A stereoselective, Sm(ii)-mediated approach to decorated cis-hydrindanes: Synthetic studies on faurinone and pleuromutilin

Article abstract of DOI:10.1039/c0ob01086c

The cis-hydrindane motif is found in a number of natural products that display important biological activity. A flexible, stereoselective approach to the framework has been developed that features highly diastereoselective, SmI₂-mediated cyclisations. The strategy has been exploited in the first synthesis of the proposed structure of faurinone and an approach to the skeleton of the antibacterial natural product, pleuromutilin.

Full text of DOI:10.1039/c0ob01086c

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 2433
www.rsc.org/obc
PAPER
A stereoselective, Sm(II)-mediated approach to decorated cis-hydrindanes:
synthetic studies on faurinone and pleuromutilin†‡
Thomas J. K. Findley,a David Sucunza,a Laura C. Miller,a Matthew D. Helm,a Madeleine Helliwell,a
David T. Daviesb and David J. Procter*a
Received 25th November 2010, Accepted 5th January 2011
DOI: 10.1039/c0ob01086c
The cis-hydrindane motif is found in a number of natural products that display important biological
activity. A flexible, stereoselective approach to the framework has been developed that features highly
diastereoselective, SmI2-mediated cyclisations. The strategy has been exploited in the first synthesis of
the proposed structure of faurinone and an approach to the skeleton of the antibacterial natural
product, pleuromutilin.
Introduction
Since its introduction to the synthetic community by Kagan,
the one-electron reducing agent samarium(II) iodide (SmI2) has
found widespread use in organic synthesis.1 The reagent has been
used to mediate processes ranging from functional group inter-
conversions to complex carbon-carbon bond-forming sequences
in which molecular complexity is increased dramatically in a
single operation.1 Cyclisation reactions are among the most useful
transformations mediated by SmI2 and these have proved to be
valuable tools for natural product synthesis.1b,d The intramolecular
addition of radicals, generated from aldehydes and halides, to
alkenes, is an important class of cyclisation mediated by the
reagent.1
The hydrindane skeleton is found in many biologically active
natural products. We wished to develop a stereoselective approach
to the cis-hydrindane skeleton 1 that would allow stereocontrolled
installation of substituents around the bicyclic structure.2
A
flexible approach to 1 would facilitate approaches to a number
of natural products, many of which display important biological
activity (Fig. 1). The sesquiterpene glycosides, dendronobilosides
A and B, display immunomodulatory activity,3 and are closely
related to faurinone 2.4 Pleuromutilin 3 has an inhibitory effect
against the bacteria Staphylococcus aureous and is known to pre-
vent bacterial protein synthesis.5 Bakkenolides, such as 4, display
a variety of biological activities including selective cytotoxicity.6
Fig. 1 Selected natural products containing a substituted cis-hydrindane
core.
Here we describe in full a flexible approach to the substituted cis-
hydrindane skeleton that exploits highly diastereoselective SmI2-
mediated cyclisations of aldehyde and halide substrates.7 We have
applied the approach in the first synthesis of the proposed structure
of rac-faurinone and in an approach to the skeleton of the
antibacterial natural product pleuromutilin.
aSchool of Chemistry, The University of Manchester, Oxford Road,
Manchester, M13 9PL, UK. E-mail: david.j.procter@manchester.ac.uk;
Fax: (+)44 161 275 4939
Results and discussion
bGlaxoSmithKline, Gunnelswood Road, Stevenage, SG1 2NY, UK
† Dedicated to Professor Athel Beckwith for his pioneering work on
organic free radicals
‡ Electronic supplementary information (ESI) available: NMR spectra
and X-ray structure of 59 CCDC reference number 802039. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob01086c
We envisaged constructing the quaternary stereocentre in 1 by
conjugate addition to substituted b-alkyl cyclohexenones. Prior to
our work, little was known about the efficacy and diastereoselec-
tivity of such additions.8 Aldehydes or halides 5 would therefore be
accessible from enones 7 via protected intermediates 6. We believed
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2433
©

View Article Online
that substrates 5 would undergo highly stereoselective 5-exo-trig
cyclisations on treatment with SmI2 (Scheme 1).
Scheme 1 A proposed approach to the cis-hydrindane skeleton (PG =
protecting group, X = H or OEt).
Aldehydes 13 and 14 were prepared to investigate the diastere-
oselectivity of the proposed SmI2-mediated construction of the
cis-hydrindane system. Addition of the Grignard reagent derived
from 3-chloropropan-1-ol to 89 according to the procedure of
Tietze,10 and protection of the primary hydroxyl gave 9 (Scheme 2).
Subsequent dimethylation of enone 9 gave 10. Treatment of enones
9 and 10 with dimethylcuprate and trapping of the resultant
enolates with Comins’ reagent11 gave enol triflates 11 and 12.
Palladium-catalyzed methoxycarbonylation, deprotection, and
oxidation then gave 13 and 14 in good overall yield (Scheme 2).
The route can be readily adapted to access a range of decorated
cyclisation substrates (Scheme 3). For example, methylation of
enone 9 and conjugate addition using a range of alkylmetals,
followed by enolate trapping gave enol triflates 15–18 in good yield
and with moderate diastereoselectivity, thus illustrating the utility
of the conjugate addition for the stereocontrolled construction
of the quaternary stereocentre. The stereochemistry of the major
diastereoisomer from the addition of methylcuprate was assigned
by NOE studies on the deprotected ketone adduct, isolated when
Comins’ reagent was omitted. Enol triflate 23 was prepared by
Scheme 2 General route to unsaturated aldehyde cyclisation substrates
(Comins’ reagent = N-(5-chloro-2-pyridyl)triflimide).
methylation of enol ether 8, Grignard addition, protection, and
methylcuprate addition-enolate trapping. Enol triflates 15–18 and
23 were then converted to cyclisation substrates19–22 and 24 using
the straightforward sequence outlined in Scheme 2.
Upon treatment with SmI2 in THF and t-BuOH, the unsat-
urated aldehyde substrates, 13, 14, 19–22 and 24, underwent
cyclisation in high yield and with high diastereoselectivity (>10 : 1
1
dr by H NMR, a- to the ester) observed in the construction of
three stereocentres (Fig. 2).
The stereochemistry of 26 and 27 was confirmed by treat-
ment with 1-naphthyl isocyanate to give carbamates 32 and 33,
Scheme 3 Synthesis of unsaturated aldehyde cyclisation substrates (Comins’ reagent = N-(5-chloro-2-pyridyl)triflimide).
2434 | Org. Biomol. Chem., 2011, 9, 2433–2451 This journal is The Royal Society of Chemistry 2011
©

View Article Online
occurs selectively from the open b-face (Fig. 3). Indirect, support
for this explanation comes from the X-ray crystal structures of 32
and 33 that clearly show different conformations.
Fig. 3 Origin of diastereoselectivity in the protonation of samar-
ium(III)-enolate intermediates.
Alkyl iodide cyclisation substrates have also prepared: alkyl
iodide 37 was prepared from 17 in three steps and b-keto iodide
42 was prepared in 10 steps from 4-isopropylcyclohexanone. In
the synthesis of 42, Grignard addition to 4-isopropylcyclohex-2-
enone and oxidative rearrangement gave 38. Conjugate addition
followed by enolate trapping gave enol triflate 39 (dr 11 : 1) and
Pd-catalyzed carbonylation and esterification of the resultant acid
then gave 40 as a single diastereoisomer. The use of formic acid
in the Pd-catalysed carbonylation, rather than MeOH, proved
crucial to avoid side reactions. Finally, allylic oxidation, to give an
inconsequential 4 : 1 mixture of allylic alcohol diastereoisomers,
and oxidation gave enone 41 that was smoothly converted to b-
keto iodide 42 using TMSI generated in situ (Scheme 5).14
Iodide 37 and b-keto iodide 42 underwent highly diastereose-
lective cyclisations on treatment with SmI2-HMPA (Scheme 6).15
In the case of 42, cyclization gave a mixture of ketone 45 and over-
reduction product, secondary alcohol 44 (obtained as a single
diastereoisomer), in 75% yield. Alcohol 44 could be oxidized
to ketone 45 in 74% yield using the Dess–Martin periodinane
(Scheme 6). The stereochemistry of 44 and 45 was assigned on
the basis of NOE studies. SmI2-mediated halide-alkene cyclisa-
tions provide a convenient alternative for the synthesis of less-
oxygenated targets.
Fig. 2 cis-Hydrindane products from stereoselective SmI2-mediated
cyclisations of aldehydes.
respectively, followed by X-ray crystallographic analysis
(Scheme 4).12 The stereochemistry of 25, 28–30 was inferred
from the stereochemistry of 27. (The stereochemistry of 28 was
also confirmed by NOE studies). The stereochemistry of 31 was
assigned on the basis of NOE studies.
Cyclisation products 27–30 possess the substitution pattern
found in the cis-hydrindane core of pleuromutilin 3, while products
31 and 45 display the cis-hydrindane cores of bakkenolide III 4
and the dendronobilosides 2a/2b, respectively (see Fig. 1).
We have exploited the approach in a concise synthesis of the
proposed structure of faurinone 2, a sesquiterpene ketone isolated
from valeriana officinalis (Fig. 1).4 Grignard addition to 4-i-
propylcyclohexenone and oxidative rearrangement of the resultant
tertiary alcohol with PCC gave enone 46.16 Highly diastereoselec-
tive organocopper addition, enolate trapping, carbonylation and
acetal deprotection then gave aldehyde cyclisation substrate 47 (dr
> 20 : 1). Alkyl iodide substrate 48 was prepared from 47 in two
steps (Scheme 7).
As expected, cyclisation of aldehyde 47 with SmI2 proceeded
with excellent stereocontrol to give 49 as a single diastereoisomer
by 1H NMR. The stereochemical outcome of the cyclisation was
confirmed by conversion of 49 to the 1-naphthyl carbamate 51
and X-ray crystallographic analysis.12 Iodide 48 also underwent
smooth cyclisation on treatment with SmI2-HMPA15 to give 50 as
a single diastereoisomer by 1H NMR (Scheme 8).
Scheme 4 Determination of stereochemistry in 26 and 27.
All substrates gave the syn,syn-diastereoisomeric products with
the exception of 14 which underwent cyclisation to give 26 as the
syn,anti-diastereoisomer. The SmI2-mediated cyclisations proceed
by reduction of the aldehyde and addition of the resulting ketyl-
radical anion to the alkene through anti-intermediate 34 to give
samarium(III)-enolates.13 Cyclisation of 13 gives samarium(III)-
enolate 35 that undergoes protonation selectively from the open a-
face. In contrast, cyclisation of 14 gives samarium(III)-enolate 36,
possessing the alternative chair conformation. Protonation then
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2435
©

View Article Online
Scheme 6 SmI2-mediated cyclisations of alkyliodides for the stereoselec-
tive construction of the cis-hydrindane skeleton.
Scheme 5 Diastereoselective synthesis of unsaturated iodide cyclisation
substrates.
Our approach to faurinone continued with the epimerisation
of 49 and formation of the bis-lactone 52. The structure of 52
was confirmed by X-ray crystallography.12 Reaction of 52 with
methyllithium gave 53 in good yield. We believe the stability of
the cyclic, bis-hemi-ketal accounts for the smooth mono-addition
of methyllithium to each carbonyl group. Conversion of 53 to
the corresponding thioimidazolide and radical deoxygenation
completes the first synthesis of the proposed structure of faurinone
2 (Scheme 9). While only partial spectroscopic data is available
for the natural product, NMR data for synthetic 2 prepared
during our studies does not match the partial, data for the natural
product reported by Bos.4 We have also prepared epi-2 from 50
(TMSCH2Li, THF, 0 ◦C, 77%). Epi-2 also does not match the
partial literature data for the natural product.4
Scheme 7 Preparation of cyclisation substrates in an approach to the
proposed structure of faurinone.
Aldehyde 54 was then converted to diene 56 by the addition of
but-3-enyl magnesium bromide and aldehyde 55 was converted to
diene 57 by the addition of vinylmagnesium bromide (Scheme 10).
Dienes 56 and 57 were obtained as mixtures of diastereoisomers.
We next investigated the formation of the 8-membered ring
of the pleuromutilin skeleton using ring-closing metathesis
(RCM).19–21 Diene 56 was subjected to the Grubbs II catalyst in
CH2Cl2 at temperatures between room temperature and reflux
but no cyclisation was observed. The corresponding acetate also
failed to undergo cyclisation. Repeating the reactions in refluxing
dichloroethane gave complex mixtures. It appeared that the i-
propenyl group was too hindered for RCM to occur. By moving the
reaction site away from the quaternary centre of the hydrindane
skeleton we hoped to successfully achieve cyclisation. It is also
We have also utilised our approach to cis-hydrindanes in a
synthesis of the tricyclic skeleton of pleuromutilin.17,18 Cyclisation
products 29 and 30 were converted to aldehydes 54 and 55,
respectively, by a protection, reduction and oxidation sequence.
2436 | Org. Biomol. Chem., 2011, 9, 2433–2451
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Scheme 10 Synthesis of RCM substrates in an approach to the tricyclic
core of pleuromutilin.
Scheme 8 Diastereoselective samarium(II)-mediated cyclisations in an
approach to the proposed structure of faurinone.
Scheme 9 Completing an approach to the proposed structure of
faurinone.
known that the presence of allylic hydroxyl groups in diene
substrates can accelerate the rate of carbene-exchange between
the proximal alkene and ruthenium alkylidenes.22 Pleasingly,
slow addition of diene 57 (2 : 1 dr) in CH2Cl2 to Grubbs’ II
catalyst in CH2Cl2 at 40 ◦C resulted in complete cyclisation after
6 h and 58 was isolated as a 2 : 1 mixture of diastereoisomers
in 83% yield. Tricycle 58 was converted to the corresponding
naphthyl carbamate 59 in 84% and recrystallisation gave a single
diastereoisomer that was subjected to X-ray crystallographic
analysis (Scheme 11).12
Scheme 11 Synthesis of the tricyclic core of pleuromutilin.
Preliminary studies have been carried out to show the feasibility
of preparing simplified analogues of pleuromutilin using our
approach. Tricycle alcohol 58 was oxidised to the corresponding
enone and vinylcuprate addition gave 60 as a 1 : 1 mixture of
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2437
©

View Article Online
diastereoisomers. Selective reduction with DIBALH gave 61 as a
separable mixture of diastereoisomers in 90% yield. Unfortunately,
NOE studies have not allowed unambiguous assignment of the
relative stereochemistry in the two diastereoisomers. We tentatively
assign the relative stereochemistry at C14 on the basis of work
by Gibbons17c and Boeckman23 who independently found that
DIBALH reduction of C14 ketones proceeds from the b-face
(Scheme 12).
dichloromethane, toluene and triethylamine were distilled over
calcium hydride and dimethyl formamide (DMF) was dried over
activated molecular sieves. All other solvents and reagents were
purchased from commercial sources and used as supplied. 1H
NMR spectra were recorded on a 300, 400 or 500 MHz spectrom-
eter; 13C NMR spectra were recorded at 75, 100 or 125 MHz. All
chemical shift values are reported in ppm, with coupling constants
in Hz. The notation of signals is: dH chemical shift in ppm (number
of protons, multiplicity, J value(s), proton assignment). dC chemical
shift in ppm (carbon assignment). If assignment is ambiguous,
for example in the case of overlapping aromatic signals, a range
of shifts is reported. Routine TLC analysis was carried out on
aluminium sheets coated with silica gel 60 F254, 0.2 mm thickness
using petroleum ether 40–60/ethyl acetate mixtures as solvent
systems. Plates were viewed with a 254 nm ultraviolet lamp and
dipped in aqueous potassium permanganate, p-anisaldehyde or
DNP. Flash column chromatography was carried out on 40–63 m,
60A silica gel. Low-resolution mass and high resolution mass
spectra were obtained using electron impact ionisation (EI) and
chemical ionisation (CI) techniques, or positive and/or negative
electrospray ionisation (ES). Melting points were measured on a
variable heater apparatus and are uncorrected. IR spectra were
recorded on a FTIR spectrometer as evaporated films (from
dichloromethane) or neat, using sodium chloride windows.
Full experimental detail, characterisation and spectra for com-
pounds 2, 8–14, 17, 18, 21, 23–26, 29, 31–33, 37, 43 and 46–53
have been previously reported.7,18
2.1 General procedure 1. Formation of vinyl triflates
To a stirred suspension of copper(I) iodide in THF at -45 ◦C
or -20 ◦C was added a solution of the Grignard reagent or
organolithium over 30 min. After stirring for a further 30 min,
a solution of the a,b-unsaturated ketone in THF was added
dropwise. The reaction was stirred at -45 ◦C or -20 ◦C until
the disappearance of the a,b-unsaturated ketone was observed
by TLC analysis of the reaction mixture. This generally occurred
after approximately 1 h. A solution of Comins’ reagent in THF was
added and the reaction was allowed to warm to room temperature
and stirred until completion as judged by TLC analysis. The
reaction was quenched by the addition of aqueous saturated
NH4Cl and the aqueous phase was extracted with Et2O (¥ 3). The
combined organic fractions were dried (Na2SO4) and concentrated
in vacuo. The crude vinyl triflate was purified by chromatography
on silica gel.
Scheme 12 Synthesis of a simplified analogue of pleuromutilin.
Acylation of the C14 hydroxyl in 61a, silyl ether deprotection
and oxidation, gave 62a in good overall yield. Finally, acetate
hydrolysis gave simplified pleuromutilin analogue 63a.
In summary, we have developed a flexible, stereoselective
approach to the cis-hydrindane motif found in a number of biolog-
ically active natural products that utilises highly diastereoselective
SmI2-mediated cyclisations of aldehyde and halide substrates. The
strategy has been exploited in the first synthesis of the proposed
structure of faurinone, a sesquiterpene ketone isolated from
valeriana officinalis, and in a preliminary approach to analogues
of the antibacterial natural product, pleuromutilin.
2.2 General procedure 2. Carbonylative coupling of vinyl triflates
with MeOH or formic acid
Carbon monoxide gas was bubbled through a suspension of
the vinyl triflate (1 equiv), palladium acetate (0.1 or 0.2 equiv),
triphenylphosphine (0.2 or 0.4 equiv), MeOH or formic acid and
triethylamine (2 equiv) in DMF for 30 min. The reaction was
Experimental
◦
then heated at 40 C under an atmosphere of carbon monoxide
1
General Procedures
until the disappearance of the vinyl triflate was observed by TLC
analysis. Upon cooling, the reaction was quenched with water and
extracted with Et2O (¥ 3). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo. The crude products
were purified by chromatography on silica gel.
All reactions were carried out under an inert nitrogen atmosphere
unless otherwise stated. Glassware for inert atmosphere reactions
was oven-dried and cooled under a flow of nitrogen. Tetrahydro-
furan (THF) was distilled over sodium wire and benzophenone,
2438 | Org. Biomol. Chem., 2011, 9, 2433–2451
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
2.3 General procedure 3. HF-pyridine mediated TBS ether
cleavage
CH2CH2OTBDMS and CH2CH2CHCH3), 1.14 (3H, d, J =
7.0 Hz, CH3CH), 1.05 (3H, s, CH3C), 0.90 (9H, s, SiC(CH3)3),
0.06 (6H, s, Si(CH3)2); 13C NMR (125 MHz, CDCl3) dC 152.4
(OTfC C), 127.0 (HC COTf), 117.1 (SO2CF3, q, J = 128 Hz),
63.5 (CH2OTBDMS), 38.4 (CH2CH2CHCH3), 36.1 (CH3C), 32.6
(CHCH3), 32.0 (CH2CH2CH2OTBDMS), 28.7 (CH2CHCH3),
27.5 (CH2CH2OTBDMS), 26.7 (CH3C), 25.9 (SiC(CH3)3),
18.3, (SiC(CH3)3), 17.7 (CH3CH), -5.3 (Si(CH3)2); nmax (liquid
To a solution of the TBS ether (1 equiv) in a 2 : 1 mixture of
acetonitrile and pyridine at 0 ◦C was added dropwise aqueous HF
(10–25 equiv). The reaction was then stirred at room temperature
until the starting alcohol had been consumed (TLC analysis).
The reaction was quenched by dropwise addition of aqueous
saturated NaHCO3. Once effervescence had subsided, the mixture
was extracted with Et2O (¥ 3). The combined organic extracts were
washed with aqueous saturated CuSO4 (¥ 2), brine (¥ 2) and then
dried (Na2SO4). Concentration in vacuo gave the alcohols which
in some cases required purification by chromatography on silica
gel.
film)/cm-1 1404 m (O
S
O), 1140 m; MS (ES+) m/z (%) 453
(100 [M + Na]+); Calcd for C18H33O4F3Ssi + Na+: 453.1713,
found: m/z 453.1705.
3.1.2 Rac-(3S,6R)-methyl 3-(3-((tert-butyldimethylsilyl)oxy)-
propyl)-3,6-dimethylcyclohex-1-enecarboxylate. General proce-
dure 2 using 15 (75 mg, 0.174 mmol; dr ~ 3 : 1), palla-
dium acetate (4 mg, 17.4 mmol), triphenylphosphine (9 mg,
34.8 mmol), MeOH (0.282 mL, 6.97 mmol) and triethylamine
(49 mL, 0.348 mmol) in DMF (1.1 mL) after 24 h gave
rac-(3S,6R)-methyl 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,6-
dimethylcyclohex-1-enecarboxylate (45 mg, 0.132 mmol, 77%; dr
~ 3 : 1) as a colourless oil. For the mixture: 1H NMR (300 MHz,
CDCl3) dH 6.63 (1H, s, C CH), 3.73 (3H, s, CO2CH3), 3.56
(2H, t, J = 6.7 Hz, CH2OTBDMS), 2.68–2.58 (1H, m, CH3CH),
1.81–1.71 (1H, m, 1H from CH2CH), 1.53–1.43 (3H, m, 1H
from CH2CH and 2H from CH2CH2OTBDMS), 1.41–1.25 (4H,
m, 2H from CH2CCH3 and 2H from CH2CH2CH2OTBDMS),
1.06 (3H, d, J = 5.8 Hz, CH3CH), 1.02 (3H, s, CH3C), 0.89
(9H, s, OSiC(CH3)3), 0.04 (6H, s, OSi(CH3)2); 13C NMR (75 MHz,
CDCl3) dC 168.5 (CO2Me), 148.0 (CH C), 133.9 (CCO2Me), 64.0
(CH2OTBDMS), 51.7 (CO2CH3), 37.9 (CH2CH2CH2OTBDMS),
35.8 (CCH3), 35.3 (CH2CH), 30.6 (CH2CH2OTBDMS), 29.1
(CH3CH), 28.5 (CHCH3), 27.1 (CH2CCH3), 26.2 (OSiC(CH3)3,
20.4 (CH3C), 18.6 ((OSiC(CH3)3), -5.0 (OSi(CH3)2); nmax (liquid
film)/cm-1 2961 m, 2361 m, 2040 m, 1720 m (C O), 1260 m,
1058 s; MS (ES+) m/z (%) 358 (100 [M + NH4]+); Calcd for
2.4 General Procedure 4. Swern oxidation
DMSO (2 equiv.) was added to a stirred solution of oxalyl chloride
(1.2 equiv.) in CH2Cl2 at -78 ◦C and the resulting solution was
stirred for 15 min. A solution of the alcohol in CH2Cl2 was added
and the solution was stirred for 1 h at -78 ◦C before triethylamine
(5 equiv.) was added. Upon warming to room temperature the
reaction was stirred for 2 h before being quenched by the addition
of aqueous saturated NaHCO3. The mixture was extracted with
Et2O (¥ 3), the combined organic fractions were dried (Na2SO4)
and concentrated in vacuo. The crude aldehyde was purified by
chromatography on silica gel.
2.5 General procedure 5. SmI2-mediated cyclisations
SmI2 in THF (0.1 M, 2.5 equiv) was added to degassed t-BuOH
and the resulting solution was stirred◦under a nitrogen atmosphere
for 20 min before being cooled to 0 C (ice bath). After cooling,
the aldehyde (1 equiv) was added dropwise as a solution in THF
and the reaction was stirred at 0 ◦C or 20 ◦C until complete
consumption of the aldehyde was observed by TLC analysis of
the reaction mixture. Upon completion, the excess SmI2 was
quenched by allowing air to reach the reaction and an aqueous
saturated solution of NaHCO3 was added. The crude reaction
mixture was then extracted with Et2O (¥ 3). The combined organic
fractions were washed with water and brine, dried (Na2SO4)
and concentrated in vacuo. The crude products were purified by
chromatography on silica gel.
+
C19H36O3Si + NH4 : 358.2772, found: m/z 358.2775.
3.1.3 Rac-(3S,6R)-methyl 3-(3-hydroxypropyl)-3,6-dimethyl-
cyclohex-1-enecarboxylate. General procedure
3 using rac-
(3S,6R)-methyl 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,6-
dimethylcyclohex-1-enecarboxylate (280 mg, 0.822 mmol; dr ~
3 : 1), aqueous 40% HF (0.308 mL, 6.16 mmol), pyridine (6.13 mL)
and MeCN (12.3 mL), after 2.5 h, gave rac-(3S,6R)-meth-
yl 3-(3-hydroxypropyl)-3,6-dimethylcyclohex-1-enecarboxylate
(182 mg, 0.804 mmol, 98%; dr ~ 3 : 1) as a colourless oil. For the
3
Formation of aldehyde cyclisation substrates
1
mixture: H NMR (300 MHz, CDCl3) dH 6.62 (1H, s, C CH),
3.72 (3H, s, CO2CH3), 3.60 (2H, t, J = 6.6 Hz, CH2OH), 2.68–2.57
(1H, m, CH3CH), 1.81–1.64 (2H, m, CH2CH), 1.58–1.50 (2H,
m, CH2CH2OH), 1.48–1.36 (4H, m, 2H from CH2 and 2H
from CH2CH2CH2OH), 1.05 (3H, d, J = 6.9 Hz, CH3CH), 1.03
(3H, s, CH3C); 13C NMR (75 MHz, CDCl3) dC 168.5 (CO2CH3),
3.1 Preparation of aldehyde 19
3.1.1 Rac-(3S,6R)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-
3,6-dimethylcyclohex-1-en-1-yl trifluoromethanesulfonate 15.
General procedure 1, at -20 ◦C using MeLi (1.6 M in Et2O,
33.73 mL, 5.96 mmol)), copper(I) iodide (567 mg, 2.98 mmol)
in THF (15 mL), 9 (400 mg, 1.49 mmol) in THF (10 mL) and
Comins’ reagent (1.05 g, 2.68 mmol) in THF (10 mL) after 24 h
gave 15 (475 mg, 1.10 mmol, 74%; dr ~ 3 : 1) as a pale yellow oil.
168.3 (CO2CH3 (minor diastereoisomer)), 147.7 (CH
C
(minor diastereoisomer)), 147.6 (CH C), 134.1 (CCO2Me),
63.7 (CH2OH), 51.7 (CO2CH3), 38.7 (CH2CH2CH2OH (minor
diastereoisomer)), 37.5 (CH2CH2CH2OH), 35.8 (CCH3 (minor
diastereoisomer)), 35.3 (CCH3), 30.7 (CH2CH2OH), 28.9
(CHCH3), 28.5 (CH2CH), 28.1 (CH3CH), 27.8 (CH3CH (minor
diastereoisomer)), 27.3 (CH2CH2CHCH3), 27.2 (CH2CH2CHCH3
(minor diastereoisomer)), 20.4 (CH3C), 20.2 (CH3C (minor
diastereoisomer)); nmax (liquid film)/cm-1 3403 m (OH), 1705 s
1
For the mixture: H NMR (500 MHz, CDCl3) dH 5.48 (1H, s,
C
CH), 3.63–3.58 (2H, m, CH2OTBDMS), 2.53–2.50 (1H, m,
CHCH3), 1.98–1.90 (1H, m, 1H from CH2CHCH3), 1.53–1.44
(4H, m, 2H CH2CH2CH2OTBDMS and 1H from CH3CHCH2
and 1H from CH2CH2OTBDMS), 1.43–1.34 (3H, m, 1H from
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2439
©

View Article Online
(C O); MS (ES+) m/z (%) 227 (100 [M + H]+); Calcd for
C13H22O3 + H+ : 227.1642, found m/z 227.1650.
procedure 2 using 16 (405 mg, 0.915 mmol; dr 4 : 1), palla-
dium acetate (21 mg, 91.5 mmol), triphenylphosphine (48 mg,
0.183 mmol), MeOH (1.86 mL, 36.8 mmol) and triethylamine
(0.255 mL, 1.83 mmol) in DMF (3 mL) after 24 h gave
rac-(3S,6R)-methyl 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-
methyl-3-vinylcyclohex-1-enecarboxylate (250 mg, 0.709 mmol,
77%; dr 4 : 1) as a colourless oil. For the mixture: 1H NMR
(500 MHz, CDCl3) dH 6.68 (1H, s, CH C), 5.74 (1H, dd, J =
17.5, 10.5 Hz, HC CH2), 5.66 (dd, J = 17.5, 10.5 Hz, HC CH2
(minor diastereoisomer)), 5.07 (1H, dd, J = 10.5, 0.9 Hz, cis
HC CHH) 5.05 (dd, J = 10.5, 0.9 Hz, cis HC CHH (minor di-
astereoisomer)), 4.92 (1H, dd, J = 17.5, 1.0 Hz, trans HC CHH),
4.81 (dd, J = 17.7, 1.0 Hz, trans HC CHH (minor diastereoiso-
mer)), 3.74 (3H, s, CO2CH3), 3.63–3.55 (2H, m, CH2OTBDMS),
2.64–2.58 (1H, m, CHCH3), 1.81–1.75 (1H, m, 1H from
CH2CHCH3), 1.61–1.56 (2H, m, CH2CH2CHCH3), 1.53–1.36
(5H, m, 1H from CH2CHCH3 and CH2CH2CH2OTBDMS and
CH2CH2OTBDMS), 1.06 (3H, d, J = 6.9 Hz, CHCH3), 0.90
(9H, s, SiC(CH3)3), 0.05 (6H, s, Si(CH3)2); 13C NMR (125 MHz,
CDCl3) dC 168.1 (C O), 144.6 (CH CH2), 143.5 (C CH),
135.5 (CCO2CH3), 113.9 (CH2 CH), 63.5 (CH2OTBDMS), 51.5
(CO2CH3), 43.4 (CCH CH2), 36.4 (CH2CH2CH2OTBDMS),
29.7 (CH2CH2OTBDMS), 28.9 (CHCH3), 27.4 (CH2CHCH3),
27.0 (CH2CH2CHCH3), 25.9 (SiC(CH3)3), 20.0 (CHCH3), 18.4
(SiC(CH3)3), -5.3 (Si(CH3)2); nmax (liquid film)/cm-1 1418 m
3.1.4 Rac-(3S,6R)-methyl
cyclohex-1-enecarboxylate 19. General procedure
3,6-dimethyl-3-(3-oxopropyl)-
using
4
DMSO (95 mL, 1.34 mmol) and oxalyl chloride (65 mL,
0.74 mmol) in CH2Cl2 (2 mL), with rac-(3S,6R)-methyl 3-(3-
hydroxypropyl)-3,6-dimethylcyclohex-1-enecarboxylate (134 mg,
0.592 mmol; dr ~ 3 : 1) in CH2Cl2 (11 mL) and triethylamine
(0.62 mL, 4.43 mmol) gave 19 (125 mg, 0.557 mmol, 94%; dr ~
1
3 : 1) as a colourless oil. For the mixture: H NMR (300 MHz,
CDCl3) dH 9.79 (1H, t, J = 1.5 Hz, CHO), 6.58 (1H, s, CH C),
3.74 (3H, s, CO2CH3), 2.68–2.60 (1H, m, CHCH3), 2.48–2.42
(2H, m, CH2CHO), 1.80–1.58 (4H, m, CH2CH2CHO and
CH2CHCH3), 1.57–1.39 (2H, m, CH2CH2CHCH3), 1.07 (3H, d,
J = 7.0 Hz, CH3CH), 1.04 (3H, s, CCH3); 13C NMR (75 MHz,
CDCl3) dC 202.4 (CHO), 168.2 (CO2CH3), 146.1 (C CH), 135.0
(CCO2CH3), 51.8 (OCH3), 39.5 (CH2CHO), 34.9 (CH2CHCH3),
33.0 (CH2CH2CHO), 30.7 (CH2CH2CHCH3), 28.5 (CHCH3),
27.1 (CCH3), 26.6 (CCH2), 20.3 (CHCH3); nmax (liquid film)/cm-1
2722 m (CHO), 1712 m (CHO), 1621 m (C O); MS (CI+)
m/z (%) 225 (100 [M + H]+); Calcd for C13H20O3 + NH4 (ES+):
242.1751, found m/z 242.1757.
3.2 Preparation of aldehyde 20
(O
S
O), 1100 m (Si–O); MS (ES+) m/z (%) 375 (100 [M +
3.2.1 Rac-(3S,6R)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-
6-methyl-3-vinylcyclohex-1-en◦-1-yl trifluoromethanesulfonate 16.
General procedure 1, at -45 C using vinyl magnesium bromide
(1.0 M in THF, 7.04 mL, 7.04 mmol), copper(I) iodide (674 mg,
3.54 mmol) in THF (20 mL), 9 (500 mg, 1.77 mmol) in THF
(12 mL) and Comins’ reagent (1.25 g, 3.19 mmol) in THF (12 mL)
after 24 h gave 16 (564 mg, 1.27 mmol, 72%; dr 4 : 1) as a pale
yellow oil. For the mixture: 1H NMR (500 MHz, CDCl3) dH
5.67 (1H, dd, J = 17.5, 10.5 Hz, HC CH2), 5.65 (dd, J = 17.5,
Na]+); Calcd for C20H36O3Si + Na+: 375.2326, found m/z 375.2325.
3.2.3 Rac-(3S,6R)-methyl 3-(3-hydroxypropyl)-6-methyl-3-
vinylcyclohex-1-enecarboxylate. General procedure using
3
rac-(3S,6R)-methyl 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-
methyl-3-vinylcyclohex-1-enecarboxylate (250 mg, 0.709 mmol;
dr 4 : 1), aqueous 40% HF (0.70 mL, 14.2 mmol), pyridine
(5.5 mL) and MeCN (11 mL), after 2.5 h, gave rac-(3S,6R)-methyl
3-(3-hydroxypropyl)-6-methyl-3-vinylcyclohex-1-enecarboxylate
(152 mg, 0.638 mmol, 90%; dr 4 : 1) as a colourless oil. For the
10.5 Hz, HC CH2 (minor diastereoisomer)), 5.55 (s, HC
C
1
(minor diastereoisomer)), 5.54 (1H, d, J = 0.5 Hz, HC C),
5.13 (1H, dd, J = 10.5, 1.1 Hz, cis HC CHH), 5.11 (dd, J =
10.5, 1.1 Hz, cis HC CHH (minor diastereoisomer)), 4.97 (dd,
J = 17.5, 1.1 Hz, trans HC CHH (minor diastereoisomer)),
4.91 (1H, dd, J = 17.5, 1.1 Hz, trans HC CHH), 3.63–3.57
(2H, m, CH2OTBDMS), 2.55–2.46 (1H, m, CHCH3), 1.86–1.80
(1H, m, 1H from CH2CHCH3), 1.53–1.38 (7H, m, 1H from
CH2CHCH3, CH2CH2CHCH3, CH2CH2CH2OTBDMS and
CH2CH2OTBDMS), 1.15 (d, J = 6.5 Hz, CH3CH (minor
diastereoisomer)), 1.13 (3H, d, J = 6.5 Hz, CH3CH), 0.90 (s,
SiC(CH3)3 (minor diastereoisomer)), 0.89 (9H, s, SiC(CH3)3),
0.05 (6H, s, (CH3)2Si); 13C NMR (125 MHz, CDCl3) dC 153.7
(COTf), 144.0 (CH CH2), 122.9 (CHCOTf), 118.5 (SO2CF3,
mixture: H NMR (500 MHz, CDCl3) dH 6.69 (1H, s, CH C),
5.74 (1H, dd, J = 17.7, 10.5 Hz, HC CH2), 5.65 (1H, dd,
J = 17.7, 10.5 Hz, HC CH2 (minor diastereoisomer)), 5.08
(1H, dd, J = 10.5, 1.0 Hz, cis HC CHH) 5.06 (1H, dd, J =
10.5, 1.0 Hz, cis HC CHH (minor diastereoisomer)), 4.92
(1H, dd, J = 17.7, 1.0 Hz, trans HC CHH), 4.81 (1H, dd,
J = 17.7, 1.0 Hz, trans HC CHH (minor diastereoisomer)),
3.74 (3H, s, CO2CH3), 3.64–3.60 (2H, m, CH2OH), 2.64–2.58
(1H, m, CHCH3), 1.82–1.76 (1H, m, 1H from CH2CHCH3),
1.64–1.55 (2H, m, CH2CH2CHCH3), 1.55–1.37 (5H, m, 1H from
CH2CHCH3 and CH2CH2CH2OH and CH2CH2OH), 1.07 (3H,
d, J = 7.1 Hz, CH3CH (minor diastereoisomer)), 1.06 (3H, d, J =
7.1 Hz, CH3CH); 13C NMR (125 MHz, CDCl3) dC 168.1 (C O),
144.5 (CH CH2), 143.1 (C CH), 135.6 (CCO2CH3), 114.1
(CH2 CH), 63.3 (CH2OH), 51.5 (CO2CH3), 42.2 (CCH CH2),
36.5 (CH2CH2CH2OH), 29.9 (CH2CH2OH), 29.0 (CHCH3),
27.9 (CH2CH2CHCH3), 27.4 (CH2CHCH3), 20.1 (CHCH3); nmax
(liquid film)/cm-1 3375 m (O–H), 1655 m (C O); MS (ES+) m/z
(%) 261 (100 [M + Na]+); Calcd for C14H22O3 + Na+: 261.1461,
found m/z 261.1466.
q,
J = 319.5), 115.2 (CH2 CH), 63.3 (CH2OTBDMS),
43.4 (CCHCOTf), 37.4 (CH2CH2CH2OTBDMS), 33.0
(CHCH3), 31.9 (CH2CH2OTBDMS), 28.3 (CH2CHCH3),
27.4 (CH2CH2CHCH3), 25.9 (SiC(CH3)3), 18.3 (SiC(CH3)3,
17.6 (CH3CH), -5.3 (Si(CH3)2); nmax (liquid film)/cm-1 1417 m
(O
S
O), 1100 m (Si–O); MS (CI+) m/z (%) 443 (100 [M +
H]+); Calcd for C19H33O4F3SSi + H+ (ES+): 443.1894, found m/z
443.1887.
3.2.4 Rac-(3S,6R)-methyl 6-methyl-3-(3-oxopropyl)-3-vinyl-
3.2.2 Rac-(3S,6R)-methyl 3-(3-((tert-butyldimethylsilyl)oxy)-
propyl) - 6 - methyl - 3 - vinylcyclohex - 1 - enecarboxylate. General
cyclohex-1-enecarboxylate 20. General procedure
DMSO (86 mL, 1.21 mmol) and oxalyl chloride (59 mL,
4 using
2440 | Org. Biomol. Chem., 2011, 9, 2433–2451
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
0.656 mmol) in CH2Cl2 (4 mL), with rac-(3S,6R)-methyl
3-(3-hydroxypropyl)-6-methyl-3-vinylcyclohex-1-enecarboxylate
(125 mg, 0.525 mmol; dr 4 : 1) in CH2Cl2 (8 mL) and triethylamine
(0.42 mL, 2.99 mmol) gave 20 (115 mg, 0.487 mmol, 93%; dr
(CH2s), 1718 s (C O), 1435 m (Si–C), 1099 m (Si–O), 836 w
(C C); MS (ES+) m/z (%) 403 (100 [M + Na]+); Calcd for
+
C22H40O3Si + NH4 : 398.3085, found m/z 398.3091.
3.3.2 Rac-(3S,6R)-methyl
3-(but-3-en-1-yl)-3-(3-hydroxy-
1
4 : 1) as a colourless oil. For the mixture H NMR (500 MHz,
propyl)-6-methylcyclohex-1-enecarboxylate. General procedure
3 using rac-(3S,6R)-methyl 3-(but-3-en-1-yl)-3-(3-((tert-butyl-
dimethylsilyl)oxy)propyl)-6-methylcyclohex-1-enecarboxylate
(1.41 g, 3.70 mmol; dr 3 : 1), aqueous 60% HF (1.23 mL,
37.0 mmol), pyridine (7.5 mL) and MeCN (15 mL), after 2.5 h,
gave rac-(3S,6R)-methyl 3-(but-3-en-1-yl)-3-(3-hydroxypropyl)-6-
methylcyclohex-1-enecarboxylate (955 mg, 3.59 mmol, 97%; dr
~ 4 : 1) as a colourless oil. For the mixture: 1H NMR (500 MHz,
CDCl3) dH 6.65 (1H, s, CHCCO2CH3), 5.84–5.73 (1H, m,
CH CH2), 5.02 (1H, d, J = 17.0 Hz, trans CH2 CH), 5.01 (dd,
J = 16.0, 1.0 Hz, trans CH2 CH (minor diastereoisomer)), 4.97
(1H, d, J = 10.0 Hz, cis CH2 CH), 4.93 (dd, J = 10.0, 1.0 Hz, cis
CH2 CH, minor diastereoisomer)), 3.73 (3H, s, CO2CH3), 3.68–
3.58 (2H, m, CH2OH), 2.68–2.65 (1H, m, CHCH3), 2.09–2.00
(1H, m, 1H from CH2CH CH2), 1.98–1.91 (1H, m, 1H from
CH2CH CH2), 1.80–1.73 (1H, m, 1H from CH2CHCH3), 1.64–
1.52 (3H, m, 1H from CH2CH2OH, 1H from CH2CH2CHCH3, 1H
from CH2CH2CH2OH), 1.48–1.43 (4H, m, 1H from CH2CHCH3,
1H from CH2CH2CHCH3, CCH2CH2CH CH2) 1.42–1.35
(3H, m, 1H from CH2CH2OH, 1H from CH2CH2CH2OH,
CH2OH), 1.06 (3H, d, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3)
dC 167.9 (C O), 146.3 (CH CCO2CH3), 138.9 (CH CH2),
134.7 ( CCO2CH3), 114.4 (CH2 CH), 63.5 (CH2OH), 51.5
(CO2CH3), 38.4 (CCH2CH2CH CH2), 37.9 (CCHCCO2CH3),
35.2 (CH2CH2CH2OH), 28.3 (CH2CH CH2), 27.8 (CHCH3),
27.3 (CH2CH2OH), 27.0 (CH2CH2CHCH3), 26.5 (CH2CHCH3),
20.1 (CH3CH); nmax/(liquid film) cm-1 3403 s (O–H), 1720 s
(C O), 1252 s (Si–C), 1059 w (Si–O), 769 w (C C); MS (ES+)
CDCl3) dH 9.76 (1H, s, CHO), 6.61 (1H, s, CH C), 5.67
(1H, dd, J = 17.7, 10.5 Hz, HC CH2), 5.59 (dd, J = 17.7,
10.5 Hz, HC CH2 (minor diastereoisomer)), 5.10 (1H, dd, J =
10.5, 1.0 Hz, cis HC CHH) 5.08 (dd, J = 10.5, 1.0 Hz, cis
HC CHH (minor diastereoisomer)), 4.93 (1H, dd, J = 17.7,
1.0 Hz, trans HC CHH), 4.83 (dd, J = 17.7, 1.0 Hz, trans
HC CHH (minor diastereoisomer)), 3.72 (3H, s, CO2CH3),
2.62–2.56 (1H, m, CHCH3), 2.48–2.39 (2H, m, CH2CHO),
1.79–1.70 (3H, m, 1H from CH2CHCH3 and CH2CH2CHO),
1.62–1.56 (1H, m, CH2CH2CHCH3), 1.45–1.35 (2H, m, 1H from
CH2CHCH3 and 1H from CH2CH2CHCH3), 1.05 (d, J = 7.0 Hz,
CH3CH (minor diastereoisomer)), 1.03 (3H, d, J = 7.0 Hz,
CHCH3); 13C NMR (125 MHz, CDCl3) dC 201.9 (CHO), 167.8
(C O), 143.7 (CH CH2), 141.7 (C CH), 136.4 (CCO2CH3),
115.0 (CH2 CH), 51.6 (CO2CH3), 42.1 (CCH CH2), 39.0
(CH2CHO), 31.7 (CH2CHCH3), 29.8 (CH2CH2CHO), 28.9
(CHCH3), 26.9 (CH2CH2CHCH3), 20.0 (CHCH3); nmax (liquid
film)/cm-1 2043 m (CHO), 1657 m (C O); MS (ES+) m/z (%)
259 (100 [M + Na]+); Calcd for C14H20O3 + Na+: 259.1305, found
m/z 259.1312.
3.3 Preparation of aldehyde 22
3.3.1 Rac-(3S,6R)-methyl
3-(but-3-en-1-yl)-3-(3-((tert-but-
yldimethylsilyl)oxy)propyl)-6-methylcyclohex-1-enecarboxylate.
General procedure 2 using 18 (2.80 mg, 5.95 mmol; dr
3 : 1), palladium acetate (262 mg, 1.19 mmol), triphenylphosphine
(390 mg, 1.49 mmol), MeOH (28 mL, 691 mmol) and triethylamine
(1.67 mL, 11.9 mmol) in DMF (20 mL) after 24 h gave rac-
(3S,6R)-methyl 3-(but-3-en-1-yl)-3-(3-((tert-butyldimethylsilyl)-
m/z (%) 289 (100 [M + Na]+); Calcd for C16H26O3 + NH4 :
+
284.2220, found m/z 282.2230.
oxy)propyl)-6-methylcyclohex-1-enecarboxylate
(1.81
mg,
3.3.3 Rac-(3S,6R)-methyl
3-(but-3-en-1-yl)-6-methyl-3-(3-
4.76 mmol, 80%; dr ~ 4 : 1) as a colourless oil. For the mixture:
1H NMR (500 MHz, CDCl3) dH 6.66 (1H, s, CHCCO2CH3),
5.85–5.75 (1H, m, CH CH2), 5.02 (1H, dd, J = 17.0, 1.5 Hz, trans
CH2 CH), 5.00 (dd, J = 17.0, 1.5 Hz, trans CH2 CH (minor
diastereoisomer)), 4.97 (1H, d, J = 10.0 Hz, cis CH2 CH), 4.93
(dd, J = 10.0, 1.0 Hz, cis CH2 CH (minor diastereoisomer)), 3.74
(3H, s, CO2CH3), 3.60–3.54 (2H, m, CH2OTBDMS), 2.69–2.64
(1H, m, CHCH3), 2.09–2.02 (1H, m, 1H from CH2CH CH2),
2.00–1.91 (1H, m, 1H from CH2CH CH2), 1.80–1.73 (1H,
m, 1H from CH2CHCH3), 1.62–1.56 (1H, m, 1H from
CH2CH2CHCH3), 1.52–1.31 (8H, m, CH2CH2OTBDMS,
oxopropyl)cyclohex-1-enecarboxylate. General procedure
using DMSO (0.85 mL, 11.9 mmol) and oxalyl chloride
(0.56 mL, 6.22 mmol) in CH2Cl2 (50 mL), with rac-
4
(3S,6R)-methyl
3-(but-3-en-1-yl)-3-(3-hydroxypropyl)-6-
methylcyclohex-1-enecarboxylate (1.38 mg, 5.18 mmol; dr
3 : 1) in CH2Cl2 (50 mL) and triethylamine (4.13 mL, 29.5 mmol)
gave 22 (1.36 g, 5.18 mmol, quant.; dr ~ 4 : 1) as a colourless
1
oil. For the mixture: H NMR (500 MHz, CDCl3) dH 9.80 (s,
CHO (minor diastereoisomer)), 9.77 (1H, s, CHO), 6.59 (1H, s,
CHCCO2CH3), 5.83–5.72 (1H, m, CH CH2), 5.03 (1H, dd,
J = 15.4, 1.6 Hz, trans CH2 CH), 5.02 (dd, J = 15.4, 1.6 Hz,
trans CH2 CH (minor diastereoisomer)), 4.96 (1H, d, J =
10.1 Hz, cis CH2 CH), 4.95 (d, J = 10.1 Hz, cis CH2 CH
(minor diastereoisomer)), 3.74 (3H, s, CO2CH3), 2.69–2.66
(1H, m, CHCH3), 2.46–2.42 (2H, m, CH2CHO), 2.09–2.01
(1H, m, 1H from CH2CH CH2), 1.98–1.91 (1H, m, 1H from
CH2CH CH2), 1.80–1.62 (5H, m, 1H from CH2CHCH3,
CH2CH2CHO, CH2CH2CHCH3), 1.49–1.39 (3H, m, 1H from
CH2CHCH3, CCH2CH2CH CH2), 1.07 (3H, d, J = 6.9 Hz,
CH3CH); 13C NMR (125 MHz, CDCl3) dC 202.0 (CHO),
167.7 (CO2CH3), 144.9 (CHCCO2CH3), 138.5 (CH CH2),
135.6 (CCO2CH3), 114.7 (CH2 CH), 51.6 (CH3O2C), 39.3
(CH2CHO (minor diastereoisomer)), 39.0 (CH2CHO), 38.6
CH2CH2CH2OTBDMS,
CCH2CH2CH CH2,
1H
from
CH2CHCH3, 1H from CH2CH2CHCH3), 1.07 (3H, d, J = 7.0 Hz,
CH3CH), 0.90 (s, OSiC(CH3)3 (minor diastereoisomer)), 0.89
(9H, s, OSiC(CH3)3), 0.06 (s, OSi(CH3)3 (minor diastereoisomer)),
0.05 (6H, s, OSi(CH3)2); 13C NMR (125 MHz, CDCl3) dC 168.0
(C O), 146.6 (CH CCO2CH3), 139.0 (CH CH2), 134.4
(
CCO2CH3), 114.3 (CH2 CH), 63.6 (CH2OTBDMS), 51.5
(CO2CH3), 38.5 (CCH2CH2CH CH2), 37.9 (CCHCCO2CH3),
35.1 (CH2CH2CH2OTBDMS), 28.4 (CH2CH CH2), 27.9
(CHCH3), 27.3 (CH2CH2OTBDMS), 27.0 (CH2CH2CHCH3),
26.5 (CH2CHCH3), 25.9 (SiC(CH3)3), 20.1 (CH3CH), 18.3
(SiC(CH3)3), -5.3 (Si(CH3)2); nmax/(liquid film) cm-1 2929 s
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2441
©

View Article Online
(CCH2CH2CH2CH CH2 (minor diastereoisomer)), 38.4
(CCH2CH2CH2CH CH2), 37.6 (CCHCCO2CH3), 30.9
(CH2CH2CHO), 28.3 (CH2CH CH2), 27.8 (CHCH3), 26.9
(CH2CH2CCH3), 26.5 (CH2CHCH3), 20.0 (CH3CH); nmax/(liquid
film) cm-1 2928 m (CH2s), 1717 m (C O), 1110 m (Si–O), 823
w (C C); MS (ES+) m/z (%) 287 (90 [M + Na]+); Calcd for
4.3 Rac-(3S,3aS,4R,5R,7aS)-methyl 7a-(but-3-en-1-yl)-3-
hydroxy-5-methyloctahydro-1H-indene-4-carboxylate 30
General procedure 5 using 22 (690 mg, 2.62 mmol; dr ~ 4 : 1) in
THF (22.5 mL), SmI2 (0.1 M in THF, 52.4 mL, 5.24 mmol) and
t-BuOH (18.8 mL) gave 30 (558 mg, 2.10 mmol, 80%, dr >10 : 1) as
a colourless oil. For the mixture: 1H NMR (500 MHz, CDCl3) dH
5.82 (1H, ddt, J = 17.0, 10.1, 6.6 Hz, CH CH2), 5.01 (1H, d, J =
17.0 Hz, trans CH2 CH), 4.92 (1H, d, J = 10.1 Hz, cis CH2 CH),
+
C16H24O3 + NH4 : 282.2064, found m/z 282.2051.
4
22
SmI2-mediated Cyclisation of aldehydes 19, 20 and 3.97 (1H, dt, J = 8.0, 4.2 Hz, CHOH), 3.71 (s, CO2CH3 minor di-
astereoisomer), 3.68 (3H, s, CO2CH3), 2.41 (1H, dd, J = 8.5, 4.7 Hz,
CHCO2CH3), 2.32 (dd, J = 11.7, 4.1 Hz, CHCHCO2CH3 (minor
diastereoisomer)), 2.20 (1H, s broad, CHOH), 2.11–2.02 (3H, m,
1H from CH2CHOH, 1H from CH2CH CH2, CHCH3), 2.00
(1H, m, 1H from CH2CH CH2), 1.92 (1H, dd, J = 8.7, 3.6 Hz,
CHCHCO2CH3), 1.65–1.46 (6H, m, 1H from CH2CHOH, 1H
from CH2CH2CHOH, CH2CH2CH CH2, CH2CHCH3), 1.33–
1.25 (1H, m, 1H from CH2CH2CHOH), 0.89 (3H, d, J = 7.3 Hz,
CHCH3), 0.86 (d, J = 6.3 Hz CHCH3 (minor diastereoisomer);
13C NMR (125 MHz, CDCl3) dC 175.7 (C O), 139.5 (CH CH2),
139.1 (CH CH2 (minor diastereoisomer)), 115.21 ((CH2 CH)
(minor diastereoisomer)), 114.0 (CH2 CH), 79.1 (CHOH), 78.7
((CHOH) (minor diastereoisomer)), 51.6 (minor diastereoiso-
mer), 51.1 (minor diastereoisomer), 51.5 (CHCHCO2CH3), 51.3
(CO2CH3), 47.4 (minor diastereoisomer), 46.5 (CHCO2CH3),
42.5 (CCH2CH2CH CH2), 38.7 (CH2CH2CH CH2), 33.5
(CH2CHCH3), 33.4 (minor diastereoisomer), 31.2 (CH2CHOH),
31.1 (minor diastereoisomer), 30.4 (minor diastereoisomer), 30.0
(minor diastereoisomer), 29.8 (CHCH3), 29.0 (CH2CH2CHOH),
28.6 (minor diastereoisomer), 28.5 (CH2CH CH2), 28.4 (mi-
nor diastereoisomer), 27.0 (CH2CH2CHCH3), 15.6 (CH3CH);
4.1 Rac-(3S,3aS,4R,5R,7aS)-methyl 3-hydroxy-5,7a-dimethyl-
octahydro-1H-indene-4-carboxylate 27
General procedure 5 using 19 (52 mg, 0.23 mmol; dr ~ 3 : 1)
in THF (2.4 mL), SmI2 (0.1 M in THF, 4.6 mL, 0.46 mmol)
and t-BuOH (1.7 mL) gave 27 (38 mg, 0.17 mmol, 74%, dr
>10 : 1) as a colourless oil. 1H NMR (500 MHz, CDCl3) dH
3.97–3.93 (1H, m, CHOH), 3.69 (3H, s, CO2CH3), 2.37 (1H,
dd, J = 9.4, 4.7 Hz, CHCO2CH3), 2.16–2.07 (2H, m, CHCH3
and 1H from CH2CHOH), 1.85 (1H, dd, J = 9.4, 3.7 Hz,
CHCHOH), 1.71–1.62 (2H, m, 1H from CH2CHOH and 1H from
CH2CH2CHOH), 1.61–1.50 (2H, m, CH2CHCH3), 1.47–1.41 (2H,
m, 1H from CH2CH2CHOH and 1H from CH2CH2CHCH3),
1.37–1.32 (1H, m, CH2CH2CHCH3), 1.14 (3H, s, CH3C), 0.89
(3H, d, J = 6.9 Hz, CH3CH); 13C NMR (125 MHz, CDCl3) dC
175.8 (C O), 79.6 (CHOH), 52.5 (CHCHOH), 51.5 (CO2CH3),
46.7 (HCCO2CH3), 39.7 (CCH3), 36.6 (CH2CH2CHOH),
31.9 (CH2CHOH), 31.5 (CH2CH2CHCH3), 29.9 (CHCH3),
28.9 (CH3C), 27.2 (CH2CHCH3), 15.5 (CH3CH); nmax/(liquid
film) cm-1 3410 s (O–H), 1730 s (C O); MS (EI+) m/z (%) 227
(100 [M + H]+); Calcd for C13H22O3 + NH4+ (ES+): 244.1907, found
m/z 244.1907.
n
max/(liquid film) cm-1 3400 s (O–H), 2949 s, 1732 s (C O), 837
w (C C); MS (ES+) m/z (%) 289 (100 [M + Na]+); Calcd for
+
C16H26O3 + NH4 : 284.2220, found m/z 284.2210.
4.2 Rac-(3S,3aS,4R,5R,7aS)-methyl 3-hydroxy-5-
methyl-7a-vinyloctahydro-1H-indene-4-carboxylate 28
5
The formation and SmI2-mediated cyclisation of
alkyl iodide 42
General procedure 5 using 20 (100 mg, 0.423 mmol; dr 4 : 1) in
THF (4.28 mL), SmI2 (0.1 M in THF, 8.47 mL, 0.847 mmol) and
t-BuOH (3.18 mL) gave 28 (75 mg, 0.317 mmol, 75%, dr 14 : 1)
as a colourless oil. 1H NMR (300 MHz, CDCl3) dH 5.96 (1H, dd,
J = 17.7, 10.7 Hz, CH CH2), 5.12 (1H, d, J = 17.7 Hz, trans
CH CH2), 5.04 (1H, d, J = 10.7 Hz, cis CH CH2), 3.92 (1H,
quint (app), J = 4.1 Hz, CHOH), 3.68 (3H, s, CO2CH3), 2.41
(1H, dd, J = 10.1, 4.9 Hz, CHCO2CH3), 2.18 (1H, dd, J = 10.1,
3.5 Hz, CHCHOH), 2.15–2.07 (2H, m, CHCH3 and 1H from
CH2CHOH), 1.77–1.69 (1H, m, 1H from CH2CHCH3), 1.66–
1.58 (4H, m, 1H from CH2CHCH3, 1H from CH2CH2CHOH
and 1H from CH2CH2CHCH3 1H from CH2CHOH), 1.54–1.47
(1H, m, 1H from CH2CH2CHOH), 1.35–1.30 (1H, m, 1H from
CH2CH2CHCH3), 0.89 (3H, d, J = 7.0 Hz, CH3CH); 13C NMR
(75 MHz, CDCl3) dC 175.4 (C O), 148.0 (HC CH2), 111.4
(HC CH2), 79.4 (HCOH), 51.6 (HCCH3), 51.5 (HCCHOH),
50.5 (CO2CH3), 46.5 (CHCO2CH3), 46.2 (CCH CH2), 33.8
(CH2CHCH3), 32.0 (CH2CH2CHCH3), 29.7 (CH2CHOH), 27.2
(CH2CH2CHOH), 15.4 (CH3CH); nmax/(liquid film) cm-1 3400 s
(O–H), 2949 s (CH2s),1732 s (C O), 837 w (C C); MS (ES+) m/z
5.1 1-Allyl-4-isopropylcyclohex-2-enol
Allyl magnesium bromide (1.0 M in THF, 58.0 mL, 58.0 mmol)
was added dropwise to a solution of 4-isopro◦pylcyclohex-2-enone7
(4.00 g, 29 mmol) in THF (80 mL) at -40 C. The reaction was
allowed to warm to 10 ◦C over 20 h before being quenched with
aqueous saturated NH4Cl (50 mL). The mixture was extracted with
EtOAc (3 ¥ 50 mL), the combined organic fractions were washed
with water and brine, dried (Na2SO4) and concentrated in vacuo to
give 1-allyl-4-isopropylcyclohex-2-enol (4.87 g, 27 mmol, 93%) as
a pale yellow oil. 1H NMR (400 MHz, CDCl3) dH 5.95–5.84 (1H,
m, CH CH2), 5.68 (1H, ddd, J = 10.3, 2.8, 1.0 Hz, CH CH),
5.59 (1H, ddd, J = 10.2, 2.4, 1.3 Hz, mm CH CH), 5.19–5.10 (2H,
m, CH CH2), 2.38–2.24 (2H, m, CH2CH CH2), 2.00–1.87 (2H,
m, 1H from CH2CH2CHCH(CH3)2 and CHCH(CH3)2), 1.76–1.66
(1H, m, 1H from CH2CHCH(CH3)2), 1.64–1.55 (2H, m, 1H from
CH2CH2CHCH(CH3)2 and CH(CH3)2), 1.47–1.37 (1H, m, 1H
from CH2CHCH(CH3)2), 0.91 (3H, d, J = 6.8 Hz, CH(CH3)2),
0.88 (3H, d, J = 6.8 Hz, CH(CH3)2); 13C NMR (125 MHz, CDCl3)
dC 133.7 (CH CH2), 133.2 (CH CH), 132.3 (CH CH),
118.7 (CH CH2), 70.5 (C(OH)), 45.7 (CH2CH CH2), 41.5
(%) 261.2 (100 [M + Na]+); Calcd for C14H22O3 + NH4 : 256.1907,
+
found m/z 256.1913.
2442 | Org. Biomol. Chem., 2011, 9, 2433–2451
This journal is The Royal Society of Chemistry 2011
©

View Article Online
(CHCH(CH3)2), 35.1 (CH2CH2CHCH(CH3)2), 31.7 (CH(CH3)2),
22.8 (CH2CHCH(CH3)2), 19.8 (CH(CH3)2), 19.5 (CH(CH3)2); nmax
(liquid film)/cm-1 2956 s, 2871 s, 1638 m, 1465 m, 1384 m, 1367
m, 1332w, 1196w, 1136w, 1030m; MS (CI+) m/z (%) 139 (100
[M-C3H5]; Calcd for C9H15O [M-C3H5]: 139.1117, found: m/z
139.1120.
16.5 (CH(CH3)2); nmax (liquid film)/cm-1 2965 m, 1592 w, 1418 s
(O
S O), 1247 w, 1209 s, 1143 s; Mass ion not detected.
5.4 Rac-(3S,6S)-3-allyl-6-isopropyl-3-methylcyclohex-
1-enecarboxylic acid
General procedure 2 using 39 (200 mg, 0.613 mmol; dr 11 : 1),
palladium acetate (42 mg, 0.184 mmol), triphenylphosphine
(97 mg, 0.368 mmol), formic acid (1.4 mL, 36.8 mmol) and
triethylamine (0.17 mL, 1.23 mmol) in DMF (10 mL) af-
ter 40 h gave rac-(3S,6S)-3-allyl-6-isopropyl-3-methylcyclohex-
1-enecarboxylic acid (122 mg, 0.550 mmol, 90%; dr 12 : 1)
as a colourless oil. For the mixture: 1H NMR (400 MHz,
CDCl3) dH 6.80 (1H, s, CH CCO2H), 6.78 (s, CH CCO2H
(minor diastereoisomer)), 5.83–5.72 (1H, m, CH CH2), 5.37–
5.25 (m, CH CH2 (minor diastereoisomer)), 5.10–5.01 (2H,
m, CH CH2), 2.49–2.44 (1H, m, CHCH(CH3)2), 2.15–2.05
(3H, m, CH(CH3)2 and CH2CH CH2, 1.67–1.58 (2H, m,
(CH3)2CHCHCH2), 1.47–1.42 (2H, m, (CH3)2CHCHCH2CH2),
1.04 (3H, s, C CHCCH3), 1.01 (s, C CHCCH3 (minor di-
astereoisomer), 0.95 (3H, d, J = 7.1 Hz, CH(CH3)2), 0.81
5.2 3-Allyl-6-isopropylcyclohex-2-enone 38
A
solution of 1-allyl-4-isopropylcyclohex-2-enol (3.00 g,
16.7 mmol) in CH2Cl2 (15 mL) was added to a suspension of
pyridinium chlorochromate (5.39 g, 25.0 mmol) and SiO2 (5.39 g)
◦
in CH2Cl2 (135 mL) at 20 C and the reaction was stirred at the
same temperature for 18 h. The mixture was filtered through a
plug of silica gel and washed through with Et2O (300 mL). The
combined washings were concentrated in vacuo to yield 38 (2.77 g,
15.3 mmol, 92%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3)
d
H 5.84 (1H, s, C CH), 5.83–5.74 (1H, m, CH CH2), 5.16–5.09
(2H, m, CH CH2), 2.92 (2H, d, J = 6.7 Hz, CH2CH CH2), 2.41–
2.31 (2H, m, 1H from (CH3)2CHCHCH2CH2 and CH(CH3)2),
2.23–2.31 (1H, m, 1H from (CH3)2CHCHCH2CH2), 2.05 (1H,
dt, J = 10.7, 4.7 Hz, CHCH(CH2)3), 1.98–1.95 (1H, m,
1H from (CH3)2CHCHCH2), 1.85–1.75 (1H, m, 1H from
(CH3)2CHCHCH2), 0.94 (3H, d, J = 6.9 Hz, CH(CH3)2), 0.85
(3H, d, J = 6.9 Hz, CH(CH3)2); 13C NMR (125 MHz, CDCl3)
dC 201.3 (C O), 162.5 (C CHC O), 133.4 (CH CH2), 126.4
(C CHC O), 118.1 (CH CH2), 51.9 (CHCH(CH3)2), 41.9
(CH2CH CH2), 28.8 ((CH3)CHCHCH2CH2), 25.8 (CH(CH3)2),
23.0 ((CH3)CHCHCH2), 20.6 (CH(CH3)2), 18.5 (CH(CH3)2); nmax
(liquid film)/cm-1 2958 m, 2871 w, 1669 s (C O), 1465 w, 1427
w, 1367 w, 1206 w; MS (ES+) m/z (%) 380 (45), 368 (43), 233 (50),
201 (100 [M + Na]+); Calcd for C12H18ONa: 201.1250, found: m/z
201.1247.
(3H, d, J
7.0 Hz, CH(CH3)2); 13C NMR (100 MHz,
CDCl3) dC 173.9 (CO2H), 149.7 (CH CCO2H), 134.2
(CH CH2), 132.7 (CH CCO2H), 117.9 (CH CH2), 46.4
(CH2CH CH2), 38.7 (CHCH(CH3)2), 35.5 (C CHCCH3), 31.6
((CH3)2CHCHCH2CH2), 29.6 (CH(CH3)2), 25.9 (C CHCCH3),
20.9 (CH(CH3)2), 19.5 ((CH3)2CHCHCH2), 18.3 (CH(CH3)2);
n
max/(liquid film) cm-1 3436 s, 2101 w, 1769 w, 1640 s (C O),
1459 w, 1170 w, 1127 w; MS (ES+) m/z (%) 465 (12), 443 (8), 221
(100 [M - H]+); Calcd for C14H21O2 [M - H]: 221.1536, found: m/z
221.1541.
5.5 Rac-(3S,6S)-methyl 3-allyl-6-isopropyl-3-methylcyclohex-
1-enecarboxylate 40
5.3 Rac-(3S,6S)-3-allyl-6-isopropyl-3-methylcyclohex-1-en-
1-yl trifluoromethanesulfonate 39
TMSCHN2 (2.0 M in hexane, 5.91 mL, 11.8 mmol) was added
to a solution of rac-(3S,6S)-3-allyl-6-isopropyl-3-methylcyclohex-
1-enecarboxylic acid (1.19 g, 5.37 mmol; dr 12 : 1) in toluene
(40 mL) and MeOH (10 mL) and the reaction was stirred
at 20 ◦C for 19 h. Concentration of the reaction mixture
in vacuo and chromatography on silica gel gave 40 (1.15 g,
4.87 mmol, 91%) as a colourless oil. 1H NMR (400 MHz,
CDCl3) dH 6.57 (1H, s, CH C), 5.82–5.70 (1H, m, CH CH2),
5.08–4.99 (2H, m, CH CH2), 3.73 (3H, s, CO2CH3), 2.50–
2.44 (1H, m, CHCH(CH3)2), 2.05 (2H, dd, J = 7.4, 1.1 Hz,
CH2CH CH2), 2.03–1.95 (1H, m, CH(CH3)2), 1.62–1.56 (2H, m,
(CH3)2CHCHCH2), 1.45–1.40 (2H, m, (CH3)2CHCHCH2CH2),
1.02 (3H, s, CH3), 0.91 (3H, d, J = 7.1 Hz, CH(CH3)2), 0.77
(3H, d, J = 6.9 Hz, CH(CH3)2); 13C NMR (100 MHz, CDCl3)
dC 169.2 (CO2CH3), 146.9 (CH CCO2CH3), 134.4 (CH CH2),
133.5 (CH CCO2CH3), 117.7 (CH CH2), 51.5 (CO2CH3), 46.5
(CH2CH CH2), 39.1 (CHCH(CH3)2), 35.3 (C CHCCH3), 31.7
((CH3)2CHCHCH2CH2), 29.6 (CH(CH3)2), 26.0 (C CHCCH3),
20.3 (CH(CH3)2), 19.5 ((CH3)2CHCHCH2), 18.3 (CH(CH3)2);
General procedure 1, at -45 ◦C using MeMgBr in Et2O (3.0 M
in THF, 4.70 mL, 14.1 mmol), copper(I) iodide (2.68 mg,
14.1 mmol) in THF (55 mL), 38 (1.67 g, 9.37 mmol) in
THF (15 mL) and Comins’ reagent (5.52 g, 14.1 mmol) in
THF (10 mL) after 72 h gave 39 (2.11 g, 6.47 mmol, 69%;
dr 11 : 1) as a pale yellow oil. For the mixture: 1H NMR
(400 MHz, CDCl3) dH 5.81–5.70 (1H, m CH CH2), 5.61
(1H, s, C CH), 5.58 (s, C CH (minor diastereoisomer)) 5.14–
5.01 (2H, m CH CH2), 2.48–2.40 (1H, m, CHCH(CH3)2),
2.21–2.10 (2H, m, 1H from CH2CH CH2 and CH(CH3)2),
2.10–2.02 (1H, m, 1H from CH2CH CH2), 1.78–1.70 (1H,
m, 1H from (CH3)2CHCHCH2), 1.65–1.54 (1H, m, 1H from
(CH3)2CHCHCH2), 1.53–1.39 (2H, m, (CH3)2CHCHCH2CH2),
1.04 (3H, s, C CHCCH3), 0.99 (d, J = 7.1 Hz, CH(CH3)2 (minor
diastereoisomer)), 0.98 (3H, d, J = 7.1 Hz, CH(CH3)2), 0.87
(d, J = 6.9 Hz, CH(CH3)2 (minor diastereoisomer)), 0.85 (3H,
d, J = 6.9 Hz, CH(CH3)2); 13C NMR (100 MHz, CDCl3) dC
151.4 (CH COTf), 133.7 (CH CH2), 128.1 (CH COTf), 118.3
(CH CH2), 47.3 (CH2CH CH2), 43.1 (CHCH(CH3)2), 36.2
(C CHCCH3), 32.8 ((CH3)2CHCHCH2CH2), 27.3 (CH(CH3)2),
25.9 (C CHCCH3), 20.0 (CH(CH3)2), 19.5 ((CH3)2CHCHCH2),
n
max/(liquid film) cm-1 3400 s, 2958 m, 2092 w, 1716 s (C O),
1644 s, 1456 w, 1247 s, 1075 w; MS (ES+) m/z (%) 495 (58), 291
(61), 259 (100 [M + Na]+); Calcd for C15H24O2: 236.1771, found:
m/z 236.1766.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2443
©

View Article Online
5.6 Rac-(3R,6S)-methyl 3-(1-hydroxyallyl)-6-isopropyl-3-
methylcyclohex-1-enecarboxylate
19.8 (CH2), 18.5 (CH(CH3)2); nmax/(liquid film) cm-1 2956 s, 2364
m, 1781w, 1718 s (C O), 1653 s (C O), 1457 w, 1387 w, 1259
m, 1098 m; MS (ES+) m/z (%) 523 (30), 289 (21), 273 (100 [M +
Na]+); Calcd for C15H26O3N: 268.1907, found: m/z 268.1906.
A solution of 40 (615 mg, 2.61 mmol) in CH2Cl2 (8 mL) was
added to a suspension of SeO2 (1.16 g, 10.4 mmol) and t-BuOOH
(3.79 mL, 20.8 mmol) in CH2Cl2 (17 mL) and the reaction
was stirred at 20 ◦C for 68 h. At this time, filtration of the
reaction mixture followed by washing of the solids with CH2Cl2
(30 mL), concentration of the filtrate in vacuo and purification
of the crude products by chromatography on silica gel gave rac-
(3R,6S)-methyl 3-(1-hydroxyallyl)-6-isopropyl-3-methylcyclohex-
1-enecarboxylate (277 mg, 1.10 mmol, 42%; dr 4 : 1) as a pale
yellow oil. For the mixture: 1H NMR (400 MHz, CDCl3) dH
6.75 (s, CH C (minor diasterisomer)), 6.65 (1H, s, CH C),
5.94 (ddd, J = 17.2, 10.6, 6.3 Hz, CH CH2 (minor diastereoiso-
mer)), 5.87 (1H, ddd, J = 17.2, 10.3, 7.1 Hz, CH CH2), 5.31–
5.21 (2H, m, CH CH2), 3.88 (1H, d, J = 7.1 Hz, CHOH),
3.74 (3H, s, CO2CH3), 2.52 (1H, m, CHCH(CH3)2), 2.14–
2.02 (1H, m, CH(CH3)2), 1.71–1.50 (3H, m, (CH3)2CHCHCH2
and 1H from (CH3)2CHCHCH2CH2) 1.44–1.38 (1H from
(CH3)2CHCHCH2CH2), 1.06 (s, CH3 (minor diastereoisomer))
1.04 (3H, s, CH3), 0.93 (3H, d, J = 6.8 Hz, CH(CH3)2), 0.76 (3H,
d, J = 6.8 Hz, CH(CH3)2), 0.75 (d, J = 6.8 Hz, CH(CH3)2 (minor di-
astereoisomer)); 13C NMR (100 MHz, CDCl3) dC 168.9 (CO2CH3),
143.8 (CH CCO2CH3), 143.4 (CH CCO2CH3 (minor di-
astereoisomer)), 137.2 (CH CH2 (minor diastereoisomer)), 136.9
(CH CH2), 135.8 (CH CCO2CH3), 135.2 (CH CCO2CH3
(minor diastereoisomer)), 117.9 (CH CH2), 79.8 (CHOH),
51.5 (CO2CH3), 39.8 (C CHCCH3), 39.6 (C CHCCH3
(minor diastereoisomer)), 39.4 (CHCH(CH3)2 (minor di-
astereoisomer)), 39.3 (CHCH(CH3)2), 29.2 (CH(CH3)2), 28.0
((CH3)2CHCHCH2CH2), 22.7 (C CHCCH3), 20.8 ((CH(CH3)2),
5.8 Rac-(3R,6S)-methyl 3-(3-iodopropanoyl)-6-isopropyl-3-
methylcyclohex-1-enecarboxylate 42
A stirred solution of NaI (294 mg, 1.96 mmol) in MeCN
(13 mL) was treated with TMSCl (0.250 mL, 1.96 mmol) and
H2O (30 mL, 1.63 mmol) at 20 ◦C before a solution of 41
(408 mg, 1.63 mL) in MeCN (7 mL) was added. After 36 h,
the reaction was quenched by the addition of H2O (20 mL)
and extracted with Et2O (3 ¥ 25 mL). The combined organic
layers were washed with saturated aqueous Na2S2O3 (80 mL),
dried (Na2SO4) and concentrated in vacuo to give 42 (481 mg,
1.27 mmol, 78%) as a yellow oil that was used without further
purification. 1H NMR (300 MHz, CDCl3) dH 6.80 (1H, s, CH C),
3.76 (3H, s, CO2CH3), 3.32–3.27 (2H, m, CH2I), 3.18–3.09 (2H,
m, CH2CH2I), 2.55–2.46 (1H, m, CHCH(CH3)2), 2.05–1.90 (2H,
m, CH(CH3)2 and 1H from (CH3)2CHCHCH2CH2), 1.75–1.61
(1H, m, 1H from (CH3)2CHCHCH2), 1.59–1.45 (2H, m, 1H
from (CH3)2CHCHCH2 and 1H from (CH3)2CHCHCH2CH2),
1.25 (3H, s, CH3), 0.93 (3H, d, J = 7.0 Hz, CH(CH3)2), 0.81
(3H, d, J = 7.7 Hz, CH(CH3)2); 13C NMR (100 MHz, CDCl3)
dC 209.2 (C O), 168.4 (CO2CH3), 139.5 (CH CCO2CH3),
136.7 (CH CCO2CH3), 51.8 (CO2CH3), 49.2 (C CHCCH3),
42.3 (CH2CH2I), 38.6 (CHCH(CH3)2), 29.9 (CH(CH3)2), 28.9
((CH3)2CHCHCH2CH2), 24.1 (C CHCCH3), 20.9 (CH(CH3)2),
20.2 ((CH3)2CHCHCH2), 18.8 (CH(CH3)2), -4.02 (CH2I);
n
max/(liquid film) cm-1 1718 s (C O), 1653 s (C O), 1437 w, 1259
m, 1083 m; MS (ES+) m/z (%) 396 (100 [M + NH4]+), 199 (35),
173 (33); Calcd for C15H27O3NI: 396.1030, found: m/z 396.1041.
19.0 ((CH3)2CHCHCH2), 17.7 ((CH(CH3)2);
nmax/(liquid
film) cm-1 3434 s, 2098 w, 1644 s, 1456 w, 1258 w; MS (ES+) m/z
(%) 527 (18), 276 (12), 275 (100 [M + Na]+), 270 (100 [M + NH4]+),
235 (13); Calcd for C15H28O3N: 270.2064, found: m/z 270.2073.
5.9 SmI2-mediated cyclisation of iodide 42:
rac-(1S,3aS,4R,5S,7aR)-methyl 1-hydroxy-5-isopropyl-7a-
methyloctahydro-1H-indene-4-carboxylate 44 and
rac-(3aS,4R,5S,7aR)-methyl 5-isopropyl-7a-methyl-
1-oxooctahydro-1H-indene-4-carboxylate 45
5.7 Rac-(3R,6S)-methyl 3-acryloyl-6-isopropyl-3-
methylcyclohex-1-enecarboxylate 41
Dess–Martin periodinane (25 mg, 59 mmol) was added to a
solution of rac-(3R,6S)-methyl 3-(1-hydroxyallyl)-6-isopropyl-3-
methylcyclohex-1-enecarboxylate (10 mg, 40 mmol; dr 4 : 1) in
CH2Cl2 (2 mL) at 20 ◦C. The reaction was stirred for 45 min before
being quenched with aqueous NaOH (1.0 M, 2 mL) and extracted
with Et2O (3 ¥ 5 mL). The combined organic fractions were dried
(Na2SO4) and concentrated in vacuo to yield 41 (10 mg, 40 mmol,
quant.) as a colourless oil. 1H NMR (300 MHz, CDCl3) dH 6.81
(1H, d, J = 1.7 Hz, CH C), 6.72 (1H, dd, J = 16.9, 10.3 Hz,
CH CH2), 6.36 (1H, dd, J = 6.9, 2.0 Hz, 1H from CH CH2),
5.69 (1H, dd, J = 10.4, 1.9 Hz, 1H from CH CH2), 3.75 (3H, s,
CO2CH3), 2.52 (1H, ddd, J = 11.3, 5.6, 1.5 Hz, CHCH(CH3)2),
2.08–1.90 (2H, m, CH(CH3)2) and CH2), 1.74–1.47 (3H, m, CH2),
1.27 (3H, s, CH3), 0.93 (3H, d, J = 7.0 Hz, CH(CH3)2), 0.80
(3H, d, J = 6.8 Hz, CH(CH3)2); 13C NMR (100 MHz, CDCl3)
dC 200.3 (C O), 168.5 (CO2CH3), 139.8 (CH CCO2CH3),
136.5 (CH CCO2CH3), 131.2 (CH CH2), 129.4 (CH CH2),
51.7 (CO2CH3), 48.3 (C CHCCH3), 38.7 (CHCH(CH3)2), 29.7
(CH(CH3)2), 28.9 (CH2), 23.5 (C CHCCH3), 20.9 (CH(CH3)2),
To a solution of 42 (50 mg, 0.132 mmol) and MeOH (54 mL,
1.32 mmol) in degassed THF (1.5 mL) was added a solution of
SmI2-HMPA in THF (made from HMPA (0.46 mL, 2.64 mmol)
dissolved in SmI2 (0.1 M in THF, 5.29◦ mL, 0.529 mmol)) at
◦
-78 C. The reaction was warmed to 20 C over 5 h, additional
SmI2 (0.1 M in THF, 1.98 mL, 0.198 mmol) was added and
the reaction stirred for further 1 h before being quenched with
saturated aqueous Na/K tartrate (2 mL). The mixture was
extracted with Et2O (5 ¥ 2 mL), the combined organic fractions
washed with brine (10 mL) and dried (Na2SO4). Concentration in
vacuo, followed by chromatography on silica gel gave 44 (16 mg,
63.4 mmol; 48%) as a pale yellow oil and 45 (9 mg, 35.4 mmol;
27%) as a pale yellow oil. For 44: 1H NMR (400 MHz, CDCl3) dH
3. 73 (1H, t, J = 8.9 Hz, CHOH), 3.64 (3H, s, CO2CH3), 2.62 (1H,
d, J = 4.5 Hz, CHCO2CH3), 2.08–1.97 (2H, m, CHCHCO2CH3
and 1H from CH2CHOH), 1.88–1.72 (3H, m, CH(CH3)2, 1H
from (CH3)2CHCHCH2 and 1H from CH2CH2CHOH), 1.71–
1.61 (1H, m, CH2), 1.61–1.48 (2H, m, 1H from CH2CHOH and
CH2), 1.38–1.22 (2H, m, CH2), 1.21–1.12 (1H, m, CHCH(CH3)2),
2444 | Org. Biomol. Chem., 2011, 9, 2433–2451
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
1.00 (3H, s, CH3), 0.95 (3H, d, J = 6.6 Hz, CH(CH3)2), 0.80
(3H, d, J = 6.8 Hz, CH(CH3)2); 13C NMR (100 MHz, CDCl3) dC
175.2 (CO2CH3), 82.9 (CHOH), 51.1 (CO2CH3), 44.9 (CHCCH3),
43.2 (CHCO2CH3), 41.3 (CHCCH3), 41.2 (CHCH(CH3)2), 29.3
(CH2CHOH), 29.2 (CH(CH3)2), 26.6 (CH2), 25.3 (CH2), 22.8
(CHCCH3), 21.8 (CH(CH3)2), 21.3 (CH2), 21.0 (CH(CH3)2);
from CH2CHOTBDPS, 1H from CH2CH2CHCH3, 1H from
CH2CHCH3), 1.70 (3H, s, CH3C CH2), 1.58–1.52 (2H, m,
1H from CH2CHOTBDPS, 1H from CH2CH2CHOTBDPS),
1.32–1.23 (2H, m, 1H from CH2CHCH3, CHCH3), 1.20–
1.13 (1H, m, 1H from CH2CH2CHOTBDPS), 1.03–0.95
(1H, m, 1H from CH2CH2CHCH3), 1.00 (9H, s, SiC(CH3)3),
0.71 (3H, d, J = 6.9 Hz, CH3CH); 13C NMR (125 MHz,
CDCl3) dC 174.5 (CO2CH3), 149.5 (H3CCCH2), 136.0 (4 ¥
CH Ar), 134.6 (C Ar), 134.0 (C Ar), 129.5 (2 ¥ CH Ar),
127.5 (4 ¥ CH Ar), 109.2 (C CH2), 77.7 (CHOTBDPS), 50.8
(CO2CH3), 49.7 (CHCHOTBDPS), 47.0 (CCCH2CH3), 44.3
(CHCO2CH3), 35.5 (CH2CHCH3), 32.1 (CH2CHOTBDPS),
31.3 (CH2CH2CHCH3), 29.3 (CHCH3), 27.0 (SiC(CH3)3), 27.0
(CH2CH2CHOTBDPS), 20.2 (CH3CCH2), 19.2 (SiC(CH3)3),
17.3 (CH3CH); nmax/(liquid film) cm-1 1640 s (C O), 1264 m
(Si–C), 1104 w (Si–O), 741 (C C); MS (ES+) m/z (%) 513 (100
[M + Na]+); Calcd for C31H42O3Si + Na+: 513.2795, found m/z
513.2802.
n
max/(liquid film) cm-1 2943 s, 2353 m, 1728 s (C O), 1458 m,
1150 m, 1021w; MS (EI+) m/z (%) 254 (16 [M]+), 222 (100), 179
(46), 151 (36), 133 (42), 95 (54); Calcd for C15H26O3: 254.1876,
found: m/z 254.1886. For 45: 1H NMR (400 MHz, CDCl3) dH 3.67
(3H, s, CO2CH3), 2.71 (1H, apparent t, J = 3.8 Hz, CHCO2CH3),
2.44 (1H, ddd, J = 19.2, 8.8, 2.8 Hz, 1H from CH2C O), 2.36
(1H, ddd, J = 10.5, 7.3, 2.9 Hz, CHCCH3), 2.21 (1H, dt, J =
19.2, 9.5 Hz, 1H from CH2C O), 2.05–1.96 (1H, m, 1H from
CH2CH2C O), 1.95–1.84 (2H, m, 1H from CH2CH2C O and
CH2), 1.83–1.74 (1H, m, CH(CH3)2), 1.62–1.53 (1H, m, CH2),
1.46–1.37 (1H, m,CH2), 1.35–1.21 (2H, m, CHCH(CH3)2 and
CH2), 1.10 (3H, s, CH3), 0.94 (3H, d, J = 6.6 Hz, CH(CH3)2), 0.85
(3H, d, J = 6.6 Hz, CH(CH3)2); 13C NMR (100 MHz, CDCl3) dC
222.0 (C O), 174.9 (CO2CH3), 51.3 (CO2CH3), 47.1 (CHCCH3),
45.1 (CHCCH3), 43.6 (CHCO2CH3), 41.4 (CHCH(CH3)2), 35.4
(CH2C O), 28.9 (CH2), 28.8 (CH(CH3)2), 24.1 (CH2CH2C O),
21.9 (CH2), 21.6 (CH(CH3)2), 21.1 (CH(CH3)2), 20.4 (CHCCH3);
6.1.2 Rac-((3S,3aS,4R,5R,7aR)-3-((tert-butyldiphenylsilyl)-
oxy)-5-methyl-7a-(prop-1-en-2-yl)octahydro-1H-inden-4-yl)me-
thanol. DIBAL-H (1.0 M in toluene, 5.54 mL, 5.54 mmol)
was added to a stirred solution of rac-(3S,3aS,4R,5R,7aR)-
methyl 3-((tert-butyldiphenylsilyl)oxy)-5-methyl-7a-(prop-1-en-
2-yl)octahydro-1H-indene-4-carboxylate (1.36 g, 2.77 mmol) in
CH2Cl2 (28 mL) at -78 ◦C and the reaction mixture stirred at
room temperature. After 3 h, the reaction mixture was quenched
with aqueous saturated Na/K tartrate (10 mL) and stirred for
30 min before extraction with EtOAc (3 ¥ 20 mL). The combined
organic layers were dried (Na2SO4) and concentrated in vacuo to
afford rac-((3S,3aS,4R,5R,7aR)-3-((tert-butyldiphenylsilyl)oxy)-
5-methyl-7a-(prop-1-en-2-yl)octahydro-1H-inden-4-yl)methanol
(1.28 mg, 2.77 mmol, 100%) as a colourless oil. 1H NMR
(500 MHz, CDCl3) dH 7.70–7.66 (4H, m, 4 ¥ CH Ar), 7.45–
7.36 (6H, m, 6 ¥ CH Ar), 4.87 (1H, s, 1 H from CH2 C),
4.83 (1H, s, 1 H from CH2 C), 4.27 (1H, q, J = 7.4 Hz,
CHOTBDPS), 3.53–3.50 (1H, m, 1 H from CH2OH), 3.44–
3.39 (1H, m, 1 H from CH2OH), 2.40 (1H, dd, J = 7.6, 2.8 Hz,
CHCHOTBDPS), 1.95–1.88 (1H, m, 1H from CH2CHOTBDPS),
1.88 (3H, s, CH3), 1.85–1.79 (2H, m, 1H from CH2CHCH3,
1H from CH2CH2CHCH3), 1.73–1.65 (1H, m, 1H from
CH2CHOTBDPS), 1.54–1.50 (1H, m, CHCH2OH), 1.34–1.28
(1H, m, CHCH3), 1.27–1.20 (1H, m, 1H from CH2CHCH3),
1.18–1.14 (2H, m, CH2CH2CHOTBDPS), 1.10–1.07 (1H, m, 1H
from CH2CH2CHCH3), 1.08 (9H, s, SiCCH3)3), 0.89 (1H, s brd,
OH), 0.70, (3H, d, J = 6.9 Hz, CH3CH); 13C NMR (125 MHz,
CDCl3) dC 150.7 (C CH2), 136.0 (4 ¥ CH Ar), 134.5 (2 ¥ C
Ar), 129.5 (2 ¥ CH Ar), 127.5 (4 ¥ CH Ar), 109.4 (C CH2),
77.1 (CHOTBDPS), 62.0 (CH2OH), 49.9 (CHCHOTBDPS),
46.4 (CCCH2CH3), 41.4 (CHCH2OH), 36.5 (CH2CHCH3), 32.9
(CH2CHOTBDPS), 32.3 (CH2CH2CHCH3), 29.1 (CHCH3), 27.7
(CH2CH2CHOTBDPS), 27.1 (SiC(CH3)3), 20.0 (CH3CCH2),
19.2 (SiC(CH3)3), 18.3 (CH3CH); nmax/(liquid film) cm-1 3431 s
(O–H), 1265 s (Si–C), 1099 w (Si–O); MS (ES+) m/z (%) 480 (100
n
max/(liquid film) cm-1 2955 m, 2360 w, 1737 s (C O), 1463 w,
1196 w, 1153 m; MS (ES+) m/z (%) 307 (82), 275 (100 [M + Na]+);
Calcd for C15H24O3: 252.1720, found: m/z 252.1726.
5.10 Oxidation of 44 to 45
Dess–Martin periodinane (38 mg, 89 mmol) was added to a
solution of 44 (15 mg, 59 mmol) in CH2Cl2 (1.5 mL) at 20 ◦C. The
reaction was stirred for 1 h before being quenched with aqueous
NaOH (1.0 M, 2 mL) and extracted with Et2O (3 ¥ 3 mL). The
combined organic fractions were dried (Na2SO4) and concentrated
in vacuo to yield 45 (11 mg, 44 mmol, 74%) as a colourless oil.
6
An approach to the tricyclic core of pleuromutilin
6.1 Formation of ring closing metathesis substrate 56
6.1.1 Rac-(3S,3aS,4R,5R,7aR)-methyl
3-((tert-butyl-
diphenylsilyl)oxy)-5-methyl-7a-(prop-1-en-2-yl)octahydro-1H-
indene-4-carboxylate. Imidazole (469 mg, 6.89 mmol) was
added to a stirred solution of 29 (965 mg, 3.83 mmol) in DMF
(10 mL) at room temperature followed by TBDPSCl (1.1 mL,
4.21 mmol). The reaction mixture was then stirred at room
temperature for 12 h, quenched with aqueous saturated NaHCO3
(50 mL) and extracted with Et2O (3 ¥ 50 mL). The organic
extracts were washed with H2O (3 ¥ 50 mL), dried (Na2SO4) and
concentrated in vacuo. The crude material was then purified by
silica gel chromatography (5% EtOAc in petroleum ether) to yield
rac-(3S,3aS,4R,5R,7aR)-methyl 3-((tert-butyldiphenylsilyl)oxy)-
5-methyl-7a-(prop-1-en-2-yl)octahydro-1H-indene-4-carboxylate
(1.46 g, 2.98 mmol, 78%) as a pale yellow oil. 1H NMR (500 MHz,
CDCl3) dH 7.62 (2H, dd, J = 8.0, 1.4 Hz, 2 ¥ CH Ar), 7.56 (2H,
dd, J = 8.0, 1.4 Hz, 2 ¥ CH Ar), 7.36–7.26 (6H, m, 6 ¥ CH Ar),
4.74 (2H, s, C CH2), 4.03 (1H, q, J = 6.6 Hz, CHOTBDPS),
3.47 (3H, s, CO2CH3), 2.54 (1H, t, J = 5.7 Hz, CHCHOTBDPS),
2.31 (1H, t, J = 4.9 Hz, CHCO2CH3), 1.77–1.69 (3H, m, 1H
[M + NH4]+); Calcd for C30H42O2Si + NH4 : 480.3292, found m/z
+
480.3292.
6.1.3 Rac-(3S,3aS,4R,5R,7aR)-3-((tert-butyldiphenylsilyl)-
oxy)-5-methyl-7a-(prop-1-en-2-yl)octahydro-1H-indene-4-carbal-
dehyde 54. Dess–Martin periodinane (2.35 g, 5.54 mmol) was
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2445
©

View Article Online
added to a stirred solution of rac-((3S,3aS,4R,5R,7aR)-3-((tert-
butyldiphenylsilyl)oxy)-5-methyl-7a-(prop-1-en-2-yl)octahydro-
1H-inden-4-yl)methanol (1.25 mg, 2.71 mmol) in CH2Cl2 (28 mL)
and the reaction mixture stirred for 3 h. The reaction mixture was
quenched with 0.5 M NaOH (10 mL) and extracted with EtOAc
(3 ¥ 20 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo to afford 54 (1.26 g, 2.73 mmol, 99%)
134.3 (C Ar), 129.7 (2 ¥ CH Ar), 129.6 (2 ¥ CH Ar (minor
diastereoisomer)), 127.6 (4 ¥ CH Ar (minor diastereoisomer)),
127.5 (4 ¥ CH Ar), 114.5 (CH2 CH), 112.9 (CH2 CH (minor
diastereoisomer)), 110.0 (CH2 C), 79.0 (CHOTBDPS), 77.5
(CHOTBDPS (minor diastereoisomer)), 72.8 (CHOH), 71.1
(CHOH (minor diastereoisomer)), 49.6 (CHCHOTBDPS), 48.7
(CHCHOTBDPS (minor diastereoisomer)), 46.1 (CH), 43.4
(CH), 37.7 (CH2), 36.1 (CH2), 35.3 (CH2), 34.8 (CH2), 34.0
(CH2), 33.4 (CH2), 32.8 (CH2), 31.3 (CH2), 30.9 (CH2), 30.3
(CHCH3), 29.9 (CH2), 29.4 (CH2), 27.1 (SiC(CH3)3 (minor
diastereoisomer)), 27.0 (SiC(CH3)3), 20.5 (CH3C CH2), 20.3
(CH3C CH2 (minor diastereoisomer)), 19.1 (SiC(CH3)3), 18.8
(CH3CH (minor diastereoisomer)) 17.2 (CH3CH); nmax/(liquid
film) cm-1 3420 s (O–H), 2928 m (CH2s), 1265 w (Si–C), 1110 m
(Si–O), 821 w (C C); MS (ES+) m/z (%) 539 (100 [M + Na]+);
Calcd for C34H48O2Si + H+: 517.3496, found m/z 517.3498.
1
as a colourless oil. H NMR (500 MHz, CDCl3) dH 9.68 (1H,
d, J = 3.5 Hz, CHO), 7.70–7.64 (4H, m, 4 ¥ CH Ar), 7.45–
7.36 (6H, m, 6 ¥ CH Ar), 4.84 (1H, s, 1H from C CH2), 4.81
(1H, s, 1H from C CH2), 4.26 (1H, q, J = 7.8 Hz, CHOTBDPS),
2.46 (1H, d, J = 8.5 Hz, CHCHOTBDPS), 2.20 (1H, d, J =
3.5 Hz, CHCHO), 1.99–1.92 (1H, m, 1H from CH2CHOTBDPS),
1.89 (1H, d brd, J = 4.5 Hz, 1H from CH2CH2CHCH3), 1.84–
1.78 (1H, m, 1H from CH2CHCH3), 1.75–1.68 (1H, m, 1H
from CH2CHOTBDPS), 1.72 (3H, s, CH3), 1.51 (1H, qd, J =
12.9, 3.0 Hz, 1H from CH2CH2CHOTBDPS), 1.33–1.26 (1H,
m, 1H from CH2CH2CHOTBDPS), 1.26–1.20 (1H, m, 1H from
CH2CHCH3), 1.13–1.05 (1H, m 1H from CH2CH2CHCH3), 1.09
(9H, s, SiC(CH3)3), 0.77 (3H, d, J = 7.3 Hz, CH3CH); 13C NMR
125 MHz, CDCl3) dC 205.9 (CHO), 148.4 (C CH2), 136.0 (4 ¥
CH Ar), 134.4 (C Ar), 134.0 (C Ar), 129.7 (2 ¥ CH Ar), 127.6 (4
¥ CH Ar), 111.3 (C CH2), 75.9 (CHOTBDPS), 51.3 (CHCHO),
51.0 (CHCHOTBDPS), 46.0 (CC CH2), 36.4 (CH2CHCH3),
32.7 (CH2CHOTBDPS), 32.3 (CH2CH2CHCH3), 28.4 (CHCH3),
27.8 (CH2CH2CHOTBDPS), 27.1 (SiC(CH3)3), 19.8 (CH3CCH2),
19.2 (SiC(CH3)3), 18.7 (CH3CH); nmax/(liquid film) cm-1 1700 m
(C O), 1260 m (Si–C), 1041 m (Si–O); MS (ES+) m/z (%) 483
6.2 Formation of ring closing metathesis substrate 57
6.2.1 Rac-(3S,3aS,4R,5R,7aS)-methyl 7a-(but-3-en-1-yl)-3-
((tert-butyldiphenylsilyl)oxy)-5-methyloctahydro-1H -indene-4-
carboxylate. Imidazole (213 mg, 3.14 mmol) was added to a
stirred solution of 30 (556 mg, 2.09 mmol, dr >10 : 1) in DMF
(10 mL) at room temperature followed by TBDPSCl (0.37 mL,
2.09 mmol). The reaction mixture was then stirred at room
temperature for 12 h. The reaction mixture was quenched with
aqueous saturated NaHCO3 (50 mL) and extracted with Et2O
(3 ¥ 50 mL). The organic extracts were washed with H2O (3 ¥
50 mL), dried (Na2SO4) and concentrated in vacuo. The crude
material was then purified by silica gel chromatography (5%
EtOAc in petroleum ether) to yield rac- (3S,3aS,4R,5R,7aS)-
(100 [M + Na]+); Calcd for C30H40O2Si + NH4 : 478.3131, found
+
m/z 478.3136.
6.1.4 Rac-1-((3S,3aS,4R,5R,7aR)-3-((tert-butyldiphenylsilyl)-
oxy)-5-methyl-7a-(prop-1-en-2-yl)octahydro-1H-inden-4-yl)pent-
4-en-1-ol 56. Butenyl magnesium bromide (0.5 M in THF,
3.64 mL, 1.82 mmol) was added dropwise to 54 (700 mg,
1.52 mmol) in THF (15 mL) at -78 ◦C. After 4 h, the reaction
mixture was quenched with aqueous saturated NH4Cl (10 mL)
and extracted with EtOAc (5 ¥ 10 mL). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The crude
material was purified by silica gel chromatography (10% EtOAc
in petroleum ether) to yield 56 (550 mg, 1.07 mmol, 70%; dr
methyl
7a-(but-3-en-1-yl)-3-((tert-butyldiphenylsilyl)oxy)-5-
methyloctahydro-1H-indene-4-carboxylate (650 g, 1.29 mmol,
74%; dr 20 : 1) as a pale yellow oil. 1H NMR (400 MHz, CDCl3)
dH 7.72 (2H, d, J = 9.4 Hz, 2 ¥ CH Ar), 7.66 (2H, d, J = 9.4 Hz,
2 ¥ CH Ar), 7.45–7.35 (6H, m, 6 ¥ CH Ar), 5.89–5.79 (1H, ddt,
J = 17.0, 10.0, 6.5 Hz, CH CH2), 5.02 (1H, dd, J = 17.0, 1.5 Hz,
trans CH2 CH), 4.93 (1H, dd, J = 10.0, 1.5 Hz, cis CH2 CH),
4.11–4.06 (1H, m, CHOTBDPS), 3.57 (3H, s, CO2CH3), 3.56
(s, CO2CH3 (minor diastereoisomer)), 2.35 (1H, t, J = 4.9 Hz,
CHCO2CH3), 2.17 (1H, t, J = 5.8 Hz, CHCHCO2CH3),
2.13–2.04 (1H, m, 1H from CH2CH CH2), 1.99–1.88 (1H,
m, 1H from CH2CH CH2), 1.88–1.78 (1H, m, 1H from
CH2CHOTBDPS), 1.71–1.60 (4H, m, 1H from CH2CHOTBDPS,
1H from CCH2CH2CH CH2, 1H from CH2CHCH3, 1H from
CH2CH2CHCH3), 1.54–1.43 (2H, 1H from CCH2CH2CH CH2,
1H from CH2CH2CHOTBDPS), 1.39–1.21 (3H, m, 1H from
CH2CHCH3, 1H from CH2CH2CHCH3, CHCH3), 1.14–1.02
(1H, m, 1H from CH2CH2CHOTBDPS), 1.10 (9H, s, SiC(CH3)3),
0.80 (3H, d, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) dC
175.2 (C O), 139.6 (CH CH2), 136.1 (CH Ar), 136.0 (CH
Ar), 135.8 (CH Ar), 134.6 (C Ar), 134.1(C Ar), 129.9 (CH
Ar), 129.6 (CH Ar), 129.5 (CH Ar), 127.5 (4 ¥ CH Ar), 113.9
(CH2 CH), 78.1 (CHOTBDPS), 52.1 (CHCHCO2CH3), 51.0
(CO2CH3), 44.3 (CHCO2CH3), 41.5 (CCH2CH2CH CH2),
1
3 : 1) as a pale yellow oil. For the mixture: H NMR (300 MHz,
CDCl3) dH 7.72–7.66 (4H, m, 4 ¥ CH Ar), 7.45–7.37 (6H, m, 6
¥ CH Ar), 5.88–5.73 (1H, m, CH CH2), 5.05 (1H, s, 1H from
CH2 CCH3), 5.06–4.92 (2H, m, CH2 CH), 4.96 (1H, s, 1H
from CH2 CCH3), 4.32 (q, J = 7.9 Hz, CHOTBDPS (minor
diastereoisomer)), 4.14 (1H, td, J = 6.3, 3.8 Hz, CHOTBDPS),
3.72–3.67 (m, CHOH (minor diastereoisomer)), 3.56–3.51 (1H,
m, CHOH), 2.42 (1H, dd, J = 9.5, 3.5 Hz, CHCHOTBDPS), 2.33
(d, J = 8.8 Hz, CHCHOTBDPS (minor diastereoisomer)), 2.25–
1.95 (1H, m), 1.92 (3H, s, CH3C CH2), 1.87 (s, CH3C CH2
(minor diastereoisomer)), 1.86–1.50 (7H, m), 1.47–1.40 (2H, m),
1.39–1.26 (3H, m), 1.23–1.13 (2H, m) 1.07 (s, SiC(CH3)3 (minor
diastereoisomer)), 1.05 (9H, s, SiC(CH3)3), 0.93 (3H, d, J = 6.9 Hz,
CH3CH), 0.81 (d, J = 6.9 Hz, CH3CH (minor diastereoisomer));
13C NMR (75 MHz, CDCl3) dC 151.7 (CH3C CH2), 151.4
(CH3C CH2 (minor diastereoisomer)), 139.0 (CH CH2
(minor diastereoisomer)), 138.8 (CH CH2), 136.0 (4 ¥ CH
Ar) 135.9 (4 ¥ CH Ar (minor diastereoisomer)), 134.5 (C Ar),
37.8
(CH2CH2CH CH2),
34.8
(CH2CHCH3),
31.9
(CH2CHOTBDPS), 31.3 (CH2CH2CHOTBDPS), 29.3 (CHCH3),
28.8 (CH2CH CH2), 27.1 (SiC(CH3)3), 26.6 (CH2CH2CHCH3),
19.2 (SiC(CH3)3), 17.2 (CH3CH); nmax/(liquid film) cm-1 2929
2446 | Org. Biomol. Chem., 2011, 9, 2433–2451
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
m (CH2s), 1744 s (C O), 1192 m (Si–C), 1100 (Si–O), 821 w
1H from CH2CH2CHOTBDPS, 1H from CH2CH2CH CH2,
1H from CH2CH2CHCH3), 1.33–1.22 (4H, CHCH3, 1H from
CH2CH2CHCH3, 1H from CH2CH2CHOTBDPS, 1H from
CH2CHCH3), 1.08 (9H, s, SiC(CH3)3), 1.04–1.02 (1H, m,
1H from CH2CH2CH CH2), 0.85 (3H, d, J = 7.0 Hz,
CH3CH); 13C NMR (100 MHz, CDCl3) dC 205.2 (CHO), 139.2
(CH CH2), 136.0 (4 ¥ CH Ar), 134.3 (2 ¥ C Ar), 129.6
(2 ¥ CH Ar), 127.6 (4 ¥ CH Ar), 114.1 (CH2 CH), 76.8
(CHOTBDPS), 52.3 (CHCHOTBDPS), 51.2 (CHCHO), 41.3
(CCH2), 37.7 (CH2CH2CHOTBDPS), 34.9 (CH2CHCH3), 32.2
(CH2CHOTBDPS), 31.6 (CH2CH2CH CH2), 28.8 (CHCH3),
28.7 (CH2CH CH2), 27.2 (CH2CH2CHCH3), 27.1 (SiC(CH3)3),
19.2 (SiC(CH3)3), 18.0 (CH3CH); nmax/(liquid film) cm-1 2928 m
(CH2s), 1717 m (C O), 1110 m (Si–O); MS (ES+) m/z (%) 497
(C C); MS (ES+) m/z (%) 527 (100 [M + Na]+); Calcd for
+
C32H44O3Si + NH4 : 522.3398, found m/z 522.3401.
6.2.2 Rac-((3S,3aS,4R,5R,7aS)-7a-(but-3-en-1-yl)-3-((tert-
butyldiphenylsilyl)oxy)-5-methyloctahydro-1H -inden-4-yl)me-
thanol. DIBAL-H (1.0 M in toluene, 3.86 mL, 3.86 mmol) was
added to a stirred solution of rac- (3S,3aS,4R,5R,7aS)-methyl
7a-(but-3-en-1-yl)-3-((tert-butyldiphenylsilyl)oxy)-5-methylocta-
hydro-1H-indene-4-carboxylate (650 mg, 1.29 mmol, dr 20 : 1) in
CH2Cl2 (10 mL) at -78 ◦C and the reaction mixture stirred at
room temperature. After 3 h, the reaction mixture was quenched
with aqueous saturated sodium/potassium tartrate (10 mL) and
extracted with EtOAc (3 ¥ 20 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo to afford rac-
((3S,3aS,4R,5R,7aS)-7a-(but-3-en-1-yl)-3-((tert-butyldiphenyl-
silyl)oxy)-5-methyloctahydro-1H-inden-4-yl)methanol (610 mg,
1.28 mmol, 99%) as a colourless oil. 1H NMR (500 MHz, CDCl3)
dH 7.70–7.66 (4H, m, 4 ¥ CH Ar), 7.45–7.37 (6H, m, 6 ¥ CH
Ar), 5.89–5.81 (1H, ddt, J = 17.0, 10.1, 6.5 Hz, CH CH2), 5.03
(1H, d, J = 17.0 Hz, trans CH2 CH), 4.94 (1H, d, J = 10.1 Hz,
cis CH2 CH), 4.19 (1H, dt, J = 7.9, 5.0 Hz, CHOTBDPS),
3.43–3.32 (2H, m, CH2OH), 2.11–2.00 (2H, m, CH2CH CH2),
1.94–1.86 (1H, m, 1H from CH2CHOTBDPS), 1.73–1.67 (2H,
m, 1H from CH2CHOTBDPS, CHCHOTBDPS), 1.66–1.57 (2H,
m, 1H from CH2CH2CH CH2, 1H from CH2CHCH3), 1.57–
1.52 (1H, m, CH2CH2CHOTBDPS), 1.50–1.42 (2H, m, 1H
from CH2CH2CH CH2, CHCH3), 1.34–1.29 (2H, m, 1H from
CH2CH2CHOTBDPS, CHCH2OH), 1.20–1.12 (3H, m, 1H from
CH2CHCH3, CH2CH2CHCH3), 1.08 (9H, m, SiC(CH3)3), 0.83
(1H, s, CH2OH), 0.72 (3H, d, J = 6.9 Hz, CH3CH); 13C
NMR (125 MHz, CDCl3) dC 139.7 (CH CH2), 136.0 (4 ¥
CH Ar), 134.6 (C Ar), 134.4 (C Ar), 129.6 (2 ¥ CH Ar),
127.5 (4 ¥ CH Ar), 113.8 (CH2 CH), 78.4 (CHOTBDPS), 63.2
(CH2OH), 52.1 (CHCHCH2OH), 42.2 (CCH2CH2CH CH2),
41.6 (CHCH2OH), 39.1 (CH2CH2CH CH2), 34.7 (CH2CHCH3),
32.7 (CH2CHOTBDPS), 30.3 (CH2CH2CHOTBDPS), 28.8
(CH2CH CH2), 28.4 (CHCH3), 27.1 (SiC(CH3)3), 27.0
(CH2CH2CHCH3), 19.2 (SiC(CH3)3), 16.3 (CH3CH); nmax/(liquid
film) cm-1 3510 s (O–H), 1264 w (Si–C), 1110 m (Si–O), 822
w (C C); MS (ES+) m/z (%) 499 (100 [M + Na]+); Calcd for
C31H44O2Si + H+: 477.3183, found m/z 477.3181.
(100 [M + Na]+); Calcd for C31H42O2Si + NH4 : 492.3292, found
+
m/z 492.3297.
6.2.4 Rac-1-((3S,3aS,4R,5R,7aS)-7a-(but-3-en-1-yl)-3-((tert-
butyldiphenylsilyl)oxy)-5-methyloctahydro-1H-inden-4-yl)prop-2-
en-1-ol 57. Vinyl magnesium bromide (0.94 M in THF, 1.08 mL,
1.01 mmol) was added dropwise to 55 (320 mg, 0.675 mmol) in
THF (10 mL) -78 ◦C and the solution allowed to warm to room
temperature. After 4 h, the reaction mixture was quenched with
aqueous saturated NH4Cl (10 mL) and extracted with EtOAc (5
¥ 10 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The crude material was purified by silica gel
chromatography (10% EtOAc in petroleum ether) to yield 57 as a
1
(305 mg, 0.607 mmol, 89%; dr 7 : 3). For the mixture: H NMR
(400 MHz, CDCl3) dH 7.74–7.66 (4H, m, 4 ¥ CH Ar), 7.46–7.35
(6H, m, 6 ¥ CH Ar), 5.94–5.74 (2H, m, 2 ¥ CH CH2), 5.14–
4.91 (4H, m, 2 ¥ CH2 CH), 4.41–4.36 (m, CHOTBDPS (minor
diastereoisomer)), 4.21 (1H, dt, J = 7.3, 3.9 Hz, CHOTBDPS),
4.08 (q, J = 5.0 Hz, CHOH (minor diastereoisomer)), 3.97
(1H, q, J = 5.0 Hz, CHOH), 2.20–2.10 (1H, m, 1H from
CH2), 2.09–2.00 (1H, m, 1H from CH2), 2.00 (1H, dd, J = 9.1,
3.3 Hz, CHCHOTBDPS), 1.95–1.92 (m, CHCHOTBDPS (minor
diastereoisomer)), 1.90–1.66 (4H, m, CHCH3, 1H from CH2, 1H
from CH2, 1H from CH2), 1.66–1.56 (2H, m, 1H from CH2,
1H from CH2), 1.56–1.44 (m, CHCH3 (minor diastereoisomer),
CH2), 1.44–1.21 (3H, m, CH2, 1H from CH2), 1.18–1.12 (1H,
m, CHCHOH), 1.07 (9H, s, SiC(CH3)3), 1.06 (s, SiC(CH3)3
(minor diastereoisomer)), 0.87 (3H, d, J = 7.3 Hz, CH3CH),
0.78 (d, J = 6.3 Hz, CH3CH (minor diastereoisomer)); 13C NMR
(100 MHz, CDCl3) dC 142.3 (CH CH2 (minor diastereoisomer)),
140.9 (CH CH2), 140.1 (CH CH2 (minor diastereoisomer)),
139.9 (CH CH2), 136.0 (4 ¥ CH Ar), 134.7 (C Ar), 134.6 (C
Ar), 134.6 (C Ar), 134.4 (C Ar), 129.7 (CH Ar), 129.6 (CH
Ar), 129.5 (CH Ar), 127.6 (CH Ar), 127.5 (CH Ar), 127.4 (CH
Ar), 114.2 (CH CH2), 114.0 (CH CH2 (minor diastereoemer)),
113.7 (CH CH2), 113.6 (CH CH2 (minor diastereoisomer)),
79.1 (CHOTBDPS), 78.9 (CHOTBDPS (minor diastereoisomer)),
74.0 (CHOH), 73.1 (CHOH (minor diastereoisomer)), 51.2
(CHCHOTBDPS), 50.5 (CHCHOTBDPS (minor diastereoiso-
mer)), 44.5 (CHCHOH), 43.1 (CHCHOH (minor diastereoiso-
mer)), 41.4 (CCH2CH2CH CH2), 39.9 (CH2), 38.8 (CH2 (mi-
nor diastereoisomer)), 35.1 (CH2 (minor diastereoisomer)), 34.1
(CH2), 33.1 (CH2), 32.4 (CH2 (minor diastereoisomer)), 30.0
(CHCH3), 29.0 (CH2), 28.8 (CHCH3 (minor diastereoisomer)),
28.7 (CH2), 28.6 (CH2), 28.3 (CH2), 27.1 (SiC(CH3)3), 19.2
6.2.3 Rac-(3S,3aS,4R,5R,7aS)-7a-(but-3-en-1-yl)-3-((tert-
butyldiphenylsilyl)oxy)-5-methyloctahydro-1H-indene-4-carbalde-
hyde 55. General procedure
4 using DMSO (0.21 mL,
2.94 mmol) and oxalyl chloride (0.14 mL, 1.54 mmol) in CH2Cl2
(10 mL), with rac-((3S,3aS,4R,5R,7aS)-7a-(but-3-en-1-yl)-3-
((tert-butyldiphenylsilyl)oxy)-5-methyloctahydro-1H-inden-4-yl)-
methanol (610 mg, 1.28 mmol) in CH2Cl2 (20 mL) and triethy-
lamine (1.02 mL, 7.30 mmol) gave 55 (600 mg, 1.27 mmol,
99%) as a yellow oil. 1H NMR (400 MHz, CDCl3) dH 9.64
(1H, s, CHO), 7.69–7.63 (4H, m, 4 ¥ CH Ar), 7.44–7.38
(6H, m, 6 ¥ CH Ar), 5.83–5.74 (1H, ddt, J = 17.0, 10.1,
6.6 Hz, CH CH2), 4.98 (1H, dq, J = 17.0, 1.7 Hz, trans
CH2 CH), 4.90 (1H, ddt, J = 10.1, 2.1, 1.1 Hz, cis CH2 CH),
4.16 (1H, td, J = 7.5, 5.4 Hz, CHOTBDPS), 2.13–2.08 (2H,
m, CHCHO, CHCHOTBDPS), 2.05–1.88 (3H, CH2CH CH2,
1H from CH2CHOTBDPS), 1.75–1.63 (2H, m, 1H from
CH2CHOTBDPS, 1H from CH2CHCH3), 1.51–1.35 (3H, m,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2447
©

View Article Online
(SiC(CH3)3 (minor diastereoisomer)), 19.1 (SiC(CH3)3), 17.3
(CH3CH (minor diastereoisomer)), 16.9 (CH3CH); nmax/(liquid
film) cm-1 3435 m (O–H), 1240 w (Si–C), 1110 m (Si–O); MS
(ES+) m/z (%) 525 (100 [M + Na]+); Calcd for C33H46O2Si + H+:
503.3340, found m/z 503.3336.
(3H, m, CHCHOTBDPS, CH2CH CH), 2.02–1.92 (2H, m, 1H
from CH2CHOTBDPS, 1H from CH2CH2CH CH2), 1.84–1.77
(2H, m, CHCHOCO, 1H from CH2CH2CHOTBDPS), 1.69–1.60
(1H, m, 1H from CH2CHOTBDPS), 1.51–1.35 (1H, m, 1H
from CH2CH2CHCH3), 1.30–1.22 (1H, m, CHCH3), 1.20–0.95
(5H, m, CH2CHCH3, 1H from CH2CH2CH CH, 1H from
CH2CH2CHCH3, 1H from CH2CH2CHOTBDPS), 1.11 (9H, s,
SiC(CH3)3), 0.80–0.59 (3H, m, CH3CH); 13C NMR (75 MHz,
CDCl3) dC 164.8 (NC O), 136.0 (4 ¥ CH Ar), 134.5 (C Ar), 134.0
(2 ¥ C Ar), 132.6 (2 ¥ C Ar), 131.9 (CH CH), 129.5 (CH Ar),
129.4 (CH Ar), 129.3 (CH CH), 128.7 (2 ¥ CH Ar), 127.5 (5 ¥
CH Ar), 126.2 (2 ¥ CH Ar), 125.9 (CH Ar), 125.8 (CH Ar), 76.7
(CHOC(O)N), 73.5 (CHOTBDPS), 50.9 (CHCHOTBDPS),
41.1 (CCH2), 39.2 (CHCHOCO), 34.4 (CH2CHCH3),
33.9 (CH2CH2CHOTBPDS), 31.9 (CH2CHOTBDPS), 31.6
(CH2CH2CH CH), 29.7 (CHCH3), 27.1 (SiC(CH3)3), 27.0
(CH2CH CH), 26.3 (CH2CH2CHCH3), 19.9 (CH3CH), 19.3
(SiC(CH3)3); nmax/(liquid film) cm-1 2340 m (O C–N), 1733 m
(C O), 1206 w (Si–C), 1110 m (Si–O); MS (ES+) m/z (%) 661
6.3 Ring closing metathesis of 57 to form 58
A solution of 57 (300 mg, 0.597 mmol; dr 7 : 3) in CH2Cl2 (20 mL)
was added dropwise to a stirred solution of Grubbs’ II catalyst
(25 mg, 0.003 mmol) in CH2Cl2 (80 mL) at room temperature
and the reaction mixture was heated under reflux. After 6 h the
reaction mixture was cooled and concentrated in vacuo. The crude
material was purified by silica gel chromatography (10% EtOAc
in petroleum ether) to afford 58 (235 mg, 0.467 mmol, 83%; dr
7 : 3) as a yellow oil. For the mixture 1H NMR (500 MHz, CDCl3)
dH 7.66 (4H, ddd, J = 9.9, 8.1, 1.3 Hz, 4 ¥ CH Ar), 7.44–7.36
(6H, m, 6 ¥ CH Ar), 5.65–5.61 (1H, m, CH2CH CH), 5.32–
5.27 (1H, m, CH CHCHOH), 4.84 (1H, s, CHOH), 4.35 (1H,
td, J = 8.8, 6.0 Hz, CHOTBDPS), 2.27 (1H, d, J = 9.2 Hz,
CHCHOTBDPS), 2.24–2.22 (1H, m, 1H from CH2CH CH),
2.00–1.92 (1H, m, 1H from CH2CHOTBDPS), 1.83–1.75 (2H, m,
1H from CH2CH2CH CH, 1H from CH2CH2CHCH3), 1.67–
1.56 (1H, m, CH2CHOTBDPS), 1.39–1.36 (1H, m, CHCHOH),
1.34–1.11 (6H, m, CH2CHCH3, 1H from CH2CH2CHCH3, 1H
from CH2CH CH, 1H from CH2CHCHOTBDPS, CHCH3),
1.11–1.08 (1H, m, CH2CH2CH CH), 1.06 (9H, s, SiC(CH3)3),
0.98–0.84 (1H, m, CH2CH2CHOTBDPS), 0.78 (3H, d,
J = 6.9 Hz, CH3CH); 13C NMR (125 MHz, CDCl3) dC
136.0 (4 ¥ CH Ar), 134.7 (C Ar), 134.6 (C Ar), 133.4
(HC CHCHOH), 130.4 (CH2CH CH), 129.5 (2 ¥ CH Ar),
127.5 (4 ¥ CH Ar), 75.9 (CHOTBDPS), 69.2 (CHOH),
51.8 (CHCHOTBPDS), 43.9 (CHCHOH), 41.4 (CCH2),
34.6 (CH2CH2CHOTBDPS), 34.2 (CH2CH2CHCH3), 32.1
(CH2CHOTBDPS), 31.9 (CH2CH2CH CH), 29.0 (CHCH3),
27.1 (SiC(CH3)3), 27.1 (CH2CHCH3), 26.6 (CH2CH CH), 21.1
(CH3CH), 19.2 (SiC(CH3)3); nmax/(liquid film) cm-1 3470 s (O–H),
1635 m (C CCOH), 1110 w (Si–O); MS (ES+) m/z (%) 497 (100
(100 [M + NH4]+); Calcd for C42H49O3Nsi + NH4 : 661.3820,
+
found m/z 661.3834.
6.5 rac-(3S,3aS,4R,9aS,12R,Z)-3-((tert-
butyldiphenylsilyl)oxy)-12-methyl-2,3,3a,4,8,9-hexahydro-4,9a-
propanocyclopenta[8]annulen-5(1H)-one
Dess–Martin periodinane (442 mg, 1.04 mmol) was added to a
stirred solution of 58 (350 mg, 0.738 mmol) in CH2Cl2 (12 mL)
and the reaction mixture stirred for 3 h. The reaction was
quenched with 0.5 M NaOH (10 mL) and extracted with EtOAc
(3 ¥ 20 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo to give a colourless oil. The crude
product was purified by silica gel chromatography (10% EtOAc in
petroleum ether) to afford rac-(3S,3aS,4R,9aS,12R,Z)-3-((tert-
butyldiphenylsilyl)oxy)-12-methyl-2,3,3a,4,8,9-hexahydro-4,9a-
propanocyclopenta[8]annulen-5(1H)-one (275 mg, 0.583 mmol,
1
79%) H NMR (400 MHz, CDCl3) dH 7.65–7.63 (4H, m, 4 ¥
CH Ar), 7.46–7.35 (6H, m, 6 ¥ CH Ar), 6.01 (1H, dt, J = 13.1,
3.9 Hz, CH CH), 5.64 (1H, dt, J = 13.1, 2.1 Hz, CH CH), 4.41
(1H, td, J = 8.7, 5.8 Hz, CHOTBDPS), 2.72 (1H, d, J = 8.8 Hz,
CHCHOTBDPS), 2.30–2.26 (2H, m, CH2CH CH2), 2.13 (1H, s,
CHCO), 2.06–1.97 (1H, m, 1H from CH2CHOTBDPS), 1.85–
1.77 (1H, m, 1H from CH2CH2CHOTBDPS), 1.74–1.67 (2H,
m, 1H from CH2CHOTBDPS, 1H from CH2CH2CH CH2),
1.59–1.50 (2H, m, CH2CHCH3), 1.22–1.10 (4H, m, CHCH3,
CH2CH2CHCH3, 1H from CH2CH2CH CH), 1.09–1.02 (1H,
m, CH2CH2CHOTBDPS), 1.06 (9H, s, SiC(CH3)3), 1.02 (3H,
d, J = 7.0 Hz, CH3CH); 13C NMR (100 MHz, CDCl3) dC 211.8
(C O), 137.0 (CH CH), 135.8 (4 ¥ CH Ar), 134.3 (2 ¥ C
Ar), 129.7 (2 ¥ CH Ar), 127.6 (4 ¥ C Ar), 127.3 (CH CH),
75.4 (CHOTBDPS), 51.2 (CHCHOTBDPS), 49.9 (CHCO), 41.6
(CCH2), 35.2 (CH2CH2CHCH3), 33.7 (CH2CH2CHOTBPDS),
31.9 (CH2CHOTBDPS), 31.0 (CH2CH2CH CH2), 29.1
(CHCH3), 27.2 (CH2CH CH), 27.0 (SiC(CH3)3), 25.9
(CH2CHCH3), 20.4 (CH3CH), 19.2 (SiC(CH3)3); nmax/(liquid
film) cm-1 2929 s (CH2s), 1700 m (C O), 1280 w (Si–C),
1110 s (Si–O), 946 w (C O); MS (ES+) m/z (%) 495 (100 [M +
[M + Na]+); Calcd for C31H42O2Si + NH4 : 492.3292, found m/z
+
492.3293.
6.4 Naphthyl carbamate 59
To a solution of 58 (30 mg, 0.060 mmol; dr 7 : 3) in THF
(3 mL) was added 1-naphthyl-isocyanate (17 ml, 0.179 mmol)
at room temperature and the reaction mixture was heated
at reflux for 24 h before being cooled to room temperature
and concentrated in vacuo to give an off white solid. The
residue was then suspended in CH2Cl2 (10 mL), the suspension
filtered, and the filtrate concentrated in vacuo. The product was
purified by silica gel chromatography (5% EtOAc in petroleum
ether) to yield 59 (32 mg, 0.050 mmol, 84%) as a sticky oil.
Subsequent crystallisation from hexane gave white needles.
◦
1
Mpt 148 C; H NMR (400 MHz, CDCl3) dH 7.90 (3H, d, J =
8.1 Hz, 3 ¥ CH Ar), 7.68–7.67 (5H, m, 5 ¥ CH Ar), 7.60–7.51
(3H, m, 3 ¥ CH Ar), 7.48–7.32 (7H, m, 7 ¥ CH Ar), 6.89
(1H, s broad, NH), 5.95 (1H, s broad, CHOCO), 5.75 (1H,
dd, J = 12.6, 2.0, CH CHCH2), 5.29 (1H, dt, J = 12.6, 2.1,
CH CHCHOCO), 4.38 (1H, s broad, CHOTBDPS), 2.36–2.21
Na]+); Calcd for C31H40O2 Si + NH4 : 490.3136, found m/z
+
490.3143.
2448 | Org. Biomol. Chem., 2011, 9, 2433–2451
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
6.6 Rac-(3S,3aS,4R,9aR,12R)-3-((tert-butyldiphenylsilyl)oxy)-
12-methyl-7-vinyloctahydro-4,9a-propanocyclopenta[8]annulen-
5(1H)-one 60
and stirred for 30 min before extraction with Et2O (5 ¥ 20 mL).
The combined organic layers were washed with brine (10 mL),
dried (Na2SO4) and concentrated in vacuo. The crude material was
purified by silica gel chromatography (1% EtOAc in petroleum
ether) to afford diastereoisomer 61a (26 mg, 0.052 mmol) and
diastereoisomer 61b (28 mg, 0.056 mmol) in an overall yield of
90%. For 61a 1H NMR (300 MHz, CDCl3) dH 7.68–7.65 (4H, m,
4 ¥ CH Ar), 7.45–7.37 (6H, m, 6 ¥ CH Ar), 5.94 (1H, ddd, J =
17.3, 10.4, 6.9 Hz, CH CH2), 5.05–4.80 (2H, m, CH2 CH),
4.40–4.35 (2H, m, CHOH, CHOTBDPS), 2.53–2.28 (1H, m,
CHCH CH2), 2.08–1.83 (4H, m, CHCHOTBDPS, 1H from
CH2CHOTBDPS, 1H from CH2, 1H from CH2), 1.70–1.61 (5H,
m, 1H from CH2CHOTBDPS, 1H from CH2, 1H from CH2,
1H from CH2, 1H from CH2), 1.52–1.50 (1H, m, CHCHOH),
1.35–1.20 (4H, from CHCH3, 1H from CH2, 1H from CH2, 1H
from CH2), 1.12–1.04 (3H, m, 1H from CH2, 1H from CH2, 1H
from CH2), 1.08 (9H, s, SiC(CH3)3), 0.85 (3H, d, J = 6.9 Hz,
CH3CH); 13C NMR (75 MHz, CDCl3) dC 146.3 (CH CH2), 136.0
(4 ¥ CH Ar), 134.7 (2 ¥ C Ar), 129.5 (2 ¥ CH Ar), 127.5 (4 ¥
CH Ar), 111.4 (CH2 CH), 76.6 (CHOTBDPS), 70.2 (CHOH),
49.3 (CHCHOTBDPS), 39.0 (CCH2), 39.0 (CHCH CH2), 37.1
(CH2CHOTBDPS), 35.8 (CH2), 34.1 (CH2), 32.0 (CH2), 31.3
(CHCHOH), 29.7 (CHCH3), 29.7 (CH2), 28.9 (CH2), 28.2 (CH2),
Vinyl magnesium bromide in THF (0.94 M in THF, 2.03 mL,
1.91 mmol) was added dropwise to a stirred suspension of
CuI (182 mg, 0.953 mmol) in THF (5 mL) at -40 ◦C. The
resulting dark brown solution was stirred for 20 min
and treated dropwise with rac-(3S,3aS,4R,9aS,12R,Z)-3-((tert-
butyldiphenylsilyl)oxy)-12-methyl-2,3,3a,4,8,9-hexahydro-4,9a-
propanocyclopenta[8]annulen-5(1H)-one (150 mg, 0.318 mmol)
in THF (4 mL). The reaction mixture was then stirred at room
temperature. After 1 h, reaction mixture was quenched with
aqueous saturated NH4Cl (10 mL) and extracted with Et2O (5
¥ 10 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo. The crude material was purified by
silica gel chromatography (1% EtOAc in petroleum ether) to
yield 60 (137 mg, 0.273 mmol, 86%; dr 1 : 1). For the mixture:
1H NMR (400 MHz, CDCl3) dH 7.69–7.65 (8H, m, 4 ¥ CH
Ar both diastereoisomers), 7.46–7.36 (12H, m, 6 ¥ CH Ar
both diastereoisomers), 6.15 (1H, ddd, J = 17.2, 10.5, 6.6 Hz,
CH CH2), 5.88 (1H, ddd, J = 17.2, 10.5, 6.6 Hz, CH CH2),
5.08–4.97 (4H, m, CH2 CH both diastereoisomers), 4.45 (2H, tt,
J = 8.6, 4.4 Hz, CHOTBDPS both diastereoisomers), 3.02 (1H,
dd, J = 11.4, 5.0 Hz, 1H from CH2C O), 2.82–2.77 (1H, m,
CHC O), 2.77–2.71 (1H, m, 1H from CH2C O), 2.57 (2H, t,
J = 8.6 Hz, CHCHCO), 2.58–2.48 (1H, m, CHCH CH2), 2.15–
2.06 (2H, m, CHCHCO, 1H from CH2C O), 2.05–1.93 (4H, m,
1H from CH2C O, 1H from CH2CHOTBDPS both diastereoiso-
mers), 1.79–1.73 (2H, m, 1H from CCH2CH2CHCH CH2 both
diastereoisomers), 1.73–1.63 (4H, m, 1H from CH2CHOTBDPS
both diastereoisomers, 1H from CH2 both diastereoisomers),
1.63–1.51 (2H, m, 1H from CH2 both diastereoisomers), 1.42–
1.24 (3H, m, CHCH3, CH2CH2CHOTBDPS both diastereoiso-
mers), 1.15–1.05 (13H, m, SiC(CH3)3 both diastereoisomers, CH2
both diastereoisomers, 1H from CCH2CH2CHCH CH2 both
diastereoisomers, 1H from CH2 both diastereoisomers), 0.93 (3H,
d, J = 6.8 Hz, CH3CH), 0.92 (3H, d, J = 6.8 Hz, CHCH3);
13C NMR (75 MHz, CDCl3) dC 214.7 (C O), 213.8 (C O),
143.4 (CH CH2), 141.6 (CH CH2), 136.0 (4 ¥ CH Ar), 135.8
(4 ¥ CH Ar), 134.2 (2 ¥ C Ar), 129.7 (CH Ar), 127.6 (CH
Ar), 113.5 (CH2 CH), 112.5 (CH2 CH), 75.5 (CHOTBDPS),
50.6 (CHCHCO), 50.1 (CHCHCO), 46.2 (CHCH CH2), 45.2
(CH2C O), 44.2 (CH2C O), 42.1 (CHC O), 41.5 (CCH2), 41.4
(CCH2), 35.3 (CH2), 35.0 (CH2), 34.9 (CH2), 34.6 (CH2), 32.5
(CH2), 31.7 (CH2CHOTBDPS), 31.4, (CH2CHOTBDPS), 28.5
(CHCH3), 28.3 (CH2), 27.1 (SiC(CH3)3), 26.0 (CH2), 25.5 (CH2),
25.3 (CH2), 19.8 (CH3CH), 19.7 (CH3CH), 19.2 (SiC(CH3)3);
1
27.2 (SiC(CH3)3), 19.3 (CH3CH), 14.2 (SiC(CH3)3). For 61b H
NMR (300 MHz, CDCl3) dH 7.72 (2H, dd, J = 7.9, 1.3 Hz,
2 ¥ CH Ar), 7.66 (2H, dd, J = 7.9, 1.3 Hz, 2 ¥ CH Ar),
7.47–7.38 (6H, m, CH Ar), 5.82 (1H, ddd, J = 17.2, 10.1,
6.8 Hz, CH CH2), 4.92 (1H, d, J = 17.2 Hz, trans CH2 CH),
4.86 (1H, d, J = 10.1 Hz, cis CH2 CH), 4.24 (1H, s brd,
CHOTBDPS), 3.62 (1H, d, J = 9.5 Hz, CHOH), 2.45–2.05 (1H, m,
CHCH CH2), 2.05–1.90 (2H, m, CHCHOTBDPS, CHCHOH),
1.68–1.57 (9H, m, CH2CHCH3, 1H from CH2CHOTBDPS, 1H
from CH2CHOH, 1H from CH2, CH2, CH2), 1.27–1.28 (3H,
m, 1H from CH2CHOTBDPS, 1H from CH2CHOH, 1H from
CH2), 1.18–1.09 (3H, m, CHCH3, CH2CH2CHOTBDPS), 1.09
(9H, s, SiC(CH3)3), 0.85 (3H, d, J = 7.3 Hz, CH3CH), 0.81 (1H, s
brd, OH); 13C NMR (75 MHz, CDCl3) dC 145.8 (CH CH2),
136.0 (4 ¥ CH Ar), 135.1 (C Ar), 134.4 (C Ar), 129.7 (2 ¥
CH Ar), 127.6 (4 ¥ CH Ar), 110.9 (CH2 CH), 80.5 (CHOH),
77.1 (CHOTBDPS), 42.3 (CHCHOTBDPS), 39.5 (CCH2), 33.9
(CH2CHOTBDPS), 32.0 (CH2), 31.0 (CH2), 29.7 (CH2), 29.4
(CH2), 29.4 (CH), 28.4 (CHCH3), 27.1 (SiC(CH)3), 22.7 (CH2),
20.3 (CH3CH), 19.3 (SiC(CH3)3); nmax/(liquid film) cm-1 3450 s
(O–H), 2928 s (CH2s), 1265 m (Si–C), 1105 m (Si–O); MS (ES+)
m/z (%) 525 (100 [M + Na]+); Calcd for C33H46O2Si + NH4 :
+
520.3605, found m/z 520.3597.
max/(liquid film) cm-1 2930 s (CH2s), 1699 s (C O), 1260 m
6.8 Rac-(3S,3aS,4R,5S,7S or 7R,9aR,12R)-3-((tert-
butyldiphenylsilyl)oxy)-12-methyl-7-vinyldecahydro-
4,9a-propanocyclopenta[8]annulen-5-yl 2-acetoxyacetate
n
(Si–C), 1076 m (Si–O); MS (ES+) m/z (%) 523 (100 [M + Na]+);
+
Calcd for C33H44O2Si + NH4 : 518.3449, found m/z 518.3449.
Et3N (67.2 mL, 0.477 mmol), acetoxyacetyl chloride (25.6 mL,
0.240 mmol) and DMAP (2 mg, 0.016 mmol) were added to a
stirred solution of 61a (40 mg, 0.080 mmol) in CH2Cl2 (2 mL) at
room temperature. After 28 h, the reaction mixture was quenched
with aqueous saturated NaHCO3 (10 mL) and extracted with
Et2O (3 ¥ 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to give a brown oil. The
crude material was purified by silica gel chromatography (2.5%
6.7 DIBAL-H reduction of 60 to give 61a and 61b
DIBAL-H (1.0 M in toluene, 0.24 mL, 0.240 mmol) was added
dropwise to a stirred solution of 60 (60 mg, 0.120 mmol, dr
1 : 1) in CH2Cl2 (2.5 mL) at -78 ◦C and the reaction mixture
stirred at room temperature. After 3 h, the reaction mixture was
quenched with aqueous saturated Na/K tartrate solution (10 mL)
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2449
©

View Article Online
EtOAc in petroleum ether) to afford rac-(3S,3aS,4R,5S,7S
or 7R,9aR,12R)-3-((tert-butyldiphenylsilyl)oxy)-12-methyl-
7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl 2-
CH2, CH2), 1.23–1.16 (2H, m, 1H from CH2CHOCO, 1H from
CH2), 0.94 (3H, d, J = 4.0 Hz, CH3CH); 13C NMR (75 MHz,
CDCl3) dC 170.2 (C O), 166.9 (C O), 144.5 (CH CH2), 112.3
(CH2 CH), 75.4 (CHOH), 75.1 (CHOCO), 61.0 (CH2OAc),
49.1 (CHCHOH), 39.7 (CCH2), 38.3 (CHCHOCO), 35.8
CH2CHOCO), 33.8 (CH2), 33.2 (CH2CHOH), 31.7 (CH2), 31.1
(CH2CHCH3), 29.7 (CHCH CH2), 28.6 (CHCH3), 28.2 (CH2),
27.9 (CH2), 20.5 (CH3CO), 18.3 (CH3CH); nmax/(liquid film) cm-1
3400 s (O–H), 1700 m (C O), 1638 m (C O); MS (ES+) m/z
(%) 387 (100 [M + Na]+); Calcd for C21H32O5 + Na+: 387.2142,
found m/z 387.2130.
1
acetoxyacetate (35 mg, 0.058 mmol, 73%). H NMR (500 MHz,
CDCl3) dH 7.66–7.62 (4H, m, 4 ¥ CH Ar), 7.44–7.36 (6H, m, 6
¥ CH Ar), 5.84 (1H, ddd, J = 17.2, 10.1, 6.6 Hz, CH CH2),
5.35 (1H, t, J = 7.1 Hz, CHOCO), 5.02 (1H, d, J = 17.2,
trans CH2 CH), 4.93 (1H, d, J = 10.1 Hz, cis CH2 CH),
4.62 (2H, s, CH2OAc), 4.34 (1H, d, J = 4.1 Hz, CHOTBDPS),
2.25–2.16 (1H, m, 1H from CH2CHOCO), 2.16 (3H, s, CH3CO),
2.09–1.92 (3H, m, CHCHOTBDPS, CHCH CH2, 1H from
CH2CHOTBDPS), 1.86 (1H, dd, J = 13.2, 10.6 Hz, CH2),
1.71–1.54 (6H, CHCHOCO, 1H from CH2CHOCO, 1H from
CH2CHCH3, 1H from CH2CHOTBDPS, CH2), 1.40–1.32
(1H, m, 1H from CH2), 1.33–1.21 (2H, m, CHCH3, 1H from
CH2), 1.19–1.13 (1H, m, 1H from CH2), 1.09–1.03 (3H, m, 1H
from CH2CHCH3, CH2), 1.07 (9H, s, SiC(CH3)3), 0.56 (3H, d,
J = 6.3 Hz, CH3CH); 13C NMR (125 MHz, CDCl3) dC 170.2
(C O), 167.0 (C O), 144.8 (CH CH2), 135.9 (4 ¥ CH Ar),
134.5 (2 ¥ C Ar), 129.6 (2 ¥ CH Ar), 127.6 (4 ¥ CH Ar),
112.2 (CH2 CH), 76.2 (CHOTBDPS), 75.2 (CHOCO), 60.9
(CH2OAc), 49.0 (CHCHOTBDPS), 39.6 (CHCH CH2), 39.0
(CCH2), 37.4 (CHCHOCO), 35.9 (CH2CHCH3), 33.8 (CH2), 33.3
(CH2CHOCO), 31.8 (CH2CHOTBDPS), 31.2 (CH2), 29.7 (CH2),
28.2 (CHCH3), 27.7 (CH2), 27.1 (SiC(CH3)3), 20.6 (CH3CO),
19.2 (SiC(CH3)3), 18.2 (CH3CH); nmax/(liquid film) cm-1 1700
m (C O), 1684 m (C O), 1265 m (Si–C), 895 w (C C); MS
(ES+) m/z (%) 625 (100 [M + Na]+); Calcd for C37H50O5Si + Na+:
625.3320, found m/z 625.3306.
6.10 Rac-(3aS,4R,5S,7R or 7S,9aR,12R)-12-methyl-3-oxo-7-
vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl
2-acetoxyacetate 62a
TPAP (0.6 mg, 0.002 mmol) and NMO (19 mg, 0.165 mmol)
were added to a stirred solution of rac-(3S,3aS,4R,5S,7S
or
7R,9aR,12R)-3-hydroxy-12-methyl-7-vinyldecahydro-4,9a-
propanocyclopenta[8]annulen-5-yl 2-acetoxyacetate (20 mg,
0.055 mmol) in CH2Cl2 (1 mL) with crushed molecular sieves at
room temperature. After 2 h, the resulting black solution was
filtered through a silica gel pad (30% EtOAc in petroleum ether)
and concentrated in vacuo to afford 62a (19.5 mg, 0.054 mmol,
1
98%). H NMR (300 MHz, CDCl3) dH 5.75 (1H, dt, J = 17.2,
10.1 Hz, CH CH2), 5.56 (1H, broad s, CHOCO), 4.99 (1H,
d, J = 17.2 Hz, trans CH2 CH), 4.91 (1H, d, J = 10.1 Hz, cis
CH2 CH), 4.67 (2H, s, CH2OAc), 2.36–2.25 (4H, m, CHC O,
CHCHOCO, CH2C O), 2.18 (3H, s, CH3CO), 2.15–2.02
(2H, m, CHCH CH2, 1H from CH2), 1.89–1.72 (3H, m,
1H from CH2, 1H from CH2, 1H from CH2), 1.66–1.42 (5H,
CHCH3, CH2, 1H from CH2, 1H from CH2), 1.42–1.23 (4H, m,
CH2, 1H from CH2, 1H from CH2), 0.92 (3H, d, J = 5.3 Hz,
CH3CH); 13C NMR (75 MHz, CDCl3) dC (C O) not observed
<220, 170.2 (C O), 166.8 (C O), 144.1 (CH CH2), 112.6
(CH2 CH), 74.0 (CHOCO), 60.9 (CH2OAc), 53.4 (CHC O),
39.2 (CHCH CH2), 38.9 (CCH2), 37.0 (CHCHOCO), 34.6
(CH2C O), 33.8 (CH2), 32.8 (CH2), 31.4 (CH2), 30.6 (CHCH3),
29.7 (CH2), 28.6 (CH2), 27.0 (CH2), 20.5 (CH3CO), 18.2
(CH3CH); nmax/(liquid film) cm-1 1700 m (C O), 1653 m
(C O); MS (ES+) m/z (%) 385 (100 [M + Na]+); Calcd for
6.9 Rac-(3S,3aS,4R,5S,7S or 7R,9aR,12R)-3-hydroxy-12-
methyl-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl
2-acetoxyacetate
HF (60% aqueous solution, 74 ml, 2.32 mmol) was added
dropwise to a solution of rac-(3S,3aS,4R,5S,7S or 7R,9aR,12R)-
3-((tert-butyldiphenylsilyl)oxy)-12-methyl-7-vinyldecahydro-4,
9a-propanocyclopenta[8]annulen-5-yl 2-acetoxyacetate (28 g,
0.046 mmol) in pyridine (1 mL) at 0 ◦C. The resulting cloudy
solution was allowed to warm to room temperature and stirred
for 12 h. The reaction was then quenched with aqueous saturated
NaHCO3 (20 mL) and extracted with EtOAc (3 ¥ 10 mL). The
combined organic layers were washed with aqueous saturated
CuSO4 (3 ¥ 5 mL), dried (Na2SO4) and concentrated in vacuo
to give a colourless oil. The crude material was purified by
silica gel chromatography (5% EtOAc in petroleum ether then
30% EtOAc in petroleum ether) to afford rac-(3S,3aS,4R,5S,7S
+
C21H30O5 + NH4 : 380.2431, found m/z 380.2429.
6.11 Rac-(3aS,4R,5S,7R or 7S,9aR,12R)-12-methyl-3-oxo-7-
vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl
2-hydroxyacetate 63a
or
7R,9aR,12R)-3-hydroxy-12-methyl-7-vinyldecahydro-4,9a-
Aqueous K2CO3 (0.17 M, 1.0 mL, 0.170 mmol) was added to a
stirred solution of 62a (30 mg, 0.083 mmol) in THF (1 mL) and
MeOH (2 mL) at room temperature. After 1.5 h, the reaction
mixture was quenched with aqueous saturated NH4Cl (5 mL)
and extracted with EtOAc (3 ¥ 5 mL). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The
crude material was purified by silica gel chromatography (20%
EtOAc in petroleum ether) to afford 63a (24 mg, 0.075 mmol,
91%). 1H NMR (400 MHz, CDCl3) dH 5.77 (1H, broad s,
CH CH2), 5.60 (1H, broad s, CHOCO), 4.96 (1H, d, J =
17.7 Hz, trans CH2 CH), 4.94–4.91 (1H, m, cis CH2 CH),
4.23 (2H, s brd, CH2OH), 2.52 (1H, s brd, OH), 2.36–2.27 (5H,
propanocyclopenta[8]annulen-5-yl 2-acetoxyacetate (15 mg,
0.041 mmol, 89%) as a colourless oil. 1H NMR (300 MHz,
CDCl3) dH 5.79 (1H, dt, J = 17.2, 10.1 Hz, CH CH2), 5.60–5.50
(1H, m, CHOCO), 4.98 (1H, d, J = 17.2, trans CH2 CH), 4.89
(1H, d, J = 10.1 Hz, cis CH2 CH), 4.67 (2H, s, CH2OAc),
4.45–4.35 (1H, m, CHOH), 2.31–2.11 (2H, m, 1H from CH2,
1H from CH2CHOH), 2.17 (3H, s, CH3CO), 2.09–1.83 (6H, m,
CHCHOH, CHCHOCO, CHCH3, 1H from CH2CHCH3, CH2),
1.80–1.57 (3H, m, 1H from CH2CHOH, 1H from CH2CHOCO,
1H from CH2), 1.55–1.41 (1H, m, 1H from CH2), 1.40–1.23 (6H,
m, CHCH CH2, 1H from CH2CHCH3, 1H from CH2, 1H from
2450 | Org. Biomol. Chem., 2011, 9, 2433–2451
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
m, CHC O, CHCH CH2, CH2C O, 1H from CH2CHOCO),
2.03 (1H, d, J = 8.3 Hz, CHCHOCO), 1.80–1.71 (3H, m, 1H
from CH2CHCH3, 1H from CH2, 1H from CH2), 1.54–1.44
(4H, CHCH3, 1H from CH2, CH2), 1.39–1.24 (5H, m, 1H from
CH2CHOCO, 1H from CH2CHCH3, 1H from CH2, CH2), 0.89
(3H, d, J = 4.8 Hz, CH3CH); 13C NMR (100 MHz, CDCl3)
dC 219.5 (C O), 172.2 (OC O), 144.0 (CH CH2), 112.6
(CH2 CH), 74.1 (CHOCO), 60.8 (CH2OH), 53.4 (CHC O),
39.4 (CHCHOCO), 38.9 (CCH2), 37.0 (CHCH CH2), 34.6
(CH2C O), 33.9 (CH2CHCH CH2), 32.6 (CH2), 31.4 (CH2),
30.6 (CHCH3), 29.7 (CH2), 28.5 (CH2), 27.1 (CH2CHCH3), 18.3
(CH3CH); nmax/(liquid film) cm-1 3400 s (O–H), 1700 m (C O),
1653 m (C O); MS (ES+) m/z (%) 343 (100 [M + Na]+); Calcd
L. B. Johansson, Mol. Microbiol., 2001, 41(5), 1091; (c) F. Schlu¨nzen,
E. Pyetan, P. Fucini, A. Yonath and J. M. Harms, Mol. Microbiol.,
2004, 54(5), 1287.
6 (a) N. Abe, R. Onoda, K. Shirahata, T. Kato, M. C. Woods, Y. Kitahara,
K. Ro and T. Kurihara, Tetrahedron Lett., 1968, 9, 1993; (b) T. J.
Brocksom, F. Coelho, J-P. Depre´s, A. E. Greene, M. E. Freire de Lima,
O. Hamelin, B. Hartmann, A. M. Kanazawa and Y. Wang, J. Am.
Chem. Soc., 2002, 124, 15313.
7 T. J. K. Findley, D. Sucunza, L. C. Miller, D. T. Davies and D. J. Procter,
Chem.–Eur. J., 2008, 14, 6862.
8 (a) A. Solladie´-Cavallo, L. Jierry, L. Boue´rat and P. Taillasson,
Tetrahedron: Asymmetry, 2001, 12, 883; (b) L. M. Urbaneja, A.
Alexakis and N. Krause, Tetrahedron Lett., 2002, 43, 7887.
9 W. F. Gannon and H. O. House, Organic Synth, 1973, Coll. Vol. 5,
539.
10 L. F. Tietze, H. Schirok and M. Wo¨hrmann, Chem.–Eur. J., 2000, 6,
510.
+
for C19H28O4 + NH4 : 338.2326, found m/z 338.2322; Anal. Calcd
for C19H28O4: C, 70.56; H, 8.55. Found: C, 70.83; H, 9.12.
11 D. L. Comins and A. Dehghani, Tetrahedron Lett., 1992, 33,
6299.
12 See ref. 7 and the ESI for CCDC numbers.
13 For a review on Sm-enolates, see: I. M. Rudkin, L. C. Miller and D. J.
Procter, Organomet. Chem., 2008, 34, 19.
Acknowledgements
14 S. Irifune, T. Kibayashi, Y. Ishii and M. Ogawa, Synthesis, 1988, 366.
15 (a) S. M. Bennett, R. K. Biboutou, Z. Zhou and R. Pion, Tetrahedron,
1998, 54, 4761; (b) For fundamental studies on the rate and mechanism
of reduction of alkyl halides by SmI2-HMPA, see: D. P. Curran,
T. L. Fevig, C. P. Jasperse and M. J. Totleben, Synlett, 1992, 943;
(c) E. Hasegawa and D. P. Curran, Tetrahedron Lett., 1993, 34, 1717;
(d) M. Shabangi and R. A. Flowers II, Tetrahedron Lett., 1997, 38,
1137.
We thank the University of Manchester (studentship, T. J. K. F.),
GlaxoSmithKline (CASE award, L. C. M.), the EPSRC (M. D. H)
and EU (D. S.) for funding.
Notes and references
16 Access to enantiomerically-enriched 4-alkylcyclohexenones allows the
asymmetric synthesis of cis-hydrindanes using our approach. For
example, see: K. Aoki, M. Nakajima, K. Tomioka and K. Koga, Chem.
Pharm. Bull., 1993, 41, 994.
1 For a review of metal-mediated radical reactions: (a) A. Gansauer and
H. Bluhm, Chem. Rev., 2000, 100, 2771; (b) For recent reviews on the
use of samarium(II) iodide: D. J. Procter, R. A. Flowers II and T.
Skrydstrup, Organic Synthesis using Samarium Diiodide: A Practical
Guide, RSC Publishing, Cambridge, 2010; (c) K. C. Nicolaou, S. P.
Ellery and J. S. Chen, Angew. Chem., Int. Ed., 2009, 48, 7140; (d) K.
Gopalaiah and H. B. Kagan, New J. Chem., 2008, 32, 607; (e) R. A.
Flowers, Synlett, 2008, 1427; (f) D. J. Edmonds, D. Johnston and D. J.
Procter, Chem. Rev., 2004, 104, 3371; (g) A. Dahle´n and G. Hilmersson,
Eur. J. Inorg. Chem., 2004, 3393; (h) H. B. Kagan, Tetrahedron, 2003,
59, 10351; (i) P. G. Steel, J. Chem. Soc., Perkin Trans. 1, 2001, 2727;
(j) H. B. Kagan and J. L. Namy, In Lanthanides: Chemistry and Use
in Organic Synthesis, S. Kobayashi, Ed.; Springer, Berlin, 1999; p 155;
(k) G. A. Molander and C. R. Harris, Tetrahedron, 1998, 54, 3321.
2 For selected, recent approaches to the hydrindane skeleton, see: (a) T.
Kusakabe, K. Kato, S. Takaishi, S. Yamamura, T. Mochida, H. Akita,
T. A. Peganova, N. V. Vologdin and O. V. Gusev, Tetrahedron, 2008, 64,
319; (b) A-S. Chapelon, C. Ollivier and M. Santelli, Tetrahedron Lett.,
2006, 47, 2747; (c) G. Pandey and S. B. Raikar, Tetrahedron Lett., 2006,
47, 2029; (d) R. Rodriguez, C. Ollivier and M. Santelli, Synlett, 2006,
312; (e) Y. Nakai and Y. Uozumi, Org. Lett., 2005, 7, 291; (f) H. Araki,
M. Inoue and T. Katoh, Synlett, 2003, 2401; (g) I. Prowotorow, W.
Stepanenko and J. Wicha, Eur. J. Org. Chem., 2002, 2727; (h) G. Mehta
and K. Islam, Angew. Chem., Int. Ed., 2002, 41, 2396; (i) D. N. Jones,
M. W. J. Maybury, S. Swallow, N. C. O. Tomkinson and W. W. Wood,
Tetrahedron Lett., 2001, 42, 2193.
17 For previous synthetic studies on pleuromutilin, see: (a) E. G. Gibbons,
J. Org. Chem., 1980, 45, 1540; (b) M. Kahn, Tetrahedron Lett., 1980, 21,
4547; (c) E. G. Gibbons, J. Am. Chem. Soc., 1982, 104, 1767; (d) L. A.
Paquette, P. C. Bulman-Page, P. D. Pansegrau and P. E. Wiedeman,
J. Org. Chem., 1988, 53, 1450; (e) L. A. Paquette, P. D. Pansegrau, P. E.
Wiedeman and J. P. Springer, J. Org. Chem., 1988, 58, 1461; (f) L. A.
Paquette, P. E. Wiedeman and P. C. Bulman-Page, J. Org. Chem., 1988,
53, 1441; (g) R. K. J. Boeckman, D. M. Springer and T. R. Alessi, J. Am.
Chem. Soc., 1989, 111, 8284; (h) E. Bacque´, F. Pautrat and S. Z. Zard,
Org. Lett., 2003, 5, 325; (i) M. D. Helm, M. Da Silva, D. Sucunza,
T. J. K. Findley and D. J. Procter, Angew. Chem., Int. Ed., 2009, 48,
9315; (j) J. Liu, S. D. Lotesta and E. J. Sorensen, Chem. Commun., 2011,
47, 1500.
18 We have reported a SmI2-mediated cascade approach to the tricyclic
core of pleuromutilin, see ref. 17i. For preliminary studies on the SmI2-
mediated cascade approach, see: (a) M. D. Helm, D. Sucunza, M. Da
Silva, M. Helliwell and D. J. Procter, Tetrahedron Lett., 2009, 50, 3224;
(b) M. D. Helm, M. Da Silva, D. Sucunza, M. Helliwell and D. J.
Procter, Tetrahedron, 2009, 65, 10816.
19 For a review on RCM, see: T. M. Trnka and R. H. Grubbs, Acc. Chem.
Res., 2001, 34, 18.
20 For a review of the use of RCM in natural product synthesis, see: K. C.
Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed., 2005,
44, 4490.
3 W. Zhao, Q. Ye, X. Tan, H. Jiang, X. Li, K. Chen and A. D. Kinghorn,
J. Nat. Prod., 2001, 64, 1196.
21 Sorenson has recently reported an RCM approach to the 8-membered
ring of pleuromutilin, see ref. 17j.
22 T. R. Hoye and H. Zhao, Org. Lett., 1999, 1, 1123.
23 R. K. J. Boeckman, Ed. Strategies and tactics in organic synthesis, 1st
edition; Academic Press, Inc., 1991; Vol. 3.
4 (a) H. Hikino, Y. Hikino, K. Agatsuma and T. Takemoto, Chem. Pharm.
Bull., 1968, 16, 1779; (b) R. Bos, H. Hendriks, J. Kloosterman and G.
Sipma, Phytochemistry, 1983, 22, 1505.
5 (a) F. Kavanagh, A. Hervey and W. J. Robbins, Proc. Natl. Acad. Sci.
U. S. A., 1951, 37, 570; (b) B. Vester, S. M. Poulsen, M. Karlsson and
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2433–2451 | 2451
©