Synthesis of an enantioenriched C2-symmetric molecule by a chiral-base-mediated kinetic resolution of an (arene)tricarbonylchromium(0) complex

Article abstract of DOI:10.1002/ejoc.200600018

Trimethylsilyl substituents have been used to control the conformational preferences of a 1,2-disubstituted (arene)tricarbonylchromium(0) complex. The kinetic resolution of the mono-methyl derivative (±)-11 using a chiral base/iodomethane quench sequence

Full text of DOI:10.1002/ejoc.200600018

FULL PAPER
DOI: 10.1002/ejoc.200600018
Synthesis of An Enantioenriched C2-Symmetric Molecule by a Chiral-Base-
Mediated Kinetic Resolution of an (Arene)tricarbonylchromium(0) Complex
M. Paola Castaldi,[a] Susan E. Gibson,*[a] and Andrew J. P. White[b]
Keywords: (Arene)tricarbonylchromium(0) complex / Asymmetric synthesis / C2 Symmetry / Chiral base / Conformational
control / Kinetic resolution
Trimethylsilyl substituents have been used to control the con-
formational preferences of a 1,2-disubstituted (arene)tricar-
bonylchromium(0) complex. The kinetic resolution of the
mono-methyl derivative ( )-11 using a chiral base/iodome-
thane quench sequence led to the synthesis of the enantioen-
riched C2-symmetric bis-ether (+)-13.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
of configuration, two well-established features of the chem-
istry of (arene)tricarbonylchromium(0) complexes.[10]
Introduction
The creation of new ligand motifs underpins the design
of more active, economic and environmentally friendly new
catalysts for use in synthetic chemistry. Ligands that are C2-
symmetric have proven to be very successful in this arena,
delivering highly enantioselective catalysts based on a wide
variety of transition metals.[1] Examples of widely used C2
ligands include bis-alcohols, such as 1,1Ј-bi-2-naphthol (bi-
nol)[2] and the α,α,αЈ,αЈ-tetraaryl-1,3-dioxolane-4,5-dimeth-
anols (taddols),[3] bis-phosphanes such as 2,3-O-isopro-
pylidene-1,4-bis(diphenylphosphanyl)butane-2,3-diol
(diop)[4] and 2,2Ј-bis(diphenylphosphanyl)-1,1Ј-binaphthyl
(binap),[5] and bis-oxazolines such as pybox.[6]
Tricarbonylchromium(0) complexes of arenes continue to
receive widespread attention.[7] Some time ago we discov-
ered a chiral-base-mediated reaction that efficiently gener-
ated a single chiral centre.[8] We showed that tricarbonyl-
chromium(0) complexes of alkyl benzyl ethers such as 1 re-
act with n-butyllithium/chiral bis-amine 2 and an electro-
phile to give the chiral ether complexes 3 in high yield and
enantiomeric excess (Scheme 1). Working with the (+)-
(R,S,S,R) enantiomer of the bis-amine, derived from (R)-α-
methylbenzylamine,[9] gives the (R) configuration at the new
stereocentre, presumably because of the preference of the
base to abstract the pro-R benzylic hydrogen. It is antici-
pated that the abstraction takes place whilst the benzylic
hydrogen is antiperiplanar to the arene centroid–chromium
axis (see structure 1Ј) to maximise the orbital overlap in the
transition state, and that alkylation proceeds with retention
Scheme 1.
More recently, as part of a study of the use of this reac-
tion to create two or three chiral centres in one pot, we
examined the reactivity of the bis-ether 4.[11] The reaction
of complex 4 with one equivalent of the bis-amine (+)-2
and two equivalents of n-butyllithium followed by quench-
ing with iodomethane gave a single mono-methylated spe-
cies (+)-5 that was isolated in 99% yield and shown to have
an enantiomeric excess of 99% by HPLC analysis
(Scheme 2).[11] The relative and absolute stereochemistry of
(+)-5 was confirmed by X-ray crystallography.[12] The reac-
tion of (+)-5 with one equivalent of the bis-amine (+)-2 and
two equivalents of n-butyllithium followed by quenching
with iodomethane subsequently gave the meso complex 6 in
[a] Department of Chemistry, Imperial College London,
South Kensington Campus, London SW7 2AY, UK
Fax: +44-207-594-5804
E-mail: s.gibson@imperial.ac.uk
[b] Department of Chemical Crystallography, Imperial College
London,
South Kensington Campus, London SW7 2AY, UK
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M. P. Castaldi, S. E. Gibson, A. J. P. White
FULL PAPER
50% yield.[13] The stereochemistry of 6 was also confirmed
In order to generate a product that will provide a C2-
symmetric molecule after decomplexation, the pro-R hydro-
gen that lies buried in the tricarbonylchromium(0) unit in
complex (+)-5, must be accessed and replaced with an elec-
trophile. Figure 1 illustrates two approaches to this chal-
lenge. In the first, represented by structure 7, the ortho sub-
stituents are tethered together to mimic the higher energy
conformation 4Ј (Scheme 2), whilst in the second, repre-
sented by structure 8, bulky substituents are introduced to
give the same effect. The methylation of the conformation-
ally constrained derivatives 7 and 8 using the (+)-(R,S,S,R)-
chiral base should give the mono-methylated complexes 9
and 10 by abstraction of the only pro-R hydrogen essen-
tially antiperiplanar to the chromium in each substrate. Re-
lease of the conformational constraints imposed by either
the tether or the bulky substituents should give the mono-
by X-ray crystallography.[12]
Scheme 2.
The results of the two reactions depicted in Scheme 2 are
explained as follows. The bis-ether complex 4 prefers to
adopt conformations in which steric interactions between
the two methoxy groups are minimised (e.g. conformation
4 rather than e.g. conformation 4Ј). The chiral base then
abstracts the only pro-R hydrogen, which can readily adopt
an antiperiplanar relationship to the arene centroid–chro-
mium axis (i.e. the hydrogen highlighted on structure 4);
methylation then occurs with retention of the configuration
to give (+)-5. In order to generate a dimethylated product
that is C2-symmetric after removal of the chromium unit,
the remaining pro-R hydrogen of 5 must be removed in the
second reaction. The examination of the conformations 5
and 5Ј reveals a problem: in conformation 5, in which the
interactions between the ortho substituents are minimised,
the pro-R hydrogen is pointing towards the tricarbonylchro-
mium(0) unit and is thus difficult to access for steric
reasons; whilst in conformation 5Ј, although the pro-R hy-
drogen can adopt the favourable antiperiplanar relationship
to the chromium, the interactions between the ortho substit-
uents are less favourable. The result of the second reaction
reveals that in this case the conformational preferences of
the substrate over-ride the preferences of the chiral base,
and the pro-S hydrogen of 5 is abstracted, albeit inef-
ficiently, to give the undesired meso complex 6.
Figure 1. Two approaches to conformational control in tricarbonyl-
chromium(0) complexes of ortho-substituted arenes.
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Synthesis of Enantioenriched C2-Symmetric Bis-Ether
FULL PAPER
methylated complex 11, that can now access a conformation readily cleaved under acidic conditions than their corre-
in which steric interactions between the ortho substituents sponding methylene acetals.[17] The thermolysis of the ketal
are minimised, and the remaining pro-R hydrogen is placed 20 with hexacarbonylchromium(0) proceeded smoothly to
antiperiplanar to the chromium. Deprotonation with the give the novel complex 21, which was readily alkylated, pro-
(+)-(R,S,S,R)-chiral base should then lead to the bis-meth- viding it was treated with the chiral base at –20 °C. Interest-
ylated product 12, which on decomplexation should afford ingly, deprotonation gets steadily more difficult in the series
the desired C2 symmetry, depicted here in the bis-ether 13. of the substrates 15, 18, 21. This is perhaps a reflection of
This paper describes a study designed to examine the feasi- the tendency of complexes 18 and 21 to adopt conforma-
bility of both of these approaches.
tions that minimise steric interactions between the acetal/
ketal group and the tricarbonylchromium(0) unit; such con-
formations make it harder for the pro-R benzylic hydrogen
on the exo face of the molecule to adopt an antiperiplanar
relationship to the arene centroid–chromium axis. With
complex (–)-22 in hand, a range of acidic conditions were
used to try to open the ketal but, once again, only starting
material and/or decomposition products were obtained.
Results and Discussion
Initially, the phthalan derivative 15 was chosen to test
the viability of the tethering approach. Thermolysis of com-
mercially available 1,3-dihydroisobenzofuran 14 with hexa-
carbonylchromium(0), and subsequent treatment of the
complex 15 with the chiral bis-amine (+)-2 and n-butyllith-
ium, followed by an iodomethane quench provided a
sample of the mono-methylated complex (–)-16
(Scheme 3).[14–16] Release of the conformational constraint
in (–)-16 was now necessary to facilitate the removal of the
remaining pro-R benzylic hydrogen by the chiral base. Un-
fortunately, all attempts to open the five-membered ring re-
sulted in either the return of starting material or a complex
mixture of decomposition products, a result consistent with
previous attempts to open the cyclic ether ( )-16 with acidic
methanol.[14]
Scheme 4. A) HCl (2.7 ), MeOH, room temp., 16 h; b) HBF4
(54% in diethyl ether), MeOH/H2O, room temp., 16 h; c) HCl (6 ),
1,4-dioxane, room temp., 16 h.
In view of the difficulties experienced in opening the
ether (–)-16, acetal (–)-19 and ketal (–)-22, a new approach
to access both pro-R benzylic hydrogen atoms was adopted.
The trimethylsilyl groups were selected to act as sterically
demanding groups designed to favour the conformation de-
picted by structure 8 (Figure 1).[20] The desired bis-ether 25
(Scheme 5) was synthesised efficiently in multigram quanti-
Scheme 3. Et2OBF3 (1.1 equiv.), MeOH, 75 °C, 16 h; b) Et2O–BF3
(1.1 equiv.), NaOMe (1 equiv.), DCM, 50 °C, 16 h; c) H2SO4 (50%
in water), room temp., 16 h; d) HBF4 (54% in diethyl ether) MeOH,
room temp. 16 h.
In order to try to facilitate the ring-opening step, it was ties from commercially available diisopropyl phthalate
decided to examine an acetal embedded in a larger ring, the through ortho-lithiation/silylation[21] to give 23, reduction
cleavage of which is well documented under acidic condi- of the esters with lithium aluminium hydride to give 24 and
tions.[17] Thermolysis of 1,3-dioxa-5,6-benzocycloheptene
a subsequent methylation. The bis-ether 25 reacted
(17)[18] with hexacarbonylchromium(0) delivered the novel smoothly with hexacarbonylchromium(0) to give the novel
complex 18 in 80% yield (Scheme 4). The methylation to tricarbonylchromium(0) complex 26 as a yellow, crystalline
give (–)-19 proceeded smoothly, once it had been recognised air-stable solid in 98% yield.
that 18 required a higher temperature than 15 for the chiral
Methylation of complex 26, which represents the key
base step (–40 °C rather than –78 °C). Attempts to cleave transformation of structure 8 to structure 10 in Figure 1,
the ring in (–)-19, however, proved fruitless. A final attempt was then examined. Initial reactions involved the chiral bis-
to employ the tethering strategy was made using the di- amide derived from (+)-(R,S,S,R)-2, but utilising a range of
methyl ketal, 2,2-dimethyl-1,3-dioxa-5,6-benzocycloheptene temperatures between –78 °C and 0 °C disappointingly
(20),[18,19] as it is recognised that dimethyl ketals are more failed to provide the desired mono-methylated product
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M. P. Castaldi, S. E. Gibson, A. J. P. White
FULL PAPER
Scheme 5.
Scheme 6.
(Scheme 5). Reasoning that the size of both the chiral bis-
amide and the flanking trimethylsilyl groups rendered them
unreactive with each other, the attention turned to smaller
chiral amides. The mono-amides derived from the commer-
cially available amine (+)-27 and the trifluoro amine (+)-28,
synthesised by a literature procedure,[22] were each added to
the bis-ether complex 26, but both proved ineffective under
a range of conditions (Scheme 6). In contrast, the mono-
amide derived from (+)-bis(α-methylbenzyl)amine (29),
used at –12 °C, delivered the mono-methylated complex 30
in 81% yield. To facilitate the stereochemical analysis of
this product, its trimethylsilyl substituents were removed
using tetrabutylammonium fluoride. Comparison of the
NMR spectra of 11 with those of 5 (Scheme 2) revealed
that they were indeed diastereoisomers, i.e. our strategy of
using bulky flanking groups to control the conformation of
the adjacent benzyl ethers had worked, and we had suc-
ceeded in removing and replacing the previously inaccess-
ible benzylic pro-R hydrogen. Our excitement proved to be
short-lived, however, as HPLC analysis of 11 revealed that
it was racemic, an outcome that may be a result of the rela-
tively high temperature needed for the deprotonation.
At this point our strategy for accessing the C2-symmetric
molecule 13 (Figure 1) was modified. As alkylation using
the mono-amide 29 was chemically efficient,[23] it was de-
cided to attempt a kinetic resolution of racemic 11. It was
anticipated that due to the preference of the chiral bis-
R hydrogen, the enantiomer of racemic 11 already bearing
an R chiral centre would react more readily than the corre-
sponding S enantiomer (Figure 2).
amide derived from (+)-2 to remove an antiperiplanar pro- Figure 2. The proposed kinetic resolution of 11.
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Synthesis of Enantioenriched C2-Symmetric Bis-Ether
FULL PAPER
After examining a range of different reaction conditions, from cold hexane. HPLC analysis revealed an enantioen-
nearly complete resolution was achieved in a two-step pro- richment of the mother liquor (98% ee), and an enantiode-
cedure. Treatment of ( )-11 with 0.55 equivalents of the bis- pletion of the crystals (71% ee). In a separate experiment a
amine and 0.5 equivalent of n-butyllithium at –78 °C for batch of (+)-12 of 84% ee gave a small sample of crystals
45 min followed by an iodomethane quench gave a 27% that were suitable for X-ray analysis. This analysis con-
yield of the bis-methylated product (+)-12 of 85% enantio- firmed the predicted relative stereochemistry of 12 (Fig-
meric excess, together with unreacted mono-methylated (–)- ure 3), but was unable to confirm our prediction of the ab-
11 in 73% yield and 35% ee by HPLC analysis (Scheme 7). solute stereochemistry, as the crystal examined proved to be
Subjecting the latter material to the same reaction condi- racemic, a result consistent with the observation of enantio-
tions gave a second sample of (+)-12 [25% yield (in the depletion on crystallisation. Nevertheless, the preference of
second reaction), 95% ee] and enhanced the enrichment of the bis-amide derived from (R)-α-methylbenzylamine to
(–)-11 to 96% ee (65% yield in the second reaction). Overall abstract the pro-R benzylic hydrogen is sufficiently well
it had proved possible to obtain a 45% yield of the bis- documented in our earlier work[8,11,24] for us to be confident
methylated (+)-12 of 90% ee, and a 47% yield of the mono- that the two stereocentres of (+)-12 are indeed R.
methylated (–)-11 of 96% ee.
Figure 3. The molecular structure of 12.
Finally the oxidative removal of the tricarbonylchro-
mium(0) unit using ceric ammonium nitrate cleanly gave the
target C2-symmetric compound (+)-13 (Scheme 8)[25] thus
demonstrating with a model electrophile that controlling
the conformational preferences of ortho-substituted ben-
zylic ethers provides a route to enantioenriched C2-symmet-
ric products.
Scheme 8.
Conclusion
Two approaches to controll the conformational prefer-
ences of ortho-substituted benzylic ethers have been exam-
ined, and the approach that relied on non-covalent interac-
tions proved successful. Although the steric demands of the
trimethylsilyl groups proved to be a liability as well as an
asset in this chemistry, due to the size of the chiral bases
Scheme 7.
In an attempt to enhance the enantiopurity of (+)-12, a used, this approach to controll conformations to generate
sample of (+)-12 of 94% ee (obtained during the optimi- C2-symmetry after decomplexation should find use in reac-
sation of the kinetic resolution procedure) was crystallised tions of 1,2-disubstituted (arene)tricarbonylchromium(0)
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M. P. Castaldi, S. E. Gibson, A. J. P. White
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C
CrH×4) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.7 (CHCH3),
complexes that rely on smaller reagents. The kinetic resolu-
tion of 11 using the chiral base worked well, and it is antici-
pated that introduction of functionalised electrophiles into
this chemistry will provide a range of C2-symmetric ligands
for use in asymmetric catalysis.
69.5 (CH2), 78.1 (CHCH3), 84.5, 89.9, 90.7 and 91.8 (CCrH), 109.5
and 110.7 (CAr), 232.8 (CϵO×3) ppm. MS (EI): m/z (%) = 270
(42) [M+], 186 (90) [M+ – 3 CO], 52 (100) [Cr].
Acetal Chromium(0) Complex 18: A 100-mL round-bottomed flask
containing a stirrer bar and fitted with a reflux condenser was
placed under nitrogen and charged with 1,3-dioxa-5,6-benzocy-
cloheptene (17, 1.00 g, 6.65 mmol), hexacarbonylchromium(0)
(1.61 g, 7.32 mmol), dry tetrahydrofuran (5 mL) and dry di-n-butyl
ether (50 mL). The suspension was thoroughly saturated with nitro-
gen, before it was heated to 135 °C and maintained under nitrogen
at the same temperature for 48 h. The yellow reaction mixture was
then cooled to room temperature and the solvent was removed in
vacuo. Purification of the crude products by flash column
chromatography (silica gel; hexane/ethyl acetate, 9:1 to 3:1) af-
forded 18 as a yellow crystalline solid (1.52 g, 80%). Rf = 0.29
(silica gel; hexane/ethyl acetate, 3:1); m.p. 170–172 °C. IR
Experimental Section
General: All reactions were performed under dry nitrogen using
standard vacuum line and Schlenk tube techniques.[26] Reactions
involving the use of (arene)tricarbonylchromium(0) complexes were
protected from sunlight. Tetrahydrofuran was distilled from sodium
benzophenone ketyl and used immediately. The concentrations of
alkyllithiums were determined by titration against diphenylacetic
acid in tetrahydrofuran.[27] Chiral bis-amine (+)-2,[9] the benzofu-
ranchromium(0) complex 15,[14] acetal 17,[18,28] ketal 18[18,19] and
the chiral amine (+)-28[22] were prepared according to the corre-
sponding literature procedure. All remaining chemicals were used
as purchased from commercial sources. Thin layer chromatography
was performed on Merck silica gel glass plates (60 F254) using UV
light (254 nm) as visualizing agent and/or vanillin or potassium
permanganate and heat as developing agents. Flash column
chromatography was performed with BDH silica gel (330–70 µm
particle size). Melting points were recorded in open capillaries with
a Buchi 510 melting point apparatus and are uncorrected. Optical
rotations were recorded with a Perkin–Elmer 241 Polarimeter using
a 1-dm path length and concentrations are given as gmL–1. IR
spectra were recorded with a Perkin–Elmer 1600 FT-IR spectrome-
ter. NMR spectra were recorded at room temperature with Bruker
AC 300F instruments in CDCl3. J values are reported in Hz and
chemical shifts in ppm. Mass spectra were recorded with Micro-
mass Platform II and Micromass AutoSpec-Q spectrometers. Ana-
lytical HPLC was performed with a Unicam Crystal 200 pump, a
Unicam 100 UV/Vis Detector and a Daicel Chiralcel AS column
(25 cm×0.46 cm). Elemental analyses were performed by the Lon-
don Metropolitan University microanalytical service.
(CH Cl ): νmax = 1970, 1891 cm–1 (CϵO). 1H NMR (300 MHz,
˜
2
2
CDCl3): δ = 4.62 (d, J = 14.0 Hz, 2 H, ArCHH×2), 4.73 (d, J =
14.0 Hz, 2 H, ArCHH×2), 4.92 (d, J = 5.0 Hz, 1 H, OCHHO),
5.03 (d, J = 5.0 Hz, 1 H, OCHHO), 5.28 (s, 4 H, CCrH×4) ppm.
13C NMR (75 MHz, CDCl3): δ = 70.5 (ArCH2 ×2), 90.8 and 91.8
(CCrH×2), 94.6 (OCH2O), 98.4 and 109.5 (CCr), 232.3
(CϵO×3) ppm. MS (EI): m/z (%) = 286 (28) [M+], 202 (57) [M+
3 CO], 52 (100) [Cr]. C12H10CrO5 (286.20): calcd. C 50.35, H 3.52;
found C 50.41, H 3.49.
–
Acetal Chromium(0) Complex (–)-19: A precooled (–40 °C) solution
of complex 18 (1.0n mmol) in tetrahydrofuran (8.0n mL) was intro-
duced dropwise through a short cannula to the reaction mixture
containing the chiral bis-amide obtained as described above. After
stirring the orange solution at –40 °C for a period of 45 min, iodo-
methane (10.0n mmol) was added in one portion, which resulted
in a colour change of the solution to yellow. The reaction mixture
was then stirred for 1.5 h at –40 °C before methanol (1.0n mL) was
added and the solvent removed in vacuo. Purification of the residue
by flash column chromatography (silica gel; hexane/ethyl acetate,
10:0 to 8.5:1.5) afforded (–)-19 as a yellow oil (0.360 g, 86%). Rf =
0.32 (silica gel; hexane/ethyl acetate, 3:1). [α]2D0 = –29.3 (c = 0.001
General Experimental for the Preparation of Chiral Bis-amide from
(+)-2: n-Butyllithium (2.50  in hexanes) (2.2n mmol) was added
dropwise to a stirred solution of the bis-amine (+)-2 (1.1n mmol)
in dry tetrahydrofuran (12.0n mL) at –78 °C under nitrogen. The
solution was then warmed to room temperature over a period of
30 min. The resulting deep red solution was recooled to –78 °C,
and a solution of heat-gun-dried lithium chloride (1.1n mmol) in
tetrahydrofuran (4.0n mL) was added dropwise through a cannula
and the reaction mixture was stirred for a further 5 min.
in CHCl ). IR (neat): ν
= 1968, 1891 cm–1 (CϵO). 1H NMR
˜
3
max
(300 MHz, CDCl3): δ = 1.55 (d, J = 6.5 Hz, 3 H, CHCH3), 4.56
(d, J = 14.0 Hz, 1 H, ArCHH), 4.80 (d, J = 14.0 Hz, 1 H, ArCHH),
4.93 (q, J = 6.5 Hz, 1 H, CHCH3), 5.00 (d, J = 6.0 Hz, 1 H,
OCHHO), 5.18 (d, J = 6.0 Hz, 1 H, OCHHO), 5.28–5.37 (m, 4 H,
C
CrH) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.2 (CH3), 71.8
(ArCH2), 76.6 (CHCH3), 90.0, 91.0, 91.3 and 92.9 (CCrH), 98.6
(OCH2O) 109.5 and 112.7 (CCr), 232.3 (CϵO×3) ppm. MS (CI):
m/z (%) = 318 (100) [M + NH4+], 301 (99) [M + H+], 271 (22)
[M+ – OCH2 + H+]. C13H12CrO5 (300.19): calcd. C 52.00, H 4.02;
found C 51.96, H 3.96.
Benzofuran Chromium(0) Complex (–)-16: A precooled (–78 °C)
solution of complex 15 (1.0n mmol) in tetrahydrofuran (8.0n mL)
was introduced dropwise through a short cannula to the reaction
mixture containing the chiral bis-amide obtained as described
above. After stirring the orange solution at –78 °C for a period of
10 min, iodomethane (10.0n mmol) was added in one portion,
which resulted in a colour change of the solution to yellow. The
reaction mixture was then stirred for 4 h at –78 °C before methanol
(1.0n mL) was added and the solvent removed in vacuo. Purifica-
tion of the residue by flash column chromatography (silica gel; hex-
Ketal Chromium(0) Complex 21: A 100-mL round-bottomed flask
containing a stirrer bar and fitted with a reflux condenser was
placed under nitrogen and charged with 2,2-dimethyl-1,3-dioxa-
5,6-benzocycloheptene (20, 0.550 g, 3.23 mmol), hexacarbonylchro-
mium(0) (0.782 g, 3.55 mmol), dry tetrahydrofuran (3 mL) and dry
di-n-butyl ether (25 mL). The suspension was thoroughly saturated
with nitrogen, before it was heated to 135 °C and maintained under
ane/ethyl acetate, 10:0 Ǟ 9:1) afforded (–)-16 as a yellow oil an inert atmosphere at the same temperature for 48 h. The yellow
(0.063 g, 60%). Rf = 0.26 (silica gel; hexane/ethyl acetate, 4:1).
reaction mixture was then cooled to room temperature and the
solvent was removed in vacuo. Purification of the crude products
by flash column chromatography (silica gel; hexane/ethyl acetate,
[α]2D0 = –8.6 (c = 0.007 in CHCl ). IR (neat): νmax = 1970, 1880 cm–1
˜
3
(CϵO). 1H NMR (300 MHz, CDCl3): δ = 1.45 (d, J = 6.5 Hz, 3
H, CHCH3), 4.86 (d, J = 12.5 Hz, 1 H, CHH), 5.00 (d, J = 12.5 Hz, 9:1 to 3:1) afforded 21 as a yellow crystalline solid (0.610 g, 60%).
1 H, CHH), 5.17 (q, J = 6.5 Hz, 1 H, CHCH3), 5.25–5.51 (m, 4 H, Rf = 0.43 (silica gel; hexane/ethyl acetate, 3:1); m.p. 100–102 °C. IR
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Synthesis of Enantioenriched C2-Symmetric Bis-Ether
(CH Cl ): ν
= 1967, 1889 cm–1 (CϵO). 1H NMR (300 MHz, before being cooled to room temperature. Upon cooling, a satu-
FULL PAPER
˜
max
2
2
CDCl3): δ = 1.51 (s, 6 H, CH3 ×2), 4.66 (s, 4 H, CH2 ×2), 5.24 (s, rated solution of potassium ()-tartrate (70 mL) was carefully
4 H, CCrH×4) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.6
added. The organic layer was separated and the aqueous layer ex-
(CH3 ×2), 63.3 (CH2 ×2), 90.7 and 90.8 (CCrH×2), 102.7 [C(CH3)2], tracted with ethyl acetate (3 × 50 mL). The combined organic layers
109.8 (CCr ×2), 232.8 (CϵO×3) ppm. MS (CI): m/z (%) = 332 (4) were washed with brine (50 mL), dried (MgSO4) and evaporated
[M + NH4+], 314 (6) [M+], 257 (100) [M+ – OC(CH3)2 + H+]. under reduced pressure. The volatiles were removed in vacuo to
C14H14CrO5 (314.29): calcd. C 53.50, H 4.49; found C 53.60, H
4.45.
give 24 as a white solid (7.10 g, 99%). Rf = 0.34 (silica gel; hexane/
ethyl acetate, 4:1); m.p. 125–127 °C. IR (CHCl ): νmax = 3424 (OH),
˜
3
1265 cm–1 (Si–CH3). H NMR (300 MHz, CDCl3): δ = 0.43 [s, 18
1
Ketal Chromium(0) Complex (–)-22: A precooled (–20 °C) solution
of complex 21 (1.0n mmol) in tetrahydrofuran (8.0n mL) was intro-
duced dropwise through a short cannula to the reaction mixture
containing the chiral bis-amide obtained as described above. After
stirring the orange solution at –20 °C for a period of 45 min, iodo-
methane (10.0n mmol) was added in one portion, which resulted
in a colour change of the solution to yellow. The reaction mixture
was then stirred for 2 h at –20 °C before methanol (0.8 mL) was
added and the solvent removed in vacuo. Purification of the residue
by flash column chromatography (silica gel; hexane/ethyl acetate,
10:0 to 9:1) afforded (–)-22 as a yellow solid (0.140 g, 60%). Rf =
H, Si(CH3)3 ×2], 4.86 (s,
C
(CH3)3 ×2], 62.9 (CH2 ×2), 134.1 (CArH×2), 142.1 (CAr ×2), 145.2
(CArSi×2) ppm. MS (CI): m/z (%) = 300 (81) [M + NH4+], 282
(100) [M+], 265 (62) [M+ – H2O]. C14H26O2Si2 (282.50): calcd. C
59.51, H 9.27; found C 59.47, H 9.27.
4
H, CH2 ×2), 7.56 (s,
2 H,
ArH×2) ppm. 13C NMR (75 MHz, CDCl3):
δ =
0.7 [Si-
Bis-ether 25: To a stirred suspension of sodium hydride (60% dis-
persion in mineral oil) (1.47 g, 36.8 mmol), previously washed with
pentane (30 mL), in tetrahydrofuran (60 mL), was added thorugh
a cannula a solution of the bis-alcohol 24 (4.15 g, 14.7 mmol), in
dry tetrahydrofuran (22 mL). The reaction mixture was stirred for
0.41 (silica gel; hexane/ethyl acetate, 4:1); m.p. 100–102 °C. [α]2D0
=
–20.7 (c = 0.001 in CHCl ). IR (neat): νmax = 1967, 1887 cm–1 1 h at 0 °C, before iodomethane (4.59 mL, 73.8 mmol) was added
˜
3
(CϵO). 1H NMR (300 MHz, CDCl3): δ = 1.48 (d, J = 6.5 Hz, 3
H, CHCH3), 1.51 (s, 6 H, CH3 ×2), 4.26 (d, J = 15.0 Hz, 1 H, 18 h. A saturated aqueous solution of ammonium chloride (40 mL)
thorugh a syringe. Stirring was continued at room temperature for
CHH), 5.04 (d, J = 15.0 Hz, 1 H, CHH), 5.13 (q, J = 6.5 Hz, 1
was then added, the organic layer was separated and the aqueous
H, CHCH3), 5.23–5.31 (m, 4 H, CCrH) ppm. 13C NMR (75 MHz, layer extracted with diethyl ether (3 × 60 mL). The combined or-
CDCl3): δ = 20.0 (CH3), 24.1 and 24.3 [C(CH3)2], 63.9 (CH2), 66.2 ganic layers were washed with brine (30 mL), dried (MgSO4) and
(CHCH3), 90.1, 91.2, 91.3 and 91.8 (CCrH), 102.4 [C(CH3)2], 111.7 evaporated under reduced pressure. Flash column chromatography
and 112.1 (CCr), 232.8 (CϵO×3) ppm. MS (CI): m/z (%) = 332
(silica gel; hexane/ethyl acetate, 10:0 to 9:1) of the crude product
(58) [M + NH4+], 328 (45) [M+], 271 (100) [M – OC(CH3)2 + H+]. afforded 25 as a white solid (4.22 g, 92%). Rf = 0.60 (silica gel;
C15H16CrO5 (328.27): calcd. C 54.88, H 4.91; found C 54.76, H
4.84.
hexane/ethyl acetate, 9:1); m.p. 62–64 °C. IR (CHCl ): ν
=
˜
3
max
1265 cm–1 (Si–CH3). H NMR (300 MHz, CDCl3): δ = 0.37 [s, 18
H, Si(CH3)3 ×2], 3.49 (s, 6 H, OCH3 ×2), 4.61 (s, 4 H, CH2 ×2),
7.52 (s, 2 H, CArH×2) ppm. 13C NMR (75 MHz, CDCl3): δ = 0.6
[Si(CH3)3 ×2], 58.4 (OCH3 ×2), 71.8 (CH2 ×2), 134.1 (CArH×2),
141.9 (CAr ×2), 142.1 (CArSi×2) ppm. MS (CI): m/z (%) = 328 (38)
[M + NH4+], 311 (24) [M + H+], 279 (100) [M+ – 2 OH + 3 H+].
C16H30O2Si2 (310.57): calcd. C 61.88, H 9.73; found C 61.84, H
9.82.
1
Bis-ester 23: Methyllithium (12.2 mL, 1.6  in hexanes, 19.5 mmol)
was added dropwise to a stirred solution of tetramethylpiperidine
(3.31 mL, 19.5 mmol) in dry tetrahydrofuran (95 mL) at –78 °C un-
der nitrogen. The solution was then warmed to 0 °C over a period
of 30 min. The resulting light yellow solution was recooled to
–78 °C and trimethylsilyl chloride (10.7 mL, 84.9 mmol) was added
followed by diisopropyl phthalate (2.0 mL, 8.49 mmol). The solu-
tion was kept at –78 °C for 20 min and then slowly warmed to
room temperature. The reaction mixture was left stirring at the
same temperature for 1 h before methanol (5 mL) was added and
the solvent evaporated under vacuum. Purification of the crude
products by flash column chromatography (silica gel; hexane/ethyl
acetate, 4:1) afforded 23 as a white solid (3.30 g, 98%). Rf = 0.8
(silica gel; hexane/ethyl acetate, 4:1); m.p. 84–86 °C. IR (CH2Cl2):
Chromium(0) Complex 26: A 250-mL round-bottomed flask con-
taining a stirrer bar and fitted with a reflux condenser was placed
under nitrogen and charged with the bis-ether 25 (1.90 g,
6.12 mmol), hexacarbonylchromium(0) (1.48 g, 6.73 mmol), dry
tetrahydrofuran (6.0 mL) and dry di-n-butyl ether (61.0 mL). The
suspension was thoroughly saturated with nitrogen, before it was
heated to 135 °C and maintained under nitrogen at the same tem-
ν
= 1722 (C=O), 1265 cm–1 (Si–CH3). 1H NMR (300 MHz, perature for 24 h. The yellow reaction mixture was then cooled to
˜
max
CDCl3): δ = 0.31 [s, 18 H, Si(CH3)3 ×2], 1.40 (d, J = 6.0 Hz, 12 H,
CHCH3 ×4), 5.18–5.24 (m, 2 H, CH3CHCH3 ×2), 7.62 (s, 2 H, of the crude product through celite afforded 26 as a yellow crystal-
ArH×2) ppm. 13C NMR (75 MHz, CDCl3): δ = –0.7 [Si-
line solid (2.68 g, 98%). Rf = 0.56 (silica gel; hexane/ethyl acetate,
(CH3)3 ×2], 21.8 (CHCH3 ×4), 69.4 (CHCH3 ×2), 135.2 (CArH×2), 4:1); m.p. 108–110 °C. IR (neat): ν
= 1962, 1889 cm–1 (CϵO).
room temperature and the solvent was removed in vacuo. Filtration
C
˜
max
137.9 (CAr ×2), 139.2 (CArSi×2), 169.8 (C=OOCH×2) ppm. MS
1H NMR (300 MHz, CDCl3): δ = 0.39 [s, 18 H, Si(CH3)3 ×2], 3.43
(CI): m/z (%) = 412 (83) [M + NH4+], 335 (100) [M+ – OCH- (s, 6 H, OCH3 ×2), 4.19 (s, 4 H, CH2 ×2), 5.31 (s, 2 H,
(CH3)2], 277 (23) [M+ – 2 OCH(CH3)2]. C20H34O4Si2 (394.65):
C δ = 0.6 [Si-
ArH×2) ppm. 13C NMR (75 MHz, CDCl3):
calcd. C 60.86, H 8.68; found C 60.94, H 8.69.
(CH3)3 ×2], 58.8 (OCH3 ×2), 70.3 (CH2 ×2), 98.1 (CArH×2), 103.3
(CAr ×2), 111.1 (CArSi×2), 232.9 (CϵO×3) ppm. MS (EI): m/z (%)
= 446 (13) [M+], 362 (72) [M+ – 3 CO], 300 (100) [M+ – 2 Si-
(CH3)3]. C19H30CrO5Si2 (446.60): calcd. C 51.09, H 6.77; found C
50.95, H 6.68.
Bis-alcohol 24: A 500-mL flask containing a magnetic stirrer was
placed under an inert atmosphere and charged with lithium alu-
minium hydride (1.93 g, 50.7 mmol). Tetrahydrofuran (80 mL) was
added through a syringe. The suspension was vigorously stirred and
then cooled to 0 °C before a solution of the phthalate 23 (10.0 g,
25.3 mmol) in tetrahydrofuran (80 mL) was introduced through a
cannula over a period of 10 min. After the addition was complete
a condenser was fitted and the reaction heated at reflux for 16 h
Chromium(0) Complex ( )-30: n-Butyllithium (0.59 mL, 2.5  in
hexanes, 1.48 mmol) was added dropwise to a stirred solution of
( )-bis-α-methybenzylamine (29, 0.34 mL, 1.48 mmol), in dry
tetrahydrofuran (10 mL) at –78 °C. The solution was then warmed
Eur. J. Org. Chem. 2006, 1867–1875
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1873

M. P. Castaldi, S. E. Gibson, A. J. P. White
FULL PAPER
to room temperature over a period of 30 min. The resulting light
yellow solution of the chiral amide was re-cooled to –12 °C and a
solution of heat-gun-dried lithium chloride (0.063 g, 1.48 mmol) in
tetrahydrofuran (10 mL) was added through a cannula. Stirring was
continued for a further 5 min before a pre-cooled solution (–12 °C)
of complex 26 (0.600 g, 1.34 mmol) in tetrahydrofuran (14 mL) was
introduced dropwise through a short cannula. After stirring the
orange solution at –12 °C for 1.5 h, iodomethane (0.83 mL,
13.4 mmol) was added in one portion leading to a colour change
of the solution to yellow. Stirring was continued for a further 1.5 h
before the reaction was quenched with methanol (0.5 mL) and the
solvent removed in vacuo. Flash column chromatography (silica
gel; hexane/ethyl acetate, 10:0 to 9.7:0.3) of the residue afforded
( )-30 as a yellow solid (0.498 g, 81%). Rf = 0.63 (silica gel; hexane/
portion, which resulted in a colour change of the solution to yellow.
The reaction mixture was then stirred for 60 min at –78 °C before
methanol (0.5 mL) was added and the solvent removed in vacuo.
Purification of the residue by flash column chromatography (silica
gel; hexane/ethyl acetate, 10:0 to 4:1) afforded complex (+)-12 as a
yellow solid (0.112 g, 27%) and complex (–)-11 as a yellow solid
(0.304 g, 73%). Enantiomeric excess for (+)-12 was determined by
HPLC analysis (Chiralcel AS, hexane/2-propanol, 99.5:0.5,
0.25 mLmin–1, 330 nm); (S,S)-enantiomer tr = 39.60 min (minor);
(R,R)-enantiomer tr = 42.20 min (major): 85% ee. Enantiomeric
excess for (–)-11 was determined by HPLC analysis (Chiralcel AS,
hexane/2-propanol, 99.5:0.5, 0.25 mLmin–1, 330 nm); (R)-enantio-
mer tr = 59.36 min (minor); (S)-enantiomer tr = 62.75 min (major):
35% ee.
ethyl acetate, 9.6:0.4); m.p. 98–100 °C. IR (neat): ν
= 1959,
˜
max
Complex (–)-11 was further reacted as follows: n-butyllithium
(0.26 mL, 1.6  in hexanes, 0.42 mmol) was added dropwise to a
stirred solution of the bis-amine (+)-2 (0.194 g, 0.46 mmol) in dry
tetrahydrofuran (8 mL) at –78 °C under nitrogen. The solution was
then warmed to room temperature over a period of 30 min. The
resulting deep red solution was recooled to –78 °C and a solution
of heat gun dried lithium chloride (0.018 g, 0.42 mmol) in tetra-
hydrofuran (5 mL) was added dropwise through a cannula. The
reaction mixture was stirred for a further 5 min before a precooled
(–78 °C) solution of the complex (–)-11 (35% ee, from the above
reaction) (0.266 g, 0.84 mmol) in tetrahydrofuran (8 mL) was intro-
duced dropwise through a short cannula. After stirring the orange
solution at –78 °C for a period of 45 min, iodomethane (0.26 mL,
4.20 mmol) was added in one portion, which resulted in a colour
change of the solution to yellow. The reaction mixture was then
stirred for 60 min at –78 °C before methanol (0.5 mL) was added
and the solvent removed in vacuo. Purification of the residue by
flash column chromatography (silica gel; hexane/ethyl acetate, 10:0
to 4:1) afforded the complex (+)-12 as a yellow solid (0.072 g, 25%)
and the complex (–)-11 as a yellow solid (0.172 g, 65%).
1886 cm–1 (CϵO). H NMR (300 MHz, CDCl3): δ = 0.40 [s, 9 H,
Si(CH3)3], 0.41 [s, 9 H, Si(CH3)3], 1.53 (d, J = 6.5 Hz, 3 H,
CHCH3), 3.41 (s, 3 H, OCH3), 3.42 (s, 3 H, OCH3), 4.12 (d, J =
11.0 Hz, 1 H, CHH), 4.59 (d, J = 11.0 Hz, 1 H, CHH), 5.17 (d, J
= 6.5 Hz, 1 H, CArH), 5.47 (d, J = 6.5 Hz, 1 H, CArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 0.9, 1.5 [Si(CH3)3], 22.3 (CHCH3),
57.1 and 58.2 (OCH3), 70.2 (CH2), 76.6 (CHCH3), 96.1 and 101.4
(CArH), 110.5 and 119.1 (CAr), 133.8 and 134.0 (CArSi), 233.3
1
(CϵO×3) ppm. MS (EI): m/z (%) = 460 (9) [M+], 376 (47) [M+
–
3 CO], 314 (100) [M+ – 2 Si(CH3)3]. C20H32CrO5Si2 (460.63): calcd.
C 52.14, H 7.00; found C 52.17, H 6.97.
Chromium(0) Complex ( )-11: To a solution of complex ( )-30
(0.080 g, 0.17 mmol) at room temperature in tetrahydrofuran
(14 mL) was added dropwise under nitrogen a solution of tetra-n-
butylammonium fluoride (0.69 mL, 1.0  in tetrahydrofuran,
0.69 mmol). The reaction mixture was stirred for 15 min and satu-
rated ammonium chloride (28 mL) was added. The mixture was
extracted with dichloromethane (3 × 30 mL), the organic extracts
were combined, washed with brine (50 mL), dried with magnesium
sulfate and then concentrated in vacuo. Purification of the crude
product by flash column chromatography (silica gel; hexane/ethyl
acetate, 4:1) afforded ( )-11 as a yellow solid (0.051 g, 95%). Rf =
Data for (–)-11: Enantiomeric excess was determined by HPLC
analysis (Chiralcel AS, hexane/2-propanol, 99.5:0.5, 0.25 mLmin–1,
330 nm); (S)-enantiomer tr = 59.36 min (minor); (R)-enantiomer tr
= 62.75 min (major): 96% ee. Rf = 0.28 (silica gel; hexane/ethyl
acetate, 4:1); m.p. 36–37 °C. [α]2D0 = –72.8 (c = 0.001 in CHCl3). All
data were identical to those obtained for ( )-11.
0.28 (silica gel; hexane/ethyl acetate, 4:1); m.p. 35–38 °C. IR (neat):
1
ν
= 1967, 1886 cm–1 (CϵO). H NMR (300 MHz, CDCl3): δ =
˜
max
1.53 (d, J = 6.5 Hz, 3 H, CHCH3), 3.33 (s, 3 H, OCH3), 3.50 (s, 3
H, OCH3), 4.12 (d, J = 12.0 Hz, 1 H, CHHOCH3), 4.29 (q, J =
6.5 Hz, 1 H, CHCH3), 4.54 (d, J = 12.0 Hz, 1 H, CHHOCH3),
5.22–5.27 (m, 1 H, CCrH), 5.40 (d, J = 6.0 Hz, 1 H, CCrH), 5.47–
5.51 (m, 1 H, CCrH), 5.64 (d, J = 6.0 Hz, 1 H, CCrH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 20.8 (CHCH3), 56.4 and 59.1
(OCH3), 70.5 (CH2OCH3), 73.9 (CHCH3), 89.5, 90.5, 93.2 and 94.2
(CCrH), 108.2 and 110.6 (CCr), 232.7 (CϵO×3) ppm. MS (EI):
m/z (%) = 316 (38) [M+], 232 (74) [M+ – 3 CO], 172 (86) [M+ – 3
CO – 2 OCH3], 52 (100) [Cr]. C14H16CrO5 (316.26): calcd. C 53.16,
H 5.09; found C 53.19, H 5.09.
Data for (+)-12: Enantiomeric excess was determined by HPLC
analysis (Chiralcel AS, hexane/2-propanol, 99.5:0.5, 0.25 mLmin–1,
330 nm); (S,S)-enantiomer tr = 39.60 min (minor); (R,R)-enanti-
omer tr = 42.20 min (major): 95% ee. Rf = 0.28 (silica gel; hexane/
ethyl acetate, 4:1); m.p. 40–42 °C. [α]2D0 = +84.2 (c = 0.001 in
CHCl ). IR (neat): ν
= 1961, 1876 cm–1 (CϵO). 1H NMR
˜
3
max
(300 MHz, CDCl3): δ = 1.48 (d, J = 6.0 Hz, 3 H, CHCH3), 1.52
(d, J = 6.0 Hz, 3 H, CHCH3), 3.36 (s, 3 H, OCH3), 3.53 (s, 3 H,
OCH3), 4.25 (q, J = 6.0, 1 H, CHCH3), 4.35(q, J = 6.0, 1 H,
CHCH3), 5.34–5.30 (m, 1 H, CCrH), 5.51–5.43 (m, 2 H, CCrH×2),
5.57–5.55 (m, 1 H, CCrH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 18.5 and 23.8 (CHCH3), 55.9 and 57.7 (OCH3), 73.3 and 73.8
(CHCH3), 88.5, 90.9, 91.1 and 93.1 (CCrH), 108.5 and 115.9 (CCr),
Chromium(0) Complexes (–)-11 and (+)-12: n-Butyllithium
(0.39 mL, 1.6  in hexanes, 0.63 mmol) was added dropwise to a
stirred solution of the bis-amine (+)-2 (0.292 g, 0.69 mmol) in dry
tetrahydrofuran (10 mL) at –78 °C under nitrogen. The solution
was then warmed to room temperature over a period of 30 min.
The resulting deep red solution was recooled to –78 °C and a solu-
tion of heat gun dried lithium chloride (0.027 g, 0.63 mmol) in
tetrahydrofuran (10 mL) was added dropwise through a cannula.
The reaction mixture was stirred for a further 5 min before a preco-
oled (–78 °C) solution of complex ( )-11 (0.400 g, 1.26 mmol) in
232.9 (CϵO×3). MS (EI): m/z (%) = 330 (14) [M+], 274 (20) [M+
–
2 CO], 246 (59) [M+ – 3 CO], 182 (100) [M+ – 2 OCH3].
C15H18CrO5 (330.29): calcd. C 54.54, H 5.49; found C 54.67, H
5.57.
Bis-ether (+)-13: Ceric ammonium nitrate (0.329 g, 0.60 mmol) was
added to a solution of complex (+)-12 (0.100 g, 0.30 mmol) in
tetrahydrofuran (11 mL) was introduced dropwise through a short methanol (7 mL). The resulting mixture was stirred at room tem-
cannula. After stirring the orange solution at –78 °C for a period
of 45 min, iodomethane (0.39 mL, 6.32 mmol) was added in one
perature for 15 min. The reaction mixture was then concentrated
in vacuo to afford the crude product which was purified by flash
1874
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1867–1875

Synthesis of Enantioenriched C2-Symmetric Bis-Ether
FULL PAPER
[9] K. Bambridge, M. J. Begley, N. S. Simpkins, Tetrahedron Lett.
1994, 35, 3391–3394.
column chromatography (silica gel; hexane/diethyl ether, 4:1) to af-
ford (+)-13 as a colourless oil (0.053 g, 91%). Rf = 0.75 (silica gel;
hexane/diethyl ether, 4:1). [α]2D0 = +151.7 (c = 0.001 in CHCl3). IR
[10] S. G. Davies, T. D. McCarthy, in: Comprehensive Organometal-
lic Chemistry II (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkin-
son), Pergamon, New York, 1995, vol. 12, p. 1057.
[11] M. P. Castaldi, S. E. Gibson, M. Rudd, A. J. P. White, Angew.
Chem. 2005, 117, 3498–3501; Angew. Chem. Int. Ed. 2005, 44,
3432–3435.
(CH Cl ): ν
= 1214 cm–1 (C–O–C). 1H NMR (300 MHz,
˜
max
2
2
CDCl3): δ = 1.47 (d, J = 6.5 Hz, 6 H, CHCH3 ×2), 3.23 (s, 6 H,
OCH3 ×2), 4.65 (q, J = 6.5 Hz, 2 H, CHCH3 ×2), 7.29–7.32 (m, 2
H, CArH×2), 7.43–7.46 (m, 2 H, CArH×2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 23.6 (CHCH3 ×2), 56.3 (OCH3 ×2), 75.4
(CHCH3 ×2), 125.7 and 127.7 (CArH×2), 140.8 (CAr ×2) ppm. MS
(CI): m/z (%) = 212 (73) [M + NH4+], 195 (48) [M + H+], 163 (100)
[M+ – OCH3]. HMRS (CI) for C12H18O2 [M + H+] calcd. 195.1389,
found 195.1384.
[12] M. P. Castaldi, S. E. Gibson, A. J. P. White, unpublished re-
sults.
[13] a) M. P. Castaldi, Ph. D. Thesis, Imperial College London,
2005; b) It has been previously reported that treatment of race-
mic 5 with BuLi followed by iodomethane gives meso complex
6: J. Blagg, S. G. Davies, N. J. Holman, C. A. Laughton, B. E.
Mobbs, J. Chem. Soc., Perkin Trans. 1 1986, 1581–1589.
[14] S. J. Coote, S. G. Davies, D. Middlemiss, A. Naylor, J. Or-
ganomet. Chem. 1989, 379, 81–88.
[15] R. A. Ewin, N. S. Simpkins, Synlett 1996, 317–318.
[16] For an other example of benzylic functionalisation of 1,3-dihy-
droisobenzofuran chromium complex see: S. Zemolka, J. Lex,
H.-G. Schmaltz, Angew. Chem. 2002, 114, 2635–2638; Angew.
Chem. Int. Ed. 2002, 41, 2525–2528.
X-ray Crystallography of ( )-12: Crystal data for ( )-12:
¯
C15H18CrO5; M = 330.29; crystal system: triclinic, P1; cell dimen-
sion: a = 8.5604(7), b = 8. 6953(8), c = 11.7914(11) Å, α =
72.248(8), β = 79.510(7), γ = 67.390(8)°; V = 769.56(12) Å3; Z = 2;
Dcalcd. = 1.425 g/cm–3; µ(Cu-Kα) = 6.284 mm–1; F(100) = 344; T =
173(2) K; pale yellow prisms; crystal dimensions: 0.07 × 0.07 ×
0.06 mm3; θ range 3.95 to 71.01°; hkl limits: –9,10/–10,10/–13,14;
number of data measured: 6883; number of data with F Ͼ 4σ(F):
2774; number of variables 190; goodness-of-fit on F2: 1.056; R1 =
0.0348; Rw = 0.0921; largest diff. peak: 0.344 e·Å–3.
[17] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Syn-
thesis, 3rd Ed., Wiley: New York, 1999, p. 201.
[18] T. P. Kumar, K. R. Reddy, R. S. Reddy, J. Chem. Res. 1994,
394–395.
CCDC-282315 contains supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
[19] N. Machinaga, C. Kibayashi, Tetrahedron Lett. 1989, 30, 4165–
4168.
[20] M. Uemura, T. Kobayashi, T. Minami, Y. Hayashi, Tetrahedron
Lett. 1986, 27, 2479–2482.
[21] T. D. Krizan, J. C. Martin, J. Am. Chem. Soc. 1983, 105, 6155–
6157.
[1] a) A. Pfaltz, W. J. Drury, Proc. Nat. Acad. Sci. 2004, 101, 5723–
5726; b) I. Ojima, Catalytic Asymmetric Synthesis, 2nd ed., [22] K. Aoki, K. Koga, Chem. Pharm. Bull. 2000, 48, 571–574.
Wiley: New York, 2000.
[23] From this point onwards, the mono-amide derived from 29 was
used in racemic form. Optimisation of the reaction of complex
26 with ( )-29/butyllithium gave ( )-30 in 81% yield.
[24] S. E. Gibson, E. G. Reddington, Chem. Commun. 2000, 989–
996 and references cited therein.
[25] For the preparation of similar compounds by catalytic enantio-
selective additions of organozincs to phthaldialdehyde see: a)
H. Kleijn, J. T. B. H. Jastrzebski, J. Boersma, G. van Koten,
Tetrahedron Lett. 2001, 42, 3933–3937; b) M. Asami, M. Wada,
S. Furuya, Chem. Lett. 2001, 1110–1111.
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Received: January 10, 2006
Published Online: February 9, 2006
Eur. J. Org. Chem. 2006, 1867–1875
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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