Stereoselective total synthesis of amicoumacin C

Article abstract of DOI:10.1016/j.tet.2015.02.014

The enantio- and diastereoselective total synthesis of amicoumacin C was achieved from l-phenylalanine in 17% overall yield through 13 steps via condensation between an amine and an acid segment. The amine segment was prepared from l-leucine in 42% yield

Full text of DOI:10.1016/j.tet.2015.02.014

Tetrahedron xxx (2015) 1e6
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Tetrahedron
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Stereoselective total synthesis of amicoumacin C
,
Tomomi Suzuki a, Tomohiro Nagasawa a, Masaru Enomoto b, Shigefumi Kuwahara a
*
a Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku,
Sendai 981-8555, Japan
b Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantio- and diastereoselective total synthesis of amicoumacin C was achieved from L-phenylalanine
Received 2 January 2015
Received in revised form 2 February 2015
Accepted 3 February 2015
Available online xxx
in 17% overall yield through 13 steps via condensation between an amine and an acid segment. The
amine segment was prepared from -leucine in 42% yield by a 7-step sequence involving a diaster-
eoselective reduction of an -dibenzylamino ketone intermediate, while the acid segment was obtained
from -phenylalanine by using acidic hydrolysis of an acetonide-protected amide accompanied by con-
comitant lactonization as a key step.
L
a
L
Keywords:
Amicoumacin
Ó 2015 Elsevier Ltd. All rights reserved.
Isocoumarin
Diastereoselective reduction
Antibacterial
Total synthesis
1. Introduction
Members of this family are produced mainly by bacteria of genus
Bacillus and share the same left-hand amine segment (6) in com-
mon, while the right-hand acid portion shows considerable struc-
tural diversity, as exemplified by 1, amicoumacins A (2) and B
(3),1,2,4 bacilosarcin A (4),5 and Y-05460M-A (5).6 Many of this class
of natural products are known to have various medicinally or ag-
riculturally important biological properties such as antibacterial,
anti-inflammatory, antiulcer, cytotoxic, and herbicidal activities.1e7
These intriguing physiological effects as well as the unique mo-
lecular architectures prompted synthetic efforts toward this family
of natural products, which culminated in the total synthesis of the
antiulcer natural product amiocumacin B (3) (also called AI-77-B)
by Shioiri’s and six other laboratories.8e14 We also succeeded in the
total synthesis of bacilosarcin A (4) and its analog (bacilosarcin B) as
well as amicoumacins A (2) and B (3) by using amicoumacin C (1) as
a common synthetic intermediate,15 and, additionally, Y-05460M-A
(5) and its higher homolog (PM-94128) by a different synthetic
approach.16
Amicoumacin C (1), an antibacterial substance first isolated
from the culture broth of Bacillus pumilus BN-103 and later from B.
subtilis 3 (probiotic strain),1,2 belongs to a family of natural products
characterized by a dihydroisocoumarin ring system linked, via an
amide bond, to an unusual amino acid in most cases (Fig. 1).3
R
O
O
O
OH COX
O
R
N
N
H
H
O
OH NH2
OH NH2
2 (amicoumacin A): X = NH2
3 (amicoumacin B): X = OH
OH
O
O
1 (amicoumacin C)
i-Bu
HO
O
Among the eight total syntheses of 3 reported so far,8e15 four
syntheses including the first one by Shioiri and co-workers utilized
diastereoselective addition of metalated aromatic esters A to Boc-
protected leucinal B for the synthesis of amine segment pre-
cursors C (Scheme 1).8,10,11,14 This type of reactions, though concise,
faced critical problems concerning the chemical yield (32e64%),
O
OH
NH2
NH
NH
R
O
R
N
N
H
O
H
OH NH2
5 (Y-05460M-A)
OH
O
OH
4 (bacilosarcin A)
6
Fig. 1. Amicoumacin C (1) and related compounds.
diastereoselectivity at the newly formed C3 stereogenic center (3b/
3
a
¼2.2:1e81:19),17 and reproducibility; the low reproducibility of
this transformation was also posed in another synthetic study on
3.9 The amine segment employed in our total synthesis of 1e5 and
* Corresponding author. Tel./fax: þ81 22 717 8783; e-mail address: skuwahar@
biochem.tohoku.ac.jp (S. Kuwahara).
http://dx.doi.org/10.1016/j.tet.2015.02.014
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
T. Suzuki et al. / Tetrahedron xxx (2015) 1e6
i-Bu
2.2. Preparation of amine segment 7
3
i-Bu
M
NHBoc
The preparation of 7 commenced with the conversion of
L-leucine
+
O
CO2R2
OHC
NHBoc
14 into the corresponding methyl ester, which upon exposure to
OR1
OR1
O
B
€
benzyl bromide in DMF in the presence of the Hunig base provided
A
C
N,N-dibenzyl-protected leucinate 15 in an excellent yield of 98% for
the two steps (Scheme 3).18 The ester 15 was derivatized into
Weinreb’s amide11 andthenallowed toreactwiththebenzyllithium
species generated by treating 10 with s-BuLi in THF. The resulting
ketone 9 obtained in 77% overall yield from 15 was subjected to
highly diastereoselective reduction under non-chelation-controlled
conditions (NaBH4 in MeOH) developed by Reetz and co-workers to
afford 16.19,20 Refluxing a solution of 16 in toluene under acidic
conditions gave lactone 17,21 the hydrogenolytic debenzylation of
which provided the amine segment 7 in 56% yield for the three steps
from 9. The amino lactone 7 was evaluated to be optically pure by 1H
NMR analysis of the corresponding (R)- and (S)-MTPA amides 70.
R1 = MOM, R2 = Me
1 = Me, R2 = Et
R1, R2 = acetonide
R1 = MOM, Me, or H
R
Scheme 1. Key steps in previous syntheses of amine segment precursors C.
related natural products was, on the other hand, prepared via BF3-
promoted ring opening of a chiral epoxide intermediate with an
aromatic nucleophile as the key carbonecarbon bond-forming
step,15,16 which also, however, resulted in a modest yield of 48%.
We describe herein a new total synthesis of amicoumacin C (1) that
includes an efficient construction of the methyl ether of the amine
i-Bu
i-Bu
15
e
i-Bu
a, b
c
segment 6 via highly diastereoselective reduction of an a-diben-
zylamino ketone intermediate.
N
HO2C
NH2
MeO2C
NBn2
MeO
NBn2
O
14
11
2. Results and discussion
i-Bu
i-Bu
d
f
NBn2
NBn2
2.1. Retrosynthetic analysis of 1
O
OH
CONEt2
CONEt2
Scheme 2 outlines our retrosynthetic analysis of 1. The amide 1
should be obtainable via condensation of amine segment 7 and acid
segment 8. To prepare 7 in a stereoselective manner, we planed to
OMe
OMe
9
16
i-Bu
i-Bu
utilize a highly diastereoselective reduction of
a-dibenzylamino
g
NHR
NBn2
ketone 9 under non-chelation control. The ketone 9 would be de-
rived by acylation of the benzylic position of N,N-diethyl amide 10
with Weinreb’s amide 11; we expected that a benzylic anion gen-
erated from 10 would be stable enough to realize its efficient ad-
dition to 11, unlike the corresponding anion prepared from ester
precursors (A in Scheme 1). The preparation of the acid segment 8,
on the other hand, is based primarily on our protocol previously
employed for the total synthesis of Y-05460M-A (5) and PM-94128,
except for additional installation of the amide functionality at the
C120 position.16,17 Thus, compound 8 was traced back to known
O
O
OMe O
OMe O
17
7: R = H
7': R = (R)- or (S)-MTPA
Scheme 3. Preparation of amine segment 7. Reagents and conditions: (a) SOCl2, MeOH,
reflux, 3 h; (b) BnBr, i-Pr2NEt, DMF, 0 ꢀC to rt, 12 h, 98% from 14; (c) Me(MeO)NH$HCl,
i-PrMgCl, THF, ꢁ20 ꢀC to rt, 5 h, 84%; (d) 10, s-BuLi, THF, ꢁ78 ꢀC, 25 min, 92%; (e)
NaBH4, MeOH, 0 ꢀC to rt, 23 h; (f) CSA, toluene, reflux, 3 d, 70% from 9; (g) H2, Pd/C,
HCl/MeOH, EtOAc, rt, 16 h, 80%.
hydroxy lactam 12 obtainable from
nient 4-step sequence of reactions; compound 12 would be con-
vertible into 8 via stereoselective dihydroxylation of an a,b-
unsaturated lactam intermediate derived from 12 and oxidative
cleavage of the benzene ring to form a carboxylic acid as the key
steps.
L
-phenylalanine 13 by a conve-
2.3. Preparation of acid segment 8
The acid segment 8 was prepared in 6 steps from the known N-
protected hydroxyl lactam 12 which, in turn, was obtainable in ca.
75%yield from
of Meldrum’s acid with N-Boc-
L
-leucinebya4-stepsequenceinvolving theacylation
L
-leucine (Scheme 4).16,22 Subjection
of 12 toa one-pot mesylation/eliminationprotocol gavedehydration
product 18 in 80% yield. Dihydroxylation of the double bond of 18
i-Bu
O
O
NH2
12'
CONEt2
+
1
OH
HO
O
OH
HO2C
O
4 steps
a
b
NHBoc
13
OMe O
ca. 75%
(ref 20)
O
O
N
N
N
7
8
Ph
Ph
Ph
Boc
12
Boc
Boc
18
19
i-Bu
OH
O
O
NBn2
O
O
c
f
O
O
N
CONEt2
HO2C
CONEt2
NHBoc
Ph
O
Boc
N
Boc
OMe
R
9
12
8
20: R = Ph
21: R = CO2H
22: R = CONEt2
4 steps
ref X
d
e
i-Bu
+
N
HO2C
MeO
NBn2
Ph
CONEt2
Scheme 4. Preparation of acid segment 8. Reagents and conditions: (a) MsCl, Et3N,
CH2Cl2, 0 ꢀC to rt, 20 h, 80%; (b) OsO4, NMO, citric acid, MeCN/Me2CO/H2O, rt, 18 h; (c)
Me2C(OMe)2, TsOH$H2O, CH2Cl2, rt, 24 h, 84% from 18; (d) RuCl3$nH2O, NaIO4, NaHCO3,
EtOAc/MeCN/H2O, rt, 3 d; (e) Et2NH, EDC$HCl, HOBt, DMAP, CH2Cl2, rt, 24 h, 60% from
20; (f) LiOH$H2O, THF/H2O, rt, 13 h.
O
NH2
13
OMe
10
11
Scheme 2. Retrosynthetic analysis of 1.
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T. Suzuki et al. / Tetrahedron xxx (2015) 1e6
3
from the less hindered
b
-face of the ring system provided diol 19, the
spectrometer (400 MHz for 1H and 100 MHz for 13C) unless oth-
erwise stated. Optical rotation values were measured with a Jasco
P-2200 polarimeter, and the mass spectra were obtained with Jeol
JMS-700 spectrometer operated in the FAB mode. Melting points
were determined with a Yanaco MP-J3 apparatus and are un-
protection of which as an acetonide furnished 20 in 84% yield for the
two steps. The benzene ring of 20 was then cleaved oxidatively by
Sharpless’ method using a catalytic amount of RuCl3 to give car-
boxylic acid 21,23 which was condensed with diethylamine to afford
22 in 60% yield from 20. Finally, selective hydrolytic opening of the
N-Boc-protected lactam ring of 22 furnished the acid segment 8.
corrected. Merck silica gel 60 (63e200 mm) was used for column
chromatography. Analytical thin-layer chromatography was per-
formed using Merck silica gel 60 F254 plates (0.25 mm thick). Sol-
vents for reactions were distilled prior to use: THF from Na and
benzophenone; CH2Cl2, MeCN, and DMF from CaH2; MeOH from
Mg(OMe)2; toluene from LiAlH4. All air- or moisture-sensitive re-
actions were conducted under a nitrogen atmosphere.
2.4. Completion of the total synthesis of 1
The final stage of our total synthesis of amicoumacin C (1) is
shown in Scheme 5. Condensation of 7 and 8 proceeded smoothly
by exposing the two segments to HBTU/Et3N in CH2Cl2/DMF, pro-
viding amide 23 in a good overall yield of 85% from 22. Removal of
the acetonide and Boc protecting groups of 23 under acidic con-
ditions brought about concomitant lactone ring formation to give
24 in 75% yield, and subsequent unmasking of the methyl-
protected phenolic hydroxy group by treatment with BBr3 in
CH2Cl2 in the presence of anisole provided amicoumacin C (1) in
87% yield.15a,24 The 1H and 13C NMR spectra of 1 were identical with
4.2. Methyl N,N-dibenzyl-
L
-leucinate (15)
-leucine (14) (4.00 g, 30.5 mmol) in
To a stirred solution of
L
MeOH (60 mL) was added dropwise SOCl2 (5.50 mL, 75.4 mmol) at
0
ꢀC. The mixture was stirred at reflux for 3 h, and then concen-
trated in vacuo to give an ester intermediate as a white power,
which was taken up in DMF (43 mL). To the solution was added i-
Pr2NEt (31.9 mL, 183 mmol) at 0 ꢀC and the mixture was stirred for
1 h at the same temperature. BnBr (10.9 mL, 91.5 mmol) was then
added, and the resulting mixture was gradually warmed to room
temperature and stirred for 12 h. The mixture was diluted with
water and extracted with hexane/EtOAc (1:1). The extract was
successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by SiO2 column
those of an authentic material,15a and the specific rotation of 1
25
[[
a
]
ꢁ120 (c 0.070, MeOH)] showed good agreement with a re-
D
ported value [[
a]
22 ꢁ123 (c 0.045, MeOH)].15a
D
i-Bu
O
O
a
N
CONEt2
NHBoc
+
7
8
chromatography (hexane/EtOAc/toluene¼48:1:1) to give 15 (9.69 g,
H
O
O
23
98% from 14) as a colorless oil. [
a
]
ꢁ120 (c 1.12, CHCl3); IR: nmax
D
1732 (s), 1495 (m), 1145 (s), 697 (vs); 1H NMR:
d 0.60 (3H, d,
OMe O
23
J¼6.6 Hz), 0.81 (3H, d, J¼6.6 Hz), 1.44e1.52 (1H, m), 1.64e1.72 (1H,
m), 1.72e1.82 (1H, m), 3.39 (1H, dd, J¼8.6, 6.1 Hz), 3.50 (2H, d,
J¼13.9 Hz), 3.75 (3H, s), 3.91 (2H, d, J¼13.9 Hz), 7.23 (2H, t,
J¼7.2 Hz), 7.31 (4H, dd, J¼7.5, 7.2 Hz), 7.35 (4H, d, J¼7.5 Hz); 13C
b
O
O
O
N
NMR:
d 21.5, 23.2, 24.4, 38.8, 51.0, 54.5 (2C), 58.7, 126.9 (2C), 128.2
H
O
d
OH NH2
(4C), 128.9 (4C), 139.7 (2C), 173.9; HRMS (FAB): m/z calcd for
C
21H28NO2 ([MþH]þ) 326.2120, found 326.2122.
OR
O
24: R = Me
1: R = H
4.3. (S)-2-(Dibenzylamino)-N-methoxy-N,4-
dimethylpentanamide (11)
Scheme 5. Synthesis of amicoumacin C (1). Reagents and conditions: (a) HBTU, Et3N,
CH2Cl2/DMF, rt, 12 h, 85% from 22; (b) 12 M HCl, DME, 85 ꢀC, 3 d, 75%; (c) BBr3, anisole,
CH2Cl2, e78 to ꢁ5 ꢀC, 12 h, 87%.
To a stirred solution of MeN(OMe)$HCl (3.45 g, 35.4 mmol) in
THF (40 mL) was added dropwise as a solution of i-PrMgCl (2.0 M in
THF, 33 mL, 66 mmol) at 0 ꢀC and the mixture was stirred at the
same temperature for 15 min. A solution of 15 (7.67 g, 23.6 mmol) in
THF (40 mL) was then added, and the resulting mixture was stirred
for 2 h at 0 ꢀC. The mixture was gradually warmed to room tem-
perature and stirred for 5 h. The mixture was quenched with satu-
rated aq NH4Cl and extracted with CH2Cl2. The extract was
successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by SiO2 column
3. Conclusion
In conclusion, the stereoselective total synthesis of amicouma-
cin C (1) was accomplished in 17% overall yield from L-phenylala-
nine 13 by a 13-step sequence. The amine segment 7, which is
common in all members of the amicoumacin family of natural
products, was prepared stereoselectively from
yield through 7 steps by making use of the highly diastereoselective
reduction of the -dibenzylamino ketone 9. The oxidative cleavage
L-leucine in 42%
a
of the benzene ring of 20 to form the carboxylic acid 21 as well as
the acidic hydrolysis of the acetonide protecting group of the amide
23 accompanied by concomitant lactone ring formation were also
employed as the key transformations in the present synthesis.
Synthetic studies on some amicoumacin family of natural products
using 1 as the pivotal intermediate are now in progress and will be
reported in due course.
chromatography (hexane/EtOAc¼5:1) to give 11 (7.00 g, 84%) as
23
a colorless oil. [
a
]
þ19.5 (c 1.26, CHCl3); IR: nmax 3028 (w), 1494
D
(m),1661 (s); 1H NMR:
d
0.79 (3H, d, J¼6.6 Hz), 0.88 (3H, d, J¼6.6 Hz),
1.44e1.56 (1H, m), 1.72e1.92 (2H, m), 3.13 (3H, s), 3.18 (3H, s), 3.75
(2H, d, J¼14.2 Hz), 3.85 (1H, br s), 3.96 (2H, br d, J¼14.2 Hz), 7.20 (2H,
t, J¼7.3 Hz), 7.28 (4H, dd, J¼7.5, 7.3 Hz), 7.38 (4H, d, J¼7.5 Hz); 13C
NMR:
d 21.7, 23.2, 24.3, 31.8, 37.3, 54.4 (2C), 54.8, 60.6, 126.6 (2C),
128.0 (4C), 128.7 (4C), 140.4 (2C), 175.5; HRMS (FAB): m/z calcd for
4. Experimental section
4.1. General
C
22H31N2O2Na ([MþNa]þ) 355.2385, found 355.2386.
4.4. (S)-2-[3-(Dibenzylamino)-5-methyl-2-oxohexyl]-N,N-di-
ethyl-6-methoxybenzamide (9)
IR spectra were recorded by a Jasco FT/IR-4100 spectrometer
using an ATR (ZnSe) attachment. NMR spectra were recorded with
TMS as an internal standard in CDCl3 by a Varian MR-400
To a stirred solution of s-BuLi (1.0 M in hexane, 8.4 mL,
8.4 mmol) in THF (7.0 mL) was added a solution of 10 (1.89 g,
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4
T. Suzuki et al. / Tetrahedron xxx (2015) 1e6
8.54 mmol) in THF (18.0 mL) at ꢁ78 ꢀC and stirred for 1 h at the
same temperature. A solution of 11 (1.48 g, 4.16 mmol) in THF
(17 mL) was then added, and the resulting mixture was stirred for
25 min. The mixture was quenched with saturated aq NH4Cl and
extracted with EtOAc. The extract was successively washed with
water and brine, dried (MgSO4), and concentrated in vacuo. The
residue was purified by SiO2 column chromatography (hexane/
EtOAc¼5:1) to give 9 as a ca. 3:2 atropisomeric mixture (1.97 g,
(1H, dd, J¼16.0, 2.2 Hz), 2.95e3.02 (1H, m), 3.12 (1H, dd, J¼16.0,
12.6 Hz), 3.94 (3H, s), 4.19 (1H, ddd, J¼12.6, 5.0, 2.2 Hz), 6.83 (1H, d,
J¼7.6 Hz), 6.92 (1H, d, J¼8.4 Hz), 7.46 (1H, t, J¼8.4, 7.6 Hz); 13C NMR:
d
21.3, 23.4, 24.2, 31.3, 42.4, 51.7, 56.0, 81.6, 110.6, 113.4, 119.2, 134.3,
141.9, 160.9, 162.4; HRMS (FAB): m/z calcd for C15H22NO3 ([MþH]þ)
264.1600, found 264.1603.
4.7. Determination of the enantiomeric excess of 7
92%). [
a
]
27 ꢁ80.1 (c 0.765, CHCl3); IR: nmax 1718 (m), 1629 (s), 1584
D
(m), 1262 (m); 1H NMR:
d
0.77 (3H, d, J¼6.4 Hz), 0.80 (3H, d,
Compound 7 was converted into the corresponding (R)- and (S)-
MTPA amides (70) by treating with 5.0 equiv of (S)- and (R)-MTPACl,
respectively, in pyridine overnight at room temperature; the dis-
appearance of the starting material 7 was checked by TLC. The C3
methine proton of the (R)-MTPA amide were observed as a de-
J¼6.4 Hz), 1.00 (0.6ꢂ3H, t, J¼7.2 Hz), 1.02 (0.4ꢂ3H, t, J¼7.2 Hz), 1.06
(0.6ꢂ3H, t, J¼7.2 Hz), 1.13 (0.4ꢂ3H, t, J¼7.2 Hz), 1.37e1.56 (2H, m),
1.64e1.76 (1H, m), 2.94e3.85 (13.4H, m), 4.01 (0.6ꢂ1H, d,
J¼18.4 Hz), 6.46 (0.4ꢂ1H, d, J¼7.7 Hz), 6.67 (0.6ꢂ1H, d, J¼7.7 Hz),
6.75 (0.4ꢂ1H, d, J¼8.4 Hz), 6.78 (0.6ꢂ1H, d, J¼8.4 Hz), 7.17 (0.6ꢂ1H,
formed triplet (J¼6.1 Hz) at
d
5.49 in 1H NMR (400 MHz, CDCl3),
5.59 as a de-
t, J¼8.1 Hz), 7.21e7.39 (10.4H, m); 13C NMR:
d
12.7, 13.3/13.6, 22.4/
while that of the (S)-MTPA amide was detected at d
22.5, 22.8/23.1, 25.3/25.4, 32.4/32.6, 38.1/38.3, 42.7, 44.9/45.1, 54.5
(2C), 55.4, 63.8/64.4, 109.0, 122.9, 123.4, 127.1/127.2 (2C), 128.36/
128.42 (4C), 128.8/129.0 (4C), 129.1/129.2, 133.0/133.3, 139.45/
139.49 (2C), 155.4, 167.6/167.7, 208.2/208.5; HRMS (FAB): m/z calcd
for C33H43N2O3 ([MþH]þ) 515.3274, found 515.3273.
formed triplet (J¼5.8 Hz). Comparison of the two spectra indicated
that the enantiomeric excess of 7 was virtually 100%.
4.8. tert-Butyl (S)-2-benzyl-5-oxo-2,5-dihydro-1H-pyrrole-1-
carboxylate (18)
4.5. (S)-3-[(S)-1-(Dibenzylamino)-3-methylbutyl]-8-
methoxyisochroman-1-one (17)
To a stirred solution of 12 (1.67 g, 5.73 mmol) and Et3N (2.40 mL,
17.2 mmol) in CH2Cl2 (45.0 mL) was added MsCl (0.76 mL,
9.8 mmol) at 0 ꢀC. The mixture was gradually warmed to room
temperature and stirred for 20 h. The mixture was quenched with
saturated aq NH4Cl at 0 ꢀC and extracted with ether. The extract
was successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by SiO2 column
chromatography (hexane/EtOAc¼3:1) to give 18 (1.26 g, 80%) as
To a stirred solution of 9 (0.861 g, 1.67 mmol) in MeOH (12.0 mL)
was added portionwise NaBH4 (0.384 g, 10.2 mmol) at 0 ꢀC. The
mixture was gradually warmed to room temperature and stirred for
22.5 h. The mixture was quenched with saturated aq NH4Cl and
extracted with EtOAc. The extract was successively washed with
water and brine, dried (MgSO4), and concentrated in vacuo to give
crude 16, which was dissolved in toluene (15 mL). The solution was
mixed with camphor sulfonic acid (1.21 g, 5.21 mmol) at room
temperature, and the resulting mixture was stirred at 110 ꢀC for 3
days. After cooling to room temperature, the mixture was succes-
sively washed with water and brine, dried (MgSO4), and concen-
trated in vacuo. The residue was purified by SiO2 column
chromatography (hexane/EtOAc¼2:1) to give 17 (0.520 g, 70% from
a pale yellow solid. Mp 92.0e93.0 ꢀC; [
a
]
20 þ224 (c 1.11, CHCl3); IR:
D
nmax 1762 (s), 1712 (w), 1688 (w), 1284 (m), 1150 (s); 1H NMR:
d
1.63
(9H, s), 2.74 (1H, dd, J¼13.1, 9.5 Hz), 3.54 (1H, dd, J¼13.1, 3.7 Hz),
4.72e4.78 (1H, m), 6.02 (1H, dd, J¼6.1, 1.6 Hz), 7.03 (1H, dd, J¼6.1,
1.4 Hz), 7.12e7.17 (2H, m), 7.23e7.34 (3H, m); 13C NMR:
d 28.2 (3C),
38.5, 63.3, 83.1, 126.6, 127.1, 128.6 (2C), 129.3 (2C), 135.5, 149.4,
149.9, 169.0; HRMS (FAB): m/z calcd for C16H20NO3 ([MþH]þ)
274.1443, found 274.1444.
9) as a white solid. Mp 55.0e58.0 ꢀC; [
a]
28 ꢁ138 (c 1.23, CHCl3); IR:
D
nmax 1728 (s), 1597 (w), 1235 (m), 1089 (s), 698 (s); 1H NMR:
d
0.79
4.9. tert-Butyl (3aS,4S,6aS)-4-benzyl-2,2-dimethyl-6-
oxotetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate
(20)
(3H, d, J¼6.5 Hz), 0.82 (3H, d, J¼6.5 Hz), 1.48e1.56 (1H, m),
1.62e1.76 (2H, m), 2.38 (1H, dd, J¼16.4, 2.3 Hz), 2.75e2.81 (1H, m),
3.42 (1H, dd, J¼16.4, 12.0 Hz), 3.55 (2H, d, J¼13.4 Hz), 3.94 (3H, s),
4.06 (2H, d, J¼13.4 Hz), 4.44 (1H, ddd, J¼11.9, 4.6, 2.4 Hz), 6.76 (1H,
d, J¼7.6 Hz), 6.89 (1H, d, J¼8.6 Hz), 7.22 (2H, t, J¼7.2 Hz), 7.29 (4H, t,
J¼7.2 Hz), 7.36 (4H, d, J¼7.2 Hz), 7.42 (1H, t, J¼8.6, 7.6 Hz); 13C NMR:
To a stirred solution of 18 (0.950 g, 3.48 mmol) in MeCN/ace-
tone/H2O (1:1:1, 15 mL) were successively added N-methyl-
morpholine N-oxide (0.814 g, 6.95 mmol), citric acid (0.668 g,
3.48 mmol), and OsO4 (44.0 mg, 0.173 mmol) at room temperature.
After 18 h of stirring, the mixture was diluted with saturated aq
NH4Cl at 0 ꢀC and extracted with CHCl3. The extract was succes-
sively washed with saturated aq Na2S2O3, 5% aq citric acid, water
and brine, dried (MgSO4), and concentrated in vacuo to give crude
19, which was taken up in CH2Cl2 (9.3 mL). To the solution were
added TsOH$H2O (70 mg, 0.37 mmol) and Me2C(OMe)2 (14.3 mL,
116 mmol) at room temperature. The mixture was stirred at room
temperature for 24 h and then poured into saturated aq NaHCO3.
The resulting mixture was extracted with ether and the extract was
successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by SiO2 column
d
22.4, 23.2, 24.7, 32.7, 33.5, 55.1 (2C), 56.1, 56.4, 79.5, 110.6, 113.8,
119.3,126.8 (2C),128.1 (4C),129.1 (4C),134.3,140.4 (2C),143.0,161.1,
162.5; HRMS (FAB): m/z calcd for C29H34NO3 ([MþH]þ) 444.2539,
found 444.2538.
4.6. (S)-3-[(S)-1-Amino-3-methylbutyl]-8-
methoxyisochroman-1-one (7)
A mixture of 17 (0.276 g, 0.622 mmol), 10% Pd/C (0.264 g), and
a HCl solution (1.25 M in MeOH, 1.87 mL, 2.33 mmol) in EtOAc/
MeOH (1:1, 7 mL) was stirred at room temperature for 15.5 h under
a hydrogen atmosphere. The mixture was filtered, and the filtrate
was concentrated in vacuo. The residue was diluted with CHCl3 and
mixed well with saturated aq NaHCO3 (5 drops) and solid NaHCO3.
The mixture was concentrated in vacuo, and the residue was pu-
rified by SiO2 column chromatography (CHCl3/MeOH¼1:0e50:1) to
chromatography (hexane/EtOAc¼5:1e2:1) to give 20 (1.01 g, 84%
21
from 18) as a white solid. Mp 113.0e115.0 ꢀC; [
a]
þ73.2 (c 1.02,
D
CHCl3); IR: nmax 1781 (s), 1703 (m), 1493 (w), 1148 (vs), 1104 (s); 1H
NMR:
d
1.29 (3H, s), 1.40 (3H, s), 1.61 (9H, s), 2.93 (1H, dd, J¼14.1,
give 7 (0.131 g, 80%) as a pale yellow oil. [
a
]
D
27 ꢁ104 (c 0.53, MeOH);
7.4 Hz), 3.11 (1H, dd, J¼14.1, 3.2 Hz), 3.90 (1H, d, J¼5.0 Hz), 4.39 (1H,
d, J¼5.0 Hz), 4.48 (1H, dd, J¼7.4, 3.2 Hz), 7.14 (2H, d, J¼7.6 Hz),
IR: nmax 1728 (s), 1599 (m), 1476 (m), 1239 (m), 1083 (m); 1H NMR:
d
0.92 (3H, d, J¼6.4 Hz), 0.96 (3H, d, J¼6.7 Hz), 1.30e1.38 (1H, m),
7.25e7.36 (3H, m); 13C NMR:
d 25.8, 27.1, 28.0 (3C), 37.8, 60.6, 75.3,
1.38e1.47 (1H, m), 1.47e1.62 (2H, br s, NH2), 1.75e1.88 (1H, m), 2.80
76.8, 83.8, 112.2, 127.4, 129.0 (2C), 129.4 (2C), 135.2, 149.7, 170.9;
Please cite this article in press as: Suzuki, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.014

T. Suzuki et al. / Tetrahedron xxx (2015) 1e6
5
HRMS (FAB): m/z calcd for C19H26NO5 ([MþH]þ) 348.1811, found
78.5, 78.9, 109.6, 110.7, 113.3, 119.4, 134.7, 142.1, 155.4, 161.1, 162.3,
169.6, 170.0; HRMS (FAB): m/z calcd for C33H52N3O9 ([MþH]þ)
634.3703, found 634.3705.
348.1809.
4.10. tert-Butyl (3aS,4S,6aS)-4-[2-(diethylamino)-2-oxoethyl]-
2,2-dimethyl-6-oxotetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-
5-carboxylate (22)
4.12. (S)-2-[(2S,3S)-3-Amino-5-oxotetrahydrofuran-2-yl]-2-
hydroxy-N-{(S)-1-[(S)-8-methoxy-1-oxoisochroman-3-yl]-3-
methylbutyl}acetamide (24)
To a stirred mixture of 20 (0.295 g, 0.849 mmol) and NaIO4
(2.57 g, 12.0 mmol) in EtOAc/MeCN/water (1:1:5, 21 mL) were
added RuCl3$xH2O (0.025 g) and NaHCO3 (0.025 g, 0.298 mmol),
and the resulting mixture was stirred vigorously for 3 days. The
mixture was filtered through a pad of Celite, and the filtrate was
extracted with CH2Cl2. The extract was successively washed with
water and brine, dried (MgSO4), and concentrated in vacuo to give
crude 21, which was then dissolved in CH2Cl2 (8.0 mL). To the so-
lution were added EDCI$HCl (140 mg, 0.730 mmol) and HOBt
(110 mg, 0.814 mmol) at ꢁ10 ꢀC. DMAP (90.0 mg, 0.737 mmol) and
Et2NH (0.14 mL, 1.4 mmol) were then added, and the resulting
mixture was stirred at room temperature for 24 h. The mixture was
diluted with 5% aq citric acid and extracted with CH2Cl2. The extract
was successively washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by SiO2 column
chromatography (hexane/EtOAc¼1:1) to give 22 (0.188 g, 60% from
To a stirred solution of 23 (21.0 mg, 0.0331 mmol) in DME
(1.0 mL) was added one drop of 12 M aq HCl at room temperature.
The mixture was heated at reflux for 3 days and then concentrated
in vacuo. The residue was diluted with CHCl3 and mixed well with
saturated aq NaHCO3 (5 drops) and solid NaHCO3. The mixture
was dried (Na2SO4) and concentrated in vacuo. The residue was
purified
by
SiO2
column
chromatography
(CHCl3/
MeOH¼1:0e20:1) to give 24 (10.4 mg, 75%) as a pale yellow oil.
25
[a
]
ꢁ123 (c 0.940, CHCl3); IR: nmax 3353 (m), 1778 (m), 1723 (s),
D
1669 (m), 1599 (m), 1239 (m); 1H NMR:
d
0.93 (3H, d, J¼6.5 Hz),
0.96 (3H, d, J¼6.6 Hz), 1.40e1.72 (4H, m), 1.41e1.50 (1H, m),
1.80e1.88 (1H, m), 2.30 (1H, dd, J¼18.0, 4.5 Hz), 2.79 (1H, br d,
J¼16.2 Hz), 2.95 (1H, dd, J¼18.0, 8.0 Hz), 3.01 (1H, dd, J¼16.2,
12.5 Hz), 3.74e3.80 (1H, m), 3.94 (3H, s), 4.29e4.39 (1H, m), 4.44
(1H, br d, J¼12.5 Hz), 4.55 (1H, d, J¼3.3 Hz), 4.64 (1H, t, J¼3.3 Hz),
6.79 (1H, d, J¼7.4 Hz), 6.90 (1H, d, J¼8.2 Hz), 7.11 (1H, d, J¼9.6 Hz,
20) as a white solid. Mp 93.0e95.0 ꢀC; [
a]
23 þ72.9 (c 1.11, CHCl3); IR:
D
nmax 1784 (s), 1701 (w), 1632 (s), 1230 (s), 1153 (vs); 1H NMR:
d
1.08
CONH, 7.44 (1H, dd, J¼8.2, 7.4 Hz); 13C NMR:
d 21.7, 23.1, 24.8, 31.7,
38.6, 40.2, 48.2, 49.1, 56.2, 71.5, 79.3, 88.2, 110.8, 113.1, 119.4, 134.9,
(3H, t, J¼7.2 Hz), 1.16 (3H, t, J¼7.2 Hz), 1.36 (3H, s), 1.46 (3H, s), 1.54
(9H, s), 2.69 (1H, dd, J¼16.4, 2.5 Hz), 3.10 (1H, dd, J¼16.4, 6.5 Hz),
3.21e3.33 (3H, m), 3.33e3.43 (1H, m), 4.36 (1H, dd, J¼6.5, 2.5 Hz),
141.8, 161.1, 162.6, 170.3, 176.3; HRMS (FAB): m/z calcd for
C
21H29N2O7 ([MþH]þ) 421.1974, found 421.1975.
4.72 (1H, d, J¼5.8 Hz), 4.98 (1H, d, J¼5.8 Hz); 13C NMR:
d 13.0, 14.2,
25.2, 26.8, 28.0 (3C), 33.8, 40.0, 41.9, 58.8, 76.9, 78.4, 83.6, 112.1,
4.13. (S)-2-[(2S,3S)-3-Amino-5-oxotetrahydrofuran-2-yl]-2-
hydroxy-N-{(S)-1-[(S)-8-hydroxy-1-oxoisochroman-3-yl]-3-
methylbutyl}acetamide (amicoumacin C) (1)
150.4, 168.0, 170.9; HRMS (FAB): m/z calcd for
C18H31N2O6
([MþH]þ) 371.2183, found 371.2184.
4.11. tert-Butyl {(S)-3-(diethylamino)-1-[(4S,5S)-5-({(S)-1-[(S)-
8-methoxy-1-oxoisochroman-3-yl]-3-methylbutyl}carba-
moyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-oxopropyl}carba-
mate (23)
To a stirred solution of 24 (10.4 mg, 0.0247 mmol) in CH2Cl2
(2.4 mL) were successively added anisole (22 mL, 0.20 mmol) and
BBr3 (1.0 M in CH2Cl2, 0.10 mL, 0.1 mmol) at ꢁ78 ꢀC. After 12 h of
stirring, the mixture was gradually warmed to ꢁ5 ꢀC and stirred
for 12 h. The mixture was quenched by the addition of saturated
aq NaHCO3 and solid NaHCO3, dried (MgSO4), and concentrated
in vacuo. The residue was purified by SiO2 column chromatog-
To a stirred solution of 22 (0.295 g, 0.796 mmol) in THF
(4.0 mL) were added water (2.0 mL) and LiOH$H2O (0.145 g,
3.46 mmol) at room temperature. After 12.5 h, the mixture was
quenched with 2 M aq HCl and extracted with EtOAc. The extract
was successively washed with water and brine, dried (MgSO4),
and concentrated in vacuo to give crude 8 (0.282 g, ca. 91% yield).
Then, a solution of crude 8 (0.252 g, ca. 0.649 mmol) in CH2Cl2/
DMF (5:2, 11.2 mL) and a solution of 7 (0.194 g, 0.737 mmol) in
CH2Cl2/DMF (5:2, 11.2 mL) were successively added to a mixture
raphy (CHCl3/MeOH¼1:0e10:1) to give 1 (8.7 mg, 87%) as a col-
25
orless oil. [
a
]
ꢁ120 (c 0.070, MeOH); IR: nmax 3271 (m), 1794
D
(m), 1675 (vs), 1618 (s), 1202 (s); 1H NMR (CD3OD):
d 0.93 (3H, d,
J¼6.5 Hz), 0.99 (3H, d, J¼6.6 Hz), 1.39e1.47 (1H, m), 1.61e1.74 (1H,
m), 1.78e1.86 (1H, m), 2.24 (1H, dd, J¼18.0, 3.2 Hz), 2.94 (1H, dd,
J¼18.0, 7.9 Hz), 2.96e3.05 (2H, m), 3.72e3.77 (1H, m), 4.32 (1H,
dt, J¼11.0, 4.3 Hz), 4.39 (1H, d, J¼2.9 Hz), 4.55 (1H, t, J¼2.9 Hz),
4.65 (1H, dt, J¼10.4, 4.3 Hz), 6.80 (1H, d, J¼7.2 Hz), 6.84 (1H, d,
of HBTU (0.295 g, 0.778 mmol) and Et3N (180 mL, 1.29 mmol) in
CH2Cl2/DMF (3.5:1, 10.3 mL) at 0 ꢀC. The mixture was gradually
warmed to room temperature and stirred for 12 h. The mixture
was diluted with water and extracted with CH2Cl2. The extract
was successively washed with water and brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by SiO2
J¼8.6 Hz), 7.46 (1H, dd, J¼8.6, 7.2 Hz); 13C NMR (CD3OD):
d 21.8,
23.8, 26.0, 30.9, 38.8, 40.5, 40.9, 50.5, 73.1, 82.7, 90.0, 109.4, 116.8,
119.6, 137.6, 141.3, 163.2, 171.0, 173.2, 178.5; HRMS (FAB, negative
ion mode): m/z calcd for C20H25N2O7 ([MꢁH]e) 405.1662, found
405.1663.
column chromatography (CHCl3/MeOH¼1:0e250:1) to give 23
25
(0.383 g, 85% from 22) as a colorless oil. [
a
]
ꢁ80.0 (c 1.26,
Acknowledgements
D
CHCl3); IR: nmax 3413 (w), 1724 (s), 1673 (m), 1634 (m), 1599 (m),
1477 (s), 1239 (s); 1H NMR:
d
0.96 (6H, br t, J¼6.9 Hz), 1.10 (3H, t,
We appreciate the help received from Ms. Teiko Yamada
(Tohoku University) with NMR and MS measurements.
J¼7.1 Hz), 1.18 (3H, t, J¼7.1 Hz), 1.36 (3H, s), 1.41 (9H, s), 1.54 (3H,
s), 1.58e1.76 (2H, m), 1.90e1.96 (1H, m), 2.62 (1H, dd, J¼15.5,
4.9 Hz), 2.77 (1H, dd, J¼16.3, 2.1 Hz), 3.03e3.12 (1H, m),
3.25e3.45 (4H, m), 3.95 (3H, s), 4.05e4.15 (1H, m), 4.29e4.37
(1H, m), 4.46 (1H, br d, J¼12.4 Hz), 4.57 (1H, d, J¼7.0 Hz), 4.78
(1H, br t, J¼7.3 Hz), 5.64 (1H, br d, J¼7.5 Hz, NH), 6.81 (1H, d,
J¼7.4 Hz), 6.91 (2H, br d, J¼8.4 Hz, AreH and NH), 7.45 (1H, dd,
Supplementary data
Supplementary data (1H and 13C NMR spectra for new com-
pounds) related to this article can be found at http://dx.doi.org/
10.1016/j.tet.2015.02.014. These data include MOL file and
InChiKey of the most important compounds described in this
article.
J¼8.4, 7.4 Hz); 13C NMR:
d 13.0, 14.3, 22.5, 24.66, 24.74, 27.1, 28.3
(3C), 31.5, 31.8, 33.2, 40.1, 40.8, 42.0, 48.4, 48.6, 56.1, 76.6, 77.7,
Please cite this article in press as: Suzuki, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.014

6
T. Suzuki et al. / Tetrahedron xxx (2015) 1e6
10. (a) Ward, R. A.; Procter, G. Tetrahedron Lett. 1992, 33, 3359e3362; (b) Ward, R.
References and notes
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3. For amicoumacin-type natural products incorporating carboxylic acid units
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rotation about the AreCO single bond (see Experimental section and Supple-
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21. The transformation of amide l0 into lactone 17 (Scheme 3) proceeded in 64%
overall yield without any need for separation of diastereomers, although it
required 3 steps. On the other hand, esters A gave lactones C in a single op-
eration (Scheme 1), but the conversions necessitated bothersome chromato-
graphic separation of diastereomers and resulted in low isolated yields of 26%
(R1¼MOM, R2¼Me),8 23% (R1¼Me, R2¼Et),10 and 45% (R1, R2¼acetonide).14
Moreover, as mentioned in Refs. 9 and 10, the direct conversion of A into C
seems to have a problem in reproducibility, while our three-step conversion of
10 into 17 is highly reproducible and considered to be more amenable to scale-
up. From these viewpoints, we think our three-step protocol via ketone in-
termediate 9 is more efficient and practical than the single-step conversion
depicted in Scheme 1.
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Please cite this article in press as: Suzuki, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.014