A practical approach to asymmetric synthesis of dolastatin 10

Article abstract of DOI:10.1039/c7ob01395g

Dolastatin 10, an antineoplastic agent for cancer chemotherapy, is a linear peptide possessing N,N-dimethyl Val-OH, l-valine, (3R,4S,5S)-dolaisoleucine, (2R,3R,4S)-dolaproine and (S)-dolaphenine. Our efficient synthesis includes the following three key features: (1) SmI₂-induced cross-coupling was employed to couple aldehyde 11 with (S)-N-tert-butanesulfinyl imine 12 to generate the required stereocenters of Dap (7); (2) asymmetric addition of chiral N-sulfinyl imine 10 provided a straightforward approach to the synthesis of the protected Doe ((S,S)-8); (3) a practical method to the key subunit Val-Dil (24a) has been established as an alternative synthetic route for the synthesis of this challenging chemical structure.

Full text of DOI:10.1039/c7ob01395g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: W. Zhou, X. Nie, Y.
Zhang, C. Si, Z. Zhou, X. Sun and B. Wei, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB01395G.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 13
View Article Online
DOI: 10.1039/C7OB01395G
Journal Name
ARTICLE
A Practical Approach to Asymmetric Synthesis of Dolastatin 10
Wen Zhou,a Xiao-Di Nie,a Yu Zhang,b Chang-Mei Si,a,* Zhu Zhou,a Xun Suna and Bang-Guo Weia,*
Received 00th January 20xx,
Accepted 00th January 20xx
Dolastatin 10, an antineoplastic agent for cancer chemotherapy, is a linear peptide possessing N,N-dimethyl Val-OH, L-
valine, (3R,4S,5S)-dolaisoleucine, (2R,3R,4S)-dolaproine and (S)-dolaphenine. Our efficient synthesis includes the following
three key features: 1) SmI2-induced cross-coupling was employed to couple aldehyde 11 with (S)-N-tert-butanesulfinyl
imine 12 to generate the required stereocenters of Dap (7); 2) Asymmetric addition of chiral N-sulfinyl imine 10 provided a
straightforward approach to protected Doe ((S,S)-8); 3) A practical method to the key subunit Val-Dil (24a) has been
established as an alternative synthetic route for synthesis of this challenging chemical structure.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Figure 1. The structures of dolastatin 10 and its analogues.
Introduction
that have been approved as antineoplastic agents for cancer
chemotherapy.3 Dolastatin 10 shows antitumor activity in sub-
nanomolar concentrations against a wide range of tumor cell
lines, and was evaluated in clinical trials.4 It functions through
a unique mode of action, which are different from paclitaxel,
vinblastine and the epothilones, and exhibits more potent
activity against a variety of cancers.5 As a result, the divergent
Linear small peptides,1 an interesting family of peptidic
secondary metabolites, displaying a variety of physiological
activities, including antimicrobial, antimalarial, antifungal,
cytotoxic and neurotoxic properties, are a class of promising
compounds for drug discovery. Due to their important
bioactivities and attractive structures, the linear peptides have
attracted significant attention in recent years. Dolastatin 10
synthesis of
1
has attracted significant attention6 and a few
and
) have entered clinical trials.7
analogues (For example,
2
3
(1), named as star molecule which was isolated from Indian
ocean sea hare Dolabella auricularia by Pettit in 1987,2 is a
highly cytotoxic compound that inspired the design of
auristatin as the potent ‘warhead’ component of antibody
conjugates (ADC)
As continuation of our interests in developing divergent
syntheses of natural products8 isolated from cyanobacteria
and investigating their structure-activity relationships, we
decided to develop an asymmetric synthesis of dolastatin 10
(
1)
and its analogues. Herein, we present an effective
O
H
approach to dolastatin 10 (1).
N
N
S
N
H
N
N
O
O
O
O
N
Results and discussion
O
Ph
The retrosynthetic analysis of dolastatin 10 (
subunits (Figure 2): N,N-dimethyl valine ( , Dov), L-valine (
Val), (3R,4S,5S)-dolaisoleucine ( , Dil), (2R,3R,4S)-dolaproine
, Dap) and protected (S)-dolaphenine ((S,S)- , protected Doe)
1) led to five
Dolastatin 10 (1)
4
5,
6
(
7
8
O
H
N
fragments. As for the syntheses of five units, (S)-dolaphenine
(Doe) could be prepared by asymmetric addition of lithium
thiazole to chiral N-tert-butanesulfinyl imines.9 (2R,3R,4S)-
N
N
H
N
N
O
O
O
X
O
O
Dolaproine (Dap) could be obtained through SmI2-induced
10
Auristatin-PE (2, X = CH)
Auristatin-PYE (3, X = N)
cross-coupling
of aldehyde with (S)-N-tert-butanesulfinyl
imine, which was established in early years and successfully
used in asymmetric synthesis of natural products.11 (3R,4S,5S)-
dolaisoleucine (Dil) could be prepared by asymmetric
reduction of ketone which was derived from isoleucine.12
Importantly, dolastatin 10 (1) was effectively synthesized
through an alternative condensation sequence of the five
subunits.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 13
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
Due to its limitation from natural sources and high
Journal Name
80%; b. 2-bromothiazole, n-BuLi, toluene, -78 oC, 3 h, 53% (complete yield
80%), dr = 2:1.
demand in preclinical and clinical chemotherapeutics studies,
dolastatin 10 and its analogues have attracted considerable
Next, we turned our attention to prepare the key
(2R,3R,4S)-dolaproine subunit
2). The chiral aldehyde
methoxybenzyloxy)butylidene)-2-methylpropane-2-
7
(Dap) of dolastatin 10 (Scheme
11 and (R)-N-(4-(4-
sulfinamide 12 were prepared according to our previous
methods.11 The SmI2-induced cross-coupling of 11 and 12 gave
desired
diastereoselectivity (dr > 99:1) in 75% yield. Treatment of 13
with tert-butyldimethylsilyl trifluoromethanesulfonate
vicinal
β-amino
alcohol
13
with
high
(TBSOTf) generated silyl ether 14 in 88% yield. After the
following two sequential steps, removal of PMB group (DDQ)16
and mesylation (MsCl, TEA), the cyclization took place under
potassium tert-butoxide conditions to give 16 in 50% overall
yield. Upon the deprotection of TBS group with
tetrabutylammonium fluoride17 (TBAF), the alcohol 17 was
converted to methyl ether 18, using methyl methanesulfonate,
in 58% overall yield. The chiral auxiliary was cleaved using
HCl/dioxane, and the resulting secondary amine was
converted to 19 in 79% overall yield. Hydrogenation (Pd/C, H2)
and oxidation with Dess-Martin periodinane18 gave crude
aldehyde, which was subjected to Pinnick oxidation19
(NaH2PO4·2H2O, NaClO2) to give free acid
yield.
7 in 54% overall
Figure 2. Our initial strategy to access dolastatin 10.
research interests and tremendous efforts have been devoted
to the development of several synthetic approaches. Among
them, several known approaches to dolaphenine (Doe) seem
to be not very efficient.6f,13 In recent years, one of our research
interests is to utilize Ellman’s chiral auxiliaries14 in asymmetric
synthesis of natural products.8g,15 As a result, we were
interested in developing a straightforward approach to the
synthesis of dolaphenine (Doe). As shown in Scheme 1, chiral
N-sulfinyl imine 10 was first prepared through the following
sequence. The commercially available phenylacetaldehyde
9
was condensed with sulfinamide in presence of anhydrous
cupric sulphate to afford the desired chiral N-sulfinyl imine 10
in 80% yield. Then 2-thiazole lithium13b, which was obtained
from the treatment of 2-bromothiazole with n-butyllithium (n-
BuLi) at -78 oC for 30 min, reacted with N-sulfinyl imine (10) to
give desired amine ((S,S)-
8)
in 53% yield and its
diastereoisomer ((R,S)-8) in 27% yield.
Scheme 2 The preparation of Dap fragment (7). Reagents and conditions: a.
SmI2, t-BuOH, THF, -78 oC, 5 h, 75% (dr > 99:1); b. TBSOTf, 2,6-lutidine,
DCM, 0 oC to rt, 4 h, 88%; c. DDQ, DCM/H2O, 0 oC, 30 min, 68%; d. (1). MsCl,
TEA, DCM, 0 oC, 15 min; (2). t-BuOK, THF, 0 oC, 15 min, for two steps 73%; e.
TBAF, THF, 0 oC to rt, 4 h, 61%; f. LiHMDS, HMPA, THF, -78 oC, 30 min, then
MeOTf, -15 oC, 15 min, 95%; g. (1). HCl/dioxane, MeOH, 0 oC, 30 min; (2).
Scheme 1 The preparation of protected Doe fragment ((S,S)-8). Reagents
and conditions: a. (S)-tert-butanesulfinamide, CuSO4, PPTS, DCM, rt, 36 h,
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 13
Journal Name
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
Boc2O, TEA, DCM, rt, 12 h, for two steps 79%; h. Pd/C, H2, MeOH, 5 h, 72%; [a] The reaction was performed with
.
6
i. (1). DMP, DCM, rt, 30 min; (2). NaH2PO4 2H2O, NaClO2, 2-methyl-2- reagent (1.1 mmol), base (6.0 mmol) in solvent (4.0 mL) overnight after
(1.0 mmol),
5 (1.0 mmol), coupling
6
butene/t-BuOH, rt, 8 h, for two steps 75%.
was deprotected with TFA; [b] Isolated yield.
The (3R,4S,5S)-dolaisoleucine (6
, Dil) of 3a was prepared pentafluorophenyl diphenylphosphinate (FDPP)26 and 2-
from (S)-N-Boc-isoleucine (21) according to a simple process20 chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)27 were also
(Scheme 3). Activation of 21 with carbonyldiimidazole and screened, and the results indicated that these classic reagents
subsequent reaction with benzyl acetate gave ketone 22 in were not very effective in our case (Table 1, entries 5-7).
80% overall yield. Reduction (KBH4, MeOH) of ketone 22 gave
Considering the ester group and N-Me of 6 affected the
secondary alcohol 23 with high diastereoselectivity (dr > 99:1) amidation28, compound 25 was prepared (Scheme 4). Removal
in 78% yield. Methylation of 23 with methyl of the Bn group in 23 and reduction of mixed anhydride
trifluoromethanesulfonate (MeOTf)6f in the presence of (NaBH4) afforded a diol, in which the primary alcohol was
lithium bis(trimethylsilyl)amide (LiHMDS) generated the regioselective protected by Bn group to give desired product
desired compound
6
in 90% yield.
25 in 62% overall yield. Removal of the Boc group in 25 and
subsequent amidation (HATU, HOAt)29 with N,N-bis[(1,1-
dimethylethoxy)carbonyl]-L-Val-OH gave 27 in 52% overall
yield. However, when 27 was subjected to methylation using
LiHMDS and methyl trifluoromethanesulfonate (MeOTf)6f, a
cyclic by-product 28 was generated in 62% overall yield.
Scheme 3 The preparation of Dil fragment (6). Reagents and conditions: a.
carbonyldiimidazole, THF, rt, 2 h, then LDA, benzyl acetate, THF, rt, 3 h,
80%; b. KBH4, MeOH, -78 oC, 10 min, then -15 oC, 35 min, 78% (dr > 99:1); c.
LiHMDS, HMPA, THF, -78 oC, 30 min, then MeOTf, -15 oC, 15 min, 90%.
The peptide formation of intermediate 24 (Dil-Val)
involved the coupling of
6 (Dil) and Val-OH moiety 5a or 5b.
When 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-
b]pyridinium 3-oxid hexafluorophosphate (HATU)21 was used,
the yield of desired 24a was only 15% yield (Table 1, entry 1).
Scheme 4 Reagents and conditions: a.(1) Pd/C, H2, MeOH, rt, 2 h; (2)
Isobutyl chloroformate, THF, 30 min, then NaBH4, H2O, rt, overnight; (3)
BnBr, NaH, DMF, 0 oC to rt, overnight, for three steps 62%; b. TFA, DCM, 0
oC, 2 h; c. N,N-bis[(1,1-dimethylethoxy)carbonyl]-L-Valine, HATU, HOAt,
DIPEA, DCM, rt, overnight, for two steps 52%; d. LiHMDS, HMPA, THF, -78
oC, 30 min, then MeOTf, -15 oC, 15 min, 62%.
Other
reagents,
benzotriazol-1-yl-
oxytripyrrolidinophosphonium hexafluorophosphate (PyBoP)22
and bis(2-oxooxazolidin-3-yl)phosphinic chloride (BOP-Cl)23
also led to limited yield of 24a (Table 1, entries 2-3).
Bromotris(dimethylamino)phosphonium hexafluophosphate
(BrOP)24 could slightly improve the yield of 24a (Table 1, entry
To establish an efficient approach to synthesize dolastatin
10, the retrosynthetic analysis of 34 was modified to use
reduction alkylation instead of condensention with N,N-
dimethyl valine (4, Dov) (Figure 3). As the N-Me in Dil fragment
4).
Additional
coupling
reagents,
1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDCI),25
was introduced before coupling with Val fragment, the
condensation of N-Me amine in fragment 29 with N-Boc-L-
valine 5a became an essential step.
Table 1. The peptide formation of subunit 24 (Dil-Val).
O
OBn
PHN
OBn
N
N
1.TFA
O
2.condition
PHN
5a P=Boc
5b P=Fmoc
COOH
Boc
O
O
O
24a P=Boc
6
24b P=Fmoc
Entries[a]
5
a
a
a
a
a
b
b
Reagents
HATU
base
solvent
DCM
Yield %[b]
1
2
3
4
5
6
7
DIPEA
DIPEA
DIPEA
DIPEA
NMM
DIPEA
NMM
15
PyBOP
BOP-Cl
BrOP
MeCN
DCM
18
16
DCM
20
EDCI/HOBt
FDPP
DMF
10
MeCN
2-MeTHF
trace
trace
CDMT
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 13
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
Journal Name
were obtained from the removal of Boc group (TFA) in 35 and
Bn group (Pd/C, H2) of 34, were coupled in the presence of
HATU and HOAt29 to give Dolastatin 10 (
1) as a viscous liquid,
which was further treated with acetone/hexane to give white
powder {[ꢀ]ꢂꢁꢃ = -63.3 (c 1.00, MeOH), lit.2 [ꢀ]ꢂꢁꢄ = -69 (c 0.01,
MeOH), lit.6f [ꢀ]ꢂꢁꢅ = -57.5 (c 1.07, MeOH)} in 60% isolated
yield. The spectroscopic and physical data of the synthetic
Dolastatin 10 (
1
) were identical to the reported data.2,6f
O
H
N
a
OBn
24a
5
+
BocHN
N
O
O
O
Figure 3. Our second strategy to access 34
.
33
The synthesis of subunit 24a is shown in Scheme 5.
Methylation (NaH, MeI) of (S)-Boc-isoleucine 21 and
(
)
O
H
N
subsequent protection (BnBr, K2CO3) gave ester 29 in 55%
overall yield.30 Once the Boc group in 29 was removed using
TFA, the crude salt was used directly to react with N-Boc-L-Val-
OH in presence of HATU and HOAt29 to give desired coupled
product 30 in 82% yield. Then 30 was treated with
carbonyldiimidazole and benzyl acetate in the presence of
LDA31 to produce ketone 31 in 80% yield. Reduction (KBH4) of
31 and subsequent methylation (LiHMDS, MeOTf)6f generated
the desired Val-Dil fragment 24a in 47% yield.
b
OBn
N
N
O
O
O
34
S
H
N
c
d
N
N
(S,S)-8 +
7
Boc
O
O
Ph
35
O
H
S
N
H
N
N
N
N
N
O
O
O
O
O
Ph
1
Scheme 6 The final synthesis of Dolastatin 10 (3a). Reagents and conditions:
a. (1). TFA, DCM, 0 oC, 2 h; (2). HATU, HOAt, DIPEA, DCM, rt, overnight, for
two steps 85%; b. (1). TFA, DCM, rt, 2 h; (2). 40% HCHO, Na(BH3)CN, CH3CN,
rt, 18 h, for two steps 82%; c. (1). HCl/dioxane, MeOH, 0 oC, 30 min; (2).
HATU, HOAt, DIPEA, DCM, rt, overnight, for two steps 80%; d. (1). TFA,
DCM, 0 oC, 2 h; (2). 34, Pd/C, H2, MeOH, 2 h; (3). HATU, HOAt, DIPEA, DCM,
rt, 24 h, for three steps 60%.
Scheme
5 The preparation of Val-Dil fragment (24a). Reagents and
conditions: a. (1). NaH, MeI, THF, rt, 48 h; (2). BnBr, K2CO3, DMSO, rt,
overnight, for two steps 55%; b. (1), TFA, DCM, rt, 2 h; (2). N-Boc-L-Valine,
HATU, HOAt, DIPEA, DCM, rt, overnight, for two steps 82%; c. (1) Pd/C, H2,
rt, 5 h; (2) carbonyldiimidazole, THF, rt, 2 h, then LDA, benzyl acetate, THF, -
78 oC, 3 h, for two steps 80%; d. KBH4, MeOH, -78 oC, 10 min, then -15oC, 35
min, 78% (dr > 99:1); e. LiHMDS, HMPA, THF, -78 oC, 30 min, then MeOTf, -
15 oC, 15 min, 60%.
Conclusions
In summary, a practical approach to natural dolastatin 10 (1)
has been established using SmI2-induced cross-coupling of
aldehyde with (S)-N-tert-butanesulfinyl imine to generate the
required stereocenters of Dap (7). The alternative strategy for
With fragments (S,S)-8 (protected Doe), 7 (Dap) and 24a
the preparation of the key subunit Val-Dil (24a) and a
straightforward approach through asymmetric addition of
chiral N-sulfinyl imine 10 to dolaphenine (Doe) were also
developed to give dolastatin 10.
(Val-Dil) in hand, we turned our attention to final assembly of
Dolastatin 10 (3a) through successive coupling reactions
(Scheme 6). The crude amine salt, prepared by removal of Boc
group in 24a (TFA), was directly coupled with
5 (HATU, HOAt)
to generate 33 in 85% yield. Upon the deprotection of Boc in
33, the subsequent dimethylation32 (40% HCHO, Na(BH3)CN)
gave the fragment 34 (Dov-Val-Dil) in 82% yield. The crude
Experimental
General
amine salt through the removal of Boc group in (S,S)-8 (TFA)
(HATU, HOAt)29 to give desired compound
THF was distilled from sodium/benzophenone. DCM was
distilled from phosphorus pentoxide. Reactions were
was coupled with
7
35 in 80% yield. Finally, the crude amine salt and acid, which
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 13
Journal Name
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
monitored by thin layer chromatography (TLC) on glass plates 1612, 1513, 1454, 1363, 1247, 1094, 1035, 822, 771, 696 cm-1;
coated with silica gel with fluorescent indicator. Flash 1H NMR (CDCl3, 400 MHz, rotamers) δ 7.38-7.28 (m, 5H), 7.27-
chromatography was performed on silica gel (300-400 mesh). 7.22 (m, 2H), 6.89-6.84 (m, 2H), 4.52-4.48 (m, 2H), 4.44-4.40
Optical rotations were measured on a polarimeter with a (m, 2H), 3.84-3.80 (m, 0.5H), 3.80-3.78 (m, 3H), 3.66-3.62 (m,
sodium lamp. HRMS were measured on a Thermo Scientific 0.5H), 3.55-3.53 (m, 1H), 3.53-3.47 (m, 3H), 3.45-3.41 (m, 1H),
LTQ Orbitrap XL apparatus. IR spectra were recorded using film 3.33-3.26 (m, 1H), 2.07-1.99 (m, 1H), 1.97-1.74 (m, 3H), 1.74-
on a Fourier Transform Infrared Spectrometer. NMR spectra 1.63 (m, 2H), 1.20-1.17 (m, 9H), 1.04-0.98 (m, 1.5H), 0.93-0.89
were recorded at 400 MHz or 600 MHz, and chemical shifts are (m, 1.5H) ppm; 13C NMR (CDCl3, 100 MHz, rotamers) δ 159.3,
reported in δ (ppm) referenced to the appropriate residual 138.1(138.3), 130.8 (130.8), 129.5 (129.5), 128.7 (128.7),
solvent peaks unless otherwise noted.
128.0, 128.0 (127.9), 114.0, 78.5 (76.7), 74.3 (74.9), 73.7
(73.6), 72.8 (72.8), 70.0 (70.1), 59.2 (58.9), 56.0 (56.1), 55.5,
35.4 (34.9), 26.3 (27.4), 25.6 (25.7), 23.0 (23.0), 14.5 (11.9)
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C27H42NO5S+:
492.2778, Found: 492.2777.
(S)-2-Methyl-N-((S)-2-phenyl-1-(thiazol-2-
yl)ethyl)propane-2-sulfinamide 8. To a solution of
9 (5.00 g,
41.61 mmol) in DCM (150 mL) was added (S)-tert-
butanesulfinamide (5.55 g, 45.77 mmol), CuSO4 (13.28 g, 83.22
mmol) and PPTS (1.05 g, 4.16 mmol), after being stirred for 36
(S)-N-((2S,3R,4S)-1-(Benzyloxy)-3-((tert-
h, the reaction mixture was filtrated, concentrated. The butyldimethylsilyl)oxy)-7-((4-methoxybenzyl)oxy)-2-
residue was purified by flash chromatography on silica gel methylheptan-4-yl)-2-methylpropane-2-sulfinamide 14. To a
(PE/EA = 20:1) to give imine 10 in 80% yield. To a cooled (-78 cooled (0 oC) solution of 13 (10.00 g, 20.34 mmol) and 2,6-
oC) solution of 2-bromothiazole (2.42 mL, 26.87 mmol) in lutidine (11.84 mL, 101.70 mmol) in DCM (80 mL) was carefully
toluene (90 mL) was added n-butyllithium (1.6 M in hexane, treated with TBSOTf (11.68 mL, 50.85 mmol) for 4 h. Then, the
22.39 mmol) slowly, after being stirred for 30 min, another reaction mixture was quenched with a saturated aqueous
solution of 10 (5.00 g, 22.39 mmol) in toluene (10 mL) was solution of NH4Cl and extracted with DCM (100 mL × 3). The
added dropwise, after 3 h of stirring, the mixture was combined organic layers were washed with brine, dried over
quenched with a saturated aqueous solution of NH4Cl and MgSO4, filtrated and concentrated. The residue was purified by
extracted with EtOAc (80 mL × 3). The combined organic layers flash chromatography on silica gel (PE/EA = 10:1) to give 14
were washed with brine, dried over MgSO4, filtrated and (10.85 g, 88%) as a colorless oil. [ꢀ]ꢂꢁꢈ = +33.6 (c 1.00, CHCl3);
concentrated. The residue was purified by flash IR (film) vmax 3449, 3296, 2955, 2928, 2856, 1610, 1513, 1455,
1
chromatography on silica gel (PE/EA = 2:1 to 1:1) to give the 1362, 1248, 1093, 1067, 1049, 836, 774 cm-1. H NMR (CDCl3,
major product (S,S)-
8
(3.66 g, 53%) and the minor product 400 MHz, rotamers) δ 7.34-7.24 (m, 7H), 6.89-6.84 (m, 2H),
is a colorless oil, [ꢀ]ꢂꢁꢆ = +31.6 (c 4.46-4.41 (m, 4H), 4.24 (d, J = 6.2 Hz, 0.5H), 4.13 (d, J = 6.2 Hz,
(R,S)-8 (1.83 g, 27%). (S,S)-
8
1.00, CHCl3); IR (film) vmax 3205, 2956, 2924, 2864, 1668, 1604, 0.5H), 3.79 (s, 3H), 3.71-3.60 (m, 2H), 3.49-3.43 (m, 2H), 3.24-
1497, 1455, 1363, 1056, 748, 700 cm-1; 1H NMR (CDCl3, 400 3.18 (m, 2H), 2.35-2.22 (m, 1H), 1.90-1.82 (m, 2H), 1.65-1.55
MHz) δ 7.76 (d, J = 3.2 Hz, 1H), 7.28-7.26 (m, 2H), 7.25-7.21 (m, (m, 2H), 1.13-1.09 (m, 9H), 0.95-1.90 (m, 3H), 0.88 (s, 6H), 0.11
2H), 7.13-7.10 (m, 2H), 4.96 (dd, J = 14.4, 7.2 Hz, 1H), 4.26 (d, J (s, 3H), 0.08 (s, 1.5H), 0.03 (s, 1.5H) ppm; 13C NMR (CDCl3,
= 7.2 Hz, 1H), 3.30-3.27 (m, 2H), 1.12 (s, 9H) ppm; 13C NMR 100MHz, rotamers) δ 159.2, 138.3 (138.3), 130.8 (130.8), 129.4
(CDCl3, 100 MHz) δ 171.5, 142.6, 136.7, 129.8, 128.6, 127.0, (129.4), 128.5, 127.8 (127.9), 127.7 (127.7), 113.8, 79.3 (78.5),
119.4, 58.9, 56.6, 43.9, 22.6 ppm; HRMS (ESI-Orbitrap) m/z: [M 73.2 (73.3), 72.7 (72.6), 71.7 (71.6), 69.9 (70.0), 60.7 (60.1),
+
+ H]+ Calcd for C15H21N2OS2 : 309.1090, Found: 309.1086. (R,S)- 55.8 (55.8), 55.4, 35.8 (35.3), 28.6 (27.7), 26.7 (26.5), 26.3,
1
, H NMR (CDCl3, 400 MHz) δ 7.82 (d, J = 3.2 Hz, 1H), 7.28- 23.0 (22.9), 18.5, 16.6 (16.4), 1.0, -3.2, -3.9 ppm; HRMS (ESI-
8
7.21 (m, 4H), 7.12-7.09 (m, 2H), 5.10 (dd, J = 12.4, 6.0 Hz, 1H), Orbitrap) m/z: [M + H]+ Calcd for C33H56NO5SSi+: 606.3643,
3.94 (d, J = 6.4 Hz, 1H), 3.54-3.48 (m, 1H), 3.43-3.38 (m, 1H), Found: 606.3643.
1.21 (s, 9H) ppm; 13C NMR (CDCl3, 150 MHz) δ 173.4, 143.3,
(S)-N-((2S,3R,4S)-1-(Benzyloxy)-3-((tert-
135.3, 130.4, 128.8, 127.3, 119.4, 58.3, 56.6, 43.2, 22.7 ppm.
butyldimethylsilyl)oxy)-7-hydroxy-2-methylheptan-4-yl)-2-
o
methylpropane-2-sulfinamide 15. To a cooled (0 C) solution
(S)-N-((2S,3R,4S)-1-(Benzyloxy)-3-hydroxy-7-((4-
methoxybenzyl)oxy)-2-methylheptan-4-yl)-2-methylpropane- of 14 (1.00 g, 1.65 mmol) in DCM (10 mL) and H2O (1 mL) was
o
2-sulfinamide 13. To a cooled (-78 C) solution of 11 (2.50 g, added DDQ (749 mg, 3.30 mmol) for three times. After being
14.00 mmol), 12 (4.36 g, 14.00 mmol) and t-BuOH (5.36 mL, stirred for 30 min, the reaction mixture was quenched with a
56.00 mmol) in THF (280 mL) was added a freshly prepared saturated aqueous solution of Na2S2O3 and extracted with
solution of samarium diiodide (0.2 M in THF, 56.00 mmol), DCM (60 mL × 3). The combined organic layers were washed
after being stirred for 5 h, the mixture was quenched with a with brine, dried over MgSO4, filtrated and concentrated. The
saturated aqueous solution of Na2S2O3 and extracted with residue was purified by flash chromatography on silica gel
EtOAc (200 mL × 3). The combined organic layers were washed (PE/EA = 1:1) to give 15 (545 mg, 68%) as a colorless oil. [ꢀ]ꢁꢂꢅ
with brine, dried over MgSO4, filtrated and concentrated. The = +24.4 (c 2.00, CHCl3); IR (film) vmax 3387, 3302, 2956, 2928,
residue was purified by flash chromatography on silica gel 2857, 1472, 1455, 1363, 1252, 1093, 1048, 835, 774, 698 cm-1;
(PE/EA = 1:1) to give 13 (5.16 g, 75%) as a colorless oil. [ꢀ]ꢁꢂꢇ
+37.1 (c 1.00, CHCl3); IR (film) vmax 3406, 2957, 2926, 2858, 2H), 4.09 (d, J = 7.2 Hz, 1H), 3.70-3.58 (m, 4H), 3.34-3.26 (m,
=
1H NMR (CDCl3, 400 MHz) δ 7.37-7.25 (m, 5H), 4.52-4.43 (m,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 13
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
Journal Name
1H), 3.23 (dd, J = 9.2, 4.8 Hz, 1H), 2.21-2.14 (m, 1H), 1.88-1.72 Orbitrap) m/z: [M + H]+ Calcd for C19H32NO3S+: 354.2097,
(m, 2H), 1.70-1.54 (m, 2H), 1.16 (s, 9H), 0.98-0.95 (m, 3H), 0.88 Found: 354.2097.
(s, 9H), 0.09 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR (CDCl3, 100
(S)-2-((1R,2S)-3-(Benzyloxy)-1-methoxy-2-methylpropyl)-
1-((S)-tert-butylsulfinyl)pyrrolidine 18. To a cooled (-78 oC)
MHz) δ 138.3, 128.5, 127.8, 127.7, 78.5, 73.2, 71.7, 62.7, 61.1,
56.0, 36.1, 29.3, 28.7, 26.2, 23.0, 18.5, 16.3, -3.3, -4.1 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C25H48NO4SSi+:
solution of 17 (2.00 g, 5.66 mmol) and HMPA (1.49 mL, 8.50
mmol) in THF (24 mL) was added LiHMDS (1 M in THF, 8.50
486.3068, Found: 486.3067.
mmol) dropwise, after being stirred for 30 min, the reaction
was warmed to -15 oC and added MeOTf (1.28 mL, 11.32
mmol), after being stirred for 15 min, it was quenched with a
(S)-2-((1R,2S)-3-(Benzyloxy)-1-((tert-
butyldimethylsilyl)oxy)-2-methylpropyl)-1-((S)-tert-
butylsulfinyl)pyrrolidine 16. To a solution of 15 (7.00 g, 14.41 saturated aqueous solution of NH4Cl and extracted with EtOAc
mmol) in DCM (58 mL) was added TEA (16.00 mL, 115.28 (60 mL × 3). The combined organic layers were washed with
mmol) followed by MsCl (3.35 mL, 43.23mmol), after being brine, dried over MgSO4, filtrated and concentrated. The
stirred for 15 min, the reaction was quenched with a saturated residue was purified by flash chromatography on silica gel
aqueous solution of NH4Cl and extracted with DCM (100 mL × (PE/EA = 5:1) to give 18 (1.98 g, 95%) as a colorless oil. [ꢀ]ꢁꢂꢈ
=
3). The combined organic layers were washed with brine, dried +65.6 (c 2.00, CHCl3); IR (film) vmax 2961, 2924, 2868, 1454,
over MgSO4, filtrated and concentrated to give a crude 1361, 1095, 1071, 1028, 949, 737, 698 cm-1; 1H NMR (CDCl3,
residue, which was dissolved in THF (58 mL), and carefully 400 MHz, rotamers) δ 7.39-7.23 (m, 5H), 4.55-4.47 (m, 2H),
treated with t-BuOK (3.23 g, 28.82 mmol), after being stirred 3.84-3.76 (m, 1H), 3.74-3.67 (m, 1H), 3.51-3.45 (m, 1.5H), 3.43-
for 15 min, the reaction mixture was quenched with a 3.41 (m, 3H), 3.36-3.28 (m, 1.5H), 2.78-2.71 (m, 1H), 1.93-1.82
saturated aqueous solution of NH4Cl and extracted with EtOAc (m, 3H), 1.81-1.67 (m, 2H), 1.22 (s, 9H), 1.01-0.93 (m, 3H) ppm;
(100 mL × 3). The combined organic layers were washed with 13C NMR (CDCl3, 100 MHz, rotamers) δ 138.6 (138.5), 128.4,
brine, dried over MgSO4, filtrated and concentrated. The 127.6, 127.5, 85.3 (84.0), 73.2 (73.1), 72.4 (73.0), 68.0 (68.7),
residue was purified by flash chromatography on silica gel 60.2 (60.8), 57.3 (57.6), 42.7 (42.2), 36.8 (36.3), 27.6 (26.9),
(PE/EA = 6:1) to give 16 (4.92 g, 73%, two steps) as a colorless 25.1 (26.3), 24.1 (24.1), 14.5 (12.3) ppm; HRMS (ESI-Orbitrap)
oil. [ꢀ]ꢂꢁꢇ = +52.1 (c 1.00, CHCl3); IR (film) vmax 2956, 2928, m/z: [M + H]+ Calcd for C20H34NO3S+: 368.2254, Found:
2856, 1472, 1455, 1361, 1252, 1072, 947, 836, 774 cm-1; 1H 368.2255.
NMR (CDCl3, 400 MHz, rotamers) δ 7.37-7.24 (m, 5H), 4.53-
tert-Butyl
(S)-2-((1R,2S)-3-(benzyloxy)-1-methoxy-2-
methylpropyl)pyrrolidine-1-carboxylate 19. To a cooled (0 oC)
solution of 18 (1.90 g, 5.17 mmol) in MeOH (20 mL) was added
HCl/dioxane (2.00 mL) dropwise, after being stirred for 30 min,
the reaction was concentrated. The resulted mixture was
diluted with DCM (20 mL), and added Boc2O (1.35 g, 6.20
mmol) and TEA (4.30 mL, 31.02 mmol), after being stirred for
12 h, the mixture was quenched with a saturated aqueous
solution of NH4Cl and extracted with DCM (60 mL × 3). The
combined organic layers were washed with brine, dried over
MgSO4, filtrated and concentrated. The residue was purified by
flash chromatography on silica gel (PE/EA = 10:1) to give 19
(1.48 g, 79%, two steps) as a colorless oil. [ꢀ]ꢂꢁꢇ = +45.2 (c 1.00,
CHCl3); IR (film) vmax 2972, 2931, 2878, 1693, 1454, 1398, 1365,
4.43 (m, 2H), 3.95-3.92 (m, 0.75H), 3.82-3.79 (m, 0.25H), 3.76-
3.71 (m, 1H), 3.68-3.61 (m, 1H), 3.50-3.42 (m, 1H), 3.37-3.31
(m, 0.75H), 3.25-3.20 (m, 0.25H), 2.72-2.63 (m, 1H), 2.12-1.96
(m, 1.75H), 1.90-1.80 (m, 1.25H), 1.76-1.66 (m, 2H), 1.21 (s,
2.25H), 1.17 (s, 6.75H), 0.95-0.91 (m, 3H), 0.90-0.87 (m, 9H),
0.11-0.01 (m, 6H) ppm; 13C NMR (CDCl3, 100 MHz, rotamers) δ
138.7 (138.7), 128.4, 127.5, 75.3, 73.2 (72.9), 72.8 (72.7), 68.3
(69.6), 57.3 (57.6), 42.6 (42.3), 39.2 (37.7), 27.7 (26.8), 26.2
(26.7), 26.1, 24.0 (24.2), 18.4 (18.5), 13.5 (11.9), -4.0 (-3.7), -
4.2 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C25H46NO3SSi+: 468.2962, Found: 468.2963.
(1R,2S)-3-(Benzyloxy)-1-((S)-1-((S)-tert-
butylsulfinyl)pyrrolidin-2-yl)-2-methylpropan-1-ol 17. To
a
cooled (0 oC) solution of 16 (4.60 g, 9.84 mmol) in THF (40 mL) 1250, 1166, 1100, 735, 698 cm-1; 1H NMR (CDCl3, 400 MHz,
was added TBAF (19.68 mL, 19.68 mmol) dropwise, after being rotamers) δ 7.38-7.24 (m, 5H), 4.55-4.46 (m, 2H), 4.02-3.84 (m,
stirred for 4 h, the reaction was quenched with a saturated 1H), 3.70-3.65 (m, 0.33H), 3.64-3.59 (m, 1H), 3.58-3.46 (m, 2H),
aqueous solution of NH4Cl and extracted with EtOAc (60 mL × 3.42-3.36 (m, 0.67H), 3.35 (s, 3H), 3.31-3.22 (m, 1H), 1.99-1.89
3). The combined organic layers were washed with brine, dried (m, 2H), 1.86-1.65 (m, 3H), 1.49-1.46 (m, 9H), 1.04-0.99 (m,
over MgSO4, filtrated and concentrated. The residue was 3H) ppm; 13C NMR (CDCl3, 100 MHz, rotamers) δ 154.4 (154.5),
purified by flash chromatography on silica gel (PE/EA = 1:1) to 138.9, 128.4, 127.7, 127.5, 83.1 (82.2), 79.5 (79.1), 73.1, 72.7
o
give 17 (2.12 g, 61%) as a white solid, m.p. 84-86 C. [ꢀ]ꢁꢂꢈ
+94.8 (c 1.00, CHCl3); IR (film) vmax 3441, 2964, 2915, 2857, 25.3 (25.0), 24.5 (24.7), 14.8 (14.5) ppm; HRMS (ESI-Orbitrap)
=
(73.0), 61.0 (60.8), 59.0 (59.1), 46.8 (47.3), 37.4 (37.6), 28.7,
1
+
1453, 1359, 1068, 1039, 955, 749, 698 cm-1; H NMR (CDCl3, m/z: [M
+
H]+ Calcd for C21H34NO4 : 364.2482, Found:
400 MHz) δ 7.38-7.26 (m, 5H), 4.57-4.50 (m, 2H), 3.82-3.73 (m, 364.2482.
2H), 3.63-3.59 (m, 1H), 3.58-3.53 (m, 2H), 2.99-2.95 (m, 1H),
tert-Butyl
(S)-2-((1R,2S)-3-hydroxy-1-methoxy-2-
2.78-2.70 (m, 1H), 1.94-1.88 (m, 1H), 1.86-1.77 (m, 3H), 1.74-
1.64 (m, 1H), 1.22 (s, 9H), 0.98-0.94 (m, 3H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 138.2, 128.5, 127.8, 127.7, 75.1, 74.2, 73.4,
68.1, 57.3, 42.8, 36.5, 27.1, 23.9, 23.9, 13.9 ppm; HRMS (ESI-
methylpropyl)pyrrolidine-1-carboxylate 20.
A solution of 19 (1.40 g, 3.85 mmol) and 10% Pd/C (1.40
g) were stirred in MeOH (100 mL) for 5 h under H2
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 7 of 13
Journal Name
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
atmosphere. Then, the mixture was filtrated, concentrated and 80%) as a colorless oil. [ꢀ]ꢂꢁꢂ = +3.0 (c 1.00, CHCl3); IR (film)
purified by flash chromatography on silica gel (PE/EA = 2:1) to vmax 3358, 2967, 2932, 2876, 1748, 1712, 1499, 1366, 1249,
give 20 (758 mg, 72%) as a colorless oil. [ꢀ]ꢂꢁꢈ = +71.4 (c 1.00, 1166, 1012, 747, 698 cm-1; 1H NMR (CDCl3, 400 MHz, rotamers)
CHCl3); IR (film) vmax 3453, 2972, 2931, 2878, 1693, 1673, 1403, δ 7.38-7.34 (m, 5H), 5.22-5.13 (m, 3H), 5.03 (d, J = 8.4 Hz, 1H),
1
1366, 1166, 1110, 1039, 771 cm-1; H NMR (CDCl3, 400 MHz, 4.32 (dd, J = 8.8, 4.4 Hz, 1H), 3.62-3.58 (m, 2H), 1.99-1.88 (m,
rotamers) δ 4.01-3.82 (m, 1H), 3.81-3.75 (m, 0.5H), 3.69-3.62 1H), 1.08-0.99 (m, 1H), 0.98-0.95 (m, 2H), 0.93-0.90 (m, 1H),
(m, 1H), 3.61-3.51 (m, 2.5H), 3.48-3.41 (m, 3.5H), 3.32-3.24 (m, 0.88-0.83 (m, 3H) ppm; 13C NMR (CDCl3, 100 MHz, rotamers) δ
1H), 3.18-3.03 (m, 0.5H), 2.06-1.99 (m, 1H), 1.99-1.92 (m, 1H), 202.3, 166.7 (172.5), 155.9 (155.4), 135.4 (135.8), 128.7, 128.6,
1.89-1.66 (m, 3H), 1.50-1.45 (m, 9H), 1.06-0.86 (m, 3H) ppm; 128.5, 80.2 (80.0), 67.4 (66.2), 64.5 (58.4), 47.4, 36.4 (37.2),
13C NMR (CDCl3, 100 MHz, rotamers) δ 154.9 (154.3), 85.4 28.4 (28.5), 24.2 (24.9), 16.2 (15.8), 11.7 (11.6) ppm; HRMS
+
(87.9), 79.5 (79.7), 67.3 (67.6), 65.8, 60.3 (61.2), 58.5 (59.3), (ESI-Orbitrap) m/z: [M + H]+ Calcd for C20H29NO5 : 364.2119,
47.1 (46.9), 38.4 (38.9), 38.0, 28.6 (28.7), 25.3 (25.7), 25.0 Found: 364.2116.
(24.3), 13.5 (14.6) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
Benzyl
(3R,4S,5S)-4-((tert-butoxycarbonyl)amino)-3-
+
Calcd for C14H28NO4 : 274.2013, Found: 274.2012.
hydroxy-5-methylheptanoate 23. To a cooled (-78 oC) solution
of 22 (6.00 g, 16.51 mmol) in MeOH (66 mL) was added KBH4
(2R,3R)-3-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-3-
methoxy-2-methylpropanoic acid 7. To a cooled (0 oC) (3.12 g, 57.79 mmol) for 3 times, after being stirred for 10 min,
solution of 20 (600 mg, 2.19 mmol) in DCM (10 mL) was slowly the reaction was warmed to -15oC and stirred for another 35
added DMP (1.12 g, 2.63 mmol), after being stirred for 30 min, min, then CH3COOH was added to adjust pH ranging from 9 to
the reaction mixture was carefully quenched with a saturated 10. The reaction mixture was evaporated, extracted with
aqueous solution of NaHCO3 and solid Na2S2O3, extracted with EtOAc (80 mL × 3). The combined organic layers were washed
DCM (30 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated and concentrated. The
with brine, dried over MgSO4, filtrated and concentrated residue was purified by flash chromatography on silica gel
without further purification to give a crude aldehyde. A (PE/EA=7:1) to give 23 (4.71 g, 78%) as a white solid, m.p. 74-
solution of above aldehyde in t-BuOH/2-methyl-2-butene (5/5 76 oC; [ꢀ]ꢁꢂꢈ = +5.1 (c 2.00, CHCl3); IR (film) vmax 3441, 3370,
mL) was treated with a solution of NaClO2 (594 mg, 6.57 2965, 2932, 2876, 1714, 1697, 1500, 1366, 1251, 1169, 1068,
mmol) and NaH2PO4•2H2O (1.02 g, 6.57 mmol) in water (5 mL), 751, 697 cm-1; 1H NMR (CDCl3, 400 MHz, rotamers) δ 7.40-7.30
after being stirred for 8 h, the reaction mixture was extracted (m, 5H), 5.16 (brs, 2H), 4.47-4.28 (m, 1H), 4.10-3.90 (m, 1H),
with EtOAc (30 mL × 3) and the combined organic layers were 3.62-3.45 (m, 1H), 3.42-3.15 (m, 1H), 2.76-2.58 (m, 1H), 2.56-
washed with brine, dried over MgSO4, filtrated and 2.43 (m, 1H), 1.84-1.74 (m, 1H), 1.63-1.49 (m, 1H), 1.45-1.42
concentrated. The residue was purified by flash (m, 9H), 1.04-0.95 (m, 1H), 0.94-0.89 (m, 6H) ppm; 13C NMR
chromatography on silica gel (DCM/MeOH = 30:1) to give
7
(CDCl3, 150 MHz) δ 173.1, 156.6, 135.7, 128.7, 128.4, 128.4,
(472 mg, 75%, two steps) as a colorless oil. [ꢀ]ꢂꢁꢅ = -57.2 (c 79.7, 69.1, 66.7, 59.1, 38.5, 34.8, 28.5, 23.5, 16.4, 11.8 ppm;
+
1.00, CHCl3); IR (film) vmax 3180, 2977, 2934, 2882, 1735, 1696, HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C20H32NO5 :
1
1671, 1401, 1367, 1166, 1099, 865, 773 cm-1; H NMR (CDCl3, 366.2275, Found: 366.2274.
400 MHz, rotamers) δ 4.01-3.85 (m, 1H), 3.83-3.77 (m, 1H),
Benzyl
(3R,4S,5S)-4-((tert-
3.62-3.46 (m, 1H), 3.45 (s, 3H), 3.28-3.20 (m, 1H), 2.58-2.48 (m,
1H), 2.01-1.84 (m, 3H), 1.80-1.70 (m, 1H), 1.50-1.45 (m, 9H),
1.30-1.26 (m, 3H) ppm; 13C NMR (CDCl3, 150 MHz, rotamers) δ
179.4 (178.5), 153.8 (154.3), 82.4 (81.1), 79.3 (78.9), 60.6
(60.2), 58.9 (58.7), 46.0 (46.5), 42.2, 27.9, 25.5 (24.9), 23.4
(23.8), 12.9 (12.8) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
butoxycarbonyl)(methyl)amino)-3-methoxy-5-
o
methylheptanoate 6. To a cooled (-78 C) solution of 23 (2.00
g, 5.47 mmol) in HMPA (2.11 mL, 12.04 mmol) and THF (20 mL)
was added a solution of LiHMDS (1M in THF, 10.94 mmol)
slowly, after being stirred for 30 min, the reaction was warmed
o
to -15 C and MeOTf (2.48 mL, 21.88 mmol) was added, then
+
Calcd for C14H26NO5 : 288.1806, Found: 288.1805.
the mixture was stirred for an additional 15 min. The reaction
Benzyl (4S,5S)-4-((tert-butoxycarbonyl)amino)-5-methyl- was quenched with a saturated aqueous solution of NH4Cl and
3-oxoheptanoate 22. A solution of 21 (5.00 g, 21.62 mmol) in extracted with EtOAc (60 mL × 3). The combined organic layers
THF was added carbonyldiimidazole (3.51 g, 21.62 mmol) and were washed with brine, dried over MgSO4, filtrated and
stirred at room temperature for 2 h to give a crude imidazolide concentrated. The residue was purified by flash
for preparation. To a suspension of bencyl acetate (9.85 mL, chromatography on silica gel (PE/EA=10:1) to give
6 (1.94 g,
69.18 mmol) in THF was added LDA (2M in THF, 64.86 mmol), 90%) as a colorless oil. [ꢀ]ꢂꢁꢂ = -17.9 (c 2.00, CHCl3); IR (film)
after stirred for 30 min, the above solution of crude vmax 2968, 2932, 2876, 1736, 1691, 1455, 1391, 1365, 1328,
imidazolide previously prepared in THF was added dropwise, 1161, 1100, 771, 749, 698 cm-1; 1H NMR (CDCl3, 400 MHz,
o
and the reaction mixture was allowed to stir for 3 h at -78 C, rotamers) δ 7.37-7.31 (m, 5H), 5.18-5.10 (m, 2H), 4.17-3.82 (m,
quenched with a saturated aqueous solution of NH4Cl and 2H), 3.50-3.33 (m, 3H), 2.70-2.65 (m, 3H), 2.57-2.51 (m, 2H),
extracted with EtOAc (80 mL × 3). The combined organic layers 1.81-1.65 (m, 1H), 1.53-1.46 (m, 1H), 1.45-1.43 (m, 9H), 1.13-
were washed with brine, dried over MgSO4, filtrated and 1.05 (m, 1H), 0.97-0.94 (m, 3H), 0.91-0.86 (m, 3H) ppm; 13C
concentrated. The residue was purified by flash NMR (CDCl3, 100 MHz, rotamers) δ 171.8 (172.1), 156.6
chromatography on silica gel (PE/EA=15:1) to give 22 (6.29 g, (156.4), 135.9 (136.0), 128.6, 128.5, 128.4 (128.3), 79.3 (79.9),
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 13
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
Journal Name
78.5 (60.8), 66.6 (66.5), 58.0 (57.8), 37.8 (37.4), 34.9 (30.6), 5H), 7.16 (d, J = 9.2 Hz, 1H), 4.56-4.48 (m, 2H), 4.14 (d, J = 10.8
34.4, 28.5 (28.5), 26.0 (25.9), 16.2 (16.4), 11.3(11.3) ppm; Hz, 1H), 3.98-3.91 (m, 1H), 3.85-3.79 (m, 1H), 3.78-3.71 (m,
+
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C22H36NO5 : 1H), 3.68-3.62 (m, 1H), 3.58 (d, J = 4.0 Hz, 1H), 2.48-2.37 (m,
393.2588, Found: 393.2588.
1H), 1.95-1.87 (m, 1H), 1.84-1.79 (m, 1H), 1.78-1.75 (m, 1H),
1.50 (s, 18H), 1.32-1.25 (m, 1H), 1.17-1.09 (m, 1H), 1.03-1.00
(m, 3H), 0.92-0.88 (m, 6H), 0.87-0.84 (m, 3H) ppm; 13C NMR
(CDCl3, 150 MHz) δ 171.1, 153.9, 138.1, 128.6, 127.8, 127.8,
83.5, 73.5, 72.2, 69.6, 68.4, 55.9, 34.2, 33.1, 28.0, 27.4, 27.3,
20.8, 19.9, 13.6, 11.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
tert-Butyl
((3R,4S,5S)-1-(benzyloxy)-3-hydroxy-5-
methylheptan-4-yl)carbamate 25. A solution of 23 (2.00 g,
5.47 mmol) and 10% Pd/C (2.00 g) were stirred in MeOH (100
mL) for 2 h under H2 atmosphere. Then, the mixture was
filtrated to give a crude acid without further purification. To a
cooled (0 oC) solution of above alcohol was added isobutyl
chloroformate (725 µL, 5.74 mmol) in THF (20 mL), after stirred
+
Calcd for C30H51N2O7 : 551.3691, Found: 551.3691.
tert-Butyl (S)-3-((3R,4S,5S)-1-(benzyloxy)-3-methoxy-5-
for 30 min, the reaction mixture was added NaBH4 (414 mg, methylheptan-4-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-
o
10.94 mmol) in water (2 mL) slowly, after being stirred carboxylate 28. To a cooled (-78 C) solution of 27 (700 mg,
overnight, the reaction mixture was quenched with
a
1.27 mmol) in HMPA (488 µL, 2.79 mmol) and THF (5 mL) was
saturated aqueous solution of NH4Cl and extracted with EtOAc added a solution of LiHMDS (1M in THF, 2.54 mmol) slowly,
(60 mL × 3). The combined organic layers were washed with after being stirred for 30 min, the reaction was warmed to -15
brine, dried over MgSO4, filtrated and concentrated. The oC and MeOTf (575 mL, 5.08 mmol) was added, then the
residue was purified by flash chromatography on silica gel mixture was stirred for an additional 15 min. The reation was
(PE/EA=1:1) to give
a crude alcohol without further quenched with a saturated aqueous solution of NH4Cl and
o
purification. To a cooled (0 C) solution of above alcohol (1.00 extracted with EtOAc (30 mL × 3). The combined organic layers
g, 3.83 mmol) was added NaH (153 mg, 60%, 3.83 mmol) and were washed with brine, dried over MgSO4, filtrated and
BnBr (455 µL, 3.83 mmol) in DMF (5 mL), after being stirred concentrated. The residue was purified by flash
overnight, the reaction mixture was quenched with
a
chromatography on silica gel (PE/EA=10:1) to give 28 (386 mg,
saturated aqueous solution of NH4Cl and extracted with EtOAc 62%) as a colorless oil. [ꢀ]ꢂꢁꢈ = -24.8 (c 0.50, CHCl3); IR (film)
(60 mL × 3). The combined organic layers were washed with vmax 2966, 2932, 2880, 2853, 1813, 1794, 1730, 1367, 1318,
brine, dried over MgSO4, filtrated and concentrated. The 1156, 1104, 794, 769 cm-1; 1H NMR (CDCl3, 400 MHz, rotamers)
residue was purified by flash chromatography on silica gel δ 7.36-7.29 (m, 5H), 4.56-4.51 (m, 1H), 4.47-4.42 (m, 1H), 4.32-
(PE/EA=6:1) to give 25 (1.20 g, 62%, three steps) as a colorless 4.08 (m, 2H), 3.96-3.66 (m, 1H), 3.56-3.52 (m, 2H), 3.37-3.32
oil. [ꢀ]ꢂꢁꢇ = +9.3 (c 1.00, CHCl3); IR (film) vmax 3449, 3344, 2962, (m, 3H), 3.31-3.28 (m, 1H), 2.55-2.42 (m, 2H), 2.14-1.96 (m,
2927, 2875, 1697, 1500, 1454, 1391, 1366, 1171, 1088, 737, 1H), 1.54 (s, 9H), 1.52-1.42 (m, 2H), 1.21-1.17 (m, 3H), 0.95-
1
698 cm-1; H NMR (CDCl3, 400 MHz) δ 7.38-7.25 (m, 5H), 4.57- 0.87 (m, 9H) ppm; 13C NMR (CDCl3, 150 MHz, rotamers) δ
4.42 (m, 3H), 3.85-3.78 (m, 1H), 3.73-3.57 (m, 3H), 3.57-3.46 171.4, 153.2 (153.7), 148.7, 138.8, 128.5, 127.7, 127.6, 84.1,
(m, 0.5H), 3.45-3.42 (m, 0.5H), 1.92-1.73 (m, 3H), 1.45-1.41 (m, 72.9, 66.7, 64.0 (63.2), 58.4 (59.3), 57.9, 57.1, 57.0, 31.8 (32.4),
9H), 1.40-1.31 (m, 1H), 1.25-1.14 (m, 1H), 0.94-0.89 (m, 3H), 31.5 (31.3), 29.8 (30.1), 28.2, 26.3 (26.0 ), 18.5 (18.3), 16.4,
0.88-0.80 (m, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 156.4, 16.3 (16.8), 16.2 (16.0), 10.5 (10.9) ppm; HRMS (ESI-Orbitrap)
+
137.9, 128.6, 127.9, 127.8, 79.3, 73.5, 72.7, 69.7, 57.2, 34.0, m/z: [M + H]+ Calcd for C27H43N2O6 : 491.3116, Found:
33.2, 28.5, 27.3, 13.6, 11.8 ppm; HRMS (ESI-Orbitrap) m/z: [M 491.3116.
+
+ H]+ Calcd for C20H34NO4 : 352.2482, Found: 352.2481.
Benzyl N-(tert-butoxycarbonyl)-N-methyl-L-isoleucinate
o
Ditert-butyl ((S)-1-(((3R,4S,5S)-1-(benzyloxy)-3-hydroxy- 29. To a cooled (0 C) solution of 21 (10.00 g, 43.24 mmol) in
5-methylheptan-4-yl)amino)-3-methyl-1-oxobutan-2-
THF (170 mL) was added NaH (8.65 g, 60%, 216.20 mmol) for
yl)carbamate 27. To a cooled (0 oC) solution of 25 (907 mg, three times, after being stirred for 30 min, MeI (18.84 mL,
2.58 mmol) in DCM (10 mL) was added TFA (2 mL) slowly, after 302.68 mmol) was added slowly. After being stirred for 48 h,
being stirred for 2 h, the mixture was concentrated under the reaction mixture was quenched with a saturated aqueous
reduced pressure. The residue was dissolved in DCM (10 mL), solution of NH4Cl and extracted with EtOAc (100 mL × 3). The
HATU (1.18 g, 3.10 mmol), HOAt (422 mg, 3.10 mmol), DIPEA combined organic layers were washed with brine, dried over
(2.70 mL, 15.48 mmol) and N,N-bis[(1,1-dimethylethoxy) MgSO4, filtrated and concentrated to give a crude acid without
carbonyl]-L-Valine (984 mg, 3.10 mmol) were added, after further purification. To a solution of the above acid in DMSO
being stirred overnight, the reaction mixture was quenched (50 mL) was treated with K2CO3 (11.95 g, 86.48 mmol) and
with a saturated aqueous solution of NH4Cl and extracted with BnBr (4.11 mL, 47.56 mmol), after being stirred overnight, the
DCM (30 mL × 3). The combined organic layers were washed reaction mixture was quenched with a saturated aqueous
with brine, dried over MgSO4, filtrated and concentrated. The solution of NH4Cl and extracted with EtOAc (100 mL × 3). The
residue was purified by flash chromatography on silica gel combined organic layers were washed with water, brine, dried
(PE/EA=5:1) to give 27 (739 mg, 52%, two steps) as a colorless over MgSO4, filtrated and concentrated. The residue was
oil. [ꢀ]ꢂꢁꢈ = +22.6 (c 0.50, CHCl3); IR (film) vmax 3445, 3336, purified by flash chromatography on silica gel (PE/EA=40:1) to
2965, 2922, 2875, 2851, 1742, 1697, 1368, 1333, 1236, 1167, give 29 (7.98 g, 55%, two steps) as a colorless oil. [ꢀ]ꢂꢁꢈ = -64.3
1129, 851, 696 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.36-7.27 (m, (c 1.00, CHCl3); IR (film) vmax 2969, 2932, 2880, 1739, 1698,
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 9 of 13
Journal Name
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
1456, 1367, 1312, 1256, 1177, 1144, 750, 697 cm-1; 1H NMR 400 MHz, rotamers) δ 7.38-7.32 (m, 5H), 5.25-5.10 (m, 3H),
(CDCl3, 400 MHz, rotamers) δ 7.40-7.27 (m, 5H), 5.19-5.10 (m, 5.06-4.85 (m, 1H), 4.39 (dd, J = 9.6, 6.8 Hz, 1H), 3.55-3.43 (m,
2H), 4.60 (d, J = 10.8 Hz, 0.5H), 4.29 (d, J = 10.8 Hz, 0.5H), 2.84- 2H), 3.10 (s, 0.33H), 2.89 (s, 2.67H), 2.09-1.99 (m, 1H), 1.97-
2.76 (m, 3H), 2.07-1.91 (m, 1H), 1.46-1.41 (m, 10H), 1.14-1.03 1.89 (m, 1H), 1.42 (s, 9H), 1.32-1.26 (m, 1H), 1.01-0.94 (m, 1H),
(m, 1H), 0.92-0.86 (m, 6H) ppm; 13C NMR (CDCl3, 100 MHz, 0.93-0.89 (m, 6H), 0.88-0.79 (m, 6H) ppm; 13C NMR (CDCl3, 100
rotamers) δ 171.2 (171.6), 155.7 (156.3), 135.8 (136.0), 128.7 MHz, rotamers) δ 198.9, 174.1, 166.7, 156.0, 135.3, 128.7,
(128.6), 128.4, 128.2 (128.1), 80.4 (80.1), 66.4 (66.3), 63.5 128.6, 128.6, 128.5, 128.2, 79.9, 67.3, 65.3, 55.6, 48.0, 31.0,
(62.1), 33.6 (33.7), 30.5 (30.3), 28.4, 25.1 (25.1), 16.0 (15.9), 30.9, 30.8, 28.4, 24.2, 19.7, 17.7, 15.8, 10.6 ppm; HRMS (ESI-
+
10.4 (10.8) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for Orbitrap) m/z: [M + H]+ Calcd for C26H41N2O6 : 477.2959,
+
C19H30NO4 : 336.2169, Found: 336.2169.
Found: 477.2960.
Benzyl
N-((tert-butoxycarbonyl)-L-valyl)-N-methyl-L-
Benzyl (3R,4S,5S)-4-((S)-2-((tert-butoxycarbonyl)amino)-
isoleucinate 30. To a cooled (0 oC) solution of 29 (7.80 g, 23.25 N,3-dimethylbutanamido)-3-hydroxy-5-methylheptanoate
o
mmol) in DCM (90 mL) was added TFA (10 mL) slowly, after 32. To a cooled (-78 C) solution of 31 (6.50 g, 13.64 mmol) in
being stirred for 2 h, the mixture was concentrated under MeOH (55 mL) was added KBH4 (2.58 g, 47.74 mmol) for 3
reduced pressure. The residue was dissolved in DCM (90 mL), times, after being stirred for 10 min, the reaction was warmed
HATU (9.72 g, 25.58 mmol), DIPEA (24.30 mL, 139.50 mmol), to -15oC and stirred for another 35 min, then CH3COOH was
and N-Boc-L-Valine (5.56 g, 25.58 mmol) were added, after added to adjust pH ranging from 9 to 10. The reation mixture
being stirred overnight, the reaction mixture was quenched was evaporated, extracted with EtOAc (80 mL × 3). The
with a saturated aqueous solution of NH4Cl and extracted with combined organic layers were washed with brine, dried over
DCM (100 mL × 3). The combined organic layers were washed MgSO4, filtrated and concentrated. The residue was purified by
with brine, dried over MgSO4, filtrated and concentrated. The flash chromatography on silica gel (PE/EA=5:1) to give 32 (5.09
residue was purified by flash chromatography on silica gel g, 78%) as a colorless oil. [ꢀ]ꢂꢁꢅ = -21.7 (c 2.00, CHCl3); IR (film)
(PE/EA 8:1) to give 30 (8.29 g, 82%, two steps) as a colorless vmax 3375, 2966, 2932, 2876, 1709, 1626, 1498, 1456, 1366,
oil. [ꢀ]ꢂꢁꢈ = -77.0 (c 2.00, CHCl3); IR (film) vmax 3431, 2966, 2932, 1254, 1170, 1102, 750, 698 cm-1; 1H NMR (CDCl3, 400 MHz,
2876, 1736, 1706, 1647, 1498, 1456, 1366, 1255, 1175, 1013, rotamers) δ 7.39-7.26 (m, 5H), 5.19-5.05 (m, 3H), 4.46-4.31 (m,
1
750, 698 cm-1; H NMR (CDCl3, 400 MHz) δ 7.37-7.28 (m, 5H), 2H), 4.29-4.20 (m, 0.5H), 3.19-3.05 (m, 3H), 2.55-2.27 (m, 2H),
5.21 (d, J = 12.0 Hz, 1H), 5.18-5.13 (m, 1H), 5.09 (d, J = 6.8 Hz, 2.14-2.03 (m, 0.5H), 2.02-1.87 (m, 1H), 1.43-1.34 (m, 9H), 1.03-
1H), 5.05 (d, J = 8.4 Hz, 1H), 4.35 (dd, J = 9.6, 7.2 Hz, 1H), 2.98 0.95 (m, 6H), 0.94-0.87 (m, 4H), 0.87-0.76 (m, 3H) ppm; 13C
(s, 3H), 2.05-1.97 (m, 1H), 1.88-1.80 (m, 1H), 1.42 (s, 9H), 1.38- NMR (CDCl3, 100 MHz, rotamers) δ 174.0 (173.6), 156.1, 135.7,
1.30 (m, 1H), 1.06-0.98 (m, 1H), 0.97-0.94 (m, 3H), 0.88-0.81 128.7, 128.5, 128.4, 128.3, 79.7, 67.8 (67.7), 66.6, 59.6 (55.7),
(m, 9H) ppm; 13C NMR (CDCl3, 100 MHz) δ 173.6, 170.8, 156.1, 39.2, 32.2 (31.6), 30.9 (31.4), 28.4 (30.7), 25.5 (28.3), 20.0
135.6, 128.7, 128.6, 128.5, 79.6, 66.7, 60.5, 55.5, 33.2, 31.4, (19.9), 15.8 (17.6), 15.6 (17.3), 10.9 ppm; HRMS (ESI-Orbitrap)
+
31.2, 28.4, 24.8, 19.4, 17.7, 16.0, 10.9 ppm; HRMS (ESI- m/z: [M + H]+ Calcd for C26H43N2O6 : 479.3116, Found:
+
Orbitrap) m/z: [M + H]+ Calcd for C24H39N2O5 : 435.2854, 479.3115.
Found: 435.2852.
Benzyl (3R,4S,5S)-4-((S)-2-((tert-butoxycarbonyl)amino)-
Benzyl (4S,5S)-4-((S)-2-((tert-butoxycarbonyl)amino)-N,3- N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate
o
24a. To a cooled (-78 C) solution of 32 (1.00 g, 2.09 mmol) in
dimethylbutanamido)-5-methyl-3-oxoheptanoate
31.
A
solution of 30 (8.00 g, 18.41 mmol) and 10% Pd/C (800 mg) HMPA (4.02 mL, 2.30 mmol) and THF (8 mL) was added a
were stirred in MeOH (500 mL) for 5 h under H2 atmosphere. solution of LiHMDS (1M in THF, 2.09 mmol) slowly, after being
Then, the mixture was filtrated to give a crude acid without stirred for 30 min, the reaction was warmed to -15 oC and
further purification. To a solution of above acid in THF (70 mL) MeOTf (473 µL, 4.18 mmol) was added, then the mixture was
was added carbonyldiimidazole (2.99 g, 18.41 mmol) and stirred for an additional 15 min. The reaction was quenched
stirred at room temperature for 2 h to give a crude imidazolide with a saturated aqueous solution of NH4Cl and extracted with
for preparation. To a suspension of bencyl acetate (8.43 mL, EtOAc (60 mL × 3). The combined organic layers were washed
58.91 mmol) in THF (70 mL) was added LDA (2M in THF, 55.23 with brine, dried over MgSO4, filtrated and concentrated. The
mmol) at -78 oC, after stirred for 30 min, the above solution of residue was purified by flash chromatography on silica gel
crude imidazolide previously prepared in THF (10 mL) was (PE/EA=8:1) to give 24a (618 mg, 60%) as a colorless oil. [ꢀ]ꢁꢂꢈ
added dropwise, and the reaction mixture was allowed to stir = -22.4 (c 1.00, CHCl3); IR (film) vmax 3329, 2965, 2929, 2876,
o
for 3 h at -78 C, quenched with a saturated aqueous solution 1735, 1172, 1639, 1497, 1366, 1251, 1167, 1102, 751, 698 cm-
1
of NH4Cl and extracted with EtOAc (100 mL × 3). The combined
;
1H NMR (CDCl3, 400 MHz, rotamers) δ 7.37-7.31 (m, 5H),
organic layers were washed with brine, dried over MgSO4, 5.18-5.14 (m, 1.33H), 5.11-5.05 (m, 1.67H), 4.45-4.40 (m, 1H),
filtrated and concentrated. The residue was purified by flash 4.39-4.32 (m, 1H), 4.13-4.07 (m, 1H), 3.29-3.27 (m, 3H), 3.07-
chromatography on silica gel (PE/EA=8:1) to give 31 (7.02 g, 3.04 (m, 3H), 2.51-2.44 (m, 1H), 2.41-2.34 (m, 1H), 2.04-1.88
80%, two steps) as a colorless oil. [ꢀ]ꢂꢁꢇ = -210.9 (c 1.00, (m, 2.67H), 1.66-1.60 (m, 0.33H), 1.42-1.36 (m, 9H), 1.30-1.25
CHCl3); IR (film) vmax 3344, 2966, 2930, 2876, 1748, 1715, 1642, (m, 1H), 0.99-0.97 (m, 3H), 0.96-0.93 (m, 3H), 0.92-0.89 (m,
1
1498, 1367, 1254, 1170, 1102, 750, 698 cm-1; H NMR (CDCl3, 3H), 0.83-0.75 (m, 3H) ppm; 13C NMR (CDCl3, 100 MHz,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 13
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
Journal Name
rotamers) δ 174.1 (173.9), 171.8 (172.1), 156.1, 135.9 (136.0), (m, 1H), 3.30-3.23 (m, 3H), 3.10-3.06 (m, 3H), 2.53-2.39 (m,
128.6, 128.5, 128.4, 128.3, 77.8 (79.5), 66.6 (66.5), 60.1 (59.8), 2H), 2.38-2.30 (m, 1H), 2.25 (s, 3H), 2,19 (s, 3H), 2.10-1.91 (m,
58.6 (58.7), 55.4 (55.6), 37.1 (36.6), 32.1 (32.0), 31.8 (31.6), 3.5H), 1.68-1.59 (m, 0.5H), 1.30-1.18 (m, 1H), 1.03-1.00 (m,
31.0 (30.9), 28.4, 25.3 (25.8), 20.0 (19.9), 17.4 (17.6), 15.9 3H), 0.99-0.96 (m, 4.5H), 0.95-0.91 (m, 6H), 0.88-0.86 (m,
(15.8), 10.8 (10.8) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ 1.5H), 0.80-0.75 (m, 3H) ppm; 13C NMR (CDCl3, 100 MHz,
+
Calcd for C27H45N2O6 : 493.3272, Found: 493.3270.
rotamers) δ 172.6, 170.9 (171.2), 170.8, 135.1 (135.2), 127.9,
127.8, 127.6, 76.5 (77.0), 75.9 (75.7), 65.9 (65.7), 59.2 (59.2),
57.9 (57.9), 52.5 (52.9), 42.2 (42.1), 36.3 (35.9), 31.3 (31.4),
30.9 (30.8), 30.3 (30.0), 27.0 (26.9), 24.6 (25.0), 19.5 (19.6),
19.5, 17.2 (17.4), 16.9 (17.1), 15.0 (15.2), 9.9 (9.9) ppm; HRMS
Benzyl (6S,9S,12S,13R)-12-((S)-sec-butyl)-6,9-diisopropyl-
13-methoxy-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-
triazapentadecan-15-oate 33. To a cooled (0 oC) solution of
24a (1.50 g, 3.04 mmol) in DCM (12 mL) was added TFA (1 mL)
+
(ESI-Orbitrap) m/z: [M + H]+ Calcd for C29H50N3O5 : 520.3745,
slowly, after being stirred for
2 h, the mixture was
Found: 520.3745.
concentrated under reduced pressure. The residue was
dissolved in DCM (12 mL), HATU (1.12 g, 3.65 mmol), HOAt
tert-Butyl
(793 (((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidine-
mg, 3.65 mmol) were added, after being stirred overnight, the 1-carboxylate 35. To a cooled (0 oC) solution of
(484 mg, 1.57
(S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-
(497 mg, 3.65 mmol), DIPEA (3.18 mL, 18.24 mmol), and
5
8
reaction mixture was quenched with a saturated aqueous mmol) in MeOH (6 mL) was added HCl/dioxane (500 µL) slowly,
solution of NH4Cl and extracted with DCM (30 mL × 3). The after being stirred for 30 min, the mixture was concentrated
combined organic layers were washed with brine, dried over under reduced pressure. The residue was dissolved in DCM (6
MgSO4, filtrated and concentrated. The residue was purified by mL), HATU (581 mg, 1.88 mmol), HOAt (256 mg, 1.88 mmol),
flash chromatography on silica gel (PE/EA=5:1) to give 33 (1.53 DIPEA (1.64 mL, 9.42 mmol), and 7 (450 mg, 1.57 mmol) were
g, 85%, two steps) as a colorless oil. [ꢀ]ꢂꢁꢈ = -23.5 (c 1.00, added, after being stirred overnight, the reaction mixture was
CHCl3); IR (film) vmax 3295, 2965, 2931, 2875, 1736, 1694, 1630, quenched with a saturated aqueous solution of NH4Cl and
1
1523, 1366, 1246, 1165, 1101, 754, 698 cm-1; H NMR (CDCl3, extracted with DCM (30 mL × 3). The combined organic layers
400 MHz, rotamers) δ 7.36-7.32 (m, 5H), 6.54-6.36 (m, 1H), were washed with brine, dried over MgSO4, filtrated and
5.19-5.15 (m, 0.5H), 5.09-5.04 (m, 2.5H), 4.83-4.78 (m, 1H), concentrated. The residue was purified by flash
4.38-4.32 (m, 1H), 4.11-4.06 (m, 1H), 3.94-3.78 (m, 1H), 3.29- chromatography on silica gel (DCM/MeOH=100:1) to give 35
3.26 (m, 3H), 3.05-3.02 (m, 3H), 2.52-2.39 (m, 1H), 2.37-2.24 (595 mg, 80%, two steps) as a white solid, m.p. 121-123 oC;
(m, 1H), 2.06-1.98 (m, 2H), 1.97-1.88 (m, 1.5H), 1.66-1.59 (m, [ꢀ]ꢂꢁꢅ = -66.4 (c 1.00, CHCl3); IR (film) vmax 3456, 3288, 2974,
0.5H), 1.43-1.41 (m, 9H), 1.24-1.11 (m, 1H), 0.98-0.95 (m, 3H), 2931, 2873, 1655, 1535, 1454, 1404, 1365, 1168, 1104, 772,
1
0.95-0.92 (m, 3H), 0.89-0.86 (m, 6H), 0.81-0.79 (m, 3H), 0.78- 698 cm-1; H NMR (CDCl3, 400 MHz, rotamers) δ 7.76-7.73 (m,
0.75 (m, 3H) ppm; 13C NMR (CDCl3, 100 MHz, rotamers) δ 1H), 7.28-7.26 (m, 1H), 7.24-7.10 (m, 5.5H), 6.50-6.46 (m,
173.1 (172.9), 171.6 (171.8), 171.6 (171.5), 155.8, 135.9 0.5H), 5.66-5.55 (m, 1H), 3.94-3.85 (m, 0.5H), 3.81-3.74 (m,
(135.8), 128.7 (128.6), 128.7 (128.5), 128.6 (128.4), 79.7 (79.8), 0.5H), 3.73-3.70 (m, 0.5H), 3.57-3.47 (m, 1H), 3.42-3.39 (m,
77.7 (59.9), 66.6 (66.7), 60.1 (60.1), 58.6 (58.7), 54.1 (53.8), 0.5H), 3.37-3.35 (m, 3H), 3.30-3.11 (m, 2.5H), 2.45-2.35 (m,
36.9 (36.7), 32.1, 31.5 (31.7), 31.4 (31.3), 31.1 (31.2), 28.4, 0.5H), 2.31-2.25 (m, 0.5H), 2.17-2.08 (m, 0.5H), 1.84-1.76 (m,
25.7 (25.4), 20.0 (20.1), 19.4 (19.3), 17.9, 17.4 (17.3), 15.9 1H), 1.76-1.64 (m, 2H), 1.62-1.55 (m, 1H), 1.50-1.46 (m, 9H),
(15.8), 10.7 (10.7) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ 1.18-1.12 (m, 3H) ppm; 13C NMR (CDCl3, 100 MHz, rotamers) δ
+
Calcd for C32H54N3O7 : 592.3956, Found: 592.3956.
173.4 (174.0), 171.2 (171.7), 154.4 (154.9), 142.6, 136.6
(137.0), 129.5, 129.4, 128.6, 127.1 (126.9), 119.0 (118.9), 83.6
(81.9), 79.9 (79.5), 60.9 (60.7), 58.7 (59.0), 52.0 (52.6), 46.6
(47.0), 44.3 (43.9), 41.5, 28.7, 25.7 (25.1), 24.4 (24.8), 14.2
(13.9) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for
C25H36N3O4S+: 474.2421, Found: 474.2422.
Benzyl
(3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-
methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-
o
methylheptanoate 34. To a cooled (0 C) solution of 33 (1.40
g, 2.37 mmol) in DCM (9 mL) was added TFA (1 mL) slowly,
after being stirred for 2 h, the mixture was concentrated under
reduced pressure, which was dissolved in CH3CN (9 mL), added
Dolastatin 10 (1). A solution of 34 (608 mg, 1.17 mmol)
40% HCHO (4 mL, 18.96 mmol) and Na(BH3)CN (447 mg, 7.11 and 10% Pd/C (600 mg) were stirred in MeOH (50 mL) for 2 h
mmol), after being stirred for 18 h, the reaction mixture was under H2 atmosphere. Then, the mixture was filtrated to give a
evaporated and extracted with EtOAc (30 mL × 3). The crude acid without further purification. To a cooled (0 oC)
combined organic layers were washed with brine, dried over solution of 35 (500 mg, 1.06 mmol) in DCM (4 mL) was added
MgSO4, filtrated and concentrated. The residue was purified by TFA (1 mL) slowly, after being stirred for 2 h, the mixture was
flash chromatography on silica gel (PE/EA/NH4OH=1:1:0.01) to concentrated. The residue was dissolved in DCM (4 mL), HATU
give 34 (1.01 g, 82%, two steps) as a colorless oil. [ꢀ]ꢂꢁꢈ = -20.4 (392 mg, 1.27 mmol), HOAt (173 mg, 1.27 mmol), DIPEA (1.11
(c 1.00, CHCl3); IR (film) vmax 3303, 2963, 2932, 2874, 2830, mL, 6.36 mmol), and the above crud acid were added, after
1737, 1633, 1620, 1456, 1164, 1101, 751, 698 cm-1; 1H NMR being stirred for 24 h, the reaction mixture was quenched with
(CDCl3, 400 MHz, rotamers) δ 7.41-7.29 (m, 5H), 6.87 (d, J = 9.2 a saturated aqueous solution of NH4Cl and extracted with DCM
Hz, 0.5H), 6.78 (d, J = 9.2 Hz, 0.5H), 5.20-5.16 (m, 0.5H), 5.10- (30 mL × 3). The combined organic layers were washed with
5.07 (m, 1.5H), 4.89-4.83 (m, 1H), 4.40-4.34 (m, 1H), 4.12-4.09 brine, dried over MgSO4, filtrated and concentrated. The
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 11 of 13
Journal Name
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
F. Loganzo and C. J. O'Donnell, J. Med. Chem., 2014, 57
10527-10543.
,
residue was purified by flash chromatography on silica gel
(DCM/MeOH=100:1 to 25:1) to give (500 mg, 60%, three
1
4
(a) R. A. Newman, A. Fuentes, J. M. Covey and J. A.
Benvenuto, Drug Metab. Dispos., 1994, 22, 428-432; (b) J. C.
Mirsalis, J. Schindler-Horvat, J. R. Hill, J. E. Tomaszewski, S. J.
Donohue and C. A. Tyson, Cancer Chemother. Pharmacol.,
1999, 44, 395-402; (c) L. M. Krug, V. A. Miller, G. P.
Kalemkerian, M. J. Kraut, K. K. Ng, R. T. Heelan, B. A. Pizzo,
steps) as a viscous liquid, which was further treated with
o
acetone /hexane to give white powder, m.p. 89-90 C, [lit.4b
o
102-106 C]. [ꢀ]ꢂꢁꢃ = -63.3 (c 1.00, MeOH); IR (film) vmax 3443,
3295, 2966, 2932, 2875, 2831, 1634, 1537, 1498, 1454, 1100,
1
1033, 753, 696, 663 cm-1; H NMR (CDCl3, 600 MHz, rotamers)
W. Perez, N. McClean and M. G. Kris, Ann. Oncol., 2000, 11
,
δ 7.74 (dd, J = 7.2, 3.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 0.5H), 7.31
(d, J = 7.8 Hz, 0.5H), 7.28-7.18 (m, 6H), 6.99-6.91 (m, 1H), 5.62-
5.55 (m, 1H), 4.92 (dd, J = 9.0, 6.0 Hz, 0.5H), 4.85 (dd, J = 9.0,
4.8 Hz, 0.5H), 4.39-4.27 (m, 2H), 4.15-4.05 (m, 1H), 3.89 (dd, J =
7.2, 2.4 Hz, 0.5H), 3.79 (dd, J = 7.2, 3.0 Hz, 0.5H), 3.47-3.39 (m,
1.5H), 3.39 (s, 1.5H), 3.38-3.36 (m, 0.5H), 3.35 (s, 1.5H), 3.34-
3.31 (m, 1H), 3.31 (s, 1.5H), 3.31-3.29 (m, 0.5H), 3.29 (s, 1.5H),
3.28-3.26 (m, 0.5H), 3.13-3.11 (m, 2.5H), 2.49-2.46 (m, 0.5H),
2.46-2.40 (m, 2H), 2.35-2.30 (m, 1H), 2.29 (s, 3H), 2.26 (s, 3H),
2.14-2.00 (m, 4H), 1.98-1.94 (m, 1H), 1.92-1.82 (m, 1H), 1.82-
1.75 (m, 1H), 1.74-1.62 (m, 2H), 1.26-1.18 (m, 1H), 1.16-1.11
(m, 3H), 1.10-1.04 (m, 3H), 1.04-0.99 (m, 6H), 0.96-0.92 (m,
6H), 0.80-0.75 (m, 3H) ppm; 13C NMR (CDCl3, 150 MHz,
rotamers) δ 173.9 (174.2), 173.0 (173.4), 172.0, 171.7 (171.6),
170.5 (170.2), 142.5 (142.5), 137.2 (137.3), 129.6 (129.5),
128.5 (128.5), 126.9 (126.8), 118.9, 81.9 (81.8), 77.6 (76.5),
76.7, 60.7 (60.9), 60.5 (60.6), 59.2, 59.2 (59.3), 53.8 (53.5),
52.7, 47.6 (47.4), 43.9 (43.8), 43.2, 42.9, 41.3 (41.0), 38.4
(38.1), 32.1 (32.4), 32.0 (31.8), 31.2 (30.0), 27.7 (27.7), 26.0
(25.5), 25.2 (25.1), 24.9 (24.6), 20.4 (20.6), 20.3 (20.2), 18.1
(18.1), 17.9 (17.2), 16.1 (15.9), 13.9 (13.6), 10.8(10.6) ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C42H69N6O6S+:
785.4994, Found: 785.4996.
227-228; (d) E. D. Saad, E. H. Kraut, P. M. Hoff, D. F. J. Moore,
D. Jones, R. Pazdur and J. L. Abbruzzese, Am. J. Clin. Oncol.,
2002, 25, 451-453; (e) P. Schoffski, B. Thate, G. Beutel, O.
Bolte, D. Otto, M. Hofmann, A. Ganser, A. Jenner, P.
Cheverton, J. Wanders, T. Oguma, R. Atsumi and M. Satomi,
Ann. Oncol., 2004, 15, 671-679; (f) S. Blagden, A. Thomas, J.
S. De-Bono, S. Ahmed, A. Greystoke, G. Attard, A. Jenner, P.
Fong and W. P. Steward, J. Clin. Oncol., 2005, 23, 3141; (g) A.
Greystoke, S. Blagden, A. L. Thomas, E. Scott, G. Attard, R.
Molife, L. Vidal, S. Pacey, D. Sarkar, A. Jenner, J. S. De-Bono
and W. Steward, Ann. Oncol., 2006, 17, 1313-1319; (h) G. J.
Riely, S. Gadgeel, I. Rothman, B. Saidman, K. Sabbath, K. Feit,
M. G. Kris and N. A. Rizvi, Lung Cancer, 2007, 55, 181-185.
(a) F. Fujita, M. Koike, M. Fujita, Y. Sakamoto and S.
Tsukagoshi, Gan to Kagaku Ryoho, 2000, 27, 451-458; (b) H.
L. Kindler, P. K. Tothy, R. Wolff, R. A. McCormack, J. L.
Abbruzzese, S. Mani, K. T. Wade-Oliver and E. E. Vokes,
Invest. New Drugs, 2005, 23, 489-493; (c) H. Piplani, C. Rana,
V. Vaish, K. Vaiphei and S. N. Sanyal, Biochim. Biophys. Acta,
Gen. Subj., 2013, 1830, 5142-5156.
(a) K. Hayashi, Y. Hamada and T. Shioiri, Pept. Chem., 1991,
28th, 43-48; (b) K. Hayashi, Y. Hamada and T. Shioiri, Tennen
Yuki Kagobutsu Toronkai Koen Yoshishu, 1991, 33rd, 109-
115; (c) K. Tomioka, M. Kanai and K. Koga, Tetrahedron Lett.,
1991, 32, 2395-2398; (d) F. Roux, I. Maugras, J. Poncet, G.
Niel and P. Jouin, Tetrahedron, 1994, 50, 5345-5360; (e) T.
Shioiri, Yuki Gosei Kagaku Kyokaishi, 1994, 52, 392-402; (f) C.
Mordant, S. Reymond, H. Tone, D. Lavergne, R. Touati, B. Ben
Hassine, V. Ratovelomanana-Vidal and J.-P. Genet,
Tetrahedron, 2007, 63, 6115-6123.
5
6
Acknowledgements
7
(a) K. Miyazaki, M. Gondo and K. Sakakibara, Pept. Chem.,
1993, 31st, 85-88; (b) T. Shioiri, K. Hayashi and Y. Hamada,
Tetrahedron, 1993, 49, 1913-1924; (c) I. K. Kim, B. S. Lee, Y.
T. Hong, A. S. Choi and N. Y. Kwon, J. Korean Chem. Soc.,
We thank the Project funded by China Postdoctoral Science
Foundation (KLF301012 to C.-M. Si), National Natural Science
Foundation of China (21472022, 21272041 to B.-G. Wei) for
financial support. The authors thank Dr. Han-Qing Dong
(Arvinas, Inc.) for helpful suggestions.
1994, 38, 763-768; (d) K. Miyazaki, M. Kobayashi, T.
Natsume, M. Gondo, T. Mikami, K. Sakakibara and S.
Tsukagoshi, Chem. Pharm. Bull., 1995, 43, 1706-1718; (e) G.
R. Pettit, J. K. Srirangam, J. Barkoczy, M. D. Williams, K. P. M.
Durkin, M. R. Boyd, R. Bai, E. Hamel, J. M. Schmidt and J.-C.
Chapius, Anti-Cancer Drug Des., 1995, 10, 529-544; (f) J.
Poncet, L. Hortala, M. Busquet, F. Gueritte-Voegelein, S.
Thoret, A. Pierre, G. Atassi and P. Jouin, Bioorg. Med. Chem.
Notes and references
1
(a) S.-H. Chen and M. Rodriguez, Drugs Fut., 2003, 28, 441-
463; (b) K. R. Meena and S. S. Kanwar, BioMed Res. Int.,
2015, 2015, 1-10; (c) D. Morita and M. Sugita, Immunology,
2016, 149, 139-145; (d) J. A. Hutchinson, S. Burholt and I. W.
Hamley, J. Pept. Sci., 2017, 23, 82-94; (e) E. Mevers, F. P. J.
Haeckl, P. D. Boudreau, T. Byrum, P. C. Dorrestein, F. A.
Valeriote and W. H. Gerwick, J. Nat. Prod., 2014, 77, 969-
975.
Lett., 1998, 8, 2855-2858; (g) X. Wang, S. Dong, D. Feng, Y.
Chen, M. Ma and W. Hu, Tetrahedron, 2017, 73, 2255-2266;
(h) A. Maderna and C. A. Leverett, Mol. Pharmaceutics, 2015,
12, 1798-1812.
8
For seleted recent works, see: (a) W. Huang, R.-G. Ren, H.-Q.
,
Dong, B.-G. Wei and G.-Q. Lin, J. Org. Chem., 2013, 78
10747-10762; (b) R.-G. Ren, J.-Y. Ma, Z.-Y. Mao, Y.-W. Liu and
B.-G. Wei, Chin. Chem. Lett., 2015, 26, 1209-1215; (c) M. Li,
P. Han, Z.-Y. Mao, W. Zhou, C.-M. Si, J. Xiong, B.-G. Wei and
J.-F. Hu, Tetrahedron Lett., 2016, 57, 5620-5623; (d) Z.-Y.
Mao, C.-M. Si, Y.-W. Liu, H.-Q. Dong, B.-G. Wei and G.-Q. Lin,
J. Org. Chem., 2016, 81, 9903-9911; (e) W. Tao, W. Zhou, Z.
Zhou, C.-M. Si, X. Sun and B.-G. Wei, Tetrahedron, 2016, 72,
5928-5933; (f) L.-P. Shao, C.-M. Si, Z.-Y. Mao, W. Zhou, T. F.
Molinski, B.-G. Wei and G.-Q. Lin, Org. Chem. Front., 2017, 4,
995-1004.
2
3
(a) G. R. Pettit, Y. Kamano, C. L. Herald, A. A. Tuinman, F. E.
Boettner, H. Kizu, J. M. Schmidt, L. Baczynskyj, K. B. Tomer
and R. J. Bontems, J. Am. Chem. Soc., 1987, 109, 6883-6885;
(b) G. R. Pettit, S. B. Singh, F. Hogan, P. Lloyd-Williams, D. L.
Herald, D. D. Burkett, P. J. Clewlow, J. Am. Chem. Soc., 1989,
111, 5463-5465.
A. Maderna, M. Doroski, C. Subramanyam, A. Porte, C. A.
Leverett, B. C. Vetelino, Z. Chen, H. Risley, K. Parris, J. Pandit,
A. H. Varghese, S. Shanker, C. Song, S. C. K. Sukuru, K. A.
Farley, M. M. Wagenaar, M. J. Shapiro, S. Musto, M.-H. Lam,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 12 of 13
View Article Online
DOI: 10.1039/C7OB01395G
ARTICLE
Journal Name
9
T. Andreassen, L.-K. Hansen and O. R. Gautun, Eur. J. Org.
Chem., 2008, 4871-4876.
M. Tellers, M. Journet, J. T. Kuethe, D. Lieberman, G.
Humphrey, F. Zhang, Z. Peng, M. S. Waters, D. Zewge, A.
Nolting, D. Zhao, R. A. Reamer, P. G. Dormer, K. M. Belyk, I.
W. Davies, P. N. Devine and D. M. Tschaen, J. Org. Chem.,
2011, 76, 7804-7815; (c) A. K. Ghosh and S. Kulkarni, Org.
Lett., 2008, 10, 3907-3909; (d) A. Kienhofer, Synlett., 2001,
1811-1812.
10 Y.-W. Zhong, Y.-Z. Dong, K. Fang, K. Izumi, M.-H. Xu and G.-Q.
Lin, J. Am. Chem. Soc., 2005, 127, 11956-11957.
11 C.-M. Si, Y.-W. Liu, Z.-Y. Mao, P. Han, Z.-T. Du and B.-G. Wei,
Tetrahedron, 2016, 72, 8091-8098.
12 A. Preciado and P. G. Williams, J. Org. Chem., 2008, 73, 9228-
9234.
13 (a) G. R. Pettit, F. Hogan, D. D. Burkett, S. B. Singh, D. kantoci,
J. Srirangam and M. D. Williams, Heterocycles, 1994, 39, 81-
100; (b) K. Tomioka, M. Satoh, D. Taniyama, M. Kanai and A. 31 R. Bai, R. B. Bates, E. Hamel, R. E. Moore, P. Nakkiew, G. R.
30 I. D’Acquarica, A. Cerreto, G. Delle Monache, F. Subrizi, A.
Boffi, A. Tafi, S. Forli and B. Botta, J. Org. Chem., 2011, 76,
4396-4407.
Iida, Heterocycles, 1998, 47, 77-80; (c) Y. Hamada, K. Hayashi
and T. Shioiri, Tetrahedron Lett., 1991, 32, 931-934.
14 M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev.,
2010, 110, 3600-3740.
Pettit and B. A. Sufi, J. Nat. Prod., 2002, 65, 1824-1829.
32 K. C. Nicolaou, J. Yin, D. Mandal, R. D. Erande, P. Klahn, M.
Jin, M. Aujay, J. Sandoval, J. Gavrilyuk and D. Vourloumis, J.
Am. Chem. Soc., 2016, 138, 1698-1708.
15 For seleted works, see: (a) C. M. Si, W. Huang, Z. T. Du, B. G.
Wei and G. Q. Lin, Org. Lett., 2014, 16, 4328-4331; (b) C.-M.
Si, Z.-Y. Mao, H.-Q. Dong, Z.-T. Du, B.-G. Wei and G.-Q. Lin, J.
Org. Chem., 2015, 80, 5824-5833; (c) C.-M. Si, Z.-Y. Mao, Y.-
W. Liu, Z.-T. Du, B.-G. Wei and G.-Q. Lin, Org. Chem. Front.,
2015, 2, 1485-1499; (d) Y. W. Liu, P. Han, W. Zhou, Z. Y. Mao,
C. M. Si and B. G. Wei, Org. Biomol. Chem., 2016, 14, 10714-
10722; (e) C. M. Si, L. P. Shao, Z. Y. Mao, W. Zhou, B. G. Wei,
Org. Biomol. Chem., 2017, 15, 649-661.
16 D. Hernandez, K. B. Lindsay, L. Nielsen, T. Mittag, K.
Bjerglund, S. Friis, R. Mose and T. Skrydstrup, J. Org. Chem.,
2010, 75, 3283-3293.
17 T. K. Chakraborty and A. K. Chattopadhyay, J. Org. Chem.,
2008, 73, 3578-3581; (b) C.-Y. Ling, Y.-L. Tao, W.-J. Chu, H.
Wang, H.-D. Wang and Y.-S. Yang, Chin. Chem. Lett., 2016,
27, 235-240.
18 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113
7277-7287.
,
19 (a) B. S. Bal, W. E. Childers and H. W. Pinnick, Tetrahedron,
1981, 37, 2091-2096; (b) S. Pal, G. Singh, S. Singh, J. K.
Tripathi, J. K. Ghosh, S. Sinha, R. S. Ampapathi and T. K.
Chakraborty, Org. Biomol. Chem., 2015, 13, 6789-6802.
20 (a) H. Benelkebir, A. M. Donlevy, G. Packham and A.
Ganesan, Org. Lett., 2011, 13, 6334-6337; (b) T. Takizawa, K.
Watanabe, K. Narita, T. Oguchi, H. Abe and T. Katoh, Chem.
Commun., 2008, 1677-1679.
21 L. A. Carpino, J. Am. Chem. Soc., 1993, 115, 4397-4398.
22 G. Prabhu, M. Krishnamurthy, M. Samarasimhareddy, N.
Narendra and V. V. Sureshbabu, Int. J. Pept. Res. Ther., 2017,
DOI: 10.1007/s10989-017-9581-9.
23 H.-T. Le, J.-F. Gallard, M. Mayer, E. Guittet and R. Michelot,
Bioorg. Med. Chem., 1996, 4, 2201-2209.
24 J. Coste, M. N. Dufour, A. Pantaloni and B. Castro,
Tetrahedron Lett., 1990, 31, 669-672.
25 (a) M. K. Dhaon, R. K. Olsen and K. Ramasamy, J. Org. Chem.,
1982, 47, 1962-1965; (b) A. F. Donnell, C. Michoud, K. C.
Rupert, X. Han, D. Aguilar, K. B. Frank, A. J. Fretland, L. Gao,
B. Goggin, J. H. Hogg, K. Hong, C. A. Janson, R. F. Kester, N.
Kong, K. Le, S. Li, W. Liang, L. J. Lombardo, Y. Lou, C. M.
Lukacs, S. Mischke, J. A. Moliterni, A. Polonskaia, A. D.
Schutt, D. S. Solis, A. Specian, R. T. Taylor, M. Weisel and S.
W. Remiszewski, J. Med. Chem., 2013, 56, 7772-7787; (c) Y.-
Y. Xu, A.-R. Qian, X.-F. Cao, C.-Y. Ling, Y.-B. Cao, R.-L. Wang,
Y.-S. Li and Y.-S. Yang, Chin. Chem. Lett., 2016, 27, 703-706.
26 P. Wipf and P. C. Fritch, J. Am. Chem. Soc., 1996, 118, 12358-
12367.
27 M. Kunishima, D. Kato, S. Nakanishi, M. Kitamura, K. Yamada,
K. Terao and T. Asano, Chem. Pharm. Bull., 2014, 62, 1146-
1150.
28 A. El-Faham and F. Albericio, Chem. Rev., 2011, 111, 6557-
6602.
29 (a) R. Maharani, R. T. C. Brownlee, A. B. Hughes and B. M.
Abbott, Tetrahedron, 2014, 70, 2351-2358; (b) Z. J. Song, D.
12 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 13 of 13
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB01395G
Dolastatin 10 has been effectively synthesized through
SmI2-induced cross-coupling for Dap, asymmetric addition
for Doe and an alternative method to Val-Dil.