Differentiation of nonconventional "carbanions" - The total synthesis of nemorosone and clusianone

Article abstract of DOI:10.1002/anie.200703886

(Chemical Equation Presented) An unconventional approach: The total syntheses of nemorosone (1) and clusianone (2) have been achieved in a direct fashion through the generation and exploitation of nonconventional anions arising from a common intermediate

Full text of DOI:10.1002/anie.200703886

Communications
DOI: 10.1002/anie.200703886
Natural Product Synthesis
Differentiation of Nonconventional “Carbanions”—The Total
Synthesis of Nemorosone and Clusianone**
Chihiro Tsukano, Dionicio R. Siegel, and Samuel J. Danishefsky*
Recently, our research group described the total synthesis of
the ChAT inhibitor garsubellin A (3) as its racemate.[1,2] The
attainment of that goal required the crafting of novel
methodology to accommodate the introduction of the three
prenyl-like moieties. In garsubellin A, one of these “prenyl
equivalents” appears in an oxidatively
cyclized form. Also incorporated in the
original synthesis of 3 was an isobutyryl
group in the context of a non-enolizable
b,b’-tricarbonyl setting. More recently, we
noted with interest the appearance of a
structurally related compound, nemoro-
sone (1), which was isolated from the
flowers of Clusia rosea.[3] In contrast to
garsubellin A, nemorosone had been
reputed to have significant cytotoxic activ-
ity, possibly associated with telomerase
inhibition as well as inhibition of ERK-1/2.
A previously isolated compound from the
family of acylphloroglucinols was the com-
pound clusianone (2; Scheme 1). Isolated
originally from Clusia congestiflora, its
structure was initially determined by
McClandish et al. by X-ray crystallogra-
phy.[4a] Subsequently, extensive 2D NMR
analysis on the family of clusianones was
Again, this structure belongs to a broad family, wherein
polyprenyloids project from a carbobicyclo[3.3.1] framework.
From a biological perspective, the anti-HIV properties
claimed on behalf of clusianone were of interest as were the
antitumor properties of nemorosone.
described by Rastrelli and co-workers.[4b] Scheme 1. Nemorosone (1) and clusianone (2).
[*] Prof. Dr. S. J. Danishefsky
Given the subtle but important differences in the struc-
Laboratory of Bioorganic Chemistry
Memorial Sloan-Kettering Cancer Center
1275 York Avenue, Box 106
New York, NY 10021 (USA)
Fax: (+1)212-772-8691
E-mail: danishes@mskcc.org
and
tures found in this class of natural products, and the range of
their profiles of biological activity, it seemed that a program in
total synthesis would be desirable to secure access to relevant
probe structures which might help revise structure–activity
relationship (SAR) patterns. In particular, we focused on
nemorosone (1) and clusianone (2). Herein we describe the
concise total syntheses of these targets.[5]
Department of Chemistry
Columbia University
Influenced by the apparent similarity of these targets to
garsubellin A, we started with the assumption that the hard-
won lessons learned in our total synthesis of the latter would
provide a clear-cut route to our new targets. The thought was
to reach both targets from a common intermediate, 4, which
would be derived through extended teachings from our earlier
garsubellin work. As matters transpired, nemorosone and
clusianone emerged as much more difficult targets than
garsubellin A. In retrospect, the existence of the fused
tetrahydrofuran ring in garsubellin A, wherein one of the
prenyl groups is uniquely presented at a higher oxidation
level, served as a stabilizing device, which was used to good
advantage in that total synthesis. Moreover, the chemical
3000 Broadway
New York, NY 10027 (USA)
Dr. C. Tsukano, Dr. D. R. Siegel
Laboratory of Bioorganic Chemistry
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 10021 (USA)
[**] This work was supported by the National Institutes of Health (grant
CA103823). A fellowship for C.T. from the Japan Society for the
Promotion of Science is gratefully acknowledged. D.R.S. is grateful
for a fellowship from the CDMRPDepartment of Defense Prostate
Cancer Research Program (W81XWH-05-1-0609).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
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frailty of nemorosone had not been
anticipated, until we were attempting to
complete its total synthesis. Nonetheless,
after considerable travail, the total syn-
theses of 1 and 2 were accomplished very
concisely. Indeed, both targets were
reached from the common intermediate
4. The differentiation of the C1 and C3
sites in 4 involved some novel chemistry.
Our route to 4 commenced with
twofold allylation of commercially avail-
able 3,5-dimethoxyphenol, through the
use of p-allylpalladium chemistry, as
shown in Scheme 2.[6] At this stage, both
allyl groups in 5 were converted into
prenyl functions through twofold cross-
metathesis (see 6, Scheme 2).[7] In our
prospective vision of the total synthesis,
we hoped to use one of the two “enan-
tiotopic” prenyl functions to provide the
wherewithal for building the all-carbon
bicyclo[3.3.1] nonane latticework in a
particularly direct fashion. Happily, it
Scheme 2. Synthesis of 8. Reagents and conditions: a) AllylOH, Pd(OAc)2, P P 3h, Ti(OiPr)4, MS
(4 Š), 508C, 50%; b) Grubbs’ 2nd generation cat., 2-methyl-2-butene/CH2Cl2, 408C, 79%;
c) LiI, 2,4,6-collidine, 1408C, 82%; d) I2, KI, KHCO3, THF/H2O, RT, 32% for 8, 29% for 9, 24%
for 10; e) Zn, THF/H2O, 658C. MS=molecular sieves.
proved possible to cleave
a single
methoxy function of through the
6
agency of lithium iodide in sym-collidine
(see 7).[8–10] However, a significant com-
plication arose in our envisioned iodo-
nium-induced carbocyclization reaction on substrate 7.[11]
Given the centrality of this step to our aspirations of high
convergency, a variety of protocols for its realization were
surveyed. However, under all the conditions studied, in
addition to the desired 8 (obtained in only 32% yield), there
were also obtained substantial quantities (namely, 50%) of a
virtually 1:1 mixture of 9 and 10. It seems very likely that
initial iodination occurs at the b-dicarbonyl locus (C7). This
reaction is, in turn, followed by “iodonium”-induced attack
with either carbon or oxygen atoms competing as the
nucleophilic arms of the cyclization. In the latter variant,
ring closure occurs through competitive 6-endo or 5-exo
modes (9 and 10, respectively).
Fortunately, though not surprisingly, both 9 and 10 could
be reconverted into 7 in very high yield by the action of zinc in
aqueous THF. Thus, the existence of seriously competing
cyclization modes was a significant complication at the
process level, rather than a crippling blow to the synthesis.
We note that the problem of competitive O cyclization in
establishing the bicyclo[3.3.1] matrix did not surface in the
initiating total synthesis of garsubellin A.[1] Perhaps the
tetrahydrofurano moiety serves to tilt the conformation of
its neighboring reverse prenyl group to favor iodinative
Scheme 3. Synthesis of intermediate 4. Reagents and conditions:
a) iPrMgCl, Et2O/THF, À788C, 93%; b) TMSI, CH2Cl2, 08C, 98%;
c) AllylSnBu3, AIBN, benzene, 808C, 84%. TMS=trimethylsilyl,
AIBN=azobisisobutyronitrile.
elegant allylation protocol of Keck and Yates,[11,12] compound
4, the intermediate we had envisioned en route to either
nemorosone (1) or clusianone (2), was in hand. Indeed, 4 had
been reached in a mere six steps from 5.
À
cyclization through strict C C bond formation (see hypo-
thetical reaction conformers (i) and (ii) in Scheme 2).
We began to explore compound 4 with respect to its
susceptibility to lithiation at either its C1 or C3 sites. An
orienting experiment in this regard arose through treatment
of 4 with lithium diisopropylamide (LDA). In the first
experiment, we employed approximately 1.05 equivalents of
base. Upon quenching with deuterated methanol, we
obtained approximately 30% deuteration at each position
(13 and 14; Scheme 4). When a large excess of base was used,
Returning to the nemorosone and clusianone total
syntheses, compound 8 was converted into the novel bridge-
head-fused cyclopropane 11 by reductive elimination
(Scheme 3). Following our earlier precedent, the latter
suffered nucleophilic ring opening through the agency of
TMSI to afford 12. Following implementation of the highly
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Communications
17. The reduction of difficult-to-deprotonate ketones by
metalated secondary amines is not without precedent.[16]
The stage was now set for introduction of the benzoyl
group at C1. Toward this end, the trimethylsilyl group would
serve the purpose of protecting C3. Reductive de-iodination
of 16 under the agency of isopropylmagnesium chloride as
shown, was followed by quenching the presumed metalated
intermediate with benzaldehyde. The aldol-like reaction was
conducted from À788C to 08C. Work-up afforded a benzal-
dehyde adduct, presumably 18, since upon oxidation under
the conditions shown, the C1-anchored benzoyl group was in
place (19). Upon cleavage of the C3-vinylsilane linkage,
compound 20 was in hand (Scheme 5).
Scheme 4. Functionalization of intermediate 4.
and this treatment was followed by quenching with MeOD, an
approximately 70–75% yield of the monodeuterated products
13 and 14 was realized.[13] We surmised that the C1 and C3
sites had been lithiated to approximately equal extents.
Although these findings did not necessarily go to the question
of relative rates of lithiation, they tended to suggest that a
site-specific deprotonation could not be conducted cleanly
and adequately with only a single equivalent of ionizing base.
The novel lithiations (bridgehead enolate at C1 and the sp
enolate at C3)[14] could be accomplished, but would be
sluggish. Hence, an excess of base would be needed to
achieve required levels of deprotonation at either C1 or C3 or
both. That being the case, we hoped to exploit differential
quenching reactions as a means of distinguishing the two
lithio derivatives. In practice, the deprotonation phase of the
experiment was conducted with approximately five equiv-
alents of LDA in the presence of trimethylsilyl chloride
(TMSCl). We were pleased to obtain a 74% yield of
compound 15.[15] Thus, if C1 had actually undergone depro-
tonation, exposure to TMSCl had not resulted in a detectable,
let alone isolable, product.
We then turned to the functionalization of 15 at C1.
Toward this end, 15 was treated with LDA, and the presumed
enolate was quenched with iodine. Unfortunately, a rather
low yield of 16 was obtained. By contrast, when 15 was
exposed to the active excess LDA in the presence of
TMSCl,[15] and the reaction mixture quenched with iodine, a
45% yield of 16 was obtained.
Scheme 5. Synthesis of nemorosone (1). Reagents and conditions:
a) iPrMgCl, À788C, THF then PhCHO, À78 to 08C; b) Dess–Martin
periodinane, CH2Cl2, RT; c) TBAF, THF, RT, 61% (3 steps); d) LDA,
THF, À788C, then lithium 2-thienylcyanocuprate, then allyl bromide,
88%; e) Grubbs’ 2nd generation cat., 2-methylpropene, 408C, 91%;
f) LiI, 2,4,6-collidine, 1408C, 31%; g) diazomethane, ether, 08C, 60%
for 23 and 7% for 22. TBAF=tetrabutylammonium fluoride.
We then asked the question as to whether one could
interface the TMSCl-mediated deprotonation and the iodi-
nation in the context of a single reaction. Toward this end, 4
was treated with excess LDA in the presence of excess
TMSCl. This step was followed by oxidative quenching with
iodine. Happily, a 51% yield of 16 was obtained directly from
4.[15] In addition to recovered 15, the reaction mixture also
contained variable amounts of the formal reduction product
The next goal en route to nemorosone was the function-
alization of C3. We proceeded with circumspection. The first
stage involved deprotonation at this C3 center. We were well-
mindful that the b,b’-carbonyl system, already present in 20,
might prove to be quite susceptible to nucleophilic cleavage.
However, in practice, it was possible to accomplish functional
deprotonation. The presumed C3 lithium intermediate was
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then transformed into the corresponding higher order thienyl
cyano cuprate.[17] With the cuprate presumed to have been
generated, the system was allylated by allyl bromide. There
was thus obtained an 88% yield of the bis-allyl compound 21.
The stage was now well set for a second twofold cross-
metathesis reaction.[7] Indeed, this transformation could be
accomplished, under the conditions shown, in the presence of
2-methylpropene, to afford a 91% yield of 22. There now
remained only the cleavage of the methyl ether to reach
nemorosone (1). It was in this end-game that we discovered
some serious vulnerabilities of nemorosone itself. As a result
of its lability, attempted cleavage of the methyl ether linkage
of 22 with a hydroxylic nucleophile was unsuccessful. How-
ever, the methyl ether function could be cleaved by nucleo-
philic de-alkylation.[8–10]
Given the instability of free nemorosone,[18] it was perhaps
not surprising that the yield in the isolation of the natural
product was rather modest (31%). The NMR spectrum
obtained on fully synthetic, albeit racemic, nemorosone,
which is actually a mixture of enol tautomers, was somewhat
variable and did not correspond exactly to that reported for
the number of natural 1 tautomers. An early concern had
been the variability of the NMR spectrum of the synthetic
nemorosone. However, the spectrum could be stabilized and
rendered identical with that reported for natural nemorosone
by the inclusion of ammonium formate in the solvent
system.[19] Finally, with regard to nemorosone, remethylation
of the enol mixture with diazomethane restored the separable
mixture (approximately 8:1 of the previously encountered 22)
and iso-nemorosone methyl ether 23.
With a novel and highly convergent total synthesis of
nemorosone accomplished, we returned to 4, which, as
described above, was perceived as a common intermediate
en route to both targets 1 and 2. We now attempted to reach
clusianone (2) by treatment of 4 with LDA and benzaldehyde,
followed by oxidation, to introduce the benzoyl group at C3
(24, Scheme 6). The earlier experiments in this study were
indicators that functional deprotonation at C1 in 4 could be
accomplished. However, the only agent which we have
successfully introduced at the presumed C1 bridgehead
carbanion arising from deprotonation at C1 in reasonable
yield was the iodo group (16) or a deuterium atom from
MeOD (13). Direct introduction of other electrophiles, such
as benzaldehyde at C1 in compound 4 following deprotona-
tion, occurred in poor yield. To complete the total synthesis of
clusianone (2), we faced the challenge of incorporation of a
prenyl function at the corresponding C1 site in 24.
Scheme 6. Synthesis of clusianone (2). Reagents and conditions:
a) LDA, THF, À788C, then PhCHO; b) Dess–Martin periodinane,
CH2Cl2, RT, 57% (two steps); c) LDA, TMSCl, THF, À78 to 08C then
I2, 48%; d) AllylSnBu3, Et3B, air, benzene, RT, 71%; e) Grubbs’ 2nd
generation cat., 2-methylpropene, 408C, 94%; f) 10% aq NaOH, 1,4-
dioxane, 908C, 64%.
fully synthetic clusianone as a tautomeric mixture of enols.[7b]
We note that the mixture of free enol tautomers of clusianone
(2) is rather more stable than the corresponding enolic form
of nemorosone (1).[18] Presumably, this reflects the stabilizing
effect of the benzoyl group in the b-dicarbonyl network. The
total synthesis of clusianone had thus been accomplished.
In summary, the total syntheses of both 1 and 2 have been
accomplished. These routes are quite direct. The key skel-
eton-building stages were allylative de-aromatization (see 5)
and iodinative cyclization (see 8). While yield issues remain,
we were able to generate and exploit nonconventional anions
(“anti-Bredt bridgehead” at C1; and “sp enolate” at C3)[14]
arising from the common intermediate 4. Progress in under-
standing these uncommon “carbanion” types and in establish-
ing structure–activity patterns in the acylphloroglucinals is
ongoing.
Received: August 23, 2007
Published online: October 12, 2007
Keywords: carbanions · cyclization · natural products ·
.
total synthesis
Fortunately, a successful two-step protocol to deal with
the end-game of the clusianone synthesis could be developed.
Thus, 24 was converted into its C1-iodo derivative, 25, by the
TMSCl-mediated process[15] (Scheme 6). The iodo group of 25
was transformed to an allyl function using allyl tributylstan-
nane and triethyl boron in the presence of air.[20] Thus was
obtained compound 26. The stage was now set for concurrent
cross-olefin metathesis at C1 and C7.[7] This double cross-
metathesis was accomplished (27). Once again, it proved
possible to cleave the methyl ether group. This conversion
was much simpler than the case of nemorosone and could be
accomplished with aqueous sodium hydroxide, thus affording
[1] D. R. Siegel, S. J. Danishefsky, J. Am. Chem. Soc. 2006, 128, 1048.
Subsequent reports will describe the synthesis of the individual
antipodes of garsubellin.
[2] For the first reported total syntheses of garsubellin, see A.
Kuramochi, H. Usuda, K. Yamatsugu, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2005, 127, 14200.
[3] a) O. Cuesta-Rubio, H. Velez-Castro, B. A. Frontana-Uribe, J.
Cardenas, Phytochemistry 2001, 57, 279; b) S. Seeber, R. A.
Hilger, D. Diaz-Carballo, PCT Int. Appl., 2003, WO
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Communications
2003043622 A1; c) O. Cuesta-Rubio, B. A. Frontana-Uribe, T.
proton at C1 is somehow occurring during the CD3OD quench-
ing process via some combination of secondary amine and
secondary lithium amide.
Ramirez-Apan, J. Z. Cardenas, Z. Naturforsch. C 2002, 57, 372.
[4] a) L. E. McCandlish, J. C. Hanson, G. H. Stout, Acta Crystallogr.
Sect. B 1976, 32, 1793; b) A. L. Piccinelli, O. Cuesta-Rubio, M. B.
Chica, N. Mahmood, B. Pagano, M. Pavone, V. Barone, L.
Rastrelli, Tetrahedron 2005, 61, 8206 – 8211.
[5] A total synthesis of clusianone has recently appeared, see a) V.
Rodeschini, N. M. Ahmad, N. S. Simpkins, Org. Lett. 2006, 8,
5283; b) N. M. Ahmad, V. Rodeschini, N. S. Simpkins, S. E.
Ward, A. J. Blake, J. Org. Chem. 2007, 72, 4803; c) P. Nuhant, M.
David, T. Pouplin, B. Delpech, C. Marazano, Org. Lett. 2007, 9,
287. The steps which we employed were actually done inde-
pendently before the appearance of the above report.
[6] T. Satoh, M. Ikeda, M. Miura, M. Nomura, J. Org. Chem. 1997,
62, 4877.
[14] cf. inter alia; a) N. G. Clemo and G. Pattenden, Tetrahedron Lett.
1982, 23, 585; b) O. Miyata, R. R. Schmidt, Angew. Chem. 1982,
94, 638; Angew. Chem. Int. Ed. Engl. 1982, 21, 637; c) O. Miyata,
R. R. Schmidt, Tetrahedron Lett. 1982, 23, 1793; d) see refer-
ence [5].
[15] At several stages of this study, the apparent deprotonation[13] and
subsequent quenching of the bridgehead enolate with electro-
philes is improved through the use of TMSCl. The reasons for
this remain to be explored in detail.
[16] a) E. P. Woo, K. T. Mak, Tetrahedron Lett. 1974, 15, 4095;
b) L. T. Scott, K. J. Carlin, T. H. Schultz, Tetrahedron Lett. 1978,
19, 4637; c) X. Creary, A. J. Rollin, J. Org. Chem. 1979, 44, 1798.
[17] B. H. Lipshutz, M. Koerner, D. A. Parker, Tetrahedron Lett.
1987, 28, 945.
[7] a) Attempts to execute the cross-metathesis with 2-methyl-2-
butene resulted in formation of significant amounts of
a
disubstituted olefin side product. To avoid this undesired side
reaction, 2-methylpropene was used in the cross-metathesis
reaction; b) A. K. Chatterjee, D. P. Sanders, R. H. Grubbs, Org.
Lett. 2002, 4, 1939; c) S. J. Spessard, B. M. Stoltz, Org. Lett. 2002,
4, 1943.
[18] With nemorosone in hand, we found that it was both light-
sensitive and air-sensitive. When nemorosone was dissolved in
chloroform, a solution of fully synthetic nemorosone and
chloroform had decomposed after a few days at room temper-
ature. In fact, a solution of nemorosone in chloroform at À208C
is also significantly decomposed after a few days. We resorted to
the use of ammonium formate because the original isolation was
such that ammonium formate would have been present in the
methanol solvent wherein the NMR spectrum of nemorosone
was measured. Through this device, a stable spectrum was
obtained.
[8] A. P. Krapcho, J. F. Weimaster, J. M. Eldridge, E. G. E., Jr.
Jahngen, A. J. Lovey, W. P. Stephens, J. Org. Chem. 1978, 43, 138.
[9] J. McMurry, Org. React. 1976, 24, 187.
[10] a) A. P. Krapcho, Synthesis 1982, 805; b) A. P. Krapcho, Syn-
thesis 1982, 893.
[11] For the earliest reported type of reaction in this general area, see
a) K. C. Nicolaou, J. A. Pfefferkorn, S. Kim, H. X. Wei, J. Am.
Chem. Soc. 1999, 121, 4724; b) K. C. Nicolaou, J. A. Pfefferkorn,
G.-Q. Cao, S. Kim, J. Kessabi, Org. Lett. 1999, 1, 807.
[12] G. E. Keck, J. B. Yates, J. Am. Chem. Soc. 1982, 104, 5829.
[13] It seems reasonable to assume that introduction of deuterium at
the bridgehead is indicative of bridgehead deprotonation by the
LDA. The alternative would be that the actual removal of the
[19] In addition to the proton spectrum, a 13C spectrum was also
obtained on fully synthetic nemorosone. Infrared and mass
spectra were all measured. These data are found in the
Supporting Information.
[20] K. Miura, Y. Ichinose, K. Nozaki, K. Fugami, K. Oshima and K.
Utimoto, Bull. Chem. Soc. Jpn. 1989, 62, 143.
8844 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8840 –8844
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