Stereocontrolled formation of three contiguous stereogenic centers by free radical cyclization - synthesis of (+)-iridomyrmecin and (-)-iso-iridomyrmecin - formal synthesis of δ-skythantine

Article abstract of DOI:10.1002/ejoc.200500711

A synthesis of (+)-iridomyrmecin (1), a naturally occurring insecticide with antibiotic properties, via free radical cyclization is described. In this key step, three contiguous stereogenic centers are generated with a high level of stereo-control. Wiley-

Full text of DOI:10.1002/ejoc.200500711

FULL PAPER
DOI: 10.1002/ejoc.200500711
Stereocontrolled Formation of Three Contiguous Stereogenic Centers by Free
Radical Cyclization – Synthesis of (+)-Iridomyrmecin and (–)-Iso-
iridomyrmecin – Formal Synthesis of δ-Skythantine
Bernd Schöllhorn[a] and Johann Mulzer*[b]
Dedicated to Professor Horst Kunz on the occasion of his 65th birthday
Keywords: Insecticides / Free radical cyclization / Stereoselectivity / α,β-Unsaturated esters / Cyclopentanes / Lactones /
Alkaloids
A synthesis of (+)-iridomyrmecin (1), a naturally occurring
insecticide with antibiotic properties, via free radical cycliza-
tion is described. In this key step, three contiguous stereo-
genic centers are generated with a high level of stereo-
control.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
hexenyl radicals is described. It leads preferentially to 1,5-
cis-disubstituted cyclopentanes, according to the Beckwith
transition state model.[3] This model postulates an early
transition state, which resembles a “chair-like” cyclohexane
ring with substituents in pseudo-equatorial rather than
pseudo-axial[4] positions.
Introduction
5-Hexenyl radicals normally cyclize via a 5-exo-trig[1]
mode.[2] With respect to the stereochemical outcome three
cases may be distinguished (Scheme 1). In the first case,
Scheme 1, Equation (1), the cyclization of 1-substituted 5-
In the second case Equation (2), we have a stereogenic
center at C-2. The substituent at C-2 leads to a high 1,2-
trans induction[5] whereas the relative cis-configuration of
C-2 and C-5 is maintained. In the third case, Equation (3),
a 5,6-trisubstituted double bond with defined E/Z-geome-
try is attacked by the free radical. The 1,2-trans and 1,5-cis
inductions should remain. However, the question arises if
there is any stereocontrol with respect to the third pro-
stereogenic center (C-6). In extension of previous work on
radical cyclizations[6] we decided to take this as an issue for
own research and chose the synthesis[7] of enantiomerically
pure (+)-iridomyrmecin (1),[8] a naturally occurring cyclic
monoterpene with insecticidal and antibiotic properties[9] as
a suitable target. En route, iso-iridomyrmecin (2)[10] and the
iridoalkaloid δ-skythantine (3)[11] (structures 1–3) were also
aimed for.
Scheme 1.
[a] Ecole Normale Superieure, Department de Chimie, UMR
CNRS 8640-PASTEUR,
24, Rue Lhomond, 75231 Paris Cedex 05, France
[b] Institut für Organische Chemie der Universität Wien,
Währinger Strasse 38, 1090 Wien, Austria
Fax: +43-1-4277-52189
E-mail: johann.mulzer@univie.ac.at
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901

B. Schöllhorn, J. Mulzer
FULL PAPER
Two main diastereomers 12 and 13 were obtained, some-
times along with minor amounts of other diastereomers.
In particular, the cyclization of 11a,b proved to be highly
stereoselective. In this step three new stereogenic centers
were generated to form two diastereomers 12/13a in a ratio
of 82:14. Although this mixture could be easily separated by
analytical HPLC, this was difficult on a preparative scale.
However, on desilylation the 12/13a–c mixtures spontane-
ously lactonized to an easily separable mixture of 1 and 2.
On treatment with base, 1 was epimerized into the thermo-
dynamically more stable epimer 2.[8b] By contrast, the mix-
ture of 12/13d was reduced to the diols 14/15, which could
also be separated chromatographically. To exclude any arte-
facts that might have resulted from working with mixtures,
a small quantity of pure 12a was procured by preparative
HPLC, reduced to 16 and desilylated to 14 which was iden-
tical with the material prepared from 12/13d. Alternatively,
14 was obtained from the LAH reduction of 1. The analyti-
cal data of our compounds 1[9b] and 2[9b] were in full agree-
ment with those reported in the literature. The conversion
of diol 14 into alkaloid 3 has already been described.[11b]
Results and Discussion
Results: Our synthesis (Scheme 2) started with the known[12]
alcohol 4, which was converted into aldehyde
7
via some routine steps. The stereoselectivity of the ensuing
Wittig reaction of 7 to the enoates 8a–c proved to be highly
solvent dependent. Thus, the olefination in diethyl ether pro-
ceeded E-selectively and furnished esters 8a (E/Z = 97:3) and
8c (E/Z = 90:10). When isolated and reacted in methanol,
aldehyde 7 afforded an 80:20 ratio of 8a/b. This mixture was
separated chromatographically and provided sufficient quan-
tities of the (Z)-ester 8b. After removal of the acetonide diols
9a–c were obtained, which were silylated or benzoylated se-
lectively at the primary hydroxy group to furnish the monop-
rotected derivatives 10a–e. Treatment with PhOC(S)Cl gave
thiocarbonates 11a–e in almost quantitative yields.
The free radical cyclization of 11a–e was carried out with
tributyltin hydride and catalytic amounts of AIBN at 80–
90 °C in a 0.02  toluene solution (Scheme 3, Table 1).[13]
Scheme 2. Reagents and conditions: a) DMSO, oxalyl chloride, CH2Cl2, –78 °C; Et3N; Ph3P=CHCO2Et, CH2Cl2/EtOH, 92%; b) H2 (1
bar), Raney-Ni, room temp., 12 h, EtOH, 96%. c) DIBAL-H, diethyl ether/toluene, –78 °C; d) 8a: Ph3P=CMeCO2Et, diethyl ether/EtOH;
E/Z = 97:3, 72% over 2 steps; 8b: Ph3P=CMeCO2Et, MeOH; (E/Z = 4:1, 68% over 2 steps)); 8c: Ph3P=CMeCO2Me, diethyl ether/EtOH;
E/Z = 9:1, 69% over 2 steps; e) TFA, H2O, EtOH (9a: 98%; 9b: 95%; 9c: 96%). f) 10a-c: tBuMe2SiCl, imidazole, DMF, 79–82%; 10d:
tBuPh2SiCl, imidazole, DMF, 82%; 10e: BzCl, DMAP, pyridine, 78%; g) 11a-e: PhOCSCl, DMAP, pyridine, CH2Cl2, 92–97%.
902
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Three Contiguous Stereogenic Centers by Free Radical Cyclization
FULL PAPER
Scheme 3. Reagents and conditions: a) nBu3SnH, AIBN, toluene, 80–90 °C, 12 h, 75–85%; b) TFA, H2O, CH2Cl2, 91%; c) LiAlH4, diethyl
ether, 82–86%; d) NaOMe, MeOH, 12 h, 85%; e) LiAlH4, diethyl ether, 87%; f) DIBAL-H, diethyl ether/n-hexane, –40 °C, 87%; g)
nBu4NF, THF, 86%.
Table 1. Diastereomeric ratios and overall yields of the radical the radicals is shielded by the cis-CH2OR1 moiety, it may
cyclization of 11a–e.
be assumed that the hydrogen donor selectively attacks
11
R1
R2
12/13/other
Overall yield [%]
from the “frontside” to give the final products 12a and 13a.
E- and Z-enoates 11a and b give the same ratio of 12a/13a,
which indicates that the equilibration of B and D is fast
compared to the hydrogen transfer. This appears plausible
as the rotation is a reaction of first order and the hydrogen
transfer one of second order. Thus, the ratio of 12a/13a to
a first approximation reflects the equilibrium composition
of D/B. The diminished selectivity of 11c may be attributed
to a lower preference for conformer D, due to the smaller
size of the OMe group. The remaining two examples 11d
and e are more complex. Obviously, conformations other
diastereomers
a (E)
b (Z)
c (E)
d (E)
e (E)
TBDMS
TBDMS
TBDMS
TBDPS
Bz
Et
Et
Me
Et
82:14 Ͻ4
82:14 Ͻ4
67:28 Ͻ5
54:34:12
60:23:17
75
75
75
80
85
Et
Discussion
For clarity, we restrict our mechanistic rationalization than B and D are also involved, so that more than two
(Scheme 4) to the stereoselective cases 11a and b. We apply diastereomers result from the cyclization.
Beckwith’s model and assume that the radicals A and C,
In conclusion, we have described the free radical cycliza-
which are formed from the (Z)-and (E)-enoates, adopt chair tion of acyclic chirally C-2-substituted 1-hexenyl radicals.
like conformations with the C-2-methyl group in a pseudo- Three contiguous stereogenic centers are formed with vary-
equatorial position. In this geometry 1,5-cyclization occurs ing stereocontrol. In the best case, only two diastereomers
to form the new radicals B and D, which may rotate freely out of eight are produced in a ratio of 82:14. The cyclopen-
around the 5,6-axis. Due to the allylic 1,3-strain[14] exerted tane derivatives thus formed were readily converted into the
by the ester carbonyl, the transoid conformer D is more natural products 1, 2 and, via a formal synthesis, also into
stable than the cisoid conformer B. As the “backside” of 3.
Eur. J. Org. Chem. 2006, 901–908
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B. Schöllhorn, J. Mulzer
FULL PAPER
Scheme 4.
Ethyl (4S,5S)-5,6-Isopropylidene-4-methylhexanoate (6): A solution
of 5 (7.0 g, 30.7 mmol) in ethanol (50 mL) was hydrogenated over
Raney-Ni (pH 7–8, 0.5–1.0 g) at 1 bar for 5 h. Filtration over Celite
and evaporation gave 6 as a colorless oil (6.75 g, 96%). [α]2D0 = +4.2
(c = 1.9, CHCl3). 1H NMR: δ = 4.13 (q, J = 7.3 Hz, 2 H), 4.00
(dd, J = 7.8 Hz, J = 6.2 Hz, 1 H), 3.85 (ddd, J = 7.8 Hz, J = 6.2
Hz, J = 5.4 Hz, 1 H), 3.60 (t, J = 7.8, J = 6.2 Hz, 1 H), 2.38 (m,
2 H), 1.95 (mc, 1 H), 1.64 (mc, 1 H), 1.49 (m, 1 H), 1.40 (s, 3 H),
1.35 (s, 3 H), 1.27 (t, J = 7.3 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H)
ppm. 13C NMR: δ = 173.51, 108.67, 80.06, 67.64, 60.06, 36.13,
Experimental Section
General Methods: NMR spectra were measured either on a Bruker
AC 250 spectrometer in CDCl3 with TMS as an internal standard
unless noted otherwise. IR spectra were recorded on a Perkin–El-
mer IR 580 B infrared spectrometer or a Nicolet FTIR-Interferom-
eter system 5 SXC using KBr pellets. Mass spectra were measured
on a Varian MAT 711 (EI). The elemental analyses were deter-
mined on a Perkin–Elmer 2400 CHN Elemental Analyser. Optical
rotations were obtained in CHCl3, unless stated otherwise, with a
Perkin–Elmer 241 polarimeter. Melting points are uncorrected.
HPLC separations were performed on Nucleosil 50 with particle
sizes 5 µm (analytical) and 7 µm (preparative), with RI and UV
detection. Preparative column chromatography was performed on
silica gel Merck 60 (0.063–0.04 mm). All reactions were carried out
under an argon atmosphere in purified solvents with magnetic stir-
ring and were controlled with TLC plates (Merck 5554).
31.88, 28.59, 26.54, 25.46, 14.94, 14.12 ppm. IR: νmax = 1730 (s)
˜
cm–1. MS: m/z = 215 (60.0%, [M – CH3]+), 185 (24.2%, [M –
C2H5O]+), 155 (61.1%, [M – C2H5O – 2CH3]+), 127 (34.9%, [M –
C2H5O – 2CH3 – CO]+), 109 (32.6%), 101 (54.5%, [C5H9O2]+), 81
(50.9%), 72 (57.2%, [C4H8O]+), 43 (100.0%, [C2H3O]+). C12H22O4
(230.31): calcd. C 62.58, H 9.63; found C 62.37, H 9.48.
Ethyl (2E,6S,7S)- and Ethyl (2Z,6S,7S)-7,8-Isopropylidenedioxy-
2,6-dimethyl-2-octenoate (8a,b): To a stirred solution of ethyl ester
6 (5.60 g, 24.32 mmol) in diethyl ether (330 mL) a 1.3  solution
of DIBAH in toluene (18.70 mL, 24.32 mmol) was added slowly
at –78 °C and stirred for 3 h at the same temperature. The mixture
was quenched with ethanol (10 mL), and the resulting aldehyde 7
was treated in situ with (ethoxycarbonylmethyliden)triphenylphos-
phorane solvated in ethanol (20 mL), stirred for 12 h and quenched
with some water. The solution was concentrated and diluted with
diethyl ether/water. The organic layer was washed with water and
brine, dried (MgSO4) and the solvents evaporated. Chromatog-
raphy on silica (hexane/ethyl acetate, 3:1) gave a 97:3 mixture of
8a/b (4.73 g, 72%). When isolating aldehyde 7 and performing the
olefination in methanol at 0 °C, a 80:20 mixture of 8a/b was ob-
tained, which was separated by HPLC (ethyl acetate/hexanes, 8:92)
to give 8a (3.54 g, 54%) and 8b (930 mg, 14%) as colorless oils.
Ethyl (4S,5S,2E)-5,6-Isopropylidene-4-methylhexenoate (5): Oxalyl
chloride (1.06 mL, 12.4 mmol) in dichloromethane (30 mL) was
treated at –78 °C with DMSO (1.2 mL, 16.5 mmol) in dichloro-
methane (3 mL). After 15 min alcohol 4 (1.32 g, 8.24 mmol) in
dichloromethane (12 mL) was added dropwise. After 20 min trieth-
ylamine (5.7 mL, 41.2 mmol) was added. After 20 min the mixture
was warmed to 0 °C and stirred for additional 20 min. Water and
ether were added, the organic phase was separated washed with
brine, dried with magnesium sulfate and concentrated under re-
duced pressure to give crude aldehyde which was diluted with THF
(50 mL) and treated with (ethoxycarbonylmethylene)triphenylphos-
phorane (4.92 g, 16 mmol) at room temp. for 12 h. The solvent was
evaporated and the residue was diluted with diethyl ether to remove
the phosphane oxide by crystallization. The mother liquor was
chromatographed (hexane/ethyl acetate, 3:1) to give pure ester 5
(1.63 g, 92%) as a colorless oil. B.p. (3 Torr) 75–80 °C. [α]2D0
=
1
1
–18.9 (c = 2.6, CHCl3). H NMR: δ = 6.97 (dd, J = 16.2 Hz, J =
7.6 Hz, 1 H), 5.87 (dd, J = 16.2 Hz, J = 1.6 Hz, 1 H), 4.20 (q, J =
8a: [α]2D0 = +0.7 (c = 2.0, CHCl3). H NMR: δ = 6.76 (dt, J = 7.3
Hz, J = 1.3 Hz, 1 H), 4.19 (q, J = 7.3 Hz, 2 H), 4.00 (dd, J = 7.5
7.3 Hz, 2 H), 4.02 (mc, 2 H), 3.64 (m, 1 H), 2.50 (mc, J = 7.6 Hz, Hz, J = 5.8 Hz, 1 H), 3.85 (ddd, J = 7.5 Hz, J = 5.8 Hz, J = 5.0
J = 6.8 Hz, J = 1.6 Hz, 1 H), 1.42 (s, 3 H), 1.36 (s, 3 H), 1.31 (t,
Hz, 1 H), 3.60 (t, J = 7.5 Hz, 1 H), 2.38–2.09 (m, 2 H), 1.86 (d, J
= 1.3 Hz, 3 H), 1.83–1.58 (m, 2 H), 1.42 (s, 3 H), 1.40 (s, 3 H),
J = 7.3 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR: δ =
166.27, 149.55, 121.58, 109.16, 78.51, 67.32, 60.09, 39.72, 26.37, 1.37–1.22 (m, 1 H), 1.31 (t, J = 7.3 Hz, 3 H), 0.88 (d, J = 7.0 Hz,
25.29, 15.07, 14.11 ppm. IR: νmax = 1720 (s), 1650 (m) cm–1. MS:
3 H) ppm. 13C NMR: δ = 168.07, 141.90, 127.77, 108.65, 80.11,
67.64, 60.26, 36.20, 32.08, 26.60, 25.89, 25.51, 14.91, 14.20, 12.24
˜
m/z = 213 (20.4%, [M – CH3]+), 183 (3.9%, [M – C2H5O]+), 153
(3.6%, [M – H2O – 2CH3]+), 125 (15.2%, [M – C2H5O – 2CH3 – ppm. IR: νmax = 1710 (s), 1650 (w) cm–1. MS: m/z = 270 (13.2%,
˜
CO]+), 101 (100.0%, [C5H9O2]+), 72 (16.9%, [C4H8O]+), 43 (62.9%,
[C2H3O]+). C12H20O4 (228.29): calcd. C 63.14, H 8.83; found C
62.82, H 8.77.
[M]+), 255 (42.3%, [M – CH3]+), 212 (17.5%, [M – CH3
–
C2H3O]+), 167 (36.6%, [M – CH3 – C2H3O – C2H5O]+), 149
(18.6%), 140 (19.36%), 121 (73.0%), 113 (14.9%), 101 (61.1%,
904
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Three Contiguous Stereogenic Centers by Free Radical Cyclization
FULL PAPER
[C5H9O2]+), 93 (31.6%), 81 (11.7%), 72 (53.9%, [C4H8O]+), 55 (43.4 %, [M – CH2OH – CH3]+), 167 (21.4 %, [M – H2O –
(25.5%), 43 (100.0%, [C2H3O]+). C15H26O4 (270.37): calcd. C
66.64, H 9.69; found C 66.13, H 9.60.
C2H5O]+), 153 (70.8 %, [M – H2O – C2H5O – CH2OH]+), 140
(24.4%), 128 (43.1%), 112 (53.0%), 95 (74.2%), 81 (33.2%), 67
(47.6 %), 55 (100.0 %), 43 (99.4 %, [C2H3O]+). HRMS calcd. for
[C12H22O4]+: 230.15181, found 230.15172. C12H22O4 (230.31):
calcd. C 62.58, H 9.63; found C 62.29, H 9.53.
1
8b: [α]2D0 = +8.8 (c = 2.2, CHCl3). H NMR: δ = 5.92 (mc, J = 1.8
Hz, 1 H), 4.20 (q, J = 7.3 Hz, 2 H), 4.00 (dd, J = 7.5 Hz, J = 5.8
Hz, 1 H), 3.87 (ddd, J = 7.5 Hz, J = 5.8 Hz, J = 5.0 Hz, 1 H), 3.60
(t, J = 7.5 Hz, 1 H), 2.62–2.37 (m, 2 H), 1.89 (d, J = 1.8 Hz, 3 H),
1.78–1.56 (m, 2 H), 1.43 (s, 3 H), 1.40 (s, 3 H), 1.36 (t, J = 7.3 Hz,
3 H), 1.31–1.15 (m, 1 H), 0.86 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR:
δ = 167.86, 142.60, 127.08, 108.46, 79.97, 67.43, 59.85, 36.14, 32.73,
Methyl (2E,6S,7S)-7,8-Dihydroxy-2,6-dimethyl-2-octenoate (9c):
1
[α]2D0 = –10.0 (c = 2.3, CHCl3). H NMR: δ = 6.74 (dt, J = 6.8 Hz,
J = 1.1 Hz, 1 H), 3.92 (s, 2 H), 3.73 (s, 3 H), 3.68 (m, 1 H), 3.51
(m, 2 H), 2.25 (mc, 2 H), 2.16 (mc, 1 H), 1.84 (d, J = 1.1 Hz, 3 H),
1.71 (m, 1 H); 1.63 (m, 1 H), 1.31 (mc, 1 H), 0.92 (d, J = 7.0 Hz,
3 H) ppm. 13C NMR: δ = 168.63, 142.43, 127.43, 75.85, 64.22,
26.70, 26.52, 25.44, 20.50, 14.61, 14.14 ppm. IR νmax = 1715 (s),
˜
1650 (w) cm–1. MS: m/z = 270 (15.0%, [M]+), 255 (41.3%, [M –
CH3]+), 212 (19.7%, [M – CH3 – C2H3O]+), 167 (44.0%, [M –
CH3 – C2H3O – C2H5O]+), 149 (52.7%), 140 (21.6%), 121 (71.9%),
101 (85.6%, [C5H9O2]+), 93 (28.0%), 72 (64.1%, [C4H8O]+), 55
(26.0%), 43 (100.0%, [C2H3O]+). C15H26O4 (270.37): calcd. C
66.64, H 9.69; found C 66.28, H 9.62.
51.61, 35.58, 31.08, 25.91, 14.94, 12.20 ppm. IR: νmax = 3391 (s),
˜
1714 (s), 1649 (m) cm–1. MS: m/z = 216 (1.6%, [M]+), 198 (11.9%,
[M – CH2OH]+), 184 (43.4%, [M – CH2OH – CH3]+), 153 (70.8%,
[M – H2O – C2H5O – CH2OH]+), 126 (43.1%), 111 (53.0%), 97
(74.2%), 95 (65.2%) 81 (24.2%), 67 (33.5%), 55 (100.0%). HRMS
calcd. for [C11H20O4]+: 216.13616, found 216.13613. C11H20O4
(216.28): calcd. C 61.09, H 9.32; found C 61.36, H 9.49.
Methyl (2E,6S,7S)-7,8-Dihydroxy-2,6-dimethyl-2-octenoate (8c): 8c
(4.45 g, 69%, E/Z = 9:1) was prepared from 6 (5.80 g, 25.2 mmol)
as described for the preparation of 8a. [α]2D0 = +2.0 (c = 2.2,
Preparation of 10a–d: To a stirred solution of 9a (4.61 g,
20.20 mmol) and imidazole (2.73 g, 40.03 mmol) in DMF (250 mL)
tBuSiMe2Cl (3.02 g, 20.20 mmol) in DMF (50 mL) was added
slowly at –12 °C and stirred for 6 h at 0 °C and for 12 h at room
temp. The mixture was quenched with cold water, concentrated,
diluted with diethyl ether/water, and extracted with diethyl ether.
The organic layer was washed with water and brine, dried (MgSO4)
and the solvents evaporated. Chromatography (hexane/ethyl ace-
tate, 3:1) gave 10a (5.58 g, 81%) as a colorless oil. 10b (1.29 g) was
prepared from 9b (1.05 g) as described for the preparation of 10a
(yield: 82 %). 10c (1.93 g) was prepared from 9c (1.60 g) as de-
scribed for the preparation of 10a (yield: 82%). 10d (1.00 g) was
prepared with tBuSiPh2Cl from 9c (600 mg) as described for the
preparation of 10a (yield 82%).
1
CHCl3). H NMR: δ = 6.76 (mc, J = 1.5 Hz, 1 H), 4.00 (dd, J =
7.5 Hz, J = 5.8 Hz, 1 H), 3.84 (ddd, J = 7.5 Hz, J = 5.0 Hz, 1 H),
3.73 (s, 3 H), 3.58 (t, J = 7.5 Hz, 1 H), 2.37–2.08 (m, 2 H), 1.84
(d, J = 1.5 Hz, 3 H), 1.81–1.57 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3
H), 1.28 (m, 1 H), 0.88 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR: δ =
168.51, 142.28, 127.47, 108.64, 80.10, 67.64, 51.54, 36.15, 32.05,
26.60, 25.88, 25.49, 14.92, 12.26 ppm. IR: νmax = 1715 (s), 1650 (w)
˜
cm–1. C14H24O4 (256.34): calcd. C 65.60, H 9.44; found C 65.39, H
9.17.
Preparation of 9a–c: To a solution of 8a (4.00 g, 14.79 mmol) in
ethanol (200 mL) TFA (8 mL) and water (4 mL) were added drop-
wise and stirred for 2 d at room temp. The mixture was concen-
trated and chromatographed (hexane/ethyl acetate, 1:2). Recovered
starting material 8a was recycled to give pure diol 9a (3.33 g, 98%)
as a colorless oil. 9b (1.05 g) was prepared from 8b (1.30 g) as de-
scribed for the preparation of 9a (yield: 95%). 9c (3.13 g) was pre-
pared from 8c (3.86 g) as described for the preparation of 9a (yield:
96%).
Ethyl (2E,6S,7S)-8-tert-Butyldimethylsiloxy-7-hydroxy-2,6-di-
1
methyl-2-octenoate (10a): [α]2D0 = –2.6 (c = 2.0, CHCl3). H NMR:
δ = 6.68 (dt, J = 7.5 Hz, J = 1.3 Hz, 1 H), 4.08 (q, J = 7.3 Hz, 2
H), 3.60 (mc, 1 H), 3.43 (mc, 1 H), 3.29 (m, 1 H), 2.52 (sbr, 1 H,
OH), 2.28–1.97 (m, 2 H), 1.76 (d, J = 1.3 Hz, 3 H), 1.66 (m, 1 H),
1.52 (m, 1 H), 1.26 (m, 1 H), 1.21 (t, J = 7.3 Hz, 3 H), 0.84 (s, 9
H), 0.84 (d, J = 7.0 Hz, 3 H), 0.02 (s, 6 H) ppm. 13C NMR: δ =
168.02, 142.04, 127.61, 75.23, 64.99, 60.16, 35.26, 31.19, 26.00,
Ethyl (2E,6S,7S)-7,8-Dihydroxy-2,6-dimethyl-2-octenoate (9a):
[α]2D0 = –8.8 (c = 2.0, CHCl3). H NMR: δ = 6.75 (dt, J = 7.0 Hz,
1
J = 1.4 Hz, 1 H), 4.18 (q, J = 7.3 Hz, 2 H), 3.84 (s, 2 H, OH), 3.71
(m, 1 H), 3.51 (m, 2 H), 2.24 (mc, 1 H), 2.16 (mc, 1 H), 1.79 (d, J
= 1.4 Hz, 3 H), 1.79–1.53 (m, 2 H), 1.37–1.21 (m, 1 H), 1.30 (t, J
= 7.3 Hz, 3 H), 0.92 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR: δ =
168.30, 142.10, 127.67, 75.84, 64.26, 60.38, 35.61, 31.10, 25.93,
25.73, 18.11, 15.07, 14.15, 12.16, –5.50, –5.56 ppm. IR: νmax = 3520
˜
(m), 1710 (s), 1650 (w) cm–1. MS: m/z = 344 (1.8%, [M]+), 299
(2.2%, [M – C2H5O]+), 287 (5.1%, [M – C4H9]+), 269 (2.9%, [M –
C2H5O – 2CH3]+), 257 (7.2%, [M – C4H9 – 2CH3]+), 241 (22.2%,
[M – C2H5O – 2CH3 – CO]+), 211 (11.4 %), 149 (22.8 %), 121
(39.3%), 105 (34.5%), 93 (19.3%), 75 (100.0%). HRMS calcd. for
[C1 8 H3 6 O4 Si]+ : 344.23829, found 344.23834; calcd. for
[C16H31O3Si]+: 299.20425, found 299.20423. C18H36O4Si (344.57):
calcd. C 62.74, H 10.53; found C 62.52, H 10.43.
14.96, 14.10, 12.16 ppm. IR: νmax = 3405 (s), 1711 (s), 1648 (w)
˜
cm–1. MS: m/z = 230 (3.4%, [M]+), 212 (1.2%, [M – H2O]+),199
(5.2%, [M – CH2OH]+), 184 (40.7%, [M – CH2OH – CH3]+), 167
(14.4%, [M – H2O–C2H5O]+), 153 (61.3%, [M – H2O – C2H5O –
CH2OH]+), 140 (23.1%), 121 (27.8%), 112 (42.4%), 95 (64.1%), 82
(36.0 %), 67 (41.5 %), 55 (78.1 %), 43 (100.0 %, [C2H3O]+).
C12H22O4 (230.31): calcd. C 62.58, H 9.63; found C 62.36, H 9.45.
HRMS calcd. for [C12H22O4]+: 230.15181, found 230.15172.
Ethyl (2Z,6S,7S)-8-tert-Butyldimethylsiloxy-7-hydroxy-2,6-di-
1
methyl-2-octenoate (10b): [α]2D0 = +5.3 (c = 2.1, CHCl3). H NMR:
δ = 5.92 (dt, J = 7.3 Hz, J = 1.6 Hz, 1 H), 4.18 (q, J = 7.3 Hz, 2
Ethyl (2Z,6S,7S)-7,8-Dihydroxy-2,6-dimethyl-2-octenoate (9b): H), 3.69 (dd, J = 8.6 Hz, J = 6.5 Hz, 1 H), 3.46 (mc, J = 8.6 Hz,
1
[α]2D0 = –11.9 (c = 2.3, CHCl3). H NMR: δ = 5.85 (dt, J = 7.8 Hz,
1 H), 3.41 (m, 1 H), 2.62 (s, 1 H, OH), 2.58–2.36 (m, 2 H), 1.88
J = 1.5 Hz, 1 H), 4.10 (q, J = 7.3 Hz, 2 H), 3.94 (s, 2 H, OH), 3.60 (d, J = 1.6 Hz, 3 H), 1.72 (mc, 1 H), 1.60 (m, 1 H), 1.30 (t, J = 7.3
(m, 1 H), 3.41 (m, 2 H), 2.44 (m, 1 H), 2.31 (mc, 1 H), 1.80 (d, J Hz, 3 H), 1.24 (m, 1 H), 0.92 (s, 9 H), 0.89 (d, J = 7.0 Hz, 3 H),
= 1.5 Hz, 3 H), 1.54 (m, 2 H), 1.30–1.13 (m, 1 H), 1.22 (t, J = 7.3
0.09 (s, 6 H) ppm. 13C NMR: δ = 167.93, 142.93, 126.96, 75.16,
Hz, 3 H), 0.80 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR: δ = 168.60, 64.95, 59.86, 35.27, 31.95, 26.81, 25.73, 20.48, 18.11, 14.93, 14.13,
142.95, 127.07, 75.74, 64.24, 60.01, 35.52, 31.86, 26.56, 20.42, –5.49, –5.56 ppm. IR: νmax = 3314 (w), 1716 (s), 1646 (w) cm–1.
˜
14.99, 14.07 ppm. IR: νmax = 3391 (s), 1714 (s), 1645 (m) cm–1. MS: MS: m/z = 344 (1.1 %, [M]+), 299 (3.2 %, [M – C2H5O]+), 287
˜
m/z = 230 (1.6%, [M]+), 212 (1.1%, [M – H]+),199 (11.9%), 184
(9.3 %, [M – C4H9]+), 269 (4.2 %, [M – C2H5O – 2CH3]+), 257
Eur. J. Org. Chem. 2006, 901–908
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
905

B. Schöllhorn, J. Mulzer
FULL PAPER
(6.3%, [M – C4H9 – 2CH3]+), 241 (22.1%, [M – C2H5O – 2CH3 –
with sat. aqueous NH4Cl, water, brine, dried (MgSO4), concen-
CO]+), 223 (15.5%), 211 (13.8%), 149 (61.8%), 121 (70.5%), 105 trated under reduced pressure and chromatographed (hexane/ethyl
(30.2%), 93 (22.5%), 75 (100.0%). HRMS calcd. for [C18H36O4Si]+: acetate, 10:1) to give thiocarbonate 11a (4.04 g, 95%). Analogously,
344.23829, found 344.23817; calcd. for [C16H31O3Si]+: 299.20425,
found 299.20320; calcd. for [C14H27O4Si]+: 287.16786, found
287.16758. C18H36O4Si (344.57): calcd. C 62.74, H 10.53; found C
62.62, H 10.38.
11b–e were prepared in 92–97% yield.
Ethyl (2E,6S,7S)-8-tert-Butyldimethylsiloxy-2,6-dimethyl-7-[(phen-
oxythiocarbonyl)oxy]-2-octenoate (11a): [α]2D0 = –13.8 (c = 1.6,
CHCl3). 1H NMR: δ = 7.52 (mc, 2 H, m-aryl-H), 7.40 (mc, 1 H, p-
aryl-H), 7.20 (mc, 2 H, o-aryl-H), 6.87 (dt, J = 7.6 Hz, J = 1.4 Hz,
1 H, 3-H), 5.41 (mc, 1 H, 7-H), 4.30 (q, J = 7.3 Hz, 2 H, ethyl
CH2), 4.01 (m, 2 H, 8-H), 2.49–2.18 (m, 3 H), 1.97 (d, J = 1.4 Hz,
3 H, 2-Me), 1.88–1.73 (m, 1 H), 1.57–1.45 (m, 1 H), 1.42 (t, 3 H,
J = 7.3 Hz, 3 H, ethyl-Me), 1.04 (d, J = 7.0 Hz, 3 H, 6-Me), 1.04
(s, 9 H, tBu), 0.24 (s, 6 H, SiMe2) ppm. 13C NMR: δ = 195.04,
168.09, 153.34, 141.46, 129.41, 128.09, 126.40, 121.93, 88.81, 61.38,
60.37, 33.24, 30.96, 26.05, 25.78, 18.18, 15.16, 14.26, 12.36, –5.44
Methyl (2E,6S,7S)-8-tert-Butyldimethylsiloxy-7-hydroxy-2,6-di-
1
methyl-2-octenoate (10c): [α]2D0 = –1.3 (c = 1.7, CHCl3). H NMR:
δ = 6.68 (dt, J = 7.3 Hz, J = 1.1 Hz, 1 H), 3.64 (s, 3 H), 3.60 (mc,
1 H), 3.37 (mc, 1 H), 3.33 (m, 1 H), 2.48 (sbr, 1 H, OH) 2.16 (mc,
1 H), 2.08 (mc, 1 H), 1.76 (d, J = 1.1 Hz, 3 H), 1.65 (mc, 1 H), 1.52
(mc, 1 H), 1.30–1.15 (m, 2 H), 0.83 (s, 9 H), 0.81 (d, J = 7.0 Hz, 3
H), 0.01 (s, 6 H) ppm. 13C NMR: δ = 168.76, 142.54, 127.62, 75.37,
65.10, 51.59, 35.40, 31.35, 26.11, 25.85, 18.24, 15.16, 12.23, –5.36,
ppm. IR: νmax = 1711 (s), 1650 (w), 1201 (s) cm–1. MS: m/z = 423
–5.43 ppm. IR: νmax = 3511 (w), 1717 (s), 1649 (w) cm–1. MS:
˜
˜
(1.5%, [M – C4H9]+), 326 (7.2%, [M – C7H5O2S – H]+), 281 (2.8%,
[M – C7H5O2S – H – C2H5O]+), 269 (46.2%, [M – C7H5O2S – H –
C4H9]+), 211 (32.2 %, [M – C7H5O2S – H – SitBuMe2]+), 151
(22.4%, [M – C7H5O2S – H – SitBuMe2 – C2H5O – CH3]+), 121
(33.0%), 89 (28.6%), 73 (100.0%). HRMS calcd. for [C21H31O5-
SSi]+: 423.16615, found 423.16600; calcd. for [C18H34O3Si]+:
326.22772, found 326.22775; calcd. for [C14H25O3Si]+: 269.15730,
found 269.15729. C25H40O5SSi (480.75): calcd. C 62.45, H 8.39;
found C 62.42, H 8.10.
m/z = 330 (5.5%, [M]+), 299 (4.2%, [M – CH3O]+), 273 (10.5%,
[M – C4H9]+), 255 (5.1%), 241 (37.5%), 223 (14.0%), 149 (22.8%),
121 (39.3%), 105 (34.5%), 93 (19.3%), 75 (100.0%). HRMS calcd.
for [C17H34O4]+: 330.22264, found 330.22328. C17H34O4Si (330.54):
calcd. C 61.77, H 10.37; found C 63.02, H 10.47.
Ethyl (2E,6S,7S)-8-tert-Butyldiphenylsiloxy-7-hydroxy-2,6-di-
1
methyl-2-octenoate (10d): H NMR: δ = 7.63 (m, 4 H), 7.37 (m, 6
H), 6.67 (dt, J = 7.6 Hz, J = 1.4 Hz, 1 H), 4.16 (q, J = 7.3 Hz, 2
H), 3.58 (m, 3 H), 2.36 (m, 1 H), 2.13 (m, 2 H), 1.80 (d, J = 1.4
Hz, 3 H), 1.56 (m, 2 H), 1.28 (t, J = 7.3 Hz, 3 H), 1.06 (s, 9 H),
1.04 (m, 1 H), 0.89 (d, J = 6.2 Hz, 3 H) ppm; MS (EI, 80eV):
m/z = 423 (0.2%, [M – C2H5O]+), 411 (2.0%, [M – C4H9]+), 393
(1.4%), 365 (13.3%), 333 (34.6%), 287 (10.9%), 299 (10.1%), 199
(100.0%, [C12H11OSi]+), 181 (14.6%), 149 (17.7%), 135 (17.6%),
121 (34.1%), 77 (15.9%, [C6H5]+). C26H40O4Si (444.70): calcd. C
70.22, H 9.07; found C 71.20, H 8.83.
Ethyl (2Z,6S,7S)-8-tert-Butyldimethylsiloxy-2,6-dimethyl-7-[(phen-
oxythiocarbonyl)oxy]-2-octenoate (11b): [α]2D0 = –7.9 (c = 1.4,
CHCl3). 1H NMR: δ = 7.39 (m, 2 H, m-aryl), 7.25 (m, 1 H, p-aryl),
7.08 (m, 2 H, o-aryl), 5.91 (dt, J = 6.8 Hz, J = 1.6 Hz, 1 H, 3-H),
5.28 (mc, 1 H, 7 H), 4.20 (q, J = 7.3 Hz, 2 H, ethyl CH2), 3.89
(ddd, J = 11.3 Hz, J = 5.4 Hz, J = 3.8 Hz, 2 H, 8-H), 2.53 (m, 2
H), 2.12 (m, 1 H), 1.90 (d, J = 1.6 Hz, 3 H, 2-Me), 1.66 (m, 1 H),
1.34 (m, 1 H), 1.32 (t, J = 7.3 Hz, 3 H, ethyl-Me), 1.02 (d, J = 7.0
Hz, 3 H, 6-Me), 0.93 (s, 9 H, tBu), 0.11 (s, 6 H, SiMe2) ppm. 13C
NMR: δ = 195.08, 168.01, 153.35, 142.22, 129.40, 127.55, 126.38,
121.97, 89.10, 61.36, 60.06, 33.29, 31.75, 26.97, 25.80, 20.72, 18.18,
Preparation of 10e: A solution of diol 9a (1.50 g, 6.94 mmol) and
pyridine (1.68 mL, 3 equiv.) in CH2Cl2 (21 mL) was treated with
DMAP (200 mg, 1.63 mmol) and benzoic acid chloride (0.81 mL,
6.94 mmol) at –12 °C, stirred for 2 h at 0 °C and 1–2 h at room
temp., quenched with a saturated aqueous solution of NH4Cl, ex-
tracted with diethyl ether, washed with water, brine, dried (MgSO4)
and chromatographed (hexane/ethyl acetate, 3:1) to give colorless
liquid benzoate 10e (1.73 g, 78%).
14.99, 14.31, –5.43 ppm. IR: νmax = 1715 (s), 1647 (w), 1202 (s)
˜
cm–1. MS: m/z = 23 (1.4 %, [M – C4H9]+), 326 (8.3 %, [M –
C7H5O2S – H]+), 303 (2.7%), 281 (4.2%, [M – C7H5O2S – H –
C2H5O]+), 269 (76.6%, [M – C7H5O2S – H – C4H5]+), 223 (27.9%),
211 (35.5%, [M – C7H5O2S – H – SitBuMe2]+), 195 (18.4%), 185
(10.4 %), 149 (39.1 %), 121 (40.4 %), 89 (27.1 %), 73 (100.0 %,
[C6H5]+). HRMS calcd. for [C21H31O5SSi]+: 423.16615, found
423.16680. C25H40O5SSi (480.75): calcd. C 62.45, H 8.39; found C
62.73, H 8.00.
Ethyl (2E,6S,7S)-8-Benzoyloxy-7-hydroxy-2,6-dimethyl-2-octenoate
(10e): [α]2D0 = –3.9 (c = 0.6, CHCl3). H NMR: δ = 8.02 (d, J = 7.3
1
Hz, 2 H), 7.56 (t, J = 7.3 Hz, 1 H), 7.42 (t, J = 7.3 Hz, 2 H), 6.74
(dt, J = 7.6 Hz, J = 1.6 Hz, 1 H), 4.47 (dd, J = 11.3 Hz, J = 3.5
Hz, 1 H), 4.28 (dd, J = 11.3 Hz, J = 7.3 Hz, 1 H), 4.16 (q, J = 7.3
Hz, 2 H), 3.80 (mc, 1 H), 2.39–2.09 (m, 3 H), 2.52 (s, 1 H, OH),
1.85 (d, J = 1.6 Hz, 3 H), 1.75 (m, 2 H), 1.41 (mc, 1 H), 1.29 (t, J
= 7.3 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR: δ =
168.12, 166.77, 141.77, 133.07, 129.55, 128.32, 127.89, 73.68, 67.51,
Methyl (2E,6S,7S)-8-tert-Butyldimethylsiloxy-2,6-dimethyl-7-
[(phenoxythiocarbonyl)oxy]-2-octenoate (11c): [α]2D0 = –14.7 (c = 1.5,
1
CHCl3). H NMR: δ = 7.36–6.93 (m, 5 H, aryl), 6.64 (dt, J = 7.3
Hz, J = 1.0 Hz, 1 H, 3-H), 5.18 (mc, 1 H, 7-H), 3.78 (m, 2 H, 8-
H), 3.61 (s, 3 H, OMe), 2.28–1.98 (m, 3 H), 1.76 (d, J = 1.0 Hz, 3
H, 2-Me), 1.58 (mc, 1 H), 1.28 (m, 1 H), 0.93 (d, J = 7.0 Hz, 3 H,
6-Me), 0.84 (s, 9 H, tBu), 0.20 (s, 6 H, SiMe2) ppm. 13C NMR: δ
= 194.90, 168.35, 153.23, 141.71, 129.29, 127.69, 126.28, 121.81,
88.64, 61.26, 51.50, 33.08, 30.81, 25.89, 25.68, 18.06,15.06, 12.28,
60.32, 35.97, 30.92, 26.02, 15.15, 14.16, 12.25 ppm. IR: νmax = 3485
˜
(m), 1718 (s), 1710 (s), 1647 (w) cm–1. MS: m/z = 334 (1.6 %,
[M]+), 316 (0.84%, [M – H2O]+), 288 ([M – H – C2H5O]+), 212
([M – C6H5 – C2H5O]+), 176, 166 ([M – PhCO – C2H5O – H2O]+),
153, 121 ([PhCO2]+), 105 ([PhCO]+), 77 ([Ph]+). HRMS calcd. for
[C19H26O5]+: 334.17803, found 334.17818; calcd. for [C17H20O4]+:
288.13616, found 288.13599. C19H26O5 (344.42): calcd. C 66.26, H
7.61; found C 66.42, H 7.59.
–5.55 ppm. IR: νmax = 1715 (s), 1651 (w), 1202 (s) cm–1. MS:
˜
m/z = 451 (0.1%, [M–CH3]+), 423 (0.3%), 409 (4.4%, [M – C4H9]+),
312 (19.5%, [M – C7H5O2S – H]+), 255 (100.0%, [M – C7H5O2S –
H – C4H9]+), 223 (28.7%, [M – C7H5O2S – H – CH3O – CO –
2CH3]+), 211 (64.6%), 185 (15.1%), 151 (32.3%), 121 (25.8%), 89
(39.1%), 73 (82.2%). C24H38O5SSi (466.72): calcd. C 61.76, H 8.20;
found C 61.99, H 8.05.
Preparation of Thiocarbonates 11a–e: A solution of alcohol 10a
(3.05 g, 8.85 mmol) and pyridine (2.15 mL, 26.55 mmol) in 18 mL
CH2Cl2 was treated with DMAP (200 mg, 1.63 mmol) and
PhOC(S)Cl (2.98 mL, 22.13 mmol) at 0 °C, stirred for 12 h at room Ethyl (2E,6S,7S)-8-tert-Butyldiphenylsiloxy-2,6-dimethyl-7-[(phen-
temp., quenched with water, extracted with diethyl ether, washed
oxythiocarbonyl)oxy]-2-octenoate (11d): 1H NMR: δ = 7.68 (m, 4
906
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 901–908

Three Contiguous Stereogenic Centers by Free Radical Cyclization
FULL PAPER
H), 7.39–7.12 (m, 9 H), 7.04 (m, 2 H), 6.72 (dt, J = 7.6 Hz, J =
1.2 Hz, 1 H, 3-H), 5.52 (mc, 1 H, 7-H), 4.18 (q, J = 7.3 Hz, 2 H,
1 H), 1.22 (t, J = 6.8 Hz, 3 H, ethyl-Me), 1.11 (m, 1 H), 1.06 (s, 9
H, tBu), 1.04 (d, J = 7.0 Hz, 3 H, 1-Me), 1.00 (d, J = 7.0 Hz, 3 H,
ethyl CH2), 3.85 (m, 2 H, 8-H), 2.25 (m, 2 H), 2.09 (m, 1 H), 1.90 3-Me) ppm. 13C NMR: δ = 176.92, 135.62, 133.87, 129.58, 127.62,
(d, J = 1.2 Hz, 3 H, 2-Me), 1.61 (m, 1 H), 1.36 (m, 1 H), 1.30 (t, 63.60, 59.90, 53.77, 49.30, 45.08, 40.32, 32.44, 29.71, 26.86, 22.52,
J = 7.3 Hz, 3 H, ethyl-Me), 1.08 (s, 9 H, tBu), 1.00 (d, J = 7.0 Hz, 19.18, 17.00, 14.21 ppm. IR: νmax = 1960 (w), 1890 (w), 1825 (w),
˜
3 H, 6-Me) ppm. 13C NMR: δ = 195.23, 168.18, 153.39, 141.32,
1730 (s) cm–1. MS: m/z = 437 (0.4%, [M – CH3]+), 407 (7.3%, [M –
135.62, 135.58, 133.04, 129.80, 129.43, 127.77, 126.43, 121.97, C2H5O]+), 395 (100.0%, [M – C4H9]+), 349 (4.5%, [M – C4H9
–
87.65, 62.40, 60.43, 33.41, 31.54, 26.73, 26.30, 19.18, 14.50, 14.29,
C2 H5 O – H]+ ), 289 (9.1 %), 227 (18.5 %), 199 (28.2 %,
12.42 ppm. IR: νmax = 1709 (s), 1650 (w), 1202 (s) cm–1. MS:
[C12H11OSi]+), 183 (17.2%), 139 (13.2%), 123 (13.0%), 95 (19.6%).
C28H40O3Si (452.71): calcd. C 74.29, H 8.91; found C 73.82, H
˜
m/z = 547 (3.4%, [M – C4H9]+), 450 (4.7%, [M – H – C7H5O2S]+),
393 (76.8 %, [M – H – C7H5O2S – C4H9]+), 335 (31.7 %), 275 8.86.
(41.9%), 227 (21.6%), 199 (59.3%, [C12H11OSi]+), 135 (48.7%), 109
(1S,2R,3S)-2-(tert-Butyldiphenylsiloxymethyl)-1-[(1R)-1-(ethoxycar-
(49.6 %), 77 (100.0 %, [C6H5]+). C35H44O5SSi (604.89): calcd. C
69.50, H 7.33; found C 69.45, H 7.10.
bonyl)ethyl]-3-methylcyclopentane (13c): 1H NMR: δ = 7.64 (m, 4
H), 7.36 (m, 6 H), 4.06 (q, J = 7.3 Hz, 2 H), 3.85 (m, 2 H), 2.42
(mc, 1 H), 2.19 (mc, 1 H), 2.01–1.57 (m, 4 H), 1.44 (m, 1 H), 1.28
(m, 1 H), 1.23 (t, J = 7.3 Hz, 3 H), 1.08 (d, J = 7.0 Hz, 3 H), 1.05
Ethyl (2E,6S,7S)-8-Benzoyloxy-2,6-dimethyl-7-[(phenoxythiocar-
bonyl)oxy]-2-octenoate (11e): [α]2D0 = –4.6 (c = 1.2, CHCl3). 1H
NMR: δ = 8.02 (mc, 2 H, aryl-H), 7.53 (m, 1 H, aryl-H), 7.38 (mc, (s, 9 H), 0.98 (d, J = 6.8 Hz, 3 H). C28H40O3Si (452.71): calcd. C
4 H, aryl-H), 7.24 (mc, 1 H, aryl-H), 7.01 (mc, 2 H, aryl-H), 6.72 74.29, H 8.91; found C 74.35, H 8.76.
(dt, J = 7.3 Hz, J = 3 Hz, 1 H, 3-H), 5.68 (dt, J = 7.3 Hz, J = 3.0
(1S,2R,3S)-2-(Benzoyloxymethyl)-1-[(1S)-1-(ethoxycarbonyl)ethyl]-
Hz, 1 H, 7-H), 4.69 (dd, J = 12.3 Hz, J = 3.0 Hz, 1 H, 8-H), 4.50
3-methylcyclopentane (12d): 1H NMR: δ = 8.00 (d, J = 7.0 Hz, 2
(dd, J = 12.3 Hz, J = 7.3 Hz, 1 H, 8-H), 4.16 (q, J = 7.3 Hz, 2 H,
H, o-aryl), 7.53 (t, J = 7.1 Hz, 1 H, p-aryl), 7.41 (t, J = 7.0 Hz, 2
ethyl CH2), 2.41–2.09 (m, 3 H), 1.87 (d, J = 1.3 Hz, 3 H, 2-Me),
H, m-aryl), 4.40 (dd, J = 11.9 Hz, J = 5.4 Hz, 1 H, 8-H), 4.25 (d,
1.74 (mc, 1 H), 1.47 (m, 1 H), 1.29 (t, J = 7.3 Hz, 3 H, ethyl-Me),
J = 11.9 Hz, 1 H, 8-H), 4.11 (q, J = 7.5 Hz, 2 H, ethyl CH2), 2.48
1.12 (d, J = 7.0 Hz, 3 H, 6-Me) ppm. 13C NMR: δ = 194.76, 167.74,
(m, 1 H), 2.21 (m, 1 H), 2.08 (mc, 1 H), 1.97 (m, 1 H), 1.72 (m, 1
165.93, 153.12, 140.80, 133.03, 129.55, 129.43, 129.27, 128.23,
H), 1.48 (m, 1 H), 1.28 (d, J = 7.0 Hz, 3 H, 1-Me), 1.21 (t, J = 7.5
126.34, 121.63, 85.28, 63.12, 60.22, 33.84, 30.93, 25.67, 14.87,
Hz, 3 H, ethyl-Me), 1.17 (m, 1 H), 1.08 (d, J = 7.0 Hz, 3 H, 3-Me).
14.08, 12.24 ppm. IR: νmax = 1724 (s), 1710 (s), 1649 (w), 1202 (s)
˜
C19H26O4 (318.42): calcd. C 71.67, H 8.23; found C 71.39, H 8.18.
cm–1. MS: m/z = 470 (0.6%, [M]+), 425 (3.9%, [M – C2H5O]+), 316
(20.1%, [M – C7H5O2S – H]+), 194 (31.7%, [M – C7H5O2S – H –
C6H5 – C2H5O]+), 149 (30.5 %), 121 (69.6 %, [PhCO2]+), 105
(100.0%, [C7H5O]+), 93 (38.6%, [C6H5O]+), 77 (65.4%, [C6H5]+).
HRMS calcd. for [C26H30O6S]+: 470.17631, found 470.17635;
calcd. for [C24H25O5S]+: 425.14227, found 425.14226. C26H30O6S
(470.58): calcd. C 66.36, H 6.43; found C 66.48, H 6.27.
Formation of 1 and 2: The mixture of silyl ethers 12/13a–b (1 mmol)
in CH2Cl2 (20 mL) was treated dropwise with TFA (1 mL) and
water (1 mL) at –12 °C and stirred for 12 h at room temp. The
mixture was diluted with CH2Cl2 (40 mL) and water (10 mL). The
organic layer was washed with water and brine, dried (MgSO4) and
the solvents evaporated. Chromatography (hexane/ethyl acetate,
3:1) gave a mixture of diastereomers, which were separated by
HPLC (2% 2-propanol/hexane) to give 1 and 2. Sublimation and
recrystallization from hexane afforded colorless needles. The mix-
ture of TBDPS ethers 12/13c (0.40 g, 0.88 mmol) in THF (4.4 mL)
was stirred with a 1.1  solution of TBAF in THF (1.46 mL,
1.33 mmol) for 12 h at room temp. Workup and purification were
the same as above (yield 95%).
Free Radical Cyclization of 11a–e to give 12/13a–d. Typical Pro-
cedure: For ensuring quantitative conversion, an excess of the stan-
nane was applied. Thus, to a stirred solution of 1 mmol nBu3SnH
and 0.05 mmol AIBN in toluene (50 mL) a solution of 1 mmol
11a–e, 2 mmol nBu3SnH and 0.05 mmol AIBN in toluene (1–3 mL)
was added slowly during 12 h at 80–90 °C. The mixture was stirred
for 2–4 h at 90 °C, evaporated and purified by chromatography
(hexane/ethyl acetate, 10:1) to give a mixture of diastereomers. The
diastereomeric ratio was determined by HPLC and 1H NMR spec-
troscopy. A preparative separation of the diastereomers was not
possible in all cases. Overall yields and ratios of 12/13a–d see
Table 1.
(4aS)-4t,4ar,7c,7ac-4,7-Dimethylhexahydrocyclopenta[c]pyran-3-one
[(+)-Iridomyrmecin (1)]: [α]2D5 = +211 (c = 1.0, CCl4); [ref.[9b] [α]1D7
= +205 (c = 0.22, CCl4)], m.p. 60–61 °C (ref.[9b] 59–60 °C). 1H
NMR: δ = 4.27 (dd, J = 11.7 Hz, J = 3.7 Hz, 1 H, 8-H), 4.16 (d,
J = 11.7 Hz, 1 H, 8-H), 2.71 (quint, J = 6.8 Hz, 1 H, 2-H), 2.60
(mc, 1 H, 3-H), 1.96–1.73 (m, 4 H, 4-H, 5-H, 6-H, 7-H), 1.16 (d, J
= 6.8 Hz, 3 H, 2-Me), 1.06 (d, J = 6.8 Hz, 3 H, 6-Me), 1.02 (m, 2
H, 4-H, 5-H) ppm; 1HNMR (270 MHz, [D6]acetone): δ = 4.36 (dd,
J = 11.3 Hz, J = 3.5 Hz, 1 H), 4.12 (d, J = 11.3 Hz, 1 H), 2.85
(quint, J = 6.8 Hz, 1 H), 2.66 (mc, 1 H), 1.92 (m, 1 H), 1.88–1.68
(m, 3 H), 1.07 (d, J = 6.3 Hz, 3 H), 1.04 (d, J = 6.8 Hz, 3 H), 0.92
(1S,2R,3S)-2-(tert-Butyldimethylsiloxymethyl)-1-[(1S)-1-(ethoxycar-
bonyl)ethyl]-3-methylcyclopentane (12a): 1H NMR: δ = 4.10 (q, J =
7.0 Hz, 2 H, ethyl CH2), 3.53 (mc, 1 H, 8-H), 3.40 (dd, J = 10.0
Hz, J = 7.3 Hz, 1 H, 8-H), 2.44 (m, 1 H), 2.04 (m, 1 H), 1.84 (m,
1 H), 1.74–1.04 (mc, 5 H), 1.23 (t, J = 7.0 Hz, 3 H, ethyl CH2),
0.93 (d, J = 6.8 Hz, 3 H, 3-Me), 0.92 (s, 9 H, tBu), 0.88 (d, J = 7.0
Hz, 3 H, 1-Me), 0.30 (s, 6 H, SiMe2) ppm. 13C NMR: δ = 177.11,
62.91, 59.90, 49.11, 45.19, 40.36, 35.89, 32.53, 29.68, 25.87, 22.68,
22.49, 17.22, 14.22, –5.52 ppm. C18H38O3Si (330.59): calcd. C
65.40, H 11.59; found C 65.62, H 11.79.
1
(m, 2 H). H NMR ([D6]benzene): δ = 3.63 (d, J = 11.3 Hz, 1 H),
3.48 (dd, J = 11.3 Hz, J = 3.8 Hz, 1 H), 1.92 (quint, J = 6.5 Hz, 1
H), 1.83 (mc, 1 H), 1.55 (mc, 1 H), 1.48–1.20 (m, 3 H), 1.02 (d, J
= 6.0 Hz, 3 H), 0.88 (mc, 1 H), 0.71 (d, J = 6.8 Hz, 3 H), 0.62 (mc,
1 H) ppm. 13C NMR: δ = 175.87, 67.86, 45.68, 43.31, 38.00, 37.27,
34.20, 29.73, 18.31, 12.64 ppm. 13C NMR ([D6]acetone): δ =
176.14, 67.85, 45.43, 41.11, 37.84, 37.21, 34.10, 29.74, 18.29, 12.65
(1S,2R,3S)-2-(tert-Butyldiphenylsiloxymethyl)-1-[(1S)-1-(ethoxycar-
bonyl)ethyl]-3-methylcyclopentane (12c): 1H NMR: δ = 7.64 (m, 4
H, aryl-H), 7.37 (m, 6 H, aryl-H), 4.07 (q, J = 6.8 Hz, 2 H, ethyl ppm. IR: νmax = 1730 (s) cm–1. MS: m/z = 168 (8.8%, [M]+), 153
˜
CH2), 3.60 (dd, J = 9.8 Hz, J = 5.0 Hz, 1 H, 8-H), 3.41 (dd, J =
(0.7 %, [M – CH3]+), 150 (2.1 %), 138 (1.2 %, [M-2CH3]+), 123
9.8 Hz, J = 7.5 Hz, 1 H, 8-H), 2.32 (mc, 1 H), 2.17 (mc, 1 H), 2.04 (1.4%), 109 (46.8%, [M – CO2 – CH3]+), 95 (100.0%), 81 (54.9%),
(mc, 1 H), 1.84 (mc, 1 H), 1.76 (mc, 1 H), 1.57 (m, 1 H), 1.32 (m, 67 (66.7%), 55 (24.9%). HRMS calcd. for [C10H16O2]+: 168.11503,
Eur. J. Org. Chem. 2006, 901–908
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
907

B. Schöllhorn, J. Mulzer
FULL PAPER
found 168.11505. C10H16O2 (168.24): calcd. C 71.39, H 9.59; found
C 71.08, H 9.48.
(380 mg, 85%) as a colorless oil. The analytical data matched with
those described above.
(–)-Isoiridomyrmecin (2): [α]2D0 = –62.4 (c = 0.7, CCl4), ref.[9b] [α]1D9
[1] J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734–736.
[2] B. Giese, T. Göbel, B. Kopping, H. Zipse, Houben-Weyl, Meth-
ods of Organic Chemistry, vol E21c Stereoselective Synthesis
(Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaum-
ann), Thieme, Stuttgart 1995, p. 2203.
1
= –64 (c = 1, CCl4); m.p. 58–59 °C (ref.[9b] 57.5–58 °C). H NMR:
δ = 4.35 (dd, J = 11.6 Hz, J = 6.2 Hz, 1 H, 8-H), 3.96 (t, J = 11.6
Hz, 1 H, 8-H), 2.36 (m, 1 H, 6-H), 2.12 (m, 1 H, 4-H), 2.04 (mc, 2
H, 5-H, 7-H), 1.90 (m, 1 H, 3-H), 1.66 (m, 1 H, 2-H), 1.29 (m, 2
H, 4-H, 5-H), 1.20 (d, J = 7.0 Hz, 3 H, 6-Me), 1.06 (d, J = 7.0 Hz,
3 H, 2-Me) ppm. 13C NMR: δ = 176.24, 69.34, 45.28, 43.16, 39.01,
[3] a) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron Lett. 1985,
26, 373–376; b) A. L. J. Beckwith, C. J. Easton, T. Lawrence,
A. K. Serelis, Aust. J. Chem. 1983, 36, 545–546.
38.22, 35.61, 33.03, 19.08, 13.89 ppm. IR: νmax = 1731 (s) cm–1.
˜
[4] D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1987, 52, 959–
MS: m/z = 168 (38.8%, [M]+), 109 (52.4%, [M – CO2 – CH3]+), 95
(100.0 %), 81 (88.0 %), 67 (81.1 %), 55 (34.1 %), 41 (64.2 %,
[C3H5]+). HRMS calcd. for [C10H16O2]+: 168.11503, found
168.11518. C10H16O2 (168.24): calcd. C 71.39, H 9.59; found C
71.12, H 9.52.
974.
[5] See for example a) G. Stork, R. Mook, Jr., S. A. Biller, S. D.
Rychnovsky, J. Am. Chem. Soc. 1983, 105, 3741–3742; b) T.
Nakai, Chem. Lett. 1985, 1725–1728.
[6] a) J. Mulzer, M. Czybowski, J.-W. Bats, Tetrahedron Lett. 2001,
42, 2961–2964; b) J. Mulzer, A. K. Kermanchahi, J. Busch-
mann, P. Luger, Liebigs Ann. Chem. 1994, 531–539.
[7] Earlier syntheses of non-racemic 1: a) D. E. Chavez, E. N. Ja-
cobsen, Org. Lett. 2003, 5, 2563–2565; b) H. Nagata, O. Hiro-
shi, K. Ogasawara, Tetrahedron Lett. 1999, 40, 6617–6620; c)
T. Horikawa, Y. Norimine, M. Tanaka, K. Sakai, H. Suemune,
Chem. Pharm. Bull. 1998, 46, 17–21; d) A. V. Stepanov, V. V.
Veselovsky, Russ. Chem. Bull. 1997, 46, 1606–1610; e) D. M.
Hodgson, A. R. Gibbs, Synlett 1997, 657–658; f) A. Nangia,
G. Prasuna, Tetrahedron 1996, 52, 3435 –3450; g) E. Lee, C. H.
Yoon, J. Chem. Soc., Chem. Commun. 1994, 479–481; h) Y.
Takahashi, M. Tanaka, X. M. Wu, K. Sakai, Nat. Prod. Lett.
1992, 1, 217–220; i) G. Agnel, Z. Owczarczyk, E. Negishi, Tet-
rahedron Lett. 1992, 33, 1543–1546; j) T. Wang, Y. Fu, F. Chi,
J. Chem. Soc., Chem. Commun. 1989, 1876–1878; k) W. Op-
polzer, E. J. Jacobsen, Tetrahedron Lett. 1986, 27, 1141–1144;
l) J. Wolinsky, T. Gibson, D. Chan, H. Wolf, Tetrahedron 1965,
21, 1247–1261.
[8] a) Isolation of 1: M. Pavan, Ricerca Sci. 1949, 19, 1011–1017;
b) Structure of 1 and isomerization of 1 to 2: R. Fusco, R.
Trave, A. Vercellone, Chim. Ind. Milan 1955, 37, 251, 958–959.
[9] Biological properties of 1: a) M. Pavan, Ricerca Sci. 1949, 19,
1011–1017; b) G. W. K. Cavill, D. L. Ford, H. D. Locksley,
Austr. J. Chem. 1956, 9, 288–293; c) A. Hefetz, H. A. Lloyd, J.
Chem. Ecol. 1983, 9, 607–613; d) M. D. Tomalski, M. S. Blum,
T. H. Jones, H. M. Fales, D. F. Howard, L. Passera, J. Chem.
Ecol. 1987, 13, 253–263; e) L. M. Roth, T. Eisner, E. A. Stein-
haus, R. F. Smith, Annu. Rev. Entomol. 1962, 7, 107–136; f) P.
Callant, R. Ongena, M. Vandewalle, Tetrahedron 1981, 37,
2085–2089; g) P. A. Grieco, Ch. V. Srinivasan, J. Org. Chem.
1981, 46, 2591–2593.
Diols 14/15: The mixture of benzoates 12/13d (0.53 g 1.66 mmol) in
diethyl ether (30 mL) was treated with LAH (0.13 g, 3.33 mmol)
at –12 °C and stirred for 3 h at 0 °C. The mixture was quenched
with a sat. aq. NH4Cl, diluted with CH2Cl2, filtered, dried
(MgSO4) and the solvents evaporated. Chromatography (hexane/
ethyl acetate, 1:2) gave a mixture of diastereomers 14/15 (0.25 g,
1.45 mmol), from which 14 was isolated by HPLC (5% 2-propanol/
hexane).
(1R,2R,3S)-2-(Hydroxymethyl)-1-[(1S)-2-hydroxy-1-methylethyl]-3-
1
methylcyclopentane (14): H NMR: δ = 3.68 (ddd, J = 10.8 Hz, J
= 5.1 Hz, J = 4.1 Hz, 2 H), 3.37 (m, 2 H), 2.16–1.88 (m, 3 H), 1.76
(m, 2 H), 1.56 (mc, 1 H), 1.37–1.07 (m, 3 H), 1.05 (d, J = 6.5 Hz,
3 H), 1.01 (d, J = 7.3 Hz, 3 H), 0.88 (m, 1 H) ppm. 13C NMR: δ
= 67.60, 62.59, 50.08, 44.23, 36.05, 35.19, 31.87, 28.88, 22.77, 16.76
ppm. IR: νmax = 3460 (m) cm–1. MS: m/z = 169 (37.0 %), 153
˜
(100.0%, [M – H2O – H]+), 139 (34.8%), 123 (65.7%), 95 (88.5%),
91 (65.3 %), 81 (54.7 %), 68 (32.5 %), 55 (43.7 %), 43 (70.0 %).
C10H20O2 (172.27): calcd. C 69.72, H 11.70; found C 69.90, H
11.66.
(1R,2R,3S)-2-(tert-Butyldimethylsiloxymethyl)-1-[(1S)-2-hydroxy-1-
methylethyl]-3-methylcyclopentane (16): Ester 12a (1.10 g,
3.35 mmol) in diethyl ether (80 mL) was treated dropwise with DI-
BAL-H (0.98  in hexane, 7.52 mL, 7.37 mmol) at –40 °C and
stirred for 1 h at –40 °C and for another 2 h at –10 °C. Workup
with sat.aq. NH4Cl and chromatography (hexane/ethyl acetate, 3:1)
furnished 16 (820 mg, 86%) as a colorless oil. [α]2D0 = –13.3 (c =
[10] Isolation of 2: T. Sakan, A. Fujino, F. Murai, A. Suzui, Y.
Batsugan, Bull. Soc. Chem. Jpn. 1959, 32, 1154–1155.
[11] Skyanthin: a) G. B. Marini-Bettolo, Gazz. Chim. Ital. 1963, 93,
1367; b) C. G. Casinovi, F. Delle Monache, G. B. Marini-
Bettolo, E. Bianchi, J. A. Garabarino, Gazz. Chim. Ital. 1962,
92, 479–487.
[12] a) K. Mori, H. Iwasawa, Tetrahedron 1980, 36, 87–90; b) R. W.
Hoffmann, W. Helbig, Chem. Ber. 1981, 114, 2803–2807; c)
K. C. Nicolaou, D. P. Papahatjis, D. A. Claremon, R. L. Mag-
olda, R. E. Dolle, J. Org. Chem. 1985, 50, 1440–1456; d) J.
Mulzer, P. de Lassalle, A. Freissler, Liebigs Ann. Chem. 1986,
1152–1157.
1
1.8, CHCl3). H NMR: δ = 3.64 (ddd, J = 10.3 Hz, J = 4.8 Hz, J
= 4.0 Hz, 2 H), 3.39 (ddd, J = 14.8 Hz, J = 7.5 Hz, J = 5.0 Hz, 2
H), 2.09 (mc, 1 H), 1.92 (m, 1 H), 1.79–1.64 (m, 3 H), 1.60 (m, 1
H), 1.35 (m,1 H), 1.28 (m, 1 H), 1.13 (m, 1 H), 1.05 (d, J = 6.8
Hz, 3 H), 1.00 (d, J = 7.3 Hz, 3 H), 0.91 (s, 9 H), 0.06 (s, 6 H)
ppm. 13C NMR: δ = 67.67, 62.79, 49.57, 44.23, 35.83, 35.17, 32.53,
29.21, 25.77, 22.69, 18.11, 16.79, –5.53 ppm. IR: ν
= 3349 (m)
˜
max
cm–1. MS: m/z = 271 (0.1%, [M – CH3]+), 255 (0.1%, [M –
CH2OH]+), 229 (0.9%, [M – C4H9]+), 211 (1.6%), 183 (1.5%), 137
(100.0%), 105 (50.5%), 95 (71.9%), 81 (79.2%), 75 (95.7%).
HRMS calcd. for [C15H31O2Si]+: 271.20933, found 271.20879.
C16H34O2 (286.54): calcd. C 67.07, H 11.96; found C 67.23, H
12.21. Treatment of 16 (750 mg, 2.62 mmol) in THF (20 mL) with
solid TBAF (5 mmol) at room temp. for 12 h delivered 14 after
aqueous workup and chromatography (hexane/ethyl acetate, 1:1)
[13] D. H. R. Barton, S. W. McCombie, J. Chem. Soc., Perkin Trans.
1 1975, 1574–1585.
[14] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841–1860.
Received: September 20, 2005
Published Online: December 5, 2005
908
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 901–908