Asymmetric transfer hydrogenation using amino acid derivatives; Further studies and a mechanistic proposal

Article abstract of DOI:10.1016/j.tet.2005.06.004

A series of investigations into the use of amino acid derivatives for the asymmetric catalysis of the transfer hydrogenation of ketones are presented. Based on the results observed, a mechanistic suggestion for the origin of the enantioselective induction

Full text of DOI:10.1016/j.tet.2005.06.004

Tetrahedron 61 (2005) 7994–8004
Asymmetric transfer hydrogenation using amino acid derivatives;
further studies and a mechanistic proposal
*
Aveline S. Y. Yim and Martin Wills
Department of Chemistry, The University of Warwick, Coventry CV4 7AL, UK
Received 15 April 2005; revised 17 May 2005; accepted 2 June 2005
Available online 28 June 2005
Abstract—A series of investigations into the use of amino acid derivatives for the asymmetric catalysis of the transfer hydrogenation of
ketones are presented. Based on the results observed, a mechanistic suggestion for the origin of the enantioselective induction is proposed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In recent years, a variety of ligands have been prepared and
their effectiveness in Ru(II) catalysed asymmetric transfer
hydrogenation (ATH) evaluated.1 Amongst the best ligands
are b-amino alcohols and monoarylsulfonylated 1,2-
diamines.1–7Applications include a- and b-substituted
substrates,5 medicinally important targets6 and unsaturated
ketones.7 A mixture of N-tosyl-(1S,2S)-diphenylethylene-
diamine (TsDPEN), [RuCl2(h6-mesitylene)]2 and TsDPEN
when heated at 80 8C for 20 min gave the catalyst 1.
Addition of acetophenone in isopropanol to 1 and KOH led
to the formation of (S)-1-phenylethanol with a yield of 95%
(97% ee) after 15 h.3
The mechanism for the catalytic cycle of transfer
hydrogenation is illustrated in Scheme 1. A ruthenium
Scheme 1. Asymmetric reduction by Ru/TsDPEN catalysts.
hydride 3 is formed, via the reaction of 16-electron
intermediate 2 with the hydrogen donor (isopropanol or
formic acid). The hydritic Ru–H and the protic N–H are
that (1R,2S)-cis-aminoindan-2-ol was also an excellent
ligand.4a
transferred simultaneously to the C]O functional group via
a six-membered transition state.2–4 Noyori has isolated and
characterised intermediates, 1, 2, and 3 by X-ray
Despite the fact that they exist naturally in abundance, are
readily accessible, and relatively inexpensive, amino
crystallography.3a
acids and peptides have not been widely applied to
asymmetric transfer hydrogenation.8a a-Amino acidate
ruthenium catalyst complexes have been synthesised
Amino alcohols represent good ligands for this application.
A combination of (1S,2S)-N-methyl-1,2-diphenylethanol 4
and [RuCl2(h6-hexamethylbenzene)]2 formed a catalyst,
by reaction of a-amino acidate anion with [RuCl2-
(arene)]2.8b,c The catalyst complex derived from L-proline
which afforded (S)-1-phenylethanol in 94% yield and 92%
ee after 1 h at 28 8C.2a Work in our group revealed
5 gave (R)-1-phenylethanol in 72% yield and 81% ee
(Scheme 2).
Chung8d reported the use of aminoamides derived from
proline as chiral ligands. Ligand 6 catalysed the reduction of
acetophenone in 97% conversion with an 80% ee in 7 h.
Keywords: Asymmetric; Transfer; Hydrogenation; Ketones; Aminoacids;
Amino alcohols; Reduction.
*
Corresponding author. Tel.: C44 24 7652 3260; fax: C44 24 7652 4112;
e-mail: m.wills@warwick.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.004

A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
7995
We wished to examine whether the amino alcohol part of
the dipeptide ligand could contain a 1,2-disubstituted
system. Towards this end, norephedrine and cis-amino
indanol were investigated in place of phenylglycinol. These
amino alcohols have been used successfully in ATH.
Ligands 11 and 12 were prepared by the coupling of the
appropriate TBS-protected amino alcohols with S-N-tBoc-
valine to give 13 and 14, respectively, followed by
desilylation. Attempted application of both ligands 11 and
Scheme 2. Ketone reduction using aminoalcohol and peptide ligands.
Faller8e et al. also researched chiral ligands derived from
L-prolinamide 7 for ruthenium catalysed asymmetric
transfer hydrogenation. In 20 h at K24 8C, 7 reduced
acetophenone to give (R)-1-phenylethanol in 90% yield and
79% ee. The asymmetric reduction of other substrates
proceeded smoothly to afford moderate to good yields and
ees. Adolfsson9 reported the use of 8, a dipeptide analogue,
as a chiral ligand. In the asymmetric reduction of a series of
ketones; (S)-1-phenylethanol was obtained in 78%
conversion and 95% ee. Other ketones were also reduced
in good conversions and ees. It was found that, although, the
chirality of the amino alcohol contributed to enhancing the
ee of the reduction product, its configuration was primarily
determined by the stereocenter of the amino acid part of the
ligand. Adolfsson also noted that the t-Boc protecting group
was critical for the reaction as, without it, no conversion was
observed.
1
12 in ATH of acetophenone was not successful. H NMR
spectra showed no formation of phenylethanol. This clearly
demonstrated that a 1,2-disubstitution pattern in the amino
alcohol is detrimental to the activity of the ligand.
Since, we have published in the area of asymmetric transfer
hydrogenation, we chose to undertake a short investigation
into this practical and effective class of ligands. Following
the conclusion of our research, Adolfsson has published
further full papers10 describing his detailed research on
dipeptide anologues in enantioselective reduction of
ketones.
Boc-L-alanine and Boc-L-phenylalanine were selected to
replace Boc-L-valine in the ligand. These were selected in
order to examine the effects of smaller and larger amido
substitutents on the selectivity of the ligands. Compound 15
was anticipated to be the matched version of the dipeptide
analogue ligand, whereas 16 the mismatched, on the basis of
analogy with Adolfsson’s results. Both ligands were
prepared via peptide couplings to give 18a and 18b,
respectively, followed by desilylation. The other dia-
stereoisomer of the alanine compound, 17 (matched), was
synthesised using the one-step coupling method between
R-phenylalanine and S-N-tBoc-valine. The yield for this
product was 76% after purification by flash column
chromatography. Adolfsson has since, reported the use of
the same ligands in ATH. Ligands 15–17 were applied to the
Ru(II)-catalysed asymmetric transfer hydrogenation of a
series of ketones. In all cases, the ligand loading was
3 mol%, and the Ru dimer 0.5 mol% representing a
threefold excess of ligand relative to Ru(II) atoms. The
reactions were carried out for 2 h at room temperature under
nitrogen and the products analysed by GC or HPLC after
isolation. The results for these asymmetric reductions are
summarised in Table 1.
2. Results and discussion
In order to confirm that our practical technique was
adequate, ligand 8 was examined first. The synthesis of 8
was achieved using EDCI/HOBt coupling of O-t-butyl-
dimethylsilyl protected R-phenylglycine 9 with S-N-tBoc-
valine to give 10, followed by desilylation. Subsequently, it
was discovered that the synthesis of similar ligands could in
some cases be reduced to just the coupling step; the
protection of the free hydroxy was not always necessary.
Ligand 8 was applied to the reduction of acetophenone,
using the conditions reported by Adolfsson, that is, 3 mol%
of 8, 0.5 mol% [RuCl2(p-cymene)], 5 mol% 0.2 M NaOH,
the reduction was run for 2 h at room temperature under
1
nitrogen. Analysis of the product by H NMR and HPLC
showed that (S)-1-phenylethanol was formed in 90%
conversion and 98% ee.

7996
A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
Table 1. Asymmetric reduction of ketones using ligands 15–17
Substrate
Ligand
15 Conv%
15 ee/%
16 Conv%
16 ee/%
17 Conv%
17 ee/%
Acetophenone
31
60
34
11
35
91 S
89 S
90 S
82 S
65 S
76
93
27
35
76
88 S
88 S
89 S
80 S
96 S
80
17
84
55
86
90 S
62 S
74 S
89 S
87 S
4-Chloroacetophenone
4-Fluoroacetophenone
4-Methoxyacetophenone
4-Acetonapthone
Ketone:ligand:[RuCl2(p-cymene)]2: NaOHZ100:3:0.5:1, 2 h.
effective ligands and analysis of these reactions by 1H NMR
showed no presence of phenylethanol even when the
reactions were heated at 80 8C for 18 h. This shows that
the presence of a carbamate may be essential for the catalyst
to be effective. This has since been substantiated by
Adolfsson.10
In order to investigate the importance of the presence of a
hydroxy group in the amino alcohol part of the ligand, 23
and 24 were synthesised. The construction of these
ligands were carried out via the EDCI/HOBt coupling
method from Boc-L-valine and S- and R-a-methylbenzyl-
amine, respectively. Purification of the compounds by
recrystallisation afforded 23 and 24 in 74 and 32% yield. In
addition, 18b, an intermediate in the synthesis of 16, was
used as a ligand in the reduction of acetophenone to test
whether the hydroxy group has to be unprotected, or if an
alkoxy group at this position was an essential requirement.
Ligands 23, 24 and 18b were applied to the Ru(II)-catalysed
reduction of acetophenone. None of these were effective
ligands and analysis of these reactions by 1H NMR showed
no presence of phenylethanol. This confirms that the
presence of a OH group is vital for the reduction.
Comparisons of results between matched alanine and
matched phenylalanine ligands (15 and 17) indicated that
ligands with the smaller R group on the amino acid residue
gave better conversions. Enantiomeric excesses for both
these ligands are good and lie within the 60–90% region.
The major enantiomer formed by all three ligands was S,
confirming that the amino acid has the dominant directing
effect.
The importance of the N termini of the amino acid part of
the ligand has been noted.9 The possibility of replacing the
Boc group with other protecting groups was investigated.
The t-Boc group was first replaced by a tosyl protecting
group. Carbamate 8 was deprotected with 50% TFA/DCM
to give 19, which was tosylated directly with TsCl and Et3N
in DCM to give 20. As the dipeptide ligands derived from
alanine in place of valine were effective in the reduction of
ketones under catalytic ATH conditions, ligand 21, with a
dibenzyl protecting group in place of the t-Boc group was
synthesised. L-alanine was refluxed with benzyl bromide
and K2CO3 in EtOH/H2O to give 22, which was then
converted to 21 via carboxyl deprotection, and coupling to
phenylglycinol.
We wished to examine whether the terminal OH group of
the ligand could be replaced by a carbonyl group such as an
ester or a carboxylic acid. The synthesis of 25 was carried
out via EDCI/HOBt coupling of benzyl ester L-alanine
tosylate and Boc-D-alanine. Compound 25 was then
deprotected to 26 using Pd/C-catalysed hydrogenation.
Compound 27 (i.e., the equivalent alcohol) was synthesised
via EDCI/HOBt coupling of S-alinol and Boc-D-alanine.
Neither 25 nor 26 were effective ligands for the asymmetric
reduction of acetophenone, however, 27 worked well. The
conversions and ees of the reduction of various ketones are
summarised in Table 2. Although the conversions are low,
several ees are reasonable.
Ligands 20 and 21 were applied to the Ru(II)-catalysed
asymmetric transfer hydrogenation of acetophenone
(3 mol% ligand, 0.5 mol% Ru(II) dimer). Neither were

A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
Table 2. Asymmetric reduction of ketones using 27
7997
Entry
Substrate
Conv/%
ee/%
1
2
3
4
5
Acetophenone
81
39
39
25
55
80 R
76 R
83 R
93 R
77 R
4-Chloroacetophenone
4-Fluoroacetophenone
4-Methoxyacetophenone
20-Acetonaphthone
Substrate:ligand 27:[RuCl2(p-cymene)]2: NaOHZ100:3:0.5:1, 2 h.
In view of the results, a mechanism for reduction using
compounds of type 27, and 15–17, is proposed. Initial
complexation involves the oxygen of the amide coordinat-
ing to ruthenium. Adolfsson has obtained evidence to
support this.10
Figure 1. Stereochemical control in the reduction.
favoured diastereoisomer of 31 is assumed to be that
depicted in Figure 1, hydrogen will be transferred to the face
which gives the S product, which matches that observed.
This mechanism would also account for the moderating
effect (on yield and ee) of the group in the amino alcohol
part of the ligand, as its position would influence the
stability and conformation of 31 during the catalytic
process.
Upon treatment with base, the amide may be deprotonated
and an N–Ru bond may form to give a negatively charged
complex 28. This has the potential to exist in equilibrium
with a cyclic form 29. Loss of a chloride from 29 could give
a neutral form 30. Since, one nitrogen atom in 30 is now sp3
hybridised, this represents a complex equivalent to the 16
electron species 2 in the TsDPEN cycle. This could enter the
catalytic cycle by abstraction of 2 hydrogen atoms from
isopropanol to give hydride 31, which then returns the
hydrogens to the substrate to yield the product and
propagate the catalytic cycle (Scheme 3).
In conclusion, application of the various dipeptide analogue
ligands to the Ru(II)-catalysed ATH of simple aromatic
ketones demonstrated that smaller R group substituents on
the amino acid part of the ligand give better conversions.
Matched versions of the ligands give higher conversions
compared to the mismatched versions. NTs protected and
NBn2 ligands are ineffective suggesting that a carbamate
group is necessary at this position. The deletion of the
terminal hydroxy group from the ligands rendered them
ineffective. The inactiveness of the norephedrine and cis-
amino indanol substituted valine ligands suggest that the
presence of a primary alcohol is desirable. The ineffective-
ness of a carboxylic acid ligand also leads to the conclusion
that a hydroxy group is specifically necessary for the
reduction, not simply an ionisable one. Only an OH group
can form the bicyclic intermediate 29 proposed in the
catalytic cycle. The ees of products formed using the
alaninol-derived ligands were comparable to those from
the phenylgylcinol ligands but the conversions were lower.
3. Experimental
Unless otherwise stated, all reactions were run under an
atmosphere of nitrogen in flame or oven dried glassware
(round bottomed flask or Schlenk tubes). Room temperature
refers to ambient room temperature (20–22 8C). Heated
experiments were conducted using thermostatically con-
trolled oil baths. Reactions were monitored by thin-layer
chromatography (TLC) using aluminium backed silica gel
60 (F254) plates, visualised using UV254 nm and PMA. Flash
column chromatography was routinely carried out using
Scheme 3. Proposed reduction mechanism.
Since the proposed metallocycle is formed by the amino
acid residue, this may explain why it acts as the dominant
stereocentre in the reaction. However, the hydroxy group is
essential in order to convert 28 to 29 and therefore, generate
the sp3 hybridised nitrogen atom. This may explain why it is
essential to have an OH group at that position.
˚
60 A silica gel (Merck). Elemental analyses were performed
using the Exeter Analytical Model CE440. Melting points
were recorded on a Stuart Scientific SMP1 instrument and
are uncorrected. Optical rotations were measured on a
Perkin-Elmer 241 polarimeter. Infrared (IR) spectra were
recorded on a Nicolet Model Avatar 320 FTIR instrument.
Nuclear magnetic resonance (NMR) spectra were recorded
on either a Bruker DPX-300 (300 MHz) or a DPX-400
(400 MHz) spectrometer. Chemical shifts are reported in d
The hydride transfer could take place from 31 via the
transition state illustrated in Figure 1. In this process, it is
known that a-amino alcohol and TsDPEN diamine ligands
favour formation of a complex, in which the group adjacent
to O or NTs is anti to the Ru–H bond. In 31 this corresponds
to an anti arrangement of Me (*) to the Ru–H bond. If the

7998
A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
units, parts per million (ppm). Coupling constants (J) are
measured in Hz. Mass spectra were recorded on a 7070E VG
mass spectrometer. Enantiomeric excesses (ee) were
determined by high pressure liquid chromatography
(HPLC) analysis (using a Merck-Hitachi L-6200 A
intelligent pump, Merck-Hitachi L-4000 UV detector,
Axiom chromatography data system and controller model
727 and a Daicel Chiralcel OD 4.6!250 mm column) or
Gas Chromatography (GC) analysis (Hewlett Packard
5890A gas chromatography, Hewlett Packard 3396A
integrator and Supelco BETA Dexe 120 fused silica
capillary column 30 m!0.25 mm!0.25 mm film thickness)
as stated. All compounds were purchased from Aldrich,
Avocado, Strem and NovabioChem.
oil (1.30 g, 58%). [a]D24K1.5 (c 1.00, CHCl3); IR (neat, cmK1
)
3303, 2956, 2928, 1682, 1650, 1519, 1247, 1171, 1123, 834,
776 and 697; dH (400 MHz; CDCl3; Si(CH3)4) 7.31–7.21
(5H, m, ArH), 6.73 (1H, d, JZ7.0 Hz, ArCHNH), 5.12–5.09
(1H, m, (CH3)2CHCHNH), 5.01–4.97 (1H, m, ArCH), 3.96–
3.94 (1H, m, (CH3)2CHCH), 3.90–3.86 (1H, m, OCHH),
3.78–3.75 (1H, m, OCHH), 2.17–2.10 (1H, m, (CH3)2CH),
1.44 (9H, s, OC(CH3)3), 0.98 (3H, d, JZ6.7 Hz, (CH3), 0.94
(3H, d, JZ6.5 Hz, (CH3), 0.85 (9H, s, SiC(CH3)3), K0.05
(3H, s, Si(CH3)) and K0.08 (3H, s, Si(CH3)); dC (100 MHz;
CDCl3; Si(CH3)4) 171.3, 156.2, 140.4, 128.7, 127.7, 127.3,
80.1, 66.5, 60.5, 54.9, 31.3, 28.7, 26.3, 19.7, 18.6, 18.0 and
K5.3; m/z (FAB) 451 (MCHC, 86%), 395 (100), 337 (16),
235 (18), 136 (6). Found: MCHC, 451.2991.
C24H43N2O4Si requires 451.2992.
3.1. General procedure 1 for the EDCI coupling of
peptides and peptide analogues11
3.1.3. Preparation of [(S)-1-((R)-2-hydroxy-1-phenyl-
ethylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-
butyl ester, 8. To a solution of {(S)-1-[(R)-2-(tert-butyl-
dimethyl-silanyloxy)-1-phenyl-ethylcarbamoyl]-2-methyl-
propyl}-carbamic acid tert-butyl ester, 10 (800 mg,
1.78 mmol, 1.0 equiv) in THF (10 mL) was added 1 M
TBAF/THF (3.6 mL, 3.55 mmol, 2.0 equiv). The reaction
mixture was stirred at room temperature for 18 h and the
solvent evaporated in vacuo. The mixture was then diluted
with EtOAc (10 mL) and washed with H2O (10 mL). The
aqueous layer was extracted with EtOAc (3!10 mL) and
the combined organic layers were dried (Na2SO4), filtered
and concentrated in vacuo. Purification by recrystallisation
(EtOAc/hexane) yielded the product 8 as a white solid
(506 mg, 84%). Mp 132–134 8C. (Found: C, 64.18; H, 8.38;
N, 8.21. C18H28N2O4 requires C, 64.26; H, 8.39; N, 8.33%);
[a]2D4C6.8 (c 1.00, CHCl3); IR (neat, cmK1) 3304, 2968,
2870, 1686, 1651, 1519, 1336, 1300, 1244, 1170, 1041 and
699; dH (400 MHz; CDCl3; Si(CH3)4) 7.28–7.25 (5H, m,
ArH), 5.37 (1H, d, JZ7.0 Hz, (CH3)2CHCHNH), 5.00 (1H,
br s, ArCH), 3.92–3.90 (1H, m, (CH3)2CHCH), 3.77–3.75
(2H, m, OCH2), 3.47 (1H, br s, ArCHNH), 2.05–2.03 (1H,
m, (CH3)2CH), 1.41 (9H, s, C(CH3)3), 0.96 (3H, d, JZ
6.0 Hz, (CH3)) and 0.92 (3H, d, JZ5.3 Hz, (CH3)); dC
(100 MHz; CDCl3; Si(CH3)4) 172.7, 156.5, 139.4, 129.0,
127.9, 127.1, 80.4, 66.3, 61.0, 56.1, 30.9, 28.7, 19.7 and
18.6; m/z (FAB) 337 (MCHC, 80%), 307 (21), 281 (74),
237 (35), 154 (100), 136 (77), 121 (24). Found: MCHC,
337.2126. C18H29N2O4 requires 337.2127.
To a stirred solution of acid (1.0 equiv) and amine
(1.5 equiv) in dry THF (10 vol) was added HOBt
(1.5 equiv). The mixture was stirred for 30 min after,
which EDCI (1.5 equiv) and DIPEA (5.0 equiv) were
added. Stirring was continued for a further 18 h at room
temperature and solvent evaporated in vacuo. EtOAc was
added and the organic layer was washed with 5% citric acid
(2!), saturated NaHCO3 (2!), NaCl (concn) and H2O. The
organic layer was then dried with Na2SO4 or MgSO4,
filtered and concentrated in vacuo. Purification of crude
product by recrystallisation or flash column chromato-
graphy afforded the product.
3.1.1. Preparation of (R)-2-(tert-butyl-dimethyl-silanyl-
oxy)-1-phenyl-ethylamine, 9.12 To a stirred solution of
R-phenylglycinol (4.20 g, 30.6 2 mmol, 1.0 equiv) in dry
THF (40 mL) was added TBSCl (5.54 g, 36.74 mmol,
1.2 equiv) and imidazole (5.21 g, 76.54 mmol, 2.5 equiv).
The reaction mixture was refluxed for 18 h and cooled to
room temperature. EtOAc (40 mL) was added and the
organic layer was washed with 0.75 M HCl (2!20 mL)
dried (Na2SO4), filtered and concentrated in vacuo.
Purification by recrystallisation (EtOAc/hexane) afforded
the product as a white solid (6.63 g, 84%). Mp 228–230 8C;
[a]2D4K16.9 (c 1.00, EtOH); IR (neat, cmK1) 2925, 2854,
1491, 1463, 1251, 1101, 835, 763 and 698; dH (400 MHz;
CD3OD) 7.36–7.23 (5H, m, ArH), 4.07 (1H, dd, JZ4.5,
7.0 Hz, ArCH), 3.80 (1H, dd, JZ4.5, 10.3 Hz, OCHCH),
3.71 (1H, dd, JZ7.0, 10.3 Hz, OCHCH), 0.85 (9H, s,
SiC(CH3)3), K0.02 (3H, s, SiCH3CH3) and K0.04 (3H, s,
SiCH3CH3); dC (100 MHz; CD3OD) 141.1, 130.0, 129.5,
128.6, 69.0, 58.7, 26.7, 19.6, K4.9 and K4.9; m/z (FAB)
252 (MCHC, 100%), 235 (37). Found: MCHC, 252.1779.
C14H26NOSi requires 252.1778.
3.1.4. Preparation of (1S,2R)-1-(tert-butyl-dimethyl-sil-
anyloxy)-indan-2-ylamine. To a stirred solution of (1R-
2S)-cis-amino indan-2-ol (2.00 g, 13.42 mmol, 1.0 equiv) in
dry THF (20 mL) was added TBSCl (2.42 g, 16.11 mmol,
1.2 equiv) and imidazole (2.28 g, 33.56 mmol, 2.5 equiv).
The reaction mixture was refluxed overnight and cooled to
room temperature. EtOAc (20 mL) was added and the
organic layer was washed with 0.75 M HCl (2!20 mL)
dried (Na2SO4), filtered and concentrated in vacuo.
Purification by flash column chromatography afforded the
product as a pale orange oil (3.01 g, 86%). [a]2D5K34.4 (c
0.80, CHCl3); IR (neat, cmK1) 2927, 2855, 1472, 1361,
1254, 1110, 1067 and 632; dH (400 MHz; CDCl3; Si(CH3)4)
7.38–7.36 (1H, m, ArH), 7.22–7.18 (3H, m, ArH), 5.36 (1H,
br s, NH), 4.47 (1H, q, JZ5.3 Hz, CHO), 4.15 (1H, d, JZ
5.3 Hz, CHN), 3.02 (1H, dd, JZ5.9, 15.8 Hz, CHHCHO),
2.89 (1H, dd, JZ5.9, 15.8 Hz, CHHCHO), 0.91 (9H, s,
3.1.2. Preparation of {(S)-1-[(R)-2-(tert-butyl-dimethyl-
silanyloxy)-1-phenyl-ethylcarbamoyl]-2-methyl-pro-
pyl}-carbamic acid tert-butyl ester, 10. Following general
procedure 1 for EDCI coupling, (R)-2-(tert-butyl-dimethyl-
silanyloxy)-1-phenyl-ethylamine, 9 (1.28 g, 5.10 mmol,
1.0 equiv), Boc-L-valine (1.28 g, 5.87 mmol, 1.5 equiv),
HOBt (1.03 g, 7.64 mmol, 1.5 equiv), EDCI (1.46 g,
7.64 mmol, 1.5 equiv), DIPEA (4.3 mL, 25.45 mmol,
5.0 equiv) in dry THF (15 mL) gave, after purification by
flash column chromatography, the product 10 as a colourless

A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
7999
C(CH3)3) and 0.12 (6H, s, Si(CH3)2); dC (100 MHz; CDCl3;
Si(CH3)4) 144.8, 140.6, 128.0, 127.1, 125.3, 125.0, 75.7,
60.0, 39.6, 26.3, 18.6, K4.1 and K4.4; m/z (EI) 264 (MC
HC, 4%), 206 (73), 189 (15), 130 (41), 115 (27), 70 (100).
Found: MCHC, 264.1775. C15H26NOSi requires 264.1778.
3.1.7. Preparation of [(S)-1-((1S,2R)-1-hydroxy-indan-2-
ylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl
ester, 12. To a stirred solution of {(S)-1-[(1S,2R)-1-(tert-
butyl-dimethyl-silanyloxy)-indan-2-ylcarbamoyl]-2-
methyl-propyl}-carbamic acid tert-butyl ester, 14 (765 mg,
1.29 mmol, 1.0 equiv) in THF (5 mL) was added 1 M
TBAF/THF (1.5 mL, 3.87 mmol, 3.0 equiv) The reaction
mixture was stirred for 18 h. EtOAc (5 mL) was added and
the organic layer was washed with H2O (2!5 mL). The
aqueous layer was extracted with EtOAc (3!5 mL) and the
combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo. Purification by flash column
chromatography (EtOAc/hexane) afforded the product 12
as a white solid (365 mg, 59%). Mp 148–151 8C;
[a]2D3K24.6 (c 0.50, CHCl3); IR (neat, cmK1) 3317, 2969,
2901, 1665, 1638, 1516, 1247, 1166, 1049 and 732; dH
(400 MHz; CDCl3; Si(CH3)4) 7.23–7.20 (4H, m, ArH), 6.76
(1H, br s, NHCO), 5.39–5.35 (1H, m, CHO), 5.13 (1H, br s,
NHCOO), 4.56–4.54 (1H, m, CHNHCO), 3.99–3.96 (1H,
m, CHNHCOO), 3.12 (1H, dd, JZ5.0, 16.6 Hz, OCHCHH),
2.91 (1H, d, JZ16.6 Hz, OCHCHH), 2.24–2.20 (1H, m,
COCH), 1.43 (9H, s, OC(CH3)3), 1.04–1.02 (3H, m, CH3)
and 0.98 (3H, d, JZ6.8 Hz, CH3); dC (100 MHz; CDCl3;
Si(CH3)4) 172.5, 156.7, 140.9, 140.7, 128.6, 127.5, 125.7,
124.8, 80.9, 73.7, 61.1, 57.8, 40.0, 30.8, 28.7, 19.8 and 18.7;
m/z (EI) 349 (MCHC, 4%), 256 (44), 148 (28), 131 (56),
116 (74), 80 (46), 68 (100). Found: MC, 348.2064.
C19H28N2O4 requires 348.2049.
3.1.5. Preparation of {(S)-1-[(1S,2R)-1-(tert-butyl-
dimethyl-silanyloxy)-indan-2-ylcarbamoyl]-2-methyl-
propyl}-carbamic acid tert-butyl ester, 14. Following
general procedure 1 for EDCI coupling, Boc-L-valine
(858 mg, 3.95 mmol, 1.0 equiv), (1S,2R)-1-(tert-butyl-
dimethyl-silanyloxy)-indan-2-ylamine (1.56 g, 5.91 mmol,
1.5 equiv), HOBt (798 mg, 5.91 mmol, 1.5 equiv), EDCI
(1.13 g, 5.91 mmol, 1.5 equiv), DIPEA (3.4 mL,
19.74 mmol, 5.0 equiv) in dry THF (20 mL) gave, after
purification by flash column chromatography, the product
14 as a beige solid (1.10 g, 60%). Mp 90–92 8C; [a]2D1C20.8
(c 1.00, CHCl3); IR (neat, cmK1) 3306, 2957, 2928, 2856,
1699, 1651, 1504, 365, 1250, 1161, 1070, 1002, 835, 776
and 739; dH (400 MHz; CDCl3; Si(CH3)4) 7.18–7.16 (1H,
m, ArH), 7.09–7.04 (3H, m, ArH), 6.59 (1H, d, JZ8.0 Hz,
NHCO), 5.29–5.26 (1H, m, CHO), 5.07 (1H, d, JZ9.0 Hz,
NHCOO), 4.52–4.51 (1H, m, CHNHCO), 3.98–3.95 (1H,
m, CHNHCOO), 3.01–2.97 (1H, m, OCHCHH), 2.83–2.79
(1H, d, JZ16.1 Hz, OCHCHH), 2.17–2.13 (1H, m, COCH),
1.34 (9H, s, OC(CH3)3), 0.90 (3H, d, JZ6.9 Hz, CH3), 0.86
(3H, d, JZ7.0 Hz, CH3), 0.78 (9H, s, SiC(CH3)2) and 0.00
(6H, s, Si(CH3)2); dC (100 MHz; CDCl3; Si(CH3)4) 169.7,
154.0, 139.5, 137.8, 125.9, 125.0, 122.9, 122.8, 79.6, 73.9,
60.0, 56.7, 40.4, 30.7, 28.2, 25.7, 19.4, 18.0 and 17.4; m/z
(CI) 463 (MCHC, 77%), 407 (49), 363 (39), 348 (53), 247
(59), 199 (61), 69 (100). Found: MCHC, 463.2982.
C25H43O4N2Si requires 463.2987.
3.1.8. Preparation of [(S)-1-((1S,2R)-2-hydroxy-1-
methyl-2-phenyl-ethylcarbamoyl)-2-methyl-propyl]-
carbamic acid tert-butyl ester, 11. To a stirred solution of
{(S)-1-[(1S,2R)-2-(tert-butyl-dimethyl-silanyloxy)-1-
methyl-2-phenyl-ethylcarbamoyl]-2-methyl-propyl}-carba-
mic acid tert-butyl ester, 13 (1.94 g, 4.17 mmol, 1.0 equiv)
in THF (20 mL) was added 1 M TBAF/THF 12.5 mL,
12.52 mmol, 3.0 equiv) The reaction mixture was stirred for
18 h. EtOAc (20 mL) was added and the organic layer was
washed with H2O (2!20 mL). The aqueous layer was
extracted with EtOAc (3!20 mL) and the combined
organic layers were dried (Na2SO4), filtered and concen-
trated in vacuo. Purification by recrytallisation (EtOAc/
hexane) afforded the product 11 as a white solid (1.22 g,
83%). Mp 144–148 8C. (Found: C, 65.29; H, 8.69; N, 8.02.
C19H30N2O4 requires C, 65.12; H, 8.63; N, 7.99%);
[a]2D4K58.6 (c 1.00, CHCl3); IR (neat, cmK1) 3298, 2970,
1684, 1650, 1515, 1366, 1244, 1170, 1041 and 698; dH
(400 MHz; CDCl3; TMS) 7.27–7.23 (5H, m, ArH), 6.48
(1H, d, JZ8.3 Hz, NHCOO), 5.23 (1H, d, JZ8.5 Hz,
NHCO), 4.84 (1H, d, JZ3.26 Hz, ArCH), 4.32–4.24 (1H,
m, CH3CH), 3.79 (1H, br s, COCH), 2.10–2.03 (1H, m,
COCHCH), 1.42 (9H, s, C(CH3)3), 1.00 (3H, d, JZ6.8 Hz,
CH3CH), 0.94 (3H, d, JZ6.8 Hz, CH3and 0.90 (3H, d, JZ
6.8 Hz, CH3); dC (100 MHz; CDCl3; TMS) 172.2, 156.5,
141.3, 80.4, 76.3, 60.7, 51, 31.2, 28.7, 19.7 and 14.6; m/z
(EI) 351 (MCHC, 9%), 244 (33), 200 (46), 144 (44), 116
(76), 79 (56), 57 (100). Found: MCHC, 351.2271.
C19H31N2O4 requires 351.2284.
3.1.6. Preparation of {(S)-1-[(1S,2R)-2-(tert-butyl-
dimethyl-silanyloxy)-1-methyl-2-phenyl-ethylcarba-
moyl]-2-methyl-propyl}-carbamic acid tert-butyl ester,
13. Following general procedure 1 for EDCI coupling, Boc-
L-valine (3.31 g, 1.52 mol, 1.0 equiv), (1S,2R)-2-(tert-butyl-
dimethyl-silanyloxy)-1-methyl-2-phenyl-ethylamine
(6.06 g, 2.28 mol, 1.5 equiv), HOBt (3.08 g, 2.28 mol,
1.5 equiv), EDCI (4.37 g, 2.28 mol, 1.5 equiv), DIPEA
(12.9 mL, 7.61 mol, 5.0 equiv) in dry THF (100 mL) gave,
after purification by flash column chromatography, the
product 13 as a white solid (4.94 g, 70%). Mp 165–167 8C.
(Found: C, 64.76; H, 9.55; N, 6.01. C25H44N2O4Si requires
C, 64.61; H, 9.54; N, 6.03%); [a]2D4K52.5 (c 1.00, CHCl3);
IR (neat, cmK1) 3318, 2859, 2929, 1683, 1645, 1524, 1249,
1170, 1079, 1064, 834, 775 and 695; dH (400 MHz; CDCl3;
Si(CH3)4) 7.21–7.20 (5H, m, ArH), 6.05 (1H, d, JZ8.5 Hz,
NHCO), 4.95 (1H, d, JZ9.0 Hz, NHCOO), 4.75–4.74 (1H,
m, ArCH), 4.18–4.10 (1H, m, CH3CHN), 3.89–3.86 (1H, m,
COCH), 2.17–2.12 (1H, m, (CH3)CH), 1.42 (9H, s,
OC(CH3)3), 0.97 (3H, d, JZ6.8 Hz, CH3CHN), 0.93–0.89
(12H, m, OSiC(CH3)3 and C(CH3CH3)), 0.84 (3H, d, JZ
7.0 Hz, C(CH3CH3)), 0.03 (3H, s, Si(CH3) and K0.19 (3H,
s, Si(CH3); dC (100 MHz; CDCl3; Si(CH3)4) 171.1, 156.4,
141.9, K128.4, 127.8, 126.8, 80.3, 60.4, 51.8, 30.9, 28.7,
26.3, 19.9, 18.6, 17.7, 14.7, K4.2, K4.7; m/z (CI) 465 (MC
HC, 38%), 409 (29), 351 (36), 333 (71), 259 (44), 221 (100).
Found: MCHC, 465.3138. C25H45N2O4Si requires
465.3143.
3.1.9. Preparation of (S)-2-(tert-butyl-dimethyl-silanyl-
oxy)-1-phenyl-ethylamine 9.13 To a stirred solution of
S-phenylglycinol (1.94 g, 14.16 mmol, 1.0 equiv) in dry
THF (15 mL) was added TBSCl (2.56 g, 17.00 mmol,

8000
A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
1.2 equiv) and imidazole (2.41 g, 35.39 mmol,
2.5 equiv).The reaction mixture was refluxed for 18 h and
cooled to room temperature. EtOAc (15 mL) was added and
the organic layer was washed with 0.75 M HCl (2!15 mL)
dried (Na2SO4), filtered and concentrated in vacuo.
Purification by recrystallisation (EtOAc/hexane) afforded
the product as a white solid (2.87 g, 64%). Mp 221–225 8C;
[a]2D4C179.6 (c 0.50, CHCl3); IR (neat, cmK1) 2925, 2363,
1592, 1252, 1103, 1074, 838, 764 and 699; dH (400 MHz;
CD3OD) 7.40–7.37 (5H, m, ArH), 4.35 (1H, dd, JZ4.5,
6.5 Hz, ArCH), 3.96 (1H, dd, JZ4.5, 11.0 Hz, CHHOH),
3.88 (1H, dd, JZ6.5, 11.0 Hz, CHHOH), 0.85 (9H, s,
C(CH3)3), 0.00 (3H, s, SiCH3CH3) and K0.02 (3H, s,
SiCH3CH3); dC (100 MHz; CD3OD) 136.3, 130.7, 130.6,
128.9, 66.5, 58.3, 26.7, 19.7, K5.1 and K5.2; m/z (FAB)
252 (MCHC, 100%), 235 (25), 138 (24), 136 (18), 121
(11). Found: MCHC, 252.1777. C14H26NOSi requires
252.1784.
CH2OH), 2.73 (1H, br s, OH), 1.43 (9H, s, C(CH3)3) and
1.39–1.36 (3H, m, CH3CH); dC (100 MHz; CDCl3;
Si(CH3)4) 173.2, 157.1, 139.2, 129.2, 128.2, 127.1, 80.9,
66.8, 56.2, 50.9, 28.7 and 18.0; m/z (FAB) 309 (MCHC,
27%), 289 (13), 253 (29), 154 (100), 136 (68). Found: MC
HC, 309.1819. C16H25N2O4 requires 309.1814.
3.1.12. Preparation of [(S)-1-((R)-2-hydroxy-1-phenyl-
ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester,
17.14,15 Following general procedure 1 for EDCI coupling,
R-phenylgylcinol (1.51 g, 10.93 mmol, 1.00 equiv), Boc-L-
alanine (2.4 g, 12.57 mmol, 1.15 equiv), HOBt (1.71 g,
12.57 mmol, 1.15 equiv), EDCI (2.43 g, 12.57 mmol,
1.15 equiv), DIPEA (2.78 mL, 16.41 mmol, 1.5 equiv) in
dry THF (40 mL) gave, after purification by flash column
chromatography, the product 17 as a white solid (2.54 g,
76%). Mp 90–92 8C; [a]D25K57.1 (c 1.00, CHCl3); IR (neat,
cmK1) 3352, 3326, 1686, 1656, 1534, 1515, 1316, 1155,
1063 and 703; dH (400 MHz; CDCl3; Si(CH3)4) 7.27–7.23
(5H, m, ArH), 5.41 (1H, d, JZ7.5 Hz, COONH), 5.09–5.04
(1H, m, ArCH), 4.26–4.23 (1H, m, CH3CH), 3.86–3.76 (2H,
m, CH2OH), 3.44 (1H, br s, CONH), 1.43 (9H, s, C(CH3)3)
and 1.34 (3H, d, JZ7.0 Hz, CH3CH); dC (100 MHz; CDCl3;
Si(CH3)4) 173.3, 156.0, 138.9, 128.7, 127.7, 126.7, 80.3,
66.1, 55.6, 50.4, 28.3 and 18.3; m/z (FAB) 309 (MCHC,
63%), 289 (13), 253 (55), 209 (15), 154 (100), 136 (70).
Found: MCHC, 309.1813. C16H25N2O4 requires 309.1814.
3.1.10. Preparation of {(S)-1-[(S)-2-(tert-butyl-dimethyl-
silanyloxy)-1-phenyl-ethylcarbamoyl]-ethyl}-carbamic
acid tert-butyl ester, 18b. Following general procedure 1
for EDCI coupling, Boc-L-alanine (1.00 g, 2.65 mmol,
1.0 equiv), (S)-2-(tert-butyl-dimethyl-silanyloxy)-1-phe-
nyl-ethylamine, 9 (500 mg, 3.98 mmol, 1.5 equiv), HOBt
(537 mg, 3.98 mmol, 1.5 equiv), EDCI (762 mg,
3.98 mmol, 1.5 equiv), DIPEA (2.25 mL, 13.26 mmol,
5.0 equiv) in dry THF (15 mL) gave, after purification by
flash column chromatography, the product 18b as a
colourless oil (700 mg, 63%). [a]2D4K15.9 (c 1.00,
CHCl3); IR (neat, cmK1) 3303, 2928, 2856, 1655, 1495,
1365, 1249, 1164, 1094, 834, 775 and 698; dH (400 MHz;
CDCl3; Si(CH3)4) 7.26–7.21 (5H, m, ArH), 6.96 (1H, br s,
ArCHNH), 5.01–4.97 (2H, m, ArCH and CH3CHNH), 4.23
(1H, br s, CH3CH), 3.90–3.86 (1H, m, OCHH), 3.80–3.76
(1H, m, OCHH), 1.44 (9H, s, OC(CH3)3), 1.37–1.34 (3H, m,
CH3CH), 0.84 (9H, s, SiC(CH3)3), K0.05 (3H, s, SiCH3)
and K0.10 (3H, s, SiCH3); dC (100 MHz; CDCl3; Si(CH3)4)
172.2, 156.1, 137.4, 128.7, 127.7, 127.2, 80.5, 66.6, 54.0,
50.3, 28.7, 26.3, 18.6 and 18.4; m/z (FAB) 423 (MCHC,
56%), 36 (100), 309 (23), 235 (60), 154 (18), 120 (23).
Found: MCHC, 423.2667. C22H39N2O4Si requires
423.2679.
3.1.13. Preparation of {(S)-1-[(R)-2-(tert-butyl-dimethyl-
silanyloxy)-1-phenyl-ethylcarbamoyl]-2-phenyl-ethyl}-
carbamic acid tert-butyl ester, 18a. Following general
procedure 1 for EDCI coupling, Boc-L-phenylalanine
(703 mg, 2.64 mmol, 1.0 equiv), (R)-2-(tert-butyl-
dimethyl-silanyloxy)-1-phenyl-ethylamine,
9
(1 g,
3.98 mmol, 1.5 equiv), HOBt (537 mg, 3.98 mmol,
1.5 equiv), EDCI (762 mg, 3.98 mmol, 1.5 equiv), DIPEA
(2.25 mL, 13.26 mmol, 5.0 equiv) in dry THF (20 mL)
gave, after purification by flash column chromatography,
the product 18 as a colourless oil (1.04 g, 79%). [a]2D5K1.8
(c 0.67, CHCl3); IR (neat, cmK1) 3277, 2928, 2856, 1686,
1647, 1522, 1248, 1169, 1114, 834, 775 and 696; dH
(400 MHz; CDCl3; Si(CH3)4) 7.26–7.18 (10H, m, ArH),
6.62 (1H, d, JZ7.0 Hz, ArCHNH), 5.01 (1H, br s,
ArCH2CHNH), 4.91 (1H, br s, ArCH), 4.42–4.40 (1H, m,
ArCH2CH), 3.69–3.67 (2H, m, ArCHCH2), 3.13–3.02 (2H,
m, ArCH2), 1.42 (9H, s, OC(CH3)3), 0.80 (9H, s,
SiC(CH3)3), K0.12 (3H, s, SiCH3) and K0.16 (3H, s,
SiCH3); dC (100 MHz; CDCl3; Si(CH3)4); 170.4, 155.5,
139.9, 136.9, 129.4, 128.7, 128.2, 126.7, 80.1, 66.1, 55.9,
54.5, 38.5, 28.3, 25.8, 18.2, K5.6 and K5.7; m/z (FAB) 499
(MCHC, 99%), 443 (100), 399 (28), 385 (20), 311 (23),
235 (31), 154 (20). Found: MCHC, 499.3005.
C28H43N2O4Si requires 499.2992. Note: 13C NMR shows
coincident peaks in the aromatic region. Therefore, only 5
instead of 6 aromatic peaks are observed.
3.1.11. Preparation of [(S)-1-((S)-2-hydroxy-1-phenyl-
ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester,
16. To a stirred solution of {(S)-1-[(S)-2-(tert-butyl-
dimethyl-silanyloxy)-1-phenyl-ethylcarbamoyl]-ethyl}-
carbamic acid tert-butyl ester, 18b (471 mg, 1.12 mmol,
1.0 equiv) in THF (20 mL) was added 1 M TBAF/THF
(3.4 mL, 3.35 mmol, 3.0 equiv) The reaction mixture was
stirred for 18 h. EtOAc (20 mL) was added and the organic
layer was washed with H2O (2!20 mL). The aqueous layer
was extracted with EtOAc (3!20 mL) and the combined
organic layers were dried (Na2SO4), filtered and concen-
trated in vacuo. Purification by flash column recrytallisation
(EtOAc/hexane) afforded the product 16 as a white solid
(250 mg, 72%). Mp 105–108 8C; [a]2D5K13.6 (c 0.50,
CHCl3); IR (neat, cmK1) 3333, 2934, 1683, 1655, 1518,
1316, 1238, 1159, 1041, 703 and 653; dH (400 MHz; CDCl3;
Si(CH3)4) 7.35–7.26 (5H, m, ArH), 7.01 (1H, br s, NHCO),
5.07–5.02 (1H, m, ArCH), 4.98 (1H, d, JZ6.8 Hz,
NHCOO), 4.19–4.18 (1H, COCH), 3.91–3.81 (2H, m,
3.1.14. Preparation of [(S)-1-((R)-2-hydroxy-1-phenyl-
ethylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-
butyl ester, 15.14 To a stirred solution of {(S)-1-[(R)-2-
(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethylcarba-
moyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester, 18a
(971 mg, 1.95 mmol, 1.0 equiv) in THF (20 mL) was added
1 M TBAF/THF (5.8 mL, 5.84 mmol, 3.0 equiv) The

A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
8001
reaction mixture was stirred for 18 h. EtOAc (20 mL) was
added and the organic layer was washed with H2O (2!
20 mL). The aqueous layer was extracted with EtOAc (3!
20 mL) and the combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo. Purification
by flash column chromatography (EtOAc/hexane) afforded
the product 15 as a white solid (400 mg, 53%). Mp 114–
116 8C; [a]2D5K8.9 (c 1.00, CHCl3); IR (neat, cmK1) 3337,
3300, 1687, 1651, 1520, 1170, 1045, 1028, 755 and 698; dH
(400 MHz; CDCl3; Si(CH3)4) 7.22–7.14 (10H, m, ArH),
6.41 (1H, d, JZ7.0 Hz, ArCHNH), 5.10–5.01 (1H, m,
ArCH2CHNH), 4.99–4.94 (1H, m, ArCH), 4.37–4.35 (1H,
m, ArCH2CH), 3.72–3.64 (2H, m, ArCHCH2), 3.12 (1H, dd,
JZ13.6, 6.4 Hz, ArCHH), 3.02 (1H, dd, JZ13.6, 7.8 Hz,
ArCHH), 2.34 (1H, br s, OH) and 1.70 (9H, s, OC(CH3)3);
dC (100 MHz; CDCl3; TMS) 171.7, 156.9, 138.9, 137.1,
129.8, 129.2, 129.2, 128.2, 127.5, 127.1, 80.9, 66.5, 56.7,
56.2, 38.9 and 28.7; m/z (FAB) 385 (MCHC, 71%), 329
(52), 307 (26), 285 (35), 154 (100), 126 (73). Found: MC
HC, 385.2140. C22H29N2O4 requires 385.2127.
C(CH3); dC (100 MHz; CD3OD) 173.0, 144.8, 141.0, 139.2,
130.7, 129.4, 128.4, 128.3, 128.2, 65.7, 63.6, 56.9, 32.9,
21.5, 19.7 and 18.3; m/z (FAB) 391 (MCHC, 33%), 359
(3), 307 (29), 289 (15), 226 (14), 154 (100), 136 (73), 120
(13). Found: MCHC, 391.1688. C20H27N2O4S requires
391.1692.
3.1.17. Preparation of (S)-2-dibenzylamino-propionic
acid benzyl ester, 22.17 To a stirred solution of L-alanine
(1.50 g, 16.84 mmol, 1.0 equiv) and K2CO3 (11.63 g,
84.18 mmol, 5.0 equiv) in EtOH (42 mL) and H2O (8 mL)
was added benzyl bromide (14.4 g, 84.18 mmol, 5.0 equiv)
in EtOH (8 mL). The reaction mixture was refluxed for 18 h
and the solvent evaporated. H2O (20 mL) was added and the
aqueous layer was extracted with EtOAc (3!20 mL). The
combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo. Purification by distillation using
Kugel Rohr afforded the product 22 as a yellow oil (3.48 g,
58%). (Found: C, 79.97; H, 7.02; N, 3.86. C24H25NO2
requires C, 80.19; H, 7.01; N, 3.90%); [a]2D3K89.3 (c 1.00,
CHCl3); IR (neat, cmK1) 3027, 1728, 1493, 1454, 1187,
1136, 730 and 694; dH (300 MHz; CDCl3; Si(CH3)4) 7.27–
7.17 (15H, m, ArH), 5.38 (1H, d, JZ12.4 Hz, ArCHH), 5.22
(1H, d, JZ12.4 Hz, ArCHH), 3.82 (2H, d, JZ13.9 Hz,
CHHNCHH), 3.64–3.51 (3H, m, CHHNCHH and COCH)
and 1.34 (3H, d, JZ7.2 Hz, COCCH3); dC (75 MHz;
CDCl3; Si(CH3)4) 174.0, 140.2, 136.6, 129.3, 129.1,
129.0, 128.7, 128.4, 127.4, 66.4, 56.6, 54.8 and 15.4; m/z
(FAB) 360 (MCHC, 32%), 282 (5), 224 (100), 181 (5).
Found: MCHC, 360.1977. C24H26NO2 requires 360.1964.
3.1.15. Preparation of (S)-2-amino-N-((R)-2-hydroxy-1-
phenyl-ethyl)-3-methyl-butyramide trifluoromethyl
acetate, 19. To a stirred solution of [(S)-1-((R)-2-hydroxy-
1-phenyl-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid
tert-butyl ester, 8 (823 mg, 2.45 mmol) in DCM (5 mL) was
added dropwise TFA (5 mL). The reaction mixture was
stirred at room temperature for 18 h and the solvent
evaporated in vacuo. The product 19 was obtained as a
brown oil (1.67 g, quantitative). [a]2D4K20.5 (c 1.00,
CHCl3); IR (neat, cmK1); 3092, 2975, 1778, 1666, 1552,
1143, 798 and 699; dH (300 MHz; CDCl3; Si(CH3)4) 7.68–
7.21 (5H, m, ArH), 5.34–5.28 (1H, m, ArCH), 4.60–4.50
(2H, m, CH2OH), 4.17–4.15 (1H, m, COCH), 2.19–2.08
(1H, m, CH(CH3)2) and 0.96–0.91 (6H, m, C(CH3)2); dC
(75 MHz; CDCl3; Si(CH3)4) 168.9, 161.7 (q, JZ41.0 Hz),
135.7, 129.7, 129.6, 127.0, 113.6 (q JZ8.6 Hz), 68.7, 59.7,
53.5, 30.9, 18.1 and 17.7; m/z (CI, NH3) 237 (MCHC,
100%), 122 (10), 205 (8), 166 (2), 128 (7), 117 (9), 106 (17),
72 (49). Found: MCHC, 237.1596. C13H21N2O2 requires
237.1598.
3.1.18. Preparation of (S)-2-dibenzylamino-propionic
acid.18 A solution of (S)-2-dibenzylamino-propionic acid
benzyl ester, 22 (3.48 g, 9.68 mmol) in dioxane/MeOH/
KOH (2 M) (18:3:9 mL) was stirred for 18 h at room
temperature. The reaction mixture was acidified with 6 M
HCl and extracted with Et2O (3!30 mL) and EtOAc (3!
30 mL). The combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo. Purification by distilla-
tion using Kugel Rohr afforded the product as a yellow oil
(2.45 g, 94%). [a]D22K13.2 (c 1.00, CHCl3); IR (neat, cmK1
)
3292, 2918, 2852, 1657, 1533, 1443, 1252, 1104, 828 and
740; dH (300 MHz; CDCl3; Si(CH3)4) 10.92 (1H, br s, OH),
7.53–7.50 (4H, m, ArH), 7.39–7.26 (6H, m, ArH), 4.30 (2H,
d, JZ13.1 Hz, CHHNCHH), 4.15 (2H, d, JZ13.1 Hz,
CHHNCHH) 3.77 (1H, q, JZ7.1 Hz, COCH), 1.60 (3H, d,
JZ7.4 Hz, COCCH3); dC (75 MHz; CDCl3; Si(CH3)4)
172.3, 132.4, 130.1, 128.9, 128.8, 58.4, 54.2, 12.4; m/z
(FAB) 270 (MCHC, 100), 224 (21), 196 (1), 180 (6), 154
(11), 134 (12).
3.1.16. Preparation of (S)-N-((R)-2-hydroxy-1-phenyl-
ethyl)-3-methyl-2-(toluene-4-sulfonylamino)-butyr-
amide, 20.16 To a stirred solution of (S)-2-amino-N-((R)-2-
hydroxy-1-phenyl-ethyl)-3-methyl-butyramide trifluoro-
methyl acetate, 19 (1.30 g, 3.71 mmol, 1.0 equiv) and
Et3N (1.55 mL, 11.13 mmol, 3.0 equiv) in DCM (10 mL)
was added TsCl (707 mg, 3.71 mmol, 1.0 equiv). The
reaction mixture was stirred for 18 h at room temperature.
The solution was concentrated in vacuo and EtOAc (10 mL)
added. The organic layer was washed with H2O (2!
10 mL), dried (Na2SO4), filtered and concentrated in vacuo.
Purification by flash column chromatography afforded the
product 20 as a colourless oil (186 mg, 13%). [a]2D4K46.8 (c
0.50, CHCl3); IR (neat, cmK1) 3317, 3259, 1640, 1547,
1318, 1159, 986, 698 and 666; dH (400 MHz; CDCl3;
Si(CH3)4) 7.75 (2H, d, JZ8.3 Hz, ArHSO2), 7.37–7.22 (7H,
m, ArHSO2 and ArH), 6.54 (1H, d, JZ7.0 Hz, CONH), 5.19
(1H, d, JZ8.0 Hz, NHSO2), 4.92–4.88 (1H, m, ArCH),
3.71–3.69 (2H, m, CH2OH), 3.53–3.50 (1H, m, COCH),
2.43 (3H, s, ArCH3), 2.14–2.05 (1H, m, CH(CH3)2), 0.84
(3H, d, JZ6.8 Hz, C(CH3) and 0.81 (3H, d, JZ7.0 Hz,
3.1.19. Preparation of (S)-2-dibenzylamino-N-((R)-2-
hydroxy-1-phenyl-ethyl)-propionamide, 21. Following
general procedure 1 for EDCI coupling, (S)-2-dibenzyl-
amino-propionic acid (670 mg, 2.49 mmol, 1.0 equiv),
R-phenylglycinol (392 mg, 2.86 mmol, 1.15 equiv), HOBt
(386 mg, 2.86 mmol, 1.15 equiv), EDCI (548 mg,
2.86 mmol, 1.15 equiv), DIPEA (0.63 mL, 3.73 mmol,
1.5 equiv) in dry THF (10 mL) gave, after purification by
flash column chromatography, the product 21 as a white
crystals (532 mg, 55%). Mp 92–96 8C; [a]2D4K20.0 (c 1.00,
CHCl3); IR (neat, cmK1) 3376, 2839, 2812, 1657 1493,
1453, 1115, 749 and 699; dH (300 MHz; CDCl3; Si(CH3)4)

8002
A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
7.33–7.13 (15H, m, ArH), 5.02–4.92 (1H, m, ArCH), 3.84–
3.68 (4H, m, OH, CHHOH and CHHNCHH), 3.45–3.36
(4H, m, CHHOH, CH3CH and CHHNCHH) and 1.34–1.29
(3H, m, CH3CH); dC (75 MHz; CDCl3; Si(CH3)4) 174.0,
138.8, 138.5, 128.8, 128.5, 127.5, 127.2, 126.7 and 126.4;
m/z (FAB) 389 (MCHC, 100%), 307 (19), 289 (9), 224
(75), 154 (67), 136 (52), 120 (10). Found: MCHC,
389.2245. C25H29N2O2 requires 389.2229.
49.8 mmol, 5.0 equiv) in dry THF (50 mL) gave, after
purification by flash column chromatography, the product
25 as a white solid (2.38 g, 68%). Mp 72–74 8C. (Found: C,
61.66; H, 7.43; N, 7.89. C18H26N2O5 requires C, 61.70; H,
7.48; N, 7.99%); [a]2D4C25.4 (c 0.50, CHCl3); IR (neat,
cmK1) 3320, 2982, 2935, 1737, 1651, 1522, 1268, 1154,
1051, 845, 728 and 648; dH (400 MHz; CDCl3; Si(CH3)4)
7.40–7.31 (5H, m, ArH), 6.79 (1H, br s, ArCH2-
OCOCHNH), 5.17 (2H, q, JZ12.3 Hz, ArCH2), 5.00 (1H,
br s, (CH3)3COCONH), 4.64–4.57 (1H, m, ArCH2-
OCOCH), 4.20 (1H, br s, (CH3)3COCONHCH), 1.44 (9H,
s, C(CH3)3), 1.41 (3H, d, JZ7.03 Hz, ArCH2OCOCHCH3)
and 1.34 (3H, d, JZ7.0 Hz, (CH3)3COCONHCHCH3); dC
(100 MHz; CDCl3; Si(CH3)4) 173.0, 172.6, 157.9, 135.7,
129.0, 128.8, 128.5, 80.6, 67.5, 50.4, 48.5, 28.7, 18.6 and
18.6; m/z (FAB) 351 (MCHC, 68%), 295 (100), 251 (46),
154 (11). Found: MCHC, 351.1918. C18H27N2O5 requires
351.1920.
3.1.20. Preparation of [(S)-2-methyl-1-((R)-1-phenyl-
ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester,
23. Following general procedure 1 for EDCI coupling, Boc-
L-valine (500 mg, 2.30 mmol, 1.0 equiv), R-a-methyl-
benzylamine (0.44 mL, 3.45 mmol, 1.5 equiv), HOBt
(466 mg, 3.45 mmol, 1.5 equiv), EDCI (662 mg,
3.45 mmol, 1.5 equiv), DIPEA (1.95 mL, 3.45 mmol,
5.0 equiv) in dry THF (10 mL) gave, after purification by
recrystallisation (EtOAc/hexane), the product 23 as a beige
solid (236 mg, 32%). Mp 135–137 8C; [a]2D5C21.9 (c 1.00,
CHCl3); IR (neat, cmK1) 3278, 2968, 1681, 1648, 1521,
1365, 1247, 1169, 1021, 794 and 698; dH (400 MHz; CDCl3;
TMS) 7.32–7.23 (5H, m, ArH), 6.41 (1H, br s, ArCNH),
5.13–5.08 (2H, m, ArCH and (CH3)2CHCHNH), 3.88–3.84
(1H, m, (CH3)2CHCH), 2.17–2.08 (1H, m, (CH3)2CH), 1.47
(3H, d, JZ7.0 Hz, ArCCH3), 1.42 (9H, s, C(CH3)3), 0.96
(3H, d, JZ6.8 Hz, C(CH3) and 0.92 (3H, d, JZ5.3 Hz,
C(CH3); dC (100 MHz; CDCl3; Si(CH3)4) 171.1 156.4 143.4
129.0 127.7 126.5, 80.3, 60.6, 49.1, 31.0, 28.7, 22.3, 19.7
and 18.4; m/z (FAB) 321 (MCHC, 78%), 265 (100), 221
(35), 172 (13), 154 (51), 136 (40). Found: MCHC,
321.2189. C18H29N2O3 requires 321.2178.
3.1.23. Preparation of (S)-2-((R)-2-tert-butoxycarbonyl-
amino-1-hydroxy-propylamino)-propionic acid 26.20 To
a stirred solution of (S)-2-((R)-2-tert-butoxycarbonylamino-
1-hydroxy-propylamino)-propionic acid benzyl ester, 25
(1.30 g, 3.70 mmol) in MeOH (15 mL) was added Pd/C
(5 mol%, 1.30 g). The reaction was hydrogenated at room
temperature for 18 h. The solution was filtered through a
plug of Celite and concentrated in vacuo. After drying under
vacuum, the product 26 was obtained as a white solid
(1.12 g, quantitative). Mp 146–150 8C; [a]2D4C15.3 (c 1.00,
EtOH); IR (neat, cmK1) 322, 3262, 2976, 1712, 1676, 1633,
1562, 1364, 1248, 1162, 1073 and 925; dH (400 MHz;
CD3OD) 4.77 (1H, br s, NH) 4.22–4.17 (1H, m, HOCOCH),
3.98–3.91 (1H, m, (CH3)3COCONHCH), 1.26 (9H, s,
C(CH3)3), 1.21 (3H, d, JZ7.3 Hz, HOCOCHCH3) and
1.12 (3H, d, JZ7.3 Hz, (CH3)3COCONHCHCH3); dC
(100 MHz; CD3OD) 176.1, 175.9, 158.0, 81.1, 58.8, 52.0,
29.1, 18.8 and 18.3; m/z (FAB) 261 (MCHC, 74%), 233
(13), 205 (100), 161 (33), 154 (41), 137 (30). Found: MC
HC, 261.1449. C11H21N2O5 requires 261.1450.
3.1.21. Preparation of [(S)-2-methyl-1-((S)-1-phenyl-
ethylcarbamoyl)-propyl]-carbamic acid tert-butyl ester,
24. Following general procedure 1 for EDCI coupling, Boc-
L-valine (500 mg, 2.30 mmol, 1.0 equiv), S-a-methyl-
benzylamine (0.44 mL, 3.45 mmol, 1.5 equiv), HOBt
(466 mg, 3.45 mmol, 1.5 equiv), EDCI (662 mg,
3.45 mmol, 1.5 equiv), DIPEA (1.95 mL, 3.45 mmol,
5.0 equiv) in dry THF (10 mL) gave, after purification by
recrystallisation (EtOAC/hexane), the product 24 as a white
solid (549 mg, 74%). Mp 140–143 8C. (Found: C, 67.31; H,
8.69; N, 8.96. C18H28N2O3 requires C, 67.47; H, 8.81; N,
8.74%); [a]2D5K59.6 (c 0.51, CHCl3); IR (neat, cmK1) 3301,
3245, 2972, 1681, 1644, 1520, 1356, 1248, 1172, 1044,
1015 and 696; dH (400 MHz; CDCl3; Si(CH3)4) 7.32–7.23
(5H, m, ArH), 6.32 (1H, d, JZ6.5 Hz, ArCNH), 5.12 (2H,br
s, ArCH and (CH3)2CHCHNH), 3.87–3.83 (1H, m, (CH3)2-
CHCH), 2.08 (1H, br s, (CH3)2CH), 1.47 (3H, d, JZ6.8 Hz,
ArCCH3), 1.42 (9H, s, C(CH3)3) and 0.89–0.86 (6H, m,
C(CH3)2); dC (100 MHz; CDCl3; Si(CH3)4) 171.1, 156.4,
143.4, 129.0, 127.7, 126.5, 80.3, 60.6, 49.1, 31.2, 28.7, 22.0,
19.8 and 18.2; m/z (FAB) 321 (MCHC, 51%), 307 (23),
265 (49), 221 (14), 154 (100), 136 (73). Found: MCHC,
321.2181. C18H29N2O3 requires 321.2178.
3.1.24. Preparation of [(R)-2-hydroxy-2-((S)-2-hydroxy-
1-methyl-ethylamino)-1-methyl-ethyl]-carbamic acid
tert-butyl ester, 27.15 A solution of S-alaninol (1.0 g,
13.31 mmol, 1.0 equiv) in dry THF (10 mL) was stirred for
1 h. To that was added dropwise over 30 min a solution of
Boc-D-alanine (2.9 g, 15.31 mmol, 1.15 equiv), HOBt
(2.1 g, 15.31 mmol, 1.15 equiv) and EDCI (2.94 g,
15.31 mmol, 1.15 equiv) in dry THF (30 mL), which was
stirred for 1 h prior. After stirring for another hour, DIPEA
(3.39 mL, 19.97 mmol, 1.5 equiv) was added dropwise.
Stirring was continued for 18 h at room temperature after
which the solvent was evaporated in vacuo. EtOAc (30 mL)
was added and the organic layer was washed with 5% citric
acid (2!30 mL), saturated NaHCO3 (2!30 mL), concn
NaCl (30 mL) and H2O (30 mL). The organic layer was then
dried (Na2SO4), filtered and concentrated in vacuo.
Purification by flash column chromatography afforded the
product 27 as a yellow oil (593 mg, 18%). [a]2D4C3.0 (c
1.00, EtOH); IR (neat, cmK1) 3288, 2976, 2933, 1646, 1520,
1365, 1246, 1161 and 1048; dH (400 MHz; CDCl3;
Si(CH3)4) 6.87 (1H, br s, OHCH2CHNH), 5.62 (1H, d,
JZ5.5 Hz, NHCOO), 4.18–4.13 (1H, m, COCH), 4.11–4.04
(1H, m, OHCH2CH), 3.91 (1H, br s, OH), 3.66–3.63 (1H, m,
3.1.22. Preparation of (S)-2-((R)-2-tert-butoxycarbonyl-
amino-1-hydroxy-propylamino)-propionic acid benzyl
ester, 25. Following general procedure 1hr for EDCI
coupling, benzyl ester L-alanine tosylate (3.50 g,
10.0 mmol, 1.0 equiv), Boc-D-alanine (2.83 g, 14.9 mmol,
1.5 equiv), HOBt (2.02 g, 14.9 mmol, 1.5 equiv), EDCI
(2.86 g, 14.9 mmol, 1.5 equiv), DIPEA (8.45 mL,

A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
8003
OHCHH), 3.49–3.45 (1H, m, OHCHH), 1.44 (9H, s,
C(CH3)3), 1.35–1.34 (3H, m, COCCH3) and 1.17–1.15
(3H, m, OHCH2CCH3); dC (100 MHz; CDCl3; Si(CH3)4)
173.8, 156.2, 80.4, 66.4, 50.7, 47.9, 28.7, 18.9, 17.2 and
15.6; m/z (FAB) 247 (MCHC, 92%), 219 (7), 191 (99), 173
(11), 154 (100), 137 (72), 120 (14). Found: MCHC,
247.1650. C11H23O4N2 requires 247.1652.
EtOH/hexane, 1 mL minK1, UV 254 nm, tR Z12.5 (S-
isomer) and 13.9 min (R-isomer).
Acknowledgements
We thank the ORS committee and Warwick University
(Warwick Postgraduate Research Fellowship) for funding
(to ASYY).
3.2. General procedure 2 for ketone reduction
A solution of [RuCl2(p-cymene)]2 (0.005 mmol, 0.5 mol%),
ligand (0.03 mmol, 3 mol%) and 0.2 M NaOH (5 mol%) in
isopropanol (5 mL) was stirred at room temperature for
15 min under nitrogen. The ketone (1 mmol, 100 mol%)
was then added and the reaction mixture stirred at room
temperature under nitrogen for 2 h. The solution was then
filtered through a pad of silica and washed through with
EtOAc (20 mL) and the filtrate was concentrated in vacuo.
The reaction mixture was analysed by either by GLC
(Supelco BETA Dexe) or 1H NMR and HPLC.
References and notes
1. (a) Palmer, M.; Wills, M. Tetrahedron: Asymmetry 1999, 10,
2045. (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30,
97. (c) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev.
1992, 92, 1051.
2. (a) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya,
T.; Noyori, R. Chem. Commun. 1996, 233. (b) Yamakawa, M.;
Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818.
3. (a) Haack, K. J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori,
R. Angew. Chem., Int. Ed. 1997, 36, 285. (b) Hashiguchi, S.;
Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1995, 117, 7562. (c) Fujii, A.; Hashiguchi, S.; Uematsu,
N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521.
(d) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1996, 118, 4916. (e) Haack, K. J.;
Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. 1997, 36, 285. (f) Murata, K.; Ikariya, T.;
Noyori, R. J. Org. Chem. 1999, 64, 2186. (g) Hamada, T.;
Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T. Org. Lett. 2002, 4,
4373.
3.2.1. 1-Phenylethanol. dH (300 MHz; CDCl3; Si(CH3)4)
7.41–7.26 (5H, m, ArH), 4.90 (1H, q, JZ6.4 Hz, CH), 1.96
(1H, br s, OH) and 1.51 (3H, d, JZ6.4 Hz, CH3); (R-isomer)
[a]2D4C45.2 (c 1.00, DCM), (lit.21 [a]DC48.6 (c 1.00,
DCM), (S-isomer) [a]D24K44.0 (c 1.00, DCM); Daicel
Chiralcel OD, 5% EtOH/hexane, 1 mL minK1, UV
254 nm, tRZ9.5 (S-isomer) and 8.2 min (R-isomer);
Supelco BETA Dexe, 115 8C, tRZ8.9 (R-isomer) and
9.3 min (S-isomer).
3.2.2. 1-(4-Chlorophenyl)ethanol. dH (300 MHz; CDCl3;
Si(CH3)4) 7.33–7.28 (2H, m, ArH), 6.94–7.01 (2H, m, ArH),
4.89 (1H, q, JZ6.4 Hz, CH), 1.92 (1H, br s, OH) and 1.46
(3H, d, JZ6.4 Hz, CH3); (R-isomer) [a]2D4C37.4 (c 1.00,
Et2O), (lit.21 [a]DC48.6 (c 0.9–1.1, Et2O), (S-isomer)
[a]2D4K56.2 (c 1.00, Et2O), (lit.22 [a]2D2K49.6 (c 1.8,
Et2O); Supelco BETA Dexe, 140 8C, tRZ10.9 (R-isomer)
and 11.3 min (S-isomer).
4. (a) Palmer, M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997,
62, 5226. (b) Nordin, S. J. M.; Roth, P.; Tarnai, T.; Alonso,
D. A.; Brandt, P.; Andersson, P. G. Chem. Eur. J. 2001, 7,
1431. (c) Everaere, K.; Mortreux, A.; Bulliard, M.; Brussee, J.;
van der Gen, A.; Nowogrocki, G.; Carpentier, J. F. Eur. J. Org.
Chem. 2001, 275. (d) Nishibayashi, Y.; Takei, I.; Uemura, S.;
Hidai, M. Organometallics 1999, 18, 2291. (e) Petra, D. G. I.;
Reek, J. N. H.; Kamer, P. C. J.; Schoemaker, H. E.; van
Leeuwen, P. W. N. M. Chem. Commun. 2000, 683. (f)
Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1199. (g)
Hannedouche, J.; Clarkson, G.; Wills, M. J. Am. Chem. Soc.
2004, 126, 986.
3.2.3. 1-(4-Fluorophenyl)ethanol. dH (300 MHz; CDCl3;
Si(CH3)4) 7.36–7.31 (2H, m, ArH), 6.97–6.92 (2H, m, ArH),
4.84 (1H, q, JZ6.4 Hz, CH), 1.90 (1H, br s, OH) and 1.47
(3H, d, JZ6.4 Hz, CH3); (R-isomer) [a]2D4C45.8 (c 1.00,
Et2O), (S-isomer) [a]2D4K51.6 (c 1.00, Et2O) (lit.23 [a]2D5
37.7 (c 0.93, MeOH); Supelco BETA Dexe, 115 8C, tRZ
9.75 (R-isomer) and 10.35 min (S-isomer).
5. (a) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem. 2002,
67, 1712. (b) Koike, T.; Murata, K.; Ikariya, T. Org. Lett.
2000, 2, 3833. (c) Murata, K.; Okano, K.; Miyagi, M.; Iwane,
H.; Noyori, R.; Ikariya, T. Org. Lett. 1999, 1, 1119. (d)
Eustache, F.; Dalko, P. I.; Cossy, J. Org. Lett. 2002, 4, 1263.
(e) Mohar, B.; Valleix, A.; Desmurs, J. R.; Felemez, M.;
Wagner, A.; Mioskowski, C. Chem. Commun. 2001, 2572. (f)
Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett. 2000, 41,
9277. (g) Kenny, J. A.; Palmer, M. J.; Smith, A. R. C.;
Walsgrove, T.; Wills, M. Synlett 1999, 1615. (h) Cross, D. J.;
Kenny, J. A.; Houson, I.; Campbell, L.; Walsgrove, T.; Wills,
M. Tetrahedron: Asymmetry 2001, 12, 1801. (i) Kawamoto,
A.; Wills, M. Tetrahedron: Asymmetry 2000, 11, 3257. (j)
Kawamoto, A. M.; Wills, M. J. Chem. Soc., Perkin Trans. 1
2001, 1916. (k) Alcock, N. W.; Mann, I.; Peach, P.; Wills, M.
Tetrahedron: Asymmetry 2002, 13, 2485.
3.2.4. 1-(4-Methoxyphenyl)ethanol. dH (300 MHz; CDCl3;
Si(CH3)4) 7.31–7.25 (2H, m, ArH), 6.89–6.85 (2H, m, ArH),
4.85 (1H, q, JZ6.4 Hz, CH), 3.81 (3H, s, OCH3), 1.81 (1H,
br s, OH) and 1.49 (3H, d, JZ6.4 Hz, CH3); (R-isomer)
[a]2D4C42.7 (c 1.00, CHCl3), (lit.19 [a]D C47.3 (c 0.90–1.1,
CHCl3), (S-isomer) [a]2D4K36.5 (c 1.00, CHCl3) (lit.24 [a]D
K51.9 (c 1.04, CHCl3); Supelco BETA Dexe, 125 8C, tRZ
23.8 (R-isomer) and 24.6 min (S-isomer).
3.2.5. 1-(2-Naphthyl)ethanol. dH (300 MHz; CDCl3;
Si(CH3)4) 7.83–7.79 (4H, m, ArH), 7.51–7.47 (3H, m,
ArH0, 5.05 (1H, q, JZ6.4 Hz, CH), 1.95 (1H, br s, OH) and
1.57 (3H, d, JZ6.4 Hz, CH3); (R-isomer) [a]2D4C35.7 (c
5.00, EtOH), (S-isomer) [a]D K22.6 (c 5.00, EtOH) (lit.25
[a]D K41.9 (c 4.92, CHCl3); Daicel Chiralcel OD, 5%
6. (a) Wills, M.; Hannedouche, J. Curr. Opin. Drug Discov. Dev.

8004
A. S. Y. Yim, M. Wills / Tetrahedron 61 (2005) 7994–8004
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2002, 5, 881. (b) Yamashita, H.; Ohtani, T.; Morita, S.;
2001, 44, 1794.
Otsubo, K.; Kan, K.; Matsubara, J.; Kitano, K.; Kawano, Y.;
Uchida, M.; Tabusa, F. Heterocycles 2002, 56, 123. (c)
Tanaka, K.; Katsurada, M.; Ohno, F.; Shiga, Y.; Oda, M.;
Miyagi, M.; Takehara, J.; Okano, K. J. Org. Chem. 2000, 65,
432. (d) Miyagi, M.; Takehara, J.; Collet, S.; Okano, K. Org.
Process Res. Dev. 2000, 4, 346.
13. Steinig, A. G.; Spero, D. M. J. Org. Chem. 1999, 64, 2406.
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Bales, C. A.; Dovey, H. F.; Dressen, D. B.; Folmer, B.;
Goldbach, E. G.; Guinn, A. C.; Latimer, L. H. Bioorg. Med.
Chem. Lett. 2002, 12, 3051.
15. Tucker, T. J.; Lumma, W. C., Jr.; Payne, L. S.; Wai, J. M.; De
Solms, S. J.; Guilliani, E. A.; Darke, P. L.; Heimbach, J. C.;
Zugay, J. A. J. Med. Chem. 1992, 35, 2525.
7. (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1997, 119, 8738. (b) Katho, A.; Carmona,
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