The journey of total synthesis toward nannocystin Ax

Article abstract of DOI:10.1016/j.tet.2018.12.021

Herein we describe the detail on our full investigations that led to the achievement of the total synthesis of nannocystin Ax, a 21-membered macrocyclic natural product composing of a tripeptide fragment and a polyketide fragment, which featured in 8 longest linear steps in with 13.9% total overall yield. The key synthetic strategy relied on the late-stage stille coupling for the macrolactonization to construct the 21-membered ring, while direct connection between the tripeptide fragment and the polyketide fragment failed. ¹H NMR experiments reveal that nannocystin Ax should exist as conformational mixtures in deuterated solvents.

Full text of DOI:10.1016/j.tet.2018.12.021

Accepted Manuscript
The journey of total synthesis toward nannocystin Ax
Rong Liu, Mengwei Xia, Yanhui Zhang, Shaomin Fu, Bo Liu
PII:
S0040-4020(18)31499-6
https://doi.org/10.1016/j.tet.2018.12.021
TET 30007
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 October 2018
Revised Date: 8 December 2018
Accepted Date: 13 December 2018
Please cite this article as: Liu R, Xia M, Zhang Y, Fu S, Liu B, The journey of total synthesis toward
nannocystin Ax, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2018.12.021.
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ACCEPTED MANUSCRIPT
Graphical Abstract
The Journey of Total Synthesis Toward
Nannocystin Ax
Leave this area blank for abstract info.
a
a
a
a
a, b
Rong Liu , Mengwei Xia , Yanhui Zhang , Shaomin Fu *, Bo Liu *,
a
College of Chemistry, Sichuan University, Chengdu 610064, PR China
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR
b
China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
The Journey of Total Synthesis Toward Nannocystin Ax
a
a
a
a*
a,b
Rong Liu , Mengwei Xia , Yanhui Zhang , Shaomin Fu , Bo Liu ∗ ,
a
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we describe present the detail on our full investigations that led to the achievement of the
total synthesis of nannocystin Ax, a 21-membered macrocyclic natural product composing of a
tripeptide fragment and a polyketide fragment, which featured in 8 longest linear steps in with
13.9 % total overall yield. The key synthetic strategy relied on the late-stage stille coupling for
the macrolactonization to construct the 21-membered ring, while direct connection between the
Available online
1
tripeptide fragment and the polyketide fragment failed. H NMR experiments reveal that
Nannocystin Ax
Total synthesis
Polyketide
nannocystin Ax should exist as conformational mixtures in deuterated solvents.
.
Peptide
Stille Coupling
[
3e,3f]
1
. Introduction
amidation as the final step for macrocyclization
. Herein, we
present our efforts toward total synthesis of nannocystin Ax in
detail.
Natural products had provided unlimited sources for the
[
1]
development of new drugs . Nearly one half of small molecule
drugs are natural products or their derivatives. In 2015,
Brönstrup`s group and Hoepfiner`s group independently
[
2]
2. Results and Disccusions
identified natural compounds of nannocystin family , which
were isolated from the fermentation of Myxobacterial genus,
Nannocystis sp. Structurally, nannocystins feature a novel 21-
membered macro-cyclic scaffold with more than 7 stereocenters
containing tripeptide and polyketide (Scheme 1). Biological
study revealed their outstanding cytotoxicity to numerous cancer
cell lines, such as HCT116 cell lines (2.5-10 nM). In addition,
nannocystin A exhibited a strong antifungal effect, inhibiting the
growth of C. albicans (IC50 = 73 nM). Moreover, it was found
that the activity target of nannocystins is EF-1α of eukaryotes,
which is identical to that of a drug candidate, dehydrodidemnin B,
although nannocystins show much better cytotoxicity.
Undoubtedly, the novel molecular structures and remarkable
bioactivities of nannocystin family have stimulated numerous
passion and endeavor among synthetic chemists. To construct the
challenging 21-membered macrocycle of this natural family,
2
.1 Total Synthesis of Nannocystin Ax - Strategy A
Considering macro-lactonization is a powerful method to
[
4]
forge macrolide, we made the first retrosynthetic analysis via
disconnecting the tripeptide moiety and polyketide moiety in
nannocystin Ax to get compounds 5 and 6ꢀScheme 2ꢁThen,
the polyketide 5 can be formed by asymmetric Mukaiyama aldol
reaction between unsaturated aldehyde 7 and vinylketene silyl N,
[
6]
O-acetal 8 . The tripeptide 6 can be constructed via double
amidation from three known compounds
[
5]
.
[
3b]
[3g]
Wang 's group
closing metathesis (RCM) strategy, while Ye 's group
and Fürstner ' s group
and
resorted to the Suzuki coupling and Heck
favored the ring-
[3a]
[
3c]
Chen 's group
reaction to fulfill this transformation, respectively. In addition,
our group utilized the Stille coupling in this key cyclization
[
3d]
—
pro
—
ces
—
s,
and He’s group, as well as Kalesse`s group, selected
a
∗
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China
b
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
e-mail: chembliu@scu.edu.cn; fsm09@aliyun.com; http://chem.scu.edu.cn./liubo/; Fax:+86 28 85413712; Tel: +86 28 85413712

2
Tetrahedron
ACCEPTED MAre
N
du
generated 19 in 64% yield for 3 steps. Reduction of 19 and
oxidation of the resultant allylic alcohol with MnO gave the
U
cti
S
on
C
o
R
f
I
1
P
7
T
followed by oxidation and Wittig reaction,
[8]
O
O
O
O
H
O
O
O
2
corresponding aldehyde 7. Due to its instability, we exposed 7
without further purification to the next Mukaiyama aldol reaction
to examine the feasibility of this process. Unfortunately, both
reactants decomposed rapidly under Lewis acid conditions such
NH
NH
HO
Cl
HO
Cl
N
O
H
N
O
O
NH
O
N
O
O
as TiCl et al. Thus, we set about for an alternative route to
achieve this polyketide (Scheme 4).
4
HO
HO
Cl
Cl
nannocystin A (1)
nannocystin Ax (2)
O
O
O
O
H
O
O
O
NH
NH
HO
H
HO
Br
N
O
N
O
O
H
NH
O
H
NH
O
O
HO
HO
nannocystin A0 (3)
nannocystin Ay (4)
Scheme 1 Structures of selected nannocystins
Scheme 4 Attempts to polyketide moiety by Asymmetric
Aldol
According to the above retrosynthetic analysis, we geared up
for the tripeptide 6 at first. The dipeptide 12 can be obtained in
the presence of HBTU, DMAP and DIPEA. Hydrolysis of 12
Witnessing comprehensive application of cross-coupling
reactions in total synthesis, we conceived a Stille cross-coupling
strategy between a vinyl iodide segment and an organostannane
segment to acquire the polyketide fragment. Accordingly, we
first attempted to make the corresponding vinyl iodide segment.
So, an asymmetric Mukaiyama-type aldol reaction between
vinylketene silyl N, O-acetal 8 and acetal 23 was utilized to
achieve compound 24 by following Kobayashi and Hosokawa’s
with LiOH•H O afforded 13 in 85% yield. Subsequent amidation
2
with 9 resulted in the tripeptide 14 in 70% yield. (Scheme 3).
[
9]
methodology.
underwent
Delightfully, this asymmetric aldol reaction
smoothly with high yield and good
diastereoselectivity (88% yield, 14: 1 dr). Subsequent removal of
the chiral auxiliary group of 24 resulted in the acid 25 with
satisfactory yield and retained ee value. Furthermore, after
Corey-Fuchs alkynylation of the chiral aldehyde 15, the resultant
compound 21 underwent hydrostannation and deprotection of the
[
10]
TBS group to afford the organostannane segment 22 . However,
the desired Stille coupling did not take place between the
unsaturated acid 25 and secondary alcohol 22 under various
[
11]
reaction
conditions
.
(Scheme
5)
Scheme 3 Synthesis of compound 14
Then, we turned our attention to synthesize the polyketide
[
7]
moiety 5. The known compound 15 was transformed to
compound 17 in 97% yield via Wittig reaction. Subsequent
Scheme 2 Strategy A based on macrolactonization

3
CBr
4
, PPh
3
, DCM, rt;
3
nBu SnH, AIBN
ACCEPTED MANUSCRIPT
nBuLi,THF, -40 o
C
o
O
toluene, 80 C;
SnBu
3
7
0 % in 2 Steps
TBAF, THF, rt
82 % in 2 Steps
OTBS
OTBS
21
OH
15
22
O
Stille Coupling
O
OTBS
I
O
26
O
2
3
.OEt
BF
3
2
, DCM
O
O
N
LiOH H
THF : H
O,30 %H
O
OH
O
2
2
2
O
O
-
78 oC to -60 o
C
2
O= 2 : 1, rt
OTBS O
N
I
O
I
OH
8
8 % dr = 14 : 1
87 % yield, 89 % ee
25
O
8
24
Scheme 5 Attempts to compound 26
Scheme 6 Strategy B Based on Stille Coupling
Scheme 7 Attempts to compound 31
Scheme 8 Synthetic attempts to compound 32
2
.2 Total Synthesis of Nannocystin Ax - Strategy B
Besides the macrolactonization, metal-catalyzed Stille
such as HBTU, HATU, EDCI, PivCl, (COCl) and Ghosez regent,
2
13]
[
couplings are efficacious tool reactions as well in constructing
were examined, all conditions failed to achieve the desired
[
14]
macro-membered rings . So, we considered the stille coupling
to cyclize the 21-membered macrocycle. To make full use of the
synthesized moiety from Strategy A, we disconnected
nannocystin Ax retrosynthetically via esterification and
amidation of the tripeptide 28 before Stille coupling of 27
product (see SI for details). Amazingly, even the model reaction
between tiglic acid 30 with the amine 29 could not furnish the
corresponding amidation product (Scheme 7). We ascribed this
difficulty in amidation to some special conformational folding of
the tripeptide.
(
Scheme 6-Strategy B).
With these in mind, we began to attempt esterification of the
tripeptide ahead of its amidation, by hydrolysis of the tripeptide
First, we tried amidation of the tripeptide with 25 ahead of
[
15]
esterification with 22. Deprotection of Boc and protection of OH
group in compound 14
was subsequently subjected to amidation reaction with the
unsaturated aicd 25. Although numerous activating reagents,
14 using LiOH•H O
to afford the acid 28. However,
2
[
12]
gave the resulting tripeptide 29, which
esterification between 28 and 22 in numerous conditions proved
infertile without compound 32 generated (see SI for details), but
resulted in decomposition of the substrate (Scheme 8). We

4
Tetrahedron
28 MANUSCRIPT
speculated that the inefficient esterification be
A
tw
C
ee
C
n
E
th
P
e a
TED
ci
d
and the secondary alcohol 22 could be ascribed to the steric
hinderance between them. The rate of esterification was so low
that the vinyltin moiety of 22 had decomposed before the desired
reaction took place. To test this possibility, compound 22 was
prepared and its esterification with 33, a much smaller compound
than 28, was examined. The tertiay alcohol of the known
[
5h]
compound 9′, was protected under TESOTf/lutidine condition,
which led to partial deprotection of Boc amide. After treatment
of the resultant mixture with Boc O and lithium hydroxide,
2
comopound 33 was obtained in satisfactory yield. Notably,
protection of the tertiary alcohol is necessary to prevent
dehydration in the coupling reaction between 22 and 33 (Table
1
). After screening various reaction conditions to promote the
esterification, the best yield achieved is just 21%, albeit better
than that in coupling reaction between 22 and 28.
Table 1 Screening of Esterification between 22 and 33
Scheme 9 Synthesis of compound 36
Table 2 Screening of Amidation between 25 and 36
O
O
1
. 2, 6- lutidine, TESOTf, DCM, 0 oC;
2. Boc O, NEt , THF, rt;
HO
TESO
O
OH
2
3
NHBoc
. LiOH . H2O, DME / H2O = 1 : 1, rt
NHBoc
33
3
9
'
63 % for 3 Steps
O
SnBu3
Conditions
TESO
O
O
SnBu3
OH
+
OH
NHBoc
NHBoc
34
2
2
33
TESO
(
1.0 equiv.)
(1.2 equiv.)
Entrya Condensing Reagent (equiv.)b
Additive (equiv.)
Yield (%)
e
1
2
3
4
5
6
7
8
DCC (3.0)
EDCI (3.0), HOAt (3.0)
EDCI (3.0), HOBt (3.0)
(COCl)2 (0.6)
DMAP (0.2)
DIPEA (4.0)
NEt3 (3.0)
0
0
0
f
f
DMF (cat), NEt3 (3.0)
DMAP (0.2), NEt3 (3.0)
DMAP (0.2), NEt3 (3.0)
DIPEA (4.0)
C.M. g
trace
0 e
Yamaguchi reagent (1.5) c
MNBA (1.5)
HATU (3.0), HOAt (3.0)
HBTU (3.0)
C.M. g
DMAP (0.2), DIPEA (3.0)
21
a
b
Scale of the reactions ranged from 0.04 to 0.12 mmol. Reactions were conducted in DCM (0.1 M)
c
at room temperature unless otherwise stated. Reaction was conducted in toluene (0.1 M) at room
temperature; d Yamaguchi reagent: 2,4,6-trichloro-benzoyl choride. e No reaction with all starting
material recovered. f The substrate 22 decomposed. g C.M.: complex mixture.
Although the yield of 34 was unsatisfactory, we still planned
to move farward to examine the practicability of strategy B.
Removing the Boc protection of 34 under the condition of
2.3 Total Synthesis of Nannocystin Ax - Strategy C
[
16]
TMSOTf and 2,6-lutidine in DCM
could give the free amine
The above successful macrocyclization of 37 through Stille
cross-coupling ensured us on the feasibility of this strategy in
total synthesis. Failure in efficient connection between 25 and 29
or 36 indicated the possible presence of destructive function of
conformation of the tripeptide on the amidation. Furthermore, we
noticed that the amidation between the amine 35 and the acid 13
proceeded smoothly. Thus, we conceived a synthetic strategy
involving forge of the tripeptide at the late stage of total synthesis,
which retrosynthetically led to compound 38 and compound 35
from compound 37, a Stille cross-coupling precursor toward the
target molecule (Scheme10-Strategy C). Amidation between 25
and the dipeptide 39 might be feasible. Since direct esterification
between compound 22 and compound 33 had been proved in low
efficacy, a Mitusnobo-type esterification toward 35 from 40 and
3
8
5 in 72% yield. Then amidation of 35 and 13 gave rise to 32 in
2% yield which further underwent Boc deprotection to generate
the amine 36 (Scheme 9). The following pivotal amidation
reaction was examined with lots of condensing methods (Table
2
). All initial attempts, such as utilizing DCC or EDCI as
condensing reagent, activating the unsaturated acid 25 with
COCl) , PivCl, Yamaguchi reagent and Ghosez reagent,
(
2
afforded no desired amidation product. We then paid our
attention to utilize HATU or HBTU as the reagents. Fortunately,
we could obtain 37 in 10 % yield in the presence of HBTU,
DIPEA and DMAP, while only trace amount of 37 could be
detected under HATU/HOAt/DIPEA condition (Table 2).
Pleasingly, exposure of trace amount of 37 in typical Stille cross-
coupling conditions, such as Pd(PPh ) /LiCl in THF and
Pd(MeCN) Cl /Ph As/CuI in DMF, afforded the cyclized product
detectable through LC-MS, which inspired us to override the
obstacles toward efficient total synthesis of nannocystin Ax.
3
4
4
1
was devised. Accordingly, based on asymmetric
2
2
3
[17]
crotylboration of aldehyde developed by Roush’s group , the
secondary alcohol 40 was prepared smoothly with 85% ee. The
acid 41 could be prepared by direct oxidation of the known

5
ACCEPTED MANUSCRIPT
Scheme 10 Strategy C based on Stille coupling
(
L-Ipc) BH, Et O
2
2
0 oC, 6 h;
Me
SnBu3
SnBu3
PhCHO, -78 o
2 %, 85 % ee
C
OH
SnBu3
2, 6- lutidine
TMSOTf
SnBu
3
PPh , DIAD
PhMe : DCM = 4 : 1
4
2
40
3
4
O
O
O
O
DCM, 0 oC, 82 %
0 oC - rt, 70 %
Fe(NO3) 9 H O
O
NH
2
3
2
NHBoc
HO
HO
TESO
TEMPO, O
2
HO
OH
NHBoc
OH
44
35
KCl, DCE, rt, 76 %
NHBoc
4
3
41
Scheme 11 Synthesis of compound 35
[
18]
compound 43.
Interestingly, when the reaction was performed
Table 3 Screening of amidation between 39 and 25
[
19]
in Mitsunobu condition in THF,
no product could be detected.
But the reaction underwent well in toluene and dichloromethane
and afforded 44 in 70% yield. Subsequent removal of Boc group
provided the amine 35 in 82% yield (Scheme 11). Deprotection
of 12 under 2,6-lutidine and TMSOTf could generate the
amidation precursor 39 in 79% yield. Then the amidation
between 39 and 25 was prudently examined with various
condensing reagents such as EDCI, HATU, HBTU, BOP,
Yamaguchi reagent and Ghosez reagent. Gratifyingly,
employment of Ghosez reagent (1.2 equiv.) and NEt (3 equiv.)
3
[
20]
could lead to the amidated product 45 in 83% yield (Table 3)
.
Then hydrolysis of 45 using LiOH•H O in DME and water
2
afforded the acid 38 in 87% yield. Pleasingly, the amidation
between the acid 38 and the amine 35 underwent smoothly with
EDCl, HOAt and DIPEA to provide 37 in 75% yield. After
executing the intramolecular Stille cross-coupling in dilute THF,
we obtained compound 46 in 62% yield in the presence of
[
21]
o
Pd(PPh ) and LiCl
at 60 C (Scheme 12), prompting us to
3
4
complete total synthesis of nannocystin Ax after final global
deprotection. Considering the lability of TES and MOM group in
[
22]
compound 46 under acidic condition , we screened different
acids to remove both protective groups in one pot (Table 4), and
found that the target molecule, nannocystin Ax, was obtained in
1
7
8% yield with para-toluenesulfonic acid. Interestingly, the H
NMR of nannocystin Ax showed it exists as a 5 : 1 mixture of
6
two isomers in d -DMSO, and characterization data of the major
one matched that of the natural product from Hoepfner`s
[
2a]
research
.

6
Tetrahedron
ACCEPTED MANUSCRIPT
I
I
O
I
O
O
SnBu
Me
H
N
3
OMe
O
O
3
5
O
O
.
LiOH H
2
O
OH
EDCI, HOAt
DIPEA
Pd(PPh
LiCl, THF, 60 o
62 %
3 4
)
OMe
N
O
N
O
H
H
NH
DME / H O = 1 : 1
2
C
N
N
NH
N
O
TESO
Cl
O
O
DCM, 0 oC to rt
TESO
Cl
N
O
rt, 87 %
O
NH
Cl
MOMO
O
Cl
O
O
7
5 %
O
O
MOMO
4
5
38
37
MOMO
46
Cl
Cl
MOMO
Cl
Cl
Scheme 12 Synthesis of compound 46
1
Further study showed that the H NMR of nannocystin Ax are
3
. Conclusion
We have completed total synthesis of nannocystin Ax after
6
a 10:1 mixture of two isomers in both d -acetone and CDCl .
These abnormal results made us suspect the presence of
conformers of nannocystin Ax. The
temperature experiments were executed at various temperatures
from 25 C to 70 C in d -DMSO, illustrating that nannocystin
Ax does exist as conformational mixtures in DMSO below 70 C
Figure 1). Then the structure of nannocystin Ax was further
confirmed by single crystal X-ray diffraction analysis (Scheme
3D). Notably, re-dissolving the sample subjected to single
crystal X-ray analysis in d -DMSO resulted in a 5:1 mixture of
conformers again by NMR analysis. According to these results,
we concluded that nannocystin Ax exists as conformational
3
1
attempting different synthetic strategies. Strategy A relying on
the late-stage macrolactonization was unsuccessful because the
precursor of macrolactonization could not be achieved. Then,
strategy B was also proved out of synthetic significance, due to
unprecedented difficulty in esterification and amidation of the
tripeptide segment with compounds 22 and 25. On the basis of
strategy A and strategy B, we implemented strategy C utilizing
the Stille cross-coupling to forge the key 21-membered ring.
Total synthesis of nannocystin Ax was thus accomplished in 8
longest linear steps with 13.9 % overall yield. To make a distinct
illustration, the full synthetic route leading to nannocystin Ax
H NMR variable-
o
o
6
o
(
1
6
6
6
mixtures in solvents such as d -DMSO, d -Acetone and CDCl .
3
(Strategy C) is outlined in Scheme 13. This successful total
Due to their structural similarity between nannocystin Ax and
nannocystin A, we attempted to transform nannocystin Ax to
nannocystin A by selective asymmetric epoxidation. Various
epoxidation conditions were tested , but none of them could
give rise to nannocystin A (see SI for details).
synthesis features asymmetric Kobayashi aldol reaction followed
by hydrolysis leading to 25, Roush`s asymmetric crotylboration
followed by Mitsunobu esterification and deprotection leading to
[
23]
3
5 and late-stage Stille cross-coupling leading to macrolide of the
target molecule. The sequence of installing different fragments is
crucial to the total synthesis because of special reactivity of the
tripeptide fragment inside. Notably, nannocystin Ax exists as
conformational mixtures with viable ratios in different solvents at
room temperature, which should be kept in mind during
experiments in organic synthesis and bioassay of this natural
product in the future.
Table 4 Deprotection of 46 and completion of total synthesis
O
O
O
O
O
O
4
4
. Experimental Section
NH
Conditions
NH
TESO
Cl
HO
Cl
N
O
H
N
O
O
NH
O
N
.1 General
O
O
Unless otherwise stated, reactions were conducted at ambient
temperature under an argon atmosphere using freshly dried
solvents. 1, 2 dimethoxyethane (DME), Terahydrofuran (THF)
was distilled by sodium using benzophenone as indicator.
Petroleum ether (PE), Ethyl acetate (EA), 1,2-dichloroethane
MOMO
HO
46
Cl
nannocystin Ax(2)
Cl
a
o
Entry
Acid (equiv.)
Temp. ( C)
Yield (%)
(
DCE), Methylene chloride (DCM), acetonitrile (MeCN),
Dimethylformamide (DMF) and Toluene were distilled by
calcium hydride. Triethylamine and N, N-
f
TMSBr (2.0) b
TMSBr (2.0) b
BBr3 (1.0) b
-45 o
-78 o
-78 o
C
C
C
1
2
3
4
5
6
---
---f
---f
---g
(NEt3)
LiBF4 (2.0) c
40 o
diisopropylethylamine (DIPEA) were distilled by calcium
hydride. The reaction was monitored by thin layer
chromatography using silica gel commercially available and were
visualized by UV, p-anisaldehyde, ninhydrin, CAM or KMnO4
stanning. Flash column chromatography was performed using
silica gel purchased from Qingdao Hailang Silica gel Desiccant
C
d
d
d
e
HCl (12, 1 M in H O)
2
2
2
rt
rt
trace
trace
HCl (12, 3 M in H O)
7
8
9
HCl (12, 6 M in H O)
rt
rt
rt
rt
trace
72
HCl (12, 3 M in H O)
2
CAS (0.5) e
75
pTsOH (0.5) e
1
0
78
1
13
Corporation. H-NMR spectra and
C-NMR spectra were
a
b
Scale of the reactions ranged from 0.01 to 0.02 mmol. Reaction was conducted in DCM (0.1 M) for
0
min. c Reaction was conducted in aqueous acetonitrile (MeCN/H2O, 1:1). d Reaction was
conducted in a mixture of THF and aqeous HCl ( 1 : 1, v/v) overnight. e Reaction was conducted in
recorded on Brucker (400 MHz and 100 MHz respectively) and
Bruker (600 MHz and 150 MHz, respectively) NMR
spectrometer with TMS as the internal standard, and are reported
relative to internal CDCl ( H, 7.26ꢂ C, 77.16), -DMSO ( H,
2
3
MeOH (0.05 M ) for 4 h. f Compound 46 decomposed. g Only desilylation took place.
1
13
d6
1
3
13
1
13
1
.50; C, 39.52) , (CD ) CO ( H, 2.05; C, 29.84). Data for H-
3 2
NMR spectra are reported as follows: chemical shift δ(ppm),
multiplicity, coupling constant (Hz) and integration
J

7
ACCEPTED MANUSCRIPT
1
6
Figure 1 H NMR variable-temperature experiments of nannocystin Ax in d -DMSO at different temperatures
Multiplicity and qualifier abbreviations are as follows: s=single,
d=double, t=triplet, q=quartet, m=multiple, br=broad,
app=apparent. Infrared (IR) spectra were recorded on a
SHIMADZU IRTracer-100 FT-IR (Fourier Transform Infrared)
5.1 Hz, 1 H), 2.88 (dd, J = 13.8, 7.7 Hz, 1 H), 2.70 (s, 3 H), 1.41
(s, 9 H), 1.41 – 1.27 (m, 2 H), 1.02 – 0.93 (m, 1 H), 0.85 (t, J =
7.3 Hz, 3 H), 0.77 (d, J = 6.0 Hz, 3 H); C NMR (101 MHz,
13
CDCl ): δ 171.2, 170.6, 157.3, 148.7, 134.2, 129.8, 129.4, 99.4,
3
-
1
Spectrometer and were reported in frequency of absorption(cm ).
80.6, 62.9, 58.2, 52.7, 52.5, 36.9, 31.5, 30.3, 28.4, 24.5, 15.8,
High resolution mass spectra (HRMS) were recorded on a
10.6; IR (KBr) νmax: 3345, 2968, 1847, 1747, 1684, 1516, 1476,
TM
-1
Thermo Fisher Q Exactive
Focus Combined Quadrupole
1313, 1256, 1206, 1159, 937, 801 cm ; HRMS–ESI (m/z):
TM
+
Orbatrip Mass Spectrometer. Optical rotations were measured
on a Jasco-P-2000 polarimeter using a 100 mm length cell at 589
nm.
[M+Na] calculated for C24 H36 Cl N Na O , 557.1797, found:
2
2
7
557.1790.
4
.2.2. Synthesis of Compound 13. To a cooled solution of
dipeptide 12 (1.84 g, 3.4 mmol, 1.0 equivalent) in 50 ml of DME
o
(
1, 2 dimethoxyethane) at 0 C, the solution of LiOH•H O (428.1
2
4
.2 Experimental procedures and data of synthetic
mg, 10.2 mmol, 3.0 equivalent) in 50 ml of H O was added
2
intermidates
slowly. The reaction was then allowed to proceed at room
temperature and stirred overnight. The reaction was cooled again
4
.2.1. Synthesis of Compound 12. To a cool solution of HBTU
o
(7.39 g, 19.5 mmol, 3 equivalent), DMAP (158.0 mg, 1.3 mmol,
to 0 C and was quenched by dropwise addition of 1M HCl
0
3
.2 equivalent) and DIPEA (3.2 ml, 19.5 mmol, 3 equivalent) in
5 ml DCM at 0 C, the solution of 10 (2.0 g, 6.5 mmol, 1.0
solution to achieve pH 2. After extracting the aqueous layer with
EA (100 ml x 3), the combined organic phase was dried over
o
equivalent) and 11 (2.42 g, 19.5 mmol, 1.5 equivalent) in 30 ml
DCM was added slowly. The reaction was allowed to warm the
reaction to room temperature and stir with additional 10 h until
the reaction completed. Filtrated through a plug of diatomite, the
solution was concentrated by rotary evaporator. The crude
product was chromatographed on silica gel (PE / EA= 5 : 1) to
provide 12 (2.98 g, 85% yield) as colorless oil. [α] = – 61.6 (c
1
J = 7.5 Hz, 1 H), 5.12 (s, 2 H), 4.77 (d, J = 5.5 Hz, 1 H), 4.09 (d,
J = 11.2 Hz, 1 H), 3.69 (s, 3 H), 3.65 (s, 3 H), 3.07 (dd, J = 14.0,
Na SO , filtrated and concentrated in vacuo. The resulting crude
2 4
product was chromatographed over silica gel (PE / EA=1 : 1) to
2
1
provide the acid 13 as viscous colorless oil (1.52 g, 85 %). [α]
D
1
= – 45.3 (c 0.11, CHCl ); H NMR (400 MHz, CDCl ): δ 7.19 (s,
3
3
2 H), 5.13 (s, 2 H), 4.78 (dd, J = 13.6, 7.0 Hz, 1 H), 4.21 (d, J =
11.2 Hz, 1 H), 3.66 (s, 3 H), 3.09 (dd, J = 14.0, 5.8 Hz, 1 H), 2.93
(dd, J = 14.0, 7.3 Hz, 1 H), 2.80 (s, 3 H), 2.01 (m , 1 H), 1.40 (s,
9 H), 1.06 – 0.97 (m, 1 H) 0.89-0.84 (m, 5 H), 0.78 (d, J = 6.1 Hz,
21
D
1
.3, CHCl ); H NMR (400 MHz, CDCl ): δ 7.08 (s, 2 H), 6.83 (d,
3
3
13
3 H); C NMR (101 MHz, CDCl
): 173.9, 169.5, 148.7, 134.4,
3
130.0, 129.3, 99.3, 81.3, 60.0, 58.2, 52.8, 36.6, 32.1, 29.8, 28.4,

8
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 13 Completion of nannocystin Ax
2
1
4.6, 15.6, 10.5. IR (KBr) νmax:3468, 2954, 2924, 2853, 2365,
760, 1548, 1157, 1101, 937 cm ; HRMS–ESI(m/z): [M+K]
1 H), 1.39 (s, 9 H), 1.26 (s, 3 H), 1.13 (s, 3 H), 0.94 – 0.86 (m, 1
H), 0.81 (m, 5 H), 0.58 (d, J = 5.9 Hz, 3 H); C NMR (101 MHz,
-
1
+
13
calculated for C H Cl N K O , 545.1218, found: 545.1209.
CDCl ): 171.5,171.0, 170.6, 156.8, 148.2, 135.0, 130.0, 128.9,
22
32
2
2
7
3
9
3
2
9.1, 80.4, 77.2, 71.3, 62.4, 60.5, 57.9, 53.6, 52.1, 37.1, 32.1,
4
(
3
.2.3. Synthesis of Compound 14. To a cooled solution of EDCI
615.5 mg, 3.2 mmol,3.0 equivalent), HOAt (437.0 mg, 3.2 mmol,
.0 equivalent) and DIPEA (0.70 ml, 4.3 mmol, 4.0 equivalent)
0.1, 28.2, 26.9, 26.7, 24.4, 15.1, 10.3. IR (KBr) νmax: 3499,
-1
955, 2924, 1718, 1458, 1375, 1159, 947 cm ; HRMS–ESI(m/z):
+
o
[M+Na] calculated for C29
6
H45 Cl
2
N
3
Na O
9
, 672.2425, found:
in 25 ml DCM at 0 C, the solution of 9 (187.5 mg, 1.28 mmol,
1
2
warm to room temperature and stir t until the reaction completed
by TLC detection. The solution was concentrated by rotary
evaporator and the crude product was chromatographed on silica
gel (PE / EA= 3 : 2) to provide 14 (486.2 mg, 70 % yield) as
yellowish oil.[α] = – 37.1 (c 0.74, CHCl ); H NMR (400 MHz,
CDCl ): δ 7.60 (s, 1 H), 7.38 (s, 1 H), 5.07 (s, 2 H), 4.94 (m, 1H),
4
3
72.2431.
.2 equivalent) and 13 (563. 0 mg, 1.07 mmol, 1.0 equivalent) in
5 ml DCM was added slowly. The reaction was allowed to
4.2.4. Synthesis of Compound 17. To the solution of the chiral
aldehyde 15 (1.91 g, 6.9 mmol) in 30 ml acetonitrile, Wittig
reagent 16 was added at room temperature and allowed to warm
o
to 70 C overnight. Concentrating the solution in vacuo, filtrating
over silica gel and washing it by PE / EA= 20 : 1. After
concentrating via rotary evaporator, the crude product was
chromatographed on silica gel (PE / EA= 20 : 1) to furnish
22
1
D
3
3
22
.51 (d, J = 8.4 Hz, 1 H), 4.05 (d, J = 11.1 Hz, 1 H), 3.71 (s, 3 H),
.62 (s, 3 H), 3.08 (m, 1 H), 2.96 (m, 1 H), 2.70 (s, 3 H), 1.91 (m,
viscous oil (2.33 g, 97 % yield).[α] = – 11.8 (c 0.21, CHCl3);
D
1
H NMR (400 MHz, CDCl ): δ 7.26 – 7.20 (m, 5 H), 6.92 (dd, J
3

9
=
1
15.8, 7.6 Hz, 1 H), 5.67 (d, J = 15.8, 1 H), 4
H), 4.14 (tt, J = 7.1, 3.5 Hz, 2 H), 2.59 – 2.51 (m, 1 H), 1.24
A
.58
C
(d
C
,
E
J =
P
5
T
.0
E
H
D
z, MA4.
N
2.7
U
. S
S
y
C
nth
R
es
I
i
P
s
T
of Compound 21. To a cooled solution of 15
o
(5.1 g, 18.2 mmol) in THF (150 ml) at 0 C, CBr (9.05 g, 27.3
4
(
dd, J = 13.8, 6.7 Hz, 3 H), 0.96 (d, J = 6.7 Hz, 3 H), 0.86 (s, 9
mmol, 1.5 equivalent) and PPh (14.32 g, 54.6 mmol, 3.0
3
13
H), 0.01 (s, 3 H), -0.23 (s, 3 H); C NMR (101 MHz,
CDCl ):166.8, 151.7, 143.0, 128.0, 127.3, 126.6, 121.2, 60.3,
4
νmax:3499, 2955, 2920, 1718, 1456, 1261, 918 cm ; HRMS–
ESI(m/z): [M+Na] calculated for C20 H32 Na O Si, 371.2013,
equivalent) was added sequentially and the resultant solution was
stirred at room temperature overnight. After filtration over a plug
of diatomite and concentration in vacuo via rotary evaporator, the
resulted crude product was chromatographed on silica gel
(PE/EA= 100 : 1) to provide the gem-vinyldibromide as
3
5.3, 29.8, 26.0, 18.4, 15.5, 14.4, 13.7, -4.5, -5.3. IR (KBr)
-1
+
3
found: 371.2021.
yellowish oil. To a cooled solution of the gem-vinyldibromide
o
(1.22 g, 2.8 mmol) in 25 ml of THF at -40 C, nBuLi solution
4
.2.5. Synthesis of Compound 19. To a cooled solution of 17
o
(2.40 M in hexane, 2.46 ml, 5.90 mmol, 2.1 equivalent) was
added dropwise. After 4 h, the reaction was quenched by addition
of 10 ml of water and the solution was slowly warmed to room
temperature and stirred for additional 1 h. After separating the
two phases and extracting the aqueous layer with EA (10 ml x 3),
the combined organic phase was dried over Na SO , filtered and
(2.33 g, 6.7 mmol, 1.0 equivalent) in 30 ml DCM at 0 C, DIBAL
(1.46 M in toluene, 14.8 ml, 21.6 mmol, 3.2 equivalent) was
o
added dropwise. After stirring overnight at 0 C, the reaction was
quenched by 150 ml saturated Rochelle salt and stirred to
clarified separated phase. After extraction by DCM (100 ml x 3),
the organic phase was dried by Na SO , filtrated and
concentrated in vacuo. The resulted crude product was
chromatographed on silica gel (PE / EA= 5 : 1) to provide
2
4
2
4
concentrated in vacuo. The resultant crude product was
chromatographed on silica gel (PE / EA= 200 : 1) to afford the
alkyne 21 (652.6 mg, 70 % yield in 2 steps) as yellowish oil.
1
corresponding allylic alcohol [1.97 g, 96 % yield, H NMR (400
22
1
[
α] = – 34.1 (c 0.18, CHCl ); H NMR (400 MHz, CDCl ) δ
D
3
3
MHz, CDCl ): δ7.65 – 7.53 (m, 5 H), 5.93 (dd, J = 15.7, 6.9 Hz,
3
7
.29 – 7.20 (m, 5 H), 4.53 (d, J = 6.5 Hz, 1 H), 2.64 – 2.57 (m, 1
1
5
H), 5.86 – 5.80 (m, 1 H), 4.84 (d, J = 5.0 Hz, 1 H), 4.32 (d, J =
.3 Hz, 2 H), 2.78 (dd, J = 12.9, 6.4 Hz, 1 H), 2.36 (s, 1 H), 1.36
H), 1.93 (d, J = 2.5 Hz, 1H), 1.14 (d, J = 6.9 Hz, 3 H), 0.82 (s, 9
13
13
H), -0.00 (s, 3 H), -0.25 (s, 3 H); C NMR (101 MHz, CDCl
43.2, 127.9, 127.5, 127.0, 86.9, 77.9, 70.2, 35.7, 26.0, 18.4, 16.6,
4.5, -4.9;. IR (KBr) νmax: 3445, 2968, 2926,1732,1651, 1258,
3
):
(d, J = 6.7 Hz, 3 H), 1.26 (s, 9H), 0.37 (s, 3 H), 0.15 (s, 3 H);
C
1
-
NMR (101 MHz, CDCl ): δ143.8, 135.48, 129.1, 127.7, 126.9,
3
7
8.8, 63.6, 45.1, 25.9, 18.3, 14.9, -4.6, -5.0.] as colorless oil. To
-1
+
1
090, 1045, 880 cm ; HRMS–ESI(m/z): [M+Na] calculated for
26 Na O Si, 297.1645 found 297.1643.
a cooled solution of this allylic alcohol (1.97 g, 6.4 mmol) in 40
o
C
17
H
ml DCM at 0 C, the freshly activated MnO (5.57 g, 64.0 mmol)
2
was added. The reaction was allowed to warmed to room
temperature and stir until the reaction completed monitored by
TLC. The solution was filtrated over a plug of silica gel and
washed by DCM. After concentrating in vacuo, the crude product
was dissolved in 30 ml DCM, Wittig reagent 18 (2.26 g, 6.2
mmol) was added and allowed to warm to room temperature
overnight. Concentrated in vacuo, filtrated over silica gel using
PE / EA = 20 : 1 as eluent, the resulted crude product was
concentrated in vacuo and chromatographed on silica gel (PE /
EA= 20 : 1) to provide ester 19 (1.66 g, 64 % yield for 3 steps) as
4.2.8. Synthesis of Compound 22. To a solution of 21 (652.6 mg,
2.38 mmol, 1.0 equivalent) in 25 ml of toluene, AIBN (19.5 mg,
0.12 mmol) and Bu SnH (1.26 ml, 4.76 mmol, 2.0 equivalent)
3
o
was added. The reaction was stirred at 80 C overnight. Then, the
reaction was cooled to room temperature and diluted by 50 ml of
EA. The organic phase was washed by 50 ml of water and then
dried over Na SO , filtered and concentrated in vacuo. The crude
2
4
product was chromatographed on silica gel (neutralized by 1%
NEt ) to afford colorless oil. To a solution of this colorless oil in
3
o
25 ml of THF at 0 C, TBAF (1.0 M in THF, 12.0 mmol) was
23
1
colorless oil. [α] = – 4.2 (c 0.33, CHCl );. H NMR (400 MHz,
added dropwise and the solution was stirred at room temperature
overnight. The reaction was quenched with 20 ml of saturated
D
3
CDCl ): δ 7.32 – 7.21 (m, 5 H), 7.11 (d, J = 11.2 Hz, 1 H), 6.24
3
(dd, J = 15.2, 11.3 Hz, 1 H), 5.98 (dd, J = 15.2, 7.7 Hz, 1 H),
NH Cl solution and the aqueous layer was extracted with EA (50
4
4
1
1
.55 (d, J = 5.4 Hz, 1 H), 4.21 (q, J = 6.9 Hz, 2 H), 2.58 (dt, J =
2.9, 6.5 Hz, 1 H), 1.89 (s, 3 H), 1.31 (td, J = 7.1, 0.7 Hz, 3 H),
.05 (d, J = 6.7 Hz, 3 H), 0.91 (s, 9 H), 0.03 (s, 3 H), -0.20 (s, 3
ml x 3). The combined organic phase was dried over Na SO ,
2
4
filtered and concentrated in vacuo. The crude product was
chromatographed on silica gel using PE / EA= 10 : 1 as eluent to
afford the vinyltin 22 as yellowish oil (650.08 mg, 82 % yield for
13
H); C NMR (101 MHz, CDCl ): δ168.8, 145.0, 143.3, 138.6,
3
22
1
1
1
1
27.8, 127.2, 126.8, 125.9, 125.7, 78.5, 60.6, 46.1, 25.9, 18.3,
2 steps). [α] = – 14.4 (c 0.31, CHCl ); H NMR (400 MHz,
D
3
4.9, 14.5, 12.7, -4.5, -4.9. IR (KBr) νmax:3476, 2958, 2924,
CDCl ) δ 7.34 – 7.23 (m, 5 H), 5.98 (dd, J = 19.1, 0.9 Hz, 1 H),
3
-
1
+
655, 1560, 1260, 1067, 960 cm ; HRMS–ESI(m/z): [M+Na]
5.84 (dd, J = 19.1, 6.4 Hz, 1 H), 4.62 (dd, J = 5.3, 4.0 Hz, 1 H),
2.61 (dd, J = 13.2, 6.6 Hz, 1 H), 1.96 (d, J = 3.8 Hz, 1 H), 1.49 –
calculated for C H Na O Si, 411.2326, found 411.2330.
23
36
3
1
.32 (m, 6 H), 1.32 – 1.24 (m, 6 H), 1.00 (d, J = 6.8 Hz, 3 H),
4
.2.6. Synthesis of Compound 7. To a cooled solution of ester 19
13
o
0.94 – 0.82 (m, 15 H); C NMR (101 MHz, CDCl
29.4, 128.0, 127.3, 127.0, 77.5, 77.2, 48.4, 29.2, 27.4, 13.8, 9.5;
IR (KBr) νmax: 3449, 2951, 2928, 1655, 1488, 1273, 1092, 918
3
):150.4, 142.8,
(1.66 g, 4.3 mmol) in 30 ml of DCM at 0 C, DIBAL (1.46 M in
1
toluene, 8.8 ml, 12.9 ml, 3.0 equivalent) was added dropwise.
After stirring overnight at 0 C, the reaction was quenched by
1
until separated phase could be observed. After extraction with
DCM (100 ml x 3), the combined organic phase was dried over
Na SO , filtered and concentrated in vacuo. The crude product
was chromatographed on silica gel (PE /EA= 5 : 1) to provide the
corresponding allylic alcohol (1.44 g, 96 % yield). To a cooled
solution of this allylic alcohol (1.44 g, 4.2 mmol) in 40 ml of
o
-1
+
cm ; HRMS–ESI(m/z): [M+Na] calculated for C H Na O Sn,
4
23
40
00 ml of saturated Rochelle salt and the solution was stirred
75.1993 found: 475.1999.
4.2.9. Synthesis of Compound 24. To a cooled solution of the
acetal 23 (2.70 g, 11.2 mmol, 1.0 equivalent) in 28 ml of DCM at
-78 C, BF OEt (1.38 ml, 11.2 mmol, 1.0 equivalent) was added
dropwise. After stirring for 15 min, a solution of 8 (1.58 g, 11.2
mmol, 1.0 equivalent) in 28 ml of DCM was added dropwise and
2
4
o
.
3 3
o
DCM was added MnO (3.65 g, 42.0 mmol) slowly and the
the resultant solution was stirred at -60 C for additional 4.5 h.
2
suspension was stirred at room temperature overnight until the
starting material was fully consumed. After passing the solution
through a plug of diatomite and concentration in vacuo, the
resultant crude product was used directly for the next step.
The reaction was quenched by addition of pyridine (3.6 ml, 44.6
o
mmol, 4.0 equivalent) at -60 C and 56 ml of saturated NaHCO
3
solution. The mixture was allowed to warm to room temperature.
The aqueous layer was extracted by DCM (100 ml x 4), and the
combined organic phase was dried over Na SO and concentrated
2
4

1
0
Tetrahedron
2
2
in vacuo. The crude product was chromato
A
gr
C
ap
C
he
E
d
P
on
T
s
E
ili
D
1
ca MAam
N
in
U
e 2
S
9
C
(1
R
02
I
.
P
8
T
mg, 77 % yield) as viscous colorless oil. [α]
=
D
1
gel (PE / EA= 5 : 1) to furnish amide 24 (4.13 g, 88 % yield, dr =
7.8 (c 0.56, CHCl ); H NMR (400 MHz, CDCl ): δ 7.73 (d, J =
3
3
24
1
4 : 1) as viscous yellowish oil. [α] = – 21.2 (c 0.2, CHCl ); H
8.0 Hz, 1 H), 7.26 (s, 2 H), 7.02 (d, J = 8.5 Hz, 1 H), 5.18 (s, 2 H),
4.69 (dd, J = 15.1, 7.9 Hz, 1 H), 4.42 (d, J = 8.9 Hz, 1 H), 3.72 (s,
6 H), 3.16 (dd, J = 14.1, 6.8 Hz, 1 H), 2.96 (dd, J = 14.1, 8.2 Hz,
1 H), 2.26 (s, 3 H), 1.81 – 1.80 (m, 2 H), 1.48 (m, 1 H), 1.37 (s, 3
D
3
NMR (400 MHz, CDCl ): δ 6.25 (s, 1 H), 5.97 (t, J = 7.2 Hz, 1
H), 4.53 – 4.48 (m, 1 H), 4.31 (t, J = 8.9 Hz, 1 H), 4.17 (dd, J =
3
8
2
0
1
1
1
.9, 5.3 Hz, 1 H), 3.73 (t, J = 6.8 Hz, 1 H), 3.20 (s, 3 H), 2.52 –
.44 (m, 1 H), 2.39 – 2.31 (m, 2 H), 1.89 (s, 3 H), 1.77 (s, 3 H),
.90 (t, J = 7.5 Hz, 6 H); C NMR (100 MHz, CDCl ): δ 171.7,
53.7, 147.2, 134.1, 132.8, 84.6, 80.0, 63.6, 58.3, 56.6, 32.8, 28.4,
8.8, 18.0, 15.2, 14.0; IR (KBr) νmax: 3056, 2965, 2922, 2852,
784, 1682, 1462, 1368, 1269, 1208, 1098, 739 cm ; HRMS–
H), 1.17 (s, 3 H), 0.99– 0.92 (m, 14 H), 0.59 (q, J = 7.9 Hz, 6 H);
13
13
C NMR (100 MHz, CDCl ):174.1, 170.2, 148.6, 134.8, 129.9,
3
3
129.5, 99.3, 74.4, 61.7, 58.1, 53.7, 51.9, 38.4, 36.5, 36.0, 27.8,
27.4, 25.2, 15.8, 11.8, 7.0, 6.5; IR (KBr) νmax: 3456, 2980, 2928,
1742, 1659, 1460, 1377, 1258, 1043, 899 cm ; HRMS–ESI(m/z):
[M+Na]+calculated for C H Cl N Na O Si, 686.2766, found:
-
1
-1
+
ESI(m/z): [M+Na] calculated for C H INNaO , 444.0648,
16
24
4
30 51
2
3
7
found: 444.0646.
686.2759.
4
.2.10. Synthesis of Compound 25. To a solution of the amide 24
4.2.13. Synthesis of Compound 32. To a cooled solution of EDCI
(92.0 mg, 0.48 mmol, 3.0 equivalent), HOAt (65.3 mg, 0.48
mmol, 3.0 equivalent) and DIPEA (0.10 ml, 0.64 mmol, 4.0
(1.05 g, 2.50 mmol, 1.0 equivalent) in 16 ml of THF and 8 ml of
water, LiOH•H O (314.7 mg, 7.50 mmol, 3.0 equivalent) and
H O (30% in H O, 0.78 ml, 7.50 mmol, 3.0 equivalent) was
2
o
equivalent) in 3 ml of DCM at 0 C, the solution of the acid 13
2
2
2
added. After stirring for 24 h at room temperature, the reaction
was quenched by aqueous HCl solution (2 M, 15.00 ml, 30.00
mmol, 12.0 equivalent). The aqueous layer was extracted with
EA (50 ml x 3), and the combined organic phase was dried over
(105.4 mg, 0.16 mmol, 1.0 equivalent) and the amine 35 (99.9
mg, 0.19 mmol, 1.2 equivalent) in 2.5 ml of DCM was added.
The reaction was stirred at room temperature for 18 h. After
filtration over a plug of diatomite and concentration in vacuo, the
residue was chromatographed on silica gel (PE / EA= 20 : 1) to
afford the amide 32 (155.3 mg, 82 % yield) as yellowish oil.
Na SO4 and concentrated in vacuo. The residue was
2
chromatographed on silica gel (PE/EA=2:1) to furnish the acid
22
1
2
5 (674.5 mg, 87 % yield, 89 % ee) as yellowish oil. The ee
[α] = – 39.8 (c 0.13, CHCl ); H NMR (400 MHz, CDCl ): δ
D
3
3
value was determined by SFC (Chiral ND 5ꢀ, CO /MeOH= 95 /
7.28 – 7.26 (m, 5 H), 7.20 (s, 2 H), 6.91 (m, 1 H), 6.65 (m, 1 H),
5.78 (d, J = 19.1 Hz, 1 H), 5.56 (dd, J = 19.0, 7.0 Hz, 1 H), 5.50
(d, J = 9.2 Hz, 1 H), 5.13 (s, 2 H), 4.62 (dd, J = 15.2, 7.5 Hz, 1
H), 4.32 (d, J = 8.5 Hz, 1 H), 4.13 (d, J = 8.0, 1 H), 3.68 (s, 3 H),
3.08 (m, 1 H), 2.90 - 2.78 (m, 5 H), 2.09 (s, 1 H), 1.90 (m, 1 H),
1.48 (s, 9 H) 1.41 – 1.18 (m, 15 H), 1.12 (d, J =8 , 3 H), 1.10 (s, 3
2
24
5
, flow rate 1.0 ml / min, λ = 254 nm). [α] = – 28.4 (c 0.4,
D
1
CHCl ); H NMR (400 MHz, CDCl ): δ 6.83 (t, J = 7.1 Hz, 1 H),
3
3
6
2
.27 (s, 1 H), 3.76 (dd, J =7.3, 6.1 Hz, 1 H), 3.21 (s, 3 H), 2.55 –
.47 (m, 1 H), 2.40 – 2.35 (m, 1 H), 1.82 (s, 3H),1.77 (s, 3 H);
1
3
C NMR (100 MHz, CDCl ): δ 173.3, 147.1, 140.1, 129.1, 84.8,
3
8
1
0.0, 56.7, 33.7, 18.9, 12.4; IR (KBr) νmax: 2927, 1687, 1645,
422, 1280, 1099 cm ; HRMS–ESI(m/z): [M+Na] calculated for
H), 1.02 (s, 3 H), 0.91 - 0.71 (m, 30 H), 0.36 (q, J = 7.9 Hz, 6 H);
-
1
+
13
C NMR (101 MHz, CDCl ):170.0, 148.4, 130.0, 129.9, 129.5,
3
C H I Na O, 332.9964, found: 332.9965.
128.4, 128.1, 128.0, 99.4, 81.0, 80.5, 74.4, 61.6, 58.2, 54.1, 46.3,
10
15
3
7
2.1, 29.8, 29.2, 29.1, 28.5, 27.6, 27.3, 24.7, 16.9, 15.9, 13.8, 9.4,
4
.2.11. Synthesis of Compound 28. To a cooled solution of 14
.0, 6.4; IR (KBr) νmax: 3458, 2986, 2930, 1744, 1458, 1375,
(205.9 mg, 0.32 mmol, 1.0 equivalent) in 3 ml of DME (1, 2
-1
+
o
1242, 1047, 815, 710 cm ; HRMS–ESI (m/z): [M+Na]
calculated for C57 H95 Cl N Na O Si Sn, 1206.5129; found:
1
dimethoxyethane) at 0 C, the solution of LiOH•H O (45.7 mg,
0
reaction was stirred at room temperature overnight. Then the
reaction was quenched by addition of aqueous HCl solution (1
M). The aqueous layer was extracted with EA (30 ml x 3) and the
combined organic phase was dried over Na SO and concentrated
2
2
3
9
.96 mmol, 3.0 equivalent) in 3 ml of H O was added and the
2
206.5134.
4.2.14. Synthesis of Compound 33. To a cooled solution of the
ester 9`(4.42 g, 18.0 mmol, 1.0 equivalent) in 180 ml of DCM at
0 C, 2,6-lutidine (16.8 ml, 144.0 mmol, 8.0 equivalent) and
o
2
4
in vacuo. The residue was chromatographed on silica gel (PE /
TESOTf (24.4 ml, 108 mml, 6.0 equivalent) was added. After
stirring at 0 C for 4 h, the reaction was quenched by addition of
o
EA=1:1) to afford the acid 28 (158.8 mg, 78 % yield) as viscous
21
1
colorless oil. [α] = – 45.2 (c 0.08, CHCl ); H NMR (400 MHz,
200 ml of saturated NaHCO solution. The aqueous layer was
D
3
3
CD OD): δ 7.35(s, 2 H), 5.11 (s, 2 H), 4.83 – 4.79 (m, 1 H), 4.33
extracted with DCM (150 ml x3), and the combined organic
phase was dried over Na SO and concentrated in vacuo. The
resultant crude product was chromatographed on silica gel (PE /
3
(
1
m, 1 H), 4.17 (d, J = 9.6 Hz, 1 H), 3.64 (s, 3 H), 3.14 (dd, J =
3.9, 8.4 Hz, 1 H), 2.83 (dd, J = 13.6, 8.6 Hz, 1 H), 2.78 (s, 3
H),1.93-1.89 (m, 1 H), 1.39 (s, 9 H), 1.19 (s, 3 H), 1.14 (s, 3 H),
2
4
EA= 2 : 1) to afford colorless oil. To a solution of this colorless
13
o
1
.00-0.98 (m, 2 H), 0.87-0.85 (m, 5 H), 0.58 (m, 3 H); C NMR
oil in 150 ml of THF at 0 C, NEt (8.3 ml, 15.0 mmol) and
3
(
101 MHz, CD OD): 172.4, 149.7, 131.1, 130.9, 130.1,107.2,
Boc O (6.9 ml, 30 mmol) was added. The reaction was stirred for
3
2
1
3
2
00.5, 81.6, 72.0, 68.7, 63.5, 61.8, 59.4, 58.4, 56.4, 37.5, 33.5,
16 h and then was quenched with 100 ml of H O. The aqueous
2
0.5, 28.6, 27.2, 26.9, 15.7, 10.7. IR (KBr) νmax: 3499, 2955,
layer was extracted with EA (100 ml x 3), and the combined
organic phase was dried over Na SO and concentrated in vacuo.
-
1
924, 1718, 1458, 1375, 1159, 947 cm ; HRMS–ESI(m/z):
2
4
+
[
M+K] calculated for C28 H43 Cl K N O , 674.2013, found:
The crude product was chromatographed on silica gel (PE / EA=
20 : 1) to afford the ester as colorless oil. To a cooled solution of
this colorless oil (1.43 g, 4.14 mmol, 1.0 equivalent) in 40 ml of
2
3
9
6
74.2011.
4
.2.12. Synthesis of Compound 29. To a cooled solution of 14
o
.
o
DME at 0 C was added a solution of LiOH H O (1.39 mg, 33.1
2
(
(
131.0 mg, 0.20 mmol) in 5 ml of DCM at 0 C, 2,6-lutidine
0.28 ml, 2.40 mmol, 12.0 equivalent) and TESOTf (0.27 ml,
mmol, 8.0 equivalent) in 40 ml of H O. After the reaction was
2
stirred at room for 6 hours, it was quenched with aqueous HCl (1
M) and the acidity was adjusted to pH 3. The aqueous layer was
extracted with EA (100 ml x 3) and the combined organic phase
was dried over Na SO and concentrated in vacuo. The residue
1
.20 mmol, 6.0 equivalent) was added sequentially. After stirring
o
for 4 h at 0 C, the reaction was quenched with 15 ml of saturated
NaHCO solution. The aqueous layer was extracted with DCM
3
2
4
(20 ml x 4), and the combined organic phase was dried over
was chromatographed on silica gel (PE / EA= 2 : 1) to afford the
Na SO4 and concentrated in vacuo. The crude product was
chromatographed on silica gel (PE / EA= 1 : 1) to afford the
22
2
acid 33 (1.27 g, 63 % yield for 3 steps) as yellowish oil. [α]
=
D
1
4
2.6 (c 0.18, CHCl ); H NMR (400 MHz, CDCl ) δ 5.28 (d, J =
3
3

1
1
8
1
.3 Hz, 1 H), 4.26 (d, J = 8.4 Hz, 1 H), 1.44 (s,
A
9 H
C
),
C
1
E
.42
P
(
T
s,
E
3
D
H),MAqu
N
en
U
ch
S
ed
C
b
R
y
I
sa
P
tu
T
rated 5 ml NaHCO . Extracted by DCM (20
3
.24 (s, 3H), 0.97 (t, J = 7.9 Hz, 10 H), 0.68 (q, J = 7.9 Hz, 6 H);
ml x 3), the combined organic phase was dried over Na SO ,
filtrated and concentrated in vacuo. The resulted crude product
2
4
1
3
C NMR (100 MHz, CDCl ):156.2, 80.4, 62.0, 29.8, 28.4, 27.5,
3
2
1
5.6, 6.9, 6.5 ; IR (KBr) νmax: 3495, 2926, 1726, 1462 1367,
159, , 947, 890 cm ; HRMS–ESI(m/z): [M+Na]+calculated for
was chromatographed on silica gel (PE / EA= 3 : 1) to afford
-
1
22
amine 36 (109.9 mg, 78 % yield). [α] = – 12.3 (c 0.50, CHCl3);
D
1
C H Cl K N O , 674.2008, found: 674.2011.
H NMR (400 MHz, CDCl ): δ 7.62 (d, J = 8.1 Hz, 1 H), 7.26 –
28
43
2
3
9
3
7
1
.22 (m, 5 H), 7.19 (s, 2 H), 6.86 (d, J = 8.4 Hz, 1 H), 5.78 (d, J =
9.1 Hz, 1 H), 5.58 (dd, J = 19.0, 7.0 Hz, 1 H), 5.51 (d, J = 9.2
4
.2.15. Synthesis of Compound 34. To a cooled solution of
HBTU (1.59 g, 4.2 mmol, 3.0 equivalent), DMAP (34.2 mg, 0.28
mmol, 0.2 equivalent) and DIPEA (0.7 ml, 4.2 mmol, 3.0
equivalent) in 15 ml of DCM at 0 C, a solution of the acid 33
Hz, 1 H), 5.12 (s, 2 H), 4.65 (dd, J = 15.2, 7.5 Hz, 1 H), 4.31 (d, J
= 8.5 Hz, 1 H), 3.66 (s, 3H), 3.26 – 3.18 (m, 1 H), 3.10 (dd, J =
1
o
4.1, 7.0 Hz, 1 H), 2.90 (dd, J = 14.0, 7.6 Hz, 1 H), 2.81 – 2.74
(758.8 mg, 1.68 mmol, 1.2 equivalent) and the secondary alcohol
(m, 2 H), 2.20 (s, 3 H), 1.38 (m, 1 H) 1.38 – 1.19 (m, 15 H), 1.10
2
2 (467.3 mg, 1.40 mmol, 1.0 equivalent) in 5 ml of DCM was
(s, 3 H), 1.04 (s, 3 H), 0.90 (d, J = 6.9 Hz, 3 H), 0.88 – 0.71 (m,
added. The reaction was stirred at room temperature overnight.
After the solution was filtrated over a plug of diatomite and
concentrated in vacuo, the residue was chromatographed on silica
gel (PE / EA= 50 : 1) to afford the ester 34 (225.2 mg, 21 % yield)
as green oil. [α] = – 20.6 (c 0.28, CHCl ); H NMR (400 MHz,
CDCl ) δ 7.26 (m, 5H), 5.77 (d, J = 19.1 Hz, 1H), 5.64 (dd, J =
13
3
2 H), 0.39 (q, J = 7.9 Hz, 6 H); C NMR (101 MHz,
CDCl ):174.1, 170.4, 169.2 148.6, 148.5, 138.6, 134.9, 130.0,
1
46.4, 38.5, 36.8, 36.2, 29.1, 28.4, 27.3, 25.3, 16.8, 16.0, 13.8,
1
1
3
29.5, 128.3, 128.0, 99.4, 81.0, 74.4, 69.9, 61.7, 58.2, 54.5, 53.9,
22
1
D
3
1.9, 9.4, 7.0, 6.5 ; IR (KBr) νmax: 3400, 2957, 2926, 2876, 1737,
3
-1
598, 1459, 1377, 1239, 1148, 1040, 802, 744 cm ; HRMS–ESI
1
1
9.0, 6.9 Hz, 1 H), 5.57 (d, J = 8.0 Hz, 1H), 5.30 (s, 1 H), 4.11 (s,
H), 2.76 (dd, J = 14.1, 7.0 Hz, 1 H), 1.43 (s, 9H), 1.26 – 1.19
+
(m/z): [M+Na] calculated for C52 H87 Cl N Na O Si Sn,
2
3
7
1
106.4605; found: 1106.4607.
(m, 21 H), 1.10 (d, J = 6.7 Hz, 3 H), 0.87–0.84 (m, 24 H), 0.83 –
13
0
.76 (m, 5 H), 0.41 (q, J = 7.9 Hz, 6 H); C NMR (100 MHz,
4.2.18. Synthesis of Compound 37. Method A: To a cooled
solution of HBTU (115.9 mg, 0.30 mmol, 3.0 equivalent),
DMAP (4.0 mg, 0.03 mmol, cat) and DIPEA (0.05 ml, 0.30
CDCl ): 170.4, 155.8, 148.7, 138.8, 129.8, 128.1, 128.0, 80.8,
7
6
8
3
9.7, 74.9, 62.9, 46.6, 29.1, 27.8, 27.4, 16.6, 13.8, 11.2, 9.5, 7.0,
o
.6. IR (KBr) νmax: 3495, 2926, 1726, 1462 1367, 1159, 947,
mmol, 3.0 equivalent) in 2 ml DCM at 0 C was added a solution
-
1
90 cm ; HRMS–ESI(m/z): [M+K]+calculated for C H Cl K
of acid 25 (42.2 mg, 0.13 mmol, 1.3 equivalent) and secondary
amine 36 (109.9 mg, 0.10 mmol, 1.0 equivalent) in 2 ml DCM.
The reaction was allowed to warm to room temperature and stir
overnight. Concentrated in vacuo, the residue was
chromatographed on silica gel (PE / EA= 5 : 1) to afford amide
28
43
2
N O , 674.2008, found: 674.2011.
3
9
4
.2.16. Synthesis of Compound 35. Method A: To a cooled
solution of ester 34 (167.3 mg, 0.22 mmol, 1.0 equivalent) in 4
ml DCM at 0 C, 2,6-lutidine (0.13 ml, 1.10 mmol, 5 equivalent)
and TESOTf (0.16 ml, 0.88 mml, 4.0 equivalent) subsequently.
After stirring at 0 C with additional 2 h was added subsequently,
the reaction was quenched by saturated 10 ml NaHCO3.
Extracted by DCM (20 ml x 3), the combined organic phase was
dried over Na SO , filtrated and concentrated in vacuo. The
resulted crude product was chromatographed on silica gel (PE /
EA= 10 : 1) to afford amine 35 (105.4 mg, 72 % yield) as a
colorless oil. Method B: To a solution of 44 (665.6 mg, 1.0 mmol)
in 10 ml DCM, 2, 6-lutidine (0.7 ml, 6.0 mmol) and TESOTf (0.9
ml, 4.0 mmol) were added at 0 ꢃ. After stirring at 0 ꢃ for 30
o
3
7 (1.4 mg, 10 % yield) as yellowish oil. Method B: o a cooled
o
solution of EDCI (172.6 mg, 0.90 mmol), HOAt (127.1 mg, 0.90
mmol), and DIPEA (0.2 ml, 1.2 mmol) in 4 ml of CH Cl at 0 ꢃ,
2
2
the solution of the acid 38 (251.0 mg, 0.35 mmol) and amine 35
202.1 mg, 0.30 mmol) in 2 ml of DCM was added. After stirring
(
2
4
for 1 h, the reaction mixture was allowed to warm to room
temperature and stirred for additional 7 h. The reaction mixture
was concentrated in vacuo and the residue was purified by
column chromatography (petroleum ether/ethyl acetate = 5 : 1) to
afford 37 (306.4 mg, 75 % yield) as colorless oil. [α] = – 40.1
22
D
1
(c 1.50, CHCl ); H NMR (400 MHz, CDCl ): δ 7.30 – 7.21 (m, 6
3
3
min, saturated aqueous NaHCO (10 ml) was added to quench the
3
H), 7.21 (s, 2H), 7.10 (d, J = 8.1 Hz, 1 H), 6.72 (d, J = 8.5 Hz, 1
H), 6.27 (s, 1 H), 5.81 (d, J = 19.0 Hz, 1 H), 5.60 (dd, J = 19.0,
reaction. After separation, the aqueous layer was extracted with
DCM (50 ml × 3). The combined organic layers were dried over
anhydrous Na SO , filtered and concentrated under reduced
pressure. The crude product was purified by column
chromatography on deactivated silica gel (PE / EA= 30 : 1) to
furnish 35 (558.7 mg, 82 % yield, dr = 14 : 1) as a colorless oil.
6
.8 Hz, 1 H), 5.51 – 5.44 (m, 2 H), 5.14 (s, 2 H), 4.64 (q, J = 7.5
Hz, 1 H), 4.49 (d, J = 11.3 Hz, 1 H), 4.33 (d, J = 8.5 Hz, 1 H),
.78 (t, J = 6.8 Hz, 1 H), 3.69 (s, 3 H), 3.22 (s, 3 H), 3.16 – 3.11
m, 1 H), 2.93 – 2.86 (m, 1 H), 2.84 (s, 3 H), 2.83 – 2.77 (m, 1 H),
2.46 (dd, J = 14.5, 6.5 Hz, 1 H), 2.36 (dd, J = 14.7, 7.3 Hz, 1 H),
.15 – 2.13 (m, 2 H),1.86 (s, 3 H), 1.78 (s, 3 H), 1.44 – 1.34 (m, 7
H), 1.29 – 1.20 (m, 7 H), 1.12 (d, J = 5.6 Hz, 3 H), 1.11 (s, 3 H),
.04 (s, 3 H), 0.93 – 0.86 (m, 13 H), 0.84 – 0.75 (m, 18 H), 0.40
2
4
3
(
22
1
[
α]
= + 5.1 (c 1.3, CHCl ); H NMR (400 MHz, CDCl ): δ
D
3
3
2
7
1
.27 – 7.22 (m, 5 H), 5.83 (d, J = 19.1 Hz, 1 H), 5.67 (dd, J =
9.1, 6.8 Hz, 1 H), 5.61 (d, J = 7.9 Hz, 1 H), 3.37 (s, 1 H), 2.76
1
(
1
(
dd, J = 14.3, 6.9 Hz, 1 H), 1.73 (s, 2 H), 1.40 – 1.34 (m, 6 H),
.25 (s, 3 H), 1.30 – 1.19 (m, 6 H), 1.08 (d, J = 6.1 Hz, 3 H), 1.07
s, 3 H), 0.91 – 0.81 (m, 18 H), 0.78 – 0.74 (m, 6 H), 0.52 (q, J =
1
(q, J = 7.7 Hz, 6 H); C NMR (101 MHz, CDCl ): δ 175.2, 170.5,
3
1
70.0, 169.3, 148.4, 147.5, 138.5, 135.1, 133.6, 130.2, 129.9,
13
129.5, 128.3, 128.1, 128.0, 127.4, 99.4, 85.2, 81.1, 79.8, 74.4,
6
2
7.1, 6.5; IR (KBr) νmax: 3319, 2958, 2927, 1739, 1688, 1608,
1518, 1460, 1374, 1257, 1161, 947 cm ; HRMS–ESI (m/z):
7
1
2
2
.9 Hz, 6 H); C NMR (101 MHz, CDCl ): δ 172.7, 148.7, 138.7,
3
1.6, 58.3, 56.6, 54.1, 46.4, 36.6, 33.6, 32.1, 31.4, 29.2, 29.1,
9.0, 28.4, 27.7, 27.4, 24.7, 18.8, 16.9, 15.8, 14.4, 13.9, 10.6, 9.5,
29.8, 128.0, 127.9, 127.9, 80.2, 75.1, 65.2, 46.3, 29.1, 28.0, 27.3,
5.5, 16.3, 13.8, 9.4, 7.1, 6.7; IR (KBr) νmax: 3400, 2957, 2926,
-
1
876, 1737, 1598, 1459, 1377, 1239, 1148, 1040, 744 cm ;
-1
+
HRMS–ESI (m/z): [M+H] calculated for C34 H64 N O Si Sn,
6
+
3
[
M+Na] calculated for C H Cl I N Na O Si Sn, 1398.4570;
62
100
2
3
9
82.3677; found: 682.3677.
found 1398.4562.
4
3
2
.2.17. Synthesis of Compound 36. To a cooled solution of amide
2 (155.3 mg, 0.13 mmol, 1.0 equivalent) in 3 ml DCM at 0 C,
,6-lutidine (0.08 ml, 0.65 mmol, 5.0 equivalent) and TESOTf
o
4.2.19. Synthesis of Compound 38. To a solution of 45 (792.7 mg,
.1 mmol) in 10 ml DME (1, 2-dimethoxyethane), LiOH•H O
1
2
(230.1 mg, 5.5 mmol) in 10 ml water was added. After stirring at
(0.10 ml, 0.52 mmol, 4.0 equivalent) was added subsequently.
o
room temperature for 8 h, the mixture was adjusted to pH = 2
with 1 M HCl at 0 ꢃ, then extracted with DCM (50 ml × 4). The
After stirring at 0 C with additional 1 hour, the reaction was

1
2
Tetrahedron
combined organic layers were dried over Na2
A
S
C
O
C
, fi
E
ltr
P
at
T
ed
E
a
D
nd MAte
NU
mp
er
S
atu
C
re
R
foIPr 4
T
h. The reaction was then quenched by addition
4
concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (DCM / MeOH
=
of saturated aqueous NaHCO (10 ml), and the aqueous layer was
3
extracted with EA (40 ml × 4). The combined organic layers
were dried over Na SO , filtered and concentrated in vacuum.
25 : 1), furnishing 38 (676.5 mg, 87 % yield) as a colorless oil.
2
4
2
2
1
[
α] = – 56.1 (c 1.20, CHCl ); H NMR (400 MHz, CDCl ): δ
The residue was purified by column chromatography on 1 %
D
3
3
7
5
4
3
3
1
1
0
1
9
2
1
.73 (s, 1H), 7.28 (d, J = 7.8 Hz, 1 H), 7.17 (s, 2H), 6.21 (s, 1H),
.40 (t, J = 6.6 Hz, 1 H), 5.10 (s, 2 H), 4.74 (d, J = 5.3 Hz, 1 H),
.52 (d, J = 11.2 Hz, 1 H), 3.70 (t, J = 6.7 Hz, 1 H), 3.65 (s, 3 H),
.15 (s, 3 H), 3.15 – 3.10 (m, 1 H), 2.92 – 2.89 (m, 1 H), 2.89 (s,
H), 2.35 (dd, J = 14.1, 7.1 Hz, 1 H), 2.27 (dd, J = 14.6, 7.3 Hz,
H), 2.07 – 2.00 (m, 1 H), 1.72 (s, 3 H), 1.71 (s, 3 H), 1.34 –
.25 (m, 1 H), 1.02 – 0.93 (m, 1 H), 0.87 (t, J = 7.2 Hz, 3 H),
NEt neutralized silica gel (PE / EA = 10 : 1), affording 44 (668.0
3
24
mg, 70 % yield, dr = 10 : 1) as colorless oil. [α] = – 41.5 (c
D
1
0.51, CHCl ); H NMR (400 MHz, CDCl ): δ 7.28 – 7.24 (m, 5
3
3
H), 5.86 (d, J = 19.0 Hz, 1 H), 5.70 – 5.63 (m, 1 H), 5.62 (d, J =
8.2 Hz, 1 H), 5.39 (d, J = 8.9 Hz, 1 H), 4.22 (d, J = 9.1 Hz, 1H),
2.80 – 2.75 (m, 1 H), 2.63 (s, 1 H), 1.44 (s, 9 H), 1.41 – 1.34 (m,
6 H), 1.29 – 1.21 (m, 6 H), 1.18 (s, 3 H), 1.12 (d, J = 6.7 Hz, 3 H),
13
13
.76 (d, J = 6.2 Hz, 3 H); C NMR (101 MHz, CDCl ): δ 175.4,
1.06 (s, 3 H), 0.88 – 0.84 (m, 9 H), 0.80 – 0.76 (m, 6 H) ;
C
3
73.3, 169.5, 148.5, 147.3, 135.0, 133.0, 130.1, 129.2, 128.1,
9.4, 85.0, 79.9, 61.4, 58.3, 56.6, 52.9, 36.6, 33.4, 32.0, 31.5,
4.8, 18.9, 15.6, 14.2, 10.6; IR (KBr) νmax: 3330, 2965, 2930,
NMR (100 MHz, CDCl ):δ 171.6, 155.9, 148.5, 138.5, 130.2,
3
128.2, 127.6, 81.1, 80.2, 72.0, 61.3, 46.5, 29.1, 28.4, 27.4, 27.1,
26.9, 26.4, 16.1, 13.9, 9.5 ; IR (KBr) νmax: 3440, 2959, 2926,
-
1
-1
737, 1681, 1610, 1475, 1402, 1257, 1162, 1099, 939, 800 cm ;
1720, 1496, 1370, 1163, 1052, 989, 698 cm ; HRMS–ESI (m/z):
+
+
HRM–ESI (m/z): [M+Na] calculated for C H Cl I N Na O ,
[M+Na] calculated for C H57 N Na O Sn, 690.3156; found
28
39
2
2
7
33
5
7
35.1077; found: 735.1082.
690.3161.
4
.2.20. Synthesis of Compound 39. To a solution of amide 12
4.2.24. Synthesis of Compound 45. To a solution of the acid 25
(632.2 mg, 2.0 mmol) in 20 ml of DCM, 1-chloro-N,N,2-
trimethylprophenylamine (0.35 ml, 2.4 mmol) was added
dropwise. After the solution was stirred at room temperature for
(1.34 g, 2.5 mmol) in 25 ml DCM was added 2, 6-lutidine (1.7 ml,
1
4.9 mmol) and TMSOTf (1.8 ml, 9.9 mmol) sequentially at 0 ꢃ.
The reaction was stirred for 1 h and quenched by adding 50 ml
saturated aqueous NaHCO . The organic layer was separated and
2 h, the amine 39 (980.2 mg, 2.2 mmol) and Et N (0.85 ml, 6.1
3
3
the aqueous layer was extracted with DCM (100 ml × 4). The
combined organic layers were dried over anhydrous Na SO and
mmol) were added sequentially and the resultant solution was
stirred overnight. The mixture was then quenched with 10 ml of
2
4
concentrated in vacuo. After purification by column
chromatography on silica gel (DCM / MeOH = 20 : 1), it
furnished amine 39 (852.8 mg, 79 % yield) as a colorless oil.
saturated aqueous NaHCO . After separation, the aqueous layer
3
was extracted with DCM (50 ml × 4). The combined organic
layer was dried over Na SO and concentrated under reduced
2
4
21
1
[
α] = – 28.2 (c 0.90, CHCl ); H NMR (400 MHz, CDCl ): δ
pressure. The residue was purified by column chromatography on
D
3
3
7
=
1
(
.67 (d, J = 7.7 Hz, 1 H), 7.09 (s, 2 H), 5.12 (s, 2 H), 4.80 (dd, J
12.8, 6.1 Hz, 1 H), 3.72 (s, 3 H), 3.65 (s, 3 H), 3.12 (dd, J =
4.0, 5.2 Hz, 1 H), 2.98 (dd, J = 13.9, 7.0 Hz, 1 H), 2.80 – 2.79
m, 1 H ), 2.25 (s, 3 H), 1.76 (s, 1 H), 1.45 – 1.41 (m, 2 H), 1.14
1.03 (m, 1 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.85 (t, J = 7.3 Hz, 3
silica gel (PE / EA= 3 : 1), furnishing 45 (1.23 g, 83 % yield) as
24
1
colorless oil. [α] = – 85.4 (c 0.60, CHCl ); H NMR (400 MHz,
D
3
CDCl ): δ 7.12 (s, 2 H), 7.03 (d, J = 8.4 Hz, 1 H), 6.23 (s, 1 H),
3
5.45 (t, J = 6.8 Hz, 1 H), 5.13 (s, 3 H), 4.77 – 4.71 (m, 1 H), 4.48
(d, J = 11.5 Hz, 1 H), 3.74 – 3.73 (m, 1H), 3.70 (s, 3 H), 3.66 (s,
3 H), 3.18 (s, 3 H), 3.10 (dd, J = 14.2, 5.0 Hz, 1 H), 2.86 (dd, J =
14.2, 8.6 Hz, 1 H), 2.80 (s, 3H), 2.44 – 2.37 (m, 1 H), 2.36 – 2.28
(m, 1 H), 2.13 – 2.07 (m, 1 H), 1.79 (s, 3 H), 1.75 (s, 3 H), 1.37 –
–
13
H); C NMR (100 MHz, CDCl ): δ 173.6, 171.6, 148.7, 134.2,
3
1
1
1
29.9, 129.4, 99.4, 69.9, 58.2, 52.5, 52.3, 38.5, 36.8, 36.4, 25.0,
5.9, 11.9; IR (KBr) νmax : 3309, 2961, 1745, 1653, 1511, 1475,
-
1
256, 1212, 1161, 935, 780 cm ; HRMS–ESI (m/z):
1.29 (m, 1 H), 1.04 – 0.95 (m, 1 H), 0.87 (t, J = 7.3 Hz, 3 H),
+
13
[
M+Na] calculated for C19 H28 Cl2 Na O , 457.1273; found:
0.82 (d, J = 6.4 Hz, 3 H); C NMR (101 MHz, CDCl ): δ 175.3,
5
3
4
57.1277.
171.3, 170.1, 148.7, 147.4, 134.3, 133.5, 129.7, 129.4, 127.6,
9
9.4, 85.1, 79.7, 60.9, 58.2, 56.6, 52.7, 52.6, 36.7, 33.1, 32.1,
4
.2.21. Synthesis of Compound 40.
The reaction was
1 13
30.9, 24.6, 18.8, 15.7, 14.3, 10.5; IR (KBr) νmax: 3316, 2962,
2930, 1745, 1682, 1613, 1527, 1474, 1257, 1162, 1100, 938, 800
cm ; HRMS–ESI (m/z): [M+Na] calculated for C29 H41 Cl I N
Na O , 749.1233; found: 749.1224.
manipulated as the paper reported and the H-NMR and C-
NMR matched with the paper . And the ee value was measured
using the method reported by the author
[
17]
-1
+
[
17]
2 2
.
7
4
.2.22. Synthesis of Compound 41. TEMPO (156.3 mg, 1.0
4
.2.25. Synthesis of Compound 46. Pd(PPh ) (15.7 mg, 0.01
3 4
mmol), Fe (NO ) ·9H O (404.0 mg, 1.0 mmol) and KCl (74.6 mg,
1
3
3
2
mmol) and LiCl (26.8 mg, 0.60 mmol) was weighted into flask in
glove box. The flask was capped with rubber septum and
removed from glove box. A solution of compound 37 (272.8 mg,
.0 mmol) were added to a stirred solution of (2R)-2-N-(Boc)
amino-3-methyl- 1,3-butanediol 43 (2.19 g, 10.0 mmol) under O2
atmosphere in 100 ml anhydrous DCE. The reaction was then
stirred at room temperature until completion of the reaction as
monitored by TLC (48 h). The reaction mixture was concentrated
in vacuo and the residue was purified by column chromatography
0
.20 mmol) in 100 ml of THF was added and the mixture was
stirred at 60 ꢃ for 18 h. After the mixture was cooled to room
temperature, 20 ml of water was added to quench the reaction.
The aqueous layer was extracted with EA (50 ml × 3). The
combined organic layers were dried over Na SO , filtrated and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (PE / EA = 3 : 1), furnishing 46
(DCM/MeOH = 20 : 1), affording 41 (1.80 g, 76 % yield) as a
2
4
yellowish solid. The spectroscopic data are consistent with those
reported in literature
[
18a]
.
22
4
.2.23. Synthesis of Compound 44. PPh (1.85 g, 7.1 mmol) and
(118.7 mg, 62 % yield) as colorless oil. [α] = – 40.3 (c 0.40,
CHCl ); H NMR (400 MHz, CDCl ): δ 7.32 – 7.22 (m, 5 H),
3 3
D
3
1
the acid 41 (510.7 mg, 2.1 mmol) was weighted into flask in
glove box. The flask was capped with rubber septum and
removed from glove box and placed in cold bath. A solution of
the alcohol 40 (645.4 mg, 1.4 mmol) in 12 ml of toluene was
added and the mixture was maintained to 0 ꢃ. DIAD (0.85 ml,
7.19 (s, 2H), 6.96 (d, J = 8.9 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 1 H),
6.30 (dd, J = 15.1, 10.7 Hz, 1 H), 5.93 (s, 1 H), 5.85 (d, J = 10.6
Hz, 1 H), 5.74 (dd, J = 15.3, 5.4 Hz, 1 H), 5.42 – 5.39 (m, 1 H),
5.11 (s, 2 H), 4.62 (d, J = 11.5 Hz, 1 H), 4.52 – 4.47 (m, 1 H),
4.40 (d, J = 8.8 Hz, 1 H), 3.65 (s, 3 H), 3.60 (dd, J = 10.6, 3.0 Hz,
1 H), 3.21 (s, 3 H), 3.06 (dd, J = 13.1, 10.3 Hz, 1 H), 2.75 (dd, J
4
.3 mmol) was added dropwise. After 30 min, to the mixture was
added 3 ml of DCM and the resultant solution was stirred at room

1
3
=
13.2, 5.3 Hz, 1 H), 2.61 (s, 3 H), 2.61 – 2.55
A
(
C
m,
C
1
E
H
P
),
T
2.
E
39
D
–
MA2.
N
81
U
(s
S
, 3
C
H
R
),
I
2.73 (dd, J = 13.8, 6.5 Hz, 1 H), 2.75 – 2.70 (m,
P
T
2
1
–
7
.36 (m, 1 H), 2.19 – 2.13 (m, 1 H), 1.82 (s, 3 H), 1.76 (s, 3 H),
.35 (s, 3 H), 1.27 – 1.20 (m, 1 H), 1.09 (d, J = 6.8 Hz, 3 H), 1.05
0.98 (m, 1 H), 0.92 – 0.87 (m, 7 H), 0.83 (s, 3 H), 0.76 (t, J =
1 H), 2.53 – 2.46 (m, 1 H), 2.43 – 2.35 (m, 1 H), 2.09 – 2.04 (m,
1 H), 1.79 (s, 3 H), 1.69 (s, 3 H), 1.44 – 1.40 (m, 1 H), 1.28 –
1.21 (m, 1 H), 1.18 (s, 3 H), 1.04 (s, 3 H), 1.03 (d, J = 5.2 Hz, 3
1
3
13
.9 Hz, 9 H), 0.37 (q, J = 7.9 Hz, 6 H); C NMR (101 MHz,
H), 0.92 (t, J = 7.2 Hz, 3 H), 0.83 (d, J = 6.3 Hz, 3 H); C NMR
CDCl ): δ 176.0, 170.6, 169.7, 169.5, 148.7, 139.2, 136.8, 135.5,
(101 MHz, CDCl ): δ 176.2, 170.9, 170.3, 169.5, 146.9, 137.9,
3
3
1
1
3
1
1
34.6, 133.6, 130.3, 129.5, 128.6, 128.2, 127.7, 127.7, 126.8,
25.6, 99.4, 85.8, 80.0, 75.7, 61.00, 60.1, 58.3, 56.1, 54.9, 42.2,
6.1, 32.4, 31.9, 30.5, 28.5, 27.4, 24.6, 16.1, 14.6, 11.6, 10.7,
0.5, 7.1, 6.6; IR (KBr) νmax: 3424, 2925, 2854, 1739, 1619, 1459,
134.9, 134.4, 133.3, 129.7, 129.1, 128.1, 128.1, 127.9, 127.2,
127.1, 126.7, 121.2, 85.0, 80.5, 72.3, 61.8, 60.8, 56.3, 53.9, 41.8,
36.1, 32.7, 31.5, 31.3, 27.0, 26.7, 25.4, 15.9, 14.4, 12.8, 12.8,
10.8; IR (KBr) νmax: 3351, 2927, 2850, 1736, 1665, 1606, 1490,
-
1
-1
+
381, 1258, 1157, 1069, 943, 800 cm ; HRMS–ESI (m/z):
1375, 1312, 1157, 1065, 970 cm ; HRMS–ESI (m/z): [M+Na]
+
[
M+Na] calculated for C H Cl N Na O Si , 980.4391; found:
calculated for C H Cl N Na O , 822.3264; found: 822.3260.
50
73
2
3
9
42 55
2
3
8
9
80.4393.
4
.2.26. To a solution of 46 (116.7 mg, 0.12 mmol) in 6 ml of
4
.3. X-ray crystallographic data
methanol, pTsOH (13.2 mg, 0.06 mmol) was added. The reaction
mixture was stirred at room temperature for 4 h. After addition of
Crystallographic data for nannocystin Ax was stored in the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK. Copies of these data may be obtained
5
ml of saturated aqueous NaHCO to quench the reaction, the
3
aqueous layer was extracted with EA (30 ml × 3). The combined
organic layers were dried over anhydrous MgSO , filtrated and
free
of
charge
from
4
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (PE / EA = 2 : 1 ),
furnishing nannocystin Ax (74.8 mg, 78 % yield) as a white solid,
which was recrystallized from methanol to give crystalline
http://www.ccdc.cam.ac.uk/products/csd/request/ by quoting the
public citation and deposition number CCDC 1519855.
23
1
needles. m.p. 177 - 178 °C. [α] = – 67.4 (c 0.30, MeOH); H
D
Acknowledgements
d6-
NMR (600 MHz, DMSO): δ 9.81 (s, 1 H), 8.52 (d, J = 9.9 Hz,
We acknowledge the financial support from the NSCF
1
2
1
1
H), 7.90 (d, J = 9.5 Hz, 1 H), 7.54 (d, J = 7.6 Hz, 2 H), 7.38 (s,
H), 7.32 (t, J = 7.6 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1 H), 6.35 (m,
H), 6.05 (m, 1 H), 6.00 (m, 1 H), 5.89 (br, 1 H), 5.16 – 5.12 (m,
H), 5.11 (s, 1 H), 4.72 (m, 1 H), 4.63 (m, 1 H), 4.52 (d, J = 11.2
(
21672153) and the Open Fund of State Key Laboratory of
Natural Medicines in China Pharmaceutical University
SKLNMKF201810). We also thank the Analytical and Testing
(
Center for Sichuan University for NMR and X-ray recording.
Hz, 1 H), 3.53 (m, 1 H), 3.08 (s, 3 H), 2.80 (m, 1 H), 2.74 (s, 3
H), 2.65 (m, 1 H), 2.59 (m, 1 H), 2.35 (m, 2 H), 1.73 (m, 1 H),
1
.72 (s, 3 H), 1.65 (s, 3 H), 1.22 (m, 1 H), 1.11 (s, 3 H), 1.02 (s, 3
References
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1
1
8
3
13
d6-
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1
3
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7
6
–
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4
1
2
1
1
0
.54 (d, J = 11.2 Hz, 1 H), 4.18 (d, J = 1.5 Hz, 1 H), 3.64 (dd, J =
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d6-
13
Hz, 3 H), 0.75 (d, J = 6.5 Hz, 3 H); C NMR (100 MHz,
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1
3
3
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