Iodocyclization reactions for the desymmetrization of cyclohexa-1,4-dienes

Article abstract of DOI:10.1021/ol701492g

Fifteen examples are presented showing that various modes of cyclization (5-endo, 5-exo, 6-endo, 6-exo, and 7-endo) can be used for the desymmetrization of cyclohexa-1,4-dienes. All take place with complete diastereocontrol and good yield.

Full text of DOI:10.1021/ol701492g

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3635-3638
Iodocyclization Reactions for the
Desymmetrization of
Cyclohexa-1,4-dienes
M. Butters,§ M. C. Elliott,*,‡ J. Hill-Cousins,‡ J. S. Paine,‡ and J. K. E. Walker‡
School of Chemistry, Cardiff UniVersity, Park Place, Cardiff, CF10 3AT, U.K., and
AstraZeneca Process R & D AVlon/Charnwood, AVlon Works, SeVern Road, Hallen,
Bristol, BS10 7ZE, U.K.
elliottmc@cardiff.ac.uk
Received June 22, 2007
ABSTRACT
Fifteen examples are presented showing that various modes of cyclization (5-endo, 5-exo, 6-endo, 6-exo, and 7-endo) can be used for the
desymmetrization of cyclohexa-1,4-dienes. All take place with complete diastereocontrol and good yield.
Desymmetrization reactions have seen considerable use in
organic synthesis.1 The distinct advantage of these reactions
is that a readily accessible symmetrical precursor can be
converted in a single step into a stereochemically complex
product, often with the formation of several stereogenic
centers. Desymmetrization reactions have been applied to
many classes of substrate, but cyclohexa-1,4-dienes are
among the more prominent and synthetically useful.2 These
compounds are readily prepared by the Birch reduction/
alkylation of aromatic compounds,3 so that the substrate has
a quaternary center which will become stereogenic upon
discrimination between the cyclohexadiene double bonds.4
Many different reactions have been used for the desymme-
trization of cyclohexa-1,4-dienes, including oxidation,5 free-
radical cyclization,6 conjugate addition,7 and other ionic
cyclizations8 and cycloadditions.9 In our own work, we have
reported selective free-radical,10 Prins,11 and anionic cycliza-
tion reactions12 onto the diastereotopic double bonds of chiral
(5) (a) Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org. Chem.
1999, 64, 9613-9624. (b) Landais, Y.; Zekri, E. Tetrahedron Lett. 2001,
42, 6547-6551.
(6) (a) Curran, D. P.; Qi, H.; DeMello, N. C.; Lin, C.-H. J. Am. Chem.
Soc. 1994, 116, 8430-9431. (b) Villar, F.; Equey, O.; Renaud, P. Org.
Lett. 2000, 2, 1061-1064. (c) Villar, F.; Kolly-Kovac, T.; Equey, O.;
Renaud, P. Chem.-Eur. J. 2003, 9, 1566-1577.
(7) (a) Fujioka, H.; Kitagaki, S.; Ohno, N.; Kitagawa, H.; Kita, Y.;
Matsumoto, K. Tetrahedron: Asymmetry 1994, 5, 333-336. (b) Wipf, P.;
Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106-11112.
(c) Bland, D.; Hart, D. J.; Lacoutiere, S. Tetrahedron 1997, 53, 8871-
8880. (d) Bland, D.; Chambournier, G.; Dragan, V.; Hart, D. J. Tetrahedron
1999, 55, 8953-8966.
§ AstraZeneca.
‡ Cardiff University.
(1) (a) Antiss, M.; Holland, J. M.; Nelson, A.; Titchmarsh, J. R. Synlett
2003, 1213-1220. (b) Spivey, A. C.; Andrews, B. I. Angew. Chem., Int.
Ed. 2001, 40, 3131-3134. (c) Willis, M. C. J. Chem. Soc., Perkin Trans.
1 1999, 1765-1784.
(2) (a) Abd Rahman, N.; Landais, Y. Curr. Org. Chem. 2002, 6, 1369-
1395. (b) Studer, A.; Schleth, F. Synlett 2005, 3033-3041.
(3) Binmore, G.; Cardellini, L.; Walton, J. C. J. Chem. Soc., Perkin Trans.
1997, 2, 757-762.
(4) Dennisova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146.
(b) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005.
(8) (a) Mori, M.; Takaki, T.; Makabe, M.; Sato, Y. Tetrahedron Lett.
2003, 44, 3797-3800. (b) Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y.
Org. Lett. 2006, 8, 4755-4758.
(9) Grainger, R. S.; Tisselli, T.; Steed, J. W. Org. Biomol. Chem. 2004,
2, 151-153.
(10) Elliott, M. C.; El Sayed, N. N. E. Tetrahedron Lett. 2005, 46, 2957-
2959.
(11) Elliott, M. C.; El Sayed, N. N. E.; Paine, J. S. Eur. J. Org. Chem.
2007, 792-803.
(12) Elliott, M. C.; El Sayed, N. N. E.; Ooi, L.-l. Tetrahedron Lett. 2007,
48, 4561-4564.
10.1021/ol701492g CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/04/2007

cyclohexadiene derivatives. Iodocyclization reactions permit
the formation of a variety of heterocyclic ring sizes under
tions (3 equivalents of iodine, sodium carbonate or sodium
hydrogen carbonate as base in acetonitrile). These reactions
give predominantly the expected 5-exo cyclization products
2, along with small amounts of the 6-endo products 3 (Table
1).
mild conditions, often with excellent stereocontrol.13
A
number of iodocyclization reactions of cyclohexa-1,4-dienes
have been reported,14,15 although the only examples which
differentiate between diastereotopic double bonds are those
utilizing chiral acetals and aminals reported recently by
Fujioka and Kita.16 The corresponding cyclization reactions
in which chirality is present in the tethering chain are
unknown, despite their considerable synthetic potential. We
can envisage the formation of a range of products via both
exo and endo cyclization modes, to give varying ring sizes
and positioning of substituents (Scheme 1).
Table 1. 5-exo and 6-endo Iodocyclization Reactions of
Compounds 1
Scheme 1. Desymmetrization of a Cyclohexa-1,4-diene
reaction
substrate
base
NaHCO3 30 min
Na2CO3 1 h
NaHCO3 1 min
time
ratio 2:3a
isolated yieldsb
1a
1b
1c
1d
1e
1f
1g
1h
1i
11:1
20:1
>99:1
30:1
17:1
19:1
10:1
19:1
10:1
1:8
2a (65.5%); 3a (5.5%)
2b (65%)
2c (89%)
2d (44%)
2e (87%)
Na2CO3
Na2CO3
30 min
30 min
NaHCO3 1 min
We now report that 5-exo, 5-endo, 6-exo, 6-endo, and
7-endo iodocyclization reactions of this type proceed with
essentially complete levels of diastereocontrol and good
levels of regiocontrol. The requisite substrates for the first
phase of the study were prepared in two steps by reaction
of the anion derived from methyl cyclohexa-2,5-diene-1-
carboxylate17 with epoxides, cyclic sulfates, acid chlorides,
or R-bromoketones, followed in each case by reduction as
described in the Supporting Information.
2f (91%)
Na2CO3
Na2CO3
Na2CO3
none
30 min
30 min
30 min
24 h
2g (59%); 3g (4%)
2h (79%); 3h (3%)
2i (62%)
1i
3i (57%)
a
Ratios of products were determined by integration of two or more
peaks in the H NMR spectra of crude reaction mixtures. In most cases,
the 6-endo product was not isolated in pure form.
1
b
With a stereogenic center adjacent to the oxygen atom
(1a-1g), the cyclization reactions all proceeded smoothly
and in high yield under essentially standard reaction condi-
Both of these product types are formed by anti-cyclization
onto only one of the diastereotopic double bonds, and so
the reactions are completely diastereoselective. The regio-
and stereochemistry of the products were determined by
extensive use of NMR (COSY, NOESY, HMBC, HSQC)
along with single-crystal X-ray diffraction on compounds
2c and 2g.18 These reactions are consistent with an envelope
transition state, in which the substituent in 1a-1g is as far
from the cyclohexadiene ring as possible. This is most easily
seen in the Chem3D representation of the cyclizing confor-
mations of iodoniranium ions 4 and 5 (Figure 1). In the latter,
the methyl group is close to the cyclohexadiene ring. It is
unlikely that coordination of iodine to only one of the double
bonds is occurring. Therefore, as with other diastereoselective
iodocyclization reactions, rapid reversible iodonium ion
(13) (a) Knight, D. W. Progress in Heterocyclic Chemistry; Gribble, G.
W., Gilchrist, T. L., Eds.; Pergamon: Amsterdam, 2002; Vol. 14, pp 19-
51. (b) da Silva, F. M.; Junior, J. J.; de Mattos, M. C. S. Curr. Org. Synth.
2005, 2, 393-414. (c) Togo, H.; Iida, S. Synlett 2006, 2159-2175. (d)
Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321-3408.
(14) (a) Chuang, C.-P.; Gallucci, J. C.; Hart, D. J.; Hoffman, C. J. Org.
Chem. 1988, 53, 3218-3226. (b) Chuang, C.-P.; Gallucci, J. C.; Hart, D.
J. J. Org. Chem. 1988, 53, 3210-3218. (c) Chuang, C.-P.; Hart, D. J. J.
Org. Chem. 1983, 48, 1782-1784.
(15) Schultz has reported the iodolactonization of cyclohexenes derived
from cyclohexadienes. For representative work, see: (a) Schultz, A. G.;
Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118, 6210-
6219. (b) Khim, S.-K.; Schultz, A. G. J. Org. Chem. 2004, 69, 7734-
7736.
(16) (a) Fujioka, H.; Kotoku, N.; Sawama, Y.; Nagatomi, Y.; Kita, Y.
Tetrahedron Lett. 2002, 43, 4825-4828. (b) Fujioka, H.; Kotoku, N.;
Sawama, Y.; Kitagawa, H.; Ohba, Y.; Wang, T.-L.; Nagatomi, Y.; Kita, Y.
Chem. Pharm. Bull. 2005, 53, 952-957. (c) Fujioka, H.; Murai, K.; Ohba,
Y.; Hirose, H.; Kita, Y. Chem. Commun. 2006, 832-834.
(17) Thominiaux, C.; Chiaroni, A.; Desmaele, D. Tetrahedron Lett. 2002,
43, 4107-4110.
(18) CCDC Nos. 646880 and 646881 contain the crystallographic data
for compounds 2c and 2g, respectively. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/data_request/cif.
3636
Org. Lett., Vol. 9, No. 18, 2007

Scheme 2. Iodocyclization of Compound 6
Figure 1. Favored (4) and disfavored (5) 5-exo cyclizations of
the iodoniranium ions derived from substrate 1a.
formation19 is followed by preferential cyclization via one
of the two possible transition states.
of the primary alcohol. Although we have no direct evidence,
we presume that hydrogen bonding of the chiral secondary
alcohol to the iodonium ion is responsible for the stereo-
control in this instance. The different amounts of cyclization
via primary and secondary alcohols between the two
compounds 9a and 9b are difficult to rationalize in terms of
Moving the stereogenic center one atom further along the
tether (substrate 1h), the reaction is also completely diaste-
reoselective and highly regioselective. Substrate 1i, with a
fused cyclohexane ring, is expected to lead to a particularly
rigid transition state and indeed gives a completely diaste-
reoselective and highly regioselective cyclization reaction.
In this case, leaving the reaction longer leads to an isomer-
ization reaction to compound 3i. With the omission of base,
compound 3i becomes the major product. Although complete
reversal of the reaction pathway is possible,20 loss of iodine
to form an oxiranium ion, followed by a thermodynamically
favored ring opening to give the tetrahydropyran ring, is also
conceivable.21 Some isomerization from 5-exo to 6-endo was
observed with the other substrates, but this was only to the
extent of ca. 2% after 24 h and so is not presently
synthetically useful. As shown in Table 1, with the exception
of compounds 3a, 3g, 3h, and 3i, the 6-endo products were
not isolated after chromatographic purification of the crude
reaction mixtures.
Scheme 3. Iodocyclization of Compounds 9a and 9b
The competition between 6-exo and 7-endo cyclization was
also investigated. Although the regioselectivity was, as
expected, somewhat lower, the diastereocontrol was, once
again, complete (Scheme 2).
Finally, 5-endo cyclization reactions were investigated with
substrates 9a and 9b (Scheme 3), in which either of the two
hydroxyl groups could attack. In the case of substrate 9a, a
very useful 7:1 regioselectivity favoring attack of the
secondary alcohol was observed, whereas with compound
9b a more modest 1.25:1 regioselectivity was observed.
However, in all cases, the products were formed as single
stereoisomers. Although we might have expected cyclization
of the secondary alcohol to proceed with some stereoselec-
tivity, we had not expected high selectivity from cyclization
nucleophilicity parameters22 and must be tentatively ascribed
to conformational effects, although more work is required
to understand the precise reasons for the difference.23
Compounds 10a and 11a proved difficult to separate, so that
only an analytical sample of each of the pure compounds
was produced. As with iodolactonization onto cyclohexa-
1,4-dienes,24 we see only the 5-endo product and none of
the 4-exo cyclization.25
The ease of preparation of hydroxymethyl-substituted
cyclohexadienes stems from the use of methyl cyclohexa-
(19) (a) Cui, X.-L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653-5658.
(b) Neverov, A. A.; Brown, R. S. J. Org. Chem. 1996, 61, 962-968. (c)
Parrilli, M.; Barone, G.; Adinolfi, M.; Mangoni, L. Gazz. Chim. Ital. 1974,
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(20) Nichols, C. J. Abstracts of Papers, 221st ACS National Meeting,
San Diego, CA, United States, April 1-5, 2001; ORGN-549.
(21) Matsuo, G.; Hori, N.; Matsukura, M.; Nakata, T. Tetrahedron Lett.
2000, 41, 7677-7680.
(22) Phan, T. B.; Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2006,
45, 3869-3874.
(23) This situation may be more complicated if the rate of I+ transfer
between the faces of the cyclohexa-1,4-diene ring (presumably not a
unimolecular process) are comparable with the rates of ring closure.
Org. Lett., Vol. 9, No. 18, 2007
3637

iodocyclization, and substrates 12a-c lacking this group
were prepared by deprotonation26 of cyclohexa-1,4-diene
followed by reaction with an epoxide. These compounds all
undergo a completely diastereoselective iodocyclization
reaction to give products 13a-c as shown in Scheme 4. In
this case, none of the corresponding 6-endo cyclization
product was observed.
Scheme 4. Iodocyclization of Compounds 12a-c
In summary, the iodocyclization reactions of cyclohexa-
1,4-diene derivatives containing a pendant hydroxy group
on a chiral tether have been investigated. Essentially
complete levels of diastereocontrol were obtained in 5-endo,
5-exo, 6-exo, 6-endo, and 7-endo cyclization modes.
Acknowledgment. We are grateful to EPSRC, Astra-
Zeneca, and Cardiff University for financial support of this
work. We would also like to thank Dr. A. Stasch (Cardiff
University) for the X-ray crystallographic study and Professor
Y. Landais (Bordeaux) for helpful discussions. We would
also like to thank Robert Jenkins and Robin Hicks (Cardiff
University) and Stephen Baldwin (AstraZeneca) for mass
spectrometric data.
Supporting Information Available: Full experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2,5-diene-1-carboxylate as a starting material and offers
considerable opportunities for further elaboration of the
products. However, this is not required for successful
OL701492G
(24) Barclay, G. L.; Quiclet-Sire, B.; Sanchez-Jiminez, G.; Zard, S. Z.
Org. Biomol. Chem. 2005, 3, 823-835.
(25) de la Torre, M. C.; Maggio, A.; Rodr´ıguez, B. Tetrahedron 2000,
56, 8007-8017.
(26) (a) Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2, 621-623.
(b) Landais, Y.; Zekri, E. Eur. J. Org. Chem. 2002, 4037-4053.
3638
Org. Lett., Vol. 9, No. 18, 2007