Synthesis of the sporolide ring framework through a cascade sequence involving an intramolecular [4+2] cycloaddition reaction of an o-quinone

Article abstract of DOI:10.1002/anie.200705334

(Chemical Equation Presented) Sea-ing is believing: The o-quinone indene intermediate 1 was generated from the corresponding catechol substrate and converted into macrocycle 2 by a cascade sequence involving a novel intramolecular [4+2] cycloaddition reaction. This sequence serves as the key process to form the core heptacyclic structure 3 of the marine-derived natural products sporolide A and B, which were isolated from the relevant actinomycete fermentation broths.

Full text of DOI:10.1002/anie.200705334

Communications
DOI: 10.1002/anie.200705334
Natural Product Synthesis
Synthesis of the Sporolide Ring Framework through a Cascade
Sequence Involving an Intramolecular [4+2] Cycloaddition Reaction
of an o-Quinone**
K. C. Nicolaou,* Jianhua Wang, and Yefeng Tang
In a recent publication, Fenical and co-workers[1] reported the
structural characterization of the two unique molecular
frameworks of sporolides A (1) and B( 2; Scheme 1). Isolated
from the fermentation broths of a strain of the marine-derived
actinomycete Salinispora tropica, these compounds feature
Scheme 2 shows the retrosynthetic analysis of the spor-
olide model system 3. Thus, the target molecule was
envisioned to arise by selective manipulation of the trioxy-
genated aromatic nucleus of hexacyclic compound 4a, whose
macrocycle and dioxane moieties were simultaneously dis-
Scheme 1. Molecular structures of sporolides A (1) and B( 2) as well
as sporolide ring framework 3.
molecular architectures that contain 24 carbon atoms (among
which only two are not oxygenated or sp2 hybridized), 10
stereogenic centers, and no less than seven rings. These
marine natural products present an intriguing synthetic
challenge in view of their unprecedented molecular structures
and the opportunity they present for the development of
novel synthetic strategies. Herein we report the construction
of model system 3, which represents the structural skeleton of
sporolide A (1) and B( 2) and contains all seven rings of the
naturally occurring molecules, through a cascade sequence
involving an unprecedented intramolecular [4+2] cycloaddi-
tion reaction of an olefinic o-quinone.
Scheme 2. Retrosynthetic analysis of sporolide ring framework 3.
mantled through a retro o-quinone [4+2] cycloaddition
reaction to reveal o-quinone ester 5 as a possible intermedi-
ate, whose generation from catechol 6 was considered
standard. While the origin of precursor 6 was clear (that is,
from building blocks 7 and 8), the transformation of
o-quinone 5 to macrocycle 4a through the intended cyclo-
addition reaction was based on a rather daring hypothesis
since we were aware of no precedent for such an intra-
molecular reaction of an o-quinone.[2,3] Furthermore, should
such a scenario be possible, its stereochemical outcome could
only be speculated upon at the outset. Encouragingly, both
molecular models and molecular mechanics calculations,
together with electronic considerations, indicated the desired
regio- and diatereoisomer to be favored. Thus, of the four
possible isomers of 4a (4a–4d, Scheme 3), the desired isomer
4a was predicted to be the most favored on the basis of
electronic (preferential activation of the C6-carbonyl oxygen
atom by the C4’-OBn moiety; conjugated addition of the C6-
carbonyl oxygen atom onto C10 of the olefinic bond,
[*] Prof. Dr. K. C. Nicolaou, J. Wang, Dr. Y. Tang
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92037 (USA)
[**] We thank Dr. D. H. Huang, Dr. G. Siuzdak, and Dr. R. Chadha for
assistance with NMR spectroscopy, mass spectrometry, and X-ray
crystallography, respectively. We also thank Michael O. Fredrick for
the Spartan ’06 calculations. Financial support for this work was
provided by the Skaggs Institute for Research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
furnished intermediate 13 (81% yield). The necessity to
remove the catechol protecting group in the presence of the
acid-sensitive indene moiety at a subsequent step dictated the
exchange of the robust methylene dioxolane with a more
labile group at this stage. Thus, 13 was sequentially treated
with Pb(OAc)4 (benzene, D) and AcOH/THF/H2O (10:5:1,
258C), and the resulting catechol (14, 95% overall yield) was
converted into the corresponding orthoester by exposure to
CH(OEt)3 in the presence of TsOH·H2O[7] (benzene, D, 96%
yield), from which the desired carboxylic acid 7 was generated
by saponification (LiOH, dioxane/H2O (5:1), 808C) in 99%
yield.
Scheme 5 summarizes the synthetic approach for the
second required building block, indene derivative 8, starting
from the benzoic acid derivative 15.[8] Reduction of the
carboxylic acid moiety of 15 with BH3·THF followed by
protection (DHP, TsOH·H2O, 95% yield) of the resulting
alcohol furnished THP ether 16. The latter was then
Scheme 3. The four possible stereoisomeric products, 4a–4d, of the
intramolecular o-quinone indene 5 [4+2] cycloaddition reaction.
R=Bn=benzyl.
Scheme 2) and steric grounds (1,3-benzylic strain between the
C2’-OMe and the C4’-OBn groups, see 5’, Scheme 2). The
latter effect was reflected in the calculated energy difference
of the activation energy of the reactions leading to the four
possible isomers, and the strain energy of the final products,
4a–4d (Scheme 3).[4]
Scheme 4 presents the synthetic approach for the required
carboxylic acid building block 7, starting from the known
phenol derivative 9.[5] Thus, deprotonation of 9 with MeMgBr
followed by quenching with ethyl glyoxolate (10) resulted in
the formation of hydroxy ester 11 in 98% yield. Selective
benzylation of the phenol group of 11 (Cs2CO3, BnBr, NaI,
92% yield) followed by methylation of the resulting second-
[6]
ary alcohol 12 with TMSCHN2 in the presence of HBF4
Scheme 5. Synthesis of building block 8. Reagents and conditions:
a) BH3·THF (1.0m in THF, 2.0 equiv), THF, 258C, 2 h, 80%; b) DHP
(1.2 equiv), TsOH·H2O (0.1 equiv), CH2Cl2, 08C, 0.5 h, 95%; c) 17
(1.3 equiv), LDA (1.3 equiv), THF/HMPA (5:1), ꢀ78!08C, 1 h; then
16 (1.0 equiv), ꢀ78!258C, 2 h, 65%; d) CrCl2 (4.0 equiv), NiCl2
(0.02 equiv), DMF, 1008C, 16 h, 76%; e) TsOH·H2O (0.1 equiv), ben-
zene, 808C, 0.5 h; then CH3OH, 258C, 0.5 h, 82%; f) DMP (1.2 equiv),
NaHCO3 (3.0 equiv), CH2Cl2, 258C, 0.5 h, 95%; g) MeOCH2PPh3Br
(1.5 equiv), KHMDS (0.5m in toluene, 1.5 equiv), THF, 0!258C, 2 h,
96%; h) HCl (aq, 2.0n, 4.0 equiv), THF, 608C, 3 h, 88%; i) NaBH4
(1.1 equiv), THF/MeOH (5:1), 08C, 0.5 h, 95%. DHP=3,4-dihydro-
2H-pyran, DMP=Dess–Martin periodinane, HMPA=hexamethylphos-
phoramide, KHMDS=potassium hexamethyldisilazane, LDA=lithium
diisopropylamide.
Scheme 4. Synthesis of building block 7. Reagents and conditions:
a) 9, MeMgBr (3.0m in Et2O, 1.2 equiv), THF, 08C, 0.5 h; then 10
(50% in toluene, 1.5 equiv), THF, 08C, 0.5 h, 98%; b) BnBr
(3.0 equiv), Cs2CO3 (2.0 equiv), NaI (1.0 equiv), DMF, 0!258C, 3 h,
92%; c) TMSCHN2 (2.0m in hexanes, 2.0 equiv), HBF4 (49% in H2O,
1.0 equiv), CH2Cl2, 0!258C, 2 h, 81%; d) Pb(OAc)4 (1.5 equiv), ben-
zene, 808C, 16 h; e) AcOH/THF/H2O (10:5:1), 258C, 6 h, 95% over 2
steps; f) CH(OEt)3 (2.0 equiv), TsOH·H2O (0.2 equiv), 4-Š M.S. (80 mg
per mmol 14), benzene, 808C, 16 h, 96%; g) LiOH (20 equiv), diox-
ane/H2O (5:1), 808C, 3 h, 99%. Ac=acetyl, DMF= N,N-dimethylfor-
mamide, M.S.=molecular sieves, TMS=trimethylsilyl, Ts=p-toluene-
sulfonyl.
employed to alkylate, under basic conditions (LDA, ꢀ78!
08C), cyclopentanone (17) to afford cyclopentanone deriva-
tive 18, which was subjected to intramolecular Nozaki–
Hiyama–Kishi coupling[9] (CrCl2, cat. NiCl2) to furnish
tricyclic tertiary alcohol 19 in 76% yield. Elimination of
H2O from 19 with concomitant removal of the THP group was
then achieved by exposure to TsOH·H2O to afford the
hydroxy indene derivative 20 (82% overall yield). The
subsequent one-carbon homologation of 20, as shown in
Scheme 5 [DMP oxidation (95% yield); Wittig reaction (96%
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Communications
yield); HCl aq hydrolysis (88% yield); and NaBH4 reduction
(95% yield)], proceeded well to furnish the target fragment 8.
The required precursor, catechol 6, was constructed from
the newly synthesized building blocks 7 and 8 as shown in
Scheme 6. Thus, facilitated by DCC and DMAP, the coupling
of carboxylic acid 7 and alcohol 8 led to the formation of ester
21 in 84% yield. Treatment of 21 with TsOH·H2O in MeOH
then furnished catechol 6 in 98% yield. Upon heating a
toluene solution of 6 (0.005m) in the presence of Ag2O
(2.0 equiv) at 1208C, we were delighted to observe the
formation of a single product whose spectroscopic data were
consistent with that of structure 4a, but did not unambigu-
ously exclude its other three isomers (4b–4d, Scheme 3).
X-ray crystallographic analysis (Figure 1) of phenol 22[10]
(m.p. 233–2348C, acetone/hexanes, obtained by hydrogenoly-
sis (H2, 20% Pd(OH)2 on carbon (cat.), 85% yield) of 4a)
confirmed its structure, and therefore the structure of 4a. This
additional structural information proves our original hypoth-
esis for both the regio- and stereochemical outcome of the
intramolecular [4+2] cycloaddition reaction of o-quinone
indene 5. The existence of intermediate o-quinone 6 was
confirmed by a stepwise sequence in which Ag2O was used to
oxidize catechol 6 at room temperature to give 5 in 99% yield
as a stable isolated intermediate. Subsequently, 5 was heated
in toluene at 1208C to produce macrocycle 4a in 50% yield.
Having secured the core skeletal framework of the
sporolide natural products through a cascade sequence
Figure 1. ORTEP plot of 22 with thermal ellipsoids at 30% probability
level.
involving the novel o-quinone [4+2] cycloaddition strategy,
we then proceeded to demonstrate the applicability of the
method by constructing the remaining structural motifs of the
[11]
molecule. Thus, oxidation of 22 with PhI(CO2CF3)2 in the
presence of PMBOH produced PMB ketal quinone 23, as a
single diastereomer, in 87% yield. Based on steric consid-
erations, the stereochemistry of the PMBketal 23 was
tentatively assigned as having the a configuration as shown
in Scheme 6, which was presumed to originate from attack of
PMBOH from the bottom face of the
cationic intermediate. This assumption was
later confirmed by the synthesis of hydroxy
epoxide 3, whose structure was confirmed by
NMR spectroscopy and X-ray crystallogra-
phy (Figure 2). The deprotection of 23 was
accomplished by using DDQ to afford hemi-
ketal 24 in 96% yield. Finally, treatment of
24 with five equivalents of tBuOOH in the
presence of catalytic amounts of DBU[12]
furnished the targeted hydroxy epoxide 3
in 60% yield as a single compound. The syn
relationship between the hydroxy and epox-
ide moieties was expected from the known
directing effect of the hydroxy group on the
epoxidation reaction.[12] The 1H and 13C
NMR spectroscopic data of 3 were consis-
tent with those of the naturally occurring
[1]
sporolides A and B. The relative configu-
ration of the epoxide moiety was confirmed
by the observed NOE interaction between
H4 and H8’, and between H8’ and the CH3O
group at position 2’, as shown in 3’
(Scheme 6). Finally, the assigned structure
of model system 3 (m.p. 218–2198C, acetone/
hexanes) was confirmed by X-ray crystallog-
raphy (Figure 2).[13]
In conclusion, we have demonstrated the
feasibility of a cascade sequence involving a
novel intramolecular [4+2] cycloaddition
reaction as a means to stereoselectively
construct the dioxane-containing macrocy-
Scheme 6. Synthesis of sporolide ring framework 3. Reagents and conditions: a) 7
(1.25 equiv), 8 (1.0 equiv), DCC (1.3 equiv), DMAP (0.2 equiv), CH2Cl2, 258C, 3 h, 84%;
b) TsOH·H2O (0.05 equiv), MeOH, 258C, 24 h, 98%; c) one-step procedure: Ag2O
(2.0 equiv), toluene (0.005m solution), 1208C, 1 h, 60%; two-step procedure: 1. Ag2O
(2.0 equiv), CH2Cl2, 258C, 99%; 2. toluene (0.005m solution), 1208C, 3 h, 50%; d) H2
(ca. 1 atm), Pd(OH)2/C (20 wt%), EtOH, 258C, 14 h, 85%; e) PhI(CO2CF3)2 (1.05 equiv),
PMBOH (10 equiv), K2CO3 (5.0 equiv), MeCN, 0!258C, 5 min, 87%; f) DDQ (1.5 equiv),
CH2Cl2/H2O (10:1), 258C, 15 h, 96%; g) tBuOOH (5.0 equiv), DBU (0.2 equiv), CH2Cl2,
=
408C, 24 h, 60%. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DCC N,N’-dicyclohexylcarbo-
diimide, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMAP=dimethylaminopyri-
dine, PMB=p-methoxybenzyl, THP=tetrahydropyranyl.
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[2] o-Quinones are capable of participating in intermolecular
[4+2] reactions with either their 1,2-dicarbonyl moiety or with
their endocyclic diene system; for reviews on o-quinone
chemistry, see a) L. Horner, H. Merz, Justus Liebigs Ann.
Chem. 1950, 570, 89 – 120; b) V. Nair, S. Kumar, Synlett 1996,
1143 – 1147.
[3] For a different type of intramolecular reaction of o-quinones, see
K. C. Nicolaou, T. Lister, R. M. Denton, C. F. Gelin, Angew.
Chem. 2007, 119, 7645 – 7649; Angew. Chem. Int. Ed. 2007, 46,
7501 – 7504.
[4] The following values were obtained using the Spartan ꢀ06
program (Wavefunction, INC): relative differences of activation
energies of reactions leading to products: 4a: DEa = 0 kcal
molꢀ1; 4b: DEa = 2.72 kcalmolꢀ1; 4c: DEa = 12.8 kcalmolꢀ1; 4d:
DEa = 9.98 kcalmolꢀ1; relative differences in strain energies of
products: 4a: DEFinal = 0 kcalmolꢀ1
; 4b: DEFinal = 3.22 kcal
molꢀ1; 4c: DEFinal = 10.4 kcalmolꢀ1; 4d: DEFinal = 7.95 kcalmolꢀ1
.
Figure 2. ORTEP plot of model system 3 with thermal ellipsoids at
30% probability level.
[5] X. Chen, J. Chen, M. De Paolis, J. Zhu, J. Org. Chem. 2005, 70,
4397 – 4408.
[6] T. Aoyama, T. Shioiri, Tetrahedron Lett. 1990, 31, 5507 – 5508.
[7] S. Danishefsky, J. Y. Lee, J. Am. Chem. Soc. 1989, 111, 4829 –
4837.
[8] S. Shankar, G. Vaidyanathan, D. Affleck, P. C. Welsh, M. R.
Zalutsky, Bioconjugate Chem. 2003, 14, 331 – 341.
[9] A. Fürstner, Chem. Rev. 1999, 99, 991 – 1046.
[10] CCDC 667552 contains the supplementary crystallographic data
for compound 22. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data_request/cif.
cle of sporolides A (1) and B( 2). In addition, we have shown
how such an efficient strategy can be employed to form the
hydroxy epoxide moiety of these natural products. Further-
more, the reported chemistry raises the possibility of such a
[4+2] cycloaddition process being involved in the biogenesis
of these structurally intriguing molecules.[14] Given the
unprecedented nature and potential of the reported cyclo-
addition reaction as well as the unusual architectures of the
sporolide family of natural products, further applications and
studies towards these molecular targets are anticipated.
[11] Y. Tamura, T. Yakura, J. Haruta, Y. Kita, J. Org. Chem. 1987, 52,
3927 – 3930.
[12] K. Zilbeyaz, E. Sahin, H. Kilic, Tetrahedron: Asymmetry 2007,
18, 791 – 796.
[13] CCDC 669253 contains the supplementary crystallographic data
for model system 3. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data_request/cif.
[14] a) W. Fenical, P. R. Jensen, Nat. Chem. Biol. 2006, 2, 666 – 673;
b) D. W. Udwary, L. Zeigler, R. N. Asolkar, V. Singan, A.
Lapidus, W. Fenical, P. R. Jensen, B. S. Moore, Proc. Natl. Acad.
Sci. USA 2007, 104, 10376 – 10381; c) C. L. Perrin, B. L. Rodgers,
J. M. OꢀConnor, J. Am. Chem. Soc. 2007, 129, 4795 – 4799.
Received: November 20, 2007
Published online: January 18, 2008
Keywords: cycloaddition · intramolecular reactions ·
.
natural products · o-quinone
[1] G. O. Buchanan, P. G. Williams, R. H. Feling, C. A. Kauffman,
P. R. Jensen, W. Fenical, Org. Lett. 2005, 7, 2731 – 2734.
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