Synthesis of a highly functionalized core of verrillin

Article abstract of DOI:10.1021/ol400872h

An efficient stereoselective synthesis of furanoverrillin (5), a highly functionalized core of verrillin (1), is reported. The synthetic strategy is based on constructing bicyclic lactone 17 prior to the 10-membered ring macrocyclization. The effect of the C₄ methyl group on the furan reactivity is also discussed.

Full text of DOI:10.1021/ol400872h

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of a Highly Functionalized Core
of Verrillin
Alec Saitman and Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, University of California, San Diego,
9500 Gilman Drive MC: 0358, La Jolla, California 92093-0358, United States
etheodor@ucsd.edu
Received March 29, 2013
ABSTRACT
An efficient stereoselective synthesis of furanoverrillin (5), a highly functionalized core of verrillin (1), is reported. The synthetic strategy is based
on constructing bicyclic lactone 17 prior to the 10-membered ring macrocyclization. The effect of the C4 methyl group on the furan reactivity is also
discussed.
Gorgonian octocorals and soft corals supply a diverse
array of diterpenes and C4-norditerpenes that biosynthe-
tically derive from a 14-membered cembrane skeleton.1
Among them, verrillin (1), bielschowskysin (2), inelegano-
lide (3) and plumarellide (4) are highlighted by a combina-
tion of intricate structural density and potent bioactivity
(Figure 1).1a,2 For example, bielschowskysin (2),3 a multi-
farious hexacyclic cembrenoid, was found to exhibit signifi-
cant antimalarial activity against Plasmodium falciparium
(IC50 ca. 10 μg/mL). In addition, potent cytotoxicity data
regarding 2 have been reported against nonsmall cell lung
cancer (EKVX, GI50 ca. 0.01 μM) and renal cancer cells
(CAKI-1, GI50 ca. 0.50 μM).3 Along these lines, inelega-
nolide (3) displays strong cytoxicity against P-388 cancer
cells (ED50 3.82 μg/mL).4 On the other hand, plumarellide
(4) exhibits moderate hemolytic activity in mice with 50%
hemolysis of mouse blood erythrocytes at 140 μM5 while
Figure 1. Structures of selected polycyclic cembrenoids.
the bioactivities of verrillin (1)6 have not yet been studied.
A commonality shared by these polycyclic cembrenoids
is an oxidative ring contraction of the 14-membered
(1) (a) Roethle, P. A.; Trauner, D. Nat. Prod. Rep. 2008, 25, 298–317.
(b) Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28, 429–440. (c) Li, Y.;
cembrane ring across the C7 and C11 carbons thereby
producing the verrillane core (6) (Figure 2).3,7 Subsequent
ring contractions across the C6 and C12 or the C6 and C14
centers would produce the bielschowskyane (9)1c,3,7 and
Pattenden, G. Nat. Prod. Rep. 2011, 28, 1269–1310.
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r
10.1021/ol400872h
XXXX American Chemical Society

the plumarane core (7),1c respectively. On the other hand,
oxidative demethylation followed by nucleophilic ring
contraction at the C4 and C13 centers could assemble the
inelegane core (8).1c
under NozakiÀHiyamaÀKishi (NHK) conditions12 could
afford the final C1ÀC2 linkage.
Scheme 1. Retrosynthetic Analysis of Furanoverrillin (5)
Scheme 2. Synthesis of Fragment 17
Figure 2. Carbocyclic scaffolds related to verrillane core 6.
Although several strategies toward the synthesis of
bielschowskysin8 (2) and plumarellide9 (4) have been
reported, none have generated a true cembrane scaffold
with relevant carbon connections and oxidation patterns.
Inspired by the challenge, we directed our efforts7,10
toward the synthesis of motif 5 that contains an appro-
priately functionalized verrillane core (Figure 2). Referred
to herein as furanoverrillin, compound 5 represents a
branching node toward the synthesis of verrillin (1) and
its more intricate brethren.
Scheme 1 highlights the key disconnections of furano-
verrillin (5) and identifies the essential synthetic fragments.
We envisioned that construction of the fused bicyclic
lactone, present in our target, could be furnished via an
Eschenmoser-Claisen rearrangement.11 This disconnec-
tion reveals allylic alcohol 13 and commercially available
amide acetal 12 as the coupling partners. Claisen alkyla-
tion of this adduct with aldehyde 11 could then create the
desired C12ÀC13 connection as well as provide the impor-
tant C13 oxidation present in this family of compounds.7
Pd(0)-coupling could then be used to join furan derivative
10 by creating the C6ÀC7 bond, while macrocylization
The synthesis of furanoverrillin (5) commenced with the
formation of lactone 17 (Scheme 2). Furfuryl alcohol 14
was rearranged to a cyclopentenone derivative under micro-
wave irradiation13 that, after TBS protection and regiose-
lective iodination,14 gave rise to iodo enone 15 (3 steps, 40%
overall yield). Nucleophilic addition onto the carbonyl with
methyl magnesium bromide yielded tertiary alcohol 13 as a
single diastereomer in good yield (52%). To our satisfac-
tion, the key Eschenmoser-Claisen rearrangement15 of 13
with 12 proceeded smoothly and in a diastereoselective
manner, to afford amide 16 (70% yield). Treatment of the
crude amide 16 with excess acid led to rapid cleavage of the
TBS group and cyclization of the resulting alcohol at the
amide carbonyl center to produce lactone 17 in 91% yield
(Scheme 2).
Deprotonation of 17 with freshly prepared LiHMDS
followed by quick addition of the previously described
aldehyde 117 supplied alcohol 18 as a 1:1.7 mixture of C13
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mined after macrocyclization via single crystal X-ray diffraction analysis
of compounds 25a and 33b.
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Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Synthesis of Furanoverrillin 5 and Derivatives
diastereomers (Scheme 3).7 These isomers, 18a and 18b,
were separated by column chromatography and used
separately in subsequent manipulations.16 TBS protection
of the newly installed alcohol functionality was markedly
slow and low yielding. Protection of the secondary alco-
hols 18a and 18b with MOMCl17 was also slow at room
temperature. Microwave irradiation conditions at 80 °C
for 10min, however, successfully yieldedthe desired MOM
protected alcohols. Selective TBS deprotection of this
crude material using PPTS in ethanol afforded primary
alcohols 19a and 19b (ca. 71% yield over 2 steps).18
The synthesis of methyl furfuryl stannane 10 was ac-
complished as shown in Scheme 4. Commercially available
furan derivative 26 was reduced to the corresponding
primary alcohol19 that, after oxidation with manganese
dioxide20 under microwave irradiation produced aldehyde
27 (2 steps, 85% yield). Stannylation of a transiently
protected aldehyde 27 with trimethyltin chloride afforded
stannane 10 in 65% yield.21 In a similar fashion, aldehyde
28 was converted to stannane 29.7,21
To our chagrin, coupling of stannane 10 with primary
alcohols19a and 19b under the previously establishedStille
conditions(Pd(PPh3)4/CuI)7,10,21 wasnotsuccessful. How-
ever, switching of reagents to catalytic Pd2(dba)3 and tri-
phenylarsine22 cleanly afforded compounds 20a and 20b in
65% average yield (Scheme 3). Appel bromination
conditions23 were employed to convert alcohols 20a and
20b to their corresponding bromides 22a and 22b (ca. 84%
yield).
The final macrocyclization event that would create the
10-membered macrocycle24 also proved to be more prob-
lematic than previously described7,10,21 leading to a com-
plex mixture of products. Changing the solvent from THF
toDMF25 greatly improved the reaction outcometoafford
furanoverrillin (5), containing the desired verrillin stereo-
chemistry at C13, together with its C13 R-isomer 24a in 30%
combined yield. The diastereoselectivity of the macrocy-
clization was 4/1 anti/syn with respect to the orientation of
the C2 alcohol and the C1 isopropene.24a
Compounds 5 and 24a were subjected to standard C2
deoxygenation conditions using triethylsilane and trifluoro-
acetic acid26 to produce deoxygenated products 30a and 30b
in lower than expected yields (ca. 40% yield) (Scheme 5).7,10,21
Scheme 4. Synthesis of Furfuryl Stannanes 10 and 29
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Org. Lett., Vol. XX, No. XX, XXXX
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Acid-induced MOM deprotection under microwave con-
ditions27 afforded the corresponding alcohols 32a and 32b
in an average yield of 72%.
nor-furanoverrillin intermediates 25a and 25b was ob-
served in good yields (ca. 60% yield). Deoxygenation at
the C2 center using triethylsilane and trifluoroacetic acid26
also cleanly produced deoxygenated intermediates 31a and
31b in noticeably increased yields. Finally, acidic removal
of the MOM group27 created alcohols 33a and 33b in
similar yields (ca. 72% yield). Along with a striking
improvement in reaction yields of the nor-furanoverrillin
derivatives was the ability to then obtain X-ray structures
for compounds 25b and 33b which confirmed the proposed
stereochemical assignments.29
Scheme 5. Synthesis of 32 and 33
In conclusion, we present herein a stereoselective synthe-
sis of furanoverrillin (5), a branching node toward the
synthesis of verrillin (1) and related polycyclic cembre-
noids. Our approach relies on introduction of the C7ÀC11
cyclopentene ring prior to the macrocyclization of the fully
functionalized verrillin core. We observed that the pres-
ence of a C4 methyl group at the furan ring increases its
susceptibility toward oxidative decomposition. In turn,
this attests to the role of the C4 methyl group in oxidative
rearrangements that account for the plethora of polycyclic
cembranes isolated thus far. The described strategy pro-
duces, for the first time, the entire carbon framework of
verrillin and allows for further functionalization toward
verrillin (1) and structurally related natural products.30
During this study, we observed modest yields in con-
verting 22a and 22b to 24a and 5, respectively (Scheme 3).
This may be due to the inherent tendency of these com-
pounds to undergo carbocationic rearrangements at the C2
center, as previously reported for certain C2 hydroxy-
furanocembrenolides and pseudottedanolides.28 An alter-
native explanation is to consider that, due to its high
electronic density, the furan ring becomes sensitive to
oxidative decomposition. To test this hypothesis we re-
peated the aforementioned sequence using the nonmethyl-
ated furfuraldehyde 28 instead of its methylated analogue
27. To this end, we coupled the previously synthesized
furfural stannane 297,10 withalcohols19a and 19b toafford
21a and 21b in comparable yields (ca. 65% yield). Appel
conditions7,10,21,23 also smoothly afforded bromides 23a
and 23b again, in nearly identical yields (ca. 84% yield).
When optimized NHK12 conditions were then applied
using DMF as a solvent,25 a clean conversion to the desired
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (NIH) for financial support of
this work through Grant Number R01 GM081484. We
thank the National Science Foundation for instrumenta-
tiongrantsCHE9709183andCHE0741968. Wealsothank
Dr. Anthony Mrse (UCSD NMR Facility), Dr. Yongxuan
Su (UCSD MS Facility) and Dr. Arnold L. Rheingold and
Dr. Curtis E. Moore (UCSD X-ray Facility). We also
thank Danaya Pratchayanan and Parawin Adisayathepkul
(UCSD, Summer Undergraduate Internship) for their
efforts in synthesizing early stage intermediates.
Supporting Information Available. Detailed experimen-
tal procedures, spectral characterization and copies of 1H
and 13C NMR data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(30) (a) Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett.
2006, 8, 5901–5904. (b) Tang, B.; Bray, C. D.; Pattenden, G. Tetrahedron
Lett. 2008, 47, 6401–6404. (c) Kimbrough, T. J.; Roethle, P. A.; Mayer,
P.; Trauner, D. Angew. Chem., Int. Ed. 2010, 49, 1–4. (d) Marshall, J. A.;
Griot, C. A.; Chobanian, H. R.; Myers, W. H. Org. Lett. 2010, 12, 4328–
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J. Med. Chem. 1995, 38, 4704–4709. (b) Rodriguez, A. D.; Shi, J.-G.; Shi,
Y.-P. J. Org. Chem. 2000, 65, 3192–3199.
(29) CCDC 929062 (25a) and 929063 (33b) contain the supplemen-
tary crystallographic data. This information can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/products/csd/request/. In the figures, some hydrogen
atoms have been removed for clarity.
The authors declare no competing financial interest.
D
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