Total synthesis of (+)-chloriolide

Article abstract of DOI:10.1039/b925644j

The first total synthesis of (+)-chloriolide, a 12-membered macrolide from Chloridium virescens (var. chlamydosporum), was accomplished in a longest linear sequence of 20 steps from commercial materials in 7% overall yield. The Royal Society of Chemistry.

Full text of DOI:10.1039/b925644j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Total synthesis of (+)-chloriolide†
Timm T. Haug and Stefan F. Kirsch*
Received 8th December 2009, Accepted 21st December 2009
First published as an Advance Article on the web 8th January 2010
DOI: 10.1039/b925644j
The first total synthesis of (+)-chloriolide, a 12-membered
macrolide from Chloridium virescens (var. chlamydosporum),
was accomplished in a longest linear sequence of 20 steps
from commercial materials in 7% overall yield.
proved to be quite challenging. Our preceding strategies for closing
the ring by formation of the C2–C3 bond via intramolecular
Horner-Wadsworth-Emmons olefination or the C5-C6 bond via
ring-closing metathesis (RCM) either showed markedly reduced
feasibility or totally failed.10 The preparation of each of the
two fragments required the asymmetric construction of an allylic
alcohol moiety. Application of the asymmetric esterification de-
veloped by Overman11,12 was expected to provide both stereogenic
centres (C4 and C7) with predictable stereochemical outcome
using catalyst control.
The synthesis of allylic alcohol 2 began with the reaction of
readily available trichloroacetimidate 411 and benzoic acid in the
presence of palladacycle (+)-COP-OAc (1 mol%).13 The Overman
esterification provided (S)-allyli◦c ester 5 in 95% yield and 96%
ee after 16 h in CH2Cl2 at 23 C (Scheme 2).11 Unfortunately,
(S)-1-hydroxybut-3-en-2-yl benzoate, which was obtained from 5
by simple removal of the p-methoxybenzyl (PMB) group, failed
to undergo direct oxidation to the corresponding aldehyde, using
all standard oxidants we surveyed. As a result, removal of the
benzoate group, subsequent silylation to form the triisopropylsilyl
(TIPS) ether, and oxidative cleavage of the p-methoxybenzyl ether
provided primary alcohol 6 in 85% overall yield. Then, clean
oxidation of this intermediate could be realized by exposing 6
to o-iodoxybenzoic acid (IBX) in EtOAc at 80 ◦C.14 The resulting
aldehyde was directly converted into ester 7 through Wittig re-
action with methyl (triphenylphosphoranylidene)acetate (E/Z >
95/5). Finally, HF-mediated removal of the TIPS protective group
gave rise to fragment 2.
Chloriolide (1), a 12-membered macrolide, was isolated together
with the known bioactive macrolides radicicol1 and pochonin B2
from solid-substrate fermentation cultures of Chloridium virescens
(var. chlamydosporum) in 2006 by Gloer and co-workers.3 The
endophytic fungus, encountered as a colonist of a decaying
hardwood branch, was considered to be fungicolous and therefore
was examined for its ability to produce bioactive metabolites.4,5
Unlike the closest known structural analogs, patulolides A–C6
and cladospolides A–D,7 that have been reported to exhibit
significant antifungal and antibacterial activity, chloriolide was
fully inactive in antifungal and antibacterial assays.3 Following
the widely accepted opinion that secondary metabolites of fungi
are intentionally produced to provide the producer an advantage,8
chloriolide was considered an attractive target for synthesis,
not only because of its novel structure, but because a chemical
synthesis would allow to reveal and further evaluate the biological
activity. The gross structure and relative configuration of the
natural product were secured by X-ray crystallographic analysis;
its absolute configuration was defined by applying the modified
Mosher method on a rearrangement product.3 A somewhat unique
structural feature of chloriolide (1) is the (2E,5Z)-4,7-dihydroxy-
2,5-dienoate subunit (C1–C7) that presents a particular challenge
for total synthesis due to the high lability already mentioned by
Gloer and co-workers.3,9 In this communication, we report the first
total synthesis of (+)-chloriolide (1).
We envisioned constructing 1 via the assembly of two simple
allylic alcohol fragments (2 and 3) and using a macrolactonization
to close the 12-membered ring (Scheme 1). The ring-closure
Scheme 1 Retrosynthetic disconnection of chloriolide (1).
Department Chemie, Technische Universita¨t Mu¨nchen, Lichtenbergstr. 4,
85747 Garching, Germany. E-mail: stefan.kirsch@ch.tum.de; Fax: (+49)
89-2891-3315
† Electronic supplementary information (ESI) available: Experimental
procedures and copies of 1H and 13C NMR of novel compounds.
Copies of HPLC traces used to determine enantiopurity of 5. See DOI:
10.1039/b925644j
Scheme 2 Synthesis of fragment 2. Reagents and conditions: (a) PhCOOH,
(+)-COP-OAc (1 mol%), 23 ◦C, CH2Cl2, 95%, 96% ee; (b) K2CO3, 23 ◦C,
MeOH, 89%; (c) TIPSCl, Im, 23 ◦C, DMF, 96%; (d) DDQ, 23 ◦C, pH 7
◦
◦
=
buffer–CH2Cl2, 99%; (e) IBX, 80 C, EtOAc; (f) Ph3P CHCOOMe, 23 C,
CH2Cl2, 78% (over two steps); (g) HF, 23 ◦C, MeCN–H2O, 88%.
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The required fragment 3 was readily obtained starting from
commercially available (S)-propylene oxide as summarized in
Scheme 3. Exposing the oxirane to lithiated benzyl propargyl
ether in the presence of BF3·OEt2 led to the expected epoxide
opening,15 and the resulting alcohol was reacted with TIPSCl and
imidazole in DMF to yield TIPS ether 8. At this stage, the TIPS
protective group was chosen because it proved compatible with
later transformations, in particular with the catalyst-controlled
creation of the C7 stereogenic centre. Complete hydrogenation of
alkyne 8 over Pd/C and Swern oxidation16 of the resulting alcohol
then provided aldehyde 9 in 94% overall yield. Olefination with
methyl (diphenylphosphono)acetate under Ando conditions17
gave the corresponding Z-olefin in 75% yield after separation
of the minor E-isomer by silica gel chromatography. The ester
was reduced with DIBAL-H, and then the Z-configured allylic
alcohol was converted into trichloroacetimidate 10. The imidate
was subsequently reacted with 4-(p-methoxybenzyloxy)butyric
acid18 in the presence of (+)-COP-OAc (5 mol%) to create the
stereogenic centre at C7. Under catalyst control, protected ester
11 was produced in excellent diastereoselectivity (>99 : 1). Our
decision to introduce the 4-(p-methoxybenzyloxy)butyryl ester
was driven by the desire to form the acetate-containing fragment
3 with a minimum of protective group manipulations. This ester,
which to the best of our knowledge has not been used before as
protective group in synthesis,19 was expected to undergo selective
removal by oxidation and lactonization in the presence of other
esters and alkene moieties. As anticipated, cleavage of the TIPS
group of 11 and subsequent treatment with Ac2O in pyridine gave
a diester intermediate that was selectively transformed into acetate
3 upon sequential exposure to DDQ and KOtBu in an overall yield
of 57%.
To complete the synthesis of (+)-chloriolide (1), we now needed
to construct the C5–C6 double bond with Z-configuration. To
this end, a silyl-tethered RCM20 was ideally suited to connect
the two fragments 2 and 3.21 By use of a high-yielding one-pot
protocol,22 allylic alcohol 2 was covalently tethered to 3 through
a diisopropylsilyl linker to generate disiloxane 12 in 77% yield
(Scheme 4). The subsequent RCM proceeded smoothly in 86%
yield. Desilylation produced the corresponding Z-diol, which
was then converted into bis-silyl ether 13. Further experiments
indicated that the simultaneous protection of the free hydroxy
groups as tert-butyldimethylsilyl (TBS) ethers was essential for the
effective completion of the synthesis. Interestingly, the desilylated
product of the RCM performed significantly worse in the later
macrolactonization step. In line with the above-mentioned lability
of the 4,7-dihydroxy-2,5-dienoate subunit, exposure of ester 13 to
a range of standard saponification conditions either resulted in
no reaction or gave rise to a series of uncharacterizable products.
In this respect, we were delighted to find that key intermediate
14 was readily accessed through reduction with DIBAL-H at
-78 ◦C in CH2Cl2 to give the diol followed by chemoselective
oxidation. The delicate oxidative transformation could be realized
in two steps by first exposing the diol to MnO2 in CH2Cl2,23 which
24
upon further oxidation with buffered NaClO2 gave acid 14 in
87% yield. Macrolactonization using the protocol of Yamaguchi25
afforded the 12-membered macrocycle in 65% yield. Finally, the
silyl groups were removed quantitatively by treatment with HF,
thus completing the total synthesis of (+)-chloriolide (1). The
spectroscopic data of synthetic chloriolide agreed perfectly with
those reported for the natural product3 as did the optical rotation:
[a]2D0 +101 (c 0.21, CH2Cl2) [lit.3 [a]2D5 +107 (c 0.2, CH2Cl2)].
In summary, an expedient asymmetric synthesis of chloriolide
(1) was accomplished in a longest linear sequence of 20 steps from
commercial materials in 7% overall yield (88% average yield per
step). The sequence features the catalytic asymmetric construction
of allylic esters through Overman esterification, the first use of
an oxidatively cleavable ester as hydroxyl protecting group, and
a silyl-tethered RCM to form a Z-alkene. Investigations into
Scheme 3 Synthesis of fragment 3. Reagents and conditions: (a) i)
◦
≡
BnOCH2C CH, nBuLi; ii) BF3·OEt2; iii) (S)-(-)-propylene oxide, -78 C,
THF, 93%; (b) TIPS-Cl, Im, 23 ◦C, DMF, 98%; (c) H2, Pd/C (5 mol%),
23 ◦C, EtOH, quant.; (d) i) (COCl)2, DMSO, -78 ◦C; ii) NEt3, -78 ◦C to rt,
CH2Cl2, 94%; (e) i) methyl (diphenylphosphono)acetate, NaH, 0 ◦C, THF;
ii) 9, -78 ◦C to -20 ◦C, THF, 75%; (f) DIBAL-H, -78 ◦C, THF, 97%; (g)
CCl3CN, DBU (10 mol%), 23 ◦C, CH2Cl2, 97%; (h) PMBO(CH2)3COOH,
(+)-COP-OAc (5 mol%), 23 ◦C, CH2Cl2, 83%, d.r. >99 : 1; (i) HF, 23 ◦C,
MeCN–H2O, 79%; (j) Ac2O, 23 ◦C, pyridine, 83%; (k) i) DDQ, 23 ◦C, pH 7
buffer–CH2Cl2; ii) KOtBu (15 mol%), 23 ◦C, THF, 87%.
Scheme 4 Synthesis of chloriolide (1). Reagents and conditions: (a) 2, (iPr)2SiCl2, 23 ◦C, pyridine, then 3, 77%; (b) Grubbs-II (5 mol%), 80 ◦C, toluene,
86%; (c) HF, 23 ◦C, MeCN–H2O, 85%; (d) TBSCl, Im, 23 ◦C, DMF, 80%; (e) DIBAL-H, -78 ◦C, CH2Cl2, quant.; (f) MnO2, 23 ◦C, CH2Cl2; (g) NaClO2,
2-methyl-2-butene, NaH2PO4, tBuOH–H2O, 87% (over two steps); (h) i) 2,4,6-trichlorobenzoyl chloride, NEt3, 23 ◦C, THF; ii) DMAP, 23 ◦C, benzene,
65%; (i) HF, 23 ◦C, MeCN–H2O, quant.
992 | Org. Biomol. Chem., 2010, 8, 991–993
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the biological activity of chloriolide are currently underway; the
modular nature of the route should enable rapid access to a variety
of new analogs for structure–activity relationships.
10 Both alternative approaches were unsuccessful, most likely because of
the lability of the (2E,5Z)-4,7-dihydroxy-2,5-dienoate subunit (C1–C7)
under the cyclization conditions.
11 S. F. Kirsch and L. E. Overman, J. Am. Chem. Soc., 2005, 127, 2866–
2867.
12 For application in synthesis, see: (a) J. T. Binder and S. F. Kirsch, Chem.
Commun., 2007, 4164–4166; (b) H. Menz and S. F. Kirsch, Org. Lett.,
2009, 11, 5634–5637.
Acknowledgements
We thank the Fonds der Chemischen Industrie (FCI) and the
Dr.-Ing. Leonhard-Lorenz Stiftung for support and Professor
Thorsten Bach for helpful discussions.
13 (a) C. E. Anderson, S. F. Kirsch, L. E. Overman, C. J. Richards and
M. P. Watson, Org. Synth., 2007, 84, 148–155; (b) A. M. Stevens and
C. J. Richards, Organometallics, 1999, 18, 1346–1348; (c) S. F. Kirsch
and L. E. Overman, J. Org. Chem., 2005, 70, 2859–2861.
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