Synthesis of (2RS,8R,10R)-YM-193221 and an improved approach to tyroscherin, bioactive natural compounds from pseudallescheria sp

Article abstract of DOI:10.1271/bbb.100361

Short-step syntheses of (2RS,8R,10R)-YM-193221 (1) and tyroscherin (2), which are biologically active compounds isolated from Pseudallescheria sp., were accomplished in six and eight steps from L-tyrosine. The relative stereochemistry of natural YM-193221 was determined to be 8R*,10*.

Full text of DOI:10.1271/bbb.100361

Biosci. Biotechnol. Biochem., 74 (10), 2056–2059, 2010
Synthesis of (2RS,8R,10R)-YM-193221 and an Improved Approach
to Tyroscherin, Bioactive Natural Compounds from Pseudallescheria sp.
y
2;
Ryo KATSUTA,1;2 Arata YAJIMA,1 Ken ISHIGAMI,2 Tomoo NUKADA,1 and Hidenori WATANABE
1Department of Applied Bio-Science, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku,
Tokyo 156-8502, Japan
2Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences,
The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Received May 12, 2010; Accepted July 1, 2010; Online Publication, October 7, 2010
[doi:10.1271/bbb.100361]
Short-step syntheses of (2RS,8R,10R)-YM-193221 (1)
and tyroscherin (2), which are biologically active
compounds isolated from Pseudallescheria sp., were
accomplished in six and eight steps from L-tyrosine. The
relative stereochemistry of natural YM-193221 was
determined to be 8RÃ,10RÃ.
29:9) were in good accordance with those of their
syn compounds. We therefore presumed the absolute
configuration of YM-193221 to be 2S,8R,10R and
commenced its synthesis.
In order to synthesize the (2S,8R,10R)-isomer (1)
most efficiently, we constructed the C-C bond between
C3 and C4 at a late stage of the synthesis. We did this by
selecting the coupling reaction of Weinreb amide 9 and
an organolithium reagent which could be generated from
iodide 6. The synthesis of 1 is shown in Scheme 1.
Enantiomerically pure aldehyde 36) was subjected to a
Wittig reaction with 3-hydroxypropyltriphenylphospho-
nium bromide (4). Although the Wittig reaction under
the usual conditions afforded an inseparable 1:1 mixture
of desired (E)- and undesired (Z)-olefins, Schlosser’s
conditions7) selectively gave (E)-olefin 5 via a trianion
intermediate in a moderate yield. Treating alcohol 5
with I2 and PPh3 afforded iodide 6, one of the coupling
units, in a good yield. On the other hand, L-tyrosine was
converted to the corresponding methyl ester, and
subsequent reductive dimethylation of the amino group
with aqueous formaldehyde and Pd–C afforded 7. After
protecting the phenolic hydroxy group with a TBS
group, resulting silyl ether was treated with MeNHO-
Key words: YM-193221; tyroscherin; total synthesis
Hayakawa et al. isolated tyroscherin (2) in 2004 from
the mycelia of Pseudallescheria sp. as a selective growth
inhibitor of IGF-1-dependent MCF-7 cells.1) Its analo-
gous compound, YM-193221 (1), was also isolated by
Kamigiri et al. in the same year from the fermentation
broth of Pseudallescheria elipsoidea as an antifungal
antibiotic.2) Both compounds contain a 2-amino-1-(4-
hydroxyphenyl)-8,10-dimethylundec-6-ene framework
with a hydroxy- or oxo-group at the C3 position. We
started the syntheses of these compounds with the
objective of further research into their bioactivity and
structure-activity relationship. We have already reported
our previous studies to revise the stereochemistry of
tyroscherin by enantioselective syntheses of its stereo-
isomers, and to evaluate the biological activities.3,4)
Maier et al. have also recently reported the synthesis of
tyroscherin by using asymmetric aldol condensation and
Curtius rearrangement as the key steps.5) We report here
the short-step synthesis of (2RS,8R,10R)-YM-193221 (1)
and the second-generation synthesis of tyroscherin (2).
.
Me HCl and i-PrMgBr to give Weinreb amide 9. This
amide was reacted with an organo-lithium reagent
generated from iodide 6 to give desired ketone 10 in a
34% yield (66% based on recovered 9). However, the C2
position of 10 was prone to epimerization, and amino-
ketone 10 was obtained only as an inseparable 1:1
mixture of diastereomers at C2 under any reaction
conditions. The total synthesis of (2RS,8R,10R)-YM-
193221 (1) was accomplished after deprotection in a
48% yield over six steps.8) The relative stereochemistry
of the natural product was clearly indicated to be 8,10-
syn, as we expected, by the similarity of spectroscopic
data between the synthesized mixture and the natural
product.2) However, the differences between both syn-
thesized diastereomers in their 1H- and 13C-NMR
spectral data (ꢀH2 ¼ 3:33 and 3.34 ppm, ꢀH7 ¼ 5:15
and 5.17 ppm, and ꢀC4 ¼ 42:6 and 42.7 ppm) were too
small and prevented us from providing any further
information about the stereochemistry of the natural
product. Reisolation of the natural product would be
Results and Discussion
Synthesis of (2RS,8R,10R)-YM-193221 (1)
The structure of YM-193221 had been proposed as 1
from the results of a spectroscopic analysis, but the
stereochemistry at the three chiral centers remained
unknown.2) Since YM-193221 and tyroscherin are
similar in their structural features and biological origins,
we assumed that the stereochemistry of both compounds
would be the same.1,3,4) In addition, Organ et al. have
reported the difference in 13C-NMR chemical shifts
between the diastereomeric 3,5-dimethylhept-1-enyl
chains,6) and the quoted chemical shifts of natural
YM-193221 (ꢀC8{Me ¼ 21:6, ꢀC10{Me ¼ 19:0, and ꢀC11
¼
y
To whom correspondence should be addressed. Fax: +81-3-5841-8019; E-mail: ashuten@mail.ecc.u-tokyo.ac.jp
Abbreviations: IGF, insulin-like growth factor; TBS, tert-butyldimethylsilyl; DMF, N,N-dimethylformamide; THF, tetrahydrofuran; DIBAL,
diisobutylaluminum hydride; TFA, trifluoroacetic acid; MOM, methoxymethyl; Boc, tert-butoxycarbonyl

Syntheses of YM-193221 and Tyroscherin
2057
Fig. 1. Structures of YM-193221 (1) and Tyroscherin (2).
Scheme 1. Synthesis of (2RS,8R,10R)-YM-193221 (1).
Reagents: (a) 4, PhLi, LiBr then 3, PhLi then t-BuOH, t-BuOK, THF, 47%, (E)-only; (b) I2, PPh3, imidazole, CH2Cl2, 84%; (c) SOCl2,
.
MeOH; (d) H2, Pd–C, aq. HCHO, MeOH, 89% in 2 steps; (e) TBSCl, imidazole, DMF, 97%; (f) MeNHOMe HCl, i-PrMgBr, THF, 92%; (g) 6, t-
BuLi, ether, then 9, 36%, 66% based on recovered 9; (h) conc. HCl, MeOH, THF, 91%.
Scheme 2. Synthesis of Tyroscherin (2).
Reagents: (a) DIBAL, ether; (b) 6, t-BuLi, ether, then 12, 32% (single diastereomer), 54% based on recovered 12; (c) TFA, MeOH, THF, H2O,
quant.
necessary to determine the stereochemistry at the C2
position.
steps and determined its relative stereochemistry to be
8,10-syn. We also achieved an improved short-step
synthesis of tyroscherin (2) in eight steps and 32%
overall yield which is five steps less than required for
our previous synthesis. Our work is still underway to
determine the absolute configuration of natural YM-
193221 by improving some steps in the synthesis.
Synthesis of tyroscherin (2)
Having succeeded in the short-step synthesis of 1, our
next objective was an improved short-step synthesis of
antitumorial tyroscherin (2) by using a similar approach.
The synthesis of 2 is shown in Scheme 2. Weinreb
amide 11,3,4) which had been prepared from L-tyrosine in
an 82% yield over five steps, was subjected to reduction
in the same manner as already reported to give aldehyde
12. This was stereoselectively reacted under Felkin-Anh
control with 5,6-dimethylnon-3-enyllithium to give 2,3-
anti-amino alcohol 13 in a 32% yield (54% based on
recovered 12) in two steps. After deprotecting with
trifluoroacetic acid and recrystallization, the short-step
synthesis of tyroscherin was achieved in a 32% yield
over eight steps from L-tyrosine. The overall yield and
number of steps were improved from our previous
synthesis of tyroscherin (19% over 13 steps).
Experimental
Optical rotation data were recorded with a Jasco P-2100 polar-
imeter, IR spectra were measured with a Jasco FT/IR-4100 spectro-
photometer, and 1H- and 13C-NMR data were recorded with a Jeol
JNM ECS400 spectrometer. Chemical shift (ꢀ) data are referenced to
the residual solvent peak of the internal standard (CDCl3: ꢀH ¼ 7:26,
ꢀc ¼ 77:0; CD3OD: ꢀH ¼ 3:30, ꢀC ¼ 49:0). Mass spectra were re-
corded with a Jeol JMS SX102 instrument. Column chromatography
was performed with Wakogel C-200 (0.075–0.150 mm) or Wakogel
FC-40 (0.020–0.040 mm).
(3E,5R,7R)-5,7-Dimethylnon-3-en-1-ol (5). To a mixture of anhy-
drous lithium bromide (487 mg, 5.61 mmol), 3-hydroxypropyltriphe-
nylphosphonium bromide (1.07 g, 2.67 mmol) and THF (35 ml) was
In summary, we succeeded in the first total synthesis
of (2RS,8R,10R)-YM-193221 (1) in a 48% yield over six

2058
R. KATSUTA et al.
27
added a solution of phenyllithium in ether/cyclohexane (ca. 3/1,
1.15 M, 4.76 ml, 5.47 mmol) at ꢀ78 ꢁC under an argon atmosphere. The
reaction mixture was stirred for 15 min at the same temperature and for
a further 15 min at room temperature. After cooling to ꢀ78 ꢁC, to the
resulting orange mixture were successively added dropwise a solution
of aldehyde 3 (342 mg, 2.67 mmol) in THF (2 ml) and a solution of
phenyllithium (1.15 M, 2.43 ml, 2.79 mmol). The reaction mixture was
stirred for 15 min at ꢀ78 ꢁC and then for 15 min at room temperature.
The cherry red solution was cooled to ꢀ78 ꢁC, before successively
adding a solution of t-BuOH (281 ml, 2.94 mmol) in THF (3 ml) and
t-BuOK (360 mg, 3.21 mmol). After stirring for 15 min at room
temperature, the reaction mixture was poured into a saturated aqueous
ammonium chloride solution and extracted with ethyl acetate. The
organic layer was successively washed with water and brine, and dried
over anhydrous magnesium sulfate. After concentrating in vacuo, the
residue was subjected to flash chromatography over silica gel. Elution
with hexane/ethyl acetate (20:1) gave 4 (212 mg, 47%) as a colorless
gave 8 (3.26 g, 97%) as a colorless oil. ½ꢁꢂD þ30 (c 1.0, MeOH). IR
(film) ꢂ cmꢀ1: 2953, 1735, 1605, 1510, 1261, 1168. 1H-NMR
(400 MHz, CDCl3) ꢀ: 0.17 (6H, s), 0.96 (9H, s), 2.37 (6H, s), 2.87
(1H, dd, J ¼ 13:1, 5.6 Hz), 2.97 (1H, dd, J ¼ 13:1, 9.9 Hz), 3.35 (1H,
dd, J ¼ 9:9, 5.6 Hz), 3.57 (3H, s), 6.74 (2H, d, J ¼ 8:4 Hz), 7.03 (2H,
d, J ¼ 8:4 Hz). ESI-TOFMS m=z: calcd. for
C
18H31NNaO3Siþ
½M þ Naꢂþ, 360.1965; found, 360.1953.
(R)-3-[4-(tert-Butyldimethylsilyloxy)phenyl]-2-(N,N-dimethylamino)-
N-methoxy-N-methylpropanamide (9). To a mixture of ester 8 (1.62 g,
4.80 mmol) and N,O-dimethylhydroxylamine hydrochloride (936 mg,
9.60 mmol) in THF (50 ml) was added a solution of isopropylmagne-
sium bromide in THF (0.67 M, 28.7 ml, 19.2 mmol) at ꢀ20 ꢁC. After
stirring for 1 h at the same temperature, the reaction mixture was
warmed to room temperature, poured into
a saturated aqueous
ammonium chloride solution and extracted with ethyl acetate. The
organic layer was successively washed with water and brine, dried over
anhydrous magnesium sulfate and concentrated in vacuo. The residue
was subjected to chromatography over silica gel. Elution with CHCl3/
24
oil. ½ꢁꢂD ꢀ29 (c 1.0, CHCl3). IR (film) ꢂ cmꢀ1: 3340, 2960, 1462,
1242, 1048. 1H-NMR (400 MHz, CD3OD) ꢀ: 0.83 (3H, d, J ¼ 6:4 Hz),
0.86 (3H, t, J ¼ 7:5 Hz), 0.94 (3H, d, J ¼ 6:8 Hz), 1.00 (1H, ddd,
J ¼ 13:5, 9.0, 5.0 Hz), 1.06–1.40 (4H, m), 2.12–2.37 (3H, m), 3.53
(2H, t, J ¼ 7:8 Hz), 5.28 (1H, dd, J ¼ 15:1, 7.3 Hz), 5.38 (1H, dt,
J ¼ 15:1, 6.7 Hz). 13C-NMR (100 MHz, CDCl3) ꢀ: 11.3, 19.0, 21.7,
29.9, 31.9, 34.5, 36.0, 44.2, 62.0, 123.8, 140.5. Anal. Found: C, 77.51;
H, 12.73%. Calcd. for C11H22O: C, 77.58; H, 13.02%.
24
MeOH (30:1) gave 9 (1.61 g, 92%) as a colorless oil. ½ꢁꢂD þ29:7
(c 1.0, CDCl3). IR (film) ꢂ cmꢀ1: 2933, 1660, 1510, 1260, 1171.
1H-NMR (400 MHz, CDCl3) ꢀ: 0.14 (6H, s), 0.96 (9H, s), 2.40 (6H, s),
2.79 (1H, dd, J ¼ 12:8, 3.6 Hz), 3.08 (3H, s), 3.11 (1H, m), 3.15 (3H,
s), 3.86 (1H, m), 6.72 (2H, d, J ¼ 8:4 Hz), 7.06 (2H, d, J ¼ 8:4 Hz).
ESI-TOFMS m=z: calcd. for C19H34N2NaO3Siþ ½M þ Naꢂþ, 389.2231;
found, 389.2259.
(3E,5R,7R)-1-Iodo-5,7-dimethylnon-3-ene (6). To a mixture of
(121 mg, 0.71 mmol), triphenylphosphine (281 mg,
alcohol
5
(2RS,6E,8R,10R)-1-[4-(tert-Butyldimethylsilyloxy)phenyl]-2-(N,N-
dimethylamino)-8,10-dimethyldodec-6-en-3-one (10). Under an argon
atmosphere, to a solution of iodide 6 (60 mg, 0.21 mmol) in ether (1 ml)
was added a solution of tert-butyl-lithium in pentane (1.76 M, 286 ml,
0.50 mmol) at ꢀ78 ꢁC, and the reaction mixture was stirred for 15 min
at the same temperature. The resulting solution of the lithium reagent
was added slowly to a solution of Weinreb amide 9 (78 mg, 0.21 mmol)
in ether (1 ml) at ꢀ78 ꢁC. The reaction mixture was then allowed to
warm to room temperature. After stirring for 1 h, the reaction mixture
was poured into a saturated ammonium chloride solution and extracted
with ethyl acetate. The organic layer was successivelywashed with 1 N
HCl, a saturated sodium bicarbonate solution and brine, and dried over
anhydrous magnesium sulfate. After concentrating, the resulting
residue was chromatographed over silica gel. Elution with toluene/
acetone (20:1) gave 10 (35 mg, 36%, 66% based on recovery) as a
1.07 mmol), imidazole (111 mg, 1.63 mmol) and CH2Cl2 (10 ml) were
added iodine beads (272 mg, 1.07 mmol) portionwise at 0 ꢁC. After
stirring for 2.5 h at room temperature, MeOH (1 ml) was added to the
reaction mixture, and the mixture was concentrated in vacuo. The
residue was subjected to flash chromatography over silica gel. Elution
25
with hexane gave 6 (167 mg, 84%) as a colorless oil. ½ꢁꢂD ꢀ24 (c 1.0,
CHCl3). IR (film) ꢂ cmꢀ1: 2959, 1457, 1241, 1168. 1H-NMR (400
MHz, CDCl3) ꢀ: 0.82 (3H, d, J ¼ 6:4 Hz), 0.85 (3H, t, J ¼ 6:4 Hz),
0.95 (3H, d, J ¼ 6:8 Hz), 1.01 (1H, ddd, J ¼ 13:6, 9.2, 5.2 Hz), 1.14
(1H, m), 1.18–1.43 (3H, m), 2.19 (1H, m), 2.50–2.57 (2H, m), 3.10–
3.19 (2H, m), 5.22–5.39 (2H, m). 13C-NMR (100 MHz, CDCl3) ꢀ: 6.4,
11.3, 18.9, 21.6, 30.0, 31.8, 34.4, 36.7, 44.1, 126.5, 139.5. Anal. Found:
C, 46.97; H, 7.33%. Calcd. for C11H21I: C, 47.15; H, 7.55%.
22
Methyl (R)-N,N-dimethyltyrosinate (7). To a mixture of L-tyrosine
(6.04 g, 33.1 mmol) and MeOH (21 ml) was added thionyl chloride
(2.67 ml, 12.6 mmol) at 0 ꢁC. The reaction mixture was refluxed for 4 h
and then concentrated in vacuo. The crude colorless solid (7.72 g) was
used for the next reaction without further purification. A mixture of the
crude solid (3.90 g), 10% Pd–C (1.0 g), a 47% aqueous formaldehyde
solution (5.65 ml, 69.7 mmol) and MeOH (75 ml) was stirred vigo-
rously for 3 h under a hydrogen atmosphere. The mixture was then
filtered through Celiteꢀ and concentrated in vacuo. To the resulting
residue was added a 10% aqueous sodium bicarbonate solution, and the
mixture extracted with ethyl acetate. The organic layer was succes-
sively washed with water and brine, dried over anhydrous magnesium
sulfate and concentrated in vacuo. The residue was subjected to
chromatography over silica gel. Elution with CHCl3/MeOH (20:1)
colorless oil and recovered 9 (36 mg). ½ꢁꢂD ꢀ14 (c 1.0, CHCl3). IR
(film) ꢂ cmꢀ1: 2958, 1715, 1607, 1509, 1261. 1H-NMR (400 MHz,
CDCl3) ꢀ: 0.16 (6H, s), 0.78 [3H, dd, J ¼ 6:8, 1.2 (J10-Me-H9a) Hz], 0.83
(3H, t, J ¼ 7:2 Hz), 0.88 (3H, d, J ¼ 6:8 Hz), 0.95 (1H, m), 0.96 (9H,
s), 1.00–1.29 (4H, m), 1.97–2.23 (4H, m), 2.34 (6H, s), 2.49 (1H, m),
2.77 (1H, dd, J ¼ 13:2, 4.0 Hz), 2.92 (1H, dd, J ¼ 13:2, 10.0 Hz), 3.33
(1H, dd, J ¼ 10:0, 4.0 Hz), 5.15 (0.5H, dd, J ¼ 15:2, 7.2 Hz), 5.16
(0.5H, dd, J ¼ 15:2, 6.7 Hz), 5.21 (1H, dt, J ¼ 15:2, 6.0 Hz), 6.72 (2H,
d, J ¼ 8:4 Hz), 7.00 (2H, d, J ¼ 8:4 Hz). 13C-NMR (100 MHz, CDCl3)
ꢀ: ꢀ4:5, 11.3, 18.2, 18.9, 21.7, 25.7, 26.3 (0.5, C5), 26.3 (0.5, C5),
29.9 (0.5, C11), 29.9 (0.5, C11), 30.7 (0.5, C1), 30.7 (0.5, C1),
31.7, 34.2, 42.1, 42.8 (0.5, C4), 42.9 (0.5, C4), 44.3, 76.7, 120.0,
126.6, 130.2, 131.5, 137.2, 153.9, 210.4. ESI-TOFMS m=z: calcd. for
C28H49NNaO2Siþ ½M þ Naꢂþ, 482.3425; found, 482.3420.
27
gave 7 (3.35 g, 89% in 2 steps) as a white solid. Mp 124–128 ꢁC. ½ꢁꢂD
þ31 (c 1.0, CHCl3). IR (nujol) ꢂ cmꢀ1: 2923, 2853, 2672, 1730, 1465,
1250. 1H-NMR (400 MHz, CDCl3) ꢀ: 2.43 (6H, s), 2.88–3.10 (2H, m),
3.44 (1H, m), 3.61 (3H, s), 6.70 (2H, d, J ¼ 8:3 Hz), 7.03 (2H, d,
J ¼ 8:3 Hz). Anal. Found: C, 64.95; H, 7.57; N, 6.43%. Calcd. for
(2RS,6E,8R,10R)-2-(N,N-Dimethylamino)-1-(4-hydroxyphenyl)-8,10-
dimethyldodec-6-en-3-one [1, (2RS,6E,8R,10R)-YM-193221]. To a
mixture of silyl ether 10 (19 mg, 0.041 mmol), THF (1 ml) and MeOH
(1 ml) was added conc. HCl (200 ml), and the reaction mixture was
stirred for 48 h at room temperature. The reaction mixture was then
concentrated in vacuo at 40 ꢁC. The resulting residue was subjected to
flash chromatography over silica gel. Elution with CH2Cl2/acetone/
isopropylamine (350:50:1) gave 1 (13 mg, 91%) as a slightly yellow
C
12H17NO3: C, 64.55; H, 7.67; N, 6.27%. The other physical
properties were identical to those reported.9)
Methyl (R)-N,N-dimethyl-O-(tert-butyldimethylsilyl)tyrosinate (8).
To a solution of phenol 7 (2.23 g, 10.0 mmol) in DMF (50 ml) were
added imidazole (1.09 g, 16.0 mmol) and TBSCl (2.26 g, 15.0 mmol) at
0 ꢁC. The reaction mixture was stirred for 18 h, diluted with ether, and
poured into a saturated aqueous sodium bicarbonate solution. The
mixture was extracted with ether, and successively washed with water
and brine. The organic layer was dried over anhydrous magnesium
sulfate and concentrated in vacuo. The resulting residue was subjected
to chromatography over silica gel. Elution with CHCl3/MeOH (25:1)
27
oil. ½ꢁꢂD ꢀ16 (c 1.0, CHCl3). IR (film) ꢂ cmꢀ1: 3363, 2959, 1714,
1614, 1516, 1456, 1247. 1H-NMR (400 MHz, CDCl3) ꢀ: 0.78 [3H, dd,
J ¼ 6:4, 1.2 (J10-Me-H9a) Hz], 0.83 (3H, t, J ¼ 7:2 Hz), 0.88 (3H, d,
J ¼ 6:8 Hz), 0.95 (1H, ddd, J ¼ 13:6, 8.8, 5.2 Hz), 1.09 (1H, m), 1.13–
1.35 (3H, m), 2.02–2.27 (4H, m), 2.34 (6H, s), 2.53 (1H, m), 2.77 (1H,
dd, J ¼ 13:6, 4.4 Hz), 2.92 (1H, dd, J ¼ 13:6, 9.6 Hz), 3.33 (0.5H, dd,
J ¼ 9:6, 4.4 Hz), 3.34 (0.5H, dd, J ¼ 9:6, 4.4 Hz), 5.15 (0.5H, dd,
J ¼ 15:6, 7.6 Hz), 5.17 (0.5H, dd, J ¼ 15:6, 7.2 Hz), 5.22 (1H, dt,

Syntheses of YM-193221 and Tyroscherin
2059
J ¼ 15:6, 5.6 Hz), 6.71 (2H, d, J ¼ 8:4 Hz), 7.00 (2H, d, J ¼ 8:4 Hz).
13C-NMR (100 MHz, CDCl3) ꢀ: 11.3, 19.0, 21.7, 26.3, 29.9, 30.6, 31.7,
34.2, 42.1, 42.6 (0.5, C4), 42.7 (0.5, C4), 44.3, 74.7, 115.3, 126.5,
chromatography over silica gel. Elution with CHCl3/MeOH (7:1)
and subsequent recrystallization from hexane/ether gave 2 (14 mg,
25
quant.) as colorless needles. Mp 122–126 ꢁC. ½ꢁꢂD ꢀ21 (c 0.35,
130.3, 130.7, 137.2, 154.1, 210.6. ESI-TOFMS m=z: calcd. for
þ
MeOH). IR (KBr) ꢂ cmꢀ1: 3239, 2961, 1671, 1203, 1185, 1146. 1H-
NMR (400 MHz, CDCl3) ꢀ: 0.83 (3H, d, J ¼ 6:4 Hz), 0.85 (3H, t,
J ¼ 7:6 Hz), 0.91 (3H, d, J ¼ 6:4 Hz), 0.99 (1H, ddd, J ¼ 13:2, 8.8,
4.2 Hz), 1.13 (1H, m), 1.17–1.38 (3H, m), 1.43–1.61 (2H, m), 2.00 (1H,
m), 2.10–2.25 (2H, m), 2.61 (3H, s), 2.86 (1H, dd, J ¼ 14:4, 8.0 Hz),
2.90 (1H, dd, J ¼ 14:4, 6.8 Hz), 3.34 (1H, m), 3.83 (1H, ddd, J ¼ 9:2,
3.2, 3.2 Hz), 5.23 (1H, dd, J ¼ 15:2, 8.4 Hz), 5.33 (1H, dt, J ¼ 15:2,
6.4 Hz), 6.77 (2H, quasi d, J ¼ 8:8 Hz), 7.10 (2H, quasi d, J ¼ 8:8 Hz).
13C NMR (100 MHz, CDCl3) ꢀ: 11.7, 19.4, 22.3, 29.9, 31.1, 32.4, 33.1,
33.2, 35.8, 45.6, 66.8, 68.7, 116.9, 127.6, 128.4, 131.3, 138.8, 158.0.
C
22H36NO2 ½M þ Hꢂþ, 346.2741; found, 346.2782.
tert-Butyl (1S,2R,5E,7R,9R)-[1-[4-(methoxymethoxy)benzyl]-2-hy-
droxy-7,9-dimethylundec-5-enyl]methylcarbamate (13). Aldehyde 12
was synthesized from Weinreb amide 11 (382 mg, 1.00 mmol) in the
same manner as that reported3,4) to give crude aldehyde 12 (323 mg) as
a colorless oil. Under an argon atmosphere, to a solution of iodide 6
(98 mg, 0.35 mmol) in ether (2 ml) was added a solution of tert-butyl-
lithium in pentane (1.76 M, 286 ml, 0.50 mmol) at ꢀ78 ꢁC, and the
mixture was stirred for 30 min at the same temperature. The resulting
solution of the lithium reagent was slowly added to a solution of crude
aldehyde 12 (113 mg, 0.349 mmol) in ether (1 ml) at ꢀ78 ꢁC. The
reaction mixture was then allowed to warm to room temperature. After
stirring for 1 h, the reaction mixture was poured into a saturated
ammonium chloride solution and extracted with ethyl acetate. The
organic layer was successively washed with 1 N HCl, a saturated
sodium bicarbonate solution and brine, and dried over anhydrous
magnesium sulfate. After concentrating in vacuo, the residue was
subjected to flash chromatography over silica gel. Elution with
CH2Cl2/acetone/isopropylamine (500:25:1) gave 13 (57 mg, 32%,
54% based on recovery) as a colorless oil and recovered 12 (26 mg,
þ
þ
ESI-TOFMS m=z: calcd. for C21H36NO2 ½M þ Hꢂ , 334.2741; found,
334.2719. The physical properties of 2 were identical to those
reported.1,3,4)
References and Notes
1) Hayakawa Y, Yamashita T, Mori T, Nagai K, Shin-ya K, and
Watanabe H, J. Antibiot., 57, 634–638 (2004).
2) Kamigiri K, Tanaka K, Matsumoto H, Nagai K, Watanabe M,
and Suzuki K, J. Antibiot., 57, 569–572 (2004).
3) Katsuta R, Shibata C, Ishigami K, Watanabe H, and Kitahara T,
Tetrahedron Lett., 49, 7042–7043 (2008).
22
29%). ½ꢁꢂD ꢀ46:3 (c 1.35, CHCl3). IR (film) ꢂ cmꢀ1: 3435, 2961,
4) Ishigami K, Katsuta R, Shibata C, Hayakawa Y, Watanabe H,
and Kitahara T, Tetrahedron, 65, 3629–3638 (2009).
5) Ugele M and Maier ME, Tetrahedron, 66, 2633–2641 (2010).
6) Organ MG, Bilokin YV, and Bratovanov S, J. Org. Chem., 67,
5176–5183 (2002).
1669, 1511, 1154. 1H-NMR (400 MHz, CDCl3) ꢀ: 0.82 (3H, d,
J ¼ 7:4 Hz), 0.84 (3H, t, J ¼ 7:3 Hz), 0.93 (3H, d, J ¼ 7:1 Hz), 0.90–
1.70 (7H, m), 1.40 (9H, s), 2.02–2.25 (3H, m), 2.49 (1.5H, s), 2.68
(1.5H, s), 2.90 (0.5H, m), 3.00–3.17 (1.5H, m), 3.44 (1.5H, s), 3.47
(1.5H, s), 3.50–3.91 (2H, m), 5.14 (2H, s), 5.15–5.45 (2H, m), 6.94
(2H, d, J ¼ 8:7 Hz), 7.06 (1H, d, J ¼ 8:7 Hz), 7.08 (1H, d, J ¼ 8:7 Hz).
ESI-TOFMS m=z: calcd. for C28H47N2NNaO5 ½M þ Naꢂþ, 500.3346;
found, 500.3356.
7) Schlosser M and Christmann KF, Liebigs Ann. Chem., 708, 1–35
(1967).
8) Alternatively, oxidation of N-methyltyroscherin (14), prepared
from tyroscherin (aq. HCHO, NaBH3CN, CH3CN, 94%), by
several reagents (PCC, Dess-Martin periodinane) resulted in
decomposition of the starting material. Oxidation of 14 was
succeeded by using TPAP, NMO, but the corresponding YM-
193221 (1) was also given as a 1:1 mixture of diastereomers at C2.
9) Huguenin R and Boissonnas RA, Helv. Chim. Acta, 44, 213–231
(1961).
(2S,3R,6E,8R,10R)-1-(4-Hydroxyphenyl)-8,10-dimethyl-2-(methyl-
amino)undec-6-en-3-ol (2, tyroscherin). To a mixture of silyl ether 13
(20 mg, 0.042 mmol), MeOH (2 ml), THF (1 ml) and water (1 ml) was
added trifluoroacetic acid (300 ml), and the mixture was stirred for 4 h
at room temperature. The reaction mixture was then concentrated in
vacuo at 60 ꢁC. The resulting residue was subjected to flash