A total synthesis of spiruchostatin A

Doi, Takayuki; Iijima, Yusuke; Shin‐ya, Kazuo; Ganesan, A.; Takahashi, Takashi

doi:10.1016/j.tetlet.2005.12.031

Cited by 58 publications

(42 citation statements)

References 25 publications

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“…[15,16] The key feature of this Scheme was expected to be a highly convergent assembly of 5 and 6 by direct condensation of segment 7 or 8 with segment 9. Segments 7 and 8 would be prepared via an aldol coupling of N-Boc-d-valinal (10) [19] or d-allo-isoleucinal (11) [20] with ethyl acetate (12), and subsequent condensation with d-cysteine dervative 13.…”

Section: Resultsmentioning

confidence: 99%

“…[21] Segment 9, which contains the most synthetically challenging unit, (3S,4E)-3-hydroxy-7-mercaptohept-4-enoic acid, would be produced via Julia-Kocienski olefination [22] of sulfone 14 (accessible from 1,3-propanediol) with aldehyde 15 [23] (accessible from l-malic acid), followed by condensation with d-alanine methyl ester (16).…”

Section: Resultsmentioning

confidence: 99%

“…In the previous two total syntheses of spiruchostatin A (1), Ganesan et al [15] successfully achieved macrolactonization of the O-triisopropylsilyl (TIPS) variant of 5 (R = TIPS) using the Yamaguchi method (2,4,6-Cl 3 C 6 H 2 COCl, Et 3 N, MeCN/THF, 0 to 208C; DMAP, toluene, 50 8C, 53 %); on the other hand, Doi, Takahashi et al [16] efficiently performed macrolactonization of O-non-protected variant of 5 (R = H) using the Shiina method [2-methyl-6-nitrobenzoic acid (MNBA), …”

Section: Synthesis Of Segmentmentioning

confidence: 99%

“…One total synthesis of FR901375 (4) has been reported by Wentworth, Janda et al [14] in 2003. In addition, three total syntheses of spiruchostatin A (1) have been reported by Ganesan et al [15] in 2004, Doi, Takahashi et al [16] in 2006 and Miller et al [17] in 2009. However, the total synthesis of spiruchostatin B (2) has not been mentioned in the literature, and the stereochemistry at C5'' (spiruchostatin numbering) of 2 has not been clearly assigned.…”

Section: Introductionmentioning

confidence: 98%

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Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5′′‐epi‐Spiruchostatin B, FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity

Narita

Kikuchi

Watanabe

et al. 2009

Chemistry A European J

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The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia-Kocienski olefination of a 1,3-propanediol-derived sulfone and a L- or D-malic acid-derived aldehyde to access the most synthetically challenging unit, (3S or 3R,4E)-3-hydroxy-7-mercaptohept-4-enoic acid, present in a D-alanine- or D-valine-containing segment; ii) a condensation of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids; and iii) a macrocyclization of a seco-acid using the Shiina method or the Mitsunobu method to construct the requisite 15- or 16-membered macrolactone. The present synthesis has established the C5'' stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell-growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure-activity relationships. It was also found that unnatural 5''-epi-spiruchostatin B shows extremely high selectivity (ca. 1600-fold) for class I HDAC1 (IC(50)=2.4 nM) over class II HDAC6 (IC(50)=3900 nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC(50) values.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Segmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5′′‐epi‐Spiruchostatin B, FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity

Narita

Kikuchi

Watanabe

et al. 2009

Chemistry A European J

View full text Add to dashboard Cite

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“…Alternaramide 1 can be obtained via either a macrolactonization or a macrolactamization event on the precursor linear peptides 5 and 6, respectively. While there are examples of the use macrolactonization in the synthesis of depsipeptides, [13][14][15][16] such a cyclisation performed on 5 may be problematic. However, due to the short synthetic sequence to give the precursor 5 we thought this would be a viable route to explore, alongside the macrolactamization approach.…”

mentioning

confidence: 99%