Synthesis of the griseusin B framework via a one-pot annulation- methylation-double deprotection-spirocyclization sequence

Article abstract of DOI:10.1021/ol400686f

A highly convergent synthesis of the griseusin B scaffold is described. The key step involves an efficient one-pot Hauser-Kraus annulation-methylation- double deprotection-spirocyclization sequence that directly affords the target parent tetracyclic ring system.

Full text of DOI:10.1021/ol400686f

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2006–2009
Synthesis of the Griseusin B
Framework via a One-Pot
AnnulationꢀMethylationꢀDouble
DeprotectionꢀSpirocyclization Sequence
Briar J. Naysmith and Margaret A. Brimble*
School of Chemical Sciences, The University of Auckland, 23 Symonds Street,
Auckland, New Zealand
m.brimble@auckland.ac.nz
Received March 14, 2013
ABSTRACT
A highly convergent synthesis of the griseusin B scaffold is described. The key step involves an efficient one-pot HauserꢀKraus
annulationꢀmethylationꢀdouble deprotectionꢀspirocyclization sequence that directly affords the target parent tetracyclic ring system.
The griseusins are a subgroup of the pyranonaphtho-
quinone family of natural products1 that contain a 6,6-
spiroketal ring fused to a juglone moiety. The first in the
family to be isolated were griseusins A 1 and B 2 from a
Streptomyces griseus K-63 bacterium found in a soil
sample in 1976 (Figure 1).2 1 contains a closed γ-lactone
ring whereas in 2 the lactone is opened to the carboxylic
acid. Since then, 15moregriseusin naturalproducts(3ꢀ17)
(Figure 1)3 have been isolated that differ in oxygenation
patterns and stereochemistry around the spiroketal ring,
with variable substitution at C-9 of the dihydropyran ring
and the C2aꢀC8a quinone double bond. 30-O-R-D-
Forosaminyl-(þ)-griseusin A 8 possesses an additional
sugar moiety3a while yoropyrazone 14 contains a novel
amide side chain and a fused 2-pyridazone ring.3g The
griseusins demonstrate a variety of antibacterial and anti-
cancer properties.2,3 Pyranonaphthoquinones in general
have been proposed to act as bioreductive alkylating
agents4 and also exhibit selective inhibitory activity against
serine/threonine AKT,5 both of which may contribute to
their mechanism of action against cancer cells. This attrac-
tive biological profile, combined with their intricate struc-
tures, makes the griseusins and their analogues appealing
synthetic targets. Our group is interested in the synthesis of
analogues of the griseusins and other pyranonaphthoqui-
nones for biological evaluation as part of an ongoing
medicinal chemistry program.6 To date, there has only
(1) For an extensive review on pyranonaphthoquinones, see: Sperry,
J.; Bachu, P.; Brimble, M. A. Nat. Prod. Rep. 2008, 25, 376.
(2) Tsuji, N.; Kobayashi, M.; Wakisaka, Y.; Kawamura, Y.;Mayama,
M.; Matsumoto, K. J. Antibiot. 1976, 29, 7.
(4) Moore, H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249.
(5) 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.-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.
(6) (a) Sperry, J.; Lorenzo-Castrillejo, I.; Brimble, M. A.; Machin, F.
Bioorg. Med. Chem. 2009, 17, 7131. (b) Hume, P. A.; Sperry, J.; Brimble,
M. A. Org. Biomol. Chem. 2011, 9, 5423. (c) Bridewell, D. J. A.; Sperry,
J.; Smith, J. R.; Kosim-Satyaputra, P.; Ching, L.-M.; Jamie, J. F.;
Brimble, M. A. Aust. J. Chem. 2013, 66, 40.
(3) (a) Maruyama, M.; Nishida, C.; Takahashi, Y.; Naganawa, H.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1994, 47, 952. (b) Igarashi, M.;
Chien, W.; Tsuchida, T.; Umekita, M.; Sawa, T.; Naganawa, H.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1995, 48, 1502. (c) Li, X.; Zheng,
Y.; Sattler, I.; Lin, W. Arch. Pharmacal Res. 2006, 29, 942. (d) Li, Y.-Q.;
Li, M.-G.; Li, W.; Zhao, J.-Y.; Ding, Z.-G.; Cui, X.-L.; Wen, M.-L.
J. Antibiot. 2007, 60, 757. (e) He, J.; Roemer, E.; Lange, C.; Huang, X.;
Maier, A.; Kelter, G.; Jiang, Y.; Xu, L.-H.; Menzel, K.-D.; Grabley, S.;
Fiebig, H.-H.; Jiang, C.-L.; Sattler, I. J. Med. Chem. 2007, 50, 5168.
(f) Abdelfattah, M. S.; Kazufumi, T.; Ishibashi, M. J. Antibiot. 2011, 64,
729. (g) Abdelfattah, M. S.; Toume, K.; Ishibashi, M. J. Antibiot. 2012,
65, 245. (h) Ding, Z.-G.; Zhao, J.-Y.; Li, M.-G.; Huang, R.; Li, Q.-M.;
Cui, X.-L.; Zhu, H.-J.; Wen, M.-L. J. Nat. Prod. 2012, 75, 1994.
(7) Kometani, T.; Takeuchi, Y.; Yoshii, E. J. Org. Chem. 1983, 48,
2311.
r
10.1021/ol400686f
Published on Web 04/05/2013
2013 American Chemical Society

Figure 1. Structures of the griseusin family of natural products.
been one total synthesis of griseusins A 1 and B 27 although
a number of syntheses of griseusin analogues have been
published.8
Scheme 1. Retrosynthesis of Griseusin B Analogue, 18
Based on previous syntheses of simpler pyranonaphtho-
quinones,9 we focused the current researchon construction
of the pyranonaphthoquinone framework of griseusin B 2
using a HauserꢀKraus (HK) annulation strategy in order
to develop a highly convergent synthetic route that could
be easily adapted to the synthesis of the natural products
and other analogues. We herein report the synthesis of
the griseusin B analogue 18. Our retrosynthetic analysis
of 18 relied on deprotection and spirocyclization of an
advanced precursor 19, itself available from HK annula-
tion between stabilized phthalide 20 and chiral enone
21 (Scheme 1). Enone 21 can in turn be accessed via a
HornerꢀWadsworthꢀEmmons (HWE) reaction between
saturated phosphonate 22 and aldehyde 23.
Thus, our synthesis began with the preparation of the
phosphonate coupling partner 22 (Scheme2). (R)-Propylene
oxide 24 was opened with the anion of commercially avail-
able ethyl propiolate 2510 followed by TBS protection of the
newly formed secondary alcohol and subsequent hydroge-
nation under standard conditions to give ester 26. Addition
Scheme 2. Synthesis of Phosphonate, 22
(8) (a) Masamoto, K.; Takeuchi, Y.; Takeda, K.; Yoshii, E. Hetero-
cycles 1981, 16, 1659. (b) Kometani, T.; Takeuchi, Y.; Yoshii, E. J. Org.
Chem. 1982, 47, 4725. (c) Brimble, M. A.; Nairn, M. R. J. Chem. Soc.,
Perkin Trans. 1 1990, 169. (d) Brimble, M. A.; Nairn, M. R. J. Chem.
Soc., Perkin Trans. 1 1992, 579. (e) Brimble, M. A.; Nairn, M. R.
Molecules 1996, 1, 3. (f) Brimble, M. A.; Nairn, M. R.; Park, J. Org. Lett.
1999, 1, 1459. (g) Brimble, M. A.; Nairn, M. R.; Park, J. S. O. J. Chem.
Soc., Perkin Trans. 1 2000, 697.
(9) (a) Gibson, J. S.; Andrey, O.; Brimble, M. A. Synthesis 2007,
2611. (b) Andrey, O.; Sperry, J.; Larsen, U. S.; Brimble, M. A. Tetra-
hedron 2008, 64, 3912. (c) Brimble, M. A.; Gibson, J. S.; Sejberg, J. J. P.;
Sperry, J. Synlett 2008, 867. (d) Sperry, J.; Gibson, J. S.; Sejberg, J. J. P.;
Brimble, M. A. Org. Biomol. Chem. 2008, 6, 4261.
of lithiated dimethyl methylphosphonate11 afforded the
R-keto phosphonate 22 in good yield over four steps.
(12) (a) Robinson, J. E.; Brimble, M. A. Org. Biomol. Chem. 2007, 5,
2572. (b) Matsuura, F.; Peters, R.; Anada, M.; Harried, S. S.; Hao, J.;
Kishi, Y. J. Am. Chem. Soc. 2006, 128, 7463.
(10) Tan, N. P. H.; Donner, C. D. Tetrahedron 2009, 65, 4007.
(11) McLeod, M. C.; Wilson, Z. E.; Brimble, M. A. J. Org. Chem.
2012, 77, 400.
(13) Uenishi, J. I.; Ohmi, M. Angew. Chem., Int. Ed. 2005, 44, 2756.
Org. Lett., Vol. 15, No. 8, 2013
2007

The aldehyde coupling partner 23 was synthesized in six
steps according to literature methods,12 using the chiral
pool material L-aspartic acid 27 as the source of the
β-hydroxy chiral center (Scheme 3). HWE reaction of
aldehyde 23 with phosphonate 22 using mild biphasic
conditions13 proceeded smoothly forming the highly sub-
stituted E-enone 21 required for the key annulation step.
Scheme 5. Synthesis of Spiroketal, 32
Scheme 3. Synthesis of Enone, 21
Synthesis of the cyanophthalide coupling partner 20 for
the HK annulation was carried out from commercially
available o-anisic acid 28 (Scheme 4). 28 was converted to
the corresponding amide 29 using a mild procedure involv-
ing activation as the N-hydroxysuccinimide (NHS) ester
followed by substitution with diethylamine in one pot.14
Phthalide 20 was generated over two additional steps from
amide 29 using literature procedures.9c,15
Table 1. HK Annulation of Enone, 21 (1 equiv), and Phthalide, 20
annulation
conditionsa
methylation
conditionsa
Scheme 4. Synthesis of Cyanophthalide, 20
entry
20
t-BuOK
NaOH
Me2SO4
yield 32
two step processb
1
2
3
1.1
1.2
1.4
1.2
20
30
30
30
45
40
10%
15%
18%
1.3
1.5
one-pot processc
Attention was next turned to the key HK annulation
reaction of phthalide 20 with enone 21, first attempted
using procedures that had previously proven successful in
our group (Scheme 5).16 HK annulations are known to
form a mixture of quinone and hydroquinone products.
Therefore, it was our intention to effect the annulation
using t-BuOK as the base followed by trapping the hydro-
quinone as a dimethyl ether. This can be achieved by fully
reducing the quinone to the hydroquinone using Na2S2O4
under hydrogen followed by the addition of base and
Me2SO4.16 Accordingly, the annulation was carried out with
t-BuOK in DMSO until TLC indicated complete consump-
tion of enone 21. The crude annulation mixture was then
subjected to reductive methylation conditions overnight
(Table 1, entry 1). Extraordinarily, the sole product isolated
was not the expected methylated hydroquinone 19, but the
double TBS-deprotected and spirocyclized product 32
(Scheme 5). It is remarkable that these seven transformations
4
5
1.9
2.2
1.5
2.0
30
30
40
40
32%
49%
a Equivalents relative to 21. b Annulation in DMSO, reduction/methy-
lation in THF (see Supporting Information). c Annulation/methylation in
one pot in THF.
take place in a simple reaction sequence. The anion of
phthalide 20 undergoes Michael addition to enone 21
followed by Dieckmann-like condensation and oxidation
to form the bicyclic system. Equilibrium between the
quinone 30 and hydroquinone 31 products is pushed
toward 31 by reduction and trapping as the dimethoxy-
hydroquinone 19. Double TBS deprotection forms the
dihydroxyketone 33, followed by spirocyclization to
give the isolated spiroketal product 32. Intermediate 19
could be observed by TLC and isolated in small amounts,
suggesting that methylation occurs prior to TBS depro-
tection and spirocyclization. An increase in yield from
10% to 18% was achieved by adding more phthalide
20 and base to the annulation reaction, as well as
additional base and Me2SO4 in the methylation step
(Table 1, entries 3ꢀ4).
(14) Cline, G. W.; Hanna, S. B. J. Am. Chem. Soc. 1987, 109, 3087.
(15) de Silva, S. O.; Reed, J. N.; Snieckus, V. Tetrahedron Lett. 1978,
19, 5099.
(16) Rathwell, K.; Sperry, J.; Brimble, M. A. Tetrahedron 2010, 66,
4002.
2008
Org. Lett., Vol. 15, No. 8, 2013

Next, an attempt was made to effect the transformation
in one pot as well as remove the Na2S2O4 reduction step
prior to methylation, as no change by TLC was observed
after reduction. Gratifyingly, the one-pot annulationꢀ
methylationꢀdouble deprotectionꢀspirocyclization pro-
cedure afforded the desired spiroketal 32 in improved yield
(32%) (Table 1, entry 4). The addition of more phthalide
20 and base in the annulation step further increased the
yield to 49% (Table 1, entry 5). This efficient reaction
sequence delivers a single isomer of a complex hetereocyc-
lic product from two relatively simple starting materials in
one pot in reasonable yield.
followed by two-step oxidation to afford the carboxylic
acid 34 in high yield. Oxidative demethylation was unsuc-
cessful using standard ceric ammonium nitrate conditions;
however, use of freshly prepared AgO18 gave 18 in a 58%
yield, for which the stereochemistry is identical to that of
the natural product 2.
Scheme 6. Synthesis of Griseusin B Analogue, 18
Computer modeling17 of the two spiroketal anomers of
32 predicts that the isomer with the C20ꢀO10 bond pseu-
doaxial is significantly lower in energy. In a parallel study,
a crystal structure of 10-epi-32 was obtained which con-
firmed that this reaction sequence selectively delivers the
more thermodynamically stable spiroketal (Figure 2). In
1
the H NMR spectrum H-10 in 32 resonates at δ 4.24,
further downfield of H-10 in 10-epi-32 that resonates at
δ 4.02. This deshielding effect for H-10 in 32 is due to
1,3-diaxial interactions between H-10 and O10. Based on
this evidence, it is concluded that the thermodynamically
favored spiroketal 32 is formed using this efficient multi-
step reaction sequence.
In summary, the synthesis of the griseusin B analogue 18
has been achieved. The synthesis involves a novel one-pot
HauserꢀKraus annulationꢀmethylationꢀdouble depro-
tectionꢀspirocyclization reaction sequence starting from
phthalide 20 and highly substituted enone 21. Conversion
of phthalide 20 and enone 21 to spiroketal 32 involves
seven transformations that take place in one pot. To the
best of our knowledge, this is the only reported example of
a one-pot annulationꢀmethylationꢀdouble deprotec-
tionꢀspirocyclization reaction to date. Studies toward
the total synthesis of griseusin B 2 and other analogues
continue in our laboratory.
Acknowledgment. The authors thank The University of
Auckland for financial support (B.J.N.).
Figure 2. Crystal structure of 10-epi-32.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
With the pyranonaphthoquinone-spiroketal skeleton
assembled, synthetic work continued toward the fully
elaborated griseusin B analogue 18 (Scheme 6). Debenzy-
lation was effected using high pressure hydrogenation
(18) Barbieri, G. A. Ber. Dtsch. Chem. Ges. B 1927, 60B, 2427.
(17) MMF conformer-AM1 geometry-HF energy (Spartan).
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
2009