Stereoselective ketal-tethered intramolecular Diels-Alder cycloadditions. An approach to the 2-oxadecalin spiroketal core of antifungal agent fusidilactone C

Article abstract of DOI:10.1021/ol0495624

Equation presented. An approach toward the 2-oxadecalin spiroketal core of fusidilactone C via a rare ketal-tethered intramolecular Diels-Alder cycloaddition is described here. This intramolecular Diels-Alder cycloaddition is highly endo-selective and ove

Full text of DOI:10.1021/ol0495624

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1939-1942
Stereoselective Ketal-Tethered
Intramolecular Diels−Alder
Cycloadditions. An Approach to the
2-Oxadecalin Spiroketal Core of
Antifungal Agent Fusidilactone C
Jiashi Wang, Richard P. Hsung,* and Sunil K. Ghosh
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received March 9, 2004
ABSTRACT
An approach toward the 2-oxadecalin spiroketal core of fusidilactone C via a rare ketal-tethered intramolecular Diels−Alder cycloaddition is
described here. This intramolecular Diels−Alder cycloaddition is highly endo-selective and overall depended upon the nature of solvents and
Lewis acids. We also observed some remarkable rate acceleration in MeOH.
Recently, three new polycyclic lactones, fusidilactones A-C
[1-3], were isolated from the culture broth of fusidium sp.,
along with cis-4-hydroxy-6-deoxyscytalone [4].1 Fusidium
sp. is a fungal endophyte isolated from the leaves of Mentha
arVensis, which is found in Germany, and ether extracts of
its cultures show promising antifungal activities toward
Eurotium repens and Fusarium oxysporum, as well as other
moderate antibacterial activities.1 We became interested first
in fusidilactones A and B [1 and 2] because of our ongoing
program in natural product syntheses employing a tandem
Knoevenagel-pericyclic ring-closure2 or a stepwise formal
oxa-[3 + 3] cycloaddition strategy.3-7 However, fusidilactone
C [3] possesses a structural complexity rivaling that of
tetrodotoxin,8,9 thereby representing a unique challenge.
Fusidilactone C [3] comprises a rare oxoadamantane struc-
tural motif1,10 and, in addition to its spiroketal, also has an
unusual ether-bridged hemiacetal held in place by the rigid
frame of oxoadamantane.11 We report here our initial efforts
toward the synthesis of the 2-oxadecalin spiroketal of
fusidilactone C featuring a ketal-tethered intramolecular
Diels-Alder cycloaddition [IMDA].
(1) Krohn, K.; Biele, C.; Drogies, K.-H.; Steingro¨ver, K.; Aust, H.-J.;
Draeger, S.; Schulz, B. Eur. J. Org. Chem. 2002, 2331.
(2) For reviews, see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. 1993, 32, 131. (b) Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 47.
10.1021/ol0495624 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/11/2004

Retrosynthetically, we envisioned that the oxo-bridge of
the two hemiacetals in fusidilactone C [3] could be derived
from hydration of diketone 5, which could be attained from
lactone 6 via a Dieckmann-type condensation or an aldol
reaction [Scheme 1]. The lactone ring in 6 may be furnished
Scheme 2
Scheme 1
To construct the ketal precursor 8 for the key Diels-Alder
cycloaddition, dihydrofuran 1012 was prepared as shown in
Schemes 2 and 3. LAH reduction of 2-allyl diethyl malonate
11 followed by protection of the diol intermediate using BnBr
led to alkene 12. Subsequent dihydroxylation followed by
periodate cleavage furnished aldehyde 13 in 72% yield over
four steps [Scheme 2]. Refluxing aldehyde 13 with Eschen-
moser’s salt in THF afforded enal 14 in 85% yield.
via an iodolactonization of acid 7, a key advanced intermedi-
ate that contains the 2-oxadecalin spiroketal of fusidilactone
C [3]. Synthesis of 7 would feature a ketal-tethered intra-
molecular [4 + 2] cycloaddition reaction, preferably in an
exo-manner using ketal 8, which can be accessed from (E)-
(E)-diene 9 and dihydrofuran 10.
Scheme 3
(3) For method development, see: (a) Hsung, R. P.; Shen, H. C.; Douglas,
C. J.; Morgan, C. D.; Degen, S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690.
(b) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J.; McLaughlin,
M. J.; Mulder, J. A.; Yao, L. J. Org. Lett. 1999, 1, 509. (c) Shen, H. C.;
Wang, J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C. D.; Douglas, C. J.;
Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.;
Wei, L.-L.; Sklenicka, H. M.; Zehnder, L. R.; Zificsak, C. A. J. Org. Chem.
2003, 68,1729.
(4) For applications in natural product synthesis, see: (a) Cole, K. P.;
Hsung, R. P. Org. Lett. 2003, 5, 4843. (b) Kurdyumov, A. V.; Hsung, R.
P.; Ihlen, K.; Wang, J. Org. Lett. 2003, 5, 3935. (c) Hsung, R. P.; Cole, K.
P.; Zehnder, L. R.; Wang, J.; Wei, L. L.; Yang, X.-F.; Coverdale, H. A.
Tetrahedron 2003, 59, 311. (d) Cole, K. P.; Hsung, R. P.; Yang, X.-F.
Tetrahedron Lett. 2002, 43, 8791.
(5) (a) For a review, see: Hsung R. P.; Wei, L.-L.; Sklenicka, H. M.;
Shen, H. C.; McLaughlin, M. J.; Zehnder, L. R. Trends Heterocycl. Chem.
2001, 7, 1-24. (b) For a recent review on stepwise [3 + 3] formal
cycloadditions leading to bridged carbocycles, pyridines, or pyridones using
enamines, enaminones, enol ethers, or â-ketoesters, see: Filippini, M.-H.;
Rodriguez, J. Chem. ReV. 1999, 99, 27.
(6) For recent related studies in syntheses of oxygen heterocycles, see:
(a) Malerich, J. P.; Trauner, D. J. Am. Chem. Soc. 2003, 125, 9554. (b)
Shen, K.-H.; Lush, S. F.; Chen, T.-L.; Liu, R.-S. J. Org. Chem. 2001, 66,
8106. (c) Cravotto, G.; Nano, G. M.; Tagliapietra, S. Synthesis 2001, 49.
(7) For a recent report on fusidilactone B, see: Gao, X.; Snider, B. B.
J. Org. Chem. 2004, 69, ASAP.
(8) For isolation and biological activities, see: (a) Kao, C. Y., Levinson,
S. R., Eds. Tetrodotoxin, Saxitoxin, and the Molecular Biology of the Sodium
Channel; New York Academy of Sciences: New York, 1986; Vol. 479.
(b) Goto, T.; Kishi, Y.; Takahashi, S.; Hirata, Y. Tetrahedron 1965, 21,
2059. (c) Mosher, H. S.; Fuhrman, F. A.; Buchwald, H. D.; Fischer, H. G.
Science 1964, 144, 1100. (d) Tsuda, K.; Ikuma, S.; Kawamura, M.;
Tachikawa, R.; Sakai, K.; Tamura, C.; Amakasu, O. Chem. Pharm. Bull.
1964, 12, 1357. (e) Woodward, R. B. Pure Appl. Chem. 1964, 9, 49. (f)
Narahashi, T. J. Toxicol., Toxin ReV. 2001, 20, 67-84.
To attach both the diene and dienophile onto a ketal tether,
we first deprotonated dihydrofuran using t-BuLi at -78 °C,
(9) For total syntheses and synthetic efforts, see: (a) Hinman, A.; Du
Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. (b) Ohyabu, N.; Nishikawa,
T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798. (c) Nishikawa, T.; Urabe,
D.; Yoshida, K.; Iwabuchi, T.; Asai, M.; Isobe, M. Pure Appl. Chem. 2003,
75, 251. (d) Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto,
T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972,
94, 9217. (e) Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto,
T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972,
94, 9219. (f) Ohtani, Y.; Shinada, T.; Ohfune, Y. Synlett 2003, 619. (g)
Itoh, T.; Watanabe, M.; Fukuyama, T. Synlett 2002, 1323.
(10) For a rare example, see: Ayer, W. A.; Browne, L. M.; Singer, A.
W.; Elgersma, P. Can. J. Chem. 1990, 68, 1300.
(11) For a rare example, see: Woodward, R. B.; Fukunaga, T.; Kelly,
R. C. J. Am. Chem. Soc. 1964, 86, 3162.
1
(12) All new compounds are characterized using H NMR, 13C NMR,
FTIR, and LRMS.
1940
Org. Lett., Vol. 6, No. 12, 2004

and addition of either aldehyde 13 or enal 14 led to
dihydrofurans 15 and 10 in 78 and 90% overall yields,
respectively, after protection with TBSCl group [Scheme 3].
The rationale for initially using a large TBS protecting group
was the concern over the stability of 10 under acidic
conditions. As it turned out, attempts to prepare ketal 16
from dihydrofuran 10 and diene 913 using PPTS or p-TsOH
were unsuccessful, for 10 decomposed under these acidic
conditions presumably due to ionization of the TBS-protected
secondary hydroxyl group and formation of a divinyl cation-
type intermediate. Thus, dihydrofuran 15 was pursued as an
alternative to construct the Diels-Alder cycloaddition pre-
cursor.
Scheme 5
Ketal 17 was successfully prepared in 79% yield as a
separable isomeric mixture with a ratio of 3-5:1 from
dihydrofuran 15 and diene 9 using PPTS [Scheme 4]. The
Scheme 4
and 20b as a 12:1 mixture. Initial NOE experiments of
desilylated 20a and 20b13 suggested that the ring junction
[C4a-C8a] of the 2-oxadecalin was cis for both cyclo-
adducts, thereby implying endo-cycloaddition pathways. An
unambiguous assignment of 20a was accomplished using the
X-ray structure of a derivative of cycloadduct 22a20 [Scheme
5], derived from the simplified ketal precursor 21 [R )
Me].20 These combined assignments rule out the exo-I
product 20c.
On the other hand, in toluene at room temperature, the
reaction was very slow [entry 2], although in toluene at 110
°C [entry 3] and in undecane at 200 °C [entry 4], reactions
(15) For reviews on IMDA, see: (a) Bear, B. R.; Sparks, S. M.; Shea,
K. J. Angew. Chem., Int. Ed. 2001, 40, 820. (b) Craig, D. In StereoselectiVe
Synthesis; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Ed.; Thieme: Stuttgardt, 1996; Vol. E21c, p 2872. (c) Roush, W. R. In
AdVances in Cycloaddition, Curran, D. P., Ed., JAI: Greenwich, CT, 1990;
Vol. 2, p91. (d) Craig, D. Chem. Soc. ReV. 1987, 16, 187. (e) Ciganek, E.
Org. React. 1984, 32, 1. (f) Fallis, A. G. Can. J. Chem. 1984, 62, 183. (g)
Taber, D. F. Intramolecular Diels-Alder Reactions and Alder-Ene Reac-
tions; Springer: Berlin, 1984.
(16) For pioneering work on acetal-tethered IMDAs, see: (a) Boeckman,
R, K., Jr.; Flann, C. J. Tetrahedron Lett. 1983, 24, 1655. (b) Boeckman, R,
K., Jr.; Estep, K. G.; Nelson, S. G.; Walters, M. A. Tetrahedron Lett. 1991,
32, 4095.
(17) For recent examples of ketal- or aminal-tethered IMDAs, see: (a)
Moses, J. E.; Commeiras, L.; Baldwin, J. E.; Adlington, R. M. Org. Lett.
2003, 5, 2987. (b) Roush, W. R.; Barba, D. A. Tetrahedron Lett. 1997, 38,
8781. (c) Wong, T.; Wilson, P. D.; Woo, S.; Fallis, A. G. Tetrahedron
Lett. 1997, 38, 7045. (d) Ainsworth, P. J.; Craig, D.; White, A. J. P.;
Williams, D. J. Tetrahedron 1996, 52, 8937. (e) Jung, M. E.; Street, L. J.
Heterocycles 1988, 27, 45. (f) Jung, M. E.; Street, L. J. J. Am. Chem. Soc.
1984, 106, 8327.
(18) For reviews on ortho-quinone ketal-tethered Diels-Alder reactions,
see: (a) Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856. (b)
Quideau, S.; Pouyse´gu, L. Org. Prep. Proc. Int. 1999, 31, 617.
(19) For the use of silyl ketal-tethered IMDAs, see: (a) Stork, G.; Chan,
T. Y.; Breault, G. J. Am. Chem. Soc. 1992, 114, 7578. (b) Gillard, J. A.;
Fortin, R.; Grimm, E. L.; Maillard, M.; Tjepkema, M.; Bernstein, M. A.;
Glaser, R. Tetrahedron Lett. 1991, 32, 1145. (c) Shea, K. J.; Zandi, K. S.;
Staab, A. J.; Carr, R. Tetrahedron Lett. 1990, 31, 5885. For leading
references on silyl ketal-tethered IMDAs from Craig’s group, see: (d)
Ainsworth, P. J.; Craig, D.; Reader, J. C.; Slawin, A. M. Z.; White, A. J.
P.; Williams, D. J. Tetrahedron 1995, 51, 11601. (e) Craig, D.; Reader, J.
C. Tetrahedron Lett. 1992, 33, 4073 and 6165.
mixture was subjected to double desilylation14 using 3.0
equiv of TBAF, followed by monoprotection of the primary
alcohol, and subsequent TPAP-NMO oxidation of the
secondary alcohol afforded ketone 18 in 66% yield over three
steps. The final enal formation, furnishing the Diels-Alder
cycloaddition precursor 19, was accomplished in 80% overall
yield using Eschenmoser’s salt, but the â-elimination of the
dimethyl amino group required the use of MeI and Na2CO3
in MeOH.
Because it was surprising to find that IMDA employing a
ketal tether is rare,15-19 we examined the reaction of ketal
19 in some detail as shown in Scheme 5. The cycloaddition
was found to be not only feasible but also exceptionally fast,
especially in MeOH [entry 1], leading to cycloadducts 20a
(13) Details for the preparation of diene 9 can be found in Supporting
Information. All NOE experiments and analyses of key coupling constants
can also be found in Supporting Information.
(14) After solidifying this as an appropriate route to the cycloaddition
ketal precursor, an acetyl protecting group for the secondary hydroxyl group
was proven to be useful on related substrates, thereby avoiding this sequence
of double-deprotection and reprotection of the primary hydroxyl group.
Org. Lett., Vol. 6, No. 12, 2004
1941

proceeded well and led to the improved formation of endo-
II product with the ratio of 20a:20b being 1:1 and 1.4:1,
respectively. In comparison with the cycloaddition in MeOH,
along with the observation that a substantial amount [10-
15%] of 20a already formed during the preparation of 19 in
MeOH at room temperature [for the â-elimination of the
dimethyl amino group], there is a pronounced solvent effect
on the reactivity and stereoselectivity of this ketal-tethered
IMDA with the protic solvent providing a much enhanced
reaction rate21 as well as stereoselectivity.
Finally, the use of various Lewis acids in CH2Cl2 favored
exclusively the formation of endo-I product 20a [entries
5-9]. It is noteworthy that with the exception of BF3‚Et2O
[entry 10], the ketal motif is very robust under these Lewis
acidic conditions.
These three transition states were chosen also on the basis
of the assumption that the furan oxygen would prefer a
pseudoaxial position given an anomeric effect of ∼1.5 kcal
mol-1.22 This assessment also supports the observation that
the formation of 20a was completely favored using Lewis
acids [or a proton from MeOH] that could chelate to the
carbonyl oxygen and the furan oxygen, which is the stronger
coordinating of the two ketal oxygen atoms.
Unsuccessful preparation of the exo-cycloadduct 20c does
not deter our effort toward a total synthesis of fusidilactone
C [3] because both endo-cycloadducts 20a and 20b are viable
entries to the trans-2-oxadecalin spiroketal of fusidilactone
C [3] via appropriate stereochemical adjustments. To dem-
Scheme 7
After the stereochemical assignment of 20a and 20b was
established, a mechanistic assessment revealed that both endo
transitions states [23a, endo-I, boat-boat; 23b, endo-II, chair-
boat] likely have an advantage over the exo-pathway [23c,
exo-I, chair-boat] due to the steric interaction between the
diene and the R group in the dienophile [Scheme 6].
Scheme 6
onstrate that we could access the trans-2-oxadecalin spiroket-
al motif in 3, ketone 24 was prepared from dihydrofuran
and diene 9 in 38% overall yield in five steps.20 During the
subsequent enone formation via addition of Eschenmoser’s
salt to the anion generated from 24 and â-elimination in
MeOH at room temperature, Diels-Alder cycloaddition
already occurred to give the endo-I product 25 as a single
diastereomer in an unoptimized 27% overall yield from 24.
An equal amount of the product resulting from the addition
of MeOH to the enone intermediate was also found.
Epimerization of C4a in 25 using K2CO3 and MeOH afforded
26 in 90% yield as a mixture with a ratio of 5:1 in favor of
26 that contains the trans-2-oxadecalin spiroketal. The
relative stereochemistry in both 25 and 26 was assigned using
NOE experiments as well as coupling constants.13
We have communicated here an approach toward the
2-oxadecalin spiroketal frame of fusidilactone C via an
intramolecular Diels-Alder cycloaddition, featuring a chiral
ketal tether, with a remarkable solvent effect on the rate and
stereoselectivity of this cycloaddition. Efforts in completing
a total synthesis of fusidilactone C, and in developing ketal-
tethered IMDA reactions, are currently underway.
Calculations [Spartan: G-31G*/B3LYP] showed that 23a is
favored by ∼1.57 kcal mol-1 over 23c, while 23a is favored
over 23b by a much smaller difference of ∼0.11 kcal mol-1.
(20) Preparations of 21 and 24 are described in Supporting Information.
The X-ray structure was obtained after desilylation of cycloadduct 22a and
acylation of i with 4-bromobenzoyl chloride that gave crystalline para-
bromobenzoic ester ii. Details are in Supporting Information.
Acknowledgment. R.P.H. thanks The Camille Dreyfus
Foundations for financial support, and J.W. thanks UMN for
a prestigious Lester C. and Joan Krogh Graduate Dissertation
Fellowship. We thank Mr. Aleksey I. Gerasyuto for providing
calculations.
Supporting Information Available: Experimental as
1
well as H NMR spectral and characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0495624
(21) For a recent example on hydrogen bonding-promoted hetero-Diels-
Alder cycloadditions, see: (a) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc.
2002, 124, 9662. For some earlier examples on the effect of aqueous or
protic solvents on Diels-Alder cycloadditions, see: (b) Grieco, P. A.;
Garner, P.; He, Z.-M. Tetrahedron Lett. 1983, 24, 1897. (c) Breslow, R.;
Maitra, U.; Rideout, D. Tetrahedron Lett. 1983, 24, 1901.
(22) For a review on the chemistry of spiroketals, see: Perron, F.;
Albizati, K. F. Chem. ReV. 1989, 89, 1617.
1942
Org. Lett., Vol. 6, No. 12, 2004