We envisaged that the trans-γ-butyrolactone could be introduced via an epoxide opening with an appropriate carbon nucleophile. The point of attack of the nucleophile on the epoxide would be expected to be from the least sterically congested direction. In a similar fashion, the regioselective epoxide opening by a nucleophile on a related system was described by Danishefsky39 and Rigby40 in their total synthesis of vernolepin, dehydrocostus lactone and estafiatin (Figure 22).
Figure 22: Trans-fused γ-butyrolactone in Natural Products
Danishefsky and co-workers employed Creger-Silbert dianion41, LiCH2CO2Li, as the carbon nucleophile for the epoxide opening of 281 to give compound 282. The direction of nucleophile attack on the epoxide was shown to be from the least hindered position (Scheme 77).
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Scheme 77: Synthesis of Vernolepin 283: Reaction Conditions: (a) p-TsOH, dean-stark, C6H6, 70 °C, (2:1 regioisomers), 62% (b) LDA, Eschenmoser salt42a, HMPA, MeI, THF, -76 °C to -42 °C to RT,
29%
In a similar fashion, Rigby and co-workers40 utilised the Creger-Silbert dianion41, LiCH2CO2Li, as the carbon nucleophile for the epoxide opening of 284 (Scheme 78). The direction of nucleophile attack on the epoxide was shown to be from the least hindered position. Hence, exposing epoxide 284 to a large excess (14 equiv) of dilithioacetate in DME at 60 °C over 5 days, gave lactone 285 in 78% yield as one regio-isomer. It was noted that if the corresponding C4- alcohol was protected with a bulky tert-butyldimethylsilyl group, no reaction occurred under identical reaction conditions after 6 days.
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Scheme 78: Synthesis of 286 and 287: Reaction Conditions: (a) TMSCl, NaI, rt, MeCN (b) Oxalyl Chloride, DMSO, DCM, NEt3, -78 °C to rt, 42% over two steps (c) nBuLi, 288, THF, -78 °C to 0 °C,
15% (d) LDA, THF, 249, -78 °C to RT, MeI, 71% (e) BF3.OEt2, C6H6, rt, 68% (f) mCPBA, DCM, 0 °C,
51%
Along the same lines, we exposed compound 245 to 14 equiv of dilithioacetate in DME at 60 oC for 7 days. Disappointingly, no reaction occurred, and the starting material was recovered (>80%). Extensive effort was undertaken to find a suitable carbon nucleophile that is able to open epoxide 245. It is noteworthy that the required nucleophile for this epoxide opening reaction cannot consist of more than two carbon unit. To this end, glacial acetic acid (>99.99% purity) was treated with different bases such as LDA, LiHMDS (lithium hexamethyl disilazide) and nBuLi to generate the requisite dianion, using a fresh bottle of dry dimethoxyethane (DME). All these efforts were to no avail, as no reactions were ever observed. We switched our attention from dianions to enolates (Figure 23) as suitable nucleophile for the epoxide opening.
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Unfortunately, no reaction occurred, starting materials were recovered and some β-keto ester products were observed. These results suggested that enolates are not suitable as nucleophiles for this reaction.
Figure 23: Enolate nucleophiles for epoxide opening
Next, we examined sp3-hybridised carbon nucleophiles (Scheme 79). Unfortunately, the desired product was not observed. The structural elucidation of the isolated product corresponds to compound 289 (relative stereochemistry was not determined). A previous report has shown that lithium halides can be used for epoxide opening to generate halohydrins of type 289.42b
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Furthermore, we examined sp2-hybridised carbon nucleophiles. Disappointingly, no reaction was observed, and the starting material was recovered (Scheme 80).
Scheme 80: Epoxide Opening with sp2-hybridised carbon nucleophiles
Previous reports have shown alkynes as an ideal two carbon unit precursor for installing the γ-butyrolactone moiety.43 We envisaged that by exposing epoxide 245 to ethynylmagnesium bromide or TIPS-protected lithium acetylene, in the hope that it would produce compound 291 (Scheme 81). The homopropagyl alcohol 291 can react with either gold or ruthenium complexes to form vinylidene carbene intermediate 292. The intramolecular nucleophilic attack by the alcohol on vinylidene carbene 292 would generate an oxacarbene species 293, and its oxidation should afford the 5-membered lactone in compound 294. This tandem cycloisomerisation and oxidation reactions should provide access to the 5-membered lactone in 294 from the homoprogyl alcohol in 291 (Scheme 81).
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Scheme 81: Au and Ru-catalysed tandem cycloisomerisation/oxidation of homopropagyl alcohols43
The epoxide 245 was exposed to ethynylmagnesium (0.5 M in THF) in THF at either –78 or 0 °C, but an undesired product, compound 289 in 46% yield (as shown in Scheme 79) was obtained. This is possibly due to the existence of Schlenk equilibrium between MgR2, RMgBr, and MgBr2 (Figure 24).44
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Switching to TIPS-protected lithium acetylene and AlClMe2 or BF3.OEt2 (Lewis acids), no reaction occurred, and only the starting material was recovered. Previous reports have demonstrated that the nucleophilicity of lithium acetylene can be increased by introducing electron donating substituents on the alkyne, for the regioselective opening of vinyl epoxides.45 A previous report has shown that ethoxy acetylene 248 is a suitable nucleophile for the synthesis of 5-membered lactone 298.46
The nucleophilic (nBuLi and ethoxyacetylene 248) attack on compound 295 gave
296. Subsequent rearrangement reaction generated ketene 297, which was trapped by the secondary alcohol in an intramolecular fashion to produce 5- membered lactone 298 (Scheme 82).46 The application of ethoxyacetylene 248 in total synthesis of natural products has been described.47
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The lithium ethoxyacetylide was generated by treating ethoxyacetylene
248 (50% weight in hexane) with nBuLi (1.6 M in hexane) at –78 °C in anhydrous THF. Subsequent addition of BF3.OEt2 and epoxide 245 at –78 °C, resulted in the formation of undesired product 299 (Scheme 83). This result suggests that, perhaps, the deprotection of TBS ether occurred, allowing the alcohol to attack the epoxide in an intramolecular fashion. Ball and stick molecular modelling showed the epoxide opening by the alcohol is feasible. Acetylation of the alcohol
299 gave compound 300 which allowed full characterisation of this proposed structure.
Scheme 83: Intramolecular epoxide opening
To prevent this side reaction from occurring, we examined the pivalate protecting group, in the hope that it could be less labile compared than the silyl ether. Compound 246 was de-silylated and then re-protected as a pivalate 298
using pivalolyl chloride in DMF and THF (1:1). Compound 298 was then subjected to Jacobsen-Katsuki asymmetric epoxidation reaction conditions and furnished compound 299 in 40% yield along with the bis-epoxide by-product obtained in 30% yield (Scheme 84).
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Scheme 84: Preparation of 303: Reaction Conditions: a) TBAF (3 equiv), THF, 0 °C to rt, 3Ǻ MS,
83% (b) NaHMDS (2 equiv), Piv-Cl (2 equiv), 0 °C to rt, DMF/THF (1:1), 84% (c) 10 mol% of R, R-
Mn(III)-Salen complex 277, mCPBA (3 equiv), NMO (5 equiv), DCM, –78 °C to rt, 40%
The addition of compound 303 to the yellow mixture of lithium ethoxyacetylene and BF3.OEt2 in THF at –78 °C, furnished compound 306 in 45% yield (Scheme
85). The poor yield could be due to the instability of the ketene 305 intermediate (not isolated). The undesired side product 299 was not observed.
181