Synthesis of the tricyclo[9.3.1.03,8]pentadecane (ABC) ring system of taxane diterpenes (original) (raw)
Related papers
Tetrahedron Letters, 1995
Solvolysis of the neopentyl triflates 14,25 and 32 resulted in ring expansion of a seven-membered ring into the eight-membered ring required for the synthesis of the taxanes diterpenoids, Our previous papers have focused on the reductive cleavage of an internal cyclopropane bond (C-l/C-11) to construct the eight-membered Bring of the taxanes. 1 An alternative approach that still utilizes the bicyclo[5.4.0]undecenones 3 (X = OTBS and X = H) is shown in Scheme 1. Conjugate addition of a methyl group to 3 leads to 2, which upon suitable activation of the C-10 alcohol and ionization (solvolysis), has the potential to undergo a semi-pinacol-type rearrangement to give 1.2 In this paper we report the implementation of this strategy. Fir '0 KOR 1 Ring expansion in the,top-half // 14 " 20 Taxane numbering \OR 3 Scheme 1 Ring expansion strategy (X = OTBS or H); TBS = ButMe2Si Me ?r2OMoM Lo5QoTBs 5 CHO ' H : Me'
Facile access to the ABC ring system of the taxane diterpenes via anionic oxy-Cope rearrangements
Tetrahedron, 1995
The anionic oxy-Cope rearrangement of bicyclo[2.2.2]octadienols serves as a key step for the construction of substituted bicyelo[5.3.1]undecenones and provides a novel entry to the AB ring system of the taxane diterpenes. The bicyclo[2.2.2]octadienols lla-e underwent facile anionically-accelerated [3,3]-sigmatropic rearrangements to give bicyclo[5.3.1]undecenones 14a-e. Such reorganizations were also found to proceed in more highly substituted systems as evidenced by the transformations 27a-c~28a-c, 30~32, and 31--,33. These bicyclo[5.3.1]undecenones were further functionalized by introducing a double bond conjugated to the carbonyl group (27a~40); moreover, oxygen functionality at C(13) could be introduced by allylic oxidation (28a~41 and 40--~42). The enolates produced in situ by the anionic oxy-Cope rearrangement could be trapped by alkylating agents. These alkylations were highly stereoselective when the ketone enolate was trisubstituted as exemplified by the reactions 44~47 and 45~48. This entry to the taxane diterpenes allows aec,~s to the tricyclic ABC framework of the taxanes by annelation of the C ring onto an AB ring subunit as illustrated by the sequence 30~49~50.
Synthesis of the bicyclo[5.3.1]undecane moiety (AB ring system) of taxanes
The Journal of Organic Chemistry, 1991
containing acetone oxime (0.10 g, 1.37 mmol), dichloro derivative If (0.10 e. 0.35 mmol). and NaHCO, (2.00 e. 23.8 mmol). The 93% yield. Acknowledgment. We are grateful for the financial support of the US. Army Armament Research Developmerit and Engineering Center, Picatinny Arsenal, NJ (Contract NOS. DAAK10-85-R-0104 and DAAA21-86-C-reaction kixture rapidly developed a"b1ue cilor, which faded to colorless during the 48-h stirring period. The reaction mixture was worked-up as described in the general procedure (vide supra). An examination of the crude product by 1H and 13C NMR indicated that the maior comDonents in the mixture were 2chloro-2-nitropropane" and unieacted If, which was recovered in 0101).
Tetrahedron, 1999
Ring A of taxol was synthesized from the bromodiene 5 and acryloyl chloride to give 6, which was resolved by separation of diastereomers 7. Allylic oxidation of 7 gave 8, which on deprotection, esterification and reduction gave 11. Heating 11 followed by reduction and protection gave 13. The C-ring component was made using asymmetric Birch reduction methodology combined with standard functional group manipulations to give 28. Combining 13 and 28 gave 29, which was converted into 33. Thermolysis of 33 did not generate a nitrile oxide but rather ionized to an oxydienyl cation, eventually leading to 34.
Synthetic studies towards pentacyclic triterpenes
Arboranes and fernanes are pentacyclic triterpenes. Isoarborinol, suggested to be a cholesterol surrogate in the membranes of some undefined bacteria (Guy Ourisson), a hybride of migrated hopanes and parkeol, contains five cycles, 9 asymmetric centers (512 possible stereoisomers) hence a feasible total synthesis requires a plan involving a very high degree of stereoselectivity. In contrast to the massive amount of research, which has been directed toward the total synthesis of taxanes and mevinic acids, little attention has been paid to arborane and fernane type pentacyclic triterpenes. The challenge was: could we achieve the synthesis of natural and unnatural analogues of arborane and fernane derivatives using the same ingredients in a common synthetic scheme whith enzyme like selectivities? Plants produce one or more cyclases that convert squalene or its epoxide into a complete series of triterpenoid products in which the molecules posses both an epimeric and antipodal steric arrangement of the ring systems. According to the literature, differences in various biological properties of these migrated hopanes could be related to the stereochemistry of the ring system and of the isopropyl group attached to C-21. Plant extraction from several tropical plants will give the exact molecule but not the nor-14 or nor-21 analogues as there is no way for removing the angular methyl group at C-14 or isopropyl group at C-21, to synthesize molecules for biological tests. We first favored an AB+DE-→ ABCDE approach, anticipating that joining the diene AB 2 and dienophile DE ring 3 precursors should correctly situate the chiral centers at C10 and C17, furthermore ensuring the right orientation. The ester group in 3 should initially serve to activate the dienophile during the [4+2] before its transformation to the C13 angular methyl group. This plan was thwarted by the wrong orientation of the reactants. The carbonyl preferred an exo orientation and led to the unnatural skeleton 7/8, the ester group having served both as a good activating group and as an exclusive control element.
Synthetic studies on taxane diterpenes X-ray structure of a key intermediate
Tetrahedron, 1984
Abbtzact-Michael condensation of the dienone (3) with the vinyllactone (19) leads to the capound (20). Attempts to construct the B ring of the taxane skeleton by direct cyclization of (20) are reported. The stereochemistry of (20) is established by X-ray structure determination. The taxanes are a group of natural products isolated from various species of TW and possess a unique carbone skeleton (1) '. This unusual structure containing a sterically congested eight-membered B ring provides a challenging synthetic target. Moreover, sane taxane derivatives, such as taxol (2) exhibit highly potent antileukemic and tumor inhibitory properties 2. The key step in taxane diterpenes synthesis is the construction of B ring. Several approaches have been reported involving an anionic Oxy-Cope rearrangement 3. an intramolecular Diels-Alder cyclization 4 or a fragmentation process 5. AcO OAc ' I.C.S.N. Postdoctoral fellow 1981. Present adress : Institut de Chimie des Substances Naturelles GIF-sur-YVETTE .
The Journal of Organic Chemistry, 1995
The coupling of an optically pure, camphor-derived, / 3, y-unsaturated, bicyclic ketone with a suitable vinyl organometallic is recognized to result in 1,2-addition from the endo face. Anionic oxy-Cope rearrangement of these carbinols proceeds via an "endo-chair" transition state to deliver a strained and reactive enolate that is formed regioselectively and is amenable to a-methylation from the top face. These steps, which are preliminary to a broad-based approach to the taxane diterpenes, had not yet accommodated suitable introduction of a C-7 oxygen substituent as required of taxol. Typically, an ether substituent at this site experiences /3-elimination once the enolate anion intermediate is accessed. Herein it is demonstrated that the parent 2-bromocyclohexenone acetal is well suited to resolving this complication. Halogen-metal exchange proceeds well to provide a suitably nucleophilic building block. Direct charge-accelerated sigmatropic rearrangement of the carbinol products does proceed with ,&elimination, but under the present circumstances the second C-0 bond remains in the form of a vinylogous ester. Alternatively, the carbinols are amenable to chemoselective hydrolysis of the acetal, thereby unmasking a conjugated cyclohexenone part structure. These intermediates have been found to rearrange along completely analogous reaction trajectories to provide enolates of a P-diketone subunit. The extent to which these anions undergo Cversus 0-methylation under various conditions has been examined. When 0-methylation does occur, it is the C-7 oxygen (and not the one at C-9) that is engaged in reaction. Our laboratory has been involved in the development of a practical synthetic route to taxol at several 1evels.l One goal has been to produce alcohols such as 1 in a highly convergent coupling reaction: to effect stereochemically well defined anionic oxy-Cope rearrangement of 1 to 2,3 and to bring about bridge migration to 3 through application of the a-keto1 r e a~~a n g e m e n t .~ Although this scheme has proven successful to various degrees and may augur well for accessing the powerfully cytotoxic 7-deoxytax01,~ proper incorporation of the C-7 oxygen substituent present in taxol has persisted as an issue requiring suitable resolution. The complication to be circumvented resides in the fact that implementation of the charge-accelerated [3,31 sigmatropic transposition6 generates an enolate anion of type 4. The formation of this reactive intermediate under