Sequencing pericyclic reactions: The ester dienolate [2,3]-wittig/oxy-cope rearrangement/carbonyl ene reaction, a new access to substituted carbocycles

Article abstract of DOI:10.1002/1099-0690(200102)2001:3<483::AID-EJOC483>3.0.CO;2-F

The sequential ester dienolate [2,3]-Wittig/oxy-Cope rearrangement/carbonyl ene reaction has been investigated. Acyclic α,β-unsaturated α-allyloxy-substituted esters 1a-j were transformed into cyclopentane- or cyclohexanecarboxylates 6a-f and 7a-7d. This study presents a domino ester dienolate [2,3]-Wittig/oxy-Cope rearrangement or a domino oxy-Cope rearrangement/carbonyl ene reaction, depending on the substrate structure. The thermal intramolecular type-I carbonyl ene reaction as the terminating ring-closing reaction proceeds with high simple diastereoselectivity, but low induced diastereoselectivity. The corresponding type-II ene reaction afforded the cyclohexanecarboxylates 7a-d in high yield with complete simple and induced diastereoselectivity. Unfortunately, an attempted auxiliary-controlled enantio-selective sequence was inefficient.

Full text of DOI:10.1002/1099-0690(200102)2001:3<483::AID-EJOC483>3.0.CO;2-F

FULL PAPER
Sequencing Pericyclic Reactions: The Ester Dienolate [2,3]-Wittig/Oxy-Cope
Rearrangement/Carbonyl Ene Reaction, a New Access to Substituted
Carbocycles
Martin Hiersemann[a]
Keywords: Carbocycles / Domino reactions / Ene reactions / Ester dienolates / Pericyclic reactions / Rearrangements
The sequential ester dienolate [2,3]-Wittig/oxy-Cope re- I carbonyl ene reaction as the terminating ring-closing reac-
arrangement/carbonyl ene reaction has been investigated.
Acyclic α,β-unsaturated α-allyloxy-substituted esters 1a−j
tion proceeds with high simple diastereoselectivity, but low
induced diastereoselectivity. The corresponding type-II ene
were transformed into cyclopentane- or cyclohexanecarb- reaction afforded the cyclohexanecarboxylates 7a−d in high
oxylates 6a−f and 7a−7d. This study presents a domino ester
yield with complete simple and induced diastereoselectivity.
dienolate [2,3]-Wittig/oxy-Cope rearrangement or a domino Unfortunately, an attempted auxiliary-controlled enantio-
oxy-Cope rearrangement/carbonyl ene reaction, depending
on the substrate structure. The thermal intramolecular type-
selective sequence was inefficient.
Introduction
The development of general and efficient synthetic
methods for CϪC bond formation remains a significant
challenge for organic chemists. A general strategy to im-
prove synthetic efficiency is to combine different CϪC-con-
necting transformations in a domino reaction.[1] Given the
importance of carbocyclic ring systems in natural product
chemistry, we are interested in developing general proced-
ures for the synthesis of carbocycles, based on sequences of
catalyzed or uncatalyzed pericyclic domino reactions.[2] We
utilize sigmatropic rearrangements of easily accessible start-
ing materials to generate an appropriate substrate for a cy-
clizing pericyclic reaction (e.g. electrocyclic reaction or ene
reaction). In this context, we set out to study a sequence
of pericyclic reactions featuring the dienolate [2,3]-Wittig
rearrangement followed by an oxy-Cope rearrangement and
terminating in an intramolecular carbonyl ene reaction of
an α-oxo ester (Scheme 1). This approach offers a number
of interesting features with regard to synthetic efficiency
and variability. The substrate synthesis would be highly
convergent, allowing access to a broad spectrum of prod-
ucts. The pivotal CϪC-connecting pericyclic reactions pro-
vide an inherent possibility of stereocontrol through well-
defined cyclic transition states.
The utility of the ester dienolate [2,3]-Wittig rearrange-
ment as an extension of the ester enolate [2,3]-Wittig re-
arrangement was recently demonstrated.[3] Furthermore, we
reported the first examples of a domino ester dienolate
[2,3]-Wittig/oxy-Cope rearrangement and of the thermal
oxy-Cope rearrangement of a 3-alkoxycarbonyl-3-hydroxy-
substituted 1,5-hexadiene.[4,5] Whereas Lewis acid pro-
[a]
Institut für Organische Chemie der Technischen Universität
Dresden,
01062 Dresden, Germany
Fax: (internat.) ϩ 49-(0)351/463-7030
E-mail: martin.hiersemann@chemie.tu-dresden.de
Scheme 1. The sequential dienolate [2,3]-Wittig/oxy-Cope re-
arrangement/carbonyl ene reaction
Eur. J. Org. Chem. 2001, 483Ϫ491
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0203Ϫ0483 $ 17.50ϩ.50/0
483

M. Hiersemann
FULL PAPER
moted intramolecular carbonyl ene reactions of unsaturated tures of diastereomers, along with the α-oxo esters 5aϪc
aldehydes have been thoroughly investigated,[6,7] apparently (Scheme 2, Table 1).
no example exists of a Lewis acid mediated or a thermal
The ratio of products for the transformation depicted in
intramolecular carbonyl ene reaction of an α-oxo ester. A Scheme 2 is apparently thermodynamically controlled.[11]
number of synthetic studies have been reported in which Table 1 indicates that the amount of remaining α-oxo ester
the synthetic potential of the oxy-Cope rearrangement was 5aϪc is independent of the reaction time and reaction tem-
combined with different types of, mostly anionic, trans- perature. Furthermore, heating different diastereomeric
formations to give domino reactions.[8] In particular, a re- mixtures of the isopropyl cyclopentanecarboxylate 6c to
ported sequence of a ring-expanding oxy-Cope rearrange- 180 °C affords the same ratio of products as was obtained
ment followed by a transannular carbonyl ene reaction is from the ene reaction of the α-oxo ester 5c.
related to our approach.[9]
Finally, it should be emphasized that, up to this point,
Our initial objective was to control the ring size of the the presence of a geminal dimethyl group in the 3-oxy-sub-
desired carbocycles by inducing ene reactions of different stituted 1,5-hexadiene (RE ϭ RZ ϭ methyl in 4-Li) is a pre-
types. This task should be achievable by an appropriate requisite for the occurrence of a domino ester dienolate
setup of the substrate structure; this is an inherent strength [2,3]-Wittig rearrangement/oxy-Cope rearrangement.
of our convergent synthesis of the starting material. We pre-
ferred to utilize thermal reaction conditions in order to
avoid the employment of large amounts of Lewis acids for
the ene reaction, or of donor solvents for the oxy-Cope re-
arrangement.
The Sequential Ester Dienolate [2,3]-Wittig Rearrangement/
Domino Oxy-Cope Rearrangement/Type-I Ene Reaction
The ester dienolate [2,3]-Wittig rearrangement of the α-
hex-2-enyloxy-substituted α,β-unsaturated esters 1dϪf af-
forded the 3-alkoxycarbonyl-3-hydroxy-substituted 1,5-
hexadienes 3dϪf in high yields and with moderate to high
diastereoselectivities (Scheme 3, Table 2, Entries 1Ϫ3).
Heating the 1,5-hexadienes 3dϪf in decane afforded the
Results and Discussion
isopropyl cyclopentanecarboxylates 6dϪf as mixtures of di-
astereomers and double-bond isomers (Scheme 3, Table 3).
In contrast to the type-I ene reaction of the α-oxo esters
5aϪc with trisubstituted double bonds, it was possible to
transform the α-oxo esters 5dϪf, with disubstituted double
bonds, completely into the type-I ene reaction products
6dϪf. As expected, the reaction temperatures and the reac-
The Sequential Ester Dienolate [2,3]-Wittig/Oxy-Cope
Rearrangement/Type-I Carbonyl Ene Reaction
The substrates 1aϪi for the dienolate [2,3]-Wittig re- tion times were pivotal for the complete consumption of
arrangement were synthesized in multigram quantities us- the intermediate α-oxo esters 5dϪf (Table 3). The necessary
ing the previously reported aldol condensation strategy.[3,10] reaction times for completion of the ene reactions in turn
The domino dienolate [2,3]-Wittig rearrangement/oxy-Cope depended on the substituent pattern on the α-oxo esters
rearrangement was accomplished by treating the esters 5dϪf (Table 3). The relative configurations of the cyclic
1aϪc with lithium diisopropylamide (LDA) in THF at Ϫ78 products were determined by NOESY experiments. Unfor-
°C, followed by warming the reaction mixture to room tem- tunately, we were unable to assign the double-bond config-
1
perature. The oxy-Cope rearrangement proceeded at room urations because of overlapping H NMR signals. In order
temperature and product formation could conveniently be to simplify the NMR spectra and to prove the existence of
followed by TLC. After an aqueous workup procedure, the double-bond isomers unequivocally, the double bonds of
crude α-oxo esters 5aϪc were used for the thermal intramo- the ene reaction products 6dϪf were hydrogenated to afford
lecular type-I carbonyl ene reaction to afford the corres- the corresponding saturated isopropyl cyclopentanecarb-
ponding isopropyl cyclopentanecarboxylates 6aϪc as mix- oxylates 8dϪf (Table 3). We briefly investigated the thermal
Scheme 2. The sequential ester dienolate [2,3]-Wittig/oxy-Cope rearrangement/type-I ene reaction
484
Eur. J. Org. Chem. 2001, 483Ϫ491

Sequencing Pericyclic Reactions: A New Access to Substituted Carbocycles
FULL PAPER
Table 1. Conditions and products for the dienolate [2,3]-Wittig/oxy-Cope rearrangement/type-I ene reaction
[a]
[b]
Reactions performed in decane using a pressure tube with a threaded plug. Ϫ Racemic products, relative configuration assigned on
[c]
the basis of NOESY experiments. Ϫ Isolated yield after column chromatography, α-oxo ester 5 can be separated.
Scheme 3. The sequential ester dienolate [2,3]-Wittig/oxy-Cope rearrangement/type-I ene reaction
Table 2. The dienolate [2,3]-Wittig rearrangement
eoselectivities, indicate that the (1R*,2R*,5R*)-6e diastereo-
mer is the kinetically and thermodynamically favored
product.
Entry Substrate Substrate R1 R2 Product Yield[a] dr[b]
(Z)/(E)
[%]
syn/anti
The type-I ene reactions of the α-oxo esters 5aϪf proceed
with very high simple diastereoselectivities, but low induced
diastereoselectivities. The most significant stereochemical
feature is the complete simple diastereoselectivity for the
formation of the 2,3-cis-substituted products. This result is
in agreement with the general stereochemical trend for ther-
mal and Lewis acid mediated intramolecular ene reactions
of 1,6-hexadienes and 5,6-unsaturated aldehydes to form
cis-configured products.[6,7h,7l] On the basis of the results of
a theoretical study of the transition structures of ene reac-
tions by Houk,[12] we propose the depicted transition struc-
tures lk-(2.6)-9 and ul-(2.6)-9 to explain the simple diaster-
eoselectivity (Scheme 4).
1
2
3
4
5
6
1d
1e
1f
61:39
Ϫ[c]
97:3
59:41
Ϫ[c]
H
H
H
3d
87
88
91
82
72
89
91:9
CH3 3e
98:2
Ph H
3f
3g
79[d]:21[d]
Ϫ
Ϫ
Ϫ
1g
1h
1i
H
H
Ph H
H
CH3 3h
95:5
3i
[a]
[b]
Isolated yield after chromatographic purification. Ϫ
Deter-
mined from 1H NMR spectra. Ϫ [c] Substrate used as a 3:1 mixture
[d]
of the β,γ- and α,β-unsaturated esters. Ϫ Exclusively (E)-config-
ured.
epimerization of the isopropyl cyclopentanecarboxylates
(1R*,2R*,5R*)- and (1R*,2R*,5S*)-6e. The (1R*,2R*,5R*)-
6e diastereomer did not isomerize or decompose when
Following Houk’s argument, we believe that the three-
heated to 180 °C in decane for 4 d. On the other hand, carbon-atom tether between C-2 and C-6 destabilizes the
heating the (1R*,2R*,5S*)-6e diastereomer to 180 °C re- ul-(2.6)-9 transition structure, because of the distortion that
sulted in a slow epimerization at the C-5 carbon atom. results from the formal trans annulation of the cyclopentane
These results, along with the observed ene reaction diaster- and the ‘‘stretched cyclopentane’’ in the bicyclo[3.3.0]oct-
Eur. J. Org. Chem. 2001, 483Ϫ491
485

M. Hiersemann
FULL PAPER
Table 3. Conditions and products for the dienolate [2,3]-Wittig/oxy-Cope rearrangement/type-I ene reaction and the subsequent hydro-
genation
[a]
[b]
Reactions performed in decane using a pressure tube with a threaded plug. Ϫ Racemic products, relative configuration assigned on
[c]
1
[d]
the basis of NOESY experiments. Ϫ Ratio determined from H NMR spectra. Isolated yield after column chromatography. Ϫ 7:3
mixture of double-bond isomers. Ϫ [e] 3:1 mixture of double-bond isomers. Ϫ [f] 2:1 mixture of double-bond isomers. Ϫ [g] The diastereom-
eric ene reaction products were separated by column chromatography but only the (1R*,2R*,5R*) diastereomer was hydrogenated.
the exclusive formation of the 1,2-cis-configured product of
the thermal ene reaction.
The Sequential Ester Dienolate [2,3]-Wittig Rearrangement/
Domino Oxy-Cope Rearrangement/Type-II Ene Reaction
The
3-alkoxycarbonyl-3-hydroxy-5-methyl-substituted
1,5-hexadienes 3gϪi are accessible on a gram scale by me-
ans of the dienolate [2,3]-Wittig rearrangement of the esters
1gϪi (Scheme 5, Table 2, Entries 4Ϫ6).
The domino oxy-Cope rearrangement/ene reactions were
performed by heating the 1,5-hexadienes 3gϪi in toluene,
and afforded the substituted cyclohexanecarboxylates 7aϪc
as single diastereomers (Table 4). No further attempts were
made to optimize the procedure by changing the solvent or
the reaction temperature.
The high induced diastereoselectivities can be explained
by a bicyclic transition state structure 10, in which R1 and
R2 are in equatorial positions (Scheme 6).
Nakai has shown that with (Ϫ)-8-phenylmenthol as a
chiral auxiliary, the ester enolate [2,3]-Wittig rearrangement
proceeds with high simple and auxiliary-induced diastereo-
selectivities.[13] It is also well known that the Lewis acid me-
diated intermolecular ene reaction of pyruvates and glyoxyl-
ates can be performed diastereoselectively if covalently bon-
ded, cyclohexyl-based chiral auxiliaries are employed.[6]
Therefore, we attempted to perform an asymmetric ester
dienolate [2,3]-Wittig/oxy-Cope rearrangement/type-II ene
reaction by using (Ϫ)-8-phenylmenthol as a chiral auxiliary.
Scheme 4. Proposed transition structures for the type-I ene reaction
of the α-oxo ester 5e
ane-type transition structure ul-(2.6)-9 (Scheme 4). The Unfortunately, and somewhat surprisingly, neither the dien-
transition structure lk-(2.6)-9 resembles a less strained cis- olate [2,3]-Wittig rearrangement nor the thermal type-II ene
annulated bicyclo[3.3.0]octane and, consequently, leads to reaction proceeded with any significant auxiliary-induced
486
Eur. J. Org. Chem. 2001, 483Ϫ491

Sequencing Pericyclic Reactions: A New Access to Substituted Carbocycles
FULL PAPER
Scheme 5. The sequential ester dienolate [2,3]-Wittig/oxy-Cope rearrangement/type-II ene reaction
diastereoselectivity (Scheme 7). This result clearly indicates
that alternative approaches toward an asymmetric reaction
sequence have to be pursued.
Table 4. Conditions and products for the dienolate [2,3]-Wittig/oxy-
Cope rearrangement/type-II ene reaction
Further work aimed at extending the method to the syn-
thesis of bicyclic carbocycles and instituting an asymmetric
reaction sequence is currently underway.
Experimental Section
General: All reactions were performed in septum-sealed, flame-
dried flasks under argon. Solvents, reagents, and substrates were
transferred by means of syringes. All solvents were dried by stand-
ard methods. Reagents were used as purchased unless otherwise
noted. Commercial decane (99ϩ%) was used as purchased without
further purification. Commercial nBuLi solutions in hexanes were
titrated following Kofron’s procedure.[14] Crude products were puri-
fied by column chromatography using silica gel (0.040Ϫ0.063 mm)
and mixtures of ethyl acetate and heptane. Ϫ 1H and 13C NMR
spectra were recorded with a Bruker AC 300 or a DRX 500 in
CDCl3. The terms Hmajor and Hminor are used to indicate separated
proton resonance for major or minor diastereomers. The assign-
ment of NMR resonance is based on COSY, HSQC, and NOESY
experiments. Ϫ IR spectra were recorded with a Nicolet 205 FT-
IR spectrometer. Ϫ Elemental analyses were obtained with a Carlo
Erba CHN-S analyzer.
[a]
Reaction performed in toluene using a pressure tube with thre-
[b]
aded plug. Temperature refers to oil bath temperature. Ϫ
Ra-
cemic products, relative configuration assigned based on NOESY
experiments. Ϫ [c] Non-optimized, isolated yield after column chro-
matography.
General Procedure I for the Domino Dienolate [2,3]-Wittig/Oxy-
Cope Rearrangement: Lithium diisopropylamide was prepared by
Scheme 6. Proposed transition structures for the type-II ene reaction
Scheme 7. The attempted auxiliary-controlled domino oxy-Cope rearrangement/type-II ene reaction proved to be inefficient
Eur. J. Org. Chem. 2001, 483Ϫ491
487

M. Hiersemann
FULL PAPER
the addition of n-butyllithium (1.1 equiv.) to a solution of diisopro-
cedure I, the ester 1b (453 mg, 2 mmol) was treated with LDA
pylamine (1.2 equiv.) in THF (2 mL/mmol of ester) at Ϫ78 °C. [prepared in situ from diisopropylamine (2.4 mmol) and nBuLi
After stirring for 30 min at Ϫ78 °C, a cooled (Ϫ78 °C) solution of
the ester 1aϪc (1 equiv.) in THF (2 mL/mmol of ester) was added.
After stirring for 30 min at Ϫ78 °C, the cooling bath was removed
and the reaction mixture was allowed to warm to room temper-
ature. The reaction mixture was then stirred at ambient temper-
ature until TLC indicated the completion of product formation
(2Ϫ4 h). The reaction was quenched by the addition of saturated
aqueous NH4Cl solution and then diluted with water and CH2Cl2.
The layers were separated and the aqueous phase was extracted
with CH2Cl2 (2 ϫ). The combined organic layers were dried
(MgSO4) and concentrated in vacuum. The crude product oil was
(2.2 mmol)] to afford the crude isopropyl 3,7-dimethyl-2-oxooct-6-
enecarboxylate (5b). Following general procedure II, the crude α-
oxo ester 5b was dissolved in decane under argon, filtered into the
reaction tube under argon and heated to 180 °C for 40 h to afford,
after chromatographic purification, the (1R*,2R*,5R*)-cyclopent-
anecarboxylate 6b (355 mg, 78%) as a 74:13:13 mixture with the
(1R*,2R*,5S*) diastereomer and isopropyl 7-methyl-2-oxooct-6-en-
ecarboxylate (5b) as slightly yellow oils. The products were separ-
ated by column chromatography (ethyl acetate/heptane, 10:1) to af-
ford 33 mg of the α-oxo ester 5b, 213 mg of the (1R*,2R*,5R*)
diastereomer and 39 mg of the (1R*,2R*,5S*) diastereomer. Ϫ
purified by column chromatography (ethyl acetate/heptane) or used (1R*,2R*,5R*) Diastereomer: 1H NMR (300 MHz, CDCl3): δ ϭ
without further purification.
0.89 (d, J ϭ 6.8 Hz, 3 H, 5-CH3), 1.27 (d, J ϭ 6.2 Hz, 3 H, OiPr-
CH3), 1.29 (d, J ϭ 6.2 Hz, 3 H, OiPr-CH3), 1.41Ϫ1.59 (m, 1 H, 4-
CH2), 1.72 [s, 3 H, C(CH3)ϭCH2], 1.82Ϫ2.03 (m, 3 H, 4-CH2 and
3-CH2), 2.34Ϫ2.48 (m, 1 H, 5-CH), 2.88 (s, 1 H, OH), 3.02 (dd,
J1 ϭ J2 ϭ 9.1 Hz, 1 H, 2-CH), 4.80 [s, 1 H, C(CH3)ϭCH2], 4.89
[s, 1 H, C(CH3)ϭCH2], 5.09 (qq, J1 ϭ J2 ϭ 6.2 Hz, 1 H, OiPr-
CH). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 12.7 (5-CH3), 21.7
(OiPr-CH3), 22.7 [C(CH3)ϭCH2], 26.7 (3-CH2), 29.9 (4-CH2), 43.7
(5-CH), 54.7 (2-CH), 69.2 (OiPr-CH), 83.7 (C-1), 112.6 [C(CH3)ϭ
General Procedure II for the Thermal Ene Reaction and for the Ther-
mal Domino Oxy-Cope Rearrangement/Carbonyl Ene Reaction: The
crude or purified α-oxo esters or 1,5-hexadienes were dissolved in
toluene or decane (0.5 ) in a pressure tube with a threaded plug,
equipped with a magnetic stirring bar. The sealed pressure tube
was heated in an oil bath to the desired temperature for the appro-
priate time. The solvent was then removed in vacuum and the crude
product oil was purified by column chromatography (ethyl acet-
ate/heptane).
CH2], 143.4 [C(CH3)ϭCH2], 175.7 O).
Ϫ IR: ν˜ ϭ 3520,
3090Ϫ2875, 1720 cmϪ1. Ϫ C13H22O3 (226.3): calcd. C 68.99, H
1
General Procedure III for the Dienolate [2,3]-Wittig Rearrangement:
Lithium diisopropylamide was prepared by the addition of n-butyl-
lithium (1.1 equiv.) to a solution of diisopropylamine (1.2 equiv.)
in THF (2 mL/mmol of ester) at Ϫ78 °C. After stirring for 30 min
at Ϫ78 °C, a cooled (Ϫ78 °C) solution of the ester 1dϪj (1 equiv.)
in THF (2 mL/mmol of ester) was added. The reaction mixture was
slowly warmed to ambient temperature overnight. Alternatively,
the dry ice cooling bath was removed after 30 min and the reaction
mixture was allowed to warm to ambient temperature. The reaction
was then quenched by the addition of saturated aqueous NH4Cl
and then diluted with water and CH2Cl2. The phases were separ-
ated and the aqueous layer was extracted with CH2Cl2 (2 ϫ). The
organic phase was dried (MgSO4) and concentrated. The crude
product could be purified by column chromatography (ethyl acet-
ate/heptane).
9.80; found C 69.07, H 10.12. Ϫ (1R*,2R*,5S*) Diastereomer: H
NMR (500 MHz, CDCl3): δ ϭ 0.96 (d, J ϭ 6.9 Hz, 3 H, 5-CH3),
1.29 (d, J ϭ 6.3 Hz, 6 H, OiPr-CH3), 1.69 [s, 3 H, C(CH3)ϭCH2],
1.22Ϫ1.32 (m, partially covered, 1 H) and 1.92Ϫ1.99 (m, 1 H, 4-
CH2), 1.77Ϫ1.89 (m, 2 H, 3-CH2), 2.14 (m, 1 H, 5-CH), 2.96 (dd,
J1 ϭ 11.4, J2 ϭ 6.9 Hz, 1 H, 2-CH), 3.07 (s, 1 H), 4.75 [s, 1 H,
C(CH3)ϭCH2], 4.87 [s, 1 H, C(CH3)ϭCH2], 5.11 (qq, J1 ϭ J2
ϭ
6.3 Hz, 1 H, OiPr-CH). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 16.2
(5-CH3), 21.9 (OiPr-CH3), 22.8 [C(CH3)ϭCH2], 28.5 (3-CH2), 32.7
(4-CH2), 48.1 (5-CH), 54.3 (2-CH), 69.5 (OiPr-CH), 84.2 (C-1),
112.5 [C(CH3)ϭCH2], 144.0 [C(CH3)ϭCH2], 175.7 (CϭO).
Isopropyl (1R*,2R*,4R*)- and (1R*,2R*,4S*)-1-Hydroxy-2-isoprop-
enyl-4-phenylcyclopentanecarboxylate (6c): Following general pro-
cedure I, the ester 1c (577 mg, 2 mmol) was treated with LDA [pre-
pared in situ from diisopropylamine (2.4 mmol) and nBuLi
(2.2 mmol)] to afford the crude isopropyl 7-methyl-2-oxo-4-
phenyloct-6-enecarboxylate (5c). Following general procedure II,
the crude α-oxo ester 5b was dissolved in decane under argon, fil-
tered into the reaction tube under argon and heated to 180 °C for
40 h to afford, after chromatographic purification, the cyclopent-
anecarboxylate 6c (412 mg, 71%) and the α-oxo ester 5c (68 mg,
12%) as slightly yellow oils. Spectral data reported for a mixture of
diastereomers (1R*,2R*,4R*)-6c/(1R*,2R*,4S*)-6c ؍ 60:40. Ϫ
(1R*,2R*,4R*) Diastereomer: 1H NMR (300 MHz, CDCl3): δ ϭ
1.30 (d, J ϭ 6.2 Hz, 3 H, OiPr-CH3), 1.32 (d, J ϭ 6.2 Hz, 3 H,
OiPr-CH3), 1.74 [s, 3 H, C(CH3)ϭCH2], 2.01 (dd, J1 ϭ 14.3, J2 ϭ
(1R*,2R*)-Isopropyl 1-Hydroxy-2-isopropenylcyclopentanecarbox-
ylate (6a): Following general procedure I, the ester 1a (455 mg,
2.14 mmol) was treated with LDA [prepared in situ from diisoprop-
ylamine (2.57 mmol) and nBuLi (2.35 mmol)] to afford the crude
isopropyl 7-methyl-2-oxooct-6-enecarboxylate 5a. Following gen-
eral procedure II, the crude α-oxo ester 5a was dissolved in decane
under argon, filtered into the reaction tube under argon and heated
to 180 °C for 7 d to afford, after chromatographic purification, the
cyclopentanecarboxylate (6a) (212 mg, 47%) as a 91:9 mixture with
the (1R*,2S*) diastereomer and isopropyl 7-methyl-2-oxooct-6-ene-
1
carboxylate (5a) (101 mg, 22%) as slightly yellow oils. Ϫ H NMR
(500 MHz, CDCl3): δ ϭ 1.26 (d, J ϭ 6.3 Hz, 3 H, OiPr-CH3), 1.27
(d, J ϭ 6.3 Hz, 3 H, OiPr-CH3), 1.69 [s, 3 H, C(CH3)ϭCH2],
1.80Ϫ1.95 (m, 5 H) and 2.18Ϫ2.26 (m, 1 H, 3-, 4-, 5-CH2), 2.80
(dd, J1 ϭ 11.4, J2 ϭ 6.9 Hz, 1 H, 2-CH), 2.88 (s, 1 H, OH), 4.79
[s, 1 H, C(CH3)ϭCH2], 4.91 [s, 1 H, C(CH3)ϭCH2], 5.06 (qq, J1 ϭ
J2 ϭ 6.3 Hz, 1 H, OiPr-CH). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ
21.7 (OiPr-CH3), 23.0 [C(CH3)ϭCH2], 22.3, 28.7, 39.2 (3-, 4-, 5-
CH2), 69.3 (OiPrϪCH), 81.7 (C-1), 113.1 [C(CH3)ϭCH2], 142.8
[C(CH3)ϭCH2], 176.2 (CϭO). Ϫ C12H20O3 (212.3): calcd. C 67.81,
H 9.50; found C 67.86, H 9.92.
8.4 Hz, 1 H, 5-CH2), 2.11Ϫ2.21 (m, 2 H, 3-CH2), 2.77 (dd, J1
14.3, J2 ϭ 10.1 Hz, 1 H, 5-CH2), 3.00 (dd, J1 ϭ 10.9, J2 ϭ 8.0 Hz,
1 H, 2-CH), 3.10 (s, 1 H, OH), 3.28 (m, 1 H, 4-CH), 4.83 [s, 1 H,
C(CH3)ϭCH2], 4.97 [s, 1 H, C(CH3)ϭCH2], 5.11 (qq, J1 ϭ J2
ϭ
ϭ
6.3, 1 H, OiPr-CH), 7.15Ϫ7.38 (m, 5 H, aryl-H). Ϫ 13C NMR
(125 MHz, CDCl3): δ ϭ 21.6 (OiPr-CH3), 22.8 [C(CH3)ϭCH2],
38.7 (3-CH2), 42.8 (4-CH), 47.7 (5-CH2), 55.9 (2-CH), 69.6 (OiPr-
CH), 81.3 (1-C), 113.4 [C(CH3)ϭCH2], 126.0, 127.2, 128.3, 142.2,
144.9 [aryl-C and C(CH3)ϭCH2), 176.1 (CϭO). Ϫ (1R*,2R*,4S*)
Diastereomer: 1H NMR (300 MHz, CDCl3): δ ϭ 1.28 (d, J ϭ
6.2 Hz, 3 H, OiPr-CH3), 1.31 (d, J ϭ 6.2 Hz, 3 H, OiPr-CH3), 1.76
[s, 3 H, C(CH3)ϭCH2], 1.94Ϫ2.06 (m, 1 H, 3-CH2), 2.28Ϫ2.37 (m,
Isopropyl (1R*,2R*,5R*)- and (1R*,2R*,5S*)-1-Hydroxy-2-isoprop-
enyl-5-methylcyclopentanecarboxylate (6b): Following general pro-
488
Eur. J. Org. Chem. 2001, 483Ϫ491

Sequencing Pericyclic Reactions: A New Access to Substituted Carbocycles
FULL PAPER
2 H, 5-CH2), 2.50 (ddd, J1 ϭ 13.2, J2 ϭ J3 ϭ 10.5 Hz, 1 H, 3- ,3R*) ϭ 98:2]. Following general procedure II, the 1,5-hexadiene
CH2), 3.08 (s, 1 H, OH), 3.28 (m, 1 H, 2-CH), 3.60 (m, 1 H, 4-
3e (481 mg, 2 mmol) was dissolved in decane and heated for 7 d at
CH), 4.87 [s, 1 H, C(CH3)ϭCH2], 4.97 [s, 1 H, C(CH3)ϭCH2], 5.17 180 °C (oil bath temperature). The solvent was then evaporated
(qq, J1 ϭ J2 ϭ 6.3 Hz, 1 H, OiPr-CH), 7.15Ϫ7.38 (m, 5 H, aryl-
under reduced pressure and the crude product was purified by chro-
H). Ϫ 13C NMR (125 MHz, CDCl3) δ ϭ 21.4 (OiPr-CH3), 22.9 matography to afford isopropyl (1R*,2R*,5R*)-2-[(E/Z)-but-1-
[C(CH3)ϭCH2], 36.4 (3-CH2), 41.6 (4-CH), 47.4 (5-CH2), 54.2 (2-
enyl]-1-hydroxy-5-methylcyclopentanecarboxylate (6e) (314 mg,
CH), 69.6 (OiPr-CH), 82.8 (1-C), 113.3 [C(CH3)ϭCH2], 126.0, 65%, 3:1 mixture of double-bond isomers) and the (1R*,2R*,5S*)
126.9, 128.4, 142.7, 146.1 [aryl-C and C(CH3)ϭCH2), 175.3 (Cϭ
diastereomer (117 mg, 24%, 2:1 mixture of double-bond isomers)
O). Ϫ IR ν˜ ϭ 3485, 3085Ϫ2875, 1720 cmϪ1. Ϫ C18H24O3 (288.4): as colorless oils. NMR-spectroscopic data determined from a mix-
calcd. C 74.97, H 8.39; found C 75.14, H 8.77.
ture of double bond isomers. Ϫ (1R*,2R*,5R*) Diastereomer: 1H
NMR (500 MHz, CDCl3): δ ϭ 0.87 (d, J ϭ 6.9 Hz, 3 H, 5-CH3),
Isopropyl (1R*,2R*)-2-[(E/Z)-But-1-enyl]-1-hydroxycyclopentane-
carboxylate (6d): Following general procedure III, the ester 1d (453
mg, 2 mmol) was treated with LDA [prepared in situ from diisopro-
pylamine (2.4 mmol) and nBuLi (2.2 mmol)] to afford isopropyl 2-
hydroxy-3-propyl-2-vinylpent-4-enecarboxylate (3d) (395 mg, 87%)
as a colorless oil after chromatographic purification [diastereomeric
ratio (2R*,3S*)/(2R*,3R*) ϭ 91:9]. Following general procedure II,
the 1,5-hexadiene 3d (395 mg, 1.75 mmol) was dissolved in decane
and heated for 7 d at 180 °C (oil bath temperature). The solvent
was then evaporated under reduced pressure and the crude product
was purified by chromatography to afford isopropyl 2-[(E/Z)-but-
1-enyl]-1-hydroxycyclopentanecarboxylate (6d) (313 mg, 79%) as a
colorless oil. NMR-spectroscopic data determined from a 69:31
0.92 (t, J ϭ 7.6 Hz, 3 H, 4Ј-CH3), 1.239 (d, J ϭ 6.3 Hz, 6 Hmajor
,
OiPr-CH3) 1.241 (d, J ϭ 6.3 Hz, 6 Hminor, OiPr-CH3), 1.42Ϫ1.50
(m, 1 H, 4-CH2), 1.65Ϫ1.74 (m, 1 H, 3-CH2), 1.82Ϫ2.07 (m, 4 H,
3-, 4-, 3Ј-CH2), 2.32Ϫ2.43 (m, 1 H, 5-CH), 2.84 (td, J1 ϭ 9.3, J2 ϭ
9.0 Hz, 2-CH), 2.89 (s, 1 Hmajor, OH), 2.97 (s, 1 Hminor, OH), 3.21
(td, J1 ϭ 9.8, J2 ϭ 9.7 Hz, 1 Hminor, 2-CH), 5.04 (qq, J1 ϭ J2
ϭ
6.2 Hz, 1 Hminor, OiPr-CH), 5.08 (qq, J1 ϭ J2 ϭ 6.3 Hz, 1 Hmajor
,
OiPr-CH), 5.34Ϫ5.48 (m, 2 H, 2Ј-, 3Ј-CH). Ϫ IR: ν˜ ϭ 3530,
2960Ϫ2875, 1720 cmϪ1. Ϫ C14H24O3 (240.3): calcd. C 69.96, H
10.06; found C 69.64, H 10.36. Ϫ (1R*,2R*,5S*) Diastereomer: 1H
NMR (300 MHz, CDCl3): δ ϭ 0.91Ϫ1.01 (series of d and t, 6 H,
5-CH3 and 4ЈCH3), 1.26Ϫ1.32 (series of d, 6 H, OiPr-CH3),
1.57Ϫ1.73 (m, 1 H, 3-CH2), 1.79Ϫ1.92 (m, 1 H, 3-CH2), 1.95Ϫ2.10
(m, 4 H, 3Ј-, 4-CH2), 2.10 Ϫ2.22 (m, 1 H, 5-CH), 2.89 (ddd, J1 ϭ
11, J2 ϭ J3 ϭ 7.5 Hz, 1 Hmajor, 2-CH), 2.98 (br s, 1 H, OH), 3.23
(ddd, J1 ϭ 10.7, J2 ϭ 9.1, J3 ϭ 7.5 Hz, 1Hminor, 2-CH), 5.10 (qq,
J1 ϭ J2 ϭ 6.4 Hz, 1 H, OiPr-CH), 5.33Ϫ5.55 (m, 2 H, 2Ј-, 3ЈCH).
1
mixture of double-bond isomers. Ϫ H NMR (500 MHz, CDCl3):
δ ϭ 0.92 (t, J ϭ 7.6 Hz, 3 Hminor, 4Ј-CH3), 0.94 (t, J ϭ 7.6 Hz, 3
Hmajor, 4Ј-CH3), 1.246 (d, J ϭ 6.3 Hz, 6 Hmajor, OiPr-CH3), 1.253
(d, J ϭ 6.3 Hz, 6 Hminor, OiPr-CH3), 1.63Ϫ2.07 (m, 7 H, 3-, 4-, 5-
, 3Ј-CH2), 2.14Ϫ2.26 (m, 1 H, 4-CH2), 2.68 (ddd, J1 ϭ 10.6 Hz,
J2 ϭ J3 ϭ 8.4 Hz, 1 Hmajor, 2-CH), 2.92 (s, 1 Hmajor, OH),
Ϫ
13C NMR (125 MHz, CDCl3, major isomer): δ ϭ 13.8 and 17.2
(4Ј-CH3 and 5-CH3), 21.8 (OiPr-CH3), 25.7 (3Ј-CH2), 30.1 (3-CH2),
32.5 (4-CH2), 46.7 (5-CH), 50.3 (2-CH), 69.2 (OiPr-CH), 85.5 (C-
1), 127.0 (1Ј-CH), 134.4 (2Ј-CH), 175.1 (CϭO). Ϫ 13C NMR
(125 MHz, CDCl3, minor isomer): δ ϭ 14.6 and 16.5 (4Ј-CH3 and
5-CH3), 21.0 (3Ј-CH2), 21.8 (OiPr-CH3), 31.5 (3-CH2), 32.9 (4-
CH2), 45.0 (2-CH), 47.4 (5-CH), 69.5 (OiPr-CH), 127.3 (1Ј-CH),
133.3 (2Ј-CH), 175.4 (CϭO).
3.01Ϫ3.08 (m, partially covered, 1 Hminor, 2-CH), 3.03 (s, 1 Hminor
,
OH), 5.00Ϫ5.09 (m, 1 H, OiPr-CH), 5.29Ϫ5.37 (m, 1 H, 2Ј-CH),
5.43Ϫ5.52 (m, 1 H, 3Ј-CH). Ϫ 13C NMR (125 MHz, CDCl3, major
isomer) δ ϭ 13.9 (4Ј-CH3), 21.9 (OiPr-CH3), 22.6 (5-CH2), 25.7
(3Ј-CH2), 30.2 (3-CH2), 37.9 (4-CH2), 53.0 (2-CH), 69.2 (OiPr-CH),
83.4 (C-1), 126.0 and 135.3 (1Ј-, 2Ј-CH), 175.9 (CϭO). Ϫ 13C NMR
(125 MHz, CDCl3, minor isomer) δ ϭ 14.6 (4Ј-CH3), 21.2 (3Ј-
CH2), 21.8 (OiPr-CH3), 23.0 (5-CH2), 31.5 (3-CH2), 38.6 (4-CH2),
47.3 (2-CH), 69.5 (OiPr-CH), 83.4 (C-1), 126.2 and 134.2 (1Ј-, 2Ј-
CH), 176.1 (CϭO). Ϫ IR: ν˜ ϭ 3530, 2980Ϫ2875, 1725 cmϪ1. Ϫ
C13H22O3 (226.3): calcd. C 68.99, H 9.80; found C 69.14, H 10.19.
Isopropyl
anecarboxylate (8e): Isopropyl (1R*,2R*5R*)-2-[(E/Z)-but-1-enyl]-
1-hydroxy-5-methylcyclopentanecarboxylate (6e) (300 mg,
(1R*,2R*,5R*)-2-Butyl-1-hydroxy-5-methylcyclopent-
1.25 mmol) was dissolved in 2-propanol (7.5 mL). 10% Pd/C (66.5
mg, 0.063 mmol Pd) was added and the reaction mixture was
stirred under H2 (balloon) for 3 d at ambient temperature. The
solvent was then removed and the crude product was purified by
column chromatography (ethyl acetate/heptane, 10:1) to afford the
Isopropyl
(1R*,2R*)-2-Butyl-1-hydroxycyclopentanecarboxylate
(8d): Isopropyl (1R*,2R*)-2-[(E/Z)-but-1-enyl]-1-hydroxycyclopen-
tanecarboxylate (6d) (257 mg, 1.14 mmol) was dissolved in 2-pro-
panol (6 mL). 10% Pd/C (60.4 mg, 0.057 mmol Pd) was added and
the reaction mixture was stirred under H2 (balloon) for 2 d at ambi-
ent temperature. The solvent was then removed and the crude prod-
uct was purified by column chromatography (ethyl acetate/heptane,
1
ester 8e as a colorless oil (264 mg, 88%). Ϫ H NMR (300 MHz,
CDCl3): δ ϭ 0.855 (t, J ϭ 7.0 Hz, 3 H), 0.864 (d, J ϭ 6.8 Hz, 3
H), 1.11Ϫ1.48 (m, partially covered, 6 H), 1.26 (d, J ϭ 6.3 Hz, 3
H), 1.27 (d, J ϭ 6.3 Hz, 3 H), 1.79Ϫ1.99 (m, 2 H), 2.23Ϫ2.37 (m,
2 H), 2.96 (s, 1 H), 5.10 (qq, J1 ϭ J2 ϭ 6.3 Hz, 1 H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 12.5, 13.9, 21.6, 21.7, 22.8, 28.9, 29.0, 30.1,
30.3, 43.8, 48.4, 69.2, 83.8, 176.5. Ϫ IR: ν˜ ϭ 3530, 2960Ϫ2870,
1720 cmϪ1. Ϫ C14H26O3 (242.4) calcd. C 69.38, H 10.81; found C
69.35, H 11.13.
1
5:1) to afford the ester 8d as a colorless oil (221 mg, 86%). Ϫ H
NMR (300 MHz, CDCl3): δ ϭ 0.86 (t, J ϭ 6.2 Hz, 3 H), 1.13Ϫ1.52
(m, partially covered, 5 H), 1.268 (d, J ϭ 6.2 Hz, 3 H), 1.273 (d,
J ϭ 6.2 Hz, 3 H), 1.63Ϫ1.98 (m, 5 H), 2.04Ϫ2.21 (m, 2 H), 3.11
(s, 1 H), 5.08 (qq, J1 ϭ J2 ϭ 6.3 Hz, 1 H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 13.8, 21.6, 22.4, 22.8, 28.0, 30.4, 39.3, 48.9, 69.1, 82.3,
176.9. Ϫ IR: ν˜ ϭ 3525, 2960Ϫ2860, 1720 cmϪ1. Ϫ C13H24O3
(228.3): calcd. C 68.38, H 10.59; found C 68.18, H 10.86.
Isopropyl (1R*,2R*,4R*)- and (1R*,2R*,4S*)-2-[(E/Z)-But-1-enyl]-
1-hydroxy-4-phenylcyclopentanecarboxylate (6f): Following general
procedure III, the ester 1f (605 mg, 2 mmol) was treated with LDA
[prepared in situ from diisopropylamine (2.4 mmol) and nBuLi
(2.2 mmol)] to afford isopropyl 2-hydroxy-2-[(E)-styryl]-3-vinyl-
hexanoate 3f (571 mg, 94%) as a colorless oil after chromatographic
purification [diastereomeric ratio (2S*,3S*)/(2S*,3R*) ϭ 79:21].
Following general procedure II, the 1,5-hexadiene 3f (571 mg,
1.89 mmol) was dissolved in decane and heated for 40 h at 180
Isopropyl (1R*,2R*,5R*)- and (1R*,2R*,5S*)-2-[(E/Z)-But-1-enyl]-
1-hydroxy-5-methylcyclopentanecarboxylate (6e): Following general
procedure III, the ester 1e (2.23 g, 9.3 mmol) was treated with LDA
[prepared in situ from diisopropylamine (11.1 mmol) and nBuLi
(10.2 mmol)] to afford isopropyl 2-hydroxy-2-isopropenyl-3-pro-
pylpent-4-enecarboxylate (3e) (1.96 g, 88%) as a colorless oil after
chromatographic purification [diastereomeric ratio (2S*,3S*)/(2S*
Eur. J. Org. Chem. 2001, 483Ϫ491
489

M. Hiersemann
FULL PAPER
°C (oil bath temperature). The solvent was then evaporated under
reduced pressure and the crude product was purified by chromato-
graphy to afford the pure (1R*,2R*,4R*) diastereomer (269 mg,
47%, 3:1 mixture of double-bond isomers) and a mixture of diaster-
orless oil after chromatographic purification. Following general
procedure II, the 1,5-hexadiene 3g (310 mg, 1.56 mmol) was dis-
solved in toluene and heated for 14 h at 200 °C (oil bath temper-
ature). The solvent was then evaporated under reduced pressure
eomers [237 mg, 42%, (1R*,2R*,4S*)/(1R*,2R*,4R*) ϭ 3:2] as col- and the crude product was purified by chromatography to afford
orless oils. The (1R*,2R*,4S*) diastereomer was isolated as a 2:1
mixture of double-bond isomers. NMR spectroscopic data deter-
mined from a mixture of double bond isomers. Ϫ (1R*,2R*,5R*)
7a (242 mg, 78%) as a colorless oil. Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.28 (d, J ϭ 6.5 Hz, 6 H), 1.66Ϫ1.95 (m, 4 H),
2.01Ϫ2.14 (m, 1 H), 2.23 (d, J ϭ 13.6 Hz, 1 H), 2.27Ϫ2.38 (m,
Diastereomer: 1H NMR (300 MHz, CDCl3): δ ϭ 0.94 (t, J ϭ partially covered, 1 H), 2.57 (d, J ϭ 13.6 Hz, 1 H), 2.95 (s, 1 H),
7.5 Hz, 3 Hminor, 4Ј-CH3), 0.96 (t, J ϭ 7.5 Hz, 3 Hmajor, 4Ј-CH3), 4.73 (d, J ϭ 2 Hz, 1 H), 4.82 (d, J ϭ 1.6 Hz, 1 H), 5.09 (qq, J1 ϭ
1.28 (d, J ϭ 6.2 Hz, 6 H, OiPr-CH3), 1.92Ϫ2.22 (m, 5 H, 3-, 5-,
3Ј-CH2), 2.75Ϫ2.90 (m, 2 H, 5-CH2, 2-CH), 3.10Ϫ3.20 (m, 2 H, 4-
J2 ϭ 6.3 Hz, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 21.7, 22.4,
33.9, 34.2, 43.6, 69.5, 110.8, 144.2, 175.7. Ϫ IR: ν˜ ϭ 3500, 1725
CH, OH), 5.08 (qq, J1 ϭ J2 ϭ 6.3 Hz, 1 Hminor, OiPr-CH), 5.09 cmϪ1. Ϫ C11H18O3 (198.3): calcd. C 66.64, H 9.15; found C 66.90,
(qq, J1 ϭ J2 ϭ 6.3 Hz, 1 Hmajor, OiPr-CH), 5.37Ϫ5.60 (m, 2 H, 1Ј-, H 9.36.
2Ј-CH), 7.13Ϫ7.21 and 7.24Ϫ7.38 (m, 5 H, aryl-H). ). Ϫ 13C NMR
Isopropyl
(1S*,2R*)-1-Hydroxy-2-methyl-5-methylenecyclohex-
(75 MHz, CDCl3, major, minor double-bond isomer): δ ϭ 13.7,
14.5 (4Ј-CH3), 21.7, 21.8 (OiPr-CH3), 25.7, 21.2 (3Ј-CH2), 40.5,
41.6 (3-CH2), 43.4, 43.8 (4-CH), 46.4, 47.0 (5-CH2), 53.7, 48.1 (2-
CH), 69.3, 69.5 (OiPr-CH), 82.74, 82.96 (C-1), 125.2, 125.4 (1Ј-
CH), 126.0, 127.3, 128.3, 135.6, 134.5 (aryl-CH), 145.4, 145.2 (2Ј-
CH), 175.5, 175.8 (CϭO).
anecarboxylate (7b): Following general procedure III, the ester 1h
(1 g, 4.71 mmol) was treated with LDA [prepared in situ from diiso-
propylamine (5.65 mmol) and nBuLi (5.18 mmol)] to afford isopro-
pyl 2-hydroxy-4-methyl-2-isopropenylpent-4-enecarboxylate (3h)
(721 mg, 72%) as a colorless oil after chromatographic purification.
Following general procedure II, the 1,5-hexadiene 3h (350 mg,
1.65 mmol) was dissolved in toluene and heated for 2 d at 200 °C
(oil bath temperature). The solvent was then evaporated under re-
duced pressure and the crude product was purified by chromato-
Isopropyl (1R*,2R*,4R*)- and (1R*,2R*,4S*)-2-Butyl-1-hydroxy-4-
phenylcyclopentanecarboxylate (8f): Isopropyl 2-[(E/Z)-but-1-enyl]-
1-hydroxy-4-phenylcyclopentanecarboxylate
(6f)
(526
mg,
1
1.74 mmol) was dissolved in 2-propanol (9 mL). 10% Pd/C (185
mg, 0.174 mmol Pd) was added and the reaction mixture was
stirred under H2 (balloon) for 3 d at ambient temperature. The
solvent was then removed and the crude product was purified by
column chromatography (ethyl acetate/heptane, 5:1) to afford the
ester 8f (483 mg, 92%) as a (4R*)/(4S*) ϭ 3:1 mixture of diastereo-
mers. The diastereomers could be separated by column chromato-
graphy. Ϫ (1R*,2R*,4R*) Diastereomer: 1H NMR (500 MHz,
graphy to afford 7b (249 mg, 71%) as a colorless oil. Ϫ H NMR
(300 MHz, CDCl3) δ ϭ 0.79 (d, J ϭ 6.8 Hz, 3 H, 2-CH3), 1.29 (d,
J ϭ 6.2 Hz, 6 H, OiPr-CH3), 1.47 (ddd, J1 ϭ 26, J2 ϭ 13, J3
ϭ
4 Hz, 1 H, 3-H), 1.55Ϫ1.65 (m, 1 H, 3-H), 1.95Ϫ2.07 (m, 1 H, 2-
H), 2.07Ϫ2.20 (m, 1 H, 4-H), 2.27 (dd, J1 ϭ 13.3, J2 ϭ 2 Hz, 1 H,
6-H), 2.35 (m, 1 H, 4-H), 2.54 (dd, J1 ϭ 13.3, J2 ϭ 2 Hz, 1 H, 6-
H), 3.00 (s, 1 H, OH), 4.72 (dd, J1 ϭ 3, J2 ϭ 1 Hz, 1 H, CϭCH2),
4.81 (dd, J1 ϭ 4, J2 ϭ 2 Hz, 1 H, CϭCH2), 5.09 (qq, J1 ϭ J2 ϭ
CDCl3): δ ϭ 0.87 (t, J ϭ 7.0 Hz, 3 H, 4Ј-CH3), 1.18Ϫ1.47 (m, 6.3 Hz, 1 H, OiPrCH). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 15.1
partially covered, 6 H, 1Ј-, 2Ј-, 3Ј-CH2), 1.29 (d, J ϭ 6.2 Hz, 6 H,
OiPr-CH3), 1.68 (ddd, J1 ϭ J2 ϭ 14.0, J3 ϭ 11.4 Hz, 1 H, 3-CH2),
(2-CH3), 21.6 and 21.8 (OiPr-CH3), 30.4 (3-CH2), 34.1 (4-CH2),
36.9 (2-CH), 44.3 (6-CH2), 69.6 (OiPr-CH), 110.6 (CϭCH2) 143.6
1.93 (dd, J1 ϭ 14.0, J2 ϭ 8.0 Hz, 1 H, 5-CH2), 2.18Ϫ2.31 (m, 2 H, (5-C), 175.7 (CϭO). Ϫ IR: ν˜ ϭ 3525, 2900Ϫ2835, 1720 cmϪ1. Ϫ
3-CH2 and 2-CH), 2.74 (dd, J1 ϭ 14.0, J2 ϭ 10.0 Hz, 1 H, 5-CH2),
3.17Ϫ3.32 (m, partially covered, 1 H, 4-CH), 3.29 (s, 1 H, OH),
5.11 (qq, J1 ϭ J2 ϭ 6.3 Hz, 1 H, OiPr-CH), 7.13Ϫ7.20 and
7.24Ϫ7.35 (m, 5 H, aryl-H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ
13.9 (4Ј-CH3), 21.6 and 21.7 (OiPr-CH3), 22.8 (3Ј-CH2), 27.6 and
30.3 (1Ј-, 2Ј-CH2), 39.3 (3-CH2), 43.4 (4-CH), 47.9 (5-CH2), 49.9
(5-CH), 69.5 (OiPr-CH), 81.8 (C-1), 125.9, 127.3, 128.3 and 145.7
C11H18O3 (212.3): calcd. C 67.89, H 9.50; found C 68.55, H 10.08.
Isopropyl (1R*,3S*)-1-Hydroxy-5-methylene-3-phenylcyclohex-
anecarboxylate (7c): Following general procedure III, the ester 1i
(549 mg, 2 mmol) was treated with LDA [prepared in situ from
diisopropylamine (2.4 mmol) and nBuLi (2.2 mmol)] to afford iso-
propyl 2-hydroxy-4-methyl-2-[(E)-styryl]pent-4-enecarboxylate (3i)
(490 mg, 89%) as a colorless oil after chromatographic purification.
Following general procedure II, the 1,5-hexadiene 3i (330 mg,
1.2 mmol) was dissolved in toluene and heated for 19 h at 200 °C
(oil bath temperature). The solvent was then evaporated under re-
duced pressure and the crude product was purified by chromato-
graphy to afford the diastereomerically pure 7c (279 mg, 85%) as a
colorless oil. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.28 (d, J ϭ
6.2 Hz, 3 H, OiPrCH3), 1.29 (d, J ϭ 6.2 Hz, 3 H, OiPr-CH3), 1.91
(m, 1 H, 2-H), 2.05 (dd, J1 ϭ J2 ϭ 12.8 Hz, 1 H, 2-H), 2.29 (dd,
J1 ϭ J2 ϭ 12.5 Hz, 1 H, 4-H), 2.35 (td, J1 ϭ 13.2, J2 ϭ 1.5 Hz, 1
H, 6-H), 2.57 (m, 1 H, 4-H), 2.65 (dd, J1 ϭ 13.3, J2 ϭ 1.3 Hz, 1
H, 6-H), 3.13 (dddd, J1 ϭ J2 ϭ 12.7, J3 ϭ J4 ϭ 3.7 Hz, 1 H, 3-H),
4.89 (dd, J1 ϭ 2.9, J2 ϭ 1.3 Hz, 1 H, CϭCH2), 4.92 (dd, J1 ϭ 3.4,
J2 ϭ 1.8 Hz, 1 H, CϭCH2), 5.09 (qq, J1 ϭ J2 ϭ 6.3 Hz, 1 H, OiPr-
CH3), 7.19Ϫ7.36 (m, 5 H, aryl-H). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 21.7 (OiPr-CH3), 39.9 (3-CH), 41.5, 41.7 (2-CH2, 4-CH2), 42.9
(6-CH2), 69.9 (OiPr-CH), 74.5 (1-C), 111.7 (CϭCH2), 126.5, 126.9,
(aryl-C), 176.8 (CϭO). Ϫ IR: ν˜ ϭ 3495, 2985Ϫ2860, 1710 cmϪ1
.
Ϫ C19H28O3 (304.4) calcd. C 74.96, H 9.27; found C 74.72, H 9.43.
1
White solid. Ϫ (1R*,2R*,4S*) Diastereomer: H NMR (500 MHz,
CDCl3): δ ϭ 0.89 (t, J ϭ 7.3 Hz, 3 H, 4Ј-CH3), 1.30 (d, J ϭ 6.3 Hz,
3 H, OiPr-CH3), 1.31 (d, J ϭ 6.3 Hz, 3 H, OiPr-CH3), 1.28Ϫ1.48
(m, partially covered, 6 H, 1Ј-, 2Ј-, 3Ј-CH2), 1.98Ϫ2.10 (m, 1 H, 2-
CH2), 2.19Ϫ2.31 (m, 2 H, 5-CH2), 2.55 (dddd, J1 ϭ J2 ϭ J3 ϭ 9.1,
J4 ϭ 5.7 Hz, 1 H, 2-CH), 3.28 (s, 1 H, OH), 3.56 (m, 1 H, 4-CH),
5.13 (qq, J1 ϭ J2 ϭ 6.2 Hz, OiPr-CH), 7.17Ϫ7.22 and 7.27Ϫ7.36
(m, 5 H, aryl-CH). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 13.9 (4Ј-
CH3), 21.6 (OiPr-CH3), 22.8 (2Ј-CH2), 28.7 and 30.3 (1Ј-, 3Ј-CH2),
38.6 (3-CH2), 41.9 (4-CH), 47.8 (5-CH2), 47.9 (5-CH), 69.5 (OiPr-
CH), 82.9(C-1), 125.9, 126.9, 128.4 and 146.5 (aryl-CH), 176.1
(CϭO).
Isopropyl 1-Hydroxy-3-methylenecyclohexanecarboxylate (7a): Fol-
lowing general procedure III, the ester 1g (397 mg, 2 mmol) was
treated with LDA [prepared in situ from diisopropylamine 128.5 (aryl-CH), 143.5, 145.2 (aryl-C, 5-C), 175.6 (CϭO). Ϫ IR:
(2.4 mmol) and nBuLi (2.2 mmol)] to afford isopropyl 2-hydroxy-
4-methyl-2-vinylpent-4-enecarboxylate (3g) (324 mg, 82%) as a col-
ν˜ ϭ 3510, 3070Ϫ2835, 1725 cmϪ1. Ϫ C17H22O3 (274.4): calcd. C
74.42, H 8.08; found C 74.19, H 8.45.
490
Eur. J. Org. Chem. 2001, 483Ϫ491

Sequencing Pericyclic Reactions: A New Access to Substituted Carbocycles
FULL PAPER
2765Ϫ2775. Ϫ [7b] K. Mikami, Y. Koizumi, A. Osawa, M. Ter-
Acknowledgments
ada, H. Takayama, K. Nakagawa, Synlett 1999, 1899Ϫ1902.
[7c]
Ϫ
H. Okamoto, H. Arita, N. Kato, H. Takeshita, Chem.
Financial support from the state of Saxony (habilitation fellow-
ship), the Fonds der Chemischen Industrie and the DFG is grate-
fully acknowledged. I thank Prof. H.-U. Reißig and Prof. P. Metz
for their support and Dr. M. Gruner for numerous NMR measure-
ments.
Lett. 1994, 2335Ϫ2338. Ϫ [7d] T. Ooi, K. Maruoka, H. Yamam-
[7e]
oto, Tetrahedron 1994, 50, 6505Ϫ6522. Ϫ
J. A. Marshall,
[7f]
M. W. Andersen, J. Org. Chem. 1993, 58, 3912Ϫ3918. Ϫ
J.
A. Marshall, M. W. Andersen, J. Org. Chem. 1992, 57,
[7g]
5851Ϫ5856. Ϫ
F. E. Ziegler, S. B. Sobolov, J. Am. Chem.
[7h]
Soc. 1990, 112, 2749Ϫ2758. Ϫ
K. Maruoka, T. Ooi, H.
Yamamoto, J. Am. Chem. Soc. 1990, 112, 9011Ϫ9012. Ϫ [7i] K.
[1]
[1a] L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137Ϫ170;
Takahashi, H. Sato, K. Mikami, T. Nakai, Chem. Lett. 1989,
[7j]
[1b]
247Ϫ250. Ϫ
M. I. Johnston, J. A. Kwass, R. B. Beal, B. B.
Angew. Chem. Int. Ed. Engl. 1993, 32, 131Ϫ312. Ϫ
L. F.
Snider, J. Org. Chem. 1987, 52, 5419Ϫ5424. Ϫ [7k] B. B. Snider,
[1c]
Tietze, Chem. Rev. 1996, 96, 115Ϫ136. Ϫ
Nachr. Chem. Tech. Lab. 1997, 12, 1181Ϫ1187.
L. F. Tietze,
[7l]
E. Ron, J. Am. Chem. Soc. 1985, 107, 8160Ϫ8164. Ϫ
N. H.
[2]
Andersen, S. W. Hadley, J. D. Kelly, E. R. Bacon, J. Org. Chem.
For selected examples of sequential pericyclic transformations,
[7m]
[2a]
1985, 50, 4144Ϫ4151. Ϫ
F. E. Ziegler, T. Wang, J. Am.
see:
720Ϫ722. Ϫ
mann, R. O. Cann, J. I. Kravitz, M. J. Martinelli, J. Org. Chem.
S. Saito, K. Shimada, H. Yamamoto, Synlett 1996,
Chem. Soc. 1984, 106, 718Ϫ721. Ϫ [7n] B. B. Snider, M. Karras,
R. T. Price, D. J. Rodini, J. Org. Chem. 1982, 47, 4538Ϫ4545.
For a review, see L. A. Paquette, Tetrahedron 1997, 41,
13971Ϫ14020.
[2b]
P. A. Jacobi, L. M. Armacost, H. L. Briel-
[8]
[9]
[2c]
1994, 59, 5292Ϫ5304. Ϫ
Nakai, J. Am. Chem. Soc. 1990, 112, 4035. Ϫ
N. Kishi, T. Nakai, Y. Fujita, Tetrahedron 1986, 42,
K. Mikami, K. Takahashi, T.
[2d]
K. Mikami,
[9a] L. Lorenc, M. Rajkovic, A. Milovanovic, M. L. Mihailovic,
[2e]
[9b]
2911Ϫ2917. Ϫ
F. E. Ziegler, J. J. Mencel, Tetrahedron Lett.
J. Chem. Soc., Perkin Trans. 1 1988, 1495Ϫ1498. Ϫ
S. Jan-
1984, 25, 123Ϫ126. Ϫ [2f] K. Mikami, S. Taya, T. Nakai, J. Org.
Chem. 1981, 46, 5449Ϫ5450.
ardhanam, K. Rajagopalan, J. Chem. Soc., Perkin Trans. 1
1992, 2727Ϫ2728. Ϫ [9c] S. Janardhanam, B. Devan, K. Rajago-
palan, Tetrahedron Lett. 1993, 34, 6761Ϫ6764. Ϫ [9d] A. Balak-
[3] [3a]
M. Hiersemann, C. Lauterbach, A. Pollex, Eur. J. Org.
[3b]
umar, S. Janardhanam, K. Rajagopalan, J. Org. Chem. 1993,
Chem. 1999, 2713Ϫ2724. Ϫ
M. Hiersemann, Tetrahedron
[9e]
58, 5482Ϫ5486. Ϫ
P. Shanmugam, K. Rajagopalan, Tetra-
1999, 55, 2625Ϫ2638.
[9f]
[4]
[5]
hedron 1996, 52, 7744. Ϫ
J. M. Warrington, G. P. A. Yap,
M. Hiersemann, Synlett 2000, 415Ϫ417.
L. Barriault, Org. Lett. 2000, 2, 663Ϫ665.
M. Hiersemann, Synthesis 2000, 9, 1279Ϫ1290.
The retro ene reaction leading to an enone with a trisubstituted
double bond is a significant side reaction when divinylcyclo-
hexanols are heated, see: J. M. Warrington, G. P. A. Yap, L.
Barriault, Org. Lett. 2000, 2, 663Ϫ665.
R. J. Loncharich, K. N. Houk, J. Am. Chem. Soc. 1987, 109,
6947Ϫ6952.
For the domino [2,3]-Wittig/oxy-Cope rearrangement of dial-
[10]
[11]
lylic ethers, see: [5a]N. Greeves, W. Lee, Tetrahedron Lett. 1997,
[5b]
36, 6445Ϫ6448. Ϫ
N. Greeves, W. Lee, Tetrahedron Lett.
[5c]
1997, 36, 6449Ϫ6452. Ϫ
N. Greeves, K. J. Vines, J. Chem.
[5d]
Soc., Chem. Commun. 1994, 1469Ϫ1470. Ϫ
N. Greeves, K.
J. Vines, Tetrahedron Lett. 1994, 35, 7077Ϫ7080.
[12]
[6]
[7]
[6a]
For reviews, see
K. Mikami, M. Shimizu, Chem. Rev. 1992,
92, 1021Ϫ1050. Ϫ [6b]J. K. Whitesell, Methods Org. Chem.
(Houben-Weyl) 1995, vol. E 21d, p. 3271Ϫ3297. Ϫ [6c]W. Op-
polzer, V. Snieckus, Angew. Chem. 1978, 90, 506Ϫ516, Angew.
Chem. Int. Ed. Engl. 1978, 17, 476Ϫ486.
[13]
[14]
O. Takahashi, K. Mikami, T. Nakai, Chem. Lett. 1987, 69Ϫ72.
W. G. Kofron, L. M. Baclawski, J. Org. Chem. 1976, 41,
1879Ϫ1880.
For selected leading references, see: [7a] P. Kocovsky, G. Ahmed,
´
Received May 18, 2000
J. Srogl, A. V. Malkov, J. Steele, J. Org. Chem. 1999, 64,
[O00247]
Eur. J. Org. Chem. 2001, 483Ϫ491
491