Asymmetric total synthesis and X-ray crystal structure of the cytotoxic marine diterpene (+)-vigulariol

Article abstract of DOI:10.1002/anie.200704678

(Figure Presented) A crystal from the China sea: The asymmetric total synthesis of (+)-vigulariol (see picture: red O, blue C, white H) has been accomplished in eight linear steps starting from (R)-cryptone, which is readily available from eucalyptus oil. Key steps involve an asymmetric homoaldol reaction of chiral allyl carbamates and THF cyclocondensation. Ring-closing metathesis led to the tricyclic framework of the cladiellin diterpenes.

Full text of DOI:10.1002/anie.200704678

Communications
DOI: 10.1002/anie.200704678
Diterpenes
Asymmetric Total Synthesis and X-Ray Crystal Structure of the
Cytotoxic Marine Diterpene (+)-Vigulariol**
Jochen Becker, Klaus Bergander, Roland Fröhlich, and Dieter Hoppe*
Dedicated to Professor Larry E.Overman on the occasion of his 65th birthday.
(+)-Vigulariol (1) is a cytotoxic, tetracyclic diterpene which
has been isolated from the sea pen Vigularia juncea.[1] It
As depicted in Scheme 1, (+)-vigulariol (1) could be
=
elaborated by stereoselective epoxidation of the C C double
bond of tricycle 4. Deprotection of the hydroxy group was
belongs to the impressively large class of the cladiellin
(eunicellin) diterpenes, of which many bear interesting
biological activities.[2] (+)-1 has shown to exhibit cyctotoxity
against A 549 (human lung adenocarcinoma) cell culture at
an IC50 of 18.33 mgmLÀ1.[1] Two other soft-coral diterpenes
sclerophytin A (2)[3,4] and polyanthellin A (3)[5,6] have shown
high cytotoxicity and antimalarial activity, respectively. Their
attractive molecular architectures and their diverse biological
activities previously led to several ingenious total syntheses of
some members of this natural product family by the research
groups of Paquette,[3a,c] Overman,[3b,c,7] Crimmins,[8] and
Kim.[5]
(+)-1 was formed as a by-product during Paquette and co-
workersꢀ synthesis of 2 before it was known to be natural
product and was therefore not fully characterized.[3a] The total
synthesis of rac-1 over 20 linear steps was quite recently
published by Clark et al.[9] Herein we present a short and
efficient total synthesis and, in addition, the solid-state
structure of enantiomerically pure (+)-vigulariol (1), by
applying our previous synthetic and mechanistic investiga-
tions.[10,11]
Scheme 1. Retrosynthetic analysis of (+)-vigulariol (1). Cb=C(O)NiPr2,
PG=protectinggroup.
envisaged to lead to subsequent intramolecular nucleophilic
ring-opening of the oxirane, followed by the introduction of
the exocyclic methylene group. Our convergent strategy for
the construction of tricycle 4 centered around three key
reactions: the asymmetric homoaldol reaction[12] of carba-
mate 6[10b] with a-stereogenic enal 7, followed by Krämer
THF synthesis[13] with acetal 8,[14] and ring-closing meta-
thesis[15] of the diene 5. (R)-4-Isopropylcyclohex-2-enone (9)
[(R)-(À)-cryptone)][16] was chosen as starting material for the
synthesis of 6. Known enantiopure diol 10[17] was identified for
the construction of 7.
Several enantioselective syntheses of (R)-9 are known,[16]
and we applied the methodology of Fuchs et al.[18] to obtain
(R)-9 with 99% ee (4 steps, 60–66% yield). But, as we became
aware that commercial eucalyptus oil contains approximately
5% of the cyclohexenone 9,[19,20] we developed the following
approach: The oil was subjected to chromatography, yielding
a mixture of (R)-9 with 97% ee (HPLC) and a sesquiterpene
bearing no carbonyl function. The mixture was reduced with
LiAlH4 to yield cycloalkenol 11[21] (d.r. = 84:16), which was
separated from the sesquiterpene by simple chromatography
on silica gel (Scheme 2). Carbamoylation of 11 and separation
of the diastereomers yielded (1S,4R)-6[10b] (97% ee).
[*] J. Becker, Dr. K. Bergander,[+] Dr. R. Fröhlich,[$] Prof. Dr. D. Hoppe
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
Fax: (+49)251-83-36531
E-mail: dhoppe@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/research/
hop/hoppe.html
[+] NMR experiments
[$] X-Ray crystal structure analysis
As it is known that a direct oxidation of silyl ethers to the
corresponding aldehydes is possible,[22] enantiomerically pure
diol 10 was quantitatively transferred into the triethylsilyl
ether 12. O-Benzyl protection of 12,[23] followed by Swern
oxidation[24] provided the required enal 14 in 69% yield over
three steps (Scheme 3).
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 424) and the Fonds der Chemischen Industrie (grant for J.B.).
We thank M. Renger, K. Gottschalk, and D. Hog for their skilful
experimental contributions.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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19 (13%). 1H NMR nOesy analysis indicated that the desired
isomer 18 was the major product.[27]
Although it was reported by Crimmins et al.[28] that
oxacyclononenes are accessible by ring-closing metathesis,
the cyclisation of 18 seemed to be critical, because the
reported attempts of Overman and Joe[29] and Jung and
Pontillo[30] to construct bi- and tricycles similar to 21 by
metathesis failed. Grubbs 1 and Hoveydaꢀs catalyst did not
lead to the formation of 21. However, the Grubbs 2 catalyst
20[31] in refluxing benzene yielded 21 (45%) along with the
oxacyclooctene 22 (17%) (Scheme 5).
Scheme 2. Preparation of carbamate 6. Reagents and conditions:
a) Flash column chromatography (FCC), 12.6 g 9 (97% ee): C15-
sesquiterpene in a ratio of 47:53 (GC) from essential oil (100 mL);
b) 1.2 equiv LiAlH4, Et2O, À788C, 30 min, FCC, 5.27 g(37.6 mmol) 11
(d.r.=84:16); c) 1.2 equiv NaH, 1.4 equiv iPr2NC(O)Cl, THF, reflux,
12 h, FCC, 78% 6 (97% ee), 12% cis-6.
Scheme 3. Synthesis of chiral aldehyde 14. Reagents and conditions:
a) 1.05 equiv TESCl, 2.0 equiv imidazole, DMF, 08C to 228C, 1.5 h,
99%; b) 2.5 equiv benzyl 2,2,2-trichloroacetimidate, 0.28 equiv
F3CSO3H, Et2O, 08C to 228C, 2.25 h, 86%; c) 1) 10.0 equiv DMSO,
5.0 equiv (COCl)2, À608C, 14 h, 2) 20.0 equiv DIPEA, 228C, 45 min,
81%. TES=triethylsilyl, Bn=benzyl, DMF=N,N-dimethylformamide,
DMSO=dimethylsulfoxide, DIPEA=diisopropylethylamine.
After stereospecific deprotonation of 6 (sBuLi, rac-trans-
N,N,N’,N’-tetramethyl-1,2-diaminocyclohexane
(TMCDA)),[10a] lithium–titanium exchange of the lithiated
species 15 was accomplished with ClTi(OiPr)3 (Scheme 4).[25]
Scheme 5. Metathesis and completion of the total synthesis of (+)-
vigulariol (1). Reagents and conditions: a) 20 (10 mol%), benzene,
reflux, 1.3 h, 45% 21, 17% 22; b) 1.1 equiv DMDO, acetone, À208C,
30 min, 81% 23, 9% a-23; c) 10% Pd/C (20 mol%), H2 (1 bar),
EtOAc, 228C, 1.25 h, 91%; d) 4.0 equiv Ph3PCH3Br, 3.5 equiv
NaHMDS (1m in THF), toluene, 808C, 45 min, 93%. DMDO=di-
methyldioxirane, NaHMDS=sodium hexamethyldisilazide, Cy=cyclo-
hexyl, Mes=2,4,6-trimethylphenyl.
Cycloalkene 21 was subjected to epoxidation by means of
dimethyldioxirane (DMDO)[32] to form oxirane 23 (b: 81%
yield, a: 9% yield). As expected, the less shielded b-face is
preferentially attacked. Hydrogenolytic O-debenzylation of
23 proceeded smoothly, and the bis(tetrahydrofuran) 25 was
isolated in 91% yield. The intermediate alcohol 24 underwent
rapid stereospecific attack onto the oxirane moiety. Finally,
introduction of the exocyclic methylene group by Wittig
olefination[33] provided the target molecule (+)-1 in essen-
tially quantitative yield.
The NMR and nOe data and the specific optical rotation
([a]2D0 = + 4.2 (c = 0.24, CHCl3), reported[1] [a]2D7 = + 3.6 (c =
0.24, CHCl3)) of our sample of (+)-1 match well with reported
data.[1,9] Surprisingly, the compound we obtained was crystal-
line (m.p. = 141.78C), whereas natural vigulariol (+)-1 was
reported to be a colorless oil.[1] For this reason, we undertook
an X-ray crystal structure analysis, which confirmed the
correct constitution and configuration of the synthetic sample
of (+)-1 (Figure 1).[34–36]
Scheme 4. Synthesis of the metathesis precursor 18 by a homoaldol
reaction and THF cyclocondensation. Reagents and conditions:
a) 1) 1.05 equiv sBuLi/TMCDA, Et2O, À788C, 2 h; 2) 1.74 equiv ClTi-
(OiPr)3 (1.74m in toluene), À788C, 2 h; 3) 2.5 equiv 14, À788C to
228C, 13.5 h, 16/17 (d.r.=83:17, 40% from 6), 69% 14 reisolated;
b) 2.1 equiv 8, 1.9 equiv BF3·OEt2, Et2O, 08C, 35 min; 71% 18, 13% 19
(from 16/17 83:17). TMCDA=rac-trans-N,N,N’,N’-tetramethyl-1,2-di-
aminocyclohexane.
The inversion of the configuration in the transmetallation step
is supported by the steric shielding of the 4-isopropyl group.
Addition of aldehyde 14 led to two inseparable diastereo-
meric homoaldol products 16 and 17 (yield 40%, d.r. =
83:17).[26] A mixture of 16 and 17 (83:17) was subjected to
BF3-mediated condensation[13] with acetal 8 to provide the
separable hexahydroisobenzofuran-4(1H)-ones 18 (71%) and
In summary, we have developed a short synthetic route for
(+)-vigulariol (1), which is based on the asymmetric homo-
aldol reaction of 6 and subsequent THF cyclisation of 16,
starting from simple enantiomerically pure starting materials.
We have also shown that the tricyclic core of the cladiellins is
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Communications
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Published online: January 22, 2008
Keywords: asymmetric synthesis · carbamates ·
.
homoaldol reactions · metathesis · total synthesis
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refined parameters, R = 0.058, wR2 = 0.161, Flack parameter
0.1(4), max. residual electron density 0.23 (À0.20) eŠÀ3, hydro-
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[34] The absolute configuration of the starting material (R)-9 was
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[35] X-ray crystal structure analysis for (+)-1: C20H32O3, Mr = 320.46,
colorless crystal 0.20 ” 0.08 ” 0.08 mm3, a = 9.0189(1), b =
10.6042(1), c = 9.7714(1) Š, b = 97.051(1)8, V= 927.45(2) Š3,
1calc = 1.148 gcmÀ3, m = 0.589 mmÀ1, empirical absorption correc-
tion (0.891 ꢀ Tꢀ 0.954), Z = 2, monoclinic, space group P21 (No.
4), l = 1.54178 Š, T= 223 K, w and f scans, 5758 reflections
collected (Æ h, Æ k, Æ l), [(sinq)/l] = 0.60 ŠÀ1, 2252 independent
(Rint = 0.079) and 2049 observed reflections [I ꢁ 2s(I)], 213
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