RETRACTED ARTICLE: Asymmetric Synthesis of Apratoxin e

Article abstract of DOI:10.1021/acs.joc.6b02086

An efficient method for asymmetric synthesis of apratoxin E 2 is described in this report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment 6. In addition to this "from nature to nature" strategy, olefin cross-metathesis (CM) was applied as an alternative approach for the formation of the double bond. Moreover, pentafluorophenyl diphenylphosphinate was found to be an efficient condensation reagent for the macrocyclization.

Full text of DOI:10.1021/acs.joc.6b02086

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Article
Asymmetric Synthesis of Apratoxin E
Zhuo-Ya Mao, Chang-Mei Si, Yi-Wei Liu, Han-Qing Dong, Bang-Guo Wei, and Guo-Qiang Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02086 • Publication Date (Web): 20 Sep 2016
Downloaded from http://pubs.acs.org on September 25, 2016
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Asymmetric Synthesis of Apratoxin E
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ZhuoꢀYa Mao,†,‡ ChangꢀMei Si,† YiꢀWen Liu,‡ HanꢀQing Dong, ‡, BangꢀGuo
Wei,*,† and GuoꢀQiang Lin†,‡
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† Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng
Road, Shanghai 201203, China
‡
Institutes of Biomedical Sciences, Fudan University, 130 Dongan Road, Shanghai 200433, China
Present address: Arvinas Inc., 5 Science Park, New Haven, CT 06511
bgwei1974@fudan.edu.cn
Abstract
An efficient method for asymmetric synthesis of apratoxin E 2 is described in this
report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was
utilized to prepare the nonꢀpeptide fragment 6. In addition to this “from nature to
nature” strategy, olefin cross metathesis (CM) was applied as an alternative approach
for the formation of the double bond. Moreover, pentafluorophenyl
diphenylphophinate (FDPP) was found to be an efficient condensation reagent for the
macrocyclization.
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Introduction
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As a class of promising compounds in drug discovery, marine cyanobacteria produce
suites of biological secondary metabolites, which possess a variety of physiological
activities including antimicrobial, antimalarial, cytotoxic and neorotoxic properties.1
Cyanobacterial cyclodepsipeptides, predominantly with structural skeletons as
depsipeptides and peptideꢀpolyketide hybrids, have attracted considerable attention as
novel pharmaceuticals. A number of them have been advanced to therapeutic lead
compounds in phase II clinical trials for cancer treatment.2 As a prime instance, a
family of apratoxins, which are cyclodepsipeptides, exhibit potent cancer growth
inhibitory activity by inducing G1 phase specific cell cycle arrest and apoptosis
(Figure 1).3
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Apratoxins A (1) and E (2) were isolated from the remarkably prolific Lyngbya
majuscula collected in Guam and Palau, while apratoxin D (3) was obtained from the
same species collected in Papua New Guinea (Figure 1). All of these isolated marine
secondary metabolites show potent in vitro cytotoxicity against LoVo cell lines (IC50:
0.36ꢀ10.8 nM) and the KB (IC50: 0.52ꢀ21.3 nM).4 Due to their unique scaffolds and
striking biological activities, tremendous efforts have been devoted to the asymmetric
synthesis of apratoxins A, C, D, F5 and corresponding analogues6, as well as the
studies on their mechanism of action7 and biosynthetic pathways.8 We demonstrated
an asymmetric method for synthesis of dehydroapratoxin A in 2011.9 Interestingly,
apratoxin E (2), a new peptideꢀpolyketide hybrid of the apratoxin class, seemed to
be ignored by synthetic chemistry. As part of our continuous efforts in searching for
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divergent synthesis of biological secondary metabolites10 to expand our knowledge
about their structureꢀactivity relationships, herein we present the first asymmetric
synthesis of apratoxin E 2.
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Figure 1. The structures for the representative apratoxins.
Results and discussions
Our strategy for asymmetric synthesis of apratoxin E 2 is illustrated in figure 2, with
stereoselective synthesis of nonꢀpeptide fragment 5 and effective macrocyclization as
our main focus in constructing this target molecule. As we aim to achieve an effective
method for synthesis of apratoxin E 2, we proposed a cross metathesis (CM)11
reaction to form the double bond between C34 and C35, and explored
macrolactamization at two different connection points for the final ring closure.
Moreover, the concept of “from nature to nature” was applied in our asymmetric
synthesis of apratoxin E. In other words, the key fragment 6 could be prepared from
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industrial waste, and another nonꢀpeptide fragment 7 could be derived from glutamic
5
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acid.
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Macrocyclization
S
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19
CM Reaction
H
O
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N
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O
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N
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Yamaguchi
Esterification
Peptide Formation
Apratoxin E 2
S
N
O
NHFmoc
AllylO
N
O
O
O
+
O
O
N
OAllyl
O
FmocN
22
5
NH2
O
TrtS
O
OH
HO
BnO
N
O
H
O
7
Glutamic Acid
+
HO
OTBS
O
O
The industrial waste
6
Figure 2. Our strategy to access apratoxin E
The preparation of nonꢀpeptide fragment 6 is shown in Scheme 1. Chiral lactone 8
was isolated from the industrial waste water during the degradation of saponin
glycosides12 in 22% yield. Treatment of 8 with benzyl chloride (BnCl) and NaOH in
toluene under refluxing conditions resulted in the ring opening and simultaneous
selective benzylation of the primary alcohol. Upon the protection of carboxylic acid,
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the crude ester 9 was reduced with LiAlH4 and the resulting diol was subjected to
oxidative cleavage (NaIO4) to give the aldehyde. The introduction of tꢀbutyl group
was achieved by nucleophilic addition with a solution of tertꢀbutylmagnesium
chloride, which obviously gave a mixture of two diasteromers (dr = 1:1). This new
stereocenter could be enriched through an oxidation and stereoselective reduction
process. Thus, compound 10 was oxidized with DMP to give desired ketone 11, which
was treated with BH3·DMS and a catalytic amount of Corey’s chiral borane, RꢀCBS
catalyst.13 This sequence led to the enhancement of desired isomer with syn/anti =
88:12, and each isomers could be separated by silica gel chromatography. The
subsequent transformations were straightforward. Protection (TBSOTf, 2,6ꢀlutidine)
of compound 12 and subsequent hydrogenation (Pd/C, H2) generated the desired
primary alcohol 13 in 76% overall yield. Iodination of the alcohol and then covered to
olefin 11 via a CopperꢀCatalyzed Grignard coupling reaction14 with vinylmagnesium
bromide in 84% overall yield.
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Scheme 1 The preparation of olefin 6. Reagents and conditions: a. (1) BnCl, NaOH, toluene,
reflux, 12 h; (2) MeOH, H2SO4, reflux, 4 h; b. (1) LiAlH4, THF, 10 h; (2) NaIO4, H2O, 1.5 h; (3)
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tꢀBuMgCl, THF, overnight, 47% (5 steps); c. DMP, NaHCO3, DCM, 3 h, 87%; d. (R)ꢀCBS,
.
BH3 DMS, toluene, ꢀ20 oCꢀ35oC, 72%; e. (1) TBSOTf, 2,6ꢀlutidine, DCM, 0oC, 3 h; (2) Pd/C,
Pd(OH)2, H2, MeOH, 3 h, 76% (2 steps); f. (1) I2, imid., PPh3, DCM, 15 min; (2) CH3=CHMgBr,
Li2CuCl4, THF, ꢀ78oCꢀrt, overnight, 84% (2 steps).
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Next, we turned our attention to prepare the peptide unit 7 of apratoxin E (Scheme 2).
Protection (Boc2O) and subsequent reduction15 (NaBH4) of the glutamic acid
derivative 14 gave the desired alcohol 15 in 69% overall yield, which was
conveniently converted to its sulfide 16 by the known method16 in 79% yield.
Deprotection (TFA) of 16 and subsequent coupling with acrylic acid using HATU17
generated amide 7 in 71% yield.
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Scheme 2. Preparation of the peptide unit 7. Reagents and conditions: a. (1) Boc2O, NaHCO3,
H2O/dioxane, 0oCꢀrt, overnight; (2) 4ꢀMethylmorpholine, ethyl chloroformate, ꢀ10 oC, 1h then
NaBH4, THF, rt, 1 h, 69% (2 steps); b. (1) MsCl, TEA, DCM, 0oC, 40 min; (2) NaH, TrtSH,
DMF, 0oCꢀrt, overnight, 79% (2 steps); c. (1) TFA, DCM, 0oC, 30 min; (2) acrylic acid, HATU,
DIPEA, DCM, 5 h, 71% (2 steps).
With the intermediates 6 and 7 in hand, the fragment 17 was prepared by CM reaction
in 60% yield (E:Z > 99:1) (Scheme 3). After the benzyl ester was switched to allylic
protection through hydrolysis (LiOH) and subsequent alkylation (AllylBr/K2CO3), the
resulting compound 18 was subjected to a solution of HCl(6N)/EtOAc to produce
the secondary alcohol 19 in 82% isolated yield, which was coupled with
NꢀFmocꢀproline under Yamaguchi conditions18 to give 20 in 89% yield. Then,
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o
compound 20 was treated with POPh3/Tf2O19 in CH2Cl2 at 0 C to form the desired
thiazoline 5 in 86% yield. Finally, the deprotection of the allyl protected carboxylic
acid in thiazoline 5 was achieved by treatment with catalytic amount of Pd(PPh3)4 in
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Nꢀmethylaniline to give the acid 21 in 88% yield. 20
STrt
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OTBS
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+
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N
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STrt
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OR
d
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19 (R= H)
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FmocN
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RO
S
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O
N
5 (R = Allyl)
21 (R = H)
f
Scheme 3. Preparation of the nonꢀpeptide fragment 21. Reagents and conditions: a. Grubbs 2nd,
DCM, reflux, 24 h, 60%; b. (1) LiOH, THF/MeOH/H2O, 0oCꢀrt, 7 h; (2) AllyBr, K2CO3, DMSO, rt,
4
h, 84% (2 steps); c. HCl, EtOAc, 0oCꢀrt,
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h, 82%; d. NꢀFmocꢀProline,
o
2,4,6ꢀtrichlorobenzoylchloride, DIPEA, DMAP, toluene, 89%; e. Ph3P=O, Tf2O, DCM, 0 C, 20
mim, 86%; f. Pd(PPh3)4, NꢀMethylaniline, THF, 1 h, 88%.
Tripeptide 22 was prepared by sequential condensation of Nꢀmethylisoleucine allyl
ester with NꢀBocꢀNꢀmethylalanine and NꢀFmocꢀOꢀmethyltyrosine by the known
method.5d Upon the treatment with Et2NH, the resulting free amine was coupled with
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carboxylic acid 21 using pentafluorophenyl diphenylphophinate (FDPP)21 in
acetonitrile to afford the amide 23 in 75% yield. The sequential cleavage of allyl ester
by Pd(PPh3)4 in Nꢀmethylaniline and removal of the Fmoc protecting group with
Et2NH/CH3CN afforded the crude cyclization precursor, which was subjected to
macrolactamization (HATU/DIPEA) to give apratoxin E 2 in 19% overall isolated
yield (Scheme 4).
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S
H
O
O
NHFmoc
N
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O
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O
a
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Fmoc
OAllyl
OAllyl
N
O
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S
N
H
N
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O
O
b
O
O
N
O
N
6
5
Apratoxin E 2
Scheme 4. The synthesis of apratoxin E (2) by macrolactamization at C5 and C6. Reagents and
conditions: a. (1) Et2NH, MeCN, 30 min; (2) 21, FDPP, DIPEA, MeCN, overnight, 75%; b. (1)
Pd(PPh3)4, NꢀMethylaniline, THF, 30 min; (2) Et2NH, MeCN, 30 min; (3) HATU, DIPEA, DCM,
40 h, 19%.
To improve the yield of macrolactamization, we turned our attention to the final
amidation between the less hindered carboxylic acid and primary amino group, ie,
C27 and C18 (Scheme 5). After the deprotection of the allyl protected carboxylic acid
in tripeptide fragment 22 and NꢀFmoc protecting group in nonꢀpeptide fragment 5, the
resulting free carboxylic acid 24 and free amine 25 were coupled in the presence
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of HATU/DIPEA to generate 26 in 73% overall yield. Similar sequential cleavage of
allyl ester by Pd(PPh3)4 in Nꢀmethylaniline and removal of the Fmoc protecting group
with Et2NH/CH3CN gave the cyclization precursor, which, upon the subsequent
macrolactamization use FDPP as condensation reagent afforded apratoxin E 2 in 43%
overall isolated yield. The product could be further purified by RP C18 HPLC with
80% aqueous CH3CN (Sepaxꢀtech Amethyst C18 semipreparative column, 250 mm ×
150 mm, 10 mL/min, refractive index detection){ [α]D23 ꢀ150.4 (c 0.24, MeOH), lit.4d
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[α]D ꢀ69 (c 0.12, MeOH)}, to afford >99% purity. Both H and 13C NMR
spectroscopic data are consistent with those in literature.4d Notably, apratoxin E 4
exists as a mixture of two conformers (2:3) in CDCl3 due to the restricted rotation
around the OꢀMeꢀTyrꢀNꢀMeꢀAla amide bond.4b,d
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RN
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6
AllylO
S
O
O
O
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AllylO
O
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S
N
H
O
5, R=Fmoc
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N
O
O
O
O
c
NHFmoc
NHFmoc
O
O
N
O
a
N
N
O
N
O
O
O
O
O
N
N
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OH
OAllyl
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24
S
N
H
O
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O
N
18
N
O
O
O
d
O
N
O
N
Apratoxin E 2
Scheme 5. The synthesis of apratoxin E 2 by macrolactamization at C18 and C27. Reagents and
conditions: a. Pd(PPh3)4, NꢀMethylaniline, THF, 1 h; b. Et2NH, MeCN, 30 min; c. HATU, DIPEA,
DCM, overnight, 73%; d. (1) Pd(PPh3)4, NꢀMethylaniline, THF, 30 min; (2) Et2NH, MeCN, 30
min; (3) FDPP, DIPEA, MeCN, 40 h, 43%.
Conclusion
In summary, we first completed the enantioselective total synthesis of natural
apratoxin E 2. The main feature of our strategy is “from nature to nature”, namely, the
nonꢀpeptide fragment 6 was effectively prepared from industrial waste generated
during the degradation of saponin glycosides. The cross metathesis (CM) was applied
as an alternative approach for the formation of the double bond. Moreover, FDPP was
found to be an efficient condensation reagent for the macrocyclization. Further efforts
on the extension of this strategy are onꢀgoing in our laboratory to synthesize other
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analogs of apratoxin E. The chemistry and related biological data will be published in
due course.
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Experimental Section
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General: THF was distilled from sodium/benzophenone. Reactions were monitored
by thin layer chromatography (TLC) on glass plates coated with silica gel with
fluorescent indicator. Flash chromatography was performed on silica gel (300–400)
with Petroleum / EtOAc as eluent. Optical rotations were measured on a polarimeter
with a sodium lamp. HRMS were measured on a LCMSꢀITꢀTOF apparatus. IR spectra
were recorded using film on a Fourier Transform Infrared Spectrometer. NMR spectra
were recorded at 400 MHz or 600 MHz, and chemical shifts are reported in δ (ppm)
1
referenced to an internal TMS standard for H NMR and CDCl3 (77.0 ppm) for 13C
NMR.
Methyl (2S,4R)-5-(benzyloxy)-2-hydroxy-4-methylpentanoate 9
The lactone 5 (5.00 g, 38.43 mmol) was dissolved in toluene (60 mL), then NaOH
(6.15 g, 153.72 mmol) and BnCl (8.80 mL, 76.86 mmol) was added. After being
refluxed for 12 h, water was added. Extraction were performed with Et2O three times,
the aqueous phase was acidified with hydrochloric acid. The resulted mixture was
extracted with EtOAc (60 mL × 3), and the combined organic layers were dried over
MgSO4, flittered and concentrated to give the crud acid without further purification.
The above crude acid was dissolved in MeOH (60 mL), and then H2SO4 (1.00 mL,
98%) was carefully dropped. After being refluxed for 4 h, the reaction was quenched
with water. The mixture was extracted with EtOAc (50 mL × 3), and the combined
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organic layers were washed with brine. Dried, filtrated and concentrated to give the
5
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crude ester without further purification. [α]D = +6.2 (c 1.00, CHCl3); IR (film): νmax
8
9
3450, 2958, 2851, 2359, 1737, 1458, 1211, 1092, 740, 701 cmꢀ1; 1H NMR (400 MHz,
CDCl3) δ 7.17ꢀ7.05 (m, 5H), 4.35ꢀ4.27 (m, 2H), 4.14ꢀ4.03 (m, 1H), 3.57 (s, 3H),
3.17ꢀ3.15 (m, 1H), 3.15ꢀ3.12 (m, 1H), 1.97ꢀ1.85 (m, 1H), 1.60ꢀ1.42 (m, 2H),
0.82ꢀ0.78 (m, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 175.8, 138.2, 133.6, 130.2,
128.4, 127.6, 75.9, 73.1, 69.3, 52.4, 39.3, 30.6, 16.8 ppm; HRMS (ESIꢀTOF) m/z: [M
+ H]+ Calcd for C14H20O4H: 253.1440, found: 253.1434.
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(R)-6-(benzyloxy)-2,2,5-trimethylhexan-3-one 11
A solution of above ester 9 in THF (30 mL) was carefully dropped to a suspension of
LAH (1.75 g, 46.15 mmol) in THF (30 mL). After being stirred for 10 h, the resulted
mixture was carefully quenched with water (0.5 mL) and filtrated. The filtrate was
concentrated to give the crude diol without further purification. The above diol was
dissolved in water (50 mL), and then the mixture was acidified with hydrochloric acid
to pH=6 at 0 oC. NaIO4 (9.87 g, 46.15 mmol) was added in one portion and stirred for
1.5 h. The mixture was extracted with EtOAc (30 mL × 3), and the combined organic
layers were washed with brine. Dried, filtrated and concentrated gave the aldehyde
without further purification. The above crude aldehyde was dissolved in dry THF (60
o
mL) and the mixture was cooled to 0 C, then a solution of tertꢀbutylmagnesium
chloride (1 M in THF, 58.0 mL, 58.00 mmol) was slowly dropped. After being stirred
for overnight, the reaction was quenched with an aqueous solution of saturated NH4Cl
and the resulted mixture was extracted with EtOAc (30 mL × 3). The combined
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organic layers were washed with brine, dried, filtrated and concentrated. The residue
was purified by flash chromatography on silica gel (PE/EA = 10:1) to give 10 (4.52 g,
47%, 5 steps) as colorless oil. The above alcohol (4.17 g, 16.65 mmol) was dissolved
in cooled DCM (60 mL, 0oC), then DMP (10.60 g, 24.98 mmol) was added in several
portion. After being stirred for 3 h, the mixture was carefully quenched with a solution
of saturated aqueous NaHCO3 and solid Na2S2O3. The resulted mixture was extracted
with DCM (30 mL × 3), and the combined organic layers were washed with brine,
dried, filtrated and concentrated. The residue was purified by flash chromatography
on silica gel (PE/EA=20:1) to give 11 (3.60 g, 87%) as a colorless oil. [α]D23 = +6.7 (c
10
11
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1
4.00, CHCl3); IR (film): νmax 2966, 1705, 1477, 1454, 1365, 1097, 738, 698 cmꢀ1; H
NMR (400 MHz, CDCl3) δ 7.38ꢀ7.24 (m, 5H), 4.49 (brs, 2H), 3.37ꢀ3.26 (m, 2H), 2.65
(dd, J = 16.8, 4.8 Hz, 1H), 2.46ꢀ2.30 (m, 2H), 1.12 (s, 9H), 0.94ꢀ0.92 (m, 3H) ppm;
13C NMR (150 MHz, CDCl3) δ 214.6, 138.0, 127.7, 126.9, 126.8, 74.3, 72.2, 43.6,
39.8, 28.6, 25.7, 16.6 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H24O2H:
249.1855, found: 249.1849.
(3S,5R)-6-(Benzyloxy)-2,2,5-trimethylhexan-3-ol 12
A solution of (R)ꢀCBS (1 M in toluene, 1.23 mL, 1.23 mmol) was dissolved in dry
.
toluene (15 mL) and cooled to ꢀ20 oC, and then BH3 DMS (0.23 mL, 2.43 mmol) was
slowly drooped. After being stirred for 30 min at the same temperature, a solution of
11 (0.61 g, 2.44 mmol) in toluene (4 mL) was slowly dropped. After being stirred for
10 h at ꢀ20 to 35oC, the mixture was concentrated and diluted with MeOH. The
resulted mixture was concentrated and the residue was purified by flash
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9
chromatography on silica gel (PE/EA = 10:1) to give 12 (0.44 g, 72%) as a colorless
oil. [α]D23 = ꢀ26.2 (c 1.00, CHCl3); IR (film): νmax 3447, 2959, 2093, 1636, 1085, 697,
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.37ꢀ7.24 (m, 5H), 4.54 (brs, 2H), 3.41ꢀ3.35 (m,
1H), 3.30ꢀ3.25 (m, 2H), 2.52 (brs, 1H), 1.97 (ddd, J = 13.6, 12.8, 6.4 Hz, 1H),
1.42ꢀ1.36 (m, 2H), 0.95ꢀ0.91 (m, 3H), 0.90 (s, 9H) ppm; 13C NMR (150 MHz, CDCl3)
δ 137.6, 127.8, 127.1, 127.0, 77.4, 75.9, 72.4, 36.2, 34.2, 31.0, 25.2, 17.0 ppm;
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H26O2H: 251.2006, found: 251.2005.
(2R,4S)-4-((tert-Butyldimethylsilyl)oxy)-2,5,5-trimethylhexan-1-ol 13
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To a cooled (0 oC) DCM (30 mL) solution of 12 (1.62 g, 6.47 mmol) and 2,6ꢀlutidine
(1.13 mL, 9.72 mmol) was carefully treated with TBSOTf (2.28 mL, 9.72 mmol) for 3
h. Then the mixture was quenched with a saturated aqueous of NH4Cl and extracted
with DCM (15 mL × 3). The combined organic layers were washed with brine, dried,
filtrated and concentrated to give the crude product without further purification. The
above product, 10% Pd/C (150 mg) and Pd(OH)2 (150 mg) was stirred in MeOH (70
mL) for 3h under H2 atmosphere. Then the mixture was filtered and the filtrate was
concentrated. The residue was purified by flash chromatography on silica gel (PE/EA
23
= 30:1) to give 13 (1.35 g, 76%, 2 steps) as colorless oil. [α]D = +25.2 (c 2.00,
CHCl3); IR (film): νmax 2345, 2082, 1635, 1249, 1084, 1031, 772 cmꢀ1; 1H NMR (400
MHz, CDCl3) δ 3.50ꢀ3.37 (m, 2H), 3.32 (dd, J = 8.4, 1.2Hz, 1H), 1.84ꢀ1.72 (m, 1H),
1.46ꢀ1.35 (m, 2H), 1.25ꢀ1.17 (m, 1H), 0.93ꢀ0.87 (m, 12H), 0.85 (s, 9H), 0.05 (s, 6H)
ppm; 13C NMR (150 MHz, CDCl3) δ 77.6, 68.7, 36.2, 35.1, 32.0, 25.8, 25.6, 17.9,
15.6, ꢀ3.9, ꢀ4.4 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H34O2SiH:
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275.2401, found: 275.2402.
5
6
7
tert-Butyldimethyl((3S,5S)-2,2,5-trimethyloct-7-en-3-yloxy)silane 6
8
9
To a stirred solution of 13 (1.08 g, 3.93 mmol) in DCM (20 mL) was added PPh3
(1.34 g, 5.11 mmol) and imidazole (0.54 g, 7.86 mmol), and then I2 (1.30 g, 5.11
mmol) was added in sereval portions. After stirring for 15 min, the reaction was
quenched with a saturated aqueous solution of Na2SO3 and extracted with DCM (30
mL × 3). The combined organic layers were washed with brine, dried, filtrated and
concentrated to give the crude product without further purification. The above crude
compound was dissolved in dry THF (20 mL) and cooled to ꢀ78oC. Once a solution of
vinylmagnesium bromide (0.7 M in THF, 28.07 mL, 19.65 mmol) was dropped, a
solution of Li2CuCl4 (0.1 M in THF, 3.90 mL, 0.39 mmol) was slowly dropped. After
being stirred for overnight at ꢀ78oC to room temperature, the mixture was quenched
with a saturated aqueous solution of NH4Cl and extracted with EtOAc (30 mL × 3).
The combined organic layers were washed with brine, dried, filtered and concentrated.
The residue was purified by flash chromatography on silica gel (PE) to give 6 (0.94 g,
84%，2 steps) as a colorless oil. [α]D25 = ꢀ14.8 (c 1.00, CHCl3); IR (film): νmax 3493,
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1
2946, 1742, 1581, 1519, 1453, 1411, 1312, 1216, 1172, 1001, 767 cmꢀ1; H NMR
(400 MHz, CDCl3) δ 5.88ꢀ5.74 (m, 1H), 5.08ꢀ5.01 (m, 2H), 3.36 (dd, J = 7.6, 2.8 Hz,
1H), 2.26ꢀ2.17 (m, 1H), 1.84ꢀ1.65 (m, 2H), 1.49 (ddd, J = 14.4, 9.2, 2.8 Hz, 1H ),
1.23 (ddd, J = 14.4, 7.6, 4.4 Hz, 1H) 0.96ꢀ0.84 (m, 21H), 0.09 (s, 6H) ppm; 13C NMR
(125 MHz, CDCl3) δ 137.1, 116.0, 78.5, 40.9, 40.4, 35.8, 29.7, 26.4, 26.2, 20.7, 18.5,
ꢀ3.4, ꢀ3.8 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C17H36OSiH: 285.2608,
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found: 285.2609.
5
6
7
Benzyl (S)-4-((tert-butoxycarbonyl)amino)-5-hydroxypentanoate 15
8
9
To a stirred solution of (S)ꢀ2ꢀaminoꢀ5ꢀ(benzyloxy)ꢀ5ꢀoxopentanoic acid 14 (5.00 g,
21.08 mmol) in H2O/dioxane (30 mL/30 mL) was added NaHCO3 (1.99 g, 23.64
mmol) and Boc2O (5.52 g, 25.30 mmol) at 0oC. The reaction mixture was allowed to
warm to room temperature and stirred for overnight. After concentrated, the aqueous
phase was acidified with hydrochloric acid, and the mixture was extracted with
EtOAc (20 mL × 3). The combined organic layers were dried, filtrated and
concentrated to give the crud acid as a colorless oil without further purification. The
above crude acid was dissolved in THF (100 mL) at room temperature, and then
4ꢀmethylmorpholine (2.32 mL, 21.08 mmol) was dropped. After stirring for 10 min,
the mixture was cooled to ꢀ10oC and ethyl chloroformate (2.42 mL, 25.30 mmol) was
dropped. The reaction mixture was stirred for another 1 h at the same temperature and
filtrated. Then a solution of NaBH4 (2.39 g, 63.24 mmol) in H2O (20 ml) was dropped
to the filtrate and stirred for 1 h at room temperature. The mixture was quenched with
a saturated aqueous solution of NH4Cl and extracted with EtOAc (20 mL × 3). The
combined organic layers were washed with brine, dried over MgSO4, filtrated and
concentrated. The residue was purified by flash chromatography on silica gel (PE/EA
= 2:1) to give 15 (4.71 g, 69%, 2 steps) as a white solid. MP. 76ꢀ77oC {lit.[15] MP.
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25
25
75ꢀ76oC; [α]D = ꢀ10.3 (c 1.00, CHCl3) { lit.[15] [α]D = ꢀ10.0 (c 1.00, MeOH)}; IR
(film): νmax 3346, 2985, 2947, 1727, 1682, 1523, 1451, 1368, 1298, 1167, 1070, 1021,
748, 697 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.42ꢀ7.33 (m, 5H), 5.15 (s, 2H), 4.86 (d,
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J = 6.8Hz, 1H), 3.71ꢀ3.62 (m, 2H), 3.61ꢀ3,54 (m, 1H), 2.60 (brs, 1H), 2.52ꢀ2.45 (m,
2H), 1.99ꢀ1.88 (m, 1H), 1.86ꢀ1.75 (m, 1H), 1.45 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) δ 173.4, 156.1, 135.6, 128.4, 128.2, 128.1, 79.5, 66.4, 65.0, 52.1, 30.7, 28.2,
26.1 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H25NO5Na: 346.1625,
found: 346.1613.
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Benzyl (S)-4-((tert-butoxycarbonyl)amino)-5-(tritylthio)pentanoate 16
Compound 15 (2.50 g, 7.73 mmol) and TEA (2.20 mL, 15.46 mmol) was stirred in
dry DCM (30 mL) for 10 min at 0oC. MsCl (0.90 mL, 11.60 mmol) was dropped and
the resulted mixture was stirred for another 30 min. Then the reaction was quenched
with a saturated aqueous solution of NH4Cl was added and the extracted with DCM
(30 mL × 3). The organic layers were washed with brine, dried over MgSO4, filtrated
and concentrated to give the intermediate without further purification. A suspension of
NaH (60 %) (0.35 g, 9.26 mmol) in DMF (10 mL) was treated with a solution of
o
TrtSH (2.35 g, 8.50 mmol) in DMF (5 mL) at C. After being stirred for 45 min, a
solution of above intermediate in DMF (15 mL) was slowly dropped and the resulted
mixture was stirred for overnight 0oC to room temperature. The resulted mixture was
quenched with water and diluted with EtOAc. The mixture was separated and the
aqueous layer was extracted with EtOAc (30 mL × 3) and the combined organic layers
were washed with water and brine respectively. Dried, filtrated and concentrated, the
residue was purified by flash chromatography on silica gel (PE/EA = 10:1) to give 16
25
(3.55 g, 79%) as a white amorphous solid. [α]D = ꢀ10.5 (c 1.00, CHCl3); IR (film):
1
νmax 3364, 3058, 3031, 2924, 2851, 1713, 1494, 1366, 1247, 1169, 1028 cmꢀ1; H
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9
NMR (400 MHz, CDCl3) δ 7.45ꢀ7.20 (m, 20H), 5.15ꢀ5.05 (m, 2H), 4.49 (d, J = 8.8
Hz, 1H), 3.75ꢀ3.60 (m, 1H), 2.38ꢀ2.33 (m, 1H), 2.32ꢀ2.27 (m, 2H), 1.85ꢀ1.65 (m, 2H),
1.45 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.8, 155.0, 144.4, 135.7, 129.4,
128.4, 128.1, 127.8, 126.6, 79.2, 66.5, 66.2, 49.2, 37.0, 30.8, 29.4, 28.2 ppm; HRMS
(ESIꢀTOF) m/z: [M + Na+] Calcd for C36H39NO4SNa: 604.2492, found: 604.2470.
Benzyl (S)-4-acrylamido-5-(tritylthio)pentanoate 7
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A cooled (0oC) solution of 16 (2.36 g, 4.05 mmol) in DCM (7 mL) was treated with
TFA (7 mL) for 30 min, then the mixture was concentrated under reduced pressure.
The residue was dissolved in dry DCM (15 mL), HATU (2.31 g, 6.08 mmol), DIPEA
(2.10 mL, 12.15 mmol) and acrylic acid (0.33 mL, 4.86 mmol) was added under N2
atmosphere. After being stirred for 5 h at room temperature, the mixture was
quenched with a saturated aqueous solution of NH4Cl and extracted with DCM (30
mL × 3). The combined organic layers were washed with brine, dried, filtrated and
concentrated. The residue was purified by flash chromatography on silica gel (PE/EA
25
= 3:1) to give the 7 (1.53 g, 71%) as a white amorphous solid. [α]D = ꢀ23.5 (c 1.00,
CHCl3); IR (film): νmax 3272, 3059, 3031, 2953, 1735, 1656, 1627, 1540, 1490, 1243,
1181, 983 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.47ꢀ7.21 (m, 20H), 6.27 (dd, J = 17.2,
1.6 Hz, 1H), 5.99 (dd, J = 17.2, 10.4 Hz, 1H), 5.79 (d, J = 8.8 Hz, 1H), 5.64 (dd, J =
10.4, 1.2 Hz, 1H), 5.10 (s, 2H), 4.16ꢀ4.05 (m, 1H), 2.50 (dd, J = 12.4, 5.6 Hz, 1H),
3.67 (dd, J = 12.4, 5.2 Hz, 1H), 2.39ꢀ2.25 (m, 2H), 1.90ꢀ1.77 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3) δ 173.2, 165.0, 144.6, 135.8, 130.8, 130.2, 129.6, 128.6, 128.3,
128.0, 127.1, 126.9, 126.7, 66.8, 66.5, 48.3, 36.6, 31.0, 29.0 ppm; HRMS (ESIꢀTOF):
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m/z: [M + Na]+ Calcd for C34H33NO3SNa: 558.2073, found: 558.2053.
Benzyl
7
8
9
(S)-4-((5S,7S,E)-7-((tert-butyldimethylsilyl)oxy)-5,8,8-trimethylnon-2-enamido)-5
-(tritylthio)pentanoate 17
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Compound 7 (1.20 g, 2.24 mmol), compound 6 (637 mg, 2.24 mmol) and Grubbs 2nd
(cat.) were refluxed in DCM (80 mL) under Ar atmosphere for 24 h to give crude
product, which was purified by flash chromatography on silica gel (PE/EA = 8:1) to
give the 17 (1.06 g, 60%) as a white amorphous solid. [α]D25 = ꢀ19.0 (c 1.00, CHCl3);
IR (film): νmax 3272, 3031, 3060, 2926, 2855, 1738, 1667, 1630, 1539, 1445, 1361,
1257, 1081, 1031 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.46ꢀ7.20 (m, 20H), 6.87ꢀ6.78
(m, 1H), 5.69 (d, J = 15.2 Hz, 1H), 5.51 (d, J = 8.8 Hz, 1H), 5.17ꢀ5.08 (m, 2H),
4.18ꢀ4.06 (m, 1H), 3.36 (dd, J = 7.2, 2.4 Hz, 1H), 2.52ꢀ2.41 (m, 2H), 2.40ꢀ2.28 (m,
3H), 1.95ꢀ1.77 (m, 4H), 1.55ꢀ1.45 (m, 1H), 1.35ꢀ1.30 (m, 1H), 0.98 (s, 3H), 0.95 (s,
9H), 0.90 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ
173.2, 165.2, 144.6, 143.6, 135.9, 129.6, 128.6, 128.3, 128.2, 128.0, 126.8, 125.0,
78.5, 66.8, 66.4, 48.1, 41.2, 38.7, 36.7, 35.9, 31.1, 29.7, 29.1, 26.4, 26.2, 21.0, 18.5,
ꢀ3.2, ꢀ3.7 ppm; HRMS (ESIꢀTOF): m/z: [M + Na]+ Calcd for C49H65NO4SSiNa:
814.4296, found: 814.4290.
Allyl
(S)-4-((5S,7S,E)-7-((tert-butyldimethylsilyl)oxy)-5,8,8-trimethylnon-2-enamido)-5
-(tritylthio)pentanoate 18
Compound 17 (0.95 g, 1.20 mmol) was dissolved in a mixture of THF, MeOH and
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H2O (12 mL V:V:V=1:1:1), then LiOH.H2O (75 mg, 1.80 mmol) was added in one
portion. After being stirred for 7 h, the mixture was quenched with a saturated
aqueous solution of NH4Cl and extracted with EtOAc (30 mL × 3). The combined
organic layers were dried over MgSO4, filtrated and concentrated. The residue was
dissolved in DMSO (4 mL), K2CO3 (332 mg, 2.40 mmol) and AllylBr (0.13 mL, 1.80
mmol) was added. After being stirred for 4 h, the reaction was diluted with water and
extracted with EtOAc (25 mL × 3). The combined organic layers were washed with
water and brine respectively, dried over MgSO4, filtrated and concentrated. The
residue was purified by flash chromatography on silica gel (PE/EA = 6:1) to give 18
(747 mg, 84%, 2 steps) as a white amorphous solid. [α]D25 = ꢀ22.4 (c 1.00, CHCl3); IR
(film): νmax 3059, 2956, 2857, 1712, 1662, 1493, 1362, 1256, 1084, 1032, 832, 758
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.46ꢀ7.41 (m, 6H), 7.35ꢀ7.20 (m, 9H), 6.81 (ddd,
J = 15.2, 8.0, 6.8 Hz, 1H), 5.96ꢀ5.85 (m, 1H), 5.70 (d, J = 15.2 Hz, 1H), 5.49 (d, J =
8.8 Hz, 1H), 5.35ꢀ5.28 (m, 1H), 5.27ꢀ5.22 (m, 1H), 4.58ꢀ4.52 (m, 2H), 4.15ꢀ4.05 (m,
1H), 3.35 (dd, J = 7.6, 2.8 Hz, 1H), 2.52ꢀ2.40 (m, 2H), 2.34ꢀ2.23 (m, 2H), 1.95ꢀ1.75
(m, 4H), 1.54ꢀ1.45 (m, 1H), 1.34ꢀ1.25 (m, 2H), 0.97ꢀ0.93 (m, 12H), 0.89 (s, 9H), 0.10
(s, 3H), 0.09 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 173.0, 165.2, 144.6, 143.6,
132.1, 129.6, 128.0, 126.8, 125.0, 118.3, 78.4, 66.8, 65.2, 48.1, 41.2, 38.7, 36.7, 31.0,
29.7, 29.1, 26.4, 26.2, 21.0, 18.5, ꢀ3.3, ꢀ3.8 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C45H63NO4SSiNa: 764.4139, found: 764.4127.
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Allyl
(S)-4-((5S,7S,E)-7-hydroxy-5,8,8-trimethylnon-2-enamido)-5-(tritylthio)pentanoa
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Compound 18 (747 mg, 1.01 mmol) was stirred in EtOAc (6 mL) at 0oC, then
hydrochloric acid (6 N, 4 mL) was dropped and the reaction was stirred for 3 h at 0 oC
to room temperature. The resulted mixture was extracted with EtOAc (10 mL × 3) and
the combined organic layers were washed with a saturated aqueous solution of
NaHCO3 and brine respectively. Dried over MgSO4, filtrated and concentrated, the
residue was purified by flash chromatography on silica gel (PE/EA = 2:1) to give 19
(521 mg, 82%) as a white amorphous solid. [α]D25 = ꢀ27.7 (c 1.00, CHCl3); IR (film):
νmax 3391, 3059, 2955, 2869, 1708, 1660, 1626, 1493, 1448, 1256, 1083, 989, 756
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.45ꢀ7.39 (m, 6H), 7.33ꢀ7.27 (m, 6H), 7.26ꢀ7.20
(m, 3H), 6.86ꢀ6.77 (m, 1H), 5.95ꢀ5.84 (m, 1H), 5.70 (d, J = 15.2 Hz, 1H), 5.49 (d, J =
8.8 Hz, 1H), 5.33ꢀ5.27 (m, 1H), 5.26ꢀ5.21 (m, 1H), 4.56ꢀ4.52 (m, 2H), 4.14ꢀ4.03 (m,
1H), 3.35ꢀ3.28 (m, 1H), 2.50ꢀ2.35 (m, 3H), 2.32ꢀ2.20 (m, 2H), 2.05ꢀ1.95 (m, 1H),
1.83ꢀ1.73 (m, 2H), 1.48ꢀ1.39 (m, 2H), 1.32ꢀ1.22 (m, 2H), 1.02ꢀ0.98 (m, 3H), 0.91 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3) δ 172.9, 165.1, 144.4, 143.5, 131.9, 129.4,
127.8, 126.7, 124.7, 118.2, 66.6, 65.1, 47.9, 38.4, 37.9, 36.6, 34.9, 30.8, 29.6, 28.9,
25.5, 20.9, 20.6 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C39H49NO4SNa:
650.3275, found: 650.3257.
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1-((9H-fluoren-9-yl)methyl)
2-((3S,5S,E)-9-(((S)-5-(allyloxy)-5-oxo-1-(tritylthio)pentan-2-yl)amino)-2,2,5-trim
ethyl-9-oxonon-7-en-3-yl) (S)-pyrrolidine-1,2-dicarboxylate 20
A cooled (0oC) toluene (5 mL) of NꢀFmocꢀProline (536 mg, 1.59 mmol) and DIPEA
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(0.40 mL, 2.38 mmol) was carefully treated with 2,4,6ꢀtrichlorobenzoylchloride
(0.37 mL, 2.38 mmol) for 30 min, then a solution of compound 19 (498 mg, 0.79
mmol) in toluene and DMAP (194 mg, 1.59 mmol) was added separately. After being
stirred for 3 h, the mixture was quenched with a saturated aqueous solution of NH4Cl
and extracted with EtOAc (20 mL × 3). The combined organic layers were washed
with brine, dried over MgSO4, filtrated and concentrated. The residue was purified by
flash chromatography on silica gel (PE/EA = 3:1) to give 20 (741 mg, 89%) as a white
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amorphous solid. [α]D = ꢀ47.1 (c 1.00, CHCl3); IR (film): νmax 3066, 3015, 2959,
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2928, 1708, 1662, 1633, 1450, 1419, 1366, 1253, 1180, 1122, 989 cmꢀ1; H NMR
(400 MHz, CDCl3, mixture of rotamers) δ 7.82ꢀ7.74 (m, 2H), 7.68ꢀ7.65 (m, 1.6H),
7.60ꢀ7.57 (m, 0.4H), 7.45ꢀ7.37 (m, 7H), 7.34ꢀ7.18 (m, 12H), 6.85ꢀ6.70 (m, 1H),
5.95ꢀ5.77 (m, 2H), 5.67ꢀ5.47 (m, 1H), 5.32ꢀ5.25 (m, 1H), 5.25ꢀ5.18 (m, 1H),
4.95ꢀ4.80 (m, 1H), 4.56ꢀ4.42 (m, 4H), 4.35ꢀ4.15 (m, 2H), 4.10ꢀ4.00 (m, 1H),
3.70ꢀ3.64 (m, 1H), 3.61ꢀ3.47 (m, 1H), 2.49ꢀ2.29 (m, 3H), 2.28ꢀ2.06 (m, 4H),
2.04ꢀ1.90 (m, 3H), 1.69ꢀ1.62 (m, 2H), 1.60ꢀ1.51 (m, 0.8H), 1.48ꢀ1.40 (m, 1.2H), 1.28
(s, 1H), 1.02ꢀ0.96 (m, 2H), 0.90 (s, 9H), 0.80ꢀ0.75 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3, mixture of rotamers) δ 172.9, 172.8, 172.7, 172.2, 165.5, 165.2, 154.8, 154.4,
144.6, 144.2, 144.1, 143.9, 143.7, 143.0, 142.7, 141.3, 132.1, 129.6, 128.0, 127.9,
127.7, 127.6, 127.1, 127.0, 126.8, 126.7, 125.5, 125.3, 125.3, 125.2, 119.9, 118.2,
79.5, 79.0, 67.7, 67.5, 66.8, 66.7, 65.2, 59.6, 59.4, 48.1, 47.9, 47.3, 47.2, 47.0, 46.4,
37.1, 36.8, 36.6, 36.4, 34.9, 34.7, 31.3, 30.9, 30.0, 29.8, 29.7, 29.4, 29.3, 29.2, 25.9,
24.3, 23.3, 20.9, 20.7 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C59H66N2O7S
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Na: 969.4483, found: 969.4459.
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1-((9H-fluoren-9-yl)methyl)
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2-((3S,5S,E)-8-((S)-4-(3-(allyloxy)-3-oxopropyl)-4,5-dihydrothiazol-2-yl)-2,2,5-Tri
methyloct-7-en-3-yl) (S)-pyrrolidine-1,2-dicarboxylate 5
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Triphenylphosphine oxide (746 mg, 2.70 mmol) was dissolved in DCM (3 mL) and
cooled to at 0oC, then trifluoromethanesulfonic anhydride (0.23 mL, 1.35 mmol) was
added at 0oC. After being stirred for 10 min, a solution of compound 20 (423 mg, 0.45
mmol) in DCM (2 mL) was dropped and the mixture was stirred for 10 min. Then the
mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted
with DCM (20 mL × 3). The combined organic layers were washed with brine,
filtrated and concentrated. The residue was purified by flash chromatography on silica
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gel (PE/EA = 4:1) to give 5 (265 mg, 86%) as a white amorphous solid. [α]D
=
ꢀ102.7 (c 1.00, CHCl3); IR (film): νmax 3018, 2961, 1706, 1580, 1419, 1357, 1245,
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1217, 1177, 1122, 990 cmꢀ1; H NMR (400 MHz, CDCl3, mixture of rotamers) δ
7.81ꢀ7.76 (m, 2H), 7.68ꢀ7.64 (m, 1.6H), 7.60ꢀ7.57 (m, 0.4H), 7.45ꢀ7.38 (m, 2H),
7.37ꢀ7.30 (m, 2H), 6.37ꢀ6.25 (m, 1.6H), 6.21ꢀ6.13 (m, 0.4H), 5.99ꢀ5.87 (m, 1H),
5.37ꢀ5.30 (m, 1H), 5.27ꢀ5.22 (m, 1H), 4.94ꢀ4.86 (m, 1H), 4.63ꢀ4.58 (m, 2H),
4.56ꢀ4.37 (m, 3.6H), 4.32ꢀ4.27 (m, 0.6H), 4.24ꢀ4.16 (m, 0.8H), 3.77ꢀ3.65 (m, 1H),
3.63ꢀ3.55 (m, 1H), 3.37ꢀ3.30 (m, 0.4H), 3.27ꢀ3.21 (m, 0.6H), 2.92ꢀ2.85 (m, 0.4H),
2.80ꢀ2.74 (m, 0.6H), 2.63ꢀ2.46 (m, 2.6H), 2.40ꢀ2.25 (m, 1H), 2.12ꢀ1.87 (m, 6H),
1.58ꢀ1.49 (m, 1H), 1.46ꢀ1.40 (m, 1H), 0.95ꢀ0.89 (m, 12H), 0.74ꢀ0.71 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3, mixture of rotamers) δ 173.0, 172.6, 172.5, 166.7, 166.4,
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154.7, 154.3, 144.4, 144.2, 144.1, 144.0, 143.8, 143.0, 141.3, 132.2, 127.7, 127.6,
127.1, 127.0, 126.9, 126.4, 125.3, 125.2, 120.0, 118.2, 79.6, 79.1, 76.0, 75.9, 67.7,
67.5, 65.2, 59.5, 59.3, 47.3, 47.0, 46.5, 38.6, 38.3, 37.1, 37.0, 36.7, 34.7, 31.5, 31.3,
30.3, 30.0, 29.7, 29.3, 28.7, 25.9, 24.5, 23.3, 20.9, 20.6 ppm; HRMS (ESIꢀTOF) m/z:
[M + H]+ Calcd for C40H50N2O6SH: 687.3462, found: 687.3459.
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1-((9H-fluoren-9-yl)methyl)
2-((3S,5S,E)-8-((S)-4-((5S,8S,11S)-11-((S)-sec-butyl)-5-(4-methoxybenzyl)-7,8,10-
Trimethyl-3,6,9,12-tetraoxo-13-oxa-4,7,10-triazahexadec-15-en-1-yl)-4,5-dihydrot
hiazol-2-yl)-2,2,5-trimethyloct-7-en-3-yl) (S)-pyrrolidine-1,2-dicarboxylate 23
To a solution of 5 (265 mg, 0.39 mmol) in THF (5 mL) was added Pd(PPh3)4 (46 mg,
0.04 mmol) and NꢀMethylaniline (0.10 mL, 0.96 mmol). After being stirred for 1 h,
the mixture was concentrated and purified by flash chromatography on silica gel
(DCM/MeOH = 10:1) to give acid 21 (221 mg, 88%) as a white amorphous solid.
Tripeptides 22 (228 mg, 0.34 mmol) was dissolved in MeCN (5 mL), then Et2NH
(2.50 mL) was added. After being stirred for 30 min, the reaction mixture was
concentrated. The residue and above acid 21 (221 mg, 0.34 mmol), FDPP (142 mg,
0.37 mmol) and DIPEA (0.08 mL, 0.51 mmol) was stirred in MeCN (2 mL) for
overnight at room temperature. The resulted mixture was quenched with a saturated
aqueous solution of NH4Cl and extracted with EtOAc (10 mL × 3). The combined
organic layers were washed with brine, dried over MgSO4, filtrated and concentrated.
The residue was purified by flash chromatography on silica gel (PE/Acetone = 2:1) to
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give 23 (274 mg, 75%) as a white amorphous solid. [α]D = ꢀ117.3 (c 1.00, CHCl3);
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IR (film): νmax 2111, 2958, 2924, 1738, 1704, 1645, 1514, 1355, 1247, 1179, 1088
cmꢀ1; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.82ꢀ7.75 (m, 2H), 7.71ꢀ7.60
(m, 2H), 7.45ꢀ7.37 (m, 2H), 7.36ꢀ7.30 (m, 2H), 7.21ꢀ7.13 (m, 2H), 6.85ꢀ6.75 (m, 2H),
6.15ꢀ6.09 (m, 0.5H), 5.98ꢀ5.77 (m, 1.5H), 5.59ꢀ5.45 (m, 1H), 5.35ꢀ5.23 (m, 2H),
4.97ꢀ4.78 (m, 2H), 4.65ꢀ4.57 (m, 2H), 4.55ꢀ4.40 (m, 3H), 4.39ꢀ4.32 (m, 1H),
4.31ꢀ4.19 (m, 1.5H), 4.13ꢀ4.07 (m, 0.5H), 3.80ꢀ3.74 (m, 3H), 3.70ꢀ3.63 (m, 1H),
3.61ꢀ3.52 (m, 1H), 3.10ꢀ2.98 (m, 2H), 2.95ꢀ2.88 (m, 1H), 2.86ꢀ2.77 (m, 3H), 2.71 (s,
3H), 2.63ꢀ2.60 (m, 0.5H), 2.53ꢀ2.50 (m, 1.5H), 2.36ꢀ2.17 (m, 3H), 2.10ꢀ1.89 (m, 4H),
1.86ꢀ1.79 (m, 1H), 1.58ꢀ1.51 (m, 1H), 1.46ꢀ1.37 (m, 2H), 1.36ꢀ1.17 (m, 8H),
0.98ꢀ0.81 (m, 18H) ppm; 13C NMR (125 MHz, CDCl3, mixture of rotamers) δ 172.6,
172.0, 171.9, 171.5, 170.7, 158.6, 154.7, 154.3, 144.2, 144.1, 141.3, 131.8, 130.4,
130.3, 128.2, 128.1, 127.7, 127.6, 127.0, 126.9, 126.3, 125.3, 125.2, 119.9, 118.6,
113.9, 79.6, 79.1, 75.9, 75.6, 67.7, 67.6, 66.0, 65.4, 60.5, 59.5, 59.3, 55.2, 50.3, 49.6,
47.3, 47.0, 46.4, 38.6, 38.1, 37.8, 37.1, 37.0, 36.7, 34.7, 33.6, 33.5, 33.3, 31.3, 31.0,
30.5, 30.0, 29.7, 29.5, 29.3, 28.7, 25.9, 25.0, 24.4, 23.3, 20.9, 20.6, 15.8, 14.3, 10.6
ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for: C61H81N5O10SNa: 1098.5596,
found: 1098.5602.
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(3S,5S,E)-8-((S)-4-(3-(allyloxy)-3-oxopropyl)-4,5-dihydrothiazol-2-yl)-2,2,5-Trime
thyloct-7-en-3-yl
N-(N-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxyphenyl)p
ropanoyl)-N-methyl-L-alanyl)-N-methyl-L-isoleucyl-L-prolinate 26
A solution of tripetide 22 (120 mg, 0.18 mmol) and Pd(PPh3)4 (24 mg, 0.02 mmol) in
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THF (3 mL) was treated with NꢀMethylaniline (0.05 mL, 0.45 mmol) for 1 h. The
mixture was concentrated and purified by flash chromatography on silica gel
(DCM/MeOH = 15:1) to give the crude acid without further purification. Compound 5
(124 mg, 0.18 mmol) was dissolved in MeCN (2 mL), then Et2NH (1 mL) was added.
After being stirred for 30 min, the reaction mixture was concentrated. The residue was
azeotroped with toluene three times and dissolved in DCM (2 mL), then above acid,
HATU (103 mg, 0.27 mmol) and DIPEA (0.09 mL, 0.54 mmol) was added. After
being stirred for overnight at room temperature, the resulted mixture was quenched
with a saturated aqueous solution of NH4Cl and extracted with EtOAc (15 mL × 3).
The combined organic layers were washed with brine, dried over MgSO4, filtrated and
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concentrated. The residue was purified by flash chromatography on silica gel
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(PE/Acetone = 2:1) to give 26 (141 mg, 73%) as a white amorphous solid. [α]D
=
ꢀ108.3 (c 1.00, CHCl3); IR (film): νmax 3800, 3320, 2958, 2214, 1736, 1640, 1513,
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1450, 1247, 1180, 1142, 1075, 1034, 742 cmꢀ1; H NMR (600 MHz, CDCl3, mixture
of rotamers) δ 7.69ꢀ7.65 (m, 2H), 7.48ꢀ7.43 (m, 2H), 7.33ꢀ7.27 (m, 2H), 7.05ꢀ7.01 (m,
2H), 6.74ꢀ6.67 (m, 2H), 6.30ꢀ6.17 (m, 2H), 5.87ꢀ5.79 (m, 1H), 5.52 (d, J = 9.0 Hz,
1H), 5.37 (dd, J = 13.8, 6.6 Hz, 1H), 5.25ꢀ5.21 (m, 1H), 5.16ꢀ5.12 (m, 1H), 4.98 (d, J
= 11.4 Hz, 1H), 4.84ꢀ4.78 (m, 2H), 4.51ꢀ4.49 (m, 2H), 4.44ꢀ4.40 (m, 1H), 4.36 (dd, J
= 5.6, 3.2 Hz, 1H), 4.28 (dd, J = 7.2, 4.8 Hz, 1H), 4.18 (dd, J = 7.2, 4.8 Hz, 1H), 4.07
(dd, J = 7.2, 6.6 Hz, 1H), 3.84ꢀ3.77 (m, 1H), 3.70ꢀ3.64 (m, 1H), 3.65 (s, 3H), 3.26 (dd,
J = 10.8, 8.4 Hz, 1H), 2.98ꢀ2.88 (m, 4H), 2.85 (s, 2.5H), 2.80 (dd, J = 10.8, 8.4 Hz,
1H), 2.77ꢀ2.70 (m, 1.5H), 2.53ꢀ2.42 (m, 3H), 2.16ꢀ2.05 (m, 2H), 1.95ꢀ1.83 (m, 5H),
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0.92ꢀ0.88 (m, 3H), 0.82ꢀ0.76 (m, 15H) ppm; C NMR (150 MHz, CDCl3, mixture of
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rotamers) δ 171.9, 171.4, 170.8, 170.5, 168.3, 165.6, 157.6, 154.7, 143.8, 142.8, 142.7,
140.2, 131.2, 129.3, 126.9, 126.7, 126.0, 125.3, 124.1, 124.0, 118.9, 117.2, 112.9,
77.8, 77.4, 74.9, 66.0, 64.1, 59.4, 58.1, 56.7, 54.1, 51.3, 48.7, 46.3, 46.1, 37.5, 37.1,
36.0, 35.8, 33.6, 32.3, 30.4, 29.5, 29.4, 29.3, 28.3, 27.2, 24.9, 23.9, 23.7, 19.9, 13.7,
13.5, 9.4 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C61H81N5O10SH:
1076.5777, found: 1076.5778.
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Apratoxin E 2
(a) Method 1: The synthesis of apratoxin E by macrolactamization at C5 and C6.
A solution of Compound 23 (220 mg, 0.20 mmol) and Pd(PPh3)4 (24 mg, 0.02 mmol)
in dry THF (5 mL) was treated with NꢀMethylaniline (0.06 mL, 0.50 mmol) for 30
min. The mixture was concentrated and the residue was purified by flash
chromatography (DCM/MeOH=20:1) to give the acid. The above acid was dissolved
in MeCN (2 mL) then Et2NH (1 mL) was added, after being stirred for 30 min at room
temperature, the mixture was concentrated, which was dissolved in DCM (200 mL).
HATU (114 mg, 0.30 mmol) and DIPEA (0.66 mL, 4.00 mmol) was added and stirred
for 40 h. The mixture was concentrated and the residue was purified by flash
chromatography on silica gel (PE/EA=1:1) to give apratoxin E 2 (30.2 mg, 19%, 3
steps).
(b) Method 2 The synthesis of apratoxin E by macrolactamization at C18 and
C27.
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A solution of compound 26 (110 mg, 0.10 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol)
in dry THF (3 mL) was treated with NꢀMethylaniline (0.03 mL, 0.25 mmol) for 30
min. Then the reaction was concentracted and purified by flash chromatography on
silica gel (DCM/MeOH=20:1) to give the acid, which was dissolved in MeCN (2 mL)
and Et2NH (1 mL) was added. After being stirred for 30 min at room temperature, the
mixture was concentrated and the residue was dissolved in MeCN (100 mL). Then
FDPP (57.6 mg, 0.15 mmol) and DIPEA (0.33 mL, 2.00 mmol) was added and the
reaction was stirred for 40 h. The mixture was concentrated and purified by flash
chromatography silica gel (PE/EA=1:1) to give apratoxin E 2 (34.2 mg, 43%, 3 steps).
[α]D24 = ꢀ150.4 (c 0.24, MeOH), { lit.[4d] [α]D20 = ꢀ69 (c 0.12, MeOH)}; 1H NMR (600
MHz, CDCl3, mixture of rotamers) δ 7.19ꢀ7.14 (m, 2H), 6.85ꢀ6.80 (m, 2H), 6.62 (d, J
= 15.6 Hz, 0.67H), 6.46ꢀ6.37 (m, 1H), 6.41ꢀ6.38 (m, 0.33H), 6.11 (d, J = 9.0 Hz,
0.67H), 5.81 (d, J = 10.2 Hz, 0.33H), 5.28ꢀ5.22 (m, 1H), 5.20ꢀ5.15 (m, 0.67H),
5.01ꢀ4.97 (m, 0.67H), 4.95ꢀ4.90 (m, 1.33H), 4.67 (dd, J = 13.2, 6.6 Hz, 0.67H),
4.36ꢀ4.32 (m, 1.33H), 4.26ꢀ4.23 (m, 0.33H), 4.12ꢀ4.06 (m, 1H), 3.80 (s, 1H), 3.79 (s,
2H), 3.73ꢀ3.68 (m, 0.67H), 3.68ꢀ3.63 (m, 1H), 3.36ꢀ3.31 (m, 1.33H), 3.13ꢀ3.08 (m,
1H), 3.00 (s, 2), 2.97ꢀ2.91 (m, 2H), 2.86 (s, 1H), 2.84 (s, 1H), 2.64 (s, 2H), 2.53ꢀ2.45
(m, 2H), 2.30ꢀ2.21 (m, 2H), 2.12ꢀ2.03 (m, 2H), 1.97ꢀ1.86 (m, 4H), 1.78ꢀ1.71 (m, 2H),
1.46ꢀ1.44 (m, 0.67H), 1.30ꢀ1.24 (m, 4H), 1.08ꢀ1.04 (m, 3H), 0.97ꢀ0.94 (m, 3H),
0.91ꢀ0.88 (m, 9H), 0.87ꢀ0.84 (m, 2.33H), 0.60ꢀ0.56 (m, 2H) ppm; 13C NMR (150
MHz, CDCl3, mixture of rotamers) δ 172.1, 171.7, 171.4, 171.0, 170.6, 169.8, 169.7,
169.5, 169.3, 169.0, 165.9, 165.6, 158.1, 158.0, 144.3, 144.0, 129.9, 129.8, 128.0,
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The Journal of Organic Chemistry
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127.9, 125.5, 125.4, 113.5, 113.2, 77.0, 76.9, 75.8, 75.7, 60.0, 58.8, 58.5, 57.2, 56.5,
54.7, 54.6, 53.4, 50.0, 49.2, 46.8, 46.7, 39.2, 37.7, 37.1, 36.7, 36.6, 36.5, 36.1, 34.5,
34.1, 33.5, 33.0, 32.6, 32.5, 30.3, 29.9, 29.7, 29.1, 28.9, 28.8, 28.7, 28.6, 28.5, 28.1,
25.5, 25.3, 24.9, 24.6, 24.5, 19.9, 18.8, 14.3, 13.5, 13.3, 13.2, 9.5, 9.4 ppm; HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C43H65N5O7SH: 796.4683, found: 796.4679.
ASSOCIATED CONTENT
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Supporting Information
1
Copies of H and 13C NMR spectra of related compounds and comparison of NMR
Data of natural and synthetic Apratoxin E. This material is avaliable free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: bgwei1974@fudan.edu.cn .
Present address
Arvinas Inc., 5 Science Park, New Haven, CT 06511
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (21472022, 21272041,
21072034) for financial support. The authors thank Dr. JingꢀYi, Ma for the
preparation of several synthetic intermediates. The authors also thank Prof.
WeiꢀSheng, Tian and Prof. ZhenꢀTing, Du provides the lactone 8.
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