Copper-catalyzed cross-coupling of amino acid-derived amides with (Z)-vinyl iodides: Unexpected solvent effect and preparation of plocabulin

Article abstract of DOI:10.1016/j.tet.2021.131953

A copper-catalyzed cross-coupling reaction of amino acid-derived amides and (Z)-vinyl iodide was studied to improve a key step in the synthesis of plocabulin, a novel microtubule destabilizer agent of marine origin. The study revealed a profound solvent effect with 1,2-dimethoxyethane (DME), which gave consistently high yields across a large variety of the amide and (Z)-vinyl iodide substrates. The protocol was successfully utilized in the preparation of plocabulin and provided a significantly improved yield.

Full text of DOI:10.1016/j.tet.2021.131953

Tetrahedron 83 (2021) 131953
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Tetrahedron
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Copper-catalyzed cross-coupling of amino acid-derived amides with
(Z)-vinyl iodides: Unexpected solvent effect and preparation of
plocabulin
,
,
, **
Leiming Wang a b, Xinsheng Lei b, Quanrui Wang a *, Yingxia Li b
a Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai, 200438, China
b School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong Zone, Shanghai, 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed cross-coupling reaction of amino acid-derived amides and (Z)-vinyl iodide was
studied to improve a key step in the synthesis of plocabulin, a novel microtubule destabilizer agent of
marine origin. The study revealed a profound solvent effect with 1,2-dimethoxyethane (DME), which
gave consistently high yields across a large variety of the amide and (Z)-vinyl iodide substrates. The
protocol was successfully utilized in the preparation of plocabulin and provided a significantly improved
yield.
Received 7 December 2020
Received in revised form
11 January 2021
Accepted 15 January 2021
Available online 19 January 2021
© 2021 Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Enamides
(Z)-vinyl iodide
Buchwald coupling
Plocabulin
1. Introduction
depolymerization through a distinct mechanism [18e20]. Espe-
€
cially, a recent study by Schoffski has revealed that plocabulin also
Enamides are a diverse family of synthetic intermediates and
represent important structural components in many biologically
active marine natural products (Fig. 1) [1e5]. The seemingly simple
enamide unit possesses unique physical and chemical properties,
such as a polar carbon-carbon double bond, configuration with
trans or cis orientation, roughly planar conformation, and as well as
hydrogen-bond acceptor or donor. To a large extent, these proper-
ties impart interesting activities to those natural products that
contain an enamide unit [6e13]. Recently, bio-assay guided in-
vestigations on marine-origin natural products have unveiled a
viable opportunity to identify new targets for cancer therapy as
well as dissimilar modes of action within typical classes drugs [14].
Thus, plocabulin (PM060184), originally isolated from the marine
sponge Lithoplocamia lithistoides, deserves much attention
[15e17]. As a novel and potent tubulin-binding agent with an IC50
value of up to pM range, this molecule targets the recently
exhibits promising antitumor effects in patients with advanced
solid tumors [21].
Our ongoing project requires a substantial supply for extensive
investigation of plocabulin biological activities. However, currently
plocabulin has to be produced by total synthesis due to its resource
rarity. Although a reliable synthetic approach has been reported by
C. Cuevas and co-workers to overcome this supply shortage, the
stereoselective assembly of the (Z)-enamide unit still appears to be
a major problem (poor yield: less than 44%) using the advanced
intermediate (vinyl iodide) and the appropriate amide (see Fig. 1)
[15]. As part of our ongoing project, we herein report an improved
copper-catalyzed cross-coupling reaction of amides and vinyl io-
dides for the construction of (Z)-enamides. A remarkable solvent
effect was observed for the reaction, where DME provided unex-
pectedly yet consistently high yields across a large variety of the
amide and vinyl iodide substrates. The reaction protocol was suc-
cessfully utilized in the key step for the preparation of plocabulin
and provided a significantly improved yield.
described maytansine site on b-tubulin different from that of vinca
alkakloids, taxanes or eribulin, and can induce microtubule
2. Results and discussion
* Corresponding author.
** Corresponding author.
E-mail address: qrwang@fudan.edu.cn (Q. Wang).
Although there are a variety of protocols for accessing enamide
https://doi.org/10.1016/j.tet.2021.131953
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L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
Table 1
The optimization on the copper-catalyzed coupling reaction.
Entry
Ligand
Base
Solvent
T (oC)
Yield (%)a,b
1
2
3
4
5
6
7
8
DMEDA
DACHA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
e
Cs2CO3
CsF
THF
Tol
DMF
1,4-Dioxane
CH3CN
DMF
DMSO
MTBE
MTBE
MTBE
MTBE
DME
DME
DME
DME
DME (H2O, 5.0 eq.)
70
95
90
55
55
55
55
55
55
55
55
55
65
45
55
55
63
63
61
43
42
66
80
84
21
8
22
92
90
89
trace
92
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Li2CO3
CsF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
Fig. 1. The representative antitumor active marine natural products containing
enamide structural units.
DMEDA
a
Reaction conditions: a solution of 1a (2.0 eq.), 2a (1.0 eq.), CuI (0.3 eq.), the
diamine ligand (0.6 eq.) and a suitable base (2.0 eq.) in the solvent (6 mL) noted in
table was stirred overnight at an appreciate temperature under N2.
2a was contaminated by minor (E)-isomer, and the E/Z isomer ratio was 13 : 87.
The isolated yield was based on (Z)-2a.
compounds, the most attractive one is the modern copper-
catalyzed cross-coupling of amides and vinyl halides in conjunc-
tion with diamine or amino acid as the catalyst’s ligand [22e26].
Such coupling reactions feature good stereoselectivities, mild
conditions, cheap catalysts/ligands, wide substrate scope and high
functional group tolerance. Therefore, they have been widely
applied in the synthesis of natural products, pharmaceuticals and
novel materials [27].
The enamide in plocabulin is representative of linear enamides
derived from amides of amino acids and (Z)-vinyl iodides. A liter-
ature survey found few examples of such enamides except those of
cyclic analogues via copper-catalyzed coupling in an intramolecular
manner [28e35]. R. R. Cesati III and co-workers have reported that
a series of enantiomerically pure amino amides could successfully
couple with (E)-1,2-disubstituted vinyl iodide without a sacrifice of
stereochemistry under the standard Buchwald condition (CuI/
MeNHCH2CH2NHMe (DMEDA)/Cs2CO3, THF, 70 ꢀC, 16 h), affording
the enamides with yields ranging from 30% to 87% [36]. In contrast
to (E)-vinyl iodides, in the same study (Z)-vinyl iodides gave much
lower yield, as exemplified by the coupling of H-Leu-NH2 (50%). In
addition, the authors suggested that the solvent THF might need to
be replaced when certain amino amides were used, possibly due to
their solubility.
To improve the (Z)-enamide formation and thus facilitate the
synthesis of plocabulin, we started to study the model reaction of
Boc-Gly-NH2 (1a) and (Z)-1-iodooct-1-ene (2a) with the Buch-
wald’s protocol [22]. As shown in Table 1, under the standard
Buchwald condition, the desired coupling product 3aa was ob-
tained in THF with a yield of 63% (Entry 1). Similar yields were
observed when using other common conditions for the coupling
reaction (Entries 2, 3) [28,37]. Notably, Inoue and co-workers sug-
gested that 1,4-dioxane was the best solvent for a related coupling
reaction in their total synthesis of Yaku’amide A or B [10]. However,
in our case the yield was discouraging (Entry 4, 43%). This result is
reminiscent of their experience, namely, “amounts of the reagents,
solvent, and concentration had to be carefully tuned to obtain high-
yielding transformations”.
b
conditions by further screening various solvents and bases (Entries
5-e8). Initial experiments showed that DMSO and methyl t-butyl
ether (MTBE) appeared to be suitable solvents, especially MTBE,
with which a much improved yield of 84% was observed (Entry 8).
However, efforts toward further improving the reaction by varying
base and temperature were not fruitful (Entries 8e11). To our
surprise, when the solvent was switched to 1,2-dimethoxyethane
(DME), the conversion became almost quantitative at 55 ꢀC with
an isolated yield of 92% (Entry 12). It was further noticed that the
reaction was not sensitive to the temperature from 45 to 65 ꢀC
when carried out overnight (Entries 12e14). A control experiment
indicated that use of ligand DMEDA was required for the reaction,
suggesting DME not playing any role as a ligand (Entry 15) [22].
Interestingly, with DME the reaction was also found insensitive to
residual water (Entry 16). Even the commercially obtained DME
worked well without pre-treatment for drying, and still gave sus-
tained high yields, implying a user-friendly feature for easy adop-
tion. The specific mechanism of how DME enhanced the coupling
reaction still needs to be explained and may merit a separate study
in the future. That being said, we have reasons to believe that the
enhancement is likely caused by the Csþ ion complexing property
of DME. In a study by Carvajal et al. [38], Csþ ion coordinated with
DME but not with THF. Such complexing plus a just-right polarity of
DME would lead to increased solubility of the inorganic base and
the corresponding amides, therefore, a favorable effect on the
oxidative addition step in the coupling reaction.
Having established the optimal reaction condition, we then
explored the substrate scope. The results are summarized in
Table 2. First, a series of Boc-protected amino acids (1a-g) were
tested to couple with 2a. All of them gave excellent yields using
DME as solvent (3aa-3ga: around 90%). For comparsion and further
verification, some of the reactions were run in parallel with DME
being replaced by DMSO or MTBE as solvent. In such cases, the
reactions in DMSO (3aa, 3ba and 3ga) and MTBE (3aa, 3da and 3ea)
Not satisfied with the yield, we set out to optimize the reaction
2

L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
Table 2
produced much lower yields.
The substrate scope: the amides of protected amino acids and vinyl iodides.
Next, several other vinyl iodides were examined. Coupling re-
action of 2b or 2c with 2a afforded consistently high yields (3 ab,
3ac). Notably, the C]C bond in 3ac did not isomerize under the
reaction conditions. In order to scrutinize the stereospecificity of
the coupling reaction, we prepared (Z)- and (E)-vinyl iodide (2d and
2e) according to a previously reported method [39,40]. When
2d or 2e were coupled with 1e under the current improved
condition, both reactions proceeded to afford the corresponding
product in excellent yields (3ed or 3ee) with full configuration
retention. These results indicated that the reaction underwent in a
stereospecific manner.
Encouraged by the above achievements, we then attempted to
apply the improved coupling reaction for preparation of the target
plocabulin according to the reported approach [15]. The synthetic
route was depicted in Scheme 1. In the original approach [15], the
enantiomerically pure epoxide (7) was prepared from racemic 7 by
Jacobsen’s hydrolytic kinetic resolution, while the other isomer was
abandoned. To overcome this shortcoming, we prepared the opti-
cally active epoxide 7 according to the modified Rapoport’s protocol
[41].
Compound 7 could be easily obtained in about 55% yield
through a 3-step sequence. Starting from (S)-aspartic acid 4, the
bromo di-acid 5 was prepared by treatment with sodium nitrite in
hydrobromide aqueous solution, which was then reduced to the
diol 6 with diborane in THF. In the presence of an excess amount of
NaH, 6 was easily converted into the epoxide, and concurrently
trapped by TBSCl, resulting in the protected epoxide 7.
The epoxide was subjected to ring opening by treatment with
prop-1-yn-1-yl lithium in the presence of BF3$OEt2, affording the
homopropargyl alcohol 8 in 85% yield. After protection of the hy-
droxyl group in 8 with TBDPS group, the alkyne bond within the
resultant OH-TBDPS protected 9 was stereoselectively reduced to
the cis-alkene 10 quantitatively through Lindlar catalytic hydroge-
nation in ethyl acetate. After that, careful treatment of 10 with PPTS
in ethanol released the primary alcohol 11, which was subsequently
subjected to oxidation under the Piancatelli’s condition [42] in the
presence of BAIB (PhI(OAc)2) and a catalytic amount of TEMPO
(2,2,6,6-tetramethylpiperidinin-1-yl)oxyl), affording aldehyde 12
in 82% yield. Wittig reaction of 12 with the ylide solution in situ
prepared from (Ph3PCH2I)þIꢁ salt and KHMDS in anhydrous THF
successfully furnished vinyl iodide 13 in 82% yield.
With intermediate 13 in hand, the construction of enamide
moiety was then undertaken. As illustrated in Scheme 1, Boc-tBu-
Gly-NH2 (1e) and (Z)-vinyl iodide (13) were allowed to react under
our improved copper-catalytic coupling reaction conditions. The
reaction proceeded smoothly to provide the desired enamide
product 14 in 85% yield. This yield was remarkably increased as
compared to that of the original coupling reaction (85% vs 44%), a
good demonstration of the utility of our coupling reaction in syn-
thesizing enamide-containing biologically active molecules. In
addition, Cbz-tBu-Gly-NH2 (1h, Entry 12 in Table 2) gave the almost
same result as 1e.
With Compound 14 readily made in sufficient quantity, the
synthesis of plocabulin was completed according to previously re-
ported method [15] and is described in the following. Because of
the acidic sensitivity of TBDPS group, the selective removal of the
Boc group in 14 had to be performed by employing pyrolysis con-
dition. To this end, a solution of 14 in ethylene glycol was heated at
200 ꢀC for a short time (about 15 min), producing the amine 15 in
72% yield. To avoid the possible epimerization, condensation of the
optically active 15 with (Z)-3-(tributylstannyl) acrylic acid was
carried out in the HOAt/HATU/DIPEA system, which was routinely
used in peptide synthesis, leading to 17 in 91% yield. The vinyl io-
dide 18 [15] was coupled with the stannane 17 under Liebeskind
3

L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
Scheme 1. The synthesis of plocabulin. Reagents and conditions: (a) KBr, NaNO2, H2SO4, ꢁ5 ꢀC, 2 h, 89%. (b) BH3$THF, THF, 25 ꢀC, 18 h, 96%. (c) NaH, TBSCl, 25 ꢀC, 18 h, 64%. (d)
Propyne, n-BuLi, BF3$Et2O, THF, ꢁ78 ꢀC, 1 h, 85%. (e) TBDPSCl, DMAP, DCM, 25 ꢀC, 18 h, 91%. (f) H2, quinoline, lindlar catalyst, EtOAc, 25 ꢀC, 7 h, 97%. (g) PPTS, EtOH, 25 ꢀC, 7 h, 98%. (h)
BAIB, TEMPO, DCM, 25 ꢀC, 18 h, 82%. (i) Ph3Pþ-CH2I Iꢁ, KHMDS, THF, ꢁ78 ꢀC, 90 min, 82%. (j) Boc-t-Bu-Gly-NH2, CuI, Cs2CO3, DMEDA, DME, 55 ꢀC, 18 h, 85%. (k) Ethyleneglycol,
200 ꢀC, 15 min, 72%. (l) 16, DIPEA, HOAt, HATU, DCM, DMF, 0 ꢀC, 30 min, 91%. (m) 18, copper(I) thiophene-2-carboxylate (CuTc), NMP, 25 ꢀC, 18 h, 73%. (n) TBAF, THF, 25 ꢀC, 60 min,
66%. (o) (i) Trichloroacetyl isocyanate, DCM, 0 ꢀC, 30 min; (ii) Al2O3, 0 ꢀC, 30 min, 68%.
condition [43], smoothly providing 19 in 73% yield. Upon treating
with TBAF in THF, the TBDPS group in 19 was removed to release
the corresponding alcohol 20. Compound 20 was then carbonated
with trichloroacetyl isocyanate in CH2Cl2 followed by removal of
the trichloroacetyl group through treatment with neutral alumina,
yielding the target plocabulin with an overall yield of 45% in the last
three steps.
appropriately. Concentration of solutions in vacuo was accom-
plished using a rotary evaporator fitted with a water aspirator.
Residual solvents were removed under high vacuum (0.1e0.2 mm
Hg). The progress of the reactions was monitored by TLC (silica-
coated glass plates) and visualized under UV light, and by using
iodine, ceric ammonium molybdate stain or phosphomolybdic acid.
1H NMR and 13C NMR spectra were recorded either on a 400 MHz
Varian Instrument at 25 ꢀC or 600 MHz Bruker Instrument at 25 ꢀC,
using TMS as an internal standard, respectively. Multiplicity is
tabulated as s for singlet, d for doublet, dd for doublet of doublet, t
for triplet, and m for multiplet. Coupling constants (J) are reported
in Hertz. 13C NMR spectra were completely hetero-decoupled and
measured at 150 MHz. HRMS spectra were recorded on Finnigan-
Mat-95 mass spectrometer, equipped with ESI source.
3. Conclusion
In summary, we have developed an efficient copper-catalyzed
cross-coupling reaction of amino acid-derived amides and (Z)-vi-
nyl iodide, where the solvent effect has demonstrated to be a
pivotal factor. Using DME as solvent, the reaction furnished a series
of enamide products with consistently high yields and full preser-
vation of the vinyl stereo-configuration. The method displayed
wide substrate scope and has been utilized to successfully improve
the key step for the total synthesis of plocabulin. The study on an
evolutionary approach to plocabulin and its extensive biological
activities is in progress, and will be reported in due course.
4.2. General procedure of condition A in the coupling reaction
A resealable Schlenk tube was charged with vinyl iodide
(0.5 mmol, 1.0 eq.) and amide (1.0 mmol, 2.0 eq.), evacuated and
backfilled with N2. 1,2-dimethoxyethane (DME) (6.0 mL), Cs2CO3
(326 mg, 1.0 mmol, 2.0 eq.), N,N0-dimethylethylene-diamine
4. Experimental
(DMEDA) (32 mL, 0.30 mmol, 0.6 eq.) and CuI (29 mg, 0.15 mmol, 0.3
eq.) were added under N2. The Schlenk tube was sealed with a
Teflon valve, immersed in a preheated oil bath; the reaction
mixture was stirred at 55 ꢀC overnight. The reaction vessel was
removed from the oil bath and the resulting pale tan suspension
was allowed to reach rt, then, it was filtered over Celite, eluting
with ethyl acetate (20 mL). The filtrate was concentrated and the
residue was purified by column chromatography on silica gel (PE/
EA) to afford the desired product. While some vinyl iodides with
inseparable (Z)- and (E)-isomers were used, the corresponding (Z)-
and (E)-coupling products were easy to isolate by column chro-
matography on silica gel.
4.1. General information
The chemicals and reagents were purchased from Acros, Alfa
Aesar, and National Chemical Reagent Group Co. Ltd., P. R. China,
and used as received without further purification. Anhydrous sol-
vents (THF, MeOH, DMF, DCM, and CH3CN) used in the reactions
were dried and freshly distilled before use. Petroleum ether (PE)
used had a boiling range of 60e90 ꢀC. All the reactions were carried
out under N2 atmosphere, unless otherwise stated. Oxygen and/or
moisture sensitive solids and liquids were transferred
4

L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
4.3. Synthetic studies
4.3.4. (Z)-Tert-butyl((4-iodo-3-methylbut-3-en-1-yl)oxy)
dimethylsilane (2d)
4.3.1. 1-Iodooct-1-ene (2a)
In a 250 mL round-bottom flask purged and maintained with an
inert atmosphere of N2, was placed ZrCp2Cl2 (1.10 g, 3.75 mmol,
0.25 eq.) followed by the addition of 1,2-dichloroethane (DCE)
(50 mL), and the resultant solution was allowed to stir for 30 min at
rt. To this solution was added AlMe3 (2.0 M in hexane, 22.5 mL,
45.0 mmol, 3.0 eq.) at 0 ꢀC, followed by the addition of alkyne 3-
butyn-1-ol (1051 mg, 15.0 mmol, 1.0 eq.) in DCE (5.2 mL) and
then the reaction was allowed to stir for 18 h at rt. The solution was
then heated to 86 ꢀC and gently refluxed for 4 days. After the
allotted reaction time, the solution was cooled to ꢁ30 ꢀC and then I2
(5.71 g, 22.5 mmol, 1.5 eq.) in THF (30 mL) was added and the re-
action was further stirred for 30 min at rt. The reaction mixture was
then quenched by the addition of half sat. aq. K2CO3 (100 mL), then
it was filtered over Celite, eluting with EA (100 mL). The aqueous
phase was extracted with EA (2 ꢂ 100 mL).The combined organic
phases were concentrated and the residue was purified by column
chromatography on silica gel (PE/EA) affording (Z)-4-Iodo-3-
methylbut-3-en-1-ol as a yellow oil (1394 mg, 44%). 1H NMR
To a suspension of iodomethyl triphenylphosphonium iodide
(15.9 g, 30.0 mmol, 1.2 eq.) in anhydrous THF (160 mL) at 0 ꢀC, a
solution of potassium hexamethyldisilazane (KHMDS) (1.0 M in
THF, 30.0 mL, 30.0 mmol, 1.2 eq.) was slowly added over a period of
10 min. After stirring for an additional 5 min, the solution was
cooled to ꢁ78 ꢀC and then 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU) (7.5 mL, 62.0 mmol, 2.5 eq.) was added,
followed by the addition of heptaldehyde (2.85 g, 25.0 mmol, 1.0
eq.) dissolved in THF (30 mL). The temperature was kept at ꢁ78 ꢀC
while the reaction mixture was stirred for 30 min. Then the reac-
tion system was allowed to warm up to 0 ꢀC in 1 h. When the re-
action was completed, the reaction mixture was quenched with sat.
aq. NaHCO3 and extracted with petroleum ether. The organic layer
was collected and concentrated. Column chromatography gave the
product (4.77 g, 57% yield). The Z/E isomer ratio (Z/E ¼ 87 : 13) was
determined by 1H NMR analysis. Major peaks in 1H NMR (600 MHz,
CDCl3)
d
: 6.20e6.13 (m, 2H), 2.17e2.09 (m, 2H), 1.47e1.19 (m, 8H),
: 141.5, 82.1, 34.7,
0.92e0.84 (m, 3H). 13C NMR (150 MHz, CDCl3)
d
(600 MHz, CDCl3)
d
: 6.00 (q, 1H, J ¼ 1.8 Hz), 3.77 (t, 2H, J ¼ 6.6 Hz),
31.7, 28.8, 27.9, 22.59, 14.1. The spectra data were in agreement with
the literature [44].
2.53 (t, 2H, J ¼ 6.6 Hz), 1.95 (d, 3H, J ¼ 1.8 Hz), 1.84 (br s, 1H).
To a solution of (Z)-vinyl iodide (1.39 g, 6.57 mmol, 1.0 eq.) in
DMF (35 mL), TBSCl (1.29 g, 8.55 mmol, 1.3 eq.) and imidazole
(895 mg, 13.1 mmol, 2.0 eq.) was added at 0 ꢀC, then the reaction
was allowed to warm to rt and stirred overnight. The reaction was
quenched with half sat. aq. NaHCO3 (100 mL) and the mixture was
extracted with PE/EA (v/v 1:2, 100 mL). After washed with water
(2 ꢂ 65 mL), the organic layers were concentrated and the residue
was purified by column chromatography on silica gel (PE/EA)
affording the desired product 2d as a colorless oil (2109 mg, 98%).
4.3.2. (2-Iodovinyl)benzene (2b)
To a suspension of iodomethyl triphenylphosphonium iodide
(6.36 g, 12.0 mmol, 1.2 eq.) in anhydrous THF (65 mL) at 0 ꢀC, a
solution of KHMDS in THF (1.0 M, 12.0 mL, 12.0 mmol, 1.2 eq.) was
slowly added. After stirring for an additional 5 min, the solution
was cooled to ꢁ78 ꢀC and then DMPU (3.2 mL, 26.5 mmol, 2.7 eq.)
was added, followed by the addition of benzaldehyde (1.06 g,
10.0 mmol, 1.0 eq.) dissolved in anhydrous THF (12 mL). The tem-
perature was kept at ꢁ78 ꢀC while the reaction mixture was stirred
for 30 min. Then the reaction system was allowed to warm up to
1H NMR (600 MHz, CDCl3)
J ¼ 7.2 Hz), 2.44 (t, 2H, J ¼ 7.2 Hz), 1.93 (d, 3H, J ¼ 1.2 Hz), 0.90 (s,
9H), 0.075 (s, 6H). The spectra data were in agreement with those
reported in the literature [39].
d
: 5.92 (q, 1H, J ¼ 1.2 Hz), 3.71 (t, 2H,
0
ꢀC. When the reaction was completed, the reaction mixture was
4.3.5. (E)-Tert-butyl((4-iodo-3-methylbut-3-en-1-yl)oxy)
dimethylsilane (2e)
quenched with sat. aq. NaHCO3 and extracted with PE. The organic
layers were collected and concentrated. Column chromatography
gave the product (1.39 g, 60% yield). The Z/E isomer ratio (Z/E ¼ 80 :
20) was determined by 1H NMR analysis. Major peaks in 1H NMR
In a 250 mL round-bottom flask purged and maintained with an
inert atmosphere of N2, was placed ZrCp2Cl2 (1.10 g, 3.75 mmol,
0.25 eq.) followed by the addition of DCM (52.5 mL) and the
resultant solution was allowed to stir for 30 min at rt. To this so-
lution was added AlMe3 (2.0 M in hexane, 22.5 mL, 45.0 mmol, 3.0
eq.) at 0 ꢀC, followed by the addition of 3-butyn-1-ol (1051 mg,
15.0 mmol, 1.0 eq.) in DCM (5.2 mL) and then the reaction was
allowed to stir for 18 h at rt. After the allotted reaction time, the
solution was cooled to ꢁ30 ꢀC and then I2 (5.71 g, 22.5 mmol, 1.5
eq.) in THF (30 mL) was added and the reaction was continuously
stirred for 30 min at rt. The reaction mixture was then quenched by
the addition of half sat. aq. K2CO3 (100 mL), then it was filtered over
Celite, eluting with EA (100 mL). The aqueous phase was extracted
with EA (2 ꢂ 100 mL). The combined extracts were concentrated
and the residue was purified by column chromatography on silica
(600 MHz, CDCl3) d: 7.69e7.64 (m, 2H), 7.45e7.31 (m, 4H), 6.61 (d,
1H, J ¼ 8.4 Hz). The spectra data were in agreement with those
reported in the literature [45].
4.3.3. (3-Iodoallyl)benzene (2c)
To a suspension of iodomethyl triphenylphosphonium iodide
(6.36 g, 12.0 mmol, 1.2 eq.) in THF (65 mL) at 0 ꢀC, a solution of
KHMDS (1.0 M in THF,12.0 mL,12.0 mmol,1.2 eq.) was slowly added
over a period of 10 min. After stirring for an additional 5 min, the
solution was cooled to ꢁ78 ꢀC and DMPU (3.2 mL, 26.5 mmol, 2.7
eq.) was then added, followed by the addition of phenyl-
acetaldehyde (1.20 g, 10.0 mmol, 1.0 eq.) dissolved in THF (12 mL).
The temperature was kept at ꢁ78 ꢀC while the reaction mixture
was stirred for 30 min. Then the reaction system was allowed to
warm up to 0 ꢀC over 1 h. When the reaction was completed, the
reaction mixture was quenched with sat. aq. NaHCO3 and extracted
with petroleum ether. The organic layers were collected and
concentrated. Column chromatography gave the product (1.03 g,
42% yield). The Z/E isomer ratio (Z/E ¼ 84 : 16) was determined by
gel (PE/EA) affording (E)-4-iodo-3-methylbut-3-en-1-ol as
a
colorless oil (2.37 g, 75%). 1H NMR (600 MHz, CDCl3)
d
: 6.02 (q, 1H,
J ¼ 1.2 Hz), 3.72 (t, 2H, J ¼ 6.0 Hz), 2.48 (td, 2H, J ¼ 6.6, 0.6 Hz), 1.88
(d, 3H, J ¼ 1.2 Hz).
To a solution of (E)-vinyl iodide (2.37 g, 11.2 mmol, 1.0 eq.) in
DMF (55 mL), TBSCl (2.19 g, 14.5 mmol, 1.3 eq.) and imidazole
(1.52 g, 22.4 mmol, 2.0 eq.) was added at 0 ꢀC, then the reaction was
allowed to warm to rt. and stirred overnight. The reaction was
quenched with half sat. aq. NaHCO3 (170 mL) and the mixture was
extracted with PE: EA 1:2 (170 mL). After washed with water
(2 ꢂ 110 mL), the organic layers were concentrated and the residue
was purified by column chromatography on silica gel (PE/EA) to
1H NMR analysis. Major peaks in 1H NMR (600 MHz, CDCl3)
d:
7.33e7.19 (m, 5H), 6.39e6.32 (m, 2H), 3.54e3.46 (m, 2H). The
spectra data were in agreement with those reported in the litera-
ture [46].
5

L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
afford the desired product 2e as a colorless oil (3.10 g, 85%). 1H NMR
(m, 8H), 0.88 (t, 3H, J ¼ 6.6 Hz). 13C NMR (150 MHz, CDCl3)
d: 171.4,
(400 MHz, CDCl3)
J ¼ 6.8 Hz), 1.85 (s, 3H), 0.88 (s, 9H), 0.038 (s, 6H). The spectra data
d
: 5.93 (s, 1H), 3.69 (t, 2H, J ¼ 6.8 Hz), 2.42 (t, 2H,
155.9, 121.2, 111.7, 80.6, 67.3, 36.6, 31.7, 30.3, 29.4, 29.0, 28.3, 25.9,
22.6, 14.1. HRMS (m/z): 361.2462 [MþNa]þ (C19H34N2O3), required
361.2462.
were in agreement with those reported in the literature [40].
4.3.6. Compound 3 in Table 2
4.3.6.7. Tert-butyl
(S,Z)-(2-(oct-1-en-1-ylamino)-2-oxo-1-phenyl-
4.3.6.1. Tert-butyl
(Z)-(2-(oct-1-en-1-ylamino)-2-oxoethyl)carba-
ethyl)carbamate (3ga). Rf ¼ 0.35 (PE: EA ¼ 10 : 1). 1H NMR
mate (3aa). Rf ¼ 0.51 (PE: EA ¼ 2 : 1). 1H NMR (600 MHz, CDCl3)
d
:
(600 MHz, CDCl3) d: 7.52 (s, 1H), 7.40e7.29 (m, 5H), 6.63 (m, 1H),
8.32 (s, 1H), 6.64 (dd, 1H, J ¼ 10.2, 9.6 Hz), 5.70 (s, 1H), 4.77 (dt, 1H,
J ¼ 7.8, 7.2 Hz), 3.83 (d, 2H, J ¼ 6.0 Hz), 2.06e1.97 (m, 2H), 1.46 (s,
9H), 1.42e1.23 (m, 8H), 0.88 (t, 3H, J ¼ 6.6 Hz). 13C NMR (150 MHz,
5.88 (s, 1H), 5.26 (s, 1H), 4.76 (dt, 1H, J ¼ 7.2, 7.2 Hz), 1.93e1.74 (m,
2H), 1.41 (s, 9H), 1.32e1.13 (m, 8H), 0.87 (t, 3H, J ¼ 6.6 Hz). 13C NMR
(150 MHz, CDCl3) d: 167.6, 155.4, 137.7, 129.1, 128.5, 127.0, 120.4,
CDCl3)
d
: 167.5, 156.8, 120.3, 112.8, 80.5, 44.8, 31.7, 29.3, 28.9, 28.3,
113.0, 80.3, 58.6, 31.6, 29.1, 28.8, 28.3, 25.6, 22.6, 14.1. HRMS (m/z):
25.8, 22.6, 14.1. HRMS (m/z): 307.1994 [MþNa]þ (C15H28N2O3),
383.2307 [MþNa]þ (C21H32N2O3), required 383.2305.
required 307.1992.
4.3.6.8. Tert-butyl (Z)-(2-oxo-2-(styrylamino)ethyl)carbamate (3ab).
4.3.6.2. Tert-butyl
(S,Z)-(1-(oct-1-en-1-ylamino)-1-oxo-3-phenyl-
Rf ¼ 0.53 (PE: EA ¼ 2 : 1). 1H NMR (600 MHz, CDCl3)
d: 8.51 (s, 1H),
propan-2-yl)carbamate (3ba). Rf ¼ 0.33 (PE: EA ¼ 10 : 1). 1H NMR
7.39e7.33 (m, 2H), 7.30e7.20 (m, 3H), 6.90 (dd, 1H, J ¼ 10.8,
10.2 Hz), 5.77 (d, 2H, J ¼ 9.6 Hz), 5.33 (s, 1H), 3.82 (d, 2H, J ¼ 5.4 Hz),
(600 MHz, CDCl3) d: 7.50 (s, 1H), 7.33e7.27 (m, 2H), 7.26e7.19 (m,
3H), 6.59 (dd, 1H, J ¼ 9.6, 9.6 Hz), 5.20 (s, 1H), 4.71 (dt, 1H, J ¼ 7.8,
7.2 Hz), 4.38 (s, 1H), 3.18e2.99 (m, 2H), 1.80e1.69 (m, 2H), 1.42 (s,
9H), 1.32e1.18 (m, 8H), 0.88 (t, 3H, J ¼ 7.2 Hz). 13C NMR (150 MHz,
1.41 (s, 9H). 13C NMR (150 MHz, CDCl3)
d: 167.6, 156.3, 135.4, 129.0,
127.9, 127.0, 121.2, 111.0, 80.6, 44.7, 28.2. HRMS (m/z): 299.1369
[MþNa]þ (C15H20N2O3), required 299.1366.
CDCl3) d: 168.5, 155.8, 136.7, 129.3, 128. 8, 127.0, 120.1, 112.8, 80.4,
55.9, 38.1, 31.6, 29.2, 28.9, 28.3, 25.5, 22.6, 14.1. HRMS (m/z):
4.3.6.9. Tert-butyl (Z)-(2-oxo-2-((3-phenylprop-1-en-1-yl)amino)-
397.2464 [MþNa]þ (C22H34N2O3), required 397.2462.
ethyl)carbamate (3ac). Rf ¼ 0.45 (PE: EA ¼ 2 : 1). 1H NMR (600 MHz,
CDCl3) d: 8.33 (br s, 1H), 7.32e7.26 (m, 2H), 7.24e7.16 (m, 3H), 6.78
4.3.6.3. Tert-butyl
no)-1-oxopropan-2-yl)carbamate (3ca). Rf ¼ 0.30 (PE: EA ¼ 10 : 1).
1H NMR (600 MHz, CDCl3)
(S,Z)-(3-(4-chlorophenyl)-1-(oct-1-en-1-ylami-
(dd, 1H, J ¼ 9.6, 9.6 Hz), 5.38 (br s, 1H), 5.00 (m, 1H), 3.80 (d, 2H,
J ¼ 5.4 Hz), 3.39 (d, 2H, J ¼ 7.8 Hz), 1.44 (s, 9H). 13C NMR (150 MHz,
d: 7.88 (s,1H), 7.25 (d, 2H, J ¼ 8.4 Hz), 7.15
CDCl3) d: 167.4, 156.7, 139.6, 128.7, 128.2, 126.3, 121.4, 110.5, 80.7,
(d, 2H, J ¼ 7.8 Hz), 6.58 (dd, 1H, J ¼ 9.6, 9.6 Hz), 5.41 (d, 1H,
J ¼ 7.8 Hz), 4.74 (dt, 1H, J ¼ 7.8, 7.2 Hz), 4.41 (s, 1H), 2.95e3.14 (m,
2H), 1.89e1.78 (m, 2H), 1.41 (s, 9H), 1.34e1.19 (m, 8H), 0.88 (t, 3H,
44.8, 31.9, 28.3. HRMS (m/z): 313.1520 [MþNa]þ (C16H22N2O3),
required 313.1523.
J ¼ 7.2 Hz). 13C NMR (150 MHz, CDCl3)
d
: 168.7, 155.9, 135.3, 132.8,
4.3.6.10. Tert-butyl (S,Z)-(1-((4-((tert-butyldimethylsilyl)oxy-2-
methylbut-1-en-1-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carba-
130.7, 128.8, 120.1, 113.2, 80.5, 55.7, 37.4, 31.7, 29.2, 28.9, 28.3, 25.6,
22.6, 14.1. HRMS (m/z): 431.2069 [MþNa]þ (C22H33N2O3Cl),
required 431.2072.
mate (3ed). Rf ¼ 0.48 (PE: EA ¼ 10 : 1). ½a D20
þ22.6 (c ¼ 1.0, CHCl3).
ꢃ
1H NMR (600 MHz, CDCl3)
d
: 7.95 (d, 1H, J ¼ 8.4 Hz), 6.55 (d, 1H,
J ¼ 9.0 Hz), 5.33 (d, 1H, J ¼ 8.4 Hz), 3.84 (d, 1H, J ¼ 9.6 Hz), 3.79 (m,
1H), 3.70 (m, 1H), 2.33 (m, 1H), 2.14 (m, 1H), 1.72 (s, 3H), 1.43 (s, 9H),
1.00 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.083 (s, 3H). 13C NMR
4.3.6.4. Tert-butyl (S,Z)-(1-(oct-1-en-1-ylamino)-1-oxopropan-2-yl)
carbamate (3da). Rf ¼ 0.46 (PE: EA ¼ 5 : 1). 1H NMR (600 MHz,
CDCl3)
d
: 8.32 (s, 1H), 6.64 (dd,1H, J ¼ 10.8, 9.0 Hz), 5.29 (s,1H), 4.75
(150 MHz, CDCl3) d: 168.3, 155.5, 119.4, 118.8, 79.4, 62.4, 62.1, 34.9,
(dt, 1H, J ¼ 7.8, 7.8 Hz), 4.26 (s, 1H), 2.07e1.95 (m, 2H), 1.46 (s, 9H),
34.9, 28.3, 26.6, 26.1, 21.0, 18.6, ꢁ5.2. HRMS (m/z): 451.2963
1.38 (d, 3H, J ¼ 7.2 Hz), 1.41e1.21 (m, 8H), 0.88 (t, 3H, J ¼ 7.2 Hz). 13
C
[MþNa]þ (C22H44N2O4Si), required 451.2963.
NMR (150 MHz, CDCl3) d: 170.1, 156.2, 120.6, 112.5, 80.4, 49.8, 31.7,
29.3, 28.9, 28.3, 25.8, 22.6, 17.2, 14.1. HRMS (m/z): 321.2149
4.3.6.11. Tert-butyl (S,E)-(1-((4-((tert-butyldimethylsilyl)oxy)-2-
methylbut-1-en-1-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carba-
[MþNa]þ (C16H30N2O3), required 321.2149.
(E)-3da: Rf ¼ 0.32 (PE: EA ¼ 5 : 1). 1H NMR (600 MHz, CDCl3):
7.75 (s, 1H), 6.68 (dd, 1H, J ¼ 13.8, 10.8 Hz), 5.19 (dt, 1H, J ¼ 14.4,
7.2 Hz), 5.07 (s, 1H), 4.19 (s, 1H), 2.04e1.96 (m, 2H), 1.45 (s, 9H), 1.37
(d, 3H, J ¼ 7.2 Hz),1.41e1.22 (m, 8H), 0.88 (t, 3H, J ¼ 7.2 Hz). 13C NMR
mate (3ee). Rf ¼ 0.36 (PE: EA ¼ 10 : 1). ½a D20
þ15.7 (c ¼ 1.0, CHCl3).
ꢃ
1H NMR (600 MHz, CDCl3)
d
: 7.17 (d, 1H, J ¼ 9.0 Hz), 6.54 (d, 1H,
J ¼ 10.2 Hz), 5.32 (d, 1H, J ¼ 7.2 Hz), 3.90 (d, 1H, J ¼ 9.0 Hz), 3.66 (t,
1H, J ¼ 7.2 Hz), 2.22 (t, 1H, J ¼ 7.2 Hz), 1.64 (s, 3H), 1.43 (s, 9H), 1.01
(150 MHz, CDCl3)
d: 169.7, 155.8, 122.0, 114.5, 80.4, 50.0, 31.7, 29.75,
(s, 9H), 0.88 (s, 9H), 0.036 (s, 6H). 13C NMR (150 MHz, CDCl3)
d:
29.72, 28.8, 28.3, 22.6, 18.0, 14.1.
168.0, 117.9, 117.0, 79.9, 62.4, 62.2, 40.0, 34.5, 28.3, 26.5, 25.9, 18.3,
15.3, ꢁ5.3. HRMS (m/z): 429.3144 [MþH]þ (C22H44N2O4Si), required
429.3143.
4.3.6.5. Tert-butyl (S,Z)-(3,3-dimethyl-1-(oct-1-en-1-ylamino)-1-
oxobutan-2-yl)carbamate (3ea). Rf ¼ 0.50 (PE: EA ¼ 10 : 1). 1H
NMR (600 MHz, CDCl3)
d
: 7.41 (d, 1H, J ¼ 10.2 Hz), 6.65 (dd, 1H,
4.3.6.12. Benzyl
((S)-1-(((S,1Z,6Z)-4-((tert-butyldiphenylsilyl)oxy)
J ¼ 10.2, 9.6 Hz), 5.40 (d, 1H, J ¼ 9.0 Hz), 4.77 (dt, 1H, J ¼ 7.8, 7.8 Hz),
3.95 (d, 1H, J ¼ 9.0 Hz), 2.02e1.93 (m, 2H), 1.43 (s, 9H), 1.41e1.20 (m,
8H), 1.02 (s, 9H), 0.89 (t, 3H, J ¼ 6.6 Hz). 13C NMR (150 MHz, CDCl3)
-octa-1,6-dien-1-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carba-
mate (3h). ½a 2D0
ꢃ
þ7.3 (c ¼ 1.0, CHCl3). 1H NMR (600 MHz, CDCl3)
d:
7.71e7.64 (m, 4H), 7.46e7.27 (m, 11H), 7.02 (d, 1H, J ¼ 10.2 Hz), 6.66
(dd, 1H, J ¼ 10.2, 9.0 Hz), 5.54 (d, 1H, J ¼ 9.0 Hz), 5.51 (m, 1H), 5.33
(m, 1H), 5.09 (d, 2H, J ¼ 9.0 Hz), 4.82 (dt, 1H, J ¼ 9.0, 7.8 Hz), 3.88 (d,
1H, J ¼ 9.6 Hz), 3.85 (m, 1H), 2.29e1.99 (m, 4H), 1.44 (d, 3H,
d
: 168.4, 156.0, 120.2, 112.7, 79.8, 62.4, 34.6, 31.7, 29.3, 28.9, 28.3,
26.5, 25.8, 22.6, 14.1. HRMS (m/z): 363.2617 [MþNa]þ (C19H36N2O3),
required 363.2618.
J ¼ 6.6 Hz), 1.06 (s, 9H), 0.96 (s, 9H). 13C NMR (150 MHz, CDCl3)
d:
4.3.6.6. Tert-butyl
(Z)-(1-(oct-1-en-1-ylcarbamoyl)cyclopsentyl)
167.9, 156.3, 136.2, 135.9, 134.1, 129.8, 129.7, 128.5, 128.2, 128.1,
127.63, 127.60, 126.5, 125.9, 121.6, 108.7, 72.4, 67.1, 62.9, 34.8, 33.8,
32.5, 27.0, 26.4, 19.3, 13.0. HRMS (m/z): 627.3616 [MþH]þ
(C38H50N2O4Si), required 627.3613.
carbamate (3fa). Rf ¼ 0.25 (PE: EA ¼ 10 : 1). 1H NMR (600 MHz,
CDCl3)
d
: 8.96 (s, 1H), 6.67 (m, 1H), 4.77 (s, 1H), 4.73 (dt, 1H, J ¼ 7.8,
7.2 Hz), 2.24e2.38 (m, 2H), 2.08e1.67 (m, 8H),1.45 (s, 9H),1.41e1.23
6

L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
4.3.7. (S)-2-Bromosuccinic acid (5)
dropwise followed by addition of BF3$Et2O (5.1 mL, 40.3 mmol, 2.0
eq). The mixture was stirred for 1 h at ꢁ78 ꢀC and for an additional
hour at 0 ꢀC. The reaction mixture was quenched with half sat. aq.
NH4Cl (50 mL) and extracted with EA/MTBE 1: 1 (3 ꢂ 50 mL). The
combined organic layers were concentrated and the residue was
purified by column chromatography on silica gel (PE/EA) to furnish
the desired product 8 as a colorless oil (4.16 g, 85%). Rf ¼ 0.25 (PE:
A 500 mL 3-necked round-bottomed flask (charged with 2
washing bottles connected in series with the first one empty and
the second one filled with 2 M NaOH) was charged with aspartic
acid 4 (13.3 g, 100 mmol, 1.00 eq.) and KBr (51.4 g, 432 mmol, 4.32
eq.). An aq. solution of H2SO4 (2.5 M, 212 mL) was added in one
portion and then the solution was cooled to ꢁ 5 ꢀC. A solution of
sodium nitrite (11.9 g,172 mmol,1.72 eq.) in H2O (28 mL) was added
with careful temperature monitoring, such that the reaction tem-
perature was maintained below 0 ꢀC. After completion of the
addition of NaNO2 the resulting dark brown reaction mixture was
stirred for 2 h at ꢁ5 ꢀC and then extracted with EA (2 ꢂ 140 mL).
The combined organic extracts were washed with half sat. aq. NaCl
(140 mL), then dried over Na2SO4 and concentrated under reduced
pressure to yield the desired product 5 as a white solid that was
used in the next step without further purification (17.5 g, 89%).
Rf ¼ 0.15 (PE: EA: EtOH ¼ 6 : 6: 1).
EA ¼ 20 : 1). 1H NMR (600 MHz, CDCl3)
d: 3.98e3.87 (m, 2H), 3.83
(m, 1H), 3.46 (br s, 1H), 2.42e2.27 (m, 2H), 1.80, (t, 3H, J ¼ 2.4 Hz),
1.83e1.69 (m, 2H), 0.90 (s, 9H), 0.08 (s, 6H). 13C NMR (150 MHz,
CDCl3)
d
: 77.7, 75.6, 70.6, 62.3, 37.4, 27.5, 25.9, 18.1, 3.6, ꢁ5.5, ꢁ5.6.
HRMS (m/z): 243.1776 [MþH]þ (C13H26O2Si), required 243.1775.
4.3.11. (S)-5-(But-2-yn-1-yl)-2,2,9,9,10,10-hexamethyl-3,3-
diphenyl-4,8-dioxa-3,9-disilaundecane (9)
To a cooled (0 ꢀC) solution of alcohol 8 (5.05 g, 20.8 mmol, 1.0
eq.), imidazole (3.33 g, 48.9 mmol, 2.4 eq.) and 4-(dimethylamino)
pyridine (DMAP) (127 mg, 1.04 mmol, 0.05 eq.) in DCM (126 mL),
tert-butyldiphenylsilyl chloride (TBDPSCl) (12.2 mL, 46.8 mmol, 2.3
eq.) was added, then the suspension was stirred at rt overnight. The
mixture was quenched with sat. aq. NH4Cl (55 mL) and extracted
with MTBE (2 ꢂ 55 mL). The combined organic layers were
concentrated and the residue was purified by column chromatog-
raphy on silica gel (PE) affording the desired product 9 as a colorless
4.3.8. (S)-2-Bromobutane-1,4-diol (6)
To a cooled (0 ꢀC) solution of 5 (12.0 g, 61.0 mmol, 1.0 eq) in THF
(125 mL) was added BH3$THF (1.0 M in THF, 183 mL, 183 mmol, 3.0
eq) over a period of 1 h. After the addition, the cooling bath was
removed and the light-yellow solution was stirred for 15 min,
resulting in the formation of a thick, milky-white suspension.
Stirring was continued at rt overnight, then the reaction mixture
was cooled to 0 ꢀC and quenched by dropwise (!) addition of H2O
(5.02 g) (formation of a clear solution). K2CO3 (5.02 g) was then
added to the reaction mixture and solids were removed by filtration
over Celite. The solid residue was washed with MTBE (140 mL) and
the combined original filtrate and MTBE washes were concentrated
to an oily, yellow residue. This material was purified by column
chromatography on silica gel (PE/EA/EtOH) affording the desired
product 6 as a yellow oil (9.86 g, 96%). Rf ¼ 0.33 (PE: EA: EtOH ¼ 6 :
oil (9.08 g, 91%). Rf ¼ 0.41 (PE). 1H NMR (600 MHz, CDCl3)
d:
7.73e7.65 (m, 4H), 7.45e7.32 (m, 6H), 3.98 (m, 1H), 3.73e3.60 (m,
2H), 2.27e2.17 (m, 2H), 1.90e1.78 (m, 2H), 1.70 (t, 3H, J ¼ 2.4 Hz),
1.06 (s, 9H), 0.85 (s, 9H), ꢁ0.002 (s, 3H), ꢁ0.007 (s, 3H). 13C NMR
(150 MHz, CDCl3) d: 135.9, 135.9, 134.4, 134.0, 129.6, 129.5, 127.6,
127.4, 77.4, 76.0, 69.7, 59.8, 39.4, 27.3, 27.0, 25.9, 19.4, 18.3, 3.5, ꢁ5.3.
HRMS (m/z): 481.2966 [MþH]þ (C29H44O2Si2), required 481.2953.
4.3.12. (S,Z)-5-(But-2-en-1-yl)-2,2,9,9,10,10-hexamethyl-3,3-
diphenyl-4,8-dioxa-3,9-disilaundecane (10)
6: 1). 1H NMR (600 MHz, CDCl3)
d: 4.34 (m, 1H), 3.94e3.76 (m, 4H),
2.19e2.05 (m, 2H). 13C NMR (150 MHz, CDCl3)
d: 67.1, 60.0, 54.9,
A flask containing a mixture of 9 (10.1 g, 21.0 mmol, 1.0 eq.),
quinoline (2.71 g, 21.0 mmol, 1.0 eq.) and Lindlar’s catalyst (2.52 g)
in EA (200 mL) was evacuated and flushed with H2. The reaction
mixture was stirred at rt under H2 (1 atm) for 7 h and then filtered
through a plug of Celite. The plug was rinsed with EA (20 mL). The
combined organic layers were concentrated and the residue was
purified by column chromatography on silica gel (PE) affording the
desired product 10 as a colorless oil (9.78 g, 97%). Rf ¼ 0.59 (PE). 1H
37.8.
4.3.9. (R)-Tert-butyldimethyl(2-(oxiran-2-yl)ethoxy)silane (7)
To a cooled (ꢁ5 ꢀC) suspension of NaH (60% in mineral oil, 6.94 g,
174 mmol, 3.2 eq.) in THF (90 mL) and DMF (90 mL) was added a
solution of 6 (9.17 g, 54.3 mmol, 1.0 eq.) in THF (92 mL) over 15 min.
After 3 h of stirring at ꢁ5 ꢀC, a solution of TBSCl (12.3 g, 81.6 mmol,
1.5 eq.) in THF (90 mL) was added over 10 min and the suspension
was stirred for further 5 min at ꢁ5 ꢀC. Then the reaction mixture
was warmed to rt and stirred overnight. When it was completed, it
was quenched with half sat. aq. NH4Cl (180 mL) below 0 ꢀC carefully
(!). The aqueous solution was extracted with EA (180 mL). The
combined organic extracts were concentrated and the residue was
purified by column chromatography on silica gel (PE/EA) affording
the desired product 7 as a colorless oil (7.05 g, 64%). Rf ¼ 0.39 (PE:
NMR (600 MHz, CDCl3) d: 7.71e7.65 (m, 4H), 7.43e7.32 (m, 6H),
5.42 (m, 1H), 5.30 (m, 1H), 3.92 (m, 1H), 3.66 (m, 1H),3.59 (m, 1H),
2.16 (dd, 2H, J ¼ 6.6, 6.6 Hz), 1.75e1.64 (m, 2H), 1.41 (dd, 3H, J ¼ 7.2,
1.2 Hz), 1.05 (s, 9H), 0.84 (s, 9H), ꢁ0.02 (s, 3H), ꢁ0.03 (s, 3H). 13
C
NMR (150 MHz, CDCl3) d: 135.9, 134.6, 134.3, 129.5, 129.4, 127.5,
127.4, 126.2, 125.6, 70.6, 60.1, 39.3, 34.5, 27.0, 25.9, 19.4, 18.3,
12.9, ꢁ5.3. HRMS (m/z): 483.3116 [MþH]þ (C29H46O2Si2), required
483.3109.
EA ¼ 20 : 1). ½a 2D0
ꢃ
þ14.1 (c ¼ 1.0, CHCl3). 1H NMR (600 MHz, CDCl3)
4.3.13. (S,Z)-3-((Tert-butyldiphenylsilyl)oxy)hept-5-en-1-ol (11)
PPTS (2.08 g, 8.3 mmol, 0.4 eq.) was added in one portion to a
solution of 10 (9.99 g, 20.7 mmol, 1.0 eq.) in ethanol (95%, 200 mL).
The reaction mixture was stirred at rt overnight and then was
concentrated. The residue was diluted in MTBE (200 mL) and
washed sequentially with sat. aq. NaHCO3 (2 ꢂ 100 mL), water
(100 mL), aq. HCl (0.3 M, 100 mL) and water (2 ꢂ 100 mL). The
organic layer was concentrated and the residue was purified by
column chromatography on silica gel (PE/EA) affording the desired
product 11 as a colorless oil (7.48 g, 98%). Rf ¼ 0.40 (PE: EA ¼ 10 : 1).
d
: 3.81e3.75 (m, 2H), 3.05 (m, 1H), 2.78 (dd,1H, J ¼ 5.4, 4.2 Hz), 2.52
(dd, 1H, J ¼ 5.4, 3.0 Hz), 1.79 (m, 1H), 1.70 (m, 1H), 0.90 (s, 9H), 0.069
(s, 3H), 0.067 (s, 3H). 13C NMR (150 MHz, CDCl3)
d: 59.9, 49.9, 47.1,
35.8, 25.8, 18.2, ꢁ5.5. HRMS (m/z): 203.1460 [MþH]þ (C10H22O2Si),
required 203.1462.
4.3.10. (S)-1-((Tert-butyldimethylsilyl)oxy)hept-5-yn-3-ol (8)
Propyne (1.0 M in THF, 40.3 mL, 40.3 mmol, 2.0 eq.) was dis-
solved in anhydrous THF (30 mL) and condensed at ꢁ78 ꢀC. n-
Butyllithium (2.5 M in hexanes, 16.1 mL, 40.3 mmol, 2.0 eq) was
added dropwise over 1 h, and the resultant white suspension was
stirred for additional 60 min at ꢁ78 ꢀC. A solution of epoxide 7
(4.08 g, 20.2 mmol) in anhydrous THF (22 mL) was then added
1H NMR (600 MHz, CDCl3)
d: 7.73e7.67 (m, 4H), 7.46e7.35 (m, 6H),
5.41 (m, 1H), 5.21 (m, 1H), 3.98 (m, 1H), 3.79 (m, 1H), 3.68 (m,1H),
2.27 (m,1H), 2.20 (m, 1H), 1.98 (br s, 1H), 1.83 (m, 1H), 1.66 (m, 1H),
1.38 (dt, 3H, J ¼ 7.2,1.2 Hz),1.07 (s, 9H). 13C NMR (150 MHz, CDCl3)
d:
7

L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
136.0, 135.9, 134.0, 133.7, 129.81, 129.75, 127.7, 127.6, 126.1, 125.6,
72.1, 59.9, 37.5, 34.1, 27.0, 19.3, 12.8. HRMS (m/z): 369.2243 [MþH]þ
(C23H32O2Si), required 369.2244.
135.9, 134.1, 134.1, 129.73, 129.70, 127.62, 127.59, 126.5, 125.9, 121.6,
108.5, 79.8, 72.4, 62.4, 34.8, 33.9, 32.4, 28.3, 27.0, 26.5, 19.3, 13.0.
HRMS (m/z): 593.3772 [MþH]þ (C35H52N2O4Si), required 593.3769.
4.3.14. (S,Z)-3-((Tert-butyldiphenylsilyl)oxy)hept-5-enal (12)
4.3.17. (S)-2-Amino-N-((S,1Z,6Z)-4-((tert-butyldiphenylsilyl)ox-y)
octa-1,6-dien-1-yl)-3,3-dimethylbutanamide (15)
(Diacetoxyiodo)benzene (BAIB) (6.28 g, 19.5 mmol, 1.1 eq.) was
added to a solution of 11 (6.53 g, 17.7 mmol, 1.0 eq.) and (2,2,6,6-
tetramethylpiperidinin-1-yl)oxyl (TEMPO) (277 mg, 1.77 mmol,
0.1 eq.) in DCM (80 mL) at 0 ꢀC. The reaction mixture was stirred at
rt overnight and then quenched with half sat. aq. NH4Cl (40 mL).
The organic layer was washed with sat. aq. NaHCO3 (40 mL) and
water (40 mL), then it was concentrated. The residue was purified
by column chromatography on silica gel (PE/EA) affording the
desired product 12 as a colorless oil (5.30 g, 82%). Rf ¼ 0.65 (PE:
A solution of the amino-protected derivative 14 (1096 mg,
1.85 mmol) in ethylene glycol (60 mL) was heated at 200 ꢀC for only
15 min. The reaction mixture was then cooled at rt, diluted with EA
(600 mL), washed with water (3 ꢂ 300 mL). The organic layer was
concentrated and the residue was purified by column chromatog-
raphy on silica gel (PE/EA) affording the desired product 15 as a
yellow oil (655 mg, 72%). Rf ¼ 0.41 (EA & 5% triethylamine). 1H NMR
(600 MHz, CDCl3)
d
: 8.49 (d, 1H, J ¼ 10.8 Hz), 7.72e7.64 (m, 4H),
EA ¼ 20 : 1). 1H NMR (600 MHz, CDCl3)
: 9.71 (t, 1H, J ¼ 2.4 Hz),
d
7.45e7.33 (m, 6H), 6.71 (dd, 1H, J ¼ 11.4, 9.6 Hz), 5.45 (m, 1H), 5.33
(m, 1H), 4.79 (dt, 1H, J ¼ 9.0, 7.2 Hz), 3.86 (m, 1H), 3.09 (s, 1H),
2.25e2.08 (m, 4H), 1.44 (d, 3H, J ¼ 6.0 Hz), 1.06 (s, 9H), 0.97 (s, 9H).
7.72e7.64 (m, 4H), 7.46e7.35 (m, 6H), 5.49 (m, 1H), 5.27 (m, 1H),
4.25 (m, 1H), 2.52e2.43 (m, 2H), 2.33e2.30 (m, 2H), 1.43 (dd, 3H,
J ¼ 6.6, 0.6 Hz), 1.05 (s, 9H). 13C NMR (150 MHz, CDCl3)
d: 202.0,
13C NMR (150 MHz, CDCl3)
d: 170.8, 135.9, 134.3, 134.2, 129.61,
135.9, 133.8, 133.5, 129.9, 129.8, 127.8, 127.6, 127.2, 124.9, 69.2, 49.9,
34.9, 26.9, 19.3, 12.9. HRMS (m/z): 367.2090 [MþH]þ (C23H30O2Si),
required 367.2088.
129.59, 127.5, 126.1, 125.9, 121.9, 107.4, 72.4, 64.2, 34.2, 33.8, 32.5,
27.0, 26.7, 19.4, 12.9. HRMS (m/z): 493.3249 [MþH]þ
(C30H44N2O2Si), required 493.3245.
4.3.15. Tert-butyl(((S,1Z,6Z)-1-iodoocta-1,6-dien-4-yl)oxy)diphe-
nylsilane (13)
4.3.18. (Z)-3-(Tributylstannyl)acrylic acid (16)
HSnBu3 (32.0 g, 110 mmol, 1.1 eq.) was added to a solution of
ethyl propiolate (9.80 g, 100 mmol, 1.0 eq) in toluene (Tol.) (350 mL)
at ꢁ78 ꢀC, then Et3B (1.0 M in THF, 20.0 mL, 20 mmol 0.2 eq.) was
added. The reaction mixture was stirred from ꢁ78 ꢀC to room
temperature for 18 h. The solvent was evaporated and the residue
was purified by flash chromatography on silica gel (PE/EA) to afford
the desired intermediate ethyl (Z)-3-(tributylstannyl)acrylate as a
To a suspension of iodomethyltriphenylphosphorane iodide
(14.9 g, 28.0 mmol, 1.7 eq.) in THF (60 mL) was slowly added a 1 M
solution of KHMDS(28.0 mL, 28.0 mmol, 1.7 eq.) in THF (160 mL) at
0 ꢀC. After being stirred for 10 min, the yellow mixture was cooled
to ꢁ78 ꢀC and a solution of 12 (6.04 g, 16.5 mmol, 1.0 eq.) in THF
(60 mL) was then added. The reaction mixture was stirred at ꢁ78 ꢀC
for 90 min, then at rt for 5 min, quenched with half sat. aq. NH4Cl
(220 mL), diluted with PE (160 mL) and filtered through a plug of
Celite. The plug was rinsed with PE (60 mL). The combined organic
phase was concentrated and the residue was purified by column
chromatography on silica gel (PE) to afford the desired product as a
colorless oil (17.9 g, 46%). 1H NMR (600 MHz, CDCl3)
d: 7.15 (d, 1H,
J ¼ 12.6 Hz), 6.73 (d, 1H, J ¼ 13.2 Hz), 4.21 (q, 2H, J ¼ 7.2 Hz),
1.56e1.40 (m, 6H), 1.34e1.24 (m, 9H), 1.04e0.83 (m, 15H). 13C NMR
(150 MHz, CDCl3)
11.0.
d: 167.7, 157.0, 135.4, 60.5, 29.2, 27.4, 14.3, 13.7,
pink oil (6.64 g, 82%). Rf ¼ 0.67 (PE). 1H NMR (600 MHz, CDCl3)
d:
A suspension of the (Z)-ester (1.17 g, 3.01 mmol, 1.0 eq.) and
LiOH$H2O (151 mg, 3.61 mmol, 1.2 eq) in THF (7.2 mL), MeOH
(3.7 mL) and H2O (7.2 mL) was heated at 60 ꢀC overnight. The
mixture was cooled down to rt and THF and MeOH were evapo-
rated. After diluted with water (25 mL), aq. HCl (1.0 M) was added
until pH ¼ 1 and the mixture was extracted with EA (2 ꢂ 25 mL).
The combined organic phases were concentrated and the residue
was purified by column chromatography on silica gel (PE/EA)
affording the desired product 16 as a yellow oil (1076 mg, 99%).
7.72e7.64 (m, 4H), 7.45e7.34 (m, 6H), 6.27 (dt, 1H, J ¼ 7.2, 7.2 Hz),
6.22 (dt, 1H, J ¼ 7.2, 1.2 Hz), 5.46 (m, 1H), 5.32 (m, 1H), 3.90 (m, 1H),
2.33e2.26 (m, 2H), 2.22e2.13 (m, 2H), 1.44 (d, 3H, J ¼ 6.6 Hz), 1.06
(s, 9H). 13C NMR (150 MHz, CDCl3)
d: 137.9, 135.9, 134.2, 134.0,
129.62, 129.60, 127.6, 127.5, 126.2, 125.8, 83.9, 71.7, 41.4, 34.2, 27.0,
19.3, 12.9. HRMS (m/z): 513.1086 [MþNa]þ (C24H31IOSi), required
513.1081.
4.3.16. Tert-butyl ((S)-1-(((S,1Z,6Z)-4-((tert-butyldiphenylsilyl)-
oxy)octa-1,6-dien-1-yl)amino) -3,3-dimethyl-1-oxobutan-2-yl)ca-
rbamate (14)
A resealable Schlenk tube was charged with vinyl iodide 13
(491 mg, 1.00 mmol, 1.0 eq.) and 1e (461 mg, 2.00 mmol, 2.0 eq),
evacuated and back filled with N2. DME (7.5 mL), Cs2CO3 (652 mg,
Rf ¼ 0.22 (PE: EA ¼ 40 : 1). 1H NMR (600 MHz, CDCl3)
d: 7.40 (d, 1H,
J ¼ 12.6 Hz), 6.78 (d, 1H, J ¼ 12.6 Hz), 1.58e1.40 (m, 6H), 1.35e1.24
(m, 6H), 1.04e0.82 (m, 15H). 13C NMR (150 MHz, CDCl3)
d: 172.9,
161.9, 134.6, 29.1, 27.3, 13.7, 11.2.
4.3.19. (S)eN-((S,1Z,6Z)-4-((Tert-butyldiphenylsilyl)oxy)octa-1,6-
dien-1-yl)-3,3-dimethyl-2-((Z)-3-(tributylstannyl)acrylamido)but-
anamide (17)
2.00 mmol, 2.0 eq.), DMEDA (65 mL, 0.60 mmol, 0.6 eq.) and CuI
(57 mg, 0.30 mmol, 0.3 eq.) were added under N2. The Schlenk tube
was sealed with a teflon valve, immerse in a preheated oil bath; the
reaction mixture was stirred at 55 ꢀC for 12 h. The reaction vessel
was removed from the oil bath and the resulting suspension was
allowed to reach room temperature, then, it was filtered through
Celite, eluting with EA (30 mL). The filtrate was concentrated and
the residue was purified by column chromatography on silica gel
(PE/EA) affording the desired product 14 as a colorless oil (505 mg,
To a solution of amine 15 (246 mg, 0.50 mmol, 1.0 eq.) and 16
(217 mg, 0.60 mmol, 1.2 eq) in DCM (14 mL) and DMF (3.5 mL) at
0 ꢀC was added diisopropylethylamine (DIPEA) (131
m
L, 0.75 mmol,
1.5 eq.) followed by 1-Hydroxy-7-azabenzotriazole (HOAt) (75 mg,
0.55 mmol, 1.1 eq.) and
N,N,N0,N0-tetramethyl-O-(7-
azabenzotriazol-1-yl)uranium hexafluorophosphate (HATU)
85%). Rf ¼ 0.50 (PE: EA ¼ 10 : 1). 1H NMR (600 MHz, CDCl3)
d
:
(247 mg, 0.65 mmol, 1.3 eq). After 30 min the reaction mixture was
quenched with a sat. aq. NH4Cl (25 mL), diluted with water (25 mL)
and extracted with MTBE (100 mL). The combined organic phases
were washed with water (50 mL), concentrated and the residue was
purified by column chromatography on silica gel (PE/EA) affording
the desired product 17 as a yellow oil (380 mg, 91%). Rf ¼ 0.55 (PE:
7.71e7.64 (m, 4H), 7.47e7.35 (m, 6H), 7.03 (d, 1H, J ¼ 10.2 Hz), 6.66
(dd, 1H, J ¼ 10.2, 10.2 Hz), 5.51 (m, 1H), 5.33 (m, 1H), 5.24 (d, 1H,
J ¼ 9.0 Hz), 4.81 (dt, 1H, J ¼ 8.4, 7.8 Hz), 3.85 (m, 1H), 3.79 (d, 1H,
J ¼ 9.0 Hz) 2.28e1.99 (m, 4H), 1.45 (d, 3H, J ¼ 7.8 Hz), 1.43 (s, 9H),
1.06 (s, 9H), 0.96 (s, 9H). 13C NMR (150 MHz, CDCl3)
d: 168.3, 155.7,
8

L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
EA ¼ 10 : 1). 1H NMR (600 MHz, CDCl3)
d
: 7.72e7.65 (m, 4H, ArH),
564
m
L, 0.564 mmol, 4.0 eq) was added. The reaction was stirred at
7.48e7.34 (m, 6H, ArH), 7.02 (d, 1H, J ¼ 12.0 Hz, C2H), 6.96 (d, 1H,
J ¼ 10.8 Hz, N5H), 6.75 (d,1H, J ¼ 12.6 Hz, C1H), 6.65 (dd,1H, J ¼ 10.8,
9.0 Hz, C6H), 6.22 (d, 1H, J ¼ 9.6 Hz, N3H), 5.51 (m, 1H, C12H), 5.34
(m, 1H, C11H), 4.82 (dt, 1H, J ¼ 8.4, 7.8 Hz, C7H), 4.31 (d, 1H,
J ¼ 9.6 Hz, C4H), 3.86 (m, 1H, C9H), 2.31e1.96 (m, 4H, C8H2, C10H2),
1.55e1.39 (m, 9H, C13H3, Sn(n-C4H9)3), 1.31e1.21 (m, 6H, Sn(n-
C4H9)3), 1.06 (s, 9H, SiPh2CMe3), 0.96 (s, 9H, CMe3), 0.99e0.80 (m,
rt for 60 min and then quenched with a sat. aq. NH4Cl (5.4 mL),
diluted with water (20 mL) and extracted with EA (50 and 20 mL).
The combined organic phases were concentrated and the residue
was purified by column chromatography on silica gel (PE/EA) to
give crude product. The crude product was purified by semi-
preparative HPLC (YMC-Pac ODS-A C18 250*20 mm, gradient H2O:
CH3CN from 30 to 100% CH3CN, UV detection, flow 9.0 mL/min) to
afford the desired product 20 as white solid (49 mg, 66%). Rf ¼ 0.14
15H, Sn(n-C4H9)3). 13C NMR (150 MHz, CDCl3)
d: 167.8, 166.0, 153.7,
(PE: EA ¼ 1 : 1). ½a D20
ꢃ
þ61.0 (c ¼ 0.1, CHCl3). 1H NMR (600 MHz,
136.1, 135.9, 134.1, 129.78, 129.75, 127.7, 127.6, 126.5, 125.8, 121.4,
108.8, 72.3, 60.4, 35.4, 33.8, 32.5, 29.3, 27.4, 27.0, 26.5, 19.3, 13.8,
13.0, 11.6. The data were in agreement with those reported in the
literature [15]. HRMS (m/z): 837.4409 [MþH]þ (C45H72N2O3SiSn),
required 837.4401.
CDCl3)
d
: 9.02 (d,1H, J ¼ 10.2 Hz), 7.26 (m,1H), 6.88 (dd,1H, J ¼ 12.0,
11.4 Hz), 6.76 (dd, 1H, J ¼ 10.2, 9.0 Hz), 6.53 (d, 1H, J ¼ 9.6 Hz), 6.16
(d, 1H, J ¼ 11.4 Hz), 5.69 (d, 1H, J ¼ 12.0 Hz), 5.67e5.60 (m, 2H), 5.42
(m,1H), 5.28 (d,1H, J ¼ 10.2 Hz), 4.89 (dt,1H, J ¼ 8.4, 7.8 Hz), 4.36 (d,
1H, J ¼ 9.6 Hz), 4.22 (ddd, 1H, J ¼ 11.4, 7.8, 4.8 Hz), 3.76 (m, 1H), 3.66
(s, 3H), 2.85 (m, 1H), 2.46e2.36 (m, 2H), 2.34e2.14 (m, 4H), 1.84 (d,
3H, J ¼ 1.2 Hz), 1.64 (d, 3H, J ¼ 6.6 Hz), 1.16 (d, 3H, J ¼ 6.6 Hz), 1.03 (s,
4.3.20. (S)-6-((S,3E,5Z)-6-iodo-4-methylhexa-3,5-dien-2-yl)-3-
methoxy-5,6-dihydro-2H-pyran-2-one (18)
Rf ¼ 0.53 (PE: EA ¼ 2 : 1). 1H NMR (600 MHz, CDCl3):
d: 6.69 (d,
9H). 13C NMR (150 MHz, CDCl3)
d: 168.6, 166.5, 161.7, 145.4, 140.3,
1H, J ¼ 8.4 Hz, C7H), 6.22 (d,1H, J ¼ 8.4 Hz, C8H), 5.64 (dd,1H, J ¼ 6.6,
2.4 Hz, C2H), 5.45 (d,1H, J ¼ 10.2 Hz, C6H), 4.22 (ddd,1H, J ¼ 11.4, 7.8,
3.6 Hz, C4H), 3.66 (s, 3H, OC1H3), 2.86 (m, 1H, C5H), 2.56 (ddd, 1H,
J ¼ 17.4, 6.6, 3.6 Hz, C3H2), 2.46 (ddd, 1H, J ¼ 17.4, 11.4, 2.4 Hz, C3H2),
1.89 (d, 3H, J ¼ 1.2 Hz, C10H3), 1.17 (d, 3H, J ¼ 6.6 Hz, C9H3). 13C NMR
137.5, 134.3,134.2, 127.8, 125.8,124.3, 123.7, 120.9,108.9,108.3, 82.0,
72.1, 60.8, 55.6, 37.5, 35.0, 34.8, 33.2, 26.8, 26.5, 17.3, 16.9, 13.2.
HRMS (m/z): 529.3277 [MþH]þ (C30H44N2O6), required 529.3272.
(150 MHz, CDCl3) d: 161.6, 145.2, 141.8, 134.5, 132.8, 108.3, 81.8, 77.4,
55.4, 37.2, 26.6, 16.5, 16.2. The Data were in agreement with those
reported in the literature [15].
4.3.23. (S,1Z,6Z)-1-((S)-2-((S,2Z,4Z,6E)-8-((S)-5-Methoxy-6-oxo-
3,6-dihydro-2H-pyran-2-yl)-6-methylnona-2,4,6-trienamido)-3,3-
dimethylbutanamido)octa-1,6-dien-4-yl carbamate (plocabulin)
To a solution of 20 (37 mg, 0.070 mmol, 1.0 eq) in DCM (5.0 mL)
4.3.21. (S,2Z,4Z,6E)-N-((S)-1-(((S,1Z,6Z)-4-((Tert-butyldiphenyl-
silyl)oxy)octa-1,6-dien-1-yl)amino)-3,3-dimethyl-1-oxobutan-2-
yl)-8-((S)-5-methoxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)-6-
methylnona-2,4,6-trienamide (19)
at 0 ꢀC, trichloroacetyl isocyanate (TCAI) (13
mL, 0.109 mmol, 1.6 eq)
was added. The reaction was stirred at 0 ꢀC for 30 min and then
neutral aluminum oxide (185 mg) was added. The mixture was
stirred for 30 min and then was soaked into a pad of aluminum
oxide. The product was washed out using a mixture of DCM/MeOH
(v/v 50:1, 30 mL). The filtrate was evaporated under vacuum and
the residue was purified by column chromatography (PE/EA) to give
crude product. The crude product was further purified by semi-
preparative HPLC (YMC-Pac ODS-A C18 250*20 mm, gradient H2O:
CH3CN from 20 to 100% CH3CN, UV detection, flow 9.0 mL/min)
To a solution of stannane 17 (161 mg, 0.193 mmol, 1.0 eq.) and 18
(81 mg, 0.233 mmol, 1.2 eq.) in 1-methyl-2-pyrrolidinone (NMP)
(15 mL) at 0 ꢀC was added Cu(I) thiophene-2-carboxylate (CuTc)
(55 mg, 0.288 mmol, 1.5 eq.). The reaction was stirred at 0 ꢀC for
45 min and then 18 h at rt. The crude mixture was filtered through a
plug of neutral alumina, washed with MTBE: EA 1:1 (75 mL) and the
combined filtrates were washed with aq. HCl 0.5 M (75 and
2 ꢂ 45 mL) and water (2 ꢂ 45 mL). The organic solution was
concentrated and the residue was purified by column chromatog-
raphy on silica gel (PE/EA) affording the desired product 19 as a
colorless oil (108 mg, 73%). Rf ¼ 0.31 (PE: EA ¼ 2 : 1). 1H NMR
affording plocabulin as a white solid (27 mg, 68%). ½a D20
ꢁ64.0
ꢃ
(c ¼ 0.1, CHCl3). 1H NMR (600 MHz, CDCl3)
: 8.70 (d, 1H, J ¼ 10.8 Hz,
d
N13H), 7.31 (dd, 1H, J ¼ 12.0, 11.4 Hz, C8H), 6.91 (ddd, 1H, J ¼ 11.4,
11.4, 0.6 Hz, C9H), 6.82 (m, 1H, C14H), 6.53 (d, 1H, J ¼ 9.6 Hz, N11H),
6.16 (d, 1H, J ¼ 11.4 Hz, C7H), 5.71 (d, 1H, J ¼ 11.4 Hz, C2H), 5.64 (dd,
1H, J ¼ 7.2, 3.0 Hz, C10H), 5.60 (m, 1H, C20H), 5.40 (m, 1H, C19H), 5.30
(d, 1H, J ¼ 9.6 Hz, C6H), 4.83 (dt, 1H, J ¼ 8.4, 8.4 Hz, C15H), 4.46 (m,
1H, C17H), 4.44 (d, 1H, J ¼ 9.6 Hz, C12H), 4.25 (ddd, 1H, J ¼ 11.4, 7.2,
4.2 Hz, C4H), 3.66 (s, 3H, OC1H3), 2.86 (m, 1H, C5H), 2.49e2.41 (m,
2H, C3H2, C16H2), 2.39 (m, 1H, C3H2), 2.38e2.33 (m, 2H, C18H2), 2.12
(m, 1H, C16H2), 1.82 (d, 3H, J ¼ 0.6 Hz, C23H3), 1.63 (d, 3H, J ¼ 1.2 Hz,
C21H3), 1.16 (d, 3H, J ¼ 7.2 Hz, C22H3), 1.04 (s, 9H, CMe3). 13C NMR
(600 MHz, CDCl3) d: 7.70e7.66 (m, 4H, ArH), 7.46e7.35 (m, 7H,
N13H, ArH), 7.25 (m, 1H, C8H), 6.89 (ddd, 1H, J ¼ 11.4, 11.4, 0.6 Hz,
C9H), 6.64 (dd, 1H, J ¼ 10.8, 9.0 Hz, C14H), 6.31 (d, 1H, J ¼ 9.0 Hz,
N11H), 6.16 (d, 1H, J ¼ 11.4 Hz, C7H), 5.66 (d, 1H, J ¼ 11.4 Hz, C2H),
5.62 (dd, 1H, J ¼ 6.0, 3.0 Hz, C10H), 5.50 (m, 1H, C20H), 5.32 (m, 1H,
C19H), 5.28 (d, 1H, J ¼ 10.2 Hz, C6H), 4.82 (dt, 1H, J ¼ 7.8, 7.8 Hz,
C15H), 4.29 (d, 1H, J ¼ 9.6 Hz, C12H), 4.21 (ddd, 1H, J ¼ 12.0, 7.2,
4.2 Hz, C4H), 3.85 (m, 1H, C17H), 3.65 (s, 3H, OC1H3), 2.84 (m, 1H,
C5H), 2.46e2.06 (m, 6H, C3H2, C16H2, C18H2), 1.84 (d, 3H, J ¼ 1.2 Hz,
C23H3), 1.44 (dd, 3H, J ¼ 6.6, 1.2 Hz, C21H3), 1.16 (d, 3H, J ¼ 6.6 Hz,
C22H3), 1.05 (s, 9H, SiPh2CMe3), 0.99 (s, 9H, CMe3). 13C NMR
(150 MHz, CDCl3) d: 168.2, 166.3, 161.7, 157.6, 145.2, 140.2, 137.5,
134.1, 133.8, 127.1, 124.9, 124.4, 124.2, 120.8, 108.3, 105.8, 81.9, 75.7,
60.7, 55.5, 37.1, 34.8, 31.4, 30.9, 26.7, 26.1, 17.1, 16.4, 13.0. HRMS (m/
z): 572.3310 [Mþ1]þ (C41H45N3O7) required 572.3330. The Data
were in agreement with those reported the literature [15].
(150 MHz, CDCl3) d: 168.0, 166.1, 161.6, 145.2, 140.2, 137.3, 135.9,
134.14, 134.11, 129.74, 129.70, 127.62, 127.58, 126.5, 125.9, 124.1,
121.4, 120.8, 109.0, 108.1, 81.8, 72.4, 60.3, 55.4, 37.3, 35.0, 33.9, 32.5,
27.0, 26.6, 26.3, 19.3, 17.2, 16.8, 13.0. The Data were in agreement
with those reported in the literature [15].
Supplementary material
4.3.22. (S,2Z,4Z,6E)-N-((S)-1-(((S,1Z,6Z)-4-hydroxyocta-1,6-dien
-1-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)-8-((S)-5-methoxy-6-
oxo-3,6-dihydro-2H-pyran-2-yl)-6-methylnona-2,4,6-trienamide
(20)
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and sub-
mitted along with the manuscript and graphic files to the appro-
priate editorial office.
To a solution of 19 (108 mg, 0.141 mmol, 1.0 eq.) in THF (20 mL)
at 0 ꢀC, n-tetrabutylammonium fluoride (TBAF) (1.0 M in THF,
9

L. Wang, X. Lei, Q. Wang et al.
Tetrahedron 83 (2021) 131953
ꢀ
Salarichs, L.F. García-Fernandez, V. Moneo, J. Jimenez-Barbero, C.M. Galmarini,
C. Cuevas, M.A. Penealva, J.F. Díaz, J.M. Andreu, ACS Chem. Biol. 8 (2013)
2084e2094.
Declaration of competing interest
All the authors claim that there are no conflicts to declare.
~
[18] A. Pantazopoulou, C.M. Galmarini, M.A. Penalva, Sci. Rep. 8 (2018) 1e19.
[19] M. Martıínez-Díez, M.J. Guillen-Navarro, B. Pera, B.P. Bouchet, J.F. Martínez-
Leal, I. Barasoain, C. Cuevas, J.M. Andreu, L.F. García-Fernandez, J.F. Díaz,
P. Aviles, C.M. Galmarini, Biochem. Pharmacol. 88 (2014) 291e302.
[20] C.M. Galmarini, M. Martin, B.P. Bouchet, M.J. Guillen-Navarro, M. Martıínez-
ꢀ
ꢀ
Acknowledgments
ꢀ
ꢀ
Díez, J.F. Martinez-Leal, A. Akhmanova, P. Aviles, BMC Canc. 18 (2018) 1e13.
We thank National Natural Science Foundation of China (No.
81773576) for the financial support.
ꢀ
ꢀ
[21] Y. Wang, A. Wozniak, J. Wellens, Y.K. Gebreyohannes, M.J. Guillen, P.M. Aviles,
€
M. Debiec-Rychter, R. Sciot, P. Schoffski, Trans. Oncol. 13 (2020), https://
doi.org/10.1016/j.tranon.2020.100832.
Appendix A. Supplementary data
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