Synthesis of enantioenriched and diastereomerically pure cis-fused bicyclic α-oxy-substituted γ-lactones via epoxidation of optically active homoaldol products

Article abstract of DOI:10.1055/s-2005-872080

By applying the (-)-sparteine-mediated asymmetric deprotonation to 1-O-(2-alkylcycloalk-1-enyl)methyl N,N-diisopropylcarbamates, combined with a lithium-titanium exchange followed by addition to achiral aldehydes, enantioenriched homoaldol products 6 were

Full text of DOI:10.1055/s-2005-872080

PAPER
2507
Synthesis of Enantioenriched and Diastereomerically Pure cis-Fused Bicyclic
a-Oxy-Substituted g-Lactones via Epoxidation of Optically Active Homoaldol
Products
F
use
d
Bicyclic
e
O
xy-Subs
d
tituted Lacto
a
nes via Epoxidati
Ü
on of
H
omoaldol
P
n
r
oducts aldi, Roland Fröhlich,1 Dieter Hoppe*
Institut für Organische Chemie, Westfälischen Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)8336531; E-mail: dhoppe@uni-muenster.de
Received 9 March 2005; revised 11 April 2005
Abstract: By applying the (–)-sparteine-mediated asymmetric
deprotonation to 1-O-(2-alkylcycloalk-1-enyl)methyl N,N-diiso-
propylcarbamates, combined with a lithium–titanium exchange fol-
lowed by addition to achiral aldehydes, enantioenriched homoaldol
products 6 were prepared. Hydroxyl-directed epoxidation resulted
in the cleavage of the oxirane ring by the migration of the N,N-di-
isopropylcarbamoyloxy group to form bicyclic g-lactols 10 via the
corresponding g-hydroxy aldehydes. After oxidation, diastereomer-
ically pure, penta-substituted g-lactones 11 were obtained.
Key words: carbamates, aldol reactions, sparteine, diastereoselec-
tivity, epoxides, bicyclic compounds, lactones
Primary 2-alkenyl N,N-diisopropylcarbamates undergo
highly stereoselective a-deprotonation by means of BuLi/
(–)-sparteine (4).2,3 Unlike simple derivatives,4 1-O-(2-
methylcycloalk-1-enyl)methyl carbamates 1a and 1c lead
to configurationally stable lithium intermediates5 2a and
2c (Scheme 1). This was demonstrated by trapping 2 by
means of chlorotrimethylsilane as silanes 3 after different
standing times.5 The same features turned out to be also
true for the 1-O-(2-butylcycloalk-1-enyl)methyl carba-
mates 1b and 1d. The silylation proceeds with inversion
of configuration.
The high configurational stability of the carbanionic inter-
mediates allows for asymmetric hydroxyalkylation with
aldehydes.5 These ‘homoaldol reactions’, when carried
out after lithium–titanium exchange (inversion of config-
Scheme 1 Silylations of substituted lithioallyl carbamates
uration), proceed via Zimmerman–Traxler transition
states, combined with essentially complete chirality trans-
fer to form enantioenriched homoaldol products 6 with the
Li·4
relative configuration (Z)-anti (Scheme 2).6
Ti(NEt2)3
We recently reported the oxidative cyclization of homoal-
( )n
OCb
( )n
OCb
dol products with formation of bicyclic g-lactones.5b
ClTi(NEt2)3
R1
R1
(R)-5
During the epoxidation of racemic homoaldol products
we observed the opening of the oxirane ring, by the mi-
grating carbamoyloxy group to form finally a lactol which
was characterized by an X-ray crystal structure analysis.7
2
R2CHO (7)
( )n
OCb
Combined with the enantioselective deprotonation and
the asymmetric homoaldol reaction, the epoxidation–rear-
OH
H
Ti(NEt2)3
( )n
R1
R2
O
OCb
R2
6
+
(ent-6)
R1
TS
SYNTHESIS 2005, No. 15, pp 2507–2520
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.07.2005
DOI: 10.1055/s-2005-872080; Art ID: T03305SS
Scheme 2 Synthesis of enantioenriched homoaldol products
© Georg Thieme Verlag Stuttgart · New York

2508
S. Ünaldi et al.
PAPER
rangement offers a versatile ‘brick-box approach’ towards yields were recorded.8 There is some evidence that the al-
complex a-oxy-g-lactones.
lyltrialkoxytitanates undergo a facile homolytic cleavage
at the Ti–C bond.9 However, when BuLi–TMEDA was
used, the intermediates, prepared from rac-2·TMEDA
and Ti(OPr-i)4 gave high yields of homoaldol products
rac-6 (Scheme 3).
Asymmetric Homoaldol Reaction
Whereas the 1-O-(2-alkylcycloalk-1-enyl)methyl carba-
mates 1a–c were smoothly deprotonated by BuLi/(–)-
sparteine in toluene below –78 °C,5 the 1-O-(2-butylcy-
clohexenyl)methyl carbamate (1d) required the applica-
tion of sec-BuLi/(–)-sparteine for complete deprotonation
under these conditions (Scheme 1). Trapping the mixtures
of epimeric ion pairs by chlorotrimethylsilane ‘in situ’ and
also after 90 min stirring before silylation, afforded essen-
tially the same enantiomeric ratios of (R)- and (S)-3b and
(R)- and (S)-3d, respectively, which demonstrates the
high configurational stability of the intermediate lithium–
sparteine complexes5 2·4 and epi-2·4 (Scheme 1). The
lithium–titanium exchange in 2/epi-2·4 with chlorotris(di-
ethylamino)titanium followed by achiral aldehydes af-
forded diastereomerically pure (dr ≥ 95:5) and
enantiomerically enriched homoaldol products 6 with
good yields (Scheme 2, Table 1). The enantiomeric ratios
(er) in compounds 6 were determined by HPLC on chiral
Li·TMEDA
( )n
OCb
OH
1. Ti(OiPr)4
2. R2CHO
( )n
OCb
R1
R1
R2
rac-6
2
Scheme 3 Synthesis of racemic homoaldol products
Epoxidation and Rearrangement of 6
The (Z)-anti-homoaldol products 6 were treated with an
excess of tert-butyl hydroperoxide in the presence of 2
mol% of VO(acac)2 in dichloromethane7, according to
Sharpless10 and Mihelich11 (Scheme 4). In the first step, a
highly diastereoface-differentiating attack is induced by
the directing hydroxyl group to form the epoxide 8. The
epoxide is not stable under the reaction conditions and is
1
columns and by chiral H NMR shift reagents (Table 1).
When Ti(OPr-i)4 or Ti(OPr-i)3Cl were used, much lower
Table 1 New Homoaldol Products 6 Prepared
Substrates Aldehyde
Product
n
R1
R2
ee (%)
Yield (%)
[of rac-6]a
5ab
5ab
5ab
5bb
5bb
5bb
5bb
5bb
5cb
5dc
5dc
5dc
5dc
5dc
5dc
4-BrC6H4CH=O (7a)
6ad
6b
6c
6d
6e
6f
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
Me
4-BrC6H4
4-ClC6H4
b-Naphthyl
Me2CH-
Ph
93
74
81
65
79
72
84
88
86
74
78
76
66
72
74
72 [81]
79 [74]
73 [78]
52 [54]
53 [54]
53 [52]
57 [55]
56 [58]
58 [79]
63 [65]
65 [68]
58 [65]
67 [68]
55 [62]
58 [68]
4-ClC6H4CH=O (7b)
b-Naphthyl-CH=O (7c)
Me2CHCH=O (7d)
PhCH=O (7e)
Me
Me
(CH2)3Me
(CH2)3Me
(CH2)3Me
(CH2)3Me
(CH2)3Me
Me
4-BrC6H4CH=O (7a)
b-Naphthyl-CH = O (7c)
CH2=CHCH=O (7f)
4-BrC6H4CH=O (7a)
a-Naphthyl-CH=O (7g)
PhCH=O (7e)
4-BrC6H4
b-Naphthyl
CH2=CH
4-BrC6H4
a-Naphthyl
Ph
6g
6h
6id
6j
(CH2)3Me
(CH2)3Me
(CH2)3Me
(CH2)3Me
(CH2)3Me
(CH2)3Me
6k
6l
4-BrC6H4CH=O (7a)
b-Naphthyl-CH=O (7c)
Me2CHCH=O (7d)
4-MeOC6H4CH=O (7h)
4-BrC6H4
b-Naphthyl
Me2CH-
4-MeOC6H4
6m
6n
6o
a Yield of rac-6, prepared via deprotonation in the presence of TMEDA.
b Deprotonation with BuLi/(–)-sparteine.
c Deprotonation with sec-BuLi/(–)-sparteine.
d For the data see ref.5
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

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Fused Bicyclic Oxy-Substituted Lactones via Epoxidation of Homoaldol Products
2509
opened with inversion of the configuration by the migrat-
ing carbamoyloxy group. The g-hydroxy aldehydes 9 are
in equilibrium with the anomeric lactols 10, which finally
are oxidized to the g-lactones 11 (Table 2).
OCb
( )n
t-BuOOH (1.5 equiv)
OH
VO(acac)2 (2 mol%)
R1
R2
6
H
O
H
OCb
O
( )n
O
O
( )n
N(i-Pr)2
OH
OH
R1
R2
R1
R2
9
8
Figure 1 Solid-state structure of 11c12
OH
OCb
OCb
O
PDC
( )n
( )n
O
O
R1
R1
R2
R2
11
10
Scheme 4 Epoxidation, rearrangement and oxidation of compounds
6
The lactones rac-11i, rac-11k and 11c were subjected to
X-ray crystal structure analyses (Figures 1–3),12 which
confirmed the expected relative configuration.12 The
enantiomeric ratios of the lactones 11 match well with
those of the utilized homoaldol product 6. As standard for
the enantiomeric lactones 11, the appropriate compounds
rac-11 were synthesised from rac-6 following the same
route.
Figure 2 Solid-state structure of 11i12
Table 2 Prepared Bicyclic a-Oxy-Substituted g-Lactones 11
Product
Yielda (%) [of rac-11]b
ee (%)
93
Product
Yielda (%) [of rac-11]b ee (%)
11a
58 [58]
11b
62 [49]
74
O
O
O
O
Br
Cl
CbO
CbO
11c
44 [47]
83
11d
66 [65]
65
O
O
O
O
CbO
CbO
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2510
S. Ünaldi et al.
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Table 2 Prepared Bicyclic a-Oxy-Substituted g-Lactones 11 (continued)
Product
Yielda (%) [of rac-11]b
ee (%)
78
Product
Yielda (%) [of rac-11]b ee (%)
72
11e
66 [69]
11f
68 [72]
70 [74]
70 [70]
Br
O
O
O
O
O
O
CbO
CbO
11g
72 [72]
82
11i
86
O
O
Br
O
CbO
CbO
11k
69 [72]
78
11l
76
Br
O
O
O
CbO
CbO
11m
73 [71]
66
11n
76 [79]
72
O
O
CbO
11o
68 [70]
73
OMe
O
O
CbO
a Yields are based on homoaldol products 6.
b Yields are based on homoaldol products rac-6.
and chiragrom-1, 60 × 2 mm purchased from GROM ANALYTIC
and HPLC GmbH, Herrenberg. The solvent systems used for the
measurement were hexane–i-PrOH (100:1), (200:1) and (500:1). 1H
and 13C NMR spectra were recorded on ARX 300, AMX 400, Bruk-
er. 2D NMR experiments were carried out by Varian Unity Plus
600. CDCl3 was used as solvent for normal NMR measurements,
C6D6 was used for 1H NMR shift experiments. Chemical shifts are
All together, the combination of asymmetric homoaldol
reaction, epoxidation with rearrangement, and oxidation
of the formed g-lactol offers a versatile access to highly
substituted bicyclic g-lactones.
BuLi (1.6 M in hexane) and sec-BuLi [1.18 M, in hexane–cyclohex-
ane (92:8)] were used. Aldehydes were distilled prior to use. (–)-
Sparteine was kept under Ar in a refrigerator after the original bot-
tles had been opened. All reactions, which are sensitive to moisture
or air, were carried out under Ar using the septum-and-syringe tech-
niques. All solvents were purified by distillation or dried (toluene,
CH2Cl2) prior to use. Flash chromatography was carried out with
silica gel (40–63 mm) using an Ar pressure of 1.2–1.4 bar. Chiral
HPLC was carried out with a chiral column: chiragrom-2, 250 × 2;
1
reported in ppm (d); H shifts are related to TMS dH = 0 and 13C
shifts CDCl3 to dC = 77.0. The NMR resonances of the diastereo-
mers were listed in brackets as far as observable. IR absorption
spectra were recorded using a IFS 28 purchased from Bruker and a
PE 298 purchased from Perkin–Elmer & Co GmbH, Überlingen.
The mps were measured on an SMP3 mp apparatus purchased from
Stuart Scientific, UK. The optical rotations were measured in a 10
cm cuvette on a polarimeter 241 purchased from Perkin–Elmer &
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

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Fused Bicyclic Oxy-Substituted Lactones via Epoxidation of Homoaldol Products
2511
+ 30 mol% Eu(hfc)3 in C6D6, Dd (1 H at d 5.82) = 0.11, signal of
major enantiomer appears at lower field.
90 min deprotonotation time: yield: 70%; 92% ee; [a]D20 +7.2
(c 0.9, CHCl3).
In situ experiment: yield: 35%; 94% ee; [a]D20 +7.3 (c 0.9, CHCl3).
rac-3b (yield: 66 mg, 75%) was prepared by applying the analogous
procedure with sec-BuLi–TMEDA (1.1 equiv) with 90 min depro-
tonation time.
IR (film): 2965, 2940, 2854, 2856, 1700 cm–1.
1H NMR (300 MHz, CDCl3): d = –0.04 (s, 9 H), 0.86 (t, 3 H), 1.21
(d, J = 6.4 Hz, 12 H), 1.15–2.42 (m, 12 H), 3.97 (br s, 2 H), 5.82 (s,
1 H).
13C NMR (75 MHz, CDCl3): d = –3.4 [Si(CH3)3], 16.3 (CH3), 21.7
(CH3), 23.4 (CH2), 24.4 (CH2), 25.3 (CH2), 26.1 (CH2), 30.1 (CH2),
31.3 (CH2), 48.0 (CH), 70.2 (CH), 130.5 (Cq), 131.3 (Cq), 158.3
(C=O).
Anal. Calcd for C20H39NO2Si (353.61): C, 67.93; H, 11.12; N, 3.96.
Found: C, 67.75; H, 11.25; N, 3.91.
Figure 3 Solid-state structure of 11k12
(R)-1-(2-Butyl-1-cyclohexenyl)-1-(trimethylsilyl)methyl N,N-
Diisopropylcarbamate (3d)
Co GmbH, Überlingen. Elemental analysis were performed at the
microanalytical section of the Organisch-Chemisches Institut,
WWU Münster on a Vario El III, purchased from Elementar-Ana-
lysen-Systeme GmbH. The mass spectral measurements were car-
ried out by electron spray ionization method (ESI) on Quatro LCZ
(Waters-Micromass; Manchester, UK) with a nanospray inlet and
exact mass measurements were carried out on Micro Tof (Bruer
Daltronics, Bremen), calibrations were done directly before the
measurements of samples with sodium formate clusters. Petroleum
ether refers to the fraction with bp 35–60 °C.
According to GP1, 3d (yield: 58 mg, 63%) was obtained from 1d
(63 mg, 0.25 mmol) with 30 min deprotonation time with sec-BuLi
as a colourless oil; Rf = 0.33 (petroleum ether–EtOAc, 10:1);
1
[a]D20 –85.0 (c 0.64, CHCl3); H NMR shift experiment: er 93:7
(86% ee); 6.3 mg + 30 mol% Eu(hfc)3 in C6D6, Dd (1 H at
d 5.72) = 0.28, signal of major enantiomer appears at lower field.
90 min deprotonotation time: yield: 81%; 86% ee; [a]D20 –85.2
(c 0.65, CHCl3).
120 min deprotonotation time: yield: 82%; 84% ee; [a]D20 –82.9
(c 0.70, CHCl3).
Deprotonation of Allyl Carbamates; General Procedure (GP1)
BuLi (1.6 M, 0.17 mL, 0.27 mmol, 1.1 equiv) or sec-BuLi (1.18 M,
0.23 mL, 0.27 mmol, 1.1 equiv) was added dropwise with vigorous
stirring to a solution of allyl carbamates 1b (70 mg, 0.25 mmol) or
1d (73 mg, 0.25 mmol) and (–)-sparteine (63 mg, 0.27 mmol, 1.1
equiv) in toluene (3 mL) at –78 °C. After the reaction mixture had
been stirred for 0–180 min at the same temperature, the electrophile
TMSCl (44 mg, 0.37 mmol, 1.5 equiv) was added. The mixture was
stirred for 1 h at –78 °C, after which it was allowed to warm to r.t.
and quenched with aq HCl (2 N; 1 mL), the mixture was poured into
an ice-cooled mixture of Et2O (10 mL) and aq HCl (2 N; 10 mL).
The aq layer was extracted with Et2O (3 × 15 mL). The combined
organic layer was dried (MgSO4) and concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel;
petroleum ether–EtOAc, 10:1).
In situ experiment: yield: 42%; 90% ee; [a]D20 –88.8 (c 0.68,
CHCl3).
rac-3d (yield: 73 mg, 80%) was prepared by applying the analogous
procedure with sec-BuLi–TMEDA (1.1 equiv) with 90 min depro-
tonation time.
IR (film): 2969, 2942, 2856, 2858, 1698 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = –0.04 (s, 9 H), 0.87 (t, 3 H), 1.25
(d, J = 6.7 Hz, 12 H), 1.05–2.50 (m, 14 H), 3.94 (br s, 2 H), 5.72 (s,
1 H).
13C NMR (75 MHz, CDCl3): d = –2.5 [Si(CH3)3], 13.2 (CH3), 19.8
(CH3), 22.2 (CH2), 24.6 (CH2), 25.9 (CH2), 28.7 (CH2), 30.6 (CH2),
31.1 (CH2), 32.0 (CH2), 46.3 (CH), 75.2 (CH), 128.5 (Cq), 129.5
(Cq), 150.9 (C=O).
Anal. Calcd for C21H41NO2Si (367.64): C, 68.61; H, 11.24; N, 3.81.
Found: C, 68.55; H, 11.35; N, 3.91.
In Situ Silylation of Carbamates
BuLi (1.6 M, 0.17 mL, 0.27 mmol, 1.1 equiv) or sec-BuLi (1.18 M,
0.23 mL, 0.27 mmol, 1.1 equiv) was added over a period of 10 min
to a solution of 1b (70 mg, 0.25 mmol) or 1d (73 mg, 0.25 mmol)
and (–)-sparteine (63 mg, 0.27 mmol, 1.1 equiv) in the presence of
TMSCl (44 mg, 0.37 mmol, 1.5 equiv) in toluene (5 mL) at –78 °C.
Stirring was continued for 30 min and the mixture was quenched
with MeOH (1 mL) at –78 °C. After usual workup, the crude prod-
uct was purified by flash column chromatography (silica gel; petro-
leum ether–EtOAc, 10:1).
Homoaldol Reactions of Allyl Carbamates for Enantioenriched
Compounds; General Procedure (GP2)
To a solution of allyl carbamate 1a–c (1.0 mmol) and (–)-sparteine
(257 mg, 1.1 mmol) in toluene (3–10 mL) at –78 °C, BuLi (1.6 M,
0.68 mL, 1.1 mmol) was added dropwise under vigorous stirring.
For 1d, sec-BuLi (1.18 M, 0.93 mL, 1.1 mmol) was used. The reac-
tion mixture was stirred at –78 °C for 10 min for the synthesis of 6i,
and 1.5 h for the synthesis of 6a–h and 6j–o. Then a precooled
(–78 °C) solution of chlorotris(diethylamino)titanium [ClTi(NEt2)3,
897 mg, 3 mmol] in toluene (1 mL) was added. The reaction mixture
was stirred for 2 h at –78 °C and subsequently the aldehyde (3
mmol), in toluene (1 mL), was added. Finally, the reaction mixture
was stirred for 1 h at –78 °C before it was allowed to warm to r.t.
The solution was poured into an ice-cooled mixture of Et2O (15 mL)
and aq HCl (2 N; 15 mL). The aq layer was extracted with Et2O
(R)-1-(2-Butyl-1-cyclopentenyl)-1-(trimethylsilyl)methyl N,N-
Diisopropylcarbamate (3b)
According to GP1, 3b (yield: 54 mg, 62%) was obtained from 1b
(60 mg, 0.25 mmol) with 30 min deprotonation time with BuLi; co-
lourless oil; Rf = 0.31 (petroleum ether–EtOAc, 10:1); [a]D20 +7.2
(c 0.9, CHCl3); 1H NMR shift experiment: er 96:4 (92% ee); 6.3 mg
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

2512
S. Ünaldi et al.
PAPER
(3 × 15 mL). The combined organic phases were dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel; petroleum ether–EtOAc, 10:1).
120.3 (Cq), 122.6 (Cq), 129.6 (CH), 131.2 (CH), 133.3 (CH), 140.6
(Cq), 152.2 (C=O).
HRMS: m/z calcd: 402.1806; found: 402.1812 [M + Na]+.
Anal. Calcd for C21H30ClNO3 (379.92): C, 66.39; H, 7.96; N, 3.69.
Found: C, 66.03; H, 7.67; N, 3.51.
Homoaldol Reactions of Allyl Carbamates for Racemic Com-
pound; General Procedure (GP3)
To a solution of allyl carbamate 1a–d (1.0 mmol) and TMEDA (131
mg, 1.1 mmol) in toluene (3–10 mL) at –78 °C, sec-BuLi (1.18 M,
0.92 mL, 1.1 mmol) was added dropwise under vigorous stirring.
The reaction mixture was stirred at –78 °C for 1 h and then a pre-
cooled (–78 °C) solution of tetraisopropoxytitanium (TiPT, 852 mg,
3 mmol) in toluene (1 mL) was added. The reaction mixture was
stirred for 30 min at –78 °C and subsequently the aldehyde (3
mmol), dissolved in toluene (1 mL), was added. Finally, the reac-
tion mixture was stirred for 1 h at –78 °C before it was allowed to
warm to r.t. The solution was poured into an ice-cooled mixture of
Et2O (15 mL) and aq HCl (2 N; 15 mL). The aq layer was extracted
with Et2O (3 × 15 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel; petroleum ether–
EtOAc, 10:1).
{1Z,1[2S,2(1R)]}-{2-[1-Hydroxy-1-(naphth-2-yl)methyl]-2-
methylcyclopentylidene}methyl N,N-Diisopropylcarbamate (6c)
According to GP2, 6c (yield: 287 mg, 73%) was obtained from allyl
carbamate 1a (239 mg, 1.0 mmol) and b-naphthaldehyde (7c, 468
mg, 3 mmol) as a colourless solid; mp 109.3 °C (petroleum ether:
Et2O, 4:1); Rf = 0.21 (petroleum ether–EtOAc, 10:1); [a]D20 +118.5
(c 0.95, CHCl3); H NMR shift experiment: er 90:9 (81% ee); 4.8
mg + 10.2 mol% Eu(hfc)3 in C6D6, Dd (1 H at d = 5.09) = 0.12, sig-
nal of major enantiomer appears at lower field.
1
According to GP3, rac-6c (yield: 308 mg, 78%) was obtained from
allyl carbamate 1a (239 mg, 1.0 mmol).
IR (KBr): 3452 (OH), 1713 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.11 (s, 3 H), 1.16 (d, J = 6.7 Hz,
12 H), 1.51 (m, 2 H), 1.66 (m, 2 H), 1.75 (m, 2 H), 3.68 (br s, 2 H),
5.09 (s, 1 H), 6.92 (t, J = 1.6 Hz, 1 H), 7.14–7.25 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 21.8 (CH3), 22.2 (CH3), 23.5
(CH2), 27.5 (CH2), 36.2 (CH2), 49.8 (CH), 51.2 (Cq), 78.3 (CH),
123.3 (Cq), 133.2 (CH), 126.1/127.4/127.8/128.1/128.8/129.7/
130.0/130.6/133.2/132.6 (CH and Cq), 152.3 (C=O).
{1Z,1[2S,2(1R)]}-{2-[1-(4-Bromophenyl)-1-hydroxymethyl]-2-
methylcyclopentylidene}methyl N,N-Diisopropylcarbamate
(6a)
According to GP2, 6a (yield: 305 mg, 72%) was obtained from allyl
carbamate 1a (239 mg, 1.0 mmol) and p-bromobenzaldehyde (7a,
556 mg, 3 mmol) as a colourless solid; Rf = 0.27 (petroleum ether–
EtOAc, 10:1); [a]D20 +113.3 (c 0.50, CHCl3); 1H NMR shift exper-
iment: er 96:3 (93% ee); {ref: 5 [a]D20 +112.5 (c 0.20, CHCl3); 92%
ee}.
Anal. Calcd for C25H33NO3 (395.53): C, 75.91; H, 8.41; N, 3.54.
Found: C, 75.73; H, 8.42; N, 3.76.
{1Z,1[2S,2(1R)]}-[2-Butyl-2-(1-hydroxy-2-methylethyl)cyclo-
pentylidene]methyl N,N-Diisopropylcarbamate (6d)
According to GP2, 6d (yield: 92 mg, 52%) was obtained from allyl
carbamate 1b (140 mg, 0.50 mmol) and 2-methylpropanal (7d, 108
mg, 1.5 mmol) as a yellow oil; Rf = 0.26 (petroleum ether–
EtOAc, 10:1); [a]D20 –17.9 (c 0.85, CHCl3); chiral HPLC (chira-
grom-1; hexane–i-PrOH, 500:1), 65% ee, major enantiomer ap-
pears at lower retention time.
According to GP3, rac-6a (yield: 343 mg, 81%) was obtained from
allyl carbamate 1a (239 mg, 1.0 mmol).
IR (KBr): 3496 (OH), 1691 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (s, 3 H), 1.22 (d, J = 6.6 Hz,
12 H), 1.38 (m, 2 H),1.56 (m, 2 H), 1.80 (m, 2 H), 3.62/4.16 (br s, 2
H), 4.88 (s, 1 H), 6.89 (br s, 1 H), 7.17 (mc, 2 H), 7.34 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.3 (CH3), 23.8 (CH3), 26.9
(CH2), 31.6 (CH2), 36.9 (CH2), 49.2 (CH), 50.4 (Cq), 76.5 (CH),
120.9 (Cq), 122.3 (Cq), 129.5 (CH), 130.1 (CH), 133.6 (CH), 140.7
(Cq), 151.7 (C=O).
According to GP3, rac-6d (yield: 95 mg, 54%) was obtained from
allyl carbamate 1b (140 mg, 0.50 mmol).
IR (film): 3482 (OH), 1721 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.99 (t, 3 H), 0.97/0.96 (2 d, 6 H),
1.07 (m, 2 H), 1.25–1.52 (m, 14 H), 1.52 (m, 2 H), 1.66 (m, 2 H),
1.78 (m, 2 H), 2.19 (m, 2 H), 3.24 (m, 1 H), 3.27 (m, 1 H), 3.86/4.25
(br s, 2 H), 7.13 (br s, 1 H).
HRMS: m/z calcd: 446.1301; found: 446.1310 [M + Na]+.
Anal. Calcd for C21H30BrNO3 (424.37): C, 59.43; H, 7.13; N, 3.30.
Found: C, 59.36; H, 6.81; N, 3.04.
13C NMR (75 MHz, CDCl3): d = 14.5 (CH3), 19.9 (CH3), 21.4
(CH3), 21.8 (CH3), 22.2 (CH2), 24.4 (CH2), 25.6 (CH2), 27.2 (CH2),
31.3 (CH2), 32.4 (CH), 32.8 (CH2), 46.3 (CH), 49.4 (Cq), 73.7 (CH),
123.9 (Cq), 131.1 (CH), 149.4 (C=O).
{1Z,1[2S,2(1R)]}-{2-[1-(4-Chlorophenyl)-1-hydroxymethyl]-2-
methylcyclopentylidene}methyl N,N-Diisopropylcarbamate
(6b)
According to GP2, 6b (yield: 302 mg, 79%) was obtained from allyl
carbamate 1a (239 mg, 1.0 mmol) and p-chlorobenzaldehyde (7b,
420 mg, 3 mmol) as a colourless solid; mp 118.7 °C (petroleum
ether–Et2O, 4:1); Rf = 0.22 (petroleum ether–EtOAc, 10:1);
[a]D20 +46.35 (c 0.85, CHCl3); 1H NMR shift experiment: er 87:13
(74% ee); 5.2 mg + 10.6 mol% Eu(hfc)3 in C6D6, Dd (1 H at
d 4.89) = 0.14, signal of major enantiomer appears at lower field.
HRMS: m/z calcd: 376.2827; found: 376.2820 [M + Na]+.
Anal. Calcd for C21H39NO3 (353.54): C, 71.34; H, 11.12; N, 3.96.
Found: C, 71.25; H, 11.15; N, 3.71.
{1Z,1[2S,2(1R)]}-[2-Butyl-2-(1-hydroxy-1-phenylmethyl)cyclo-
pentylidene]methyl N,N-Diisopropylcarbamate (6e)
According to GP2, 6e (yield: 102 mg, 53%) was obtained from allyl
carbamate 1b (140 mg, 0.50 mmol) and benzaldehyde (7e, 160 mg,
According to GP3, rac-6b (yield: 280 mg, 74%) was obtained from
allyl carbamate 1a (239 mg, 1.0 mmol).
IR (KBr): 3413 (OH), 1691 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.04 (s, 3 H), 1.22 (d, J = 6.4 Hz,
12 H), 1.51 (m, 2 H), 1.59 (m, 2 H), 1.76 (m, 2 H), 3.70/4.21 (br s,
2 H), 4.89 (s, 1 H), 6.88 (br s, 1 H), 7.13 (mc, 2 H), 7.27 (mc, 2 H).
1.5 mmol) as
a yellow oil; Rf = 0.25 (petroleum ether–
1
EtOAc, 10:1); [a]D20 –45.1 (c 1.05, CHCl3); H NMR shift experi-
ment: er 89:10 (79% ee); 5.1 mg + 26.3 mol% Eu(hfc)3 in C6D6, Dd
(1 H at d 5.01) = 0.23, signal of major enantiomer appears at lower
field.
13C NMR (75 MHz, CDCl3): d = 20.5 (CH3), 21.2 (CH3), 24.4
(CH2), 32.7 (CH2), 36.2 (CH2), 46.5 (CH), 51.0 (Cq), 76.9 (CH),
According to GP3, rac-6e (yield: 104 mg, 54%) was obtained from
allyl carbamate 1b (140 mg, 0.50 mmol).
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

PAPER
Fused Bicyclic Oxy-Substituted Lactones via Epoxidation of Homoaldol Products
2513
IR (film): 3429 (OH), 1704 (C=O) cm–1.
{1Z,1[2S,2(1R)]}-[2-Butyl-2-(1-hydroxy-2-propenyl)cyclopen-
tylidene]methyl N,N-Diisopropylcarbamate (6h)
1H NMR (300 MHz, CDCl3): d = 0.83 (t, 3 H), 0.97 (m, 2 H), 1.27–
1.54 (m, 14 H), 1.57 (m, 2 H), 1.64 (m, 2 H), 1.73 (m, 2 H), 2.18 (m,
2 H), 3.93/4.25 (br s, 2 H), 5.01 (s, 1 H), 6.89 (br s, 1 H), 7.15–7.35
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 13.5 (CH3), 19.9 (CH3), 22.6
(CH2), 24.8 (CH2), 25.3 (CH2), 27.8 (CH2), 31.4 (CH2), 32.6 (CH2),
44.3 (CH), 46.6 (Cq), 75.7 (CH), 125.3 (CH), 128.9 (Cq), 130.6
(CH), 131.7 (CH), 133.7 (CH), 138.4 (Cq), 150.8 (C=O).
According to GP2, 6h (yield: 132 mg, 56%) was obtained from allyl
carbamate 1b (196 mg, 0.70 mmol) and 2-propenal (7f, 117 mg, 2.1
mmol) as a yellow oil; Rf = 0.25 (petroleum ether–EtOAc, 10:1);
[a]D20 +16.5.1 (c 1.05, CHCl3); chiral HPLC (chiragrom-2: hexane–
i-PrOH, 200:1), 88% ee, major enantiomer appears at lower reten-
tion time.
According to GP3, rac-6h (yield: 136 mg, 58%) was obtained from
allyl carbamate 1b (140 mg, 0.50 mmol).
IR (film): 3460 (OH), 1695 (C=O) cm–1.
Anal. Calcd for C24H37NO3 (387.56): C, 74.38; H, 9.62; N, 3.61.
Found: C, 74.82; H, 9.60; N, 3.41.
1H NMR (300 MHz, CDCl3): d = 0.84 (t, 3 H), 0.95 (m, 2 H), 1.22–
1.44 (m, 14 H), 1.53 (m, 2 H), 1.65 (m, 2 H), 1.73 (m, 2 H), 2.18 (m,
2 H), 3.85 (br s, 2 H), 5.03 (d, J = 6.7 Hz, 1 H), 5.07 (dd, J = 10.6,
1.6 Hz, 1 H), 5.18 (dd, J = 17.4, 1.6 Hz, 1 H), 5.74 (ddd, J = 6.7,
10.6, 17.4 Hz, 1 H), 6.85 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.4 (CH3), 20.6 (CH3), 22.8
(CH2), 24.9 (CH2), 25.4 (CH2), 27.7 (CH2), 30.8 (CH2), 32.5 (CH2),
45.9 (CH), 46.6 (Cq), 75.7 (CH), 114.6 (CH2), 129.9 (Cq), 132.2
(CH), 138.2 (CH), 153.8 (C=O).
{1Z,1[2S,2(1R)]}-{2-[1-(4-Bromophenyl)-1-hydroxymethyl]-2-
butylcyclopentylidene}methyl N,N-Diisopropylcarbamate (6f)
According to GP2, 6f (yield: 123 mg, 53%) was obtained from allyl
carbamate 1b (140 mg, 0.50 mmol) and p-bromobenzaldehyde (7a,
277 mg, 1.5 mmol) as a yellow oil; Rf = 0.24 (petroleum ether–
EtOAc, 10:1); [a]D20 +35.7 (c 1.05, CHCl3); 1H NMR shift experi-
ment: er 86:14 (72% ee); 9.8 mg + 11 mol% Eu(hfc)3 in C6D6, Dd
(1 H at d 4.91) = 0.13, signal of major enantiomer appears at higher
field.
HRMS: m/z calcd: 360.2509; found: 360.2530 [M + Na]+.
According to GP3, rac-6f (yield: 121 mg, 52%) was obtained from
allyl carbamate 1b (140 mg, 0.50 mmol).
IR (film): 3426 (OH), 1691 (C=O) cm–1.
Anal. Calcd for C20H35NO3 (337.50): C, 71.18; H, 10.45; N, 4.15.
Found: C, 71.02; H, 10.60; N, 4.11.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, 3 H), 0.98 (m, 2 H), 1.29–
1.48 (m, 14 H), 1.54 (m, 2 H), 1.62 (m, 2 H), 1.74 (m, 2 H), 2.15 (m,
2 H ), 3.98/4.26 (br s, 2 H), 4.91 (s, 1 H), 6.86 (br s, 1 H), 7.11 (mc,
2 H), 7.32 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.2 (CH3), 19.6 (CH3), 22.4
(CH2), 24.5 (CH2), 25.4 (CH2), 27.6 (CH2), 30.6 (CH2), 32.2 (CH2),
44.9 (CH), 46.6 (Cq), 75.6 (CH), 125.2 (Cq), 129.9 (Cq), 130.2 (CH),
131.1 (CH), 133.2 (CH), 138.1 (Cq), 150.9 (C=O).
{1Z,1[2S,2(1R)]}-{2-[1-(4-Bromophenyl)-1-hydroxymethyl]-
methylcyclohexylidene}methyl N,N-Diisopropylcarbamate (6i)
According to GP2, 6i (yield: 177 mg, 58%) was obtained from allyl
carbamate 1c (177 mg, 0.70 mmol) and p-bromobenzaldehyde (7a,
389 mg, 2.1 mmol) as a colourless solid; Rf = 0.26 (petroleum
ether–EtOAc, 10:1); mp 119 °C (petroleum ether–Et2O, 4:1);
1
[a]D20 –45.7 (c 0.43, CHCl3); H NMR shift experiment: er 93:7
(86% ee) {Lit. [a]D20 –46.3 (c 0.44, CHCl3), 87% ee5}.
According to GP3, rac-6i (yield: 240 mg, 79%) was obtained from
allyl carbamate 1c (177 mg, 0.70 mmol).
IR (KBr): 3453 (OH), 1680 (C=O) cm–1.
HRMS: m/z calcd: 490.1776; found: 488.1784 [M + Na]+.
Anal. Calcd for C24H36NO3Br (466.45): C, 61.80; H, 7.78; N, 3.00.
Found: C, 61.22; H, 7.90; N, 3.09.
1H NMR (300 MHz, CDCl3): d = 1.08 (s, 3 H), 1.12 (d, J = 6.4 Hz,
12 H), 1.42 (m, 2 H), 1.56 (m, 2 H), 1.72 (m, 2 H), 2.12 (m, 2 H),
3.66/4.17 (br s, 2 H), 5.02 (s, 1 H), 6.95 (br s, 1 H), 7.25 (m, 2 H),
7.44 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.8 (CH3), 21.6 (CH3), 21.9
(CH2), 26.9 (CH2), 29.3 (CH2), 36.9 (CH2), 44.6 (CH), 45.9 (Cq),
74.2 (CH), 121.1 (Cq), 124.9 (Cq), 129.6 (CH), 130.5 (CH), 133.2
(CH), 139.1 (Cq), 152.4 (C=O).
{1Z,1[2S,2(1R)]}-{2-Butyl-2-[1-hydroxy-1-(naphth-2-yl)meth-
yl]cyclopentylidene}methyl N,N-Diisopropylcarbamate (6g)
According to GP2, 6g (yield: 124 mg, 57%) was obtained from allyl
carbamate 1b (140 mg, 0.50 mmol) and b-naphthaldehyde (7c, 234
mg, 1.5 mmol) as an amorphous solid; Rf = 0.27 (petroleum ether–
EtOAc, 10:1); [a]D20 +96.7 (c 0.45, CHCl3); 1H NMR shift experi-
ment: er 92:8 (84% ee); 7.2 mg + 31.2 mol% Eu(hfc)3 in C6D6, Dd
(1 H at d 5.12) = 0.18, signal of major enantiomer appears at lower
field.
HRMS: m/z calcd: 462.1440; found: 461.1461 [M + Na]+.
Anal. Calcd for C22H32BrNO3 (438.40): C, 60.27; H, 7.36; N, 3.19.
Found: C, 60.86; H, 7.22; N, 2.87.
According to GP3, rac-6g (yield: 120 mg, 55%) was obtained from
allyl carbamate 1b (140 mg, 0.50 mmol).
IR (KBr): 3430 (OH), 1691 (C=O) cm–1.
{1Z,1[2S,2(1R)]}-{2-Butyl-2-[1-hydroxy-1-(naphth-1-yl)meth-
yl]cyclohexylidene}methyl N,N-Diisopropylcarbamate (6j)
According to GP2, 6j (yield: 142 mg, 63%) was obtained from allyl
carbamate 1d (147 mg, 0.50 mmol) and a-naphthaldehyde (7g, 234
mg, 1.5 mmol) as a colourless oil; Rf = 0.25 (petroleum ether–
EtOAc, 10:1); [a]D20 +70.3 (c 0.55, CHCl3); 1H NMR shift experi-
ment: er 87:13 (74% ee); 4.3 mg + 23 mol% Eu(hfc)3 in C6D6, Dd
(1 H at d 5.14) = 0.23, signal of major enantiomer appears at lower
field.
1H NMR (300 MHz, CDCl3): d = 0.80 (s, 3 H), 0.95 (m, 2 H), 1.26–
1.43 (m, 14 H), 1.58 (m, 2 H), 1.68 (m, 2 H), 1.70 (m, 2 H), 2.18 (m,
2 H), 3.92/4.23 (br s, 2 H), 5.12 (s, 1 H), 6.83 (br s, 1 H), 7.35–7.81
(m, 7 H).
13C NMR (75 MHz, CDCl3): d = 14.3 (CH3), 20.6 (CH3), 22.5
(CH2), 24.8 (CH2), 26.2 (CH2), 27.3 (CH2), 30.4 (CH2), 32.7 (CH2),
44.5 (CH), 48.5 (Cq), 75.3 (CH), 128.9 (Cq), 133.4 (CH), 126.9/
127.2/127.9/128.4/129.6/130.3/131.2/132.3/132.9/132.6 (CH and
Cq), 151.3 (C=O).
According to GP3, rac-6j (yield: 146 mg, 65%) was obtained from
allyl carbamate 1d (147 mg, 0.50 mmol).
IR (film): 3451 (OH), 1691 (C=O) cm–1.
Anal. Calcd for C28H39NO3 (437.61): C, 76.85; H, 8.98; N, 3.20.
Found: C, 76.95; H, 8.95; N, 73.37.
1H NMR (300 MHz, CDCl3): d = 0.86 (t, 3 H), 1.08 (m, 2 H), 1.22–
1.49 (m, 14 H), 1.54 (m, 2 H), 1.61 (m, 2 H), 1.76 (m, 2 H), 2.12 (m,
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

2514
S. Ünaldi et al.
PAPER
2 H), 2.27 (m, 2 H), 3.89/4.11 (br s, 2 H), 5.14 (s, 1 H), 6.88 (t,
J = 1.9 Hz, 1 H), 7.43–7.86 (m, 7 H).
{1Z,1[2S,2(1R)]}-{2-Butyl-2-[1-hydroxy-1-(naphth-2-yl)meth-
yl]cyclohexylidene}methyl N,N-Diisopropylcarbamate (6m)
According to GP2, 6m (yield: 151 mg, 67%) was obtained from al-
lyl carbamate 1d (147 mg, 0.50 mmol) and b-naphthaldehyde (7c,
234 mg, 1.5 mmol) as a yellow oil; Rf = 0.25 (petroleum ether–
13C NMR (75 MHz, CDCl3): d = 14.2 (CH3), 20.8 (CH3), 23.4
(CH2), 24.8 (CH2), 25.4 (CH2), 27.7 (CH2), 28.7 (CH2), 31.6 (CH2),
32.6 (CH2), 45.8 (CH), 48.3 (Cq), 75.5 (CH), 128.9 (Cq), 125.6/
126.7/127.4/128.3/128.5/129.7/130.5/131.9/132.4/132.7 (CH and
Cq), 131.3 (CH), 153.3 (C=O).
1
EtOAc, 10:1); [a]D20 –47 (c 0.55, CHCl3); H NMR shift experi-
ment: er 83:17 (66% ee); 4.3 mg + 36 mol% Eu(hfc)3 in C6D6, Dd
(1 H at d 5.11) = 0.11, signal of major enantiomer appears at higher
field.
HRMS: m/z calcd: 474.2984; found: 474.2995 [M + Na]+.
Anal. Calcd for C29H41NO3 (451.64): C, 77.12; H, 9.15; N, 3.10.
Found: C, 77.08; H, 9.19; N, 3.20.
According to GP3, rac-6m (yield: 153 mg, 68%) was obtained from
allyl carbamate 1d (147 mg, 0.50 mmol).
IR (film): 3451 (OH), 1691 (C=O) cm–1.
{1Z,1[2S,2(1R)]}-[2-Butyl-2-(1-hydroxy-1-phenylmethyl)cyclo-
hexylidene]methyl N,N-Diisopropylcarbamate (6k)
According to GP2, 6k (yield: 130 mg, 65%) was obtained from allyl
carbamate 1d (147 mg, 0.50 mmol) and benzaldehyde (7e, 160 mg,
1H NMR (300 MHz, CDCl3): d = 0.87 (t, 3 H), 1.03 (m, 2 H), 1.24–
1.49 (m, 14 H), 1.56 (m, 2 H), 1.66 (m, 2 H), 1.77 (m, 2 H), 2.13 (m,
2 H), 2.24 (m, 2 H), 3.90/4.10 (br s, 2 H), 5.16 (s, 1 H), 6.93 (t,
J = 1.9 Hz, 1 H), 7.45–7.89 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 14.3 (CH3), 20.4 (CH3), 23.7
(CH2), 24.5 (CH2), 25.6 (CH2), 27.3 (CH2), 28.7 (CH2), 31.7 (CH2),
32.9 (CH2), 45.8 (CH), 48.6 (Cq), 75.6 (CH), 128.2 (Cq), 127.3/
125.4/126.2/127.4/128.9/129.6/130.2/131.2/132.5/132.8 (CH and
Cq), 131.9 (CH), 154.1 (C=O).
1.5 mmol) as
a yellow oil; Rf = 0.25 (petroleum ether–
EtOAc, 10:1); [a]D20 +96.2 (c 1.05, CHCl3); 1H NMR shift experi-
ment: er 89:11 (78% ee), 4.6 mg + 10 mol% Eu(hfc)3 in C6D6, Dd
(1 H at d 4.98) = 0.21, signal of major enantiomer appears at lower
field.
According to GP3, rac-6k (yield: 136 mg, 68%) was obtained from
allyl carbamate 1d (147 mg, 0.50 mmol).
IR (film): 3429 (OH), 1704 (C=O) cm–1.
HRMS: m/z calcd: 474.2984; found: 474.2977 [M + Na]+.
Anal. Calcd for C29H41NO3 (451.64): C, 77.12; H, 9.15; N, 3.10.
Found: C, 77.15; H, 8.95; N, 3.07.
1H NMR (300 MHz, CDCl3): d = 0.86 (t, 3 H), 1.07 (m, 2 H), 1.18–
1.42 (m, 14 H), 1.55 (m, 2 H), 1.67 (m, 2 H), 1.78 (m, 2 H), 2.11 (m,
2 H), 2.25 (m, 2 H), 3.99/4.15 (br s, 2 H), 4.98 (s, 1 H), 6.87 (t,
J = 1.9 Hz, 1 H), 7.15–7.35 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 13.4 (CH3), 19.8 (CH3), 23.5
(CH2), 24.6 (CH2), 25.2 (CH2), 27.7 (CH2), 28.2 (CH2), 30.8 (CH2),
31.6 (CH2), 44.7 (CH), 46.9 (Cq), 75.8 (CH), 125.4 (Cq), 126.2 (Cq),
128.0 (CH), 129.2 (CH), 131.6 (CH), 138.5 (CH), 151.1 (C=O).
{1Z,1[2S,2(1R)]}-{2-Butyl-2-[1-hydroxy-1-(2-methylethyl)]cy-
clohexylidene}methyl N,N-Diisopropylcarbamate (6n)
According to GP2, 6n (yield: 100 mg, 55%) was obtained from allyl
carbamate 1d (147 mg, 0.50 mmol) and 2-methylpropanal (7d, 108
mg, 1.5 mmol) as a yellow oil; Rf = 0.30 (petroleum ether–
EtOAc, 10:1); [a]D20 +2.52 (c 1.15, CHCl3); chiral HPLC (chira-
grom-2; hexane–i-PrOH, 200:1), 72% ee, major enantiomer ap-
pears at higher retention time.
HRMS: m/z calcd: 424.2822; found: 424.2821 [M + Na]+.
Anal. Calcd for C25H39NO3 (401.58): C, 74.77; H, 9.79; N, 3.49.
Found: C, 74.80; H, 9.80; N, 3.43.
According to GP3, rac-6n (yield: 113 mg, 62%) was obtained from
allyl carbamate 1d (147 mg, 0.50 mmol).
IR (film): 3451 (OH), 1691 (C=O) cm–1.
{1Z,1[2S,2(1R)]}-{2-[1-(4-Bromophenyl)-1-hydroxymethyl]-2-
butylcyclohexylidene}methyl N,N-Diisopropylcarbamate (6l)
According to GP2, 6l (yield: 139 mg, 58%) was obtained from allyl
carbamate 1d (147 mg, 0.50 mmol) and p-bromobenzaldehyde (7a,
277 mg, 1.5 mmol) as a colourless oil; Rf = 0.25 (petroleum ether–
EtOAc, 10:1); [a]D20 –23.3 (c 1.05, CHCl3); 1H NMR shift experi-
ment: er 88:12 (76% ee), 9.8 mg + 45 mol% Eu(hfc)3 in C6D6, Dd
(1 H at d = 4.93) = 0.41, signal of major enantiomer appears at low-
er field.
1H NMR (300 MHz, CDCl3): d = 0.96 (t, 3 H), 0.98 (d, 3 H), 0.97
(d, 3 H), 1.07 (m, 2 H), 1.22–1.49 (m, 14 H), 1.51 (m, 2 H), 1.68 (m,
2 H), 1.73 (m, 2 H), 2.19 (m, 2 H), 2.22 (m, 2 H), 3.12 (d, J = 2.9
Hz, 1 H), 3.26 (m, 1 H), 3.85/4.15 (br s, 2 H), 7.09 (t, J = 1.8 Hz, 1
H).
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 18.8 (CH3), 21.2
(CH3), 21.5 (CH3), 23.6 (CH2), 24.3 (CH2), 25.7 (CH2), 27.6 (CH2),
28.4 (CH2), 30.2 (CH), 30.8 (CH2), 34.6 (CH2), 46.7 (CH), 50.9
(Cq), 73.8 (CH), 126.2 (Cq), 129.2 (CH), 154.1 (C=O).
According to GP3, rac-6l (yield: 156 mg, 65%) was obtained from
allyl carbamate 1d (147 mg, 0.50 mmol).
IR (KBr): 3429 (OH), 1704 (C=O) cm–1.
Anal. Calcd for C22H41NO3 (367.57): C, 71.89; H, 11.24: N, 3.81.
Found: C, 71.25; H, 11.55; N, 3.71.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, 3 H), 0.98 (m, 2 H), 1.25–
1.43 (m, 14 H), 1.52 (m, 2 H), 1.63 (m, 2 H), 1.78 (m, 2 H), 2.10 (m,
2 H), 2.22 (m, 2 H), 3.94/4.22 (br s, 2 H), 4.93 (s, 1 H), 6.83 (t,
J = 1.9 Hz, 1 H), 7.08 (mc, 2 H), 7.36 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.2 (CH3), 19.8 (CH3), 22.9
(CH2), 24.2 (CH2), 25.9 (CH2), 27.4 (CH2), 28.7 (CH2), 30.6 (CH2),
32.0 (CH2), 44.6 (CH), 46.3 (Cq), 75.2 (CH), 125.2 (Cq), 129.9 (Cq),
130.2 (CH), 131.1 (CH), 133.2 (CH), 138.1 (Cq), 150.9 (C=O).
{1Z,1[2S,2(1R)]}-{2-Butyl-2-[1-hydroxy-1-(4-methoxyphe-
nyl)methyl]cyclohexylidene}methylN,N-Diisopropylcarbamate
(6o)
According to GP2, 6o (yield: 125 mg, 58%) was obtained from allyl
carbamate 1d (147 mg, 0.50 mmol) and p-methoxybenzaldehyde
(7h, 204 mg, 1.5 mmol) as a yellow oil; Rf = 0.25 (petroleum ether–
EtOAc, 10:1); [a]D20 –45.5 (c 0.43, CHCl3); [a]D20 –74.4 (c 0.45,
CHCl3); shift experiment: er 87:13 (74% ee); 9.8 mg + 45 mol%
Eu(hfc)3 in C6D6, Dd (1 H at d 4.92) = 0.15, signal of major enantio-
mer appears at higher field.
HRMS: m/z calcd: 502.1927; found: 502.1959 [M + Na]+.
Anal. Calcd for C25H38NO3Br (480.48): C, 62.49; H, 7.97; N, 2.92.
Found: C, 62.42; H, 7.70; N, 2.81.
According to GP3, rac-6o (yield: 146 mg, 68%) was obtained from
allyl carbamate 1d (147 mg, 0.50 mmol).
IR (film): 3469 (OH), 1695 (C=O) cm–1.
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

PAPER
Fused Bicyclic Oxy-Substituted Lactones via Epoxidation of Homoaldol Products
2515
1H NMR (300 MHz, CDCl3): d = 0.84 (t, 3 H), 0.92 (m, 2 H), 1.29–
1.45 (m, 14 H), 1.54 (m, 2 H), 1.61 (m, 2 H), 1.75 (m, 2 H), 2.09 (m,
2 H), 2.21 (m, 2 H), 3.90/4.21 (br s, 2 H), 3.86 (s, 3 H), 4.92 (s, 1
H), 6.73 (t, J = 1.9 Hz, 1 H), 7.01 (mc, 2 H), 7.32 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.0 (CH3), 19.7 (CH3), 21.8
(CH2), 23.2 (CH2), 25.4 (CH2), 26.7 (CH2), 28.1 (CH2), 30.3 (CH2),
32.5 (CH2), 43.2 (CH), 46.5 (Cq), 55.1 (OCH3), 72.2 (CH), 125.6
(Cq), 128.3 (Cq), 131.2 (CH), 131.9 (CH), 133.3 (CH), 138.7 (Cq),
158.9 (C=O).
rac-10c was obtained from rac-6c, yield: 69%.
1H NMR (300 MHz, CDCl3): d = 0.72 (s, 3 H), 1.16 (d, 12 H), 1.49
(m, 2 H), 1.43–1.85 (m, 2 H), 2.47 (m, 2 H), 3.78 (br s, 2 H), 5.12
[5.19] (s, 1 H), 5.72 [5.81] (s, 1 H), 7.36–7.77 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 14.1 [14.5] (CH3), 22.1 [20.6]
(CH3), 25.3 [26.2] (CH2), 27.2 [28.3] (CH2), 29.3 [30.2] (CH2), 47.2
(Cq), 49.1 [50.6] (CH), 77.3 (CH), 92.4 (Cq), 101.6 (CH), 122.4/
123.9/124.9/125.3/126.8/130.3/131.6/132.3/133.4/139.9 (CH and
Cq), 154.3 (C=O).
HRMS: m/z calcd: 454.2933; found: 454.2926 [M + Na]+.
(1S,2RS,4R,5R)-5-Butyl-1-(N,N-diisopropylaminocarbonyl-
oxy)-4-(2-methylethyl)-3-oxabicyclo[3.3.0]octan-2-ol (10d)
According to GP4, 10d and minor epimer (yield: 77 mg, 85%) was
synthesized as a colourless oil with the diastereomeric ratio 3.2:1.0
from 6d (87 mg, 0.25 mmol); Rf = 0.23 (petroleum ether–
Et2O, 4:1).
Anal. Calcd for C26H41NO4 (431.61): C, 72.35; H, 9.57; N, 3.25.
Found: C, 72.67; H, 9.05; N, 3.81.
Lactols 10; General Procedure (GP4)
A solution of enol carbamate 6 (0.25 mmol) and VO(acac)2 (1.3
mg, 2 mol%) in anhyd CH2Cl2 (5 mL) was stirred at 20 °C for 12 h
with tert-butyl hydroperoxide (42 ml, 0.37 mmol), dissolved in
CH2Cl2 (1 mL). Subsequently, dimethyl sulfide (13 ml, 2.4 mmol)
was added and stirring was continued for a further 30 min. For
workup, the mixture was extracted by sat. aq NaHCO3 (2 × 20 mL),
sat. aq KCl (15 mL), and dried (MgSO4). Evaporation of the solvent
under reduced pressure, followed by chromatography (silica gel;
petroleum ether–Et2O, 4:1) afforded products 10 and minor epimer.
Characterization by elemental analysis and enantiometric excesses
were performed at the stage of lactones 11.
rac-10d was obtained from rac-6d, yield: 86%.
1H NMR (300 MHz, CDCl3): d = 0.78 (t, 3 H), 1.13 (m, 2 H), 1.22
(m, 14 H), 1.43 (m, 2 H), 1.45 (m, 2 H), 1.73–1.81 (m, 2 H), 2.30
(m, 2 H), 2.34 (m, 6 H), 3.27 (m, 1 H), 3.60 (br s, 2 H), 3.82 [3.94]
(d, 1 H), 6.21 [6.25] (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.5 [13.9] (CH3), 20.5 [19.2]
(CH3), 20.6 [20.2] (CH3), 20.6 [20.3] (CH2), 21.0 [21.5] (CH2), 22.1
[22.6] (CH2), 23.5 [23.4] (CH2), 26.4 [26.6] (CH2), 29.8 [30.1]
(CH2), 30.4 (CH), 44.6 (Cq), 48.5 (CH), 78.8 (CH), 93.8 (Cq), 101.3
(CH), 151.2 (C=O).
(1S,2RS,4R,5R)-4-(4-Bromophenyl)-1-(N,N-diisopropylami-
nocarbonyloxy)-5-methyl-3-oxabicyclo[3.3.0]octan-2-ol (10a)
According to GP4, 10a and minor epimer (yield: 83 mg, 76%) was
synthesized as a colourless oil with the diastereomeric ratio 2.1:1.0
from 6a (105 mg, 0.25 mmol); Rf = 0.23 (petroleum ether–
Et2O, 4:1).
(1S,2RS,4R,5R)-5-Butyl-1-(N,N-diisopropylaminocarbonyl-
oxy)-4-phenyl-3-oxabicyclo[3.3.0]octan-2-ol (10e)
According to GP4, 10e and minor epimer (yield: 116 mg, 83%) was
synthesized as a colourless oil with the diastereomeric ratio 1.1:1.0
from 6e (135 mg, 0.35 mmol); Rf = 0.25 (petroleum ether–
Et2O, 4:1).
rac-10a was obtained from rac-6a, yield: 71%.
1H NMR (300 MHz, CDCl3): d = 0.67 (s, 3 H), 1.14 (d, 12 H), 1.47
(m, 2 H), 1.53–1.85 (m, 2 H), 2.42 (m, 2 H), 3.86 (br s, 2 H), 4.90
[4.69] (s, 1 H), 5.62 [5.74] (s, 1 H), 7.20 (mc, 2 H), 7.37 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 15.6 (CH3), 19.3 [21.1] (CH3),
27.2 [28.4] (CH2), 34.7 [37.5] (CH2), 36.6 [38.3] (CH2), 46.6 (Cq),
56.3 [58.8] (CH), 84.5 [86.2] (CH), 95.3 [99.7] (Cq), 100.5 [102.2]
(CH), 121.6 (Cq), 131.1 (CH), 131.4 (CH), 139.6 (Cq), 155.6 (C=O).
rac-10e was obtained from rac-6e, yield: 85%.
1H NMR (300 MHz, CDCl3): d = 0.77 (t, 3 H), 1.13 (m, 2 H), 1.21
(m, 14 H), 1.43 (m, 2 H), 1.58 (m, 2 H), 1.78–1.92 (m, 2 H), 2.48
(m, 2 H), 3.65 (br s, 2 H), 4.96 [4.95] (s, 1 H), 5.56 [5.37] (s, 1 H),
7.15–7.23 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.2 [14.6] (CH3), 20.7 [21.7]
(CH3), 21.6 [21.8] (CH2), 23.9 [24.7] (CH2), 24.4 [25.3] (CH2), 26.6
[27.6] (CH2), 28.3 [29.6] (CH2), 29.5 [30.3] (CH2), 47.7 (Cq), 49.6
[50.8] (CH), 78.5 (CH), 93.5 (Cq), 101.4 (CH), 121.3 [122.4]/123.9
[124.5]/126.2 [127.6]/137.4 [138.9] (CH and Cq), 154.9 (C=O).
(1S,2RS,4R,5R)-4-(4-Chlorophenyl)-1-(N,N-diisopropylami-
nocarbonyloxy)-5-methyl-3-oxabicyclo[3.3.0]octan-2-ol (10b)
According to GP4, 10b and minor epimer (yield: 88 mg, 83%) was
synthesized as a colourless oil with a diastereomeric ratio of 1.9:1.0
from 6b (100 mg, 0.27 mmol); Rf = 0.23 (petroleum ether–
Et2O, 4:1).
(1S,2RS,4R,5R)-4-(4-Bromophenyl)-5-butyl-1-(N,N-diisopro-
pylaminocarbonyloxy)-3-oxabicyclo[3.3.0]octan-2-ol (10f)
According to GP4, 10f and minor epimer (yield: 126 mg, 82%) was
synthesized as a colourless oil with the diastereomeric ratio 4.6:1.0
from 6f (148 mg, 0.32 mmol); Rf = 0.23 (petroleum ether–
Et2O, 4:1).
rac-10b was obtained from rac-6b, yield: 66%.
1H NMR (300 MHz, CDCl3): d = 0.69 (s, 3 H), 1.15 (d, 12 H), 1.42
(m, 2 H), 1.50–1.89 (m, 2 H), 2.47 (m, 2 H), 3.78 (br s, 2 H), 4.92
[4.71] (s, 1 H), 5.62 [5.74] (s, 1 H), 7.16–7.25 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 14.6 (CH3), 19.5 [21.1] (CH3),
26.8 [27.1] (CH2), 28.9 [29.1] (CH2), 29.9 [30.3] (CH2), 46.9 (Cq),
49.9 (CH), 84.2 [86.7] (CH), 95.6 [99.8] (Cq), 100.2 [102.6] (CH),
121.5 (Cq), 131.4 (CH), 131.6 (CH), 139.9 (Cq), 155.2 (C=O).
rac-10f was obtained from rac-6f, yield: 89%.
1H NMR (300 MHz, CDCl3): d = 0.77 (t, 3 H), 1.11 (m, 2 H), 1.23
(m, 14 H), 1.45 (m, 2 H), 1.58 (m, 2 H), 1.78–1.82 (m, 2 H), 2.34
(m, 2 H), 3.64 (br s, 2 H), 4.95 [4.98] (s, 1 H), 5.53 [5.36] (s, 1 H),
7.15 (mc, 2 H), 7.24 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.7 [14.9] (CH3), 21.3 [19.8]
(CH3), 21.7 [21.9] (CH2), 23.2 [22.4] (CH2), 25.3 [24.2] (CH2), 26.1
[27.1] (CH2), 28.8 [29.5] (CH2), 31.0 [32.1] (CH2), 47.6 (Cq), 49.8
[50.3] (CH), 79.6 (CH), 93.6 (Cq), 101.4 (CH), 121.6 [122.9] (Cq),
131.1 (CH), 132.9 (CH), 139.7 (Cq), 153.4 (C=O).
(1S,2RS,4R,5R)-1-(N,N-Diisopropylaminocarbonyloxy)-5-
methyl-4-(naphth-2-yl)-3-oxabicyclo[3.3.0]octan-2-ol (10c)
According to GP4, 10c and minor epimer (yield: 80 mg, 75%) were
synthesized as a colourless oil with the diastereomeric ratio 2.3:1.0
from 6c (102 mg, 0.26 mmol); Rf = 0.23 (petroleum ether–
Et2O, 4:1).
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

2516
S. Ünaldi et al.
PAPER
(1S,2RS,4R,5R)-5-Butyl-1-(N,N-diisopropylaminocarbonyl-
oxy)-4-(naphth-2-yl)-3-oxabicyclo[3.3.0]octan-2-ol (10g)
According to GP4, 10g and minor epimer (yield: 104 mg, 86%)
were synthesized as a colourless oil with the diastereomeric ratio
3.2:1.0 from 6g (117 mg, 0.27 mmol); Rf = 0.22 (petroleum ether–
Et2O, 4:1).
13C NMR (75 MHz, CDCl3): d = 14.1 [14.3] (CH3), 21.3 [19.8]
(CH3), 20.7 [20.9] (CH2), 24.2 [23.4] (CH2), 25.9 [24.7] (CH2), 26.1
[27.1] (CH2), 28.8 [29.5] (CH2), 30.6 [29.2] (CH2), 31.0 [32.1]
(CH2), 47.0 (Cq), 49.8 [50.1] (CH), 76.8 (CH), 93.4 (Cq), 101.9
(CH), 121.5 [122.9] (Cq), 131.2 (CH), 137.7 (CH), 139.9 (Cq), 153.9
(C=O).
rac-10g was obtained from rac-6g, yield: 87%.
(1R,6S,7RS,9R)-1-Butyl-6-(N,N-diisopropylaminocarbonyl-
oxy)-9-(naphth-2-yl)-8-oxabicyclo[4.3.0]nonan-7-ol (10m)
According to GP4, 10m and minor epimer (yield: 127 mg, 90%)
were synthesized as a colourless oil with the diastereomeric ratio
2.0:1.0 from 6m (135 mg, 0.30 mmol); Rf = 0.22 (petroleum ether–
Et2O, 4:1).
1H NMR (300 MHz, CDCl3): d = 0.78 (t, 3 H), 1.12 (m, 2 H), 1.25
(m, 14 H), 1.43 (m, 2 H), 1.45 (m, 2 H), 1.78–1.91 (m, 2 H), 2.30
(m, 2 H), 3.64 (br s, 2 H), 4.96 [4.93] (s, 1 H), 5.54 [5.37] (s, 1 H),
7.17–7.25 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 14.3 [14.7] (CH3), 21.3 [19.6]
(CH3), 21.8 [21.3] (CH2), 23.8 [24.6] (CH2), 25.4 [24.9] (CH2), 26.3
[27.4] (CH2), 28.5 [29.7] (CH2), 29.7 [30.7] (CH2), 47.9 (Cq), 49.3
[50.4] (CH), 77.2 (CH), 93.2 (Cq), 101.4 (CH), 122.5/123.4/125.3/
125.8/126.4/130.9/131.1/132.4/132.4/139.6 (CH and Cq), 154.9
(C=O).
rac-10m was obtained from rac-6m, yield: 90%.
1H NMR (300 MHz, CDCl3): d = 0.77 (t, 3 H), 1.14 (m, 2 H), 1.23
(m, 14 H), 1.42 (m, 2 H), 1.57 (m, 2 H), 1.79–1.93 (m, 2 H), 2.11
(m, 2 H), 2.56 (m, 2 H), 3.67 (br s, 2 H), 4.96 [4.94] (s, 1 H), 5.51
[5.34] (s, 1 H), 7.15–7.33 (m, 7 H).
(1R,6S,7RS,9R)-9-(4-Bromophenyl)-6-(N,N-diisopropylami-
nocarbonyloxy)-1-methyl-8-oxabicyclo[4.3.0]nonan-7-ol (10i)
According to GP4, 10i and minor epimer (yield: 136 mg, 86%) were
synthesized as a colourless oil with the diastereomeric ratio 1.6:1.0
from 6i (153, 0.35 mmol); Rf = 0.22 (petroleum ether–Et2O, 4:1).
13C NMR (75 MHz, CDCl3): d = 14.5 [14.6] (CH3), 21.2 [21.7]
(CH3), 21.3 [21.9] (CH2), 23.6 [24.4] (CH2), 24.8 [25.6] (CH2), 26.3
[27.4] (CH2), 28.5 [29.7] (CH2), 30.5 [30.7] (CH2), 31.8 [32.1]
(CH2), 47.7 (Cq), 49.5 [50.6] (CH), 77.7 (CH), 93.4 (Cq), 101.5
(CH),
121.5/123.6/125.7/126.8/127.4/130.4/132.6/139.9/131.1/
132.9 (CH and Cq), 154.9 (C=O).
rac-10i was obtained from rac-6i, yield: 88%.
1H NMR (300 MHz, CDCl3): d = 0.87 (s, 3 H), 1.14 (d, J = 6.4 Hz,
12 H), 1.57 (m, 2 H), 1.63–1.82 (m, 2 H), 2.14 (m, 2 H), 2.46 (m, 2
H), 3.13 (br s, 2 H), 4.95 [5.29] (s, 1 H), 5.50 [5.68] (s, 1 H), 7.07
(mc, 2 H), 7.39 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.1 [14.3] (CH3), 19.8 [21.3]
(CH3), 26.1 [27.1] (CH2), 28.8 [29.5] (CH2), 30.6 [29.2] (CH2), 31.0
[32.1] (CH2), 47.0 (Cq), 48.5 [47.9] (CH), 81.0 [81.7] (CH), 86.1
[86.1] (Cq), 101.0 [101.7] (CH), 121.6 [122.5] (Cq), 128.5 [128.9]
(CH), 131.2 (CH), 137.7 (Cq), 155.4 [155.2] (C=O).
(1R,6S,7RS,9R)-1-Butyl-6-(N,N-diisopropylaminocarbonyl-
oxy)-9-(2-methylethyl)-8-oxabicyclo[4.3.0]nonan-7-ol (10n)
According to GP4, 10n and minor epimer (yield: 86 mg, 90%) were
synthesized as a colourless oil with the diastereomeric ratio 1.0:1.0
from 6n (91 mg, 0.25 mmol); Rf = 0.23 (petroleum ether–
Et2O, 4:1).
rac-10n was obtained from rac-6n, yield: 93%.
1H NMR (300 MHz, CDCl3): d = 0.75 (t, 3 H), 1.12 (m, 2 H), 1.15
(m, 14 H), 1.43 (m, 2 H), 1.56 (m, 2 H), 1.76–1.91 (m, 2 H), 2.06
(m, 2 H), 2.34 (m, 2 H), 2.39 (m, 6 H), 2.41 (m, 6 H), 3.66, (d, 1 H),
3.84 [3.93] (br s, 2 H), 6.19 [6.23] (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.3 [13.8] (CH3), 20.3 [19.2]
(CH3), 20.6 [19.9] (CH3), 20.6 [20.9] (CH2), 21.0 [21.2] (CH2), 22.1
[22.3] (CH2), 23.5 [23.9] (CH2), 26.4 [26.2] (CH2), 29.8 [30.2]
(CH2), 38.6 [39.2] (CH2), 30.5 (CH), 44.4 (Cq), 48.4 (CH), 76.4
(CH), 93.4 (Cq), 101.9 (CH), 153.7 (C=O).
(1R,6S,7RS,9R)-1-Butyl-6-(N,N-diisopropylaminocarbonyl-
oxy)-9-phenyl-8-oxabicyclo[4.3.0]nonan-7-ol (10k)
According to GP4, 120 and minor epimer (yield: 103 mg, 82%) was
synthesized as a colourless oil with the diastereomeric ratio 1.1:1.0
from 6k (120 mg, 0.30 mmol); Rf = 0.25 (petroleum ether–
Et2O, 4:1).
rac-120 was obtained from rac-60, yield: 85%.
1H NMR (300 MHz, CDCl3): d = 0.77 (t, 3 H), 1.13 (m, 2 H), 1.21
(m, 14 H), 1.43 (m, 2 H), 1.58 (m, 2 H), 1.78–1.92 (m, 2 H), 2.13
(m, 2 H), 2.48 (m, 2 H), 3.65 (br s, 2 H), 4.96 [4.95] (s, 1 H), 5.56
[5.37] (s, 1 H), 7.17–7.28 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.2 [14.6] (CH3), 20.7 [21.7]
(CH3), 21.6 [21.8] (CH2), 23.9 [24.7] (CH2), 24.4 [25.3] (CH2), 26.6
[27.6] (CH2), 28.3 [29.6] (CH2), 30.4 [30.7] (CH2), 31.4 [32.5]
(CH2), 47.8 (Cq), 49.6 [50.8] (CH), 78.5 (CH), 93.5 (Cq), 101.4
(CH), 121.3/126.2/129.4/138.9 (CH and Cq), 154.9 (C=O).
(1R,6S,7RS,9R)-1-Butyl-6-(N,N-diisopropylaminocarbonyl-
oxy)-9-(4-methoxyphenyl)-8-oxabicyclo[4.3.0]nonan-7-ol (10o)
According to GP4, 10o and minor epimer (yield: 114 mg, 85%)
were synthesized as a colourless oil with the diastereomeric ratio
1.6:1.0 from 6o (129 mg, 0.30 mmol); Rf = 0.22 (petroleum ether–
Et2O, 4:1).
rac-10o was obtained from rac-6o, yield: 85%.
1H NMR (300 MHz, CDCl3): d = 0.83 (t, 3 H), 1.15 (m, 2 H), 1.21
(d, 14 H), 1.47 (m, 2 H), 1.58 (m, 2 H), 1.78–1.92 (m, 2 H), 2.04 (m,
2 H), 2.49 (m, 2 H), 3.68 (br s, 2 H), 3.88 (s, 3 H), 4.98 [4.97] (s, 1
H), 5.55 [5.34] (s, 1 H), 7.19–7.27 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 14.3 [14.4] (CH3), 21.4 [19.7]
(CH3), 20.9 [20.9] (CH2), 24.5 [23.7] (CH2), 25.3 [24.6] (CH2), 26.3
[27.6] (CH2), 28.5 [29.7] (CH2), 30.5 [29.7] (CH2), 31.5 [32.6]
(CH2), 47.3 (Cq), 49.9 [50.4] (CH), 54.6 (CH3), 78.4 (CH), 93.5
(Cq), 101.7 (CH), 121.4 [122.5] (Cq), 131.6 (CH), 137.4 (CH), 139.5
(Cq), 153.1 (C=O).
(1R,6S,7RS,9R)-9-(4-Bromophenyl)-1-butyl-6-(N,N-diisopro-
pylaminocarbonyloxy)-8-oxabicyclo[4.3.0]nonan-7-ol (10l)
According to GP4, 10l and minor epimer (yield: 108 mg, 87%) were
synthesized as a colourless oil with the diastereomeric ratio 1.6:1.0
from 6l (120 mg, 0.25 mmol); Rf = 0.22 (petroleum ether–
Et2O, 4:1).
rac-10l was obtained from rac-6l, yield: 87%.
1H NMR (300 MHz, CDCl3): d = 0.81 (t, 3 H), 1.14 (m, 2 H), 1.19
(m, 14 H), 1.43 (m, 2 H), 1.63 (m, 2 H), 1.75–1.88 (m, 2 H), 2.04
(m, 2 H), 2.49 (m, 2 H), 3.63 (br s, 2 H), 4.93 [4.97] (s, 1 H), 5.50
[5.32] (s, 1 H), 7.15 (mc, 2 H), 7.24 (mc, 2 H).
Lactones 11; General Procedure (GP5)
A solution of 10 (0.25–0.50 mmol) in anhyd CH2Cl2 (5–10 mL) was
oxidized with PDC (376–752 mg, 0.50–1.00 mmol) at r.t. for 15 h.
After dilution with H2O (10 mL) and extraction with Et2O (3 × 10
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

PAPER
Fused Bicyclic Oxy-Substituted Lactones via Epoxidation of Homoaldol Products
2517
mL) the mixture was dried (MgSO4). Evaporation of the solvent un-
der reduced pressure, followed by chromatography (silica gel; pe-
troleum ether–Et2O, 4:1) afforded products 11.
13C NMR (75 MHz, CDCl3): d = 13.3 (CH3), 19.2 (CH3), 22.8
(CH2), 27.9 (CH2), 29.4, (CH2), 45. 8 (Cq), 51.9 (CH), 86.9 (CH),
87.2 (Cq), 127.2/127.3/129.3/129.8/130.1/131.5/131.9/132.8/134.7/
134.3 (CH and Cq), 152.4 (C=O), 166.7 (C=O).
(1S,4R,5R)-4-(4-Bromophenyl)-1-(N,N-diisopropylaminocar-
bonyloxy)-5-methyl-3-oxabicyclo[3.3.0]octan-2-one (11a)
According to GP5, 11a (yield: 63 mg, 76%) was synthesized as a
colourless solid; mp 146.1 °C (petroleum ether–Et2O, 4:1); from
10a (83 mg, 0.19 mmol); Rf = 0.22 (petroleum ether–Et2O, 4:1);
[a]D20 –24.3 (c 0.85, CHCl3); chiral HPLC (chiragrom-1; hexane–i-
PrOH, 100:1), 93% ee, major enantiomer appears at lower retention
time.
HRMS: m/z calcd: 432.2145; found: 432.2163 [M + Na]+.
Anal. Calcd for C25H31NO4 (409.52): C, 73.32; H, 7.63; N, 3.42.
Found: C, 73.41; H, 7.69; N, 3.48.
X-ray crystal structure analysis for HOP3117: formula C25H31NO4,
M = 409.51,
colourless
crystal
0.20 × 0.10 × 0.06
mm,
a = 10.910(1), b = 12.345(1), c = 16.977(1) Å, V = 2286.5(3) Å3,
rcalc = 1.190 g·cm–3, 6.40 cm–1, no absorption correction (0.883 £
T £ 0.963), Z = 4, orthorhombic, space group P212121 (No. 19),
l = 1.54178 Å, T = 223 K, w and j scans, 11009 reflections collect-
ed ( h, k, l), [(sinq)/g] = 0.58 Å–1, 3636 independent and 3333
observed reflections [I ≥ s(I)], 276 refined parameters, R1 = 0.042,
wR2 = 0.101, Flack parameter 0.0(2), max. residual electron density
0.12 (–0131) e·Å–3, hydrogens calculated and refined as riding at-
oms.
rac-11a was obtained from rac-10a, yield: 81%.
IR (KBr): 1782 (C=O), 1700 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.77 (s, 3 H), 1.11 (d, J = 6.3 Hz,
12 H), 1.61 (m, 2 H), 1.61–1.92 (m, 2 H), 2.34 (m, 2 H), 3.69/3.90
(br s, 2 H), 4.97 (s, 1 H), 7.28 (mc, 2 H), 7.43 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.2 (CH3), 19.4 (CH3), 20.4
(CH2), 20.5 (CH2), 28.7 (CH2), 45.8 (Cq), 50.9 (CH), 87.2 (CH),
88.9 (Cq), 121.0 (Cq), 127.6 (CH), 130.1 (CH), 135.3 (Cq), 152.4
(C=O), 175.1 (C=O).
(1S,4R,5R)-5-Butyl-1-(N,N-diisopropylaminocarbonyloxy)-4-
(2-methylethyl)-3-oxabicyclo[3.3.0]octan-2-one (11d)
According to GP5, 11d (yield: 54 mg, 78%) was synthesized as a
colourless oil from 10d (70 mg, 0.19 mmol); Rf = 0.22 (petroleum
ether–Et2O, 4:1); [a]D20 –10.6 (c 0.85, CHCl3); chiral HPLC (chira-
grom-1; hexane–i-PrOH, 200:1), 65% ee, major enantiomer ap-
pears at lower retention time.
HRMS: m/z calcd: 460.1094; found: 460.1093 [M + Na]+.
Anal. Calcd for C21H28NO4Br (438.36): C, 57.54; H, 6.44; N, 3.20.
Found: C, 57.62; H, 6.80; N, 3.20.
(1S,4R,5R)-4-(4-Chlorophenyl)-1-(N,N-diisopropylaminocar-
bonyloxy)-5-methyl-3-oxabicyclo[4.3.0]octan-2-one (11b)
According to GP5, 11b (yield: 65 mg, 75%) was synthesized as an
amorphous solid from 10b (88 mg, 0.22 mmol); Rf = 0.24 (petro-
leum ether–Et2O, 4:1); [a]D20 –12.8 (c 0.90, CHCl3); chiral HPLC
(chiragrom-2; hexane–i-PrOH, 200:1), 74% ee, major enantiomer
appears at higher retention time.
rac-11d was obtained from rac-10d, yield: 76%.
IR (film): 1770 (C=O), 1701 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.84 (t, 3 H), 1.21 (m, 2 H), 1.28
(m, 14 H), 1.50 (m, 2 H), 1.58 (m, 2 H), 1.69–1.86 (m, 2 H), 2.22
(m, 2 H), 2.37 (m, 6 H), 3.14 (m, 1 H), 3.68 (d, 1 H), 3.89/4.09 (br
s, 2 H).
rac-11b was obtained from rac-10b, yield: 74%.
IR (KBr): 1778 (C=O), 1695 (C=O) cm–1.
13C NMR (75 MHz, CDCl3): d = 13.8 (CH3), 20.8 (CH3), 21.6
(CH3), 21.5 (CH3), 20.6 (CH2), 21.7 (CH2), 22.6 (CH2), 23.4 (CH2),
26.6 (CH2), 29.1 (CH2), 30.2 (CH), 44.5 (Cq), 48.7 (CH), 86.4 (CH),
98.7 (Cq), 154.6 (C=O), 173.5 (C=O).
1H NMR (300 MHz, CDCl3): d = 0.76 (s, 3 H), 1.14 (d, J = 6.3 Hz,
12 H), 1.51 (m, 2 H), 1.62–1.92 (m, 2 H), 2.31 (m, 2 H), 3.68/3.91
(br s, 2 H), 4.99 (s, 1 H), 7.25 (mc, 2 H), 7.36 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.2 (CH3), 19.9 (CH3), 21.1
(CH2), 22.2 (CH2), 30.3 (CH2), 47.5 (Cq), 52.6 (CH), 88.5 (CH),
88.9 (Cq), 122.7 (Cq), 131.8 (CH), 132.2 (CH), 136.9 (Cq), 154.1
(C=O), 176.8 (C=O).
Anal. Calcd for C21H37NO4 (367.52): C, 68.63; H, 10.15; N, 3.81.
Found: C, 68.80; H, 10.25; N, 3.76.
HRMS: m/z calcd: 390.2620; found: 390.2634 [M + Na]+.
(1S,4R,5R)-5-Butyl-1-(N,N-diisopropylaminocarbonyloxy)-4-
phenyl-3-oxabicyclo[3.3.0]octan-2-one (11e)
HRMS: m/z calcd: 416.1599; found: 416.1619 [M + Na]+.
According to GP5, 11e (yield: 80 mg, 80%) was synthesized as an
amorphous solid from 10e (101 mg, 0.25 mmol); Rf = 0.22 (petro-
Anal. Calcd for C21H28NO4Cl (393.90): C, 64.03; H, 7.16; N, 3.56.
Found: C, 64.32; H, 7.19; N, 3.82.
1
leum ether–Et2O, 4:1); [a]D20 +9.8 (c 1.05, CHCl3); H NMR shift
experiment: er 89:11 (78% ee); 5.3 mg + 24 mol% Eu(hfc)3 in C6D6,
Dd (1 H at d 5.15) = 0.14, signal of major enantiomer appears at
lower field.
(1S,4R,5R)-1-(N,N-Diisopropylaminocarbonyloxy)-5-methyl-4-
(naphth-2-yl)-3-oxabicyclo[3.3.0]octan-2-one (11c)
According to GP5, 11c (yield: 47 mg, 59%) was synthesized as co-
lourless crystal (mp 118.2 °C, petroleum ether–Et2O, 4:1) from 10c
(80 mg, 0.19 mmol); Rf = 0.22 (petroleum ether–Et2O, 4:1); [a]D
–28.1 (c 0.85, CHCl3); chiral HPLC (chiragrom-2; hexane–i-
PrOH, 500:1), 83% ee, major enantiomer appears at lower retention
time.
rac-11e was obtained from rac-10e, yield: 81%.
IR (KBr): 1767 (C=O), 1700 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, 3 H), 1.24 (m, 2 H), 1.29
(m, 14 H), 1.58 (m, 2 H), 1.61 (m, 2 H), 1.78–1.94 (m, 2 H), 2.48
(m, 2 H), 3.65/3.89 (br s, 2 H), 5.15 (s, 1 H), 7.15–7.23 (m, 5 H).
20
rac-11c was obtained from rac-10c, yield: 68%.
IR (KBr): 1780 (C=O), 1698 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.79 (s, 3 H), 1.16 (d, J = 6.4 Hz,
12 H), 1.56 (m, 2 H), 1.65–1.89 (m, 2 H), 2.28 (m, 2 H), 3.70/3.90
(br s, 2 H), 5.19 (s, 1 H), 7.13–7.36 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH3), 21.1 (CH3), 21.6
(CH2), 24.4 (CH2), 25.4 (CH2), 26.7 (CH2), 28.2 (CH2), 30.4 (CH2),
47.1 (Cq), 49.4 (CH), 86.2 (CH), 99.4 (Cq), 121.3/126.4/132.6/134.1
(CH and Cq), 154.9 (C=O), 174.9 (C=O).
HRMS: m/z calcd: 424.2463; found: 424.2469 [M + Na]+.
Anal. Calcd for C24H35NO4 (401.54): C, 71.79; H, 8.79; N, 3.49.
Found: C, 71.62; H, 8.69; N, 3.34.
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

2518
S. Ünaldi et al.
PAPER
(1S,4R,5R)-4-(4-Bromophenyl)-5-butyl-1-(N,N-diisopropylami-
nocarbonyloxy)-3-oxabicyclo[3.3.0]octan-2-one (11f)
According to GP5, 11f (yield: 100 mg, 83%) was synthesized as an
amorphous solid from 10f (120 mg, 0.25 mmol); Rf = 0.22 (petro-
leum ether–Et2O, 4:1); [a]D20 –50.9 (c 0.50, CHCl3); 1H NMR shift
experiment: er 86:14 (72% ee); 4.8 mg + 45 mol% Eu(hfc)3 in C6D6,
Dd (1 H at d = 5.26) = 0.21, signal of major enantiomer appears at
lower field.
HRMS: m/z calcd: 452.1436; found: 452.1429 [M + H]+.
Anal. Calcd for C22H30BrNO4 (451.38): C, 58.41; H, 6.68; N, 3.10.
Found: C, 58.82; H, 6.81; N, 2.81.
X-ray crystal structure analysis for HOP3061: formula
C22H30BrNO4, M = 452.38, colourless crystal 0.25 × 0.15 × 0.10
mm, a = 7.485(1), b = 20.720(1), c = 14.092(1) Å, b = 98.50(1)º,
V = 2161.5(3) Å3, rcalc = 1.390 g cm–3, 19.29 cm–1, empirical ab-
sorption correction (0.644 £ T £ 0.831), Z = 4, monoclinic, space
group P21/c (No. 14), l = 0.71073 Å, T = 198 K, w and j scans,
13084 reflections collected ( h, k, l), [(sinq)/l] = 0.66 Å–1, 5126
independent and 3326 observed reflections [I £ 2 s(I)], 258 refined
parameters, R = 0.047, wR2 = 0.096, max. residual electron density
0.32 (–0.46) e Å–3, hydrogens calculated and refined as riding at-
oms.
rac-11f was obtained from rac-10f, yield: 81%.
IR (KBr): 1769 (C=O), 1693 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (t, 3 H), 1.15 (m, 2 H), 1.24
(m, 14 H), 1.58 (m, 2 H), 1.64 (m, 2 H), 1.74–1.96 (m, 2 H), 2.32
(m, 2 H), 3.65/3.92 (br s, 2 H), 5.26 (s, 1 H), 7.25 (mc, 2 H), 7.40
(mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.2 (CH3), 21.8 (CH3), 21.9
(CH2), 23.4 (CH2), 25.2 (CH2), 26.2 (CH2), 28.2 (CH2), 30.5 (CH2),
47.8 (Cq), 49.8 (CH), 86.3 (CH), 98.9 (Cq), 121.3 (Cq), 131.4 (CH),
132.5 (CH), 133.5 (Cq), 153.1 (C=O), 174.2 (C=O).
(1R,6S,9R)-1-Butyl-6-(N,N-diisopropylaminocarbonyloxy)-9-
phenyl-8-oxabicyclo[4.3.0]nonan-7-one (11k)
According to GP5, 11k (yield: 79 mg, 84%) was synthesized as co-
lourless crystals from 10k (95 mg, 0.23 mmol); Rf = 0.22 (petro-
1
leum ether–Et2O, 4:1); [a]D20 –42 (c 0.50, CHCl3); H NMR shift
HRMS: m/z calcd: 480.1749; found: 480.1754 [M + H]+.
experiment: er 89:11 (78% ee); 4.8 mg + 45 mol% Eu(hfc)3 in C6D6,
Dd (1 H at d = 5.14) = 0.31, signal of major enantiomer appears at
lower field.
Anal. Calcd for C24H34NO4Br (480.44): C, 60.00; H, 7.13; N, 2.92.
Found: C, 60.03; H, 7.09; N, 2.83.
rac-11k was obtained from rac-10k, yield: 85%.
IR (KBr): 1767 (C=O), 1700 (C=O) cm–1.
(1S,4R,5R)-5-Butyl-1-(N,N-diisopropylaminocarbonyloxy)-4-
(naphth-2-yl)-3-oxabicyclo[3.3.0]octan-2-one (11g)
According to GP5, 11g (yield: 80 mg, 84%) was synthesized as a
colourless oil from 10g (95 mg, 0.21 mmol); Rf = 0.22 (petroleum
1H NMR (300 MHz, CDCl3): d = 0.86 (t, 3 H), 1.18 (m, 2 H), 1.23
(m, 14 H), 1.53 (m, 2 H), 1.68 (m, 2 H), 1.74–1.96 (m, 2 H), 2.12
(m, 2 H), 2.54 (m, 2 H), 3.55/3.88 (br s, 2 H), 5.14 (s, 1 H), 7.03–
7.20 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.6 (CH3), 21.7 (CH3), 21.6
(CH2), 24.9 (CH2), 25.4 (CH2), 26.6 (CH2), 28.6 (CH2), 30.5 (CH2),
31.7 (CH2), 47.3 (Cq), 49.2 (CH), 86.5 (CH), 99.5 (Cq), 121.2/126.5/
129.1/138.2 (CH and Cq), 155.1 (C=O), 174.7 (C=O).
1
ether–Et2O, 4:1); [a]D20 –28.1 (c 0.45, CHCl3); H NMR shift ex-
periment: er 90:8 (82% ee); 5.1 mg + 29 mol% Eu(hfc)3 in C6D6, Dd
(1 H at d 5.15) = 0.15, signal of major enantiomer appears at lower
field.
rac-11g was obtained from rac-10g, yield: 83%.
IR (film): 1771 (C=O), 1693 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (t, 3 H), 1.23 (m, 2 H), 1.26
(m, 14 H), 1.55 (m, 2 H), 1.63 (m, 2 H), 1.76–1.96 (m, 2 H), 2.42
(m, 2 H), 3.63/3.90 (br s, 2 H), 5.15 (s, 1 H), 7.17–7.25 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH3), 21.6 (CH3), 21.3
(CH2), 24.8 (CH2), 25.9 (CH2), 26.4 (CH2), 28.7 (CH2), 30.7 (CH2),
47.6 (Cq), 49.4 (CH), 86.2 (CH), 98.6 (Cq), 122.4/123.7/125.2/
125.5/126.8/130.3/131.4/132.5/132.6/139.7 (CH and Cq), 154.1
(C=O), 174.3 (C=O).
HRMS: m/z calcd: 438.2615; found: 438.2621 [M + Na]+.
Anal. Calcd for C25H37NO4 (415.27): C, 72.26; H, 8.97; N, 3.37.
Found: C, 72.32; H, 8.90; N, 3.34.
X-ray crystal structure analysis for HOP2926: formula C25H37NO4,
M = 415.56,
colourless
crystal
0.50 × 0.10 × 0.05
mm,
a = 9.784(1), b = 15.337(1), c = 16.151(1) Å, b = 92.96(1)º,
V = 2420.3(3) Å3, rcalc = 1.140 g·cm–3, 6.05 cm–1, empirical absorp-
tion correction (0.752 £ T £ 0.970), Z = 4, monoclinic, space group
P21/c (No. 14), l = 1.54178 Å, T = 223 K, w and j scans, 11513 re-
flections collected ( h, k, l), [(sin q)/l] = 0.58 Å–1, 3200 indepen-
HRMS: m/z calcd: 474.2620; found: 474.2626 [M + Na]+.
Anal. Calcd for C28H37NO4 (451.60): C, 74.47; H, 8.26; N, 3.10.
Found: C, 74.32; H, 8.38; N, 3.11.
dent and 1686 observed reflections [I
2 s(I)], 276 refined
parameters, R1 = 0.050, wR2 = 0.131, due to shape and quality
poorly diffracting crystal, max. residual electron density 0.23
(–0.18) e·Å–3, hydrogens calculated and refined as riding atoms.
(1R,6S,9R)-9-(4-Bromophenyl)-6-(N,N-diisopropylaminocar-
bonyloxy)-1-methyl-8-oxabicyclo[4.3.0]nonan-7-one (11i)
According to GP5, 11i (yield: 99 mg, 82%) was synthesized as co-
lourless crystals from 10i (123 mg, 0.27 mmol); Rf = 0.27 (petro-
leum ether–Et2O, 4:1); mp 127.5 °C (petroleum ether–Et2O, 4:1);
[a]D20 +50 (c 0.50, CHCl3); chiral HPLC (chiragrom-1; hexane–i-
PrOH, 200:1), 86% ee, major enantiomer appears at lower retention
time.
(1R,6S,9R)-9-(4-Bromophenyl)-1-butyl-6-(N,N-diisopropylami-
nocarbonyloxy)-8-oxabicyclo[4.3.0]nonan-7-one (11l)
According to GP5, 11l (yield: 80 mg, 80%) was synthesized as an
amorphous solid from 10l (100 mg, 0.20 mmol); Rf 0.27 (petroleum
1
ether–Et2O, 4:1); [a]D20 –56.1 (c 0.50, CHCl3); H NMR shift ex-
periment: er 88:12 (76% ee); 4.8 mg + 33 mol% Eu(hfc)3 in C6D6,
Dd (1 H at d 5.18) = 0.31, signal of major enantiomer appears at
lower field.
rac-11i was obtained from rac-10i, yield: 84%.
IR (KBr): 1773 (C=O), 1702 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.67 (t, 3 H), 1.11 (d, 12 H), 1.61
(m, 2 H), 1.61–1.92 (m, 2 H), 2.04 (m, 2 H), 2.43 (m, 2 H), 3.13/
3.45 (br s, 2 H), 5.19 (s, 1 H), 7.09 (mc, 2 H), 7.42 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d 14.2 (CH3), 21.3 (CH3), 20.4 (CH2),
25.4 (CH2), 27.8 (CH2), 31.2 (CH2), 47.2 (Cq), 49.4 (CH), 86.4
(CH), 99.4 (Cq), 121.5 (Cq), 131.2 (CH), 132.3 (CH), 134.9 (Cq),
153.2 (C=O), 174.1 (C=O).
rac-11l was obtained from rac-10, yield: 81%.
IR (KBr): 1770 (C=O), 1700 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.79 (t, 3 H), 1.12 (m, 2 H), 1.18
(m, 14 H), 1.45 (m, 2 H), 1.61 (m, 2 H), 1.75–1.91 (m, 2 H), 2.01
(m, 2 H), 2.46 (m, 2 H), 3.53/3.86 (br s, 2 H), 5.18 (s, 1 H), 7.15 (mc,
2 H), 7.23 (mc, 2 H).
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

PAPER
Fused Bicyclic Oxy-Substituted Lactones via Epoxidation of Homoaldol Products
2519
13C NMR (75 MHz, CDCl3): d = 14.2 (CH3), 21.3 (CH3), 20.4
(CH2), 24.5 (CH2), 25.4 (CH2), 26.5 (CH2), 27.8 (CH2), 31.2 (CH2),
33.2 (CH2), 47.2 (Cq), 49.4 (CH), 86.4 (CH), 99.4 (Cq), 121.5 (Cq),
131.2 (CH), 132.3 (CH), 134.9 (Cq), 153.2 (C=O), 174.1 (C=O).
Dd (1 H at d 5.04) = 0.14, signal of major enantiomer appears at
higher field.
rac-11o was obtained from rac-10o, yield: 82%.
IR (film): 1771 (C=O), 1700 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, 3 H), 1.17 (m, 2 H), 1.13
(m, 14 H), 1.48 (m, 2 H), 1.64 (m, 2 H), 1.73–1.96 (m, 2 H), 2.03
(m, 2 H), 2.42 (m, 2 H), 3.64/3.98 (br s, 2 H), 3.85 (s, 3 H), 5.05 (s,
1 H), 7.17 (mc, 2 H), 7.25 (mc, 2 H).
13C NMR (300 MHz, CDCl3): d = 14.5 (CH3), 21.2 (CH3), 20.9
(CH2), 24.1 (CH2), 25.4 (CH2), 26.4 (CH2), 28.8 (CH2), 30.5 (CH2),
31.4 (CH2), 47.2 (Cq), 49.5 (CH), 53.6 (OCH3), 85.6 (CH), 99.5
(Cq), 121.2 (Cq), 133.1 (CH), 132.5 (CH), 135.5 (Cq), 154.2 (C=O),
174.5 (C=O).
Anal. Calcd for C25H36BrNO4 (493.46): C, 60.73; H, 7.34; N, 2.83.
Found: C, 60.96; H, 7.48; N, 3.07.
(1R,6S,9R)-1-Butyl-6-(N,N-diisopropylaminocarbonyloxy)-9-
(naphth-2-yl)-8-oxabicyclo[4.3.0]nonan-7-one (11m)
According to GP5, 11m (yield: 94 mg, 81%) was synthesized as an
amorphous solid from 10m (116 mg, 0.25 mmol); Rf = 0.22 (petro-
leum ether–Et2O, 4:1); [a]D20 –30.0 (c 0.55, CHCl3); 1H NMR shift
experiment: er 83:17 (66% ee); 4.6 mg + 48 mol% Eu(hfc)3 in C6D6,
Dd (1 H at d 5.15) = 0.14, signal of major enantiomer appears at
lower field.
Anal. Calcd for C26H39NO5 (445.50): C, 70.08; H, 8.82; N, 3.14.
Found: C, 69.98; H, 8.75; N, 3.11.
rac-11m was obtained from rac-10m, yield: 79%.
IR (KBr): 1769 (C=O), 1693 (C=O) cm–1.
1H NMR (76 MHz, CDCl3): d = 0.83 (t, 3 H), 1.15 (m, 2 H), 1.18
(m, 14 H), 1.43 (m, 2 H), 1.58 (m, 2 H), 1.78–1.94 (m, 2 H), 2.13
(m, 2 H), 2.49 (m, 2 H), 3.65/3.97 (br s, 2 H), 5.15 (s, 1 H), 7.15–
7.25 (m, 7 H).
Acknowledgement
The work was supported by the Deutsche Forschunggemeinschaft,
(SFB 424) and the Fonds der Chemischen Industrie.
13C NMR (300 MHz, CDCl3): d = 14.6 (CH3), 21.4 (CH3), 21.3
(CH2), 24.3 (CH2), 25.8 (CH2), 26.7 (CH2), 28.9 (CH2), 30.9 (CH2),
31.2 (CH2), 47.7 (Cq), 49.0 (CH), 85.4 (CH), 99.0 (Cq), 121.3/123.5/
125.6/126.7/127.0/130.7/132.0/132.4/133.3/134.7 (CH and Cq),
154.9 (C=O), 174.1 (C=O).
References
(1) Responsible for X-ray structure data.
(2) Review: Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 2282; Angew. Chem. 1997, 109, 2376.
(3) Reviews: (a) Hoppe, D.; Marr, F.; Brüggemann, M.
Organolithiums in Enantioselective Synthesis, Topics in
Organometallic Chemistry, Vol 5; Hodgson, D. M., Ed.;
Springer-Verlag: Berlin, 2003, 61–138. (b) Hoppe, D.;
Christoph, G. The Chemistry of Organolithium Compounds,
Vol 2; Rappoport, Z.; Marek, I., Eds.; Wiley: Chichester,
2004, 1055–1164.
(4) (a) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. Engl.
1989, 28, 69; Angew. Chem. 1989, 101, 67. (b) Paulsen, H.;
Graeve, C.; Hoppe, D. Synthesis 1996, 141. (c) Deiters, A.;
Hoppe, D. J. Org. Chem. 2001, 66, 2842. (d) Beckmann,
E.; Hoppe, D. Synthesis 2005, 217. (e) Zeng, W.; Fröhlich,
R.; Hoppe, D. Tetrahedron 2005, 61, 3281.
(5) (a) Özlügedik, M.; Kristensen, J.; Wibbeling, B.; Fröhlich,
R.; Hoppe, D. Eur. J. Org. Chem. 2002, 414.
(b) Özlügedik, M.; Kristensen, J.; Reuber, J.; Fröhlich, R.;
Hoppe, D. Synthesis 2004, 2303.
(6) Zhu, Y.; Manske, K. J.; Shi, Y. J. Am. Chem. Soc. 1999, 121,
4080.
(7) (a) Hoppe, D.; Lüßmann, J.; Jones, P. G.; Schmidt, D.;
Sheldrick, G. M. Tetrahedron Lett. 1986, 27, 3591.
(b) Lüßmann, J.; Hoppe, D.; Jones, P. G.; Fittschen, C.;
Sheldrick, G. M. Tetrahedron Lett. 1986, 31, 3595.
(8) Reuber, J.; Fröhlich, R.; Hoppe, D. Org. Lett. 2004, 6, 783.
(9) Reuber, J. Dissertation; University of Münster: Germany,
2005, see also ref. 5a and 8.
HRMS: m/z calcd: 488.2776; found: 488.2783 [M + Na]+.
Anal. Calcd for C29H39NO4 (465.62). C, 74.81; H, 8.44; N, 3.01.
Found C, 75.36; H, 8.58; N, 3.61.
(1R,6S,9R)-1-Butyl-6-(N,N-diisopropylaminocarbonyloxy)-9-
(2-methylethyl)-8-oxabicyclo[4.3.0]nonan-7-one (11n)
According to GP5, 11n (yield: 67 mg, 84%) was synthesized as a
colourless oil from 10n (80 mg, 0.21 mmol); Rf = 0.22 (petroleum
ether–Et2O, 4:1); [a]D20 –17.9 (c 1.15, CHCl3); chiral HPLC (chira-
grom-1; hexane–i-PrOH, 200:1), 72% ee, major enantiomer ap-
pears at higher retention time.
rac-11n was obtained from rac-10n, yield: 85%.
IR (film): 1771 (C=O), 1702 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, 3 H), 1.24 (m, 2 H), 1.35
(m, 14 H), 1.56 (m, 2 H), 1.62 (m, 2 H), 1.84–1.94 (m, 2 H), 2.11
(m, 2 H), 2.35 (m, 6 H), 2.55 (m, 2 H), 2.63 (m, 6 H), 3.79 (d, 1 H),
3.85/4.18 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 21.3 (CH3), 21.6
(CH3), 21.9 (CH2), 22.6 (CH2), 23.1 (CH2), 23.9 (CH2), 26.2 (CH2),
29.3 (CH2), 29.5 (CH), 37.7 (CH2), 43.4 (CH), 47.5 (Cq), 83.8 (CH),
97.5 (Cq), 154.8 (C=O), 174.5 (C=O).
Anal. Calcd for C22H39NO4 (381.55): C, 69.25; H, 10.30; N, 3.67.
Found: C, 69.18; H, 10.15; N, 3.59.
(1R,6S,9R)-1-Butyl-6-(N,N-diisopropylaminocarbonyloxy)-9-
(4-methoxyphenyl)-8-oxabicyclo[4.3.0]nonan-7-one (11o)
According to GP5, 11o (yield: 89 mg, 80%) was synthesized as a
colourless oil from 10o (111 mg, 0.25 mmol); Rf = 0.22 (petroleum
(10) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979,
12, 63.
(11) Mihelich, E. D.; Daniels, D.; Eickhoff, D. J. J. Am. Chem.
Soc. 1981, 103, 7690.
1
ether–Et2O, 4:1); [a]D20 +40.2 (c 0.50, CHCl3); H NMR shift ex-
periment: er 86:13 (73% ee), 5.3 mg + 25 mol% Eu(hfc)3 in C6D6,
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York

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S. Ünaldi et al.
PAPER
this paper. This data can be obtained free of charge at
www.cam.ac.uk/conts/retrieving.html [or from Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: (internat.) +44 (1223)336-033; E-mail:
deposit@ccdc.cam.ac.uk].
(12) Data sets were collected with Nonius Kappa CCD
diffractometers, in case of Mo-radiation equipped with a
rotating anode generator. Programs used: (a) Data
collection: Nonius, B. V. COLLECT 1998. (b) Data
reduction Denzo-SMN: Otwinowski, Z.; Minor, W. Methods
in Enzymology 1997, 276, 307. Absorption correction
SORTAV: (c) Blessing, R. H. Acta Cryst. 1995, A51, 33.
(d) Blessing, R. H. J. Appl. Cryst. 1997, 30, 421; Denzo:
Otwinowski Z., Borek D., Majewski W., Minor W.; Acta
Cryst.; 2003, A59: 228;. (e)Structuresolution SHELXS-97:
Sheldrick, G. M. Acta Cryst. 1990, A46, 467. (f) Structure
refinement SHELXL-97: Sheldrick, G. M. Universität
Göttingen 1997. (g) Graphics Diamond: Brandenburg, K.
Universität Bonn 1997. (h) CCDC-264379, 264380, and
264831 contain the supplementary crystallographic data for
Synthesis 2005, No. 15, 2507–2520 © Thieme Stuttgart · New York