Expedient synthesis of ialibinones A and B by manganese(III)-mediated oxidative free radical cyclisation

Article abstract of DOI:10.1016/j.tetlet.2010.07.025

The tricyclic natural products ialibinone A and ialibinone B were prepared as a 41:59 mixture in four steps starting from phloroglucinol. The synthetic sequence involved (i) acylation of phloroglucinol under Friedel-Crafts conditions, (ii) double prenylat

Full text of DOI:10.1016/j.tetlet.2010.07.025

Tetrahedron Letters 51 (2010) 4823–4826
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expedient synthesis of ialibinones A and B by manganese(III)-mediated
oxidative free radical cyclisation
*
Nigel S. Simpkins , Michael D. Weller
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The tricyclic natural products ialibinone A and ialibinone B were prepared as a 41:59 mixture in four
steps starting from phloroglucinol. The synthetic sequence involved (i) acylation of phloroglucinol under
Friedel–Crafts conditions, (ii) double prenylation using phase-transfer methodology, (iii) dearomatising
methylation, and (iv) oxidative free radical cyclisation using manganese(III) acetate.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 May 2010
Revised 24 June 2010
Accepted 5 July 2010
Available online 4 August 2010
Keywords:
Acylphloroglucinol
Dearomatisation
Free radical cyclisation
Electron-rich aromatics
Total synthesis
COPh
OH
R
O
R
O
Recent years have witnessed sustained interest in the synthesis
of members of the polyprenylated polycyclic acylphloroglucinol
(PPAP) family of natural products.1 This reflects both the synthetic
challenge presented by the complex functionalised frameworks of
these structures and the diverse biological properties that they
possess.
O
O
OH
R
O
O
i
R
R
Ph(O)C
Pr(O)C
OH
H
O
R
R
R
Like several other groups, we have focused our attention on key
representatives of this family possessing a core bicyclo[3.3.1]non-
ane structure, for example, clusianone (1), nemorosone (2) and
garsubellin A (3), Figure 1.2
1
2
3
Figure 1. Bicyclo[3.3.1]nonane PPAP structures (R = prenyl).
Total syntheses of 1–3 have employed diverse strategies for
assembling the core structure, including malonyl dichloride enol
ether annulation,2,3 iodonium-induced cyclisation,4 ring-closing
metathesis5 and dearomatising Michael addition.6 Most recently,
Shibasaki and co-workers described the synthesis of hyperforin
using an aldol reaction to close the bicyclic core structure.7
These syntheses tend to involve many steps, and efforts to de-
velop shorter biomimetic routes have also been described, most
notably employing cationic cyclisations or by manganese(III)-med-
iated oxidative cyclisation.8,9 This last approach appeared to us to
be applicable to the synthesis of more unusual types of PPAP hav-
ing a bicyclo[3.2.1]octane core, for example, enaimeone A (4), aiss-
atone (5), epimeric takaneones A and B (6) and ialibinones A and B
(7), Figure 2.10–12
i
O
Pr
O
Me
OH
O
OH
Me
O
R
R
O
O
H
OH
5
4
i
O
O
Pr
i
R
Pr
O
O
O
OH
Me
Me
COMe
In these cases, the key cyclisation step for assembling the core
structure is required to proceed with complimentary regiochemist-
O
O
H
H
6
7
* Corresponding author. Tel.: +44 (0)121 414 8905; fax: +44 (0)121 414 4403.
E-mail address: n.simpkins@bham.ac.uk (N.S. Simpkins).
Figure 2. Bicyclo[3.2.1]octane PPAP structures (R = prenyl).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.025

4824
N. S. Simpkins, M. D. Weller / Tetrahedron Letters 51 (2010) 4823–4826
ry, compared to the established methods for the [3.3.1] systems
such as 1–3. Here we describe a particularly rapid access to ialibi-
nones A and B (7), using an oxidative cyclisation approach, which
mimics the likely biosynthesis of these compounds.
The epimeric ialibinones A and B (7) were isolated, along with
three other closely related substances, from the leaves of Hyperi-
cum papuanum, by Sticher and co-workers in 2000.11 They feature
an interesting tricyclic core which is very closely related to that in
the takaneones A–C.10c,13 They exhibit antibacterial activity against
Bacillus cerus, Staphylococcus epidermidis and Micrococcus luteus,
and are also cytotoxic against KB cell lines.10a,11
Owing to these intriguing properties, and their structural simi-
larity to several of our previous PPAP targets, we elected to inves-
tigate a short total synthesis of ialibinones A and B (7). Our
proposed synthesis is outlined in retrosynthetic form in Scheme 1.
Key to this approach is the aforementioned manganese(III)-
mediated cyclisation, which we required to effect an oxidative free
radical cascade, initiating at C-1 in intermediate 8, and proceeding
by two successive 5-exo-trig cyclisations to give 7. Whilst this ap-
peared eminently reasonable, we were mindful of the previous
applications of the Mn(III) chemistry in the arena of PPAP construc-
tion, Scheme 2.9,14
O
OEt
O
OEt
O
O
Mn(OAc)
3
Cu(OAc)
AcOH
2
10
11 60%
O
Ph
O
Ph
3
O
OH
Pr
O
O
H
Mn(OAc)
Cu(OAc)
3
Et
2
Pr
AcOH
Pr
OMe
OMe
12
13 66%
Scheme 2. PPAP synthesis using Mn(III)-mediated oxidative cyclisations.
O
iPr
HO
OH
(i)iPrCOCl, AlCl3
HO
OH
In the cyclisation of keto ester 10 to give a simple PPAP model
11, Kraus and co-workers indicated that less than 5% of the corre-
sponding [3.2.1] system was produced.14a,b Cyclisation of derivatives
such as 12 was found to proceed via an apparent 8-endo mode of
cyclisation, to give 13, by initiation at C-3, although here the regi-
oselectivity is controlled by partial O-methylation of the core ring.
With issues of regiocontrol being a remaining concern, we set
about the preparation of the key intermediate 8, Scheme 3.15
The bis-prenylated acylphloroglucinol 15 was prepared in two
steps from phloroglucinol by Friedel–Crafts acylation (to give 9)
followed by double prenylation of the electron-rich benzene ring,
Scheme 3.16 At this point, our synthesis required regioselective
addition of a methyl group with concomitant dearomatisation of
the phloroglucinol core. After experimentation, we observed that
treatment of 15 with sodium methoxide (5 equiv) and iodometh-
ane (5 equiv) at À20 °C, followed by warming of the reaction mix-
ture to 0 °C, gave 8 in a satisfactory yield of 70%. Since the
methylated compound 8 was obtained as a complex mixture of
tautomers, it was converted selectively into enol acetate 16, by
treatment with Ac2O in pyridine, to facilitate the complete assign-
ment of its 1H and 13C NMR spectra.8,17,18 We were now in a posi-
tion to investigate the key oxidative cyclisation, which was carried
out using the classic Snider protocol,14 Scheme 4.
(ii) prenyl bromide, pH 12
[ref. 16]
OH
OH
15
14
47% (2 steps)
O
iPr
O
OH
NaOMe, MeI
MeOH
OX
º
º
-20 C to 0 C
8 X = H 70%
16 X = Ac 73%
Ac2O, pyr
Scheme 3. Synthesis of key intermediate 8.
O
iPr
O
iPr
HO
O
HO
+
O
Mn(OAc)3
Exposure of 8 to Mn(OAc)3 (2 equiv) and Cu(OAc)2 (1 equiv) in
acetic acid led to a very rapid consumption of the starting material
and formation of the target natural products, ialibinone A (7a) and
ialibinone B (7b), as an inseparable mixture (by column chroma-
tography) in 35% overall yield.19
8
Cu(OAc)2
AcOH
O
O
H
H
7b
35%
7a
Full characterisation of our final product was hampered by the
presence of two epimers—each of which exists in a mixture of tau-
tomeric forms. The initial evidence for the formation of ialibinones
Scheme 4. Synthesis of ialibinone A (7a) and ialibinone B (7b).
A and B was provided by the 13C NMR data of the mixture of 7a and
7b which closely matched that reported by Sticher and co-work-
ers.11 Two components in a ratio of 41:59 (subsequently deter-
mined to be 7a:7b) were observed by analytical HPLC, indicating
that the double cyclisation was very weakly diastereoselective.
The mixture was subsequently separated by reversed-phase HPLC
using a semi-prep C18(2) column to afford purified samples of 7a
and 7b.19 The separated epimers of 7 provided spectroscopic data
in complete accord with those described previously, and in both
cases, the major tautomeric isomer is apparently the one shown
in Scheme 4.20
i
i
O
Pr
O
Pr
i
O
Pr
3
O
OH
O
OH
HO
OH
1
O
OH
OH
H
7
8
9
Given the established reactivity of compound 12 at C-3, we
might have expected to observe product formation arising from
Scheme 1. Retrosynthesis of ialibinones A and B (1).

N. S. Simpkins, M. D. Weller / Tetrahedron Letters 51 (2010) 4823–4826
4825
13. An enantiospecific approach to the tricyclic core structure of ialibinones and
takaneones has been reported previously: Srikrishna, A.; Beeraiah, B.; Gowri, V.
Tetrahedron 2009, 65, 2649–2654.
14. (a) Kraus, G. A.; Dneprovskaia, E.; Nguyen, T. H.; Jeon, I. Tetrahedron 2003, 59,
8975–8978; (b) Cole, B. M.; Han, L.; Snider, B. B. J. Org. Chem. 1996, 61, 7832–
7847; For a review of manganese(III)-mediated radical cyclisation, see: (c)
Snider, B. B. Chem. Rev. 1996, 96, 339–363.
15. Despite our concerns regarding the regiocontrol of cyclisation, 5-exo-trig
cyclisations are known, for example: Pettus, T. R. R.; Chen, X.-T.; Danishefsky, S.
J. J. Am. Chem. Soc. 1998, 120, 12684–12685.
16. Burckhardt, U.; Werthemann, L.; Troxler, R. J. U.S. Patent 4,101,585, 1978 (CAN
89:6114).
this mode of reaction with our acylphloroglucinol derivative 8.
However, we were unable to isolate any regioisomeric products
from the reaction mixture, and the substantial mass loss presum-
ably represents over-oxidation, which is a known issue in these
processes.14c Interestingly, attempts to change the regioselectivity
of the cyclisation by oxidation of acetate derivative 16 were unsuc-
cessful, this compound being unreactive under the conditions used
for compound 8.
To conclude, we have described a facile access to ialibinones A
and B, which are the first PPAP natural products having a core bicy-
clo[3.2.1]octane structure to be synthesised. In terms of bond for-
mation, our synthesis can be considered biomimetic, although
whether compounds such as ialibinones arise in Nature through
radical or cationic intermediates is unclear. The 5-exo mode of ini-
tial ring formation contrasts with that seen in the examples in
Scheme 2, and it appears that the regiochemistry of initial bond
formation and the ring size formed might be controllable by vary-
ing the substituent pattern in the starting material, and by the judi-
cious use of enol derivatives. We are currently exploring these
avenues in more detail.
17. Tagashira, M.; Watanabe, M.; Uemitsu, N. Biosci. Biotech. Biochem. 1995, 59,
740–742.
18. Enol acetate 16 (from 15): NaOMe (423 mg, 7.83 mmol) was added in one
portion to a solution of acylphloroglucinol 15 (520 mg, 1.57 mmol) in MeOH
(15 mL) at À20 °C. After 15 min, MeI (488
lL, 7.83 mmol) was added at
À20 °C. The reaction mixture was allowed to warm to 0 °C and after 1 h,
satd aq NH4Cl solution (25 mL) was added. The layers were separated and
the aqueous layer was extracted with EtOAc (3 Â 25 mL). The combined
organic layers were washed with H2O (3 Â 25 mL), brine (3 Â 25 mL), and
dried (Na2SO4). The solvent was removed under reduced pressure and the
purification of the residue by flash column chromatography (10% EtOAc in
petroleum ether) gave the methylated product 8 as a yellow oil (379 mg,
70%); selected data: Rf = 0.43 (20% EtOAc in petroleum ether); m/z (TOF ES-)
377.3 ([M+MeOHÀH]À, 38%), 345.3 (100, [MÀH]À); HRMS m/z (TOF ES-)
found (MÀH)À 345.2063. C21H29O4 requires 345.2066. For the acetylation
step, Ac2O (414 lL, 4.38 mmol) and pyridine (442 lL, 5.47 mmol) were
added to a solution of 8 (379 mg, 1.09 mmol) in acetone (12 mL). After 1 h,
satd aq NH4Cl solution (25 mL) was added and the work-up procedure of
the previous step was repeated. The solvent was removed under reduced
pressure and purification of the residue by flash column chromatography
Acknowledgements
We thank the Engineering and Physical Sciences Research
(5% EtOAc in petroleum ether) gave enol acetate 16 as
(309 mg, 73%); Rf = 0.57 (20% EtOAc in petroleum ether);
a
m
colourless oil
Council (EPSRC) for
a research fellowship (to M.D.W.). The
max(film)/cmÀ1
NMR instruments used in this research were obtained through
Birmingham Science City: Innovative Uses for Advanced Materi-
als in the Modern World (West Midlands Centre for Advanced
Materials Project 2), with support from Advantage West Mid-
lands (AWM) and part funded by the European Regional Devel-
opment Fund (ERDF).
2971w, 2932m, 1778m (C@O), 1667 m (C@O), 1642s (C@O), 1535s, 1438s,
1366 m, 1186vs, 1153vs, 1091s, 883w; dH (300 MHz, CDCl3) mixture of two
tautomers: 1.11–1.18 (12H, m), 1.27 (3H, s), 1.40 (3H, s), 1.51–1.59 (12H,
m), 1.65–1.71 (12H, m), 2.26 (3H, s), 2.27 (3H, s), 2.34 (dd, J 13.7, 7.5, 1H),
2.44 (dd, J 13.8, 7.4, 1H), 2.63 (app. td, J 14.0, 8.2, 2H), 2.83 (app. td, J 15.3,
7.3, 2H), 3.08 (dd, J 15.3, 6.9, 2H), 3.98 (septet, J 6.8, 1H), 4.11 (septet, J 6.8,
1H), 4.75–4.87 (2H, m), 4.94–5.05 (2H, m); dC (100 MHz, CDCl3) mixture of
two tautomers: 17.7, 17.8, 18.67, 18.71, 18.8, 19.0, 20.6, 22.3, 22.5, 23.3,
23.6, 25.66, 25.72, 25.74, 25.8, 35.6, 36.5, 37.8, 38.9, 48.9, 53.8, 108.1, 110.4,
117.4, 118.1, 120.1, 120.9, 124.7, 129.1, 132.1, 133.0, 135.2, 136.1, 157.2,
162.7, 166.8, 167.0, 183.3, 189.2, 195.6, 196.8, 208.7, 210.8 (1 resonance
obscured); m/z (EI) 388 ([M]+, 5%), 318 (70, [MÀCOiPr+H]+), 276 (88,
[MÀCOiPr-Ac+2H]+), 234 (100); HRMS m/z (EI) found (M)+ 388.2232.
We also thank Graham D. Burns for assistance with HPLC.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.025.
C23H32O5 requires 388.2250.
19. Ialibinone A (7a) and ialibinone
B
(7b): Manganese(III) acetate dihydrate
(379 mg, 1.41 mmol) and copper(II) acetate monohydrate (141 mg, 0.71 mmol)
were added to a solution of 8 (245 mg, 0.71 mmol) in glacial AcOH (15 mL) at
room temperature. After 30 min, the reaction mixture was diluted with
petroleum ether (20 mL) and filtered through a short silica plug, eluting with
20% Et2O in petroleum ether (60 mL). The solvent was removed under reduced
pressure and purification of the residue by flash column chromatography (10%
Et2O in petroleum ether) gave a 41:59 mixture of ialibinone A (7a) and
References and notes
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2010, 49, 1103–1106.
ialibinone
B (7b) as a yellow oil (85 mg, 35%); Rf = 0.50 (20% EtOAc in
petroleum ether). The mixture was separated by reversed-phase HPLC using a
Phenomenex Luna C18(2) semi-prep column and MeCN–H2O–TFA
(70:29.95:0.05) as the eluent. The retention times (25 °C, flow rate: 3 mL/
min) were as follows: ialibinone A (7a) 49.6 min; ialibinone B (7b) 53.4 min.
After separation, the MeCN was removed under reduced pressure and the
aqueous layer was extracted with Et2O (3 Â 20 mL). The combined organic
layers were washed with brine (20 mL) and dried (Na2SO4). Removal of the
solvent under reduced pressure afforded the title compounds as yellow oils
(24 mg of 7a and 36 mg of 7b). Ialibinone A (7a): m
max(CHCl3)/cmÀ1 3382w br
(O–H), 2969s, 2872 m, 1763s (C@O), 1668s (C@O), 1546s, 1458 m, 1321 m,
1216m, 1092w, 894m, 758s; dH (300 MHz, CDCl3) mixture of two tautomers:
0.81–0.87 (3H, m, including [0.83 (s), 0.86 (s)]), 0.94–1.00 (3H, m, including
[0.97 (s), 0.98 (s)]), 1.08–1.22 (6H, m, including [1.11 (d, J 6.8), 1.15 (d, J 6.8),
1.20 (d, J 6.8)]), 1.32–1.41 (3H, m, including [1.33 (s), 1.39 (s)]), 1.61–1.75 (1H,
m), 1.75–1.79 (3H, m, including [1.76 (s), 1.78 (s)]), 2.00–2.57 (5H, m), 3.86–
4.08 (1H, m, including [3.94 (sept, J 6.8), 4.01 (sept, J 6.8)]), 4.73–4.82 (1H, m),
4.89–4.97 (1H, m), OH resonance outside of the range; dC (100 MHz, CDCl3)
mixture of two tautomers: 12.4, 13.1, 18.5, 18.6, 19.0, 19.2, 23.56, 23.62, 24.38,
24.44, 24.9, 25.70, 25.74, 25.8, 33.4, 34.3, 34.4, 34.8, 42.8, 43.4, 54.5, 54.9, 55.5,
57.7, 61.3, 65.1, 67.9, 72.1, 109.4, 109.6, 113.45, 113.52, 143.2, 143.3, 191.0,
194.6, 200.1, 201.6, 206.1, 207.0, 207.6, 208.6; m/z (TOF ES-) 343.1 ([MÀH]À,
100%); HRMS m/z (TOF ES-) found (MÀH)À 343.1906. C21H27O4 requires
8. Couladouros, E. A.; Dakanali, M.; Demadis, K. D.; Vidali, V. P. Org. Lett. 2009, 11,
4430–4433.
9. Mitasev, B.; Porco, J. A., Jr. Org. Lett. 2009, 11, 2285–2288.
10. (a) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. Helv. Chim. Acta
2001, 84, 3380–3392; (b) Baldé, A. M.; Pieters, L.; Apers, S.; De Bruyne, T.; Van
den Heuvel, H.; Claeys, M.; Vletinck, A. J. Nat. Prod. 1999, 62, 364–366; (c)
Tanaka, N.; Kashiwada, Y.; Sekiya, M.; Ikeshiro, Y.; Takaishi, Y. Tetrahedron Lett.
2008, 49, 2799–2803.
11. Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J. Nat. Prod. 2000,
63, 104–108.
343.1909. Ialibinone
B (7b): m
max(CHCl3)/cmÀ1 3326w br (O–H), 2969m,
2873m, 1759s (C@O), 1668s (C@O), 1548s, 1455m, 1324m, 1174w, 1094w,
891m, 757m; dH (300 MHz, CDCl3) mixture of two tautomers: 0.54–0.61 (3H,
m, including [0.57 (s), 0.58 (s)]), 0.93–1.00 (3H, m, including [0.95 (s), 0.97 (s)]),
1.08–1.22 (6H, m, including [1.13 (d, J 6.8), 1.14 (d, J 6.8), 1.18 (d, J 6.8)]), 1.29–
1.40 (3H, m, including [1.31 (s), 1.38 (s)]), 1.70–1.91 (4H, m, including [1.77 (s),
1.79 (s), 1.86 (dd, J 12.4, 4.9)]), 2.03–2.32 (3H, m), 2.37–2.57 (2H, m), 3.92–4.14
12. Other structurally related compounds include tricycloillicinone and semi-
synthetic transformation products of humulone and colupulone: (a)
Fukuyama, Y.; Shida, N.; Kodama, M.; Chaki, H.; Yugami, T. Chem. Pharm.
Bull. 1995, 43, 2270–2272; (b) John, G. D.; Shannon, P. V. R. J. Chem. Soc., Perkin
Trans. 1 1978, 1633–1636; (c) De Potter, M.; De Keukeleire, D.; De Bruyn, A.;
Verzele, M. Bull. Soc. Chim. Belg. 1978, 87, 459–469.

4826
N. S. Simpkins, M. D. Weller / Tetrahedron Letters 51 (2010) 4823–4826
(1H, m), 4.73–4.86 (1H, m), 4.92–5.02 (1H, m), OH resonance outside of the
(TOF ES-) 343.1 ([MÀH]À, 100%); HRMS m/z (TOF ES-) found (MÀH)À 343.1911.
range; dC (100 MHz, CDCl3) mixture of two tautomers: 12.4, 13.1, 16.4, 16.9,
18.7, 18.8, 18.85, 18.91, 23.7, 23.8, 24.2, 24.9, 27.2 (Â2), 31.1, 32.7, 34.7, 35.0,
44.8, 45.1, 55.8, 58.14, 58.47, 58.6, 62.1, 66.2, 68.3, 72.4, 107.9, 108.0, 113.6,
113.8, 142.8, 143.0, 191.0, 193.6, 200.3, 201.7, 206.7, 207.3, 209.1, 209.6; m/z
C21H27O4 requires 343.1909.
20. Winkelmann et al. (Ref. 11) propose that there is a destabilising effect of the
neighbouring five-membered ring system on the enolic hydroxy group relative
to the methyl substituent.