Synthesis of two bioactive natural products: FR252921 and pseudotrienk acid B

Article abstract of DOI:10.1002/chem.200802649

Concise and highly convergent syntheses of the immunosuppressive agent FR252921 and the related antimicrobial natural product pseudotrienic acid B were achieved from a common intermediate by using optically active titanium complexes to control the configuration of the stereogenic centers, a highly stereoand regioselective cross-metathesis to generate the triene moieties, and a Stille cross-coupling to install the dienic units.

Full text of DOI:10.1002/chem.200802649

FULL PAPER
DOI: 10.1002/chem.200802649
Synthesis of Two Bioactive Natural Products:
FR252921 and Pseudotrienic Acid B
Dominique Amans, Vꢀronique Bellosta, and Janine Cossy*[a]
Abstract: Concise and highly convergent syntheses of the immunosuppressive
agent FR252921 and the related antimicrobial natural product pseudotrienic acid
Keywords: asymmetric catalysis
·
cross-coupling · metathesis · natural
products · polyenes
B were achieved from a common intermediate by using optically active titanium
complexes to control the configuration of the stereogenic centers, a highly stereo-
and regioselective cross-metathesis to generate the triene moieties, and a Stille
cross-coupling to install the dienic units.
Introduction
From 2003–2005, five structurally related natural products
were discovered: two antimicrobial agents pseudotrienic
acids A (1a) and B (1b) isolated from Pseudomonas sp. MF
381-IODS[1] and three novel immunosuppressive agents
FR252921 (2b), FR252922 (2a) and FR256523 incorporating
a 19-membered lactone isolated from the culture broth of
Pseudomonas fluorescens No 408813 (Scheme 1).[2] The
overall backbone structure of the three 19-membered mac-
rolactones FR252921, FR252922 and FR256523 was clearly
established by Fujine et al. but the absolute stereochemistry
of their three stereogenic centers remained unknown.[2] On
the other hand, while pseudotrienic acids A and B were iso-
lated as a 1:1 mixture of epimers at C22, the absolute con-
figuration at C12 and C13 were well defined as (S) and (R),
respectively.[1] The molecular architecture of pseudotrienic
acids A and B is further characterized by a (E,E,E)-trienic
conjugated acid, two amide bonds and a trisubstituted con-
jugated (E,E)-diene. Interestingly, Pohanka et al. observed
that pseudotrienic acids A and B were prone to macrolacto-
nization upon treatment with trifluoroacetic acid, leading to
[a] Dr. D. Amans, Dr. V. Bellosta, Prof. J. Cossy
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS
10 rue Vauquelin, 75231 Paris Cedex 05 (France)
Fax : (+33)140-79-46-60
E-mail: janine.cossy@espci.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802649: Experimental proce-
dures and characterization data for compounds (S,S)-11, 13–17, (S)-
21, (S)-22, 25, (S)-27, (S)-28, (S)-29, (S,S)-30, (S,R)-31, (S,S)-31, (S,R)-
32, 33, 37, 38, 41 and 42.
Scheme 1. Pseudotrienic acids A and B and macrolactones FR252921,
FR252922 and FR256523.
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the formation of the naturally occurring lactones FR252922
and FR252921 respectively (Scheme 1).[1] On the basis of
this transformation, it seemed reasonable to assume that the
absolute configuration of FR252921 was (S) at C12, and (R)
at C13, but the absolute configuration of the stereogenic
center at C18 remained unknown. In 2007 and during our
studies, Falck et al. unequivocally established, by chemical
synthesis, that the absolute configuration of FR252921 is
(12S,13R,18R).[3]
Herein, we describe the full account of a program direct-
ed toward the synthesis and the elucidation of the absolute
configuration of FR252921. These efforts culminated in an
expedient and stereocontrolled synthesis of both
FR252921[4] and pseudotrienic acid B.[5]
Results and Discussion
Total synthesis of FR252921: FR252921 displayed significant
immunosuppressive activity against murine splenocyte pro-
liferation stimulated with lipopolysaccharide (LPS) or anti-
CD3 mAb in vitro without blocking T-cell activation. Fur-
ther studies also revealed that FR252921 inhibits protein-1
(AP-1) transcription activity and acts dominantly against an-
tigen-presenting cells (APC) compared to T-cells. Impor-
tantly, it was shown that FR252921 strongly synergizes the
effects of FK506 in vitro and in vivo. It is worth noting that
the site and mechanism of action of this new immunosup-
pressive agent seem to be distinct from those of FK-506 and
cyclosporin A, thus making it a good candidate for rejection
control in clinical use.[2] Due to its unique pharmacological
profile and challenging structure and, in order to unambigu-
ously suppress the uncertainties surrounding its stereochemi-
cal assignment, we were as other groups[3,6] interested in the
total synthesis of FR252921.
Scheme 2. Retrosynthetic analysis of FR252921.
As the absolute configuration of the three stereogenic
centers of FR252921 was unknown when we started our
studies, a flexible and versatile strategy was devised in order
to provide access to all possible diastereoisomers. The over-
all approach employed to achieve our goal is depicted retro-
synthetically in Scheme 2. It relied on a macrolactonization
of seco-acid A to form the 19-membered ring lactone 2b.
The diamide A would result from a peptide coupling be-
tween carboxylic acid E and amino alcohol B, which in turn
would be synthesized via an additional peptide coupling be-
tween trienic amine C and carboxylic acid D. A palladium-
catalyzed cross-coupling between vinyl iodide F and alkenyl
metal G would allow the elaboration of the (E,E)-dienic
side chain E. The absolute configuration of the three stereo-
genic centers at C12, C13 and C18 would be controlled by
using highly face-selective allyl- and crotylmetal complexes.
In order to establish the absolute and relative configura-
tion of the stereogenic centers present in FR252921, we de-
cided to synthesize the four syn,syn-, syn,anti-, anti,syn- and
anti,anti-diastereomers of seco-acid A possessing the (S)-
configuration at C12 (Scheme 3). Macrocyclization of one of
these four diastereomers should in principle provide either
FR252921 or its enantiomer, thus establishing the stereo-
chemistry of the natural product.
The synthesis of the amino-trienic ester of type C was
achieved by using the methodology developed in our labora-
tory for the chemo- and stereoselective synthesis of conju-
gated 1,3-dienes by cross-metathesis.[7] Thus, cross-metathe-
sis between methyl sorbate 3 and an excess of allylbromide
(5 equiv), in the presence of the Grubbs–Hoveyda catalyst
[Ru]-I[8] (5 mol%), in CH2Cl2 at RT, furnished the desired
dienic allylic bromide 4 in 48% yield and with excellent ste-
reoselectivity [(E,E)/ACHTNUTGRNEUNG
(E,Z) > 95:5].[9] Subsequent treatment
of 4 under Michaelis–Arbuzov conditions led to the desired
diethylphosphonate 5 in near quantitative yield. It is worth
mentioning that dienic phosphonate 5 can be directly ob-
tained by cross-metathesis between commercially available
diethyl allylphosphonate and methyl sorbate 3 in a similar
yield. However, this procedure resulted in a diminished
[(E,E)/ACHTNUTRGENNUG(E,Z)] selectivity [(E,E)/ACHTUNTGREN(NUGN E,Z) 85:15] as well as diffi-
culties associated with the removal of ruthenium by-prod-
ucts from phosphonate 5.[7]
A Horner–Wadsworth–Emmons olefination between the
N-Boc protected amino aldehyde 6 and the lithium salt of
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In order to obtain the enan-
tiopure amino alcohol of type
D with the syn relationship be-
tween the two substituents at
C12 and C13, the use of a con-
figurationally stable optically
active crotylmetal complex of Z
configuration was required.[14]
We therefore considered to use
the configurationally stable (Z)-
configured optically active cro-
tylboranes
derived
from
a-pinene, developed by Brown
et al.[15] Thus, addition of
(Z)-(ꢀ)-crotylbis(isopinocam-
pheyl)borane (ꢀ)-Ipc-III gener-
ated in situ, on the Si face of al-
dehyde 9, allowed the forma-
tion of the corresponding ho-
moallylic alcohol (R,S)-10 pos-
sessing the syn-relationship
between the methyl and the hy-
droxy substituents present at
C12 and C13 (dr > 95:5, ee
> 95%) in 53% yield. Conver-
sion of the amino alcohol (R,S)-
10 into the required carboxylic
acid (S,S)-11 was accomplished
in an analogous fashion as for
the synthesis of its diastereoiso-
mer (S,R)-11 (77% yield, two
steps) (Scheme 5).
Scheme 3. FR252921 or ent-FR252921 possible stereoisomers.
allylic phosphonate 5 allowed the stereoselective formation
of the corresponding (E,E,E)-trienic ester. Subsequent
TFA-mediated deprotection of the tert-butoxycarbonyl
group ultimately furnished the desired free amine 7 (52%,
two steps). Thus, trienic ester 7 (compound of type C) was
efficiently prepared in four steps from the commercially
available methyl sorbate 3 in 25% overall yield (Scheme 4).
Preparation of both syn and anti diastereoisomers of the
amino alcohol of type D, incorporating two contiguous ste-
reogenic centers at C12 and C13, was then considered.
The synthesis of the amino acids of type D, possessing the
anti-relationship between the two substituents at C12 and
C13, has been achieved starting from the N-Boc protected
glycine methyl ester 8. The latter was carefully transformed
into the corresponding aldehyde 9 upon reduction with
DIBAL-H (CH2Cl2, ꢀ788C),[10] and then directly treated
with the highly enantioselective crotyltitanium complex
(S,S)-II,[11] which gave rise to the corresponding homoallylic
amino alcohol (R,R)-10 (57% yield) with the requisite anti-
relationship between the methyl and the hydroxy substitu-
ents at C12 and C13 (dr > 95:5), and with high enantiose-
lectivity for the major isomer (ee > 95%).[12] Subsequent
protection of the resulting amino alcohol as N,O-acetonide
followed by ruthenium-catalyzed oxidative cleavage of the
terminal olefin (RuCl3/NaIO4, CCl4/CH3CN/H2O)[13] led to
the desired carboxylic acid (S,R)-11 with an overall yield of
75% for the two steps (Scheme 5).
Scheme 4. Synthesis of the amino-trienic ester 7.
We then turned our attention toward the synthesis of the
optically active b-hydroxyester F. The latter could be ac-
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with Saccharomyces cerevisiae (type II) in the presence of
glucose (H2O/EtOH, 308C) to afford the optically active
secondary alcohol 14 of R configuration in 72% yield with
an enantiomeric excess of 92%.[16,17] It is worth mentioning
that the stereochemical outcome of this reaction is con-
trolled by the presence of the trimethylsilyl group at the
acetylenic position. Indeed, it has been shown that the enzy-
matic reduction of the corresponding terminal alkyne, in
similar conditions, would deliver the S enantiomer of b-hy-
droxyester 14.[18] Removal of the acetylenic trimethylsilyl
group in 14 under standard conditions followed by protec-
tion of the propargylic alcohol as its tert-butyldimethylsilyl
ether afforded the resulting terminal alkyne 15. The latter
was then subjected to a stannylcupration–methylation se-
quence [Bu
G
HMPA/THF, ꢀ788C to RT][19] to give the trisubstituted
(E)-configured alkenyl stannane 16 (51–72% yield). A sub-
sequent iododestannylation (I2, Et2O, 0 8C) ultimately fur-
nished the required (E)-vinyl iodide 17 in 88% yield
(Scheme 7).
Scheme 5. Synthesis of the amino acids (S,R)-11 and (S,S)-11.
cessed by performing an enzymatic reduction of a b-keto-
ester of type H. Alternatively, addition of a chiral allyltitani-
um complex or an optically active titanium enolate onto al-
dehyde 20 would also provide the required enantiopure b-
hydroxyester F (Scheme 6).
The enzymatic reduction of b-ketoester 13 (of type H),
was first explored. The synthesis of b-ketoester 13 was readi-
ly accomplished by performing a Claisen condensation be-
tween the lithium enolate of ethyl acetate and the commer-
cially available ethyl trimethylsilylpropiolate (12) (ꢀ858C,
THF, 91% yield). The resulting b-ketoester 13 was subjected
to an enantioselective enzymatic reduction on treatment
Scheme 7. Synthesis of vinyl iodide 17 by enzymatic reduction.
While vinyl iodide 17 could be obtained efficiently from
ethyl trimethylsilylpropiolate 12 in six steps and in 10%
yield, this route turned out to be not amenable for large-
scale preparation. Consequently, we decided to explore a
more practical route which would allow the access to both R
and S enantiomers of b-hydroxyester of type F on a large
scale.
To this end, the enantioselective addition of allyltitanium
reagents onto aldehyde 20 was considered in order to con-
trol the configuration of the C18 stereogenic center. The
requisite aldehyde 20 was obtained by MnO2 oxidation of
the known allylic alcohol 19,[20] prepared by performing a
Scheme 6. Retrosynthetic analysis of the b-hydroxyester of type F.
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Bioactive Natural Products
FULL PAPER
stereo- and regioselective zirconium-assisted carboalumina-
tion of propargylic alcohol 18 followed by iodolysis.[21] The
resulting aldehyde 20 was directly submitted to an enantio-
selective allylmetalation with allyltitanium complexes[11]
(R,R)-IV or (S,S)-IV to produce, after TBS protection, com-
pounds (S)-21 and (R)-21, respectively, in good yield and
high enantioselectivity (ee > 95%). A three-step sequence
[regioselective oxidative cleavage of the terminal double
bond (OsO4/NMO then NaIO4), oxidation of the resulting
could be even shortened by treating aldehyde 20 with the
optically active titanium enolate V,[23] generated in situ from
tert-butylacetate lithium enolate and CpTiACTHNURTGNENG(U ODAG)2Cl titani-
um complex derived from d-glucose, which directly fur-
nished b-hydroxyester (R)-23 in 71% yield and with high
optical purity (ee > 95%)[24] (Scheme 8). This protecting
group free strategy provides a very short and efficient access
to the desired b-hydroxyester of R configuration, but this
method is unfortunately not suitable for the preparation of
the S enantiomer since the non-natural l-diacetone glucofur-
anose is not readily available.
The synthesis of the final fragment, vinyl stannane of type
G, was needed to build the dienic side chain of FR252921.
Its preparation involved a stereo- and regioselective hydro-
zirconation of non-1-yne 24 by the Schwartz reagent
Cp2ZrHCl, generated in situ ([Cp2ZrCl2], DIBAL-H,
THF),[25] followed by iodolysis (I2, THF) to give (E)-alkenyl
iodide 25 as a single stereoisomer in 89% yield. Subsequent
halogen–metal exchange with tBuLi, followed by trapping
the resulting vinyl lithium species with tri-n-butyltin chloride
gave rise to the required vinyl stannane 26 (compound of
type G) in 95% yield (Scheme 9).
aldehyde into
a carboxylic acid (NaClO2, NaH2PO4,
2-methyl-2-butene),[22] esterification with trimethylsilyldiazo-
methane], applied to each enantiomer of 21 provided access
to both enantiomers (S)-22 and (R)-22 in satisfactory yield
(61 and 59%, respectively) (Scheme 8). This alternative ap-
proach, undoubtedly more efficient than the previous one,
allowed the synthesis of both enantiomers of the b-hydroxy-
esters of type F in synthetically useful quantities.
While the synthetic sequence outlined above provided ef-
ficient access to both enantiomers (S)-21 and (R)-21, it
Scheme 9. Synthesis of vinyl stannane 26.
Having established efficient syntheses of fragments C, D,
F and G, we turned our attention to their coupling into
FR252921. The order in which these four fragments would
be assembled needed to be considered. In order to minimize
the risk of b-elimination of the extremely labile C18 hy-
droxy group, we reasoned that fragment E, resulting from
the coupling between vinyl iodide F and vinyl stannane G,
should be introduced at the late stage of the synthesis.
Coupling of vinyl stannane 26 and alkenyl iodide (S)-22
was achieved by performing a [PdCl2ACTHNUGTRNEG(UN CH3CN)2]-catalyzed
Stille cross-coupling in DMF, which successfully led to
(E,E)-diene (S)-27. Deprotection of the TBS ether with
TBAF followed by saponification with LiOH resulted in the
formation of hydroxycarboxylic acid (S)-29 in 89% yield
over the two steps. Its enantiomer (R)-29 was obtained in an
identical fashion, and in similar yields (Scheme 10).
It was also possible to perform the Pd-catalyzed Stille
coupling under the previously described conditions between
alkenyl stannane 26 and vinyl iodide (R)-23 which possesses
a free hydroxy group. After saponification of the tert-butyl
Scheme 8. Enantioselective syntheses of vinyl iodides of type F involving
chiral titanium complexes.
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30 and (S,S)-30. Subsequent protection of the free hydroxyl
group at C13 as a TIPS ether (2 equiv of TIPSOTf; 2,6-luti-
dine) led to the amino alcohols (S,R)-31 and (S,S)-31 in ex-
cellent yields. It is worth mentioning that under these condi-
tions, the tert-butoxycarbamate was transformed into a TIPS
carbamate,[26] which was merely cleaved upon treatment
with TFA in CH2Cl2 to furnish the corresponding free
amines (S,R)-32 and (S,S)-32 quantitatively (Scheme 12).
Scheme 10. Synthesis of dienes (S)-29 and (R)-29.
Scheme 12. Synthesis of amino alcohols (S,R)-32 and (S,S)-32.
ester (NaOH, MeOH, 708C), the dienic b-hydroxyacid
(R)-29 was isolated in 52% yield (two steps) (Scheme 11).
The amino acids of type D, (S,R)-11 and (S,S)-11, were
then coupled with the aminotrienic ester 7 [N-hydroxyben-
zotriazole (HOBt), O-(1H-benzotriazole-1-yl)-N,N,N’,N’-tet-
ramethyluronium hexafluorophosphate (HBTU) and
N-methylmorpholine (NMM) in acetonitrile] to produce,
after cleavage of the N,O-dimethyloxazolidine under acidic
conditions, the corresponding N-Boc-amino alcohols (S,R)-
Possessing now the two diastereomeric amino alcohols of
type B, (S,R)-32 and (S,S)-32, as well as the two enantiomers
of the dienic b-hydroxy acids of type E, we were in a favora-
ble position to synthesize the four diastereomers of seco-
acid A, one of which being the precursor of the natural
product FR252921 (or its enantiomer).
Being aware of the structural analogy existing between
FR252921 and pseudotrienic acid B of (12S,13R) configura-
tion, the synthesis of both anti,syn-(12S,13R,18R) and
anti,anti-(12S,13R,18R) diastereoisomers was first consid-
ered. Thus, (S,R)-32 was assembled with (R)-29 under classi-
cal peptide coupling conditions (HOBt, HBTU, NMM) to
give after saponification the corresponding anti,anti-
(12S,13R,18R) seco-acid 33 in 71% yield (Scheme 13). With
hydroxy-acid 33, the stage was set for the crucial macrolac-
tonization step.[27] To this end, we decided to explore in a
first place the macrolactonization of seco-acid 33 under Mit-
sunobu conditions. Unfortunately, when a solution of diiso-
propyl azodicarboxylate (DIAD) was slowly added to a
dilute solution of hydroxy acid 33 and triphenylphosphine in
benzene (c=0.0035m), no trace of the desired macrolactone
34 could be detected. Alternative protocols based on the ac-
tivation of the carboxylic acid in 33 were also attempted, to
no avail. Concerned about the risk of a b-elimination of the
hydroxy group at C18 under basic conditions, camphorsul-
fonic acid-catalyzed macrolactonization involving an ethoxy-
Scheme 11. Synthesis of diene (R)-29.
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ꢀ
isomerization of the C2 C3 double bond into a Z olefin.
The subsequent fluoride-mediated cleavage of the TIPS-
ether proceeded uneventfully and furnished the trienic mac-
rolactone 38 of (2Z,12S,13R,18R) configuration, stereoiso-
mer of FR252921 (Scheme 14).
Scheme 14. Synthesis of (2Z,12S,13R,18R)-macrolactone 38.
Scheme 13. Synthesis of seco-acid 33 and first attempts of macrolactoni-
zation.
Considering these results, we wondered whether the rela-
tive configuration at C12, C13 and C18 could influence the
cyclization process since some conformational restrictions
could be the result of the relative orientation of the substitu-
ents located on these three stereogenic centers. Therefore,
the anti,anti- and syn,anti-diastereomers of the seco-acid 33
were also synthesized by using the same two-step procedure
and subsequently underwent macrolactonization under Ya-
maguchi conditions to provide the anti,anti-seco-acid
(12S,13R,18S)-39 in 71% yield [2 steps from (12S,13R)-32
and (S)-29] and syn,anti-seco-acid (12S,13S,18R)-40 in 76%
yield [two steps from (12S,13S)-32 and (R)-29]. As previous-
ly, Yamaguchi macrolactonization of seco-acids 39 and 40
followed by cleavage of the TIPS ether by TBAF furnished
the macrolactones 41 and 42 respectively (Scheme 15). Un-
vinyl ester, readily obtained from the corresponding carboxy-
lic acid, was examined.[28] Along these lines, the seco-acid 33
was treated with ethoxyacetylene, in the presence of a cata-
lytic amount of [RuCl2ACTHNUTRGNEUNG
(p-cymene)]2,[29] to provide the corre-
sponding sensitive ethoxyvinyl ester. This compound was
not purified but directly added to a dilute solution of CSA
in toluene (c=0.005m). Unfortunately, the desired macro-
lactone 35 was not obtained under these conditions
(Scheme 13).
On the basis of these negative results, more forcing condi-
tions were assayed for the macrolactonization. To our de-
light, under classical Yamaguchi conditions (2,4,6-trichloro-
benzoyl chloride, Et3N, 4-DMAP, toluene, c=0.0015m,
658C)[30] seco-acid 33 underwent macrolactonization. How-
ever, close examination of the NMR spectra revealed the
formation of unexpected macrolactone 37, the result of an
ꢀ
fortunately, isomerization of the C2 C3 double bond into a
Z olefin was observed in these cases as well. Based on these
ꢀ
isomerization of the C2 C3 double bond initially of E con-
observations, we concluded that the isomerization of the
1
figuration into a Z olefin. Indeed, COSY H–1H correlation
C2 C3 double bond was not related to the configuration of
ꢀ
showed that the most deshielded proton, which was usually
attributed to H3 since it is localized in the deshielding plane
of the carbonyl group, turned out to be H4 and more strik-
ingly the value of the coupling constant between H2 and H3
was 11.5 Hz, which is abnormally small for a E-configured
double bond. These results confirmed the hypothesis of an
the three stereogenic centers, but rather to the conditions
used for the macrolactonization (Scheme 15).[31] We believe
that the use of excess DMAP at elevated temperatures
could be responsible for the observed isomerization of the
ꢀ
C2 C3 double bond, presumably involving a ketene inter-
mediate.[32,33]
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These results allowed us to
conclude that the presence of
the bulky TIPS ether at C13
could be indirectly responsible
for the displacement of the
thermodynamic
equilibrium
toward the formation of the pu-
tative more stable lactone of
(2Z,4E,6E)-configuration, which
would consequently prevent the
formation of the natural prod-
uct FR252921. In order to test
this hypothesis, the macrolacto-
nization without any protecting
group for the alcohol at C13
was considered.
Being aware at that time of
the results published by Falck
et al., who disclosed the total
synthesis of FR252921 from the
corresponding seco-acid with a
free hydroxy group at C13,[3] we embarked in the synthesis
of the seco-acid of (12S,13R,18R)-configuration.
Scheme 16. Total synthesis of FR252921.
et al. involving the macrolactonization of seco-acid 47 under
Shiinaꢁs conditions.[35] Thus, treatment of the previously ob-
tained hydroxy-acid 47 by 2-methyl-6-nitrobenzoic anhy-
dride (MNBA), in the presence of 4-DMAP in a highly di-
luted THF solution (c=0.0006m), allowed the formation of
FR252921 in poor yield (ꢁ5%) accompanied by significant
impurities, which could only be separated from the natural
product by reverse phase chromatography (Scheme 16).[36–38]
Total synthesis of pseudotrienic acid B: Due to the structur-
al similarities between pseudotrienic acid B and FR252921,
a straightforward synthesis of pseudotrienic acid B was en-
visaged starting from a common intermediate, compound
(S,R)-30. The strategy employed to synthesize pseudotrienic
acid B relied on a palladium-catalyzed Stille cross-coupling
between vinyl iodide 57 and the alkenyl stannane 56 to gen-
erate the (E,E)-diene. Compound 57 would be obtained
through amide bond formation between carboxylic acid 52
and amino alcohol (S,R)-30 that we previously obtained in
the course of the total synthesis of FR252921 (Scheme 17).
We therefore needed to synthesize vinyl iodide 52 and al-
kenyl stannane 56. The required (E)-vinyl iodide 52, which
Scheme 15. Synthesis of stereomeric lactones of FR252921.
Along these lines, treatment of N-Boc-amino alcohol
(S,R)-30 with TFA in CH2Cl2, followed by peptide coupling
with (R)-29 (HOBt, HBTU, NMM, CH3CN) gratifyingly fur-
nished diamide 46 in 78% over two steps. Saponification of
46 with LiOH resulted in seco-acid 47, precursor of
FR252921, in near quantitative yield (Scheme 16). It should
be noted that the NMR spectral data of seco-acid 47 are
highly dependent on sample concentration (in particular for
the chemical shifts of H2, H3, C1, C2, C5) and fortunately
one of our NMR 1H spectra was in total agreement with
one of the NMR spectra provided by Falck et al.[34] Further-
more, the optical rotation value of our seco-acid 47 corre-
sponds to the one published by Falck.
ꢀ
corresponds to the C16 C19 fragment of pseudotrienic acid
B, was synthesized in three steps from the commercially
available pent-3-yn-1-ol 48 as outlined in Scheme 18. A
regio- and stereoselective stannylcupration using the mixed
higher order cuprate [(Bu3Sn)BuCu(CN)Li2][19] in the pres-
ence of MeOH[39] afforded the vinyl stannanes 49 and 50 in
a 9:1 ratio with a combined yield of 74%. These two re-
gioisomers were easily separated by flash chromatography
on silica gel and the desired (E)-vinyl stannane 49 was sub-
sequently subjected to iododestannylation (I2, Et2O) to give
alkenyl iodide 51 in good yield (94% yield). Oxidation of
the primary alcohol with Jones reagent (CrO3·H2SO4, ace-
tone) successfully led to the desired carboxylic acid 52 in
92% yield (Scheme 18).
The completion of the total synthesis of FR252921 was
performed according to the protocol described by Falck
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Bioactive Natural Products
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Scheme 19. Synthesis of vinyl stannane 56.
Scheme 17. Retrosynthetic analysis for pseudotrienic acid B.
Scheme 18. Synthesis of alkenyl iodide 52.
ꢀ
The last fragment, vinyl stannane 56 (C20 C29 fragment),
was prepared in three steps from octanal 53. After addition
of ethynylmagnesium bromide (THF, 08C), the resulting
propargylic alcohol 54 (81% yield) was exposed to N-bro-
mosuccinimide (NBS) in the presence of AgNO3 to give the
bromoalkyne 55 in 93% yield.[40] A regio- and stereocon-
trolled [>95% E isomer] palladium-mediated hydrostanny-
lation of bromoalkyne 55 {[PdCl2ACHTNUGTRENG(UN PPh3)2], nBu3SnH, THF,
08C} afforded the desired (E)-configured alkenyl stannane
56 in 70% yield (Scheme 19).
With the four fragments at hand, the coupling reactions
were performed as shown in Scheme 20. Treatment of
N-Boc-amino alcohol (S,R)-30 with TFA in CH2Cl2, fol-
lowed by a coupling with carboxylic acid 52 under classical
peptide coupling conditions (HOBt, HBTU, NMM, CH3CN)
furnished amide 57 in 79% yield (two steps). The vinyl
Scheme 20. Total synthesis of pseudotrienic acid B.
iodide 57 was subsequently involved in a Pd-catalyzed Stille
cross-coupling {[PdCl2ACTHNUTRGNE(UNG MeCN)2], DMF, 12 h} with vinyl
Chem. Eur. J. 2009, 15, 3457 – 3473
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3465

J. Cossy et al.
the residue was purified by flash column chromatography (PE/EtOAc
stannane 56 bearing a non-protected hydroxy group, which
successfully gave rise to the core structure of pseudotrienic
acid B, ester 58, as a mixture of two epimers at C20 (51%
yield). It is worth mentioning that only one set of NMR sig-
nals is observed, which suggests that these two epimers
cannot be distinguished by NMR spectroscopy. Finally, after
saponification of 58 with LiOH, the expected pseudotrienic
acid B was isolated in 75% yield. The spectroscopic data
were in total agreement with those reported in the literature
for the natural product (Scheme 20).[1,41]
98:2 ! 95:5) to give diene 4 (118 mg, 48%) as a mixture of diastereoiso-
mers [(E,E)-4/ACTHNUGTRNEUNG(E,Z)-4 32:1], contaminated by traces of methyl 8-bro-
moocta-2,4,6-trienoate. Rf ꢁ0.25 (PE/EtOAc 95:5); 1H NMR (400 MHz,
CDCl3): d=7.19 (dd, 1H, J=15.4, 11.0 Hz), 6.32 (dd, 1H, J=15.0,
11.0 Hz), 6.18 (dt, 1H, J=15.0, 7.5 Hz), 5.87 (d, 1H, J=15.4 Hz), 3.97 (d,
2H, J=7.5 Hz), 3.69 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d
=
166.9 (s), 142.8 (d), 136.7 (d), 131.9 (d), 122.8 (d), 51.8 (q), 31.2 ppm (t);
IR (neat): n˜ =2950, 1713, 1643, 1614, 1434, 1336, 1249, 1194, 1147, 1113,
ACTHNUTRGNEUNG
995 cmꢀ1; MS (EI, 70 eV): m/z (%): 206 (15) [M(81Br)+], 204 (15) [M-
A
E
N
145 (4), 125 (100), 97 (12), 94 (23), 93 (57), 79 (14), 66 (50), 65 (37).
Methyl (2E,4E)-6-(diethoxyphosphoryl)hexa-2,4-dienoate (5): Triethyl-
phosphite (29 mL, 170 mmol, 12.0 equiv) was added dropwise to a solu-
tion of bromodiene 4 (3.10 g, 14.2 mmol, 1.0 equiv) in toluene (29 mL).
The mixture was heated to reflux for 1 h, was then allowed to reach RT
and the volatiles were removed in vacuo. Purification of the crude resi-
due by flash chromatography on silica gel (PE/EtOAc 50:50 ! 20:80)
furnished the desired phosphonate (3.65 g, 99%) as a colorless oil.
Rf ꢁ0.2 (EtOAc); 1H NMR (400 MHz, CDCl3): d=7.27 (dd, 1H, J=
15.5, 11.0 Hz), 6.32 (ddd, 1H, J=15.5, 11.0, JH,P =5.2 Hz), 6.07 (m, 1H),
5.86 (dd, 1H, J=15.5, 2.4 Hz), 4.11 (m, 4H), 3.74 (s, 3H), 2.72 (dd, 2H,
Conclusion
In conclusion, a short and highly convergent strategy al-
lowed us to achieve the total synthesis of FR252921 from
methyl sorbate 3 in ten steps (longest linear sequence), as
well as three potentially useful analogues for biological eval-
uation. This work illustrates the crucial role that total syn-
thesis plays in the structural assignment of natural products,
and also highlights the difficulties associated with a macro-
lactonization strategy toward this type of constrained poly-
enic macrolide. Moreover, a concise, efficient and highly
convergent stereoselective synthesis of related pseudotrienic
acid B has been achieved from methyl sorbate 3 in 5.8%
overall yield over ten steps (longest linear sequence) which
constitutes, to our knowledge, the first total synthesis of this
naturally-occurring molecule.
J
H,P =23.1, 7.6 Hz), 1.32 ppm (t, 6H, J=7.1 Hz); 13C NMR (100 MHz,
CDCl3): d = 167.2 (s), 143.7 (d), 132.6 (d, JC,P =20.1 Hz), 131.7 (d, JC,P
=
20.1 Hz), 120.7 (d), 62.1 (2t), 51.5 (q), 31.2 (t, JC,P =140.9 Hz), 16.4 ppm
(2q); IR (neat): n˜ =3467, 2983, 2982, 1716, 1644, 1617, 1436, 1340, 1247,
1149, 1025, 957, 791, 729 cmꢀ1; MS (EI, 70 eV): m/z (%): 262 (16) [M+],
247 (10) [MꢀOMe+], 233 (2), 231 (8), 191 (7), 175 (9), 125 (12), 124
(100), 111 (18), 109 (32), 94 (11), 93 (11), 91 (10), 81 (21), 66 (18), 65
(13), 59 (7); HRMS (CI+, NH3): m/z: calcd for C11H20O5P: 263.1048;
found: 263.1044 [M+H]+.
tert-Butyl 2-formylethylcarbamate (6): A solution of Dess–Martin peri-
odinane (1.36 g, 6.27 mmol, 1.1 equiv) in CH2Cl2 (15 mL) was added
dropwise to a solution of N-Boc-aminopropan-1-ol (1.0 g, 5.70 mmol,
1.0 equiv) in CH2Cl2 (25 mL) at 08C. After 2 h at RT, the reaction mix-
ture was diluted with Et2O (30 mL) and then hydrolyzed by adding a sa-
turated aqueous solution of NaHCO3 containing solid Na2S2O3 (5 g). The
aqueous layer was extracted with Et2O (3ꢃ50 mL) and the combined or-
ganic layers were successively washed with a saturated aqueous solution
of NaHCO3 (2ꢃ30 mL), brine (2ꢃ30 mL) then dried over MgSO4, fil-
tered and concentrated under reduced pressure. The obtained crude alde-
hyde 6 was immediately used in the next step without purification.
Experimental Section
General methods: TLC was performed on Merck 60F254 silica gel plates
and visualized either with a UV lamp (254 nm), or by using a solution of
p-anisaldehyde/sulfuric acid/acetic acid in EtOH followed by heating.
Flash chromatography was performed with Merck Geduran Si60 silica
gel (40–63mm).
Methyl (2E,4E,6E)-9-aminonona-2,4,6-trienoate (7)
Methyl
(2E,4E,6E)-9-(tert-butoxycarbonylamino)nona-2,4,6-trienoate:
Infrared (IR) spectra were recorded on a Perkin-Elmer 298 or on a
nBuLi (2.8 mL, 7.4 mmol, 1.3 equiv) was added dropwise to a solution of
diisopropylamine (1.1 mL, 7.4 mmol, 1.3 equiv) in THF (6 mL) at 08C.
After 20 min of stirring, the reaction mixture was cooled down to ꢀ788C
and a solution of phosphonate 5 (2.05 g, 7.4 mmol, 1.3 equiv) in THF
(10 mL) was added dropwise. After 15 min, a solution of the crude alde-
hyde 6 (5.70 mmol, 1.0 equiv) in THF (10 mL) was added dropwise and
stirring was continued for 15 min at ꢀ788C, then 15 min at 08C. The re-
action mixture was hydrolyzed by adding a saturated aqueous solution of
NH4Cl (20 mL). The aqueous phase was extracted with Et2O (3ꢃ50 mL)
and the combined organic layers were washed with brine (50 mL), dried
over MgSO4, filtered and concentrated under reduced pressure. Purifica-
tion of the residue by flash chromatography on silica gel (PE/EtOAc
85:15) furnished methyl (2E,4E,6E)-9-(tert-butoxycarbonylamino)nona-
2,4,6-trienoate (944 mg, 55%) as a yellow oil which solidified upon stand-
ing in the fridge at ꢀ208C. Rf ꢁ0.25 (PE/EtOAc 80:20); 1H NMR
(400 MHz, CDCl3): d=7.29 (dd, 1H, J=15.4, 12.1 Hz), 6.52 (dd, 1H, J=
14.8, 10.8 Hz), 6.24 (dd, 1H, J=14.8, 11.3 Hz), 6.19 (dd, 1H, J=15.2,
10.8 Hz), 5.87 (d, 1H, J=15.2 Hz), 5.86 (m, 1H), 4.65 (brs, 1H, NH),
3.74 (s, 3H), 3.22 (m, 2H), 2.34 (m, 2H), 1.44 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=167.5 (s), 155.9 (s), 144.7 (d), 139.2 (d), 135.4 (d),
131.9 (d), 128.7 (d), 119.8 (d), 79.3 (s), 51.5 (q), 39.8 (t), 33.6 (t),
28.4 ppm (3q); IR (neat): n˜ =3297, 2978, 2949, 2932, 1701, 1680, 1618,
1531, 1277, 1246, 1171, 1135, 1007, 994, 877, 850 cmꢀ1; MS (EI, 70 eV): m/
z (%): 281 (1), 225 (38), 208 (19), 207 (19), 194 (13), 139 (54), 176 (21),
Bruker TENSOR 27 (IRFT), wavenumbers are indicated in cmꢀ1
.
1H NMR spectra were recorded on a Bruker AVANCE 400 at 400 MHz
and data are reported as follows: chemical shift in ppm from tetramethyl-
silane as an internal standard, multiplicity (s=singlet, d=doublet, t=
triplet, q=quartet, quint=quintuplet, m=multiplet or overlap of non
equivalent resonances), integration. 13C NMR spectra were recorded on a
Bruker AC 300 at 75 MHz or on a Bruker AVANCE 400 at 100 MHz
and data are reported as follows: chemical shift in ppm from tetramethyl-
silane with the solvent as an internal indicator (CDCl3 d 77.0 ppm), mul-
tiplicity with respect to proton (deduced from DEPT experiments, s=
quaternary C, d=CH, t=CH2, q=CH3). Mass spectra with electronic
impact (MS) were recorded from a Hewlett-Packard tandem 5890 A GC
(12 m capillary column), 5971 MS (70 eV). High resolution mass spectra
(HRMS) were performed by the Groupe de Spectromꢂtrie de Masse de
l’Universitꢂ Pierre et Marie Curie (Paris).
All the reactions were performed under an argon atmosphere.
Methyl (2E,4E)-6-bromohexa-2,4-dienoate (4): Grubbs–Hoveyda catalyst
[Ru]-I (18.5 mg, 0.030 mmol, 0.025 equiv) was added to a solution of
methyl sorbate
3 (150 mg, 1.2 mmol, 1.0 equiv) and allylbromide
(6.0 mmol, 5.0 equiv) in CH2Cl2 (15 mL). After 24 h of stirring at RT, an-
other portion of Grubbs–Hoveyda catalyst [Ru]-I was added (18.5 mg,
0.030 mmol, 0.025 equiv). Stirring was continued for 24 h, and silica was
added to the reaction mixture. The volatiles were removed in vacuo and
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Bioactive Natural Products
FULL PAPER
164 (47), 152 (66), 151 (15), 148 (10), 133 (14), 132 (45), 131 (19), 120
(28), 119 (57), 118 (12), 105 (71), 104 (20), 98 (21), 93 (24), 92 (31), 91
(100), 79 (16), 78(13), 77 (20), 66 (16), 65 (15), 59 (53), 57 (95), 56 (21),
55 (12).
concentrated in vacuo. Purification of the residue by flash chromatogra-
phy on silica gel (PE/EtOAc 95:5) furnished the title N,O-dimethyloxazo-
lidine (1.17 g, 96%) as a colorless oil. The physical and spectroscopic
properties matched those reported in the literature.[13a] Rf ꢁ0.9 (PE/
EtOAc 80:20); [a]D20 = ꢀ19.6 (c = 0.61, CHCl3) {lit.[13a] [a]D25 = ꢀ19.08
Trifluoroacetic acid (13.5 mL) was added dropwise to a solution of
1
(c = 2.7, CHCl3)}; H (400 MHz, CDCl3): d=5.84 (m, 1H), 5.14–5.03 (m,
methyl
(2E,4E,6E)-9-(tert-butoxycarbonylamino)nona-2,4,6-trienoate
2H), 3.92 (dtapp, 1H, J=9.5, 6.9 Hz), 3.58 (m, 1H), 3.13 (m, 1H), 2.37
(sextupletapp, 1H, J=6.9 Hz), 1.57 (s, 3H), 1.53 (s, 3H), 1.48 (s, 9H),
1.02 ppm (d, 3H, J=6.7 Hz); 13C NMR (100 MHz, CDCl3): d=152.4 and
152.0 (s), 139.8 (d), 115.1 (t), 93.5 and 93.1 (s), 80.0 and 79.4 (s), 77.1 and
76.9 (d), 48.8 and 48.7 (t), 40.4 (d), 28.5 (3q), 27.1, 26.0, 25.2 and 24.2
(2t), 14.4 ppm (q); IR (neat): n˜ =2977, 2935, 2874, 1697, 1388, 1365, 1253,
1175, 1148, 1093, 1051, 874, 769 cmꢀ1; MS (EI, 70 eV): m/z (%): 255 (3),
240 (20), 200 (2), 185 (11), 184 (100), 140 (21), 100 (25), 81 (20), 72 (11),
57 (73); HRMS (CI+, CH4): m/z: calcd for C14H26O3N: 256.1913; found:
256.1911 [M+H]+.
(1.29 g, 4.6 mmol, 1.0 equiv) in CH2Cl2 (55 mL) at 08C. After 45 min at
RT, the resulting brown solution was concentrated in vacuo. The resulting
trifluoroacetate ammonium salt was diluted with CH2Cl2 (30 mL), and
was treated by a saturated aqueous solution of Na2CO3 (30 mL). The
aqueous phase was vigorously extracted with CH2Cl2 (6ꢃ30 mL) and the
combined organic layers were washed with brine (50 mL), dried over
MgSO4, filtered and concentrated under reduced pressure to give amine
7 (794 mg, 95%) as a viscous brown oil. This compound was not purified
but directly used in the subsequent peptide coupling step (see formation
of compound 30).
Sodium periodate (2.53 g, 11.82 mmol, 4.0 equiv) and RuCl3 (31 mg,
0.148 mmol, 0.05 equiv) were successively added to a solution of tert-
butyl (5R)-5-[(1R)-1-methylprop-2-en-1-yl]-2,2-dimethyloxazolidine-3-car-
boxylate (755 mg, 2.96 mmol, 1.0 equiv) in a CCl4/CH3CN/H2O (7:7:10,
24 mL) mixture. After 12 h of vigorous stirring at RT, CH2Cl2 (20 mL)
and water (20 mL) were added. The resulting green heterogeneous mix-
ture was filtered over Celite to get rid of ruthenium salts, and the aque-
ous layer was extracted with CH2Cl2 (3ꢃ30 mL). The combined organic
layers were washed with brine (30 mL), dried over MgSO4, filtered and
concentrated under reduced pressure. Purification of the residue by flash
chromatography on silica gel (EtOAc/CH3COOH 100:1) furnished car-
boxylic acid (S,R)-11 (635 mg, 78%) as a brown solid. The physical and
spectroscopic properties matched those reported in the literature.[13a] Rf
ꢁ0.3 (PE/EtOAc 50:50); m.p. 1028C; [a]2D0 = ꢀ17.9 (c = 2.1, CHCl3)
tert-Butyl (2-oxoethyl)carbamate (9): DIBAL-H (1.0m in toluene,
26.2 mL, 26.2 mmol, 1.1 equiv) was added dropwise over 45 min via sy-
ringe pump to
a solution of N-Boc glycine methyl ester 8 (4.5 g,
23.8 mmol, 1.0 equiv) in CH2Cl2 (90 mL) at ꢀ788C. After 1 h of stirring
at ꢀ788C, the reaction mixture was hydrolyzed by adding a saturated
aqueous solution of Rochelleꢁs salt (6 mL) and the mixture was allowed
to warm to RT. The resulting gel was filtered over Celite and the filtrate
was concentrated under reduced pressure, to give the crude aldehyde 9
(2.58 g, 69%) as a colorless oil. This extremely unstable compound was
immediately used in the next step without purification.
tert-Butyl [(2R,3R)-2-Hydroxy-3-methylpent-4-enyl]carbamate [(R,R)-
10]: 2-Butenylmagnesium chloride (0.5m in THF, 32.7 mL, 16.3 mmol,
1.3 equiv) was added dropwise to
a
stirred suspension of
cyclopentadienyl[(4S,trans)-2,2-dimethyl-a,a,a’,a’-tetraphenyl-1,3-dioxo-
ACHTUNGTRENNUNG
1
{lit.[13a] [a]D20 = ꢀ15.2 (c = 2.07, CHCl3)}; H NMR (400 MHz, CDCl3, ro-
lane-4,5-dimethanolato-O,O’]titanium chloride (12.3 g, 20.1 mmol,
1.6 equiv) in anhydrous Et2O (160 mL) at 08C. After 2 h at 08C, the
brown reaction mixture was cooled to ꢀ788C and a solution of the crude
aldehyde 9 (2.0 g, 12.56 mmol, 1.0 equiv) in Et2O (40 mL) was added
dropwise via cannula. After 5 h at ꢀ788C, the reaction was quenched by
addition of water (80 mL). The reaction mixture was stirred for 48 h at
RT and then filtered over Celite. The layers were separated and the
aqueous phase was extracted with Et2O (3ꢃ100 mL). The combined or-
ganic extracts were washed with brine (150 mL), dried over MgSO4, fil-
tered and concentrated in vacuo. The residue was then diluted with pen-
tane (60 mL) and filtered to remove (4S,trans)-2,2-dimethyl-a,a,a’,a’-tet-
raphenyl-1,3-dioxolane-4,5-dimethanol. After removal of pentane under
reduced pressure, purification of the residue by flash chromatography on
silica gel (PE/EtOAc 90:10 ! 80:20) provided the desired enantioen-
riched homoallylic alcohol (R,R)-10 (2.26 g, 83%) as a colorless oil. The
physical and spectral data were in accordance with those reported in the
literature.[42] Rf ꢁ0.2 (PE/EtOAc 80:20); [a]D20 = ꢀ2.58 (c = 1.4, CHCl3)
tamers): d=4.30 (m, 1H), 3.65 (brm, 1H), 3.20 (m, 1H), 2.70 (m, 1H),
1.65 (s, 3H), 1.60 (m, 3H), 1.50 (s, 9H), 1.20 ppm (d, 3H, J=6.7 Hz);
13C NMR (100 MHz, CDCl3, rotamers): d=179.0 (s), 152.4 and 151.9 (s),
93.9 and 93.5 (s), 80.6 and 79.8 (s), 74.3 (d), 48.4 and 48.1 (t), 43.1 and
42.8 (d), 28.2 (3q), 27.1, 26.0, 25.2 and 24.3 (2t), 12.8 and 12.6 ppm (q);
IR (neat): n˜ =2977, 2938, 2889, 1736, 1699, 1645, 1461, 1417, 1367, 1247,
1214, 1165, 1146, 1122, 1054, 872, 764, 635 cmꢀ1; MS (EI, 70 eV): m/z
(%): 258 (14) [MꢀMe+], 202 (62), 200 (10), 158 (60), 98 (11), 70 (12), 57
(100) ; HRMS (CI+, CH4): m/z: calcd for C13H24O5N: 274.1654; found:
274.1649 [M+H]+.
(E)-3-Iodo-2-methylacrylaldehyde (20): MnO2 (33 g, 384 mmol, 20 equiv)
was added in one portion at RT to a stirred solution of (E)-3-iodo-2-
methylprop-2-en-1-ol 19[43] (3.80 g, 19.2 mmol, 1.0 equiv) in CH2Cl2
(120 mL). The resulting dark mixture was stirred vigorously for 48 h,
then Celite was added and the heterogeneous mixture was filtered
through a plug of Celite to remove the manganese salts. CH2Cl2 was re-
moved under reduced pressure, thus affording the crude a,b-unsaturated
aldehyde 20 (3.31 g, 87%) as a brown oil which was used in the next step
without further purification.
1
{lit.[42] [a]D25 = ꢀ2.63 (c = 5.8, CHCl3)}; H NMR (400 MHz, CDCl3): d=
5.76 (m, 1H), 5.16–5.09 (m, 2H), 5.01 (brs, 1H, NH), 3.49 (brm, 1H,
H2), 3.36 (m, 1H), 3.07 (ddd, 1H, J=13.6, 8.0, 5.3 Hz), 2.47 (brs, 1H,
OH), 2.24 (sextapp, 1H, J=7.4 Hz), 1.45 (s, 9H), 1.06 ppm (d, 3H, J=
6.9 Hz); 13C NMR (100 MHz, CDCl3): d=156.7 (s), 139.9 (d), 116.6 (t),
79.5 (s), 74.2 (d), 44.2 (t), 42.4 (d), 28.4 (3q), 16.1 ppm (q); IR (neat): n˜ =
3368, 3077, 2976, 2932, 1690, 1515, 1367, 1251, 1170 cmꢀ1; MS (EI,
70 eV): m/z (%): 160 (3), 159 (4), 142 (7), 131 (3), 104 (60), 86 (10), 76
(20), 75 (39), 57 (100); HRMS (ESI): m/z: calcd for C11H21O3NNa:
238.1413; found: 238.1414 [M+Na]+.
(+)-tert-Butyl (E)-(R)-3-hydroxy-5-iodo-4-methylpent-4-enoate (23):
Solid diacetone-d-glucose (6.1 g, 23.34 mmol, 2.0 equiv) was added in one
portion at RT to a solution of [CpTiCl3] (2.56 g, 11.67 mmol, 1.0 equiv) in
anhydrous Et2O (80 mL). After stirring for 5 min, freshly distilled Et3N
(4.64 mL, 33.4 mmol, 2.85 equiv) dissolved in anhydrous Et2O (40 mL)
was added via cannula to the previous solution. The resulting thick slurry
was stirred at RT for 15 h, and the triethylamine salts were removed by
filtration under an argon atmosphere. The yellow 0.095m stock solution
in Et2O of chloro(cyclopentadienyl)-bis(1,2:5,6-di-O-isopropylidene-a-d-
glucofuranos-3-O-yl) titanate thus obtained was kept for the next reac-
tion under an argon atmosphere in the fridge at 08C.
(2S)-2-[(5R)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidin-5-yl]propa-
noic acid [(S,R)-11]
tert-Butyl (5R)-5-[(1R)-1-methylprop-2-en-1-yl]-2,2-dimethyloxazolidine-
3-carboxylate: 2,2-Dimethoxypropane (10.5 mL, 86.11 mmol, 18 equiv)
and p-toluenesulfonic acid monohydrate (82 mg, 0.478 mmol, 0.1 equiv)
were successively added to a solution of amino alcohol (R,R)-10 (1.03 g,
4.78 mmol, 1.0 equiv) in acetone (40 mL). After 5 min of stirring at RT,
the reaction mixture was hydrolyzed by adding a saturated aqueous solu-
tion of NaHCO3 (10 mL). The layers were separated and the aqueous
phase was extracted with CH2Cl2 (3ꢃ50 mL). The combined organic
layers were washed with brine (50 mL), dried over MgSO4, filtered and
A solution of tBuOAc (403 mL, 2.99 mmol, 1.5 equiv) in Et2O (5 mL) was
added dropwise to a solution of freshly prepared LDA (2.99 mL, 1m in
THF/n-hexanes, 2.99 mmol, 1.5 equiv) in anhydrous Et2O (40 mL) at
ꢀ788C. After stirring for 30 min, a solution of the titanium reagent de-
scribed above (42 mL, 0.095m in Et2O, 3.98 mmol, 2 equiv) was subse-
quently added via cannula dropwise over 20 min, and stirring was carried
on for further 30 min. The temperature was then slowly raised to ꢀ308C,
Chem. Eur. J. 2009, 15, 3457 – 3473
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3467

J. Cossy et al.
and after stirring at this temperature for 45 min the solution was finally
re-cooled to ꢀ788C. The previously obtained crude (E)-3-iodo-2-methyl-
acrylaldehyde (20) (390 mg, 1.99 mmol, 1.0 equiv) was azeotroped three
times with toluene, then dissolved in anhydrous Et2O (15 mL) and subse-
quently added dropwise within 10 min to the previous solution. After stir-
ring at ꢀ788C for 1 h, the reaction was quenched by addition of a THF/
H2O solution (1:1, 60 mL) and the mixture was stirred for 1 h. The result-
ing white slurry was filtered through a short pad of Celite in order to
remove the solid titanium salts, and the filtrate was washed with brine
(80 mL). The aqueous layers were extracted with Et2O (3ꢃ80 mL) and
the combined organic phases where dried over MgSO4, filtered and
evaporated to dryness under reduced pressure. The resulting crude resi-
due was purified by flash chromatography on silica gel (PE/EtOAc 95:5)
to yield compound 23 (441 mg, 71%) as a colorless oil. Rf ꢁ0.25 (PE/
EtOAc 95:5); [a]2D0 = +15.5 (c = 1.11, CHCl3); 1H NMR (400 MHz,
CDCl3): d=6.39 (quintapp, 1H, J=1.1 Hz), 4.52 (m, 1H), 3.24 (brd, 1H,
J=3.7 Hz, OH), 2.54–2.43 (m, 2H), 1.83 (d, 3H, J=1.1 Hz), 1.46 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): d=171.4 (s), 147.7 (s), 81.8 (d), 79.1
(s), 72.5 (d), 40.8 (t), 28.1 (3q), 20.5 ppm (q); IR (neat): n˜ =3401, 2977,
(+)-tert-Butyl
(4E,6E)-(R)-3-hydroxy-4-methyltetradeca-4,6-dienoate:
[PdCl2ACTHUNGTREN(UNG MeCN)2] (13 mg, 0.049 mmol, 0.05 equiv) was added to a stirred
solution of vinyl iodide (R)-23 (305 mg, 0.98 mmol, 1.0 equiv) and vinyl
stannane 26 (811 mg, 1.95 mmol, 2.0 equiv) in anhydrous and degassed
DMF (10 mL) at RT. After 12 h of stirring at RT, the resulting dark reac-
tion mixture was diluted with Et2O (20 mL) and poured into a saturated
aqueous NH4Cl solution (15 mL). The aqueous layer was extracted with
Et2O (3ꢃ20 mL) and the combined organic layers were washed with
brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. Pu-
rification of the residue by flash chromatography on silica gel (PE/
EtOAc 95:5 ! 90:10) provided the title (E,E)-diene (161 mg, 53%) as a
yellow oil. Rf ꢁ0.5 (PE/EtOAc 90:10); [a]2D0 = +1.2 (c = 0.95, CHCl3);
1H NMR (400 MHz, CDCl3): d=6.21 (brdd, 1H, J=15.0, 10.8 Hz), 6.05
(d, 1H, J=10.8 Hz), 5.69 (dt, 1H, J=14.9, 7.0 Hz), 4.41 (brdd, 1H, J=
7.8, 4.6 Hz), 2.95 (brs, 1H, OH), 2.52–2.41 (m, 2H), 2.09 (qapp, 2H, J=
7.2 Hz), 1.73 (s, 3H), 1.45 (s, 9H), 1.37 (m, 2H), 1.32–1.24 (m, 8H),
0.87 ppm (t, 3H, J=6.2 Hz); 13C NMR (100 MHz, CDCl3): d=172.0 (s),
135.8 (d), 135.0 (s), 125.8 (d), 125.7 (d), 81.3 (s), 73.3 (d), 41.1 (t), 33.0
(t), 31.8 (t), 29.4 (t), 29.2 (2t), 28.1 (3t), 22.7 (t), 14.1 (q), 12.5 ppm (q);
IR (neat): n˜ =3420, 2923, 2855, 1719, 1457, 1368, 1250, 1150, 1063, 841,
737 cmꢀ1; HRMS (ESI): m/z: calcd for C19H34O3Na: 333.2400; found:
333.2405 [M+Na]+.
2917, 1704, 1367, 1248, 1149, 1038, 1018, 954, 840 cmꢀ1
.
(E)-1-Iodonon-1-ene (25): A solution of DIBAL-H (313 mg, 2.2 mmol,
1.1 equiv) in anhydrous THF (1 mL) was slowly added to a stirred solu-
tion of [Cp2ZrCl2] (643 mg, 2.2 mmol, 1.1 equiv) in anhydrous THF
(5 mL) at 08C under argon. After stirring the resulting white suspension
Solid NaOH (57 mg, 1.72 mmol, 5 equiv) was added in one portion to a
stirred solution of tert-butyl (4E,6E)-(R)-3-hydroxy-4-methyltetradeca-
4,6-dienoate (89 mg, 0.287 mmol, 1.0 equiv) in MeOH/H2O (2:1, 6 mL) at
RT. The resulting mixture was heated to 708C, and stirring was carried
on for 2 h. The mixture was allowed to cool to RT, and then concentrated
under reduced pressure to remove MeOH. EtOAc (15 mL) was added
and the resulting solution was acidified with a saturated aqueous solution
of NaH2PO4 (pH 4.5, 10 mL). The layers were separated and the aqueous
phase was extracted with EtOAc (3ꢃ10 mL). The combined organic
layers were washed with brine (10 mL), dried over MgSO4, filtered and
concentrated in vacuo to provide the corresponding crude carboxylic acid
(R)-29 (72 mg, 99%) as a viscous yellow oil which was used in the next
step without further purification.
for 30 min at 08C,
a solution of non-1-yne 24 (248 mg, 2.0 mmol,
1.0 equiv) in THF (1 mL) was added dropwise. The reaction mixture was
allowed to warm to RT and stirred until a homogeneous solution (ca.
45 min) was obtained, and was then cooled to ꢀ788C. A solution of I2
(660 mg, 2.6 mmol, 1.3 equiv) in THF (3 mL) was added dropwise to the
previous solution, and after 30 min at ꢀ788C, the reaction mixture was
hydrolyzed with 1m HCl (5 mL). The aqueous layer was extracted with
Et2O (3ꢃ20 mL), and the combined organic phases were successively
washed with a saturated aqueous solution of NaHCO3 (20 mL), a saturat-
ed aqueous solution of Na2S2O3 (20 mL), and brine (20 mL) followed by
drying over MgSO4, filtration and concentration in vacuo. Purification of
the residue by flash chromatography on silica gel (100% hexanes) pro-
vided the desired 25 (449 mg, 89%) as a colorless oil. Rf ꢁ0.9 (PE);
1H NMR (400 MHz, CDCl3): d=6.51 (dt, 1H, J=14.3, 7.2 Hz), 5.97 (dt,
1H, J=14.3, 1.4 Hz), 2.05 (m, 2H), 1.38 (m, 2H), 1.32–1.22 (m, 8H),
0.88 ppm (brt, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3): d=146.8
(d), 74.3 (s), 36.1 (t), 31.8 (t), 29.2 (t), 29.0 (t), 28.4 (t), 22.7 (t), 14.1 ppm
(t); IR (neat): n˜ =2954, 2921, 2852, 1679, 1605, 1458, 1377, 1210, 1196,
944, 722, 659 cmꢀ1; MS (EI, 70 eV): m/z (%): 253 (7), 252 (68), 167 (9),
166 (36), 154 (30), 83 (60), 70 (16), 69 (100), 67 (10), 57 (19), 56 (19), 55
(60), 54 (10), 53 (10).
(+)-Methyl
(2E,4E,6E)-9-[(2S,3R)-4-(tert-butoxycarbonylamino)-3-hy-
droxy-2-methylbutanamido]nona-2,4,6-trienoate [(S,R)-30]
(ꢀ)-(5R)-tert-Butyl 5-[(1S)-1-((3E,5E,7E)-8-methoxycarbonylocta-3,5,7-
trienylcarbamoyl)ethyl]-2,2-dimethyloxazolidine-3-carboxylate:
1-Hy-
droxybenzotriazole (358 mg, 2.65 mmol, 1.2 equiv), O-(1H-benzotriazole-
1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.0 g,
2.65 mmol, 1.2 equiv) and N-methylmorpholine (728 mL, 6.62 mmol,
3.0 equiv) were successively added to a solution of carboxylic acid (S,R)-
11 (603 mg, 2.21 mmol, 1.0 equiv) and trienic amine
7 (480 mg,
2.65 mmol, 1.2 equiv) in anhydrous CH3CN (50 mL) at 08C. The solution
was allowed to warm to RT and after stirring for 6 h, the resulting brown
mixture was hydrolyzed by addition of water (25 mL). The bulk of
CH3CN was removed under reduced pressure and the resulting aqueous
layer was extracted with EtOAc (3ꢃ30 mL). The combined organic
layers were successively washed with a saturated aqueous solution of
NaHCO3 (30 mL), a saturated aqueous solution of NH4Cl (30 mL) and
brine (30 mL). The organic layer was dried over MgSO4, filtered and
evaporated to dryness under reduced pressure. The residue thus obtained
was purified by flash chromatography on silica gel (PE/EtOAc 50:50)
which provided the desired title compound (922 mg, 96%) as a waxy
Tributyl[(E)-non-1-enyl]stannane (26): tBuLi (2.56 mL, 1.7m in pentane,
4.36 mmol, 2.2 equiv) was added dropwise to a stirred solution of 25
(500 mg, 1.98 mmol, 1.0 equiv) in anhydrous Et2O (5 mL) at ꢀ788C.
After stirring at this temperature for 45 min, Bu3SnCl (537 mL,
1.98 mmol, 1.0 equiv) was slowly added dropwise and the solution was al-
lowed to warm to RT. After stirring for further 45 min, the reaction mix-
ture was hydrolyzed with an aqueous saturated solution of NH4Cl
(15 mL) and the layers were separated. The aqueous phase was extracted
with Et2O (3ꢃ15 mL) and the combined organic layers were washed with
brine (15 mL), dried over MgSO4, filtered and concentrated under re-
duced pressure. Purification of the crude residue by flash chromatogra-
phy on silica gel (hexanes/Et3N 99:1) provided the desired alkenyl stan-
nane 26 (779 mg, 95%) as a colorless oil, contaminated by unidentified
stannylated impurities. Rf ꢁ0.95 (PE); 1H NMR (400 MHz, CDCl3): d=
5.95 (dt, 1H, J=18.9, 5.9 Hz), 5.86 (d, 1H, J=18.9 Hz), 2.13 (qapp, 2H,
J=7.1 Hz), 1.54–1.45 (m, 4H), 1.36–1.26 (m, 12H), 0.92–0.86 ppm (m,
24H); 13C NMR (100 MHz, CDCl3): d=149.9 (d), 126.9 (d), 37.9 (t), 31.9
(t), 30.8 (2t), 29.3 (t), 29.1 (3t), 27.3 (3t), 22.7 (t), 14.1 (q), 13.7 (3q),
9.4 ppm (3t); IR (neat): n˜ =2954, 2920, 2844, 1599, 1463, 1376, 1071, 987,
960, 873, 863, 685, 659 cmꢀ1; HRMS (ESI): m/z: calcd for C21H45Sn:
415.2536; found: 415.2734 [M+H]+.
solid. Rf ꢁ0.2 (PE/EtOAc 50:50); [a]D20
=
ꢀ4.5 (c
= 1.36, MeOH);
1H NMR (400 MHz, CDCl3): d=7.29 (dd, 1H, J=15.2, 11.2 Hz), 6.51
(dd, 1H, J=14.8, 10.8 Hz), 6.30–6.15 (m, 2H+NH), 5.87 (m, 1H), 5.87
(d, 1H, J=15.2 Hz), 4.09 (m, 1H), 3.75 (s, 3H), 3.64 (brs, 1H), 3.37 (m,
2H), 3.11 (tapp, 1H, J=9.9 Hz), 2.37 (m, 3H, J=5.7 Hz), 1.56 (brs, 3H),
1.51 (brs, 3H), 1.47 (s, 9H), 1.14 ppm (brs, 3H); 13C NMR (100 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); IR (neat): n˜ =3424,
3338, 2978, 2938, 1693, 1658, 1616, 1542, 1392, 1367, 1253, 1140, 1007,
839 cmꢀ1; HRMS (CI+, NH3): m/z: calcd for C23H37O6N2: 437.2652;
found: 437.2643 [M+H]+.
ACHTUNGTRENNUNG(4E,6E)-(R)-3-Hydroxy-4-methyltetradeca-4,6-dienoic acid [(R)-29]
3468
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3457 – 3473

Bioactive Natural Products
FULL PAPER
p-Toluenesulfonic acid (132 mg, 0.695 mmol, 0.5 equiv) was added in one
portion to a stirred solution of the previously obtained N,O-dimethyloxa-
zolidine (609 mg, 1.39 mmol, 1.0 equiv) in MeOH (10 mL). After stirring
for 4 h at RT, the reaction mixture was hydrolyzed by addition of a satu-
rated aqueous solution of NaHCO3 (5 mL) and the resulting aqueous
layer was extracted with Et2O (3ꢃ15 mL). The combined organic layers
were successively washed with a saturated aqueous solution of NaHCO3
(15 mL), a saturated aqueous solution of NH4Cl (15 mL) and brine
(15 mL). The organic layer was dried over MgSO4, filtered and evaporat-
ed in vacuo. The obtained residue was purified by flash chromatography
on silica gel (CH2Cl2/MeOH 98:2) which provided the desired N-Boc
protected amino alcohol (S,R)-30 (451 mg, 82%) as a yellow foam. Rf
Solid LiOH (46 mg, 1.92 mmol, 20 equiv) was added in one portion to a
stirred solution of trienic ester 46 (51.1 mg, 0.096 mmol, 1.0 equiv) in
THF/MeOH/H2O (2:2:1, 12.5 mL) at 08C and the resulting yellow mix-
ture was then allowed to reach RT. After stirring for 12 h, the mixture
was concentrated under reduced pressure to remove THF and MeOH, di-
luted with EtOAc (15 mL) and acidified with a saturated aqueous solu-
tion of NaH2PO4 (pH 4.5, 10 mL). The layers were separated and the
aqueous phase was extracted with EtOAc (3ꢃ10 mL). The combined or-
ganic layers were washed with brine (10 mL), dried over MgSO4, filtered
and concentrated in vacuo to provide the corresponding crude carboxylic
acid 47 (49.1 mg, 99%) as a white solid with a satisfying level of purity.
Rf ꢁ0.15 (CH2Cl2/MeOH 90:10); [a]2D0 + 8.8 (c 1.38, MeOH) {lit.[3] [a]2D0
= +7.7 (c = 1.2, MeOH)}; 1H NMR (400 MHz, CD3OD): d=7.94 (brt,
1H, J=5.8 Hz, NH), 7.89 (brt, 1H, J=5.8 Hz, NH), 7.29 (dd, 1H, J=
15.2, 11.2 Hz), 6.60 (dd, 1H, J=14.9, 10.6 Hz), 6.32 (dd, 1H, J=14.9,
11.2 Hz), 6.31–6.22 (m, 2H), 6.04 (d, 1H, J=10.8 Hz), 5.95 (dt, 1H, J=
15.1, 7.2 Hz), 5.84 (d, 1H, J=15.2 Hz), 5.68 (dt, 1H, J=14.9, 7.0 Hz),
4.43 (dd, 1H, J=8.5, 4.8 Hz), 3.71 (m, 1H), 3.42 (dd, 1H, J=13.8,
4.0 Hz), 3.32–3.25 (m, 2H), 3.15 (dd, 1H, J=13.8, 7.0 Hz), 2.49–2.33 (m,
5H), 2.11 (qapp, 2H, J=7.0 Hz), 1.75 (s, 3H), 1.39 (m, 2H), 1.34–1.25 (m,
8H), 1.12 (d, 3H, J=7.0 Hz), 0.90 ppm (t, 3H, J=7.0 Hz); 13C NMR
(100 MHz, CD3OD): d=177.5 (s), 174.3 (s), 170.6 (s), 146.6 (d), 142.2
(d), 137.7 (d), 137.3 (s), 136.2 (d), 133.1 (d), 129.8 (d), 127.3 (d), 126.8
(d), 121.6 (d), 75.1 (d), 73.3 (d), 45.4 (d), 44.5 (t), 43.2 (t), 39.7 (t), 34.0
(t), 33.9 (t), 33.6 (t), 30.6 (t), 30.3 (2t), 23.7 (t), 15.2 (q), 14.5 (q),
12.4 ppm (t); IR (neat): n˜ =3306, 2922, 2853, 1685, 1617, 1551, 1458,
1435, 1364, 1238, 1141, 1006, 965, 886, 675 cmꢀ1; HRMS (ESI): m/z: calcd
for C29H46O6N2Na: 541.3248; found: 541.3257 [M+Na]+.
1
ꢁ0.25 (CH2Cl2/MeOH 98:2); [a]2D0 = +11.3 (c = 1.04, CHCl3); H NMR
(400 MHz, CDCl3): d=7.29 (dd, 1H, J=15.2, 11.2 Hz), 6.52 (dd, 1H, J=
14.9, 10.8 Hz), 6.40 (brm, 1H, NH), 6.25 (dd, 1H, J=15.1, 11.2 Hz), 6.21
(dd, 1H, J=15.3, 10.8 Hz), 5.87 (d, 1H, J=15.2 Hz), 5.86 (m, 1H), 5.0
(brm, 1H, NH), 4.16 (m, 1H), 3.75 (s, 3H), 3.64 (brm, 1H, OH), 3.42–
3.28 (m, 3H), 3.08 (m, 1H), 2.42–2.28 (m, 3H), 1.44 (s, 9H), 1.25 ppm (d,
3H, J=7.1 Hz); 13C NMR (100 MHz, CDCl3): d=175.6 (s), 167.5 (s),
156.8 (s), 144.7 (d), 140.5 (d), 135.9 (d), 133.0 (d), 128.7 (d), 120.2 (d),
79.6 (s), 73.5 (d), 51.5 (q), 45.0 (t), 43.2 (d), 38.5 (t), 33.0 (t), 28.3 (3q),
15.5 ppm (q); IR (neat): n˜ =3307, 2978, 2932, 1714, 1662, 1639, 1620,
1534, 1247, 1233, 1171, 1137, 1002, 729 cmꢀ1; HRMS (CI+, NH3): m/z:
calcd for C20H33O6N2: 397.2339; found: 397.2343 [M+H]+.
(+)-Methyl (2E,4E,6E)-9-{(2S,3R)-4-[(4E,6E)-(R)-3-hydroxy-4-methylte-
tradeca-4,6-dienoylamino]2-methylbutyrylamino}nona-2,4,6-trienoate
(46): Trifluoracetic acid (1 mL) was added dropwise to a stirred solution
of carbamate (S,R)-30 (133 mg, 0.335 mmol, 1.0 equiv) in anhydrous
CH2Cl2 (4 mL) at 08C. The resulting brown mixture was allowed to warm
to RT, and after 45 min of stirring the solution was concentrated in
vacuo. The ammomium trifluoroacetate thus obtained was used in the
next step without further purification.
(ꢀ)-(13E,15E,17E)-(2R,7R,8S)-7-Hydroxy-8-methyl-2-[(1E,3E)-1-methyl-
undeca-1,3-dienyl]-1-oxa-5,10-diazacyclononadeca-13,15,17-triene-4,9,19-
trione [FR252921 (2b)]: A solution of seco-acid 47 (42 mg, 0.081 mmol,
1.0 equiv) in THF (10 mL) was added via syringe pump over 20 h to a so-
lution of 2-methyl-6-nitrobenzoic anhydride (84 mg, 0.243 mmol,
3.0 equiv) and 4-DMAP (33 mg, 0.292 mmol, 3.6 equiv) in THF
(130 mL). After 96 h of stirring at RT, the reaction mixture was hydro-
lyzed by adding water (25 mL). The layers were separated and the aque-
ous phase was extracted with EtOAc (3ꢃ20 mL). The combine organic
layers were washed with brine (50 mL) dried over Na2SO4, filtered and
concentrated under reduced pressure. Purification of the residue by flash
chromatography on silica gel (CH2Cl2/MeOH 20:1 to 95:5) furnished
1-Hydroxybenzotriazole (50 mg, 0.368 mmol, 1.1 equiv), O-(1H-benzo-
triazole-1-yl)-N,N,N’,N’-tetramethyluronium
hexafluorophosphate
(140 mg, 0.368 mmol, 1.1 equiv) and N-methylmorpholine (110 mL,
1.01 mmol, 3.0 equiv) were successively added to a solution of the ammo-
nium trifluoroacetate previously obtained (0.335 mmol, 1.0 equiv) and
carboxylic acid (R)-29 (85 mg, 0.335 mmol, 1.0 equiv) in anhydrous
CH3CN (15 mL) at 08C. The mixture was allowed to reach RT, and after
6 h of stirring, the resulting brown mixture was hydrolyzed by adding
water (5 mL). CH3CN was evaporated under reduced pressure and
EtOAc (15 mL) was added. After decantation, the aqueous layer was ex-
tracted with EtOAc (3ꢃ15 mL). The combined organic layers were suc-
cessively washed with a saturated aqueous solution of NaHCO3 (15 mL),
a saturated aqueous solution of NH4Cl (15 mL) and brine (15 mL). The
organic layer was dried over MgSO4, filtered and evaporated to dryness
under reduced pressure. The residue thus obtained was purified by flash
chromatography on silica gel (CH2Cl2/MeOH 95:5) which provided the
desired diamide 46 (138 mg, 78% over 2 steps) as a yellow foam. Rf
ꢁ0.15 (CH2Cl2/MeOH 90:10); [a]2D0 = 11.2 (c = 1.55, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.26 (dd, 1H, J=15.2, 11.3 Hz), 6.93 (brm, 1H,
NH), 6.65 (brt, 1H, J=5.7 Hz, NH), 6.49 (dd, 1H, J=14.8, 10.7 Hz), 6.21
(dd, 1H, J=14.8, 11.3 Hz), 6.21–6.12 (m, 2H), 6.04 (d, 1H, J=11.1 Hz),
5.85 (d, 1H, J=15.2 Hz), 5.84 (m, 1H), 5.68 (dt, 1H, J=14.9, 7.0 Hz),
4.67 (m, 1H, OH), 4.41 (brd, 1H, J=7.0 Hz), 3.95 (brs, 1H, OH), 3.72
(s, 3H), 3.71 (m, 1H), 3.59 (ddd, 1H, J=11.3, 7.2, 4.1 Hz), 3.30 (m, 2H),
3.01 (ddd, 1H, J=12.6, 7.6, 4.7 Hz), 2.48–2.26 (m, 5H), 2.07 (qapp, 2H,
J=7.1 Hz), 1.71 (s, 3H), 1.34 (m, 2H), 1.31–1.21 (m, 8H), 1.19 (d, 3H,
J=7.0 Hz), 0.86 ppm (t, 3H, J=7.1 Hz); 13C NMR (100 MHz, CDCl3):
d=175.7 (s), 172.9 (s), 167.6 (s), 144.7 (d), 140.4 (d), 136.0 (d), 135.8 (d),
135.4 (s), 132.0 (d), 128.9 (d), 125.6 (d), 125.5 (d), 120.4 (d), 73.7 (d), 72.9
(d), 51.5 (q), 44.1 (t), 43.7 (d), 41.7 (t), 38.6 (t), 33.0 (2t), 31.9 (t), 29.4 (t),
29.2 (2t), 22.7 (t), 15.5 (q), 14.1 (q), 12.6 ppm (t); IR (neat): n˜ =3305,
14.8 mg of
a yellow oil containing multiple products according to
1H NMR analysis. The residue was re-purified by preparative TLC (SiO2,
CHCl3/MeOH 92:8) which yielded 1.9 mg of FR252921 (2b) contaminat-
ed by an unidentified impurity. Further purification by analytic HPLC
using a Kromasil 100 C18 5mm (Bios Analytique, Higgins Analytical)
column, (CH3CN/H2O 50:50 ! 80:20) allowed to obtain FR252921 (2b)
as a white solid (ꢁ1 mg) in pure form. Rf ꢁ0.55 (CHCl3/MeOH 10:1);
[a]2D0 has been measured but is not reliable on such a small quantity
(msample < 1 mg). Its sign was (ꢀ). {lit.[2] [a]D20 = ꢀ222 (c=0.2, DMSO)};
1H NMR (500 MHz, DMSO): d=7.93 (brt, 1H, J=4.6 Hz, NH), 7.72
(brt, 1H, J=6.0 Hz, NH), 7.31 (dd, 1H, J=15.3, 11.3 Hz), 6.95 (dd, 1H,
J=14.6, 11.7 Hz), 6.41 (dd, 1H, J=14.7, 11.3 Hz), 6.27–6.20 (m, 2H),
5.97 (brd, 1H, J=10.8 Hz), 5.80 (m, 1H), 5.79 (d, 1H, J=15.3 Hz), 5.69
(dt, 1H, J=15.0, 7.1 Hz), 5.23 (dd, 1H, J=11.1, 3.1 Hz), 5.00 (brs, 1H,
OH), 3.60 (m, 1H), 3.50–3.28 (m, 1H), 3.28–3.23 (m, 1H), 3.11–3.04 (m,
1H), 2.82 (ddd, 1H, J=13.2, 8.5, 4.3 Hz), 2.69 (dd, 1H, J=13.9, 11.3 Hz),
2.49–2.41 (m, 1H), 2.38 (dd, 1H, J=14.0, 3.4 Hz), 2.35–2.24 (m, 2H),
2.08 (brqapp, 2H, J=7.0 Hz), 1.71 (s, 3H), 1.36 (m, 2H), 1.33–1.20 (m,
8H), 0.94 (d, 3H, J=7.2 Hz), 0.87 ppm (t, 3H, J=7.0 Hz); 13C NMR
(125 MHz, DMSO): d=173.6 (s), 169.0 (s), 164.9 (s), 144.9 (d), 136.7 (d),
135.2 (d), 135.1 (d), 133.1 (s), 130.0 (d), 129.8 (d), 125.7 (d), 125.1 (d),
120.4 (d), 75.6 (d), 71.5 (d), 44.5 (d), 42.6 (t), 39.9 (t), 38.4 (t), 32.3 (t),
31.2 (t), 28.8 (t), 28.6 (t), 28.5 (2t), 22.1 (t), 13.9 (q), 12.8 (q), 12.3 ppm
(q); HRMS (ESI): m/z: calcd for C29H45N2O5: 501.3328; found: 501.3317
[M+H]+.
2923, 2854, 1717, 1641, 1618, 1546, 1434, 1262, 1234, 1137, 1006, 966 cmꢀ1
;
HRMS (ESI): m/z: calcd for C30H48O6N2Na: 555.3405; found: 555.3409
[M+Na]+.
(E)-4-Tributylstannylpent-3-en-1-ol (49): nBuLi (2.5m in THF, 30.5 mL,
76.1 mmol, 8.0 equiv) was added dropwise to a suspension of CuCN
(3.41 g, 38.1 mmol, 4.0 equiv) in THF (100 mL) at ꢀ788C. The solution
was warmed to ꢀ658C and was stirred 10 min at this temperature to give
(+)-(2E,4E,6E)-9-{(2S,3R)-4-[(4E,6E)-(R)-3-Hydroxy-4-methyltetradeca-
4,6-dienoylamino]-2-methylbutyrylamino}nona-2,4,6-trienoic acid (47):
Chem. Eur. J. 2009, 15, 3457 – 3473
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3469

J. Cossy et al.
a homogeneous, colorless solution. The reaction mixture was cooled
down to ꢀ788C and tri-n-butyltin hydride (20.5 mL, 76.1 mmol,
8.0 equiv) was added dropwise (the solution becomes yellow). After
10 min at ꢀ788C, methanol (56.5 mL, 150 equiv) was added. The solution
was warmed to ꢀ408C (the mixture becomes red) and pent-3-yn-1-ol
(48) (877 mL, 9.51 mmol, 1.0 equiv) was added dropwise. After 15 h of
stirring at ꢀ408C, the reaction mixture was hydrolyzed by adding a satu-
rated aqueous solution of NH4Cl containing 10% of aqueous ammoniac
(200 mL). The cold bath was removed and a vigorous stirring was main-
tained for 30 min. The mixture was then filtered over Celite, and the
aqueous phase was extracted with EtOAc (3ꢃ100 mL). The combined or-
ganic layers were washed with brine (100 mL), dried over MgSO4, fil-
tered and concentrated under reduced pressure. Purification of the resi-
bromide (0.5m in THF, 3.9 mL, 25 mmol, 1.0 equiv) in THF (50 mL) at
08C. After 12 h of stirring at RT, the reaction mixture was poured into a
saturated aqueous solution of NH4Cl (30 mL) cooled down to 08C. The
aqueous phase was extracted with ether (3ꢃ30 mL) and the combined or-
ganic layers were washed with brine, dried over MgSO4, filtered and con-
centrated under reduced pressure. Purification of the residue by flash
chromatography on silica gel (PE/EtOAc 95:5 ! 90:10) furnished prop-
argylic alcohol 54 (3.11 g, 81%) as a colorless oil. Rf ꢁ0.5 (PE/EtOAc
85:15); 1H NMR (400 MHz, CDCl3): d=4.37 (td, 1H, J=6.7, 2.1 Hz),
2.46 (d, 1H, J=2.1 Hz), 1.88 (brs, 1H, OH), 1.71 (m, 2H), 1.45 (m, 2H),
1.36–1.22 (m, 8H), 0.88 ppm (brt, 3H, J=7.0 Hz); 13C NMR (100 MHz,
CDCl3): d=85.0 (s), 72.8 (s), 62.3 (d), 37.7 (t), 31.8, 29.2 and 25.0 (4t),
22.7 (t), 14.1 ppm (q); IR (neat): n˜ =3311, 2922, 2855, 1464, 1378, 1118,
1045, 1021, 651, 625 cmꢀ1; MS (EI, 70 eV): m/z (%): 125 (1), 121 (5), 107
(16), 97 (16), 95 (8), 94 (9), 93 (25), 91 (8), 84 (9), 83 (33), 81 (17), 80
(15), 79 (46), 77 (10), 70 (57), 69 (19), 68 (14), 67 (16), 57 (100), 56 (26),
55 (80), 53 (10).
due by flash chromatography on silica gel (pentane/EtOAc 100:0
!
85:15) furnished vinyl stannane 49 (2.37 g, 67%) and its regioisomer 50
(264 mg, 7%) both as a colorless oil. The physical and spectra data for 49
were in accordance with those reported in the literature.[44] Rf ꢁ0.6 (PE/
EtOAc 85:15); 1H NMR (400 MHz, CDCl3): d=5.51 (brtq, 1H, J=7.0,
1.8 Hz), 3.65 (q, 2H, J=6.4 Hz), 2.42 (brq, 2H, J=6.5 Hz), 2.31 (brd,
3H, J=1.2 Hz), 1.52–1.43 (m, 6H+OH), 1.30 (sextapp, 6H, J=7.3 Hz),
0.88 ppm (t, 15H); 13C NMR (100 MHz, CDCl3): d=142.4 (s), 135.7 (d),
62.2 (t), 31.7 (t), 29.2 (3t), 27.4 (3t), 19.3 (q), 13.7 (3q), 7.5 ppm (3t); IR
(neat): n˜ =3317, 2955, 2922, 2871, 2852, 1611, 1462, 1376, 1043, 1020, 874,
1-Bromodec-1-yn-3-ol (55): N-Bromosuccinimide (1.28 g, 7.21 mmol,
1.1 equiv) and silver nitrate (111 mg, 0.656 mmol, 0.1 equiv) were succes-
sively added to a solution of alkyne 54 (1.01 g, 6.56 mmol, 1.0 equiv) in
acetone (20 mL) at RT. After 12 h of stirring in the dark, the reaction
mixture was filtrated over Celite. The Celite was successively washed
with water and acetone (3ꢃ30 mL) and the bulk of acetone was evapo-
rated under reduced pressure. Ethyl acetate (50 mL) was then added and
the aqueous phase was extracted with EtOAc (3ꢃ30 mL). The combined
organic layers were washed with brine (30 mL), dried over MgSO4, fil-
tered and concentrated in vacuo. Purification of the residue by flash
chromatography on silica gel (PE/EtOAc 95:5 ! 90:10) furnished the
bromoalkyne 55 (1.43 g, 93%) as a colorless oil. Rf ꢁ0.6 (PE/EOAc
90:10); 1H NMR (400 MHz, CDCl3): d=4.37 (brt, 1H, J=6.3 Hz), 2.17
(brs, 1H, OH), 1.69 (m, 2H), 1.42 (m, 2H), 1.35–1.20 (m, 8H), 0.88 ppm
(brt, 3H, J=6.3 Hz); 13C NMR (100 MHz, CDCl3): d=81.2 (s), 63.5 (d),
45.0 (s), 37.6 (t), 31.8 (t), 29.2 (2t), 25.0 (t), 22.6 (t), 14.1 ppm (q); IR
863, 686, 660 cmꢀ1
.
(E)-4-Iodopent-3-en-1-ol (51): I2 (1.73 g, 6.79 mmol, 1.5 equiv) was added
in one portion to a solution of vinyl stannane 49 (1.7 g, 4.53 mmol,
1.0 equiv) in Et2O (100 mL) at 08C. After 30 min at 08C and 2 h at RT,
the reaction mixture was hydrolyzed by adding a 1m aqueous solution of
KF (10 mL) and acetone (10 mL). The mixture was vigorously stirred for
2 h at RT, then filtered over Celite. The aqueous phase was extracted
with AcOEt (3ꢃ50 mL) and the combined organic layers were succes-
sively washed with a saturated aqueous solution of Na2S2O3 (50 mL),
brine (50 mL) then dried over MgSO4, filtered and concentrated under
reduced pressure. Purification of the residue by flash chromatography on
silica gel (pentane/Et2O 100:0 ! 50:50) furnished the vinyl iodide 51
(899 mg, 94%) as a yellow oil. The physical and spectral properties of
compound 51 were in accordance with those described in the literature.[45]
Rf ꢁ0.25 (PE/EtOAc 85:15); 1H NMR (400 MHz, CDCl3): d=6.19 (tq,
1H, J=7.5, 1.5 Hz), 3.65 (t, 2H, J=6.4 Hz), 2.41 (brq, 3H, J=1.3 Hz),
2.31 (qapp, 2H, J=6.6 Hz), 1.90 (brs, 1H, OH); 13C NMR (100 MHz,
CDCl3): d=137.1 (d), 96.2 (s), 61.4 (t), 34.0 (t), 27.8 (q); HRMS (CI+,
CH4): m/z: calcd for C5H9OI: 211.9698; found: 211.9695 [M+H]+.
(neat): n˜ =3303, 2921, 2854, 1707, 1458, 1377, 1046, 1019, 909, 725 cmꢀ1
;
MS (EI, 70 eV): m/z (%): 233 (1) [M]+, 177 (2), 175 (2), 163 (3), 161 (4),
150 (12), 148 (14), 136 (8), 135 (100), 133 (99), 107 (10), 105 (8), 97 (32),
95 (11), 93 (15), 91 (8), 83 (19), 82 (14), 81 (12), 79 (18), 69 (21), 67 (16),
57 (45), 55 (35).
(E)-1-Tributylstannyldec-1-en-3-ol
(56):
[PdCl
G
(139 mg,
0.198 mmol, 0.05 equiv) and tri-n-butyltin hydride (4.25 mL, 15.81 mmol,
4.0 equiv) in THF (20 mL) were successively added to a solution of bro-
moacetylene 55 (921 mg, 3.95 mmol, 1.0 equiv) in THF (100 mL) at 08C.
After 4 h of stirring at this temperature, the reaction mixture was concen-
trated under reduced pressure. Purification of the residue by flash chro-
matography on silica gel (pentane/EtOAc 100:0 ! 96:45) provided the
vinyl stannane 56 (1.23 g, 70%) as a colorless oil. Rf ꢁ0.5 (PE/EtOAc
90:10); 1H NMR (400 MHz, CDCl3): d=6.12 (dd, 1H, J=19.1, 0.8 Hz),
5.99 (dd, 1H, J=19.2, 5.5 Hz), 4.06 (m, 1H), 1.57–1.45 (m, 8H), 1.36–
1.23 (m, 14H + OH), 0.92–0.85 (m, 11H), 0.89 ppm (t, 9H, J=7.2 Hz);
13C NMR (100 MHz, CDCl3): d=151.1 (d), 127.6 (d), 75.7 (d), 37.0 (t),
31.8 (t), 29.6 (t), 29.3 (t), 29.1 (3t), 27.3 (3q), 25.4 (t), 22.7 (t), 14.1 (q),
13.7 (3q), 9.5 ppm (3t); IR (neat): n˜ =3321, 2955, 2921, 1601, 1463, 1377,
(E)-4-Iodopent-3-enoic acid (52): Preparation of Jones reagent
CrO3·H2SO4: Sulfuric acid (500 mL, 11 mmol, 2 equiv) was added drop-
wise to CrO3 (570 mg, 5.5 mmol, 1 equiv) at 08C. At the end of the addi-
tion, water (2 mL) was added and the mixture was allowed to warm to
RT.
A solution of freshly prepared Jones reagent (650 mL, 3.0 equiv) was
added dropwise to
a solution of alcohol 51 (100 mg, 0.472 mmol,
1.0 equiv) in acetone at 08C. After 30 min of stirring at this temperature,
methanol (1.5 mL) was slowly added at 08C. The reaction mixture was
filtered over Celite to remove the chromium salts and the filtrate was
concentrated under reduced pressure. Water (10 mL) and EtOAc
(10 mL) were added, and the aqueous phase was extracted with AcOEt
(3ꢃ10 mL). The combined organic layers were washed with brine
(10 mL), dried over MgSO4, filtered and concentrated under reduced
pressure. Purification of the residue by flash chromatography on silica gel
(PE/EtOAc 90:10) furnished carboxylic acid 52 (98 mg, 92%) as a yellow
oil which recrystallized upon standing in the fridge at ꢀ208C. Rf ꢁ0.15
(PE/EtOAc 70:30); 1H NMR (400 MHz, CDCl3): d=11.26 (brs, 1H,
COOH), 6.31 (tq, 1H, J=7.2 Hz and J=1.5 Hz), 3.10 (dq, 2H, J=7.5,
0.9 Hz), 2.40 ppm (brd, 3H, J=1.3 Hz); 13C NMR (100 MHz, CDCl3):
d=176.6 (s), 131.1 (d), 97.5 (s), 35.3 (t), 27.8 ppm (q); IR (neat): n˜ =
2916, 2847, 1705, 1639, 1617, 1422, 1377, 1293, 1217, 1169, 1085, 1057,
821 cmꢀ1; HRMS (CI+, CH4): m/z: calcd for C5H7O2I: 225.9491; found:
225.9491 [M]+.
1071, 1045, 989, 908, 735 cmꢀ1
; HRMS (ESI): m/z: calcd for
C22H46ONaSn: 469.2467; found: 469.2461 [M+Na]+.
(+)-Methyl (2E,4E,6E)-9-[(2S,3R)-3-hydroxy-4-((E)-4-iodopent-3-enami-
do)-2-methylbutanamido]nona-2,4,6-trienoate (57): Trifluoracetic acid
(2 mL) was added dropwise to a stirred solution of carbamate (S,R)-30
(123 mg, 0.310 mmol, 1.0 equiv) in anhydrous CH2Cl2 (8 mL) at 08C. The
resulting brown mixture was allowed to warm to RT, and after 45 min of
stirring, the solution was concentrated in vacuo. The ammonium trifluoro-
acetate thus obtained was diluted with CHCl3 (10 mL), treated by a satu-
rated aqueous solution of Na2CO3 (10 mL) and the aqueous layer was
vigorously extracted with CHCl3 (3ꢃ10 mL). The combined organic
layers were washed with brine (20 mL), dried over MgSO4, filtered and
concentrated under reduced pressure to provide the corresponding free
amine (91 mg, 100%) as a viscous brown oil, which was used in the next
step without further purification.
Dec-1-yn-3-ol (54): A solution of octanal 53 (3.9 mL, 25 mmol, 2.0 equiv)
in THF (10 mL) was added dropwise to a solution of ethynylmagnesium
3470
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3457 – 3473

Bioactive Natural Products
FULL PAPER
1-Hydroxybenzotriazole (46 mg, 0.338 mmol, 1.1 equiv), O-(1H-benzo-
over MgSO4, filtered and concentrated in vacuo. Purification of the resi-
due by preparative TLC (SiO2, CH2Cl2/MeOH 90:10) provided pseudo-
trienic acid B (1b) (5 mg, 75%) as a colorless oil. The physical and spec-
tral properties of 1b were in agreement with those reported in the litera-
ture.[1] Rf ꢁ0.1 (CH2Cl2/MeOH 90:10); [a]2D0 = +4.8 (c = 0.17, MeOH)
{lit.[1] [a]D20 +1.9 (c = 0.4, CHCl3)}; 1H NMR (400 MHz, CD3OD): d=
7.28 (dd, 1H, J=15.8, 11.6 Hz), 6.60 (dd, 1H, J=14.8, 10.5 Hz), 6.32 (dd,
1H, J=14.4, 11.6 Hz), 6.27 (dd, 1H, J=15.3, 8.8 Hz), 6.26 (d, 1H, J=
15.3 Hz), 5.95 (brdt, 1H, J=14.8, 7.4 Hz), 5.86 (d, 1H, J=14.4 Hz), 5.65
(dd, 1H, J=15.3, 6.5 Hz), 5.63 (brt, 1H, J=7.9 Hz), 4.08 (qapp, 1H, J=
7.0 Hz), 3.71 (brdt, 1H, J=7.4, 4.6 Hz), 3.41 (dd, 1H, J=14.4, 3.3 Hz),
3.29 (m, 2H), 3.16 (brdd, 1H, J=14.4, 6.0 Hz), 3.13 (d, 2H, J=7.4 Hz),
2.43–2.30 (m, 3H, J=7.0 Hz), 1.80 (m, 3H), 1.60–1.45 (m, 2H), 1.39–1.25
(m, 10H), 1.14 (d, 3H, J=7.4 Hz), 0.91 ppm (t, 3H, J=7.0 Hz);
13C NMR (100 MHz, CD3OD): d=177.2 (s), 174.1 (s), 170.5 (s), 146.0
(d), 141.7 (d), 137.3 (s), 137.2 (d), 135.0 (d), 132.8 (d), 132.1 (d), 129.5
(d), 124.8 (d), 121.6 (d), 73.4 (d), 73.0 (d), 45.4 (d), 44.3 (t), 39.3 (t), 38.3
(t), 36.2 (t), 33.6 (t), 32.7 (t), 30.5 (t), 30.4 (t), 26.3 (t), 23.4 (t), 14.8 (q),
14.1 (q), 12.6 ppm (q); IR (neat): n˜ =3296, 2926, 2856, 1741, 1640, 1548,
1390, 1350, 1233, 1139, 1112, 1006, 702 cmꢀ1; HRMS (ESI): m/z: calcd for
C29H46O6N2Na: 541.3248; found: 541.3241 [M+Na]+.
triazole-1-yl)-N,N,N’,N’-tetramethyluronium
hexafluorophosphate
(128 mg, 0.338 mmol, 1.1 equiv) and N-methylmorpholine (101 mL,
0.921 mmol, 3.0 equiv) were successively added to a solution of the previ-
ously obtained amine (91 mg, 0.307 mmol, 1.0 equiv) and carboxylic acid
52 (70 mg, 0.307 mmol, 1.0 equiv) in CH3CN (15 mL) at 08C. After 6 h of
stirring at RT, the resulting brown mixture was hydrolyzed by adding
water (5 mL). The bulk of CH3CN was removed under reduced pressure,
and the aqueous phase was extracted with EtOAc (3ꢃ20 mL). The com-
bined organic layers were successively washed with a saturated aqueous
solution of NaHCO3 (15 mL), a saturated aqueous solution of NH4Cl
(15 mL), brine (15 mL) then dried over MgSO4, filtered and concentrated
in vacuo. Purification of the residue by flash chromatography on silica
gel (CH2Cl2/MeOH 98:2) furnished diamide 57 (121 mg, 79%) as a color-
less oil. Rf ꢁ0.2 (CH2Cl2/MeOH 98:2); [a]2D0 + 6.93 (c 0.88, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.28 (dd, 1H, J=15.3, 11.3 Hz), 6.78
(brm, 1H, NH), 6.57 (brm, 1H, NH), 6.52 (dd, 1H, J=14.9, 10.8 Hz),
6.31 (brt, 1H, J=7.5 Hz), 6.25 (dd, 1H, J=14.9, 11.3 Hz), 6.20 (dd, 1H,
J=15.4, 10.8 Hz), 5.87 (d, 1H, J=15.3 Hz), 5.87 (m, 1H), 4.61 (m, 1H),
3.74 (s, 3H), 3.66 (brm, 1H, OH), 3.51 (ddd, 1H, J=11.5, 6.6, 4.2 Hz),
3.34 (m, 2H), 3.12 (ddd, 1H, J=12.5, 7.5, 4.9 Hz), 2.97 (d, 2H, J=
7.5 Hz), 2.40 (s, 3H), 2.40–2.31 (m, 3H), 1.24 ppm (d, 3H, J=7.0 Hz);
13C NMR (100 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); IR (neat): n˜ =3293, 2930, 1711, 1639, 1616, 1541, 1433,
1263, 1233, 1136, 1004, 732, 618 cmꢀ1; HRMS (CI+, NH3): m/z: calcd for
C20H30O5N2I: 505.1199; found: 505.1195 [M+H]+.
Acknowledgements
We wish to thank the Sociꢂtꢂ de Chimie Thꢂrapeutique/SERVIER for fi-
nancial support of this work. We also wish to acknowledge Professor
J. R. Falck and Dr. A. He (University of Texas Southwestern Medical
Center) for helpful discussions and for providing NMR spectra of some
intermediates. Dr. K. Fujine (Fujisawa Pharmaceutical, Inc.) is greatly ac-
knowledged for providing NMR data of the natural product. We are
grateful to Dr. Sablꢂ and Dr. Herman from Sanofi-Aventis (Vitry sur
Seine) for helping in the purification of FR252921.
(+)-Methyl
methyltetradeca-3,5-dienamido]-2-methylbutanamido}nona-2,4,6-trien-
oate (58): [PdCl2A(MeCN)2] (5 mg, 0.02 mmol, 0.05 equiv) was added to a
(2E,4E,6E)-9-{(2S,3R)-3-hydroxy-4-[(3E,5E)-7-hydroxy-4-
CHTUNGTRENNUNG
solution of vinyl iodide 57 (205 mg, 0.406 mmol, 1.0 equiv) and vinyl stan-
nane 56 (270 mg, 0.609 mmol, 1.2 equiv) in DMF (10 mL) degassed with
argon. After 12 h of stirring at RT and in the dark, the reaction mixture
was diluted with Et2O (50 mL) and then poured into a saturated aqueous
solution of NH4Cl (30 m). The aqueous phase was extracted with Et2O
(3ꢃ50 mL) and the combined organic layers were washed with brine
(30 mL), dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was first filtered over a plug of silica gel (3 cm) on
top of which was added solid KF beforehand to remove stannylated im-
purities, and then purified by flash chromatography on silica gel (CH2Cl2/
MeOH 98:2) to give 58 (111 mg, 51%) as a viscous yellow oil which re-
crystallized upon standing in the fridge at ꢀ788C. Rf ꢁ0.1 (CH2Cl2/
MeOH 98:2); [a]2D0 = +7.37 (c = 0.38, CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.22 (dd, 1H, J=15.2, 11.2 Hz), 6.45 (dd, 1H, J=14.7,
10.7 Hz), 6.29 (m, 1H, NH), 6.20 (d, 1H, J=15.7 Hz), 6.20–6.04 (m, 2H+
NH), 5.81 (m, 1H), 5.80 (d, 1H, J=15.2 Hz), 5.62 (dd, 1H, J=15.6,
6.8 Hz), 5.53 (brt, 1H, J=7.6 Hz), 4.33 (d, 1H, J=5.9 Hz, OH), 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 (qapp, 2H, J=6.8 Hz), 2.22 (m, 1H), 1.70 (s, 3H), 1.55–1.40 (m,
2H), 1.30–1.15 (m, 10H +OH), 1.18 (d, 3H, J=7.6 Hz), 0.81 ppm (t, 3H,
J=6.7 Hz); 13C NMR (100 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); IR (neat): n˜ =3308, 2956, 2927,
[1] A. Pohanka, A. Broberg, M. Johansson, L. Kenne, J. Levenfors, J.
Nat. Prod. 2005, 68, 1380–1385.
[2] a) K. Fujine, M. Tanaka, K. Ohsumi, M. Hashimoto, S. Takase, H.
Ueda, M. Hino, T. Fujii, J. Antibiot. 2003, 56, 55–61; b) K. Fujine, F.
Abe, N. Seki, H. Ueda, M. Hino, T. Fujii, J. Antibiot. 2003, 56, 62–
67; c) K. Fujine, H. Ueda, M. Hino, T. Fujii, J. Antibiot. 2003, 56,
68–71.
[3] J. R. Falck, A. He, H. Fukui, H. Tsutsui, A. Radha, Angew. Chem.
2007, 119, 4611–4613; Angew. Chem. Int. Ed. 2007, 46, 4527–4529.
[4] For
a preliminary communication on the total synthesis of
FR252921, see: D. Amans, V. Bellosta, J. Cossy, Org. Lett. 2007, 9,
4761–4764.
[5] For a preliminary communication on the total synthesis of pseudo-
trienic acid B, see: D. Amans, V. Bellosta, J. Cossy, Angew. Chem.
2006, 118, 6002–6006; Angew. Chem. Int. Ed. 2006, 45, 5870–5874.
[6] S. Yu, F. Liu, D. Ma, Tetrahedron Lett. 2006, 47, 9155–9157.
[7] L. Ferriꢂ, D. Amans, S. Reymond, V. Bellosta, P. Capdevielle, J.
Cossy, J. Organomet. Chem. 2006, 691, 5456–5465.
[8] J. S. Kingsbury, J. P. A. Harrity, P. J. Bonitatebus, Jr., A. H. Hoveyda,
J. Am. Chem. Soc. 2000, 122, 8168–8179.
[9] The bromodiene 4 was contaminated by traces of mono- and poly-
unsaturated w-bromoesters, inseparable by flash chromatography on
silica gel.
2856, 1720, 1646, 1619, 1546, 1459, 1435, 1271, 1137, 1074, 1007, 739 cmꢀ1
;
HRMS (CI+, NH3): m/z: calcd for C30H49O6N2: 533.3591; found: 533.3597
[M+H]+.
(+)-(2E,4E,6E)-9-{(2S,3R)-3-Hydroxy-4-[(3E,5E)-7-hydroxy-4-methylte-
tradeca-3,5-dienamido]-2-methylbutanamido}nona-2,4,6-trienoic
acid
[10] D. A. Powell, R. A. Batey, Org. Lett. 2002, 4, 2913–2916.
[11] A. Hafner, R. O. Duthaler, R. Marti, J. Rihs, P. Rhote-Streit, F.
Schwarzenbach, J. Am. Chem. Soc. 1992, 114, 2321–2336.
[12] The enantiomeric excess and the absolute configuration of the asym-
metric carbon bearing the hydroxy substituent in compound (R,R)-
[pseudotrienic acid B (1b)]: LiOH (6 mg, 0.263 mmol, 20 equiv) was
added in one portion to a solution of methyl ester 58 (7 mg, 0.013 mmol,
1.0 equiv) in THF/MeOH/H2O (2:2:1, 2 mL) at 08C. After 12 h of stirring
at RT, the reaction mixture was concentrated under reduced pressure to
remove THF and MeOH. The resulting solution was diluted with EtOAc
(3 mL) and acidified by adding a saturated aqueous solution of NaH2PO4
(pH 4.5, 3 mL). The aqueous phase was extracted with EtOAc (3ꢃ5 mL)
and the combined organic layers were washed with brine (5 mL), dried
1
10 were confirmed by the H NMR spectra of the two corresponding
mandelates, following the procedure described by: J. M. Seco, E.
QuiÇoa, R. Riguera, Tetrahedron: Asymmetry 2001, 12, 2915–2925.
The R configuration of the other stereogenic center is deduced by
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J. Cossy et al.
the anti-relationship between the hydroxy and methyl substituents,
inferred by the crotyltitanation reaction.
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[24] The enantiomeric excess and the absolute configuration of 23 were
[13] a) A. V. Statsuk, D. Liu, S. A. Kozmin, J. Am. Chem. Soc. 2004, 126,
9546–9547; b) P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharp-
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1
confirmed by the H NMR spectra of the two corresponding mande-
lates; see ref. [12].
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[14] The crotyltitanium complexes of Z configuration are not stable and
isomerize, upon fast allylic metallotropic equilibrium, into crotylic
complexes of E configuration, giving rise to the corresponding anti
diastereoisomer.
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under Yamaguchi conditions was reported by Ma et al.[6] The
1H NMR data reported for the resulting macrolactone 44 turn out to
[15] H. C. Brown, K. S. Bhat, J. Am. Chem. Soc. 1986, 108, 5919–5923.
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1
confirmed by the H NMR spectra of the two corresponding mande-
lates, following the procedure described by Seco et al., see ref. [12].
[18] It has been shown that the enzymatic reduction of the corresponding
terminal alkyne, in similar conditions, would deliver the (S)-enantio-
mer of the b-hydroxyester 14; see: M. H. Ansari, T. Kusumoto, T.
Hiyama, Tetrahedron Lett. 1993, 34, 8271–8274.
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ꢀ
be also consistent with an isomerization of the C2 C3 double bond
into a (Z)-olefin and correspond to the (2Z,12R,13R,18R)-isomer of
FR252921.
´
[32] a) A. Fꢄrstner, C. Aꢅssa, C. Chevrier, F. Teply, C. Nevado, M. Trem-
blay, Angew. Chem. 2006, 118, 5964–5969; Angew. Chem. Int. Ed.
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´
Tremblay, C. Chevrier, F. Teply, C. Aꢅssa, E. Moulin, O. Mꢄller, J.
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5768–5796.
[33] In order to propose a rationalization for the isomerization of the
ꢀ
C2 C3 double bond, the mechanism depicted in the following
Scheme can be suggested. After formation of the mixed anhydride
36, nucleophilic attack of 4-DMAP at the C3 position of the trienic
ester would generate, after elimination of 2,4,6-trichlorobenzoate,
ketene 45 existing under various conformations. The attack of the
alcohol at C18 on conformer 45 would generate two epimeric eno-
3472
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Chem. Eur. J. 2009, 15, 3457 – 3473

Bioactive Natural Products
FULL PAPER
lates, which after elimination of 4-DMAP would give rise to the for-
mation of either the desired (2E,4E,6E) trienic lactone 35 or lactone
37 possessing the (2Z,4E,6E)-configuration. Similarly, conformer 45’
could also provide access to both isomeric lactones 35 and 37. The
transition state energy of this elimination would determine the
double bond stereochemistry in a kinetically controlled process. Al-
ternatively, 4-DMAP could catalyze the interconversion of the
(E) and (Z)-isomers 35 and 37 via the same enolate intermediates,
in which case a thermodynamic argument would prevail.
the natural product. Presumably, as for seco-acid 47, dilution phe-
nomena associated with inter- or intramolecular hydrogen bonding
may explain these differences observed by NMR spectroscopy.
[38] The 1H NMR spectrum shows an estimated purity of ca. 95% for
compound 2b.
[39] J.-F. Betzer, A. Pancrazi, Synlett 1998, 1129–1131.
[40] a) H. X. Zhang, F. Guibꢂ, G. Balavoine, J. Org. Chem. 1990, 55,
1857–1867; b) C. D. J. Boden, G. Pattenden, T. Ye, J. Chem. Soc.
Perkin Trans. 1 1996, 2417–2419.
[34] See Experimental Section for spectra.
[41] The 1H NMR spectrum shows an estimated purity of ca. 90% for
compound 1b.
[35] a) I. Shiina, M. Kubota, R. Ibuka, Tetrahedron Lett. 2002, 43, 7535–
7539; b) I. Shiina, M. Kubota, H. Oshiumi, M. Hashizume, J. Org.
Chem. 2004, 69, 1822–1830.
[42] A. V. Statsuk, D. Liu, S. A. Kozmin, J. Am. Chem. Soc. 2004, 126,
9545–9547.
[36] Under the same conditions, Falck et al. have isolated FR252921 in
10% yield by reverse phase chromatography.
[43] Z. Tan, E-i. Negishi, Org. Lett. 2006, 8, 2783–2785.
[44] L. Commeiras, S. Maurice, J.-L. Parrain, Org. Lett. 2001, 3, 1713–
1716.
[45] V. Fargeas, P. le Mꢂnez, I. Berque, J. Ardisson, A. Pancrazi, Tetrahe-
dron 1996, 52, 6613–6634.
[37] Some differences in the chemical shift of certain ethylenic protons
were observed by 1H and 13C NMR spectroscopy. However, the
value of the coupling constants and the splitting pattern of the
triene moiety were absolutely consistent with the presence of a
triene of (E,E,E)-configuration. Furthermore, the obtained spectra
are in accordance with the structure proposed by Fujine et al. for
Received: December 17, 2008
Published online: February 13, 2009
Chem. Eur. J. 2009, 15, 3457 – 3473
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3473