Synthesis of novel pyranoquinones using an acyl radical cyclization strategy

Article abstract of DOI:10.1016/j.tetlet.2011.12.084

The thiol-catalysed cyclization of acyl radicals generated directly from benzaldehyde precursors has been investigated. Hindered β- benzyloxyacrylates cyclize efficiently providing a tin-free radical cyclization approach to the serine/threonine kinase AKT inhibitor frenolicin B, whilst γ-aryloxy crotonates give good yields of benzopyran-4-ones. This method is applied to the synthesis of a novel tetracyclic analogue of the pyranonaphthoquinone antibiotics.

Full text of DOI:10.1016/j.tetlet.2011.12.084

Tetrahedron Letters 53 (2012) 1105–1107
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel pyranoquinones using an acyl radical cyclization strategy
Christopher D. Donner a,b, , Myriam I. Casana c
⇑
a School of Chemistry, The University of Melbourne, Victoria 3010, Australia
b Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
c ECPM, School of Chemistry, Polymers and Materials Science, The University of Strasbourg, 67000 Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The thiol-catalysed cyclization of acyl radicals generated directly from benzaldehyde precursors has been
Received 2 November 2011
Revised 15 December 2011
Accepted 20 December 2011
Available online 30 December 2011
investigated. Hindered b-benzyloxyacrylates cyclize efficiently providing a tin-free radical cyclization
approach to the serine/threonine kinase AKT inhibitor frenolicin B, whilst c-aryloxy crotonates give good
yields of benzopyran-4-ones. This method is applied to the synthesis of a novel tetracyclic analogue of the
pyranonaphthoquinone antibiotics.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Acyl radical cyclization
Polarity reversal catalysis
Pyranonaphthoquinone
Frenolicin B
Amongst the increasing variety of precursors and reagents used
in radical reactions1 the aldehyde group is gaining popularity due
to its ability to form ketyl radicals under a variety of conditions.2,3
Additionally, and possibly more importantly, the subsequent reac-
tion of aldehyde-derived ketyl radicals results in the generation of
products with increased stereochemical complexity and retention
of functionality, an important consideration in the synthesis of
complex natural and unnatural molecules.3
The key step in our recent strategy for the synthesis of pyrano-
quinones was the cyclization of benzaldehyde precursors such as 3
(Scheme 1) via a ketyl radical intermediate. However, under these
conditions the undesired trans product 5 predominated (4:5 1:3.5,
59% yield).5 Thus, we sought other conditions under which the cis-
lactone 4 could be formed with greater selectivity and considered a
stereoselective reduction of ketone 6, which we planned to gener-
ate directly from benzaldehyde 3 by applying an acyl radical cycli-
zation. Whilst the direct formation of acyl radicals from aldehydes
is well known to proceed under conditions of polarity reversal
catalysis,9 few practical procedures that exploit this process have
As part of our ongoing interest in the synthesis of pyranoquinone
natural products,4 we recently applied a ketyl radical cyclization ap-
proach to a formal synthesis of frenolicin B (1),5 a potent inhibitor of
serine/threonine kinase AKT (AKT1 IC50 = 0.313 l
M),6 which is just
one member of a large family of pyranonaphthoquinone natural
products that show a broad range of antibiotic activities.7 The bioac-
tivity of this class of natural products, examples of which include
frenolicin B (1) and kalafungin (2), has been proposed to result from
a bioreductive alkylation mechanism, in which both the quinone
MeO
MeO
MeO
MeO
O
O
+
CO2Et
and c
-lactone moieties play essential roles.8,6b
Bu3SnH
AIBN
O
OH
OH
O
R
MeO
MeO
5
4
O
O
CO2Et
O
CHO
MeO
MeO
O
O
RSH
ABCN
O
O
3
1 frenolicin B (R=Pr)
2 kalafungin (R=Me)
CO2Et
O
6
⇑
Corresponding author. Tel.: +61 3 8344 2411; fax: +61 3 9347 8189.
E-mail address: cdonner@unimelb.edu.au (C.D. Donner).
Scheme 1. Radical cyclization strategies to benzopyrans.
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.084

1106
C. D. Donner, M. I. Casana / Tetrahedron Letters 53 (2012) 1105–1107
been reported. Tomioka and co-workers have described a thiol
-catalysed acyl radical cyclization approach in the formation of
carbocyclic systems from aldehyde precursors,10 a method we have
applied to the synthesis of dioxaspiro systems using b-disubsti-
tuted acrylate substrates.11 Herein we describe our recent
investigation into the cyclization of acyl radicals derived directly
from benzaldehydes and its application in the synthesis of novel
pyranoquinone structures.
R
R
R
CO2Et
O
O
a
CO2Et
CHO
O
R
13 R=H
R=OMe
14 R=H
6 R=OMe
3
Our initial investigation into the acyl radical cyclization of benz-
aldehydes began with the phenyl ether substrate 7 (Scheme 2),
which is readily prepared from salicylaldehyde.12 When 7 was sub-
jected to the reported thiol-mediated polarity reversal catalysis
conditions (tert-dodecanethiol, 1,10-azobis(cyclohexanecarbonitri-
le) [ABCN]),10,13 benzopyran-4-one 9 was formed in a 68% isolated
yield (with 26% recovered aldehyde). The conversion of 7 into 9, as
with the reported conversion of 8 into 10 (Scheme 2),10 represents
a radical equivalent of the Stetter reaction and thus an alternative
Scheme 3. Reagents and conditions: (a) t-C12H25SH (0.3 equiv), ABCN (0.3 equiv),
PhMe, reflux, 22 h (6 23% [48% recovered 3]).
MeO
MeO
CO2Et
O
O
a
CO2Et
CHO
MeO
O
method for the synthesis of c-ketoesters from formyl alkenoates.
MeO
16 β-Pr
15
Under Luche reduction conditions the alkyl group in 9 is ex-
pected to impart the desired syn selectivity.14 Thus, treatment of
9 with CeCl3 and NaBH4 gave the cis-lactone 11 in a 69% yield as
the exclusive product. Notably, the preparation of 11 and 12 has
previously been achieved directly from benzaldehyde 7 via a ketyl
radical cyclization, however, under these conditions an inseparable
mixture of 11 and 12 was obtained in a 1.6:1 ratio.15
We then explored the acyl radical cyclization of b-benzyloxyac-
rylates 3 and 13 (Scheme 3) as anticipated precursors to pyranoqui-
nones such as 1. Attempted acyl radical cyclization of the
unsubstituted benzaldehyde 13 resulted in only low (<10%) conver-
sion into the expected product 14. The more functionalized benzal-
dehyde 3, a substrate we previously used successfully under ketyl
radical cyclization conditions,5 gave a modest improvement in con-
version into the desired product 6 (a 23% isolated yield of 6, 44%
based on recovered 3). We have previously observed that competi-
tive decarbonylation of acyl radicals occurs in related aliphatic sys-
tems,11 however, recovery from these reactions of unchanged
benzaldehydes 13 and 3 shows that, as would be expected, decarb-
onylation of the acyl radical intermediate is not occurring in the
present case.
The difference in reactivity observed for substrates 7 and 8
(Scheme 2) as compared to benzyl ethers 3 and 13 (Scheme 3) indi-
cates that substrates containing a benzylic ether are not ideally sui-
ted for acyl radical formation/cyclization under the conditions
employed. Presumably, hydrogen atom abstraction by the thiyl rad-
ical is occurring from the activated benzylic C–H bond, as has been
observed in related ether16 and amine17 systems. This problem
could be circumvented by introducing further substitution at the
benzylic position. Subjecting the propyl-substituted precursor 155
to the acyl radical cyclization conditions resulted in the formation
17 α-Pr
c
b
MeO
OH
O
O
ref. 5
O
O
O
MeO
O
O
1
18 β-Pr
19 α-Pr
O
Scheme 4. Reagents and conditions: (a) t-C12H25SH (3.0 equiv), ABCN (1.0 equiv),
PhCl, 100 °C, 4 h (62%); (b) CeCl3ꢂ7H2O, NaBH4, CH2Cl2, MeOH, ꢁ78 °C, 1 h, then
pTsOHꢂH2O, CHCl3, 18 h (58%); (c) Bu3SnH, AIBN, benzene, reflux, 3 h (19 66%).5
of a mixture of diastereoisomeric benzopyrans in which the trans
product 16 predominates (16:17 ꢀ9:1) (Scheme 4). Reduction of
the inseparable ketones 16 and 17 under Luche conditions gave
the lactones 18 and 19 in a 58% yield. Notably, the cis,cis-stereoiso-
mer 19, the minor diastereoisomer in the present study, is obtained
as the major product when formed directly from benzaldehyde 15
via an O-stannylketyl radical cyclization.5 The two-step conversion
of 15 into 18 provides a tin-free alternative for the synthesis of fren-
olicin B (1) via radical cyclization methodology.
The successful acyl radical cyclization of phenyl ether 7 (Scheme
2) provided an incentive for us to explore the synthesis of pyrano-
naphthoquinones having isomeric heterocyclic systems to those
that occur naturally. To this end, 2,5-dimethoxysalicylaldehyde
(21) was firstly prepared from phenol 20 (Scheme 5) via ortho-lith-
iation of the corresponding THP–ether.18 Crotylation of 21 gave the
required cyclization precursor 22. Acyl radical cyclization of 22 pro-
ceeded smoothly to generate benzopyran 23 in a 64% yield and sub-
sequent Luche reduction gave exclusively the cis-lactone 24 in an
83% yield. Oxidation of benzopyran 24 was best achieved using
phenyliodine(III) bis(trifluoroacetate) (PIFA), conditions that gave
benzoquinone 25 in a 76% yield without dimerization taking place.19
The regioselective nature of Diels–Alder reactions between ben-
zoquinones and oxygenated butadienes is a well recognized meth-
od for the synthesis of naphthoquinones and a strategy we have
previously used to good effect in the synthesis of pyranonaphtho-
quinones.4b,c In the present case, the directing effects of both the
X
X
CO2Me
a
CO2Me
CHO
O
b
7 X=O
9 X=O
8 X=CH2
10 X=CH2
O
O
CO2Me
pyran oxygen substituent in 2520 and the
c
-lactone ring21 are
O
OH
complementary. Thus, the reaction of benzoquinone 25 with diene
26 gave a single regioisomeric product identified as naphthoqui-
none 27.22
In conclusion, the synthesis of pyranonaphthoquinone 27, a no-
vel analogue of the established bioactive natural product kalafungin
O
12
11
Scheme 2. Reagents and conditions: (a) t-C12H25SH (3.0 equiv), ABCN (1.5 equiv),
PhCl, 100 °C, 20 h (9 68%, 10 76%10); (b) CeCl3.7H2O, NaBH4, CH2Cl2, MeOH, ꢁ78 °C,
1 h, then pTsOH.H2O, CHCl3, 2 h (11 69%).

C. D. Donner, M. I. Casana / Tetrahedron Letters 53 (2012) 1105–1107
1107
MeO
MeO
MeO
MeO
MeO
MeO
O
CO2Me
O
O
OH
OH
a,b
c
d
CO2Me
CHO
22
CHO
MeO
MeO
23
20
21
e
OTMS
OMe
26
O
MeO
MeO
O
O
O
O
O
O
f
MeO
g
MeO
O
O
O
MeO
O
O
O
27
25
24
Scheme 5. Reagents and conditions: (a) 3,4-dihydro-2H-pyran, HCl; (b) n-BuLi, DMF, THF, ꢁ70 °C to rt, 3 h, then 6 M HCl (60%, 2 steps); (c) methyl 4-bromocrotonate, K2CO3,
DMF, 20 h (80%); (d) t-C12H25SH (3.0 equiv), ABCN (1.5 equiv), PhCl, 100 °C, 18 h (64%); (e) CeCl3ꢂ7H2O, NaBH4, CH2Cl2, MeOH, ꢁ78 °C, 1 h, then pTsOHꢂH2O, CHCl3 (83%); (f)
PIFA, MeCN, H2O, 1 h (76%); (g) CH2Cl2, 2 h, then SiO2, air, 1 h (55%).
Cai, P.; Levin, J. I.; Mansour, T. S.; Gibbons, J. J.; Abraham, R. T.; Yu, K. Mol. Cancer
Ther. 2007, 6, 3028–3038; (b) Salaski, E. J.; Krishnamurthy, G.; Ding, W.-D.; Yu,
K.; Insaf, S. S.; Eid, C.; Shim, J.; Levin, J. I.; Tabei, K.; Toral-Barza, L.; Zhang, W.-
(2), has been realized using an acyl radical cyclization and stereose-
lective reduction strategy. In addition, the tin-free acyl radical cycli-
zation conditions have been applied to the formal synthesis of
frenolicin B (1). The key radical-mediated hydroacylation step in this
strategy demonstrates an operationally simple alternative to the io-
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, 2181–2184.
7. Brimble, M. A.; Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999, 16, 267–281.
8. Moore, H. W. Science 1977, 197, 527–532.
nic Stetter reaction for the formation of c-ketoesters.
9. Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25–35.
10. Yoshikai, K.; Hayama, T.; Nishimura, K.; Yamada, K.; Tomioka, K. J. Org. Chem.
2005, 70, 681–683.
11. Aitken, H. M.; Schiesser, C. H.; Donner, C. D. Aust. J. Chem. 2011, 64, 409–415.
12. Ciganek, E. Synthesis 1995, 1311–1314.
Acknowledgments
Financial support from the Australian Research Council through
the Centres of Excellence program is gratefully acknowledged. Pro-
fessor Carl Schiesser, The University of Melbourne, and Professor
Philippe Renaud, University of Berne, are acknowledged for useful
discussions.
13. Representative procedure for acyl radical cyclization: A solution of benzaldehyde
7
(0.91 mmol) in PhCl (10 mL) with ABCN (1.37 mmol) and t-C12H25SH
(2.73 mmol) was flushed with argon for 30 min then heated at 100 °C for
20 h. After removal of the solvent in vacuo, purification by column
chromatography (EtOAc–PE, 1:2) gave benzopyran
9 (136 mg, 68% [92%
based on recovered 7]) and recovered benzaldehyde 7 (52 mg, 26%).
14. Hobson, S. J.; Parkin, A.; Marquez, R. Org. Lett. 2008, 10, 2813–2816.
15. Bentley, J.; Nilsson, P. A.; Parsons, A. F. J. Chem. Soc., Perkin Trans. 1 2002, 1461–
1469.
Supplementary data
16. Fielding, A. J.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 4061–4064.
17. (a) Escoubet, S.; Gastaldi, S.; Timokhin, V. I.; Bertrand, M. P.; Siri, D. J. Am. Chem.
Soc. 2004, 126, 12343–12352; (b) Escoubet, S.; Gastaldi, S.; Vanthuyne, N.; Gil,
G.; Siri, D.; Bertrand, M. P. Eur. J. Org. Chem. 2006, 3242–3250.
18. Wriede, U.; Fernandez, M.; West, K. F.; Harcourt, D.; Moore, H. W. J. Org. Chem.
1987, 52, 4485–4489.
19. Tohma, H.; Morioka, H.; Harayama, Y.; Hashizume, M.; Kita, Y. Tetrahedron Lett.
2001, 42, 6899–6902.
20. Tapia, R. A.; Algería, L.; Valderrama, J. A.; Cortés, M.; Pautet, F.; Fillion, H.
Tetrahedron Lett. 2001, 42, 887–889.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.084.
References and notes
1. For recent reviews, see: (a) Rowlands, G. J. Tetrahedron 2010, 66, 1593–1636;
(b) Rowlands, G. J. Tetrahedron 2009, 65, 8603–8655.
2. (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693–2698;
(b) Enholm, E. J.; Prasad, G. Tetrahedron Lett. 1989, 30, 4939–4942.
21. Kraus, G. A.; Li, J.; Gordon, M. S.; Jensen, J. H. J. Am. Chem. Soc. 1993, 115, 5859–
5860.
22. Selected physical and spectroscopic data for 27: mp 225–230 °C; 1H NMR
(CDCl3, 500 MHz) d 2.36 (1H, d, J 16.0 Hz), 2.93 (2H, m), 3.82 (1H, m), 3.96 (3H,
s), 3.97 (3H, s), 4.51 (1H, dd, J 11.6, 4.9 Hz), 5.53 (1H, d, J 5.3 Hz), 6.70 (1H, d, J
2.5 Hz), 7.33 (1H, d, J 2.5 Hz); 13C NMR (CDCl3, 125 MHz) d 31.1 (CH2), 31.8
(CH), 56.1, 56.5 (CH3), 66.0 (CH2), 68.5, 103.7, 103.9 (CH), 113.2, 114.7, 136.0,
158.2, 162.6, 165.6, 174.0, 175.8, 182.5 (C); IR (neat) 2949, 1767, 1665, 1631,
1595, 1336, 1236, 1217, 1160 cmꢁ1; HRMS (ESI) found 331.0813, C17H15O7
[M+H]+ requires 331.0812.
3. (a) Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005, 61, 10377–10441; (b)
Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371–3403; (c)
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237–1286.
4. (a) Donner, C. D. Tetrahedron Lett. 2007, 48, 8888–8890; (b) Tewierik, L. M.;
Dimitriadis, C.; Donner, C. D.; Gill, M.; Willems, B. Org. Biomol. Chem. 2006, 4,
3311–3318; (c) Donner, C. D.; Gill, M. J. Chem. Soc., Perkin Trans. 1 2002, 938–948.
5. Donner, C. D. Synthesis 2010, 415–420.
6. (a) Toral-Barza, L.; Zhang, W.-G.; Huang, X.; McDonald, L. A.; Salaski, E. J.;
Barbieri, L. R.; Ding, W.-D.; Krishnamurthy, G.; Hu, Y. B.; Lucas, J.; Bernan, V. S.;