Total synthesis of alotaketal A

Article abstract of DOI:10.1021/ol302570k

The total synthesis of the cAMP signaling pathway activator (-)-alotaketal A is reported. A convergent approach to the unusual alotane sesterterpenoid skeleton was employed, exploiting a remarkable LiDBB-mediated coupling of an (R)-carvone-derived δ-lactone with an allyl bromide side chain, followed by spiroacetalization.

Full text of DOI:10.1021/ol302570k

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5492–5495
Total Synthesis of Alotaketal A
Mengyang Xuan, Ian Paterson, and Stephen M. Dalby*
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW,
United Kingdom
sd344@cam.ac.uk
Received September 18, 2012
ABSTRACT
The total synthesis of the cAMP signaling pathway activator (À)-alotaketal A is reported. A convergent approach to the unusual alotane
sesterterpenoid skeleton was employed, exploiting a remarkable LiDBB-mediated coupling of an (R)-carvone-derived δ-lactone with an allyl
bromide side chain, followed by spiroacetalization.
The marine environment continues to provide an un-
rivalled array of novel, biologically prevalidated natural
products, which offer an important source of lead com-
pounds for the development of new chemotherapeutic
agents and tools for chemical biology.1 In search of such
structures, recent screening of extracts of the marine
sponge Hamigera sp., collected off the coast of Papua
New Guinea by Andersen and co-workers, led to the isolation
of alotaketal A (1, Scheme 1). Structurally, this sesterterpe-
noid is characterized by its unprecedented “alotane” carbon
skeleton, consisting of a hydrobenzopyranyl spiroacetal
core appended with a geranyl side chain.2 Notably, alota-
ketal A induces potent activation of the cAMP signaling
pathway in HEK293 cells (EC50 = 18 nM), which given
the importance of cAMP signaling to cellular function,
bestows upon it potential utility as a small-molecule lead
for further drug development as well as a potentially im-
portant probe for cell biology research.3
activity against a range of human cancer cell lines, and may
find use for the treatment of osteoporosis.5
The recent first total synthesis of alotaketal A (1) by
Yang and co-workers6 served to verify the full configura-
tional assignment of the alotaketals as suggested by Rho3
and refined by Andersen.7 As part of our ongoing interest
in the synthesis of new bioactive marine natural products,8
we now describe our own stereocontrolled total synthesis
of alotaketal A (1), enabling access to synthetic material
for further biological evaluation.
As outlined retrosynthetically in Scheme 1, our ap-
proach to alotaketal A (1) would exploit thermodynamic
control in assembling the doubly anomerically stabilized
spiroacetal upon deprotection of the C16 TES ether of 2.
Hemiacetal 2 would itself arise through addition of a
suitably metalated derivative of side-chain allyl bromide 3 to
the bicyclic lactone core 4.9 Allyl bromide 3 would be formed
through elaboration of geraniol (5), including an asym-
metricacetate aldol reaction toinstall the C16 stereocenter.
The closely related phorbaketals were subsequently iso-
lated by Rho and co-workers from the Korean marine
sponge Phorbas sp.,4and shown to exhibit low micromolar
(5) Byun, M. R.; Kim, A. R.; Hwang, J.-H.; Sung, M. K.; Lee, Y. K.;
Hwang, B. S.; Rho, J.-R.; Hwang, E. S.; Hong, J.-H. FEBS Lett. 2012,
586, 1086.
(6) Huang, J.; Yang, J. R.; Zhang, J.; Yang, J. J. Am. Chem. Soc.
2012, 134, 8806.
(1) (a) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.;
Prinsep, M. R. Nat. Prod. Rep. 2012, 29, 144. (b) Dalby, S. M.; Paterson,
I. Curr. Opin. Drug Discovery Dev. 2010, 13, 777. (c) Paterson, I.;
Anderson, E. A. Science 2005, 310, 451.
(2) Forestieri, R.; Merchant, C. E.; de Voogd, N. J.; Matainaho, T.;
Kieffer, T. J.; Andersen, R. J. Org. Lett. 2009, 11, 5166.
(3) (a) Pavan, B.; Biondi, C.; Dalpiaz, A. Drug Discovery Today 2009,
14, 982. (b) Beavo, J. A.; Brunton, L. L. Nat. Rev. Mol. Cell. Biol. 2002,
3, 710.
(7) Daoust, J.; Fontana, A.; Merchant, C. E.; de Voogd, N.; Patrick,
B. O.; Kieffer, T. J.; Andersen, R. J. Org. Lett. 2010, 12, 3208.
(8) (a) Paterson, I.; Maltas, P.; Dalby, S. M.; Lim, J. H.; Anderson,
E. A. Angew. Chem., Int. Ed. 2012, 51, 2749. (b) Paterson, I.; Naylor,
ꢀ
G. J.; Gardner, N. M.; Guzman, E.; Wright, A. E. Chem. Asian J. 2011,
6, 459. (c) Paterson, I.; Paquet, T.; Dalby, S. M. Org. Lett. 2011, 13, 4398.
(9) A similar generalized approach was employed by Yang and
co-workers; see ref 6.
(4) Rho, J.-R.; Hwang, B. S.; Sim, C. J.; Joung, S.; Lee, H. Y.; Kim,
H.-J. Org. Lett. 2009, 11, 5590.
r
10.1021/ol302570k
Published on Web 10/24/2012
2012 American Chemical Society

Lactone 4 meanwhile was considered to represent an
oxidized (C1, C9) derivative of (R)-carvone (6), which
might subsequently undergo esterification/intramolecular
HornerÀWadsworthÀEmmons lactonization.
Scheme 2. Preparation of Oxidized Carvone Scaffold 11
Scheme 1. Retrosynthetic Analysis of Alotaketal A
CH2Cl2 at À78 °C.13 Pleasingly, this provided R-hydroxy
ketone 9 in a highly regio- and diastereoselective (>95:5 dr)
manner.14À16 Subsequent diastereoselectivereduction with
NaBH4 (>95:5 dr) provided the corresponding diol, which
was straightforwardly differentiated through TBS protec-
tion of the secondary C5 alcohol to provide 10. Treatment
of 10 with PDC in refluxing CH2Cl2 then induced smooth
allylic transposition of the C3 tertiary alcohol to establish
the requisite C1 oxygenation as the corresponding ketone.17
Subsequent reduction with L-Selectride proceeded stereo-
selectively (>95:5 dr) to finally provide the targeted, doubly
oxidized carvone scaffold 11 for elaboration to the bicyclic
δ-lactone core of alotaketal A (4).14
Initial attempts to incorporate the C1 and C9 oxygena-
tion directly through a regioselective double allylic oxi-
dation reaction of (R)-carvone (6), or its C5-TBS ether
derivative, proved unrewarding.10 In response, sequential
introduction of both oxygens was carried out, commenc-
ing with regioselective allylic chlorination of (R)-carvone
(6, Scheme 2).11 Basic hydrolysis and silylation then pro-
vided the allylic ether 7 (47%, 3 steps).
As shown in Scheme 3, this process commenced with
regioselective oxidative cleavage of the less hindered/
electron rich C8ÀC10 alkene of 11 under modified
Introduction of the C1 oxygenation would now be achieved
through preparation and oxidation of the corresponding
dienyl ether. Accordingly, regioselective enolization of
enone 7 (MeMgBr, FeCl3) and trapping with TMSCl
provided silyl dienyl ether 8,12 which optimally was sub-
mitted crude to Rubottom oxidation with m-CPBA in
(14) Stereochemical determination was achieved through NOE-
based NMR analysis. See Supporting Information for details.
(15) The modest yield relates primarily to the formation of bypro-
ducts having incorporated an additional methyl group at C2 during the
enolization step.
(16) Direct installation of the C1 oxygenation from silyl dienyl ether 9
was also investigated through photooxidation with singlet oxygen.
Optimally, irradiation of a solution of 8 in CH2Cl2 at À78 °C under
an oxygen atmosphere using a TPP sensitizer provided, after reductive
workup of the C1 peroxide with thiourea, the targeted keto-alcohol 12 in
low yield (26%) with much diminished diastereoselectivity (3:2 dr). Use
of the nitrosobenzene oxygen equivalent proved similarly unfruitful in
this case; Tian, G.-Q.; Yang, J.; Rosa-Perez, K. Org. Lett. 2010, 12,
5072.
(10) (a) Bulman Page, P. C.; McCarthy, T. J. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U.K., 1991; Vol.
7, p 83. (b) CrO3, SeO2, Mn(OAc)3, Pd(OH)2 and Rh2(cap)4 based
methods were all investigated.
(11) Hegde, S. G.; Vogel, M. K.; Saddlerqq, J.; Hrinyo, T.; Rockwell,
N.; Haynes, R.; Oliver, M.; Wolinsky, J. Tetrahedron Lett. 1980, 21, 441.
(12) (a) Krafft, M. E.; Holton, R. A. J. Am. Chem. Soc. 1984, 106,
7619. (b) Saraber, F. C. E.; Baranovsky, A.; Jansen, B. J. M.; Posthumus,
M. A.; Groot, A. de Tetrahedron 2006, 62, 1726.
(13) Rubottom, G. M.; Vazques, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319.
Org. Lett., Vol. 14, No. 21, 2012
5493

JohnsonÀLemieux conditions.18 Yamaguchi esterification
of the ensuing alcohol 13 with phosphonate 14 then
provided keto-phosphonate 15, set for HWE ring closure.
Inthe event, treatment withBa(OH)2 inwet THF delivered
bicyclic δ-lactone 4 in excellent yield (95%).19
Scheme 4. Synthesis of Allyl Bromide 3
Scheme 3. Completion of the Bicyclic Lactone Core 4
The synthesis of the side-chain coupling partner, allyl
bromide 3, commenced with regioselective allylic chlorina-
tion of geraniol with t-BuOCl (Scheme 4). This provided a
secondary allylic chloride, which was reduced with LiAlH4
in refluxing THF to effect overall isomerization to the
terminal alkene.20 Allylic oxidation with MnO2 then pro-
vided aldehyde 16 in readiness for a Nagao acetate aldol
reaction to install the C16 stereocenter.21 In the event,
exposure of 16 to the tin(II) enolate of thioimide 17 at
À78 °C afforded the desired aldol adduct 18 in excellent
yield and diastereoselectivity (92%, >95:5 dr). Methano-
lytic cleavage of the auxiliary (K2CO3, MeOH) followed
by silyl protection then provided methyl ester 19 (68%,
2 steps). Elaboration of methyl ester 19 to allyl bromide 3
was carried out by way of the corresponding allyl silane 20.
Accordingly, addition of two equivalents of freshly pre-
pared TMSCH2MgCl to 19 provided the corresponding
tertiary alcohol, which underwent smooth, acid-mediated
Petersen elimination upon prolonged (15 h) stirring over
silica gel to give allyl silane 20.22 Finally, brief (30 min),
low temperature (À78 °C) exposure of 20 to NBS in the
presence of propylene oxide led to smooth bromination
of the allyl silane without accompanying reaction of the
C23ÀC24 alkene.
total synthesis of alotaketal A (1) could be investigated.
Initial model studies, involving the addition of various
metalated derivatives of methallyl bromide to 4, revealed
that while lithiated derivatives (t-BuLi/n-BuLi) failed to
undergo any productive reaction, the corresponding Grignard
(Mg) and zinc (Zn, Cp2TiCl2)23 derivatives were highly
competent allyl donors. Translating these results to allyl
bromide 3 proved problematic however, with difficulties
encountered in forming the requisite allyl metal derivatives
of 3, which then could not be coaxed into undergoing
productive reaction with 4.24 Ultimately, it was found that
addition of an excess of LiDBB25 (ca. 5 equiv, titrated until
color persisted) to a mixture of lactone 4 and allyl bromide
3 (1.2 equiv) in THF at À78 °C led to rapid (<5 min)
With both key fragments, bicyclic lactone 4 and allyl
bromide 3 in hand, the pivotal coupling reaction for the
(23) (a) Fleury, L.; Ashfeld, B. Org. Lett. 2009, 11, 5670. (b) Ding, Y.;
Zhao, G. Tetrahedron Lett. 1992, 33, 8117.
(17) (a) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
(b) Luzzio, F. A. Org. React. 1998, 53, 1.
(18) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(19) Paterson, I.; Yeung, K.-S.; Smaill, J. B Synlett 1993, 10, 774.
(20) Novak, L.; Poppe, L.; Szantay, C. Synthesis 1985, 10, 939.
(21) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Shiro, M. J. Org. Chem.
1989, 54, 5211.
(22) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28,
6261.
(24) The allyl Grignard and allyl zinc derivatives of 3 were prepared
from iodide 21, neither of which underwent addition to lactone 4. The
corresponding allyl lithium species could be prepared from bromide 3
(t-BuLi), although in line with model studies this, and the organocerium
derivative (CeCl3) also failed in adding to lactone 4. Unreacted 4 and
dehalogenated 22 were returned in each case. Similar observations were
made by Yang and co-workers; see ref 6.
(25) (a) Freeman, P. K.; Hutchinson, L. L. Tetrahedron Lett. 1976,
17, 1849. (b) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924.
5494
Org. Lett., Vol. 14, No. 21, 2012

Scheme 5. Total Synthesis of Alotaketal A (1)
consumption of lactone 4 and formation of the targeted
hemiacetal 23, which was isolated as a single (presumably
stabilized) anomer in 56% yield (Scheme 5). The mode of
addition proved critical to the success of the reaction,
where addition of lactone 4 to the preformed organolithium
derivative of 3 led only to recovery of debrominated 22
without formation of 23.26
Double oxidation of 25 cleanly provided the correspond-
ing keto-aldehyde, which finally underwent selective re-
duction of the C9 aldehyde with NaBH(OAc)3 to deliver
alotaketal A (1, 63%) together with some over-reduced 25
(25%) which could be further recycled.
Synthetic alotaketal A exhibited spectral characteristics
(1H/13C NMR, IR, HRMS) identical in all respects to that
reported for the natural sample,2 together with the mea-
sured specific rotation ([R]2D0 = À63.6 (c 0.11, MeOH), lit:
[R]2D0 =À38.9 (c 0.01, MeOH), thus confirming the integrity
of the total synthesis.
In summary, we have completed the total synthesis of
alotaketal A in 0.5% yield over 17 steps. This convergent
approach, utilizing readily available carvone and geraniol
to construct the novel alotane skeleton, should also be
appropriate for preparing the phorbaketals,4 and amena-
ble to the generation of a range of non-natural analogs for
SAR studies and further biological evaluation.
Spiroacetalisation ofthe rather acid-sensitivehemiacetal
23 was then accomplished through removal of the C16
TES-ether upon treatment with buffered HF py, which
3
provided 24 as a single diastereomer, in addition to ca. 15%
of a chromatographically separable C12ÀC13 alkene isomer.
That the newly formed C11 spiroacetal (δC = 96.8 ppm)
adopted the correct, anomerically stabilized configuration
was confirmed by a diagnostic NOE enhancement observed
from H16 to H1, also observed for the natural product.14
Completion of the total synthesis of alotaketal A re-
quired deprotection and adjustment of the C5 oxidation
state. Since selective deprotection of the C5 TBS-ether
proved elusive, removal of both silyl ethers was carried
Acknowledgment. We thank the EPSRC National Mass
Spectrometry Service (Swansea) for mass spectra and Clare
College, Cambridge (Fellowship to S.M.D.).
out using HF py. While access to diol 25 could be effected
directly from 23 (HF py), increased amounts (ca. 30%) of
3
3
the undesired and now chromatographically inseparable
C12ÀC13 alkene isomer were encountered in doing so.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) The success of this procedure is in marked contrast to that using
t-BuLi and might point to either the formation of a subtly different
organometallic species or an alternate reaction mechanism leading to 23.
For a related case, see: Meyers, A. I.; Rawson, D. J. Tetrahedron Lett.
1991, 32, 2095.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5495