Regioselective annulation of 1,5-diketones: Access to functionalized Hagemann's esters

Article abstract of DOI:10.1002/1099-0690(200009)2000:18<3165::AID-EJOC3165>3.0.CO;2-7

The synthesis of the 'functionalized' Hagemann's ester (S)-18 was investigated. The common starting material in these approaches was enamino ester (S,Z)-5, which was prepared through the condensation of keto diester 4 with (S)-1-phenylethylamine. The Michael addition reaction of 5 with methyl vinyl ketone gave the expected adduct (S)-6 with an ee ≥ 95%. However, all attempts at annulation of 6 invariably afforded the unwanted cyclohexenone derivatives 7 or 8. The addition of 5 to Nazarov reagent 9 furnished adduct (S)-10 with an ee ≥ 95%. The Triton B-induced annulation of 10 unexpectedly gave aldol 11. Depending on the reaction conditions, annulation of 11 afforded either the bicyclic lactone 12, or cyclohexenones 13 or 15. An efficient way of reversing the sense of the regiochemistry of the previous annulation was found, based on the use of diethyl 2-oxo-3-vinylphosphonate (16) as a Michael acceptor. Thus, the condensation of 5 with 16 gave (S)-17 with an ee ≥ 95%, and cyclization of (S)-17 under Horner-Wadsworth-Emmons conditions gave the desired Hagemann's ester (S)-18. The structural assignments for 18 were ascertained by chemical correlation with the known hydrindenedione (S)-21.

Full text of DOI:10.1002/1099-0690(200009)2000:18<3165::AID-EJOC3165>3.0.CO;2-7

FULL PAPER
Regioselective Annulation of 1,5-Diketones: Access to Functionalized
Hagemann’s Esters
[a]
[a]
[b]
[a]
´
Abdoulaye Gassama, Jean d’Angelo,* Christian Cave, Jacqueline Mahuteau, and
Claude Riche[c]
Keywords: Aldol reactions / Annulation / Asymmetric synthesis / Ketones / Michael additions
The synthesis of the ‘‘functionalized’’ Hagemann’s ester (S)-
18 was investigated. The common starting material in these
approaches was enamino ester (S,Z)-5, which was prepared
ditions, annulation of 11 afforded either the bicyclic lactone
12, or cyclohexenones 13 or 15. An efficient way of reversing
the sense of the regiochemistry of the previous annulation
through the condensation of keto diester 4 with (S)-1-pheny- was found, based on the use of diethyl 2-oxo-3-vinylphos-
lethylamine. The Michael addition reaction of 5 with methyl
vinyl ketone gave the expected adduct (S)-6 with an ee Ն
phonate (16) as a Michael acceptor. Thus, the condensation
of 5 with 16 gave (S)-17 with an ee Ն 95%, and cyclization
95%. However, all attempts at annulation of 6 invariably af- of (S)-17 under Horner−Wadsworth−Emmons conditions
forded the unwanted cyclohexenone derivatives 7 or 8. The
addition of 5 to Nazarov reagent 9 furnished adduct (S)-10
gave the desired Hagemann’s ester (S)-18. The structural as-
signments for 18 were ascertained by chemical correlation
with an ee Ն 95%. The Triton B-induced annulation of 10 with the known hydrindenedione (S)-21.
unexpectedly gave aldol 11. Depending on the reaction con-
Results and Discussion
Introduction
We first decided to reexamine the annulation of diketone
The Hagemann’s esters 1, which are key intermediates in
the synthesis of a variety of complex molecules,[1] are essen-
tially elaborated through the annulation of 1,5-diketones 2.
A well known problem arises, however, from the fact that
the desired aldol condensation regiochemistry of diketones
2 may be not that found under the usual conditions. It has
long been established that the course of this cyclization is
guided mainly by steric factors.[2] Thus, while the an-
nulation of diketone 2, R ϭ H can be cleanly directed to-
wards the Hagemann’s ester 1, R ϭ H,[1] ring closure of the
functionalized homologue 2, R ϭ CH2COOMe furnished
exclusively the unwanted regioisomer 3, R ϭ CH2COOMe
(Scheme 1).[2,3] In connection with our work on the syn-
thesis of specifically labeled 17-ketosteroids, we were re-
cently faced with the elaboration of the Hagemann’s ester 1,
R ϭ CH2COOMe and analogs. We report here an efficient,
highly selective approach to such compounds.
2, R ϭ CH2COOMe. This compound, in the proper ‘‘nat-
ural’’ (S) configuration (6), was synthesized by an original
route involving the asymmetric Michael addition of chiral
β-enamino esters to electrophilic alkenes (Scheme 2).[4]
When the enamino ester (S,Z)-5, prepared from keto diester
4
[5] and (S)-1-phenylethylamine (80% yield), was exposed to
methyl vinyl ketone in the presence of 1 equiv. of ZnCl2,
the expected Michael adduct (S)-6 was obtained in 80%
yield and ee Ն 95% (determined by 1H NMR spectroscopy,
after adding Eu(hfc)3 as a chiral shift reagent).
Scheme 2. Synthesis and Michael addition reaction of enamino es-
ter 5 with methyl vinyl ketone: reagents and conditions: (a) (S)-1-
phenylethylamine, 12 h, 80 °C; (b) i: methyl vinyl ketone, ZnCl2,
THF, 2 h, 0 °C, ii: AcOH, H2O
As previously reported,[2] MeONa-induced annulation of
6 exclusively furnished the cyclohexenone (S)-7 in 90%
Scheme 1. Annulation of diketones 2: the two competing pathways
yield, instead of the desired regioisomer 1,
R ϭ
[a]
CH2COOMe. Several other conditions for cyclization of 6
were also attempted, but they all exclusively furnished the
compound 8, arising from the removal of the methoxycar-
bonyl function of enone 7 (1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU): 90% yield; Triton B: 95% yield; piperidine,
AcOH: 70% yield, Scheme 3). Thus, the intramolecular al-
dol condensation of 6 invariably involved the methylene
´
´
Unite de Chimie Organique Associee au CNRS, Centre
´
d’Etudes Pharmaceutiques, Universite Paris Sud,
´
ˆ
5 rue J.-B. Clement, 92296, Chatenay-Malabry, France
Fax: (internat.) ϩ33-1/46835752
E-mail: jean.dangelo@cep.u-psud.fr
[b]
[c]
´
Laboratoire de Chimie Organique, Faculte de Pharmacie,
7 Bld Jeanne d’Arc, 21033 Dijon, France
ICSN, CNRS,
Avenue de la Terrasse, 91198, Gif sur Yvette, France
Eur. J. Org. Chem. 2000, 3165Ϫ3169
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0918Ϫ3165 $ 17.50ϩ.50/0
3165

´
A. Gassama, J. d’Angelo, C. Cave, J. Mahuteau, C. Riche
FULL PAPER
group at C-(3) and the carbonyl at C-(8), rather than the
methyl at C-(9) and the hindered carbonyl at C-(4) (the
atom numbering system here has been arbitrarily used
throughout this paper, except in the Experimental Section).
Scheme 5. Synthesis and X-ray crystal structure of bicyclic lactone
12: reagents and conditions: (a) benzene at reflux (7 days), or
CF3COOH at 20 °C (7 days), or dry HCl in CH2Cl2 at 20 °C (12 h),
or MsCl, Et3N at 40 °C (2 days)
Scheme 3. Annulation of Michael adduct 6: reagents and condi-
tions: (a) NaOMe in MeOH, 20 °C; (b) DBU in toluene at reflux,
or Triton B in THF at reflux, or piperidine in AcOH at reflux
In view of the above results, we assumed that the intro-
duction of an ester group at C-(9) in 6, considerably increas-
ing the kinetic acidity of this center, might redirect the regi-
ochemistry of the six-center annulation in the sense desired.
Addition of the enamino ester 5 to Nazarov reagent 9,[6] in
exact analogy with protocol [5 Ǟ 6], gave compound (S)-
10 in 78% yield and an ee Ն 95%. However, quite unexpec-
tedly, cyclization of 10 with Triton B again took place at
the C-(3) and C-(8) centers, giving the aldol (3S,5S,8R)-11
in 70% yield (Scheme 4). The structure of 11 in its energetic-
ally preferred conformation was established by NMR spec-
troscopy, including COSY, HMQC, HMBC, and NOESY
experiments.
Scheme 6. Synthesis of cyclohexenones 13 and 15: reagents and
conditions: (a) Triton B, 12 h, 65 °C; (b) Burgess’ inner salt 14
(Et3NϩSO2NϪCOOMe), 50 °C
(S)-17 in 70% yield and an ee Ն 95%. The internal
HornerϪWadsworthϪEmmons condensation of 17 (DBU,
LiCl)[9] now proceeded with the desired regiochemistry, fur-
nishing our initial target Hagemann’s ester (S)-18, in 70%
yield (Scheme 7).
Scheme 4. Michael addition reaction of enamino ester 5 with Naza-
rov reagent 9, and annulation of the resulting adduct 10: reagents
and conditions: (a) i: enamino ester 5, ZnCl2, THF, 2 h, 0 °C, ii: A-
cOH, H2O; (b) Triton B, 20 min, 65 °C
Scheme 7. Synthesis of Hagemann’s ester 18 by Michael addition
reaction of enamino ester
5
with acceptor 16, and
HornerϪWadsworthϪEmmons annulation of the resulting adduct
17: reagents and conditions: (a) i: enamino ester 5, ZnCl2, THF,
2 h, 0 °C, ii: AcOH, H2O; (b) DBU, LiCl, THF, 1 h, Ϫ78 °C, then
12 h, 20 °C
The dehydration of aldol 11, an apparently straightfor-
ward task in view of the trans, diaxial relationship between
the OH group at C-(8) and the H atom at C-(3), was exam-
ined next. Surprisingly, the sole product formed from 11
was the bicyclic lactone (3S,5S,8R)-12, whether by simple
heating in benzene (55% yield), by treatment with strong
acids (CF3COOH: 67% yield, or dry HCl: 60% yield), or
by treatment with MsCl in the presence of Et3N (44%
yield). The correctness of the structural assignments for lac-
tone 12 was verified by X-ray diffraction analysis
(Scheme 5).
Prolonged exposure of aldol 11 to Triton B furnished the
cyclohexenone (Ϯ)-13 in 70% yield, this product arising
from the dehydration of 11 with concomitant removal of
the methoxycarbonyl function at C-(5), while treatment
with Burgess’ inner salt 14[7] gave the enone (S)-15 in 72%
yield (Scheme 6).
The structural assignments for Hagemann’s ester (S)-18,
including the absolute configuration and the ee, were ascer-
tained by converting the compound into the known hydrin-
denedione (S)-21 (Scheme 8).[10] For that purpose, 18 was
first
transformed
into
the
ketal
19
using
TMSOCH2ϪCH2OTMS in the presence of TMSOTf, in
85% yield.[11] NaOMe-induced Dieckmann cyclization of 19
then gave the bicyclic derivative 20 (65% yield), which was
finally converted into the dione (S)-21 by heating in DMSO
in the presence of MgCl2 hexahydrate (90% yield).[12,13]
Finally, an efficient way of reversing the sense of the regi-
ochemistry in these annulations was found. Based on the
use of diethyl 2-oxo-3-vinylphosphonate (16)[8] as a Michael
acceptor, the condensation of enamino ester 5 with 16, in
Scheme 8. Chemical derivatization of Hagemann’s ester 18 into bi-
cyclic dione 21: reagents and conditions: (a) TMSOCH2CH2-
OTMS, TMSOTf, 20 h, Ϫ 78 °C; (b) MeONa, benzene at reflux,
exact analogy with protocol [5 Ǟ 6], afforded the adduct 2 h; (c) MgCl2 hexahydrate, DMSO, 130 °C
3166 Eur. J. Org. Chem. 2000, 3165Ϫ3169

Regioselective Annulation of 1,5-Diketones
FULL PAPER
Conclusion
(c ϭ 3.0, MeOH). Ϫ IR (neat) ν˜ ϭ 3266 cmϪ1 (NH), 1741 (CϭO),
1645 (CϭO), 1599 (CϭC). Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ
1.4 (d, J ϭ 6 Hz, 3 H, CH3ϪCH), 1.7 (s, 3 H, CH3ϪCϭC), 1.9Ϫ2.6
(m, 4 H, CH2ϪCH2), 3.6 (s, 3 H, CH3ϪO), 3.7 (s, 3 H, CH3ϪO),
4.5 (quint, J ϭ 6 Hz, 1 H, CHϪCH3), 7.1Ϫ7.3 (m, 5 H, aromatic
H), 9.5 (d, J ϭ 6 Hz, 1 H, NH). Ϫ 13C NMR (CDCl3, 50 MHz):
δ ϭ 11.9 (CH3, CH3ϪCH), 24.1 (CH2), 25.2 (CH3, CH3ϪCϭ),
31.4 (CH2), 50.4 (CH, CH3ϪCH), 51.6 (CH3, CH3ϪO), 52.9 (CH3,
CH3ϪO), 88.2 (C, NϪCϭC), 125.4 (2 CH, aromatic C), 126.9 (CH,
aromatic C), 128.6 (2 CH, aromatic C), 145.6 (C, aromatic C),
160.3 (C, CϭCϪN), 171.5 (C, CϭO), 172.4 (C, CϭO). Ϫ
C17H23NO4 (305.16): calcd. C 66.86, H 7.59, N 4.59; found C
66.46, H 7.82, N 4.37.
The aim of this project was to synthesize the ‘‘func-
tionalized’’ Hagemann’s ester (S)-18. To attain this goal,
several strategies were evolved, all based on a Michael
additionϪRobinson annulation sequence, starting from the
enamino ester (S,Z)-5. The use of methyl vinyl ketone and
Nazarov reagent as Michael acceptors was unsuccessful,
since all efforts to cyclize the diketones (S)-6 and (S)-10
invariably furnished cyclohexenones of the unwanted regi-
ochemistry.
The key tactical element for orientating the regiochemis-
try of the annulation of the intermediary 1,5-diketones in
the required sense was the utilization of 2-oxo-3-vinylphos-
Dimethyl (S)-2-Methyl-3-oxo-2-(3-oxobutyl)hexanedioate (6): To a
solution of freshly distilled methyl vinyl ketone (0.14 g, 2.0 mmol),
ZnCl2 (0.14 g, 1.0 mmol) and hydroquinone (5 mg) in THF
(20 mL) at 0 °C was added enamino ester 5 (0.31 g, 1.0 mmol). The
mixture was stirred for 2 h at this temperature and 5 mL of 20%
aqueous acetic acid were added. The solvents were removed under
reduced pressure and 1  hydrochloric acid (10 mL) was added.
The mixture was extracted with dichloromethane and the combined
organic phases were washed with brine, dried and concentrated.
Chromatographic purification over silica gel (cyclohexane/AcOEt
phonate (16) as
a Michael acceptor. The internal
HornerϪWadworthϪEmmons condensation of adduct (S)-
17 indeed proceeded with the desired regiochemistry, fur-
nishing our target (S)-18. This Hagemann’s ester was thus
elaborated with a high degree of regio- and stereocontrol,
in only three steps starting from the keto diester 4, with an
overall yield of 40%. In this respect, this strategy represents
an efficient solution to the old and vexing problem of con-
trolling the regioselectivity of the annulation of 1,5-dike-
tones. Further synthetic developments of this promising
methodology are currently under investigation in our labor-
atory.
2:1) gave diketo diester 6 (0.22 g, 80%) as a colorless oil. Ϫ [α]2D0
ϭ
ϩ7.6 (c ϭ 3.3, MeOH). Ϫ IR (neat) ν˜ ϭ 1749 cmϪ1 (CϭO), 1717
(CϭO). Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ 1.2 (s, 3 H, CH3ϪC),
2.0 (s, 3 H, CH3ϪCϭO), 2.1 (m, 2 H, CH2), 2.4 (m, 2 H, CH2),
2.5 (m, 2 H, CH2), 2.7 (m, 2 H, CH2), 3.6 (s, 3 H, CH3ϪO), 3.7 (s,
3 H, CH3ϪO). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 19.2 (CH3,
CH3ϪC), 27.4 (CH2), 28.4 (CH2), 29.6 (CH3, CH3ϪCϭO), 32.8
(CH2), 38.2 (CH2), 51.4 (CH3, CH3ϪO), 52.2 (CH3, CH3ϪO), 58.0
(C, C-2), 172.5 (C, CϭO), 172.7 (C, CϭO), 205.7 (C, CϭO), 207.0
(C, CϭO). Ϫ C13H20O6 (272.13): calcd. C 57.34, H 7.40; found C
57.47, H 7.63.
Experimental Section
General: Infrared (IR) spectra were measured on a PerkinϪElmer
841 spectrometer as neat films between NaCl plates or KBr pellets.
Only the most significant absorptions are listed. Ϫ The 1H and 13
C
Methyl
(S)-3-(Methoxycarbonyl)methyl-1,4-dimethyl-2-oxocyclo-
NMR spectra were recorded on Bruker AC 200 P (200 MHz and
50 MHz, for 1H and 13C, respectively), or Bruker ARX 400
(400 MHz and 100 MHz, for 1H and 13C, respectively) spectro-
meters. Recognition of methyl, methylene, methine, and quaternary
carbon nuclei in 13C NMR spectra is based on the J-modulated
spin-echo sequence. Ϫ Optical rotations were measured at 20 °C
on a Perkin-Elmer 241 MC polarimeter in a 1 dm cell. Ϫ Analytical
thin-layer chromatography was performed on Merck silica gel
60F254 glass precoated plates (0.25 mm layer). Ϫ Column chroma-
tography was performed using Merck silica gel 60 (230Ϫ400 mesh
ASTM). Tetrahydrofuran (THF) was distilled from sodium-benzo-
phenone ketyl. Ϫ CH2Cl2 was distilled from calcium hydride. All
reactions involving air- or water-sensitive compounds were rou-
tinely conducted in glassware flame-dried under a positive pressure
of nitrogen. Organic fractions were dried with anhydrous MgSO4.
Chemicals obtained from commercial suppliers were used without
further purification. Ϫ All elemental analyses were performed by
the Service de microanalyse, Centre d’Etudes Pharmaceutiques,
hex-3-enecarboxylate (7): To a solution of sodium methoxide
(0.17 g, 0.73 mmol) in methanol (5 mL) was added diketo diester 6
(0.20 g, 0.73 mmol). The mixture was stirred for 40 min at 20 °C,
the solvent was removed and dichloromethane (30 mL) was added.
The mixture was washed with 1  hydrochloric acid (10 mL), dried
and concentrated under reduced pressure. Chromatographic puri-
fication over silica gel (cyclohexane/AcOEt 4:1) gave keto diester 7
(0.17 g, 91%) as a colorless oil. Ϫ [α]2D0 ϭ ϩ16.4 (c ϭ 2.75, MeOH).
Ϫ IR (neat): ν˜ ϭ 1733 cmϪ1 (CϭO), 1721 (CϭO), 1669 (CϭO),
1635 (CϭC). Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ 1.4 (s, 3 H,
CH3ϪC), 1.80 (m, 1 H), 1.90 (s, 3 H, CH3ϪCϭC), 2.2Ϫ2.7 (m, 3
H), 3.4 (s, 2 H, CH2ϪCϭO), 3.6 (s, 3 H, CH3ϪO), 3.7 (s, 3 H,
CH3ϪO). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 20.5 (CH3), 21.5
(CH3), 29.9 (CH2), 31.0 (CH2), 32.2 (CH2), 43.6 (C, C-1), 52.1
(CH3, CH3ϪO), 52.4 (CH3, CH3ϪO), 128.2 (C, CϭCϪCϭO),
157.5 (C, CϭCϪCϭO), 171.5 (C, CϭO), 173.2 (C, CϭO), 195.4
(C, CϭO). Ϫ C13H18O5 (254.3): calcd. C 61.40, H 7.14; found C
61.07, H 7.48.
ˆ
Chatenay-Malabry, France, with a PerkinϪElmer 2400 analyzer.
1-tert-Butyl 10-Methyl (S)-6-Methoxycarbonyl-6-methyl-3,7-dioxo-
decanedioate (10): To a solution of freshly distilled Nazarov reagent
Dimethyl (S,Z)-2-Methyl-3-(1-phenylethylamino)hex-2-enedioate
(5): A solution of ketodiester 4[5] (1.97 g, 9.75 mmol), (S)-1-pheny- 9[6] (0.14 g, 0.82 mmol), ZnCl2 (0.14 g, 1.00 mmol) and hydroquin-
lethylamine (1.83 g, 14.60 mmol) and p-toluenesulfonic acid
one (5 mg) in THF (20 mL) at 0 °C was added enamino ester 5
(20 mg) in anhydrous toluene (14 mL) was refluxed for 12 h with
(0.20 g, 0.66 mmol). The mixture was stirred for 2 h at this temper-
azeotropic removal of water. The solution was cooled to 20 °C, ature and 5 mL of 10% aqueous acetic acid were added. The solv-
and the solvent was removed in vacuum to give an oil, which was
chromatographed over silica gel (cyclohexane/AcOEt 4:1) to afford
enamino ester 5 as a colorless oil (2.40 g, 80%). Ϫ [α]2D0 ϭ ϩ419
ents were removed under reduced pressure and 1  hydrochloric
acid (10 mL) was added. The mixture was extracted with dichloro-
methane (30 mL) and the combined organic phases were washed
Eur. J. Org. Chem. 2000, 3165Ϫ3169
3167

´
A. Gassama, J. d’Angelo, C. Cave, J. Mahuteau, C. Riche
FULL PAPER
3
with brine, dried and concentrated. Chromatographic purification
over silica gel (cyclohexane/AcOEt 4:1) gave diketo triester 10
(0.19 g, 78%) as a colorless oil. Ϫ [α]2D0 ϭ ϩ8.6 (c ϭ 4.0, MeOH).
V ϭ 892.8 (5) A , dcalc ϭ 1.27 g cmϪ3, F(000) ϭ 364, λ (Cu-Kα) ϭ
˚
1.5418 A, µ ϭ 0.82 mmϪ1. Nonius CAD4 diffractometer, 3482 col-
˚
lected reflections, 3001 unique (Rint ϭ 0.034), 2114 observed [I Ն
Ϫ IR (neat): ν˜ ϭ 1741 cmϪ1 (CϭO), 1723 (CϭO). Ϫ 1H NMR 2σ(I)]. The structure was refined by full-matrix, least-squares with
(CDCl3, 200 MHz): δ ϭ 1.3 (s, 3 H, CH3ϪC), 1.4 (s, 9 H, SHELX93, R ϭ 0.052 for 2501 observed reflections and w R2
ϭ
(CH3)3ϪC), 2.1 (m, 2 H), 2.5 (m, 4 H), 2.7 (m, 2 H), 3.3 (s, 2 H,
0.150 for 3001 unique reflections. Residual electron density between
3 [14]
COϪCH2ϪCO), 3.6 (s, 3 H, CH3ϪO), 3.7 (s, 3 H, CH3ϪO). Ϫ 13C Ϫ0.20 and 0.17 eA .
˚
NMR (CDCl3, 50 MHz): δ ϭ 19.1 (CH3, CH3ϪC-6), 28.1 (CH2),
Methyl (S)-9-Diethoxyphosphoryl-5-methoxycarbonyl-5-methyl-4,8-
dioxononanoate (17): To
solution of reagent 16[8] (1.5 g,
28.2 [3 CH3, (CH3)3ϪC], 28.4 (CH2), 31.5 (CH2), 37.8 (CH2), 48.8
(CH2), 50.5 (CH3, CH3ϪO), 51.7 (CH3, CH3ϪO), 58.2 (C, C-6),
81.9 (C, OϪCϪC), 166.2 (C, CϭO), 172.8 (C, CϭO), 172.9 (C, Cϭ
O), 201.7 (C, CϭO), 205.8 (C, CϭO). Ϫ C18H28O8 (372.5): calcd. C
58.05, H 7.58; found C 57.78, H 7.65.
a
7.4 mmol), ZnCl2 (0.9 g, 6.2 mmol) and hydroquinone (5 mg) in
THF (20 mL) at 0 °C was added enamino ester 5 (1.9 g, 6.2 mmol).
The mixture was stirred for 2 h at this temperature and 10% aque-
ous acetic acid (10 mL) was added. The solvents were removed un-
der reduced pressure and 1  hydrochloric acid (10 mL) was added.
The mixture was extracted with dichloromethane (30 mL) and the
combined organic phases were washed with brine, dried, and con-
centrated. Chromatographic purification over silica gel (cyclohex-
Methyl (1S,3S,4R)-4-tert-(Butoxycarbonyl)methyl-4-hydroxy-3-(me-
thoxycarbonyl)methyl-1-methyl-2-oxocyclohexanecarboxylate (11):
To a solution of diketo triester 10 (0.37 g, 1.0 mmol) in THF
(45 mL) was added a 40% solution of Triton B in methanol
(0.1 mL, 0.2 mmol). The mixture was refluxed for 20 min, the solv-
ent was removed and dichloromethane (30 mL) was added. The
mixture was washed with 1  hydrochloric acid (10 mL), dried and
concentrated under reduced pressure. Chromatographic purifica-
tion over silica gel (cyclohexane/AcOEt 4:1) gave aldol 11 (0.26 g,
70%) as a colorless oil. Ϫ [α]2D0 ϭ ϩ44.3 (c ϭ 1.6, MeOH). Ϫ IR
(neat) ν˜ ϭ 3508 cmϪ1 (OH), 1745 (CϭO), 1729 (CϭO). Ϫ 1H
NMR (C6D6, 400 MHz): δ ϭ 1.27 (s, 3 H, CH3ϪC-1), 1.34 [s, 9 H,
(CH3)3ϪC], 1.77 (ddd, J ϭ 14, 4, 3 Hz, 1 H, H-5eq), 1.89 (ddd,
J ϭ 14, 14, 4 Hz, 1 H, H-6ax), 2.07 (d, J ϭ 15 Hz, 1 H, CH2ϪC-
4), 2.13 (ddd, J ϭ 14, 14, 4 Hz, 1 H, H-5ax), 2.19 (d, J ϭ 15 Hz,
1 H, CH2ϪCH2ϪC-4), 2.32 (ddd, J ϭ 14, 4, 3 Hz, 1 H, CH2, H-
6eq), 2.40 (dd, J ϭ 20, 5 Hz, 1 H, CH2ϪCH2ϪC-3), 3.33 (s, 3H,
CH3O), 3.38 (s, 3H, CH3O), 3.89 (br s, 1 H, OH). Ϫ 13C NMR
(C6D6, 50 MHz): δ ϭ 21.4 (CH3, CH3ϪC-1), 27.9 (3 CH3,
(CH3)3ϪC), 28.8 (CH2), 32.0 (CH2), 34.4 (CH2), 44.9 (CH2), 51.3
(CH3, CH3ϪO), 52.1 (CH3, CH3ϪO), 53.7 (CH, C-3), 56.2 (C, C-
1), 76.6 (C, C-4), 81.5 (C, OϪCϪC), 171.5 (C, CϭO), 173.0 (C, Cϭ
O), 173.4 (C, CϭO), 203.4 (C, CϭO). Ϫ C18H28O8 (372.5): calcd. C
58.05, H 7.58; found C 58.36, H 7.85.
ane/AcOEt 1:2) gave 17 (1.8 g, 70%) as a colorless oil. Ϫ [α]2D0
ϭ
Ϫ1.2 (c ϭ 16.0, MeOH). Ϫ IR (neat) ν˜ ϭ 1735 cmϪ1(CϭO), 1716
1
(CϭO). Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 1.2 (t, J ϭ 7 Hz, 6
H, 2 CH3ϪCH2), 1.3 (s, 3 H, CH3ϪC-5), 1.9Ϫ2.2 (m, 2 H), 2.4Ϫ2.6
(m, 4 H), 2.65Ϫ2.8 (m, 2 H), 3.0 (d, J ϭ 23 Hz, 2 H, CH2ϪP), 3.6
(s, 3 H, OCH3), 3.7 (s, 3 H, OCH3), 4.1 (q, J ϭ 7 Hz, 4 H, 2
CH2ϪCH3). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 16.2 (CH3,
CH3ϪCH2) 16.3 (CH3, CH3ϪCH2), 19.4 (CH3, CH3ϪC-5), 27.7
(CH2), 28.4 (CH2), 33.1 (CH2), 39.0 (CH2), 41.1 (C, C-5), 43.6
(CH2), 51.7 (CH3, OCH3), 52.5 (CH3, OCH3), 62.5 (CH2,
CH2ϪCH3), 62.6 (CH2, CH2ϪCH3), 172.8 (C, CϭO), 173.5 (C,
CϭO), 200.6 (C, CϭO), 205.8 (C, CϭO).
Methyl (S)-2-[2-(Methoxycarbonyl)ethyl]-1-methyl-4-oxocyclohex-
2-enecarboxylate (18): To a solution of 17 (2.00 g, 4.9 mmol) and
LiCl (0.23 g, 5.4 mmol) in THF (80 mL) at Ϫ 78 °C was added a
solution of DBU (0.81 g, 5.4 mmol) in THF (20 mL). The mixture
was stirred for 40 min at Ϫ 78 °C, allowed to warm to 20 °C and
kept at this temperature for 4 h. The solvent was removed under
reduced pressure and the residue was chromatographed over silica
gel (cyclohexane/AcOEt 1:2) to give enone 18 (0.96 g, 70%) as a
colorless oil. Ϫ [α]2D0 ϭ Ϫ56.3 (c ϭ 3.0, MeOH). Ϫ IR (neat) ν
˜ ϭ
Methyl (3aS,5S,7aR)-7a-tert-Butoxycarbonylmethyl-5-methyl-2,4-
dioxooctahydrobenzofuran-5-carboxylate (12): A solution of trifluo-
roacetic acid (0.20 mL, 2.6 mmol) and aldol 11 (0.44 g, 1.2 mmol)
in dichloromethane (15 mL) was kept at 20 °C for 7 days. The mix-
ture was washed with a 2  aqueous solution of sodium hydroxide,
dried and concentrated under reduced pressure. The residue was
crystallized from methanol to give bicyclic lactone 12 (0.27 g, 67%)
as a colorless solid. Ϫ m.p. 95 °C (MeOH). Ϫ [α]2D0 ϭ ϩ8.4 (c ϭ
1.55, MeOH). Ϫ IR (KBr): ν˜ ϭ 1796 cmϪ1 (CϭO), 1738 (CϭO),
1730 cmϪ1 (CϭO), 1678 (CϭO), 1623 (CϭC). Ϫ 1H NMR (CDCl3,
200 MHz): δ ϭ 1.45 (s, 3 H, CH3ϪC-1), 1.80Ϫ2.0 (m, 1 H),
2.3Ϫ2.45 (m, 3 H), 2.55 (br s, 4 H, 2 CH2), 3.65 (s, 3 H, OCH3),
3.7 (s, 3 H, OCH3), 5.8 (s, 1H, HϪCϭC). Ϫ 13C NMR (CDCl3,
50 MHz): δ ϭ 22.4 (CH3, CH3ϪC-1), 27.9 (CH2), 31.3 (CH2), 34.1
(CH2), 34.6 (CH2), 47.6 (C, C-1), 51.8 (CH3, OCH3), 52.6 (CH3,
OCH3), 126.1 (CH, C-3), 162.8 (C, C-2), 174.5 (C, CϭO), 177.3
(C, CϭO), 197.9 (C, CϭO).
1715 (CϭO). Ϫ 1H NMR (CDCl3, 400 MHz): δ ϭ 1.28 (s, 3 H, Methyl (S)-7-[2-(Methoxycarbonyl)ethyl]-8-methyl-1,4-dioxaspiro-
CH3ϪC-5), 1.41 (s, 9 H, (CH3)3ϪC), 1.67 (ddd, J ϭ 18, 14, 4 Hz, [4.5]dec-6-ene-8-carboxylate (19): To a solution of enone 18 (0.36 g,
1 H, CH2, H-7), 2.06 (ddd, J ϭ 15, 4, 4 Hz, 1 H, CH2, H-6), 2.19 1.4 mmol) and TMSOTf (0.02 mL, 0.77 mmol) in dichloromethane
(ddd, J ϭ 15, 4, 4 Hz, 1 H, H-6), 2.29 (ddd, J ϭ 18, 14, 4 Hz, 1 H, (1 mL) at Ϫ78 °C was added 1,2-bis(trimethylsilyloxy)ethane
CH2, H-7), 2.51 (d, J ϭ 15 Hz, 1 H, OCϪCH2ϪC-7a), 2.61 (d, J ϭ
(0.7 mL, 2.9 mmol). The mixture was stirred for 20 h at this tem-
15 Hz, 1 H, OCϪCH2ϪC-7a), 2.74 (dd, J ϭ 18, 9 Hz, 1 H, CH2, perature. Pyridine (0.2 mL) was added and the solution was poured
H-3), 3.30 (dd, J ϭ 18, 1 Hz, 1 H, CH2, H-3), 3.68 (dd, J ϭ 9, into an aqueous solution of sodium hydrogen carbonate. After ex-
1 Hz, 1 H, CH), 3.72 (s, 3 H, OCH3). Ϫ 13C NMR (CDCl3, traction with dichloromethane (15 mL), the combined organic
100 MHz): δ ϭ 20.9 (CH3, CH3ϪC-5), 27.9 (3 CH3, (CH3)3ϪC), phases were washed with brine, dried and concentrated. Chromato-
28.8 (CH2), 29.9 (CH2), 30.5 (CH2), 44.6 (CH2), 49.1 (CH), 52.7 graphic purification over silica gel (cyclohexane/AcOEt/triethylam-
(CH3, OϪCH3) 55.0 (C, C-5), 82.1 (C, (CH3)3ϪC), 87.4 (C, C-7a), ine 20:80:1) gave 19 (0.36 g, 85%) as a white solid. Ϫ m.p. 58 °C.
168.3 (C, CϭO), 172.2 (C, CϭO), 174.7 (C, CϭO), 203.9 (C, Cϭ Ϫ [α]2D0 ϭ Ϫ20.3 (c ϭ 4.5, MeOH). Ϫ IR (neat): ν˜ ϭ 1731 cmϪ1
O). Ϫ C17H24O7 (340.4): calcd. C 59.99, H 7.11; found C 59.89, H
7.13. Ϫ Crystal data of 12: C17H24O7 MW ϭ 340.36, colorless crys- 8), 1.75 (m, 1 H), 1.80 (m, 2 H), 2.18 (ddd, J ϭ 13.1, 8.3, 3.5 Hz,
(CϭO). Ϫ 1H NMR (CDCl3, 400 MHz): δ ϭ 1.33 (s, 3 H, CH3ϪC-
tal of 0.04 ϫ 0.10 ϫ 0.60 mm, monoclinic, space group P21, Z ϭ
2, a ϭ 10.592 (4), b ϭ 6.053 (2), c ϭ 13.926 (4) A, β ϭ 90.75(3)°,
1 H, CH2ϪC-9), 2.32 (m, 2 H), 2.48 (m, 2 H), 3.66 (s, 6 H, 2
OCH3), 4.01 (m, 4 H, 2 CH2ϪO), 5.37 (t, J ϭ 1.5 Hz, 1 H, HϪCϭ
˚
3168
Eur. J. Org. Chem. 2000, 3165Ϫ3169

Regioselective Annulation of 1,5-Diketones
C); 13C NMR (CDCl3, 50 MHz): δ ϭ 22.6 (CH3, CH3ϪC-8), 27.1 HϪCϭC), 198.0 (C, CϭO), 216.4 (C, CϭO). Ϫ C10H12O2 (164.2):
FULL PAPER
(CH2), 30.2 (CH2), 32.4 (CH2), 33.6 (CH2), 46.9 (C, C-8), 52.2
(CH3, OCH3), 53.0 (CH3, OCH3), 64.5 (2 CH2, CH2ϪO), 105.5 (C,
C-5), 123.9 (CH, HϪCϭC), 143.9 (C, HϪCϭC), 173.3 (C, CϭO),
176.0 (C, CϭO). Ϫ C15H22O6 (298.1): calcd. C 60.39, H 7.43; found
C 60.42, H 7.49.
calcd. C 73.15, H 7.37; found C 73.21, H 7.38.
[1] [1a]
[1b]
H. M. E. Cardwell, J. Chem. Soc. 1949, 715Ϫ719. Ϫ
W.
S. Johnson, N. P. Jensen, J. Hooz, E. J. Leopold, J. Am. Chem.
[1c]
Soc. 1968, 90, 5872Ϫ5881. Ϫ
Am. Chem. Soc. 1983, 105, 3732Ϫ3734. Ϫ
R. Dodds, Can. J. Chem. 1987, 65, 2397Ϫ2404. Ϫ
Ackland, J. T. Pinhhey, J. Chem. Soc. Perkin Trans. 1 1987,
K. Sakan, B. M. Craven, J.
[1d]
J. B. Jones, D.
[1e]
D. J.
Methyl
(2R,3aS)-6-Ethylenedioxy-3a-methyl-3-oxo-2,3,3a,4,5,6-
[1f]
2689Ϫ2694. Ϫ
R. E. Hormann, Eur. Pat. Appl. 773216 A1
hexahydro-1H-indene-2-carboxylate (20): A solution of sodium me-
thoxide (70 mg, 1.30 mmol) and 19 (120 mg, 0.40 mmol) in benzene
(20 mL) was refluxed for 12 h. The mixture was cooled at 20 °C,
and a solution of 10% aqueous acetic acid was added. The mixture
was poured into an aqueous solution of sodium hydrogen carbon-
ate. After extraction with dichloromethane (15 mL), the combined
organic phases were washed with brine, dried and concentrated.
Chromatographic purification over silica gel (cyclohexane/AcOEt
[1g]
14 May 1997; Chem. Abstr. 1997, 127, P 34126 b. Ϫ
C.
´
Cave, I. Valancogne, R. Casas, J. d’Angelo, Tetrahedron Lett.
1998, 39, 5872Ϫ5881.
[2]
[3]
D. Nasipuri, M. Guha, J. Indian Chem. Soc. 1964, 41,
243Ϫ250.
S. Terashima, S. Sato, K. Koga, Tetrahedron Lett. 1979,
3469Ϫ3472.
[4] [4a]
´
C. Cave, D. Desmae¨le, J. d’Angelo, C. Riche, J. Org. Chem.
[4b]
´
C. Cave, A. Gassama, J. Mahu-
1996, 61, 4361Ϫ4368. Ϫ
1:2) gave 20 ( 69 mg, 65%) as a white solid. Ϫ m.p. 82 °C. Ϫ [α]2D0
ϭ
teau, J. d’Angelo, C. Riche, Tetrahedron Lett. 1997, 38,
[4c]
ϩ130.4 (c ϭ 3.4, MeOH). Ϫ IR (neat) ν˜ ϭ 1757 cmϪ1 (CϭO), 1722
(CϭO), 1688 (CϭO). Ϫ 1H NMR (CDCl3, 400 MHz): δ ϭ 1.22 (s,
3 H, CH3ϪC-3a), 1.70 (ddd, J ϭ 3.8, 13.2, 13.2 Hz, 1 H, CH2ϪC-
5), 1.85Ϫ2.00 (m, 3 H), 2.79 (dd, J ϭ 15.0, 9.0 Hz, 1 H, CH2ϪC-
1), 3.17 (ddd, J ϭ 15.0, 10.7, 1.4 Hz, 1 H, CH2ϪC-1), 3.34 (dd,
J ϭ 10.7, 9.1 Hz, 1 H, CHϪC-2), 3.77 (s, 3 H, OCH3), 4.06 (m, 4
H, OϪCH2ϪCH2ϪO), 5.53 (t, J ϭ 1.4 Hz, 1 H, HϪCϭC). Ϫ 13C
NMR (CDCl3, 50 MHz): δ ϭ 19.7 (CH3, CH3ϪC-3a), 28.7 (CH2),
30.0 (CH2), 31.0 (CH2), 48.4 (C, C-3a), 52.7 (CH3, OCH3), 54.4
(CH), 64.5 (CH2, CH2ϪO), 64.7 (CH2, CH2ϪO), 106.0 (C, C-6),
121.8 (CH, HCϭC), 145.5 (C, HCϭC), 169.3 (C, CϭO), 210.0 (C,
CϭO). Ϫ C14H18O5 (266.1): calcd. C 63.15, H 6.81; found C 63.23,
H 7.01.
´
4773Ϫ4776. Ϫ
J. d’Angelo, C. Cave, D. Desmae¨le, Isr. J.
Chem. 1997; 37, 81Ϫ85. Ϫ [4d] C. Cave, Y. Le Porhiel-Castellon,
´
V. Daley, C. Riche, A. Chiaroni, J. d’Angelo, Tetrahedron Lett.
[4e]
´
A.J. Da Silva Goes, C. Cave, J.
[4f]
1997, 38, 8703Ϫ8706. Ϫ
d’Angelo, Tetrahedron Lett. 1998, 39, 1339Ϫ1340. Ϫ
J.
´
d’Angelo, C. Cave, D. Desmae¨le, A. Gassama, C. Thominiaux,
[4g]
C. Riche, Heterocycles 1998, 47, 725Ϫ746. Ϫ
C. Thomin-
´
iaux, S. Rousse, D. Desmae¨le, J. d’Angelo, C. Riche, Tetrahed-
ron: Asymmetry 1999, 10, 2015Ϫ2021. Ϫ [4h] V. Daley, J. d’Ang-
´
elo, C. Cave, J. Mahuteau, A. Chiaroni, C. Riche, Tetrahedron
Lett. 1999, 40, 1657Ϫ1660.
[5]
[6]
H. Schick, R. Ludwig, Synthesis 1992, 369Ϫ370.
S. Ohta, A. Shimabayashi, S. Hatano, M. Okamoto, Synthesis
1983, 715Ϫ717.
[7]
E. M. Burgess, H. R. Penton Jr., E. A. Taylor, J. Org. Chem.
1973, 38, 26Ϫ31.
[8] [8a]
F. Mathey, Ph. Savignac, Tetrahedron 1978, 34, 649Ϫ654.
[8b]
Ϫ
E. Wada, S. Kanemasa, O. Tsuge, Bull. Chem. Soc. Jpn.
(S)-7a-Methyl-2,3,7,7a-tetrahydro-6H-indene-1,5-dione (21): A so-
lution of 20 (50 mg, 0.19 mmol), MgCl2 hexahydrate (50 mg,
0.24 mmol) in DMSO (4 mL) was heated at 130 °C for 4 h. The
mixture was allowed to cool to 20 °C, and 6 mL of water were
added. After extraction with dichloromethane (15 mL), the com-
bined organic phases were washed with brine, dried, and concen-
trated. Chromatographic purification over silica gel (cyclohexane/
AcOEt 1:1.5) gave 21 (27 mg, 90%) as a white solid. Ϫ m.p. 68 °C
(ref.[10] m.p. 66 °C). Ϫ [α]2D0 ϭ ϩ 352 (c ϭ 1.1, benzene) (ref.[10]
[α]2D0 ϭ ϩ367 (c ϭ 1.0, benzene)). Ϫ IR (neat): ν˜ ϭ 1744 cmϪ1(Cϭ
1989, 62, 860Ϫ868. Ϫ [8c] E. Wada, J. Funakoshi, S. Kanemasa,
Bull. Chem. Soc. Jpn. 1992, 65, 2456Ϫ2464.
M. A. Blanchette, W. Choy, J. T. Davis, Tetrahedron Lett. 1984,
25, 2183Ϫ2186.
Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615Ϫ1621.
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21, 1357Ϫ1358.
[9]
[10]
[11]
[12]
[13]
[14]
T. Kametani, N. Kanaya, M. Ihara, J. Chem. Soc. Perkin I
1981, 959Ϫ963.
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38, 7271Ϫ7274.
Crystallographic data for the structure reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication with deposition number
CCDC-103105. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
1
O), 1663 (CϭO). Ϫ H NMR (CDCl3, 400 MHz): δ ϭ 1.31 (s, 3
H, CH3ϪC-7a), 1.85 (ddd, J ϭ 13.5, 7.4, 5.0 Hz, 1 H, 3-H), 2.12
(dddd, J ϭ 13.5, 7.4, 5.0, 2.5 Hz, 1 H, 3-H), 2.45Ϫ2.58 (m, 3 H),
2.70Ϫ2.83 (m, 2 H), 2.95 (dddd, J ϭ 13.4, 11.1, 9.8, 2.5 Hz, 1 H,
6-H), 5.95 [t, J ϭ 2.5 Hz,1 H, HϪCϭC]). Ϫ 13C NMR (CDCl3,
50 MHz): δ ϭ 20.6 (CH3, CH3ϪC-7a), 26.8 (CH2), 29.2 (CH2), 32.9
(CH2), 35.8 (CH2), 48.7 (C, C-7a), 123.9 (CH, HϪCϭC), 169.7 (C,
Received March 1, 2000
[O00103]
Eur. J. Org. Chem. 2000, 3165Ϫ3169
3169