Intramolecular Diels-Alder reactions using chiral ruthenium Lewis acids and application in the total synthesis of ent-ledol

Article abstract of DOI:10.1039/c1ob06121f

One-point binding chiral ruthenium Lewis acids incorporating the C ₂-symmetric electron-poor bidentate phosphinite ligand BIPHOP-F and a Cp or an indenyl 'roof' can efficiently catalyze asymmetric intramolecular Diels-Alder reactions of trienes to form bicyclic adducts with good to excellent asymmetric induction. This reaction forms the key step in a total synthesis of ent-ledol in 96% ee. The synthesis also helps to clarify the stereochemical assignment of ledol and inconsistencies in the measured optical rotation.

Full text of DOI:10.1039/c1ob06121f

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PAPER
Intramolecular Diels–Alder reactions using chiral ruthenium Lewis acids and
application in the total synthesis of ent-ledol†
Sirinporn Thamapipol and E. Peter Ku¨ndig*
Received 8th July 2011, Accepted 18th August 2011
DOI: 10.1039/c1ob06121f
One-point binding chiral ruthenium Lewis acids incorporating the C2-symmetric electron-poor
bidentate phosphinite ligand BIPHOP-F and a Cp or an indenyl ‘roof’ can efficiently catalyze
asymmetric intramolecular Diels–Alder reactions of trienes to form bicyclic adducts with good to
excellent asymmetric induction. This reaction forms the key step in a total synthesis of ent-ledol in 96%
ee. The synthesis also helps to clarify the stereochemical assignment of ledol and inconsistencies in the
measured optical rotation.
Introduction
The Diels–Alder reaction is arguably the most powerful method
to access six-membered rings compounds. The reaction generates
up to four stereogenic centers in a single step. 6-Membered
rings are ubiquitous in biologically active natural products. Over
recent years, asymmetric catalytic Diels–Alder methodologies
have experienced an enormous advancement,1 but less reactive
dienes or dienophiles are still inherently difficult to engage in this
reaction.
Fig. 1 Chiral Ru Lewis acid catalysts.
mode leads to opposite asymmetric inductions. One-point binding
chiral Lewis acid catalysts for this reaction are therefore scarce.
Successful solutions were reported by Corey and by Hawkins
using chiral boron Lewis acids.6 Another approach was chosen
by MacMillan and Northrup via formation of a chiral iminium
salt using a chiral imidazolidinone as catalyst.7 In an earlier
publication we have shown that the chiral catalysts 1 are also
able to give high asymmetric induction in intermolecular [4 + 2]
cycloaddition reactions.8 We found that while the ground state
structure of [Ru(BIPHOP-F)(Cp)(methyl vinyl ketone) shows a
preferential anti-s-trans conformation in the X-ray structure, the
reacting conformation apparently is the one having a syn-s-
trans arrangement. This study also included a first example of
an intramolecular Diels–Alder (IMDA) reaction as depicted in
Scheme 1.
We have developed single-point binding chiral Ru Lewis acid
catalysts based on cationic half-sandwich complexes incorporating
a pentafluorophenyldiphosphinite ligand (Fig. 1). This ligand
creates the chiral environment around the coordination site of the
catalyst. The electron poor ligand also offsets the donor properties
of the electron rich arene roof and thus enhances the Lewis acidity
of the metal center. These catalysts were first employed successfully
in intermolecular Diels–Alder (DA) cycloaddition reactions of
enals with various dienes.2 Applications in asymmetric 1,3-
dipolar cycloadditions of nitrones3 and nitrile oxides3c,4 followed.
Furthermore, catalyst 1a was successfully applied in Michael
addition reactions of enones with diverse thiophenols.5 In all these
reactions the enals coordinated to the transition metal center and
the ground state anti-s-trans conformation of the coordinated enal
was also the one undergoing reaction as indicated by the product’s
absolute configuration. Slow addition of the dipolarophile helped
in cases of competitive coordination.
a,b-Unsaturated ketones are far more difficult substrates since
they lack the high lone pair differentiation of aldehydes. Coordi-
nation is in the anti-s-trans conformation and that conformation
Scheme 1 A first IMDA reaction catalyzed by 1a.
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest
Ansermet, CH-1211, Geneva, Switzerland. E-mail: peter.kundig@unige.ch;
Fax: (+)41-22-379-3215; Tel: (+)41-22-379-6093
† Electronic supplementary information (ESI) available: general experi-
mental information, full experimental procedure and characterization data
for unknown compounds. See DOI: 10.1039/c1ob06121f
We here report on a follow-up of asymmetric IMDA reaction
of triene 2 and its application in the total synthesis of ent-ledol.
This first synthesis is performed in order to clarify the conflicting
data for ledol and related diastereomers (globulol and viridiflorol).
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Although there have been many reports on the isolation of ledol
from various natural sources, several inconsistencies remain in the
reported structures and spectral assignments. As shown below, our
data confirm those of Goh,9a Gottlieb9b and Szafranek9c Moreover,
we also detail the use of CpRu 1a and IndRu 1b in IMDA reactions
with trienes 4–15 (Fig. 2).
and by ourselves using the chiral Ru Lewis acid 1a (Scheme 2).
We have now scaled up this reaction in order to provide sufficient
material for the synthesis of ent-ledol by using (S,S)-1a with triene
2 to provide the crucial intermediate (S)-3 in good yield with
excellent ee.
Scheme 2
The X-ray structure of the CpRu Lewis acid complex helps to
rationalize the observed enantioselectivity in the IMDA reaction
as shown in Fig. 4. The syn-s-trans conformation of the enone
(orange) is arranged such as to avoid adverse steric interactions
between the three methylene groups of the side chain and the Cp
ligand of the catalyst. The diene (blue) approaches the Si-face of
the dienophile in endo fashion because the Re-face is shielded by
a pentafluorophenyl group of the ligand.
Fig. 2 Trienes probed in the chiral [Ru] catalyzed IMDA reactions.
Synthesis of ent-ledol
Ledol is a sesquiterpene that belongs to the class of aro-
madendrenes. Its structural characteristics include
a gem-
dimethylcyclopropane ring fused to a hydroazulene skeleton
(Fig. 3). It exhibits antitussive10a,b and antifungal10c (Coriolus
renatus) properties. Ledol was first isolated from Ledum palustre
(Rhododendron tomentosum, also commonly known as Labrador
tea or wild rosemary), a plant common to sphagnum meadows.11a
Its relative stereochemistry was elucidated by X-ray diffraction.12
An asymmetric synthesis of ledol was previously reported start-
ing from (+)-aromadendrene.13 A racemic synthesis via IMDA
reaction was reported by Shea.14 A literature survey of ledol
shows many conflicting stereochemical assignments and due to
different solvents used there is confusion about the sign of optical
rotation. We therefore decided to prepare ent-ledol to compare
spectroscopic data and optical rotation. The present synthesis will
help to solve several structure misassignments15 and be useful for
the study of biological activity.
Fig. 4 Modelled approach of trienone 2 coordinated to Ru in (S,S)-1a in
a syn-s-trans orientation (catalyst part taken from the X-ray structure of
[Ru(acetone)(Cp)((S,S)-BIPHOP-F)][SbF6]).2a
With (S)-3 in hand, we proceeded with the synthesis of ent-
ledol by following to a large extent Shea’s route.14 Treatment
of 3 with MeLi and alcohol protection with TBSOTf afforded
the endo product 16 as a single diastereomer with an ee of
92%. Ozonolysis of 16 furnished diketone 17 in 76% yield. Aldol
condensation provided the expected enone which was directly used
in a highly diastereoselective hydrogenation leading to the [7,5]-
fused ring compound 18 in 90% yield in 2 steps. Isolation at this
step also showed the material to have higher enantiomeric purity
(Scheme 3).
Generation of bicyclic alkene 19 involved formation of the enol
phosphate and hydrogenolysis (Scheme 4).
Next the dimethylcyclopropane moiety needed to be installed.
Seyferth’s reagent18 was previously employed to furnish the dibro-
mocyclopropane precursor.14 To avoid the use of a mercury reagent
and benzene as solvent, we investigated more environmentally
benign conditions. The haloform cyclopropanation procedure
fulfils these requirements.19 This procedure was first optimized
on the model alkene 21, obtained from bicyclic ketone 20. The
Fig. 3 Ledol and its diastereoisomers globulol and viridiflorol.
Asymmetric type 2 IMDA reactions were previously docu-
mented by Shea with dual function Ru catalysts16 (modest induc-
tion) and by MacMillan with organocatalysis17 (high induction),
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This cyclopropanation procedure was applied to the cis-fused
ring compound 19 to furnish dibromocyclopropane 24, fol-
lowed by gem-dimethylation with methyl cyano cuprate providing
dimethylated compound 25 in excellent diastereoselectivity and
thus retaining the high enantiomeric excess (Scheme 6). Cleavage
of the TBS group of 25 by refluxing with TBAF in THF then
yielded ent-ledol in excellent enantioselectivity. Its spectroscopic
data matched literature data.9,14a
Scheme 3
Scheme 6
The 1H-NMR resonances C(1a)–H and C(7b)–H are the
principal distinguishing spectroscopic characteristics for ledol and
its diastereomers. These are found at d = 0.33 and 0.72 ppm for
ledol, at 0.51 and 0.59 ppm for globulol, and at 0.11 and 0.61
ppm for viridiflorol. Another characteristic is the melting point:
103–105 ◦C for ledol, 86–88 ◦C for globulol, and 72–74 ◦C for
viridiflorol.9,13
To confirm the absolute configuration of the synthesized ent-
ledol, the specific optical rotation ([a]2D5) was measured and
compared to literature data of ledol (Table 1). In an early, brief
report on the isolation of ledol, Naves reported the [a]2D0 to have a
negative sign in chloroform but a positive one in ethanol.21b This
note was overlooked and a negative sign measured in chloroform
led to confusion and what must have been ledol was erroneously
assigned to ent-ledol.15a
Scheme 4
reaction yielded dibromocyclopropane 22 in high yield with
excellent diastereoselectivity. Treatment of 22 with in situ generated
lithium dimethylcuprate, and then with MeI,20 yielded the corre-
sponding gem-dimethyl compound 23 (Scheme 5). The relative
stereochemistry in 23 was established by Nuclear Overhauser
Effect Spectroscopy (NOESY). The observed NOE’s are shown in
Scheme 5 and they show that, as expected, the product obtained
was the one issued from cyclopropanation on the convex face of
21.
Moreover, a negative Cotton effect in the CD spectrum of ent-
ledol in EtOH is indicated (Fig. 5) but not in CHCl3 and toluene
because of the overlapping between solvent and ledol peaks.
Fig. 5 CD Spectrum of ent-ledol in EtOH showing a negative Cotton
effect.
Asymmetric IMDA reactions
We next probed type 1 IMDA reactions.22 Triene 423 was unreac-
tive, and coordination to 1a does not appear to occur as evidenced
Scheme 5
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22
Table 1 Optical rotations of ledol (lit. data) and of ent-ledol
Table 2 Optimized IMDA reactions conditions of triene 7a
Entry Solvent
[a]2D5 of Ledol
Cond.a
[a]2D5 of ent-Ledolb
-2.3
1
EtOH
+1.921a
+2.621b
+2.09b
-4.39a
25 ◦C (0.98)
20 ◦C (0.05)
nrc (1.40)
2
3
MeOH
CHCl3
—
+4.6
nrc (0.42)
-5.621b
20 ◦C (0.05)
nrc (1.50)
-5.813d
c
4
5
6
Toluene
CH3CN
THF
—
-9.8
+0.5
+0.4
Entry
Cat.
Cond.a
Conv.b
% yieldc (ee)d
c
—
c
—
1
2
3
4
5
—
1a
1a
1b
1b
rt, 7 d
2
100
96
100
100
(0)
82 (72)
70 (69)
92 (84)
82 (82)
a Temperature (concentration) for measurement of [a]D. b This study,
average value of three determinations at 25 ◦C (c = 0.10 g L-1) with cuvette
cell. c Temperature not specified.
rt, 9 d
40 ◦C, 4 d
rt, 7 d
40 ◦C, 4 d
a All reactions were carried out at least 3 times in 0.2–0.3 M concentration
and were followed by TLC (10% Et2O in pentanes). b % Conversion was
determined by 1H NMR. c Isolated yield. d ee of the endo-isomer was
determined by chiral GC (Hydrodex-b, H2, 100 ◦C hold 30 min then
heating at 0.5 ◦C min-1 to 120 ◦C: tR of endo product (min) = 33.69 (minor),
35.30 (major)).
1
by the lack of change in the H-NMR spectrum when mixing
trienone 4 with an equimolar quantity of complex 1a. Ketone 4
may be too bulky to fit into the Lewis acidic site. The same holds
for triene 5. Moreover, this compound presented an additional
difficulty in that it underwent IMDA reaction spontaneously on
generation via oxidation of trienol 26 (Scheme 7).24
Triene 9, previously investigated in the asymmetric IMDA
reaction with a chiral acyloxy borane catalyst,26c was prepared
and used in IMDA reactions with chiral Ru catalysts 1a and 1b
(Table 3). As expected cycloadduct 28, incorporating a quaternary
carbon center, was formed with high enantioselectivities, although
diastereoselectivities were modest and reaction times long.
More efficient catalytic IMDA reactions resulted with trienals
10 and 11. This can be attributed largely to the Thorpe–Ingold
effect of the dimethyl malonate moiety. It also made the synthesis
of this triene more efficient. The reaction of triene 10 was followed
by in situ IR analysis recording the decay of the aldehyde nCO band
associated with 10. TLC was unsuitable because of an overlap of
starting material and product spots. Reactions were considerably
faster with cycloadducts being formed in hours rather than days.
Trienal 10 undergoes spontaneous, uncatalyzed cycloaddition
(Table 4, entry 1). While the catalysts accelerate the reaction and
impart asymmetric induction, the background reaction prevents
Scheme 7
Trienone 6 afforded low product yield with low ee (CH2Cl2,
40 ◦C, 7 d and rt, 10 d). 1H NMR data indicates enone 6 to coor-
dinate to the catalyst. On mixing 6 with 1a (ratio 10 : 1, CH2Cl2,
1
15 min) resulted in important H NMR shifts (7.51 (COCH
CH), 2.60 (CH3) and 2.51 (COCH CHCH2) compared to the
values of 6.82, 2.24 and 2.27 respectively, for 6 alone. Also in the
IR spectrum, the nCO band shifted from 1672 to 1640 cm-1.
We conclude that either the activation provided by 1a is
insufficient to promote IMDA reaction or that the substrate
cannot adopt a folding leading to IMDA reaction. Based on the
results discussed below we favor the first explanation. At this stage
it is important to remind the reader that these catalysts are weak
Lewis acids best compared to ZnCl2.25
Table 3 IMDA reactions of triene 9a
22
We then turned to aldehyde substrates. Without catalyst, trienal
7 did not undergo cycloaddition (Table 2, entry 1). The catalytic
reaction, while very slow, afforded products in good yield and
in high diastereoselectivity and enantioselectivity, albeit that the
yields did not reach the values previously reported by Yamamoto
and coworkers.26a,b 2,6-Lutidine was added to scavenge traces of
acid in order to suppress the acid catalyzed reaction leading to
the racemic product. The data shows that both the yield and
the ee are higher when catalyst 1b is used rather than 1a. The
first is likely to be linked to a looser ion pair in complex 1b
enabling more efficient turnover.2d The higher enantioselectivity
may result from a more restricted space in the reaction site in
the indenyl catalyst when compared to the Cp catalyst.2b,22 As
detailed in the preliminary communication of this paper, the
absolute configuration of 27 was ascertained by an X-ray structure
determination after derivatization.22
Entry
Cat.
Cond.a
endo : exob
% yieldc (ee)d
1
2
3
4
5
—
1a
1a
1b
1b
rt, 6 d
—
1e(–)
82 (92, 91)
66 (88, 90)
85 (84, 90)
60 (78, 87)
rt, 7 d
84 : 16
82 : 18
81 : 19
79 : 21
40 ◦C, 4 d
rt, 6 d
40 ◦C, 4 d
a All reactions were carried out in 0.2–0.3 M concentration. The progress
of the reaction was followed by TLC (10% Et2O in pentanes). b Determined
1
by H NMR. c Isolated yield. d ee of endo- and exo-isomers, respectively
were determined by chiral GC (Hydrodex-b, H2, 100 ◦C hold 30 min then
heating 0.5 ◦C min-1 to 120 ◦C): tR of exo product (min) = 34.82 (major),
38.03 (minor) and tR of endo product (min) = 40.85 (minor), 41.52 (major)).
e % Conversion was determined by 1H NMR.
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Table 4 IMDA reactions of trienals 10 and 11a22
BIPHOP-F ligand (Fig. 6). This results in the observed product
stereochemistry of 27.
Entry
Cat.
Triene
Cond.
2,6-Lutidineb
% yieldc (ee)
1
2
3
4
5
6
7
—
1a
1a
1b
—
1a
1b
10
10
10
10
11
11
11
rt, 5 h
rt, 5 h
rt, 5 h
rt, 4 h
rt, 5 h
rt, 5 h
rt, 4 h
5
2
5
2
5
5
5
26d (0)
quant (49)e
quant (55)e
quant (56)e
5d (0)
quant (43)f
quant (84)f
Fig. 6 Modelled approach of trienal 7 coordinated to Ru in (S,S)-1b in
an anti-s-trans orientation (catalyst part taken from the X-ray structure of
[Ru(Cl)((S,S)-BIPHOP-F)(Indenyl)][SbF6]).2b
a All reactions were carried out in 0.2–0.3 M concentration and monitored
by IR spectroscopy. b 2–5 mol% of 2,6-lutidine was added to scavenge acid
impurities. c Isolated yield. d % Conversion was determined by 1H NMR.
e ee of endo-isomer was determined by chiral GC. f ee of endo-isomer,
determined by 1H NMR of its chiral imine derivative.22
The absolute configurations of 28–30 were assigned based on
direct comparison of their CD spectra with that of the hydrazone
derivative of adduct 27 after transforming to their corresponding
hydrazone compounds.22
the obtention of the product with high enantiomeric enrichment
(systematic optimization was performed as shown in Table 4).
Chiral Ru Lewis acid-catalysed IMDA reactions of trienes 10
and 11 furnished the endo-isomer as a major product in a 99 : 1
ratio. The ee of 29 could not be increased to more than 56%
(entries 3 and 4) due to the competitive background reaction.
The uncatalyzed reaction was much less important with the less
electron rich diene of triene 11 (entry 5) and, with catalyst 1b, high
yields and asymmetric induction were achieved (entry 7).
Extension to more challenging systems such as trienes 8, 12
and 13 would provide [6,6]- and [6,7]-fused bicyclic systems,
respectively. The optimal conditions of entries 2 and 4 in Table
2 were used for IMDA of triene 8 but low conversion and ee were
observed with both catalysts (with 1a, rt, 7d: 7% conv., 99 : 1 of
endo : exo, 0% ee and with 1b, rt, 7d: 18% conv., 99 : 1 endo : exo,
19% ee). Unfortunately, poor diastereo- and enantioselectivities
were observed for triene 12 (with 1a, rt, 7d: 100% conv., 66 : 34
endo : exo, 9% ee for endo-isomer and 18% ee for exo-isomer and
with 1b, rt, 7d: 74% conv., 54 : 46 endo : exo, 33% ee for both
isomers). Triene 13 did not yield a Diels–Alder product under
Lewis acid catalysed conditions.27 Unfavorable energetics to form
the transition state leading to the [6,7]-fused bicyclic systems might
be the reason.
Conclusions
The first catalytic IMDA reaction with chiral one-point binding
transition metal Lewis acids have been probed. The bridgehead
adduct (S)-3 was used in the first synthesis of ent-ledol. The
overall yield of ent-ledol is 13% in 6 steps with 96% ee. The
investigation of IMDA reaction was extended. Modest to excellent
enantioselectivities and diastereoselectivities of adducts were
obtained, especially with the 3 carbon tethers of trienals. With
trienones only the type 2 IMDA reaction leading to product 3
proved efficient. The observed stereochemistry of the Diels–Alder
products is in agreement with a model based on the X-ray structure
of catalysts.
Experimental section
Synthesis of ent-ledol
Triene 2 was prepared as detailed by Shea and coworkers.14a
Spectral data (1H, 13C, IR and MS) of 3, 16–19 and 25 are in
agreement with those already reported.14a 1H and 13C NMR of
ent-ledol are represented in the electronic experimental section.
Our results suggest only [6,5]-trans fused ring adducts can be
readily formed by IMDA reactions with the chiral Ru Lewis acids
1. This encouraged us to explore IMDA reactions of trienones
14 and 15. Unfortunately, the IMDA background reactions were
high for both trienones, resulting in products of less than 10% ee.
X-ray structures of chiral Ru Lewis acid/substrate complexes
have been very helpful for the interpretation of observed selec-
tivities in cycloaddition reactions.2–4,5,8 For the IMDA reaction
involving triene 7 the diene approach leading to the observed endo
product 27 was modelled using the X-ray structure of (S,S)-1a. We
propose that the enal dienophile (orange) coordinates to the Ru
in an anti-s-trans conformation and the diene (blue) approaches
the Re-face of the enal moiety in an endo mode. The Ca-Si-
face is shielded by the pentafluorophenyl moiety of the (S,S)-
(S)-7-Methylbicyclo[4.3.1]dec-6-en-2-one (3). In a 50 mL
Schlenk tube equipped with a magnetic stirring bar and ac-
˚
tivated powder molecular sieve 4 A (50 mg), at r.t. and un-
der N2, [Ru(acetone)((S,S)-BIPHOP-F)(Cp)][SbF6] (1a) (140 mg,
0.10 mmol, 0.05 eq) was dissolved in anhydrous CH2Cl2 (3.00 mL).
To the stirring mixture, 2,6-lutidine (2.8 mL, 0.012 mmol, 0.006 eq)
and a solution of triene 2 (328 mg, 2 mmol, 1 eq) in CH2Cl2
(2.00 mL) were carefully added, and the yellow–orange solution
stirred at room temperature (r.t.) and under N2 for 5 days. The
reaction was then monitored by GC by injecting 2 mL aliquots. At
the end of the reaction, CH2Cl2 was removed under vacuum and
hexane (30 mL) was added, and the mixture was filtered through
a Celite 545 plug. Volatiles were removed in vacuo and the residue
was purified by flash column chromatography (f.c.) using a silica
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gel column (1–5% Et2O in pentanes) to give a pale yellow oil of
adduct 3 (230 mg, 1.40 mmol, 70% yield). Chiral GC (Hydrodex-
b, H2, 100 ◦C hold 30 min then heating 0.5 ◦C min-1 to 120 ◦C):
tert-Butyl(((1S,3aR,4S,8aR)-1,4-dimethyl-1,2,3,3a,4,5,6,8a-
octahydroazulen-4-yl)oxy)dimethylsilane (19). To a stirred solu-
tion of diisopropylamine (0.19 mL, 1.3 mmol, 5 eq) in THF
(1.7 mL) at -78 ◦C was added n-BuLi (1.6 M in hexanes, 0.50 mL,
0.78 mmol, 3 eq). After 45 min, to this LDA was added the
ketone 18 (80 mg, 0.26 mmol, 1 eq) as a solution in dry TMEDA
(0.43 mL). The reaction mixture was warmed up to -30 ◦C. After
being stirred at -30 ◦C for 10 min, the diethyl chlorophosphonate
(0.19 mL, 1.3 mmol, 5 eq) was added and cooling bath was
removed. After 1 h, the reaction mixture was poured into ice-water
and extracted with CH2Cl2 (3 ¥ 10 mL). The combined organics
were washed with brine, dried (anh. MgSO4) and concentrated in
vacuo. The obtained yellow oil was dissolved in t-BuOH (0.08 mL)
and THF (5.7 mL) and was added to a solution of lithium (excess)
in liquid ammonia at -78 ◦C. After 1 h, the reaction was carefully
quenched with sat. NH4Cl and was extracted with CH2Cl2 (3 ¥
10 mL). The combined organics were dried (anh. MgSO4) and
concentrated in vacuo. F.c. on silica gel (100% pentanes) gave the
alkene 19 as a colorless oil (40 mg, 0.136 mmol, 52% yield). Chiral
GC (CP-Chirasil-Dex CB, H2, 100 ◦C hold 5 min then heating
tR of product (min) = 53.9 (major)/55.0 (minor), 92% ee. [a]D25
+24.1 (c = 0.25, CH2Cl2)
=
tert-Butyl(((2S)-2,7-dimethylbicyclo[4.3.1]dec-6-en-2-yl)oxy)
dimethylsilane (16). To a stirred solution of the ketone (200 mg,
1.2 mmol, 1 eq) in THF (8.75 mL) at -78 ◦C was added MeLi
(1.6 M in Et2O, 0.78 mL, 2.4 mmol, 2 eq). After 30 min, the
reaction was warmed to r.t. and was quenched with sat. NH4Cl.
The mixture was extracted with CH2Cl2 (2 ¥ 10 mL). The combined
organics were dried and concentrated in vacuo. To a stirred
solution of the crude alcohol◦in CH2Cl2 (8 mL) and pyridine
(0.3 mL, 3.6 mmol, 3 eq) at 0 C was added TBSOTf (0.42 mL,
1.8 mmol, 1.5 eq). The reaction was allowed to warm to r.t. When
the reaction was complete monitoring by TLC, the mixture was
diluted with hexanes and poured into sat. NaHCO3. The organics
were separated and further washed once with brine. The organics
were dried (anh. MgSO4) and concentrated in vacuo. The residue
was chromatographed on silica gel (100% pentanes) to give the
protected alcohol 16 as a colorless oil (315 mg, 1.◦07 mmol, 89%
yield). Chiral GC (CP-Chirasil-Dex CB, H2, 100 C hold 5 min
1
◦C min-1 to 170 ◦C hold 20 min): tR of product (min) = 54.6
(major)/55.3 (minor), 95% ee. [a]2D5 -47.8 (c 0.50, CH2Cl2).
◦
then heating 1 C min-1 to 170 ◦C hold 20 min): tR of product
tert-Butyldimethyl(((1aS,4S,4aR,7S,7aR,7bR)-1,1,4,7-tetrame-
(min) = 54.2 (major)/54.8 (minor)1, 92% ee. [a]2D5 = +42.1 (c =
thyldecahydro-1H-cyclopropa[e]azulen-4-yl)oxy)
silane
(25).
1.00, CH2Cl2).
Bicyclic alcohol 19 (30 mg, 0.1 mmol, 1 eq) was dissolved in
CH2Cl2 (0.2 mL) followed by addition of CHBr3 (0.36 mL,
4 mmol, 40 eq) and powdered NaOH (68 mg, 1.70 mmol, 17 eq).
The reaction mixture was stirred at 50–60 ◦C for 48 h. This
mixture was diluted with water (1 mL) and extracted with CH2Cl2
(3 ¥ 2 mL). The combined organic phases were dried (anh.
MgSO4) and were filtered. Solvents were removed in vacuo. The
residue was directly used in the next step. Tricyclic 24 was added
as a solution in THF (1.3 mL) to a mixture of CuCN (33 mg,
0.36 mmol, 3 eq) and MeLi (1.6 M in Et2O, 0.38 mL, 0.60 mmol,
5 eq) in THF (1.3 mL) at -78 ◦C. The reaction was slowly
warmed to -20 ◦C for 3–4 h. After that, MeI (0.15 mL, 2.4 mmol,
(3R,4S)-4-((tert-Butyldimethylsilyl)oxy)-4-methyl-3-(3-oxobut-
yl)cycloheptanone (17). Ozone gas was bubbled through a so-
lution of the TBS ether 16 (220 mg, 0.75 mmol, 1 eq) in MeOH
(14 mL) at -78 ◦C until the characteristic light blue color appeared.
The reaction was then purged of ozone with oxygen and trimethyl
phosphite (0.162 mL, 1.37 mmol, 1.8 eq) was added. The reaction
was allowed to warm to r.t. and stirred for 1.5 h. The mixture
was poured into sat. NH4Cl and extracted with CH2Cl2 (3 ¥
10 mL). The combined organics were dried (anh. MgSO4) and
concentrated in vacuo. The residue was chromatographed on silica
gel (10–20% EtOAc in pentanes) to give the diketone 17 as a
colorless oil (185 mg, 0.57 mmol, 76% yield). GC conditions could
not be found to determine ee. [a]2D5 -23.6 (c 1.00, CH2Cl2).
◦
20 eq) was added at -63 C and this mixture was stirred for 1 h
and poured into sat. NaHCO3. This was extracted with CH2Cl2
(3 ¥ 5 mL). The combined organics were dried (anh. MgSO4)
and concentrated in vacuo. FC on silica gel (100% pentanes)
gave a colorless solid of gem-dimethylcyclopropane 25 (30 mg,
0.089 mmol, 74% yield). Chiral GC (CP-Chirasil-Dex CB, H2,
(3S,3aS,8S,8aR)-8-((tert-Butyldimethylsilyl)oxy)-3,8-dimethyl-
octahydroazulen-4(1H)-one (18). To a stirred solution of the
diketone 17 (145 mg, 0.44 mmol, 1 eq) in MeOH (45 mL) was
added KOH (1.36 g, 24.2 mmol, 55 eq). The reaction was heated
to 60 ◦C for 3 h when TLC analysis showed the reaction was
complete. The mixture was cooled and poured into sat. NH4Cl
and was extracted with CH2Cl2 (3 ¥ 7 mL). The combined organics
were dried (anh. MgSO4) and concentrated in vacuo to give the
bicyclic enone as pale yellow oil (Rf 0.16, 10% Et2O in pentanes).
This enone and Pd–C (10%, 76 mg, 0.075, 0.17 eq) in EtOH
(17 mL) were hydrogenated under H2 pressure (25 psi) and shaken
in a Parr apparatus. After 4.5 h, the reaction mixture was filtered
through a Celite plug and concentrated in vacuo. The residue was
chromatographed on silica gel (10% Et2O in pentanes) to give
ketone 18 as a colorless oil (122 mg, 0.39 mmol, 90% yield). Chiral
GC (CP-Chirasil-Dex CB, H2, 100 ◦C hold 5 min, then heating
◦
100 ◦C hold 5 min then heating 1 C min-1 to 170 ◦C hold 20
min): tR of product (min) = 66.9 (major)/55.2 (minor), 95% ee.
[a]2D5 -9.5 (c 0.50, CH2Cl2).
ent-Ledol. The silyl ether 25 (15 mg, 0.045 mmol) was treated
with TBAF (1 M in THF 1.5 mL, 50 eq). The reaction was heated
to reflux. After 24 h, the mixture was added with water (1 mL)
and extracted with ether (3 ¥ 5 mL). The combined organics were
dried (anh. MgSO4) and concentrated in vacuo. FC on silica gel
(20% Et2O in hexanes) gave ent-ledol (7 mg, 0.032 mmol, 70%
yield) with mp 104–105 ◦C. Chiral GC (CP-Chirasil-Dex CB, H2,
100 ◦C hold 5 min then heating 1 ◦C min-1 to 170 ◦C hold 20 min):
tR of product (min) = 48.2 (minor)/50.0 (major), 96% ee. [a]2D5 -2.3
(c 0.10, EtOH), +4.6 (c = 0.10, CHCl3), -9.8 (c = 0.10, toluene),
+0.5 (c = 0.25, CH3CN), +0.4 (c = 0.10, THF).
1
◦C min-1 to 170 ◦C hold 20 min): tR of product (min) = 70.0
(major)/71.4 (minor), 95% ee. [a]2D5 = +42.4 (c = 0.50, CH2Cl2).
This journal is
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General experimental procedure for IMDA of trienal 7, 9, 10 and
1122
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In a 50 mL oven-dried Schlenk tube equipped with a magnetic
stirring bar at r.t. and under N2, Ru catalyst (70 mg, 0.05 mmol,
0.05 eq) was dissolved in dry CH2Cl2 (1.80 mL). To the stirred
mixture, 2,6-lutidine (2.3 mL, 0.02 mmol, 0.02 eq) and a solution
of triene (1.00 mmol, 1 eq) in dry CH2Cl2 (1.50 mL) was carefully
added, and the resulting solution was stirred at r.t. under N2.
The progress of the reaction was monitored by TLC or IR. At
the end of the reaction, CH2Cl2 was removed under vacuum and
hexane (20 mL) was added. The suspension was filtered through a
Celite 545 plug. The Ru catalyst could be recovered. Volatiles were
removed in vacuo and the residue was purified by f.c. using a silica
gel column to give the Diels–Alder product.
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25 C. Saudan, Ph.D. thesis no. 3244, University of Geneva.
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Acknowledgements
We are grateful for financial support from the Swiss National
Science Foundation and the University of Geneva.
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27 Racemic cycloadditions were tried with HCl, AlEt2Cl, AlCl3 and TiCl4
at various temperatures but all failed and gave recovered starting
materials, polymerization products and complex mixtures.
7570 | Org. Biomol. Chem., 2011, 9, 7564–7570
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The Royal Society of Chemistry 2011
©