Total synthesis of pseudotrienic acid B: A bioactive metabolite from Pseudomonas sp. MF 381-IODS

Article abstract of DOI:10.1002/anie.200601114

(Chemical Equation Presented) Acid advancement: An efficient and highly convergent stereoselective synthesis of pseudotrienic acid B (see structure) has been achieved. Synthetic highlights include a crotyltitanation reaction to control the stereogenic centers at C11 and C20, a cross-metathesis reaction to synthesize the triene moiety, and a Stille cross-coupling reaction to complete the assembly of the carbon framework of the natural product.

Full text of DOI:10.1002/anie.200601114

Communications
Natural Product Synthesis
DOI: 10.1002/anie.200601114
Total Synthesis of Pseudotrienic Acid B:
A Bioactive Metabolite from Pseudomonas sp.
MF 381-IODS**
Dominique Amans, VØronique Bellosta, and
Janine Cossy*
In memory of Pierre Potier
Pseudotrienic acids A and B are two bioactive metabolites
with antimicrobial activity that have been recently isolated
from Pseudomonas sp. MF 381-IODS.[1] Their structures were
established by 1H NMR (600 MHz) and 13C NMR (150 MHz)
spectroscopy and by ESI mass spectrometry. Each of the
pseudotrienic acids A and B was isolated as a 1:1 mixture of
epimers at C20, but the absolute configurations at C11 and
C12 were well defined as S and R, respectively. The molecular
architecture of these compounds is further characterized by a
E,E,E trienic conjugated acid (C1–C7), two amide bonds, and
a trisubstituted conjugated E,E diene (C16–C19).
Both pseudotrienic acids A and B inhibit growth of
Staphylococcus aureus (minimum inhibitory concentration
(MIC) of 70 mgmLꢀ1) and Pseudomonas syringae pv. syringae
(MIC of 70 mgmLꢀ1). Moreover, Pohanka et al.[1] observed
that pseudotrienic acids A and B were prone to macro-
lactonization in an acidic environment and, therefore, could
be transformed into two naturally occurring 19-membered-
ring lactones, FR252922 and FR252921, respectively, by
treatment with trifluoroacetic acid (TFA) (Scheme 1). These
two macrolactones, isolated in 2003 by Fujine et al.[2] from the
culture broth of Pseudomonas fluorescens no. 408813, showed
immunosuppressive activity against murine splenocyte pro-
liferation stimulated with a lipopolysaccharide (LPS) or anti-
CD3 in vitro.[2] Interestingly, their site and mechanism of
action seem to be distinct from those of FK-506 and cyclo-
sporin A (CsA).[2] To date, the configuration of the three
stereocenters in FR252922 and FR252921 has not been
established. However, it was suggested that the pseudotrienic
acids A and B are derived from ring opening of the two
macrolactones FR252922 and FR252921, respectively, by a
nucleophilic attack of H2Oat C20 according to a nonstereo-
specific SN’’ substitution, thus leading to a mixture of epimers
at C20 (Scheme 1).[1] However, since the biosynthesis of
polyketides of this type is usually stereospecific, the possi-
[*] D. Amans, Dr. V. Bellosta, Prof. J. Cossy
Laboratoire de Chimie Organique associØ au CNRS
ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05 (France)
Fax: (+33)1-40-79-46-60
E-mail: janine.cossy@espci.fr
[**] We wish to thank the SociØtØ de Chimie ThØrapeutique/SERVIER for
financial support of this work and Dr. D.-H. Caignard for scientific
discussions. We also wish to acknowledge Dr. Fisher and Dr.
Trimmer from Materia, USA, for a generous gift of the Grubbs–
Hoveyda catalyst.
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Scheme 1. Lactone formation of FR252921 and FR252922 under acidic
conditions.
bility that an epimerization took place during the isolation
process of the natural product cannot be ruled out.
Scheme 2. Retrosynthetic analysis of pseudotrienic acid B. Boc=tert-
butyloxycarbonyl, HWE=Horner–Wadsworth–Emmons reaction.
Based on these observations, it seems reasonable to
assume that FR252922 and FR252921 possess the absolute
configuration S at C11 and R at C12, but the configuration at
C16 in the two latter compounds remains to be established.
One can suggest that if both epimers at C20 of pseudotrienic
acid B were prepared, an SN2’’ reaction carried out in an anti
stereospecific fashion could transfer the configuration from
C20 in pseudotrienic acid B to C16 in FR252921. This should
then lead to a correct assignment of this stereogenic center in
FR252921. The inherent structure of pseudotrienic acids A
and B, as well as the biomimetic transformation, makes these
antimicrobial agents interesting targets for total synthesis.
Herein, we report the first highly convergent total synthesis of
pseudotrienic acid B as a mixture of epimers at C20.
The strategy employed to synthesize pseudotrienic acid B
is depicted in Scheme 2. It relied on a Stille coupling between
the vinyl iodide 20 and the vinyl stannane 17 to generate the
E,E diene. The alkenyl iodide 20 could be obtained by
combining two key fragments, carboxylic acid 13 and trienic
protected amine 18, through amide formation. A previous
amide formation between the carboxylic acid 8 and the trienic
amine 5 would install the second amide bond. Finally, a cross-
metathesis/HWE sequence was envisaged for the initial
synthesis of the trienic ester 5 from commercially available
methyl sorbate (1).
Scheme 3. Synthesis of amino trienoate 5. Reagents and conditions:
a) allyl bromide (5 equiv), A (2 mol%), CH2Cl2, RT, 48 h, 48%;
b) P(OEt)3, toluene, reflux, 1 h, 99%; c) LDA (1.4 equiv), aldehyde 4,
THF, ꢀ788Cfor 15 min then 0 8Cfor 30 min; d) TFA/CH 2Cl2 (1:5),
08C!RT, then Na2CO3, 52% (2 steps). LDA=lithium diisopropyl-
amide, THF=tetrahydrofuran.
treated with allyl bromide (5 equiv) in CH2Cl2 at room
temperature for 48 h, in the presence of the Grubbs–Hoveyda
catalyst[3] (A, 2 mol%), to produce 2 in 48% yield with good
stereoselectivity (E,E/E,Z > 95:5).[4] Subsequent phosphona-
tion of the dienic allylic bromide 2 under Michaelis–Arbuzov
conditions led to the formation of diethylphosphonate 3 in
99% yield.[5] It is worth noting that a cross-metathesis
Scheme 3 delineates the synthesis of the amino trienoate
5, which commenced with methyl sorbate (1) and proceeded
through cross-metathesis and a Horner–Wadsworth–Emmons
reaction as the key steps. Thus, methyl sorbate (1) was first
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reaction between methyl sorbate and diethyl allylphospho-
nate also furnishes 3 with a similar yield but, with this
procedure, the purification of 3 was complicated by difficul-
ties in the removal of ruthenium byproducts from this highly
polar compound. Horner–Wadsworth–Emmons olefination
between phosphonate 3 and the N-Boc-protected amino
aldehyde 4 was accomplished in the presence of LDA[6] and
resulted, after TFA-mediated deprotection, in the formation
of the free trienic amine 5 in 52% yield. Thus, the trienic ester
5 was synthesized efficiently in four steps from methyl sorbate
(1) in approximately 25% overall yield.
The synthesis of the amino acid 8, which was to be coupled
with 5 to produce the C1–C14 fragment of pseudotrienic
acid B, was achieved by starting from the N-Boc-protected
glycine methyl ester 6 (Scheme 4). In order to control the
Scheme 5. Synthesis of vinyl iodide 13. Reagents and conditions:
a) CuCN (4.0 equiv), nBuLi (8.0 equiv), nBu3SnH (8.0 equiv), MeOH
(0.2 equiv), THF, ꢀ408C , 12 h, 74%; b) 2I, Et2O, 08C!RT, 94%;
c) CrO3–H2SO4 (3.1 equiv), acetone, 08C, 30 min, 92%.
(94%).[12] Oxidation with Jonesꢀ reagent afforded the desired
carboxylic acid 13 in 92% yield.
The last fragment, the vinyl stannane 17 (C20–C29
fragment), was prepared from the commercially available
octanal (14) (Scheme 6). After addition of ethynyl magne-
sium bromide, the resulting propargylic alcohol 15 (81%
yield)[13,14] was treated with NBS in the presence of AgNO3,
thus leading to the bromoalkyne 16 in 93% yield. Regio- and
stereocontrolled (> 95% E isomer) Pd-mediated hydrostan-
nylation[15] of bromoalkyne 16 with nBu3SnH in the presence
of 5 mol% of [PdCl2(PPh3)2] afforded the desired alkenyl
stannane 17 in 70% yield (Scheme 6).
Scheme 4. Synthesis of carboxylic acid 8. Reagents and conditions:
a) DIBAL-H in toluene (1.1 equiv), CH2Cl2, ꢀ788C, 2 h; b) (S,S)-B
(1.3 equiv), Et2O, ꢀ788C, 12 h, 57% (2 steps); c) 2,2-DMP, pTsOH
(0.1 equiv), acetone, RT, 5 min; d) RuCl3 (0.05 equiv), NaIO4
(4.0 equiv), CCl4/CH3CN/H2O (2:2:3), RT, 12 h, 75% (2 steps). DIBAL-
H=diisobutylaluminum hydride, 2,2-DMP=2,2-dimethoxypropane,
pTsOH=toluene-4-sulfonic acid.
configuration of the two stereogenic centers C11 and C12 in
pseudotrienic acid B, the amino ester 6 was transformed into
the corresponding aldehyde by reduction with DIBAL-H,[7]
and then treated directly with the highly face-selective
crotyltitanium complex (S,S)-B,[8] which gave rise to the
homoallylic amino alcohol 7 in 57% yield with high diastereo-
selectivity (d.r. > 95:5) and enantioselectivity (> 95% ee).[9]
Subsequent protection of the obtained amino alcohol as the
N,O-acetonide by using 2,2-DMP followed by ruthenium-
catalyzed oxidative cleavage of the terminal olefin under
Sharpless conditions[10] led to the desired carboxylic acid 8
with an overall yield of 75% for the two steps (Scheme 4).
The E vinyl iodide 13, which corresponds to the C16–C19
fragment of pseudotrienic acid B, was synthesized in three
steps from the commercially available pent-3-yn-1-ol (9) as
outlined in Scheme 5. Regio- and stereoselective stannyl-
cupration with the mixed higher-order cuprate reagent
[(Bu3Sn)BuCu(CN)Li2][11] in the presence of MeOH afforded
the two known vinyl stannanes 10 and 11 in a 9:1 ratio with a
combined yield of 74%. These two regioisomers were
separated by flash chromatography on silica gel and the
desired E vinyl stannane 10 was subjected to iododestannyl-
ation to give the known vinyl iodide 12 in very high yield
Scheme 6. Synthesis of vinyl stannane 17. Reagents and conditions:
ꢁ
a) HC CMgBr (2.0 equiv), THF, 08C!RT, 12 h, 81%; b) NBS
(1.1 equiv), AgNO3 (0.1 equiv), acetone, 12 h, RT, 93%; c) nBu3SnH
(4.0 equiv), [PdCl2(PPh3)2] (0.05 equiv), THF, 08C, 4 h, 70%. NBS=
N-bromosuccinimide.
With the four fragments in hand, the coupling reactions
were performed as shown in Scheme 7. First, the carboxylic
acid 8 was coupled with the amino trienic ester 5 by using
HOBt, HBTU, and NMM in acetonitrile and amide 18 was
isolated in 96% yield (Table 1). In order to obtain the C1–C19
fragment of pseudotrienic acid B, compound 18 was treated
with pTsOH in MeOH to afford the N-Boc-protected amino
alcohol 19 in 82% yield.[16] After removal of the tert-
butyloxycarbonyl group, the resulting amino alcohol was
coupled with the carboxylic acid 13 to produce compound 20,
the C1–C19 fragment of pseudotrienic acid B (Table 1).
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Table 1: Selected analytical data for compounds 18, 20, and 21.
18: [a]2D0 =ꢀ4.50 (c=1.36, MeOH); IR (film): n˜max =3424, 3338, 2978,
2938, 1693, 1658, 1616, 1542, 1392, 1367, 1253, 1140, 1007, 839 cmꢀ1
1H NMR (400 MHz, CDCl3): d=7.29 (dd, J=15.2, 11.2 Hz, 1H), 6.51
;
(dd, J=14.8, 10.8 Hz, 1H), 6.30–6.15 (m, 2H and NH), 5.87 (m, 1H),
5.87 (d, J=15.2 Hz, 1H), 4.09 (m, 1H), 3.75 (s, 3H), 3.64 (brs, 1H),
3.37 (m, 2H), 3.11 (t, J=9.9 Hz, 1H), 2.37 (m, 3H), 1.56 (brs, 3H), 1.51
(brs, 3H), 1.47 (s, 9H), 1.14 ppm (brs, 3H); 13C NMR (75 MHz, CDCl3):
d=173.2 (s), 167.5 (s), 152.2 and 151.8 (s), 144.6 (d), 140.4 (d), 136.1
(d), 131.9 (d), 128.8 (d), 120.4 (d), 94.0 and 93.5 (s), 80.4 and 79.8 (s),
75.0 (d), 51.5 (q), 49.6 and 49.5 (t), 44.2 and 44.0 (d), 38.5 (t), 33.1 (t),
28.3 (3q), 27.3, 26.2, 25.2, and 24.4 (2q), 13.4 ppm (q); HRMS (CI+,
NH3): calcd for C23H37O6N2 [M+H+]: 437.2652; found: 437.2643.
20: [a]2D0 =+6.93 (c=0.88, CHCl3); IR (film): n˜max =3293, 2930, 1711,
1639, 1616, 1541, 1433, 1263, 1233, 1136, 1004, 732, 618 cmꢀ1; 1H NMR
(400 MHz, CDCl3): d=7.28 (dd, J=15.3, 11.3 Hz, 1H), 6.78 (brm, NH,
1H), 6.57 (brm, NH, 1H), 6.52 (dd, J=14.9, 10.8 Hz, 1H), 6.31 (brt,
J=7.5 Hz, 1H), 6.25 (dd, J=14.9, 11.3 Hz, 1H), 6.20 (dd, J=15.4,
10.8 Hz, 1H), 5.87 (d, J=15.3 Hz, 1H), 5.87 (m, 1H), 4.61 (m, 1H), 3.74
(s, 3H), 3.66 (brm, OH, 1H), 3.51 (ddd, J=11.5, 6.6, 4.2 Hz, 1H), 3.34
(m, 2H), 3.12 (ddd, J=11.5, 7.5, 4.9 Hz, 1H), 2.97 (d, J=7.5 Hz, 2H),
2.40 (s, 3H), 2.40–2.31 (m, 3H), 1.24 ppm (d, J=7.0 Hz, 3H); 13CNMR
(75 MHz, CDCl3): d=175.8 (s), 170.2 (s), 167.5 (s), 144.7 (d) 140.4 (d),
135.7 (d), 132.8 (d), 132.1 (d), 128.9 (d), 120.3 (d), 97.8 (s), 73.2 (d),
51.6 (q), 44.4 (t), 43.2 (d), 38.5 (t), 37.7 (t), 33.0 (t), 27.9 (q), 15.7 ppm
(q); HRMS (CI+, NH3): calcd for C20H30O5N2I [M+H+]: 505.1199; found:
505.1195.
21: [a]2D0 =+7.37 (c=0.38, CHCl3); IR (film): n˜max =3308, 2956, 2927,
2856, 1720, 1646, 1619, 1546, 1459, 1435, 1271, 1137, 1074, 1007,
739 cmꢀ1; 1H NMR (400 MHz, CDCl3): d=7.22 (dd, J=15.2, 11.2 Hz,
1H), 6.45 (dd, J=14.7, 10.7 Hz, 1H), 6.29 (m, NH, 1H), 6.20 (d,
J=15.7 Hz, 1H), 6.20–6.04 (m, 2H and NH), 5.81 (m, 1H), 5.80 (d,
J=15.2 Hz, 1H), 5.62 (dd, J=15.6, 6.8 Hz, 1H), 5.53 (t, J=7.6 Hz, 1H),
4.33 (d, J=5.9 Hz, OH, 1H), 4.09 (m, 1H), 3.68 (s, 3H), 3.55 (brm,
1H), 3.45 (m, 1H), 3.29 (m, 2H), 3.03 (m, 3H), 2.31 (q, J=6.8 Hz, 2H),
2.22 (m, 1H), 1.70 (s, 3H), 1.55–1.40 (m, 2H), 1.30–1.15 (m, 10H and
OH), 1.18 (d, J=7.6 Hz, 3H), 0.81 ppm (t, J=6.7 Hz, 3H); 3CNMR
(75 MHz, CDCl3): d=175.6 (s), 172.0 (s), 167.6 (s), 144.7 (d), 140.4 (d),
137.6 (s), 135.7 (d), 133.9 (d), 132.2 (d), 132.0 (d), 128.9 (d), 123.2 (d),
120.4 (d), 73.5 (d), 72.9 (d), 51.6 (q), 44.4 (t), 43.2 (d), 38.5 (t), 37.5 (t),
36.2 (t), 33.0 (t), 31.8 (t), 29.6 (t), 29.3 (t), 25.5 (t), 22.7 (t), 15.7 (q), 14.1
(q), 12.8 ppm (q); HRMS (CI+, NH3): calcd for C30H49O6N2 [M+H+]:
533.3591; found: 533.3597.
Scheme 7. Completion of the total synthesis of pseudotrienic acid B.
Reagents and conditions: a) 5 (1.2 equiv), HOBT (1.2 equiv), HBTU
(1.2 equiv), NMM (3.0 equiv), CH3CN, 08C!RT, 6 h, 96%; b) pTsOH
(0.5 equiv), MeOH, 4 h, RT, 82%; c) TFA/CH2Cl2 (1:5), 08C!RT,
45 min; d) 13 (1.1 equiv), HOBT (1.1 equiv), HBTU (1.1 equiv), NMM
(3.0 equiv), CH3CN, 08C!RT, 12 h, 78% (2 steps); e) 17 (1.5 equiv),
[PdCl2(MeCN)2] (0.05 equiv), DMF degassed with Ar, RT, 12 h, 51%;
f) LiOH (30 equiv), MeOH/THF/H2O (2:2:1), RT, 12 h, 75%.
HOBT=N-hydroxybenzotriazole, HBTU=O-(1H-benzotriazol-1-yl)-
N,N,N’,N’-tetramethyluronium hexafluorophosphate, NMM=N-meth-
ylmorpholine, DMF=N,N-dimethylformamide, TFA=trifluoroacetic
acid.
The synthesis of pseudotrienic acid B was completed by
performing a [PdCl2(MeCN)2]-catalyzed Stille cross-coupling
reaction in DMF[17] between vinyl iodide 20 and vinyl
stannane 17 with a nonprotected allylic alcohol, thus produc-
ing the core structure of pseudotrienic acid B in 51% yield as
a mixture of two diastereoisomers, epimeric at C20 (com-
pound 21) (Table 1). It is noteworthy that only one set of
NMR signals is observed, a fact suggesting that these two
diastereoisomers cannot be distinguished by NMR spectros-
copy since they give an identical spectrum. Finally, a simple
saponification of the methyl ester 21 with LiOH afforded the
expected pseudotrienic acid B in 75% yield.[18] The spectro-
scopic data for synthetic pseudotrienic acid B were in agree-
ment with those reported in the literature for the natural
product.[1]
to control the stereogenic centers at C11 and C20, a cross-
metathesis reaction to synthesize the triene moiety, and a
palladium-catalyzed Stille cross-coupling reaction to com-
plete the assembly of the carbon framework of pseudotrienic
acid B. This rapid and flexible synthetic approach will allow
access to a wide variety of analogues for biological evaluation.
The possibility of assigning the configuration at C16 in
FR252921 by the stereoselective synthesis of each of the two
epimers of pseudotrienic acid B is currently under investiga-
tion.
Received: March 21, 2006
Revised: May 10, 2006
Published online: July 31, 2006
In conclusion, a concise, efficient, and highly convergent
stereoselective synthesis of the bioactive natural product
pseudotrienic acid B has been achieved, with a longest linear
sequence of 10 steps from methyl sorbate (1) (5.8% overall
yield). Synthetic highlights include a crotyltitanation reaction
Keywords: cross-coupling · crotyltitanation · metathesis ·
.
natural products · total synthesis
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