Synthesis of C2 symmetric 2,2′-bipyridyl imidazolidinone and oxazaborolidine derivatives

Article abstract of DOI:10.3987/com-01-s(k)12

4,4′-Bis(bromomethyl)-2,2′-bipyridine reacts with (4R, 5R)-1-propanoyl-4,5-diphenylimidazolidinone to form a C₂ symmetric chiral bipyridine derivative. Similarly reaction of 4,4′-bis(bromomethyl)-2,2′-bipyridine with an amino alcohol prepared from L-tyrosine affords a C₂ symmetric diaminodiol. Treatment of the latter product with either borane or trimethylboroxine forms oxazaborolidines that have been used as catalysts in the asymmetric reduction of acetophenone. High enantiomeric excesses are obtained.

Full text of DOI:10.3987/com-01-s(k)12

HETEROCYCLES, Vol. 56, 2002, pp. 157 - 170, Received, 7th May, 2001
SYNTHESIS OF C2 SYMMETRIC 2,2′-BIPYRIDYL
IMIDAZOLIDINONE AND OXAZABOROLIDINE
DERIVATIVES†
Robert S. Ward,a Denis Branciard,a Rosemary A. Dignan,a and Martyn C.
Pritchardb
aUniversity of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK
e-mail: r.s.ward@swan.ac.uk
bPfizer Global Research and Development, Robinson Way, Cambridge CB2 2QB,
UK
Abstract - 4,4′-Bis(bromomethyl)-2,2′-bipyridine reacts with (4R,5R)-1-
propanoyl-4,5-diphenylimidazolidinone to form a C2 symmetric chiral bipyridine
derivative. Similarly reaction of 4,4′-bis(bromomethyl)-2,2′-bipyridine with an
amino alcohol prepared from L-tyrosine affords a C2 symmetric diaminodiol.
Treatment of the latter product with either borane or trimethylboroxine forms
oxazaborolidines that have been used as catalysts in the asymmetric reduction of
acetophenone. High enantiomeric excesses are obtained.
INTRODUCTION
The advantage of solid-phase synthesis, in which a substrate, a reagent or a catalyst is attached to an
insoluble support, is that the bound component can be isolated and purified simply by filtration.1-3
However difficulties are often encountered in adapting previously optimised solution-phase procedures
to solid-phase methods. The heterogeneous reaction conditions lead to different kinetic behavior,
differences of reactivity and solvation, and other problems not encountered in solution-phase reactions.
Methods for combining solution-phase reactions with solid-phase separation have been developed
involving selective precipitation and selective solubility.4-7 As part of a programme aimed at combining
the advantages of solution-phase chemistry with solid-phase separation in asymmetric synthesis, 8,9 we
have synthesised two C2 symmetric bipyridine derivatives suitable for use in asymmetric
† This paper is dedicated to Professor Jim Kutney on the occasion of his 70th birthday.

alkylation and reduction reactions.
RESULTS AND DISCUSSION
Direct bromination of 4,4′-dimethyl-2,2′-bipyridine (1) using NBS gave a mixture of brominated
products (Scheme 1), and after purification gave only a 10% yield of the desired 4,4′-bis(bromomethyl)-
2,2′-bipyridine (2).10 Increasing the amount of NBS and the reaction time increased the amounts of the
tri- and tetrabromo products but did not significantly alter the yield of 2. This compound could also be
prepared by a four-step sequence via the corresponding N,N′-dioxide (3) in 13.5% overall yield (Scheme
2).9-11 However the most efficient synthesis of 2 was via the corresponding 4,4′-bis(trimethylsilyl)
derivative (6) which afforded 2 in two steps in 94% overall yield (Scheme 3).12
CH3
BrCH2
N
N
NBS
10%
+
mono-, tri- and tetra-
bromo products
N
N
CH3
CH2Br
1
2
Scheme 1
_
CH3
CH3
O
AcO
Ac2O
+
N
N
N
MCPBA
97%
HOAc
44%
+
N
N
N
_
CH3
O
CH3
OAc
4
1
3
NaOH
44%
Br
HO
N
N
HBr
H2SO4
73%
Br
N
N
OH
2
5
Scheme 2

TMS
Br
CH3
N
N
N
BrCF2CF2Br
1. LDA
CsF
95%
2. TMSCl
99%
N
N
N
CH3
TMS
Scheme 3
Br
1
6
2
Our original intention was to prepare the C2 symmetric chiral bipyridine derivative (8) by reacting the
dibromide (2) with the imidazolidinone (7), prepared from norephedrine (Scheme 4). However the
attempted preparation of 7 was unsuccessful yielding instead the oxazolidinone (9), as previously
reported.13,14 In this respect norephedrine differs from ephedrine itself, but resembles pseudoephedrine
(Scheme 5).13,14
O
Ph
CH3
O
N
HN
Ph
NH
HO
Ph
NH2
CH3
urea
HN
N
N
NH
Ph
CH3
N
O
norephedrine
CH3
7
Ph
N
CH3
O
N
O
N
N
N
O
N
O
CH3
Ph
8
Scheme 4
We therefore chose to react 4,4′-bis(bromomethyl)-2,2′-bipyridine (2) with (4R,5R)-1-propanoyl-4,5-
diphenylimidazolidinone (12),15 prepared from (1R,2R)-1,2-diphenylethane-1,2-diamine (10), which
yielded the C2 symmetric chiral bipyridine derivative (13) (Scheme 6). When longer reaction times
were employed increasing amounts of the de-acylated products (14) and (15) were also obtained.

O
O
HN
Ph
NH
HO
Ph
NH2
CH3
O
NH
urea
X
CH3
Ph
CH3
norephedrine
9
7
O
O
HN
Ph
NCH3
CH3
HO
Ph
NHCH3
O
NCH3
CH3
urea
X
CH3
Ph
ephedrine
O
O
HN
Ph
NCH3
CH3
HO
Ph
NHCH3
CH3
O
NCH3
CH3
urea
X
Ph
pseudoephedrine
Scheme 5
O
O
O
N
H2N
Ph
NH2
Ph
urea
1. C4H9Li
HN
Ph
NH
Ph
HN
Ph
2. C2H5COCl
Ph
10
11
12
1. C4H9Li
2. 2
Ph
R1N
Ph
O
N
7
3
6
8
N
10
NR2
N
9
13 14 15
2
4
5
1
2
13 R = R = COCH2CH3
14 R1 = H, R2 = COCH2CH3
15 R1 = R2 = H
12
11
1N
O
Ph
Ph
Scheme 6
Our second objective was to prepare the C2 symmetric diaminodiol (18) to use as a precursor for the
generation of the C2 symmetric oxazaborolidines (19) (Scheme 7). To this end the dibromide (2) was
reacted with the amino alcohol (17),16 prepared by treating L-tyrosine methyl ester (16) with phenyl

magnesium bromide, affording 18 in 73% yield. BH3.THF or BH3.(CH3)2S and trimethylboroxine were
then used to convert 18 into 19a and 19b respectively. Typically BH3.THF (4.4 equiv.) was added
dropwise to 18 in THF at -78°C and the mixture stirred overnight at 30°C under nitrogen. Alternatively,
BH3.(CH3)2S (8 equiv.) was added dropwise to 18 in THF at 30°C and the mixture stirred overnight
under nitrogen.17 The oxazaborolidine (19a) was not isolated but was stored in THF under nitrogen
until required. To prepare 19b, trimethylboroxine (1.34 equiv.) was added to 18 in toluene at room
temperature and the solution stirred for 2 h before being heated to reflux overnight.18 Removal of the
toluene at atmospheric pressure followed by azeotropic removal of three further portions of toluene to
remove water and excess methylboronic acid (as trimethylboroxine), and drying in vacuo, gave 19b.
The 1H and 13C NMR spectra of 19b showed singlets at 0.0 ppm and 1.0 ppm respectively, due to the B-
CH3 group. However, other singlets were also present in this region suggesting that the product reacts
with moisture during isolation or on solution in CDCl3. Hence both 19a and 19b were stored in THF
under nitrogen until required.
Ph
Ph
CO2CH3
OH
PhMgBr
NH2
NH2
HO
HO
16
17
1. NaH
2. 2
6
5
4
1
N
13
2
O
12
NH2
8
7
3
2
11
9
HO 16
Ph
15
14
10
Ph
18
BH3 or CH3B(OH)2
N
2
R
B
O
H
O
N
Ph
Ph
19a R = H
19b R = CH3
Scheme 7

The oxazaborolidines (19a) and (19b) were used in the asymmetric reduction of acetophenone with
either BH3.THF or BH3.(CH3)2S. In each case the reducing agent used for the reduction was the same as
that used for formation of the oxazaborolidine. Enantiomeric excesses (ees) were determined by chiral
HPLC. The results which are summarised in the Table 1 show that high ees are obtained with both
catalysts. While in most cases the reductions were complete after 1 h and gave an essentially
quantitative yield, the one with 19b using BH3.THF (Entry 3) was incomplete after 20 h and gave only
78% ee. When the reaction was repeated and allowed to run for 72 h the reaction was still incomplete
and the ee was still only 75%. When BH3.(CH3)2S was used (Entry 4) instead of BH3.THF a precipitate
appeared after 20 min but the reaction was complete in 1 h and gave 91% ee. With 0.05 equiv. of 19b
no precipitate was observed (Entry 5). However, the lower number of equivalents of the catalyst leads
to a decrease in ee. At low catalyst concentrations non-catalysed reduction presumably takes place.
Table 1. Asymmetric reduction of acetophenone
Entry
Catalyst
19a
Equivalents
0.63
Boron Source
BH3.THF
ee%
87
1
2
3
4
5
0.50
BH3.(CH3)2S
BH3.THF
87
19a
0.50
78
19b
0.50
BH3.(CH3)2S
BH3.(CH3)2S
91
19b
0.05
84
19b
A molecular modelling investigation was carried out to compare the energy profiles of 13 and 18 with
bipyridine. It was expected that 13 and 18 would be less stable in the cisoid conformation than
bipyridine due to the presence of the large substituent groups. This would be an important consideration
in any investigation of the metal-binding properties of these compounds. The structures were
constructed using Sybyl software and energetically optimised using Tripos Force Field. A systematic
search procedure was applied in order to obtain the energy profile for each molecule. Rotation around
the relevant bond was performed with 10° increments over a range of 0° (cisoid) to 180° (transoid). The
energy at each step was calculated to produce an energy profile for each compound (Figure 1). The
difference in energy between the cisoid conformation and the global minimum energy conformation was
determined for each compound (Table 2). The low energy difference for bipyridine shows that it can
readily adopt the cisoid conformation. In the case of 13 and 18 the higher energy difference between the
cisoid conformation and the global energy minimum indicates that as expected these compounds will
find it harder to adopt a cisoid conformation.

6.00
5.00
4.00
3.00
2.00
1.00
0.00
13
18
bipyridine
0
180
Angle
Figure 1. Energy profiles for bipyridine, 13, and 18
Table 2. Energy values (kcal/mol)
Bipyridine
1.72
13
18
Emin
Ecisoid
0.39
3.94
3.55
0.55
5.57
5.02
3.46
1.74
∆Ecisoid-min
EXPERIMENTAL
1H NMR spectra were recorded at 400 MHz on a Bruker AC spectrometer. 13C NMR spectra were
recorded on a Bruker AC spectrometer at 100 MHz. All spectra were run in CDCl3 unless otherwise
indicated. The MS spectra were recorded on a VG Analytical Quattro II triple quadrupole mass
spectrometer, whilst accurate MS measurements were obtained on a Finnigan MAT 900 XL instrument.
Melting points were recorded on an Electrothermal IA9100 digital melting point apparatus and are
uncorrected. Chiral HPLC was carried out on a Daicel Chiralcel OJ column, eluent 95% hexane/5%
isopropanol, using a Milton Roy instrument comprising 3100 SpectroMonitor, 3000 ConstaMetric pump,
and CI-4100 computing integrator. Thin layer chromatography was carried out on Whatman Al Sil
G/UV fluorescent plates and revealed by UV at 254 nm. Flash chromatography was performed with
silica gel (Fisher, Matrex Silica 60, 35-70 µ).

Solvents were purified and dried when necessary using standard methods.19 Reactions were carried out
under an inert atmosphere using argon or nitrogen from the cylinder passed through H2SO4 and CaCl2.
Dry solids were obtained by drying in vacuo over P2O5 in a pistol. Low temperature baths were
prepared by making a slurry of solid CO2 in acetone (-78°C) or of ice in acetone (-10°C). Solutions of
n-butyllithium in hexane were purchased from Aldrich Chemical Co. Ltd. and were estimated before use
following the standard procedure.19 NBS was purified by literature methods.19 Diisopropylamine was
dried by distilling from KOH.
Preparation of 4,4′-bis(bromomethyl)-2,2′-bipyridine (2) : Method A
To a mixture of 4,4′-dimethyl-2,2′-bipyridine (1) (4.0 g, 21.7 mmol) and NBS (8.0 g, 44.9 mmol) in
refluxing dry CCl4 was added AIBN (0.25 g, 1.58 mmol). The resulting solution was stirred for 3 h
under nitrogen. The reaction was monitored by TLC, eluent : 98% DCM/2% acetone, the silica plates
were deactivated in 10% triethylamine/90% hexane prior to use, Rf (2) = 0.47. Then the solution was
cooled in an ice bath and filtered to remove precipitated succinimide. The yellow solution was
evaporated to dryness and the residue was dissolved in a minimum of DCM and purified by flash
chromatography, eluent : 98% DCM/2% acetone. A double recrystallisation from DCM/hexane of the
appropriate fractions afforded 2 as a pale brown solid (0.76 g, 10.1%), mp 119-121°C (lit.,12 116-118°C).
Preparation of 4,4′-bis(bromomethyl)-2,2′-bipyridine (2) : Method B
a) Preparation of 4,4′-dimethyl-2,2′-bipyridinyl-1,1′-dioxide (3)
m-CPBA ( 43%, 56.3 g, 136.0 mmol) was added to a solution of 1 (10.0 g, 54.3 mmol) in DCM (250
mL), followed by anhydrous Na2SO4 (15.0 g, 105.6 mmol). After stirring at rt for 4 h, the mixture was
filtered. The reaction was monitored by TLC, eluent : 90% DCM/10% methanol, Rf (3) = 0.35. The
solvent was removed in vacuo and the crude product purified by flash chromatography, eluent : 90%
DCM/10% methanol, to afford 3 as a pale yellow solid (11.4 g, 97.1%), mp 235-237°C (lit.,9 240°C).
b) Preparation of 4,4′-bis(acetoxymethyl)-2,2′-bipyridine (4)
Acetic anhydride (5.2 g, 51.0 mmol) was added to a solution of 3 (5.0 g, 23.1 mmol) in acetic acid (40
mL) and the resulting mixture heated to reflux for 4 h. The reaction was monitored by TLC, eluent 90%
DCM/10% methanol, Rf (4) = 0.44. The solvents were removed in vacuo, the residue taken up in ethyl
acetate, washed with 15% aq. K2CO3 and brine, and dried (MgSO4). The product was purified by flash
chromatography, eluent 60% DCM/40% ethyl acetate, to give 4 as a pale yellow solid (3.0 g, 43.5%),

mp 102-104°C (lit.,9 99°C).
c) Preparation of 4,4′-bis(hydroxymethyl)-2,2′-bipyridine (5)
A solution of 4 (7.0 g, 23.3 mmol) and NaOH (2.8 g, 70.0 mmol) in methanol (60 mL)/water (15 mL)
was heated to reflux for 3 h. The reaction was monitored by TLC, eluent 90% DCM/10% methanol, Rf
(5) = 0.09. Then the solvent was removed and the residue dissolved in a mixture of water and ethyl
acetate. The aqueous layer was washed with ethyl acetate and the combined organic fractions were
washed with brine and then dried (MgSO4). The crude product was recrystallised from ethyl acetate to
afford 5 as a pale yellow powder (2.22 g, 44.0%), mp 160-162°C (lit.,9 159°C).
d) Preparation of 4,4′-bis(bromomethyl)-2,2′-bipyridine (2)
A solution of 5 (0.9 g, 4.2 mmol) in 48% hydrobromic acid (16.2 mL, 136 mmol) was heated at reflux
for 5 h. The reaction was monitored by TLC, eluent : 90% DCM/10% methanol, Rf (2) = 0.68. The
reaction mixture was then cooled to 0°C and 6N NaOH solution added until pH = 7. The precipitate was
filtered and dried in vacuo to afford 2 as pale brown crystals (1.03 g, 72.3%), mp 119-121°C, identical to
the sample prepared by Method A.
Preparation of 4,4′-bis(bromomethyl)-2,2′-bipyridine (2) : Method C
a) Preparation of 4,4′-bis(trimethylsilyl)-2,2′-bipyridine (6)
To diisopropylamine (3.8 mL, 27.1 mmol) in dry THF (30 mL) at -78°C was added n-C4H9Li (1.45 M in
hexane, 16.5 mL, 23.9 mmol). The solution was stirred at -78°C for 20 min. Then 1 (2.0 g, 10.9 mmol)
was dissolved in dry THF (40 mL) and transferred dropwise via a cannula to the LDA solution. The
flask and cannula were rinsed with THF (2 x 3 mL). The dark-brown solution was stirred at -78°C for
20 min, warmed to -10°C for 25 min and then cooled to -78°C before addition of TMSCl (3.6 mL, 28.4
mmol). After 5-10 sec the reaction was quenched with ethanol (5 mL). Saturated aq. NaHCO3 was
added to the cold reaction mixture. The solution was then allowed to warm to rt. The product was
extracted into ethyl acetate and the combined organic fractions were washed with brine and then dried
(Na2SO4). Filtration and concentration afforded 6 as a slightly off-white powder (3.55 g, 99.0%), mp
93-95°C (lit.,12 90-92°C).
b) Preparation of 4,4′-bis(bromomethyl)-2,2′-bipyridine (2)
To a dry DMF solution (40 mL) of 6 (4.98 g, 15.2 mmol) and BrCF2CF2Br (5.4 mL, 45.4 mmol) was
added anhydrous CsF (6.8 g, 45.5 mmol). The reaction was stirred at rt for 3 h. The reaction was

monitored by TLC, the silica plates being deactivated in 10% triethylamine/90% hexane prior to use and
dried under high vacuum for at least 10 min prior to developing, eluent : 80% hexane/20% ethyl acetate,
Rf (2) = 0.14. The reaction mixture was poured into a mixture of ethyl acetate and water. The aqueous
layer was extracted with ethyl acetate and the combined organic fractions were washed with water and
brine, and then dried (Na2SO4). Filtration and concentration in vacuo gave 2 as pale brown crystals
(4.92 g, 94.8%), mp 117-119°C, identical to the sample prepared by Method A.
Preparation of (4R,5R)-4,5-diphenylimidazolidinone (11)
(1R,2R)-1,2-Diphenylethane-1,2-diamine (10) (3.02 g, 14.2 mmol), urea (0.91 g, 15.1 mmol), and water
(10 drops) were heated at 200°C until no starting material could be detected by TLC (approx. 1 h).
Flash chromatography of the residue, eluting with ethyl acetate, gave 11 as a white solid (2.56 g, 75%),
mp 197-198°C (lit.,15 196-197.5°C).
Preparation of (4R,5R)-4,5-diphenyl-1-propionylimidazolidinone (12)
To a solution of 11 (1.87 g, 6.31 mmol) in THF (30 mL) was added n-C4H9Li (1.3 M, 12.0 mL, 12.6
mmol) dropwise at -10°C and stirred for 30 min before propionyl chloride (0.73 g, 7.89 mmol) was
added. The reaction temperature was allowed to reach rt and stirring was continued overnight. The
reaction mixture was quenched with satd. NH4Cl (5 mL), diluted with DCM (20 mL) and the organic
layer separated. The aqueous layer was extracted with DCM (2 x 50 mL) and the combined organic
fractions were dried (MgSO4) and evaporated. Flash chromatography of the residue, eluting with 80%
hexane/20% ethyl acetate, gave 12 as a white solid (1.875 g, 81%), mp 118-119°C (lit.,15 120-121°C).
Preparation of 4,4′-bis[1-(4,5-diphenyl-3-propionylimidazolidinonyl)methyl]-2,2′-bipyridine (13)
NaH (60% suspension, 0.027g, 0.675mmol) was washed 3 times with dry petroleum spirit (bp 40-60°C)
under a nitrogen atmosphere. Dry DMF (10 mL) was added and the solution was cooled to -10°C before
the addition of a solution of 12 (0.201 g, 0.676 mmol) in DMF (5 mL). The reaction mixture was stirred
at -10°C for 20 min when a solution of 2 (0.120 g, 0.351 mmol) in DMF (5 mL) was added. The
reaction mixture was stirred at -10°C for 1 h and then quenched with methanol and the DMF was
removed in vacuo. The residue was extracted into DCM (3 x 40 mL), and the combined extracts were
washed with water (2 x 10 mL), dried (MgSO4), filtered and concentrated in vacuo. Separation by
1
reverse phase flash chromatography afforded 13 as a pink gum (0.132 g, 51%). H NMR (CDCl3) : 8.57
(2H, d, J = 4.4 Hz, H-6), 8.15 (2H, s, H-3), 7.15-7.40 (22H, m, phenyl and H-5), 5.15 (2H, d, J = 2.9 Hz,
H-12), 5.04 (2H, d, J = 15.9 Hz, H-7a), 4.24 (2H, d, J = 2.9 Hz, H-11), 3.84 (2H, d, J = 15.9 Hz, H-7b),

3.11 (4H, q, J = 7.3 Hz, COCH2CH3), 1.17 (6H, t, J = 7.3 Hz, COCH2CH3) . 13C NMR (CDCl3) : 173.9
(COCH2CH3), 155.1 (C-9), 149.2 (C-6), 145.3 (C-2), 140.5 (C-4), 137.9, 129.6, 129.2, 129.1, 128.2,
126.4, 125.2, (phenyl), 123.0 (C-5), 120.4 (C-3), 64.9 (C-12), 63.6 (C-11), 44.6 (C-7), 29.5 and 29.7
(COCH2CH3), 8.5 (COCH2CH3). m/z (FAB) : 791 (M+Na, 17%), 769 (M+H, 80). Acc. FAB (M+H) =
769.3501. C48H45N6O4 requires 769.3502.
Preparation of L-tyrosine methyl ester hydrochloride (16)
Thionyl chloride (6.7 mL, 91.1 mmol) was added dropwise to a solution of L-tyrosine (15.0 g, 82.8
mmol) in methanol (50 mL) at 0°C. The mixture was heated to reflux for 3 h then cooled to rt and the
solvent removed in vacuo to afford 16 as an off-white powder (19.15 g, 99.8%), mp 194-196°C (lit.,20
190°C).
Preparation of (2S)-2-amino-3-(4-hydroxyphenyl)-1,1-diphenylpropan-1-ol (17)
A dry three-necked flask was charged with magnesium turnings (7.4 g, 304.4 mmol) under nitrogen and
dry THF (30 mL) was added. One crystal of iodine was then added and the mixture stirred until the
brown colour disappeared. Neat bromobenzene (1 mL, 9.2 mmol) was added and the flask heated with a
hot air gun until the reaction started. Then a solution of bromobenzene (31 mL, 295 mmol) in THF (60
mL) was added at such a rate that the mixture boiled gently without external heating. The mixture was
then stirred for 3 h at rt when 16 was added in small portions. The brown suspension was stirred
overnight at rt and was then slowly poured onto ice. 6N HCl was added until pH = 1. The solution was
stirred for 1 h and then made alkaline by adding ammonia. The solution was stirred for a further 1 h.
The organic layer was separated, the aqueous layer was extracted with ethyl acetate, and the combined
organic fractions were washed with brine and water, then dried (MgSO4) and evaporated. The crude
product was recrystallised from ethanol to afford 17 as off-white crystals (6.27 g, 65.0%), mp 213-
215°C (lit.,16 215-217°C).
Preparation of (S,S)-4,4′-bis[4-(2-amino-3-hydroxy-3,3-diphenylpropyl)phenoxymethyl]-2,2′-bi-
pyridine (18)
A solution of 17 (3.74 g, 11.7 mmol) in dry DMF (20 mL) was added dropwise at rt to NaH (60%, 0.71
g, 17.7 mmol). After the evolution of hydrogen was complete 2 (2.0 g, 5.8 mmol) was added dropwise.
The resulting mixture was stirred at rt under nitrogen for 3 h. The solution was then poured into a
mixture of water and DCM. The aqueous layer was extracted with DCM and the combined organic
fractions were dried (MgSO4). The solvent was removed and the crude product was recrystallised from

1
ethanol/ethyl acetate to afford 18 as pale brown crystals (3.45 g, 72.8%), mp 97-99°C. H NMR : 2.32
(2H, dd, J = 14.0, 10.8 Hz, H-14a), 2.50 (2H, dd, J = 14.0, 2.4 Hz, H-14b), 4.05 (2H, dd, J = 10.8, 2.4
Hz, H-15), 5.08 (4H, s, H-7), 6.84 (4H, d, J = 8.6 Hz, H-9,13), 7.03 (4H, d, J = 8.6 Hz, H-10,12), 7.11
(4H, m, H-4′,4′′), 7.24 (8H, m, H-2′,6′,2′′,6′′), 7.35 (2H, dd, J = 1.4, 5.0 Hz, H-5), 7.54 (8H, m, H-
3′,5′,3′′,5′′), 8.38 (2H, d, J = 1.4 Hz, H-3), 8.60 (2H, d, J = 5.0 Hz, H-6). 13C NMR (CDCl3) : 35.8 (C-
14), 58.2 (C-15), 68.4 (C-7), 78.5 (C-16), 115.1 (C-9,13), 119.0 (C-5), 121.8 (C-3), 125.4, 125.8, 126.5,
126.8, 128.2, 128.5, 144.3, 146.8 (2 x phenyl), 130.2 (C-10,12), 132.4 (C-11), 147.5 (C-4), 149.5 (C-6),
156.1 (C-8), 156.9 (C-2). m/z (CI) : 819 (M+H, 16%), 635 (13), 413 (16), 391 (20), 259 (18), 183 (29),
152 (36), 135 (50). m/z (FAB) : 841 (M+Na, 44%), 819 (M+H, 100), 796 (8). Acc. FAB (M+H) =
819.3893. C54H51N4O4 requires 819.3910.
Reduction of acetophenone by 19a with BH3.THF
To a solution of 18 (0.51 g, 0.63 mmol) in dry THF (10 mL) BH3.THF (1M, 2.75 mL, 2.75 mmol) was
added slowly at -78°C under nitrogen. The mixture was then warmed to 30°C and stirred overnight. A
solution of acetophenone (0.11 mL, 1.0 mmol) in dry THF (2 mL) was added dropwise simultaneously
with BH3.THF (1 M, 1.2 mL, 1.2 mmol). The reaction was monitored by TLC, eluent 95% DCM/5%
ethyl acetate, Rf of acetophenone = 0.74, Rf of 1-phenylethanol = 0.48. After the addition the mixture
was stirred for 1 h at 30°C and was then quenched with 2N HCl (1 mL). The solvent was removed and
the residue was taken up in ether and 17 precipitated as its hydrochloride salt. The precipitate was then
collected on a glass filter and washed with ether. The ether extracts were washed with brine, dried
(MgSO4) and evaporated to give 1-phenylethanol as a colourless oil which was analysed by HPLC (see
Table 1, Entry 1).
Reduction of acetophenone by 19a with BH3.DMS
To a solution of 18 (0.41 g, 0.5 mmol) in dry THF (10 mL) BH3.DMS (0.38 mL, 4.0 mmol) was added
slowly at 30°C under nitrogen. The mixture was stirred overnight at 30°C. BH3.DMS (0.11 mL, 1.2
mmol) was added slowly and the solution stirred for 1 h. A solution of acetophenone (0.11 mL, 1.0
mmol) in dry THF (2 mL) was then added dropwise. After the addition the mixture was stirred for 1 h at
30°C and was then quenched with 2N HCl (1 mL). The product was isolated as described above and
analysed by HPLC (see Table 1, Entry 2).
Reduction of acetophenone by 19b with BH3.THF
To a solution of 18 (0.41 g, 0.5 mmol) in dry toluene (20 mL) trimethylboroxine (0.095 mL, 0.68 mmol)

was added under nitrogen. The solution was heated to reflux overnight. The solution was concentrated
(1 atm) to ca. 5 mL. Toluene (20 mL) was added and the solution was again concentrated at 1 atm. The
process was repeated twice more. Finally the solvent was removed in vacuo and the residue was
dissolved in dry THF (10 mL). A solution of acetophenone (0.11 mL, 1.0 mmol) in dry THF (2 mL)
was added dropwise simultaneously with BH3.THF (1.M, 1.2 mL, 1.2 mmol) at 30°C. The reaction was
incomplete after 72 h but was nevertheless quenched with 2N HCl (1 mL). The product was isolated as
described above and analysed by HPLC (see Table 1, Entry 3).
Reduction of acetophenone by 19b with BH3.DMS
To a solution of 18 (0.41 g, 0.5 mmol) in dry toluene (20 mL) trimethylboroxine (0.095 mL, 0.68 mmol)
was added under nitrogen. The solution was heated to reflux overnight. The solution was concentrated
(1 atm) to ca. 5 mL. Toluene (20 mL) was added and the solution was again concentrated at 1 atm. The
process was repeated twice more. Finally the solvent was removed in vacuo and the residue was
dissolved in dry THF (10 mL). BH3.DMS (0.11 mL, 1.2 mmol) was added slowly at 30°C and the
solution was stirred for 1 h. A solution of acetophenone (0.11 mL, 1.0 mmol) in dry THF (2 mL) was
added dropwise. The reaction was stirred for 1 h at 30°C before being quenched with 2N HCl (1 mL).
The product was isolated as described above and analysed by HPLC (see Table 1, Entry 4).
ACKNOWLEDGEMENTS
Financial support from Pfizer and EPSRC (to RAD), and Socrates funding (to DB), are gratefully
acknowledged.
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