A directed aldol approach to (+)-milbemycin β<sub>3</sub>

Kocieński, Philip; Street, S. D. A.; Yeates, Clive; Campbell, Simon F.

doi:10.1039/p19870002171

Cited by 59 publications

(35 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9 There are several noteworthy aspects of the synthesis reported herein: there are no arduous chromatographic separations required and the one diastereoisomeric separation is easy; there is compensation for the regrettable stereorandom Grignard reaction of aldehyde (16) in the ease with which the undesired isomer (18) is converted to the desired isomer (17); the yields were generally good; and the reactions could be run on a substantial scale. The configuration of the acetal centre in (30) was governed by the anomeric effect l 3 and the equatorial View Article Online disposition of the four substituents.…”

mentioning

confidence: 93%

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β₃. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

Kocieński¹,

Yeates²,

Street³

et al. 1987

J. Chem. Soc., Perkin Trans. 1

Self Cite

View full text Add to dashboard Cite

A more efficient synthesis of the title compound (12), previously used in a total synthesis of ( + )milbemycin p3 (Z), is described. The key step in the sequence involves a nucleophilic cleavage of the oxirane (33) by the organocuprate (28) derived from metallation of (2R,3S) -2,3-dimethyl-3,4-dihydro-2H-pyran (26).The 4-hydroxy-1,7-dioxaspiro[5.5]undecane moiety (1) is a key structural feature of the milbemycins and avermectins which are prized for their pesticidal activity.' As part of a programme

show abstract

mentioning

confidence: 93%

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β₃. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

Kocieński¹,

Yeates²,

Street³

et al. 1987

J. Chem. Soc., Perkin Trans. 1

Self Cite

View full text Add to dashboard Cite

show abstract

“…The low stereoselectivity of this reaction is insignificant, since in the course of the synthesis this stereogenic center is destroyed in the last step by oxidation of the alcohol to a keto group. The further stages in the preparation of 4 are the cleavage of the protecting group at the tertiary alcohol in 13 with sodium in liquid ammonia [13] at À 78 8C, the acetalisation of the resulting diol 14 with anisaldehydedimethylacetal and p-toluenesulfonic acid (PTSA) [14] to give 15, the desilylation of the protected primary alcohol with tetrabutylammonium fluoride to afford the alcohol 16 and finally the transformation into the iodide 17 according to the Appel procedure [15] with a total yield of 70 %. The reaction to 15 could also be performed with p-methoxybenzyl methyl ether and dichlorodicyanobenzoquinone (DDQ) in 78 % yield.…”

Section: Resultsmentioning

confidence: 99%

“…Optical rotations were measured on a Perkin ± Elmer 241 digital polarimeter in a 1 dm cell. IR spectra were recorded on a Bruker IFS 25 FT-IR instrument, and 1 H and 13 C NMR spectra with a Bruker AM-300 and a Varian VXR-200. Chemical shifts were reported on the d scale relative to CDCl 3 as an internal standard.…”

Section: Methodsmentioning

confidence: 99%

First Total Synthesis and Determination of the Absolute Configuration of the Stress Factor (+)-Hydroxymyoporone

Tietze¹,

Wegner²,

Wulff³

1999

Chem. Eur. J.

View full text Add to dashboard Cite

The first total synthesis of the stress factor ()-hydroxymyoporone (4) is presented. The key step is an asymmetric allylation of the methyl ketone 10 which proceeds with excellent selectivity and yield. In addition, it was proven that the assignment of the absolute configuration of hydroxymyoporone published in the literature is incorrect; the correct structure of the ()-enantiomer is depicted in the structural formula 4.

show abstract

“…Existing methods for asymmetric synthesis of 5 have utilized (S)-malic acid as a chiral pool 12 dien-4-ol. 13 The later method gives 5 in only a 65% ee and general methods to prepare both enantiomers of syn-and anti-5 have not yet been described.…”

Section: Methodsmentioning

confidence: 99%

Resolution of 2-Silyloxy-1-oxiranyl-4-pentenes by HKR: Total Synthesis of (5S,7R)-Kurzilactone

Kim

Tae²

2006

Synlett

View full text Add to dashboard Cite

Enantiomerically pure syn-and anti-2-silyloxy-1-oxiranyl-4-pentenes were prepared by using Jacobsen's hydrolytic kinetic resolution (HKR) method. A resolved epoxypentenol generated in this fashion was used in the total synthesis of (5S,7R)-kurzilactone by a pathway employing epoxide ring-opening and RCM reactions in key steps.1,3-Diol subunits are present in numerous biologically active natural products and pharmaceuticals. 1 As a result, a large effort has been devoted to the development of methods for the stereoselective synthesis of 1,3-diols. 2 Common procedures developed to date rely on chiral pool strategies 3 or asymmetric reaction methodologies 4 for the introduction of the first asymmetric centers in these substances. Installation of the second asymmetric centers is typically orchestrated by the initial hydroxyl group by using various 1,3-syn-or anti-selective ketone reduction methods. 5 Figure 1Jacobsen's method for hydrolytic kinetic resolution (HKR) of 2-hydroxy-1-oxiranes 6 represents another potential enantiocontrolled strategy for 1,3-diol synthesis.Importantly, nucleophilic ring-opening reactions of the epoxides formed in this way could enable easy access to structurally diverse 1,3-diol units found in many biologically active compounds (Figure 1), exemplified by apicularen (1), 7 kurzilactone (2), 8 milbemycin b 3 (3), 9 and atorvastatin (4). 10 Only few examples, in which the HKR method has been used to prepare enantiomerically pure 2-hydroxy-1-oxirane units, have been reported thus far. However, in these cases the alcohol moieties were introduced first by using known asymmetric methods and then HKR was employed to resolve the diastereomeric epoxides. 11 Consequently, the two asymmetric centers were installed separately through the use of two asymmetric reactions.We envisioned an alternative approach to chiral 1,3-diol synthesis that utilizes kinetic resolution of racemic syn-or anti-2-hydroxy-1-oxirane derivatives. In this strategy, the relative stereochemistry between the alcohol and the epoxide groups is established prior to the HKR step and in this way a single asymmetric reaction can be used to form the key enantiomerically pure 2-hydroxy-1-oxirane intermediates. Below, we describe the results of studies of HKR reactions of racemic syn-and anti-2-hydroxy-1-oxiranes and an application to the asymmetric synthesis of (5S,7R)-kurzilactone.Enantiomerically pure syn-and anti-2-alkoxy-1-oxiranyl-4-pentenes 5 (Scheme 1) are versatile synthetic building blocks. Ring-opening reactions of these substances with aryl or vinyl nucleophiles could lead to alkenyl-1,3-diols 6, structural units found in apicularen (1) and milbemycin b 3 (3). In addition, carbon frameworks found in kurzilactone (2) and atorvastatin (4) could be accessed by ringopening reactions of 5 with acyl anion equivalents (Scheme 1). Scheme 1Existing methods for asymmetric synthesis of 5 have utilized (S)-malic acid as a chiral pool 12 reactant or enzyme-catalyzed asymmetric epoxidation of 1,6-hepta-

show abstract

A directed aldol approach to (+)-milbemycin β₃

Cited by 59 publications

References 15 publications

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β₃. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β₃. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

First Total Synthesis and Determination of the Absolute Configuration of the Stress Factor (+)-Hydroxymyoporone

Resolution of 2-Silyloxy-1-oxiranyl-4-pentenes by HKR: Total Synthesis of (5S,7R)-Kurzilactone

Contact Info

Product

Resources

About

A directed aldol approach to (+)-milbemycin β3

Cited by 59 publications

References 15 publications

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β3. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β3. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

First Total Synthesis and Determination of the Absolute Configuration of the Stress Factor (+)-Hydroxymyoporone

Resolution of 2-Silyloxy-1-oxiranyl-4-pentenes by HKR: Total Synthesis of (5S,7R)-Kurzilactone

Contact Info

Product

Resources

About

A directed aldol approach to (+)-milbemycin β₃

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β₃. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β₃. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane