Convergent stereoselective synthesis of the visual pigment A2E

Article abstract of DOI:10.1021/ol052512u

(Chemical Equation Presented) A stereoselective total synthesis of the visual pigment A2E has been achieved with use of palladium-catalyzed cross-coupling reactions in all key steps: a regioselective Suzuki or Negishi coupling of 2,4-dibromopyridine, a Sonogashira reaction, and a double Stille cross-coupling to complete the bispolyenyl skeleton.

Full text of DOI:10.1021/ol052512u

ORGANIC
LETTERS
2
005
Vol. 7, No. 25
737-5739
Convergent Stereoselective Synthesis of
the Visual Pigment A2E
5
Cristina Sicre and M. Magdalena Cid*
Departamento de Qu ´ı mica Org a´ nica, UniVersidade de Vigo,
Campus Lagoas-Marcosende, 36310 Vigo, Spain
mcid@uVigo.es
Received October 17, 2005
ABSTRACT
A stereoselective total synthesis of the visual pigment A2E has been achieved with use of palladium-catalyzed cross-coupling reactions in all
key steps: a regioselective Suzuki or Negishi coupling of 2,4-dibromopyridine, a Sonogashira reaction, and a double Stille cross-coupling to
complete the bispolyenyl skeleton.
Deposition of a fluorophoric material, known as lipofuscin,
in lysosomes of retinal pigment epithelium cells has been
speculated to be one of the biomarkers of age-related macular
degeneration. Pyridinium bisretinoids, A2E and its 1′-Z-
The confirmation of the role of A2E was given by recent
studies on transgenic mice that have shown that accumulation
of lipofuscin by the RPE is followed by RPE atrophy. Its
3
cationic nature along with two hydrophobic retinal chains
suggests that it can disrupt the membrane integrity by its
detergent-like activity and can thus cause cellular damage.4
Also, it was found that A2E, at low concentrations, causes
apoptosis in cultured human retinal pigment epithelial cells5
and a possible mechanism for A2E toxicity may include
photochemical processes leading to photooxidation products,
1
photoisomer (see Scheme 1 for numbering), iso-A2E, have
Scheme 1. Strategy for the Synthesis of A2E
6
mainly epoxides in the acyclic side chains, through free
7
8
radicals or singlet oxygen intermediacy.
Biosynthetic studies revealed that detectable levels of
A2-PE, the A2E precursor generated from two units of all-
trans-retinal and phosphatidylethanolamine, are formed
(1) (a) Eldred, G. E.; Lasky, M. R. Nature 1993, 361, 724. (b) Sakai,
N.; Decatur, J.; Nakanishi, K.; Eldred, G. E. J. Am. Chem. Soc. 1996, 118,
1
559.
(2) Review: Lamb, L. E.; Simon, J. D. Photochem. Photobiol. 2004,
7
9, 127.
(3) Karan, G.; Lillo, C.; Yang, Z.; Cameron, D. J.; Locke, K. G.; Zhao,
Y.; Thirumalaichary, S.; Li, C.; Birch, D. G.; Vollmer-Snarr, H. R.;
Williams, D. S.; Zhang, K. Proc. Nat. Acad. Sci. U.S.A. 2005, 102, 4164.
(4) De, S.; Sakmar, T. P. J. Gen. Physiol. 2002, 120, 147.
been characterized as fluorophores of lipofuscin. Several
modes of toxicity have been suggested through which A2E
can affect the health of the retinal pigment epithelium (RPE).
(
5) (a) Shaban, H.; Borr a´ s, C.; Vi n˜ a, J.; Richter, C. Exp. Eye Res. 2002,
5, 99. (b) Suter, M.; Rem e´ , C.; Grimm, C.; Wenzel, A.; J a¨ a¨ ttela, M.; Esser,
P.; Kociok, N.; Leist, M.; Richter, C. J. Biol. Chem. 2000, 275, 39625.
7
2
1
0.1021/ol052512u CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/15/2005

within the photoreceptor outer segments following light-
at 25 °C proved to be highly regioselective (6:7 ratio of 16:
1) yielding the 2-alkenyl-4-bromopyridine 6 in 70% yield.
Cross-coupling with zinc derivative 5b under Negishi condi-
9
induced release of endogenous all-trans-retinal. This scheme
1
,10
was followed in the reported A2E biomimetic synthesis,
1
6
where A2E was prepared in 50% yield by simple mixing of
tions also proceeded at 25 °C and provided compound 6
1
7
all-trans-retinal and hydroxylamine, and also in a formal
(separated from ca. 10% of 7) in 73% yield.
1
1
synthesis through a 6π-azaelectrocyclization reaction.
The next target was the incorporation of the substituent
at the 4-position of the pyridine nucleus and it turned out
that Sonogashira cross-coupling served very well to attach
the alkyne moiety at this position. So, reaction of 6 with
ethynyltrimethylsilane under the usual Sonogashira condi-
tions followed by deprotection of both silyl groups and
Dess-Martin oxidation rendered 11a in good overall yield
(58%) (Scheme 3).
The first total synthesis of the ocular pigment A2E was
achieved by a nonstereoselective double Wittig-olefination
of a pyridyl bisaldehyde and 2 equiv of a retinoid-C-15
phosphonium salt containing the moiety common to both
1
2
sidearms.
Here, we report the first stereoselective synthesis of A2E
(
1) through a convergent process involving a two-directional
2
2
palladium-catalyzed C(sp )-C(sp ) bond formation between
the properly functionalized pyridine 3 and the trienyliodide
2
(Scheme 1).
Scheme 3. Synthesis of the Pyridine Core 3
The synthesis of the pyridine core 3 was envisioned from
the corresponding bisalkynylpyridine, itself prepared from
,4-dibromopyridine (4), through regioselective and sequen-
2
tial palladium cross couplings, under the assumption that the
two halogens should exhibit differential reactivity toward
palladium[0] in cross-coupling reactions due to their different
electronic environments.13
Scheme 2. Preparation of the Monosubstituted Pyridine
The transformation of the aldehyde 11a into the corre-
sponding alkyne 12b under different conditions was sluggish
and yields were poor (15-20%).
To circumvent these difficulties, presumably due to the
acidity of the acetylenic hydrogen, the silyl ether group of
The reaction between 2,4-dibromopyridine (4)14 and bo-
ronic ester 5a, prepared in situ from the corresponding
iodide by halogen-lithium exchange and further treatment
15
with triisopropoxyborate, in the presence of Pd[0] and TlOH
(
11) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem.
(6) (a) Dillon, J.; Wang, Z.; Avalle, L. B.; Gaillard, E. R. Exp. Eye Res.
2001, 66, 3099.
2
004, 79, 537. (b) Radu, R. A.; Mata, N. L.; Bagla, A.; Travis, G. H. Proc.
(12) Ren, R. X.-F.; Sakai, N.; Nakanishi, K. J. Am. Chem. Soc. 1997,
119, 3619.
(13) 2-Bromo-4-chloropyridine was also used. But although monosub-
stituted pyridine 6b was successfully obtained, the incorporation of the
substituent at position 4 was hampered by the low reactivity of the chlorine
atom under different Sonogashira reaction conditions. See the Supporting
Information for further details.
Nat. Acad. Sci. U.S.A. 2004, 101, 5928. (c) Sparrow, J. R.; Vollmer-Snarr,
H. R.; Zhou, J.; Jang, Y. P.; Jockusch, S.; Itagaki, Y.; Nakanishi, K. J.
Biol. Chem. 2003, 278, 18207.
7) Gaillard, E. R.; Avalle, L. B.; Keller, L. M. M.; Wang, Z.; Reszka,
K. J.; Dillon, J. P. Exp. Eye Res. 2004, 79, 313.
8) (a) Ben-Shabat, S.; Itagaki, Y.; Jockusch, S.; Sparrow, J. R.; Turro,
(
(
N. J.; Nakanishi, K. Angew. Chem., Int. Ed. 2002, 41, 814. (b) Roberts, J.
E.; Kukielczak, B. M.; Hu, D.-N.; Miller, D. S.; Bilski, P.; Sik, R. H.;
Motten, A. G.; Chignell, C. F. Photochem. Photobiol. 2002, 75, 184. (c)
Kanofski, J. R.; Sima, P. D.; Richter, C. Photochem. Photobiol. 2003, 77,
(14) 2,4-Dibromopyridine was prepared by using a modified version of
the method reported by den Hertog: den Hertog, H. J. Recl. TraV. Chim.
1944, 63, 85.
(15) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47.
(16) Bach, T.; Heuser, S. Angew. Chem., Int. Ed. 2001, 40, 3184.
(17) We also tried a Stille coupling with the corresponding stannane 5
(M ) SnBu3) but its reactivity was low at 25 °C, and even at 95 °C after
68 h, conversion was not complete and selectivity was low, this being
attributable to the methyl cis to the C-metal bond. Besides, this C-metal
bond is very labile.
2
35.
9) (a) Liu, J.; Itagaki, Y.; Ben-Shabat, S.; Nakanishi, K.; Sparrow, J.
(
R. J. Biol. Chem. 2000, 275, 29354. (b) Mata, N. L.; Weng, J.; Travis, G.
H. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7154.
(10) Parish, C. A.; Hashimoto, M.; Nakanishi, K.; Dillon, J.; Sparrow,
J. Proc. Nat. Acad. Sci. U.S.A. 1998, 95, 14609.
5738
Org. Lett., Vol. 7, No. 25, 2005

compound 6 was removed by treatment with TBAF in THF
before running the Sonogashira coupling. Thus, reaction of
pyridine 8 under Sonogashira conditions provided enynyl
pyridine 10c, which after treatment with Dess-Martin
periodinane led to aldehyde 11b in an overall 85% yield.
The preparation of alkyne 12 was now successfully ac-
Scheme 4. Preparation of the Ocular Pigment A2E
18
complished either directly with TMSC(Li)N
2
or through
Corey-Fuchs-type conditions (Scheme 3).19
Subsequent treatment of the bisethynylpyridine 12b with
20
(Bu
3
Sn)
2
CuCNLi
2
at -40 °C afforded the double func-
tionalized bisstannylpyridine 3 in 56% yield, the presence
of MeOH throughout the reaction being critical for the
success of the stannylcupration. Although the reaction was
totally regio- and stereoselective at the alkyne at position-4
to give the E-stannyl derivative, at the enynyl chain at
position-2 the selectivity was lower and the internal isomer
dered stereoselectively the all-trans bispolyenyl pyridine 14
(50%) (Scheme 4). Alkylation of 14 with iodoethanol in
nitromethane for 19 h gave A2E (1) in an overall 14% yield
from 2,4-dibromopyridine. All spectroscopic data of A2E
13 was also obtained in a ratio of 2.8:1. This ratio increased
1b
were identical with those previously reported.
to 4.2:1 when the reaction was run at -10 °C, but the yield
was slightly lower (50% for compound 3) most likely as a
result of decomposition processes. The structures of both
stannanes 3 and 13 were assigned by using 2D NMR experi-
ments and some characteristic NMR data along with the main
To summarize, a stereoselective total synthesis of A2E
has been achieved that uses palladium-catalyzed cross-
coupling reactions in all key bond-forming steps: regiose-
lective Suzuki (or Negishi) coupling of 2,4-dibromopyridine,
Sonogashira reaction, and 2-fold Stille cross-coupling to
complete the bispolyenyl skeleton.
1
13
H- C long distance couplings are shown in Figure 1.
Acknowledgment. We thank MEC, Spain (SAF2004-
0
7131), and Xunta de Galicia for financial support. C.S. is
a recipient of a F.P.U. fellowship.
Supporting Information Available: Experimental pro-
1
13
cedures and characterization ( H NMR, C NMR, HRMS,
or EA) for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL052512U
(19) The transformation of the 1,1-dibromoalkenyl derivative into the
Figure 1. Structural assignments for stannanes 3 and 13: 1H and
corresponding alkyne was achieved by using 6 equiv of LDA as the base.
When t-BuO was used, instead, a complex mixture of products was
obtained, probably due to its higher nucleophilic character. Simpkins, S.
-
13
C NMR shifts and crucial 13C- H correlations.
1
M. E.; Kariuki, B. M.; Aric o´ , C. S.; Cox, L. R. Org. Lett. 2003, 5, 3971.
(20) (a) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet, J.
J. Org. Chem. 1997, 62, 7768. (b) Nicolaou, K. C.; Namoto, K.; Ritz e´ n,
A.; Ulven, T.; Shoji, M.; Li, J.; D’Amico, G.; Liotta, D.; French, C. T.;
Wartmann, M.; Altmann, K.-H.; Giannakakou, P. J. Am. Chem. Soc. 2001,
Last, a double Stille coupling of the bisstannane 321
with the trienyliodide 222 with use of Farina conditions or
1
23, 9313.
2 2 2
Pd(PhCN) Cl in the presence of H u¨ nig base, i-Pr NEt, ren-
(21) Different mixtures of 13 and 3 were used as starting material. See
the Supporting Information for details.
(22) AÄ lvarez, S.; AÄ lvarez, R.; de Lera, A. R. Tetrahedron: Asymmetry
2004, 15, 839.
(
18) (a) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun.
1
973, 151. (b) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107.
Org. Lett., Vol. 7, No. 25, 2005
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