PART I: TOTAL SYNTHESIS AND RACEMIZATION OF (–)-SINORACUTINE
1. INTRODUCTION
1.3. Project Aims
2.2.3. Introduction of the Quaternary Stereocenter
Having constructed the tricyclic framework of sinoracutine, we proceeded with the introduction of the last ring. The first strategy pursued was analogous to the Mulzer–Trauner morphine synthesis, i.e. vinylcuprate addition to an enone.[141] Andreas Bellan showed that Pauson-Khand product 99 could undergo 1,4-addition with vinylmagnesium bromide, but despite several optimization attempts, the reaction was low-yielding and irreproducible, and plagued by the concomitant formation of 1,2-addition product (Scheme 22).[127] Therefore, the addition of ionic vinyl- or allylmetal species was not further investigated.
Scheme 22: Previously investigated 1,4-addition with vinylcopper reagent.
Next, the conjugate addition of allyltributylstannane to enone 94 was investigated in collaboration with Till Reinhardt according to the procedure developed by Trauner and coco-workersworkers.[142] They reported the successful 1,4-addition to cyclic enones upon prior electrophilic activation of the carbonyl with trifluoroacetic anhydride (TFAA) or trifluoromethanesulfonic anhydride (Tf2O).[143]
Table 13. Conditions examined for the 1,4-allylation and enolate trapping.
Entry Activating agent Allyltributyltin Additives Solvent Yield (101 or 102)a 1 TFAA (1.2 eq.) 1.2 eq. DTBP, 4 Å MS CH2Cl2/MeCN = 1/1 no reaction
2 TFAA (1.2 eq.) 1.2 eq. DTBP, 4 Å MS CH2Cl2 no reaction
3 Tf2O (1.2 eq.) 1.4 eq. DTBP, 4 Å MS CH2Cl2/MeCN = 1/1 101, 47%
4 Tf2O (1.2 eq.) 1.4 eq. DTBP, 4 Å MS CH2Cl2 101, 26%
DTBP = 2,6-di-tert-butylpyridine; a) stereochemsitry of the addition not determined.
As shown in Table 13, TFAA was not successful in activating enone 94, and neither the enol trifluoroacetate 102 nor its desired hydrolysis product 103 could be observed. On the other hand, the reaction with Tf2O furnished a single intermediate, tentatively assigned as vinyl triflate 101.
Attempted hydrolysis of this compound to the desired ketone 103 could not be effected under several base-mediated conditions (Scheme 23).[144,145] Therefore, we explored an alternative strategy that would yield intermediate 103 by intramolecular allyl transfer – namely the anionic oxy-Cope reaction.
Scheme 23. Attempted hydrolysis of presumed enol triflate to ketone 103.
2.2.3.2. Oxy-Cope Rearrangement
The oxy-Cope reaction has been successfully employed in various alkaloid syntheses that bear a benzylic quaternary stereocenter.[55,56,105]
In contrast to the neutral variant of the reaction that requires prolonged times at elevated temperature (> 200 °C), the [3,3]-sigmatropic rearrangement of 1,5-diene alkoxides proceeds at very high rates due to the weakening effect by the alkoxide anion on the adjacent carbon-carbon bond.[146] This allows the reaction to be performed at cryogenic temperatures within a few hours. A literature review reveals a strong counterion dependence (order of reactivity:
K>Na>Li), and that further acceleration can be achieved by addition of appropriate ionophores to
24). It proved unstable to silica gel chromatography and was subjected to anionic oxy-Cope reaction conditions immediately after aqueous workup.
Scheme 24. Preparation of tertiary allylic alcohol 104.
Table 14. Conditions applied for the anionic oxy-Cope rearrangement of 104.
Entrya Base Additive Temp. (°C) Time (h) Yield (%)
1b KOt-Bu (2.0 eq.) 18-crown-6 (2.0 eq.) 0 to rt 3 10
2 KHMDS (3.0 eq.) 18-crown-6 (3.0 eq.) 0 to rt 3 41
3 KHMDS (3.0 eq.) 18-crown-6(3.0 eq.) –5 to rt 3 48 4 KHMDS(1.5 eq.) 18-crown-6 (1.5 eq.) –5 to rt 3 43 5 LiHMDS (1.5 eq.) 12-crown-4 (1.5 eq.) 0 to rt to 60 48 - 6 NaHMDS (1.5 eq.) 18-crown-5 (1.5 eq.) 0 to rt to 60 48 - a) all reactions conducted in THF b) TBS-cleavage product 105 was isolated in 46% yield.
As seen in Table 14, employing KOt-Bu as base afforded the desired product 103 only in poor yield. Additionally, cleavage of the TBS group was observed. Under the reaction conditions and in the presence of the crown ether, the naked t-butoxy anion was able to attack and cleave the silyl ether.
Hence, we decided to employ the non-nucleophilic base KHMDS and were able to improve the yield to 48% (Entry 3). While no TBS-cleavage product was observed in this case, the starting material was completely consumed and gave rise to non-specific decomposition products as evidenced by darkening of the reaction mixture. By comparison, the corresponding lithium and sodium HMDS-bases with the appropriately sized crown ether ionophores were investigated (Entries 5 and 6). Even after prolonged reaction times, no rearrangement product was observed, and the starting allylic alcohol slowly decomposed. Due to these problems and the limited options for improvement, primarily due to the instability of alcohol 103, we decided to investigate an alternative approach.
2.2.3.3. Claisen Rearrangement
The required allylic alcohol for the introduction of the quaternary carbon at C13 by Claisen
reaction was expected to be highly diastereoselective, as the addition of allylMgBr had proceeded in a completely diastereoselective manner (Scheme 24). After successful rearrangement, the last ring could be formed by cyclization of the pendant amine onto cyclopentene 108 (Scheme 25).
Scheme 25. Envisaged synthesis of sinoracutine via Claisen rearrangement of allyl alcohol 106.
Reduction of 94 was successful using different reducing agents (NaBH4/CeCl3, DIBALH), but LiAlH4 provided the cleanest reaction profile and most convenient workup, merely necessitating a filtration of the reaction mixture over a pad of silica after quenching with H2O and NaOH (Scheme 26). As anticipated, 106 was formed as a single diastereomer and its relative stereochemistry could be established through X-ray crystallographic analysis by Nynke Vepřek.
Scheme 26. Diastereoselective reduction of enone 94 and X-ray structure of allylic alcohol 106.
With gram-quantities of alcohol 106 in hand, we turned our attention to the Claisen rearrangement. First, an Eschenmoser–Claisen reaction was attempted (Scheme 27).[148] Unfortunately, the starting material decomposed within 5 minutes upon heating to 100 °C and the reaction mixture turned bright red, suggesting that a major decomposition pathway might include quinoidal intermediates likely to be formed after solvolytic removal of the benzylic silyl ether by liberated methanol (112) or by ionization of the conjugated allylic alcohol (113). The same red color was
rearrangement reaction, resulted in the same red color, confirming the instability of intermediate 106 to protic solvent at high temperatures.
Scheme 27. Attempted Claisen-type rearrangements and possible decomposition intermediates.
Next, protocols that involve the formation and rearrangement of vinyl ether 114 were examined. As shown in Table 15, palladium-mediated vinyl ether formation was attempted.[150,151]
Unfortunately, the desired product was not formed (Entries 1 to 4). Therefore, we turned to the well-precedented formation of vinyl ethers assisted by mercury salts.[152] As previously shown by Nynke Vepřek, reacting 106 with mercury acetate in the presence of either ethyl vinyl ether or the higher-boiling butyl vinyl ether afforded 114, which was used after filtration over alumina to remove Hg-salts (Entries 5 and 6). Unfortunately, heating of 114 in either xylene or benzonitrile did not form any aldehyde product and resulted in decomposition (Table 16). We also tested the rearrangement in wet dioxane, which was reported by Grieco to occur at lower temperatures, but this resulted in no product formation and hydrolysis of the labile vinyl ether (Entry 3).[153]
Table 15. Conditions examined for the formation of vinyl ether 114 from alcohol 106.
Entry Catalysta Vinyl Ether Donor Temp. (°C) Yield (%)
1 116 tris(diethyleneglycol) divinyl ether 130 complex mixture
2 116 butyl vinyl ether 75 no reaction
3 115 butyl vinyl ether 75 no reaction
4 115 ethyl vinyl ether 35 no reaction
5 Hg(OAc)2 ethyl vinyl ether 35 83b
6 Hg(OAc)2 butyl vinyl ether 75 61b
a) 10 mol% b) crude yield reported; product contaminated with unidentified impurities.
Table 16. Conditions examined for the thermal rearrangement of vinyl ether 114.
Entry Solvent Temp. (°C) Time (h) Yield Comment
1 benzonitrile 160 5 n.d. decomposition
2 xylene 140 5 n.d. decomposition
3 dioxane/H2O 110 48 n.d. no rearrangement, hydrolysis to 106
The results involving the synthesis and isolation of vinyl ether 114 led us to consider a Claisen strategy originally reported by Mandai in which the isolation of hemistable vinyl ether 114 is not necessary.[154] Instead, the required intermediate is formed in situ starting from sulfoxide 117 which undergoes Grieco-type elimination with expulsion of a sulfenic acid at elevated temperature (>150
°C), where the subsequent sigmatropic rearrangement occurs readily (Scheme 28). Therefore, we prepared sulfoxide 117 through conjugate addition of 106 to phenyl vinyl sulfoxide using NaH and catalytic KH. The adduct was isolated in very good yield as an inseparable mixture with excess vinyl sulfoxide. Thankfully, subjection of the crude reaction mixture to methylamine in isopropanol scavenged unreacted vinyl sulfoxide and rendered the isolation of pure 117 possible.
Scheme 28. Synthesis of sulfoxide 117 and proposed conversion into aldehyde 107.
Heating of 117 in o-dichlorobenzene showed that the desired product was formed, but yields were variable and longer reaction times were necessary on larger scales, which resulted in side product formation and lower overall yield.[155] Attempts to shorten the reaction time by the use of microwave irradiation were also unsuccessful.[156] Therefore, we investigated the reaction variables in more detail.
As can be seen in Table 17 the reaction provides variable yields, even if set up in parallel on the same scale (Entries 2 to 5). In line with the original report, NaHCO3 was the base of choice but we observed higher yields when a large excess of base was used (>50 eq.), as opposed to 30 eq. in the original publication. Furthermore, NaHCO3 outperformed other bases such as NaOAc and KOAc (Entries 20 and 21). The absence of base resulted in no product formation, whereas the use of a thiophilic scavenger (PPh3) to trap liberated sulfenic acid was possible, but not advantageous (Entries 22 and 23).[157] For reactions conducted in screw-cap vials using a heated metal block, a temperature of 165 °C was optimal (Entries 24 - 26), while lower temperatures resulted in prolonged reaction times and a slight decrease in yield (entries 6 to 11). Reactions above 200 mg of substrate, exemplified by entry 27, were conducted in a round bottom flask and heated in an oil bath set at a temperature of 10 °C higher than desired to compensate for heat dissipation. The reaction was monitored by 1H NMR of reaction aliquots withdrawn every hour.
Figure 9 shows that the starting material is consumed at a higher rate compared to the rate of product formation. Additionally, the product aldehyde 107 is not stable under the reaction conditions, resulting in low isolated yields if the reaction is not monitored frequently and stopped after the disappearance of 117. Taking these findings into account, the reaction reproducibly afforded aldehyde 107 in 60 to 65% isolated yield on scales up to 3 mmol.
Table 17. Conditions examined for the thermolysis and Claisen rearrangement of sulfoxide 117.
Entrya Scale (mg) Base Eq. Solvent Conc. (mM) Temp. (°C) Time (h)b Yield (%)c
1 8 NaHCO3 30 Mesitylene 4 150 8 31
2 10 NaHCO3 30 1,2-DCB 4 150 6 42
3 10 NaHCO3 30 1,2-DCB 4 150 6 41
4 10 NaHCO3 30 1,2-DCB 4 150 6 27
5 10 NaHCO3 30 1,2-DCB 4 150 6 28
6 66 NaHCO3 30 1,2-DCB 4 150 11 40
7 9 NaHCO3 5 1,2-DCB 5 150 8 51
8 9 NaHCO3 10 1,2-DCB 5 150 8 55
9 9 NaHCO3 25 1,2-DCB 5 150 8 56
10 9 NaHCO3 50 1,2-DCB 5 150 8 58
11 9 NaHCO3 100 1,2-DCB 5 150 8 49
12 10 NaHCO3 50 1,2-DCB 5 170 5 29
13 53 NaHCO3 50 1,2-DCB 5 170 2 38
14 48 NaHCO3 50 1,2-DCB 5 170 2 37
15 48 NaHCO3 50 1,2-DCB 2.5 170 2 29
16 50 NaHCO3 83 1,2-DCB 5 170 2 38
17 40 NaHCO3 100 1,2-DCB 5 170 2 35
18 40 NaHCO3 100 1,2-DCB 5 160 4 35
19 40 NaHCO3 100 1,2-DCB 5 160 5 40
20 36 NaOAc 35 1,2-DCB 5 170 2 27
21 36 KOAc 35 1,2-DCB 5 170 2 29
22 36 PPh3 3 1,2-DCB 5 170 2 25
23 36 PPh3 10 1,2-DCB 5 170 2 36
24 90 NaHCO3 80 1,2-DCB 5 165 6 85
25 90 NaHCO3 80 1,2-DCB 5 165 4 72
26 90 NaHCO3 80 1,2-DCB 5 165 4 81
27d 1818 NaHCO3 90 1,2-DCB 5 175 6 73
a) all reactions carried out with catalytic amounts of BHT as additive; b) time until disappearance of starting material as monitored by 1H NMR every hour; c) NMR yield using phenanthrene as internal standard; d) isolated yield: 61%.
a) Product distribution calculated by 1H NMR against phenanthrene as internal standard;
Figure 9. Time-dependent formation and decomposition of aldehyde 107.
Hoping to improve the yield further, we turned to the reaction of p-chloro phenyl sulfone 118, reported to give higher yields than the parent phenyl sulfone 117.[154] Table 18 shows that, for chloro-substituted arene 118, KOAc was the best base for the transformation. Although 140 °C was sufficient to effect the rearrangement (Entry 7), shorter reaction times were achieved at 160 °C (Entry 6).
Interestingly, NaHCO3 was ineffective for this substrate (Entries 2 and 14). Nevertheless, yields were lower compared to the parent system using 117. Given that p-chloro phenyl vinyl sulfoxide is not commercially available and requires multistep synthesis, the use of 118 was not implemented.[158]
Table 18. Conditions examined for the thermolysis and Claisen rearrangement of sulfoxide 118.
Entrya Base Eq. Temp. (°C) Timeb (h) Yield (%)c
1 no base 10 175 3 0
2 NaHCO3 10 175 3 0
3 NaOAc 10 175 3 33
4 KHCO3 10 175 3 16
5 KOAc 10 175 3 59
6 KOAc 10 160 2 71
7 KOAc 10 140 16 68
8 KOAc 10 150 18 60
9 BaCO3 10 150 3 0
10 no base 10 150 18 35
11 KHCO3 10 150 18 73
12 KH2PO3 10 150 18 0
13 K2HPO3 10 150 18 0
14 NaHCO3 10 150 18 0
15 NaH2PO3 10 150 18 0
16 Na2HPO3 10 150 18 0
a) all reactions carried out using 10 mg of 118 in 1,2-DCB (4 mM) and catalytic 0%
20%
40%
60%
80%
100%
120%
0 h 2 h 4 h 6 h 8 h 31 h 52 h 79 h
Yielda
Starting material (117) Product (107)