Synthesis of protected α-alkyl lanthionine derivatives

Article abstract of DOI:10.1016/j.tet.2014.05.004

Protected α-alkyl lanthionine derivatives were synthesized in five steps starting from a known phenyloxazoline precursor. This approach involved the synthesis of a family of substituted cyclic sulfamidates and their regioselective opening by nucleophilic attack with a protected cysteine. This efficient multistep strategy affords various α-alkylated lanthionine derivatives in high yields.

Full text of DOI:10.1016/j.tet.2014.05.004

Tetrahedron xxx (2014) 1e8
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Synthesis of protected
a-alkyl lanthionine derivatives
*
€
ꢀ
Thibaut Denoel, Astrid Zervosen , Christian Lemaire, Alain Plenevaux, Andre Luxen
ꢁ
ꢁ
Cyclotron Research Center, University of Liege, B30 Sart-Tilman, 4000 Liege, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Protected a-alkyl lanthionine derivatives were synthesized in five steps starting from a known phenyl-
Received 11 March 2014
Received in revised form 30 April 2014
Accepted 2 May 2014
oxazoline precursor. This approach involved the synthesis of a family of substituted cyclic sulfamidates
and their regioselective opening by nucleophilic attack with a protected cysteine. This efficient multistep
strategy affords various
a
-alkylated lanthionine derivatives in high yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Available online xxx
Keywords:
Lanthionine
Sulfamidate
a
-Alkyl amino acid
Peptidoglycan
Protected amino acid
1. Introduction
carbon16 have also been described. In contrast to the natural
methyl lanthionine, the -methyl lanthionine has been much less
covered in the literature.16 A synthetic study aiming to produce
b-
a
Lanthionine is a non-proteinogenic diamino diacid, the mono-
sulfur analogue of diaminopimelic acid (Fig. 1). Since its discovery
by Horn1 and synthesis by Du Vigneaud,2 it has been found to play
the role of crosslinker in the peptidoglycan of several Fusobacterium
species.3 It has also become an important fragment in a family of
polypeptidic antibiotics known as lantibiotics.4
labionin, an a-alkyl lanthionine, was described but did not include
the crucial thioether functionalization step.19 Nevertheless, these
interesting molecules have been used in several fields of research,
such as lantibiotic chemistry4,20 and lanthionine enkephalin16,21
analogue synthesis.
2. Results and discussion
2.1. Retrosynthetic analysis
Fig. 1. meso-Lanthionine and meso-diaminopimelic acid.
Retrosynthesis hinted that a lanthionine could result from the
SN2 opening of a suitable cyclic sulfamidate precursor with a pro-
tected cysteine.7,22 The sterically crowded sulfamidate can be derived
The aim of this work was to synthesize protected lanthionines
11aed (Scheme 3) bearing an a-alkyl group useful for the prepa-
ration of peptidoglycan building block analogues. Although several
methods are known to produce protected lanthionines,4e8 most are
plagued with various side reactions or defects. In particular, race-
from an a
-alkylated serine.7 This can be obtained from a 4-alkylated
oxazoline23 by reductive24 opening of the ring (Scheme 1).
mization due to
b
-elimination9 and subsequent Michael
2.2. Preparation of precursor
addition,10e12 or regioisomerization through formation of an azir-
idine intermediate13,14 have been reported. Other competing side
reactions are thioester formation through O-acyl fission,15,16 or
homocoupling after disulfide exchange.17,18 In addition, sluggish
An alternative route to the known23 4-unsubstituted phenyl-
oxazoline precursor 5 was devised. This compound was obtained in
a multigram quantity as follows: first, serine methyl ester hydro-
chloride25 was reacted with ethyl benzimidate 1 (Scheme 2). The
previously published procedure26 used CH2Cl2 and NEt3, which
gave rise to undesired diketopiperazine by-product. In order to
circumvent this problem the reaction was conducted with benzi-
midate freebase in MeOH. The benzimidate 1 has previously been
reaction14 or lack of reactivity due to a sterically hindered
a-
* Corresponding author. Tel.: þ32 4 366 3383; fax: þ32 4 366 2946; e-mail ad-
dress: azervosen@ulg.ac.be (A. Zervosen).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.004
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2
Scheme 1. Retrosynthetic approach to producing
P1¼Me, P2¼Boc, P3¼Bn, P4¼tBu.
a-alkylated lanthionine derivatives.
Scheme 2. Synthesis of the oxazoline precursor. Reagents and conditions: (i) (1)
Na2CO3, CH2Cl2, (2) Ser Me ester*HCl, MeOH, reflux, 2 h, 84%; (ii) aq NaOH, MeOH,
acetone, rt, 1 h, 92%; (iii) aq HCl, 0 ꢀC, 1 h, 87%; (iv) Boc2O (2 equiv), DMAP (10 mol %),
1:1 CH2Cl2/tert-BuOH, reflux, 1 h, 75%.
Scheme 3. Synthesis of a-alkylated lanthionines. Reagents and conditions: (i) RX, KOH
(5 equiv), TBAB (10 mol %), 1:1 toluene/CH2Cl2; (ii) NaBH3CN (6 equiv), AcOH, rt, 16 h;
(iii) SOCl2, imidazole, NEt3, ꢁ10 ꢀC/rt, 2 h; (iv) NaIO4 (1.2 equiv), RuCl3 (1 mol %),
aq CH3CN, rt, 4 h; (v) Boc L-cysteine Me ester (1.1 equiv), DBU (1.1 equiv), CH3CN, rt, 1 h;
(vi) 10% aq NaH2PO4, EtOAc, 50 ꢀC, 2 h.
prepared using the Pinner reaction of EtOH with benzonitrile.27 In
place of gassing the reaction mixture with HCl (g) we chose a more
practical approach, involving the use of AcCl and EtOH to generate
anhydrous HCl in situ. The methyl ester of oxazoline 2 was then
hydrolyzed following the literature method.28 The sodium salt 3
was converted to oxazolinic acid 4 by using HCl at 0 ꢀC according to
Fry’s procedure.28 The crude acid was dried and reacted with Boc2O
and DMAP by applying the protocol reported by Takeda.29 The poor
solubility of the acid 4 was increased in a tert-BuOH/CH2Cl2 solvent
mixture. Other methods, such as DCC/tert-BuOH or tert-butyl tri-
chloroacetimidate led to extensive side reactions and produced 5 in
very low yields. Finally, after five steps from serine and a re-
crystallization in hexanes 5 was obtained on a multigram scale with
a global yield of 50% (Scheme 2).
with thionyl chloride and imidazole31 to create the cyclic sulfami-
dites 8aed. These were isolated as a mixture of diastereomers in
92e99% yield (step iii). The crude products were then oxidized22 by
catalytic RuCl3$xH2O and NaIO4 to give the corresponding sulfa-
midates 9aed with good to excellent yields (77e99%, step iv).
Subsequently, the sulfamidates 9aed were used in a coupling
reaction22 with the methyl ester of Boc-
L-cysteine in CH3CN and
DBU as a base (Scheme 3: steps v). The N-sulfamate intermediates
10aed were subsequently hydrolyzed32 at 50 ꢀC for 2 h in aqueous
10% NaH2PO4 (Scheme 3: steps vi). Interestingly, the cleavage of the
sulfamate group failed when the hydrolysis was carried out at rt.32
It is noteworthy that despite16 the presence of a sterically hindered
a-carbon in compounds 9aed, the SN2 reaction at Cb occurred re-
markably well, providing protected lanthionines 11aed in excellent
yields (90e99%). The outstanding reactivity22,33 of cyclic sulfami-
dates with thiolate nucleophiles in basic conditions is hereby
confirmed. It should be noted that an alternative mechanism based
on SO2 extrusion followed by aziridine formation was observed
under neutral conditions for isomeric sulfamidates.34 However,
under our basic conditions, the formation of N-sulfamate products
10aed suggests the probable mechanism to be SN2.
2.3. N-Benzyl lanthionines synthesis from 5
Using the oxazoline precursor 5 various racemic 4-alkylated
oxazolines 6aed were synthesized23,30 (Scheme 3). In our first
approach, tetrabutylammonium bromide (TBAB) was employed as
an achiral phase transfer catalyst (PTC) along with solid KOH as
a base.30 Four electrophiles were used: two alkyl bromides (EtBr, n-
PrBr) and two benzyl bromides (BnBr, 4-FeBnBr). Good yields
(79e90%) of the racemic alkylated oxazolines 6aed (Scheme 3: step
i) were obtained.
2.4. Debenzylation of 11c
Next, the reductive24 opening of the racemic oxazolines was
performed. Compounds 6aed were protonated in acetic acid and
reduced at rt with NaBH3CN. Under these mild reaction conditions
the cleavage of both the tert-butyl ester and the N-benzyl groups
could be avoided, which is a significant advantage over the harsh
hydrolysis conditions (6 N HCl) reported in the literature.23 Using
this method four suitably protected racemic alkylated serines 7aed
were obtained in near quantitative yields (94e98%, Scheme 3: step
ii). Transformation of the N-benzyl protected serines 7aed into
their respective cyclic sulfamidates22 was then performed in two
steps (Scheme 3: steps iiieiv). Amino alcohols 7aed were reacted
It is known that the deprotection of an N-benzyl can be chal-
lenging in the presence of a sulfide group.35 As an example, the
debenzylation of the nitrogen atom of lanthionine 11c (Scheme 4)
was explored. Indeed, our initial attempts to deprotect the N-ben-
zyl group of the chromatographically purified a-benzyl lanthionine
11c by hydrogenation with Pd/C as a catalyst were unsuccessful,
despite testing several reaction conditions. Furthermore, partially
irreproducible N-debenzylation was observed when Pd(OH)2/C
(Pearlman’s catalyst) was substituted for Pd/C.35 Fortunately, the
use of the more active Pd black in acidic aqueous MeOH at 70 ꢀC36
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T. Denoel et al. / Tetrahedron xxx (2014) 1e8
3
(9/1/0.3: MeOH/H2O/AcOH) gave the N-debenzylated protected
a
-
gave sulfamidates 9aed in 75e92% yields in two steps. An efficient
benzyl lanthionine 12 in a good and reproducible yield (Scheme 4).
SN2 reaction on the cyclic sulfamidates was highly successful, de-
spite the sterically crowded a-carbon, in producing protected lan-
thionines 11aed in excellent yields (90e99%). The challenging
debenzylation of 11c was overcome by means of Pd black in warm
acidic aqueous MeOH. Finally, for the enantioselective alkylation of
5, an enantiomeric excess of 97% was obtained with fewer equiv-
alents (1.5 vs 5) of the electrophilic agent. These debenzylated
products are excellent starting blocks for peptide synthesis.
4. Experimental section
Scheme 4. Hydrogenation of the N-benzyl group of 11c. Reagents and conditions: (i)
H2 (7 bars), Pd black (25% w/w), 9/1/0.3: MeOH/H2O/AcOH, 70 ꢀC, 16 h.
4.1. Reagents
All solvents and chemicals were of analytical grade and used
without further purification. CH3CN was dried on 3 A molecular
2.5. Enantioselective alkylation of 5
ꢂ
sieves. TLC: Macherey-Nagel Polygram SIL G/UV254 using UV light
or a stain anisaldehyde/sulfuric acid/AcOH/EtOH: 1/1/0.04/18:v/v/
v/v. CC: silica gel Acros, 0.060e0.200 mm, 60 A. HPLC: Waters
By using an optically pure PTC developed by the Maruoka’s
group (Fig. 2) compounds 6aed were obtained enantioselectively
by Jew.23 This approach was also used for the synthesis of the (R)-4-
Bn analogue 6c (entry 1, Table 1). In order to reduce the amount of
the electrophilic agent required, the synthesis of which can be
difficult, various reaction conditions were investigated. It was
found that enantiomeric purity decreased with a smaller excess of
electrophile (entries 1 and 2, Table 1). In contrast, higher catalyst
loading (entries 2e4), or a decrease in temperature (entries 4e7),
increased the enantiomeric excess (ee). At a lower temperature
(ꢁ10 ꢀC) and at a high catalyst loading (10 mol %) we obtained an
excellent ee (97%) by using only 1.5 molar equivalent of the elec-
trophile (entry 7). The high price of the catalyst and high loading
was a drawback of this alkylation approach.
ꢂ
system (600 pump, 717 autosampler, 996 PDA detector) with
a column XTerra RP18 (4.6ꢂ150 mm; 3.5
m
m). Chiral HPLC: Chiracel
OD-H column (Daicel,150 mmꢂ4 mm, 5
mm); mobile phase: n-Hex/
€
ꢀ
i-PrOH:98/2; 0.8 mL/min; 37 C. Mp: Buchi Melting Point B-545
calibrated on three points (83, 136 and 237 ꢀC). 1H and 13C NMR:
Bruker Avance DRX 400 (1H at 400 MHz and 13C at 101 MHz) and
Bruker AM 250 (1H at 250 MHz and 13C at 63 MHz)
d in parts per
million relative to 13C or the residual proton signal of deuterated
solvent, T¼298 K. MS: Thermoquest Finnigan TSQ 7000 mass
spectrometer operating in full scan MS mode with an ESI source.
HRMS: ESI-FT-ICR mass spectrometer (SolariX, Bruker) in positive
ion mode. For some samples 1 mM LiI was used for adducts. Ex-
ternal calibration was done over the range of m/z 150 to 700 and
mean residual error obtained was <1 ppm. Elemental analysis:
Flash EA 1112 Series (Thermo Electron Corporation).
4.2. Ethyl benzimidate 1
AcCl (75 mL, 1.05 mol) was added dropwise over 30 min at 0 ꢀC
to a solution of dry EtOH (124 mL, 2.1 mol) in dry Et2O (200 mL)
under nitrogen and protected from moisture. The mixture was left
to stir for 15 min and benzonitrile (103 g, 1 mol) was added. The
solution was poured into a brown glass reagent bottle, which was
closed and left at 2 ꢀC for one month. The bottle was shattered and
the crystals were suspended in Et2O and decanted from glass
fragments. The product was filtered and dried in vacuo to constant
weight to give the title compound (101 g, 54%) as colourless crystals.
Mp 123e124 ꢀC (lit.37 122e123 ꢀC); 1H NMR (250 MHz, MeOD) dH
8.13e8.03 (m, 2H, AreH), 7.84e7.76 (m, 1H, AreH), 7.71e7.58 (m,
2H, AreH), 4.69 (q, J¼7.0 Hz, 2H, OCH2), 1.62 (t, J¼7.0 Hz, 3H, CH3);
13C NMR (63 MHz, MeOD) dC 174.24 (CN), 136.82 (AreC), 130.50
(AreC), 130.07 (AreC), 127.13 (AreC), 71.40 (CH2), 13.91 (CH3); m/z
(ESI) 150 [MH]þ.
Fig. 2. Maruoka’s chiral PTC (R,R)-3,4,5-trifluorophenyleNAS bromide used for the
alkylation of 5 in Jew’s paper23 and in Table 1 of this work.
Table 1
Enantioselective alkylation of 5 with BnBr to (R)-6ca
Entry
BnBr (equiv)
PTC (mol %)
T (ꢀC)
ee (%)
Yield (%)
1
2
3
4
5
6
7
5
3
3
1.5
1.5
1.5
1.5
2.5
2.5
5
10
10
10
10
ꢁ5
ꢁ5
ꢁ5
5
97
77
85
90
92
94
97
85
75
77
82
81
80
84
0
ꢁ5
ꢁ10
a
4.3. Methyl 2-phenyloxazoline-4-carboxylate 2
Reaction conditions: 5, toluene, BnBr, Maruoka’s chiral PTC, KOH (5 equiv),
1200 rpm stir under N2 at the chosen temperature until completion (HPLC).
The protocol of Huang26 was modified as follows: The freebase
of ethyl benzimidate 1 (37.25 g, 250 mmol), generated from the salt
by basification with saturated aqueous Na2CO3 and extraction in
CH2Cl2, was dissolved in 250 mL of MeOH. To this solution serine
methyl ester hydrochloride (39 g, 250 mmol) was added and this
was heated under reflux for 2 h. The mixture was cooled and di-
luted with acetone (250 mL). NH4Cl was filtered and washed with
acetone. The solvents were evaporated, the residue was dissolved
in CH2Cl2 (50 mL) and Et2O (200 mL) and filtered again. The organic
layer was washed twice with water, with brine and dried on MgSO4.
After filtration and removal of the solvents in vacuo, the title
3. Conclusion
In this paper, a straightforward synthesis of various protected a-
alkyl lanthionines 11aed was developed. This synthetic scheme
started with the disclosure of a multigram preparation of the
known oxazoline precursor 5. Alkylation of 5 gave the compounds
6aed in good yields (79e90%) by using TBAB as an achiral PTC. A
smooth reductive cleavage provided protected serines 7aed in
excellent yields (94e98%). Cyclization with SOCl2 and oxidation
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4
compound (43 g, 84%) was obtained as a pale pink oil. NMR data
were in agreement with the literature;38 m/z (ESI) 206 [MH]þ.
at rt until the end of the reaction, which was monitored by TLC (1:4
EtOAc/hexanes, anisaldehyde stain). The suspension was diluted
with CH2Cl2 (50 mL) and then filtered. The organic layer was
washed with water and the solvent was evaporated. The residue
was flash chromatographed on 40 g of silica first with hexanes to
remove excess electrophile then with 1:4 (EtOAc/hexanes) and the
solvent was removed in vacuo to give the product.
4.4. Sodium 2-phenyloxazoline-4-carboxylate 3
The synthesis was done by following the protocol described by
Fry.28 A cold solution of NaOH (32 g, 800 mmol) in water (200 mL)
was added to the methyl ester 2 (152 g, 741 mmol). The mixture
was stirred vigorously with intermittent cooling in an ice bath for
20 min. The suspension was diluted with MeOH (200 mL) and left
to stir for 1 h. The suspension was diluted with acetone (2 L) and
4.8. tert-Butyl 4-ethyl-2-phenyloxazoline-4-carboxylate 6a
(rac)
ꢀ
€
left at 2 C for 2 h. The product was filtered on Buchner and washed
with acetone (1 L) then dried in vacuo to constant weight. The title
compound (169 g, 92%) was obtained as pink crystals. 1H NMR
(250 MHz, MeOD) dH 8.04e7.90 (m, 2H, AreH), 7.58e7.36 (m, 3H,
Following the general method for the preparation of 4-alkyl
oxazolines and using EtBr (15 mL, 200 mmol) as an electrophile,
the title compound was obtained as a pale yellow oil (4.7 g, 85%).
NMR data were in agreement with the literature;30 m/z (ESI) 276
[MH]þ.
AreH), 4.76 (dd, J¼10.4, 8.6 Hz, 1H, H- ), 4.65 (dd, J¼10.4, 7.9 Hz,
a
1H, CH2), 4.53 (dd, J¼8.6, 7.9 Hz, 1H, CH2); 13C NMR (63 MHz,
MeOD) dC 178.83 (CO), 166.68 (CN), 132.73 (AreC), 129.43 (AreC),
4.9. tert-Butyl 2-phenyl-4-propyloxazoline-4-carboxylate 6b
129.41 (AreC), 128.71 (AreC), 72.54 (C-
b
), 71.94 (C-
a
); m/z (ESI) 190
(rac)
[M]ꢁ.
Following the general method for the preparation of 4-alkyl
oxazolines and using n-PrBr (18 mL, 200 mmol) as an electro-
phile, the title compound was obtained as a pale yellow oil (4.7 g,
81%). 1H NMR (400 MHz, CDCl3) dH 8.20e7.75 (m, 2H, AreH),
7.64e7.28 (m, 3H, AreH), 4.70 (d, J¼8.8 Hz, 1H, CH2O), 4.21 (d,
J¼8.8 Hz, 1H, CH2O), 2.03e1.77 (m, 2H, CH2), 1.49 (s, 9H, C(CH3)3),
1.42e1.22 (m, 2H, CH2CH3), 0.95 (t, J¼7.3 Hz, 3H, CH3); 13C NMR
(101 MHz, CDCl3) dC 172.17 (CO), 164.12 (CN), 131.59 (AreC), 128.66
4.5. 2-Phenyloxazoline-4-carboxylic acid 4
The synthesis was done by following the protocol described by
Fry.28 The sodium salt 3 (169 g, 679 mmol) was suspended in water
(1.2 L) and cooled to 0 ꢀC. After cooling to 0 ꢀC, 3 N aqueous HCl
solution (220 mL), was added dropwise until pH<3 to precipitate
€
the acid. The product was filtered on Buchner and washed with cold
water (500 mL) then dried by repeated suspension in CH3CN and
evaporation in vacuo to constant weight. The title compound
(112.8 g, 87%) was obtained as pink crystals that were pure enough
for the next step. Mp 156e157 ꢀC; 1H NMR (250 MHz, DMSO) dH
7.95e7.82 (m, 2H, AreH), 7.58e7.42 (m, 3H, AreH), 4.88 (t, J¼9.1 Hz,
(AreC), 128.32 (AreC), 127.61 (AreC), 81.84 (C(CH3)3), 78.64 (C-a),
73.89 (CH2O), 40.45 (CH2), 28.09 (C(CH3)3), 17.22 (CH2CH3), 14.36
(CH3); m/z (ESI) 290 [MH]þ.
4.10. tert-Butyl 4-benzyl-2-phenyloxazoline-4-carboxylate 6c
(rac)
1H, H-
a
), 4.57 (d, J¼9.1 Hz, 2H, CH2); 13C NMR (63 MHz, DMSO) dC
172.61 (CO), 164.26 (CN), 131.86 (AreC), 128.69 (AreC), 128.05
(AreC), 127.00 (AreC), 69.92 (C-
b
), 68.60 (C-
a
); m/z (ESI) 190 [M]ꢁ.
Following the general method for the preparation of 4-alkyl
oxazolines and using BnBr (7.1 mL, 60 mmol) as an electrophile,
the title compound was obtained as a pale yellow solid (6.1 g, 90%).
This can be recrystallized from 1:4 (Et2O/hexanes) to give a col-
ourless solid (4.9 g, 73%). Mp 68e69 ꢀC; NMR data were in agree-
ment with the literature;30 m/z (ESI) 338 [MH]þ.
4.6. tert-Butyl 2-phenyloxazoline-4-carboxylate 5
The esterification was done as proposed by Takeda29 with spe-
cial emphasis on the poor solubility of the acid 4. Compound 4
(19.1 g, 100 mmol), DMAP (2.44 g, 20 mol %), CH2Cl2 (125 mL) and t-
BuOH (125 mL) were placed under nitrogen in a 500 mL round
bottom flask equipped with an efficient condenser. The solution
was heated at reflux and Boc2O (43.6 g, 200 mmol) was added via
syringe in two portions. CAUTION: This step produces substantial
gas evolution. The mixture was then heated for 1 h and the solvents
were evaporated. The yellow oil was dissolved in CH2Cl2 (200 mL)
and then filtered through 40 g of silica. The solvent was removed in
vacuo, the oil was dissolved in 1:9 (Et2O/hexanes) and filtered
through 40 g of silica then eluted with the same mixture (500 mL).
The yellow oil (25 g) that remained after evaporation of the solvents
was crystallized from hexanes to give the title compound (18.5 g,
75%) as off-white crystals. Mp 42e44 ꢀC (lit.30 42e45 ꢀC); Anal.
(C,H,N) C14H17NO3; NMR data were in agreement with the litera-
ture;30 m/z (ESI) 248 [MH]þ.
4.11. tert-Butyl 4-(4-fluorobenzyl)-2-phenyloxazoline-4-
carboxylate 6d (rac)
Following the general method for the preparation of 4-alkyl
oxazolines and using 4-FeBnBr (7.5 mL, 60 mmol) as an electro-
phile, the title compound was obtained as a pale yellow solid (5.6 g,
79%). This can be recrystallized from 1:4 (Et2O/hexanes) to give
a colourless solid (4.1 g, 58%). Mp 69e71 ꢀC; 1H NMR (250 MHz,
CDCl3) dH 8.09e7.97 (m, 2H, AreH), 7.64e7.40 (m, 3H, AreH),
7.40e7.24 (m, 2H, AreH), 7.08e6.94 (m, 2H, AreH), 4.74 (d,
J¼8.9 Hz,1H, CH2O), 4.36 (d, J¼8.9 Hz,1H, CH2O), 3.34 (d, J¼13.9 Hz,
1H, CH2Ar), 3.27 (d, J¼13.9 Hz, 1H, CH2Ar), 1.56 (s, 9H, C(CH3)3); 13
C
NMR (63 MHz, CDCl3) dC 171.46 (CO), 164.79 (CN), 162.03 (d,
3
1JCeF¼245.1 Hz, AreC), 132.01 (d, JCeF¼7.9 Hz, AreC), 131.70
4
(AreC), 131.52 (d, JCeF¼3.3 Hz, AreC), 128.60 (AreC), 128.34
2
4.7. General method for the preparation of 4-alkyl oxazolines
6aed
(AreC), 127.38 (AreC), 115.04 (d, JCeF¼21.1 Hz, AreC), 82.33
(C(CH3)3), 78.88 (d, 6JCeF¼1.2 Hz, C-
a), 73.08 (CH2O), 42.50 (CH2Ar),
28.04 (C(CH3)3); m/z (ESI) 356 [MH]þ.
The protocol of Jew23 was modified as follows: Phenyloxazoline
5 (4.94 g, 20 mmol) was dissolved in toluene (10 mL) and CH2Cl2
(10 mL) and the alkyl bromide and TBAB (644 mg, 2 mmol,
10 mol %) were added. The flask was cooled to 0 ꢀC and flushed with
nitrogen then finely powdered KOH (6.6 g, 85%, 100 mmol) was
added. The flask was capped and the mixture was vigorously stirred
4.12. General method for the reduction of oxazolines 7aed
The protocol of Reddy24 was modified as follows: A freshly
prepared solution of NaBH3CN (3.8 g, 60 mmol) in AcOH (60 mL),
cooled to 0 ꢀC, was added to the oxazoline 6aed (10 mmol) and the
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mixture was stirred at rt for 16 h. The solvent was removed in vacuo
and the residue was partitioned between EtOAc and an excess of
a saturated Na2CO3 solution. The pH was adjusted to >12 with 10%
NaOH and the organic layer was decanted. The basic aqueous layer
was extracted two more times with EtOAc and the pooled fractions
were washed twice with brine. The solution was dried on MgSO4,
was filtered and the solvent was removed in vacuo to give the
product.
C(CH3)3); 13C NMR (63 MHz, CDCl3) dC 172.78 (CO), 162.09 (d,
3
1JCeF¼245.2 Hz, AreC), 139.72 (AreC), 131.98 (d, JCeF¼7.9 Hz,
AreC), 131.39 (d, 4JCeF¼3.3 Hz, AreC), 128.79 (AreC), 128.28 (AreC),
2
127.54 (AreC), 115.15 (d, JCeF¼21.2 Hz, AreC), 82.43 (C(CH3)3),
6
67.16 (d, JCeF¼1.2 Hz, C-
a), 60.67 (CH2O), 47.59 (CH2Ph), 39.55
(CH2Ar), 28.27 (C(CH3)3); m/z (ESI) 360 [MH]þ.
4.17. General method for the formation of sulfamidites 8aed
The protocol of Dolence31 was modified as follows: In a dry
round bottom flask under nitrogen N-benzyl serine 7aed (5 mmol),
imidazole (1.36 g, 20 mmol), NEt3 (2.1 mL, 15 mmol) and CH2Cl2
(25 mL) were added. The mixture was cooled to ꢁ10 ꢀC and then
with stirring SOCl2 (0.54 mL, 7.5 mmol) was added dropwise via
syringe. The solution was kept for 30 min at ꢁ10 ꢀC then allowed to
return to rt during 2 h. The mixture was diluted with water (10 mL)
and then with 10% aqueous NaHSO4 (30 mL). The organic layer was
separated and the aqueous layer was extracted once more with
CH2Cl2. The pooled fractions were washed four times with water
and azeotropically dried by evaporation with CH3CN in vacuo to
give the product.
4.13. tert-Butyl 2-(benzylamino)-2-(hydroxymethyl)buta-
noate 7a (rac)
Following the general method for the reduction of oxazolines
and using 6a (2.75 g, 10 mmol), the title compound was obtained as
a colourless solid (2.66 g, 95%). Mp 52e53 ꢀC; 1H NMR (400 MHz,
CDCl3) dH 7.48e7.05 (m, 5H, AreH), 3.73 (d, J¼11.0 Hz, 1H, CH2O),
3.65 (d, J¼12.0 Hz, 1H, CH2Ph), 3.59 (d, J¼12.0 Hz, 1H, CH2Ph), 3.58
(d, J¼11.0 Hz, 1H, CH2O), 2.30 (b, 2H, NH, OH), 1.75e1.56 (m, 2H,
CH2), 1.49 (s, 9H, C(CH3)3), 0.88 (t, J¼7.5 Hz, 3H, CH3); 13C NMR
(101 MHz, CDCl3) dC 173.53 (CO), 140.05 (AreC), 128.66 (AreC),
128.31 (AreC), 127.35 (AreC), 81.78 (C(CH3)3), 66.70 (C-a), 61.85
(CH2O), 46.90 (CH2Ph), 28.21 (C(CH3)3), 26.38 (CH2), 7.97 (CH3); m/z
(ESI) 280 [MH]þ.
4.18. tert-Butyl 3-benzyl-4-ethyl-2-oxo-1,2,3-oxathiazolidine-
4-carboxylate 8a
4.14. tert-Butyl 2-(benzylamino)-2-(hydroxymethyl)penta-
noate 7b (rac)
Following the general method for the formation of sulfamidites
and using 7a (1.40 g, 5 mmol), the title compound was obtained as
a yellow oil (1.49 g, 92%). 1H NMR (400 MHz, CDCl3) dH 7.47e7.26
(m, 5H, AreH), 5.35 (d, J¼8.3 Hz, 0.5H, CH2O), 5.01 (d, J¼9.0 Hz,
0.5H, CH2O), 4.71 (d, J¼9.0 Hz, 0.5H, CH2O), 4.61 (d, J¼14.2 Hz, 0.5H,
CH2Ph), 4.47 (d, J¼14.9 Hz, 0.5H, CH2Ph), 4.41 (d, J¼14.9 Hz, 0.5H,
CH2Ph), 4.26 (d, J¼14.2 Hz, 0.5H, CH2Ph), 4.14 (d, J¼8.3 Hz, 0.5H,
CH2O), 2.19e2.01 (m, 1H, CH2), 1.92e1.81 (m, 0.5H, CH2), 1.78e1.63
(m, 0.5H, CH2), 1.53 (s, 4.5H, C(CH3)3), 1.49 (s, 4.5H, C(CH3)3), 0.93 (t,
J¼7.5 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) dC 170.05 (0.5C, CO),
169.98 (0.5C, CO), 137.22 (0.5C, AreC), 137.11 (0.5C, AreC), 128.92
(AreC), 128.83 (AreC), 128.72 (AreC), 128.66 (AreC), 127.97 (AreC),
83.18 (0.5C, C(CH3)3), 82.88 (0.5C, C(CH3)3), 77.81 (0.5C, CH2O),
Following the general method for the reduction of oxazolines
and using 6b (2.89 g, 10 mmol), the title compound was obtained as
a colourless solid (2.76 g, 94%). Mp 44e46 ꢀC; 1H NMR (400 MHz,
CDCl3) dH 7.37e7.29 (m, 4H, AreH), 7.29e7.20 (m, 1H, AreH), 3.73
(d, J¼11.0 Hz, 1H, CH2O), 3.65 (d, J¼12.0 Hz, 1H, CH2Ph), 3.60 (d,
J¼12.0 Hz, 1H, CH2Ph), 3.57 (d, J¼11.0 Hz, 1H, CH2O), 2.31 (br, 2H,
NH, OH), 1.70e1.51 (m, 2H, CH2), 1.49 (s, 9H, C(CH3)3), 1.35e1.23 (m,
2H, CH2CH3), 0.92 (t, J¼7.3 Hz, 3H, CH3); 13C NMR (63 MHz, CDCl3)
dC 173.60 (CO), 140.01 (AreC), 128.63 (AreC), 128.29 (AreC), 127.32
(AreC), 81.76 (C(CH3)3), 66.32 (C-a), 62.26 (CH2O), 46.93 (CH2Ph),
35.92 (CH2), 28.20 (C(CH3)3), 16.98 (CH2CH3), 14.51 (CH3); m/z (ESI)
294 [MH]þ.
75.60 (0.5C, CH2O), 71.55 (0.5C, C-a), 69.51 (0.5C, C-a), 46.26 (0.5C,
CH2Ph), 46.20 (0.5C, CH2Ph), 28.04 (1.5C, C(CH3)3), 28.00 (1.5C,
C(CH3)3), 27.51 (0.5C, CH2), 27.07 (0.5C, CH2), 9.28 (0.5C, CH3), 8.51
(0.5C, CH3).
4.15. tert-Butyl 2-benzyl-2-(benzylamino)-3-
hydroxypropanoate 7c (rac)
Following the general method for the reduction of oxazolines
and using 6c (3.37 g, 10 mmol), the title compound was obtained as
a colourless solid (3.31 g, 97%). Mp 69e70 ꢀC; 1H NMR (400 MHz,
CDCl3) dH 7.52e7.25 (m, 10H, AreH), 3.87 (d, J¼11.4 Hz, 1H, CH2O),
3.86 (d, J¼12.0 Hz, 1H, CH2N), 3.80 (d, J¼12.0 Hz, 1H, CH2N), 3.74 (d,
J¼11.4 Hz, 1H, CH2O), 3.15 (d, J¼13.4 Hz, 1H, CH2Ph), 3.04 (d,
J¼13.4 Hz, 1H, CH2Ph), 2.45 (br, 2H, NH, OH), 1.54 (s, 9H, C(CH3)3);
13C NMR (63 MHz, CDCl3) dC 173.60 (CO), 140.01 (AreC), 128.63
4.19. tert-Butyl 3-benzyl-2-oxo-4-propyl-1,2,3-
oxathiazolidine-4-carboxylate 8b
Following the general method for the formation of sulfamidites
and using 7b (1.46 g, 5 mmol), the title compound was obtained as
a yellow oil (1.59 g, 94%). 1H NMR (400 MHz, CDCl3) dH 7.50e7.27
(m, 5H, AreH), 5.34 (d, J¼8.2 Hz, 0.5H, CH2O), 5.01 (d, J¼9.0 Hz,
0.5H, CH2O), 4.71 (d, J¼9.0 Hz, 0.5H, CH2O), 4.61 (d, J¼14.2 Hz,
0.5H, CH2Ph), 4.47 (d, J¼15.0 Hz, 0.5H, CH2Ph), 4.42 (d, J¼15.0 Hz,
0.5H, CH2Ph), 4.26 (d, J¼14.2 Hz, 0.5H, CH2Ph), 4.12 (d, J¼8.2 Hz,
0.5H, CH2O), 2.14e1.96 (m, 1H, CH2), 1.82e1.70 (m, 0.5H, CH2),
1.67e1.58 (m, 0.5H, CH2), 1.52 (s, 4.5H, C(CH3)3), 1.48 (s, 4.5H,
C(CH3)3), 1.36e1.23 (m, 2H, CH2CH3), 0.94 (t, J¼7.3 Hz, 1.5H, CH3),
0.88 (t, J¼7.3 Hz, 1.5H, CH3); 13C NMR (101 MHz, CDCl3) dC 170.12
(0.5C, CO), 170.01 (0.5C, CO), 137.20 (0.5C, AreC), 137.07 (0.5C,
AreC), 128.92 (AreC), 128.83 (AreC), 128.71 (AreC), 128.65
(AreC), 127.97 (AreC), 83.15 (0.5C, C(CH3)3), 82.85 (0.5C, C(CH3)3),
(AreC), 128.29 (AreC), 127.32 (AreC), 81.76 (C(CH3)3), 66.32 (C-a),
62.26 (CH2O), 46.93 (CH2Ph), 35.92 (CH2), 28.20 (C(CH3)3), 16.98
(CH2CH3), 14.51 (CH3); m/z (ESI) 342 [MH]þ.
4.16. tert-Butyl 2-(benzylamino)-2-(4-fluorobenzyl)-3-
hydroxy propanoate 7d (rac)
Following the general method for the reduction of oxazolines
and using 6d (3.55 g, 10 mmol), the title compound was obtained as
a colourless solid (3.52 g, 98%). Mp 67e69 ꢀC; 1H NMR (400 MHz,
CDCl3) dH 7.38e7.29 (m, 4H, AreH), 7.29e7.23 (m, 1H, AreH),
7.21e7.15 (m, 2H, AreH), 6.99e6.91 (m, 2H, AreH), 3.71 (d,
J¼11.5 Hz, 1H, CH2O), 3.71 (d, J¼12.0 Hz, 1H, CH2Ph), 3.66 (d,
J¼12.0 Hz, 1H, CH2Ph), 3.57 (d, J¼11.5 Hz, 1H, CH2O), 2.99 (d,
J¼13.5 Hz, 1H, CH2Ar), 2.87 (d, J¼13.5 Hz, 1H, CH2Ar), 1.42 (s, 9H,
78.08 (0.5C, CH2O), 75.73 (0.5C, CH2O), 71.01 (0.5C, C-
a), 68.96
(0.5C, C- ), 46.31 (0.5C, CH2Ph), 46.21 (0.5C, CH2Ph), 36.75 (0.5C,
a
CH2), 36.20 (0.5C, CH2), 28.04 (1.5C, C(CH3)3), 27.98 (1.5C,
C(CH3)3), 18.40 (0.5C, CH2CH3), 17.67 (0.5C, CH2CH3), 14.47 (0.5C,
CH3), 14.42 (0.5C, CH3).
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6
4.20. tert-Butyl 3,4-dibenzyl-2-oxo-1,2,3-oxathiazolidine-4-
carboxylate 8c
CH2O), 4.60 (d, J¼15.9 Hz, 1H, CH2Ph), 4.48 (d, J¼15.9 Hz, 1H,
CH2Ph), 4.31 (d, J¼8.7 Hz, 1H, CH2O), 1.94e1.75 (m, 1H, CH2),
1.73e1.52 (m, 1H, CH2), 1.49 (s, 9H), 1.32e1.09 (m, 2H, CH2CH3), 0.82
(t, J¼7.2 Hz, 3H, CH3); 13C NMR (63 MHz, CDCl3) dC 168.35 (CO),
136.05 (AreC), 128.56 (AreC), 128.33 (AreC), 127.97 (AreC), 84.20
Following the general method for the formation of sulfamidites
and using 7c (1.71 g, 5 mmol), the title compound was obtained as
a yellow oil (1.94 g, 99%). 1H NMR (250 MHz, CDCl3) dH 7.57e7.11 (m,
10H, AreH), 5.10 (d, J¼8.5 Hz, 0.5H, CH2O), 4.90 (d, J¼9.2 Hz, 0.5H,
CH2O), 4.83 (d, J¼9.2 Hz, 0.5H, CH2O), 4.75 (d, J¼14.2 Hz, 0.5H,
CH2N), 4.63 (d, J¼14.9 Hz, 0.5H, CH2N), 4.52 (d, J¼14.9 Hz, 0.5H,
CH2N), 4.44 (d, J¼14.2 Hz, 0.5H, CH2N), 4.34 (d, J¼8.5 Hz, 0.5H,
CH2O), 3.61 (d, J¼13.3 Hz, 0.5H, CH2Ph), 3.47 (d, J¼13.3 Hz, 0.5H,
CH2Ph), 3.15 (d, J¼13.3 Hz, 0.5H, CH2Ph), 2.87 (d, J¼13.3 Hz, 0.5H,
CH2Ph), 1.47 (s, 9H, C(CH3)3); 13C NMR (63 MHz, CDCl3) dC 168.80
(0.5C, CO), 168.74 (0.5C, CO), 136.97 (0.5C, AreC), 136.86 (0.5C,
AreC), 134.97 (0.5C, AreC), 134.21 (0.5C, AreC), 129.84 (AreC),
129.71 (AreC), 128.88 (AreC), 128.83 (AreC), 128.67 (AreC), 127.98
(0.5C, AreC), 127.95 (0.5C, AreC), 127.63 (0.5C, AreC), 127.49 (0.5C,
AreC), 83.42 (0.5C, C(CH3)3), 83.22 (0.5C, C(CH3)3), 77.91 (0.5C,
(C(CH3)3), 72.49 (CH2O), 69.11 (C-a), 46.91 (CH2Ph), 35.80 (CH2),
27.87 (C(CH3)3), 16.60 (CH2CH3), 14.04 (CH3); HRMS m/z (ESþ) Calcd
for C17H25LiNO5S 362.1608, found 362.1607 [MLi]þ.
4.25. tert-Butyl 3,4-dibenzyl-2,2-dioxo-1,2,3-oxathiazolidine-
4-carboxylate 9c (rac)
Following the general method for the formation of sulfamidates
and using 8c (1.94 g, 5 mmol), the title compound was obtained as
a colourless solid (1.66 g, 82%). Mp 88e90 ꢀC; 1H NMR (250 MHz,
CDCl3) dH 7.67e7.55 (m, 2H, AreH), 7.55e7.29 (m, 6H, AreH),
7.29e7.10 (m, 2H, AreH), 4.80 (d, J¼15.9 Hz, 1H, CH2N), 4.77 (d,
J¼8.8 Hz,1H, CH2O), 4.73 (d, J¼15.9 Hz, 1H, CH2N), 4.56 (d, J¼8.8 Hz,
1H, CH2O), 3.50 (d, J¼13.4 Hz, 1H, CH2Ph), 2.92 (d, J¼13.4 Hz, 1H,
CH2Ph), 1.54 (s, 9H, C(CH3)3); 13C NMR (63 MHz, CDCl3) dC 167.13
(CO), 136.11 (AreC), 132.57 (AreC), 130.00 (AreC), 128.95 (AreC),
128.74 (AreC), 128.51 (AreC), 128.16 (AreC), 128.05 (AreC), 84.71
CH2O), 76.04 (0.5C, CH2O), 70.73 (0.5C, C-a), 69.36 (0.5C, C-a), 46.27
(0.5C, CH2N), 46.21 (0.5C, CH2N), 40.84 (CH2Ph), 27.90 (1.5C,
C(CH3)3), 27.78 (1.5C, C(CH3)3).
4.21. tert-Butyl 3-benzyl-4-(4-fluorobenzyl)-2-oxo-1,2,3-
oxathiazolidine-4-carboxylate 8d
(C(CH3)3), 72.40 (CH2O), 69.18 (C-a), 47.01 (CH2N), 40.10 (CH2Ph),
27.89 (C(CH3)3); HRMS m/z (ESþ) Calcd for C21H25LiNO5S 410.1608,
found 410.1607 [MLi]þ.
Following the general method for the formation of sulfamidites
and using 7d (1.80 g, 5 mmol), the title compound was obtained as
a yellow oil (1.99 g, 98%) that was used ‘as is’ for the next step.
4.26. tert-Butyl 3-benzyl-4-(4-fluorobenzyl)-2,2-dioxo-1,2,3-
oxathiazolidine-4-carboxylate 9d (rac)
4.22. General method for the formation of sulfamidates 9aed
Following the general method for the formation of sulfamidates
and using 8d (1.99 g, 4.9 mmol), the title compound was obtained as
a colourless solid (1.59 g, 77%). 1H NMR (250 MHz, CDCl3) dH
7.52e7.44 (m, 2H, AreH), 7.42e7.30 (m, 3H, AreH), 7.09e6.92 (m,
4H, AreH), 4.68 (d, J¼15.8 Hz, 1H, CH2Ph), 4.65 (d, J¼8.8 Hz, 1H,
CH2O), 4.58 (d, J¼15.8 Hz, 1H, CH2Ph), 4.42 (d, J¼8.8 Hz, 1H, CH2O),
3.36 (d, J¼13.6 Hz,1H, CH2Ar), 2.80 (d, J¼13.6 Hz,1H, CH2Ar),1.44 (s,
9H, C(CH3)3); 13C NMR (63 MHz, CDCl3) dC 167.06 (CO), 162.51 (d,
The protocol of Boulton22 was modified as follows: The crude
sulfamidite 8aed (ca. 5 mmol) was dissolved in CH3CN (50 mL) and
the solution was cooled to 0 ꢀC. Next, RuCl3$xH2O (11 mg, 1 mol %)
was added, followed by NaIO4 (1.2 g, 5.6 mmol) and water (25 mL).
The greenish-brown solution with a white precipitate was stirred
for 15 min at 0 ꢀC and was allowed to return to rt. After 4 h the
mixture was diluted with Et2O (50 mL) and brine (50 mL). The
aqueous layer was extracted with Et2O (3ꢂ50 mL) and the pooled
fractions were washed twice with saturated NaHCO3 and brine. The
organic layer was dried on MgSO4, filtered and the solvents were
evaporated in vacuo to yield the crude product. This was flash
chromatographed on silica with 1:4 (EtOAc/hexanes) and the sol-
vents were removed in vacuo to give the pure compound.
3
1JCeF¼247.4 Hz, AreC), 136.00 (AreC), 131.66 (d, JCeF¼8.1 Hz,
4
AreC), 128.77 (AreC), 128.48 (AreC), 128.38 (d, JCeF¼3.4 Hz,
2
AreC), 128.21 (AreC), 115.90 (d, JCeF¼21.4 Hz, AreC), 84.90
(C(CH3)3), 72.18 (CH2O), 69.14 (d, 6JCeF¼1.5 Hz, C-
a), 47.03 (CH2Ph),
39.17 (CH2Ar), 27.88 (C(CH3)3); HRMS m/z (ESþ) Calcd for
C
21H24FLiNO5S 428.1514, found 428.1513 [MLi]þ.
4.27. General method for the formation of lanthionines
4.23. tert-Butyl 3-benzyl-4-ethyl-2,2-dioxo-1,2,3-
11aed
oxathiazolidine-4-carboxylate 9a (rac)
To a degassed solution of sulfamidate 9aed (1 mmol) and Boc
cysteine methyl ester (259 mg, 1.1 mmol) in CH3CN (10 mL), DBU
(182 mg, 1.2 mmol) in degassed CH3CN (1 mL) was added via syringe
and the reaction mixture was stirred for 1 h at rt under nitrogen. The
solution was diluted with EtOAc (25 mL) and 10% aqueous NaH2PO4
(25 mL) and this was heated with stirring at 50 ꢀC for 2 h. The re-
action mixture was then basified by pouring in an excess of saturated
Na2CO3 solution. The organic layer was decanted and the aqueous
layer was extracted with EtOAc (3ꢂ50 mL). The pooled fractions
were washed with brine and dried on MgSO4, were filtered and the
solvent was evaporated in vacuo to yield the crude product. This was
chromatographed on silica with 1:3 (EtOAc/hexanes) and the sol-
vents were removed in vacuo to give the pure compound.
Following the general method for the formation of sulfamidates
and using 8a (1.41 g, 4.3 mmol), the title compound was obtained as
a colourless oil (1.45 g, 99%). 1H NMR (400 MHz, CDCl3) dH 7.47e7.39
(m, 2H, AreH), 7.39e7.27 (m, 3H, AreH), 4.92 (d, J¼8.7 Hz,1H, CH2O),
4.61 (d, J¼15.8 Hz, 1H, CH2Ph), 4.49 (d, J¼15.8 Hz,1H, CH2Ph), 4.31 (d,
J¼8.7 Hz, 1H, CH2O), 2.01e1.90 (m, 1H, CH2), 1.75e1.63 (m, 1H, CH2),
1.50 (s, 9H, C(CH3)3), 0.84 (t, J¼7.5 Hz, 3H, CH3); 13C NMR (63 MHz,
CDCl3) dC 168.20 (CO), 136.10 (AreC), 128.54 (AreC), 128.29 (AreC),
127.95 (AreC), 84.17 (C(CH3)3), 72.28 (CH2O), 69.45 (C-
a), 46.84
(CH2Ph), 27.84 (C(CH3)3), 26.93 (CH2), 7.46 (CH3).
4.24. tert-Butyl 3-benzyl-2,2-dioxo-4-propyl-1,2,3-
oxathiazolidine-4-carboxylate 9b (rac)
4.28. tert-Butyl 2-benzylamino-3-((R)-2-(tert-butoxycarbonyl
Following the general method for the formation of sulfamidates
and using 8b (1.5 g, 4.4 mmol), the title compound was obtained as
a colourless oil (1.54 g, 98%). 1H NMR (250 MHz, CDCl3) dH 7.50e7.38
(m, 2H, AreH), 7.38e7.23 (m, 3H, AreH), 4.90 (d, J¼8.7 Hz, 1H,
amino)-3-methoxy-3-oxopropylthio)-2-ethyl propanoate 11a
Following the general method for the formation of lanthionines
and using 9a (341 mg, 1 mmol), the title compound was obtained as
€
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7
a colourless oil (495 mg, 99%). 1H NMR (250 MHz, CDCl3) dH
7.45e7.13 (m, 5H, AreH), 5.82 (br, 0.5H, NH-Boc), 5.52 (br, 0.5H, NH-
Boc), 4.52 (br, 1H, H-a), 3.72 (s, 1.5H, OCH3), 3.68 (s, 1.5H, OCH3),
128.41 (AreC), 128.38 (AreC), 128.34 (AreC), 128.17 (AreC), 128.15
(AreC), 127.13 (0.5C, AreC), 127.09 (0.5C, AreC), 126.89 (0.5C,
AreC), 126.86 (0.5C, AreC), 82.08 (0.5C, C(CH3)3), 82.05 (0.5C,
3.68e3.59 (m, 1H, CH2Ph), 3.59e3.50 (m, 1H, CH2Ph), 3.04 (d,
J¼12.9 Hz, 1H, SCH2C), 3.04e2.94 (m, 2H, CHCH2S), 2.90 (d,
J¼12.9 Hz, 0.5H, SCH2C), 2.89 (d, J¼12.9 Hz, 0.5H, SCH2C), 2.17 (br,
1H, NH), 1.90e1.62 (m, 2H, CH2CH3), 1.50 (s, 9H, C(CH3)3), 1.44 (s,
4.5H, C(CH3)3), 1.43 (s, 4.5H, C(CH3)3), 0.96e0.80 (m, 3H, CH3); 13C
NMR (63 MHz, CDCl3) dC 173.23 (0.5C, CO), 173.16 (0.5C, CO), 171.42
(CO), 155.11 (Boc-CO), 140.00 (0.5C, AreC), 139.90 (0.5C, AreC),
128.37 (AreC), 128.28 (AreC), 128.26 (AreC), 126.96 (0.5C, AreC),
126.93 (0.5C, AreC), 81.43 (0.5C, C(CH3)3), 81.42 (0.5C, C(CH3)3),
C(CH3)3), 80.02 (C(CH3)3), 66.40 (C-a), 53.53 (CH-a), 52.48 (0.5C,
OCH3), 52.44 (0.5C, OCH3), 47.54 (0.5C, CH2N), 47.48 (0.5C, CH2N),
41.39 (CH2Ph), 37.52 (0.5C, SCH2C), 37.32 (0.5C, SCH2C), 35.65
(CHCH2S), 28.31 (1.5C, C(CH3)3), 28.28 (1.5C, C(CH3)3), 28.10
(C(CH3)3); m/z (ESI) 559 [MH]þ; HRMS m/z (ESþ) Calcd for
C
30H43N2O6S 559.2836, found 559.2838 [MH]þ.
4.31. tert-Butyl 2-benzylamino-3-((R)-2-(tert-butoxycarbonyl
amino)-3-methoxy-3-oxopropylthio)-2-(4-fluorobenzyl)
propanoate 11d
79.82 (0.5C, C(CH3)3), 79.75 (0.5C, C(CH3)3), 65.86 (0.5C, C-
a), 65.73
(0.5C, C- ), 53.63 (0.5C, CH- ), 53.48 (0.5C, CH- ), 52.30 (0.5C,
a
a
a
OCH3), 52.26 (0.5C, OCH3), 47.23 (0.5C, CH2Ph), 47.00 (0.5C, CH2Ph),
37.79 (0.5C, SCH2C), 37.55 (0.5C, SCH2C), 35.70 (0.5C, CHCH2S),
35.49 (0.5C, CHCH2S), 28.21 (1.5C, C(CH3)3), 28.19 (1.5C, C(CH3)3),
28.07 (0.5C, CH2), 27.99 (C(CH3)3), 27.83 (0.5C, CH2), 7.89 (0.5C,
CH3), 7.86 (0.5C, CH3); m/z (ESI) 497 [MH]þ; HRMS m/z (ESþ) Calcd
for C25H41N2O6S 497.2680, found 497.2677 [MH]þ.
Following the general method for the formation of lanthionines
and using 9d (421 mg, 1 mmol), the title compound was obtained as
a colourless oil (564 mg, 98%); 1H NMR (250 MHz, CDCl3) dH
7.44e7.10 (m, 7H, AreH), 7.05e6.81 (m, 2H, AreH), 5.53 (br, 0.5H,
NH-Boc), 5.41 (br, 0.5H, NH-Boc), 4.51 (br, 1H, H-a), 3.77 (d,
J¼11.4 Hz, 1H, CH2Ph), 3.72 (s, 1.5H, OCH3), 3.70 (s, 1.5H, OCH3), 3.64
(d, J¼11.4 Hz, 0.5H, CH2Ph), 3.62 (d, J¼11.4 Hz, 0.5H, CH2Ph),
3.24e2.83 (m, 5H, CHCH2S, SCH2C, CH2Ph), 2.76 (d, J¼12.6 Hz, 1H,
SCH2C), 1.88 (br, 1H, NH), 1.48e1.36 (m, 18H, C(CH3)3); 13C NMR
(63 MHz, CDCl3) dC 172.77 (0.5C, CO),172.72 (0.5C, CO),171.53 (0.5C,
CO), 171.46 (0.5C, CO), 161.90 (d, 1JCeF¼245.1 Hz, AreC), 155.14 (Boc-
CO), 139.76 (0.5C, AreC), 139.70 (0.5C, AreC), 131.77 (d,
4JCeF¼4.3 Hz, AreC), 131.75 (d, 3JCeF¼7.7 Hz, AreC), 128.46 (AreC),
128.45 (AreC), 128.33 (AreC), 128.30 (AreC), 127.18 (0.5C, AreC),
127.15 (0.5C, AreC), 114.95 (d, 2JCeF¼21.1 Hz, 0.5C, AreC), 114.92 (d,
2JCeF¼21.1 Hz, 0.5C, AreC), 82.21 (0.5C, C(CH3)3), 82.18 (0.5C,
4.29. tert-Butyl 2-benzylamino-3-((R)-2-(tert-butoxycarbonyl
amino)-3-methoxy-3-oxopropylthio)-2-(1-propyl) propanoate
11b
Following the general method for the formation of lanthionines
and using 9b (355 mg, 1 mmol), the title compound was obtained as
a colourless oil (511 mg, 99%). 1H NMR (250 MHz, CDCl3) dH
7.40e7.17 (m, 5H, AreH), 5.79 (br, 0.5H, NH-Boc), 5.44 (br, 0.5H, NH-
Boc), 4.51 (br, 1H, H-a), 3.72 (s, 1.5H, OCH3), 3.67 (s, 1.5H, OCH3),
3.63 (d, J¼11.7 Hz, 1H, CH2Ph), 3.54 (d, J¼11.7 Hz, 1H, CH2Ph), 3.00
(m, 3H, CHCH2S, SCH2C), 2.88 (d, J¼12.8 Hz, 0.5H, SCH2C), 2.86 (d,
J¼12.8 Hz, 0.5H, SCH2C), 1.92 (br, 1H, NH), 1.81e1.56 (m, 2H, CH2),
1.48 (s, 9H, C(CH3)3), 1.43 (s, 4.5H, C(CH3)3), 1.42 (s, 4.5H, C(CH3)3),
1.33e1.22 (m, 2H, CH2CH3), 0.95e0.85 (m, 3H, CH3); 13C NMR
(63 MHz, CDCl3) dC 173.49 (0.5C, CO), 173.42 (0.5C, CO), 171.56 (CO),
155.17 (Boc-CO), 140.15 (0.5C, AreC), 140.04 (0.5C, AreC), 128.48
(AreC), 128.39 (AreC), 127.07 (0.5C, AreC), 127.04 (0.5C, AreC),
81.61 (0.5C, C(CH3)3), 81.58 (0.5C, C(CH3)3), 80.03 (0.5C, C(CH3)3),
C(CH3)3), 80.04 (C(CH3)3), 66.34 (C-a), 53.57 (CH-a), 52.49 (0.5C,
OCH3), 52.46 (0.5C, OCH3), 47.48 (0.5C, CH2Ph), 47.44 (0.5C, CH2Ph),
40.35 (0.5C, CH2Ar), 40.30 (0.5C, CH2Ar), 37.48 (0.5C, SCH2C), 37.25
(0.5C, SCH2C), 35.62 (CHCH2S), 28.29 (C(CH3)3), 28.10 (C(CH3)3); m/z
(ESI) 577 [MH]þ; HRMS m/z (ESþ) Calcd for C30H42FN2O6S 577.2742,
found 577.2747 [MH]þ.
4.32. tert-Butyl 2-amino-2-benzyl-3-((R)-2-(tert-butox-
ycarbonylamino)-3-methoxy-3-oxopropylthio)propanoate
79.93 (0.5C, C(CH3)3), 65.63 (0.5C, C-
a), 65.50 (0.5C, C-a), 53.75
(0.5C, CH- ), 53.57 (0.5C, CH- ), 52.46 (0.5C, OCH3), 52.42 (0.5C,
a
a
Compound 11c (300 mg, 0.54 mmol) was dissolved in MeOH
(90 mL) and water (10 mL) and the solution was placed in
a hydrogenator containing a magnetic stir bar. Pd black (75 mg, wet
with water) was then added cautiously followed by AcOH (3 mL).
The reactor was closed and purged four times with H2 then placed
under H2 pressure (7 bars). The vessel was externally heated to
70 ꢀC and the reaction was allowed to proceed for 16 h with stirring.
The vessel was cooled to rt, the H2 was removed and the reactor
was opened. The solution was decanted from palladium and filtered
on a fritted funnel. The solvent was evaporated in vacuo and the
residue was basified with saturated Na2CO3 and extracted twice
with CH2Cl2. The solvent was removed and the crude oil was pu-
rified by column chromatography on silica with 1:1 (EtOAc/
hexanesþ1% NEt3) to produce, after evaporation of the solvents in
vacuo, the title compound as a pale oil (73%). 1H NMR (250 MHz,
CDCl3) dH 7.23e7.03 (m, 5H, AreH), 6.32 (br, 0.5H, NH-Boc), 5.77 (br,
OCH3), 47.41 (0.5C, CH2Ph), 47.16 (0.5C, CH2Ph), 38.43 (0.5C, SCH2C),
38.15 (0.5C, SCH2C), 37.76 (0.5C, CH2), 37.51 (0.5C, CH2), 35.91 (0.5C,
CHCH2S), 35.71 (0.5C, CHCH2S), 28.33 (1.5C, C(CH3)3), 28.31 (1.5C,
C(CH3)3), 28.12 (C(CH3)3), 16.98 (0.5C, CH2CH3), 16.93 (0.5C,
CH2CH3), 14.42 (0.5C, CH3), 14.40 (0.5C, CH3); m/z (ESI) 511 [MH]þ;
HRMS m/z (ESþ) Calcd for C26H43N2O6S 511.2836, found 511.2834
[MH]þ.
4.30. tert-Butyl 2-benzyl-2-benzylamino-3-((R)-2-(tert-bu-
toxy carbonylamino)-3-methoxy-3-oxopropylthio)propanoate
11c
Following the general method for the formation of lanthionines
and using 9c (403 mg, 1 mmol), the title compound was obtained as
a colourless oil (503 mg, 90%); 1H NMR (250 MHz, CDCl3) dH
7.47e7.15 (m, 10H, AreH), 5.57 (br, 0.5H, NH-Boc), 5.43 (br, 0.5H,
0.5H, NH-Boc), 4.44 (br, 1H, H-a), 3.63 (s, 1.5H, OCH3), 3.62 (s, 1.5H,
NH-Boc), 4.55 (br, 1H, H-
a
), 3.81 (d, J¼11.5 Hz, 0.5H, CH2N), 3.80 (d,
OCH3), 3.09 (d, J¼13.0 Hz, 0.5H, SCH2C), 3.02 (d, J¼13.0 Hz, 0.5H,
SCH2C), 3.01e2.89 (m, 3H, CHCH2S, CH2Ph), 2.71 (d, J¼13.1 Hz, 1H,
CH2Ph), 2.63 (d, J¼13.0 Hz, 0.5H, SCH2C), 2.59 (d, J¼13.0 Hz, 0.5H,
SCH2C), 1.75 (br, 2H, NH2), 1.36 (s, 4.5H, C(CH3)3), 1.35 (s, 4.5H,
C(CH3)3), 1.34 (s, 9H, C(CH3)3); 13C NMR (63 MHz, CDCl3) dC 173.64
(0.5C, CO), 173.59 (0.5C, CO), 171.14 (0.5C, CO), 171.12 (0.5C, CO),
155.12 (0.5C, Boc-CO), 155.01 (0.5C, Boc-CO), 135.51 (0.5C, AreC),
135.48 (0.5C, AreC), 129.93 (AreC), 129.90 (AreC), 128.07 (AreC),
128.03 (AreC),126.85 (0.5C, AreC),126.80 (0.5C, AreC), 81.71 (0.5C,
J¼11.5 Hz, 0.5H, CH2N), 3.74 (s, 1.5H, OCH3), 3.71 (s, 1.5H, OCH3),
3.66 (d, J¼11.5 Hz, 0.5H, CH2N), 3.65 (d, J¼11.5 Hz, 0.5H, CH2N),
3.20e3.04 (m, 3H, SCH2C, CH2Ph), 3.04e2.96 (m, 2H, CHCH2S), 2.81
(d, J¼12.5 Hz, 0.5H, SCH2C), 2.79 (d, J¼12.7 Hz, 0.5H, SCH2C), 1.87
(br, 1H, NH), 1.45 (m, 18H, C(CH3)3); 13C NMR (63 MHz, CDCl3) dC
172.85 (0.5C, CO), 172.79 (0.5C, CO), 171.58 (0.5C, CO), 171.50 (0.5C,
CO), 155.16 (Boc-CO), 139.86 (0.5C, AreC), 139.79 (0.5C, AreC),
136.01 (0.5C, AreC), 130.27 (AreC), 130.25 (AreC), 128.43 (AreC),
€
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T. Denoel et al. / Tetrahedron xxx (2014) 1e8
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C(CH3)3), 81.69 (0.5C, C(CH3)3), 79.59 (0.5C, C(CH3)3), 79.49 (0.5C,
C(CH3)3), 62.78 (0.5C, C- ), 62.66 (0.5C, C- ), 53.85 (0.5C, CH- ),
53.57 (0.5C, CH- ), 52.18 (0.5C, OCH3), 52.14 (0.5C, OCH3), 45.26
(0.5C, CH2Ph), 45.08 (0.5C, CH2Ph), 43.29 (0.5C, SCH2C), 43.08 (0.5C,
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[MH]þ; HRMS m/z (ESþ) Calcd for C23H37N2O6S 469.2367, found
469.2367 [MH]þ.
a
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This work was financed by an ARC (grant 03/08-297) of the
Belgium French community and by the FP6 European Integrated
Project EurIntafar (LSHM-CT-2004-512138). We thank Professor
Albert Demonceau for insightful discussions and correction of the
draft. We thank Erik Ziegler for English support. We thank Dr. Ga-
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NMR spectra of the newly synthesized molecules are repro-
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