Progress towards the total synthesis of guanacastepene A. Approaches to the construction of quaternary carbons and the 5-7-6 tricyclic carbon skeleton

Article abstract of DOI:10.1016/S0040-4039(02)00729-3

The construction of the 5-7-6 tricyclic skeleton of guanacastepene A, including the quaternary carbons, has been achieved. The C-11 and C-8 quaternary carbons were constructed by cuprate addition and carbene insertion, respectively. The 5-7-6 tricyclic core was generated by a selective aldol and SmI₂-induced intramolecular aldehyde-alkene coupling.

Full text of DOI:10.1016/S0040-4039(02)00729-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4033–4036
Progress towards the total synthesis of guanacastepene A.
Approaches to the construction of quaternary carbons and the
5-7-6 tricyclic carbon skeleton
Truc M. Nguyen and Daesung Lee*
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Received 2 April 2002; revised 8 April 2002; accepted 9 April 2002
Abstract—The construction of the 5-7-6 tricyclic skeleton of guanacastepene A, including the quaternary carbons, has been
achieved. The C-11 and C-8 quaternary carbons were constructed by cuprate addition and carbene insertion, respectively. The
5-7-6 tricyclic core was generated by a selective aldol and SmI2-induced intramolecular aldehyde–alkene coupling. © 2002 Elsevier
Science Ltd. All rights reserved.
Guanacastepene A (1) is a diterpene antibiotic isolated
by Clardy and co-workers in 2000 from the extracts of
fungus living on the branch of a Daphnopsis americana
tree (Fig. 1).1 In the screening for antibiotic activity
against drug-resistant strains of Staphylococcus aureus
and Enterococcus faecalis, guanacastepene A was dis-
covered and has shown excellent activity against methi-
cillin-resistant S. aureus (MRSA) and vancomycin-
resistant E. faecalis (VREF), which are two of the most
problematic drug-resistant pathogens. This promising
biological profile and the challenges associated with the
construction of a previously unreported guanacastane
skeleton have drawn much attention from synthetic
chemists. The challenges in the total synthesis of 1
include two ring-junction quaternary methyl groups
and a 5-7-6 tricyclic carbon skeleton having a dense
array of oxygen functionalities and double bonds only
on the northern hemisphere of the molecule. Several
groups, including Danishefsky,2 Snider,3 Magnus,4 and
Mehta,5 have disclosed approaches to the synthesis of
guanacastepene A, but the total synthesis has not been
achieved. These approaches have in common the for-
mation of a hydroazulene core, followed by the intro-
duction of the six-membered ring onto the existing
seven-membered ring.
Our approach towards the total synthesis of gua-
nacastepene A (1) involves a conceptually different
strategy whereby the seven-membered ring would be
formed at the later stage of the synthesis from an
elaborated A and C ring-containing precursor. More
specifically, the a,b-unsaturated ketoaldehyde 3, pos-
sessing the necessary C-8 and C-11 quaternary carbons
and the C-12 isopropyl group in their correct stereo-
chemical relationship, would serve as a pivotal sub-
strate for the formation of the seven-membered ring via
the C-2 and C-3 bond formation to generate a complete
5-7-6 carbocyclic core 2 of guanacastepene A (Scheme
1). Ketoaldehyde 3 would be derived from cyclopentene
4, which in turn was envisioned to be constructed from
two readily available building blocks, verbenone 6 and
citronellyl bromide 7 via the intermediacy of 5. For the
installation of the C-11 quaternary carbon, a conjugate
addition of a suitable carbon nucleophile to the
facially-biased homochiral verbenone was chosen, while
the C-8 quaternary carbon was planned to be created
by a stereospecific carbene insertion reaction from a
precursor having the strategically positioned C-16
methyl group.6,7
OHC
O
OH
AcO
Figure 1. Structure of guanacastepene A (1).
In practice, we used (S)-citronellyl bromide to generate
8 due to the higher cost of (R)-isomer 7,8 which would
give the opposite stereochemistry of the C-8 quaternary
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00729-3

4034
T. M. Nguyen, D. Lee / Tetrahedron Letters 43 (2002) 4033–4036
15
OHC
O
O
OH
OH
O
O
1
2
3
AcO
5
3
12
8
11
8
11
17
16
18
2
3
Guanacastepene A (1)
OTBS
2
OTBS
O
14
1
18
+
8
11
10
12
Br
4
5
6
7
Scheme 1. Retrosynthetic analysis of guanacastepene A (1).
carbon compared to that of guanacastepene A upon
carbene insertion. The decision entails the inversion of
stereochemistry at C-8. This seemingly difficult task
would be realized rather easily by repositioning the
double bond from C-3 and C-4 to C-6 and C-7 position
on a compound like 14b (R=H) that has a freely
rotating bond between C-8 and C-9 position. Having
set the inversion strategy for C-8 quaternary center, the
most urgent agenda to be addressed in our current
synthesis plan for guanacastepene A is the formation of
CꢀC bond between C-2 and C-3 with substrate similar
to 3. In order to test the viability of this bond-forming
process at the earliest possible stage, we decided to
construct C-8 epimer 19.
THF, −78°C) and TBS protection of the corresponding
secondary alcohol (TBSCl, imidazole, DMF) gave the
TBS ether 10 as a single diastereomer (95% for two
steps). Ozonolysis and reductive workup (O3, CH2Cl2,
−78°C; Me2S) afforded the unstable aldehyde 11 (60%),
which was directly reacted with ethyl Grignard reagent
to give the ethyl carbinol (85%). The epimeric mixture
of the secondary alcohols was oxidized with Dess–Mar-
tin periodinane, producing the ethyl ketone 12 (56%),
which was treated with lithium(trimethylsilyl)diazo-
methane (Me3SiCHN2, n-BuLi, THF, −78°C) to
smoothly generate the cyclopentene 13 (93%).7 Oxida-
tive cleavage of cyclopentene 13 (O3, CH2Cl2, −78°C;
Me2S) followed by immediate treatment of the
ketoaldehyde with KOH in MeOH led to the formation
of cyclohexenone 14 in 81% yield (Scheme 3).7a,b
Deprotection of the TBS ether (Bu4NF, THF, 70°C, 8
h) produced the secondary alcohol 15, which occurred
under relatively harsh conditions, presumably due to
The copper-catalyzed addition of Grignard reagent 8,
derived from (S)-citronellyl bromide, to (1S)-verbenone
6 led to the formation of 1,4-adduct 9 in 85% yield
(Scheme 2).9 Reduction of the carbonyl group (LiAlH4,
O
O
OTBS
8
BrMg
1. LAH
2. TBSCl
10
8
11
CuI
6
9
10
O3; DMS
OTBS
O
N2
OTBS
OTBS
4
1. EtMgBr
2. Dess-Martin
5
Li
TMS
3
O
8
13
12
11
Scheme 2. Generation of C-11 and C-8 quaternary carbons.

T. M. Nguyen, D. Lee / Tetrahedron Letters 43 (2002) 4033–4036
4035
R
OTBS
OTBS
4
O
R=H
4
O
1. O3; DMS
2. KOH
5
3
5
3
8
1. 180° rot.
5
8
8
2. reposition
double bond
14b
13
14a, R=Me
1. TBAF
2. NaH, CS2, MeI, HMPA
O
O
O
2
OX
O
O
1
14
1. OsO4, NMO
2. NaIO4
Bu3SnH
AIBN
14
2
1
12
18
15, X=H
16, X=C(S)SMe
18
17
Scheme 3. Generation of C-12 isopropyl group and preparation for formation of 5-7-6 tricyclic carbon skeleton.
coupling between enal and enone although one of the
double bonds would be lost during the coupling. Pleas-
ingly, treatment of aldehyde 19 with SmI2 in THF in
the presence of t-BuOH provided the 5-7-6 tricyclic
core 21 of guanacastepene A (1) as two diastereomers
(45%) (Scheme 4).16 Extensive NMR spectroscopic
studies and mass spectrometry have confirmed the con-
nectivity of the tricyclic carbon skeleton. However, the
assignment of stereochemistry of the newly generated
stereogenic centers was inconclusive based on NOESY
experiments.
the steric nature of the dimethylmethano-bridge of the
bicyclic system. Optimization of reaction conditions for
the deprotection was achieved by using p-toluenesul-
fonic acid in MeOH at 25°C for 3 h to afford the
alcohol in 90% yield. Formation of the xanthate 16
(NaH, CS2, THF/HMPA; MeI, 70°C, 86%)10 followed
by subsequent treatment with tributyltin hydride
(Bu3SnH, AIBN, toluene, 110°C) led to the cyclobutane
ring-opened alkene 17 (68%) together with varying
amounts of the simple reduction product. Selective
cleavage of the more electron-rich double bond of 17
via the standard two-step protocol (OsO4, NMO, THF/
H2O; NaIO4) produced the bis-aldehydes 18.11
In summary, we have delineated a unique and viable
approach to the synthesis of the quaternary carbons
and the 5-7-6 tricyclic carbon skeleton of guanacaste-
pene A (1). The C-11 quaternary carbon can be synthe-
sized in a highly stereoselective manner by cuprate
addition to verbenone while the C-8 quaternary carbon
can be generated stereospecifically by alkylidene inser-
tion chemistry. Further progress on the total synthesis
of guanacastepene A (1) by using the current approach
will be reported in due course.
At this juncture, it was not obvious which aldol forma-
tion would be favored under what reaction conditions.
Pleasingly, reaction of the bis-aldehydes 18 with excess
piperidine in diethyl ether at room temperature led to
the selective formation of a,b-unsaturated aldehyde 19
(52% from 17) over the other possible aldol reaction
product 20 in a ca. 5:1 ratio (Scheme 4).12 Interestingly,
a careful monitoring of the conversion of 18 to 19
showed the classical Curtin–Hammett kinetic behavior.
It was observed that at the early stage of the reaction
the undesired regioisomeric aldol product formed pre-
dominantly, but it did not undergo rapid water elimina-
tion to give 20. Instead, the reversible retroaldol process
slowly drained the undesired aldol to 19 via the faster
water elimination from the desired minor aldol interme-
diate. Securing the synthesis of aldehyde 19 has set the
stage for exploring a number of cyclization reactions to
form the seven-membered ring. Initially, we have tried
those cyclization reactions that will maintain the unsat-
uration on the six-membered ring after the cyclization,
such as ene reaction,13 nitrile oxide-mediated cycloaddi-
tion,14 and the thiazolium-catalyzed Stetter reaction.15
But none of these reactions provided the desired tri-
cyclic structure. Instead, under these reaction condi-
tions either the substrate decomposed or no reaction
occurred. At this point we decided to do reductive
O
O
O
O
O
14
14
2
2
1
piperidine
SmI2
3
1
19
18
+
OH
O
2
O
14
1
3
O
2 diastereomers
20
21
Scheme 4. Generation of the 5-7-6 tricyclic carbon skeleton of
guanacastepene A.

4036
T. M. Nguyen, D. Lee / Tetrahedron Letters 43 (2002) 4033–4036
F.; Christos, T. E.; Neubert, T. D.; Batra, D. J. Org.
Acknowledgements
Chem. 1999, 64, 9673; (d) Gilbert, J. C.; Giamalva, D. H.;
Weerasooriya, U. J. Org. Chem. 1983, 48, 5251.
8. (S)-Citronellyl bromide is ca. 3.5 times less expensive
than (R)-citronellyl bromide. Aldrich: (S)-citronellyl bro-
mide $31.70/5 g, (R)-citronellyl bromide $108.70/5 g.
9. Watanabe, M.; Awen, B. Z.; Kato, M. J. Org. Chem.
1993, 58, 3923.
10. (a) Hicks, D. R.; Fraser-Reid, B. Can. J. Chem. 1975, 53,
2017; (b) Crich, D.; Beckwith, A. L. J.; Chen, C.; Yao,
Q.; Davison, I. G. E.; Longmore, R. W.; De Parrodi, C.
A.; Quintero-Cortes, L.; Sandoval-Ramirez, J. J. Am.
Chem. Soc. 1995, 117, 8757; (c) Kanie, K.; Tanaka, Y.;
Suzuki, K.; Kuroboshi, M.; Hiyama, T. Bull. Chem. Soc.
Jpn. 2000, 73, 471.
11. DeCamp, A. E.; Mills, S. G.; Kawaguchi, A. T.;
Desmond, R.; Reamer, R. A.; DiMichele, L.; Volante, R.
P. J. Org. Chem. 1991, 56, 3564.
12. Takazawa, O.; Kogami, K.; Hayashi, K. Bull. Chem. Soc.
Jpn. 1985, 58, 2427.
13. Anderson, N. H.; Hadley, S. W.; Kelly, J. D.; Bacon, E.
R. J. Org. Chem. 1985, 50, 4144 and references cited
therein.
14. Zheng, W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.;
Cook, L. R.; Oinuma, H.; Kishi, Y. J. Am. Chem. Soc.
1996, 118, 7946.
We thank the University of Wisconsin-Madison for
startup research funding and the Camille and Henry
Dreyfus Foundation for a New Faculty Award. NMR
support through grants NSF CHE-8813550, NIH 1 S10
RR04981-01 and NSF CHE-9629688 are greatly appre-
ciated.
References
1. (a) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J.
Am. Chem. Soc. 2000, 122, 2116; (b) Brady, S. F.; Bondi,
S. M.; Clardy, J. J. Am. Chem. Soc. 2001, 123, 9900; (c)
Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.;
Clardy, J. J. Antibiot. 2000, 53, 256.
2. (a) Dudley, G. B.; Danishefsky, S. Org. Lett. 2001, 3,
2399; (b) Dudley, G. B.; Tan, D. S.; Kim, G.; Tanski, J.
M.; Danishefsky, S. Tetrahedron Lett. 2001, 42, 6789.
3. Snider, B. B.; Hawryluk, N. A. Org. Lett. 2001, 3, 569.
4. Magnus, P.; Waring, M. J.; Ollivier, C.; Lynch, V. Tetra-
hedron Lett. 2001, 42, 4947.
5. Mehta, G.; Umarye, J. D. Org. Lett. 2002, 4, 1063.
6. Reviews of asymmetric quaternary carbon synthesis: (a)
Fuji, K. Chem. Rev. 1993, 93, 2037; (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
7. (a) Taber, D. F.; Walter, R.; Meagley, R. P. J. Org.
Chem. 1994, 59, 6014; (b) Taber, D. F.; Meagley, R. P.;
Doren, D. J. J. Org. Chem. 1996, 61, 5723; (c) Taber, D.
15. (a) Ciganek, E. Synthesis 1995, 1311; (b) Stetter, H.;
Kuhlmann, H. Org. React. 1991, 40, 407.
16. Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem.
Soc. 1988, 110, 5064.