Synthesis of enantioenriched secondary and tertiary alcohols via tricarbonylchromium(0) complexes of benzyl allyl ethers

Article abstract of DOI:10.1002/ejoc.200900007

Allyl ethers of the tricarbonylchromium(0) complexes of benzylic alcohols undergo highly enanlioselective benzylic funclionalisation using a chiral base/electrophilic quench sequence; the allyl group is readily removed to reveal a hydroxy group as demonst

Full text of DOI:10.1002/ejoc.200900007

FULL PAPER
DOI: 10.1002/ejoc.200900007
Synthesis of Enantioenriched Secondary and Tertiary Alcohols via
Tricarbonylchromium(0) Complexes of Benzyl Allyl Ethers
Keren Abecassis,[a] Susan E. Gibson,*[a] and Mar Martin-Fontecha[a]
Keywords: Alcohols / Allylic compounds / Chiral base / Chromium / Enantioselectivity / Alkylation
Allyl ethers of the tricarbonylchromium(0) complexes of ben-
zylic alcohols undergo highly enantioselective benzylic func-
tionalisation using a chiral base/electrophilic quench se-
quence; the allyl group is readily removed to reveal a hy-
droxy group as demonstrated in the syntheses of enantioen-
riched imidazole alcohols, a triol and a tertiary alcohol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Some time ago, we demonstrated that tricarbonylchro-
mium(0) complexes of benzyl ethers 1 react with the chiral
diamide derived from butyllithium/chiral diamine 2 and an
electrophile, e.g. iodomethane, to give chiral ether com-
plexes such as 3. The reactions typically gave very good
yields of products, and the products were generated in high
enantiomeric excess when the substrate was a methyl ether
(like 1a), or benzyl ether (like 1b). Poorer enantiomeric ex-
cesses were obtained with some other substrates, e.g. the
isopropyl ether 1c (Scheme 1).[1]
Figure 1. Examples of molecules made using chiral base chemistry.
In order to expand the scope of the chemistry, it would
be useful to be able to convert the ether functional group
into an alcohol. For example, conversion of the ethers in
dendrimer 5 and its homochiral partner into alcohols would
enable us to explore and compare the effect of hydrogen
bonding on the conformational equilibria of the two den-
drimers. In order to effect the desired functional group
transformation, it was necessary to i. identify an ether that
can be readily converted to an alcohol and that also un-
dergoes the deprotonation/alkylation reaction depicted in
Scheme 1, ii. ascertain that the selectivity of the reaction is
maintained with the new ether, and iii. demonstrate that
the selected ether can be converted into the corresponding
alcohol without loss of enantiopurity at the newly formed
stereocenter. A study which led to the identification of an
appropriate ether, and the application of the resulting pro-
tecting-group chemistry in the synthesis of enantioenriched
alcohols is described herein.
Scheme 1. Asymmetric functionalisation of tricarbonylchro-
mium(0) ether complexes.
As a consequence of the high enantioselectivity observed
with methyl ethers, subsequent applications of this chemis-
try, such as our recent syntheses of the tris-pyridine ligand
4,[2] and dendrimers with either a homochiral or a hetero-
chiral relationship between their layers such as the hetero-
chiral dendrimer 5[3] (Figure 1) have been based predomi-
nantly on methyl ethers.
[a] Department of Chemistry, Imperial College London,
South Kensington Campus, London SW7 2AZ, UK
Fax: +44-207-594-5804
Results and Discussion
Given that benzyl ether substrates such as 1b undergo
the deprotonation/electrophilic quench sequence to give al-
kylated products in good yield and enantiomeric excess, we
E-mail: s.gibson@imperial.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
1606
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1606–1611

Synthesis of Enantioenriched Secondary and Tertiary Alcohols
carried out a study some time ago on complex 6, formed
by a double alkylation of 1b,[4] to determine whether or
not its benzyl ether could be removed under hydrogenation
conditions to give an alcohol. Four sets of conditions were
investigated, but all led to the recovery of starting material
in between 80 and 87% yield (Scheme 2), an outcome which
may reflect the degree of steric crowding around the benzyl
group of 6.[5]
Scheme 2. An early attempt to convert a benzyl ether to its alcohol.
At the outset of this current study, we considered the use
of a p-methoxyphenyl ether, predicting that this group
would also give good yields and enantioselectivities, and
that it would be amenable to removal using methods such
as ceric ammonium nitrate or DDQ.[6] The use of an ether
group containing an aromatic ring was eventually dis-
missed, however, as the aromatic ring would dictate that the
protecting group must be introduced after the chromium
complex had been formed, in order to avoid an undesirable
competition between relatively similar aromatic rings dur-
ing the complexation step. In light of the above, we elected
to test whether or not an allyl ether would enable us to
extend our chiral base chemistry to the synthesis of enantio-
pure alcohols.
Scheme 3. Use of an allyl ether leads to high selectivities for meth-
ylation and the protecting group is readily removed without loss of
enantioselectivity [(+) series depicted here].
Scheme 4. Deprotonation at a higher temperature (–50 °C rather
than –78 °C) leads to a Wittig rearrangement.[7]
To prepare a suitable model substrate, 4-tert-butylbenzyl
alcohol 7, was treated with sodium hydride followed by allyl
bromide to give the novel allyl ether 8, and this was treated
with hexacarbonylchromium(0) to give its tricarbonylchro-
mium(0) complex 9, as a yellow solid (Scheme 3). To depro-
tonate ether 9, diamine (+)-2 was treated with n-butyllith-
ium, and complex 9 was added to the resulting deep red
solution at –78 °C. After the addition of iodomethane at
–78 °C and work-up, a yellow oil was obtained that was
identified as the methylated complex (+)-10 on the basis of
some experimentation, deprotection of samples of (+)- and
(–)-11 to give (+)- and (–)-12, respectively was achieved by
dissolving the allyl ether in methanol, adding 5 mol-% tet-
rakis(triphenylphosphane)palladium(0) followed by 3 equiv.
of potassium carbonate, and heating under reflux for 48 h.
The product mixture was then neutralised with acid, taking
care to stop at pH 7 to avoid racemisation. Analysis of both
products by chiral HPLC revealed that 12 had been formed
in each case in Ն 98% ee, and that the deprotection step
had proceeded without loss of enantiopurity.
Having established that the protection of benzyl alcohol
7 as an allyl ether was compatible with the chiral base reac-
tion in terms of yield and enantioselectivity and that the
allyl group could be removed without loss of enantiopurity,
in the case of the electrophile iodomethane, we proceeded
to challenge the system with i) a more complex electrophile,
ii) the triple functionalisation of a triol, and iii) the synthe-
sis of a tertiary alcohol.
1
its elemental analysis, IR, H NMR, 13C NMR and mass
spectra. In order to establish the stereoisomeric composi-
tion of (+)-10, the reaction was repeated using diamine (–)-
2. Analysis of both products by chiral HPLC revealed that
10 had been formed in each case in Ն 98% ee, thus estab-
lishing that allyl ethers do indeed support an enantioselec-
tive alkylation reaction.
It is interesting to contrast this result with the outcome
of the reaction between the benzyl allyl ether complex 13,
and the chiral base derived from (+)-2 at –50 °C, followed
by a methanol quench.[7] Presumably as a result of the
slightly higher reaction temperature, this led to an enantio-
selective [2,3]-Wittig rearrangement that generated alcohol
(–)-14 (Scheme 4).
Synthesis of Enantiopure Imidazole Alcohols
Initially we examined the introduction of a function-
The tricarbonylchromium(0) unit was subsequently re- alised electrophile. Imidazoles derived from the amino acid
moved from the samples of (+)- and (–)-10 by air/light oxi- histidine are common ligands for metals found in biological
dation to give the ethers (+)- and (–)-11, respectively. After systems e.g. for iron in cytochrome c peroxidase[8] and zinc
Eur. J. Org. Chem. 2009, 1606–1611
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1607

K. Abecassis, S. E. Gibson, M. Martin-Fontecha
FULL PAPER
in carbonic anhydrase and matrix metalloproteinases,[9] and Synthesis of an Enantiopure Triol
it was thus of interest to us to determine whether or not we
In order to test whether or not the allyl protecting group
could generate chiral molecules containing both an imid-
azole and an alcohol, with a view to exploring their metal-
binding properties and potential applications in catalysis.
The electrophile to be tested, 4-bromomethyl-1-trityl-1H-
imidazole (15) was synthesised from the corresponding
alcohol[10] using N-bromosuccinimide/triphenylphosphane
in 84% yield. Electrophile 15 proved difficult to handle due
to its pronounced instability in solution, but after some ex-
perimentation it was found that using it freshly prepared
and adding it as a suspension in THF led to a satisfactory
reaction with allyl ether complex 9 and the formation of
the protected imidazole alcohol (+)-16 in good yield
(Scheme 5). Synthesis of (–)-16 and HPLC analysis revealed
that the enantiomeric excess of both (+)-16 and (–)-16 was
Ն 99%. Removal of the chromium unit from 16 proceeded
smoothly to give 17 from which point two deprotection
paths were followed. Application of the palladium-catalysed
deallylation protocol developed above for chiral allyl ether
11 (Scheme 3) gave the imidazole alcohol 18, in which one
of the imidazole nitrogen atoms remained protected, whilst
acid-catalysed removal of the trityl group from 17 followed
by deallylation gave the completely deprotected imidazole
alcohol 20 via 19. HPLC analysis revealed that both (+)-
and (–)-18 had been generated in high enantiomeric excess
(Ն 99%). HPLC analysis of (+)- and (–)-19, and (+)- and
(–)-20 proved more difficult and whilst peaks for the minor
enantiomers were not observed in all cases, the quality of
the data only allowed us to define their enantiopurities as
Ն 95% and Ն 90%, respectively.
strategy could be used to satisfactorily generate more than
one chiral alcohol in a substrate using the chiral base ap-
proach, the triol, 1,3,5-tris(hydroxymethyl)benzene,[2b] was
subjected to allyl ether formation, alkylation, and deprotec-
tion (Scheme 6). Allylation of the triol to give the tris ether
21, and subsequent formation of its chromium tricarbonyl
complex 22 proceeded without incident. Deprotonation of
22 using chiral bases (+)- and (–)-2 and quenching with
benzyl bromide gave (+)-23 and (–)-23 in 78 and 91% yield,
respectively, and Ն 99% ee as determined by HPLC. The
chromium tricarbonyl group was removed from both
enantiomers to give the two separate chiral ethers 24, and
it was gratifying to find that the ethers could be deprotected
using the same palladium-based protocol described above
to give the chiral triols (–)- and (+)-25 in 84% and 80%
yield, respectively. Although it was impossible to identify
HPLC conditions that gave a satisfactory separation of the
1
enantiomers of 25, careful inspection of their H and 13C
NMR spectra in CDCl3 and C6D6 failed to reveal any evi-
dence for the presence of diastereoisomers of 25 i.e. com-
pounds that would be expected to be present had epimer-
isation taken place. It is therefore reasonable to assume that
the enantiopurity of the enantiomers of 25 is the same as
that of the enantiomers of 23.
Scheme 6. Synthesis of an enantiopure triol.
The successful use of the allyl protecting group in the
synthesis of a chiral triol paves the way for the synthesis of
analogues of 5 in which i) all of the ether groups are re-
Scheme 5. Synthesis of two imidazole alcohols.
1608
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1606–1611

Synthesis of Enantioenriched Secondary and Tertiary Alcohols
placed by alcohols, or ii) the three “inner ethers” or the loss of enantiopurity using catalytic amounts of tetrakis(tri-
six “outer ethers” are selectively replaced by alcohols, thus phenylphosphane)palladium(0). Successful application of
enabling us to study the effect of several different hydrogen the protocol to the synthesis of imidazole alcohols, a triol,
bonding arrays on the conformational equilibria of these and a tertiary alcohol indicates that the allyl protecting
dendrimers. Furthermore, conversion of the three hydroxy group chemistry described herein is robust and versatile.
groups of 25 into phosphites should provide an interesting
set of ligands, given the widespread use of phosphites in for
example, rhodium-,[11] and copper[12]-catalysed asymmetric
synthesis.
Experimental Section
General: All reactions and manipulations involving organometallic
compounds were performed under dry nitrogen, using standard
vacuum line Schlenk techniques.[15] Reactions and operations in-
volving the use of (arene)tricarbonylchromium(0) complexes were
Synthesis of an Enantiopure Tertiary Alcohol
Methods for the synthesis of enantiopure tertiary
alcohols are limited compared to those available for the
synthesis of enantiopure secondary alcohols. This may be
attributed in part to the difficulties associated with de-
veloping conditions for the selective addition of nucleo-
philes to ketones compared to aldehydes,[13] and also to the
steric demands of tertiary alcohols and their derivatives
which have rendered them a challenge to methods based on
enzymatic kinetic resolutions.[14] The synthesis of an
enantiopure tertiary alcohol thus seemed an excellent chal-
lenge for the chiral base/allyl protecting group chemistry.
Allylation of (+)- and (–)-10, using methodology developed
previously that was shown to proceed with retention of con-
figuration,[4] gave (+)- and (–)-26 in good yield (Scheme 7).
Removal of the chromium from both of the enantiomers
gave the enantiomers of 27, which were subjected to the
allyl deprotection protocol followed by a careful work-up.
To our delight, HPLC analysis of the enantiomers of 28
revealed that these tertiary alcohols had been generated in
Ն 99% ee.
protected from light. Tetrahydrofuran was distilled from sodium
benzophenone ketyl and used immediately. Dichloromethane was
distilled from calcium hydride. The concentration of n-butyllithium
was determined by titration against diphenylacetic acid in tetra-
hydrofuran.[16] The diamines (+)- and (–)-2[17] were prepared ac-
cording to literature procedures. All other chemicals were used as
purchased from commercial sources. Thin-layer chromatography
(TLC) was performed on Merck silica gel glass plates 60 (F254),
using UV light (254 nm) as visualizing agent and/or vanillin, ninhy-
drin, or potassium permanganate as developing agents. Flash col-
umn chromatography was performed using BDH silica gel (particle
size 33–70 µm). Melting points were recorded with a Sanyo Gallen-
kamp melting point apparatus in open capillaries and are uncor-
rected. Optical rotations were recorded with an AA 10 polarimeter
from Index Instruments or with a Perkin–Elmer 241 polarimeter
using a 1-dm path length; concentrations are given as g/100 mL.
IR spectra were recorded with Perkin–Elmer Spectrum RX and
100 FT-IR spectrometers. NMR spectra were recorded at room
temperature with Bruker AV 400 instrument in CDCl3, unless
otherwise stated. Chemical shifts are reported in ppm. Mass spec-
tra were recorded with Micromass Platform II and Micromass Au-
toSpec-Q instruments by the mass spectrometry service at Imperial
College London. Elemental analyses were performed by the Lon-
don Metropolitan University microanalytical service. Analytical
HPLC was performed using a Unicam Crystal 200 pump, a Un-
icam 100 UV/Vis detector and a Daicel Chiralcel OD-H column
(25ϫ0.46 cm).
Typical Procedure for the Synthesis of Allyl Ethers
1-Allyloxymethyl-4-tert-butylbenzene (8): 4-tert-Butylbenzyl alcohol
(7, 2.65 mL, 15 mmol) was added to a suspension of sodium hy-
dride (60% dispersion in mineral oil; 717 mg, 17.9 mmol, pre-
viously washed with hexane) in dry THF (50 mL) and the mixture
was stirred for 1 h at 0 °C before allyl bromide (2.6 mL, 30 mmol)
was added in one portion and stirring continued for a further 16 h
at room temperature. After this time, methanol (1 mL) was added
and the solvent was removed in vacuo. The resulting crude product
was filtered through a long silica gel column, eluted with 200 mL
of hexane/diethyl ether, 80:20, and then 200 mL of hexane/diethyl
ether, 70:30. After removal of the solvents, ether 8 was obtained as
a colourless oil (3.06 g, 100%). Rf = 0.39 (SiO2; hexane/diethyl
Scheme 7. Synthesis of an enantiopure tertiary alcohol.
ether, 98:2). IR (CHCl ): ν = 1647 (m, νC=C), 1267 (s, νC–O), 1086
˜
3
(s, νC–O). 1H NMR (400 MHz): δ = 1.32 [s, 9 H, C(CH3)3], 4.03 (d,
J = 5.5 Hz, 2 H, OCH2CH=CH2), 4.50 (s, 2 H, OCH2Ar), 5.20 (d,
J = 10.5 Hz, 1 H, CH=CHHcis), 5.31 (d, J = 17 Hz, 1 H,
CH=CHHtrans), 5.96 (ddt, J = 17, 10.5, 5.5 Hz, 1 H, CH=CH2),
Conclusions
Allyl ethers of the tricarbonylchromium(0) complexes of
benzylic alcohols have been shown to undergo highly
stereoselective functionalisation at their benzylic positions
using a chiral base/electrophilic quench reaction sequence.
7.29 (d, J = 8.5 Hz, 2 H, CArH ϫ2), 7.38 (d, J = 8.5 Hz, 2 H, CAr
H
ϫ2) ppm. 13C NMR (100 MHz): δ = 31.4 [C(CH3)3], 34.6
[C(CH3)3], 71.2 (OCH2CH=CH2), 72.0 (OCH2CAr), 117.1 (CH=
The resulting chiral ethers are readily deprotected without CH2), 125.4, 127.7 (CArH ϫ4), 134.9 (CH=CH2), 135.3 (CArCH2),
Eur. J. Org. Chem. 2009, 1606–1611
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1609

K. Abecassis, S. E. Gibson, M. Martin-Fontecha
FULL PAPER
150.6 [CArC(CH3)3] ppm. MS (EI): m/z (%) = 204 (16) [M+], 189
7.36–7.37 (m, 9 H, CArH ϫ9), 7.44 (s, 1 H, 2-H imid) ppm. 13C
NMR (100 MHz, CDCl3): δ = 31.0 [C(CH3)3], 33.9 [C(CH3)3], 37.9
(72) [M+ – CH3], 162 (29) [M+ – 3CH3 + 3 H], 148 (41) [M+
–
C(CH3)3 + H], 147 (100) [M+ – C(CH3)3], 57 (94) [C(CH3)3+]. (CH2-imid), 71.7 (OCH2), 75.2 [C(C6H5)3], 78.1 (OCH), 90.0
C14H20O (204.15): calcd. C 82.30, H 9.87; found C 82.21, H 9.80.
(CCrH), 90.4 (CCrH), 90.5 (CCrHϫ2), 112.2 [CCrCH(CH2imid)-
OAllyl], 117.1 (CH2=CH), 119.8 (5-CH imid), 123.5 [CCrC-
(CH3)3], 128.1 [CAr(trityl)H ϫ 6], 129.7 [CAr(trityl)H ϫ 9], 134.4
(CH2 =CH), 136.6 (4-C imid), 138.1 (2-CH imid), 142.3
[CAr(trityl) ϫ3], 233.6 (CϵOϫ3) ppm. MS (EI): m/z (%) = 578 (12)
[M+ – 3 CO], 536 (31) [M+ – 3 CO – CH2CH=CH2], 526 (10) [M+ –
Cr(CO)3], 283 (93) [M+ – Cr(CO)3 – CH2CH=CH2], 243 (100)
[CPh3+]. C40H38CrN2O4 (662.74): calcd. C 72.49, H 5.78, N 4.23;
found C 72.45, H 5.70, N 4.14.
Typical Procedure for the Synthesis of an (Arene)tricarbonylchro-
mium(0) Complex
(1-Allyloxymethyl-4-tert-butylbenzene)tricarbonylchromium(0) (9):
Allyl ether 8 (2.68 g, 13.1 mmol) and hexacarbonylchromium(0)
(3.20 g, 14.5 mmol) were added to dry di-n-butyl ether (130 mL)
and THF (15 mL) and the mixture was degassed 10 times and
shielded from ambient light. The reaction mixture was heated un-
der reflux for 24 h at 135 °C and then cooled to room temperature.
The solvents were removed under reduced pressure and the crude
mixture was purified by flash column chromatography (SiO2; hex-
ane/diethyl ether, 100:0 Ǟ 90:10) to yield complex 9 (3.82 g, 86%)
as a yellow solid; m.p. 39–40 °C. Rf = 0.20 (SiO2; hexane/diethyl
(–)-(S)-[4-[2-(Allyloxy)-2-(4-tert-butylphenyl)ethyl]-1-trityl-1H-imid-
azole]tricarbonylchromium(0) [(–)-16]: Complex (–)-16 was prepared
from complex 9 (230 mg, 0.68 mmol), diamine (–)-2 (284 mg,
0.68 mmol) and bromide 15 (660 mg, 2.0 mmol), following the pro-
cedure described for complex (+)-16. 69% yield, yellow solid; ee Ն
99%. [α]2D0 = –23 (c = 1.35, CHCl3). All other analytical data were
identical to those obtained for (+)-16.
ether, 90:10). IR (CHCl ): ν = 1966 (s, νCO), 1891 (s, νCO). 1H NMR
˜
3
(400 MHz): δ = 1.28 [s, 9 H, C(CH3)3], 4.11 (d, J = 5.5 Hz, 2 H,
OCH2CH=CH2), 4.23 (s, 2 H, OCH2Ar), 5.22–5.30 (m, 3 H,
CH=CHHcis and CCrH ϫ2), 5.33 (d, J = 17 Hz, 1 H,
Typical Procedure for Oxidative Decomplexation
CH=CHHtrans), 5.56 (d, J = 7 Hz, 2 H, CCrH ϫ2), 5.93 (ddt, J =
17, 10.5, 5.5 Hz, 1 H, CH=CH2) ppm. 13C NMR (100 MHz): δ =
31.2 [C(CH3)3], 34.0 [C(CH3)3], 70.2 (OCH2CH=CH2), 72.2
(+)-(R)-4-[2-(Allyloxy)-2-(4-tert-butylphenyl)ethyl]-1-trityl-1H-imid-
azole [(+)-17]: Complex (+)-16 (310 mg, 0.47 mmol) was dissolved
in diethyl ether (50 mL) and was left standing for 48 h by the win-
dow. The solvent of the resulting brown suspension was evaporated
under reduced pressure and the residue was purified by flash col-
umn chromatography (SiO2; hexane/ethyl acetate, 90:10 Ǟ 70:30)
to afford compound (+)-17 as a white solid (201 mg, 82%); m.p.
57–58 °C. Rf = 0.32 (SiO2; hexane/ethyl acetate, 70:30). [α]2D0 = +18
(OCH2CCr), 90.6, 92.5 (CCrH ϫ4), 108.0 (CCrCH2), 118.0
(CH=CH2), 121.9 [CCrC(CH3)3], 134.0 (CH=CH2), 233.4 (CϵO
ϫ3) ppm. MS (CI): m/z (%) = 358 (83) [M + NH4+], 341 (100) [M
+ H+], 285 (17) [M + H+ – 2 CO], 284 (38) [M+ – 2 CO], 283 (97)
[M – 2 CO – H+]. C17H20CrO4 (340.08): calcd. C 59.99, H 5.92;
found C 60.04, H 5.94.
(c = 1.30, CHCl ). IR (KBr): ν = 1130 (m, υC–O), 1086 (m, υC–O).
˜
3
1H NMR (400 MHz, CDCl3): δ = 1.33 [s, 9 H, C(CH3)3], 2.87 (dd,
J = 14.5, 6.0 Hz, 1 H, CH2-imid), 3.10 (dd, J = 14.5, 8.0 Hz, 1 H,
CH2-imid), 3.75 (dd, J = 12.5, 5.5 Hz, 1 H, OCH2), 3.91 (dd, J =
12.5, 5.0 Hz, 1 H, OCH2), 4.63 (apparent t, J = 7.0 Hz, 1 H, OCH),
5.09 (d, J = 10.5 Hz, 1 H, CH=CHHcis), 5.16 (d, J = 17.5 Hz, 1
H, CH=CHHtrans), 5.80 (dddd, J = 17.5, 10.5, 5.5, 5.0 Hz, 1 H,
Typical Procedure for Benzylic Enantioselective Alkylation
(+)-(R)-[4-[2-(Allyloxy)-2-(4-tert-butylphenyl)ethyl]-1-trityl-1H-imid-
azole]tricarbonylchromium(0) [(+)-16]: n-Butyllithium (0.6 mL,
2.5  in hexane, 1.5 mmol) was added dropwise to a stirred solution
of diamine (+)-2 (313 mg, 0.74 mmol) in THF (7 mL) at –78 °C.
The solution was warmed to room temperature over a period of
30 min. The resulting deep red solution was then recooled to
–78 °C. A solution of heat-gun-dried lithium chloride (32 mg,
0.74 mmol) in THF (6 mL) was added through a cannula and the
reaction mixture was stirred for a further 5 min before a precooled
solution (–78 °C) of complex 9 (230 mg, 0.68 mmol) in THF (7 mL)
was added dropwise through a cannula. The reaction was stirred
at –78 °C for 45 min before a solution of compound 15 (653 mg,
1.9 mmol) in THF was added through a cannula. Stirring was con-
tinued for a further 2 h at –78 °C and then the reaction mixture was
quenched with methanol (2 mL) and the solvents were removed in
vacuo to give a yellow solid. Purification of the crude product by
flash column chromatography (SiO2; hexane/ethyl acetate, 80:20 Ǟ
60:40) yielded complex 16 (327 mg, 73%) as a yellow solid; m.p.
60–61 °C. Rf = 0.31 (SiO2; hexane/ethyl acetate, 70:30). Enantio-
metric excess was determined by HPLC analysis (Chiralcel OD-H,
n-hexane/iPrOH, 90:10, 1.0 mL/min, 330 nm); (R)-enantiomer
tr = 10.6 min (major); (S)-enantiomer tr = 24.0 min (minor): Ն 99%
CH=CH2), 6.49 (s, 1 H, 5-H imid), 7.10–7.12 [m, 6 H, CAr(trityl)
H
ϫ6], 7.22 (d, J = 8.0 Hz, 2 H, CArHϫ2), 7.29–7.37 [m, 12 H,
CAr(trityl)H ϫ 9, CArH ϫ 2 and 2-H imid] ppm. 13C NMR
(100 MHz, CDCl3): δ = 31.4 [C(CH3)3], 34.5 [C(CH3)3], 37.5 (CH2-
imid), 69.7 (OCH2), 75.1 [C(C6H5)3], 80.8 (OCH), 116.5
(CH2=CH), 119.6 (5-CH imid), 125.1 (CAr H ϫ 2), 126.4
(CArHϫ2), 127.9 [CAr(trityl)Hϫ9], 129.8 [CAr(trityl)Hϫ 6], 135.0
(CH2=CH), 137.8 [CArCH(CH2imid)OAllyl and 2-CH imid], 139.0
(4-C imid), 142.5 [CAr(trityl) ϫ3], 150.1 [CArC(CH3)3] ppm. MS (EI):
m/z (%) = 526 (8) [M+], 485 (34) [M+ – CH2CH=CH2], 283 (13)
[M+ – CPh3], 243 (100) [CPh3+]. C37H38N2O (526.71): calcd. C
84.37, H 7.27, N 5.38; found C 84.45, H 7.18, N 5.38.
(–)-(S)-4-[2-(Allyloxy)-2-(4-tert-butylphenyl)ethyl]-1-trityl-1H-imid-
azole [(–)-17]: Compound (–)-17 was prepared from complex (–)-
16 (220 mg, 0.42 mmol) following the procedure described for imid-
azole (+)-17. 79% yield, white solid. [α]2D0 = –19 (c = 1.60, CHCl3).
All other analytical data were identical to those obtained for (+)-
17.
ee. [α]2D0 = +22 (c = 1.03, CHCl ). IR (KBr): ν = 1959 (s, υ ),
˜
3
CO
1877 (s, υCO ). 1H NMR (400 MHz, CDCl3): δ = 1.30 [s, 9 H,
Typical Procedure for Deallylation
C(CH3)3], 2.92 (dd, J = 14.5, 5.0 Hz, 1 H, CH2-imid), 2.99 (dd, J
= 14.5, 5.0 Hz, 1 H, CH2-imid), 4.02 (dd, J = 12.5, 5.5 Hz, 1 H, (+)-(R)-1-(–4-tert-Butylphenyl)-2-(1-trityl-1H-imidazol-4-yl)ethanol
OCH2), 4.27 (dd, J = 12.5, 5.0 Hz, 1 H, OCH2), 4.47 (apparent t, [(+)-18]: Pd(PPh3)4 (14 mg, 0.013 mmol) was added to a stirred
J = 5.5 Hz, 1 H, OCH), 5.13–5.15 (m, 2 H, CH=CHHcis and solution of allyl protected alcohol (+)-17 (130 mg, 0.25 mmol) in
CCrH), 5.25 (d, J = 17.5 Hz, 1 H, CH=CHHtrans), 5.35 (d, J =
anhydrous methanol (5 mL) under nitrogen. The slightly yellow
7.0 Hz, 1 H, CCrH), 5.42 (d, J = 6.5 Hz, 1 H, CCrH), 5.55 (d, J = solution was stirred for 5 min, and K2CO3 (104 mg, 0.75 mmol)
6.5 Hz, 1 H, CCrH), 5.82 (dddd, J = 17.5, 10.5, 5.5, 5.0 Hz, 1H
CH=CH2), 6.64 (s, 1 H, 5-H imid), 7.14–7.16 (m, 6 H, CArH ϫ6),
was added. The reaction mixture was refluxed for 24 h and once at
room temperature, was neutralised with 1  HCl and extracted with
1610
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1606–1611

Synthesis of Enantioenriched Secondary and Tertiary Alcohols
dichloromethane (3ϫ25 mL). The combined organic layers were
washed with brine, dried with Na2SO4 and evaporated under re-
duce pressure. Purification by flash column chromatography (SiO2;
hexane/ethyl acetate, 70:30 Ǟ 50:50) gave compound (+)-18 as a
white solid (103 mg, 85%); m.p. 180–181 °C. Rf = 0.22 (SiO2; hex-
ane/ethyl acetate, 70:30). Enantiometric excess was determined by
HPLC analysis (Chiralcel OD-H, n-hexane/iPrOH, 97:3, 0.75 mL/
min, 220 nm); (S)-enantiomer tr = 54.4 min (minor); (R)-enan-
[1]
[2]
a) E. L. M. Cowton, S. E. Gibson, M. J. Schneider, M. H.
Smith, Chem. Commun. 1996, 839–840; b) M. Rudd, Ph. D.
Thesis, Imperial College London, 2006.
a) M. P. Castaldi, S. E. Gibson, M. Rudd, A. J. P. White, An-
gew. Chem. Int. Ed. 2005, 44, 3432–3435; b) M. P. Castaldi,
S. E. Gibson, M. Rudd, A. J. P. White, Chem. Eur. J. 2006, 12,
138–148.
a) A. R. E. Brewer, A. F. Drake, S. E. Gibson, J. T. Rendell,
Org. Lett. 2007, 9, 3487–3490; b) A. R. E. Brewer, A. F. Drake,
S. E. Gibson, J. T. Rendell, Tetrahedron 2008, 64, 6615–6627.
S. E. Gibson, P. C. V. Potter, M. H. Smith, Chem. Commun.
1996, 2757–2758.
P. C. V. Potter, Ph. D. Thesis, Imperial College London, 1996.
a) R. Johansson, B. Samuelsson, J. Chem. Soc., Perkin Trans.
1 1984, 2371–2374; b) K. C. Nicolaou, W. E. Brenzovich, P. G.
Bulger, T. M. Francis, Org. Biomol. Chem. 2006, 4, 2119–2157.
S. E. Gibson, P. Ham, G. R. Jefferson, Chem. Commun. 1998,
123–124.
[3]
[4]
tiomer tr = 60.4 min (major): Ն 99% ee. [α]2D0 = +9 (c = 1.35,
1
CHCl ). IR (KBr): ν = 3250 (υOH). H NMR (400 MHz, CDCl3):
˜
3
δ = 1.33 [s, 9 H, C(CH3)3], 2.00 (br. s, 1 H, OH), 2.89 (dd, J = 14.5,
8.5 Hz, 1 H, CH2-imid), 2.97 (dd, J = 14.5, 3.5 Hz, 1 H, CH2-imid),
5.00 (dd, J = 8.5, 3.5 Hz, 1 H, CHOH), 6.55 (s, 1 H, 5-H imid),
[5]
[6]
7.12–7.14 [m, 6 H, CAr(trityl)H ϫ6], 7.28–7.37 [m, 13 H, CAr(trityl)
H
ϫ 9 and CArH ϫ 4], 7.43 (s, 1 H, 2-H imid) ppm. 13C NMR
(100 MHz, CDCl3): δ = 31.4 [C(CH3)3], 34.5 [C(CH3)3], 37.0 (CH2-
imid), 73.6 (CHOH), 75.3 [C(C6H5)3], 118.9 (5-CH imid), 125.1
(CArH ϫ 2), 125.6 (CArH ϫ 2), 128.1 [CAr(trityl)H ϫ 9], 129.8
[CAr(trityl)Hϫ6], 138.3 [CArCH(CH2imid)OH], 138.5 (2-CH imid),
141.2 (4-C imid), 142.3 [CAr(trityl) ϫ3], 149.9 [CArC(CH3)3] ppm.
MS (EI): m/z (%) = 486 (22) [M+], 467 (4) [M+ – H2O], 243 (100)
[CPh3+]. C34H34N2O (486.65): calcd. C 83.91, H 7.04, N 5.76;
found C 83.89, H 6.95, N 5.64.
[7]
[8]
[9]
J. Hirst, S. K. Wilcox, P. A. Williams, J. Blankenship, D. E.
McRee, D. B. Goodin, Biochemistry 2001, 40, 1265–1273.
G. Parkin, Chem. Rev. 2004, 104, 699–767.
[10] R. Millet, J. Domarkas, R. Houssin, P. Gilleron, J.-F. Goossens,
P. Chavatte, C. Logé, N. Pommery, J. Pommery, J.-P. Hénichart,
J. Med. Chem. 2004, 47, 6812–6820.
[11] M. T. Reetz, Angew. Chem. Int. Ed. 2008, 47, 2556–2588.
[12] A. Alexakis, J. Burton, J. Vastra, C. Benhaim, X. Fournioux,
A. van den Heuvel, J.-M. Levêque, F. Mazé, S. Rosset, Eur. J.
Org. Chem. 2000, 4011–4027.
[13] C. Garcia, V. S. Martin, Curr. Org. Chem. 2006, 10, 1849–1889.
[14] a) R. Kourist, S. Bartsch, U. T. Bornscheuer, Adv. Synth. Catal.
2007, 349, 1393–1398; b) M. M. Elenkov, H. W. Hoeffken, L.
Tang, B. Hauer, D. B. Janssen, Adv. Synth. Catal. 2007, 349,
2279–2285.
(–)-(S)-1-(4-tert-Butylphenyl)-2-(1-trityl-1H-imidazol-4-yl)ethanol
[(–)-18]: Compound (–)-18 was prepared from allyl-protected
alcohol (–)-17 (205 mg, 0.39 mmol) following the procedure de-
scribed for compound (+)-18. 71% yield, white solid; ee Ն 99%.
[α]2D0 = –10 (c = 1.00, CHCl3). All other analytical data were iden-
tical to those obtained for (+)-18.
Supporting Information (see also the footnote on the first page of
this article): Full experimental details and analytical data.
[15] D. F. Shriver, M. A. Drezdzon, The Manipulation of Air Sensi-
tive Compounds, Wiley, Chichester, 1986.
[16] W. G. Kofron, L. M. Baclawski, J. Org. Chem. 1976, 41, 1879–
1880.
Acknowledgments
Financial support for a post-doctoral stipend from the Spanish
Ministerio de Educación y Ciencia (MEC) (to M. M.-F) and a stu-
dentship from the Engineering and Physical Sciences Research
Council (EPSRC) (to K. A.) is gratefully acknowledged.
[17] V. Rodeschini, N. S. Simpkins, F. Zhang, Org. Synth. 2007, 84,
306–316.
Received: January 6, 2009
Published Online: February 18, 2009
Eur. J. Org. Chem. 2009, 1606–1611
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1611