Bryostatin 16 synthesis reaction

Bryostatin 7 (3) was the first member of the bryostatin family that was accessible by total synthesis. Its preparation was described by Masamune et al. already briefly after its isolation from Bugula neritina [8]. Their concept was based on a combination of the four synthons 4-7 (Figure 2) The (R,R)-2,5-dimethylborolanyl triflate mediated aldol reaction of aldehyde 4 with the enolate derived from ketone 5 leads after a sequence of deprotection steps, cycliza-... 

The samarium-catalyzed reduction was utilized in the asymmetric synthesis of the marine macrolide bryostatin 2 (42) to furnish an intermediate (46)12 (Scheme 4.21). The ketone 43 underwent an aldol reaction with the ketoaldehyde 44 via the isopinylboryl enolate to give the aldol adduct 45 in good yield and 93 7 diastereoselectivity. Subsequent samarium-catalyzed Evans-Tishchenko reduction of the (3-hydroxy ketone 45 provided the p-nilrobenzoale 46 with excellent stereoselectivity. Silylation and saponification readily converted compound 46 into the alcohol 47 in 88% yield over two steps. 

The already called Smith-Tietze coupling reaction has been used in the synthesis of the bryostatin B ring by using glycidol 192 as the only electrophile317. When C2-symmetric... 

A very short asymmetric synthesis of the bryostatin C1-C9 segment was achieved by use of three sequential 3f-promoted aldol reactions under reagent control [43f]. This synthetic methodology is based on the direct asymmetric incorporation of two acetate and one isobutyrate synthones into a framework (Sch. 1). 

Several other chiral boron reagents are available for asymmetric aldol reactions however, each of these compounds must be synthesized in the laboratory. In certain situations, some will give higher stereocontrol than the Ipc ligands, and hence for a given reaction their application could be pursued. Chiral reagents 53 and 54 have been used in the synthesis of bryostatin 7 [36] and the Taxol side-chain [37], respectively, while bis-sulfonamide 55 has been used in the synthesis of a C24-C35 segment of FK-506 (Scheme 9-18) [38]. 

Masamune s synthesis of bryostatin 7 (114) [36] contains early examples of double asymmetric induction, where the aldol reaction of chiral ketones could be... 

Evans synthesis of bryostatin 2 (113) also relied upon asymmetric aldol reactions for the introduction of most of the 11 stereocenters [58], At different points, the synthesis used control from an auxiliary, a chiral Lewis acid, chiral ligands on the enolate metal and substrate control from a chiral aldehyde. Indeed, this represents the current state of the art in the aldol construction of complex polyketide natural products. 

The synthesis of the C1-C9 fragment 120 began with an auxiliary controlled aldol reaction of the chloroacetimide 121, where chlorine is present as a removable group to ensure high diastereoselectivity in what would otherwise have been a non-selective addition (Scheme 9-39). The Lewis acid-catalyzed, Mukaiyama aldol reaction of dienyl silyl ether 122 with / -chiral aldehyde 123 proceeded with 94%ds, giving the 3-anti product 124, as predicted by the opposed dipoles model [3]. Anti reduction of the aldol product and further manipulation then provided the C1-C9 fragment 120 of the bryostatins. 

Other approaches to the bryostatins have also used enantio- or diastereoselective aldol reactions. An interesting iterative strategy for the synthesis of the Cj-Cg polyacetate region 134 has been disclosed where each aldol addition proceeds with excellent stereocontrol (99 1) under the catalytic influence of oxazaborolidine 135 (Scheme 9-42) [60J. Finally, a moderately selective, auxiliary controlled, acetate aldol reaction has been used for the introduction of the C3 stereocenter of the bryostatins giving adduct 136 (84% d.s) [61]. 

The synthesis of another Ci-Ce ketone 210 used an asymmetric Mukaiyama aldol reaction catalyzed by oxazaborolidine 135 (Scheme 9-58) [78]. This concise synthesis is reminiscent of an earlier approach to the bryostatins (see Scheme 9-42) and can also be compared with the chromium-mediated addition of a-bromoimide 211 to simple aldehyde 212 to give 213, which proceeded with excellent stereo-control (>99 1) [76]. 

As already illustrated, the AD reaction still requires some investigation to obtain good selectivity other than that with simple substrates. Another example is in work toward the synthesis of Bryostatin-C where reasonable selectivity was seen with 9 as a substrate for an AD reaction with AD-mix [3. However, the selectivity fell significantly with the more substituted cyclic and acyclic analogues of 9 required for the synthesis of the natural product. A survey of commercially... 

We referred above to a synthesis of bryostatin that contained a reduction controlled by a 1,3-relationship. Evans synthesis34 contains a 1,3-selective aldol as well as a 1,3-controlled reduction The aldehyde 202, made by an asymmetric aldol reaction, was combined with the double silyl enol ether of methyl acetoacetate to give, as expected, the anti-aldol 203. However, the only Lewis acid that gave this good result was (<-PrO)2TiCl2 and not BF3 thus emphasising the rather empirical aspect of this type of control. Evans s own 1,3-controlled reduction gave the anti,anti-triol 204 that was incorporated into bryostatin. 

Application of the external chiral boron reagent (90) in the totd synthesis of bryostatin, a natural product, is shown in Scheme 45. The convergent approach adopted involves coupling of the boron enolate derived from (111) with aldehyde (112). The reaction mediated by an achiral boron reagent (Et2BOTf) provides only a 2 1 preference for the formation of the desired isomer (115) in adduct (113). The use of chiral (2/ ,5 )-dimethylborolanyl triflate in this reaction increases the selectivity to a 6 1 preference as... 

Similar results were observed in the synthetic efforts toward the C16-C27 segment of bryostatin l.25 The synthesis of the fragment utilized a Luche reduction as the final step. This particular reaction using NaBH and CeCb reduced from the least hindered side of the C20 ketone in 21 producing a 90% yield of the single stereoisomer 22. The resulting C17-C27 bryostatins produced in these studies have shown potential anti-cancer properties. 

There are a number of examples of 6-endo radical cyclization of vinylic ether substrates. For example, Thomas reported synthesis of the tetrahydropyran fragment 76 of bryostatin 1 via radical cyclization reaction of the a-alkoxyacrylate 75, capitalizing on the higher activity of Z-vinyl radicals [51] (Scheme 27). In the syn-... 

The methodology was adapted to the synthesis of a simplified fragment of bryostatin. As in the previous example, an aldehyde (130) was reacted with (2-chloromethyl)allylstannane 131 using BINOL/Ti(Oi-Pr)4 catalysis to obtain 132. In parallel, aldehyde 133 was subjected to a Keck reaction employing the silylated stannane 134. The resulting allylsilane 135... 

The intramolecular alkyne coupling of diyne 11.281 was used in a synthesis of bryostatin 11.283 to close the macrocycle 11.282 (Scheme 11.94). This reaction was followed by a gold(l)-catalysed 6-endo ring closure of 11.282 and some routine transformations to complete the synthesis. As so often in macrocyclizations, a low concentration (0.002 M) was found to be important. 

In the total synthesis of bryostatins, chiral HWE reagents have been used for the stereocontrolled transformation of the C13 ketone to the C13-C30-unsaturated enoate [68]. The reaction of macrocyde 102a with chiral phosphonate 31a provided the a,j8-unsaturated ester of Z-stereochemistry, 103a, with a diastereoselectivity of Z/E = 85 15 (75% isolated yield of the Z-isomer, 103a). The obtained Z-isomer 103a was successfully converted into bryostatin by several subsequent chemical... 

A subsequent report by Wender and Schrier implemented a similar late-stage macrocyclization in the synthesis of bryostatin 9 (Scheme 43) [87]. The Lewis acid, TMSOTf, was abandoned in favor of pyridinium p-toluenesulfonate (PPTS) in order to mitigate side reactions due to the ketal functionality in the A ring. As a result, treatment of allylsilane aldehyde 163 with PPTS in MeOH unveiled the... 

Kiyooka, S. and Maeda, H. (1997) Enantioselective acyclic stereoselection under catalyst control. III. A very short asymmetric synthesis of the bryostatin C1-C9 segment using the chiral oxazaborolidinone-promoted aldol reaction. Tetrahedron Asymmetry,... 

In the course of their synthesis of a ring-expanded bryostatin analog 131, Trost et al. studied the RCM cyclization of substrate 128, which was armed for a potential RRCM reaction (Scheme 9.31) [36]. This complex polyene cycUzed very cleanly under the action of [Ruj-III to produce the cyclic diene 129. There was no evidence of formation of the smaller RRCM product The rate of the relay event here is presumably lowered by the pair of quatemized carbons aUylic ( ) and homoallylic (A) to C17 in the alkylidene derived from 128. 

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