A concise synthesis of the functionalized [5-7-6] tricyclic skeleton of guanacastepene A

Article abstract of DOI:10.1016/j.tetlet.2004.09.187

The six membered ring of guanacastepene A was constructed by a Diels-Alder reaction of 1,1,4-trisubstituted diene to set up the correct relative stereochemistry at the C8 quaternary center and the remote C5 stereocenter. In 10 efficient steps from the Die

Full text of DOI:10.1016/j.tetlet.2004.09.187

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8843–8846
A concise synthesis of the functionalized [5–7–6] tricyclic
skeleton of guanacastepene A
Xiaohui Du, Hiufung V. Chu and Ohyun Kwon*
Department of Chemistry & Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East,
Los Angeles, CA 90095-1569, USA
Received 9 September2004; revised 28 September2004; accepted 30 September2004
Abstract—The six membered ring of guanacastepene A was constructed by a Diels–Alder reaction of 1,1,4-trisubstituted diene to set
up the correct relative stereochemistry at the C8 quaternary center and the remote C5 stereocenter. In 10 efficient steps from the
Diels–Alderadduct 9, the desired highly functionalized [5–7–6] tricyclic skeleton 2 was synthesized. Key steps involve trimethylsilyl
chloride (TMSCl) assisted Michael addition to form enol ether and the usage of the enol ether in the following intramolecular
Mukaiyama aldol reaction to form the middle seven membered ring of guanacastepene A.
Ó 2004 Elsevier Ltd. All rights reserved.
Guanacastepene A (1), isolated from a fungus growing
on the tree Daphnopsis Americana by Clardy and co-
workers, showed antibiotic activity against both methi-
cillin-resistant Staphylococcus aureus (MRSA) and
vancomycin-resistant Entercoccus faecalis (VREF).1 La-
terpublication 2 showed that guanacastepene A also has
hemolytic activity reducing its therapeutic potential as an
antibiotic agent on its own. Nevertheless, efficient syn-
thesis of guanacastepene A presents an opportunity for
the production of its analogs that can be therapeutically
useful. Structurally, guanacastepene A possesses inter-
esting features such as a [5–7–6] fused tricyclic frame-
[5–7–6] tricyclic core structure of guanacastepene A.3u
In applying the basic reaction tools that were developed
in our model studies, there remained many challenges
associated with building the fully functionalized system
2 with C5 oxygenation and C8, C11 quaternary methyls
in place (Scheme 1). To set the correct relative stereo-
chemistry between C5 and C8 via intermolecular Diels–
Alder reaction, we decided to employ 1,1,4-trisubstituted
diene 5.4 Organocuprate coupling between b-iodocyclo-
pentenone (3) and six-membered ring moiety 4 followed
by Michael addition/intramolecular Mukaiyama aldol
work,
a densely functionalized top half and a
hydrophobic bottom half. The three stereocenters at
C5, C8, and C11 that are separated by two methylene
units from each other are challenging to set up. These
structural challenges and the promising biological profile
of guanacastepene A have made it an attractive synthetic
target.3 Danishefsky and co-workers reported the first
and only total synthesis,3f,3g followed by Sniderꢀs3c and
Hannaꢀs3t formal total synthesis. Eleven more groups
have disclosed various synthetic approaches to the bicy-
clic and tricyclic core structures of 1. Ourgorup also
communicated a convergent approach to build a model
Mukaiyama
Aldol
CO2Me
OHC
OH
OEt
O
O
H
3
5
1
8
13
AcO
11
2
1
Organocuprate coupling
OEt
CO2Me
O
O
OEt
O
I
BnO
+
Keywords: Guanacastepene A; [5–7–6] Tricycle; Intermolecular Diels–
Aldereraction; A tandem Michael addition/intarmolecularMukaiy-
ama aldol reaction.
Diels-Alder
5
I
4
3
*
Corresponding author. Tel.: +1 310 267 4954; fax: +1 310 206
3722; e-mail: ohyun@chem.ucla.edu
Scheme 1. Retrosynthetic analysis for guanacastepene A.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.187

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X. Duet al. / Tetrahedron Letters 45 (2004) 8843–8846
reaction was to provide the tricyclic structure 2. The C12
isopropyl group and C13 acetoxy group can be intro-
duced at a laterstage from intermediate 2. Herein, we re-
port synthesis of the highly functionalized tricycle 2.
O
R
COOMe
OEt
3a:
O
O
a
OEt
BnO
BnO
10 R = COOH
11 R = CHO
b
9
The required diene 5 was synthesized in an efficient two-
step process (Scheme 2). Hydrostannation of ethoxy-
acetylene (6) catalyzed by Pd(PPh3)4 generated the (b-
E-ethoxyvinyl)tributyltin (7) as the majorisome.r The
minor a-isomerdid not patricipate in the subsequent
Stille reaction. Two known procedures5 to prepare 7
were tried but brought inferior results. Stille coupling
with benzyl-protected (E)-vinyl iodide 86 applying Hibi-
noꢀs condition7 was rapid and high yielding. The desired
Diels–Alder reaction between the very sensitive diene 5
and maleic anhydride proceeded in 70% yield with exclu-
sive endo-selectivity. The success of the reaction was
dependent on the addition of hydroquinone and high
purity of the diene.
OMe
OMe
MeO
MeO
COOMe
COOMe
c
d
OEt
OEt
RO
BnO
13 R = Bn
14 R = H
12
e
O
O
O
COOMe
OEt
OHC
h
3b:
f
g
9
OEt
BnO
BnO
15
16 R = COOH
17 R = CHO
O
O
j
i
COOMe
OEt
Methanolysis of 9 was sluggish with a much loweryield
compared to the model system lacking the C5 ethoxy
and C8 methyl group, presumably due to rigidity of
the ring and increased steric hindrance (Scheme 3).
Functional group interchange of carboxylic acid 10 to
aldehyde 11 and to acetal 12 proceeded smoothly in four
steps. Hydrogenation to simultaneously remove the
double bond and benzyl group failed with 10% Pd/C
and a variety of other conditions. Hydrogenation of
12 with 5% Pd/C furnished compound 13, which was dif-
ficult to characterize initially because a rapid conforma-
tional exchange between two conformers of 13 resulted
in disappearance of proton and carbon signals in the
NMR at room temperature. The structure of 13 was
confirmed through variable temperature NMR experi-
ments.8 Hydrogenolysis of 13 was problematic due to
reaction of the resulting hydroxyl group with the di-
methyl acetal moiety to form a cyclic acetal. Sensitive
alcohol 14 could be secured by adding a pH7 buffer to
the hydrogenation mixture. However, the formation of
cyclic acetal was observed again upon the direct conver-
sion of the hydroxy group in 14 to the corresponding io-
dide. Two step approach, mesylation followed by the
Finkelstein reaction, failed as well. These difficulties
led us to develop the improved sequence of reactions
shown in Scheme 3b.
RO
18 R = Bn
19 R = H
Scheme 3. Reagents and conditions: (a) MeOH, 80°C, 3d, 51%; (b) (i)
ClCOOEt, NMM, THF, 10min, (ii) NaBH4 (2equiv), THF–
MeOH = 1:1.3, 25min, (iii) oxalyl chloride, DMSO, Et3N, À60°C,
30min, 82% forthere steps; (c) Bu
4NBr3 (0.01equiv), MeOH,
CH(OMe)3, 1.5h, 90%; (d) H2, 5% Pd/C (0.1equiv), EtOAc, 81%; (e)
H2, Pd(OH)2 (0.3equiv), MeOH–buffer(pH = 7) 3:1, 17h, quantita-
tive; (f) H2, 10% Pt/C (0.1equiv), EtOAc, 92%; (g) MeOH, 80°C, 46h,
85%; (h) BH3ÆMe2S (1.1equiv), rt to 40°C, Et2O/THF (5:1), 1h, then
PCC (2.5equiv), CH2Cl2, reflux, 1.5h, 72%; (i) Bu4NBr3 (0.01equiv),
HOCH2CH2OH (5.4equiv), CH(OMe)3 (2equiv), 1.3h, 92%; (j) H2,
Pd(OH)2 (0.3equiv), MeOH–buffer(pH = 7) 3:1, 5h, 88%.
Hydrogenation of 9 with 10% Pt/C provided compound
15 in 92% yield. To ourdelight, methanolysis of com-
pound 15 proceeded faster than 9 to give 85% of the de-
sired carboxylic acid 16 as the only regioisomer. We
adopted Brownꢀs one-pot procedure for converting an
acid to an aldehyde.9 The boroxine intermediate from
borohydride reduction of acid 16 was directly oxidized
without workup into aldehyde 17 with an overall 72%
yield. Acetalization of aldehyde 17 with ethylene glycol
generated compound 18 in 92% yield. Hydrogenation
under buffered conditions provided alcohol 19, which
could be purified through crystallization. The improved
sequence to generate compound 19 in Scheme 3b was
superior in the number of steps, the overall yield and
the ease of operation compared to the sequence shown
in Scheme 3a.
I
BnO
a
OEt
8
OEt
Bu3Sn
OEt
b
6
7
O
O
O
c
Alcohol 19 was converted to iodide 4 in 99% yield
(Scheme 4). Compound 4 was coupled with b-iodocyclo-
pentenone (3) by applying Knochelꢀs organozinc chemis-
try.10 In practice, iodide 4 was converted to the alkylzinc
iodide, which was then converted to the highly function-
alized copper reagent by transmetallation with the solu-
ble CuCNÆ2LiCl salt. This organocuprate intermediate
was efficiently coupled to b-iodocyclopentenone (3) to
form compound 20 in 82% yield.
OEt
BnO
BnO
5
9
Scheme 2. Reagents and conditions: (a) Bu3SnH, Pd(PPh3)4, CH2Cl2,
5h, 92%, b-E–a 1.0:0.6; (b) Pd(PPh3)2Cl2 (0.05equiv), Et4NCl
(1equiv), DMF, 80°C, 2h, 83%; (c) maleic anhydride (3equiv),
hydroquinone (0.023equiv), benzene (degassed, 0.4M of 5), pressure
tube, 105°C, 3.5d, 70%.

X. Duet al. / Tetrahedron Letters 45 (2004) 8843–8846
8845
O
O
O
COOMe
OEt
O
COOMe
OEt
O
O
COOMe
OEt
O
a
b
HO
I
19
4
20
HO
HO
COOMe
OEt
O
2
COOMe
OEt
O
1
O
2
O
O
H
H
c
1
+
8
8
11
11
21b
21a
d
d
COOMe
COOMe
O
H
OEt
H
OEt
22
2
Scheme 4. Reagents and conditions: (a) PPh3 (1.2equiv), I2 (1.2equiv),
imidazole (1.2equiv), Et2O–CH3CN = 3:1, 0°C to rt, 1h, 99%; (b)
activated zinc, 40°C, 4h, CuCNÆ2LiCl, À10°C, 10min then b-
iodocyclopentenone (3), 0°C to rt, 2h, 82%; (c) (i) Me2CuLi, TMSCl,
Et3N, HMPA, 0°C to rt, 77%; or MeMgBr (1.4eq), CuBrÆMe2S
˚
(0.05equiv), HMPA, TMSCl, 50%, (ii) TiCl4 (2equiv), 4A MS,
CH2Cl2, 0°C, 1h, 54% from Me2CuLi, 64% from MeMgBr; (d)
TsOHÆH2O, benzene, 80°C, 30min, 73% from 21a, 79% from 21b.
Sequential conjugate addition/intramolecular Mukaiy-
ama aldol reaction was applied to form the [5–7–6] tricy-
clic ring system of guanacastepene A. In the event,
treatment of 20 with lithium dimethylcuprate in the
presence of TMSCl resulted in the conjugate addition
of a methyl group and in situ formation of the TMS enol
ether. The intramolecular Mukaiyama aldol reaction of
the TMS enol etherwith the dioxolane acetal was medi-
ated by titanium tetrachloride. Due to the robust nature
of dioxolane,11 it was necessary to carry out the
Mukaiyama aldol reaction at a higher temperature than
in the case of dimethyl acetal. Only two isomers, 21a and
21b, were formed in the cyclization, with some elimi-
nated products 2 and 22. Elimination of the C2
hydroxyethoxy group from 21a and 21b was facilitated
by treatment with a catalytic amount of p-toluenesulf-
onic acid to furnish 2 and 22, respectively. The ethoxy
group at C5 survived the elimination conditions. The
structures of compounds 2 and 22 were unequivocally
established by X-ray crystallographic analysis (Fig.
1).12 The ratio of the sum of the desired trans-dimethyl
isomers 21a and 2 to the sum of the cis-dimethyl isomers
21b and 22 was 1:1 with conjugate addition of lithium
dimethylcuprate. The ratio improved to 1.2:1 with
methyl magnesium bromide addition catalyzed by cop-
Figure 1. X-ray structures of compounds 2 and 22.
reaction. Future work will include improvement of the
stereoselectivity of the C11 methyl introduction and
completion of the total synthesis.
Acknowledgements
We gratefully acknowledge UCLA (Seed Grant) and
Amgen Inc. (Young Investigatorꢀs Award to O.K.) for
financial support. H.V.C. acknowledges a USPHS na-
tional research service award (GM08496). We thank
Dr. Saeed Khan for X-ray structure determination of
2 and 22. NMR spectra were collected on an Avance
500 supported by the National Science Foundation un-
derequipment grant # CHE-9974928.
Supplementary data
Experimental procedures and characterization data for
compounds 9–22 (PDF). Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2004.09.187.
13
perbromide dimethyl sulfide complex.
In summary, we have synthesized a highly functional-
ized [5–7–6] tricyclic framework 2 of guanacastepene A
with C11 and C8 methyls and C5 oxygenation in 12
steps from (trans-ethoxyvinyl)tributyltin (7). The con-
vergent synthesis of a highly functionalized intermediate
2 was possible through the intermolecular Diels–Alder
reaction between 1,1,4-trisubstituted diene 5 and maleic
anhydride, coupling of advanced six membered ring pre-
cursor 4 with b-iodocyclopentenone (3), and the sequen-
tial conjugate addition/intramolecular Mukaiyama aldol
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