Symmetry breaking of novel C2 chiral across-ring 1,3-dienes

Full text of DOI:10.1021/jo981296i

6772
J . Org. Chem. 1998, 63, 6772-6773
Sch em e 1. C2 Sym m etr y-Br ea k in g of Dien es I by
Mea n s of a Mon ofu n ction a liza tion Str a tegy (a ) a n d by
a Sym m etr y-Dr iven Str a tegy (b)
Sym m etr y Br ea k in g of Novel C2 Ch ir a l
Acr oss-Rin g 1,3-Dien es
Pedro Noheda,*,‡ Germa´n Garc´ıa-Ruiz,‡
Mar´ıa C. Pozuelo,‡ Khalid Abbassi,‡
Eva Pascual-Alfonso,‡ J ose´ M. Alonso,§ and
J esu´s J ime´nez-Barbero‡
Departamento de S´ıntesis, Instituto de Quı´mica Orga´nica
General, CSIC, J uan de la Cierva 3, E-28006 Madrid, Spain,
and Centro de Investigacio´n Qu´ımica, J ANSSEN-CILAG SA.,
J arama s/ n, 45070 Toledo, Spain
Sch em e 2a
Received J uly 6, 1998
Enantiomerically pure C2-symmetric compounds are pow-
erful tools for chemistry.1 Nevertheless, their use as chiral
templates for the synthesis of unsymmetrical targets is only
efficient provided that no additional elements or steps are
required to improve the statistical results of the symmetry-
breaking step.2 Monofunctionalization has been the unique
strategy described for C2 symmetry breaking.3,4 Up to now,
the possibility of a C2 symmetry breaking induced by a
symmetry-driven functionalization at both homotopic sites
remains experimentally unexplored.
We herein report on this possibility by using the formation
of the unsymmetrical structures II as model. In this context,
the Diels-Alder reaction of the hitherto unknown chiral C2
across-ring 1,3-dienes I5,6 and a D∞h symmetric acetylene
(Scheme 1) has been carried out. The driving force for C2
symmetry breaking is now the conservation of the orbital
symmetry7 of a 4πs + 2πs process. In addition, dienes I have
been transformed into the structures III by an osmium-
a
Key: (i) p-NO2C6H4CO2H (YOH), PPh3, DEAD, THF, rt; (ii) LiOH
(1 N), THF/MeOH (2:1); (iii) ClCH2OEt (Cl-EOM), i-Pr2EtN, CH2Cl2,
-20 °C to rt; (iv) n-BuLi, ClSnMe3, THF, -78 °C to rt; (v) Cu(NO3)2-
(OH2)3, THF, rt; (vi) dimethylhexylsilyl chloride (Cl-THS), imidazole,
DMF, 0 °C to rt; (a) i, ii (71%, two steps); (b) iii (93%), iv (83%); (c) v
(88%); (d) i (72%); (e) vi (87%), ii (96%); (f) iii (93%), iv, v (61% two
steps); (g) vi (92%), iii (95%), iv (78%); (h) v (73%).
* To whom correspondence should be addressed. Tel.: 34-(1)-91562 2900.
Fax: 34-(1)-91564 4853. E-mail: iqonm32@pinar1.csic.es.
‡ Instituto de Qu´ımica Orga´nica General.
§ Centro de Investigacio´n Qu´ımica.
catalyzed bis-hydroxylation reaction. This process8 illus-
trates that monofunctionalization, as defined above, can also
be applied on dienes I to induce C2 symmetry breaking.
Preparation of bis-2,2′-cyclohexenol derivative 3 was first
addressed (Scheme 2). Both enantiomers of the chosen
starting precursor, 2-bromo-2-cyclohexenol (1), can be ef-
ficiently prepared,9 and they can be interconnected10 by
taking advantage of their chirality plane.11 Therefore,
structures II and III or their enantiomers could be synthe-
sized from 1 or ent-1.
The protection of the allylic alcohols of 1 and ent-1 as their
ethoxymethoxy derivatives (EOM) followed by transmeta-
lation (n-BuLi, THF, -78 °C) and subsequent treatment
with trimethyltin chloride (THF, -78 °C to rt) gave, respec-
tively, the corresponding trimethylvinylstannanes 2 and
ent-2 (77% from 1 and ent-1, respectively). The key homo-
coupling processes from each 2 and ent-2 were performed
by treatment with Cu(NO3)2(OH2)3 (THF, rt, 88%).12,13
When the same protocol was used starting from rac-1, a
mixture of rac-3 and meso-3 (1:1)14 was obtained.
(1) As chiral ligands: (a) Whitesell, J . K. Chem. Rev. 1989, 1581-1590.
(b) Kagan, H. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic
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in Organic Synthesis; J ohn Wiley and Sons: New York, 1994. (d) Ojima, I.
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templates, see: (e) Ho, T.-L. Tactics of Organic Synthesis; J ohn Wiley and
Sons: New York, 1994; pp 348-373. (f) Ho, T.-L. Symmetry. A Basis for
Synthesis Design; J ohn Wiley and Sons: New York, 1995.
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Nes, W. D.; Venkatramesh, M. In Isopentenoids and Other Natural Products;
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Synthesis 1997, 967-974. (g) Virgili, M.; Moyano, A.; Perica`s, M. A.; Riera,
A. Tetrahedron Lett. 1997, 38, 6921-6924.
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the synthesis of natural products: (a) Fringuelli, F.; Tatichi, A. Dienes in
the Diels-Alder Reaction; J ohn Wiley and Sons: New York, 1990; pp 171-
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C.; Sato, M.; Miller, N. D.; Gunzner, J . L.; Renaud, J .; Untersteller, E.
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S0022-3263(98)01296-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/05/1998

Communications
J . Org. Chem., Vol. 63, No. 20, 1998 6773
Sch em e 3a
Sch em e 4a
a
Key: (a) 4-methylmorpholine N-oxide, OsO4, acetone, H2O, rt, 77%
for 16, 63% for 17; (b) t-BuOOH, VO(acac)2, PhH, rt, 70%.
appropiate dienophile is used. Thus, reaction of 3 with (a)
1-cyanovinyl acetate followed by one-pot reduction with
excess NaBH4 or with (b) fumaronitrile yielded 14 (75%) and
15 (82%), respectively, as unique products (Scheme 3).
On the other hand, we decided to study the C2 symmetry-
breaking process induced by the osmium-catalyzed bis-
hydroxylation reaction of dienes 3 and 6. Under standard
conditions,20 (4-methylmorpholine N-oxide, OsO4, acetone,
rt), diols 16 (77%) and 17 (63%) were the only products
formed (Scheme 4). In this case, proximity, as defined by
Bertz,2a is now active. In addition, functionalization of diols
16 and 17 as allylic alcohols allows further substrate-
directable reactions. Thus, as a preliminary example, we
have found that the vanadium-catalyzed epoxidation of 16
(t-BuOOH, VO(acac)2, PhH, rt)21 yields epoxy diol 18 (70%)
(Scheme 4).
In conclusion, we have described two different strategies
for the efficient C2 symmetry breaking of enantiomerically
pure novel chiral C2 across-ring 1,3-dienes.22 The first one,
which is unprecedent, uses a symmetry-driven functional-
ization. The second one is based on the usual monofunc-
tionalization strategy. A synthetic correlation between the
unsymmetrical backbone of the morphinans and of the
bicyclic core of zaragozic acids (squalestatins) throughout
dienes I is currently underway as a further application of
these new methods.
a
Key: (a) DMAD, PhH, reflux, 86% for 10, 97% for 11; (b) (i) (E)-
NO2CHdCHSO2Ph, reflux, (ii) n-Bu3SnH, AIBN, PhMe, reflux, 70%
for 12 (two steps), 73% for 13 (two steps).
The introduction of two additional oxygenated groups to
the structure of diene 3 prompted us to prepare dienes 6
and 9 to facilitate eventual synthetic manipulations on the
cyclohexenyl moiety. Scheme 2 shows the synthesis of
diastereoisomeric dienes 6 and 9 from enantiomerically pure
diol 4.15
We subsequently focused on the C2 symmetry breaking
of dienes 3 and 6 induced during 4πs-2πs processes. We
used two different 2π partners, dimethyl acetylenedicar-
boxylate (DMAD) (D∞h symmetry) and a synthetic equivalent
of acetylene16 (Scheme 3). We have used the sequence
Diels-Alder reaction of dienes 3 and 6 with (E)-1-nitro-2-
(phenylsulfonyl)ethylene17 followed by treatment of the
crude mixture with tri-n-butyltin18 as synthetic equivalent
of acetylene. In all cases, adducts 10-13 (86, 97, 70, and
73% yield, respectively) were formed as unique products. The
most important features19 of the unsymmetrical structure
of such products are as follows: (1) a global concave-convex
shape, (2) an equatorial orientation of the substituent on
C-5 (see Scheme 3 for numbering), and (3) the disposition
over the convex surface of the axial substituent on C-4
(Scheme 3).
Remarkably, a complete control of the regiochemistry can
be coupled whith the C2 symmetry breaking when an
Ack n ow led gm en t . Financial support by DGICYT
(Grant No. PB95-0065) and DGES (Grant No. PB96-0832)
is acknowledged. G.G.-R. is grateful to the Ministerio de
Educacio´n y Cultura for a predoctoral fellowship. We are
grateful to Dr. Gregg Whited (Genencor International, Inc.)
for the generous gift of the cis-diol for 4 and to Drs. M.
Bernabe´ and B. Herrado´n for helpful discussions.
(12) (a) Ghosal, S.; Luke, G. P.; Kyler, K. S. J . Org. Chem. 1987, 52,
4296-4298. (b) Beddoes, R. L.; Cheeseright, T.; Wang, J .; Quayle, P.
Tetrahedron Lett. 1995, 36, 283-286. In our hands, the preparation of diene
3 by the procedure of Piers was unsuccessful. (c) Piers, E.; McEachern, E.
J .; Romero, M. A. Tetrahedron Lett. 1996, 37, 1173-1176.
(13) This homocoupling process only proceeds after addition of 3 equiv
of water when Cu(NO3)2 is used.
(14) (a) meso-3 and rac-3 can be readily separated by taking advantage
of the fact that they are solid and liquid, respectively, at 0 °C. For a study
on the conformational equilibrium of dienes meso-3 and rac-3, see: (b)
Poveda, A.; Noheda, P.; Pozuelo, M. C.; Garc´ıa, G.; Vicent, C.; Penade´s,
S.; J ime´nez-Barbero, J . II. Electronic NMR Poster Session.
http://bellatrix.pcl.ox.ac.uk./eps2, 1996.
(15) Boyd, D. R.; Sharma, N. D.; Dalton, H.; Clarke, D. A. J . Chem Soc.,
Chem. Commun. 1996, 45-46.
(16) Larock, R. C. Comprehensive Organic Transformations; VCH Pub-
lishers: New York, 1989; pp 271-272.
(17) (a) Ono, N.; Kamimura, A.; Kaji, A. J . Org. Chem. 1986, 51, 2139-
2142. For a discussion about the importance of degenerate operations in
organic synthesis, see: (b) Hudlicky, T. Chem. Rev. 1996, 96, 3-30. (c)
Hudlicky, T.; Natchus, M. G. in Organic Synthesis. Theory and Applications;
Hudlicky, T., Ed.; J AI Press: Greenwich, CT, 1993; pp 8, 13, and 14.
(18) Ono, N.; Kamimura, A.; Kaji, A. Tetrahedron Lett. 1986, 27, 1595-
1598.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectral data for compounds 3, meso-3, 6 and 9-18.
Molecular mechanics protocol and discussion. Table 1 showing
the steric energy values for the conformers of 10 and 12. Figures
with a view of the most stable conformers (15 pages).
J O981296I
(20) (a) Park, C. Y.; Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1991,
32, 1003-1006. (b) Xu, D.; Crispino, G. A.; Sharpless, K. B. J . Am. Chem.
Soc. 1992, 114, 7570-7571.
(21) Sharpless, K. B.; Michaelson, R. C. J . Am. Chem. Soc. 1973, 95,
6136-6137.
(22) Satisfactory spectroscopic data (1H and 13CNMR, MS, IR, optical
rotations, and elemental analysis) were obtained for all new compounds.
The structure of compounds 10-18 was established by NOESY and J
coupling analysis.
(19) Deduced from NMR data and MM3* calculations; see the Supporting
Information.