Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination: High potency in induction of differentiation on HL-60 cells

Keiichiro Ono, Akihiro Yoshida, Nozomi Saito, Toshie Fujishima, Shinobu Honzawa, Yoshitomo Suhara, Seishi Kishimoto, Takayuki Sugiura, Keizo Waku, Hiroaki Takayama, Atsushi Kittaka

Research output: Contribution to journalArticle

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Abstract

Six novel 2-substituted analogues of 1α,25-dihydroxy-19-norvitamin D3, 6a,b-8a,b, were efficiently synthesized utilizing (-)-quinic acid as the A-ring precursor. The C2-modified A-rings were prepared as 4-alkylated (3R,5R)-3,5-dihydroxycyclohexanones 12-15 from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The new type of the CD-ring coupling partner 23 was synthesized from 25-hydroxy Grundmann's ketone 19 to apply to the modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were 47-62%. After the separation of the diastereomers based on C2 stereochemistry, the structure (2α or 20) was determined by 1H NMR experiments and compared to DeLuca's 2-methyl- and 2-ethyl-1α,25-dihydroxy-19-norvitamin D3. Thus, the synthesized 2α(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D 3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone 1, while its β-isomer 8b had only a 3% affinity. Both 2α-allyl- and 2α-propyl-1α,25-dihydroxy-19-norvitamin D3 (6a and 7a) and their 2β-analogues (6b and 7b) possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1, and interestingly, even the weaker ligand 8b showed a 6.7-fold higher potency in the cell differentiation activity than that of 1.

Original languageEnglish
Pages (from-to)7407-7415
Number of pages9
JournalJournal of Organic Chemistry
Volume68
Issue number19
Publication statusPublished - 2003 Sep 19
Externally publishedYes

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Calcitriol Receptors
Quinic Acid
Allylation
Ligands
Thymus
Stereochemistry
Ketones
Isomers
Nuclear magnetic resonance
Hormones
1,25-dihydroxy-19-norvitamin D3
Experiments

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination : High potency in induction of differentiation on HL-60 cells. / Ono, Keiichiro; Yoshida, Akihiro; Saito, Nozomi; Fujishima, Toshie; Honzawa, Shinobu; Suhara, Yoshitomo; Kishimoto, Seishi; Sugiura, Takayuki; Waku, Keizo; Takayama, Hiroaki; Kittaka, Atsushi.

In: Journal of Organic Chemistry, Vol. 68, No. 19, 19.09.2003, p. 7407-7415.

Research output: Contribution to journalArticle

Ono, K, Yoshida, A, Saito, N, Fujishima, T, Honzawa, S, Suhara, Y, Kishimoto, S, Sugiura, T, Waku, K, Takayama, H & Kittaka, A 2003, 'Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination: High potency in induction of differentiation on HL-60 cells', Journal of Organic Chemistry, vol. 68, no. 19, pp. 7407-7415.
Ono, Keiichiro ; Yoshida, Akihiro ; Saito, Nozomi ; Fujishima, Toshie ; Honzawa, Shinobu ; Suhara, Yoshitomo ; Kishimoto, Seishi ; Sugiura, Takayuki ; Waku, Keizo ; Takayama, Hiroaki ; Kittaka, Atsushi. / Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination : High potency in induction of differentiation on HL-60 cells. In: Journal of Organic Chemistry. 2003 ; Vol. 68, No. 19. pp. 7407-7415.
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abstract = "Six novel 2-substituted analogues of 1α,25-dihydroxy-19-norvitamin D3, 6a,b-8a,b, were efficiently synthesized utilizing (-)-quinic acid as the A-ring precursor. The C2-modified A-rings were prepared as 4-alkylated (3R,5R)-3,5-dihydroxycyclohexanones 12-15 from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The new type of the CD-ring coupling partner 23 was synthesized from 25-hydroxy Grundmann's ketone 19 to apply to the modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were 47-62{\%}. After the separation of the diastereomers based on C2 stereochemistry, the structure (2α or 20) was determined by 1H NMR experiments and compared to DeLuca's 2-methyl- and 2-ethyl-1α,25-dihydroxy-19-norvitamin D3. Thus, the synthesized 2α(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D 3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone 1, while its β-isomer 8b had only a 3{\%} affinity. Both 2α-allyl- and 2α-propyl-1α,25-dihydroxy-19-norvitamin D3 (6a and 7a) and their 2β-analogues (6b and 7b) possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1, and interestingly, even the weaker ligand 8b showed a 6.7-fold higher potency in the cell differentiation activity than that of 1.",
author = "Keiichiro Ono and Akihiro Yoshida and Nozomi Saito and Toshie Fujishima and Shinobu Honzawa and Yoshitomo Suhara and Seishi Kishimoto and Takayuki Sugiura and Keizo Waku and Hiroaki Takayama and Atsushi Kittaka",
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T1 - Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination

T2 - High potency in induction of differentiation on HL-60 cells

AU - Ono, Keiichiro

AU - Yoshida, Akihiro

AU - Saito, Nozomi

AU - Fujishima, Toshie

AU - Honzawa, Shinobu

AU - Suhara, Yoshitomo

AU - Kishimoto, Seishi

AU - Sugiura, Takayuki

AU - Waku, Keizo

AU - Takayama, Hiroaki

AU - Kittaka, Atsushi

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N2 - Six novel 2-substituted analogues of 1α,25-dihydroxy-19-norvitamin D3, 6a,b-8a,b, were efficiently synthesized utilizing (-)-quinic acid as the A-ring precursor. The C2-modified A-rings were prepared as 4-alkylated (3R,5R)-3,5-dihydroxycyclohexanones 12-15 from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The new type of the CD-ring coupling partner 23 was synthesized from 25-hydroxy Grundmann's ketone 19 to apply to the modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were 47-62%. After the separation of the diastereomers based on C2 stereochemistry, the structure (2α or 20) was determined by 1H NMR experiments and compared to DeLuca's 2-methyl- and 2-ethyl-1α,25-dihydroxy-19-norvitamin D3. Thus, the synthesized 2α(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D 3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone 1, while its β-isomer 8b had only a 3% affinity. Both 2α-allyl- and 2α-propyl-1α,25-dihydroxy-19-norvitamin D3 (6a and 7a) and their 2β-analogues (6b and 7b) possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1, and interestingly, even the weaker ligand 8b showed a 6.7-fold higher potency in the cell differentiation activity than that of 1.

AB - Six novel 2-substituted analogues of 1α,25-dihydroxy-19-norvitamin D3, 6a,b-8a,b, were efficiently synthesized utilizing (-)-quinic acid as the A-ring precursor. The C2-modified A-rings were prepared as 4-alkylated (3R,5R)-3,5-dihydroxycyclohexanones 12-15 from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The new type of the CD-ring coupling partner 23 was synthesized from 25-hydroxy Grundmann's ketone 19 to apply to the modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were 47-62%. After the separation of the diastereomers based on C2 stereochemistry, the structure (2α or 20) was determined by 1H NMR experiments and compared to DeLuca's 2-methyl- and 2-ethyl-1α,25-dihydroxy-19-norvitamin D3. Thus, the synthesized 2α(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D 3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone 1, while its β-isomer 8b had only a 3% affinity. Both 2α-allyl- and 2α-propyl-1α,25-dihydroxy-19-norvitamin D3 (6a and 7a) and their 2β-analogues (6b and 7b) possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1, and interestingly, even the weaker ligand 8b showed a 6.7-fold higher potency in the cell differentiation activity than that of 1.

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