BINOL-Ti-Catalyzed carbonyl-ene cyclization by tuning the 6-Br-ligand for the synthesis of 2-methyl-19-nor-22-oxa vitamin D analogue with significant differentiation activity

Article abstract of DOI:10.1055/s-1999-2989

Transition state control in BINOL-Ti-catalyzed asymmetric carbonyl-ene cyclization by tuning the 6-Br-BINOL ligand completes the synthesis of the A ring of the 2-methyl-19-nor-22-oxa D₃ analogue (2), which shows the significant activity in differentiation of HL-60 cell.

Full text of DOI:10.1055/s-1999-2989

LETTER
1899
BINOL-Ti-Catalyzed Carbonyl-Ene Cyclization by Tuning the 6-Br-Ligand
for the Synthesis of 2-Methyl-19-nor-22-oxa Vitamin D Analogue with
Significant Differentiation Activity1
Koichi Mikamia*, Yurika Koizumia, Ayako Osawaa, Masahiro Teradaa, Hiroaki Takayamab, Kimie Nakagawac,
Toshio Okanoc
aDepartment of Chemical Technology, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
bFaculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan
cDepartment of Hygienic Sciences, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan
Fax +81-3-5734-2776; E-mail: kmikami@o.cc.titech.ac.jp
Received 22 July 1999
a significant activity in the inhibition of cancer cell
Abstract: Transition state control in BINOL-Ti-catalyzed asym-
growth.6 We have thus reported the hybridization ana-
metric carbonyl-ene cyclization by tuning the 6-Br-BINOL ligand
completes the synthesis of the A ring of the 2-methyl-19-nor-22-oxa
D3 analogue (2), which shows the significant activity in differentia-
logue,7 19-nor-22-oxa-1a,25(OH)2D3 (1) on the basis of
asymmetric carbonyl-ene cyclization8b catalyzed by a bi-
tion of HL-60 cell.
naphthol-derived titanium (BINOL-Ti) complex.9 Recent
papers10 prompt us to report the synthesis of 2-methyl-19-
nor-22-oxa vitamin D3 analogue (2)1,11 by tuning the
chiral ligands for the ene cyclization12 (Scheme 1) and the
significant activity in differentiation of myelocytic leuke-
mia, HL-60 cell.
Key words: vitamin D, ene reaction, binaphthol, titanium complex,
asymmetric catalysis
Basic research on the synthesis of analogues of the biolog-
ically active form of vitamin D3, 1a,25-dihydroxyvitamin
D3 [1a,25(OH)2D3], has brought about the development of
an important new field in medicinal chemistry.2 A number
of analogues have been synthesized and used to clarify the
mode of action of vitamin D hormones and find new ther-
apeutically useful compounds. These analogues are useful
not only for calcium metabolism disorder and bone dis-
eases, but also for differentiation of myelocytic leukemias
and the treatment of psoriasis.3 10-Oxo-19-nor-
25(OH)2D3 has been reported to exhibit a selective activi-
ty for differentiation of myelocytic leukemias.4 19-Nor-
1a,25(OH)2D3 also shows a selective activity profile, i.e.,
high potency in differentiation of malignant cells, but low
calcitropic liability.5 22-Oxa-1a,25(OH)2D3 (OCT) shows
The preparation of the 2-methyl ene-cyclization substrate
((R,R)-3) is worth mentioning (Scheme 2). The allylic al-
cohol (7) was obtained through highly regioselective pro-
piolate-ene reaction using triisopropylsilyl ethers (5)13
(regioisomer ratio = 94:6)14 with methyl propiolate (6) us-
ing EtAlCl2 as the promoter. The ene substrate 3 was pre-
pared in 96% ee via catalytic enantioselective epoxidation
of allylic alcohol15 (7) with (S,S)-diethyl tartrate (DET),
H'
OTIPS
OTIPS
OTIPS
a
b
c
5
H
+
(2 steps: 70%)
HO
regioisomeric ratio
94 : 6
(78%)
MeO2C
6
MeO2C
O
O
7
OH
OH
OTIPS
OTIPS
OBn
f,g,h,i
(50%)
d,e
O
(91%)
OMPM
O
O
HO
OH
HO
OH
O
HO
(R,R)-3
1
2
OMe
OBn
OBn
(R)-6-Br-BINOL-Ti
a) EtAlCl2, CH2Cl2, rt; b) DIBAL-H, toluene, –78 °C; c) (–)-DET
/ Ti(OPri)4 (20 mol% each), TBHP, MS 4A, CH2Cl2, –30 °C; d)
MeMgCl, CuBr•Me2S (10 mol%), THF/Et2O, –40 °C to –20 °C; e)
p-anisaldehyde dimethylacetal, PPTS, CH2Cl2, rt; f) TBAF, THF;
g) BnBr, NaH, TBAI; h) DIBAL-H, CH2Cl2, 0 °C to rt; i) PCC, MS
3A, CH2Cl2, rt
(cat.)
2
OMPM
HO
3
1
OMPM
O
(R,R)-3
(1R,2S,3R)-4
Scheme 2
Scheme 1
Synlett 1999, No. 12, 1899–1902 ISSN 0936-5214 © Thieme Stuttgart · New York

1900
K. Mikamia et al.
LETTER
nation of the enantiomeric (S)-6-Br-BINOL-Ti catalyst
and (S,S)-3 lead to the opposite enantiomer (1S,2R,3S)-4
preferentially (Run 4). The importance of the chirality of
BINOL-Ti catalysts should be emphasized in comparison
with the lower trans selectivity observed in the reaction
promoted by Me2AlCl as an equimolar reagent (Run 5).
Br
OH
OH
OBn
trans,Z-4
1
OMPM
Br
(R)-6-Br-BINOL
2
3
HO
The 6-(2,4)8b carbonyl-ene cyclization of 3 catalyzed by a
(R)-BINOL-Ti complex would proceed via chair-like
transition states (Scheme 3),19 where 1-MPMO group oc-
cupied an equatorial position and carbonyl group at C-3
position oriented to the axial direction to provide the de-
sired (Z)-cyclohexanediol 4 in high trans (1R,3R)-selec-
tivity. This b-form like transition state may be in close
resemblance to the binding conformation of
1a,25(OH)2D3.20 Z/E stereochemistry is critically depen-
dent on the balance of acyclic allylic 1,2-strain21 in TZ and
repulsion between the bulky BINOL-Ti catalyst and ben-
zyloxymethyl group (TE). By tuning the electron with-
drawing and sterically demanding 6-Br-BINOL ligand,
(Z)-geometrical selectivity significantly increases to 83%,
presumably because of the steric repulsion between 6-Br-
BINOL-Ti complex with the benzyloxymethyl moiety.
+
OH
OH
or
BnO
(R)-BINOL
/ Cl2Ti(OPri)2
(10 mol% each)
trans,E-4
OBn
HO
OMPM
+
+
OBn
OMPM
O
MS4A
rt, 12 h
(R,R)-3
cis,Z-4
OMPM
HO
BnO
cis,E-4
OMPM
HO
Table Asymmetric carbonyl ene-cyclization catalyzed by
BINOL-Ti or 6-Br-BINOL-Ti complex.
TiL*n
Ln*Ti
BnO
H
H
O
O
OBn
yield
trans,Z-4 trans,E-4 cis,Z-4
cis,E-4
Run
Cat
3
H
H
1a (R,R)
2b (R,R)
–
1
–
–
–
3
76%
63%
83%
84%
60%
68
53
82
83
66
28
29
16
15
8
4
17
2
(R)-BINOL-Ti
(S)-BINOL-Ti
3a (R,R) (R)-6-Br-BINOL-Ti
4a,c (S,S) (S)-6-Br-BINOL-Ti
OMPM
OMPM
1
H
H
Me
Me
TZ
TE
2
AlCl (1.0 eq.)
(R,R) Me2
26
5
a 4% of endo olefin was obtained as by-products. b 27% of endo
olefin was obtained as by-products. c The opposite enantiomers
were obtained.
OBn
BnO
HO
OMPM
HO
OMPM
titanium tetraisopropoxide, and tert-butyl hydroperoxide
(TBHP) and the following regioselective ring-opening
with methylcopper reagent prepared from methyl chlo-
ride-derived Grignard reagent.16
trans,Z-4
trans,E-4
Scheme 3
The carbonyl-ene cyclization of (R,R)-3 by the parent (R)-
BINOL-Ti catalyst (10 mol%) took place at room temper-
ature in CH2Cl2 to give the ene cyclization product (4) in
extremely high (1R,2S,3R)-stereochemistry with moder-
ate geometrical selectivity [(trans, Z) : (trans, E) = 68:28
as determined by HPLC analysis17], in 76% isolated yield
(Table, Run 1). Although the absolute configuration of the
newly created stereogenic center at C-3 is primarily con-
trolled by the chirality of the ene substrate 3 (Runs 1, 2),
the combination of (R,R)-3 and (R)-BINOL-Ti catalyst re-
sulted in higher trans (1R,3R)-selectivity than the combi-
nation with (S)-BINOL-Ti catalyst (Run 1 vs. 2). It is
noteworthy that the use of electronically withdrawing and
sterically demanding 6-bromo-binaphthol (6-Br-
BINOL)18 ligand leads to the significant increase in chem-
ical yield and (Z)-geometrical selectivity up to 83% and
82%, respectively (Run 3). Likewise, the opposite combi-
The (trans, Z)-4 can be easily separated from the geomet-
rical isomer (trans, E)-4 and transformed to the A-ring in-
termediate 8. Further transformation of the (1R,2S,3R)-8
to the Wittig reagent 9 for olefination with 22-oxa-C,D
ring 10 lead to the hybrid analogue of 2-methyl-19-nor-
22-oxa-1a,25(OH)2D3 (2) (Scheme 4).
1a,25(OH)2D3 mediates its biological activities through
specific binding to VDR which forms a hetero dimer with
a nuclear accessary factor (NAF) i.e., retinoid X receptor
(RXR) and subsequently the hetero dimer binds to the vi-
tamin D responsive element (VDRE) to induce gene tran-
scriptions. Therefore, a high binding affinity for VDR has
been considered necessary for analogues to possess high
biological activity. By contrast, we found a counter exam-
ple to this principle that our hybrid analogue (2) thus syn-
thesized has an equally high activity to active
1a,25(OH)2D3 in cell differentiation activity of HL-60
Synlett 1999, No. 12, 1899–1902 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
BINOL-Ti-Catalyzed Carbonyl-Ene Cyclization by Tuning the 6-Br-Ligand
1901
(5) Perlman, K. L.; Siciniski, R. R.; Schnoes, H. K.; DeLuca, H.
F. Tetrahedron Lett. 1990, 31, 1823-1824. Perlman, K. L.;
Swenson, R. E.; Paaren, H. E.; Schnoes, H. K.; DeLuca, H. F.
Tetrahedron Lett. 1991, 32, 7663-7666. Perlman, K. L.;
DeLuca, H. F. Tetrahedron Lett. 1992, 33, 2937-2940.
(6) Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.;
Matsunaga, I. Chem. Pharm. Bull. 1986, 34, 4410-4413.
Kubodera, N.; Watanabe, H.; Kawanishi, T.; Matsumoto, M.;
Chem. Pharm. Bull. 1992, 40, 1494-1499.
(7) 19-Nor-22-oxa-1a,25(OH)2D3 (1): Mikami, K.; Osawa, A.;
Isaka, A.; Sawa, E.; Shimizu, M.; Terada, M.; Kubodera, N.;
Nakagawa, K.; Tsugawa, N.; Okano, T. Tetrahedron Lett.
1998, 39, 3359-3362. 3-Dehydroxy-19-nor-22-oxa-
1a,25(OH)2D3, 19-nor-22-oxa-25(OH)D3, 3-dehydroxy-19-
nor-1a,25(OH)2D3, and 19-nor-25(OH)D3: Okano, T.;
Nakagawa, K.; Tsugawa. N.; Ozono, K.; Kubodera, N.;
Osawa, A.; Terada, M.; Mikami, K. Biol. Pharm. Bull. 1998,
21, 1300-1305.
OH
a, b, c
(58%)
d, e, f
(70%)
trans,Z-4
TBDMSO
OTBDMS
O
8
OTMS
POPh2
10
O
g, h
2
TBDMSO
OTBDMS
(54%)
9
(8) Reviews on ene reactions: (a) Mikami, K.; Terada, M. In
Comprehensive Asymmetric Catalysis; Jacobsen, H. E.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Heidelberg, in
press. (b) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92,
1021-1050. (c) Snider, B. B. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: London,
1991; Vol. 2, p 527-561 and Vol. 5, p 1-27. (d) Taber, D. F. In
Intramolecular Diels-Alder and Alder Ene Reactions;
Springer-Verlag: Berlin, 1984, p 61-97. (e) Oppolzer, W.;
Snieckus, V. Angew. Chem. Int. Ed. Engl. 1978, 17, 476-486.
(f) Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1969, 8,
556-577.
(9) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990,
112, 3949-3954. (b) Mikami, K.; Terada, M.; Nakai, T. J. Am.
Chem. Soc. 1989, 111, 1940-1941. (c) Mikami, K.; Terada,
M.; Narisawa, S.; Nakai, T. Org. Synth. 1992, 71, 14-21. (d)
Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc.
1994, 116, 2812-2820. (e) Terada, M.; Matsumoto, Y.;
Nakamura, Y.; Mikami, K. Chem. Commun. 1997, 281-282.
(10) Quite recently, the synthesis of 2-methyl analogue of
1a,25(OH)2D3 was reported: Konno, K.; Maki, S.; Fujishima,
T.; Liu, Z.; Miura, D.; Chokki, M.; Takayama, H. Bioorg.
Med. Chem. Lett. 1998, 8, 151-156. 20-epi-2-methyl analogue
of 1a,25(OH)2D3: Fujishima, T. Liu, Z.; Miura, D.; Chokki,
M.; Ishizuka, S.; Konno, K.; Takayama, H. Bioorg. Med.
Chem. Lett. 1998, 8, 2145-2148. 2-Methyl-19-nor analogue of
1a,25(OH)2D3: Sicinski, R. R.; Prahl, J. M.; Smith, C. M.;
DeLuca, H. F. J. Med. Chem. 1998, 41, 4662-4674.
(11) In contrast, 2-hydroxylated analogue has high calcitropic
activity: Review: Kubodera, N.; Sato, K.; Nishii, Y. In
Vitamin D; Feldman, D.; Glorieux, F. H.; Pike, J. W., Eds.;
Academic: New York, 1997; Chap. 63, p 1071-1086. Also see.
Sicinski, R. R.; Perlman, K. L.; DeLuca, H. F. J. Med. Chem.
1994, 37, 3730-3738.
a) CAN, CH3CN, rt; b) TBDMSCl, imidazole, DMF, rt; c) Li, NH3,
–78 °C; d) NCS, Me2S, CH2Cl2, –20 °C to rt; e) PhPLi, THF, 0 °C;
f) H2O2, THF/H2O, rt; g) 10, n-BuLi, THF, –78 °C; h) TBAF, THF,
rt
Scheme 4
myelocytic leukemia cell in spite of significantly low
binding affinity for VDR by three order of magnitude
(0.008 relative to 1a,25(OH)2D3).
In summary, we have reported the transition state control
in BINOL-Ti-catalyzed asymmetric carbonyl-ene cy-
clization by tuning the 6-Br-BINOL ligand for the synthe-
sis of the A ring of the 2-methyl-19-nor-22-oxa D
analogue 2, which shows the significant activity in cell
differentiation activity of HL-60 myelocytic leukemia.
Acknowledgement
We are grateful to Drs. Noboru Kubodera and Akira Kawase of
Chugai Pharmaceutical Co. Ltd. for kindly giving OCT.
References and Notes
(1) A part of this work has been reported in Osawa’s Master
Thesis, Tokyo Institute of Technology, February (1997).
Mikami, K.; Koizumi, Y.; Osawa, A.; Terada, M.; Kubodera,
N.; Nakagawa, K.; Okano T. 76th Annual Meeting of the
Chemical Society of Japan, Kanagawa, March 28th, 1999,
Abstract No. 1C104.
(2) Reviews on the synthesis and structure-function relationships
of vitamin D analogues: Vitamin D; Feldman, D.; Glorieux, F.
H.; Pike, J. W., Eds.; Academic: New York, 1997. Bouillon,
R.; Okamura, W. H.; Norman, A. W. Endocrine Reviews
1995, 16, 200-257. Zhu, G.-D.; Okamura, W. H. Chem. Rev.
1995, 95, 1877-1952. Dai, H.; Posner, G. H. Synthesis 1994,
1383-1398. Special issue: Uskokovic, M. ed. BioMed. Chem.
Lett. 1993, 3, No. 9.
(12) For asymmetric (2,4) and (3,4) ene cyclizations of the
substrates without any geminal disubstituents catalyzed by
binaphthol-derived titanium complex, see: Mikami, K.; Sawa,
E.; Terada, M. Tetrahedron Asymmetry 1991, 2, 1403-1412.
(13) Regioselective carbonyl-ene reactions with allylic and
homoallylic alcohols: Mikami, K.; Shimizu, M.; Nakai, T. J.
Org. Chem. 1991, 56, 2952-2953.
(14) High regioisomer ratio (H- vs. H’-shift = 94:6) was attained
by the use of triisopropylsilyl ether as a protecting group
instead of benzyl ether (H- vs. H’-shift = 73:27).
(15) Reviews: Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-
299. Johnson, R. A.; Sharpless, K. B. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon:
London, 1991; Vol 7, p 389-436. For the A-ring synthesis in
1a,25(OH)2D3, see: Nagasawa, K.; Zako, Y.; Ishihara, H.;
Shimizu, I. Tetrahedron Lett. 1991, 32, 4937-4940. Kabat, M.
M.; Lange, M.; Wovkulich, P. M.; Uskokovic, M. R.
(3) Ettinger, R. A.; DeLuca, H. F. Adv. Drug Res. 1996, 28, 269-
312. Vitamin D: A Chemical, Biochemical, and Clinical
Update; Norman, A. W.; Schaefer, K.; Grigoleit, H. G.;
Herrath, D., Eds.; Walter de Gruyter: Berlin, 1985.
(4) Gray, T. K.; Millington, D. S.; Maltby, D. A.; Williams, M. E.;
Cohen, M. S.; Dodd, R. C., Proc. Natl. Acad. Sci. USA 1985,
82, 8218-8221.
Synlett 1999, No. 12, 1899–1902 ISSN 0936-5214 © Thieme Stuttgart · New York

1902
K. Mikamia et al.
LETTER
Tetrahedron Lett. 1992, 33, 7701-7704. Nagasawa, K.;
Ishihara, H.; Zako, Y.; Shimizu, I. J. Org. Chem. 1993, 58,
2523-2529. Courtney, L. F.; Lange, M.; Uskokovic, M. R.
Tetrahedron Lett. 1998, 39, 3393-3396.
Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 9011-
9012; Ooi, T.; Maruoka, K.; Yamamoto, H. Tetrahedron
1994, 50, 6505-6522. Also see: Marshall, J. A.; Anderson, M.
W. J. Org. Chem. 1992, 57, 5851-5856. However, they
proposed an equatorial arrangement of carbonyl group
complexed with sterically bulky MABR leading to 1,3-cis-
cyclohexanol. For the formation of 1,3-trans-cyclohexanols
by using Me2AlCl, see: Johnston, M. I.; Kwass, J. A.; Beal, R.
B.; Snider, B. B. J. Org. Chem. 1987, 52, 5419-5424.
(20) The conformation of the A ring in the 1,25(OH)2D3 crystal is
frozen exclusively in the b-form in which the hydroxy groups
at C-1 and C-3 are in equatorial and axial orientation,
respectively: Suwinska, K.; Kutner, A. Acta Cryst. 1996, B52,
550-554.
(16) Considerable amount of iodinated product was obtained by
the use of MeMgI instead of MeMgCl. Tius, M. A.; Fauq, A.
H. J. Org. Chem. 1983, 48, 4131-4132. Also see: Johnson, M.
R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979, 20, 4343-
4346.
(17) Ratio of the ene cyclized products (4) were determined by
HPLC analysis with an Inertsil SIL column (hexane/ethyl
acetate = 2/1; flow rate 0.8 mL/min; 254 nm; trans,Z-4
tR = 23.9 min; trans,E-4 tR = 19.6 min; cis,Z-4 tR = 16.8 min;
cis,E-4 tR = 12.3 min).
(18) Mikami, K.; Motoyama, Y.; Terada, M. Inorg. Chim. Acta
1994, 222, 71-75. Terada, M.; Motoyama, Y.; Mikami, K.
Tetrahedron Lett. 1994, 35, 6693-6696. Terada, M.; Mikami,
K. J. Chem. Soc., Chem. Commun. 1995, 2391-2392.
(19) Mikami, K.; Loh, T.-P.; Nakai, T. Tetrahedron Lett. 1988, 29,
6305-6308. For STO-3G and 3-21G calculations on 5-
membered transition states (ref. 8f) of thermal ene reactions,
see: Loncharich, R. J.; Houk, K. N. J. Am. Chem. Soc. 1987,
109, 6947-6952. For axial vs. equatorial orientation of
carbonyl group in ene cyclization reactions, see: Maruoka, K.;
(21) Reviews: Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860.
Mikami, K.; Shimizu, M. In "Advances in Detailed Reaction
Mechanisms " Coxon, J. Ed.; JAI Press: London, 1994; Vol. 3,
pp. 45-77,. For cyclic allylic strain concept, see: Johnson, F.
Chem. Rev. 1968, 68, 375-413.
Article Identifier:
1437-2096,E;1999,0,12,1899,1902,ftx,en;Y14499ST.pdf
Synlett 1999, No. 12, 1899–1902 ISSN 0936-5214 © Thieme Stuttgart · New York