSO4 and evaporated to dryness under reduced
pressure. The crude 1H NMR spectrum of this material
showed a 5:1 cis/trans mixture of (±)-11a and (±)-11b,
respectively. The mixture of naphthopyrans was
I.; Tabei, K.; Toral-Barza, L.; Zhang, W.-G.; McDonald, L.
A.; Honores, E.; Hanna, C.; Yamashita, A.; Johnson, B.; Li,
Z.; Laakso, L.; Powell, D.; Mansour, T. S. J. Med. Chem.
2009, 52, 2181.
(2) Sperry, J.; Lorenzo-Castrillejo, I.; Brimble, M. A.; Machin,
F. Bioorg. Med. Chem. 2009, 17, 7131.
(3) Hong, J.-H.; Yu, E. S.; Han, A.-R.; Nam, J.-W.; Seo, E.-K.;
Hwang, E. S. Biochem. Biophys. Res. Commun. 2008, 371,
278.
(4) Song, S.-H.; Min, H.-Y.; Han, A.-R.; Nam, J.-W.; Seo, E.-
K.; Park, S. W.; Lee, S. H.; Lee, S. K. Int.
Immunopharmacol. 2009, 9, 298.
(5) Gibson, J.; Andrey, O.; Brimble, M. A. Synthesis 2007,
2611.
(6) Sawant, R. T.; Jadhav, S. G.; Waghmode, S. B. Eur. J. Org.
Chem. 2010, 4442.
(7) Fernandes, R. A.; Chavan, V. P.; Ingle, A. B. Tetrahedron
Lett. 2008, 49, 6341.
(8) Tewierik, L. M.; Dimitriadis, C.; Donner, C. D.; Gill, M.;
Willems, B. Org. Biomol. Chem. 2006, 4, 3311.
(9) Kobatashi, K.; Uchida, M.; Uneda, T.; Tanmatsu, M.;
Morikawa, O.; Konishi, H. Tetrahedron Lett. 1998, 39,
7725.
chromatographed on silica using light petroleum (bp 40–60
°C)–EtOAc (6:1) as eluent to yield 11a as a white solid (550
mg, 68% over 2 steps). It was not possible to separate the
trans-naphthopyran 11b from the cis-naphthopyran, (±)-
11a, at this juncture, only 136 mg (17% over 2 steps) of a
mixture (1:1 by 1H NMR spectroscopy) was isolated (total
combined yield 85%). Data for 11a: mp 104–106 °C (Lit.1a
mp 106–107 °C). IR (ATR): 1570, 1071, 1058 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 1.42 (d, J = 6.0 Hz, 3 H), 1.69
(d, J = 6.0 Hz, 3 H), 2.59 (dd, J = 11.1, 16.2 Hz, 1 H), 3.06
(dd, J = 1.8, 16.2 Hz, 1 H), 3.65–3.71 (m, 1 H), 3.77 (s, 3 H),
3.99 (s, 3 H), 4.01 (s, 3 H), 5.25 (q, J = 6.0 Hz, 1 H), 6.83 (d,
J = 7.5 Hz, 1 H), 7.37 (t, J = 8.1 Hz, 1 H), 7.68 (dd, J = 0.6,
8.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 21.9, 23.2,
31.9, 56.1, 61.2, 61.6, 69.4, 71.3, 105.4, 114.5, 119.3, 125.9,
126.1, 129.8, 130.3, 148.5, 149.1, 156.1. MS (EI–CI): m/z
[M + H+] calcd for C18H22O4: 303.1591; found: 303.1596.
(13) Synthesis of Eleutherin (3a): A solution of cerium(IV)
ammonium nitrate (1.99 g, 3.64 mmol) in H2O (2 mL) was
added to a solution of the cis-naphthopyran (±)-11a (550 mg,
1.82 mmol) in MeCN (4 mL) at r.t. After stirring for 2 h, the
reaction was partitioned between CH2Cl2 (50 mL) and H2O
(50 mL). The organic phase was separated and the aqueous
phase was re-extracted twice with CH2Cl2 (2 × 30 mL). The
combined organic fractions were washed with brine, dried
over anhyd MgSO4 and concentrated under reduced
(10) Duffy, L. J.; Garcia-Torres, J.; Jones, R. C. F.; Allin, S. M.
Synlett 2012, 23, 1821.
(11) (a) X-ray crystal data for 7: C23H21IO5, M = 504.30,
monoclinic, space group P21/c, a = 14.3715(5), b =
15.6087(5), c = 9.0761(3) Å, β = 94.3888(5), V =
2029.98(12) Å3, T = 150 K, Z = 4, crystal dimensions 0.56 ×
0.22 × 0.12 mm3, Mo–Kα monchromated radiation (λ =
0.71073 Å), μ = 1.610 mm–1, 23393 data measured using a
Bruker APEX 2 CCD diffractometer. 6173 data were
unique, Rint = 0.022; all unique data used in refinement
against F2 values to give final wR = 0.0622 (on F2 for all
data), R = 0.0236 {for 5369 data with F2 >4σ(F2)}. Programs
used were Bruker APEX 2 (see ref. 11b), SAINT (see ref.
11b), SHELXTL (see refs. 11c and 11d) and local programs.
Crystallographic data (excluding structure factors) for the
structure in this paper has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 854341. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [Fax:
pressure. The crude quinone was chromatographed on silica
gel using light petroleum (bp 40–60 °C)–EtOAc (2:1) as
eluent to give (±)-eleutherin (3a) as a yellow solid (462 mg,
93%). Data for 3a: mp 156–157 °C (Lit.1a mp 155–156 °C).
IR (ATR): 1651, 1584, 1276, 1059 cm–1. 1H NMR (300
MHz, CDCl3): δ = 1.37 (d, J = 6.0 Hz, 3 H), 1.54 (d, J = 6.0
Hz, 3 H), 2.20 (ddd, J = 3.6, 10.2, 18.3 Hz, 1 H), 2.75 (dt, J
= 2.7, 18.3 Hz, 1 H), 3.56–3.62 (m, 1 H), 4.00 (s, 3 H), 4.83–
4.89 (m, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.64 (t, J = 7.8 Hz,
1 H), 7.73 (dd, J = 0.9, 7.5 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 20.8, 21.3, 29.9, 56.5, 68.7, 70.3, 117.7, 119.0,
120.2, 133.9, 134.6, 139.9, 148.7, 159.4, 183.8, 184.1. MS
(EI–CI): m/z [M + H+] calcd for C16H16O4: 273.1121; found:
273.1124.
+44(1223)336033 or e-mail: deposit@ccdc.ac.uk].
(b) APEX 2 and SAINT Software for CCD Diffractometers;
Bruker AXS Inc: Madison WI, 2008. (c) Sheldrick, G. M.
SHELXTL User Manual, Version 5; Bruker AXS Inc:
Madison WI, 1994. (d) Sheldrick, G. M. Acta Crystallogr.,
Sect. A 2008, 64, 112.
(12) Synthesis of Eleutherin Precursor, 11a:
Step (1): Methyllithium (2.01 mL, 3.23 mmol; 1.6 M
solution in decane) was added dropwise to 5,9,10-
trimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-
1-one (9; 813 mg, 2.69 mmol) in anhyd THF–Et2O (1:1;
50mL) at 0 °C. The reaction mixture was stirred vigorously
and allowed to reach r.t. overnight. The reaction was stopped
by careful addition of sat. aq NH4Cl (50 mL) and the aqueous
layer was extracted three times with EtOAc (3 × 30 mL). The
combined organic phases were dried over anhyd MgSO4 and
concentrated under reduced pressure. The crude white foam
recovered (10, 856 mg) was taken forward to the lactol
reduction step without purification.
(14) Isolation of an Analytical Sample of Isoeleutherin (3b): A
solution of cerium(IV) ammonium nitrate (493 mg, 0.90
mmol) in H2O (1 mL) was added to a solution of 1:1 (±)-
11a/b (136 mg, 0.90 mmol) in MeCN (2 mL) at r.t. After 2
h stirring the reaction was partitioned between CH2Cl2 (50
mL) and H2O (50 mL). The organic phase was separated and
the aqueous phase was extracted twice more with CH2Cl2 (2
× 30 mL). The combined organic fractions were washed with
brine, dried over anhyd MgSO4 and concentrated under
reduced pressure. The crude quinone was chromatographed
on silica gel using light petroleum (bp 40–60 °C)–EtOAc
(4:1) as eluent to give a 1:1 mixture of (±)-eleutherin (3a)
and (±)-isoeleutherin (3b) as a yellow solid (109 mg, 89%).
It was only possible to isolate an analytical sample (7 mg) of
(±)-isoeleutherin (3b) as a yellow solid for characterisation
purposes; mp 151–152 °C (Lit.1a mp 154–155 °C). IR
(ATR): 1651, 1584, 1276, 1058 cm–1. 1H NMR (300 MHz,
Step (2): Lactol 10 (856 mg, 2.69 mmol) was dissolved in
anhyd CH2Cl2 (20 mL) and cooled to −78 °C before
successive dropwise addition of BF3·OEt2 (1.02 mL, 8.07
mmol) and TES (1.29 mL). The red solution was stirred
© Georg Thieme Verlag Stuttgart · New York
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188
L. J. Duffy et al.
LETTER
CDCl3): δ = 1.35 (d, J = 6.0 Hz, 3 H), 1.54 (d, J = 6.9 Hz, 3
H), 2.24 (ddd, J = 2.1, 10.2, 19.2 Hz, 1 H), 2.70 (dd, J = 3.3,
18.9 Hz, 1 H), 3.96–4.01 (m, 1 H), 4.01 (s, 3 H), 5.02 (q, J =
6.6 Hz, 1 H), 7.29 (d, J = 8.7 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1
H), 7.76 (dd, J = 0.9, 7.5 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 19.8, 21.5, 29.5, 56.5, 62.4, 67.4, 117.8, 119.1,
119.3, 134.0, 134.8, 139.4, 148.0, 159.7, 182.8, 184.3. MS
(EI–CI): m/z [M + H+] calcd for C16H16O4: 273.1121; found:
273.1127.
Synlett 2013, 24, 185–188
© Georg Thieme Verlag Stuttgart · New York