Asymmetric total synthesis of (-)-laulimalide: Exploiting the asymmetric glycolate alkylation reaction

Article abstract of DOI:10.1021/ja026269v

A concise total synthesis of the potent antitumor macrolide (-)-laulimalide is described. The observation that homoallylic (or latent homoallylic) C-O bonds are present at C5, C9, C15, C19, and C23 led to the strategic decision to rely heavily on the asym

Full text of DOI:10.1021/ja026269v

Published on Web 05/04/2002
Asymmetric Total Synthesis of (-)-Laulimalide: Exploiting the Asymmetric
Glycolate Alkylation Reaction
Michael T. Crimmins,* Matthew G. Stanton, and Shawn P. Allwein
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received March 21, 2002
Laulimalide 1 is a potent cell growth inhibitor with low
nanomolar IC50 values that was isolated from Cacospongia my-
cofijiensis,1 Hyatella sp.,2 and Fasciospongia rimosa.3 Laulimalide
stimulates tubulin polymerization by a mechanism similar to that
of taxol, but unlike taxol, inhibits proliferation of SKVLB-1, a
multidrug-resistant cell line.4 The promising biological activity of
laulimalide has inspired substantial effort toward its synthesis,
culminating in the first total synthesis from the Ghosh laboratory,5
and subsequent syntheses by Paterson,6 Mulzer,7 and Wender.8
Reports of partial syntheses by Davidson,9 Nishayama,10 and Lee11
have also appeared.
Strategically, our synthetic design focused on hydroxy acid 2 as
the macrolactonization substrate since the 2,3-Z-enoate was known
to isomerize during standard based induced macrolactonizations.5
Thus, exploiting a Mitsunobu macrolactonization12,6 of hydroxy acid
2 would obviate a base-catalyzed lactonization. A diastereoselective
allylstannane addition13 was envisioned to connect the two advanced
synthetic fragments 3 and 4. The observation that homoallylic (or
latent homoallylic) C-O bonds are present at C5, C9, C15, C19,
and C23 led to the strategic decision to rely heavily on the glycolate
variation14 of the Evans asymmetric alkylation15 to construct both
the C1-C14 fragment and the C15-C27 subunit. The C1-C14
fragment 4 of laulimalide was constructed as shown in Scheme 1.
Treatment of (S)-citronellal with the Brown chiral borane16 produced
the homoallylic alcohol 5. The alcohol 5 was alkylated with
bromoacetic acid to provide the substituted glycolic acid, which
was acylated with the D-valine-derived oxazolidinone to produce
the acyloxazolidinone 6. The alkylation of glycolyl oxazolidinone
6 with the Z-allylic iodide 7 proceeded with excellent diastereo-
selectivity (>97:3). The diastereoselectivity of complex glycolate
alkylations of this type are apparently unaffected by adjacent or
nearby stereogenic centers.17 Direct reduction18 of the glycolate
alkylation product from 6 delivered the alcohol 8, which was
efficiently processed to the tetraene 9 by Swern oxidation19 and
Wittig olefination. The tetraene 9 was exposed to the Grubbs
catalyst,20 leading to exclusive formation of the dihydropyran 10.
Selective cleavage of the trisubstituted alkene, R-methylenation of
the resultant aldehyde, and immediate reduction of the unsaturated
aldehyde gave the allylic alcohol 11. The alcohol was readily
transformed to the tributylstannane 4 under standard conditions.
The C22-C27 subunit was also prepared by taking advantage
of the asymmetric glycolate alkylation (see Scheme 2). The
O-allylglycolyl-oxazolidinone 12 was alkylated with methylallyl
iodide to provide the oxazolidinone 13 (96:4 dr). Ring-closing
metathesis of the diene with the Grubbs catalyst,20 reductive removal
of the auxiliary, and Swern oxidation of the alcohol provided the
required aldehyde 14. The extreme sensitivity of the aldehyde
Figure 1. Retrosynthesis of (-)-laulimalide.
Scheme 1. Synthesis of the C1-C14 Fragmenta
a a) NaH, BrCH2CO2H, THF, 97%; b) Me3CCOCl, Et3N, THF, -78 to
0 °C; (S)-5-lithio-4-isopropyl-oxazolidin-2-one, 89%; c) NaN(SiMe3)2, THF,
-78 to -45 °C, iodide 7, 86%; d) LiBH4, MeOH, Et2O, 0 °C; e) (COCl)2,
DMSO, Et3N; f) Ph3PdCH2, 66% 3 steps; g) (Cy3P)2Cl2RudCHPh, CH2Cl2,
40 °C, 85%; h) m-CPBA; HClO4, NaIO4; i) Me2N+)CH2, 84%; 2 steps; j)
NaBH4, CeCl3, 78%; k) MsCl, Et3N, CH2Cl2, l) Bu3SnLi, THF, 85% 2
steps.
dictated that it be prepared immediately prior to its use in the next
transformation.
The C15-C27 fragment was constructed as shown in Scheme
3. Again, the asymmetric glycolate alkylation was utilized, in this
instance to establish the C19 stereocenter. Alkylation of the
p-methoxybenzyl-protected glycolate 15 with allyl iodide 16
produced the oxazolidinone 17. Hydrolytic cleavage of the auxiliary
* To whom correspondence should be addressed. E-mail: crimmins@
email.unc.edu.
9
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10.1021/ja026269v CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Completion of the Synthesis of (-)-Laulimalidea
Scheme 2. Synthesis of the C21-C27 Aldehydea
a a) NaN(SiMe3)2, CH2dC(Me)CH2I, THF, 85%; b) (Cy2P) 2Cl2RudCHPh,
CH2Cl2, 40 °C 86%; c) NaBH4, H2O, THF, 0 °C; 88% d) (COCl)2, DMSO,
Et3N, CH2Cl2; 90%.
Scheme 3. Synthesis of the C15-C27 Fragmenta
a a) Me3Al, CH2Cl2, 3:1 72% major isomer; b) TBSOTf, 2,6-lutidine
97%; c) DDQ, H2O, CH2Cl2, 90%; d) MnO2, 91:9 Z:E; e) NaClO2, 75% 2
steps; f) DEAD, Ph3P, THF, -20 °C, 46%; g) Et3N-3HF, CH3CN, 75%.
macrolactone to Et3NHF26 led to clean conversion to (-)-laulimalide
without isomerization of the 2,3-Z-enoate or epoxide-opening to
isolaulimalide. Synthetic (-)-laulimalide was identical in all respects
to that reported previously by Ghosh,5 Paterson,6 and Mulzer.7
Acknowledgment. This work was supported by a research grant
(CA63572) and a postdoctoral fellowship (GM20817 for S.P.A.)
from the National Institutes of Health. A fellowship for M.G.S.
from Merck and Co. is gratefully acknowledged. We thank Charles
Ross, III, at Merck and Co. for obtaining mass spectral data.
Supporting Information Available: 1H and 13C spectra of synthetic
laulimalide (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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