Stereoselective Total Synthesis of (+)-Norrisolide

Article abstract of DOI:10.1002/anie.200352868

In a convergent approach to the marine natural product (+)-norrisolide (1) the two bicyclic ring systems are coupled through the C9-C10 bond to assemble the carbon framework in a late stage of the synthesis. Other highlights of the synthetic strategy incl

Full text of DOI:10.1002/anie.200352868

Angewandte
Chemie
Natural Products Synthesis
Our retrosynthetic strategy towards norrisolide (1) is
illustrated in Scheme 2. As we were concerned about the
Stereoselective Total Synthesis of
(+)-Norrisolide**
potential reactivity of the fused g-lactone–g-lactol motif
Thomas P. Brady, Sun Hee Kim, Ke Wen, and
Emmanuel A. Theodorakis*
In memory of David J. Faulkner
Nudibranch molluscs are known to harvest a variety of
chemical metabolites from sponges and use them for their
own defense.[1,2] In an effort to understand this behavior from
a chemical perspective, Faulkner and co-workers isolated a
novel diterpene named norrisolide (1) from the skin extracts
of the dorid nudibranch Chromodoris norrisi.[3] Further
studies led to the isolation of 1 from different species of
sponges that support the feeding patterns of these molluscs.[4]
From a structural standpoint, norrisolide belongs to a
family of marine diterpenes that also includes macfarlandin C
(2) and dendrillolide A (3; Scheme 1).[5] These natural
Scheme 2. Strategic bond disconnections of 1. TBDPS=tert-butyldi-
phenylsilyl.
towards nucleophilic attack, we attempted the synthesis of 1
via the less-oxygenated and more-stable precursor 4.[9] In the
forward direction, we envisaged that 4 could be converted
into the natural product through oxidation at C14 and
subsequent insertion of an oxygen atom between the C19
and C21 centers. The latter manipulation would be possible, in
principle, by a Baeyer–Villiger oxidation, which was expected
[10]
to proceed in a regio-and stereoselective manner.
Dis-
Scheme 1. Representative natural products with a fused
tetrahydrofuran–g-lactone ring system
ꢀ
connection at the C9 C10 bond in 4 unveils components 5
and 6, which could be connected in the desired manner by a
nucleophilic reaction at the aldehyde in 6. It was planned to
construct the bicyclic framework of 6 from the lactone 8,
which contains the desired cis stereochemistry at the C11 and
C12 centers. The trans-fused hydrindane motif of 5 could be
formed from the enantiomerically enriched enone (+)-7. Our
efforts to bring this plan to fruition are highlighted in the
schemes that follow.
products share a common structural motif characterized by
a fused g-lactone–g-lactol ring system attached to a hydro-
phobic bicyclic core. The unusual pattern of functionalities
encountered in this highly oxygenated system confers to these
molecules a high degree of chemical reactivity, the biological
significance of which remains largely unexplored.[6] Herein we
describe a stereoselective synthesis of (+)-norrisolide (1). Not
only have our studies led to the first synthesis of any member
of this family of diterpenes, but they have also established the
absolute configuration of 1 to be that shown in Scheme 1.[7,8]
Our synthetic approach began with the optically pure
enone 7, which was available through an l-phenylalanine-
mediated asymmetric Robinson annulation (55–65% yield,
> 95% ee after a single recrystallization).[11] Selective reduc-
tion at the more reactive C9 carbonyl group, followed by
protection of the resulting alcohol, afforded the silyl ether 9 in
76% yield over the two steps (Scheme 3).[12] Methylation of
the extended enolate of 9 at the C5 center produced ketone 10
(66% yield), the reduction and radical deoxygenation of
which led to the alkene 11 in 83% yield (from 10). Several
methods were examined for the conversion of the alkene 11
into the trans-fused bicycle 12.[13] The best results were
obtained by hydroxylation of the double bond (ratio at C6:
trans/cis 2.5:1) and subsequent reduction of the resulting
alcohol (52% yield from 11). The use of the bulky TBDPS
group to protect the C9 hydroxy group was found to be crucial
in terms of the diastereomeric outcome of the hydroxylation
reaction.[11d] Fluoride-induced desilylation of 12 followed by
[*] T. P. Brady, S. H. Kim, K. Wen, Prof. E. A. Theodorakis
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, MC, 0358 La Jolla, CA 92093-0358 (USA)
Fax: (+1)858-822-0386
E-mail: etheodor@chem.ucsd.edu
[**] Financial support from the NIH (CA 086079) is gratefully acknowl-
edged. We also thank Dr. L. N. Zakharov and Dr. P. Gantzel (UCSD,
X-Ray Facility) for the crystallographic studies reported and
Professor D. J. Faulkner (Scripps Institute of Oceanography) for a
sample of natural norrisolide.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200352868
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Communications
Scheme 3. Reagents and conditions: a) NaBH4 (0.33 equiv), EtOH,
Scheme 4. Reagents and conditions: a) AlCl3 (0.33 equiv), CH2Cl2,
608C, 6 days, 85%; b) DIBAL-H (1.2 equiv), CH2Cl2, ꢀ788C, 0.5 h,
98%; c) OsO4 (0.01 equiv), NMO (1.1 equiv), pyridine (3 drops),
acetone/H2O (10:1), 258C, 8 h; d) Pb(OAc)4 (1.2 equiv), CH2Cl2, 08C,
0.5 h, 64% (over two steps); e) MeOH (1.2 equiv), amberlyst 15,
molecular sieves (3 ꢀ), Et2O, 258C, 10 h, 77% (18a/18b 1:1);
f) NaBH4 (1.5 equiv), MeOH, 258C, 0.5 h; g) imidazole (2.2 equiv),
PPh3 (1.1 equiv), I2 (1.2 equiv), THF, 258C, 0.5 h, 93% (over two
steps); h) (PhSe)2 (0.55 equiv), NaBH4 (1.5 equiv), EtOH, 258C, 0.5 h,
92%; i) NaIO4 (1.6 equiv), MeOH/H2O (5:2), 258C, 1 h, then Et3N/
PhH (1:1), reflux, 0.5 h, 90%; j) OsO4 (0.05 equiv), NMO (1.1 equiv),
pyridine (3 drops), acetone/H2O (10:1), 258C, 10 h; k) Pb(OAc)4
(1.2 equiv), CH2Cl2, 08C, 0.5 h, 94% (over two steps). DIBAL-H=
diisobutylaluminum hydride, NMO=4-methylmorpholine N-oxide.
ꢀ258C, 0.5 h, 99%; b) imidazole (2.5 equiv), TBDPSCl (2.0 equiv),
DMAP (0.1 equiv), DMF, 258C, 4 h, 77%; c) tBuOK, MeI, DMF, 258C,
1 h, 66%; d) NaBH4 (1.2 equiv), MeOH, 08C, 1 h, 100%; e) nBuLi
(1.2 equiv), 08C, 0.5 h, CS2 (10 equiv), 2 h, then MeI (3.0 equiv), THF,
0.5 h, 95%; f) nBu3SnH (2.5 equiv), AIBN (0.1 equiv), toluene, 1208C,
0.25 h, 87%; g) BH3·THF (3.0 equiv), THF, 08C, 12 h, then aqueous
NaOH (3m, 20 equiv), H2O2 (20 equiv), 258C, 12 h, 80% (56% trans,
24% cis); h) nBuLi (1.2 equiv), 08C, 0.5 h, CS2 (10 equiv), 2 h, then
MeI (3.0 equiv), THF, 08C, 0.5 h; i) nBu3SnH (2.5 equiv), AIBN
(0.1 equiv), toluene, 1208C, 0.25 h, 92% (over two steps); j) TBAF
(3.0 equiv), THF, 608C, 8 h, 99%; k) PCC (4.5 equiv), celite, CH2Cl2,
258C, 1 h, 92%; l) N2H4·H2O (30 equiv), Et3N (4.0 equiv), EtOH,
reflux, 5 h, 88%; m) I2 (until N2 evolution has ceased), Et3N
(10 equiv), THF, 258C, 0.25 h, 62%. AIBN=azobisisobutyronitrile,
DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide,
PCC=pyridinium chlorochromate TBAF=tetrabutylammonium
fluoride.
structure was confirmed unambiguously by X-ray crystallo-
graphic analysis.[15]
The remaining steps in the synthesis of 1 are illustrated in
Scheme 5. Lithiation of the vinyl iodide 5, followed by
addition of the aldehyde 6 and oxidation of the resulting
alcohol, afforded the enone 21 in 71% yield. Hydrogenation
PCC oxidation provided the ketone 13 in 91% yield.[14] The
treatment of 13 with hydrazine then produced the hydrazone
14. Single-crystal X-ray diffraction analysis of 14 showed the
trans junction of the bicycle unambiguously.[15] Finally, treat-
ment of 14 with I2/Et3N led to the formation of the desired
vinyl iodide 5 (62% yield).[16]
ꢀ
of the C8 C9 double bond proceeded exclusively from the
more accessible a face of the bicyclic core to form the ketone
22 in 75% yield. Standard olefination procedures (Wittig,
Peterson) failed to convert 22 into 4, presumably as a result of
the steric hindrance at the C10 carbonyl group. This obstacle
was circumvented by implementing a two-step procedure that
included methylation of the ketone 22 (MeLi, DME) and
treatment of the resulting alcohol with SOCl2 in the presence
of pyridine.[22] This manipulation produced the alkene 4 in
64% yield from 22.
The construction of aldehyde 6 is highlighted in Scheme 4.
The C11 and C12 centers were connected by a Diels–Alder
reaction between the butenolide 15[17] and butadiene (16).
Under Lewis acid catalysis this cycloaddition proceeded
exclusively from the opposite face to that with the bulky
TBDPS group to afford 8 as a single isomer (85% yield).[18]
Reduction of the lactone unit at C20, followed by oxidative
cleavage of the alkene in the other ring, produced the fused
lactol 17 in 63% yield as a 1:1 mixture of isomers at C14.
These compounds were separated[19] after conversion into the
corresponding methyl ether 18.[20] The aldehyde 18 (b isomer
with respect to C14) was then converted into the selenide 19,
which underwent oxidation and elimination to give the alkene
20 (61% from 18).[21] Osmylation of 20, followed by oxidative
cleavage of the resulting diol, furnished the aldehyde 6 (two
steps, 94% yield). The aldehyde 6 was crystalline and its
With substrate 4 in hand the stage was now set for the final
functionalization of the oxygenated bicycle (Scheme 5). The
silyl ether at C21 was cleaved (99% yield), and the resulting
alcohol was then oxidized to the aldehyde 23[23] and sub-
sequently converted into the ketone 24 (MeMgBr, then Dess–
Martin oxidation, 68% yield). Treatment of 24 with CrO3 in
aqueous acetic acid produced the lactone 25 in 80% yield.[24]
Finally, Baeyer–Villiger oxidation of 25 (MCPBA, NaHCO3,
60% yield) led to insertion of the oxygen atom as desired
between the C19 and C21 centers with complete retention of
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Chemie
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[6] For recent biological data on related metabolites, see: M. Arno,
L. Betancur-Galvis, M. A. Gonzalez, J. Sierra, R. J. Zaragoza,
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[9] For a catalytic asymmetric Diels–Alder approach to a related
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Letavic, J. Am. Chem. Soc. 1995, 117, 9616 – 9617.
[10] For selected reports on the Baeyer–Villiger reaction, see: a) M.
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[12] All new compounds exhibited satisfactory spectroscopic and
analytical data (see Supporting Information). Yields refer to
spectroscopically and chromatographically homogeneous mate-
rials.
[13] All hydrogenation conditions produced a mixture of cis (major
product) and trans bicycles, which were difficult to separate by
using standard chromatographic techniques.
[14] For an alternative synthetic route to 13, see: a) L. Paquette, H.-
L. Wang, Tetrahedron Lett. 1995, 36, 6005 – 6008; b) L. Paquette,
H.-L. Wang, J. Org. Chem. 1996, 61, 5352 – 5357.
[15] CCDC-216393 (14) and CCDC-216394 (6) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrie-
ving.html (or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB21EZ, UK; fax: (+ 44)1223-
336-033; or deposit@ccdc.cam.ac.uk).
Scheme 5. Reagents and conditions: a) 5 (1.5 equiv), tBuLi (3.0 equiv),
THF, ꢀ78!ꢀ408C, 0.5 h, then 6, THF, ꢀ788C, 1 h, 75%; b) Dess–
Martin periodinane (8.0 equiv), CH2Cl2, 258C, 10 h, 95%; c) 10% Pd/
C, H2, MeOH, 258C, 10 h, 85%; d) MeLi (5.0 equiv), THF/DME (1:3),
08C, 0.5 h, 75%; e) SOCl2 (10.0 equiv), pyridine (20.0 equiv), CH2Cl2,
08C, 0.5 h, 85%; f) TBAF (2.0 equiv), THF, 258C, 8 h, 99%; g) IBX
(3.0 equiv), MeCN, 808C, 2 h, 96%; h) MeMgBr (10.0 equiv), THF,
08C, 0.5 h, 72%; i) Dess–Martin periodinane (2.5 equiv), CH2Cl2, 258C,
6 h, 94%; j) CrO3 (10 equiv), AcOH/H2O (2:1), 258C, 6 h, 80%;
k) MCPBA (2.5 equiv), NaHCO3 (2.5 equiv), CH2Cl2, 08C, 4 h, 60%.
DME=dimethoxyethane, DM[O]=Dess–Martin oxidation, IBX=1-hy-
droxy-1,2-benziodoxol-3(1H)-one 1-oxide, MCPBA=m-chloroperben-
zoic acid.
configuration[10] to produce norrisolide (1). Synthetic 1 was
spectroscopically and analytically identical to natural norri-
solide (1).
In conclusion, we have presented herein a synthesis of
(+)-norrisolide (1) that also establishes its absolute stereo-
chemistry. Our strategy is highlighted by the union of
fragments 5 and 6 to produce the natural product after
manipulations of the oxygenated bicyclic moiety. The syn-
thetic approach paves the way for the preparation of
analogues of 1 and will be helpful for the evaluation of the
biological potential of norrisolide and related metabolites.
Received: September 15, 2003 [Z52868]
Keywords: alkylation · Diels–Alder reaction · natural products ·
.
synthetic methods · total synthesis
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