Synthesis of the 5-7-6 core of guanacastepenes. Construction of C8 quaternary carbon via the inversion of stereochemistry.

Article abstract of DOI:10.1021/ol026820t

[formula: see text] An efficient and unique route to the 5-7-6 core of guanacatepene A (1) is described. The installation of the desired stereochemistry at the C8 position was achieved via the desymmetrization of the cyclohexadienone by reductive ring clo

Full text of DOI:10.1021/ol026820t

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3959-3962
Synthesis of the 5-7-6 Core of
Guanacastepenes. Construction of C8
Quaternary Carbon via the Inversion of
Stereochemistry
Truc M. Nguyen, Robert J. Seifert, Dale R. Mowrey, and Daesung Lee*
Department of Chemistry, UniVersity of Wisconsin-Madison,
Madison, Wisconsin 53706
dlee@chem.wisc.edu
Received August 29, 2002
ABSTRACT
An efficient and unique route to the 5-7-6 core of guanacatepene A (1) is described. The installation of the desired stereochemistry at the C8
position was achieved via the desymmetrization of the cyclohexadienone by reductive ring closure of the seven-membered ring. That the
closure of the seven-membered ring produced only the desired isomer is hypothesized to be a result of the more stable trans relationship
between the C8 and C11 methyl groups.
Guanacastepene A (1) is a new class of diterpene natural
product isolated from the extracts of endophytic fungus living
on the branch of a Daphnopsis americana tree in the
Guanacaste Conservation Area in Costa Rica (Figure 1).1 In
the screening for antibiotic activity against drug-resistant
strains of Staphylococcus aureus and Enterococcus faecalis,
guanacastepene A has initially shown an excellent activity
against methicillin-resistant S. aureus (MRSA) and vanco-
mycin-resistant E. faecalis (VREF), which are two of the
most problematic drug-resistant pathogens.2 Subsequent study
indicates that 1 exerts its biological effect by nonspecific
membrane lysis, causing hemolysis in human red blood
cells.1c The initially observed promising biological profile
and the challenges associated with the construction of a
previously unreported guanacastane skeleton have invited
much attention from synthetic chemists. The challenges in
the total synthesis of 1 include two ring-junction quaternary
methyl groups and a new 5-7-6 tricyclic carbon skeleton
having a dense array of oxygen and unsaturated function-
alities. While many groups disclosing approaches to the
synthesis of 1,3 including Danishefsky’s recent total
synthesis,3f,g propose formation of a hydroazulene core,
(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.
Figure 1. A reductive ring closure for the construction of the 5-7-6
tricyclic core of 8-epi-guanacastane.
(2) Swartz, M. N. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2420.
10.1021/ol026820t CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/25/2002

followed by the introduction of the six-membered ring onto
the existing seven-membered ring.3a-g Our route entails
closure of the seven-membered ring with the existing five-
and six-membered rings connected at C8 and C11 by a C9-
C10 two-carbon linker, forming the complete tricyclic
skeleton (Figure 1).4
Scheme 1
As an initial effort for the total synthesis of 1, we have
demonstrated that a reductive ring closure of 2 afforded the
8-epi-guanacastane 3 in moderate yield. As noted in our
previous communication,4 we have used (S)-citronellyl
bromide to generate 2 due to the higher cost of (R)-isomer,5
which would give the opposite stereochemistry of the C8
quaternary carbon compared to that of guanacastepene A
upon carbene insertion. The decision necessitates the inver-
sion of stereochemistry at C8. We had hypothesized that this
seemingly difficult task could be accomplished by reposi-
tioning the double bond from C3-C4 to C6-C7 on a
compound that contains a psuedosymmetry plane that bisects
the C8 and C5 carbons of the C ring.
Herein we report two procedures to fix the stereochemistry
at C8 via indirect inversion. To explore the inversion at C8,
aldehyde 4 was selected as a branching point and constructed
in high yield based on procedures analogous to the ethyl
series of the previous communication.4 Addition of meth-
ylmagnesium bromide to 4 followed by oxidation of the
secondary carbinols (5 mol % RuCl2(PPh3)3, 2.5 equiv of
NMO, acetone, 25 °C, 3 h)6 gave a good yield of the
corresponding methyl ketone 5. Treatment of ketone 5 with
lithium(trimethylsilyl)diazomethane (Me3SiCHN2, n-BuLi,
THF, -78 to 25 °C) smoothly generated the cyclopentene 6
in 92%,7 which was oxidatively cleaved by a two-step
protocol (OsO4, NMO, THF-H2O; NaIO4) to the corre-
sponding keto aldehyde. Direct treatment of this unstable
keto aldehyde with KOH in MeOH at room temperature
delivered the expected cyclohexenone derivative 7 without
any complication (76% in three steps). Removal of the TBS
group from 7 (Bu4NF, THF, 25 °C, 98%) followed by
xanthate formation8 under our modified conditions (NaH,
THF, CS2; MeI, HMPA)9 gave the desired xanthate 8 along
with 9 (Scheme 1). The formation of 9 is the consequence
of competing enolization of the carbonyl group followed by
reaction of the enolate with CS2 and two molecules of MeI.10
Subsequent treatment of this inseparable mixture of
xanthates 8 and 9 with tributylstannane (Bu3SnH, AIBN,
toluene, 100 °C) yielded the desired cyclobutane ring-opened
product 10 in moderate yield (45-50%, 2 steps). Osmylation
of the more electron-rich double bond of 10 then smoothly
afforded a 5:1 diastereometic mixture of the diols 11 (Scheme
2).
Scheme 2
(3) (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. (c) Snider, B. B.; Hawryluk, N. A. Org.
Lett. 2001, 3, 569. (d) Magnus, P.; Waring, M. J.; Ollivier, C.; Lynch, V.
Tetrahedron Lett. 2001, 42, 4947. (e) Mehta, G.; Umarye, J. D. Org. Lett.
2002, 4, 1063. (f) Tan, D. S.; Dudley, G. B.; Danishefsky, S. Angew. Chem.,
Int. Ed. 2002, 41, 2185. (g) Lin, S.; Dudley, G. B.; Tan D. S.; Danishefsky,
S. Angew. Chem., Int. Ed. 2002, 42, 2188. (h) Gradl, S. N.; Kennedy-Smith,
J. J.; Kim, J.; Trauner, D. Synlett 2002, 3, 411. (i) Shipe, W. D.; Sorensen,
E. J. Org. Lett. 2002, 4, 2063. (j) Nakazaki, A.; Sharma, U.; Tius, M. A.
Org. Lett. 2002, 4, 3363.
(4) Nguyen, T. M.; Lee, D. Tetrahedron Lett. 2002, 43, 4033.
(5) (S)-Citronellyl bromide is ca. 3.5 times less expensive than (R)-
citronellyl bromide. Aldrich: (S)-citronellyl bromide $31.70/5 g, (R)-
citronellyl bromide $108.70/5 g.
(6) Baker, R.; Brimble, M. Tetrahedron Lett. 1986, 27, 3311.
(7) (a) Ohira, S.; Ishi, S.; Shinohara, K.; Nozaki, H. Tetrahedron Lett.
1990, 31, 1039. (b) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc. Chem.
Commun. 1992, 721. (c) Taber, D. F.; Walter, R.; Meagley, R. P. J. Org.
Chem. 1994, 59, 6014. (d) Ohira, S.; Sawamoto, T.; Yamato, M.
Tetrahedron Lett. 1995, 36, 1537. (e) Taber, D. F.; Meagley, R. P.; Doren,
D. J. J. Org. Chem. 1996, 61, 5723. (f) Taber, D. F.; Yu, H.; Incarvito, C.
D.; Rheingold, A. L. J. Am. Chem. Soc. 1998, 120, 13285. (g) Taber, D.
F.; Christos, T. E.; Neubert, T. D.; Batra, D. J. Org. Chem. 1999, 64, 9673.
(h) Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 3541.
The indirect inversion process of the C8 stereochemistry
was initiated by protection of the diol 11 as its acetonide
(73% from 10) (Scheme 3). With the diol protected,
introduction of a carboethoxy group at the C6 position (LDA,
3960
Org. Lett., Vol. 4, No. 22, 2002

C7 double bond during the cyclization by forming the C2-
C3 bond to generate the guanacastane tricycle with the
desired trans stereochemical relationship between the C16
and C17 methyl groups. This hypothesis is not unreasonable
because the sterically more favorable trans relationship
between the C16 and C17 angular methyl groups in the
natural guanacastanes is assumed to be the consequence of
a thermodynamically driven process. To test this hypothesis,
the above route was branched at enone 11. This compound
was converted to the cyclohexadienone 15, whereby the
stereogenic C8 carbon becomes nonstereogenic and the two
double bonds at C3-C4 and C6-C7 become identical (43%,
3 steps). Diol cleavage of 15 (NaIO4, THF-H2O) followed
by intermolecular aldol condensation (piperidine, Et2O, 25
°C) delivered aldehyde 16 (45%, 2 steps) and the corre-
sponding regioisomer in a maximum 5:1 ratio. Treatment
of 16 under SmI2-mediated reductive cyclization conditions14
delivered a single isomer of the tricyclic core of guanacastane
17 (70% yield). The structure of 17 was unambiguously
assigned by the spectroscopic and X-ray crystallographic
analysis.15 The tricycle 18 with the â-methyl stereochemistry
at C8 was not observed, confirming our hypothesis that the
trans stereochemical arrangement of the C16 and C17 angular
methyl groups is more favorable.
Scheme 3
THF, EtO2CCN) afforded a diastereomeric mixture of 12.11
Subsequent removal of the double bond at the C2-C4
position (H2, Pd/C, EtOAc) followed by subjection of the
â-dicarbonyl compound to the known dehydrogenation
conditions developed by Reich and co-workers12 delivered
the desired unsaturated enone diol 13 after removal of the
acetonide (33%, 5 steps). The overall consequence of this
five-step transformation is the inversion of the C8 methyl
stereochemistry and the introduction of the C20 carbon at
the C4 position as a form of carboethoxy group. The
carboethoxy group at C4 is critical for the post-cyclization
functionalization because the more sterically congested nature
of the C4 carbon compared to C6 hinders the introduction
of unsaturation between C3 and C4 after the formation of
the tricyclic skeleton. Oxidative cleavage of diol 13 (NaIO4,
THF-H2O) and immediate treatment of the resultant dial-
dehyde with excess piperidine in ether at room temperature
produced the enal 14 (67%, 2 steps) together with its
regioisomer in varying ratios (5:1 to 2:1).13 The intramo-
lecular reductive cyclization of 14 (SmI2, THF, t-BuOH, 25
°C) proceeded poorly. The major product formed was a
mixture of inseparable compounds, the characterization of
which was not actively pursued, albeit traces of the desired
Scheme 4
1
tricycle were observed in the crude H NMR.
The lengthy steps for the preparation of 14 and its reduced
efficiency for the seven-membered-ring closure brought our
attention to a rather bold hypothesis that compounds like 16
could self-differentiate the diastereotopic C3-C4 and C6-
(8) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574. (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.
(9) Without HMPA, no xanthate formation was observed.
(10) Dieter, R. K. J. Org. Chem. 1981, 46, 5031. On a closely related
compound 9 bearing a methyl group at the C4 position, this reaction did
not occur.
With this successful route to the tricycle complete, the
formation of xanthates 8 and 9 was revisited. To eliminate
the formation of undesired xanthate 9, the C6-C7 double
bond was introduced on compound 8, thereby blocking the
unwanted enolization (Scheme 5). Removal of the TBS group
from this compound and subsequent xanthate formation
proceeded as expected, producing only the xanthate 19 (39%
(11) Mander, L. N.; Sethi, P. Tetrahedron Lett. 1983, 24, 5425.
(12) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Org. Chem. 1974, 39,
2133.
(13) (a) 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.
(b) Takazawa, O.; Kogami, K.; Hayashi, K. Bull. Chem. Soc. Jpn. 1985,
58, 2427.
(14) (a) Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem. Soc.
1988, 110, 5064. (b) Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1989,
111, 8236. For review, see: (c) Molannder, G. A.; Harris, C. R. Chem.
ReV. 1996, 96, 307.
Org. Lett., Vol. 4, No. 22, 2002
3961

tricyclic core intermediate of the guanacastanes. The final
reductive ring closure of this utilized route not only proves
efficient (70% yield) but also provides only a single
diasteromer. Further progress on the total synthesis of
guanacastepene A (1) by using the current approach will be
reported in due course.
Scheme 5
Acknowledgment. We thank the University of Wisconsin-
Madison for startup research funding and the Camille and
Henry Dreyfus Foundation for financial support. NMR
support through grants NSF CHE-8813550, NIH 1 S10
RR04981-01, and NSF CHE-9629688 are greatly appreci-
ated. We also thank Dr. Vestling and Dr. Guzei for mass
spectral and X-ray crystallographic information, respectively,
and Professor Hans Reich for helpful discussions.
Supporting Information Available: Experimental de-
tails, characterization data for key new compounds, and
X-ray crystallographic information for compound 17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026820T
(15) Spectroscopic information for 17: 1H NMR (CDCl3, 300 MHz) δ
6.49 (dd, J ) 10, 2 Hz, 1H), 6.00 (dd, J ) 10, 1 Hz, 1H), 5.72 (br s, 1H),
3.91 (br d, J ) 10 Hz, 1H), 3.08 (br d, J ) 17 Hz, 1H), 2.69 (dd, J ) 17,
5 Hz, 1H), 2.37 (ddd, J ) 16, 8, 3 Hz, 1H), 1.96 (ddt, J ) 16, 10, 2 Hz,
1H), 1.90-1.40 (m, 8H), 1.25 (s, 3H), 1.70 (dd, J ) 15, 10 Hz, 1H), 0.97
(d, J ) 6 Hz, 3H), 0.91 (s, 3H), 0.90 (d, J ) 6 Hz, 3H); 13C NMR (CDCl3,
75.4 MHz) δ 199.35, 158.08, 157.00, 128.57, 121.91, 166.20, 66.59, 54.07,
53.31, 48.78, 39.28, 37.36, 36.17, 35.57, 33.17, 29.63, 28.76, 22.95, 20.27.
Crystallographic information for 17: monoclinic crystal system (size )
0.40 × 0.30 × 0.30 mm3), space group P21, unit cell constants a ) 6.3772
(6) Å, b ) 8.5780(7) Å, c ) 15.5692(14) Å, R ) 90°, â ) 91.385(2)°, γ
) 90°, V ) 851.44(13) Å3, Z ) 2, density ) 1.125 Mg/m3. The crystal
evaluation and data collection were performed on a Bruker CCD-1000
diffractometer with Mo KR (λ ) 0.71073 Å) radiation in a stream of cold
nitrogen at 100(2) K. A total of 44 reflections was obtained. The reflections
were successfully indexed by an automated indexing routine built in the
SMART program. The final cell constants were calculated from a set of
4515 strong reflections from the actual data collection. A successful solution
by the direct methods provided most non-hydrogen atoms from the E-map.
The remaining non-hydrogen atoms were located in an alternating series
of least-squares cycles and difference Fourier maps. All non-hydrogen atoms
were refined with anisotropic displacement coefficients. All hydrogen atoms
were included in the structure factor calculation at idealized positions and
were allowed to ride on the neighboring atoms with relative isotropic
displacement coefficients. The final least-squares refinement of 195
parameters against 3416 data resulted in residuals R (based on F2 for I g
2) and wR (based on F2 for all data) of 0.0433 and 0.1089, respectively.
yield, 3 steps). However, the attempts to generate 20 directly
from 19 by the cyclobutane ring opening were capricious
due to the instability of the cyclohexadienone under the
reaction conditions. To alleviate this problem, the carbonyl
group of 19 was reduced (DIBAL-H, CH2Cl2, -78 °C, 77%)
to a bisallylic alcohol 21 prior to treatment with tributyl-
stannane. Compound 21 underwent reductive cyclobutane
ring-opening cleanly under high dilution conditions, resulting
in the desired compound 20 after oxidation of the bisallylic
alcohol (PCC, 3 Å MS, CH2Cl2, 64%, 2 steps). Osmylation
(OsO4, NMO, acetone-H2O, 73%) of 20 to the diol 15
completes an alternative route to an advanced intermediate
tricycle 17, eliminating problems associated with the forma-
tion of xanthate 9 in Scheme 2. Via this route 17 is produced
in 18 steps and an overall 1.2% yield from commercially
available starting materials.
In summary, we have disclosed two variations of an
inversion strategy for the synthesis of quaternary carbons
and used one of them for the synthesis of an advanced
3962
Org. Lett., Vol. 4, No. 22, 2002