A facile enantioselective synthesis of the dimeric pyranonaphthoquinone core of the cardinalins

Article abstract of DOI:10.1055/s-2008-1042896

The enantioselective synthesis of a dimeric pyranonaphthoquinone closely related to cardinalin 3 is described. Key steps include the Hauser-Kraus annulation between a cyanophthalide and a chiral enone to create the naphthalene skeleton, a Suzuki-Miyaura h

Full text of DOI:10.1055/s-2008-1042896

LETTER
867
A Facile Enantioselective Synthesis of the Dimeric Pyranonaphthoquinone
Core of the Cardinalins
Synthesis of the
D
imer
a
ic Pyranon
r
g
inone Cor
e
o
a
f
the
C
ard
r
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 11 January 2008
selective total synthesis of the topoisomerase II inhibitor
eleutherin.5 Thus in the present work, model dimer 1 was
envisaged to be accessible via a double stereoselective
reduction6 of a bislactol that in turn would be accessible
Abstract: The enantioselective synthesis of a dimeric pyranonaph-
thoquinone closely related to cardinalin 3 is described. Key steps in-
clude the Hauser–Kraus annulation between a cyanophthalide and a
chiral enone to create the naphthalene skeleton, a Suzuki–Miyaura
homocoupling of an aryl triflate to construct the biaryl bond and a by double intramolecular pyran ring formation. The naph-
double stereoselective lactol reduction to install the 1,3-cis stereo-
chemistry of the pyran rings.
thoquinone core can be formed using a Hauser–Kraus
annulation7,8 and a late stage Suzuki–Miyaura homocou-
Key words: cardinalin, pyranonaphthoquinone antibiotics, Haus-
er–Kraus annulation, homocoupling
pling of a suitable aryl triflate to form the key biaryl bond.
O
OMe
OH
O
O
The pyranonaphthoquinone family of antibiotics exhibits
activity against a variety of Gram-positive bacteria, patho-
genic fungi and yeasts1 and they have been proposed to act
as bioreductive alkylating agents.2 Whilst the synthesis of
monomeric members of this important family of antibiot-
ics is well documented,1b,c the enantioselective total syn-
thesis of a dimeric pyranonaphthoquinone antibiotic has
yet to be achieved.1,3
8'
O
O
8
O
OH
MeO
cardinalin 3
stereocontrolled
lactol reduction
O
O
The cardinalins are a series of biologically active dimeric
pyranonaphthoquinone pigments isolated from the New
Zealand toadstool Dermocybe cardinalis4 that have
aroused considerable interest in our laboratory. The sim-
plest member of the family, cardinalin 3 possesses two
cis-1,3-dimethylpyran rings that are fused to their respec-
tive naphthoquinone nuclei that in turn are linked via a
C8–C8¢ biaryl bond and exists as a single atropisomer
(Scheme 1). Our long-standing interest in the synthesis of
pyranonaphthoquinones1b,c combined with the challeng-
ing dimeric structure and biological activity of the cardi-
nalins prompted us to instigate a synthetic program
towards their synthesis.
O
O
pyran
formation
O
O
homocoupling
of aryltriflate
1
Hauser–Kraus
annulation
MeO
O
TfO
OTBDPS
MeO
In light of the fact that no enantioselective synthesis of a
dimeric pyranonaphthoquinone currently exists in the lit-
erature, it was decided to focus initially on the asymmetric
synthesis of the biaryl core of cardinalin 3, namely model
dimeric pyranonaphthoquinone 1 (Scheme 1). This work
follows on from several syntheses of dimeric pyranonaph-
thoquinones where the issue of enantioselectivity was not
addressed.1,3
2
O
O
BnO
OTBDPS
O
+
CN
4
3
The retrosynthesis is based on our own methodology for
the stereoselective construction of cis-1,3-dimethylpyran
rings which has recently been implemented in an enantio-
Scheme 1 Retrosynthetic analysis of model dimer 1
During our preliminary synthetic efforts towards the relat-
ed dimeric pyranonaphthoquinone crisamicin A, we en-
countered limited success using a double Hauser–Kraus
annulation with a biscyanophthalide as a means to access
SYNLETT 2008, No. 6, pp 0867–0870
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042896; Art ID: D02008ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

868
M. A. Brimble et al.
LETTER
the biaryl core.9 Our revised strategy reported herein fo-
cuses on conducting the key homocoupling step to forge
the biaryl unit at an advanced stage of the synthesis. To-
wards this end, Hauser–Kraus annulation of a suitably
protected cyanophthalide with an enone coupling partner
was envisaged as a crucial step to construct an appropri-
ately functionalized monomeric naphthalene ring. Given
that chiral enone 4 was in hand,5 attention turned to the
synthesis of the benzyl-protected cyanophthalide 3 that
upon annulation with enone 4 could be easily converted
into an aryl triflate substrate ready for the proposed late-
stage homocoupling.
Thus, by simple modification of a literature procedure,10
6-methoxyphthalide11 was subjected to radical ring open-
ing with N-bromosuccinimide. The resulting crude acid
thus obtained was then converted into its diethylamide via
the acid chloride furnishing amide 5.12 The methyl ether
surprisingly resisted all attempts to effect its cleavage
with conventional Lewis acids (BBr3, BCl3, AlCl3), lead-
ing to degradation and only trace amounts of product be-
ing isolated. Fortunately, the use of thiophenol in the
presence of catalytic quantities of potassium carbonate at
elevated temperature in N-methylpyrrolidinone13 success-
fully furnished phenol 6 in good yield. Smooth benzyla-
tion followed by ring closure by using trimethylsilyl
cyanide in the presence of catalytic quantities of potassi-
um cyanide and 18-crown-614 delivered the cyanophtha-
lide annulation precursor 3 (Scheme 2).
O
O
BnO
OTBDPS
O
+
CN
4
3
(i)
MeO
MeO
O
RO
OTBDPS
7
R = Bn 7
(ii)
R = H 8
R = Tf 2
(iii)
Scheme 3 Reagents and conditions: (i) KOt-Bu, DMSO, r.t., 30 min
then Me2SO4, K2CO3, Me2SO4, TBAI, Na2S2O4, THF–H2O, r.t., 2 h,
87%; (ii) H2, Pd/C, MeOH, r.t., 18 h, 97%; (iii) PhN(OTf)2, DMAP,
Et3N, CH2Cl2, r.t., 1 h, 95%.
coupling precursor
(Scheme 3).
2
in excellent overall yield
Next, the key Suzuki–Miyaura homocoupling step was
undertaken. After careful optimization, it was found that
microwave irradiation (300 W, 150 °C) of a dioxane solu-
tion of triflate 2 with precisely 0.5 equivalents of bis(pina-
colato)diboron, three equivalents of freshly ground dried
potassium carbonate under Cl2Pd(dppf)–dppf catalysis
(10 mol%) for one hour gratifyingly afforded the homo-
coupled product 915 in 51% yield in a one-pot operation
(Scheme 4).
O
MeO
CONEt2
CHO
MeO
(i)–(iii)
O
5
(iv)
With a synthetic route to biaryl 9 successfully established,
the double pyran ring formation could next be attempted.
Treatment of biaryl 9 with an excess of tetrabutylammo-
nium fluoride in tetrahydrofuran effected removal of both
O
BnO
HO
CONEt2
CHO
(v), (vi)
O
MeO
O
CN
6
3
TfO
Scheme 2 Reagents and conditions: (i) NBS, CCl4–PhH, reflux, 6 h
then H2O, 90 °C, 2 h; (ii) SOCl2, 70 °C, 2 h; (iii) HNEt2, CH2Cl2, 0 °C
to r.t., 2 h, 42% (3 steps); (iv) PhSH, K2CO3, NMP, 130 °C, 2 h, 77%;
(v) BnBr, K2CO3, acetone, r.t., 16 h; (vi) TMSCN, 18-crown-6, KCN,
CH2Cl2, 0 °C to r.t., 2 h then AcOH, r.t., 16 h, 90% (2 steps).
OTBDPS
MeO
2
(i)
With cyanophthalide 3 in hand, the stage was now set for
the key Hauser–Kraus annulation. Thus, reaction of cy-
anophthalide 3 with enone 4 proceeded smoothly in the
presence of potassium tert-butoxide in DMSO. Immediate
reductive methylation of the crude annulation product
with potassium carbonate and dimethylsulfate under
phase-transfer conditions was necessary to facilitate isola-
tion of the product 7. Facile debenzylation delivered phe-
nol 8 that underwent smooth triflate formation using N-
trifluoromethanesulfonimide in the presence of DMAP
and triethylamine furnishing the key aryl triflate homo-
OMe
OMe
MeO
O
TBDPSO
OTBDPS
O
9
MeO
Scheme 4 Reagents and conditions: (i) Cl2Pd(dppf) (10 mol%),
dppf, K2CO3, bis(pinacolato)diboron, dioxane, microwave, 150 °C,
1 h, 51%.
Synlett 2008, No. 6, 867–870 © Thieme Stuttgart · New York

LETTER
Synthesis of the Dimeric Pyranonaphthoquinone Core of the Cardinalins
869
OMe
MeO
OH
(i)
O
HO
9
O
OMe
(ii)
10
MeO
O
O
OMe
OMe
O
O
MeO
H
NOE
O
O
(iii)
O
O
H
1
11
MeO
Scheme 5 Reagents and conditions: (i) TBAF, THF, r.t., 72 h (ii) TFA, CH2Cl2, –78 °C, 30 min then Et3SiH, r.t., 16 h, 70% (2 steps);
(iii) CAN, MeCN–H2O, r.t., 45 min, 63%.
(3) For racemic syntheses of dimeric pyranonaphthoquinones,
see: (a) Brimble, M. A.; Duncalf, L. J.; Neville, D. J. Chem.
Soc., Perkin Trans. 1 1998, 4165. (b) Brimble, M. A.; Lai,
M. Y. H. Org. Biomol. Chem. 2003, 1, 4227. (c) Brimble,
M. A.; Lai, M. Y. H. Org. Biomol. Chem. 2003, 1, 2084.
(d) For a racemic synthesis of cardinalin 3, see: Govender,
S.; Mmutlane, E. M.; van Otterlo, W. A. L.; de Koning, C.
B. Org. Biomol. Chem. 2007, 5, 2433.
tert-butyldiphenylsilyl ether protecting groups with con-
comitant in situ cyclization. Due to the unstable nature of
bislactol 10 it was immediately reduced to the bis-cis-1,3-
dimethylpyran 1116 with trifluoroacetic acid and triethyl-
silane following the procedure described by Kraus.6 The
1
formation of a single product was observed by H NMR
indicating the formation of the all cis-diastereomer result-
ing from pseudo-axial delivery of the hydride during the
reduction step.6
(4) (a) Gill, M.; Buchanan, M. S.; Yu, J. J. Chem. Soc., Perkin
Trans. 1 1997, 919. (b) Gill, M.; Buchanan, M. S.; Yu, J.
Aust. J. Chem. 1997, 50, 1081.
The 1,3-cis stereochemistry was confirmed unequivocally
by the NOE correlation between the axial protons at C1
and C3 on the pyran ring. Finally, CAN-mediated oxida-
tive demethylation provided the bisquinone 7,7¢-
demethoxy-9,9¢-deoxycardinalin 3 (1,17 Scheme 5).
(5) Gibson, J. S.; Andrey, O.; Brimble, M. A. Synthesis 2007,
2611.
(6) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem. Soc.,
Chem. Commun. 1986, 1568.
(7) (a) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178.
(b) Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 19,
2263.
(8) For recent reviews on the Hauser–Kraus annulation, see:
(a) Rathwell, K.; Brimble, M. A. Synthesis 2007, 643.
(b) Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892.
(9) Andrey, O.; Sperry, J.; Larsen, U. S.; Brimble, M. A.
Tetrahedron 2008, in press.
(10) (a) Denes, B.; Szantay, C. Arch. Pharm. 1958, 342. (b) For
a similar example employing molecular bromine, see:
Abaev, V. T.; Dmitriev, A. S.; Gutnov, A. V.; Podelyakin, S.
A.; Butin, A. V. J. Heterocycl. Chem. 2006, 43, 1195.
(11) Brimble, M. A.; Burgess, C. V. Synthesis 2007, 754.
(12) Mill, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989,
54, 4372.
In conclusion, we have achieved an efficient synthesis of
the dimeric core structure of cardinalin 3, representing the
first enantioselective synthesis of a dimeric pyranonaph-
thoquinone. The combined use of a Hauser–Kraus annu-
lation followed by a Suzuki–Miyaura homocoupling
provides a flexible synthetic strategy for the synthesis of
the cardinalins and related dimeric pyranonaphthoquino-
nes. Work towards this end is in progress.
Acknowledgment
The authors thank the Royal Society of New Zealand Marsden fund
for financial support.
(13) Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1997,
38, 8749.
(14) Kaiser, F.; Schwink, L.; Velder, J.; Schmalz, H.-H. J. Org.
Chem. 2002, 67, 9248; and references therein.
References and Notes
(15) Compound 9: colorless oil; [a]D25 –21.8 (c 2.5, CH2Cl2); IR
(oil): nmax = 3070, 3049, 2959, 2932, 2894, 1679, 1588,
1450, 1427, 1348, 1330, 1204, 1112 cm–1. 1H NMR (400
MHz, CDCl3): d = 0.97 [18 H, s, 2 × C(CH3)3], 0.98 (6 H, d,
3JHH = 6.0 Hz, 2 × CH3), 2.48 (6 H, s, 2 × C=OCH3), 2.90 (2
H, dd, 2JHH = 13.4 Hz, 3JHH = 7.5 Hz, 2 × CHH), 3.11 (2 H,
dd, 2JHH = 13.4 Hz, 3JHH = 6.7 Hz, 2 × CHH), 3.81 (6 H, s,
2 × OCH3), 3.90 (6 H, s, 2 × OCH3), 4.27 [2 H, ddq (app.
sext), 3JHH = 7.5, 6.7, 6.0 Hz, 2 × CH], 7.27 (4 H, m, ArH),
7.38 (8 H, m, ArH), 7.54 (4 H, dd, J = 8.1, 1.3 Hz, ArH), 7.66
(4 H, dd, J = 8.1, 1.6 Hz, ArH), 7.93 (2 H, dd, J = 8.8, 1.8
Hz, ArH), 8.15 (2 H, d, J = 8.8 Hz, ArH), 8.36 (2 H, d, J =
(1) For reviews regarding isolation, structure, and synthesis of
pyranonaphthoquinone antibiotics, see: (a) Brimble, M. A.;
Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999, 16, 267.
(b) Brimble, M. A.; Nairn, M. R.; Prabaharan, H.
Tetrahedron 2000, 56, 1937. (c) Sperry, J.; Bachu, P.;
Brimble, M. A. Nat. Prod. Rep. 2008, in press; DOI:
10.1039/b708811f.
(2) Moore, H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249.
Synlett 2008, No. 6, 867–870 © Thieme Stuttgart · New York

870
M. A. Brimble et al.
LETTER
(2 × OCH3), 69.6 (2 × CH), 71.3 (2 × CH), 120.4
(2 × CHarom), 122.8 (2 × CHarom), 125.5 (2 × Carom), 125.7
(2 × CHarom), 126.6 (2 × Carom), 127.7 (2 × Carom), 129.9
(2 × Carom), 138.3 (2 × Carom), 148.8 (2 × Carom), 149.0
(2 × Carom). MS (EI): m/z (%) = 542 (100) [M]+, 527 (39),
199 (22), 105 (32), 57 (40), 44 (72). HRMS (EI): m/z calcd
for C34H38O6 [M]+: 542.2668; found: 542.2667.
1.8 Hz, ArH). 13C NMR (100 MHz, CDCl3): d = 19.1
{2 × Si[C(CH3)3]}, 23.4 (2 × CHCH3), 27.0
{2 × Si[C(CH3)3]}, 32.8 (2 × C=OCH3), 37.0 (2 × CH2),
61.8 (2 × OCH3), 63.7 (2 × OCH3), 69.6 (2 × CH), 120.6
(2 × CHarom), 123.7 (2 × CHarom), 124.8 (2 × Carom), 126.8
(2 × CHarom), 127.4 (8 × CHarom), 127.9 (2 × Carom), 128.3
(2 × Carom), 129.40 (2 × CHarom), 129.43 (2 × CHarom),
134.27 (2 × Carom), 134.31 (2 × Carom), 134.7 (2 × Carom),
135.8 (4 × CHarom), 135.9 (4 × CHarom), 138.6 (2 × Carom),
149.3 (2 × Carom), 151.6 (2 × Carom), 205.3 (2 × C=O). MS–
FAB: m/z (%) = 1050 (4) [M]+, 993 (6) [M – C(CH3)3]+, 795
(14), 397 (10), 197 (40), 135 (100). HRMS–FAB: m/z calcd
(17) Compound 1: yellow solid; mp 239–240 °C; [a]D23 +356.1 (c
0.15, CH2Cl2). IR (CH2Cl2): nmax = 3432, 3025, 1663, 1265,
736, 705 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.40 (6 H,
d, 3JHH = 6.1 Hz, 2 × CHCH3), 1.58 (6 H, d, 3JHH = 6.5 Hz,
2 × CHCH3), 2.31 (2 H, ddd, JHH = 18.7, 10.2, 4.0 Hz,
2 × CHaxH), 2.82 (2 H, dt, JHH = 18.7, 2.5 Hz, 2 × CHeqH),
3.64 (2 H, m, 2 × CHCH3), 4.89 (2 H, m, 2 × CHCH3), 8.02
(2 H, dd, 3JHH = 8.0 Hz, 4JHH = 1.9 Hz, ArH), 8.20 (2 H, d,
3JHH = 8.0, ArH), 8.35 (2 H, 4JHH = 1.9 Hz, ArH). 13C NMR
(100 MHz, CDCl3): d = 20.8 (2 × CHCH3), 21.2
for C66H74O8Si2 [M]+: 1050.4922; found: 1050.4921.
24
(16) Compound 11: cream-colored solid; mp 268–269 °C; [a]D
+36.2 (c 0.12, CH2Cl2). IR (CH2Cl2): nmax = 3418, 3053,
2986, 1638, 1421, 1264, 733 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.44 (6 H, d, 3JHH = 6.0 Hz, 2 × CHCH3), 1.73
(6 H, d, 3JHH = 6.6 Hz, 2 × CHCH3), 2.66 (2 H, dd, 2JHH
16.2 Hz, 3JHH = 11.0 Hz, 2 × CHH), 3.11 (2 H, dd, 2JHH
16.2 Hz, 3JHH = 1.5 Hz, 2 × CHH), 3.74 (2 H, m,
2 × CHCH3), 3.91 (6 H, s, 2 × OCH3), 3.95 (6 H, s,
=
=
(2 × CHCH3), 30.5 (2 × CH2), 68.7 (2 × CH), 70.0 (2 × CH),
125.0 (2 × CHarom), 127.3 (2 × CHarom), 131.4 (2 × CHarom),
131.9 (2 × Carom), 133.0 (2 × Carom), 143.0 (2 × Carom), 144.2
(2 × Carom), 147.0 (2 × Carom), 183.4 (2 × C=O), 183.7
(2 × C=O). MS (EI): m/z (%) = 482 (100) [M]+, 467 (20),
237 (15), 199 (20), 131 (21), 91 (99), 77 (25), 57 (37), 40
(85). HRMS (EI): m/z calcd for C30H26O6 [M]+: 482.1729;
found: 482.1720.
2 × OCH3), 5.26 (2 H, q, 3JHH = 6.6 Hz, 2 × CHCH3), 7.89 (2
H, dd, 3JHH = 8.8 Hz, 4JHH = 1.6 Hz, ArH), 8.18 (2 H, d, 3JHH
= 8.8 Hz, ArH), 8.37 (2 H, d, 4JHH = 1.6 Hz, ArH). 13C NMR
(75 MHz, CDCl3): d = 21.8 (2 × CHCH3), 22.4
(2 × CHCH3), 32.0 (2 × CH2), 61.1 (2 × OCH3), 61.4
Synlett 2008, No. 6, 867–870 © Thieme Stuttgart · New York