Stereocontrolled synthesis of the C1-C7 fragment of enigmazole a

Article abstract of DOI:10.3987/COM-13-12905

An enantio- and stereoselective synthesis of the C1-C7 fragment of enigmazole A is described. The three asymmetric centers of the molecule were constructed efficiently by using Evans chiral auxiliary protocol.

Full text of DOI:10.3987/COM-13-12905

HETEROCYCLES, Vol. 89, No. 2, 2014
515
HETEROCYCLES, Vol. 89, No. 2, 2014, pp. 515 - 522. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 2nd December, 2013, Accepted, 17th December, 2013, Published online, 18th December, 2013
DOI: 10.3987/COM-13-12905
STEREOCONTROLLED SYNTHESIS OF THE C1-C7 FRAGMENT OF
ENIGMAZOLE A
Takayuki Kishi, Yuka Fujisawa, Hiroyoshi Takamura, and Isao Kadota*
Department of Chemistry, Graduate School of Natural Science and Technology,
Okayama University, 3-1-1 Tsushimanaka, Kitaku, Okayama 700-8530, Japan
e-mail: kadota-i@okayama-u.ac.jp
Abstract – An enantio- and stereoselective synthesis of the C1-C7 fragment of
enigmazole A is described. The three asymmetric centers of the molecule were
constructed efficiently by using Evans chiral auxiliary protocol.
Enigmazole A (1), an 18-membered macrolide, was isolated from the sponge Cinachyrella enigmatica as
the first family of marine phosphomacrolide in 2010.1 This compound shows potent cytotoxicity against
the 60 human tumor cell lines.
The unique structural features, including a phosphate, an
exomethylenetetrahydropyran, and a 2,4-disubstituted oxazole ring make the molecule an attractive
synthetic target.2 The first total synthesis of 1 was reported by Molinski and co-workers in 2010.3 In
this paper, we wish to describe the stereocontrolled synthesis of the C1-C7 fragment of enigmazole A (1)
as a part of total synthetic study of 1.
O
HO
P
O
O
OMe
Me
HO
24
Me
1
O
7
N
O
Me Me
17
O
OH
1
enigmazole A ( )
Figure 1. Structure of enigmazole (1)
Stereoselective aldol reaction of chiral oxazolidinone 2 and aldehyde 3 was carried out with
n-Bu2BOTf/Et3N to furnish the known compound 44 as a single stereoisomer in 97% yield.5 Protection

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HETEROCYCLES, Vol. 89, No. 2, 2014
of the hydroxy group of 4 with MOMCl/i-Pr2NEt/DMAP gave 5 in 98% yield. Reductive removal of
the chiral auxiliary of 5 with LiBH4 afforded alcohol 6 in 91% yield.6 Oxidation of 6 with
TEMPO/PhI(OAc)2,7 followed by the Wittig reaction of the resulting aldehyde with Ph3P=CHCO2Me
provided ,-unsaturated ester 7 in 88% overall yield. Hydrogenation of 7 with H2/Pd-C gave 8 in 96%
yield. Deprotection of the MOM group of the ester 8 and subsequent lactonization were performed with
a catalytic amount of CSA in refluxing benzene to furnish lactone 9 in 84% yield. As an initial attempt,
we tested the substrate-controlled installation of the C2 methyl group at this stage. Thus, the lactone 9
was treated with KHMDS in the presence of DMPU followed by MeI. Unfortunately, the product was
obtained as a 5:1 inseparable mixture of desired compound 10 and its diastereoisomer 11 in 37% yield.
Since several attempts to improve this process resulted in failure, we next examined an alternative
approach, the auxiliary-controlled alkylation.
O
O
O
O
CHO
OH
O
MOMO
O
BnO
b
c
Me
3
N
O
BnO
N
O
BnO
N
O
Me
Me
a
d
Bn
Bn
Bn
2
4
5
MOMO
MOMO
MOMO
e
f
CO2Me
CO2Me
BnO
OH
BnO
BnO
O
Me
O
Me
Me
6
7
8
O
2
Me
Me
O
O
O
g
2
+
BnO
BnO
BnO
Me
Me
Me
9
10
11
Scheme 1. Reagents and conditions: (a) n-Bu2BOTf, Et3N, CH2Cl2, -78 ºC, then 3, -78 to 0 ºC, 97%; (b)
MOMCl, i-Pr2NEt, DMAP, CH2Cl2, 30 ºC, 98%; (c) LiBH4, Et2O/H2O, 0 ºC to rt, 91%; (d) (i) TEMPO,
PhI(OAc)2, CH2Cl2, rt; (ii) Ph3P=CHCO2Me, benzene, 80 ºC, 88% (2 steps); (e) H2, Pd-C, THF, rt, 96%;
(f) CSA, benzene, reflux, 84%; (g) KHMDS, DMPU, THF, -78 ºC, then MeI, -78 ºC to rt, 37% (10:11 =
ca. 5:1).
Saponification of the ester 8 with LiOH, followed by treatment of the resulting carboxylic acid with
PivCl/Et3N and (S)-4-benzyl-2-oxazolidinone/LiCl afforded the corresponding oxazolidinone 12 in 97%
overall yield.8 Stereoselective alkylation of 12 was performed with NaHMDS and MeI to provide 13 as
a single stereoisomer in 86% yield.9 The stereochemistry at the C2 position was unambiguously

HETEROCYCLES, Vol. 89, No. 2, 2014
517
1
confirmed by H NMR analysis and NOE experiments on the lactone 10, prepared from 13 by using
LiOH·H2O in THF/H2O followed by treatment with 4M HCl in 65% yield, as shown in Figure 2.
Removal of the chiral auxiliary of 13 with LiBH4, and protection of the resulting primary alcohol 14 with
TBSCl/imidazole gave 15 in 97% overall yield. Debenzylation of 15 was carried out with H2/Pd-C to
furnish the C1-C7 fragment 16 in 98% yield.
O
O
OMOM
O
OMOM
O
a
c
b
BnO
N
O
BnO
N
O
8
Me
Me Me
Bn
Bn
12
13
OMOM
OMOM
OMOM
7
1
d
e
BnO
OH
BnO
OTBS
HO
OTBS
Me Me
14
Me Me
15
Me Me
16
Scheme 2. Reagents and conditions: (a) (i) LiOH·H2O, THF/H2O, 50 ºC; (ii) PivCl, Et3N, THF, -20 ºC,
then (S)-4-benzyl-2-oxazolidinone, LiCl, -20 ºC to rt, 97% (2 steps); (b) NaHMDS, THF, -78 ºC, then
MeI, -78 ºC, 86%; (c) LiBH4, Et2O/H2O, 0 ºC to rt; (d) TBSCl, imidazole, CH2Cl2, rt, 97% (2 steps); (e)
H2, Pd-C, THF, rt, 98%.
H
O
O
BnO
Me
H
Me
H
10
NOE
Figure 2. Observed NOE is shown by an arrow.
In conclusion, we have achieved the enantio- and stereoselective synthesis of the C1-C7 fragment of
enigmazole A (1) via the Evans stereoselective aldol and alkylation methodologies. Further studies
towards the the total synthesis of 1 are in progress in our laboratory.
EXPERIMENTAL
All reactions involving air- and/or moisture-sensitive materials were carried out under argon with dry
solvents purchased from Wako or Kanto chemicals. On workup, extracts were dried over MgSO4.
Reactions were monitored by thin-layer chromatography carried out on 0.25 mm Merck silica gel plates

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HETEROCYCLES, Vol. 89, No. 2, 2014
(60F-254). Column chromatography was performed with Kanto Chemical silica gel 60N (40-100 mesh,
spherical, neutral). Yields refer to chromatographically and spectroscopically homogeneous materials.
The NMR spectra were recorded on JEOL JNM-AL400 (1H, 13C NMR). Chemical shifts were reported
in delta units () relative to chloroform (7.24). IR spectra were recorded on a JASCO FT/IR-460 Plus.
Optical rotations were measured by a JASCO DIP-1000. Mass spectra were measured by Micromass
LCT (ESI TOF-MS).
MOM Ether 5. To a solution of 44 (103 mg, 0.26 mmol) in CH2Cl2 (2.6 mL) were added DIPEA (0.44
mL, 2.6 mmol), MOMCl (0.17 mL, 2.2 mmol), and DMAP (32 mg, 0.26 mmol). After stirring for 34 h
at room temperature, the reaction mixture was quenched with saturated aqueous NaHCO3 solution, and
extracted with CH2Cl2. The organic layer was washed with brine. Concentration and column
chromatography (hexane/EtOAc, 5:1) gave 5 (112 mg, 98%): yellow oil; Rf = 0.61 (hexane/EtOAc, 1:1);
[]23D -83.2 (c 0.92, CHCl3); IR (neat) 2932, 1779, 1697, 1210, 1105 cm-1; 1H NMR (400 MHz, CDCl3) 
7.32-7.17 (m, 10H), 4.59 (s, 2H), 4.58-4.52 (m, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H),
4.08-3.91 (m, 4H), 3.61-3.52 (m, 2H), 3.31 (s, 3H), 3.26 (dd, J = 13.0, 3.2 Hz, 1H), 2.73 (dd, J = 13.1, 9.7
Hz, 1H), 2.01-1.85 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)  174.8, 153.0, 138.4,
135.3, 129.3, 128.8, 128.2, 127.6, 127.4, 127.2, 96.7, 76.9, 72.9, 66.7, 66.0, 56.0, 55.7, 41.7, 37.9, 32.7,
12.8; HRMS (ESI TOF) calcd for C25H31NO6Na (M+Na)+ 464.2049, found 464.2045.
Alcohol 6. To a solution of 5 (247 mg, 0.56 mmol) in ether (6 mL) and H2O (30 µL) at 0 °C was added
LiBH4 (39 mg, 1.8 mmol). After stirring for 70 min at room temperature, the reaction mixture was
quenched with saturated aqueous NH4Cl solution at 0 °C. The mixture was extracted with ether, and the
organic layer was washed with brine. Concentration and column chromatography (hexane/EtOAc, 5:1)
gave 6 (136 mg, 91%): colorless oil; Rf = 0.31 (hexane/EtOAc, 1:1); []23 +22.1 (c 1.37, CHCl3); IR
D
(neat) 3434, 3030, 1496, 1208, 1152 cm-1; 1H NMR (400 MHz, CDCl3)  7.28-7.17 (m, 5H), 4.56 (d, J =
6.8 Hz, 1H), 4.53 (d, J = 6.8 Hz, 1H), 4.41 (s, 2H), 3.84-3.80 (m, 1H), 3.56-3.41 (m, 4H), 3.30 (s, 3H),
2.62 (dd, J = 7.3, 4.9 Hz, 1H), 1.90-1.67 (m, 2 H), 0.76 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
 138.2, 128.3, 127.6, 127.5, 97.1, 77.2, 73.1, 67.0, 65.2, 55.9, 38.7, 31.9, 11.3; HRMS (ESI TOF) calcd
for C15H24O4Na (M+Na)+ 291.1572, found 291.1579.
,-Unsaturated Ester 7. To a solution of 6 (472 mg, 1.76 mmol) in CH2Cl2 (17.6 mL) at room
temperature were added PhI(OAc)2 (1.42 g, 4.41 mmol) and TEMPO (45 mg, 0.29 mmol). After stirring
for 4.5 h at room temperature, the reaction mixture was quenched with saturated aqueous Na2S2O3
solution, and extracted with EtOAc.
The organic layer was washed with saturated NaHCO3, water, and
brine. Concentration gave the corresponding aldehyde which was used for the next reaction directly.
To a solution of the crude aldehyde obtained in benzene (9 mL) was added Ph3P=CHCO2Me (380 mg,

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1.14 mmol), and the mixture was refluxed for 6.5 h. Concentration and column chromatography
(hexane/EtOAc, 7.5:1) gave 7 (178 mg, 88%): colorless oil; Rf = 0.23 (hexane/EtOAc, 4:1); []24 -66.9
D
1
(c 1.12, CHCl3); IR (neat) 2950, 1724, 1655, 1273, 1103 cm-1; H NMR (400 MHz, CDCl3)  7.34-7.24
(m, 5H), 7.03 (dd, J = 15.9, 7.1 Hz, 1H), 5.82 (dd, J = 15.9, 1.5 Hz, 1H), 4.61 (s, 2H), 4.47 (s, 2H), 3.74
(s, 3H), 3.71-3.67 (m, 1H), 3.54 (dd, J = 7.3, 5.3 Hz, 2H), 3.34 (s, 3H), 2.64 (dd, J = 12.3, 5.3 Hz, 1H),
13
1.84-1.76 (m, 1H), 1.71-1.62(m, 1H), 0.94 (d, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3)  166.8,
150.7, 138.3, 128.3, 127.6, 127.5, 121.1, 96.6, 78.3, 73.0, 66.8, 55.8, 51.4, 40.2, 31.8, 14.6; HRMS (ESI
TOF) calcd for C18H26O5Na (M+Na)+ 345.1678, found 345.1681.
Ester 8. A mixture of 7 (2.55 g, 7.90 mmol) and a catalytic amount of 10% Pd-C in THF (80 mL) was
stirred for 1 h under H2 atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The
residue was purified by column chromatography (hexane/EtOAc, 4:1) to give 8 (3.39 g, 96%): colorless
oil; Rf = 0.23 (hexane/EtOAc, 4:1); []24D -24.4 (c 0.40, CHCl3); IR (neat) 3029, 2951, 1737, 1496, 1152
cm-1; 1H NMR (400 MHz, CDCl3)  7.34-7.26 (m, 5H), 4.60 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H), 3.62-3.58
(m, 1H), 3.55-3.51 (m, 2H), 3.33 (s, 3H), 2.41-2.25 (m, 2H), 1.91-1.82 (m, 1H), 1.79-1.65 (m, 3H),
13
1.48-1.39 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3)  174.1, 138.4, 128.3, 127.6,
127.5, 96.3, 78.7, 73.0, 67.3, 55.7, 51.5, 36.0, 32.4, 31.2, 27.4, 14.8; HRMS (ESI TOF) calcd for
C18H28O5Na (M+Na)+ 347.1834, found 347.1835.
Oxazolidinone 12. To a solution of 8 (3.39 g, 10.5 mmol) in THF (18 mL) and H2O (6 mL) was added
LiOH·H2O (660 mg, 16 mmol). After stirring for 2.0 h at 50 °C, the reaction mixture was cooled to 0 °C,
and acidified with 1M HCl. The mixture was extracted with EtOAc, and the organic layer was washed
with brine. Concentration gave the corresponding carboxylic acid which was used for the next reaction
directly.
To a solution of the crude carboxylic acid obtained in THF (100 mL) at -20 °C were added Et3N (4.4 mL,
31.5 mmol) and PivCl (1.4 mL, 11.6 mmol). After stirring for 2 h at the same temperature, LiCl (670
mg, 15.8 mmol) and (S)-4-benzyl-2-oxazolidinone (1.86 g, 10.5 mmol) were added, and the resulting
mixture was stirred for an additional 4 h at room temperature. The reaction mixture was quenched with
saturated aqueous NH4Cl solution at 0 °C, and extracted with EtOAc. The organic layer was washed
with brine. Concentration and column chromatography (hexane/EtOAc, 4:1 to 3:1) gave 12 (4.76 g,
97% from 8): colorless oil; Rf = 0.35 (hexane/EtOAc, 2:1); []22 +8.7 (c 2.05, CHCl3); IR (neat) 3028,
D
1782, 1698, 1212, 1151 cm-1; 1H NMR (400 MHz, CDCl3)  7.38-7.22 (m, 10H), 4.71-4.65 (m, 1H), 4.69
(d, J = 6.8 Hz, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4.54 (s, 2H), 4.23-4.16 (m, 2H), 4.23-4.16 (m, 2H),
3.70-3.66 (m, 1H), 3.62-3.59 (m, 2H), 3.40 (s, 3H), 3.32 (dd, J = 13.1, 3.2 Hz, 1H), 3.04-2.99 (m, 2H),
2.79 (dd, J = 13.3, 9.6 Hz, 1H), 2.04-1.95 (m, 1H), 1.87-1.81 (m, 3H), 1.59-1.48 (m, 1H), 0.97 (d, J = 6.8

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HETEROCYCLES, Vol. 89, No. 2, 2014
13
Hz, 3H); C NMR (100 MHz, CDCl3)  173.2, 153.3, 138.4, 135.2, 129.3, 128.9, 128.3, 127.6, 127.4,
127.2, 96.4, 78.8, 73.0, 67.3, 66.1, 55.7, 55.2, 38.0, 36.0, 33.8, 31.2, 26.8, 15.0; HRMS (ESI TOF) calcd
for C27H35NO6Na (M+Na)+ 492.2362, found 492.2361.
Synthesis of 13. To a solution of 12 (122 mg, 0.26 mmol) in THF (1.0 mL) at -78 °C was added
NaHMDS (1 M in THF, 0.4 mL, 0.4 mmol), and the mixture was stirred for 30 min at the same
temperature. To the resulting mixture, MeI (48.6 µL, 0.780 mmol) was added, and stirring was
continued for 3.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and
extracted with EtOAc. The organic layer was washed with brine. Concentration and column
chromatography (hexane/EtOAc, 4:1) gave 13 (108 mg, 86%): colorless oil; Rf = 0.56 (hexane/EtOAc,
1
1:1); []24 +20.1 (c 1.62, CHCl3); IR (neat) 3029, 2931, 1779, 1697, 1209 cm-1; H NMR (400 MHz,
D
CDCl3)  7.38-7.23 (m, 10H), 4.68-4.63 (m, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.52
(s, 2H), 4.16 (d, J = 5.1 Hz, 2H), 3.92-3.83 (m, 1H), 3.63-3.52 (m, 3H), 3.37 (s, 3H), 3.28 (dd, J = 13.4,
9.5 Hz, 1H), 2.79 (dd, J = 13.4, 9.5 Hz, 1H), 1.91-1.72 (m, 3H), 1.65 (t, J = 7.1 Hz, 2H) 1.23 (d, J = 6.8
13
Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3)  177.3, 152.8, 138.4, 135.3, 129.3,
128.8, 128.2, 127.6, 127.4, 127.2, 96.4, 79.1, 72.9, 65.9, 55.7, 67.3, 55.4, 37.9, 35.3, 33.8, 31.0, 17.2,
15.2; HRMS (ESI TOF) calcd for C28H37NO6Na (M+Na)+ 506.2519, found 506.2516.
Lactone 10. To a mixture of 13 (7.1 mg, 15 mol) in THF (0.5 mL) and H2O (0.5 mL) at 0 °C was
added LiOH·H2O (2.5 mg, 60 mol), and the mixture was stirred for 1.5 h at room temperature. The
reaction mixture was cooled to 0 °C and acidified by adding 4M HCl. After strring for 15 h at 80 °C, the
mixture was diluted with ether, then washed with water and brine. Concentration and column
chromatography (hexane/EtOAc, 4:1) gave 10 (108 mg, 86%): colorless oil; Rf = 0.59 (hexane/EtOAc,
1
1:1); IR (neat) 1731, 1198, 1100 cm-1; H NMR (400 MHz, C6D6)  7.29-7.24 (m, 2 H), 7.22-7.16 (m, 2
H), 7.12-7.06 (m, 1H), 4.30 (d, J = 11.7 Hz, 1H), 4.25 (d, J = 11.7 Hz, 1H), 4.23-4.18 (m, 1H), 3.48 (ddd,
J = 9.0, 9.0, 5.0 Hz, 1H), 3.38-3.30 (m, 1H), 2.25-2.12 (m, 1H), 1.71-1.60 (m, 1H), 1.52-1.41 (m, 1H),
1.37-1.26 (m, 1H), 1.24-1.15 (m, 1H), 1.10 (d, J = 7.1 Hz, 3H), 1.08-1.01 (m, 1H), 0.53 (d, J = 7.3 Hz,
3H); HRMS (ESI TOF) calcd for C16H22O3Na (M+Na)+ 285.1467, found 285.1467.
TBS Ether 15. To a mixture of 13 (178 mg, 37 μmol) in ether (0.4 mL) and H2O (2 µL) at 0 °C was
added LiBH4 (2.4 mg, 0.11 mmol). After stirring for 1 h at room temperature, the reaction mixture was
quenched with saturated aqueous NH4Cl solution at 0 °C, and extracted with ether. The organic layer
was washed with brine. Concentration and short column chromatography gave the crude alcohol 14
which was used for the next reaction without further purification.
To a mixture of the alcohol 14 obtained above in CH2Cl2 (0.4 mL) at room temperature were added
imidazole (7.5 mg, 0.11 mmol) and TBSCl (11 mg, 70 µmol). After stirring for 2 h, the reaction mixture

HETEROCYCLES, Vol. 89, No. 2, 2014
521
was quenched with MeOH, diluted with ether, then washed with water and brine. Concentration and
column chromatography (hexane/EtOAc, 4:1) gave 15 (15 mg, 97% from 13): colorless oil; Rf = 0.53
1
(hexane/EtOAc, 4:1); []26 -35.7 (c 1.24, CHCl3); IR (neat) 2955, 2928, 1208, 1152, 1094 cm-1; H
D
NMR (400 MHz, CDCl3)  7.32-7.25 (m, 5H), 4.62 (d, J = 6.8 Hz, 1H), 4.60 (d, J = 6.8 Hz, 1H), 4.48 (s,
2H), 3.57-3.52 (m, 3H), 3.41-3.32 (m, 2H), 3.33 (s, 3H), 1.84-1.59 (m, 4H), 1.21-1.12 (m, 1H), 1.10-1.02
13
(m, 1H), 0.87 (s, 9H), 0.84 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H), 0.02 (s, 6H); C NMR (100
MHz, CDCl3)  128.3, 127.6, 127.4, 96.4, 79.8, 73.0, 69.2, 67.5, 55.7, 35.2, 33.3, 31.3, 26.0, 18.4, 16.2,
15.0, -5.2; HRMS (ESI TOF) calcd for C24H44O4SiNa (M+Na)+ 447.2906, found 447.2909.
Alcohol 16. A mixture of 15 (36 mg, 84 µmol) and a catalytic amount of 10% Pd(OH)2-C in THF (0.8
mL) was stirred for 2 h under H2 atmosphere. The catalyst was filtered off, and the filtrate was
concentrated. The residue was purified by column chromatography (hexane/EtOAc, 4:1) to give 16 (28
mg, 98%): colorless oil; Rf = 0.28 (hexane/EtOAc, 2:1); []26 -79.9 (c 1.29, CHCl3); IR (neat) 3433,
D
2955, 2857, 1215, 1097 cm-1; 1H NMR (400 MHz, CDCl3)  4.68 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.8 Hz,
1H), 3.81-3.68 (m, 2H), 3.64-3.57 (m, 1H), 3.40 (s, 3H), 3.37 (dd, J = 6.3, 2.7 Hz, 2H), 2.39 (s, 1H),
1.85-1.74 (m, 1H), 1.72-1.60 (m, 3H), 1.27-1.19 (m, 1H), 1.17-1.08 (m, 1H), 0.88 (s, 9H), 0.85 (d, J = 6.8
13
Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H), 0.02 (s, 6 H); C NMR (100 MHz, CDCl3)  96.7, 81.2, 69.2, 60.3,
56.0, 35.1, 33.6, 33.3, 33.2, 26.0, 18.4, 16.1, 15.2, -5.2; HRMS (ESI TOF) calcd for C17H38O4SiNa
(M+Na)+ 357.2437, found 357.2435.
ACKNOWLEDGEMENTS
This work was financially supported by the Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
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