Chem 242b Chemical Synthesis

Transcription

1 Lecture 7 [2+2] Cycloaddition Strategies 7A. verview of Ketene Cycloaddition Strategies (andout 4) If you need a cyclobutanone and desire to make it by [2+2] addition of ketene to an olefin, you will always see it made by addition of dichloroketene and then reduction of the chloro groups. owever, ketene itself is not as synthetically useful as dichloroketene. + 3 CC Zn C 3 Zn-Cu, P 3 C 3 Zn, Ac or Bu 3 Sn A. E. Greene, rg. Syn. Coll. Vol. 8, 377. In an intramolecular case, you are more likely to see ketenes generated from Wolff rgt. or elimination from the acid chloride. Why does the 4π e- addition of ketenes to olefins occur thermally? (Isn t 4πeforbidden?) C 2 RC Et 2 R n-bu 3 N RC 2 C benzene, 80 o C C 3 Et 3 N R C R C hν not from R C C C 2 R C Rationalization 1: Just like 4π e- electrocyclic reactions can be considered thermally forbidden for disrotatory ( + ) and allowed for conrotatory ( + 2a), so can cycloaddition reactions be considered thermally forbidden for ( + ) and thermally allowed for ( + 2a). In most cases, the π + π2a transition state is too hindered to be possible, but ketenes present no steric hindrance at the C= group and may cycloadd by the T.S. below. Rationalization 2: A more creative proposal suggests that the three π systems of the ketene all participate in a π+π+π transition state. R S R L 2a π + π2a ketene cycloaddition R S R L π + π +π ketene cycloaddition 2a conrot. π + σ2a 2a π + π2a cycloaddn Thermally Allowed disrot. π + σ π + π cycloaddn Thermally Forbidden (In this designation, s denotes that the reacting subunit is participating suprafacially and a describes an antarafacial participation.)

2 7B. Aphidicolin (Ireland JACS 1981, 103, 2446.JC 1979, 44, 4323) The DNA polymerase α inhibitor aphidicolin was targeted by Ireland using an annulation strategy on a decalin precursor containing a spiro- six membered ring. At the outset of this work, intramolecular enolate acylation (Dieckmann) or Lewis-acid-catalyzed addition of an acid halide to a substituted cyclohexene were investigated, but all such cyclization attempts failed. Then in the 1979 paper, while generating the methyl ester (R = ) by Wolff rearrangement (via the ketene), an unexpected product was obtained and its structure postulated. What was this mystery side product? Would it prove to be the key to completing the synthesis of Aphidicolin? Aphidicolin α- or β- R very challenging C 2 R Ireland s synthesis of aphidicolin is noteworthy in many respects including one of the first complex uses of an organosilane-containing functional group as a key feature of a total synthesis. This group was introduced by hetero-da reaction followed by aisen rearrangement of the vinyl intermediate shown. Generation of the α-diazoketone was performed as shown below, however, nowadays many more convenient reagents and methods are available for α-diazotization of ketones. (Problem Set 2) C 2 Si 3 C C hydroquinone 7:3 dr (80% yield) C 2 C 2 Si 3 1. DiBAl- top face addn, endo-adduct 2. Ph 3 P=C 2 C 2 Si 3 C 2 Si 3 C 2 Si 3 C 2 Si C sealed tube (aisen rgt.) 1. n-buli 2. i-amn N N 4, Na TF " "

3 7B. Aphidicolin (cont.) In the 1979 publication, the discovery of the ketene cycloaddition product was first disclosed (in the series containing the C 3 group in place of the C 2 Si 3 ). The product was incorrectly assigned as the normal adduct which would have been of no help to the synthesis. owever, the a referee suggested that the undesired byproduct might actually be the crossed adduct. What s more impressive is that in the 1981 publication, Ireland actually credited the anonymous referee for the suggestion. Just to make sure that it is clear what is going on here In the simplified case at right, the normal adduct actually contains two strained four membered rings fused together whereas the crossed adduct though initially funnylooking is actually a much less strained bicyclic system. C or "normal adduct" "crossed adduct" hν TF, -60 C C X (wanted methyl ester) incorrectly assigned as this referees suggested it might be crossed adduct: Synthesis was completed using this discovery. C C 3 C 3 ere is the classy footnote. Doesn t this make you want to be a diligent reviewer? (9) The structure shown here for this unstable cyclobutanone 7 differs from that previously suggested for the stable cyclobutanone formed in the de-(trimethylsilylsilyl) series. We are very grateful to a referee for calling to our attention this alternate structural possibility and, as a result, have extensively reexamined and refined the spectral data for both the silylated system and the previous, stable de(trimethylsilyl) compound

4 7C. Aphidicolin (cont.) Chem 242b Chemical Synthesis In the trimethylsilyl substituted series, the intramolecular ketene-olefin cycloaddition afforded a trimethylsilylmethyl cyclobutanone which was unstable to silica gel chromatography. f the two seemingly equivalent cyclobutane bonds which could be fragmented, only a single isomeric product was obtained. This suggests that the alignment of the TMS group anti to the desired bond was important as shown in the Newman projection. Finally (for this discussion), reduction and protection of the resulting alcohol was followed by dihydroxylation. C 2 Si 3 C 2 Si 3 hν Et 2, -75 C C C 3 ~ Si 3 Si 2 hexanes ~ + Si 3 selective cyclobutane cleavage 60% yield from oxime C 2 3. s 4 1. DiBAl- 2. TBS 14 steps crossed adduct Aphidicolin TBS

5 7C. Retigeranic Acid (Corey JACS 1985, 107, 4339, Engler - Strategies and Tactics vol. 2, pp ) Corey s synthesis of the complex sesterterpene ( = 2½ x C 10 ) Retigeranic acid took advantage of the DA-ozonolysis-aldol tactical combination which had been applied to his gibberelic acid synthesis. Construction of the triquinane was planned using an intramolecular ketene-olefin [2+2] and subsequent ring expansion. C 2 Diels-Alder/ 3 /Aldol TC The synthesis got off to a rocky start when it was found that the hydrindenone below cleanly gave the undesired cis- ring fusion when it was reduced with lithium in liquid ammonia. So unexpected was this result that the cis material was carried several steps further until an X-ray analysis of a Diels-Alder adduct showed it to be erroneous. Although there are hydroxyl-directed hydrogenation methods available, these were attempted to no avail. Finally, the stereospecific concerted allylic sulfenic acid rearrangement was used to obtain the hydrindene with the desired trans- fusion. Several additional steps were used to convert this to the originally sought after hydrindenone and then the DA adduct shown. C N EtAl 2 76% Li, N 3 1 eq. Et LiAl 4 C Li/N 3 was expected to give trans- C 3 CS DEAD, PPh 3 (Mitsunobu) 1. LiAl C 1. 9-BBN SCC 3 2. mcpba, C C to rt S [3,3]~ sulfenic acid rearrangement Jones ox. 1. C 2 =CMgBr 2. +, Δ C C 2 C C 2 5.3:1.3:1 prep hplc

6 7C. Retigeranic Acid (cont.) Chem 242b Chemical Synthesis As the real system was being stockpiled, a simpler model system served to test out the ipr 2 NEt ketene-olefin cyclization. eating the acid C chloride with unig s base gave a mixture of toluene, two cyclobutanones, however neither was the 120 o C desired poroduct. In addition to the crossed Incorrect cyclobutanone adduct, the incorrect cyclobutanone was obtained resulting from fragmentation of the initially formed crossed adduct. This C fragmentation to regenerate a ketene is best understood by hemolytic fragmentation of the acyl bond (~) followed by breaking the dashed bond. The interconversion was reversible at crossed adduct (vinyl ketene) 120 C and required considerable detective work to elucidate. The original plan was modified as shown below affording the cyclobutanone product which was ring expanded to the cyclopentenone, equilibrated and deoxygenated. Dihydroxylation and lead tetraacetate cleavage afforded a ketoaldehyde which was cyclized and oxidized (C -> C 2 ) to retigeranic acid. ~ C C 2 Ph 3 P C 2 1. LiAl 4 2. o- C 6 4 SeCN 3. [] Na C 2 3. (C) 2 benzene, cat. DMF 4. Et 3 N, benzene, Δ C 2 C S Li S TF, -78 C S S CuTf S 1. 2, Pd(C) 2. Na (base equil.) 1. TsN 2. B (Kabalka deoxyg.) C= -> C 2 1. s 4, py 2. Pb(Ac) 4 Retigeranic Acid 3. neutral Al 2 3 4Å sieves 4. Na 2