Construction of the biaryl-part of vancomycin aglycon via atropo-diastereoselective Suzuki-Miyaura coupling

Article abstract of DOI:10.1039/c2ob25373a

An atropo-diastereoselective synthesis with dr up to 98/2 towards the biaryl subunit of vancomycin based on the use of enantiopure β-hydroxysulfoxide derivatives as novel chiral auxiliary is reported.

Full text of DOI:10.1039/c2ob25373a

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PAPER
Construction of the biaryl-part of vancomycin aglycon via
atropo-diastereoselective Suzuki–Miyaura coupling†
Timo Leermann, Pierre-Emmanuel Broutin, Frédéric R. Leroux* and Françoise Colobert*
Received 21st February 2012, Accepted 19th March 2012
DOI: 10.1039/c2ob25373a
An atropo-diastereoselective synthesis with dr up to 98/2 towards the biaryl subunit of vancomycin based
on the use of enantiopure β-hydroxysulfoxide derivatives as novel chiral auxiliary is reported.
Introduction
The discovery of penicillin1 as a drug to treat infectious diseases
followed by the development of several other antibacterial agents
marked a milestone in the fight of humankind against bacteria.
However, these antibacterial drugs saved millions of lives but
were not able to tame bacteria after all. In contrast, this war led
to the emergence of newer and even more dangerous bacterial
strains, which responded defiantly against a variety of known
antibiotics.
For several decades vancomycin, a prominent member of the
glycopeptide class of antibacterial agents,2 proved to be a drug
of “last resort”, used only after treatment with other antibiotics
had failed. Due to its medical importance and intriguing mode
of action3 in combination with its unusual molecular architec-
ture4 vancomycin was and still is a fascinating target for syn-
thetic organic chemists. During the last decades numerous
studies towards the total synthesis of vancomycin were
published.5–14 Especially the synthesis of the AB biaryl ring
system of vancomycin proved to be a highly challenging task.
Nicolaou and co-workers achieved the formation of the vanco-
mycin biaryl ring system utilising a stereocontrolled Suzuki–
Miyaura coupling reaction of boronic acid 1 and aryl iodide 2,
which was derived from p-hydroxyphenylglycine.15 The stereo-
chemical outcome of the coupling reaction is controlled by the
benzylic stereogenic center of the boronic acid building block 1
(see Scheme 1).
Scheme 1 (a) Pd(Ph3P)4, Na2CO3, toluene–MeOH–H2O (10 : 1 : 0.5),
4 h, 90 °C, 84% (aS/aR = 2 : 1).
Recently, we published a methodology for an atropo-diastereo-
selective Suzuki–Miyaura coupling reaction, using enantiopure
β-hydroxysulfoxide derivatives as novel chiral auxiliaries
(Scheme 2).16 The advantages of sulfoxides are the possibility to
Scheme 2 Atropo-diastereoselective Suzuki–Miyaura coupling reac-
tion using enantiopure β-hydroxysulfoxide derivatives as novel chiral
auxiliaries.
CNRS/Université de Strasbourg (ECPM), UMR 7509, 25 Rue Becquerel,
F-67087 Strasbourg, France. E-mail: frederic.leroux@unistra.fr,
francoise.colobert@unistra.fr; Fax: +33 (0)3 68 85 27 42;
Tel: +33 (0)3 68 85 27 44
†Electronic supplementary information (ESI) available: 1H-NMR
spectra and X-ray data of compounds (aS)-4, (aS)-5. CCDC reference
numbers 871940 and 871941. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2ob25373a
get them in an enantiomerically pure form and that they can be
easily converted into a multitude of synthetically valuable func-
tional groups (either by desulfurization, the Pummerer reaction
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Scheme 4 (a) Boc2O, NaOH, H2O–dioxane 2 : 1, 4 h, 20 °C, 99%; (b)
K2CO3, MeI, acetone, 16 h, 50 °C, 99%; (c) I2, AgTFA, CHCl3, 15 h,
20 °C, 91%; (d) HBpin, 2-(dicyclohexylphosphino)-biphenyl, Pd-
(OAc)2, NEt3, dioxane, 30 min, 85 °C, 69%.
Scheme 3 Retrosynthetic approach to Nicolaou’s synthon using enan-
tiopure β-hydroxysulfoxide derivatives as chiral auxiliaries.
or by sulfoxide/metal interconversion followed by trapping with
one of the numerous electrophiles).17
The excellent diastereoselectivities that we have observed in
the formation of the biaryl axis prompted us to investigate if the
developed method would also be applicable for the preparation
of the biaryl synthon 3, which Nicolaou used in his total syn-
thesis of vancomycin.
From a retrosynthetic point of view boronic ester 6 and aryl
iodides 7 and 8 represent suitable building blocks for the envi-
saged synthesis of Nicolaou’s synthon (see Scheme 3).
Results and discussion
Boronic ester 6 was synthesized as summarized in Scheme 4.
Protection of the amino group of commercially available (D)-4-
hydroxyphenylglycine (9) with Boc2O in the presence of sodium
hydroxide furnished derivative 10 (99% yield), which upon
treatment with potassium carbonate and methyl iodide led to
fully protected compound 11 in 99% yield. Subsequent iodina-
tion of compound 11 with iodine in the presence of silver trifl-
uoroacetate gave iodide 12 in an excellent yield of 91%. It is
known that α-amino acid derivatives, particularly those of
phenylglycine, can suffer significant racemization when they
are submitted to reaction conditions that are considered to be
typical for Suzuki–Miyaura couplings (e.g. basic conditions,
prolonged reaction times at elevated temperatures).18 In con-
clusion, the palladium catalyzed coupling of iodide 12 with pina-
colborane had to be conducted under very mild conditions to
avoid any unwanted racemization. Therefore, iodide 12 was
reacted with pinacolborane in the presence of 2-(dicyclohexyl-
phosphino)-biphenyl,19 palladium acetate and triethylamine at
85 °C for 30 min to yield boronic ester 6 (69% yield). Using
dppf as ligand20 or DPEPhos21 gave respectively 32 and 38%
yields.
Scheme 5 (a) I2, AgTFA, CHCl3, 2 h, 20 °C, 65% (89% based on
recovered starting material); b) LDA, (+)-(R)-methyl p-tolylsulfoxide,
THF, 12 h, −15–20 °C, 80%; (c) ZnBr2, DIBAL, THF, 5 h, −78–20 °C,
90%, de > 98%; (d) Ac2O, pyridine, 2 h, 20 °C, 98%; (e) NaH, MeI,
DMF, 40 min, −20 °C, 91%.
deliver iodide 14 (65% yield, 89% based on recovered starting
material). β-Keto sulfoxide 15 was prepared by the conversion
of iodide 14 with (+)-(R)-methyl p-tolylsulfoxide, which was
deprotonated using a freshly prepared lithium diisopropylamide
solution (80% yield).
Aryl iodides 7 and 8 were prepared as shown in Scheme 5.
Commercially available methyl 3,5-dimethoxybenzoate (13) was
reacted with iodine in the presence of silver trifluoroacetate to
Subsequent diastereoselective reduction of β-keto sulfoxide
15 with diisobutylaluminium hydride in the presence of
4096 | Org. Biomol. Chem., 2012, 10, 4095–4102
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Table 1 Atropo-diastereoselective Suzuki–Miyaura coupling
dr
Time [h] Yieldb [%] [aS/aR]c
Entry Reagents
“Pd”/liganda
1d
2e
3e
4e
5e
6e
7e
6 + 7 (2 : 1) Pd(OAc)2/dppf
6 + 7 (2 : 1) Pd(OAc)2/dppf
6 + 7 (2 : 1) Pd(OAc)2/S-Phos
6 + 7 (2 : 1) Pd2(dba)3/S-Phos
6 + 8 (2 : 1) Pd(OAc)2/dppf
6 + 8 (2 : 1) Pd(OAc)2/S-Phos
6 + 8 (2 : 1) Pd2(dba)3/S-Phos
55
2
2
2
2
2
2
54
51
65
69
53
68
71
90 : 10
>98 : 2
>98 : 2
>98 : 2
85 : 15
85 : 15
85 : 15
Fig. 1 Conformational rotamers of the biaryl (aS)-4.
a 10 mol% “Pd” are used; in the case of dppf 15 mol% are used; in the
case of S-Phos 20 mol% are used. b Combined yield (aS and aR).
c Determined by NMR. d Anhydrous dioxane. e Wet dioxane.
zinc bromide is known to provide the [2(R),S(R)]-β-hydroxysulf-
oxide 16 in which the OH group is syn to the bulky
substituent of the sulfoxide.22 In this case 16 was obtained in
a yield of 90% with an excellent diastereoselectivity of de
> 98%. To complete the synthesis of the building blocks, acetate
7 and methyl ether 8 were prepared by conversion of alcohol
16 with acetic anhydride in pyridine (98% yield) and methyl
iodide in the presence of sodium hydride (91% yield),
respectively.
Fig. 2 X-ray crystal structure of the biaryl (aS)-4.
The absolute configuration of the major atropoisomer (aS)-4
has been confirmed by single crystal X-ray analysis (see
Fig. 2).‡
In our previous studies on the atropo-diastereomeric Suzuki–
Miyaura coupling we had already realized a strong influence of
the substituent at the C-2 side-chain position. Therefore, we
employed next the methoxy compound 8. In wet dioxane
the yields increased also in this case when changing from
Pd(OAc)2/dppf (53%, Table 1 entry 5), over S-Phos (68%,
Table 1 entry 6) to Pd2(dba)3/S-Phos (71%, Table 1 entry 7).
We noticed also a slightly decrease of diastereoselectivity
(dr 85/15). Once again the absolute configuration of the major
atropoisomer (aS)-5 has been confirmed by single crystal X-ray
analysis (see Fig. 3).‡
With the boronic acid derivative 6 and the two iodide building
blocks 7 and 8 in hand, the next step to achieve in the reaction
sequence towards Nicolaou’s synthon 3 was the Suzuki–Miyaura
coupling to form biaryls 4 and 5, respectively. Thus, in a first
test boronic ester 6 and iodide 7 bearing an acetoxy substituent
at the side-chain (in order to make the deprotection easier)
entered smoothly into a Suzuki–Miyaura coupling reaction [Pd-
(OAc)2, dppf, CsF, 1,4-dioxane, 70 °C, 55 h] to afford a 90/
10 mixture of atropoisomers (aS)-4 and (aR)-4 in 54% combined
yield (Table 1, entry 1). Surprisingly, when we performed the
reaction in wet dioxane, we obtained the coupling product in 2 h
reaction time and an excellent diastereoselectivity. No trace of
the other diastereoisomer was detectable in the 1H and 13C NMR
spectra (Table 1, entry 2). An explanation could be the formation
of CsOH by reaction of CsF with water which accelerates the
reaction and thus avoids racemization due to shorter reaction
times (2 h compared to 55 h). The exchange of dppf as the
ligand by S-Phos raised the yield to 65% (Table 1, entry 3). A
further improvement of the yield (69%) was achieved by using
Pd2(dba)3 instead of Pd(OAc)2 as the palladium source (Table 1,
entry 4). Under these conditions only one atropoisomer (aS)-4
has been observed.
Conclusions
In the present work we developed an atropo-diastereoselective
approach to the biaryl subunit of vancomycin based on the use
of enantiopure β-hydroxysulfoxide as chiral auxiliaries during
‡Crystal data: for (aS)-4: C34H41NO10S, M = 655.74, orthorhombic, a =
9.5048(3) Å, b = 18.9754(6) Å, c = 19.2401(7) Å, α = 90.00°, β =
90.00°, γ = 90.00°, V = 3470.1(2) Å3, T = 296(2) K, space group
P212121, Z = 4, MoKα, 15 051 reflections measured, 5726 independent
reflections (Rint = 0.0412). The final R1 values were 0.0714 (I > 2σ(I)).
The final wR(F2) values were 0.1969 (I > 2σ(I)). The final R1 values
were 0.0804 (all data). The final wR(F2) values were 0.2074 (all data).
For (aS)-5: C33H41NO9S, M = 627.73, monoclinic, a = 10.6718(5) Å,
b = 11.6816(6) Å, c = 14.2167(7) Å, α = 90.00°, β = 111.9350(10)°, γ =
90.00°, V = 1644.01(14) Å3, T = 173(2) K, space group P21, Z = 2,
MoKα, 17 874 reflections measured, 6187 independent reflections (Rint
= 0.0157). The final R1 values were 0.0268 (I > 2σ(I)). The final wR(F2)
values were 0.0666 (I > 2σ(I)). The final R1 values were 0.0296 (all
data). The final wR(F2) values were 0.0686 (all data).
1
In the H NMR two sets of signals can be detected, corre-
sponding to conformational rotamers around the aminoester
moiety (Fig. 1). These rotamers are stable at room temperature
due to steric hindrance between the aminoester and p-tolyl
substituents.
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(aS)-4: 1st rotamer. 1H-NMR (CDCl3, 300 MHz): δ 1.42 (9H,
s, tBu), 1.96 (3H, s, Ac), 2.40 (3H, s, CH3pTol ), 2.98 (2H, AB,
JAB = 13.3 Hz, JAX = 9.3 Hz, JBX = 4.1 Hz, Δν = 99 Hz, CH2),
3.64 (3H, s, OMeAr-2), 3.66 (3H, s, OMeAr-2′), 3.73 (3H, s,
CO2Me), 3.85 (3H. s, OMeAr-4), 5.21 (1H, d, J = 8.0 Hz, CH
(NHBoc)), 5.82 (1H, X, JAX = 9.3 Hz, JBX = 4.1 Hz, CH(OAc)),
6.13 (1H, d, J = 8.0 Hz, NH), 6.48 (1H, d J = 2.3 Hz, HAr-3),
6.63 (1H, d, J = 2.3 Hz, HAr-5), 6.82 (1H, d, J = 8.5 Hz, HAr-3′),
7.03 (1H, d, J = 2.5 Hz, HAr-6′), 7.25 (4H, A2B2, JAB = 8.1 Hz,
Δν = 28 Hz, HpTol ), 7.32 (1H, m, HAr-4′); Anal. calcd for
C34H41NO10S: C, 62.28; H, 6.30. Found: C, 62.29; H, 6.31%.
Fig. 3 X-ray crystal structure of the biaryl (aS)-5.
the Suzuki–Miyaura coupling reaction. The absolute stereo-
chemistry of the major atropoisomers has been confirmed by
single crystal X-ray analysis.
(aS)-4: 2nd rotamer. 1H-NMR (CDCl3, 300 MHz): δ 1.44
(9H, s, tBu), 2.05 (3H, s, Ac), 2.42 (3H, s, CH3pTol ), 2.97 (2H,
AB, JAB = 13.4 Hz, JAX = 10.5 Hz, JBX = 3.0 Hz, Δν = 129 Hz,
CH2), 3.63 (3H, s, OMeAr-2), 3.66 (3H, s, OMeAr-2′), 3.77 (3H,
s, CO2Me), 3.84 (3H. s, OMeAr-4), 5.29 (1H, d, J = 7.2 Hz, CH
Experimental section
(NHBoc)), 5.52 (1H, d, J = 7.2 Hz, NH), 5.78 (1H, X, JAX
=
10.5 Hz, JBX = 3.0 Hz, CH(OAc)), 6.47 (1H, d J = 2.4 Hz,
General
HAr-3), 6.64 (1H, d, J = 2.4 Hz, HAr-5), 6.79 (1H, d, J = 8.7 Hz,
HAr-3′), 6.93 (1H, d, J = 1.9 Hz, HAr-6′), 7.26 (4H, A2B2, JAB
=
Starting materials, if commercial, were purchased and used as
such, provided that adequate checks (melting ranges, refractive
indices, and gas chromatography) had confirmed the claimed
purity. When known compounds had to be prepared according to
literature procedures, pertinent references are given. Air- and
moisture-sensitive materials were stored in Schlenk tubes or
Schlenk burettes. They were protected by and handled under an
atmosphere of argon, using appropriate glassware. Et2O and
THF were dried by distillation from sodium after the character-
istic blue color of sodium diphenyl ketyl (benzophenone–sodium
“radical–anion”) had been found to persist. Ethereal or other
organic extracts were dried by washing with brine and then by
storage over sodium sulfate. If no reduced pressure is specified,
boiling ranges (b.p.) refer to ordinary atmosphere conditions
(725 25 Torr). Melting ranges (m.p.) given were found to be
reproducible after recrystallization, unless stated otherwise
(“decomp.”), and are uncorrected. Thin-layer chromatography
(TLC) were carried out on 0.25 mm Merck silica-gel (60-F254).
Column chromatography was carried out on a column packed
with silica-gel 60N spherical neutral size 63–210 μm.
8.1 Hz, Δν = 21 Hz, HpTol ), 7.26 (1H, m, HAr-4′); 13C-NMR
(CDCl3, 75 MHz): δ 20.9 (OAc), 21.4 (CH3pTol ), 28.3 (C
(CH3)3), 52.6 (OMe), 55.3 (OMe), 55.5 (OMe), 55.8 (OMe),
57.0 (CH(NHBoc)CO2Me), 62.9 (CH2), 68.0 (CH), 80.0 (C
(CH3)3), 98.8 (CHAr), 102.0 (CHAr), 111.2 (CHAr), 117.4 (CAr),
124.1 (CHpTol ), 128.1 (CHAr), 130.0 (CHpTol ), 131.4 (CHAr),
139.4 (CAr), 140.0 (CAr), 141.3 (CAr), 141.3 (CAr), 155.0 (CAr),
156.5 (CAr), 158.2 (CAr), 159.9 (CAr), 160.5 (CvO), 169.8
(CvO), 171.9 (CvO); Anal. calcd for C34H41NO10S: C, 62.28;
H, 6.30. Found: C, 62.26; H, 6.28%.
(aR)-4: 1st rotamer. 1H-NMR (CDCl3, 300 MHz): δ 1.44
(9H, s, tBu), 2.06 (3H, s, OAc), 2.44 (3H, s, CH3pTol), 3.12 (2H,
AB d′ABX, JAB = 13.3 Hz, JAX = 11.3 Hz, JBX = 2.3 Hz, Δν =
175 Hz, CH2), 3.49 (3H, s, OMeAr-2), 3.61 (3H, s, OMeAr-2′),
3.71 (3H, s, CO2Me), 3.83 (3H, s, OMeAr-4), 5.29 (1H, d large, J
= 7.0 Hz, CH(NHBoc)), 5.44 (1H, d large, J = 7.0 Hz, NH),
5.51 (1H, X d′ABX, JAX = 11.3 Hz, JBX = 2.3 Hz, CH(OAc)),
6.43 (1H, d, J = 2.2 Hz, HAr-3), 6.58 (1H, d, J = 8.2 Hz, HAr-3′),
6.59 (1H, d, J = 2.2 Hz, HAr-5), 7.06 (1H, s large, HAr-6′), 7.20
(4H, A2B2, JAB = 8.02 Hz, Δν = 37 Hz, HpTol ), 7.53 (1H, m,
HAr-4′).
Methyl [aS,1R,7′R,(S)R]-tert-butoxycarbonylamino-{6-
[1-acetoxy-2-(4-tolylsulfinyl)-ethyl]-2,4,2′-trimethoxy-biphenyl-
5′-yl}acetate (4)
A solution of iodide 7 (100.0 mg, 0.204 mmol) and the catalytic
system (Pd-catalyst and ligand, see Table 1) in dioxane (3.0 ml)
is stirred at 20 °C for 1 h. A second solution is prepared from
boronic ester 6 (172.5 mg, 0.409 mmol, 2 eq.) and CsF
(124.4 mg, 0.820 mmol, 4 eq.) in dioxane (3.0 ml) and stirred
for 30 min at 20 °C before the first solution is added via syringe.
The reaction mixture is heated to 70 °C for 2 h, quenched by the
addition of H2O and extracted with CH2Cl2. The solvent is evap-
orated and the crude product is purified by column chromato-
graphy (cyclohexane–EtOAc = 4 : 1) to yield (aS)-4 and (aR)-4
as colorless solids.
(aR)-4: 2nd rotamer. 1H-NMR (CDCl3, 300 MHz): δ 1.47
(9H, s, tBu), 2.03 (3H, s, OAc), 2.42 (3H, s, CH3pTol), 3.14 (2H,
AB d′ABX, JAB = 13.3 Hz, JAX = 11.3 Hz, JBX = 2.3 Hz, Δν =
212 Hz, CH2), 3.50 (3H, s, OMeAr-2), 3.61 (3H, s, OMeAr-2′),
3.80 (3H, s, CO2Me), 3.84 (3H, s, OMeAr-4), 5.22 (1H, d large, J
= 7.0 Hz, CH(NHBoc)), 5.50 (1H, d large, J = 7.0 Hz, NH),
5.86 (1H, X d′ABX, JAX = 11.3 Hz, JBX = 2.3 Hz, CH(OAc)),
6.43 (1H, d, J = 2.2 Hz, HAr-3), 6.58 (1H, d, J = 8.2 Hz, HAr-3′),
6.59 (1H, d, J = 2.2 Hz, HAr-5), 7.00 (1H, s large, HAr-6′), 7.22
(4H, A2B2, JAB = 11.7 Hz, Δν = 27 Hz, HpTol ), 7.71 (1H, m,
HAr-4′).
(aS)-4 (major) : (aR)-4 (minor) = 90 : 10
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Methyl [aS,1R,7′R,(S)R]-tert-butoxycarbonylamino-
{2,4,2′-trimethoxy-6-[1-methoxy-2-(4-tolylsulfinyl)-ethyl]-
biphenyl-5′-yl}acetate (5)
15 min. The reaction mixture is heated to 85 °C for 30 min
(color changes from light yellow to dark green), quenched by the
addition of a saturated aqueous NH4Cl-solution (150 ml) and
extracted with ethyl acetate (4 × 200 ml). The crude product can
be purified either by column chromatography (cyclohexane–
EtOAc = 9 : 1–3 : 7) or by crystallization from cyclohexane.
Yield: 4.18 g (9.7 mmol, 69%) colorless solid. 1H-NMR
(CDCl3, 300 MHz): δ 1.35 (12H, s, CH3 pinacol), 1.43 (9H, s,
CH3 Boc), 3.71 (3H, s, OCH3), 3.82 (3H, s, CO2CH3), 5.23
(1H, bs, CH), 5.40 (1H, bs, NH), 6.82 (1H, d, J = 8.7 Hz,
HAr-5), 7.37 (1H, dd, J = 8.7, 2.3 Hz, HAr-6), 7.62 (1H, d, J = 2.3
Hz, HAr-2); 13C-NMR (CDCl3, 75 MHz): δ 24.8 (2 × CH3
pinacol), 28.3 (CH3 Boc), 52.5 (CO2CH3), 55.9 (OCH3), 57.1
(CH), 74.8 (C(CH3) Boc), 83.6 (C(CH3) pinacol), 110.8
(CHAr-5), 128.1 (CAr-1), 131.4 (CHAr-6), 135.4 (CHAr-2), 154.8
(CAr-4), 164.2 (CO2tBu), 171.9 (CO2Me); 11B-NMR (CDCl3,
128 MHz): δ 34,07; IR (neat): ν 3360 (NH), 2978, 1747 (CvO),
1713 (CvO), 1606, 1495, 1422, 1371, 1349, 1253, 1144, 1074,
1028, 966, 857; [α]D20 = −76.9 (c = 0.7, CHCl3); Anal. calcd for
C21H32BNO7: C, 59.87; H, 7.66. Found: C, 59.84; H, 7.65%.
A solution of iodide 8 (94.4 mg, 0.204 mmol) and the catalytic
system (Pd-catalyst and ligand, see Table 1) in dioxane (3.0 ml)
is stirred at 20 °C for 1 h. A second solution is prepared from
boronic ester 6 (172.5 mg, 0.409 mmol, 2 eq.) and CsF
(124.4 mg, 0.820 mmol, 4 eq.) in dioxane (3.0 ml) and stirred
for 30 min at 20 °C before the first solution is added via syringe.
The reaction mixture is heated to 70 °C for 2 h, quenched by the
addition of H2O and extracted with CH2Cl2. The solvent is evap-
orated and the crude product is purified by column chromato-
graphy (cyclohexane–EtOAc 4 : 1) to yield (aS)-5 and (aR)-5 as
colorless solids.
(aS)-5 (major) : (aR)-5 (minor) = 85 : 15
(aS)-5. M.p. 140–142 °C. 1H-NMR (CDCl3, 300 MHz): δ
1.43 (9H, s, tBu), 2.41 (3H, s, CH3pTol), 3.05 (3H, s, OMe), 3.30
(2H, AB, JAB = 12.6 Hz, JAX = 9.3 Hz, JBX = 4.5 Hz, Δν = 219
Hz, CH2), 3.51 (3H, s, OMe), 3.62 (3H, s, OMe), 3.70 (1H, X,
JAX = 9.3 Hz, JBX = 4.5 Hz, CH(OMe)), 3.76 (3H, s, OMe),
3.84 (3H, s, OMe), 5.26 (1H, d, J = 7.0 Hz, CH(NHBoc)), 6.22
(1H, d, J = 7.0 Hz, NH), 6.46 (1H, d, J = 2.5 Hz, HAr-3), 6.66
(1H, d, J = 8.5 Hz, HAr-3′), 6.68 (1H, d, J = 2.5 Hz, HAr-5), 7.01
(1H, d, J = 2.5 Hz, HAr-6′), 7.19 (4H, A2B2, JAB = 7.9 Hz, Δν =
26 Hz, HpTol), 7.33 (1H, dd, J = 8.5, 2.5 Hz, HAr-4′); 13C-NMR
(CDCl3, 75 MHz): δ 21.4 (CH3pTol ), 28.3 (C(CH3)3), 52.5
(OMe), 54.9 (OMe), 55.4 (OMe), 55.6 (OMe), 56.2 (OMe), 57.1
(CH(NHBoc)CO2Me), 64.0 (CH2), 75.5 (CH(OMe)), 79.8 (C
(CH3)3), 98.5 (CHAr), 100.9 (CHAr), 110.6 (CHAr), 118.6 (CAr),
124.1 (CAr), 124.2 (CHpTol ), 128.2 (CHAr), 128.5 (CAr), 129.7
(CHpTol ), 131.7 (CHAr), 139.4 (CAr), 140.2 (CAr), 141.1 (CAr),
155.2 (CAr), 155.8 (CAr), 156.0 (CAr), 160.8 (CvO), 172.0
(CvO); IR (neat): ν 3340 (NH), 2957, 1740 (CvO), 1706
(CvO), 1602, 1523, 1505, 1490, 1463, 1342, 1264, 1201, 1161,
1069, 1054, 1035, 983, 934, 809; [α]D20 = −76.4 (c = 1, CHCl3);
Anal. calcd for C33H41NO9S: C, 63.14; H, 6.58. Found: C,
63.16; H, 6.57%.
(+)-[1R,(S)R]-1-(2-Iodo-3,5-dimethoxyphenyl)-2-(4-tolylsulfinyl)-
ethyl acetate (7)
To a solution of β-hydroxy-sulfoxide 16 (2.11 g, 4.7 mmol) in
pyridine (20 ml) is added acetic anhydride (0.5 ml) and the
mixture is stirred for 2 h at ambient temperature. A saturated
aqueous solution of NH4Cl is added and the mixture is extracted
with ethyl acetate. The combined organic phases are dried over
MgSO4, filtered and evaporated. The crude product is purified
by column chromatography (Et2O–cyclohexane 4 : 1). Yield:
2.25 g (4.6 mmol, 98%) colorless solid. 1H-NMR (CDCl3,
300 MHz): δ 2.13 (3H, s, OAc), 2.42 (3H, s, CH3pTol ), 3.25 (2H,
AB, JAB = 13.6 Hz, JAX = 10 Hz, JBX = 3.0 Hz, Δν = 30 Hz,
CH2), 3.80 (3H, s, OMe), 3.82 (3H, s, OMe), 6.20 (1H, X, JAX
= 10 Hz, JBX = 3.0 Hz, CH), 6.35 (1H, d, J = 2.6 Hz, HAr), 6.59
(1H, d, J = 2.6 Hz, HAr), 7.49 (4H, A2B2, JAB = 8.1 Hz, Δν = 74
Hz, HpTol); 13C-NMR (CDCl3, 75 MHz): δ 20.9 (OAc), 21.5
(CH3pTol), 55.6 (OMe), 56.5 (OMe), 62.6 (CH2), 74.4 (CH),
77.8 (CAr-2), 98.4 (CHAr-4), 104.0 (CHAr-6), 124.6 (CHpTol ),
130.1 (CHpTol ), 140.4 (CpTol-1), 142.0 (CpTol-4), 142.8 (CAr-1),
158.9 (CAr-5), 161.6 (CAr-3), 169.3 (CO); IR (neat): ν 2938, 1743
(CvO), 1579, 1452, 1431, 1371, 1350, 1319, 1221, 1202, 1160,
1079, 1035, 1010, 984, 927, 836, 808; [α]D20 = +45.6 (c = 1.05,
CHCl3); Anal. calcd for C19H21IO5S: C, 46.73; H, 4.33. Found:
C, 46.74; H, 4.33%.
(aR)-5. 1H-NMR (CDCl3, 300 MHz): δ 1.44 (9H, s, tBu),
2.43 (3H, s, CH3pTol), 3.06 (3H, s, OMe), 3.43 (2H, AB, JAB
=
10.5 Hz, JAX = 3.2 Hz, JBX = 12.6 Hz, CH2), 3.49 (3H, s,
OMe), 3.63 (3H, s, OMe), 3.77 (1H, X, m, CH(OMe)), 3.82
(3H, s, OMe), 3.85 (3H, s, OMe), 5.34 (1H, d, J = 7.5 Hz, CH
(NHBoc)), 5.59 (1H, d, J = 7.5 Hz, NH), 6.45 (1H, d, J = 2.5
Hz, HAr-3), 6.63 (1H, d, J = 8.5 Hz, HAr-3′), 6.69 (1H, d, J = 2.5
Hz, HAr-5), 6.89 (1H, d, J = 2.5 Hz, HAr-6′), 7.20 (4H, A2B2, JAB
= 8.5 Hz, HpTol), 7.31 (1H, dd, J = 8.5, 2.5 Hz, HAr-4′); Anal.
calcd for C33H41NO9S: C, 63.14; H, 6.58. Found: C, 63.10; H,
6.52%.
(−)-[1R,(S)R]-2-Iodo-3,5-dimethoxy-1-[1-methoxy-2-
(4-tolylsulfinyl)-ethyl]benzene (8)
NaH (37.6 mg, 0.94 mmol, 60% in paraffin) is washed with
hexane, filtered and dried in vacuo before a solution of
β-hydroxy-sulfoxide 16 (350 mg, 0.78 mmol) in anhydrous
DMF (6.0 ml) is added at −20 °C. The reaction mixture is
stirred for 10 min before MeI (0.1 ml, 1.57 mmol) is added drop
wise via syringe. After 30 min at −20 °C saturated aqueous
NH4Cl-solution is added and the mixture is extracted with Et2O.
The combined organic phases are dried over MgSO4, filtered and
Methyl (−)-(2R)-tert-butoxycarbonylamino-[4-methoxy-3-
(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetate (6)
To a solution of iodide 12 (6.0 g, 14.2 mmol) and 2-(dicyclohex-
ylphosphino)-biphenyl (987 mg, 2.8 mmol) in dry 1,4-dioxane
(80 ml) are added Pd(OAc)2 (180 mg, 0.7 mmol) and NEt3
(7.9 ml, 56.8 mmol). The resulting solution is degassed and
pinacolborane (6.1 ml, 42.6 mmol) is added via syringe over
This journal is © The Royal Society of Chemistry 2012
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evaporated. The crude product is purified by column chromato-
is added, the mixture is acidified (pH ∼ 2) with 10% H2SO4 and
the phases are separated. The aqueous phase is extracted with
ethyl acetate (2 × 150 ml). The combined organic phases are
washed with brine (150 ml), dried over MgSO4, filtered and
evaporated. The crude product is purified by column chromato-
graphy (cyclohexane–EtOAc 2 : 3). Yield: 2.38 g (5.4 mmol,
graphy (Et2O). Yield: 329.0 mg (0.72 mmol, 91%) colorless
1
solid. M.p. 110–112 °C. H-NMR (CDCl3, 300 MHz): δ 2.44
(3H, s, CH3pTol ), 3.14 (2H, AB, JAB = 13.0 Hz, JAX = 3.0 Hz,
J
BX = 10.4 Hz, Δν = 68 Hz, CH2), 3.17 (3H, s, OMe), 3.81 (3H,
s, OMeAr-5), 3.83 (3H, s, OMeAr-3), 4.49 (1H, X, JAX = 3.0 Hz,
BX = 10.4 Hz, CH(OMe)), 6.37 (1H, d, J = 2.7 Hz, HAr-6), 6.69
1
J
80%) light yellow solid. H-NMR (CDCl3, 300 MHz): δ 2.40
(1H, d, J = 2.7 Hz, HAr-4), 7.42 (4H, A2B2, JAB = 7.9 Hz, Δν =
91 Hz, HpTol); 13C-NMR (CDCl3, 75 MHz): δ 21.5 (CH3pTol ),
55.6 (OMeAr-5), 56.4 (OMeAr-3), 57.0 (OMe), 63.5 (CH2), 79.0
(CAr-2), 82.5 (CH(OMe)), 99.0 (CHAr), 103.4 (CHAr), 125.0
(CHpTol ), 130.0 (CHpTol), 142.0 (CpTol-1), 143.2 (CpTol-4), 152.9
(CAr-1), 158.7 (CAr-3), 161.9 (CAr-5); IR (neat): ν 2940, 1591,
1573, 1456, 1429, 1317, 1218, 1152, 1109, 1069, 1035, 1026,
1010, 979, 930, 859, 807, 765; [α]D20 = −14.5 (c = 1.0, CHCl3);
Anal. calcd for C18H21IO4S: C, 46.97; H, 4.60. Found: C, 46.94;
H, 4.62%.
(3H, s, CH3pTol ), 3.77 (3H, s, OMeAr-5), 3.85 (3H, s, OMeAr-3),
4.43 (2H, AB, J = 14.1 Hz, Δν = 43 Hz, CH2), 6.35 (1H, d, J =
2.6 Hz, HAr-6), 6.46 (1H, d, J = 2.6 Hz, HAr-4), 7.45 (4H, A2B2,
J
AB = 8.0 Hz, Δν = 83 Hz, HpTol ); 13C-NMR (CDCl3, 75 MHz):
δ 21.4 (CH3pTol ), 55.7 (OMeAr-5), 56.6 (OMeAr-3), 68.7 (CH2),
72.3 (CAr-2), 101.1 (CHAr), 104.9 (CHAr), 124.5 (CHpTol ), 130.1
(CHpTol ), 142.2 (CAr-3), 142.2 (CpTol-1), 142.2 (CpTol-4), 158.9
(CAr-3), 161.4 (CAr-5), 196.3 (CO); IR (neat): ν 2948, 1692
(CvO), 1585, 1447, 1411, 1334, 1290, 1205, 1171, 1150, 1076,
1029, 1007, 937, 850, 806, 815, 774; [α]D20 = +122.0 (c = 1.0,
CHCl3); Anal. calcd for C17H17IO4S: C, 45.96; H, 3.86. Found:
C, 45.91; H, 3.79%.
Methyl 2-iodo-3,5-dimethoxybenzoate (14)
A solution of iodine (5.18 g, 20.4 mmol) in chloroform (200 ml)
is added drop wise to a stirred solution of methyl 3,5-dimethoxy-
benzoate 13 (4.0 g, 20.4 mmol) in chloroform (50 ml) contain-
ing suspended silver trifluoroacetate (4.51 g, 20.4 mmol). After
the addition the precipitated silver iodide is collected by filtration
and washed with dichloromethane. The combined filtrates are
washed with water (100 ml), saturated aqueous Na2S2O3 (2 ×
100 ml) and brine (100 ml). The organic layer is dried over
Na2SO4, filtered and the solvent is evaporated. The crude
product is purified by column chromatography (cyclohexane–
EtOAc 5 : 1). Yield: 4.3 g (13.3 mmol, 65%, 89% based on
recovered starting material) colorless solid. M.p. 68–72 °C.
1H-NMR (CDCl3, 300 MHz): δ 3.82 (3H, d, J = 1.1 Hz, OMe),
3.87 (3H, d, J = 1.1 Hz, OMe), 3.93 (3H, d, J = 1.1 Hz,
CO2Me), 6.52 (1H, dd, J = 2.6, 1.1 Hz, HAr), 6.80 (1H, dd, J =
2.6, 1.1 Hz, HAr); 13C-NMR (CDCl3, 75 MHz): δ 52.6 (OCH3),
55.7 (OCH3), 56.6 (CO2CH3), 75.7 (CAr-2), 101.3 (CHAr), 138.9
(CAr-1), 159.4 (CAr-OMe), 160.9 (CAr-OMe), 168.0 (CO2CH3);
IR (neat): ν 2952, 1719 (CvO), 1576, 1453, 1442, 1428, 1330,
1240, 1211, 1150, 1070, 1051, 1012, 881, 848, 816, 781, 754;
Anal. calcd for C10H11IO4: C, 37.29; H, 3.44. Found: C, 37.35;
H, 3.49%.
(−)-[1R,(S)R]-1-(2-Iodo-3,5-dimethoxyphenyl)-2-(4-tolylsulfinyl)-
ethanol (16)
To flame dried ZnBr2 (3.6 g, 15.6 mmol) is added a solution of
β-ketosulfoxide 15 (2.32 g, 5.2 mmol) in dry THF (100 ml) at
0 °C. The reaction mixture is stirred at 0 °C for 15 min before it
is cooled to −78 °C. Then a solution of DIBAL (10.4 ml,
10.4 mmol, 1 M in toluene) is added at −78 °C and the mixture
is stirred for 5 h. A saturated aqueous solution of disodium tar-
trate is added, the phases are separated and the aqueous phase is
extracted with ethyl acetate. The combined organic phases are
dried over MgSO4, filtered and evaporated. The crude product is
purified by column chromatography (EtOAc–CH2Cl2 1 : 4).
Yield: 2.11 g (4.7 mmol, 90%) colorless solid. M.p. 58–62 °C.
1H-NMR (CDCl3, 300 MHz): δ 2.41 (3H, s, CH3pTol ), 3.01 (2H,
AB, JAB = 13.2 Hz, JAX = 10.0 Hz, JBX = 1.5 Hz, Δν = 89 Hz,
CH2), 3.81 (3H, s, OMeAr-5), 3.84 (3H, s, OMeAr-3), 5.69 (1H,
X, JAX = 10.0 Hz, JBX = 1.5 Hz, CH(OH)), 6.37 (1H, d, J = 2.8
Hz, HAr-6), 6.90 (1H, d, J = 2.8 Hz, HAr-4), 7.45 (4H, A2B2, JAB
= 8.3 Hz, Δν = 73 Hz, HpTol ); 13C-NMR (CDCl3, 75 MHz): δ
21.4 (CH3pTol), 55.6 (OMeAr-5), 56.5 (OMeAr-3), 62.3 (CH2),
75.2 (CH(OH)), 77.6 (CAr-2-I), 98.9 (CHAr), 103.8 (CHAr),
123.9 (CHpTol ), 130.2 (CHpTol), 140.4 (CpTol-1), 142.2 (CpTol-4),
145.8 (CAr-1), 158.5 (CAr-3), 161.6 (CAr-5); IR (neat): ν 3270
(OH), 2937, 1578, 1450, 1427, 1413, 1316, 1214, 1197, 1156,
1066, 1008, 989, 807; [α]D20 = −52.8 (c = 1.0, CHCl3); Anal.
calcd for C17H19IO4S: C, 45.75; H, 4.29. Found: C, 46.04; H,
4.35%.
(+)-[(S)R]-1-(2-Iodo-3,5-dimethoxyphenyl)-2-(4-tolylsulfinyl)-
ethanone (15)
To a solution of diisopropylamine (1.9 ml, 13.6 mmol) in anhy-
drous THF (60 ml) is added a solution of n-BuLi (9.0 ml,
13.6 mmol, 1.6 M in hexane) at −15 °C. After completion of the
addition the reaction mixture is kept at −15 °C for a further
30 min before it is warmed to 0 °C. A solution of (+)-(R)-methyl
p-tolylsulfoxide (2.1 g, 13.6 mmol) in dry THF (60 ml) is
slowly added using a cannula and the mixture is stirred for an
additional 30 min. Then the prepared mixture is slowly trans-
ferred via cannula to a solution of ester 14 (2.2 g, 6.8 mmol) in
THF (60 ml) at 0 °C. After completion of the addition the reac-
tion mixture is allowed to warm to ambient temperature and
stirred for 12 h. A saturated aqueous solution of NH4Cl (150 ml)
N-(tert-Butyloxycarbonyl)-D-(4-hydroxyphenyl)-glycine (10)
To a solution of NaOH (0.72 g, 18.0 mmol) in H2O–dioxane
2 : 1 (54.0 ml) are added D-(4-hydroxyphenyl)-glycine 9 (3.0 g,
18.0 mmol) and a solution of Boc2O (4.29 g, 19.7 mmol) in
dioxane (18.0 ml) and the reaction mixture is stirred for 4 h at
ambient temperature. The dioxane is evaporated and the remain-
ing aqueous phase is washed with a small amount of Et2O. Then
the aqueous phase is acidified with KHSO4 (pH ∼ 2–3) and
4100 | Org. Biomol. Chem., 2012, 10, 4095–4102
This journal is © The Royal Society of Chemistry 2012

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extracted with ethyl acetate. The combined organic phases are
dried over MgSO4, filtered and evaporated. The resulting residue
is taken up in CHCl3 and the solvent is evaporated to give a
white powder, which can be used for the next reaction step
without any further purification. Yield: 4.8 g (17.95 mmol, 99%)
colorless powder. M.p. 205 °C decomp. (Lit. 199 °C).5f
1H-NMR (CDCl3, 300 MHz): δ 1.37 (9H, s, tBu), 6.94 (1H, d,
J = 7.5 Hz, CH(CO2H)NHBoc), 6.93 (4H, A2B2, JAB = 8.5 Hz,
Δν = 140 Hz, HAr), 7.37 (1H, d, J = 7.5 Hz, NHBoc), 9.42 (1H,
bs, OH), 12.58 (1H, bs, CO2H); 13C-NMR (CDCl3, 75 MHz):
δ 28.1 (CO2C(CH3)3), 57.0 (CH(CO2H)NHBoc), 79.1 (CO2C
(CH3)3), 115.0 (CHAr), 127.4 (CAr-1), 128.8 (CHAr), 155.0
2979, 1741 (CvO), 1697(CvO), 1511, 1341, 1250, 1214,
1157, 1052, 1028, 980, 894, 832; [α]D20 = −80.5 (c = 1.6,
CHCl3); Anal. calcd for C15H20INO5: C, 42.77; H, 4.79. Found:
C, 42.62; H, 4.71%.
Acknowledgements
We thank sincerely the CNRS and the “Ministère de l’Education
Nationale et de la Recherche”, France for funding. T.L. is much
grateful to the French Embassy in Germany for a postdoctoral
grant.
(CAr-4-OH), 156.9 (CO2H), 172.6 (CO2C(CH3)3); [α]D20
−130.9 (c = 1.24, EtOH), Lit.5f [α]2D0 = 130.0 (c = 1.08, EtOH).
=
Notes and references
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N-(tert-Butyloxycarbonyl)-D-(4-methoxyphenyl)-glycine methyl
ester (11)
To a solution of 10 (8.0 g, 29.9 mmol) in acetone (150 ml) are
added K2CO3 (16.55 g, 119.7 mmol) and MeI (5.59 ml,
89.8 mmol) and the mixture is heated to reflux for 16 h. After
cooling to ambient temperature the reaction mixture is filtered
over a pad of celite, which is afterwards washed with Et2O. The
organic phase is washed with brine, dried over MgSO4, filtered
and evaporated. The crude product is purified by column chrom-
atography (Et2O–cyclohexane 2 : 1). Yield: 8.8 g (29.8 mmol,
99%) colorless solid. M.p. 70–75 °C. 1H-NMR (CDCl3,
300 MHz): δ 1.34 (9H, s, tBu), 3.63 (3H, s, OMe), 3.71 (3H, s,
OMe), 5.17 (1H, bd, J = 7.1 Hz, CH), 5.40 (1H, bd, J = 7.1 Hz,
NH), 6.99 (4H, A2B2, JAB = 8.7 Hz, Δν = 121 Hz, HAr);
13C-NMR (CDCl3, 75 MHz): δ 28.3 (tBu), 52.6 (OMe), 55.3
(CO2CH3), 57.0 (CH), 80.1 (C(CH3)3), 114.3 (CHAr), 128.4
(CHAr), 129.0(CAr), 154.8 (CAr), 159.6 (CO2Me), 171.9
(CO2tBu); IR (neat): ν 3369 (NH), 2979, 1741 (CvO), 1697
(CvO), 1511, 1341, 1250, 1214, 1157, 1052, 1028, 980, 894,
832; [α]D20 = −106.3 (c = 1.1, CHCl3); Anal. calcd for
C15H21NO5: C, 61.00; H, 7.17. Found: C, 60.86; H, 6.99%.
3 D. H. Williams, Nat. Prod. Rep., 1996, 13, 469.
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S. Natarajan, R. Hughes, M. E. Solomon, H. Lui, J. M. Ramanjulu,
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M. Ramanjulu, T.-Y. Yue, S. Natarajan, X.-J. Chu, S. Bräse and
F. Rübsam, Chem.–Eur. J., 1999, 5, 2584; (e) K. C. Nicolaou,
C. N. C. Boddy, H. Li, A. E. Koumbis, R. Hughes, S. Natarajan, N.
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A. Evans, C. J. Dinsmore, A. M. Ratz, D. A. Evrard and J. C. Barrow, J.
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3251; (g) D. A. Evans, J. C. Barrow, P. S. Watson, A. M. Ratz, C.
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N-(tert-Butyloxycarbonyl)-D-(3-iodo-4-methoxyphenyl)-glycine
methyl ester (12)
To a solution of 11 (1.0 g, 3.39 mmol) in CHCl3 (7.0 ml) is
added silver trifluoroacetate (1.65 g, 7.45 mmol) followed by
iodine (1.03 g, 4.06 mmol) and the reaction mixture is stirred for
15 h at ambient temperature. The mixture is diluted with Et2O
and filtered over a pad of celite, which is washed afterwards with
Et2O. The organic phase is washed with a saturated aqueous sol-
ution of Na2S2O3, dried over MgSO4, filtered and evaporated.
The crude product is purified by column chromatography
(CH2Cl2). Yield: 1.3 g (3.09 mmol, 91%) colorless solid. M.
1
p. 91–93 °C. H-NMR (CDCl3, 300 MHz): δ 1.42 (9H, s, tBu),
3.72 (3H, s, OMe), 3.86 (3H, s, OMe), 5.20 (1H, bd, J = 7.2 Hz,
CH), 5.54 (1H, bd, J = 7.2 Hz, NH), 6.77 (1H, d, J = 8.5 Hz,
HAr-5), 7.31 (1H, dd, J = 8.5, 2.2 Hz, HAr-6), 7.74 (1H, d, J = 2.2
Hz, HAr-2); 13C-NMR (CDCl3, 75 MHz): δ 28.2 (tBu), 52.8
(OMe), 56.3 (CH), 56.4 (CO2CH3), 80.3 (C(CH3)3), 86.3 (CAr),
110.9 (CHAr), 128.5 (CHAr), 131.1 (CAr), 137.9 (CHAr), 154.7
(CAr), 158.2 (CO2Me), 171.4 (CO2tBu); IR (neat): ν 3369 (NH),
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