Unified Total Synthesis of Hetiamacins A–D

Article abstract of DOI:10.1002/ejoc.201901114

A concise enantioselective total synthesis of hetiamacin A has been accomplished from a known l-aspartic acid derivative by an eight-step sequence that features ammonolytic opening of the γ-lactone moiety of amicoumacin C followed by 1,3-oxazinane ring formation in one pot. Hetiamacins B–D with putatively assigned stereochemistries have also been synthesized from amicoumacin C, each in three steps involving tetrahydro-4(1H)-pyrimidinone ring formation. The excellent NMR spectroscopic agreement of the synthetic materials with the corresponding natural products, coupled with biosynthetic considerations, has enabled the full stereochemical assignments of hetiamacins B–D.

Full text of DOI:10.1002/ejoc.201901114

A Journal of
Accepted Article
Title: Unified Total Synthesis of Hetiamacins A–D
Authors: Shogo Tsukaguchi, Masaru Enomoto, Ryo Towada, Yusuke
Ogura, and Shigefumi Kuwahara
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901114
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901114
Supported by

10.1002/ejoc.201901114
European Journal of Organic Chemistry
FULL PAPER
＿Unified Total Synthesis of Hetiamacins A–D
Shogo Tsukaguchi,[a] Masaru Enomoto,*[a] Ryo Towada,[a] Yusuke Ogura,[a] and Shigefumi
Kuwahara*[a]
Abstract: A concise enantioselective total synthesis of hetiamacin A
has been accomplished from a known L-aspartic acid derivative by
an eight-step sequence that features ammonolytic opening of the γ-
O
OH
lactone moiety of amicoumacin C followed by 1,3-oxazinane ring
formation in one pot. Hetiamacins B–D with putatively assigned
stereochemistries have also been synthesized from amicoumacin C,
each in three steps involving tetrahydro-4(1H)-pyrimidinone ring
formation. The excellent NMR spectroscopic agreement of the
synthetic materials with the corresponding natural products, coupled
with biosynthetic considerations, has enabled the full stereochemical
assignments of hetiamacins B–D.
8’
10’
N
CONH2
H
O
O
NH
OH
O
hetiamacin A (1)
O
OH
3
10’
O
N
H
O
OH HN 14’ NH
R1 R2
OH
O
hetiamacin B: R1 = R2 = Me
hetiamacin C: R1 = H, R2 = Me
hetiamacin D: R1 = H, R2 = Et
Introduction
Hetiamacins A (also called PJS) (1), an antibacterial and
cytotoxic substance isolated by Sun and co-workers from the
endophytic bacterium Bacillus subtilis subsp. inaquosorum,[1]
belongs to the amicoumacin family of natural products (Figure 1).
Many members of this family are known to exhibit various
biological properties such as antiulcer, antimicrobial, anticancer,
and herbicidal activities.[2] This class of secondary metabolites
produced mainly by bacteria of the genus Bacillus structurally
features a dihydroisocoumarin unit composed of an aromatic
tetraketide and a leucin molecule (left-hand amine segment)
linked through an amide bond to an unusual amino acid of
considerable structural diversity (right-hand acid segment), as
exemplified by amicoumacins A–C,[2a,3] xenocoumacins 1 and
2,[4] and bacilosarcins A–C.[2b,5] In their first report on the
structure of hetiamacin A, Sun et al. proposed another structure
for hetiamacin A on the basis of spectroscopic analysis,[1] but
later they revised the structure to 1 through total synthesis of the
initially proposed structure as well as the newly assigned one
1.[6] They also isolated three additional amicoumacin-type
natural products from the same species of bacterium and named
them hetiamacins B, C, and D, among which hetiamacin B was
found to exhibit significant antibacterial activity against Gram-
positive bacteria.[7,8] Extensive spectroscopic analysis including
HMBC experiments enabled them to propose the planar
structures of the three hetiamacins as depicted in Figure 1.
Additionally, analysis of their coupling constants and ROESY
experiments indicated that the 3-H and 10’-H of hetiamacin B
and the 3-H, 10’-H, and 14’-H of hetiamacins C and D should all
be axially oriented.[9]
Figure 1. Hetiamacin A (1) and structures of hetiamacins B–D proposed by
Sun et al.
Although full stereochemical assignments for hetiamacins B,
C, and D were not shown in the paper by Sun et al.,[7] we
presumed that their absolute stereostructures would most likely
be represented by structures 2, 3, and 4, respectively (Figure 2).
This presumption is based on the following considerations: (1)
the absolute configurations of all amicoumacins reported so far
are, without exception, 3S, 5’S, 8’S, 9’S, and 10’S as shown in
2–4; and (2) the putatively assigned stereochemistries of 3 and
4 are consistent with the assignments by Sun et al. that the
protons at the C10’ and C14’ positions are both axially oriented.
As part of our ongoing efforts toward the total synthesis of
amicoumacin-type natural products,[10] we describe herein a
unified total synthesis of hetiamacins A (1) and the candidate
structures for hetiamacins B–D (2–4), which led to the complete
stereochemical assignments of hetiamacins B–D.
O
OH
5’
3
8’
10’
O
N
H
O
OH HN 14’ NH
R1 R2
OH
O
hetiamacin B (2): R1 = R2 = Me
hetiamacin C (3): R1 = H, R2 = Me
hetiamacin D (4): R1 = H, R2 = Et
Figure 2. Putative stereochemistries (2–4) assigned to hetiamacins B–D.
[a]
S. Tsukaguchi, Assoc. Prof. Dr. M. Enomoto, Dr. R. Towada, Dr. Y.
Ogura, Prof. Dr. S. Kuwahara
Graduate School of Agricultural Science, Tohoku University
468-1 Aramaki-Aza-Aoba, Aoba-ku, Sendai 980-0845, Japan
E-mail: shigefumi.kuwahara.e1@tohoku.ac.jp;
Results and Discussion
masaru.enomoto.a2@tohoku.ac.jp
http://www.agri.tohoku.ac.jp/yuuki/seibutsuyuki/index.html
Scheme 1 outlines our retrosynthetic analysis of 1–4 via
amicoumacin
C (6) as a common synthetic intermediate.
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under https://doi.org/10.1002/ejoc.
Hetiamacin A (1) which features a 1,3-oxazinane structural unit
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10.1002/ejoc.201901114
European Journal of Organic Chemistry
FULL PAPER
would be obtained from amicoumacin A (5a) by cyclic N,O-
acetalization with formaldehyde at the 1,3-amino alcohol moiety.
The amide 5a is known to be preparable by selective
diastereomeric mixture. We, therefore, sought a more efficient
approach to the acid segment 8, which commenced with a two-
step conversion of the protected L-aspartic acid 10 into the
corresponding aldehyde 12 in 71% yield via thioester 11
(Scheme 2).[12,13] The Horner–Wadsworth–Emmons olefination
of 12 with phosphonate 13 under Ando’s conditions gave Z-
olefin 9 in 90% isolated yield along with its E-isomer (9%),[14] the
former of which was then subjected to the Sharpless asymmetric
dihydroxylation using (DHQD)2PHAL as a chiral ligand.[15] This
dihydroxylation reaction was accompanied by concomitant
lactonization to directly afford a ca. 2:1 mixture of 14 [(8’S,9’S)-
isomer] and its diastereomer [(8’R,9’R)-isomer], from which the
desired product 14 was readily isolated in an acceptable yield of
59% by SiO2 column chromatography. It is worth mentioning that
the dihydroxylation of 9, when conducted in the absence of the
chiral ligand or in the presence of (DHQ)2PHAL [instead of
(DHQD)2PHAL], gave 14 and the (8’R,9’R)-isomer in a ratio of
1:1.2 or 1:4.6, respectively, favoring the undesired isomer.[16]
Removal of the t-butyl protecting group of 14 with TFA in CH2Cl2
completed the preparation of the lactonic acid 8. This new
approach to 8, which was realized in nearly 38% overall yield
from the commercially available aspartic acid derivative 10
through 5 steps, is considered to be superior to our above-
mentioned approach to the N-Boc version of 8 in overall yield as
well as in conciseness, although the diastereoselectivity of the
dihydroxylation step (9 → 14) was modest (ca. 2:1).[17] The acid
segment 8 thus obtained was condensed with the amine
segment 7 which was prepared according to our previously
reported protocol,[10j] giving rise to amide 15. Finally, the
protected phenol and amine moieties were unmasked by
treating with BBr3 in CH2Cl2 in the presence of anisole to furnish
ammonolysis of the γ-lactone of amicoumacin
C (6), as
described in our previous study.[10g] Synthesis of 2–4, on the
other hand, would be possible by the following sequence of
reactions: (1) prior TBS-protection of the two hydroxy groups of
6 to prevent the formation of the 1,3-oxazinane ring as found in
1; (2) ammonolytic opening of the γ-lactone ring to afford 5b; (3)
N,N-acetal ring formation between the β-amino amide moiety of
5b and acetone, acetaldehyde, or propanal; and (4) removal of
the protecting groups of the resulting N,N-acetalization products
to furnish 2, 3, and 4, respectively. The amide 6 was then
dissected into amine segment 7 and acid segment 8. The
enantioselective preparation of 7 from methyl N,N-dibenzyl-L-
leucinate in 43% overall yield through 5 steps had already been
established in our total synthesis of amicoumacin C (6).[10j] To
obtain the lactonic intermediate 8, we planned to utilize the
Sharpless asymmetric dihydroxylation on (Z)-α,β-unsaturated
ester 9, which in turn would be easily prepared from known
aspartic acid derivative 10.[11]
O
OH
O
N
MeO2C
NBn2
1–4
H
O
OR NH2 NH2
ref. 10j
OR
O
5a (amicoumacin A): R = H
5b: R = TBS
NH2
20
amicoumacin C (6) ([α]D = –120 (c = 0.070, MeOH); lit.[10g]
O
O
22
25
[α]D = –123 (c = 0.045, MeOH), lit. [10j] [α]D = –120 (c = 0.070,
MeO
O
O
O
MeOH)) in 23% overall yield from 10 through 7 steps.[10g,18]
7
+
N
O
H
O
OH NH2
O
ClCO2iBu
Et3N, EtSH
10% Pd/C
Et3SiH
OH
O
HO2C
CO2Me
O
CO2Me
6 (amicoumacin C)
HO2C
OH NHZ
EtS
CH2Cl2, 0 °C
76%
acetone, rt
93%
8
NHZ
NHZ
11
CO2Me
MeO2C
10
HO2C
O
P(OPh)2
NHZ
10
t-BuO2C
NHZ
OsO4, NMO
(DHQD)2PHAL
13
CO2Me
CO2Me
CO2tBu
9
OHC
THF/acetone/H2O
0 °C to rt
NaI, DBU, THF
–78 to –20 °C
90%
NHZ
tBuO2C
NHZ
Scheme 1. Retrosynthetic analysis of 1–4.
59%
12
9
O
7, EDC·HCl
HOBt, DMAP
CH2Cl2/DMF
O
O
Our synthesis of the key intermediate 6 via the condensation
of the amine segment 7 with the lactonic acid segment 8 is
shown in Scheme 2. We previously reported the preparation of
the N-Boc version of 8 from benzyl 4-oxo-2-butenoate by a six-
step sequence beginning with the Córdova asymmetric
epoxidation of the α,β-unsaturated aldehyde.[10g] The synthetic
route, however, required careful ozonolytic cleavage of a diene
ester (benzyl sorbate) to obtain the starting unsaturated
aldehyde, and, unfortunately, gave the N-Boc protected lactonic
acid in a modest overall yield of 20% as an inseparable 5:1
O
O
9’
N
H
RO2C 8’
–10 °C
71% from 14
O
OH NHZ
OH NHZ
OMe O
BBr3, anisole
CH2Cl2, –78 °C to rt
88%
14: R = tBu
8: R = H
15
TFA, CH2Cl2
0 °C to rt
6
(amicoumacin C)
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10.1002/ejoc.201901114
European Journal of Organic Chemistry
FULL PAPER
Scheme 2. Synthesis of amicoumacin C (6).
14’-epi-3, 4, and 14’-epi-4 were corroborated by some diagnostic
NOE correlations and coupling constants shown in Figure 3.
Based on the excellent agreement of the 1H and 13C NMR
spectra of 2–4 with those of hetiamacins B–D of microbial origin,
respectively, we concluded that the relative stereostructures of
hetiamacins B, C, and D should be represented by 2, 3, and 4,
respectively (see Supporting Information for comparison of their
13C NMR data with authentic data). At present, non-availability of
chiroptical information on natural hetiamacins B–D precludes
decisive determination of their absolute configuration. However,
considering the stereochemical commonality of amicoumacin-
type natural products produced by bacteria of the genus Bacillus,
the absolute configurations of hetiamacins B, C, and D would
also surely be shown by 2, 3, and 4, respectively.
With the pivotal intermediate 6 in hand, we first undertook its
conversion into hetiamacin A (1) (Scheme 3). Ammonolysis of 6
in methanol gave amicoumacin
A
(5a) as
a
labile
intermediate,[10g] which was, without isolation, allowed to react
with paraformaldehyde to form the N,O-acetal ring, providing
20
22
hetiamacin A (1) ([α]D = –106 (c = 0.260, MeOH); lit.[6] [α]D
=
–140.0 (c = 0.01, MeOH)) in 44% yield. The H and 13C NMR
spectra of 1 were identical with those of natural and synthetic
hetiamicin A.[1,6] Formation of the 1,3-oxazinane ring was
ensured by HMBC correlations from the 14’-H2 to 8’-C.
1
O
O
O
O
NH3/MeOH
–5 °C
O
O
N
H
TBSOTf
2,6-lutidine
O
OH NH2
N
H
6
CH2Cl2, 0 °C
94%
O
NH2
OTBS
OH
O
6
NH3/MeOH
–5 °C
TBSO
O
16
O
OH
N
CONH2
H
O
OH
O
OH NH2
N
CONH2
OH
O
5a
H
R2O
O
NH2
(amicoumacin A)
acetone, rt
OR1
O
17a: R1 = R2 = TBS
(CH2O)n, rt
44%
O
OH
8’
17b: R1 = H, R2 = TBS
N
H
CONH2
O
OH
O
O
NH
O
1) (a) MeCHO for 3, rt
14’
N
(b) EtCHO for 4, rt
2) TBAF, THF
0 °C to rt
OH
O
1
H
R2O
O
HN
NH
OR1
O
Scheme 3. Conversion of amicoumacin C (6) into hetiamacin A (1).
21% for 3
48% for 4
18a: R1 = R2 = TBS
18b: R1 = H, R2 = TBS
2: R1 = R2 = H
TBAF, THF
0 °C to rt
73% from 16
The synthesis of 2–4, in which the cyclic N,N-acetal unit is
embedded instead of the N,O-acetal ring in hetiamacin A (1),
was performed as shown in Scheme 4. Exposure of
amicoumacin C (6) to TBSOTf (3 equiv) and 2,6-lutidine (6
equiv) in CH2Cl2 gave bis-TBS ether 16. Ammonolytic opening of
the γ-lactone moiety of 16 afforded a mixture of amide 17a and
its partially deprotected derivative 17b,[19] the in-situ treatment of
which with acetone then provided a mixture of N,N-acetals 18a
and 18b. Finally, removal of their TBS protecting groups with
O
OH
9’
C9’
O
O
N
10’
H
HN
NH
14’
O
OH HN
NH
14’
R
OH
O
R
3: R = Me
4: R = Et
14’-epi-3: R = Me (20%)
14’-epi-4: R = Et (22%)
Scheme 4. Conversion of amicoumacin C (6) into 2–4.
1
TBAF furnished hetiamacin B (2) in 73% yield from 16. The H
and 13C NMR spectra of 2 were identical with those of natural
hetiamacin B.[6] On the other hand, treatment of a mixture of 17a
and 17b with acetaldehyde and subsequent TBS-deprotection
delivered a mixture of 3 and its epimer (14’-epi-3), from which
the former was isolated in 21% yield and the latter in 20% yield
by repeated silica gel column chromatography. Application of the
same two-step sequence (N,N-acetal ring formation and TBS-
deprotection) to 17a/17b using propanal instead of acetaldehyde
afforded 4 and its epimer (14’-epi-4) in isolated yields of 48%
4.2 Hz
6.0 Hz
4.2 Hz
5.4 Hz
H
H
H
H
H
H
H
N
H
N
H
N
H
N
H
H
O
O
O
O
C9’
HN
C9’
HN
C9’
HN
C9’
HN
H
H
H
H
H
H
H
H
11.4 Hz
8.3 Hz
14’-epi-3
coupling constant
11.7 Hz
8.7 Hz
14’-epi-4
3
4
NOE
1
and 22%, respectively. The H and 13C NMR spectra of 3 and 4
Figure 3. Diagnostic NOE correlations and coupling constants for 3, 14’-epi-3,
4, and 14’-epi-4.
were also in good agreement with those of natural hetiamacins
C and D, respectively.[6] The stereochemical assignments for 3,
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10.1002/ejoc.201901114
European Journal of Organic Chemistry
FULL PAPER
concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane/EtOAc = 3:1–1:1) to give 12 (0.758 g, 93%) as
a white solid. M.p. 68–70 °C; [α]D24 = −10 (c = 0.15, CHCl3); IR (ATR): ν =
3353 (s), 3034 (w), 2954 (w), 1732 (s), 1523 (s), 1455 (w), 1438 (w),
1365 (w), 1261 (s), 1058 (w); 1H NMR (400 MHz, CDCl3): δ = 2.86 (dd, J
= 4.6, 17.4 Hz, 1H), 3.04 (dd, J = 4.6, 17.4 Hz, 1H), 3.69 (s, 3H), 4.44
(ddd, J = 4.6, 4.6, 9.2 Hz, 1H), 5.14 (s, 2H), 5.90 (br d, J = 9.2 Hz, 1H),
7.32–7.38 (m, 5H), 9.66 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 34.2,
52.2, 56.3, 67.4, 128.2, 128.4, 128.6, 135.8, 156.1, 171.4, 198.6; HRMS
(FAB): m/z calcd. for C13H16O5N ([M+H]+) 266.1023, found 266.1025.
Conclusions
In conclusion, an eight-step enantioselective total synthesis of
hetiamacin A (1) was accomplished in 12% overall yield from the
protected aspartic acid 10 via ammonolytic opening of the γ-
lactone moiety of amicoumacin C (6) followed by in-situ 1,3-
oxazinane ring formation. Transformation of 6 to the putative
structures (2–4) of hetiamacins B–D was also performed each in
3 steps consisting of protection, N,N-acetal ring formation, and
deprotection. Base on the excellent agreement of the NMR
spectra of the synthetic materials with those of respective
authentic samples as well as biosynthetic considerations of the
hetiamacins, the absolute configurations of hetiamacins B–D
were concluded to be represented by structures 2, 3, and 4,
respectively.
1-(tert-Butyl) 6-Methyl (S,Z)-4-{[(benzyloxy)carbonyl]amino}hex-2-
enedioate (9). To a stirred solution of 13 (0.946 g, 2.72 mmol) in THF
(27 mL) were successively added NaI (0.487 g, 3.25 mmol) and DBU
(0.445 mL, 2.98 mmol) at 0 °C. The mixture was stirred at the same
temperature for 15 min and then cooled to –78 °C. To the mixture was
added a solution of 12 (0.720 g, 2.71 mmol) in THF (6.8 mL) and the
stirring was continued for 1.5 h. The mixture was warmed to –20 °C,
quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The
extract was successively washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by silica gel column chromatography (toluene/EtOAc = 10:1) to
Experimental Section
General Information. IR spectra were recorded by a Jasco FT/IR-4100
spectrometer using an ATR (ZnSe) attachment. 1H NMR spectra were
recorded with TMS as an internal standard in CDCl3, while 13C NMR
were obtained using residual solvent peaks as internal standards (CHCl3,
δ 77.0; CHD2OD, δ 49.0) by a Varian 400-MRTT spectrometer (400 MHz
for 1H and 100 MHz for 13C) or a Varian 600TT spectrometer (600 MHz
for 1H and 150 MHz for 13C). Optical rotation values were measured with
a Jasco P-2200 polarimeter. 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 uncorrected. Kanto
Chemical silica gel 60N (spherical neutral, 40–50 µm or 63–210 µm) was
used for column chromatography. Analytical thin-layer chromatography
was performed using Merck silica gel 60 F254 plates (0.25 mm thick).
Solvents for reactions were distilled prior to use: THF from Na and
benzophenone; CH2Cl2 and DMF from CaH2; acetone from CaCl2. All air-
or moisture-sensitive reactions were conducted under an argon
atmosphere.
24
give 9 (0.891 g, 90%) as a white solid. M.p. 43–46 °C; [α]D = +37 (c =
0.45, CHCl3); IR (ATR): ν = 3350 (s), 2979 (m), 1714 (s), 1527 (m), 1411
(w), 1369 (w), 1244 (m), 1159 (m), 1048 (m), 827 (w), 749 (w); 1H NMR
(400 MHz, CDCl3): δ = 1.49 (9H, s), 2.79 (dd, J = 4.8, 16.6 Hz, 1H), 2.91
(dd, J = 4.4, 16.6 Hz, 1H), 3.68 (s, 3H), 5.09 (s, 2H), 5.40-5.51 (m, 1H),
5.73 (d, J = 11.6 Hz, 1H), 5.82 (br d, J = 7.6 Hz, 1H), 6.24 (dd, J = 8.2,
11.6 Hz, 1H), 7.29−7.36 (m, 5H); 13C NMR (100 MHz, CDCl3): δ = 28.1,
38.8, 46.2, 51.8, 66.7, 81.1, 122.5, 128.1, 128.5 (2C), 136.4, 146.5,
155.6, 164.9, 172.0; HRMS (FAB): m/z calcd. for C19H26O6N ([M+H]+)
364.1755, found 364.1758.
tert-Butyl
(S)-2-((2S,3S)-3-{[(Benzyloxy)carbonyl]amino}-5-
(14). To stirred
oxotetrahydrofuran-2-yl)-2-hydroxyacetate
a
suspension of (DHQD)2PHAL (45.0 mg, 0.0578 mmol) and OsO4 (2.2 mg,
0.0087 mmol) in acetone/H2O (1:1, 4.4 mL) was added a solution of 9
(0.199 g, 0.548 mmol) in THF (2.2 mL) at 0 °C. After 25 min, NMO (0.129
g, 1.10 mmol) was added, and the resulting mixture was stirred at 0 °C
for 24 h. The mixture was warmed to room temperature and the stirring
was continued for another 15 h. Na2SO3 (0.139 g, 1.10 mmol) was then
added, and the resulting mixture was stirred for 24 h. The mixture was
diluted with brine and extracted with EtOAc. The extract was
successively washed with saturated aqueous NH4Cl, saturated aqueous
NaHCO3, and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was passed through a short pad of silica gel (hexane/EtOAc =
2:1), and the eluate was concentrated in vacuo. The residue was purified
by repeated silica gel column chromatography (hexane/Et2O = 1:1) to
give 14 (0.119 g, 59%) as a white solid. M.p. 136–138 °C; [α]D25 = –12 (c
= 0.45, CHCl3); IR (ATR): ν = 3345 (s), 2980 (m), 1786 (s), 1728 (s),
1536 (s), 1456 (w), 1396 (w), 1371 (w), 1259 (s), 1157 (s), 1048 (w); 1H
NMR (400 MHz, CDCl3): δ = 1.48 (s, 9H), 2.49 (dd, J = 4.6, 18.2 Hz, 1H),
3.05 (dd, J = 9.0, 18.2 Hz, 1H), 3.18 (d, J = 3.6 Hz, 1H), 4.35–4.43 (m,
Methyl
(S)-3-{[(Benzyloxy)carbonyl]amino}-4-(ethylthio)-4-
oxobutanoate (11). To a stirred solution of 10 (2.00 g, 7.11 mmol) in
CH2Cl2 (24 mL) were successively added ClCO2iBu (1.03 mL, 7.94
mmol) and Et3N (1.09 mL, 7.82 mmol) at 0 °C. After 15 min of stirring,
EtSH (0.682 mL, 9.21 mmol) and Et3N (0.995 mL, 7.14 mmol) were
successively added at 0 °C and the resulting mixture was stirred for 15
min at the same temperature. The reaction mixture was quenched with
H2O and extracted with CH2Cl2. The extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by silica
gel column chromatography (hexane/EtOAc = 7:1–4:1) to give 11 (1.76 g,
20
76%) as a white solid. M.p. 81–82 °C; [α]D = +2.7 (c = 0.74, CHCl3); IR
(ATR): ν = 3341 (m), 2954 (m), 1729 (s), 1683 (m), 1506 (m), 1225 (m),
1052 (w); 1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.6 Hz, 3H), 2.75
(dd, J = 4.5, 17.4 Hz, 1H), 2.89 (dq, J = 1.1, 7.6 Hz, 2H), 3.15 (dd, J = 4.5,
17.4 Hz, 1H), 3.68 (s, 3H), 4.70 (ddd, J = 4.5, 4.5, 9.8 Hz, 1H), 5.18 (s,
2H), 5.94 (br d, J = 9.8 Hz, 1H), 7.30–7.41 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ = 14.3, 23.6, 36.1, 52.1, 57.0, 67.4, 128.1, 128.3, 128.6, 136.0,
155.9, 171.4, 200.2; HRMS (FAB): m/z calcd. for C15H20O5NS ([M+H]+)
326.1057, found 326.1065.
2H), 4.71 (br s, 1H), 5.01 (br s, 1H), 5.10 (s, 2H), 7.26–7.40 (m, 5H); 13
C
NMR (100 MHz, CDCl3): δ = 27.9, 35.6, 48.1, 67.2, 71.1, 84.8, 85.6,
128.3, 128.4, 128.6, 135.8, 155.1, 169.7, 174.2; HRMS (FAB): m/z calcd.
for C18H23O7NNa ([M+Na]+) 388.1367, found 388.1368.
Benzyl
{(2S,3S)-2-[(S)-1-Hydroxy-2-({(S)-1-[(S)-8-methoxy-1-
oxoisochroman-3-yl]-3-methylbutyl}amino)-2-oxoethyl]-5-
Methyl (S)-3-{[(Benzyloxy)carbonyl]amino}-4-oxobutanoate (12). To
a stirred mixture of 11 (1.00 g, 3.07 mmol) and 10% Pd/C (0.171g) in
acetone (3.1 mL) was added dropwise Et3SiH (0.734 mL, 4.61 mmol) at
room temperature. After 20 min, the mixture was diluted with CH2Cl2. The
resulting mixture was filtered through a pad of Celite, and the filtrate was
oxotetrahydrofuran-3-yl}carbamate (15). To a stirred suspension of 14
(0.119 g, 0.326 mmol) in CH2Cl2 (3.4 mL) was added dropwise CF3CO2H
(1.0 mL) at 0 °C. After 15 h of stirring at room temperature, the resulting
solution was concentrated in vacuo and the residue (8) (0.101 g) was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901114
European Journal of Organic Chemistry
FULL PAPER
taken up in a mixture of CH2Cl2 (3.8 mL) and DMF (2.0 mL). To the
solution were successively added EDC·HCl (75.0 mg, 0.391 mmol),
HOBt (59.6 mg, 0.389 mmol), DMAP (7.8 mg, 0.064 mmol) and a
solution of 7 (97.4 mg, 0.370 mmol) in CH2Cl2 (4.0 mL) at –10 °C. The
resulting mixture was stirred at the same temperature for 20 h, quenched
with saturated aqueous NH4Cl, and then extracted with Et2O. The extract
was washed with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by silica gel column chromatography (CHCl3/MeOH
= 40:1) to give 15 (0.128 g, 71% from 14) as a white solid. M.p. 125–
chromatography (CHCl3/MeOH = 40:1) to give 1 (9.4 mg, 44%) as a
white solid. M.p. 100–102 °C; [α]D28 –106 (c = 0.260, MeOH); IR (ATR): ν
= 3341 (s), 2957 (m), 1674 (s), 1533 (m), 1464 (w), 1408 (w), 1232 (m),
1
1112 (w), 756 (w); H NMR (600 MHz, CD3OD): δ = 0.94 (d, J = 6.6 Hz,
3H), 0.98 (d, J = 6.6 Hz, 3H), 1.44 (ddd, J = 4.2, 9.6, 13.8 Hz, 1H), 1.65–
1.72 (m, 1H), 1.83 (ddd, J = 4.5, 11.1, 13.8 Hz, 1H), 2.28 (dd, J = 9.0,
15.0 Hz, 1H), 2.68 (dd, J = 3.0, 15.0 Hz, 1H), 2.89 (dd, J = 2.4, 16.4 Hz,
1H), 2.96 (ddd, J = 3.0, 9.0, 9.0 Hz, 1H), 3.08 (dd, J = 12.9, 16.4 Hz, 1H),
3.29 (dd, J = 9.0, 9.0 Hz, 1H), 3.82 (d, J = 9.0 Hz, 1H), 4.21 (d, J = 10.2
Hz, 1H), 4.34–4.37 (m, 1H), 4.56 (d, J = 10.2 Hz, 1H), 4.65 (d, J = 12.0
Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 7.44 (dd, J =
7.8, 7.8 Hz, 1H); 13C NMR (150 MHz, CD3OD): δ = 22.0, 23.8, 25.9, 30.9,
38.2, 40.7, 50.2, 58.8, 70.4, 79.4, 81.4, 82.8, 109.4, 116.7, 119.5, 137.5,
141.7, 163.2, 171.1, 173.0, 176.8; HRMS (FAB): m/z calcd. for
C21H30O7N3 ([M+H]+) 436.2078, found 436.2081.
28
130 °C (dec.); [α]D = –100 (c = 1.78, CHCl3); IR (ATR): ν = 3394 (s),
3329 (s), 2957 (m), 1784 (s), 1720 (s), 1666 (s), 1600 (w), 1585 (w),
1531 (s), 1477 (m), 1247 (s), 1173 (w), 1073 (w), 913 (w), 733 (m), 698
(w); 1H NMR (600 MHz, CDCl3): δ = 0.85 (d, J = 4.4 Hz, 3H), 0.91 (d, J =
4.0 Hz, 3H), 1.32–1.37 (m, 1H), 1.55–1.65 (m, 1H), 1.77–1.84 (m, 1H),
2.50 (d, J = 18.4 Hz, 1H), 2.68 (d, J = 15.9 Hz, 1H), 2.95 (dd, J = 12.6,
15.9 Hz, 1H), 3.04 (dd, J = 8.7, 18.4 Hz, 1H), 3.86 (s, 3H), 4.21–4.26 (m,
1H), 4.27 (d, J = 12.6 Hz, 1H), 4.31–4.36 (m, 1H), 4.61 (dd, J = 2.4, 5.4
Hz, 1H), 4.88–4.99 (m, 3H), 5.06 (d, J = 12.0 Hz, 1H), 5.89 (br s, 1H),
6.72 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.24–7.34 (m, 5H), 7.36
(d, J = 9.6 Hz, 1H), 7.39 (dd, J = 7.8, 8.4 Hz, 1H); 13C NMR (150 MHz,
CDCl3): δ = 21.6, 23.0, 24.7, 31.5, 36.7, 40.0, 48.0, 49.1, 56.1, 67.0, 71.7,
79.3, 85.4, 110.7, 112.8, 119.4, 128.2 (2C), 128.5, 134.9, 135.9, 141.9,
155.7, 160.9, 162.9, 170.0, 176.0; HRMS (FAB): m/z calcd. for
C29H35O9N2 ([M+H]+) 555.2337, found 555.2339.
(S)-2-[(2S,3S)-3-Amino-5-oxotetrahydrofuran-2-yl]-2-[(tert-
butyldimethylsilyl)oxy]-N-((S)-1-{(S)-8-[(tert-butyldimethylsilyl)oxy]-
1-oxoisochroman-3-yl}-3-methylbutyl)acetamide (16). To
a stirred
solution of (41.9 mg, 0.103 mmol) in CH2Cl2 (2.0 mL) were
6
successively added 2,6-lutidine (72 µL, 0.62 mmol) and TBSOTf (71 µL,
0.31 mmol) at 0 °C and the mixture was stirred at 0 °C for 25 min. The
reaction mixture was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2. The extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by silica
gel column chromatography (CHCl3/MeOH = 1:0–100:1) to give 16 (61.5
(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) (6). To a stirred solution of 15 (0.109 g, 0.197 mmol)
and anisole (85 µL, 0.78 mmol) in CH2Cl2 (11 mL) was added dropwise
BBr3 (1.0 M in CH2Cl2, 0.79 mL, 0.79 mmol) at –78 °C. The mixture was
gradually warmed to 0 °C over a period of 3 h and stirred at 0 °C for 18 h
and then at room temperature for another 20 min. The reaction mixture
was quenched by successive addition of solid NaHCO3 (1.1 g) and
saturated aqueous NaHCO3 (0.79 mL) at 0 °C, stirred for 15 min,
warmed to room temperature, and then mixed with anhydrous Na2SO4.
After 30 min of stirring, the mixture was filtered and the filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (CHCl3/MeOH = 1:0–20:1) to give 6 (70.4 mg, 88%) as a
26
mg, 94%) as a white amorphous solid. [α]D –88 (c = 0.84, CHCl3); IR
(ATR): ν = 3414 (w), 2956 (s), 2931 (s), 2859 (m), 1785 (s), 1737 (s),
1676 (m), 1519 (w), 1470 (s), 1255 (m), 1228 (m), 1058 (w), 844 (m); 1H
NMR (400 MHz, CDCl3) : δ = 0.06 (s, 3H), 0.13 (s, 3H), 0.23 (s, 3H), 0.25
(s, 3H), 0.92 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H),
1.03 (s, 9H), 1.46–1.54 (m, 1H), 1.54–1.66 (m, 1H), 1.81 (ddd, J = 5.4,
10.0, 13.8 Hz, 1H), 2.28 (dd, J = 4.2, 18.0 Hz, 1H), 2.77 (dd, J = 2.5, 16.0
Hz, 1H), 2.86 (dd, J = 8.1, 18.0 Hz, 1H), 2.93 (dd, J = 12.5, 16.0 Hz, 1H),
3.75 (ddd, J = 3.6, 4.2, 8.1 Hz, 1H), 4.26–4.34 (m, 1H), 4.45 (ddd, J = 2.4,
2.5, 12.5 Hz, 1H), 4.55 (d, J = 2.4 Hz, 1H), 4.66 (dd, J = 2.4, 3.6 Hz, 1H),
6.81 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 9.6 Hz, 1H),
7.36 (dd, J = 8.0, 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = –5.3, –5.0,
–4.4, –4.3, 17.9, 18.5, 21.9, 23.0, 24.9, 25.6, 25.8, 31.9, 38.8, 40.6, 47.7,
49.0, 73.2, 78.6, 88.4, 115.9, 120.1, 120.8, 134.3, 140.9, 157.9, 161.4,
169.7, 175.2; HRMS (FAB): m/z calcd. for C32H55O7N2Si2 ([M+H]+)
635.3542, found 635.3542.
20
white amorphous solid. [α]D = –120 (c = 0.070, MeOH); IR (ATR): ν =
3401 (s), 2957 (m), 1789 (m), 1733 (m), 1670 (s), 1618 (m), 1465 (w),
1232 (w), 1165 (w), 1113 (w), 1046 (w); 1H NMR (400 MHz, CD3OD): δ =
0.93 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 1.43 (ddd, J = 4.0, 10.0,
14.5 Hz, 1H), 1.61–1.74 (m, 1H), 1.82 (ddd, J = 4.0, 11.0, 14.5 Hz, 1H),
2.24 (dd, J = 3.1, 18.0 Hz, 1H), 2.94 (dd, J = 7.9, 18.0 Hz, 1H), 2.96–3.06
(m, 2H), 3.74 (ddd, J = 3.1, 3.1, 7.9 Hz, 1H), 4.32 (ddd, J = 4.0, 8.4, 11.0
Hz, 1H), 4.39 (d, J = 3.1 Hz, 1H), 4.55 (dd, J = 3.1, 3.1 Hz, 1H), 4.65
(ddd, J = 4.4, 4.4, 8.4 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 8.4
Hz, 1H), 7.46 (dd, J = 8.4, 7.4 Hz, 1H); 13C NMR (100 MHz, CD3OD): δ =
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, 119.5, 137.6, 141.3, 163.2, 171.0, 173.2, 178.5; HRMS (FAB): m/z
calcd. for C20H27O7N2 ([M+H]+) 407.1813, found 407.1823.
(2S,3S)-3-[(S)-2,2-Dimethyl-6-oxohexahydropyrimidin-4-yl]-2,3-
dihydroxy-N-{(S)-1-[(S)-8-hydroxy-1-oxoisochroman-3-yl]-3-
methylbutyl}propanamide (hetiamacin B) (2). A solution of 16 (10.2
mg, 16.1 µmol) in 7 M NH3/MeOH (1.1 mL) was stirred at –5 °C for 24 h.
The mixture was warmed to room temperature and acetone (12 µL, 0.16
mmol) was added. The mixture was stirred for 24 h, and then additional
acetone (6 µL, 0.08 mmol) was added. After another 19 h of stirring,
acetone (6 µL, 0.08 mmol) was added again and the mixture was stirred
for 5 h. Additional acetone (6 µL, 0.08 mmol) was added once more, and
the resulting mixture was stirred for 3 h. The reaction mixture was
concentrated in vacuo and the resulting residue (18a/18b) was mixed
with a solution of TBAF (0.1 M in THF, 0.320 mL, 32.0 µmol) at 0 °C and
stirred at room temperature for 5 min. To the mixture were successively
added THF (1.4 mL) and silica gel [Kanto Chemical silica gel 60N (40–50
µm), 0.55 g] at 0 °C, and the resulting slurry was stirred at room
temperature for 1 h. The mixture was filtered and the filtrate was
concentrated in vacuo. The residue was purified by repeated silica gel
column chromatography (CHCl3/MeOH = 20:1) to give 2 (5.4 mg, 73%
(4S,5S,6S)-4-(2-Amino-2-oxoethyl)-5-hydroxy-N-{(S)-1-[(S)-8-
hydroxy-1-oxoisochroman-3-yl]-3-methylbutyl}-1,3-oxazinane-6-
carboxamide (hetiamacin A) (1). Compound 6 (20.0 mg, 49.2 µmol)
was mixed with a solution of NH3 in MeOH (7 M, 1.0 mL) at –5 °C. After
18 h of stirring at –5 °C, an additional 0.20 mL of the ammonia solution
was added and the resulting mixture was stirred for 17 h at –5 °C. The
mixture was warmed to room temperature and paraformaldehyde (15.7
mg, 0.523 mmol) was added. The mixture was stirred for 70 min and then
additional paraformaldehyde (15.3 mg, 0.509 mmol) was added. After 5 h
of stirring, paraformaldehyde (7.8 mg, 0.26 mmol) was added again and
the mixture was stirred for 5 min. The mixture was concentrated in vacuo
and the residue was purified by repeated silica gel column
27
from 16) as a white solid. M.p. 103−105 °C; [α]D = –115 (c = 0.080,
CHCl3); IR: ν = 3288 (s), 2956 (m), 1659 (s), 1528 (w), 1462 (m), 1231
(m), 1111 (m), 754 (w); 1H NMR (600 MHz, CDCl3): δ = 0.95 (d, J = 6.6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901114
European Journal of Organic Chemistry
FULL PAPER
Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.42 (s, 3H), 1.44 (s, 3H), 1.44–1.50 (m,
1H), 1.60−1.68 (m, 1H), 1.87 (ddd, J = 5.1, 10.2, 14.1 Hz, 1H), 2.22 (dd, J
= 11.3, 17.4 Hz, 1H), 2.61 (dd, J = 3.6, 17.4 Hz, 1H), 2.82 (dd, J = 3.0,
16.2 Hz, 1H), 3.07 (dd, J = 12.6, 16.2 Hz, 1H), 3.45 (ddd, J = 3.6, 6.6,
11.3 Hz, 1H), 3.59 (dd, J = 6.6, 9.6 Hz, 1H), 4.02 (d, J = 9.6 Hz, 1H),
4.32–4.38 (m, 1H), 4.62 (ddd, J = 3.0, 3.0, 12.6 Hz, 1H), 4.90 (br s, 1H),
6.25 (s, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 7.28 (d, J
= 12.0 Hz, 1H), 7.42 (dd, J = 7.8, 7.8 Hz, 1H), 10.79 (s, 1H); 13C NMR
(150 MHz, CDCl3): δ = 21.8, 23.1, 24.8, 28.5, 30.3, 31.4, 32.6, 40.5, 48.7,
51.2, 68.1, 72.4, 73.2, 81.1, 108.0, 116.2, 118.3, 136.6, 139.3, 162.1,
169.5, 170.1, 174.6; HRMS (FAB): m/z calcd. for C23H34O7N3 ([M+H]+)
464.2391, found 464.2401.
for 24 h, and then additional propionaldehyde (14 µL, 0.19 mmol) was
added. After another 24 h of stirring, the mixture was concentrated in
vacuo, and the residue was mixed with a solution of TBAF (0.1 M in THF,
0.576 mL, 57.6 µmol) at 0 °C and stirred at room temperature for 25 min.
To the mixture were successively added THF (2.5 mL) and silica gel
[Kanto Chemical silica gel 60N (40–50 µm), 0.98 g] at 0 °C, and the
resulting slurry was stirred at room temperature for 1 h. The mixture was
filtered and the filtrate was concentrated in vacuo. The residue was
purified by repeated silica gel column chromatography (CHCl3/MeOH =
20:1) to give 4 (4.3 mg, 48%) as a white solid and 14’-epi-4 (2.0 mg,
27
22%) as a white solid. 4: M.p. 97–101 °C; [α]D = –97 (c = 0.155,
CHCl3); IR: ν = 3297 (s), 2960 (m), 1665 (s), 1530 (w), 1463 (m), 1232
(m), 1111 (m), 755 (w); 1H NMR (600 MHz, CDCl3): δ = 0.95 (d, J = 6.6
Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.01 (t, J = 7.5 Hz, 3H), 1.45–1.51 (m,
1H), 1.58–1.70 (m, 2H), 1.83–1.89 (m, 1H), 2.27 (dd, J = 11.7, 17.6 Hz,
1H), 2.73 (dd, J = 4.2, 17.6 Hz, 1H), 2.83 (dd, J = 2.7, 16.4 Hz, 1H), 3.07
(dd, J = 13.2, 16.4 Hz, 1H), 3.25 (ddd, J = 4.2, 7.4, 11.7 Hz, 1H), 3.54 (dd,
J = 7.4, 8.7 Hz, 1H), 4.06 (d, J = 8.7 Hz, 1H), 4.27 (t, J = 6.0 Hz, 1H),
4.36 (ddd, J = 3.9, 6.3, 14.1 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H), 4.91 (br s,
1H), 6.33 (br s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H),
7.26 (br d, J = 7.2 Hz, 1H), 7.42 (dd, J = 8.4, 7.8 Hz, 1H), 10.79 (s, 1H);
13C NMR (150 MHz, CDCl3): δ = 8.7, 21.8, 23.1, 24.8, 29.4, 30.3, 34.0,
40.5, 48.7, 56.3, 68.8, 73.0, 73.2, 81.0, 108.0, 116.2, 118.3, 136.6, 139.3,
(2S,3S)-2,3-Dihydroxy-N-{(S)-1-[(S)-8-hydroxy-1-oxoisochroman-3-
yl]-3-methylbutyl}-3-[(2R,4S)-2-methyl-6-oxohexahydropyrimidin-4-
yl]propanamide (hetiamacin C) (3) and 14’-epi-3. A solution of 16
(10.8 mg, 17.0 µmol) in 7 M NH3/MeOH (1.1 mL) was stirred at –5 °C for
24 h. The mixture was warmed to room temperature and acetaldehyde
(19 µL, 0.34 mmol) was added. The mixture was stirred for 24 h, and
then additional acetaldehyde (19 µL, 0.34 mmol) was added. After
another 2 h of stirring, the mixture was concentrated in vacuo, and the
residue was mixed with a solution of TBAF (0.1 M in THF, 0.340 mL, 34.0
µmol) at 0 °C and stirred at room temperature for 1 h. To the mixture
were successively added THF (0.85 mL) and silica gel [Kanto Chemical
silica gel 60N (40–50 µm), 0.54 g] at 0 °C, and the resulting slurry was
stirred at room temperature for 1 h. The mixture was filtered and the
filtrate was concentrated in vacuo. The residue was purified by repeated
silica gel column chromatography (CHCl3/MeOH = 10:1) to give 3 (1.6
mg, 21%) as a white solid and 14’-epi-3 (1.5 mg, 20%) as a white solid.
162.1, 169.5, 170.5, 174.4; HRMS (FAB): m/z calcd. for C23H34O7N3
27
([M+H]+) 464.2391, found 464.2397. 14’-epi-4: M.p. 104–107 °C; [α]D
=
–91 (c = 0.085, CHCl3); IR: ν = 3296 (s), 2959 (m), 1668 (s), 1527 (w),
1463 (m), 1232 (m), 1111 (m), 756 (w); 1H NMR (600 MHz, CDCl3): δ =
0.96 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H),
1.47–1.53 (m, 1H), 1.59–1.72 (m, 2H), 1.83–1.89 (m, 1H), 2.44 (dd, J =
8.7, 17.9 Hz, 1H), 2.71 (dd, J = 5.4, 17.9 Hz, 1H), 2.83 (dd, J = 3.0, 16.4
Hz, 1H), 3.07 (dd, J = 13.2, 16.4 Hz, 1H), 3.41 (ddd, J = 5.4, 8.7, 8.7 Hz,
1H), 3.54 (dd, J = 8.7, 8.7 Hz, 1H), 4.07 (d, J = 8.7 Hz, 1H), 4.25 (t, J =
6.0 Hz, 1H), 4.33–4.39 (m, 1H), 4.63 (ddd, J = 1.8, 3.0, 13.2 Hz, 1H),
5.00 (br s, 1H), 6.37 (br s, 1H), 6.71 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 8.4
Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 7.42 (dd, J = 7.2, 8.4 Hz, 1H), 10.80 (s,
1H); 13C NMR (150 MHz, CDCl3): δ = 9.5, 21.9, 23.0, 24.8, 28.8, 30.3,
33.9, 40.5, 48.7, 52.9, 66.4, 72.1, 73.6, 81.0, 108.0, 116.2, 118.3, 136.6,
139.3, 162.1, 169.5, 170.2, 174.3; HRMS (FAB): m/z calcd. for
C23H34O7N3 ([M+H]+) 464.2391, found 464.2394.
26
3: M.p. 104–106 °C; [α]D = –99 (c = 0.115, CHCl3); IR: ν = 3295 (s),
2957 (m), 1666 (s), 1529 (w), 1464 (m), 1232 (m), 1111 (m), 756 (w); 1H
NMR (600 MHz, CDCl3): δ = 0.95 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 7.2 Hz,
3H), 1.34 (d, J = 6.0 Hz, 3H), 1.44–1.49 (m, 1H), 1.59–1.67 (m, 1H),
1.83–1.89 (m, 1H), 2.28 (dd, J = 11.4, 17.6 Hz, 1H), 2.60 (dd, J = 4.2,
17.6 Hz, 1H), 2.83 (dd, J = 3.0, 16.4 Hz, 1H), 3.08 (dd, J = 12.9, 16.4 Hz,
1H), 3.28 (ddd, J = 4.2, 6.6, 11.4 Hz, 1H), 3.61 (dd, J = 6.6, 9.0 Hz, 1H),
4.02 (d, J = 9.0 Hz, 1H), 4.33–4.38 (m, 1H), 4.46 (q, J = 6.0 Hz, 1H), 4.62
(ddd, J = 1.5, 3.0, 12.9 Hz, 1H), 4.86 (br s, 1H), 6.33 (br s, 1H), 6.70 (d, J
= 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 9.6 Hz, 1H), 7.42 (dd,
J = 7.2, 8.4 Hz, 1H), 10.78 (s, 1H); 13C NMR (150 MHz, CDCl3): δ = 21.8,
22.5, 23.1, 24.8, 30.3, 32.6, 40.5, 48.7, 55.3, 63.9, 72.2, 73.3, 81.1,
108.0, 116.2, 118.3, 136.6, 139.3, 162.1, 169.6, 170.9, 174.5; HRMS
(FAB): m/z calcd. for C22H31O7N3 ([M+H]+) 450.2235, found 450.2242.
Acknowledgments
26
14’-epi-3: M.p. 106–108 °C; [α]D = –122 (c = 0.075, CHCl3); IR: ν =
This work was financially supported by AMED (Grant No.
JP18am0101100). We are grateful to Ms. Yuka Taguchi (Tohoku
University) for her help with NMR and MS measurements.
3289 (s), 2956 (m), 1665 (s), 1528 (w), 1462 (m), 1231 (m), 1111 (m),
758 (w); 1H NMR (600 MHz, CDCl3): δ = 0.95 (d, J = 6.6 Hz, 3H), 0.97 (d,
J = 6.6 Hz, 3H), 1.38 (d, J = 5.7 Hz, 3H), 1.46–1.52 (m, 1H), 1.60–1.69
(m, 1H), 1.82–1.88 (m, 1H), 2.44 (dd, J = 8.3, 17.7 Hz, 1H), 2.62–2.70 (m,
1H), 2.83 (dd, J = 3.0, 16.5 Hz, 1H), 3.07 (dd, J = 13.2, 16.5 Hz, 1H),
3.45 (ddd, J = 6.0, 8.3, 13.8 Hz, 1H), 3.55–3.60 (m, 1H), 4.06 (d, J = 9.0
Hz, 1H), 4.33–4.34 (m, 1H), 4.53 (q, J = 5.7 Hz, 1H), 4.63 (d, J = 13.2 Hz,
1H), 4.97 (s, 1H), 6.52 (br s, 1H), 6.71 (d, J = 7.2 Hz, 1H), 6.89 (d, J =
8.4 Hz, 1H), 7.29 (d, J = 9.6 Hz, 1H), 7.42 (dd, J = 7.8, 7.8 Hz, 1H), 10.79
(s, 1H); 13C NMR (150 MHz, CDCl3): δ = 21.9, 22.1, 23.0, 24.8, 30.3, 33.2,
40.5, 48.7, 52.6, 61.1, 72.2, 73.3, 81.0, 108.0, 116.2, 118.3, 136.6, 139.3,
162.1, 169.5, 170.5, 174.3; HRMS (FAB): m/z calcd. for C22H31O7N3
([M+H]+) 450.2235, found 450.2238.
Keywords: Alkaloids • Hetiamacin • Natural products • Nitrogen
heterocycles • Total synthesis
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A concise total synthesis of
Natural Product Synthesis
hetiamacins A–D, members of the
amicoumacin family of natural
products that feature naturally rare
heterocyclic ring systems, has been
achieved using amicoumacin C as a
common intermediate. This work is
the first synthesis of hetiamacins B–D
which has enabled their full
Shogo Tsukaguchi, Masaru Enomoto,*
Ryo Towada, Yusuke Ogura, Shigefumi
Kuwahara*
Page No. – Page No.
Unified Total Synthesis of
Hetiamacins A–D
stereochemical assignments.
*one or two words that highlight the emphasis of the paper or the field of the study
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