Stereoselective synthesis of the fully functionalized core fragment of terpentecin

Article abstract of DOI:10.1016/S0040-4039(02)02314-6

A stereoselective synthesis of the core fragment 4 of terpentecin is presented. The five contiguous asymmetric centers of 4 were prepared from enone 8 via a sequence of steps highlighted by: oxygenation of the C6 center by epoxidation of enone 18, methylenation of the C8 carbonyl group of 20 by means of the Peterson olefination, stereoselective construction of the C8 center of 21 using homogeneous catalytic hydrogenation and stereoselective oxygenation of the C7 center.

Full text of DOI:10.1016/S0040-4039(02)02314-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9019–9022
Stereoselective synthesis of the fully functionalized core fragment
of terpentecin
Taotao Ling, Fatima Rivas and Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla,
CA 92093-0358, USA
Received 24 September 2002; accepted 16 October 2002
Abstract—A stereoselective synthesis of the core fragment 4 of terpentecin is presented. The five contiguous asymmetric centers
of 4 were prepared from enone 8 via a sequence of steps highlighted by: oxygenation of the C6 center by epoxidation of enone
18, methylenation of the C8 carbonyl group of 20 by means of the Peterson olefination, stereoselective construction of the C8
center of 21 using homogeneous catalytic hydrogenation and stereoselective oxygenation of the C7 center. © 2002 Elsevier Science
Ltd. All rights reserved.
Clerocidin (1),1 terpentecin (2)2 and UCT4B (3)3 (Fig.
1) constitute a select group of clerodane diterpenes that
display very promising antibacterial and antitumor
properties. The latter are postulated to result from their
ability to induce topoisomerase II-mediated DNA dam-
age, leading ultimately to cellular death.4,5 The intricate
details of this event suggest a new mode of ‘topoiso-
merase poisoning’ with potential implications for the
development of novel anticancer drugs.6
From
a
chemical point-of-view, these microbial
metabolites bear a common structural motif, distin-
guished by the attachment of a highly functionalized
side chain (C9–C15) at the C9 carbon of a trans decalin
core. The inherent reactivity of this side chain gives rise
to several forms in equilibrium, shown in Fig. 1, that
present an interesting synthetic challenge. It has been
suggested that the side chain is responsible for the
‘topoisomerase poisoning’ activity of all these natural
products. Moreover, the enhanced biological activities
displayed by terpentecin (2) and UCT4B (3) could be
attributed to the additional oxygenation at the C6 and
C7 carbons of the decalin ring.
The combination of intriguing structural and biological
characteristics has stimulated the interest in the synthe-
sis of these compounds. Among them, the structurally
simplest family member, clerocidin (1) has yielded to a
total synthesis.7 However, despite all reported efforts8
no synthesis has been described for the more densely
functionalized terpentecin (2) and UCT4B (3). As a
prelude to their total synthesis we present herein an
efficient and stereoselective synthesis of decalin 4, which
represents the core fragment of terpentecin.
Our synthetic approaches toward compound 4 are high-
lighted in Fig. 2. We envisioned that the C7 hydroxyl
group could be installed by hydroxylation of ketone 5.
Two approaches were considered for a stereocontrolled
formation of the C8 stereocenter: conjugate reduction
of enone 6, or hydrogenation of alkene 7. Both 6 and 7
could be produced from readily available Wieland-
Miescher-type enone 8, thereby increasing the synthetic
convergency.
Figure 1. Structures of clerocidin (1), terpentecin (2) and
UCT4B (3).
* Corresponding author. Tel.: +1-858-822-0456; fax: +1-858-822-0386;
e-mail: etheodor@ucsd.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02314-6

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T. Ling et al. / Tetrahedron Letters 43 (2002) 9019–9022
the one required for the terpentecin core structure. It
was evident from these studies that a conjugate reduc-
tion of enone 6 proceeded predominantly from the least
hindered a-face of the decalin ring, forcing the C8
methyl group to reside in the equatorial position.
The results of the above studies prompted us to exam-
ine the possibility to produce the desired compound 5
via a stereoselective hydrogenation of the C8–C17 dou-
ble bond. This approach is highlighted in Scheme 2.
Figure 2. Retrosynthetic analysis of fragment 4.
Our synthetic approach toward the core fragment of
terpentecin began with enantiomerically enriched enone
8, which was readily available through a L-phenylala-
nine-mediated asymmetric Robinson annulation (60–
65% yield, >95% ee) (Scheme 1).9 Selective protection
of the more reactive C4 carbonyl group, followed by
reductive alkylation of the enone functionality with
allylbromide afforded ketone 9 in 70% overall yield.
Conversion of ketone 9 to silyl ether 10 was accom-
plished via ozonolysis of the terminal double bond and
reduction of the resulting aldehyde, acid-catalyzed
deprotection of the C4 ketal and selective silylation of
the primary alcohol (57% combined yield). Exposure of
ketone 10 to Wittig methylenation conditions, afforded
the exocyclic olefin, which after oxidation of the C8
hydroxyl group and acid-catalyzed isomerization of the
double bond produced ketone 11 in 74% yield. O-silyla-
tion of ketone 11, followed by a-selenylation and in situ
oxidation/elimination of the phenylselenide produced
enone 12 in 82% yield.10 This compound was treated
with methyl lithium and the resulting tertiary allyl
alcohol was subjected to a PCC-mediated oxidative
rearrangement11 to furnish enone 6 in 78% yield.
Scheme 1. Reagents and conditions: (a) 1.0 equiv. (CH2OH)2,
0.1 equiv. TsOH, 80°C, benzene, 12 h, 90%; (b) 5.0 equiv.
Li(0), NH3, −80 to −30°C, 1.0 equiv. H2O, 5.0 equiv.
CH2ꢀCHCH2Br, −80 to −30°C, 5 h, 78%; (c) O3, CH2Cl2,
−78°C then 3.0 equiv. LiAlH4, Et2O, 0–25°C, 1 h, 65%; (d)
0.1N HCl, THF, 3 h, 25°C, 93%; (e) 1.0 equiv. TIPSOTf, 1.3
equiv. 2,6-lutidine, CH2Cl2, −80°C, 0.5 h, 95%; (f) 2.0 equiv.
CH3PPh3Br, 1.5 equiv. NaHMDS, THF, 65°C, 10 h, 91%; (g)
1.3 equiv. Dess–Martin periodinane, CH2Cl2, 1 h, 25°C, 91%;
(h) 0.01 equiv. I2, xylenes, 150°C, 12 h, 89%; (i) 2.0 equiv.
LDA, 2.2 equiv. TMSCl, THF, −80°C, 1 h; (j) 1.1 equiv.
PhSeCl, CH2Cl2, −80°C, 10 min; 1.1 equiv. H2O2 (30%
aqueous), CH2Cl2, 25°C, 18 h, 82% (two steps); (k) 1.5 equiv.
MeLi, Et2O, 0°C, 0.5 h, 95%; (l) 1.0 equiv. PCC, CH2Cl2,
25°C, 4 h, 82%; (m) 4.0 equiv. Li, NH3 (liq), −33°C, 1 h, 82%;
(n) 1.2 equiv. Dess–Martin periodinane, CH2Cl2, 25°C, 1 h,
92%; (o) 1.6 equiv. KHMDS, 1.6 equiv. 2-(phenylsulfonyl)-3-
phenyloxaziridine, THF, −80°C, 1 h, 91%; (p) 1.0 equiv.
TBAF, THF, 25°C, 1 h, 94%; (q) 2.2 equiv. 4-bromobenzoyl
chloride, 2.5 equiv. pyridine, 0.1 equiv. DMAP, CH2Cl2,
25°C, 95%.
The stage was now set for the conjugate reduction of 6.
Initial efforts to perform this reduction with hydrides
met with failure, presumably due to the sterically hin-
dered environment of the C8 center. However, exposure
of 6 to Li in ammonia resulted in the formation of a
mixture of alcohols that after Dess–Martin oxidation12
afforded ketone 13 as the predominant diastereomer
(>10:1) at the C8 carbon center. Since at this point it
was difficult to assign unambiguously the stereochem-
istry of the C8 methyl group, we decided to further
functionalize the C7 center and ultimately characterize
the final product. To this end, ketone 13 was a-hydroxyl-
ated using Kobayashi’s strategy8f to furnish 14,13 which
upon treatment with TBAF·THF produced diol 15
(86% overall).14 A definitive stereochemical assignment
of compound 15 was obtained by X-rays diffraction
studies of the crystalline dibenzoate 16. These studies
revealed that both the C8 methyl group and the C7
hydroxyl group had the opposite stereochemistry than

T. Ling et al. / Tetrahedron Letters 43 (2002) 9019–9022
9021
removing the C8 carbonyl group. Our initial attempts
to achieve this goal by directly epoxidizing enone 18
with H2O2/NaOH or mCPBA failed, presumably due
to the steric hindance of the C6 neopentylic carbon.
To overcome this problem, the C8 carbonyl group was
first reduced with LiAlH4 to afford exclusively the
b-allylic alcohol which was smoothly epoxidized with
mCPBA (74% overall). The resulting epoxy alcohol
was further oxidized to ketone 19 and subsequently
treated with PhSeNa15 to afford b-hydroxy ketone 20
(89% yield). Our efforts to methylenate the C8 car-
bonyl group of 20 under the standard Wittig condi-
tions proved problematic and gave rise to substantial
amounts of enone 18. This problem was attributed to
the base-like reactivity of the Wittig ylid, which could
deprotonate the C7 carbon center leading to a b-elimi-
nation of the C6 hydroxyl group. This obstacle was
overcome by implementing the Peterson olefination
conditions16 in which the more nucleophilic
TMSCH2MgCl is used as the alkylating agent. After
treatment of the resulting alcohol with HF·pyr we
isolated diol 7 in which all protecting groups were
removed (81% yield).
With compound 7 at hand we examined the possibility
to hydrogenate the C8–C17 double bond from the
b-face. This reaction proceeded with no selectivity
when Pd/C was used as the catalyst and afforded 21
as a 1:1 mixture at the C8 center in 90% combined
yield. Gratifyingly, hydrogenation of 7 using Wilkin-
son’s catalyst17 afforded diol 21 as the only product
(>20:1) in 92% yield.
Selective silylation of the primary alcohol of 21, fol-
lowed by Wittig methylenation of the C4 carbonyl
group and oxidation of the secondary alcohol pro-
duced ketone 22 in 80% overall yield. The exocyclic
olefin was then isomerized to the more stable com-
pound 5 (94% yield). Hydroxylation at the C7 center
afforded exclusively hydroxy ketone 23, which after
fluoride-mediated desilylation produced the terpentecin
core 4 in 82% yield (Scheme 2). The structure of
compound 4 was unambiguously confirmed using a
variety of spectroscopic studies and revealed that both
the C8 methyl group and the C7 hydroxyl functional-
ity have been introduced with the desired orienta-
tion.18,19
Scheme 2. Reagents and conditions: (a) O3, CH2Cl2, −78°C
then 3.0 equiv. LiAlH4, Et2O, 0–25°C, 1 h, 65%; (b) 1.0
equiv. TIPSOTf, 1.3 equiv. 2,6-lutidine, CH2Cl2, −80°C, 0.5
h, 98%; (c) 1.4 equiv. Dess–Martin periodinane, CH2Cl2, 1
h, 25°C, 87%; (d) 2.0 equiv. LDA, 2.2 equiv. TMSCl, THF,
−80°C, 1 h; (e) 1.1 equiv. PhSeCl, CH2Cl2, −80°C, 10 min;
1.1 equiv. H2O2 (30% aqueous), CH2Cl2, 25°C, 18 h, 89%
(two steps); (f) 1.0 equiv. LiAlH4, THF, −40°C, 0.5 h, 93%;
(g) 1.0 equiv. mCPBA, CH2Cl2, 25°C, 10 h, 80%; (h) 1.1
equiv. Dess–Martin periodinane, CH2Cl2, 25°C, 0.5 h, 94%;
(i) 3.0 equiv. (PhSe)2, 6.0 equiv. NaBH4, EtOH, 0–25°C, 10
h, 95%; (j) 1.1 equiv. TMSCH2MgCl, Et2O, 25°C, 2 h; (k)
1.0 equiv. HF·pyridine, Et2O, 25°C, 6 h; 81% (two steps); (l)
0.01 equiv. (Ph3P)3RhCl, H2 (60 psi), benzene, 8 h, 92%; (m)
1.1 equiv. TIPSOTf, 1.5 equiv. 2,6-lutidine, CH2Cl2, −80°C,
0.5 h, 95%; (n) 3.0 equiv. CH3PPh3Br, 2.5 equiv. NaHMDS,
THF, 25°C, 18 h, 93%; (o) 1.1 equiv. Dess–Martin periodi-
nane, CH2Cl2, 25°C, 0.5 h, 91%; (p) 0.04 equiv. I2, xylenes,
150°C, 18 h, 94%; (q) 1.5 equiv. KHMDS, 1.5 equiv. 2-
(phenylsulfonyl)-3-phenyloxaziridine, THF, −80°C, 1 h, 87%;
(r) 1.0 equiv. HF·pyridine, THF, 25°C, 2 h, 95%.
In conclusion we have developed a synthesis of the
core fragment 4 of terpentecin. The five contiguous
asymmetric centers found in 4 were installed in 17
steps and 15% overall yield starting from ketone 9.
Highlights of this strategy include the oxygenation of
the C6 center by epoxidation of enone 18, the
methylenation of the C8 carbonyl group of 20 by
means of the Peterson olefination, the stereoselective
construction of the C8 center of 21 using homoge-
neous catalytic hydrogenation and the stereoselective
oxygenation of the C7 center. This strategy could now
be utilized for the completion of the synthesis of ter-
pentecin and related natural products.
Ketone 9 was converted to enone 18 via a sequence of
five steps, as described in Scheme 1. The next task was
to introduce an oxygen atom at the C6 center without

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T. Ling et al. / Tetrahedron Letters 43 (2002) 9019–9022
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Financial support from the NIH (CA85600) is grate-
fully acknowledged. We also thank the NSF for a
MASEM Fellowship to F.R. and Dr. P. Gantzel
(UCSD, X-ray Facility) for the reported crystallo-
graphic studies.
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