Cleavage of steroidal epoxides with organoaluminum cyanides

Nagata, Wataru; Yoshioka, M.; Okumura, Tamotsu

doi:10.1016/s0040-4039(01)99694-7

Cited by 36 publications

(9 citation statements)

References 10 publications

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“…Epoxide 1 was prepared from naphthalene by Birch reduction (Na/NH 3 ; 74 % yield) then epoxidation (CH 3 CO 3 H; 87 % yield) 10. Ring opening with Et 2 AlCN,11 followed by completely diastereoselective epoxidation and trans ‐diaxial ring opening with Me 3 Al gave triol 4 . Selective mesylation then anti elimination in neat DBU furnished the requisite diallylic alcohol 5 .…”

Section: Methodsmentioning

confidence: 99%

Enantioselective Desymmetrization ofmeso-Decalin Diallylic Alcohols by a New Zr-Based Sharpless AE Process: A Novel Approach to the Asymmetric Synthesis of PolyhydroxylatedCelastraceae Sesquiterpene Cores

Spivey¹,

Woodhead²,

Weston³

et al. 2001

Angew. Chem.

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Crude plant extracts of the Celastraceae have been valued since antiquity for their stimulant, appetite suppressive, antiarthritic, antibacterial, insect repellent, and memoryrestorative properties. [1] Pervasive among the secondary metabolites isolated from this class of plants is a large family of polyhydroxylated sesquiterpene esters having a dihydro-bagarofuran skeleton. [2] Many members of this family, partic-ularly esters of three polyhydroxylated agarofurans: euonyminol, 4b-hydroxyalatol, and 14-deoxyalatol, exhibit significant biological activity. These include: triptogelins A-1/A-6 [3a] and celhin A [3b] (antitumor), wilfortrine [4] (immunosuppressive), wilforine [5] (insecticidal), and celangulin [6a] and cathedulins E-3/E-4/E-5 [6b] (insect antifeedant). Additionally, hypoglaunine B and related macrocyclic lactone derivatives of euonyminol have recently been shown to display significant anti-HIV activity [7] (Scheme 1). A B RO RO OR OR OR OH RO RO OR OR OR OH O HO HO OH OH X 1 O OH H X 2 X 4 X 3 AcO AcO OAc O AcO O OAc H O OH O N O OH O O O euonyminol: X 1 ,X 2 ,X 3 ,X 4 = OH 4β-hydroxyalatol: X 1 ,X 3 = OH, X 2 ,X 4 = H 14-deoxyalatol: X 1 ,X 2 ,X 3 ,X 4 = H epoxidative enantioselective desymmetrization hypoglaunine B 4 14 Scheme 1. Desymmetrization strategy. R protecting group, Ac acetyl.One striking feature of the three core structures common to these natural products is a symmetric array of hydroxyl groups on the top face of their ªnorthernº periphery. We were intrigued by the possibility of exploiting this symmetry to facilitate their synthesis. In particular, we identified epoxide B as a pivotal intermediate for the preparation of all the core structures and we envisaged that a two-directional synthesis of meso-diallylic alcohol A followed by epoxidative enantioselective desymmetrization [8] would provide an efficient route to this intermediate (Scheme 1). Here we describe how the successful implementation of this plan required the development of a Zr-based Sharpless asymmetric epoxidation (AE) process for tertiary diallylic alcohols.At the outset of our work, only one trans-decalinic diallylic alcohol had been reported. [9] In view of this limited precedent, and the potentially labile nature of the structure, we opted to evaluate the feasibility of our strategy on simple model system 5 (Scheme 2). Epoxide 1 was prepared from naphthalene by Birch reduction (Na/NH 3 ; 74 % yield) then epoxidation (CH 3 CO 3 H; 87 % yield). [10] Ring opening with Et 2 AlCN, [11] followed by completely diastereoselective epoxidation and trans-diaxial ring opening with Me 3 Al gave triol 4. Selective mesylation then anti elimination in neat DBU furnished the requisite diallylic alcohol 5. This alcohol was prone to partial [1,3]-allylic rearrangement to give the corresponding conjugated dienyl alcohol on silica, but could be obtained pure after chromatography on grade 1 basic alumina.Sharpless AE [12] with either catalytic [13] or stoichiometric [13] amounts of Ti(OiPr) 4 /d-(À)-diisopropyl tartrate (DIPT) pro-...

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Section: Methodsmentioning

confidence: 99%

Enantioselective Desymmetrization ofmeso-Decalin Diallylic Alcohols by a New Zr-Based Sharpless AE Process: A Novel Approach to the Asymmetric Synthesis of PolyhydroxylatedCelastraceae Sesquiterpene Cores

Spivey¹,

Woodhead²,

Weston³

et al. 2001

Angew. Chem.

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“…Soon thereafter, and much to our surprise, we established the unorthodox stereochemistry (‐CN, ‐OH cis to each other) of the compound as suggested by NOE experiments. There are three possible mechanistic rationales for this unexpected stereochemical outcome: in the first (Scheme 10 b, top), our favored scenario, a molecule of Et 2 AlCN19 reacts with the hydroxyl group of 61 furnishing complex 61 a , which suffers nucleophilic attack by cyanide from the more accessible convex site made possible by considerable weakening of one of the epoxide CO bonds. This mode of attack would then be accompanied by the observed retention of stereochemistry at C‐12 (CP numbering).…”

Section: The Maleic Anhydride Hurdlementioning

confidence: 99%

The CP Molecule Labyrinth: A Paradigm of How Endeavors in Total Synthesis Lead to Discoveries and Inventions in Organic Synthesis

Nicolaou¹,

Baran²

2002

Angew. Chem. Int. Ed.

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Imagine an artist carving a sculpture from a marble slab and finding gold nuggets in the process. This thought is not a far-fetched description of the work of a synthetic chemist pursuing the total synthesis of a natural product. At the end of the day, he or she will be judged by the artistry of the final work and the weight of the gold discovered in the process. However, as colorful as this description of total synthesis may be, it does not entirely capture the essence of the endeavor, for there is much more to be told, especially with regard to the contrast of frustrating failures and exhilarating moments of discovery. To fully appreciate the often Herculean nature of the task and the rewards that accompany it, one must sense the details of the enterprise behind the scenes. A more vivid description of total synthesis as a struggle against a tough opponent is perhaps appropriate to dramatize these elements of the experience. In this article we describe one such endeavor of total synthesis which, in addition to reaching the target molecule, resulted in a wealth of new synthetic strategies and technologies for chemical synthesis. The total synthesis of the CP molecules is compared to Theseus' most celebrated athlos (Greek for exploit, accomplishment): the conquest of the dreaded Minotaur, which he accomplished through brilliance, skill, and bravery having traversed the famous labyrinth with the help of Ariadne. This story from Greek mythology comes alive in modern synthetic expeditions toward natural products as exemplified by the total synthesis of the CP molecules which serve as a paradigm for modern total synthesis endeavors, where the objectives are discovery and invention in the broader sense of organic synthesis.

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“…Thus, exposure of 19 to PhI(OCOCF 3 ) 2 and CaCO 3 in methanol according to the procedure of Stork and Zhao [11] led to compound 20 (81 %), which was reduced with DIBAL-H to afford allylic alcohol 21 (95 %). Vanadium-assisted epoxidation of 21 [12] led to the corresponding b-epoxide (83 % yield, b:a approximately 10:1), whose opening with Et 2 AlCN (Nagata reagent) [13] in toluene led smoothly to cyano diol 22 (73 %). The anomalous stereochemical outcome of this opening (proven by NOE studies) may be attributed to the special environment of the epoxide moiety within the CP skeleton.…”

Section: Coohmentioning

confidence: 99%

Total Synthesis of the CP Molecules CP-263,114 and CP-225,917— Part 1: Synthesis of Key Intermediates and Intelligence Gathering

Nicolaou¹,

Baran²,

Zhong³

et al. 1999

Angew. Chem. Int. Ed.

103

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The CP molecules, 114 (1, Scheme 1) and 917 (2), exemplify architectures of unprecedented molecular connectivity and complexity and possess intriguing biological activities. Isolated from an unidentified fungal species by a group at Pfizer (Croton, USA), [1] these substances (absolute configuration unknown) exhibit impressive cholesterol-lowering properties through inhibition of squalene synthase. [1,2] Furthermore, they inhibit farnesyl transferase, an enzyme implicated in cancer, and as such they stand as leads to potential drug candidates for cancer chemotherapy. [1,3] The daunting molecular frameworks coupled with the array of sensitive functionalities present within these structures amount to a formidable synthetic challenge to which synthetic chemists have already begun to respond. [4] In this and the following communication [5] we recount our studies that led to the successful completion of the total synthesis of the CP molecules (1 and 2, racemic), in which a number of novel strategies and cascade reactions were discovered and developed. We begin here with the description of the overall strategy, the construction of a key intermediate (27, see Scheme 2), and of two unsuccessful, and yet highly useful in terms of intelligence gathering, attempts to reach the CP molecules 1 and 2.The key strategic bond disconnections and retrosynthetic blueprint shown in Scheme 1 serve as a conceptual overview of our synthetic rationale. Because of the known conversion of 2 into 1 under anhydrous acid catalysis [1] and the inability of 1 to generate 2 under aqueous acidic conditions [1] it seemed more prudent to target 2. However, the hope of transforming 1 to 2 under basic conditions (for a mechanistic rationale of this expectation see Scheme 2 in the following communication) [5] led us to accept that reaching either of the CP molecules was an opportunity to access the other as well. We soon discovered that seemingly logical routes to 1 or 2 from the intermediate compound 3 (Scheme 1) were plagued with countless unpredictable failures, which presumably arose from the unique peculiarities of the CP skeleton and its sensitive functionalities. Herein we report the lessons learned from two such expeditions. Proper implementation of novel chemistry harvested as a result of these synthetic blockades and explorations finally culminated in a fine-tuned synthetic stratagem capable of effectively addressing these issues.Diverse model studies aimed at deconvoluting this synthetic maze pointed towards the use of key intermediate 27 as a beachhead from which all further synthetic tactics would diverge (Scheme 2). Notable among the envisioned operations of the forward sequence en route to compound 27 were: 1) the intramolecular Diels ± Alder reaction of the prochiral precursor 4 casting the basic elements of the bicyclic core of the CP molecules, [6] 2) stereoselective fastening of the ªupperº side chain by using substrate-directed dithiane chemistry, [7] 3) the installment of the anhydride moiety onto the periphery of the bicyclic CP...

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Cleavage of steroidal epoxides with organoaluminum cyanides

Cited by 36 publications

References 10 publications

Enantioselective Desymmetrization ofmeso-Decalin Diallylic Alcohols by a New Zr-Based Sharpless AE Process: A Novel Approach to the Asymmetric Synthesis of PolyhydroxylatedCelastraceae Sesquiterpene Cores

Enantioselective Desymmetrization ofmeso-Decalin Diallylic Alcohols by a New Zr-Based Sharpless AE Process: A Novel Approach to the Asymmetric Synthesis of PolyhydroxylatedCelastraceae Sesquiterpene Cores

The CP Molecule Labyrinth: A Paradigm of How Endeavors in Total Synthesis Lead to Discoveries and Inventions in Organic Synthesis

Total Synthesis of the CP Molecules CP-263,114 and CP-225,917— Part 1: Synthesis of Key Intermediates and Intelligence Gathering

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