A three-component coupling approach to the ACE-ring substructure of C19-diterpene alkaloids

Article abstract of DOI:10.1038/ja.2017.69

C19-diterpene alkaloids are a class of alkaloids with pharmacologically important activities having an intricately fused hexacyclic ABCDEF-ring system. Here we report expeditious assembly of the ACE-ring substructure 4a by applying a three-component coupling strategy. A radical-polar crossover reaction between an AE-ring radical precursor, a C-ring radical acceptor and an aldehyde was realized by the actions of Et 3 B and O 2, resulting in the installation of three new stereocenters and extension of the carbon chain corresponding to the B-ring. As the ACE-ring 4a possesses the correct C4,11-quaternary and C10-tertiary carbons, 4a would serve as an advanced intermediate for constructing the entire C19-diterpene alkaloid structures.

Full text of DOI:10.1038/ja.2017.69

The Journal of Antibiotics (2017), 1–7
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ORIGINAL ARTICLE
A three-component coupling approach to the ACE-ring
substructure of C19-diterpene alkaloids
Kosuke Minagawa, Daisuke Urabe and Masayuki Inoue
C19-diterpene alkaloids are a class of alkaloids with pharmacologically important activities having an intricately fused hexacyclic
ABCDEF-ring system. Here we report expeditious assembly of the ACE-ring substructure 4a by applying a three-component
coupling strategy. A radical–polar crossover reaction between an AE-ring radical precursor, a C-ring radical acceptor and an
aldehyde was realized by the actions of Et3B and O2, resulting in the installation of three new stereocenters and extension of the
carbon chain corresponding to the B-ring. As the ACE-ring 4a possesses the correct C4,11-quaternary and C10-tertiary carbons,
4a would serve as an advanced intermediate for constructing the entire C19-diterpene alkaloid structures.
The Journal of Antibiotics advance online publication, 14 June 2017; doi:10.1038/ja.2017.69
INTRODUCTION
installation of the three new stereocenters, and thus significantly
C19-diterpene alkaloids are a class of natural products present in the increased the molecular complexity in a single step.
plants of the genera Aconitum and Delphinium, and many exhibit
To explore efficient strategies for synthesizing the C19-diterpene
pharmacologically important biological activities.1 The structures of alkaloids, we decided to construct the ACE-ring system 4a with the
talatisamine and puberuline C are depicted in Scheme 1a as C6-8 carbon chain by employing the radical–polar three-component
representative examples. The intricately fused hexacyclic ABCDEF- reaction (Scheme 1b). We planned to assemble the structure of 4a
ring system of the C19-diterpene alkaloids has inspired chemists to from the azabicyclo[3.3.1]nonane AE-ring 1, 5-membered C-ring 2a
invent synthetic methods for their assembly,2–6 culminating in the full and the C6-8 carbon chain 3a. Et3B/O2-promoted C-I bond cleavage
chemical construction of several members of this family.7–11 Recently, of 1 would produce the nucleophilic C11-bridgehead radical A that
we successfully synthesized the ABCDE-ring system12 of talatisamine would add to the electron-deficient double bond of C-ring 2a, leading
and the ABCDEF-ring system13 of puberuline C based on our to Ba.27,28 Then, radical Ba would be captured by Et3B to form boron
development of a new radical-based strategy. In these synthetic studies, enolate Ca29 that would undergo the aldol reaction with aldehyde
a C11-bridgehead radical of the AE-ring moiety undergoes cyclization 3a.30–32 Hence, the one-pot radical and polar additions were expected
with the C-ring enone to form a seven-membered B-ring. The success to afford 4a possessing the correct C4,11-quaternary and C10-tertiary
of the intramolecular C11-radical addition led us to explore its carbon centers of the C19-diterpene alkaloids, such as talatisamine and
intermolecular version, because intermolecular multicomponent puberuline C (highlighted by small circles).
Before investigating the key coupling reactions, we prepared the
optically active AE-ring 1 from 2-(methoxycarbonyl)cyclohexanone
(7) (Scheme 2). Bromination of 7, followed by exchange of the
bromide of 8 with iodide using NaI, led to 9. The resultant 9
underwent the double Mannich reaction in the presence of formalde-
hyde and ethyl amine, giving rise to the azabicyclo[3.3.1]nonane
structure ( )-10 as the racemate.33 The methyl ester and the ketone
groups of ( )-10 were in turn simultaneously reduced with DIBAL-H
reactions generally ensure more convergent, and thus more efficient,
approaches to complex molecular architectures.14–19 Here we report
the three-component coupling reaction between the bicyclic AE-ring,
the 5-membered C-ring and the C6-8 carbon chain to assemble
the ACE-ring substructure 4a with the correct C4,11-quaternary and
C10-tertiary carbons in a single step (Scheme 1b).
RESULTS AND DISCUSSION
We previously realized a three-component reaction between 2a, 3b (diisobutylaluminium hydride) to the primary and secondary hydroxy
and O,Te-acetal 5 using a reagent combination of Et3B and O2 groups of ( )-11 (dr at C5= 1:1). Then, the racemic ( )-11 was
(Scheme 1c).20,21 Treatment of O,Te-acetal 5 with Et3B/O2 generated subjected to enzymatic resolution to obtain enantio-enriched (− )-11.
the highly reactive bridgehead radical species D22–26 that sequentially Although ( )-11 possesses two potentially reactive hydroxy groups
coupled with α,β-unsaturated ketone 2a and aldehyde 3b via a radical– for the enzymatic acylation, screening of enzymes and acylating
polar crossover mechanism to provide adduct 6. This method reagents permitted us to realize the chemo- and enantioselective
intermolecularly connected the three simple units with stereoselective functionalization of the C18-primary hydroxy group. Namely,
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
Correspondence: Professor M Inoue, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hong, Bunkyo-ku, Tokyo 113-0033, Japan.
E-mail: inoue@mol.f.u-tokyo.ac.jp
Dedicated with respect and admiration to Professor KC Nicolaou for his many outstanding contributions to natural product synthesis.
Received 5 April 2017; revised 1 May 2017; accepted 7 May 2017

A three-component coupling approach to the ACE-ring substructure
K Minagawa et al
2
Scheme 2 Synthesis of optically active AE-ring fragment 1. Reagents and
conditions: (a) Br2, Et2O; (b) NaI, acetone; (c) aq HCHO, aq EtNH2, MeOH,
45 °C, 83% (3 steps); (d) DIBAL-H, THF, 87%, (dr at C5 = 1:1); (e) lipase
from Candida rugosa, vinyl butyrate, i-Pr2O, 28 °C, 39% for ( − )-11 (dr at
C5= 1:1), 39% for (+)-12 (dr at C5 = 1.7:1); (f) Me3O∙BF4, 2,6-di-tert-
butylpyridine, CH2Cl2; (g) AZADO, DMAP, 2,2’-bipyridine, CuCl, air, CH3CN,
48% (2 steps); (h) Ac2O, pyridine, 100% from ( − )-11; (i) Dess–Martin
reagent, CH2Cl2, 80%, 13a: 13b = 9: 1; (j) 1M KOH, MeOH, 73% from
(+)-12; (k) Ac2O, pyridine, 100%; (l) Dess–Martin reagent, CH2Cl2, 84%,
13a: 13b = 1: 5.5.
Scheme 1 (a) Structures of the C19-diterpene alkaloids, talatisamine and
puberuline C. (b) Plan for assembly of the AE-ring, C-ring and C6-8 carbon
chain of the C19-diterpene alkaloids by the three-component coupling
reaction. (c) Previously developed radical–polar crossover three-component
coupling reaction.
treatment of diol ( )-11 (dr at C5= 1:1) with Candida rugosa
lipase34–36 and vinyl butyrate in i-Pr2O at 28 °C provided ( − )-11 radical reaction of 1 occurred from the opposite side of the
(39% yield) along with (+)-12 having a C18-butyrate group (39% preexisting tert-butyldimethylsilyl (TBS)-oxy and acetonide groups,
yield). The C4,11-absolute configurations of ( − )-11 were elucidated providing 14a (51%) and 14c (52%), respectively, in
a
by NMR experiments of derivatives of 4a (Table 1, see Supplementary C11-stereospecific and C10-stereoselective manner. Thus, the sterically
Information for details). To determine the enantiomeric ratio of the cumbersome bond between the C11-quaternary and C10-tertiary
C5-diastereomeric mixtures ( − )-11 and (+)-12, the corresponding carbon atoms of 14a-c were intermolecularly connected under mild
C5-ketone 13a/b was prepared separately from these compounds, and conditions, corroborating the potent reactivity of radical A.
then analyzed with the chiral HPLC. Acetylation of the C18-hydroxy
The bridgehead radical reaction was next extended to the radical–
group of ( − )-11, and subsequent Dess–Martin oxidation of the polar crossover three-component reactions. Et3B/O2 successfully
C5-hydroxy group provided 13a and 13b in a 9:1 enantiomeric ratio. promoted the reaction between iodide 1, chiral cyclopentenone 2a
On the other hand, basic hydrolysis of the butyrate of (+)-12 was and benzaldehyde (3b) in CH2Cl2 at room temperature to afford
followed by acetylation and oxidation to afford 13a and 13b in a 1:5.5 adduct 4b in a C8,9,10-stereoselective manner (53%, entry 4).
ratio. Finally, compound ( − )-11 (er = 9:1) was converted to the (Trimethylsilyl)propynal (3a) participated in the coupling with
requisite AE-ring fragment 1 in two steps; site-selective methyl ether 1 and 2a in the presence of Et3B and O2 to selectively yield 4a
formation by the action of Me3O∙BF4 and 2,6-di-tert-butylpyridine, (55%, dr at C8= 4:1, entry 5). No radical reaction to the triple bond of
and 2-azaadamantane N-oxyl (AZADO)-catalyzed C5-oxidation in the 3a or 4a was observed, showing the high chemoselectivity of the
presence of CuCl.37
present method. Moreover, acid/base-sensitive aldehyde 3c with the
To evaluate the reactivity of AE-ring iodide 1 as a radical precursor, β-silyloxy group functioned as an effective electrophile to provide 4c
we first examined the formation of the corresponding radical A and (52%, dr at C8= 2.9:1, entry 6). The newly generated C8,9,10-
subsequent addition to the cyclopentenone derivatives (2a–c) stereochemistry of coupling products 4a-c was consistent, and
(Table 1). Upon treatment of 1 and cyclopentenone 2b with Et3B determined by extensive NMR experiments using their derivatives
and O2 in CH2Cl2 at room temperature, the C-I bond at the congested (see Supplementary Information for details). Significantly, the
bridgehead position was homolytically cleaved to generate bridgehead C9-substituted ACE-ring systems 4a–c with the two quaternary
radical A that reacted with 2b to furnish 14b in 65% yield (dr at carbons (C4,11) and one tertiary carbon (C10) of the C19-diterpene
C10 = 1:1, entry 1). When the enantiopure cyclopentenone derivatives alkaloids were built in a single operation in neutral media at room
2a and 2c38 were used under the same conditions (entries 2 and 3), the temperature. In contrast to the successful formation of 4a–c, the three-
The Journal of Antibiotics

A three-component coupling approach to the ACE-ring substructure
K Minagawa et al
3
Table 1 The two- and three-component radical coupling reactions
of 1a
Scheme 3 Rationale of the different reactivity between 2a and 2c, and the
stereoselectivity of the three-component coupling reaction.
component adduct 4d was obtained from 1, 2c and 3b in only 10%
yield, and the two-component adduct 14c was mainly generated in
36% yield (entry 7). The distinct behavior of 2a and 2c indicated that
the C-ring structure influenced the efficiency of the aldol reaction.
The reaction mechanism of the selective generation of 4b and 14c
from 2a and 2c, respectively, is outlined in Scheme 3. Addition of
bridgehead radical A to 2a from the opposite side of the TBS-oxy
group installs the C10-stereochemistry. After the formation of boron
enolate Ca, aldehyde 3b approaches from the less hindered face to
avoid the bulky AE-ring, and forms the boron-chelating 6-membered
transition state Ea, from which the C8,9-stereochemistry of 4b is
established.39,40 In the case of 2c, the radical reaction of 2c and the
radical termination of Et3B occurred similarly to 2a, producing Cc.
The approach of 3b toward one face of the enolate Cc, however, is
blocked by the AE-ring, and the approach toward the other face is
hindered by the acetonide-protected 1,2-diol. Because of the structural
differences in the Y,Z-functionalities between Ec and Ea, the aldol
reaction via Ec becomes less efficient compared with Ea. As a result,
the yield of the three-component coupling adduct 4d is significantly
decreased, and hydrolysis of Cc mainly occurs to produce the
two-component adduct 14c.
In conclusion, we investigated the two- and three-component
reactions of 1, and realized the expeditious assembly of the functio-
nalized ACE-ring substructure 4a of the C19-diterpene alkaloids by
applying the radical–polar crossover reaction. AE-ring 1, C-ring 2a
and C6-8 chain 3a were coupled to generate 4a using Et3B and O2
through formation of the bridgehead radical from iodide 1, radical
addition to cyclopentenone 2a and polar addition of the resultant
boron enolate to aldehyde 3a. Remarkably, this operationally simple
reaction enabled connection of the hindered C10-11 and C8-9 bonds,
and installation of the C8,9,10-stereocenters under mild conditions in
a single step. As the thus obtained 4a bears the C4,11-quaternary and
C10-tertiary carbon centers, and the C6-8 chain of the C19-diterpene
alkaloids, the compound would function as a valuable advanced
intermediate for their total syntheses.
aConditions: 1 (er = 9:1, 1 equiv), 2a-c (3 equiv), 3a-c (0 or 3 equiv), Et3B (3 equiv), CH2Cl2,
O2, room temperature.
bThe product contained a small amount of the diastereomer that would be derived from the
minor enantiomer of 1 (14a: its diastereomer =9.1:1, 14c: its diastereomer= 14:1).
cThe product did not contain the diastereomer derived from the minor enantiomer of 1.
d14c was generated in 36% yield.
eThe yield was calculated by 1H NMR analysis, because 4d and 14c were inseparable.
The Journal of Antibiotics

A three-component coupling approach to the ACE-ring substructure
K Minagawa et al
4
EXPERIMENTAL PROCEDURES
General methods
and EtOAc (15 ml) were successively added. After being stirred at room
temperature for 1 h, the resultant mixture was extracted with EtOAc
(10 ml × 3). The combined organic layers were dried over Na2SO4, filtered
and concentrated. The residue was purified by flash column chromatography
on silica gel (40 g, hexane/EtOAc 50:1 to 5:1) to afford a 1:1 C5-diastereomeric
mixture of diol ( )-11 (431 mg, 1.33 mmol) in 87% yield: yellow oil; IR (film)
ν 3403, 2970, 2925, 2809, 1471, 1452, 1394, 1327, 1291, 1227, 1146, 1076, 1025,
959, 943 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.03 (3H × 1/2, t, J =6.8 Hz, N
(CH2CH3), 1.04 (3H × 1/2, t, J = 7.2 Hz, N(CH2CH3), 1.32–1.50 (2H and
1H × 1/2, m), 1.44–1.48 (1H × 1/2, m), 2.03–2.10 (1H, m), 2.23–2.40 (3H, m),
2.54 (1H × 1/2, d, J =9.2 Hz), 2.58–2.93 (5H and 1H × 1/2, m), 2.97 (1H × 1/2,
dd, J = 8.7 1.9 Hz), 3.18 (1H, m), 3.34 (1H, m), 3.43 (1H × 1/2, d, J = 8.7 Hz),
3.48 (1H × 1/2, d, J = 9.2 Hz), 3.59 (1H × 1/2, dd, J = 9.2, 1.8 Hz), 3.88
(1H × 1/2, s), 3.89 (1H × 1/2, s); 13C NMR (100 MHz, CDCl3) δ 12.5 (1C
× 1/2), 12.6 (1C × 1/2), 24.8 (1C × 1/2), 25.3 (1C × 1/2), 25.4 (1C × 1/2), 33.9
(1C), 38.9 (1C × 1/2), 42.3 (1C × 1/2), 45.9 (1C × 1/2), 51.2 (1C × 1/2), 51.7
(1C × 1/2), 53.0 (1C × 1/2), 60.4 (1C × 1/2), 62.5 (1C × 1/2), 63.4 (1C × 1/2),
69.0 (1C × 1/2), 70.3 (1C × 1/2), 70.9 (1C × 1/2), 80.3 (1C), 81.1 (1C × 1/2);
HRMS (ESI) calcd for C11H21INO2 [M+H]+ 326.0611, found 326.0622.
All reactions sensitive to air or moisture were carried out under argon
atmosphere in dry solvents under anhydrous conditions, unless otherwise
noted. THF, CH2Cl2 and Et2O were purified by Glass Contour solvent
dispensing system (Nikko Hansen, Osaka, Japan). All other reagents were used
as supplied unless otherwise stated. Analytical TLC was performed using
E. Merck Silica gel 60 F254 precoated plates (Merck, Darmstadt, Germany).
Preparative TLC was performed using E. Merck Silica gel 60 F254 precoated
plates with 0.50 mm thickness. Flash chromatography was performed using
40–50 μm Silica Gel 60N (Kanto Chemical, Tokyo, Japan), 40–100 μm Silica
Gel 60N (Kanto Chemical), 100–210 μm Silica Gel 60N (Kanto Chemical) and
32–53 μm Silica gel BW-300 (Fuji Silysia Chemical, Aichi, Japan). Optical
rotations were measured on a JACSO P-200 Digital Polarimeter at room
temperature using the sodium D line (JASCO, Tokyo, Japan). IR spectra were
recorded on a JASCO FT/IR-4100 spectrometer. 1H- and 13C-NMR spectra
were recorded on a JEOL JNM-ECX-500 (500 MHz), a JNM-ECA-500
(500 MHz) or a JNM-ECS-400 (400 MHz) spectrometer (JEOL, Tokyo, Japan).
Chemical shifts were reported in ppm on the δ scale relative to CHCl3 (δ = 7.26
for 1H NMR), CDCl3 (δ =77.0 for 13C NMR), C6D5H (δ = 7.16 for 1H-NMR)
and C6D6 (δ = 128.0 for 13C-NMR) as internal references. Signal patterns are
indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad
peak. The numbering of compounds corresponds to that of natural product.
Electrospray ionization mass spectra were measured on a JEOL JMS-T100LP or
a Bruker microTOF II instrument.
Diol (− )-11 and butyrate (+)-12
Lipase from C. rugosa (1009 U mg−1, 1.27 g) and vinyl butyrate (1.2 ml,
9.7 mmol) were successively added to a solution of diol ( )-11 (1.27 g,
3.91 mmol) in i-Pr2O (40 ml) at 28 °C. The reaction mixture was stirred at
28 °C for 1 h. Then, the mixture was filtered through a pad of Celite with Et2O.
After the filtrate was concentrated, brine (15 ml) was added. The resultant
solution was extracted with EtOAc (15 ml × 3), and the combined organic
layers were dried over Na2SO4, filtered and concentrated. The residue was
purified by flash column chromatography on silica gel (30 g, hexane/EtOAc
50:1 to 1:1) to afford a 1:1 C5-diastereomeric mixture of diol (− )-11 (491 mg,
1.51 mmol) and a 1.7:1 C5-diastereomeric mixture of butyrate (+)-12 (632 mg,
1.54 mmol) in 39% and 39% yields, respectively. The enantiopurity of ( − )-11
and (+)-12 was evaluated by the chiral HPLC analysis of compound 13 derived
from ( − )-11 and (+)-12, respectively (see Scheme 2). The enantiomeric ratio
(er) of 13a/13b from ( − )-11 was 9:1 and that from (+)-12 was 1:5.5. The
analytical detail was described in the Supplementary Information. Diol (− )-11:
Iodide ( )-10
Br2 (200 μl, 7.96 mmol) was added to a solution of 7 (1.13 g, 7.24 mmol) in
Et2O (4.8 ml) at 0 °C. The reaction mixture was warmed to room temperature
and stirred for 3 h. Then, saturated aqueous NaHCO3 (5 ml) was added. The
resulting mixture was extracted with Et2O (5 ml × 3), and the combined
organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and
concentrated to afford the crude bromide 8. The crude 8 was divided into three
equal parts. One-third of the crude 8 was used in the next iodination.
NaI (470 mg, 3.13 mmol) was added to a solution of one-third of the above
crude bromide 8 (2.41 mmol) in acetone (4.8 ml) at room temperature. The
reaction mixture was stirred at room temperature for 1.5 h. Then, the reaction
mixture was filtered through a pad of Celite and the filter cake was washed with
acetone. The resultant solution was concentrated to afford the crude 9 that was
used in the next reaction without further purification.
23
26
yellow oil; [α]D −3.5 (c 1.00, CHCl3). Butyrate (+)-12: [α]D 8.0 (c 1.00,
CHCl3); IR (film) ν 3500, 2966, 2931, 2875, 2807, 1739, 1454, 1416, 1384, 1304,
1
1261, 1181, 1132, 1081, 1048, 1091, 991 cm− 1; H NMR (400 MHz, CDCl3) δ
0.95 (3H × 5/8, t, J =7.4 Hz, COCH2CH2CH3), 1.03 (3H × 3/8, t, J = 7.3 Hz,
NCH2CH3), 1.33 (1H × 3/8, m), 1.42-1.46 (2H × 5/8, m), 1.67 (2H, qt, J = 7.4,
7.4 Hz, COCH2CH2CH3), 1.77 (1H, m), 2.19–2.33 (5H, m), 2.40 (1H × 3/8, d,
J = 11.0 Hz, NHAHB), 2.55 (1H × 5/8, d, J = 11.0 Hz, NHAHB), 2.56–2.70 (1H,
m), 2.72–2.90 (3H, m), 2.95 (1H × 5/8, d, J = 11.0 Hz, NHAHB), 3.19 (1H
× 5/8, s, H-5), 3.56 (1H × 5/8, d, J = 11.0 Hz, NHAHB), 3.74-3.80 (1H and 1H
× 3/8, m), 4.06 (1H × 5/8, d, J = 11.0 Hz, H-18a), 4.10 (1H × 3/8, d,
J = 11.0 Hz, H-18a); 13C NMR (125 MHz, C6D6) δ 12.5, 12.6, 13.77, 13.79,
18.7, 18.8, 25.5, 25.7, 25.8, 33.8, 36.1, 36.2, 39.4, 41.9, 42.1, 46.6, 51.4, 51.8,
53.6, 60.8, 61.8, 63.0, 63.1, 69.36, 69.39, 69.9, 76.9, 78.2, 173.1, 173.2; HRMS
(ESI) calcd for C15H27INO3 [M+H]+ 396.1030, found 396.1017.
Aqueous EtNH2 (70% in water, 465 μl, 7.23 mmol) was added to a solution
of the above crude 9 in MeOH (8.0 ml) and aqueous HCHO (37% in water,
2.3 ml, 28.9 mmol) at 0 °C over 3 h. The reaction mixture was warmed to
45 °C and stirred for 5 h. After the mixture was cooled to room temperature,
H2O (16 ml) was added. The resultant mixture was extracted with EtOAc
(8 ml × 3), and the combined organic layers were washed with brine (5 ml),
dried over Na2SO4, filtered and concentrated. The residue was purified by flash
column chromatography on silica gel (100 g, hexane/EtOAc 50:1 to 5:1) to
afford iodide ( )-10 (703 mg, 2.00 mmol). The yield was determined to be
83% yield over 3 steps based on one-third amount of the starting compound 7:
pale yellow oil; IR (film) ν 2969, 2949, 2932, 2811, 1739, 1731, 1454, 1435,
1292, 1259, 1224, 1208, 1175, 1131, 1112, 1098, 1090 cm−1 1H NMR
;
Iodide 1
(400 MHz, CDCl3) δ 1.11 (3H, t, J = 7.3 Hz, NCH2CH3), 1.51 (1H, m), 2.30
(1H, dddd, J = 14.2, 6.4, 2.3, 2.3 Hz), 2.43 (2H, m, NCH2CH3), 2.57 (1H, m),
2.80 (1H, m), 2.99 (1H, dddd, J = 13.7, 5.9, 2.3, 2.3 Hz), 3.03 (1H, dd, J = 11.9,
2.3 Hz, NCHAHB), 3.16 (1H, m, NCHAHB), 3.18 (1H, m), 3.30 (1H, dd,
J = 11.9, 2.3 Hz, NCHAHB), 3.74 (1H, dd, J = 8.7, 2.8 Hz), 3.76 (3H, s, OMe);
13C NMR (100 MHz, CDCl3) δ 12.6, 24.4, 36.6, 49.4, 50.3, 52.5, 56.2, 59.0,
61.2, 71.6, 170.5, 203.1; HRMS (ESI) calcd for C12H18INO3Na [M+Na]+
374.0224, found 374.0225.
Me3O∙BF4 (564 mg, 3.81 mmol) was added to
a solution of a 1:1
C5-diastereomeric mixture of diol (− )-11 (620 mg, 1.91 mmol) and 2,6-di-
tert-butylpyridine (1.3 ml, 5.7 mmol) in CH2Cl2 (38 ml) at 0 °C. The reaction
mixture was warmed to room temperature and stirred for 2 h. Then, saturated
aqueous NaHCO3 (20 ml) was added. The resultant mixture was extracted with
EtOAc (15 ml × 3), and the combined organic layers were dried over Na2SO4,
filtered and concentrated. The residue was purified by flash column chromato-
graphy on silica gel (30 g, hexane/EtOAc 50:1 to 5:1) to afford the crude methyl
ether that was used in the next reaction without further purification.
Diol ( )-11
CuCl (227 mg, 2.29 mmol) and AZADO (87.2 mg, 573 μmol) were succes-
DIBAL-H (1.0 M in hexane, 9.2 ml, 9.2 mmol) was added to a solution of sively added to a solution of the above crude methyl ether, DMAP (93.3 mg,
(
)-10 (536 mg, 1.53 mmol) in THF (15 ml) at 0 °C. The reaction mixture
764 μmol) and 2,2′-bipyridine (59.7 mg, 382 μmol) in CH3CN (9.6 ml) at
was warmed to room temperature and stirred for 30 min. Then, saturated room temperature. The reaction mixture was stirred at room temperature for
aqueous NH4Cl (10 ml), saturated aqueous potassium sodium tartrate (15 ml) 15 min. Then, saturated aqueous Na2S2O3 (10 ml) was added. The resultant
The Journal of Antibiotics

A three-component coupling approach to the ACE-ring substructure
K Minagawa et al
5
mixture was extracted with Et2O (10 ml × 3), and the combined organic layers was purified by flash column chromatography on silica gel (4 g, CH2Cl2 to
22
were dried over Na2SO4, filtered and concentrated. The residue was purified by CH2Cl2/EtOAc 10:1). [α]D -65.0 (c 1.00, CHCl3); IR (film) ν 2979, 2934,
flash column chromatography on silica gel (20 g, hexane/EtOAc 80:1 to 10:1) to 2810, 1757, 1706, 1453, 1381, 1242, 1210, 1157, 1112, 1041, 1004, 976 cm− 1
;
afford iodide 1 (309 mg, 916 μmol) in 48% yield over 2 steps: colorless oil; [α] 1H NMR (500 MHz, CDCl3) peaks of the major isomer: δ 1.10 (3H, t, J = 7.5 Hz,
22
− 0.59 (c 1.00, CHCl3); IR (film) ν 2973, 2925, 2894, 2807, 1727, 1452, NCH2CH3), 1.33 (3H, s, acetonide), 1.43 (3H, s, acetonide), 1.50 (1H, m), 1.67
D
1385, 1348, 1318, 1289, 1235, 1202, 1164, 1112, 1020, 965, 935 cm− 1; 1H NMR
(1H, ddd, J =12.6, 12.6, 6.3 Hz), 1.81 (1H, ddd, J = 13.2, 13.2, 6.3 Hz), 1.97
(400 MHz, CDCl3) δ 1.09 (3H, t, J =7.3 Hz, NCH2CH3), 1.44 (1H, m), 1.75
(1H, ddd, J = 13.3, 13.3, 2.3 Hz), 2.34–2.40 (4H, m), 2.74 (1H, ddd, J = 13.3,
13.3, 2.3 Hz), 2.97 (1H, m), 3.09 (1H, d, J = 11.0 Hz), 3.18 (1H, m), 3.31–3.37
(2H, m), 3.34 (3H, s, OMe), 3.44 (1H, d, J = 9.6 Hz), 3.73 (1H, dd, J = 11.0,
2.3 Hz); 13C NMR (100 MHz, CDCl3) δ 12.6, 24.6, 37.5, 49.8, 50.3, 51.6, 59.2,
59.4, 61.9, 71.7, 76.2, 207.3; HRMS (ESI) calcd for C12H20INO2 [M+Na]+
360.0431, found 360.0432.
(1H, m), 2.04 (1H, m), 2.22 (1H, m), 2.38–2.45 (3H, m), 2.53 (1H, d,
J = 11.5 Hz, NCHAHB), 2.63 (1H, dd, J = 19.5, 10.3 Hz), 2.67 (1H, m), 2.76
(1H, d, J = 11.5 Hz, NCHAHB), 2.97 (1H, dd, J = 11.5, 1.7 Hz, NCHAHB), 3.09
(1H, dd, J = 11.5, 1.2 Hz, NCHAHB), 3.26 (1H, d, J = 9.8 Hz, H-18a), 3.32
(3H, s, OMe), 3.36 (1H, d, J = 9.8 Hz, H-18b), 4.61 (1H, d, J = 6.9 Hz, H-12),
4.68 (1H, d, J =6.9 Hz, H-13); 13C NMR (100 MHz, CDCl3) peaks of the major
isomer: δ 12.6, 19.6, 24.7, 26.9, 37.2, 37.8, 38.9, 45.7, 50.2, 51.2, 51.7, 59.6, 62.2,
63.0, 75.8, 79.65, 79.68, 111.8, 212.8, 217.4; HRMS (ESI) calcd for
C20H31NO5Na [M+Na]+ 388.2094, found 388.2088.
General procedure A: two-component radical coupling reaction
Compound 14b
General procedure B: three-component coupling reaction
Et3B (0.99 M in hexane, 370 μl, 370 μmol) was added to a solution of
cyclopentenone 2b (31 μl, 370 μmol) and iodide 1 (41.3 mg, 123 μmol) in Compound 4b
CH2Cl2 (250 μl) at 0 °C over 30 min. The mixture was warmed to room
temperature under air and stirred for 30 min. Then, saturated aqueous
NaHCO3 (2 ml) was added. The resultant mixture was extracted with EtOAc
(2 ml × 3), and the combined organic layers were passed through a pad of silica
gel with EtOAc. After the filtrate was concentrated, the residue was purified by
flash column chromatography on silica gel (4 g, hexane/EtOAc 100:1 to 1:1) to
afford a 1:1 C10-diastereomeric mixture of 14b (23.4 mg, 79.8 μmol) in 65%
Et3B (0.99 M in hexane, 350 μl, 350 μmol) was added to a solution of
cyclopentenone 2a (enantiopure, 75.4 mg, 355 μmol), aldehyde 3b (36 μl,
350 μmol) and iodide 1 (er =9:1, 39.9 mg, 118 μmol) in CH2Cl2 (240 μl) at
0 °C over 30 min. The reaction mixture was warmed to room temperature
under air and stirred for 30 min. Then, saturated aqueous NaHCO3 (2 ml) was
added. The resultant mixture was extracted with EtOAc (2 ml × 3), and the
combined organic layers were passed through a pad of silica gel with EtOAc.
After the filtrate was concentrated, the residue was purified by flash column
chromatography on silica gel (4 g, CH2Cl2/EtOAc 100:1 to 1:1) to afford 4b
(33.2 mg, 62.7 μmol) in 53% yield: colorless oil; [α]D26 3.13 (c 1.00, CHCl3); IR
(film) ν 3462, 2952, 2928, 2894, 2857, 2807, 1708, 1472, 1456, 1388, 1253,
26
yield: [α]D − 0.43 (c 1.00, CHCl3); IR (film) ν 2957, 2930, 1731, 1710, 1459,
1
1362, 1330, 1208, 1165, 1112, 1058 cm− 1; H NMR (500 MHz, CDCl3) δ 1.08
(3H × 1/2, t, J = 6.9 Hz, NCH2CH3), 1.09 (3H × 1/2, t, J = 6.9 Hz, NCH2CH3),
1.40–1.50 (1H, m), 1.63–1.70 (1H, m), 1.73–1.80 (2H, m), 1.95-2.07 (2H, m),
2.10-2.19 (2H, m), 2.21–2.27 (1H, m), 2.29–2.42 (7H, m), 2.72–2.90 (1H, m),
2.92 (1H × 1/2, dd, J = 11.0, 1.8 Hz, NHAHB), 3.01 (1H × 1/2, dd, J = 11.0,
1.8 Hz, NHAHB), 3.14 (1H × 1/2, dd, J = 11.5 Hz, NHAHB), 3.17 (1H × 1/2, dd,
J = 11.5 Hz, NHAHB), 3.29 (1H × 1/2, d, J = 9.2 Hz, H-18a), 3.30 (1H × 1/2, d,
J = 9.2 Hz, H-18a), 3.34 (3H, s, OMe), 3.38 (1H, d, J = 9.2 Hz, H-18b); 13C
NMR (125 MHz, CDCl3) δ 12.56, 12.57, 20.36, 20.37, 20.53, 20.54, 23.4, 23.7,
35.9, 36.3, 36.41, 36.42, 36.52, 36.53, 38.5, 38.7, 39.5, 39.8, 40.9, 41.2, 50.8,
50.9, 51.1, 52.3, 59.2, 59.3, 61.5, 61.6, 63.2, 63.6, 212.5, 212.6, 218.5, 218.7;
HRMS (ESI) calcd for C17H27NO3Na [M+Na]+ 316.1883, found 316.1880.
1172, 1113, 1061 cm−1 1H NMR (400 MHz, CDCl3) δ 0.11 (3H, s, CH3 of
;
TBS), 0.19 (3H, s, CH3 of TBS), 0.94 (9H, s, t-Bu of TBS), 0.98 (3H, t,
J = 6.9 Hz, NCH2CH3), 1.34-1.38 (1H, m), 1.44-1.53 (2H, m), 1.61 (1H, ddd,
J = 12.0, 12.0, 6.3 Hz), 1.68 (1H, br d, J = 10.9 Hz), 2.12-2.19 (5H, m), 2.34
(1H, d, J = 18.9 Hz), 2.36 (1H, m), 2.64 (1H, dd, J = 11.4, 1.8 Hz), 2.64-2.74
(2H, m), 3.02 (1H, dd, J = 11.4, 1.4 Hz), 3.13 (1H, d, J = 9.6 Hz, H-18a), 3.33
(3H, s, OMe), 3.39 (1H, d, J = 9.6 Hz, H-18b), 4.43 (1H, d, J = 6.0 Hz), 4.48
(1H, s), 4.92 (1H, d, J = 7.8 Hz), 7.29-7.38 (5H, m, aromatic); 13C NMR
(100 MHz, CDCl3) δ − 4.6, 12.5, 17.8, 20.0, 25.7, 37.3, 37.4, 49.6, 50.3, 51.2,
52.1, 55.3, 56.7, 59.5, 62.1, 63.1, 71.1, 76.0, 76.3, 127.2, 127.8, 128.2, 141.2,
216.4, 220.4; HRMS (ESI) calcd for C30H47NO5SiNa [M+Na]+ 552.3116, found
552.3117.
Compound 14a
According to the general procedure A, a 9.1:1 mixture of 14a and the
diastereomer presumably originated from the minor enantiomer of
1
(25.7 mg, 60.7 μmol) was obtained in 51% yield by using cyclopentenone 2a
(enantiopure, 75.8 mg, 359 μmol), iodide 1 (er = 9:1, 40.1 mg, 119 μmol) and
Et3B (0.99 M in hexane, 360 μl, 360 μmol) in CH2Cl2 (240 μl). The crude was
purified by flash column chromatography on silica gel (4 g, CH2Cl2/EtOAc
100:1 to 1:1). [α]D 23.0 (c 1.00, CHCl3); IR (film) ν 2950, 2929, 2895, 2808,
1747, 1707, 1470, 1389, 1361, 1254, 1204, 1164, 1112, 1007, 979, 940,
;
908 cm−1 1H NMR (400 MHz, CDCl3) peaks of the major isomer: δ 0.03
(3H, s, CH3 of TBS), 0.07 (3H, s, CH3 of TBS), 0.86 (9H, s, t-Bu of TBS), 1.09
(3H, t, J =7.3 Hz, NCH2CH3), 1.46 (1H, m), 1.65–1.82 (2H, m), 2.15–2.28
(5H, m), 2.33 (1H, d, J = 7.8 Hz), 2.36 (2H, q, J =7.3 Hz, NCH2CH3), 2.58
(1H, d, J = 11 Hz, NCHAHB), 2.70 (1H, dd, J = 17.8, 7.4 Hz), 2.84 (1H, m),
2.95 (1H, dd, J = 11.0, 2.3 Hz, NCHAHB), 3.14 (1H, ddd, J = 11.4, 1.8, 1.8 Hz,
NCHAHB), 3.32 (1H, d, J = 9.6 Hz, H-18a), 3.33 (3H, s, OMe), 3.37 (1H, d,
J = 9.6 Hz, H-18b), 4.50 (1H, dd, J =6.0, 6.0 Hz, H-12); 13C NMR (100 MHz,
CDCl3) peaks of the major isomer: δ − 4.7, −3.9, 12.8, 17.7, 20.4, 25.7, 37.9, 40.3,
40.6, 49.3, 50.4, 50.8, 51.4, 52.0, 59.6, 62.3, 62.8, 70.9, 76.0, 216.1, 217.2; HRMS
(ESI) calcd for C23H41NO4SiNa [M+Na]+ 446.2697, found 446.2708.
Compound 4a
According to the general procedure B, C8(S)-4a (29.0 mg, 52.7 μmol) and C8
(R)-4a (7.4 mg, 13.5 μmol) were obtained in 44% and 11% yields, respectively,
by using cyclopentenone 2a (enantiopure, 76.7 mg, 361 μmol), aldehyde 3a
(53 μl, 361 μmol), iodide 1 (er = 9:1, 40.6 mg, 120 μmol) and Et3B (0.99 M in
hexane, 370 μl, 370 μmol) in CH2Cl2 (240 μl). The crude was purified by flash
column chromatography on silica gel (4 g, CH2Cl2/EtOAc 100:1 to 5:1). C8(S)-
26
26
4a: [α]D − 0.11 (c 1.00, CHCl3); IR (film) ν 3454, 2955, 2929, 2897, 2857,
2809, 2175, 1743, 1709, 1472, 1462, 1388, 1361, 1286, 1251, 1172, 1112, 1066,
1006, 976 cm− 1; 1H NMR (400 MHz, CDCl3) δ 0.07 (3H, s, CH3 of TBS), 0.13
(3H, s, CH3 of TBS), 0.16 (9H, s, CH3 of TMS), 0.86 (9H, s, t-Bu of TBS), 1.09
(3H, t, J = 6.8 Hz, NCH2CH3), 1.49 (1H, m), 1.66 (1H, m), 1.87 (1H, m), 2.02
(1H, m), 2.22-2.41 (7H, m), 2.54 (1H, d, J = 11.0 Hz, NCHAHB), 2.81 (2H, dd,
J = 18.3, 5.5 Hz), 3.01 (1H, d, J = 11.0 Hz, NCHAHB), 3.13 (1H, d, J = 11.0 Hz,
NCHAHB), 3.26 (1H, d, J = 9.6 Hz, H-18a), 3.32 (3H, s, OMe), 3.36 (1H, d,
J = 9.2 Hz, H-18b), 3.70 (1H, s, OH), 4.43 (1H, d, J = 5.5 Hz, H-12), 4.66 (1H,
d, J =7.8 Hz, H-8); 13C NMR (100 MHz, CDCl3) δ − 4.7, − 4.5, − 0.2, 12.7,
17.7, 20.0, 25.6, 37.4, 38.9, 49.1, 50.4, 51.3, 52.3, 55.3, 55.5, 59.6, 62.2, 63.8,
Compound 14c
65.3, 71.0, 75.9, 91.0, 103.6, 216.7, 218.6; HRMS (ESI) calcd for C29H51NO5-
According to the general procedure A, a 14:1 mixture of 14c and the Si2Na [M+Na]+ 572.3198, found 572.3192. C8(R)-4a: [α]D 5.21 (c 1.00,
diastereomer presumably originated from the minor enantiomer of CHCl3); IR (film) ν 3441, 2955, 2929, 2898, 2857, 2810, 2172, 1743, 1713, 1471,
25
1 (23.4 mg, 64.0 μmol) was obtained in 52% yield by using cyclopentenone 1459, 1389, 1250, 1173, 1113, 1065 cm−1; H NMR (400 MHz, CDCl3) δ 0.07
1
2c (enantiopure, 56.8 mg, 368 μmol), iodide 1 (er = 9:1, 41.4 mg, 123 μmol) (3H, s, CH3 of TBS), 0.14 (3H, s, CH3 of TBS), 0.16 (9H, s, CH3 of TMS), 0.87
and Et3B (0.99 M in hexane, 370 μl, 370 μmol) in CH2Cl2 (250 μl). The crude (9H, s, t-Bu of TBS), 1.08 (3H, t, J = 7.3 Hz, NCH2CH3), 1.25 (1H, s, OH),
The Journal of Antibiotics

A three-component coupling approach to the ACE-ring substructure
K Minagawa et al
6
1.45, (1H, m), 1.71 (1H, m), 1.94 (1H, m), 2.13 (1H, m), 2.23-2.44 (7H, m), ACKNOWLEDGEMENTS
2.49 (1H, d, J = 11.0 Hz, NCHAHB), 2.69 (1H, m), 2.80 (1H, dd, J = 19.2,
6.4 Hz), 2.88 (1H, dd, J = 11.0, 1.8 Hz, NCHAHB), 3.12 (1H, dd, J = 11.0,
1.4 Hz, NCHAHB), 3.29 (1H, d, J = 9.6 Hz, H-18a), 3.32 (3H, s, OMe), 3.34
(1H, d, J = 9.6 Hz, H-18b), 4.39 (1H, d, J = 4.4 Hz, H-12), 4.70 (1H, d,
J = 7.8 Hz, H-8); 13C NMR (125 MHz, CDCl3) δ − 4.8, − 4.5, −0.2, 12.6, 17.7,
20.4, 25.7, 37.4, 38.5, 49.0, 50.3, 51.3, 52.4, 55.2, 55.3, 59.6, 62.0, 63.6, 65.2,
70.8, 75.8, 77.3, 103.6, 217.0, 218.4, one 13C peak was not observed; HRMS
(ESI) calcd for C29H51NO5Si2Na [M+Na]+ 572.3198, found 572.3200.
This research was financially supported by the Funding Program for a Grant-
in-Aid for Scientific Research (A) (JSPS Grant Number 26253003) to MI and a
Grant-in-Aid for Young Scientists (A) (JSPS Grant Number 16H06213) to DU.
1
2
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Compound 4c
According to the general procedure B,
meric mixture of 4c (39.2 mg, 64.0 μmol) was obtained in 52% yield by using
cyclopentenone 2a (enantiopure, 78.4 mg, 369 μmol), aldehyde 3c (69.5 mg,
369 μmol), iodide 1 (er = 9:1, 41.5 mg, 123 μmol) and Et3B (0.99 M in hexane,
380 μl, 380 μmol) in CH2Cl2 (250 μl). The crude was purified by flash column
a
2.9:1 C8-diastereo-
3
4
5
6
7
8
9
26
chromatography on silica gel (4 g, CH2Cl2/EtOAc 100:1 to 5:1). [α]D 2.48
(c 1.00, CHCl3); IR (film) ν 3471, 2953, 2930, 2892, 2857, 2810, 1740, 1470,
1387, 1362, 1295, 1254, 1188, 1171, 1006, 973, 938 cm− 1; 1H NMR (400 MHz,
CDCl3) peaks of the major isomer: δ 0.04 (6H, s, CH3 of TBS × 2), 0.06 (3H, s,
CH3 of TBS), 0.11 (3H, s, CH3 of TBS), 0.87 (18H, s, t-Bu of TBS × 2), 1.06
(3H, t, J = 7.3 Hz, NCH2CH3), 1.42–1.44 (1H, m), 1.60–1.80 (3H, m), 1.93
(1H, m), 2.02–2.06 (1H, m), 2.13 (1H, s), 2.20–2.37 (6H, m), 2.47 (1H, d,
J = 11.0 Hz, NCHAHB), 2.67–2.73 (1H, m), 2.82 (1H, m), 2.96 (1H, d,
J = 11.0 Hz, NCHAHB), 3.14 (1H, dd, J = 11.4, 1.8 Hz, NCHAHB), 3.26 (1H,
d, J = 10.1 Hz, H-18a), 3.31 (3H, s, OMe), 3.35 (1H, d, J = 9.6 Hz, H-18b), 3.80
(2H, m), 3.84 (1H, s, OH), 4.02-4.05 (1H, m), 4.40 (1H, m); 13C NMR
(100 MHz, CDCl3) δ − 5.5 (2C × 3/4), -5.4 (2C × 1/4), − 4.8 (1C × 1/4),
-4.7 (1C × 3/4), -4.4 (1C × 1/4), −4.3 (1C × 3/4), 12.61 (1C × 3/4), 12.64
(1C × 1/4), 17.7 (1C), 18.20 (1C × 1/4), 18.21 (1C × 3/4), 20.2 (1C × 3/4), 20.4
(1C × 1/4), 25.66 (3C × 1/4), 25.69 (3C × 3/4), 25.9 (3C × 3/4), 26.0 (3C × 1/4),
36.5 (1C), 37.2 (1C × 1/4), 37.5 (1C × 3/4), 39.0 (1C × 3/4), 50.0 (1C × 1/4),
50.1 (1C × 3/4), 50.2 (1C × 1/4), 50.3 (1C × 3/4), 51.2 (1C × 1/4), 51.3
(1C × 3/4), 53.1 (1C × 1/4), 53.2 (1C × 3/4), 55.9 (1C × 3/4), 56.5 (1C × 1/4),
56.6 (1C × 3/4), 59.5 (1C), 61.3 (1C × 1/4), 61.5 (1C × 3/4), 62.1 (1C × 3/4),
62.4 (1C × 1/4), 63.3 (1C × 3/4), 63.5 (1C × 1/4), 70.8 (1C), 73.0 (1C × 1/4),
73.2 (1C × 3/4), 75.8 (1C × 1/4), 75.9 (1C × 3/4), 216.8 (1C × 3/4), 217.7
(1C × 3/4), 218.1 (1C × 1/4), 221.0 (1C × 1/4), two 13C peaks of the minor
diastereomer were not observed; HRMS (ESI) calcd for C32H61NO6Si2Na
[M+Na]+ 634.3930, found 634.3943.
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Compound 4d
According to the general procedure B, a 3.6:1 mixture of 14c and 4d (22.3 mg,
44.9 μmol for 14c, 12.5 μmol for 4d) was obtained by using cyclopentenone 2c
(enantiopure, 57.8 mg, 375 μmol), aldehyde 3b (38 μl, 370 μmol), iodide 1
(er = 9:1, 42.1 mg, 125 μmol) and Et3B (0.99 M in hexane, 380 μl, 380 μmol) in
CH2Cl2 (250 μl). The crude was purified by flash column chromatography on
silica gel (4 g, CH2Cl2/EtOAc 100:1 to 5:1). The yields were calculated to be
36% for 14c and 10% for 4d, respectively. A small amount of the mixture was
repurified by flash column chromatography to obtain pure 4d for characteriza-
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a
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acetonide), 1.45–1.49 (1H, m), 1.59 (3H, s, acetonide), 1.77 (1H, br s, OH),
2.04–2.07 (1H, m), 2.25–2.30 (2H, m), 2.33–2.40 (1H, m), 2.49 (1H, d,
J = 10.3 Hz, H-9), 2.85–2.87 (2H, m), 2.86 (1H, d, J = 11.5 Hz), 3.19 (1H, d,
J = 9.8 Hz, H-18a), 3.29 (3H, s, OMe), 3.31 (1H, d, J = 9.8 Hz, H-18b), 4.00
(1H, s), 4.65-4.69 (2H, m, H-12 and H-13), 4.75 (1H, d, J = 10.3 Hz, H-8),
7.26–7.37 (5H, m, aromatic); 13C NMR (100 MHz, CDCl3) δ 12.3, 14.1, 18.4,
22.3, 24.1, 26.5, 37.2, 49.9, 51.0, 51.7, 56.5, 59.5, 61.7, 62.4, 76.0, 79.4, 80.2,
111.5, 127.7, 128.2, 128.3, 140.3, 216.1, 217.4; HRMS (ESI) calcd for
C27H37NO6Na [M+Na]+ 494.2513, found 494.2497.
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CONFLICT OF INTEREST
The authors declare no conflict of interest.
The Journal of Antibiotics

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K Minagawa et al
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