Total Synthesis of the Proposed Microcyclamides MZ602 and MZ568

Article abstract of DOI:10.1021/acs.joc.0c02541

The first convergent total synthesis for the proposed structures of microcyclamides MZ602 (1) and MZ568 (2) has been accomplished in 11 linear steps with 12.5 and 16.8% overall yield, respectively. Key features of the syntheses include a one-pot cascade r

Full text of DOI:10.1021/acs.joc.0c02541

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Total Synthesis of the Proposed Microcyclamides MZ602 and MZ568
Yi Liu,* Xiangyun Zhao, Hongbo Wang, Huili Liu, Zhuyin Sui, Bingfei Yan, and Yuguo Du*
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ABSTRACT: The first convergent total synthesis for the proposed structures of microcyclamides MZ602 (1) and MZ568 (2) has
been accomplished in 11 linear steps with 12.5 and 16.8% overall yield, respectively. Key features of the syntheses include a one-pot
cascade reaction to construct core Boc-L-Ile-Thz-OAllyl fragment 5, and a removable pseudoproline (ΨMe,Me pro) inducer assisted
cyclization of thiazole-containing all-L linear peptides. The spectral data (1H NMR, 13C NMR, and HRMS) of synthetic MZ602 (1)
were quite similar to those of the proposed natural microcyclamide MZ602, except to an opposite sign of the optical rotation value.
Surprisingly, the synthetic MZ568 (2) presented large discrepancies in characteristic spectral data from those of the reported natural
product, although the absolute configuration of key intermediate 36 was unambiguously determined by single-crystal X-ray analysis
in our work. These findings revealed that the proposed structures of natural microcyclamides MZ602 and MZ568 required revision.
INTRODUCTION
■
With the outbreak of cyanobacteria blooms worldwide, the
potential risks of their secondary metabolites to environmental
safety and human health have become an ever-growing
concern.1 These metabolites were found not only to be
associated with the off-flavors in aquatic animals or
contamination of drinking water but also to be responsible
for a range of lethal and sublethal effects in plants and
animals.1a,2 For example, very recently, the mass death of ∼350
African elephants in Botswana was suspected to be associated
with the contamination of toxic secondary metabolites of
cyanobacteria.3
Microcyclamides MZ602 and MZ568 were two cyclic
hexapeptide-type cyanobacteria secondary metabolites isolated
from the freshwater Microcystis sp. bloom in 2010 by Carmeli
and co-workers (Figure 1).4 In a limited biological screening,
microcyclamide MZ602 exhibited a mild inhibitory activity
against Molt4 cells (20% cell growth inhibition at 83 μM) and
a moderate inhibitory activity against chymotrypsin (IC50 = 75
μM). Compared to MZ602, microcyclamide MZ568 showed a
more potent inhibitory activity against Molt4 cells with cell
growth inhibition of 36% at 1.8 μM, but not active on
chymotrypsin. In addition, there are more than 50 hexapep-
tides that were characterized from these metabolites
(didmolamides,5 balgacyclamides,6a venturamides,6b etc.),
and many of them exhibited engaging biological activities,
Figure 1. Representative bioactive cyanobacterial metabolites.
Received: October 26, 2020
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such as antineoplastic activity,5 antiparasitic activity,6 and
acid residues L-Thr(Bzl)-OAllyl, Boc-L-Phe-OH, and Boc-Gly-
OH.
antimicrobial activity.7
The structures of microcyclamides MZ602 and MZ568 were
deduced on the basis of extensive spectroscopic data (1D and
2D NMR, UV), and the absolute configurations of amino acid
residues were established as all-L (L-Thr, L-Phe, L-Ala, L-Val,
and L-Ile) by using the classical Marfey’s method.4 Unlike
other hexapeptide-type metabolites containing two or more
five-membered heterocycles, microcyclamides MZ602 and
MZ568 are structurally unusual and possess only one thiazole
ring in the skeleton (Figure 1). Although much effort has been
devoted to the preparation of heterocycle-containing cyclo-
peptides, to the best of our knowledge, few total synthesis of
these single thiazole-containing all-L cyclic peptides have been
reported.8 Intrigued by their unique structures and potential
biological activities, we are interested in developing an efficient
synthetic procedure to access heterocycle-containing cyclic
hexapeptides and wish to synthesize microcyclamides MZ602
and MZ568, for the first time, to confirm their absolute
structures.
As seen in Scheme 2, our approach commenced with the
preparation of dipeptide 3, which was synthesized in 90% yield
Scheme 2. Route A Towards MZ602 Synthesis
Cyclization of the small linear peptide, especially to all-L
linear peptide precursor, remains a notoriously difficult task.9
The challenges come from the fact that amide bonds preferred
to exist in S-transoid conformation due to their strong π-
character, and thus enhanced the rigidity of linear peptide. It
turns out that the cyclization of these peptides suffers several
difficulties, such as poor yield, cyclodimerization, or partial
epimerization.10 Although some turn-promoting residues, such
as L-proline, L-glycine, N-alkylated amino acids, and even
unnatural D-amino acid derivatives were proven to be useful for
the macrocyclization, and many studies revealed that it is the
sequence of linear peptide precursor that plays the key role in
forming of the target cyclic structure.9
from commercially available Boc-L-Phe-OH and L-Thr(Bzl)-
OAllyl using EDCI/NMM as coupling agents. On the other
hand, dipeptide 4 was obtained in 86% yield by coupling
reaction of Boc-Gly-OH and L-Thr(Bzl)-OAllyl. However,
partial epimerization of tetrapeptide 11 was observed in
EDCI/NMM or PyBop/DMAP promoted coupling reactions.
When the coupling agents HATU/DIPEA were applied,
desired tetrapeptide 11 was obtained in 84% yield. Next, the
one-pot cascade thiazole formation reaction was investigated.
As expected, the reaction proceeded smoothly following our
reported procedure,11 and the desired thiazole 5 was achieved
in 69% yield from Boc-L-Ile-OH 9 and β-azido disulfide diallyl
ester 10 by sequential treatment with 8.0 equiv PPh3, 4.0 equiv
pentafluorophenyl diphenylphosphinate (FDPP), 10.0 equiv
Et3N, 12.0 equiv DBU, and 10.0 equiv BrCCl3. Hydrolysis of
tetrapeptide 11 and subsequent coupling with the free amine
5a generated from thiazole 5, afforded the linear peptide 12 in
57% yield over three steps. Unfortunately, sequential removal
of the allyl and Boc groups in 12 by LiOH and trifluoroacetic
acid (TFA), followed by macrolactamization did not achieve
the desired cyclic peptide 13 under different coupling
conditions (see Table 1).
RESULTS AND DISCUSSION
Our first retrosynthetic analysis of all-L cyclic hexapeptide
microcyclamide MZ602 is outlined in Scheme 1. To minimize
■
Scheme 1. Retrosynthetic Analysis of Microcyclamide
MZ602
We speculated that the possible reason behind this hard
formation of 13 could be ascribed to the all-L configuration of
constituent amino acids and the rigidity of the thiazole unit.
This frustration prompted us to change the synthetic strategy
to prepare the desired microcyclamide MZ602. It is well
the influence of steric hindrance and epimerization during
macrocyclization, the smaller glycine and thiazole unit were
chosen as the N- and C-terminal residues, respectively. Linear
precursor 12 could be achieved by a convergent synthetic
procedure from fragments 3, 4, and 5. The key building block
Boc-L-Ile-Thz-Oallyl (5) could be obtained from commercially
available Boc-L-Ile-OH using a one-pot cascade reaction
previously established in our laboratory.11 Dipeptides 3 and
4 could be readily obtained by coupling reaction from amino
Table 1. Macrolactamization Conditions
entry
coupling conditions
13 (%)
a
1
2
3
4
HATU, HOBt, DCM/DMF (1/1)
FDPP, DIPEA, CH3CN
PyBop, HOBt, DIPEA, DCM
DPPA, Et3N, DCM
trace
a
trace
b
ND
b
ND
a
b
Detected by LC−MS. ND means no desired product.
B
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documented that the pseudoproline (ΨMe,Me pro) derived from
threonine, serine, or cysteine might induce a significant effect
on cis-conformer amide bond formation and substantially
increase the head-to-tail cyclization efficiency in many cyclic
peptides.9,10 Since MZ602 contain two threonine residues in
the skeleton, we envisaged that two embedded ΨMe,Me pro in
the linear peptide precursor would improve the cis/trans amide
bond ratio and eventually increase the head-to-tail cyclization
yield (Figure 2). In this context, a new selective protection
strategy (Cbz/Boc/ΨMe,Me pro) was established and applied to
prepare MZ602 (Scheme 3).
containing dipeptide 17 was prepared in 90% yield upon
treatment of 16 with 3.0 equiv of 2-methoxypropene and
catalytic amount of (+)-camphorsulfonic acid. Coupling
reaction of Boc-L-Phe-OH with L-Thr-OMe in the presence
of EDCI/DIPEA rendered dipeptide 18 in 95% yield. Notably,
the spectral features of the synthesized dipeptides 16 and 18
were in full consistent with those of reported previously.10,13
Next, the dipeptide 17 was saponified with LiOH and then
coupled with N-deprotected 18a to give the mono-ΨMe,Me pro-
containing tetrapeptide 19 in 75% yield. Di-ΨMe,Me pro 20 was
obtained from 19 in 72% yield under reflux overnight with
2,2′-dimethoxypropene (2,2′-DMP), and pyridinium p-tolue-
nesulfonate (PPTS) at 80 °C. Hydrolysis of 20, followed by
coupling with N-deprotected thiazole fragment 5a, utilizing the
HATU/DIPEA promoter to give linear macrolactam precursor
21 in 63% yield. With 21 in hand, its allyl and Cbz groups was
sequentially removed and then subjected to macrolactamiza-
tion using HATU/HOBt agents under diluted conditions
(0.001 M). To our delight, this type of the ΨMe,Me pro strategy
works well, and the desired cyclic peptide 23 was obtained in
55% yield over three steps. Finally, removal of two ΨMe,Me pro
groups on treatment with 30% TFA in DCM at 0 °C
accomplished 1 in 86% yield. All spectroscopic features (1H
NMR, 13C NMR, and HMBC) of synthetic compound 1 were
quite similar to those of the isolated MZ602 (see Supporting
Information, Table S1), except for the optical rotation
Figure 2. Pseudoproline-assisted Cis/Trans Conformer Equilibrium.
Scheme 3. Route B Towards MZ602 Synthesis
4
24
{observed for 1: [α]D22−24.3 (c 0.7, MeOH), lit.: [α]D
+
53 (c 0.06, MeOH)}.
With this unexpected result, we re-examined the absolute
structure of our synthetic thiazole 5 and di-ΨMe, Me pro-
containing tetrapeptide 20 (Scheme 5). First, the fragment
Boc-D-allo-Ile-Thz-OAllyl 24 was synthesized using the similar
procedure as described in the preparation of its diastereomer 5.
1
By comparison of H NMR spectra between 24 and 5, we
concluded that there was no epimerization at the α-stereogenic
center of intermediate 5 using our previously reported thiazole-
formation method11a (see Supporting Information, Figure S8).
Second, methyl ester 25 was prepared quantitatively by
transesterification of 5 in the presence of K2CO3/MeOH.
The spectroscopic data of 25 were in full agreement with those
reported in the literature.12 Third, the di-ΨMe,Me pro group of
20 was cleaved with 30% TFA in DCM to generate
tetrapeptide Cbz-Gly-L-Thr-L-Phe-L-Thr-OMe (26) in 87%
yield. Alternatively, a direct coupling of dipeptides 16a and 18a
also generated 26 in 78% yield (Scheme 4). As expected, the
physical and spectroscopic data of 26 obtained from two
Scheme 4. Synthesis of Thiazoles 24, 25, and Tetrapeptide
26
The new synthetic approach began with the preparation of
dipeptide 16, which was achieved from commercial available L-
Thr-OMe and Cbz-Gly-OH in 86% yield. ΨMe,Me Pro-
C
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different synthetic methods were in full agreement with each
other. This demonstrated that no epimerization occurred
during the di-ΨMe,Me pro deprotection process. All of the above
evidences support that our synthetic 1 is in a right structure of
cyclo-[L-Thr-L-Phe-L-Thr-Gly-L-Ile(Thz)].
However, the true structure of natural microcyclamide
MZ602 is still shrouded in mystery. The literature search
revealed that MZ568 and MZ602 were isolated and elucidated
in the same metabolites family, and MZ602 presents just two
different amino acid units than MZ568. The amino acids in
microcyclamide MZ568 were also determined as all-L using the
same Marfey’s analysis procedures, as reported for MZ602. We
believed that a total synthesis of microcyclamide MZ568 would
provide some extra clues on the structure determination of
natural product MZ602.
Following the similar synthetic procedure to MZ602,
dipeptides 28 and 31 were respectively obtained in 84 and
77% yields from commercially available Boc-L-Val-OH, L-Thr-
OMe, and Boc-L-Ala-OH (Scheme 5). The spectral features of
synthetic dipeptides 28 and 31 were identical to those reported
previously.14,15 Pseudoproline dipeptide 29 was achieved in
86% yield from 28 on treatment with 3.0 equiv 2-
methoxypropene and 0.1 equiv D-(+)-CSA. Removal of the
Boc group on 31, followed by coupling with the corresponding
acid 29a in the presence of HATU/DIPEA, generated
tetrapeptide 32 in 76% yield. Compound 32 was then
converted into di-ΨMe,Me pro 33 under DMP/PPTS con-
ditions. Saponification of 33, followed by coupling with
thiazole fragment 5a, gave the linear peptide 34 in 55% yield
over three steps. Sequential removal of Boc and allyl ester on
34 (→ 35), then subjected to macrocyclization to afford the
desired cyclic peptide 36 in 65% yield. Treatment of 36 with
TFA for 15 h furnished 2 in 95% yield.
1
Surprisingly, the H and 13C NMR spectral data of the
synthetic 2 were significantly different from those of the
reported MZ568 (see Supporting Information, Table S2), as
well as the optical rotation value {observed for compound 2:
[α]D25−260 (c 0.1, MeOH), lit.:4 [α]D24−225 (c 0.03,
MeOH)}. Luckily, the prism-shaped crystals of 36, that is
the direct precursor for 2, was obtained from hexane and ethyl
acetate. X-ray analysis unambiguously confirmed the absolute
all-L configuration of amino acid residues in our synthetic
compound. These results indicated that the structure of natural
microcyclamide MZ568 requires further revision.
To unravel the structure mystery of microcyclamides
MZ602 and MZ568, we decided to recheck the Marfey’s
method, which was used to determine the absolute
configuration of natural MZ602 and MZ568.4 As reported,
this method included four steps: (1) acid degradation (6 N
HCl) of the natural microcyclamides MZ602 and MZ568, (2)
derivatization with Marfey’s reagent (1-fluoro-2,4-dinitrophen-
yl-5-L-alanine amide, i.e., FDAA), (3) HPLC analysis of
different FDAA-derivatized analytes at 340 nm, and (4)
comparison with the standard samples to determine the
configuration of the amino acids in an original natural product.
The recent studies, however, revealed that the classical
Marfey’s method had failed to distinguish the FDAA derivative
of L-isoleucine from L-allo-isoleucine, and failed to distinguish
the FDAA derivative of L-threonine from L-allo-threonine as
well.16 Both microcyclamides MZ602 and MZ568 happen to
contain one Ile and two Thr residues in their skeleton, and
there were no comparison results among the analytes, the
standard L-allo-Ile-FDAA and L-allo-Thr-FDAA derivatives in
the published work.4
Scheme 5. Route Towards the Total Synthesis of MZ568
Based on these findings, we believed that there might be one
or more L-allo-Thr or L-allo-Ile residue presented in the
structures of microcyclamides MZ568 and MZ602, instead of
L-Thr or L-Ile. In this context, it might have to prepare 16
isomers (MZ602: 23 = 8 isomers, MZ568: 23 = 8 isomers) to
unambiguously determine the structures of natural micro-
cyclamides MZ568 and MZ602.
SUMMARY
■
Two all-L cyclic hexapeptides cyclo-[L-Thr-L-Phe-L-Thr-Gly-L-
Ile(Thz)] (1) and cyclo-[L-Thr-L-Val-L-Thr-L-Ala-L-Ile(Thz)]
(2), as proposed structures for microcyclamides MZ602 and
MZ568, were synthesized for the first time via a convergent
synthetic route from commercial available amino acids in 11
longest linear steps with good yields. Synthetic 1 was found to
be quite similar in all respects to the isolated microcyclamide
MZ602, except for the optical rotation. The spectral data of
synthetic 2 were found to be significantly different with the
natural microcyclamide MZ568. Our findings suggested that
the proposed structures of natural microcyclamides MZ602
and MZ568 need to be revised both. The highlights of our
synthetic method include one-pot cascade thiazole-formation
D
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reaction and removable pseudoprolines (ΨMe,Me pro) assisted
cyclization strategy. Further studies toward other possible
isomers of micrcocyclamides MZ602 and MZ568, and other
cyanobacteria secondary metabolites (balgacyclamides A-C,
aerucyclamides A-D) are currently in progress in our lab.
peptide (1 mmol) in 15 mL CH2Cl2. The reaction mixture was stirred
at room temperature until the reaction was complete, as judged by
TLC (typically 3 h). The solvent was removed by rotary evaporation
with toluene to give the desired free amine.
General Procedure for the Formation of Pseudoproline(ΨMe,Me
pro) Method F. 2-Methoxypropene (3.0 mmol) was added to a
cooled solution of a substrate (1.0 mmol) in 20 mL CH2Cl2. Then, D-
(+)-camphorsulfonic acid (D-(+)-CSA) (10 mol %) was slowly added
into the solution. The solution immediately became red, and the
reaction mixture was stirred at 0 °C for further 5 h. The reaction was
quenched and diluted with 10 mL of CH2Cl2, and washed with 20 mL
NaHCO3(aq). The organic fraction was dried over MgSO4, filtered,
and concentrated, and the residue was purified by flash chromatog-
raphy to give the desired ΨMe,Me pro-containing product.
EXPERIMENTAL SECTION
■
General Experimental Details. Unless other indicated, all
reagents were purchased from commercial corporations. All reactions
were performed in oven-dried glassware under standard conditions.
Flash chromatography (FC) was performed using silica gel (200−300
meshes). High-resolution mass spectrometry data were acquired using
a Q-TOF analyzer. Optical rotations were recorded on a Rudolph
Polarimeter Autopol 111. Melting points were analyzed on a Melt-
Method G. 2,2-Dimethoxypropane (6.0 mmol) and PPTS (0.3
mmol) were added to a solution of the threonine-containing substrate
(1 mmol) in 15 mL toluene at room temperature. The reaction
mixture was heated to 80 °C using oil bath and stirred overnight. The
solution was cooled to room temperature and CH2Cl2 (20 mL) was
added. Then, the solution was washed with 20 mL NaHCO3(aq) and
extracted with CH2Cl2. The combined organic phase was washed with
saturated brine, dried (Na2SO4), and concentrated, and the residue
was purified by flash chromatography to give the desired ΨMe,Me pro-
containing product.
Temp II capillary melting point apparatus. H NMR, 13C NMR, and
1
HMBC were measured on 400 MHz/100 MHz Bruker spectrometers
or JEOL JNM-ECZ400S spectrometers (NMR in CDCl3 with TMS
as an internal standard). Chemical shifts (δ) are given in ppm relative
1
to residual solvent (usually chloroform: δ 7.26 for H NMR or 77.23
1
for proton decoupled 13C NMR; DMSO; δ 2.50 for H NMR or
39.53 for proton decoupled 13C NMR; MeOH; δ 3.31 for 1H NMR or
49.03 for proton decoupled 13C NMR), and coupling constants (J) in
Hz. Signals are reported as follows: s (singlet), d (doublet), t (triplet),
q (quartet), dd (doublet of doublets), dt (doublet of triplets), ddt
(doublet of doublets of triplets), dq (doublet of quartets), br s (broad
singlet), and m (multiplet). β-azido disulfide 10 was prepared
Cbz-Gly-L-Thr-OMe (16).10 The reaction was performed according
to the method A using Cbz-Gly-OH 15 (1.5 g, 7.2 mmol) and NH2-L-
Thr-OMe 14 (1.0 g, 7.2 mmol) for 18 h, and the crude mixture was
purified using EtOAc/petroleum ether = 4:1 as an eluent to give
according to our previous report11a
.
compound 16 as a white solid (2.0 g, 86%). Data are consistent with a
General Procedure for the Peptide Coupling Reaction Method A.
Under anhydrous conditions, N-methylmorpholine (NMM) (2.2
mmol) was added to a solution of N-protected amino acid (1.0
mmol), EDCI (1.5 mmol), and HOBt (1.2 mmol) in 15 mL THF.
After stirring at 0 °C for 10 min, a solution of amine (1.0 mmol),
NMM (1.2 mmol) in 10 mL DMF was added into the mixture. The
reaction was allowed to warm to room temperature and stirred
overnight. The reaction was then quenched by H2O and extracted
with EtOAc. The combined organic phase was washed with saturated
brine, dried (Na2SO4), and evaporated. The crude compound was
purified by flash chromatography to give the desired peptide.
Method B. HATU (1.5 mmol) was added to the solution of N-
protected substrate (1.0 mmol) and DIPEA (2.0 mmol) in 20 mL
CH2Cl2. After stirring at room temperature for 10 min, amine (1.0
mmol) was added into the reaction mixture and stirred overnight. The
reaction was quenched by saturated aqueous NH4Cl and extracted
with 30 mL CH2Cl2 three times. The combined organic phase was
washed with brine, dried (Na2SO4), and evaporated. The crude
compound was purified by flash chromatography to give the desired
coupled peptide.
General Procedure for Hydrolysis Method C. LiOH aqueous (0.5
N, 8 mL) was added dropwise to a solution of methyl ester or allyl
ester (1 mmol) in MeOH (10 mL)/THF (10 mL). The reaction
mixture was stirred at room temperature until the reaction was
complete, as judged by TLC (typically 3 to 5 h). The reaction mixture
was diluted with H2O and acidified to pH 3 by the 10% aqueous
solution of citric acid. The mixture was extracted with EtOAc. The
combined organic phase was washed with saturated brine, dried
(Na2SO4), and concentrated under reduced pressure to give the crude
carboxylic acid.
previously characterized compound.10 mp 101−105 °C, [α]D
=
25
−3.6 (c 1.0, CH3OH). [Lit.10 [α]D = −5.2 (c 1.0, CH3OH)]. H
NMR (400 MHz, CDCl3) δ: 7.33 (m, 5H), 7.11 (s, 1H), 5.79 (br, s,
1H), 5.11 (s, 2H), 4.58 (d, J = 8.0 Hz, 1H), 4.31 (s, 1H), 3.94 (s,
2H), 3.73 (s, 3H), 2.74 (s, 1H), 1.17 (s, 3H). HRMS (ESI) m/z: [M
+ Na]+ calcd for C15H20N2O6Na 347.1214; found 347.1212.
1
Cbz-Gly-L-Thr(ψMe, MePro)-OMe (17).10 According to the method F,
condensation of the dipeptide 16 (130 mg, 0.4 mmol) with 2-
methoxypropene, and the crude mixture was purified using EtOAc/
petroleum ether = 1:2 as an eluent to give the desired product 17
(131 mg, 90%) as a colorless oil. Data are consistent with a previously
characterized compound.10 [α]D25−40.0 (c 5.5, CHCl3). [Lit.10 [α]D
1
= −27.73 (c 4.4, CHCl3]. H NMR (400 MHz, DMSO) δ: 7.35 (m,
5H), 5.03 (s, 2H), 4.56 (d, J = 5.2 Hz, 1H), 4.34 (m, 1H), 3.83 (dd, J
= 16.8, 5.6 Hz, 1H), 3.75 (s, 3H), 3.65 (m, 1H), 3.43 (dd, J = 16.8,
6.4 Hz, 1H), 1.58 (s, 3H), 1.44 (s, 3H), 1.36* (d, J = 6.0. Hz, 3H)
(*minor rotamer); HRMS (ESI) m/z: [M + Na]+ calcd for
C18H24N2O6Na 387.1532; found 387.1530.
Boc-L-Phe-L-Thr-OMe (18). The reaction was performed according
to the method A using compound 7 (2.2 g, 8.3 mmol) and compound
14 (1.1 g, 8.3 mmol) as substrates and stirred for 18 h. The crude
mixture was purified using EtOAc/petroleum ether = 1:1 as an eluent
to give compound 18 as a glassy solid (3.0 g, 95%). [α]D25−5.3 (c 1.0,
CHCl3). [Lit.13 [α]D = −6.6 (c 1.0, CHCl3].# 1H NMR (400 MHz,
29
CDCl3) δ: 7.21−7.26 (m, 5H), 6.75−6.80 (m, 1H), 5.07−5.11 (m,
1H), 4.57 (dd, J = 8.8, 2.0 Hz, 1H), 4.37−4.41 (m, 1H), 4.28 (dd, J =
6.4, 2.0 Hz, 1H), 3.72 (s, 1H), 3.13 (dd, J = 14.0, 6.4 Hz, 1H), 3.05
(dd, J = 13.2, 6.4 Hz, 1H), 2.57 (br. s, 1H), 1.39 (s, 9H), 1.16 (d, J =
6.4 Hz, 3H); 13C{1H} NMR (100 MHz) δ: 171.7, 171.0, 155.5,
136.4, 129.3, 128.5, 126.7, 80.3, 66.2, 57.2, 55.8, 52.5, 37.8, 28.2, 19.7;
HRMS (ESI) m/z: [M + Na]+ calcd for C19H28N2O6Na 403.1845;
found 403.1856.
General Procedure for Removal of Cbz Group Method D. A 0.1
mmol catalytic Pd/C (10 mol %) was added to a solution of the Cbz-
protected peptide (1 mmol) in MeOH (20 mL), The flask was
evacuated and then filled with H2(g) and the procedure was repeated
three times, then the mixture was stirred under H2(g) at room
temperature for 5 h. After which, the contents of the flask were filtered
through a pad of Celite. The Celite was then washed several times
(CH2Cl2/MeOH/NH3(aq) 90:9:1), the organic fractions were
combined, and the solvent was removed by rotary evaporation to
give the desired free amine.
Cbz-Gly-L-Thr(ψMe,MePro)-L-Phe-L-Thr-OMe (19). Following the
general method C, 17a was obtained from 17 (327 mg, 0.9 mmol)
and used for the next step without purification. Following the general
method E, 18a was obtained from 18 (342 mg, 0.9 mmol) and used
for the next step without purification. Following the general method
B, the desired tetrapeptide 19 (416 mg, 75% for two steps) was
obtained as a glassy solid. EtOAc/petroleum ether 1:1 (v/v) was used
as an eluent. [α]D25−31.0 (c 0.8, CHCl3); 1H NMR (400 MHz,
DMSO) δ: 8.69 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 9.6 Hz, 1H), 8.32 (s,
General Procedure for Removal of Boc Group Method E. A 6 mL
trifluoroacetic acid was added to a solution of the Boc-protected
E
https://dx.doi.org/10.1021/acs.joc.0c02541
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1H), 7.42−7.27 (m, 6H), 7.13 (t, J = 7.2 Hz, 2H), 7.00 (t, J = 7.2 Hz,
1H), 5.07 (d, J = 4.8 Hz, 1H), 5.07−4.99 (m, 2H),4.88 (t, J = 12.0
Hz, 1H), 4.31 (dd, J = 8.4, 3.2 Hz, 1H), 4.19−4.10 (m, 1H), 4.01 (d, J
= 7.2 Hz, 1H), 3.96−3.87 (m, 1H), 3.63 (s, 3H), 3.11 (td, J = 18.0,
4.0 Hz, 2H), 2.77 (t, J = 10.8 Hz,1H), 1.50 (s, 3H), 1.40 (s, 3H), 1.33
(d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ: 171.6#, 168.9#, 157.5#, 137.7, 135.8, 129.1, 128.5,
128.3, 128.1, 127.9, 126.8#, 94.7#, 73.2#, 67.5, 60.4, 58.7#, 55.3#, 52.6,
43.5, 38.6, 28.5, 25.0, 19.8, 18.4 (#minor rotamer); mp75−76 °C;
ESI-HRMS calcd for ([M + Na]+), found. HRMS (ESI) m/z: [M +
Na]+ calcd for C31H40N4O9Na 635.2693; found 635.2657.
69.2, 68.6, 67.3, 66.3, 57.0, 38.0, 37.4, 35.7, 28.7, 26.9, 25.1, 24.1,
22.0, 19.4, 16.7, 10.0; HRMS (ESI) m/z: [M + Na]+ calcd for
C34H46N6O7SNa 705.3046; found 705.3052.
Synthetic Microcyclamide MZ602 (1). To a solution of compound
23 (10 mg, 0.01 mmol) in CH2Cl2 (5 mL) was added TFA (1.5 mL)
at 0 °C. Then, the mixture was warmed to room temperature and
stirred until TLC showed complete consumption of the starting
material (∼14 h). The organic phase was concentrated under reduced
pressure, and the residue was purified by flash column chromatog-
raphy (CH2Cl2/MeOH, 10:1) to give 1 as a glassy solid (7.6 mg,
86%). {Observed for compound 1:[α]D22−24.3 (c 0.7, MeOH), lit.4
24
1
Cbz-Gly-L-Thr(ψMe,MePro)-L-Phe-L-Thr(ψMe,MePro)-OMe (20). Ac-
cording to the method G, the tetrapeptide 19 (122 mg, 0.2 mmol)
reacted with 2,2-dimethoxypropane to give the desired pseudoproline
protected tetrapeptide 20 (94 mg, 72%) as a colorless oil. EtOAc/
petroleum ether (2:3, v/v) was used as an eluent. [α]D25−20.9 (c 3.5,
microcyclamide MZ602: [α]D + 53 (c 0.06, MeOH)}; H NMR
(400 MHz, DMSO) δ: 8.53 (t, J = 5.6 Hz, 1H), 8.22 (s, 1 H), 8.15 (d,
J = 7.2 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H),
7.74 (d, J = 8.8 Hz, 1H), 7.30−7.16 (m, 5H), 5.16 (br s, 1H), 5.11
(dd, J = 8.4, 5.6 Hz, 1H), 4.84 (br s, 1H), 4.49 (m, 1H), 4.16 (m,
1H), 4.02−3.82 (m, 5H), 3.32 (m, 1H), 2.87 (dd, J = 14.0, 10.8 Hz,
1H), 2.05−1.97 (m, 1H), 1.46−1.39 (m, 1H), 1.15−1.06 (m, 1H),
1.09 (d, J = 6.4, 3H), 0.87 (d, J = 6.8, 3H), 0.86 (t, J = 7.2, 3H), 0.82
(d, J = 6.0, 3H); 13C{1H} NMR (100 MHz, DMSO) δ: 172.0, 170.6,
169.9, 169.1, 168.8, 161.1, 148.8, 138.0, 129.2, 128.2, 126.4, 124.0,
66.1, 65.3, 61.0, 60.7, 55.1, 54.4, 43.6, 39.2, 37.2, 24.6, 20.5, 20.2,
15.7, 11.8; HRMS (ESI) m/z: [M + Na]+ calcd for C28H38N6O7SNa
625.2420; found 625.2380.
1
CHCl3); H NMR (400 MHz, DMSO) δ: 8.90 (d, J = 8.8 Hz, 1H),
7.38−7.15 (m, 10H), 5.02 (q, J = 12.4 Hz, 2H), 4.55 (q, J = 8.0 Hz,
1H), 4.18−4.13 (m, 2H), 4.06 (t, J = 6.0 Hz, 1H),3.87 (d, J = 6.0 Hz,
1H), 3.66 (s, 3H), 3.40 (dd, J = 16.8, 6.0 Hz, 1H), 3.04 (dd, J = 16.8,
6.0 Hz, 1H), 2.96−2.83 (m, 2H), 1.54 (s, 3H), 1.45 (s, 3H), 1.43 (s,
3H), 1.40 (s, 3H), 1.34 (d, J = 6.0 Hz, 3H), 1.10 (d, J = 6.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ: 170.6, 168.9, 167.8, 166.0,
156.2, 136.5, 135.6, 129.5, 128.7, 128.5, 128.0, 127.4, 97.3, 97.1, 75.9,
74.3, 66.8, 65.6, 60.4, 54.0, 53.4, 43.9, 40.7, 26.6, 26.0, 23.9, 23.4,
19.9, 19.1; HRMS (ESI) m/z: [M + Na]+ calcd for C34H44N4O9Na
675.3006; found 675.2979.
Boc-L-Phe-L-Thr(Bzl)-OAllyl (3). The reaction was performed
according to the method A using compound 7 (2.0 g, 7.5 mmol)
and compound 6 (1.8 g, 7.5 mmol) as substrates and stirred for 18 h.
The crude mixture was purified by flash column chromatography to
give compound 3 as a colorless oil (3.4 g, 90%). EtOAc/petroleum
ether (1:1, v/v) was used as an eluent. [α]D25 + 28.9 (c 4.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ: 7.34−7.25 (m, 5H), 7.23−7.20 (m,
5H), 6.62 (d, J = 9.6 Hz, 1H), 5.87−5.77 (m, 1H), 5.28 (dq, J = 17.2,
1.6 Hz, 1H), 5.21 (dq, J = 10.4, 1.2 Hz, 1H), 5.04 (br s, 1H), 4.65
(dd, J = 9.2, 2.4 Hz, 1H), 4.59 (dt, J = 6.0, 1.2 Hz, 1H), 4.53 (d, J =
12.0 Hz, 2H), 4.44 (br s, 1H), 4.35 (d, J = 11.6 Hz, 1H), 4.13 (qd, J =
6.4, 2.4 Hz, 1H), 3.14 (dd, J = 14.0, 6.0 Hz, 1H), 3.05 (dd, J = 12.8,
6.4 Hz, 1H), 1.39 (s, 9H), 1.16 (d, J = 6.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ: 171.9, 169.9, 155.3, 137.8, 136.6, 131.6, 129.6,
129.5, 129.4, 128.7, 128.6, 128.4, 127.9, 127.8, 127.0, 119.0, 80.1,
74.3, 70.9, 66.1, 56.8, 55.7, 38.3, 28.3, 16.2; HRMS (ESI) m/z: [M +
Na]+ calcd for C28H36N2NaO6 519.2471; found 519.2466.
Cbz-Gly-L-Thr(ψMe,MePro)-L-Phe-L-Thr(ψMe,MePro)-L-Ile-Thz-OAllyl
(21). Following the general method C, 20a was obtained from 20
(260 mg, 0.4 mmol) and used for the next step without purification.
Following the general method E, 5a was obtained from 5 (142 mg, 0.4
mmol) and used for the next step without purification. Following the
general method B, the desired tetrapeptide 21 (220 mg, 63% for two
steps) was obtained as a colorless oil. EtOAc/petroleum ether (1:1, v/
1
v) was used as an eluent. [α]D25−84.7 (c 0.5, CH3OH); H NMR
(400 MHz, CD3OD) δ: 8.29 (s, 1H), 7.42−7.14 (m, 10H), 6.05 (ddt,
J = 16.8, 10.8, 1.2 Hz, 1H), 5.40 (dd, J = 16.8, 1.2 Hz, 1H), 5.27 (dd, J
= 10.8, 1.2 Hz, 1H), 5.13−5.07 (m, 2H), 5.04 (d, J = 6.0 Hz, 1H),
4.80 (d, J = 6.0 Hz, 2H), 4.65−4.61 (m, 1H), 4.25−4.18 (m, 1H),
4.13 (d, J = 7.6 Hz, 1H), 3.97 (t, J = 6.4 Hz, 1H), 3.81 (d, J = 6.4 Hz,
1H), 3.61 (d, J = 16.8 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 3.07−2.94
(m, 2H), 2.11 (br s, 1H), 1.77−1.68 (m, 2H), 1.62 (s, 3H), 1.48 (s,
3H), 1.45 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H),
0.99 (t, J = 6.4 Hz, 3H), 0.90 (t, J = 6.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CD3OD) δ: 173.5, 170.7, 170.3, 169.8, 168.5, 162.3,
158.7, 147.3, 138.2, 137.5, 133.4, 130.7, 129.7, 129.4, 129.0, 128.9,
128.2, 118.8, 98.1, 97.9#, 77.3, 76.9, 67.8#, 67.2, 66.8, 58.4#, 55.4#,
44.6#, 40.6, 39.9, 27.2, 27.0, 26.7, 24.2, 19.9, 19.1#, 15.8#, 12.1#
(#minor rotamer); HRMS (ESI) m/z: [M + Na]+ calcd for
C45H58N6O10SNa 897.3833; found 897.3803.
Boc-Gly-L-Thr(Bzl)-OAllyl (4). The reaction was performed
according to the method A using Boc-Gly-OH 8 (2.0 g, 11.4
mmol) and L-Thr(Bzl)-OAllyl 6 (2.8 g, 11.4 mmol) as substrates, and
stirred overnight. The crude mixture was purified by flash column
chromatography to give compound 4 as a colorless oil (4.0 g, 86%).
25
EtOAc/petroleum ether (1:1, v/v) was used as an eluent. [α]D
−
15.2 (c 3.0, MeOH); 1H NMR (400 MHz, CDCl3) δ: 7.34−7.23 (m,
5H), 6.91 (d, J = 9.2 Hz, 1H), 5.82 (ddt, J = 10.4, 5.6, 1.2 Hz, 1H),
5.40 (br. s, 1H), 5.28 (dd, J = 16.8, 1.2 Hz, 1H),5.10 (d, J = 10.4 Hz,
1H), 4.70 (dd, J = 9.2, 2.0 Hz, 1H), 4.60 (dd, J = 13.2, 5.6 Hz, 1H),
4.56 (d, J = 12.0 Hz, 1H), 4.51 (dd, J = 13.2, 5.6 Hz, 1H), 4.36 (d, J =
12.0 Hz, 1H), 4.17 (dq, J = 6.0, 2.0 Hz, 1H), 3.86 (dq, J = 16.8, 5.6
Hz, 2H), 1.53 (s, 9H), 1.31 (d, J = 6.0 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ: 170.2, 170.1, 156.0, 137.8, 131.6, 128.4, 127.8,
118.9, 80.0, 74.2, 70.7, 66.1, 56.6, 44.2, 28.3, 16.1; ESI-HRMS calcd
Cyclo-[Gly-L-Thr(ψMe,MePro)-L-Phe-L-Thr(ψMe,MePro)-L-Ile-Thz] (23).
Following the method C and method D, linear peptide 21 (88 mg, 0.1
mmol) generate the intermediate 22. Next, 22 was added to a solution
of HATU (76 mg, 0.2 mmol) and HOBt (14 mg, 0.1 mmol) in
CH2Cl2/DMF (3/1, 100 mL) at room temperature. The mixture
(0.001 M) was stirred until TLC showed complete consumption of
the starting material (∼24 h). The reaction was quenched by
saturated NH4Cl (50 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic phase was washed with H2O, dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified by
flash column chromatography (CH2Cl2/MeOH, 30:1) to give
compound 23 as colorless oil (38 mg, 55% for three steps).
+
for C21H30N2O6Na ([M + Na] ) 429.2002, found 429.2011. HRMS
(ESI) m/z: [M + Na]+ calcd for C21H30N2O6Na 429.2002; found
429.2011.
Boc-L-Ile-Thz-OAllyl (5). To a solution of compound 9 (115 mg,
0.5 mmol) in CH2Cl2 (10 mL) was added pentafluorophenyl
diphenylphosphinate (FDPP) (200 mg, 0.5 mmol) and triethylamine
(TEA) (125 mg, 1.0 mmol) at room temperature. After stirring for 15
min, 10 (40 mg, 0.125 mmol) and PPh3 (270 mg, 1.0 mmol) was
added into the solution and heated to reflux for further 5 h away from
light. After cooling to 0 °C, 1,8-diazabicycloundec-7-ene (DBU) (228
mg, 1.5 mmol) and bromotrichloromethane (248 mg, 1.25 mmol)
were introduced via spyringe over 5 min and stirred for further 30 min
at room temperature. The solvent was quenched with saturated
NH4Cl solution and extracted with DCM (20 mL × 3). The
[α]D25−86.5 (c 0.1, CHCl3); H NMR (400 MHz, CD3OD) δ: 8.26
1
(s, 1 H), 8.17 (br. s, 1H),7.29−7.27 (m, 2H), 7.20−6.95 (m, 5H),
5.12 (d, J = 16.8 Hz, 1H), 4.73−4.68 (m, 1H), 4.43−4.37 (m, 1H),
4.34−4.27 (m, 2H), 3.65 (d, J = 16.8 Hz, 1H), 3.44 (s, 1H), 3.18−
3.07 (m, 2H), 2.96 (dd, J = 14.8, 5.6 Hz, 1H), 2.65−2.55 (m, 1H),
1.72 (s, 2H), 1.66−1.62 (m, 12H), 1.57−1.49 (m, 3H), 0.95−0.82
(m, 9H); 13C{1H} NMR (100 MHz, CD3OD) δ: 171.9, 170.3, 169.5,
168.7, 168.4, 136.5, 130.6, 130.1, 129.6, 129.0, 128.2, 98.8, 78.4, 77.4,
F
https://dx.doi.org/10.1021/acs.joc.0c02541
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
,
combined organic layer was washed with brine and dried over
anhydrous Na2SO4, filtered, concentrated in vacuo (below 45 °C),
and purified by flash column chromatography (EtOAc/petroleum
ether, 1:5) to give compound 5 as a colorless oil (61 mg, 69% yield).
[α]D25−18.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.05 (s,
1H), 5.95 (ddt, J = 8.4, 4.4, 0.8 Hz, 1H), 5.35 (s, 1H), 5.33 (dd, J =
14.0, 0.8 Hz, 1H), 5.21 (dd, J = 8.4, 0.8 Hz, 1H), 4.87 (br s, 1H), 4.77
(d, J = 4.4 Hz, 2H), 2.09 (br s, 1H), 1.36 (s, 9H), 1.11−1.09 (m, 1H),
0.87−0.81 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ: 173.1,
160.9, 155.4, 146.9, 132.0, 127.2, 118.8, 80.0, 66.9, 57.5, 39.7, 28.3,
24.5, 15.8, 11.5; HRMS (ESI) m/z: [M + Na]+ calcd for
C17H26N2NaO4S 377.1511; found 377.1522.
Data are consistent with a previously characterized compound.11a 12
[α]D20−18.2 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.04 (s,
1H), 5.31 (d, J = 8.4 Hz, 1H), 4.88 (s, br, 1H), 3.87 (s, 3H), 2.08−
2.26 (m, 1H), 1.37 (s, 9H), 1.05−1.12 (m, 1H), 0.81−0.87 (m, 6H);
HRMS (ESI) m/z: [M + Na]+ calcd for C15H24N2O4SNa 351.1349;
found 351.1346.
Cbz-Gly-L-Thr-L-Phe-L-Thr-OMe (26). Following the general
method C and B, compound 26 was obtained from 16 (97 mg, 0.3
mmol) and 18 (114 mg, 0.3 mmol) as a colloidal solid (134 mg, 78%
yield); [α]D25−37.2 (c 1.0, CH3OH); 1H NMR (400 MHz, CD3OD)
δ: 7.36−7.18 (m, 10H), 5.11 (s, 2H), 4.73 (dd, J = 8.8, 5.6 Hz, 1H),
4.43 (d, J = 3.6 Hz, 1H), 4.30 (d, J = 4.0 Hz, 1H), 4.25 (m, 1H), 4.09
(m, 1H), 3.83 (d, J = 1.2 Hz, 2H), 3.71 (s, 3H), 3.24 (dd, J = 13.6, 5.2
Hz, 1H), 2.98 (dd, J = 14.0, 8.8 Hz, 1H), 1.15 (d, J = 6.4 Hz, 3H),
1.10 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ:
172.4, 171.3, 170.9, 170.8, 157.8, 137.1, 136.7, 129.0, 128.2, 128.1,
127.7, 127.5, 126.4, 67.2, 66.8, 66.6, 58.2, 54.7, 51.5, 43.7, 37.0, 18.9,
18.5; HRMS (ESI) m/z: [M + Na]+ calcd for C28H36N4O9Na
595.2374; found 595.2375.
Boc-Gly-L-Thr(Bzl)-L-Phe-L-Thr(Bzl)-OAllyl (11). Following the
general method C, 4a was obtained from 4 (1.1 g, 2.7 mmol) and
used for the next step without purification. Following the general
method E, 3a was obtained from 3 (1.3 g, 2.7 mmol) and used for the
next step without purification. Following the general method B, the
desired tetrapeptide 11 (1.7 g, 84% for two steps) was obtained as a
glassy solid. EtOAc/petroleum ether (1:1, v/v) was used as an eluent.
[α]D25 + 10.1 (c 5.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.39−
7.15 (m, 15H), 5.86−5.72 (m, 1H), 5.47 (dt, J = 22.0, 4.0 Hz 1H),
5.31−5.24 (m, 1H), 5.22−5.16 (m, 1H), 4.99−4.91 (m, 1H), 4.71 (t,
J = 10.0 Hz, 1H),4.60−4.37 (m, 6H), 4.30 (d, J = 12.0 Hz, 1H),
4.17−4.12 (m, 1H), 3.89−3.75 (m, 1H), 3.64−3.73 (m, 1H), 3.13 (d,
J = 12.0 Hz, 1H), 2.88 (dq, J = 20.0, 12.0 Hz, 1H), 1.40 (s, 9H),
1.09−0.97 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ: 171.7,
170.1, 169.6, 169.4, 156.2, 138.1, 137.9, 136.7, 131.8, 129.5, 129.4,
128.5, 128.4, 128.0, 127.9, 126.9, 118.9, 80.0, 75.2, 74.1, 71.3, 70.8,
66.1, 56.8, 56.0, 54.5, 44.2, 38.5, 28.4, 28.3, 16.1, 14.9; HRMS (ESI)
m/z: [M + Na]+ calcd for C41H52N4O9Na 767.3632; found 767.3625.
Boc-Gly-L-Thr(Bzl)-L-Phe-L-Thr(Bzl)-L-Ile-Thz-OAllyl (12). Follow-
ing the general method C, 11a was obtained from 11 (521 mg, 0.7
mmol) and used for the next step without purification. Following the
general method E, 5a was obtained from 5 (248 mg, 0.7 mmol) and
used for the next step without purification. Following the general
method B, the desired hexapeptide 12 (375 mg, 57% yield for two
steps) was obtained as a glassy solid. EtOAc/petroleum ether (1:1, v/
v) was used as an eluent. [α]D25 −11.2 (c 4.0, CHCl3); 1H NMR (400
MHz, CD3OD) δ: 8.25 (s, 1H), 7.28−7.19 (m, 18H), 6.00 (ddt, J =
16.4, 10.8, 6.4 Hz, 1H), 5.37 (dd, J = 16.4, 1.6 Hz, 1H), 5.27 (dd, J =
10.8, 1.6 Hz, 1H), 5.17 (d, J = 8.0 Hz, 1H), 4.80 (dd, J = 8.0, 1.6 Hz,
1H), 4.76 (d, J = 6.0 Hz, 2H), 4.59−4.53 (m, 3H), 4.50 (d, J = 12.0
Hz, 1H), 4.45−4.31 (m, 4H), 4.10−3.99 (m, 2H), 3.70 (d, J = 4.4 Hz,
2H), 3.17 (dd, J = 13.6, 4.4 Hz, 1H), 2.97 (dd, J = 13.6, 8.0 Hz, 1H),
2.11−2.05 (m, 1H), 1.56−1.50 (m, 1H), 1.41 (s, 9H), 1.13 (d, J = 6.4
Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H), 0.88−0.82 (m, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ: 172.3, 170.9, 169.9, 169.9, 169.3, 161.0,
146.6, 137.9, 137.8, 132.0, 129.1, 128.8, 128.5, 128.4, 128.2, 128.0,
127.9, 127.6, 127.2, 118.9, 80.6, 74.1, 73.4, 71.7, 71.5, 65.9, 57.0, 56.7,
55.2, 39.1, 37.5, 32.0, 30.0, 29.8, 29.4, 28.4, 27.3, 15.8, 15.4, 14.2,
11.4; HRMS (ESI) m/z: [M + Na]+ calcd for C50H64N6O10SNa
963.4302; found 963.4297.
Cbz-L-Ala-L-Thr-OMe (28).14 The reaction was performed accord-
ing to the method A using compound 27 (2.0 g, 8.9 mmol) and
compound 14 (1.2 g, 8.9 mmol) as substrates and stirred overnight.
The crude mixture was purified using EtOAc/petroleum ether = 1:1
as an eluent to give compound 28 (2.5 g, 84%) as a white solid. Data
are consistent with a previously characterized compound.14 mp 128−
131 °C; [α]D25−14.8 (c 1.0, CH3OH); 1H NMR (400 MHz, CDCl3)
δ: 7.83 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.36−7.12 (m,
5H), 5.03 (d, J = 1.6 Hz, 2H), 4.29 (dd, J = 8.4, 2.8 Hz, 1H), 4.20 (m,
1H), 4.14 (m, 1H), 3.62 (s, 3H), 1.23 (d, J = 7.2 Hz, 3H), 1.06 (d, J =
6.4 Hz, 3H); HRMS (ESI) m/z: [M + Na]+ calcd for C16H22N2O6Na
361.1376; found 361.1374.
Cbz-L-Ala-L-Thr(ψMe,MePro)-OMe (29). According to the method F,
the reaction of the dipeptide 28 (203 mg, 0.6 mmol) with 2-
methoxypropene/D-(+)-CSA and the crude mixture was purified
using EtOAc/petroleum ether = 1:2 as eluent to give the desired
pseudoproline protected dipeptide 29 (195 mg, 86%) as a colorless
1
oil. [α]D25−75.2 (c 1.0, CH3OH); H NMR (400 MHz, CDCl3) δ:
7.35−7.28 (m, 5H), 5.69, 5.50* (d, J = 7.6 Hz, 1H), 5.08 (m, 2H),
4.68*, 4.31 (m, 1H), 4.14 (m, 1H), 4.13*, 4.06 (d, J = 6.0 Hz, 1H),
3.76, 3.73* (s, 3H), 1.80*, 1.63 (s, 3H), 1.67*, 1.58 (s, 3H), 1.46,
1.39* (d, J = 6.4 Hz, 3H), 1.37*, 1.29 (d, J = 6.8 Hz, 3H) (*minor
rotamer); 13C{1H} NMR (100 MHz, CDCl3) δ: 170.5#, 169.7,
155.3#, 136.6#, 128.5, 128.1, 128.0, 97.2#, 75.0#, 72.9, 66.7#, 65.6,
53.4#, 49.5#, 26.4, 23.8, 19.9#, 18.5 (#minor rotamer); HRMS (ESI)
m/z: [M + Na]+ calcd for C19H26N2O6Na 401.1689; found 401.1683.
Boc-L-Val-L-Thr-OMe (31).15 The reaction was performed accord-
ing to the method A using compound 30 (1.5 g, 6.9 mmol) and
compound 14 (0.9 g, 6.9 mmol) as substrates, and stirred for 18 h.
The crude mixture was purified using EtOAc/petroleum ether = 1:2
as an eluent to give compound 31 (1.8 g, 77%) as a colorless oil. Data
are consistent with a previously characterized compound.15 [α]D
−
25
1
39.2 (c 1.0, CH3OH); H NMR (400 MHz, CDCl3) δ: 7.06 (d, J =
8.0 Hz, 1H), 5.31 (d, J = 8.0 Hz, 1H), 4.60 (dd, J = 8.0, 4.0 Hz, 1H),
4.33 (dd, J = 6.4, 2.4 Hz, 1H), 3.94 (t, J = 8.8 Hz, 1H), 3.73 (s, 3H),
2.07−2.02 (m, 1H), 1.40 (s, 9H), 1.17 (d, J = 6.8 Hz, 3H), 0.97−0.92
(m, 6H); HRMS (ESI) m/z: [M + Na]+ calcd for C15H28N2O6Na
355.1845; found 355.1843.
Boc-D-allo-Ile-Thz-OAllyl (24). Following the same procedure as
for compound 5, compound 24 was prepared in the solution as
colorless oil (56 mg, 64% yield). [α]D20−10.9 (c 0.5, CHCl3); H
1
NMR (400 MHz, CDCl3) δ: 8.08 (s, 1H); 6.01 (ddt, J = 8.8, 4.8, 1.2
Hz, 1H), 5.38 (dd, J = 14.0, 1.2 Hz, 1H), 5.27 (dd, J = 8.4, 1.2 Hz,
1H), 5.24 (s, br, 1H), 5.04 (s, br, 1H), 4.82 (d, J = 4.4 Hz, 2H),
2.23−2.25 (m, 1H), 1.46−1.48 (m, 2H), 1.44 (s, 9H), 0.94 (t, J = 6.0
Hz, 3H), 0.82 (d, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ: 174.6, 161.1, 155.6, 147.1, 132.0, 127.2, 119.0, 80.3, 66.1,
56.6, 39.7, 28.4, 26.5, 14.0, 11.7; HRMS (ESI) m/z: [M + Na]+ calcd
Cbz-L-Ala-L-Thr(ψMe,MePro)-L-Val-L-Thr-OMe (32). Following the
general method C, 29a was obtained from 29 (227 mg, 0.6 mmol)
and used for the next step without purification. Following the general
method E, 31a was obtained from 31 (202 mg, 0.6 mmol) and used
for the next step without purification. Following the general method
B, the desired hexapeptide 32 (264 mg, 76% for two steps) was
obtained as a glassy solid. EtOAc/petroleum ether (2:1, v/v) was used
for C17H26N2O4SNa 377.1511; found 377.1520.
Boc-L-Ile-Thz-OMe (25)11a 12
.
Compound 5 (35 mg, 0.1 mmol)
,
1
was dissolved in 5 mL MeOH, then K2CO3 (69 mg, 0.5 mmol) was
added into the solution and stirred for 3 h. The reaction mixture was
diluted with 15 mL H2O and extracted with 15 mL EtOAc three
times. The combined organic phase was washed with saturated brine,
dried (Na2SO4), and concentrated, and the residue was purified by
flash chromatography to give the desired 25 in 32 mg (99% yield).
as an eluent. [α]D25−110.8 (c 1.0, CH3OH); H NMR (400 MHz,
CD3OD) δ: 7.34−7.27 (m, 5H), 5.06 (s, 2H), 4.48 (d, J = 2.8 Hz,
1H), 4.30−4.09 (m, 5H), 3.73 (s, 3H), 3.35 (s, 1H), 2.15 (s, 1H),
1.62 (s, 6H), 1.41 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.4
Hz, 3H), 1.04 (t, J = 8.0 Hz, 6H); 13C{1H} NMR (100 MHz,
CD3OD) δ: 172.6, 171.0, 169.8, 156.2, 136.9, 128.2, 127.7, 127.5,
G
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Article
1
96.9, 76.1, 67.1, 66.2, 60.3, 57.9, 51.5, 49.5, 29.9, 25.5, 19.0, 18.5,
17.3; HRMS (ESI) m/z: [M + Na]+ calcd for C28H42N4O9Na
601.2849; found 601.2850.
microcyclamide MZ568: [α]D24−225 (c 0.03, MeOH)}; H NMR
(400 MHz, DMSO) δ: 8.50 (d, J = 10.0 Hz, 1H), 8.17 (s, 1H), 7.97
(d, J = 9.2 Hz, 1H), 7.94 (d, J = 5.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H),
5.04 (d, J = 3.2 Hz, 1H), 5.02 (s, 1H), 5.00−4.97 (m, 1H), 4.57 (dd, J
= 10.0, 7.2 Hz, 1H), 4.30 (d, J = 3.2 Hz, 1H), 4.27 (d, J = 2.8 Hz,
1H), 4.15 (q, J = 6.0 Hz, 1H), 3.84 (t, J = 5.2 Hz, 1H), 3.79 (dd, J =
7.6, 5.6 Hz, 1H), 2.18−2.09 (m, 2H), 1.57−1.50 (m, 1H), 1.45 (d, J =
7.2 Hz, 3H), 1.14−1.07 (m, 1H), 1.13 (d, J = 6.0 Hz, 3H), 1.08 (d, J
= 6.4 Hz, 3H), 0.93 (d, J = 6.8 Hz, 6H), 0.86 (t, J = 7.6 Hz, 3H), 0.79
(d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ: 171.9,
171.2, 170.8, 169.6, 167.8, 161.2, 150.1, 123.5, 67.8, 65.2, 62.0, 59.9,
57.6, 53.8, 49.9, 38.4, 29.6, 24.8, 21.0, 19.9, 19.1, 17.8, 17.6, 15.4,
10.9; HRMS (ESI) m/z: [M + Na]+ calcd for C25H40N6O7SNa
591.2571; found 591.2572.
Cbz-L-Ala-L-Thr(ψMe,MePro)-L-Val-L-Thr(ψMe,MePro)-OMe (33). Ac-
cording to the method G, tetrapeptide 32 (175 mg, 0.3 mmol)
reacted with 2,2-dimethoxypropane to give the desired di-pseudopro-
line protected tetrapeptide 33 (135 mg, 73%) as a colorless oil.
25
EtOAc/petroleum ether (1:1, v/v) was used as an eluent. [α]D
−
124.8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.33−7.28 (m,
5H), 5.87 (s, 1H), 5.03 (m, 2H), 4.49 (m, 1H), 4.19 (m, 2H), 4.13 (t,
J = 6.8 Hz, 1H), 4.07 (m, 2H), 3.92 (m, 1H), 3.76 (s, 3H), 1.96 (m,
1H), 1.68 (d, J = 5.2 Hz, 3H), 1.65 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H),
1.53 (s, 3H), 1.45 (d, J = 5.6 Hz, 3H), 1.32 (t, J = 7.2 Hz, 6H), 0.93
(d, J = 5.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ: 170.6,
169.9, 169.6, 168.3, 154.9#, 136.7#, 128.5, 127.9, 97.2, 74.8, 68.4, 66.2,
57.5#, 53.6, 53.3, 49.8, 48.2, 33.5#, 26.1#, 19.9, 18.9, 18.5 (#minor
rotamer); HRMS (ESI) m/z: [M + Na]+ calcd for C31H46N4O9Na
641.3162; found 641.3153.
ASSOCIATED CONTENT
■
sı
* Supporting Information
Cbz-L-Ala-L-Thr(ψMe,MePro)-L-Val-L-Thr(ψMe,MePro)-L-Ile-Thz-OAllyl
(34). Following the general method C, 33a was obtained from 33
(100 mg, 0.2 mmol) and used for the next step without purification.
Following the general method E, 5a was obtained from 5 (43 mg, 0.2
mmol) and used for the next step without purification. Following the
general method B, the desired hexapeptide 34 (118 mg, 75% for two
steps) was obtained as a colorless oil. EtOAc/petroleum ether (1:1, v/
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02541.
X-ray crystallographic data for 36; comparison of
spectroscopic data of our synthetic natural products
with isolation reports; reference; data of control
experiments; and copies of NMR spectra of synthesized
compounds 1−4, 11, 12, 16−21, 23, 28, 29, 31−34, and
36 (PDF)
FAIR Data and including the primary NMR FID files
for compounds 1−5, 11, 12, 16−21, 23−26, 28, 29,
31−34, and 36 (ZIP)
v) was used as an eluent. [α]D25−182.8 (c 1.0, CH3OH); H NMR
1
(400 MHz, CD3OD) δ: 8.32 (d, J = 19.2 Hz, 1H), 7.33−7.28 (m,
5H), 6.09−6.00 (m, 1H), 5.41 (m, 1H), 5.28 (m, 1H), 5.11 (d, J = 5.2
Hz, 1H), 5.04 (m, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.33 (d, J = 7.2 Hz,
1H), 4.24 (m, 2H), 4.15 (m, 1H), 4.08 (m, 2H), 2.09 (m, 2H), 1.80
(s, 1H), 1.75 (s, 1H), 1.62 (d, J = 7.6 Hz, 6H), 1.53 (s, 3H), 1.49 (d, J
= 6.4 Hz, 3H), 1.40 (d, J = 5.6 Hz, 3H), 1.34 (q, J = 4.4 Hz, 6H), 1.02
(d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 7.2 Hz, 3H),
0.88 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ:
172.3, 170.5, 169.4, 168.8, 161.0, 146.1, 132.2, 128.1, 127.7, 127.5,
117.5, 96.6, 75.9, 75.6, 66.6, 65.5, 57.9, 57.1, 56.3, 49.7, 38.6, 32.4,
29.4, 25.9, 25.3, 25.2, 23.1, 22.5, 18.2, 18.0, 17.8, 16.9, 14.2, 10.8;
HRMS (ESI) m/z: [M + Na]+ calcd for C42H60N6O10SNa 863.3989;
found 863.3984.
Accession Codes
CCDC 2038866 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Cyclo-[L-Ala-L-Thr(ψMe,MePro)-L-Val-L-Thr(ψMe,MePro)-L-Ile-Thz]
(36). Following the method C and method D, linear peptide 34 (126
mg, 0.15 mmol) generates the intermediate 35. Next, 35 was added to
the solution of HATU (114 mg, 0.3 mmol) and HOBt (20 mg, 0.15
mmol) in CH2Cl2/DMF (3/1, 150 mL) at room temperature. The
mixture (0.001 M) was stirred until TLC showed complete
consumption of the starting material (∼24 h). The reaction was
quenched by saturated NH4Cl (50 mL) and extracted with CH2Cl2 (3
× 50 mL). The combined organic phase was washed with H2O, dried
(Na2SO4), and concentrated under reduced pressure. The residue was
purified by flash column chromatography (CH2Cl2/MeOH, 30:1) to
give compound 36 as a glassy solid (63 mg, 65% for three steps).
[α]D25−74.8 (c 1.0, CH3OH); 1H NMR (400 MHz, CD3OD) δ: 8.12
(s, 1H), 5.01 (q, J = 8.0 Hz, 1H), 4.57 (s, 1H), 4.32 (m, 2H), 4.09 (d,
J = 2.0 Hz, 1H), 4.05 (d, J = 7.2 Hz, 1H), 3.82 (d, J = 2.8 Hz, 1H),
2.55 (s, 1H), 2.13 (m, 1H), 1.86 (s, 3H), 1.73 (s, 3H), 1.71 (s, 3H)
1.64 (s, 3H), 1.59 (m, 2H), 1.46 (d, J = 2.8 Hz, 3H), 1.44 (d, J = 2.4
Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.83 (dd, J
= 6.8, 5.2 Hz, 6H), 0.75 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100
MHz, CD3OD) δ: 171.1, 170.1, 169.1, 168.7, 161.2, 123.8, 98.5, 97.8,
78.3, 76.6, 67.6, 66.9, 57.1, 31.7, 30.5, 30.1, 29.4, 29.4, 29.1, 27.1,
26.4, 25.5, 25.2, 21.5, 18.2, 16.4, 15.3, 9.3; HRMS (ESI) m/z: [M +
Na]+ calcd for C31H48N6O7SNa 671.3203; found 671.3197.
AUTHOR INFORMATION
■
Corresponding Authors
Yi Liu − School of Chemistry and Chemical Engineering,
Yantai University, Yantai 264005, China; orcid.org/
0000-0003-1513-8638; Email: liuyi@ytu.edu.cn
Yuguo Du − State Key Laboratory of Environmental
Chemistry and Eco-toxicology, Research Center for Eco-
Environmental Sciences, Chinese Academy of Sciences, Beijing
100085, China; orcid.org/0000-0002-2081-9668;
Email: duyuguo@rcees.ac.cn
Authors
Xiangyun Zhao − School of Chemistry and Chemical
Engineering, Yantai University, Yantai 264005, China
Hongbo Wang − Key Laboratory of Molecular Pharmacology
and Drug Evaluation (Yantai University), Ministry of
Education, Yantai University, Yantai 264005, China
Huili Liu − Key Laboratory of Molecular Pharmacology and
Drug Evaluation (Yantai University), Ministry of Education,
Yantai University, Yantai 264005, China
Zhuyin Sui − School of Chemistry and Chemical Engineering,
Yantai University, Yantai 264005, China
Bingfei Yan − School of Chemistry and Chemical Engineering,
Yantai University, Yantai 264005, China
Synthetic Microcyclamide MZ568 (2). To a solution of compound
36 (26 mg, 0.04 mmol) in CH2Cl2 (5 mL) was added TFA (1.5 mL)
at 0 °C. Then, the mixture was warmed to room temperature and
stirred until TLC showed complete consumption of the starting
material (∼14 h). The organic phase was concentrated under reduced
pressure, and the residue was purified by flash column chromatog-
raphy (CH2Cl2/MeOH, 10:1) to give 2 as a glassy solid (21 mg,
93%). {Observed for compound 2: [α]D25−260 (c 0.1, MeOH), lit.4
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02541
H
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(12) Pena, S.; Scarone, L.; Manta, E.; Stewart, L.; Yardley, V.; Croft,
̃
Notes
S.; Serra, G. Synthesis of a Microcystis Aeruginosa Predicted
Metabolite with Antimalarial Activity. Bioorg. Med. Chem. Lett.
2012, 22, 4994−4997.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) Long, B.; Zhang, J.; Tang, X.; Wu, Z. Total Synthesis of
Wewakazole B. Org. Biomol. Chem. 2016, 14, 9712−9715.
This work was supported in partial by National Key Research
and Development Program of China (no. 2019YFC1605802),
NNSFC project (No. 21402192, 82073888), and The Science
and Technology Support Program for Youth Innovation in
Universities of Shandong (2019KJM009). We thank Dr.
Suefeng Sun for high resolution mass determination.
(14) (a) Maeji, N. J.; Inoue, Y.; Chujo, R. Conformational Study of
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O-glycosylated Threonine Containing Peptide Models. Int. J. Pept.
Protein Res. 1987, 29, 699−707.
(15) Ferreira, P. M. T.; Monteiro, L. S.; Pereira, G. Synthesis and
Electrochemical Behaviour of β-Halodehydroamino Acid Derivatives.
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(16) (a) Vijayasarathy, S.; Prasad, P.; Fremlin, L. J.; Ratnayake, R.;
Salim, A. A.; Khalil, Z.; Capon, R. J. C3 and 2D C3 Marfey’s Methods
for Amino Acid Analysis in Natural Products. J. Nat. Prod. 2016, 79,
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