Synthesis of the C18–C26 tetrahydrofuran-containing fragment of amphidinolide C congeners via tandem asymmetric dihydroxylation and SN2 cyclization

Article abstract of DOI:10.1016/j.tet.2018.02.021

The C18–C26 fragment of amphidinolide C congeners has been synthesized starting from methyl acetoacetate in 14 steps in >17.0% overall yield. The C20 stereogenic center was secured by asymmetric hydrogenation of a β-keto ester and the configuration at both C23 and C24 was introduced by asymmetric dihydroxylation (AD). The trans-2,5-disubstituted tetrahydrofuran ring was assembled via the tandem AD–S_N2 sequence. The latter protocol could be employed for accessing the corresponding cis-2,5-disubstituted tetrahydrofuran rings from the same alkene substrates simply by choosing a suitable AD ligand. Moreover, functional group compatibility was observed for the Ru(II)-catalyzed hydrogenation of β-keto esters and the Pd(0)–Cu(I)-catalyzed Sonogashira cross-coupling reaction. These findings should be valuable for general synthetic design and application.

Full text of DOI:10.1016/j.tet.2018.02.021

Accepted Manuscript
Synthesis of the C18–C26 tetrahydrofuran-containing fragment of amphidinolide C
congeners via tandem asymmetric dihydroxylation and S 2 cyclization
N
Ye-Xiang Su, Wei-Min Dai
PII:
S0040-4020(18)30146-7
10.1016/j.tet.2018.02.021
TET 29292
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 January 2018
Revised Date: 7 February 2018
Accepted Date: 8 February 2018
Please cite this article as: Su Y-X, Dai W-M, Synthesis of the C18–C26 tetrahydrofuran-containing
fragment of amphidinolide C congeners via tandem asymmetric dihydroxylation and S 2 cyclization,
N
Tetrahedron (2018), doi: 10.1016/j.tet.2018.02.021.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of the C18–C26 tetrahydrofuran-containing
fragment of amphidinolide C congeners via tandem
asymmetric dihydroxylation and SN2 cyclization
Ye-Xiang Su, Wei-Min Dai*
Leave this area blank for abstract info.
RO
OMs
RO
TMS
26
modified AD-mix-β
0 oC, 36 h (82%)
18
O
H
H
R = TBDPS
TMS
OH
OH
RO OMs
TMS
OH

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of the C18–C26 tetrahydrofuran-containing fragment of amphidinolide C
congeners via tandem asymmetric dihydroxylation and SN2 cyclization
Ye-Xiang Su, Wei-Min Dai
Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong SAR, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The C18–C26 fragment of amphidinolide C congeners has been synthesized starting from
methyl acetoacetate in 14 steps in >17.0% overall yield. The C20 stereogenic center was secured
by asymmetric hydrogenation of a β-keto ester and the configuration at both C23 and C24 was
introduced by asymmetric dihydroxylation (AD). The trans-2,5-disubstituted tetrahydrofuran
ring was assembled via the tandem AD–SN2 sequence. The latter protocol could be employed for
accessing the corresponding cis-2,5-disubstituted tetrahydrofuran rings from the same alkene
substrates simply by choosing a suitable AD ligand. Moreover, functional group compatibility
was observed for the Ru(II)-catalyzed hydrogenation of β-keto esters and the Pd(0)–Cu(I)-
catalyzed Sonogashira cross-coupling reaction. These findings should be valuable for general
synthetic design and application.
Available online
Keywords:
Amphidinolide C
Asymmetric dihydroxylation
Enyne
Intramolecular SN2 reaction
Sonogashira cross-coupling
Tetrahydrofuran
© 2018 Elsevier Ltd. All rights reserved
.
O
1. Introduction
OR3
16
O
27
15
Bu
29
18
Amphidinolide C congeners have five known members,
among which, amphidinolide C1–C3 (1–3)1–3 and F (5)4 were
produced by symbiotic marine dinoflagellates Amphidinum spp.
(Y-5, Y-26, Y-56, Y-59 and Y-71 strains) (Fig. 1). These
macrolides consist of a common 25-membered macrolactone
core featured with two 2,5-trans-substituted tetrahydrofuran
subunits, and one each conjugated diene (at C9–C11), anti-
vicinal diol (at C7–C8) and 1,4-diketone (at C15–C18) moieties.
Their structures differ only from the alkenyl motif connected to
C26 on the side chains which are remarkably important to their
cytotoxicity against murine lymphoma L1210 and P388, and
human epidermoid carcinoma KB cell lines (Fig. 1). Recently,
amphidinolide C4 (4)5 was isolated from the Brazilian octocoral
Stragulum bicolor along with other amphidinolides.6 It possesses
essentially the same macrolactone core as the above-mentioned
amphidinolide C congeners except for the depleted C8 hydroxy
group in 4. The preliminary cytotoxicity data given in Fig. 1
clearly indicate that both the C8 and C29 hydroxy groups are the
structural requirements necessary for high cytotoxicity of this
class of 25-membered macrolides.7
13
12
20
Me
Me
Me
Me
OH
R2
a: R3 = H; b: R3 = Ac
23
H
O
H
H
10
HO
24
26
H
O
O
8
O
9
7
Bu
6
3
c:
R1
O
4
Me
OH
Me
1: amphidinolide C1, R1 = OH, R2 = a
2: amphidinolide C2, R1 = OH, R2 = b
3: amphidinolide C3, R1 = OH, R2 = c
4: amphidinolide C4, R1 = H, R2 = d
5: amphidinolide F, R1 = OH, R2 = e
Pr
d:
e:
Me
Me
Me
1
2
3b
7.6
4
5
c
L1210a
KBa
0.0058
0.8
1.5
−
c
−
0.0046
3.0
10.0
3.2
a IC50 in µg/mL. b 2.9 µg/mL for P388 cell line. c Inactive.
Fig. 1. The structures and cytotoxicity of ampidinolide C1–C4 and F.
The structural complexity and scarce availability of
amphidinolide C1 and the congeners isolated from cell cultures
render them suitable targets for chemical synthesis. Both Carter
and Fürstner’s groups have completed total synthesis of
amphidinolide C1 and F via macrolactonization8 and ring-closing
———
Corresponding author. Tel.: +852 23587365; fax: +852 23581594; e-mail address: chdai@ust.hk.

2
Tetrahedron
alkyne metathesis (RCAM)9 as the key steps, respectively, for
1. TBAF
2. Dibal-H
ACCEPTED MANUSCRIPT
19
23
18
20
23
construction of the macrolactone core. In Carter’s total
synthesis,8 amphidinolide C1 and F were disconnected into the
C1–C8, C9–C14, and C15–C25 fragments; the side chains were
coupled to the C25 aldehyde through Wittig olefination of the
Tamura/Vedejs-type tributylphosphonium-derived allylic ylides10
before macrolactonization. In our planned diverted total synthesis
of amphidinolide C1–C3 and F, the macrolactone core 6 was
envisioned as the common advanced intermediate which would
be connected to different alkenyl motifs via Pd-catalyzed
Suzuki–Miyaura or Stille cross-coupling reaction at C26
position.11 Thus, the intermediate 6 would be assembled from the
C1–C8, C9–C17, and C18–C26 fragments 7–9 by formation of
the C8–C9 bond using a modified Carter’s dienyllithium
addition8,12 and the C17–C18 bond through alkyl metal addition
or dithiane carbanion alkylation.11a,12 We report here on the
synthesis of the C18–C26 alkenyl iodide fragment 9 from the
propargylic alcohol 10 which could be obtained via tandem
asymmetric dihydroxylation (AD) and SN2 cyclization13,14 from
the enyne 11.15
OBn
OH
TBSO
O
3. silylation
4. H2, Pd/C
HO
E
24
24
H
R
12: E = CO2Et
13a: R = β-H (43%)
13b: R = α-H (43%)
1. I2, NaHCO3
(90%; dr = 3:1)
23
20
OH
E
E
23
O
H
R
20
2. recrystallization
OH
E
HO
E
I
14: E = CO2Et (73% ee)
15a: R = β-H (20%)
15b: R = α-H
(65%; 93% ee)
Me
Me
Hartung's
Co-complex
Me
Me
OH
O
O
23
20
O
O
E
E
R
γ-terpinene
air, 80 oC
23
O
20
H
H
OTBS
OTBS
(73%, dr > 20:1)
16: E = CO2Me
17
Co(nmp)2
t-BuOOH, O2 (1 atm)
23
20
23
20
OH
alkyl metal addition
or dithiane carbanion
alkylation
O
i-PrOH, 55 oC
(19a, 97%; 19b, 84%)
R
O
OH
H
H
16
O
18
20
15
19a,b
18a,b
13
12
a: R = (CH2)2OTBS; b: R = CH2C≡CMe
Me
Me
Me
OH
1−3,5
23
24
H
O
H
H
I
Co
10
HO
O
O
26
H
9
O
8
O
Co
CF3
7
macro-
3
6
O
O
NMe
Me
lactonization
OH
O
4
N
dienyl metal addition
Me
t-Bu
6
O
CF3
Hartung's Co-complex
2
2
Co(nmp)2
PMBO
17
PG
O
Scheme 2. The known synthesis of the C18–C25 fragment of amphidinolide
15
OTBS
C congeners via various alkenol cyclization processes.
13
12
Me
Me
Me
20
23
18
I
O
O
TBS
TBSO
H
10
+
OTES26
H
H
H
Various metal-catalyzed processes have been used for the
synthesis of the C18–C25 (or C26) fragment of amphidinolide C
congeners (Scheme 3). The tetrahydrofuran compound 21
possessing an alkynyl group could be formed from 20 by the
SnCl4-mediated [3+2]-annulation in > 20:1 dr.11a A RCM–
hydrogenation sequence was employed using the seco diene 24
as the substrate; the latter was obtained from the Cu(OTf)2-
catalyzed reaction of the chiral vinyl epoxide 23 with the chiral
allylic alcohol 22.21 Cyclization within the allylic carbonate 25
(E:Z = ≥ 9:1) in the presence of Pd(PPh3)4 afforded the 2,5-trans-
26 in 88% yield along with 5–8% of the cis isomer.22 Finally, two
cyclization reactions were established for accessing the trans-2,5-
disubstituted dihydrofuranone 28 and the dihydrofuran 30,
respectively, via the Cu(acac)2-catalyzed cyclization of the diazo
ketone 2723 and the Ag(I)-catalyzed cyclization of the propargylic
benzoate 29.8 Both 28 and 30 were also transformed into the C1–
C8 fragments of amphidinolide C congeners.8,12
O
9
8
7
+
1
3
6
I
9
O
OPMB
4
8
Me
7
PG
PG
O
OMs
O
TMS
24
18
26
18
20
O
23
H
H
26 TMS
PG = protecting group
OH
11
10
Scheme 1. Retrosynthetic bond disconnection of amphidinolide C congeners.
2. Results and discussion
The target C18–C26 fragment 9 contains a 2,5-trans-
disubstituted tetrahydrofuran ring which has been accessed by
different approaches as illustrated in Schemes 2 and 3.
Cyclization of ε-hydroxy enoates seems a straightforward method
to a THF ring system. The TBAF-mediated oxa-Michael addition
within 12 was found non-stereoselective, after further
transformations, to give both 2,5-cis-13a and 2,5-trans-13b in a
1:1 diastereomeric ratio (dr) (Scheme 2).1d Alternatively, an
iodoetherification within 14 was performed to afford a 1:3 dr of
2,5-cis-15a and 2,5-trans-15b; after fractional recrystallization,
the desired product 15b was enriched to 93% ee.16 Moreover, a
much higher dr value of > 20:1 was reported for the product 2,5-
trans-1711b,17 formed from 16 via aerobic oxidative cyclization in
the presence of Hartung’s Co-complex.18 In a similar manner, the
terminal alkenols 18a,b underwent the Mukaiyama-type aerobic
oxidative cyclization using Pagenkopf’s Co(nmp)2 catalyst19 to
furnish the products 2,5-trans-19a,b in exellent yields.9,20
Our work commenced with examination of the AD–SN2
process using the substrate 35 (Schame 4). The chiral alcohol
3124 was oxidized to the corresponding aldehyde 32 which was
then reacted with the stabilized phosphonium ylide,
Ph3P=CHCO2Me, to give the methyl enoate 33. Treatment of the
acetal 33 with a catalytic amount of PPTS in MeOH formed the
1,3-diol 34. The latter was then selectively converted into the
primary TBDPS ether by reacting with TBDPSCl and imidazole
in the presence of catalytic amounts of DMAP and n-Bu4NI25 in
DMF at room temperature. n-Bu4NI could shorten the reaction
time from 10 h to 5 h. The resultant secondary alcohol was
transformed into the mesylate 35 followed by the AD reaction
using 1 mol% of Os and 10 mol% of (DHQD)2PHAL as the

3
catalyst. After 24 h at 0 ºC, the AD product was heated at 90 ºC
in the presence of pyridine to furnish the tetrahydrofuran product
synthetic sequence toward the geometrically pure enyne 42 was
developed as described in Scheme 7.
ACCEPTED MANUSCRIPT
36 in 70% overall yield from the mesylate 35 (Scheme 4).
Me
O
Me
O
Me
O
Me
O
DMP
20
19
EtO2C
SnCl4
SiMe2Ph
21
NaHCO3
CH2Cl2 (92%)
O
OH
SiMe2Ph TES
O
TES
21
18
20
23
23
19
26
26
31
32
23
24
EtO2C
O
−78 oC, < 1 h
(62%; dr > 20:1)
H
H
OTBS
OTBS
Me
Me
O
CO2Me
Ph3P
PPTS (cat)
20
21
O
PhMe, 65 oC
5 h (90%)
MeOH, rt (99%)
CO2Me
OPMB
OPMB
Cu(OTf)2
33
23
20
19
20
23
+
OH
BnO
BnO
CH2Cl2, rt
(67%)
O
19
O
H
H
H
1. TBDPSCl, imidazole, DMAP (cat)
n-Bu4NI (cat), DMF, rt, 5 h (97%)
OH
OH OH
22
23
24
CO2Me 2. MsCl, Et3N, DMAP (cat)
CH2Cl2, 0 oC (97%)
OCO2Me
Pd(PPh3)4
23
PMBO
25
34
20
20
23
25
E
E
O
i-Pr2NEt, THF
H
PMBO
OH
H
1. K2OsO4•2H2O (2 mol%)
(DHQD)2PHAL (5 mol%)
60 oC (88%)
RO
OMs
25: E = P(O)(OMe)2
26
K2CO3, K3Fe(CN)6, MeSO2NH2
t-BuOH−H2O, 0 oC, 24 h
18
CO2Me
35: R = TBDPS
20
O
O
20
N2
Cu(acac)2
2. py, 90 oC (70% for 2 steps)
23
20
19
OTBS
OTBS
23
THF, reflux
(95%)
OTBS
O
19
O
H
H
RO
RO
1. PMBOC(=NH)CCl3
BF3•OEt2 (cat)
27
28
CO2Me
OH
O
OH OTBS
2. Dibal-H, −78 oC to rt
(91% for 2 steps)
H
H
OBz
AgBF4
PivO
36: R = TBDPS
23
23
20
20
PhH, 80 oC
(65−70%; dr > 20:1)
OH
O
H
H
PivO
OBz
OH
1. DMP, NaHCO3
CH2Cl2 (86%)
OH
RO
29
30
23
20
I
Scheme 3. The reported synthesis of the C18–C25 (or C26) fragment of
18
O
O
2. CHI3, CrCl2
THF−1,4-dioxane
0 oC (55%;
26
H
H
H
H
amphidinolide C congeners via various processes.
OPMB
OPMB
38: R = TBDPS
37: R = TBDPS
E:Z = 5:1)
The mesylate 35 could be used for synthesis of the cis-2,5-
disubstituted tetrahydrofuran via the similar AD–SN2 protocol
(Scheme 5). The AD reaction of 35 with (DHQ)2PHAL as the
chiral ligand followed by heating the diol product in pyridine at
90 ºC gave the diastereomeric tetrahydrofuran product dia-36 in
68% overall yield for the two steps.
Scheme 4. Synthesis of the C18–C26 alkenyl iodide 38 via AD–SN2.
1. K2OsO4•2H2O (10 mol%)
RO
(DHQ)2PHAL (10 mol%)
20
23
CO2Me
35
O
24
K2CO3, K3Fe(CN)6, MeSO2NH2
t-BuOH−H2O, 0 oC, 24 h
2. py, 90 oC (68% for 2 steps)
H
H
OH
dia-36: R = TBDPS
With the compound 36 in hand, synthesis of the target C18–
C26 alkenyl iodide 38 was carried out (Scheme 4). After the
alcohol 36 was protected as the PMB ether, the ester group was
reduced by Dibal-H to form the primary alcohol 37 in 91%
overall yield. Oxidation of 37 with DMP gave an 86% yield of
the corresponding aldehyde which was subjected to the Takai
reaction (3 equiv of CHI3, 10 equiv of CrCl2, THF–1,4-dioxane =
1:6, 0 ºC) to furnish the alkenyl iodide 38 in 55% yield and in an
E:Z ratio of 5:1.26 Use of the mixed solvent system was expected
to improve the E:Z ratio but no effect was observed for this
substrate.27 Due to large amount of the reagents were used,
purification of the product 38 from the reaction mixture was
difficult. In view of both the moderate yield and E:Z ratio of the
Takai reaction, an alternative approach to the alkenyl iodide was
required.
Scheme 5. Synthesis of the 2,5-cis-THF compound dia-36 via AD–SN2.
In order to obtain enyne compounds in pure E geometry, the
Pd(0)–Cu(I)-catalyzed Sonogashira cross-coupling of the (E)-
alkenyl chloride 44 was selected (Scheme 7). Starting from
methyl acetoacetate, alkylation of the dianion of methyl
acetoacetate with (E)-1,3-dichloropropene gave the (E)-alkenyl
chloride 44 in 87% yield.30 Initially, the Sonogashira cross-
coupling reaction of 44 with ethynyltrimethylsilane was
attempted and, after extensive screening on the reaction
conditions, the enyne 48 was obtained in 60% yield with
incomplete conversion of 44 (Table 1, entries 1–6). The sluggish
cross-coupling reaction of 44 might be attributed to the
complexation ability of the β-keto ester, resulting in catalyst
poisoning. Unfortunately, catalyst deactivation was encountered
again in the Noyori assymmetric hydrogenation of the β-keto
ester 48 possessing the enyne moiety. Under the standard
conditions using (S)-BINAP and Ru(II) as the catalyst,31 the
desired β-hydroxy ester 49 was obtained in only 7.8% yield after
48 h at 50 ºC (Scheme 8).
As depicted in Scheme 6, the enyne compound 40 was
prepared from the aldehyde 32 and the phosphonate 3928 at –78
ºC in 80% yield and in an E:Z ratio of 4:1.29 The HWE reaction at
–90 ºC did not improve the E:Z ratio but gave a lower yield of
71%. The acetal 40 was converted into the 1,3-diol 41 (92%)
which was selectively transformed into the mesylate 42 in
excellent overall yield. Upon subjecting 42 to the AD conditions
using (DHQD)2PHAL as the chiral ligand, the forming diol
spontaneously cyclized to the tetrahydrofuran product 43 in 78%
yield. These results were very encouraging and an improved

4
Tetrahedron
ACCEPTED MANUS
TMS
Pd(PhCN)2Cl2 (5 mol%)
CuI (10 mol%), HC≡CTMS
O
P
O
CRIPT
O
EtO
MeO
Cl
piperidine, rt − 35 oC, 4 days
EtO
39
Me
O
Me
O
44
(60%)
NaHMDS
−78 oC, 3 h
32
(S)-BINAP (2 mol%), H2 (1 atm)
(COD)Ru(2-methylallyl)2 (2 mol%)
(80%, E:Z = 4:1)
O
O
TMS
40
MeO
MeO
acetone, HBr, MeOH
50 oC, 48 h (7.8%)
OH OH
PPTS (cat)
TMS
48
MeOH, rt (92%)
TMS
41
O
OH
1. TBDPSCl, imidazole
DMAP (cat), n-Bu4NI (cat)
DMF, rt (97%)
TMS
RO
OMs
49
2. MsCl, Et3N, DMAP (cat)
CH2Cl2, 0 oC (97%)
Pd(0), CuI
HC≡CTMS
Me
O
Me
Me
Me
O
TMS
TMS
42: R = TBDPS
O
O
base
Cl solvent
K2OsO4•2H2O (2 mol%)
(DHQD)2PHAL (5 mol%)
TMS
TMS
RO
50
51 (not formed)
23
20
O
24
K2CO3, K3Fe(CN)6
MeSO2NH2, t-BuOH−H2O
0 oC, 36 h (78%)
H
Pd(0), CuI
HC≡CTMS
H
OH
43: R = TBDPS
RO
OH
RO
OH
base
Cl
Scheme 6. Synthesis of the C18–C26 propargylic alcohol 43 via AD–SN2.
solvent
53: R = TBDPS
52: R = TBDPS
(not formed)
LDA (2 equiv)
(E)-ClCH2C=CHCl
Scheme 8. Attempted synthesis of the enynes 49, 51, and 53.
O
O
O
O
O
THF, −78 oC − rt
MeO
Me
MeO
MeO
Cl
Cl
Table 1
44
(87%)
Results of Sonogashira cross-coupling reactions of alkenyl chlorides
(S)-BINAP (2 mol%), H2 (1 atm)
(COD)Ru(2-methylallyl)2 (2 mol%)
OH
R
Pd, CuI
R
+
H
TMS
Cl
TMS
acetone, HBr, MeOH
50 oC, 24 h (86%; 96−98% ee)
(2.5−4 equiv)
42,48,51,53
44,47,50,52
45
TBDPSO
47,42: R =
OMs
O
O
1. TBDPSCl, imidazole
DMAP (cat), n-Bu4NI (cat)
DMF, rt (92%)
44,48: R =
MeO
OH OH
LiAlH4
Me
O
Me
O
Et2O, 0 oC
(94%)
2. MsCl, Et3N, DMAP (cat)
CH2Cl2, 0 oC (80−97%)
TBDPSO
52,53: R =
OH
Cl
46
50,51: R =
Pd(PhCN)2Cl2 (7.5 mol%)
CuI (10 mol%), HC≡CTMS
Entry
Sub.
44
44
44
44
44
44
50
50
52
52
47
Reaction Conditionsa
Yield (%)b
48 (NR)
48 (trace)
48 (NR)
48 (trace)
48 (trace)
48 (60)
RO
OMs
1
Cat A, piperidine, THF, rt, 1 day
Cat B, piperidine, rt–35 ºC, 3 days
Cat C, piperidine, rt–35 ºC, 2 days
Cat C, i-PrNH2, MeCN, rt–35 ºC, 3 days
Cat D, i-PrNH2, dioxane, rt–35 ºC, 3 days
Cat A, piperidine, rt–35 ºC, 4 days
Cat A, piperidine, rt–50 ºC, 1 day
Cat D, i-PrNH2, rt–82 ºC, 1 day
Cat A, piperidine, rt–50 ºC, 2 days
Cat D, i-PrNH2, dioxane, rt–82 ºC, 1 day
Cat A, piperidine, rt, 12–30 h
42
Cl
piperidine, rt (86−97%)
47: R = TBDPS
Scheme 7. Improved synthesis of the enyne 42.
2
3
4
To circumvent the low reactivity of 48 toward Noyori
asymmetric hydrogenation, the β-keto ester 44 was subjected to
the same chiral catalyst in MeOH at 50 ºC for 24 h to afford the
desired β-hydroxy ester 45 in 86% yield and in 96–98% ee
(Scheme 7). Reduction of 45 using LiAlH4 gave the 1,3-diol 46
in 94% yield. In order to facilitate the Sonogashira coupling, the
diol 46 was treated with 2-methoxypropene in the presence of a
catalytic amount of PPTS in acetone at room temperature to form
the cyclic acetal 50 in 96% yield. However, the Pd(0)–Cu(I)-
catalyzed cross-coupling of 50 with ethynyltrimethylsilane failed
again (Scheme 8 and Table 1, entries 7 and 8). Alternatively,
selective mono-silylation of the diol 46 was achieved to produce
the alcohol 52 in 96% yield (Schemes 7 and 8). To our
disappointment, the hydroxy alkenyl chloride 52 failed to form
the enyne 53 under the similar conditions optimized for 44
(Scheme 8 and Table 1, entries 9 and 10). Finally, the diol 46 was
converted into the mesylate 47 which furnished the enyne
product 42 in excellent yields (Scheme 7 and Table 1, entry 11).
5
6
7
51 (NR)
51 (NR)
53 (NR)
53 (NR)
42 (86–97)c
8
9
10
11
a Cat A: 5 mol% Pd(PhCN)2Cl2, 10 mol% CuI; Cat B: 5 mol%
Pd(MeCN)2Cl2, 10 mol% CuI; Cat C: 5 mol% Pd(PPh3)2Cl2, 10 mol% CuI;
Cat D: 5 mol% Pd(PhCN)2Cl2, 10 mol% P(t-Bu)3, 10 mol% CuI.
b Isolated yields. NR = no reaction
c 97% yield of 42 was obtained on 0.1 mmol scales and 86% of 42 was
obtained on ca. 6 mmol scales. Addition of another portion of 2.5 mol%
Pd(PhCN)2Cl2 and 2 equivalents of ethynyltrimethylsilane was necessary for
completion of the cross-coupling reaction within 24 h.

5
From the geometrically pure enyne (E)-42, the tandem AD–
SN2 sequence was carried out to afford the tetrahydrofuran
product 43 in a higher yield of 82% (Scheme 9). Removal of both
TBDPS and TMS groups by treating with HFꢀH2O in MeCN and
K2CO3 in MeOH, respectively, gave the diol 54 in 96% overall
yield for the 2 steps. Global silylation of 54 produced the bis-
TES ether 55 (92%) which was transformed into the alkenyl
iodide 56 by the Pd(0)-catalyzed hydrostannylation followed by
iodination in 76% overall yield. Selective cleavage of the primary
TES ether gave the alcohol 57 in 73% yield. Finally, Dess–
Martin periodinane (DMP) oxidation of 57 furnished the
aldehyde 58 in 95% yield.
solvent peaks are used as the internal reference; the signals at
ACCEPTED MANUSCRIPT
7.26 and 77.16 ppm are set for 1H and 13C NMR spectra,
respectively, taken in CDCl3 while the signals at 2.05 and 206.26
ppm are set for H and 13C NMR spectra, respectively, taken in
1
acetone-d6. IR spectra were taken on an FT-IR
spectrophotometer. High resolution mass spectra (HRMS) were
measured by TOF MS under the +CI or –CI conditions. Silica gel
plates pre-coated on glass were used for thin-layer
chromatography using UV light, or 7% ethanolic
phosphomolybdic acid and heating as the visualizing methods.
Silica gel was used for flash column chromatography. Yields
refer to chromatographically and spectroscopically (1H NMR)
homogeneous materials. Reagents were obtained commercially
and used as received unless otherwise mentioned. Dry THF, Et2O
and toluene were freshly distilled from sodium and
benzophenone, and dry CH2Cl2 was freshly distilled over calcium
hydride, respectively, under a N2 atmosphere.
K2OsO4•2H2O (2 mol%)
(DHQD)2PHAL (5 mol%)
TMS
RO
(E)-42
O
K2CO3, K3Fe(CN)6
MeSO2NH2, t-BuOH−H2O
0 oC, 36 h (82%)
H
H
OH
43: R = TBDPS
4.2. Methyl (E)-7-Chloro-3-oxohept-6-enoate (44)
OH
TESOTf
To a solution of i-Pr2NH (7.06 mL, 50.4 mmol, dried over
CaH2) in dry THF (50 mL) cooled at –78 °C under N2 was added
n-BuLi (24.6 mL, 49.2 mmol, 2.0 M) dropwise. The resultant
solution was allowed to warm to 0 ºC followed by stirring for 1 h
at the same temperature to form a yellow solution of lithium
diisopropylamide (LDA).
2,6-lutidine
CH2Cl2, −78 oC
1. HF•H2O, MeCN, rt
O
H
H
2. K2CO3, MeOH, rt
(96% for 2 steps)
OH
54
(92%)
1. Pd(PPh3)4, n-Bu3SnH, THF, 0 oC
TESO
2. NIS, THF, 0 oC (76% for 2 steps)
O
H
H
H
To the above prepared LDA solution cooled at –78 °C, was
added slowly methyl acetoacetate (2.59 mL, 24 mmol) followed
by stirring at 0 °C for 1 h. To the resultant solution cooled at –78
ºC was added a solution of (E)-1,3-dichloropropene (1.85 mL, 20
mmol) in dry THF (10 mL) using a syringe followed by stirring
for 10 min at the same temperature. The reaction was allowed to
warm to 0 ºC; after stirring at 0 °C for 16 h and at room
temperature for another 2 h, the reaction was quenched by
addition of H2O (50 mL). The reaction mixture was extracted
with EtOAc (50 mL × 3). The combined organic layer was
washed with brine (50 mL) and dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography over silica gel
(17% EtOAc in hexane) to afford the product 44 (3.31 g, 87%) as
a colorless oil. IR (film): 2955, 2929, 1747, 1717, 1633, 1438,
OTES
55
TESO
OH
AcOH−THF−H2O (1:20:20, v/v/v)
I
0 oC (73%)
O
H
OTES
I
56
O
DMP, NaHCO3
23
20
I
18
CH2Cl2, 0 oC
(95%)
26
O
O
H
H
H
H
OTES
OTES
57
58
Scheme 9. Synthesis of the C18–C26 aldehyde 58.
1
1323, 1261 cm–1; H NMR (400 MHz, CDCl3) δ 5.96 (d, J=13.2
3. Conclusion
Hz, 1H), 5.82 (dt, J=13.2, 7.2 Hz, 1H), 3.68 (s, 3H), 3.41 (s, 2H),
2.61 (t, J=7.2 Hz, 2H), 2.30 (dt, J=7.2, 7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 201.2, 167.4, 131.7, 118.4, 52.5, 49.0, 41.8,
24.6; HRMS (+CI) calcd for C8H12ClO3 191.0475 (M+H+), found
191.0470 and C8H1237ClO3 193.0445 (M+H+), found 193.0448.
In summary, we have established a synthesis of the C18–C26
fragment of amphidinolide C congeners starting from methyl
acetoacetate in 14 steps in >17.0% overall yield. The C20
stereogenic center was secured by asymmetric hydrogenation of
the β-keto ester and the configuration at both C23 and C24 was
installed by asymmetric dihydroxylation (AD). The trans-2,5-
disubstituted tetrahydrofuran ring was assembled via the tandem
AD–SN2 sequence. The latter protocol could be employed for
accessing the corresponding cis-2,5-disubstituted tetrahydrofuran
rings from the same alkene substrates simply by choosing a
suitable AD ligand. By combination of both asymmetric
hydrogenation of β-keto esters and asymmetric dihydroxylation,
four diastereomers of cis- and trans-2,5-disubstituted
tetrahydrofuran derivatives could be synthesized using the AD–
SN2 sequence. Moreover, the observed functional group
compatibility for the Ru(II)-catalyzed hydrogenation of β-keto
esters and the Pd(0)–Cu(I)-catalyzed Sonogashira cross-coupling
reaction should be valuable for general synthetic application.
4.3. General procedure for Sonogashira cross-coupling
To a suspension of PdCl2(PhCN)2 (124.1 mg, 3.23 × 10–1
mmol, 5 mol%), alkenyl chloride 47 (3.11 g, 6.46 mmol), and
CuI (123.2 mg, 6.46 mmol × 10–1, 10 mol%) in piperidine (32
mL) under a N2 atmosphere was added ethynyltrimethylsilane
(2.29 mL, 16.15 mmol, 2.5 equiv) via a syringe. The resultant
mixture was stirred at room temperature for 30 h. The reaction
was treated with saturated aqueous solution of NH4Cl (15 mL).
The aqueous layer was extracted with Et2O (150 mL × 3). The
combined organic layer was washed sequentially with aqueous
HCl (0.2 M, 100 mL), aqueous NaHCO3 (100 mL) and H2O (200
mL × 2). The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography over silica gel
(14% EtOAc in hexane) to afford the enyne 42 (3.02 g, 86%).
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded in CDCl3 or acetone-
d6 (400 MHz for 1H and 100 MHz for 13C, respectively). Residual

6
Tetrahedron
4.3.1. (4E,1S)-1-[2′-((tert-Butyldiphenylsilyl)-
Prepared from the β-keto ester 48 at 50 ºC for 48 h in 7.8%
ACCEPTED MANUSCRIPT
1
oxy)ethyl] -7-trimethylsilylhept-4-en-6-ynyl
Methanesulfonate (42)
Prepared from 47 at room temperature for 30 h, (if adding
another 2.5 mol% Pd(PhCN)2Cl2 and 2.0 equiv of
ethynyltrimethylsilane, the reaction was completed at room
yield as a colorless oil. H NMR (400 MHz, CDCl3) δ 6.20 (dt,
J=15.6, 6.8 Hz, 1H), 5.54 (d, J=15.6 Hz, 1H), 4.05–3.96 (m, 1H),
3.71 (s, 3H), 2.97 (br s, 1H, OH), 2.49 (ABqd, J=16.4, 3.2 Hz,
1H), 2.41 (ABqd, J=16.4, 8.8 Hz, 1H), 2.36–2.14 (m, 2H), 1.67–
1.56 (m, 1H), 1.56–1.44 (m, 1H), 0.17 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 173.4, 145.1, 110.6, 104.0, 93.2, 67.2, 52.0, 41.2,
35.3, 29.2, 0.1 (×3).
25
temperature for 24 h), in 82–97% yields as a colorless oil. [α]D
+32.8 (c 1.0, CHCl3); IR (film): 2958, 2932, 2858, 2137, 1356,
1175, 1109 cm–1; H NMR (400 MHz, CDCl3) δ 7.69–7.60 (m,
1
4.5. (6E,3S)-7-Chlorohept-6-ene-1,3-diol (46)
4H), 7.45–7.38 (m, 6H), 6.16 (dt, J=16.0, 6.8 Hz, 1H), 5.55 (d,
J=16.0 Hz, 1H), 4.99–4.89 (m, 1H), 3.81–3.68 (m, 2H), 2.94 (s,
3H), 2.21 (td, J=7.6, 6.8 Hz, 2H), 1.97–1.75 (m, 4H), 1.07 (s,
9H), 0.18 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 143.9, 135.7
(×4), 133.5, 133.4, 130.0, 130.0, 127.9 (×4), 111.1, 103.7, 93.6,
80.2, 59.6, 38.5, 37.2, 33.9, 28.5, 27.0 (×3), 19.3, 0.1 (×3);
HRMS (+CI) calcd for C29H43O4SSi2 543.2421 (M+H+), found
543.2415.
To the stirred solution of the ester 45 (4.44 g, 23.04 mmol) in
dry Et2O (115 mL) cooled at 0 ºC was added LiAlH4 (2.62 g,
69.14 mmol) in portions. The resultant mixture was stirred for 1
h at the same temperature. The reaction was quenched at 0 ºC by
sequentially adding EtOAc and saturated aqueous sodium
potassium tartrate (100 mL), and the solution was stirred for
overnight. The reaction mixture was extracted with EtOAc (50
mL × 3) and the combined organic layer was washed with brine
(00 mL), dried over anhydrous Na2SO4, filtered, concentrated
under reduced pressure. The residue was purified by flash
4.3.2. Methyl (E)-3-oxo-9-trimethylsilylnon-6-en-8-
ynoate (48)
Prepared from 44 at room temperature to 35 ºC for 4 days in
column chromatography over silica gel (50% EtOAc in hexane)
1
60% yield as a colorless oil. H NMR (400 MHz, CDCl3) δ 6.14
25
to afford the 1,3-diol 46 (3.45 g, 91%) as a colorless oil. [α]D
–
(dt, J=16.0, 7.2 Hz, 1H), 5.51 (d, J=15.6 Hz, 1H), 3.71 (s, 3H),
3.42 (s, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.37 (dt, J=7.2, 7.2 Hz, 2H),
0.14 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 201.2, 167.5, 143.3,
111.2, 103.5, 93.7, 52.5, 49.1, 41.7, 26.7, 0.0 (×3).
4.0 (c 1.0, CHCl3); IR (film): 3380 (br), 2955, 2920, 1726, 1446,
1059 cm–1; H NMR (400 MHz, CDCl3) δ 5.97 (d, J=13.6 Hz,
1
1H), 5.89 (dt, J=13.6, 6.4 Hz, 1H), 3.98–3.72 (m, 3H), 3.15 (s,
2H, OH ×2), 2.30–2.06 (m, 2H), 1.75–1.47 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 133.4, 117.5, 71.0, 61.5, 38.4, 36.7, 27.1;
HRMS (+CI) calcd for C7H14ClO2 165.0682 (M+H+), found
165.0685.
4.4. General procedure for asymmetric hydrogenation of β-
keto esters
A flame dried two-necked flask was charged with (S)-BINAP
(280.2 mg, 0.45 mmol) and (COD)Ru(2-methylallyl)2 (143.8 mg,
0.45 mmol). The load flask was evacuated and backfilled with N2
for three times. Degassed dry acetone (25 mL) and a solution of
HBr in dry MeOH (3.88 mL, 1.13 mmol, 0.29 M solution
prepared from diluting 48% aqueous HBr in MeOH) were added
via a syringe. After the resultant dark red mixture was stirred at
room temperature for 30 min, the solvent was removed under
reduced pressure to give a reddish brown solid, which was used
as the hydrogenation catalyst.
4.6. (6E,3S)-1-[(tert-Butyldiphenylsilyl)oxy]-7-chlorohept-6-
en-3-ol (52)
To a stirred solution of the 1,3-diol 46 (3.45 g, 20.96 mmol),
DMAP (256.5 mg, 2.1 mmol), imidazole (2.85 mg, 41.96 mmol)
and n-Bu4NI (775.7 mg, 2.1 mmol) in dry DMF (35 mL) was
added TBDPSCl (5.99 mL, 23.05 mmol) at room temperature
under N2. The resultant mixture was stirred for 5 h at room
temperature and was then quenched by saturated aqueous
NaHCO3 (50 mL). The reaction mixture was extracted with
EtOAc (50 mL × 3), and the combined organic layer was dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column
chromatography over silica gel (6% EtOAc in hexane) to afford
The flask with the chiral Ru(II) catalyst was evacuated and
backfilled with H2 for 3 times and degassed dry MeOH (30 mL)
was added to dissolve the catalyst. The β-ketone ester 44 (2.99 g,
15.73 mmol) was added and the resultant mixture was stirred at
50 °C for 24 h. The reaction mixture was allowed to cool to room
temperature and the volatile components were removed under
reduced pressure. The residue was purified by flash column
chromatography over silica gel (14% EtOAc in hexane) to afford
the product 45 (2.60 g, 86%).
25
the alcohol 52 (7.77 g, 92%) as a colorless oil. [α]D –13.8 (c
1.0, CHCl3); IR (film): 3447 (br), 2932, 2858, 1637, 1428, 1110
cm–1; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=6.9 Hz, 4H),
7.50–7.38 (m, 6H), 6.00 (d, J=13.6 Hz, 1H), 5.93 (dt, J=13.6, 6.8
Hz, 1H), 3.96–3.84 (m, 3H), 3.36 (br s, 1H, OH), 2.33–2.11 (m,
2H), 1.81–1.68 (m, 1H), 1.68–1.57 (m, 2H), 1.57–1.47 (m, 1H),
1.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.7 (×2), 135.7
(×2), 133.7, 133.0, 132.9, 130.0, 130.0, 128.0 (×4), 117.3, 71.0,
63.6, 38.4, 36.6, 27.1, 26.9 (×3), 19.1; HRMS (+CI) calcd for
C23H32ClO2Si 403.1860 (M+H+), found 403.1866 and
C23H3237ClO2Si 405.1833 (M+H+), found 405.1819.
4.4.1. Methyl (6E,3S)-7-Chloro-3-hydroxyhept-6-
enoate (45)
Prepared from β-keto ester 44 at 50 ºC for 24 h in 86% yield
as a colorless oil. [α]D25 +8.7 (c 1.0, CHCl3); IR (film): 3425 (br),
2954, 2923, 1732, 1440, 1176 cm–1; 1H NMR (400 MHz, CDCl3)
δ 5.97 (d, J=13.2 Hz, 1H), 5.88 (dt, J=13.2, 6.8 Hz, 1H), 4.05–
3.93 (m, 1H), 3.69 (s, 3H), 3.10–2.85 (br s, 1H, OH), 2.48
(ABqd, J=16.4, 2.8 Hz, 1H), 2.41 (ABqd, J=16.4, 8.4 Hz, 1H),
2.29–2.10 (m, 2H), 1.66–1.55 (m, 1H), 1.55–1.43 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 173.3, 133.1, 117.7, 67.0, 51.9, 41.2,
35.6, 27.0; HRMS (+CI) calcd for C8H14ClO3 193.0631 (M+H+),
found 193.0633 and C8H1437ClO3 195.0601 (M+2+H+), found
195.0616.
4.7. (4E,1S)-1-[2′-((tert-Butyldiphenylsilyl)oxy)ethyl]-5-
chloropent-4-enyl Methanesulfonate (47)
To a solution of the alcohol 52 (5.65 g, 14.01 mmol) in dry
CH2Cl2 (60 mL) cooled at 0 °C was added DMAP (256.6 mg, 2.1
mmol), Et3N (19.55 mL, 140.1 mmol), and MsCl (2.71 mL,
35.04 mmol) followed by stirring at room temperature for 1 h.
The reaction was quenched by addition of H2O (40 mL) and the
reaction mixture was extracted with CH2Cl2 (50 mL × 3). The
combined organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
4.4.2. Methyl (6E,3S)-3-Hydroxy-9-trimethylsilyl-
non-6-en-8-ynoate (49)

7
was purified by flash column chromatography over silica gel (9%
3289, 2939, 2885, 1640, 1056 cm–1; 1H NMR (400 MHz,
ACCEPTED MANUSCRIPT
EtOAc in hexane) to afford the mesylate 47 (6.25 g, 93%) as a
CDCl3) δ 4.23–4.08 (m, 3H), 3.83–3.70 (m, 2H), 3.29 (br s, 1H,
OH), 2.90 (br s, 1H, OH), 2.43 (dd, J=5.8, 2.2 Hz, 1H), 2.16–
1.97 (m, 2H), 1.90–1.58 (m, 3H), 1.67–1.54 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 82.3, 81.9, 79.3, 73.8, 65.0, 61.1, 37.5,
32.3, 27.9; HRMS (–CI) calcd for C9H14O3 170.0943 (M–), found
170.0949.
25
colorless oil. [α]D +11.3 (c 1.0, CHCl3); IR (film): 2931, 2857,
1353, 1173, 1108, 908 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.70–
7.60 (m, 4H), 7.44–7.35 (m, 6H), 6.00 (d, J=13.2 Hz, 1H), 5.86
(dt, J=13.2, 7.2 Hz, 1H), 4.94 (quintet, J=6.0 Hz, 1H), 2.93 (s,
3H), 2.17 (dt, J=7.2, 7.2 Hz, 2H), 1.96–1.87 (m, 1H), 1.87–1.75
(m, 3H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.7 (×4),
133.4, 132.3 (×2), 130.0 (×2), 130.0, 128.0 (×4), 118.4, 80.1,
59.6, 38.5, 37.2, 34.2, 27.0 (×3), 26.5, 19.3; HRMS (+CI) calcd
for C24H34ClO4SSi 481.1636 (M+H+), found 481.1631 and
C24H3437ClO4SSi 483.1606 (M+H+), found 483.1611.
4.10. (2R,5R,1"R)-2-[(2′-Triethylsilyloxy)ethyl]-5-[(1"-
triethylsilyloxy)prop-2"-ynyl]tetrahydrofuran (55)
To a solution of the diol 54 (1.13 g, 6.63 mmol) and 2,6-
lutidine (3.48 mL, 29.88 mmol) in dry CH2Cl2 (60 mL) cooled at
–78 °C was added TESOTf (4.80 mL, 26.55 mmol) under N2.
The resultant mixture was stirred at the same temperature for 3 h
and the reaction was quenched by saturated aqueous NaHCO3 (20
mL). The reaction mixture was extracted with CH2Cl2 (50 mL ×
3) and the combined organic layer was washed with brine (50
mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (2% Et2O in hexane) to
afford the bis-TES ether 55 (2.43 g, 92%) as a colorless oil.
4.8. (1R,2′R,5′R)-1-{5′-[2"-((tert-Butyldiphenylsilyl)oxy)-
ethyl]tetrahydrofuran-2′-yl}-3-trimethylsilylprop-2-yn-1-ol
(43)
A mixture of (DHQD)2PHAL (474.2 mg, 6.08 × 10–1 mmol, 5
mol%), K3Fe(CN)6 (12.02 g, 36.51 mmol), K2CO3 (5.05 g, 36.51
mmol), MeSO2NH2 (2.32 g, 24.34 mmol) in a mixed t-BuOH and
H2O (1:1 v/v, 50 mL) was stirred at 0 °C for 1 h. Then,
K2OsO4·2H2O (89.7 mg, 2.43 × 10–1 mmol, 2 mol%) was added.
After stirring for 30 min, the enyne 42 (6.61 g, 12.17 mmol) was
added followed by stiring at 0 ºC for 36 h. The reaction was
quenched with saturated aqueous Na2S2O3. After stirring for 1.5 h
at room temperature, the organic layer was extracted with EtOAc
(50 mL × 3). The combined organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column
chromatography over silica gel (12.5% EtOAc in hexane) to
25
[α]D –17.6 (c 1.0, CHCl3); IR (film): 2955, 2924, 2877, 1461,
1087, 1010 cm–1; 1H NMR (400 MHz, CDCl3) δ 4.38 (dd, J=6.0,
2.0 Hz, 1H), 4.16–4.06 (m, 1H), 4.03 (td, J=6.8, 6.0 Hz, 1H),
3.76–3.62 (m, 2H), 2.34 (d, J=2.0 Hz, 1H), 2.13–2.01 (m, 2H),
2.01–1.87 (m, 1H), 1.88–1.76 (m, 1H), 1.75–1.61 (m, 1H), 1.58–
1.45 (m, 1H), 1.04–0.89 (m, 18H), 0.71–0.53 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 100.1, 83.5, 81.4, 73.1, 66.0, 60.4, 39.0,
32.3, 27.9, 6.9 (×3), 6.8 (×3), 4.8 (×3), 4.5 (×3); HRMS (+CI)
calcd for C21H43O3Si2 399.2751 (M+H+), found 399.2752.
25
afford the product 43 (4.79 g, 82%) as a colorless oil. [α]D
+2.73 (c 1.0, CHCl3); IR (film): 3416, 2958, 2859, 2174, 1251,
4.11. (2R,5R,1"R)-2-[(3"-Iodo-1"-triethylsilyloxy)allyl]-5-[(2′-
triethylsilyloxy)ethyl]tetrahydrofuran (56)
1
1109, 1084 cm–1; H NMR (400 MHz, CDCl3) δ 7.72–7.69 (m,
4H), 7.48–7.36 (m, 6H), 4.18 (d, J=7.2 Hz, 1H), 4.20–4.10 (m,
1H), 3.99 (dt, J=6.8, 6.8, 6.0 Hz, 1H), 3.86–3.73 (m, 2H), 2.68
(br s, 1H, OH), 2.08–1.96 (m, 2H), 1.94–1.83 (m, 2H), 1.83–1.71
(m, 1H), 1.64–1.52 (m, 1H), 1.08 (s, 9H), 0.19 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 135.7 (×4), 133.9, 133.8, 129.7 (×2), 127.7
(×4), 103.9, 90.3, 81.7, 78.1, 66.4, 61.4, 39.0, 31.4, 27.9, 27.0
(×3), 19.3, –0.1 (×3); HRMS (–CI) calcd for C28H40O3Si2
480.2516 (M–), found 480.2517.
To a solution of the terminal alkyne 55 (2.10 g, 5.626 mmol)
and Pd(PPh3)4 (303.9 mg, 2.63 × 10–1 mmol) in degassed THF
(25 mL) cooled at 0 °C was added n-Bu3SnH (1.74 mL, 6.31
mmol) followed by stirring at the same temperature for 20 min.
The solvent was removed under reduced pressure and the residue
was purified by flash chromatography (2% Et2O in hexane) to
afford the alkenyl tin as a colorless oil which was used directly in
the next step.
4.9. (1R,2′R,5′R)-1-[5′-(2"-Hydroxyethyl)tetrahydrofuran-2′-
yl]propynol (54)
To a solution of the above alkenyl tin in dry THF (40 mL)
cooled at 0 ºC was added a solution of NIS (1.42 g, 6.31 mmol,
dissolved in 12 mL of THF). The reaction was stirred at 0 ºC for
30 min, and was quenched with saturated aqueous Na2SO3 (30
mL) and KF (30 mL, 1 M). The reaction mixture was extracted
with Et2O (50 mL × 3) and the combined organic layer was dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column
chromatography over silica gel (2% Et2O in hexane) to afford the
alkenyl iodide 56 (2.10 g, 76%) as a colorless oil. [α]D25 –12.7 (c
To the stirred solution of the silyl ether 43 (3.81 g, 7.92 mmol)
in MeCN (16 mL) was added aqueous HF (5.74 mL, 48%, 158.5
mmol) at room temperature followed by stirring for 4 h at the
same temperature. The reaction was quenched by adding solid
NaHCO3, and the reaction mixture was filtered through a pad of
NaHCO3. The filtrate was concentrated under reduced pressure
and the residue was used for the next step. An analytic sample
25
was used for collecting the characterization data. [α]D –1.1 (c
1.0, CHCl3); IR (film): 3428 (br), 2958, 2892, 2173, 1251, 1059
1
1
1.0, CHCl3); IR (film) 2955, 2877, 1461, 1088, 1010 cm–1; H
cm–1; H NMR (400 MHz, CDCl3) δ 4.19 (dd, J=6.8, 4.4 Hz,
NMR (400 MHz, CDCl3) δ 6.58 (dd, J=14.4, 5.2 Hz, 1H), 6.31
(dd, J=14.4, 1.2 Hz, 1H), 4.14 (ddd, J=5.2, 5.2, 1.2 Hz, 1H),
4.03–3.95 (m, 1H), 3.93 (td, J=7.2, 5.2 Hz, 1H), 3.75–3.62 (m,
2H), 2.03–1.84 (m, 2H), 1.82–1.62 (m, 3H), 1.55–1.42 (m, 1H),
0.96 (t, J=8.0 Hz, 9H), 0.94 (t, J=8.0 Hz, 9H), 0.60 (q, J=8.0 Hz,
6H), 0.59 (q, J=8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
145.7, 81.1, 77.5 (overlapped with a solvent residual peak), 77.1,
77.1, 60.4, 39.1, 32.3, 27.1, 6.9 (×3), 6.9 (×3), 5.0 (×3), 4.6 (×3);
13C NMR (100 MHz, acetone-d6) δ 147.3, 82.2, 78.7, 78.3, 77.5,
61.1, 40.2, 33.2, 28.4, 7.4 (×6), 5.7 (×3), 5.3 (×3); HRMS (+CI)
calcd for C21H44IO3Si2 527.1874 (M+H+), found 527.1863.
1H), 4.16–4.10 (m, 1H), 4.06 (dt, J=6.8, 6.8 Hz, 1H), 3.80–3.67
(m, 2H), 3.40 (d, J=4.4 Hz, 1H, OH), 3.11 (br s, 1H, OH), 2.11–
2.00 (m, 2H), 1.87–1.70 (m, 3H), 1.63–1.50 (m, 1H), 0.13 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 103.9, 90.4, 82.1, 79.0, 65.6,
60.9, 37.5, 32.2, 28.0, –0.1 (×3).
A suspension of the above crude product and solid K2CO3
(832.0 mg, 6.02 mmol) in wet MeOH (40 mL) was stirred at
room temperature for 5 h. The reaction mixture was concentrated
under reduced pressure and the residue was purified by flash
column chromatography on silica gel (66% EtOAc in hexane) to
afford the terminal alkyne 54 (3.03 g, 96% for the 2 steps) as a
4.12. (2R,5′R,1"R)-2-{5′-[(3"-Iodo-1"-triethylsilyloxy)allyl]-
tetrahydrofuran-2′-yl}ethanol (57)
25
colorless oil. [α]D –12.8 (c 1.0, CHCl3); IR (film): 3391 (br),

8
Tetrahedron
ACCEPTED MANUSCRIPT
To a solution of the bis-TES ether 56 (104.0 mg, 1.97 × 10–1
Tetrahedron 2001, 57, 5975−5977. (d) Kubota, T.; Tsuda, M.;
Kobayashi, J. Tetrahedron 2003, 59, 1613−1625.
mmol) in THF (11.1 mL) and H2O (11.1 mL) cooled at 0 °C was
added AcOH (0.55 mL) followed by stirring at the same
temperature for 1 h. The reaction was quenched by saturated
aqueous NaHCO3 (15 mL) and the reaction mixture was
extracted with CH2Cl2 (15 mL × 3). The combined organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
2. For isolation and structure of amphidinolide C2, see: Kubota, T.;
Sakuma, Y.; Tsuda, M.; Kobayashi, J. Mar. Drugs 2004, 2, 83–87.
3. For isolation and structure of amphidinolide C3, see: Kubota, T.;
Suzuki, A.; Yamada, M.; Baba, S.; Kobayashi, J. Heterocycles
2010, 82, 333–338.
4. For isolation and structure of amphidinolide F, see: Kobayashi, J.;
Tsuda, M.; Ishibashi, M.; Shigemori, H.; Yamasu, T.; Hirota, H.;
Sasaki, T. J. Antibiot. 1991, 44, 1259–1261.
column chromatography on silica gel (17% EtOAc in hexane) to
afford the alcohol 57 (59.0 mg, 73%) as a colorless oil. [α]D
5. For isolation and structure of amphidinolide C4, see: Nuzzo, G.;
Gomes, B. A.; Luongo, E.; Torres, M. C. M.; Santos, E. A.;
Cutignano, A.; Pessoa, O. D. L.; Costa-Lotufo, L. V.; Fontana, A.
J. Nat. Prod. 2016, 79, 1881–1885.
25
–
4.43 (c 1.0, CHCl3); IR (film): 3421 (br), 2955, 2878, 1063, 1012
cm–1; H NMR (400 MHz, CDCl3) δ 6.56 (dd, J=14.4, 5.6 Hz,
1
6. For reviews on amphidinolides, see: (a) Ishibashi, M.; Kobayashi,
J. Heterocycles 1997, 44, 543−572. (b) Chakraborty, T. K.; Das, S.
Curr. Med. Chem. Anti-cancer Agents 2001, 1, 131−49. (c)
Kobayashi, J.; Shimbo, K.; Kubota, T.; Tsuda, M. Pur. App. Chem.
2003, 75, 337−342. (d) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep.
2004, 21, 77−93. (e) Colby, E. A.; Jamison, T. F. Org. Biomol.
Chem. 2005, 3, 2675−2684. (f) Jia, R.; Huang, X.-C.; Guo, Y.-W.
Chin. J. Nat. Med. 2006, 4, 15–24. (g) Kobayashi, J.; Kubota, T. J.
Nat. Prod. 2007, 70, 451−460. (h) Kobayashi, J. J. Antibiot. 2008,
61, 271−284. (i) Fürstner, A. Israel J. Chem. 2011, 51, 329−345.
(j) Lorente, A.; Lamariano-Merketegi, J.; Albericio, F.; Álvarez,
M. Chem. Rev. 2013, 113, 4567−4610.
1H), 6.33 (dd, J=14.4, 1.2 Hz, 1H), 4.16–4.06 (m, 2H), 4.01–3.93
(m, 1H), 3.84–3.72 (m, 2H), 2.75 (br s, 1H, OH), 2.05–1.86 (m,
2H), 1.73–1.65 (m, 3H), 1.60–1.50 (m, 1H), 0.94 (t, J=8.0 Hz,
9H), 0.59 (q, J=8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
145.5, 81.5, 80.2, 77.9, 77.0, 61.9, 37.4, 32.4, 26.9, 6.9 (×3), 4.9
(×3); HRMS (+CI) calcd for C15H30IO3Si 413.1009 (M+H+),
found 413.0995.
4.13. (2R,5′R,1"R)-{5′-[(3"-Iodo-1"-triethylsilyloxy)allyl]-
tetrahydrofuran-2′-yl}acetaldehyde (58)
7. Amphidinolide U, a 20-membered macrolide possessing the same
side chain as amphidinolide C1, exhibiting significantly reduced
cytotoxicity against murine lymphoma L1210 and human
epidermoid carcinoma KB cell lines (IC50: 12 and 20 µg/mL), see:
Tsuda, M.; Endo, T.; Kobayashi, J. Tetrahedron 1999, 55, 14565–
14570.
8. For Carter’s total synthesis of amphidinolide C1 and F, see: (a)
Mahapatra, S. Carter, R. G. Angew. Chem. Int. Ed. 2012, 51,
7948–7951. (b) Mahapatra, S.; Carter, R. G. J. Am. Chem. Soc.
2013, 135, 10792–10803.
9. For Fürstner’s total synthesis of amphidinolide C1 and F, see: (a)
Valot, G.; Regents, C. S.; O’Malley, D. P.; Godineau, E.;
Takikawa, H.; Fürstner, A. Angew. Chem. Int. Ed. 2013, 52, 9534–
9538. (b) Valot, G.; Malihol, D.; Regents, C. S.; O’Malley, D. P.;
Godineau, E.; Takikawa, H.; Philipps, P.; Fürstner, A.. Chem. Eur.
J. 2015, 21, 2398–2408.
To a suspension of the alcohol 57 (60.7 mg, 1.47 × 10–1
mmol) and solid NaHCO3 (123.5 mg, 1.47 mmol) in dry CH2Cl2
(1 mL) cooled at 0 ºC was added DMP (187.3 mg, 0.44 mmol,
dissolved in 6 mL CH2Cl2) followed by stirring at the same
temperature for 10 min and at room temperature for another 1.5
h. The reaction was quenched at 0 °C by saturated aqueous
NaHCO3 (5 mL) and Na2S2O3 (5 mL) and the reaction mixture
was extracted with CH2Cl2 (5 mL × 3). The combined organic
layer was washed with brine (5 mL) and dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography over silica gel (6%
Et2O in hexane) to afford the aldehyde 58 (57.3 mg, 95%) as a
25
colorless oil. [α]D –11.1 (c 1.0, CHCl3); IR (film): 2955, 2877,
1725, 1080 cm–1; 1H NMR (400 MHz, CDCl3) δ 9.79 (dd, J=2.4,
1.6 Hz, 1H), 6.57 (dd, J=14.4, 5.6 Hz, 1H), 6.34 (dd, J=14.4, 1.2
Hz, 1H), 4.42–4.30 (m, 1H), 4.13 (ddd, J=5.6, 5.6, 1.2 Hz, 1H),
4.00–3.95 (m, 1H), 2.65 (ABqdd, J=16.4, 7.2, 2.4 Hz, 1H), 2.54
(ABqdd, J=16.0, 5.2, 1.8 Hz, 1H), 2.15–2.07 (m, 1H), 2.00–1.88
(m, 1H), 1.81–1.70 (m, 1H), 1.60–1.50 (m, 1H), 0.97–0.90 (m,
9H), 0.63–0.53 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 201.2,
145.4, 81.6, 77.9, 76.9, 74.7, 49.6, 32.2, 27.0, 6.9 (×3), 4.9 (×3);
HRMS (+CI) calcd for C15H28IO3Si 411.0852 (M+H+), found
411.0856.
10. (a) Tamura, R.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org. Chem.
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13. For seleted examples of formation THF rings via SN2 cyclization,
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Acknowledgements
This work is supported in part by a General Research Fund
grant (600913) from the Research Grant Council, The Hong
Kong Special Administrative Region, P. R. China and the
Department of Chemistry, HKUST.
Supplementary data
14. For selected examples of formation THF rings via AD–SN2
cyclization sequence, see: (a) Das, S.; Li, L.-S.; Abraham, S.;
Chen, Z.; Sinha, S. C. J. Org. Chem. 2005, 70, 5922–5931. (b)
Marshall, J. A.; Sabatini, J. J. Org. Lett. 2006, 8, 3557–3560. (c)
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Lett. 2009, 50, 6276–6279. (d) Kanto, M.; Sasaki, M. Org. Lett.
2016, 18, 112–115.
Synthetic procedures for compounds 31–43 of Schemes 4–6
and copies of 1H and 13C NMR spectra for the compounds 31–49,
52, 54–58, and the related compounds are available.
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.00.000.
15. For our previous studies on total synthesis of amphidinolide T1–
T4, X, and Y, see: (a) Chen, Y.; Jin, J.; Wu, J.; Dai, W.-M. Synlett
2006, 1177–1180. (b) Jin, J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W.-M.
Org. Lett. 2007, 9, 2585–2588. (c) Dai, W.-M.; Chen, Y.; Jin, J.;
Wu, J.; Lou, J.; He, Q. Synlett 2008, 1737–1741. (d) Luo, J.; Li,
H.; Wu, J.; Xing, X.; Dai, W.-M. Tetrahedron 2009, 65, 6828–
6833. (e) Li, H.; Wu, J.; Luo, J.; Dai, W.-M. Chem. Eur. J. 2010,
16, 11530–11534. (f) Wu, D.; Li, H.; Jin, J.; Wu, J.; Dai, W.-M.
References and notes
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9
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ACCEPTED MANUSCRIPT
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Tetrahedron