Lewis Acid Catalyzed Diels-Alder Reactions of Highly Hindered Dienophiles

Full text of DOI:10.1021/jo9801667

J . Org. Chem. 1998, 63, 4143-4146
4143
subjected to a variety of Lewis acids and reaction condi-
tions in the presence of cyclopentadiene. Surprisingly,
the majority of catalysts examined were ineffective at
promoting the DA reaction, and recovery of starting
dienophile coupled with decomposition of the diene was
the typical result. Concerned that residual water in the
solution might be interfering with the cycloaddition, we
decided to pretreat the dienophile solution with a chemi-
cal desiccant. Indeed, treatment of a solution of the
dienophile with 0.05 equiv of Al(CH3)3 at 0 °C for 15 min,7
followed by addition of AlCl3 and cyclopentadiene at 4
°C, provided a 50% conversion of 9 to 10 after 48 h (entry
9). These same conditions afforded the DA adduct 11b
from 8b in 89% yield with 2:1 endo:exo selectivity after
24 h (entry 10).8 Since one potential mechanistic role
for Al(CH3)3 in this process is as a chemical desiccant,
we tested the effect of substituting other known desic-
cants for Al(CH3)3. Bis(cylopentadienyl)dimethylzir-
conocene (Cp2Zr(CH3)2) has been used for this purpose
by Bergman9 and others; however, we found Cp2Zr(CH3)2
to be significantly less efficient than Al(CH3)3, providing
only 20% conversion of 8b to 11b after 24 h (entry 12).
Although the DA reaction had proceeded cleanly at
room temperature, we were curious as to the effects of
temperature on product selectivity and reaction rate. To
explore this, a 0.5 M solution of dienophile 8c in toluene
was treated at 0 °C with 0.05 equiv of Al(CH3)3 for 15
min, and then with AlCl3 for 10 min. The solution was
then brought to the appropriate reaction temperature,
and cyclopentadiene was added as a 5 M solution in
toluene. As expected, as the temperature is decreased
from room temperature to -20 °C the diastereoselectivity
increases significantly, from 3:1 to 7:1 in favor of the endo
diastereomer (Table 2). At temperatures lower than -20
°C, the reaction rate becomes too slow to be synthetically
useful; for example, only 20% conversion was observed
after 48 h at -30 °C.
Once reaction conditions were optimized, we were
ready to probe how changing the ester moiety would
influence the diastereoselectivity of the cycloaddition. We
found that changing the ester from propyl (8b) or
phenethyl (8c) to methyl (8a ) or 3-phenylpropyl (8d ) had
little effect on the diastereomeric excess, which remains
consistently around 88%, or 7:1 endo:exo. Because of
their higher reactivity in the DA reaction, it is likely that
the use of a γ,γ-disubstituted R,â-unsaturated ketone
would allow the DA reaction to proceed at lower temper-
atures, potentially enhancing the diastereoselectivity. We
are currently exploring whether this is indeed the case.
The significantly lower reactivity observed for cyclo-
hexane-substituted dienophile 9 relative to the cyclopen-
tane substituted dienophiles 8a -d deserves comment.
Conformational searches using molecular mechanics10 of
8b and 9 provide the minimum-energy conformers shown
Lew is Acid Ca ta lyzed Diels-Ald er
Rea ction s of High ly Hin d er ed Dien op h iles
Robert D. Hubbard and Benjamin L. Miller*
Department of Chemistry, University of Rochester,
Rochester, New York, 14627
Received J anuary 29, 1998
In the course of examining oligomeric cyclopentanoid
compounds as potential peptidomimetics, we required
synthetic access to structures such as 1. We envisioned
1 as being derived from the substituted norbornene 2,
which in turn could result from the Diels-Alder reaction
of dienophile 3 and cyclopentadiene 4 (Scheme 1). How-
ever, despite the status of the Diels-Alder (DA) reaction
as one of the most widely utilized and thoroughly
examined strategy-level reactions in organic chemistry,1
we were surprised to discover that intermolecular DA
reactions employing a γ,γ-disubstituted, nonaromatic
dienophile such as 3 were relatively rare. In the few
literature examples that we were able to uncover in
which this type of substitution was present, cyclic dieno-
philes,2 or autoclave temperatures and high pressure,3
were required to promote the reaction. For numerous
substrates, of course, the use of a Lewis acid catalyst
provides both an increase in reaction rate and enhanced
diastereoselectivity. However, we found in a series of
preliminary experiments (vide infra) that a variety of
standard Lewis acid catalysts were ineffective at promot-
ing DA cycloadditions between 3 (where R ) OCH3, R′ )
H) and 4. We describe herein the development of an
effective means of performing DA reactions with steri-
cally hindered dienophiles such as 3.
A series of γ,γ-disubstituted dienophiles was synthe-
sized by Arbuzov coupling of triisopropyl phosphite with
an R-bromo ester (5a -d )4 (Scheme 2) followed by Hor-
ner-Wadsworth-Emmons olefination with cyclohexane-
carboxaldehyde or cyclopentanecarboxaldehyde.5 Use of
the diisopropyl phosphonate reagents provided excellent
E:Z selectivity, in accord with the results observed by
Kishi and co-workers in their synthesis of Rifamycin S.6
With a series of dienophiles in hand, we were ready to
probe what conditions and additives might allow the DA
reaction to occur. As shown in Table 1, 8b and 9 were
* Corresponding author. Phone: 716-275-8383. Fax: 716-473-6889.
e-mail: miller@miller1.chem.rochester.edu.
(1) For recent reviews of the Diels-Alder reaction, including Lewis
acid catalysis, see: (a) Kobayashi, S. Synlett 1994, 689-701. (b)
Kagan, H. B.; Riaut, O. Chem. Rev. 1992, 92, 1007-1019. (c) Oppolzer,
W. Angew. Chem., Int. Ed. Engl. 1984, 23, 876-889.
(2) . (a) Miesch, M.; Cotte´, A.; Franck-Neumann, M. Tetrahedron
Lett. 1993, 34, 8085-8086. (b) Dauben, W. G.; Kowalczyk, B. A.;
Lichtenthaler, F. W. J . Org. Chem. 1990, 55, 2391-2398. (c) Williams,
R. V.; Sung, C.-L.; Kurtz, H. A.; Harris, T. M. Tetrahedron Lett. 1988,
29, 19-20.
(3) (a) Kitano, K.; Katagiri, N.; Kaneko, C. Chem. Lett. 1994, 1285-
1288. (b) Netherlands Patent 86-1541 860613.
(7) Al(CH3)3 is well-known to react with acidic hydrogens with loss
of methane; for example, see: Davidson, N.; Brown, H. C. J . Am. Chem.
Soc. 1942, 64, 316-324.
(8) The major product was assigned as the endo diastereomer by
analysis of a DQF-COSY spectrum.
(9) Proulx, G.; Bergman, R. G. Organometallics 1996, 15, 684-692.
(10) Monte Carlo multiple minimum searchers were conducted on
8b and 9 using the MM2* force field and GB/SA model for CHCl3 as
implemented in Macromodel 6.0 (Still, W. C., et al., Columbia
University, 1997).
(4) Methyl bromoacetate and propyl bromoacetate are commercially
available and were used without further purification. Compounds 5a
and 5d were made according to the procedure of Bradley, J . C., Bu¨chi,
G. J . Org. Chem. 1976, 41, 699-700, and used without purificaiton.
(5) Cyclohexanecarboxyaldehyde (7b) was purchased from Aldrich
Chemical Co. and used without further purification. Cyclopentan-
ecarboxyaldehyde (7a ) was prepared according to the procedure of
Olah, G.; Prakash, S.; Arvanaghi, M. Synthesis 1984, 228-230.
(6) Nagoaka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873-3888.
S0022-3263(98)00166-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/20/1998

4144 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Sch em e 1
Ta ble 1. Diels-Ald er Con d ition s for th e Rea ction of Dien op h iles 8b a n d 9 w ith Cyclop en ta d ien e12
entry
dienophile
Lewis acid (equiv)
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
9
9
9
9
9
9
8b
8b
9
8b
8b
8b
8b
8b
TiCl4 (1.0)13a
rta
rt
rt
rt
rt
rt
rt
rt
rt
NRb
NR
NR
NR
NR
NR
NR
NR
BF3·O(Et)2 (1.0)13e
5.0 M LiOCl4 in Et2O (5.0)13g
ZnCl2 (0.5)13d
Sc(OTf)3 (0.1)13f
AlCl3 (0.5)13c
(Et)2AlCl (1.0)13b
Al(CH3)3 (0.05)/B(Br)3 (1.0)
Al(CH3)3 (0.05)/AlCl3 (1.0)
Al(CH3)3 (0.05)/AlCl3 (1.0)
Al(CH3)3 (0.05)/AlCl3 (0.5)
Cp2Zr(CH3)2 (0.05)/AlCl3 (0.5)
Al(CH3)3 (0.55)
10 (50% conversion after 48 h)
11b (89% yield, 2:1 endo:exo)
11b (91% yield, 7:1 endo:exo)
20% conversion after 24 h
NR
rt
-20
-20
-20
-20
Al(CH3)3 (0.05)/(Et)2AlCl (0.5)
NR
a
b
rt = room temperature. NR = no reaction.
Sch em e 2
the DA cycloaddition of cyclopentadiene with a range of
sterically hindered dienophiles. This method relies on
the use of Al(CH3)3 in conjunction with AlCl3 as a Lewis
acid catalyst. Further mechanistic studies, development
of asymmetric variants, and efforts to incorporate this
methodology into the synthesis of oligocyclopentanoid
peptidomimetics are underway.
(11) Transition states for the Lewis acid-catalyzed cycloaddition of
relatively unsubstituted dienes and dienophiles have been modeled
extensively; for representative examples, see: (a) Houk, K. N.; Strozier,
R. W. J . Am. Chem. Soc. 1973, 95, 4094-4096. (b) Guner, O. F.;
Ottenbrite, R. M.; Shillady, D. D.; Alston, P. V. J . Org. Chem. 1987,
52, 391-394. (c) Yamabe, S.; Dai, T.; Minato, T. J . Am. Chem. Soc.
1995, 117, 10994-10997. (d) Garcia, J . I.; Mayoral, J . A.; Salvatella,
L. J . Am. Chem. Soc. 1996, 118, 11680-11681. (e) Garcia, J . I.;
Mayoral, J . A.; Salvatella, L. Tetrahedron 1997, 53, 6057-6064.
(12) Reactions were performed at a concentration of 0.5 M using
toluene as the solvent. Al(CH3)3 and AlCl3 were used as supplied by
Aldrich. Further details are supplied in the experimental methods
section.
(13) (a) Musselman, R. A., Ph.D. Dissertation. University of Roch-
ester; Rochester, New York, 1994. (b) Tomioka, K.; Hamada, N.;
Suengaga, T.; Koga, K. J . Chem. Soc., Perkin Trans. 1 1991, 426-
428. (c) Angell, E. C.; Fringuelli, F.; Guo, M.; Minuti, L.; Taticchi, A.;
Wenkert, E. J . Org. Chem. 1988, 53, 4325-4328. (d) Masamune, S.;
Reed III, L. A.; Davis, J . T.; Choy, W. J . Org. Chem. 1983, 48, 4441-
4444. (e) Drian, C. L.; Greene, A. E. J . Am. Chem. Soc. 1982, 104,
5473-5483. (f) Kobayashi, S.; Haciya, I.; Akari, M.; Isnitani, H.
Tetrahedron Lett. 1993, 34, 3755-3758. (g) Grieco, P. A.; Nunes, J .
J .; Gaul, M. D. J . Am. Chem. Soc. 1990, 112, 4595-4596.
(14) The endo:exo selectivity was determined by integration of the
diastereomeric vinyl resonances in the crude 400 MHz proton spec-
trum.
in Figure 1. To the extent that these are representative
of the reactive conformations of these dienophiles, it is
immediately apparent that either an endo or exo ap-
proach by a diene to either dienophile would be severely
hindered by methylene units attached to the γ-carbon.11
However, when the R-, â-, and γ-carbon atoms of these
conformers are superimposed, it becomes readily appar-
ent that the hydrogen atoms δ to the carbonyl are slightly
more oriented toward the CR-Câ double bond for 9 than
for 8b due to subtle differences in torsional angles
between the five- and six-membered rings (Figure 2).
In conclusion, we have demonstrated methodology for

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4145
F igu r e 1. Minimum energy conformers for 8b (left) and 9 (right) found using molecular mechanics.
The reaction was warmed to room temperature and quenched
with 0.5 mL of pyridine. The contents of the reaction were
filtered through silica and concentrated in vacuo to give a tan
oil. The residue was chromatographed via radial chromatogra-
phy (hexanes:ether 95:5) to give a pale yellow oil (11b, 51.4 mg,
91%, 88% de). IR (thin film) 1731, 1186, 716 cm-1 1H NMR
;
(500 MHz, CDCl3): δ 6.27 (1H, dd, J ) 3, 6 Hz), 5.96 (1H, dd, J
) 3, 6 Hz) 3.96-4.02 (2H, m), 3.13 (1H, m), 2.67-2.68 (1H, m),
2.54-2.56 (1H, m), 1.76-1.88 (2H, m), 1.65-1.67 (2H, m), 1.59-
1.65 (4H, m), 1.50-1.56 (2H, m), 1.40-1.42 (1H, m), 1.23-1.28
(3H, m), 0.95 (3H, t, J ) 8 Hz); 13C NMR (75 MHz, CDCl3): δ
175.0, 138.7, 133.2, 65.6, 50.4, 49.3, 49.3, 46.5, 46.4, 46.3, 45.9,
44.5, 32.1, 32.0, 25.1, 22.1. HRMS calcd for C16H24O2 (M+)
248.1776 found 248.1776. A minor diastereomer was also
observed in crude NMR spectra, but could not be isolated cleanly.
Cycloadducts 11a , 11c, and 11d were prepared in an analo-
gous fashion to 11b:
F igu r e 2. Superimposition of 8b (black) and 9 (white).
Ta ble 2: Dep en d en ce of th e Dia ster eoselectivity of th e
Diels-Ald er Rea ction of 8c w ith Cyclop en ta d ien e in th e
P r esen ce of Al(CH3)3 a n d AlCl3
Cycloa d d u ct 11a . From cyclopentadiene and 8a : 71%, 85%
de, pale yellow oil. IR (thin film) 3026, 1735, 1196 cm-1; 1H NMR
(500 MHz, CDCl3): δ 6.27 (1H, dd, J ) 3, 6 Hz), 5.95 (1H, dd, J
) 3, 6 Hz), 3.63 (3H, s), 3.12-3.13 (1H, m), 2.67-2.68 (1H, m),
2.54-2.56 (1H, m), 1.85-1.89 (1H, m), 1.74-1.78 (1H, m), 1.61-
1.69 (3H, m), 1.51-1.59 (3H, m), 1.40-1.42 (1H, m), 1.21-1.28
(3H, m); 13C NMR (75 MHz, CDCl3): δ 177.0, 138.8, 133.1, 51.5,
50.1, 49.4, 46.5, 46.4, 46.3, 32.1, 32.0, 25.2, 25.1, 10.5. HRMS
calcd for C14H20O2 (M+) 220.1463 found 220.1463.
Cycloa d d u ct 11c. From cyclopentadiene and 8c: 85%, 88%
de, clear oil. IR (thin film) 3053, 1726, 1264, 737 cm-1; 1H NMR
(500 MHz, CDCl3): δ 7.22-7.33 (5H, m), 6.23 (1H, dd, J ) 3, 5
Hz), 5.79 (1H, dd, J ) 3, 5 Hz), 4.22-4.30 (2H, m), 3.06 (1H,
m), 2.93 (2H, t, J ) 7 Hz), 2.65 (1H, m), 2.51 (1H, m), 1.60-1.65
(2H, m), 1.49-1.59 (7H, m), 1.37-1.39 (1H, m), 1.17-1.26 (2H,
m); 13C NMR (75 MHz, CDCl3): δ 174.8, 138.7, 138.0, 133.1,
128.9, 128.4, 126.5, 64.6, 50.2, 49.3, 46.5, 46.4, 46.2, 45.8, 35.1,
32.1, 32.0, 25.1, 25.1. HRMS calcd for C21H27O2 (M + H)+
311.1933 found 311.2011.
Cycloa d d u ct 11d . From cyclopentadiene and 8d : 75%, 85%
de, clear oil. IR (thin film) 1730, 1263, 716 cm-1; 1H NMR (500
MHz, CDCl3): δ 7.19-7.32 (5H, m), 6.28 (1H, dd, J ) 3, 6 Hz),
5.97 (1H, dd, J ) 2, 6 Hz), 4.00-4.10 (2H, m), 3.12 (1H, m),
2.68-2.71 (3H, m), 2.56-2.58 (1H, m), 1.85-1.97 (4H, m), 1.75-
1.79 (1H, m), 1.60-1.70 (3H, m), 1.51-1.57 (2H, m), 1.42-1.43
(1H, m), 1.23-1.30 (3H, m); 13C NMR (75 MHz, CDCl3): δ 174.9,
141.3, 138.8, 128.4, 128.3, 126.0, 63.4, 50.4, 49.4, 46.5, 46.4, 46.3,
45.9, 44.6, 32.2, 32.1, 32.0, 30.4, 25.1, 25.1. HRMS calcd for
C22H28O2 (M+) 324.2089 found 324.2089.
entry
temp (°C)
yield (%)
endo:exo (% de)
1
2
3
4
RT
4
-15
-20
92
86
89
85
3:1 (75)
4:1 (80)
7:1 (88)
7:1 (88)
Exp er im en ta l Meth od s
Gen er a l P r oced u r es. Unless otherwise indicated, all reac-
tions were performed with glassware that had been flame-dried
under an atmosphere of N2. THF was distilled from sodium-
benzophenone ketyl prior to usage. Methylene chloride and
toluene were distilled from calcium hydride prior to usage. All
commercially available reagents were purchased from Aldrich
Chemical Co. and used without further purification. Flash
chromatography was performed by using silica gel 60 purchased
from EM Science. Radial chromatography was performed by
using a Chromatotron from Harrison Research.
P r ep a r a tion of Cyloa d d u ct 11b . A 0.5 M solution of ester
8b (41.3 mg, 0.23 mmol) was prepared in toluene and cooled to
0 °C. Al(CH3)3 (5.6 uL, 0.011 mmol, 2.0 M in hexanes) was added
to the solution and stirred for 15 min at 0 °C. To this clear
solution was added AlCl3 (0.113 mL, 0.113 mmol, 1.0 M in
nitrobenzene). The resulting solution was stirred at 0 °C for 15
min and then cooled to -20 °C. After 10 min at -20 °C,
cyclopentadiene (0.45 mmol, 5.0 M in toluene) was added to the
dienophile. The reaction was allowed to stir for 18 h at -20 °C.
Ack n ow led gm en t. We would like to thank Profes-
sor Robert K. Boeckman and Dr. Michelle A. Laci for
helpful comments. The authors also thank one of the
referees for bringing some of the examples in references
2 and 3 to their attention. This paper is dedicated to
the memory of Professor Richard H. Schlessinger.

4146 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Su p p or tin g In for m a tion Ava ila ble: Proceedures for the
preparation of compounds 6a -d , 8a -d , 9, and 11a -d ; 1H and
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
1
13C spectra for all compounds, as well as the 500 MHz H-1H
DQCOSY spectrum of 11b (32 pages). This material is
J O9801667
contained in libraries on microfiche, immediately follows this