Stereoselective Synthesis of the C3−C17 Bis-Oxane Domain of Phorboxazole A

Cink, Russell D.; Forsyth, Craig J.

doi:10.1021/jo9708755

Cited by 60 publications

(14 citation statements)

References 15 publications

(11 reference statements)

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“…Treatment of mesylate 11a with 1 equivalent of potassium tert -butoxide in tert -BuOH (0.01 M) between 40–50 °C provided ent - 3a in 75% yield and 10:1 selectivity for the dihydropyran product and a diene resulting from an undesired E2 elimination (Figure 3 , entry 1). [ 26 , 27 ] This result was particularly gratifying since Thomas has reported that attempts to cyclized suitably activated 1,5-diol substrates under basic conditions did not afford dihydropyran products. [ 28 ] It was necessary to carry out the reactions under dilute conditions in order to minimize elimination to diene 14 .…”

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allylic alcohol unit followed by mesylate formation and base-promoted nucleophilic displacement.Page 1 of (page number not for citation purposes) 6 FindingsWe recently reported a one-pot double allylboration reaction sequence which provides (Z)-1,5-syn-endiols from simple aldehyde starting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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“…Dihydropyrone 15 was not connected as such with the combretastatin A‐4 fragment, but as its O ‐silyl derivative 28 (Scheme ), which was also prepared according to the previous methodology. Brown′s asymmetric allylation of known aldehyde 20 23 furnished alcohol 21 , which was then converted into methyl ether 22 . The latter was then sequentially subjected to a two‐step oxidative cleavage of the olefinic bond, followed by Brown's asymmetric allylation to yield 23 .…”

Section: Resultsmentioning

confidence: 99%

A Single Mutation at the Ferredoxin Binding Site of P450 Vdh Enables Efficient Biocatalytic Production of 25‐Hydroxyvitamin D₃

et al. 2013

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Vitamin D3 hydroxylase (Vdh) from Pseudonocardia autotrophica is a cytochrome P450 monooxygenase that catalyzes the two-step hydroxylation of vitamin D3 (VD3 ) to produce 25-hydroxyvitamin D3 (25(OH)VD3 ) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 VD3 ). These hydroxylated forms of VD3 are useful as pharmaceuticals for the treatment of conditions associated with VD3 deficiency and VD3 metabolic disorder. Herein, we describe the creation of a highly active T107A mutant of Vdh by engineering the putative ferredoxin-binding site. Crystallographic and kinetic analyses indicate that the T107A mutation results in conformational change from an open to a closed state, thereby increasing the binding affinity with ferredoxin. We also report the efficient biocatalytic synthesis of 25(OH)VD3 , a promising intermediate for the synthesis of various hydroxylated VD3 derivatives, by using nisin-treated Rhodococcus erythropolis cells containing VdhT107A . The gene-expression cassette encoding Bacillus megaterium glucose dehydrogenase-IV was inserted into the R. erythropolis chromosome and expressed to avoid exhaustion of NADH in a cytoplasm during bioconversion. As a result, approximately 573 μg mL(-1) 25(OH)VD3 was successfully produced by a 2 h bioconversion.

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“…10 As depicted in Scheme 2, their strategy involved a BF 3 -catalyzed HDA reaction between isopropylidene-(S)-glyceraldehyde 3 and TES-protected Danishefsky's diene 4, which afforded 5a as the major product of a 16:4:1 mixture of diastereomers. The outcome of the reaction was rationalized by the authors as the result of good Felkin selectivity and stabilization of the endo transition state through interactions of secondary orbitals.…”

Section: Resultsmentioning

confidence: 99%

Insights into the stereoselective BF3-catalyzed hetero Diels–Alder reaction of Garner’s aldehyde with Danishefsky’s diene

Fontana

Incerti

Moyna

et al. 2010

Tetrahedron: Asymmetry

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Stereoselective Synthesis of the C3−C17 Bis-Oxane Domain of Phorboxazole A

Cited by 60 publications

References 15 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

A Single Mutation at the Ferredoxin Binding Site of P450 Vdh Enables Efficient Biocatalytic Production of 25‐Hydroxyvitamin D₃

Insights into the stereoselective BF3-catalyzed hetero Diels–Alder reaction of Garner’s aldehyde with Danishefsky’s diene

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Stereoselective Synthesis of the C3−C17 Bis-Oxane Domain of Phorboxazole A

Cited by 60 publications

References 15 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

A Single Mutation at the Ferredoxin Binding Site of P450 Vdh Enables Efficient Biocatalytic Production of 25‐Hydroxyvitamin D3

Insights into the stereoselective BF3-catalyzed hetero Diels–Alder reaction of Garner’s aldehyde with Danishefsky’s diene

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A Single Mutation at the Ferredoxin Binding Site of P450 Vdh Enables Efficient Biocatalytic Production of 25‐Hydroxyvitamin D₃