Tandem Glycolate Claisen Rearrangement/Ring-Closing Metathesis:  A Stereochemically General Synthesis of Substituted Dihydropyran-2-carboxylates

Burke, Steven D.; Ng, Raymond; Morrison, J. A.; Alberti, Michael J.

doi:10.1021/jo980163u

Cited by 48 publications

(32 citation statements)

References 63 publications

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“…2,6-Disubstituted dihydropyrans are common structural elements of many biologically active natural products. [ 2 , 3 ] A number of methods have been developed to synthesize substituted dihydropyrans including: (i) hetero-Diels-Alder cycloadditions,[ 4 - 7 ] (ii) electrophile-initiated alkylation of glycals,[ 8 - 11 ] (iii) ring closing metathesis,[ 12 , 13 ] (iv) vinylsilane cyclization of oxocarbenium ions,[ 14 ] and (v) intramolecular allylations. [ 15 , 16 ] However, we were unaware of any reports that describe the direct conversion of 1,5-diols containing an internal olefin such as 2 directly to 2,6- trans -disubstituted 5,6-dihydropyrans.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 2,6-trans-disubstituted 5,6-dihydropyrans from (Z)-1,5-syn-endiols

Flamme¹,

Roush²

2005

Beilstein J. Org. Chem.

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Certain (Z)-1,5-syn-diols 2 may be converted into 2,6-trans-5,6-dihydropyrans by using phosphonium salt 4 or phosphorane 5 as dehydrating agents. A more general four step procedure converts the (Z)-1,5-syn-endiols into enantiomeric dihydropyrans ent-3 via regioselective silylation of the allylic alcohol unit followed by mesylate formation and base-promoted nucleophilic displacement.Page 1 of (page number not for citation purposes) 6 FindingsWe recently reported a one-pot double allylboration reaction sequence which provides (Z)-1,5-syn-endiols from simple aldehyde starting materials with excellent diastereo-and enantioselectivity.[1] In connection with an ongoing natural product synthesis project, we were interested in developing methods to transform diols 2 into dihydropyrans 3 or the enantiomeric dihydropyrans ent-3 through complementary, regioselective cyclodehydration processes (Scheme 1).2,6-Disubstituted dihydropyrans are common structural elements of many biologically active natural products. [2,3] A number of methods have been developed to synthesize substituted dihydropyrans including: (i) hetero-Diels-Alder cycloadditions, [4][5][6][7] (ii) electrophile-initiated alkylation of glycals, [8][9][10][11] (iii) ring closing metathesis, [12,13] (iv) vinylsilane cyclization of oxocarbenium ions, [14] and (v) The challenge of synthesizing dihydropyrans 3 or ent-3 from 1,5-diols such as 2 lies in the differentiation of the two hydroxyl groups. Selective activation of the allylic alcohol in 2 as a leaving group followed by nucleophilic attack by the homoallylic alcohol will lead to dihydropyran 3. However, activation of the homoallylic alcohol followed by nucleophilic attack by the allylic alcohol will provide the enantiomeric dihydropyan ent-3. Cyclic ethers of various ring size have been synthesized by the cyclodehydration of diols through the use of oxyphosphonium salts and phosphorane reagents. [18][19][20][21][22][23] We reasoned that because the rate determining step of these cyclizations is believed to be the nucleophilic substitution step, selective formation of 3 should be possible owing to the superior leaving group ability of the activated allylic hydroxyl. [21] Diol 2a (R 1 = R 2 = CH 2 CH 2 Ph) was used initially in the development of a suitable cyclodehydration protocol (Figure 1). Because the R 1 and R 2 substituents of 2a are identical, steric effects on the activation of the two hydroxyl groups are eliminated. Therefore, the enantioselectivity of the ring closing step will depend only on the relative rates of the competing cyclization processes leading to 3a and ent-3a. Initial attempts at cyclization of 2a using Ph 3 P and diethyl azodicarboxylate or Ph 3 P-CCl 4 were low yielding (entries 1, 2).[22] Interestingly, small amounts of the 2,6-cis-disubstituted dihydropyran 6a were detected under these conditions, suggesting the intervention of a competitive double inversion process or a carbocationmediated cyclization process. In order to avoid the presence of nucleophilic counter ions, w...

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Section: Resultsmentioning

confidence: 99%

Synthesis of 2,6-trans-disubstituted 5,6-dihydropyrans from (Z)-1,5-syn-endiols

Flamme¹,

Roush²

2005

Beilstein J. Org. Chem.

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“…Burke’s strategy41 involved a very clever tandem glycolate Claisen rearrangement/ring-closing metathesis [RCM] sequence to obtain the C1–C8 fragment 104 starting from glycolate 101 [Scheme 25]. Under the standard Ireland-Claisen conditions, [3,3]-sigmatropic rearrangement afforded metathesis precursor 103 with a reasonable yield as well as selectivity via silyl ketene acetal intermediate 102 .…”

Section: Highlights Of Various Synthetic Approachesmentioning

confidence: 99%

Challenges in the synthesis of a unique mono-carboxylic acid antibiotic, (+)-zincophorin

2009

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Abstract(+)-Zincophorin, also referred to as M144255 or griseochellin, is a polyoxygenated ionophoric antibiotic that was isolated from Streptomyces griseus in 1984. It possesses strong in vivo activity against Gram-positive bacteria and Clostridium coelchii. Its methyl ester was reported in a patent as having strong inhibitory properties against influenza WSN/virus with reduced toxicity for the host cell. Its ability to strongly bind with Zn 2+ , which is also present in its X-ray structure, is the basis for its name. Over the last two decades, (+)-zincophorin h as attracted an impressive array of synthetic efforts including Danishefsky's first total synthesis along with two recent elegant total syntheses reported by Cossy and Miyashita as well as our own formal total synthesis. This Account provides a comparison of the different synthetic efforts on this novel mono-carboxylic acid antibiotic and documents its interesting isolation, structure determination, and biological activities.

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“…8 This material 8 was transformed without any purification into the 1,ω-diene 10, which was done by azeotropic esterification in the presence of 0.05 equiv p-TsOH. The yields over these two transformations vary between 61% and 69%.…”

Section: Figurementioning

confidence: 99%

1,4-Dioxamacrolides: Preparation and Sensory Properties

Eh¹

2003

Synthesis

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The synthesis of 3-methyl-1,4-dioxacylopentadecan-2one (12c) and 3-methyl-1,4-dioxacylohexadecan-2-one (12d), two new musk odorants, is described starting from methyl 2-bromopropionic acid (6b) and allylic alcohol, respectively. The key step of the synthesis is the ring-closing olefin metathesis (RCM) to the unsaturated 1,4-dioxamacrolides. Insight into the structure-odor relationship (SOR) is provided by the synthesis of ten related unsubstituted or methyl substituted oxamacrolides. Finally, a four step enantioselective synthesis of both (3R)-(+)-and (3S)-(-)-3-methyl-1,4-dioxacyclopentadecan-2-one as well as (3R)-(+)-and (3S)-(-)-3-methyl-1,4-dioxacyclohexadecan-2-one reveals that mainly the (3R)-(+) enantiomers are responsible for the powerful musky odor characteristic. Their synthesis starts from ethyl (2S)-2hydroxypropanoate (14) or isobutyl (2R)-2-hydroxypropanoate (15) which were treated under acidic conditions with allyl trichloroacetimidate (16), followed by titanate mediated transesterification, ring-closing olefin metathesis and hydrogenation.

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Tandem Glycolate Claisen Rearrangement/Ring-Closing Metathesis: A Stereochemically General Synthesis of Substituted Dihydropyran-2-carboxylates

Cited by 48 publications

References 63 publications

Synthesis of 2,6-trans-disubstituted 5,6-dihydropyrans from (Z)-1,5-syn-endiols

Synthesis of 2,6-trans-disubstituted 5,6-dihydropyrans from (Z)-1,5-syn-endiols

Challenges in the synthesis of a unique mono-carboxylic acid antibiotic, (+)-zincophorin

1,4-Dioxamacrolides: Preparation and Sensory Properties

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