Intramolecular Michael reactions by iron(III) catalysis

Article abstract of DOI:10.1016/S0040-4020(00)00045-4

Seven-membered ring annulation is achieved by an intramolecular Michael reaction catalyzed by iron(III) chloride hexahydrate. Reaction conditions are mild and non-basic, and chemo- and stereoselectivity is excellent. Contrastingly, this method fails for a 17-membered ring annulation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00045-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1339–1344
Intramolecular Michael Reactions by Iron(III) Catalysis
*
Jens Christoffers and Heiko Oertling
¨
¨
Technische Universitat Berlin, Institut fur Organische Chemie, Sekretariat C3, Strabe des 17. Juni 135, D-10623 Berlin, Germany
Received 7 December 1999; accepted 10 January 2000
Abstract—Seven-membered ring annulation is achieved by an intramolecular Michael reaction catalyzed by iron(III) chloride hexahydrate.
Reaction conditions are mild and non-basic, and chemo- and stereoselectivity is excellent. Contrastingly, this method fails for a
17-membered ring annulation. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
Seven-membered ring annulation
Iron(III) chloride hexahydrate is to date the most efficient
catalyst for the Michael reaction of b-keto esters with vinyl
ketones.1–3 Owing to the mild and non-basic reaction con-
ditions, the chemoselectivity of this process is superior to
that offered by base catalysis,4–8 since the latter suffers from
various unwanted side- and subsequent reactions, such as
aldol cyclizations, ester solvolysis or retro-Claisen type
decompositions. Moreover, since conversions are quanti-
tative within hours at room temperature, the isolated yields
are generally very good.9 Inspired by these results on inter-
molecular Michael reactions we considered FeCl3·6H2O
to be also an efficient catalyst for intramolecular con-
versions,10–15 with special respect to macrocyclizations
still being a challenging goal in synthetic organic chemistry.
In the past some reports on macrocyclizations by intra-
molecular Michael reactions have been reported by
others.16–19 Herein we wish to report on our results on
seven-20 and seventeen-membered carboannulations by
intramolecular Michael reactions catalyzed by FeCl3·6H2O.
Donor–acceptor functionalized precursor 1a was cleanly
converted with a catalytic amount of FeCl3·6H2O to the
bicyclo[5.5.0]-dodecane derivative 2a (Scheme 1). The
reaction proceeded at ambient temperature in CH2Cl2 as
solvent within a few hours, and the isolated yield was
good (80%). Separation of the product from all iron-
containing materials was simply accomplished by filtration
through SiO2. Basic reaction conditions were avoided, thus,
no side- or subsequent products were observed. Moreover,
no dimeric or oligomeric species resulting from an inter-
molecular process were detectable by GC-MS. Besides a
very high chemoselectivity, quantitative stereoselectivity
was observed: only one diastereoisomer of the racemic
material 2a was isolated. After assignment of all proton
and carbon NMR resonances by H,H-COSY, DEPT,
HMBC and HMQC experiments the relative configuration
was established to be trans: A J-resolved 500 MHz 1H NMR
Scheme 1. Iron(III) chloride catalyzed intramolecular Michael reactions; reagents and conditions: 1a, 5 mol% FeCl3·6H2O, CH2Cl2, 23ЊC, 12 h, 80% yield of
2a, 11% of 1a was recovered; 1b, 10 mol% FeCl3, CH2Cl2, 2 h ultrasonication at 23ЊC, then 6 h stirring at 23ЊC.
Keywords: annulation; catalysis; iron compounds; Michael reactions.
* Corresponding author. Tel.: ϩ49-30/314-23189; fax: ϩ49-30/723-1233; e-mail: jchr@wap0105.chem.tu-berlin.de
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00045-4

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J. Christoffers, H. Oertling / Tetrahedron 56 (2000) 1339–1344
Scheme 2. Reagents, conditions, and yields: (a) 1. Mg, THF (ultrasound for 3b), 2. CuI, Ϫ20ЊC, 1 h, 3. 4 (0.7 equiv.), Ϫ78ЊC to 23ЊC, 5a: 85%, 5b: 36%; (b)
SeO2 (2 equiv.), tBuO2H (5 equiv.), CH2Cl2, 23ЊC, 15 h, 6a: 38% (1a: 30%, 5a: 27% recovered), 6b: 60%; (c) for 6a: 1. PCC (1.5 equiv.), CH2Cl2, 23ЊC, 4 h, 2.
˚
HCl–H2O, 1a: 80%; (d) for 6b: NMO (6 equiv.), TPAP (0.07 equiv.), mol. sieves (4 A), CH2Cl2, 0ЊC, 1 h, 1b: 86%.
spectrum gave a triplet–triplet coupling pattern of the 7-H
(methine) signal at 1.71 ppm, representing a strictly
symmetrical environment of this proton with two equatorial
(Jˆ3 Hz) and two axial (Jˆ11 Hz) vicinal protons. Such a
high symmetry can only be achieved with trans-connection
of the two seven-membered rings.
1H NMR spectroscopy. The latter shows no more olefinic
signals, but four distinguished MeO resonances in equal
ratio at 3.70 to 3.75 ppm being due to the existence of two
relatively stable conformers each of two diastereoisomers.
Syntheses of precursors
Seventeen-membered ring annulation
Syntheses of donor–acceptor functionalized substrates 1a,b
started with v-bromo-a-olefins 3a,b being converted after
Grignard formation (ultrasonication was required in case of
3b) and transmetallation with CuI22 with the 2-acceptor
substituted cycloalkenone 4 to yield cyclic oxoesters 5a,b
with an v-alkenyl side chain. In case of 5b the low yield
(36%) might be due to the tautomerization of 4 to the corre-
sponding dienol,23 which was isolated in 34% yield as a
byproduct and could protonate the cuprate derived from
3b under reaction conditions.
Encouraged by the latter result we converted the starting
material 1b bearing a C15-side chain with a catalytic amount
of FeCl3·6H2O under both high-dilution and pseudo-high-
dilution conditions.21 To our surprise we found conversion
of 1b to products with either water or MeOH (from the
CH2Cl2 solvent applied) being added to the vinyl ketone
moiety. Consequently, in further experiments we excluded
moisture, applied anhydrous FeCl3 and used MeOH-free
CH2Cl2 as solvent.
Subsequently, compounds 5a,b were submitted to allylic
oxidation with freshly sublimated SeO2 and tBuO2H.24–26
In case of 5a besides the product 6a (38%), enone 1a
(30%) was formed and starting material 5a was recovered
(27%). All three compounds were separable by column
chromatography. In case of 5b allylic alcohol 6b was
obtained in 60% yield. In both cases increase of reaction
times or temperatures did not raise yields, but lead to
unspecified decomposition making the purification of
products more difficult.
However, at ambient temperature under pseudo-high-
dilution conditions (addition of a solution of substrate 1b
to up to 10 equiv. of a 10 g/l solution of FeCl3 in CH2Cl2
over a period up to 5 days) only starting material was
recovered almost quantitatively. Thus, we decided to run
the reaction at elevated temperature (up to 70ЊC in a sealed
flask) under diluted conditions (1.5–25 mmol/l in THF or
CH2Cl2 with 0.1–1 equiv. FeCl3), but again only starting
material was recoverable after workup in 14–40% yield,
and no other unique material was identified after chroma-
tography. It is important to note, that we were neither able to
accomplish the conversion of 1b to 2b with a basic catalyst
(Cs2CO3 in THF).
Allylic alcohol 6a was oxidized to the enone 1a by PCC27 in
80% yield, compound 6b was oxidized by the system
TPAP-NMO28 to give 1b in 86% yield (Scheme 2).
Finally, compound 1b was converted with 0.1 equiv. FeCl3
in 100 mmol/l CH2Cl2. Immediate precipitation of a iron-
dionato complex occurred, but after 2 h of ultrasonication at
ambient temperature a homogeneous mixture was obtained,
which was further stirred for 6 h. After workup and twice
chromatography about 8% of product 2b was isolated
besides various presumably dimeric or oligomeric species
(Scheme 1). Characterization of 2b is based on HRMS and
Whereas v-bromo-a-olefin 3a was commercially available,
compound 3b was not and had to be prepared by copper
cross-coupling reaction29 of a a,v-dibromo alkane 7 with an
allyl Grignard reagent (Scheme 3). An optimal yield of 47%
of 3b was obtained and a,v-diolefin 8 was isolated as the
byproduct in 12% yield. The separation of 7, 3b and 8 was
accomplished by column chromatography.

J. Christoffers, H. Oertling / Tetrahedron 56 (2000) 1339–1344
1341
Scheme 3. Cu-catalyzed cross-coupling reaction to yield a v-bromo-a-olefin, reagents, conditions, and yields: LiCl (0.4 equiv.), CuCl2 (0.2 equiv.), allyl-
MgCl (1.5 equiv.), THF, 0ЊC, 1 h, 3b: 47%, 7: 24% recovered, 8: 12%.
Conclusion
30 min at room temperature. Then the layers were
separated, and the aqueous layer extracted with MTB
(three times 50 ml). The combined organic layers were
washed with brine (20 ml) and dried over MgSO4. After
filtration and evaporation of the solvent the crude product
mixture was separated by chromatography (SiO2, PE) to
give three fractions: First, byproduct 8 (colorless wax,
Rfˆ0.56, 1.19 g, 4.75 mmol, 12%) was obtained. Secondly,
title compound 3b was eluted (colorless oil, Rfˆ0.41,
5.37 g, 18.6 mmol, 47%). As the third fraction, starting
material 7 was recovered (Rfˆ0.35, 3.15 g, 9.60 mmol,
24%). 1H NMR (CDCl3, 400 MHz): dˆ1.26–1.54 (m,
20H), 1.85 (pentet, Jˆ7.1 Hz, 2H, 14-CH2), 2.04 (q,
Jˆ7.1 Hz, 2H; 3-CH2), 3.40 (t, Jˆ6.9 Hz, 2H; 15-CH2),
4.93 (d, Jˆ10.2 Hz, 1H; E-1-CH), 5.01 (dq, Jˆ17.1 Hz,
Jˆ1.7 Hz, 1H; Z-1-CH), 5.82 (ddt, Jˆ17.0 Hz,
Jˆ10.2 Hz, Jˆ6.6 Hz, 1H; 2-CH) ppm. 13C{1H} NMR
(CDCl3, 50 MHz): dˆ28.18 (CH2), 28.77 (CH2), 28.94
(CH2), 29.14 (CH2), 29.44 (CH2), 29.50 (CH2), 29.53
(CH2), 29.59 (CH2), 29.62 (CH2), 29.69 (CH2), 32.85
(CH2), 33.81 (CH2), 33.87 (CH2), 114.05 (CH2), 139.16
(CH) ppm. IR (ATR): 1/lˆ2917 (vs), 2851 (vs), 1641
(m), 1472 (m), 1463 (m), 1438 (m), 992 (m), 909 (s), 717
(m) cmϪ1. MS (EI, 70 eV), m/z (%): 288 (2) [Mϩ], 97 (66),
83 (80), 69 (83), 55 (100) [CH2vCH–(CH2)ϩ2 ]. C15H29Br
(289.30): Anal. calcd C 62.28, H 10.10; found C 62.30, H
10.46. Mol. mass calcd 288.1453, found 288.1457 (Mϩ,
HRMS).
Iron(III) chloride hexahydrate is an efficient catalytic
system for seven-membered carboannulation by intra-
molecular Michael reaction of a cyclic oxoester with a
vinyl ketone moiety. The reaction conditions are mild and
not basic, the separation of the product from the catalyst is
simply accomplished by filtration through SiO2, the yield is
high and the diastereoselectivity quantitatively trans. In
contrast to this, the above mentioned method is not suitable
for a macrocarboannulation reaction. The synthesis of
substrates for an intramolecular Michael reaction was
achieved in a straightforward manner by introduction of
an v-alkenyl side chain by cuprate addition to an
a,b-unsaturated oxoester followed by stepwise allylic
oxidation to the enone moiety.
Experimental
General
1H NMR spectra were recorded with Bruker DRX 500
(500 MHz), AM 400 (400 MHz) and AC 200 (200 MHz).
13C NMR spectra were recorded with Bruker DRX 500
(125 MHz) and AC 200 (50 MHz). H and 13C resonances
1
were assigned by DEPT, HMBC, HMQC and H,H-COSY
experiments. MS spectra were obtained with a Varian MAT
711 and MAT 955Q (high resolution). IR spectra were
recorded with a Nicolet Magna IR 750. Elemental analyses
were obtained with an Analytik Jena Vario EL.
1,17-Octadecadiene (8). Rf (SiO2, PE)ˆ0.56. 1H NMR
(CDCl3, 400 MHz): dˆ1.17–1.38 (m, 24H), 2.04 (q,
Jˆ7.1 Hz, 4H; 3-CH2, 16-CH2), 4.92 (dq, Jˆ10.2 Hz,
Jˆ1.7 Hz, 2H; E-1-CH, E-18-CH), 4.99 (dq, Jˆ17.1 Hz,
Jˆ1.6 Hz, 2H; Z-1-CH, Z-18-CH), 5.81 (ddt, Jˆ17.0 Hz,
Jˆ10.3 Hz, Jˆ6.8 Hz, 2H; 2-CH, 17-CH) ppm. 13C{1H}
NMR (CDCl3, 50 MHz): dˆ26.93 (CH2), 28.97 (CH2),
29.18 (CH2), 29.53 (CH2), 29.64 (CH2), 29.72 (CH2),
33.84 (CH2), 114.06 (CH2), 139.27 (CH) ppm. IR (ATR):
1/lˆ3077 (m), 2977 (m), 2923 (vs), 2853 (s), 1641 (m),
1466 (m), 1440 (m), 992 (m), 909 (s), 721 (m) cmϪ1. MS
(EI, 70 eV), m/z (%): 250 (1) [Mϩ], 97 (42), 83 (49), 69 (62),
55 (100) [CH2vCH–(CH2)ϩ2 ]. C18H34 (250.46): Mol. mass
calcd 250.2661, found 250.2663 (Mϩ, HRMS).
Column chromatography was accomplished with Merck
silica gel (Type 60, 0.063–0.200 mm). All manipulations
involving Grignard or cuprate reagents were carried out in
flame dried glassware under an atmosphere of N2 and with
absolute THF, which was freshly distilled from potassium.
CuCl2, CuI, and LiCl were dried in high vacuum, Mg was
activated with I2, and SeO2 freshly sublimated prior to use.
All other reagents were used as purchased. All starting
materials were commercially available, except methyl
7-oxo-1-cycloheptene-1-carboxylate (4), which was
obtained according to a literature protocol.30 Solutions of
allyl magnesium chloride and tert-butyl hydroperoxide were
purchased from the Aldrich Chemical Co.
Methyl 3-(4-penten-1-yl)cycloheptanone-2-carboxylate
(5a). A Grignard solution prepared from 5-bromo-1-pentene
(3a) (1.77 g, 11.9 mmol) and Mg turnings (442 mg,
18.2 mmol) in THF (10 ml) was added at Ϫ20ЊC to a
suspension of CuI (1.82 g, 9.55 mmol) in THF (20 ml).
After stirring for 1 h at Ϫ20ЊC the mixture was cooled to
Ϫ78ЊC, and a solution of acceptor 4 (1.42 g, 8.42 mmol) in
THF (2 ml) was added. The mixture was stirred for 15 min
at Ϫ78ЊC, then warmed up to room temperature within 1 h.
NH4Cl (50 ml of a saturated solution in H2O) and conc.
hydrochloric acid (2 ml) were added, and the resulting
15-Bromo-1-pentadecene (3b). Solutions of LiCl (672 mg,
15.8 mmol) and CuCl2 (1.07 g, 7.92 mmol) in abs. THF
(each 30 ml) were combined and stirred over night at
room temperature. 1,12-Dibromododecane (7) (13.0 g,
39.6 mmol) was added in one portion, and allyl magnesium
chloride (60.0 mmol, 30.0 ml of a 2 mol/l solution in THF)
was added within 30 min at 0ЊC, and the resulting mixture
was stirred for 60 min at this temperature. Hydrochloric acid
(100 ml, 1 mol/l) was added, and the mixture was stirred for

1342
J. Christoffers, H. Oertling / Tetrahedron 56 (2000) 1339–1344
suspension was extracted with MTB (three times 50 ml).
After drying (Na2SO4) and filtration the combined organic
layers were evaporated and the residue chromatographed on
SiO2 (PE/MTB 1:1, Rfˆ0.50) to yield the compound 5a as a
(CH2), 43.10 (CH2), 37.33 (3-CH), 51.47 (OMe), 62.22
(2-CH), 113.91 (150-CH2), 138.90 (140-CH), 170.32
(CvO), 208.23 (CvO) ppm. IR (ATR): 1/lˆ2923 (vs),
2852 (vs), 1746 (s), 1708 (vs), 1640 (m), 1462 (m), 1435
(m), 1230 (m), 1198 (m), 1158 (m), 994 (m), 908 (m), 720
(m) cmϪ1. MS (EI, 70 eV), m/z (%): 378 (1) [Mϩ], 169 (92),
137 (46), 111, 97 (50), 83 (85), 69 (63), 55 (100)
[CH2vCH(CH2)ϩ2 ]. C24H42O3 (378.59): Anal. calcd C
76.14, H 11.18; found C 76.04, H 11.33. Mol. mass calcd
378.3134, found 378.3134 (Mϩ, HRMS).
1
colorless oil (1.70 g, 7.13 mmol, 85%). H NMR (CDCl3,
400 MHz), a mixture of two diastereoisomers, trans/
cisˆ2:1, trans: dˆ1.73–2.08 (m, 12H), 2.18–2.24 (m,
1H), 2.36–2.43 (m, 1H), 2.63–2.82 (m, 1H), 3.27 (d,
Jˆ9.6 Hz, 1H; 2-CH), 3.71 (s, 3H; OMe), 4.92–5.01 (m,
2H; 50-CH2), 5.71–5.83 (m, 1H; 40-CH) ppm; cis: dˆ1.73–
2.08 (m, 13 H), 2.44–2.50 (m, 1H), 2.55–2.61 (m, 1H), 3.71
(s, 3H; OMe), 3.73 (d, Jˆ6.3 Hz, 1H; 2-CH), 4.92–5.01 (m,
2H; 50-CH2), 5.71–5.83 (m, 1H; 40-CH) ppm. 13C{1H}
NMR (CDCl3, 50 MHz), a mixture of two diastereoisomers,
trans (major): dˆ25.74 (CH2), 25.89 (CH2), 27.79 (CH2),
31.71 (CH2), 33.63 (CH2), 34.26 (CH2), 37.81 (CH), 41.88
(CH2), 52.32 (CH2), 65.89 (CH3), 114.68 (CH2), 138.40
(CH), 170.21 (CvO), 208.05 (CvO) ppm; cis (minor):
dˆ24.03 (CH2), 26.65 (CH2), 26.88 (CH2), 27.03 (CH2),
31.24 (CH2), 32.00 (CH2), 37.33 (CH), 43.30 (CH2), 51.77
(CH), 62.34 (CH3), 114.55 (CH2), 138.56 (CH), 170.54
(CvO), 208.63 (CvO) ppm. IR (ATR): 1/lˆ2930 (s),
2859 (m), 1744 (vs), 1707 (vs), 1640 (m), 1435 (s), 1303
Methyl 3-(3-hydroxy-4-penten-1-yl)cycloheptanone-2-
carboxylate (6a). Oxoester 5a (1.50 g, 6.30 mmol), SeO2
(1.36 g, 12.6 mmol), tBuO2H (33 mmol, 5.5 ml of a
6.0 mol/l solution in decane) and CH2Cl2 (10 ml) were
mixed and stirred for 15 h at room temperature. The super-
natant was decanted, the residue washed twice with CH2Cl2
(after drying, this material could be resubmitted to SeO2
sublimation), and from the combined CH2Cl2 solutions all
volatile materials were removed in vacuo. The resulting
crude oil was chromatographed on SiO2 (PE/MTB 1:1) to
yield three fractions: First, starting material 5a was
recovered (colorless oil, Rfˆ0.50, 789 mg of a mixture
(m), 1232 (s), 1200 (s), 1157 (s), 995 (m), 911 (m) cmϪ1
.
with tBuO2H, molar ratio 1:2.5 by H NMR, 1.70 mmol,
1
MS (EI, 70 eV), m/z (%): 238 (2) [Mϩ], 206 (17), 169 (100)
[MϩϪ(CH2)3CHvCH2], 137 (44). C14H22O3 (238.33): Mol.
mass calcd 238.1569, found 238.1567 (HRMS).
27%; this mixture was directly resubmitted to another
SeO2 oxidation). Secondly, enone 1a was yielded (colorless
oil, Rfˆ0.17, 476 mg, 1.89 mmol, 30%). And finally, allylic
alcohol 6a was obtained as a colorless oil (Rfˆ0.12, 608 mg,
1
Methyl 3-(14-pentadecen-1-yl)cycloheptanone-2-carboxy-
late (5b). A Grignard solution prepared from 3b (2.54 g,
8.77 mmol) and activated Mg turnings (320 mg,
13.2 mmol) in THF (20 ml, ultrasonication was required
to start the reaction) was added at Ϫ30ЊC to a suspension
of CuI (1.31 g, 6.89 mmol) in THF (20 ml). After stirring
for 2 h at Ϫ15ЊC the mixture was cooled to Ϫ78ЊC, and a
solution of acceptor 4 (1.05 g, 6.27 mmol) in THF (10 ml)
was added. The mixture was stirred for 15 min at Ϫ78ЊC,
then warmed up to room temperature within 1 h. NH4Cl
(300 ml of a saturated solution in H2O) was added, and
the resulting suspension was filtered through a glass frit.
The aqueous layer was extracted with MTB (three times
100 ml). After drying (Na2SO4) and filtration the combined
organic layers were evaporated and the residue chroma-
tographed twice on SiO2 (1. PE/MTB 2: 1, Rfˆ0.50; 2.
PE/MTB 10:1, Rfˆ0.16) to yield the compound 5b as a
2.39 mmol, 38%). H NMR (CDCl3, 400 MHz), a mixture
of four diastereoisomers: dˆ1.24–2.77 (m, 13 H), 3.13–
3.32 (m, 1H; 3-CH), 3.71 (s, 3 H; OMe), 3.66–3.82 (m,
1H; 2-CH), 4.04–4.11 (m, 1H; 30-CH), 5.07–5.11 (m, 1H;
50-CHH), 5.18–5.24 (m, 1H; 50-CHH), 5.77–5.88 (m, 1H;
40-CH) ppm. 13C{1H} NMR (CDCl3, 50 MHz), a mixture of
four diastereoisomers, two major and two minor isomers,
major isomers: dˆ25.62 (2 CH2), 27.45 (2 CH2), 30.17
(CH2), 30.28 (CH2), 31.44 (CH2), 31.57 (CH2), 33.54
(CH2), 33.59 (CH2), 37.38 (CH), 37.49 (CH), 41.72 (2
CH2), 52.21 (CH), 52.24 (CH), 65.45 (CH3), 65.48 (CH3),
72.36 (CH), 72.76 (CH), 114.43 (CH2), 114.68 (CH2),
140.75 (CH), 140.84 (CH), 170.04 (CvO), 170.12
(CvO), 207.79 (CvO), 207.86 (CvO) ppm; minor
isomers: dˆ23.72 (CH2), 23.79 (CH2), 24.62 (CH2), 25.98
(CH2), 26.31 (CH2), 26.61 (CH2), 31.84 (CH2), 34.70 (CH2),
34.84 (CH2), 34.97 (CH2), 36.49 (CH), 37.11 (CH), 43.13
(CH2), 43.18 (CH2), 51.69 (CH), 51.73 (CH), 61.87 (CH3),
62.05 (CH3), 72.04 (2 CH), 114.29 (CH2), 114.54 (CH2),
141.10 (2 CH), 170.69 (CvO), 174.09 (CvO), 208.41
(CvO), 208.46 (CvO) ppm. IR (ATR): 1/lˆ3460 (s),
2934 (s), 2861 (m), 1738 (vs), 1703 (vs), 1435 (m), 1349
(m), 1318 (m), 1265 (m), 1227 (m), 1199 (s), 1158 (s), 1057
(m), 993 (m), 923 (m) cmϪ1. MS (EI, 70 eV), m/z (%): 253
(1) [MϩϪH], 237 (10), 219 (17), 205 (100)
[MϩϪOHϪMeOH], 137 (80). C14H22O4 (254.33): Mol.
mass calcd 253.1439 (for C14H21O4), found 253.1436
(MϩϪH, HRMS).
1
colorless oil (845 mg, 2.23 mmol, 36%). H NMR (CDCl3,
400 MHz), trans-isomer (the cis-isomer is less than 5%):
dˆ1.09–1.89 (m, 30H; 15 CH2), 2.01 (q, Jˆ7.0 Hz, 2H;
130-CH2), 2.18–2.47 (m, 3H; 7-CH2, 3-CH), 3.26 (d,
Jˆ9.5 Hz, 1H; 2-CH), 3.70 (s, 3H; OMe), 4.90 (d,
Jˆ10.1 Hz, 1H; 150-E-CHH), 4.97 (dd, Jˆ17.0 Hz,
Jˆ1.8 Hz, 1H; 150-Z-CHH), 5.79 (ddt, Jˆ17.0 Hz,
Jˆ10.2 Hz, Jˆ6.7 Hz, 1H; 140-CH) ppm. 13C{1H} NMR
(CDCl3, 50 MHz), a mixture of two diastereoisomers,
trans (major): dˆ23.97 (CH2), 25.76 (CH2), 26.33 (CH2),
27.54 (CH2), 27.68 (CH2), 28.80 (CH2), 29.00 (CH2), 29.37
(CH2), 29.50 (br., 5 CH2), 31.61 (CH2), 33.66 (CH2), 34.70
(CH2), 37.77 (3-CH), 41.70 (CH2), 52.01 (OMe), 65.75
(2-CH), 113.91 (150-CH2), 138.90 (140-CH), 170.03
(CvO), 207.63 (CvO) ppm; cis-isomer (missing signals
are hidden by the major isomer): dˆ22.53 (CH2), 24.51
(CH2), 24.78 (CH2), 26.67 (CH2), 26.75 (CH2), 29.71
(CH2), 31.72 (CH2), 31.76 (CH2), 31.87 (CH2), 34.99
Methyl 3-(13-hydroxy-14-pentadecen-1-yl)cyclohepta-
none-2-carboxylate (6b). A mixture of oxoester 5b
(766 mg, 2.02 mmol), SeO2 (460 mg, 4.14 mmol) and
tBuO2H (12 mmol, 2.0 ml of a 6.0 mol/l solution in decane)
was stirred for 16 h at ambient temperature. After filtration
and evaporation of volatile materials the filtrate was

J. Christoffers, H. Oertling / Tetrahedron 56 (2000) 1339–1344
1343
chromatographed on SiO2 (PE/MTB 1:1, Rfˆ0.38) to yield
the title compound 6b (481 mg, 1.21 mmol, 60%) as a color-
less oil. H NMR (CDCl3, 400 MHz), only one signal set,
(m), 1017 (m), 993 (m) cmϪ1. MS (EI, 70 eV), m/z (%): 252
(1) [Mϩ], 193 (4), 182 (38), 169 (14), 150 (34), 137 (36), 55
(100) [CH2CHCOϩ]. C14H20O4 (252.31): Mol. mass calcd
252.1362, found 252.1367 (Mϩ, HRMS).
1
minor diastereoisomer not detectable: dˆ1.15–1.30 (m,
21H), 1.45–1.65 (m, 7H), 1.72–1.90 (m, 3H), 2.15–2.25
(m, 1H), 2.35–2.45 (m, 1H), 2.70–2.83 (m, 1H), 3.27 (d,
Jˆ9.5 Hz, 1H; 2-CH), 3.71 (s, 3H; OMe), 4.08 (q,
Jˆ6.3 Hz, 1H; 130-CH), 5.08 (dt, Jˆ10.4 Hz, Jˆ1.1 Hz,
1H; E-150-CH), 5.20 (dt, Jˆ17.3 Hz, Jˆ1.1 Hz, 1H;
Z-150-CH), 5.85 (ddd, Jˆ16.8 Hz, Jˆ10.4 Hz, Jˆ6.2 Hz,
1H; 140-CH) ppm. 13C{1H} NMR (CDCl3, 50 MHz), a
mixture of two diastereoisomers, major: dˆ25.30 (CH2),
25.92 (CH2), 26.47 (CH2), 27.81 (CH2), 29.43 (CH2),
29.49 (CH2), 29.57 (CH2), 29.62 (CH2), 31.71 (CH2),
34.82 (CH2), 37.04 (CH2), 37.93 (CH), 41.89 (CH2), 52.29
(CH), 65.97 (CH3), 73.24 (CH), 114.45 (CH2), 141.34 (CH),
170.31 (CvO), 208.22 (CvO) ppm; minor isomer (missing
signals are hidden by the major isomer): dˆ26.76 (CH2),
27.68 (CH2), 31.82 (CH2), 31.99 (CH2), 37.45 (CH), 43.30
(CH2), 51.76 (CH), 62.44 (CH3), 170.60 (CvO), 208.42
(CvO) ppm. IR (ATR): 1/lˆ3446 (br, m), 2925 (vs),
2853 (vs), 1743 (s), 1706 (s), 1457 (m), 1435 (m), 1318
(m), 1262 (m), 1231 (m), 1198 (m), 1158 (m), 991 (m),
919 (m), cmϪ1. MS (EI, 70 eV), m/z (%): 376 (2)
Methyl 3-(13-oxo-14-pentadecen-1-yl)cycloheptanone-2-
carboxylate (1b). NMO (874 mg, 6.47 mmol) and ground
˚
molecular sieves (4 A, 828 mg) were added at ambient
temperature to
a solution of alcohol 6b (426 mg,
1.08 mmol) in abs. CH2Cl2 (10 ml). TPAP (60 mg,
0.16 mmol) was added and the mixture stirred for 1 h at
0ЊC. After filtration through SiO2 (MTB) and evaporation,
chromatography on SiO2 (PE/MTB 2:1, Rfˆ0.30) yielded
the compound 1b (366 mg, 0.932 mmol, 86%) as a colorless
oil. 1H NMR (CDCl3, 400 MHz), only one signal set, minor
diastereoisomer not detectable: dˆ1.19–1.33 (m, 13H),
1.51–1.62 (m, 8H), 1.74–2.04 (m, 5H), 2.30–2.43 (m,
3H), 2.57 (t, Jˆ7.4 Hz, 2H; 120-CH2), 2.74–2.80 (m, 2H;
7-CH2), 3.27 (d, Jˆ9.5 Hz, 1H; 2-CH), 3.72 (s, 3H; OMe),
5.81 (dd, Jˆ10.4 Hz, Jˆ0.9 Hz, 1H; E-150-CH), 6.21 (dd,
Jˆ17.5 Hz, Jˆ0.8 Hz, 1H; Z-150-CH), 6.35 (dd, Jˆ17.7 Hz,
Jˆ10.4 Hz, 1H; 140-CH) ppm. 13C{1H} NMR (CDCl3,
50 MHz), a mixture of two diastereoisomers, major:
dˆ24.03 (CH2), 25.34 (CH2), 26.49 (CH2), 27.83 (CH2),
29.26 (CH2), 29.41 (CH2), 29.45 (CH2), 29.57 (CH2),
29.64 (CH2), 31.73 (CH2), 34.85 (CH2), 39.67 (CH2),
41.92 (CH2), 52.30 (CH), 65.99 (CH3), 127.80 (CH2),
136.61 (CH), 170.30 (CvO), 201.12 (CvO), 208.21
(CvO) ppm; minor isomer (missing signals are hidden by
the major isomer): dˆ24.11 (CH2), 26.79 (CH2), 26.91
(CH2), 27.70 (CH2), 32.01 (CH2), 43.32 (CH2), 51.76
(CH), 170.60 (CvO), 208.78 (CvO) ppm. IR (ATR):
1/lˆ2925 (vs), 2853 (s), 1743 (s), 1706 (s), 1457 (m), 1435
(m), 1262 (m), 1231 (m), 1198 (m), 1158 (m), 991 (m), 919
(m) cmϪ1. MS (EI, 70 eV), m/z (%): 392 (4) [Mϩ], 361 (18),
333 (12), 323 (22), 291 (38), 169 (100)
[MϩϪ(CH2)12COCHvCH2]. C24H40O4 (392.58): Mol.
mass calcd. 392.2927, found 392.2929 (Mϩ, HRMS).
[MϩϪH2O], 323
(5),
291 (10), 169
(100)
[MϩϪ(CH2)12CH(OH)CHvCH2], 137 (40), 111 (30).
C24H42O4 (394.59 g/mol): Mol. mass calcd 376.2977 (for
C24H40O3), found 376.2973 (MϩϪH2O, HRMS).
Methyl 3-(3-oxo-4-penten-1-yl)cycloheptanone-2-carboxy-
late (1a). A mixture of the allylic alcohol 6a (500 mg,
1.98 mmol), PCC (641 mg, 2.97 mmol) and CH2Cl2
(10 ml) was stirred for 4 h at room temperature, then hydro-
chloric acid was added (20 ml, 1 mol/l). The liquid layers
were decanted, and the residue dissolved in hydrochloric
acid (2 ml, 6 mol/l). The combined aqueous layers were
extracted with CH2Cl2 (2×10 ml), and finally, the combined
organic layers were filtered through a SiO2 column (10 cm,
elution with MTB), which yielded compound 1a (400 mg,
1.58 mmol, 80%) as a colorless oil pure by TLC (PE/MTB
1:5, Rfˆ0.43) and 1H NMR. 1H NMR (CDCl3, 400 MHz), a
mixture of two diastereoisomers, trans/cisˆ2:1, trans:
dˆ1.51–1.94 (m, 8H; 4 CH2), 2.22–2.78 (m, 5H; 3-CH, 2
CH2), 3.31 (d, Jˆ9.5 Hz, 1H; 2-CH), 3.71 (s, 3H; OMe),
5.83 (d, Jˆ10.4 Hz, 1H; E-50-CHH), 6.21 (dd, Jˆ17.6 Hz,
Jˆ0.9 Hz, 1H; Z-50-CHH), 6.34 (dd, Jˆ17.7 Hz,
Jˆ10.4 Hz, 1H; 40-CH) ppm; cis: dˆ1.51–1.94 (m, 8H; 4
CH2), 2.22–2.78 (m, 5H; 3-CH, 2 CH2), 3.71 (s, 3H; OMe),
3.72 (d, Jˆ4.1 Hz, 1H; 2-CH), 5.83 (d, Jˆ10.4 Hz, 1H;
E-50-CHH), 6.22 (dd, Jˆ17.7 Hz, Jˆ1.0 Hz, 1H; Z-50-
CHH), 6.35 (dd, Jˆ17.7 Hz, Jˆ10.5 Hz, 1H; 40-CH) ppm.
13C{1H} NMR (CDCl3, 50 MHz), a mixture of two dia-
stereoisomers, trans (major): dˆ25.70 (CH2), 27.52
(CH2), 28.61 (CH2), 31.69 (CH2), 36.63 (CH2), 37.35
(CH), 41.87 (CH2), 52.45 (CH3), 65.38 (CH), 128.23
(50-CH2), 136.32 (40-CH), 169.98 (CvO), 199.81 (CvO),
207.60 (CvO) ppm; cis (minor): dˆ23.93 (CH2), 26.36
(CH2), 26.69 (CH2), 32.29 (CH2), 36.93 (CH), 37.76
(CH2), 43.25 (CH2), 51.91 (CH3), 62.04 (CH), 127.69
(50-CH2), 136.50 (40-CH), 170 (CvO), 200.12 (CvO),
208.19 (CvO) ppm. IR (ATR): 1/lˆ2932 (s), 2862 (m),
1739 (s), 1704 (vs), 1616 (m), 1447 (m), 1436 (m), 1405
(m), 1352 (m), 1317 (m), 1264 (m), 1199 (s), 1156 (s), 1092
trans-Methyl
bicyclo[5.5.0]dodecan-2,11-dione-1-car-
boxylate (2a). Compound 1a (89 mg, 0.35 mmol) and
FeCl3·6H2O (4.7 mg, 0.017 mmol) were stirred in CH2Cl2
(1 ml) for 12 h at ambient temperature. Subsequently, the
reaction mixture was transferred onto the top of a silica gel
column, and the product 2a was eluted with PE/MTB (1:2,
Rfˆ0.33) to yield 71 mg (80%) of 2a as a colorless oil. Also,
an amount of about 10 mg (11%) of the starting material 1a
1
was recovered (Rfˆ0.38). H NMR (CDCl3, 500 MHz):
dˆ1.36 (m, 1H; 5-H), 1.56 (m, 1 H; 4-H), 1.71 (tt,
Jˆ11 Hz, Jˆ3 Hz, 1H; 7-H), 1.71–1.81 (m, 2H; 6-H,
8-H), 1.89–1.95 (m, 2H; 4-H, 5-H), 2.08–2.22 (m, 3H;
6-H, 8-H, 12-H), 2.27 (ddd, Jˆ15 Hz, Jˆ6 Hz, Jˆ3 Hz,
1H; 12-H), 2.51 (ddd, Jˆ16 Hz, Jˆ6 Hz, Jˆ3 Hz, 1H;
11-H), 2.54 (ddd, Jˆ15 Hz, Jˆ6 Hz, Jˆ4 Hz, 1H; 9-H),
2.57 (m, 1H; 3-H), 2.61 (m, 1H; 9-H), 2.65 (ddd,
Jˆ16 Hz, Jˆ12 Hz, Jˆ3 Hz, 1H; 11-H), 2.70 (ddd,
Jˆ13 Hz, Jˆ6 Hz, Jˆ5 Hz, 1H; 3-H), 3.83 (s, 3H; CH3)
ppm. 13C{1H} NMR (CDCl3, 50 MHz): dˆ24.36 (4-C),
28.44 (5-C), 29.51 (8-C), 31.20 (12-C), 36.17 (6-C), 39.47
(11-C), 41.49 (3-C), 42.57 (9-C), 46.11 (7-C), 52.02 (OMe),
66.14 (1-C), 171.84 (CO2Me), 209.68 (2-C), 212.71 (10-C)
ppm. IR (ATR): 1/lˆ2935 (s), 2862 (m), 1735 (vs), 1703
(vs), 1447 (s), 1449 (m), 1225 (s), 1158 (s), 1106 (m), 1019

1344
J. Christoffers, H. Oertling / Tetrahedron 56 (2000) 1339–1344
(m), 936 (m), 799 (m) cmϪ1. MS (EI, 70 eV), m/z (%): 252
(27) [Mϩ], 234 (10), 220 (16), 192 (26), 182 (52), 169 (46),
137 (100) [cyclo–(CH2)4CHC(CO)COϩ]. C14H20O4
(252.31): Mol. mass calcd 252.1362, found 252.1366
(HRMS).
109, 1290–1311; Angew. Chem. Int. Ed. Engl. 1997, 36, 1236–
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5. Review: Perlmutter, P. Conjugate Addition Reactions in
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chemistry; Eliel, E. L.; Wilen, S. H. Eds.; Wiley Interscience:
New York, 1989; Vol. 19, 227–407.
7. Review: Tomioka, K.; Koga, K. In Asymmetric Synthesis;
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201–224.
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9. Christoffers, J. Org. Synth. in press.
10. Ruel, R.; Deslongchamps, P. Can. J. Chem. 1990, 68, 1917–
1922.
11. Lavallee, J.-F.; Deslongchamps, P. Tetrahedron Lett. 1987,
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12. Berthiaume, G.; Lavallee, J.-F.; Deslongchamps, P.
Tetrahedron Lett. 1986, 27, 5451–5454.
13. Lavallee, J.-F.; Berthiaume, G.; Deslongchamps, P.
Tetrahedron Lett. 1986, 27, 5455–5458.
14. Krohn, K.; Mu¨ller, U.; Priyono, W.; Sarstedt, B.; Stoffregen,
A. Liebigs Ann Chem. 1984, 306–318.
15. Review: Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.;
McLoughlin, J. I. Org. React. 1995, 47, 315–552.
16. Ullmann, A.; Reibig, H.-U.; Rademacher, O. Eur J. Org.
Chem. 1998, 2541–2549.
17. Crevisy, C.; Couturier, M.; Dugave, C.; Dory, Y. L.;
Deslongchamps, P. Bull. Chem. Soc. Fr. 1995, 132, 360–370.
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1995, 132, 371–383.
Methyl bicyclo[15.5.0]docosan-4,22-dione-1-carboxylate
(2b). Anhydrous FeCl3 (97.5 mg, 0.0601 mmol) was added
to a solution of oxoester 1b (236 mg, 0.601 mmol) in abs.
CH2Cl2 (6 ml). After stirring for 15 min a brown material
precipitated. The mixture was kept for 2 h in an ultrasound
bath resulting in a homogeneous dark brown solution, which
was further stirred for 16 h at room temperature. Half conc.
HCl (5 ml) was added, and the mixture extracted three times
with CH2Cl2. The combined extracts were filtered through
SiO2 (CH2Cl2) and evaporated. Twice chromatography on
SiO2 (PE/MTB 2:1, Rfˆ0.24) yielded the macrocyclic
product 2b (20 mg, 0.051 mmol, 8%) as a colorless
material. IR (ATR): 1/lˆ2925 (vs), 2853 (s), 1736 (s),
1707 (vs), 1447 (m), 1435 (m), 1365 (m), 1350 (m), 1319
(m), 1223 (m), 1197 (m), 1158 (m) cmϪ1. MS (EI, 70 eV),
m/z (%): 392 (8) [Mϩ], 364 (17), 360 (24), 332 (38), 304
(26), 277 (16), 169 (93), 137 (46), 109 (40), 95 (48), 81 (67),
69 (51), 67 (49), 57 (43), 55 (100). C24H40O4 (392.58): Mol.
mass calcd 392.2927 (for C24H40O4), found 392.2928 (Mϩ,
HRMS). 1H NMR (CDCl3, 500 MHz): very broad multiplets
between 1.00 and 2.80 ppm, four signals to be assigned to
CO2Me groups of four isomers: two diastereoisomers each
having two conformers, dˆ3.70, 3.71, 3.73, 3.74 ppm.
13C{1H} NMR (CDCl3, 125 MHz): very broad signals, due
to bad signal to noise ratio no assignments possible.
19. Deslongchamps, P.; Roy, B. L. Can J. Chem. 1986, 64, 2068–
2075.
Acknowledgements
20. Christoffers, J. Tetrahedron Lett. 1998, 39, 7083–7084.
¨
21. Rossa, L.; Vogtle, F. Top. Curr. Chem. 1983, 113, 1–86.
This work was supported by the Fonds der Chemischen
Industrie and the Deutsche Forschungsgemeinschaft. We
are also grateful to Prof. S. Blechert and the Institut fu¨r
22. Bruhn, J.; Heimgartner, H.; Schmid, H. Helv. Chim. Acta
1979, 62, 2630–2654.
¨
23. Christoffers, J. J. Org. Chem. 1998, 63, 4539–4540.
24. Marshall, J. A.; Jenson, T. M.; DeHoff, B. S. J. Org. Chem.
1987, 52, 3860–3866.
25. Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99,
5526–5528.
Organische Chemie der Technischen Universitat Berlin
for support. J. C. also thanks the Deutsche Forschungsge-
meinschaft and H. O. the Graduiertenkolleg ‘Synthetische,
mechanistische und reaktionstechnische Aspekte von
Metallkatalysatoren’ for fellowships.
26. Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1972, 94,
7154–7155.
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