A-Ring Synthons of 19-Nor Type Vitamin D Derivatives

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Journal of Steroid Biochemistry & Molecular Biology xxx (2016) xxx–xxx

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Review

A-Ring Synthons of 19-Nor Type Vitamin D Derivatives Yusuke Akagi, Koji Yasui, Kazuo Nagasawa* Tokyo University of Agriculture and Technology, Department of Biotechnology and Engineering, Japan

A R T I C L E I N F O

Article history: Received 31 May 2016 Accepted 9 July 2016 Available online xxx Keywords: 19-Norvitamin D A-ring synthon Ring-closing metathesis Suzuki-Miyaura reaction

A B S T R A C T

Various 19-nor vitamin D analogs, which lack the methylene group at C19, exhibit significant vitamin D (VD)-related biological activities, but generally show a reduced calcemic side-effect compared with VD itself. Among them, paricalcitol is already used clinically for treatment and prevention of secondary hyperparathyroidism associated with chronic renal failure. Therefore, considerable synthetic efforts have been directed towards 19-nor VD analogs, focusing especially on A-ring synthons suitable for use in convergent synthetic strategies based on coupling of CD-ring synthons and A-ring synthons. For example, we have recently developed a new synthetic route to A-ring synthons from linear dienes based upon a ring-closing olefin metathesis strategy. Here, we review recent synthetic approaches to A-ring synthons for 19-nor VD derivatives. ã 2016 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of A-ring synthons via chiral cyclohexane derivatives Synthesis of A-ring synthons via chiral acyclic compounds . . . Conclusion and prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ReferecesReferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.. . .. .. .. ..

1. Introduction 1a,25-Dihydroxyvitamin D2 (1) and D3 (3) are active forms of vitamin D2 and D3 (VD2 and VD3) respectively (Fig. 1) [1], and are involved in regulation of calcium and phosphorus homeostasis, bone mineralization, cell differentiation, and immune regulation [1,2]. Many structure-activity relationship studies have been carried out with the aim of separating and/or enhancing these activities [3]. As a result of these studies, some derivatives are already in clinical use [4]. Among VD analogs, A-ring modified 19nor analogs, which lack the methylene group at C19, are particularly attractive, since they generally show a reduced calcemic side-effect compared to the corresponding 1,25 VDs. Among the 19-nor analogs, paricalcitol (5), which is derived from 1,

* Corresponding author. E-mail address: [email protected] (K. Nagasawa).

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00 00 00 00 00 00

is already in clinical use for treatment and prevention of secondary hyperparathyroidism associated with chronic renal failure [5]. In this context, many synthetic studies 19-nor VD derivatives, including 5 and 6, have been reported [6–12]. DeLuca and co-workers reported the first synthesis of 19-nor VD3 (6) in 1990. They synthesized 6 directly from 25-hydroxyvitamin D3 (4) via oxidative degradation of the A-ring [7][7a]. A similar direct conversion strategy was subsequently employed by our group to obtain 19-nor VD2 (5) from 25-hydroxyvitamin D2 (2) [7][7b]. On the other hand, a convergent synthetic strategy based on coupling with CD-ring synthons and A-ring synthons is more attractive from the viewpoints of structural diversity and synthetic efficiency. DeLuca and co-workers were the first to employ such a convergent strategy, utilizing Horner-Wittig type reaction between ketone (CD-rings) and phosphine oxide (A-ring) [8][8a]. Since then, other convergent strategies, i.e., the Julia-type olefination strategy and the Suzuki-Miyaura coupling strategy,

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Please cite this article in press as: Y. Akagi, et al., A-Ring Synthons of 19-Nor Type Vitamin D Derivatives, J. Steroid Biochem. Mol. Biol. (2016), http://dx.doi.org/10.1016/j.jsbmb.2016.07.003

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R1

R

H

H

H 19

10

HO

3

H 10

R2

1

HO

1 ,25-dihydroxyvitamin D2 (1) : R2 = OH 25-hydroxyvitamin D2 (2) : R2 = H R1 =

3

1

OH

19-nor-1 ,25-dihydroxyvitamin D2 (5)

25

25

R= OH

OH

1 ,25-dihydroxyvitamin D3 (3) : R2 = OH : R2 = H 25-hydroxyvitamin D3 (4) R1 =

19-nor-1 ,25-dihydroxyvitamin D3 (6)

25

25

R= OH

OH

Fig. 1. Structures of 1a,25-dihydroxyvitamin D2 (1) and D3 (3), and their 19-nor derivatives 5 (paricalcitol) and 6.

have been developed (Fig. 2) [10,11], and various A-ring synthons have been synthesized for use in these strategies. Two synthetic approaches, i.e., from chiral cyclohexane derivatives and chiral acyclic compounds, have mainly been studied to obtain A-ring synthons for 19-nor type VD analogs. Here, we review recent progress in both approaches.

2. Synthesis of A-ring synthons via chiral cyclohexane derivatives An A-ring synthon bearing phosphine oxide 12 was synthesized from (
)-quinic acid (7) by DeLuca and co-workers in 1991 (Scheme 1) [8][8a]. Ketone 10 was prepared from alcohol 8 by

R P(O)Ph2

H + O

R1O

H

OR1 X

Horner-Wittig reaction 13~95% [8a,9] R

R R

H

H

H H (R2O)2B Y

R1O

+

Suzuki-Miyaura coupling 38~85% [11]

Julia-type olefination 47~92% [10]

H

O Ar

O S

H +

O

OR1

HO

OH

R1O

X

X

OR1 X

R=

OH etc.

Fig. 2. Convergent synthetic strategies for 19-norvitamin D analogs.

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HOOC

OH

MeO2C

1. (imid)2C=S 91% 2. Bu3SnH, AIBN 90%

OH

2 steps HO

OH

2

TBSO

OH (-)-Quinic acid (7)

OH 8

1. DIBAL-H 60%

MeO2C

OTBS Barton-McCombie TBSO Deoxygenation

OH

2

OTBS

9

1. EtO2C LDA

O

3

TMS OH

86%

2. NaIO4 78%

TBSO

2. DIBAL-H 78-95%

OTBS 10

TBSO

OTBS 11

P(O)Ph2

1. NCS, Me2S 80% 2. Ph2PH, n-BuLi then H2O2 82%

TBSO

OTBS 12

Scheme 1. A-Ring synthon 12 from (
)-quinic acid (7) (DeLuca).

removing the hydroxyl group at C2 via Barton-McCombie deoxygenation. Then, phosphine oxide 12 was synthesized through the allylic alcohol 11 in 4 steps. Shimizu and co-workers obtained an A-ring synthon 17 bearing phosphine oxide and a hydroxyl group at C2, starting from Dglucose (13) (Scheme 2) [9][9e,f]. Pyranoside 14 was converted to carbocycle 16 by Pd-catalyzed Ferrier rearrangement via 15. Ketone 16 was successfully converted into 17 in 12 steps in a similar manner to that used to obtain 12 from 10. 3. Synthesis of A-ring synthons via chiral acyclic compounds The use of chiral acyclic compounds as starting materials for A-ring synthons is attractive because it is possible to install a variety of substituents efficiently. Vandewalle and co-workers reported a five-step synthesis of the phosphine oxide precursor 23

OH

HO

9 steps

PdCl2

O 2

OH OH

D-Glucose

O

OMe OH

O

starting from an optically active 1,2:4,5-diepoxypentane 18, which was prepared from 2,4-pentanedione (Scheme 3) [12]. In this synthesis, the two epoxides in 18 were reacted with lithiated alkyne 19, followed by bromide anion, to generate bromohydrin. A phosphine oxide precursor of cyclic allyl alcohol 23 was synthesized from acyclic alkyne with bromohydrin 21 via radical cyclization in the presence of SmI2. Groups led by Mikami and Uskokovic independently reported the synthesis of phosphine oxide precursor 11 from an acyclic precursor via an enantioselective carbonyl-ene cyclization in the presence of a chiral Lewis acid catalyst [9][9b,c]. Mikami’s approach is outlined in Scheme 4. Regioselective ene-reaction of propiolate 24 with 25 proceeded in the presence of EtAlCl2 to give unsaturated ester 26, which was subsequently converted into chiral aldehyde 28 through Sharpless asymmetric epoxidation with allylic alcohol. Enantioselective cyclization of 28 was carried

OBn 14

(13)

OBn

dioxane, H2O 92% Ferrier rearrangement

OH

O

2

OBn

OBn 15

P(O)Ph2 12 steps

O

OBn

TBSO

2

OBn

OTBS OTMS

16

17

Scheme 2. A-Ring synthon 17 from D-glucose (13) (Shimizu).

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OMPM 1. Li2NiBr4 91% 2. TBDPSCl 80%

OMPM Li O

19

O

O 53%

HO

18

OMPM Br RO

20

OR

21 : R= TBDPS

OMPM

OH DDQ

SmI2

61%

63%

TBDPSO

22

OTBDPS

TBDPSO

OTBDPS

23

Scheme 3. Synthesis of A-ring synthon 23 (Vandewalle).

1. DIBAL-H 98% (-)-DET,Ti(OiPr)4 2. OBn TBHP 58%

OBn 25 MeO2C

EtAlCl2

OBn 4 steps

67% propiolate-ene reaction

24

HO

26

27

(R)-BINOL Cl2Ti(OiPr)2

OBn

65% Z : E = 77: 23

OMPM

O

O

CO2Me

28

OH

OBn 3 steps HO

TBSO

OMPM

OTBS

29

carbonyl-ene cyclization

11

Scheme 4. Synthesis of A-ring synthon 11 based upon enantioselective ene-reaction (Mikami).

out by means of carbonyl-ene cyclization in the presence of Cl2Ti (OiPr)2 and (R)-BINOL to generate alcohol 29, which was converted into phosphine oxide precursor 11 in 3 steps. We have applied the ring-closing metathesis (RCM) strategy for construction of the carbocyclic skeleton of A-ring synthon 35

(Scheme 5) [11][11c]. Chiral acyclic allyl acetate 31 was subjected to RCM reaction in the presence of Grubbs’ (II) catalyst 32 to give cyclic acetate 33 in 95% yield. Then, allyl acetate was converted into vinyl bromide 35 via palladium-catalyzed reduction of allyl acetate

OAc HO

TBSO

30

31

OTBS

PhMe 95%

1. Br2, NaHCO3 THF 2. tBuOK, THF

Pd(PPh3)4 HCO2H Et3N THF 90%

32

OTBS 12 steps

O

OAc

TBSO

34

OTBS

43% (2 steps)

TBSO

OTBS

33

Br Mes N

TBSO

35

OTBS

N Mes

Cl Ru Cl PCy3 Ph 32

Scheme 5. Synthesis of A-ring synthon 35 via ring-closing metathesis reaction (Nagasawa).

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Y. Akagi et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2016) xxx–xxx

TBSO

O O

TBSO

CH2Cl2 87%

36

O

TBSO

H2O2 aq NaOH

O

O

O

O

37

38

OH

83% (2 steps)

B O

Ni(cod) H-Bpin PCy3

32 ethylene

5

P(O)Ph2 2 steps

TBSO

O

TBSO

O

O

O

39

40

Scheme 6. Synthesis of A-ring synthon 40 based upon ene-yne metathesis reaction (Okamoto).

with formic acid and simultaneous isomerization of the endocyclic double bond. Okamoto and co-workers have recently reported a synthesis of A-ring phosphine oxide 40 bearing a hydroxyl group at C2 (Scheme 6) [9][9i]. They applied the intramolecular ene-yne metathesis reaction of 36 catalyzed by Grubbs’ (II) catalyst 32 to generate 37 in 87% yield. The resulting diene 37 was further converted into allyl alcohol 39 with Ni-catalyzed 1,4-selective hydroboration reaction followed by oxidative reaction. Then, phosphine oxide 40 was obtained from 39 in 2 steps. 4. Conclusion and prospects Here, we have reviewed recent work on A-ring synthons for three convergent synthetic strategies leading to 19-norvitamin D analogs. Both cyclic and acyclic compounds have been employed as starting materials to obtain A-ring synthons for use in these strategies, and they offer various advantages from the viewpoints of structural diversity and synthetic efficiency, enabling synthesis of a wide range of 19-nor VD derivatives. This should make it possible in the future to conduct detailed structure-activity relationship studies of 19-nor VD derivatives, and as a result it may become feasible to separate the multiple biological activities of VD, providing both research tools for investigating the biological mechanisms of the individual activities and candidate drugs with highly specific activities and minimal side effects. Acknowledgment This work was supported in part by AMED-CREST, Japan Agency for Medical Research and Development. ReferecesReferences [1] (a) G. Jones, S.A. Strugnell, H.F. DeLuca, Current understanding of the molecular actions of vitamin D, Physiol. Rev. 78 (1998) 1193–1231; (b) A.S. Dusso, A.J. Brown, E. Slatopolsky, Vitamin D, Am. J. Physiol. Renal. Physiol. 289 (2005) F8–F28. [2] R. Bouillon, G. Carmeliet, L. Verlinden, E. van Etten, A. Verstuyf, H.F. Luderer, L. Lieben, C. Mathieu, M. Demay, Vitamin D and human health: lessons from vitamin D receptor null mice, Endocr. Rev. 29 (2008) 726–776. [3] (a) S. Nagpal, S. Na, R. Rathnachalam, Noncalcemic actions of vitamin D receptor ligands, Endocr. Rev. 26 (2005) 662–687; (b) S.A. Birlea, G.E. Costin, D.A. Norris, New insights on therapy with vitamin D analogs targeting the intracellular pathways that control repigmentation in human vitiligo, Med. Res. Rev. 29 (2009) 514–546; (c) I. Sibilska, K.M. Barycka, R.R. Sicinski, L.A. Plum, H.F. DeLuca, 1-Desoxy

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