A concise and scalable synthesis of a novel L-allo-enduracididine derivative

Full text of DOI:10.1016/j.tetlet.2020.152148

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A Concise and Scalable Synthesis of a Novel L-allo-Enduracididine Deriva‐
tive
Xianwei Sui, Guang Huang, Nameer Ezzat, Yu Yuan
PII:
S0040-4039(20)30608-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152148
TETL 152148
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Tetrahedron Letters
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Revised Date:
Accepted Date:
14 April 2020
9 June 2020
11 June 2020
Please cite this article as: Sui, X., Huang, G., Ezzat, N., Yuan, Y., A Concise and Scalable Synthesis of a Novel
L-allo-Enduracididine Derivative, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152148
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A Concise and Scalable Synthesis of a Novel L-allo-Enduracididine
Derivative
Xianwei Sui*, Guang Huang, Nameer Ezzat, Yu Yuan*
Department of Chemistry, University of Central Florida, Orlando, Florida 32816, United States
Introduction
Antimicrobial resistance has become one of the biggest threats to human health. For example,
multiresistant bacteria, particularly methicillin-resistant S. aureus (MRSA) have caused numerous
hospital and community-acquired infections recently. Therefore, There is an urgent need for more
efforts to develop efficient antimicrobial compound.[1] In early 2015, a nature publication described
isolation and characterization of a novel peptidic natural product called Teixobactin (Figure 1),
which exhibit excellent activities against multiple bacteria strains including MRSA by binding
bacteria cell wall lipid-2 and lipid-3.[2a] Since the discovery, great attention has been paid to the
synthesis and activities study of Teixobactin and its analogues.[2]
H2N
O
O
O
O
OH
NH
H
H
H
H
N
N
N
N
N
N
N
H
H
H
O
O
O
O
OH
O
O
NH
O
O
Teixobactin
NH HN
O
PG1N
OPG3
NH
NH
L-allo-Enduracididine
HN
O
C4
PG2N
NH
NPG2
L-allo-Enduracididine derivatives or building blocks
Figture 1. Teixobactin and L-allo-Enduracididine
Structurally, Teixobactin contains a 13-membered depsipeptide ring composed of 4 D-amino acids
with an unusual amino acid L-allo-Enduracididine. Development of efficient methods to install L-
allo-Enduracididine fragment is essential in the synthesis of Teixobactin and its analogues (Figture
1). However, only few examples were described for the synthesis of L-allo-Enduracididine building
blocks or derivatives currently.[3] One of the main challenges is to establish the C4 chiral center in
a highly stereoselective way. To address these challenges, our lab has been focused on this research
area, and we have previously reported a highly stereoselective and scalable synthesis of L-allo-
Enduracididine and its’ building block from commercially available starting material trans-
hydroxyproline. An excellent stereoselectivity (dr = >50:1) was achieved in this approach.[4] As is
shown in Scheme 1, the reductive ring opening reaction is a key step. Amide 1 was selectively
reduced to hydroxyl group in the presence of tert-butyl ester, of which the stability is essential to

this strategy. Reduction reaction of Azide 2 followed by treatment with Goodman’s reagent
constructed the Cbz-protected guanidine moiety in excellent regioselectivity, delivering the L-allo-
Enduracididine derivative 4 efficiently. Notably, it was found that trace of compound 7 was isolated
when a methyl group (6) instead of tert-butyl group was used to mask the carboxylate during the
study of the reductive ring opening reaction. Compound 7 contains two free hydroxyl group which
may allow us to achieve the synthesis of a novel L-allo-Enduracididine derivative 12 or 13 bearing
a Boc-protected guanidine moiety, meanwhile, simply using azido group as the amine protecting
group. The oxidation reaction would be employed as a key manipulation to generate the carboxylic
acid intermediate. To the best of our knowledges, synthesis of Boc-protected guanidine building
block was rarely reported.[5] Herein, we report a novel synthesis of a L-allo-Enduracididine
derivative bearing a Boc-protected guanidine moiety from commercially available trans-
hydroxyproline. The reductive ring-opening reaction and oxidation reaction were the key steps in
this synthesis. The chirality was achieved in a highly stereoselectivity. The oxidation/methylation
condition was explored as well.
NCbz
NCbz
N3
HO
N3
O
CbzHN
MsO
CbzN
NH
Regio-specific
Ring Formation
NH
BocHN
BocN
Previous work:
BocHN
BocHN
OtBu
O
OtBu
OtBu
O
OtBu
O
O
1
2
4
3
Cbz-protected L-allo-Enduracididine derivative
N3
N3
N3
O
O
N3
O
BocN
N3
Optimized
Oxidation
HO
MeO
HO
HN
HO
HN
BocHN
This work:
HN
N
OMe
N
O
N
BocN
OH
BocN
BocN
Boc
Boc
Boc
6
7
11
12
13
Boc-protected L-allo-Enduracididine derivative
Scheme 1. Strategy of the Boc-protected L-allo-Enduracididine synthesis
Results and discussion
Our synthesis commenced with the transformation of hydroxyl functional group to azido group in
5 which is derived from commercially available trans-hydroxyproline by methylation (Scheme 2).
Reaction of 5 with methanesulfonyl chloride in the presence of Et3N gave the corresponding
mesylate, which was treated with sodium azide without purification to inverse the chirality giving
the corresponding azidoproline, and subsequent Sharpless oxidation worked well to deliver the
lactam 6 as a single diastereomer (1H NMR) in high yield over three steps.[6] The combined three
steps are more efficient compared to our former work.[4]

1) MsCl, Et3N, CH2Cl2, rt, 3 h
2) NaN3, DMF, 80 oC, overnight
3) RuCl3.H2O, NaIO4, ethyl acetate/H2O
rt, 30 h
N3
O
OH
BocN
BocN
O
O
O
O
81% (for three steps)
5
6
Scheme 2. Installation of Lactam and Azido Functionalities
Reductive lactam ring-opening reaction is the key transformation in our synthesis (Table 1).
Reduction of both lactam and methyl ester functionalities in one step was explored. The use of
tetrahydrofuran or dioxane resulted in poor conversion. When EtOH was employed as the solvent,
lactone product was formed as the major compound as reported in our previous work (Entry 2 and
4).[4] Fortunately, when 2.5 equivalents NaBH4 was used in MeOH, trace of desired product was
isolated successfully (Entry 3). More stronger reducing regents, such as LiAlH4, was also tested to
give a good conversion, however, the reaction delivered complicated mixtures (Entry 1). Increasing
NaBH4 to six equivalents delivered 7 in 88% yield as a single diastereomer (1H NMR) (Entry 8).
Decreasing the reaction time to 18 h resulted in a low conversion (Entry 6). Improving the reaction
temperature resulted in more complicated transformation and a lower yield was obtained (Entry 7).
It should be noted that the reduction using t-butyl ester derivative as the substrate resulted in a low
conversion probably owing to the steric hindrance. Thus, all the chiral carbon centers required for
the protocol were built successfully.
Table 1. A General Reduction Conditiona
N3
O
N3
HO
reduction
rt, 36 h
BocN
BocHN
O
O
OH
7
6
Entry
condition
7 (%)b
1
2
3
4
5
6
7
8
2.5 equiv. LiAlH4 in THF
-
-
2.5equiv. NaBH4 in THF or dioxane
2.5equiv. NaBH4 in MeOH
2.5equiv. NaBH4 in EtOH
4 equiv. NaBH4 in MeOH
6 equiv. NaBH4 in MeOHc
4 equiv. NaBH4 in MeOHd
6 equiv. NaBH4 in MeOH
5
-
51
45
36
88

atert-butyl group instead of methyl delivered trace desired product.
bisolated yield. cthe reaction time is 18 h. dthe temperature is 50 oC
In order to protect the hydroxyl group selectively, 2,2-dimethoxypropane was employed to give a
five-membered ring in the presence of p-toluenesulfonic acid (Scheme 3). Subsequent protection of
the other hydroxyl functional group using allyl chloroformate afforded 8 in 76% yield over two
steps. To install the guanidine moiety in 9, 4 N HCl was used to liberate the amine and hydroxyl
functional groups, and the guanidinylation reaction was achieved after treatment with Bis-Boc-
pyrazolocarboxamidine. An excellent conversion was realized to afford 9 in 85% yield. Cyclization
reaction was performed employing methanesulfonyl chloride under basic condition, generating 10
in remarkable yield. Thus, the Boc-protected guanidine skeleton was successfully constructed in
this approach. Deprotection reaction worked smoothly in the presence of palladium catalyst to
generate hydroxyl group, delivering 11 in excellent yield.
1) 2,2-dimethoxypropane, p-toluenesulfonic acid
actone, rt, 6 h
2) AllocCl, pyridine, 4-DMAP, CH2Cl2, rt, 8 h
N3
HO
O
N3
AllocO
BocHN
N
Boc
76% (for two steps)
8
OH
7
1) 4 N HCl in dioxane, rt, overnight
85% (for two steps)
2) Bis-Boc-pyrazolocarboxamidine, Et3N,
dioxane/H2O, 45 oC, 24 h
OH
NH
NHBoc
N3
NBoc
NBoc
N3
MsCl, Et3N, CH2Cl2, rt, 12 h
96%
AllocO
O
O
O
N
H
BocN
10
9
Pd(PPh3)4, morpholine, THF
rt, 1 h
95%
NBoc
NBoc
N3
HO
N
H
11
Scheme 3. Construction of the Boc-protected Guanidine Moiety
After establishing the requisite stereochemistry and guanidine fragment, we next tried to introduce
the carboxylic acid functionality. The oxidation of hydroxyl group was the other key step for this
strategy. However, it was found that the carboxylic acid intermediate was hard to purify by column

and decomposed slowly in solution, probably owing to the instabilities caused by the interaction
between carboxylic acid and Boc-protecting group. Therefore, methyl iodide was employed to trap
the acid to form the methyl ester derivative. Hence, we optimized the reaction conditions for these
two steps. It was found that the oxidation reaction was sensitive to oxidants and solvents. When the
reaction was performed in the presence of quantitative TEMPO and NaClO under basic condition,
only 10 % target product was delivered (Table 1, Entry 1). After an organic oxidant
(trichloroisocyanuric acid) was used, the reaction gave more desired product while no product was
.
monitored under buffer conditions (Entry 2, 8).[7] The use of Jones reagent or RuCl3 xH2O failed to
generate the target ester derivative. In addition, DMP was explored aiming to generate aldehyde,
however, no desired product was found. Fortunately, when the reaction condition was switched to
NaClO2/NaClO in presence of a catalytic amount of TEMPO, 31% methyl ester derivative was
isolated after 30 mins (Entry 5).[8] Increasing the reaction time to 1 h gave 12 in 72% yield while
1.5 h resulted in a lower yield (Entry 6, 7). This optimized condition enables the generation of the
carboxylate functionality through an oxidation strategy, where sensitive moieties such as Boc-
protected guanidine can be tolerated. It should be noted that all these synthetic routes are gram-scale
processes. Thus, we accomplished the synthesis of a Boc-protected L-allo-Enduracididine
derivative efficiently. Further research is ongoing to apply this derivative in the synthesis of
Teixobactin analogues.
Table 2. Optimization of Oxidation Conditions
NBoc
NBoc
MeI, K2CO3, acetone, rt, 1 h
70% for two steps
NBoc
NBoc
NBoc
NBoc
N3
Oxidation
N3
N3
HO
O
HO
N
N
N
H
H
H
O
O
12
11
13
Entry
Oxidation condition
The yield of methyl ester
derivative 13a
1
2
3
4
5
6
7
8
9
TEMPO (1.1 eq.)/NaOCl/KBr/NaHCO3/acetone
TEMPO (cat.)/A/NaBr/NaHCO3/acetoneb
Jones reagent
10%
15%
-
.
RuCl3 xH2O/NaIO4/CCl4/CH3CN/H2O
-
TEMPO (cat.)/NaClO2/NaClO/buffer/30 min
TEMPO (cat.)/NaClO2/NaClO/buffer/1 h
TEMPO (cat.)/NaClO2/NaClO/buffer/1.5 h
TEMPO (cat.)/A/NaBr/buffer/acetone
31%
72%
49%
-
DMP or DMP/NaHCO3 then Pinnick Oxidationc
-
aisolated yield. bA = trichloroisocyanuric acid. cno aldehydes product was formed.

Conclusion
we report a novel synthesis of a L-allo-Enduracididine derivative bearing a Boc-protected guanidine
moiety from commercially available trans-hydroxyproline. The reduction reaction and oxidation
reaction were the key steps in the synthesis. The chirality was achieved in a highly stereoselectivity.
The oxidation/methylation condition was explored as well.
Acknowledgment
This work is supported by the University of Central Florida.
Appendix A. Supplementary data
Supplementary data to this article can be found online
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Highlights
● 12 steps and 29% overall yield to a novel Boc-protected L-allo-Enduracididine derivative
● Gram-scale synthesis for all steps
● Excellent stereoselectivity starting from methylated trans-hydroxyproline