Diastereoselective Diels-Alder reactions of a novel cyclopropenyl- containing chiral auxiliary

Article abstract of DOI:10.1021/ol702280q

(Chemical Equation Presented) A novel cyclopropenyl-containing 1,3-spiroaminoalcohol auxiliary has been used in a variety of asymmetric Diels-Alder reactions providing endo adducts with diastereomeric ratios ranging from 2:1 up to >99:1. In addition, unexpected regiochemistry was observed for a Diels-Alder reaction between cyclopropenyl dienophile and 4-vinyl-1,2-dihydronapthalene.

Full text of DOI:10.1021/ol702280q

ORGANIC
LETTERS
2
007
Vol. 9, No. 25
167-5170
Diastereoselective Diels
Reactions of a Novel
−Alder
5
Cyclopropenyl-Containing Chiral
Auxiliary
Jeff R. Henderson, Masood Parvez, and Brian A. Keay*
Department of Chemistry, UniVersity of Calgary, Calgary, AB, T2N 1N4, Canada
keay@ucalgary.ca
Received September 18, 2007
ABSTRACT
A novel cyclopropenyl-containing 1,3-spiroaminoalcohol auxiliary has been used in a variety of asymmetric Diels−Alder reactions providing
endo adducts with diastereomeric ratios ranging from 2:1 up to >99:1. In addition, unexpected regiochemistry was observed for a Diels
−Alder
reaction between cyclopropenyl dienophile and 4-vinyl-1,2-dihydronapthalene.
The amino alcohol family of chiral auxiliaries has exhibited
1
great success within many reactions. Although 1,2-amino
Scheme 1. Synthesis of a Novel 1,3-Spiro-amino Alcohol
alcohols are most commonly used because of their ready
availability, 1,3-amino alcohols are beginning to be used
more widely in asymmetric transformations. In 2003 we
Auxiliary
2
reported the synthesis and application of (1R,5R,6R)-6-(2,2-
dimethylpropionyl-amino)spiro[4.4]non-1-yl ester (3) in asym-
metric Diels-Alder reactions with a variety of symmetrical
3
and unsymmetrical dienes. Either enantiomer of 2 was
readily available via a short, highly efficient synthesis starting
3
from δ-valerolactone (1) (Scheme 1). Dienophile 3, made
Owing to the success of auxiliary 3 in Diels-Alder
reactions, it was desirable to change the dienophile compo-
nent in 3 to broaden the scope and explore its limitations.
gem-Dimethyl substituents are prevalent within natural
by treating 2 with acryloyl chloride, provided Diels-Alder
products with very high endo selectivity (>99:1) and high
diastereoselectivity (>98% de). The auxiliary was easily
removed through saponification with sodium hydroxide to
afford the corresponding Diels-Alder adducts with high %
ee’s.
4
products but are often troublesome to install. One method
for the introduction of gem-dimethyl groups involves a
Diels-Alder reaction with â,â-dimethyl substituted dieno-
philes but this reaction generally results in poor reactivity
(
(
(
1) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835.
2) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. ReV. 2007, 107, 767.
3) Lait, S. M.; Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry 2003,
(4) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238.
1
4, 749.
1
0.1021/ol702280q CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/13/2007

5
7
and selectivity. An alternative to this strategy involves using
presence of triethylamine to afford a mixed anhydride that
cyclopropylidene-containing dienophile 6 (Scheme 2). A
was reacted with spirocyclic alcohol 2 to afford 10 in 80%
yield.
With 10 in hand, a variety of Lewis acids were screened
by NMR spectroscopy to determine how many equiv are
required to activate 10, the compatibility of the Lewis acids
with 10, and under what reaction conditions 10 would react
with cyclopentadiene. It is well-known that cyclopropenyl
systems are very good Michael acceptors, and we wished to
Scheme 2
1
1
minimize potential side reactions.
3
As with our previously reported system (Scheme 1, 3), 2
equiv of Lewis acid were necessary for complete coordina-
tion to the dienophile. The first equivalent of Lewis acid
coordinated to the more basic amide moiety (determined by
Diels-Alder reaction with 6 should provide a spiro[5.2]-
octene system 5 in which the cyclopropyl ring could be
hydrogenated to provide cyclohexanes 4 containing gem-
dimethyl groups.6
1
a noteable downfield shift of Hb and Hc in the H NMR
spectrum of 10) while the second equivalent activated the
When we started working on this project in 2004, previous
reports with dienophiles such as 6 had been limited to their
use in thermal Diels-Alder and 1,3-dipolar cycloaddition
reactions but there were few reports in which the alcohol
cyclopropenyl ester (noteable downfield shift of Ha in the
H NMR spectrum of 10). Aside from BI , none of the other
3
1
Lewis acids gave halide-incorporated Michael addition
products from 10 at -78 °C in CD Cl (see 12 Scheme 4).
2
2
7
moiety in ester 6 had been replaced with a chiral auxiliary.
More recently, Kuethe et al. have reported the asymmetric
Diels-Alder reaction between â,â-cyclopropyl-R,â-unsatur-
ated N-acyloxazolidinones and cyclopentadiene. Since they
Scheme 4. Major Byproduct Pathways
6
only reported a Diels-Alder reaction with cyclopentadiene,
we decided to use spiro-amido-alcohol 2 (Scheme 1) in which
the dienophile contains a cyclopropylidene unit and expand
the scope of the Diels-Alder reaction by employing a range
of symmetrical and unsymmetrical dienes.
Compound 10 was prepared in four steps from ethyl
2-chloropropionate (7, Scheme 3). Treatment of 7 with
Scheme 3
For completeness, Child’s Lewis acidity measurements12
were measured and are summarized in Table 1 with the
entries organized by decreasing Lewis acid strength. Of all
the Lewis acids tried, BCl
3
gave both the best conversion
(87%) to adduct 11 and dr (6.7:1) for the endo-isomers.
2
Although MeAlCl gave a higher dr (7.1:1), the conversion
to product (10%) was very low owing to polymerization of
the cyclopentadiene.
The high conversion and promising dr with BCl
us to further investigate its use in Diels-Alder reactions of
0 with various dienes. Lowering the reaction temperature
to -100 °C for the Diels-Alder reaction with cyclopenta-
diene resulted in a higher dr of 7.1:1 (Table 2, entry 1). In
addition, the Diels-Alder reaction occurred with a variety
of other dienes. Reaction of 10 with furan proceeded at
3
prompted
1
sodium metal provided hemiacetal 8,8,9 which was subjected
to an acid-catalyzed Wittig reaction giving cyclopropylidene
ester 6. Mild saponification of 6 with lithium hydroxide in
aqueous THF gave acid 9 in 85% yield.10 Cyclopropenyl
acid 9 was reacted with trimethylacetyl chloride in the
-100 °C but exhibited a 9:1 endo:exo ratio with an 11:1 dr
for the endo isomers; only one exo isomer was observed by
H NMR spectroscopy. Unfortunately, this reaction only gave
(
5) Muroi, H.; Kubo, I. Biosci. Biotechnol. Biochem. 1994, 10, 1925.
1
(6) Kuethe, J. T.; Zhao, D.; Humphrey, G. R.; Journet, M.; McKeown,
A. E. J. Org. Chem. 2006, 71, 2192.
(
(
(
(
7) Spitzner, D.; Swoboda, H. Tetrahedron Lett. 1986, 27, 1281.
8) Ruehlmann, K.; Synthesis 1971, 236.
9) The silylhemiacetal of 8 is now commercially available from Aldrich.
10) In our hands, attempts to make acid 9 via another synthetic route
(11) (a) Seyed-Mahdavi, F.; Teichmann, S.; Meijere, A. Tetrahedron Lett.
1986, 27, 6185. (b) Wesjohann, L.; Kress, N.; Yu, D.; Meijere, A.; Chem.
Ber. 1992, 125, 867-882. (c) Belov, V. N.; Sauchenko, A. I.; Sokolov, V.
V.; Straub, A.; Meijere, A. Eur. J. Org. Chem. 2003, 3, 551-561.
(12) Childs, R. F.; Mulholland, D. L.; Nixon, A. Can. J. Chem. 1982,
60, 801.
resulted in low yields and was subsequently abandoned. Limbach, M.; Dalai,
S.; de Meijere, A. AdV. Synth. Catal. 2004, 346, 760.
5168
Org. Lett., Vol. 9, No. 25, 2007

at this temperature four isomers were observed (Table 2,
entry 3). The reactions with 2,3-dimethyl-1,3-butadiene, 1,3-
cyclohexadiene, and anthracene with BCl (not shown in
3
Table 1. Diels-Alder Reaction of 10 with Cyclopentadiene
Using a Variety of Lewis Acids
Table 2) were quite sluggish and lower yielding when
compared with cyclopentadiene owing to the formation
1
4
of 12 and 13 (Scheme 4) at temperatures at or above
23 °C. These side reactions could be minimized at
temperatures below -23 °C and by using newly purchased
bottles of BCl , however the reactions took over 2 days to
-
3
complete. Because of these limitations, aluminum-based
Lewis acids were investigated further in this Diels-Alder
reaction with 10.
a
conversion (%)c
drc
Lewis acid
∆δ of Ha (ppm)
BI3
BBr3
BCl3
BF3‚OEt2
AlCl3
MeAlCl2
EtAlCl2
AlMe3
Me2AlCl
Et2AlCl
1.5
1.4
1.2
0b
50
100
87
6.7:1
5.3:1
6.7:1
2 2
Generally, the weaker Lewis acid EtAlCl (and Me AlCl)
did not promote Diels-Alder reactions with dienes that were
less reactive than cyclopentadiene. The reaction with isoprene
at 0 °C gave a mixture of four isomers (entry 4, no reaction
occurred below 0 °C), and no reaction was observed with
0.8
100
10
90
0
50
10
1.5:1
7.1:1
2.4:1
0.78
0.75
0.60
0.55
0.5
2
5
,3-dimethyl-1,3-butadiene and 1,3-cyclohexadiene (entries
and 6) at the same temperature. Fortunately, switching to
5:1
5.3:1
MeAlCl
MeAlCl
2
provided some useful results. Although the use of
with 10 and cyclopentadiene led to polymerization
a
∆
δ values were obtained from 400 MHz NMR spectra at -78 °C in
2
b
CD2Cl2. BF3‚OEt2 only coordinated with the amide moiety even when
c
of the diene its use with other dienes provided much higher
yields of products and better diastereomeric ratios. The
used in excess. Conversion and diastereomeric ratios were determined
using 300 MHz NMR and GC-MS analysis.
15
reaction with isoprene, 2,3-dimethyl-1,4-butadiene, and 1,3-
cyclohexadiene gave yields ranging from 20 to 43 after 18
h with drs ranging from 15:1 (for isoprene) to >99:1 (for
1,3-cyclohexadiene) (entries 7-10). The yield with 2,3-
dimethyl-1,4-butadiene was significantly improved with
longer time leading to to formation of 16 in 73% yield after
5
0% conversion due to the adducts preferentially complexing
1
3
to the Lewis acid.
The reaction with other dienes were more problematic.
No reaction was observed below -23 °C with isoprene, and
Table 2. Diels-Alder Reaction of 10 with a Variety of Dienes
entry
Lewis acid
temp (°C)
time (hours)
diene
cyclopentadiene
product
% yielda
drb
1
2
BCl3
BCl3
-100
-100
8
8
11
14
88 [95]
52 [91]
7.1:1
9 endo (11:1):
furan
1
exo (1:0)
3
4
5
6
7
8
9
0
1
2
3
BCl3
-23
0
9
18
18
18
18
18
48
18
18
18
24
isoprene
isoprene
complex mixturec
complex mixture
54 [90]
30 [80]
d
EtAlCl2
EtAlCl2
EtAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
0
0
2,3-dimethyl-1,3-butadiene
1,3-cyclohexadiene
isoprene
2,3-dimethyl-1,3-butadiene
2,3-dimethyl-1,3-butadiene
1,3-cyclohexadiene
anthracene
no reaction
no reaction
15
16
16
17
no reaction
18
19
-23
-23
-23
-23
-23
0
40 [85]
43 [81]
73
15:1
25:1
>99:1
>99:1
1
1
1
1
20 [70]
anthracene
4-vinyl-1,2-dihydronapthalene
80 [99]
59 [89]
>99:1
10:1
e
-23
a
Square brackets indicate the yield based on recovered starting material. b Diastereomeric ratios determined by integration of 300 MHz NMR spectra
c
d
and/or by GC analysis. All possible isomers (stereo and regio) were observed by GC-MS in a 15:9:3.7:1 ratio. All possible isomers (stereo and regio)
e
were observed by GC-MS in a 16.7:1.3:1.3:1 ratio. 4-Vinyl-1,2-dihydronapthalene was prepared from the reaction of vinylmagnesium bromide with the
corresponding ketone followed by elimination of the resulting alcohol.
Org. Lett., Vol. 9, No. 25, 2007
5169

4
8 h (entry 9). Finally there was no reaction with anthracene
stereoelectronic arguments. Previous work with 3 and diene
20 gave the endo product with the expected regiochemistry3
while it appears that the introduction of the cyclopropenyl
group in 10 results in a reversal of this regiochemistry
(Scheme 5). Molecular modeling of this reaction indicated
and 10 at -23 °C but warming the mixture to 0 °C resulted
in an 79% yield and 99:1 dr of adduct 18.
The stereochemistry of the products obtained from sym-
metrical dienes were verified through X-ray crystallography.
In all cases, (+)-10 lead to exclusively endo adducts with a
R configuration adjacent to the ester moiety while (-)-10
resulted in Diels-Alder adducts with a S configuration at
the same stereogenic center.
Scheme 5. Unexpected Product from Diene 15
In addition to the reaction with isoprene, the stereo- and
regioselectivity for the reaction of 10 with 4-vinyl-1,2-
dihydronaphthalene was investigated (entry 13). Treatment
of 10 and 4-vinyl-1,2-dihydronaphthalene (20) with 2 equiv
MeAlCl at -23 °C provided a 10:1 mixture of products.
2
The major isomer crystallized and its structure was confirmed
as 19 by obtaining an X-ray crystal structure (Figure 1);
an increased steric interaction between one of the cyclopro-
penyl -CH groups and the allylic hydrogen atoms on the
2
diene (eq 2, Scheme 5), which was absent in the opposite
approach of the dienophile (eq 1, Scheme 5). The adducts
in Table 2 could be cleaved from chiral auxiliary as
3
previously described and the auxilary 2 reused.
In summary, a novel chiral cyclopropenyl containing 1,3-
spiro-amino alcohol compound 10 has been synthesized and
applied to the Diels-Alder reaction with a variety of dienes.
A unique reversal of regiochemistry was observed for the
Diels-Alder reaction of 10 with 4-vinyl-1,2-dihydronaptha-
lene. Studies are ongoing to enhance the scope and limita-
tions of these reactions.
Figure 1. ORTEP of Diels-Alder adduct with 4-vinyl-1,2-
dihydronapthalene.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC) and the University
of Calgary for financial support. Special thanks to A. Zuccolo
and C.C. Ling at the University of Calgary for use of their
CB-60 cryobath.
compound 21 was not detected in the reaction mixture.
Interestingly, this Diels-Alder reaction led to an unexpected
reversal in the expected regiochemistry on the basis of
Supporting Information Available: Experimental pro-
cedures for preparation of 10 and subsequent Diels-Alder
reactions. X-ray crystal structures and data for 11, 16, 18,
and 19. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
13) (a) Hunt, I. R.; Rauk, A.; Keay, B. A. J. Org. Chem. 1996, 61,
51-757. (b) Hunt, I. R.; Rogers, C.; Woo, S.; Rauk, A.; Keay, B. A. J.
Am. Chem. Soc. 1995, 117, 1049-1056.
14) For example, compound 12 was formed quickly when 1.0 M HCl
in ether was added to 10 at room temperature.
15) The regiochemistry was determined by removal of the chiral
7
(
(
auxiliary with sodium hydroxide and acquiring a COSY NMR spectrum
on the corresponding carboxylic acid of 15.
OL702280Q
5170
Org. Lett., Vol. 9, No. 25, 2007