Doing it twice: Asymmetric deprotonation/alkylation of weiss diketone derivatives as key steps in the functionalization of bicyclo[3.3.0]octanes

Article abstract of DOI:10.1002/ejoc.201201409

The silyl-protected allylhydropentalenone derivative 9, derived from the Weiss diketone, was functionalized by enantioselective deprotonation in the presence of lithium bis(1-phenylethyl)amide/LiCl as the chiral base, which was generated in situ from bis(1-phenylethyl)ammonium chloride [(R,R)- or (S,S)-14] and BuLi, and trapping of the resulting enolate with alkyl halide electrophiles to give pseudo-C₂ or -C_s-symmetrical bicyclo[3.3.0] octanones 10 and 11. The influence of the chiral base and electrophiles on the regioselectivity and double stereodifferentiation was investigated. Taking the double stereocontrol into account, a matched selectivity for the pseudo-C ₂ pair (1R,4R)-10/(1S,4R)-10 and a mismatched selectivity for the pseudo-C_s pair (1S,6R)-11/(1R,6R)-11 were observed in the presence of (R,R)-14. The use of (S,S)-14, however, produced a mismatched selectivity for (1R,4R)-10/(1S,4R)-10 and a matched selectivity for (1S,6R)-11/(1R,6R)-11 with complementary diastereoselectivity depending on the electrophile. Furthermore, the hydropentalenone derivative 10a provided an alternative route to the bicyclo[3.3.0]octene core of the macrocyclic tetramic acid lactam, cylindramide (5). Pseudo-C₂-symmetrical bicyclo[3.3.0]octanones 2 have been prepared from enantiopure α-substituted derivatives 1 of the Weiss diketone. The symmetrical bicyclo[3.3.0]octanones 2 were then converted into the hydropentalene core of macrocyclic polyketide tetramic acid lactams such as cylindramide. Copyright

Full text of DOI:10.1002/ejoc.201201409

FULL PAPER
DOI: 10.1002/ejoc.201201409
Doing it Twice: Asymmetric Deprotonation/Alkylation of Weiss Diketone
Derivatives as Key Steps in the Functionalization of Bicyclo[3.3.0]octanes
Vanessa Lutz,[a] Natja Park,[a] Christian Rothe,[a] Claudia Krüger,[a] Angelika Baro,[a] and
Sabine Laschat*[a]
Dedicated to Professor Larry E. Overman on the occasion of his 70th birthday
Keywords: Alkylation / Asymmetric synthesis / Bicyclic compounds / Stereoselectivity / Natural products
The silyl-protected allylhydropentalenone derivative 9, de-
rived from the Weiss diketone, was functionalized by enan-
tioselective deprotonation in the presence of lithium bis(1-
tivity for the pseudo-C2 pair (1R,4R)-10/(1S,4R)-10 and a mis-
matched selectivity for the pseudo-Cs pair (1S,6R)-11/
(1R,6R)-11 were observed in the presence of (R,R)-14. The
phenylethyl)amide/LiCl as the chiral base, which was gener- use of (S,S)-14, however, produced a mismatched selectivity
ated in situ from bis(1-phenylethyl)ammonium chloride
[(R,R)- or (S,S)-14] and BuLi, and trapping of the resulting
enolate with alkyl halide electrophiles to give pseudo-C2 or
-Cs-symmetrical bicyclo[3.3.0]octanones 10 and 11. The in-
fluence of the chiral base and electrophiles on the regioselec-
tivity and double stereodifferentiation was investigated. Tak-
ing the double stereocontrol into account, a matched selec-
for (1R,4R)-10/(1S,4R)-10 and a matched selectivity for
(1S,6R)-11/(1R,6R)-11 with complementary diastereoselectiv-
ity depending on the electrophile. Furthermore, the hydro-
pentalenone derivative 10a provided an alternative route to
the bicyclo[3.3.0]octene core of the macrocyclic tetramic acid
lactam, cylindramide (5).
Introduction
The enantioselective desymmetrization of meso ketones
by asymmetric deprotonation with chiral bases and subse-
quent electrophilic trapping was pioneered by Koga,[1,2]
Simpkins[3] and Leonard[4] and their co-workers and later
extended by other groups[5] because this strategy provides
efficient access to enantiomerically pure α-substituted
ketones. Bicyclo[3.3.0]octane derivatives of the Weiss di-
ketone 1 (Scheme 1), which is readily available even on a
multigram scale,[6] are particularly attractive for this pur-
pose. Functionalized bicyclo[3.3.0]octanes are important
key building blocks of a variety of natural products and
biologically or medicinally important compounds. Promi-
nent examples include carbacycline (2),[7] ptychenolide (3)[8]
and complex tetramic acid lactams[9] such as the geodin A
magnesium salt (4)[9b,10] and cylindramide (5;[11] Scheme 1).
Although several routes to functionalized bicyclo[3.3.0]-
octanes are known,[12] some methods suffer from harsh re-
action conditions, toxic reagents, poor regio- or stereoselec-
tivity or the use of complex starting materials requiring
multistep syntheses. In contrast, Weiss diketone derivatives
Scheme 1. Weiss diketone 1 and selected examples of prominent
biologically important bicyclo[3.3.0]octane-containing compounds.
allow a bottom-up functionalization through enantioselec-
tive desymmetrization, as was shown for the deprotonation/
electrophilic trapping by Koga,[2c] Leonard[4] and Gais,[13,14]
for cuprate addition by Gais[15] and for enzymatic demeth-
oxycarbonylation by Petzoldt[16] and Mulzer.[17] In particu-
lar, stereogenic centres can be introduced at a later stage on
demand. Recently, we reported on the application of reac-
tive electrophiles like methyl iodide or benzyl, prenyl or allyl
halides for the desymmetrization of Weiss diketone deriva-
tives such as 6, which gave products 8 with high diastereo-
[a] Institut für Organische Chemie der Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: +49-711-685-64285
E-mail: sabine.laschat@oc.uni-stuttgart.de
Homepage: www.laschat.oc.uni-stuttgart.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201409.
Eur. J. Org. Chem. 2013, 761–771
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
761

V. Lutz, N. Park, C. Rothe, C. Krüger, A. Baro, S. Laschat
FULL PAPER
selectivity via silyl enol ether
7
as intermediate
(Scheme 2).[18] Based on these results, we surmised that the
conversion of hydropentalenone derivative 8 into ketone 9
should open up the possibility of a second deprotonation/
alkylation sequence to give either pseudo-C2- or -Cs-sym-
metrical bicyclo[3.3.0]octanones 10 and 11.
Scheme 3. TBDPS = tert-butyldiphenylsilane, TsOH = p-tolu-
enesulfonic acid.
Scheme 2. First deprotonation/alkylation via intermediate silyl enol
ether 7[18] and envisioned follow-up reaction of hydropentalenone
derivatives 8.
shows the regioselectivity to be in favour of the pseudo-C2-
symmetrical regioisomers (1R,4R)-10a,b/(1S,4R)-10a,b in
the presence of (R,R)-14/nBuLi independently of the elec-
trophile (entries 1 and 2). Derivatives (1R,4R)-10a,b were
found to be the major diastereomers, whereas low dia-
stereomeric ratios were observed for the pseudo-Cs-sym-
metrical pairs (1S,6R)-11a,b/(1R,6R)-11a,b (dr = 65:35 and
52:48). In the presence of the enantiomeric (S,S)-14 and
nBuLi, both the pseudo-C2/pseudo-Cs regioselectivity and
the diastereoselectivity of (1R,4R)-10/(1S,4R)-10 were re-
versed, irrespective of the electrophile (methyl or allyl), pre-
The second deprotonation/alkylation sequence is not
only of more general interest with regard to regioselectivity
and double stereodifferentiation in such highly congested
substrates, but would also provide a convenient access to
the core units of macrocyclic tetramic acid lactams such as
geodin A (4) or cylindramide (5). The results are described
below.
Results and Discussion
For the current investigations, acetals 8[18] were chosen ferring the pseudo-Cs regioisomers (1S,6R)-11a,b/(1R,6R)-
because enantioselectivities of the α-substituted ketones 11a,b and diastereomers (1S,4R)-10a,b (entries 3 and 4).
could be determined by capillary GC without further func- The electrophile, however, strongly influenced the pseudo-
tionalization. As the allyl substituent provides many more Cs pairs (1S,6R)-11a,b/(1R,6R)-11a,b, leading to a comple-
opportunities for further derivatization than the methyl mentary diastereoselectivity. Enolate trapping with methyl
group, the α-allylated precursor 9 was considered to be syn- iodide gave exclusively (1S,6R)-11a (entry 3), whereas
thetically more valuable. As shown in Scheme 3, the prepa- ketone (1R,6R)-11b was the major diastereomer in the allyl-
ration of 9 commenced with the reduction of bicyclo[3.3.0]- ation (entry 4). With regard the double stereocontrol, the
octanone 8b with NaBH4 to give alcohol 12 in 64% yield, base (R,R)-14 produced a matched selectivity for the
which was protected with TBDPSCl and imidazole. Subse- pseudo-C2 pair (1R,4R)-10/(1S,4R)-10, favouring (1R,4R)-
quent deprotection of the acetal moiety in 13 with p-tolu- 10, and a mismatched selectivity for the pseudo-Cs pair
enesulfonic acid yielded ketone 9 quantitatively.
(1S,6R)-11/(1R,6R)-11. In contrast, the base (S,S)-14 pro-
With ketone 9 in hand, first the effect of the chiral base duced a mismatched selectivity for the pseudo-C2 (1R,4R)-
on the regio- and diastereoselectivity of the deprotonation/ 10/(1S,4R)-10, favouring (1S,4R)-10, and a matched selec-
alkylation step was studied (Scheme 3, Table 1). Lithium tivity for the pseudo-Cs pair (1S,6R)-11/(1R,6R)-11, with
bis(1-phenylethyl)amide/LiCl as the chiral base was gener- complementary diastereoselectivity depending on the sub-
ated in situ from (R,R)-14 or (S,S)-14 and nBuLi in THF stituents.
at –78 °C.[13,18,19b] Then derivative 9 was deprotonated with
The observed double stereodifferentiation and regio-
1.2 equiv. of the base in THF at –100 °C for 2 h, followed chemical control is not determined by the presence of the
by addition of methyl or allyl iodide at –40 °C. After 12 h, base, but rather by the enolate, as was proven by performing
the mixture was submitted to aqueous work-up. Table 1 the two-step reaction via a silyl enol ether (Scheme 4). Fol-
762
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 761–771

Functionalization of Bicyclo[3.3.0]octanes
Table 1. Asymmetric deprotonation/alkylation of ketone 9 with lithium bis(1-phenylethyl)amide/LiCl derived from (R,R)- or (S,S)-14/
nBuLi.[a]
Entry
Base
10,11
Regioisomeric ratio
(1R,4R)-10/(1S,4R)-10/
(1S,6R)-11/(1R,6R)-11
Yield of
Yield of
dr
dr
Pseudo-C2
Pseudo-Cs
10 [%][b]
11 [%][c]
(R,R)-10/
(S,R)-10
(S,R)-11/
(R,R)-11
1
2
3
4
5
6
(R,R)-14
(R,R)-14
(S,S)-14
(S,S)-14
(R,R)-14
(R,R)-14
a
b
a
79:21
76:24
21:79
20:80
84:16
76:24
58
28
16
17
43
28
15
9
60
68
9
99.5:0.5
98:2
13:87
29:71
99.5:0.5
98:2
65:35
52:48
100:0
1:99
65:35
52:48
matched
matched
mismatched
mismatched
mismatched
mismatched
matched
b
matched
a[d]
b[d]
9
[a] Reaction conditions as in Scheme 3. [b] Yield of (1R,4R)-10 + (1S,4R)-10. [c] Yield of (1S,6R)-11 + (1R,6R)-11. [d] Alkylation via
silyl enol ether 15, as outlined in Scheme 4.
lowing a previously described method,[13,18] ketone 9 was
deprotonated with (R,R)-14/nBuLi and the resulting enolate
was trapped as silyl enol ether 15 by addition of chlorotri-
ethylsilane.
Scheme 5.
Although Shapiro reactions are reported to form prefer-
entially the less substituted double bond,[21] we were ini-
tially concerned that a strong base might induce elimination
of the tosylhydrazone to yield the undesired regioisomer, a
more substituted C=C double bond. Therefore we started
with model reactions using acetals 8 as the starting materi-
als (Scheme 6). α-Allylated ketone 8b (87% ee) was treated
Scheme 4.
Subsequent treatment of 15 with MeLi regenerated the
lithium enolate prior to alkylation with methyl or allyl iod-
ide. As shown in Table 1, the regioisomers (1R,4R)-10a,b/
(1S,4R)-10a,b and (1S,6R)-11a,b/(1R,6R)-11a,b were iso-
lated in ratios and diastereoselectivities (entries 5 and 6)
similar to those obtained in the in situ deprotonation.
Applying the in situ deprotonation/alkylation route to
the α-methyl-substituted analogue of 9 resulted in poor re-
gioselectivities and yields. Replacing the tert-butyl(di-
phenyl)silyl protecting group in 9 by TBS did not change
the stereoselection. In the presence of the chiral base (R,R)-
14/nBuLi, the TBS-protected analogue of 9 provided com-
parable results to those obtained with 9 (see the Supporting
Information).
To use the functionalized ketones 9 and 10 in the synthe-
sis of the bicyclo[3.3.0]octene core precursors 16 and 17 of
cylindramide (5) and geodin A (4), respectively, we planned
to introduce the required double bond through a Shapiro
reaction (Scheme 5).[20]
Scheme 6. TMEDA = tetramethylethylenediamine.
Eur. J. Org. Chem. 2013, 761–771
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
763

V. Lutz, N. Park, C. Rothe, C. Krüger, A. Baro, S. Laschat
FULL PAPER
with tosylhydrazine in EtOH[22] to give the corresponding
tosylhydrazone 19b in 80% yield with an E/Z ratio of 80:20.
Derivative 19b was treated with 2.5 equiv. of nBuLi and
TMEDA in THF at –78 °C for 30 min. The reaction mix-
ture was then warmed to room temperature over 5 h and,
after aqueous work-up, the desired alkene 20b was obtained
quantitatively, albeit with a considerable loss of enantio-
meric purity (56% ee). In this case, racemization may occur
during a [3,3]sigmatropic Cope rearrangement between 20b
and 21. Indeed, in a control experiment, tosylhydrazone 19a
derived from α-methyl-substituted ketone 8a (84% ee) gave,
under the Shapiro conditions, the desired alkene 20a, which
could be isolated in 54% yield with similar optical purity
(80% ee) as starting 8a (84% ee).
The Shapiro route was then applied to the starting
ketone 10a (99% de) for the synthesis of the hydropentalene
core 16 of cylindramide (Scheme 7). This strategy obviates
the kilogram amounts of toxic lead tetraacetate that were
necessary in the first-generation synthesis of 5 starting from
cycloocta-1,5-diene.[23] The conversion of (1R,4R)-10a into
tosylhydrazone 18a proceeded in 87% yield under the usual
conditions. Hydrazone 18a was then deprotected at the
TBDPS ether with 6 equiv. of TBAF to give alcohol 22
quantitatively. The latter was oxidized with Dess–Martin
periodinane[24] to yield ketone 23 in 64% yield. Finally,
Scheme 8. Synthesis of the geodin A core unit 17. Reagents and
conditions: a) nBuLi (2.5 equiv.), TMEDA, –78 °CǞr.t., 4 h, 70%;
Shapiro reaction of 23 provided tetrahydropentalenone 16 b) NaHCO3 (5 equiv.), MCPBA (2 equiv.), abs. CH2Cl2, r.t., 1 h,
48%; c) TMEDA (5 equiv.), LDA (2.5 equiv.), Et2O, r.t., 6 h, 59%;
in 27% yield.
d) DMP (1.3 equiv.), abs. CH2Cl2, 0 °C, 2 h. MCPBA = meta-chlo-
roperoxybenzoic acid.
opening[26] with LDA to yield a 1:1 mixture of the allylic
alcohols 27 and 28 in 59% yield, followed by oxidation with
Dess–Martin periodinane. Chromatographic purification
afforded the desired enone 17 and its regioisomer 29 in
yields of 34 and 24%, respectively.
Conclusions
Scheme 7. Application of the Shapiro reaction to ketone 10a.
The secondary functionalization of the α-allylated hydro-
pentalenone derivative 9 has been investigated with regard
to stereoselectivity of the resulting alkylated bicyclo[3.3.0]-
TBAF = tetrabutylammonium fluoride, DMP = Dess–Martin
periodinane.
The monofunctionalized bicyclo[3.3.0]octanone 9 should octanes 10 and 11 and possible follow-up reactions. The
provide access to geodin A core precursor 17 (Scheme 8). enolate formed in the direct asymmetric deprotonation/alk-
The conversion of 9 into tosylhydrazone 18b followed by ylation sequence was found to determine both the stereodif-
the Shapiro reaction resulted in an inseparable 1:1 mixture ferentiation and the regiochemical control. Although the re-
of regioisomeric alkenes 24 and 24Ј in a 70% combined actions in the presence of the base (R,R)-14/nBuLi were in-
yield. Their treatment with MCPBA gave a 48% yield of a dependent of the incoming electrophile, complementary
mixture of four regio- and diastereomeric epoxides 25, epi- diastereoselectivity was observed when (S,S)-14 was used.
25, 26 and epi-26 in a ratio of 50:3.5:45:1.5, as determined
The synthetic strategy presented herein offers an ap-
by GC.
proach to hydropentalene precursors, as has been demon-
Analysis of the NMR spectra identified exo-epoxide 25 strated for derivative 10a. The latter was submitted to a
as the major product. Under the assumption that the attack Shapiro reaction and subsequent oxidation gave the bicy-
of MCPBA on alkene 24 and 24Ј occurs preferentially from clo[3.3.0]octene core of cylindramide (5). Shapiro reaction
the sterically less hindered exo face, the regioisomeric epox- followed by epoxidation of the resulting alkene, epoxide
ide 26 was expected to be the other major product.[25] The opening and oxidation converted derivative 9 into the po-
epoxide mixture was submitted to base-induced epoxide tential geodin A precursor 17.
764
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 761–771

Functionalization of Bicyclo[3.3.0]octanes
warmed to room temperature and the layers were separated. The
organic layer was dried (MgSO4) and concentrated. The regener-
ated 14 was precipitated by the addition of n-pentane and filtered
off. The filtrate was concentrated and the residue purified by
chromatography on SiO2 with hexanes/EtOAc/NEt3 (50:1:1) to give
15 (849 mg, 1.59 mmol, 94%, 80% purity by GC) as a colourless
oil. Rf = 0.89 (hexanes/EtOAc = 5:1). [α]2D0 = –12.6 (c = 1.0,
Experimental Section
General Methods: NMR spectra were recorded with a Bruker
Avance 500 spectrometer in CDCl3 with TMS (δ = 0.00 ppm) as
an internal standard. IR spectra were recorded with a Bruker FTIR
Vektor 22 spectrometer equipped with an MKII golden gate single
reflection Diamant ATR system. Mass spectra were recorded with
a Finnigan MAT 95 spectrometer (CI, APCI) with ammonia 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. The
reactions and purity of the products were monitored by GC using a
Hewlett–Packard HP 6890 instrument with a HP-5 column (30 mϫ
0.32 mm), hydrogen as carrier gas and different temperature pro-
grams. Enantioselectivities were determined by GC on chiral sta-
tionary phases Amidex C (Amidex-pob-12-un-5.0-Et-133) or Bon-
dex un-β-5.5 (pure β-cyclodextrin phase) using different tempera-
ture programs. Flash chromatography was performed on silica gel
(grain size 40–63 μm, Fluka).
1
CH2Cl2). H NMR (500 MHz, CDCl3): δ = 0.67 [q, J = 8.0 Hz, 6
H, Si(CH2CH3)3], 0.97 [t, J = 8.0 Hz, 9 H, Si(CH2CH3)3], 1.04 [s,
9 H, SiC(CH3)3], 1.53 (dt, J = 12.9, 6.5 Hz, 1 H, 4-Ha), 1.75–1.89
(m, 2 H, 1Ј-Ha, 6-H), 1.96–2.03 (m, 2 H, 4-Hb, 6a-H), 2.23–2.35
(m, 1 H, 1-Ha), 2.40–2.50 (m, 3 H, 1-Hb, 1Ј-Hb, 3a-H), 3.60–3.67
(m, 1 H, 5-H), 4.55–4.65 (m, 1 H, 3-H), 4.89–4.97 (m, 2 H, 3Ј-H),
5.71 (ddt, J = 17.0, 10.1, 6.9 Hz, 1 H, 2Ј-H), 7.34–7.43 (m, 6 H, m-
H, mЈ-H, p-H, pЈ-H), 7.63–7.69 (m, 4 H, o-H, oЈ-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 4.8 [Si(CH2CH3)3], 6.7 [Si(CH2-
CH3)3], 19.3 [SiC(CH3)3], 27.0 [SiC(CH3)3], 40.1 (C-6a), 40.5 (C-
1Ј), 41.7 (C-4), 45.2 (C-1), 49.0 (C-3a), 55.1 (C-6), 78.4 (C-5), 107.2
(C-3), 115.7 (C-3Ј), 127.56, 127.60 (C-m, C-mЈ), 129.6, 129.71 (C-
p, C-pЈ), 134.3, 134.7 (C-i, C-iЈ), 135.9 (C-o, C-oЈ), 137.8 (C-2Ј),
152.6 (C-2) ppm.
All reactions were performed under nitrogen in oven-dried glass-
ware. All reagents were used as purchased unless otherwise noted.
Alkyl halides were distilled prior to use. 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 visualized with an ethanolic solution of
p-anisaldehyde and sulfuric acid.
General Procedure for Desilylation with TBAF (GP3): TBAF·3H2O
(2.5 or 6 equiv.) was dried with 4 Å molecular sieves (15–20 pellets)
under high vacuum at 40 °C for 1 h and then dissolved in THF
(5 mL). The corresponding silyl ether (1 equiv.) was dried with 4 Å
molecular sieves (5–10 pellets) under high vacuum, dissolved in abs.
THF (3 mL) and cooled to 0 °C. The TBAF solution was added
dropwise through a syringe and the reaction mixture stirred for
30 min. Then the mixture was warmed to room temperature and
stirred for a further 12 h. A saturated solution of NaHCO3/H2O
(5 mL) was added and the organic solvent removed. The aqueous
layer was extracted three times with CH2Cl2. The combined organic
extracts were dried (MgSO4), concentrated and the residue purified
by chromatography on SiO2 with hexanes/EtOAc.
General Procedure for the Enantioselective Deprotonation/Alkylation
of 9 (GP1): A 1.6 m solution of nBuLi in hexane (1.95 equiv.) was
added dropwise to a solution of 14 (1 equiv.) in THF (20 mL) at
–78 °C . The mixture was warmed to room temperature until it
became a clear yellow solution (1 h). It was recooled to –100 °C, a
solution of 9 (0.8 equiv.) in THF (5 mL) was added dropwise and
the reaction mixture stirred at –100 °C for a further 2 h. After de-
protonation, the reaction mixture was treated with the correspond-
ing electrophile (1.7–3.3 equiv.), warmed to –40 °C and stirred for
12 h. A saturated solution of NaHCO3/H2O (2–10 mL) was added,
the mixture was warmed to room temperature and the organic sol-
vent was removed. The aqueous layer was extracted three times
with CH2Cl2. The combined extracts were dried (MgSO4), concen-
trated and the residue purified by chromatography on SiO2 with
hexanes/EtOAc.
General Procedure for the Preparation of p-Tosylhydrazones (GP4):
p-Tosylhydrazine (1 equiv.) was added to a solution of the corre-
sponding ketone (1 equiv.) in absolute ethanol (2 mL) and dis-
solved by careful warming. The reaction mixture was then stirred
at room temperature for 16 h. Precipitated tosylhydrazone was fil-
tered off and dried under high vacuum. Otherwise the solvent was
removed and the residue purified by chromatography on SiO2 with
hexanes/EtOAc.
General Procedure for the Alkylation of 9 via Silyl Enol Ether 15
(GP2): A 1.6 m solution of MeLi in Et2O (1.1 equiv.) was added
dropwise to a solution of 15 (1 equiv.; see below for the preparation
of 15) in THF (5 mL) at –10 °C. The reaction mixture was warmed
to room temperature and stirred for 2 h. Then it was cooled to
–40 °C and treated with the corresponding electrophile R2I
(2 equiv.). After stirring the mixture for 22 h at –40 °C, a saturated
solution of NaHCO3/H2O (2–10 mL) was added, the mixture was
warmed to room temperature and the organic solvent was removed.
The aqueous layer was extracted three times with CH2Cl2. The
combined organic extracts were dried (MgSO4), concentrated and
the residue purified by chromatography on SiO2 with hexanes/
EtOAc.
(3aЈS,4ЈR,5ЈR,6aЈR)-4Ј-Allyl-5,5-dimethylhexahydro-1ЈH-spiro-
[1,3-dioxane-2,2Ј-pentalen]-5Ј-ol (12): Finely powered NaBH4
(321 mg, 8.49 mmol) was added portionwise to a solution of 8b
(749 mg, 2.83 mmol) in abs. methanol (20 mL) at 0 °C and the reac-
tion mixture was stirred for 1.5 h. After addition of H2O (5 mL),
the mixture was extracted with CH2Cl2 (3ϫ 30 mL). The combined
extracts were washed with brine (5 mL), dried (MgSO4) and con-
centrated. The residue was purified by chromatography on SiO2
(hexanes/EtOAc = 10:1) to give 12 (483 mg, 1.81 mmol, 64%, 97%
purity by GC) as a colourless oil. Rf = 0.16 (hexanes/EtOAc = 5:1),
1
[α]2D0 = –9.2 (c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ =
0.95 [s, 3 H, C(CH3)2], 0.97 [s, 3 H, C(CH3)2], 1.44–1.51 (m, 1 H,
6Ј-Ha), 1.64–1.71 (m, 1 H, 4Ј-H), 1.76–1.83 (m, 2 H, 1Ј-Ha, 3Ј-Ha),
1.88 (br. s, 1 H, OH), 2.06–2.29 (m, 6 H, 1Ј-Hb, 3Ј-Hb, 3aЈ-H, 1ЈЈ-
Ha, 1ЈЈ-Hb, 6Ј-Hb), 2.37–2.46 (m, 1 H, 6aЈ-H), 3.46 (s, 2 H, OCH2),
3.49 (s, 2 H, OCH2), 3.71–3.79 (m, 1 H, 5Ј-H), 5.00–5.12 (m, 2 H,
[((3aS,5R,6R,6aS)-6-Allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-1,3a,4,
5,6,6a-hexahydropentalen-2-yl)oxy](triethyl)silane (15): Deproton-
ation according to GP1, from (R,R)-14 (579 mg, 2.21 mmol) in
THF (25 mL), nBuLi (2.69 mL, 1.6 m in hexane, 4.31 mmol) and 9
(212 mg, 1.70 mmol). After stirring for 1 h at –100 °C, the mixture 3ЈЈ-Ha, 3ЈЈ-Hb), 5.87 (dddd, J = 14.5, 10.1, 7.6, 6.9 Hz, 1 H, 2ЈЈ-
was warmed to –78 °C, treated with ClSiEt3 (570 μL, 512 mg,
3.40 mmol) and stirred for a further 2 h. A saturated solution of
NaHCO3/H2O (5 mL) was added, the reaction mixture was
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 22.5 [C(CH3)2], 22.6
[C(CH3)2], 30.1 (C-5), 35.9 (C-6aЈ), 37.8 (C-1ЈЈ), 40.1 (C-1Ј), 40.3
(C-3Ј), 41.3 (C-6Ј), 43.9 (C-3aЈ), 53.8 (C-4Ј), 72.0 (OCH2), 72.2
Eur. J. Org. Chem. 2013, 761–771
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
765

V. Lutz, N. Park, C. Rothe, C. Krüger, A. Baro, S. Laschat
FULL PAPER
(OCH2), 79.2 (C-5Ј), 110.4 (C-2Ј), 116.1 (C-3ЈЈ), 137.5 (C-2ЈЈ) ppm. 1265 (s), 896 (w), 731 (vs), 703 (s), 565 (w) cm–1. MS (APCI): m/z
FTIR (ATR): ν = 3402 (br), 3075 (w), 2953 (m), 2933 (m), 2863
= 419.3 [M + H]+, 341.2 [M + H – C6H6]+, 295.2, 263.2 [M + H –
˜
(m), 2374 (w), 2184 (w), 11974 (br), 1640 (w), 1456 (w), 1327 (w),
2C6H6]+, 177.1 [M + H – HSitBuPh2]+, 145.1. HRMS (ESI): calcd.
1313 (w), 1105 (s), 1039 (w), 1014 (w), 908 (s), 870 (w), 735 (s) 599 for C27H34O2SiNa+ [M + Na]+ 441.2220; found 441.2217.
(w) cm–1. MS (APCI): m/z (%) = 267.2 (37) [M + H]+, 249.2 (18)
(1R,3aS,4R,5R,6aS)-4-Allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-1-
methylhexahydropentalen-2(1H)-one [(1R,4R)- and (1S,4R)-10a] and
(1S,3aR,5R,6R,6aS)-6-Allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-1-
methylhexahydropentalen-2(1H)-one [(1S,6R)- and (1R,6R)-11a]:
[M – H2O]+, 229.2 (9), 181.1 (14) [C11H17O2]+, 163.1 (100) [M –
C5H13O2]+, 145.1 (37), 135.1 (50), 121.1 (20), 105.1 (20) [C5H13O2]+,
93.1 (4). HRMS (APCI): calcd. for C16H27O3+ [M + H]+ 267.1995;
found 267.1953.
a) According to GP1, from (R,R)-14 (1.26 g, 4.82 mmol), nBuLi
(5.88 mL, 9.40 mmol), 9 (1.68 g, 4.02 mmol) and MeI (0.50 mL,
1.14 g, 8.04 mmol), flash chromatography on SiO2 [hexanes/EtOAc
= 50:1, (R,R)- and (S,R)-10a: Rf = 0.75; (S,R)- and (R,R)-11a: Rf
= 0.70 (hexanes/EtOAc = 10:1)] gave (R,R)- and (S,R)-10a [1.01 g,
2.33 mmol, 58%, Ͼ99% purity by 1H NMR; dr = 99.5:0.5 (99%
de, ODH); [α]2D0 = –12.0 (c = 1.0, CH2Cl2)] and (S,R)- and (R,R)-
11a [251 mg, 0.58 mmol, 15%, Ͼ99% purity by 1H NMR; dr =
65:35 (30% de, ODH); [α]2D0 = –8.6 (c = 0.8, CH2Cl2)] as colourless
oils. In a first fraction, the two-fold methylated ketone was isolated
as a byproduct (137 mg, 0.31 mmol, 8%). The diastereomeric mix-
tures were separated by preparative HPLC on a Kromasil 100 Sil
5 μm column [hexanes/EtOAc = 100:1, flow 2.5 mL/min, tR(R,R-
10a) = 10.91 min, tR(S,R-10a) = 9.62 min; tR(S,R-11a) = 16.09 min,
tR(R,R-11a) = 10.48 min].
{[(3aЈS,4ЈR,5ЈR,6aЈR)-4Ј-Allyl-5,5-dimethylhexahydro-1ЈH-spiro-
[1,3-dioxane-2,2Ј-pentalen]-5Ј-yl]oxy}(tert-butyl)diphenylsilane (13):
Imidazole (395 mg, 5.80 mmol) was added to a solution of 12
(617 mg, 2.32 mmol) in abs. DMF (5 mL) at 0 °C followed by the
dropwise addition of TBDPSCl (0.72 mL, 764 mg, 2.78 mmol) over
10 min. The reaction mixture was stirred at 0 °C for 30 min and at
room temperature for a further 4 h. The reaction was quenched
with H2O (3 mL) and the resulting slurry extracted with CH2Cl2
(3ϫ 30 mL). The combined organic layers were dried (MgSO4) and
concentrated. The residue was purified by chromatography on SiO2
(hexanes/EtOAc = 10:1) to give 13 (960 mg, 1.90 mmol, 82 %,
Ͼ99% purity by GC) as a colourless oil. Rf = 0.75 (hexanes/EtOAc
= 5:1). [α]2D0 = –14.8 (c = 1.3, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 0.94 [s, 3 H, C(CH3)2], 0.96 [s, 3 H, C(CH3)2], 1.05 [s,
9 H, SiC(CH3)3], 1.45 (dt, J = 12.3, 7.7 Hz, 1 H, 6Ј-Ha), 1.68–1.82
(m, 3 H, 1ЈЈ-Ha, 4Ј-H, 6Ј-Hb), 1.94–1.99 (m, 1 H, 3aЈ-H), 2.19–2.26
(m, 4 H, 1ЈЈ-Hb, 3Ј-Ha, 3Ј-Hb, 6aЈ-H), 2.43 (dd, J = 10.1, 1.9 Hz, 1
H, 1Ј-Ha), 2.47 (dd, J = 8.8, 1.9 Hz, 1 H, 1Ј-Hb), 3.44 (s, 2 H,
OCH2), 3.47 (s, 2 H, OCH2), 3.77 (dt, J = 6.0, 7.7 Hz, 1 H, 5Ј-H),
4.86–4.93 (m, 2 H, 3ЈЈ-H), 6.62 (dddd, J = 17.0, 13.8, 10.1, 6.9 Hz,
1 H, 2ЈЈ-H), 7.34–7.39 (m, 4 H, m-H), 7.40–7.45 (m, 2 H, p-H),
7.63–7.68 (m, 4 H, o-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
19.2 [C(CH3)2], 22.8 [C(CH3)2], 26.9 [SiC(CH3)3], 30.1 [SiC(CH3)3],
36.3 (C-6aЈ), 37.4 (C-1ЈЈ), 40.9 (C-6Ј), 42.8 (C-3aЈ), 45.2 (C-1Ј), 54.1
(C-4Ј), 71.0 (OCH2), 72.6 (OCH2), 80.2 (C-5Ј), 110.3 (C-2Ј), 115.5
(C-3ЈЈ), 127.4, 127.5 (C-m), 129.47, 129.53 (C-p), 134.2, 134.6 (C-
b) According to GP1, from (S,S)-14 (251 mg, 0.96 mmol), nBuLi
(1.17 mL, 1.87 mmol), 9 (335 mg, 0.80 mmol) and MeI (100 μL,
227 mg, 1.60 mmol), flash chromatography on SiO2 (hexanes/
EtOAc = 30:1) and subsequent separation by preparative HPLC
gave (R,R)- and (S,R)-10a [54.0 mg, 125 μmol, 16%, 88% purity
by GC; dr = 13:87 (74% de, ODH); [α]2D0 = –4.2 (c = 0.8, CH2Cl2)]
and (S,R)- and (R,R)-11a [208 mg, 481 μmol, 60%, 82% purity by
GC; dr = 100:0 (Ͼ99% de, ODH); [α]2D0 = –2.2 (c = 1.0, CH2Cl2)]
as colourless oils.
c) According to GP2, from 15 (42.6 mg, 80.0 μmol), MeLi
(0.55 mL, 88.0 μmol) and MeI (10.0 μL, 22.7 mg, 160 μmol), the
isomers (R,R)- and (S,R)-10a (15.0 mg, 34.7 μmol, 43%, 96% pu-
rity by GC, dr = 99.5:0.5) and (S,R)- and (R,R)-11a (3.00 mg,
6.93 μmol, 9%, 88% purity by GC, dr = 65:35) were obtained as
colourless oils.
i), 136.0 (C-o), 137.3 (C-2ЈЈ) ppm. FTIR (ATR): ν = 3072 (w), 2953
˜
(m), 2857 (m), 2185 (w), 1961 (br), 1640 (w), 1472 (m), 1428 (m),
1393 (w), 1362 (w), 1330 (w), 1261 (m), 1109 (vs), 1047 (m), 996
(w), 909 (m), 822 (m), 740 (m), 702 (s), 612 (m) cm–1. MS (ESI):
m/z = 505.3 [M + H]+, 341.2, 249.2 [M – HSitBuPh2]+, 163.1.
HRMS (ESI): calcd. for C32H44O3SiNa+ [M + Na]+ 527.2952;
found 527.2960.
1
(R,R)- and (S,R)-10a: H NMR (500 MHz, CDCl3): δ = 1.04 (d, J
= 6.9 Hz, 3 H, 1Ј-H), 1.04 [s, 9 H, SiC(CH3)3], 1.62 (dt, J = 13.2,
4.6 Hz, 1 H, 6-Ha), 1.79–1.88 (m, 2 H, 1ЈЈ-Ha, 4-H), 2.01 (ddd, J
= 13.2, 8.0, 6.4 Hz, 1 H, 6-Hb), 2.07 (dq, J = 8.4, 4.2 Hz, 1 H, 6a-
H), 2.09–2.19 (m, 2 H, 1ЈЈ-Hb, 3a-H), 2.32–2.39 (m, 2 H, 1-H, 3-
Ha), 2.43 (dd, J = 19.1, 9.1 Hz, 1 H, 3-Hb), 3.96 (dt, J = 6.5, 5.3 Hz,
1 H, 5-H), 4.85–4.90 (m, 2 H, 3ЈЈ-H), 5.55 (ddt, J = 14.9, 12.3,
6.9 Hz, 1 H, 2ЈЈ-H), 7.35–7.40 (m, 4 H, m-H, mЈ-H), 7.41–7.45 (m,
2 H, p-H, pЈ-H), 7.63–7.67 (m, 4 H, o-H, oЈ-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.2 (C-1Ј), 19.1 [SiC(CH3)3], 27.0
[SiC(CH3)3], 37.1 (C-1ЈЈ), 40.2 (C-6), 40.5 (C-3a), 43.4 (C-3), 45.9
(C-6a), 50.2 (C-1), 54.9 (C-4), 80.2 (C-5), 116.3 (C-3ЈЈ), 127.58,
127.61 (C-m, C-mЈ), 129.65, 129.71 (C-p, C-pЈ), 133.9, 134.1 (C-i,
C-iЈ), 135.90, 135.93 (C-o, C-oЈ), 136.4 (C-2ЈЈ), 221.8 (C-2) ppm.
(3aS,4R,5R,6aR)-4-Allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-
hexahydropentalen-2(1H)-one (9): A catalytic amount of pTsOH
(2 mol-%) was added to a solution of 13 (926 mg, 1.83 mmol) in
abs. acetone (10 mL). After stirring at room temperature for 3 h,
the reaction was quenched by the addition of Et3N (3 drops). The
solvent was removed and the residue purified by chromatography
on SiO2 (hexanes/EtOAC = 15:1) to give 9 (766 mg, 1.83 mmol,
quant., Ͼ99% purity by GC) as a colourless oil. Rf = 0.59 (hexanes/
EtOAc = 5:1). [α]2D0 = –6.0 (c = 0.5, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 1.04 [s, 9 H, SiC(CH3)3], 1.50–1.56 (m, 1 H, 6-Ha),
1.78–1.87 (m, 2 H, 1Ј-Ha, 4-H), 2.00 (ddd, J = 13.4, 8.2, 6.2 Hz, 1
H, 6-Hb), 2.06–2.11 (m, 1 H, 1Ј-Hb), 2.23–2.36 (m, 3 H, 1-Ha, 3-
Ha, 3a-H), 2.41–2.51 (m, 2 H, 1-Hb, 3-Hb), 2.54–2.62 (m, 1 H, 6a-
H), 3.92 (dt, J = 6.0, 5.1 Hz, 1 H, 5-H), 4.85–4.91 (m, 2 H, 3Ј-H),
5.50–5.59 (m, 1 H, 2Ј-H), 7.35–7.39 (m, 4 H, m-H), 7.41–7.45 (m,
2 H, p-H), 7.63–7.67 (m, 4 H, o-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 19.1 [SiC(CH3)3], 27.0 [SiC(CH3)3], 36.5 (C-6a), 37.1
FTIR (ATR): ν = 3071 (w), 2929 (m), 2857 (m), 1737 (vs), 1640
˜
(w), 1589 (w), 1471 (w), 1427 (m), 1375 (w), 1107 (vs), 1042 (s),
998 (m), 910 (m), 821 (m), 741 (m), 702 (vs), 611 (m) cm–1. MS
(ESI): m/z = 455.2 [M + Na]+, 356.2 [M + H – C6H6]+, 254.1,
159.1. HRMS (ESI): calcd. for C28H36O2SiNa+ [M + Na]+
455.2377; found 455.2350.
1
(C-1Ј), 41.7 (C-6), 42.6 (C-3a), 44.8, 45.2 (C-1, C-3), 55.1 (C-4), (S,R)- and (R,R)-11a: H NMR (500 MHz, CDCl3): δ = 1.04 [s, 9
80.0 (C-5), 116.2 (C-3Ј), 127.58, 127.61 (C-m), 129.65, 129.70 (C-
p), 133.9, 134.1 (C-i), 135.9, 136.0 (C-o), 136.5 (C-2Ј), 220.7 (C- 6.7 Hz, 1 H, 6-Ha), 1.79 (dddt, J = 13.6, 8.8, 7.6, 1.2 Hz, 1 H, 1ЈЈ-
2) ppm. FTIR (ATR): ν = 3055 (m), 2987 (m), 2307 (w), 1422 (m), Ha), 1.84 (dt, J = 4.3, 8.3 Hz, 1 H, 3a-H), 1.94 (ddt, J = 9.1, 4.5,
H, SiC(CH3)3], 1.06 (d, J = 7.3 Hz, 3 H, 1Ј-H), 1.55 (dt, J = 13.5,
˜
766
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 761–771

Functionalization of Bicyclo[3.3.0]octanes
4.5 Hz, 1 H, 4-H), 2.01–2.03 (m, 1 H, 1ЈЈ-Hb), 2.05 (ddd, J = 13.5,
(w), 1108 (vs), 997 (m), 912 (s), 822 (m), 740 (m), 701 (vs), 612
8.2, 6.3 Hz, 1 H, 6-Hb), 2.32 (ddd, J = 18.7, 4.8, 1.8 Hz, 1 H, 1- (s) cm–1. MS (ESI): m/z = 481.3 [M + Na]+, 381.2, 261.1, 203.1,
Ha), 2.37–2.42 (m, 1 H, 3-H), 2.42 (dd, J = 18.7, 9.1 Hz, 1 H, 1-
185.1. HRMS (ESI): calcd. for C30H38O2SiNa+ [M + Na]+
Hb), 2.45–2.53 (m, 1 H, 6a-H), 3.97 (dt, J = 4.7, 6.1 Hz, 1 H, 5- 481.2553; found 481.2520.
H), 4.86–4.91 (m, 2 H, 3ЈЈ-H), 5.54 (dddd, J = 17.4, 9.7, 7.1, 6.6 Hz,
1
(S,R)- and (R,R)-11b: H NMR (500 MHz, CDCl3): δ = 1.03 [s, 9
1 H, 2ЈЈ-H), 7.36–7.40 (m, 4 H, m-H, mЈ-H), 7.41–7.45 (m, 2 H, p-
H, pЈ-H), 7.63–7.67 (m, 4 H, o-H, oЈ-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 14.5 (C-1Ј), 19.1 [SiC(CH3)3], 27.0 [SiC(CH3)3], 34.3
(C-6a), 37.5 (C-1ЈЈ), 41.8 (C-6), 43.8 (C-1), 49.3 (C-3), 51.5 (C-3a),
54.1 (C-4), 80.6 (C-5), 116.2 (C-3ЈЈ), 127.6 (C-m, C-mЈ), 129.66,
129.72 (C-p, C-pЈ), 133.9, 134.1 (C-i, C-iЈ), 135.86, 135.91 (C-o, C-
H, SiC(CH3)3], 1.54 (dt, J = 13.4, 5.7 Hz, 1 H, 4-Ha), 1.78–1.87
(m, 1 H, 1ЈЈ-Ha), 1.90–1.99 (m, 2 H, 1ЈЈ-Hb, 6-H), 2.00–2.09 (m, 2
H, 4-Hb, 6a-H), 2.15–2.22 (m, 1 H, 1Ј-Ha), 2.32–2.42 (m, 2 H, 1Ј-
Hb, 3-Ha), 2.43 (dd, J = 18.8, 9.2 Hz, 1 H, 3-Hb), 2.48–2.57 (m, 2
H, 1-H, 3a-H), 3.98 (dt, J = 5.7, 4.7 Hz, 1 H, 5-H), 4.83–4.89 (m,
2 H, 3ЈЈ-H), 5.00–5.07 (m, 2 H, 3Ј-H), 5.45–5.54 (m, 1 H, 2ЈЈ-H),
5.71 (ddt, J = 17.1, 10.0, 7.1 Hz, 1 H, 2Ј-H), 7.35–7.39 (m, 4 H, m-
H, mЈ-H), 7.41–7.45 (m, 2 H, p-H, pЈ-H), 7.62–7.66 (m, 4 H, o-H,
oЈ-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 19.0 [SiC(CH3)3],
27.0 [SiC(CH3)3], 34.8 (C-3a), 34.9 (C-1Ј), 37.2 (C-1ЈЈ), 41.7 (C-4),
44.9 (C-3), 48.7 (C-6a), 54.0 (C-1), 54.2 (C-6), 80.4 (C-5), 116.4 (C-
3ЈЈ), 117.1 (C-3Ј), 127.58, 127.61 (C-m, C-mЈ), 129.6, 129.7 (C-p,
C-pЈ), 133.9, 134.0 (C-i, C-iЈ), 135.6 (C-2ЈЈ), 135.87, 135.94 (C-o,
oЈ), 136.7 (C-2ЈЈ), 222.0 (C-2) ppm. FTIR (ATR): ν = 3072 (w),
˜
2929 (m), 2857 (m), 1737 (vs), 1640 (w), 1472 (w), 1427 (m), 1373
(w), 1264 (m), 1107 (vs), 1041 (s), 997 (s), 912 (s), 822 (m), 739 (s),
700 (vs), 611 (s), 505 (s) cm–1. MS (ESI): m/z = 455.2 [M + Na]+,
356.2 [M + H – C6H6]+, 282.2, 203.7, 159.1. HRMS (ESI): calcd.
for C28H36O2SiNa+ [M + Na]+ 455.2377; found 455.2370.
(1R,3aS,4R,5R,6aS)-1,4-Diallyl-5-{[tert-butyl(diphenyl)silyl]oxy}-
hexahydropentalen-2(1H)-one [(1R,4R)- and (1S,4R)-10b] and
(1S,3aR,5R,6R,6aS)-1,6-Diallyl-5-{[tert-butyl(diphenyl)silyl]oxy}-
hexahydropentalen-2(1H)-one [(1S,6R)- and (1R,6R)-11b]: a) Ac-
cording to GP1, from (R,R)-14 (314 mg, 120 mmol), nBuLi
(1.46 mL, 2.34 mmol), 9 (419 mg, 1.00 mmol) and allyl iodide
(180 μL, 336 mg, 2.00 mmol), flash chromatography on SiO2 [hex-
anes/EtOAc = 30:1, (R,R)- and (S,R)-10b: Rf = 0.34; (S,R)- and
(R,R)-11b: Rf = 0.30] gave (R,R)- and (S,R)-10b [128 mg,
0.28 mmol, 28%, 98% purity by GC, dr = 98:2; [α]2D0 = –16.0 (c =
0.7, CH2Cl2)] and (S,R)- and (R,R)-11b [40.0 mg, 90.0 μmol, 9%,
92% purity by GC, dr = 52:48; [α]2D0 = +1.6 (c = 0.5, CH2Cl2)] as
colourless oils. The diastereoisomers were separated by preparative
HPLC on a Kromasil 100 Sil 5 μm column (hexanes/EtOAc =
100:1, flow 2.5 mL/min, detection wavelength 254 nm).
C-oЈ), 136.5 (C-2Ј), 221.3 (C-2) ppm. FTIR (ATR): ν = 3072 (w),
˜
2930 (m), 2858 (m), 1736 (vs), 1640 (w), 1590 (w), 1472 (w), 1428
(m), 1390 (w), 1259 (w), 1111 (vs), 1063 (w), 998 (m), 912 (s), 852
(w), 822 (m), 741 (m), 703 (vs), 612 (m) cm–1. MS (ESI): m/z =
481.3 [M + Na]+, 381.2, 261.1, 203.1, 185.1. HRMS (ESI): calcd.
for C30H38O2SiNa+ [M + Na]+ 481.2553; found 481.2527.
4-Methyl-NЈ-[(3aЈS,4ЈR,5ЈE/Z,6aЈR)-4Ј,5,5-trimethyltetrahydro-
1ЈH-spiro[1,3-dioxane-2,2Ј-pentalen]-5Ј(3ЈH)-ylidene]benzenesulf-
onohydrazide (19a): According to GP4, from 8a (102 mg,
0.45 mmol) and p-tosylhydrazine (84.0 mg, 0.45 mmol), the precipi-
tate was filtered off and dried under high vacuum; yield 112 mg
(0.28 mmol, 61%, Ͼ95% purity by 1H NMR, E/Z = 89:11), colour-
less resin. [α]2D0 = –11.8 (c = 1.0, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 0.93 [s, 3 H, C(CH3)2], 0.94 [s, 3 H, C(CH3)2], 1.03 (d,
J = 6.8 Hz, 3 H, 1ЈЈ-H), 1.58 (dd, J = 13.6, 8.1 Hz, 1 H, 1Ј-Ha),
1.79 (dd, J = 13.9, 4.3 Hz, 1 H, 3Ј-Ha), 2.04–2.12 (m, 2 H, 3aЈ-H,
6Ј-Ha), 2.18 (ddd, J = 13.9, 8.4, 1.1 Hz, 1 H, 3Ј-Hb), 2.28 (ddd, J
= 13.6, 8.4, 0.9 Hz, 1 H, 1Ј-Hb), 2.40 (dd, J = 9.0, 1.7 Hz, 1 H, 6Ј-
Hb), 2.43 (s, 3 H, p-CH3), 2.43–2.49 (m, 1 H, 4Ј-H), 2.60–2.69 (m,
1 H, 6aЈ-H), 3.36 (d, J = 3.9 Hz, 2 H, OCH2), 3.44 (s, 2 H, OCH2),
4.89–4.94 (m, 2 H, 3ЈЈ-H), 5.59 (dddd, J = 14.2, 10.3, 7.6, 6.7 Hz,
1 H, 2ЈЈ-H), 7.05 (br. s, 1 H, NH), 7.30 (d, J = 8.2 Hz, 2 H, m-H),
7.84 (d, J = 8.2 Hz, 2 H, o-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 16.7 (C-1ЈЈ), 21.6 (p-CH3), 22.3, 22.4 [C(CH3)2], 30.0
[C(CH3)2], 32.6 (C-6Ј), 36.3 (C-6aЈ), 38.7 (C-3Ј), 41.2 (C-1Ј), 44.8
(C-4Ј), 47.9 (C-3aЈ), 71.8 (OCH2), 72.3 (OCH2), 110.0 (C-2Ј), 128.1
(C-o), 129.4 (C-m), 135.4 (C-p), 143.9 (C-i), 170.0 (C-5Ј) ppm (sig-
nals of the Z isomer were not assigned due to overlapping). FTIR
b) According to GP1, from (S,S)-14 (251 mg, 0.96 mmol), nBuLi
(1.17 mL, 1.87 mmol), 9 (335 mg, 0.80 mmol) and allyl iodide
(150 μL, 269 mg, 1.60 mmol), flash chromatography on SiO2 (hex-
anes/EtOAc = 30:1) and subsequent separation by preparative
HPLC gave (R,R)- and (S,R)-10b [62.0 mg, 135 μmol, 17%, 81%
purity by GC; [α]2D0 = –11.4 (c = 1.0, CH2Cl2)] and (S,R)- and
(R,R)-11b [251 mg, 547 μmol, 68%, 92% purity by GC; [α]2D0 = –6.4
(c = 0.8, CH2Cl2)] as colourless oils.
c) According to GP2, from 15 (528 mg, 0.99 mmol), MeLi
(0.66 mL, 1.09 mmol) and allyl iodide (0.18 mL, 333 mg,
1.98 mmol), (R,R)- and (S,R)-10b (128 mg, 0.28 mmol, 28%, 96%
purity by GC, dr = 98:2) and (S,R)- and (R,R)-11b (40.0 mg,
0.09 mmol, 9%, 96% purity by GC, dr = 52:48) were obtained as
colourless oils.
(ATR): ν = 3415 (br, w), 2989 (m), 2933 (m), 1603 (w), 1456 (m),
˜
1
(R,R)- and (S,R)-10b: H NMR (500 MHz, CDCl3): δ = 1.04 [s, 9
1434 (w), 1396 (w), 1380 (m), 1243 (m), 1217 (s), 1164 (s), 1063
(vs), 991 (m), 909 (w), 876 (w), 860 (w), 782 (w), 753 (w), 729 (m),
100 (s) cm–1. MS (ESI): m/z = 429.2 [M + Na]+, 407.2 [M + H]+,
321.1 [M + H – C5H10O]+, 305.1, 263.1, 251.2, 236.2 [M + H –
C7H8NO2S]+, 165.1, 150.1, 132.1, 108.1. HRMS (ESI): calcd. for
C21H31N2O4S+ [M + H]+ 407.1999; found 407.2003.
H, SiC(CH3)3], 1.61 (dt, J = 13.6, 5.1 Hz, 1 H, 6-Ha), 1.76–1.86
(m, 2 H, 1ЈЈ-Ha, 4-H), 1.99 (ddd, J = 13.6, 7.9, 6.1 Hz, 1 H, 6-Hb),
2.03–2.12 (m, 2 H, 1Ј-Ha, 1ЈЈ-Hb), 2.14–2.21 (m, 1 H, 3a-H), 2.22–
2.29 (m, 1 H, 6a-H), 2.35–2.47 (m, 4 H, 1Ј-Hb, 1-H, 3-Ha, 3-Hb),
3.94 (dt, J = 5.1, 5.6 Hz, 1 H, 5-H), 4.84–4.94 (m, 2 H, 3ЈЈ-H),
4.97–5.04 (m, 2 H, 3Ј-H), 5.48–5.57 (m, 1 H, 2ЈЈ-H), 5.65–5.75 (m,
1 H, 2Ј-H), 7.35–7.40 (m, 4 H, m-H, mЈ-H), 7.41–7.45 (m, 2 H, p- NЈ-[(3aЈS,4ЈR,5ЈE/Z,6aЈR)-4Ј-Allyl-5,5-dimethyltetrahydro-1ЈH-
H, pЈ-H), 7.63–7.67 (m, 4 H, o-H, oЈ-H) ppm. 13C NMR (125 MHz,
spiro[1,3-dioxane-2,2Ј-pentalen]-5Ј(3ЈH)-ylidene]-4-methylbenzene-
CDCl3): δ = 19.1 [SiC(CH3)3], 27.0 [SiC(CH3)3], 34.8 (C-1Ј), 37.1 sulfonohydrazide (19b): According to GP4, from 8b (493 mg,
(C-1ЈЈ), 40.6 (C-3a), 41.1 (C-6), 43.0 (C-6a), 44.3 (C-3), 55.0 (C-1), 2.00 mmol) and p-tosylhydrazine (373 mg, 2.00 mmol), the precipi-
55.1 (C-4), 80.2 (C-5), 116.2 (C-3ЈЈ), 116.7 (C-3Ј), 127.57, 127.61
tate was filtered off and dried under high vacuum; yield 686 mg
(C-m, C-mЈ), 129.65, 129.70 (C-p, C-pЈ), 133.9, 134.1 (C-i, C-iЈ), (1.58 mmol, 80%, Ͼ99% purity by GC, E/Z = 80:20), colourless
135.7 (C-2Ј), 135.91, 135.94 (C-o, C-oЈ), 136.4 (C-2ЈЈ), 221.0 (C- resin. [α]2D0 = –21.2 (c = 0.5, CH2Cl2). 1H NMR (500 MHz, CDCl3):
2) ppm. FTIR (ATR): ν = 3073 (w), 2930 (m), 2857 (m), 1736 (vs),
δ = 0.92 [s, 3 H, C(CH3)2], 0.93 [s, 3 H, C(CH3)2], 1.58 (dd, J =
˜
1640 (w), 1589 (w), 1472 (w), 1427 (m), 1390 (w), 1362 (w), 1259 13.6, 7.4 Hz, 1 H, 1Ј-Ha), 1.72 (dd, J = 13.9, 5.4 Hz, 1 H, 3Ј-Ha),
Eur. J. Org. Chem. 2013, 761–771
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
767

V. Lutz, N. Park, C. Rothe, C. Krüger, A. Baro, S. Laschat
2.00–2.08 (m, 1 H, 1ЈЈ-Ha), 2.12 (dd, J = 18.3, 4.3 Hz, 1 H, 6Ј-Ha), thermal, 10 °C/min gradient to 140 °C, then 1 °C/min gradient to
FULL PAPER
1
2.17 (ddd, J = 13.9, 8.4, 1.3 Hz, 1 H, 3Ј-Hb), 2.25 (ddd, J = 13.6,
200 °C). H NMR (500 MHz, CDCl3): δ = 0.96 [s, 6 H, C(CH3)2],
8.4, 1.3 Hz, 1 H, 1Ј-Hb), 2.25–2.35 (m, 2 H, 3a-H, 1ЈЈ-Hb), 2.41 1.00 (d, J = 7.1 Hz, 3 H, 1ЈЈ-H), 1.54–1.61 (m, 2 H, 1Ј-Ha, 3Ј-Ha),
(ddd, J = 18.3, 9.3, 1.7 Hz, 1 H, 6Ј-Hb), 2.43 (s, 3 H, p-CH3), 2.48– 2.24 (dq, J = 8.4, 2.4 Hz, 1 H, 3aЈ-H), 2.28–2.35 (m, 2 H, 1Ј-Hb,
2.55 (m, 1 H, 4Ј-H), 2.59–2.68 (m, 1 H, 6aЈ-H), 3.35 (d, J = 3.5 Hz,
3Ј-Hb), 2.45–2.52 (m, 1 H, 4Ј-H), 3.18–3.24 (m, 1 H, 6aЈ-H), 3.45
2 H, OCH2), 3.43 (s, 2 H, OCH2), 4.89–4.94 (m, 2 H, 3ЈЈ-H), 5.59 (d, J = 1.9 Hz, 2 H, OCH2), 3.50 (d, J = 3.2 Hz, 2 H, OCH2), 5.53
(dddd, J = 14.2, 10.3, 7.6, 6.7 Hz, 1 H, 2ЈЈ-H), 7.28 (br. s, 1 H, (dt, J = 5.6, 2.0 Hz, 1 H, 6Ј-H), 5.57 (dt, J = 5.6, 2.0 Hz, 1 H, 5Ј-
NH), 7.30 (d, J = 8.2 Hz, 2 H, m-H), 7.83 (d, J = 8.2 Hz, 2 H, o-
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.4 (C-1ЈЈ), 22.5, 22.6
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.6 (p-CH3), 22.40, [C(CH3)2], 30.1 [C(CH3)2], 38.6 (C-1Ј), 39.8 (C-3Ј), 46.5 (C-4),
22.42 [C(CH3)2], 30.0 [C(CH3)2], 33.3 (C-6Ј), 37.0 (C-1ЈЈ), 37.7 (C- 46.77 (C-3aЈ), 46.80 (C-6aЈ), 71.6 (OCH2), 72.7 (OCH2), 109.2 (C-
6aЈ), 40.3 (C-3Ј), 41.3 (C-1Ј), 44.7 (C-3aЈ), 49.8 (C-4Ј), 71.8
(OCH2), 72.3 (OCH2), 109.7 (C-2Ј), 116.6 (C-3ЈЈ), 128.1 (C-o),
2Ј), 133.3 (C-6Ј), 135.0 (C-5Ј) ppm. FTIR (ATR): ν = 3044 (w),
2952 (s), 2859 (s), 1968 (br), 1730 (w), 1640 (w), 1468 (m), 1394
˜
129.5 (C-m), 135.4 (C-p), 135.8 (C-2ЈЈ), 144.0 (C-i), 168.9 (C- (w), 1315 (m), 1217 (m), 1110 (vs), 1056 (w), 999 (m), 909 (m), 798
5Ј) ppm (signals of the Z isomer were not assigned due to low in-
(w), 742 (m) cm–1. MS (EI): m/z (%) = 222.2 (76) [M]+, 207.1 (18)
tensity and overlapping). FTIR (ATR): ν = 3214 (br), 2950 (m),
[M – Me]+, 152.1 (12), 136.1 (37) [M – C5H10O]+, 128.1 (100), 121.1
˜
2863 (m), 1967 (br), 1643 (w), 1598 (w), 1398 (m), 1335 (s), 1217 (11) [M – Me – C5H10O]+, 107.1 (22), 93.1 (42), 79.1 (15), 69.1
(35), 57.1 (11), 43.0 (15). HRMS (EI): calcd. for C14H22O2 [M]+
222.1620; found 222.1617.
+
(w), 1164 (s), 1112 (m), 1012 (m), 916 (m), 814 (m), 671 (m), 549
(m), 499 (w) cm–1. MS (EI): m/z (%) = 432.2 (12) [M]+, 277.2 (100)
[M – C7H7O2S]+, 262.2 (7) [M – C7H7NO2S]+, 191.1 (40), 163.1
(10), 133.1 (5), 105.1 (6), 91.0 (11) [C7H7]+, 79.0 (7), 69.0 (14), 55.0
(3), 40.9 (10). HRMS (ESI): calcd. for C23H33N2O4S+ [M + H]+
433.2156; found 433.2165.
NЈ-[(1R,2E,3aS,4R,5R,6aS)-4-Allyl-5-{[tert-butyl(diphenyl)silyl]-
oxy}-1-methylhexahydropentalen-2(1H)-ylidene]-4-methylbenzene-
sulfonohydrazide (18a): According to GP4, from 10a (130 mg,
0.30 mmol) and p-tosylhydrazine (56.0 mg, 0.30 mmol),
chromatography on SiO2 (hexanes/EtOAc = 10:1); yield 157 mg
(0.26 mmol, 87%, Ͼ99% purity by GC), colourless fluffy resin. Rf
(3aЈR,4ЈS,6aЈS)-4Ј-Allyl-5,5-dimethyl-3Ј,3aЈ,4Ј,6aЈ-tetrahydro-1ЈH-
spiro[1,3-dioxane-2,2Ј-pentalene] (20b): A 1.6 m solution of nBuLi
in hexane (0.73 mL, 1.16 mmol) was added dropwise to a solution
of 19b (216 mg, 0.50 mmol) in abs. THF (7 mL) and TMEDA
(1 mL) at –78 °C in a Schlenk flask, and the reaction mixture was
warmed to room temperature with a colour change from orange
to brown. After stirring for a further 5 h, a saturated solution of
NaHCO3/H2O (3 mL) was added and the organic solvent removed.
The remaining aqueous layer was extracted with CHCl3 (3 ϫ
30 mL), and the combined organic extracts were dried (MgSO4)
and concentrated. The residue was purified by chromatography on
SiO2 (hexanes/EtOAc = 5:1) to give 20b (123 mg, 0.5 mmol, quant.,
Ͼ95% purity by 1H NMR) as a colourless viscous resin. Rf = 0.88.
[α]2D0 = –8.2 (c = 1.0, CH2Cl2); e.r. = 78:22 (56% ee, GC: Amidex
= 0.53 (hexanes/EtOAc = 5:1). [α]2D0 = –26.4 (c = 1.0, CH2Cl2). H
1
NMR (500 MHz, CDCl3): δ = 0.99 (d, J = 6.9 Hz, 3 H, 1Ј-H), 1.01
[s, 9 H, SiC(CH3)3], 1.46 (dt, J = 13.1, 5.5 Hz, 1 H, 6-Ha), 1.67–
1.78 (m, 2 H, 4-H, 1ЈЈ-Ha), 1.82 (dq, J = 5.0, 8.0 Hz, 1 H, 6a-H),
1.88 (dt, J = 13.1, 7.4 Hz, 1 H, 6-Hb), 2.05 (dq, J = 3.9, 8.0 Hz, 1
H, 3a-H), 2.10–2.16 (m, 1 H, 1ЈЈ-Hb), 2.15 (dd, J = 18.1, 3.9 Hz, 1
H, 3-Ha), 2.37 (ddd, J = 18.1, 3.9, 1.5 Hz, 1 H, 3-Hb), 2.42 (s, 3 H,
pЈЈ-CH3), 2.56 (dq, J = 8.0, 6.9 Hz, 1 H, 1-H), 3.83 (q, J = 6.4 Hz,
1 H, 5-H), 4.82–4.90 (m, 2 H, 3ЈЈ-H), 5.54 (dddd, J = 17.0, 13.9,
10.3, 6.7 Hz, 1 H, 2ЈЈ-H), 6.90 (br. s, 1 H, NH), 7.28–7.31 (m, 2 H,
mЈЈ-H), 7.34–7.38 (m, 4 H, m-H, mЈ-H), 7.40–7.44 (m, 2 H, p-H,
pЈ-H), 7.60–7.64 (m, 4 H, o-H, oЈ-H), 7.83–7.87 (m, 2 H, oЈЈ-
C, temperature program: 100 °C isothermal, 1 °C/min gradient to H) ppm. 13C NMR (125 MHz, CDCl3): δ = 16.7 (C-1Ј), 19.1
1
200 °C). H NMR (500 MHz, CDCl3): δ = 0.96 [s, 6 H, C(CH3)2], [SiC(CH3)3], 21.6 (pЈЈ-CH3), 27.0 [SiC(CH3)3], 32.8 (C-3), 36.9 (C-
1.52–1.60 (m, 2 H, 1Ј-Ha, 3Ј-Ha), 2.01–2.07 (m, 1 H, 1ЈЈ-Ha), 2.10– 1ЈЈ), 39.5 (C-6), 43.2 (C-3a), 46.0 (C-1), 47.5 (C-6a), 54.2 (C-4),
2.16 (m, 1 H, 1ЈЈ-Hb), 2.28–2.38 (m, 3 H, 1Ј-Hb, 3aЈ-H, 3Ј-Hb), 78.0 (C-5), 116.3 (C-3ЈЈ), 127.5, 127.6 (C-m, C-mЈ), 128.1 (C-oЈЈ),
2.47–2.52 (m, 1 H, 4Ј-H), 3.13–3.20 (m, 1 H, 6aЈ-H), 3.44 (s, 2 H,
OCH2), 3.50 (s, 2 H, OCH2), 4.79–5.04 (m, 2 H, 3ЈЈ-H), 5.55 (dt,
J = 5.2, 2.3 Hz, 1 H, 6Ј-H), 5.63 (dt, J = 5.2, 2.3 Hz, 1 H, 5Ј-H),
129.4 (C-mЈЈ), 129.6, 129.7 (C-p, C-pЈ), 133.9, 134.2 (C-i, C-iЈ),
135.5 (C-pЈЈ), 136.5 (C-o, C-oЈ), 136.5 (C-2ЈЈ), 143.9 (C-iЈЈ), 170.3
(C-2) ppm. FTIR (ATR): ν = 3055 (m), 2988 (m), 2539 (w), 1422
˜
5.78 (tt, J = 9.1, 6.9 Hz, 1 H, 2ЈЈ-H) ppm. 13C NMR (125 MHz, (w), 1264 (s), 896 (w), 731 (s), 703 (s), 544 (w) cm–1. MS (ESI): m/z
CDCl3): δ = 22.4, 22.5 [C(CH3)2], 30.0 [C(CH3)2], 38.4 (C-1Ј), 40.1
= 601.3 [M + H]+, 363.0, 345.2 [M + H – TBDPSOH]+, 257.1,
(C-3Ј), 40.2 (C-1ЈЈ), 43.9 (C-3aЈ), 46.6 (C-6aЈ), 52.1 (C-4Ј), 71.5 189.1 [M + H – TBDPSOH – C7H8O2S]+, 174.1 [M + H –
(OCH2), 72.7 (OCH2), 109.0 (C-2Ј), 115.6 (C-3ЈЈ), 132.7 (C-6Ј), TBDPSOH – C7H8O2S – CH3]+, 133.1. HRMS (ESI): calcd. for
134.4 (C-5Ј), 137.1 (C-2ЈЈ) ppm. FTIR (ATR): ν = 3044 (w), 2952 C35H45N2O3SSi+ [M + H]+ 601.2915; found 601.2929.
˜
(s), 2859 (s), 1968 (br), 1730 (w), 1640 (w), 1468 (m), 1394 (w),
NЈ-[(1R,2E,3aS,4R,5R,6aS)-4-Allyl-5-hydroxy-1-methylhexahydro-
pentalen-2(1H)-ylidene]-4-methylbenzenesulfonohydrazide (22): Ac-
cording to GP3, from 18a (61.0 mg, 100 μmol) and TBAF (189 mg,
1315 (m), 1217 (m), 1110 (vs), 1056 (w), 999 (m), 909 (m), 798 (w),
742 (m) cm–1. MS (EI): m/z (%) = 248.2 (66) [M]+, 207.2 (91) [M –
C3H5]+, 162.2 (17) [M – C5H10O]+, 128.1 (100), 121.1 (33), 104.1
600 μmol), chromatography on SiO2 (hexanes/EtOAc = 2:1); yield
(13), 93.1 (23), 79.1 (43), 57.1 (11), 41.0 (17). HRMS (EI): calcd.
1
38.0 mg (100 μmol, quant., Ͼ95% purity by H NMR), colourless
for C16H24O2 [M]+ 248.1776; found 248.1776.
+
sticky resin. Rf = 0.50 (hexanes/EtOAc = 1:1). [α]2D0 = –38.4 (c =
(3aЈR,4ЈS,6aЈS)-4Ј,5,5-Trimethyl-3Ј,3aЈ,4Ј,6aЈ-tetrahydro-1ЈH-
spiro[1,3-dioxane-2,2Ј-pentalene] (20a): As described above for the
synthesis of 20b, from 19a (83.0 mg, 0.20 mmol) in abs. THF
1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 1.06 (d, J = 6.9 Hz,
3 H, 1Ј-H), 1.25 (br. s, 1 H, OH), 1.42 (ddd, J = 13.6, 7.5, 5.2 Hz,
1 H, 6-Ha), 1.53–1.59 (m, 1 H, 4-H), 1.96 (ddd, J = 16.4, 8.2,
(5 mL) and TMEDA (1 mL), nBuLi (0.29 mL, 0.47 mmol), 4 h at 5.2 Hz, 1 H, 3a-H), 2.13–2.21 (m, 4 H, 6a-H, 1ЈЈ-Ha, 1ЈЈ-Hb, 3-Ha),
room temperature, extraction with CH2Cl2 and flash chromatog-
raphy on SiO2 (hexanes/EtOAc = 10:1); yield 25.0 mg (0.11 mmol,
54%, Ͼ95% purity by 1H NMR), colourless viscous resin. Rf =
0.76 (hexanes/EtOAc = 5:1). [α]2D0 = –1.4 (c = 0.5, CH2Cl2); e.r. =
90:10 (80% ee, GC: Amidex C, temperature program: 40 °C iso-
2.29 (dt, J = 13.6, 7.5 Hz, 1 H, 6-Hb), 2.40–2.51 (m, 2 H, 3-Hb, 1-
H), 2.43 (s, 3 H, p-CH3), 3.91 (q, J = 7.5 Hz, 1 H, 5-H), 5.01–5.12
(m, 2 H, 3ЈЈ-H), 5.82 (dddd, J = 17.4, 14.7, 10.3, 7.2 Hz, 1 H, 2ЈЈ-
H), 7.02 (br. s, 1 H, NH), 7.30 (d, J = 8.8 Hz, 2 H, m-H), 7.84 (d,
J = 8.8 Hz, 2 H, o-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.6
768
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 761–771

Functionalization of Bicyclo[3.3.0]octanes
(p-CH3), 26.6 (C-1Ј), 32.3 (C-3), 37.1 (C-1ЈЈ), 39.2 (C-6), 44.0 (C-
HRMS (ESI): calcd. for C12H17O+ [M + H]+ 177.1274; found
6a), 46.6 (C-1), 46.8 (C-3a), 53.1 (C-4), 79.1 (C-5), 116.8 (C-3ЈЈ), 177.1269.
128.1 (C-o), 129.5 (C-m), 136.8 (C-2ЈЈ, C-p), 144.1 (C-i), 170.0 (C-
NЈ-[(2E/Z,3aS,4R,5R,6aS)-4-Allyl-5-{[tert-butyl(diphenyl)silyl]-
2) ppm. FTIR (ATR): ν = 3069 (br), 2958 (m), 2927 (m), 2872 (m),
˜
oxy}hexahydropentalen-2(1H)-ylidene]-4-methylbenzenesulfono-
hydrazide (18b): According to GP4, from 9 (50.0 mg, 120 μmol) and
p-tosylhydrazine (22.3 mg, 120 μmol), repeated freezing with liquid
N2 under high vacuum gave 18b (70.0 mg, 120 μmol, quant., Ͼ99%
purity by GC, E/Z = 1:1 by 13C NMR) as a colourless viscous resin.
2859 (m), 2254 (w), 1732 (s), 1455 (w), 1359 (w), 1165 (s), 1087 (w),
1008 (w), 904 (vs), 814 (m), 725 (vs), 683 (m), 650 (m), 554
(m) cm–1. MS (ESI): m/z = 385.2 [M + Na]+, 363.2 [M + H]+, 345.2
[M + H – H2O]+, 226.2 [M + H – H2O – C7H8 – C2H4]+, 192.1 [M
+ H – C7H9NO2S]+, 105.1. HRMS (ESI): calcd. for C19H27N2O3S+
[M + H]+ 363.1737; found 363.1739.
1
Rf = 0.28 (hexanes/EtOAc = 5:1). H NMR (500 MHz, CDCl3): δ
= 1.00 [s, 9 H, SiC(CH3)3], 1.40 (dq, J = 12.5, 6.3 Hz, 1 H, 6-Ha),
1.67–1.80 (m, 2 H, 4-H, 1Ј-Ha), 1.85–1.93 (m, 1 H, 6-Hb), 2.02–
2.08 (m, 1 H, 1Ј-Hb), 2.08–2.24 (m, 2 H, 3a-H, 3-Ha), 2.27–2.36
(m, 1 H, 6a-H), 2.37–2.46 (m, 2 H, 3-Hb, 1-Ha), 2.42 (s, 3 H, pЈ-
CH3), 2.61 (ddt, J = 10.5, 8.9, 1.4 Hz, 1 H, 1-Hb), 3.82 (dt, J =
12.5, 6.3 Hz, 1 H, 5-H), 4.82–4.91 (m, 2 H, 3Ј-H), 5.52 (dddd, J =
16.7, 13.4, 10.2, 6.7 Hz, 1 H, 2Ј-H), 7.06 (br. s, 1 H, NH), 7.31 (d,
J = 8.4 Hz, 2 H, mЈ-H), 7.33–7.38 (m, 4 H, m-H), 7.40–7.44 (m, 2
H, p-H), 7.59–7.63 (m, 4 H, o-H), 7.84 (d, J = 8.4 Hz, 2 H, oЈ-
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.4 [SiC(CH3)3*], 19.0
[SiC(CH3)3], 21.6 (pЈ-CH3, pЈ-CH3*), 27.0 [SiC(CH3)3, SiC-
(CH3)3*], 34.1 (C-3), 34.5 (C-3*), 36.9 (C-1Ј*), 37.0 (C-1Ј), 37.9 (C-
6a), 39.0 (C-6a*), 39.2 (C-1*), 39.7 (C-1), 40.9 (C-6), 41.4 (C-6*),
44.2 (C-3a), 44.8 (C-3a*), 53.8 (C-4*), 54.6 (C-4), 79.8 (C-5), 79.9
(C-5*), 116.1 (C-3Ј*), 116.3 (C-3Ј), 127.5 (C-m*), 127.6 (C-m),
128.0 (C-oЈ, C-oЈ*), 129.6 (C-mЈ, C-mЈ*), 129.7 (C-p, C-p*), 133.9
(C-i, C-i*), 134.1 (C-pЈ, C-pЈ*), 135.6 (C-iЈ, C-iЈ*), 135.9 (C-o, C-
o*), 136.5 (C-2Ј*), 136.6 (C-2Ј), 144.0 (C-2, C-2*) ppm (* denotes
signals of the Z isomer).
NЈ-[(1R,2E,3aS,4R,6aS)-4-Allyl-1-methyl-5-oxohexahydropenta-
len-2(1H)-ylidene]-4-methylbenzenesulfonohydrazide (23): DMP
(105 mg, 250 μmol) was added to a solution of 22 (50.0 mg,
140 μmol) in abs. CH2Cl2 (5 mL) at 0 °C in a Schlenk flask and
the reaction mixture was stirred for 2 h. A saturated solution of
NaHCO3/H2O (3 mL) was added and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (2ϫ 20 mL) and the
combined organic layers were dried (MgSO4) and concentrated.
The residue was purified by chromatography on SiO2 (hexanes/
EtOAc = 2:1) to give 23 (33.0 mg, 90.0 μmol, 64%, Ͼ90% purity
by 13C NMR) as a colourless sticky resin. Rf = 0.42. [α]2D0 = –11.2
1
(c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 1.10 (d, J =
6.1 Hz, 3 H, 1Ј-H), 1.83–1.91 (m, 1 H, 4-H), 2.15 (dt, J = 15.1,
7.6 Hz, 1 H, 1ЈЈ-Ha), 2.19–2.25 (m, 2 H, 1-H, 6a-H), 2.20–2.39 (m,
3 H, 3-Ha, 6-Ha, 6-Hb), 2.44 (s, 3 H, p-CH3), 2.45–2.57 (m, 3 H,
1ЈЈ-Hb, 3a-H, 3-Hb), 5.00–5.08 (m, 2 H, 3ЈЈ-H), 5.68 (ddt, J = 17.1,
9.9, 7.2 Hz, 1 H, 2ЈЈ-H), 7.32 (d, J = 8.2 Hz, 2 H, m-H), 7.48 (br.
s, 1 H, NH), 7.85 (d, J = 8.2 Hz, 2 H, o-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 15.3 (C-1Ј), 21.6 (p-CH3), 33.1 (C-6), 33.8
(C-1ЈЈ), 42.2 (C-3), 42.4 (C-3a), 44.4, 44.7 (C-1, C-6a), 52.8 (C-4),
117.7 (C-3ЈЈ), 128.1 (C-o), 129.5 (C-m), 134.8 (C-2ЈЈ), 135.2 (C-p),
{[(1R,2R,3aS,6aR)-1-Allyl-1,2,3,3a,4,6a-hexahydropentalen-2-
yl]oxy}(tert-butyl)diphenylsilane (24) and {[(2R,3R,3aS,6aR)-3-
Allyl-1,2,3,3a,4,6a-hexahydropentalen-2-yl]oxy}(tert-butyl)diphen-
ylsilane (24Ј): As described above for the synthesis of 20b, from 18b
(1.11 g, 1.90 mmol), TMEDA (1.50 mL, 9.91 mmol) in abs. THF
(12 mL) and nBuLi (3.32 mL, 5.31 mmol), 4 h at room tempera-
ture, extraction with CHCl3 (3ϫ 150 mL), flash chromatography
on SiO2 (hexanes/EtOAc = 20:1); yield 535 mg (1.33 mmol, 70%,
95% purity by GC, 1 signal) of a 1:1 mixture of 24 and 24Ј (by
NMR). Rf = 0.95 (hexanes/EtOAc = 5:1). 1H NMR (500 MHz,
CDCl3): δ = 1.04 [s, 9 H, SiC(CH3)3], 1.23–1.35 (m, 1 H, 3-Ha),
1.31 (tt, J = 13.2, 9.1 Hz, 1 H, 3-Ha*), 1.64 (dq, J = 8.5, 4.2 Hz, 1
H, 1-H), 1.79 (dt, J = 13.6, 8.7 Hz, 1 H, 1Ј-Ha), 1.82–1.92 (m, 1 H,
3-Hb), 1.84–1.90 (m, 2 H, 1Ј-Ha*, 3-Hb*), 2.04–2.12 (m, 2 H, 4-Ha,
6a-H), 2.05–2.10 (m, 1 H, 6a-H*), 2.14–2.20 (m, 1 H, 6-Ha*), 2.35–
2.41 (m, 1 H, 1Ј-Hb), 2.44–2.58 (m, 2 H, 3a-H, 4-Hb), 2.44–2.52
(m, 1 H, 6-Hb*), 2.74–2.81 (m, 1 H, 3a-H*), 3.68 (dq, J = 8.9,
6.1 Hz, 1 H, 2-H), 4.88–4.98 (m, 2 H, 3Ј-H), 5.51–5.54 (m, 1 H, 6-
H, 4-H*), 5.57–5.60 (m, 1 H, 5-H*), 5.62–5.65 (m, 1 H, 5-H), 5.66–
6.76 (m, 1 H, 2Ј-H), 7.34–7.39 (m, 4 H, m-H, mЈ-H), 7.40–7.45 (m,
2 H, p-H, pЈ-H), 7.64–7.70 (m, 4 H, o-H, oЈ-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 19.2 [SiC(CH3)3], 27.0 [SiC(CH3)3], 36.8
(C-1Ј*), 37.6 (C-1Ј), 39.6 (C-6*), 39.7 (C-4), 40.1 (C-3), 42.3 (C-
6a,6a*), 42.3 (C-3*), 53.1 (C-1), 53.4 (C-3a), 54.6 (C-1*), 78.3 (C-
2), 78.7 (C-2*), 115.4 (C-3Ј), 127.4, 127.5 (C-m, C-mЈ), 127.8 (C-
6), 127.9 (C-4*), 129.4, 129.5 (C-p, C-pЈ), 134.2, 134.3 (C-i, C-iЈ),
134.5 (C-5), 134.6 (C-5*), 135.9, 136.0 (C-o, C-oЈ), 137.4 (C-2Ј),
137.7 (C-2Ј*) ppm (* denotes signals of 24Ј).
144.1 (C-i), 167.0 (C-2), 218.5 (C-5) ppm. FTIR (ATR): ν = 3213
˜
(br, w), 3074 (w), 2964 (w), 2928 (m), 2872 (w), 2254 (w), 1733 (s),
1641 (w), 1598 (w), 1404 (m), 1337 (m), 1164 (s), 1093 (m), 1019
(m), 906 (vs), 614 (m), 729 (vs), 669 (m), 649 (m), 550 (m) cm–1.
MS (ESI): m/z = 361.2 [M + H]+, 263.1, 205.2 [M + H – C7H8-
O2S]+, 190.1 [M + H – C7H8NO2S]+, 148.1, 139.0, 123.1, 108.1.
HRMS (ESI): calcd. for C19H25N2O3S+ [M + H]+ 361.1580; found
361.1586.
(1R,3aR,4S,6aS)-1-Allyl-4-methyl-3,3a,4,6a-tetrahydropentalen-
2(1H)-one (16): As described above for 20b, from 23 (81.0 mg,
0.23 mmol) in abs. THF (3 mL) and TMEDA (0.5 mL), nBuLi
(0.33 mL, 0.56 mmol), 2 h at room temperature, extraction with
CHCl3 (3 ϫ 50 mL), flash chromatography on SiO2 (hexanes/
EtOAc = 70:1); yield 11.0 mg (60.0 μmol, 27%, Ͼ90% purity by
13C NMR) containing up to 10% starting material, yellowish oil.
Rf = 0.27 (hexanes/EtOAc = 20:1). [α]2D0 = –4.2 (c = 1.0, CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 1.05 (d, J = 7.1 Hz, 3 H, 1ЈЈ-H),
1.93 (dd, J = 19.1, 6.6 Hz, 1 H, 1-Ha), 2.03 (ddt, J = 14.9, 7.6,
1.1 Hz, 1 H, 1Ј-Ha), 2.43–2.50 (m, 2 H, 3-H, 6a-H), 2.50–2.56 (m,
1 H, 6-H), 2.57–2.63 (m, 1 H, 1Ј-Hb), 2.64 (ddd, J = 19.1, 10.2,
1.8 Hz, 1 H, 1-Hb), 3.60–3.65 (m, 1 H, 3a-H), 5.05 (dq, J = 10.2,
1.4 Hz, 1 H, 3Ј-Ha), 5.13 (dq, J = 13.6, 1.4 Hz, 1 H, 3Ј-Hb), 5.61
(dt, J = 5.7, 1.5 Hz, 1 H, 4-H), 5.77 (dt, J = 5.7, 2.5 Hz, 1 H, 5-
H), 5.89 (dddd, J = 13.6, 10.2, 7.7, 5.9 Hz, 1 H, 2Ј-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 18.8 (C-1ЈЈ), 30.3 (C-1Ј), 41.5 (C-3),
42.8 (C-1), 47.0 (C-6), 48.0 (C-3a), 50.2 (C-6a), 114.9 (C-3Ј), 127.0
(C-4), 135.5 (C-2Ј), 137.1 (C-5), 217.9 (C-2) ppm. FTIR (ATR): ν
{[(1aR,1bS,3R,4R,4aS,5aS)-4-Allyloctahydropentaleno[1,2-b]oxiren-
3-yl]oxy}(tert-butyl)diphenylsilane (25 and epi-25) and
˜
= 3429 (br, vs), 2251 (m), 2128 (w), 1660 (br, s), 1051 (s), 1023 (vs),
1003 (vs), 1373 (w), 822 (s), 759 (s), 731 (m), 624 (m) cm–1. MS {[(1aS,1bS,2R,3R,4aS,5aR)-2-Allyloctahydropentaleno[1,2-b]oxiren-
(EI): m/z (%) = 176.1 (72) [M]+, 161.1 (37) [M – Me]+, 147.1 (11)
[M – H2O – Me]+, 134.1 (51), 119.1 (41) [M – Me – C3H6]+, 105.1 (129 mg, 0.75 mmol) was added to a suspension of 24, 24Ј (150 mg,
(25), 96.1 (76), 91.0 (69), 79.0 (100), 65.0 (12), 55.0 (17), 38.9 (20). 0.37 mmol) and NaHCO3 (156 mg, 1.86 mmol) in abs. CH2Cl2
3-yl]oxy}(tert-butyl)diphenylsilane (26 and epi-26): MCPBA
Eur. J. Org. Chem. 2013, 761–771
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
769

V. Lutz, N. Park, C. Rothe, C. Krüger, A. Baro, S. Laschat
FULL PAPER
(5 mL) in a Schlenk flask and the reaction mixture was stirred for
1 h at room temperature. The reaction was quenched with a satu-
rated solution of Na2S2O5 (10 mL) and the layers were separated.
The organic layer was washed with a saturated solution of
NaHCO3/H2O (10 mL), dried (MgSO4) and concentrated. The resi-
due was purified by chromatography on SiO2 (hexanes/EtOAC =
20:1) to give a mixture of epoxides 25, epi-25, 26 and epi-26 in a
53.0 (C-6a*), 54.9 (C-3a), 79.4 (C-5*), 79.5 (C-5), 84.6 (C-1), 85.0
(C-1*), 116.2 (C-3Ј*), 116.3 (C-3Ј), 127.81, 127.84 (C-m, C-mЈ),
127.88, 127.89 (C-m*, C-mЈ*), 129.90, 129.91 (C-p, C-pЈ), 129.9,
130.0 (C-p*, C-pЈ*), 130.6 (C-2*), 130.7 (C-2), 134.36, 134.42 (C-i,
C-iЈ), 136.27, 136.29 (C-o, C-oЈ), 137.4 (C-2Ј*), 138.0 (C-2Ј), 140.3
(C-3), 140.4 (C-3*) ppm (* denotes signals of 28). 28: 1H NMR
(500 MHz, CDCl3): δ = 1.03 [s, 9 H, SiC(CH3)3], 1.43 (dt, J = 13.2,
ratio of 50:3.5:45:1.5 (by GC; 73.0 mg, 0.17 mmol, 48%, 87% pu- 7.6 Hz, 1 H, 4-Ha), 1.54 (br. s, 1 H, OH), 1.58–1.64 (m, 1 H, 6-H),
rity by GC) as a colourless oil. Rf = 0.52 (hexanes/EtOAc = 10:1). 1.76–1.79 (m, 1 H, 1Ј-Ha), 1.94–1.99 (m, 1 H, 4-Hb), 2.20 (ddt, J
1H NMR (500 MHz, CDCl3): δ = 1.05 [s, 9 H, SiC(CH3)3], 1.42 = 16.4, 8.2, 1.9 Hz, 1 H, 3a-H), 2.22–2.28 (m, 1 H, 1Ј-Hb), 2.77–
(ddd, J = 8.4, 4.8, 2.1 Hz, 1 H, 6-Ha), 1.47 (ddd, J = 13.2, 5.0, 2.82 (m, 1 H, 6a-H), 3.77 (dt, J = 5.4, 7.4 Hz, 1 H, 5-H), 4.58–4.60
2.3 Hz, 1 H, 3-Ha), 1.65–1.90 (m, 5 H, 1-H, 1Ј-Ha, 3-Hb, 6-Hb, 3a- (m, 1 H, 1-H), 4.90–4.97 (m, 2 H, 3Ј-H), 5.63 (dddd, J = 17.1, 14.3,
H), 2.01–2.10 (m, 1 H, 1Ј-Hb), 2.48 (dt, J = 8.5, 8.5 Hz, 1 H, 6a-
H), 3.36 (d, J = 2.8 Hz, 1 H, 4-H), 3.53–3.55 (m, 1 H, 5-H), 3.85–
3.89 (m, 1 H, 2-H), 4.84–4.94 (m, 2 H, 3Ј-H), 5.54 (dddd, J = 14.5,
11.1, 7.3, 4.6 Hz, 1 H, 2Ј-H), 7.35–7.40 (m, 4 H, m-H, mЈ-H), 7.40–
7.45 (m, 2 H, p-H, pЈ-H), 7.63–7.67 (m, 4 H, o-H, oЈ-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 19.3 [SiC(CH3)3], 27.1 [SiC(CH3)3],
36.1 (C-6), 37.7 (C-1Ј), 41.0 (C-3), 43.0 (C-6a), 50.0 (C-3a), 55.4
(C-1), 60.0 (C-5), 62.1 (C-4), 80.8 (C-2), 116.4 (C-3Ј), 127.96,
127.73 (C-m, C-mЈ), 129.77, 129.84 (C-p, C-pЈ), 134.3, 134.4 (C-i,
10.0, 6.9 Hz, 1 H, 2Ј-H), 5.64–5.68 (m, 1 H, 2-H), 5.94 (dd, J =
5.7, 2.5 Hz, 1 H, 3-H), 7.34–7.39 (m, 4 H, m-H, mЈ-H), 7.40–7.45
(m, 2 H, p-H, pЈ-H), 7.62–7.67 (m, 4 H, o-H, oЈ-H) ppm.
(3aR,4R,5R,6aS)-4-Allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-4,5,
6,6a-tetrahydropentalen-1(3aH)-one (17) and (3aR,5R,6R,6aS)-6-
Allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-4,5,6,6a-tetrahydropentalen-
1(3aH)-one (29): DMP (38.0 mg, 90.0 μmol) was added to a mix-
ture of 27 and 28 (31.0 mg, 70.0 μmol) in abs. CH2Cl2 (3 mL) at
0 °C and the suspension was stirred for 2 h. Then a saturated solu-
tion of NaHCO3/H2O (3 mL) was added and the layers were sepa-
rated. The aqueous layer was extracted with CHCl3 (3ϫ 10 mL).
The combined organic layers were dried (MgSO4) and concen-
trated. The residue was purified by chromatography on SiO2 (hex-
anes/EtOAc = 10:1) to give in the first fraction 29 (7.00 mg,
C-iЈ), 136.0, 136.1 (C-o, C-oЈ), 136.7 (C-2Ј) ppm. FTIR (ATR): ν
˜
= 2931 (w), 2858 (w), 2253 (w), 1428 (w), 1110 (m), 904 (vs), 726
(vs), 649 (s), 613 (w) cm–1. MS (CI): m/z (%) = 419.3 (11) [M +
H]+, 401.3 (22), 361.2 (100) [M – C4H9]+, 341.2 (38) [M – C6H5]+,
283.1 (25), 199.1 (21), 163.1 (5) [M – C16H19OSi]+, 145.1 (37).
HRMS (CI): calcd. for C27H35O2Si+ [M + H]+ 419.2400; found
419.2405.
1
16.8 μmol, 24%, Ͼ95% purity by H NMR) as a colourless oil, in
the second fraction a mixture of 17 and 29 (5.00 mg, 12.0 μmol,
17%) and in the third fraction 17 and 29 in a GC ratio of 95:5
(10.0 mg, 24.0 μmol, 34%, 95% purity by GC) as a colourless oil.
Ketone 17: Rf = 0.44 (hexanes/EtOAc = 5:1). [α]2D0 = –9.2 (c = 1.0,
CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 0.98 [s, 9 H, SiC-
(3aS,4R,5R,6aS)-4-Allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-
1,3a,4,5,6,6a-hexahydropentalen-1-ol (27) and (3aR,5R,6R,6aS)-6-
Allyl-5-{[tert-butyl(diphenyl)silyl]oxy}-1,3a,4,5,6,6a-hexahydro-
pentalen-1-ol (28): A solution of the epoxide mixture 25,epi-25, 26,
epi-26 (62.0 mg, 0.15 mmol) and TMEDA (111 μL, 0.74 mmol) in (CH3)3], 1.79 (dd, J = 13.5, 7.7 Hz, 1 H, 1Ј-Ha), 1.86 (ddd, J =
Et2O (2 mL) was slowly added to a solution of LDA [prepared in
situ by the dropwise addition of nBuLi (230 μL, 0.37 mmol, 1.6 m
in n-hexane) to a solution of diisopropylamine (53.0 μL,
0.37 mmol) in Et2O (1 mL) at –20 °C and then warming to room
temperature] and the reaction mixture was stirred at room tempera-
ture for 6 h. The reaction was quenched by the addition of a satu-
rated solution of NH4Cl/H2O (3 mL), the layers were separated and
the aqueous layer was extracted with CHCl3 (3ϫ 25 mL). The com-
bined organic layers were dried (MgSO4) and concentrated. The
residue was purified by chromatography on SiO2 [hexanes/EtOAc
= 5:1, Rf = 0.29 (27), Rf = 0.27 (28)] to give a 1:1 mixture (by GC
and NMR) of 27 and 28 (37.0 mg, 88.0 μmol, 59%, Ͼ90% purity
12.1, 6.1, 3.1 Hz, 1 H, 6a-H), 1.95–2.03 (m, 3 H, 1Ј-Hb, 6-Ha, 6-
Hb), 2.69 (tt, J = 5.0, 4.9 Hz, 1 H, 4-H), 2.95–2.99 (m, 1 H, 3a-H),
3.92 (q, J = 7.7 Hz, 1 H, 5-H), 4.89–4.94 (m, 2 H, 3Ј-H), 5.43–5.53
(m, 1 H, 2Ј-H), 6.08 (dd, J = 5.5, 2.0 Hz, 1 H, 2-H), 7.35–7.39 (m,
4 H, m-H, mЈ-H), 7.40–7.44 (m, 2 H, p-H, pЈ-H), 7.58–7.62 (m, 4
H, o-H, oЈ-H), 7.65 (dd, J = 5.5, 2.9 Hz, 1 H, 3-H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 18.9 [SiC(CH3)3], 26.8 [SiC(CH3)3], 36.7
(C-6), 37.6 (C-1Ј), 47.7 (C-4), 50.5 (C-6a), 51.4 (C-3a), 80.2 (C-5),
116.6 (C-3Ј), 127.57, 127.59 (C-m, C-mЈ), 129.7 (C-p, C-pЈ), 132.1
(C-2), 133.6, 133.8 (C-i, C-iЈ), 135.9 (C-o, C-oЈ), 136.1 (C-2Ј), 167.3
(C-3), 213.1 (C-1) ppm. FTIR (ATR): ν = 2932 (m), 2858 (w), 2364
˜
(w), 1702 (s), 1588 (w), 1428 (w), 1110 (s), 1063 (m) cm–1. MS
(ESI): m/z = 439.2 [M + Na]+, 339.2 [M + H – C6H6]+. HRMS
(ESI): calcd. for C27H32O2SiNa+ [M + Na]+ 439.2064; found
439.2072. Ketone 29: Rf = 0.51 (hexanes/EtOAc = 5:1). [α]2D0 = –8.7
by 13C NMR) as a colourless oil. FTIR (ATR): ν = 3073 (w), 2930
˜
(m), 2858 (w), 2362 (m), 2253 (w), 2178 (w), 2014 (w), 1716 (w),
1472 (w), 1428 (m), 1377 (m), 1261 (w), 1111 (s), 1007 (w), 903
(vs), 821 (w), 725 (vs), 650 (s) cm–1. MS (ESI): m/z = 441.2 [M +
1
(c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 0.96 [s, 9 H,
Na]+, 401.2 [M + Na – C3H6]+, 341.2, 329.2, 301.1, 223.2, 203.1, SiC(CH3)3], 1.68 (d, J = 13.7 Hz, 1 H, 4-Ha), 1.84–1.93 (m, 3 H,
145.1, 119.1. HRMS (ESI): calcd. for C27H34O2SiNa+ [M + Na]+
441.2220; found 441.2209. 27: 1H NMR (500 MHz, CDCl3): δ =
1.03 [s, 9 H, SiC(CH3)3], 1.22–1.29 (m, 1 H, 6-Ha), 1.54 (br. s, 1 H,
4-Hb, 1Ј-H), 2.33–2.39 (m, 1 H, 6-H), 2.49 (dd, J = 6.1, 2.1 Hz, 1
H, 6a-H), 3.29–3.34 (m, 1 H, 3a-H), 3.97 (dt, J = 4.0, 2.0 Hz, 1 H,
5-H), 4.86–4.91 (m, 2 H, 3Ј-H), 5.48 (dddd, J = 16.4, 13.7, 9.6,
OH), 1.73–1.78 (m, 1 H, 4-H), 1.83 (dt, J = 3.2, 6.3 Hz, 1 H, 6- 6.8 Hz, 1 H, 2Ј-H), 6.12 (dd, J = 5.5, 2.0 Hz, 1 H, 2-H), 7.34–7.38
Hb), 1.83–1.90 (m, 1 H, 1Ј-Ha), 1.92–1.97 (m, 1 H, 3a-H), 2.35–
2.42 (m, 1 H, 1Ј-Hb), 2.99–3.06 (m, 1 H, 6a-H), 3.77 (dt, J = 5.4,
(m, 4 H, m-H, mЈ-H), 7.40–7.44 (m, 2 H, p-H, pЈ-H), 7.57–7.61 (m,
4 H, o-H, oЈ-H), 7.68 (dd, J = 5.5, 2.9 Hz, 1 H, 3-H) ppm. 13C
7.4 Hz, 1 H, 5-H), 4.66–4.68 (m, 1 H, 1-H), 4.95–5.03 (m, 2 H, 3Ј- NMR (125 MHz, CDCl3): δ = 18.9 [SiC(CH3)3], 26.7 [SiC(CH3)3],
H), 5.64–5.68 (m, 1 H, 2-H), 5.78 (dddd, J = 17.0, 14.6, 10.1,
7.6 Hz, 1 H, 2Ј-H), 5.89 (dd, J = 5.7, 2.5 Hz, 1 H, 3-H), 7.34–7.39
36.2 (C-4), 37.5 (C-1Ј), 45.4 (C-3a), 51.4 (C-6), 53.8 (C-6a), 79.9
(C-5), 116.6 (C-3Ј), 127.5, 127.6 (C-m, C-mЈ), 129.6, 129.7 (C-p, C-
(m, 4 H, m-H, mЈ-H), 7.40–7.45 (m, 2 H, p-H, pЈ-H), 7.62–7.67 pЈ), 132.7 (C-2), 133.4, 134.0 (C-i, C-iЈ), 135.8, 136.0 (C-o, C-oЈ),
(m, 4 H, o-H, oЈ-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 19.5 136.9 (C-2Ј), 167.8 (C-3), 212.4 (C-1) ppm. FTIR (ATR): ν = 3072
˜
[SiC(CH3)3], 27.3 [SiC(CH3)3], 37.8 (C-1Ј), 37.9 (C-1Ј*), 39.1 (C-
4*), 39.2 (C-6), 46.0 (C-6a), 48.6 (C-3a*), 51.9 (C-6*), 52.2 (C-4),
(m), 2857 (m), 2253 (w), 1703 (s), 1588 (w), 1427 (w), 1109 (s), 1070
(s) cm–1. MS (ESI): m/z = 434.2 [M + NH4]+, 339.2 [M + H –
770
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 761–771

Functionalization of Bicyclo[3.3.0]octanes
C6H6]+. HRMS (ESI): calcd. for C27H32O2SiNH4 [M + NH4]+
434.2510; found 434.2515.
+
J. Gais, Eur. J. Org. Chem. 2011, 5991–6008; e) T. Hata, S.
Sujaku, N. Hirone, K. Nakano, J. Imoto, H. Imade, H. Urabe,
Chem. Eur. J. 2011, 17, 14593–14602; f) Y. Onizawa, M. Hara,
T. Hashimoto, H. Kusama, N. Iwasawa, Chem. Eur. J. 2010,
16, 10785–10796; g) A. Srikrishna, G. Neetu, Tetrahedron:
Asymmetry 2010, 21, 2067–2071; h) J. A. Henderson, A. J. Phil-
lips, Angew. Chem. 2008, 120, 8627–8629; Angew. Chem. Int.
Ed. 2008, 47, 8499–8501; i) T. Anderl, M. Emo, S. Laschat,
A. Baro, W. Frey, Synthesis 2008, 1619–1627; j) C. Oger, Y.
Brinkmann, S. Bouazzaoui, T. Durand, J.-M. Galano, Org.
Lett. 2008, 10, 5087–5090; k) C. Hofmann, A. Baro, S. Laschat,
Synlett 2008, 1618–1622; l) A. J. Phillips, A. C. Hart, J. A. Hen-
derson, Tetrahedron Lett. 2006, 47, 3743–3745; m) A.
Becheanu, A. Baro, S. Laschat, W. Frey, Eur. J. Org. Chem.
2006, 2215–2225.
Supporting Information (see footnote on the first page of this arti-
cle): Further experimental results, NOESY spectra for spectral as-
signments and NMR spectra of all new compounds.
Acknowledgments
Generous financial support by the Deutsche Forschungsgemein-
schaft (DFG), the Fonds der Chemischen Industrie, and the Minis-
terium für Wissenschaft, Forschung und Kunst des Landes Baden-
Württemberg is gratefully acknowledged.
[13] I. Vaulont, H.-J. Gais, N. Reuter, E. Schmitz, R. K. L. Ossen-
kamp, Eur. J. Org. Chem. 1998, 805–826.
[1] For reviews, see: a) P. O’Brien, J. Chem. Soc. Perkin Trans. 1
1998, 1439–1457; b) P. O’Brien, J. Chem. Soc. Perkin Trans. 1
2001, 95–113; c) N. S. Simpkins, Quim. Nova 1995, 18, 295–
297; d) N. S. Simpkins, Chem. Soc. Rev. 1990, 19, 335–354; e)
P. J. Cox, N. S. Simpkins, Tetrahedron: Asymmetry 1991, 2, 1–
26.
[2] 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.
[14] 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. J. 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.
[15] a) H.-J. Gais, G. J. Kramp, D. Wolters, L. R. Reddy, Chem. Eur.
J. 2006, 12, 5610–5617; b) M. van Bergen, H.-J. Gais, J. Am.
Chem. Soc. 2002, 124, 4321–4328.
[16] K. Petzoldt, H. Dahl, W. Skuballa, H. Gottwald, Liebigs Ann.
Chem. 1990, 1087–1091.
[17] J. Mulzer, U. Kaselow, K.-D. Graske, H. Kühne, A. Sieg, H. J.
Martin, Tetrahedron 2004, 60, 9599–9614.
[3] a) R. P. C. Cousins, N. S. Simpkins, Tetrahedron Lett. 1989, 30,
7241–7244; b) N. S. Simpkins, Chem. Ind. 1988, 387–389.
[4] J. Leonard, D. Ouali, S. K. Rahman, Tetrahedron Lett. 1990,
31, 739–742.
[18] V. Lutz, A. Baro, P. Fischer, S. Laschat, Eur. J. Org. Chem.
2010, 1149–1157.
[19] a) C. G. Overberger, N. P. Marullo, R. G. Hiskey, J. Am. Chem.
Soc. 1961, 83, 1374–1378; b) M. van de Sande, Ph. D., RWTH
Aachen, Germany, 2006.
[20] a) R. H. Shapiro, M. F. Lipton, K. J. Kolonko, R. L. Buswell,
L. A. Capuano, Tetrahedron Lett. 1975, 16, 1811–1814; for a
review, see: b) R. H. Shapiro, Org. React. 1976, 23, 405–507; c)
R. M. Adlington, A. G. M. Barrett, Acc. Chem. Res. 1983, 16,
55–59; d) J. C. Caille, M. Farnier, R. Guilard, Can. J. Chem.
1986, 64, 824–830.
[5] a) L. S. Bennie, W. J. Kerr, M. Middleditch, A. J. B. Watson,
Chem. Commun. 2011, 47, 2264–2266; b) O. Muñoz-Muñiz, E.
Juaristi, Tetrahedron 2003, 59, 4223–4229; c) H. Abe, T. Tsu-
jino, K. Araki, Y. Takeuchi, T. Harayama, Tetrahedron: Asym-
metry 2002, 13, 1519–1527; d) K. W. Henderson, W. J. Kerr,
J. H. Moir, Tetrahedron 2002, 58, 4573–4587; e) K. W. Hender-
son, W. J. Kerr, J. H. Moir, Chem. Commun. 2000, 479–480; f)
J. Busch-Petersen, E. J. Corey, Tetrahedron Lett. 2000, 41,
6941–6944; g) V. K. Aggarwal, P. S. Humphries, A. Fenwick,
Angew. Chem. 1999, 111, 2178–2180; Angew. Chem. Int. Ed. [21] a) R. H. Shapiro, M. J. Heath, J. Am. Chem. Soc. 1967, 89,
1999, 38, 1985–1986; h) P. Knochel, Angew. Chem. 1992, 104,
1486–1488; Angew. Chem. Int. Ed. Engl. 1992, 31, 1459–1461.
[6] 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.
[7] D. Schinzer, in: Organic Synthesis Highlights II (Ed.: H. Wald-
mann), VCH, Weinheim, Germany, 1995, pp. 301–307.
[8] V. Singh, G. Chandra, S. M. Mobin, Synlett 2008, 3111–3114.
[9] 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.
5734–5735; b) G. Kaufman, F. Cook, H. Shechter, J. Bayless,
L. Friedman, J. Am. Chem. Soc. 1967, 89, 5736–5737; c) R. H.
Shapiro, Tetrahedron Lett. 1968, 9, 345–347; d) J. Meinwald, F.
Uno, J. Am. Chem. Soc. 1968, 90, 800.
[22] O. P. Törmäkangas, R. J. Toivola, E. K. Karvinen, A. M. P.
Koskinen, Tetrahedron 2002, 58, 2175–2181.
[23] 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; c) M. A. Dyadchenko, G. A. Dani-
lova, I. Shpanig, G. Shik, K. K. Pivnitskii, Zh. Org. Khim.
1990, 26, 2536–2542; d) P. M. Henry, M. Davies, G. Ferguson,
S. Phillips, R. Restivo, J. Chem. Soc., Chem. Commun. 1974,
112–113.
[10] A. M. S. Mayer, M. T. Hamann, Comp. Biochem. Physiol., Part
C: Toxicol. Pharmacol. 2002, 132, 315–339.
[11] S. Kanazawa, N. Fusetani, S. Matsunaga, Tetrahedron Lett.
1993, 34, 1065–1068.
[12] For selected recent examples, see: a) K. Shibatomi, F. Kobaya-
shi, A. Narayama, I. Fujisawa, S. Iwasa, Chem. Commun. 2012,
48, 413–415; b) J.-F. Brazeau, S. Zhang, I. Colomer, B. K.
[24] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
[25] J. Leonard, N. Hussain, J. Chem. Soc. Perkin Trans. 1 1994,
61–70.
Corkey, F. D. Toste, J. Am. Chem. Soc. 2012, 134, 2742–2749; [26] J.-C. Fiaud, J.-Y. Legros, J. Org. Chem. 1987, 52, 1907–1911.
c) N. Cos¸kun, J. Ma, S. Azimi, C. Gärtner, I. Erden, Org. Lett.
2011, 13, 5952–5955; d) S. Acikalin, G. Raabe, J. Runsink, H.-
Received: October 23, 2012
Published Online: December 10, 2012
Eur. J. Org. Chem. 2013, 761–771
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
771