Total syntheses and structural revision of α- and β-diversonolic esters and total syntheses of diversonol and blennolide C

Article abstract of DOI:10.1002/anie.200802632

Expedient total syntheses of the originally proposed structures of the naturally occurring α- and β-diversonolic esters (1 and 2) and diversonol (3) lead to the revision of the structures of 1 and 2 to 4 and 5, respectively (see structures). (Chemical Equ

Full text of DOI:10.1002/anie.200802632

Angewandte
Chemie
DOI: 10.1002/anie.200802632
Natural Product Synthesis
Total Syntheses and Structural Revision of a- and b-Diversonolic Esters
and Total Syntheses of Diversonol and Blennolide C**
K. C. Nicolaou* and Ang Li
The structures of a- and b-diversonolic esters (1 and 2;
Figure 1)[1] define the key structural motifs of a growing
xanthone family of natural products,some members of which
Scheme 1. Structures of a- and b-diversonolic esters (1, 2, 4, and 5)
and diversonol (3).
Figure 1. ORTEP plots of compounds 2, 3, 18, and 22 derived from X-
ray crystallographic analysis (non-hydrogen atoms are shown with
ellipsoids at 30% probability).
In a program directed towards the total synthesis of these
molecules,we focused initially on the development of new
synthetic technologies for the synthesis of the basic molecular
framework of these xanthones; therefore,we turned our
attention to a- and b-diversonolic esters (1 and 2) and
diversonol (3),the simplest members of the family. Herein,we
report the development of an expedient synthetic strategy for
the construction of the diversonolic architecture,its applica-
tion to the concise total syntheses of all three structures 1–3,
and the revision of the originally proposed structures for a-
and b-diversonolic esters 1 and 2 to 4 and 5,respectively.
Scheme 2 summarizes the devised synthesis of the origi-
nally assigned structures of a- and b-diversonolic esters 1 and
2. Thus,treatment of racemic enone 6 with Et2AlCN followed
by trapping with TMSCl in the presence of pyridine furnished
the corresponding enol ether,which was transformed (with-
out isolation) into nitrile enone 7 through the action of
IBX·MPO,[6] in 62% overall yield. Conversion of 7 into its
ester enone counterpart 8 required reduction with DIBAL-H
(hydroxy aldehyde),oxidation with DMP (keto aldehyde;
83% yield over two steps),Pinnick oxidation,and treatment
with TMSCHN2 (90% yield over two steps). Ester enone 8
was then converted into bromo hydroxy ester 9 (ca. 1.3:1 d.r.)
through sequential treatment with bromine and Et3N (bromo
enone; 94% yield),followed by reduction with NaBH 4/CeCl3
(91% yield). Deprotonation of 9 with MeLi (1.1 equiv)
exhibit striking antibiotic activities. Among them are diver-
sonol (3; Scheme 1),[2] the first member of the monomeric
series within the class,as well as the rugulotrosins, [3] secalonic
acids[4] and hirtusneanoside,[5] all of which are dimeric in
nature.
[*] Prof. Dr. K. C. Nicolaou, A. Li
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 92093 (USA)
[**] We thank Dr. R. K. Chadha, Dr. D. H. Huang, and Dr. G. Siuzdak for
X-ray crystallographic, NMR spectroscopic, and mass spectrometric
assistance, respectively. We also gratefully acknowledge Prof. S.
Bräse and Prof. R. J. Capon for providing the spectra of synthetic
diversonol and natural rugulotrosins, respectively, as well as Dr.
D. J. Edmonds and Dr. A. F. Lenzen for helpful discussions. This
work was supported by the National Institutes of Health, the Skaggs
Institute for Chemical Biology, and a Bristol-Myers Squibb Graduate
Fellowship (to A.L.).
Supporting information for this article is available on the WWW
underhttp://dx.doi.org/10.1002/anie.200802632.
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At this stage,and not yet knowing the true structures of a-
and b-diversonolic esters,we turned our attention to the
synthesis of diversonol (3) through application of the
synthetic strategy we had developed. Thus,by substituting
the nitrile moiety with a methyl group in the starting enone
(now 13; Scheme 3) and following a similar route as before,
Scheme 2. Synthesis of the proposed structures of a- and b-diverso-
nolic esters (1 and 2). Reagents and conditions: a) Et2AlCN (1.0m in
toluene, 1.2 equiv), toluene, 238C, 30 min; then pyridine (3.0 equiv),
TMSCl (1.8 equiv), 0!238C, 1 h; b) IBX (1.2 equiv), MPO (1.2 equiv),
DMSO, 238C, 1 h, 62% (over2 steps); c) DIBAL-H (1.0 m in CH2Cl2,
2.5 equiv), toluene, ꢀ78!ꢀ408C, 30 min; then DMP (1.2 equiv),
CH2Cl2, 238C, 45 min, 83%; d) NaClO2 (3.0 equiv), 2-methyl-2-butene
(10 equiv), NaH2PO4 (5.0 equiv), tBuOH/H2O (1:1), 238C, 1 h;
e) TMSCHN2 (2.0m in diethyl ether, 2.0 equiv), MeOH, 08C, 20 min,
90% (over2 steps); f) Br 2 (1.05 equiv), CH2Cl2, 08C, 5 min; then Et3N
(1.5 equiv), 08C, 5 min, 94%; g) CeCl3·7H2O (1.2 equiv), NaBH4
(2.0 equiv), MeOH, 08C, 30 min, 91% (ca. 1.3:1 d.r.); h) MeLi (1.6m
in diethyl ether, 1.1 equiv), diethyl ether, ꢀ788C, 15 min; then tBuLi
(1.7m in pentane, 2.2 equiv), ꢀ788C, 15 min; then 10 (1.5 equiv),
ꢀ78!ꢀ408C, 40 min; i) IBX (2.0 equiv), DMSO, 238C, 1 h, 41% (over
2 steps); j) HF·py/THF (1:5), 238C, 12 h, 89%; k) nBu3SnH
Scheme 3. Total synthesis of diversonol (3). Reagents and conditions:
a) Br2 (1.05 equiv), CH2Cl2, 08C, 5 min; then Et3N (1.5 equiv), 08C,
5 min, 90%; b) DIBAL-H (1.0m in hexanes, 1.5 equiv), THF, ꢀ78!
ꢀ408C, 30 min, 95% (ca. 1:1 d.r.); c) MeLi (1.6m in diethyl ether,
1.1 equiv), diethyl ether, ꢀ788C, 15 min; then tBuLi (1.7m in pentane,
2.2 equiv), ꢀ788C, 15 min; then 15 (1.5 equiv), ꢀ78!ꢀ408C, 40 min;
d) IBX (3.0 equiv), DMSO, 238C, 1 h, 72% (over2 steps); e) HF·py/
THF (1:5), 238C, 12 h, 96%; f) nBu3SnH (2.2 equiv), AcOH (2.2 equiv),
[Pd(PPh3)4] (0.05 equiv), benzene, 238C, 1 h, 90% (17/18 ca. 2:1 d.r.);
g) MMPP (0.75 equiv), EtOH, 238C, 30 min; h) NaBH4 (1.0 equiv),
MeOH/CH2Cl2 (1:1), ꢀ788C, 15 min, 73% (over2 steps).
(2.2 equiv), AcOH (2.2 equiv), [Pd(PPh3)4](0.05 equiv), benzene, 238C,
1 h, 60% (1/2 ca. 2:1 d.r.). DIBAL-H=diisobutylaluminum hydride,
DMP=Dess–Martin periodinane, DMSO=dimethyl sulfoxide, IBX=o-
iodoxybenzoic acid, MPO=4-methoxypyridine-N-oxide, py=pyridine,
TMS=trimethylsilyl, TBS=tert-butyldimethylsilyl.
MMPP=magnesium monoperoxophthalate.
followed by sequential treatment with tBuLi and acyl cyanide
10 afforded the expected alcohol (ca. 1.3:1 d.r.),which was
oxidized with IBX to give diketone 11 in 41% overall yield.
Finally,desilylation of 11 (HF·py) followed by deallylation
(nBu3SnH,[Pd(PPh 3)4] cat.) furnished compounds 1 and 2 (1/
2 ca. 2:1,separated by chromatography),presumably through
but proceeding through intermediates 14–19 (17/18 ca. 2:1),
we arrived at diversonol (3) in eight steps as summarized in
Scheme 3. The spectroscopic data (1H and 13C NMR analysis)
of synthetic diversonol matched those reported for the natural
substance[2] and those of another sample of synthetic diver-
sonol,which was kindly provided by Professor S. Bräse
(whose group was the first to synthesize this natural
product).[9] The structures of synthetic compounds 18
(m.p. 154–1558C,EtOAc/hexanes 1:1) and 3 were also con-
firmed by X-ray crystallographic analysis (see the ORTEP
plot; Figure 1).[8]In what turned out to be a fortunate twist of
fate,and while aiming to improve and streamline our
synthesis of diversonol (3),we decided to employ MOM
1
intermediate 12. However,the spectroscopic data ( H and
13C NMR analysis) of these compounds did not match those
reported[1] for the natural products a- and b-diversonolic
esters. The skeletal connectivity of compounds 1 and 2 was
established by HMBC studies and their relative stereochem-
istry was assigned by comparison of NMR data with similar
compounds.[7] The structure of 2 (m.p. 183–1848C,EtOAc/
hexanes 1:1) was verified by X-ray crystallographic analysis
(see the ORTEP plot; Figure 1).[8]
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protecting groups on the aromatic segment of the
molecule (aldehyde 20; Scheme 4). Therefore,we
proceeded with preparing intermediate 21
(Scheme 3) by the same route as above,and where
global removal of the protecting groups of 21,under
acidic conditions,was expected to give compound 17
(Scheme 3) in one step rather than two steps,thus
avoiding the organometallic reagent and catalyst
employed in the first route. Upon exposure of 21 to
aqueous HClO4,however,we did not observe any of
the expected products (i.e. 17 and 18; Scheme 3),but
instead we obtained two new compounds (ca. 2:1,
chromatographically separated,silica gel,EtOAc/
hexanes 1:1) which were isomeric in nature relative to
the previously obtained products (17 and 18). For-
tunately,one of these compounds (the less polar)
crystallized from EtOAc/hexanes (1:1) to form beau-
tiful colorless needles (m.p. 175–1768C,EtOAc/hex-
anes 1:1). Single crystal X-ray analysis (see the
ORTEP plot; Figure 1)[8] revealed its structure as
22,and hence,the structure of the other isomer was 23
(Scheme 3).
Scheme 5. Postulated mechanism of the formation of 22 and 23.
Scheme 6. Total synthesis of the revised structures of a- and b-
diversonolic esters (4 and 5). Reagents and conditions: a) MeLi (1.6m
in diethyl ether, 1.1 equiv), diethyl ether, ꢀ788C, 15 min; then tBuLi
(1.7m in pentane, 2.2 equiv), ꢀ788C, 15 min; then 20 (1.5 equiv),
ꢀ78!ꢀ408C, 40 min; b) IBX (2.0 equiv), DMSO, 238C, 1 h, 45%
(over2 steps); c) 1.0 m aqueous HClO4/THF (1:1), 508C, 2 h, 80%
(4/5 ca. 1:3 d.r.).
Scheme 4. Construction of compounds 22 and 23. Reagents and
conditions: a) MeLi (1.6m in diethyl ether, 1.1 equiv), diethyl ether,
ꢀ788C, 15 min; then tBuLi (1.7m in pentane, 2.2 equiv), ꢀ788C,
15 min; then 20 (1.5 equiv), ꢀ78!ꢀ408C, 40 min; b) IBX (3.0 equiv),
DMSO, 228C, 1 h, 78% (over2 steps); c) 1.0 m aqueous HClO4/THF
(1:1), 408C, 2 h, 90% (22/23 ca. 2:1 d.r.). MOM=methoxymethyl.
The proposed mechanism for the formation of compounds
22 and 23 from 21,through postulated intermediates 24–26
(Scheme 5),served as the basis for the total synthesis and
structural revision of the a- and b-diversonolic esters.
Apparently,the initially formed structures undergo skeletal
rearrangements to give structures such as 22 and 23 under the
acidic conditions employed for the deprotection. The simi-
larity of the NMR data of 22 and 23 to those of the natural
diversonolic esters led us to propose structures 4 and 5 as the
revised structures of 1 and 2,respectively. Scheme 6 summa-
rizes our syntheses of 4 and 5 starting with the hydroxy bromo
ester 9 and bisMOM-protected acyl cyanide 27,and which
proceeds through intermediate 28 (4/5 ca. 1:3 d.r.). The
spectroscopic properties of synthetic diversonolic esters 4
and 5 were consistent with their structures and matched those
reported[1] for the naturally occurring substances. The struc-
tural connectivity of 4 and 5 were established by HMBC
studies,and their relative stereochemistries were assigned by
nOe analysis. The revised structures of a- and b-diversonolic
esters (4 and 5) also explain the ambiguities in the spectro-
scopic and chemical properties of these compounds which
were described in the original isolation report.[1]
In a final twist,a naturally occurring compound named
blennolide C,bearing the structure of 2,was reported [10] while
this manuscript was in preparation. Although a natural
product with the structure 1 has not yet been reported,it
can be predicted to exist,especially as it is present as a
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Communications
[4] B. Franck,E. M. Gottschalk,U. Ohnsorge,G. Baumann, Angew.
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monomeric unit in some dimeric natural products such as the
rugulotrosins.[3]
Besides uncovering the true structures of a- and b-
diversonolic esters and thus rendering them,diversonol,and
blennolide C readily available,the described chemistry opens
an expedient entry into these and the more complex members
of this class of natural products,which include their enantio-
merically pure forms and their analogues. As both enantio-
mers of the starting materials (6[11] and 13[12]) are known,the
as yet undetermined absolute stereochemistry of all three
natural products (3–5) should now be easily discernable.
Finally,biological investigations using the synthesized com-
pounds may reveal interesting properties.
[7] P. H. Ducrot,J. Y. Lallemand,M. L. Milat,J. P. Blen,
Tetrahe-
dron Lett. 1994, 35,8797 – 8800. The spectra of 1 and 2 also
showed great similarity to those of 18 and 17,respectively.
[8] CDCC 689919 (2),CDCC 689920 ( 3),CDCC 689921 ( 18),and
CDCC 689922 (22) contain the supplementary 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.
[9] C. F. Nising,U. K. Ohnemüller,S. Bräse, Angew. Chem. 2006,
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Schulz, Chem. Eur. J. 2008, 14,4913 – 4923. These authors
recognized that the structure of the diversonoic ester needed to
be revised. The spectroscopic data of the synthesized compound
2 were identical to those reported for natural blennolide C.
[11] a) Z. Hua,W. Yu,M. Su,Z. Jin, Org. Lett. 2005, 7,1939 – 1942;
b) J. E. Audia,L. Boisvert,A. D. Patten,A. Villalobos,S. J.
Danishefsky, J. Org. Chem. 1989, 54,3738 – 3740.
Received: June 4,2008
Published online: July 24,2008
Keywords: natural products · structural reassignment ·
.
total synthesis · xanthones
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