Polycyclic Polyprenylated Acylphloroglucinols (PPAPs) are a unique group of natural products which have densely substituted bicyclo[3.3.1] nonanone core. Hyperforin (1), isolated from St. John's wort (Hypericum perforatum) in 1971, is one of the representatives of this family. Recent studies revealed that hyperforin has several interesting biological activities, such as mild antidepressant activity, antimalarial activity and drug-drug interaction through inducing CYP3A4. Because of its complex structure and potential utility as pharmaceutical lead, extensive synthetic studies have been reported, but none of them accomplished the total synthesis of hyperforin. Herein, I report the first catalytic asymmetric total synthesis of ent-hyperforin.

1. Retrosynthetic Analysis

Planned approach toward ent-hyperforin is shown below (Scheme 1). C2 oxidation and C3 alkylation could retrosynthetically lead to bicyclo compound 2. The bicyclo[3.3.1] core of the key intermediate 2 could be constructed through Claisen rearrangement-intramolecular aldol cyclization sequence from O-allylated intermediate 4. The Claisen rearrangement precursor 4 could be produced from multi substituted cyclohexene 5, and it could be constructed by a catalytic asymmetric Diels-Alder reaction between dienophile 6 and diene 7 in high yield, high dr and high ee.1)

2. Construction of Bicyclo[3.3.1] Core

Construction of a bicyclo[3.3.1] core in correct stereochemistry depends on the diastereoselectivity of the planned Claisen rearrangement. Terefore, the stereoselectivity of the Claisen rearrangement was examined first using model substrates (Scheme 2). This study showed the importance of stereochemistry of C5 prenyl groups. The a-prenyl substrate 9 rearranged stereoselectively constructing desired Cl quaternary carbon center. On the other hand, the J3-prenyl substrate 11 rearranged to give 12 which has undesired stereochemistry at Cl quaternary carbon. These results demonstrated that the C5 prenyl group was a main factor in determining the conformation during the transition state and the rearrangement proceeded from the indicated face, avoiding steric repulsion between the pseudo axial methyl group at C8 and the allyl group.2)

The Claisen rearrangement of the actual substrate 4 also proceeded in high diastereoselectivity (Scheme 3). Following selective hydroboration and oxidation afforded the intramolecular aldol reaction precursor 14. The critical cyclization proceeded smoothly under basic conditions, and the obtained secondary alcohol was oxidized to give key bicyclo[3.3.1] compound 2.

3. Completion of the Total Synthesis

Remaining tasks were C3, C7 prenyl introduction and a C2 oxidation. Among these tasks, installation of the C7 prenyl group was conducted first. Cleavage of the C7 MOM ether under acidic conditions proceeded with concomitant protection of the homoprenyl group at C8 to give 15. Swern oxidation of 15 followed by the addition of a vinyl Grignard reagent afforded allylic alcohol 16 as a single isomer, which was deoxygenated through acetylation and a palladium-catalyzed allylic reduction. The subsequent cross-metathesis with isobutene using the Hoveyda-Grubbs 2nd generation catalyst produced a third prenyl group at C7. The obtained product 18 was oxidized to enone 19 through a conventional palladium mediated Saegusa-Ito oxidation.

Next is an introduction of oxygen functionality at C2 position. After extensive investigation, it turned out to be difficult to functionalize C2. 1,4-addition of several kinds of nucleophiles resulted in failure due to the steric hindrance around C2 position. The key of the C2 functionalization was a vinylogous-Pummerer rearrangement. Enone 19 was converted to sulfoxide 22 through a [1.3]-xanthate rearrangement. When the obtained 22 was treated with TFAA in the presence of bulky pyridine derivative, 2,6-di-tert-butylpyridine, a rearrangement proceeded preferentially in 1,4-manner. The product 23 was oxidized to sulfoxide 24, which was treated with allyl alcohol under basic conditions to give O-allyl intermediate 25. Next, Claisen rearrangement was examined to introduce a C3 prenyl group. Although thermal or Lewis acid-mediated conditions gave only a trace amount of the rearranged product, a palladium-catalyzed allyl transfer followed by acetylation afforded the product 26 in moderate yield. Subsequent cross metathesis and deacetylation finally afforded ent-hyperforin.3)

Hyperforin (1)

Scheme 1. Retrosynthetic analysis.

Scheme 2. Diastereoselectivity of Claisen rearrangement.

Scheme 3. Construction of bicyclo[3.3.1] core. Reagents and conditions: (a) toluene, N, N-diethylaniline, 170℃, >99% (dr=12:1). (b) (Sia)2BH, THF; H202 aq., NaOH aq., EtOH, 81%. (c) DMP, CH2C12, 91%. (d) NaOEt, EtOH. (e) DMP, CH2C12, 86% (2 steps).

Scheme 4. Introduction of C7 prenyl group. Reagents and conditions: (a) (+)-CSA, MeOH, 66% (3 cycles). (b) (COCl)2, DMSO, CH2C12; NEt3, 95%. (c) vinylmagnesium bromide, THF, 92% (dr>33:1). (d) Ac2O, DMAP, 1Pr2NEt, CH2C12, 98%. (e) Pd(PPh3)4 (20 mol%), HCO2NH4, toluene, 95%. (f) Hoveyda-Grubbs 2nd cat. (15 mol%), 2-methyl-2-butene, CH2C12, >99%. (g) TMSC1, NEt3, DMAP, 84%. (h) Pd(OAc)2, DMSO, O2, >99%

Scheme 4. Completion of the total synthesis. Reagents and conditions: (a) NaBH4, Me0H, 95% (dr>33:1). (b) CS2, NaH, THF; Mel, >99%. (c) toluene, 150℃. (d) EtSLi, THF; Mel, NEts, 98% (2 steps). (e) NaBO3・4H2O, AcOH (dr=1.3:1), 95%. (f) TFAA, 2,6-di-t-butylpyridine, CH2Cl2, -40℃; H20, 65% (dr>33:1). (g) H2O2, HFIP, 87% (dr=9:1). (h) DMP, CH2Cl2, 86%. (i) Amberlyst 15DRY, toluene, 55%. (j) LiH, allyl alcohol, 67%. (k) Pd2dbas・CHC13 (10 mol%), (S)-tol-BINAP (20 mol%), THF; Ac2O, pyridine, 50%. (1) Hoveyda-Grubbs 2nd cat. (15 mol%), 2-methyl-2-butene, CH2Cl2, 34%. (m) K2CO3, MeOH, 94%.

清水洋平は、「ent-Hyperforinの触媒的不斉全合成」というタイトルで、以下の述べる博士課程の研究を行った。

セイヨウオトギリソウより単離されたhyperforinは抗欝作用、抗マラリア活性やCYP3A4の発現を促進し、薬物間相互作用を起こすなど様々な生物活性を有する興味深い化合物である。合成的な観点からも、置換基が密に存在するビシクロ[3.3.1]骨格、連続する3つの不斉点を含む4つの不斉中心、また2つの橋頭位がいずれも4級炭素となっているなど、その全合成には困難が予想される、清水は独自に開発した触媒的不斉Diels-Alder反応基盤とし、世界初となるent-hyperforinの全合成を達成した。

既報の触媒的不斉Diels-Alder反応によって得られた化合物5よりClaisen転位前駆体であるO-アリル化体4を合成した。これをトルエン中170℃に加熱することでClaisen転位が高収率、高立体選択的に進行し、1位4級炭素の構築に成功した。続いて、末端二重結合選択的にヒドロホウ素化し酸化的処理に付すことでアルデヒド14へと変換した。ビシクロ[3.3.1]骨格構築の鍵となる分子内アルドール反応は塩基性条件下円滑に進行し、得られた2級アルコールを酸化することで重要中間体2の合成に成功した(Scheme 1)。

さらなる変換により、7位プレニル基を導入したのち、中間体15を用いて2位への酸素官能基導入を行った。隣接する1位4級炭素に由来する立体障害により2位への酸素官能基導入は非常に困難であったが、詳細な検討により、vinylogous-Pummerer転位が良好に進行することを見出した。すなわち、キサンテート16の[1.3]転位によって4位に導入された硫黄原子を利用しスルホキシド18を合成した。これをTFAAにて処理することによってvinylogous-Pummerer転位が進行し、2位への酸素官能基導入に成功した。続く3位へのアリル基の導入をパラジウム触媒を用いた転位反応によって行い、クロスメタセシスおよびアセチル基の除去によってent-hyperfortinの触媒的不斉全合成に世界で初めて成功した(Scheme 2)。

以上のように、清水の業績は医薬品等の生物活性化合物の触媒的不斉合成に有意に貢献するものであり、博士(薬学)の授与に相当するものと判断した。