Development of a strategy for the asymmetric synthesis of polycyclic polyprenylated acylphloroglucinols via N-amino cyclic carbamate hydrazones: Application to the total synthesis of (+)-clusianone

Article abstract of DOI:10.1021/ol1022728

A broadly applicable asymmetric synthetic strategy utilizing N-amino cyclic carbamate alkylation that provides access to the various stereochemical permutations of a common structural motif found in many polycyclic polyprenylated acylphloroglucinols is de

Full text of DOI:10.1021/ol1022728

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5234-5237
Development of a Strategy for the
Asymmetric Synthesis of Polycyclic
Polyprenylated Acylphloroglucinols via
N-Amino Cyclic Carbamate Hydrazones:
Application to the Total Synthesis of
(+)-Clusianone
Michelle R. Garnsey, Daniel Lim, Julianne M. Yost, and Don M. Coltart*
Department of Chemistry, Duke UniVersity, Durham,
North Carolina 27708, United States
don.coltart@duke.edu
Received September 21, 2010
ABSTRACT
A broadly applicable asymmetric synthetic strategy utilizing N-amino cyclic carbamate alkylation that provides access to the various
stereochemical permutations of a common structural motif found in many polycyclic polyprenylated acylphloroglucinols is described. The
utility of this methodology is demonstrated through the first asymmetric total synthesis of the antiviral agent (+)-clusianone.
The polycyclic polyprenylated acylphloroglucinols (PPAPs)
are a large and remarkably interesting class of natural
products.1 Not only do these compounds exhibit wide-
ranging biological activity but also they possess intriguing
structures. Consequently, they have attracted considerable
interest from the synthetic community, and a number of
PPAPs have now been synthesized using a variety of
innovative approaches.2 Despite the impressive advances
resulting from this work, only a small number of syntheses
have been conducted in an asymmetric fashion.2e,i,3 We
recently described a new method for the asymmetric R-alkyl-
ation of ketones based on the use of chiral N-amino cyclic
carbamate (ACC) auxiliaries.4 In what follows, we outline
a general asymmetric synthetic strategy utilizing this alkyl-
ation method that provides access to the various stereochemical
permutations of a common structural motif found in many
PPAPs. The synthetic potential of the resulting intermediates
is highlighted by the first asymmetric total synthesis of the
antiviral5,6 agent (+)-clusianone (Scheme 1).
(2) (a) Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128,
1048–1049. (b) Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 14200–14201. (c) Nuhant, P.;
David, M.; Pouplin, T.; Delpech, B.; Marazano, C. Org. Lett. 2007, 9, 287–
289. (d) Rodeschini, V.; Ahmad, N. M.; Simpkins, N. S. Org. Lett. 2006,
8, 5283–5285. (e) Rodeschini, V.; Simpkins, N. S.; Wilson, C. J. Org. Chem.
2007, 72, 4265–4267. (f) Ahmad, N. M.; Rodeschini, V.; Simpkins, N. S.;
Ward, S. E.; Blake, A. J. J. Org. Chem. 2007, 72, 4803–4815. (g) Tsukano,
C.; Siegel, D. R.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 8840–
8844. (h) Qi, J.; Porco, J. A. J. Am. Chem. Soc. 2007, 129, 12682–12683.
(i) Shimizu, Y.; Shi, S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew.
Chem., Int. Ed. 2010, 49, 1103–1106.
(3) Simpkins has reported the synthesis of optically active (+)-
clusianone, but this was achieved through chiral resolution of an advanced
intermediate. See ref 2e.
(4) Lim, D.; Coltart, D. M. Angew. Chem., Int. Ed. 2008, 47, 5207–
5210.
(1) Ciochina, R.; Grossman, R. B. Chem. ReV. 2006, 106, 3963–3986.
10.1021/ol1022728  2010 American Chemical Society
Published on Web 10/26/2010

Scheme 1
.
Asymmetric Total Synthesis of (+)-Clusianone via
Scheme 2
.
Asymmetric Alkylation of Ketones via Chiral ACC
Auxiliaries
Asymmetric ACC Alkylation
Presently, well over 100 PPAPs are known.1 They are
categorized as type A, B, and C, depending on the position
of the benzoyl moiety (Figure 1a);1,7 (+)-clusianone is a type
These undergo rapid deprotonation to the azaenolates, which
alkylate on up to a multigram scale with excellent stereo-
selectivity and yield (9 f 10). Moreover, the auxiliaries can
be recovered quantitatively and recycled (10 f 11 + H2NY).
It occurred to us that this alkylation procedure could provide
the basis for an efficient and general asymmetric approach
to the desired 2,3,3,4-tetrasubstituted cyclohexanone core and
thus open the door to the asymmetric total synthesis of a
range of PPAPs.
The synthetic strategy that we envisioned is shown in
Scheme 3. A 2-substituted cyclohexenone 148 would serve
Scheme 3
.
Proposed General Strategy for the Asymmetric
Synthesis of the PPAP Core Structure
Figure 1. (a) Type A, B, and C PPAPs. (b) Naturally occurring
stereochemical permutations of the C3- and C4-alkyl groups.
B system. The 2,3,3,4-tetrasubstituted cyclohexanone scaffold
is a common structural motif that is shared by the majority
of all known PPAPs.1 In these systems, the 2- and 4-positions
are always stereogenic, and the 3-position is either dimethyl-
ated or substituted with a methyl and a homoprenyl group
and, therefore, also stereogenic. With regard to absolute
configuration, the naturally occurring substitution patterns1
are shown in Figure 1b. We reasoned that if a general
asymmetric synthesis of the 2,3,3,4-tetrasubstituted cyclo-
hexanone core was available that provided access to these
naturally occurring stereochemical patterns then it could
provide the basis for the asymmetric total synthesis of a
substantial proportion of all PAPPs.
as the substrate for enantioselective ACC alkylation, ulti-
mately giving enone 15. Grignard addition would then be
used to install the C3 methyl group (15 f 16), which would
be followed by a Babler-Dauben oxidation9 producing
transposed enone 17. At this point, the cyclohexenone would
undergo either methyl cuprate addition to produce the C3
gem-dimethyl moiety or diastereoselective 1,4-addition10
using a homoprenyl cuprate to secure the C3 stereocenter
(17 f 18).
We recently described the use of chiral N-amino cyclic
carbamate (ACC) auxiliaries for the asymmetric R-alkylation
of ketones (Scheme 2).4 ACC auxiliaries react readily with
ketones to afford the corresponding hydrazones (8 f 9).
(5) Piccinelli, A. L.; Cuesta-Rubio, O.; Chica, M. B.; Mahmood, N.;
Pagano, B.; Pavone, M.; Barone, V.; Rastrelli, L. Tetrahedron 2005, 61,
8206–8211.
(8) For representative synthetic approaches to such compounds, see: (a)
Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1976, 41, 636–643. (b) Taber,
D. F. J. Org. Chem. 1976, 41, 2649–2650.
(6) Ito, C.; Itoigawa, M.; Miyamoto, Y.; Onoda, S.; Sundar Rao, K.;
Mukainaka, T.; Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2003,
66, 206–209.
(9) Babler, J. H.; Coghlan, M. J. Synth. Commun. 1976, 6, 469–474.
Dauben, W. G.; Michno, D. M. J. Am. Chem. Soc. 1977, 42, 682–685.
(10) Breit, B.; Dremel, P. Copper-mediated Diastereoselective Conjugate
Addition and Allylic Substitution Reactions. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; pp 188-223.
(7) Cuesta-Rubio, O.; Velez-Castro, H.; Frontana-Uribe, B. A.; Cardenas,
J. Phytochemistry 2001, 57, 279–283
.
Org. Lett., Vol. 12, No. 22, 2010
5235

We began our studies by preparing enone 1 using a
quence. To do this, 2 was treated with MeMgBr, forming
tertiary allylic alcohol 26 as a mixture of diastereomers (Scheme
5). These were used without separation in a Babler-Dauben
combination of literature procedures (Scheme 4).2c,8a Thus, 1,3-
Scheme 4. Asymmetric Synthesis of Advanced Ketone
Intermediate 2 by Using Enantioselective ACC Alkylation
Scheme 5. Synthesis of Representative PPAP Core Structures
oxidation9 to produce enone 27. Compound 27 is common to
the preparation of the different PPAP motifs shown in Figure
1 and marks a divergence point in the synthetic strategy. As
such, to access the gem-dimethyl function (cf. 5), the Simpkins
conjugate addition protocol2d was employed, which provided
smooth access to 28. Silyl enol ether 28 could be readily
hydrolyzed to give ketone 29 as a mixture of diastereomers.
Separately, the ꢀ-homoprenyl substituent was installed in an
analogous fashion using a homoprenyl Grignard reagent.15 We
were pleased to find that this transformation proceeded with
excellent diastereoselectivity, with 30 being the only conjugate
addition product detected.16 In this case, however, the silyl enol
ether function was not sufficiently stable to silica gel17 chro-
matography to give a high yield of pure 30, so we chose to
hydrolyze it directly to ketones 31. The relative configuration
between the C3 and C4 substituents was confirmed by X-ray
crystallography of the p-tolyl-N-sulfonyl hydrazone derivative
of the 2-ꢀ diastereomer of 31.14
cyclohexadione (19) was prenylated, and the product was
subsequently treated with oxalyl chloride to generate ꢀ-chloro
enone 21. Metallic reduction (21 f 1) gave the desired enone
substrate for the ACC alkylation sequence.4 On the basis of
our previous success with auxiliary 13 in various alkylations,4
hydrazone 22 was prepared. It was then alkylated in excellent
yield by treatment with LDA and prenyl bromide (22 f 23).
The auxiliary was removed from the alkylated product
(23 f 2) by treatment with p-TsOH·H2O in acetone/H2O,
which gave the desired ketone with excellent overall asym-
metric induction (er ) 98:2).11,12 The (S)-configuration at
the new stereogenic center was inferred by analogy to our
previous studies.4 With ketone 1 in hand, we also tested the
alkylation using the phenylalanine-based auxiliary 12. To
our surprise, unlike our previous experience with acyclic
ketones,4 the enantioselectivity (er ) 99:1)11,12 of the alkylation
was even better in this case than it was when auxiliary 13
was used.13 The stereochemical outcome of this reaction was
deduced by comparison to the methylation of the corre-
sponding 2-methylcyclohexenone-derived ACC hydrazone,
for which a crystal structure of the product was obtained.14
With a reliable route to advanced ketone 2 secured, we
initiated the proposed methylation/carbonyl transposition se-
Satisfied that we had established a suitably general approach
to the key PPAP motifs identified above (see Figure 1), we
undertook the extension of this strategy to the first asymmetric
total synthesis of (+)-clusianone.3 (+)-Clusianone has been
shown to possess antiviral activity against both HIV (EC50
)
0.020 ( 0.003 µM)5 and Epstein-Barr virus (17.4 ( 1.2% of
cells were EBV-EA positive in the presence of 32 nmol of 3).6
As such, it is a compelling target for further biological
investigation as an antiviral agent.
Our initial approach to (+)-clusianone utilized silyl enol ether
28. Inspired by work from the Stoltz laboratory,18 we intended
(11) Major enantiomer shown.
(12) Established using chiral HPLC by reference to independently
prepared racemic material. See the Supporting Information for details.
(13) Investigations into the origins of this differential selectivity are
underway.
(15) Ohloff, G.; Giersch, W.; Decorzant, R.; Buechi, G. HelV. Chim.
Acta 1980, 63, 1589–1597.
(16) Small amounts (<10%) of the 1,2-addition products were also
produced.
(14) See the Supporting Information for details.
(17) Pre-treated with 1:1:98 Et3N-EtOAc-hexanes.
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Org. Lett., Vol. 12, No. 22, 2010

to engage 28 in an Effenberger cyclization19 to access the
bicyclic framework of 32 diastereoselectively (Scheme 6).
produce more of 33 and 34. Methylation of crude cyclized
product 32 gave 35 in 30% yield over the two steps (71% based
on recovered 29). Next, 35 was subjected to bridgehead
prenylation, which gave 36 in excellent yield. Subsequent
addition of the benzoyl group (36 f 37), followed by methyl
enol ether hydrolysis (37 f 3), gave (+)-clusianone.
To determine the enantiomeric purity of our synthetic
material, the above synthetic sequence was carried out in a
racemic fashion to the stage of the penultimate compound. Thus,
enone 1 was subjected to LDA-mediated prenylation, producing
(()-2 (Scheme 8). This compound was then subjected to the
transformations developed above to give (()-37. Conditions
Scheme 6
.
Initial Attempt at the Synthesis of Advanced
Bicyclic Intermediate 32
Unfortunately, our attempts to effect this transformation were
uniformly unsuccessful. We therefore utilized an alternative
strategy for the remaining transformations developed by Sim-
pkins in his synthesis of racemic clusianone,2d which instead
employed methyl enol ethers 33 and 34 for the Effenberger
cyclization. The enol ethers were readily prepared as outlined
in Scheme 7 and indeed underwent the intended cyclization.
Scheme 8. Synthesis of (()-37
were then established that gave baseline resolution of the
enantiomers of (()-37 by chiral HPLC. Subsequent analysis
of our synthetic 37 revealed an er ) 99:1.14
Scheme 7. Asymmetric Total Synthesis of (+)-Clusianone (3)
In conclusion, we have developed an effective synthetic
strategy that provides access to the 2,3,3,4-tetrasubstituted
cyclohexanone scaffold, a common structural motif that is
shared by the majority of the over 100 known PPAPs. A key
transformation of this synthetic sequence is a highly enanti-
oselective (er ) 99:1) ketone R-alkylation sequence, which is
achieved using our recently developed ACC alkylation method.4
Subsequent methylation and carbonyl transposition produces
the key advanced intermediate 27, for either methylation or
diastereoselective homoprenylation, thus securing the 2,3,3,4-
tetrasubstituted cyclohexanone core. To demonstrate the utility
of this strategy for the synthesis of PPAPs, the first asymmetric
total synthesis of (+)-clusianone3 was conducted, taking
advantage of late-stage transformations developed by Simpkins
in his synthesis of racemic clusianone.2d Further investigations
are underway on the asymmetric total synthesis of other PPAPs
using this general strategy.
Acknowledgment. M.R.G. is grateful for support from
the Pharmacological Sciences Training Program - Duke
University. We thank Gregory P. Tracy and Dr. Kristin
Kirschbaum (University of Toledo) for X-ray crystal structure
determination. This work was supported by Duke University
and NCBC (2008-IDG-1010).
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds, as well
as CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL1022728
(18) Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943–1946.
(19) Schonwalder, K. H.; Kollat, P.; Stezowski, J. J.; Effenberger, F.
Chem. Ber. 1984, 117, 3280–3296.
Careful acid/base extraction was required to separate the desired
product (32) from 29, and the latter was able to be recycled to
Org. Lett., Vol. 12, No. 22, 2010
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