Preparation of selectively protected L-dopa derivatives: Oxidation of tyrosine-3-boronates

Article abstract of DOI:10.1071/CH03181

Conversion of 3-iodo-L-tyrosine to protected tyrosine-3-boronate esters, followed by oxidation with hydrogen peroxide, provides a mild and efficient method for the preparation of selectively protected L-dopa derivatives.

Full text of DOI:10.1071/CH03181

Full Papers
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 1095–1098
Preparation of Selectively Protected l-Dopa Derivatives:
Oxidation of Tyrosine-3-boronates
Luke HunterA and Craig A. HuttonA,B,C
A School of Chemistry, University of Sydney, Sydney 2006, Australia.
B School of Chemistry, University of Melbourne, Melbourne 3010, Australia.
C Author to whom correspondence should be addressed (e-mail: chutton@unimelb.edu.au).
Conversion of 3-iodo-l-tyrosine to protected tyrosine-3-boronate esters, followed by oxidation with hydrogen
peroxide, provides a mild and efficient method for the preparation of selectively protected l-dopa derivatives.
Manuscript received: 16 July 2003.
Final version: 28 August 2003.
AcHN
O
Introduction
O
O
OH
HN
l-Dopa derivatives are important components of a variety of
biologically active cyclic peptides, including bouvardin,[1]
K-13 ((1); Scheme 1),[2] the RA compounds,[3] and the
ustiloxins (e.g. (2)).[4]
NHMe
OH
O
HN
N
H
O
HN
CO2H
NH
O
HO2C
O
Most methods for the preparation of selectively pro-
tected l-dopa derivatives (6) have used l-tyrosine (3) as a
convenient starting material, and proceed via an acylation–
oxidation protocol to install the oxygen functionality at the
3-position on the aromatic ring (Scheme 2).[5–8] The acyla-
tion reactions employed in these preparations often require
harsh conditions that can result in significant racemization,
proceed in low conversion, or are not suitable for compounds
containing sensitive functional groups. For example, the
Friedel–Crafts acylation of l-tyrosine to give 3-acetyltyro-
sine results in 5–15% racemization.[5] Jung and Lazarova[6]
employed a Reimer–Tiemann formylation of Boc-l-tyrosine
in their preparation of selectively protected l-dopa deriva-
tives, but isolated only 33% of the acylated tyrosine prod-
uct (Boc = t-butoxycarbonyl). Additionally, Baeyer–Villiger
oxidations of 3-acyl-l-tyrosine derivatives (4) often fur-
nish the corresponding l-dopa derivatives (5) in low
yield. Modified and improved methods have been reported,
including benzylic hydroperoxide rearrangements,[5] Dakin
reactions[6] and optimized Baeyer–Villiger oxidations of spe-
cific substrates,[7] in order to provide improved yields of the
corresponding differentially protected l-dopa derivatives.
Morera and Ortar[8] have prepared 3-formyltyrosine
derivatives from 3-iodotyrosine, via a palladium-catalyzed
hydroformylation reaction. This procedure allows for the
mild acylation of the iodotyrosine derivative, but requires the
use of carbon monoxide gas. Herein we report a mild, effi-
cient synthesis of selectively protected l-dopa derivatives via
tyrosine-3-boronate esters, employing 3-iodo-l-tyrosine (or
l-tyrosine) as the starting material.
HO
HO
(1)
(2)
Scheme 1.
H2N
CO2H
R1HN
CO2R2
O
acylation at
3'-position
oxidation
R
protection
HO
R3O
(3)
(4)
R1HN
CO2R2
R1HN
CO2R2
O
R
hydrolysis
O
HO
R3O
R3O
(5)
(6)
Scheme 2. Acylation–oxidation protocol for conversion of tyrosine
derivatives to dopa derivatives.
Results and Discussion
The 3-iodo-l-tyrosine derivatives (8a)–(8c) were prepared as
shown in Scheme 3. 3-Iodo-l-tyrosine (7), available com-
mercially or by iodination of l-tyrosine (3),[9] was converted
to the corresponding methyl ester hydrochloride, which
was N-protected by treatment with benzyl chloroformate.
© CSIRO 2003
10.1071/CH03181
0004-9425/03/111095

1096
L. Hunter and C. A. Hutton
H2N
CO2H
CbzHN
CO2Me
CbzHN
CO2Me
CbzHN
(9a)
CO2Me
TBS-Cl
O
B
O
B
(pinB)2, KOAc,
Pd(dppf)Cl2
1. MeOH, SOCl2
2. CbzCl, Na2CO3
I
I
O
O
imidazole
DMSO
93%
HO
RO
66%
TBSO
HO
(8a) R = H
(8b) R = Me
(8c) R = Bn
(7)
MeI, K2CO3, 99%
BnBr, K2CO3,
Cs2CO3, 96%
(11)
CbzHN
(12)
CO2Me
CbzHN
CO2Me
CbzHN
CO2Me
CbzHN
CO2Me
O
B
HO
TBSO
HO
H2O2
ϩ
H2O2
HO
RO
MeOH, H2O
50%
O
MeOH, H2O
TBSO
RO
(9a) R = H (32%)
(9b) R = Me (80%)
(9c) R = Bn (88%)
(13)
(10b) R = Me (91%)
(10c) R = Bn (93%)
Scheme 4.
R1 R2
Scheme 3. Cbz: carbobenzyloxy; (pinB)2: bis(pinacolato)diboron;
dppf:1,1ꢀ-bis(diphenylphosphino)ferrocene; DMSO: dimethylsulfoxide.
O
CbzHN
HO
CO2Me
1. H2, Pd/C
Ph
HN
CO2Me
Alkylation of (8a) with iodomethane or benzyl bromide
then provided the 4-O-methyl- and 4-O-benzyl-protected
derivatives, (8b) and (8c), respectively, in excellent yield.
Treatment of the protected iodotyrosine derivatives (8b)
and (8c) with bis(pinacolato)diboron according to Miyaura’s
protocol[10] provided the 4-O-methyl- and 4-O-benzyl-
protected tyrosine-3-boronate esters (9b) and (9c) in good
yield. Corresponding treatment of the iodotyrosine deriva-
tive (8a) possessing a free phenolic group gave the boronate
(9a) in good crude yield, but significant loss of product
occurred during purification by chromatography on silica,
with the pure boronate (9a) isolated in only 32% yield.
In our experience, while chromatographic purification of
4-O-protected tyrosine-3-boronates generally proceeds effi-
ciently, significant decomposition occurs during purification
of boronates containing an ortho-phenolic group, presumably
via hydrolysis to the corresponding boronic acid.
2. EDC, (R)-MTPA
or (S)-MTPA
HO
HO
BnO
(10c)
(14a) R1 = CF3, R2 = OMe
(14b) R1 = OMe, R2 = CF3
Scheme 5. MTPA: α-methoxy-α-(trifluoromethyl)phenylacetic acid;
EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
EDC, gave the amides (14a) and (14b), which were shown
to be >97% diastereomerically pure by H and 19F NMR
1
spectroscopy.
In conclusion, this procedure represents a mild, short,
high-yielding preparation of selectively protected dopa
derivatives, requiring only a two-step manipulation of the
aromatic functionality, in addition to requisite protecting
group strategies, from 3-iodo-l-tyrosine. Dopa derivatives
(10b) and (10c) have been prepared in 73 and 67% yield,
respectively, in four mild steps from 3-iodo-l-tyrosine (3).
Oxidation of the tyrosine-3-boronates (9b) and (9c) was
performed in methanol/30% aqueous hydrogen peroxide,[11]
affording the corresponding 4-O-methyl and 4-O-benzyl
dopa derivatives (10b) and (10c), respectively, in excellent
yield.
Other 4-O-protecting groups were also investigated.
Attempted preparation of silyl-protected boronate (11) via
borylationofthecorrespondingsilyl-protected3-iodotyrosine
derivative resulted in removal of the t-butyldimethylsilyl
(TBS) protecting group. However, preparation of (11) was
accomplished by TBS-protection of tyrosine-3-boronate (9a)
(Scheme 4). Oxidation of (11) gave a 1 : 1 mixture of the
mono-silyl protected dopa derivatives (12) and (13), pre-
sumably arising through reversible silyl migration from
the 4-oxygen of the initial product (12) to yield the 3-O-
silylated product (13). An analogous facile scrambling of a
4-O-pivaloyl protected dopa derivative has been reported.[12]
Confirmation of the enantiomeric purity of the dopa
derivatives was achieved through preparation of the Mosher
amide derivatives (14a) and (14b) (Scheme 5). Deprotec-
tion of the dopa derivative (10c) by catalytic hydrogenation,
followed by treatment with either (R)- or (S)-MTPA and
Experimental
(S)-N-Benzyloxycarbonyl-3-(4-hydroxy-3-iodophenyl)alanine
methyl ester (8a)
To methanol (40 mL) cooled to 0◦C was slowly added thionyl chlo-
ride (1.3 mL, 17.9 mmol). The resulting solution was warmed to room
temperature, 3-iodo-l-tyrosine (5.0 g, 16.3 mmol) was added, and the
mixture was stirred for 18 h at room temperature. The mixture was con-
centrated in vacuo to give 3-iodo-l-tyrosine methyl ester hydrochloride
as a white solid (5.6 g). The solid was dissolved in methanol (40 mL),
Na2CO3 (2.6 g, 24.5 mmol) was added, and a solution of benzylchloro-
formate in toluene (50% v/v, 6.11 mL, 21.4 mmol) was added. The
resulting mixture was stirred at 0◦C for 2 h. Saturated aqueous NH4Cl
(200 mL) was added and the mixture was extracted with ethyl acetate
(3 × 200 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo to give the crude product as a clear oil. Purifi-
cation by flash chromatography on silica eluting with 20–50% ethyl
acetate/hexane gave (8c) as a white solid (6.92 g, 93%). mp 109–111◦C
(lit.[8] mp 101–102◦C). [α]D25 +1 (c 1.0, MeOH) (lit.[8] [α]2D5 +2 (c 1.0,
MeOH)); 1H and 13C NMR data in accordance with literature values.[8]

Selectively Protected l-Dopa Derivatives: Oxidation of Tyrosine-3-boronates
1097
(S)-N-Benzyloxycarbonyl-3-(3-iodo-4-methoxyphenyl)alanine
(S)-N-Benzyloxycarbonyl-3-(4-methoxy-3-(4,4,5,5-tetramethyl-
methyl ester (8b)[13,14]
[1,3,2]dioxaborolan-2-yl)phenyl)alanine methyl ester (9b)[13,14]
To a solution of (8a) (1.20 g, 2.64 mmol) and K2CO3 (2.2 g, 15.9 mmol)
in dry dimethylformamide (DMF; 12 mL) was added iodomethane
(2.5 mL, 40.2 mmol), and the resulting mixture was stirred at room
temperature in the dark for 20 h. Water (80 mL) was added, and the
mixture was extracted with ethyl acetate (3 × 80 mL). The combined
organic layers were washed with brine (2 × 80 mL), dried (MgSO4),
and concentrated in vacuo to give the crude product as a yellow oil.
Purification by flash chromatography on silica eluting with 30–50%
ethyl acetate/hexane gave (8b) as a clear oil (1.23 g, 99%). [α]2D5 +50
(c 1.2, CHCl3). νmax/cm–1 3348, 2949, 1742, 1716, 1491, 1250. δH
(300 MHz; CDCl3) 7.54 (1H, d, J 2.1, ArH2), 7.41–7.29 (5H, m, Ph),
7.05 (1H, dd, J 8.4, 2.1, ArH6), 6.72 (1H, d, J 8.4, ArH5), 5.28 (1H,
br d, J 9.1, NH), 5.14 (1H, d, J 12.3, PhCHH), 5.09 (1H, d, J 12.3,
PhCHH), 4.62 (1H, m, α-H), 3.85 (3H, s, OMe), 3.74 (3H, s, OMe),
3.06 (1H, dd, J 14.1, 5.7, ArCHH), 2.98 (1H, dd, J 14.1, 6.0, ArCHH).
δC (75 MHz; CDCl3) 172.0, 157.6, 155.8, 140.4, 136.5, 130.5, 130.1,
128.8, 128.4, 128.3, 111.1, 86.2, 67.3, 56.6, 55.1, 52.6, 37.1. m/z (ESI)
492 ([M + Na]+, 100%).Anal. calcd for C19H20INO5: C 55.06, H 4.44,
N 2.57. Found: C 55.17, H 4.37, N 2.62.
To a mixture of bis(pinacolato)diboron (0.536 g, 2.33 mmol),
Pd(dppf)Cl2 · CH2Cl2 (0.05 g, 0.057 mmol, 0.03 equiv), and anhydrous
potassium acetate (0.731 g, 7.46 mmol) under dry nitrogen was added
a solution of (8b) (0.906 g, 1.9 mmol) in DMSO (19 mL). The mixture
was stirred at 80◦C under nitrogen for 22 h. Ethyl acetate (100 mL)
was added, and the mixture filtered through sintered glass. The fil-
trate was added to aqueous NaCl (20%, 100 mL) and the aqueous phase
was extracted with ethyl acetate (2 × 100 mL). The combined organic
layers were washed with brine (3 × 50 mL), dried (Na2SO4), and con-
centrated in vacuo to give the crude product as a viscous brown oil.
Purification by flash chromatography on silica eluting with 20–50%
ethyl acetate/hexane gave (9b) as a white foam (0.722 g, 80%). [α]2D5+38
(c 7.2, CHCl3). νmax/cm−1 3432, 3361, 2978, 2928, 2248, 1745, 1723,
1603, 1493, 910, 733. δH (200 MHz; CDCl3) 7.41 (1H, d, J 2.4, ArH2),
7.37–7.29(5H, m, Ph), 7.13(1H, dd, J 8.5, 2.4,ArH6), 6.76(1H, d, J 8.5,
ArH5), 5.22 (1H, br d, J 8.3, NH), 5.10 (2H, s, PhCH2), 4.62 (1H, m,
α-H), 3.81 (3H, s, OMe), 3.72 (3H, s, OMe), 3.13–2.95 (2H, m,ArCH2),
1.34 (12H, s, Me × 4). δC (75 MHz; CDCl3) 172.4, 163.7, 155.9, 137.8,
136.6, 133.4, 128.8, 128.4, 128.3, 127.2, 111.0, 83.8, 67.2, 56.1, 55.3,
52.5, 37.6, 25.1 (carbon bearing boron substituent not observed). m/z
(ESI) 492 ([M + Na]+, 100%), 470 ([M + H]+, 21). HRMS m/z (ESI)
calcd for C25H33BNO7 470.2350, found 470.2350.
(S)-N-Benzyloxycarbonyl-3-(4-benzyloxy-3-iodophenyl)alanine
methyl ester (8c)[15]
To a solution of (8a) (22.0 g, 48.3 mmol) in methanol (250 mL) was
added Cs2CO3 (8.6 g, 26.4 mmol) and K2CO3 (3.0 g, 21.7 mmol). The
resulting solution was stirred for 15 min, then concentrated in vacuo
to give a pale yellow foam. The residue was dissolved in dry DMF
(250 mL), benzyl bromide (8.82 mL, 74.2 mmol) was added and the
mixture was stirred at room temperature for 2 h. Ethyl acetate (800 mL)
was added, and the mixture was washed with water (3 × 800 mL). The
organic layer was dried (Na2SO4) and concentrated to give a clear oil
(30.7 g). Purification by flash chromatography on silica eluting with
20–50% ethyl acetate/hexane gave (8c) as a clear oil (25.1 g, 96%).
[α]D25 + 41 (c 2.7, CHCl3). νmax/cm–1 3341, 3033, 2947, 1743, 1720,
1488, 1250. δH (300 MHz; CDCl3) 7.57 (1H, d, J 2.1,ArH2), 7.51–7.29
(10H, m, Ph × 2), 7.02 (1H, dd, J 8.4, 2.1, ArH6), 6.75 (1H, d, J 8.4,
ArH5), 5.25 (1H, br d, J 7.9, NH), 5.16–5.07 (4H, m, PhCH2 × 2), 4.62
(1H, m, α-H), 3.73 (3H, s, OMe), 3.06 (1H, dd, J 14.2, 5.8, ArCHH),
2.99 (1H, dd, J 14.2, 6.2, ArCHH). δC (75 MHz; CDCl3) 172.0, 156.7,
155.8, 140.5, 136.7, 136.5, 130.5, 128.8, 128.5, 128.3, 128.2, 127.3,
112.8, 87.1, 71.2, 67.3, 55.1, 52.6, 37.2. m/z (ESI) 568 ([M + Na]+,
100%). Anal. calcd for C25H24INO5: C 48.63, H 4.30, N 2.98. Found:
C 48.73, H 4.26, N 3.03.
(S)-N-Benzyloxycarbonyl-3-(4-benzyloxy-3-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)phenyl)alanine methyl ester (9c)[15]
To
a mixture of bis(pinacolato)diboron (12.38 g, 53.9 mmol),
Pd(dppf)Cl2 · CH2Cl2 (1.00 g, 1.22 mmol, 0.03 equiv), and anhydrous
potassium acetate (16.96 g, 173 mmol) under dry nitrogen was added
a solution of (8c) (24.36 g, 44.7 mmol) in DMSO (430 mL). The mix-
ture was stirred at 80◦C for 24 h. Ethyl acetate (800 mL) was added,
and the mixture filtered through sintered glass. The filtrate was added
to aqueous NaCl (20%, 800 mL) and the aqueous phase was extracted
with ethyl acetate (800 mL). The combined organic layers were washed
with brine (2 × 400 mL), dried (Na2SO4), and concentrated to give the
crude product as a viscous brown oil (32.0 g). Purification by flash
chromatography on silica eluting with 20% ethyl acetate/hexane gave
(9c) as a clear oil (21.48 g, 88%). [α]2D5 +35 (c 1.6, CDCl3). νmax/cm–1
3351, 2973, 1741, 1720, 1605, 1494. δH (200 MHz; CDCl3) 7.62–7.58
(2H, m, ArH), 7.45 (1H, d, J 2.4, ArH), 7.41–7.29 (8H, m, ArH), 7.14
(1H, dd, J 8.4, 2.4, ArH), 6.84 (1H, d, J 8.4, ArH), 5.22 (1H, br d,
J 8.0, NH), 5.04 (4H, s, PhCH2 × 2), 4.62 (1H, m, α-H), 3.71 (3H, s,
OMe), 3.14–2.95 (2H, m, ArCH2), 1.36 (12H, s, Me × 4). δC (75 MHz;
CDCl3) 172.4, 162.8, 155.9, 137.8, 136.5, 133.4, 130.5, 128.7, 128.4,
128.2, 127.8, 127.6, 127.0, 115.2, 112.5, 83.7, 70.3, 67.2, 55.3, 52.4,
37.6, 25.2 (carbon bearing boron substituent not observed). m/z (ESI)
568 ([M + Na]+, 100%). HRMS m/z (ESI) calcd for C31H36BNNaO7
568.2483, found, 568.2470.
(S)-N-Benzyloxycarbonyl-3-(4-hydroxy-3-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)phenyl)alanine methyl ester (9a)
To
a mixture of bis(pinacolato)diboron (0.353 g, 1.52 mmol),
Pd(dppf)Cl2 · CH2Cl2 (0.032 g, 0.041 mmol, 0.03equiv), andanhydrous
potassium acetate (0.472 g, 5.52 mmol) under dry nitrogen was added
a solution of (8a) (0.628 g, 1.38 mmol) in DMSO (11 mL). The mix-
ture was stirred at 80◦C under nitrogen for 24 h. Ethyl acetate (100 mL)
was added, and the mixture filtered through sintered glass. The filtrate
was added to aqueous NaCl (20%, 100 mL) and the aqueous phase was
extracted with ethyl acetate (2 × 100 mL). The combined organic layers
were washed with brine (3 × 50 mL), dried (MgSO4) and concentrated
in vacuo to give the crude product as a viscous brown oil (0.835 g).
Purification by flash chromatography on silica eluting with 5–100%
ethyl acetate/dichloromethane gave (9a) as a clear oil (0.202 g, 32%).
[α]D25+22 (c 1.0, CHCl3). νmax/cm−1 3434, 2974, 1718, 1622, 1483. δH
(200 MHz; CDCl3) 7.74 (1H, s, OH), 7.36–7.30 (6H, m, Ph and ArH2),
7.10 (1H, dd, J 8.4, 2.4, ArH6), 6.80 (1H, d, J 8.4, ArH5), 5.21 (1H,
br d, J 7.9, NH), 5.10 (2H, s, PhCH2), 4.60 (1H, m, α-H), 3.72 (3H, s,
OMe), 3.11–2.93 (2H, m, ArCH2), 1.36 (12H, s, Me × 4). δC (75 MHz;
CDCl3) 172.4, 163.1, 156.0, 136.6, 134.9, 128.8, 128.4, 128.3, 126.7,
116.0, 84.8, 67.2, 55.3, 52.5, 37.7, 30.0, 25.1 (carbon bearing boron
substituent not observed). m/z (ESI) 456 ([M + H]+, 92%). HRMS
m/z (ESI) calcd for C24H31BNO7 456.2194, found 456.2192.
(S)-N-Benzyloxycarbonyl-3-(3-hydroxy-4-methoxyphenyl)alanine
methyl ester (10b)
To a solution of (9b) (0.529 g, 1.1 mmol) in methanol (40 mL) was
added a solution of H2O2 in water (30%, 9 mL), and the resulting
mixture was stirred at room temperature for 30 min. The volume was
reduced by about 20 mL in vacuo, and the mixture was extracted with
dichloromethane (3 × 30 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to give the crude product as a pale
yellow oil. Purification by flash chromatography on silica eluting with
5–40% ethyl acetate/dichloromethane gave (10b) as a clear oil (0.369 g,
91%). [α]2D5 +46 (c 1.5, CHCl3) (lit.[16] [α]D25 +48 (c 0.65, CHCl3)).
δC (75 MHz; CDCl3) 172.3, 155.9, 146.0, 145.9, 136.5, 129.0, 128.7,
128.4, 128.3, 121.0, 115.7, 111.0, 67.2, 56.1, 55.1, 52.5, 37.8. 1H NMR
data in accordance with literature values.[16]
(S)-N-Benzyloxycarbonyl-3-(4-benzyloxy-3-hydroxyphenyl)alanine
methyl ester (10c)
To a solution of (9c) (10.08 g, 18.5 mmol) in methanol (400 mL) was
added a solution of H2O2 in water (30%, 150 mL), and the mixture

1098
L. Hunter and C. A. Hutton
was stirred at room temperature for 30 min. The mixture was concen-
trated to about 400 mL in vacuo, and the mixture was extracted with
dichloromethane (3 × 250 mL).The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to give a yellow oil (10.11 g).
Purification by flash chromatography on silica eluting with 20–50%
ethyl acetate/hexane gave (10c) as a clear oil (7.49 g, 93%). [α]2D5 + 42
(c 1.6, CHCl3) (lit.[8] [α]D25 + 44 (c 1.0, CHCl3)). 1H and 13C NMR data
in accordance with literature values.[5,8]
(S)-MTPA derivative (14b)
Derivative (14b) was prepared in a manner analagous to that reported
for (14a), using (S)-α-methoxy-α-(trifluoromethyl)phenylacetic acid
in place of (R)-α-methoxy-α-(trifluoromethyl)phenylacetic acid. (14b)
was obtained as a white solid. Rf 0.45 (70% ethyl acetate/hexane). δH
(300 MHz; CDCl3) 7.45–7.38 (5H, m, Ph), 7.05 (1H, br d, J 8.4, NH),
6.67 (1H, d, J 8.1, ArH5), 6.36 (1H, dd, J 8.1, 2.0, ArH6), 6.21 (1H, d,
J 2.0, ArH2), 5.24 (1H, br s, OH), 5.12 (1H, br s, OH), 4.97 (1H, m, α-
H), 3.77 (3H, s, OMe), 3.47 (3H, q, JHF 1.7, OMe), 3.05 (1H, dd, J 14.2,
5.2,), 2.90 (1H, dd, J 14.2, 7.1,ArCHH). δF (282 MHz; CDCl3) −63.90.
(S)-N-Benzyloxycarbonyl-3-(4-tert-butyldimethylsilyloxy-3-
(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl)alanine
methyl ester (11)
Acknowledgments
To a solution of (9a) (0.084 g, 0.19 mmol) and imidazole (0.032 g,
0.46 mmol) in dry DMF (0.7 mL) at 0◦C was added tert-butyl-
dimethylsilyl chloride (0.033 g, 0.22 mmol).The mixture was warmed to
room temperature and stirred for 17 h. Diethyl ether (10 mL) was added,
and the mixture was washed with water (10 mL). The organic layer was
dried (Na2SO4) and concentrated in vacuo to give the crude product
as a clear oil (0.139 g). Purification by flash chromatography on silica
eluting with 20% ethyl acetate/hexane gave (11) as a clear oil (0.069 g,
66%). [α]2D5 + 32 (c 1.4, CHCl3). νmax/cm−1 3431, 3345, 2974, 2950,
2929, 2855, 1743, 1724, 1604, 1490. δH (300 MHz; CDCl3) 7.44 (1H,
d, J 2.4, ArH2), 7.38–7.29 (5H, m, Ph), 7.03 (1H, dd, J 8.3, 2.4, ArH6),
6.70 (1H, d, J 8.3, ArH5), 5.20 (1H, br d, J 7.7, NH), 5.10 (2H, s,
PhCH2), 4.61 (1H, m, α-H), 3.71 (3H, s, OMe), 3.09–2.97 (2H, m,
ArCH2), 1.32 (12H, s, Me × 4), 1.03 (9H, s, But), 0.23 (6H, s, SiMe2).
δC (75 MHz; CDCl3) 172.1, 159.8, 155.6, 137.9, 136.3, 132.9, 128.5,
128.1, 128.0, 127.4, 119.4, 83.3, 66.9, 55.0, 52.1, 37.4, 25.8, 25.0, 24.9,
18.3, −4.2 (carbon bearing boron substituent not observed). m/z (ESI)
592 ([M + Na]+, 100%). HRMS m/z (ESI) calcd for C30H44BNNaO7Si
592.2878, found, 592.2874.
This work was supported by the Australian Research
Council (DP0208190). L.H. thanks the School of Chemistry,
University of Sydney, for a Gritton Award.
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(R)-MTPA derivative (14a)
To a deoxygenated solution of (10c) (0.246 g, 0.56 mmol) in methanol
(7 mL) was added palladium on charcoal (10%, 0.054 g), and the
mixture was stirred under an atmosphere of hydrogen for 90 min.
The mixture was filtered through celite, washed with methanol,
and the filtrate was concentrated in vacuo to give the deprotected
intermediate as
a dark grey oil (0.119 g, 100%), which was
used in the next step without further purification. A solution of
the crude intermediate (0.022 g, 0.104 mmol), (R)-α-methoxy-α-
(trifluoromethyl)phenylacetic acid (0.024 g, 0.104 mmol) and 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.022 g,
0.125 mmol)inDMF(0.1 mL)wasstirredfor17 h. Ethylacetate(20 mL)
was added, and the mixture was washed with water (3 × 20 mL). The
organic layer was dried (Na2SO4) and concentrated in vacuo to give
the crude product as a brown solid (0.017 g). Purification by flash chro-
matography on silica eluting with 30% ethyl acetate/hexane gave (14a)
as a clear oil. Rf 0.45 (70% ethyl acetate/hexane). δH (300 MHz; CDCl3)
7.52–7.50 (2H, m, ArH), 7.44–7.36 (3H, m, ArH), 7.32 (1H, br d, J 7.8,
NH), 6.78 (1H, d, J 8.1, ArH), 6.65 (1H, d, J 1.6, ArH), 6.54 (1H, dd,
J 8.1, 1.6,ArH), 5.58 (1H, br s, OH), 5.35 (1H, br s, OH), 4.86 (1H, m, α-
H), 3.74 (3H, s, OMe), 3.26 (3H, q, JHF 1.4, OMe), 3.11 (1H, dd, J 14.7,
5.6,), 2.99 (1H, dd, J 14.7, 6.9,ArCHH). δF (282 MHz; CDCl3) −63.94.
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