SYNTHETIC STUDIES OF ANTITUMOR MACROLIDE LAULIMALIDE: ENANTIOSELECTIVE SYNTHESIS OF THE C₃-C₁₄ SEGMENT BY A CATALYTIC HETERO DIELS-ALDER STRATEGY

Abstract

The C₃-C₁₄ segment of the novel antitumor agent laulimalide has been constructed enantioselectively by utilizing a catalytic asymmetric hetero Diels-Alder reaction of benzyloxyacetaldehyde and Danishefsky’s diene followed by Ferrier rearrangement and asymmetric conjugate reaction as the key steps.

Laulimalide 1 also known as figianolide B, is a 20-membered macrolide isolated from the Indonesian sponge Hyattella Sp.¹ More recently, laulimalide has also been isolated from an Okinawan sponge Fasciospongia rimosa.² Laulimalide represents a new and novel class of macrolide with potent cytotoxicity against the KB cell line with an IC₅₀ value of 15 ng/mL.^1b The cytotoxicity of laulimalide against P388, A549, HT29 and MEL28 cell lines is also in the range of 10–50 ng/mL (IC₅₀ values).^2b The gross structure of laulimalide was established by NMR studies and more recently its absolute configuration has been elucidated by X-ray crystallographic analysis.^2a In view of its limited supply and unique structural features as well as its potential utility as an anticancer agent, synthetic studies of laulimalide became of interest to us. Herein, we report on the asymmetric synthesis of the C₃-C₁₄ segment of laulimalide in which a chiral bis(oxazoline)-metal complex catalyzed hetero DielsAlder reaction, a Ferrier type rearrangement of the derived glycal and diastereoselective conjugate addition were utilized to set the C-9, C-5 and C-11 asymmetric centers.

Chiral bis(oxazoline)-metal complex catalyzed cycloaddition reactions have received increasing attention in recent years.³ We recently reported⁴ constrained chiral bis(oxazoline)-metal complex catalyzed hetero Diels-Alder reactions of Danishefsky^′s diene and alkyl glyoxalates to provide dihydropyranone derivatives up to 72% ee. In an effort to further improve the enantioselectivity in this catalytic process, we have. investigated the scope and utility of readily accessible bidentate aldehydes such as benzyloxyacetaldehyde 5 and 1,3-dithianecarboxaldehyde 6. Of particular interest, dihydropyranone derivatives⁶ resulting from such cyclocondensation reactions are appropriately functionalized for the synthesis of laulimalide segment 2. As shown in Table 1, cyclocondensation of aldehyde 5⁷ and Danishefsky’s diene 4 in the presence of 10% Cu(II)-bis(oxazoline) complex provided good yield (62–76%) of versatile dihydropyranone 7⁸ in high enantiomeric excess. Constrained ligands 9 and 12^3e are particularly effective providing 2S and 2R-dihydropyranones in 85 and 87% ee’s respectively. In comparison, phenyl and t-butyl based bis(oxazoline) ligands 10 and 11 are less effective (51 and 38% ee). Cyclocondensation of 1,3-dithianecarboxaldehyde 6⁹ with constrained Cu(II)-bis(oxazoline) 12 complex also afforded the dihydropyranone 8 in 46% yield and 81% ee compared to Cu(ll)-bis(oxazoline) ligand 10 which has shown 59% ee ¹⁰ and only 20% isolated yield.

Table 1.

Cu(II)-bis(oxazoline) catalyzed Hetero Diels-Alder Reaction at −78°C

Entry	Aldehyde	Ligand	Time(h)	% Yielda	% eeb	Config.c
1.	5	10	9	76	51	2S
2.	5	11	9	72	38	2R
3.	5	9	11	76	85	2S
4.	5	12	9	62	87	2R
5.	6	12	9	46	81C	2S
6.	6	10	10	20	59C	2R

^aAfter silica gel chromatography.

^bBy chiral HPLC and comparison of optical rotation.

^cBy comparison of optical rotation.

For synthesis of the C₃-C₁₄ segment of laulimalide, dihydropyranone 7 was prepared on a multigram scale.¹¹ To append the hydroxyethyl side chain and to establish the C-5 stereocenter appropriately, a Ferrier type rearrangement of the corresponding glycal acetate was sought. Thus, dihydropyranone 7 was reduced with 1.5 equiv of DIBAL in benzene at 0° to 5°C for 2 h and the resulting glycal was acetylated with 1.5 equiv of Ac₂O and 3 equiv of Et₃N in CH₂Cl₂ in the presence of a catalytic amount of DMAP at 23°C for 6 h to provide 13 in 66% yield (from 7). Ferrier rearrangement of 13 with 2 equiv of tert-butyldimethylsilyl vinyl ether¹² and stoichiometric amount of Montmorillonite clay K-10¹³ as the Lewis acid in CH2C12 at 0°C followed by NaBH4 reduction of the resulting mixture of aldehydes afforded good yield (65–70% from 13) of the dihydropyran 14 (diastereomeric ratio >95:5 by ¹H and ¹³C-NMR). Protection of the alcohol with MOMCl and iPr₂NEt furnished the MOM derivative 15 in 88% yield.

To elaborate the C-11 methyl group with appropriate stereochemistry, the benzyl group in 15 was deprotected by exposure to sodium in liquid ammonia (65% yield). Mesylation of the resulting alcohol followed by displacement with tetraethylammonium cyanide provided the cyanide 16 (77% yield). Reduction of 16 with DIBAL resulted in aldehyde which was immediately exposed to a Horner-Emmons olefination reaction to afford the trans α, ß-unsaturated ester 17 in 45% yield. Saponification of 17 with aqueous LiOH afforded the corresponding α, ß-unsaturated acid which was converted to N-enoylsultam 18 (73% yield) utilizing (1S)-(+)-2,10-camphorsultam. Treatment of 18 with 4 equiv of Me₂CuLi in Et₂O at −78°C for 8 h afforded the conjugate addition product 19 in 68% yield (based on 30% recovery of 18). The ¹H-NMR (400 MHz) analysis after chromatography reveals the presence of a mixture of (90:10) diastereomers. Interestingly, reaction of Me₂CuLi with the Nenoylsultam derived from (1R)-(+)-2,10-camphorsultam proceeded smoothly in 3 h (no recovery of 18), providing the corresponding diastereomers (mixture ratio 5:95 by ¹H-NMR) in 76% isolated yield. The depicted configuration is assigned based on Oppolzer’s model.¹⁴ However, either C-11 methyl isomer of laulimalide can be prepared selectively by an appropriate choice of camphorsultam.

Our next synthetic strategy was to convert the sultam 19 to the methyl ketone 2 which would enable us to introduce the C-15 hydroxyl group by an aldol type reaction with an appropriately functionalized epoxyaldehyde 3. Thus, removal of the chiral auxiliary afforded the corresponding acid which was treated with 5 equiv of MeLi at 0°C followed by workup with excess of TMSCI according to Rubottom procedure ¹⁵ to furnish 2 (${\alpha }_D^{{23}^{°}}$−55.6; c, 0.18, CHC13) in 63 % yield.¹⁶

In summary, the C₃-C₁₄ segment of antitumor macrolide laulimalide has been synthesized in optically active form utilizing dihydropyranone 7, prepared enantioselectively by a chiral bis(oxazoline)-metal complex catalyzed hetero Diels-alder reaction as the key step. Further synthetic studies of laulimaide are currently under investigation.

Scheme 1:

(a) K-10, OTBS, CH₂Cl₂, 0°C, 2 h; (b) NaBH₄, MeOH, 0°C, 30 min; (c) MOMCl, iPr₂NEt, CH₂Cl₂, 23°C, 8 h; (d) liq. NH₃, −78°C, 1 h; (e) MCl, Et₃N, DMAP, CH₂Cl₂, 0°C, 30 min; (f)n-Et4N⁺CN^-, CH₃CN-PhH (1:1), reflux,4 h; (g) Diba1-H, Et₂O, −78°C, 4h; (h) NaH, THF, 0°C, (EtO)₂P(O)CH₂CO₂Et, 1 h;(i) 1 M LiOH, 23°C, 6 h; (j) Me₃CCOC1, Et₃N, THF, 0°C then N-lithiosultam, −78°C, 2 h; (k) Me₂CuLi, Et₂O, −78°C, 8 h; (m) 1M LiOH, 23°C, 5 h; (n) MeLi, THF, 0°C then TMSC1.