An efficient synthesis of (±)-frondosin B using a Stille-Heck reaction sequence

Article abstract of DOI:10.1039/b924542a

A concise, convergent synthesis of (±)-frondosin B has been developed based on the application of a Stille-Heck reaction sequence of 2-chloro-5-methoxybenzo[b]furan-3-yl triflate and 2-(3-butenyl)-3- (trimethylstannyl)cyclohex-2-enone giving the racemic natural product in a 34% overall yield.

Full text of DOI:10.1039/b924542a

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An efficient synthesis of ( )-frondosin B using a Stille–Heck reaction
sequence†
Kye-Simeon Masters‡ and Bernard L. Flynn*
Received 23rd November 2009, Accepted 19th January 2010
First published as an Advance Article on the web 1st February 2010
DOI: 10.1039/b924542a
A concise, convergent synthesis of ( )-frondosin B has been
developed based on the application of a Stille–Heck reac-
tion sequence of 2-chloro-5-methoxybenzo[b]furan-3-yl trif-
late and 2-(3-butenyl)-3-(trimethylstannyl)cyclohex-2-enone
giving the racemic natural product in a 34% overall yield.
vinylstannanes 7 (Stille–Heck acceptor) may provide a useful and
modular method for obtaining carbocycles 8 (Scheme 1), including
the bicyclo[5.4.0]undecane ring system that is common to all
frondosins A–E.5 Herein we report the application of this reaction
to a high yielding, flexible approach to ( )-frondosin B.
Frondosins A–E, 1–5 (Fig. 1), are a family of related marine
sesquiterpenoids isolated from the marine sponges Dysidea fron-
dosa (1–5) and Eurospongia (1 and 4).1 Interestingly, those isolated
from Dysidea frondosa are in the dextro-rotary form and those
from Eurospongia in the levo-rotatory form. Frondosins A–E are
compounds of interest due to their promising interleukin-8 (IL-8)
affinity and protein kinase C inhibition.1a IL-8 antagonists are
of particular interest in view of their anti-inflammatory,2a anti-
HIV,1b,2b and antitumor2c–f properties. The biological activities of
the frondosins thus warrant further investigation and medicinal
chemistry studies. While a number of syntheses of the frondosins
have been reported,3 they are either low yielding or lack the
generality required for structure–activity relationship studies.
Recently, we reported that the sequential Stille–Heck coupling
of 2-bromo (or chloro)-alkenyl triflates 6 with alkenyl tethered
Scheme 1 Stille–Heck reaction.
The planned approach to frondosin B required the initial prepa-
ration of 2-halo-5-methoxybenzo[b]furan-3-yl-triflates, namely
bromide 12 and chloride 13 (Scheme 2). Despite their poten-
tial utility in the synthesis of 2,3-disubstituted benzo[b]furans,
there have been no prior reports on the preparation of 2-
halo-benzo[b]furan-3-yl-triflates.6 We envisaged that these po-
tentially useful benzo[b]furan derivatives could be prepared
by a-halogenation and enoltriflation of the corresponding
benzo[b]furan-3-one. Accordingly, we sought to a-brominate and
a-chlorinate commercially available 5-methoxybenzo[b]furan-3-
one 9 using CuBr2 and SO2Cl2, respectively (Scheme 2).5 The best
yield obtained for 2-bromo-5-methoxybenzo[b]furan-3-one 10 was
24% with competitive decomposition of 9 and dibromination
being the key limiting factors. The corresponding 2-chloro-5-
methoxybenzo[b]furan-3-one 11, was obtained in a good yield
(83%). Enol-triflation of 10 and 11 was readily achieved using
triethylamine and triflic anhydride at low temperature giving 12
(73%) and 13 (quantitative), respectively, (Scheme 2).6
Scheme 2 Synthesis of 2-halobenzo[b]furan-3-yl triflates. Conditions: a)
CuBr2, EtOAc, CHCl3; b) SO2Cl2, CHCl3; c) Et3N, Tf2O, CH2Cl2, -78 ◦C
to RT.
Fig. 1 (+)-Frondosins A–E.4
The Stille–Heck acceptor 14 was prepared from 1,3-
dimethoxybenzene in four steps as previously described
(Scheme 3).5a Reaction of the 2-bromo-5-methoxybenzo[b]furan-
1-yl triflate 12 with 14 under our previously developed domino
Stille–Heck reaction conditions, involving Pd(dba)2, tri-(2-
furyl)phosphine (TFP), ZnCl2 and copper(I) thiophenecarboxy-
late (CuTC) in N-methylpyrrolidine (NMP),5 gave the two
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical
Sciences, 381 Royal Parade, Parkville, VIC 3052, Australia. E-mail:
bernard.flynn@pharm.monash.edu.au; Fax: +61 3 9903 9582
† Electronic supplementary information (ESI) available: Experimental
procedures and 1H and 13C NMR spectra of products. See DOI:
10.1039/b924542a
‡ Current Address: Institut fu¨r Organische Chemie, Universita¨t Karlsruhe
(TH), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany
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Scheme 4 Two step Stille–Heck reaction of 13 and 14.
altered the outcome substantially (Method B, Table 1).7 The extent
of the Heck reaction was considerable, with all of the starting
material converted to Heck cyclised products 17a,b (41%) and 20
(59%).
Heck product 20 presumably arises from initial migration of the
terminal olefin (internalisation), followed by 1,6-Heck reaction
and aromatization. One possible explanation is that the thermally
induced burst of catalytic activity generated under MWI may in
turn lead to a rapid accumulation of HPdCl(t-Bu3P)2, which results
from the b-hydride elimination step in the catalytic cycle and that
this Pd(II) species catalyses double-bond isomerism at a faster rate
than the biphasic, base (Cs2CO3) mediated reductive elimination
of HCl from the catalyst.8 Accordingly, the homogeneous base
dicyclohexylmethylamine was used to replace the heterogeneous
base Cs2CO3 in order to increase the rate of catalyst regeneration
(Method C, Table 1). While these conditions had the desired effect
of reducing the amount of 1,6-Heck product 20 (not observed), the
overall reaction was less efficient, giving a modest yield of 17a,b
(13%) and starting material 19 (87%).
Based on recent reports on the use of 2¢,4¢,6¢-diisopropyl-
1,1¢-biphenyl-2-yldicyclohexylphosphine (X-Phos, Fig. 2) in pro-
moting the intramolecular arylation of aryl bromides and in
the intermolecular Heck reaction of arylchlorides we utilised
this ligand and MWI in the intramolecular Heck reaction of
19 and obtained an excellent yield of 17a,b (83%, a : b 9 : 1)
(Table 1, Method D).9 In this case, double-bond isomerism in
19 and subsequent cyclisation to give 20 was avoided. Possibly
the acetate anions, introduced as the pre-catalyst Pd(OAc)2,
may have provided sufficient basicity to prevent accumulation of
HPdCl(tBu3P)2, effectively acting as a phase-transfer catalyst for
K2CO3.
Scheme 3 Domino Stille–Heck reaction of triflate 12 and stannane 14.
regioisomers 17 (51%) and 18 (29%), which could be separated
by chromatography, but were each isolated as a mixture of
inseparable double-bond isomers a and b. The two regiosiomers
17 and 18 appear to have resulted from competitive oxidative
insertion of the palladium(0) catalyst into the C3-OTf and C2-
Br bonds, giving initially the two Stille intermediates 15 and
16 (not isolated), respectively. This is opposed to the previous
examples of regioselective Stille–Heck reaction processes involving
2-bromoalkenyl triflates,5 which show highly selective reaction
initially at the triflate. Presumably, the increased reactivity of the
bromide in a 2-bromobenzo[b]furan reduces this regioselectivity.
When the 2-chloro-5-methoxybenzo[b]furan-1-yl triflate 13 and
14 were subjected to the same reaction conditions as used
above for the domino Stille–Heck, only the Stille reaction was
observed, which proceeded entirely through the triflate moiety
to give 19 in an excellent yield (94%, Scheme 4). As with other
2-chloroalkenyl triflates under these conditions,5 the reaction
stopped after the Stille coupling and further heating did not lead to
any intramolecular-Heck product. In other systems, we had been
successful in achieving intramolecular-Heck reactions of alkenyl
chlorides in an efficient manner with Pd(t-Bu3P)2 and Cs2CO3 in
◦
NMP at 85 C,5 however, when applied to 19 this only gave a
low yield of 17a,b (31%) (a : b 1 : 1) and returned mostly starting
material (Method A, Table 1). Increasing the reaction time did
not improve the outcome (not shown) and the low conversion
of substrate was attributed to competitive decomposition of the
catalyst. Interestingly, the use of microwave irradiation (MWI)
Fig. 2 X-Phos.
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Table 1 Intermolecular Heck reaction of chloride 19 (Scheme 4)
Method
Catalyst, Base, Solvent
Heating Method/◦C
Bath (85)c
Time/h
Product (Yield%)
A
B
Pd(t-Bu3P)2, aCs2CO3, NMP
Pd(t-Bu3P)2, aCs2CO3, NMP
Pd(t-Bu3P)2, aCy2NMe, NMP,
Pd(X-Phos)2, bK2CO3, DMA
6
17a,b (31)
19 (69)
17a,b (41)
20 (59)
17a,b (13)
19 (87)
17a,b (83)
MWI (85)d
1
C
D
MWI (85)d
1
MWI (100)d
0.5
a Preformed catalyst (0.2 eq.). b Catalyst formed in situ by addition of Pd(OAc)2 (0.10 equiv.) and X-Phos (0.20 eq.) to reaction mixture. c External mercury
thermometer in oil bath. d Internal infrared thermometer.
Mixtures of double-bond isomers 17a,b were quantitatively con-
verted to the thermodynamically more stable internal double-bond
isomer, 17b, upon reaction with RhCl3 in ethanol (Scheme 5).5a
Notes and references
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Tetracycle 17b is a common intermediate with our previously
described total synthesis of ( )-frondosin B.3e It is converted
into ( )-frondosin B through a sequence of gem-dimethylation of
the ketone (Me2TiCl2), chemoselective hydrogenation of the D7,8
double-bond and cleavage of the methylphenyl ether. In its longest
linear sequence, 9 steps from 1,3-dimethoxybenzene, this synthesis
gives frondosin B in an overall 34% yield and 47% yield (8 steps)
from commercially available 9.
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2003, 9, 2786–2797; (d) Y. M. Zhu, S. J. Webster, D. Flower and P. J. Woll,
Br. J. Cancer, 2004, 91, 1970–1976; (e) B. M. Mian, C. P. Dinney, C. E.
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and M. Bar-Eli, Clin. Cancer Res., 2003, 9, 3167–3175; (f) D. J. Brat, A. C.
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4 The absolute stereochemistry depicted for (+)-frondosins is tentatively
depicted as (S)- based on previous asymmetric synthesis efforts, see ref.
3i,j and references cited therein.
Scheme 5 Formal synthesis of ( )-frondosin B.
5 (a) K.-S. Masters and B. L. Flynn, J. Org. Chem., 2008, 73, 8081–8084;
(b) K.-S. Masters and B. L. Flynn, Adv. Synth. Catal., 2009, 351, 530–
536.
6 For a previous report of benzo[b]furan-3-yl-triflates see: C. Morice, F.
Garrido, A. Mann and J. Suffert, Synlett, 2002, 501–503.
7 For previous reports on the application of MWI to Heck reactions see:
(a) G. K. Datta, K. S. A. Vallin and M. Larhed, Mol. Diversity, 2003,
7, 107; (b) B. M. Choudary, S. Madhi, N. S. Chowdari, M. L. Kantam
and B. Sreedhar, J. Am. Chem. Soc., 2002, 124, 14127; (c) K. Dahle´n,
E. A. A. Walle´n, M. Grøtli and K. Luthman, J. Org. Chem., 2006, 71,
6863.
8 Fu has previously described accumulation of HPdCl(t-Bu3P)2 in the
Heck reaction of alkenyl chlorides with Cs2CO3 where the Pd-hydride
becomes the resting-state in the catalytic cycle; (a) I. D. Hills and G. C.
Fu, J. Am. Chem. Soc., 2004, 126, 13178–9; (b) A. F. Littke and G. C.
Fu, J. Org. Chem., 1999, 64, 10–11.
In conclusion, an efficient synthesis of ( )-frondosin B has been
achieved that utilises functional-group tolerant Stille and Heck
reaction protocols as key steps, providing an excellent opportunity
to explore different substituents and ring sizes in SAR studies of
the frondosins. The capacity to access both double isomers, 17a
and 17b, in this synthesis will improve our chances of achieving
an enantioselective hydrogenation using chiral catalysts, which is
currently under investigation. Furthermore, the preparation of the
2-chlorobenzo[b]furan-1-yl triflates and the selective substitution
of its OTf and Cl moieties using palladium catalysis is likely
to have broad applicability in the preparation of other 2,3-
disubstituted benzo[b]furans. In particular, the combination of
MWI and X-Phos ligands in promoting palladium mediated
reactions of aryl/alkenyl chlorides is also likely to find broader
applicability.
9 (a) D. Garc´ıa-Cuadrado, A. A. C. Braga, F. Maseras and A. M.
Echavarren, J. Am. Chem. Soc., 2006, 128, 1066; (b) J.-P. Ebran, H. L.
Hansen, T. M. Ggsig and T. Skrydstrup, J. Am. Chem. Soc., 2007, 129,
6931.
1292 | Org. Biomol. Chem., 2010, 8, 1290–1292
This journal is
The Royal Society of Chemistry 2010
©