Functionalization via radical cyclization of cyclohexenediol derivatives bound to polystyrene

Article abstract of DOI:10.1055/s-1999-2759

Radical cyclization reactions involving precursors derived from cyclohexadiene diols were investigated, both, in solution and on the solid phase. A straightforward sequence was established in solution to obtain bicyclic compounds with potential for diversity. Optimized reaction procedures were applied to solid phase synthesis.

Full text of DOI:10.1055/s-1999-2759

LETTER
1121
Functionalization via Radical Cyclization of Cyclohexenediol Derivatives
Bound to Polystyrene
Sabine Berteina, Alain De Mesmaeker, Sebastian Wendeborn*
Novartis AG, Basel, Switzerland
Fax +41-61-697-8529; E-mail: sebastian.wendeborn@cp.novartis.com
Received 26 April 1999
Abstract: Radical cyclization reactions involving precursors de-
rived from cyclohexadiene diols were investigated, both, in solution
and on the solid phase. A straightforward sequence was established
in solution to obtain bicyclic compounds with potential for diversi-
ty. Optimized reaction procedures were applied to solid phase syn-
thesis.
Key words: Solid phase synthesis, epoxide opening, radical cy-
clization
The emergence of combinatorial chemistry stimulated in-
tensive efforts in the application of reactions broadly used
in solution to the solid phase synthesis.1 While a number
of reaction conditions have been widely applied to the sol-
id support, examples for radical reactions on solid phase
are still limited to only a few.2 Recently, we demonstrated
that (1S,2S)-3-halocyclohexa-3,5-diene-1,2-diols, which
are readily available through fermentation of the corre-
sponding halobenzenes, can be used as valuable and ver-
satile building blocks in solid phase chemistry.3 In this
paper we describe radical cyclization reactions with this
substrate.
openings with anilines were only accomplished through
this lewis acid catalysis),5 gave a mixture of the chloride
containing epimers 9a,b as well as the over reduced com-
pound 9c and some non-cyclized, reduced compound 10
(Scheme 3). Only the b- derivative 9a and 10 could be iso-
lated in pure
The general strategy of this approach is outlined in
Scheme 1. Epoxide opening of 1 with a nucleophile carry-
ing vinylic or arylic iodide or bromide should give struc-
tures of type 2, which should be prone to radical
cyclization upon homolytic cleavage of the halogen-car-
bon bond to give cis fused bicyclic compounds 3.
This hypothesis was first tested with compound 5, ob-
tained in 77% yield from epoxide 4,4 which cyclized
readily when treated with one equivalent of nBu3SnH and
AIBN in refluxing benzene to give 6 as a mixture of dia-
steromers (Scheme 2) in 70% yield. Treatment of 6 with
excess of nBu3SnH resulted in reduction of the chloride
to 7.
form, 9b and 9c were inseparable by flash chromatogra-
phy and isolated together in 53% combined yield in a ratio
1
of 1.79:1 (determined by H-NMR). Epoxide 4 was also
In analogy, compound 8, derived from Lewis acid assisted
epoxide opening of 4 with 2-iodoaniline (clean epoxide
reacted with vinylhalides 11 and 12 in 50 mM LiClO4/2,6-
lutidine to give compounds 13 and 14 in excellent yields
Synlett 1999, No. 07, 1121–1123 ISSN 0936-5214 © Thieme Stuttgart · New York

1122
S. Berteina et al.
LETTER
(Scheme 4). When treated with a slight excess of clization of 22, which was synthesized from 18, gave
nBu3SnH and catalytic AIBN both, the vinyl iodide and similar results: upon acylation of the crude reaction prod-
the vinyl bromide, cyclized readily to compound 15 as a ucts compounds 23a,b as well as substantial amounts of
mixture of diastereomers. Acetylene 16 reacted through reduced compound 24 were isolated.
radical addition of nBu3SnH followed by cyclization to
give a mixture of vinylstannanes 17a,b,c in 48% yield
(Scheme 5). In the crude product, 17a,b,c were present in
a ratio of 72:8:20. Upon flash chromatography, only β-
isomer 17a could be isolated in pure form, while 17b,c
were obtained as a mixture in combined 15% yield.
We were not able to achieve complete reduction of com-
pounds 20a through additional nBu3SnH/AIBN during the
cyclization reaction without increasing the yield of undes-
ired 21. We, therefore, decided to improve our synthetic
strategy by removing the vinylic halogen present in the
starting material. Product mixtures derived from incom-
plete reduction during the cyclization step could then be
avoided.
We addressed this problem by removing the vinylic halo-
gen present in the starting material. At the same time we
made the sequence more convergent, which would allow
us to readily introduce diversity. This sequence was first
established in solution. Treatment of 26 with tBuLi fol-
lowed by an acidic quench gave compound 27 (Scheme
7).7 A number of different conditions were examined to
effect reductive alkylation with vinyl iodide 28. However,
only the use of NaBH(OAc)3 in CH2Cl2 allowed for isola-
tion of 11% product. We reasoned that less hindered bro-
mides would react much more readily in the amine
alkylation sequence. Indeed, when unsaturated aldehydes
30-328 were reacted with 27, better yields of the corre-
sponding alkylated products were obtained (37%-54%).
The resulting product 33-35 were cyclized with nBu3SnH/
AIBN to give the corresponding bicyclic systems. Due to
the rather modest yield of this sequence (Scheme 7) we
did not undertake the preparation of a library of com-
pounds. In conclusion, we have demonstrated that cyclo-
hexadienes can be efficiently derivatized to highly
functionalized polycycles in a reaction sequence involv-
The above examples demonstrated the synthesis of highly
functionalized bicyclic systems from readily available
starting materials through radical cyclizations in solution.
Therefore, we repeated this strategy on a solid phase
bound substrate. As indicated in Scheme 6, the reaction
proceeded well on resin bound substrates, even though
larger amounts of reduced, non-cyclized products were
obtained. Solid phase bound epoxide 183a reacted with 2-
iodophenol in the presence of Schwesinger base at
100 °C.6 The resulting intermediate 19 was treated in nine
portions with AIBN and nBu3SnH. Upon acidic cleavage
from the resin a mixture of 20a,b (71%) was obtained to-
gether with non cyclized compound 21 (20%). The cy-
Synlett 1999, No. 07, 1121–1123 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Functionalization of Cyclohexenediol Derivatives Bound to Polystyrene
1123
(3) a) Wendeborn, S.; Brill, W. K.-D.; De Mesmaeker, A. Synlett
1998, 865. b) for a recent review of cyclohexadiene-cis-diol
chemistry see: Hudlicky, T.; Thrope, A. J. Chem. Commun.
1996, 1993. c) Carless, H. A. J. Tetrahedron Asymmetry 1992,
3, 795.
ing epoxidation, epoxide opening with suitable nucleo-
philes, followed by radical cyclizations. Several examples
demonstrated the feasibility of this approach for solid
phase chemistry.9
(4) Hudlicky, T.; Luna, H.; Olivo, H. F.; Anderson, C.; Nugent, T.
C.; Price, J. D. J. Chem. Soc., Perkin Trans 1 1991, 2907.
(5) Brill, W. K.-D.; De Mesmaeker, A.; Wendeborn, S. Synlett
1998, 1085.
(6) Phosphazene base P(4)-tBu, Schwesinger, R.; Schlemper, H.
Angew. Chem. 1987, 99, 1212.
(7) Pitzer, K.; Hudlicky, T. Synlett 1995, 803.
(8) Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem.
1982, 47, 5088.
(9) Representative protocols for reactions on the solid phase:
18→19:2-Iodophenol (428 mg, 1.94 mmol) was dissolved in
dioxane (5 ml) and cooled to 0 °C. 2-Tert-butylimino-2-
diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorin
(521 µl, 1.94 mmol) was added. The resulting phenolate was
added to as suspension of 18 (600 mg, 0.324 mmol) in dioxane
(10 ml) and the mixture was heated to reflux for 90 h. The
reaction was cooled to room temperature, the solid phase was
filtered and washed with 5 ml each of dioxane (6 x), H2O (6
x), H2O:EtOH (1:1, 6 x), EtOH (6 x) dioxane (6 x), MeOH,
CH2Cl2 (alternating, 6 x), and Et2O (3 x). In order to determine
the yield and purity of the product, a fraction (67 mg) of the
resin was treated with CF3COOH : H2O : CH2Cl2 (5:1:94) for
1.5 h, filtered, and the resin was washed with THF and MeOH.
The combined organic phases were concentrated and twice
coevaporated with toluene. The crude product (quantitative
yield) was analyzed by 1H NMR(400 MHz) and shown to be
>80% pure.
19→20, 21:19 (205 mg, 0.1 mmol) was suspended in degassed
benzene and heated to reflux under an argon atmosphere.
nBu3SnH (200 µl of the 0.25 M solution in degassed benzene,
0.05 mmol) and AIBN (100 µl of the 0.1 M solution in
degassed benzene, 0.01 mmol) were added. 8 Additional such
additions of nBu3SnH and AIBN were made in 0.5 h intervals.
At this point (after 4.5 h) an excess of nBu3SnH (4 ml of a 0.25
M solution in benzene) and AIBN (0.5 ml of a 0.1 M solution
in benzene) were added and the reaction mixture was refluxed
for 12 h. The mixture was cooled to room temperature, the
solid phase was filtered and washed with 4 ml each of dioxane
(6 x), toluene (6 x), hexane (6 x), CH2Cl2 (6 x), EtOH (6 x),
dioxane (6 x), CH2Cl2, MeOH (alternating, 3 x), CH2Cl2 (1 x)
and Et2O (3 x). The resin was dried under high vacuum (to
give 196 mg) and treated with CF3COOH : H2O : CH2Cl2
(5:1:94, 3.3 ml) for 1.5h at room temperature. The resin was
filtered and washed with THF (3 ml) and MeOH (3 ml). The
combined organic layers were concentrated and dried under
high vacuum to give 19.8 mg of the crude product mixture
20a,b, 21.7 Selected 1H NMRdata for 20b:1H NMR (400
MHz, CD3OD): δ = 7.06 (d, 1H, arom); 6.94 (d, 1H, arom);
6.72 (t, 1H, arom); 6.63 (d, 1H, arom); 4.39 (dd, 1H, CHOH);
3.93 (m07, 1H, CHAr), 3.86 (dd, 1H, CHOH); 3.45 (m, 2H,
CHOH and CHOAr); 2,06 (m, 2H, CH2); 1.88 (m, 2H, CH2).
References and Notes
(1) a) Balkenhohl, F.;v.d. Bussche-Hünnefeld,C.; Lansky, A.;
Zechel, C. Angew. Chem. Int. Ed. Engl. 1996, 35, 2288.
b) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
Tetrahedron 1996, 52, 4527. c) Gallop, M. A.; Barrett, R. W.;
Dower, W. J.; Foder, S. P. A.; Gordon, E. M. J. Med. Chem.
1994, 37, 1233. d) Gordon, E. M.; Barrett, R. W.; Dower, W.
J; Foder, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37,
1385.
(2) a) Berteina, S.; De Mesmaeker, A. Tetrahedron Lett. 1998, 39,
5759. b) Berteina, S.; Wendeborn, S.; De Mesmaeker, A.
Synlett 1998, 1231. c) Routledge, A.; Abell, C.;
Balasubramanian, S. Synlett 1997, 61. d) Du, X.; Amstrong,
R. W. J. Org. Chem. 1997, 62, 5678.
Article Identifier:
1437-2096,E;1999,0,07,1121,1123,ftx,en;L02999ST.pdf
Synlett 1999, No. 07, 1121–1123 ISSN 0936-5214 © Thieme Stuttgart · New York