4.5: Homo and Bishomo Sesquiterpenes ii Cecropia Juvenile Hormones

The Cecropia juvenile hormones are biogenetic close relatives of farnesol that contain one or two extra carbon atoms in their sesquiterpenoid carbon skeletons. These terpenoid homologues are referred to as homo and bishomo sesquiterpenes respectively. The extra carbon atoms arise through the incorporation of one or two molecules of propionate in place of acetate during a biosynthetic skeletal construction that is otherwise identical to that of farnesol. Thus, propionyl CoA condenses with two molecules of acetyl CoA to give homomevalonic acid (124) after reduction with NADPH. Conversion of 124 to 125 via decarboxylative elimination and isomerization to 126 is followed by addition of the allylic electrophile 126 to the terminal C=C bond in Δ³-isopentenyl-PP (5) or to its six carbon homologue (125). The allylic electrophiles 127 or 128 then alkylate Δ³-isopentenyl-pyrophosphate to deliver homo and bishomo farnesylpyrophosphates 129 or 130, respectively. These are oxidized to the corresponding acids by hydride donation to NAD+. Enantio-selective epoxidation, and O-methylation of the carboxyl by methyl transfer from S-adenosyl-methionine (SAM, 133) gives optically active epoxyesters 131 and 132 which are known as C₁₇ and C₁₈ juvenile hormones respectively.

Stereocontrolled Generation of Trisubstituted Alkenes

The primary synthetic challenge presented by the Cecropia juvenile hormones is stereocontrol during the construction of trisubstituted C=C double bonds. Temporary rings may be effectively utilized to control alkene geometry. A variety of different applications of this tactic have been employed to achieve stereocontrolled syntheses of juvenile hormones. These syntheses generally involve stereocontrolled construction of methyl bishomo farnesoate (134), that is converted into C₁₈-JH (132) by regioselective epoxidation as in the biosynthesis of 132. Polar analysis of 134 suggests a synthesis from the phosphono ester-stabilized carbanion 136 and dienone 135.

A Temporary Bridge Strategy

One tactic for stereocontrolled synthesis of 135 employs temporary thioether bridges in 137 to enforce the 5-E and 9-Z configurations.8 The sulfur bridges are reductively cleaved after the carbon skeleton of 135 is complete. Both of dihydrothiapyran fragments in 137 were derived from a common intermediate, tetrahydro-1,4-thiapyrone (138). Sulfur serves a dual strategic role in this scheme. Besides enforcing the required configuration at the carbon-carbon p-bonds (stereocontrol), sulfur stabilizes a neighboring nucleophilic center (reactivity control) in the carbanions 139 and 140. The mercapto and sulfide functional groups readily provide activation for either nucleophilic or electrophilic reactivity. They are biphilic functional groups, and, as previously encountered for the biphilic nitrile functional group (see pages 19 and 31), they can be used to produce polar reactivity inversion. We encountered this phenomenon previously in the conversion of an electrophilic carbonyl into a nucleophilic dithiane carbanion, an acyl carbanion equivalent.

In the present synthesis of JH, the electrophilic β-carbon of methyl acrylate is transformed by the thioether functional group into a nucleophilic center in 139 and 140.

Another instance of biphilic activation by sulfur is found in the reaction of the electrophilic carbonyl carbon of 138 with dimethyloxosulfonium methylide (141), a sulfur stabilized nucleophile, to produce epoxide 143. Sulfur then provides electrophilic activation at the same carbon by serving as a nucleofuge in the intermediate betaine 142.

SEC in Fragmentations

Another stereocontrolled synthesis of 135 exploits reversible stereospecific, anti-periplanar addition to a carbon-carbon π-bond to transpose the stereochemical relationships in monocyclic and bicyclic intermediates into those of acyclic products.⁹ The anti-periplanar arrangement allows continuous overlap during a concerted fragmentation. Thus, the E configuration of the 5,6-π-bond in 135 is preserved in latent form in the cyclic intermediate 144 by a dislocation involving anti-periplanar addition of a carbon electrophile and hydroxyl nucleophile to 1 3 5 . A new electrophilic carbonyl carbon is generated by the dislocation 144 fi 145. The Z configuration of the C=C bond in 145 is preserved in latent form by a dislocation involving antiperiplanar addition of a carbon electrophile and hydroxyl nucleophile to the C=C bond in 145. Thus, all of the stereochemical information in the acyclic intermediate 135 is contained in latent form in the bicyclic precursor 146. Control of alkene geometry in an acyclic carbon skeleton is thereby transposed to control of relative stereochemistry in a multicyclic carbon network. Since the conformations of multicyclic carbon networks are more rigid than acyclic ones, the influences of steric and neighboring group effects are more easily predicted and usually more pronounced.

Fragmentation of bonds a and b in 146 was promoted by converting hydroxyl into toluenesulfonate leaving groups. The triol 146 was readily selectively monotosylated at the least sterically congested secondary hydroxyl. Fragmentation of the resulting b-tosyloxy 3° alcohol delivering the Z-alkene 145 proceeded stereospecifically upon treatment with \(\ce{NaH}\). Addition of \(\ce{MeLi}\) to the tetrahydropyranyl derivative of 145 occurred stereoselectively (57%). After deprotection and selective tosylation of the secondary hydroxyl in the resulting diol, fragmentation of an intermediate β-tosyloxy 3° alcohol occurred smoothly to afford 135 stereospecifically (80%).

Since the functionality in 146 was introduced by polar reactions, it is a foregone conclusion that the functional groups are connected by consonant circuits. Polar analysis of 146 shows that all circuits in the cyclohexane ring are consonant. This allows disconnection of bonds to the ring fusion common atoms. However, activation of nucleophilic reactivity vicinal to the secondary hydroxyls requires conjugation that is only afforded by carbonyl groups as in 147. Polar disconnection of 147 then suggests propyl vinyl ketone and 2-ethylcyclopentan-1,3-dione as starting materials.

A synthesis of 146 based on the strategy outlined above began with Robinson annelation of 2-ethylcyclopentane-1,3-dione with propyl vinyl ketone. Steric approach controlled hydride delivery to the resulting dione provided 148 after protection of the hydroxyl. Steric approach control also resulted in stereoselective methylation from the less sterically congested α-face of the enolate from 148. Similarly, hydride delivery to the less sterically congested face of 1 4 9 gave 1 5 0 stereoselectively. The stereochemistry of the final hydroxyl group required for the triol 146 was dictated by the effect of the neighboring hydroxyl in 150 on the epoxidation of this alkene. The hydroxyl group hydrogen bonds with MCPBA thereby enforcing oxygen delivery cis to the neighboring hydroxyl as for 250 in section 3.6.

SEC Through Preferred Conformations

Conformational effects in cyclic transition states can also result in substantial, as well as predictable, stereoselectivity in the generation of acyclic alkenes. In another stereocontrolled synthesis of C₁₈-JH (132), Claisen rearrangement of the allyl vinyl ether 153 from transketalization of 152 with 151, followed by elimination, generates the γ,δ-unsaturated ketone 154 stereoselectively.10 A chair transition state with an equatorial carbomethoxyl substituent is preferred for this [3.3] sigmatropic rearrangement. Borohydride reduction of 154 gives an allylic alcohol 155, which was again homologated stereoselectively with 152 to give allylic alcohol 158 via 156 and 157. A cyclic transition state is also the key to a stereocontrolled conversion of 158 to the allylically transposed chloride 159. Thus, the chlorosulfite ester 160 of 158 gives 159 via S_Ni' rearrangement involving a chair conformation with the bulky substituent in an equatorial position.

Another synthesis of C₁₈-JH (132) that exploits a Claisen rearrangement to generate the 6,7-trisubstituted double bond stereoselectively is outlined below.¹¹ An interesting step in this synthesis is the selective destruction of an undesired byproduct 162. This allylic chloride is more reactive than the isomers 161 and 163 and, therefore, selectively forms a water soluble pyridinium salt. Claisen rearrangement occurs via a transition state conformation 164 with an equatorial chloroethyl group. The 2,3-double bond is generated stereoselectively by cis-1,4-addition of an organocuprate derived from 165 to methyl 2-butynoate.

In this synthesis, the epoxide is produced by base-induced cyclization of a chlorohydrin rather than epoxidation of an olefin. Stereoselective HO generation of the Z-epoxide is possible because the reaction of chloroketone 166 with methyl magnesium chloride leads predominately to one diastereomer, the threo chlorohydrin 167.

This stereoselectivity is not the consequence of a cyclic transition state. Rather, for acyclic ketones which contain polar α-substituents (e.g. halogens) that are unlikely to coordinate with metal atoms, a combination of torsional strain, steric interactions, and electrostatic interactions must be considered. Two models have been formulated to explain such stereoselectivity. One model presumes that the reactive conformation of such ketones is a structure (e.g., 168) in which the carbonyl group and the polar α substituent are anti-periplanar to minimize dipole-dipole repulsion. Alternatively, the transition state may resemble 169 that allows maximum separation of the electronegative a substituent and the negatively charged nucleophilic reagent. Another example of such stereoelectronically controlled stereoselection is provided by the 48 + 49 → 53 conversion presented in Chapter 3 (section 3.3).

Other TB Strategies

Two tactics for stereoselective construction of trisubstituted C=C bonds not encountered in the previous examples are exploited in a strategy for synthesis of C₁₈-JH that was devised by Corey.¹² The 2,3-E configuration in 134 can be assured by a temporary ring during pseudo-intramolecular hydroalumination of a propargyl alcohol 171 that produces an intermediate vinyl alane 170 which is subsequently alkylated. This tactic can also produce the 6,7-E configuration by a similar hydroalumination-alkylation sequence applied to 172. The fact that a terminal alkyne is a latent carbanion suggests a polar dislocation of 172 to a propargyl alcohol-derived acetylide nucleophile and an electrophilic precursor 173. The E configuration of 173 can be assured by a temporary bridge that is suggested by dislocation to a more highly functionalized precursor 174 with differentiated carbonyl groups. Thus, reductive coupling of these two carbonyl groups provides a bridged latent dicarbonyl precursor 175.

Especially noteworthy is the synthetic role of the aldehyde carbonyl group in 174. This functional group is exploited solely to facilitate stereocontrol.

The substituents in the acyclic product 176, from selective oxidative cleavage of 175, are necessarily cis since only a cis double bond can be accommodated in a six membered ring. The cis relationship between the aluminum and hydroxymethyl substituent enforced in the intermediate 177 by a temporary bridge is preserved in the subsequent halogenolysis of the C-Al bond and alkylation of the resulting vinyl iodide delivering 178. Both transformations occur with retention of configuration. A similar sequence delivers 180 stereoselectively from 179. Conversion of the allylic alcohol 180 into key intermediate 134 requires oxidation followed by O-methylation.

SEC Through Preferred Conformations

Highly stereoselective formation of trisubstituted alkenes can sometimes be achieved by processes not involving intermediates with temporary bridges or cyclic transition states. Thus, occasionally, a combination of conformational and stereoelectronic effects may produce high stereoselectivity in reactions of acyclic molecules. For example, the 6,7-C=C bond of JH can be generated stereoselectively during transformation of the cyclopropyl carbinyl bromide 181 into the homoallylic bromide 182.¹³

Stereoselectivity arises from a stereoelectronic preference for an anti-periplanar arrangement of cleaving bonds that leads to generation of the new carbon-carbon double bond in a concerted stereocontrolled fashion. That is, a coplanar arrangement of the breaking C-C and C-Br bonds allows coupling of these bond cleavages with carbon-carbon double bond formation. Either transition state conformation 183 or 184 satisfies this requirement, but 183 is clearly preferred because the cyclopropyl group eclipses only hydrogen. Thus, a conformational bias, coupled with a stereoelectronic preference, favors a transition state 183, that leads to E-olefin 182.

The preparation of an early intermediate, 188, for the C1 to C4 segment of 181 illustrates a useful tactic for the synthesis of pure stereoisomers: selective destruction of one of two isomeric products from a nonstereoselective reaction. Thus, N-bromosuccinimide brominates dimethyl acrylic acid (185) nonselectively to give a mixture of bromoacids 186 and 187.

The undesired Z-isomer 187 undergoes spontaneous lactonization, leaving the desired E-isomer 186 as the only acidic organic product, that can be extracted into mild base and subsequently methylated to provide the intermediate 188 for the synthesis of JH. This is combined with a nucleophile derived from ketoester 190 that is available, in turn, from 1-acetyl-γ-buryrolactone 189. Symmetry was exploited during completion of the JH carbon skeleton by alkylation of the enolate of 3,5-heptanedione with 182. Chlorination of the product gave 191. The extra propionyl group was cleaved in a retro Claisen reaction by \(\ce{Ba(OH)2}\). The resulting chloroketone 166 reacted stereoselectively with MeMgCl to give 167 with less than 8% of the unwanted diastereomer (see section 4.6). Base-induced heterocyclization of the threo chlorohydrin 167 delivered racemic C₁₈-JH.¹³