Highly diastereoselective Diels-Alder reactions of Baylis-Hillman adducts

Article abstract of DOI:10.1021/ol050584f

(Chemical Equation Presented) Baylis-Hillman adducts were found to be excellent dienophiles in Diels-Alder reactions, providing essentially complete diastereocontrol (although mixtures of endo/exo isomers) with all dienes.

Full text of DOI:10.1021/ol050584f

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2555-2557
Highly Diastereoselective Diels
−Alder
Reactions of Baylis Hillman Adducts
−
Varinder K. Aggarwal,* Amaury Patin,† and Steve Tisserand
School of Chemistry, UniVersity of Bristol, Cantock’s Close, BS8 1TS Bristol, UK
V.aggarwal@bristol.ac.uk
Received March 17, 2005
ABSTRACT
Baylis−Hillman adducts were found to be excellent dienophiles in Diels−Alder reactions, providing essentially complete diastereocontrol (although
mixtures of endo/exo isomers) with all dienes.
The Baylis-Hillman reaction1,2 is a C-C bond-forming
reaction between a Michael acceptor (e.g., an acrylate) and
an electrophile (e.g., an aldehyde). Although the reaction
traditionally suffered limited substrate scope, improved
reaction conditions now allow a much broader range of
Michael acceptors and electrophiles to be employed.3 The
utility of the Baylis-Hillman reaction lies in the dense
functionality that is generated, providing handles for further
manipulation.4 Although a broad array of synthetic trans-
formations have been carried out on Baylis-Hillman adducts,
a surprising omission is that of Diels-Alder reactions. Such
reactions, especially if they could be made diastereoselective,
would enhance the synthetic utility of the Baylis-Hillman
reaction still further. We believed that through hydrogen
bonding or metal chelation between the two oxygens of the
hydroxyl and the carbonyl group, the conformation of the
dienophile (Baylis-Hillman adduct) could be controlled, thus
promoting diastereocontrol (Scheme 1).
Indeed, enones bearing R-hydroxyalkyl substituents have
been employed in highly selective Diels-Alder reactions in
the presence of Brønsted acids.5 In such a system, the diene,
approaching in the endo mode, sits directly above the
carbinol stereocenter, providing high levels of stereocontrol
(Scheme 2).
It was not clear whether Baylis-Hillman adducts could
offer similar levels of stereocontrol, as the carbinol stereo-
center is positioned remotely from the diene (Scheme 1).
On the basis of these uncertainties, we undertook a study of
Diels-Alder reaction between a series of representative
Baylis-Hillman adducts bearing groups of different steric
hindrance (phenyl, cyclohexyl, and ethyl) and both cyclic
and acyclic dienes.
The Baylis-Hillman adducts were prepared in good yield
and short reaction time using our optimized conditions, which
consist of quinuclidine (0.25 equiv) and methanol (0.75
equiv) (Scheme 3).3
† Current address: Laboratoire de Synthe`se et Me´thodologie Organiques,
Universite´ Claude Bernard Lyon 1, Bat. 308, 43, Bd. du 11 Novembre 1918,
69622 Villeurbanne Cedex, France.
(1) Baylis, A. B.; Hillman, M. E. D. Offenlegungsschrift 2155113, 1972;
U.S. Patent 3,743,669; Chem. Abstr. 1972, 77, 34174.
(2) For reviews, see: (a) Langer, P. Angew. Chem., Int. Ed. 2000, 39,
3049. (b) Ciganek, E. Org. React. 1997, 51, 201. (c) Basavaiah, D.; Rao,
P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001. (d) Drewes, S. E.; Roos,
G. H. P. Tetrahedron 1988, 44, 4653.
Scheme 1
(3) Aggarwal, V. K.; Emme, I.; Fulford. S. J. Org. Chem. 2003, 68,
692.
(4) Basavaiah, D.; Rao A. J.; Satyanarayana T. Chem ReV. 2003, 103,
811.
10.1021/ol050584f CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/28/2005

Scheme 2
Scheme 4
The Diels-Alder reaction of each of these adducts with
cyclopentadiene under thermal conditions was initially
investigated (Table 1).
Scheme 3
enantiomers 4(R) + 4(S) (or 5(R) + 5(S)), whereas if they
had been exo/endo isomers 2c/2c′ (or 3c/3c′), this would have
furnished a mixture of diastereomeric ketones 4(R) + 5(R)
(or 4(S) + 5(S)). In the event, oxidation of the two separated
compounds obtained after the DA reaction yielded two
different ketones 4(R) + 5(R) (or 4(S) + 5(S)), establishing
that either 2c/2c′ or 3c/3c′ had been formed. From X-ray
analysis of related adducts (see later), we believe that the
isomers obtained are 2c/2c′ with the exo isomer being favored
over the endo isomer, as proved by NOESY (see Supporting
Information).
Four Diels-Alder isomers can be formed in the reaction,
a diastereomeric pair of exo isomers (2c/3c, illustrated with
R ) Ph) and a diastereomeric pair of endo isomers (2c′/
3c′), but only two isomers were observed in all cases
(Scheme 4).
Attempts to improve the endo/exo ratio with Lewis or
Brønsted acids were unsuccessful.6 In fact, using EtAlCl2, a
mixture of exo:endo adducts was obtained but now with the
endo isomer predominating (28/72). Exo isomers are favored
for the methacrylates 5 (3:1)7 and actually dominate for
R-exo-methylene cyclic enones/lactones/lactams 6 (95:5)
(Scheme 5).8 The high exo selectivity is believed to result
from the fixed cisoid conformation9 of the dienophile and
subsequent minimization of the overall dipole moment of
the transition state 7.8 Interestingly, the Baylis-Hillman
dienophile is uniquely locked in a transoid conformation9
(especially in the presence of Lewis acids); thus, minimiza-
tion of the dipole cannot be an issue in this case, as the
dipoles of the diene and dienophile are perpendicular (8,
Scheme 5). Instead, we believe that the exo/endo ratio is
controlled by a balance of steric and electronic factors. The
usual secondary orbital interaction favors the endo isomer,
Table 1. Results of Diels-Alder Reaction with
Cyclopentadiene under Thermal Conditions
product
time
yield (%)
exo/endo
d.r.a
2a, R ) cyclohexyl
2b, R ) ethyl
2c, R ) phenyl
20 h
14 h
8 h
85
88
89
70/30
62/38
60/40
>98:2
>98:2
>98:2
a Diastereomeric ratio of exo (2a-c:3a-c) and endo (2a′-c′:3a′-c′)
1
isomers determined by H NMR.
We proved that the mixture of isomers obtained were exo/
endo isomers 2c and 2c′ rather than a pair of exo (or endo)
isomers 2c/3c (or 2c′/3c′) by oxidation of the alcohols
obtained to the corresponding ketones (Scheme 4). If they
had been a pair of exo (or endo) isomers 2c/3c (or 2c′/3c′),
this would have furnished a single ketone 4 as a mixture of
(6) Lewis acid (2 equiv) was used at -78 C for 3 h, warming to room
temperature for 1 h in each case: EtAlCl2 (exo/endo 28/72); ZnBr2 (exo/
endo 30/70). Using SnCl4, TiCl4, Ti(OiPr)4, or TFA, no Diels-Alder adducts
were obtained.
(7) Berson, J. A.; Hamlet, J.; Mueller, W. A. J. Am. Chem. Soc. 1962,
84, 297.
(8) Roush W. R.; Brown B. B. J. Org. Chem. 1992, 57, 3380.
(9) Cisoid or transoid conformation refers to the conformation around
the σ-bond linking the alkene and the carbonyl group in the Baylis-Hillman
dienophile.
(5) Palomo, C.; Oiarbide M.; Garcia, J. M.; Gonzalez, A.; Lecumberri,
A.; Linden, A. J. Am. Chem. Soc. 2002, 124, 10288.
2556
Org. Lett., Vol. 7, No. 13, 2005

Scheme 5. exo:endo Ratios Obtained from Diels-Alder
Reactions with Cyclopentadiene
Figure 1. X-ray structure of 9a.
but this transition state is destabilized by steric interactions
between the C7 syn hydrogen and the carbinol.10
hydrogen-bonded chelate controls the conformation of the
dieneophile to create two diastereotopic faces. The diene then
approaches the face of the dienophile opposite the R
substituent. If the diene approaches in the endo mode, it is
surprising that very high diastereocontrol is achieved with
the smallest of the Baylis-Hillman adducts (1b, R ) Et),
especially in the case of isoprene where steric interactions
differentiating the two possible approaches must be minimal
(Scheme 6).
We next investigated the Diels-Alder reaction with
isoprene, a more demanding diene due to its lower reactivity
and issues of regioselectivity. Although thermal reactions
gave a mixture of stereo- and regioisomers, we found that
use of EtAlCl2 furnished essentially a single diastereoisomer
and regioisomer in every case (Table 2).
Table 2. Results of Diels Alder Reaction with Isoprene in
Presence of Lewis Acid
Scheme 6
product
yield (%)
dr
9a, R ) cyclohexyl
9b, R ) ethyl
9c, R ) phenyl
90 (98a)
95 (96a)
52 (98a)
98:2
96:4
97:3
a Di-tert-butylpyridine (1 equiv) was added to the reaction before addition
of EtAlCl2.
In conclusion, we have found that Baylis-Hillman adducts
are excellent dienophiles in Diels-Alder reactions, providing
essentially complete diastereocontrol with all dienes. Al-
though exo/endo stereoisomers were formed with cyclopen-
tadiene, no regioisomers were obtained with isoprene. The
emerging asymmetric Baylis-Hillman reaction coupled with
these new Diels-Alder reactions rapidly builds up complex
architectures in a stereocontrolled process from very simple
and inexpensive starting materials, and this will no doubt
find applications in synthesis. Efforts in this area are currently
ongoing.
Although good yields were obtained in cases where R )
alkyl, low yields were observed in the case of R ) Ph due
to the sensitivity of the substrate toward acid-promoted
carbocation formation. To suppress this pathway, we tested
the use of hindered bases to buffer the reaction medium and
found that di-tert-butylpyridine was highly effective. Adding
this base to the reaction medium resulted in essentially
quantitative yield for not only the alkyl but also the aryl
carbinols. The base did not interfere with the progress of
the reaction presumably because it was too hindered to
complex with the Lewis acid. Thus, the base and Lewis acid
were able to fulfill their respective roles without interference
from each other.
Acknowledgment. We thank ICI for financial support.
We thank J. P. H. Charmant and A. Kantacha for X-ray
analysis and P. Lawrence for the NMR and MS analysis.
The X-ray structure of the cyclohexyl adduct 9a proved
the relative stereochemistry (Figure 1). With this information,
we propose a simple rationale for the stereochemical outcome
of the Diels-Alder reaction. In this model, a metal or
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808.
OL050584F
Org. Lett., Vol. 7, No. 13, 2005
2557