Formal synthesis of tirandamycin B

Article abstract of DOI:10.1016/j.tet.2017.05.042

A formal synthesis of tirandamycin B is described. The key intermediate is synthesized by Marshall allenyl zinc method, litiofuran coupling, and Achmatowicz reaction to construct the bicyclic core of tirandamycin B.

Full text of DOI:10.1016/j.tet.2017.05.042

Accepted Manuscript
Formal synthesis of tirandamycin B
Keisuke Takahashi, Rintaro Harada, Yurika Hoshino, Taichi Kusakabe, Susumi
Hatakeyama, Keisuke Kato
PII:
S0040-4020(17)30517-3
10.1016/j.tet.2017.05.042
TET 28708
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 April 2017
Revised Date: 8 May 2017
Accepted Date: 10 May 2017
Please cite this article as: Takahashi K, Harada R, Hoshino Y, Kusakabe T, Hatakeyama S, Kato K,
Formal synthesis of tirandamycin B, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.042.
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Formal Synthesis of Tirandamycin B
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Keisuke Takahashia*, Rintaro Haradaa, Yurika Hoshinoa, Taichi Kusakabea, Susumi Hatakeyamab and Keisuke
Katoa*
aSchool of Pharmaceutical Sciences Toho University, 2-2-1 Miyama, Funabashi ,Chiba 274-8510, Japan.
bMedical Innovation Center, Nagasaki University,1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
OTIPS
O
PMBO
MsO
H
OTIPS
O
CO2Et
O
OH
O
O
HO
O
O
O
O
H
O
O
NH
key intermediate
Tirandamycin B

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Formal Synthesis of Tirandamycin B
Keisuke Takahashia*, Rintaro Haradaa, Yurika Hoshinoa, Taichi Kusakabea, Susumi Hatakeyamab and
Keisuke Katoa*
aSchool of Pharmaceutical Sciences Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
bMedical Innovation Center, Nagasaki University,1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A formal synthesis of tirandamycin B is described. The key intermediate is synthesised by
Marshall allenyl zinc method, litiofuran coupling, and Achmatowicz reaction to construct the
bicyclic core of tirandamycin B.
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Natural product
Tirandamycin B
Filariasis
1. Introduction
In 2011, Shen et al. reported the isolation of tirandamycins
from Streptomyces species,1 among which tirandamycin B
(1) was shown to exhibit potent inhibition activity toward
the tRNA synthetase of the parasite Brugia malayi. This
parasite causes lymphatic filariasis, a serious neglected
tropical disease (NTD) affecting over 200 million people.
Low concentrations of tirandamycin B efficiently kill the
adult worm, and thus this natural product holds promise as a
lead scaffold for drugs to combat lymphatic filariasis. The
biological activities and its molecular architecture (involving
Figure 1. Tirandamycin B
2. Results and discussion
Our synthetic strategy is shown in Scheme 1.
Tirandamycin B ( ) can be synthesized by coupling and
developed previously.2 Bicyclic compound
can be
assembled by Achmatowicz reaction from furan derivative 4,
1
2
3,
a bicyclic core, triene, and tetramic acid) make
1 an
3
attractive synthetic target. The first total synthesis of
2a
3
racemic
Miyashita’s formal synthesis of the antipode of
In 2016, Hatakeyama reported the enantioselective total
synthesis of
in its natural form.2c In this paper, we report a
1
was reported by DeShong in 1990 followed by
which is synthesized by cross-metathesis between
Intermediate , possessing four stereocenters, can be
synthesized from
5 and 6.
1
in 1996.2b
6
4,5
7, 8 and 9 using the Marshall method
and lithiofuran coupling. Marshall method is convenient for
the construction of the two stereocenters at the same time.
1
formal synthesis of 1 based on the addition of a chiral allenyl
zinc species to aldehyde 8.
*Corresponding authors: K. Takahashi
(keisuke.takahashi@phar.toho-u.ac.jp) and K. Kato
(kkk@phar.toho-u.ac.jp) i

2
Tetrahedron
ACCEPTED MANUSCRIPT
Table 1. Hydrogenation of 14
Entry
Conditions
Yield of 16
63%
(unreproducible)
1
Lidlar cat. 5 w%, AcOEt
5% Pd-PEI 10 w%, MeOH-
Dioxane 1:4
2
3
no reaction
71%
5% Pd-PEI 10 w%, MeOH
Partial hydrogenation of alkyne 14 was investigated as shown
in Table 1. The initial attempt, using a typical poisoned catalyst
gave 16 in moderate yield (entry 1) but the yield was not
reproducible due to the reduction of alkene 16. We next tried
using the Pd-PEI (palladium-polyethyleneimine) catalyst
7
developed by Sajiki et al. Conditions using a 1:4 mixture of
MeOH and dioxane as solvent did not give 16 (entry 2), whereas
the reaction in MeOH proceeded efficiently to give 16 in
satisfactory yield and with good reproducibility (entry3).
Scheme 1. Synthetic plan
The synthesis of 14 is depicted in Scheme 2. Methyl (S)-3-
hydroxy-2-methylpropionate (10) was protected using 11 under
acidic conditions to give PMB ether 12. Intermediate 12 was
subjected to LAH reduction followed by Dess-Martin oxidation
to give aldehyde 13. Significant racemization of aldehyde 13 was
observed when prepared from 12 directly by using DIBALH.
Following the procedure developed by Marshall et al.,4,5 13 was
coupled with optically active mesylate 9 prepared from
commercially available 15 to give 14 possessing three continuous
stereocenters in satisfactory yield and with satisfactory
stereoselectivity. 6
Scheme 3. Coupling between 7 and 19
Aldehyde 19 was synthesized from 16 via a three-step sequence
(Scheme 3); protection of the secondary alcohol 16, followed by
removal of the PMB group, afforded 18, which was treated with
Dess-Martin reagent to afforded aldehyde 19 in 68% yield. Furan
derivative 7 was prepared from 22 in 2 steps. Lithiofuran
generated from 7 was coupled with aldehyde 19 to give 21 as the
Scheme 2. Synthesis of 14

The ratio of
Based on a previously developed procedure,2 21 was subjected to
Achmatowicz reaction using mCPBA to give 24 (Scheme 5).
This result was gratifying because the terminal alkene of 21 was
unaffected. Removal of the TES group from 24 using HF and
H2SiF6 in acetonitrile promoted cyclization, forming the bicyclic
core of 25. Cross metathesis between 25 and 5 was unsuccessful,
major product with 3:1 diastereoselectivitAy. CCEPTED MANUSCRIPT
1
stereoisomers was determined from the H NMR spectra of the
crude product. This stereoselective outcome of the reaction can
be explained by the Felkin-Anh model for 20. At this point, the
were fixed.
of 21 or conversion to the
corresponding acetonide from 21 were difficult due to the
instability of the derivatives, configuration of the coupling
product 21 and its epimer were estimated based on the coupling
constants of the protons attached to the generated stereocenters.10
required four continuous stereocenters of
Formation of MTPA ester
1
8
9
as with 21, and thus we had to use an alternative method.
11
Johnson-Lemieux oxidation
of 25 giving aldehyde 26, and
subsequent Wittig reaction using ylide 27, furnished intermediate
3. The synthetic route of 1 from 3 involving the coupling with 2
12,2
and epoxidation is reported in the literatures,
and thus we
archived a formal synthesis of 1. Proton and carbon NMR
spectra, and optical rotation data of synthesized 3, show good
agreements with those reported in the literature.
3. Conclusions
We have developed a formal synthesis of tirandamycin B in
13 steps starting from methyl (S)-3-hydroxy-2-methylpropionate
(10). This synthetic route involves the Marshall’s method, Sajiki
hydrogenation of terminal alkyne, lithiofuran coupling, and
construction of the bicyclic core based on the Achmatowicz
reaction.
Scheme 4. Attempted Cross-metathesis
We attempted to synthesize known intermediate 23 2 by cross-
metathesis reaction3 between obtained 21 and ethyl ester 5.
However, reactions employing Grubbs 1st, Grubbs 2nd, and
Hoveyda-Grubbs 2nd catalysts did not give desired product 22
(Scheme 4). We attributed this disappointing result to the
instability of the furan ring moiety in 21 and therefore decided to
install the ethyl ester moiety after forming the bicyclic core of 1.
4. Experimental
4.1 General
Where appropriate, reactions were performed in flame-dried
glassware under argon atmosphere under room temperature. All
extracts were dried over MgSO4 and concentrated by rotary
evaporation below 30 °C at 25 Torr unless otherwise noted.
Commercial reagents and solvents were used as supplied.
Column chromatography was performed using silica gel (particle
size 100-210 ꢀm (regular), 40-50 ꢀm (flush)). Optical rotations
were recorded on a digital polarimeter at ambient temperature.
Infrared spectra were measured on a Fourier transform infrared
1
spectrometer. H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were measured using CDCl3 as solvent, and chemical
shifts are reported as δ values in ppm based on internal (CH3)4Si
1
(0.00 ppm, H) or solvent peak. HRMS spectra were taken in EI
(dual focusing sector field) or FAB (dual focusing sector field)
mode.
4.2 Experimental procedures
4.2.1.Methyl(S)-3-((4-methoxybenzyl)oxy)-2-
methylpropanoate (12
To a stirred solution of 11 (3.4 g, 12.1 mmol) in Et2O (51
mL) at 0 C, were added 10 (1.0 g, 8.47 mmol) and TfOH
(34 L, 0.33 mmol). After being stirred under room
).
°
µ
temperature for 16 h, saturated NaHCO3 was added. The
mixture was extracted with Et2O, washed with brine, dried,
concentrated and chromatographed (SiO2 50 g, hexane:
AcOEt = 10:1) to give 12 (1.61 g, 6.8 mmol, 80%) as a
1
colorless oil. [
MHz, CDCl3)
2H), 4.45 (s, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 3.62 (dd,
7.2, 8.8 Hz, 1H), 3.45 (dd, = 6.0, 8.8 Hz, 1H), 2.81-2.72
(m, 1H), 1.16, (d,
= 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) 175.2, 159.2, 130.1, 129.1, 113.6, 72.6, 71.5, 55.1,
α
δ
]
17+9.34 (
c
1.13, CHCl3); H NMR (400
D
7.23 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz,
J
=
J
Scheme 5. Formal Synthesis of Tirandamycin B
J
δ

4
Tetrahedron
ACCEPTED MANUSCRIPT
(s, 2H), 3.80 (s, 3H), 3.60-3.48 (m, 3H), 3.36-3.32 (m, 1H), 2.71-
51.6, 40.1, 13.9; FT-IR (KBr) 2950, 2862, 1738, 1613,
1514, 1248, 1091 cm-1; HRMS (EI) calcd for C13H18O4 (M+),
238.1205, found 238.1205.
2.64 (m, 1H), 2.17-2.06 (m, 1H), 2.09 (d, J = 2.4 Hz, 1H), 1.29
(d, J = 7.2 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 159.2, 129.8, 129.3, 113.7, 85.0, 78.2, 74.7, 73.0,
70.2, 55.2, 37.2, 30.1, 17.8, 13.8; FT-IR (KBr) 3464, 3292, 2967,
2934, 2872, 1513, 1247, 1080 cm-1; HRMS (EI) calcd for
C16H22O3 (M+) 262.1569, found 262.1569.
4.2.2. (S)-3-((4-Methoxybenzyl)oxy)-2-methylpropanal (13).
To a suspension of LiAlH4 (1.6 g, 42 mmol) in THF (160 mL)
was added 12 (20 mL THF solution, 6.7 g, 28 mmol) dropwisely
over 30 min at -78 °C. The mixture was gradually warmed up to
room temperature, stirred for 13 h and then cooled to 0 °C. Water
(1.5 mL), 15% NaOH (1.5 mL) and additional water (4.6 mL)
were added to the mixture. The mixture was filtered through
Celite, concentrated and chromatographed (SiO2 200 g, hexane:
AcOEt = 2:1) to give the corresponding alcohol (4.8 g, 23 mmol,
4.2.5. (2S,3R,4R)-1-((4-Methoxybenzyl)oxy)-2,4-dimethylhex-5-
en-3-ol (16).
Under argon atmosphere, 5% Pd-PEI (13 mg) was added to a
solution of 15 (131 mg, 0.50 mmol) in MeOH (2 mL) and then a
hydrogen gas balloon was attached. The mixture was stirred for 7
h, diluted with Et2O, washed with water, brine, dried,
concentrated, and chromatographed (SiO2 8 g, hexane:AcOEt =
25:1) to give 16 (94 mg, 0.36 mmol, 71%) as a colorless oil.
[α]D17 +11.2 (c 1.16, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.24
(d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.94-5.85 (m, 1H),
5.07 (d, J = 0.7 Hz, 1H), 5.04-5.02 (m, 1H), 4.44 (s, 2H), 3.79 (s,
3H), 3.55 (dd, J = 9.2, 4.4 Hz, 1H), 3.49-3.45 (m, 2H), 3.37-3.33
(m, 1H), 2.38-2.30 (m, 1H), 1.96-1.86 (m, 1H), 1.09, (d, J = 7.1
Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H); 13C NMR (100MHz, CDCl3) δ
159.2, 139.7, 129.8, 129.3,115.1, 113.4, 79.2, 75.1, 73.1, 55.2,
41.0, 36.1, 17.7, 13.9; FT-IR (KBr) 3493, 2963, 2932, 1248,
1084, 1036, cm-1; HRMS (EI) calcd for C16H24O3 (M+) 264.1725,
found 264.1726.
82%) as a colorless oil. [α]D23+18.1 (c 1.00, CHCl3), H NMR
1
(400 MHz, CDCl3) δ 7.24 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7
Hz, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.61-3.56 (m, 2H), 3.51 (ddd,
J = 0.8, 4.8, 9.2 Hz, 1H), 3.39 (dd, J = 8.0, 9.2 Hz, 1H), 2.72 (s,
1H), 2.10-1.99 (m, 1H), 0.87 (d, J = 7.1 Hz, 3H); 13C NMR
(100MHz, CDCl3) δ 159.2, 130.0, 129.2, 113.7, 75.0, 72.5, 67.7,
55.2, 35.5, 13.4.; FT-IR (KBr) 3434, 2955, 2867, 1514, 1249,
1176, 1035 cm-1; HRMS (EI) calcd for C12H18O3 (M+), 210.1256,
found 210.1256. To a stirred solution of the alcohol above
obtained (449 mg, 2.13 mmol) in CH2Cl2 (7 mL) at 0 °C was
added DMPI (1.27 g, 3.00 mmol). After being stirred under the
room temperature for 1 h, saturated Na2S2O3 (20 mL) was added
to the mixture at 0 °C. The mixture was extracted with Et2O,
washed with saturated NaHCO3 and brine, dried, concentrated
and chromatographed (SiO2 10 g, hexane:AcOEt = 4:1) to give
13 (418 mg, 2.01 mmol, 94%) as a colorless oil. [α]D21+30.5 (c
1.04, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.70 (d, J = 1.6 Hz,
1H), 7.23 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.45 (s,
2H), 3.80 (s, 3H), 3.67-3.58 (m, 2H), 2.68-2.60 (m, 1H), 1.11, (d,
J = 7.2 Hz, 3H); 13C NMR (100MHz, CDCl3) δ 203.9, 159.2,
129.9, 129.2, 113.7, 72.9, 69.7, 55.2, 46.7, 10.6; FT-IR (KBr)
2936, 2861, 1724, 1514, 1248, 1094, 1034 cm-1; HRMS (EI)
calcd for C12H16O3(M+) 208.1099, found 208.1100.
4.2.6. Triethyl(((2S,3R,4R)-1-((4-methoxybenzyl)oxy)-2,4-
dimethylhex-5-en-3-yl)oxy)silane (17).
To a solution of 16 (1.21 g, 4.59 mmol) in CH2Cl2 (36 mL),
were added Et3N (1.28 mL, 9.19 mmol), TESCl (1.15 mL, 6.89
mmol) and DMAP (55 mg, 0.45 mmol) at 0 °C. After being
stirred for 19 h under room temperature, The mixture was diluted
with AcOEt, washed with 1 M HCl, saturated NaHCO3 and brine,
dried, concentrated and chromatographed (SiO2 89 g,
hexane:AcOEt = 50:1) to give 17 (1.58 g, 4.2 mmol, 91%) as a
colorless oil. [α]D17-14.9 (c 0.82, CHCl3), H NMR (400 MHz,
1
CDCl3) δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.86
(ddd, J = 8.0, 10.6, 18.8 Hz, 1H), 5.00-4.97 (m, 1H), 4.95 (d, J =
0.7, 1H), 4.44 (d, J = 11.7 Hz, 1H), 4.38 (d, J = 11.7 Hz, 1H),
3.80 (s, 3H), 3.53-3.48 (m, 2H), 3.30 (dd, J = 7.3, 8.9 Hz, 1H),
2.39-2.31 (m, 1H), 1.94-1.84 (m, 1H), 1.02 (d, J = 6.9 Hz, 3H),
0.96-0.94 (m, 12H), 0.59 (q, J = 8.2 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 159.0, 141.1, 131.0, 129.1, 114.1, 113.6, 78.4,
72.7, 72.5, 55.2, 41.7, 37.9, 18.1, 14.9, 7.1, 5.4; FT-IR (KBr)
2957, 2877, 1513, 1246, 1090, 1041 cm-1; HRMS (EI) calcd for
C22H38O3Si (M+) 378.2590, found 378.2590.
4.2.3. (S)-But-3-yn-2-yl methanesulfonate (9).
To a stirred solution of 15 (2.0 g, 28.5 mmol) in CH2Cl2 (50
mL) were added Et3N (6.0 mL, 42. 8 mmol), MsCl (2.6 mL, 34. 2
mmol) and DMAP (206 mg, 1.43 mmol) under the room
temperature. After being stirred for 3 h, water (50 mL) was added
at 0 °C. The mixture was extracted with Et2O, washed with
saturated NaHCO3 and brine, dried, concentrated and
chromatographed (SiO2 58 g, hexane: Et2O = 3:2) to give 9 (4.0 g,
27.2 mmol, 95%) as a colorless oil. [α]D17-119.7 (c 1.11, CHCl3);
1H NMR (400 MHz, CDCl3) δ 5.29 (ddd, J = 2.0, 6.8, 13.2 Hz,
1H), 3.13 (s, 3H), 2.72 (d, J = 2.0 Hz, 1H), 1.66 (d, J = 6.8 Hz,
3H); 13C NMR (100MHz, CDCl3) δ 80.1, 76.3, 67.4, 39.1, 22.4;
FT-IR (KBr) 3283, 3029, 2998, 2942, 2125, 1358, 1177, 1123,
1090, 1017 cm-1; HRMS (EI) calcd for C5H7O3S [(M-H)+]
147.0116, found 147.0116.
4.2.7. (2S,3R,4R)-2,4-Dimethyl-3-((triethylsilyl)oxy)hex-5-en-1-
ol (18).
To a solution of 17 (1.48 g, 3.9 mmol) in CH2Cl2 (64 mL) were
added phosphate buffer (pH 7, 0.4 M, 16 mL) and DDQ (2.5 g,
11.0 mmol) at 0 °C. After being stirred for 15 minutes under
room temperature, the mixture was diluted with Et2O, washed
4.2.4. (2S,3R,4R)-1-((4-Methoxybenzyl)oxy)-2,4-dimethylhex-5-
yn-3-ol (14).
with
2
M NaOH and brine, dried, concentrated and
chromatographed (SiO2 55 g, hexane: AcOEt = 15:1) to give 18
Pd(OAc)2 (163 mg, 0.73 mmol) and PPh3 (204 mg, 0.78 mmol)
were dissolved in THF (25 mL) and cooled to -78 °C. 13 (1.45 g,
7.0 mmol) and 9 (2.0 g, 14.0 mmol) were added via cannula.
After 10 minutes, Et2Zn (1 M in THF, 14 mL, 14 mmol) was
added at the same temperature. The resulting mixture was stirred
for 15 h at -20 °C . 1 N HCl was added to the mixture. The
mixture was extracted with Et2O, washed with NaHCO3, and
brine, dried, concentrated and chromatographed (SiO2 100 g,
hexane:AcOEt = 10:1) to give 14 (1.39 g, 5.3 mmol, 76%) as a
(825 mg, 3.2 mmol, 82%) as a colorless oil. [α]D20-8.36 (c 1.03,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 5.83 (ddd, J = 7.7, 10.4,
17.2 Hz, 1H ), 5.06 (t, J = 1.4 Hz, 1H ), 5.03-5.00 (m, 1H), 3.68-
3.61 (m, 1H), 3.61-3.57 (m, 2H), 2.69 (t, J = 5.8 Hz, 1H ), 2.43-
2.41 (m, 1H), 1.87-1.78 (m, 1H), 1.04, (d, J = 6.4 Hz, 3H ), 0.97
(t, J = 8.0 Hz, 9H ), 0.96 (d, J = 6.4 Hz, 3H ), 0.65, (q, J = 8.0
Hz, 6H ); 13C NMR (100 MHz, CDCl3) δ 141.5, 115.3, 82.1,
66.7, 43.7, 38.1, 16.9, 16.4, 7.6, 5.9; FT-IR (KBr) 3396, 2958,
2878, 1459, 1239, 1037, 1007 cm-1; HRMS (EI) calcd for
C12H25O2 Si [(M-Et)+] 229.1624, found 229.1624.
1
colorless oil. [α]D16+9.8 (c 0.90, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.25 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.45

Hz, 1H), 3.66 (d, J = 2.4 Hz, 1H), 2.52-2.44 (m, 1H), 2.24 (s,
ACCEPTED MANUSCRIPT
4.2.8. (2R,3R,4R)-2,4-Dimethyl-3-((triethylsilyl)oxy)hex-5-enal
(19).
3H), 2.23-2.18 (m, 1H), 1.15-0.98 (m, 33H), 0.73-0.61 (m, 9H);
13C NMR (100 MHz, CDCl3) δ 152.8, 147.0, 140.8, 119.7, 114.5,
108.6, 81.0, 71.3, 57.5, 43.2, 40.9, 18.0, 16.1, 15.4, 12.0, 11.9,
6.9, 5.2; FT-IR (KBr) 3451, 2955, 2870, 1462, 1240, 1063, 1008
cm-1; HRMS (EI) calcd for C29H56O4Si2 (M+) 524.3717, found
524.3719.
To a stirred solution of 18 (387 mg, 1.50 mmol) in CH2Cl2 (6
mL), was added DMPI (1.0 g, 2.4 mmol) at 0 °C. After being
stirred for 2 h under room temperature, saturated Na2S2O3 was
added at 0 °C and stirred for 30 minutes. The mixture was
extracted with Et2O, washed with NaHCO3 and brine, dried,
concentrated and chromatographed (SiO2 35 g, hexane:AcOEt =
50:1) to give 19 (348 mg, 1.36 mmol, 91%) as a colorless oil.
4.2.11. (2S)-6-Hydroxy-6-methyl-2-((2S,3R,4R)-4-methyl-3-
((triethylsilyl)oxy)hex-5-en-2-yl)-5-
1
[α]D20-53.8 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) δ 9.78
(((triisopropylsilyl)oxy)methyl)-2H-pyran-3(6H)-one (24).
To a stirred solution of 21 (104 mg, 0.20 mmol) in CH2Cl2 was
added mCPBA (48 mg, 0.28 mmol) at 0 °C. After being stirred
for 4 h at the same temperature, the mixture was diluted with
AcOEt, washed with saturated Na2S2O3, saturated NaHCO3, and
brine, dried, concentrated and chromatographed (SiO2 8 g,
hexane:AcOEt = 50:1) to give 24 (100 mg, 0.19 mmol, 95%) as a
colorless solid. [α]D15-10.7 (c 0.98, CHCl3); mp 73-76 °C ;1H
NMR (400 MHz, CDCl3) δ 6.25 (t, J = 1.6 Hz, 1H), 5.97-5.88
(m, 1H), 5.02 (d, J = 2.4 Hz, 1H), 5.00 (s, 1H), 4.70 (d, J = 2.0
Hz, 1H), 4.49 (t, J = 2.0 Hz, 2H),3.69 (dd, J = 2.0, 10.4 Hz, 1H),
2.84 (s, 1H), 2.46-2.40 (m, 1H), 2.34 (s, 1H), 1.56 (s, 3H), 1.20-
0.96 (m, 33H), 0.75-0.60 (m, 9H); 13C NMR (100MHz, CDCl3) δ
198.3, 160.8, 140.0, 121.5, 114.4, 93.4, 76.5, 75.1, 61.5, 41.2,
38.7, 26.5, 17.9, 17.7, 11.8, 7.1, 5.5; FT-IR (KBr) 3410, 2948,
2871, 1669, 1463, 1118, 1054, 1011 cm-1; HRMS (FAB) calcd
for C29H56O5Si2Na [(M+Na)+] 563.3564, found 563.3563.
(d, J = 2.4 Hz, 1H ), 5.88-5.79 (m, 1H ), 5.08-5.07 (m, 1H ),
5.05-5.03 (m, 1H), 3.82 (dd, J = 4.0, 5.2 Hz, 1H ), 2.57-2.50 (m,
1H), 2.44-2.38 (m, 1H), 1.06, (d, J = 6.8 Hz, 3H ), 1.05 (d, J =
6.8 Hz, 3H ), 0.96 (t, J = 8.0 Hz, 9H ), 0.62, (q, J = 8.0 Hz, 6H );
13C NMR (100MHz, CDCl3) δ 205.3, 139.9, 115.4, 78.1, 50.0,
42.9, 16.3, 11.9, 6.9, 5.2; FT-IR (KBr) 2959, 2879, 1726, 1460,
1240, 1120, 1075 cm-1; HRMS (EI) calcd for C12H23O2 Si [(M-
Et)+] 227.1467, found 227.1467.
4.2.9 Triisopropyl((2-methylfuran-3-yl)methoxy)silane (7).
To a suspension of LiAlH4 (2.4 g, 64 mmol) in THF (140 mL)
was added 22 (10 mL THF solution, 5.0 g, 32 mmol) dropwisely
over 30 min at -78 °C. The mixture was gradually warmed up to
room temperature, stirred for 2.5 h and then cooled to 0 °C.
Water (2.0 mL), 15% NaOH (2.5 mL) and additional water (6.5
mL) were added to the mixture. The mixture was filtered through
Celite and concentrated. The resulting crude alcohol was
dissolved in CH2Cl2 (37 mL). Imidazole (3.6 g, 32 mmol) and
TIPSCl (10. 1 mL, 48 mmol) were added. The mixture was
stirred under room temperature for 15 h, diluted with Et2O,
washed with 1 M HCl, saturated NaHCO3 and brine, dried,
concentrated and chromatographed (SiO2 160 g, hexane: AcOEt
4.2.12. (1S,3R,4R,5S)-3-((R)-But-3-en-2-yl)-1,4-dimethyl-8-
(((triisopropylsilyl)oxy)methyl)-2,9-dioxabicyclo[3.3.1]non-7-en-
6-one (25).
To a stirred solution of 24 (141 mg, 0.26 mmol) in MeCN (40
mL) were added 48% HF (13 µL) and 25% H2SiF6 (14 µL) under
room temperature. After being stirred for 2 minutes, saturated
NaHCO3 was added. The mixture was diluted with Et2O, washed
with water and brine, dried, concentrated and chromatographed
(SiO2 15 g, hexane : AcOEt = 40:1) to give 25 (68 mg, 0.17
mmol, 65%) as a colorless solid. [α]D19-163.9 (c 1.28, CHCl3);
mp 54-56 °C; 1H NMR (400 MHz, CDCl3) δ 6.52 (t, J = 2.0 Hz,
1H), 5.86 (ddd, J = 9.2, 10.4, 19.4 Hz, 1H), 5.08-5.05 (m, 1H),
5.05-5.00 (m, 1H), 4.50 (dd, J = 2.4, 17.6 Hz, 1H), 4.22 (dd, J =
2.4, 18.0 Hz, 1H), 4.05 (d, J = 6.0 Hz, 1H), 3.40 (dd, J = 2.4,
11.2 Hz, 1H), 2.43-2.35 (m, 1H), 2.20-2.10 (m, 1H), 1.45 (s, 3H),
1.18-1.06 (m, 21H), 1.03 (d, J = 6.8 Hz, 3H), 0.73 (d, J = 7.2 Hz,
3H); 13C NMR (100MHz, CDCl3) δ 195.7, 158.2, 138.7, 123.2,
115.7, 94.6, 79.1, 60.8, 39.3, 33.0, 24.1, 18.0, 18.0, 17.5, 11.9,
11.3; FT-IR (KBr) 2954, 2867, 1679, 1460, 1141, 1061 cm-1;
HRMS (FAB) calcd for C23H41O4Si [(M+H)+] 409.2274, found
409.2275.
1
= 80:1) to give 7 (5.8 g, 22 mmol, 69%) as a colorless oil. H
NMR (400 MHz, CDCl3) δ 7.23 (d, J = 1.8 Hz, 1H), 6.35 (d, J =
1.6 Hz, 1H), 4.58 (s, 2H), 2.26 (s, 3H), 1.18-1.05 (m, 21H); 13C
NMR (100MHz, CDCl3) δ 147.7, 140.0, 119.3, 110.9, 57.5, 18.0,
12.0, 11.8; FT-IR (KBr) 2943, 2867, 1465, 1085, 1066 cm-1;
HRMS (EI) calcd for C15H28O2Si (M)+ 268.1859, found
268.1857.
4.2.10. (1S,2S,3R,4R)-2,4-Dimethyl-1-(5-methyl-4-
(((triisopropylsilyl)oxy)methyl)furan-2-yl)-3-
((triethylsilyl)oxy)hex-5-en-1-ol (21).
To a stirred solution of 7 (318 mg, 1.17 mmol) in THF (1
mL) was added sec-BuLi (0.7 M in hexane, 1.1 mL, 0.77 mmol)
at -78 °C. After being stirred for 40 minutes, 19 (150 mg, 0.59
mmol) was added and stirred for 1 h under the same temperature.
The reaction was quenched with water, and the mixture was
extracted with Et2O. The organic phase was washed with brine,
dried concentrated and chromatographed (SiO2 14 g,
hexane:AcOEt = 50:1) to give 21 (173 mg, 0.33 mmol, 56% )
and its epimer (56 mg, 0.11 mmol, 18%) as a colorless oil. Data
4.2.13. (S)-2-((1S,3S,4R,5S)-1,4-dimethyl-6-oxo-8-
(((triisopropylsilyl)oxy)methyl)-2,9-dioxabicyclo[3.3.1]non-7-en-
3-yl)propanal (26).
1
for 21; [α]D14-6.6 (c 1.11, CHCl3); H NMR (400 MHz, CDCl3)
To a stirred solution of 25 (32.7 mg, 0.08 mmol) in THF (0.4
mL) were added OsO4 (0.1M in H2O, 100 µL, 0.01 mmol) and
NaIO4 (42 mg, 0,20 mmol) at room temperature. After being
stirred for 2 h, saturated Na2S2O3 was added. The mixture was
extracted with AcOEt, washed with brine, dried, concentrated
and chromatographed (SiO2 4 g, hexane : AcOEt = 15:1) to give
26 (14 mg, 0.034 mmol, 43%) as a colorless oil. [α]D17-142.1 (c
0.84, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.79 (d, J = 2.4 Hz,
1H), 6.56 (dd, J = 1.6. 2.0 Hz, 1H), 4.51 (dd, J = 2.4, 18.4 Hz,
1H), 4.23 (dd, J = 2.0, 18.4 Hz, 1H), 4.11 (d, J = 5.6 Hz, 1H),
3.73 (dd, J = 2.0, 11.6 Hz, 1H), 2.58-2.51 (m, 1H), 2.41-2.31 (m,
1H), 1.46 (s, 3H), 1.25-1.06 (m, 24H), 0.82 (d, J = 7.2 Hz, 3H);
13C NMR (100MHz, CDCl3) δ 203.4, 194.7, 157.6, 123.7, 94.9,
δ 6.16 (s, 1H), 5.90 (ddd, J = 7.2, 10.4, 17.2 Hz, 1H), 5.11-4.99
(m, 3H), 4.54 (s, 2H), 3.65 (t, J = 4.6 Hz, 1H), 3.14 (d, J = 2.8
Hz, 1H), 2.52-2.47 (m, 1H), 2.23 (s, 3H), 2.07-2.04 (m, 1H),
1.16-0.95 (m, 27H), 0.98 (t, J = 8.0 Hz, 9H), 0.67 (q, J = 8.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 153.6, 146.5, 141.2, 119.7,
114.9, 107.0, 80.8, 68.4, 57.6, 42.5, 39.3, 18.0, 17.1, 12.7, 11.9,
11.8, 7.07, 5.4; FT-IR (neat) 3493, 2954, 2870, 1462, 1132,
1060, 1004 cm-1; HRMS (EI) calcd for C29H56O4Si2 (M+)
524.3717, found 524.3717. Data for the epimer of 21;
[α]D15+10.5 (c 0.89, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.19
(s, 1H), 5.87 (ddd, J = 7.2, 10.0, 17.6 Hz, 1H), 5.06-5.00 (m, 2H),
4.54 (s, 2H), 4.52 (dd, J = 2.4, 8.8 Hz, 1H), 3.70 (dd, J = 4.0, 6.0

6
Tetrahedron
(b) Hagenmaier H, Jaschke KH, Santo L, Scheer M,
78.8, 76.2, 60.8, 47.0, 33.3, 24.0, 17.99, 17.96, 11.9, 11.7, 11.2;
ACCEPTED MANUSCRIPT
Zähner H. Arch Microbiol. 1976;109:65.
2. (a) Shimshock SJ, Waltermire RE, DeShong P. J Am
Chem Soc. 1991;113:8791.
FT-IR (KBr) 2943, 2874, 1727, 1687, 1466, 1376, 1225, 1139,
1058 cm-1. HRMS (FAB) calcd for C22H39O5Si [(M+H)+]
411.2567, found 411.2560.
(b) Shiratani T, Kimura K, Yoshihara K, Hatakeyama
S, Irie H, Miyashita M. Chem Commun. 1996;21.
(c) Yoshimura, H. Takahashi K, Ishihara J,
Hatakeyama S. Chem Commun. 2015;51:17004.
3. For a review, see; Connon SJ, Blechert S. Angew
Chem Int Ed. 2003;42:1900.
4.2.14. Intermediate 3.
To a stirred solution of 26 (14 mg, 0.034 mmol) in benzene
(0.5 mL) was added ylide 27 (24 mg, 0.066 mmol). The mixture
was refluxed for 6 h, evaporated, chromatographed (SiO2 4 g,
hexane : AcOEt = 20:1) to give 3 (12 mg, 0.024 mmol, 71%) as a
4. For a review see; Marshall JA. J Org Chem.
2007;72:8153.
colorless oil. [α]D19-105.5 (c 1.05, CHCl3); H NMR (400 MHz,
1
5. Marshall JA, Adams ND. J Org Chem. 2002;67:733.
6. Stereoselective outcome of the reaction was
determined from 1H NMR spectra of ent-14
synthesized by the similar methodology.5
7. Sajiki H, Mori S, Ohkubo T, Ikawa T, Kume A,
Maegawa T, Monguchi Y. Chem Eur J.
2008;14:5109. Pd-PEI was purchased from Wako
Pure Chemical Industries.
8. Hoye TR, Jeffrey CS, Shao F. Nat Protoc,
2007;2:2451.
9. Rychnovsky SD, Rogers BN, Richardson TI. Acc
Chem Res. 1998;31:9.
CDCl3) δ 6.88 (dd, J = 1.2, 10.0 Hz, 1H), 6.51 (t, J = 1.6 Hz,
1H), 4.45 (dd, J = 2.4, 17.2 Hz, 1H), 4.23-4.17 (m, 3H), 4.03 (d,
J = 6.0 Hz, 1H), 3.46 (dd, J = 2.0, 11.2 Hz, 1H), 2.81-2.73 (m,
1H), 2.04-1.94 (m, 1H), 1.83 (d, J = 1.6 Hz, 3H), 1.47 (s, 3H),
1.30 (t, J = 6.8 Hz, 3H), 1.19-1.05 (m, 21H), 1.01 (d, J = 6.8 Hz,
3H), 0.71 (d, J = 6.8 Hz, 3H); 13C NMR (100MHz, CDCl3) δ
195.4, 168.0, 158.2, 141.3, 128.4, 123.3, 94.7, 78.9, 60.8, 60.6,
34.0, 33.5, 24.1, 18.01, 17.97, 16.4, 14.3, 12.5, 11.9, 11.7; FT-IR
(KBr) 2941, 2867, 1709, 1459, 1383, 1298, 1250, 1132 cm-1.
HRMS (FAB) calcd for C27H47O6Si [(M+H)+] 495.3142, found
495.3099.
10. Bouzide A. Org Lett. 2002;4:1347.
11. Pappo R, Allen Jr. DS, Lemieux RU, Johnson WS.
J
Org Chem. 1956;21:478.
Acknowledgments
12. In addition to
1, tirandamycins A, C, D, and
tirandalydigin were also synthesised from
3 by
Hatakeyama et al.2c
This work was supported by JSPS KAKENHI Grant
Number (JP 25460017), The Tokyo Biochemical Research
Foundation (TBRF) and Meiji Seika Pharma Award in
Synthetic Organic Chemistry, Japan.
Supplementary Material
1H and 13C NMR spectra of synthesized compounds.
References and notes
1. (a) Yu Z, Vodanovic-Jankovic SN, Ledeboer N,
Huang S-X, Rajski SR, Kron M, Shen B. Org Lett
2011;13:2034.
.