An alternative approach to the synthesis of the three fragments of anachelin H

Article abstract of DOI:10.1039/d0ob00315h

The synthesis of the fully protected peptide, polyketide and alkaloid fragments of anachelin H is presented. The peptide fragment was prepared using a liquid phase peptide synthesis; the polyketide fragment was synthetized using a cross metathesis and an intramolecular oxa-Michael reaction as the key steps to introduce the desired stereochemistry; finally, the alkaloid fragment was obtained by an oxidative cyclization of a catechol derivative using potassium ferricyanide. The synthesis of all fragments was based on the use of natural amino acids as sources of asymmetry. The independent synthesis of the three fragments should allow more efficient biological studies on the fragments instead of the whole natural product. Experiments to illustrate the coupling of fragments and the effectiveness of the convergent strategy are also described.

Full text of DOI:10.1039/d0ob00315h

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DOI: 10.1039/D0OB00315H
ARTICLE
An Alternative Approach to the Synthesis of the Three Fragments
of Anachelin H
Fabián Garzón-Posse,a Joëlle Prunet b and Diego Gamba-Sánchez *a
Received 00th January 20xx,
Accepted 00th January 20xx
The synthesis of the fully protected peptide, polyketide and alkaloid fragments of Anachelin H are presented. The peptide
fragment was prepared using a liquid phase peptide synthesis; the polyketide fragment was synthetized using a cross
metathesis and an intramolecular oxa-Michael reaction as the key steps to introduce the desired stereochemistry; finally,
the alkaloid fragment was obtained by an oxidative cyclization of a catechol derivative using potassium ferricyanide. The
synthesis of all fragments was based on the use of natural aminoacids as sources of asymmetry. The independent synthesis
of the three fragments should allow more efficient biological studies, on the fragments instead the whole natural product.
Experiments to illustrate the coupling of fragments and the effectiveness of the convergent strategy are also described.
DOI: 10.1039/x0xx00000x
structure of anachelin H translates into a challenge for synthetic
organic chemists and it is also responsible for the very few
synthetic reports described to date.
Introduction
Antimicrobial resistance is one of the largest public health
problems worldwide.1 Generally bacteria and other
microorganisms evolve quickly enough to develop resistance in
just a few years (even months) after the antibiotic drug is on the
market;2 in consequence multiple strategies to develop new
antibiotics are highly important in medical, biological and
chemical research, among others.3 Anachelin H (Figure 1) is a
naturally occurring iron chelator (siderophore) that was isolated
from the freshwater blue green algae Anabaena cylindrica in
2000.4 It has shown moderate antibacterial activity against the
respiratory track pathogen Moraxella catarrhalis;5 on the other
hand it has been demonstrated that anachelin H enhances
growth of the cyanobacterium Microcystis aeruginosa with
simultaneous allelopathic activity against green algae
Kirchneriella contorta, thus suggesting a dual mode of action.6
Finally, the alkaloid fragment of anachelin H has been used in
biomimetic surface modifications showing amazing results.7
Having in mind the aforementioned properties of anachelin H,
its specific function as siderophore, as well as its particular and
uncommon structure (composed of three fragments,
polyketide, peptide and alkaloid), it seems plausible to assume
that an expeditious synthesis of the natural product will derive
in more conclusive and advanced biological studies, in order to
determine the potential applications of anachelin H and its
fragments. In consequence, the development of new synthetic
strategies for molecules that can act as siderophores or
sideromycins is highly desirable;8 unfortunately, the complex
Figure 1. Structure of anachelin H, highlighting the three fragments.
Gademann and coworkers described its total synthesis in 2004,9
then some additional studies culminated with improvements in
the synthesis of some fragments;5-6,10 it is noteworthy to
mention that some of those fragments may also act as
siderophores and have shown interesting properties.
Inspired by those features, we decided to study the synthesis of
anachelin H fragments, since a shorter and more efficient
synthesis of the fragments will make them available for
biological trials. Herein we detail our approaches and some
unsuccessful strategies to construct independent fragments of
anachelin H, a new synthesis of the polyketide unit and a
significant improvement in the alkaloid portion synthesis. All
our approaches are based on naturally occurring amino acids as
source of asymmetry.
Results and Discussion
Our retrosynthetic analysis is based on the independent
synthesis of the three fragments (see Figure 1). The synthesis of
peptide 2 was accomplished in gram scale and 70% overall yield,
starting with commercially available O-benzyl-L-serine methyl
ester 1 and using subsequent couplings of D-serine and L-
threonine by the BOP strategy (Scheme 1);11 as this is a common
a. Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry Department,
Universidad de los Andes. Cra 1 No. 18A-12 Q:305. Bogotá 111711 (Colombia)
b. WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building,
University Avenue, Glasgow G12 8QQ, UK.
Email: da.gamba1361@uniandes.edu.coAddress here.
†Electronic Supplementary Information (ESI) available: copies of all NMR spectra are
provided See DOI: 10.1039/x0xx00000x
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Ph
O
and well documented peptide synthesis we will not discuss it
here.
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DOI: 10.1039/D0OB00315H
O
O
O
PGO
OR
HN
3
BnO
A
B
PhCHO
Intramolecular
Oxa-Michael
1.
PhCHO
Intramolecular
Oxa-Michael
2. Selective Reduction
OH
O
O
OH
O
PGO
OR
RO
OR1
HN
O
HN
O
BnO
BnO
Scheme 1 Synthesis of fully protected peptide fragment 2.
More challenging was the polyketide fragment; since one of our
research topics is the diastereoselective construction of syn 1,3-
diols using intramolecular oxa-Michael reactions (so-called
Evans-Prunet reaction),12 we envisaged to use this method to
generate the desired stereochemistry in the fully protected
polyketide fragment 3.
Scheme 2 Retrosynthetic analysis for polyketide fragment.
The retrosynthetic analysis in Scheme 2 shows two possibilities.
In route A, two stereogenic centers may be installed in a single
step. However, our previous studies with similar molecules
showed that highly electrophilic aldehydes or ketones - such as
p-nirobenzaldehyde or trifluoroacetophenone - are the only
suitable carbonyl substrates for the desired transformation,13
and even if the desired stereochemistry was obtained, the
stability of the corresponding acetals would make route A risky.
In consequence, we turned our attention to route B and started
our investigation using commercially available benzyloxy
benzoic acid 4 and L-serine methyl ester (Scheme 3). The first
step was the generation of the acyl chloride using oxalyl
chloride and catalytic DMF, and the crude acid chloride reacted
in situ with the amino acid ester to afford compound 5 in good
yield. Because of future transformations the protection of the
primary alcohol is mandatory; this was accomplished by
installing
a
tert-butyldiphenylsilyl group under classic
conditions yielding compound 6 quantitatively. The reduction of
the methyl ester in 6 with DIBAL-H proved complicated and not
reproducible, presumably because of the instability of the
aldehyde, so complete reduction and further oxidation was a
plausible alternative.
Scheme 3 Synthesis of polyketide precursor.
After trying different conditions, the reduction using calcium
borohydride14 (formed in situ) afforded the best results and the
alcohol 7 was obtained in 99% yield. Unfortunately, oxidation to
the aldehyde showed similar problems to those observed for
the ester reduction, which means the aldehyde is difficult to
purify and degradation is observed during the chromatography,
no matter the oxidant used. However, Swern oxidation15
produced the cleanest crude aldehyde product, which was used
directly in the allylation step without further purification.
The literature describes allylation reactions on similar
substrates giving the syn 1,2-amino alcohol, generally using
Osomi-Sakurai allylation.16 In our hands, the desired syn isomer
was obtained as the major product but the best diastereomeric
2 | J. Name., 2012, 00, 1-3
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ratio was only 1.6:1 using SnCl4, and after separation of the anachelin H was accomplished in 22.4% overall yVieielwd,ArwtichleiOchnlinies
isomers by flash chromatography compound 8 was obtained in superior to the yield of the previous syntDhOeIs:i1s0b.1y03G9a/Dd0eOmBa0n0n31.5H
35% yield. All other attempts (direct allylation with allyl halides We then turned our attention to the synthesis of the alkaloid
and metals) to perform a diastereoselective allylation were fragment 12. It is noteworthy to mention that the 3-
impractical, commonly the diastereoselectivity was low, aminohydroquinolines are common fragments in natural
consequently, we decided to try a matched Roush allylation17 products with a variety of biological activities,20 so we decided
for better results, and the syn isomer 8 was the only isolated to explore two alternative routes starting from L-dopa (Scheme
product in 50% yield over two steps. To investigate the 6).
stereochemical integrity of compound 8, we performed TDBPS
cleavage followed by acetonide formation (Scheme 4). The
coupling constant in ketal 10 (obtained by homonuclear
decoupling 1H NMR experiments) proved unequivocally the syn
1,2-stereochemistry; trans coupling constants are typically
between 9 and 9.5 Hz and cis coupling constants are less than
2.0 Hz;18 in our case the measured constant was 1.6 Hz which is
in entire agreement with the literature values. Cross metathesis
of compound 8 and methyl acrylate provided product 9 in 88%
yield.
Scheme 6 Plausible precursors for alkaloid 12.
OH
O
O
H
H
O
TBDPSO
1. TBAF, THF
2. 2,2-dimethoxypropane
TsOH
HN
O
HN
O
BnO
85%
HO
HO
1. SOCl2, EtOH
2. CbzCl, NaHCO3
BnO
OEt
NHCbz
L-dopa
10
8
99%
15
CH3I, K2CO3
or Cs2CO3, BnBr
O
O
O
O
O
R
H
H
H
H
O
RO
RO
RO
RO
OEt
OEt HNO3,AcOH
HN
HN
R
NHCbz
NHCbz
NO2
= Irradiated protons
16a R = Me 85%
16b R = Bn 91%
Jtrans expected = 9.5 Hz
Jcis expected= 1.5 Hz
J found = 1.6 Hz
17a
17b
Fe, AcOH
NHCbz
1. H2, Pd/C
2. BH3.Me2S
RO
RO
NH2
Scheme 4 Confirmation of stereocenters.
RO
N
H
O
RO
N
H
18a 81%
18b 70%
19a 90%
Scheme 7 Synthesis of alkaloid core 19a.
Both approaches are founded on intramolecular cyclizations,
route A is based on a reductive lactamization reaction from the
nitro derivative of L-dopa; on the other hand, an intramolecular
Michael reaction performed with the oxidized intermediate 14
should provide the desired alkaloid (route b, Scheme 6)
Route A (Scheme 7) started with esterification of L-dopa using
the acyl chloride formed in situ, followed by protection of the
amine to provide compound 15 in 99% yield. We then installed
two different protecting groups on the aromatic hydroxyls, and
both methyl 16a and benzyl 16b ethers where obtained in
excellent yields. The literature emphasizes the role of nitrogen
protecting group for the following nitration and reductive
cyclization; apparently Alloc is the only group compatible with
this sequence,21 but in our case the Cbz proved adequate and
the nitro compounds 17a and 17b were obtained in excellent
yields.
Scheme 5 Intramolecular oxa-Michael reaction performed on compound 9.
The intramolecular oxa-Michael reaction is usually performed
with substoichiometric amounts of base and an excess of
benzaldehyde. In this case, the amide proton is acidic enough19
to react with the base, producing undesirable byproducts; in
consequence, a variation to the typical procedure was
necessary. First, we used one equivalent of base to ensure the
complete deprotonation of the amide followed by successive
additions of base and benzaldehyde as is usual in this reaction;
to our delight the benzylidene acetal 11 was obtained as a single
diastereomer and in very good yield (Scheme 5). In summary,
the synthesis of the fully protected polyketide fragment of
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Compounds 17a and 17b were used without further purification without any success. Accordingly, we moved back to compound
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DOI: 10.1039/D0OB00315H
in the cyclisation step; in both cases the reductive cyclisation 19a (see Scheme 8b), which may be used without any
proceeded smoothly and compounds 18a and 18b were purification. Protection of the amine gave compound 23, which
isolated in good overall yields. The lactam reduction on was formylated to afford compound 24; the formamide group
compound 18b proved difficult and complex mixtures of was selectively reduced with BH3.THF complex yielding the
products were obtained in all cases; besides all the attempts for methylated alkaloid 25, and 26 was obtained after phthaloyl
selective cleavage of the carbamate on the same compound cleavage. Efforts to obtain the quaternary salts of compounds
were also unsuccessful. In consequence, compound 18a was 22, 23 and 25 were absolutely impractical, so we started our
deprotected with subsequent reduction of the lactam to afford investigation of route B (see Scheme 6).
the alkaloid core 19a, which was used in subsequent reactions Route B (Scheme 9) started with protection and amidation of L-
without any purification. Unfortunately, the high stability of the dopa, which produced dimethyl amide 27 in 65% yield over two
methyl ethers may be anticipated as a big issue in deprotection steps. Then benzylation of the phenols and a sequence of Boc
experiments, thus taking us to study an alternative route for the cleavage, amide reduction and protection of the primary amine
benzylated analogue (Scheme 8a).
provided the diamine 29 in good overall yield. According to
Direct protection of the amine in L-dopa or its corresponding literature precedents, the ring closure using free hydroxyl
ester with a phthaloyl group was very complicated, so we were groups and dianisyl tellurium oxide (DTO) as the oxidant
forced to perform the following sequence: esterification, then proceeded by a Michael-rearomatization reaction.23 Having in
protection of the amine with a Boc, followed by benzylation and mind the toxicity of the tellurium derivative and that its
Boc cleavage, and finally the free amino group was protected preparation is mandatory and also requires two steps from
using phthalic anhydride to give compound 20 in 80% yield over commercial starting materials,24 we decided to explore other
the five steps (Scheme 8a).
oxidants. Habitually, the oxidation of catechols is accomplished
25
using NaIO4 or Ag2O;26 however, those reagents as well as
a.
O
1. SOCl2, EtOH
2. Boc2O, NaHCO3
3. BnBr, K2CO3
4. TFA, DCM
hypervalent iodine reagents were inactive with our substrate.
Inspired by the work of ElSohly and Francis,27 we used
BnO
BnO
OEt
L-dopa
NPht
5. Phthalic anhydride
1
K3[Fe(CN)6], observing the desired hydroquinoline salt by H
20 80% for five steps
NMR of the crude reaction mixture, but its isolation was
problematic. Freeze-drying of the aqueous phase followed by
benzylation afforded the Boc protected quaternary salt in
higher yield compared with the use of DTO.
1. HNO3,AcOH
2. Fe, AcOH
1. NH2NH2, EtOH
2. BH3.Me2S
3. NBoc-OBn L-ser
NMM, CBzCl
BnO
BnO
NPht
N
O
NHBoc
H
H
At this point we had in hand the three fragments of anachelin H
and some analogues, particularly the tertiary amine 26.
Previous works on anachelin H synthesis are based on the
construction of alkaloid-peptide fragment by growing the
peptide using the alkaloid as a template, which means the
alkaloid fragment is usually obtained with one amino acid
attached to it (similar to compound 22), then a dipeptide is
introduced to produce the desired fragment, and posterior
coupling with the polyketide leads to the synthesis of the
natural product. Having this in mind, we were interested in the
coupling of the alkaloid and peptide fragments, in order to
demonstrate that our strategy is more convergent than the
previously reported approaches.
21 55% for two steps
BnO
BnO
N
OBn
O
N
H
22 45% for three steps
b.
MeO
NH2
MeO
NPht
Phthalic anhydride
65%
MeO
N
H
MeO
N
H
23
19a
AcOH
HCHO
90%
MeO
MeO
NPht
MeO
MeO
NPht
BH3 THF
70%
N
N
25
24
H2NNH2
99%
O
H
MeO
MeO
NH2
We prepared the alkaloid-peptide fragment of anachelin H
using carbonyl imidazole as the coupling auxiliary, leading to
compound 31 in reasonable yield (Scheme 10a). We also
performed the saponification of the polyketide ester to acid 32,
followed by its coupling with a dipeptide to afford compound
33, which illustrates the potential construction of the natural
N
26
Scheme 8 a. Alternative route to alkaloid fragment. b. methylation of secondary
nitrogen.
The nitration and successive reductive cyclisation provided the
protected lactam 21 in good yield. All our attempts to reduce
the lactam were ineffective, with reduction of the phthalimide
as a side reaction. We thus cleaved the phthaloyl group,
reduced the lactam and inserted the L-serine fragment using
the mixed anhydride technique22 with CbzCl, producing an
advanced fragment of anachelin H in 45% yield (compound 22),
but a significant amount of the regioisomer was observed. We
then tried the formation of the quaternary salt of anachelin H
product following
a convergent strategy based on the
independent construction of the three fragments. The same
coupling between the alkaloid analogue 26 and peptide 2 was
performed, yielding fragment 34; this could be linked to the
polyketide fragment in acceptable yield, to produce the fully
protected analogue 35. It is noteworthy to mention that
transformations in Schemes 10 and 11 help to demonstrate
coupling of fragments, affording advanced material in the
potential synthesis of the natural product
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O
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HO
HO
1. Boc2O, NaOH
2. NHMe2, NMM, CbzCl
DOI: 10.1039/D0OB00315H
N
L-Dopa
HN
Boc
27 65% over two steps
BnBr, Cs2CO3
95%
O
NMe2
BnO
BnO
BnO
1. TFA
2. BH3.Me2S
3. Boc2O
N
NHBoc
HN
Boc
BnO
28
29 65% over three steps
1. H2, Pd/C
2. Oxidant, lyophilisation
3. BnBr, Cs2CO3
BnO
NHBoc
Oxidant and yield over three steps:
DTO: 40%
K3[Fe(CN)6]: 55%
30
BnO
N
Br-
Me2
Scheme 9 Synthesis of alkaloid fragment of anachelin H.
Scheme 11 Coupling experiments.
Experimental section
General information. All reactions were performed under
argon atmosphere. All solvents were distilled from appropriate
drying agents prior to use. All reagents were used as received
from commercial suppliers. Reactions progress was monitored
by thin layer chromatography (TLC) performed on aluminum
plates coated with silica gel F254 with 0.2 mm thickness. Flash
column chromatography was performed using silica gel 60 (230-
400 mesh). Neat infrared spectra were recorded using a
THERMO NICOLET-NEXUS (FT-IR) with PIKE MIRacle ATR cell.
Wavenumbers (νmax) are reported in cm-1. High Resolution
Mass spectrometry was recorded using a Finnigan MAT 8200 or
(70 eV) or an Agilent 5973 (70 eV) spectrometer, using
electrospray ionization (ESI). All 1H NMR and 13C NMR spectra
were recorded using a BRUKER Avance III HD Ascend 400
spectrometer. Chemical shifts were given in parts per million
(ppm, δ), referenced to the TMS, solvent peak of CDCl3 defined
at δ = 7.26 ppm (1H NMR) and δ = 77.16 (13C NMR). Coupling
constants are quoted in Hz (J). 1H NMR splitting patterns were
designated as singlet (s), broad singlet (bs), doublet (d), triplet
(t), quartet (q), double quartet (dq), and multiplet (m). Splitting
patterns that could not be interpreted or easily visualized were
designated as multiplet (m).
Scheme 10 Coupling experiments.
Conclusions
The synthesis of all three fragments of anachelin H was completed,
along with the synthesis of advanced portions of the target molecule.
The preparation of all the fragments was achieved using amino acids
as starting materials, thus making this route inexpensive and
potentially scalable. We also described the use potassium
ferricyanide - a cheaper and less toxic reagent - as an alternative to
the use of DTO (dianisyl tellurium oxide) for the crucial cyclisation
step in the alkaloid synthesis. The synthesis of the fully protected
polyketide fragment is also described by a shorter reaction sequence
compared with previous reports.
L-Ser(OBn)-D-Ser(OBn)-BocL-Thr(OBn) methyl ester (2). Boc-D-
Ser-(Bzl)-OH (960 mg, 3.25 mmol) was dissolved in dry DMF (6.0
mL), and BOP reagent (1.36 g, 2.95 mmol) and O-Bzl-L-Serine
methyl ester (730 mg, 2.95 mmol) were successively added.
After 5 min, DIPEA (1.42 mL, 8.12 mmol) was added, and the
reaction mixture was stirred at room temperature for 24 hours,
then saturated aqueous NaHCO3 was added. The mixture was
extracted with DCM (3 x 20 mL), the organic phases were
combined, washed three times with water, brine, aqueous
KHSO4 (1.0 M), dried over anhydrous Na2SO4 filtered and
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concentrated in vacuo. The crude dipeptide was used without NaHCO3 was added, and the aqueous phase was eVxiterwaAcrttieclde Ownilitnhe
DOI: 10.1039/D0OB00315H
further purification. It was dissolved in dry DCM (15 mL), then DCM (3 x 20 mL). The combined organic phases were washed
cooled to 0 °C, and TFA (3.5 mL, 45 mmol) was slowly added. with brine, dried over anhydrous Na2SO4, filtered and
The reaction mixture was stirred for 2.5 hours, the volatiles concentrated in vacuo, and the crude product was purified by
were evaporated. The crude product was directly used in the flash chromatography (CHX : DCM 1 : 10) to give the titled
next step, dissolving it in dry DMF (6.0 mL) and mixing it with compound as a colorless oil (2.85 g, 99% yield). [α]D21.7: -1.4 (c
BOP Reagent (1.43 g, 3.25 mmol). Then Boc-L-Thr-(Bzl)-OH (1.05 1.0, CHCl3). IR (neat): 3392, 2953, 2931, 2856, 1745, 1651, 1209,
g, 3.25 mmol) and DIPEA (1.42 mL, 8.12 mmol) were 1047, 733 cm -1. 1H NMR (400 MHz, CDCl3), : 8.91 (d, J = 7.7 Hz,
successively added, the reaction mixture was stirred for 12 1H), 8.18 (dd, J = 7.8, 1.9 Hz, 1H), 7.49 – 7.59 (m, 4H), 7.20 – 7.42
hours, and saturated aqueous NaHCO3 was added. The mixture (m, 12H), 7.05 (m, 1H), 6.95 (dd, J = 8.4, 1 Hz, 1H), 5.23 (q, J =
was extracted with DCM (3 x 20 mL), the organic phases were 12.8 Hz, 2H), 4.92 – 4.97 (m, 1H), 4.10 (dd, J = 10.1, 3.3 Hz, 1H),
combined, washed with saturated aqueous NaHCO3, brine, 3.97 (dd, J = 10.1, 3.3 Hz, 1H), 3.68 (s, 3H), 0.95 (s, 9H). 13C NMR
dried over anhydrous Na2SO4 filtered and concentrated in (100 MHz, CDCl3), : 171.0, 164.8, 156.9, 135.8, 135.5, 135.4,
vacuo. The crude product was purified by flash chromatography 133.1, 132.9, 132.5, 129.8, 129.7, 128.7, 128.1, 127.7, 127.6,
(DCM : EtOAc 30:1) to give the desired compound as a white 127.2, 121.4, 113.2, 70.9, 64.4, 60.4, 54.9, 52.2, 26.9, 26.6, 19.2.
21.7
solid. Melting point 127-129 °C. (1.54 g, 70% yield). [α]D
:
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C34H38NO5Si 568.2514;
+19.8 (c 0.66, CHCl3). IR (neat): 3294, 2926, 1747, 1635, 1390, found 568.2510.
1247, 1056 cm-1. 1H NMR (400 MHz, CDCl3), δ: 7.17 – 7.42 (m, (R)-2-(Benzyloxy)-N-(1-((tert-butyldiphenylsilyl)oxy)-3-
17 H), 5.50 (d, J = 7.1 Hz, 1H), 4.70 – 4.77 (m, 1H), 4.66 (m, 1H), hydroxypropan-2-yl)benzamide (7). To a 0 °C solution of the
4.54 (m, 2H), 4.50 (s, 1H), 4.38 - 4.48 (m, 3H), 4.30 (d, J = 5.5 Hz, protected L-serine methyl ester derivative (6) (2.02 g, 3.5
1H), 4.18 (d, J = 4.3 Hz, 1H), 3.86 (m, 2H), 3.68 (s, 3H), 3.64 (dd, mmol), in dry ethanol (13.0 mL), was added CaCl2 (800 mg, 7
J = 9.5, 3.5 Hz, 1H), 3.54 (dd, J = 9.3, 6.7 Hz, 1H), 1.44 (s, 9H), mmol), keeping the same temperature, and NaBH4 (540 mg, 14
1.14 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3), : 170.4, mmol). The reaction mixture was slowly warmed up to room
170.2, 169.5, 155.9, 137.9, 137.5, 137.4, 128.4, 128.3, 128.3, temperature and stirred for 18 hours, poured into ice/citric acid
127.8, 127.8, 127.7, 127.7, 127.6, 80.2, 74.3, 73.4, 73.2, 71.5, mixture and extracted with AcOEt (3 x 20 mL). The combined
69.3, 69.1, 58.1, 52.9, 52.8, 52.5, 28.3, 15.8. HRMS (ESI-TOF) organic phases were washed with saturated aqueous NaHCO3,
m/z: [M+H] Calcd for C37H48N3O9 678.3385; found 678.3380.
brine and dried over anhydrous Na2SO4. Filtration and
Methyl (2-(benzyloxy)benzoyl)-L-serinate (5). To a 0 °C solution evaporation of the solvent afforded the product as a colorless
of 2-benzyloxy benzoic acid (3.75 g, 15.7 mmol) in cyclohexane oil (1.92 g, 99 % yield). [α]D21.7: -22.8 (c 1.0, CHCl3). IR (neat):
(60 mL), DMF (0.10 mL) was added, and after 2 min oxalyl 3392, 2854, 1639, 1520, 1228, 1112, 740 cm -1. 1H NMR (400
chloride (4.20 mL, 50 mmol) was added dropwise. The reaction MHz, CDCl3),  : 8.26 (d, J = 7.7 Hz, 1H), 8.09 (dd, J = 7.8, 1.3 Hz,
mixture was then refluxed for 12 hours, and the crude acid 1H), 7.50 (dd, J = 9.6, 8.0 Hz, 4H), 7.11 – 7.32 (m, 12H), 6.95 (t, J
chloride obtained after concentration was dissolved in 25 mL of = 7.6 Hz, 1H) 6.87 (d, J = 8.3 Hz, 1H), 5.00 (d, J = 1.8 Hz, 2H), 4.11
dry dioxane. The L-serine methyl ester hydrochloride (2.44 g, – 4.22 (m, 1H), 3.50 – 3.75 (m, 4H), 2.65 – 2.92 (bs, 1H), 0.90 (s,
15.7 mmol) was dissolved in 100 mL of dry dioxane and freshly 9H). 13C NMR (100 MHz, CDCl3), : 165.7, 156.8, 135.6, 135.5,
distilled triethylamine (7.60 mL, 55 mmol) was slowly added, 135.5, 133.1, 132.9, 132.8, 132.4, 129.8, 129.8, 128.7, 128.5,
then the initial solution of the acid chloride was slowly added 127.8, 127.7, 127.6, 121.8, 121.6, 112.9, 71.3, 63.6, 63.6, 60.4,
and the reaction mixture was stirred at room temperature for 52.8, 26.8, 19.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
12 hours. It was filtered and extracted with DCM (3 x 20 mL), C33H38NO4Si 540.2565; found 540.2550.
and the combined organic extracts were washed with brine, 2-(Benzyloxy)-N-((2S,3S)-1-((tert-butyldiphenylsilyl)oxy)-3-
dried over anhydrous Na2SO4, filtered and evaporated under hydroxyhex-5-en-2-yl)benzamide (8). a) Swern oxidation. To a
reduced pressure. The crude product was purified by flash solution of oxalyl chloride (0.13 mL, 1.56 mmol) in dry DCM (2.0
chromatography (DCM : EtOAc 2:10) to give the desired mL) at -63 ºC was slowly added dry dimethyl sulfoxide (0.14 mL,
compound as a yellow solid. (3.36 g, 65 % yield). The 2.07 mmol) dissolved in dry DCM (1.0 mL). The reaction mixture
spectroscopy data and physical constants of (5) were in good was stirred at -63 °C for 30 min, then a solution of L-serine
agreement with those reported in the literature.28 Melting derivative alcohol (7) (280 mg, 0.52 mmol) in dry DCM (1.0 mL)
28
point: 130°C. lit. 129°C. [α]D21.7: +26.4 (c 1.0, CHCl3). Lit. [α] was added dropwise. The mixture was stirred for 2 hours
1
26: +25.33 (c 1.4, MeOH). H NMR (400 MHz, CDCl3), : 8.70 (d, keeping the same temperature, after that, freshly distilled
D
J = 6.5 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.29 – 7.44 (m, 6H), 7.01 triethylamine (0.43 mL, 3.12 mmol) was slowly added, and the
(m, 2H), 5.21 – 5.13 (m, 2H), 4.77 (dt, J = 7.5, 3.9 Hz, 1H), 3.83 reaction mixture was slowly warmed up to room temperature.
(dd, J = 9.1, 4.8 Hz, 2H), 3.62 (s, 3H), 2.11 (s, 1H).
It was then diluted with DCM and washed with 10% aqueous
Methyl N-(2-(benzyloxy)benzoyl)-O-(tert-butyldiphenylsilyl)- HCl, then saturated aqueous NaHCO3, and brine. The combined
L-serinate (6). To a stirred solution of the L-serine ester organic extracts were dried over anhydrous Na2SO4, filtered and
derivative (5) (1.66 g, 5 mmol) in dry DCM (20 mL), imidazole concentrated in vacuo. The crude aldehyde was kept at -20 °C
(410 mg, 6 mmol) and TBDPSCl (1.50 mL, 5.5 mmol) were and directly used without further purification. b) Roush
successively added, and the reaction mixture was stirred at allylation. The crude aldehyde (280 mg, 0.52 mmol) was
room temperature for 24 hours. Then saturated aqueous dissolved in dry toluene (3.0 mL), and warmed up to room
6 | J. Name., 2012, 00, 1-3
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temperature, then 0.15 g of activated 4 Ǻ molecular sieves were at room temperature, 2,2 dimethoxypropane (0V.3ie5w AmrticLle, O2n.l8in8e
DOI: 10.1039/D0OB00315H
added, and the mixture was stirred for 30 min. It was then mmol) and p-toluenesulfonic acid (7 mg, 0.03 mmol) were
cooled to -78 °C and Roush allylboronate solution29 (approx. successively added, and the reaction mixture was stirred for 24
0.54 mmol of Roush allyboronate per milliliter, 1.85 mL, 1 hours. Then saturated aqueous NaHCO3 was added, and the
mmol) was added dropwise. The reaction mixture was stirred aqueous phase was extracted with AcOEt (3 x 10 mL). The
for 8 hours at –78 °C, and slowly warmed up to room combined organic phases were washed with brine, dried over
temperature and stirred for 3 hours. The residue was filtered, anhydrous Na2SO4 and concentrated in vacuo. The crude
diluted with ether and mixed with 30 mL of 1 M aqueous NaOH, product was purified by flash chromatography (DCM: EtOAc 6:1)
under vigorous stirring for 1 hour. The phases were separated to give the title compound as a yellow oil (120 mg, 85% yield).
and the aqueous one was extracted with ether, the combined [α]D19: +6.6 (c 2.4, CHCl3). IR (neat): 3321, 2891, 1655 516, 1308,
organic phases were washed with NaHCO3, brine, dried over 1212 cm-1. 1H NMR (400 MHz, CDCl3), : 8.58 (d, J = 8.7 Hz, 1H),
anhydrous Na2SO4, filtered and concentrated in vacuo. The 8.21 (dd, J = 7.8, 1.4 Hz, 1H), 7.30 – 7.45 (m, 6H,), 6.93 – 7.16
crude product was purified by flash chromatography (CHX : (m, 2H), 5.61 – 5.88 (m, 1H), 5.28 (s, 2H), 5.05 (d, J = 5.7 Hz, 1H),
DCM 1 : 80) to give the desired compound as a colorless oil and 5.02 (s, 1H), 4.06 – 4.19 (m, 2H), 4.01 (t, J = 6.2 Hz, 1H), 3.84 (d,
as a single diastereomer (150 mg, 50% yield). [α]D21.7: + 22.0 (c J = 11.9 Hz, 1H), 2.14 (t, J = 6.9 Hz, 2H), 1.44 (s, 3H), 1.22 (s, 3H).
1.0, CHCl3). IR (neat): 3391, 2955, 2928, 2856, 1639, 1619, 1427, 13C{1H} NMR (100 MHz, CDCl3), : 165.1, 156.7, 135.5, 133.7,
1111, 997 cm -1. 1H NMR (400 MHz, CDCl3), : 8.46 (d, J = 8.3 Hz, 132.7, 132.4, 128.9, 128.4, 127.9, 122.0, 121.4, 117.4, 112.8,
1H), 8.20 (dd, J = 7.8, 1.9 Hz, 1H), 7.56 – 7.63 (m, 4H), 7.19 – 7.44 98.9, 71.1, 71.1, 64.9, 45.7, 36.4, 29.7, 18.6. HRMS (ESI-TOF)
(m, 14H), 5.73 – 5.85 (m, 1H), 5.20 (q, J = 11.8 Hz, 2H), 5.00 – m/z: [M+H]+ Calcd for C23H28NO4 382.2013; found 382.2020.
5.08 (m, 2H), 4.16 – 4.24 (m, 1H), 4.06 (t, J = 6.7 Hz, 1H), 3.85 Methyl
2-((2S,4R,6S)-6-((S)-1-(2-(benzyloxy)benzamido)-2-
(qd, J = 10.3, 4.5 Hz, 2H), 2.78 (d, J = 2.3 Hz, 1H), 2.20 (t, J = 6.8 ((tert-butyldiphenylsilyl)oxy)ethyl)-2-phenyl-1,3-dioxan-4-
Hz, 2H), 1.00 (s, 9H). 13C NMR (100 MHz, CDCl3), : 165.3, 156.8, yl)acetate (11). To a 0°C stirred solution of the homoallylic
135.5, 135.4, 134.5, 132.7, 132.6, 132.5, 129.8, 129.7, 128.7, alcohol (9) (100 mg, 0.15 mmol) in dry THF (1.5 mL) was added
128.4, 127.9, 127.8, 127.7, 121.9, 121.4, 117.7, 112.7, 71.4, freshly distilled benzaldehyde (0.02 mL, 0.17 mmol). After 5 min
71.1, 65.6, 53.2, 38.6, 29.7, 26.8, 19.1. HRMS (ESI-TOF) m/z: t-BuOK (20 mg, 0.15 mmol) was added, the mixture was stirred
[M+H]+ Calcd for C36H42NO4Si 580.2878; found 580.2880.
Methyl (5S,6S,E)-6-(2-(benzyloxy)benzamido)-7-((tert- (0.02 mL, 0.17 mmol) was added followed by t-BuOK (2 mg, 0.01
butyldiphenylsilyl)oxy)-5-hydroxyhept-2-enoate (9). To mmol). The resulting solution was stirred for 15 min at 0 °C. This
at the same temperature for 20 min, after that, benzaldehyde
a
room temperature solution of the homoallylic alcohol (8) (380 sequence (addition/stirring) was repeated three times. The
mg, 0.66 mmol), in dry DCM (12 mL), methyl acrylate (0.3 mL, reaction mixture was quenched with saturated aqueous NH4Cl.
3.3 mmol) and Grubbs II catalyst (30 mg, 0.02 mmol) were The aqueous phase was extracted with diethyl ether (3 x 10 mL)
successively added, and the reaction mixture was refluxed for and the combined organic extracts were washed with brine,
12 hours. It was then concentrated in vacuo and directly dried over anhydrous Na2SO4, filtered and concentrated. The
purified by flash chromatography (DCM : EtOAc 1:20), affording crude product was purified by flash chromatography (DCM) to
the product as a colorless oil (370 mg, 88% yield). [α]D21.7: +3.0 give the titled compound as a yellow oil (90 mg, 80% yield).
(c 1.0, CHCl3). IR (neat). 3358, 2933, 2901, 2866, 1697, 1573, [α]D21.7: +13.6 (c. 0.8 CHCl3). IR (neat): 3210, 2981, 2821, 2832,
1411, 1284, 1188, 995, 740. cm -1. 1H NMR (400 MHz, CDCl3), : 1721, 1511, 1256, 1238, 859, 741cm-1. 1H NMR (400 MHz,
8.38 (d, J = 8.2 Hz, 1H), 8.11 (dd, J = 7.8, 1.8 Hz, 1H), 7.46 – 7.56 CDCl3), : 8.18 (dd, J = 15.8, 8.4 Hz, 2H), 7.63 (dd, J = 18.9, 7.1
(m, 4H), 7.13 – 7.37 (m, 12H), 6.95 – 7.04 (m, 2H), 6.80 - 6.93 Hz, 4H), 7.00 – 7.42 (m, 18H), 6.90 (d, J = 8.3 Hz, 1H), 5.53 (s,
(m, 1H), 5.74 (d, J = 15.6 Hz, 1H), 5.10 (q, J = 11.6 Hz, 2H), 4.01 1H), 4.99 (m, 2H), 4.43 – 4.58 (m, 2H), 4.38 (m, 1H), 3.61 – 3.81
– 4.12 (m, 2H), 3.76 (d, J = 4.4 Hz, 2H), 3.61 (s, 3H), 2.82 (d, J = (m, 5H), 2.66 (dd, J = 15.8, 7.5 Hz, 1H), 2.48 (dd, J = 15.8, 5.4 Hz,
2.9 Hz, 1H), 2.22 (t, J = 6.7 Hz, 2H), 0.93 (s, 9H). 13C NMR (100 1H), 1.64 – 1.77 (m, 2H), 1.05 (s, 9H). 13C NMR (100 MHz, CDCl3),
MHz, CDCl3), : 166.7, 165.4, 156.9, 145.4, 135.5, 135.5, 135.4, : 171.1, 165.4, 156.6, 138.3, 135.6, 135.6, 135.5, 133.4, 133.3,
132.9, 132.7, 132.6, 132.5, 129.9, 129.9, 128.8, 128.6, 128.0, 132.7, 132.3, 129.7, 129.6, 128.6, 128.2, 128.0, 127.7, 127.7,
127.8, 127.8, 127.7, 127.7, 123.1, 121.7, 121.4, 112.7, 71.2, 127.1, 126.0, 121.9, 121.4, 113.0, 100.4, 73.6, 73.2, 70.8, 61.5,
70.6, 65.4, 53.8, 51.3, 37.1, 26.9, 19.1. HRMS (ESI-TOF) m/z: 53.6, 51.7, 40.8, 32.9, 26.9, 19.3. HRMS (ESI-TOF) m/z: [M+H]+
[M]+ Calcd for C38H43NO6Si 637.2860; found 637.2862.
N-((4S,5S)-4-allyl-2,2-dimethyl-1,3-dioxan-5-yl)-2-
Calcd for C45H50NO7Si 744.3351; found 744.3367.
Ethyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(3,4-
(benzyloxy)benzamide (10). To solution of the protected dihydroxyphenyl)propanoate (15). To a 0 °C stirred suspension
alcohol (8) (210 mg, 0.36 mmol) in dry THF (4 mL) at 0 ºC, 1.0 M of L-dopa (1.5 g, 7.6 mmol) in dry EtOH (40.0 mL) was dropwise
TBAF in THF (0.6 mL, 0.6 mmol) was slowly added. The reaction added thionyl chloride (1 mL, 13.7 mmol). After 15 min, the
mixture was stirred for 4 hours at the same temperature, slowly mixture was refluxed for 24 hours, then, the excess of thionyl
warmed up to room temperature, diluted with water and chloride was removed under an air flux and the resulting white
extracted four times with AcOEt. The combined organic phases solid was dried for 3 hours under high vacuum. The solid was
were washed with saturated aqueous NaHCO3, brine, dried over dissolved in water (50 mL), and NaHCO3 (1.27 g, 15.2 mmol) and
anhydrous Na2SO4, filtered and concentrated in vacuo. The benzyl chloroformate (1.2 mL, 9.12 mmol) dissolved in THF (20
crude product was directly dissolved in 4 mL of dry THF, then, mL), were successively added. The reaction mixture was stirred
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for 24 hours. The volatiles were evaporated, and the aqueous (2.2 mL), then, concentrated aqueous nitric acid (0.80 mL, 13.3
View Article Online
DOI: 10.1039/D0OB00315H
phase was extracted with EtOAc (3 x 15 mL). The combined mmol) dissolved in glacial acetic acid (2 mL) was added
organic phases were washed with water, 5% aqueous HCl, dropwise. The reaction mixture was stirred at 0 °C for 2 hours,
brine, dried over anhydrous Na2SO4 and concentrated in vacuo, water was added, and the mixture was filtered. The obtained
affording the title compound as a colorless oil (2.72 g, 99 % solid was dried under high vacuum and directly dissolved in
yield). [α]D18: + 28.2 (c. 2,8 CHCl3). IR (neat): 3250, 2981, 1731, glacial acetic acid (4 mL). The mixture was heated at 80 °C, then
1511, 1223, 1157 cm-1. 1H NMR (400 MHz, CDCl3), : 7.15 – 7.45 iron powder (1.09 g, 19.5 mmol) was added in three portions.
(m, 5H), 6.56 – 6.78 (m, 2H), 6.47 (dd, J = 8.0, 1.5 Hz, 1H), 5.42 After 2 hours of reflux, the cold reaction mixture was filtered
– 5.52 (m, 1H), 5.05 (s, 2H), 4.49 – 4.62 (m, 1H), 4.06 – 4.18 (m, through a pad of celite, poured into water and 6 M aqueous
2H), 2.94 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, NaOH was added until pH 14. The aqueous layer was extracted
CDCl3), : 172.0, 156.1, 143.9, 143.2, 136.0, 128.5, 128.2, 128.1, with EtOAc (3 x 5 mL). The combined organic layers were dried
127.9, 121.5, 116.2, 115.3, 67.2, 61.8, 55.0, 37.6, 14.1. HRMS over anhydrous Na2SO4, filtered and concentrated in vacuo. The
(ESI-TOF) m/z: [M+H]+ Calcd for C19H22NO6 360.1442; found product was obtained after column chromatography (DCM :
360.1439.
Ethyl
EtOAc 10:3) as a white solid (310 mg, 81% yield). Melting point:
(S)-2-(((benzyloxy)carbonyl)amino)-3-(3,4- 171°C. [α ]18D: - 28.8 (c 0.3, CHCl3). IR: 16725, 1698, 1505, 1260,
dimethoxyphenyl)propanoate (16a). N-Cbz L-dopa ethyl ester 1095 cm-1. 1H NMR (400 MHz, CDCl3), : 9.20 (s, 1H), 7.24 – 7.44
(15) (470 g, 1.30 mmol) was dissolved in dry acetone (20 mL), (m, 5H), 6.68 (s, 1H), 6.42 (s, 1H), 6.03 (d, J = 5.3 Hz, 1H), 5.14 (s,
then dry K2CO3 (1.55 g, 11.1 mmol) was added, and after 5 min, 2H), 4.38 (m, 1H), 3.82 (s, 3H), 3.83 (s, 3H), 3.36 (dd, J = 12.9, 6.1
iodomethane (1.38 mL, 22 mmol) was added dropwise. The Hz, 1H), 2.78 (t, J = 5.8 Hz, 1H). 13C NMR (100 MHz, CDCl3), :
reaction mixture was stirred at reflux for 6 hours. Then it was 169.6, 157.2, 156.2, 148.7, 145.2, 136.2, 128.5, 128.2, 128.1,
filtered, and the filtrate was concentrated in vacuo then 114.0, 111.9, 100.7, 67.0, 56.3, 56.2, 50.5, 31.9. HRMS (ESI-TOF)
dissolved in EtOAc. This organic phase was washed with water, m/z: [M+H]+ Calcd for C19H21N2O5 357.1445; found 357.1454.
brine, dried over anhydrous Na2SO4, affording the product as a Benzyl
(S)-(6,7-bis(benzyloxy)-2-oxo-1,2,3,4-
colorless oil (420 mg, 85% yield). [α]D18: +34.0 (c 4.4, CHCl3), : tetrahydroquinolin-3-yl)carbamate (18b). The protected L-
IR: 1747, 1695, 1516, 1456, 1271, 1139, 1026 cm-1. 1H NMR (400 dopa derivative (16b) (120 mg, 0.22 mmol) was dissolved at 0
MHz, CDCl3) 7.25 – 7.40 (m, 5H), 6.76 (d, J = 8.1 Hz, 1H), 6.58 – °C in glacial acetic acid (1.0 mL), then concentrated aqueous
6.70 (m, 2H), 5.24 (d, J = 7.7 Hz, 1H), 5.10 (m, 2H), 4.52 – 4.68 nitric acid (0.15 mL, 13.3 mmol) dissolved in glacial acetic acid
(m, 1H), 4.17 (dd, J = 14.3, 7.2 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H), (1.0 mL) was added dropwise. The reaction mixture was stirred
3.06 (t, J = 5.8 Hz, 2H), 1.25 (t, J = 7.1, Hz, 3H). 13C NMR (100 at 0 °C for 3 hours, water was added, and the mixture was
MHz, CDCl3), : 171.8, 155.9, 148.9, 148.1, 136.5, 128.5, 128.4, filtered. The obtained solid was dried under high vacuum and
128.0, 127.9, 121.4, 112.5, 111.3, 111.0, 66.7, 61.4, 55.7, 55.6, directly dissolved in glacial acetic acid (2.0 mL). The mixture was
55.2, 37.6, 14.1. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for heated at 80 °C, and iron powder (220 mg, 3.9 mmol) was added
C21H25NNaO6 410.1574; found 410.1595.
in one portion. After 1.5 hours of reflux, the cold reaction
Ethyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(3,4- mixture was filtered through a pad of celite, poured into water,
bis(benzyloxy)phenyl)propanoate (16b). N-Cbz L-dopa ethyl and 6 M aqueous NaOH was added until pH 14. The aqueous
ester (15) (1.20 g, 3.33 mmol) was dissolved in dry acetone (50.0 layer was extracted with EtOAc (3 x 5 mL). The combined
mL), then K2CO3 (1.55 g, 13.3 mmol) was added, and after 5 min organic layers were dried over anhydrous Na2SO4, filtered and
benzyl bromide (1.4 mL, 11.6 mmol) and NaI (0.05 g, 0.33 mmol) concentrated in vacuo. The product was obtained after column
were successively added. The reaction mixture was stirred at chromatography (DCM : EtOAc 10:1) as a brown oil (79 mg, 70%
reflux for 30 hours. The solvent was evaporated, the residue yield). [α ]18D: +12.6 (c 0.6, CHCl3). IR (neat): 1716, 1685, 1508,
was dissolved in DCM, washed with water, 5% HCl and brine, 1388, 1226 cm-1. 1H NMR (400 MHz, CDCl3), : 7.74 (s, 1H), 7.22
dried over anhydrous Na2SO4 and concentrated in vacuo. The – 7.48 (m, 15H), 6.78 (s, 1H), 6.37 (s, 1H), 5.85 (s, 1H), 5.11 (m,
crude product was purified by flash chromatography (CHX : 6H), 4.34 (m, 1H), 3.36 (dd, J = 14.3, 5.2 Hz, 1H), 2.74 (t, J = 14.6
DCM 1:1) to give the title compound as a white solid (1.60 g, Hz, 1H). 13C NMR (100 MHz, CDCl3), : 169.4, 156.1, 148.7,
91% yield). Melting point: 140°C. [α ]18D: +25.3 (c 0.6, CHCl3). IR: 145.1, 137.1, 136.8, 136.2, 130.0, 128.6, 128.6, 128.2, 128.2,
1747, 1681, 1523, 1454, 1276 cm-1. 1H NMR (400 MHz, ), : 7.36 128.1, 128.0, 127.4, 127.3, 116.0, 115.0, 103.8, 72.0, 71.5, 67.0,
(m, 15H), 6.82 (d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 6.62 (d, J = 8.1 Hz, 50.4, 31.8.
1H), 5.02 – 5.20 (m, 7H), 4.57 (d, J = 6.6 Hz, 1H), 4.00 – 4.15 (m, HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H29N2O5 509.2071;
2H), 3.00 (d, J = 5.3 Hz, 2H), 1.18 (t, J = 7.0 Hz, 3H). 13C NMR (100 found 509.2073.
MHz, CDCl3), : 171.5, 155.6, 148.9, 148.2, 137.3, 137.1, 136.2, Ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-(1,3-dioxoisoindolin-2-
129.0, 128.5, 128.5, 128.2, 128.1, 127.8, 127.8, 127.3, 127.3, yl)propanoate (20). To a 0 °C stirred suspension of L-dopa (1.5
122.4, 116.2, 115.1, 71.3, 66.9, 61.4, 54.8, 37.8, 14.1. HRMS g, 7.6 mmol) in dry EtOH (40 mL) was added dropwise thionyl
(ESI-TOF) m/z: [M+H]+ Calcd for C33H34NO6 540.2381; found chloride (1 mL, 13.7 mmol). After 15 min, the mixture was
540.2377.
refluxed for 24 hours, then, the excess of thionyl chloride was
Benzyl (S)-(6,7-dimethoxy-2-oxo-1,2,3,4-tetrahydroquinolin- removed with an airflow and the resulting white solid was dried
3-yl)carbamate (18a). The protected L-dopa derivative (16a) for 3 hours under vacuum. It was then dissolved in water (50
(420 mg, 1.08 mmol) was dissolved at 0 °C in glacial acetic acid mL) and NaHCO3 (1.3 g, 15.2 mmol) and Boc2O (1.84 g, 8.4
8 | J. Name., 2012, 00, 1-3
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mmol), previously dissolved in 25 mL of THF, were successively = 5.1, 3.2 Hz, 2H), 7.71 (dd, J = 5.1, 3.2 Hz, 2H), 7V.3ie6w A(mrtic,le1O0nHlin)e,
added. The reaction mixture was stirred at room temperature 6.73 (s, 1H), 6.38 (s, 1H), 5.10 (m, 5H), 3D.8O7I:(1t0,.J10=391/5D.00OHB0z,0311H5H),
for 16 hours, the volatiles were evaporated, and the aqueous 2.84 (dd, J = 14.9, 6.7 Hz, 1H). 13C NMR (100 MHz, CDCl3), :
phase was extracted with EtOAc (3 x 15 mL). The combined 167.7, 166.4, 148.9, 144.8, 137.1, 136.7, 134.2, 131.9, 130.5,
organic phases were washed with water, 5% aqueous HCl, 128.6, 128.5, 128.0, 127.9, 127.4, 127.4, 123.6, 116.2, 114.0,
brine, dried over anhydrous Na2SO4 and concentrated in vacuo, 103.6, 72.3, 71.5, 48.7, 29.4. HRMS (ESI-TOF) m/z: [M+H]+Calcd
affording N-protected L-dopa ester intermediate, which was for C31H25N2O5 505.1758; found 505.1763.
directly dissolved in acetone (35 mL). K2CO3 (2.6 g, 19 mmol) tert-Butyl ((S)-3-(benzyloxy)-1-(((S)-6,7-bis(benzyloxy)-1,2,3,4-
and BnBr (2 mL, 16.7 mmol) were successively added, and the tetrahydroquinolin-3-yl)amino)-1-oxopropan-2-yl)carbamate
reaction mixture was refluxed for 48 hours. The solvent was (22). The protected tetrahydroquinolin derivative (21) (136 mg,
evaporated, the residue was dissolved in DCM, and the organic 0.27 mmol) was dissolved in dry EtOH (5.0 mL), then hydrazine
phase was washed with water, brine and concentrated in vacuo. hydrate (0.1 mL, 3.2 mmol) was added. The reaction mixture
The obtained solid was repeatedly washed with cold MeOH (-15 was refluxed for 40 hours, cooled and diluted with EtOH, then it
°C), dried under high vacuum and directly dissolved in dry DCM was filtered. The filtrate was concentrated in vacuo and the
(40 mL). The solution was cooled to 0 °C and TFA (6.2 mL, 80 deprotected product was directly dissolved in dry THF (10.0 mL)
mmol) was slowly added. The reaction mixture was stirred at and the resulting solution cooled at 0 °C. Then 2 M BH3-SMe2 in
this temperature for 2 hours, warmed up to room temperature THF (1 mL, 2 mmol) was slowly added, and the reaction mixture
and stirred for 24 hours. The volatiles were evaporated, and the was refluxed for 30 hours. It was then cooled at 0 °C and 5 mL
residue was dissolved in DCM, then saturated aqueous NaHCO3 of 10% aqueous HCl were added. The mixture was refluxed for
was added until pH 10, and the mixture was extracted with 1 hour, cooled to 0 °C and basified with 3 M aqueous NaOH. The
EtOAc (3 x 10 mL). The organic phases were washed with brine aqueous phase was extracted with EtOAc (3 x 10 mL), and the
and concentrated in vacuo. The obtained crude free amine was combined organic phases were dried over anhydrous Na2SO4,
dissolved in dry toluene (40.0 mL), and phthalic anhydride (1.2 filtered and concentrated in vacuo. The crude diamine was used
g, 8.3 mmol) was added. The reaction mixture was refluxed for without any further purification. NBoc L serine (OBn) (80 mg,
24 hours, the solvent was evaporated, and the crude product 0.27 mmol) was dissolved in dry DCM (1.5 mL) and cooled to -
purified by flash chromatography (CHX : DCM 2:1) to give the 78 °C, then NMM (0.03 mL, 0.27 mmol) and CbzCl (0.04 mL, 0.27
desired compound as a colorless oil (3.25 g, 80% yield). [α]D18: - mmol) were successively added. After 15 min, the crude
64.4 (c 0.3, CHCl3). IR (neat): 3299, 1721, 1621, 1544, 1289, 1060 diamine dissolved in DCM (2.0 mL) was added dropwise, the
cm-1. 1H NMR (400 MHz, CDCl3), : 7.78 (dd, J = 5.1, 3.3 Hz, 2H), reaction mixture was stirred at -78 °C for 2 hours, and slowly
7.68 (dd, J = 5.1, 3.3 Hz, 2H), 7.21– 7.39 (m, 10H), 6.75 (d, J = warmed up to room temperature and stirred for 4 hours. The
8.1Hz, 2H), 6.69 (d, J = 8.1 Hz, 1H), 5.10 (dd, J = 10.9, 5.7 Hz, 1H), solvent was evaporated, and the crude product was directly
5.02 (s, 2H), 4.93 (q, J = 11.9 Hz, 2H), 4.24 (m, 2H), 3.48 (m, 2H), purified by flash chromatography (Pentane : EtOAc 1:2) to give
18
1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3), : 167.6, the desired compound as a yellow oil (78 mg, 45% yield). [α]D
:
166.7 166.6, 149.0, 145.0, 137.1, 136.7, 134.2, 132.0, 130.5, + 6.8 (c 1, CHCl3). IR (neat): 3094, 1778, 1693, 1357, 961 cm-1.
128.5, 128.5, 128.0, 127.9, 127.5, 127.4, 123.5, 116.4, 114.1, 1H NMR (400 MHz, CDCl3), : 7.18 – 7.52 (m, 16H), 6.57 (s, 1H),
103.8, 72.4, 71.6, 49.6, 48.8, 29.7, 14.1. HRMS (ESI-TOF) m/z: 6.09 (s, 1H), 5.39 (s, 1H), 5.01 (m, 4H), 4.30 – 4.41 (m, 3H), 4.21
[M+H]+ Calcd for C33H30NO6 536.2068; found 536.2077.
(bs, 1H), 3.77 – 3.92 (m, 1H), 3.51 – 3.60 (m, 1H), 3.43 (bs, 1H)
(S)-2-(6,7-bis(benzyloxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-
3.25 (m, 1H), 3.01 – 3.15 (m, 1H), 2.88 – 3.00 (m, 1H), 2.57 (d, J
yl)isoindoline-1,3-dione (21). The protected L-dopa derivative = 16.7 Hz, 1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3), : 169.8,
(20) (250 mg, 0.47 mmol) was dissolved at 0 °C in glacial acetic 169.8, 155.4, 149.0, 149.0, 141.8, 138.4, 138.3, 137.9, 137.5,
acid (1.0 mL), then, concentrated aqueous nitric acid (0.35 mL, 137.5, 137.4, 128.5, 128.4, 128.4, 128.3, 127.8, 127.8, 127.7,
5.8 mmol) dissolved in glacial acetic acid (1.0 mL) was added 127.6, 127.6, 127.2, 127.2, 119.2, 110.7, 102.5, 80.1, 73.4, 73.0,
dropwise. The reaction mixture was stirred at 0 °C for 1.5 hours, 71.4, 70.2, 45.4, 42.5, 42.4, 32.1, 28.2. HRMS (ESI-TOF) m/z:
water was added, and the mixture was filtered. The obtained [M+H]+ Calcd for C38H44N3O6 638.3225; found 638.3229.
solid was dried under high vacuum and directly dissolved in (S)-2-(6,7-Dimethoxy-1,2,3,4-tetrahydroquinolin-3-
glacial acetic acid (2.0 mL). The mixture was heated at 80 °C, yl)isoindoline-1,3-dione
(23).
The
protected
iron powder (470 mg, 8.4 mmol) was added in three portions, tetrahydroquinoline carbamate (18a) (360 mg, 1.03 mmol) was
and after 1.5 hours of reflux, the cold reaction mixture was dissolved in methanol (10.0 mL), and under hydrogen
filtered through a pad of celite, poured into water, and 6 M atmosphere, Pd/C (90 mg) was added. The reaction mixture was
aqueous NaOH was added until pH 14. The aqueous phase was stirred under hydrogen at room temperature for 6 hours and
extracted with EtOAc (3 x 5 mL). The combined organic phases filtered through celite. Solvent evaporation afforded the free
were dried over anhydrous Na2SO4, filtered and concentrated in amide intermediate, which was directly dissolved in dry THF
vacuo. The product was obtained after column chromatography (12.0 mL). Then at 0°C, 2 M BH3-SMe2 in THF (4.12 mL, 8.2 mmol)
(DCM : EtOAc 10:1) as a yellow solid. (130 mg, 55% yield). was slowly added, the reaction mixture was refluxed during 24
Melting point 190 °C, lit. 192 °C.21.[α]D18: - 22.8 (c 0.4, CHCl3), lit. hours, cooled to 0 °C, and 10% HCl (8 mL) was slowly added, the
[α]D - 1.4 (c 5, DMF).21 IR (neat): 1716, 1689, 1512, 1454, 1388, reaction mixture was refluxed during 2 hours, cooled and
1261 cm-1. 1H NMR (400 MHz, CDCl3), : 8.02 (s, 1H), 7.86 (dd, J basified with 8 M aqueous NaOH. The aqueous phase was
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extracted with EtOAc (3 x 5 mL), and the combined organic 98.2, 56.8, 56.1, 52.8, 46.0, 39.9, 30.6. HRMS (ESI-TOF) m/z:
View Article Online
+
DOI: 10.1039/D0OB00315H
phases were concentrated in vacuo. The resulting free diamine [M+H] Calcd for C20H21N2O4 353.1496; found 353.1501.
was dissolved in dry toluene (3.0 mL) and dry DMF (0.3 mL), (S)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroquinolin-3-
then phthalic anhydride (160 mg, 1.1 mmol) was added. The amine (26). The methylated diamine (25) (60 mg, 0.17 mmol)
reaction mixture was refluxed for 12 hours, the solvent was was dissolved in EtOH (2.0 mL), then hydrazine hydrate (0.03
evaporated, and the crude product purified by flash mL, 0.42 mmol) was added. The reaction mixture was refluxed
chromatography (DCM : EtOAc 20:1) to give the desired 24 hours and concentrated in vacuo. Purification by column
compound as a yellow oil (220 mg, 70% yield). [α]D19: + 48.4 (c chromatography (DCM : EtOAc 10:1) afforded the product as a
0.76, CHCl3). IR (neat): 2929, 1722, 1627, 1386, 1228, 1062 cm- yellow oil (38 mg, 99 % yield). [α]D19: + 22.4 (c 0.55, CHCl3). IR
1. 1H NMR (400 MHz, CDCl3), : 7.85 (m, 2H), 7.73 (m, 2H), 6.52 (neat): 3296, 2958, 2926, 1523, 1465, 1386, 1286, 1072 cm-1. 1H
(s, 1H), 6.20 (s, 1H), 4.74 (m, 1H), 3.97 (t, J = 10.8 Hz, 1H), 3.82 NMR (400 MHz, CDCl3), : 6.52 (s, 1H), 6.20 (s, 1H), 3.80 (s, 3H)
(s, 3H), 3.79 (s, 3H), 3.65 (dd, J = 15.4, 11.3 Hz, 1H), 3.24 – 3.31 3.77 (m, 4H), 3.24 (s, 2H), 3.08 (dd, J = 16.3, 3.7 Hz, 1H), 2.84 (m,
(m, 1H), 2.78 (dd, J = 15.3, 6.2 Hz, 1H). 13C NMR (100 MHz, 4H), 1.90 (s, 2H). 13C NMR (100 MHz, CDCl3), : 148.7, 141.6,
CDCl3), : 168.1, 148.6, 142.0, 137.5, 134.0, 131.9, 123.4, 123.2, 140.0, 114.2, 109.7, 97.7, 56.6, 56.0, 53.9, 44.8, 39.4, 32.2.
113.7, 111.0, 100.0, 56.7, 55.9, 46.6, 44.0, 29.8. HRMS (ESI-TOF) HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H19N2O2 223.1441;
m/z: [M+H]+ Calcd for C19H19N2O4 339.1339; found 339.1350.
found 223.1451.
(S)-3-(1,3-Dioxoisoindolin-2-yl)-6,7-dimethoxy-3,4-
tert-Butyl (S)-(3-(3,4-dihydroxyphenyl)-1-(dimethylamino)-1-
dihydroquinoline-1(2H)-carbaldehyde (24). The protected oxopropan-2-yl)carbamate (27): L-dopa (1g, 5 mmol) was
diamine (23) (120 mg, 0.35 mmol) was refluxed with formic acid suspended in dioxane (8 mL), then water (5 mL) and 1M
(0.50 mL, 14 mmol) and acetic anhydride (0.50 mL, 5.24 mmol) aqueous NaOH (5.6 mL, 5.6 mmol) were successively added.
for 1.5 hours, and the cold mixture was diluted with DCM. The After 5 minutes, (Boc)2O (1.22 g, 5.6 mmol) previously dissolved
volatiles were evaporated, and the product was obtained after in dioxane (3.0 mL) was added and the reaction mixture was
column chromatography (DCM : EtOAc 10:1) as a yellow oil (110 stirred overnight. The volatiles were evaporated, and the
mg, 90 % yield). [α]D18: +14.85(c 0.6, CHCl3). IR (neat): 3211, aqueous residue was acidified with 5% aqueous HCl and
1
1703, 1649, 1528, 1330, 1257, 1116, 1060 cm-1. H NMR (400 extracted with EtOAc. The organic phases were dried over
MHz, CDCl3), : 8.74 (s, 1H), 7.86 (m, 2H), 7.76 (m, 2H), 6.69 (s, anhydrous Na2SO4, filtered and concentrated in vacuo. The
1H), 6.68 (s, 1H), 4.63 (m, 1H), 4.45 (dd, J = 12.2, 4.5 Hz, 1H), crude product was directly used in the next step without further
4.02 (d, J = 12.2 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.56 (dd, J = purification. The protected L-dopa was dissolved in THF (20 mL)
12.1, 10.9 Hz, 1H), 2.98 (dd, J = 15.9, 6.0 Hz, 1H). 13C NMR (100 and cooled to -78 °C, then NMM (0.66 mL, 6 mmol) and CbzCl
MHz, CDCl3), : 167.8, 160.6, 148.5, 147.0, 134.4, 134.2, 131.7, (0.86 mL, 6 mmol) were successively added. The reaction
129.5, 123.5, 123.4, 118.3, 112.4, 102.0, 56.2, 56.2, 45.5, 40.9, mixture was stirred for 20 min and 1 M dimethylamine (11 mL,
30.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H19N2O5 11 mmol) in THF was dropwise added. The reaction mixture was
367.1288; found 367.1290.
(S)-2-(6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroquinolin-3-
stirred at -78 °C for 1 hour and then it was slowly warmed up to
room temperature and stirred for 12 hours. The solvent was
yl)isoindoline-1,3-dione (25). The formylated amide (24) (100 evaporated, and the obtained residue was dissolved in ethyl
mg, 0.29 mmol) was dissolved in dry THF (5.0 mL) and 1 M acetate, washed three times with 10% aqueous citric acid,
BH3.THF in THF (3.4 mL, 3.4 mmol) was added dropwise. The saturated aqueous NaHCO3 and brine. The solvent was
reaction mixture was stirred under argon atmosphere for 12 evaporated, and the product was purified by column
hours, then 2.5 M aqueous NaOH was added dropwise until the chromatography (DCM : EtOAc 1:1) affording the product as a
release of gas stopped. The mixture was extracted with DCM, white solid (1.05 g, 65% yield). The spectroscopy data and
the combined organic phases were washed with brine, dried physical constants of (27) were in good agreement with those
with anhydrous Na2SO4, filtered and concentrated in vacuo. The reported in the literature.10c Melting point: 157°C, lit. 156 – 157
crude product was mixed with 0.5 mL of acetic acid and 3 mL of °C. [α]D18: + 46.7 (c 0.15, CHCl3). lit. [α]D25: + 56.8 (c 1, CHCl3).1H
10% aqueous HCl and it was stirred at room temperature for 24 NMR (400 MHz, CDCl3), : 7.78 (bs, 1H), 6.69 – 6.83 (m, 2H),
hours, cooled to 0 °C and basified with aqueous NH3. The 6.61 (d, J = 6.6 Hz, 1H), 6.25 (bs, 1H), 5.42 (d, J = 7.0 Hz, 1H), 4.80
aqueous phase was extracted with DCM (3 x 5 mL), and the (s, 1H), 2.62 – 2.94 (m, 8H), 1.42 (s, 9H).
combined organic phases were washed with brine, dried with tert-Butyl
anhydrous Na2SO4, filtered and concentrated in vacuo. The (dimethylamino)-1-oxopropan-2-yl)carbamate
(S)-(3-(3,4-bis(benzyloxy)phenyl)-1-
(28). The
crude product was purified by flash chromatography (DCM : protected L-dopa amide derivative (27) (0.86 g, 2.6 mmol) was
EtOAc 20:1) to give the desired compound as a yellow oil (71 dissolved in acetone (20 mL), then Cs2CO3 (2.6 g, 8 mmol) was
mg, 70% yield). [α]D19: +12.75 (c 0.13, CHCl3). IR (neat): 1719, added, and the mixture was stirred at room temperature for 15
1667, 1433, 1199, 1008 cm-1. 1H NMR (400 MHz, CDCl3), : 7.84 min. Then BnBr (0.95 mL, 8 mmol) was added and the reaction
(bs, 2H), 7.73 (bs, 2H), 6.57 (s, 1H), 6.33 (s, 1H), 4.82 (s, 1H), 3.84 mixture was refluxed for 4 hours. The solvent was evaporated,
(m, 7H), 3.61– 3.73 (m, 1H), 3.14 (d, J = 8.4 Hz, 1H), 2.90 (s, 3H), and the residue was dissolved in EtOAc, washed three times
2.81 (dd, J = 14.9, 4.3 Hz, 1H). 13C NMR (100 MHz, CDCl3), : with 10 % aqueous citric acid, saturated aqueous NaHCO3 and
168.1, 148.6, 141.3, 140.6, 134.0, 131.8, 123.2, 114.1, 112.5, brine. The solvent was evaporated, and the product was
purified by column chromatography (EtOAc : DCM 1:10)
10 | J. Name., 2012, 00, 1-3
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affording the product as a white solid. (1.27 g, 95% yield). The reaction mixture was stirred at room temperature for three
View Article Online
DOI: 10.1039/D0OB00315H
spectroscopy data and physical constants of (28) were in good hours. The reaction mixture was then extracted with water (4 x
agreement with those reported in the literature.9 Melting point: 5 mL), the aqueous phase was washed with DCM, and
89°C. lit. 85 – 88 °C. [α]D19: +33.1 (c 0.4, CHCl3). lit. [α]D28.5: + 27.5 lyophilized
affording
the
expected
intermediate
1
(c 1.05, CHCl3). H NMR (400 MHz, CDCl3), : 7.20 – 7.52 (m, tetrahydroquinolinium compound. This compound was
10H), 6.84 (d, J = 8.3 Hz, 2H), 6.69 (dd, J = 8.1, 1.4 Hz, 1H), 5.39 dissolved in dry acetone (10.0 mL), and Cs2CO3 (185 mg, 0.57
(d, J = 8.4 Hz, 1H), 5.12 (s, 2H) 5.13 (s, 2H), 4.73 (dd, J = 14.7, 8.9 mmol) and BnBr (0.07 mL, 0.57 mmol) were successively added.
Hz, 1H), 2.78 – 3.02 (m, 2H), 2.77 (s, 3H), 2.47 (s, 3H), 1.42 (s, The mixture was stirred at reflux for 16 hours, and the solvent
9H).
was evaporated. The residue was dissolved in water and
tert-Butyl
(S)-(1-(3,4-bis(benzyloxy)phenyl)-3- extracted with EtOAc (4 x 5 mL), the organic phase was washed
(dimethylamino)propan-2-yl)carbamate (29). At 0 °C the amide with brine and dried over anhydrous Na2SO4, filtered and
product (28) (1.18 g, 2,3 mmol) was dissolved in dry DCM (10.0 concentrated in vacuo. The crude product was purified by flash
mL), then TFA (1.8 mL, 23 mmol) was added dropwise. The chromatography (DCM: MeOH 15:1) to give the desired
reaction mixture was stirred at 0 °C for 1 hour, slowly warmed compound as a white solid (43 mg, 40%). The spectroscopy data
up to room temperature and stirred for 12 hours. The solvent and physical constants of (30) were in good agreement with
18
was evaporated and the residue was redissolved in water and those reported in the literature.9 [α]D + 7.4 (c 0.9, CHCl3). lit.
basified by the addition of 10% aqueous NaOH. The aqueous [α]D25.6: + 8.16 (c 1 CHCl3). 1H NMR (400 MHz, CDCl3), : 7.65 (s,
phase was extracted with EtOAc (3 x 15 mL), and the combined 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.23 – 7.43 (m, 8H), 6.60 (s,1H), 6.18
organic phases were dried over anhydrous Na2SO4, filtered and (s, 1H), 5.40 (d, J = 6.6 Hz, 2H), 5.07 – 5.15 (d, 2H), 3.99 – 4.30
concentrated in vacuo. The crude deprotected product was (m, 2H), 3.91 (s, 3H), 3.76 (s,3H), 3.15 – 3.31 (m, 1H), 2.98 (m,
directly dissolved in dry THF (10 mL) and cooled to 0°C, then 2 1H), 2.10 (s,1H), 1.43 (s,9H).
M BH3-SMe2 in THF (6.5 mL, 13 mmol) was added dropwise and b) Oxidation with K3[Fe(CN)6]. The deprotected diamine
the reaction was refluxed for 16 hours, cooled to 0°C and 10% intermediate (60 mg, 0.19 mmol) was directly dissolved in
aqueous HCl was slowly added until pH 2. The mixture was acetonitrile (1 mL) and mixed with 45 mL of buffer solution (pH
refluxed for 1 hour, cooled to room temperature and 2M 6.5 NaH2PO4/Na2HPO4, 0.008M). Then K3[Fe(CN)6] (625 mg, 1.9
aqueous NaOH was added to reach pH 13. The basic phase was mmol) was added, the reaction mixture was stirred at room
extracted with EtOAc (3 x 10 mL), the combined organic phases temperature for two hours, and lyophilization gave the
were dried over anhydrous Na2SO4 and concentrated in vacuo. intermediate tetrahydroquinolinium compound. The solid
The crude free diamine was dissolved in water (3.5 mL) and intermediate was dissolved in dry acetone (20.0 mL) and Cs2CO3
dioxane (2.5 mL) was added, then (Boc)2O (620 mg, 2,8 mmol) (185 mg, 0.57 mmol) and BnBr (0.07 mL, 0.57 mmol) were
and 1M aqueous NaOH (2.6 mL, 2.6 mmol) were successively successively added. The mixture was stirred at reflux for 16
added and the mixture was stirred at room temperature for 24 hours, and the solvent was evaporated. The residue was
hours. The organic solvent was evaporated and the aqueous dissolved in water and extracted with EtOAc (4 x 5 mL), the
phase was extracted with EtOAc (3 x 5 mL). the combined combined organic phases were washed with brine, dried over
organic phases were washed with brine and concentrated in anhydrous Na2SO4, filtered and concentrated in vacuo. The
vacuo. The crude product was purified by column crude product was purified by flash chromatography (DCM:
chromatography (EtOAc : MeOH 1:10) affording the product as MeOH 15:1) to give the desired compound as a white solid (59
colorless oil. (730 mg, 65% yield). The spectroscopy data and mg, 55%).
physical constants of (29) were in good agreement with those (S)-3-Amino-6,7-bis(OBn)-1,1-dimethyl-1,2,3,4-
reported in the literature.9 [α]D19: + 19.7 (c 0.9, CHCl3). lit. tetrahydroquinolin-1-ium
L-ser(OBn)-D-Ser
(OBn)-BocL-
[α]D27.1 + 19.95 (c 1.05, CHCl3). 1H NMR (400 MHz, CDCl3), : 7.21 Thr(OBn) (31). To a 0 °C stirred solution of the compound (30)
– 7.53 (m, 10H), 6.77 – 6.96 (m, 2H), 6.69 (d, J = 8.1 Hz, 1H), 5.14 (58 mg, 0.1 mmol) in dry DCM (2 mL) was added dropwise TFA
(s, 2H), 5,12 (s, 2H) 4.64 (bs, 1H), 3.79 (bs, 1H), 2.83 (d, J = 12.3 (0.2 mL, 2.5 mmol). The reaction mixture was stirred for 1 hour
Hz, 1H), 2.71 (dd, J = 13.6, 6.4 Hz, 1H) , 2.17 (m, 8H), 1.43 (s, 9H). keeping the same temperature and then it was slowly heated to
(S)-6,7-bis(Benzyloxy)-3-((tert-butoxycarbonyl)amino)-1,1-
dimethyl-1,2,3,4-tetrahydroquinolin-1-ium (30).
room temperature and stirred for 12 hours. The solvent was
The evaporated, and the free amine product was dried under high
benzylated diamine (29) (200 mg, 0.41 mmol) was dissolved in vacuum.
MeOH (5.0 mL), then, under hydrogen atmosphere, catalytic To a 0 °C stirred solution of the ester (2) (67 g, 0.098 mmol) in
Pd/C (0.04 g) was added. The reaction mixture was stirred under methanol (2.0 mL) was added in small portions 1M aqueous
hydrogen at room temperature for 24 hours, filtered through NaOH (1 mL, 1 mmol). The reaction mixture was stirred for 1
Celite and eluted with hot MeOH. Solvent evaporation afforded hour keeping the same temperature and then it was slowly
the deprotected diamine intermediate.
warmed up to room temperature and stirred for 6 hours. Then
a) Oxidation with dianisyltellurium oxide. The deprotected the mixture was diluted with water and acidified with 5%
diamine intermediate (60 mg, 0.19 mmol) was directly dissolved aqueous HCl. The aqueous phase was extracted with EtOAc (4 x
in dry DCM (7.0 mL) under argon atmosphere, then 5 mL), and the combined organic phases were washed with
dianisyltellurium oxide (72 mg, 0.21 mmol) (prepared according brine, dried over anhydrous Na2SO4, filtered and concentrated.
to the procedure described by Silberman24), was added and the The crude carboxylic acid was directly dissolved in dry DCM (1.5
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mL) and CDI (25 mg, 0.15 mmol) was added. The reaction 45.5, 45.3, 19.6, 12.0. HRMS (ESI-TOF) m/z: [M+VHie]w+ ACrtaicllcedOnflioner
DOI: 10.1039/D0OB00315H
mixture was stirred at room temperature for 45 min, then the C66H74N3O11Si 1112.5087; found 1112. 5096.
free amine (0.1 mmol) previously mixed with NMM (0.05 mL, (S)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroquinolin-3-
0.45 mmol) in dry DCM (1.5 mL), was added. The reaction amine-L-ser (OBn)-D-Ser(OBn)-BocL-Thr(OBn) (34). To a 0 °C
mixture was stirred at room temperature for 24 hours. The stirred solution of the ester (2) (110 mg, 0.16 mmol) in methanol
solvent was evaporated, and the crude product was directly (2.0 mL) was added in small portions 1M aqueous NaOH (2 mL,
purified by column chromatography, (DCM : MeOH:20:1) 2 mmol). The reaction mixture was stirred for 1 hour keeping
affording the product as a colorless oil (43 mg, 42% yield). The the same temperature and then it was slowly heated to room
spectroscopy data and physical constants of (35) were in good temperature and stirred for 6 hours. Then the mixture was
agreement with those reported in the literature 9 [α]D18 +6.29 (c diluted with water and acidified with 5% aqueous HCl. The
0.2, CHCl3). lit. [α]D25.1 +4.36 (c 1.82, CHCl3). 1H NMR (400 MHz, aqueous phase was extracted with EtOAc (3 x 5 mL), and the
CDCl3), : 8.37 (d, J = 7.0 Hz, 1H), 8.22 (d, J = 6.6 Hz, 1H), 7.26 combined organic phases were washed with brine, dried over
(m, 31H), 6.56 (s, 1H), 5.70 – 5.61 (m, 1H), 5.30 (m, 2H), 5.11 (m, anhydrous Na2SO4, filtered and concentrated. The crude
2H), 4.76 (m, 2H), 4.43 (m, 7H), 4.08 (s, 2H), 3.93 – 3.71 (m, 3H), carboxylic acid was directly dissolved in dry DCM (2.0 mL), and
3.67 – 3.50 (m, 3H), 3.39 (s, 2H), 3.24 – 3.04 (m, 1H), 2.81 (m, cooled to -78°C, then NMM (0.017 mL, 0.16 mmol) was added
1H), 1.35 (s, 9H), 1.13 (d, J = 5.6 Hz, 3H).
2-((2S,4R,6S)-6-((S)-1-(2-(OBn)benzamido)-2-
((TBDPS)oxy)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetic
dropwise. After 5 min, CbzCl (0.023 mL, 0.16 mmol) was added
dropwise, keeping the same temperature, and after 10 min a
acid-L- solution of the diamine (26) (0.038 g, 0.17 mmol) dissolved in
Thr(OBn)-D-Ser(OBn) (33). To a 0°C stirred solution of NBoc L- dry DCM (1.5 mL) was added. The reaction mixture was stirred
Thr (OBn)-D-Ser(OBn) methyl ester (60 mg, 0.12 mmol), at –78 °C for one hour, slowly warmed up to room temperature
prepared according to Gademann et al.10c in dry DCM (2 mL), and filtered. The crude material was directly purified by flash
was slowly added TFA (0.1 mL, 1.3 mmol). The reaction mixture chromatography (Pentane : EtOAc 1:1) to give the desired
18
was stirred for 1 hour keeping the same temperature and then compound as a colorless oil (80 mg, 65% yield). [α]D - 34.0 (c
it was slowly warmed up to room temperature and stirred for 0.73, CHCl3). IR (neat): 3310, 2927, 1707, 1651, 1519, 1215 cm-
12 hours. The solvent was evaporated, and the free NH2 1. 1H NMR (400 MHz, CDCl3), : 7.04 – 7.50 (m, 17H), 6.87 (dd, J
dipeptide product was dried under high vacuum.
= 18.6, 7.9 Hz, 1H), 6.49 (d, J = 4.3 Hz, 1H), 6.20 (s, 1H), 5.49 (dd,
To a 0 °C stirred solution of the ester (11) (80 mg, 0.10 mmol) in J = 15.8, 7.2 Hz, 1H), 4.32 – 4.67 (m, 8H), 4.10 – 4.36 (m, 2H),
methanol (2.0 mL) was added in small portions 1M aqueous 3.62 - 4.06 (m, 9H), 3.32 – 3.58 (m, 2H), 3.18 (t, J = 11.6 Hz, 1H),
NaOH (1 mL, 1 mmol). The reaction mixture was stirred for 1 2.97 (dd, J = 15.9, 5.4 Hz, 1H), 2.88 (dd, J = 11.5, 5.5 Hz, 1H), 2.68
hour keeping the same temperature and then it was slowly – 2.79 (m, 3H) 2.63 (dd, J = 16.2, 4.8 Hz, 1H), 1.43 (s, 9H), 1.13
warmed up to room temperature and stirred for 6 hours. Then, (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) : 170.6, 170.5,
the mixture was diluted with water and acidified with 5% 169.0, 155.8, 148.4, 141.3, 140.3, 137.8, 137.3, 137.2, 128.4,
aqueous HCl, and extracted with EtOAc (3 x 5 mL). The 128.4, 128.4, 127.8, 127.7, 127.6, 127.5, 127.3, 114.2, 114.2,
combined organic phases were washed with brine, dried over 111.2, 103.3, 97.6, 80.2, 73.4, 73.3, 73.3, 73.1, 71.3, 69.4, 68.9,
anhydrous Na2SO4, filtered and concentrated. The crude 56.6, 56.0, 54.7, 53.3, 52.6, 43.3, 39.6, 39.5, 32.9, 29.7, 28.2,
carboxylic acid was directly cooled to -78 °C and dissolved in dry 15.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C48H62N5O10
DCM (2 mL) then NMM (0.011 mL, 0.10 mmol) and CbzCl (0.014 868.4491; found 868.4490.
mL, 0.10 mmol) were successively added. The reaction mixture 2-((2S,4R,6S)-6-(S)-1-(2-(OBn)benzamido)-2-
was stirred for 20 min. then the free NH2 dipeptide (50 mg, 0.12 ((TBDPS)oxy)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetic acid-L-Thr
mmol), dissolved in DCM (1.5 mL) was added. The reaction OBn)-D-Ser(OBn)-L-Ser(OBn)-(S)-6,7-dimethoxy-1-methyl-
mixture was stirred at -78 °C for 1 hour, then it was slowly 1,2,3,4-tetrahydroquinolin -3-amine (35). To a 0 °C stirred
warmed up to room temperature and stirred for 6 hours. The solution of the compound (34) (30 mg, 0.039 mmol) in dry DCM
crude product was directly purified by column chromatography (2 mL) was added TFA (0.04 mL, 0.54 mmol). The reaction
(EtOAc : DCM 2:10) affording the product as a yellow oil (61 mg, mixture was stirred for 1 hour keeping the same temperature
18
55% yield). [α]D +3.87 (c 1.2, CHCl3). IR (neat): 3301, 2989, and then it was slowly heated to room temperature and stirred
1881, 1731, 1650, 1158 cm-1. 1H NMR (400 MHz, CDCl3), : 8.17 for 12 hours. The solvent was evaporated, and the free amine
(d, J = 6.7 Hz, 2H), 7.62 (dd, J = 22.6, 7.1 Hz, 4H), 7.10 – 7.42 (m, product was dried under high vacuum.
22H), 7.04 (dd, J = 15.4, 7.6 Hz, 5H), 6.92 (d, J = 8.3 Hz, 1H), 6.71 To a 0 °C stirred solution of the ester (11) (28 mg, 0.037 mmol)
(d, J = 6.8 Hz, 1H), 5.53 (s, 1H), 4.91 – 5.09 (m, 2H), 4.69 – 4.76 in methanol (1.0 mL) was added in small portions 1 M aqueous
(m, 1H), 4.62 – 4.69 (m, 1H), 4.33 – 4.61 (m, 7H), 4.05 – 4.17 (m, NaOH (0.37 mL, 0.37 mmol). The reaction mixture was stirred
1H), 3.78 – 3.88 (m, 1H), 3.58 – 3.75 (m, 6H), 2.39 (m, 2H), 1.66 for 1 hour keeping the same temperature and then it was slowly
(m, 2H), 1.26 (bs, 2H) 1.03 (s, 9H), 0.96 (d, J = 6.3 Hz, 3H). 13C heated to room temperature and stirred for 6 hours. Then the
NMR (100 MHz, CDCl3), : 163.2, 163.0, 161.9, 158.2, 149.4, mixture was diluted with water and acidified with 5% aqueous
128.3, 126.0, 125.9, 125.5, 125.1, 121.4, 121.1, 121.1, 121.0, HCl, and the aqueous phase was extracted with EtOAc. The
120.7, 120.6, 120.5, 120.4, 120.3, 119.8, 118.8, 114.6, 114.2, combined organic phases were washed with brine, dried over
105.6, 93.1, 66.6, 66.4, 65.9, 64.2, 63.4, 62.1, 54.0, 48.9, 46.2, anhydrous Na2SO4, filtered and concentrated. The crude
carboxylic acid was directly cooled to -78 °C and dissolved in dry
12 | J. Name., 2012, 00, 1-3
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Page 13 of 13
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
Int. Ed., 2017, 129, 6990; (b) D. M. Livermore, CVliinew. MArtiicclreoObniloinle.
DCM (1.0 mL) then NMM (0.004 mL, 0.037 mmol) and CbzCl
(0.005 mL, 0.037 mmol) were successively added. The reaction
mixture was stirred for 20 min and the free amine dissolved in
dry DCM (2.0 mL) was added. The reaction mixture was stirred
at -78 °C for 1 hour, then it was slowly warmed up to room
temperature and stirred for 6 hours. The crude product was
directly purified by column chromatography (Pentane : EtOAc
:1:1) affording the product as a yellow oil (30 mg, 55% yield).
Infect., 2006, 12, 11; (c) A. Mor, Drug Dev. Res., 2000, 50, 440.
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18
[α]D +3.29 (c 0.2, CHCl3). IR (neat): 3201, 2989, 1881, 1701,
1
1008, cm-1. H NMR (400 MHz, CDCl3), : 8.15 – 8.28 (m, 1H),
7.59 – 7.72 (m, 2H), 7.16 – 7.47 (m, 34H), 7.07 (d, J = 6.4 Hz, 2H),
6.87 – 6.99 (m, 2H), 6.53 (d, J = 5.2 Hz, 1H), 6.24 (d, J = 13.6 Hz,
1H), 5.85 (dd, J = 20.1, 6.7 Hz, 1H), 5.00 – 5.21 (m, 4H), 4.29 –
4.56 (m, 8H), 4.10 – 4.18 (m, 2H), 3.69 – 3.93 (m, 14H), 3.46 –
3.62 (m, 2H), 3.20 (m, 1H), 2.88 – 3.08 (m, 3H), 2.63 – 2.78 (m,
4H), 2,53 (m, 1H) 2.22 – 2.40 (m, 1H), 1.99 – 2.12 (m, 1H), 1.72
(m, 1H), 1.09 – 1.40 (m, 12H). 13C NMR (101 MHz, CDCl3) δ 171.0,
170.5, 170.0, 169.9, 169.4, 169.1, 165.4, 156.6, 156.3, 148.4,
141.34, 141.3, 140.3, 138.4, 138.3, 137.7, 137.4, 137.3, 135.6,
135.5, 133.3, 133.2, 132.7, 132.3, 132.1, 129.7, 129.6, 128.8,
128.7, 128.57, 128.55, 128.52, 128.46, 128.44, 128.42, 128.40,
128.38, 128.33, 128.3, 128.26, 128.22, 128.2, 128.11, 128.1,
128.0, 127.9, 127.81, 127.8, 127.7, 127.67, 127.62, 127.59,
127.5, 127.4, 127.3, 127.1, 126.1, 121.8, 121.4, 114.3, 114.2,
113.0, 111.2, 106.8, 100.4, 97.7, 74.0, 73.6, 73.4, 73.4, 73.3,
73.2, 73.0, 71.4, 71.1, 70.8, 69.5, 69.4, 68.9, 67.2, 66.8, 61.5,
58.7, 58.3, 56.7, 56.6, 56.0, 55.9, 54.7, 53.6, 53.4, 52.7, 43.4,
39.7, 39.6, 38.7, 32.9, 32.8, 31.9, 31.2, 30.3, 29.7, 29.3, 28.2,
27.2, 26.8, 26.8, 22.6, 19.2, 16.1, 15.5, 14.1.
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HRMS (ESI-TOF) m/z: [M+H]+: Calcd for C87H99N6O14Si, 1479.
6983; found: 1479.6991
Conflicts of interest
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There are no conflicts to declare.
Acknowledgements
This work was supported by the Chemistry Department and the
Faculty of Science of the Universidad de los Andes, and the
University of Glasgow. F. G-P. acknowledges COLCIENCIAS and
Universidad de los Andes and especially the Chemistry
Department for fellowships.
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