Strategies for the synthesis of fusicoccanes by nazarov reactions of dolabelladienones: Total synthesis of (+)-fusicoauritone

Article abstract of DOI:10.1002/anie.200603853

Attaining closure: A synthetic pathway leading to (+)-fusicoauritone (1) is highlighted by the use of a Julia condensation for preparation of an eleven-membered-dolabelladienone precursor for subsequent Nazarov cyclization to yield the 5-8-5 tricyclic dit

Full text of DOI:10.1002/anie.200603853

Angewandte
Chemie
DOI: 10.1002/anie.200603853
Diterpene Total Synthesis
Strategies for the Synthesis of Fusicoccanes by Nazarov Reactions of
Dolabelladienones: Total Synthesis of (+)-Fusicoauritone**
David R. Williams,* Leslie A. Robinson, C. Richard Nevill, and Jayachandra P. Reddy
The fusicoccanes are representative of a family of terpenes
that feature a fused 5-8-5 carbocyclic skeleton.[1] Substances
exhibiting this structural motif have been isolated from a
variety of sources including the wax secretions of scale insects,
fungi, liverworts, and more recently, from higher plants.
Fusicoccanes,[2] cotylenins,[3] and fusicoplagins[4] are diterpe-
noid examples, whereas the ophiobolins[5] and ceroplastols[6]
are sesterterpenes. Fusicoccins and cotylenins exhibit signifi-
cant phytohormonal activities associated with the activation
of plasma membrane H+-ATPase, and fusicoccin-binding
proteins are considered to be key elements in intracellular
signal transduction pathways.[7] The putative biogenesis of this
tricyclic framework is described by a p-cation cyclization to
form an eleven-membered ring, and further transannular
events from a [9.3.0]cyclotetradecane precursor lead to
fusicoccanes as exemplified by fusicoauritone (1)
(Scheme 1).[8] The initial carbocyclization of geranylgeranyl
pyrophosphate yields the dolabellanes, a widely distributed
class of marine natural products, by means of hydration or
elimination from cation 2.[9] In fact, 3,7-dolabelladienes are
key biogenic precursors to fusicoccanes and neodolabellanes
as well as the dolastanes (clavularanes), a class of 5-7-6
tricyclic marine terpenes.[10] Interestingly, marine sources
produce relatively fewexamples of secondary metabolites
bearing the 5-8-5 skeleton.[11]
Recognizing the central importance of the dolabellane
nucleus in the biosynthesis of several families of diterpenes,
we have examined strategies for its preparation,[12] and our
efforts have described stereocontrolled transannular reac-
tions to dolastanes and relevant rearrangement products.[13]
Recently, synthesis studies toward dolabellane and dolastane
diterpenes have been reviewed.[14] A convergent strategy
toward the fusicoccanes has been described in a body of work
by Kato, Takeshita, and co-workers, culminating in the total
[16]
synthesis of (À)-cotylenol.[15] Kishi et al.
and Boeckman
[17]
et al.
have independently developed syntheses of ophio-
bolin C and (Æ )-ceroplastol I, respectively, and distinctive
routes for the synthesis of epoxydictymene have also been
reported.[18] Unabated interest in the synthesis of the
dicyclopenta[a,d]cyclooctane ring system continues.[19]
Herein, we communicate the successful application of our
retrosynthetic hypothesis (Scheme 1), which features forma-
tion of an eleven-membered ring by means of an intra-
molecular alkylation from 3 for utilization of the Nazarov
reaction[20] of dolabelladienone 4 to provide a 5-8-5 tricyclic
skeleton as the basis for an effective total synthesis of
fusicoauritone (1).
Preparation of the appropriately functionalized cyclo-
pentane of 1 required elaboration of three contiguous
stereogenic sites (C10, C11, and C14). This task was under-
taken (Scheme 2) beginning with optically active cyclopen-
tenyl alcohol 5[21] by Claisen rearrangement of the Johnson
orthoester. The sigmatropic process occurred with high
stereoselectivity,[22] and hydride reduction with subsequent
protection gave 7 (MEM = CH2OCH2CH2OCH3). Hydrobo-
ration of the exocyclic olefin 7 led to a primary alcohol that
proved to be a single diastereomer at C10, and low-temper-
ature Swern oxidation[23] gave an aldehyde that was directly
utilized without chromatographic purification to avoid epi-
merization. Our efforts to extend the alkyl chain and
introduce the remote stereocenter at C7 were rewarded by
further studies of the Claisen rearrangement. Towards this
end, (Z)-propenyllithium was prepared according to the
Whitesides procedure,[24] and nucleophilic addition with crude
aldehyde in ether at À508C afforded approximately a 6:1
mixture of Z-allylic alcohols (82% yield). Upon chromato-
graphic separation, the major product 8 was obtained in 65%
yield.[25]
Scheme 1. Merging concepts of biosynthesis with a retrosynthetic
design toward 1. P P=pyrophosphate.
[*] Dr. D. R. Williams, L. A. Robinson, Dr. C. R. Nevill, Dr. J. P. Reddy
Department of Chemistry
Indiana University
Bloomington, IN 47405-7102 (USA)
Fax: (+1)812-855-8300
E-mail: williamd@indiana.edu
[**] We thank the National Institutes of Health [National Institute of
General Medical Sciences (GM42897)] for support of this research.
We also thank Dr. Josef Zapp (Saarland University) for providing us
with NMR and MS spectra of authentic 1.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 2. Reagents and conditions: a) (EtO)3CCH3, H3CCH2COOH
(cat.), 1458C, 79%, then LiAlH4, Et2O, 08C, 95%; b) MEM-Cl, iPr2NEt,
DMAP, CH2Cl2, 92%; c) BH3·THF, 08C, then aq. H2O2, NaOH, 75%;
d) (COCl)2, DMSO, CH2Cl2 at À788C, then Et3N at À508C, 99%;
e) (Z)-1-propenyllithium, Et2O, À508C, 65%; f) (EtO)3CCH3,
H3CCH2COOH (cat.), 1458C; then LiBH4, MeOH, 70%; g) Na0,
HMPA, tBuOH, 97%; h) TsCl, Et3N, DMAP, CH2Cl2, 89%; i) NaI,
H3CCOC2H5, reflux, then NaO2SC6H4CH3, DMF, 708C, 93%.
DMAP=N,N-dimethylaminopyridine, DMSO=dimethyl sulfoxide,
HMPA=hexamethylphosphoramide, Ts=toluene-4-sulfonyl,
DMF=N,N-dimethylformamide.
Scheme 3. Reagents and conditions: a) (COCl)2, DMSO, À788C, then
Et3N; b) (carbethoxyethylidene)triphenylphosphorane, CH2Cl2, 228C,
96%; c) DIBAL, CH2Cl2, À788C, then PCC, CH2Cl2, 86%; d) 15 was
added to benzene, sodium t-amylate, 358C, 5 min, reaction was then
quenched with HOAc, 73%; e) (COCl2), DMSO, À788C, then Et3N,
followed by KOtBu, THF, 2-[(p-chlorophenyl)sulfonyl]-3-(p-chlorophen-
yl)oxaziridine, À788C, 85%; f) BF3·Et2O, ClCH2CH2Cl, reflux, 77%.
DIBAL=diisobutylaluminum hydride, PCC=pyridinium chlorochro-
mate.
corresponding a-sulfonylketones (5:1 ratio). However, the
dehydroelimination of the a-sulfonyl substituent was not
feasible. On the other hand, oxidation of the resulting enolate
of this system with Davis oxaziridine[29] directly produced
diketone 18 (85%). Although enolic tautomerization is not
Treatment of 8 with triethylorthoacetate in the presence
of catalytic propanoic acid at 1458C produced a facile Claisen
rearrangement, and direct hydride reduction of the resulting
ethyl ester gave alcohol 9 as a single diastereomer (70% for
two steps).[26] Subsequent reduction of the E double bond in 9
proved to be a challenging problem. A variety of hydro-
genation catalysts led to products of double-bond migration.
Rhodium on alumina efficiently transformed 9 into the
corresponding olefin with an endocyclic (C10–C14) tetrasub-
stituted double bond. Other techniques, such as the use of
diimide were totally ineffective. Fortunately, a dissolving-
metal reduction using sodium in a concentrated solution of
HMPA and tert-butyl alcohol[27] cleanly yielded the saturated
alcohol 10 (97%) for straightforward conversion to the
desired sulfone 12.
To effect carbocyclization of the eleven-membered
[9.3.0]tetradecane system, we utilized modifications of the
Julia condensation.[12] Thus, primary alcohol 13 was prepared
by deprotection of 12 (HBF4; aq. MeOH (85%)), and
oxidation followed by Wittig olefination gave the ester 15
with the E double bond (Scheme 3). Conversion to the
aldehydic sulfone 16 was followed by rapid addition into a
vigorously stirred solution of sodium tert-amylate (0.15m in
benzene at 358C). The gold-colored solution was stirred for
an additional one to two minutes and quenched with glacial
acetic acid leading to the b-hydroxysulfones 17 (d.r. 5:1) in
yields ranging from 73% to 82% with the recovery of
additional amounts of enal 16 (12%). The major cyclization
product proved to be the trans-b-hydroxysulfone,[28] although
this stereochemistry was inconsequential for our studies.
Transformation of 17 to an appropriate divinylketone sub-
strate required an initial Swern oxidation[23] yielding the
1
evident in the H NMR spectroscopic data of 18, treatment
with BF3 etherate catalyzed formation of the putative
divinylketone intermediate for facile Nazarov cyclization,
yielding a-hydroxycyclopentenone 19.[30] Characterization of
19 with extensive NMR data, using nOe difference experi-
ments, confirmed the all-syn stereochemistry of HA, HB, and
HC as well as the relationship of the bridgehead methyl group
(at C11) and the newly created a-methylketone.[31]
To effect ring contraction of the dolabelladiene precursor
through the Nazarov cyclization with control of enone
regiochemistry as presented in 1, we chose to examine the
less substituted divinylketone substrate 23.[32] As illustrated in
Scheme 4, phenylselenation of a-sulfonyl ketone 20 (major
product from 17, Scheme 3) gave 21 for immediate oxidation,
Scheme 4. Reagents and conditions: a) NaHMDS, THF, À788C,
PhSeCl, 08C, then aq. H2O2, 98%; b) DIBAL, À788C, 95%; c) sodium
naphthalide, THF, À788C, 1 min, then MnO2, PhH, 70%; d) TsOH
(cat.), ClCH2CH2Cl, 92%; e) tBuOCl, aq. acetone, 40%; f) air oxida-
tion; g) CH2Cl2; aq. NaHSO3 (95%). HMDS=1,1,1,3,3,3-hexamethyl-
disilazane.
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Heidebrecht, Jr., J. Am. Chem. Soc. 2003, 125, 1843, and
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yielding exclusively the a,b-unsaturated sulfone 22 with E
configuration.[33] This electron-deficient system exhibited
diminished reactivity under Lewis acid catalyzed Nazarov
conditions. A three-step sequence effected replacement of the
sulfonyl group with a hydrogen atom. Carbonyl reduction
gave solely the b alcohol,[34] and desulfonylation with sodium
naphthalide at À788C in THF selectively occurred with
retention of double-bond geometry. Mild allylic oxidation
provided the Z enone of 23 as indicated by the vicinal
[10] A. D. Rodriguez, E. Gonzµlez, C. Ramirez, Tetrahedron 1998,
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1
coupling constant (JAB = 10.7 Hz) in the H NMR spectrum.
Finally, treatment of 23 under protic or Lewis acid conditions
resulted in a smooth Nazarov reaction to 24 (and its C6
epimer).[35] Upon standing for several days, chloroform
solutions of 24 yielded colorless crystals, which were unam-
biguously identified by X-ray crystallography as the hydro-
peroxide 25,[36] and subsequent reduction with sodium hydro-
gen sulfite gave 1. Autoxidation of 24 was postulated to occur
by enolization and capture of the conjugated enol by
dissolved oxygen. This slow, serendipitous reaction to 25
was not pursued as a viable synthetic conversion. Completion
of the total synthesis of fusicoauritone was more efficiently
rendered by direct oxidation of a mixture of 24 and its C6
epimer with tert-butylhypochlorite in aqueous acetone pro-
viding a 40% yield of synthetic 1, which proved to be identical
to the natural substance in all respects (optical rotation data
and spectroscopic characterizations).[37]
Received: September 19, 2006
Revised: October 20, 2006
Published online: December 15, 2006
Keywords: fusicoccanes · Julia condensation ·
.
medium-ring compounds · Nazarov cyclization ·
total synthesis
[20] M. A. Tius, Eur. J. Org. Chem. 2005, 2193.
[21] By slight modification of a known procedure, (S)-limonene
oxide was converted into 5 in 50% overall yield. J. D. White, J. F.
Ruppert, M. A. Avery, S. Torii, J. Nokami, J. Am. Chem. Soc.
1981, 103, 1813.
[22] a) G. Mehta, N. Krishnamurthy, Tetrahedron Lett.1987, 28, 5945;
b) For a related [2,3] sigmatropic rearrangement from 5: J.
Wright, G. J. Drtina, R. A. Roberts, L. A. Paquette, J. Am.
Chem. Soc. 1988, 110, 5806.
[23] A. J. Mancuso, S.-L. Huang, D. J. Swern, J. Org. Chem. 1978, 43,
2480.
[24] G. Linstrumelle, J. K. Krieger, G. M. Whitesides in Organic
Synthesis, Vol. 55 (Ed.: S. Masamune), Wiley, NewYork, 1976,
pp. 103 – 113.
[1] N. A. Petasis, M. A. Patane, Tetrahedron 1992, 48, 5757.
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b) A. Ballio, C. G. Casinovi, V. DꢀAlessio, G. Grandolini, G.
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examples: S. Kim, D.-S. Shin, T. Lee, K.-B. Oh, J. Nat. Prod.
2004, 67, 448.
[3] For a leading reference: T. Sassa, T. Ooi, M. Nukina, N. Kato,
Biosci. Biotechnol. Biochem. 1998, 62, 1815.
[4] T. Hashimoto, M. Tori, Z. Taira, Y. Asakawa, Tetrahedron Lett.
1985, 26, 6473.
[25] The diastereomeric allylic alcohols were separately subjected to
Johnson orthoester Claisen conditions leading to the assignment
of stereochemistry as described for 8. Inversion of the undesired
alcohol epimer to provide additional quantities of 8 was not
feasible.
[5] S. Nozoe, M. Morisaki, K. Tsuda, Y. Iitaka, N. Takahashi, S.
Tamura, K. Ishibashi, M. Shirasaka, J. Am. Chem. Soc. 1965, 87,
4968.
[6] Y. Iitaka, I. Watanabe, I. T. Harrison, S. Harrison, J. Am. Chem.
Soc. 1968, 90, 1092.
[26] The stereochemistry of the newly formed chiral center (C7) was
confirmed by degradation. The g,d-unsaturated ester obtained
from Claisen rearrangement of 8 was reduced (LiBH4), followed
by ozonolysis with a NaBH4 quench to produce (R)-2-methyl-
butane-1,4-diol, [a]2D4 = + 22.6 (c = 0.6, CHCl3). M. Lautens,
T. A. Stammers, Synthesis 2002, 14, 1993.
[7] a) B. DeBoer, Trends Plant Sci. 1997, 2, 60; b) K. Asahi, Y.
Honma, K. Hazeki, T. Sassa, Y. Kubohara, A. Sakurai, N.
Takahashi, Biochem. Biophys. Res. Commun. 1997, 238, 758.
[8] a) H.-J. Liu, C.-L. Wu, H. Becker, J. Zapp, Phytochemistry 2000,
53, 845; b) J. Zapp, G. Burkhardt, H. Becker, Phytochemistry
1994, 37, 787; c) S. Huneck, G. Baxter, A. F. Cameron, J. D.
Connolly, D. S. Rycroft, Tetrahedron Lett. 1983, 24, 3787.
[9] a) A. Banjeri, R. B. Jones, G. Mellows, L. Phillips, K.-Y. Sim, J.
Chem. Soc. Perkin Trans. 1 1976, 2221; b) For the production of
these metabolites in liverwort: Y. Asakawa, X. Lin, M. Tori, K.
Kondo, Phytochemistry 1990, 29, 259; c) D. R. Williams, R. W.
[27] G. M. Whitesides, W. J. Ehmann, J. Org. Chem. 1970, 35, 3565.
[28] The trans-b-hydroxysulfone is distinguished by a large vicinal
1
coupling constant (J = 10 Hz) in the H NMR spectrum of the
major product indicating a diaxial disposition of methine
hydrogens. Each sulfone diastereomer independently underwent
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desulfonylation with 6% Na/Hg in methanol to yield identical
samples of allylic alcohol.
[34] Assignment of stereochemistry for the hydride reduction of 22
was made following treatment with 6% Na/Hg in EtOH which
produced the allylic alcohols diastereomeric at C4, and these
were compared with the desulfonylation product from 17.
[35] Cyclopentenone 24 undergoes facile C6 epimerization. Flash
silica gel chromatography led to an incomplete separation of
these diastereomers, which afforded fractions of pure 24 for
complete characterization.
[29] For a leading reference: D. R. Williams, L. A. Robinson, G. S.
Amato, M. H. Osterhout, J. Org. Chem. 1992, 57, 3740.
[30] Initial attempts at the Nazarov cyclization also gave varying
amounts of the isomeric ketone shown below, with tentative
stereochemical assignments labeled as shown. This cis-fused
arrangement is found in naturally occurring ophiobolins. Treat-
ment of the isomeric ketone with BF3·Et2O led to tautomeriza-
tion to ketone 19.
[36] Crystal data for 25: colorless block, 0.3 ” 0.3 ” 0.2 mm, C20H32O3,
Mw = 320.47, monoclinic, a = 12.571(3), b = 8.897(2), c =
16.858(4) Š, b = 109.545(10)8, V= 1776.8(8) Š3, T= 108(2) K,
space group P21/n, Z = 4, 1calcd = 1.198 MgmÀ3, m = 0.0781 mmÀ1
,
MoKa (l = 0.71073). A total of 3045 reflections were measured.
The final residuals was R = 0.0565 with GOF = 1.341 and largest
residual peak 0.21 eŠÀ3. CCDC-624501 contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[37] Synthetic and natural 1 were identical in all respects. Optical
rotation for natural fusicoauritone was recorded as [a]2D0 = + 14.0
(c = 0.16, CHCl3). Characterization of synthetic 1: Rf = 0.28
(30% EtOAc/hexanes); [a]2D4 = + 13.3 (c = 0.21, CHCl3); IR
(neat): n˜ = 3445, 2970, 2935, 2880, 1702, 1468, 1390, 1050, 1020,
[31] NMR studies of 19 demonstrated that irradiation of HB (d =
3.00 ppm) gave a 6% nOe enhancement of HA (d = 2.61 ppm)
and no nOe was observed for the methyl substituent at the
bridgehead (C11). Irradiation of HA gave an 8% enhancement
of the signal for HB (JAB = 6.0 Hz) and induced a negative 3%
nOe of the axial HC (d = 2.85 ppm).
975, 955 cmÀ1 1H NMR (400 MHz, CDCl3): d = 2.71 (d, J =
;
12.8 Hz, 1H), 2.46 (d, J = 18.4 Hz, 1H), 2.27 (d, J = 18.4 Hz,
1H), 2.22 (d, J = 13.2 Hz, 1H), 2.19–2.10 (m, 3H), 2.05 (s, 1H),
1.73 (s, 3H), 1.71–1.55 (m, 6H), 1.30–1.25 (m, 3H), 1.11 (d, J =
7.2 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H),
0.79 ppm (s, 3H); 13C NMR (101 MHz, CDCl3): d = 207.8, 173.6,
139.6, 83.1, 48.5, 47.2, 46.9, 44.3, 44.0, 40.3, 33.4, 30.2, 28.0, 24.5,
24.4, 22.9, 20.0, 19.5, 17.6, 9.5 ppm; MS (CI, NH3) m/z (rel.
intensity) 304 (M+), 179 (100), 137 (80), 95 (72); HRMS (CI,
NH3) calcd for C20H33O2 [M++1]: 305.2475, found: 305.2471.
[32] A reviewer requested some insight into alternative strategies
explored toward enone 24. In fact, we also investigated the use of
a Pausen–Khand reaction for cyclization of the eight-membered
ring as well as the desired cyclopentenone in a single operation.
The required alkyne was readily prepared, but the cyclization
was not successful in our hands.
[33] The E double-bond geometry in 22 was established by irradi-
ation of the aromatic protons of the tolyl group which induced an
nOe with the adjacent HB.
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