Synthesis of functionalized hydropentalenes by an asymmetric deprotonation/alkylation strategy

Article abstract of DOI:10.1002/ejoc.200901154

The functionalization of differently substituted hydropentalenone derivatives 9, derived from the Weiss diketone (8) by enantioselective deprotonation in the presence of lithium (R,R)-bis(1-phenylethyl)amide/LiCl (11-LiCl) as the chiral base is described. In the first route the resulting enolate was treated, directly with alkyl halides as electrophiles to give the target a-alkylhydropentalenones 12, whereas in the second route the enolate was trapped as one of the triethylsilyl enol ethers 17, from which the enolate was regenerated, by treatment with MeLi prior to alkylation with alkyl halides. The substituents on 9 seemed to influence which strategy is favored: for the OTBS-substituted hydropentalenone 9a the direct deprotonation/alkylation is preferred, whereas for the acetal-substituted hydropentalenone 9b the silyl enol ether route is more suitable. In all cases the α-alkylated hydropentalenones 12 and 15 were isolated with good diastereoselectivities.

Full text of DOI:10.1002/ejoc.200901154

FULL PAPER
DOI: 10.1002/ejoc.200901154
Synthesis of Functionalized Hydropentalenes by an Asymmetric
Deprotonation/Alkylation Strategy
Vanessa Lutz,[a] Angelika Baro,[a] Peter Fischer,[a] and Sabine Laschat*[a]
Keywords: Alkylation / Asymmetric synthesis / Bicyclic compounds / Chiral bases / Weiss diketone / Chiral auxiliaries
The functionalization of differently substituted hydropent-
alenone derivatives 9, derived from the Weiss diketone (8)
by enantioselective deprotonation in the presence of lithium
(R,R)-bis(1-phenylethyl)amide/LiCl (11·LiCl) as the chiral
base is described. In the first route the resulting enolate was
treated directly with alkyl halides as electrophiles to give the
target α-alkylhydropentalenones 12, whereas in the second
route the enolate was trapped as one of the triethylsilyl enol
ethers 17, from which the enolate was regenerated by treat-
ment with MeLi prior to alkylation with alkyl halides. The
substituents on 9 seemed to influence which strategy is fa-
vored: for the OTBS-substituted hydropentalenone 9a the di-
rect deprotonation/alkylation is preferred, whereas for the
acetal-substituted hydropentalenone 9b the silyl enol ether
route is more suitable. In all cases the α-alkylated hydro-
pentalenones 12 and 15 were isolated with good diastereo-
selectivities.
Introduction
Functionalized hydropentalenes are important building
blocks of natural secondary metabolites and pharmacologi-
cally active compounds. Attractive examples include sesqui-
terpenes such as silphiperfolene (1),[1] neorogiolane (2),[2]
ptychenolide (3),[3] and carbacycline (4)[4] or the class of
tetramic acid lactams,[5–8] such as cylindramide (5)[5]
(Scheme 1). Consequently, a variety of synthetic approaches
directed towards the formation and functionalization of hy-
dropentalenes[9] have been developed; these include radical
cyclization,[10] Diels–Alder reactions,[11] tandem-carbene-
carbene rearrangements,[12] Pauson–Khand reactions,[13]
metal-catalyzed cyclizations,[14] Lewis-acid-catalyzed Naza-
rov cyclizations,[15] ring-opening metathesis,[16] carbonyl-ene
reactions,[17] sequential oxidative transannular cyclization
of cycloocta-1,3- or -1,4-dienes followed either by enzy-
matic resolution[18,19] or by 1,4-allylation,[20] and oxadi-π-
methene rearrangements.[3]
Scheme 1.
An alternative strategy directed towards functionalized
hydropentalenes is the enantioselective desymmetrization of
Cs-symmetric ketones derived from the Weiss diketone (8)
through sequential deprotonation with a chiral lithium base
and subsequent electrophilic trapping of the enolate 7
(Scheme 2). The Weiss diketone (8) is readily available on a
multigram scale,[21] and both enantiomers of 6 are access-
ible by suitable choice of the base.[22]
Scheme 2.
bases were pioneered by Simpkins,[23,24] Koga,[25] and Leo-
nard[26] and further developed by other groups.[27,28]
Koga[25c] and Leonard[26] were the first to study the enan-
tioselective deprotonation of Cs-symmetrical hydropent-
alene ketones. The method was utilized by Koga[25c] and
Gais[29] for the preparation of metabolically stable carba-
cyclines. Surprisingly, it is mostly aldehydes, trialkylchloro-
Enantioselective deprotonations with the aid of chiral
[a] Institut für Organische Chemie der Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: +49-711-68564285
E-mail: sabine.laschat@oc.uni-stuttgart.de
Eur. J. Org. Chem. 2010, 1149–1157
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1149

V. Lutz, A. Baro, P. Fischer, S. Laschat
FULL PAPER
silanes, ethyl cyanoacetate, and NBS that have been used as
trapping electrophiles. Gais[30] further extended this work
to Cs-symmetrical hydropentalene hydrazones, which were
desymmetrized with the aid of chiral cuprates.[31] Simple
alkyl and allyl halides have not been used as electrophiles,
however, although allyl halides in particular might allow
further functionalization. This prompted us to explore the
enantioselective deprotonation of hydropentalenes in more
detail and to study whether the stereoselectivity of the alky-
lation is compromised by base-catalyzed epimerization of
the resulting ketones or by double alkylation.[32] The results
are reported below.
Results and Discussion
Scheme 4.
With respect to the deprotonation, two stereochemical
possibilities have to be considered: abstraction of the dia-
stereotopic H atoms, leading to the same enolate, or ab-
straction of the enantiotopic H atoms, leading to enantio-
meric enolates (Scheme 3).
13 (Entry 1). Enantioselectivities could be improved by
decreasing the temperature (Entries 2–4). The best result
was obtained at –40 °C, with the methylated ketone 12a be-
ing obtained in 68% yield with dr = 98:2 and er = 96:4. No
trace of the dimethylated ketone 13 was detected (En-
try 5).[35]
Table 1. Temperature effect on the asymmetric deprotonation/
methylation of the silyl ether 9a to afford the α-methylated ketone
12a.[a,b]
En-
try
T [°C]
Time
[h]
Yield
[%]
dr
er
[α]2D0 (CH2Cl2)
1
2
3
4
5
–50 to 0
–10
–20
–30
–40
6
30[c]
71
40
64
68
99:1 80:20
99:1 91:9
99:1 92:8
98.5:1.5 93:7
98:2 96:4
–7.6 (c = 0.80)
–8.0 (c = 1.00)
–6.7 (c = 1.00)
–9.7 (c = 1.00)
–22.0 (c = 1.00)
23
23
23
23
Scheme 3.
[a] Reaction conditions as in Scheme 4. [b] Diastereomeric ratio
(dr) determined by capillary GC, enantiomeric ratio (er) by capil-
lary GC on a chiral stationary phase. [c] The α,αЈ-dimethylated
ketone 13 was isolated in 12% yield.
Because we were interested to see whether or not the sec-
ond cyclopentane moiety and its substituents might exert
any influence on the deprotonation and subsequent alky-
lation of the cyclopentanone, both the TBS ether 9a and
Because –40 °C had been found to be most suitable, fur-
the acetal 9b[33] were investigated in the presence of lithium ther alkylations with other alkyl halides as electrophiles
(R,R)-bis(1-phenylethyl)amide/LiCl (11·LiCl) as the chiral were performed at this temperature (Table 2). Unlike those
base. The presence of LiCl is known to be crucial for the of ketone 12a, the enantioselectivities of ketones 12b–d
selectivity of the deprotonation.[25a,29] The amide 11·LiCl could not be determined by capillary GC on a chiral sta-
was generated in situ from the corresponding (+)-(R)-1- tionary phase; therefore, desilylation to the corresponding
phenylethylamine-derived (R,R)-bis(1-phenylethyl)ammo- hydroxy ketones 14b–d by treatment with TBAF was re-
nium chloride (10)[34] and nBuLi (1.95 equiv.) in THF at quired prior to GC analyses.[35]
–78 °C (Scheme 4).[29]
The allylated hydroxy ketone 14b was obtained in 72%
The temperature effect on the asymmetric deprotonation/ yield over two steps with dr = 84:16 and er = 97:3 (Entry 4),
alkylation was studied first, by use of the TBS ether 9a, whereas the prenylated and benzylated hydroxy ketones 14c
which was deprotonated with 11·LiCl in THF at –100 °C and 14d were isolated in total yields of 31% (dr = 86:14, er
over 23 h, followed by addition of methyl iodide (2 equiv.) = 94:6) and 8% (dr = 81:19, er = 91:9), respectively (En-
at varying temperatures. After quenching with a saturated tries 5 and 6). It should be noted that desilylation with
solution of NaHCO3/H2O and aqueous workup, the α- TBAF compromised the diastereomeric purities of the α-
methylated ketone 12a (Scheme 4, Table 1) was obtained alkylated ketones, presumably due to base-catalyzed epi-
(for determination of the absolute configuration see dis- merization of the α-stereogenic centers via the enolates. The
cussion below). Raising the temperature gradually from TBS ether 12b, with an α-allyl substituent, for example, was
–50 °C to 0 °C over 6 h gave 12a in 30% yield (er = 80:20) obtained in 84% and dr = 97:3, whereas the derived hy-
together with a 12% yield of the α,αЈ-dimethylated ketone droxy ketone 14b showed only a dr = 84:16.
1150
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1149–1157

Functionalized Hydropentalenes by Asymmetric Deprotonation/Alkylation
Table 2. Enantioselective alkylation of the silyl ether 9a and de-
silylation of the alkylated products 12 to afford the alcohols 14.[a,b]
En-
try
R–X
Product Yield
[%]
dr
er
[α]2D0 (CH2Cl2)
[c]
1
2
3
4
5
6
allyl iodide
prenyl bromide
12b
12c
12d
14b
14c
14d
84
40
24
86
78
35
97:3
97:3
93:7
–
–12.9 (c = 0.80)
–9.8 (c = 1.00)
–8.6 (c = 1.00)
[c]
–
[c]
Bn–Br
–
–
–
–
84:16 97:3 –11.2 (c = 1.00)
86:14 94:6 –9.6 (c = 1.00)
81:19 91:9 –7.6 (c = 1.00)
[a] Reaction conditions as in Scheme 4. [b] Diastereomeric ratio
(dr) determined by capillary GC. [c] Enantiomeric ratio (er) of 12b–
d could not be determined by capillary GC on a chiral stationary
phase; therefore, 12b–d were converted into the alcohols 14b–d.
When the acetal 9b was subjected to the sequential de-
protonation/alkylation conditions described above we faced
severe problems, because the desired α-alkylated ketones
15a–c could not be separated from the dialkylated products
16 and the chiral base (Scheme 5).
Scheme 6. Enantioselective alkylation of hydropentalenones 9 via
silyl enol ethers 17.
Table 3. Enantioselective alkylation of hydropentalenones 9a and
9b via the triethylsilyl enol ethers 17a and 17b to afford products
12, 14, and 15.[a,b]
Entry
R–X
Time [h] Product Yield [%]
dr
er
1
2
3
4
5
6
7
8
9
Me–I
allyl iodide
prenyl bromide
Bn–Br
20
20
24
22
23
23
23
23
2
15a
15b
15c
15d
12a
12b
12c
12d
14b
14c
14d
50
70[c]
65
35
33
48
41
26
90
85
93
93:7
95:5
94:6
92:8
98:2 82.5:17.5[d]
96:4
98:2
99:1
91:9
95:5
Me–I
[e]
allyl iodide
prenyl bromide
Bn–Br
–
[e]
97:3
–
[e]
86:14
81:19
84:16
84:16
–
–
–
–
91:9
88:12
76:24
10
11
2
2
Scheme 5.
[a] Reaction conditions as in Scheme 6. [b] Diastereomeric ratio
(dr) determined by capillary GC, enantiomeric ratio (er) by capil-
lary GC on a chiral stationary phase. [c] Compound 16b was iso-
lated in 30% yield (dr = 97:3). [d] Determined after reduction of
15c to alcohol 18. [e] Enantiomeric ratio could not be determined;
therefore, compounds 12b–d were converted into 14b–d.
The acetal 9b was therefore deprotonated with lithium
(R,R)-bis(1-phenylethyl)amide/LiCl (11·LiCl) at –100 °C in
THF over 1 h, and the resulting enolate was trapped by
addition of chlorotriethylsilane according to Gais’s pro-
cedure.[29] After chromatographic purification, the silyl enol
ether 17b was isolated in 87% yield (Scheme 6). The abso- ketone 15c, the enantioselectivity could not be determined
lute configuration of silyl enol ether 17b was determined by directly; therefore, the derivative 15c was reduced with
comparison of its optical rotation {[α]2D0 = +2.1 (c = 9.8, NaBH4 to give the alcohol 18 as a single diastereomer in
THF)} with that reported by Gais {[α]2D0 = +0.6 (c = 9.8, 92% yield (er = 82.5:17.5). A disappointing yield of 35%
THF)[29]}. By a methodology reported by Seebach,[36] the was obtained for ketone 15d, but the selectivities were
silyl enol ether 17b was treated with MeLi to regenerate promising (dr = 96:4, er = 91:9, Entry 4).
the lithium enolate, which was treated with the appropriate
The silyl enol ether route was also applied for the TBS
electrophiles to give the ketones 15a–d after workup as de- ether 9a (Scheme 6, Table 3). Conversion of 9a into the cor-
scribed above (Scheme 6, Table 3). It should be noted that responding silyl enol ether 17a proceeded uneventfully in
all attempts to enhance the reactivity of the silyl enol ether 65% yield. Subsequent treatment with MeLi, followed by
or the electrophile by addition of a Lewis acid failed. Only addition of the electrophile as described above, gave the
cleavage of the silyl group was observed, and the starting alkylated ketones 12a–d in moderate to good yields and
monoketal 9b was reisolated.
with good diastereoselectivities (Table 3, Entries 5–8). It
As can be seen from Table 3, the α-methyl-substituted should be noted that the yields of the benzylated and meth-
hydropentalenone 15a was isolated in 50% yield (dr = 93:7, ylated products 15d and 12a (Entries 4 and 5) could not be
er = 94:6, Entry 1), and the allylated product 15b was ob- improved by performing the alkylation of the silyl enol
tained in 70% yield with dr = 95:5 and er = 92:8. As a ethers 17 in the presence of Lewis acids such as BF3·OEt2
byproduct, the corresponding α,αЈ-diallylhydropentalenone or TMSOTf. In the case of 12a, the enantioselectivity was
16b was formed (Entry 2). In the case of the prenylated determined directly (er = 95:5, Entry 5). Ketones 12b–d,
Eur. J. Org. Chem. 2010, 1149–1157
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1151

V. Lutz, A. Baro, P. Fischer, S. Laschat
FULL PAPER
ATR system. Reaction progress and purity were monitored by GC
however, were deprotected to afford the hydroxy ketones
14b–d for er determination (Entries 9–11). As can be seen
from Tables 1 and 2, the direct functionalization of the TBS
ether 9a resulted in much higher enantioselectivities than
the silyl enol ether route, which furthermore requires two
additional steps.[35]
with
a
Hewlett Packard HP 6890 with HP-5 column
(30 mϫ0.32 mm), hydrogen as carrier gas, and different tempera-
ture programs. Enantioselectivities were determined by GC on chi-
ral stationary phases [Amidex C (Amidex-pob-12-un-5.0-Et-133) or
Bondex un-β-5.5 (pure β-cyclodextrin phase)]. The enantiomers are
stated as major and minor enantiomers with their exact retention
times. Flash chromatography was performed on silica gel, grain size
40–63 µm (Fluka). All reactions were performed under nitrogen in
oven-dried glassware. All reagents were used as purchased, unless
otherwise noted. THF was distilled from sodium/benzophenone,
CH2Cl2 and toluene from CaH2, and MeOH from magnesium. The
reactions were monitored by TLC (Merck 60 F254 plates) and visu-
alized by use of an ethanolic solution of p-anisaldehyde and sul-
Conclusions
We have shown that desymmetrization of the Cs-symmet-
ric hydropentalenones 9a and 9b could be achieved by enan-
tioselective deprotonation with the aid of a chiral base, fol-
lowed by alkylation either in a sequential one-pot fashion furic acid.
or through trapping of the enolates as the triethylsilyl enol
ethers 17a and 17b. In the case of the OTBS-substituted
hydropentalene derivative 9a the direct route turned out to
be superior to the two-step silyl enol ether route with re-
spect to diastereo- and enantioselectivities. In contrast, for
the acetal-substituted hydropentalene derivative 9b the di-
rect route led to inseparable mixtures, whereas the two-step
silyl enol ether route resulted in high diastereoselectivities
and good enantioselectivities. In particular, the allyl-substi-
tuted products can be further functionalized by, for exam-
ple, epoxidation, hydroboration, dihydroxylation, or cross
metathesis and are therefore valuable building blocks for
the tetramic acid lactam family. Application of this method-
ology to the synthesis of more complex hydropentalene sys-
tems is currently in progress in our laboratory.
General Procedure for the Enantioselective Deprotonation/Alkylation
of 9a (GP 1): A solution of nBuLi in hexane (1.6 , 1.95 equiv.)
was added dropwise at –78 °C to a solution of 10 (1 equiv.) in THF
(5 mL). The mixture was allowed to warm to room temperature
until it became a clear yellow solution (1 h). It was recooled to
–100 °C, a solution of 9a (0.7–0.9 equiv.) in THF (5 mL) was added
dropwise, and the reaction mixture was stirred at –100 °C for a
further 1 h. After deprotonation, the reaction mixture was warmed
to –78 °C and treated with the appropriate electrophile (1.1–
2 equiv.). The mixture was stirred at the given temperature for the
given time (Tables 1 and 4). A saturated solution of NaHCO3/H2O
(5 mL) was added, the mixture was allowed to warm to room tem-
perature, and the layers were separated. The organic layer was con-
centrated in vacuo and extracted with Et2O (3ϫ15 mL). The com-
bined extracts were dried (MgSO4) and concentrated in vacuo, and
the residue was chromatographed on SiO2 with hexanes/EtOAc
(20:1) to give the product 12.
General Procedure for the Alkylation of Compounds 9 via Silyl Enol
Ethers 17 (GP 2): A solution of MeLi in Et2O (1.6 , 1.1 equiv.)
was added dropwise at –10 °C to a solution of the appropriate com-
pound 17 (1 equiv.) in THF. The reaction mixture was allowed to
warm to room temperature and stirred for 2 h. It was then cooled
to –45 °C and treated with the corresponding electrophile RX
(2 equiv.). After the mixture had been stirred at –40 °C for 22 h, a
saturated solution of NaHCO3/H2O (5 mL) was added, the mixture
was allowed to warm to room temperature, and the layers were
separated. The organic layer was concentrated in vacuo and ex-
tracted with CH2Cl2. The combined organic extracts were dried
(MgSO4) and concentrated in vacuo, and the residue was chro-
matographed on SiO2 with hexanes/EtOAc to give products 12 or
15.
Experimental Section
Materials and Methods: NMR spectra were recorded with Bruker
Avance 300 or Avance 500 spectrometers in CDCl3 with TMS (δ =
0.00 ppm) as an internal standard. Alternatively, in the case of TBS
ethers, δ is also given relative to the residual non-deuterated signal
for 1H NMR (CHCl3: δ = 7.26 ppm) and relative to the deuterated
solvent signal for 13C NMR (CDCl3: δ = 77.0 ppm). Signals
marked * denote the minor diastereomer. Mass spectra were re-
corded with a Finnigan MAT 95 spectrometer (CI, APCI) with am-
monia as carrier gas, a Varian MAT 711 (EI, 70 eV) and a Bruker
Daltonics micrOTOF Q (ESI) with nitrogen as carrier gas. Optical
rotations were measured with a Perkin–Elmer 241 polarimeter at
20 °C. IR spectra were recorded with a Bruker Vektor 22 FT-IR (1R,3aS,5S,6aS)-5-(tert-Butyldimethylsiloxy)-1-methyl-hexahydro-
spectrometer with an MKII golden-gate single-reflection Diamant
pentalen-2(1H)-one (12a): This compound was prepared according
Table 4. Alkylation of 9a according to the General Procedure.
Starting materials [mmol]
T [°C]
t [h]
Products and yields
% (mmol, mg)
9a
10
nBuLi
RX
12
0.50
0.28
0.30
0.28
0.51
0.30
0.51
0.25
0.25
0.75
0.30
0.33
0.30
0.59
0.45
0.55
0.30
0.30
1.56
0.59
0.64
0.59
1.07
0.89
1.07
0.59
0.59
Me–I
Me–I
Me–I
Me–I
Me–I
0.80
0.64
0.64
0.64
1.00
0.64
1.00
0.50
0.50
–50Ǟ0
–10
–20
–30
–40
–20
–40
–45
–45
6
12a[a]
12a
12a
12a
12a
12a
12b
12c
12d
30 (0.15, 40)
71 (0.20, 54)
40 (0.12, 33)
64 (0.18, 47)
68 (0.34, 90)
63 (0.19, 50)
84 (0.43, 127)
40 (0.10, 31)
24 (0.06, 21)
23
23
23
23
23
23
23
23
Me–I
allyl iodide
prenyl bromide
Bn–Br
[a] Compound 13 was obtained as byproduct in 12% yield.
1152
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1149–1157

Functionalized Hydropentalenes by Asymmetric Deprotonation/Alkylation
to GP 2, from 17a (272 mg, 0.80 mmol) in THF (5 mL), MeLi
(1.6  in Et2O, 0.55 mL, 0.88 mmol), and iodomethane (0.10 mL,
pared according to GP 2, from 17a (339 mg, 1.00 mmol) in THF
(7 mL), MeLi (1.6  in Et2O, 0.69 mL, 1.10 mmol), and 1-bromo-
227 mg, 1.60 mmol), with extraction with Et2O (3ϫ15 mL) and 3-methylbut-2-ene (0.23 mL, 298 mg, 2.00 mmol), with extraction
chromatography with hexanes/EtOAc (20:1); yield: 71.0 mg, with Et2O (3ϫ15 mL) and chromatography with hexanes/EtOAc
0.26 mmol, 33% (dr = 98:2, er = 95:5) as a colorless oil. Rf = 0.48
(30:1); yield: 135 mg, 0.41 mmol, 41% (dr = 97:3) as a colorless oil.
Rf = 0.64 (hexanes/EtOAc, 10:1), [α]2D0 = –11.0 (c = 1.00,
CH2Cl2).[37] 1H NMR (500 MHz, CDCl3): δ = 0.03 [s, 6 H, Si-
(CH3)2], 0.85 [s, 9 H, SiC(CH3)3], 1.53 (dddd, J = 13.4, 5.7, 4.4,
1.4 Hz, 1 H, 4-Ha), 1.59–1.64 (m, 1 H, 6-Ha), 1.61 (s, 3 H, 4Ј-H/
5Ј-H), 1.69 (s, 3 H, 4Ј-H/5Ј-H), 2.02–2.13 (m, 3 H, 1Ј-Ha, 4-Hb, 6-
(hexanes/EtOAc, 10:1), [α]2D0 = –18.0 (c = 1.00, CH2Cl2).[37] tR
=
35.09 min (minor), 35.58 min (major) on Bondex un-β. 1H NMR
(500 MHz, CDCl3): δ = 0.04 [s, 6 H, Si(CH3)2], 0.86 [s, 9 H
SiC(CH3)3], 1.08 (d, J = 7.2 Hz, 3 H, 1Ј-H), 1.52–1.59 (m, 1 H, 6-
Ha), 1.63–1.69 (m, 1 H, 4-Ha), 2.05–2.15 (m, 2 H, 4-Hb, 6-Hb),
2.20–2.27 (m, 1 H, 3a-H), 2.34–2.43 (m, 2 H, 1-H, 3-Ha), 2.48 (dd, Hb), 2.31–2.41 (m, 4 H, 1Ј-Hb, 1-H, 3-Ha, 6a-H), 2.46 (dd, J =
J = 19.1, 9.6 Hz, 1 H, 3-Hb), 2.60–2.68 (m, 1 H, 6a-H), 4.34–4.39
(m, 1 H, 5-H) ppm. 13C NMR (125 MHz, CDCl3): δ = –4.9
[Si(CH3)2], 14.7 (C-1Ј), 18.0 [SiC(CH3)3], 25.8 [SiC(CH3)3], 35.5 (C-
6a), 42.0 (C-4), 43.3 (C-6), 44.3 (C-3), 47.0 (C-3a), 50.1 (C-1), 75.6
18.9, 10.6 Hz, 1 H, 3-Hb), 2.60–2.68 (m, 1 H, 3a-H), 4.32 (dddd, J
= 9.6, 8.3, 5.5, 4.1 Hz, 1 H, 5-H), 5.06–5.13 (m, 1 H, 2ЈЈ-H) ppm.
13C NMR (125 MHz, CDCl3): δ = –5.9 [Si(CH3)2], 16.8 [C-4Ј/C-5Ј,
SiC(CH3)3], 24.9 [C-4Ј/C-5Ј, SiC(CH3)3], 28.1 (C-1Ј), 34.6 (C-3a),
(C-5), 222.2 (C-2) ppm. FT-IR (ATR): ν = 2954 (m), 2928 (m), 41.8 (C-6), 42.5 (C-4), 43.2 (C-1), 44.0 (C-3), 54.7 (C-6a), 74.6 (C-
˜
2856 (m), 1967 (w), 1738 (vs), 1462 (m), 1372 (m), 1253 (m), 1111 5), 120.2 (C-2Ј), 132.5 (C-3Ј), 220.9 (C-2) ppm. FT-IR (ATR): ν =
˜
(m), 1036 (m), 899 (m), 833 (s), 774 (s), 672 (w) cm–1. MS (ESI):
m/z = 269.2 [M + H]+, 251.2, 137.1, 119.1, 109.1, 95.1. HRMS
(ESI): calcd. for C15H29O2Si [M + H]+ 269.1931; found 269.1933.
2954 (m), 2928 (m), 2856 (m), 2252 (w), 1735 (vs), 1471 (w), 1462
(w), 1376 (w), 1254 (s), 1110 (m), 1036 (s), 902 (vs), 834 (s), 773
(s), 730 (vs), 648 (w) cm–1. MS (ESI): m/z = 323.2 [M + H]+, 305.2,
191.1, 173.1, 145.1, 135.1, 105.1. HRMS (ESI): calcd. for
C19H34NaO2Si [M + Na]+ 345.2220; found 345.2219.
(1R,3S,3aR,6aS)-5-(tert-Butyldimethylsilyloxy)-1,3-dimethyl-hexa-
hydropentalen-2(1H)-one (13): Yield: 18.0 mg, 0.06 mmol, 12%. Rf
= 0.56 (hexanes/EtOAc, 10:1). 1H NMR (500 MHz, CDCl3): δ =
0.04 [s, 6 H, Si(CH3)2], 0.85 [s, 9 H SiC(CH3)3], 1.06 (d, J = 6.9 Hz,
6 H, 1Ј-H, 1ЈЈ-H), 1.65–1.71 (m, 2 H, 4-Ha, 6-Ha), 2.04–2.11 (m, 2
H, 4-Hb, 6-Hb), 2.12–2.20 (m, 2 H, 3a-H, 6a-H), 2.46–2.54 (m, 2
H, 1-H, 3-H), 4.37–4.42 (m, 1 H, 5-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = –5.9 [Si(CH3)2], 13.3 (C-1Ј), 17.0 [SiC(CH3)3], 24.8
[SiC(CH3)3], 41.1 (C-4, C-6), 43.5 (C-3a, C-6a), 48.0 (C-1, C-3),
(1R,3aS,5S,6aS)-1-Benzyl-5-(tert-butyldimethylsilyloxy)-hexahydro-
pentalen-2(1H)-one (12d): This compound was prepared according
to GP 2, from 17a (339 mg, 1.00 mmol) in THF (7 mL), MeLi
(1.6  in Et2O, 0.69 mL, 1.10 mmol), and (bromomethyl)benzene
(0.24 mL, 342 mg, 2.00 mmol), with extraction with Et2O
(3ϫ15 mL) and chromatography with hexanes/EtOAc (30:1); yield:
86.0 mg, 0.26 mmol, 26% (dr = 86:14) as a yellow oil. Rf = 0.49
74.9 (C-5), 221.0 (C-2) ppm. FT-IR (ATR): ν = 2954 (m), 2928 (hexanes/EtOAc, 10:1), [α]2D0 = –9.2 (c = 1.00, CH2Cl2).[37] 1H NMR
˜
(m), 2857 (m), 2553 (w), 2370 (w), 1965 (w), 1737 (vs), 1456 (m), (500 MHz, CDCl3): δ = –0.03 [s, 3 H, Si(CH3)2], –0.01 [s, 3 H,
1372 (w), 1254 (s), 1108 (m), 1039 (s), 898 (s), 835 (s), 774 (s) cm–1.
MS (ESI): m/z = 283.2 [M + H]+, 187.1, 151.1, 133.1, 123.1, 107.1,
95.1. HRMS (ESI): calcd. for C16H31O2Si [M + H]+ 283.2088;
found 283.2078.
Si(CH3)2], 0.80 [s, 9 H, SiC(CH3)3], 1.23–1.29 (m, 1 H, 6-Ha), 1.48–
1.56 (m, 1 H, 4-Ha), 1.79 (dddd, J = 13.7, 8.6, 5.6, 0.8 Hz, 1 H, 6-
Hb), 2.04 (dddd, J = 13.7, 8.6, 4.9, 0.8 Hz, 1 H, 4-Hb), 2.35–2.45
(m, 2 H, 3-Ha, 6a-H), 2.45 (dd, J = 18.7, 9.4 Hz, 1 H, 3-Hb), 2.52–
2.63 (m, 1 H, 3a-H), 2.54 (dd, J = 13.6, 9.4 Hz, 1 H, CH2Ph), 2.67–
2.72 (m, 1 H, 1-H), 3.11 (dd, J = 13.6, 4.6 Hz, 1 H, CH2Ph), 4.21–
4.29 (m, 1 H, 5-H), 7.15–7.21 (m, 3 H, o-H, p-H), 7.25–7.30 (m, 2
H, m-H) ppm. 13C NMR (125 MHz, CDCl3): δ = –6.0 [Si(CH3)2],
17.0 [SiC(CH3)3], 24.8 [SiC(CH3)3], 34.6 (C-3a), 35.6 (CH2Ph), 41.1
(C-6), 42.4 (C-4), 43.2 (C-6a), 43.9 (C-3), 55.8 (C-1), 74.7 (C-5),
125.1 (p-C), 127.4, 128.1 (m-C, o-C), 138.9 (i-C), 220.2 (C-2) ppm.
(1R,3aS,5S,6aS)-1-Allyl-5-(tert-butyldimethylsilyloxy)-hexahydro-
pentalen-2(1H)-one (12b): This compound was prepared according
to GP 2, from 17a (271 mg, 0.80 mmol) in THF (5 mL), MeLi
(1.6  in Et2O, 0.55 mL, 0.88 mmol), and 3-iodoprop-1-ene
(0.15 mL, 269 mg, 1.60 mmol), with extraction with Et2O
(3ϫ15 mL) and chromatography with hexanes/EtOAc (10:1); yield:
111 mg, 0.38 mmol, 48% (dr = 99:1) as a pale yellow oil. Rf = 0.52,
[α]2D0 = –14.6 (c = 1.00, CH2Cl2).[37] 1H NMR (500 MHz, CDCl3):
δ = 0.03 [s, 6 H, Si(CH3)2], 0.85 [s, 9 H, SiC(CH3)3], 1.52–1.58 (m,
1 H, 6-Ha), 1.60–1.68 (m, 1 H, 4-Ha), 2.01–2.14 (m, 3 H, 4-Hb, 6-
Hb, 1Ј-Ha), 2.33–2.51 (m, 3 H, 3a-H, 1-H, 1Ј-Hb), 2.37 (ddd, J =
18.9, 5.6, 1.2 Hz, 1 H, 3-Ha), 2.48 (dd, J = 18.9, 9.8 Hz, 1 H, 3-
Hb), 2.60–2.69 (m, 1 H, 6a-H), 4.31–4.36 (m, 1 H, 5-H), 5.00–5.10
(m, 2 H, 3Ј-H), 5.71–5.80 (m, 1 H, 2Ј-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –5.9 [Si(CH3)2], 17.1 [SiC(CH3)3], 24.8
FT-IR (ATR): ν = 2956 (w), 2930 (w), 2856 (w), 2253 (w), 1717
˜
(w), 1471 (w), 1386 (w), 1256 (w), 1103 (w), 1039 (w), 902 (vs), 836
(w), 723 (vs), 649 (m) cm–1. MS (ESI): m/z = 367.2 [M + Na]+,
335.1, 301.1, 289.2, 240.2, 226.2, 136.1, 105.1. HRMS (ESI): calcd.
for C21H32NaO2Si [M + Na]+ 367.2064; found 367.2071.
General Procedure for the Desilylation of 12b–d with TBAF (GP 3):
A solution of TBAF·3H2O (2 equiv.) in THF was added dropwise
at 0 °C to a solution of a compound 12 (1 equiv.) in THF. After
[SiC(CH3)3], 34.3 (C-1Ј), 34.6 (C-6a), 41.9 (C-4), 42.4 (C-6), 43.1 stirring at 0 °C for 30 min, the mixture was allowed to warm to
(C-3a), 44.0 (C-3), 54.2 (C-1), 74.5 (C-5), 115.8 (C-3Ј), 135.0 (C- room temperature and stirred for a further 1 h. A saturated solu-
2Ј), 220.5 (C-2) ppm. FT-IR (ATR): ν = 2953 (m), 2928 (m), 2856
tion of NaHCO3/H2O (5 mL) was added, and the layers were sepa-
rated. The organic layer was concentrated in vacuo and extracted
with CH2Cl2. The combined organic extracts were dried (MgSO4)
and concentrated in vacuo, and the residue was chromatographed
˜
(m), 1965 (w), 1735 (vs), 1641 (w), 1471 (w), 1433 (w), 1408 (w),
1361 (w), 1254 (s), 1111 (s), 1031 (s), 898 (s), 833 (vs), 773 (vs), 702
(w) cm–1. MS (CI): m/z (%) = 589.4 (2) [2 M + H]+, 531.3 (4), 369.2
(8), 295.2 (56) [M + H]+, 237.1 (96), 226.2 (92), 210.1 (100), 191.2 on SiO2 with hexanes/EtOAc (1:1) to give the product 14.
(12), 181.1 (8), 163.1 (41), 145.1 (41), 139.1 (39), 120.1 (9), 105.1
(1R,3aS,5S,6aS)-1-Allyl-5-hydroxy-hexahydropentalen-2(1H)-one
(14b): This compound was prepared according to GP 3, from 12b
(107 mg, 0.36 mmol) in THF (3 mL) and TBAF·3H2O (229 mg,
(49), 91.1 (4), 79.1 (7), 75.0 (9), 69.1 (4). HRMS (ESI): calcd. for
C17H31O2Si [M + H]+ 295.2088; found 295.2083.
(1R,3aS,5S,6aS)-5-(tert-Butyldimethylsilyloxy)-1-(3-methylbut-2- 0.73 mmol) in THF (1.5 mL), with extraction with CH2Cl2
enyl)-hexahydropentalen-2(1H)-one (12c): This compound was pre-
(3ϫ20 mL); yield: 56 mg, 0.31 mmol, 86% (dr = 84:16, er = 97:3)
Eur. J. Org. Chem. 2010, 1149–1157
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1153

V. Lutz, A. Baro, P. Fischer, S. Laschat
FULL PAPER
as a yellow oil. Rf = 0.32, [α]2D0 = –11.2 (c = 1.00, CH2Cl2).[37] tR
=
(1R,3aS,5S,6aS)-1-Benzyl-5-hydroxy-hexahydropentalen-2(1H)-one
(14d): This compound was prepared according to GP 3, from 12d
(215 mg, 0.62 mmol) in THF (5 mL) and TBAF·3H2O (402 mg,
47.09 min (major), 48.43 min (minor) on Amidex C. 1H NMR
(500 MHz, CDCl3): δ = 1.32 (ddd, J = 7.1, 10.3, 13.1 Hz, 0.2 H, 6-
Ha*), 1.48–1.50 (m, 0.2 H, 4-Ha*), 1.51–1.57 (m, 2.2 H, 6-Ha, OH, 1.28 mmol) in THF (3 mL), with extraction with CH2Cl2
OH*), 1.61–1.66 (m, 1 H, 4-Ha), 1.93–2.00 (m, 0.2 H, 1Ј-Hb*), (3ϫ25 mL); yield: 51 mg, 0.22 mmol, 35% (dr = 81:19, er = 91:9)
2.01–2.07 (m, 0.2 H, 6-Hb*), 2.09–2.16 (m, 1.2 H, 1Ј-Ha, 3-Ha*), as a colorless oil. Rf = 0.25, [α]2D0 = –7.6 (c = 1.00, CH2Cl2).[37] tR
2.19–2.26 (m, 2 H, 4-Hb, 6-Hb), 2.29–2.40 (m, 2.4 H, 1-H, 3-Ha, 1- = 33.95 min (major), 34.70 min (minor) on Amidex C. 1H NMR
H*, 4-Hb*), 2.41–2.54 (m, 3.2 H, 3a-H, 1Ј-Hb, 3-Hb, 3a-H*), 2.60– (500 MHz, CDCl3): δ = 1.23–1.28 (m, 1 H, 6-Ha), 1.33–1.43 (m,
2.72 (m, 1.4 H, 6a-H, 1Ј-Hb*, 3-Hb*), 2.76–2.84 (m, 0.2 H, 6a-H*), 1.3 H, OH, 6-Ha*), 1.46–1.57 (m, 1.6 H, 4-Ha, OH*, 4-Ha*), 1.96
4.37–4.46 (m, 1.2 H, 5-H, 5-H*), 5.00–5.11 (m, 2.4 H, 3Ј-Ha, 3Ј-
Hb, 3Ј-Ha*, 3Ј-Hb*), 5.76 (dddd, J = 6.6, 7.5, 10.2, 14.2 Hz, 1 H,
2Ј-H), 5.82 (dddd, J = 5.8, 7.7, 10.1, 13.5 Hz, 0.2 H, 2Ј-H*) ppm.
13C NMR (125 MHz, CDCl3): δ = 30.8 (C-1Ј*), 35.3 (C-1Ј), 35.8
(C-6a), 36.5 (C-6*), 42.2 (C-6a*), 42.4 (C-4, C-4*), 43.0 (C-6), 44.0
(C-3a, C-1*), 44.6 (C-3*), 44.7 (C-3), 52.5 (C-3a*), 55.2 (C-1), 74.2
(C-5*), 75.1 (C-5), 115.9 (C-3Ј*), 116.9 (C-3Ј), 135.7 (C-2Ј), 136.5
(dddd, J = 13.9, 8.6, 6.3, 0.9 Hz, 1 H, 6-Hb), 2.05–2.10 (m, 0.3 H,
6-Hb*), 2.15–2.23 (m, 1 H, 4-Hb), 2.24–2.31 (m, 0.3 H, 4-Hb*), 2.36
(ddd, J = 18.9, 4.9, 1.5 Hz, 1 H, 3-Ha), 2.38–2.48 (m, 1.6 H, 6a-H,
6a-H*, 1Ј-Ha*), 2.47 (dd, J = 18.9, 9.8 Hz, 1 H, 3-Hb), 2.53–2.73
(m, 3.9 H, 1-H, 3a-H, 1Ј-Ha, 3a-H*, 3-Ha*, 3-Hb*), 2.75–2.81 (m,
0.3 H, 1-H*), 3.13 (dd, J = 12.8, 3.7 Hz, 1 H, 1Ј-Hb), 3.29 (dd, J
= 14.3, 3.9 Hz, 0.3 H, 1Ј-Hb*), 4.30–4.40 (m, 1.3 H, 5-H, 5-H*),
(C-2Ј*), 218.7 (C-2*), 221.1 (C-2) ppm. FT-IR (ATR): ν = 3412 7.15–7.31 (m, 6.5 H, o-H, o*-H, m-H, m*-H, p-H, p*-H) ppm. 13
C
˜
(br), 2930 (m), 2183 (w), 1969 (w), 1728 (s), 1641 (w), 1436 (w), NMR (125 MHz, CDCl3): δ = 32.4 (C-1Ј*), 35.1 (C-3a*), 35.7 (C-
1264 (s), 1170 (w), 1088 (w), 993 (w), 915 (m), 732 (vs), 703 (vs)
cm–1. MS (EI): m/z (%) = 180.1 (70) [M]+, 162.1 (100), 147.1 (27),
133.1 (43), 121.1 (59), 105.1 (22), 93.1 (41), 79.0 (55), 67.1 (45),
3a), 36.5 (C-1Ј, C-3*), 36.9 (C-6*), 42.2 (C-6), 42.3 (C-6a*), 42.8
(C-4), 44.1 (C-6a), 44.4 (C-4*), 44.5 (C-3), 54.9 (C-1*), 57.0 (C-1),
74.2 (C-5*), 75.0 (C-5), 126.0 (C-p*), 126.2 (C-p), 128.4, 128.5,
55.1 (15), 41.0 (40). HRMS (ESI): calcd. for C11H16O2Na [M + 129.1 (C-o, C-o*, C-m, C-m*), 139.5 (C-i), 140.4 (C-i*), 218.2 (C-
Na]+ 203.1043; found 203.1039.
2*), 220.6 (C-2) ppm. FT-IR (ATR): ν = 3410 (br), 2929 (m), 2857
˜
(w), 2369 (w), 2188 (w), 1973 (w), 1730 (s), 1495 (w), 1454 (w),
1264 (m), 1176 (w), 1068 (w), 983 (w), 734 (vs), 701 (vs) cm–1. MS
(EI): m/z (%) = 230.1 (100) [M]+, 212.1 (46), 197.1 (4), 184.1 (25),
171.1 (25), 146.1 (23), 129.1 (10), 121.1 (13), 91.0 (67). HRMS
(ESI): calcd. for C15H18O2Na [M + Na]+ 253.1199; found 253.1198.
This compound was also prepared according to GP 3, from 12b
prepared via 17a (100 mg, 0.34 mmol) in THF (3 mL) and
TBAF·3H2O (214 mg, 0.68 mmol) in THF (1.5 mL), with extrac-
tion with CH2Cl2 (3ϫ20 mL) to afford 14b (55 mg, 0.31 mmol,
90%, dr = 81:19, er = 91:9) as a yellow oil. [α]2D0 = –10.0 (c = 1.00,
CH2Cl2).[37]
This compound was also prepared according to GP 3 from 12d
prepared via 17a (47.0 mg, 0.14 mmol) in THF (2 mL) and
TBAF·3H2O (110 mg, 0.35 mmol) in THF (1 mL), with extraction
with CH2Cl2 (3ϫ10 mL) to afford 14d (30.0 mg, 0.13 mmol, 93%,
dr = 84:16, er = 76:24) as a colorless oil. [α]2D0 = –6.2 (c = 1.00,
CH2Cl2).[37]
(1R,3aS,5S,6aS)-5-Hydroxy-1-(3-methylbut-2-enyl)-hexahydropent-
alen-2(1H)-one (14c): This compound was prepared according to
GP 3, from 12c (121 mg, 0.36 mmol) in THF (3 mL) and TBAF·
3H2O (230 mg, 0.73 mmol) in THF (1.5 mL), with extraction with
CH2Cl2 (3ϫ15 mL); yield: 58 mg, 0.28 mmol, 78% (dr = 86:14, er
= 94:6) as a colorless oil. Rf = 0.38, [α]2D0 = –9.6 (c = 1.00,
CH2Cl2).[37] tR = 23.63 min (major), 25.18 min (minor) on Bon-
dex un-β. 1H NMR (500 MHz, CDCl3): δ = 1.27–1.34 (ddd, J =
7.0, 10.2, 13.0 Hz, 0.2 H, 6-Ha*), 1.44–1.55 (m, 2.4 H, 6-Ha, OH,
4-Ha*, OH*), 1.58–1.64 (m, 4.6 H, CH3, CH3*, 4-Ha), 1.70 (s, 3.6
(3aЈS,4ЈR,6aЈR)-4Ј,5,5-Trimethyl-tetrahydro-1ЈH-spiro[[1,3]-diox-
ane-2,2Ј-pentalen]-5Ј(3ЈH)-one (15a): This compound was prepared
according to GP 2, from 17b (67.7 mg, 0.20 mmol), MeLi (1.6 
in Et2O, 138 µL, 0.22 mmol), and iodomethane (25.0 µL, 57.0 mg,
0.40 mmol), with chromatography (hexanes/EtOAc, 10:1); yield:
H, CH3, CH3*), 1.88–1.96 (m, 0.2 H, 1Ј-Ha*), 1.98–2.04 (m, 0.2 H, 23.0 mg, 0.10 mmol, 50% (dr = 93:7, er = 94:6) as a colorless oil.
6-Hb*), 2.08–2.15 (m, 2.2 H, 4-Hb, 6-Hb, 3-Ha*), 2.27–2.45 (m, 4.4
Rf = 0.40 (hexanes/EtOAc, 5:1), [α]2D0 = –16.2 (c = 1.00, CH2Cl2).[37]
H, 1-H, 1Ј-Hb, 3a-H, 3-Ha, 1-H*, 4-Hb*), 2.46–2.55 (m, 1.2 H, 3- tR = 48.86 min (minor), 49.24 min (major) on Amidex C. 1H NMR
Hb, 3a-H*), 2.59–2.70 (m, 1.4 H, 6a-H, 1Ј-Hb*, 3-Hb*), 2.73–2.81 (500 MHz, CDCl3): δ = 0.89 [s, 3 H, C(CH3)2], 0.91 [s, 3 H,
(m, 0.2 H, 6a-H*), 4.36–4.45 (m, 1.2 H, 5-H, 5-H*), 5.05–5.13 (m, C(CH3)2], 1.00 (d, J = 6.7 Hz, 3 H, 1ЈЈ-H), 1.66 (ddd, J = 13.7, 8.3,
1.2 H, 2Ј-H, 2Ј-H*) ppm. 13C NMR (125 MHz, CDCl3): δ = 17.8 1.0 Hz, 1 H, 1Ј-Ha), 1.88–1.94 (m, 1 H, 3Ј-Ha), 2.07–2.13 (m, 1 H,
(CH3*), 17.9 (CH3), 25.1 (C-1Ј*), 25.79 (CH3*), 25.82 (CH3), 29.0 4Ј-H), 2.16–2.24 (m, 3 H, 3Ј-Hb, 3aЈ-H, 6Ј-Ha), 2.31 (ddd, J = 13.8,
(C-1Ј), 25.8 (C-6a), 36.7 (C-6*), 42.3 (C-6a*), 42.4 (C-4), 42.9 (C- 8.6, 1.1 Hz, 1 H, 1Ј-Hb), 2.38 (dd, J = 19.1, 9.2 Hz, 1 H, 6Ј-Hb),
6), 44.1 (C-3a, C-1*), 44.6 (C-3), 44.7 (C-3*), 53.3 (C-3a*), 55.8
(C-1), 74.3 (C-5*), 75.1 (C-5), 121.1 (C-2Ј), 121.9 (C-2Ј*), 132.7 (C-
3Ј*), 133.5 (C-3Ј), 221.1 (C-2Ј), 221.5 (C-2Ј*) ppm. FT-IR (ATR):
2.64–2.73 (m, 1 H, 6aЈ-H), 3.39 (s, 2 H, OCH2), 3.43 (s, 2 H, OCH2)
ppm. 13C NMR (125 MHz, CDCl3): δ = 13.2 (C-1ЈЈ), 21.4
[C(CH3)2], 29.1 [C(CH3)2], 33.7 (C-6aЈ), 39.4 (C-3Ј), 40.2 (C-1Ј),
42.2 (C-6Ј), 44.8 (C-3aЈ), 48.0 (C-4Ј), 71.0 (OCH2), 71.3 (OCH2),
ν = 3409 (br), 2927 (m), 2548 (w), 2368 (w), 2181 (w), 1965 (w),
˜
1729 (s), 1436 (w), 1264 (s), 1175 (w), 1088 (w), 984 (w), 915 (m), 109.2 (C-2Ј), 220.5 (C-5Ј) ppm. FT-IR (ATR): ν = 2954 (br), 2932
˜
732 (vs), 703 (vs) cm–1. MS (EI): m/z (%) = 208.1 (100) [M]+, 190.1
(21), 175.1 (34), 163.1 (19), 147.1 (17), 140.1 (36), 122.1 (49), 109.1
(br), 2869 (w), 1967 (br), 1734 (s), 1644 (w), 1454 (w), 1314 (m),
1111 (s), 1040 (w), 1006 (m), 990 (m), 814 (br), 764 (m), 701 (m)
(32), 95.1 (37), 82.0 (19), 69.1 (34), 41.0 (44). HRMS (ESI): calcd. cm–1. MS (ESI): m/z = 239.2 [M + H]+, 153.1, 135.1, 107.1, 95.0.
for C13H20O2Na [M + Na]+ 231.1356; found 231.1358.
HRMS (ESI): calcd. for C14H23O3 [M + H]+ 239.1642; found
239.1647.
This compound was also prepared according to GP 3 from 12c
prepared via 17a (125 mg, 0.38 mmol) in THF (3 mL) and (3aЈS,4ЈR,6aЈR)-4Ј-Allyl-5,5-dimethyl-tetrahydro-1ЈH-spiro-[[1,3]di-
TBAF·3H2O (237 mg, 0.75 mmol) in THF (1.5 mL), with extrac-
tion with CH2Cl2 (3ϫ15 mL) to afford 14c (67 mg, 0.32 mmol,
85%, dr = 84:16, er = 88:12) as a colorless oil. [α]2D0 = –8.8 (c =
1.00, CH2Cl2).[37]
oxane-2,2Ј-pentalen]-5Ј(3ЈH)-one (15b): This compound was pre-
pared according to GP 2, from 17b (67.7 mg, 0.20 mmol), MeLi
(1.6  in Et2O, 138 µL, 0.22 mmol), and 3-iodoprop-1-ene (37.0
µL, 68.0 mg, 0.40 mmol), with chromatography (hexanes/EtOAc,
1154
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1149–1157

Functionalized Hydropentalenes by Asymmetric Deprotonation/Alkylation
10:1); yield: 37.0 mg, 0.14 mmol, 70% (dr = 95:5, er = 92:8) as a
colorless oil. Rf = 0.43 (hexanes/EtOAc, 5:1), [α]2D0 = –13.6 (c =
1.00, CH2Cl2).[37] tR = 58.41 min (major), 60.18 min (minor) on
pared as in GP 2, from 17b (67.7 mg, 0.20 mmol), MeLi (1.6  in
Et2O, 138 µL, 0.22 mmol), and (bromomethyl)benzene (48.0 µL,
68.4 mg, 0.40 mmol), with chromatography (hexanes/EtOAc, 10:1);
Amidex C. 1H NMR (500 MHz, CDCl3): δ = 0.96 [s, 6 H, yield: 21.0 mg, 0.07 mmol, 35% (dr = 96:4, er = 91:9) as a colorless
C(CH3)2], 1.73 (ddd, J = 13.7, 7.6, 1.2 Hz, 1 H, 3Ј-Ha), 1.92 (ddd, oil. Rf = 0.38 (hexanes/EtOAc, 5:1), [α]2D0 = –20.8 (c = 1.00,
J = 13.7, 4.3, 1.2 Hz, 1 H, 1Ј-Ha), 2.09–2.16 (m, 1 H, 1ЈЈ-Ha), 2.20–
CH2Cl2).[37] tR = 55.14 min (major), 55.73 min (minor) on Bon-
2.25 (m, 2 H, 4Ј-H, 6Ј-Ha), 2.28 (ddd, J = 13.7, 8.6, 1.4 Hz, 1 H, dex un-β. 1H NMR (500 MHz, CDCl3): δ = 0.82 [s, 3 H, C(CH3)2],
1Ј-Hb), 2.34 (ddd, J = 13.7, 8.6, 1.4 Hz, 1 H, 3Ј-Hb), 2.41–2.52 (m,
3 H, 1ЈЈ-Hb, 6Ј-Hb, 6aЈ-H), 2.70–2.79 (m, 1 H, 3aЈ-H), 3.44 (s, 2 H,
0.87 [s, 3 H, C(CH3)2], 1.49–1.53 (m, 1 H, 3Ј-Ha), 1.61 (ddd, J =
13.7, 7.8, 1.1 Hz, 1 H, 1Ј-Ha), 1.92 (ddd, J = 14.1, 8.3, 1.4 Hz, 1 H,
OCH2), 3.49 (s, 2 H, OCH2), 5.02–5.09 (m, 2 H, 3ЈЈ-Ha, 3ЈЈ-Hb), 3Ј-Hb), 2.16–2.22 (m, 1 H, 6Ј-Ha), 2.24 (ddd, J = 13.8, 8.7, 1.3 Hz,
5.74 (dddd, J = 14.1, 10.2, 7.5, 6.7 Hz, 1 H, 2ЈЈ-H) ppm. 13C NMR 1 H, 1Ј-Hb), 2.30–2.35 (m, 3 H, 3aЈ-H, 4Ј-H, 6Ј-Hb), 2.37 (dd, J =
(125 MHz, CDCl3): δ = 22.4 [C(CH3)2], 30.1 [C(CH3)2], 34.7 (C- 13.8, 8.7 Hz, 1 H, CH2Ph), 2.43–2.54 (m, 1 H, 6aЈ-H), 3.03 (dd, J
1ЈЈ, C-3aЈ), 40.9 (C-1Ј), 41.3 (C-3Ј), 42.8 (C-6aЈ), 43.9 (C-6Ј), 54.0
(C-4Ј), 72.0 (OCH2), 72.2 (OCH2), 109.7 (C-2Ј), 117.0 (C-3ЈЈ), (m, 2 H, o-H), 7.11–7.15 (m, 1 H, p-H), 7.19–7.23 (m, 2 H, m-H)
135.5 (C-2ЈЈ), 220.6 (C-5Ј) ppm. FT-IR (ATR): ν = 3077 (w), 2953
ppm. 13C NMR (125 MHz, CDCl3): δ = 21.3 [C(CH3)2], 21.4
= 13.8, 4.2 Hz, 1 H, CH2Ph), 3.20–3.39 (m, 4 H, OCH2), 7.07–7.10
˜
(br), 2857 (m), 1736 (vs), 1641 (w), 1473 (m), 1436 (m), 1396 (w), [C(CH3)2], 29.0 [C(CH3)2], 33.6 (C-6aЈ), 35.1 (CH2Ph), 36.3 (C-3Ј),
1378 (m), 1260 (w), 1213 (w), 1167 (w), 1113 (vs), 1040 (w), 1007 40.5 (C-1Ј), 41.9 (C-3aЈ), 42.7 (C-6Ј), 55.0 (C-4Ј), 70.9 (OCH2), 71.1
(m), 910 (s), 794 (w), 737 (w) cm–1. MS (ESI): m/z = 265.2 [M +
H]+, 179.1, 161.1, 151.1, 137.1, 121.1, 109.1, 91.1. HRMS (ESI):
calcd. for C16H25O3 [M + H]+ 265.1798; found 265.1792.
(OCH2), 108.7 (C-2Ј), 125.3 (C-p), 127.5 (C-o), 128.2 (C-m), 138.4
(C-i), 219.3 (C-5Ј) ppm. FT-IR (ATR): ν = 3027 (w), 2952 (m),
˜
2931 (m), 2857 (m), 1736 (s), 1603 (w), 1455 (w), 1396 (w), 1327
(w), 1112 (s), 1015 (w), 701 (m) cm–1. MS (ESI): m/z = 315.2 [M +
H]+, 301.1, 229.1, 211.1, 171.1, 147.1, 91.1. HRMS (ESI): calcd.
for C20H26NaO3 [M+ + Na] 337.1774; found 337.1771.
Byproduct 16b: Yield: 30% (19.0 mg, 0.06 mmol, dr = 97:3). Rf =
1
0.61 (hexanes/EtOAc, 5:1). H NMR (500 MHz, CDCl3): δ = 0.90
[s, 6 H, C(CH3)2], 1.75–1.81 (m, 2 H, 1Ј-Ha, 3Ј-Ha), 1.96–2.04 (m,
2 H, 1ЈЈ-Ha), 2.21–2.28 (m, 4 H, 1Ј-Hb, 3Ј-Hb 4Ј-H, 6Ј-H), 2.31–
2.42 (m, 4 H, 3aЈ-H, 1ЈЈ-Hb, 6aЈ-H), 3.38 (s, 3 H, OCH2), 3.42 (s,
3 H, OCH2), 4.94–5.02 (m, 4 H, 3ЈЈ-Ha, 3ЈЈ-Hb), 5.62–5.71 (m, 2
H, 2ЈЈ-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.4 [C(CH3)2],
29.1 [C(CH3)2], 33.3 (C-1ЈЈ), 39.6 (C-3aЈ, C-6aЈ), 39.9 (C-1Ј, C-3Ј),
52.6 (C-4Ј, C-6Ј), 70.9 (OCH2), 71.3 (OCH2), 108.7 (C-2Ј), 115.9
(2S,3aS,6aS)-tert-Butyldimethyl-5-(triethylsilyloxy)-1,2,3,3a,4,6a-
hexahydropentalen-2-yloxysilane (17a): Deprotonation was carried
out according to GP 1, from 10 (81.8 mg, 0.30 mmol) in THF
(5 mL), nBuLi (1.6  in hexanes, 370 µL, 0.59 mmol), and 9a
(70.0 mg, 0.28 mmol) in THF (3 mL). After stirring at –100 °C for
1 h, the mixture was warmed to –78 °C, treated with ClSiEt3
(100 µL, 89.0 mg, 0.60 mmol), and stirred for a further 30 min. A
saturated solution of NaHCO3/H2O (5 mL) was added, the reac-
tion mixture was allowed to warm to room temperature, and the
layers were separated. The organic layer was concentrated in vacuo
and extracted with Et2O (3ϫ20 mL). The combined organic ex-
tracts were dried (MgSO4) and concentrated in vacuo, and the resi-
due was chromatographed on SiO2 with hexanes/EtOAc/NEt3
(20:1:1) to give 17a (65.0 mg, 0.18 mmol, 64%) as a colorless oil.
Rf = 0.52 (hexanes/EtOAc, 20:1). [α]2D0 = –3.5 (c = 1.00, CH2Cl2),
[α]2D0 = –5.2 (c = 13.2, THF). 1H NMR (500 MHz, CDCl3): δ =
0.04 [s, 6 H, Si(CH3)2], 0.67 [q, J = 8.0 Hz, 6 H, Si(CH2CH3)3],
0.88 [s, 9 H, SiC(CH3)3], 0.97 [t, J = 8.0 Hz, 9 H, Si(CH2CH3)3],
1.20–1.26 (m, 1 H, 1-Ha), 1.35 (dt, J = 12.0, 9.6 Hz, 1 H, 3-Ha),
2.02–2.10 (m, 3 H, 1-Hb, 3-Hb, 4-Ha), 2.39–2.47 (m, 1 H, 3a-H),
2.53 (ddt, J = 15.9, 9.6, 1.9 Hz, 1 H, 4-Hb), 2.85–2.92 (m, 1 H, 6a-
H), 4.03 (dddd, J = 12.3, 9.3, 6.3, 5.8 Hz, 1 H, 2-H), 4.61–4.63 (m,
1 H, 6-H) ppm. 1 3 C NMR (125 MHz, CDCl3 ): δ = –5.7
[Si(CH3)2], 3.7 [Si(CH2CH3)3], 5.6 [Si(CH2CH3)3], 17.2 [SiC-
(CH3)3], 24.9 [SiC(CH3)3], 34.3 (C-3a), 39.4 (C-4), 41.2 (C-1), 42.3
(C-3), 42.4 (C-6a), 73.0 (C-2), 106.1 (C-6), 151.5 (C-5) ppm. FT-
(C-3ЈЈ), 134.8 (C-2ЈЈ), 219.2 (C-5Ј) ppm. FT-IR (ATR): ν = 3077
˜
(w), 2954 (br), 2930 (br), 2857 (m), 1963 (br), 1733 (s), 1640 (w),
1472 (m), 1436 (m), 1395 (w), 1329 (w), 1217 (w), 1109 (s), 1045
(w), 1004 (m), 910 (s), 870 (w), 804 (w) cm–1. MS (ESI): m/z =
305.2 [M + H]+, 219.1, 201.1, 191.1, 177.1, 161.1, 149.1, 133.1,
119.1, 107.1. HRMS (ESI): calcd. for C19H29O3 [M + H]+
305.2111; found 305.2104.
(3aЈS,4ЈR,6aЈR)-5,5-Dimethyl-4Ј-(3-methylbut-2-enyl)-tetrahydro-
1ЈH-spiro[[1,3]dioxane-2,2Ј-pentalen]-5Ј(3ЈH)-one (15c): This com-
pound was prepared according to GP 2, from 17b (67.7 mg,
0.20 mmol), MeLi (1.6  in Et2O, 138 µL, 0.22 mmol), and 1-
bromo-3-methylbut-2-ene (46.0 µL, 59.6 mg, 0.40 mmol), with
chromatography (hexanes/EtOAc, 20:1); yield: 38.0 mg, 0.13 mmol,
65% (dr = 98:2) as a colorless oil. Rf = 0.48 (hexanes/EtOAc, 5:1),
[α]2D0 = –18.4 (c = 1.00, CH2Cl2).[37] 1H NMR (500 MHz, CDCl3):
δ = 0.89 [s, 3 H, C(CH3)2], 0.91 [s, 3 H, C(CH3)2], 1.54 (s, 3 H, 4ЈЈ-
H/5ЈЈ-H), 1.63 (s, 3 H, 4ЈЈ-H/5ЈЈ-H), 1.61–1.66 (m, 1 H, 3Ј-Ha), 1.85
(dd, J = 13.7, 4.5 Hz, 1 H, 1Ј-Ha), 2.01–2.13 (m, 2 H, 1ЈЈ-Ha, 4Ј-
H), 2.14–2.23 (m, 2 H, 3Ј-Hb, 6Ј-Ha), 2.24–2.32 (m, 1 H, 1Ј-Hb),
2.29 (ddd, J = 13.7, 8.5, 1.2 Hz, 1 H, 1ЈЈ-Hb), 2.33–2.41 (m, 1 H,
6aЈ-H), 2.37 (dd, J = 19.0, 9.4 Hz, 1 H, 6Ј-Hb), 2.62–2.71 (m, 1 H,
3aЈ-H), 3.38 (s, 2 H, OCH2), 3.42 (s, 2 H, OCH2), 4.98–5.03 (m,
1 H, 2ЈЈ-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 16.8 (C-4ЈЈ/C-
5ЈЈ), 21.4 [C(CH3)2], 24.8 (C-4ЈЈ/C-5ЈЈ), 27.5 (C-1ЈЈ), 29.0
[C(CH3)2], 33.8 (C-3aЈ), 40.0 (C-1Ј, C-3Ј), 41.8 (C-6aЈ), 42.8 (C-6Ј),
53.6 (C-4Ј), 70.9 (OCH2), 71.3 (OCH2), 108.8 (C-2Ј), 199.9 (C-2ЈЈ),
IR (ATR): ν = 2953 (m), 2929 (m), 2878 (m), 2857 (m), 1973 (w),
˜
1644 (s), 1461 (m), 1361 (m), 1342 (m), 1326 (m), 1243 (s), 1190
(m), 1110 (vs), 1005 (s), 898 (s), 834 (vs), 773 (s), 744 (s), 729 (s)
cm–1. MS (EI): m/z (%) = 368.2 (5) [M]+, 353.2 (2), 311.2 (100),
237.1 (1), 209.1 (4), 115.1 (4), 87.1 (9), 75.0 (5), 59.0 (4). HRMS
(ESI): calcd. for C20H41O2Si2 [M + H]+ 369.2640; found 369.2631.
132.7 (C-3ЈЈ), 220.0 (C-5Ј) ppm. FT-IR (ATR): ν = 2952 (m), 2930
˜
(3aЈR,6aЈS)-5,5-Dimethyl-3Ј,3aЈ,4Ј,6aЈ-tetrahydro-1ЈH-spiro-[[1,3]-
dioxane-2,2Ј-pentalen]-5Ј-yloxytriethylsilane (17b):[34b] This com-
pound was prepared as described above for 17a, from 10 (5.11 g,
19.5 mmol) in THF (150 mL), nBuLi (1.6  in hexane, 23.8 mL,
38.0 mmol), 9b (3.37 g, 15.0 mmol) in THF (15 mL), ClSiEt3
(5.04 mL, 30.0 mmol), and a saturated solution of NaHCO3/H2O
(10 mL), with extraction with CH2Cl2 (3ϫ75 mL) and chromatog-
raphy on SiO2 with hexanes/EtOAc/NEt3 (50:1:1); yield: 4.43 g
(m), 2856 (m), 1966 (w), 1735 (s), 1472 (br), 1395 (w), 1352 (w),
1327 (w), 1215 (w), 1175 (w), 1111 (s), 1040 (w), 1007 (w), 824 (br),
766 (w), 701 (w) cm–1. MS (ESI): m/z = 293.2 [M + H]+, 275.2,
207.1, 189.1, 171.1, 151.1, 131.1, 107.1. HRMS (ESI): calcd. for
C18H28NaO3 [M + Na]+ 315.1931; found 315.1927.
(3aЈS,4ЈR,6aЈR)-4Ј-Benzyl-5,5-dimethyl-tetrahydro-1ЈH-spiro-[[1,3]-
dioxane-2,2Ј-pentalen]-5Ј(3ЈH)-one (15d): This compound was pre-
Eur. J. Org. Chem. 2010, 1149–1157
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1155

V. Lutz, A. Baro, P. Fischer, S. Laschat
FULL PAPER
[3] V. Shingi, G. Chandra, S. M. Mobin, Synlett 2008, 3111–3114.
[4] D. Schinzer, in Organic Synthesis Highlights II (Ed.: H. Wald-
mann), VCH, Weinheim, 1995, p. 301–307.
[5] S. Kanazawa, N. Fusetani, S. Matsunaga, Tetrahedron Lett.
1993, 34, 1065–1068.
[6] H. Shigemori, M.-A. Bae, K. Yazawa, T. Sasaki, J. Kobayashi,
J. Org. Chem. 1992, 57, 4317–4320.
[7] M.-A. Bae, K. Yamada, Y. Ijuin, T. Tsuji, K. Yazawa, Y. To-
mono, D. Uemura, Heterocycl. Commun. 1996, 2, 315–318.
[8] a) R. J. Capon, Eur. J. Org. Chem. 2001, 633–645; b) R. J. Ca-
pon, C. Skene, E. Lacey, J. H. Gill, D. Wadsworth, T. Friedel,
J. Nat. Prod. 1999, 62, 1256–1259.
(13.1 mmol, 87%) as a pale yellow oil. Rf = 0.82 (hexanes/EtOAc,
5:1). [α]2D0 = +0.2 (c = 1.00, CH2Cl2), [α]2D0 = +2.1 (c = 9.8, THF).
1H NMR (500 MHz, CDCl3): δ = 0.60 [q, J = 7.9 Hz, 6 H,
Si(CH2CH3)3], 0.90 [t, J = 7.9 Hz, 9 H, Si(CH2CH3)3], 0.90 [s, 6 H,
C(CH3)2], 1.42–1.51 (m, 2 H, 1Ј-Ha, 3Ј-Ha), 1.92–1.98 (m, 1 H, 3Ј-
Hb), 2.20–2.33 (m, 2 H, 1Ј-Hb, 4Ј-Ha), 2.45–2.60 (m, 2 H, 4Ј-Hb,
3aЈ-H), 2.96–3.04 (m, 1 H, 6aЈ-H), 3.38 (s, 2 H, OCH2), 3.42 (s, 2
H, OCH2), 4.53–4.56 (m, 1 H, 6Ј-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 3.7 [Si(CH2CH3)3], 5.7 [Si(CH2CH3)3], 21.6
[C(CH3)2], 29.1 [C(CH3)2], 34.5 (C-3aЈ), 38.9 (C-3Ј), 39.1 (C-4Ј),
40.2 (C-1Ј), 42.1 (C-6aЈ), 70.4 (OCH2), 71.8 (OCH2), 106.1 (C-6Ј),
[9] Reviews on hydropentalene syntheses: a) R. Haag, A. de Mei-
jere, Top. Curr. Chem. 1998, 196, 137–165; b) E. Negishi, Pure
Appl. Chem. 1992, 64, 323–334; c) T. Hudlicky, G. Sinai-
Zingde, M. G. Natchus, B. C. Ranu, P. Papadopolous, Tetrahe-
dron 1987, 43, 5685–5721; d) M. Demuth in Modern Synthetic
Methods (Ed.: R. Scheffold), Springer, Berlin, 1986, vol. 4, pp.
89–124; e) S. V. Ley, Chem. Ind. (London, U.K.) 1985, 101–106.
[10] M. Nagai, J. Lazor, C. S. Wilcox, J. Org. Chem. 1990, 55, 3440–
3442.
107.8 (C-2Ј), 151.7 (C-5Ј) ppm. FT-IR (ATR): ν = 3059 (w), 2953
˜
(m), 2913 (w), 2876 (m), 2851 (w), 1644 (s), 1461 (w), 1322 (s), 1248
(s), 1192 (s), 1113 (vs), 1004 (s), 927 (m), 814 (s), 746 (s) cm–1. MS
(ESI): m/z = 339.3 [M + H]+, 253.2, 235.2, 195.1, 133.1, 115.1.
HRMS (ESI): calcd. for C19H35O3Si [M + H]+ 339.2350; found
339.2354.
(3aЈS,4ЈR,5ЈR,6aЈR)-5,5-Dimethyl-4Ј-(3-methylbut-2-enyl)-hexahy-
dro-1ЈH-spiro-[[1,3]dioxane-2,2Ј-pentalen]-5Ј-ol (18): NaBH4 (27.0
mg, 0.72 mmol) was added dropwise at 0 °C to a solution of 15c
(70.0 mg, 0.24 mmol) in MeOH (3 mL). After the system had been
stirred at 0 °C for 1.5 h, H2O (1.5 mL) was added and the mixture
was allowed to warm to room temperature. The mixture was ex-
tracted with CH2Cl2 (3ϫ10 mL) and the combined extracts were
washed with brine (5 mL), dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed on SiO2 with hexanes/
EtOAc (10:1) to give 18 (65.0 mg, 0.22 mmol, 92%, dr Ͼ 99:1, er
= 82.5:17.5) as a colorless oil. Rf = 0.21 (hexanes/EtOAc, 5:1),
[α]2D0 = –16.9 (c = 0.80, CH2Cl2). tR = 105.66 min (major), 106.66
[11] a) A. G. Griesbeck, Synthesis 1990, 144–147; b) A. G. Gries-
beck, J. Org. Chem. 1989, 54, 4981–4982.
[12]
a) U. H. Brinker, I. Fleischhauer, Tetrahedron 1981, 37, 4495–
4502; b) U. H. Brinker, I. Fleischhauer, Angew. Chem. 1980, 92,
314–315; Angew. Chem. Int. Ed. Engl. 1980, 18, 396–397.
A. Becheanu, A. Baro, S. Laschat, W. Frey, Eur. J. Org. Chem.
2006, 2215–2252.
A. Heumann, S. Kaldy, A. Tenaglia, J. Chem. Soc., Chem.
Commun. 1993, 420–422.
L. A. Paquette, W. E. Fristad, D. S. Dime, T. R. Bailey, J. Org.
Chem. 1980, 45, 3017–3028.
A. J. Phillips, A. C. Hart, J. A. Henderson, Tetrahedron Lett.
2006, 47, 3743–3745.
T. Anderl, M. Emo, S. Laschat, A. Baro, W. Frey, Synthesis
2008, 1619–1627.
C. Oger, Y. Brinkmann, S. Bouazzaoui, T. Durand, J.-M. Gal-
ano, Org. Lett. 2008, 10, 5087–5090.
a) N. Cramer, M. Buchweitz, S. Laschat, W. Frey, A. Baro, D.
Mathieu, C. Richter, H. Schwalbe, Chem. Eur. J. 2006, 12,
2488–2503; b) N. Cramer, S. Laschat, A. Baro, H. Schwalbe,
C. Richter, Angew. Chem. 2005, 117, 831–833; Angew. Chem.
Int. Ed. 2005, 44, 820–822.
[13]
[14]
[15]
[16]
[17]
[18]
[19]
1
min (minor) on Amidex C. H NMR (500 MHz, CDCl3): δ = 0.87
[s, 3 H, C(CH3)2], 0.91 [s, 3 H, C(CH3)2], 1.35 (ddd, J = 17.5, 12.3,
8.7 Hz, 1 H, 6Ј-Ha), 1.52–1.56 (m, 1 H, 4Ј-Ha), 1.55 [s, 3 H, 4ЈЈ-H],
1.64 [s, 3 H, 5ЈЈ-H], 1.68 (ddd, J = 13.3, 6.5, 1.2 Hz, 1 H, 1Ј-Ha),
1.74 (ddd, J = 13.1, 5.6, 1.2 Hz, 1 H, 3Ј-Ha), 1.90–1.97 (m, 1 H,
1ЈЈ-Ha), 2.01 (ddd, J = 9.8, 8.4, 5.6 Hz, 1 H, 3aЈ-H), 2.06–2.16 (m,
4 H, 1ЈЈ-Hb, 1Ј-Hb, 3Ј-Hb, 6Ј-Hb), 2.28–2.38 (m, 1 H, 6aЈ-H), 3.40
(s, 2 H, OCH2), 3.41 (s, 2 H, OCH2), 3.66 (ddd, J = 15.1, 8.8,
6.4 Hz, 1 H, 5Ј-H), 5.11–5.17 (m, 1 H, 2ЈЈ-H) ppm. 13C NMR
(125 MHz, CDCl3):
δ = 16.8 (C-4ЈЈ), 21.5 [C(CH3)2], 21.6
[20]
[21]
C. Hofmann, A. Baro, S. Laschat, Synlett 2008, 1618–1622.
a) S. H. Bertz, J. M. Cook, A. Gawish, U. Weiss, Org. Synth.
1986, 64, 27–38; b) G. Kubiak, J. M. Cook, U. Weiss, J. Org.
Chem. 1984, 49, 561–564.
[C(CH3)2], 24.8 (C-5ЈЈ), 29.0 [C(CH3)2], 30.2 (C-1ЈЈ), 34.9 (C-6aЈ),
39.1 (C-1Ј), 39.2 (C-3Ј), 40.2 (C-6Ј), 42.8 (C-3aЈ), 53.5 (C-4Ј), 70.9
(OCH2), 71.2 (OCH2), 78.2 (C-5Ј), 109.4 (C-2Ј), 121.6 (C-2ЈЈ),
131.8 (C-3ЈЈ) ppm. FT-IR (ATR): ν = 3427 (br), 3054 (w), 2955
˜
[22]
For enantioselective desymmetrizations based on the Wittig re-
action, see: a) J. Mulzer, U. Kaselow, K.-D. Graske, H. Kühne,
A. Sieg, H. J. Martin, Tetrahedron 2004, 60, 9599–9614; b) K.
Petzoldt, H. Dahl, W. Skuballa, M. Gottwald, Liebigs Ann.
Chem. 1990, 11, 1087–1091.
(m), 2865 (m), 1446 (w), 1395 (w), 1327 (w), 1264 (s), 1108 (m),
1016 (w), 907 (w), 728 (vs), 703 (s) cm–1. MS (EI): m/z (%) = 294.2
(100) [M]+, 277.2 (9), 251.2 (15), 223.1 (61), 183.1 (19), 165.1 (18),
141.1 (11), 128.1 (48), 95.1 (16), 69.1 (57), 41.0 (43). HRMS (ESI):
calcd. for C18H29O3 [M – H]+ 293.2111; found 293.2102.
[23]
[24]
a) R. P. C. Cousins, N. S. Simpkins, Tetrahedron Lett. 1989, 30,
7241–7244; b) N. S. Simpkins, Chem. Ind. (London, U.K.)
1988, 387–389.
Acknowledgments
Reviews: a) P. O’Brien, J. Chem. Soc. Perkin Trans. 1 1998,
1439–1457; b) P. O’Brien, J. Chem. Soc. Perkin Trans. 1 2002,
95–113; c) N. S. Simpkins, Quim. Nova 1995, 18, 295–297; d)
N. S. Simpkins, Chem. Soc. Rev. 1990, 19, 335–354; e) J. Cox,
N. S. Simpkins, Tetrahedron: Asymmetry 1991, 2, 1–26.
a) K. Sugasawa, M. Shindo, H. Noguchi, K. Koga, Tetrahedron
Lett. 1996, 37, 7377–7380; b) K. Aoki, H. Noguchi, K. To-
mioka, K. Koga, Tetrahedron Lett. 1993, 34, 5105–5108; c) H.
Izawa, R. Shirai, H. Kawasaki, H.-d. Kim, K. Koga, Tetrahe-
dron Lett. 1989, 30, 7221–7224; d) R. Shirai, M. Tanaka, K.
Koga, J. Am. Chem. Soc. 1986, 108, 543–545.
Generous financial support by the Deutsche Forschungsgemein-
schaft, the Ministerium für Wissenschaft, Forschung und Kunst
des Landes Baden-Württemberg, and the Fonds der Chemischen
Industrie is gratefully acknowledged. We would also like to thank
Ina Fettig for technical support with GC analyses.
[25]
[1] a) J. K. Dickson, F. Fraser-Reid, J. Chem. Soc., Chem. Com-
mun. 1990, 20, 1440–1443; b) L. A. Paquette, R. A. Roberts, G.
Drtina, J. Am. Chem. Soc. 1984, 106, 6690–6693.
[2] a) A. Srikrishna, V. Gowri, Tetrahedron: Asymmetry 2007, 18,
1663–1666; b) G. Guella, F. Pietra, Helv. Chim. Acta 2000, 83,
2946–2952.
[26]
[27]
J. Leonard, D. Ouali, S. K. Rahman, Tetrahedron Lett. 1990,
31, 739–742.
a) O. Muñoz-Muñiz, E. Juaristi, Tetrahedron 2003, 59, 4223–
4229; b) H. Abe, T. Tsujino, K. Yasuo, T. Harayama, Tetrahe-
1156
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1149–1157

Functionalized Hydropentalenes by Asymmetric Deprotonation/Alkylation
dron: Asymmetry 2002, 13, 1519–1527; c) J. Busch-Petersen,
E. J. Corey, Tetrahedron Lett. 2000, 41, 6941–6944; d) V. K.
Aggarwal, P. S. Humphries, A. Fenwick, Angew. Chem. 1999,
111, 2178–2180; Angew. Chem. Int. Ed. 1999, 38, 1985–1986;
e) P. Knochel, Angew. Chem. 1992, 104, 1486–1488; Angew.
Chem. Int. Ed. Engl. 1992, 31, 1459–1461.
[32]
It should be noted that Coquerel and Rodriguez recently re-
ported diastereoselective alkylation of hydropentalene β-oxo
esters during their work on retro-Dieckmann fragmentation
and RCM directed towards bicyclo[6.3.0]undecenes. However,
enantioselectivity was not considered in this work. For details,
see: A. Michaut, S. Miranda-García, J. C. Menéndez, Y. Co-
querel, J. Rodriguez, Eur. J. Org. Chem. 2008, 4988–4998.
[28] a) K. W. Henderson, W. J. Kerr, J. H. Moir, Tetrahedron 2002,
58, 4573–4587; b) K. W. Henderson, W. J. Kerr, J. H. Moir,
Chem. Commun. 2000, 479–480.
[29] I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossen-
kamp, Eur. J. Org. Chem. 1998, 805–826.
[30] a) M. van de Sande, H.-J. Gais, Chem. Eur. J. 2007, 13, 1784–
1795; b) M. Kim, H.-J. Gais, J. Org. Chem. 2006, 71, 4642–
4650; c) G. Kramp, M. Kim, H.-J. Gais, C. Vermeeren, J. Am.
Chem. Soc. 2005, 127, 17910–17920; d) M. Lerm, H.-J. Gais,
K. Cheng, C. Vermeeren, J. Am. Chem. Soc. 2003, 125, 9653–
9667.
[31] a) H.-J. Gais, G. J. Kramp, D. Wolters, L. R. Reddy, Chem. Eur.
J. 2006, 12, 5610–5617; b) H.-J. Gais, M. van Bergen, J. Am.
Chem. Soc. 2002, 124, 4321–4328.
[29]
[33]
[34]
Compounds 9a and 9b were prepared according to ref.
a) C. G. Overberger, N. P. Marullo, R. G. Hiskey, J. Am. Chem.
Soc. 1961, 83, 1374–1378; b) M. van de Sande, Dissertation,
RWTH Aachen, 2006.
[35] Incomplete conversions (as monitored by TLC of the reaction
mixtures) resulted in decreased yields.
[36] D. Seebach, T. Weller, G. Protschuk, A. K. Beck, M. S. Hoek-
stra, Helv. Chim. Acta 1981, 64, 716–735.
[37] Optical rotations are given for the mixture of stereoisomers.
Received: October 13, 2009
Published Online: January 12, 2010
Eur. J. Org. Chem. 2010, 1149–1157
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1157