Synthesis of the C1–C13 fragment of eribulin mesylate

Article abstract of DOI:10.1016/j.tet.2019.06.050

Synthesis of the C1–C13 fragment of eribulin mesylate has been accomplished. It features a highly stereoselective construction of a trans-dihydropyran framework using three key reactions: (1) Sharpless epoxidation, (2) regioselective ring opening, and (3) olefin metathesis.

Full text of DOI:10.1016/j.tet.2019.06.050

Accepted Manuscript
Synthesis of the C1–C13 fragment of eribulin mesylate
Hyosun Lee, Yongseo Park, Heesun Jung, Sung Tak Kim, Seunghee Sin, Eunjung
Ko, In-Soo Myeong, Hyungwook Moon, Changhun Seol, Yunkyung Jung, Eunim
Jung, Junkyu Lee, Keeyoung Lee, Changyoung Oh, Juyoung Song, Suhwan Yoon,
Wonjae Kang, Jaehun Jung, Hyunik Shin
PII:
S0040-4020(19)30722-7
https://doi.org/10.1016/j.tet.2019.06.050
TET 30442
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 May 2019
Revised Date: 21 June 2019
Accepted Date: 28 June 2019
Please cite this article as: Lee H, Park Y, Jung H, Kim ST, Sin S, Ko E, Myeong I-S, Moon H, Seol C,
Jung Y, Jung E, Lee J, Lee K, Oh C, Song J, Yoon S, Kang W, Jung J, Shin H, Synthesis of the C1–C13
fragment of eribulin mesylate, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.06.050.
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ACCEPTED MANUSCRIPT
O
O
H
OTBS
OTBS
HO
O
H
H
H
O
O
O
O
I
O
OHC
O
O
O
O
O
O
OTBS

ACCEPTED MANUSCRIPT
Synthesis of the C1-C13 Fragment of Eribulin Mesylate
a
a
a
a
a
a
Hyosun Lee, Yongseo Park, Heesun Jung, Sung Tak Kim, Seunghee Sin, Eunjung Ko, In-
b
a
a
a
a
Soo Myeong, Hyungwook Moon, Changhun Seol, Yunkyung Jung, Eunim Jung, Junkyu
a
a
a
a
a
a
Lee, Keeyoung Lee, Changyoung Oh, Juyoung Song, Suhwan Yoon, Wonjae Kang,
a
a
Jaehun Jung, Hyunik Shin*
hishin@yonsungchem.co.kr
a
R&D Center, Yonsung Fine Chemicals Co. Ltd. Innoplex-2-dong, 306 Sinwon-ro,
Youngtong-gu, Suwon-si, Kyeonggi-do 16675, Republic of Korea
b
School of Pharmacy, Sungkyunkwan University, Seobu-ro 2066, Suwon-si, Gyeonggi-do
1
6419, Republic of Korea
ABSTRACT
O
O
OTBS
OTBS
HO
O
H
H
H
H
O
O
O
O
I
O
OHC
O
O
O
O
O
O
OTBS
Synthesis of the C1-C13 fragment of eribulin mesylate has been accomplished. It features a
highly stereoselective construction of a trans-dihydropyran framework using three key
reactions: (1) Sharpless epoxidation, (2) regioselective ring opening, and (3) olefin metathesis.
1
. Introduction
Influencing the tubulin dynamic is an important tool for the control of cell cycle arrest. In
this context, various anticancer therapeutics incorporating tubulin dynamic stabilization have
been developed, and their use effectively induces cell cycle arrest of cancerous cells. In
1
2
particular, paclitaxel is the most popular regimen, following which ixabepilone and eribulin
3
mesylate have been added to this armamentarium for combatting refractory cancer cases.
Halavan (the commercial name of eribulin mesylate 1) is a modified (truncated) marine
natural product of halichondrin B and was launched in the United States in 2010 for the
®
4
5
treatment of recurring breast cancer after first-line anthracycline/capecitabine action.
Although it has proved to be successful as a new chemotherapeutic treatment option, its
complex structure presents a significant challenge to its commercial production. Despite its
considerable complexity, derived from 19 chiral centers, eribulin mesylate has been
successfully commercialized by Eisai pharmaceutical Company using NHK reactions as a
4
d
key C-C bond-forming tool. In its commercial synthesis, eribulin has been assembled from
4
e
4f
two fragments: C1-C13, and C14-C35 subunits (Scheme 1). Furthermore, the synthesis
has continuously evolved and is now much greener and more efficient in terms of the
purification operations used in the generation of rigid intermediates, making it possible to
1

ACCEPTED MANUSCRIPT
4
i
eliminate chromatography processes, particularly in the synthesis of C14-C26 fragment.
OMe
1
3
5
H
O
O
O
H
O
H
H
2
N
OH
O
27
O
CH SO H
3
3
O
O
O
23
Me
H
1
3
Eribulin mesyate (1)
OMe
O
2
SO Ph
OTBS
TBSO
TBSO
H
H
H
O
35
11
13 I
O
27
O
+
OHC
O
1
3
OTBS
OTBS
Me
5
2
1
4
OH
C1-C13 (2)
20
17
C14-C35
Scheme 1. Commercial synthesis of Eribulin mesylate (1).
2
. Results and discussion
Taking this background into account, a synthesis of the C1-C13 fragment (2) of eribulin
mesylate (1) was devised using two key reactions: (1) the regioselective vinyl epoxide ring
opening to form the trans dihydropyran framework and (2) subsequent intramolecular olefin
metathesis reaction to complete the bicyclic structure of the C1-C13 motif (Scheme 2).
OTBS
O
H
H
H
H
O
H
O
O
O
I
OHC
O
O
O
OTBS
OTBS
O
2
7
b
O
O
H
O
H
O
O
HO
O
O
O
O
O
O
3b
6
b
Scheme 2. Synthetic strategy of C1-C13 fragment (2).
2

ACCEPTED MANUSCRIPT
The synthesis started from the known intermediate 3b, prepared in a single step from
6
readily available
D
-(-)-gulono-1,4-lactone (3a, Scheme 3) in a 66% yield. DIBAL reduction
7
of 3b to lactol and its Wittig olefination provided α,β–unsaturated ester 4a.
O
O
OR1
H
R O
3
O
TESO
O
O
EtO C
2
O
O
OR2
HO
d
a
c
O
O
R
1
O
OR
2
O
3
3
a: R =H, R =H
1
2
b: R , R =
1
2
4
a: R =H
3
5
b
4b: R =TES
3
O
O
H
H
O
O
O
O
R
3
O
H
H
H
O
O
O
O
f
R O
4
O
h
i
O
O
O
O
O
O
7
a: R =H
4
g
6
a: R =TES
3
7b: R4=
8
e
6b: R =H
3
O
OH
H
H
H
OH
OTBS
OTBS
OTBS
O
H
O
H
H
H
H
O
EtO C
I
I
2
j
O
k
OR2
EtO C
OHC
2
OR
1
O
H
OTBS
OTBS
O
OTBS
9
: R , R =
1 2
10
2
1
1: R =H, R =H
1 2
Scheme 3. Synthesis of 2. Reagents and conditions: (a) i. DIBAL, THF/toluene, −10
℃
, 15 h; ii. Ph P=CHCO Et,
3 2
benzoic acid, CH Cl , 50℃, 24 h, 64% (for two steps); (b) i. TESOTf, 2,6-lutidine, CH Cl , 0℃, 1 h, quant.; ii. 5
2
2
2
2
mol% PBu , THF, 50℃, 24 h, 78%; (c) DIBAL, CH Cl , −20 , 88%; (d) i. (−)-DET, Ti(OiPr) , CH Cl , 0℃, 15
℃
4 2 2
3
2
2
h, 62%; ii. DMP, CH Cl , 0℃, 1.5 h, 97%; iii. MePPh Br, NaHMDS, THF, 0℃, 1 h, 71%; (e) TBAF, THF, 0℃, 1
2
2
3
nd
h, 82%; (f) PPTS, CH Cl , 0℃, 7 h, 93%; (g) acrylic acid, DIC, DMAP, CH Cl , rt, 5 h, 80%; (h) i. Grubbs’ 2
2
2
2
2
cat., toluene, reflux, 24 h, 88%; ii. Pd/C, H , EtOAc, 6 h, 99%; (i) i. DIBAL, THF/toluene, −10 , 15 h; ii.
℃
2
triethyl phosphonoacetate, t-BuOK, THF, 60℃, 20 h, 80% (for two steps); iii. AcOH, 40℃, 5 h, 91%; (j) using
ref. 4e conditions: i. NaIO , EtOAc, 15°C, quant.; ii. CrCl , NiCl , 1-bromo-2-trimethylsilylethene, DMSO,
4
2
2
MeCN, 30°C, 64%; iii. AcOH, H O, 95°C, crystallization, 66%; iv. TBSOTf, 2,6-lutidine, MTBE, 30°C,
2
crystallization, 97%; v. NIS, MeCN, toluene, TBSCl, 35°C, 89%; and (k) DIBAL, BHT, toluene, −65
2%.
℃
, 1 h,
9
At this olefination stage, a significant undesired reaction was encountered after methylene
chloride reflux, where the tetrahydrofuranyl side product was formed as a major product via
the oxa-Michael addition of the secondary hydroxyl group to α,β–unsaturated ester (Entry 1,
8
9
Table 1). This problem could be resolved by the addition of benzoic acid with moderate E/Z
stereoselectivity in a ratio of 5:1 (Entry 2). Horner–Wadsworth–Emmons reaction conditions
were used, but only oxa-Michael reaction adduct 13 was afforded (Entries 3-5). The lowered
stereoselectivity could be improved marginally to 6:1 in toluene (Entries 6 and 7) and to 7:1
3

ACCEPTED MANUSCRIPT
in THF at 50℃(Entries 8 and 9). Next, the secondary alcohol of 4a was protected as a TES
group to provide 4b. At this point, the moderate E/Z stereoselectivity of 4a could be
enhanced under thermodynamically controlled conditions — when 4b was heated at 50℃for
1
0
2
4 h in the presence of 5 mol% of tributylphosphine, the E/Z ratio was better than 30:1.
Table 1. Olefination of 3b.
O
O
O
H
O
OH
H
O
O
O
O
O
X
Y
O
O
1
) DIBAL
EtO C
2
2
) Olefination conditions
O
O
O
O
3
b
13
4
a: X=CO Et, Y=H
2
1
2: X=H, Y=CO Et
2
a
b
Entry
Reagents and additive
Ph P=CHCO Et
Solvent Temp. Time Ratio (4a:12:13) Yield (%)
1
2
3
4
5
6
7
8
DCM
DCM
THF
THF
THF
reflux 48 h
reflux 48 h
13 only
5:1:0
75
70
63
57
62
51
61
73
66
3
2
Ph P=CHCO Et, benzoic acid
3
2
Triethyl phosphonoacetate, KHMDS
Triethyl phosphonoacetate, LiHMDS
Triethyl phosphonoacetate, LiCl, DIPEA
Ph P=CHCO Et, benzoic acid
rt
rt
rt
4 h
4 h
4 h
4 h
13 only
13 only
13 only
6:1:2
toluene 90 ℃
3
2
Ph P=CHCO Et, benzoic acid
toluene 50 ℃ 24 h
6:1:0
3
2
Ph P=CHCO Et, benzoic acid
THF
THF
50 ℃ 48 h
60 ℃ 48 h
7:1:0
3
2
9
Ph P=CHCO Et, benzoic acid
7:1:3
3
2
a
1
Ratios were determined by H NMR analysis.
Yields refer to two-step yields of mixed products.
b
Reduction of the ester group of 4b afforded the allylic alcohol 5. For the introduction of
the epoxide group, mCPBA epoxidation was performed, which resulted in low
1
stereoselectivity in a ratio of 2:1 by H NMR analysis. Next, diastereoselective Sharpless
11
epoxidation at 0℃using (−)-diethyltartarate, t-BuOOH, and titanium isopropoxide provided
the epoxide intermediate in a high diastereoselectivity of 30:1. Initially, t-BuOOH was used
as an oxidant, which was changed to cumyl hydroperoxide considering its ready availability
on a large scale and at low cost with the same outcome. To guide the regioselectivity of
cyclization, the vinyl group was introduced via oxidation-Wittig olefination to provide 6a.
Subsequent deprotection of the TES group by TBAF afforded 6b. As was well demonstrated
1
2
in Nicolau’s research, the cyclization under mild acid catalysis of PPTS induced 6-endo
cyclization exclusively to provide the pyran intermediate, the secondary alcohol group of
which was condensed with acrylic acid in the presence of DIC and a catalytic amount of
1
3
DMAP to afford 7b. Next, the intramolecular metathesis reaction of 7b in the presence of
Grubb’s second-generation catalyst in toluene at 80°C was attempted, and it provided α,β-
unsaturated lactone in an excellent yield of 88%. Hydrogenation using palladium as a catalyst
provided the lactone 8.
Reduction of 8 by DIBAL afforded a lactol intermediate. Its Horner–Wadsworth–Emmons
4

ACCEPTED MANUSCRIPT
1
4
reaction provided a transient α,β-unsaturated ester intermediate, which underwent
cyclization by the oxa-Michael addition of the hydroxyl group to the double bond to form
compound 9. At this step, it is critical to run the reaction for at least 20 h to enrich the
thermodynamically more stable 9 in which the carboxymethyl substituent occupies the
equatorial position via a Michael–retro-Michael reaction sequence. At an early stage of the
reaction, the axial and equatorial diastereomers were observed in a 1:1 ratio, which slowly
merged to 9 in a 98:2 ratio after 20 h. In the course of selective deprotection of the
cyclohexylidene groups, a small portion of fully deprotected tetraol compound 11 was
purified, which forms a good crystal for singe-crystal X-ray analysis in which the
ethoxycarbonyl methyl group exists in the disordered form (Figure 1). This provided
unambiguous structural information, particularly for the induced stereogenic centers.
Although methyl ester of 9 is known in the literature, ethyl ester 9 has not been reported. In
this regard, in the present study, 9 was transformed to 10 following conversion conditions
4
e
used with the methyl ester of 9 to provide 10 with comparable results. Final reduction of the
ester group of 10 provided 2, whose properties showed good agreement with the reported
4
d
data. The full details about synthesis from 9 to 10 are in the Supporting Information.
Figure 1. X-ray crystal structure of 11.
3
. Conclusion
In conclusion, a synthetic route to the C1-C13 fragment of eribulin mesylate was devised.
This synthesis used the regioselective ring opening of the vinyl epoxide of 6 and
intramolecular olefin metathesis reaction as key steps in high regioselectivity and
stereoselectivity.
4
. Experimental section
5

ACCEPTED MANUSCRIPT
4
.1. General methods
1
13
Optical rotations were measured with a polarimeter in the solvent specified. H and
C
nuclear magnetic resonance (NMR) spectroscopic data were recorded with a Fourier
transform NMR (FT-NMR) spectrometer at 75 or 300 MHz. Chemical shift values are
reported in parts per million (ppm) relative to TMS or CDCl as the internal standard, and
3
coupling constants are reported in hertz. Infrared (IR) spectra were measured with a Fourier
transform IR (FT-IR) spectrometer. Mass spectroscopic data were obtained with a Jeol JMS
7
00 high-resolution mass spectrometer equipped with a magnetic-sector–electric-sector
double-focusing analyzer. Flash chromatography was performed using mixtures of ethyl
acetate and hexane as eluents. Unless otherwise stated, all the nonaqueous reactions were
carried out under an argon atmosphere with commercial-grade reagents and solvents.
Tetrahydrofuran (THF) was distilled from sodium and benzophenone. Dichloromethane was
distilled from calcium hydride.
4
.2. (E)-ethyl 3-((2S,3R)-3-((S)-hydroxy((R)-1,4-dioxaspiro[4.5]decan-2-yl)methyl)-1,4-
dioxaspiro[4.5]decan-2-yl)acrylate (4a)
To a solution of 3b (30 kg, 89 mol) in THF (110 L) and toluene (75 L) was added DIBAL (89
L, 11 mol) at −10 . The reaction mixture was stirred at −10 for 0.5 h and quenched with an
℃
℃
aqueous KNa tartrate·4H O (120 L) solution. The layers were separated, and the aqueous
2
layer was extracted with MTBE (30 L). The mixture was filtered through a pad of Celite and
concentrated in vacuo. The resulting substance was immediately used without further
purification. To a solution of the above resulting substance (37 g, 110 mmol) in CH Cl (370
2
2
mL) were added Ph P=CHCO Et (1.6 kg, 220 mmol) and benzoic acid (1.3 g, 11 mmol) at
3
2
5
0℃. The reaction mixture was stirred at 50℃ for 24 h, after which time thin-layer
chromatography (TLC) analysis indicated a complete reaction. The reaction mixture was
filtered and washed with MTBE/heptane (1:10, 90 mL X 3). The solvent was removed in
vacuo. Purification by silica gel chromatography (hexanes:ethyl acetate = 5:1) gave the
2
0
product 4a (29 kg, 70.0 mol, 64%, two steps) as a colorless oil; [α]D +1.8 (c 0.5, CHCl ); IR
(
3
−
1 1
neat) ν max 3447, 2936, 2861, 1719, 1449, 1367, 1280, 1164, 1100, 1136, 930, 756 cm ; H
NMR (300 MHz, CDCl ): δ 5.47 (s, 1H), 4.67-4.70 (m, 1H), 4.62 (d, J = 6.0 Hz, 1H), 4.10-
3
1
3
4
.40 (m, 4H), 3.70-3.75 (m, 1H), 1.38-1.66 (m, 20H); C NMR (75 MHz, CDCl ): δ 113.7,
3
1
10.4, 101.7, 85.2, 82.8, 79.6, 75.4, 65.7, 36.3, 35.7, 35.0, 34.4, 25.1, 25.0, 24.0, 24.0, 23.8,
+
+
2
3.8; HRMS (ESI+) [(M+Na) ] m/z calcd. for C H O +Na 433.2197; found 433.2197.
2
2
34
7
4
.3. (E)-ethyl
yl)(triethylsilyloxy)methyl)-1,4-dioxaspiro[4.5]decan-2-yl)acrylate (4b)
To a solution of 4a (87 g, 210 mmol) in CH Cl (440 mL) was added 2,6-lutidine (32 mL,
3-((2S,3S)-3-((S)-((R)-1,4-dioxaspiro[4.5]decan-2-
2
2
2
70 mmol) and TESOTf (53 mL, 230 mmol) at 0℃. The reaction mixture was stirred at 0℃
for 1 h and quenched with aqueous 20% NH Cl (0.4 L) solution. The layers were separated,
4
dried over Na SO , and concentrated in vacuo. Purification by silica gel chromatography
2
4
(
[
hexanes:ethyl acetate = 10:1) gave the product 4b (87 g, 170 mmol, 78%) as a colorless oil;
2
0
α]D +155.6 (c 0.5, CHCl ); IR (neat) ν max 2936, 2875, 1715, 1448, 1415, 1366, 1232, 1194,
3
6

ACCEPTED MANUSCRIPT
−
1 1
1
166, 1108, 1033, 935, 827, 740 cm ; H NMR (300 MHz, CDCl ): δ 7.02 (dd, J = 15.0, 6.0
3
Hz, 1H), 6.05 (dd, J = 15.0, 3.0 Hz, 1H), 4.67-4.79 (m, 1H), 4.09-4.31 (m, 2H), 3.89-4.00 (m,
1
3
1
H), 3.76-3.86 (m, 2H), 1.39-1.77 (m, 20H), 0.93-0.98 (m, 9H), 0.55-0.69 (m, 6H); C NMR
(
3
75 MHz, CDCl ): δ 166.0, 144.6, 123.4, 109.8, 78.6, 76.5, 76.1, 71.3, 65.4, 60.5, 37.3, 35.9,
3
+
4.8, 25.2, 25.1, 24.0, 24.0, 23.8, 23.8, 14.2, 6.9, 5.2; HRMS (ESI+) [(M+Na) ] m/z calcd. for
+
C H O Si+Na 547.3062; found 547.3060.
28
48
7
4
.4. (E)-3-((2S,3S)-3-((S)-((R)-1,4-dioxaspiro[4.5]decan-2-yl)(triethylsilyloxy)methyl)-
,4-dioxaspiro[4.5]decan-2-yl)prop-2-en-1-ol (5)
To a solution of 4b (12 kg, 22 mol) in CH Cl (58 L) was added DIBAL (45 L, 53 mol) at
1
2
2
−20℃. The reaction mixture was stirred at −10 for 0.5 h and quenched with KNa
℃
tartrate·4H O (24 kg) and water (70 kg). The layers were separated, and the aqueous layer
2
was extracted with CH Cl (24 L). The mixture was filtered through a pad of Celite and
2
2
concentrated in vacuo. Purification by silica gel chromatography (hexanes:ethyl acetate =
2
0
1
0:1) gave the product 5 (9.5 kg, 20 mol, 88%) as a colorless oil; [α]D −12.5 (c 1.0, CHCl );
3
−1
IR (neat) ν
3422, 2936, 2874, 1448, 1365, 1281, 1232, 1164, 1105, 1006, 936, 741 cm ;
H NMR (300 MHz, CDCl ) : δ 5.79-5.95 (m, 2H), 4.58-4.62 (m, 1H), 4.09-4.19 (m, 4H),
max
1
3
3
.93-3.98 (m, 1H), 3.80-3.86 (m, 1H), 3.72-3.76 (m, 1H), 1.32-1.75 (m, 20H), 0.94-1.00 (m,
1
3
9
7
H), 0.65-0.70 (m, 6H); C NMR (75 MHz, CDCl ): δ 133.9, 128.1, 109.9, 109.3, 78.6, 77.8,
3
6.1, 71.3, 65.4, 62.9, 37.6, 35.8, 35.2, 35.0, 25.2, 25.2, 24.0, 23.9, 23.9, 23.8, 7.0, 5.3;
+
+
HRMS (ESI+) [(M+Na) ] m/z calcd. for C H O Si+Na 505.2956; found 505.2951.
2
6
46
6
4
.5. (1S)-((R)-1,4-dioxaspiro[4.5]decan-2-yl)((2R,3S)-3-((2S,3R)-3-vinyloxiran-2-yl)-
,4-dioxaspiro[4.5]decan-2-yl)methanol (6b)
To a solution of (−)-DET (2.1 mL, 12 mmol) with 3 ÅMS in CH Cl (110 mL) was added
1
2
2
Ti(i-PrO) (1.8 mL, 6.2 mmol) and 80% cumene hydroperoxide (17 mL, 93 mmol) at −10 .
℃
4
Compound 5 (30 g, 62 mol) in CH Cl (110 mL) solution was added to a solution of the
2
2
above mixture. The reaction mixture was stirred for 15 h and quenched with NaOH solution
160 mL). The mixture was filtered through a pad of Celite and concentrated in vacuo.
(
Purification by silica gel chromatography (hexanes:ethyl acetate = 5:1) gave the epoxide (19
g, 39 mmol, 62%). To a solution of epoxide (19 g, 39 mmol) in CH Cl (86 mL) was added
2
2
DMP (33 g, 77 mmol) at 0℃. The reaction mixture was stirred at room temperature for 1.5 h
and quenched with 20% Na S O (170 mL) and 5% NaHCO (170 mL). The layers were
2
2
3
3
separated, dried over Na SO , and concentrated in vacuo. The resulting aldehyde was
2
4
immediately used without further purification. To a solution of MePPh Br (18 g, 50 mmol) in
3
THF (76 mL) was added 2 M NaHMDS (24 mL, 48 mmol) at 0℃. The resulting aldehyde (19
g, 39 mmol) in THF (38 mL) solution was added to a solution of the above mixture. The
reaction mixture was stirred for 3 h and quenched with sat. NH Cl solution (76 mL). The
4
layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined
organic phase was separated, dried over Na SO , and concentrated in vacuo. Purification by
2
4
silica gel chromatography (hexanes:ethyl acetate = 15:1) gave 6a (14 g, 28 mmol, 71%). To a
solution of 6a (10 g, 20 mmol) in THF (100 mL) was added TBAF (26 mL, 27 mmol) at 0℃.
The reaction mixture was stirred for 1 h and quenched with sat. NH Cl (42 mL). The layers
4
were separated, dried over Na SO , and concentrated in vacuo. Purification by silica gel
2
4
7

ACCEPTED MANUSCRIPT
2
0
chromatography (hexanes:ethyl acetate = 1:1) gave 6b (6.3 g, 16 mmol, 82%); [α] −11.3 (c
D
−
1 1
0
.5, CHCl ); IR (neat) ν
3446, 2929, 2855, 1457, 1365, 1100, 930, 772 cm ; H NMR
max
3
(300 MHz, CDCl ): δ 5.48-5.65 (m, 2H), 5.30-5.34 (m, 1H), 4.22-4.31 (m, 2H), 4.06-4.16 (m,
3
2
2
H), 3.89-3.94 (m, 2H), 3.74-3.79 (m, 1H), 3.29-3.32 (m, 1H), 3.20 (dd, J = 8.1, 2.1 Hz, 1-H),
1
3
.48 (d, J = 7.6 Hz, 1H), 1.40-1.75 (m, 20H); C NMR (75 MHz, CDCl ): δ 134.3, 120.2,
3
1
2
10.2, 110.2, 77.8, 77.2, 76.1, 69.2, 65.6, 58.3, 57.5, 37.0, 36.1, 34.9, 34.4, 25.2, 25.1, 24.0,
+
+
3.8, 23.7; HRMS (ESI+) [(M+Na) ] m/z calcd. for C H O +Na 403.2191; found 403.2085.
2
1
32
6
4
.6. (3aR,4S,6S,7S,7aS)-4-((R)-1,4-dioxaspiro[4.5]decan-2-yl)-6-vinyltetrahydro-3aH-
spiro[[1,3]dioxolo[4,5-c]pyran-2,1'-cyclohexan]-7-ol (7a)
To a 6b (6.3 g, 16 mmol) in CH Cl (31 mL) was added PPTS (2.1 g, 8.3 mmol) at 0℃. The
2
2
reaction mixture was stirred for 7 h. TEA (2.3 mL) was added to the reaction mixture. The
solvent was removed in vacuo. Purification by silica gel chromatography (hexanes:ethyl
2
0
acetate = 3:1) gave the 7a (5.8 g, 15 mmol, 93%); [α]D −19.8 (c 0.3, CHCl ); IR (neat) ν
3
3
max
−1 1
423, 2931, 2855, 1449, 1366,1281, 1165, 1100, 932, 848, 772 cm ; H NMR (300 MHz,
CDCl ): δ 5.95-6.06 (m, 1H), 5.51-5.58 (m, 1H), 5.23-5.27 (m, 1), 4.51-4.55 (m, 1H), 4.27-
3
4
1
7
.38 (m, 2H), 4.21-4.24 (m, 1H), 4.09-4.14 (m, 1H), 3.77-3.82 (m, 1H), 3.53-3.64 (m, 2H),
1
3
.30-1.82 (m, 20H); C NMR (75 MHz, CDCl ): δ 135.9, 116.1, 111.5, 110.1, 75.8, 74.7,
3
3.7, 73.5, 72.5, 68.9, 65.3, 36.5, 35.7, 35.1, 34.7, 25.2, 25.1, 24.0, 24.0, 23.8; HRMS (ESI+)
+
+
[
(M+Na) ] m/z calcd. for C H O +Na 403.2091; found 403.2097.
21 32 6
4
.7. (3aR,4S,6S,7S,7aR)-4-((R)-1,4-dioxaspiro[4.5]decan-2-yl)-6-vinyltetrahydro-3aH-
spiro[[1,3]dioxolo[4,5-c]pyran-2,1'-cyclohexane]-7-yl acrylate (7b)
To a solution of 7a (5 g, 13 mmol) in CH Cl (75 mL) was added acrylic acid (3.6 mL, 53
2
2
mmol), DIC (8.3 mL, 53 mmol), and DMAP (0.32 g, 2.7 mmol) at 0℃. The reaction mixture
was stirred at room temperature for 5 h until TLC showed complete reaction. Diethyl ether
(83 mL) was added to the reaction mixture. The reaction mixture was filtered, and the solvent
was removed in vacuo. Purification by silica gel chromatography (hexanes:ethyl acetate = 1:1)
2
0
gave 7b (4.6 g, 11 mmol, 80%) as a colorless oil; [α]D −55.6 (c 0.5, CHCl ); IR (neat) ν
2
3
max
−
1 1
934, 2858, 1731, 1449, 1407, 1366, 1277, 1186, 1104, 937, 848 cm ; H NMR (300 MHz,
CDCl ): δ 6.46-6.52 (m, 1H), 6.16-6.25 (m, 1H), 5.77-5.92 (m, 2H), 5.54-5.61 (m, 2H), 5.18-
3
5
.23 (m, 2H), 4.56-5.01 (m, 1H), 4.31-4.38 (m, 1H), 4.24 (dd, J = 7.7, 1.8 Hz, 1H), 4.15 (dd,
J = 8.4, 6.4 Hz, 1H), 3.77 (dd, J = 8.4, 6.9 Hz, 1H), 3.56 (dd, J = 8.1, 1.8 Hz, 1H), 1.22-1.88
1
3
(
m, 20H); C NMR (75 MHz, CDCl ): δ 165.5, 134.7, 132.1, 127.8, 116.1, 112.0, 110.2, 75.7,
3
7
4.4, 73.8, 72.2, 71.5, 70.1, 65.3, 36.5, 35.6, 35.1, 35.1, 25.1, 25.1, 24.0, 23.9, 23.8; HRMS
+
+
(ESI+) [(M+Na) ] m/z calcd. for C H O +Na 457.2197; found 457.2199.
24 34 7
4
.8. Ethyl
’,5’,8’,13’-tetraoxaspiro[cyclohexane-1,4’-tricyclo[7.4.0.0 ]tridecane]-12’-
yl]acetate (9)
To a solution of 7b (5 g, 12 mmol) in toluene (250 mL) was added a second Grubbs catalyst
0.4 g, 0.5 mmol). The reaction mixture was stirred at reflux for 24 h. The solvent was
2-[1’S,2’S,6’S,7’S,9’S,12’R]-7’-[(2R)-1,4-dioxaspiro[4,5]decan-2-yl]-
2,6
3
(
removed in vacuo. Purification by silica gel chromatography (hexanes:ethyl acetate = 1:1)
gave a bicyclic product (4.1 g, 10 mmol, 88%). To a solution of bicyclic product (4.1 g, 10
8

ACCEPTED MANUSCRIPT
mmol) in EtOAc (20 mL) was added 10% Pd/C (0.41 g). The reaction mixture was stirred
under H for 6 h. The reaction mixture was filtered through a pad of Celite and concentrated
2
in vacuo. The resulting substance 8 (4.1 g, 10.0 mmol, 99%) was immediately used without
further purification. To a solution of 8 (4.1 g, 10.0 mmol) in THF (10 mL) and toluene (7 mL)
was added DIBAL (8.4 mL, 12 mmol) at −10
.5 h and quenched with aqueous KNa tartrate·4H O (10 mL) solution. The layers were
. The reaction mixture was stirred at −10 for
℃ ℃
0
2
separated, and the aqueous layer was extracted with MTBE (10 mL). The combined organic
phase was separated, dried over Na SO , and concentrated in vacuo. The resulting substance
2
4
was immediately used without further purification. To a solution of triethyl phosphonoacetate
3.4 g, 15 mmol) in THF (38 mL) was added t-BuOK (1.7 g, 15 mmol). The resulting
(
substance (4.1 g, 10 mmol) was added to a solution of reaction mixture. The reaction mixture
was stirred at 60℃for 20 h and quenched with sat. NH Cl solution (21 mL). The layers were
4
separated, and the aqueous layer was extracted with ethyl acetate (8.4 mL). The combined
organic phase was separated, dried over Na SO , and concentrated in vacuo. Purification by
2
4
silica gel chromatography (hexanes:ethyl acetate = 3:1) gave an ester compound (4.6 g, 9.7
mol, 96%). To the ester compound (4.6 g, 9.7 mmol) was added AcOH (75 mL) and water
(18 mL). The reaction mixture was stirred at 40℃for 5 h. Toluene (90 mL) was added to the
reaction mixture. The solvent was removed in vacuo. Purification by silica gel
chromatography (dichloromethane:methanol = 20:1) gave 9 (3.6 g, 8.9 mmol, 91%) as a
2
0
colorless oil; [α]D −40.8 (c 1.0, CHCl ); IR (neat) ν
1
3447, 2936, 2863, 1733, 1448, 1371,
max
3
−
1 1
339, 1285, 1196, 1164, 1102, 1033, 952, 756 cm ; H NMR (300 MHz, CDCl ): δ 4.56 (dd,
3
J=8.3, 2.8 Hz, 1H), 4.45 (dd, J=8.4, 1.5 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.72-3.97 (m, 6H),
3
2
1
3
4
.51 (dd, J=10.3, 2.9 Hz, 1H), 2.70 (dd, J=16.0, 6.8 Hz, 1H), 2.41 (dd, J=16.0, 6.1 Hz, 1H),
1
3
.05-2.17 (m, 1H), 1.33-1.84 (m, 13H), 1.20-1.29 (m, 4H); C NMR (75 MHz, CDCl ): δ
3
71.0, 111.1, 110.1, 76.3, 75.2, 74.2, 71.8, 71.4, 66.1, 65.5, 60.5, 40.5, 36.3, 35.6, 35.3, 33.5,
+
+
0.0, 25.1, 24.0, 23.8, 23.7, 14.2; HRMS (ESI+) [(M+Na) ] m/z calcd. for C H O +Na
2
0
32
8
23.1989; found 423.1987.
4
.9. Ethyl 2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis(tert-butyldimethylsilyloxy)-6-((S,E)-1-(tert-
butyldimethylsilyloxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)acetate (10)
2
0
Colorless oil; [α]D −32.2 (c 0.4, CHCl ); IR (neat) ν
1
2953, 2930, 2857, 1740, 1472, 1254,
max
3
−
1 1
080, 835, 777 cm ; H NMR (300 MHz, CDCl ) : δ 6.86 (dd, J = 14.6, 7.8 Hz, 1H), 6.28
3
(dd, J = 14.6, 0.7 Hz, 1H), 4.88-4.92 (m, 1H), 4.07-4.21 (m, 3H), 3.77-3.90 (m, 3H), 3.42-
3
1
0
8
1
.51 (m, 1H), 2.93 (dd, J = 9.6, 2.2 Hz, 1H), 2.53 (dd, J = 15.4, 8.1 Hz, 1H), 2.36 (dd, J =
5.4, 5.1 Hz, 1H), 1.92-1.97 (m, 1H), 1.70-1.82 (m, 1H), 1.23-1.28 (m, 3H), 0.94 (s, 9H),
1
3
.92 (s, 9H), 0.86 (s, 9H), 0.02-0.11 (s, 18H); C NMR (75 MHz, CDCl ): δ 171.3, 146.7,
3
1.3, 78.8, 77.6, 74.1, 73.6, 72.7, 70.7, 64.3, 60.5, 40.9, 30.6, 28.8, 26.7, 26.3, 26.1, 19.1,
+
8.7, 18.2, 14.2, −3.4, −3.8, −3.9, −-4.3, −4.5, −4.7 ; HRMS (ESI+) [(M+Na) ] m/z calcd. for
+
C H IO Si +Na 807.1989; found 807.1987.
33
65
7
3
4
.10.
tert-butyldimethylsilyloxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-
yl)acetaldehyde (2)
2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis(tert-butyldimethylsilyloxy)-6-((S,E)-1-
(
To a solution of 10 (120 g, 160 mmol) and BHT (0.8 g, 3 mmol) in toluene (1.6 L) was added
9

ACCEPTED MANUSCRIPT
DIBAL (16 mL, 190 mmol) at −65℃. The reaction mixture was stirred at −65℃for 1 h and
quenched with an aqueous 1 N HCl (1.3 L) solution. The layers were separated, and the
aqueous layer was extracted with MTBE (1 L) and washed with 5% NaHCO (1.2 L) and 10%
3
NaCl (1.2 L). The mixture was filtered through a pad of Celite and concentrated in vacuo.
Purification by silica gel chromatography (hexanes:ethyl acetate = 10:1) gave 2 (110 g, 140
2
0
mol, 92%) as a colorless oil; [α]D −38.6 (c 0.5, CHCl ); IR (neat) ν
2
9
2953, 2929, 2857,
max
3
−
1 1
360, 1732, 1472, 1361, 1254, 1082, 835, 777, 669 cm ; H NMR (300 MHz, CDCl ) : δ
.78-9.79 (m, 1H), 6.85 (dd, J = 14.6, 7.9 Hz, 1H), 6.29 (dd, J = 14.6, 0.7 Hz, 1H), 4.88-4.92
3
(m, 1H), 4.08-4.11 (m, 1H), 3.81-3.93 (m, 3H), 3.45-3.53 (m, 1H), 2.95 (dd, J = 9.6, 2.3 Hz,
1
1
H), 2.63 (ddd, J = 16.5, 8.5, 2.6 Hz, 1H), 2.44 (ddd, J = 16.4, 4.4, 1.7 Hz, 1H), 1.95-1.98 (m,
H), 1.74-1.79 (m, 1H), 1.32-1.46 (m, 2H), 0.94 (s, 9H), 0.93 (s, 9H), 0.86 (s, 9H), 0.02-0.11
1
3
(s, 18H); C NMR (75 MHz, CDCl ): δ 200.8, 146.7, 81.3, 79.0, 77.7, 73.6, 72.8, 72.6, 70.7,
3
6
4.2, 30.9, 28.8, 26.7, 26.3, 26.1, 19.1, 18.8, 18.2, −3.4, −3.8, −3.9, −4.4, −4.6; HRMS (ESI+)
+
+
[
(M+Na) ] m/z calcd. for C H IO SI +Na 763.2713; found 763.2705.
31 61 6 3
5
. Acknowledgments
This work was supported by the Advanced Technology Center (ATC) Program (No.10048257)
funded by the Ministry of Trade, industry & Energy (MI, Korea). We thank Prof. Ok-Sang
Jung at Pusan National University for X-ray crystal structural analysis of 11 and Prof. James
D. White at Oregon State University for his insightful comments.
6
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Wadsworth, D.; Schupp III, O.; Seus, E.; Ford Jr, J. J. Org. Chem. 1965, 30, 680-685.
1
2