Stereoselective synthesis of ent-communiols A-C

Article abstract of DOI:10.1016/j.tetlet.2005.09.115

The first total synthesis of the non-natural enantiomers of the fungal metabolites communiols A-C is reported. A stereochemical misassignment has been corrected and the absolute configurations of the natural products have been unambiguously established.

Full text of DOI:10.1016/j.tetlet.2005.09.115

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8199–8202
Stereoselective synthesis of ent-communiols A–C
Juan Murga,a,* Eva Falomir,a Miguel Cardaa and J. Alberto Marcob
aDepart. de Q. Inorga´nica y Orga´nica, Univ. Jaume I, Castello´n, E-12071 Castello´n, Spain
bDepart. de Q. Orga´nica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
Received 18 July 2005;revised 15 September 2005;accepted 19 September 2005
Available online 6 October 2005
Abstract—The first total synthesis of the non-natural enantiomers of the fungal metabolites communiols A–C is reported. A stereo-
chemical misassignment has been corrected and the absolute configurations of the natural products have been unambiguously
established.
Ó 2005 Elsevier Ltd. All rights reserved.
The communiols A–H 1–8 (Fig. 1) constitute a group of
eight polyketide metabolites very recently isolated from
a strain of the coprophilous fungus Podospora communis
(Speg.) Niessl.1,2 Except for 7, these molecules are char-
acterized by containing at least one tetrahydrofuran ring
in their structures, a feature present in many relevant
bioactive metabolites such as lignans3 and annonaceous
acetogenins.4 Furthermore, communiols E 5 and F 6 dis-
play an isolated cyclopenta[b]furan system, a not very
common feature in natural products from fungal origin.
Some of the communiols exhibit antibacterial activity
against strains of Bacillus subtilis and Staphylococcus
aureus.1,2 In the course of our ongoing research program
aimed at the stereoselective synthesis of bioactive natu-
ral products, we have decided to undertake the stereo-
selective preparation of these molecules. Our initial
targets were communiols A–C, which exhibit the puta-
tive structures 1–3.
COOH
COOH
O
O
O
OH
OH
OH
OH
1
3
2
H
OH
COOH
O
O
H
4
H
H
O
In our design of an efficient and convergent synthetic
plan for these metabolites, we envisaged the stereoselec-
tive build-up of the tetrahydrofuran ring as the first
structural feature to be created. There are a good deal
of synthetic methods for the preparation of polysubsti-
tuted tetrahydrofuran systems.5 Our retrosynthetic
concept is shown in Scheme 1. Compounds 1–3 are
retrosynthetically related to tetrahydrofuran 9, to be
obtained by means of a two-step reduction of lactone
10, prepared in turn through stereoselective allylation
of the known compound 11.6
O
OH
OH
OH
H
H
OH
O
OH
OH
5
6
CHO
O
O
HO
8
7
Figure 1. Proposed structures of communiols A–H.
Scheme 2 depicts the details of the synthesis. Lactone 11
has been previously prepared in four steps from L-glu-
tamic acid6 but we have obtained it in two steps from
the known unsaturated ester 12.7 Sharpless dihydroxyl-
ation8 of the latter gave the expected c,d-dihydroxy ester,
which then spontaneously cyclized to 11. Protection as
Keywords: Communiols;Fungal metabolites;Stereoselective synthesis;
Tetrahydrofuran rings;Mitsunobu reaction.
*
Corresponding author. Tel.: +34 964 728174;fax: +34 964 728214;
e-mail: jmurga@qio.uji.es
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.115

8200
J. Murga et al. / Tetrahedron Letters 46 (2005) 8199–8202
formed using a two-step procedure10 via the intermediate
4
2
6
5
COOH
lactol. Oxidative cleavage of the olefinic bond in 9 was
performed via an osmylation-periodate sequence11 and
gave aldehyde 14. The latter was then subjected to oxida-
tion to acid 15 and subsequent deprotection to 3, which
has the structure published for communiol C. Unexpect-
edly, the physical and spectral properties12 of the syn-
thetic compound 3 turned out to be different from
those reported for communiol C. After a careful revision
of the published spectral data, we wondered whether the
relative configuration reported for the oxygenated car-
bon atoms C-5 and C-6 might be wrong. Thus, acid 15
was methylated and desilylated to ester 17, which was
then subjected to hydroxyl inversion by means of the
Mitsunobu reaction.13 This yielded ester 18, saponifica-
tion of which provided acid 19. The latter proved identi-
cal with communiol C in all its spectral properties (the
question of the optical rotation will be addressed below,
together with the other communiols).
3
1
9
7
8
11
O
10
OH
1, 2
2
3
4
O
OTBS
COOH
1
5
7
6
9
9
8
O
3
OH
O
O
O
OTBS
O
OH
10
11
Scheme 1.
It thus appeared that the stereostructure of communiol
C had not been correctly assigned as regards the hydr-
oxyl-bearing side chain. In view of this fact, we assumed
that the same configurational misassignment was also
present in all other members of the series. Accordingly,
our initial synthetic plan was modified. Scheme 3 shows
the reactions, which led eventually to the preparation of
communiols A and B.
OH
orthoester Claisen
ref. 7
COOEt
COOEt
12
a
HO
O
O
OR
OH
11 R = H
13 R = TBS
b
Aldehyde 14 was subjected to a Horner–Wadsworth–
Emmons olefination under mild conditions.14 This pro-
vided conjugated ester 20, which was then desilylated
to alcohol 21. Mitsunobu inversion of the secondary
hydroxyl group in the latter afforded 22. Sequential
saponification15 of the two ester residues gave hydroxy
acid 24, which exhibited spectral properties distinctly
matching those published for communiol B.1 Finally,
c
CHO
e
R
O
OTBS
O
OTBS
14
10 R = O
9 R = H2
d
f
COOEt
a
COOR
COOR
c
i
14
O
O
O
OR
OR´
OR´
20 R = TBS
21 R = H
b
15 R = H, R´ = TBS
3 R,R´ = H
16 R = Me, R´ = TBS
17 R = Me, R´ = H
18 R = Me, R´= pNO2C6H4CO
19 R,R´ = H
g
j
h
g
COOR
COOH
e
Scheme 2. Reagents and conditions: (a) AD-mix-a, aq t-BuOH, 18 h,
0 °C, 84%;(b) TBSOTf, 2,6-lutidine, CH 2Cl2, 1 h, rt, 93%;(c) LDA,
THF, 1 h, À78 °C, then allyl bromide, 1 h, À78 °C, 83% (d.r. 92:8);(d)
DIBAL, THF, À78 °C, 15 min, then CF3COOH, Et3SiH, CH2Cl2,
À40 °C, 30 min, 86% overall;(e) OsO 4, NMO, t-BuOH, aq THF, 1.5 h,
rt, then NaIO4, 1 h, rt, 77% overall;(f) NaClO 2, 2-methyl-2-butene, aq
t-BuOH, NaH2PO4, 3 h, rt, 91%;(g) 48% aq HF, MeCN, 1 h, rt, 90%;
(h) CH2N2, Et2O, rt, 97%;(i) DIAD, Ph 3P, p-NO2C6H4COOH, THF,
2 h, rt, 83%;(j) NaOH, MeOH, 2 h, rt, 77%.
O
O
OR´
OH
24
25
22 R = Et, R´ = pNO2C6H4CO
23 R = Et, R ´=H
d
f
COOH
O
OH
the TBS (t-butyldimethylsilyl) derivative was followed by
a-allylation via the lithium enolate.9 The reaction took
place with a very good stereoselectivity and provided lac-
tone 10 in 83% yield as a separable 92:8 diastereomeric
mixture. Reduction of 10 to tetrahydrofuran 9 was per-
Scheme 3. Reagents and conditions: (a) (EtO)2P(O)CH2COOEt, LiCl,
DIPEA, MeCN, 12 h, rt, 81%;(b) 48% aq HF, MeCN, 1 h, rt, 88%;(c)
DEAD, Ph3P, p-NO2C6H4COOH, THF, 2 h, rt, 78%;(d) LiOH, aq
THF, 2 h, rt, 91%;(e) NaOH, aq THF, 5 h, D, 85%;(f) H 2, Pd/C,
EtOAc, 2 h, 96%.

J. Murga et al. / Tetrahedron Letters 46 (2005) 8199–8202
8201
hydrogenation of the olefinic bond in 24 furnished
hydroxy acid 25, with spectral properties identical to
those published for communiol A.1
In summary, we have performed the first stereoselective
synthesis of the non-natural enantiomers of the fungal
metabolites communiols A–C. Furthermore, we have
corrected a misassignment in the reported relative ste-
reostructures and determined the absolute configura-
tions of the natural compounds. A more detailed
account of the preparation of these and other commun-
iols will be reported in the near future.
With the relative stereostructures of communiols A–C
now unambiguously assigned, we went on to establish
their absolute configurations. The question, however,
proved to be somewhat less clear-cut than expected.
Communiols A–C, most particularly communiol B,
were isolated in very small amounts, thus the reported
optical rotation values16 are likely affected by non-negli-
gible errors. To complicate matters still more, we have
found that both absolute value and sign of the optical
rotations of synthetic 19, 24 and 25 are markedly depen-
dent on the concentration. For instance, the following
values have been observed: 19, [a]D À13.4 (c 0.30,
CH2Cl2);[ a]D À58.9 (c 0.13, CH2Cl2); 24, [a]D À2.1 (c
0.7, CH2Cl2);[ a]D +18.6 (c 0.14, CH2Cl2);[ a]D +64.3
(c 0.07, CH2Cl2); 25, [a]D +0.5 (c 2.2, CH2Cl2);[ a]D
+7.1 (c 0.55, CH2Cl2);[ a]D +18.8 (c 0.22, CH2Cl2);
[a]D +91.8 (c 0.05, CH2Cl2). Such changes in value
and sign are well precedented in chiral carboxylic acids,
and have been attributed to association phenomena.17
Note added in proof
After our manuscript was sent to the journal, a synthesis
of communiols A–C was published alongside a reaction
sequence essentially identical to ours (see Ref. 18).
Acknowledgements
Financial support has been granted by the Spanish Min-
istry of Education and Science (project BQU2002-
00468), and by the AVCyT (projects GRUPOS03/180
and GV05/52). J.M. thanks the Spanish Ministry of
´
Education and Science for a contract of the Ramon y
At concentration values similar to those used in the
original publication,1 the optical rotations of synthetic
hydroxy acids 24 and 25 are opposite in sign to those
of the natural compounds, even if the absolute numeri-
cal values are appreciably different. Assuming that the
reported optical rotation values and signs of natural
communiols A and B1,16 are reliable at such dilute con-
centrations, we may conclude that synthetic compounds
24 and 25 are the enantiomers of these naturally occur-
ring metabolites (Fig. 2). The case of communiol C is
special, as the negative sign of the optical rotation is
the same in both the natural and the synthetic com-
pound. However, the NMR spectra of the natural sam-
ple, kindly sent by Professor Gloer, shows visible
amounts of an impurity, which is, in all likelihood, com-
muniol B. Since the negative optical rotation of the lat-
ter is much higher in its absolute value than that of
communiol C (assumedly positive), it is likely that this
impurity has affected the measured value of the optical
rotation of communiol C, even to the point of changing
the sign. Since it is not logical from the biosynthetic
point of view that communiol C belongs to a different
stereochemical series than the other members of the
group, we may safely conclude that the latter compound
has the absolute configuration depicted in Figure 2.
Cajal program. The authors further thank Professor J.
B. Gloer, from the Department of Chemistry at the Uni-
versity of Iowa, USA, for his help in kindly sending the
NMR spectra of the communiols.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.09.115.
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Figure 2. Absolute stereostructures of communiols A–C.

8202
J. Murga et al. / Tetrahedron Letters 46 (2005) 8199–8202
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