Total synthesis of unguisin A

Article abstract of DOI:10.1021/jo200813a

The first synthesis of the γ-aminobutyric acid (GABA)-containing cyclic heptapeptide unguisin A is reported, confirming the structure of this natural product. Macrocyclization of a flexible GABA-containing linear precursor is found to proceed rapidly and in good yield.

Full text of DOI:10.1021/jo200813a

NOTE
pubs.acs.org/joc
Total Synthesis of Unguisin A
Luke Hunter* and Jonathan H. Chung
School of Chemistry, The University of Sydney, NSW 2006, Australia
S Supporting Information
b
ABSTRACT: The first synthesis of the γ-aminobutyric acid (GABA)-containing cyclic
heptapeptide unguisin A is reported, confirming the structure of this natural product.
Macrocyclization of a flexible GABA-containing linear precursor is found to proceed rapidly
and in good yield.
aturally occurring cyclic peptides have attracted consider-
N
able attention due to their diverse biological activity and
1
significant therapeutic potential. Cyclic peptides possess several
pharmacokinetic advantages relative to their linear counterparts
including greater metabolic stability, higher hydrophobicity, and
increased conformational rigidity, and as such they are attractive
2
scaffolds for drug development. Natural cyclic peptides are also of
intrinsic interest due to their fascinating structural variety, often
featuring unusual amino acid components that can be created through
3
posttranslational modification of a ribosomally assembled peptide or
4
by nonribosomal incorporation of nonproteinogenic amino acids.
Unguisins AꢀC (1ꢀ3, Figure 1) are cyclic heptapeptides
5,6
isolated from the marine fungus Emericella unguis. Notable
structural features of these molecules include a predominance of
hydrophobic amino acid side chains, a high proportion of D-amino
acids, and the highly unusual feature of a γ-aminobutyric acid
Figure 1. Structures of unguisins AꢀC.
(
GABA) residue contained within the macrocycle. Several natural
Unguisins A and B are reported to possess moderate anti-
bacterial activity against Staphylococcus aureus; however, these
5
products containing β-hydroxy-γ-aminobutyric acid (GABOB)
residues have previously been described (e.g., microsclerodermins
effects have not been quantified, and full biological profiling is
lacking. It has been speculated that the GABA components of 1ꢀ3
may impart some degree of conformational flexibility which may
allow the macrocycles to adopt the required shape for optimal
biological activity; however, this has not been explored through
structureꢀactivity relationship studies. Therefore, to further in-
vestigate this intriguing molecular scaffold, we undertook to
perform, and report herein, a total synthesis of unguisin A (1).
The retrosynthetic analysis of 1 (Scheme 1) involves discon-
nection of the macrocycle between the phenylalanine carboxyl
group and the adjacent valine amino group. This disconnection
site was chosen for two reasons. First, in the forward sense
the synthesis would involve a macrocyclization reaction between
7
AꢀE from Theonella sp. and Microscleroderma sp. ), and other
natural products containing GABA residues within linear peptide
segments have been identified (e.g., imacidins AꢀE from Strepto-
8
myces olivaceus and some N-acylasparagylpolyamines from Nephi-
9
lengys borbonica ); however, to the best of our knowledge, the
unguisins (1ꢀ3) are the only natural products reported to date that
contain a GABA residue within a cyclic peptide structure. This
feature strongly suggests a nonribosomal biosynthetic origin, and
this hypothesis is also supported by the results of precursor-directed
biosynthesis experiments. When E. unguis was cultured in the
presence of excess L-leucine, a new metabolite (denoted unguisin D)
6
was isolated in which a D-valine residue of unguisin B is replaced by
L-leucine, and this finding was attributed to the characteristically
6
low specificity exhibited by some nonribosomal peptide synthase
multienzymes.
Received: April 20, 2011
Published: May 25, 2011
10
r 2011 American Chemical Society
5502
dx.doi.org/10.1021/jo200813a
|J. Org. Chem. 2011, 76, 5502–5505

The Journal of Organic Chemistry
NOTE
Scheme 1. Retrosynthetic Analysis of Unguisin A (1)
a
Scheme 2. Synthesis of Unguisin A (1)
Table 1. Selected Coupling Constants (Hz) from the GABA
Residue of 1
a,b
2
3
4
5
6
7
H
H
H
H
H
H
1
2
3
4
5
6
H
H
H
H
H
H
6.2
4.8
0.0
7.0
7.0
0.0
6.0
0.0
0.0
0.0
5.8
8.0
0.0
0.0
0.0
7.7
5.2
14.0
6.0
14.0
13.4
2
a 1
b
4
H NMR spectrum acquired at 400 MHz in DMSO-d . Nuclei H , H ,
and H are interchangeable with nuclei H , H , and H .
6
6
3
5
7
Synthesis of the required linear precursor 4 was achieved using
12
Fmoc-strategy solid phase peptide synthesis (Scheme 2). Wang
resin preloaded with Fmoc-L-phenylalanine (5) was subjected to an
iterative deprotection/peptide coupling sequence, employing
HBTU/H €u nig’s base as the coupling reagents, to give the fully
assembled resin-bound heptapeptide 6. The linear peptide was then
cleaved from the resin, with simultaneous removal of the D-trypto-
phan side chain protecting group, to give 4 in relatively high purity
and 96% overall yield. A long-range correlation between γ-H of
valine #1 and R-H of valine #2 was observed in the ROESY spectrum
of 4 (Scheme 2), suggesting that this peptide exhibits sufficient
conformational flexibility to bring the head and tail proximal in space,
13
at least transiently. A single set of resonances were observed in the
a
Abbreviations: black sphere = Wang resin, 100ꢀ200 mesh, amino acid
1
13
H and C NMR spectra of 4, indicating that any conformational
mobility is fast on the NMR time scale at room temperature.
Cyclization of 4 was performed at 5 mM in DMF, using
loading 0.65 mmol/g; DMF = N,N-dimethylformamide; HBTU =
0
0
O-benzotriazole-N,N,N ,N -tetramethyluronium hexafluorophosphate;
DIPEA = diisopropylethylamine; TFA = trifluoroacetic acid; TIS =
triisopropylsilane; DMTMM = 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-
methylmorpholinium tetrafluoroborate.
14
DMTMM as the coupling reagent (Scheme 2). Gratifyingly the
cyclization reaction was found to be rapid and efficient, with
LCMS analysis of the reaction mixture revealing that the starting
þ
L- and D-amino acid residues, which has previously been identi-
material (m/z [MH ] = 777) was completely consumed and
fied as beneficial in reducing epimerization and cyclooli-
replaced by a single product of mass consistent with the desired
cyclic product (m/z [MH ] = 759) within a reaction time of ten
minutes. The target cyclic peptide 1 was isolated in 81% yield
after preparative reverse-phase HPLC purification. No products
arising from epimerization or cyclooligomerization side reac-
tions were observed. The characterization data for synthetic 1
11
þ
gomerization reactions. Second, the chosen disconnection site
would position the GABA residue in the center of the linear
precursor 4, and this flexible central component could poten-
tially facilitate the folded conformation required for efficient
macrocyclization.
5
503
dx.doi.org/10.1021/jo200813a |J. Org. Chem. 2011, 76, 5502–5505

The Journal of Organic Chemistry
NOTE
1
13
(
H NMR, C NMR, HRMS, UV, CD) were in good agreement
(d, J = 7.5 Hz, 1H, Ala #2 NH), 7.90 (t, J = 5.5 Hz, 1H, GABA NH), 7.58
(d, J = 9.3 Hz, 1H, Val #2 NH), 7.55 (d, J = 8.0 Hz, 1H, Trp ArH4), 7.31
(d, J = 8.1 Hz, 1H, Trp ArH7), 7.26ꢀ7.15 (m, 5H, Phe ArH), 7.09 (d,
J = 2.0 Hz, ArH2), 7.04 (dd, J = 8.1, 7.3 Hz, 1H, Trp ArH6), 6.95 (dd,
J = 8.0, 7.3 Hz, 1H, Trp ArH5), 4.48ꢀ4.42 (m, 2H, Phe RH þ Trp RH),
with those reported for the natural sample of 1, confirming the
original structural assignment of this metabolite.
5
1
The H NMR spectrum of 1 was analyzed in detail to probe
the conformational characteristics of the GABA component.
This segment of the molecule constitutes a seven-spin system,
with each proton giving rise to a unique signal in the H NMR
spectrum (Table 1). The complex multiplets corresponding to
each proton in the spin system were deconvoluted using a
software-based simulation/iteration sequence. It emerges that
4.40 (dq, J = 7.3, 7.1 Hz, 1H, Ala #1 RH), 4.32 (dq, J = 7.5, 7.1 Hz, 1H,
1
Ala #2 RH), 4.17 (dd, J = 9.3, 5.9 Hz, 1H, Val #2 RH), 3.59 (m, 1H, Val
#
1 RH), 3.09 (dd, J = 13.6, 4.4 Hz, 1H, Phe βH), 3.08ꢀ2.91 (m, 4H, Trp
0
βH þ Trp βH þ 2 ꢁ GABA γH), 2.83 (dd, J = 13.6, 10.4 Hz, 1H, Phe
0
15
βH ), 2.06ꢀ1.97 (m, 3H, Val #1 βH þ 2 ꢁ GABA RH), 1.80 (m, 1H,
3
Val #2 βH), 1.53 (m, 2H, GABA 2 ꢁ βH), 1.22 (d, J = 7.1 Hz, 3H, Ala #1
the J spinꢀspin coupling constants of the GABA residue are
HH
16
βH), 1.15 (d, J = 7.1 Hz, 3H, Ala #2 βH), 0.89 (d, J = 7.0 Hz, 3H, Val #1
mostly intermediate in magnitude (Table 1), confirming that
this region of the natural product does indeed exhibit conforma-
tional flexibility.
0
γH), 0.88 (d, J = 6.8 Hz, 3H, Val #1 γH ), 0.64 (d, J = 6.8 Hz, 3H, Val #2
0
13
1
γH), 0.56 (d, J = 6.8 Hz, 3H, Val #2 γH ); C { H} NMR (100 MHz,
DMSO-d , DEPT, HMBC) δ 172.9 (Phe CdO), 172.2 (Ala #2 CdO),
71.7 (GABA CdO), 171.4 (Ala #1 CdO), 170.9 (Trp CdO), 170.7
Val #2 CdO), 167.4 (Val #1 CdO), 137.6 (Phe ArC1), 136.1 (Trp
6
In summary, the first total synthesis of unguisin A (1) is
reported, confirming the structure of this natural product. A
noteworthy feature of this synthesis is the rapid and efficient
cyclization reaction of a GABA-containing linear precursor;
this result may have broader implications in terms of a strategy
for facilitating the synthesis of analogues of “difficult” cyclic
peptides. In the immediate context of unguisin A (1), this work
will enable more thorough biological profiling to be performed,
and it provides a platform for the production of non-natural
analogues for structureꢀactivity relationship studies, especially
analogues that are conformationally constrained in the GABA
1
(
ArC7a), 129.1 (Phe ArC2/C3), 128.1 (Phe ArC4/C5), 127.4 (Trp
ArC3a), 126.4 (Phe ArC6), 123.5 (Trp ArC2), 120.8 (Trp ArC6), 118.4
(Trp ArC4), 118.2 (Trp ArC5), 111.3 (Trp ArC7), 109.8 (Trp ArC3),
57.3 (Val #1 RC), 57.1 (Val #2 RC), 53.7 (Trp RC), 53.4 (Phe RC), 48.3
1
7
(
(
(
Ala #1 RC), 48.1 (Ala #2 RC), 38.2 (GABA RC), 36.8 (Phe βC), 32.5
GABA γC), 30.9 (Val #2 βC), 29.8 (Val #1 βC), 28.0 (Trp βC), 25.2
GABA βC), 19.1 (Val #2 γC), 18.3 (Val #1 γC), 18.2 (Ala #1 βC), 17.8
0
0
(Ala #2 βC), 17.6 (Val #1 γC ), 17.3 (Val #2 γC ); HRMS (ESI, þve)
þ
0 57 8 8
þ
C H N O [MH ] requires m/z 777.4294, found 777.4301.
4
1
8
region.
Unguisin A (1). To a solution of 4 TFA (14.7 mg, 16.5 μmol) in
3
DMF (2 mL) was added a solution of DMTMM BF (16.2 mg,
4
3
4
9.5 μmol) in DMF (0.94 mL) followed by DIPEA (10.3 μL, 59.4
’
EXPERIMENTAL SECTION
μmol), and the resulting mixture was stirred at room temperature under
a nitrogen atmosphere. At time intervals, an aliquot (2 μL) was with-
drawn from the reaction mixture, diluted with 0.1% TFA/MeOH
1
13
General Experimental Methods. H and C NMR spectra
were recorded at 400 and 100 MHz, respectively, and detailed peak
assignments were made with the aid of COSY, ROESY, DEPT, and
HMBC experiments. All reagents and solvents were used as obtained
commercially.
(80 μL), and directly analyzed by LCMS. After 5 h the reaction mixture
was concentrated in vacuo, and the residue was subjected to preparative
reverse-phase HPLC employing 0.1% TFA/H O as eluent A and 0.1%
2
TFA/MeCN as eluent B (gradient: 100% A for 10 min, then ramped to
D-ValineꢀD-AlanineꢀD-TryptophanꢀGABAꢀD-
80% B over 40 min). The appropriate fraction (retention time = 32.6
AlanineꢀD-ValineꢀL-Phenylalanine (4). Solid-phase peptide
synthesis was conducted manually on 0.05 mmol scale in a sinter-fitted
polypropylene syringe according to the following general procedures.
Resin preparation: Wang resin (100ꢀ200 mesh) preloaded with Fmoc-L-
phenylalanine (0.65 mmol/g) was immersed in DCM and agitated for
min) was freeze-dried to give 1 as a fluffy white solid (10.1 mg, 81%); mp
ꢀ
1
>
3
250 °C; [R]
D
þ29.6 (289 nm, c 0.36, EtOH); IR (neat) vmax (cm
)
293, 1667, 1659, 1635, 1542, 1523, 1506, 1201, 1183, 1143; UV
(
(
EtOH) λmax (log ε) 290 (3.60), 282 (3.65), 274 (3.63), 217 (4.40); CD
1
EtOH) λ ext (Δε) 222 (4.72), 204 (ꢀ12.33); H NMR (400 MHz,
1
h, then drained and washed with DMF (5 ꢁ 1 min). Fmoc deprotection:
DMSO-d , COSY, ROESY) δ 10.82 (d, J = 1.8 Hz, 1H, Trp ArNH), 8.55
The resin was agitated in 10% piperidine/DMF (3 ꢁ 3 min), then washed
with DMF (3 ꢁ 1 min), DCM (3 ꢁ 1 min), and DMF (5 ꢁ 1 min).
The collected deprotection solutions were diluted 100-fold with 10% piper-
idine/DMF, and the resin loading was estimated by measuring the absorbance
6
(
d, J = 8.3 Hz, 1H, Phe NH), 8.40 (d, J = 4.6 Hz, 1H, Ala #1 NH), 8.11 (d,
J = 4.2 Hz, 1H, Val #2 NH), 8.02 (d, J = 7.0 Hz, 1H, Trp NH), 7.87 (d, J =
.7 Hz, 1H, Val #1 NH), 7.82 (d, J = 6.0 Hz, 1H, Ala #2 NH), 7.69 (dd, J
6.2, 4.8 Hz, 1H, GABA NH), 7.53 (d, J = 7.8 Hz, 1H, Trp ArH4), 7.33
9
=
ꢀ1
ꢀ1
of the piperidineꢀfulvene adduct at 301 nm (ε = 7800 M cm ). Peptide
coupling: A solution was prepared of the appropriate Fmoc-protected
amino acid (3 equiv relative to resin loading) and HBTU (2.9 equiv) in
minimal DMF. DIPEA (6 equiv) was added, and the resulting solution
was immediately added to the resin and agitated for 1 h. The resin was
drained and washed with DMF (3 ꢁ 1 min), DCM (3 ꢁ 1 min), and
DMF (5 ꢁ 1 min). Cleavage: After the last Fmoc deprotection, the resin
was washed with DCM (3 ꢁ 1 min) and then dried in vacuo. A solution
(
(
d, J = 8.1 Hz, 1H, Trp ArH7), 7.24ꢀ7.17 (m, 4H, Phe ArH2,3,5,6), 7.13
m, 1H, Phe ArH4), 7.11 (d, J = 1.8 Hz, 1H, Trp ArH2), 7.07 (dd, J = 8.1,
7.1 Hz, 1H, Trp ArH6), 6.98 (dd, J = 7.8, 7.1 Hz, 1H, Trp ArH5), 4.33
(ddd, J = 12.0, 8.3, 3.4 Hz, 1H, Phe RH), 4.22 (dq, J = 6.9, 6.0 Hz, 1H, Ala
#2 RH), 4.09 (dd, J = 9.7, 9.7 Hz, 1H, Val #1 RH), 4.05 (dt, J = 7.6, 7.0
Hz, Trp RH), 3.95 (dq, J = 7.0, 4.6 Hz, 1H, Ala #1 RH), 3.49 (dd, J = 8.5,
4.2 Hz, 1H, Val #2 RH), 3.27 (dd, J = 13.1, 3.4 Hz, 1H, Phe βH), 3.19 (d,
J = 7.1 Hz, 2H, 2 ꢁ Trp βH), 3.12 (dddd, J = 14.0, 7.0, 6.2, 6.0 Hz, 1H,
2
of TFA/H O/triisopropylsilane (95:2.5:2.5) was added to the resin and
0
agitated for 2 h. The resin was drained and washed with TFA (2 ꢁ 1
min). The combined cleavage solutions were concentrated in vacuo to
give a clear glassy solid. Diethyl ether was added, and the supernatant
decanted (4 ꢁ ). The residue was dried in vacuo to afford 4 (TFA salt) as
GABA γH), 2.95 (dddd, J = 14.0, 7.0, 6.0, 4.8 Hz, 1H, GABA γH ), 2.60
0
(dd, J = 13.1, 12.0 Hz, 1H, Phe βH ), 2.10 (ddd, J = 13.4, 8.0, 5.8 Hz, 1H,
GABA RH), 2.01 (ddd, J = 9.8, 6.8, 6.6 Hz, 1H, Val #1 βH), 1.96 (ddd,
0
J = 13.4, 7.7, 5.2 Hz, 1H, GABA RH ), 1.69 (ddddd, J = 14.0, 7.7, 7.0, 7.0,
0
a white solid (41 mg, 96% overall yield); mp 105ꢀ115 °C; [R] þ24
5.8 Hz, 1H, GABA βH), 1.61ꢀ1.51 (m, 2H, Val #2 βH þ GABA βH ),
D
ꢀ
1
1
(
(
c 0.40, MeOH); IR (neat) v (cm ) 3276, 1660, 1539; H NMR
1.16 (d, J = 7.0 Hz, 3H, Ala #1 βH), 1.14 (d, J = 6.9 Hz, 3H, Ala #2 βH),
0.75 (d, J = 6.8 Hz, 3H, Val #1 γH), 0.73 (d, J = 6.7 Hz, 3H, Val #2 γH),
max
6
400 MHz, DMSO-d , COSY, ROESY) δ 10.77 (d, J = 2.0 Hz, 1H, Trp
ArNH), 8.50 (d, J = 7.3 Hz, 1H, Ala #1 NH), 8.25 (d, J = 8.3 Hz, 1H, Phe
NH), 8.07 (br s, 3H, Val #1 NH ), 8.04 (d, J = 8.1 Hz, 1H, Trp NH), 7.95
0
0
0.67 (d, J = 6.6 Hz, 3H, Val #1 γH ), 0.28 (d, J = 6.7 Hz, 3H, Val #2 γH );
C { H} NMR (100 MHz, DMSO-d , DEPT, HMBC) δ 173.1 (Ala #2
1
3
1
3
6
5
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dx.doi.org/10.1021/jo200813a |J. Org. Chem. 2011, 76, 5502–5505

The Journal of Organic Chemistry
NOTE
CdO), 172.7 (Ala #1 CdO), 171.9 (GABA CdO), 171.63 (Val #1
CdO), 171.57 (Val #2 CdO), 171.2 (Trp CdO), 170.6 (Phe CdO),
S.-L.; Bailly, C.; Linssen, R. C. M.; Waring, M. J. Anti-Cancer Drug Des.
1995, 10, 373. (b) Chen, S.-L.; Wong, R. N. S.; Lo, V.; Chang, S.; Chiang,
C.-D.; Sheh, L. Anti-Cancer Drug Des. 1998, 13, 501. (c) Sheh, L.; Chen,
B.-L.; Chen, C.-F. Int. J. Pept. Protein Res. 1990, 35, 55. (d) Chen, Y.-C.;
Muhlrad, A.; Shteyer, A.; Vidson, M.; Bab, I.; Chorev, M. J. Med. Chem.
138.5 (Phe ArC1), 136.3 (Trp ArC7a), 129.2 (Phe ArC2/3), 128.1 (Phe
ArC4/5), 127.1 (Trp ArC3a), 126.2 (Phe ArC6), 123.8 (Trp ArC2),
1
1
5
3
2
1
21.1 (Trp ArC5), 118.4 (Trp ArC4 þ Trp ArC6), 111.4 (Trp ArC7),
10.6 (Trp ArC3), 60.9 (Val #2 RC), 58.8 (Val #1 RC), 55.3 (Phe RC),
5.2 (Trp RC), 49.9 (Ala #1 RC), 47.9 (Ala #2 RC), 38.5 (GABA RC),
6.4 (Phe βC), 32.9 (GABA γC), 30.3 (Val #1 βC), 28.5 (Val #2 βC),
6.0 (GABA βC), 25.2 (Trp βC), 19.7 (Val #2 γC), 18.9 (Val #1 γC),
2
002, 45, 1624.
18) Hunter, L; Jolliffe, K. A.; Jordan, J. T.; Jensen, P.; Macquart,
R. B. Chem.—Eur. J. 2011, 17, 2340.
(
0
0
8.7 (Val #1 γC ), 18.4 (Val #2 γC ), 18.1 (Ala #2 βC), 17.3 (Ala #1
þ
þ
βC); MS (ESI, þve) m/z 759 (MH , 100%), 781 (MNa , 10%);
þ
þ
HRMS (ESI, þve) C H N O Na [MNa ] requires m/z 781.4008,
40 54 8 7
found 781.4004.
’
ASSOCIATED CONTENT
S
Supporting Information. Characterization data (NMR
b
spectra, HPLC traces) of compounds 1 and 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
’
AUTHOR INFORMATION
Corresponding Author
luke.hunter@sydney.edu.au
’
ACKNOWLEDGMENT
This work was funded by a University of Sydney Postdoctoral
Research Fellowship awarded to L.H.
’
REFERENCES
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1
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1
997, 97, 2651.
(
(
(
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(
3
(
(
8) Laatsch, H. Liebigs Ann. Chem. 1982, 28.
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(10) Thiericke, R.; Rohr, J. Nat. Prod. Rep. 1993, 10, 265.
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(
(
2000.
(
13) Skropeta, D.; Jolliffe, K. A.; Turner, P. J. Org. Chem. 2004,
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(
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(
(
(
15) Bruker TopSpin software, version 2.1, 2007.
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17) Non-natural GABA-containing cyclic peptides have previously
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5
505
dx.doi.org/10.1021/jo200813a |J. Org. Chem. 2011, 76, 5502–5505