Asymmetric Total Synthesis of Nannocystin A

Article abstract of DOI:10.1021/acs.joc.7b01502

Nannocystin A is a novel 21-membered macrolactone isolated from myxobacterium Nanocystis sp. It is a potent elongation factor 1 inhibitor and inhibits cancer cell line growth at nanomolar concentrations. In this work, a concise asymmetric total synthesis of nannocystin A has been developed, which features Sharpless epoxidation, Stille coupling, and final macrolactamization.

Full text of DOI:10.1021/acs.joc.7b01502

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Note
Asymmetric Total Synthesis of Nannocystin A
Qiang Liu, Ping Hu, and Yun He
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01502 • Publication Date (Web): 08 Aug 2017
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Asymmetric Total Synthesis of Nannocystin A
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Qiang Liu, Ping Hu* and Yun He*
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School of Pharmaceutical Sciences and Chongqing Key Laboratory of Natural Drug Research, Chongqing University, 55
Daxuecheng South Rd., Shapingba, Chongqing 401331, P.R. China.
Supporting Information Placeholder
ABSTRACT: Nannocystin A is a novel 21-membered macrolactone isolated from myxobacterium Nanocystis sp. It is a potent elon-
gation factor 1 inhibitor and inhibits cancer cell line growth at nanomolar concentrations. In this work, a concise asymmetric total
synthesis of nannocystin A has been developed, which features Sharpless epoxidation, Stille coupling and final macrolactamization.
community. A number of research labs have engaged in its total
synthesis. Ye4 and co-workers finished the first total
Natural products play key roles in drug discovery due to their
unique architectures and interesting biological activities.1 They
either serve as drugs or inspire medicinal chemists to design
natural product-like drugs. In 2015, two research teams led by
Brönstrup2 and Hoepfner3 independently reported the discovery
of nannocystin A (1), which is a novel and potent elongation
factor 1 inhibitor with an IC50 of 1 nM against PC3 cell line.2
Nannocystin A (Figure 1) is a 21-membered macrolactone
which consists of a tripeptide, a polyketide and an epoxyamide
moiety. The absolute configurations of the nine stereocenters
were confirmed by X-ray crystallography analysis.
Figure 1. Structure of nannocystin A (1)
Due to its promising biological profiles and limited availabil-
ity, nannocystin A has drawn much attention in the synthetic
Scheme 1. Retrosynthetic analysis of nannocystin A
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synthesis of nannocystin A, while Wang5, Zhang and Chen6 labs
finished its synthesis soon after. Recently, Liu7 finished the syn-
thesis of nannocystin Ax. Continuing our interest in natural
products with medicinal potential,8 we pursued the total synthe-
sis of nannocystin A, and successfullydeveloped a concise and
efficient asymmetric synthetic strategy.
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Our retrosynthetic analysis of nannocystin A is outlined in
Scheme 1. Nannocystin
A
could be prepared via
macrolatamization from a key precursor 2, which could be
assembled from intermediate iodide 3 and stannane 4 by
intermolecular Stille coupling.9 Stannane 4 could be accessed
from propargyl alcohol 7 and acid 8 with DCC coupling, and
iodide 3 could be assembled from epoxy fragment 5 and amine
6. Fragment 5 could in turn be derived from N-methyl-L-
isoleucine methy ester 910 and aldehyde 10. At last, amine 6
could be prepared from 11 and 12 via Negishi reaction.
As outlined in Scheme 2, the synthesis of fragment 5 started
from the preparation of the known unsaturated aldehyde 10
according to the literature procedure.11 Methylation of the free
hydroxyl in 10 turned out to be a challenge. The starting
aldehyde 10 decomposed with NaH/MeI, and the use of
Ag2O/MeI led to a sluggish reaction. To our delight,
methylation with Meerwein’s salt (Me3OBF4) and proton
sponge proceeded smoothly to furnish the corresponding ether
in 78% yield,12 which was reduced with DIBAL-H to provide
allylic alcohole 14 in 93% yield. Sharpless asymmetric
epoxidation13 of 14 gave epoxy alcohol 154,6 in excellent yield,
which was converted to epoxy acid directly with
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Scheme 4. Synthesis of stannane fragment 4
As shown in Scheme 4, intermediate 17 was synthesized
according to Evans’ protocol from the corresponding
benzaldehyde.16 Alkyne 18 was prepared from alcohol 17 via
PCC oxidation, followed by a modified Seyferth–Gilbert
homologation.17 Removal of the TBS group with TBAF
provided alcohol 7 in 95% yield. Subsequent esterification of 7
with acid 8 proved to be another unexpected challenge. After
various explorations, we finally found that the TES protection
in 8 was crucial for the successful transformation.18 Palladium
catalyzed hydrostannylation (Pd(PPh3)4, Bu3SnH)19 of 19
provided vinyl stannane 4 in 83% yield.
PhI(OAc)2/TEMPO/NaClO2 in MeCN/buffer (PH
= 7).
Subsequent condensation of the resulting acid with amine 9 led
to fragment 5 in 70% yield.
Scheme 2. Synthesis of fragment 5
Amino ester 6 was prepared from β-iodo-D-alanine ester
1114 in three steps (Scheme 3). Ester 11 and aryl iodide 12 were
first combined under Negishi condition, and the best result was
achieved by applying the combination of Pd2(dba)3 and SPhos
in DMF,15 furnishing the desired amine derivative 16 in 82%
yield. After deprotection of the Boc group with TFA, amine 6
was isolated in 85% yield.
Scheme 5. Total synthesis of nannocystin A
The assembly of nannocystin A is shown in Scheme 5.
Hydrolysis of methyl ester 5 with lithium hydroxide in
THF/H2O successfully furnished the corresponding carboxylic
acid, which was coupled with amine 6 using HATU/DIPEA.
Interestingly, the TBS group was removed under the amide
coupling condition, furnishing iodide
3 directly. With
precursors 3 and 4 in hand, we turned our attention to construct
the key macrolactamization precursor 21 with the Stille reaction.
Various
catalytic
systems
were
screened
and
Pd2(dba)3/AsPh3/DIPEA was found to be most effective for the
intermolecular Stille coupling,20 providing 21 in 74% yield. The
TES and Fmoc groups were removed with TBAF solution in
Scheme 3. Synthesis of amino ester fragment 6
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o
equiv) at 0 C. The reaction mixture was stirred at room tem-
one pot, giving rise to the corresponding amino ester 2 in 78%
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perature for 3 h. After quenching with saturated Na2S2O3 (40
mL) and EtOAc (50 mL), the layers were separated, and the
aqueous layer was extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were dried over MgSO4, filtered, and con-
centrated under reduced pressure. The resulting white solid was
used directly for the next step. The above product was dis-
solved in CH2Cl2 (30 mL), imidazole (2.0 g, 30 mmol, 15 equiv)
and TBSCl (4.5 g, 30 mmol, 1.5 equiv) were added, and the
reaction was stirred at room temperature for 8 h. After quench-
ing with H2O (30 mL), the organic layer was collected and the
aqueous layer was extracted with CH2Cl2 (20 mL × 2). The
combined organic layers were washed with brine, dried over an-
hydrous Na2SO4, concentrated and purified with silica gel col-
umn chromatography (eluted with petroleum ether) to afford
compound 12 (7.0 g, 87%) as colorless oil. IR (KBr) νmax 3456,
2933, 2858, 1638, 1458, 1281, 908, 806 cm-1;1H NMR (400
MHz, CDCl3) δ 7.56 (s, 2H), 1.04 (s, 9H), 0.28 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 148.7, 137.0, 127.8, 82.0, 25.9,
18.9, -3.1; HRMS (EI): calcd for C12H17Cl2IOSi+ [M+]
401.9471, found 401.9468.
yield. Finally, nannocystin A was achieved via a two step
sequence. The methyl ester was first hydrolyzed with lithium
hydroxide, and the resulting carboxylic acid was then treated
with HATU/DIPEA to furnish nannocystin A in 40% overall
yield. The spectral data (1H NMR, 13C NMR, HRMS) of
nannocystin A (1) were identical to those reported by Dr.
Dominic Hoepfner and co-workers (See SI for details).3
In summary, we have developed a concise strategy for the
synthesis of nannocystin A. Overall, nannocystin A was pre-
pared in 11 longest linear steps from 10 (5.3 % overall yield).
This convergent strategy is amenable for diverse analog prepa-
rations. The structure–activity-relationship (SAR) studies of
nannocystin A are currently ongoing in our laboratory, and the
results will be reported in due course.
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EXPERIMENTAL SECTION
General information. Unless otherwise noted, all reactions
were carried out in oven-dried glassware under nitrogen atmos-
phere. Tetrahydrofuran (THF) were dried and distilled from so-
dium. Dichloromethane (CH2Cl2) were distilled from calcium
hydride. Methanol (MeOH) was dried under reflux with mag-
nesium and then distilled. N,N-Dimethylformamide (DMF) was
dried over calcium hydride and distilled under vacuum. Reac-
tions were monitored by analytical thin-layer chromatography
(TLC) on Merck silica gel 60 F254 plates (0.25 mm), visualized
by ultraviolet light and/or by staining with ceric ammonium
Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-((tert-bu-
tyldimethylsilyl)oxy)-3,5-dichlorophenyl)propanoate (16).
Zn dust (9.5 g, 146 mmol, 6.0 equiv) was added to a flame-
dried, two-necked round bottom flask under a N2 atmosphere.
Dry DMF (20 mL) was added, followed by a catalytic amount
of iodine (617 mg, 2.4 mmol, 0.1 equiv). A solution of 11 (8.0
g, 24 mmol, 1.0 equiv) in DMF (8 mL) was added slowly at
room temperature. The solution was stirred at room temperature
for 4 h under N2, and then stood for half an hour. The superna-
tant was used for the next step directly. To a solution of com-
pound 12 (6.0 g, 15 mmol, 0.6 equiv) in dry DMF (15 mL), were
added Pd2(dba)3 (1.2 g, 1.5 mmol, 0.06 equiv) and SPhos (1.2
g, 5 mmol, 0.2 equiv) at room temperature. The above superna-
tant was added slowly to the solution in 3 batches with an inter-
val of 30 min. The resulting mixture was stirred at room tem-
perature for 8 h under N2. DMF was evaporated in vacuo and
the residue was diluted with EtOAc (20 mL). The mixture was
washed with H2O (15 mL), and the aqueous layer was extracted
with EtOAc (15 mL × 2). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, concentrated
and purified with silica gel column chromatography (petroleum
ether : EtOAc, 15:1) to afford the product 16 (5.8 g, 82%) as
1
molybdate or potassium permanganate. H NMR spectra were
obtained on an Agilent 400MR or 600MR DD2 spectrometer at
ambient temperature. Data were reported as follows: chemical
shift on the δ scale using residual proton solvent as internal
standard [δ 7.26 (CDCl3), 2.50 (DMSO-d6),], multiplicity (br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, m = mul-
tiplet), integration, and coupling constant (J) in Hertz. 13C NMR
spectra were obtained with proton decoupling on an Agilent
400MR or 600MR DD2 (100 MHz or 150 MHz) spectrometer
and were reported in ppm with residual solvent for internal
standard [δ 77.0 (CDCl3), 39.51 (DMSO-d6)]. High resolution
mass spectra were obtained on a Bruker SolariX 7.0T FT-ICR
MS spectrometer. Optical rotations were measured with a Ru-
dolph polarimeter. IR spectra were recorded on a Bruker 100
FT-IR spectrometer and are reported in terms of frequency of
absorption (cm–1). Abbreviations: Boc = tert-butoxycarbonyl,
DCC = dicyclohexylcarbodiimide, DIBAL-H = diisobutyl alu-
minium hydride, DIPEA = N,N-diisopropylethylamine, DMAP
= 4-dimethylaminopyridine, DMF = N,N-dimethylformamide,
DMP = Dess-Martin periodinane, Fmoc = 9-fluorenylmethox-
ycarbonyl, HATU = 1-[bis(dimethylamino)methylene]-1H-
1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate,
Ohira-Bestmann reagent = dimethyl (1-diazoacetonyl)phospho-
nate, Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium, SPhos
= 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, TBAF =
tetrabutylammonium fluoride, TBS = tert-butyldimethylsilyl,
TES = triethylsilyl, TFA = trifluoroacetic acid, THF = tetrahy-
drofuran, Tf = trifluoromethanesulfonyl, PCC = pyridinium
chlorochromate, TEMPO = (2,2,6,6-tetramethyl-piperidin-1-
yl)oxyl.
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yellow oil. [α]D = -45 (c 0.2, CHCl3); IR (KBr) νmax 3440,
1
3360, 2936, 2860, 1715, 1477, 1289, 1168, 844, 796 cm-1; H
NMR (400 MHz, CDCl3) δ 7.02 (s, 2H), 5.03 (d, J = 8 Hz, 1H),
4.55-4.47 (m, 1H), 3.72 (s, 3H), 3.02 (dd, J = 14, 5.6 Hz, 1H),
2.89 (dd, J = 13.6, 6 Hz, 1H), 1.43 (s, 9H), 1.04 (s, 9H), 0.27 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 171.9, 154.9, 147.3, 130.4,
129.5, 126.5, 80.1, 54.2, 52.3, 37.1, 28.2, 25.9, 18.8, -3.2;
HRMS (ESI): calcd for C21H33Cl2NNaO5Si+ [M+Na+]
500.1397, found 500.1390.
Methyl (R)-2-amino-3-(4-((tert-butyldimethylsilyl)oxy)-3,5-
dichlorophenyl) propanoate (6).
To a solution of 16 (1.0 g, 2.1 mmol, 1.0 equiv) in CH2Cl2 (5
mL), were added TFA (0.5 mL) at 0 oC. The reaction was stirred
at this temperature for 8 h. After quenching with H2O (10 mL),
the organic layer was collected and the aqueous layer was ex-
tracted with CH2Cl2 (20 mL × 3). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, concen-
Experimental Procedures.
tert-Butyl(2,6-dichloro-4-iodophenoxy)dimethylsilane (12).
To a solution of 2,6-dichlorophenol (3.2 g, 20 mmol, 1.0
equiv) in THF (50 mL), were added NIS (6.6 g, 30 mmol, 1.5
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trated and purified with silica gel column chromatography (pe- washed with brine, dried over anhydrous Na2SO4, concentrated
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6
7
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troleum ether:EtOAc, 1:2) to afford compound 6 (670 mg, 85%)
as colorless oil and the spectroscopic data are consistent with
those reported in literature6.1H NMR (400 MHz, CDCl3) δ 7.10
(s, 2H), 3.71 (s, 3H), 3.67 (dd, J = 7.6, 5.2 Hz, 1H), 2.94 (dd, J
= 13.6, 4.8 Hz, 1H), 2.73 (dd, J = 14, 8 Hz, 1H), 1.04 (s, 9H),
0.28 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 175.1, 147.1,
131.5, 129.4, 126.6, 55.6, 52.1, 39.8, 26.0, 18.8, -3.1, -3.2.
and purified with silica gel column chromatography (petroleum
ether:EtOAc, 4:1) to afford compound 15 (600 mg, 82%) as col-
orless oil and the spectroscopic data are consistent with those
reported in literature4,6. 1H NMR (400 MHz, CDCl3) δ 6.30 (s,
1H), 3.83 (t, J = 8 Hz, 1H), 3.65 (dd, J = 12, 4 Hz, 1H), 3.53
(dd, J = 12, 8 Hz, 1H), 3.21 (s, 3H), 3.01-2.95 (m, 1H), 2.02-
1.94 (m, 1H), 1.76 (s, 3H), 1.25 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 147.1, 83.9, 79.8, 65.2, 60.7, 56.9, 56.4, 32.6, 18.6,
14.4.
(R,2E,6E)-7-Iodo-5-methoxy-2,6-dimethylhepta-2,6-dienal
(13).
9
tert-Butyldimethyl(((1S,2R)-2-methyl-1-phenylbut-3-yn-1-
yl)oxy)silane (18).
10
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To a solution of 10 (100 mg, 0.36 mmol, 1.0 equiv) (1H NMR
(400 MHz, CDCl3) δ 9.40 (s, 1H), 6.50 (t, J = 4 Hz, 1H), 6.40
(s, 1 H), 4.38 (t, J = 6.4 Hz, 1H), 2.62 (t, J = 8 Hz, 2 H), 1.86
(s, 3 H), 1.75 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 194.8,
148.9, 148.6, 141.2, 79.3, 75.2, 34.5, 20.0, 9.5) in CH2Cl2 (5
mL) was added proton sponge (230 mg, 1 mmol, 3.0 equiv) and
trimethyloxonium tetrafluoroborate (133 mg, 0.9 mmol, 2.5
equiv) at room temperature. After 3 h, the reaction was
quenched with H2O (5 mL), the organic layer was collected and
the aqueous layer was extracted with CH2Cl2 (10 mL × 3). The
combined organic layers were washed with brine, dried over an-
hydrous Na2SO4, concentrated and purified with silica gel col-
umn chromatography (petroleum ether:EtOAc, 30:1) to afford
compound 13 (83 mg, 78%) as colorless oil. [α]D28 =+4.8 (c 0.1,
CHCl3); IR (KBr) νmax 3456, 1681, 1641, 1267, 1097, 740 cm-
To a solution of 17 (1.0 g, 3.6 mmol, 1.0 equiv) (1HNMR
(400 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 4.83 (d, J = 4.4 Hz,
1H), 3.58 (dd, J = 10.8, 8.4 Hz, 1H), 3.44 (dd, J = 10.4, 4.4 Hz,
1H), 2.65-2.50 (m, 1H), 2.10-2.00 (m, 1H), 0.91 (s, 9 H), 0.77
(d, J = 7.2 Hz, 3H), 0.05 (s, 3H), -0.18 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 142.3, 127.8, 127.1, 126.7, 77.4, 65.4, 42.9,
25.8, 18.1, 11.8, -4.7, -5.3) in CH2Cl2 (10 mL) was added PCC
o
(2.3 g, 10.7 mmol, 3.0 equiv) at 0 C. The reaction was stirred
at room temperature for 3 h. the mixture filtered through Celite
in filter funnel with EtOAc. The solvent was removed under re-
duced pressure to provide the aldehyde, which was used in the
next step without further purification. To a solution of aldehyde
in MeOH (10 mL) at 0 oC was added Ohira-Bestmann Reagent
(770 mg, 4 mmol, 1.4 equiv) and K2CO3 (478 mg, 3.4 mmol,
1.2 equiv). The reaction was stirred at room temperature for 4
h. The reaction was quenched by the addition of water (10 mL),
The layers were separated, and the aqueous layer was extracted
with EtOAc (3 × 20 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatog-
raphy (petroleum ether : EtOAc, 20:1) to give the product 18
(550 mg, 60%) as colorless oil. [α]D28 =-31.5 (c 0.7, CHCl3); IR
(KBr) νmax 3307, 2936, 2860, 2114, 1462, 1255, 1082, 1016,
1
1. H NMR (400 MHz, CDCl3) δ 9.40 (s, 1 H), 6.48-6.40 (m,
1H), 6.30 (s, 1 H), 3.85-3.76 (m, 1H), 3.23 (s, 3H), 2.70-2.57
(m, 1H), 2.57-2.45 (m, 1H), 1.79 (s, 3H), 1.73 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 194.9, 149.1, 146.8, 140.8, 84.5,
79.9, 56.6, 33.5, 18.9, 9.4; HRMS (DART): calcd for
+
C10H19O2NI+ [M+NH4 ] 312.0460, found 312.0455.
(R,2E,6E)-7-Iodo-5-methoxy-2,6-dimethylhepta-2,6-dien-1-
ol (14).
1
To a solution of 13 (550 mg, 1.8 mmol, 1.0 equiv) in CH2Cl2
(15 mL) at -40 °C was added DIBAL-H (2.8 mL, 2.8 mmol, 1.5
equiv, 1 M in toluene) in 5 min. The reaction was stirred at this
temperature for 1 h, the reaction was quenched with saturated
sodium potassium tartrate (15 mL), the mixture was extracted
with CH2Cl2 (30 mL × 3). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, concentrated
and purified with silica gel column chromatography (petroleum
ether:EtOAc, 5:1) to afford compound 14 (495 mg, 93%) as col-
orless oil and the spectroscopic data are consistent with those
reported in literature4,6. 1H NMR (400 MHz, CDCl3) δ 6.19 (s,
1H), 5.33 (t, J = 6.8 Hz, 1H), 4.00 (s, 2H), 3.66 (t, J = 6.8 Hz,
1H), 3.20 (s, 3H), 2.40-2.30 (m, 1H), 2.29-2.17 (m, 1 H), 1.75
(s, 3H), 1.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.5,
137.1, 120.9, 85.7, 79.1, 68.6, 56.5, 32.1, 18.8, 13.9.
840, 778, 635 cm-1; H NMR (400 MHz, CDCl3) δ 7.38-7.23
(m, 5H), 4.60 (d, J = 6.4 Hz, 1H), 2.71-2.63 (m, 1H), 1.99 (d, J
= 2 Hz, 1H), 1.21 (d, J = 6.8 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 3H),
-0.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.1, 127.7,
127.3, 126.8, 86.7, 77.7, 70.0, 35.5, 25.8, 18.2, 16.4, -4.7, -5.0;
+
HRMS (DART): calcd for C11H16ON+ [M+NH4 ] 178.1232,
found 178.1226.
(1S,2R)-2-Methyl-1-phenylbut-3-yn-1-ol (7).
To a solution of 18 (2.2 g, 8 mmol, 1.0 equiv) in THF (20
mL) was added TBAF (4.2 g, 16 mmol, 2.0 equiv) at room tem-
perature, The reaction was stirred at room temperature for 3 h.
The reaction was quenched by the addition of water (20 mL),
The layers were separated, and the aqueous layer was extracted
with EtOAc (3 × 20 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatog-
raphy using a solution of hexane : EtOAc (2 : 1) as the eluent to
give the product 7 (1.2 g, 95%) as colorless oil. [α]D28 = -45 (c
0.3, CHCl3); IR (KBr) νmax 3296, 2981, 2885, 2112, 1494, 1454,
1026, 754, 701, 564 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-
7.28 (m, 5H), 4.72-4.68 (m, 1H), 3.00-2.82 (m, 1H), 2.60-2.45
((2S,3S)-3-((R,E)-4-Iodo-2-methoxy-3-methylbut-3-en-1-yl)-
2-methyloxiran-2-yl)methanol (15).
A suspension of Ti(Oi-Pr)4 (68 mg, 0.24 mmol, 0.1 equiv),
L-(+)-DET (100 mg, 0.48 mmol, 0.2 equiv), t-BuOOH (3.6 mL,
12 mmol, 5 equiv, 3.3 M in toluene) and 4Å MS (2 g) at –40 oC
were stirred in CH2Cl2 (10 mL) for 1 h. A solution of 14 (700
mg, 2.4 mmol, 1.0 equiv) in CH2Cl2 (3 mL) was added drop-
wise, the reaction was stirred for 24 h. The reaction was
quenched with H2O (15 mL), the mixture was filtered through
a pad of Celite by CH2Cl2. The layers were separated, the or-
ganic layer was collected and the aqueous layer was extracted
with CH2Cl2 (20 mL × 3). The combined organic layers were
(m, 1H), 2.12 (d, J = 2.4 Hz, 1H), 1.15 (d, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 141.2, 128.1, 127.8, 126.5, 85.8,
76.1, 70.9, 33.9, 15.5; HRMS (DART): calcd for C17H30ONSi+
+
[M+NH4 ] 292.2097, found 292.2091.
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The Journal of Organic Chemistry
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-me-
(1S,2R,E)-2-Methyl-1-phenyl-4-(tributylstannyl)but-3-en-1-
yl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-me-
thyl-3-((triethylsilyl)oxy)butanoate (4).
1
2
3
4
5
6
7
8
thyl-3-((triethylsilyl)oxy)butanoic acid (8).
To a solution of 8a21 (270 mg, 1.15 mmol, 1.0 equiv) in
CH2Cl2 (10 mL) and followed by the addition of TFA (2 mL).
The reaction was stirred at room temperature for 10 h. Volatiles
were removed by vacuo, the deprotected product was used for
next step directly.
To a solution of 19 (600 mg, 1 mmol, 1.0 equiv) in THF (20
o
mL) at -20 C was added Pd(PPh3)4 (60 mg, 0.05 mmol, 0.05
eq) and followed by the addition of Bu3SnH (436 mg, 1.5 mmol,
1.5 eq). After the reaction was stirred at -20 oC for 1 h, the re-
action was quenched by the addition of water (20 mL), The lay-
ers were separated, and the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography us-
ing a solution of hexane : EtOAc (20 : 1) as the eluent to give
The aforementioned crude product was dissolved in H2O (2
mL) and MeCN (2 mL), followed by the addition of NaHCO3
(290 mg, 3.45 mmol, 3.0 equiv), FMOC-Cl (600 mg, 2.30
mmol, 2.0 equiv). The reaction was stirred at room temperature
for 4 h. The solution was diluted with water (10 mL) and EtOAc
(10 mL), the layers were separated and the aqueous layer was
extracted with EtOAc (10 mL × 3), The combined organic lay-
ers were washed with brine, dried over MgSO4, concentrated,
the crude product was used for next step directly.
The above crude product in CH2Cl2 (10 mL) and followed by
the addition of TESCl (345 mg, 2.30 mmol, 2.0 equiv), imidaz-
ole (240 mg, 3.45 mmol, 3.0 equiv). The reaction was stirred at
room temperature for 24 h before it was quenched with H2O (10
mL), The layers were separated, and the aqueous layer was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash column
(CH2Cl2 : MeOH, 20:1) to give the product 8 (370 mg, 69%, 3
steps) as colorless oil. [α]D28 =+26 (c 0.3, CHCl3); IR (KBr) νmax
3421, 2955, 2882, 1716, 1527, 1237, 1072, 738 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.2
Hz, 2H), 7.45-7.35 (m, 2H), 7.31 (t, J = 7.2 Hz, 2H), 5.60 (d, J
= 8.8 Hz, 1H), 4.41 (d, J = 7.2 Hz, 2H), 4.33-4.20 (m, 2H), 1.43
(s, 3H), 1.28 (s, 3H), 0.98 (t, J = 8 Hz, 9H), 0.67 (q, J = 7.6 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 173.2, 156.5, 143.8, 143.6,
141.3, 127.7, 127.0, 125.1, 119.9, 76.2, 67.2, 62.5, 47.1, 27.4,
26.3, 6.8, 6.4; HRMS (ESI): calcd for C26H35NNaO5Si+
[M+Na+] 492.2176, found 492.2167.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
28
the product 4 (750 mg, 83%) as colorless oil. [α]D = -22.5 (c
0.2, CHCl3); IR (KBr) νmax 3442, 2957, 2923, 1732, 1598, 1503,
1196, 1048, 742 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J
= 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H),
7.36-7.20 (m, 7H), 5.90-5.78 (m, 1H), 5.70-5.60 (m, 3H), 4.48-
4.32 (m, 2H), 4.31-4.17 (m, 2H), 2.86-2.70 (m, 1H), 1.48-1.32
(m, 6H), 1.33-1.20 (m, 12H), 1.18-1.07 (m, 3H), 0.95-0.81 (m,
18H), 0.80-0.70 (m, 6H), 0.56-0.43 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 169.8, 156.1, 148.4, 144.0, 143.8, 141.3, 138.5,
129.8, 128.0, 127.8, 127.6, 127.0, 125.2, 119.9, 80.9, 74.7, 67.0,
63.1, 47.2, 46.3, 28.9, 28.5, 27.6, 27.2, 16.5, 13.6, 9.3, 6.9, 6.4;
HRMS (ESI): calcd for C49H73NNaO5SiSn+ [M+Na+] 926.4182,
found 926.4170.
Methyl methyl-L-isoleucinate (9)
To a solution of methyl N-(tert-butoxycarbonyl)-N-methyl-
L-isoleucinate22 (3.3 g, 12.7 mmol, 1.0 equiv) in CH2Cl2 (25
mL) at oC was added TFA (3 mL). After the reaction was stirred
at room temperature for 3 h, the solvent was removed by vacuo,
purified with silica gel column chromatography (petroleum
ether : EtOAc, 1:1) to afford compound 9 (2.0 g, 99%) as col-
orless oil. 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 3.75 (d,
J = 3.6 Hz, 1H), 2.72 (s, 3H), 2.12-2.02 (m, 1H), 1.60-1.48 (m,
1H), 1.00-0.93 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 167.7,
65.3, 52.7, 35.8, 32.4, 26.5, 14.2, 11.5; HRMS (ESI): calcd for
C8H17NNaO2+ [M+Na+] 182.1152, found 182.1152.
(1S,2R)-2-Methyl-1-phenylbut-3-yn-1-yl(S)-2-((((9H-flu-
oren-9-yl)methoxy)carbonyl)amino)-3-methyl-3-((triethylsi-
lyl)oxy)butanoate (19).
To a solution of 7 (270 mg, 1.7 mmol, 1.0 equiv) and 8 (900
mg, 2 mmol, 1.2 equiv) in CH2Cl2 (10 mL) was added DCC
(520 mg, 2.5 mmol, 1.5 equiv) and DMAP (20 mg, 0.17 mmol,
0.1 equiv). The reaction was stirred at room temperature for 8
h, the reaction was quenched by the addition of water (20 mL),
The layers were separated, and the aqueous layer was extracted
with EtOAc (3 × 20 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatog-
raphy (petroleum ether : EtOAc, 10:1) to give the product 19
(700 mg , 68%) as colorless oil. [α]D28 =-21 (c 0.15, CHCl3); IR
(KBr) νmax 3441, 3305, 2938, 2880, 2119, 1723, 1660, 1506,
1455, 1214, 1047, 743 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.77
(d, J = 7.6 Hz, 2H), 7.64-7.58 (m, 2H), 7.44-7.36 (m, 4H), 7.34-
7.27 (m, 5H), 5.72 (d, J = 8 Hz, 1H), 5.63 (d, J = 9.2 Hz, 1H),
4.43-4.30 (m, 2H), 4.27-4.17 (m, 2 H), 3.11-3.02 (m, 1H), 2.02-
1.96 (m, 1H), 1.32-1.20 (m, 9H), 0.89 (t, J = 8 Hz, 9H), 0.50 (q,
J = 8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 169.5, 156.1,
144.0, 143.8, 141.3, 137.3, 128.4, 128.0, 127.9, 127.7, 127.0,
126.5, 125.2, 120.0, 84.1, 78.7, 74.7, 71.3, 67.1, 63.2, 47.2,
31.9, 28.4, 27.6, 17.6, 6.9, 6.4; HRMS (ESI): calcd for
C37H45NNaO5Si+ [M+Na+] 634.2959, found 634.2959.
Methyl N-((2R,3S)-3-((R,E)-4-iodo-2-methoxy-3-methylbut-
3-en-1-yl)-2-methyloxirane-2-carbonyl)-N-methyl-L-isoleu-
cinate (5).
To a solution of 15 (100 mg, 0.32 mmol, 1.0 equiv) in MeCN
(5 mL) and buffer (PH = 7, 5 mL) at 0 oC were added PhI(OAc)2
(10 mg, 0.03 mmol, 0.1 equiv), TEMPO (10 mg, 0.06 mmol,
0.2 equiv) and NaClO2 (75 mg, 0.95 mmol, 3.0 equiv). The re-
action was stirred for 2 h at room temperature. The solution was
diluted with water (10 mL) and EtOAc (10 mL), the layers were
separated and the aqueous layer was extracted with EtOAc (20
mL × 3), The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, concentrated and filtered through
silica gel in filter funnel with EtOAc to give the acid, which was
used for next step without further purification.
To a solution of above mentioned acid and 9 (88 mg, 0.55
mmol, 2.0 equiv) in DMF (5 mL) were sequentially added
HATU (210 mg, 0.55 mmol, 2.0 equiv) and DIPEA (140 mg,
1.1 mmol, 4.0 equiv) at room temperature. The reaction was
stirred at room temperature for 12 h. Solvent was removed by
vacuo and purified with silica gel column chromatography (pe-
troleum ether : EtOAc, 4:1) to afford compound 5 (106 mg,
83%) as colorless oil (1:1 mixture of rotamers). [α]D28 = -59 (c
0.3, CHCl3); IR (KBr) νmax 3554, 3477, 3415, 2967, 2933, 1742,
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The Journal of Organic Chemistry
Page 6 of 7
1648, 1460, 1402, 1261, 1198, 1098, 1003 cm-1; 1H NMR (400
δ 7.77 (d, J = 7.2 Hz, 2H), 7.64-7.57 (m, 2H), 7.42-7.36 (m,
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 6.32 (s, 1H), 4.82 (d, J = 10.4 Hz, 0.5H), 4.59
(d, J = 10.8 Hz, 0.5H), 3.85 (q, J = 6.4 Hz, 1H), 3.72 (s, 1.5H),
3.67 (s, 1.5H), 3.21 (s, 3H), 3.10-3.04 (m, 0.5H), 3.05 (s, 1.5H),
3.0-2.94 (m, 0.5H), 2.79 (s, 1.5H), 2.10-1.83 (m, 2H), 1.76 (s,
3H), 1.76-1.68 (m, 1H), 1.51 (s, 1.5H), 1.47 (s, 1.5H), 1.37-1.25
(m, 1H), 1.10-0.97 (m, 1H), 0.96-0.83 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 171.3, 171.0, 170.8, 170.4, 146.7, 83.7, 83.5,
80.2, 80.0, 63.7, 60.8, 60.6, 60.0, 59.4, 59.2, 56.5, 52.0, 51.8,
33.6, 32.9, 32.8, 32.4, 30.7, 28.7, 24.6, 24.1, 18.7, 18.6, 15.8,
2H), 7.33-7.28 (m, 2H), 7.28-7.25 (m, 5H), 7.04 (s, 2H), 6.64
(d, J = 7.8 Hz, 1H), 6.12 (dd, J = 15, 10.8 Hz, 1H), 5.93 (s, 1
H), 5.89 (d, J = 10.2 Hz, 1H), 5.68 (d, J = 9.6 Hz, 1H), 5.65 (d,
J = 7.8 Hz, 1H), 5.43 (dd, J = 15.6, 7.8 Hz, 1H), 4.75-4.67 (m,
1H), 4.46-4.36 (m, 2H), 4.35-4.28 (m, 1H), 4.24 (t, J = 7.2 Hz,
1H), 4.20 (d, J = 9.6 Hz, 1H), 3.77-3.11 (m, 1H), 3.68 (s, 3H),
3.64 (t, J = 6.6 Hz, 1H), 3.12 (s, 3H), 3.09-3.01 (m, 2H), 2.94
(s, 3H), 2.89-2.81 (m, 2 H), 2.15-2.07 (m, 1H), 1.81-1.75 (m,
2H), 1.43 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 1.22 (s, 3H), 1.12
(d, J = 6.6 Hz, 3H), 1.09-1.03 (m, 1H), 1.00-0.94 (m, 1H), 0.91-
0.78 (m, 15H), 0.49 (q, J = 7.8 Hz, 6H); 13C NMR (150 MHz,
CDCl3) δ 171.6, 171.0, 169.8, 169.3, 156.2, 146.9, 144.0, 143.8,
141.3, 138.1, 134.9, 134.7, 129.6, 128.8, 128.2, 128.0, 127.7,
127.7, 127.0, 126.7, 125.2, 121.1, 120.0, 84.6, 80.4, 74.7, 67.1,
63.2, 61.4, 60.2, 59.7, 56.0, 52.8, 52.4, 47.2, 42.1, 36.4, 33.0,
30.8, 28.4, 27.6, 24.3, 16.5, 15.5, 14.9, 11.0, 10.4, 6.9, 6.5;
HRMS (ESI): calcd for C64H83Cl2N3NaO12Si+ [M+Na+]
1206.5015, found 1206.4992.
9
+
15.7, 15.2, 11.5, 10.6; HRMS (ESI): calcd for C18H30INNaO5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[M+Na+] 490.1060, found 490.1055.
Methyl (R)-3-(3,5-dichloro-4-hydroxyphenyl)-2-((2S,3S)-2-
((2R,3S)-3-((R,E)-4-iodo-2-methoxy-3-methylbut-3-en-1-yl)-
N,2-dimethyloxirane-2-carboxamido)-3-methylpentaaido)pro-
panoate (3).
To a solution of 5 (80 mg, 0.17 mmol, 1.0 equiv) in THF/H2O
(2/2 mL) at 0 oC was added LiOH (8 mg, 0.34 mmol, 2.0 equiv),
the reaction was allowed to stirred at room temperature for 12
h. Diluted with EtOAc (10 mL) and H2O (5 mL), the layers were
separated and the aqueous layer was extracted with EtOAc (10
mL × 3), The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, concentrated and filtered through
silica gel in filter funnel with EtOAc to give the acid used for
the following step directly.
(1S,2R,3E,5E,7R)-8-((2S,3R)-3-(((2S,3S)-1-(((R)-3-(3,5-Di-
chloro-4-hydroxyphenyl)-1-methoxy-1-oxopropan-2-
yl)amino)-3-methyl-1-oxopentan-2-yl)(methyl)carbamoyl)-3-
methyloxiran-2-yl)-7-methoxy-2,6-dimethyl-1-phenylocta-3,5-
dien-1-yl (S)-2-amino-3-hydroxy-3-methylbutanoate (2).
To a solution of 21 (20 mg, 0.017 mmol, 1.0 equiv) in THF
(5 mL) was added TBAF (13 mg, 0.051 mmol, 3.0 equiv) at
room temperature, the reaction was stirred at this temperature
for 2 h. Solvent was removed by vacuo and purified with silica
gel column chromatography (EtOAc) to afford compound 2 (12
mg, 78%) as colorless oil; [α]D28 =-19 (c 0.1, EtOAc); IR (KBr)
νmax 3653, 3443, 3302, 3185, 2924, 2853, 1740, 1577, 1376,
1244, 1048, 557 cm-1; 1H NMR (600 MHz, DMSO) δ 8.42 (d, J
= 7.8 Hz, 1H), 7.40-7.20 (m, 7H ), 6.22 (dd, J = 15, 11.4 Hz,
2H), 5.95 (d, J = 10.8 Hz, 1H), 5.63 (d, J = 6.6 Hz, 1H), 5.57
(dd, J = 15, 7.8 Hz, 1H), 4.56-4.47 (m, 2H), 3.72-3.65 (m, 1H),
3.59 (s, 3H), 3.05 (s, 3H), 3.03-2.96 (m, 1H), 2.91-2.86 (m, 1H),
2.86 (s, 3H), 2.83-2.71 (m, 3H), 1.88-1.78 (m, 1H), 1.78-1.69
(m, 2H), 1.58 (s, 3H), 1.34 (s, 3H), 1.17-1.09 (m, 1H), 1.09 (s,
3H), 1.00 (d, J = 6.6 Hz, 3H), 0.98 (s, 3H), 0.87-0.78 (m, 1H),
0.74 (t, J = 7.2 Hz, 3H), 0.49 (d, J = 6 Hz, 3H); 13C NMR (150
MHz, DMSO) δ 171.4, 169.9, 168.8, 147.5, 138.8, 135.3, 134.8,
130.5, 129.2, 127.9, 127.6, 127.0, 126.4, 121.8, 83.5, 78.6, 70.5,
63.5, 59.7, 59.1, 58.6, 55.3, 52.6, 51.9, 41.6, 34.4, 32.1, 31.2,
29.9, 26.6, 25.6, 23.9, 15.7, 14.7, 14.6, 11.0, 10.3; HRMS (ESI):
calcd for C43H60Cl2N3O10 [M+H+] 848.3650, found 848.3648.
The resulting crude acid was dissolved in DMF (5 mL), 6 (200
mg, 0.54 mmol, 3.0 equiv), HATU (90 mg, 0.34 mmol, 2.0
equiv) and DIPEA (70 mg, 0.54 mmol, 3.0 equiv) was added at
room temperature, the reaction was stirred at this temperature
for 1 day. Solvent was removed by vacuo and purified with sil-
ica gel column chromatography (petroleum ether : EtOAc, 2:1)
to afford compound 3 (66 mg, 56%, 2 steps) as colorless oil.
28
[α]D = -23 (c 0.3, CHCl3); IR (KBr) νmax 3551, 3478, 3414,
2960, 2925, 2854, 1744, 1639, 1491, 1464, 1280, 1093, 795,
614 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 2H), 6.60 (d,
J = 8 Hz, 1H), 6.35 (s, 1H), 5.84 (s, 1H), 4.77-4.67 (m, 1H),
4.45 (d, J = 11.6 Hz, 1H), 3.89 (t, J = 6.4 Hz, 1H), 3.72 (s, 3H),
3.23 (s, 3H), 3.11-3.00 (m, 2H), 2.96 (s, 3H), 2.90-2.81 (m, 1H),
2.20-2.05 (br, 1H), 1.93-1.82 (m, 2H), 1.79 (s, 3H), 1.46 (s, 3H),
1.35-1.26 (m, 1H), 1.05-0.93 (m, 1H), 0.92-0.78 (m, 6 H); 13C
NMR (100 MHz, CDCl3) δ 171.4, 171.1, 169.3, 146.9, 146.7,
129.6, 128.9, 121.1, 83.7, 80.2, 61.5, 60.5, 59.2, 56.5, 52.8,
52.5, 36.6, 32.8, 30.8, 30.7, 24.3, 18.8, 15.5, 15.1, 10.4; HRMS
(ESI): calcd for C27H37Cl2IN2NaO7+ [M+Na+] 721.0914, found
721.0905.
(1S,2R,3E,5E,7R)-8-((2S,3R)-3-(((2S,3S)-1-(((R)-3-(3,5-Di-
chloro-4-hydroxyphenyl)-1-methoxy-1-oxopropan-2yl)amino)-
3-methyl-1-oxopentan-2-yl)(methyl)carbamoyl)-3-
methyloxiran-2-yl)-7-methoxy-2,6-dimethyl-1-phenylocta-3,5-
dien-1-yl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-
3-methyl-3-((triethylsilyl)oxy)butanoate (21).
To a solution of 3 (16 mg, 0.023 mmol, 1.0 equiv) and 4 (25
mg, 0.028 mmol, 1.2 equiv) in DMF (2 mL) were added
Pd2(dba)3 (4 mg, 0.0046 mmol, 0.2 equiv), As(Ph)3 (14 mg, 0.46
mmol, 2.0 equiv) and DIPEA (16 mg, 0.125 mmol, 5.0 equiv)
at room temperature, the reaction was stirred at this temperature
for 8 h. Solvent was removed by vacuo and purified with silica
gel column chromatography (petroleum ether : EtOAc, 1:1) to
afford compound 21 (20 mg, 74%) as colorless oil. [α]D28 = -40
(c 0.2, CHCl3); IR (KBr) νmax 3453, 2962, 2924, 1639, 1492,
1452, 1327, 1085, 794, 743 cm-1; 1H NMR (600 MHz, CDCl3)
(1R,4S,7R,10S,13S,14R,15E,17E,19R,21S)-4-((S)-Sec-bu-
tyl)-7-(3,5-dichloro-4-hydroxybenzyl)-10-(2-hydroxypropan-2-
yl)-19-methoxy-1,3,14,18-tetramethyl-13-phenyl-12,22-dioxa-
3,6,9-triazabicyclo[19.1.0]docosa-15,17-diene-2,5,8,11-
tetraone (1).
To a solution of 2 (10 mg, 0.012 mmol, 1.0 equiv) in THF (1
o
mL) and H2O (0.2 mL) at 0 C was added 1 M LiOH (18 uL,
0.018 mmol, 1.5 equiv). After 1 h, diluted with EtOAc (5 mL)
and H2O (2 mL), the layers were separated and the aqueous
layer was extracted with EtOAc (5 mL × 3), The combined or-
ganic layers were washed with brine, dried over anhydrous
Na2SO4, concentrated and filtered through silica gel in filter
funnel with EtOAc to give the corresponding acid (HRMS
(ESI): calcd for C42H58Cl2N3O10H+ [M+H+] 834.3494, found
834.3511) used for the following step directly.
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The Journal of Organic Chemistry
(2) Hoffmann, H.; Kogler, H.; Heyse, W.; Matter, H.; Caspers, M.;
The resulting acid was dissolved in DMF (5 mL), HATU (9
mg, 0.024 mmol, 2.0 equiv) and DIPEA (8 mg, 0.06 mmol, 5.0
equiv) was added at room temperature, the reaction was stirred
for 8 h. Solvent was removed by vacuo and purified with silica
gel column chromatography (petroleum ether : EtOAc, 1:1) to
afford compound 1 (4 mg, 40%, 2 steps) as a solid; [α]D28 = -32
(c 0.3, MeOH); IR (KBr) νmax 3460, 2959, 2925, 2854, 1732,
1655, 1491, 1463, 1378, 1204, 1094 cm-1; 1H NMR (600 MHz,
DMSO) δ 9.80 (s, 1H), 8.61 (d, J = 10.2 Hz, 1H), 8.05 (d, J =
9.6 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.37 (s, 2H), 7.32 (t, J =
7.8 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 6.42-6.33 (m, 1H), 6.18
(dd, J = 15.6, 4.8 Hz, 1H), 6.11 (d, J = 10.8 Hz, 1H), 5.89 (br,
1H), 5.14 (s, 1H), 4.73-4.64 (m, 2H), 4.47 (d, J = 11.4 Hz, 1H),
3.64-3.59 (m, 1H), 3.09 (s, 3H), 2.97 (s, 3H), 2.81 (d, J = 12 Hz,
1H), 2.68-2.59 (m, 2H), 2.50 (m, 1 H, overlap), 2.12 (t, J = 12
Hz, 1H), 1.70 (s, 3H), 1.70 (m, 1H), 1.50-1.44 (m, 1H), 1.43 (s,
3H), 1.23-1.17 (m, 1H), 1.14 (s, 3H), 1.03 (s, 3H), 0.96 (d, J =
6.6 Hz, 3H), 0.89-0.83 (m, 1H), 0.77 (t, J = 7.2 Hz, 3H), 0.33
(d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, DMSO) δ 170.6,
170.5, 169.3, 168.7, 147.3, 140.0, 138.4, 133.3, 130.9, 129.7,
129.0, 127.8, 127.0, 126.0, 124.6, 121.5, 84.0, 78.9, 71.9, 61.4,
59.2, 59.2, 58.1, 55.2, 52.7, 41.9, 37.1, 31.0, 30.6, 29.7, 28.2,
24.4, 24.2, 14.9, 14.5, 10.7, 10.1, 9.5; HRMS (ESI): calcd for
C42H55Cl2N3NaO9+ [M+Na+] 838.3207, found 838.3203.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS
Publications website.
Experimental Spectra
Comparison of 1H NMR Data of Natural and Synthetic Nannocys-
tin A (Table S1)
Comparison of 13C NMR Data of Natural and Synthetic Nannocys-
tin A (Table S2)
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AUTHOR INFORMATION
Corresponding Author
* E-mail: ping.hu@cqu.edu.cn.
* E-mail: yun.he@cqu.edu.cn.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the financial support from the National Natural
Science Foundation of China (Nos. 21572027 and 21372267).
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