Total synthesis and stereochemistry assignment of 15-membered peptide alkaloids abyssenine B and mucronine E

Article abstract of DOI:10.1016/j.tetlet.2007.07.142

The total synthesis of 15-membered peptide alkaloids abyssenine B and mucronine E was accomplished via olefination of phenylalanine-embodied aldehydes followed by CuI/N,N-dimethylglycine-catalyzed coupling of vinyl iodides with amides and FDPP-mediated ma

Full text of DOI:10.1016/j.tetlet.2007.07.142

Tetrahedron Letters 48 (2007) 6717–6721
Total synthesis and stereochemistry assignment of 15-membered
peptide alkaloids abyssenine B and mucronine E
Jing Wang, Lutz Schaeffler, Gang He and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 25 June 2007; revised 16 July 2007; accepted 17 July 2007
Available online 27 July 2007
Abstract—The total synthesis of 15-membered peptide alkaloids abyssenine B and mucronine E was accomplished via olefination of
phenylalanine-embodied aldehydes followed by CuI/N,N-dimethylglycine-catalyzed coupling of vinyl iodides with amides and
FDPP-mediated macrocyclization in the key steps. From the total synthesis the stereochemistry of these two natural products
was tentatively assigned to be S,S,S.
Ó 2007 Elsevier Ltd. All rights reserved.
Abyssenines A–C,1 mucronines A–C,2 and E–H1 (Fig. 1)
are 15-membered macrocycles that were isolated 30
years ago from the bark of Zizyphus abyssinica Hochst.
Ex A. Rich, and the crude base of Z. abyssinica Willd,
respectively. Some of these compounds were found to
have significant antifungal (against Pythium debaryanum
and Trichoderma viride) and antibacterial (against Bacil-
lus subtilis and Escherichia coli) activities. Structurally,
they belong to a growing family of cyclopeptide alka-
loids including over 200 members.3 During the past
decades, considerable synthetic efforts have been de-
voted to these cyclopeptide alkaloids, mainly because
of their unique structure and interesting biological prop-
erties.3–11 Comparing to 13- and 14-membered cyclopep-
tide alkaloids, little attention has been directed to the
synthesis of 15-membered cyclopeptides alkaloids,3–10
which is evident from the fact that only the total synthe-
sis of mucronine B has been reported to date.11
iodides and amides, which proceeds under mild condi-
tions, may offer a solution to this problem.12 Indepen-
dently, the Evano group9 and we10 successfully applied
this method in the total synthesis of 13-membered cyclo-
peptide alkaloids paliurine F and ziziphine N. In this
report, we wish to disclose our studies toward the syn-
thesis of 15-membered cyclopeptide alkaloids abyssenin
B and mucromines E by using this strategy.
As depicted in Figure 1, we planned to elaborate 15-
membered cyclopeptide alkaloids via a CuI-catalyzed
cross-coupling of vinyl iodides C with a suitable amide
and subsequent macrocyclization. The vinyl iodides C
can be obtained via Wittig olefination13 of the corre-
sponding aldehydes D. Thus, the asymmetric synthesis
of these polysubstituted phenylalanine derivatives
became our first task. Another problem we faced in
the total synthesis of these natural products is that their
stereochemistry is still unknown. We assumed that the
configuration at the three chiral centers is S,S,S, respec-
tively, because mucronine B, a structurally related
compound isolated from the same species, was synthe-
sized by Schmidt and assigned to have S,S,S
stereochemistry.11
The major challenge in elaborating the cyclopeptide
alkaloids, mentioned above, is the construction of their
enamide moiety.3–8,11 Different elimination reactions
were employed to reach this goal (see Fig. 1 for an exam-
ple).3–8,11 Since the elimination was performed after the
macrocyclization step, the tedious and low-yielding
manipulations greatly decreased the synthetic efficiency.
The recently developed Cu-catalyzed coupling of vinyl
Aldehyde 17, required for the assembly of abyssenin B,
was elaborated via an asymmetric Strecker reaction14 as
shown in Scheme 1. Treatment of aldehyde 11 with (R)-
phenylglycinol and TMSCN in methanol at room tem-
perature gave a mixture of diastereomeric aminonitriles
in a ratio of 1:1. Upon heating this mixture in a sealed
*
Corresponding author. Tel.: +86 2154925130; fax: +86
2164166128; e-mail: madw@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.142

6718
J. Wang et al. / Tetrahedron Letters 48 (2007) 6717–6721
MeO
R
tube at 80 °C, the ratio of the desired diastereomer 12
was raised to 9:1.14b Aminonitrile 12 was isolated in
78% overall yield and exposed to methanolic hydrogen
chloride to afford amino ester 13. After hydrogenolysis
of 13, to remove the chiral auxiliary, the resulting amine
was protected with trifluoroacetic anhydride to provide
amide 14. After initial attempts to perform a Vilsmeier
formylation on 14 failed, we found that aldehyde 15
could be constructed by the treatment of 14 with
Cl2CHOMe and TiCl4 in 98% yield.15 Next, we decided
to switch the N-protecting group to Boc in order to
avoid possible racemization of the amino acid moiety
during the CuI-catalyzed coupling step.16 Direct cleav-
age of the trifluoroacetyl in 15 under both acidic and
basic conditions was found to be difficult. Reaction of
15 with di-tert-butyl dicarbonate afforded a carbamate,
which was treated with 1 N K2CO3 to remove the triflu-
oroacetyl group. The resulting Boc-protected amino
ester was then methylated with Ag2O/MeI to afford
ester 16. Hydrolysis of 16, followed by condensation
with L-isoleucine allyl ester furnished aldehyde 17.
R'
N
O
R"
NH
O
N
H
O
R
N
H
Abyssenin A (1): R = R' = H, R" = CH3, R = CH2CH(CH3)2
Abyssenin B (2): R = R' = H, R" = CH3, R = CH(CH 3)C2H5
Abyssenin C (3): R = R' = R" = H, R = CH(CH3)C2H5
Mucronine A (4): R = H, R' = R" = Me, R = Bn
Mucronine B (5): R = H, R' = H, R" = Me, R = Bn
Mucronine C (6): R = H, R' = H, R" = Me, R = CH2CH(CH3)2
Mucronine E (7): R = OMe, R' = H, R" = Me, R = CH2CH(CH3)2
Mucronine F (8): R = OMe, R' = R" = H, R = CH2CH(CH3)2
Mucronine G (9): R = OMe, R' = R" = H, R = CH(CH3)C2H5
Mucronine H (10): R = R' = R" = H, R = Bn
present approach
Schmidt approach
MeO
R
MeO
R
NH2
X
R'
R'
+
O
R
N
N
O
R"
R"
NH
O
N
I
AllocHN
H
X
O
O
C
R
N
H
A
Wittig olefination13 of 17 with Ph3P+(CH2I)Iꢀ/
LiHMDS produced vinyl iodide 18 in 86% yield as a
mixture of Z- and E-isomers in a ratio of 6:1. This mix-
ture was inseparable by column chromatography and
thus we decided to use it as is for the next step. To
our delight, CuI/N,N-dimethylglycine-catalyzed cou-
pling of 18 with N-alloxycarbonyl-L-isoleucine amide
worked well in dioxane at 80 °C, affording separable
enamide 19 (61% yield from 18) and its E-isomer
(ꢁ5% yield from 18). After the removal of the allyl
and alloxycarbonyl protecting groups with Pd(PPh3)4
and diethylamine, a strongly diluted solution of the
liberated amino acid in DMF was treated with FDPP/
DIPEA to afford macrolactam 20 in 27% yield. Finally,
the removal of the Boc group in 20 with ZnBr2 in meth-
MeO
R
X
MeO
R
R'
N
R'
CHO
R"
NH
H2N
N
R
O
R"
X
CO2H
N
O
O
H
D
B
Figure 1. Structures of abyssenines A–C, mucronines A–C, and E–H,
and their retrosynthetic analysis.
1. (
R)-phenylglycinol, TMSCN
ylene chloride afforded 2. The optical rotation of syn-
MeOH, rt
22
MeO
thetic 2 (½aꢂD +161 (c 0.7, MeOH)) is in close
H
MeO
2. MeOH, 80 oC
N
Ph
proximity to that reported for natural abyssenin B
78%
20
CHO
(½aꢂD +151 (c 0.17, MeOH)).1 In addition, its 1H
CN
OH
12
11
NMR data was found to be indistinguishable from the
literature reference, except for some additional peaks,
which were recorded at d 3.07–3.30 (m, 2H), 3.44 (dd,
J = 13.6, 7.8 Hz, 1H), and 3.02 (d, J = 13.8 Hz, 1H) in
our sample (see Table 1). These peaks apparently belong
to the signals from H-5, H-8, H-12, and H-13 of abysse-
nin B and were not reported previously. These results
offer additional support for the S,S,S configuration of
abyssenin B (Scheme 2).
1. Pd/C, HCO2H
MeOH, 30 o
C
HCl/MeOH
86%
MeO
MeO
H
N
2. (CF3CO)2O
82%
Ph
CO2Me
MeO2C
NHCOCF3
OH
13
14
CHO
1. (Boc)2O, Et3N, DMAP
then aq K2CO3
Cl2CHOMe, TICl4
CH2Cl2, 0 oC, 98%
MeO
Our synthetic pathway toward mucronine E is outlined
in Scheme 3. The known amino ester 21, prepared from
L-tyrosine in five steps,17 was reported to amide 22 via
Pd/C-catalyzed hydrogenolysis and subsequent protec-
tion of the liberated amine with (CF3CO)2O. Vilsmeier
formylation worked well in this case, affording aldehyde
23 in 97% yield, after exposure of 22 to POCl3/DMF.
The higher nucleophilicity of 22 was accounted for the
difference in reactivity compared to anisole 14. After
changing the N-protecting group to Boc, methylation
with Ag2O/MeI afforded amino ester 24b. Hydrolysis
of 24b followed by coupling with L-isoleucine allyl ester
2. Ag2O, MeI, DMF
77%
CO2Me
NHCOCF3
15
MeO
CHO
Boc
1. LiOH/THF/MeOH
CHO
MeO
N
2. HATU, DIPEA, 89%
Me
CO2Me
Boc
NH
O
H2N
O
O
N
OAllyl
Me
OAllyl
17
16
Scheme 1.

J. Wang et al. / Tetrahedron Letters 48 (2007) 6717–6721
6719
Table 1. 1H NMR and 13C NMR data and their assignment to
MeO
abyssenin B 2a
Ph3P+(CH2I)I-
LiHMDS
CuI/N,N-dimethylglycine
Cs2CO3, dioxane, 61%
Boc
Me
N
20
16
15
17
MeO
17
NH
O
HMPA/THF
86%
NHAlloc
NH2
21
H
I
O
1
12, 13
14
OAllyl
18
2
11
N
19
9
O
10 NH
N
O
Me
H 3
18
22
4
O
8
5
23
27
29
24
7
MeO
N
MeO
N
O
6 H28
30
1. Pd(PPh3)4
Et2NH
Boc
Me
Boc
Me
25
26
N
O
O
2
2. FDPP
DIPEA
DMF
NH
O
NH
O
N
N
H
H
O
d(1H)
Multi- No. of
Assign-
J
d(13C) Assign-
N
HN
27%
O
O
H
[ppm]
plicity H atoms ment
[Hz] [ppm] ment
Alloc
20
9.60
8.48
8.25
7.09
6.99
d
d
d
d
1H
1H
1H
1H
1H
H9
H3
H6
H19
H17
8.0 176.1 C7
11.0 172.7 C10
8.0 169.1 C4
1.8 156.2 C15
8.7, 129.8 C17
2.4
8.7, 129.0 C19
2.9
9.6 128.9 C14
9.6 125.1 C18
8.2, 120.3 C2
3.2
19
MeO
H
N
O
ZnBr2, CH2Cl2
85%
Me
dd
NH
O
N
H
O
N
6.89
dd
1H
H16
H
2
6.81
5.61
4.42
d
d
dd
1H
1H
1H
H2
H1
H11
Scheme 2.
3.85
3.44
s
dd
3H
1H
H20
H12,13
111.6 C16
13.6, 109.5 C1
7.8
MeO
OMe
1. Pd/C, H2
2. (CF3CO)2O/Et3N
MeO
N
OMe
3.07–3.30
3.02
2.54–2.59
2.48
2.34–2.43
2.25
1.52–1.56
1.45–1.51
1.29–1.39
1.08–1.18
1.04
m
d
m
s
m
br
m
m
m
m
d
2H
1H
1H
3H
1H
1H
1H
1H
1H
1H
3H
3H
3H
3H
H5,8
H12,13
H23
H22
H27
H21
H29
H25
H29
H25
H28
H30
H24
H26
66.2 C5,8
POCl3/DMF
97%
13.8
66.0 C5,8
59.2 C11
55.7 C20
36.8 C27
36.5 C22
33.3 C23
31.2 C12,13
25.8 C29
24.2 C25
16.7 C28
15.5 C24
12.2 C30
9.7 C26
Bn
75%
H
N
CO2Me
CO2Me
Cbz
COCF3
21
22
MeO
OMe
MeO
OMe
1. LiOH
2. HATU, DIPEA
H2N
1. (Boc)2O
2. 1 N K2CO3
CHO
CHO
O
81%
R
H
N
CO2Me
6.9
7.3
6.8
7.4
N
CO2Me
OAllyl
94%
Boc
Ag2O/MeI
81%
0.99
0.91
0.87
t
d
t
COCF3
23
24a: R = H
24b: R = Me
MeO
OMe
MeO
OMe
CHO
a All assignments were based on the COSY, NOSEY, HMBC, and
HMQC studies of 2.
Ph3P+(CH2I)I-
LiHMDS
Boc
Me
Me
N
N
NH
O
Boc
HMPA/THF
-78 oC to rt
86%
NH
O
I
O
O
OAllyl
under the action of HATU provided dipeptide 26. Olef-
ination of 26 with Ph3P+(CH2I)Iꢀ/LiHMDS led to vinyl
iodide 27 as a mixture of Z- and E-isomers in a ratio of
6:1. This mixture was also inseparable by column chro-
matography. However, its coupling products with N-all-
oxycarbonyl-L-leucine amide were easily separated to
deliver the desired enamide 28 (60% yield from 27)
and its E-isomer (ꢁ5% yield from 27). Next, the treat-
ment of enamide 28 with Pd(PPh3)4/Et2NH to remove
both allyl and alloxycarbonyl groups afforded a cycliza-
tion precursor, which was subjected to FDPP-mediated
macrocyclization to furnish lactam 29. Finally, the
cleavage of the Boc group in 29 with ZnBr2 yielded
the target molecule 7.
OAllyl
26
27
MeO
OMe
N
Boc
CuI/N,N-dimethylglycine
Cs2CO3, dioxane, 60%
1. Pd(PPh3)4
Et2NH
N
Me
O
NH
O
NHAlloc
NH2
2. FDPP
DIPEA
DMF
O
H
HN
17%
O
Alloc
O
28
MeO
OMe
MeO
OMe
H
Boc
Me
ZnBr2
N
N
CH2Cl2
O
N
H
Me
O
NH
O
NH
O
N
65%
O
H
O
N
H
22
N
Synthetic 7 (½aꢂD ꢀ86.5 (c 0.34, MeOH)) showed almost
H
7
identical optical rotation to that reported for mucronine
29
20
1
E (½aꢂD ꢀ89 (c 0.084, MeOH)).1 Its H NMR data was
Scheme 3.
found to be indistinguishable from that reported in the

6720
J. Wang et al. / Tetrahedron Letters 48 (2007) 6717–6721
Table 2. 1H NMR and 13C NMR data and their assignment to mucronine E 7a
21
20
16
MeO 15
17 OMe
22
H
N
12, 13
1
14
18
2
11
9
19
O
10 NH
N
Me
H 3
4
5
23
O
8
24
25
28
7
N
6 H
26O
30
29
27
31
7
d(1H) [ppm]
Multiplicity
No. of H atoms
Assignment
J [Hz]
d(13C) [ppm]
Assignment
9.34
8.40
8.12
7.03
6.83
6.47
5.76
4.44
3.88
3.83
3.25
3.18
2.92
2.54
2.47
2.25
1.87–1.94
1.64–1.72
1.41–1.46
1.04–1.08
0.93
0.89
0.82
0.77
d
d
d
s
dd
s
d
m
s
s
dd
m
dd
m
s
br
m
m
m
m
d
1H
1H
1H
1H
1H
1H
1H
1H
3H
3H
1H
2H
1H
1H
3H
1H
1H
2H
1H
1H
3H
3H
3H
3H
H9
H3
H6
H19
H2
9.3
11.4
7.2
172.3
169.8
157.3
157.1
130.0
120.2
117.5
116.3
104.7
95.9
66.2
65.3
55.8
52.4
40.9
36.2
33.6
31.1
25.7
25.0
23.4
21.1
15.1
9.7
C7,10
C4
C17
C15
C19
C2
C14
C18
C1
C16
C5,8
C5,8
C20,21
C11
C28
C23
C24
C12,13
C26
C29
C30
C31
C25
C27
9.6, 9.9
9.9
H16
H1
H11
H20,21
H20,21
H12,13
H5,8
H12,13
H24
H23
H22
H28
H28,29
H26
H26
H31
H30
H25
H27
14.6, 3.0
14.6, 1.2
6.4
6.4
6.8
7.4
d
d
t
a All assignments were based on the COSY, NOSEY, HMBC, and HMQC studies of 7.
literature, except for some additional peaks, which were
References and notes
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