Concise asymmetric total synthesis of ent -guadinomic acid from an epoxy alkenol

Article abstract of DOI:10.1055/s-0029-1218003

A highly efficient asymmetric total synthesis of ent-guadinomic acid [(-)-K01-0509 B] was accomplished from the known epoxy alkenol which is resolved by HKR method. Cross metathesis of the alkene part with acrylate and epoxide opening with azide followed

Full text of DOI:10.1055/s-0029-1218003

LETTER
2949
Concise Asymmetric Total Synthesis of ent-Guadinomic Acid from an Epoxy
Alkenol
S
ynthesis of ent-G
y
uadinomic
A
e
cid from an
m
Epoxy Alkenol i Kim, Myung-Yeol Kim, Jinsung Tae*
Department of Chemistry and Center for Bioactive Molecular Hybrids (CBMH), Yonsei University, Seoul 120-749, Korea
Fax +82(2)3647050; E-mail: jstae@yonsei.ac.kr
Received 29 July 2009
Over the past few years, we have demonstrated the syn-
Abstract: A highly efficient asymmetric total synthesis of ent-gua-
thetic usefulness of the optically pure epoxy alkenol 111
which is readily prepared by Jacobsen’s hydrolytic kinetic
resolution (HKR) method. Many different functionalities
dinomic acid [(–)-K01-0509 B] was accomplished from the known
epoxy alkenol which is resolved by HKR method. Cross metathesis
of the alkene part with acrylate and epoxide opening with azide fol-
lowed by intramolecular guanidine formation reactions furnished could be introduced by nucleophilic epoxide-opening
ent-guadinomic acid.
chemistry, and the alkene moiety can be further function-
alized by metathesis chemistry to access natural products
containing 1,3-diol and related subunits (Scheme 1).
Key words: cyclic guanidine, epoxides, guadinomic acid, meta-
thesis, total synthesis
O
Guadinomic acid (K01-0509 B) and guadinomines A–D,
which have an unusual carbamoylated cyclic guanidine,
were isolated from the culture broths of Streptomyces sp.
K01-0509.1 Among them, guadinomines A–C exhibited
selective inhibitory effects for type III secretion system
(TTSS).1–3 Recently, Omura group have determined the
absolute configurations of guadinomic acid and gua-
dinomines B and C1 by asymmetric total synthesis4,
(Figure 1). The unique cyclic guanidinyl moiety is found
only in a few natural products, such as NA22598A1,6
enduracidin,7 mannopeptimycin,8 enduracididine,9 and
anatoxin a.10
OH
O
metathesis
Nu
RCM
CM
OH
O
2
1
OH OH
Nu
resolved by HKR
(ref. 11a)
Nu
Z
3
Scheme 1 Synthetic utilities of the epoxy alkenol 1
We envisioned that the main skeleton of guadinomic acid
could be readily accessed by the epoxide opening–
metathesis strategy. Azide-mediated nucleophilic opening
of the epoxide 8 would provide the terminal amine group,
and cross-metathesis of the alkene part with acrylate will
introduce the carboxylic acid (Scheme 2). The five-
membered guanidine ring of guadinomic acid could be
prepared by an intramolecular cyclization strategy as de-
scribed in the synthesis by Omura group.4 Since the total
synthesis of natural guadinomic acid has been reported,
we planned to synthesize the enantiomer of guadinomic
acid (4) starting from the known epoxy alkenol 1.
H2N
CO2H
N
HN
O
NH
OH
guadinomic acid
(K01-0509)
O
H
N
O
OH
N
H
CO2H
H2N
O
NH2
N
NH
OH
NH2
HN
The PMP-protected epoxide 9 was prepared from the
known epoxy alkenol (–)-111a by Mitsunobu inversion of
the secondary alcohol using 4-MeOC6H4OH. Cross-
metathesis12 of 9 with 3 equivalents of tert-butyl acrylate
catalyzed by second-generation Grubbs catalyst (10) in
refluxing dichloromethane furnished the epoxy a,b-unsat-
urated ester 11 (Scheme 3). Among many known reaction
conditions for the ring opening of epoxides with azide nu-
cleophile, sodium azide with suitable additives proved to
be effective for the opening of epoxide 11 (Table 1). The
CeCl3-mediated regioselective epoxide opening13 in aque-
ous acetonitrile gave only moderate yield (42%) of azi-
dohydrin 12 (Table 1, entry 1). Classical protocols14 using
NH4Cl and NaN3 in aqueous methanol solution yielded 12
in good yield (91%), however, the regioisomer (7:1 ratio)
guadinomine B
O
H
N
O
OH
N
H
CO2H
H2N
O
NH
N
NH
OH
HN
O
HN
guadinomine C2
Figure 1 Guadinomic acid (K01-0509) and guadinomines B and C1
SYNLETT 2009, No. 18, pp 2949–2952
Advanced online publication: 02.10.2009
DOI: 10.1055/s-0029-1218003; Art ID: U07709ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

2950
H. Kim et al.
LETTER
HN
N
BocN
HN
OH
NH
OP
NBoc
O
CO2H
CO2R
H2N
ent-guadinomic acid (4)
5
intramolecular
guanidine formation
OH OP
H
N
BocHN
CO2R
6
NBoc
OP
OH OP
O
N3
CO2R
8
7
CM
N3
Scheme 2 Retrosynthetic analysis of ent-guadinomic acid (4)
(4-MeO)C6H4OH
Ph3P, DIAD, THF
OPMP
O
OH
O
65%
9
1
10 (10 mol%)
N
N
Mes
Mes
CH2Cl2 (0.3 M), reflux
Cl
Ru
(3 equiv)
CO2t-Bu
91%
Cl
Ph
PCy3
10
OH OPMP
OPMP
conditions
Table 1
O
N3
CO2t-Bu
CO2t-Bu
12
11
Scheme 3 Synthesis of azidohydrin 12
was also formed as minor product (Table 1, entry 2). The However, we could not isolate the corresponding mesy-
regioselectivity problem was readily solved by changing late, instead, the cyclic guanidine compound 15 was ob-
solvent system to aqueous DMF solution (Table 1, entry tained directly from the reaction mixture, but the yield
3).15 Therefore, the terminal amine and the carboxylic was only 39% (Table 2, entry 1). Intramolecular Mitsuno-
acid units of ent-guadinomic acid (4) were rapidly intro- bu reaction was not appropriate for the synthesis of the
duced with the proper stereochemistries from the known cyclic guanidine 15 (Table 2, entry 2). Since the Ms2O-
compound 1.
mediated cyclization reaction was slow, we tried with
more reactive Tf2O as the activating reagent. Although the
cyclization yield with Tf2O/Et3N was 40%, the reaction
time was significantly reduced from 24 hours to 4 hours
even at low temperature (Table 2, entry 3). Optimal cy-
clization yield for the formation of cyclic guanidine was
achieved by using Tf2O and i-Pr2NEt in dichloromethane
at –78 °C (Table 2, entry 4).17
Next, treatment of 12 with Pd/C and hydrogen gas re-
duced the azide and the alkene functional groups to give
the 1,2-amino alcohol 13 (Scheme 4). Subsequently, the
primary amine was treated with N,N¢-di-Boc-N¢¢-
triflylguanidine16 to yield the di-Boc-protected guanidine
14. For synthesis of the five-membered guanidine, com-
pound 14 was treated with Ms2O to induce intramolecular
cyclization as described in the synthesis by Omura group.4
Table 1 Azide-Mediated Epoxide Opening of 11 to Azidohydrin 12
Entry
Reagents (equiv)
NaN3 (2)
Additives (equiv)
CeCl3·7H2O (2)
NH4Cl (2)
Conditions
Yield (%)a
42
1
MeCN–H2O (9:1), reflux, 3 h
MeOH–H2O (8:1), reflux, 1 h
DMF–H2O (7:1), reflux, 1 h
2
NaN3 (2)
91 (7:1)b
97
3
NaN3 (2)
NH4Cl (2)
a Isolated yields.
b Regioisomer was also formed as a minor product.
Synlett 2009, No. 18, 2949–2952 © Thieme Stuttgart · New York

LETTER
Synthesis of ent-Guadinomic Acid from an Epoxy Alkenol
2951
OH OPMP
the order of deprotections (reacting TFA then CAN)
caused problems in the purification steps due to the inor-
ganic cerium salts. The spectral data of 4 are identical to
H2, 10% Pd/C
EtOH, 3 atm
H2N
CO2t-Bu
12
84%
13
25
the natural product while the optical rotation value {[a]D
Et3N, CH2Cl2
reflux, 24 h
99%
BocHN
NTf
NHBoc
+31.9 (c 0.10, MeOH)} of 4 is opposite to the natural val-
ue {[a]D20 –30.9 (c 0.11, MeOH)}.
OH OPMP
H
BocN
N
CO2t-Bu
In summary, we have completed asymmetric total synthe-
sis of ent-guadinomic acid [(–)-K01-0509 B] starting
from the known epoxy alkenol 1 in nine steps. Key steps
include cross metathesis of the alkene with acrylate, nu-
cleophilic opening of the epoxide with azide, and intramo-
lecular cyclization of the guanidine derivative.
14
NHBoc
intramolecular
cyclization
BocN
HN
Table 2
OPMP
NBoc
CO2t-Bu
15
Synthesis of Azidohydrin 12 by Epoxide Opening
Scheme 4 Synthesis of the protected cyclic guanidine 16
To a mixture of epoxide 11 (365 mg, 1.09 mmol) and NH4Cl (116
mg, 2.1 mmol) in DMF and H2O (7:1, 3.6 mL) was added NaN3
(141 mg, 2.1 mmol). The reaction mixture was stirred reflux tem-
perature for 1 h. After completion as indicated by TLC, the reaction
mixture was extracted with CH2Cl2 (3 × 5 mL), the combined organ-
ic layer was washed with H2O (3 mL) and brine (3 mL), dried over
MgSO4, and evaporated under reduced pressure. The residue was
purified by silica gel chromatography (hexane–EtOAc = 10:1) to
give 400 mg of 12 (97%) as a yellow oil; Rf = 0.20 (silica gel,
hexane–EtOAc = 3:1); [a]D20 +37.3 (c 0.65, CHCl3). 1H NMR (400
MHz, CDCl3): d = 6.90–6.78 (m, 5 H), 5.79 (d, J = 15.6 Hz, 1 H),
4.58–4.52 (m, 1 H), 4.08–4.05 (m, 1 H), 3.77 (s, 3 H), 3.44–3.40
(dd, J = 12.4, 3.6 Hz, 1 H), 3.32–3.27 (dd, J = 12.4, 7.6 Hz, 1 H),
2.54–2.51 (m, 2 H), 2.29 (br s, 1 H), 1.76 (t, J = 5.6 Hz, 2 H), 1.47
(s, 9 H). 13C NMR (100 MHz, CDCl3): d = 165.6, 154.6, 151.6,
142.2, 126.2, 118.0, 115.0, 80.5, 74.7, 67.5, 57.5, 55.8, 38.6, 36.5,
28.2. IR (film): 3461, 2974, 2925, 2835, 2100, 1708, 1646, 1507,
1454, 1364, 1323, 1283, 1221, 1156, 1103, 980, 829, 768 cm–1.
HRMS: m/z [M]+ calcd for C19H27O5N3: 377.1951; found:
377.1953.
Table 2 Intramolecular Cyclization of 14 to Cyclic Guanidine 15
Entry Reagents
Conditions
Yield (%)a
1
2
3
4
Ms2O, Et3N, DMAP
CH2Cl2, r.t., 24 h
THF, 0 °C to r.t.
CH2Cl2, –78 °C, 4 h
CH2Cl2, –78 °C, 4 h
39
5
Ph3P, DIAD
Tf2O, Et3N
40
83
Tf2O, i-Pr2NEt
a Isolated yields (Ms = MeSO2; DIAD = i-PrCO2N = NCO2i-Pr,
Tf = CF3SO2).
BocN
PMP-NCO
OPMP
NBoc
O
benzene
N
15
CO2t-Bu
r.t., 8 h
86%
PMPNH
16
Intramolecular Cyclization of 14 to Cyclic Guanidine 15
To a solution of 14 (234 mg, 0.45 mmol) in anhyd CH2Cl2 (18 mL)
was added trifluoromethanesulfonic anhydride (82 mL, 0.49 mmol)
containing diisopropylethylamine (374 mL, 2.26 mmol) at –78 °C.
The solution was stirred for 4 h, and then the mixture was warmed
at 0 °C. The reaction mixture was quenched with sat. aq NaHCO3
(20 mL), brine (10 mL), and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried over
MgSO4. The crude product was purified by column chromatogra-
phy using hexane and EtOAc (1:1 v/v) to give 191 mg of 15 (83%)
as a pale yellow oil; Rf = 0.17 (silica gel, hexane–EtOAc = 1:1);
HN
N
CAN (4 equiv)
MeCN–H2O (4:1)
0 °C, 30 min
1.
2.
OH
O
NH
O
OH
63%
H2N
ent-guadinomic acid (4)
TFA–H2O (3:1)
r.t., 1 h
[α]D20 –30.9 (c 0.11, MeOH)
63%
natural guadinomic acidref.1
[α]D25 +31.9 (c 0.10, MeOH)
20
1
[a]D +14.2 (c 0.50, CHCl3). H NMR (400 MHz, CDCl3): d =
6.82–6.74 (m, 4 H), 4.47 (m, 1 H), 4.20–4.15 (m, 1 H), 3.76 (m, 4
H), 3.58 (m, 1 H), 2.21 (t, J = 6.4 Hz, 2 H), 2.17–2.08 (m, 1 H), 1.96
(m, 1 H), 1.67–1.63 (m, 5 H), 1.55 (s, 9 H), 1.44 (s, 9 H), 1.41 (s, 9
H). 13C NMR (100 MHz, CDCl3): d = 172.5, 154.1, 151.9, 116.8,
114.8, 83.2, 80.3, 74.5, 55.7, 53.8, 38.3, 35.3, 33.4, 28.2, 28.2, 20.5.
IR (film): 3346, 2962, 2921, 2848, 1736, 1675, 1614, 1503, 1446,
1368, 1315, 1250, 1189, 1140, 1058, 1029, 992, 768 cm–1. HRMS:
m/z [M + H]+ calcd for C30H48O8N3: 578.3441; found: 578.3448.
..
Scheme 5 Completion of total synthesis of ent-guadinomic acid (4)
With the cyclic guanidine 15 in hand, we then attempted
to introduce the carbamoyl function on the guanidyl nitro-
gen. Direct carbamoylations with reagents, such as
KNCO18 and ClSO2NCO,19 were unsatisfactory. Instead,
introduction of carbamoyl group using PMPNCO4,5 gave
the PMP-protected carbamoyl compound 16 in 86% yield
(Scheme 5). Finally, deprotection of the p-methoxyphe-
nyl (PMP) by ceric ammonium nitrate (CAN) in aqueous
acetonitrile solution followed by deprotections of tert-
butyl ester and Boc groups with TFA–CH2Cl2 completed
the total synthesis of ent-guadinomic acid (4). Reversing
ent-Guadinomic Acid (4)
White powder; decomposed at 180–200 °C; [a]D –30.9 (c 0.11,
20
MeOH). 1H NMR (400 MHz, D2O): d = 4.26–4.20 (m, 2 H), 3.81–
3.74 (m, 2 H), 2.48 (t, J = 7.2 Hz, 2 H), 1.83–1.78 (m, 2 H), 1.71–
1.67 (m, 1 H), 1.61–1.68 (m, 1 H), 1.52–1.48 (m, 2 H). 13C NMR
(100 MHz, D2O): d = 182.1 156.4, 155.9, 68.3, 51.2, 50.5, 40.6,
36.3, 36.0, 21.3. IR (film): 3342, 3179, 2917, 1724, 1675, 1556,
Synlett 2009, No. 18, 2949–2952 © Thieme Stuttgart · New York

2952
H. Kim et al.
LETTER
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1397, 1221, 1197, 768 cm–1. HRMS: m/z [M + H]+ calcd for
C10H19O4N4: 259.1406; found: 259.1413.
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Acknowledgment
This work was supported by the Center for Bioactive Molecular
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Synlett 2009, No. 18, 2949–2952 © Thieme Stuttgart · New York

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