Bicyclic cyclobutanes synthesis

Asymmetric [2 + 2] Photocycloadditions. Intramolecular copper-catalyzed [2 + 2] photocycloaddition is a useful methodology for the preparation of bicyclic cyclobutanes and recent studies deal with its asymmetric version albeit with variable success. Diastereoselective reactions are achieved under the control of stereogenic centers incorporated in the dienic precursors. Both CuOTf and the more stable and easy to handle Cu(OTf)2 are suitable catalysts in this context. In the latter case, it is assumed that the copper(I) species is generated from Cu(OTf)2 under the photochemical conditions. A noteworthy example is the application of the CuOTf-catalyzed [2 + 2] photocycloaddition in the stereoselective total synthesis of the tricyclic sesquiterpene kel-soene (eq 128). ... 

In a recent total synthesis of the novel neurotrophic agent merrilactone A (22, Scheme 4) by Inoue and Hirama [24], key intermediate 21 with the cis-bicyclo[3.3.0] octane framework embedded within the caged pentacycle 22 was elaborated from cyclobutane 18 by a sequence of RCM and immediate cleavage of the resulting bicyclic vicinal diol 19 to raeso-diketone 20. Cyclooctenedione 20 then underwent regioselective transannular aldol reaction at low temperature (LHMDS, THF, -100 °C) to produce a 3 1 mixture of isomers in 85% combined yield. The major isomer 21 with the required stereochemistry was then converted into the racemic natural compound ( )-22 in 19 steps. 

A key step in the synthesis in Scheme 13.11 was a cycloaddition between an electron-rich ynamine and the electron-poor enone. The cyclobutane ring was then opened in a process that corresponds to retrosynthetic step 10-IIa 10-IIIa in Scheme 13.10. The crucial step for stereochemical control occurs in Step B. The stereoselectivity of this step results from preferential protonation of the enamine from the less hindered side of the bicyclic intermediate. 

The ciT-substituted cyclobutane ester 502 is of interest as intermediate for the synthesis of carbocyclic 503 (equation 218). Ring opening of the bicyclic (-l-)-Nopinone 501... 

Intramolecular cyclopropanation of diazoketones to furnish [3.1.0] and [4.1.0] bicyclic systems are the most common and effective reactions in this category. Two recent examples are shown in equations 48 and 49. The bicyclic ketone 34 has been used in the synthesis of polycyclic cyclobutane derivatives77, whereas ketone 35 is the key intermediate in the total synthesis of ( )-cyclolaurene78. When the olefinic double bond is attached to, or is part of, a ring system, the cyclopropanation process also works well. Copper oxide catalysed decomposition of diazoketone 36 produces the strained tricyclic ketone 37 in 86% yield (equation 50)79. In another case, in which the cyclopropanation of diazoketone 38 gave stereospecifically the cyclopropyl ketone 39, copper sulphate catalysis was used. The cyclopropyl ketone 39 is the key intermediate in the total synthesis of ( )-albene 40 (equation 51). ... 

A modified de-Mayo reaction (shown in Scheme 21) also served as a tool in the first synthesis of a saturated taxane framework with a geminal dimethyl group (79,80). Photocycloaddition of cyclohexene (functioning as a ring C model) to a bicyclic 1,3-diketone derivative from 85 is the key step. In the course of the cyclobutane annealing, the C-8 a ring connection is established contrary to C-3,... 

Subsequently, the absolute configuration of the natural lineatin was determined as (lR,4S,5R,7R)-77 by our second synthesis, as shown in Figure 4.16.35 The first step was the cycloaddition of dichloroketene to isoprene to construct a cyclobutane ring. The symmetrical cyclobutanone A was then converted to ( )-bicyclic lactone B. Enantiomer separation (optical resolution) of ( )-B was executed as follows. Reaction of ( )-B with the resolving agent C (derived from chrysanthemic acid) yielded a diastereomeric mixture... 

Cyclobutane.—One of the most interesting novelties recently discovered is a monoterpene representative of the cyclobutanes (apart from the bicyclic systems containing cyclobutanes). The sex attractant of the male boll weevil (Anthonomus grandis, Boheman) was identified as the cis-substituted cyclobutane (73), a stereospecific synthesis of which (Scheme 4) was reported shortly afterwards. ... 

Similarly the bicyclic cyclopropyl ketone 134 is readily converted to the tricyclo[5.3.0.0 - ]decane 135 under similar conditions via a domino ring opening/Michael/aldol reaction sequence as shown in the Scheme 4.27 [45]. The selective attack of the iodide ion at the 6-position of 136 leading to the intermediate 137 may be due to the effective overlap between cleaved bond and the % orbital of the carbonyl group. This novel domino reaction producing polycyclic cyclobutanes was exploited for the synthesis of natural products like ( )-anthoplalone and ( )-lepidozene by the same workers [45]. 

The photocycloaddition-retro-Mannich-Mannich methodology is featured in a concise synthesis of mesembrine. Irradiation of vinylogous amide 114 effects photocycloaddition-re/ro-Maimich sequence to give product 116 via the cyclobutane intermediate 115. Methylation with trimethyloxonium tetrafluoroborate followed by treatment with DMAP produces mesembrine in 84% yield. Other applications include construction of the bicyclic core of peduncularine and synthetic approaches to hetisine alkaloids and 8-substituted 6-azabicyclo[3.2.1]octan-3-ones. ... 

A variety of different routes to cyclobutane systems involving non-photochemical means has also been devised. Acid catalyzed rearrangement of fused cyclopropyl ether (61) by Wenkert et al. (97, 98) afforded the bicyclic dione (62), which through a thioketal-desulfurization process and treatment with hydroxylamine yielded oxime (58) (Scheme 12). The shortest synthesis of grandisol is that reported by Billups et al. (Scheme 13) (99). Dimerization of isoprene in the presence of a zero-valent bis-cyclooctadienyl-nickel-phosphite complex gave the cis-cyclobutane diolefin (65), which could be separated in 12—15% yield from the complex product mixture by low-temperature distillation. Selective hydroboration and oxidation afforded grandisol. 

The route employed to prepare indanone 51 involved the cycloaddition-hydrolysis-aldol sequence shown in Scheme 3.9. Accordingly, condensation of cyclopentenone 52 with ynamine 53 (84) afforded the bicyclic enamine 54 which was converted to indanones 51 and 55 by hydrolytic cyclobutane ring opening followed by intramolecular aldol condensation. Interestingly, treatment of 54 with aqueous formic acid yielded indanone 51 which has stereochemistry complementary to that at C(15) and C(20) in reserpine. In contrast, hydrolysis of this substance with aqueous hydrochloric acid afforded the trans-fused indanone 55. Subsequent to this work, the Ficini group found that esterification of 51 followed by photochemically induced addition of methanol afforded adduct 56 which has four of the reserpine stereocenters in place (23). While no further work on this problem has been reported, these preliminary investigations demonstrate a novel use of [2 -h 2] photocycloaddition chemistry in potential approaches to yohimbane alkaloid synthesis. 

---