1. Introduction
Saxitoxin (STX, 1), firstly isolated as a paralytic shellfish poison, is a potent and specific blocker of voltage-gated sodium channels.1 So far, more than 50 members in this family were discovered.2 Among this big family, only 11-saxitoxinethanoic acid (SEA, 5)3 and zetekitoxin AB (ZTX, 6)4 characteristically contain an unusual C-C bond at the C11 position (Figure 1), which may suggest a new biosynthetic pathway for these STX derivatives.5 This report described a total synthesis of SEA (5).
2. Previous achievements in our laboratory
Our group has reported a series of synthetic studies of saxitoxin and its derivatives.6 In these synthesis, we commenced 1,3-dipolar reaction of nitro olefin 7 and nitrone 8 followed by epimerization and hemi-reduction to obtain 9. After conversion of 9 into bicyclic guanidine 10 in 5 steps, compound 11 was obtained with sequential oxidation and reduction, and introduction of guanidine group. Then, cyclization of guanidine at C4 gave 12, which is a key synthetic intermediate for STXs. With the intermediate 12, we have achieved synthesis of STX (1) and its derivatives 2~4 (Scheme 1).
Scheme 1. Our achievements in the synthesis of STX (1) and its derivatives 2 ~ 4.
3. Synthetic strategies of SEA (5)
In the synthesis of SEA (5), construction of the C-C bond at C11 is the crucial issue. In the retrosynthetic analysis, we planned two approaches (Scheme 2), i.e., (i) early stage introduction of acetate group by utilizing nitrone 13 (strategy 1), and (ii) later stage construction of C-C bond at C11 by reacting with enolate 14 and electrophile 15 (strategy 2). Both approaches were examined as follows.
Scheme 2. Two approaches for SEA (5).
4. Synthesis of SEA (5)
(1) Strategy 1: Early stage introduction of acetate group at C11 by utilizing nitrone 13.
Based upon our previous synthetic works for STXs (Scheme 1), we chose nitrone 13, which contains a protected acetic acid group at the C11, as a key compound for the synthesis of SEA (5). Synthesis of nitrone 13 was examines as shown in Scheme 3. Diol 17, derived from L-(+)-tartaric acid, was converted into ketone 18 by selective protection of hydroxyl group with TIPS ether followed by Swern oxidation in 65%. Then, aldol reaction of ketone 18 with acetate was examined. Reaction of 18 with tert-butyl acetate in the presence of NaHMDS gave aldol 19 in 85% as a diastereomer mixture (dr = 7:1), which was further purified by a recrystallization. With 19 in hand, then we examined to remove the hydroxyl group under various conditions. Unfortunately, the hydroxyl group was less reactive due to its sterically hindered environment, and we could not obtain 20or 21. Then, we examined to oxidize 19 into nitrone 22. After deprotection of Ts group, the resulting pyrrolidine was subjected under variety oxidation conditions, however, we obtained nitrones 22 and 23 as 1:1.1 ratio with an inseparable mixture.
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1. Introduction
Saxitoxin (STX, 1), firstly isolated as a paralytic shellfish poison, is a potent and specific blocker of voltage-gated sodium channels.1 So far, more than 50 members in this family were discovered.2 Among this big family, only 11-saxitoxinethanoic acid (SEA, 5)3 and zetekitoxin AB (ZTX, 6)4 characteristically contain an unusual C-C bond at the C11 position (Figure 1), which may suggest a new biosynthetic pathway for these STX derivatives.5 This report described a total synthesis of SEA (5).
2. Previous achievements in our laboratory
Our group has reported a series of synthetic studies of saxitoxin and its derivatives.6 In these synthesis, we commenced 1,3-dipolar reaction of nitro olefin 7 and nitrone 8 followed by epimerization and hemi-reduction to obtain 9. After conversion of 9 into bicyclic guanidine 10 in 5 steps, compound 11 was obtained with sequential oxidation and reduction, and introduction of guanidine group. Then, cyclization of guanidine at C4 gave 12, which is a key synthetic intermediate for STXs. With the intermediate 12, we have achieved synthesis of STX (1) and its derivatives 2~4 (Scheme 1).
Scheme 1. Our achievements in the synthesis of STX (1) and its derivatives 2 ~ 4.
3. Synthetic strategies of SEA (5)
In the synthesis of SEA (5), construction of the C-C bond at C11 is the crucial issue. In the retrosynthetic analysis, we planned two approaches (Scheme 2), i.e., (i) early stage introduction of acetate group by utilizing nitrone 13 (strategy 1), and (ii) later stage construction of C-C bond at C11 by reacting with enolate 14 and electrophile 15 (strategy 2). Both approaches were examined as follows.
Scheme 2. Two approaches for SEA (5).
4. Synthesis of SEA (5)
(1) Strategy 1: Early stage introduction of acetate group at C11 by utilizing nitrone 13.
Based upon our previous synthetic works for STXs (Scheme 1), we chose nitrone 13, which contains a protected acetic acid group at the C11, as a key compound for the synthesis of SEA (5). Synthesis of nitrone 13 was examines as shown in Scheme 3. Diol 17, derived from L-(+)-tartaric acid, was converted into ketone 18 by selective protection of hydroxyl group with TIPS ether followed by Swern oxidation in 65%. Then, aldol reaction of ketone 18 with acetate was examined. Reaction of 18 with tert-butyl acetate in the presence of NaHMDS gave aldol 19 in 85% as a diastereomer mixture (dr = 7:1), which was further purified by a recrystallization. With 19 in hand, then we examined to remove the hydroxyl group under various conditions. Unfortunately, the hydroxyl group was less reactive due to its sterically hindered environment, and we could not obtain 20or 21. Then, we examined to oxidize 19 into nitrone 22. After deprotection of Ts group, the resulting pyrrolidine was subjected under variety oxidation conditions, however, we obtained nitrones 22 and 23 as 1:1.1 ratio with an inseparable mixture.
Scheme 3. Synthetic approaches for nitrone 13.
(2) Strategy 2: Later stage construction of C-C bond at the C11 with 14 and 15.
We next examined the second strategy. In this strategy, C-C bond formation was investigated with ketone 14 and electrophiles. Synthesis of ketone 27, corresponds to 14, was carried out based upon our previously reported strategy (Scheme 4). Bicyclic guanidine 246c was converted into guanidine 25 in 5 steps. Treatment of 25 with acetic anhydride followed by reacting with zinc chloride at -20 °C gave 26 in 98% yield without losing protecting groups on the guanidine. After protection of NH group in guanidine as MOM ether, hydrolysis of acetate with potassium carbonate followed by oxidation of resulting alcohol with TPAP gave ketone 27.
Scheme 4. Synthesis of ketone 27.
Firstly, we examined direct alkylation of 27with ethyl 2-haloacetate in the presence of variety bases and conditions. However, the conversion was extremely low, and only trace amount of the desired product 28 was obtained together with dialkylation product of 29, and 27 was mostly recovered. These results indicated that the reactively at C11 in 27 is very low.
Scheme 5. Unsuccessful alkylation of ketone 27.
Then, we investigated the Mukaiyama aldol reaction for constructing C-C bond at C11 in 27 (Scheme 6). Acetate 26 was converted into silyl enol ether 30, and Mukaiyama aldol reaction was examined with ethyl glyoxylate under various conditions. At beginning, Lewis acid catalysts, such as TiCl4 and BF3・Et2O, were tested for the reaction, however, substrate 30 was decomposed. Then, fluoride anion-promoted reaction was investigated. In case of Bu4NF, no reaction occurred. On the other hand, in case of [Bu4N][Ph3SnF2] known as anhydrous fluoride anion reagent, the desired product 31 was obtained in 96% yield.7 This reaction is powerful, and variety of aromatic aldehydes are available to give corresponding aldol condensation adducts in good yield.
Scheme 6. Mukaiyama aldol reaction of silyl enol ether 30 with ethyl glyoxylate.
Table 1. Mukaiyama aldol reaction of 30 with various aromatic aldehydes.
With the success for constructing C-C bond at C11, next we turned our attention to the reduction of double bond and deprotection of MPM group at C13. For the reduction of double bond, metal catalyst of Pd, Pt, Rh and Ir was tested under hydrogenation conditions, however, these efficacies were quite low. After many attempts, we found L-selectride was effective, and 32 was obtained in 76% yield (Scheme 7). Then, deprotection of MPM group at C13 was investigated, and it was troublesome. We previously found that the combination of NBS-Et3B4c was effective for the deprotection of MPM group, however, reaction did not proceed at all in case of 32. After our many efforts, we decided to change the protecting group from MPM to TBS ether at earlier stage.
Scheme 7. Reduction of double bond in 31 and deprotection of MPM group.
Thus, we changed the MPM group of 24 at C13 into TBS ether to give 34(Scheme 8), and silyl enol ether 36was obtained by following the scheme developed for 30. Then, the Mukaiyama aldol reaction was carried out. Under the conditions with [Bu4N][Ph3SnF2], reaction of 36 with ethyl glyoxylate proceeded nicely, and aldol condensation adduct was obtained in 85% yield. In this reaction, TBS ether at C13 was intact. Then, the reduction of resulting double bond was reduced with L-selectride to give 37. Deprotection of the TBS group in 37 took place smoothly by using HF-Et3N complex, and carbamoyl group was introduced to the resulting hydroxyl group to give 38. Finally, hydrolysis of ethyl ester with potassium carbonate followed by deprotection of Boc group with TFA gave 11-Saxitoxinethanoic acid (5).
Scheme 8. A synthesis of SEA (5)
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