Total synthesis of laulimalide: Assembly of the fragments and completion of the synthesis of the natural product and a potent analogue

Article abstract of DOI:10.1002/chem.201102899

Herein, we present a full account of our efforts to couple the northern and the southern building blocks, the synthesis of which were described in the preceding paper, along with the modifications required to ultimately lead to a successful synthesis of laulimalide. Key highlights include an exceptionally efficient and atom-economical intramolecular ruthenium-catalyzed alkene-alkyne coupling to build the macrocycle, followed by a highly stereoselective 1,3-allylic isomerization promoted by a rhenium complex. Interestingly, the designed synthetic route also allowed us to prepare an analogue of the natural product that possesses significant cytotoxic activity. We also report a second generation route that provides a more concise synthesis of the natural product. All in one piece: Efforts to couple the northern and southern building blocks, synthesized in the preceding paper, along with modifications required to lead to a successful synthesis of laulimalide are discussed. Interestingly, the designed synthetic route also allowed the preparation of an analogue of the natural product that possesses significant cytotoxic activity (see scheme). A more concise, second-generation route to the natural product is also described. Copyright

Full text of DOI:10.1002/chem.201102899

FULL PAPER
DOI: 10.1002/chem.201102899
Total Synthesis of Laulimalide: Assembly of the Fragments and Completion
of the Synthesis of the Natural Product and a Potent Analogue
Barry M. Trost,* Dominique Amans, W. Michael Seganish, and Cheol K. Chung[a]
Abstract: Herein, we present a full ac-
count of our efforts to couple the
northern and the southern building
blocks, the synthesis of which were de-
scribed in the preceding paper, along
with the modifications required to ulti-
mately lead to a successful synthesis of
laulimalide. Key highlights include an
exceptionally efficient and atom-eco-
nomical intramolecular ruthenium-cat-
alyzed alkene–alkyne coupling to build
the macrocycle, followed by a highly
stereoselective 1,3-allylic isomerization
promoted by a rhenium complex. Inter-
estingly, the designed synthetic route
also allowed us to prepare an analogue
of the natural product that possesses
significant cytotoxic activity. We also
report a second generation route that
provides a more concise synthesis of
the natural product.
Keywords: alkene–alkyne coupling ·
laulimalide · rhodium · ruthenium ·
total synthesis · vinylidene com-
plexes
Introduction
cess, the transformation proved to be synthetically challeng-
ing, as outlined in Table 1. Classical esterification methods,
such as Steglich conditions[1] (N,N’-dicyclohexylcarbodiimide
(DCC)/DMAP) and related protocols or conversion of the
carboxylic acid into an acyl chloride[2] or acyl fluoride[3] fol-
lowed by addition of alcohol 2, all failed to give the desired
ester 4. The use of the Ghosez reagent[4] (Table 1, entry 1)
proved to be efficient in providing a coupling product,
which, in fact, turned out to be exclusively allene 6 with no
trace of the desired coupling product 4. We believed that
acidic conditions would be best suited because these would
prevent the formation of the allene. We therefore attempted
the esterification by using the conditions described by Kita
et al. (Table 1, entry 2),[5] which unfortunately did not pro-
vide the desired ester 4. Transesterification between the
methyl ester of 3 and alcohol 2 in the presence of the Otera
catalyst[6] provided the desired ester 4, albeit in low yield
(Table 1, entry 3). The use of the Shiina mixed anhydride[7]
(Table 1, entry 4) was disappointing because it only yielded
traces of the coupling product, as judged by TLC. The best
result was obtained by using the Yonemitsu modification[8]
of the Yamaguchi protocol[9] (Table 1, entry 5), which yield-
ed ester 4 in an 18% yield.
In the preceding paper, we described the synthesis of the
two required fragments (2 and 3) for our synthesis of lauli-
malide (1). The preparation of these fragments highlights
the use of our dinuclear-zinc catalyst (R,R)-I to install the
two contiguous stereogenic centers bearing hydroxy groups
in a syn relationship on the northern fragment 2 and the uti-
lization of a rhodium-catalyzed cycloisomerization to elabo-
rate the dihydropyran moiety of the southern fragment 3
(Scheme 1). Herein, we report our efforts to utilize these
building blocks for the synthesis of laulimalide and the
modifications of the southern fragment needed to complete
the synthesis. In addition, we report a second-generation
route that shortens the overall synthesis.
Results and Discussion
At this juncture, we were in a favorable position to explore
the coupling between the two fragments 2 and 3 to obtain
enyne 4, thus, setting the stage for the crucial macrocycliza-
tion step through an intramolecular ruthenium-catalyzed
alkene–alkyne coupling reaction (4!5; Scheme 2). Al-
though this esterification seemed, at first, to be a trivial pro-
Despite the lack of an efficient protocol to achieve this
esterification, these disappointing attempts allowed us to
collect sufficient material to investigate the crucial rutheni-
um-catalyzed alkene–alkyne coupling reaction. Gratifyingly,
exposure of enyne 4 to [CpRuACTHNUTRGENNUG(CH3CN)3]AHCTUGNTERNN[UNG PF6] (10 mol%) in
[a] Prof. B. M. Trost, Dr. D. Amans, Dr. W. M. Seganish,
Dr. C. K. Chung
acetone at 508C resulted in the stereo-, regio-, and chemose-
lective formation of the desired branched 1,4-diene 5, as a
single diastereoisomer in 36% yield (not optimized). From
Department of Chemistry, Stanford University
Stanford, California, 94305-5080 (USA)
Fax : (+1)650-725-0002
1
the H NMR analysis of the crude reaction mixture, which
E-mail: bmtrost@stanford.edu
revealed complete consumption of the starting material and
nearly exclusive formation of the desired product, we be-
lieve that this transformation occured in a much higher yield
(Scheme 3).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102899. It contains detailed
experimental procedures and full characterization of compounds 4, 5,
16, 21–31, and 33.
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Scheme 1. Completed northern and southern fragments (PMB=para-methoxybenzyl, MOM=methoxymethyl).
Scheme 2. Proposed esterification and intramolecular alkene–alkyne coupling.
Table 1. Attempts at esterification.[a]
Scheme 3. Intramolecular
i) [CpRu(MeCN)3][PF6] (10 mol%), acetone, 508C, 5 h, c=0.001m (Cp=
cyclopentadienyl).
Ru-catalyzed
alkene–alkyne
coupling.
A
ACHTUNGTRENNUNG
Conditions
Results ([%])
At this point in our synthesis, the frustrating esterification
clearly needed to be addressed because our ruthenium-cata-
lyzed strategy to form the macrocycle had proven to be
viable. We reasoned that a slight modification of our strat-
egy could help us to reach our goal. Accordingly, the (Z)-
alkene at C2–C3 could be installed by performing an inter-
molecular Still–Gennari olefination between the b-keto-
phosphonate 8 and the aldehyde 10, both fragments being,
in principle, readily available from the previously synthe-
sized compounds 2 and 9, respectively (Scheme 4).
The coupling between the previously obtained alcohol 2
and carboxylic acid 7 under Yamaguchi conditions proceed-
ed uneventfully to give the required b-ketophosphonate 8 in
near quantitative yield (Scheme 5). It is believed that the
facile acylation of sterically hindered alcohol 2 involves the
in situ formation of a more reactive ketene intermediate
from phosphonoacetic acid 7, facilitated by the presence of
a strongly electron-withdrawing substituent in the a position
of the carboxylic acid group.[10] The required aldehyde 10
was successfully obtained through a highly diastereoselective
Ferrier-type addition of tert-butyldimethylsilyl vinyl ether
onto vinylogous acetal 9 in the presence of Montmorillonite
i) 3,
6;
35
1
2
ii) 2, Et3N, CH2Cl2
i) 3, ethyl ethynyl ether,
[{RuCl2(para-cymene)}2]
(5 mol%), toluene
ii) 2, CSA (10 mol%), DCE
2, methyl ester of 3, MS
(4 ꢁ), toluene, 1108C
ethoxy vinyl ester formed (TLC)
no esterification
3
13
3, 2, DMAP, Et3N, CH2Cl2,
4
5
traces of 4 by TLC
3, 2, 2,4,6-trichlorobenzoyl-
chloride, Et3N, DMAP, THF
18
[a] CSA=camphorsulphonic acid, DCE=dichloroethane, MS=molecu-
lar sieves, DMAP=4-dimethylaminopyridine.
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Total Synthesis of Laulimalide and a Potent Analogue
FULL PAPER
Scheme 5. Synthesis of b-ketophosphonate 8 and aldehyde 10. i) 7, 2,4,6-
trichlorobenzoyl chloride, iPr2EtN, THF; ii) DMAP, benzene; iii) tert-bu-
tyldimethylsilyl vinyl ether, Montmorillonite K-10, CH2Cl2.
strikingly, only 15 min were required to transform enyne 11
into macrolactone 12 in a chemo-, regio-, and stereoselective
fashion. Importantly, exclusive formation of the E stereoiso-
mer of the newly formed C15–C16 allylic double bond
1
within the macrocycle was observed according to H NMR
analysis (JH15 H16 =16 Hz), which would set the stage for the
ꢀ
subsequent installation of the required trans-epoxide. It is
worth noting that no isomerization of the (Z)-alkene at C2–
1
C3 could be detected as judged by H NMR spectroscopy. In
addition, the core reaction is highly atom economical, and
the solvent is easily recoverable and can be recycled because
the workup involves simple removal of the solvent by evap-
oration, making the process reasonably eco-friendly.
Scheme 4. Revised retrosynthetic analysis (Bn=benzyl).
This intramolecular alkene–alkyne coupling deserves
some attention as to its mechanistic rationale. It has previ-
ously been stipulated that coordination of the ruthenium
catalyst to both the alkene and the alkyne (A) would lead
to an oxidative cyclization, giving rise to the ruthenacyclo-
pentene B, which in turn would undergo a syn b-hydride
K-10 (82% yield).[11] This produced the desired product with
the required anti relationship for the dihydropyran moiety
formed, as confirmed by the absence of a nOe between the
H5 and H9 protons (Scheme 5).
With the two required fragments in hand, the Still–Gen-
nari olefination could be implemented (Scheme 6). Conden-
sation of the potassium salt of phosphonate 8 with aldehyde
10, in the presence of 18-crown-
elimination to yield the vinylruthenium species
C
(Scheme 7).[12] Reductive elimination of the latter would ul-
6, gave rise to the formation of
the desired alkene 11 as a 1:5
mixture of E/Z isomers, which
could be easily separated by
flash column chromatography
on silica gel. To our delight, the
subsequent key intramolecular
alkene–alkyne
reaction proceeded
coupling
extra-
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
(10 mol%) in acetone at 508C
generated the desired branched
1,4-diene 12 in a spectacular
Scheme 6. Still–Gennari olefination and Ru-catalyzed alkene–alkyne coupling. i) potassium hexamethyldisil-
azide (KHMDS), 18-crown-6, THF, ꢀ788C; ii) [CpRu
ACHUTNGTERNG(NU MeCN)3]ACHTUNGTREN[NUGN PF6] (10 mol%), acetone, 508C, 10 min, c=
99% yield (Scheme 6). More 0.001m.
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B. M. Trost et al.
timately provide the branched 1,4-diene 12 with regenera-
tion of the [CpRu(CH3CN)3][PF6] catalyst. It is worth men-
tioning that, in this case, the coordination (Scheme 7, A)
and subsequent cyclization (Scheme 7, B) occurs such that
With macrocycle 12 in hand, we were in a favorable posi-
tion to tackle the envisaged Payne rearrangement. To this
end, removal of the MOM protecting group proceeded
smoothly in tBuOH in the presence of PPTS to give allylic
alcohol 13 in a 66% yield. A hydroxyl-directed, diastereose-
lective Sharpless epoxidation[15] of 13 in the presence of
(+)-DET ultimately gave the trans-epoxide 14 as a single
diastereoisomer (Scheme 8). The stage was now set to probe
the challenging Payne rearrangement, which should, in prin-
ciple, after removal of the PMB group, lead to the natural
product laulimalide.
G
ACHTUNGTRENNUNG
Scheme 8. Synthesis of the epoxyalcohol precursor of laulimalide. i) pyri-
dinium para-toluenesulfonate (PPTS), tBuOH, 858C, 8 h; ii) (+)-diethyl-
tartrate ((+)-DET), TiACHTUNTRGNE(UNG iPrO)4, tert-butylhydroperoxide (TBHP), CH2Cl2,
Scheme 7. Proposed catalytic cycle for the Ru-catalyzed alkene–alkyne
coupling. i) [CpRuACHTUNGTRENNUNG(MeCN)3]ACHUTNGTREN[NGUN PF6] (5 mol%), acetone, 508C, 10 min, c=
ꢀ208C; iii) Payne rearrangement; iv) 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ).
0.001m.
As summarized in Table 2, various conditions were inves-
tigated to promote the formation of the Payne-rearranged
product 15. In the initial report by Payne,[16] it is stated that
the epoxide migration works best by using sodium hydrox-
ide in an aqueous solution. Interestingly, under these condi-
tions and after one hour at room temperature, no saponifi-
cation of the lactone, isomerization of the (Z)-alkene or for-
mation of the desired Payne-rearrangement product were
observed. An alternative approach, involving the formation
of the trimethylsilyl ether of the starting epoxyalcohol 14
upon exposure to bis(trimethylsilyl)trifluoroacetamide
(BSTFA), followed by treatment with a fluoride source,
such as tris(dimethylamino)sulfonium difluorotrimethylsili-
cate (TAS-F; Table 2, entry 3), also failed to generate any
Payne-rearranged product. Finally, epoxyalcohol 14 was ex-
posed to sodium hydride in THF at 08C, which resulted in
the formation of a new product by TLC. However, spectro-
scopic analysis (1H NMR, COSY) indicated the formation of
the ring-contracted lactone 16, in 50% yield (95% based on
recovered starting material (BRSM)), resulting from an in-
tramolecular attack of the alkoxy group a to the epoxide
onto the ester functionality (Table 2, entry 4). This last
result discouraged us from pursuing this transformation be-
the group attached to the terminal alkyne is opposite the
ruthenium, thus, giving rise exclusively to the desired
branched 1,4-diene 12. On the path to such branched prod-
ꢀ
ucts, steric interactions occuring during the C C bond-form-
ing event and cyclization lead to the kinetically favored
ruthenacycle B. As it can be assumed that the ruthencyclo-
pentene formation is fast and reversible,[12] the product is
only determined at the b-hydride elimination step, which is
presumably slower than the ruthenacyclopentene formation.
As b-hydride elimination is favored on the path toward the
branched product, the latter is generally favored with mono-
substituted alkenes and terminal alkynes, which explains the
regioselectivity obtained in our case.[12] The formation of
highly functionalized macrocycles, which highlights the che-
moselectivity of this reaction, has also been illustrated in the
case of the synthesis of amphidinolide A by our group,
albeit with lower efficiency.[13] The synthesis of pinnatoxi-
n A[14] through this method, in which the alkene–alkyne
macrocyclization proceeded in 79% yield, further illustrates
the power of the Ru-catalyzed coupling reaction and repre-
sents a new technique to form macrocycles in an atom-eco-
nomical fashion.
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Total Synthesis of Laulimalide and a Potent Analogue
Table 2. Attempts at the Payne rearrangement.
FULL PAPER
secondary allylic selenoxide to
perform the aforementioned
transformation since, after ex-
posure of the allylic alcohol 13
to a phenylselenol under Mitsu-
nobu-type conditions, the allyl
selenide 18 would be obtained
with inversion of configuration
(Scheme 10).[18] Oxidation of
the phenyl selenide 18 to the
corresponding selenoxide 19
should set the stage for a [2,3]-
sigmatropic shift, leading to the
desired rearranged allylic alco-
hol 17. Unfortunately, the use
of standard Mitsunobu-type
conditions (2-nitrophenylsele-
nol, trimethyl or tributylphos-
phine, THF) failed to convert
allylic alcohol 13 into the corre-
sponding selenide product 18
and the starting material was
recovered.
Conditions
Results ([%])
1
2
tBuOK, tBuOH, RT, 20 min
NaOH, H2O, Et2O, RT, 1 h
i)
decomposition
no rearrangement
starting material
+unidentified product
3
ii) Si
THF, RT, 45 min
ACHTUNGTRENNUNG HCATUNGTREN(NUNG CH3)2]3 (TAS-F),
(CH3)3F2ꢁ ꢂS[N
4
NaH, THF, 08C, 30 min
16 (50)
cause the formation of the ring-contracted lactone seemed
to be thermodynamically favored over the formation of the
desired translocated epoxyalcohol 15 under basic conditions.
Being unable to perform the epoxide translocation as
planned in our retrosynthetic analysis necessitated the de-
velopment of a new strategy that would allow us to obtain
laulimalide (1). We anticipated that a selective 1,3-isomeri-
zation of the previously prepared allylic alcohol 13 would
give rise to the rearranged allylic alcohol 17, allowing us to
access laulimalide (1; Scheme 9).
A number of chemical transformations that, in principle,
can provide the rearranged allylic alcohol 17 from 13, for-
mally through a 1,3-allylic transposition, have been de-
scribed in the literature.[17] We first attempted to utilize a
Scheme 10. 1,3-Allylic transposition by using an allylic selenoxide.
i) ArSeCN (Ar=ortho-NO2Ph), PR3 (R=Bu or Me), THF; ii) H2O2, pyr-
idine.
It has been shown that the isomerization of allylic alco-
hols by 1,3 transposition of the hydroxy group can be cata-
lyzed by a number of high oxidation state transition-metal
oxo complexes, such as vanadium, tungsten, molybdenum,
and rhenium complexes.[19] Rhenium oxo catalysts have sev-
eral advantages over the other metal complexes. They are
active at low temperatures and do not undergo reduction at
the metal center by the alcohol, which usually causes a loss
of catalytic activity over time (as in the case of Mo).[19] Ap-
plying the rhenium oxo catalysis conditions developed by
Osborn et al.,[20] and extensively utilized by Grubbs et al., to
Scheme 9. 1,3-Allylic transposition: a revised strategy.
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B. M. Trost et al.
allylic alcohol 13,[21] which involve the highly active triphe-
nylsilyl perrhenate complex [O3ReOSiPh3],[22] resulted in
the formation of the rearranged product 20 in good yield,
with retention of configuration in the product (Scheme 11).
sis of laulimalide as it would avoid the oxidation/CBS-reduc-
tion sequence. To that end, the required b-ketophosphonate
28 was prepared by using the same strategy as for the syn-
thesis of its epimer 8, starting from the known homoallylic
alcohol 21 (derived from commercially available (R)-tosyl-
glycidol; Scheme 12).[26] Protection of 21 as a MOM ether,
followed by cleavage of the 1,3-dithiane acetal under stan-
dard conditions gave b-hydroxyaldehyde 22 (63% yield over
2 steps), setting the stage for the direct zinc-catalyzed aldol
reaction by using a-hydroxyacetyl 2-ethylpyrrole 23. Grati-
fyingly, the use of (R,R)-dinuclear zinc catalyst I (15 mol%)
gave rise to the formation of the syn-1,2-diol 24 in a 10:1
d.r., in 53% isolated yield. This result further demonstrates,
as highlighted in the preceding paper, that the dinuclear
zinc-aldol reaction proceeds with catalyst control as the ste-
reochemistry of the remote allylic alcohol protected as a
MOM ether on substrate 22 has no influence on the stereo-
chemical outcome of the obtained syn-1,2-diol 24. Protec-
tion of the 1,2-diol as a PMP acetal, followed by cleavage of
the acylpyrrole by using sodium borohydride in THF, afford-
ed primary alcohol 25 in 70% yield (over 2 steps). Oxida-
tion of 25 with the Dess–Martin periodinane gave rise to the
corresponding aldehyde, which was treated with the lithium
salt of sulfone 26 in a THF/HMPA mixture to give the cor-
responding alkene as a single (E)-geometric isomer. Regio-
selective opening of the PMP acetal upon treatment with
DIBAL-H provided the desired secondary alcohol 27. The
coupling between alcohol 27 and carboxylic acid 7 under
Yamaguchi conditions ultimately furnished the desired b-ke-
tophosphonate 28 in excellent yield (Scheme 12).
Scheme 11. Completion of the synthesis of laulimalide. i) [O3ReOSiPh3]
(1 equiv), Et2O, ꢀ508C, 5 min; ii) Dess—Martin periodinane; iii) (R)-
CBS (Corey–Bakshi–Shibata), BH3·THF; iv) (+)-DET, TiACHTUNTGRNENG(U iPrO)4, TBHP,
molecular sieves (4 ꢁ), CH2Cl2, ꢀ208C; v) DDQ, CH2Cl2/H2O.
We found the optimum conditions to be the use of one
equivalent of the rhenium complex for 5 min in Et2O at
ꢀ508C, obtaining the rearranged allylic product 20, which
was easily separated from the starting material 13 by flash
column chromatography on silica gel, in 78% yield
(97% BRSM). Inversion of the C15 stereogenic center by
using an oxidation/Corey–Bakshi–Shibata (CBS)-reduc-
tion[23] sequence allowed us to
Condensation of the potassium salt of phosphonate 28
with aldehyde 10, in the presence of 18-crown-6, gave rise to
the formation of the desired alkene 29 as a 1:5 mixture of E/
Z isomers, which could be easily separated by flash column
chromatography on silica gel (Scheme 13). The subsequent
obtain the desired epimeric al-
lylic alcohol 17. Epoxidation of
the allylic alcohol under Sharp-
less conditions, followed by
DDQ deprotection ultimately
completes the synthesis of lauli-
malide 1. Spectral and physical
data for the synthetic sample
were in complete agreement
with those reported in the liter-
ature for the natural prod-
uct.[24,25]
A potential improvement in
the synthesis would be to use
the epimer at C17 of allylic al-
cohol 13 initially. This epimer
should indeed directly provide
Scheme 12. Synthesis of b-ketophosphonate 28. i) MOMCl, CH2Cl2; ii) MeI, CaCO3, MeCN/H2O, 45 8C, 3 h;
iii) 23, (R,R)-I (15 mol%), THF, 12 h, RT; iv) para-anisaldehyde dimethyl acetal, CSA, CH2Cl2, RT; v) NaBH4,
THF (PMP=para-methoxyphenyl); vi) Dess–Martin periodinane, CH2Cl2; vii) sulfone 26, LiHMDS, DMF/hex-
amethylphosphoramide (HMPA; 3:1), ꢀ358C to RT; viii) diisobutylaluminum hydride (DIBAL-H), CH2Cl2,
intermediate 17 under the rhe-
nium oxo-catalysis conditions
described above and therefore
provide a more efficient synthe- ꢀ78 to 08C; ix) 7, 2,4,6-trichlorobenzoyl chloride, iPr2EtN, THF, then DMAP, benzene.
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Total Synthesis of Laulimalide and a Potent Analogue
FULL PAPER
intramolecular alkene–alkyne coupling proceeded with
through an SN2-type attack of the hydroxy group situated on
the lateral chain at C20 onto the epoxide at C17, thus, lead-
ing to the formation of isolaulimalide (32; Scheme 14).
exceptional
efficiency,
in
the
presence
of
A
R
ACHTUNGTRENNUNG
the desired branched 1,4-diene 30 almost instantaneously in
98% yield. Removal of the MOM protecting group under
mild acidic conditions finally provided the desired allylic al-
cohol 31.
With compound 31 in hand, the crucial rhenium-catalyzed
allylic transposition could be investigated. Allylic alcohol 31
was therefore exposed to the triphenylsilyl perrhenate cata-
lyst [O3ReOSiPh3] under identical conditions to those used
for its epimer 13 (Et2O at ꢀ508C for 5 min). To our dismay,
the equilibrium between the two regioisomers 17 (product)
and 31 (starting material) in this case lay towards the start-
1
Scheme 14. Acid-catalyzed conversion of laulimalide into isolaulimalide.
ing material 31, as judged by H NMR analysis of the crude
mixture (17/31=1:4), since prolonged reaction times did not
improve this ratio further (Scheme 13). Furthermore, the
two regioisomers 17 and 31 could not be separated by flash
column chromatography on silica gel. The separation was,
therefore, performed by using HPLC on an achiral column
and successfully provided 16% of the desired allylic alcohol
17 (formal synthesis), along with 62% recovered starting
material 31 (50% BRSM).
In the original isolation along with laulimalide (1; IC50 =
7 nm), isolaulimalide 32 was isolated, but the latter possesses
significantly diminished activity in comparison with its con-
gener (IC50 =20000 nm). It was shown that under mild acidic
conditions laulimalide (1) is prone to furan formation
This observation undoubtedly indicates that there is a
need to synthesize new analogues designed in such a way
that prevents the furan formation, but at the same time re-
tains a similar or even improved activity to laulimalide. Our
synthesis of laulimalide provided an opportunity to access a
novel analogue. Accordingly, we performed the PMB depro-
tection of compound 14 by exposing it to DDQ, which led
to the formation of laulimalide analogue 33 (Scheme 15).
We were happy to note that our analogue displayed signifi-
cant activity against Granta 519 and Jurkat cell lines with an
IC50 of 200 and 182 nm, respectively.[27] Even though this an-
alogue displays inferior potency
to that of laulimalide, it shows
much better activity than iso-
laulimalide and possesses en-
hanced stability over the natu-
ral product laulimalide as furan
formation is no longer possible.
Conclusion
By using several atom-economi-
cal transformations, such as a
rhodium-catalyzed cycloisome-
rization reaction to form the
endocyclic trans-dihydropyran,
an enantio- and diastereoselec-
tive zinc-catalyzed glycolate
aldol reaction to prepare the
syn-1,2-diol, and an exception-
ally efficient ruthenium-cata-
lyzed alkene–alkyne coupling
reaction to build the macrocy-
cle, we were able to obtain a
novel biologically active ana-
logue of laulimalide 33. Re-
markably, this analogue dis-
Scheme 13. Completion of the synthesis of laulimalide through a shorter route. i) KHMDS, 18-crown-6, THF,
(MeCN)3][PF6] (5 mol%), acetone, 508C, 15 min, c=0.001m; iii) PPTS, tBuOH, 858C, 8h;
iv) [O3ReOSiPh3] (1 equiv), Et2O, ꢀ508C.
played
nanomolar
potency
ꢀ788C; ii) [CpRu
G
ACHTUNGTRENNUNG
against some cancer cell lines.
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B. M. Trost et al.
2-{(2R,6R)-6-[(S)-2-Methylpent-4-ynyl]-5,6-dihydro-2H-pyran-2-yl}ace-
taldehyde (10): Montmorillonite K-10 (70 mg) was added in one portion
to
a
solution of dihydropyrane
9 (64 mg, 0.237 mmol) and tert-
butyldimethylAHCTUNGTRENNUNG
(vinyloxy)silane[29] (75 mg, 0.473 mmol) in CH2Cl2 (1 mL)
at 08C. The cold bath was removed and the resulting slurry was stirred
for 45 min at RT. The reaction mixture was then filtered through cotton
and the resulting crude residue was purified by flash column chromatog-
raphy on silica gel (petroleum ether/EtOAc=95:5 to 90:10) to provide
aldehyde 10 (40 mg, 82%) as a colorless oil. IR (neat): n˜ =3294, 3034,
2959, 2924, 2727, 1725, 1459, 1431, 1391, 1260, 1214, 1179, 1096, 804,
701 cmꢀ1 1H NMR (600 MHz, CDCl3): d=9.81 (dd, J=3.6, 1.8 Hz, 1H),
;
5.88 (ddt, J=10.2, 14.8, 2.4 Hz, 1H), 5.69 (m, 1H), 4.79 (m, 1H), 3.75 (m,
1H), 2.74 (ddd, J=16.2, 9.0, 3.6 Hz, 1H), 2.54 (ddd, J=16.2, 4.8, 1.8 Hz,
1H), 2.17 (ddd, J=16.8, 6.0, 3.0 Hz, 1H), 2.12 (ddd, J=16.8, 6.6, 3.0 Hz,
1H), 2.03 (m, 1H), 1.98–1.87 (m, 2H), 1.96 (t, J=3.0 Hz, 1H), 1.72 (ddd,
J=14.4, 10.2, 4.2 Hz, 1H), 1.28 (ddd, J=14.4, 9.6, 3.6 Hz, 1H), 0.99 ppm
(d, J=6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=198.6, 125.4, 123.2,
80.6, 67.1, 65.4, 63.4, 45.6, 38.8, 28.5, 28.4, 26.0, 24.2 ppm; HRMS (ESI):
m/z calcd for C13H18O2Na: 229.1207 [M+Na]+; found: 229.1204.
Scheme 15. Synthesis of a potent laulimalide analogue. i) DDQ, CH2Cl2/
H2O.
The application of a 1,3-allylic isomerization promoted by a
rhenium complex ultimately allowed us to synthesize the
natural product laulimalide (1). This work clearly demon-
strates that the development of new methodologies within
our laboratories allowed for a very efficient synthesis of lau-
limalide but also, conversely, that the inherent synthetic
challenges arising from the natural product truly served as a
springboard for the development of new methodologies. The
latter point was thoroughly illustrated in the preceding
paper by the work conducted around the dinuclear zinc cat-
alysis to form the syn-1,2-diol by using, for the first time, a
donor partner at the carboxylic acid oxidation state.
(Z)-{(3S,4S,6R,E)-3-(4-Methoxybenzyloxy)-6-(methoxymethoxy)-1-[(S)-
4-methyl-3,6-dihydro-2H-pyran-2-yl]nona-1,8-dien-4-yl}-4-{(2R,6R)-6-
[(S)-2-methylpent-4-ynyl]-5,6-dihydro-2H-pyran-2-yl}but-2-enoate (11):
KHMDS (0.35m in THF) was added to a mixture of phosphonate 8
(146 mg, 0.204 mmol) and 18-crown-6 (247 mg, 0.934 mmol) in THF
(7 mL) at ꢀ788C. After 45 min at this temperature, a solution of alde-
hyde 10 (35 mg, 0.1698 mmol) in THF (3.5 mL) was added dropwise and
the mixture was stirred for 25 min. The reaction mixture was hydrolyzed
by adding saturated aqueous ammonium chloride. Ethyl acetate was
added and the layers were separated. The aqueous phase was extracted
with EtOAc and the combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo. 1H NMR spec-
troscopy of the crude residue indicated the quantitative formation of the
desired alkene as a 1:5 mixture of E/Z geometric isomers. Purification of
the crude residue by flash column chromatography on silica gel (petrole-
um ether/EtOAc=95:5 to 80:20) furnished the desired Z isomer 11
(56 mg, 50%) as a colorless oil, along with some of the undesired E
isomer (14 mg, 12%; combined yield: 62%) as a colorless oil. Excess
Experimental Section
phosphonate 8 was entirely recovered (23 mg, 92% recovery). [a]D25
=
(3S,4S,6R,E)-3-(4-Methoxybenzyloxy)-6-(methoxymethoxy)-1-[(S)-4-
methyl-3,6-dihydro-2H-pyran-2-yl]nona-1,8-dien-4-yl-2-[bis(2,2,2-trifluo-
ACHTUNGTRENNUNGroethoxy)phosphoryl]acetate (8): Alcohol 2 (65 mg, 0.150 mmol) and 2-
ꢀ73.3 (c=1.18 in CHCl3); IR (neat): n˜ =3294, 3032, 2927, 1717, 1643,
1613, 1514, 1439, 1380, 1364, 1300, 1248, 1212, 1168, 1093, 1037, 918,
819 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.21 (m, 2H), 6.84 (m, 2H),
;
[bis(2,2,2-trifluoroethoxy)phosphoryl]acetic acid[28] (105 mg, 0.346 mmol)
were azeotroped together three times with toluene in a round-bottom
flask. Then, THF (15 mL), iPr2NEt (120 mL, 0.690 mmol), and 2,4,6-tri-
chlorobenzoylchloride (68 mL, 0.435 mmol) were added sequentially at
RT. The resulting mixture was stirred for 10 min at RT. The solvent was
removed in vacuo and the residue was dissolved in benzene (15 mL).
DMAP (126 mg, 1.035 mmol) was added in one portion at RT and the re-
sulting white suspension was stirred for 2 h. The mixture was then diluted
with EtOAc and the resulting solution was successively washed with satu-
rated aqueous sodium bicarbonate, KHSO4 (1m), and brine. The organic
layer was dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatography on
6.42 (ddd, J=11.5, 7.5, 6.5 Hz, 1H), 5.88 (dt, J=11.5, 2.0 Hz, 1H), 5.81
(m, 1H), 5.76 (m, 1H), 5.67 (m, 1H), 5.59 (ddd, J=16.0, 7.0, 1.8 Hz, 1H),
5.42 (brm, 1H), 5.24 (ddd, J=10.0, 5.0, 2.5 Hz, 1H), 5.09–5.04 (m, 2H),
4.64 (d, J=7.0 Hz, 1H), 4.58 (d, J=7.0 Hz, 1H), 4.57 (d, J=12.0 Hz,
1H), 4.31 (d, J=12.0 Hz, 1H), 4.27 (brm, 1H), 4.18 (m, 2H), 4.05 (m,
1H), 3.87 (m, 1H), 3.80–3.74 (m, 1H), 3.79 (s, 3H), 3.55 (m, 1H), 3.34 (s,
3H), 2.97 (dddd, J=16.5, 8.0, 4.5, 2.0 Hz, 1H), 2.88 (dddd, J=16.0, 9.5,
6.5, 2.0 Hz, 1H), 2.33–2.28 (m, 2H), 2.21 (ddd, J=16.5, 5.5, 2.5 Hz, 1H),
2.12 (ddd, J=17.0, 7.0, 3.0 Hz, 1H), 2.07–1.85 (m, 5H), 1.96 (t, J=3.5 Hz,
1H), 1.78–1.66 (m, 3H), 1.70 (s, 3H), 1.31–1.21 (m, 2H), 0.98 ppm (d, J=
7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=165.9, 159.3, 147.5, 135.4,
134.4, 131.5, 130.5, 129.7, 129.2 (2C), 127.1, 124.9, 121.0, 119.9, 117.8,
113.9 (2C), 96.7, 83.4, 79.5, 74.4, 73.6, 72.3, 71.2, 70.5, 69.6, 65.8, 65.6,
56.0, 55.5, 41.7, 40.1, 35.9, 35.6, 33.8, 31.4, 28.8, 26.8, 23.2, 19.1 ppm;
HRMS (ESI): m/z calcd for C40H54O8Na: 685.3716 [M+Na]+; found:
685.3715.
silica gel (petroleum ether/EtOAc=80:20) provided compound
8
(107 mg, 99%) as a colorless oil. [a]2D5 =ꢀ22.7 (c=1.06 in CHCl3); IR
(neat): n˜ =3076, 2931, 2852, 1741, 1641, 1613, 1514, 1445, 1421, 1383,
1301, 1268, 1174, 1101, 1071, 1037, 964, 917, 888, 845, 783 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d=7.20 (m, 2H), 6.85 (m, 2H), 5.83 (dd, J=15.5,
5.5 Hz, 1H), 5.75 (m, 1H), 5.59 (ddd, J=15.5, 7.5, 1.0 Hz, 1H), 5.43 (brs,
1H), 5.24 (ddd, J=10.5, 5.0, 2.5 Hz, 1H), 5.10–5.05 (m, 2H), 4.64 (d, J=
7.0 Hz, 1H), 4.56 (d, J=7.0 Hz, 1H), 4.55 (d, J=11.5 Hz, 1H), 4.48–4.38
(m, 4H), 4.27 (d, J=11.5 Hz, 1H), 4.18 (brs, 2H), 4.06 (m, 1H), 3.84 (dd,
J=7.0, 5.5 Hz, 1H), 3.80 (s, 3H), 3.57 (m, 1H), 3.34 (s, 3H), 3.18–3.06
(m, 2H), 2.37–2.24 (m, 2H), 2.05 (m, 1H), 1.90 (m, 1H), 1.77 (ddd, J=
14.5, 10.0, 2.5 Hz, 1H), 1.71 (s, 3H), 1.68 ppm (m, 1H); 13C NMR
(125 MHz, CDCl3): d=164.4 (d, 2JPC =4.0 Hz), 159.5, 136.3, 134.1, 131.5,
130.1, 129.8 (2C), 126.5, 119.9, 118.1, 114.0 (2C), 96.6, 79.5, 74.1, 73.9,
73.4, 70.4, 65.9, 63.4–62.2 (m, 2C), 56.1, 55.5, 39.9, 35.9, 35.4, 34.2 (d,
1JPC =143.9 Hz), 23.2 ppm, CF3-signals missing (2C); HRMS (ESI): m/z
calcd for C31H41O10NaPF6: 741.2224 [M+Na]+; found: 741.2239.
(1R,3Z,7S,9S,10E,15S,17R)-7-{(S,E)-1-(4-Methoxybenzyloxy)-3-[(S)-4-
methyl-3,6-dihydro-2H-pyran-2-yl]allyl}-9-(methoxymethoxy)-15-methyl-
13-methylene-6,21-dioxabicyclo
ACHTUNGTREN[NUNG 15.3.1]henicosa-3,10,19-trien-5-one (12):
[CpRu(CH3CN)3][PF6] (3.4 mg, 7.85 mmol) was added in one portion to a
A
ACHTUNGTRENNUNG
solution of enyne 11 (103 mg, 0.157 mmol) in freshly distilled acetone
(160 mL) at 508C. The resulting light-brown solution was stirred at this
temperature for 15 min, at which time TLC indicated complete consump-
tion of the starting material. The mixture was filtered over a short plug
of silica gel to remove the Ru catalyst and was concentrated in vacuo.
Purification of the residue by flash column chromatography on silica gel
(petroleum ether/EtOAc=80:20) gave 1,4-diene 12 (103 mg, 99%) as a
colorless oil. [a]2D5 =ꢀ145 (c=2.56 in CHCl3); IR (neat): n˜ =2925, 1717,
2968
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2961 – 2971

Total Synthesis of Laulimalide and a Potent Analogue
FULL PAPER
1641, 1613, 1513, 1460, 1378, 1248, 1172, 1092, 1034, 975, 919, 820 cmꢀ1
;
1H), 5.67 (dd, J=10.2, 1.8 Hz, 1H), 5.64 (ddd, J=15.6, 7.2, 0.6 Hz, 1H),
5.43 (brs, 1H), 5.24 (quintapp, J=4.8 Hz, 1H), 4.91 (brs, 1H), 4.79 (brs,
1H), 4.58 (d, J=12.0 Hz, 1H), 4.33 (d, J=11.4 Hz, 1H), 4.24 (brm, 1H),
4.19 (brs, 2H), 4.06 (m, 1H), 3.93 (tapp, J=6.0 Hz, 1H), 3.88 (m, 1H),
3.84 (m, 1H), 3.80 (s, 3H), 3.41 (dt, J=13.8, 8.4 Hz, 1H), 2.99 (td, J=6.0,
1.8 Hz, 1H), 2.87 (t, J=2.4 Hz, 1H), 2.38 (m, 1H), 2.30–2.28 (m, 2H),
2.21–2.17 (m, 2H), 2.06 (m, 1H), 1.98 (ddd, J=15.0, 6.0, 4.2 Hz, 1H),
1.92–1.72 (m, 5H), 1.71 (s, 3H), 1.68 (m, 1H), 1.57 (brs, OH), 1.11 (ddd,
J=13.8, 7.8, 6.0 Hz, 1H), 0.88 ppm (d, J=6.6 Hz, 3H); 13C NMR
(150 MHz, CDCl3): d=165.9, 159.5, 147.2, 144.0, 136.1, 131.5, 130.2,
129.6 (2C), 128.8, 126.5, 124.8, 122.0, 119.9, 114.5, 114.0 (2C), 79.4, 73.5,
71.9, 71.5, 70.7, 67.5, 67.4, 65.9, 60.6, 55.5, 54.6, 44.7, 42.5, 38.4, 35.9, 34.7,
33.9, 31.1, 27.8, 23.2, 20.3 ppm; HRMS (ESI): m/z calcd for C38H50O8Na:
657.3403 [M+Na]+; found: 657.3388.
1H NMR (500 MHz, CDCl3): d=7.22 (m, 2H), 6.84 (m, 2H), 6.28 (ddd,
J=11.5, 9.5, 5.5 Hz, 1H), 5.88–5.80 (m, 3H), 5.69 (m, 1H), 5.61 (ddd, J=
16.0, 7.0, 1.5 Hz, 1H), 5.58 (dd, J=14.5, 7.0 Hz, 1H), 5.42 (brm, 1H),
5.31 (brdd, J=15.5, 8.5 Hz, 1H), 5.17 (ddd, J=9.5, 5.0, 2.5 Hz, 1H), 4.80
(brs, 1H), 4.69 (brs, 1H), 4.67 (d, J=6.5 Hz, 1H), 4.57 (d, J=12.0 Hz,
1H), 4.45 (d, J=7.0 Hz, 1H), 4.34 (d, J=11.5 Hz, 1H), 4.30 (brm, 1H),
4.17 (m, 2H), 4.04 (m, 1H), 3.90 (m, 1H), 3.79 (s, 3H), 3.75 (brm, 1H),
3.42 (m, 1H), 3.32 (s, 3H), 2.81 (dd, J=15.0, 7.0 Hz, 1H), 2.68 (dd, J=
15.0, 7.0 Hz, 1H), 2.35 (m, 1H), 2.13 (m, 1H), 2.09–1.98 (m, 3H), 1.92–
1.72 (m, 6H), 1.70 (s, 3H), 1.49 (dt, J=14.0, 7.0 Hz, 1H), 1.19 (m, 1H),
0.85 ppm (d, J=6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=165.7,
159.3, 146.5 (2C), 135.8, 133.2, 131.6, 130.8, 130.5, 129.6 (2C), 129.0,
126.8, 125.2, 122.4, 120.0, 113.9 (2C), 113.3, 93.3, 79.5, 74.9, 73.6, 72.8,
71.7, 70.5, 67.1, 65.8, 55.7, 55.5, 43.5, 43.2, 40.3, 36.2, 35.9, 34.7, 31.5, 28.8,
23.2, 20.7 ppm; HRMS (ESI): m/z calcd for C40H54O8Na: 685.3716
[M+Na]+; found: 685.3720.
(1R,3Z,7S,9E,11R,15S,17R)-11-Hydroxy-7-{(S,E)-1-(4-methoxybenzyl-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(1R,3Z,7S,9S,10E,15S,17R)-9-Hydroxy-7-{(S,E)-1-(4-methoxybenzyloxy)-
3-[(S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]allyl}-15-methyl-13-methyl-
ene-6,21-dioxabicycloACHTUNGTRENNUNG[15.3.1]henicosa-3,10,19-trien-5-one (13): A solution
box, [O3ReOSiPh3] (16.5 mg, 0.032 mmol, 1.0 equiv) was inserted into a
flame-dried round-bottom flask. Out of the glove box, Et2O (2.5 mL) was
added under an argon atmosphere. The flask was cooled to ꢀ508C and
the solution was stirred at this temperature for 10 min. A solution of the
allylic alcohol 13 (19.8 mg, 0.032 mmol, 1.0 equiv) in Et2O (2.5 mL) was
then added dropwise and the mixture was stirred for 5 min. The reaction
mixture was quenched by successively adding silica gel and Et3N
(200 mL) and was allowed to warm to RT. After removal of the solvent in
vacuo, the crude reaction mixture was analyzed by 1H NMR spectrosco-
py, which indicated the presence of the desired rearranged product 20,
along with the starting material 13, in a 4:1 ratio in favor of the rear-
ranged product 20. Purification of the residue by flash column chroma-
tography on silica gel (hexanes/EtOAc=90:10 to 85:15) gave the desired
compound 20 (15.4 mg, 78%) as a colorless oil. Moreover, 3.9 mg of the
starting material 13 could be recovered (yield=97% BRSM). [a]2D5 =ꢀ85
(c=0.46 in CHCl3); IR (neat): n˜ =3439, 2958, 2921, 2854, 1718, 1644,
1613, 1513, 1421, 1381, 1297, 1250, 1213, 1169, 1085, 1036, 971, 811,
of MOM-protected macrolactone 12 (103 mg, 0.156 mmol) in tBuOH
(6.5 mL) was placed in a reaction vial containing a stirring bar, and PPTS
(508 mg, 2.02 mmol) was added in one portion. The vial was sealed and
then immersed in an 858C oil bath. After stirring for 8 h at this tempera-
ture, the reaction mixture was allowed to cool to RT and then poured
into water. The aqueous layer was extracted with EtOAc (ꢂ3) and the
combined organic layers were washed with brine, dried over MgSO4, fil-
tered, and concentrated in vacuo. Purification of the residue by flash
column chromatography on silica gel (petroleum ether/EtOAc=80:20 to
70:30) provided allylic alcohol 13 (63.6 mg, 66%) as a colorless oil.
[a]2D5 =ꢀ118 (c=1.14 in CHCl3); IR (neat): n˜ =3445, 3031, 2956, 2921,
2835, 1714, 1642, 1613, 1513, 1422, 1380, 1300, 1247, 1175, 1085, 1035,
973, 892, 819 cmꢀ1 1H NMR (600 MHz, CDCl3): d=7.22 (m, 2H), 6.85
;
(m, 2H), 6.29 (ddd, J=11.4, 9.5, 5.4 Hz, 1H), 5.88–5.81 (m, 3H), 5.69 (m,
1H), 5.65–5.55 (m, 2H), 5.50 (dd, J=15.6, 7.2 Hz, 1H), 5.42 (brm, 1H),
5.15 (quintapp, J=3.6 Hz, 1H), 4.81 (brs, 1H), 4.70 (brs, 1H), 4.58 (d, J=
11.4 Hz, 1H), 4.34 (d, J=11.4 Hz, 1H), 4.28 (brm, 1H), 4.18 (m, 2H),
4.14 (m, 1H), 4.06 (m, 1H), 3.95 (tapp, J=6.6 Hz, 1H), 3.80 (s, 3H), 3.75
(brm, 1H), 3.42 (dt, J=15.0, 9.0 Hz, 1H), 2.79 (dd, J=15.0, 7.2 Hz, 1H),
2.67 (dd, J=15.0, 7.2 Hz, 1H), 2.36 (m, 1H), 2.12–1.96 (m, 4H+OH),
1.92–1.72 (m, 5H), 1.70 (s, 3H), 1.53 (dt, J=13.6, 6.0 Hz, 1H), 1.16 (dt,
J=13.8, 6.6 Hz, 1H), 0.86 ppm (d, J=6.0 Hz, 3H); 13C NMR (150 MHz,
CDCl3): d=165.8, 159.4, 146.7, 146.5, 135.9, 133.7, 131.5, 130.4, 130.3,
129.6 (2C), 128.9, 126.6, 125.1, 122.0, 119.9, 114.0 (2C), 113.1, 79.3, 73.5,
72.6, 72.2, 71.3, 70.6, 67.0, 65.8, 55.5, 43.6, 43.1, 40.2, 37.9, 35.9, 34.6, 31.4,
28.4, 23.2, 20.6 ppm; HRMS (ESI): m/z calcd for C38H50O7Na: 641.3454
[M+Na]+; found: 641.3458.
756 cmꢀ1 1H NMR (600 MHz, CDCl3): d=7.21 (m, 2H), 6.86 (m, 2H),
;
6.31 (td, J=10.8, 4.8 Hz, 1H), 5.88 (brd, J=12.0 Hz, 1H), 5.85 (dd, J=
15.6, 5.4 Hz, 1H), 5.85–5.79 (m, 1H), 5.70 (m, 1H), 5.63–5.54 (m, 2H),
5.49 (dd, J=15.6, 7.2 Hz, 1H), 5.43 (brs, 1H), 5.09 (ddd, J=7.8, 3.6,
2.4 Hz, 1H), 4.86 (s, 1H), 4.84 (s, 1H), 4.59 (d, J=11.4 Hz, 2H), 4.31 (d,
J=12.0 Hz, 1H), 4.20 (brs, 2H), 4.15 (m, 1H), 4.12–4.06 (m, 2H), 3.83
(tapp, J=6.6 Hz, 1H), 3.80 (s, 3H), 3.78 (sept, J=4.2 Hz, 1H), 3.71 (m,
1H), 2.31 (m, 1H), 2.27–2.14 (m, 4H), 2.11–2.01 (m, 3H), 1.95–1.83 (m,
3H), 1.79–1.72 (m, 2H), 1.71 (s, 3H), 1.67 (ddd, J=12.0, 7.8, 3.6 Hz, 1H),
0.93 ppm (d, J=6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=165.6,
159.4, 147.6, 144.6, 136.1, 135.9, 131.5, 130.4, 129.6 (2C), 128.6, 127.9,
126.7, 125.0, 121.7, 119.9, 115.8, 113.9 (2C), 79.5, 73.5, 72.9, 71.8, 70.3,
70.2, 67.8, 65.8, 55.5, 43.9, 40.7, 36.0, 34.3, 34.0, 31.6, 28.5, 23.2, 21.2 ppm;
HRMS (ESI): m/z calcd for C38H50O7Na: 641.3454 [M+Na]+; found:
641.3461.
(1R,3S,7S,9S,10S,12S,18R,Z)-10-Hydroxy-12-{(S,E)-1-[(4-methoxybenzy-
l)oxy]-3-[(S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]allyl}-3-methyl-5-meth-
ylene-8,13,22-trioxatricyclo[16.3.1.07,9]docosa-15,19-dien-14-one
(14):
(+)-Diethyl-l-tartrate (28 mL, 0.134 mmol) and TiAHCNUTGTERG(NNUN OiPr)4 (34 mL,
(1R,3Z,7S,9E,11S,15S,17R)-11-Hydroxy-7-{(S,E)-1-(4-methoxybenzyl-
AHCTUNGTRENNUNG
0.113 mmol) were sequentially added to a suspension of flame-dried mo-
lecular sieves (4 ꢁ, 100 mg) in CH2Cl2 (2 mL) at ꢀ208C. The resulting
mixture was stirred for 15 min at this temperature and tert-butylhydroper-
oxide (5.5m in dodecane, 40 mL, 0.218 mmol) was then added dropwise.
The mixture was stirred for another 15 min and then a solution of allylic
alcohol 13 (10.9 mg, 0.0176 mmol) in CH2Cl2 (4 mL) was added dropwise.
After stirring for 1 h at ꢀ208C, the reaction mixture was hydrolyzed by
adding a mixture of sodium hydroxide (4n, 2 mL) and brine (2 mL). The
resulting mixture was stirred at 08C for 1 h, and EtOAc was added. The
layers were separated and the aqueous phase was extracted with EtOAc
(ꢂ3). The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the residue
by flash column chromatography on silica gel (hexanes/EtOAc=80:20)
yielded epoxide 14 (9.6 mg, 86%) as a colorless oil. [a]2D5 =ꢀ78.3 (c=0.49
in CHCl3); IR (neat): n˜ =3435, 2922, 1715, 1643, 1612, 1513, 1445, 1379,
AHCTUNGTRENNUNG
Oxidation: The Dess–Martin periodinane (14 mg, 0.0327 mmol, 2.0 equiv)
was added in one portion to a solution of allylic alcohol 20 (10.1 mg,
0.0163 mmol, 1.0 equiv) in CH2Cl2 (1 mL) at 08C. The resulting mixture
was stirred for 2 h at RT. The reaction mixture was poured into a 1:1 mix-
ture of saturated aqueous sodium bicarbonate and saturated aqueous
sodium thiosulfate and then Et2O (2 mL) was added. The layers were
separated and the aqueous phase was extracted with Et2O (ꢂ3). The
combined organic layers were washed with brine, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. Purification of the resi-
due by flash column chromatography on silica gel (hexanes/EtOAc=
80:20) furnished the product (9.6 mg, 96%) as a colorless oil. [a]2D5 =ꢀ71
(c=0.84 in CHCl3); IR (neat): n˜ =3032, 2921, 1719, 1671, 1640, 1614,
1513, 1421, 1380, 1248, 1212, 1168, 1087, 1035, 976, 896, 818 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=7.22 (m, 2H), 6.86 (m, 2H), 6.72 (ddd,
J=16.2, 7.8, 6.6 Hz, 1H), 6.37 (ddd, J=11.4, 10.2, 4.8 Hz, 1H), 6.09 (d,
J=16.2 Hz, 1H), 6.88–6.83 (m, 3H), 5.69 (m, 1H), 5.63 (ddd, J=15.6,
1247, 1213, 1172, 1086, 1034, 974, 896, 821 cmꢀ1 1H NMR (600 MHz,
;
CDCl3): d=7.22 (m, 2H), 6.85 (m, 2H), 6.34 (ddd, J=11.4, 9.6, 6.6 Hz,
1H), 5.91 (d, J=12.0 Hz, 1H), 5.85 (dd, J=15.6, 5.4 Hz, 1H), 5.83 (m,
Chem. Eur. J. 2012, 18, 2961 – 2971
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. M. Trost et al.
7.2, 1.2 Hz, 1H), 5.43 (brs, 1H), 4.90 (s, 1H), 4.82 (s, 1H), 4.59 (d, J=
12.0 Hz, 1H), 4.33 (d, J=12.0 Hz, 1H), 4.26 (m, 1H), 4.20 (m, 2H), 4.08
(m, 1H), 3.92 (tapp, J=6.0 Hz, 1H), 3.80 (s, 3H), 3.72 (m, 1H), 3.55 (dt,
J=15.6, 10.2 Hz, 1H), 3.25 (d, J=15.6 Hz, 1H), 3.11 (d, J=15.0 Hz, 1H),
2.54–2.44 (m, 2H), 2.34 (m, 1H), 2.09–2.00 (m, 3H), 1.95–1.86 (m, 2H),
1.78 (dd, J=13.8, 10.2 Hz, 1H), 1.71 (s, 3H), 1.49 (ddd, J=14.4, 8.4,
5.4 Hz, 1H), 1.19 (ddd, J=14.4, 8.4, 2.0 Hz, 1H), 0.83 ppm (d, J=6.6 Hz,
3H); 13C NMR (150 MHz, CDCl3): d=198.4, 165.6, 159.4, 148.8, 143.4,
142.1, 136.2, 132.1, 131.4, 130.2, 129.6 (2C), 128.8, 126.2, 125.4, 120.9,
119.9, 116.1, 114.0 (2C), 79.2, 73.4, 72.8, 72.3, 70.5, 66.6, 65.8, 55.5, 46.5,
44.7, 43.7, 35.9, 34.3, 33.6, 31.8, 28.1, 23.2, 19.9 ppm; HRMS (ESI): m/z
calcd for C38H48O7Na: 639.3298 [M+Na]+; found: 639.3316.
3.79–3.75 (m, 1H+OH), 3.03 (m, 1H), 2.87 (m, 1H), 2.37 (dd, J=13.8,
4.8 Hz, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 2.11–1.86 (m, 8H), 1.77 (dd, J=
13.2, 10.2 Hz, 1H), 1.71 (s, 3H), 1.47–1.40 (m, 2H), 1.35–1.30 (m, 1H),
0.82 ppm (d, J=6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=166.1,
159.4, 150.3, 145.2, 136.0, 131.5, 130.2, 129.7 (2C), 128.8, 126.3, 125.4,
121.0, 120.0, 114.0 (2C), 112.6, 79.3, 73.4, 71.1, 70.6, 68.1, 66.7, 65.9, 60.8,
55.5, 52.4, 45.9, 43.7, 37.3, 35.9, 33.9, 33.3, 31.9, 30.0, 23.2, 21.1 ppm;
HRMS (ESI): m/z calcd for C38H50O8Na: 657.3403 [M+Na]+; found:
657.3411.
Final removal of the PMB group: DDQ (5.8 mg, 25.6 mmol) was added in
one portion to a solution of the previously obtained PMB ether (5.4 mg,
8.52 mmol) in CH2Cl2 (1.5 mL), pH7 buffer (75 mL) and tBuOH (75 mL).
The resulting green mixture was stirred at RT for 30 min. Another por-
tion of DDQ (5.8 mg, 25.6 mmol) was then added. After stirring for 1 h,
more DDQ (5.8 mg, 25.6 mmol) was added and the mixture was stirred
for another hour. The resulting orange suspension was then washed with
saturated aqueous sodium bicarbonate and the aqueous phase was ex-
tracted CH2Cl2 (ꢂ3). The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification
of the residue by flash column chromatography on silica gel (hexanes/
EtOAc=80:20 to 50:50) gave laulimalide (1, 3.9 mg, 89%) as a colorless
oil. The analytical and spectroscopic data perfectly matched those report-
ed in the literature.[24] [a]D25 =ꢀ193 (c=0.15 in CHCl3); 1H NMR
(600 MHz, CDCl3): d=6.44 (ddd, J=11.4, 9.6, 3.6 Hz, 1H), 3.91 (m,
1H), 5.88 (ddd, J=15.6, 6.4, 1.2 Hz, 1H), 5.86–5.82 (m, 1H), 5.75 (ddd,
J=15.6, 6.0, 1.2 Hz, 1H), 5.69 (m, 1H), 5.42 (brs, 1H), 5.16 (ddd, J=
Diastereoselective reduction: (R)-2-Methyl-CBS-oxazaborolidine (1.0m in
toluene, 61 mL, 0.0609 mmol, 5.0 equiv) followed by BH3·THF (1.0m in
THF, 43 mL, 0.0426 mmol, 3.5 equiv) were slowly added at 08C through a
syringe to a solution of the previously obtained a,b-unsaturated ketone
(7.5 mg, 0.0122 mmol, 1.0 equiv) in THF (1.5 mL). The reaction mixture
was stirred for 5 min at this temperature, and hydrolyzed by adding H2O
(1.5 mL). The resulting mixture was warmed to RT, Et2O was added, and
the organic phase was washed with aqueous HCl (1.0m). The aqueous
phase was extracted with Et2O (ꢂ3) and the organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated in vacuo.
1H NMR spectroscopy of the crude residue indicated the presence of
only one diastereoisomer. Purification of the residue by flash column
chromatography on silica gel (hexanes/EtOAc=85:15) gave the allylic al-
cohol 17 (7.3 mg, 97%) as
a
colorless oil. [a]2D5 =ꢀ105 (c=0.59 in
11.4, 5.4, 1.8 Hz, 1H), 4.86 (s, 1H), 4.85 (s, 1H), 4.31 (m, 1H), 4.22 (qapp
,
CHCl3); IR (neat): n˜ =3433, 2924, 2854, 1720, 1644, 1612, 1513, 1450,
J=5.4 Hz, 1H), 4.20–4.16 (m, 2H), 4.08 (m, 1H), 4.03 (m, 1H), 3.79–3.69
(m, 2H), 3.07 (m, 1H), 2.90 (t, J=2.4 Hz, 1H), 2.40–2.35 (m, 2H), 2.40–
2.35 (m, 2H), 2.22 (m, 1H), 2.12 (brd, J=15.6 Hz, 1H), 2.05–1.84 (m,
6H), 1.78 (dd, J=13.2, 10.2 Hz, 1H), 1.70 (s, 3H), 1.49 (ddd, J=14.4,
11.4, 9.6 Hz, 1H), 1.45 (m, 1H), 1.33 (ddd, J=14.4, 4.2, 3.0 Hz, 1H),
0.83 ppm (d, J=6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=166.0,
150.4, 144.8, 133.9, 131.2, 128.7, 128.5, 125.2, 120.5, 119.7, 112.5, 73.5, 73.1
(2C), 72.2, 67.9, 66.5, 65.6, 60.6, 52.0, 45.5, 43.4, 37.0, 35.6, 33.7, 33.4,
31.6, 29.5, 22.9, 20.7 ppm; HRMS (ESI): m/z calcd for C30H42O7Na:
537.2828 [M+Na]+; found: 537.2825.
1379, 1248, 1166, 1087, 1037, 974, 815 cmꢀ1; H NMR (600 MHz, CDCl3):
1
d=7.21 (m, 2H), 6.85 (m, 2H), 6.32 (ddd, J=11.4, 9.6, 5.4 Hz, 1H), 5.90
(d, J=11.4 Hz, 1H), 5.84 (dd, J=15.6, 5.4 Hz, 1H), 5.84–5.80 (m, 1H),
5.70 (m, 1H), 5.63–5.58 (m, 3H), 5.42 (brs, 1H), 5.07 (ddd, J=10.2, 5.4,
3.0 Hz, 1H), 4.84 (s, 2H), 5.59 (d, J=12.0 Hz, 1H), 4.31 (d, J=11.4 Hz,
1H), 4.19 (brs, 2H), 4.18–4.10 (m, 2H), 4.07 (m, 1H), 3.89–3.83 (m, 2H),
3.80 (s, 3H), 3.53 (m, 1H), 2.35–2.18 (m, 5H), 2.15 (dd, J=13.2, 4.2 Hz,
1H), 2.11 (dd, J=14.4, 9.6 Hz, 1H), 2.07–2.01 (m, 1H), 1.90 (brd, J=
16.8 Hz, 1H), 1.85–1.71 (m, 3H), 1.70 (s, 3H), 1.64 (ddd, J=13.8, 8.4,
4.8 Hz, 1H), 1.35–1.26 (m, 1H), 1.12 (ddd, J=12.0, 7.8, 4.2 Hz, 1H),
0.85 ppm (d, J=6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=165.6,
159.4, 146.9, 145.1, 135.8, 135.3, 131.5, 130.4, 129.7 (2C), 128.6, 127.2,
126.7, 124.9, 121.9, 119.9, 114.6, 114.0 (2C), 79.5, 74.1, 73.5, 71.4, 70.3,
70.0, 67.8, 65.9, 55.5, 45.0, 43.5, 42.4, 36.0, 34.5, 33.6, 31.1, 28.4, 23.2,
19.9 ppm; HRMS (ESI): m/z calcd for C38H50O7Na: 641.3454 [M+Na]+;
found: 641.3464.
Acknowledgement
Laulimalide (1):
We gratefully acknowledge P. Crews (UC Santa Cruz) for providing an
authentic sample of laulimalide (1). We also thank J. Flygare, J.-P. Ste-
phan, and P. Chan at Genentech for biological testing of our laulimalide
analogue (33). We thank the General Medical Sciences Institute of the
NIH (GM 33049) for their generous support of our programs. We thank
Johnson–Matthey for their gifts of palladium and ruthenium and Aldrich
for generous supply of the ProPhenol ligand. W.M.S. thanks the National
Institutes of Health for a post-doctoral fellowship. C.K.C. thanks Eli Lilly
& Co. for a graduate fellowship.
Sharpless epoxidation: (+)-Diethyl-l-tartrate (18 mL, 0.0860 mmol) and
TiACHTUNGTRENNUNG(OiPr)4 (21 mL, 0.0725 mmol) were sequentially added to a suspension
of flame-dried molecular sieves (4 ꢁ 85 mg) in CH2Cl2 (1.5 mL) at
ꢀ208C. The resulting mixture was stirred for 15 min at this temperature
and tert-butylhydroperoxide (5.5m in dodecane, 25 mL, 0.140 mmol) was
then added dropwise. The mixture was stirred another 15 min and a solu-
tion of the previously obtained allylic alcohol 17 (7.0 mg, 0.0113 mmol) in
CH2Cl2 (3 mL) was subsequently added dropwise. After stirring for 1 h at
ꢀ208C, the reaction mixture was hydrolyzed by adding a mixture of
sodium hydroxide (4n, 1.5 mL) and brine (1.5 mL). The resulting mixture
was stirred at 08C for 1 h, and then EtOAc was added. The layers were
separated and the aqueous phase was extracted with EtOAc (ꢂ3). The
combined organic layers were washed with brine, dried over MgSO4, fil-
tered, and concentrated in vacuo. Purification of the residue by flash
column chromatography on silica gel (hexanes/EtOAc=80:20) yielded
the desired epoxide (6.4 mg, 88%) as a colorless oil. [a]2D5 =ꢀ141 (c=
0.41 in CHCl3); IR (neat): n˜ =3452, 2918, 1720, 1643, 1612, 1513, 1421,
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1378, 1300, 1247, 1213, 1171, 1115, 1084, 1033, 977, 891, 814 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=7.21 (m, 2H), 6.86 (m, 2H), 6.42 (dt,
J=10.8, 3.6 Hz, 1H), 5.89 (brd, J=11.4 Hz, 1H), 5.84 (dd, J=15.6,
5.4 Hz, 1H), 5.83 (m, 1H), 5.68 (m, 1H), 5.59 (dd, J=15.6, 6.6 Hz, 1H),
5.43 (brs, 1H), 5.21 (dd, J=10.8, 4.8 Hz, 1H), 4.85 (s, 1H), 4.83 (s, 1H),
4.58 (d, J=11.4 Hz, 1H), 4.32 (d, J=12.0 Hz, 1H), 4.32–4.28 (m, 1H),
4.19 (brs, 2H), 4.06 (m, 2H), 3.88 (tapp, J=6.0 Hz, 1H), 3.80 (s, 3H),
2970
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Chem. Eur. J. 2012, 18, 2961 – 2971

Total Synthesis of Laulimalide and a Potent Analogue
FULL PAPER
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laulimalide provided by P. Crews (UC Santa Cruz) was identical to
the spectrum we obtained for the synthetic sample by using the
same NMR instrument (Varian, 600 MHz)—see the experimental
section for details.
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Received: September 15, 2011
Published online: February 3, 2012
Chem. Eur. J. 2012, 18, 2961 – 2971
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2971