New synthetic approach to cyclopenta-fused heterocycles based upon a mild nazarov reaction. 2. Further studies on the torquoselectivity

Article abstract of DOI:10.1021/jo0489263

Conjugated alkoxytrienes in which one of the double bonds is embedded in a heterocyclic moiety are obtained by the Pd-catalyzed coupling reaction of lactam- and lactone-derived vinyl triflates with α-alkoxydienylboronates. These compounds undergo a 4π ele

Full text of DOI:10.1021/jo0489263

New Syn th etic Ap p r oa ch to Cyclop en ta -F u sed Heter ocycles Ba sed
u p on a Mild Na za r ov Rea ction . 2. F u r th er Stu d ies on th e
Tor qu oselectivity
Cristina Prandi,*,† Alessandro Ferrali,‡ Antonio Guarna,‡ Paolo Venturello,§ and
Ernesto G. Occhiato*,‡
Dipartimento di Scienze dell’Ambiente e della Vita, Universita` del Piemonte Orientale,
Spalto Marengo 33, 15100 Alessandria, Italy, Dipartimento di Chimica Organica “U. Schiff”,
Universita` di Firenze, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy, and
Dipartimento di Chimica Generale ed Organica Applicata, Universita` di Torino,
Corso Massimo D’Azeglio, 48, I-10125 Torino, Italy
cristina.prandi@unito.it; ernesto.occhiato@unifi.it
Received J une 25, 2004
Conjugated alkoxytrienes in which one of the double bonds is embedded in a heterocyclic moiety
are obtained by the Pd-catalyzed coupling reaction of lactam- and lactone-derived vinyl triflates
with R-alkoxydienylboronates. These compounds undergo a 4π electrocyclization process (Nazarov
reaction) under acidic conditions and afford cyclopenta-fused heterocycles in good yields. As a
continuation of a previous study, the torquoselectivity of this Nazarov reaction has been investigated
using 2-alkyl-substituted pyrrolidinone and 2- and 4-substituted δ-valerolactone derivatives. High
or complete stereoselectivity has only been observed with the 2-alkyl-substituted heterocycles. Both
steric and stereoelectronic effects could contribute to determining the stereoselection of the ring
closure.
SCHEME 1
In tr od u ction
Since the initial discovery that divinyl ketones 1
(Scheme 1) undergo a 4π electrocyclization under strong
acidic conditions to form 2-cyclopentenones 2 (the Naz-
arov reaction),1,2 steady progress has been made in ex-
panding the synthetic value of this reaction, primarily
by the use of Lewis acids as cyclization initiators3 and
by procedures called “directed Nazarov cyclization”4 and
“interrupted Nazarov reaction”.5 The recently reported
palladium(II)-catalyzed Nazarov reaction,6 and the first
catalytic asymmetric Nazarov reactions promoted by
chiral Lewis acids,7 are the latest important achieve-
ments.
Suitable precursors of the pentadienyl cationic inter-
mediate (Scheme 1) have also been used for carrying out
the electrocyclization.2a,c,d We have recently shown that
conjugated ethoxytrienes 5 (Scheme 2), obtained by Pd-
catalyzed cross-coupling reaction of the corresponding
lactam- and lactone-derived vinyl triflates or phosphates
3 with R-ethoxydienylboronates 4,8 undergo cyclization
when treated with the acidic Amberlyst 15 resin in CHCl3
* To whom correspondence should be addressed. (C.P.) Tel: +39-
011-6707647. Fax: +39-0131-287416. (E.G.O.) Tel: +39-055-4573480.
Fax: +39-055-4573531.
(4) For processes involving â-silyl- or â-stannyl-substituted dienones,
see: (a) Denmark, S. E.; J ones, T. K. J . Am. Chem. Soc. 1982, 104,
2642-2645. (b) J ones, T. K.; Denmark, S. E. Helv. Chim. Acta 1983,
66, 2377-2396. (c) Peel, M. R.; J ohnson, C. R. Tetrahedron Lett. 1986,
27, 5947-5950. For processes involving fluorine-substituted dienones,
see: (d) Ichikawa, J .; Miyazaki, J .; Fujiwara, M.; Minami, T. J . Org.
Chem. 1995, 60, 2320-2321. (e) Ichikawa, J .; Fujiwara, M.; Okauchi,
T.; Minami, T. Synlett 1998, 927-929.
(5) (a) Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221-10228.
(b) Wang, Y.; Arif, A. M.; West, F. G. J . Am. Chem. Soc. 1999, 121,
876-877. (c) Bender, J . A.; Blize, A. E.; Browder, C. C.; Giese, S.; West,
F. G. J . Org. Chem. 1998, 63, 2430-2431.
(6) Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927-4930.
(7) (a) Aggarwal, V. K.; Belfield, A. J . Org. Lett. 2003, 5, 5075-
5078. (b) Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett. 2003, 5, 4931-
4934. (c) Liang, G.; Trauner, D. J . Am. Chem. Soc. 2004, 126, 9544-
9545.
(8) Balma Tivola, P.; Deagostino, A.; Prandi, C.; Venturello, P. Org.
Lett. 2002, 4, 1275-1277.
† Universita` del Piemonte Orientale.
‡ Universita` di Firenze.
§ Universita` di Torino.
(1) (a) Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Izv. Akad.
Nauk. SSSR Khim. Nauk. 1942, 200. (b) Braude, E. A.; Forbes, W. F.
J . Chem. Soc. 1953, 2208-2216.
(2) (a) Habermas, K. L.; Denmark, S. E.; J ones, T. D. Org. React.
1994, 45, 1-158. (b) Denmark, S. E. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 5, pp 751-784. (c) Harrington, P. E.; Tius, M. A. J . Am. Chem.
Soc. 2001, 123, 8509-8514 and references therein. (d) Forest, J .; Bee,
C.; Cordaro, F.; Tius, M. A. Org. Lett. 2003, 5, 4069-4072 and
references therein.
(3) (a) Paquette, L. A.; Fristad, W. E.; Dime, D. S.; Bailey, T. R. J .
Org. Chem. 1980, 45, 3017-3028. (b) He, W.; Sun, X.; Frontier, A. J .
J . Am. Chem. Soc. 2003, 125, 14278-14279. (c) J anka, M.; He, W.;
Frontier, A. J .; Eisenberg, R. J . Am. Chem. Soc. 2004, 126, 6864-
6865. (d) Chiu, P.; Li, S. Org. Lett. 2004, 6, 613-616.
10.1021/jo0489263 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/05/2004
J . Org. Chem. 2004, 69, 7705-7709
7705

Prandi et al.
SCHEME 2a
SCHEME 3a
a
Key: (a) KHMDS, PhNTf2, THF, -78 °C; (b) 4a , (Ph3P)2PdCl2
(5%), THF, 2 M Na2CO3, 55-60 °C; (c) 0.02 M HCl, MeOH-H2O
4:1, rt; (d) Amberlyst 15, CHCl3; (e) neat TFA, rt.
Resu lts a n d Discu ssion
a
Key: (a) Amberlyst 15, CHCl3, 25 °C.
To synthesize the azacycles, we coupled vinyl triflates
10a ,b (Scheme 3) with ethoxydienylboronate 4a in order
to obtain the required ethoxytriene derivatives 11a ,b .
Commercially available, racemic 5-methyl-pyrrolidin-2-
one was converted into the N-tosyl derivative,9a,17 and this
quantitatively transformed into the corresponding triflate
10a by trapping the enolate with N-phenyl triflimide.18
Since 10a was rather prone to decomposition on standing,
it was promptly coupled with 4a by using (PPh3)2PdCl2
(5%) as a catalyst in THF, in the presence of aqueous 2
M Na2CO3 as a base. The reaction was complete within
3 h at 55 °C and afforded, after chromatographic puri-
fication, 11a in 50% yield (from the N-tosyl pyrrolidinone,
two steps). In the case of five-membered azacycle deriva-
tives as 11a , the direct Nazarov cyclization under mild
acidic conditions is prevented by the ring strain in the
cationic azabicyclo[3.3.0]octenyl intermediate and the
corresponding R,â-unsaturated ketone is thus obtained.
The latter can be treated with TFA to give the corre-
sponding Nazarov compound.9a The best conditions to
obtain 12a were found by carrying out the hydrolysis
with 0.02 M HCl in H2O-MeOH 1:4 (100% conversion).
Subsequent treatment of crude 12a with neat TFA
provided cyclopenta-fused pyrroline 13a (50% overall
yield from 11a ) as a single diastereomer in which the
two methyl groups are incorporated in a cis relationship.
This structural assignment was based on the analysis of
a series of NOESY 1D and 2D spectra of 13a , in which
diagnostic cross-peaks between H3 (which resonates at
2.10 ppm) and the two methyl groups on C2 and C4 were
present (Figure 1a).
at room temperature to give the cyclopenta-fused het-
erocycles 9 in good yields.9 For this process, we proposed
a Nazarov-type mechanism which includes protonation
of the distal double bond and generation of the 3-alkoxy-
pentadienylic cation 6, then electrocyclization to form the
oxyallyl intermediate 7, and eventually, loss of a proton
to give 9. A minor product that is sometimes formed in
this process is divinyl ketone 8, which is not an inter-
mediate in the cyclization process under these mild acidic
conditions.9b The stabilization of the positive charge in 7
by the electron-donor atom (nitrogen or oxygen) in the
adjacent heterocycle accounts for the mild reaction condi-
tions required.9a
We have also shown that the ring closure is highly
diastereoselective in the cases of 2- and 4-alkyl-substi-
tuted δ-valerolactam derivatives, which provide 2,5- and
4,5-cis disubstituted hexahydro[1]pyrindines 9 (Scheme
2, X ) N-Cbz, N-Ts). In the present work, we report on
the torquoselectivity2a in the cyclization of 2-substituted
five-membered azacycle and 2- and 4-substituted six-
membered oxacycle derivatives. Such a study should
provide a more complete picture of the diastereoselection
in the Nazarov cyclization of these conjugated ethoxy-
trienes, making the whole procedure useful for the
construction of cyclopenta-fused heterocycles found in
several natural and biologically active compounds, among
which are, for example, roseophilin,10 streptazolin,11
abikoviromycin,12 pyrindicin,13 nakadomarin,14 prosta-
cyclin and its analogues,15 and serratinin.16
The same synthetic sequence was applied to enan-
tiopure (S)-5-hydroxymethylpyrrolidin-2-one. This was
suitably O- and N-protected19 and converted into the
corresponding triflate 10b. Pd-catalyzed coupling with
(9) (a) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Venturello,
P. J . Org. Chem. 2003, 68, 9728-9741. (b) Occhiato, E. G.; Prandi, C.;
Ferrali, A.; Guarna, A.; Deagostino, A.; Venturello, P. J . Org. Chem.
2002, 67, 7144-7146.
(10) For a review on the chemistry and biology of roseophilin, see:
Fu¨rstner A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603.
(11) Nomura, I.; Mukai, C. J . Org. Chem. 2004, 69, 1803-1812 and
references therein.
(15) J ohnson, R. A.; Nidy, E. G. J . Org. Chem. 1980, 45, 3802-3810.
(16) Morita, H.; Kobayashi, J . J . Org. Chem. 2002, 67, 5378-5381.
(17) Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron 2001,
57, 6353-6359.
(18) For a recent review on the chemistry of lactam-derived vinyl
triflates, see: Occhiato, E. G. Mini-Rev. Org. Chem. 2004, 1, 149-
162.
(12) Maruyama, H.; Okamoto, S.; Kubo, Y.; Tsuji, G.; Fujii, I.;
Ebizuka, Y.; Furihata, K.; Hayakawa, Y.; Nagasawa, H.; Sakuda, S. J
Antibiot. 2003, 56, 801-804.
(13) Omura, S.; Tanaka, H.; Awaya, J .; Narimatsu, Y.; Konda, Y.;
Hata T. Agric. Biol. Chem. 1977, 38, 899-906.
(14) Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171-1174 and
references therein.
(19) Nagashima, H.; Wakamatsu, H.; Ozaki, N.; Ishii, T.; Watanabe,
M. J . Org. Chem. 1992, 57, 1682-1689.
7706 J . Org. Chem., Vol. 69, No. 22, 2004

Synthetic Approach to Cyclopenta-Fused Heterocycles
ture.20 The six-membered lactones were converted into
the corresponding vinyl triflates 14a -d (by treatment
with LHDMS in THF at -78 °C followed by trapping of
the enolates with PhNTf2) which in our hand proved more
stable than the corresponding phosphates.21 The cross-
coupling reactions between crude triflates 14a -d and
ethoxydienylboronates 4a ,b were performed in THF,
using aqueous 2 M K2CO3 as a base and (PPh3)2PdCl2
(5%) as a catalyst at room temperature. Ethoxytrienes
15a -f were all obtained in good yields (56-79%) after
chromatographic purification and were fully character-
ized.
F IGURE 1. Observed NOE enhancements in compounds
13a ,b and 17a trans
.
TABLE 1. Syn th esis of Eth oxytr ien es 15a -fa
Standard conditions to perform the Nazarov reaction
were achieved either by using Amberlyst 15 in com-
mercial anhydrous DCM or by performing the reaction
in a 0.2 M CF3SO3H solution in anhydrous DCM under
argon or nitrogen atmosphere. When 15a (R1 ) Me,
R2 ) R3 ) R4 ) H) was subjected to hydrolysis under the
former conditions (Table 2, entry 1), less than 5% of
dienone 16a was detected in the crude reaction mixture,
whereas the 2,5-dimethyl substituted Nazarov compound
17a (R1 ) Me, R2 ) R3 ) R4 ) H) was obtained as the
main product (as a diastereomeric mixture, see the
following text) along with a minor compound which was
identified as 6-oxaspiro[4.5]decenone 18a (R1 ) Me,
R2 ) R3 ) R4 ) H).22 Our attempts to separate 18a from
the Nazarov compound by flash chromatography were
unsuccessful and we were only able to obtain an enriched
chromatographic fraction of 18a that allowed us to obtain
a complete structural characterization. Typical 1H NMR
signals of 18a (see the Supporting Information) are the
pentuplet at 7.62 ppm and the doublet of triplets at 6.18
ppm, which are ascribed to the double bond protons, and
the broad singlet a 2.77 ppm due to the CH2 protons in
the five-membered ring. In the 13C NMR spectrum the
quaternary spiro C atom resonates diagnostically at 79.4
ppm. Interestingly, 18a was obtained as a single dia-
stereomer (stereochemistry not assigned). The hydrolysis
of 15a with triflic acid (Table 2, entry 2) afforded the
same relative amount of spiro compound.
The cyclization process that gave 17a took place with
a fair stereocontrol, the diastereomeric ratio between
17a trans and 17a cis being about 16:1 under both the
reaction conditions tested (entries 1 and 2). This ratio
decreased to 10:1 when isolated dienone 16a (see the
Experimental) was treated with neat TFA to give the
Nazarov compound 17a . We assigned to the major
diastereomer of 17a the trans relative stereochemistry
(referring to the relative position of the two methyl
groups) on the basis of a NOE study, with the correlations
between H2, H4, and 5-Me being diagnostic of the trans
stereochemistry (Figure 1c).
entry
15
R1
R2
R3
R4
yieldb (%)
1
2
3
4
5
6
a
b
c
d
e
f
Me
H
H
H
Me
H
H
H
H
Me
H
H
H
H
H
H
Me
Me
56
79
77
58
77
78
Me
Me
Ph
H
Me
Me
a
Coupling conditions: (Ph3P)2PdCl2 (5%), THF, 2 M K2CO3, rt.
b Yield of purified products after silica gel column chromatography.
ethoxydienylboronate 4a afforded ethoxybuta-1,3-dienyl
derivative 11b in 65% yield (two steps). One-pot hydroly-
sis and removal of the TBDMS protection by treatment
with 0.02 M HCl in H2O-MeOH 1:4 furnished the
corresponding dienone 12b in quantitative yield after 6
h at room temperature. This was directly converted,
without prior purification, into the Nazarov product 13b
(42%, over two steps) by treatment with neat TFA. The
OTBDMS protection was maintained when the hydrolysis
of 11b was carried out in the presence of Amberlyst 15
in chloroform although attempts at purification of di-
enone 12c by chromatography led to partial decomposi-
tion and to an isolated yield of 32%. In contrast to the
previous case, electrocyclization of 12b did not furnish a
diastereopure compoundsa second set of signals, assign-
able to the minor trans diastereomer (present in a 1:10
1
ratio), was present in the H NMR spectrum of 13b. The
assignment of the cis relative stereochemistry to the
major diastereomer was possible because of the observed
NOESY cross-peak between the proton on C3 (at 1.96
ppm) having a cis relative stereochemistry to the CH2-
OH group and the methyl group on C4 (Figure 1b).
In the case of the oxacycle derivatives, we coupled
ethoxydienylboronates 4a ,b with δ-valerolactone-de-
rived vinyl triflates 14a -d to obtain ethoxytrienes 15a -f
(Table 1). 4-Methyltetrahydropyran-2-one and 4,4-di-
methyltetrahydropyran-2-one were obtained by reduction
of the corresponding anhydrides, whereas 4-phenyltet-
rahydropyran-2-one was synthesized according to litera-
(20) Tokoroyama, T.; Kusaka, H. Can. J . Chem. 1996, 74, 2487-
2502.
(21) In other cases we prepared, and successfully used in coupling
reactions, the lactone-derived vinyl phosphates; see ref 9a. For the use
of lactone-derived vinyl phosphates in Pd-catalyzed coupling reactions,
see: Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J . L.; Gartner, P.; Yang, Z.
J . Am. Chem. Soc. 1997, 119, 5467-5468.
(22) We have found that hydrolysis carried out in CHCl3 and in the
presence of Amberlyst 15 afford the separable mixture of divinyl ketone
16 and cyclopenta-fused heterocycle 17 in a ratio strongly depending
on the amount of water (or protic solvents such as alcohols) present in
the solvent. For example, the hydrolysis of 15a with Amberlyst 15 in
commercial chloroform afforded dienone 16a in 18% yield (see the
Experimental Section).
J . Org. Chem, Vol. 69, No. 22, 2004 7707

Prandi et al.
TABLE 2. Hyd r olysis P er for m ed on Eth oxytr ien es 15
yield of
yield of
ratio of
17trans/17cis
ratio of
c,d
entry
substrate
conditions
T (°C)/time (h)
16a (%)
17 + 18b (%)
17/18d
1
2
3
4
5
6
7
8
9
15a
15a
15b
15b
15c
15d
15e
15f
15f
Amberlyst 15/DCM
0.2 M CF3SO3H in DCM
Amberlyst 15/DCM
0.2 M CF3SO3H in DCM
Amberlyst 15/DCM
Amberlyst 15/DCM
Amberlyst 15/DCM
Amberlyst 15/DCM
0.2 M CF3SO3H in DCM
rt/2
rt/0.5
rt/4
rt/0.5
rt/2.5
rt/15
rt/1
<5
85
56
88
85
69
39
78
30
67
16:1
16:1
1:2
90:10
91:9
76:24
94:6
90:10
100:0
100:0
100:0
100:0
n.d.e
n.d.
n.d.
n.d.
45
1:2
1:3
18
57
n.d.
rt/6
rt/0.5
a
b
Yield of open-chain ketone isolated after flash chromatography. Yield of the mixture after flash chromatography. c The terms trans
d
and cis refer only to 2,5- and 4,5-disubstituted compounds, i.e., 17a , 17b, and 17d . Ratio determined by integration of proton signals in
the 1H NMR spectrum of the unresolved mixture obtained after flash chromatography and GC analysis. e Not detected
SCHEME 4
In the hydrolysis of 4-methyl-substituted 15b, the
stereochemical control was worse and 17b (R1 ) H, R2 )
Me, R3 ) R4 ) H) was recovered as a 2:1 mixture of
inseparable cis and trans diastereomers (Table 2, entry
3). In this case, the reaction with Amberlyst 15 provided
a mixture of Nazarov compound 17b and spiro compound
18b in a 3:1 ratio. The relative amount of spiro compound
decreased when the reaction was carried out in a 0.2 M
CF3SO3H solution in DCM (entry 4). Unfortunately, the
complexity of the 1H NMR spectrum of 17b made any
attempt at assigning the stereochemistry to the major
diastereomer unfruitful, and we may only assume that
it has a cis relative stereochemistry (see below). We
thought that an increase of steric hindrance at the C4
would further favor the formation of the spiro compound.
However, the hydrolysis of the 4,4-dimethyl-substituted
derivative 15c (entry 5) furnished the same 17/18 ratio
as in the case of entry 1. The presence of a phenyl group
in position 4 (Table 2, entry 6) made the electrocyclization
process more difficult. In this case, dienone 16d was
recovered in 45% yield after chromatography along with
17d (R1 ) H, R2 ) Ph, R3 ) R4 ) H) as a 3:1 mixture of
diastereomers 17d cis and 17d trans (39% yield). The forma-
tion of the spiro compound 18d was not observed in this
temperature (direct treatment of ethoxydienes 15 with
neat TFA affords the Nazarov compounds in poor yield
and the reaction is characterized by a large amount of
degradation products). In any case, the use of CF3SO3H
(entry 9) allowed for the complete conversion into the
Nazarov product.
The formation of the spiro byproducts 18 (not found
in our previous study on unsubstituted δ-valerolactone
derivatives),9a should take place through protonation of
the endocyclic double bond favored by the presence of the
heteroatom (Scheme 4). This is followed by an alternative
Nazarov electrocyclization pathway, the first intermedi-
ate in Scheme 4 being just a resonance form of a
pentadienyl cation.24 When dienones 16 are treated with
TFA they do not give the corresponding spiro compounds.
Apart from the detrimental effect of the 3-methyl group
in the ethoxydiene moiety of 15e,f on the formation of
the spiro compounds, there is no clear relationship
between the structure of ethoxytriene 15 or the reaction
conditions and the relative amount of 18 after the
hydrolysis. This can be seen from the results presented
in Table 2.
1
case. In the H NMR spectrum of the 3:1 diastereomeric
mixture, the methyl group of the minor component
resonates at 1.04 ppm whereas in the major diastereomer
it is upfield shifted to 0.83 ppm. This is consistent with
the cis relative stereochemistry of the major diastereomer
since, as suggested by a molecular modeling study,23 only
through this spatial arrangement can the methyl group
undergo the shielding effect of the facing phenyl ring.
Finally, when we subjected trienes 15e,f (R4 ) Me in
both cases) to hydrolysis (Table 2, entry 7-9), no spiro
compounds were detected, but the yields of 16e,f were
enhanced. In these cases, byproducts 16 can be easily
transformed into 17 by treatment with neat TFA at room
We have previously suggested that steric interactions
play a part in the selection between the two possible
conrotatory pathways in the cyclization of 2- and 4-meth-
yl substituted six-membered lactam derivatives which
lead, in both cases, to the exclusive formation of the cis
(23) The MM2* force field was used for the energy minimization
with MacroModel software. Mohamadi, F.; Richards, N. G.; Guida, W.
C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.;
Still, W. C. MacroModelsAn Integrated Software System for Modeling
Organic and Bioorganic Molecules Using Molecular Mechanics. J .
Comput. Chem. 1990, 11, 440-467.
(24) We thank one of the reviewers for the suggestion regarding the
possible mechanism of cyclization that leads to the spiro compounds.
7708 J . Org. Chem., Vol. 69, No. 22, 2004

Synthetic Approach to Cyclopenta-Fused Heterocycles
diastereomer.9a Instead, in the hydrolysis of 2-methyl
substituted lactone derivative 15a (eq 1), the relative
stereochemistry of the major product is trans (17a trans).
Thus the formation of the new C-C bond must take place
on the same side of the 2-methyl group (through a
transition structure in which the pyran ring has a
boatlike conformation), although nonbonded interactions
between this substituent and the incipient C4a-C5 bond
should be negligible as the methyl is in a pseudoequa-
torial position. This should also be true in the case of a
clockwise conrotation (eq 2) which would impose a
chairlike conformation for the six-membered heterocycle
in the transition structure.25 The reasons why the
counterclockwise conrotation mode is preferred are un-
clear. Stereoelectronic effects could play a role: in
particular it is possible that there may be a better orbital
overlap in the formation of the new C4a-C5 bond when
the pyran ring adopts a boatlike conformation in the
transition state.
tion structure, which leads to the formation of cis isomer
20 only. As for the 2-alkyl-substituted pyrrolidinone
derivatives (eq 4), the substituent is axially oriented and
the new bond develops on the opposite site, which
provides the cis-substituted compounds 13a and 13b with
high or total selectivity.
With the 4-substituted lactone derivatives, the forma-
tion of the major 4,5-cis isomer 17d cis in the hydrolysis
of 4-phenyl-substuituted derivative 15d is in accordance
with Denmark’s results in the silicon-directed Nazarov
cyclization.27 The attack occurs on the less hindered face
of the endocyclic double bond, i.e., opposite the 4-sub-
stituent, leading to the cis product. On these grounds it
is reasonable to think that 17bcis is the major diastere-
omer formed in the hydrolysis of 15b. In the former case,
the higher diastereomeric ratio (3:1) in favor of the cis
product could depend on the increased steric demand of
the substituent. The low relative amount of Nazarov
compound 17d (39%, Table 2, entry 6) which is formed
in the hydrolysis of 15d (dienone 16d is obtained in 45%
yield), could be due to the enhanced bulk of the 4-sub-
stituent. In fact, complete conversion into the dienone
has been already observed by us with a lactam derivative
when the sterically more demanding 4-tert-butyl group
was present in the ring.9a
Con clu sion . In the present study we provide a com-
plete depiction of the torquoselectivity in the Nazarov
reaction of lactam- and lactone-derived ethoxytrienes that
furnishes cyclopenta-fused heterocycles. The reaction is
highly diastereoselective with 2-substituted five-mem-
bered lactam derivatives 11a and 11b and leads to cis
disubstituted cyclopenta-fused pyrrolines 13a and 13b,
respectively. This occurs through a conrotation in the
3-hydroxypentadienyl cationic intermediate which in-
volves the less hindered face of the endocyclic double
bond. The same is true for 2- and 4-substituted δ-vale-
rolctam derivatives. In contrast, the trans product 17a trans
is predominantly formed with the 2-methyl-substituted
δ-valerolactone derivative 15a , whereas modest selectiv-
ity is observed with 4-substituted lactone derivatives 15b
and 15d . Both steric and stereoelectronic effects could
contribute to determining the stereoselection in the ring
closure. Ab initio calculations are currently being per-
formed to assess this. The possibility of controlling the
stereochemical outcome in such a process makes the
methodology potentially useful for the synthesis of natu-
ral products and biologically active compounds.
Our previous results obtained with 2-methyl-substi-
tuted δ-valerolactam derivatives9a confirm that a boatlike
structure for the heterocycle in the transition state is
possible. As shown in eq 3, the methyl group is forced to
assume an axial orientation because of the N protecting
group.26 Consequently, the reaction proceeds via a coun-
terclockwise conrotation involving the less hindered face
of the endocyclic double bond through a boatlike transi-
Ack n ow led gm en t. We thank MIUR and the Uni-
versity of Florence (COFIN 2002-2004) for financial
support. Mr. Maurizio Passaponti and Mrs. Brunella
Innocenti are acknowledged for their technical support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and copies of the 1H NMR spectra of compounds 11a ,b,
13a ,b, 15a -c,e,f, 17a , 17a /18a 1:1 mixture, 17b/18b 3:1
mixture, and 17c,e and the 13C NMR spectra of the 17a /18a
1:1 mixture. This material is available free of charge via the
Internet at http://pubs.acs.org.
(25) In our earlier paper (see ref 9a), we assumed that a transition
structure in which the heterocycle had a chairlike conformation could
be favored.
(26) (a) Comins, D. L.; J oseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J ., Ed.; J AI Press: Greenwich, CT, 1996; Vol.
2, pp 251-294. (b) Kuethe, J . T.; Brooks, C. A.; Comins, D. L. Org.
Lett. 2003, 5, 321-323. (c) Ha, J . D.; Kang, C. H.; Belmore, K. A.; Cha,
J . K. J . Org. Chem. 1998, 63, 3810-3811. (d) Toyooka, N.; Okumura,
M.; Takahata, H.; Nemoto, H. Tetrahedron 1999, 55, 10673-10684.
(e) Luker, T.; Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1997, 62,
3592-3596.
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(27) Denmark, S. E.; Habermas, K. L.; Hite, G. A.; J ones, T. K.
Tetrahedron 1986, 42, 2821-2829.
J . Org. Chem, Vol. 69, No. 22, 2004 7709