Full text of DOI:10.1016/S0040-4039(01)02190-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 359–362
Synthesis of the core ring system of the sclerophytin diterpenes
utilizing a Lewis acid-promoted [4+3] annulation strategy
Gary A. Molander* and Scott C. Jeffrey
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
PA 19104-6323, USA
Received 24 October 2001; accepted 15 November 2001
Abstract—The synthesis of the core ring system of the sclerophytin diterpenes is described. The key tetrahydrofuran-containing
intermediate is assembled via a Lewis acid-promoted [4+3] annulation reaction between a mixed dimethyl acetal and a bis-TES
dienol ether. The resulting b-keto ester was homologated, cyclized, and ring expanded to afford the sclerophytin ring system.
© 2002 Elsevier Science Ltd. All rights reserved.
Recent reports from the arena of cladiellin natural
product synthesis1 have prompted us to report part of
our efforts in this area, specifically our work toward the
synthesis of the sclerophytin diterpenes (Fig. 1). Our
work was directed toward the previously assigned struc-
tures—molecules with an oxygen bridge between C-3
and C-7 forming a tetrahydropyran ring. The successful
synthesis of sclerophytin analogs reported in this com-
munication pre-date recent corrections to the structure
of the sclerophytins.2
to assemble the tetrahydrofuran-containing nucleus of
the sclerophytins through the use of a [4+3] annulation
reaction employing a 1,4-dialdehyde. However, because
of the inherent instability of 1,4-dialdehydes and their
propensity to form cyclic hydrates, our efforts met with
little success. As an alternative to using a dialdehyde,
Chan and Brownbridge used a tetrahydrofuran-1,4-
dimethyl acetal, a 1,4-dialdehyde surrogate, as a sub-
strate in a [4+3] annulation reaction (Eq. (1)).4 The
synthetic viability of a dimethyl acetal-containing inter-
mediate was appealing, thus we began investigating a
route to cyclic acetal 1 (Scheme 1).
Novel annulation methods developed in these laborato-
ries have been shown to have utility for synthesizing
medium-sized ring-containing natural products.3 These
annulation methods employ bis(trimethylsilyl)dienyl
ethers with diketones or keto-aldehydes to assemble
oxygen-bridged, seven- and eight-membered ring sys-
tems. It was our goal to extend this method toward the
synthesis of cladiellin natural products, namely the
diterpenes sclerophytins A and B. Our initial plan was
H
OCH3
O
-78 °C
TiCl4, DCM,
OTMS
O
O
O
OCH3
(1)
H
OCH3
OTMS
O
Our efforts to construct the mixed acetal 1 began with
racemic cryptone (2)—the substrate for a 1,4-vinyl
addition reaction promoted by a copper bromide–
dimethyl sulfide complex.5 The resulting enolate was
trapped with chlorotrimethylsilane to afford dienol
ether 3. Exposure of 3 to Lewis acid in the presence of
trimethyl orthoformate6 resulted in dimethyl acetal 4.
The trans–trans-stereochemistry about the cyclohex-
H
7
OR
O
HO
3
H
OH
Sclerophytin A (R=H)
Sclerophytin B (R=Ac)
1
anone ring of 4 was assigned based on the H NMR
spectrum that displayed axial–axial coupling constants
between the adjacent stereogenic center methine pro-
tons (J=10.8 Hz for each relationship). The vinyl
group of 4 was cleaved using ozone, and a dimethyl
Figure 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02190-6

360
G. A. Molander, S. C. Jeffrey / Tetrahedron Letters 43 (2002) 359–362
O3, CH2Cl2 / MeOH (4:1),
NaHCO3, -78 °C;
Me2S
CuBr•SMe2, CH2CHMgBr,
TMSCl, TMEDA, THF,
O
OTMS
O
OCH3
OCH3
TMSOTf (cat.), (CH3O)3CH,
CH2Cl2, -78 °C, 14h
-78 °C to rt
91%
89%
81%
(+/-)-cryptone (2)
4
3
O
OCH3
OCH3
O
Ph3P+CH3 Br-,
OCH3
OCH3
CH3OH / 10% HCl (9:1)
9-BBN, THF, reflux;
NaOH, H2O2
1
rt 12h; 80 °C, 5h
t-BuOK, THF
O
O
3
CHO
95%
OCH3
OCH3
92%
5
7
Ratio
CH3OH / 10% HCl
(9:1)
rt 12h; 80 °C, 5h
2.4 6a 1β, 3β
1.5 6b 1α, 3β
1.4 6c 1β, 3α
59% with recycling
of minor isomers 2X
TiCl4 (2.0 equiv.),
TESO OCH3
RO
H3CO
O
H3CO
OCH3
O
OCH3
9
OTES
O
O
O
O
O
OCH3
CH2Cl2, -85 °C, 24h;
warm to 0 °C
H3CO
8 R=H
1 R=CH3
10a
10b
CH3I, NaH, THF
50%
2.5:1
95%
Scheme 1.
sulfide workup provided the aldehyde 5 in high yield.
This acetal was isomerized under acidic conditions to a
2.5:1.5:1.4 mixture of tetrahydrofuran dimethyl acetals
6a–c, respectively. Only material derived from the
major isomer 6a, i.e. methyl ether 1, proved to be a
suitable substrate for the key [4+3] annulation reaction
(vide infra). Isomeric acetals of 1, derived from 6b and
6c, gave little, if any desired product in the [4+3]
annulation reaction. Thus, the major isomer 6a was
isolated from the mixture of acetals 6a–c via chro-
matography and the minor isomers 6b and 6c were
combined and resubmitted to the isomerizing condi-
tions. Two iterations of minor isomer recycling and
chromatography afforded the cis-isomer 6a in good
yield for the combined material. The cis-ring fusion and
acetal carbon stereochemistry of 6a was confirmed
through single crystal X-ray analysis of a 2,4-dini-
trobenzoate ester derived from 6a. Olefination of 6a
using triphenylphosphine methylide gave 7, which was
converted to the primary carbinol through a hydrobo-
ration and oxidation sequence. The free hydroxyl of 8
was capped as its methyl ether (1), which was the
substrate for the [4+3] annulation reaction. The best
results in the annulation reaction were achieved by
treating a cold solution of acetal 1 with freshly distilled
titanium tetrachloride, added dropwise. This was fol-
lowed by the slow addition of bis(triethylsilyl)dienyl
ether 9.7 The mixture was kept cold and allowed to
react for 24 h, at which time it was allowed to warm to
an ambient temperature and was then poured into a
saturated solution of sodium bicarbonate. An extractive
workup afforded a modest yield of a 2.5:1 mixture of
bicyclic keto esters 10a and 10b, with the desired keto
ester 10a being the major product. Single crystal X-ray
analysis of 10a demonstrated that the five stereogenic
centers of 10 had been set, as depicted (Fig. 2).
With the advanced intermediate 10a in hand, homolo-
gation and ring expansion began with the alkylation of
10a with the primary iodide 11, using sodium hydride
as base (Scheme 2). This transformation was straight-
forward and gave a good yield of the sulfone 12. As
expected, the alkylation of 10a occurred from the con-
vex face of the bicyclic ring system. Saponification of
Figure 2. ORTEP of 10a.

G. A. Molander, S. C. Jeffrey / Tetrahedron Letters 43 (2002) 359–362
361
CH3O
11
CH3O
CH3O
NaH, THF, reflux,
SO2Ph
Tf2O, DTBP,
-78 °C to 0 °C
OH
I
SO2Ph
O
t-BuOK, DMSO
80%
O
O
O
O
HO2C
14
CO2R
CO2CH3
82%
63%
10a
SO2Ph
LiOH, CH3OH / H2O (1:1)
12 R=
CH3
13 R=H
76%
O3, CH2Cl2 / CH3OH(4:1),
NaHCO3, -78 °C,
then Me2S
CH3O
CH3O
CH3O
Tf2NPh, NaH, DMF
140 °C, neat
7
SO2Ph
O
O
O
O
SO2Ph
SO2Ph
O
24%
O
78% two steps
3
O
15
16
17
CH3O
CH3O
CH3O
R
CH3
SO2Ph
SO2Ph
O
Me3Al, CH2Cl2
t-BuOK, DMSO
94%
O
O
O
SO2Ph
76%
O
HO
CH3
20
Me4Sn,
21
Pd2dba3, LiCl,
PhO)3P, THF
18 R=OTf
19 R=CH3
87%
Scheme 2.
the methyl ester of 12 also proceeded smoothly to
afford the keto acid 13. Brief exposure of a DMSO
solution of 13 to a solution of potassium tert-butoxide
in DMSO, followed by an acetic acid quench, afforded
the polycyclic hydroxy acid 14. Lactone formation
using trifluoromethanesulfonic anhydride in the pres-
ence of 2,6-di-tert-butylpyridine was followed by ther-
molysis of neat b-lactone 15 to afford the
tetrasubstituted olefin 16. Ozonolysis of 16 resulted in
the formation of diketone 17.
crystallographic studies performed on a model system
to 21 (Fig. 3).
In summary, a route to construct the core ring system
of the sclerophytin diterpenes has been established. This
route utilizes a Lewis acid-promoted [4+3] annulation
reaction to assemble the tetrahydrofuran-containing
intermediate 10a. This key compound was further
homologated and ring expanded to the core sclero-
phytin ring system. Additional studies in this area are
in progress.
The goal at this point of the synthesis was to install the
methyl groups at C-3 and C-7 followed by construction
of the tetrahydropyran ring. The first step toward this
goal was the selective formation of enol triflate 18,
which would set the stage for the introduction of the
first methyl group through the use of a Stille reaction.
Treatment of the diketone 17 with sodium hydride and
N-phenyltriflamide as triflating reagent cleanly pro-
duced the desired enol triflate 18 in low yield.8 Expo-
sure of 18 to tetramethyltin and a palladium catalyst,
under refluxing conditions,9 gave the desired C-7
methylated product 19. The second methyl group was
installed by treating 19 with trimethylaluminum, thus
completing the assembly of the cladiellin carbon frame-
work.10 Tetrahydropyran formation was accomplished
through exposure of 20 to potassium tert-butoxide in
DMSO to afford 21. The resulting stereochemistry of
both the methyl addition reaction and the tetra-
hydropyran ring forming reaction were inferred from
Figure 3. ORTEP plot of model 21.

362
G. A. Molander, S. C. Jeffrey / Tetrahedron Letters 43 (2002) 359–362
2. Friedrich, D.; Doskotch, R. W.; Paquette, L. A. Org.
Acknowledgements
Lett. 2000, 2, 1879.
3. (a) Molander, G. A.; Andrews, S. W. Tetrahedron Lett.
1989, 30, 2351; (b) Molander, G. A.; Carey, J. S. J. Org.
Chem. 1995, 60, 4845.
4. Brownbridge, P.; Chan, T.-H. Tetrahedron Lett. 1979,
4437.
The authors would like to thank Bruce Knoll at the
University of Colorado at Boulder for assistance with
crystallography. Funding for this research was provided
by the NIH (GM-38066).
5. Johnson, C.; Marren, T. J. Tetrahedron Lett. 1987, 28,
27.
6. Marata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc.
1980, 102, 3248.
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