Synthesis of iodinated analogues of all trans retinoic acid (ATRA) for SPECT imaging

Article abstract of DOI:10.1016/j.tetlet.2004.05.103

Two derivatives of all trans retinoic acid in which one of the methyl groups has been replaced by iodine have been prepared.

Full text of DOI:10.1016/j.tetlet.2004.05.103

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5673–5676
Synthesis of iodinated analogues of all trans
retinoic acid (ATRA) for SPECT imaging
Haibing Li and Christophe Morin*
LEDSS-UMR 5616, Dꢀepartement de Chimie (ICMG-IFR 2607), Universitꢀe Joseph Fourier-Grenoble-1,
38402 Saint Martin d’Hꢁeres, France
Received 20 April 2004; revised 19 May 2004; accepted 19 May 2004
Available online 11 June 2004
Abstract—Two derivatives of all trans retinoic acid in which one of the methyl groups has been replaced by iodine have been
prepared.
Ó 2004 Elsevier Ltd. All rights reserved.
A common situation met in the procurement of tracers
for SPECT (Single Photon Emission Computed
Tomography) medical imaging is that the introduction
of a label onto a drug leads to a compound, which differs
in its overall architecture from the parent molecule.
However there are some cases in which it is conceivable
to introduce the marker into a region of the molecule in
a way, which is expected to have minimal adverse effects
on its physicochemical properties, compared to those of
the original molecule. 123I is a c-emitting radionucleide
commonly used for SPECT and since iodine resembles a
methyl group in terms of bulkiness and lipophilicity, the
preparation of a derivative in which iodine would re-
place a methyl group present in the drug could be a
fruitful approach in the design of SPECT-compatible
tracers.
acid) (1) is used to induce remission of acute promyelo-
cytic leukaemia (APL) in current oncological practice.2;3
Since there is a need for imaging of ATRA uptake, the
synthesis of derivatives suitable for SPECT has been
considered; in light of the above considerations,
replacement by iodine of one of the ATRA methyl
groups has been favoured4 and the preparation of two
such derivatives is presented.
The preparation (see Scheme 1) of the first of these, 9-
iodo-9-nor-ATRA(2), was planned by assembly of
C10+C4+C5 fragments:
The C4 iodinated partner 35 was obtained after desym-
metrization6 of but-2-yne-1,4-diol; this was followed by
formation of an alanate,7 which was reacted with
molecular iodine8 to get 3; since the stereochemical
outcome of this process is controlled by the adjacent
hydroxymethyl group, the Z configuration was assign-
ed.9 Oxidation of 3 was performed efficiently with IBX10
and the intermediate aldehyde11 was condensed with
phosphonate 4 under the conditions found suitable for
such Wadsworth–Emmons–Horner condensations.12
This afforded 5, the configuration of which was assigned
Retinoids are inducers of cell differentiation and apop-
tosis1 and, more specifically, ATRA (all trans retinoic
Keywords: Iodine; Retinoic; Cross-coupling; Labelling.
* Corresponding author. Fax: +33-476-514-927; e-mail: Christophe.
Morin@ujf-grenoble.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.103

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H. Li, C. Morin / Tetrahedron Letters 45 (2004) 5673–5676
Scheme 1. Reagents and conditions: (a) (1) TBDMSiCl, Et3N, DMAP––Ref. 6, (2) Red-Al, then I2 (91%). (b) (1) IBX (95%); E-(EtO)2P(O)CH2–
C(CH3)@CHCOOEt (4), LDA, DMPU (94%). (c) TBAF. (d) (1) HF-py (95%); (2) Swern (92%). (e) NaBH4–CeCl3Æ7H2O, CH3OH, 4 °C (97%). (f)
Ref 15. (g) 9, )70 °C, n-BuLi, then 7 (93%). (h) 1.75 M NaOH, 1:1 H2O/EtOH), 50 °C, 45 min (98%).
Scheme 2. Reagents and conditions: (a) (1) n-BuLi, TMSiCl; (2) n-BuLi, ClCOOEt; (3) Lil, AcOH (76%). (b) Swern (88%). (c) (1) CH2@CHMgBr;
(2) PPh3ÆHBr––Ref 18. (d) (1) LDA, DMPU, then 14 (74%). (e) Pd(PPh3)4, Me6Sn2, DIEA (55%). (f) NaOH (1.75 M in 1:1 H2O/EtOH), 50 °C,
45 min. (g) I2/CH2Cl2 (63% from 17).

H. Li, C. Morin / Tetrahedron Letters 45 (2004) 5673–5676
5675
7. Red-Al has been shown to be the reagent of choice for this
transformation: Denmark, S. E.; Jones, T. K. J. Org.
Chem. 1982, 47, 4595; for related examples see: Blanchette,
M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.;
Somfai, P.; Whritenour, D. C.; Masamune, S. J. Org.
Chem. 1989, 54, 2817; Denis, R. C.; Gravel, D. Tetrahe-
dron Lett. 1994, 35, 4531.
8. Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H.
J. Am. Chem. Soc. 1967, 89, 4245.
9. The Z configuration of 3 has been secured by its
conversion to nakienone B. See: Pour, M.; Negishi, E.-I.
Tetrahedron Lett. 1996, 37, 4679.
10. More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
11. This aldehyde (1H NMR, 200 MHz, CDCl3, d: )0.10 (s,
6H, SiCH3), 0.92 (s, 9H, SiC(CH3)3), 4.42 (d, J ¼ 2:1 Hz,
2H, H-4), 6.69 (dt, J ¼ 6:5 Hz, J ¼ 2:1 Hz, 1H, H-2), 9.67
(d, J ¼ 6:5 Hz, 1H, H-1). 13C NMR (75 MHz, CDCl3) d:
)5.7 (SiCH3), 18.2 (SiC(CH3)3), 26.7 (C(CH3)3), 72.3
(C-4), 128.8 (C-3), 129.1(C-2), 196.5 (C-1) can be purified
by column chromatography but should be freshly pre-
pared before use.
as E from the large coupling constant observed for the
newly introduced vinylic protons.13 At this stage, re-
moval of the silyl ether using tetrabutylammonium
fluoride led to loss of iodine (to give alkyne 6) but the
use of milder conditions (HF-py) allowed regeneration
of the hydroxyl group; this was followed by Swern
oxidation to get 7.14 The b-cyclogeranyl partner 9 was
conventionally obtained15 from b-cyclogeraniol 8,
which, in this work, was obtained by NaBH4/
CeCl3Æ7H2O reduction of b-cyclocitral thus improving
literature procedures.16 Condensation of the ylide
derived from 9 with freshly prepared 7 afforded ester 10,
the saponification of which led to 9-iodo-9-nor-retinoic
acid, 2.17
To get the 13-iodo-13-nor-ATRA isomer (11) the
assembly of a C15 fragment18 with 1319 was planned
(Scheme 2). The iodinated derivative 12 was prepared in
three sequential steps from propargylic alcohol by (1) in
20
situtransient protection of the hydroxyl group,
(2)
12. Mata, E. G.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1
1995, 785.
formation of the acetylide followed by its quenching
with ethyl chloroformate and (3) 1–4 addition of lithium
iodide to the conjugated ester. The Z stereochemistry of
the product 12 can be deduced from mechanistic con-
siderations21 but it has been proven by observation of an
NOE effect between the vinylic proton and the methyl-
ene group.22 Oxidation of 12 by manganese dioxide19
gave a mixture of E/Z aldehydes as was the case when
IBX was used; however Swern oxidation gave pure 13.
This sensitive aldehyde was condensed with the ylide
derived from 14,18 which gave ester 15.23 In contrast
with results for the vinylogous 9-iodo series (i.e.,
saponification of 10), cleavage of the ester group of 15
proved troublesome: whether acidic or basic conditions
were used, the only product, which could be character-
ized was acetylenic derivative 16.24 This situation could
be overcome by conversion of 15 to tin derivative 1725
whose saponification to 18 could be achieved satisfac-
torily. Iodolysis of the tin–carbon bond then gave 13-
iodo-13-nor-ATRA, 11.17 In view of the lability of the
carbon–iodine bond in this compound however (par-
ticularly under basic conditions), 9-iodo-9-nor-ATRA 2
would appear to be a more suitable candidate for
SPECT imaging.26
1
13. 5: H NMR (300 MHz, CDCl3) d: )0.10 (s, 6H, SiCH3),
0.93 (s, 9H, SiC(CH3)3), 1.28 (t, J ¼ 7:1 Hz, 3H,
OCH2CH3), 2.34 (d, J ¼ 1:1 Hz, 2H, CH3-3), 4.12 (q,
J ¼ 7:1 Hz, 2H, OCH2CH3), 4.35 (s, 2H, H-8), 5.83 (s, 1H,
H-2), 6.41 (d, J ¼ 14:7 Hz, 1H, H-4), 6.66 (m, 2H, H-5, H-
6). 13C NMR (75 MHz, CDCl3) d: )5.3 (Si–CH3), 13.7
(CH3), 14.3 (CH3), 18.3 (SiC(CH3)3), 25.8 (C(CH3)3), 59.8
(OCH2CH3), 71.7 (C-8), 111.7 (C-7), 120.6 (C-2), 131.1,
135.1, 138.8 (C-4, C-5, C-6), 151.7 (C-3), 166.8 (C-1).
14. In contrast to oxidation of 3, the use of IBX resulted here
in configurational scrambling as a 1:1.8 E/Z mixture was
detected.
15. Dawson, M. I.; Hobbs, P. D.; Chan, R. L.-S.; Chao,
W.-R. J. Med. Chem. 1981, 24, 1214.
€
16. Pommer, H. Angew. Chem. 1960, 72, 811; Buchi, G.;
White, G. D. J. Am. Chem. Soc. 1964, 86, 2884; Behr, D.;
Wahlberg, I.; Nishida, T.; Enzell, C. R. Acta Chem. Scand.
1977, 31B, 793; Crombie, B. S.; Smith, C.; Varnavas, C.
Z.; Wallace, T. W. J. Chem. Soc., Perkin Trans. 1 2001,
206.
17. NMR assignments of ATRA, for 1H see: Perly, B.;
Pappalardo, G. C.; Klaus, M.; Montoneri, E. Z. Natur-
forsch. 1988, 43b, 1072; for 13C see: Bernard, M.; Ford,
W. T.; Nelson, E. C. J. Org. Chem. 1983, 48, 3164;
2: 1H NMR (300 MHz, CDCl3) d: 1.10 (s, 6H, CH3-1),
1.4–1.7 (m, 4H, H-2, H-3), 1.73 (s, 3H, CH3-5), 2.04 (m,
2H, H-4), 2.39 (large s, 3H, CH3-13), 5.85 (s, H-14), 5.83
and 6.64 (AB system, J ¼ 15 Hz, H-7, H-8), 6.46 (d,
J ¼ 11 Hz, H10), 6.48 (d, J ¼ 15 Hz, H12), 7.03 (dd,
J ¼ 11 Hz, J ¼ 15 Hz, 1H, H11). 13C NMR (75 MHz,
CDCl3) d: 14.0 (CH3-13), 19.1 (C-3), 21.8 (C-5), 28.9
(CH3-5), 33.3 (C-4), 34.4 (C-1), 39.6 (C-2), 112.4 (C-9),
119.2 (C-14), 132.1, 136.9 (C-5, C-6), 134.2, 135.2, 137.7,
138.3, 139.1 (C-7, C-8, C-10, C-11, C-12), 154.5 (C-13),
References and notes
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Guillemot, I.; Menot, L.; Degos, L.; Fenaux, P.; Chomi-
enne, C. Blood 2001, 98, 2862.
4. For a derivative of 9-cis retinoic acid in which iodine
substitutes a vinylic hydrogen see: Klaus, M.; Lovey, A. J.;
Mohr, P.; Rosenberg, M. Eur. Patent Appl. No. 728742,
1996.
1
171.2 (C-15). 11: H NMR (300 MHz, CDCl3) d: 1.04 (s,
6H, CH3-1), 1.47 (m, 2H, H-2), 1.61 (m, 2H, H-3), 1.72 (s,
3H, CH3-5), 2.04 (m+s, 5H, H-4, CH3-5), 6.20, 6.37 (AB
system, J ¼ 15:7 Hz, H-7, H-8), 6.39 (m, 1H), 6.62 (large s,
1H) and 7.13–7.26 (m, 2H): (H-10, H-11, H-12, H-14). 13
C
NMR (75 MHz, CDCl3) d 13.1 (CH3-9), 19.2 (C-3), 21.8
(CH3-5), 29.0 (CH3-1), 33.2 (C-4), 34.3 (C-1), 39.7 (C-2),
124.7 (C-13), 127.0, 128.6, 128.7, 130.5, 145.2 (C-7, C-10,
C-11, C-12, C-14), 130.9 (C-5), 137.0 (C-8), 137.6 (C-6),
143.6 (C-9), 168.0 (C-15).
5. This compound has recently been obtained by a free-
radical approach; see: Commeiras, L.; Santelli, M.; Par-
rain, J.-L. Tetrahedron Lett. 2003, 44, 2311.
6. MacMahon, S.; Fong, R.; Baran, P. S.; Safonov, I.;
Wilson, S. R.; Schuster, D. I. J. Org. Chem. 2001, 66, 5449.
18. Curley, R. W., Jr.; DeLuca, H. F. J. Org. Chem. 1984, 49,
1941.

5676
H. Li, C. Morin / Tetrahedron Letters 45 (2004) 5673–5676
19. Shinada, T.; Yoshihara, K. Chem. Pharm. Bull. 1996, 44,
264.
6 to 4:1 E/Z ratio was observed after reaction with the
ylide derived from 9 (see Ref. 19).
20. O-TMS propargyl alcohol is very moisture sensitive and was
directly used after in situ formation that is without isolation.
For use of a tert-butyldimethylsilyl ether, see: Piers, E.;
Chong, M.; Morton, H. E. Tetrahedron 1989, 45, 363.
21. Ma, S.; Lu, X. J. Chem. Soc., Chem. Commun. 1990, 1643.
22. Shinada, T.; Sekiya, N.; Boojkova, N.; Yoshihara, K.
Tetrahedron 1999, 55, 3675.
24. For the elimination of iodine in such a conjugated ester,
see: Brisdon, B. J.; Brown, D. W.; Willis, C. R.; Drew,
M. G. B. J. Chem. Soc., Dalton Trans. 1986, 2405.
25. The less toxic bis(tributyl)ditin was ineffective for this
transformation.
26. To enable the preparation of material with high specific
activity, 2 was converted to the corresponding trimethyltin
derivative (Me3Sn)2/Pd (0), 73%); 2 could be regenerated
(90%) after reaction with iodine.
23. Under those conditions, NMR analysis of the crude
material showed 92% E configurational purity; note that a