One-pot enantiomeric synthesis of thiazole-containing amino acids: Total synthesis of venturamides A and B

Article abstract of DOI:10.1021/acs.joc.8b00244

An effective one-pot procedure for enantiomerical synthesis of thiazole-containing amino acid (TCAA) has been established via a cascade disulfide cleavage/thiocarbonylation/intramolecular Staudinger reduction/aza-Wittig/oxidation reaction. Starting from the commercially available amino acid building blocks, a number of TCAAs were prepared in good yields and with excellent optical purities. This method bears features of mild reaction conditions, wide substrate adaptability, and good functional group tolerance. The power of this method was also demonstrated through the concise total synthesis of cyclic hexapeptide Venturamides A and B.

Full text of DOI:10.1021/acs.joc.8b00244

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One-pot Enantiomeric Synthesis of Thiazole-containing
Amino Acids: Total Synthesis of Venturamides A and B
Yi Liu, Peng He, Yang Zhang, Xiangyu Zhang, Jun Liu, and Yuguo Du
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00244 • Publication Date (Web): 13 Mar 2018
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One-pot Enantiomeric Synthesis of Thiazole-containing Amino
Acids: Total Synthesis of Venturamides A and B
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Yi Liu,†,‡ Peng He,†,§ Yang Zhang,†,§ Xiangyu Zhang,‡ Jun Liu,† Yuguo Du*,†,§
†State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for
‡
Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; School of
§
Chemistry and Chemical Engineering, Yantai University, Yantai 264005, China; School of
Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing
100049, China.
Authors to whom correspondence should be addressed at duyuguo@rcees.ac.cn
ABSTRACT
An effective one-pot procedure for enantiomerical synthesis of thiazole-containing
amino acid (TCAA) has been established via a cascade disulfide cleavage /
thiocarbonylation / intramolecular Staudinger Reduction / aza-Wittig / oxidation
reaction. Starting from the commercially available amino acid building blocks, a
number of TCAAs were prepared in good yields and in excellent optical purities. This
method bears features of mild reaction conditions, wide substrate adaptability, and
good functional group tolerance. The power of this method was also demonstrated
through the concise total synthesis of cyclic hexapeptide Venturamides A and B.
O
R
O
S
One-Pot
N
PGHN
H
OH
Staudinger reaction
N
R1
O
N
R1
+
Thiocarbonylation
R2
O
N
*
PGHN
O
aza-Wittig reaction
N3 Oxidation
NH
HN
S
N3
S
S
N
O
17 examples
O
O
S
62-81% yields
R2
R2
Venturamide A
Venturamide B
R = CH3
R = (R)-
93-99% ee
CHOHCH3
INTRODUCTION
Cyclic peptides which contain 2, 4-disubstituted thiazole units have been continuously
isolated from marine organisms and attracted significant interests in drug discovery
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and development.1-3 Researchers believe that these heterocycles play the key roles in
favoring bioactive conformation with the decreased flexibility, inclining the
lipophilicity of the whole molecule, serving as recognition targets, and even tuning
the binding properties of biomolecules such as DNAs, RNAs, and proteins. Looking
carefully about the chemical structures of those promising cyclic peptides (Figure 1),
the specific α-stereogenic position of the thiazole units captured our attention due to
the frequently reported racemization during the synthesis of thiazole-containing
amino acids (TCAAs).1,2
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Figure 1. Representive natural products having TCAA building blocks
To date, there are very few practical approaches that adapt for the preparation of
enantiomerically enriched TCAAs which are essential and unique substructures in
various bioactive natural products and pharmaceutical lead compounds.3 One
currently well recognized procedure comes from the modified Hantzsch reaction
using thioamides and α-halo carbonyl compounds as substrates, that requires relative
harsh reaction conditions and suffers from partial epimerization at the α-stereogenic
center in many case studies.2 An alternative way for the preparation of optically pure
TCAAs was through a dehydrogenation of pre-existing thiazoline or thiazolidine
substrates via oxidation. However, only a few oxidants have been successfully applied
to the total synthesis of natural products having TCAA building blocks.1,4 In addition,
the Lawesson reagent mediated thionation-cyclization of -ketoamide derivatives,5 as
well as the asymmetric alkylation of pre-existing thiazole heterocycles1,6 were also
explored in the synthesis of chiral TCAA units. Unfortunately, the encountered
generation of partial racemic products, requirement of stoichiometric amounts of
organometallic reagents, and intolerance of sensitive functional groups under
cyclization / dehydrogenation conditions have badly limited the practicability and
generality of these methods.1,2 Therefore, developing a straightforward and effective
method to build TCAAs from easily available precursors is highly demanding.4,7 Here
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we would like to disclose our findings in one-pot cascade synthesis of
thiazole-containing amino acid with elevated optical purity.
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RESULTS AND DISCUSSION
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Based on our previous studies,7 we envisaged a tandem phosphine-promoted
intramolecular Staudinger-aza-Wittig reaction8 to form thiazoline intermediate 7 using
N-protected amino acids 2 and β-azido disulfides 3 as substrates (Scheme 1), followed
by a subsequent dehydrogenation of 7 to form the desired chiral TCAA 1 under
suitable conditions. It was expected that the mild reaction conditions and the general
applicability of Staudinger-aza-Wittig reaction could make this strategy a valuable
tool in assembling high enantiomerically enriched TCAAs.
Scheme 1. Hypothetical mechanisms for TCAA synthesis
To test the feasibility, N-Boc-L-Phe-OH (2a) and β-azido disulfide ester (3a) were
selected as the model substrates, EDCI/DIPEA as combined coupling reagents, PPh3
as organophosphine source, and DBU/BrCCl3 as dehydrogenation reagents.9 The
experiments turned out the desired thiazole 1a in 73% yield, but showing only 55% of
enantiomeric excess value (Table 1, entry 1) under the optimized reaction conditions.
We initially ascribed this optical purity loss to the dehydrogenation under excessive
1,8-Diazabicycloundec-7-ene
(DBU).
Thus,
the
thiazoline
residue
Boc-L-Phe-thiazoline-OMe was firstly prepared7a and then subjected to neutral
oxidant MnO2,10 instead of DBU/BrCCl3 in CH2Cl2, to prepare the thiazole 1a.
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However, the chiral analysis of 1a achieved only 56% ee value (Table 1, entry 2). To
have a better understanding of this racemic phenomenon, more conditions were
investigated and some of the representative results are summarized in Table 1. To our
surprise, all of the tested carbodiimide coupling reagents11 (EDCI/DIPEA,
EDCI/HOBt, EDC, DCC/DMAP and DCC/HOBt) afforded thiazole 1a with
unsatisfactory ee values (entries 1-6), while no target product was obtained when
Mitsunobu reagent12 was employed to the same reaction (entry 7). We postulated that
carbodiimides may generate racemic TCAAs via oxazolone intermediate under our
refluxing reaction conditions (see ESI, Scheme S1).
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Table 1. Screening of the optimal reaction conditionsa
One-Pot
PPh3
coupling reagents
MeO
O
N3
S
S
N3
O
solvent, additives
N
S
HO
+

O
O
BocHN
then BrCCl3, DBU
OMe
MeO
BocHN
3a
2a
1a
entry
1
coupling conditionsb
EDCI, DIPEA
solvent
DCM
DCM
DCM
DCM
DCM
DCM
THF
yield (%)c
73
ee (%)d
55
2
EDCI, DIPEA
71
56e
74
52
3
EDC
56
4
EDCI, HOBt (8.0 eq)
DCC, DMAP (0.2 eq)
DCC, HOBt (8.0 eq)
70
5
71
25
27
--
6
66
7
DEAD (4.0 eq), PPh3 (4.0 eq)
DPPA, TEA
--
8
DMF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
trace
15
--
9
DPPA, TEA
96
65
47
55
85
96
92
10
11
12
13
14
15
DPP-Cl, TEA
72
DPP-Cl, DIPEA
DPP-Cl, TMEDA (2.0 eq)
SDPP, TEA
75
69
72
FDPP, TEA
73
NDPP, TEA
67
aUnless otherwise noted, the conditions were carried out with 0.125 mmol of 3a, 0.5 mmol of
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2a, 0.5 mmol of coupling combined reagents, 1.0 mmol organic base and 1.0 mmol PPh3 in 10
ml DCM. After refluxed for 5 hrs, the solution was cooled down to 0 oC and 1.0 mmol BrCCl3
b
and 1.5 mmol DBU was added. DPPA: Diphenylphosphoryl Azide; TEA: Triethylamine;
7
8
9
DPP-Cl: Diphenylphosphinyl Chloride; SDPP: N-Succinimidyl Diphenylphosphate; FDPP:
Pentafluorophenyl
Diphenylphosphinate;
NDPP:
Norborn-5-ene-2,3-dicarboximido
c
d
Diphenylphosphate. Isolated yields. Determined by chiral HPLC (CHIRALPAK IA column).
eUsing activated MnO2 (1.25 mmol) as oxidant.
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Fortunately enough, when organophosphorous reagent DPPA13 was used as
coupling reagent (entries 8, 9) in CH2Cl2, a remarkable ee enhancement was observed
(up to 96%) for the product despite of a very low yield. This result encouraged us to
search more widely the better organophosphorous reagents.11 Diphenylphosphinyl
chloride (DPPCl)14a was firstly tried and got some positive results in this reaction
(entries 10-12). The racemic by-product might be caused by the hydrogen chloride
generated in situ (see also ESI, Scheme S1). When a number of halogen free
organophosphorous reagents such as SDPP14b, FDPP14c, and NDPP14d were applied,
the exciting results with dramatically increased ee values for the desired chiral
products were obtained (entries 13-15). To our delight, FDPP so far gave the best
result (73% yield, 96% ee, entry 14). The plausible mechanism for this
stereo-selectivity is thus proposed based on our experimental results, as shown in
Scheme 2. The bulky diphenylphosphinate blocked the oxazolone intermediate
formation through an intramolecular SN2 reaction.15
O
O
O
P
O
O
P
O
FDPP
P
Ph
O
R1
R1
H
R1
HN
O
Ph
O
O
OH
O
N
N
F
Thiocarbonylation
S
O
F
F
F
R3
R3
R3
Base
N
Ph3P
O
2
13
14
O
5
F
R2
R3
HN
O
S
R1
O
aza-Wittig reaction
Oxidation
R1
R2
N
N
Ph3P
O
R3
NH
O
S
O
6
1
R2
Scheme 2. Plausible mechanism for ee improvement
The scope of our one-pot TCAA formation was also explored as illustrated in Table
2. It was found that both D- and L-phenylalanine analogs were good substrates for
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this reaction and the chirality of the corresponding thiazole was retained. Compounds
with Boc- or Cbz-protected amine, as well as t-butyl or weinreb amide blocked
carboxylic acids, were tolerant to the reaction conditions and afforded the products in
excellent ee values and fairly good yields. Notably, the amino acid substrates with
aliphatic substituent always afforded higher ee values, implying that electron donating
aliphatic groups were more favorable to the retention of α-stereogenic center. Glycine,
alanine, isoleucine, valine, tryptophan, glutamic acid, lysine, proline, and threonine
are all good amino acid substrates for this one-pot cascade reaction (see Table 2).
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Table 2. Synthesis of enantiomerically pure TCAAsa
R1
One-Pot
O
N3
S
S
N3
R2
O
PGHN
N
1
FDPP, Et3N, PPh3
PGHN
OH
+
O
O
S
then BrCCl3, DBU
R1
R2
R2
2
3
R2 = OMe, N(Me)OMe or OAll
PG = BOC or CBz
MeO
N
MeO
MeO
MeO
MeO
O
N
S
O
N
S
O
N
S
O
N
S
O
S
BocHN
BocHN
BocHN
CbzHN
BocHN
1d
1e
1c
70% yield, 97% ee
1a
1b
71% yield
65% yield, 98%
ee
73% yield, 96% ee
66% yield, 94% ee
MeO
N
MeO
N
MeO
MeO
NH
O
N
O
O
N
S
O
S
S
S
BocHN
BocHN
BocHN
BocHN
1f
1g
1h
1i
81% yield, 95% ee
67% yield, 99% eeb
64% yield, 99% eeb
66% yield, 99%
ee
MeO
N
MeO
NHBoc
O
NHCbz
tBu
BocHN
O
BnO
N
S
O
O
N
S
O
N
S
O
S
N
BocHN
Boc
OMe
OMe
1j
1l
1m
1k
62% yield, 97% ee
65% yield, 96% ee
63% yield, 99% ee
63% yield, 98% ee
O
N
O
AllylO
AllylO
N
N
O
N
S
O
N
S
O
N
O
S
BocHN
BocHN
BocHN
S
BocHN
1n
68% yield, 93% ee
1o
1p
68% yield, 96% ee
1q
67% yield, 99% ee
72% yield, 95% ee
aUnless otherwise noted, the optimal conditions was used as described in experiment section; The ee
(%) values were determined by HPLC (CHIRALPAK IA column). bDetermined by 1H NMR
spectroscopy.
As the methodology has been established, we next turned our attention to the total
synthesis of a bisthiazole-embodied cyclopeptide venturamides A and B16 using our
one-pot cascade process. These two cyclic hexapeptides, holding D-Val-Thz,
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D-Ala-Thz or D-allo-Thr-Thz structural units (Thz stands for thiazole residue), were
isolated from the marine cycanobacterium Oscillatoriasp and exhibited good
antimalarial activity against Plasmodium falciparum with the IC50 values of 8.2 μM
and 5.2 μM, respectively. Although the total synthesis of venturamide A has been
reported17 with
a
modified Hantzsch method, there is no report on
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the total synthesis of venturamide B so far.
Our synthetic strategy comes from the disconnection of three amide bonds
generating three azole-based amino acid residues 1518, 16 and 17a,b (Scheme 3). As
expected, condensation of β-azido disulfides 3a and 3c with their amino acid
counterparts
N-Boc-D-Val-OH
(2r),
N-Boc-D-Ala-OH
(2s)
and
N-Boc-D-allo-Thr-OH (2t) under our typical one-pot thiazole formation procedure
afforded TCAA fragments N-Boc-D-Val-Thz-OMe (16), N-Boc-D-Ala-Thz-Oallyl
(17a) and N-Boc-D-allo-Thr-Thz-Oallyl (17b) in 63% yield (> 99% ee), 61% yield
(97% ee), and 60% yield (98% ee), respectively.
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Scheme 3. Total synthesis of venturamides A and B
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7
8
9
Assembling of three azole fragments to furnish the total syntheses of natural
venturamides A and B (Scheme 3) was quite straightforward. Treatment of 16 with
LiOH got 18 in free acid form, while removal of Boc on 15 with TFA afforded free
amine salt 19. PyBOP promoted coupling reaction between 18 and 19 rendered the
bis-heterocycle 20 in a yield of 83%. After making free acid on 20 with LiOH and
free amine on 17a,b with TFA, compounds 22a and 22b were successfully prepared
with these fragments in 86% and 80% yield applying PyBOP/DIPEA as coupling
reagents. Cleavage of allyl groups from esters 22a and 22b with
Pd(OAc)2/PhSiH3/polymer-supported triphenylphosphine19 and removal of Boc with
TFA, followed by PyBOP/DMAP/DIPEA catalyzed macrolactamization under diluted
concentration (2 mM/L, DCM/DMF, v/v = 2/1) provided glassy venturamides A and B
in yields of 75% and 76%, respectively. The physical data of the synthetic
venturamides A and B were in consistent with those of the natural products
{venturamide A: [α]25 +53.6 (c 1, MeOH), (lit.16 [α]25 +53.4 (c 0.001, MeOH));
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D
D
venturamide B: [α]25D +51.6 (c 0.5, MeOH), (lit.16 [α]25D +53.6 (c 0.0004, MeOH))}.
CONCLUSIONS
In summary, a flexible and efficient one-pot approach to prepare enantiomerical
TCAA from commercially available N-protected amino acids was reported for the
first time. This reaction showed a broad substrate scope and excellent functional
group tolerance to afford versatile TCAAs in excellent ee values (93-99%) and good
yields (63-81%). The distinctive advantages of this protocol were also demonstrated
through the total synthesis of antimalarial natural cyclopeptide venturamides A and B
(32.7% and 30.7% overall yield, respectively). Further application of this cascade
one-pot reaction to the synthesis of other promising natural TCAAs, as well as their
biological evaluations, is currently in progress in our Lab.
EXPERIMENTAL SECTION
General.
Unless other indicated, all reagents were purchased from commercial corporations.
All reactions under standard conditions were monitored by thin-layer chromatography
(TLC) on gel F254 plates. Flash chromatography (FC) was performed using silica gel
(200-300 meshes). Visualization was accomplished with UV light, iodine or KMnO4
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solution. Optical rotations were recorded on a Rudolph Polarimeter Autopol 111.
High-resolution mass spectrometry data were acquired using a Q-TOF analyzer.
Melting points were analyzed on a Melt-Temp II capillary melting point apparatus.
High performance liquid chromatography (HPLC) analysis was performed using
1
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Waters® Alliance HT® liquid chromatograph with a CHIRALPAK IA column. H
13
NMR, C NMR were measured on 400 MHz or 100 MHz spectrometers (NMR in
CDCl3 with TMS as an internal standard). Chemical shifts (δ) are given in ppm
relative to residual solvent (usually chloroform; δ 7.26 for 1H NMR or 77.23 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), m (multiplet). β-azido disulfides 3a and 3b were prepared according
to our previous report7. Pentafluorophenyl Diphenylphosphinate (FDPP),
N-Succinimidyl Diphenylphosphate (SDPP) and Norborn-5-ene-2,3-dicarboximido
Diphenylphosphate (NDPP) were prepared according to the reported procedures.14b-d
Typical process of making chiral TCAAs: preparation of 1a from substrate 3a
To a solution of Boc-L-Phe-OH (133 mg, 0.5 mmol) in CH2Cl2 (10 mL) was added
Pentafluorophenyl Diphenylphosphinate (FDPP) (184 mg, 0.5 mmol) and
triethylamine (TEA) (101 mg, 1.0 mmol) at room temperature. After stirring for 15
min, 3a (40 mg, 0.125 mmol) and PPh3 (262 mg, 1.0 mmol) was added into the
o
solution and heated to reflux for further 5 h away from light. After cooling to 0 C,
1,8-Diazabicycloundec-7-ene
(DBU)
(273
mg,
1.5
mmol)
and
Bromotrichloromethane (198 mg, 1.0 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 combined
organic layer was washed with brine and dried over anhydrous Na2SO4, filtered,
o
concentrated in vacuo (below 45 C), and purified by FC (silica gel, Hexanes/EtOAc
3:1) to give compound 1a (66 mg, 73% yield, 96% ee) as white solid; data are
consistent with a previously characterized compound.4a m.p. 99-100 C; H NMR
o
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(400 MHz, CDCl3) δ: 1.38 (s, 9H), 3.19-3.36 (m, 2H), 3.96 (s, 3H), 5.29 (s, br, 2H),
13
7.08-7.10 (m, 2H), 7.20-7.27 (m, 3H), 8.06 (s, 1H); C NMR (100 MHz, CDCl3) δ:
28.4, 41.7, 52.7, 54.0, 80.5, 127.2, 127.7, 128.8, 129.6, 136.3, 147.1, 155.1, 162.0,
173.5; IR (film) 2979, 2931, 1718, 756 cm-1; ESI-HRMS calcd for C18H22N2NaO4S
([M + Na]+) 385.1192, found 385.1214. The ee value was determined to be 96%.
[Determined by HPLC with a Chiralpak IA-H column (90:10 hexane: isopropanol, 1
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mL/ min, 254 nm, 20 oC); t (minor) = 11.7 min, t (major) = 13.9 min]. [α]D20 -16.2 (c
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1, CHCl3). The absolute configuration was assigned as (S) by analogy.
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(2R,2’R)-Diallyl-3,3’-disulfanediylbis(2-azidopropanoate) (3c)
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A solution of tetrabutylammonium bromide (2.58 g, 8.0 mmol) and allyl bromide
(1.93 g, 16.0 mmol) in DCM (50 mL) was added to a solution of pre-prepared crude
acid (2R,2’R)-3,3’-disulfanediylbis(2-azidopropanic acid)7a and NaHCO3 (1.3 g, 16.0
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mmol) in H2O (35 mL) at 0 C. The suspension was stirred vigorously at room
temperature overnight, then H2O (60 mL) was added. The reaction mixture was
extracted with DCM (40 mL × 3) and the combined organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification
of the residue by FC (silica gel, Hexanes/EtOAc 3:1) yielded 1.01 g (72% from L-Cys)
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of compound 3c as yellow oil; [α]D -112.6 (c 1.5, CHCl3); H NMR (400 MHz,
CDCl3) δ: 2.98 (dd, J = 8.0 Hz, J = 14.0 Hz, 2H), 3.19 (dd, J = 8.0 Hz, J = 14.0 Hz,
2H), 4.24 (dd, J = 5.6 Hz, J = 8.0 Hz, 2H), 4.69 (d, J = 6.0 Hz, 4H), 5.28 (dd, J = 1.2
Hz, J = 10.8 Hz, 2H), 5.36 (dd, J = 1.2 Hz, J = 15.2 Hz, 2H), 5.87-5.97 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ: 39.9, 61.0, 66.8, 119.6, 130.9, 168.4; IR (film) 2924,
+
2115, 1743 cm-1; ESI-HRMS calcd for C12H16N6NaO4S2 ([M + Na] ) 395.0572,
found 395.0561.
Boc-D-Phe-Thz-OMe (1b)4d
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Yield (66%). White solid, m.p. 99-100 C; [α]D +16.3 (c 1, CHCl3). H NMR (400
MHz, CDCl3) δ: 1.39 (s, 9H), 3.22-3.38 (m, 2H), 3.96 (s, 3H), 5.27 (s, br, 2H),
13
7.08-7.10 (m, 2H), 7.22-7.28 (m, 3H), 8.06 (s, 1H); C NMR (100 MHz, CDCl3) δ:
28.4, 41.7, 52.7, 54.0, 80.5, 127.2, 127.7, 128.8, 129.6, 136.3, 147.1, 155.1, 162.0,
173.5; IR (film) 2979, 2931, 1718, 756 cm-1; ESI-HRMS calcd for C18H22N2NaO4S
([M + Na]+) 385.1192, found 385.1205. The ee value was determined to be 94%.
[Determined by HPLC with a Chiralpak IA-H column (90:10 hexane: isopropanol, 1
o
mL/ min, 254 nm, 20 C); t (major) = 11.6 min, t (minor) = 14.0 min]. The absolute
configuration was assigned as (R) by analogy.
Cbz-L-Phe-Thz-OMe (1c)4e
Yield (70%). Colorless gum; [α]D20 -19.1 (c 0.2, CHCl3). 1H NMR (400 MHz, CDCl3)
δ: 3.34 (d, J = 6.4 Hz, 2H), 3.97 (s, 3H), 5.08 (s, 2H), 5.36 (dt, J = 6.4 Hz, J = 14.4
Hz, 1H), 5.53 (d, J = 7.6 Hz, 1H), 7.06-7.08 (m, 2H), 7.20-7.25 (m, 4H), 7.28-7.37 (m,
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4H), 8.06 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 41.3, 52.3, 54.2, 66.9, 126.9, 127.4,
127.8, 128.0, 128.3, 128.5, 129.2, 135.6, 135.8, 146.7, 155.3, 161.6, 172.2; IR (film)
2968, 2925, 1716, 752 cm-1; ESI-HRMS calcd for C21H20N2NaO4S ([M + Na]+)
419.1041, found 419.1073. The ee value was determined to be 97%. [Determined by
HPLC with a Chiralpak IA-H column (90:10 hexane: isopropanol, 1 mL/ min, 254 nm,
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20 C); t (major) = 27.0 min, t (minor) = 30.0 min]. The absolute configuration was
assigned as (S) by analogy.
Boc-Gly-Thz-OMe (1d)4d
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Yield (71%). White solid, m.p. 111-113 C; H NMR (400 MHz, CDCl3) δ: 1.45 (s,
9H), 3.94 (s, 3H), 4.64 (d, J = 6.0 Hz, 2H), 5.33 (s, 1H), 8.13 (s, 1H); 13C NMR (100
MHz, CDCl3) δ: 28.2, 42.3, 52.4, 80.4, 128.0, 146.4, 155.5, 161.6, 170.0; IR (film)
2979, 2931, 1717, 756 cm-1; ESI-HRMS calcd for C11H16N2NaO4S ([M + Na]+)
295.0723, found 295.0727.
Boc-L-Ala-Thz-OMe (1e)4e
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Yield (65%). White solid, m.p. 86-89 C; [α]D -36.4 (c 0.5, MeOH). H NMR (400
MHz, CDCl3) δ: 1.44 (s, 9H), 1.61 (d, J = 6.4 Hz, 3H), 3.93 (s, 3H), 5.03-5.14 (m,
13
1H), 5.20 (s, br, 1H), 8.10 (s, 1H); C NMR (100 MHz, CDCl3) δ: 21.7, 28.3, 48.9,
52.4, 80.3, 127.4, 146.8, 154.8, 161.8, 175.1; IR (film) 2979, 1715, 758 cm-1;
ESI-HRMS calcd for C12H18N2NaO4S ([M + Na]+) 309.0885, found 309.0883. The ee
value was determined to be 98%. [Determined by HPLC with a Chiralpak IA-H
column (95:5 hexane: isopropanol, 1 mL/ min, 254 nm, 20 oC); t (major) = 27.2 min, t
(minor) = 30.4 min]. The absolute configuration was assigned as (S) by analogy.
Boc-L-Val-Thz-OMe (1f)4d
Yield (66%). White solid, m.p. 116-118 oC; [α]D20 -16.3 (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3) δ: 0.89 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H),
2.40-2.45 (m, 1H), 3.93 (s, 3H), 4.88 (dd, J = 6.0 Hz, J = 8.0 Hz, 1H), 5.28 (d, J =
8.0 Hz, 1H), 8.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 17.2, 19.4, 28.3, 33.3, 52.5,
58.0, 80.2, 127.1, 146.9, 155.5, 161.8, 173.5; IR (film) 2967, 1716, 757 cm-1;
ESI-HRMS calcd for C14H22N2NaO4S ([M + Na]+) 337.1192, found 337.1214. The ee
value was determined to be 99%. [Determined by HPLC with a Chiralpak IA-H
column (96:4 hexane: isopropanol, 0.5 mL/ min, 254 nm, 20 oC); t (minor) = 26.7 min,
t (major) = 28.6 min]. The absolute configuration was assigned as (S) by analogy.
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Boc-L-Ile-Thz-OMe (1g)4d
Yield (67%). Colorless oil; [α]D20 -18.2 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ:
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0.87-0.93 (m, 6H), 1.10-1.17 (m, 1H), 1.43 (s, 9H), 2.08-2.26 (m, 1H), 3.93 (s, 3H),
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4.92 (s, 1H), 5.31 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H); C NMR (100 MHz, CDCl3) δ:
11.4, 15.7, 24.4, 28.2, 39.6, 52.4, 57.4, 80.1, 127.0, 146.8, 155.3, 161.8, 173.2; IR
(film) 2967, 2932, 1717, 759 cm-1; ESI-HRMS calcd for C15H24N2NaO4S ([M + Na]+)
351.1349, found 351.1365. The ee value was determined by 1H NMR chiral shift.
Boc-D-allo-Ile-Thz-OMe (1h)20a
o
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Yield (64%). White solid, m.p. 101-103 C; [α]D +14.1 (c 0.5, CHCl3); H NMR
(400 MHz, CDCl3) δ: 0.81 (d, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H), 1.21-1.26 (m,
1H), 1.42 (s, 9H), 2.20-2.23 (m, 1H), 3.91 (s, 3H), 5.03 (s, 1H), 5.24 (d, J = 7.2 Hz,
13
1H), 8.07 (s, 1H); C NMR (100 MHz, CDCl3) δ: 11.4, 13.7, 26.4, 28.2, 39.5, 52.3,
57.5, 80.2, 127.0, 146.9, 155.4, 161.7, 174.5; IR (film) 2968, 2934, 1717, 758 cm-1;
ESI-HRMS calcd for C15H24N2NaO4S ([M + Na]+) 351.1349, found 351.1375. The ee
value was determined by 1H NMR chiral shift.
Boc-D-Trp-Thz-OMe (1i)
Yield (81%). Yellow solid, m.p. 109-111 oC; [α]D20 +33.5 (c 1, CHCl3). 1H NMR (400
MHz, CDCl3) δ: 1.27 (s, 9H), 3.44 (dd, J = 4.0 Hz, J = 13.2 Hz, 1H), 3.54 (d, J =
13.2 Hz, 1H), 3.97 (s, 3H), 5.38 (s, br, 2H), 6.88 (d, J = 0.8 Hz, 1H), 7.07 (dd, J = 7.6
Hz, J = 7.6 Hz, 1H), 7.17 (dd, J = 7.6 Hz, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H),
13
7.44 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 8.13 (s, 1H); C NMR (100 MHz, CDCl3) δ:
27.9, 30.9, 52.1, 53.1, 79.9, 109.7, 110.8, 118.3, 119.4, 121.9, 122.9, 127.2, 135.7,
146.4, 154.7, 161.6, 173.9; IR (film) 2924, 2855, 1715, 741 cm-1; ESI-HRMS calcd
for C20H23N3NaO4S ([M + Na]+) 424.1307, found 424.1321. The ee value was
determined to be 95%. [Determined by HPLC with a Chiralpak IA-H column
(96:6.7:3.3 hexane: alcohol: dichloromethane, 1.0 mL/ min, 254 nm, 20 oC); t (major)
= 17.7 min, t (minor) = 19.9 min]. The absolute configuration was assigned as (R) by
analogy.
Boc-L-Glu(OtBu)-Thz-OMe (1j)
Yield (62%). White solid, m.p. 135-136 oC; [α]D20 -22.8 (c 0.3 CHCl3). 1H NMR (400
MHz, CDCl3) δ: 1.43 (s, 18H), 2.11-2.20 (m, 1H), 2.32-2.42 (m, 3H), 3.92 (s, 3H),
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4.95-5.02 (m, 1H), 5.56 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H); C NMR (100 MHz,
CDCl3) δ: 27.7, 27.9, 29.9, 31.6, 52.1, 52.7, 79.9, 80.6, 127.1, 146.7, 154.9, 161.4,
172.2, 173.8; IR (film) 2979, 1721, 1697, 750 cm-1; ESI-HRMS calcd for
C18H28N2NaO6S ([M + Na]+) 423.1566, found 423.1527. The ee value was
determined to be 97%. [Determined by HPLC with a Chiralpak IA-H column (95:5
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hexane: isopropanol, 1.0 mL/ min, 254 nm, 20 C); t (minor) = 22.3 min, t (major) =
26.0 min]. The absolute configuration was assigned as (S) by analogy.
N-Cbz-N’-Boc-L-Lys-Thz-OMe (1k)
Yield (65%). Colorless gum; [α]D20 -25.8 (c 0.9, CHCl3). 1H NMR (400 MHz, CDCl3)
δ: 1.38 (s, 9H), 1.39-1.48 (m, 4H), 1.86-1.91 (m, 1H), 2.00-2.02 (m, 1H), 3.06 (t, J =
5.6 Hz, 2H), 3.91 (s, 3H), 4.65 (s, br, 1H), 5.01-5.05 (m, 1H), 5.09 (s, 2H), 5.90 (d, J
= 2.4 Hz, 2H), 7.32 (s, 5H), 8.07 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 22.6, 28.5,
29.8, 35.0, 39.7, 52.6, 53.6, 67.3, 79.3, 127.5, 128.3, 128.6, 136.2, 147.0, 156.1, 156.4,
161.9, 173.9; IR (film) 2949, 1716, 751 cm-1; ESI-HRMS calcd for C23H31N3NaO6S
([M + Na]+) 500.1831, found 500.1789. The ee value was determined to be 96%.
[Determined by HPLC with a Chiralpak IA-H column (92:8 hexane: isopropanol, 1.0
o
mL/ min, 254 nm, 20 C); t (major) = 45.5 min, t (minor) = 51.7 min]. The absolute
configuration was assigned as (S) by analogy.
Boc-L-Pro-Thz-OMe (1l)20b
o
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Yield (63%). Pale yellow solid, m.p. 69-71 C; [α]D -34.7 (c 0.5, CHCl3). H NMR
(400 MHz, CDCl3) (multiple rotamers) δ: 1.29&1.46 (s, 9H), 1.85-1.93 (m, 2H),
2.20-2.36 (m, 2H), 3.40-3.60 (m, 2H), 3.93 (s, 3H), 5.15-5.24 (m, 1H), 8.07 (s, 1H);
13C NMR (100 MHz, CDCl3) (multiple rotamers) δ: 23.0&23.8, 28.1&28.3,
32.9&34.2, 46.6&47.0, 52.3, 59.1&59.5, 80.4, 126.9&127.2, 146.7, 154.1&154.6,
161.8, 176.1&177.1; IR (film) 2976, 1739, 1698, 765 cm-1; ESI-HRMS calcd for
C14H20N2NaO4S ([M + Na]+) 335.1036, found 335.1052. The ee value was
determined to be 99%. [Determined by HPLC with a Chiralpak IA-H column
o
(92:6.4:1.6 hexane: isopropanol: dichloromethane, 0.4 mL/ min, 254 nm, 20 C); t
(major) = 29.3 min, t (minor) = 31.6 min]. The absolute configuration was assigned as
(S) by analogy.
Boc-L-Thr(Bzl)-Thz-OMe (1m)
Yield (63%). Colorless gum; [α]D20 -34.6 (c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3)
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δ: 1.30 (d, J = 6.4 Hz, 3H), 1.47 (s, 9H), 3.94 (s, 3H), 4.23 (d, J = 11.2 Hz, 1H),
4.33-4.37 (m, 1H), 4.47 (d, J = 11.2 Hz, 1H), 5.04 (d, J = 8.4 Hz, 1H), 5.71 (d, J =
8.4 Hz, 1H), 7.04-7.06 (m, 2H), 7.23-7.26 (m, 3H), 8.10 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ: 16.5, 28.4, 52.5, 57.7, 71.6, 76.3, 80.5, 127.5, 127.7, 127.8, 128.4, 137.8,
147.0, 155.8, 161.9, 174.5; IR (film) 3445, 1725, 750 cm-1; ESI-HRMS calcd for
C20H26N2NaO5S ([M + Na]+) 429.1460, found 429.1431. The ee value was
determined to be 98%. [Determined by HPLC with a Chiralpak IA-H column (97:3
hexane: alcohol, 1.0 mL/ min, 254 nm, 20 oC); t (major) = 18.5 min, t (minor) = 23.7
min].
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Boc-L-Phe-Thz-N(OMe)Me (1n)
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Yield (68%). Colorless oil; [α]D -12.5 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) δ:
1.39 (s, 9H), 3.30-3.35 (m, 2H), 3.40 (s, 3H), 3.76 (s, 3H), 5.27 (s, br, 2H), 7.07-7.09
13
(m, 2H), 7.20-7.26 (m, 3H), 7.89 (s, 1H); C NMR (100 MHz, CDCl3) δ: 28.2, 34.2,
41.4, 53.7, 61.4, 80.1, 124.8, 126.8, 129.3, 136.2, 148.4, 154.9, 162.8, 171.2; IR (film)
2978, 2932, 1712, 1640, 754 cm-1; ESI-HRMS calcd for C19H25N3NaO4S ([M + Na]+)
414.1457, found 414.1451. The ee value was determined to be 93%. [Determined by
HPLC with a Chiralpak IA-H column (90:10 hexane: isopropanol, 1.0 mL/ min, 254
o
nm, 20 C); t (minor) = 17.7 min, t (major) = 22.0 min]. The absolute configuration
was assigned as (S) by analogy.
Boc-L-Ala-Thz-N(OMe)Me (1o)
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Yield (72%). Colorless oil; [α]D -28 (c 1, CHCl3). H NMR (400 MHz, CDCl3) δ:
1.45 (s, 9H), 1.62 (d, J = 6.4 Hz, 1H), 3.42 (s, 3H), 3.79 (s, 3H), 5.11-5.16 (m, 2H),
7.94 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 21.5, 28.2, 34.3, 48.6, 61.5, 80.1, 124.8,
148.3, 154.8, 162.9, 172.8; IR (film) 2978, 2933, 1712, 1642, 758 cm-1; ESI-HRMS
calcd for C13H21N3NaO4S ([M + Na]+) 338.1145, found 338.1153. The ee value was
determined to be 95%. [Determined by HPLC with a Chiralpak IA-H column (97:3
o
hexane: methanol, 0.3 mL/ min, 254 nm, 20 C); t (major) = 84.3 min, t (minor) =
91.7 min]. The absolute configuration was assigned as (S) by analogy.
Boc-L-Phe-Thz-OAllyl (1p)
20
Yield (68%). Colorless oil; [α]D -16.5 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) δ:
1.39 (s, 9H), 3.32-3.37 (m, 2H), 4.87 (d, J = 7.0 Hz, 2H), 5.25-5.30 (m, 2H), 5.31 (dd,
J = 1.6 Hz, J = 10.4 Hz, 1H), 5.42 (dd, J = 1.6 Hz, J = 17.2 Hz, 1H), 6.00-6.10 (m,
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1H), 7.09-7.11 (m, 2H), 7.22-7.28 (m, 3H), 8.07 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ: 28.2, 41.4, 53.8, 65.9, 80.2, 118.9, 126.9, 127.4, 128.5, 129.3, 131.8, 136.1, 146.8,
154.8, 160.9, 173.0; IR (film) 2978, 2930, 1716, 756 cm-1; ESI-HRMS calcd for
C20H24N2NaO4S ([M + Na]+) 411.1349, found 411.1338. The ee value was determined
to be 96%. [Determined by HPLC with a Chiralpak IA-H column (90:10 hexane:
isopropanol, 1.0 mL/ min, 254 nm, 20 oC); t (major) = 12.4 min, t (minor) = 14.9 min].
The absolute configuration was assigned as (S) by analogy.
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Boc-L-Ala-Thz-OAllyl (1q)
20
Yield (67%). Colorless oil; [α]D -28.6 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) δ:
1.44 (s, 9H), 1.61 (d, J = 6.8 Hz, 3H), 4.85 (d, J = 5.6 Hz, 2H), 5.07-5.14 (m, 2H),
5.22 (s, br, 1H), 5.29 (dd, J = 1.2 Hz, J = 10.4 Hz, 1H), 5.40 (dd, J = 1.2 Hz, J = 10.4
Hz, 1H), 6.02 (ddt, J = 1.2 Hz, J = 10.4 Hz, J = 16.0 Hz, 1H), 8.10 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ: 21.7, 28.2, 48.8, 65.9, 80.2, 118.8, 127.4, 131.8, 146.7, 154.8,
160.9, 174.9; IR (film) 2979, 2932, 1716, 757 cm-1; ESI-HRMS calcd for
C14H20N2NaO4S ([M + Na]+) 335.1036, found 335.1037. The ee value was
determined to be 99%. [Determined by HPLC with a Chiralpak IA-H column (90:10
o
hexane: isopropanol, 1.0 mL/ min, 254 nm, 20 C); t (minor) = 8.2 min, t (major) =
10.2 min]. The absolute configuration was assigned as (S) by analogy.
Boc-D-Ala-Oxz-OMe (15)10
The compound 15 was obtained in 188 mg (66% yield, 99% ee) as white solid from
Boc-D-Ala-L-Thr-OMe (304 mg, 1.0 mmol) following the reported procedure10. m.p.
69-72 oC; [α]D20 +46.6 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 1.42 (s, 9H), 1.51
(d, J = 7.2 Hz, 3H), 2.60 (s, 3H), 3.89 (s, 3H), 4.86-4.95 (m, 1H), 5.19 (s, br, 1H); 13C
NMR (100 MHz, CDCl3) δ: 11.9, 20.2, 28.2, 44.5, 51.9, 80.0, 127.2, 154.8, 156.4,
162.5, 162.9; IR (film) 2979, 1717, 1518 cm-1; ESI-HRMS calcd for C13H20N2NaO5
([M + Na]+) 307.1264, found 307.1254. The ee value was determined to be 99%.
[Determined by HPLC with a Chiralpak IA-H column (95:5 hexane: isopropanol, 1.0
o
mL / min, 240 nm, 20 C); t (major) = 9.6 min, t (minor) = 14.0 min]. The absolute
configuration was assigned as (R) by analogy.
Boc-D-Val-Thz-OMe (16)4d
The compound 16 was obtained in 1.18 g (63% yield, >99% ee) as white solid from
3a (0.96 g, 3.0 mmol) and Boc-D-Val-OH (1.95 g, 9.0 mmol) following the typical
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procedure as described above. m.p. 116-118 C; [α]D +16.6 (c 1, CHCl3). H NMR
(400 MHz, CDCl3) δ: 0.89 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.44 (s, 9H),
2.40-2.45 (m, 1H), 3.94 (s, 3H), 4.88 (dd, J = 6.0 Hz, J = 8.0 Hz, 1H), 5.27 (d, J =
8.0 Hz, 1H), 8.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 17.1, 19.3, 28.2, 33.2, 52.4,
58.0, 80.1, 127.0, 146.9, 155.3, 161.8, 173.5; IR (film) 2967, 1717, 1503, 756 cm-1;
ESI-HRMS calcd for C14H22N2NaO4S ([M + Na]+) 337.1192, found 337.1202. The ee
was determined to be >99%. [Determined by HPLC with a Chiralpak IA-H column
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(96:4 hexane: isopropanol, 0.5 mL/ min, 254 nm, 20 C); t (major) = 26.5 min, t
(minor) = 29.2 min]. The absolute configuration was assigned as (R) by analogy.
Boc-D-Ala-Thz-OAllyl (17a)
The compound 17a was obtained in 1.15 g (61% yield, 97% ee) as colorless oil from
3c (1.12 g, 3.0 mmol), Boc-D-Ala-OH (1.70 g, 9.0 mmol) following the typical
procedure as described above. [α]D20 +28.7 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3)
δ: 1.44 (s, 9H), 1.61 (d, J = 6.8 Hz, 3H), 4.83 (d, J = 6.0 Hz, 2H), 5.07-5.14 (m, 1H),
5.23 (s, br, 1H), 5.28 (dd, J = 1.2 Hz, J = 10.4 Hz, 1H), 5.40 (dd, J = 1.2 Hz, J = 10.4
Hz, 1H), 6.02 (ddt, J = 1.2 Hz, J = 10.4 Hz, J = 16.0 Hz, 1H), 8.10 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ: 21.4, 28.1, 48.7, 65.7, 80.0, 118.7, 127.3, 131.6, 146.5, 154.8,
160.7, 175.0; IR (film) 2980, 2935, 1717, 755 cm-1; ESI-HRMS calcd for
C14H20N2NaO4S ([M + Na]+) 335.1036, found 335.1060. The ee was determined to be
97%. [Determined by HPLC with a Chiralpak IA-H column (90:10 hexane:
isopropanol, 1.0 mL/ min, 254 nm, 20 oC); t (major) = 8.3 min, t (minor) = 10.3 min].
The absolute configuration was assigned as (R) by analogy.
Boc-D-allo-Thr-Thz-OAllyl (17b)
The compound 17b was obtained in 204 mg (60% yield, 99% ee) as colorless oil as
colorless oil from 3c (186 mg, 0.5 mmol), Boc-D-allo-Thr-OH (438 mg, 2.0 mmol)
20
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following the typical procedure as described above. [α]D +22.8 (c 0.8, CHCl3). H
NMR (400 MHz, CDCl3) δ: 1.20 (d, J = 6.4 Hz, 3H), 1.39 (s, 9H), 3.73 (br, 1H), 4.19
(dq, J = 1.2 Hz, J =6.4 Hz, 1H), 4.79 (d, J = 6.4 Hz, 2H), 4.91 (s, 1H), 5.26 (dd, J =
1.2 Hz, J = 10.4 Hz, 1H), 5.36 (dd, J = 1.2 Hz, J = 16.4 Hz, 1H), 5.81 (d, J = 8.4 Hz,
1H), 5.98 (ddt, J = 1.2 Hz, J = 6.4 Hz, J = 10.4 Hz, 1H), 8.11 (s, 1H); 13C NMR (100
MHz, CDCl3) δ: 19.6, 28.2, 57.1, 65.8, 69.9, 80.3, 118.8, 127.9, 131.7, 146.3, 155.3,
160.7, 170.3; IR (film) 2926, 1709, 753 cm-1; ESI-HRMS calcd for C15H22N2NaO5S
([M + Na]+) 365.1147, found 365.1165. The 98% ee was determined by H NMR
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Boc-L-Thr-Thz-OAllyl (17c)
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The compound 17c was obtained in 232 mg (68% yield, 99% ee) as colorless oil from
3c (186 mg, 0.5 mmol), Boc-L-Thr-OH (438 mg, 2.0 mmol) following the typical
procedure as described above. This compound was used to make a clear structural
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determination for 17b. [α]D -59.2 (c 0.5, CHCl3). H NMR (400 MHz, CDCl3) δ:
1.28 (d, J = 6.0 Hz, 3H), 1.44 (s, 9H), 3.28 (br, 1H), 4.61 (d, J = 6.0 Hz, 1H), 4.79 (d,
J = 6.0 Hz, 2H), 4.89 (d, J = 8.4 Hz, 1H), 5.26 (dd, J = 1.6 Hz, J = 10.4 Hz, 1H),
5.38 (dd, J = 1.6 Hz, J = 17.2 Hz, 1H), 5.76 (d, J = 8.4 Hz, 1H), 5.99 (ddt, J = 1.6 Hz,
J = 6.0 Hz, J = 10.4 Hz, 1H), 8.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 19.2, 28.2,
57.1, 65.9, 68.3, 80.2, 118.9, 127.9, 131.7, 146.3, 155.8, 160.8, 173.0; IR (film) 2979,
1712, 764 cm-1; ESI-HRMS calcd for C15H22N2NaO5S ([M + Na]+) 365.1147, found
365.1183. The 99% ee was determined by 1H NMR chiral shift.
Boc-D-Val-Thz-D-Ala-Oxz-Me (20)20c
Thiazole fragment 16 (314 mg, 1.0 mmol) was dissolved in THF/MeOH/H2O (2/2/1)
(15 ml), and 0.5 N LiOH (5.0 ml) was slowly added to the solution at 0oC. The
reaction was stirred at 0 oC and monitored by TLC until thiazole 16 was depleted. The
solution was then diluted with water and carefully acidified with saturated aqueous
KHSO4 to pH 3~4. The aqueous layer was extracted with EA (30 ml × 3). The
combined organic extracts were washed with saturated aqueous NaCl and dried over
anhydrous Na2SO4, filtered, concentrated in vacuo to give crude carboxylic acid. The
crude acid was used in the next step without further purification.
In another flask, trifluoracetic acid (3 mL) was added to a solution of 15 (284 mg, 1.0
o
mmol) in DCM (7 mL) at 0 C, and the resulting mixture was stirred at room
temperature for 1 h to ensure complete removal of the Boc protecting group. After
concentration in vacuo, the reaction mixture was azeotroped to dryness with toluene
(2 × 20 mL), and the resulting free amine was dissolved in DCM (20 mL). A solution
of above free carboxylic acid, PyBOP (780 mg, 1.5 mmol), DIPEA (258 mg, 2.0
mmol) in 20 ml DCM was added. The resulting mixture was stirred for overnight.
Regular workup and purified by FC (silica gel, Hexanes/EtOAc 2:1) to yield 387 mg
of compound 20 (83% yield) as colorless oil. data are consistent with a previously
characterized compound20c. [α]D25 +9.6 (c 0.5, MeOH); 1H NMR (400 MHz, CDCl3) δ:
0.91 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 1.44 (s, 9H), 1.67 (d, J = 6.8 Hz,
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3H), 2.29-2.41 (m, 1H), 2.60 (s, 3H), 3.88 (s, 3H), 4.82 (dd, J = 6.0 Hz, J = 8.4 Hz,
1H), 5.24 (d, J = 8.4 Hz, 1H), 5.43 (dq, J = 6.8 Hz, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4
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Hz, 1H), 8.01 (s, 1H); C NMR (100 MHz, CDCl3) δ: 12.0, 17.5, 19.4, 19.7, 28.3,
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33.1, 42.8, 52.0, 57.9, 80.2, 123.4, 127.4, 149.3, 155.4, 156.6, 160.3, 162.5, 162.6,
172.7; IR (film) 3585, 2927, 1710, 750 cm-1; ESI-HRMS calcd for C21H30N4NaO6S
([M + Na]+) 489.1784, found 489.1789.
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Boc-D-Val-Thz-D-Ala-Oxz-D-Ala-Thz-OAllyl (22a)
Compound 20 (107 mg, 0.23 mmol) was dissolved in THF/MeOH/H2O (2/2/1) (10
ml), and 0.5 N LiOH (4.0 ml) was slowly added into the solution at 0oC. The
reaction was stirred at 0 oC and monitored by TLC until compound 20 was depleted.
The solution was then diluted with water and carefully acidified with saturated
aqueous KHSO4 to pH 3~4. The aqueous layer was extracted with EA (30 ml × 3).
The combined organic extracts were washed with saturated aqueous NaCl and dried
over anhydrous Na2SO4, filtered, concentrated in vacuo to give crude carboxylic
acid. The crude acid was used in the next step without further purification.
In another flask, trifluoracetic acid (2 mL) was added to a solution of 17a (94 mg,
o
0.30 mmol) in DCM (6 mL) at 0 C, and the resulting mixture was stirred at room
temperature for 1 h to ensure complete removal of the Boc protecting group. After
concentration in vacuo, the reaction mixture was azeotroped to dryness with toluene
(2 × 10 mL), and the resulting free amine was dissolved in DCM (15 mL). A
solution of above free carboxylic acid, PyBOP (260 mg, 0.5 mmol), DIPEA (129
mg, 1.0 mmol) in 5 ml DCM was added into the mixture. The resulting mixture was
stirred for overnight. Regular workup and the residues purified by FC (silica gel,
Hexanes/EtOAc 1:1) to yield 127 mg of compound 22a (86% yield) as white solid.
m.p. 90-91 oC; [α]D25 +67.3 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 0.91 (d, J
= 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H), 1.65 (d, J = 6.8 Hz, 3H), 1.74
(d, J = 6.8 Hz, 3H), 2.29-2.34 (m, 1H), 2.60 (s, 3H), 4.82-4.84 (m, 2H), 4.84-4.86
(m, 1H), 5.18 (d, J = 8.4 Hz, 1H), 5.27 (dd, J = 1.2 Hz, J = 10.4 Hz, 1H), 5.36-5.43
(m, 2H), 5.53 (dq, J = 6.8 Hz, J = 13.6 Hz, 1H), 6.03 (ddt, J = 1.2 Hz, J = 5.6 Hz, J
= 10.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H),
8.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 11.9, 17.7, 19.5, 19.6, 21.2, 28.5, 33.3,
43.1, 47.0, 58.2, 66.1, 80.5, 119.0, 123.7, 127.8, 128.7, 132.0, 147.0, 149.5, 154.3,
155.5, 160.5, 161.1, 161.4, 161.5, 173.3, 173.8; IR (film) 3339, 2925, 2852, 1715,
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1661, 757 cm-1; ESI-HRMS calcd for C29H38N6NaO7S2 ([M + Na]+) 669.2136,
found 669.2185.
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The compound was prepared following the typical procedure from fragment 17b (103
mg, 0.3 mmol) and 20 (93 mg, 0.2 mmol) as described above. Compound 22b was
obtained in 108 mg (80% yield) as colorless oil; [α]D25 +8 (c 1, CHCl3); 1H NMR (400
MHz, CDCl3) δ: 0.93 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.4
Hz, 3H), 1.42 (s, 9H), 1.62 (d, J = 6.4 Hz, 3H), 2.25-2.34 (m, 1H), 2.58 (s, 3H),
4.32-4.43 (m, 1H), 4.81 (d, J = 6.4 Hz, 2H), 4.81-4.86 (m, 1H), 5.27 (dd, J = 0.8 Hz,
J = 10.4 Hz, 2H), 5.34-5.40 (m, 3H), 5.99 (ddt, J = 1.6 Hz, J = 10.8 Hz, J = 16.4 Hz,
1H), 7.72 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 8.14 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ: 11.4, 17.2, 19.0, 19.7, 27.9, 32.7, 42.6, 54.8, 57.6, 65.6,
69.4, 79.9, 118.6, 123.2, 127.8, 128.0, 131.4, 146.0, 148.9, 153.9, 155.1, 160.0, 160.3,
160.8, 161.1, 169.0, 172.7; IR (film) 3396, 2971, 1660, 831 cm-1; ESI-HRMS calcd
for C30H40N6NaO8S2 ([M + Na]+) 699.2247, found 669.2275.
Venturamide A
Pd(OAc)2 (6.7 mg, 0.03 mmol) and PS-triphenylphosphine (151 mg, 1.59 mmolg-1,
0.24 mmol) were added to a flask containing DCM (15 mL). After stirring for 10 min,
compound 22a (100 mg, 0.155 mmol) and PhSiH3 (54 mg, 0.5 mmol) were added
separately. TLC showed that the starting material disappeared in 1 h. After removing
the solvent, the residue was passed through a short silica gel column and eluted with
CHCl3/MeOH to give the crude carboxylic acid. The crude acid dissolved in 5 ml
o
DCM and then trifluoracetic acid (5 mL) was added into the solution at 0 C. The
mixture was stirred at room temperature for 1 h. After concentration in vacuo, the
reaction mixture was azeotroped to dryness with toluene (2 × 20 mL), and the
resulting amino acid was dissolved in 50 mL DCM/DMF (2/1). The mixture of
PyBOP (161 mg, 0.31 mmol), DIPEA (60 mg, 3.0 mmol) and DMAP (3.6 mg, 0.03
mmol) in 25 ml DCM/DMF (2/1) was added into the solution slowly. After the
addition was complete, the resulting mixture was stirred for overnight. Regular
workup and the residues purified by FC (silica gel, Hexanes/EtOAc 1:1) to yield 57
mg of Venturamide A (75% yield) as colorless glass; [α]D25 +53.2 (c 1, MeOH) (lit.16
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[α]25 +53.4 (c 0.001, MeOH)); H NMR (400 MHz, CDCl3) δ: 1.01 (d, J = 6.8 Hz,
D
3H), 1.08 (d, J = 6.8 Hz, 3H), 1.68 (d, J = 6.8 Hz, 3H), 1.72 (d, J = 6.8 Hz, 3H), 2.28
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(dq, J = 6.8 Hz, J = 13.2 Hz, 1H), 2.68 (s, 3H), 5.27 (dq, J = 6.8 Hz, J = 13.2 Hz,
1H), 5.42 (dq, J = 6.8 Hz, J = 13.2 Hz, 1H), 5.47 (dd, J = 6.0 Hz, J = 13.2 Hz, 1H),
8.10 (s, 1H), 8.14 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.60 (d, J = 6.8 Hz, 1H), 8.63 (d,
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J = 6.8 Hz, 1H); C NMR (100 MHz, CDCl3) δ: 11.6, 18.5, 18.8, 20.8, 24.9, 35.5,
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44.0, 47.5, 55.7, 123.2, 124.2, 128.4, 148.7, 149.2, 153.9, 159.6, 159.9, 160.5, 161.7,
168.4, 171.3; IR (film) 3396, 2930, 1672, 759 cm-1; ESI-HRMS calcd for
C21H24N6NaO4S2 ([M + Na]+) 511.1192, found 511.1196.
Venturamide B
The compound was prepared following the typical procedure from linear macrocycles
precursors 22b (80 mg, 0.118 mmol) as described above. Venturamide B was obtained
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in 47 mg (76 % yield) as colorless glass; [α]D +51.6 (c 0.5, MeOH) (lit.16 [α]25
D
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+53.6 (c 0.0004, MeOH)); H NMR (400 MHz, CDCl3) δ: 1.01 (d, J = 6.8 Hz, 3H),
1.07 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), 1.69 (d, J = 6.8 Hz, 3H), 2.27 (dq,
J = 6.8 Hz, J = 13.2 Hz, 1H), 2.69 (s, 3H), 4.25 (dq, J = 6.0 Hz, J = 10.0 Hz, 1H),
5.28 (dq, J = 6.8 Hz, J = 13.2 Hz, 1H), 5.47 (dd, J = 6.0 Hz, J = 11.2 Hz, 1H), 5.49 (t,
J = 6.0 Hz, 1H), 8.10 (s, 1H), 8.21 (s, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.60 (d, J = 6.8
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Hz, 1H), 8.65 (d, J = 6.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ: 11.8, 18.1, 18.5,
18.9, 20.8, 35.5, 44.0, 55.7, 58.1, 73.0, 123.3, 125.1, 127.8, 148.9, 149.1, 154.8, 159.5,
159.9, 161.9, 162.5, 166.4, 168.4; IR (film) 3390, 2973, 1670, 769 cm-1; ESI-HRMS
calcd for C22H26N6NaO5S2 ([M + Na]+) 541.1304, found 541.1300.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website at DOI:
Additional information for optimization of the reaction conditions. Chiral-phase
1
13
HPLC analysis and H, C NMR spectra of 1a-1q, 15, 16, 17a, 17b, 17c, 22a, 22b,
Venturamide A, Venturamide B in JEPG format (JEPG).
AUTHOR INFORMATION
Corresponding Author
*E-mails: duyuguo@rcees.ac.cn
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ACKNOWLEDGMENT
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This work was supported in partial by Strategic Priority Research Program of CAS
(XDB14040201) and NNSFC projects (21402192, 21672255 and 21621064). We
thank Xuefeng Sun, Qi Yu and Wei Liu for high resolution mass determination.
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