Total synthesis of coleophomone D

Article abstract of DOI:10.1039/b208236p

A concise total synthesis of coleophomone D that exists as a dynamic mixture of four isomeric compounds, using a strategy based on a benzoyl cyanide coupling reaction to assemble the key tricarbonyl motif, is reported.

Full text of DOI:10.1039/b208236p

Total synthesis of coleophomone D†
K. C. Nicolaou,* Tamsyn Montagnon and Georgios Vassilikogiannakis
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, USA and Department of Chemistry and
Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
E-mail: kcn@scripps.edu
Received (in Cambridge, UK) 22nd August 2002, Accepted 10th September 2002
First published as an Advance Article on the web 10th October 2002
A concise total synthesis of coleophomone D that exists as a
dynamic mixture of four isomeric compounds, using a
strategy based on a benzoyl cyanide coupling reaction to
assemble the key tricarbonyl motif, is reported.
1c, diastereoisomers), plus another two isomers which are open-
chain keto-aldehydes (1b and 1d, tautomeric atropisomers).
The synthetic challenge posed by coleophomone D (1) lies in
the construction of the sensitive tricarbonyl moiety with its
adjacent quaternary center and 1,2,3-trisubstituted aromatic
ring. In aiming for an optimally convergent approach, we chose,
in our retrosynthesic analysis, to disconnect coleophomone D
(1) into two domains (II and III) through scission of its
tricarbonyl moiety in the manner indicated in Fig. 1 (bottom).
Our previous investigations into effecting C-acylation of
1,3-diketones, over the preferred O-acylation,4 led us to target
the substituted benzoyl cyanide 10 whose construction starting
from 1,2-dimethyl anisole (7) is shown in Scheme 1. Thus,
benzaldehyde derivative 8 was prepared in 83% overall yield
from 7 by a modified two-step literature procedure.8 Treatment
of this aldehyde (8) with Nagata’s reagent afforded the desired
cyanohydrin 9 as the major product contaminated with the
regio-isomeric acetate formed by migration of the acetyl group
(ca. 4+1 ratio, 74% combined yield). Oxidation of this mixture
with PCC followed by chromatographic separation led to pure
benzoyl cyanide 10 in 51% yield.
A recent report1 from a group at Shionogi disclosed the
structure and biological activity of the latest member, desig-
nated as I-A (1, Fig. 1), of a novel class of natural products.2,3
In line with our recently proposed nomenclature for these
compounds,4 we coined the name coleophomone D for this
compound.5 Coleophomone D was isolated from a broth
produced by the fungi Stachybothys parvispora Hughes-1952
and the reported biological profile of coleophomone D (1) was
shown to be akin to its siblings2,3 and includes antifungal
activity1 and inhibition of human heart chymase.1,6 The
reported structure of coleophomone D (1), which it was claimed
exists in solution as a mixture of rapidly equilibrating isomers
(D1–4, 1a–d, Fig. 1 top), posed an interesting biosynthetic
conundrum, since, in addition to the notable absence of the
strained macrocycle, it exhibits a different regiochemistry to
that of the other members of the coleophomone family (2–4,
Fig. 2) with respect to the substitution pattern on the aromatic
nucleus. In this communication, we wish to report an expedient
total synthesis of coleophomone D (1)7 which confirms its
existence as a mixture of four isomers, two spirocycles (1a and
The synthesis of 1,3-cyclohexenedione 16 proceeded from
5-methyl-1,3-cyclohexadione (11) along the pathway shown in
Scheme 2. Thus, methylation of 11 followed by sequential
prenylations according to our recently developed methodology4
Fig. 2 Stuctures of coleophomones A–C (2–4).
Fig. 1 Isomeric structures of coleophomone D (1: D1–D4; 1a–d) (top) and
retrosynthetic analysis (bottom).
Scheme 1 Synthesis of the coupling partner benzoyl cyanide 10. Reagents
and conditions: (a) Et2AlCN (1.0 equiv), toluene, 0 °C, 2 h, 59% of 9 plus
15% of the regioisomeric migrated acetate; (b) PCC (4.0 equiv), CH2Cl2, 40
°C, 4 h, 51%. PCC = pyridinium chlorochromate.
† Electronic supplementary information (ESI) available: selected physical
data for compound 18. See http://www.rsc.org/suppdata/cc/b2/b208236p/
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This journal is © The Royal Society of Chemistry 2002

led to compound 12. Selenation of compound 12 was smoothly
accomplished through the formation of its vinylogous enolate
(LDA–HMPA, 278 °C) followed by quenching with phenyl-
selenyl chloride (278 °C) to afford the corresponding phenyl-
selenide which was formed as a mixture of diastereoisomers;
the use of HMPA as an additive proved essential for the high
yield observed in this transformation. In situ oxidation of this
selenide with H2O2 to the corresponding selenoxides was
followed by spontaneous syn-elimination forming the desired
diene 13 in 78% overall yield. Attempted hydrolysis of the latter
compound (13) under various conditions using protic acids
invariably led to the aromatized product 15 as the major
component of a mixture also containing minor amounts of the
targeted 1,3-cyclohexenedione system 16. This rather intriguing
transformation (13?15) presumably proceeds via the stabilized
carbocation 14 whose conversion to the aromatic system 15
requires loss of a proton and a molecule of isoprene (Scheme 2).
In order to circumvent the unanticipated fragility of the
intermediates involved in this sequence, hydrolysis of 13 under
the alternative basic conditions was explored. Gratifyingly,
when this vinylogous ester 13 was treated with LiOH·H2O in
methanol+H2O (2+1) at 80 °C for 12 h, clean conversion to the
desired 1,3-cyclohexenedione (16) was observed (91% yield).
With requisite building blocks 10 and 16 in hand, the stage
was set for their coupling to afford the desired bicyclic systems.
To our delight, and contrary to the previous case,4 the desired
coupling reaction to furnish 17 (see Scheme 3) proceeded
smoothly and in 80% yield when a full equivalent of Et3N was
added to the reaction mixture without catalytic 4-DMAP in THF
at ambient temperature.4
Scheme 3 Coupling of benzoyl cyanide 10 with dione 16 and completion of
the total synthesis of coleophomone D (1). Reagents and conditions: (a) 16
(1.0 equiv), 10 (1.0 equiv), Et3N (2.0 equiv), 4-DMAP (1.0 equiv), THF, 25
°C, 72 h, 80%; (b) K2CO3 (3.0 equiv), MeOH, 25 °C, 24 h, 94%; (c) MnO2
(10 equiv), Et2O, 36 °C, 4 h, 83%.
Only two steps, acetate cleavage and oxidation, separated
coupling product 17 from the targeted molecules. These
transformations were readily accomplished by exposure of 17 to
K2CO3 in methanol to afford alcohol 18 (94% yield) followed
by treatment with MnO2 in refluxing diethyl ether to afford
coleophomone D (1) (83% yield) as shown in Scheme 3. The 1H
and 13C NMR spectra of synthetic coleophomone D revealed
the presence of its postulated isomers (1a–d) whose signals
matched exactly those reported by the Shionogi group.1
In conclusion, an expedient total synthesis of coleophomone
D (1) based on a convergent strategy comprising of only seven
steps from known starting materials (88 and 124) has been
accomplished. The described synthesis, and that of the related
compounds coleophomones B and C,4 required the develop-
ment of a benzoyl cyanide-based coupling protocol. Applicable
to the selective C-acylation of sterically congested 1,3-dike-
tones, this new synthetic technology may find broad applica-
tions in organic synthesis and to coleophomone analogue
construction. The reported synthesis also serves to confirm the
proposed dynamic equilibrium between coleophomones D’s
four structural isomers (1a–d) and the different substitution
pattern of its aromatic nucleus from that of its more complex
relatives coleophomones A–C (2–4). The latter observation is
intriguing in that it may have implications in the biosynthesis of
these naturally occurring substances, a puzzling question in
itself.
We thank the NIH and the Skaggs Institute for Chemical
Biology for financial support.
Notes and references
1 T. Kamigaichi, M. Nakajima and H. Tami, Jpn. Pat. 11158109, 1999.
2 T. Kamigaichi, M. Nakajima and H. Tami, Jpn. Pat. 10101666, 1998.
3 K. E. Wilson, N. N. Tsou, Z. Guan, C. L. Ruby, F. Pelaez, J.
Gorrochategui, F. Vicente and H. R. Onishi, Tetrahedron Lett., 2000, 41,
8705.
Scheme 2 Synthesis of the coupling partner 5-methyl-6,6-diprenyl-
1,3-cyclohexene-4-dione (16). Reagents and conditions: (a) conc. H2SO4
(cat.), MeOH, 65 °C, 12 h, 85%; (b) LiHMDS (1.05 equiv), THF, 278 °C,
1 h; then prenyl-Br (1.1 equiv), 278 ? 0 °C, 3 h, 85%; (c) LDA (1.1 equiv),
THF, slow addition of a solution of the starting material in THF+HMPA =
7+1, 278 °C, 1 h; then prenyl-Br (2.0 equiv), 278 ? 20 °C, 12 h, 89 %; (d)
LDA (2.0 equiv), THF+HMPA = 50+1, 278 ? 0 °C, 2 h; then PhSeCl (1.5
equiv), 278 ? 20 °C, 30 min; then 30% aq. H2O2 (excess), 45 °C, 1 h, 78%;
(e) 1 M HCl+THF = 1+5, 25 °C, 48 h, 50% of 15 plus 30% of 16; (f)
LiOH·H2O (5.0 equiv), MeOH+H2O = 2+1, 80 °C, 12 h, 91%. LiHMDS =
lithium bis(trimethylsilyl)amide; LDA = lithium diisopropylamide; HMPA
= hexamethylphosphoramide.
4 K. C. Nicolaou, G. Vassilikogiannakis and T. Montagnon, Angew.
Chem., Int. Ed., 2002, 41, 3276.
5 For nomenclature uniformity, we coined the name coleophomone D for
Shionogi’s I-A compound,1 despite the fact that it was not reported by the
Merck group in their coleophoma sp. study.3.
6 H. Urata, A. Kinoshita, K. S. Misono, F. M. Bumpus and A. Husain, J.
Biol. Chem., 1990, 265, 22348.
7 An alternate synthesis of coleophomone D was recently presented as a
poster at the IUPAC 14th International Conference on Organic Synthesis
(ICOS) at Christchurch, New Zealand, July 14–19, 2002 by J. W. Bode,
Y. Hachisu and K. Suzuki.
8 V. G. S. Box and G. P. Yiannikouros, Heterocycles, 1990, 31, 1261.
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