Total synthesis of sordaricin

Article abstract of DOI:10.1021/ol0342599

(Matrix presented) The total synthesis of sordaricin, the diterpene aglycone of an important class of antifungal compounds, is described. Two approaches were explored, the first of which utilized a possible biogenetic intramolecular [4 + 2] cycloaddition to form the complete carbon skeleton of the target molecule. A second approach using a tandem cycloreversion/intramolecular [4 + 2] cycloaddition sequence is also detailed.

Full text of DOI:10.1021/ol0342599

ORGANIC
LETTERS
2
003
Vol. 5, No. 8
321-1324
Total Synthesis of Sordaricin
1
Lewis N. Mander* and Regan J. Thomson
Research School of Chemistry, Australian National UniVersity, Canberra,
ACT 0200, Australia
mander@rsc.anu.edu.au
Received February 13, 2003
ABSTRACT
The total synthesis of sordaricin, the diterpene aglycone of an important class of antifungal compounds, is described. Two approaches were
explored, the first of which utilized a possible biogenetic intramolecular [4 + 2] cycloaddition to form the complete carbon skeleton of the
target molecule. A second approach using a tandem cycloreversion/intramolecular [4 + 2] cycloaddition sequence is also detailed.
The sordarins are an emerging class of potent antifungal
compounds, of which sordarin (4), isolated in 1971 from
We were intrigued by the sordarins, not only because of
their interesting biological activity but also because of their
unusual structures and possible biosynthesis. The diterpene
1
4
the ascomycete Sordaria araneosa Cain, is the structural
prototype. The sordarins exhibit remarkable in vitro activity
against a wide range of fungal pathogens such as Candida
aglycone sordaricin (3) has been shown to be biosynthetically
5
derived from cycloaraneosene (1), and it is tempting to
2
albicans, causative agent of the common thrush infection.
speculate that a biogenetic route from 1 to 3 might proceed
by means of an intramolecular [4 + 2] cycloaddition, such
as that shown by the conversion of 2 to 3. Two key model
Additionally, sordarins show encouraging in vivo activity
against several pathogenic fungi, including Pneumocystis
2
6
carnii, the major cause of lethal pneumonia among immu-
studies showed the validity of such a postulate, by demon-
nocompromised patients. Unlike the other major antifungals,
which are targeted against fungal ergosterol biosynthesis, the
sordarins are selective inhibitors of fungal protein synthesis
strating that such an intramolecular [4 + 2] cycloaddition
was possible. These reports were followed by a successful
total synthesis of the methyl ester (10) subsequently by Kato
and co-workers in which the final step was the cycloaddition
through a specific interaction with Elongation Factor 2
3
7
(
EF2), a remarkable feat considering the high degree of EF2
9 f 10, although 9 was not actually isolated. Our interest
homology (85%) between fungi and higher order Eukaryotes.
The combination of potent biological activity and a novel
mode of action has made the sordarins lead compounds for
the development of new antifungal agents.
in sordaricin (3) was 2-fold: to develop a short, flexible
synthesis and to conduct a thorough study of the postulated
biosynthetic intramolecular [4 + 2] cycloaddition.
Our synthetic strategy (Scheme 1) involved the alkylation
between iodide 6 and nitrile 5 to afford 7. Elaboration of 7,
via 8, would then give aldehyde 9, which would undergo
(
1) Hauser, D.; Sigg, H. P. HelV. Chim. Acta 1971, 54, 1178.
(2) For a review of sordarin biological activity, see: Gargallo-Viola, D.
Curr. Opin. Anti-Infect. InVest. Drugs 1999, 1, 297.
3) Justice, M. C.; Hsu, M. J.; Tse, B.; Ku, T.; Balkovec, J.; Schmatz,
D.; Neilsen, J. J. Biol. Chem. 1998, 273, 3148.
4) Vasella, A. T. Ph.D. Dissertation, Eidgenossischen Technischen
Hochschule, Zurich, 1972.
5) Borschberg, H. J. Ph.D. Dissertation, Eidgenossischen Technischen
Hochschule, Zurich, 1975.
6) (a) Mander, L. N.; Robinson, R. P. J. Org. Chem. 1991, 56, 3595.
b) Kato, N.; Wu, X.; Takeshita, H. Chem. Express 1991, 6, 687.
7) Kato, N.; Kusakabe, S.; Wu, X.; Kamitamari, M.; Takeshita, H. J.
Chem. Soc., Chem. Commun. 1993, 1002.
(
(
(
(
(
(
1
0.1021/ol0342599 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/28/2003

Scheme 1
Scheme 2
the aforementioned intramolecular [4 + 2] cycloaddition to
give us the target natural product (3) after demethylation.
We also considered that ketone 8 might be converted into
aldehyde 11, which we hoped would undergo a tandem
cycloreversion/intramolecular [4 + 2] cycloaddition to form
the sordaricin carbon skeleton in a single operation. Produc-
tion of the iodide 6 and nitrile 5 fragments was planned to
which was converted to allylic alcohol 18 (49% from 16)
upon exposure to lithium cyclohexylisopropyl amide (LICA).
Allylic alcohol 18 had been prepared previously from
carvone as part of an earlier study. Protection of the
hydroxy group as a MOM ether, followed by TBS ether
removal with TBAF, gave the parent alcohol, which was
readily converted into the target iodide 6 (84% over 3 steps)-
1
1
8
come from (+)- and (-)-12, respectively.
Synthesis of the iodide 6 (Scheme 2) commenced with
9
2
the 1,4-addition of the cuprate derived from MOMOCH Li
3
using iodine/Ph P/imidazole.
Construction of the requisite nitrile fragment 5 (Scheme
to enone (+)-12, to give a silyl enol ether, which was then
treated with MeLi followed by methyl iodide, to afford the
syn-substituted tricycle 13 (60% over 2 steps, 95:5 dr).
Heating 13 in 1,2-dichlorobenzene at reflux effected smooth
cycloreversion to cyclopentenone 14 (85%), which upon
exposure to CuI/isopropenylmagnesium bromide gave the
trisubstituted cyclopentanone 15 (70%). Carbonyl deletion
3
) was readily achieved by the 1,4-addition of KCN to enone
12
(-)-12, followed by ketalisation using ethylene glycol and
Dowex 50-W resin (72% over 2 steps). Having achieved a
synthesis of both required fragments, examination of the
required alkylation was addressed. After extensive experi-
mentation the desired product 7 could be obtained as a single
diastereomer in yields between 55% and 67%, based on
iodide consumption. Nitrile 7 was then reduced to the
corresponding aldehyde by treatment with DIBAL-H fol-
lowed by mild acidic hydrolysis using 1.0 M aqueous oxalic
acid. Next, reduction of the aldehyde to the corresponding
was next carried out over three steps, using the Barton-
McCombie10 protocol, to give the key cyclopentane 16 in
good overall yield (88%). Unfortunately, all attempts to
epoxidize the alkene bond present in 16 with a view to
preparing 6 led to a facile [1,2] hydride shift, to form
aldehyde 17, even under the neutral conditions of dimethyl
dioxirane (DMDO). However, conversion of the MOM ether
4
alcohol was achieved using NaBH , and protection of the
hydroxyl group as a MOM ether was subsequently carried
out using standard conditions (MOMCl, DIPEA, and
16 to the corresponding TBS ether, and subsequent treatment
with m-CPBA gave an excellent yield of the desired epoxide,
1
3
DMAP). Ketone 8 was then obtained using TsOH in
(
8) For preparation of (+)- and (-)-12, see: (a) Takano, S.; Inomata,
K.; Takahashi, M.; Ogasawara, K. Synlett 1991, 636. (b) Tanako, S.; Moriya,
M.; Tanaka, K.; Ogasawara, K. Synthesis 1994, 687.
(11) Robinson, R. Unpublished work.
(12) Bugel, J. P.; Ducos, P.; Gringore, O.; Rouessac, F. Bull. Soc. Chim.
Fr. 1972, 4371.
(13) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; John Wiley and Sons: New York, 1991; Chapter 2.
(
(
9) Linderman, R. J.; Godfrey, A.; Horne, K. Tetrahedron 1989, 45, 495.
10) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1
1975, 1574.
1322
Org. Lett., Vol. 5, No. 8, 2003

as THF led to complete formation of the undesired enol
carbonate. Next, synthesis of 20 was carried out by first
converting the â-keto ester into the corresponding enol
triflate, followed by the addition of the higher order cuprate
Scheme 3
1
5
derived from 2-Th(Cu)CNLi and isopropylmagnesium
chloride (56% over 3 steps). Removal of the MOM groups
1
6
(
MgBr
allylic alcohol function (MnO
(86% over 2 steps). Aldehyde 9, as expected, cyclized
2
‚Et
2
O, n-butanethiol) and selective oxidation of the
2
) afforded the target aldehyde
7
9
over 3 days at 40 °C to give a quantitative yield of 10, which
could be demethylated to give sordaricin (3), mp 189-191
1
°
-
C, [R]
D
-55 (c 0.2, MeOH) [lit. mp 190-191 °C, [R]
D
1
58 (c 0.2, MeOH)] (79% yield); spectroscopic data ( H
and C NMR, MS, IR) were identical to those of natural
material.
1
3
There is some speculation as to whether the [4 + 2]
cycloaddition detailed here is involved in the biosynthesis
of the sordarins. Cyclization of 9 proceeded slowly at
temperatures as low as 10 °C, indicating that it is not
necessary for the reaction to be enzyme-activated. However,
these experiments do not prove the absence of enzyme
1
7
involvement. Interestingly, cyclization of diol 21 gave 22
as the only regioisomer, but in order to achieve a significant
rate of reaction heating at 100 °C (3 days) was required,
indicating that oxidation at C17 most likely precedes
cyclization in the putative biosynthetic pathway.
The slower rate of cyclization relative to that of the
aldehyde 9 is consistent with frontier orbital considerations;18
taking the reaction between 2,4-pentadienoic acid with either
acrylic acid or propene as appropriate models for the
sordaricin intermediates, it is apparent that the more favorable
orbital interactions are between the HOMO of the diene and
1
9
the LUMO of either dienophile. Then the ∆E for the
HOMO of 2,4-pentadienoic acid and the LUMO of acrylic
acid is 10.01 eV, while the energy gap to the LUMO of
2
0
propene is 11.21 eV, thus indicating that the latter process
should proceed more slowly.
Investigation into the possible tandem cycloreversion/
intramolecular [4 + 2] cycloaddition approach to sordaricin
(3) began with the previously described ketone 8 (Scheme
4). Installation of the requisite carboxy and isopropyl groups
was achieved in a manner similar to that detailed for the
synthesis of 20 from 19 (see Scheme 3), to give 23 (69%
over 3 steps). Removal of the MOM groups (MgBr
2
‚Et
) afforded the
target aldehyde 8 (92% from 23). In the event, heating 8 in
2
O,
1
6
butanethiol) followed by oxidation (MnO
2
1
4
,2-dichlorobenzene at 180 °C for 1 h gave an inseparable
:1 mixture of the desired product 10 and a second compound
acetone. This entire sequence, from 7, could be carried out
without the need for chromatography until after the final step
to give a 90% overall yield of the ketone 8. Heating 8 at
tentatively identified as the regioisomer iso-10 (76% com-
180 °C overnight effected a smooth cycloreversion, affording
(15) Lipshultz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987,
cyclopentenone 19 (96%). C-Acylation at C5 of 19 was
carried out by enolization with LiHMDS/hexanes in ether,
followed by the addition of MeOCOCN1 to afford the
28, 945.
(
(
16) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett 1991, 183.
17) For a recent publication providing evidence of an enzyme-assisted
4a
cycloaddition, see: Johansson, M.; K o¨ pcke, B.; Anke, H.; Sterner, O. Angew.
Chem., Int. Ed. 2002, 41, 2158.
(18) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: Chicester, 1996.
corresponding â-keto ester as a 1:1 mixture of keto and enol
tautomers. The use of ether14b for this reaction was essential,
(
19) Houk, K. N. J. Am. Chem. Soc. 1973, 95, 4092.
(
14) (a) Mander, L. N.; Sethi, S. P.; Tetrahedron Lett. 1983, 24, 5425.
(20) Values taken from Smith, M. B. Organic Synthesis; McGraw-Hill:
Singapore, 1994; pp 1104-1109.
(
b) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1991, 70, 256.
Org. Lett., Vol. 5, No. 8, 2003
1323

In summary, an enantioconvergent total synthesis of
sordaricin (3) has been achieved in 26 steps (longest linear
sequence) from (+)-12 in 3% overall yield, using (-)- and
Scheme 4
(+)-12 as starting materials for key fragments 5 and 6,
respectively. This synthesis was predicated on the postulated
biogenetic intramolecular [4 + 2] cycloaddition as a key step
in constructing the carbon framework. A second approach
to 3 utilized a tandem cycloreversion/intramolecular [4 +
2] cycloaddition as a key step but was somewhat less efficient
in giving the target compound. Full details of these, and
other, experiments will be reported in due course.
Acknowledgment. We thank the ANU Graduate School
(Graduate School Scholarship to R.J.T), the Research School
of Chemistry (Alan Sargeson Merit Award to R.J.T), and
Dr. Jim Balkovec (Merck) for an authentic sample of
sordaricin.
Supporting Information Available: Experimental pro-
cedures and characterization for selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
bined yield). Further experimentation did not lead to any
improvement in the product ratio.
OL0342599
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Org. Lett., Vol. 5, No. 8, 2003