Syn -Selective crotylation of aldehydes using bismuth-crotyl bromide-(1-butyl-3-methylimidazolium bromide) combination: Some synthetic applications

Article abstract of DOI:10.1039/c7ob00626h

The Bi-[bmim][Br] combination has been found to offer high syn-selectivity in the crotylation of aldehydes with crotyl bromide using practically stoichiometric amounts of the reagents. The room temperature ionic liquid (RTIL), [bmim][Br], activated Bi metal in the presence of oxygen to produce crotylbismuthdibromide, which reacted with the aldehydes at room temperature. The major anti-syn diastereomeric product obtained from the crotylation of (R)-cyclohexylideneglyceraldehyde was utilized for the synthesis of dictyostatin and cryptophycin segments, and (+)-cis-aerangis lactone, using standard synthetic protocols.

Full text of DOI:10.1039/c7ob00626h

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DOI: 10.1039/C7OB00626H
Organic & Biomolecular Chemistry
ARTICLE
Syn-selective Crotylation of Aldehydes Using Bismuth-Crotyl
Bromide-(1-Butyl-3-methylimidazolium Bromide) Combination:
Some Synthetic Applications
Received 00th January 20xx,
Accepted 00th January 20xx
Dibakar Goswami, Mrunesh Koli, Sucheta Chatterjee, Subrata Chattopadhyay and Anubha
Sharma*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India
[e-mail: anubhas@barc.gov.in Fax:+91 22 25505151] ESI available: See DOI: 10.1039/X0XX00000X
The Bi-[bmim][Br] combination has been found to offer high syn-selectivity in the crotylation of aldehydes with crotyl
bromide, using practically stoichiometric amounts of the reagents. The room temperature ionic liquid (RTIL), [bmim][Br],
activated Bi-metal in presence of oxygen to produce crotylbismuthdibromide, that reacted with the aldehydes at room
temperature. The major anti-syn diastereomeric product, obtained from the crotylation of (R)-
cyclohexylideneglyceraldehyde was utilized for the synthesis of dictyostatin and cryptophycin segments, and (+)-cis-
aerangis lactone, using standard synthetic protocols.
Keywords: Asymmetric synthesis, Bi-metal, [bmim][Br], (R)-cyclohexylideneglyceraldehyde, ionic liquid, syn-selective
crotylation
both these criteria. Unlike most of the chiral pool materials,
Introduction
the compound
1 and its enantiomer are amenable from the
inexpensive D-mannitol and L-ascorbic acid respectively.5 Also,
we have observed that its cyclohexylidene moiety provides
considerable steric bias in the addition of organometallics to
its aldehyde function, and ensures easy separation of the
resultant epimeric carbinols by column chromatography.6 We
were particularly interested in expanding the substrate-
controlled strategy, since the alcohol stereomers obtained by
Asymmetric allylation/crotylation of aldehydes1a is one of the
most extensively studied reactions for carbon–carbon bond
formation, driven in part by the versatility of the homoallylic
alcohols as synthetic intermediates.1b Crotylation reaction is
more valuable as it generates products with adjacent methyl
branching [-CH(CH3)-] and secondary carbinol bearing
stereogenic centres that are often encountered in several
important biologically active molecules.2 Different approaches
involving various metals, crotylating agents and solvents have
been explored to address issues such as regio-, diastereo- and
enantioselectivities.3 The Barbier-type protocols are more
convenient for this, since the reactive metal-crotyl complexes
are produced in situ. Amongst the various metals used for the
Barbier-type reactions, the group 13 metals, In4a,b and Ga4c-g
are being extensively used of late. The asymmetric version of
crotylation is accomplished by incorporating a chiral auxiliary
in the substrate and/ or the reagent. However, the design and
synthesis of the required chiral reagent are often taxing, and at
times, frustrating. Further, syntheses of the sterically robust
chiral auxiliaries may require several steps, and involve
expensive reagents. Instead, a substrate-controlled method
using natural chiral pool-derived templates offers a suitable
alternative for the designated transformation, provided the
chiral substrate is available as its enantiomers and possesses
diverse functionalities for subsequent organic transformations.
crotylation of
various target compounds.
1 are functionally enriched for elaboration to
Room temperature ionic liquids (RTILs) are often used as
alternatives to traditional organic solvents. These can facilitate
heterogenous reactions by dissolving various organic and
inorganic materials. Also, reaction outcome varies on
substituting a molecular solvent by an ionic one.7 Usually, the
hydrophobic RTILs are preferred for carrying out various
organic reactions including the Barbier-type protocols.8
However, we have shown that due to its stronger oxidizing
power and moderate acidity, the hydrophilic RTIL, [bmim][Br]
can act both as a solvent and a metal activator in the Ga-
mediated allylation/crotylation of various aldehydes including
1
even at room temperature.9 More importantly, the
crotylation
of
1
proceeded
with
excellent
diastereoselectivity.9a Bismuth is an inexpensive, safe and
environmentally benign metal. It is also used in cosmetics and
anti-viral creams, and as a component of oral gastrointestinal
formulation.10 The readily available Bi powder has been used
The aldehyde
1 (Scheme 1) and its various congeners fulfil
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for allylation of aldehydes in organic solvents (DMF, THF and Bi-metal in H2O-THF (1:4) in good yield as well asViniewDAMrticFleiOnnl2in4e
acetonitrile),11a-c
water,11d
and
under
solvent-free h.12d However, currently, no appreciable reaction was noticed
DOI: 10.1039/C7OB00626H
conditions.11e New protocols for metal activation such as use of when the reaction was carried out in H2O-THF (1:1, entry 4).
bimetallic systems (Al–BiCl3 and Zn–Bi-trihalides),11b,12a-d in-situ The reaction in DMF furnished the product homoallylic
reduction of BiCl3 by NaBH4,12e nanometer-sized Bi,12f as well as alcohols (2a
,
2b and 2c) in 67% yield and 2a:2b:2c::3:55:42
ball milling12g have been used to carry out Bi-mediated ratio after 24 h (entry 5). To our delight, the reaction in
allylation reactions. [bmim][Br] was very fast, and could be carried out with almost
Against the above backdrop, we explored the possibility of stoichiometric amounts of the reagents to furnish the products
using the Bi-[bmim][Br] combination for the asymmetric in an improved yield (89%). Most importantly, there was a
crotylation of
1 with the objective of tuning the reaction striking difference in the product composition, and the
diastereoselectivity. It was gratifying to note that this synthetic compounds 2a, 2b and 2c were obtained in 11:85:4 ratio
strategy led to a preponderance of syn-selectivity with regard (entry 6). The diastereomeric ratios were calculated from the
to the newly formed stereogenic centres. The strategy was isolated yields of the individual diastereomers, since there
subsequently extended to some achiral substrates including were overlapping resonances in the NMR spectra of the crude
aliphatic and variously substituted aromatic aldehydes to reaction mixture. To confirm that all the products were
obtain their corresponding syn-crotylated alcohols in high extracted efficiently from the reaction mixture, the RTIL
diastereomeric excesses. The major diastereomeric remaining after extraction was analyzed using 1H NMR
homoallylic alcohol, obtained by the crotylation of
1, was spectroscopy (ESI, Fig. 8, page 23). No trace of products in the
subsequently used for the syntheses of the C1-C9 segment of residual RTIL confirmed the efficiency of extraction. Based on
dictyostatin, the octadienoic ester fragment of the our previous experience with Ga-mediated carbonyl
desoxycryptophycins, and (+)-cis-aerangis lactone.
allylation,9b we used 2 mL of RTIL per mmol of
1 to carry out
the reaction. Under these conditions, the mole fractions of
[bmim][Br] and [bmim][BF4] in the reaction mixture were 0.79
and 0.77 respectively. Interestingly, in absence of O2, no
crotylation was noticed in [bmim][Br] even up to 12 h (entry
7). Also, there was no reaction (entry 8) in [bmim][BF4] that is
widely used in Barbier-type reactions. The enantiomeric
Results and Discussion
The initial motivation for the present work was our
previous observation that the diastereoselectivity in
purities of 2a
, 2b and 2c were determined by HPLC analyses of
crotylation of
combinations.13 Earlier, we have observed that the Barbier-
type crotylation of furnishes a mixture of the diastereomeric
alcohols 2a-c as the isolable products as shown in Scheme 1
1 can be tuned by changing the metal-solvent
their corresponding benzoate esters. The stereochemistry of
2b was confirmed by converting it to the γ-lactone
3 followed
1
1
by H NMR analysis as reported earlier.9a Formation of 2b as
.
the major product in this protocol is noteworthy, since
With Zn in wet THF, the reaction proceeded with modest anti,
anti selectivity to give 2a-c in ~2:33:65 ratio.6c,13a However,
with In/H2O, 2b and 2c were obtained in almost equal
amounts.13b On the other hand, the anti,anti selectivity
improved significantly to produce 2c as the major product in
the Ga-mediated reaction in [bmim]Br.9a The key issue for such
transformations is metal activation that is generally
accomplished by Rieke’s method,14a the metal-graphite
method,14b as well as addition of a catalytic amount of a
second metal and/ or additive(s) to the target metals.14c-h
Indeed, different strategies have also been adopted to activate
Bi metal.11,12 It was envisaged that because of its strong
oxidizing power (Eo = 0.641 V),9b [bmim][Br] may activate Bi-
metal without any additional chemical reagent or
ultrasonication.
crotylation of 1 generally produces 2c as the major product.
Scheme 1. Bi-mediated crotylation of 1.
To probe this, the Bi-mediated crotylation of the aldehyde
1
was carried out in different solvents viz. THF, H2O, aqueous
THF, DMF, [bmim][BF4] and [bmim][Br] (Scheme 1), and the
results are summarized in Table 1. As expected, all the
successful reactions furnished a mixture of 2a-c, albeit in
different ratios. The reaction proceeded with moderate yield
and diastereoselectivity in H2O, but required a large excess of
the reagents (entry 1). There was no reaction in THF as such or
even in the presence of KF that was earlier reported to
activate Bi-metal (entries 2,3).15 Earlier, allylation of carbonyls
with allyl bromide was achieved using in situ prepared active
2 | J. Name., 2012, 00, 1-3
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Table 1. Reaction course of the Bi-mediated crotylation of 1a
Table 2. Effect of [bmim][Br] concentrations on the Bi-mediated crotylation of 1a
View Article Online
DOI: 10.1039/C7OB00626H
Entry
Crotyl
bromide /
Bi
Solvent
Time
(h)
Yieldb
Entry
Crotyl
Mole
Solvent
Time
(h)
Yieldc
(%)
(%) (2a:2b:2c)c
bromide / Bi/
[bmim][Br]
(equiv.)
fraction of
[bmim][Br]b
(2a:2b:2c)d
(equiv.)
4.0 / 2.5
4.0 / 2.5
4.0 / 2.5
4.0 / 2.5
4.0 / 2.5
1.2 / 1.0
1.2 / 1.0
1.2 / 1.0
1
2
3
4
5
6
7
8
H2O
THF
12
20
24
24
24
4
67 (7:31:62)
NR
1
4.0 / 2.5 / 0.1
3.5 x 10-4
H2O
12
65
(9:35:56)
7 (ND)
5-9 (ND)
65
2
3
4
4.0 / 2.5 / 0.1
4.0 / 2.5 / 0.1
4.0 / 2.5 / 0.1
1.4 x 10-3
5.6 x 10-4
1.4 x 10-3
THF
H2O-THFe
DMF
24
28
24
THFd
NR
H2O-THFe
DMF
5-7 (ND)
67 (3:55:42)
89 (11:85:4)
NR
(4:56:40)
69
(9:41:50)
61
(21:63:16)
58
(15:74:11)
71
[bmim][Br]
[bmim][Br]f
[bmim][BF4]
5
6
7
8
4.0 / 2.5 / 1.0
4.0 / 2.5 / 1.0
4.0 / 2.5 / 1.0
4.0 / 2.5 / 1.0
3.5 x 10-3
1.4 x 10-2
5.6 x 10-3
1.4 x 10-2
H2O
THF
8
12
24
NR
20
22
20
[a]All reactions were carried out at 2 mmol scale at 25 oC [b]Combined yields of all
the diastereomers. [c]Based on isolated yields of individual diastereomers. [d]The
H2O-THF
DMF
[e]
reaction was carried out in the presence of aqueous 10% KF as the additive.
H2O-THF (1:1, v/v) was used. [f]The reaction was carried out in absence of air by
purging with N2 gas. NR = no reaction, ND = not determined.
(6:71:24)
[a]The reactions were carried out at 2 mmol scale at 25 oC using 0.1 or 1.0
equivalent of [bmim][Br]. [b]Calculated considering the total reaction mixture.
[c]Combined yields of all the diastereomers. [d]Based on isolated yields of
individual diastereomers. [e]H2O-THF (1:1, v/v) was used. ND = not determined.
The observation that the reaction in [bmim]Br proceeded
without requiring any metal activator, suggested that [bmim][Br]
may be used as a Bi-metal activator. To confirm this, we carried out
the Bi-mediated crotylation of 1 in THF, DMF and THF-H2O in
presence of catalytic (10 mol%) and stoichiometric amounts of
[bmim][Br]. The results are summarized in Table 2. The RTIL did not
Mechanistic aspects. With regard to the activation of Bi
have any significant effect when the reaction was carried out in metal, we envisaged a dipole-induced dipole interaction with
water (entries 1 and 5). In organic solvents, use of a catalytic [bmim][Br] that is consistent with their respective redox
1
amount of [bmim][Br] also did not alter the reaction outcome potentials. This was reflected from the change in the H NMR
appreciably (entries 2-4, Table 2 vis-à-vis entries 2-5, Table 1). spectrum of the reaction mixture, containing Bi (1.0 mmol) and
However, when used in stoichiometric amount, [bmim][Br] [bmim][Br] (1.0 mmol). After 10 min of incubation, the 1H NMR
improved the reaction yield and made it faster. Nevertheless, the spectrum, recorded in D2O, showed upfield shifts of the
yields and diastereoselectivities were inferior (entries 5-8) [bmim][Br] protons, with maximum shifts for the H-2 (20 Hz),
compared to those obtained in [bmim][Br] alone (entry 6, Table 1). and H-4 and H-5 (18 Hz each). As expected, considering the
Our results are consistent with a previous observation that the maximum positive charge density at C-2 of the imidazole ring,
reaction outcome depends on mole fraction of the ionic liquid in the shifts gradually decreased with increasing distance of the
the reaction mixture.7j The RTIL used in catalytic or stoichiometric butyl chain protons from the imidazolium core. The terminal
amounts could not be reused. Hence, we carried out all subsequent CH3 protons of the butyl chain showed minimum shift. Since
1
studies in [bmim][Br] alone.
such magnitudes of H NMR shifts are generally attributed to
Next, we carried out the reaction at 2 mmol scale in different charge transfer phenomenon,16a-c it is proposed that the
volumes (4, 2 and 1 mL) of [bmim]][Br] to optimize the amount of combination of Bi and [bmim][Br] initially forms ion pairs,
the RTIL. Reduction of the solvent volume from 4 mL to 2 mL leading to activation of Bi. The imidazolium-based ionic liquids
reduced the yields of the products marginally from 89% to 84%. were reported to promote electron transfer reactions
However, when the reaction was carried out in 1 mL of [bmim]][Br], remarkably.7b,16d-e Earlier, the dipole-induced dipole
the overall yield of the products decreased to 71%. Such interaction between Ga and [bmim][Br] helped in the transfer
dependence of the reaction outcome on the ionic character of the of one electron to the dissolved oxygen in the RTIL.9b,17 The
medium is not unprecedented.7j,k Moreover, we found that resultant superoxide radical anion is stabilized by the acidic C-2
recovery of the solvent was also difficult when lower amounts were hydrogen of [bmim][Br], facilitating the process.18 Our results
used. To explore the practical feasibility of the process, we also showed that the Bi-mediated crotylation in [bmim][Br]
carried out the reaction on 20 mmol scale using only 25 mL of necessarily requires O2 (Table 1, entries 6,7). On the other
[bmim][Br] to obtain 2a:2b:2c in a similar yield (85-88%) and same hand, the reaction did not take place in [bmim][BF4], possibly
relative ratio. The higher-scale experiments were repeated 5 times because its C-2 hydrogen is not acidic.18d Further, to confirm
to confirm the consistency of the results.
the role of C-2 hydrogen in activating Bi metal, the reaction
was carried out in THF in presence of a stoichiometric amount
of 1-butyl-2,3-dimethylimidazolium bromide ([bmmim][Br]),
lacking the C-2 hydrogen. Under these conditions, no
crotylation was evident unlike the reaction profile shown
under similar conditions with [bmim][Br] (entry 6, Table 2).
This clearly demonstrated that presence of the acidic C-2
hydrogen is crucial for the activation of Bi metal.
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Based on our similar observations with Ga, the formation
Journal Name
a new olefinic multiplet at δ 5.65 ppm, indicatingVfioewrmArtaictleioOnnlionef
1
DOI: 10.1039/C7OB00626H
of an N-heterocyclic carbene (NHC), and eventually an NHC-Bi
complex in the reaction mixture was envisaged. In order to
explore the formation of NHC-Bi complex, a mixture of Bi
metal (1 mmol) and [bmim][Br] (1 mmol) in an NMR tube was
an η -Bi-crotyl coordination complex. This is consistent with
the fluxional behaviour of the allylbismuth species, as reported
earlier.22a We assigned the crotyl-Bi reagent as an η1-complex,
since the 1H NMR spectrum of the alternative η3-complex
would be broad without well-defined peaks, unlike that
observed in this study.
1
incubated for 1 h under dry conditions, and the H and 13C
NMR spectra recorded in DMSO-d6. The 1H NMR spectrum (ESI,
Fig. 2-3, page 17-18) displayed new sets of signals in addition
to those of the RTIL. Similar to those reported in literature,19a
the in situ generated NHC complex showed two new doublets
at 7.65 and 7.68 ppm corresponding to the H4 and H5
protons of the imidazol-2-ylidine ring. In addition, the 13C NMR
Similar to the results of the previous solution NMR studies
with crotylmagnesium bromide,22b and crotyltitanium
reagents,22c our NMR spectra also did not show any peak
corresponding to the α-methylallyl metal species. Thus,
formation of the γ-adduct in the reaction indicated that the
addition of the active organometallic species to the carbonyl
substrate proceeded via an allylic rearrangement.22d It has
been proposed that tris(allyl)bismuth is unreactive and
requires Lewis acid activation for allylation of aldehydes.22a
Hence, we excluded the possibility of tris(crotyl)bismuth as the
active crotylating species in the present case. Moreover, the
powder X-ray diffraction studies of the solid residue left in the
reaction mixture revealed it to be Bi(O)Br. However, no Bi(O)Br
was formed after stirring Bi-metal in [bmim][Br] even for 6 h.
These suggested that the active crotylating species contains at
spectrum showed a peak at
 164.2 ppm (carbene) along with
two peaks at 122.4 and 121.3 ppm (imidazol-2-ylidine C4 and

C5). All these confirmed formation of the proposed NHC and
its in situ binding to Bi metal. Although we could not isolate
any NHC-Bi complex, this type of reaction is well established in
M-NHC chemistry.19 Similar rapid conversion of imidazolium
ion to the NHC on the surface of a nanoparticle is also
reported.20 Moreover, a similar oxidative addition of the
imidazolium salts to Pt(0) was shown to be exothermic by DFT
calculations.21 Eventually, due to poor stability of the sterically
less hindered cyclic NHCs, the complex furnished the active
crotyl-Bi species in presence of crotyl bromide in the reaction least one bromine atom, coming from crotyl bromide. Earlier,
mixture (Scheme 2.).
we could carry out the Ga-mediated allylation of
aldehydes/ketones using 0.5 eq. of Ga-metal, due to formation
of diallyl-GaBr as the active allylating species.9b However,
reduction of the amount of Bi-metal in the crotylation led to
++
H
H
H
H
H
H
incomplete reactions and significant recovery of
1 (data not
1/4 O2
BiBr
Br-
+
+
Bi
N
N
N
N
Br
+
shown). Hence, we feel that dicrotyl-BiBr may not be involved
in the reaction. A recent report described allylbismuth
dibromide as the most active allylating species in water.12d In
analogy, we presume that crotylbismuth dibromide (I, Scheme
2.) is also the active crotylating species for the present
N
N
C4H9
+
C4H9
C4H9
-
H
H
Bi
H
-
Transient
1/4 O2
[bmim][Br]
1/2 H2O
H
-
H
reaction.
Br
Bi-NHC
N
N
BiBr2
C4H9
OH
..
I
O
Br
R
" In-situ formed NHC"
R
H
Bi, [bmim][Br]
4a-o
5a-o
Scheme 2. Plausible mechanism of formation of the active crotyl-Bi species.
Scheme 3. Bi metal mediated crotylation of aldehydes in [bmim][Br].
Next we probed the nature of the organometallic
species responsible for the reaction. Very recently, Lichtenberg
et al. crystallized tris(methylallyl)bismuth at a low temperature
and characterized it as an 1 complex.22a To the best of our
knowledge, the crotyl-Bi reagent has never been
characterized. In our effort, we attempted to identify the
crotyl-Bi reagent by in situ 1H NMR spectroscopy of the
reaction mixture, comprising of crotyl bromide and Bi in
[bmim][Br]. For this, the mixture was stirred for 1.5 h at 25 oC,
Inspired by the high syn-selectivity obtained in the
crotylation of 1, we extended this protocol to both aromatic
and aliphatic achiral aldehydes (Scheme 3, Table 3). All these
studies were executed at 2 mmol scale in [bmim][Br] (2
mL/mmol). All the aromatic substrates (4a
electron withdrawing or electron donating substituents, were
completely transformed in 3-7 to the corresponding
homoallylic alcohols 5a in high yields and good syn-
-j), bearing either
h
-
j
selectivity. For both p- and o-nitrobenzaldehydes, 4b and 4c
respectively, the corresponding crotylated products were
obtained without any reduction of nitro functionality, as
observed earlier.13e However, in case of 4c, the expected
product 5c was produced along with the α-crotylated product
(~30%) as an inseparable mixture. The geometric composition
1
and the H NMR spectra of the aliquots in CD2Cl2 (ESI, Fig. 4,
page 19) were recorded as such or after cooling the sample to
1
-70 °C. The H NMR spectrum, recorded at room temperature
did not show any additional peak corresponding to the crotyl-
Bi species. However, the spectrum of the cooled sample and
recorded at -70 ºC showed a doublet at δ 2.87 ppm along with
4 | J. Name., 2012, 00, 1-3
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1
of the α-crotylated product was E:Z :: 72:28, based on H NMR
spectrum. The reaction with o-hydroxybenzaldehyde (4d) was
clean and furnished 5d in good yield, in contrast to the earlier
report where the reaction was unsuccessful due to the
formation of various side-products.13e The conjugated
aldehyde 4k furnished the 1,2-addition product 5k exclusively,
revealing the chemoselectivity of our protocol. Heteroaromatic
aldehyde, 2-furfural (4l), followed similar trend in terms of
yield and syn-selectivity like other aromatic aldehydes. With
Table 3. Reaction course of the Bi-mediated crotylation of the aldehydes 4a-o in
View Article Online
[bmim][Br]a
DOI: 10.1039/C7OB00626H
Entry
R
Time
(h)b
3
3
5
syn:antic
Yield
(%)d
90
1
2
3
C6H5 (4a)
p-NO2C6H4 (4b)
o-NO2C6H4 (4c)
87:13
86:14
γ (syn:anti): α (E:Z)
70 (89:11):30 (72:28)
72:28
93
91e
4
5
6
7
8
o-OHC6H4 (4d)
p-OMeC6H4 (4e)
3,5-(MeO)2C6H3 (4f)
m-BrC6H4 (4g)
p-BrC6H4 (4h)
p-ClC6H4 (4i)
C6H5-CH2-CH2 (4j)
C6H5-CH=CH (4k)
C4H3O (4l)
7
4
3
4
3
5
5
4
7
6
6
5
88
92
90
92
90
86
88
84
91
87
86
88
aliphatic aldehydes (4m-o), the syn-homoallylic alcohols were
87:13
82:18
90:10
87:13
89:11
79:21
78:22
75:25
obtained in good yields and diastereoselectivity. Except 5f and
5o, the syn/anti ratios of the other aromatic and aliphatic
1
homoallylic alcohols were determined by comparing their H
9
NMR spectra with those reported (vide experimental). For 5f
,
10
11
12
13
14
15
the downfield doublet at δ 4.54 ppm was assigned to the syn-
1
isomer by comparing the H NMR spectrum with that of 5e
,
and the syn/anti ratio in 5f was determined from the relative
peak intensities at δ 4.54 and at δ 4.29 ppm. For 5o, the more
downfield multiplet (δ 3.48-3.51 ppm) was assigned to the syn-
C5H11 (4m)
C8H17 (4n)
C11H23 (4o)
88:12
88:12
80:20
1
isomer in analogy with the H NMR spectra of other aliphatic
[a]All reactions were carried out at 2 mmol scale at 25 oC under similar conditions
as stated in entry 6, Table 1. [b]Completion of the reactions (cf. TLC). [c]Based on
1H NMR spectra of the crude reaction mixtures.23 [d]Isolated yields of the
diastereomeric mixtures. [e]Total yield of the γ- and α-products.
homoallylic alcohol products (5m and 5n). Thus, the syn/anti
ratio in 5o was determined from the relative peak intensities
of the two multiplets (δ 3.48-3.51 and 3.38-3.41 ppm). In all
the reactions, the products could be conveniently isolated by
extracting the reaction mixture three times with Et2O followed
by concentration. The reactions were clean without any side-
products and/ or starting materials.
Crotyl bromide is commercially available as a mixture of
E/Z (5:1) isomers. To explore the role of E/Z stereochemistry of
the
γ-substituted allylic halide, we reacted aldehyde 1
The observed syn-selectivity in the reaction can be
explained by considering an acyclic antiperiplanar transition
structure, which is favored because of the minimization of
steric hindrance to the bulky substituent on the α-carbon of
the crotylbismuth intermediate (Scheme 4).24 Notably, only
synclinal and antiperiplanar transition structures are
considered so as to avoid the unfavourable interactions in the
eclipsed configurations. Given that ionic size of Bi is
significantly higher than those of In or Ga, such an assumption
is justified. Consistent with this hypothesis, much higher
selectivity in formation of 2c over 2b was observed in the Ga-
separately with (E)- and (Z)-2-nonenyl bromides, prepared
according to a previously reported procedure.27 This furnished
1
the homoallylic alcohols (6a-c). In this case also, the H NMR
spectrum of the crude reaction mixture showed overlapping
resonances. Hence, the diastereoselectivity was calculated
based on isolated yields of the individual diastereomers, In
both the cases, the syn-isomer was produced preferentially,
albeit in a moderate diastereomeric excess (Scheme 5, Table
4). This proved that the E/Z stereochemistry of the starting
bromide may not have any significant effect on the outcome of
the reaction. This is consistent with some previous reports,
wherein increased bulk of the R group in the substituted allyl
bromide led to more anti-product, but the alkene geometry
did not have any bearing on product composition.28
mediated crotylation of
was carried out in [bmim][Br]. Among the four possible acyclic
transition structures, both and furnish the syn-product,
whereas and furnish the anti-product. Transition structure
is preferred over due to minimal steric interactions
1 vis-à-vis with In, when the reaction
A
B
C
D
A
B–D
between the bulky R and the methyl group of the crotyl-Bi
species. This would yield the syn-product preferentially. We
could not explain the solvent-dependent variation in the 3,4-
diastereoselectivity of the reaction with
effect of nature of the solvent was earlier reported in the
metal-mediated Barbier-type crotylation of 1 13
This may be
1. However, profound
.
due to different extents of aggregation / solvation of the active
Bi-crotyl species. The diastereoselectivity depends on a large
number of factors such as nature of the metal,12e,25 nature of
the counter ion, and aggregation state of the nucleophiles26 in
the chosen solvent. Given the relatively modest energy
differences necessary to reverse the diastereoselection,
extricating the individual contributions of solvent, metal and
substrate may prove challenging.
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ARTICLE
Journal Name
type-I reagents was accomplished with croVtyielw ArrteicalegOennlintes
30
DOI: 10.1039/C7OB00626H
attached to molecules with chiral directing properties. In
addition, the type-II crotylmetal reagents, in presence of Lewis
acids, predominantly furnish syn-diastereomers.31a,b This
strategy has also been extended to asymmetric crotylation,
using chiral catalysts,31c-e or by modification of ligands
attached to the crotylmetal reagent.3e This aspect has been
excellently reviewed by Denmark and Fu.24a In an innovative
approach, Krische et al. reported syn-selective carbonyl
crotylation via a ruthenium-catalyzed hydrohydroxyalkylation
of 2-silyl-butadienes.32a Very recently, nickel-catalyzed double
bond transposition of alkenyl boronates has also been used for
this purpose.32b
Most of the above protocols are carried out with
preformed crotylating agents that are synthesized under
strictly anhydrous conditions using chiral modifiers or in
presence of a Lewis acid. Some of these also use exotic but
expensive reagents. In contrast, reports on the syn-selective
crotylation reactions by operationally simple Barbier protocol

O
R
H
Me
H

OH
BiBr2
A
R

O
-syn product
R
H
Me
BiBr2

B

H
RCHO
BiBr2
O
R
H
H
Me

with commercially available crotyl bromide (E/Z 5:1) are
OH
R
12e,13d,e
limited.12e,13d,e However these protocols
suffered either
BiBr2
from substrate specificity13d or from lower yields and syn-
selectivity13e particularly in aliphatic aldehydes. Recently, a
moderately syn-selective crotylation of benzaldehyde by
crotyltributyltin, prepared from commercially available crotyl
C

-anti product
O
R
H
H
BiBr2
chloride, was reported using p-nitrobenzoic acid as
promoter.33a However, the regio- and diastereoselectivity were
inferior to those reported herein. In another study,33b
a

Me
D
a
combination of n-Bu4NBr/PbI2 was used as a Lewis acid
catalyst in syn-selective crotylation of aldehydes in water using
crotyltributyltin irrespective of its E/Z stereochemistry. This
protocol, however, required the use of PbI2, which is toxic to
the environment.33c
Scheme 4. Plausible transition structures for Bi-mediated crotylation of aldehydes.
To this end, our present methodology employing Bi and
crotyl bromide in [bmim][Br] is unique, cheaper, operationally
simple and advantageous (vide infra). Moreover, for achiral
substrates, our protocol is applicable to a variety of substrates
(compared to only one substrate reported by Da et. al.),12e and
the syn-selectivity obtained herein is significantly higher
compared to the earlier reports.13e Also, formation of 2b as the
C6H13
Br
OR
Br
O
O
O
C6H13
C6H13
C6H13
C6H13
Bi, [bmim][Br]
+
O
+
1
O
O
OH
6a
OH
6b
OH
6c
Scheme 5. Bi metal mediated reaction of 1 with E/Z-nonenyl bromide in [bmim][Br].
major product in the crotylation of the aldehyde 1 makes the
new protocol a powerful tool in asymmetric organic synthesis.
In particular, compound 2b has an α-disposed Me substituent
that is often encountered in several natural products. The
latent functionality in 2b would be attractive for its
derivatization to various targets. The stereochemistry of the
carbinol centre can be easily inverted by several methods, as
has been demonstrated (vide infra) by converting 2b into (i)
the C1-C9 segment of dictyostatin; (ii) the octadienoic ester
unit (unit A1) of the cryptophycins C/D. The above segments
and cis-aerangis lactone (IV) were chosen as targets based on
their importance in medicinal chemistry and fragrance
industries. The chemical structures of the targets are shown in
Fig. 1. The marine-derived macrolide, dictyostatin (II) was
isolated from the Maldives marine sponge in the genus
Spongia34a,b as well as from the Lithistida sponge of the family
Corallistadae, harvested near Jamaica.34c It inhibits the growth
Table 4. Reaction course of the Bi-mediated reaction of 1 with E/Z 2-nonenyl bromides
in [bmim][Br]a
Entry
Bromide
Time
(h)
4
Yield (%)b
(6a:6b:6c)c
84 (12:56:32)
81 (11:51:38)
1
2
(E)-2-nonenyl bromide
(Z)-2-nonenyl bromide
4
[a]All reactions were carried out on 2 mmol scale at 25 oC using the same
conditions as stated in entry 6, Table 1. [b]Total yield of the diastereomeric
mixtures. [c]Based on the yields of isolated individual diastereomers
Earlier, diastereoselective type-I crotylation using E/Z
crotylsilanes or crotylboranes in presence of achiral and chiral
Lewis acids provided syn/anti products depending on the
geometrical purity (E/Z) of the starting crotyl reagents.29 On
the other hand, the asymmetric syn-selective crotylation using
6 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
was converted to the corresponding dimesylate with
DOI: 10.1039/C7OB00626H
MsCl/Et3N and subsequently heated with KOAc in DMF to
obtain the diacetate 11 as a single stereomer as revealed from
the NMR spectra. This on treatment with K2CO3/MeOH
afforded (3S,4R)-10 in good yield. Its silylation with tert-
of a variety of cancer cell lines (including the Taxol®-resistant
lines) at nM levels due to its action on tubulin
polymerization.34c On the other hand, the cryptophycins,
isolated from the blue-green algae Nostoc sp. ATCC 53789,35a,b
as well as from GSV 224,35c are potent, tumor-selective
tubulin-binding antimitotic agents with excellent activity
against multidrug-resistant cancer cells,36 and some of these
are currently under clinical trials.37 Amongst these,
cryptophycins C/D (IIIa/b) show significantly lesser cytotoxicity
against cancer cell lines, compared to the other
cryptophycins.38 Cis-aerangis lactone is the main odor
component of the African “moth orchids” (Aerangis confusa
and Aerangis kirkii).39a-c The fragrance of (+)-cis-aerangis
lactone [(4R,5R)-4-methyl-5-decanolide, IV] resembles that of
δ-decalactone and cocos, and contributes to the perfume and
flavor of many compounds.39d
View Article Online
butyldimethylsilyl chloride (TBSCl)/Et3N/DMAP furnished 12
,
without formation of any regioisomeric and/ or disilylated
products. The cross-metathesis reaction43 between 12 and
acrolein proceeded smoothly in the presence of Hoveyda-
Grubbs II catalyst to furnish the conjugated aldehyde 13 in
89% yield. The E-geometry of its olefin function, ascertained
from the J-values of the 1H NMR olefinic resonances was
consistent with the proposed model for the cross-metathesis
reaction.43f Finally, the aldehyde 13 was subjected to a Z-
selective
Wittig-Horner
reaction
with
ethyl
diphenylphosphonoacetate44 and NaH in THF to get the
dictyostatin C1-C9 segment 14 in 96/4 Z/E ratio (based on
isolation after column chromatography). The pure 2Z-ester
was isolated in 71% yield by column chromatography.
OH
20
15
O
HO
X
O
O
O
HN
O
O
O
1
OH
OMe
N
H
O
10
RO
HO
O
iv
ii
5
O
OH OH
87%
77%
Cryptophycin C/D (IIIa/b): X = Cl/H
OTBDPS
OH
Dictyostatin (II)
OR
8 R = H
9 R = Bz
(3R,4R)-10
iii
95%
i
2b R = H
7 R = TBDPS
92%
EtO
O
O
1
viii
89%
TBSO
HO
vii
87%
RO
OH
OEt
v
5
OH
PgO
OR
11 R = Ac
(3S,4R)-10 R = H
84%
Octadienoic ester fragment of III
––––––––
12
9
vi
(unit A1)
85%
C1-C9 segment of II
CO2Et
TBSO
TBSO
ix
CHO
71%
OH
OH
13
CH3(CH2)4
O
O
14
i) TBDPSCl/imidazole/DMAP/CH2Cl2/25 oC/7 h, ii) Aqueous 80% TFA/CH2Cl2
/0 oC/3 h, iii) BzCN/Et3N/CH2Cl2/0 oC/2 h, iv) MsCl/Et3N/CH2Cl2/0 oC/1 h;
LiAlH4/THF/reflux/24 h, v) MsCl/Et3N/CH2Cl2/0 oC/4 h; KOAc/DMF/130 oC/22 h,
vi) K2CO3/MeOH/25 oC/2 h, vii) TBSCl/Et3N/ DMAP/CH2Cl2/25 oC/7 h,
viii) Acrolein/Hoveyda-Grubbs II/CH2Cl2/40 oC/8 h, ix) NaH/Ethyl
diphenylphosphonoacetate/THF/0 oC/1 h; -78 oC/3 h.
(+)-cis-Aerangis lactone (IV)
Figure 1. Structures of dictyostatin, cryptophycins, their segments and (+)-cis-aerangis
lactone.
Scheme 6. Synthesis of the C1-C9 segment of dictyostatin.
Synthesis of the C1-C9 segment of dictyostatin (II).
In view of its significant therapeutic potential, several
syntheses of II 40 as well as its several analogs and hybrids41
,
Among the earlier attempts to synthesise C1-C9 segment
of dictyostatin, Marshall reaction,42a anti-aldol strategy,42b and
reagent-controlled asymmetric crotylation42c-d have been
prominent to establish the stereocentres in the target.
However, the common refrain is availability, cost and stability
of the chiral reagents involved. In the most recent attempt,42e
the target was synthesized in eleven steps in 9% yield, using
Sharpless asymmetric epoxidation as the key step. In addition,
the synthesis also involved an atom uneconomic cross-
metathesis. In comparison, our synthetic scheme allows easy
access to the target in nine steps and 22% overall yield starting
have been reported. Herein, we describe our synthesis of the
C1-C9 segment 14 of dictyostatin, which was earlier
synthesized by Jagel and Maier.42a Several other syntheses of
C1-C9 segment of II are also reported.42b-e Our synthesis of 14
(Scheme 6) commenced by silylation of the alcohol 2b with
tert-butyldiphenylsilyl chloride (TBDPSCl) in the presence of
imidazole and 4-dimethylaminopyridine (DMAP) to furnish
Acidic hydrolysis of its acetal function with aqueous
trifluoroacetic acid (TFA) furnished the diol . A regioselective
benzoylation (BzCN/Et3N) of the primary carbinol function in
furnished the monobenzoate . This was mesylated with
7.
8
8
9
from 2b
.
methanesulfonyl chloride (MsCl)/Et3N and the resultant
product subjected to LiAlH4 reduction under refluxing
conditions to furnish the diol (3R,4R)-10 via a concomitant
desilylation. For inversion of the carbinol stereochemistry, it
Synthesis of the octadienoic ester segment (unit A1) of
desoxycryptophycins.
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ARTICLE
The importance of the cryptophycins as anti-cancer drugs
Journal Name
View Article Online
DOI: 10.1039/C7OB00626H
has resulted in a large number of formal and total syntheses of
these and their structural variants.45 The major innovations in
these methods have been achieved in the synthesis of the
octadienoic acid fragment, as the other required units (the
protected D-tyrosine, β-amino acid and hydroxy acid
derivatives) are easily available.46 Despite being less
biologically active amongst the cryptophycins, the
desoxycryptophycins have been the precursors of the epoxide-
containing cryptophycins. Most of the syntheses of the
epoxide-containing cryptophycins relied on construction of the
A1 unit (Fig. 2) by the Moore-Tius’ method,46a,d followed by a
single late-stage epoxidation with m-CPBA or dimethyl
dioxirane. In addition, the A1 unit has also been synthesized
using a multitude of strategies ranging from classical aldol and
Diels-Alder methods to chemoenzymatic approaches as well as
methods based on carbon-carbon bond formation via
transition metal complexes.35c,e,46f-q
O
iii
O
i
ii
7
O
O
88%
98%
85%
CHO
OTBDPS
OH
TBDPSO
OH
15
16
OH
RO
iv
91%
HO
O
vi
Ph
Ph
O
OTBDPS
Ph
OH
91%
OTBDPS
17
(3R,4R)-20
18 R = H
19 R = Bz
v
93%
RO
Ph
vii
ix
OR
EtO2C
Ph
63%
viii
89%
21 R = Ac
(3S,4R)-20 R = H
75%
OH
22
i)OsO4/NMO/acetone:H2O (8:1)/25 oC/6 h, ii) NaIO4/Aqueous 60% CH3CN
/25 oC/2 h, iii) n-BuLi/diethyl benzylphosphonate/THF/-78 oC/2 h, 25 oC/6 h, iv )
Aqueous 80% TFA/CH2Cl2/0 oC/3 h, v) BzCN/Et3N/ CH2Cl2/0 oC/2 h, vi)
MsCl/Et3N/CH2Cl2/0 oC/1 h; LiAlH4/THF/reflux/24 h, vii) MsCl/Et3N/CH2Cl2/0
oC/1 h; KOAc/DMF/130 oC/22 h, viii) K2CO3/MeOH/25 oC/2 h, ix)
TEMPO/BAIB/CH3CN/25 oC/2 h; NaH/ triethylphosphonoacetate/THF/25 oC/1h.
In the present endeavor towards the synthesis of the A1
unit equivalent of desoxycryptophycins, the silylated derivative
7
was subjected to Upjohn dihydroxylation (OsO4/NMO) to
obtain the diol 15 as a mixture of C-2 epimers. Since the diol
was to be subsequently cleaved, the C-2 stereochemistry was
inconsequential in the context of the synthesis. Reaction of 15
with NaIO4 gave the aldehyde 16, which on a Wittig-Horner
reaction with diethyl benzylphosphonate47/n-BuLi furnished
the alkene 17 as the sole product. TFA-catalyzed hydrolysis of
its acetal function gave the diol 18. As before, regioselective
monobenzoylation (BzCN/Et3N) at the primary carbinol of 18
Scheme 7. Synthesis of the octadienoic ester segment (unit A1) of desoxycryptophycins.
The earlier syntheses of the A1 unit, based on Sharpless
epoxidation,46f Brown’s asymmetric crotylation,46g Noyori’s
reduction,46h asymmetric aldol addition46i,j etc. employed
expensive and air/moisture-sensitive chiral reagents
/auxiliaries and afforded the target in 8-14 steps with 11-29%
global yields. The chemoenzymatic routes were shorter (6-9
steps), but inferior in terms of the overall yields (6-12%).46k,l
The syntheses, using chiral pool materials like (S)-2-
acetoxysuccinic anhydride,46m methyl (S)-malate,46n (S)-malic
acid46o etc. were circuitous (11-16 steps) and low-yielding (4-
14%). Our approach (10 steps and 22% yield) is much better
than the above routes. However, the syntheses involving a
chiral indanol directed aldol reaction46p and an asymmetric CBS
reduction46q are admittedly superior in terms of brevity and
efficiency, but required expensive chiral auxiliaries.
furnished the monobenzoate 19
. This on mesylation
(MsCl/Et3N) followed by LiAlH4 reduction furnished the diol
(3R,4R)-20. This was dimesylated and subsequently reacted
with KOAc to obtain the diacetate 21 with inverted
stereochemistry at C-3. Its base-catalyzed deacetylation gave
(3S,4R)-20. Finally, a chemoselective oxidation of its primary
carbinol with [bis(acetoxy)iodo]benzene (BAIB)/TEMPO gave
the intermediate
-hydroxyaldehyde, which on a Wittig-
Horner reaction with triethyl phosphonoacetate afforded the
target cryptophycin segment 22, the A1 unit equivalent of the
cryptophycins (Scheme 7.).46o
Synthesis of (+)-cis-aerangis lactone.
The cis-aerangis lactone enantiomers, their mixture and
the corresponding trans-diastereomers possess different odors
of varying intensities.39c The mixture of cis- and trans-aerangis
lactones provides creamery notes of various perfume and
flavoring compounds.39b All these highlight the complex
stereochemistry-odor relationship of IV, leading to several
syntheses of (-)-cis- and trans-aerangis lactones,48a-d but those
of (+)-cis-aerangis lactone have been limited.48e-g
8 | J. Name., 2012, 00, 1-3
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has been suggested. The reaction was carried out with
View Article Online
DOI: 10.1039/C7OB00626H
commercially available reagents in a much lesser time with the
least
expensive
imidazole-containing
RTIL.
The
OH
diastereoselectivity of the present protocol is drastically
different from that reported in our previous papers,6c,9a,13a-c
but not unprecedented. Earlier, Barbier-type crotylation of
aldehydes using a combination of SnCl2.2H2O/Al in aqueous
THF and commercially available crotyl bromide, produced poor
syn-selectivity with aromatic aldehydes, and no selectivity with
OHC
O
HO
iii
ii
i
2b
O
80%
97%
96%
OBn
25
OBn
24
OBn
23
vi
iv
77%
v
CO2Et
95%
85%
OBn
27
OBn
26
aliphatic
2a:2b:2c::5:75:20).13e Another report involved the reaction
between crotyl bromide and with SnCl2.2H2O/Zn to give 2b
with similar diastereoselectivity (2a:2b:2c::7:78:15).13d Besides,
was the only aldehyde studied using the protocol. In
aldehydes
with
the
exception
of
1
(
vii
1
CO2Et
65%
O
O
OH
28
IV
1
i) NaH/THF/BnBr/Bu4NI/reflux/5 h, ii) 2N HCl-Methanol/25 oC/6 h, iii) NaIO4
/MeCN-H2O (6:4)/25 oC/2 h, iv) CH3(CH2)3PPh3Br/n-BuLi/THF/-40 oC/3 h/25
oC/12 h, v) Ethyl acrylate/Hoveyda-Grubbs' II/CH2Cl2/25 oC/2 h, vi) H2/10% Pd-
C/EtOH/6 h, vii) Aqueous H2SO4/THF/reflux/12 h..
comparison, our methodology has a much enhanced substrate
scope, and affords higher yields and diastereoselectivity.
Because of their close Rf-values, separation of the
products, 2a-c by column chromatography critically depends
on their ratio in the mixture. The ratio between the two major
isomers 2b/2c were 5.3 and 3.8 respectively in the Sn-
mediated methods.13d,e This (major isomers, 2b/2a) was much
higher (7.7) in the Bi-mediated protocol, offering a distinct
practical advantage in their isolation. Moreover, both the Sn-
based protocols required use of large excesses of the reagents.
Considering the human and environmental toxicity of Sn metal
and related compounds used/produced in these protocols,49
our procedure is more user and environment friendly. It is
worth-mentioning that we have reused [bmim][Br] at least
three times without any purification, and obtained similar
results. Presumably the amount of the RTIL-based by-products
formed during Bi-activation is too less to change the property
of the medium. The versatility of the major crotylated product
2b was established by converting it to the dictyostatin and
cryptophycin segments, and (+)-cis-aerangis lactone, using
standard synthetic protocols. Although numerous reports till
date have described the synthesis of these targets, our report
Scheme 7. Synthesis of (+)-cis-aerangis lactone.
In the present synthesis of IV
, compound 2b was
benzylated with BnBr/Bu4NI/NaH to produce 23, which on
treatment with HCl/MeOH furnished the diol 24. Cleavage of
its diol function with NaIO4 to the aldehyde 25, followed by a
Wittig reaction with n-BuPPh3Br/n-BuLi afforded 26. Since the
incipient olefin would be eventually hydrogenated for the
synthesis of the target compound, we did not analyze the
olefin geometry of 26. Next, compound 26 was subjected to a
cross-metathesis reaction with an excess of ethyl acrylate in
the presence of Hoveyda-Grubbs II catalyst to furnish 27. This
on catalytic hydrogenation afforded the hydroxy ester 28. On
refluxing with aqueous H2SO4 in THF, it furnished the target
lactone IV directly (Scheme 8.).
Previously, Kaiser et. al48e employed a strategy involving a
nonselective Baeyer-Villiger oxidation as the crucial step. This
furnished IV along with the other three stereomers. The other
syntheses48f,g of enantiopure IV describe a TiCl4-mediated Evans
asymmetric aldolisation as the key reaction to get the target in 6-7
steps (excluding the synthesis of chiral auxiliary) with an overall
yield of 28%. Our synthesis is equally concise and provided IV in
30% yield, but scores over the earlier efforts in terms of operational
simplicity, use of easily available materials/reagents and
reproducibility.
provides
a stereodivergent synthetic strategy, which is
inexpensive, simple, flexible, efficient and scalable. We expect
that the present protocol will open up many applications in
organic synthesis.
Experimental Section
The chemicals were procured from Fluka or Sigma Aldrich and
were used as received. Other reagents were of AR grade. All
anhydrous reactions were carried out under an Ar
atmosphere, using freshly dried solvents. All organic extracts
were dried over anhydrous Na2SO4. IR spectra were recorded
Conclusion
Overall, we have developed an expedient Bi-mediated
diastereoselective crotylation protocol for aldehydes in
[bmim][Br] with nearly stoichiometric amounts of Bi and crotyl
bromide without using any additional metal activator. This
suggested that [bmim][Br] may not only be acting as the
solvent, but also as the metal activator. To the best of our
1
as films with a JASCO model A-202 spectrophotometer. H and
13C NMR spectra were recorded in CDCl3 (unless otherwise
mentioned) with a Bruker AC-200 instrument. or 500 MHz
Varian NMR spectrometer. Optical rotations were recorded on
a JASCO DIP-360 digital polarimeter. Elemental analyses were
recorded on Elementar Vario micro cube. The chiral HPLC
analyses were performed with a JASCO HPLC system using
CHIRALCEL OD-H column with HPLC grade n-hexane and
isopropanol as the eluents.
knowledge, this is the first example of
a Bi-mediated
crotylation of any carbonyl moiety in an RTIL. The nature of the
active crotylbismuth species formed in [bmim][Br] has been
probed for the first time and a plausible reaction mechanism
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
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Journal Name
Preparation of 1-Butyl-3-methylimidazolium bromide 115.5, 139.6. Anal. Found: C, 68.8; H, 9.9. Calc. for C13H22O3: C,
View Article Online
[bmim][Br].50a A solution of bromobutane (27.0 mL, 0.25 mol) 69.0; H, 9.8%. HPLC (benzoate ester; isoDpOroI:p1a0n.1o03l/9h/Ce7xOanB0e0562/69H5
and 1-methylimidazole (19.9 mL, 0.25 mol) in toluene (50 mL) @ 0.5 mL/min, λ = 254 nm): Rt = 8.18 min.
24
23
was heated at 70 °C with stirring for 72 h. The top phase, 2b: colorless oil; [α]D +29.8 (c 1.40 in CHCl3), (lit.13a [α]D
containing unreacted starting material, was decanted off, and +29.65 (c 1.45 in CHCl3)); νmax/cm−1 3474, 1640, 998; δH (500
the bottom phase was washed with dry Et2O (3 x 25 mL). The MHz, CDCl3) 1.11 (3H, d, J = 6.5 Hz), 1.39-1.41 (2H, m), 1.56-
resultant product was dried under vacuum to yield pure 1.66 (8H, m), 2.08 (1H, br s), 2.23-2.28 (1H, m), 3.65-3.68 (1H,
[bmim][Br] (49.8 g, 91%). light brown viscous liquid; δH (500 m), 3.87-3.90 (1H, m), 3.95-3.99 (1H, m), 4.09-4.13 (1H, m),
MHz, D2O) 0.98 (3H, br t, J = 7.5 Hz), 1.36-1.42 (2H, m), 1.88- 5.05-5.09 (2H, m), 5.71-5.78 (1H, m); δC (125 MHz, CDCl3) 15.3,
1.94 (2H, m), 3.96 (3H, s), 4.26 (2H, t, J = 7.5 Hz), 7.50 (1H, s), 23.7, 23.9, 25.1, 34.8, 36.2, 40.6, 64.3, 73.7, 76.3, 109.2, 115.2,
7.55 (1H, s), 8.79 (1H, s); δC (125 MHz, D2O) 12.7, 18.8, 31.3, 140.3. Anal. Found C, 69.1; H, 9.9. Calc. for C13H22O3: C, 69.0; H,
35.8, 49.3, 122.2, 123.5, 135.8. Anal. Found: C, 43.6; H, 7.2; N, 9.8%. HPLC (benzoate ester; isopropanol/hexane 5/95 @ 0.5
12.7. Calc. for C8H15BrN2: C, 43.9; H, 6.9; N, 12.8%.
mL/min, λ = 254 nm): Rt = 7.83 min.
Typical procedure for Bi-mediated crotylation of 1 in 2c: colorless oil; [α]D24 +2.4 (c 1.17 in CHCl3), (lit.13a [α]D23 +2.60
aqueous or organic media. Finely powdered Bi-metal (1.05 g, (c 2.05 in CHCl3); νmax/cm−1 3408, 1657, 997; δH (500 MHz,
5.00 mmol) was added in portions to a mixture of
1 (340 mg, CDCl3) 1.09 (3H, d, J = 7.0 Hz), 1.39-1.41 (2H, m), 1.56-1.65 (8H,
2.00 mmol) and crotyl bromide (1.07 g, 8.00 mmol) in m), 1.91 (1H, d, J = 4.0 Hz), 2.39-2.43 (1H, m), 3.59-3.62 (1H,
respective solvents (10 mL) and the mixture was stirred m), 3.89-3.92 (1H, m), 3.98-4.01 (1H, m), 4.04-4.08 (1H, m),
magnetically for the specified time (Table 1). One set of 5.11-5.15 (2H, m), 5.83-5.90 (1H, m); δC (125 MHz, CDCl3) 16.5,
reaction in THF was also carried out by adding an aqueous 23.8, 24.0, 25.1, 34.9, 36.3, 40.3, 65.1, 74.8, 76.7, 109.2, 116.1,
solution of KF (10 mol%). The mixture was filtered, extracted 139.4. Anal. Found C, 68.7; H, 9.6. Calc. for C13H22O3: C, 69.0; H,
1
with Et2O (2

10 mL), concentrated in vacuo and the H NMR 9.8%. HPLC (benzoate ester; isopropanol/hexane 5/95 @ 0.5
spectrum of the crude reaction mixture recorded for analyzing mL/min, λ = 254 nm): Rt = 7.65 min.
the diastereomeric ratio (dr). However, due to the overlapping
General procedure for Bi-mediated crotylation of
signals, the dr could not be determined unambiguously. In all aldehydes in [bmim][Br]. A mixture of finely powdered Bi
the cases, the product mixtures were subjected to column metal and crotyl bromide in specified quantities in [bmim][Br]
chromatography (silica gel, 0-15% EtOAc/hexane) to obtain (2 mL/mmol) was stirred at room temperature for 0.5 h,
pure 2a
-
c
.
followed by addition of the aldehydes 4a-o. On completion of
Studies on the effect of [bmim][Br] concentration on the the reaction (cf. TLC, time specified in Table 3), the individual
Bi-mediated Barbier-type crotylation of 1 in aqueous or reaction mixtures were extracted with Et2O (3 x 10 mL), the
organic media. To a mixture of
1 (340 mg, 2.00 mmol), crotyl ether extract evaporated in vacuo to obtain the respective
bromide (1.07 g, 8.00 mmol) and [bmim][Br] (10 or 100 mol%) crude products. The diastereomeric ratios of the products 5a-o
in different solvents (10 mL each, Table 2) was added Bi were ascertained from the 1H NMR spectra (recorded in CDCl3)
powder (1.05 g, 5.00 mmol) in portions. After stirring for the of aliquots of the crude products. The rest of the product
specified time, the mixture was worked up and processed as mixtures were subjected to column chromatography to isolate
above to isolate the pure diastereomers.
the pure products as mixtures of diastereomers (by column
Typical procedure for Bi-mediated crotylation of 1 in RTIL. chromatography). Complete extraction of each of the products
To a magnetically stirred mixture of
1 (340 mg, 2.00 mmol) and from the reaction medium was also confirmed, as above.
crotyl bromide (320 mg, 2.40 mmol) in [bmim][Br] (4 mL, mole 5a50b: colorless oil; νmax/cm−1 3426, 920; δH (500 MHz, CDCl3)
fraction 0.79) was added Bi powder (420 mg, 2.00 mmol) in 0.88 (anti) and 1.02 (syn) (3H, two d, J = 6.5 and 7.0 Hz), 2.02
portions. After stirring the mixture for 4 h, it was extracted in (1H, br s), 2.57-2.59 (anti) and 2.60-2.62 (syn) (1H, two m),
Et2O (3
 10 mL), the organic extract concentrated in vacuo 4.37 (anti) and 4.62 (syn) (1H, two d, J = 7.5 and 5.5 Hz), 5.04-
and subjected to column chromatography to get pure 2a
-
c. 5.19 (syn) and 5.20-5.23 (anti) (2H, two m), 5.73-5.81 (1H, m),
The 1H NMR spectra of the residual reaction mixture was 7.26-7.36 (5H, m); δC (125 MHz, CDCl3) 14.0, 16.5, 44.6, 46.2,
recorded in CDCl3 to ascertain the extraction efficiency of the 77.3, 77.9, 115.4, 116.6, 126.5, 126.8, 127.3, 127.6, 128.0,
products by Et2O from the reaction mixture. Similar reactions 128.2, 140.3, 140.6, 142.6. Anal. Found: C, 81.8; H, 8.9. Calc.
were also carried out using [bmim][Br] (1 mL, mole fraction for C11H14O: C, 81.4; H, 8.7%.
0.48; or 2 mL, mole fraction 0.65). Additional experiments 5b50c: light yellow oil; νmax/cm−1 3443, 926; δH (500 MHz, CDCl3)
were attempted in [bmim][BF4] (4 mL) as well as under Ar in N2 0.93 (anti) and 0.97 (syn) (3H, two d, J = 7.0 Hz each), 2.17 (1H,
(g)-purged [bmim][Br] (4 mL).
br s), 2.45-2.49 (anti) and 2.57-2.62 (syn) (1H, two m), 4.52
(anti) and 4.77 (syn) (1H, two d, J = 7.5 and 5.0 Hz), 5.06-5.16
24
23
2a: colorless oil; [α]D +45.9 (c 1.81 in CHCl3), (lit.13a [α]D
+47.14 (c 1.4 in CHCl3)); νmax/cm−1 3408, 1648, 990; δH (500 (syn) and 5.20-5.22 (anti) (2H, two m), 5.74-5.81 (1H, m), 7.48-
MHz, CDCl3) 1.11 (3H, d, J = 7.0 Hz), 1.38-1.41 (2H, m), 1.57- 7.52 (2H, m), 8.17-8.20 (2H, m); δC (125 MHz, CDCl3) 13.4, 16.2,
1.65 (8H, m), 2.26-2.30 (2H, m merged with br s), 3.38-3.40 44.6, 76.1, 76.8, 116.5, 123.2, 123.3, 127.2, 127.6, 139.1,
(1H, m), 3.71-3.74 (1H, m), 3.98-4.01 (1H, m), 4.07-4.11 (1H, 139.4, 149.9, 150.0. Anal. Found: C, 64.0; H, 6.5; N, 6.6. Calc.
m), 5.03-5.11 (2H, m), 5.85-5.92 (1H, m); δC (125 MHz, CDCl3) for C11H13NO3: C, 63.8; H, 6.3; N, 6.8%.
16.7, 23.8, 24.0, 25.1, 35.0, 36.3, 41.4, 65.9, 75.3, 76.6, 109.8,
10 | J. Name., 2012, 00, 1-3
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5c33b: light yellow oil; νmax/cm−1 3442, 978; δH (500 MHz, CDCl3) 5i33b: colorless oil; νmax/cm−1 3410, 931; δH (500VMiewHAzrt,iclCeDOnCliln3e)
DOI: 10.1039/C7OB00626H
1.03 (syn) and 1.05 (anti) (3H, two d, J = 7.0 Hz each), 2.17 (1H, 0.88 (anti) and 0.99 (syn) (3H, two d, J = 7.0 Hz each), 1.94
br s), 2.60-2.66 (anti) and 2.67-2.71 (syn) (1H, two m), 5.03- (syn) and 2.16 (anti) (1H, two br s), 2.42-2.46 (anti) and 2.52-
5.11 (syn) and 5.15-5.17 (anti) (2H, two m), 5.31 (syn) (0.9H, d, 2.59 (syn) (1H, two m), 4.36 (anti) and 4.61 (syn) (1H, two d, J =
J = 5.5 Hz), 5.81-5.88 (1.1H, m), 7.40-7.43 (1H, m), 7.61-7.65 8.0 and 5.5 Hz), 5.04-5.10 (syn) and 5.19-5.22 (anti) (2H, two
(1H, m), 7.79-7.80 (1H, m), 7.90-7.92 (1H, m); δC (125 MHz, m), 5.71-5.78 (1H, m), 7.23-7.32 (4H, m); δC (125 MHz, CDCl3)
CDCl3) 13.3, 16.8, 43.4, 45.1, 72.0, 72.2, 115.8, 124.3, 125.8, 13.8, 16.3, 44.6, 76.6, 77.2, 115.8, 127.8, 128.2, 128.3, 133.0,
127.9, 128.1, 128.9, 129.1, 132.8, 138.0, 138.8, 140.2, 148.3. 139.9, 141.0. Anal. Found: C, 67.3; H, 6.6. Calc. for C11H13ClO:
Anal. Found: C, 64.1; H, 6.4; N, 6.4. Calc. for C11H13NO3: C, 63.8; C, 67.2; H, 6.7%.
H, 6.3; N, 6.8%.
5j50e: colorless oil; νmax/cm−1 3420, 908; δH (500 MHz, CDCl3)
5d33b: colorless oil; νmax/cm−1 3390, 910; δH (500 MHz, CDCl3) 1.04 (3H, d, J = 6.5 Hz), 1.59-1.74 (2H, m merged with br. s),
0.91 (anti) and 1.10 (syn) (3H, two d, J = 6.5 and 7.0 Hz), 2.56 1.80-1.87 (1H, m), 2.29-2.31 (anti) and 2.32-2.34 (syn) (1H, two
(syn) and 2.81 (anti) (1H, two br s), 2.68-2.72 (1H, m), 4.45 m), 2.63-2.69 (1H, m), 2.84-2.90 (1H, m), 3.41-3.46 (anti) and
(anti) and 4.82 (syn) (1H, two d, J = 9.0 and 5.5 Hz), 5.11-5.15 3.52-3.55 (syn) (1H, two m), 5.08-5.15 (2H, m) 5.75-5.82 (1H,
(syn) and 5.26-5.31 (anti) (2H, two m), 5.79-5.86 (1H, m), 6.81- m), 7.18-7.23 (3H, m), 7.27-7.31 (2H, m); δC (125 MHz, CDCl3)
6.96 (3H, m), 7.15-7.20 (1H, m), 7.95 (anti) and 8.10 (syn) (1H, 14.2, 16.2, 32.2, 32.4, 35.8, 36.1, 43.7, 44.3, 74.1, 115.4, 116.3,
two s); δC (125 MHz, CDCl3) 13.3, 16.8, 44.4, 44.7, 79.4, 79.5, 125.8, 128.3, 128.4, 140.2, 140.8, 142.2, 142.3. Anal. Found: C,
116.2, 117.2, 117.3, 118.0, 119.3, 127.9, 128.7, 128.8, 129.1, 81.8; H, 9.2. Calc. for C13H18O: C, 82.1; H, 9.5%.
139.8, 140.3, 156.0. Anal. Found: C, 74.4; H, 7.7. Calc. for 5k50c: colorless oil; νmax/cm−1 3421, 911; δH (500 MHz, CDCl3)
C11H14O2: C, 74.1; H, 7.9%.
1.08 (anti) and 1.10 (syn) (3H, two d, J = 6.5 and 7.0 Hz), 1.89
5e50b: colorless oil; νmax/cm−1 3423, 919; δH (500 MHz, CDCl3) (1H, br. s), 2.37-2.41 (anti) and 2.46-2.53 (syn) (1H, two m),
0.85 (anti) and 1.03 (syn) (3H, two d, J = 6.5 Hz each), 1.90 (1H, 4.07 (anti) and 4.22 (syn) (1H, two t, J = 7.0 and 5.5 Hz), 5.14-
br s), 2.44-2.48 (anti) and 2.53-2.60 (syn) (1H, two m), 3.81 5.21 (2H, m), 5.83-5.90 (1H, m), 6.22-6.27 (1H, m), 6.61 (1H, d,
(3H, s), 4.31 (anti) and 4.55 (syn) (1H, two d, J = 8.0 and 5.5 J = 16.0 Hz), 7.25-7.27 (1H, m), 7.31-7.35 (2H, m), 7.39-7.41
Hz), 5.02-5.06 (syn) and 5.17-5.23 (anti) (2H, two m) 5.70-5.79 (2H, m); δC (125 MHz, CDCl3) 14.8, 16.0, 43.9, 44.6, 75.8, 76.1,
(1H, m), 6.87-6.90 (2H, m), 7.22-7.25 (2H, m); δC (125 MHz, 115.9, 126.5, 127.6, 128.5, 129.1, 130.1, 131.2, 131.7, 136.8,
CDCl3) 14.3, 16.5, 44.7, 55.2, 76.7, 77.1, 113.5, 113.7, 115.3, 140.0, 140.2. Anal. Found: C, 82.9; H, 8.7. Calc. for C13H16O: C,
127.6, 127.9, 134.8, 140.4, 158.9. Anal. Found: C, 74.8; H, 8.7. 82.9; H, 8.6%.
Calc. for C12H16O2: C, 75.0; H, 8.4%.
5l50c: colorless oil; νmax/cm−1 3421, 927; δH (500 MHz, CDCl3)
5f: colorless oil; νmax/cm−1 3426, 927; δH (500 MHz, CDCl3) 0.90 0.95 (anti) and 1.07 (syn) (3H, two d, J = 7.0 Hz each), 2.04 (1H,
(anti) and 1.02 (syn) (3H, two d, J = 6.5 and 7.0 Hz), 1.26 (1H, br s), 2.67-2.73 (1H, m), 4.43 (anti) and 4.57 (syn) (1H, two d, J
br. s), 2.45-2.50 (anti) and 2.54-2.61 (syn) (1H, two m), 3.80 = 7.5 and 6.0 Hz), 5.06-5.12 (syn) and 5.17-5.24 (anti) (2H, two
(6H, s), 4.30 (anti) and 4.56 (syn) (1H, two d, J = 7.5 and 5.5 m) 5.72-5.79 (1H, m), 6.23 (syn) and 6.27 (anti) (1H, two d, J =
Hz), 5.06-5.10 (syn) and 5.17-5.23 (anti) (2H, two m), 5.76-5.83 3.0 Hz each), 6.32-6.34 (1H, m), 7.36-7.39 (1H, m); δC (125
(1H, m), 6.37-6.39 (1H, m), 6.48-6.51 (2H, m); δC (125 MHz, MHz, CDCl3) 15.0, 16.1, 43.0, 43.5, 71.4, 106.7, 107.1, 110.0,
CDCl3) 13.9, 16.6, 44.4, 46.0, 55.3, 77.3, 78.0, 99.2, 99.6, 104.5, 115.8, 116.7, 139.6, 139.9, 141.6, 141.9, 155.2, 155.4. Anal.
104.8, 115.4, 140.4, 140.6, 145.2, 160.6. Anal. Found: C, 70.6; Found: C, 70.9; H, 8.1. Calc. for C9H12O2: C, 71.0; H, 8.0%.
H, 7.9. Calc. for C13H18O3: C, 70.2; H, 8.2%.
5m50f: colorless oil; νmax/cm−1 3400, 912; δH (500 MHz, CDCl3)
5g50d: colorless oil; νmax/cm−1 3420, 918; δH (500 MHz, CDCl3) 0.89 (3H, t, J = 7.0 Hz), 1.02-1.04 (3H, two d merged together, J
0.90 (anti) and 0.99 (syn) (3H, two d, J = 7.0 Hz each), 1.99 (1H, = 7.0 Hz each), 1.26-1.39 (6H, m), 1.47-1.51 (2H, m), 1.62 (1H,
br s), 2.43-2.45 (anti) and 2.52-2.59 (syn) (1H, two m), 4.33 br s), 2.26-2.28 (anti) and 2.28-2.30 (syn) (1H, two m), 3.48-
(anti) and 4.60 (syn) (1H, two d, J = 5.0 and 7.5 Hz), 5.06-5.11 3.49 (anti) and 3.50-3.52 (syn) (1H, two m), 5.07-5.13 (2H, m),
(syn) and 5.19-5.22 (anti) (2H, two m), 5.73-5.80 (1H, m), 7.18- 5.77-5.84 (1H, m); δC (125 MHz, CDCl3) 13.9, 14.0, 16.2, 22.6,
7.24 (2H, m), 7.38-7.40 (1H, m), 7.47-7.50 (1H, m); δC (125 25.4, 25.7, 31.9, 34.0, 34.3, 43.4, 44.0, 74.7, 115.0, 116.0,
MHz, CDCl3) 13.7, 16.4, 44.6, 46.2, 76.5, 77.0, 115.9, 117.2, 140.4, 141.1. Anal. Found: C, 76.9; H, 12.9. Calc. for C10H20O: C,
122.3, 122.4, 125.1, 125.5, 129.6, 129.7, 130.3, 130.7, 139.9, 76.9; H, 12.9%.
144.8, 145.0. Anal. Found: C, 54.8; H, 5.4. Calc. for C11H13BrO: 5n50c: colorless oil; νmax/cm−1 3418, 922; δH (500 MHz, CDCl3)
C, 54.8; H, 5.4%.
0.88 (3H, t, J = 7.0 Hz), 1.02-1.04 (3H, two d merged together, J
5h50b: colorless oil; νmax/cm−1 3425, 915; δH (500 MHz, CDCl3) = 7.0 Hz each), 1.26-1.39 (12H, m), 1.46-1.52 (2H, m), 1.63 (1H,
0.87 (anti) and 0.98 (syn) (3H, two d, J = 7.0 Hz each), 2.09 br s), 2.19-2.23 (anti) and 2.24-2.31 (syn) (1H, two m), 3.38-
(syn) and 2.26 (anti) (1H, two br s), 2.40-2.44 (anti) and 2.51- 3.40 (anti) and 3.48-3.51 (syn) (1H, two m), 5.07-5.13 (2H, m)
2.57 (syn) (1H, two m), 4.32 (anti) and 4.57 (syn) (1H, two d, J = 5.77-5.84 (1H, m); δC (125 MHz, CDCl3) 14.0, 16.2, 22.6, 25.7,
7.5 and 5.0 Hz), 5.03-5.09 (syn) and 5.17-5.21 (anti) (2H, two 26.0, 29.2, 29.5, 29.7, 31.8, 34.1, 34.3, 43.4, 44.0, 74.7, 115.0,
m), 5.71-5.80 (1H, m), 7.16-7.21 (2H, m), 7.44-7.47 (2H, m); δC 140.4, 141.1. Anal. Found: C, 79.1; H, 13.0. Calc. for C13H26O: C,
(125 MHz, CDCl3) 13.8, 16.4, 44.6, 76.5, 77.2, 116.0, 121.1, 78.7; H, 13.2%.
128.2, 128.5, 131.1, 131.3, 139.8, 140.1, 141.5. Anal. Found: C, 5o: colorless oil; νmax/cm−1 3425, 915; δH (500 MHz, CDCl3) 0.89
54.6; H, 5.4. Calc. for C11H13BrO: C, 54.8; H, 5.4%.
(3H, t, J = 7.0 Hz), 1.02-1.04 (3H, two d merged together, J =
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7.0 Hz each), 1.26-1.38 (18H, m), 1.48-1.51 (2H, m), 1.58 (1H, CDCl3)14.1, 19.6, 23.9, 24.0, 25.2, 27.1, 34.6, 36.1, 40.8, 66.5,
View Article Online
DOI: 10.1039/C7OB00626H
br. s), 2.19-2.25 (anti) and 2.26-2.31 (syn) (1H, two m), 3.39- 76.0, 78.8, 108.8, 114.6, 127.4, 127.5, 129.6, 129.7, 133.7,
3.41 (anti) and 3.48-3.51 (syn) (1H, two m), 5.07-5.13 (2H, m) 133.8, 136.1, 140.3. Anal. Found: C, 75.2; H, 8.8. Calc. for
5.73-5.84 (1H, m); δC (125 MHz, CDCl3) 14.0, 16.2, 22.6, 25.7, C29H40O3Si: C,74.95; H, 8.7%.
26.0, 29.3, 29.6, 29.6, 29.7, 31.9, 34.1, 34.3, 43.4, 74.7, 115.0, (2R,3S,4R)-3-tert-Butyldiphenylsilyloxy-4-methylhex-5-ene-
141.1. Anal. Found: C, 80.3; H, 13.6. Calc. for C16H32O: C, 79.9; 1,2-diol 8. A mixture of
7 (4.10 g, 8.82 mmol) and aqueous
H, 13.4%. 80% TFA (10 mL) in CH2Cl2 (15 mL) was stirred at 0 °C. On
Bi-mediated reaction of 1 with E/Z 2-nonenyl bromide in completion of the reaction (cf. TLC, 3 h), the mixture was
[bmim][Br]. The reactions were carried out using a similar treated with aqueous saturated NaHCO3, diluted with water
protocol as described in the crotylation of
bromide with E- or Z-2-nonenyl bromide. After stirring for 4 h, organic layers were washed successively with water (2
the mixture was extracted with Et2O (3 10 mL), concentrated mL) and brine (1 10 mL), and dried. Solvent removal in vacuo
in vacuo, and the residue subjected to column followed by column chromatography of the residue (silica gel,
chromatography (silica gel, 0-15% EtOAc/hexane) to obtain 0-5% MeOH/CHCl3) furnished pure (2.6 g, 77%). colorless
pure 6a-c as colorless oils (yields and diastereomeric ratio viscous liquid; [α]D25 +5.0 (c 2.11 in CHCl3); νmax/cm-1 3434, 918;
mentioned in Table 4). δH (200 MHz, CDCl3) 0.94 (3H, d, J = 6.8 Hz), 1.09 (9H, s), 2.03
1
replacing crotyl (15 mL) and extracted with CHCl3 (3

15 mL). The combined

10


8
24
23
6a: colorless oil; [α]D -0.31 (c 1.2 in CHCl3), (lit.27 [α]D -0.29 (2H, br s), 2.40-2.43 (1H, m), 3.65-3.68 (3H, m), 3.76-3.79 (1H,
(c 1.4 in CHCl3)); νmax/cm-1 3464, 1637; δH (200 MHz, CDCl3) m), 4.96-5.04 (2H, m), 5.75-5.89 (1H, m), 7.37-7.46 (6H, m),
0.84 (3H, br t, J = 6.4 Hz), 1.23 (10H, m), 1.37 (2H, m), 1.47- 7.69-7.74 (4H, m); δC (50 MHz, CDCl3) 15.3, 19.6, 27.2, 41.2,
1.61 (8H, m), 1.88-1.95 (1H, m), 2.14 (1H, br s), 3.42-3.48 (1H, 63.9, 73.7, 77.7, 114.6, 127.6, 127.7, 129.8, 133.4, 136.0,
m), 3.63 (1H, t, J = 6.6 Hz), 3.90-4.11 (2H, m), 4.80-5.20 (2H, 136.1, 140.7. Anal. Found: C, 71.95; H, 8.6. Calc. for C23H32O3Si:
m), 5.62-5.85 (1H, m); δC (50 MHz, CDCl3) 14.1, 22.6, 23.8, C, 71.8; H, 8.4%.
24.0, 25.1, 27.1, 29,2, 31.3, 31.8, 35.0, 36.4, 47.2, 65.6, 74.9, (2R,3S,4R)-1-Benzoyloxy-3-tert-butyldiphenylsilyloxy-4-
77.2, 109.8, 116.7, 138.1.
methylhex-5-en-2-ol 9. To a cooled (0
C) and stirred solution
24
23
6b: colorless oil; [α]D +11.96 (c 1.8 in CHCl3), (lit.27 [α]D
of (2.58 g, 6.71 mmol) and Et3N (1.03 mL, 7.39 mmol) in
8
+12.04 (c 4.6 in CHCl3)); νmax/cm-1 3476, 1706; δH (200 MHz, CH2Cl2 (20 mL) was dropwise added BzCN (0.89 g, 6.77 mmol).
CDCl3) 0.86 (3H, t, J = 6.4 Hz), 1.21-1.26 (10H, m), 1.36-1.39 After stirring for 2 h at 0
(2H, m), 1.55-1.61 (7H, m), 1.65-1.94 (2H, m), 2.33 (1H, t, J = cold water (20 mL), the organic layer separated and the
6.8 Hz), 3.72 (1H, dd, J = 8.4, 3.4 Hz), 3.80-3.96 (2H, m), 4.08- aqueous portion extracted with CHCl3 (3 10 mL). The
4.16 (1H, m), 4.95-5.15 (2H, m), 5.42-5.65 (1H, m). δC (50 MHz, combined organic extracts were washed with water (2 10
CDCl3) 14.0, 22.5, 23.7, 23.8, 24.9, 26.7, 29,2, 30.3, 31.7, 34.8, mL) and brine (1 5 mL), and dried. Removal of solvent in
C, the mixture was poured into ice-



36.0, 47.5, 63.4, 72.5, 76.5, 109.0, 116.7, 138.5.
vacuo followed by column chromatography (silica gel, 0-15%
6c: colorless oil; [α]D24 +17.4 (c 1.2 in CHCl3), (lit.27 [α]D23 +17.71 EtOAc/hexane) of the residue afforded pure
9 (3.1 g, 95%).
(c 2.6 in CHCl3)); νmax/cm-1 3465, 913; δH (200 MHz, CDCl3) 0.87 pale yellow oil; [α]D +7.5 (c 1.08 in CHCl3); νmax/cm-1 3541,
(3H, t, J = 6.4 Hz), 1.20-1.28 (10H, m), 1.35-1.39 (2H, m), 1.54- 1716; δH (200 MHz, CDCl3) 0.89 (3H, d, J = 6.8 Hz), 1.11 (9H, s),
1.66 (8H, m), 2.15-2.39 (1H, m), 3.68 (1H, t, J = 4.6 Hz), 3.85- 2.14 (1H, br s), 2.42-2.52 (1H, m), 3.76-3.82 (1H, m), 3.89-4.07
4.10 (3H, m), 4.71 (1H, br s), 5.01-5.22 (2H, m), 5.60-5.82 (1H, (2H, m), 4.19-4.30 (1H, m), 4.87-5.07 (2H, m), 5.93-6.10 (1H,
m); δC (50 MHz, CDCl3) 14.0, 22.6, 23.8, 24.0, 25.1, 27.1, 29,2, m), 7.35-7.90 (15H, m); δC (50 MHz, CDCl3) 15.4, 15.9, 19.5,
31.0, 31.8, 34.9, 36.3, 46.4, 65.4, 73.9, 77.0, 109.0, 117.5, 27.1, 41.0, 66.6, 72.1, 77.6, 114.8, 127.5, 127.6, 128.2, 129.6,
25
137.9.
129.7, 132.9, 133.2, 133.3, 136.0, 140.1, 140.6, 166.6. Anal.
Found: C, 73.4; H, 7.6. Calc. for C30H36O4Si: C, 73.7; H, 7.4%.
(3R,4S,5R)-4-tert-Butyldiphenylsilyloxy-5,6-cyclohexylidene-
dioxy-3-methylhexene 7. To a cooled (-30
solution of 2b (2.22 g, 9.81 mmol), imidazole (1.00 g, 14.71
mmol) and DMAP (catalytic) in CH2Cl2 (20 mL) was dropwise mL, 9.21 mmol) in CH2Cl2 (20 mL) was injected MsCl (0.71 mL,
added TBDPSCl (3.01 mL, 11.77 mmol). After stirring for 7 h at 9.21 mmol). After stirring for 1 h at 0 C, the mixture was
room temperature, the mixture was poured into ice-cold water poured into ice-cold water (20 mL), the organic layer
(20 mL), the organic layer separated and the aqueous portion separated and the aqueous portion extracted with CHCl3 (3
extracted with CHCl3 (3 10 mL). The combined organic 10 mL). The combined organic extracts were washed with
extracts were washed with water (2 10 mL) and brine (1 water (2 10 mL) and brine (1 5 mL), and dried. Removal of

C) and stirred (3R,4R)-4-Methylhex-5-ene-1,3-diol (3R,4R)-10. To a cooled (0

C) and stirred solution of (3.00 g, 6.14 mmol) and Et3N (1.28
9





5


mL), and dried. Removal of solvent in vacuo followed by solvent in vacuo afforded the crude mesylate as a pale-yellow
column chromatography (silica gel, 0-5% EtOAc/hexane) of the oil, which was used as such for the next step.
residue afforded pure
7
(4.2 g, 92%). colorless thick liquid;
To a stirred suspension of LiAlH4 (530 mg, 13.82 mmol) in
[α]D25 +2.2 (c 1.45 in CHCl3); νmax/cm-1 1638, 999; δH (200 MHz, THF (30 mL) under Ar was added the above mesylate (3.19 g,
CDCl3) 0.93 (3H, d, J = 7.0 Hz), 1.05 (9H, s), 1.24-1.35 (2H, m), 5.64 mmol) in THF (30 mL). After the evolution of H2 subsided,
1.36-1.56 (8H, m), 2.28-2.39 (1H, m), 3.59-3.67 (1H, m), 3.74- the mixture was refluxed for 24 h, brought to room
3.88 (2H, m), 4.00-4.07 (1H, m), 4.89-5.01 (2H, m), 5.80-5.97 temperature, treated with aqueous saturated Na2SO4 and
(1H, m), 7.33-7.44 (6H, m), 7.67-7.74 (4H, m); δC (50 MHz, filtered. The solid residue was thoroughly washed with Et2O,
12 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
Page 13 of 19
Journal Name
ARTICLE
the combined organic filtrates concentrated in vacuo to obtain column chromatography (silica gel, 0-10% EtOAVci/ewheAxrtiaclneeO)nlionef
DOI: 10.1039/C7OB00626H
a residue, which on column chromatography (silica gel, 0-25% the residue afforded pure 12 (194 mg, 87%). colorless thick
25
Et2O/hexane) afforded pure (3R,4R)-10 (692 mg, 87% in two liquid; [α]D +8.3 (c 1.04 in CHCl3); νmax/cm-1 3467; δH (200
25
steps). colorless liquid; [α]D +3.2 (c 1.64 in CHCl3); νmax/cm-1 MHz, CDCl3) 0.12 (6H, s), 0.94 (9H, s), 1.08 (3H, d, J = 6.8 Hz),
3385, 997; δH (200 MHz, CDCl3) 1.02 (3H, d, J = 6.8 Hz), 1.61- 1.63-1.73 (2H, m), 2.20-2.43 (1H, m), 2.50 (1H, br s), 3.63-3.97
1.71 (2H, m), 2.20-2.31 (1H, m), 3.21 (2H, br s), 3.64-3.84 (3H, (3H, m), 4.99-5.15 (2H, m), 5.79-5.97 (1H, m); δC (50 MHz,
m), 4.88-5.12 (2H, m), 5.65-5.83 (1H, m); δC (50 MHz, CDCl3) CDCl3) -5.4, 15.7, 18.1, 18.3, 25.8, 35.5, 43.9, 62.8, 75.0, 115.1,
15.3, 27.2, 41.2, 63.9, 73.7, 114.6, 140.7. Anal. Found: C, 64.5; 140.7. Anal. Found: C, 63.7; H, 11.75. Calc. for C13H28O2Si: C,
H,10.7. Calc. for C7H14O2: C, 64.6; H, 10.8%.
63.9; H, 11.55%.
(3R,4S)-4,6-Diacetoxy-3-methylhex-1-ene 11. Mesylation of (4R,5S)-7-tert-Butyldimethylsilyloxy-5-hydroxy-4-methylhept-
(3R,4R)-10 (650 mg, 5.00 mmol) with MsCl (1.4 mL, 18.02 2E-enal 13. A mixture of 12 (136 mg, 0.56 mmol), acrolein
mmol) and Et3N (2.8 mL, 20.05 mmol) in CH2Cl2 (30 mL) (0.22 mL, 3.34 mmol) and Hoveyda-Grubbs II catalyst (18 mg, 5
o
followed by isolation as above afforded the corresponding mol%) in CH2Cl2 (30 mL) was refluxed at 40 C for 8 h. After
dimesylate as a yellow oil. A mixture of the dimesylate and concentrating the mixture in vacuo, the residue was subjected
KOAc (5.48 g, 55.88 mmol) in dry DMF (40 mL) was to preparative thin layer chromatography (silica gel, 10%
o
magnetically stirred at 130 C for 22 h. The reaction mixture EtOAc/hexane) to get pure 13 (136 mg, 89%). pale yellow
24
was brought to room temperature, poured into ice-cold water liquid; [α]D +10.0 (c 1.12 in CHCl3); νmax/cm-1 3463, 2720,
(100 mL) and extracted with EtOAc (3

30 mL). The organic 1686; δH (200 MHz, CDCl3) 0.06 (6H, s), 0.87 (9H, s), 1.13 (3H,
d, J = 6.8 Hz), 1.59-1.69 (2H, m), 2.46-2.56 (1H, m), 3.75-3.94
extract was washed with water (2 10 mL) and brine (1

 5
mL), and dried. Removal of solvent followed by column (4H, m), 6.12 (1H, dd, J = 15.6, 7.8 Hz), 6.97 (1H, dd, J = 15.6,
chromatography of the residue (silica gel, 0-20% 7.8 Hz), 9.51 (1H, d, J = 7.8 Hz); δC (50 MHz, CDCl3) -4.9, 16.4,
EtOAc/hexane) furnished 11 (913 mg, 84% in two steps). 18.8, 26.5, 36.5, 43.9, 63.8, 76.3, 133.6, 161.3, 195.0. Anal.
25
colorless oil; [α]D -13.4 (c 1.12 in CHCl3); νmax/cm-1 1735, Found: C, 61.6; H, 10.5. Calc. for C14H28O3Si: C, 61.7; H, 10.4%.
1240; δH (200 MHz, CDCl3) 0.99 (3H, d, J = 6.8 Hz), 1.76-1.87 Ethyl
(6R,7S)-9-tert-Butyldimethylsilyloxy-7-hydroxy-6-
o
(2H, m), 2.02 (6H, s), 2.30-2.47 (1H, m), 4.04 (2H, t, J = 6.4 Hz), methylnona-2Z,4E-dienoate 14. To a cooled (0 C) and stirred
4.90-5.09 (3H, m), 5.59-5.78 (1H, m); δC (50 MHz, CDCl3) 15.4, suspension of hexane-washed NaH (34 mg, 0.72 mmol, 50%
20.7, 20.8, 30.2, 41.5, 60.7, 73.1, 115.7, 138.8, 170.4, 170.8; suspension in oil) in THF (5 mL) was added ethyl
Anal. Found: C, 61.5; H, 8.8. Calc. for C11H18O4: C, 61.7; H, diphenylphosphonoacetate (192 mg, 0.60 mmol) in THF (10
8.5%.
mL). After 1 h, the mixture was brought to -78 oC, and a
(3S,4R)-4-Methylhex-5-ene-1,3-diol (3S,4R)-10. A mixture of solution of 13 (120 mg, 0.44 mmol) in THF (5 mL) was injected
11 (240 mg, 1.12 mmol) and K2CO3 (380 mg, 2.68 mmol) in into it. After 3 h, the mixture was poured into ice-cold water
MeOH (15 mL) was stirred at room temperature for 2 h. The (10 mL) and extracted with Et2O (3
mixture was filtered, concentrated in vacuo, diluted with H2O extracts washed with water (2 5 mL) and brine (1
(20 mL), and extracted with EtOAc (2 20 mL). The combined dried, concentrated in vacuo, and the residue purified by
organic extracts were washed with H2O (2 10 mL) and brine preparative thin layer chromatography (silica gel, 10%
(1

10 mL), the organic


5 mL),



5 mL), and dried. Removal of solvent in vacuo followed by Et2O/hexane) to obtain pure 14 (106 mg, 71%). colorless liquid;
24
column chromatography of the residue (silica gel, 0-15% [α]D +4.8 (c 1.05 in CHCl3); νmax/cm-1 3470, 1709; δH (200
EtOAc/hexane) afforded pure (3S,4R)-10 (124 mg, 85%). MHz, CDCl3) 0.11 (6H, s), 0.93 (9H, s), 1.15 (3H, d, J = 7.0 Hz),
25
colorless oil; [α]D +20.5 (c 1.12 in CHCl3); νmax/cm-1 3409, 1.33 (3H, t, J = 7.2 Hz), 1.62-1.73 (2H, m), 2.34-2.49 (1H, m),
1063; δH (200 MHz, CDCl3) 1.01 (3H, d, J = 6.8 Hz), 1.54-1.72 2.84 (1H, br s), 3.78-3.99 (3H, m), 4.21 (2H, q, J = 7.2 Hz), 5.62
(2H, m), 2.12-2.33 (1H, m), 3.00-3.12 (2H, br m), 3.58-3.68 (1H, (1H, d, J = 11.4 Hz), 6.18 (1H, dd, J = 15.4, 8.2 Hz), 6.62 (1H, t, J
m), 3.73-3.84 (2H, m), 4.89-5.12 (2H, m), 5.64-5.82 (1H, m); δC = 11.4 Hz), 7.44 (1H, dd, J = 15.4, 11.2 Hz); δC (50 MHz, CDCl3) -
(50 MHz, CDCl3) 15.8, 35.2, 44.5, 61.5, 74.7, 116.4, 140.1; Anal. 4.8, 15.1, 16.9, 18.9, 26.6, 36.6, 44.0, 60.6, 63.8, 78.4, 116.8,
Found: C, 64.3; H, 10.7. Calc. for C7H14O2: C, 64.6; H, 10.8%.
127.8, 146.0, 147.7, 167.3. Anal. Found: C, 63.0; H,10.1%.
To ascertain the enantiomeric purity of (3S,4R)-10, A part of it Calcd. for C18H34O4Si: C, 63.1; H, 10.0%.
was monosilylated with TBDPSCl/Et3N/DMAP, purified and (2R/S,3R,4S,5R)-4-tert-Butyldiphenylsilyloxy-5,6-
subjected to chiral HPLC. HPLC (isopropanol/hexane 5/95 @ cyclohexylidenedioxy-3-methylhexane-1,2-diol 15. To
a
0.5 mL/min, λ = 254 nm): Rt = 8.53 min.
stirred solution of
7 (5.00 g, 10.76 mmol) and NMO (2.91 g,
(3S,4R)-1-tert-Butyldimethylsilyloxy-4-methylhex-5-en-3-ol
21.52 mmol) in acetone:water (8:1) was added a solution of
12. To a stirred solution of (3S,4R)-10 (120 mg, 0.92 mmol), OsO4 (140 mg, 0.54 mmol) in tert-butanol (0.5 mL). After
Et3N (192 µL, 1.38 mmol) and DMAP (catalytic) in CH2Cl2 (20 stirring the mixture for 6 h at room temperature, the reaction
mL) was added TBSCl (138 mg, 0.92 mmol). After stirring for 7 was quenched with aqueous saturated NaHSO3, concentrated
h at room temperature, the mixture was poured into ice-cold in vacuo, the residue diluted with H2O (20 mL) and extracted
water (20 mL), the organic layer separated, and the aqueous with EtOAc (3
portion extracted with CHCl3 (3 10 mL). The combined H2O (2 10 mL) and brine (1
organic extracts were washed with H2O (2 10 mL) and brine solvent in vacuo followed by column chromatography of the
(1 5 mL), and dried. Removal of solvent in vacuo followed by residue (silica gel, 0-30% EtOAc/hexane) afforded pure 15 (5.3

20 mL). The organic extract was washed with



5 mL), and dried. Removal of


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J. Name., 2013, 00, 1-3 | 13
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
25
g, 98%). thick liquid; [α]D +22.4 (c 1.20 in CHCl3); νmax/cm-1 CHCl3); νmax/cm-1 3409, 3024; δH (200 MHz, CDCl3) 1.04-1.09
View Article Online
3448, 1060; δH (200 MHz, CDCl3) 0.89 (3H, d, J = 7.0 Hz), 1.06 (12H, merged s and d, J = 7.2 Hz), 2.39 (2DHO,Ib: 1r0s.1)0, 329.5/C07-O2B.60206(216HH,
(9H, s), 1.25-1.52 (10H, m), 1.91-2.05 (1H, m), 2.30 (2H, br s), m), 3.62-3.74 (3H, m), 3.79-3.84 (1H, m), 6.14 (1H, dd, J = 16.0,
3.26-3.46 (2H, m), 3.58-3.73 (2H, m), 3.77-3.85 (1H, m), 3.93- 7.2 Hz), 6.29 (1H, d, J = 16.0 Hz), 7.14-7.30 (5H, m), 7.32-7.49
3.97 (1H, m), 4.16-4.26 (1H, m), 7.35-7.49 (6H, m), 7.63-7.75 (6H, m), 7.67-7.70 (4H, m); δC (50 MHz, CDCl3) 15.8, 19.7, 27.2,
(4H, m); δC (50 MHz, CDCl3) 10.7, 11.6, 19.3, 19.5, 23.8, 25.0, 40.2, 63.4, 73.3, 78.7, 126.0, 127.0, 127.6, 127.7, 128.4, 129.7,
27.0, 34.4, 34.6, 36.0, 38.6, 64.9, 67.9, 73.2, 76.0, 77.2, 109.4, 129.8, 129.9, 132.7, 133.2, 133.4, 136.1, 136.2, 137.4. Anal.
127.6, 127.7, 127.8, 129.9, 130.2, 132.7, 133.2, 133.4, 135.9, Found: C, 75.8; H, 7.8. Calc. for C29H36O3Si: C, 75.6; H, 7.9%.
136.1. Anal. Found: C, 70.0; H, 8.65. Calc. for C29H42O5Si: C, (2R,3S,4R)-1-Benzoyloxy-3-tert-butyldiphenylsilyloxy-4-
69.8; H, 8.5%.
methyl-6-phenylhex-5E-en-2-ol 19. Benzoylation of 18 (3.06 g,
(2S,3S,4R)-3-tert-Butyldiphenylsilyloxy-4,5-
6.64 mmol) with BzCN (870 mg, 6.65 mmol) and Et3N (1.02 mL,
cyclohexylidenedioxy-2-methylpentanal 16. To a cooled (10 7.32 mmol) in CH2Cl2 (20 mL) at 0 C, followed by isolation and
oC) and stirred solution of 15 (5.16 g, 10.35 mmol) in aqueous column chromatography (silica gel, 0-15% EtOAc/hexane)
60% CH3CN (20 mL) was added NaIO4 (3.32 g, 15.52 mmol) in afforded pure 19 (3.5 g, 93%). colorless oil; [α]D25 +65.8 (c 1.17
portions. After stirring for 2 h at 25 oC, the mixture was in CHCl3); νmax/cm-1 3471, 1709, 1602; δH (200 MHz, CDCl3) 1.13
filtered, the filtrate treated with aqueous 10% NaHSO3 and (12H, m), 2.30 (1H, br s), 2.57-2.73 (1H, m), 3.87-3.90 (1H, m),
thoroughly extracted with CHCl3 (3

10 mL). The organic 3.92-4.09 (1H, m), 4.36-4.46 (1H, m), 4.54-4.61 (1H, m), 6.16
5 mL), (1H, dd, J = 16.0, 7.2 Hz), 6.31 (1H, d, J = 16.0 Hz), 7.13-7.22
extract was washed with H2O (2 10 mL) and brine (1


and concentrated in vacuo to get a residue, which on column (5H, m), 7.25-7.41 (8H, m), 7.45-7.60 (1H, m), 7.70-7.74 (4H,
chromatography (silica gel, 0-10% EtOAc/hexane) furnished m), 7.95 (2H, d, J = 7.4 Hz); δC (50 MHz, CDCl3) 15.3, 19.7, 27.2,
pure 16 (4.1 g, 85%). colorless liquid; νmax/cm-1 2721, 1722; δH 40.2, 66.5, 72.2, 78.4, 126.0, 126.9, 127.5, 127.6, 128.2, 128.3,
(200 MHz, CDCl3) 0.95 (9H, s), 1.20 (3H, d, J = 7.2 Hz), 1.24-1.52 129.6, 129.8, 130.0, 132.6, 133.0, 133.5, 136.1, 136.2, 137.4,
(10H, m), 2.62-2.74 (1H, m), 3.40-3.46 (1H, m), 3.73-3.80 (1H, 166.8. Anal. Found: C, 76.7; H, 7.3. Calc. for C36H40O4Si: C, 76.6;
m), 4.06-4.19 (2H, m), 7.37-7.43 (6H, m), 7.62-7.69 (4H, m), H, 7.1%.
9.54 (1H, s); δC (50 MHz, CDCl3) 7.3, 19.4, 23.7, 23.8, 25.0, 26.8, (3R,4R)-4-Methyl-6-phenylhex-5E-ene-1,3-diol
34.5, 36.1, 49.9, 67.6, 73.8, 75.9, 109.6, 127.5, 127.8, 129.8, Mesylation of 19 (2.97 g, 5.26 mmol) with MsCl (0.61 mL, 7.90
130.1, 132.1, 133.3, 135.8, 136.1, 204.3. Anal. Found: C, 72.2; mmol) and Et3N (1.10 mL, 7.90 mmol) in CH2Cl2 (20 mL) at 0 C,
followed by isolation afforded the crude mesylate as a pale
(3R,4R)-20.

H, 8.45. Calc. for C28H38O4Si: C, 72.1; H, 8.2%.
(3R,4S,5R)-4-tert-Butyldiphenylsilyloxy-5,6-cyclohexylidene-
yellow oil. The above compound was reduced with LiAlH4 (0.39
dioxy-3-methyl-1-phenylhex-1E-ene 17. To a cooled (-78 oC) g, 10.31 mmol) in THF (30 mL) to obtain pure (3R,4R)-20 (977
and stirred solution of diethyl benzylphosphonate (2.63 mL, mg, 91%) after column chromatography (silica gel, 0-30%
25
12.61 mmol) in THF (20 mL) was injected n-BuLi (6.57 mL, Et2O/hexane). colorless thick liquid; [α]D +56.9 (c 1.03 in
10.51 mmol, 1.6 M in hexane). After stirring for 1 h at -78 oC, a CHCl3); νmax/cm-1 3399; δH (200 MHz, CDCl3) 1.14 (3H, d, J = 6.8
solution of 16 (4.00 g, 8.57 mmol) in THF (15 mL) was dropwise Hz), 1.63-1.77 (2H, m), 2.52-2.72 (3H, m), 3.73-3.87 (3H, m),
added into the mixture, stirring continued at -78 oC for 1 h, the 6.02 and 6.13 (1H, two overlapping dd, J = 15.8, 8.6 Hz and
mixture brought to room temperature and stirred further for 6 16.0, 8.0 Hz), 6.43 (1H, dd, J = 16.0, 2.2 Hz), 7.16-7.38 (5H, m);
h. Following addition of aqueous saturated NH4Cl (5 mL), the δC (50 MHz, CDCl3) 16.4, 35.4, 44.1, 61.7, 75.4, 126.0, 126.1,
mixture was extracted with Et2O (3
organic extracts washed with H2O (1


40 mL), the combined 127.3, 128.5, 131.6, 131.7, 137.0. Anal. Found: C, 76.0; H, 8.5.
30 mL) and brine (1 Calc. for C13H18O2: C, 75.7; H, 8.8%.
 5
mL), dried, and concentrated in vacuo. The residue was (3R,4S)-4,6-Diacetoxy-3-methyl-1-phenylhex-1E-ene
21.
purified by column chromatography (silica gel, 0-5% Mesylation of (3R,4R)-20 (450 mg, 2.18 mmol) with MsCl (0.51
EtOAc/hexane) to give pure 17 (4.1 g, 88%). viscous liquid; mL, 6.56 mmol) and Et3N (1.06 mL, 7.43 mmol) in CH2Cl2 (20
25
[α]D +122.8 (c 1.04 in CHCl3); νmax/cm-1 3051, 3023, 980; δH mL) at 0
C, followed by isolation afforded the crude
(200 MHz, CDCl3) 1.05-1.12 (12H, merged s and d, J = 7.2 Hz), dimesylate as a yellow oil. This was heated with KOAc (2.22 g,
o
1.38-1.40 (2H, m), 1.51-1.54 (8H, m), 2.52-2.58 (1H, m), 3.64- 22.65 mmol) in DMF (30 mL) at 130 C to furnish 21 (475 mg,
3.72 (1H, m), 3.82-3.90 (2H, m), 4.08-4.19 (1H, m), 6.23-6.25 75%) after column chromatography (silica gel, 0-20
%
25
(2H, m), 7.17-7.44 (11H, m), 7.69-7.72 (4H, m); δC (50 MHz, EtOAc/hexane). colorless liquid; [α]D -12.5 (c 1.05 in CHCl3);
CDCl3) 14.2, 19.6, 23.8, 23.9, 25.2, 27.1, 34.6, 36.1, 40.1, 66.9, νmax/cm-1 3020, 1732, 1217; δH (200 MHz, CDCl3) 1.10 (3H, d, J
76.0, 78.1, 108.9, 126.0, 126.8, 127.4, 127.5, 128.4, 129.7, = 6.8 Hz), 1.85-2.07 (8H, m containing two s at δ 2.04 and
132.8, 133.4, 133.8, 136.2, 137.6. Anal. Found: C, 77.9; H, 8.25. 2.06), 2.41-2.65 (1H, m), 3.99-4.12 (2H, m), 4.93-5.19 (1H, m),
Calc. for C35H44O3Si: C, 77.7; H, 8.2%.
(2R,3S,4R)-3-tert-Butyldiphenylsilyloxy-4-methyl-6-
6.07 (1H, dd, J = 15.8, 8.2 Hz), 6.38 (1H, dd, J = 15.8, 9.6 Hz),
7.14-7.36 (5H, m); δC (50 MHz, CDCl3) 16.3, 20.9, 30.6, 37.5,
phenylhex-5E-ene-1,2-diol 18. Compound 17 (3.98 g, 7.36 41.3, 60.9, 70.0, 126.0, 126.1, 128.4, 128.5, 130.6, 131.1,
mmol) was deacetalized at 0 °C with aqueous 80% TFA (10 mL) 135.1, 137.1, 170.4, 170.6. Anal. Found: C, 70.6; H, 7.65. Calc.
in CH2Cl2 and worked up as above to obtain pure 18 (3.1 g, for C17H22O4: C, 70.3; H, 7.6%.
91%) after column chromatography (silica gel, 0-5% (3S,4R)-4-Methyl-6-phenylhex-5-ene-1,3-diol
MeOH/CHCl3). colorless thick liquid; [α]D +102.2 (c 1.02 in Hydrolysis of 21 (300 mg, 1.03 mmol) with K2CO3 (314 mg, 2.27
(3S,4R)-20.
26
14 | J. Name., 2012, 00, 1-3
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mmol) in MeOH (15 mL) at room temperature, followed by 5.02-5.15 (2H, m), 5.80-6.00 (1H, m), 7.35-7.39 (5H, m); δC (50
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isolation and column chromatography (silica gel, 0-30% MHz, CDCl3) 16.9, 23.8, 23.9, 25.1, 34.7,D3O6I:.210, .41003.97/,C675O.B60,076226.0H,
EtOAc/hexane) afforded pure (3S,4R)-20 (190 mg, 89%). 74.3, 83.1, 108.7, 114.9, 127.5, 127.6, 128.1, 138.2, 138.6,
colorless viscous liquid; [α]D25 +28.1 (c 1.01 in CHCl3); νmax/cm-1 140.1. Anal. Found: C 75.9, H 8.9. Calc. for C20H28O3: C 75.9, H
3408, 1071; δH (200 MHz, CDCl3) 1.12 (3H, d, J = 6.8 Hz), 1.40- 8.9%;
1.69 (2H, m), 1.78 (2H, br s), 2.43-2.57 (1H, m), 3.40-3.50 (1H, (2R,3S,4R)-3-Benzyloxy-4-methylhex-5-ene-1,2-diol 24.
A
m), 3.60-3.70 (1H, m), 3.75-3.89 (1H, m), 6.13 (1H, dd, J = 16.0, mixture of 23 (3.00 g, 9.48 mmol) and HCl in MeOH (5 mL, 2N)
8.0 Hz), 6.40 (1H, d, J = 16.0 Hz), 7.16-7.35 (5H, m); δC (50 MHz, was stirred at 25 oC till completion of the reaction (cf. TLC, 6 h).
CDCl3) 20.5, 34.1, 40.1, 66.6, 70.5, 126.0, 127.0, 128.3, 128.4, Most of the solvent was removed in vacuo, the residue diluted
128.5, 136.1, 137.4. Anal. Found: C, 75.7; H, 8.9. Calc. for with H2O (30 mL) and extracted with EtOAc (3
C13H18O2: C, 75.7; H, 8.8%.

20 mL). The
combined organic extracts were washed successively with H2O
10 mL), aqueous 10% NaHCO3 (2 10 mL), H2O (2 10
5 mL), and dried. Solvent removal in vacuo
Ethyl (2E,7E,5S,6R)-5-Hydroxy-6-methyl-8-phenylocta-2E,7E- (3



dienoate 22. To a solution of (3S,4R)-20 (164 mg, 0.80 mmol) mL) and brine (1

and TEMPO (12 mg, 0.08 mmol) in CH3CN (20 mL) was added followed by column chromatography (silica gel, 0-5%
BAIB (334 mg, 1.04 mmol) and the mixture stirred at room MeOH/CHCl3) of the residue gave pure 24 (1.8 g, 80%). viscous
o
23
temperature for 2 h. The mixture was cooled to 0 C, treated liquid; [α]D +31.5 (c 1.25 in CHCl3); νmax/cm-1 3399, 1629,
with the ylide generated from triethyl phosphonoacetate (534 914; δH (200 MHz, CDCl3) 1.12 (3H, d, J = 7.0 Hz), 2.52-2.64 (3H,
mg, 2.38 mmol) and hexane-washed NaH (172 mg, 3.58 mmol, m), 3.43-3.48 (1H, m), 3.64-3.78 (3H, m), 4.56 (1H, d, J = 11.2
50% dispersion in oil) in THF (10 mL), and stirred for an Hz), 4.67 (1H, d, J = 11.2 Hz), 5.05-5.15 (2H, m), 5.85-6.03 (1H,
additional 1 h at room temperature. The reaction was m), 7.32-7.34 (5H, m); δC (50 MHz, CDCl3) 17.1, 39.5, 63.4,
quenched with aqueous saturated Na2S2O3, the mixture 72.1, 74.3, 83.6, 114.9, 127.4, 128.0, 138.1, 139.9. Anal. Found:
concentrated in vacuo, water (10 mL) added into it, and C 71.1, H 8.6. Calc. for C14H20O3: C 71.2, H 8.5%;
extracted with EtOAc (2

20 mL). The organic layer was (2S,3R)-2-Benzyloxy-3-methyl-4-pentenal 25. Reaction of 24
5 mL), and dried. (1.50 g, 6.35 mmol) with NaIO4 (2.72 g, 12.70 mmol) in MeCN-
washed with water (2 10 mL) and brine (1


Removal of solvent in vacuo followed by column H2O (6:4, 20 mL), followed by usual isolation and purification
chromatography of the residue (silica gel, 0-30% by column chromatography (silica gel, 0-10% Et2O/hexane)
25
EtOAc/hexane) afforded pure 22 (138 mg, 63%). colorless oil; gave pure 25 (1.26 g, 97%). colorless oil; [α]D -47.6 (c 1.14 in
23
23
[α]D +58.9 (c 1.05 in CHCl3) (lit.38f [α]D +62.8 (c 1.06 in CHCl3); νmax/cm-1 2962, 1731; δH (200 MHz, CDCl3) 1.12 (3H, d, J
CHCl3)); νmax/cm-1 3406, 1730; δH (200 MHz, CDCl3) 1.11 (3H, d, = 7.0 Hz), 2.61-2.78 (1H, m), 3.63-3.67 (1H, m), 4.52 (1H, d, J =
J = 6.6 Hz), 1.27 (3H, t, J = 7.0 Hz), 1.67 (1H, br s), 2.21-2.35 12.0 Hz), 4.71 (1H, d, J = 12.0 Hz), 5.05-5.13 (2H, m), 5.79-5.97
(2H, m), 2.39-2.54 (1H, m), 3.87-3.96 (1H, m), 4.17 (2H, q, J = (1H, m), 7.32-7.38 (5H, m), 9.63 (1H, d, J = 2.4 Hz); δC (50 MHz,
7.2 Hz), 5.83 (1H, d, J = 15.6 Hz), 6.11 (1H, dd, J = 15.8, 7.2 Hz), CDCl3) 15.9, 39.6, 72.7, 86.5, 115.8, 127.8, 128.3, 137.2, 138.0,
6.37 (1H, d, J = 15.8 Hz), 6.87-7.02 (1H, m), 7.19-7.36 (5H, m); 203.6. Anal. Found: C 76.4, H 7.9. Calc. for C13H16O2: C 76.4, H
δC (50 MHz, CDCl3) 14.2, 20.1, 36.4, 39.6, 60.2, 73.8, 122.8, 7.9%;
126.1, 127.1, 128.5, 128.9, 134.9, 137.4, 147.2, 166.5. Anal. (3R,4S)-4-Benzyloxy-3-methylnona-1,5E/Z-diene 26. To
Found: C, 74.55; H, 8.1. Calc. for C17H22O3: C,74.4; H, 8.1%.. cooled (-40 C) and stirred suspension of n-BuPPh3Br (3.60 g,
HPLC (isopropanol/hexane 5/95 @ 1.0 mL/min, λ = 254 nm): Rt 9.05 mmol) in THF (30 mL) was added n-BuLi (6.0 mL, 9.0
a
o
= 5.71 min.
mmol, 1.5 M in hexane). After stirring the mixture for 0.5 h, 25
(3R,4S,5R)-4-Benzyloxy-5,6-cyclohexylidenedioxy-3-
(1.20 g, 5.88 mmol) in THF (10 mL) was added. The mixture
methylhex-1-ene 23. To a stirred suspension of NaH (586 mg, was stirred at the same temperature for 3 h and at room
50% suspension in oil, 12.21 mmol) in THF (20 mL) was added temperature for 12 h, poured into ice-cold water (25 mL) and
2b (2.30 g, 10.17 mmol)) in THF (10 mL) under Ar. After the extracted with EtOAc (3
evolution of H2 subsided, the mixture was refluxed for 1 h, extracts were washed successively with water (2
brought to room temperature, and a mixture of Bu4NI (10 brine (1 5 mL), and dried. Solvent removal in vacuo followed

15 mL). The combined organic

10 mL) and

mol%) and BnBr (1.45 mL, 12.20 mmol) in THF (10 mL) by column chromatography (silica gel, 0-10% EtOAc/hexane) of
dropwise added. The mixture was refluxed till consumption of the residue gave pure 26 (1.1 g, 77%). colorless oil; [α]D22 -13.3
2b (cf. TLC, ~4 h), brought to room temperature, and treated (c 1.10 in CHCl3); νmax/cm-1 3020, 1519; δH (200 MHz, CDCl3)
with ice-cold H2O (30 mL). The organic layer was separated, 0.91 (3H, t, J = 7.4 Hz), 1.00 (3H, d, J = 7.0 Hz), 1.24-1.45 (2H,
the aqueous portion extracted with Et2O (3
combined organic extracts were washed successively with H2O 4.33 (1H, d, J = 12.0 Hz), 4.59 (1H, d, J = 12.0 Hz), 4.95-5.10
(2 10 mL) and brine (1 5 mL), and dried. Solvent removal (2H, m), 5.26-5.42 (1H, m), 5.60-5.72 (1H, m), 5.80-5.99 (1H,
 15 mL). The m), 1.94-2.02 (2H, m), 2.32-2.45 (1H, m), 3.88-4.00 (1H, m),


followed by column chromatography (silica gel, 0-10% m), 7.28-7.34 (5H, m); δC (50 MHz, CDCl3) 13.7, 15.7, 22.7,
EtOAc/hexane) of the residue furnished 23 (3.1 g, 96%). 29.8, 42.6, 69.6, 77.4, 114.1, 127.1, 127.4, 128.0, 128.3, 128.8,
27
colorless oil; [α]D +22.7 (c 1.23 in CHCl3); νmax/cm-1 3060, 134.2, 138.9, 141.0. Anal. Found: C 83.6, H 9.9. Calc. for
1644; δH (200 MHz, CDCl3) 1.12 (3H, d, J = 7.0 Hz), 1.39-1.50 C17H24O: C 83.55, H 9.9%;
(2H, m), 1.59-1.70 (8H, m), 2.48-2.58 (1H, m), 3.56-3.61 (1H, Ethyl (4R,5S)-5-Benzyloxy-4-methyldeca-2E,6E/Z-dienoate 27.
m), 3.84-4.04 (2H, m), 4.09-4.19 (1H, m), 4.55-4.77 (2H, m), A mixture of 26 (1.00 g, 4.10 mmol), ethyl acrylate (2.13 mL,
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Journal Name
Berlin, 1990; (b) D. M. Tapiolas, M. Roman, W. Fenical, T. J.
20.00 mmol) and Hoveyda-Grubbs II catalyst (31 mg, 5 mol%)
in CH2Cl2 (5 mL) was stirred for 2 h. After concentrating the
mixture in vacuo, the residue was subjected to column
chromatography (silica gel, 0-15% EtOAc/hexane) to give pure
Stout and J. Clardy, J. Am. Chem. Soc. 1991,
DOI: 101.11033,9Vi/4eCw678AOr2tBi–c0l4e06O682nl36inH.e
3. (a) R. A. Batey, A. N. Thadani, D. V. Smil and A. J. Lough,
Synthesis 2000, 990–998; (b) M. Sui and J. S. Panek, Org. Lett.
2001, 3, 2439–2442; (c) T. Hu, N. Takenaka and J. S. Panek, J.
26
27 (1.1 g, 85%). colorless oil; [α]D -7.6 (c 1.29 in CHCl3);
Am. Chem. Soc. 2002, 124, 12806–12815; (d) S. R. Chemler
and W. R. Roush, J. Org. Chem. 2003, 68, 1319–1333; (e) T.
Hirashita, T. Kamei, M. Satake, T. Horie, H. Shimizu and S.
νmax/cm-1 1714, 977; δH (500 MHz, CDCl3) 1.09 (3H, d, J = 7.0
Hz), 1.29-1.33 (6H, m merged with t at δ 1.31, J = 7.0 Hz), 1.37-
1.39 (2H, m), 1.95-1.99 (2H, m), 2.57-2.61 (1H, m), 4.15-4.19
(1H, m), 4.25 (2H, q, J = 7.0 Hz), 4.33-4.35 (1H, m), 4.59-4.62
(1H, m), 5.21-5.31 (1H, m), 5.67-5.71 (1H, m), 5.79-5.83 (1H,
m), 6.97 (1H, dd, J = 15.8, 7.4 Hz), 7.25-7.28 (1H, m), 7.31-7.35
(4H, m); δC (125 MHz, CDCl3) 14.4, 15.1, 22.2, 22.9, 30.7, 41.6,
61.5, 70.3, 83.4, 119.2, 121.4, 121.6, 127.6, 127.8, 128.2,
128.4, 128.5, 133.8, 135.4, 136.3, 138.6, 150.6, 165.2. Anal.
Found: C 75.9, H 9.0. Calc. for C20H28O3: C 75.9, H 8.9%;
Araki, Org. Biomol. Chem. 2003,
1, 3799–3803; (f) J. R. Zbieg,
J. Moran and M. J. Krische, J. Am. Chem. Soc. 2011, 133
,
10582–10586; (g) J. R. Zbieg, E. Yamaguchi, E. L. McInturff
and M. J. Krische, Science 2012, 336, 324–327; (h) Y. Huang,
L. Yang, P. Shao and Y. Zhao, Chem. Sci. 2013, 4, 3275–3281.
4. (a) V. Nair, S. Ros, C. N. Jayan and B. S. Pillai, Tetrahedron
2004, 60, 1959–1982; (b) J. Augé, N. Lubin-Germain and J.
Uziel, Synthesis 2007, 1739–1764; (c) S. Araki, H. Ito and Y.
Butsugan, Appl. Organomet. Chem. 1988, 2, 475–478; (d) J.
Nokami, M. Ohga, H. Nakamoto, T. Matsubara, I. Hussain and
K. Kataoka, J. Am. Chem. Soc. 2001, 123, 9168–9169; (e) P.C.
Andrews, A. C. Peatt, C. L. Raston, Tetrahedron Lett. 2004,
45, 243–248; (f) S. Hayashi, K. Hirano, H. Yorimitsu, K.
Ethyl (4R,5R)-5-Hydroxy-4-methyldecanoate 28. A mixture of
27 (1.00 g, 3.16 mmol) and 10% Pd-C (50 mg) in EtOH (10 mL)
was stirred at room temperature under a slight positive
pressure of H2 for 6 h. The mixture was diluted with Et2O (25
mL), filtered through a 1” pad of florisil and the filtrate
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 0-15% EtOAc/hexane) to give pure
28 (690 mg, 95%). colorless oil; [α]D25 +24.3 (c 1.10 in CHCl3);
νmax/cm-1 3453, 1720; δH (500 MHz, CDCl3) 0.95 (3H, d, J = 7.0
Hz), 1.00 (3H, t, J = 7.5 Hz), 1.23-1.26 (8H, m), 1.44-1.49 (1H,
m), 1.51-1.57 (2H, m), 1.64-1.73 (2H, m), 1.97-2.08 (2H, m),
2.51-2.54 (2H, m), 4.14 (2H, q, J = 7.2 Hz), 4.18-4.22 (1H, m); δC
(125 MHz, CDCl3) 10.2, 12.5, 14.3, 25.2, 26.3, 26.9, 29.1, 29.3,
29.9, 60.9, 84.7, 172.6. Anal. Found: C 67.5, H 11.5. Calc. for
C13H26O3: C 67.8, H 11.4%;
Oshima, Org. Lett. 2005, 7, 3577–3579; (g) S. Hayashi, K.
Hirano, H. Yorimitsu, K. Oshima, J. Organomet. Chem. 2007,
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M. Benaglia, M. Caporale and A. Puglisi, Enantiomer 2002,
383–385.
7,
6. (a) A. Sharma and S. Chattopadhyay, Tetrahedron:
Asymmetry 1999, 10 883–890; (b) A. Sharma and S.
Chattopadhyay, Enantiomer 2000, 175–179; (c) A.
,
5
,
Salaskar, N. V. Mayekar, A. Sharma, A. Chattopadhyay, S. K.
Nayak and S. Chattopadhyay, Synthesis 2005, 2777–2781; (d)
A. Salaskar, A. Sharma and S. Chattopadhyay,
Tetrahedron:Asymmetry 2006, 17, 325-329.
7. (a) P. Wasserscheid and W. Keim, Angew. Chem. Int. Ed.
Engl. 2000, 39, 3772–3789; (b) In Ionic Liquids in Synthesis
(Eds.: P. Wasserscheid and T. Welton) Wiley-VCH, 2002; (c) In
Chemistry in Alternative Reaction Media (Eds.: D. J. Adams, P.
J. Dyson and S. J. Taverner) Wiley, 2003; (d) A. Alizadeh, M.
M. Khodaei and A. Eshgi, J. Org. Chem. 2010, 75, 8295–8298;
(e) G. Aridoss and K . K. Laali, J. Org. Chem. 2011, 76, 8088–
8094; (f) A. Kumar and V. K. Rao, Synlett 2011, 2157–2162;
(g) D. Sarkar, R. Bhattarai, A. D. Headley and B. Ni,
Synthesis 2011, 1993–1997; (h) A. Sarkar, S. R. Roy, N. Parikh
and A. K. Chakraborti, J. Org. Chem. 2011, 76, 7132–7140; (i)
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H. M. Yau, S. T. Keaveney, B. J. Butler, E. E. L. Tanner, M. S.
Guerry, S. R. D. George, M. H. Dunn, A. K. Croft and J. B.
(4R,5R)-4-Methyl-5-decanolide (IV). A solution of 28 (650 mg,
2.82 mmol) and aqueous H2SO4 (1.0 mL, 0.73 M) in THF (5 mL)
was refluxed for 12 h. The mixture was brought to room
temperature, diluted with H2O (20 mL) and extracted with Et2O
(3

15 mL). The combined organic extracts were washed
10 mL) and brine (1 5 mL), and
successively with H2O (2


dried. Solvent removal in vacuo followed by column
chromatography (silica gel, 0-10% EtOAc/hexane) of the
residue gave pure IV (338 mg, 65%). colorless oil; [α]D24 +64.1
(c 1.02 in CHCl3) (lit.40f [α]D14 +63.9 (c 0.92 in CHCl3)); νmax/cm-1
1730; δH (500 MHz, CDCl3) 0.92 (3H, t, J = 7.0 Hz), 0.98 (3H, d, J
= 7.0 Hz), 1.25-1.42 (5H, m), 1.48-1.58 (2H, m), 1.66-1.73 (2H,
m), 2.00-2.09 (2H, m), 2.55 (2H, t, J = 7.5 Hz), 4.30-4.32 (1H,
m); δC (125 MHz, CDCl3) 12.4, 13.9, 22.4, 25.2, 26.0, 26.7, 29.2,
31.5, 31.8, 83.0, 171.9. Anal. Found: C 71.8, H 10.9. Calc. for
C11H20O2: C 71.7, H 10.9%; HPLC (isopropanol/hexane 5/95 @
0.5 mL/min, λ = 220 nm): Rt = 12.54 min.
Harper, Pure Appl. Chem. 2013, 85
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(b) T. Welton, Chem. Rev. 1999, 99, 2071–2084; (c) M. C.
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249–267; (b) P. J. Sadler, H. Li and H. Sun, Coord. Chem. Rev.
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1
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18 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00626H
Highly syn-selective crotylation of aldehydes was achieved using Bi-[bmim][Br]-crotyl bromide
combination, leading to an easy, stereodivergent access to important targets.
Dictyostatin
segment
Bi
OH
[bmim][Br]
Desoxycryptophycin
segment
RCHO
R
crotyl bromide
(+)-cis-aerangis
R = alkyl / aryl
16 examples
syn:anti upto 90:10
lactone
Yield 84-93%
[bmim][Br] acts as a solvent and a Bi-metal activator