Total synthesis of Jerangolid A

Article abstract of DOI:10.1021/ol101103q

(Figure Presented) The first total synthesis of the antifungal polyketide jerangolid A has been accomplished. Starting with the readily available (R)-Roche ester and (S)-glycidol as chirons, the synthesis involved a highly syn-selective Lewis acid catalyz

Full text of DOI:10.1021/ol101103q

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3172-3175
Total Synthesis of Jerangolid A
Stephen Hanessian,* Thilo Focken, and Rupal Oza
Department of Chemistry, UniVersite´ de Montre´al, C. P. 6128, Succ. Centre-Ville,
Montre´al, QC H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received May 13, 2010
ABSTRACT
The first total synthesis of the antifungal polyketide jerangolid A has been accomplished. Starting with the readily available (R)-Roche ester
and (S)-glycidol as chirons, the synthesis involved a highly syn-selective Lewis acid catalyzed 6-endo-trig cyclization for the construction of
the dihydropyran subunit. The lactone segment was built through a tandem NaOMe conjugate addition-lactonization reaction, and further
functionalized through a sequence consisting of iodination, I-Mg exchange, and hydroxymethylation. Other key steps in the synthesis featured
a novel application of a phosphonamide-anion based olefination and a Julia-Kocienski reaction.
The antifungal polyketide jerangolid A (1a) belongs to a
family of at least five naturally occurring members (A, B,
D, E, and H), which were isolated in 1992 from myxobac-
terium Sorangium cellulosum So ce307 (Figure 1). Jerangolid
A shows potent antifungal activity against a range of
pathogens, including Hansenula anomala and Mucor hiema-
lis (MIC 0.07 µg/mL), Debaryomyces hansenii and Trisporo
terrestre (0.1 - 0.4 µg/mL), and Candida albicans (4.2 µg/
mL).1
The jerangolids share a common segment with the am-
bruticins, another group of naturally occurring, potent
antifungal polyketides, isolated from closely related myxo-
bacterium Polyangium cellulosum2b or Sorangium cellulosum
So ce10, respectively.2a,3 Due to their close resemblance in
terms of structural features and biochemical profiles, as well
as their common biosynthesis,4 the jerangolids may be
considered as truncated analogues of the ambruticins.
Figure 1. Selected members of the jerangolid and ambruticin
families, isolated from Sorangium cellulosum.
It is suggested that ambruticins induce the high osmolarity
glycerol (HOG) signaling pathway by targeting hik1, a
histidine kinase.5
(1) (a) Reichenbach, H.; Ho¨fle, G.; Gerth, K.; Washausen, P. PCT Int.
Appl. WO97/31912, 1997. (b) Gerth, K.; Washausen, P.; Ho¨fle, G.; Irschik,
H.; Reichenbach, H. J. Antibiot. 1996, 49, 71.
Despite the intriguing biological activity of jerangolid A
(1a), no total synthesis has been reported yet.6 The synthesis
(2) (a) Ho¨fle, G.; Steinmetz, H.; Gerth, K.; Reichenbach, H. Liebigs
Ann. Chem. 1991, 941. (b) Connor, D. T.; Greenough, R. C.; von
Strandtmann, M. J. Org. Chem. 1977, 42, 3664.
(5) (a) Dongo, A.; Bataille´-Simoneau, N.; Campion, C.; Guillemette,
T.; Hamon, B.; Iacomi-Vasilescu, B.; Katz, L.; Simoneau, P. Appl. EnViron.
Microbiol. 2009, 75, 127. (b) Vetcher, L.; Menzella, H. G.; Kudo, T.;
Motoyama, T.; Katz, L. Antimicrob. Agents Chemother. 2007, 51, 3734.
(c) Knauth, P.; Reichenbach, H. J. Antibiot. 2000, 53, 1182.
(3) Review on ambruticins: Michelet, V.; Geneˆt, J.-P. Curr. Org. Chem.
2005, 9, 405
.
(4) (a) Wenzel, S. C.; Mu¨ller, R. Nat. Prod. Rep. 2007, 24, 1211. (b)
Julien, B.; Tian, Z.-Q.; Reid, R.; Reeves, C. D. Chem. Biol. 2006, 13, 1277.
10.1021/ol101103q  2010 American Chemical Society
Published on Web 06/21/2010

of jerangolid D (1b), in which the hydroxymethyl group is
replaced by a methyl, was achieved by Posp´ısˇil and Marko´
in 2007.7 Herein, we report our efforts leading to the first
total synthesis of jerangolid A (1a), reportedly, the most
active member in the series.1,8
Scheme 2. Synthesis of the Dihydropyran Ring of Jerangolid A
Scheme 1. Synthesis of the Lactone Subunit of Jerangolid A
5 in the presence of pyridine in DMF furnished the iodo
lactone 6 in 97% yield. Treatment of the latter with i-PrMgCl
led to a smooth I-Mg exchange at -78 °C.12 Reaction of
the generated organomagnesiate with a solution of freshly
cracked formaldehyde13 furnished hydroxymethyl lactone 7
in 53% yield. Conversion into its TBS-ether and removal of
the PMB-protecting group proceeded uneventfully, delivering
alcohol 8 in 75% yield. Oxidation under Swern conditions
gave unstable aldehyde 9, which was prone to form hy-
drates.14,15 Workup at low temperature proved to be essential
for obtaining aldehyde 9 in sufficient purity for subsequent
conversion. Other methods for oxidation such as Dess-Martin
periodinane, PCC, TEMPO, and TPAP either yielded impure
aldehyde or resulted in overoxidation products.
Our synthetic plan toward the construction of the dihy-
dropyran ring was aimed at using a transition-metal-catalyzed
methodology for the formation of pyran units developed by
Uenishi and others.16 Allylic diols are known to undergo
stereoselective 6-exo- or 6-endo-trig cyclization upon treat-
ment with catalytic amounts of Pd(CH3CN)2Cl2 forming
tetrahydro- or dihydropyrans, respectively, with the selectiv-
ity being controlled by the relative configuration of the diol.
To this end, the allylic diols were synthesized via opening
of (R)-glycidol benzyl ether (10) with dithiane 11, followed
In our synthetic strategy, we envisaged a convergent, late-
stage assembly of two advanced ring segments through our
phosphonamide anion based olefination methodology9 and
a Julia-Kocienski reaction, respectively. It was thought that
the lactone ring would arise from addition of ethyl propiolate
to an ether derivative of (S)-glycidol, followed by conjugate
addition of methanol and lactonization. The construction of
the syn-dihydropyran ring would employ a highly diaste-
reoselective 6-endo-trig cyclization of an allylic 1,3-diol, also
starting from (S)-glycidol. In spite of this relatively straight-
forward assembly strategy, we were cognizant of the sensitive
nature of the unsaturated lactone toward a number of planned
transformations.
As shown in Scheme 1, our initial approach to build the
lactone subunit started from (R)-glycidol PMB ether (3) and
took advantage of an efficient, tandem conjugate addition-
lactonization sequence. Thus, opening of epoxide 3 with the
anion generated from ethyl propiolate in the presence of
BF3·OEt2 delivered quantitatively known alkyne 4.10 Treat-
ment of the latter with NaOMe in MeOH led to a conjugate
addition followed by attack of the free hydroxyl group on
the ester to furnish lactone 5 in 80% yield.11
(11) For selected, related examples, see: (a) Taniguchi, T.; Tanabe, G.;
Muraoka, O.; Ishibashi, H. Org. Lett. 2008, 10, 197. (b) Donner, C. D.
Tetrahedron Lett. 2007, 48, 8888. (c) Friesen, R. W.; Vanderwal, C. J.
Org. Chem. 1996, 61, 9103.
Introduction of the hydroxymethyl group was done
employing a two-step sequence. Thus, iodination of lactone
(12) Selected references: (a) Knochel, P.; Dohle, W.; Gommermann,
N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew.
Chem., Int. Ed. 2003, 42, 4302. (b) Thibonnet, J.; Vu, V. A.; Be´rillon, L.;
Knochel, P. Tetrahedron 2002, 58, 4787. (c) Vu, V. A.; Be´rillon, L.;
Knochel, P. Tetrahedron Lett. 2001, 42, 6847.
(6) For other syntheses of the right hand segment, cf. ref 3.
(7) (a) Posp´ısˇil, J.; Marko´, I. E. Tetrahedron Lett. 2008, 49, 1523. (b)
Posp´ısˇil, J.; Marko´, I. E. J. Am. Chem. Soc. 2007, 129, 3516
(8) To the best of our knowledge, no biological activity for jerangolids
B, D, E, and H has been reported; cf. ref 1.
.
(13) Schlosser, M.; Jenny, T.; Guggisberg, Y. Synlett 1990, 704.
(14) See also Casar, Z.; Kosmrlj, J. Synlett 2009, 1144.
(15) See the Supporting Information for details.
(9) (a) Hanessian, S.; Bennani, Y. L.; Leblanc, Y. Heterocycles 1993,
35, 1411. Asymmetric olefination with cyclic phosphonamides: (b) Han-
essian, S.; Beaudoin, S. Tetrahedron Lett. 1992, 33, 7655–7659. (d)
Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. J. Am. Chem. Soc.
1984, 106, 5754. (e) See also: Bennani, Y. L.; Hanessian, S. Chem. ReV.
1997, 97, 3161.
(16) Pd catalysis: (a) Kawai, N.; Hande, S. M.; Uenishi, J. Tetrahedron
2007, 63, 9049. (b) Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J.
Org. Chem. 2006, 71, 4530. (c) Uenishi, J.; Ohmi, M.; Ueda, A.
Tetrahedron: Asymmetry 2005, 16, 1299. (d) Uenishi, J.; Ohmi, M. Angew.
Chem., Int. Ed. 2005, 44, 2756. (e) Miyazawa, M.; Hirose, Y.; Narantsetseg,
M.; Yokoyama, H.; Yamaguchi, S.; Hirai, Y. Tetrahedron Lett. 2004, 45,
2883. Au catalysis: Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008,
10, 669.
(10) Ahmed, A.; Hoegenauer, E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig,
¨
H.; Ohler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026.
Org. Lett., Vol. 12, No. 14, 2010
3173

by unmasking of the enone system and stereoselective
reduction (Scheme 2). The required dithiane 11 was obtained
as a 9:1 mixture of E/Z isomers from treatment of 2-methyl-
2-pentenal with 1,3-propanedithiol and BF3·OEt2.15,17 Inter-
estingly, only the anion derived from the E-isomer by
deprotonation with n-BuLi reacted with epoxide 10 furnish-
ing adduct 12 in 97% yield. Protection of the hydroxyl group
in 12 proved to be necessary in order to unmask the R,ꢀ-
unsaturated system. Thus, exposure of adduct 12 to TBSOTf
in the presence of 2,6-lutidine provided the corresponding
TBS-ether in 93% yield. After some optimization, we found
that the dithiane moiety could be removed conveniently from
the latter compound by treatment with benzeneseleninic
anhydride18 giving the relatively sensitive enone 13 in 73%
yield.
Table 1. Formation of Dihydropyrans from Allylic 1,3-Diols via
a Pd-Catalyzed 6-Endo-Trig Cyclization
yield
entry diol
catalyst (equiv)
solvent (%) syn/anti
1
2
3
4
5
6
7
8
9
14c Pd(CH3CN)2Cl2 (1.0)
14d Pd(CH3CN)2Cl2 (1.0)
14a Pd(CH3CN)2Cl2 (1.0)
14b Pd(CH3CN)2Cl2 (1.0)
14b Pd(CH3CN)2Cl2 (1.0)
THF
THF
THF
THF
54
54
53
53
56
73
72
72
82
81
1:5
99:1
1.5:1
1.4:1
6:1
25:1
25:1
25:1
20:1
16:1
Reduction of enone 13 with either (R)-Me-CBS or (S)-
Me-CBS followed by treatment with TBAF furnished the
diastereomerically pure diols 14a and 14b, respectively.
Using a similar sequence of steps, the analogs 14c and 14d
were prepared from the corresponding enone, lacking the
vinylic methyl group (Table 1).15
CH2Cl2
14b Pd(CH3CN)2(BF4)2 (0.1) CH2Cl2
14a Pd(CH3CN)2(BF4)2 (0.1) CH2Cl2
14aa Pd(CH3CN)2(BF4)2 (0.05) CH2Cl2
14aa BF3·OEt2 (0.1)
CH2Cl2
CH2Cl2
10
14aa TfOH (0.1)
a Obtained from Luche reduction of 13, dr ) 3.6:1.
While cyclization of the latter compounds under Uenishi’s
conditions (Pd(CH3CN)2Cl2, THF) proceeded as expected
yielding the anti- or syn-pyran 18 selectively from 14c or
14d, respectively (Table 1, entries 1 and 2), we were
surprised to find that the introduction of a methyl substituent
was detrimental for selectivity. Thus, treatment of diols 14a
and 14b with Pd(CH3CN)2Cl2 in THF both led to a 1.4:1
syn/anti mixture of dihydropyran 15 (Table 1, entries 3 and
4). The selectivity could be enhanced to 6:1 by employing
CH2Cl2 as solvent (Table 1, entry 5). Inspired by Gouv-
erneur’s study on the formation of pyranones from enones,19
we decided to use the cationic complex Pd(CH3CN)4(BF4)2
as a catalyst in the reaction.
yield, albeit with slightly lower selectivity (Table 1, entries
9 and 10).21
The benzyl group of 15 was removed under Birch
conditions, giving rise to 16 in 88% yield. Swern oxidation,
and reaction of the resulting aldehyde with MeMgBr,
followed by a second Swern oxidation provided the desired
ketone 17 in 72% yield (three steps).22
The final steps of the synthesis of jerangolid A (1a) are
depicted in Scheme 3. The connection of the two ring
systems was considered using two subsequent olefination
reactions, commencing with methyl ketone 17. The latter
was subjected to an olefination reaction with cyclic phos-
phonamides 21a-c, which are obtained from alkylation of
1,3-dialkyl-2-oxo-1,3,2-diazaphospholidines 20a-c with io-
dide 19,23 derived from (R)-Roche ester. The deprotonation
of phosphonamides 21a-c at low temperature using n-BuLi
followed by addition of ketone 17 and quenching with AcOH
at -78 °C furnished separable mixtures of E/Z isomers of
TBS-ether 24a, with the desired compound as the major
product (Table 2).
Condensation of dimethyl phosphonamide 21a with 17
gave 24a with a 3:1 E/Z ratio, albeit in modest yield with
recovery of starting materials (Table 2, entry 1). The E/Z
ratio improved to 6:1 when the reaction mixture was allowed
to equilibrate at room temperature before addition of AcOH
(Table 2, entry 2). Increasing the steric demand of the
phosphonamide substituents also helped to enhance the E/Z
Remarkably, the diastereomeric diols 14a and 14b both
yielded the same syn-pyran in excellent selectivity (>25:1)
upon treatment with Pd(CH3CN)4(BF4)2 (Table 1, entries 6
and 7). Thus, the stereochemistry of the allylic alcohol was
of no importance in the cyclization reaction, strongly
suggesting a cationic mechanism. Consequently, for prepara-
tive purposes we later applied Luche conditions (NaBH4 and
CeCl3) for the reduction of enone 13. Subsequent treatment
with TBAF gave a 3.6:1 diastereomeric mixture of diols in
80% yield favoring 14a.15 Using this mixture, the same syn-
selectivity was obtained in the cyclization (Table 1, entry
8). Excited by the possibility that the Lewis acidity of the
cationic Pd complex might induce the cyclization, we
therefore tested the applicability of BF3·OEt2 and the Brøn-
sted acid TfOH in the reaction.20 Indeed, the desired syn-
dihydropyran 15 was obtained in both cases in excellent
(17) For the preparation of an analogous dithiane, see: Ziegler, F. E.;
Fang, J.-M.; Tam, C. C. J. Am. Chem. Soc. 1982, 104, 7174
.
(21) The syn- and anti-pyrans 15 are stable under the reaction conditions
and do not epimerize when treated with BF3·OEt2.
(22) For previous syntheses of 17, see: (a) Kirkland, T. A.; Colucci, J.;
Geraci, L. S.; Marx, M. A.; Schneider, M.; Kaelin, D. E., Jr.; Martin, S. F.
J. Am. Chem. Soc. 2001, 123, 12432. (b) Lukesh, J. M.; Donaldson, W. A.
Tetrahedron Lett. 2005, 46, 5529. See also ref 7b.
(18) Cussans, N. J.; Ley, S. V.; Barton, D. H. R. J. Chem. Soc., Perkin
Trans. 1 1980, 1654.
(19) Reiter, M.; Turner, H.; Gouverneur, V. Chem.sEur. J. 2006, 27,
7190.
(20) For a recent Lewis acid mediated synthesis of 2,6-disubstituted
pyrans, see: Gue´rinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.;
Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808.
(23) For alkylation of phosphorus acid diamides, see: Koeller, K. J.;
Spilling, C. D. Tetrahedron Lett. 1991, 32, 6297.
3174
Org. Lett., Vol. 12, No. 14, 2010

Scheme 3
.
Completion of the Synthesis of Jerangolid A (1a)
Table 2. Olefination of Ketone 17 Employing Cyclic
Phosphonamides 21a
entry
phosphonamide
product
yieldb (%)
E/Z
1
2
3
4
5
(R)-21a:R3 ) Me
(R)-21a: R3 ) Me
(R)-21b: R3 ) Et
(R)-21c: R3 ) i-Pr
(S)-21a: R3 ) Me
24a
24a
24a
24a
24b
57
62
38
20
63
3:1
6:1c
5:1
13:1
19:1
a Reaction conditions: 21 (1.5-2.0 equiv), n-BuLi (1.4-1.8 equiv), THF,
-78 °C, 1 h; 17 (1.0 equiv), -78 °C, 1 h; then AcOH (excess), -78 °C to
rt. b Recovery of ketone 17: 20-60%. c Addition of AcOH at rt.
by using LiHMDS in the solvent system DMF/HMPA,26 we
obtained almost exclusively the desired E-olefin (46%, E/Z
> 25:1), with recovered 23 (ca. 30%). Finally, removal of
the TBS group under mild acidic conditions led to jerangolid
A (1a). The spectroscopic data of the synthetic compound
matched those reported for the natural product.1,15
In summary, we have reported the first total synthesis of
jerangolid A (1a) in 16 linear steps and 6% yield starting
from glycidol 10. Relevant reactions involved a highly
diastereoselective BF3·OEt2 or Pd-catalyzed formation of
dihydropyran 17 and elaboration of the lactone 9, both
starting from a common chiron. Stereoselective olefinations
wereachievedusingphosphonamideanionandJulia-Kocienski
couplings.
selectivity. Thus, changing the substituents from methyl to
isopropyl increased the selectivity from 3:1 to 13:1, con-
cominant with a decline in yield from 57% to 20% and
increased recovery of starting materials (Table 2, entries 1
and 4). A corresponding Julia-Kocienski olefination24a,b
employing a phenyltetrazole sulfone (PT-sulfone) and
LiHMDS in CH2Cl2 gave, at best, a 3:1 E/Z ratio of olefin
24a, while employing the classical Julia-Lythgoe
conditions24c,d reportedly gave an E/Z ratio of 95:1.7 Intrigu-
ingly, employing the (S)-enantiomer of dimethyl phospho-
namide 21a in the olefination of 17 resulted in an excellent
19:1 E/Z selectivity, forming diastereomer 24b (Table 2,
entry 5).
Acknowledgment. We thank Syngenta (Basel, Switzer-
land) for generous financial assistance and Dr. R. Beaude-
gnies (Syngenta) for useful discussions. We thank Dr. P.
Washausen (Helmholtz Centre for Infection Research) for
supplying us with NMR spectra of natural jerangolid A.
We also acknowledge funding from NSERC and FQRNT.
Removal of the TBS group from 24a with TBAF afforded
alcohol 22 in 90% yield. Transformation into known PT-
sulfone 237,25 was achieved in 81% yield by treatment of
22 with 1-phenyltetrazole-5-thiol (PTSH) under Mitsunobu
conditions and subsequent oxidation. The fully elaborated
PT-sulfone 23 was eventually used for coupling with
aldehyde 9 to access the corresponding olefination product
in moderate yield. After some optimization, we found that
Supporting Information Available: Experimental pro-
1
cedures and copies of H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(b) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26. (c) Kocienski, P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin Trans.
OL101103Q
1 1978, 829. (d) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14, 4833
(25) Lee, E.; Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min, S. J.;
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Org. Lett., Vol. 12, No. 14, 2010
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