Synthesis of the tricyclic core of labiatin A and Australin A

Article abstract of DOI:10.1021/ol201498g

A concise synthesis of the tricyclic core of the marine diterpene natural products labiatin A and australin A has been accomplished. The key ring-forming transformation is a cascade reaction comprising generation of a copper carbenoid from a diazo ketone,

Full text of DOI:10.1021/ol201498g

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3980–3983
Synthesis of the Tricyclic Core of Labiatin
A and Australin A
J. Stephen Clark,* David Vignard, and Andrew Parkin
WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building,
University Avenue, Glasgow G12 8QQ, United Kingdom
stephen.clark@glasgow.ac.uk
Received June 3, 2011
ABSTRACT
A concise synthesis of the tricyclic core of the marine diterpene natural products labiatin A and australin A has been accomplished. The key ring-
forming transformation is a cascade reaction comprising generation of a copper carbenoid from a diazo ketone, intramolecular reaction of the
carbenoid with a cyclic ether, and rearrangement of the resulting free oxonium ylide or its metal-bound equivalent with ring expansion of the
original cyclic ether.
Labiatin A and australin A are members of the cladiellin
(eunicillin) family of marine diterpene natural products.
These compounds differ structurally from the other cladiel-
lins in that they possess an ether bridge between C-2 and C-6
(cladiellin numbering) rather than the usual C-2ÀC-9 ether
linkage (Figure 1).1 Neither of these natural products has
been the subject of published synthetic endeavors by other
research groups, and so they present new challenges to those
working in the area of marine diterpene synthesis.
Labiatin A was first isolated from extracts of the gorgo-
nianEunicella Labiata collected by Fenical and co-workers
in the Atlantic Ocean off the coast of Senegal.2 Fenical and
co-workers determined the structure of labiatin A, apart
from its absolute configuration, along with those of four
other cladiellins;labiatins B and C and labiatamides A
and B;isolated from the same source. Labiatin A was
found to be structurally anomalous because it possesses a
C-2ÀC-6 ether bridge instead of the C-2ÀC-9 ether linkage
foundintheotherditerpenesisolatedfromthesamesample
of Eunicella Labiata. Although bioactivity data for labiatin A
were not disclosed by Fenical and co-workers, labiatin B was
reported to exhibit significant cytotoxicity against human
colon cancer cells (HCT-116; ED50 = 0.85 μg mLÀ1).2
In 2005, Sheu and co-workers reported the structural
characterization (absolute stereochemistry excepted) of a
group of new cladiellin natural products isolated from
extracts of the soft coral Cladiella australis collected off the
south coast of Taiwan and named them australins AÀD.3
Interestingly, australins A and D possess the same unusual
C-2ÀC-6 ether bridged core structure as labiatin A. In fact,
australin A is simply the doubly deacetylated analogue of
labiatin A, possessing free hydroxyl groups at C-3 and C-7.
Biological evaluation of australins B and D revealed that
australin B has modest cytotoxic activity and that australin
D has weak activity against MDA-MB-231 cells (ED50 =
24.4 μg mLÀ1).3 Very recently, four additional members of
the australin family (EÀH) possessing the unusual C-2ÀC-6
(1) (a) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531–
556. (b) Sung, P.-J.; Chen, M.-C. Heterocycles 2002, 57, 1705–1715.
(2) Roussis, V.; Fenical, W.; Vagias, C.; Kornprobst, J.-M.; Miralles,
J. Tetrahedron 1996, 52, 2735–2742.
(3) Ahmed, A. F.; Wu, M.-H.; Wang, G.-H.; Wu, Y.-C.; Sheu, J.-H.
J. Nat. Prod. 2005, 68, 1051–1055.
r
10.1021/ol201498g
Published on Web 07/06/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Analysis of Labiatin A
Figure 1. A selection of labiatins, labiatamides, and australins.
ether bridged core have been isolated from a Cladiella
species and one of them (australin E) has been shown to
activate the inositol 5-phosphate SHIP1 in vitro.4
enantioselective deprotonation with Koga’s base8 and in
situ enolate quench with trimethylsilyl chloride and then
Saegusa oxidation of the resulting silyl enol ether using a
substoichiometric amount of palladium(II) acetate.9 (R)-
Cryptone (2) was then subjected to a MoritaÀBaylisÀHill-
man reaction with formaldehyde to give the hydroxyenone
3.10 The reaction failed to reach completion, but (R)-cryptone
was recovered and resubmitted to the reaction. Luche reduc-
tion converted the hydroxyenone 3into the corresponding diol
(10:1 dr), and the major diastereomer was then transformed
into the benzylidene acetal 4. Regioselective acetal reduction
We became interested in the synthesis of labiatin A and
australin A as part of our wider research program con-
cerning the development of a completely general and
flexible approach to the synthesis of the entire cladiellin
family of natural products.5,6 In particular, we wanted to
discover whether our recently developed synthetic strategy
could be applied tothe synthesis of labiatin A and australin
A and our key ring-forming reaction could be used to
constructthe ABringsystemwhile simultaneouslygrafting
this onto the preformed C ring.
Our retrosynthetic analysis was guided by previous
model studies (Scheme 1).7 It commences with removal
of the acetate groups, disconnection of two of the methyl
groups, and replacement of the ring B carbonyl group with
a C-9ÀC-10 alkene to give the diketone i. Disconnection of
the A and B rings by recognition of the key rearrangement
of an oxonium ylide or a metal-bound equivalent in the
forward direction leads to the diazo ketone ii. Removal of
the methyl (C-16) and diazo groups gives the simple
dihydrofuranone iii, and disconnection of the ring by
identification of a carbenoid CÀH insertion reaction in
the forward direction leads tothe diazo ketone iv. Removal
of the diazo group and disconnection of the ether linkage
reveals the alcohol v and (R)-cryptone as starting materials.
Synthesis of the tricyclic core commenced with construc-
tion of ring C (Scheme 2). The commercially available
enone 1 was converted into (R)-cryptone (2) in high ee by
Scheme 2. Enantioselective Synthesis of Ring C
(4) Williams, D. E.; Amlani, A.; Dewi, A. S.; Patrick, B. O.; van
Ofwegen, L.; Mui, A. L.-F.; Andersen, R. J. Aust. J. Chem. 2010, 63,
895–900.
(5) Clark, J. S.; Hayes, S. T.; Wilson, C.; Gobbi, L. Angew. Chem.,
Int. Ed. 2007, 46, 437–440.
(6) Clark, J. S.; Berger, R.; Hayes, S. T.; Thomas, L. H.; Morrison,
A. J.; Gobbi, L. Angew. Chem., Int. Ed. 2010, 49, 9867–9870.
(7) Clark, J. S.; Baxter, C. A.; Castro, J. L. Synthesis 2005, 3398–
3404.
(8) Aoki, K.; Koga, K. Tetrahedron Lett. 1997, 38, 2505–2506.
Org. Lett., Vol. 13, No. 15, 2011
3981

using DIBAL-H11 gave the alcohol 5, and this was converted
into the bromide 6 via the corresponding mesylate.
of alcohols from which the alcohol 13 was isolated in
54% yield (Scheme 4). Acetylation of the alcohol 13
followed by removal of the PMB group using DDQ
afforded the alcohol 14. DessÀMartin oxidation of
this alcohol to give the aldehyde 15 followed by Pin-
nick-type oxidation delivered the carboxylic acid 16.13
Deprotonation of the carboxylic acid and reaction
with oxalyl chloride afforded the acid chloride which
was immediately treated with diazomethane to deliver
the diazo ketone 17.
The alcohol 7, prepared from D-mannitol using a proce-
dure described by us previously,12 was coupled to the
bromide 6 using standard etherification conditions
(Scheme 3). The resulting ether (8) was then treated with
pyridinium p-toluenesulfonate(PPTS)inethyleneglycol to
cleave the acetonide, and the resulting 1,2-diol was sub-
jected to periodate cleavage to furnish the aldehyde 9.
Oxidation13 gave the carboxylic acid 10, and this was
converted into the diazo ketone 11 by formation of a mixed
anhydride and subsequent treatment with diazomethane.
The carbenoid CÀH insertion reaction was performed
using rhodium(II) trifluoroacetamide in THF at room tem-
perature.7 The reaction delivered a diastereomeric mixture
of dihydrofuranones (66% yield; 7:1 favoring 12) resulting
from insertion at the allylic site adjacent to the ether.
Diastereomers were not separated, and the mixture
was used directly in the next reaction.
Scheme 4. Construction of the Key Cyclization Precursor
Scheme 3. Fragment Coupling and Dihydrofuranone
Formation
The construction of the diazo ketone 17 allowed the
pivotal carbenoid cyclization reaction to be investigated
(Scheme 5). Treatment of the substrate 17 with copper-
(II) hexafluoroacetylacetonate in dichloromethane at
reflux resulted in formation of the required tricyclic
ketone 18 in 76% yield as a single stereoisomer, in
contrast to the outcome of related reactions and that of
the model substrate.7 The reaction is believed to pro-
ceed by generation of a copper carbenoid followed by
reaction of this highly reactive electrophilic species
with the ether-oxygen and subsequent ring-expanding
[2,3] rearrangement of a free oxonium ylide or reorga-
nization of its metal-bound equivalent to give the
ketone 18.12,14À16 The methyl group at C-3 (C-15)
was then installed in a highly stereoselective manner
by treatment of the ketone 18 with MeLi at À78 °C to
give the tertiary alcohol 19 as a single isomer, the
The dihydrofuranone 12 was treated with methyl
lithium at low temperature to deliver a mixture (8:1)
(9) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–
1013. (b) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.;
Zheng, D. Tetrahedron Lett. 1995, 36, 2423–2426.
(10) Kabat, M. M.; Kiegel, J.; Cohen, N.; Toth, K.; Wovkulich,
ꢀ
P. M.; Uskokovic, M. R. J. Org. Chem. 1996, 61, 118–124.
(11) Schreiber, S. L.; Wang, Z.; Schulte, G. Tetrahedron Lett. 1988,
29, 4085–4088.
(12) Clark, J. S.; Baxter, C. A.; Dossetter, A. G.; Poigny, S.; Castro,
J. L.; Whittingham, W. G. J. Org. Chem. 2008, 73, 1040–1055.
(13) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091–2096.
3982
Org. Lett., Vol. 13, No. 15, 2011

In summary, an advanced intermediate for the synthesis
of the marine natural products labiatin A and australin A
has been constructed in 21 steps. Rearrangement of a
catalytically generated oxonium ylide or its metal-bound
equivalent has been used to construct the tricyclic core
possessing a C-2ÀC-6 ether bridge instead of the C-2ÀC-9
ether linkage found in most other cladiellin natural pro-
ducts. Further studies concerning the total synthesis of the
labiatins and australins will be reported in due course.
Scheme 5. Formation of the Complete Tricyclic Core 19 of
Labiatin A and Australin A
Acknowledgment. WestCHEM and the University of
Glasgow for funding (D.V.). We thank Dr. Louis Farrugia
(University of Glasgow) for assistance with X-ray crystal-
lography data.
Supporting Information Available. Spectroscopic and
other data for compounds 2À6, 8, 9, 11À15, 17À19 plus
X-ray data (CIF files) for compound 19. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) (a) Clark, J. S.; Krowiak, S. A.; Street, L. J. Tetrahedron Lett.
1993, 34, 4385–4388. (b) Clark, J. S.; Whitlock, G.; Jiang, S.; Onyia, N.
Chem. Commun. 2003, 2578–2579.
(15) West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994, 59,
6892–6894.
(16) Karche, N. P.; Jachak, S. M.; Dhavale, D. D. J. Org. Chem.
2001, 66, 6323–6332.
structure of which was confirmed by X-ray crystal-
lography (Scheme 5).
Org. Lett., Vol. 13, No. 15, 2011
3983