Total synthesis of the antitumor agent (-)-laulimalide

Article abstract of DOI:10.1016/S0040-4039(02)00472-0

A stereocontrolled synthesis of the title compound is described. Key steps are an allylsilane addition to a chiral acetal as the major coupling step and a Yamaguchi macrolactonization for ring closure.

Full text of DOI:10.1016/S0040-4039(02)00472-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3381–3383
Total synthesis of the antitumor agent (−)-laulimalide
Johann Mulzer* and Martin Hanbauer
Institut fu¨r Organische Chemie der Universita¨t Wien, Wa¨hringer Str. 38, A-1090 Vienna, Austria
Received 7 March 2002; accepted 8 March 2002
Abstract—A stereocontrolled synthesis of the title compound is described. Key steps are an allylsilane addition to a chiral acetal
as the major coupling step and a Yamaguchi macrolactonization for ring closure. © 2002 Elsevier Science Ltd. All rights reserved.
The antimitotic macrolide laulimalide (1), also known
as fijianolide B, was isolated from several sponges
(Cacospongia mycofijiensis,1a Hyattella sp.,1b Fas-
ciospongia rimosa1c) and shows high cytotoxicity
against several NCI cell lines. The IC50 value of 1
against the KB cell line is 15 ng/mL and, addition-
ally, the compound maintains a high level of potency
against the multidrug resistant cell line SKVLB-1
(IC50=1.2 mM).2 Recently 1 was identified as sharing
the same mechanism of action as the anticancer drug
Taxol™ (paclitaxel). Apart from its potent micro-
tubule-stabilizing properties 1 also inhibits the P-gly-
coprotein, which is responsible for multiple-drug
resistance in tumor cells. The unique structural fea-
tures and the restricted natural supply of 1 have trig-
gered synthetic activities world-wide,3 resulting in the
first total synthesis by the Ghosh group4a,b followed
by two syntheses from our laboratory4c,e and one by
Paterson and coworkers.4d
Herein we report an approach to 1 via a Yamaguchi
macrolactonization of seco acid 2, the carbon skeleton
of which was assembled by an addition of allylsilane
4 to the chiral acetal 3 (Scheme 1). Building blocks 3
and 4 have been prepared from (S)-a-hydroxybutyro-
lactone and ethyl (S)-2-methyl-3-hydroxypropionate,
respectively.
The synthesis of 3 starts with TBDPS protected (S)-
a-hydroxybutyrolactone
8 (Scheme 2) which was
reacted with the lithium salt of diethyl methanephos-
phonate. Treatment with a second equivalent of base,
quenching with TESCl and aqueous work-up deliv-
ered the phosphonate 6.5
OH
OR
14
H
O
14
H
O
O
15
15
O
O
OH
H
HO
OR
COOH
H
H
H
O
O
2
1
14
TMS
H
OMOM
22
H
15
O
O
H
TBSO
O
21
OTBDPS
O
3
3
4
Scheme 1.
Keywords: marine metabolites; antitumor compounds; macrolactonization; allylsilane addition; chiral acetal.
* Corresponding author. Tel.: +431427752190; fax: +431427752189; e-mail: johann.mulzer@univie.ac.at
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00472-0

3382
J. Mulzer, M. Hanbauer / Tetrahedron Letters 43 (2002) 3381–3383
Scheme 2. Reagents and conditions: (a) TBDPSCl, imidazole, DMF, rt (93%). (b) (i) (EtO)2P(O)CH3, BuLi, THF, −78°C then
8, (ii) LDA, TESCl, THF, −78°C to rt, (iii) NH4Cl, H2O (79%).
Phosphonate 6 was used in a Horner–Wadsworth–
Emmons (HWE)-olefination with the known aldehyde
5 (Scheme 3).3d 1,2-Reduction of the resulting ketone
under Luche conditions6 delivered the desired syn iso-
mer 9 almost exclusively (>20:1). Protection of the
secondary alcohol as MOM ether, deprotection of the
TES ether and Parikh–Doering oxidation7 yielded
aldehyde 10, which was used in another HWE-olefi-
nation to produce the Weinreb amide 11. Reduction
to the unsaturated aldehyde and acetal formation
with (R,R)-(−)-2,4-pentandiol8 completed the synthesis
of the C15–C27 fragment 3.
Addition of allyl silane 4 to the chiral acetal 3 was
performed with several Lewis acids (SnCl4/DMF,
EtAlCl2, TiCl4/TEA) (Scheme 5); the best results were
obtained with TEA-treated TiCl4 to generate
diastereomerically pure adduct 15 in 57% yield. After
Dess–Martin oxidation of alcohol 15 to methyl
ketone 16 the chiral auxiliary was removed in a retro-
hetero-Michael reaction to form alcohol 17 which was
protected as the MOM ether. Both the TBS and the
TBDPS-protective groups were exchanged for TES,
and selective Swern oxidation of the primary TES
ether11 yielded aldehyde 21 which was submitted to
an Ando–Horner–Emmons olefination12 with (diphen-
oxy-phosphoryl)-acetic acid 2-trimethylsilanyl-ethyl
ester. Treatment of the resulting (Z)-enoate with
TBAF yielded the seco acid 22 which was cyclized
under Yamaguchi conditions to macrolactone 23 as a
mixture of Z and E isomer (Z/E=1/2.7, separation
of Z-isomer). Deprotection of the MOM ethers and
selective Sharpless epoxidation as described earlier4c
completed the synthesis of 1, which was identical (1H
and 13C NMR spectra, HPLC Rf) spectra with the
compound described previously.1,4a,c,d,f
For the synthesis of allylsilane 4 (Scheme 4), the
known aldehyde 12, readily available from (S)-2-
methyl-3-hydroxypropionate in eight steps,3c was
reduced to the alcohol and protected as the TBS
ether. Removal of the PMB group yielded the alcohol
13, which was elaborated into methyl ketone 14.
Deprotonation under kinetic control, treatment of the
9
resulting enolate with PhNTf2 to generate the enol
triflate and palladium catalyzed coupling with
TMSCH2MgCl10 in the presence of LiCl4e delivered
allyl silane 4.
OH
OMOM
H
H
H
O
OTES
O
O
O
c,d,e
a,b
O
TBDPSO
OTBDPS
5
9
10
OMOM
OMOM
Me
H
H
O
O
f
O
N
g,h
OMe
OTBDPS
O
OTBDPS
O
3
11
Scheme 3. Reagents and conditions: (a) 6, LiCl, TEA, THF, 0°C to rt (81%). (b) NaBH4, CeCl3, MeOH, −78°C (94%). (c)
MOMCl, DIEA, TBAI, DMF, rt. (d) pTsOH, MeOH, rt (85% over two steps). (e) Py·SO3, DMSO, TEA, DCM, rt (95%). (f)
(EtO)2P(O)CH2C(O)N(OMe)Me, NaH, THF, rt (92%). (g) DIBAH, THF, −78°C (89%). (h) (R,R)-(−)-2,4-Pentandiol, montmoril-
lonite K-10, toluene, 40°C (99%).
O
TMS
H
OPMB
H
OH
OTBS
TBSO
OTBS
O
g,h
d,e,f
a,b,c
H
H
H
H
H
H
O
O
O
O
4
12
14
13
Scheme 4. Reagents and conditions: (a) NaBH4, MeOH, 0°C (95%). (b) TBSCl, imidazole, DMF, rt (90%). (c) DDQ, DCM/H2O
(10/1), rt (86%). (d) pTsCl, TEA, DMAP, DCM, rt. (e) NaCN, DMSO, 80°C (87% over two steps). (f) MeLi, Et2O, 0°C (96%).
(g) (i) KHMDS, THF, −100°C then 14, (ii) PhNTf2, THF, −100 to rt (81%). (h) TMSCH2MgCl, LiCl, Pd(PPh3)4, Et2O, rt (93%).

J. Mulzer, M. Hanbauer / Tetrahedron Letters 43 (2002) 3381–3383
3383
Scheme 5. Reagents and conditions: (a) TiCl4, TEA, DCM, −60 to −20°C (57%). (b) DMP, NaHCO3, DCM, rt (79%). (c) K2CO3,
MeOH, rt (89%). (d) MOMCl, DIEA, TBAI, DMF, rt (97%). (e) TBAF, THF, rt (96%). (f) TESCl, pyridine, rt (89%). (g)
(COCl)2, DMSO, DCM, TEA, −50°C to rt (90%). (h) (PhO)2P(O)CH2C(O)OCH2CH2TMS, KHMDS, 18-crown-6, THF, −78°C
(80%). (i) TBAF, THF, rt (89%). (j) (i) 2,4,6-Trichlorbenzoyl chloride, DIEA, THF, benzene, (ii) DMAP, benzene (60%).
In conclusion, we have described a total synthesis of
laulimalide which is highly convergent and stereocon-
trolled except for the macrocyclization. The longest
linear sequence is 27 steps with an overall yield of
2.1%.
Lee, I. Y. C. Bull. Kor. Chem. Soc. 2001, 22, 791–792.
4. (a) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000,
122, 11027–11028; (b) Ghosh, A. K.; Wang, Y. Tetra-
8
hedron Lett. 2001, 42, 3399–3401; (c) Mulzer, J.; Ohler,
E. Angew. Chem., Int. Ed. 2001, 40, 3842–3846; (d)
Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3,
3149–3152; (e) Enev, V. S.; Ka¨hlig, H.; Mulzer, J. J.
Am. Chem. Soc. 2001, 123, 10764–10765; (f) Ghosh, A.
K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66,
8973–8982.
References
1. (a) Quin˜oa`, E.; Kakou, Y.; Crews, P. J. Org. Chem.
1988, 53, 3642–3644; (b) Corley, D. G.; Herb, R.;
Moore, R. E.; Scheuer, P. J.; Paul, V. J. J. Org. Chem.
1988, 53, 3644–3646; (c) Jefford, C. W.; Bernardinelli,
G.; Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37,
159–162.
2. Mooberry, S. L.; Tien, G.; Hernandez, A.; Plubrukarn,
A.; Davidson, B. S. Cancer Res. 1999, 59, 653–660.
3. (a) Shimizu, A.; Nishiyama, S. Tetrahedron Lett. 1997,
38, 6011–6014; (b) Shimizu, A.; Nishiyama, S. Synlett
1998, 1209–1210; (c) Mulzer, J.; Hanbauer, M. Tetra-
5. For a related protocol, see: Ditrich, K.; Hoffmann, R.
W. Tetrahedron Lett. 1985, 26, 6325–6328.
6. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
7. Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967,
89, 5505–5507.
8. Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry
1990, 1, 477–511.
9. Scott, W.; McMurry, E. Acc. Chem. Res. 1988, 21, 47–
59.
10. Kusam, H.; Hara, R.; Kawahara, S.; Nishimori, T.;
Kashima, H.; Nakamura, N.; Morihira, K.; Kuvajima,
I. J. Am. Chem. Soc. 2000, 122, 3811–3820.
11. Tolstikov, G. A.; Miftakhov, M. S.; Vostrikov, N. S.;
Komissarova, N. G.; Adler, M. E.; Kuznetsov, O. M.
J. Org. Chem. USSR (Engl. Transl.) 1988, 24, 224–225.
12. Ando, K. J. Org. Chem. 1999, 64, 8406–8408.
8
hedron Lett. 2000, 41, 33–36; (d) Dorling, E. K.; Ohler,
E.; Mulzer, J. Tetrahedron Lett. 2000, 41, 6323–6326;
(e) Nadolski, G. T.; Davidson, B. S. Tetrahedron Lett.
2001, 42, 797–800; (f) Messenger, B. T.; Davidson, B.
S. Tetrahedron Lett. 2001, 42, 801–803; (g) Dorling, E.
8
K.; Ohler, E.; Mantoulidis, A.; Mulzer, J. Synlett 2001,
1105–1108; (h) Lee, H. W.; Jeong, C. S.; Yoon, S. H.;