A general route toward the synthesis of the cladiellin skeleton utilizing a SmI2-mediated cyclization

Article abstract of DOI:10.1021/jo052290d

An efficient synthesis of the cladiellin skeleton is reported utilizing methods that were previously developed in this laboratory. The approach is based on a SmI₂-mediated cyclization reaction for the construction of the oxacyclononane unit. A

Full text of DOI:10.1021/jo052290d

A General Route toward the Synthesis of the Cladiellin Skeleton
Utilizing a SmI2-Mediated Cyclization
Gary A. Molander,* Barbara Czako´, and David J. St. Jean, Jr.
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed NoVember 4, 2005
An efficient synthesis of the cladiellin skeleton is reported utilizing methods that were previously developed
in this laboratory. The approach is based on a SmI2-mediated cyclization reaction for the construction of
the oxacyclononane unit. A [4 + 3] annulation strategy was used to create the octahydroisobenzo-
furan moiety. This route provides the cladiellin skeleton in only 14 steps without the use of protecting
groups. The present approach also enabled the synthesis of the 3,7-diastereomer of the natural product
polyanthellin A.
Introduction
Cladiellin diterpenes belong to a family of marine metabolites
isolated from gorgonians and soft corals.1 The first member of
this family, eunicellin, was isolated by Djerassi and co-workers
in 1968, and since then more than 60 cladiellin natural products
have been reported.1,2 Cladiellins possess unique structural fea-
tures: a rare oxabicyclic ring system that is composed of an
octahydroisobenzofuran moiety and an oxacyclononane unit
(Figure 1).1 Furthermore, these molecules contain at least six
stereogenic centers. In addition to their intriguing structure, sev-
eral members of this family exhibit interesting biological activity
such as cytotoxic activity, antiinflammatory effects, and anti-
malarial properties.1 The challenging structure of these com-
pounds, coupled with their diverse biological properties, has
made them attractive synthetic targets for several research
groups.3-13
FIGURE 1. Cladiellin skeleton.
Construction of medium-sized ring compounds is often
problematic, and there are only a limited number of methods
(4) Friedrich, D.; Doskotch, R. W.; Paquette, L. A. Org. Lett. 2000, 2,
1879-1882.
(5) Friedrich, D.; Paquette, L. A. J. Nat. Prod. 2002, 65, 126-130.
(6) Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L. A.;
Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 135-137.
(7) Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. Org. Lett.
2000, 2, 1875-1878.
(8) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117,
10391-10392.
(1) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531-556.
(2) Kennard, O.; Watson, D. G.; Riva di Sanseverino, L.; Tursch, B.;
Bosmans, R.; Djerassi, C. Tetrahedron Lett. 1968, 2879-2884.
(3) Bernardelli, P.; Moradei, O. M.; Friedrich, D.; Yang, J.; Gallou, F.;
Dyck, B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. A. J. Am. Chem.
Soc. 2001, 123, 9021-9032.
(9) Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683-2686.
(10) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am.
Chem. Soc. 2001, 123, 9033-9044.
(11) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2003, 125, 6650-6652.
10.1021/jo052290d CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/04/2006
1172
J. Org. Chem. 2006, 71, 1172-1180

General Route to Synthesis of the Cladiellin Skeleton
SCHEME 1. First Synthetic Approach to the Cladiellin
Skeleton
SCHEME 2. Initial Steps of the Synthesis
previously developed procedure.13 According to this route,
compound 6 could be obtained in only three steps from com-
mercially available (R)-(-)-R-phellandrene. First, (R)-(-)-R-
phellandrene was reacted in a [2 + 2] ketene olefin cycload-
dition.18 This reaction was followed by a photorearrangement
to provide bis-acetal 8.19-21 Tricycle 6 could be formed by a
TiCl4-mediated [4 + 3] annulation reaction between bis-acetal
8 and 1-methoxy-1,3-bis(triethylsilanyloxy)-1,3-butadiene.17
Subsequent methylation of the dianion derived from the [4 +
3] annulation product 6, Krapcho decarboxylation, and epimer-
ization led to the desired methyl ketone 9.13,22 The next task
was to create the quaternary carbon stereocenter alpha to the
carbonyl. Direct allylation of the anion derived from methyl
ketone 9 proved to be problematic due to decomposition of
the substrate under various conditions. Eventually, this trans-
formation could be realized in a two-step sequence. Treatment
of R-methyl ketone 9 with potassium hydride and tert-butyl-
dimethylsilyl chloride provided the thermodynamic silyl enol
ether with high regioselectivity. Introduction of the allyl group
was achieved via a silver trifluoroacetate-mediated allylation
using allyl iodide.23 Subsequently, the primary hydroxyl func-
tionality was formed through a chemoselective hydroboration
of the terminal alkene with dicyclohexylborane in the presence
of the trisubstituted double bond and the ketone providing
compound 5.24,25
available for creating these systems. It was demonstrated
previously that medium-sized rings can be efficiently synthe-
sized by SmI2-mediated cyclization.14-16 The focus of the
present research was to devise a concise route toward the syn-
thesis of the cladiellin skeleton wherein a SmI2-mediated
cyclization was utilized to create the oxacyclononane subunit.
For constructing the octahydroisobenzofuran moiety, a [4 + 3]
annulation reaction was employed.13,17
Results and Discussion
The initial synthetic approach is depicted in Scheme 1. The
strategy was based on a SmI2-mediated acyl substitution
reaction, a method that was developed and widely studied in
this group, to create the oxacyclononane subunit of the
skeleton.16 The SmI2-mediated cyclization precursor 2 was
envisioned to derive from hydroxy lactone 3 that in turn could
be derived from tricyclic ketone 4 via a Baeyer-Villiger
oxidation. The tertiary acetoxy functionality at the C-11 position
is prevalent in several cladiellin diterpene natural products, and
this functional group was to be introduced at this stage of the
synthesis. Compound 5 could be obtained from [4 + 3]
annulation product 6.
Previous studies had indicated that some compounds contain-
ing the 8-oxabicylo[3.2.1]octa-3-one subunit, as in structure 5,
do not undergo Baeyer-Villiger oxidation readily.26 However,
the viability of this transformation was tested again using
(18) Thap Do, M.; Strausz, O. P. J. Am. Chem. Soc. 1970, 92, 1766-
The initial steps of the sequence are depicted in Scheme 2.
The [4 + 3] annulation product 6 was synthesized following a
1768.
(19) Morton, D. R.; Lee-Ruff, E.; Southam, R. M.; Turro, N. J. J. Am.
Chem. Soc. 1970, 92, 4349-4357.
(12) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126,
(20) Morton, D. R.; Turro, N. J. J. Am. Chem. Soc. 1973, 95, 3947-
10264-10266.
3957.
(13) Molander, G. A.; St. Jean, D. J., Jr.; Haas, J. J. Am. Chem. Soc.
(21) Turro, N. J.; Morton, D. R. J. Am. Chem. Soc. 1971, 93, 2569-
2571.
2004, 126, 1642-1643.
(14) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
(22) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett. 1967,
102, 2693-2698.
215-217.
(15) Molander, G. A.; Etter, J. B. Tetrahedron Lett. 1984, 25, 3281-
(23) Jefford, C. W.; Sledeski, A. W.; Lelandais, P.; Boukouvalas, J.
3284.
Tetrahedron Lett. 1992, 33, 1855-1858.
(16) Molander, G. A.; McKie, J. A. J. Org. Chem. 1993, 58, 7216-
(24) Kabalka, G. W.; Yu, S.; Li, N.-S. Tetrahedron Lett. 1997, 38, 5455-
7227.
5458.
(17) Molander, G. A.; Andrews, S. W. Tetrahedron Lett. 1989, 30, 2351-
2354.
(25) Kabalka, G. W.; Yu, S.; Li, N.-S. Can. J. Chem. 1998, 76, 800-
805.
J. Org. Chem, Vol. 71, No. 3, 2006 1173

Molander et al.
SCHEME 3. Baeyer-Villiger Oxidation Studies
SCHEME 4. Baeyer-Villiger Oxidation Studies
SCHEME 5. Second Synthetic Approach to the Cladiellin
Skeleton
compound 5. Several oxidizing agents were tried (m-CPBA,
magnesium monoperoxyphthalate, trifluoroperacetic acid, per-
acetic acid, and bis(trimethylsilyl) peroxide) under a variety of
conditions (changing the temperature, applying buffers and
radical scavengers), but in all instances only epoxidation
occurred and no traces of the Baeyer-Villiger oxidation product
could be isolated (Scheme 3).27
SCHEME 6. Synthesis of the SmI2-Mediated Cyclization
Precursor 17
Simultaneously, studies on model systems were also con-
ducted (Scheme 4). Interestingly, applying trifluoroperacetic acid
(TFPAA) generated from trifluoroacetic anhydride (TFAA) and
90% H2O2 on model ketone 9 led to the desired lactone 13,
while no lactone formation occurred on ketone 14.28
These results may imply that the rate-determining step of this
Baeyer-Villiger oxidation is the nucleophilic attack of the
trifluoroperoxy acid to the ketone.29,30 The outcome of the model
studies could thus be explained by examining the three-
dimensional structures of compounds 9 and 14 (Figure 2). In
both cases, nucleophilic addition of trifluoroperacetic acid to
the ketone is expected to occur from the less hindered convex
face of the ring system. The 3D structures of compounds 9 and
14 reveal that in the case of compound 9, where the methyl
substituent is on the concave face, the attack of the peracid can
take place without difficulty. However, when the methyl group
is situated on the convex side of the ring system, as in compound
14, the ketone is sterically encumbered, and thus the attack of
the peracid is hindered (Figure 2).
The above findings prompted a revision of the synthetic
strategy. The modified approach, shown in Scheme 5, diverged
from the original synthesis after the [4 + 3] annulation. In this
route, the allyl side chain was introduced onto the annulation
product 6 directly. Subsequent functionalization would provide
the required Baeyer-Villiger oxidation precursor 19. As in the
previous approach, the construction of the oxacyclononane ring
system was envisioned via a SmI2-mediated acyl substitution.
The synthetic sequence investigating this approach is depicted
in Scheme 6. The route started with the allylation of the [4 +
3] annulation product 6 using n-BuLi and allyl iodide, providing
the product as the only diastereomer. Subsequent Krapcho
decarboxylation and epimerization led to a 3:1 mixture of
compound 21 and its epimer.22 After separation, the minor
(26) Haas, J. Application of the (4+3) Annulation Reactions to Natural
Product Synthesis. Ph.D. Thesis, University of Pennsylvania, Philadelphia,
PA, 2002.
(27) Krow, G. R. Org. React. 1993, 43, 251-798.
(28) Cofre, P.; Sawyer, D. T. Inorg. Chem. 1986, 25, 2089-2092.
(29) Mosome, T.; Atarashi, S.; Muraoka, O. Tetrahedron Lett. 1974, 42,
3697-3700.
FIGURE 2. 3D representation of compounds 9 and 14.
1174 J. Org. Chem., Vol. 71, No. 3, 2006
(30) Hunt, K. W.; Grieco, P. A. Org. Lett. 2000, 2, 1717-1719.

General Route to Synthesis of the Cladiellin Skeleton
SCHEME 7. SmI2-Mediated Reaction
diastereomer could be recycled and epimerized to the desired
product. Selective hydroboration/oxidation could be achieved
as before using dicyclohexylborane,24,25 and the resulting alcohol
was easily protected as a tert-butyldimethylsilyl ether.31 Intro-
duction of the tertiary acetate group was realized in a three-
step sequence providing compound 19. First, halohydrin for-
mation was achieved using N-bromosuccinimide and water.32
Removal of the bromide was accomplished in a radical reaction
utilizing tributyltin hydride.33,34 Subsequent acylation proved
to be problematic due to the propensity of the tertiary alcohol
to eliminate. After extensive optimization, it was found that this
transformation could be effected using acetic anhydride, tri-
ethylamine, and substoichiometric quantities of DMAP, provid-
ing the Baeyer-Villiger oxidation precursor.35 Gratifyingly,
Baeyer-Villiger oxidation of compound 19 readily occurred
using 90% trifluoroperacetic acid.27 Further optimization of the
oxidation was attempted using m-chloroperbenzoic acid, mag-
nesium monoperoxyphthalate, and peracetic acid under various
conditions, but trifluoroperacetic acid proved to be the most
efficient oxidant. Subsequent formation of the cyclization
precursor 17 was realized in two steps, first by removing the
TBDPS protecting group using TBAF and forming the corre-
sponding iodide by triphenylphosphine and iodine.31,36
FIGURE 3. Minimum energy conformation of iodolactone 17.
SCHEME 8. Third Synthetic Approach to the Cladiellin
Skeleton
With compound 17 in hand, the SmI2-mediated acyl substitu-
tion was attempted in the presence of HMPA or NiI2 (Scheme
7).16,37 However, these transformations led only to reduced
material, and no cyclization product could be observed.
The outcome of this reaction can be rationalized by unfavor-
able conformational effects. In the minimum energy conforma-
tion, the organosamarium side chain is in a quasi-equatorial
orientation.38 For the transformation to occur, this side chain
must rotate into a quasi-axial orientation, and the attack on the
lactone needs to occur from the concave face of the ring system
(Figure 3). On the basis of MMFF calculations, the energy
difference between the minimum energy conformation and the
conformation where the side chain is in a quasi-axial orientation
is 8.05 kcal/mol.
would then be obtained via elimination and oxidative cleavage
of the resulting double bond.
To arrive at the cyclization precursor 26, the sequence began
with compound 27, a known intermediate in the previous
approach (Scheme 9). First, selective hydroboration of mono-
substituted alkene was carried out with dicyclohexylborane.24,25
To avoid protecting group manipulations, the primary alcohol
was transformed into the corresponding alkyl chloride using
hexachloroacetone and triphenylphosphine.39 Introduction of the
tertiary acetate could be achieved as before, in a three-step
sequence.32-35 To form the SmI2-mediated cyclization precursor,
the alkyl chloride was transformed to the corresponding alkyl
iodide 26 via a Finkelstein reaction.40 Gratifyingly, the key SmI2-
mediated Barbier reaction provided compound 25 in excellent
yield.15 Regioselective syn elimination of the tertiary alcohol
could be effected using the Burgess reagent to give compound
24 as the only product in high yield.41 Ozonolysis of the
tetrasubstituted double bond provided the desired product 23, a
compound that incorporates all of the carbon atoms of the
cladiellin skeleton.42 With this transformation, the goal of
constructing the cladiellin core was achieved.
As the SmI2-mediated acyl substitution did not lead to the
desired product, a third approach was devised, which also
included a SmI2-mediated cyclization. However, the cyclization
was planned to be performed on the more reactive and sterically
more feasible iodo ketone 26 (Scheme 8). The cladiellin skeleton
(31) Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975-2977.
(32) Guss, C. O.; Rosenthal, R. J. Am. Chem. Soc. 1955, 77, 2549.
(33) Kupchik, E. J.; Connolly, R. E. J. Org. Chem. 1961, 26, 4747-
4748.
Having synthesized the skeleton of the cladiellin natural
products, the challenge to differentiate between the two carbonyl
functionalities of compound 23 remained. Studies conducted
on compound 23 indicated that a Wittig reaction, carried out
(34) Noltes, J. G.; van der Kerk, G. J. M. Chem. Ind. 1959, 294.
(35) Hoefle, G.; Steglich, W.; Vorbrueggen, H. Angew. Chem. 1978, 90,
602-615.
(36) Verheyden, J. P. H.; Moffatt, J. G. J. Am. Chem. Soc. 1964, 86,
2093-2095.
(39) Magid, R. M.; Fruchey, O. S.; Johnson, W. L. Tetrahedron Lett.
1977, 2999-3002.
(37) Machrouhi, F.; Hamann, B.; Namy, J. L.; Kagan, H. B. Synlett 1996,
633-634.
(40) Finkelstein, H. Ber. 1910, 43, 1528-1532.
(41) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Am. Chem. Soc.
1970, 92, 5224-5226.
(38) Spartan ’04, Molecular Mechanics Model, MMFF94 Forcefield,
Conformation Distribution Calculation; Wavefunction, Inc.: Irvine, CA,
2004.
(42) Bailey, P. S. Chem. ReV. 1958, 58, 925-1010.
J. Org. Chem, Vol. 71, No. 3, 2006 1175

Molander et al.
SCHEME 9. Synthesis of the Cladiellin Skeleton
FIGURE 4. X-ray structure of diketone 23 and minimum energy
conformation of keto alkene 29.
SCHEME 10. Chemoselective Wittig Reaction of
Dicarbonyl 23
FIGURE 5. NOESY correlation of the 3,7-diastereomer of poly-
anthellin A.
under carefully controlled conditions, occurs with very high
selectivity at the C-3 carbonyl providing compound 29 (Scheme
10).43 The structure of the product was unambiguously dem-
onstrated by 2D-NMR experiments. The HMBC spectrum of
molecule 29 shows a correlation between H-2 and C-3, H-2
and C-18, and H-18 and C-2 that clearly indicates the position
of the double bond.
not be unambiguously proven by analysis of NOESY data of
compound 30. To elucidate the stereochemistry, the tertiary
alcohol was transformed into compound 31 via oxymercuration
with mercury trifluoroacetate and subsequent reduction (Scheme
11).46
Several cladiellin natural products possess a tertiary alcohol
at the C-7 position. Having compound 29 in hand, the formation
of this functionality via methyl addition to the C-7 ketone was
examined, devoting special attention to the diastereoselectivity
of the transformation. On the basis of the crystal structure of
diketone 23, as well as the minimum energy conformation of
keto alkene 29 (Figure 4),13,44 addition was expected to occur
from the more open convex face or “outside” of the ring system,
providing the stereochemistry desired for several target struc-
tures.
Initial studies showed that methyl addition to the carbonyl
could not be realized by methyllithium or methylmagnesium
bromide. In these cases, only starting material was recovered,
perhaps owing to enolization of the carbonyl. However, by using
MeLi/Yb(OTf)3 efficient carbonyl addition was effected.45
Unfortunately, the stereochemistry of the resulting product could
The structure of the final product was established on the basis
of 2D-NMR experiments. To our surprise, the unanticipated
diastereomer was formed in high yield. Proton and carbon
assignments were made based on COSY, HMQC, and HMBC
experiments, and the stereochemistry was confirmed based on
NOESY experiments. The characteristic correlation between H-2
and CH3-18, and H-8R and CH3-19, and the absence of
correlations between H-1 and CH3-18 and H-10 and CH3-19 in
the NOESY spectrum unambiguously established the stereo-
chemistry of the product (Figure 5). These results indicated that
methyl addition occurred from a conformation different than
that predicted on the basis of the calculated and crystal
structures, suggesting that, in the reactive conformation, che-
lation between the oxygen of the tetrahydrofuran ring and the
ketone might play a key role. Unfortunately, addition of a polar,
aprotic solvent such as HMPA to the MeLi/Yb(OTf)3 reagent,
(43) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 97, 1318-1330.
(44) According to MMFF calculations, the energy difference between
the minimum energy conformation and the conformation where the ketone
is rotated out is 5.35 kcal/mol.
(45) Molander, G. A.; Burkhardt, E. R.; Weinig, P. J. Org. Chem. 1990,
55, 4990-4991.
(46) Broka, C. A.; Lin, Y. T. J. Org. Chem. 1988, 53, 5876-5885.
1176 J. Org. Chem., Vol. 71, No. 3, 2006

General Route to Synthesis of the Cladiellin Skeleton
solvent was evaporated. The residue was purified via column
chromatography applying EtOAc-hexane (3%) as eluent to provide
compound 33 (1.75 g, 90%). 1H NMR (500 MHz, CDCl3): δ 10.8
(s, 1H), 5.86 (m, 1H), 5.52 (s, 1H), 5.12 (d, J ) 16.2 Hz, 1H),
5.11 (s, 1H), 4.66 (s, 1H), 3.93 (s, 1H), 3.52 (s, 3H), 2.58 (d, J )
14.1 Hz, 1H), 2.5 (d, J ) 7.5 Hz, 1H), 2.36 (m, 1H), 2.29 (d, J )
7.1 Hz, 1H), 2.08 (dd, J ) 9.8, 3.6 Hz, 1H), 2.0 (m, 2H) 1.73 (s,
3H), 1.43 (m, 1H), 1.38 (m, 1H), 0.91 (d, J ) 6.8 Hz, 3H), 0.78
(d, J ) 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 171.2, 170.3,
135.8, 133.9, 122.3, 117.2, 103.2, 81.5, 74.9, 51.5, 50.6, 47.0, 44.2,
42.3, 35.5, 29.0, 23.1, 21.5, 21.4, 21.0. IR (film): 3800-3000 (bs),
2955, 2867, 1658, 1618, 1442, 1363, 1305, 1260, 1248, 1203, 1147,
1081 cm-1. [R]20D -78.9 (c 1.2, CHCl3). HRMS calcd for C20H28O4
[M + Na]+ 355.1885, found 355.1879.
FIGURE 6. Polyanthellin A.
SCHEME 11. Synthesis of the 3,7-Diastereomer of
Polyanthellin A
Preparation of (1R,2R,6R,7R,8R,9R)-9-Allyl-6-isopropyl-3-
methyl-12-oxatricyclo[6.3.1.02,7] dodec-3-en-10-one (27). A round-
bottom flask was charged with compound 33 (1.75 g, 5.27 mmol),
LiCl (1.17 g, 26.3 mmol, 5 equiv), DMSO (100 mL), and H2O
(378 µL). The solution was warmed to 130 °C and stirred at this
temperature for 4 h. After cooling the mixture to room temperature,
a saturated NaCl solution (35 mL) was added. This mixture was
extracted with Et2O (5 × 20 mL). The combined organic phases
were washed with a concentrated NaCl solution, dried (MgSO4),
and filtered. The solvent was removed under reduced pressure. The
residue was purified via column chromatography applying EtOAc-
hexane (3%) as eluent to provide compound 27 (1.24 g, 86%). 1H
NMR (500 MHz, CDCl3): δ 5.74 (m, 1H), 5.54 (s, 1H), 5.09 (d,
J ) 15.1 Hz, 1H), 5.06 (d, J ) 9.3 Hz, 1H), 4.46 (d, J ) 5.1 Hz,
1H), 4.15 (s, 1H), 2.76 (dd, J ) 15.0 5.1 Hz, 1H), 2.43 (m, 2H),
2.24 (series of multiplets, 3H), 2.15 (t, J ) 6.5 Hz, 1H), 1.95 (d,
J ) 8.3 Hz, 1H), 1.55 (m, 1H), 1.66 (s, 3H), 1.60 (m, 1H), 1.32
(m, 1H), 0.90 (d, J ) 6.8 Hz, 3H), 0.76 (d, J ) 6.8 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ 209.9, 134.7, 132.3, 122.9, 117.4,
82.2, 78.6, 57.7, 47.6, 47.0, 45.1, 41.4, 35.2, 28.9, 22.4, 22.1, 21.5,
18.1. IR (film): 3070, 2956, 2868, 1712, 1442, 1385, 1184, 1036
which would prevent chelate formation, again resulted in the
recovery of starting material.
Compound 31 is the 3,7-diastereomer of a cladiellin natural
product, polyanthellin A (Figure 6), which was isolated from
the gorgonian Briareum polyanthes in 2002. The synthesis of
this compound was achieved in only 17 overall steps without
the use of protecting groups from commercially available (R)-
(-)-R-phellandrene.
cm-1. [R]20 -156.0 (c 1.0, CHCl3). HRMS calcd for C18H26O2
+
D
[M]+ 275.2011, found 275.1997.
Conclusion
Preparation of (1R,2R,6R,7R,8R,9R)-9-(3-Hydroxypropyl)-6-
isopropyl-3-methyl-12-oxatricyclo[6.3.1.02,7]dodec-3-en-10-one
(34). Compound 27 (770 mg, 2.81 mmol) was dissolved in THF
(36 mL), and a solution of dicyclohexylborane (1 M in THF, 2.81
mL, 1 equiv) was added at room temperature under argon. The
resulting solution was stirred for 30 min at room temperature.
Subsequently, NaBO3‚H2O (1.29 g, 8.43 mmol, 3 equiv) and H2O
(10 mL) were added, and the reaction was stirred for an additional
4 h. Then the reaction mixture was diluted with Et2O (10 mL), and
the phases were separated. The aqueous phase was extracted with
EtOAc (3 × 5 mL). The combined organic phases were washed
with a concentrated NaCl solution, dried (MgSO4), and filtered.
The solvent was removed under reduced pressure. The residue was
purified via column chromatography applying EtOAc-hexane
(20%) as eluent to provide compound 34 (618 mg, 75% based on
recovered starting material). 1H NMR (500 MHz, CDCl3): δ 5.56
(s, 1H), 4.48 (d, J ) 4.95 Hz, 1H), 4.15 (s, 1H), 3.65 (t, J ) 5.5
Hz, 2H), 2.81 (dd, J ) 15.0, 5.2 Hz, 1H), 2.42-2.20 (series of
multiplets, 3H), 2.16 (t, J ) 6.5 Hz, 1H), 1.95 (d, J ) 15.0 Hz,
1H), 1.92-1.70 (series of multiplets, 4H), 1.68 (s, 3H), 1.68-1.51
(series of multiplets, 3H), 1.31 (m, 1H), 0.93 (d, J ) 6.8 Hz, 3H),
0.78 (d, J ) 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 210.8,
132.3, 123.0, 83.5, 78.7, 62.2, 57.8, 47.4, 46.8, 45.2, 41.5, 29.9,
28.9, 27.4, 22.4, 22.1, 21.6, 18.1. IR (film): 3600-3100 (bs), 3070,
An efficient approach to the synthesis of the cladiellin skel-
eton was devised, featuring two methods that were previously
developed in our research group. The medium-sized oxacy-
clononane subunit of the skeleton was created by a SmI2-
mediated cyclization.15 The octahydroisobenzofuran moiety was
synthesized via a [4 + 3]-annulation method.13,17 Following
this strategy, the cladiellin skeleton could be synthesized in
only 14 steps without the use of protecting groups. This route
also enabled the synthesis of the 3,7-diastereomer of poly-
anthellin A.
Experimental Section
Preparation of (1R,2R,3R,7S,8R,11R)-11-Allyl-10-hydroxy-3-
isopropyl-6-methyl-12-oxatricyclo[6.3.1.02,7]dodeca-5,9-diene-9-
carboxylic Acid, Methyl Ester (33). A flask containing LiCl (4.9
g, 116.4 mmol, 20 equiv) was flame-dried three times. After the
salt was cooled to room temperature under an argon, a solution of
compound 20 (1.7 g, 8.2 mmol) in THF (58 mL) was added.
Subsequently, the solution was cooled to -78 °C, and n-BuLi (2.5
M in hexane, 5 mL, 12.5 mmol, 2.15 equiv) was added dropwise.
The reaction was stirred at this temperature for 35 min. This process
was followed by the dropwise addition of allyl iodide (793 µL, 8.7
mmol, 1.5 equiv). The reaction was allowed to warm to -50 °C
and stirred for 40 min. The reaction was quenched with a saturated
ammonium chloride solution (20 mL) at -50 °C. After warming
to room temperature, the mixture was diluted with Et2O and the
phases were separated. The aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic phases were washed
with a concentrated NaCl solution and dried over MgSO4, and the
2956, 2868, 1711, 1446, 1385, 1366, 1187, 1146, 1064 cm-1. [R]20
D
-107.7 (c 1.0, CHCl3). HRMS calcd for C18H28O3 [M + Na]+
315.1936, found 315.1928.
Preparation of (1R,2R,6R,7R,8R,9R)-9-(3-Chloropropyl)-6-
isopropyl-3-methyl-12-oxatricyclo[6.3.1.02,7]dodec-3-en-10-one
(28). To a solution of compound 27 (450 mg, 1.54 mmol) in
CH2Cl2 (30 mL) was added Ph3P (504 mg, 1.92 mmol, 1.25 equiv)
under a nitrogen atmosphere at room temperature. The resulting
J. Org. Chem, Vol. 71, No. 3, 2006 1177

Molander et al.
solution was cooled to -10 °C, and hexachloroacetone (373 µL,
2.46 mmol, 1.6 equiv) was added. The reaction was stirred at this
temperature for 20 min. Then H2O (10 mL) was added, and the
phases were separated. The aqueous phase was extracted with
CH2Cl2 (3 × 5 mL). The combined organic phases were washed
with saturated NaCl solution, dried (MgSO4), and filtered. The
solvent was removed under reduced pressure. The resulting residue
was purified via column chromatography applying EtOAc-hexane
(10%) as eluent to provide compound 28 (470 mg, 88%). 1H NMR
(500 MHz, CDCl3): δ 5.56 (d, J ) 4.3 Hz, 1H), 4.48 (d, J ) 5.0
Hz, 1H), 4.12 (s, 1H), 3.55 (m, 2H), 2.81 (dd, J ) 15.0, 5.2 Hz,
1H), 2.35 (d, J ) 6.2 Hz, 1H), 2.26 (d, J ) 15.7 Hz, 1H), 2.24 (t,
J ) 6.2 Hz, 1H), 2.17 (t, J ) 6.2 Hz, 1H), 1.97 (d, J ) 15.7 Hz,
1H), 1.95-1.82 (series of multiplets, 3H), 1.82-1.72 (series of
multiplets, 2H), 1.68 (s, 3H), 1.62 (dd, J ) 15.0, 6.2 Hz, 1H), 1.31
(m, 1H), 0.92 (d, J ) 6.8 Hz, 3H), 0.80 (d, J ) 6.8 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ 210.1, 132.4, 123.0, 83.7, 78.8, 57.5,
47.4, 46.9, 45.2, 44.3, 41.6, 29.9, 29.0, 28.2, 22.4, 22.1, 21.6, 18.2.
IR (film): 3070, 2954, 2933, 2894, 2864, 1705, 1409, 1379, 1292,
[6.3.1.02,7]dodec-3-yl Ester (41). To a solution of compound 40
(113 mg, 0.34 mmol) in CH2Cl2 (3.4 mL) was added Et3N (143
µL, 1.03 mmol, 3 equiv), Ac2O (100 µL, 1.05 mmol, 3.05 equiv),
and DMAP (17 mg, 0.14 mmol, 0.4 equiv). The reaction was stirred
at room temperature for 6 h. Addition of Et3N and Ac2O was
repeated twice. Then the reaction was cooled to -10 °C and stirred
overnight at this temperature. Upon completion of the reaction, H2O
(5 mL) was added, and the phases were separated. The aqueous
phase was extracted with CH2Cl2 (3 × 2 mL). The combined
organic phases were washed with saturated NaCl solution and dried
(MgSO4). The solvent was evaporated under reduced pressure. The
resulting residue was purified via column chromatography applying
EtOAc-hexane (10%) as eluent to provide compound 41 (65 mg,
66% BRSM). 1H NMR (500 MHz, CDCl3): δ 4.34 (bs, 1H), 3.99
(s, 1H), 3.54 (m, 2H), 2.78 (dd, J ) 15.0, 4.3 Hz, 1H), 2.39 (d, J
) 13.0 Hz, 1H), 2.33 (d, J ) 15.5 Hz, 1H), 2.26 (m, 1H), 2.16 (m,
1H), 2.06 (dd, J ) 10.0, 8.0 Hz 1H), 1.95 (s, 3H), 1.90-1.72 (m,
4H), 1.64 (m, 1H), 1.5 (s, 3H), 1.45 (m, 1H), 1.40-1.20 (series of
multiplets, 2H), 1.13 (m, 1H), 0.94 (d, J ) 6.8 Hz, 3H), 0.82 (d, J
) 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 209.6, 169.9, 84.8,
82.2, 75.3, 54.6, 52.9, 49.6, 46.0, 44.3, 42.0, 30.8, 30.5, 29.8, 29.3,
23.9, 22.3, 21.3, 18.3, 16.6. IR (film): 2956, 2872, 1728, 1712,
1191, 1128, 1104, 1083 cm-1. [R]20 -108.5 (c 0.55, CHCl3).
D
HRMS calcd for C18H27ClO2 [M]+ 333.1597, found 333.1589.
Preparation of (1R,2R,3S,4S,6R,7R,8R,9R)-4-Bromo-9-(3-
chloropropyl)-3-hydroxy-6-isopropyl-3-methyl-12-oxatricyclo-
[6.3.1.02,7]dodecan-10-one (39). Compound 28 (450 mg, 1.45
mmol) was dissolved in a mixture of THF (17.4 mL) and H2O (3.2
mL). To this solution was added NBS (334 mg, 1.89 mmol, 1.3
equiv) in three portions over 1 h at 0 °C under nitrogen. The reaction
was allowed to warm to room temperature and stirred for 4 h. Then
the mixture was diluted with H2O (3 mL) and Et2O (5 mL) The
phases were separated, and the aqueous phase was extracted with
EtOAc (3 × 3 mL). The combined organic phases were washed
with a saturated NaCl solution, dried (MgSO4), and filtered. The
solvent was removed under reduced pressure. The resulting residue
was purified via column chromatography applying EtOAc-hexane
(20%) as eluent to provide compound 39 (450 mg, 71%). 1H NMR
(500 MHz, CDCl3): δ 4.81 (d, J ) 4.5 Hz, 1H), 4.11 (m, 2H),
3.53 (t, J ) 6.1 Hz, 2H), 2.81 (dd, J ) 15.5, 5.0 Hz, 1H), 2.27 (d,
J ) 15.5 Hz, 1H), 2.12-2.07 (series of multiplets, 5H), 2.0 (m,
1H), 1.9-1.6 (m, 6H), 1.41 (s, 3H), 0.91 (d, J ) 6.8 Hz, 3H), 0.82
(d, J ) 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 209.5, 84.2,
77.5, 72.3, 62.8, 57.0, 53.2, 47.8, 44.9, 44.2, 39.7, 30.9, 30.3, 29.7,
28.3, 21.8, 21.2, 15.7. IR (film): 3600-3100, 2957, 2873, 1710,
1462, 1443, 1366, 1258, 1190, 1145, 1119 cm-1. [R]20 -13.4 (c
D
0.7, CHCl3). HRMS calcd for C20H31ClO4 [M + Na]+ 393.1808,
found 393.1824.
Preparation of (1R,2R,3S,6R,7R,8R,9R)-Acetic Acid 9-(3-
Iodopropyl)-6-isopropyl-3-methyl-10-oxo-12-oxatricyclo[6.3.1.02,7]-
dodec-3-yl Ester (26). To a solution of compound 41 (75 mg, 0.20
mmol) in acetone (2 mL) was added sodium iodide (304 mg, 2.02
mmol, 10 equiv). The reaction was warmed to 57 °C and stirred
for 14 h under nitrogen at this temperature. Upon completion, the
reaction was cooled to room temperature, and the solvent was
removed under reduced pressure. The resulting residue was purified
via column chromatography applying EtOAc-hexane (10%) as
eluent to provide compound 26 (83 mg, 89% BRSM).
1H NMR (500 MHz, CDCl3): δ 4.35 (bs, 1H), 3.98 (s, 1H),
3.18 (t, J ) 6.25 Hz, 2H), 2.79 (dd, J ) 15.0, 3.5 Hz, 1H), 2.40 (d,
J ) 13 Hz, 1H), 2.34 (d, J ) 15.5 Hz, 1H), 2.27 (d, J ) 4.45 Hz,
1H), 2.16 (m, 1H), 2.06 (dd, J ) 10.25, 8.0 Hz, 1H), 1.95 (s, 3H),
1.90-1.78 (series of multiplets, 3H), 1.65 (m, 1H), 1.59 (m, 1H),
1.51 (s, 3H), 1.56 (m, 1H), 1.39-1.25 (series of multiplets, 2H),
1.14 (dt, J ) 15.6, 3.5 Hz, 1H), 0.95 (d, J ) 6.8 Hz, 3H), 0.82 (d,
J ) 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 209.5, 169.9,
84.8, 82.2, 75.3, 54.4, 52.9, 49.6, 46.0, 44.3, 42.0, 32.8, 30.8, 30.5,
23.9, 22.3, 21.3, 18.3, 16.6, 5.7. IR (film): 2955, 2872, 1728, 1711,
1453, 1434, 1410, 1371, 1349, 1229, 1171, 1123, 1037 cm-1. [R]20
D
+20.3 (c 1.5, CHCl3). HRMS calcd for C18H28BrClO3 [M]+
429.0808, found 429.0824.
Preparation of (1R,2R,3S,6R,7R,8R,9R)-9-(3-Chloropropyl)-
3-hydroxy-6-isopropyl-3-methyl-12-oxatricyclo[6.3.1.02,7]dodecan-
10-one (40). To a solution of compound 39 (450 mg, 1.10 mmol)
and AIBN 18 mg, 0.11 mmol) in benzene (11 mL) was added
n-Bu3SnH (355 µL, 1.32 mmol, 1.2 equiv) under an argon atmos-
phere. The reaction was warmed to 90 °C and stirred at this
temperature for 1 h. Subsequently, the reaction was cooled to room
temperature, and the solvent was removed under reduced pressure.
The resulting residue was purified via column chromatography
applying EtOAc-hexane (20%) as eluent to provide compound 40
1462, 1442, 1366, 1257, 1191, 1118 cm-1 [R]20 -14.5 (c 0.4,
D
CHCl3). HRMS calcd for C20H31IO4 [M + Na]+ 485.1164, found
485.1154.
Preparation of Tetracyclic Quaternary Alcohol 25. Preparation
of the SmI2 solution: To a slurry of Sm (59 mg, 0.39 mmol, 3.6
equiv) in THF (2.4 mL) was added CH2I2 (26 µL, 0.33 mmol, 3
equiv) in two portions, dropwise, under an argon atmosphere at
room temperature. The solution was stirred for 4 h. Then the
solution was cooled to 0 °C, and HMPA (420 µL, 1.98 mmol, 18
equiv) was added. The solution was then stirred for 15 min at 0
°C. Procedure for the SmI2-mediated cyclization: A solution of
compound 26 (52 mg, 0.11 mmol) in THF (1.1 mL) was added
dropwise via cannula to the SmI2 solution. The reaction was allowed
to warm to room temperature and stirred for 1 h. Upon completion,
the reaction was quenched with Rochelle’s salt solution (1 mL),
and the mixture was stirred at room temperature for 20 min. This
was followed by the addition of H2O (2 mL) and Et2O (3 mL).
The phases were separated, and the aqueous phase was extracted
with EtOAc (3 × 1.5 mL). The combined organic phases were
washed with a saturated NaCl solution, dried (MgSO4), and filtered.
The solvent was evaporated under reduced pressure. The resulting
residue was purified via column chromatography applying EtOAc-
hexane (20%) as eluent to provide compound 25 (32 mg, 88%).
1H NMR (500 MHz, CDCl3): δ 4.09 (bs, 1H), 3.78 (s, 1H), 3.27
1
(360 mg, 94%). H NMR (500 MHz, CDCl3): δ 4.31 (bs, 1H),
4.01 (s, 1H), 3.53 (m, 2H), 1.77 (dd, J ) 15, 4.3 Hz, 1H), 2.31 (d,
J ) 15 Hz, 1H), 2.15 (t, J ) 6.7 Hz, 1H), 2.08 (dd, J ) 10.0, 8.0
Hz, 1H), 1.97 (m, 1H), 1.88-1.73 (series of multiplets, 3H), 1.66
(m, 1H), 1.62 (s, 1H), 1.56 (m, 1H), 1.47-1.25 (series of multiplets,
4H), 1.24 (s, 3H), 0.94 (d, J ) 6.8 Hz, 3H), 0.91 (t, J ) 7.3 Hz,
1H), 0.82 (d, J ) 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ
210.2, 84.7, 76.5, 70.3, 55.3, 55.2, 50.1, 46.5, 44.8, 42.3, 35.4, 31.0,
30.3, 29.7, 29.6, 22.0, 18.4, 17.1. IR (film): 3600-3100, 2956,
2870, 1709, 1463, 1410, 1396, 1287, 1196, 1075 cm-1. [R]20D -6.93
(c 1.6, CHCl3). HRMS calcd for C18H29ClO3-H2O [M - H2O]+
310.1699, found 310.1695.
Preparation of (1R,2R,3S,6R,7R,8R,9R)-Acetic Acid 9-(3-
Chloropropyl)-6-isopropyl-3-methyl-10-oxo-12-oxatricyclo-
1178 J. Org. Chem., Vol. 71, No. 3, 2006

General Route to Synthesis of the Cladiellin Skeleton
(d, J ) 8.4, 1H), 2.25-2.13 (series of multiplets, 2H), 2.08-1.97
(series of multiplets, 2H), 1.97 (s, 3H), 1.80-1.56 (series of
multiplets, 9H), 1.54 (s, 3H), 1.52-1.38 (series of multiplets, 2H),
1.30-1.12 (series of multiplets, 2H), 0.92 (d, J ) 6.8 Hz, 3H),
0.82 (d, J ) 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 70.3,
83.8, 83.5, 77.5, 74.7, 50.1, 48.8, 46.3, 45.0, 44.5, 42.0, 31.3, 31.2,
30.9, 23.7, 22.6, 22.5, 21.4, 18.5, 16.5. IR (film): 3600-3100 (bs),
The reaction was monitored by thin-layer chromatography. Upon
consumption of the starting material, the reaction was quenched
with a saturated NaCl solution (1 mL). The phases were separated,
and the aqueous phase was extracted with benzene (2 × 0.5 mL)
and EtOAc (2 × 0.5 mL). The combined organic phases were dried
(MgSO4) and filtered, and the solvent was removed under reduced
pressure. The resulting residue was purified via column chroma-
tography applying Et2O-hexane (10%) solvent system as eluent
to provide compound 29 (16 mg, 77%). 1H NMR (500 MHz,
CDCl3): δ 4.96 (s, 1H), 4.90 (s, 1H), 4.25 (s, 1H), 5.15 (t, J ) 6.5
Hz, 1H), 3.25 (dd, J ) 11.5, 6.0 Hz, 1H), 2.85-2.75 (series of
multiplets, 2H), 2.63 (d, J ) 14 Hz, 1H), 2.39 (dd, J ) 11.5, 6.5
Hz, 1H), 2.34 (d, J ) 11.5 Hz, 1H), 2.30-2.15 (series of multiplets,
2H), 2.20-2.05 (series of multiplets, 2H) 2.00, (s, 3H), 1.75 (m,
1H), 1.50 (s, 3H), 1.48 (m, 1H), 1.39-1.08 (series of multiplets,
4H), 0.94 (d, J ) 6.5 Hz, 3H), 0.78 (d, J ) 6.5 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 213.5, 169.9, 148.4, 113.7, 85.2, 82.4, 76.7,
48.5, 48.3, 44.4, 42.1, 40.7, 34.1, 29.7, 28.7, 26.0, 24.4, 22.4, 21.6,
18.5, 15.6. IR (film): 2956, 2929, 2872, 1729, 1705, 1367, 1245,
2952, 2871, 1728, 1442, 1383, 1252, 1148 cm-1. [R]20 +40.5 (c
D
0.2, CHCl3). HRMS calcd for C20H32O4 [M]+ 359.2198, found
359.2196.
Preparation of Tetracyclic Alkene 24. To a solution of
compound 25 (55 mg, 0.164 mmol) in MeCN (1.6 mL) was added
the Burgess reagent3 (86 mg, 0.36 mmol, 2.2 equiv) under a nitrogen
atmosphere. The solution was warmed to 70 °C and stirred for 40
min. Upon completion, the reaction mixture was allowed to cool
to room temperature, and H2O (1 mL) was added. The phases were
separated, and the aqueous phase was extracted with Et2O (3 ×
0.5 mL). The combined organic phases were washed with a
saturated NaCl solution, dried (MgSO4), and filtered. The solvent
was removed under reduced pressure. The resulting residue was
purified via column chromatography applying Et2O-hexane (10%)
solvent system as eluent to provide compound 24 (45 mg, 88%).
1H NMR (500 MHz, CDCl3): δ 4.14 (bs, 1H), 4.10 (s, 1H), 2.59
(d, J ) 16.5 Hz, 1H), 2.46 (m, 1H), 2.40 (d, J ) 14 Hz, 1H),
2.35-2.25 (series of multiplets, 3H), 2.21 (m, 1H), 2.12 (t, J )
8.5, 1H), 1.97 (s, 3H), 1.88 (series of multiplets, 2H), 1.74 (d, J )
16.5 Hz, 1H), 1.66 (m, 1H), 1.55 (s, 3H), 1.48-1.32 (series of
multiplets, 2H), 1.27 (t, J ) 13 Hz, 1H), 1.12 (t, J ) 13 Hz, 1H),
0.95 (d, J ) 6.5 Hz, 3H), 0.84 (d, J ) 6.5 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 170.1, 137.8, 131.5, 83.4, 80.4, 74.5, 53.2, 48.2,
41.8, 36.2, 34.9, 32.3, 31.2, 30.7, 24.6, 22.4, 22.2, 21.3, 19.0, 17.0.
IR (film): 2956, 2872, 1725, 1442, 1366, 1247, 1185, 1143, 1040
cm-1. [R]20D -8.66 (c 0.3, CHCl3). HRMS calcd for C20H30O3 [M]+
318.2194, found 318.2190.
Preparation of (1R,2S,3R,6R,7R,8R)-Acetic Acid 6-Isopropyl-
3-methyl-9,13-dioxo-15-oxatricyclo[6.6.1.02,7]pentadec-3-yl Ester
(23). A solution of compound 24 (45 mg, 0.14 mmol) in CH2Cl2
(1.4 mL) was cooled to -78 °C, and O3 was bubbled through the
solution until a faint blue color persisted (approximately 10 s). The
solution was purged with argon at -78 °C for 10 min to remove
excess O3, and then Me2S (100 µL) was added. The reaction was
stirred overnight at room temperature. The solvent was evaporated
under reduced pressure, and the resulting residue was purified via
column chromatography applying EtOAc-hexane (30%) solvent
system as eluent to provide compound 23 (40 mg, 83%). 1H NMR
(500 MHz, C6D6): δ 3.90 (dd, J ) 9.5, 6.5 Hz, 1H), 3.83 (s, 1H),
2.96 (dd, J ) 12.0, 5.5 Hz, 1H), 2.87 (dd, J ) 11.5, 6.5 Hz 1H),
2.8 (dd, J ) 5.5, 2.5 Hz, 1H), 2.69 (d, J ) 14.5 Hz, 1H), 2.59 (t,
J ) 6.5, 2.5 Hz, 1H), 2.47 (t, J ) 6.5 Hz, 1H), 2.21 (q, J ) 14 Hz,
1H), 2.06 (d, J ) 11.5 Hz, 1H), 2.00-1.85 (series of multiplets,
2H), 1.59 (s, 3H), 1.55-1.45 (m, 1H), 1.27-1.03 (series of
multiplets, 3H), 0.98 (m, 1H), 0.80 (t, J ) 6.5 Hz, 1H), 0.81 (d, J
) 6.5 Hz, 3H), 0.74, (d, J ) 6.5 Hz, 3H). 13C NMR (125 MHz,
C6D6): δ 210.7, 210.1, 169.4, 88.4, 81.2, 78.4, 48.2, 48.0, 44.1,
40.3, 40.2, 39.5, 31.8, 30.0, 28.8, 24.5, 23.1, 21.7, 18.8, 15.5. IR
(film): 2956, 2872, 1725, 1442, 1367, 1241, 1185, 1143, 1072,
1017 cm-1. [R]20D +50 (c 0.15, CHCl3). HRMS calcd for C20H30O4
[M + Na]+ 373.1990, found: 373.1992.
1144, 1045, 1020 cm-1 [R]20 +7.0 (c 0.1, CHCl3). HRMS calcd
D
for C21H32O4 [M]+ 348.2300, found 348.2298.
Preparation of (1R,2S,3R,6R,7R,8R,13R)-Acetic Acid 13-
Hydroxy-6-isopropyl-3,13-dimethyl-9-methylene-15-oxatricyclo-
[6.6.1.02,7]pentadec-3-yl Ester (30). Procedure for the preparation
of the Yb(OTf)3‚MeLi solution: Yb(OTf)3 (285 mg, 0.46 mmol)
was dissolved in THF (4.6 mL) under an argon atmosphere. The
slurry was stirred for 15 min at room temperature, and then it was
cooled to -78 °C. This was followed by the addition of MeLi (1
M in hexane, 460 µL, 0.46 mmol), and the resulting deep red
solution was stirred at this temperature for 30 min.
Procedure for methyl addition to carbonyl: Compound 29 (11
mg, 0.031 mmol) was dissolved in THF (310 µL), and the resulting
solution was cooled to -78 °C under an argon atmosphere. To
this mixture an excess of the Yb(OTf)3‚MeLi stock solution was
added until a faint red color persisted. The reaction was followed
by thin-layer chromatography. Upon consumption of the starting
material, the reaction was queched at -78 °C with saturated
NaHCO3 (400 µL). The mixture was allowed to warm to room
temperature and was diluted with diethyl ether (500 µL). The phases
were separated, and the aqueous phase was extracted with EtOAc
(3 × 200 µL). The combined organic phases were washed with a
saturated NaCl solution, dried (MgSO4), and filtered. The solvent
was removed under reduced pressure. The resulting residue was
purified via column chromatography applying Et2O-hexane (10%)
solvent system as eluent to provide compound 30 (9 mg, 80%). 1H
NMR (500 MHz, CDCl3): δ 4.93 (s, 1H), 4.87 (s, 1H), 4.14 (s,
1H), 4.04 (m, 1H), 2.63 (t, J ) 5.5 Hz, 1H), 2.46-2.35 (series of
multiplets, 3H), 2.29 (dd, J ) 8.0, 5.5 Hz, 1H), 2.00 (s, 3H), 1.99
(m, 1H), 1.85 (dd, J ) 14.5, 11.0 Hz, 1H), 1.77-1.71 (series of
multiplets, 2H), 1.53 (m, 1H), 1.46 (s, 3H), 1.43 (m, 1H), 1.30-
1.23 (series of multiplets, 4H), 1.20 (m, 1H), 1.13 (s, 3H), 0.94 (d,
J ) 7 Hz, 3H), 0.88 (t, J ) 7 Hz, 1H), 0.82 (d, J ) 7 Hz, 3H). 13
C
NMR (125 MHz, CDCl3): δ 170.1, 152.3, 110.9, 85.3, 82.6, 76.1,
73.1, 53.8, 47.3, 43.5, 41.4, 41.06, 37.6, 31.3, 30.8, 29.6, 26.8, 24.2,
22.5, 21.6, 18.3, 16.2. IR (film): 3650-3000, 2951, 2914, 2851,
1727, 1470, 1375, 1250, 1080 cm-1. [R]20D +52.0 (c 0.1, CHCl3).
HRMS calcd for C21H36O4 [M + Na]+ 387.2511, found 387.2498.
Preparation of 3,7-Diastereomer of Polyanthellin A (31). To
a solution of compound 30 (2.8 mg, 0.0077 mmol) in THF (300
µL) was added a solution of Hg(OCOCF3) (6.5 mg, 0.0153 mmol,
2 equiv) in THF (300 µL) under an argon atmosphere. The reaction
mixture was warmed to 55 °C and stirred at this temperature for 3
h. Subsequently, the reaction was cooled to room temperature, and
NaBH4 (3.5 mg, 0.092 mmol, 12 equiv) was added. The reaction
was stirred for 30 min. Then it was quenched with saturated
NaHCO3 solution (500 µL), and the mixture was diluted with Et2O
(600 µL). The phases were separated, and the aqueous phase was
extracted with diethyl ether (3 × 200 µL). The combined organic
phases were washed with a saturated NaCl solution, dried (MgSO4),
Preparation of (1R,2S,3R,6R,7R,8R)-Acetic Acid 6-Isopropyl-
3-methyl-9-methylene-13-oxo-15-oxatricyclo[6.6.1.02,7]pentadec-
3-yl Ester (29). Procedure for the preparation of the phosphorus
ylide: To a solution of Ph3PCH3Br (214 mg, 0.625 mmol) in
benzene (5 mL) was added KOt-Bu (56 mg, 0.5 mmol). The mixture
was stirred at 40 °C for 30 min.
Procedure for the Wittig reaction: Compound 23 (21 mg, 0.06
mmol) was dissolved in benzene (600 µL), and the stock solution
of the ylide (700 µL, 0.625 mmol, 1.1 equiv) was added under an
argon atmosphere. The reaction was warmed to 80 °C and was
stirred for 30 min. The addition of the stock solution was repeated.
J. Org. Chem, Vol. 71, No. 3, 2006 1179

Molander et al.
and filtered. The solvent was removed under reduced pressure. The
resulting residue was purified via column chromatography applying
Et2O-hexane (10%) solvent system as eluent to provide the 3,7-
diastereomer of polyanthellin A (1.6 mg, 60%). 1H NMR (500 MHz,
CDCl3): δ 4.046 (t, J ) 5.5 Hz, 1H), 3.74 (s, 1H), 3.26 (t, J ) 5.5
Hz, 1H), 2.24 (dd, J ) 14.0, 5.5 Hz, 1H), 2.17-2.13 (series of
multiplets, 2H), 2.00 (s, 3H), 1.85 (m, 1H), 1.69-1.54 (series of
multiplets, 6H), 1.49 (s, 3H), 1.46-1.35 (series of multiplets, 3H),
1.25 (s, 6H), 1.32-1.2 (series of multiplets, 2H), 0.94 (d, J ) 7
Hz, 3H), 0.82 (d, J ) 7 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ
170.1, 152.3, 110.9, 85.3, 82.6, 76.1, 73.1, 53.8, 47.3, 43.5, 41.4,
41.0, 37.6, 31.3, 30.8, 29.6, 26.8, 24.2, 22.5, 21.6, 18.3, 16.2. IR
(film): 2951, 2914, 2851, 1727, 1462, 1443, 1257, 1076, 1013,
796 cm-1. [R]20D +47.5 (c 0.05, CHCl3). HRMS calcd for C22H36O4
[M + H]+ 365.2676, found 365.2685.
Acknowledgment. We acknowledge the National Institutes
of Health, Merck Research Laboratories, and Amgen for the
generous support of this work. We are grateful to Eli Lilly and
Company for the graduate fellowship for Barbara Czako´. We
also thank Dr. George Furst for his assistance in performing
the NOESY experiments.
Supporting Information Available: Experimental details and
structural data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO052290D
1180 J. Org. Chem., Vol. 71, No. 3, 2006