Total synthesis of microtubule-stabilizing agent (-)-laulimalide

Article abstract of DOI:10.1021/jo010854h

An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents with significant clinical potential. The synthesis is convergent and involved the assembly of C₃-C₁₆ segment 4 and C₁₇-C₂₈ segment 5 by Julia olefination. The sensitive C₂-C₃ cis-olefin functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed by hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts of intramolecular Still's variant of Horner - Emmons olefination between the C₁₉-phosphonocetate and C₃-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photo-isomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefin metathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalize the dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C₂₀-hydroxyl stereochemistry, and a novel Julia olefination protocol for the installation of the C₁₃-exomethylene unit. The sensitive epoxide at C₁₆-C₁₇ was introduced in a highly stereoselective manner by Sharpless epoxidation at the final stage of the synthesis.

Full text of DOI:10.1021/jo010854h

J . Org. Chem. 2001, 66, 8973-8982
8973
Tota l Syn th esis of Micr otu bu le-Sta bilizin g Agen t (-)-La u lim a lid e1
Arun K. Ghosh,* Yong Wang, and J oseph T. Kim
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
arunghos@uic.edu
Received August 21, 2001
An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably
potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the
Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents
with significant clinical potential. The synthesis is convergent and involved the assembly of
C3-C16 segment 4 and C17-C28 segment 5 by J ulia olefination. The sensitive C2-C3 cis-olefin
functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed
by hydrogenation of the resulting alkynoic lactone over Lindlar’s catalyst. Initial attempts of
intramolecular Still’s variant of Horner-Emmons olefination between the C19-phosphonocetate and
C3-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photo-
isomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefin
metathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalize
the dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C20-
hydroxyl stereochemistry, and a novel J ulia olefination protocol for the installation of the C13-exo-
methylene unit. The sensitive epoxide at C16-C17 was introduced in a highly stereoselective manner
by Sharpless epoxidation at the final stage of the synthesis.
In tr od u ction
Macrocyclic marine natural products continue to pro-
vide a rich source of structurally diverse antitumor
agents with significant therapeutic potential.2 One such
compound is laulimalide, a novel 18-membered macrolide
which has exhibited remarkably potent antitumor prop-
erties. Laulimalide (1), also known as figianolide B, was
isolated from the marine sponge Cacospongia mycofijien-
sis by Crews and co-workers in 1988.3a Moore et al. also
isolated laulimalide from the Indonesian sponge Hyat-
tella sp. in 1988.3b More recently, Higa and co-workers
have isolated laulimalide (1, Figure 1) and isolaulimalide
(2) from the Okinawan sponge Fasciospongia rimosa.4
Upon treatment with 0.01 N HCl in acetone, laulimalide
readily isomerizes to the tetrahydrofuran-containing
metabolite isolaulimalide (2) via epoxide opening at C17
by the C20-hydroxyl group. The gross structure of 1 was
initially established by NMR studies.3 Subsequently, its
absolute configuration has been determined through
F igu r e 1.
X-ray analysis by Higa and co-workers.4 Laulimalide
against the multidrug resistant cell line SKVLB-1 (IC50
) 1.2 µM). In contrast, isolaulimalide is significantly less
potent against the KB cell line (IC50 > 200 nM) as well
as the SKVLB-1 line (IC50 ) 1.6 mM).5 These results
indicate that the epoxide moiety of laulimalide is critical
for enhanced antitumor activities.
exhibited very potent antitumor activity against numer-
ous NCI cell lines. It displayed cytotoxicity against the
KB cell line with an IC50 value of 15 ng/mL. Its cytotox-
icity against P388, A549, HT29, and MEL28 cell lines
ranged from 10 to 50 ng/mL (IC50 values).3 Furthermore,
laulimalide has maintained a high level of potency
Recently, Mooberry and co-workers have revealed that
laulimalide shares the same mechanism of action as the
anticancer drug Taxol (paclitaxel).5 Thus far, only three
other nontaxane natural products (epothilones,6 disco-
(1) This work is dedicated to Professor A. I. Meyers with profound
admiration and respect for his innumerable contributions to organic
synthesis.
(2) Harris, C. R.; Danishefsky, S. J . J . Org. Chem. 1999, 64, 8434.
(3) (a) Quinoa, E.; Kakou, Y.; Crews, P. J . Org. Chem. 1988, 53,
3642. (b) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J .; Paul, V.
J . J . Org. Chem. 1988, 53, 3644.
(5) Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plubrukarn, A.;
Davidson, B. S. Cancer Res. 1999, 59, 653.
(4) (a) J efford, C. W.; Bernardinelli, G.; Tanaka, J .-I.; Higa, T.
Tetrahedron Lett. 1996, 37, 159. (b) Tanaka, J .-I.; Higa, T.; Bernar-
dinelli, G.; J efford, C. W. Chem. Lett. 1996, 255.
(6) Bollag, D. M.; McQuency, P. A.; Zhu, J .; Hensens, O.; Koupal,
L.; Liesch, J .; Goetz, M.; Laziides, E.; Woods, C. M. Cancer Res. 1995,
55, 2325.
10.1021/jo010854h CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/30/2001

8974 J . Org. Chem., Vol. 66, No. 26, 2001
Ghosh et al.
dermolide,7 and eleutherobin8) have shown similar mi-
crotubule stabilizing properties. One of the intriguing
characteristics of laulimalide is that it not only exhibits
potent microtubule-stabilizing properties but also inhibits
the P-glycoprotein that is responsible for multiple-drug
resistance in tumor cells. It has been shown that lauli-
malide is as much as 100-fold more potent than Taxol in
multi-drug-resistant cell lines.5 Thus, laulimalide repre-
sents a new class of microtubule-stabilizing agents with
significant clinical potential.
The unique structural features, potent microtubule-
stabilizing properties and low natural abundance of
laulimalide, stimulated immense interest in its synthesis
and structure-activity studies. Several synthetic ap-
proaches toward fragments of laulimalide have been
reported by us9 and others.10 Paterson recently reported
the synthesis of the laulimalide core in which the key
step was an intramolecular Mitsunobu reaction to form
the macrolactone ring.10a Mulzer also reported the syn-
thesis of the C1-C12 and C15-C28 fragments of laulimalide
in which the key step was ring-closing olefin metathesis
to form the dihydropyran ring.10b Nishiyama and David-
son also reported stereoselective syntheses of various
fragments of laulimalide.10d-f Recently, we completed the
first total synthesis of (-)-laulimalide (1).11 An intramo-
lecular Horner-Emmons reaction between the C19-bis-
(2,2,2-trifluroethyl)phophonoacetate and C3-aldehyde was
utilized in the key macrocyclization step. However, this
macrocyclization reaction provided a mixture of C2-C3
cis- and trans-macrolactones. The isomers were sepa-
rated, and the major trans-isomer was photoisomerized
to the cis-isomer.11 Subsequently, we have incorporated
this sensitive C2-C3 cis-olefin functionality by macrolac-
tonization of a hydroxy alkynoic acid followed by hydro-
genation of the resulting alkyne derivative.12 Herein, we
report the full details of our synthetic studies.
Resu lts a n d Discu ssion
Our synthetic strategy is outlined in Figure 2. Strategic
disconnection of (-)-1 at C2-C3 and removal of the
epoxide functionality at C16-C17 provide the proper
precursor (3) for the synthesis of (-)-1. An intramolecular
Horner-Emmons reaction between the C19-phosphonoac-
etate and the C3-aldehyde, or Yamaguchi lactonization
followed by Sharpless epoxidation would install the
sensitive epoxide at C16-C17 at the final stage of the
synthesis. In a retrosynthetic manner, the synthesis of
3 requires the assembly of C3-C16 fragment 4 and C17-
C28 fragment 5 by J ulia olefination. Thus, this convergent
F igu r e 2. Retrosynthetic analysis.
approach involves the synthesis of key fragments 4 and
5 in enantiomerically pure form followed by coupling to
form 3. Aldehyde fragment 4 could be derived from
alkylation of R-sulfonyl-γ-lactone (6) with iodide 8 fol-
lowed by J ulia olefination. Iodide 8 could be synthesized
starting from known alcohol 10 using ring-closing olefin
metathesis as the key step. Fragment 5 would be derived
from a nucleophilic addition of 7-derived alkynyl anion
to aldehyde 9. The corresponding stereogenic centers in
7 and 9 could be derived from glycidol THP ether 11. Both
dihydropyran rings of laulimalide would be constructed
by ring-closing metathesis utilizing Grubbs’ catalyst as
the key step.13
(7) (a) Hung, D. T.; Chen J .; Schreiber, S. L. Chem. Biol. 1996, 3,
287. (b) Kowalski, R. J .; Giannakakou, P.; Gunasekera, S.; Longley,
R. E.; Day, B. W.; Hamel, E. Mol. Pharmacol. 1997, 52, 613, and
references therein.
(8) (a) Long, B. H.; Carboni, J . M.; Wasserman, A. J .; Cornell, L.
A.; Casazza, A. M.; J ensen, P. R.; Lindel, T.; Fenical, W.; Fairchild, C.
R. Cancer Res. 1998, 58, 1111. (b) Lindel, T.; J ensen, P. R.; Fenical,
W.; Long, B. H.; Casazza, A. M.; Carboni, J . M.; Fairchild, C. R. J .
Am. Chem. Soc. 1997, 119, 8744, and references therein.
(9) (a) Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000, 41, 4705. (b)
Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000, 41, 2319. (c) Ghosh,
A. K.; Mathivanan, P.; Cappiello, J . Tetrahedron Lett. 1997, 38, 2427.
(10) (a) Paterson, I.; Savi, C. D.; Tudge, M. Org. Lett. 2001, 3, 213.
(b) Mulzer, J .; Hanbauer, M. Tetrahedron Lett. 2000, 41, 33. (c) Mulzer,
J .; O¨ hler, E.; Dorling, E. K. Tetrahedron Lett. 2000, 41, 6323. (d)
Shimizu, A.; Nishiyama, S. Synlett 1998, 1209. (e) Shimizu, A.;
Nishiyama, S. Tetrahedron Lett. 1997, 38, 6011. (f) Messenger, B. T.;
Davidson, B. Tetrahedron Lett. 2001, 42, 797. (g) Nadolskir, G. T.;
Davidson, B. Tetrahedron Lett. 2001, 42, 801.
Syn th esis of C3-C16 F r a gm en t 4. As depicted in
Scheme 1, synthesis of the C3-C16 fragment began with
(11) Ghosh, A. K.; Wang, Y. J . Am. Chem. Soc. 2000, 122, 11027.
(12) Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2001, 42, 3399.
(13) For an excellent review, see: Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413.

Microtubule-Stabilizing Agent (-)-Laulimalide
J . Org. Chem., Vol. 66, No. 26, 2001 8975
Sch em e 1a
Sch em e 2a
a
Key: (a) MsCl, Et3N, CH2Cl2, 0 °C; (b) NaCN, DMSO, 60 °C
(95%); (c) DIBAL, CH2Cl2, 0 °C (93%); (d) CH2dCHCH2B[(-)-Ipc]2,
THF, -100 °C (75%); (e) (S)-BINOL, Ti(OiPr)4, allyltributyltin,
CH2Cl2, -20 °C (46%).
known optically active alcohol 10,14 which is readily
prepared in two steps from commercially available meth-
yl (S)-3-hydroxy-2-methylpropionate. Reaction of alcohol
10 with mesyl chloride and triethylamine in CH2Cl2 at 0
˚C for 30 min followed by displacement of the resulting
mesylate with sodium cyanide in dimethylsulfoxide
(DMSO) at 60 °C for 2 h gave cyanide 12 in 95% yield
for two steps. DIBAL reduction of cyanide 12 in CH2Cl2
at 0 °C for 30 min afforded aldehyde 13 in 93% yield.
Subjection of aldehyde 13 to Brown’s asymmetric allybo-
ration protocol with allyldiisopinocampheylborane af-
forded homoallylic alcohol 14 diastereoselectively in 75%
yield.15 A diastereomeric ratio of 96:4 was determined by
1H- and 13C-NMR analysis. Alcohol 14 was also prepared
diastereoselectively by an alternative procedure utilizing
Keck’s allylation protocol employing a catalytic amount
of (S)-BINOL and titanium isopropoxide.16 The observed
a
Key: (a) CH2dCHCOCl, Et3N, CH2Cl2, 0 to 23 °C (76%); (b)
Cl2(PCy3)2RudCHPh (10%), Ti(OiPr)4 (30%), CH2Cl2, 40 °C (72%);
(c) DIBAL, CH2Cl2, -78 °C; (d) CSA, EtOH (82%); (e) acrolein
diethyl acetal, PPTS, benzene (83%); (f) Cl2(PCy3)2RudCHPh (10
mol %), CH2Cl2 (97%).
prepared by ring-closing metathesis of diene 17.20 Thus,
transketalization of alcohol 14 with acrolein diethyl
acetal in the presence of a catalytic amount of PPTS
afforded diene 17 in 83% yield. Ring-closing olefin meta-
thesis of 17 with Grubbs’ catalyst13 gave a mixture (1:1)
of ethyl glycosides 18 and 19 in 97% yield.
The C5 side chain was introduced by a highly stereo-
selective anomeric alkylation reaction. As illustrated in
Scheme 3, ethyl acetals 18 and 19 were reacted with tert-
butyldimethylsilyl vinyl ether in CH2Cl2 at 23 °C in the
presence of Montmorillonite K-10 as the Lewis acid.9c The
resulting aldehyde was reduced by NaBH4 to furnish the
corresponding dihydropyran derivative. The 1H- and 13C-
NMR analysis revealed the presence of a single isomer,
and the assigned stereochemistry was supported by
NOESY experiments. The hydroxyl group was protected
with TBSCl and imidazole to provide TBS ether 20.
Exposure of 20 to lithium in liquid ammonia removed
the benzyl group, and the corresponding alcohol was
obtained in 95% yield. Exposure of the resulting alcohol
to iodine, triphenylphosphine, and imidazole in a mixture
(2:1) of Et2O and CH3CN provided iodide 8.21
1
diastereoselectivity was comparable (de 92% by H- and
13C-NMR analysis) to Brown’s asymmetric allylation pro-
cedure; however, the reaction yield was poor (46% yield).
To construct the dihydropyran ring of fragment 4 with
the appropriate stereochemistry, our plan was to form
an R,â-unsaturated δ-lactone and then append the side
chain at C5 stereoselectively. For the synthesis of the
corresponding R,â-unsaturated δ-lactone, we utilized the
ring-closing olefin metathesis protocol described re-
cently.17 As shown in Scheme 2, alcohol 14 was reacted
with acryloyl chloride and Et3N in CH2Cl2 at 0 °C to
afford acrylate ester 15 in 76% yield. Acrylate ester 15,
upon exposure to a catalytic amount of commercial
Grubbs’ catalyst (10 mol %) in CH2Cl2 in the presence of
a catalytic amount (30%) of Ti(OiPr)4 at 40 °C for 5 h,
provided R,â-unsaturated δ-lactone in 72% yield after
silica gel chromatography. Reduction of δ-lactone 16 with
DIBAL at -78 °C followed by reaction of the resulting
lactol with EtOH in the presence of CSA furnished ethyl
glycoside 18 in 82% yield. Glycoside 18 was formed as a
single anomer due to the anomeric effect.18,19 A mixture
of anomeric ethyl glycosides 18 and 19 has also been
The C13-methylene unit and C15-hydroxyl group were
installed by a novel protocol utilizing alkylation of 6
followed by a J ulia olefination reaction.22 The requisite
sulfonyl lactone 6 was prepared in multigram quantities
by reaction of known23 glycidol PMB ether 21 with the
sodium enolate of methyl phenylsulfonyl acetate in EtOH
at 23 °C for 12 h. Lactone 6 was isolated in 83% yield as
a 2.4:1 mixture of diastereomers. Alkylation of 6 was
(14) Keck, G. E.; Palani, A.; McHardy, S. F. J . Org. Chem. 1994,
59, 3113.
(15) (a) J adhav, P. K.; Bhat, K. S.; Perumaal, T.; Brown, H. C. J .
Org. Chem. 1986, 51, 432. (b) Racgerlaa, U. S.; Brown, H. C. J . Org.
Chem. 1991, 56, 401. (c) Molander, G. A.; Haar, J . P. J . Am. Chem.
Soc. 1993, 115, 40.
(16) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J . Am. Chem. Soc. 1994,
115, 8467.
(17) (a) Ghosh, A. K.; Cappiello, J .; Shin, D. Tetrahedron Lett. 1998,
39, 4651. (b) Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743. (c)
Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J .; van Delft, F. L.
Angew. Chem., Int. Ed. Engl. 1998, 37, 1874.
(18) Dahanukar, V. H.; Rynchnovsky, S. D. J . Org. Chem. 1994, 61,
8317.
(19) The stereochemistry of 18 was supported by NOESY (CDCl3)
experiment in which no NOE was observed between the C5 proton and
C1 proton. However, a NOE was observed for the isomer 19, which
was prepared as a mixture in subsequent experiments.
(20) This approach was also utilized by Mulzer and Hanbauer during
their synthesis of C1-C12 fragment of laulimalide; see: ref 10b.
(21) Garegg, P. J .; Samuelsson, B. Chem. Commun. 1979, 978.
(22) J ulia, M.; Paris, J . M. Tetrahedron Lett. 1973, 14, 4833.
(23) Smith, A. B.; Zhuang, L.; Brook, C. S.; Boldi, A. M.; MaBriar,
M. D.; Moser, W. H.; Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin,
Q. Tetrahedron Lett. 1997, 38, 8667.

8976 J . Org. Chem., Vol. 66, No. 26, 2001
Ghosh et al.
Sch em e 3a
Sch em e 4a
a
Key: (a) Isopropenylmagnesium bromide, CuCN (10%), THF,
-78 to +23 °C (94%); (b) KH, 18-crown-6 (cat.), allyl bromide, THF,
0 to 23 °C (quantitative); (c) Cl2(PCy3)2RudCHPh (10%), CH2Cl2;
i
(d) CSA, MeOH (81%); (e) DMSO, (COCl)2, Pr2NEt, CH2Cl2, -78
°C; (f) CBr4, PPh3, CH2Cl2, 0-23 °C (67%).
Sch em e 5a
a
Key: (a) K-10, CH2dCHOTBS, CH2Cl2, 23 °C; (b) NaBH4,
MeOH, 0 °C (54%); (c) TBSCl, imidazole, DMF, 23 °C (75%); (d)
Li, NH3 (95%); (e) I2, PPh3, imidazole, Et2O/CH3CN (96%); (f) NaH,
PhSO2CH2CO2Me, EtOH, 23 °C (83%); (g) NaH, DMF, 0 °C then
iodide 8, 60 °C (89%); (h) Red-Al, THF, 0 °C; (i) PhCOCl, Et3N,
DMAP (cat.), CH2Cl2; (j) Na(Hg), Na2HPO4, MeOH, -20 to +23
°C (72%); (k) MOMCl, iPr2NEt, CH2Cl2; (l) DDQ, pH 7 buffer (81%);
i
(m) DMSO, (COCl)2, Pr2NEt, CH2Cl2, -78 °C (85%).
a
Key: (a) PhSO2CH3, nBuLi, THF, 0 °C, 1 h then HMPA, 11,
effectively carried out by treatment of 6 with NaH and
iodide 8 in DMF initially at 0 °C for 15 min and then at
60 °C for 12 h. Alkylated lactone 22 was obtained in 89%
yield as a mixture of isomers (4.2:1) by 1H-NMR analysis.
No attempts were made to determine the stereochemistry
of the alkylated products, and the mixture was utilized
in the next reaction. Red-Al reduction of lactone mixture
22 afforded the corresponding diols. Benzoylation of the
resulting diols furnished the dibenzoate derivatives.
Exposure of these dibenzoates to Na(Hg) in MeOH at
-20° to +23 °C afforded 23 in 72% yield over the three
step sequence.24 Thus, the above methodology efficiently
introduced the C13-methylene unit and C15-hydroxyl
group in 23, and this protocol may find further use in
synthesis. Our subsequent synthetic plan was to convert
23 to aldehyde fragment 4. This was accomplished in a
three step sequence involving: (1) protection of the C15
-hydroxyl group as a MOM ether, (2) removal of the PMB
group by exposure to DDQ, and (3) Swern oxidation of
the resulting alcohol to furnish C3-C16 segment 4 in 69%
yield (from 23).
Syn th esis of C17-C28 F r a gm en t 5. The synthesis of
fragment 5 began with tetrahydropyranyl glycidol 1125
and utilized ring-closing olefin metathesis as the key step.
Epoxide opening by isopropenylmagnesium bromide in
the presence of a catalytic amount of CuCN at -78 to
+23 °C for 2 h afforded the homoallylic alcohol in 94%
yield. Treatment of the homoallylic alcohol with potas-
sium hydride and allyl bromide in the presence of a
catalytic amount of 18-crown-6 in THF furnished allyl
-78 to +23 °C (94%); (b) NaH, PMBCl, DMF, 0-23 °C (85%); (c)
i
CSA, MeOH (91%); (d) DMSO, (COCl)2, Pr2NEt, CH2Cl2, -78 °C
(90%); (e) NaClO2, 2-methyl-2-butene, NaH2PO4, tBuOH; (f)
MeONHMe‚HCl, N-methylpiperidine, isobutyl chloroformate,
CH2Cl2, 0-23 °C (83%).
ether 24 in quantitative yield. Exposure of 24 to Grubbs’
catalyst (10 mol %) in CH2Cl2 at 23 °C for 2 h afforded
the dihydropyran derivative which, upon exposure to
CSA in methanol, provided alcohol 25 in 81% yield over
two steps. Our next synthetic plan requires the conver-
sion of dihydropyran 25 to dibromo olefin 7, an alkynyl
anion precursor. Thus, Swern oxidation of 25 followed
by exposure of the resulting aldehyde to Corey-Fuchs’
homologation conditions26 with carbon tetrabromide and
triphenylphosphine in CH2Cl2 at 0-23 °C for 30 min
afforded dibromo olefin 7 in 67% yield over two steps
(Scheme 4).
Optically active glycidol derivative 11 was also utilized
in the preparation of aldehyde 9 and Weinreb amide 27.
As shown in Scheme 5, opening of epoxide 11 with
lithiated methyl phenylsulfone in the presence of HMPA
at -78 to +23 °C for 2 h provided the corresponding
alcohol in 94% yield. Protection of the resulting alcohol
with NaH and PMBCl in DMF at 0-23 °C furnished
PMB ether 26. Removal of the THP group by treatment
with CSA in methanol followed by Swern oxidation of the
resulting alcohol afforded aldehyde 9 in 82% for the two
step sequence. Oxidation of aldehyde 9 by NaClO2 gave
the corresponding acid which was exposed to isobutyl
chloroformate, N-methylpiperidine and N,O-dimethylhy-
droxyamine in CH2Cl2 at 0 °C to give Weinreb amide 27
in 83% yield for two steps.27 Thus, with the preparation
(24) Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S.
Tetrahedron Lett. 1995, 36, 5607.
(25) Meng, D.; Bertinato, P.; Balog, A.; Su, D.; Kamenecka, T.;
Sorensen, E.; Danishefsky, S. J . J . Am. Chem. Soc. 1997, 119, 10073.
(26) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1973, 14, 376.

Microtubule-Stabilizing Agent (-)-Laulimalide
J . Org. Chem., Vol. 66, No. 26, 2001 8977
Sch em e 6a
Sch em e 7a
a
Key: (a) nBuLi, -78 °C, THF, 1 h and 23 °C, 1 h then 9, -78
°C (64%); (b) Dess-Martin, CH2Cl2, 23 °C (81%); (c) nBuLi, -78
°C, THF, 1 h and 23 °C, 1 h then 27, -78 °C (59%); (d) L-Selectride,
THF, -78 °C (87%); (e) Red-Al, THF, -20 °C (81%); (f) CF3CO2H,
CH2Cl2, 23 °C; (g) p-MeO-Ph-CH(OMe)2, CSA, CH2Cl2, 23 °C
(71%); (h) DIBAL, CH2Cl2, -78 °C (74%); (i) Me2C(OMe)2, CSA,
CH2Cl2, 23 °C (70%).
a
Key: (a) nBuLi, -78 °C, THF, 15 min, and then 4, -78 to -40
°C; (b) Ac2O, Et3N, DMAP (cat.); CH2Cl2; (c) Na(Hg), Na2HPO4,
MeOH, -20 to +23 °C.
of aldehyde 9, the stage was set for coupling with dibromo
olefin 7-derived alkynyl anion.
as a PMB ether. Thus, the C19-PMB group was removed
by exposure to TFA30 and the resulting diol was treated
with p-methoxybenzylidene acetal and CSA in CH2Cl2 to
provide acetal 32 as a mixture of isomers in 71% com-
bined yield (isomer ratio 4.3:1 by 13C-NMR). DIBAL re-
duction of acetal 32 at -78 °C afforded C17-C28 sulfone
As illustrated in Scheme 6, coupling of the anion of 7
and aldehyde 9 was carried out by treatment of 7 with
nBuLi followed by reaction of the resulting alkynyl anion
with aldehyde 9 to provide an inseparable mixture of syn-
alcohol 28 and anti-alcohol 29 (syn:anti ) 1.8:1) in 64%
yield. The selectivity for the desired syn isomer was
improved by an oxidation/reduction sequence. Thus, the
mixture of alcohols 28 and 29 were oxidized by Dess-
Martin periodinane28 to give alkynyl ketone 30. Reduc-
tion of ketone 30 by L-selectride at -78 °C provided
desired syn-alkynyl alcohol 28 as a single diasteromer
1
segment 5 as a single regioisomer by H- and 13C-NMR
analysis. The observed regioselectivity of Dibal reduction
is presumably due to stabilization of Al chelation by the
sulfone oxygens.31 To ascertain the C20-hydroxyl stereo-
chemistry and the C21-C22 trans-olefin geometry, the
PMB group of 31 was removed with trifluoroacetic acid
in CH2Cl2 and the resulting diol was converted to iso-
propylidene derivative 33. In compound 33, NOEs were
observed between HA and HC as well as between the
1
by H- and 13C-NMR analysis. The reaction presumably
proceeded via a Felkin-Anh model as described previ-
ously.29 Attempts to obtain 28 by nucleophilic addition
of the 7-derived alkynyl anion to aldehyde 9 under
chelation control were unsuccessful. Treatment of the
dibromo olefin 7-derived alkynyl anion with Weinreb
amide 27 at -78 °C also provided an alternative access
to alkynyl ketone 30 in 59% yield.
Reduction of alkynyl alcohol 28 with Red-Al in THF
at -20 °C for 1 h set the C21-C22 trans-olefin geometry.
Trans-allylic alcohol 31 was obtained exclusively in 81%
isolated yield. As outlined in our retrosynthetic analysis,
fragment 5 requires the protection of the allylic alcohol
â-sulfonyl hydrogens and HB. The coupling constant (J CD
of 15.5 Hz provided evidence of trans-olefin geometry.
)
Cou p lin g of F r a gm en ts 4 a n d 5. With the efficient
preparation of C3-C16 aldehyde fragment 4 and C16-C28
sulfone fragment 5, our synthetic efforts were then
focused on the assembly of these fragments by J ulia
olefination.22 As shown in Scheme 7, sulfone 5 was first
lithiated with 2.1 equiv of nBuLi in THF at -78 °C for
15 min. The resulting dianion was reacted with aldehyde
4 at -78 to -40 °C for 2 h to provide the corresponding
(27) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(28) Merger, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(29) Larcheveque, M.; Lalanov, J . Chem. Commun. 1985, 83.
(30) Yan, L.; Kahne, D. Synlett 1995, 523.
(31) We are currently investigating similar chelation controlled
reduction in our laboratory.

8978 J . Org. Chem., Vol. 66, No. 26, 2001
Ghosh et al.
Sch em e 8a
Sch em e 9a
a
Key: (a) DIBAL, CH2Cl2, -78 °C, and then Ac2O, pyridine,
DMAP, -78 to +23 °C; (b) BF3‚OEt2, CH2Cl2, CH2dCHCH2SiMe3,
-78 °C (82%); (c) TIPSOTf, 2,6-lutidine, CH2Cl2, 0-23 °C (80%);
(d) DDQ, pH 7 buffer, CH2Cl2 (43%); (e) acryloyl chloride, Et3N,
CH2Cl2, 0 °C (49%); (f) Cl2(PCy3)2RudCHPh (10%), CH2Cl2.
a
i
Key: (a) (CF3CH2O)2P(O)CH2CO2H, Cl3C6H2COCl, Pr2NEt,
DMAP, benzene; (b) AcOH-THF-H2O (3:1:1), 23 °C (99%); (c)
Dess-Martin, CH2Cl2, 23 °C (79%); (d) K2CO3, 18-crown-6, toluene,
-20 to 0 °C (84%).
mixture of R-hydroxy sulfone derivatives. Acylation of the
resulting mixture with Ac2O, Et3N, and a catalytic
amount of DMAP followed by exposure of the resulting
diacetate to Na(Hg) in methanol at -20 to +23 °C
furnished a mixture (3.4:1) of C16-C17 trans-olefin 3 and
cis-olefin 34 in 44% combined yield. Both isomers were
separated by silica gel chromatography. Similarly, J ulia
reaction of isomeric sulfone 31 with aldehyde 4 as
described above provided a mixture (2.7:1) of trans-olefin
35 and cis-olefin 36 in 63% combined yields. The isomers
were again readily separated by silica gel chromatogra-
phy.
under a variety of reaction conditions resulted in decom-
position of the starting material. We then focused our
attention on the following intramolecular Horner-Em-
mons olefination-based approach.
Ma cr ocycliza t ion b y In t r a m olecu la r Hor n er -
Em m on s Rea ction . Intramolecular Horner-Emmons
reactions have been utilized in the syntheses of many
functionalized macrolactones.32 Recently, Forsyth33 em-
ployed this reaction to install the key cis-macrolactone
moiety of phorboxazole. Encouraged by this precedence,
we planned to carry out the intramolecular Horner-
Emmons reaction between the C19-phosphonoacetate and
C3-aldehyde using Still’s protocol.34 As outlined in Scheme
9, acylation of the C19-hydroxy group with bis(2,2,2-
trifluoroethyl)phosphonoacetic acid under Yamaguchi
conditions afforded the corresponding ester.35 Removal
of the TBS group by exposure to aqueous acetic acid in
THF at 23 °C furnished alcohol 40a in near quantitative
yield. Oxidation of alcohol 40a with Dess-Martin perio-
dinane28 followed by treatment of the resulting aldehyde
with K2CO3 in the presence of 18-crown-6 in toluene at
-20 to 0 °C afforded a mixture (1:2) of cis- and trans-
macrolactones 41a and 42b in 84% isolated yield. Both
isomers were separated by silica gel chromatography.
Many attempts to improve the ratio of the desired cis-
isomer by changing the protecting group at C20 were
Attem pted Macr ocyclization by Rin g-Closin g Ole-
fin Meta th esis. With successful J ulia coupling of the
key fragments, we now approached the crucial macrocy-
clization step which required the formation of an 18-
membered R,â-unsaturated macrolactone with C2-C3 cis-
olefin geometry. Initially, we relied upon a ring-closing
olefin metathesis approach to construct the macrolac-
tone.13 To incorporate the corresponding allyl side chain
at C5, δ-lactone 16 was utilized. As depicted in Scheme
8, reduction of 16 with DIBAL at -78 °C followed by
reaction of the resulting lactol with acetic anhydride,
pyridine, and DMAP, as described by Dahanukar and
Rychnovsky provided the corresponding glycosyl ac-
etate.18 Exposure of the acetate to allyltrimethylsilane
in the presence of BF3‚Et2O in CH2Cl2 at -78 °C afforded
anomeric allyation product 37 as a single isomer (82%
from 16). Allyl derivative 37 was transformed into the
key macrolactonization precursor 38 as described above.
Protection of 38 as a TIPS ether followed by removal of
the PMB group by DDQ and acylation with acryloyl
chloride and Et3N afforded acrylate ester 39. Unfortu-
nately, attempted ring-closing olefin metathesis of 39
(32) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(33) Forsyth, C. J .; Ajmed, F.; Cink, R. D.; Lee, C. S. J . Am. Chem.
Soc. 1998, 120, 5597.
(34) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(35) Inanaga, J .; Hirata, K.; Saeki, T.; Yamaguchi, M. Bull. Chem.
Soc. J pn. 1979, 53, 1989.

Microtubule-Stabilizing Agent (-)-Laulimalide
J . Org. Chem., Vol. 66, No. 26, 2001 8979
Sch em e 10a
Sch em e 11a
a
Key: (a) hν, Et2O (66%).
unsuccessful. Horner-Emmons reaction of 40b with the
C20 alcohol protected as a TIPS ether under the above
reaction conditions provided a mixture of macrolactones
41b and 42b (cis:trans ) 1:10) in 64% yield. Small
protecting groups such as MOM and MEM (40c for
MOM) resulted in a slight improvement in the cis-isomer
ratio. Formation of (diphenylphosphono)acetate deriva-
tive 40d and subsequent Horner-Emmons reaction
resulted in only slight improvement of cis-selectivity (cis:
trans ) 1:1.7) at the expense of yield.36 Attempts to
improve the ratio by forming the C16-C17 epoxide or
changing reaction conditions were also unsuccessful.
To improve the overall yield of cis-macrolactone 41, we
attempted photoisomerization of trans-macrolactone 42a .
As depicted in Scheme 10, irradiation of 41a was per-
formed in ether under UV in a Rayonet photochemical
reactor for 50 min to furnish a 1:1 mixture of trans-
macrolactone 42a and cis-macrolactone 41a in 66%
yield.37 Reaction time is critical as prolonged time of
irradiation did not increase the yield of the cis-isomer,
but resulted in decomposition of both isomers. Since both
isomers were separated, the overall yield of desired cis-
macrolactone 41a was improved to 47% after photo-
isomerization. The identity of the olefin geometry of the
cis- and trans-isomers were established by their observed
coupling constants (J ) 11.6 Hz for 41a and 17 Hz for
42b).
Ya m a gu ch i Ma cr ocycliza tion . To set the cis-olefin
geometry, we investigated the Yamaguchi macrolacton-
ization of the appropriate cis-R,â-unsaturated acid. Prepa-
ration of such a sensitive cis-R,â-unsaturated acid was
previously reported by Roush during the synthesis of
verrucarin B.38 We therefore examined the macrolacton-
ization between the C19-hydroxyl group and the C1-
alkenyl acid utilizing Yamaguchi protocol. As illustrated
in Scheme 11, we chose to use a 2-(trimethylsilyl)ethyl
ester as the precursor for the C1-alkenyl acid. It has been
shown by Roush and Blizzard that such an ester blocking
group can be removed under mild conditions.38b It should
be noted that attempts to obtain the Z-acid by hydrolyz-
ing the corresponding methyl ester resulted in deconju-
gation and isomerization, which was also observed by
a
Key: (a) Dihydropyran, PPTS, CH2Cl2; (b) TBAF, THF (76%);
(c) Dess-Martin, CH2Cl2; (d) KN(TMS)2, 18-crown-6, (PhO)2P(O)-
CH2CO2CH2CH2SiMe3, THF, -78 °C (64%); (e) DDQ, pH 7 buffer;
(f) TBAF, THF (60%); (g) Cl3PhCOCl, iPr2NEt, THF and then
DMAP, benzene (65%).
Paterson.10a Thus, alcohol 35 was reacted with dihydro-
pyran and a catalytic amount of PPTS in CH2Cl2 and the
resulting THP ether was treated with TBAF in THF to
provide the corresponding primary alcohol in 76% yield
for two steps. Oxidation of the primary alcohol with
Dess-Martin periodinane28 and subsequent Horner-
Emmons reaction of the resulting aldehyde with (PhO)2P-
(O)CH2CO2CH2CH2SiMe3, KN(TMS)2, and 18-crown-6
furnished cis-R,â-unsaturated ester 43 in 64% yield as a
single isomer by 1H-NMR (400 MHz) analysis. Successive
treatment of 43 with DDQ and TBAF in THF resulted
in the removal of the PMB ether and silyl ester, respec-
tively. The corresponding cis-hydroxy acid was obtained
in 60% yield. Exposure of the resulting acid to Yamaguchi
lactonization conditions35 at 23 °C, however, provided a
mixture of cis- and trans-macrolactones 44 and 45 (cis:
trans ) 1:2) in 65% isolated yield. Roush had previously
observed such an isomerization of a cis-olefin during the
macrolactonization step of the verrucarin B synthesis.
He proposed that the reason for this olefin isomerization
was probably due to the reversible Michael addition of
the acylating catalyst (DMAP) to the active acylating
agent.38 Numerous attempts to effect this cyclization
under a variety of reaction conditions (base, acylating
agent, etc.) did not increase the ratio of desired cis-isomer
44. The inability of the Horner-Emmons reaction or the
Yamaguchi macrolactonization of the cis-R,â-unsaturated
acid to set the Z-olefin geometry efficiently prompted us
to investigate the Yamaguchi macrolactonization of a
hydroxy alkynoic acid. Once this alkynyl macrolactone
is formed, one can easily set the cis-olefin geometry by
selective hydrogenation of the alkyne functionality.
As shown in Scheme 12, the C19-alcohol of 3 was first
protected as a THP ether by treatment with dihydropy-
ran in the presence of PPTS in CH2Cl2. Subsequent
removal of the TBS ether by reaction with nBu4N+F- in
THF furnished primary alcohol 46 in 87% yield for the
two step sequence. Oxidation of alcohol 46 with Dess-
(36) Ando, K. J . Org. Chem. 1999, 64, 8409, and references therein.
(37) Smith, A. B.; Lupo, A. T.; Ohba, M.; Chen, K. J . Am. Chem.
Soc. 1989, 111, 6648.
(38) (a) Roush, W. R.; Spada, A. P. Tetrahedron Lett. 1983, 24, 3693.
(b) Roush, W. R.; Blizzard, T. A. J . Org. Chem. 1994, 59, 7549.

8980 J . Org. Chem., Vol. 66, No. 26, 2001
Ghosh et al.
Sch em e 12a
Sch em e 13a
a
Key: (a) PPTS, tert-butyl alcohol, 84 °C (45%); (b) TBHP, (+)-
DET, Ti(OiPr)4, CH2Cl2, -20 °C; (c) DDQ, pH 7 buffer, CH2Cl2
(48%).
reflux for 8 h.40 The desired allylic alcohol was obtained
in 45% isolated yield. Attempts to improve this selective
deprotection with other acid-catalyzed reaction conditions
were less effective because of substantial decomposition
of the molecule. Sharpless epoxidation41 of the resulting
alcohol with (+)-DET proceeded uneventfully to afford
1
epoxide 49 as a single isomer by H-NMR and 13C-NMR
analysis. Removal of the C20-PMB ether by exposure to
DDQ furnished synthetic (-)-laulimalide (1) in 48% yield
for the two step sequence. Spectral data (1H- and 13C-
NMR) and TLC characteristics of synthetic laulimalide
([R]23 ) -196 c 0.23, CHCl3) are in full agreement with
D
a sample of natural laulimalide (lit.4 [R]29D ) -200 c 1.03,
a
Key: (a) Dihydropyran, PPTS, CH2Cl2; (b) TBAF, THF (87%);
(c) Dess-Martin, CH2Cl2; (d) CBr4, PPh3, CH2Cl2, 0 °C; (e) nBuLi,
THF, -78 °C, and then ClCO2Me, -78 °C (59%); (f) CSA, MeOH;
(g) LiOH, THF, H2O (74%); (h) Cl3PhCOCl, iPr2NEt, THF and then
DMAP, benzene (68%); (i) H2, Lindlar’s catalyst, 1-hexene, EtOAc
(94%).
CHCl3) kindly provided by Professor Higa.
Con clu sion
A stereocontrolled and convergent synthesis of (-)-
laulimalide has been achieved in 30 steps (the longest
linear sequence). A number of key features of this
synthesis are noteworthy. The synthesis features a J ulia
reaction for coupling of the C3-C16 and C17-C28 frag-
ments and development of both intramolecular Horner-
Emmons reaction and Yamaguchi lactonization protocols
for the construction of the macrolactone with cis-olefin
geometry. The trans-macrolactone could be photoisomer-
ized to a 1:1 mixture of cis- and trans-isomers. Other key
steps included the ring-closing olefin metathesis to
construct both dihydropyran rings, a highly diastereo-
selective anomeric alkylation to append the side chain
of one of the dihydropyrans, and a novel J ulia reaction
protocol for installation of the C13-exo-methlene and C15-
hydroxy group. The present synthesis will provide con-
venient access to a variety of structural analogues of
laulimalide for biological studies.
Martin periodinane provided the aldehyde which was
subjected to Corey-Fuchs’ homologation conditions26
using CBr4 and PPh3 in CH2Cl2 at 0 °C to afford the
corresponding dibromo olefin. This olefin was then
converted to alkynyl ester 47 in a one-pot procedure.
Thus, reaction of the dibromo olefin with nBuLi at -78
°C afforded the alkynyl anion, which, upon treatment
with methyl chloroformate at -78 °C, furnished 47 in
59% yield for the three-step sequence. Removal of the
THP ether by exposure to CSA in methanol followed by
saponification of the methyl ester by treatment with
aqueous lithium hydroxide afforded the precursor hy-
droxy acid in 74% yield. We now arrived at the critical
macrolactonization step. Thus, subjection of the hydroxy
acid to Yamaguchi conditions35 with 2,4,6-trichloroben-
zoyl chloride, N,N-diisopropylethylamine and DMAP
furnished macrolactone 48 in 68% yield. Hydrogenation
of lactone 48 over Lindlar’s catalyst in a mixture (1:1) of
1-hexene and EtOAc provided cis-macrolactone 41a as a
single isomer in 94% yield.39
Exp er im en ta l Section
Melting points were recorded and are uncorrected.Anhy-
drous solvents and reagents were obtained as follows: tet-
rahydrofuran and diethyl ether, distillation from sodium and
benzophenone; methylene chloride, distillation from CaH2;
triethylamine, distillation from CaH2. All other solvents were
HPLC grade. Column chromatography was performed with
Whatman 240-400 mesh silica gel under low pressure of 5-10
Syn th esis of La u lim a lid e. The completion of the
synthesis of (-)-laulimalide is outlined in Scheme 13. At
this point, our synthetic plan required selective removal
of the C15-MOM protecting group to effect selective
epoxidation of the resulting allylic alcohol utilizing
Sharpless epoxidation. Thus, the C15-MOM group of 41a
was selectively removed by treatment with excess PPTS
in tBuOH followed by heating the resulting mixture at
(40) Monti, H.; Leandri, G.; Klos-Ringquet, M.; Corriol, C. Synth.
Commun. 1983, 37, 1013.
(41) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 103-
158.
(39) Ho, T.-L.; Liu, S. H. Synth. Commun. 1987, 17, 969.

Microtubule-Stabilizing Agent (-)-Laulimalide
J . Org. Chem., Vol. 66, No. 26, 2001 8981
psi. Thin-layer chromatography (TLC) was carried out with
E. Merck silica gel 60 F-254 plates.
Hz, 2H), 6.85 (d, J ) 8.6 Hz, 2H), 5.91 (m, 1H), 5.86-5.50 (m,
4H), 5.42 (s, 1H), 5.28 (m, 1H), 4.83 (s, 1H), 4.78 (s, 1H), 4.67
(d, J ) 6.8 Hz, 1H), 4.57 (d, J ) 11.6 Hz, 1H), 4.44 (d, J ) 6.8
Hz, 1H), 4.31 (d, J ) 11.6 Hz, 2H), 4.18 (s, 2H), 4.10-3.99 (m,
3H), 3.88 (m, 1H), 3.83-3.69 (m, 4H), 3.79 (s, 3H), 3.73 (s, 3H),
3.41 (m, 1H), 3.31 (s, 3H), 2.61 (dd, J ) 16.8, 6.7 Hz, 2H), 2.41-
1.79 (m, 11H), 1.71 (s, 3H), 1.68-1.41 (m, 6H), 1.11 (m, 1H),
0.88 (d, J ) 6.1 Hz, 3H). HRMS (FAB). Calcd for C46H64O10Na
[(M + Na)+]: 799.4397. Found: 799.4395.
Alcoh ol 46. To a stirred solution of alcohol 3 (125 mg, 0.17
mmol) in CH2Cl2 (3 mL) was added dihydropyran (0.3 mL)
followed by PPTS (10 mg). The resulting mixture was stirred
at 23 °C for 5 h. After this period, the mixture was washed
with saturated aqueous NaHCO3 and brine. The organic layer
was dried over anhydrous Na2SO4 and concentrated under
reduced pressure. After azeotropic removal of water with
benzen, the residue was dissolved in THF. TBAF (0.5 mL, 1.0
M in THF; 0.5 mmol) was added dropwise. The resulting
mixture was stirred at 23 °C for 3 h. The mixture was
quenched with saturated aqueous NH4Cl and extracted with
EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (40%
EtOAc/hexane) to afford alcohol 46 as a colorless oil (102 mg,
Ma cr ola cton e 48. To a stirred solution of ester 47 (34 mg,
0.044 mmol) in MeOH (2 mL) was added CSA (4 mg). The
resulting mixture was stirred for 1 h. After this period, Et3N
(1 drop) was added. The mixture was concentrated under
reduced pressure. The residue was dissolved in THF (2.5 mL).
A solution of LiOH (10 mg, 0.24 mmol) in H2O (0.5 mL) was
added. The resulting mixture was stirred for 2 h. After this
period, saturated aqueous NH4Cl was added. The mixture was
extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated. The residue was
purified by silica gel chromatography (20% MeOH/EtOAc) to
afford the hydroxy acid (22 mg, 74%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ 7.23 (d, J ) 8.6 Hz, 2H), 6.86 (d, J ) 8.6
Hz, 2H), 5.85-5.60 (m, 5H), 5.43 (s, 1H), 5.37 (dd, J ) 15.6,
7.5 Hz 1H), 4.85 (s, 1H), 4.78 (s, 1H), 4.63 (d, J ) 6.9 Hz, 1H),
4.59 (d, J ) 11.8 Hz, 1H), 4.47 (d, J ) 6.8 Hz, 1H), 4.32 (m,
1H), 4.28 (d, J ) 11.8 Hz, 1H), 4.20 (brs, 2H), 4.14-4.08 (m,
2H), 3.80 (s, 3H), 3.74-3.63 (m, 3H), 3.30 (s, 3H), 2.71 (dd, J
) 17.4, 11.1 Hz, 1H), 2.37 (dd, J ) 17.4, 2.7 Hz, 1H), 2.34-
1.79 (m, 12H), 1.71 (s, 3H), 1.68-1.63 (m, 2H), 1.08 (m, 1H),
0.82 (d, J ) 6.4 Hz, 3H). HRMS (FAB). Calcd for C40H54O9Na
[(M + Na)+]: 701.3666. Found: 701.3677.
1
87%). H NMR (400 MHz, CDCl3): δ 7.22 (d, J ) 8.4 Hz, 2H),
6.86 (d, J ) 8.4 Hz, 2H), 5.87-5.75 (m, 2H), 5.72-5.63 (m,
2H), 5.57 (m, 1H), 5.43 (s, 1H), 5.29 (m, 1H), 4.84 (s, 1H), 4.78
(s, 1H), 4.68 (d, J ) 6.8 Hz, 1H), 4.57 (d, J ) 11.6 Hz, 1H),
4.46 (d, J ) 6.8 Hz, 1H), 4.36 (m, 1H), 4.35 (d, J ) 11.6 Hz,
2H), 4.19 (s, 2H), 4.15-4.05 (m, 2H), 3.88 (m, 1H), 3.83-3.70
(m, 5H), 3.80 (s, 3H), 3.42 (m, 1H), 3.31 (s, 3H), 2.38-1.78 (m,
20H), 1.72 (s, 3H), 1.69-1.63 (m, 2H), 1.10 (m, 1H), 0.87 (d, J
) 6.7 Hz, 3H). HRMS (FAB). Calcd for C43H64O9Na [(M +
Na)+]: 747.4448. Found: 747.4479.
Alk yn yl Ester 47. To a stirred solution of alcohol 46 (100
mg, 0.138 mmol) in wet CH2Cl2 (3 mL) was added Dess-
Martin periodinane (114 mg, 0.263 mmol). The resulting white
suspension was stirred for 30 min. After this period, the
mixture was subjected to direct silica gel chromatography
eluting with 20-25% EtOAc/hexane to afford the aldehyde
(87.5 mg, 88%) as a colorless oil which was used for next
To a stirred solution of the above hydroxy acid (14 mg, 0.02
i
mmol) in THF (1.5 mL) was added Pr2NEt (0.17 mL, 0.4 M in
benzene; 0.07 mmol) and trichlorobenzoyl chloride (0.11 mL,
0.4 M in benzene; 0.044 mmol). The resulting mixture was
stirred for 30 min. The mixture was concentrated under
reduced pressure. The residue was dissolved in benzene (21
mL). DMAP (10 mg, 0.082 mmol) in benzene (3 mL) was added
dropwise over a period of 30 min. The resulting suspension
was stirred for 12 h. The mixture was diluted with EtOAc and
washed with saturated aqueous NaHCO3 and aqueous 1 M
NaHSO4. The aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by silica
gel chromatography (20% EtOAc/hexane) to afford lactone 48
1
reaction immediately. H NMR (400 MHz, CDCl3): δ 9.80 (t,
J ) 1.4 Hz, 1H), 7.22 (d, J ) 8.4 Hz, 2H), 6.86 (d, J ) 8.4 Hz,
2H), 5.87-5.75 (m, 2H), 5.72-5.63 (m, 2H), 5.57 (m, 1H), 5.43
(s, 1H), 5.29 (m, 1H), 4.84 (s, 1H), 4.78 (s, 1H), 4.68 (d, J ) 6.8
Hz, 1H), 4.57 (d, J ) 11.6 Hz, 1H), 4.46 (d, J ) 6.8 Hz, 1H),
4.35 (d, J ) 11.6 Hz, 2H), 4.19 (s, 2H), 4.15-4.05 (m, 2H),
3.89-3.70 (m, 4H), 3.80 (s, 3H), 3.42 (m, 1H), 3.31 (s, 3H), 2.73
(m, 1H), 2.52 (dd, J ) 15.9, 4.5 Hz, 1H), 2.38-1.78 (m, 16H),
1.72 (s, 3H), 1.69-1.63 (m, 2H), 1.10 (m, 1H), 0.86 (d, J ) 6.7
Hz, 3H).
To a stirred solution of CBr4 (102 mg, 0.31 mmol) in
CH2Cl2 (3 mL) at 0 °C was sequentially added triphenylphos-
phine (161 mg, 0.61 mmol) and triethylamine (0.1 mL, 0.7
mmol). The resulting yellow solution was stirred for 10 min.
A solution of the above aldehyde in CH2Cl2 (3 mL) was added
dropwise. The mixture was stirred at 0 °C for 30 min. After
this period, the mixture was washed with saturated aqueous
NaHCO3, 1 M NaHSO4, and brine. The organic layer was dried
over anhydrous Na2SO4 and concentrated. The residue was
purified by silica gel chromatography (15% EtOAc/hexane) to
provide the dibromide (94.3 mg, 89%) which was used for next
23
1
as a colorless oil (9.2 mg, 68%). [R]D -46 (c 0.92, CHCl3). H
NMR (400 MHz, CDCl3): δ 7.23 (d, J ) 8.6 Hz, 2H), 6.86 (d,
J ) 8.6 Hz, 2H), 5.89 (m, 1H), 5.86 (dd, J ) 15.6, 5.6 Hz, 1H),
5.63-5.57 (m, 3H), 5.51 (dd, J ) 15.6, 6.8 Hz, 1H), 5.43 (s,
1H), 5.10 (m, 1H), 4.85 (s, 1H), 4.78 (s, 1H), 4.63 (d, J ) 6.9
Hz, 1H), 4.59 (d, J ) 11.8 Hz, 1H), 4.47 (d, J ) 6.8 Hz, 1H),
4.43 (brd, 11.0 Hz, 1H), 4.32 (d, J ) 11.8 Hz, 1H), 4.20 (brs,
2H), 4.08 (m, 1H), 3.85 (t, J ) 6.4 Hz, 1H), 3.80 (s, 3H), 3.69
(m, 1H), 3.30 (s, 3H), 2.71 (dd, J ) 17.4, 11.1 Hz, 1H), 2.37
(dd, J ) 17.4, 2.7 Hz, 1H), 2.34-1.79 (m, 12H), 1.71 (s, 3H),
1.58 (m, 1H), 1.08 (m, 1H), 0.82 (d, J ) 6.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 165.2, 159.1, 153.1, 144.7, 135.8, 134.9,
131.3, 130.1, 129.3, 127.6, 126.9, 126.7, 126.2, 119.7, 113.7,
113.5, 94.0, 86.8, 79.2, 76.2, 73.9, 73.2, 71.1, 70.1, 65.6, 65.1,
55.4, 55.2, 45.0, 43.2, 41.1, 35.7, 32.2, 31.3, 26.0, 24.0, 23.0,
1
reaction immediately. H NMR (400 MHz, CDCl3): δ 7.22 (d,
J ) 8.4 Hz, 2H), 6.86 (d, J ) 8.4 Hz, 2H), 6.50 (t, J ) 6.7 Hz,
1H), 5.87-5.75 (m, 2H), 5.72-5.63 (m, 2H), 5.57 (m, 1H), 5.43
(s, 1H), 5.29 (m, 1H), 4.84 (s, 1H), 4.78 (s, 1H), 4.68 (d, J ) 6.8
Hz, 1H), 4.57 (d, J ) 11.6 Hz, 1H), 4.46 (d, J ) 6.8 Hz, 1H),
4.35 (d, J ) 11.6 Hz, 2H), 4.19 (s, 2H), 4.15-4.05 (m, 2H),
3.89-3.70 (m, 4H), 3.80 (s, 3H), 3.42(m, 1H), 3.31 (s, 3H),
2.43-1.49 (m, 17H), 1.72 (s, 3H), 1.10 (m, 1H), 0.87 (d, J )
6.7 Hz, 3H).
18.5. HRMS (FAB). Calcd for
683.3560. Found: 683.3593.
C
40H52O8Na [(M + Na)+]:
Ma cr ola cton e 41a (fr om 48). To a solution of lactone 48
(8.5 mg, 0.013 mmol) in 1-hexene (1 mL) and EtOAc (1 mL)
was added Lindlar catalyst (2 mg). The resulting suspension
was vigorously stirred under a hydrogen balloon for 1.5 h. The
mixture was filtered through a pad of Celite and washed with
EtOAc. Concentration of the filtrate gave a residue, which was
purified by silica gel chromatography (20% EtOAc/hexane) to
afford cis-macrolactone 41a (8.0 mg, 94%).
Ep oxid e 49. A mixture of macrolactone 41a (15.6 mg, 0.024
mmol) and PPTS (81 mg, 0.32 mmol) in tert-butyl alcohol (1
mL) was heated at 83 °C for 8 h. The mixture was cooled to
23 °C and poured into water. The resulting mixture was
extracted with 25% EtOAc/hexane. The combined organic
To a stirred solution of the above dibromide (94.3 mg, 0.108
mmol) in THF (3 mL) at -78 °C was added nBuLi (0.15 mL,
1.6 M in hexane; 0.24 mmol) dropwise. The resulting red
mixture was stirred for 10 min. ClCO2Me (20 µL, 0.258 mmol)
was added dropwise. The mixture was stirred at -78 °C for
30 min before being quenched by saturated aqueous NH4Cl.
The mixture was extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by silica gel chromatography (20% EtOAc/
hexane) to afford alkynyl ester 47 (63 mg, 75% yield, 59% for
three steps). 1H NMR (400 MHz, CDCl3): δ 7.20 (d, J ) 8.6

8982 J . Org. Chem., Vol. 66, No. 26, 2001
Ghosh et al.
layers were washed with brine, dried over anhydrous Na2SO4,
and evaporated. The residue was chromatographed over silica
gel eluting with 20% EtOAc/hexane to furnish the allylic
mmol). The green mixture was stirred at 23 °C for 2 h. The
resulting orange suspension was then washed with saturated
aqueous NaHCO3. The aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried over anhy-
drous Na2SO4 and evaporated. The residue was chromato-
graphed over silica gel eluting with 25% EtOAc/hexane to give
23
alcohol as a colorless oil (6.5 mg, 45%). [R]d ) -125 (c 0.14,
1
CHCl3). IR (thin film): 3500, 1718 cm-1. H NMR (400 MHz,
CDCl3): δ 7.22 (d, J ) 8.6 Hz, 2H), 6.86 (d, J ) 8.6 Hz, 2H),
6.31 (m, 1H), 5.91(d, J ) 11.6 Hz, 1H), 5.84 (dd, J ) 15.6, 6.2
Hz, 1H), 5.83 (m, 1H), 5.70 (d, J ) 10.6 Hz, 1H), 5.63-5.58
(m, 3H), 5.43 (s, 1H), 5.06 (m, 1H), 4.84 (s, 2H), 4.59 (d, J )
11.8 Hz, 1H), 4.31 (d, J ) 11.8 Hz, 1H), 4.19 (s, 2H), 4.15-
4.06 (m, 3H), 3.85 (m, 1H), 3.80 (s, 3H), 3.55 (m, 1H), 2.33-
1.76 (m, 12H), 1.71 (s, 3H), 1.65 (m, 1H), 1.37-1.12 (m, 3H),
0.79 (d, J ) 6.8 Hz, 3H). MS (ESI): 641 (M+ + Na).
23
synthetic laulimalide 1 as a colorless oil (2.6 mg, 48%). [R]D
) -196 (c 0.23, CHCl3); lit.5c [R]D29 ) -200 (c 0.23, CHCl3). IR
1
(thin film): 3427, 1716 cm-1. H NMR (400 MHz, CDCl3): δ
6.45 (m, 1H), 5.91 (d, J ) 10.3 Hz, 1H), 5.84 (ddd, J ) 16.2,
5.3, 0.9 Hz, 1H), 5.83 (m, 1H), 5.74 (ddd, J ) 16.2, 6.2, 0.9 Hz,
1H), 5.69 (brd, J ) 10.1 Hz, 1H), 5.42 (s, 1H), 5.16 (ddd, J )
11.2, 5.2, 1.6 Hz, 1H), 4.86 (s, 1H), 4.85 (s, 1H), 4.31 (brd, J )
9.1 Hz, 1H), 4.22 (m, 1H), 4.17 (brs, 2H), 4.07 (m, 1H), 4.03
(m, 1H), 3.76 (m, 1H), 3.72 (m, 1H), 3.08 (m, 1H), 2.90 (t, J )
2.6 Hz, 1H), 2.38 (m, 1H), 2.36 (m, 1H), 2.22 (m, 1H), 2.12
(brd, J ) 15.7 Hz, 1H), 2.02-1.72 (m, 7H), 1.69 (s, 3H), 1.49
(m, 1H), 1.45 (m,1H), 1.33 (m, 1H), 0.82 (d, J ) 6.3 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 166.5, 150.7, 145.3, 134.3,
131.6, 129.1, 128.9, 125.6, 120.9, 120.1, 113.0, 73.9, 73.5, 73.4,
72.7, 68.3, 67.0, 66.1, 61.1, 52.5, 46.0, 43.8, 37.5, 36.0, 34.2,
33.8, 32.1, 29.9, 23.3, 21.2. MS (ESI): 515 (M+ + H). HRMS
(FAB). Calcd for C30H42O7Na [(M + Na)+]: 537.2828. Found:
537.2851.
To a suspension of powdered 4 Å molecular sieves (50 mg)
in CH2Cl2 (1 mL) at -20 °C were sequentially added diethyl-
D-tartrate (16.4 mg, 0.08 mmol) and Ti(OiPr)4 (20 µL, 0.067
mmol). The resulting mixture was stirred for 15 min at -20
°C, and then tert-butyl hydroperoxide (20 µL, 0.13 mmol; 6.7
M in n-decane) was added dropwise. The mixture was stirred
for 15 min, and then a solution of the above alcohol (6.5 mg,
0.011 mmol) in CH2Cl2 (2 mL) was added dropwise. The
resulting mixture was stirred for 1 h at -20 °C. After this
period, a mixture of 4 N NaOH (1 mL) and brine (1 mL) was
added and the resulting mixture was stirred at 0 °C for 1 h.
The layers were separated. The aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated to give
a residue which was used for next reaction immediately. An
analytical sample of 49 was isolated by silica gel chromatog-
raphy (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ
7.21 (d, J ) 8.6 Hz, 2H), 6.86 (dd, J ) 6.8, 2.0 Hz, 2H), 6.42
(dt, J ) 11.3, 3.6 Hz, 1H), 5.91-5.81 (m, 3H), 5.68 (d, J )
10.2 Hz, 1H), 5.59 (ddd, J ) 15.8, 6.9, 1.1 Hz, 1H), 5.43 (s,
1H), 5.21 (dd, J ) 10.4, 5.1 Hz, 1H), 4.84 (s, 1H), 4.83 (s, 1H),
4.59 (d, J ) 11.7 Hz, 1H), 4.32 (d, J ) 11.7 Hz, 1H), 4.30 (m,
1H), 4.19 (s, 2H), 4.09-4.03 (m, 3H), 3.87 (t, J ) 6.0 Hz, 1H),
3.80 (s, 3H), 3.75 (m, 1H), 3.04 (m, 1H), 2.87 (t, J ) 2.5 Hz,
1H), 2.40-1.74 (m, 12H), 1.59 (s, 3H), 1.45-1.30 (m, 3H), 0.82
(d, J ) 6.3 Hz, 3H).
Ack n ow led gm en t. Financial support by the Na-
tional Institutes of Health (GM 55600) is gratefully
acknowledged. We thank Dr. Marcus No¨tzel and Mr.
Geoff Bilcer for helpful discussions. The authors thank
Professor Higa for a sample of natural laulimalide and
NMR spectra.
Su p p or tin g In for m a tion Ava ila ble: Text describing
experimental details for synthesis of 3-9, 12, 13, 16, 18-37,
1
and 39-45 and figures showing H and 13C NMR spectra for
compounds 1, 3-9, 15, 16, 20, 22-23, 27, 30-33, 40a , 42a
1
and H NMR for 37-39, 41a , 43-45, and 48, 49. This material
is available free of charge via the Internet at http://pubs.acs.org.
La u lim a lid e 1. To a suspension of epoxide 49 in CH2Cl2 (1
mL) and pH 7 buffer (50 µL) was added DDQ (8 mg, 0.0352
J O010854H