Stereocontrolled Synthesis of a Possible Stereoisomer of Laurenidificin and a Formal Total Synthesis of (+)-Aplysiallene Featuring a Stereospecific Ring Contraction

Article abstract of DOI:10.1021/acs.joc.5b02595

We report a highly stereocontrolled total synthesis of one of the possible stereoisomers of laurenidificin. Highlights of the synthesis include the formation of the 2,6-dioxabicyclo[3.3.0]octane framework by a stereospecific bromolactonization-α-bromination-ring contraction sequence, followed by a stereoselective propargylation, an insertion of the Z-enyne side chain by a hydroindation/cross coupling reaction, and ethylation at C13 with an organocuprate reagent. While the synthetic compound was not identical to the natural product, the absolute stereochemistry of the natural product was proposed on the basis of NMR analyses. Moreover, a formal total synthesis of (+)-aplysiallene was achieved by extending the ring contraction strategy. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02595

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Article
Stereocontrolled Synthesis of a Possible Stereoisomer
of Laurenidificin and a Formal Total Synthesis of (+)-
Aplysiallene Featuring a Stereospecific Ring Contraction
Shoji Kobayashi, Taiki Yokoi, Tomoharu Inoue, Yutaka Hori,
Tomoaki Saka, Taiki Shimomura, and Araki Masuyama
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02595 • Publication Date (Web): 19 Jan 2016
Downloaded from http://pubs.acs.org on January 29, 2016
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Stereocontrolled Synthesis of a Possible Stereoisomer of Laurenidificin and a Formal Total Synthesis
of (+)-Aplysiallene Featuring a Stereospecific Ring Contraction
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Shoji Kobayashi,* Taiki Yokoi, Tomoharu Inoue, Yutaka Hori, Tomoaki Saka, Taiki Shimomura and Araki
Masuyama
Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Ohmiya,
Asahi-ku, Osaka 535-8585, Japan
*E-mail: shoji.kobayashi@oit.ac.jp
ABSTRACT:
stereospecific ring contraction
stereospecific ring contraction
H
H
organocuprate addition
H
12R
OH
TBSO
H
O
O
O
OH
7S
4S
7R
10S
HO
OH
6R
9S
6R
9S
13S
O
O
OH
H
H
H
Br
H
hydroindation-cross coupling
intermediate of (+)-aplysiallene
2-deoxy-D-ribose
(6R,7S,9S,10S,12R,13S)-laurenidificin
We report a highly stereocontrolled total synthesis of one of the possible stereoisomers of laurenidificin.
Highlights of the synthesis include the formation of the 2,6-dioxabicyclo[3.3.0]octane framework by a
stereospecific bromolactonization−α-bromination−ring contraction sequence, followed by a stereoselective
propargylation, an insertion of the Z-enyne side-chain by a hydroindation/cross coupling reaction, and
ethylation at C13 with an organocuprate reagent. While the synthetic compound was not identical to the
natural product, absolute stereochemistry of the natural product was proposed on the basis of NMR analyses.
Moreover, a formal total synthesis of (+)-aplysiallene was achieved by extending the ring contraction
strategy.
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INTRODUCTION
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Halogenated C15-acetogenins are widely distributed in red algae Laurencia species.1 More than 180
compounds have been elucidated since the first discovery of laurencia by the Irie group in 1965.2
Structurally, most of them contain small- or medium-sized ether rings ranging from four to twelve members
and one or more bromine or chlorine atoms. Murai and co-workers proposed biogenetic pathways of
brominated C15-acetogenins on the basis of enzymatic reactions with commercially available
lactoperoxidase (LPO) or partially purified bromoperoxidase (BPO) isolated from natural Laurencia
species.3 They suggested that an enzyme-bound bromonium ion, generated by the two-electron oxidation of
bromide ion with BPO and hydrogen peroxide, provoked bromoetherification of unsaturated molecules to
give rise to a variety of cyclic bromoether products. Importantly, the acyclic (6S,7S)- or (6R,7R)-laurediols
are suggested to be biosynthetic precursors of the brominated C15-acetogenins.3,4
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Among this family, laurenenynes A (1E) and B (1Z),5 laurenidificin (2),6 (−)-kumausallene (3),7 and
(−)-aplysiallene (4)8 are grouped into the 2,6-dioxabicyclo[3.3.0]octane class (Figure 1). A notable
structural feature is that a thermodynamically unfavorable conjugated Z-enyne or an unusual bromoallene
side chain is bound to a cis-fused bicyclic core. In addition, there are more than five chiral centers as well as
double-bond isomerism, which expands the structural diversity of this class.9 While the bioactivities of 1, 2,
and 3 remain unknown, it is reported that 4 exhibited Na, K-ATPase inhibitory activity at IC50 = 0.7 µM.8b
Their structural complexity, unrevealed biological activity, and limited availability from natural sources
have made them attractive synthetic targets.8d,10-13 To date, one racemic and two asymmetric total syntheses
of 3, and one asymmetric total synthesis of 4 have been reported by Overman,10 Evans,11 Tang,12 and
Pagenkopf,8d respectively, while total syntheses of 1 and 2 have yet to be achieved.13 Laurenidificin (2) was
discovered from Laurencia nidifica ten years after the discovery of 1.6 While its structure and the absolute
configuration at C6 were determined by NMR methods, the remaining stereochemistries from C7 to C13
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including the relationships between C6 and C7, and C12 and C13 were not elucidated. By considering the
NOE correlations observed from H9, H10 to H12 and H7, a cis relationship was proposed for H7, H9, H10
and H12.6 However, this stereochemical prediction is not definitive as it is known that the structure
determination by the NOE method occasionally leads to misassignment of the relative stereochemistry.14
Indeed, the originally proposed structure of aplysiallene8a-c was revised by the Pagenkopf group through the
total synthesis of putative stereoisomers.8d Thus, unequivocal confirmation of the proposed structure by the
total synthesis remains of great importance, in particular, in the area of marine-derived halogenated natural
products.15 In this context, we undertook a synthetic study to determine all the stereochemistry of 2 and to
develop a general synthetic route of this class of natural products. Herein, we report a highly
stereocontrolled total synthesis of one of the possible stereoisomers of laurenidificin featuring stereospecific
ring contraction. While our effort did not culminated in full assignment of the structure of the natural
product, the relative stereochemistry between C6 and C7 was suggested on the basis of NMR analyses,
which led to a prediction of the most plausible structure of laurenidificin. Moreover, a highly stereospecific
ring contraction strategy was extended to the formal total synthesis of (+)-aplysiallene (ent-4).
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H
H
H
Br
H
H
12R
O
H
O
H
10S
9R
13S
O
O
H
Br
Br
Br
(–)-kumausallene (3)
laurenenyne A (E isomer) (1E)
laurenenyne B (Z isomer) (1Z)
*Absolute configuration had not been determined, while
all-cis relationship was proposed for H7, H9, H10 and H12
H
H
Br
H
OH
6R
H
12
O
7
H
O
H
10
7S
9
9R
6S
4R
13
O
Br
H
O
H
Br
H
(–)-aplysiallene (4)
proposed structure of laurenidificin (2)
Figure 1. Examples of brominated C15-acetogenins bearing 2,6-dioxabicyclo[3.3.0]octane skeletons.
RESULTS AND DISCUSSION
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To begin, the unidentified stereochemistry from C9 to C13 in 2 was assumed to be the same as that of 1E
and 1Z by considering their structural similarities and the biogenetic viewpoint. In short, structure 5 was
selected as the initial synthetic target (Scheme 1). It was planned that the thermodynamically unfavorable
Z-enyne side chain could be introduced by a hydroindation/cross-coupling sequence onto alkyne 6 by
following Oshima’s method.16 Recently, we demonstrated that the base-induced ring contraction (i.e.,
oxy-Favorskii rearrangement) of bicyclic α-bromolactones was a powerful method to obtain cis-fused
bicyclic hydrofurans with an α−substituent of the ether oxygen.17,18 This method was successfully applied
to the total synthesis of (±)-communiol E.17 Since the main backbone of 5 was similar to that of communiol
E, we decided to apply this methodology to the formation of the dioxabicyclo[3.3.0]octane framework of
5.19 Thus, α-bromolactone 7 was planned as a precursor to 6. It was expected that 7 would be obtained from
the known ester 820 via one-carbon elongation, halolactonization, reduction, and α-bromination. We
envisioned that the entire synthetic sequence would be stereospecific due to the inflexible molecular
architecture of the intermediates, which would provide 5 in a stereocontrolled manner.
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Scheme 1. Retrosynthetic analysis of 5
H
H
HO
H
O
O
H
12R
OH
O
7S
10S
6R
9S
13S
O
OMe
O
H
H
H
H
Br
5
6
H
H
H
Br
O
TrO
O
TrO
O
CO2Et
H
O
7
8
The synthesis commenced with DIBAL-H reduction and Wittig olefination of the known ester 8 that was
prepared from 2-deoxy-D-ribose in three steps20 (Scheme 2). More than three equivalents of the Wittig
reagent with the addition of aldehyde at low temperature were necessary to obtain enol ether 9 in good yield.
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The product 9 was submitted to hydrolysis under acidic conditions followed by Lindgren-Kraus oxidation21
to provide the requisite carboxylic acid 10. The stage was now set for the consecutive stereospecific
reactions involving halolactonization, α-bromination of the resultant lactone, and ring contraction. In the
hope that this method could be applied to both laurenidificin (2) and laurenenynes (1), the latter of which
bears the bromine substituent at C8, bromolactonization was planned rather than iodolactonization. After
exploration of several conditions, Braddock’s conditions with NBS and tetramethylguanidine as the
organocatalyst22 turned out to be appropriate. While the isolated yield of the bromolactone after silica gel or
Florisil chromatography was about 60%, NMR studies in deuterated solvent (CDCl3) indicated clean
conversion without forming considerable byproducts. The use of freshly distilled CHCl3 enhanced
reproducibility, which suggested that a small amount of EtOH contained as a stabilizer of CHCl3 induced
side reactions such as ethanolysis of the lactone to give the ring-opening product. Since the bromolactone
was unstable on silica gel, it was submitted to radical reduction without purification to give the bicyclic
lactone 11 in 84% isolated yield over two steps.
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Next, we focused our attention on α-bromination to set up the rearrangement. The lactone 11 was treated
with LiHMDS and TMSCl to generate a silyl ketene acetal, which was treated with NBS at −78 °C to
provide α-bromolactone 7 as a single stereoisomer. In accordance with the previous results, addition of NBS
occurred at the less hindered convex face.17 Since the product 7 was again unstable, it was submitted,
without chromatography, to the ring contraction in the presence of K2CO3 in MeOH at −78 °C to room
temperature. Remarkably, the expected bicyclic ether 12 was obtained as the sole stereoisomer in almost
quantitative yield without epimerization at C12.23 It appears that the R-configuration at C12 arose from
backside attack of alkoxide A, generated by methanolysis of the lactone, to the 12S-configured secondary
bromide. The syn relationship between H6 and H12 was confirmed by the NOE enhancement after
detritylation of 12 with TsOH/MeOH to give alcohol 12a (91% yield from 11, Figure 2). The C6-alcohol
12a was then oxidized with Dess-Martin periodinane24 in the presence of NaHCO3 as the acid scavenger to
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afford aldehyde 13.
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Next, our attention was focused on the synthesis of the Z-enyne side chain by employing hydroindation
chemistry.16,25 To introduce the requisite alkyne terminal, propargylation of 13 was carried out with
propargyl bromide and zinc dust using 1,2-dibromoethane as the activator of zinc.26 Remarkably, the
6R-configured alcohol 6 was exclusively produced in 67% yield. The absolute configuration at C6 was later
determined by the modified Mosher method (vide infra). It is likely that the complete diastereoselectivity is
set by the Re face addition of the organozinc reagent via the Felkin-Anh conformation B (Figure 3).27 This
selectivity was in accordance with the previous results, where propargylation under Barbier conditions
tended to occur from the Re face of the carbonyl group.28
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With the desired 6R-hydroxy alkyne 6 in hand, the Z-selective hydroindation/cross-coupling sequence16
was examined after optimizing the reaction conditions with a model study (Scheme 3). Thus, alkyne 6 was
treated with HInCl2, generated from anhydrous InCl3 and DIBAL-H, in the presence of Et3B at −78 °C for 3
h. The vinylindium intermediate was then trapped by molecular iodine to afford the corresponding vinyl
iodide, which was, without purification, coupled with ethynyltrimethylsilane under Hagihara-Sonogashira
conditions29 to provide the desired Z-enyne 14 as a single isomer in 70% overall yield for two steps. The
coupling constant, JH3-H4 = 11 Hz, indicated the Z-configuration with respect to the C3−C4 olefin. To make
the process more efficient, the one-pot operation was attempted with a model substrate II (Scheme 3). Thus,
the solutions of (iodoethynyl)trimethylsilane, Pd2(dba)3·CHCl3, and tri-2-furylphosphine were added
sequentially to the transient vinylindium solution (D) at room temperature. The desired Z-enyne IV was
obtained in 42% yield, together with a slight amount of alkene V (4% yield). While the one-pot process was
not applied to the actual substrate 6, this preliminary achievement offers a promising approach of Z-enyne
structures starting from terminal alkynes.30 Back to Scheme 2, after desilylation of 14 with TBAF and
conversion to the corresponding MTPA esters 15S and 15R, the stereochemistry at C6 was determined by
the modified Mosher method.31 The signs of ΔδH(S−R) values for 15 and the MTPA derivatives of 26 were all
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identical, which suggested that both compounds had the 6R-configuration.
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Scheme 2. Stereocontrolled synthesis of the dioxabicyclo[3.3.0]octane framework and insertion of the
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enyne moiety
O
HO
OH
OH
2-deoxy-D-ribose
ref. 20 (3 steps)
1. NBS
Me2NC(=NH)NMe2
rt, dist. CHCl3
H
H
H
1. THF-HCl aq
(100:1), rt, 98%
H
1. DIBAL-H, CH2Cl2
–78 °C, 95%
H
TrO
O
TrO
O
TrO
O
TrO
O
CO2Et
7S
10S
2. NaClO2, NaH2PO4
sat. NaHCO3 aq
2-methyl-2-butene
t-BuOH-THF-H2O
(4:2:1), 0 °C, 94%
2. Ph3PCH2OMe·Cl
LiHMDS, THF
–78 to 0 °C, 94%
2. n-Bu3SnH, AIBN
toluene, 95 °C
84% (2 steps)
CO2H
H
OMe
9 (E/Z = 3:1)
H
O
O
H
H
10
11
8
H
H
H
H
1. TsOH, MeOH, rt
91% (3 steps)
LiHMDS, TMSCl
THF, –78 to 0 °C
H
H
TrO
H
O
H
O
12S Br
CO2Me
O
Br
O
O
O
TrO
K2CO3, MeOH
–78 °C to rt
O
12S
6
12R
2. DMP, NaHCO3
CH2Cl2, rt
H
then NBS, –78 °C
O
O
OMe
H
OMe
H
H
H
O
O
O
H
H
7 (dr > 20:1)
12 (dr > 20:1)
A
13
+0.03
(–0.06)
TMS
1. InCl3-DIBAL-H
Et3B then I2
THF, –78 °C
–0.06
–0.14
(–0.15)
H
H
propargyl bromide
Zn, (CH2Br)2
H
O
H
H
OR
O
–0.08
HO
H
O
O
1. TBAF, THF, rt, 92%
H
OH
O
O
+0.07
0
6R
3
THF, 0 °C
67% (2 steps)
O
OMe
O
TMS
2. (R) or (S)-MTPACl
Et3N, DMAP
CH2Cl2
OMe 2.
H–0.13
6
H
+0.13 +0.06
O
–0.11
H
OMe
H
H
(Ph3P)2PdCl2, CuI
i-Pr2NH, THF, rt
70% (2 steps)
4
–0.07
Δδ = δS–δR
6 (dr > 20:1)
14 (Z/E > 20:1)
15S: R = (S)-MTPA
15R: R = (R)-MTPA
6
12
NOE
12a
Figure 2. NOE correlations for 12a. The energy-minimized structure was obtained by the molecular
mechanics calculation with MMFF force field.
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H
O
H
O
Nu
Nu
H
H
O
H
H
O
6
7
8
9
O
H
H
ZnBr
O
R
H
MeO2C
CO2Me
H
B
C
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6R
(observed)
6S
(not observed)
Figure 3. Stereochemical outcome for propargylation (13→6).
Scheme 3. Model studies to construct the Z-enyne moiety of laurenidificin.
propargyl bromide
Zn, (CH2Br)2
InCl3-DIBALH
Et3B
O
H
OH
O
O
I OH
O
Cl2In OH
O
I2
THF, –12 °C
99%
THF, –78 °C
–78 °C
I
II
D
III
TMS
(Ph3P)2PdCl2, CuI
i-Pr2NH, THF, rt
70% (from II)
TMS
OH
TMS
Pd2(dba)3·CHCl3
tri-2-furylphosphine
I
1
OH
O
O
THF-DMI (2:1), rt
42% (from II)
5
IV
V
The remaining tasks were insertion of the C14−C15 carbon chain and bromination at C13. At first, the
C6-hydroxyl group of 14 was protected as the TES ether (Scheme 4). Next, the methyl ester was carefully
reduced with DIBAL-H to afford the aldehyde. The next ethylation was, however, problematic. When EtLi
was added in THF at 0 °C,17 the reaction produced a complex mixture of unidentifiable products, among
which the desired ethylation product was isolated in only 2% yield after HPLC. Therefore, we searched for
more efficient conditions with model studies. After extensive screening of organometallic nucleophiles
(EtMgBr, EtLi), additives (CuBr·SMe2, CuBr·SMe2/BF3·Et2O, CuI, CuCN, CuCN/BF3·Et2O), solvents
(THF, ether) and temperatures (from −78 °C to 0 °C), either a 2:1 combination of EtMgBr and CuBr·SMe2
or a 2:1:1 combination of EtLi, CuCN, and BF3·Et2O were found to be suitable.32 Application of the latter
conditions (two cycles) gave rise to ethylation product 16 as the only detectable stereoisomer.33 The
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C13-stereochemistry was again confirmed by the modified Mosher method,31 which revealed that, to our
delight, the major product had the desired 13R-configuration.34 The product 16 was subjected to
bromination10-12 with Ph3P and CBr4 in the presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to
provide the expected bromide in 32% overall yield for three steps.35 While the assignment of the
stereochemistry at C13 was not possible at this stage, the general SN2 reaction mode tentatively defined the
absolute configuration of C13 as 13S.36 Finally, two silyl groups were simultaneously removed by TBAF to
furnish the target molecule 5.
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Scheme 4. Total synthesis of a possible stereoisomer of laurenidificin (5)
TMS
OTES
H
1. TESOTf, 2,6-lutidine
CH2Cl2, rt, 90%
2. DIBAL-H, CH2Cl2, –78 °C
H
H
13R
O
14
3. Et2Cu(CN)Li2, BF3·Et2O
THF, –78 to –20 °C
O
H
OH
16
1. Ph3P, CBr4, DTBMP
benzene-CH2Cl2 (1:1.5)
rt, 32% (3 steps)
H
H
12R
OH
7S
6R
O
10S
9S
2. TBAF, THF, rt, 76%
13S
O
H
H
O
Br
5
TMS
–0.15
H
–0.07
–0.06
H
–0.01
H
12R
OH
7R
H
OTBS
10R
O
6R
+0.11
9R
–0.02
–0.04
13S
O
H
+0.14
O
0
H–0.08
H
20
Br
–0.01
–0.04 –0.06
H
OR
Δδ = δS–δR
–0.14
17S: R = (S)-MTPA
17R: R = (R)-MTPA
Contrary to our initial expectations, comparison of the NMR data suggested that 5 was not identical to the
natural product.6,37 In whole, substantial differences in the chemical shifts and the coupling constants were
observed, which indicated that the shapes of the two molecules were considerably different. While the
stereochemistry at C6 was the same in both, a large difference in the chemical shifts for H6 was observed (δ
3.69 and δ 3.93 for 2 and 5, respectively). This observation implied that the relative stereochemistry around
the C6 center was not the same. To deduce the stereochemical relationship between C6 and C7, the
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6S-configured alcohol 19 was synthesized from the corresponding 6R-alcohol 14 via Mitsunobu inversion
with monochloroacetic acid38,39 (Figure 4). Proton and carbon chemical shift differences (ΔδH and ΔδC)
between the synthetic compound (18 or 19) and the natural product (2) suggested that 19, rather than 18,
was more analogous to the natural product, specifically because of the relationship around the C6 center (a
vs. b, and c vs. d). Additionally, the ΔδH values at C9 in both 18 and 19 exceeded 0.3 ppm, which indicated
that the steric environments of the bicyclic core were different. By taking these results and the reported
NOE data6 (vide supra), as well as a possible biosynthetic route,5,40 into consideration, the most plausible
structure of laurenidificin was proposed as 20 with 6R,7R,9R,10R,12R,13S-configurations (Scheme 4).41,42
Toward the synthesis of 20, it would be essential to find an ingenious method for constructing all-cis
stereochemistry regarding hydrogens on the dioxabicyclo[3.3.0]octane ring and to obtain an alternative
starting material that can readily access to the 7R-configuration.43
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R
1. ClCH2CO2H, Ph3P
1
1
DEAD, toluene
–78 °C to rt, 23%
H
H
H
OH
O
OH
H
O
O
O
7S
7S
10S
10S
6R
6S
9S
9S
12R
12R
2. K2CO3, MeOH
–78 to –40 °C
53%
O
O
OMe
OMe
H
H
H
H
TBAF
92%
14: R = TMS
18: R = H
19
0.40%%
0.4
0.40%%
0.4
(a)
(b)
0.20%%
0.2
0.20%%
0.2
ΔδHꢀ
ΔδHꢀ
ΔδH
ΔδH
0.00%%
0
0
0.00%%
!0.20%%
–0.2
–0.2
!0.20%%
1% 3% 4% 5a% 5b% 6% 7% 8a% 8b% 9% 10%11a%11b%
1% 3% 4% 5a% 5b% 6% 7% 8a% 8b% 9% 10%11a%11b%
proton numberꢀ
proton numberꢀ
1.0%%
1
1.0%%
1
(c)
(d)
0.0%%
0.0%%
0
0
ΔδCꢀ
ΔδCꢀ
ΔδC
ΔδC
!1.0%%
–1
!1.0%%
–1
!2.0%%
–2
!2.0%%
–2
1% 2% 3% 4% 5% 6% 7% 8% 9% 10% 11%
1% 2% 3% 4% 5% 6% 7% 8% 9% 10% 11%
carbon numberꢀ
carbon numberꢀ
Figure 4. Chemical shift differences between the synthetic compound (18 or 19) and the natural
laurenidificin. The x-axis represents proton or carbon number. The y-axis shows chemical shift differences
in ppm. (a) ΔδH = (18) – (natural product). (b) ΔδH = (19) – (natural product). (c) ΔδC = (18) – (natural
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product). (d) ΔδC = (19) – (natural product).
4
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9
Having proved a great potential of the ring contraction strategy for the synthesis of the cis-fused
dioxabicyclo[3.3.0]octane class of halogenated acetogenins, we then extended the strategy to the other
stereochemical type. As shown in Figure 1, (−)-aplysiallene (4) has a trans relationship with respect to H4
and H6, and H7 and H9,8d which seemed ideal for executing the ring contraction reaction. With the
established strategy described in Scheme 2 in hand, we decided to carry out the synthesis of (+)-aplysiallene
(ent-4) bearing the 4S,6R,7R,9S-configurations. Of special note is that ent-4 had been never synthesized8d
nor biologically tested.8b The synthesis again began with 2-deoxy-D-ribose by following the Borhan’s report
(Scheme 5).44 A reliable five-step conversion afforded secondary alcohol 21 with the 7R-configuration in
68% overall yield. Dehydration of 21 with triflic anhydride followed by hydroboration/oxidation and
oxidation with a TEMPO oxoammonium salt/NaClO2 system45 provided carboxylic acid 23, whose
stereochemistry at C7 was epimeric to that of 10. Bromolactonization22 of 23 and reduction with n-Bu3SnH
using Et3B/air as the radical initiator gave rise to the somewhat unstable bicyclic lactone 24. Subsequent
bromination of 24 occurred at the convex face of the bicyclic molecule (E) to provide β-bromolactone 25 as
an only detectable stereoisomer. The ring contraction proceeded through alkoxide F in an SN2 fashion,
affording the expected bicycle ether 26 with the 9S-configuration in 60% overall yield from 24. It should be
noted that a bromination/ring contraction sequence was achieved in one-pot to provide 26 in 57% overall
yield. In the latter case, a small amount of 9-epi-26 was detected (5% yield), which might be arising from
epimerization at C9 in 25 under basic conditions.17 The cis-relationship between H4 and H9 on 26 was
confirmed by a strong NOE enhancement of H9 upon irradiation of H4 (Figure 5). The product 26 was then
converted into alcohol 27 via a deprotection-reprotection sequence followed by ester reduction with LiAlH4.
The NMR spectra of 27 matched those of ent-27 that was prepared in the course of total synthesis of
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(−)-aplysiallene (4).8d
5
6
7
8
9
Scheme 5. Formal total synthesis of (+)-aplysiallene (ent-4)
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H
1. 9-BBN, THF, rt;
NaOH aq, H2O2, 94%
H
Tf2O, 2,6-lutidine
H
ref. 42
O
TrO
O
TrO
O
–78 °C; DBU, rt
TrO
O
4S
HO
7R
7R
OH
2. TEMPO+·BF4–, NaClO2
MeCN-H2O (1:1), rt, 72%
CO2H
CH2Cl2, 98%
(5 steps)
OH
2-deoxy-
HO
H
D
-ribose
21
22
23
convex
H
Br+
H
1. Me2NC(=NH)NMe2
NBS, dist CHCl3, rt
LiHMDS, TMSCl
THF, –78 to 0 °C;
Br
O
TrO
O
TrO
K2CO3
MeOH
–78 °C to rt
O
9R
Si
O
H
O
2. n-Bu3SnH, Et3B
air, toluene
68% (2 steps)
then NBS, –78 °C
O
O
O
O
H
H
24
R
E
25
OMe
1. TsOH, MeOH, rt
2. TBSCl, imidazole
DMF, rt
H
H
H
Br
9R
TBSO
H
O
4S
TrO
H
O
ref. 8d
O
4S
O
7R
(+)-aplysiallene
(ent-4)
H
CO2Me
9S
6R
9S
3. LiAlH4, THF, 0 °C
54% (3 steps)
60% (stepwise)
57% (one-pot)
(2 steps)
O
OH
O
(10 steps)
H
OMe
H
O
H
H
H
27
F
26
9
4
NOE
Figure 5. NOE correlations for 26. The energy-minimized structure was obtained by the molecular
mechanics calculation with MMFF force field.
CONCLUSIONS
In summary, we have achieved a stereocontrolled total synthesis of one possible stereoisomer of
laurenidificin, which led to the prediction of the stereochemistry of the natural product. Our synthesis
features the formation of the 2,6-dioxabicyclo[3.3.0]octane framework by
a
stereospecific
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bromolactonization−α-bromination−ring contraction sequence, followed by a stereoselective propargylation,
an insertion of the Z-enyne side-chain by a hydroindation/cross coupling reaction, and ethylation with an
organocuprate reagent. Furthermore, we extended the ring contraction method to the formation of the other
stereoisomer (cf. 26), which constituted a formal total synthesis of (+)-aplysiallene. The overall
transformations from carboxylic acids (10 and 23) to the ring contraction products (12 and 26) were reliable
and beneficial for the construction of the branched bicyclic ethers condensed with five-membered rings. Of
particular note is that all synthetic sequences from the known substrates were stereoselective and free from
separation of stereoisomers. Additional studies directed toward the total synthesis of the most plausible
structure of laurenidificin and application of the present method to other halogenated acetogenins are
ongoing in our laboratory.
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EXPERIMENTAL SECTION
General Techniques. All reactions utilizing air- or moisture-sensitive reagents were performed under an
atmosphere of argon or nitrogen. Commercially available dry solvents were used for DMF, CH2Cl2, THF,
and MeOH. Triethylamine, pyridine, 1,1,1,3,3,3-hexamethyldisilazane and TMSCl were distilled from CaH2.
n-Bu3SnH was distilled by a Kugelrohr apparatus without a drying agent. i-Pr2NH was distilled from KOH.
CHCl3 was distilled from CaCl2. NBS was recrystallized from water. Ph3P was recrystallized from
−
EtOAc/MeOH. CBr4 was recrystallized from EtOH. TEMPO+BF4 was prepared according to literature
method.46 Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel
plates (60-F254) that were analyzed by fluorescence upon 254 nm irradiation or by staining with
p-anisaldeyde/AcOH/H2SO4/EtOH, 12MoO3·H3PO4/EtOH, or (NH4)6Mo7O24·4H2O/H2SO4. The products
were purified by either open chromatography on silica gel (spherical, neutral, 70-230 µm) or flash
chromatography on silica gel (spherical, neutral, 40-50 µm) and, if necessary, HPLC equipped with
pre-packed column using hexane/EtOAc as eluent. NMR spectra were recorded with a 300 MHz (1H: 300
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MHz, 13C: 75 MHz) or a 400 MHz (1H: 400 MHz, 13C: 100 MHz) spectrometer and referenced to the
solvent peak at 7.26 ppm (1H) and 77.16 ppm (13C) for CDCl3. Splitting patterns are indicated as follows: br,
broad; s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet; sept, septet; m, multiplet. Infrared spectra were
recorded with a FT/IR spectrometer and reported as wavenumber (cm-1). Low- and high-resolution FAB
mass spectra were recorded with a double-focusing magnetic sector mass spectrometer in positive or
negative ion mode. High-resolution ESI, APCI, and APPI mass spectra were recorded with an Orbitrap
analyzer in positive or negative ion mode. The carbon numbering described in the peak assignment
corresponds to that of laurenidificin and aplysiallene. The NMR peak assignments were confirmed by
1H−1H COSY analysis.
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Synthetic Procedures and Analytical Data. (4S,5R)-5-((Trityloxy)methyl)tetrahydrofuran-2,4-diol.47
In a 500 mL round-bottom flask were placed 2-deoxy-D-ribose (17.3 g, 129 mmol). The substrate was dried
by coevaporation with dry pyridine (3 × 8 mL) and then dissolved in the same anhydrous solvent (146 mL).
Trityl chloride (43.2 g, 155 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (112 mg, 0.913
mmol) were added and the resulting solution was stirred for 23 h at 50 °C. Then the solution was cooled to
0 °C and quenched with water. The resulting mixture was evaporated to remove most of pyridine before
extraction with EtOAc (2×). The combined organic layer was washed with saturated KHSO4 solution, brine,
dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by open chromatography
(n-hexane/EtOAc = 4 → 1) to give the title compound (19.9 g, 53.0 mmol, 41%) as a colorless amorphous
1
solid. The compound contained a small amount of inseparable isomer. H-NMR (300 MHz, CDCl3) δ
7.49-7.20 (m, 15H), 5.62 (t, 1H, J = 5.0 Hz), 4.36 (td, 1H, J = 4.8, 1.2 Hz), 4.27 (br t, 1H, J = 6.5 Hz), 3.15
(dd, 1H, J = 9.9, 4.5 Hz), 3.11 (dd, 1H, J = 9.9, 5.0 Hz), 2.19 (dt, 1H, J = 14, 5.4 Hz), 2.04 (br d, 1H, J = 14
Hz).
Ethyl 2-((2R,4S,5R)-4-hydroxy-5-((trityloxy)methyl)tetrahydrofuran-2-yl)acetate.20a In a three-necked
round-bottom flask was placed t-BuOK (4.18 g, 37.2 mmol). THF (62 mL) was added and the suspension
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was cooled to 0 °C. Ethyl diethylphosphonoacetate (6.86 mL, 34.6 mmol) was added and the mixture was
stirred at 0 °C for 30 min. Then a solution of (4S,5R)-5-((trityloxy)methyl)tetrahydrofuran-2,4-diol (10.0 g,
26.6 mmol) in THF (89 mL) was added and the resulting mixture was stirred at the same temperature for 30
min. The reaction mixture was quenched by the addition of saturated NH4Cl solution and extracted with
EtOAc (2×). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and
concentrated. The residue was purified by open chromatography (hexane/EtOAc = 5 → 3→ 2) followed by
flash chromatography (n-hexane/EtOAc = 6 → 4→ 2) to give the title compound (8.76 g, 19.6 mmol, 67%)
as a colorless amorphous solid, and its diastereomer (2.21 g, 4.94 mmol, 17%) as a colorless amorphous
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1
solid. Data for title compound: H-NMR (300 MHz, CDCl3) δ 7.47-7.41 (m, 6H), 7.33-7.20 (m, 9H),
4.61-4.51 (m, 1H), 4.36-4.30 (m, 1H), 4.15 (q, 2H, J = 7.2 Hz), 3.93 (ddd, 1H, J = 5.7, 4.5, 2.4 Hz), 3.24
(dd, 1H, J = 9.6, 4.5 Hz), 3.09 (dd, 1H, J = 9.6, 5.7 Hz), 2.66 (dd, 1H, J = 15, 7.2 Hz), 2.51 (dd, 1H, J = 15,
6.0 Hz), 2.06 (ddd, 1H, J = 13, 5.4, 2.1 Hz), 1.84 (ddd, 1H, J = 13, 9.9, 6.3 Hz), 1.75 (d, 1H, J = 3.6 Hz),
1.25 (t, 3H, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3) δ 171.2, 143.9, 128.8, 128.0, 127.2, 86.9, 85.9, 74.8,
74.7, 64.8, 60.7, 40.9, 40.7, 14.3. Data for diastereomer: 7.47-7.37 (m, 6H), 7.33-7.20 (m, 9H), 4.50 (qui,
1H, J = 6.5 Hz), 4.35-4.28 (m, 1H), 4.16 (q, 2H, J = 7.2 Hz), 4.08-4.03 (m, 1H), 3.24 (dd, 1H, J = 9.6, 4.5
Hz), 3.09 (dd, 1H, J = 9.6, 6.3 Hz), 2.73 (dd, 1H, J = 16, 6.6 Hz), 2.65 (dd, 1H, J = 16, 6.0 Hz), 2.47 (d, 1H,
J = 5.1 Hz), 2.45 (dt, 1H, J = 13, 6.9 Hz), 1.78 (ddd, 1H, J = 13, 6.3, 4.8 Hz), 1.26 (t, 3H, J = 7.2 Hz);
13C-NMR (75 MHz, CDCl3) δ 171.6, 143.9, 128.8, 128.0, 127.2, 87.0, 84.9, 74.9, 64.7, 60.7, 40.9, 39.9,
14.3.
Ethyl 2-((2S,5S)-5-((trityloxy)methyl)-2,5-dihydrofuran-2-yl)acetate (8).20b To a solution of ethyl
2-((2R,4S,5R)-4-hydroxy-5-((trityloxy)methyl)tetrahydrofuran-2-yl)acetate (5.00 g, 11.2 mmol) in CH2Cl2
(112 mL) were added 2,6-lutidine (3.89 mL, 33.6 mmol) and Tf2O (2.83 mL, 16.8 mmol) at −78 °C. The
mixture was stirred for 30 min at −78 °C followed by the addition of DBU (16.7 mL, 112 mmol). The
resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched
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by the addition of saturated NaHCO3 solution. After removal of CH2Cl2 by evaporation, the residue was
extracted with hexane/EtOAc (5/1) (2×). The combined organic layer was washed with 1 M aqueous HCl,
brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash
chromatography (n-hexane/EtOAc = 10) to give alkene 8 (3.70 g, 8.63 mmol, 77%) as a colorless solid.
1H-NMR (300 MHz, CDCl3) δ 7.49-7.44 (m, 6H, Tr), 7.33-7.20 (m, 9H, Tr), 5.94 (ddd, 1H, J = 6.3, 2.1, 1.5
Hz, H8), 5.85 (br dt, 1H, J = 6.3, 1.8 Hz, H9), 5.28-5.22 (m, 1H, H10), 5.00-4.95 (m, 1H, H7), 4.16 (q, 2H,
J = 7.1 Hz, OEt), 3.20 (dd, 1H, J = 9.6, 5.4 Hz, H6), 3.11 (dd, 1H, J = 9.6, 4.5 Hz, H6), 2.72 (dd, 1H, J = 15,
7.2 Hz, H11), 2.55 (dd, 1H, J = 15, 6.3 Hz, H11), 1.26 (t, 3H, J = 7.1 Hz, OEt); 13C-NMR (75 MHz, CDCl3)
δ 171.1, 144.1, 130.2, 128.9, 128.8, 127.9, 127.1, 86.6, 86.0, 82.7, 67.0, 60.7, 42.2, 14.4; FT-IR (film on
ZnSe) 3058, 3022, 2981, 2868, 1729, 1597, 1491, 1449, 1373, 1300, 1262, 1220, 1173, 1076 cm-1; HRMS
(FAB): m/z calcd for C28H28O4 [M + Na]+ 451.1885, found 451.1915.
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(2S,5S)-2-(3-Methoxyallyl)-5-((trityloxy)methyl)-2,5-dihydrofuran (9). To a solution of ester 8 (5.77 g,
13.5 mmol) in CH2Cl2 (112 mL) was added DIBAL-H (1.04 M in hexane, 15.5 mL, 16.2 mmol) through a
dropping funnel over 20 min at −78 °C. After 10 min at −78 °C, the reaction mixture was quenched by the
addition of saturated Rochelle salt solution. The resulting mixture was stirred at room temperature until two
phases were clearly separated (3 h). After removal of CH2Cl2 by evaporation, the residue was extracted with
hexane (2×). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and
concentrated. The residue was purified by flash chromatography (n-hexane/EtOAc = 5 → 2) to give
aldehyde (4.92 g, 12.8 mmol, 95%) as a colorless amorphous solid and a small amount of the corresponding
1
alcohol (202 mg, 0.522 mmol, 4%). Data for aldehyde: [α]27 −60.6 (c 1.03, CHCl3); H-NMR (300 MHz,
D
CDCl3) δ 9.82 (t, 1H, J = 1.8 Hz, CHO), 7.47-7.20 (m, 15H, Tr), 5.90 (ddd, 1H, J = 6.3, 2.1, 1.5 Hz, H5),
5.86 (ddd, 1H, J = 6.0, 2.1, 1.2 Hz, H4), 5.35-5.28 (m, 1H, H3), 5.01-4.95 (m, 1H, H6), 3.19 (dd, 1H, J =
9.6, 5.3 Hz, H7), 3.13 (dd, 1H, J = 9.6, 4.1 Hz, H7), 2.79 (ddd, 1H, J = 17, 7.5, 2.1 Hz, H2), 2.68 (ddd, 1H,
J = 17, 5.1, 1.5 Hz, H2); 13C-NMR (75 MHz, CDCl3) δ 201.0, 144.0, 129.9, 128.8, 127.9, 127.1, 86.5, 86.1,
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81.2, 66.7, 50.6; FT-IR (film on ZnSe) 3086, 3058, 3023, 2921, 2867, 1725, 1596, 1492, 1449, 1360, 1265,
1219, 1183, 1154, 1090 cm-1; HRMS (ESI-pos): m/z calcd for C26H24O3Na [M + Na]+ 407.1618, found
407.1611.
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To a suspension of (methoxymethyl)triphenylphosphonium chloride (15.2 g, 44.5 mmol) in THF (60 mL)
was added fleshly prepared LiHMDS (0.5 M in THF, 76.2 mL, 38.1 mmol) through a dropping funnel over
20 min at 0 °C. After completion of the addition, the mixture was stirred for 1 h at 0 °C. The suspension was
then cooled to −78 °C followed by the addition of aldehyde (4.88 g, 12.7 mmol) in THF (67 mL) over 20
min. The resulting mixture was gradually warmed to 0 °C and stirred for 2 h. The reaction mixture was
quenched by the addition of saturated NaHCO3 solution and extracted with ether (2×). The combined
organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue
was purified by open chromatography (n-hexane/EtOAc = 100 → 50→ 10) to give enol ether 9 (4.91 g,
11.9 mmol, 94%, E/Z = 3:1) as a colorless solid. The following analytical data was collected as a mixture of
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stereoisomers. H-NMR (300 MHz, CDCl3) δ 7.50-7.46 (m, 6H, Tr), 7.32-7.19 (m, 9H, Tr), 6.31 (br d,
0.75H, J = 13 Hz, H13), 5.91 (dt, 0.25H, J = 6.3, 1.4 Hz, H13), 5.88-5.76 (m, 2H, H8, H9), 5.01-4.95 (m,
1H, H7), 4.89-4.80 (m, 1H, H10), 4.70 (dt, 0.75H, J = 13, 7.6 Hz, H12), 4.44 (dt, 0.25H, J = 7.5, 6.3 Hz,
H12), 3.55 (s, 0.75H, OMe), 3.44 (s, 2.25H, OMe), 3.200 (dd, 0.25H, J = 9.3, 6.0 Hz, H6), 3.193 (dd, 0.75H,
J = 9.3, 5.7 Hz, H6), 3.070 (dd, 0.25H, J = 9.3, 4.5 Hz, H6), 3.065 (dd, 0.75H, J = 9.6, 4.2 Hz, H6),
2.40-2.12 (m, 2H, H11); FT-IR (film on ZnSe) 3086, 3059, 3033, 2929, 2862, 1656, 1596, 1491, 1449,
1389, 1358, 1215, 1153, 1132, 1075 cm-1; HRMS (ESI-pos): m/z calcd for C28H28O3Na [M + Na]+ 435.1931,
found 435.1920.
3-((2S,5S)-5-((Trityloxy)methyl)-2,5-dihydrofuran-2-yl)propanoic acid (10). To a solution of enol ether 9
(4.91 g, 11.9 mmol) in THF (120 mL) was added 1M aqueous HCl (1.2 mL). The mixture was stirred at
room temperature for 13 h. After dilution with Et2O, the reaction mixture was quenched by the addition of
saturated NaHCO3 solution. The resulting mixture was stirred for 1 h before extraction with EtOAc (2×).
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The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated.
The residue was purified by open chromatography (n-hexane/EtOAc = 2) to give aldehyde (4.64 g, 11.6
mmol, 98%) as a pale yellow amorphous solid. [α]25D −53.3 (c 1.66, CHCl3); 1H-NMR (300 MHz, CDCl3) δ
9.73 (t, 1H, J = 1.5 Hz, H13), 7.49-7.45 (m, 6H, Tr), 7.33-7.20 (m, 9H, Tr), 5.84-5.78 (m, 2H, H8, H9),
4.99-4.94 (m, 1H, H7), 4.94-4.87 (m, 1H, H10), 3.20 (dd, 1H, J = 9.6, 5.7 Hz, H6), 3.11 (dd, 1H, J = 9.6,
4.2 Hz, H6), 2.54 (td, 2H, J = 7.5, 1.5 Hz, H12), 2.00 (dtd, 1H, J = 14, 7.5, 4.2 Hz, H11), 1.84 (dq, 1H, J =
14, 7.5 Hz, H11); 13C-NMR (75 MHz, CDCl3) δ 202.3, 144.1, 130.6, 128.9, 128.6, 127.9, 127.1, 86.6, 85.7,
85.3, 67.2, 40.0, 28.6; FT-IR (film on ZnSe) 3085, 3057, 3032, 2921, 2863, 2724, 1724, 1596, 1492, 1449,
1410, 1389, 1372, 1321, 1220, 1183, 1154 cm-1; HRMS (ESI-pos): m/z calcd for C27H26O3Na [M + Na]+
421.1774, found 421.1764.
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To a solution of aldehyde (4.64 g, 11.6 mmol) in THF (35 mL) were added t-BuOH (69 mL),
2-methyl-2-butene (6.42 mL, 60.5 mmol), and saturated aqueous NaHCO3 solution (23.4 mL). After cooling
at 0 °C, a mixed solution of NaH2PO4 (4.36 g, 36.3 mmol) and NaClO2 (3.28 g, 36.3 mmol) in water (17
mL) was added. The resulting mixture was stirred for 20 min at 0 °C before addition of CHCl3 and 1 M
aqueous HCl. The organic layer was separated and the aqueous phase was extracted with CHCl3 (2×). The
combined organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated.
The residue was purified by open chromatography (n-hexane/EtOAc = 5 → 2 containing 3% MeOH) to give
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carboxylic acid 10 (4.55 g, 11.0 mmol, 94%) as a colorless solid. [α]24 −26.9 (c 1.02, CHCl3); H-NMR
D
(300 MHz, CDCl3) δ 7.50-7.45 (m, 6H, Tr), 7.33-7.19 (m, 9H, Tr), 5.83-5.78 (m, 2H, H8, H9), 5.00-4.93 (m,
1H, H7), 4.94-4.88 (m, 1H, H10), 3.19 (dd, 1H, J = 9.6, 6.0 Hz, H6), 3.10 (dd, 1H, J = 9.6, 4.2 Hz, H6),
2.47 (t, 2H, J = 7.6 Hz, H12), 1.99 (dtd, 1H, J = 15, 7.6, 4.1 Hz, H11), 1.84 (dq, 1H, J = 15, 7.4 Hz, H11);
13C-NMR (75 MHz, CDCl3) δ 178.8, 144.1, 130.5, 128.9, 128.5, 127.9, 127.1, 86.5, 85.8, 85.3, 67.2, 31.2,
30.0; FT-IR (film on ZnSe) 3087, 3057, 3023, 2925, 2867, 1708, 1597, 1491, 1449, 1414, 1217, 1183, 1157,
1034 cm-1; HRMS (ESI-pos): m/z calcd for C27H26O4Na [M + Na]+ 437.1723, found 437.1713.
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(2S,3aS,7aS)-2-((Trityloxy)methyl)hexahydro-5H-furo[3,2-b]pyran-5-one (11). To
a
solution of
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carboxylic acid 10 (215 mg, 0.519 mmol) in fleshly distilled CHCl3 (5.2 mL) were added
1,1,3,3-tetramethylguanidine (19.5 µL, 0.156 mmol) and NBS (140 mg, 0.785 mmol). The mixture was
stirred for 2.5 h at room temperature and quenched by the addition of saturated aqueous Na2SO3 solution.
The resulting mixture was extracted with ether (2×), and the combined organic layer was washed with
saturated aqueous NaHCO3 solution, brine, dried over anhydrous MgSO4, filtered and concentrated.
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Bromolactone was obtained as a yellow amorphous solid (256 mg). H-NMR (300 MHz, CDCl3) δ
7.52-7.18 (m, 15H, Tr), 4.98 (br d, 1H, J = 4.8 Hz, H9), 4.43 (q, 1H, J = 4.2 Hz, H10), 4.24-4.17 (m, 2H,
H7, H8), 3.37 (dd, 1H, J = 10, 3.0 Hz, H6), 3.28 (dd, 1H, J = 10, 4.8 Hz, H6), 2.67 (ddd, 1H, J = 17, 12, 5.7
Hz, H12), 2.45 (dt, 1H, J = 17, 5.1 Hz, H12), 2.28-2.05 (m, 2H, H11); FT-IR (film on ZnSe) 3087, 3057,
3022, 2925, 2873, 1756, 1597, 1490, 1449, 1414, 1379, 1357, 1317, 1246, 1218, 1182, 1157 cm-1.
The crude bromolactone (256 mg) was dissolved in toluene (5.2 mL) followed by the addition of
n-Bu3SnH (0.18 mL, 0.69 mmol) and AIBN (17.6 mg, 0.107 mmol). The mixture was warmed to 95 °C and
stirred for 1 h. Then the reaction mixture was cooled to room temperature and quenched by the addition of
saturated aqueous KF solution. The resulting mixture was vigorously stirred for 16 h and filtered through a
pad of Celite. The filter cake was thoroughly washed with EtOAc, and the filtrate was washed with brine,
dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by 10% w/w KF-Florisil
chromatography48 (n-hexane/EtOAc = 6 → 1 → 0.5) to give lactone 11 (181 mg, 0.437 mmol, 84%) as a
colorless solid. [α]26D +5.4 (c 1.00, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 7.49-7.44 (m, 6H, Tr), 7.34-7.20
(m, 9H, Tr), 4.87 (ddd, 1H, J = 7.2, 4.5, 2.7 Hz, H9), 4.17-4.08 (m, 2H, H7, H10), 3.27 (dd, 1H, J = 9.9, 6.3
Hz, H6), 3.16 (dd, 1H, J = 9.9, 3.9 Hz, H6), 2.62 (ddd, 1H, J = 17, 11, 6.0 Hz, H12), 2.50-2.34 (m, 2H, H8,
H12), 2.23-2.04 (m, 2H, H11), 1.93 (ddd, 1H, J = 14, 7.5, 2.7 Hz, H8); 13C-NMR (75 MHz, CDCl3) δ 170.9,
143.9, 128.8, 127.9, 127.2, 86.7, 81.6, 77.3, 74.3, 65.9, 37.3, 25.8, 23.4; FT-IR (film on ZnSe) 3058, 3020,
2918, 2869, 1733, 1596, 1490, 1449, 1377, 1315, 1315, 1293, 1259, 1218, 1185, 1158 cm-1; HRMS
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(ESI-pos): m/z calcd for C27H26O4Na [M + Na]+ 437.1723, found 437.1712.
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Methyl (2R,3aS,5S,6aS)-5-(hydroxymethyl)hexahydrofuro[3,2-b]furan-2-carboxylate (12a). To a solution
of lactone 11 (376 mg, 0.907 mmol) in THF (4.6 mL) was added LiHMDS (0.5 M solution in THF, 2.4 mL,
1.2 mmol) at −78 °C. After 1 h at −78 °C, TMSCl (173 µL, 1.36 mmol) was added and the resultant mixture
was warmed to 0 °C. After 30 min, the solution was again cooled to −78 °C followed by the addition of
NBS (275 mg, 1.54 mmol) in THF (4.5 mL). The reaction mixture was stirred for 1 h at −78 °C and
quenched by the addition of pH 7 phosphate buffer. The resulting mixture was extracted with ether (2×),
and the combined organic layer was washed with saturated aqueous NaHCO3 solution, brine, dried over
anhydrous MgSO4, filtered and concentrated. Bromolactone 7 (568 mg) was obtained as a pale yellow
amorphous solid. As the product was unstable on silica gel, it was submitted to the next reaction without
further purification. To a solution of crude bromolactone 7 (568 mg) in MeOH (19 mL) was added K2CO3
(252 mg, 1.82 mmol) at −78 °C. The suspension was warmed to room temperature and stirred for 20 min.
The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution and extracted with
EtOAc (2×). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and
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concentrated to give methyl ester 12 (418 mg) as a pale yellow amorphous solid. Analytical sample was
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obtained by column chromatography (n-hexane/EtOAc = 5 → 2). [α]28 −9.1 (c 0.96, CHCl3); H-NMR
D
(300 MHz, CDCl3) δ 7.50-7.45 (m, 6H, Tr), 7.33-7.20 (m, 9H, Tr), 4.83 (ddd, 1H, J = 6.3, 3.9, 2.1 Hz, H9),
4.61-4.56 (m, 2H, H10, H12), 4.18 (qd, 1H, J = 6.9, 3.9 Hz, H7), 3.75 (s, 3H, OMe), 3.26 (dd, 1H, J = 9.9,
6.6 Hz, H6), 3.09 (dd, 1H, J = 9.9, 3.9 Hz, H6), 2.53 (dd, 1H, J = 14, 6.6 Hz, H11), 2.25 (ddd, 1H, J = 14,
8.1, 6.6 Hz, H8), 2.06 (ddd, 1H, J = 14, 9.6, 4.8 Hz, H11), 1.87 (ddd, 1H, J = 14, 6.9, 2.1 Hz, H8);
13C-NMR (75 MHz, CDCl3) δ 172.8, 144.1, 128.9, 127.9, 127.1, 86.6, 85.4, 84.0, 79.8, 76.6, 66.4, 52.3,
37.7, 36.3; FT-IR (film on ZnSe) 3086, 3057, 3020, 2951, 2871, 1754, 1596, 1496, 1450, 1362, 1322 cm-1;
HRMS (ESI-pos): m/z calcd for C28H28O5Na [M + Na]+ 467.1829, found 467.1823.
To a solution of crude methyl ether 12 (418 mg) in MeOH (9 mL) was added TsOH·H2O (86.3 mg, 0.454
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mmol). After 1.5 h at room temperature, the reaction mixture was quenched by the addition of Et3N (635 µL,
4.56 mmol). The resulting mixture was concentrated and directly purified by flash chromatography
(n-hexane/EtOAc/MeOH = 20/100/3 → 10/100/3) to give alcohol 12a (167 mg, 0.826 mmol, 91% for 3
steps) as a colorless oil. [α]26D +22.7 (c 0.75, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 4.86 (ddd, 1H, J = 6.6,
3.9, 2.4 Hz, H9), 4.68 (dd, 1H, J = 9.0, 6.6 Hz, H12), 4.55 (t, 1H, J = 4.2 Hz, H10), 4.09 (qd, 1H, J = 7.0,
3.3 Hz, H7), 3.75 (s, 3H, OMe), 3.72 (dd, 1H, J = 12, 3.3 Hz, H6), 3.59 (dd, 1H, J = 12, 6.3 Hz, H6), 2.50
(dd, 1H, J = 14, 6.9 Hz, H11), 2.26 (ddd, 1H, J = 14, 7.2, 6.9 Hz, H8), 2.07 (ddd, 1H, J = 14, 9.3, 5.1 Hz,
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H11), 1.89 (ddd, 1H, J = 14, 7.2, 2.1 Hz, H8); C-NMR (75 MHz, CDCl3) δ 172.7, 85.6, 84.0, 81.0, 76.7,
65.0, 52.4, 37.4, 35.0; FT-IR (film on ZnSe) 3477, 2958, 2928, 2855, 1743, 1442, 1373, 1260, 1213, 1173
cm-1; HRMS (ESI-pos): m/z calcd for C9H15O5 [M + H]+ 203.0914, found 203.0913.
Methyl (2R,3aS,5S,6aS)-5-((R)-1-hydroxybut-3-yn-1-yl)hexahydrofuro[3,2-b]furan-2-carboxylate (6). To
a solution of alcohol 12a (10.4 mg, 0.0514 mmol) in CH2Cl2 (1.0 mL) were added NaHCO3 (34.5 mg, 0.411
mmol) and Dess-Martin periodinane (65.3 mg, 0.154 mmol) at 0 °C. The mixture was warmed to room
temperature and stirred for 1.5 h. After dilution with CH2Cl2 (1.5 mL), the reaction mixture was quenched
by the addition of saturated aqueous NaHCO3 solution and saturated aqueous Na2S2O3 solution. The
resulting mixture was stirred for 30 min and extracted with CH2Cl2 (2×). The combined organic layer was
washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give aldehyde 13 as a pale
yellow solid (9.5 mg). As the polarity of 13 was very high and exhibited tailing on TLC, aldehyde 13 was
submitted to the next reaction without purification. Data for 13: 1H-NMR (300 MHz, CDCl3) δ 9.62 (d, 1H,
J = 1.2 Hz, CHO), 4.81-4.76 (m, 2H, H9, H12), 4.68 (t, 1H, J = 7.8 Hz, H10), 4.41 (br dd, 1H, J = 9.6, 2.4
Hz, H7), 3.74 (s, 3H, OMe), 2.72 (br dd, 1H, J = 14, 7.8 Hz, H11), 2.51 (br dd, 1H, J = 14, 3.0 Hz, H8),
2.36 (ddd, 1H, J = 14, 9.9, 3.9 Hz, H8), 2.24 (ddd, 1H, J = 14, 7.8, 4.8 Hz, H11).
To a suspension of Zn dust (124 mg, 1.91 mmol) in THF (2 mL) was added 1,2-dibromoethane (18.9 µL,
0.219 mmol). The suspension was heated at reflux for 6 min, followed by the addition of propargyl bromide
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(71.6 µL, 0.950 mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C, followed by the addition of crude
aldehyde (9.5 mg) in THF (1.5 mL). The resulting mixture was stirred for 15 min at 0 °C and quenched by
the addition of saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (2×). The
combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated.
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The residue was purified by flash chromatography (n-hexane/EtOAc = 1/10) to give alcohol 6 (7.6 mg,
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0.032 mmol, 67%, dr > 20:1) as a colorless viscous oil. [α]25 −4.6 (c 1.00, CHCl3); H-NMR (300 MHz,
D
CDCl3) δ 4.86 (ddd, 1H, J = 6.3, 3.9, 2.1 Hz, H9), 4.66 (dd, 1H, J = 9.0, 6.9 Hz, H12), 4.54 (br dd, 1H, J =
4.5, 4.2 Hz, H10), 4.03 (td, 1H, J = 7.4, 5.4 Hz, H7), 3.87 (td, 1H, J = 6.0, 5.7 Hz, H6), 3.76 (s, 3H, OMe),
2.50 (dd, 1H, J = 14, 6.9 Hz, H11), 2.47-2.44 (m, 2H, H5), 2.29 (ddd, 1H, J = 14, 7.5, 6.3 Hz, H8), 2.13
(ddd, 1H, J = 14, 7.2, 2.1 Hz, H8), 2.09 (ddd, 1H, J = 14, 9.0, 4.8 Hz, H11), 2.05 (t, 1H, J = 2.9 Hz, H3);
13C-NMR (75 MHz, CDCl3) δ 172.7, 85.5, 83.9, 82.1, 80.2, 76.6, 71.1, 70.9, 52.4, 37.4, 33.9, 23.9 cm-1;
FT-IR (film on ZnSe) 3473, 3280, 2952, 2911, 2118, 1957, 1747, 1440, 1373, 1287, 1261, 1216, 1171 cm-1;
HRMS (ESI-pos): m/z calcd for C12H17O5 [M + H]+ 241.1071, found 241.1062.
Methyl
(2R,3aS,5S,6aS)-5-((R,Z)-1-hydroxy-6-(trimethylsilyl)hex-3-en-5-yn-1-yl)hexahydrofuro[3,2-b]furan-2-carb
oxylate (14). In a 20 mL two-necked round-bottom flask was placed InCl3 (74.8 mg, 0.338 mmol). The solid
was thoroughly dried by a heat-gun in vacuo. THF (1 mL) was added and the suspension was cooled to
−78 °C. DIBALH (1.0 M solution in hexane, 0.317 mL, 0.317 mmol) was added over 6 min and the mixture
was stirred for 30 min at −78 °C. A solution of alcohol 6 (29.2 mg, 0.122 mmol) in THF (1 mL) and Et3B (1
M solution in THF, 61.0 µL, 0.0610 mmol) were added sequentially and the resulting mixture was stirred
for 3 h at −78 °C. Iodine (186 mg, 0.733 mmol) was then added in one portion and the stirring was
continued for 15 min at −78 °C. The reaction mixture was quenched by the addition of saturated aqueous
NaHCO3 solution followed by saturated aqueous Na2S2O3 solution and extracted with EtOAc (2×). The
combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to
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give vinyl iodide as a yellow oil (44.9 mg), which was used for the next reaction without purification.
1H-NMR (300 MHz, CDCl3) δ 6.38-6.28 (m, 2H, H3, H4), 4.87 (ddd, 1H, J = 6.6, 4.2, 2.7 Hz, H9), 4.68 (dd,
1H, J = 8.7, 6.6 Hz, H12), 4.52 (t, 1H, J = 4.8 Hz, H10), 3.97-3.89 (m, 2H, H6, H7), 3.76 (s, 3H, OMe),
2.52 (dd, 1H, J = 14, 6.9 Hz, H11), 2.35-2.13 (m, 4H, H5, H8), 2.09 (ddd, 1H, J = 14, 8.7, 4.8 Hz, H11).
In a 20 mL two-necked round-bottom flask were placed (Ph3P)2PdCl2 (8.6 mg, 0.024 mmol), CuI (4.6 mg,
0.024 mmol), ethynyltrimethylsilane (33.8 µL, 0.244 mmol), and i-Pr2NH (51.8 µL, 0.366 mmol). A
solution of vinyl iodide (44.9 mg) in THF (2 mL) was added and the mixture was stirred for 1 h at room
temperature. Additional portion of (Ph3P)2PdCl2 (0.8 mg, 2 µmol) was added and the stirring was continued
for 30 min. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution and
extracted with EtOAc (2×). The combined organic layer was washed with brine, dried over anhydrous
MgSO4, filtered and concentrated. The residue was purified by flash chromatography (n-hexane/EtOAc = 1)
to give enyne 14 (29.0 mg, 0.0857 mmol, 70% for 2 steps, Z/E > 20:1) as a yellow oil. [α]27D +20.2 (c 0.81,
CHCl3); 1H-NMR (300 MHz, CDCl3) δ 6.01 (ddd, 1H, J = 11, 8.4, 6.6 Hz, H4), 5.60 (dt, 1H, J = 11, 1.4 Hz,
H3), 4.88 (ddd, 1H, J = 6.9, 4.2, 2.7 Hz, H9), 4.67 (dd, 1H, J = 9.0, 6.6 Hz, H12), 4.51 (dd, 1H, J = 4.8, 4.2
Hz, H10), 3.96-3.85 (m, 2H, H6, H7), 3.75 (s, 3H, OMe), 2.58 (dddd, 1H, J = 14, 8.4, 6.0, 1.2 Hz, H5), 2.50
(dd, 1H, J = 14, 6.6 Hz, H11), 2.52-2.38 (m, 1H, H5), 2.27 (dt, 1H, J = 14, 6.9 Hz, H8), 2.12 (ddd, 1H, J =
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14, 7.8, 3.0 Hz, H8), 2.07 (ddd, 1H, J = 14, 9.2, 4.8 Hz, H11), 0.18 (s, 9H, TMS); C-NMR (75 MHz,
CDCl3) δ 172.6, 140.1, 111.9, 101.6, 99.8, 85.4, 83.6, 83.0, 76.5, 71.1, 52.4, 37.3, 34.4, 32.9, 0.1; FT-IR
(film on ZnSe) 3508, 3025, 2952, 2897, 2148, 1743, 1616, 1436, 1370, 1249, 1210, 1171 cm-1; HRMS
(ESI-pos): m/z calcd for C17H27O5Si [M + H]+ 339.1622, found 339.1615.
Methyl (2R,3aS,5S,6aS)-5-((R,Z)-1-hydroxyhex-3-en-5-yn-1-yl)hexahydrofuro[3,2-b]furan-2-carboxylate
(18). To a solution of enyne 14 (28.2 mg, 0.0833 mmol) in THF (0.8 mL) was added TBAF (1 M solution in
THF, 125 µL, 0.125 mmol). The mixture was stirred for 30 min at room temperature and directly subjected
to flash chromatography (n-hexane/EtOAc = 1 → 0.5) to give alcohol 18 (20.5 mg, 0.0770 mmol, 92%) as a
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yellow oil. [α]26D +9.9 (c 0.79, CHCl3); 1H-NMR (300 MHz, CDCl3) δ 6.09 (dddd, 1H, J = 11, 7.8, 6.9, 0.9
Hz, H4), 5.57 (ddt, J = 11, 2.6, 1.5 Hz, H3), 4.86 (ddd, 1H, J = 6.6, 3.9, 2.4 Hz, H9), 4.67 (dd, 1H, J = 8.9,
6.8 Hz, H12), 4.51 (t, 1H, J = 4.5 Hz, H10), 3.94-3.85 (m, 2H, H6, H7), 3.75 (s, 3H, OMe), 3.11 (d, 1H, J =
1.8 Hz, H1), 2.57 (dddd, 1H, J = 14, 8.1, 5.1, 1.2 Hz, H5), 2.49 (dd, 1H, J = 14, 6.8 Hz, H11), 2.49-2.37 (m,
1H, H5), 2.26 (dt, 1H, J = 14, 6.9 Hz, H8), 2.11 (ddd, 1H, J = 14, 7.2, 2.4 Hz, H8), 2.07 (ddd, 1H, J = 14,
9.2, 5.1 Hz, H11); 13C-NMR (75 MHz, CDCl3) δ 172.6, 141.1, 110.8, 85.4, 83.6, 83.1, 82.3, 80.2, 76.5, 71.3,
52.4, 37.3, 34.4, 33.0; FT-IR (film on ZnSe) 3490, 3291, 3028, 2952, 2898, 2095, 1746, 1616, 1436, 1375,
1286, 1261, 1216, 1170 cm-1. HRMS (APCI-pos): m/z calcd for C14H19O5 [M + H]+ 267.1227, found
267.1228.
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Methyl
(2R,3aS,5S,6aS)-5-((R,Z)-1-(((S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)oxy)hex-3-en-5-yn-1-yl)hexa
hydrofuro[3,2-b]furan-2-carboxylate (15S). To a solution of alcohol 18 (3.2 mg, 12 µmol) in CH2Cl2 (0.5
mL) were added DMAP (5.9 mg, 0.049 mmol), Et3N (2.5 µL, 0.018 mmol) and (R)-(−)-MTPACl (4.5 µL,
0.024 mmol). The mixture was stirred for 3 h at room temperature. As TLC indicated incomplete
esterification, additional portions of DMAP (5.9 mg, 0.049 mmol), Et3N (47.6 µL, 0.342 mmol) and
(R)-(−)-MTPACl (4.5 µL, 0.024 mmol) were added and the mixture was stirred at 80 °C for 17 h. The
reaction mixture was concentrated and the residue was purified by flash chromatography (n-hexane/EtOAc
= 2) to give (S)-MTPA ester 15S (1.5 mg, 3.1 µmol, 26%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ
7.57-7.50 (m, 2H, Ph), 7.42-7.37 (m, 3H, Ph), 6.02 (br dt, 1H, J = 11, 7.5 Hz, H4), 5.59 (ddt, J = 11, 2.1, 1.6
Hz, H3), 5.34 (dt, 1H, J = 6.9, 5.7 Hz, H6), 4.81 (ddd, 1H, J = 7.2, 4.2, 2.7 Hz, H9), 4.45 (t, 1H, J = 4.7 Hz,
H10), 4.37 (dd, 1H, J = 9.3, 6.6 Hz, H12), 3.90 (ddd, 1H, J = 8.1, 6.9, 6.0 Hz, H7), 3.75 (s, 3H, OMe), 3.56
(s, 3H, OMe), 3.15 (br d, 1H, J = 2.4 Hz, H1), 2.80 (br t, 2H, J = 7.2 Hz, H5), 2.31 (br dd, 1H, J = 14, 6.9
Hz, H11), 2.18 (dt, 1H, J = 14, 6.9 Hz, H8), 1.97 (ddd, 1H, J = 15, 9.3, 5.4 Hz, H11), 1.83 (ddd, 1H, J = 14,
8.1, 2.7 Hz, H8); FT-IR (film on ZnSe) 3287, 3064, 3032, 2954, 2853, 1747, 1492, 1451, 1440, 1369, 1268,
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1218, 1171, 1122, 1085, 1019 cm-1; HRMS (ESI-pos): m/z calcd for C24H29O7NF3 [M + NH4]+ 500.1891,
found 500.1867.
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Methyl
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(2R,3aS,5S,6aS)-5-((R,Z)-1-(((R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)oxy)hex-3-en-5-yn-1-yl)hex
ahydrofuro[3,2-b]furan-2-carboxylate (15R). To a solution of alcohol 18 (2.3 mg, 8.3 µmol) in CH2Cl2 (0.3
mL) were added DMAP (4.4 mg, 0.036 mmol), Et3N (1.4 µL, 0.010 mmol) and (S)-(+)-MTPACl (3.2 µL,
0.017 mmol). The mixture was stirred for 30 min at room temperature and quenched by the addition of
water. The resulting mixture was extracted with EtOAc (2×). The combined organic layer was washed with
brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash
chromatography (n-hexane/EtOAc = 2) to give (R)-MTPA ester 15R (2.8 mg, 5.8 µmol, 67%) as a colorless
oil. 1H-NMR (300 MHz, CDCl3) δ 7.57-7.51 (m, 2H, Ph), 7.43-7.37 (m, 3H, Ph), 5.89 (dtd, 1H, J = 9.9, 6.3,
0.9 Hz, H4), 5.52 (ddt, J = 11, 2.1, 1.5 Hz, H3), 5.34 (ddd, 1H, J = 6.6, 5.7, 4.8 Hz, H6), 4.88 (ddd, 1H, J =
7.5, 4.2, 3.3 Hz, H9), 4.52 (dd, 1H, J = 9.6, 6.9 Hz, H12), 4.51 (t, 1H, J = 4.7 Hz, H10), 3.98 (ddd, 1H, J =
8.7, 6.9, 4.5 Hz, H7), 3.74 (s, 3H, OMe), 3.53 (s, 3H, OMe), 3.12 (dd, 1H, J = 2.4, 0.9 Hz, H1), 2.77 (br dt,
1H, J = 15, 5.7 Hz, H5), 2.73 (br dt, 1H, J = 15, 7.2 Hz, H5), 2.45 (dd, 1H, J = 14, 6.9 Hz, H11), 2.31 (dt,
1H, J = 14, 6.9 Hz, H8), 2.03 (ddd, 1H, J = 14, 9.6, 5.1 Hz, H11), 1.94 (ddd, 1H, J = 14, 9.0, 3.0 Hz, H8);
FT-IR (film on ZnSe) 3292, 3064, 3030, 2952, 2852, 1752, 1494, 1451, 1440, 1367, 1259, 1217, 1172,
1122, 1087 cm-1; HRMS (ESI-pos): m/z calcd for C24H29O7NF3 [M + NH4]+ 500.1891, found 500.1873.
(R)-1-((2R,3aS,5S,6aS)-5-((R,Z)-1-((tert-Butyldimethylsilyl)oxy)-6-(trimethylsilyl)hex-3-en-5-yn-1-yl)hex
ahydrofuro[3,2-b]furan-2-yl)propyl (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (17S). To a solution
of alcohol 14 (19.4 mg, 0.0573 mmol) in CH2Cl2 (1 mL) were added 2,6-lutidine (27 µL, 0.30 mmol) and
TBSOTf (15 µL, 0.086 mmol). After 40 min at room temperature, 2,6-lutidine (6.6 µL, 0.057 mmol) and
TBSOTf (5.0 µL, 0.029 mmol) were additionally added. After 1 h, 2,6-lutidine (17 µL, 0.14 mmol) and
TBSOTf (10 µL, 0.057 mmol) were added. After 40 min, 2,6-lutidine (20 µL, 0.17 mmol) and TBSOTf (15
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µL, 0.086 mmol) were additionally added. After 30 min, the reaction mixture was quenched by the addition
of saturated aqueous NH4Cl solution. The resulting mixture was extracted with EtOAc (2×). The combined
organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue
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was purified by flash chromatography (n-hexane/EtOAc = 5) to give TBS ether (21.6 mg, 0.0478 mmol,
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83%) as a colorless oil. [α]28 −18.1 (c 1.03, CHCl3); H-NMR (300 MHz, CDCl3) δ 5.98 (dt, 1H, J = 11,
D
7.5 Hz, H4), 5.55 (dt, 1H, J = 11, 1.4 Hz, H3), 4.88 (ddd, 1H, J = 7.5, 4.8, 3.3 Hz, H9), 4.62 (dd, 1H, J = 9.9,
6.3 Hz, H12), 4.46 (t, 1H, J = 4.8 Hz, H10), 3.91 (td, 1H, J = 5.4, 4.5 Hz, H6), 3.75 (s, 3H, OMe), 3.72 (ddd,
1H, J = 9.0, 6.3, 4.2 Hz, H7), 2.55-2.48 (m, 2H, H5), 2.42 (dd, 1H, J = 14, 6.3 Hz, H11), 2.22 (dt, 1H, J =
14, 6.9 Hz, H8), 2.06-1.93 (m, 2H, H8, H11), 0.88 (s, 9H, TBS), 0.18 (s, 9H, TMS), 0.08 (s, 6H, TBS);
13C-NMR (75 MHz, CDCl3) δ 172.7, 140.5, 111.3, 101.9, 99.3, 85.3, 83.1, 82.8, 76.2, 71.8, 52.3, 37.5, 36.1,
34.2, 25.9, 18.2, 0.1, −4.3; FT-IR (film on ZnSe) 3030, 2955, 2929, 2897, 2858, 2149, 1759, 1744, 1472,
1463, 1437, 1389, 1361, 1251, 1208, 1173, 1091 cm-1; HRMS (ESI-pos): m/z calcd for C23H41O5Si2 [M +
H]+ 453.2487, found 453.2479.
To a solution of TBS ether (22.0 mg, 0.0486 mmol) in CH2Cl2 (2 mL) was added DIBAL-H (1.0 M
solution in n-hexane, 73 µL, 0.073 mmol) at −78 °C. After 1.2 h at −78 °C, additional portion of DIBAL-H
(1.0 M solution in n-hexane, 73 µL, 0.073 mmol) was added and the stirring was continued for 1 h at
−78 °C. The reaction mixture was quenched by the addition of saturated aqueous Rochelle salt solution and
then stirred at room temperature until two phases were clearly separated. The mixture was extracted with
n-hexane/EtOAc (5:1) (2×). The combined organic layer was washed with brine, dried over anhydrous
MgSO4, filtered and concentrated. Aldehyde was obtained as a colorless oil (21.7 mg), which was used for
the next reaction without purification. Data for aldehyde: 1H-NMR (300 MHz, CDCl3) δ 9.66 (s, 1H, CHO),
5.99 (ddd, 1H, J = 11, 7.5 Hz, H4), 5.56 (dt, 1H, J = 11, 1.2 Hz, H3), 4.83 (ddd, 1H, J = 7.5, 4.2, 3.6 Hz,
H9), 4.50-4.44 (m, 2H, H10, H12), 3.91 (ddd, 1H, J = 11, 6.6, 5.4 Hz, H6), 3.74 (ddd, 1H, J = 11, 6.6, 4.2
Hz, H7), 2.56-2.50 (m, 2H, H5), 2.32 (dd, 1H, J = 14, 6.6 Hz, H11), 2.23 (dd, 1H, J = 14, 6.6 Hz, H8), 2.02
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(ddd, 1H, J = 14, 9.0, 3.3 Hz, H8), 1.87 (ddd, 1H, J = 14, 10, 5.1 Hz, H11), 0.89 (s, 9H, TBS), 0.19 (s, 9H,
TMS), 0.08 (s, 6H, TBS).
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To a solution of CuBr·SMe2 (108 mg, 0.527 mmol) in THF (1 mL) was added EtMgBr (1.0 M solution in
THF, 1.03 mL, 1.03 mmol) at −78 °C. After 1 h at −78 °C, the crude aldehyde (21.7 mg) in THF (2 mL)
was added and the resulting mixture was gradually warmed to 0 °C. After 23.5 h, the reaction mixture was
quenched by the addition of saturated aqueous NH4Cl solution and extracted with EtOAc (2×). The
combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated.
The residue was purified by flash chromatography (n-hexane/EtOAc = 20 → 5) to give a 1.9:1 mixture of
13R-alcohol and starting aldehyde (8.2 mg), a 1:1 mixture of 13S-alcohol and aldehyde (4.1 mg), and a
recovery of aldehyde (4.7 mg). The calculated yields of 13R-alcohol, 13S-alcohol and starting aldehyde
were 25%, 10% and 46%, respectively. The mixtures were additionally purified by normal-phase HPLC
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using n-hexane/EtOAc as eluent for the spectral analyses. Data for 13R-alcohol: [α]28 −20.9 (c 0.22,
D
CHCl3); 1H-NMR (300 MHz, CDCl3) δ 6.00 (dt, 1H, J = 11, 7.5 Hz, H4), 5.55 (dt, 1H, J = 11, 1.2 Hz, H3),
4.72 (dt, 1H, J = 7.8, 4.4 Hz, H9), 4.44 (t, 1H, J = 5.1 Hz, H10), 3.99 (dt, 1H, J = 11, 5.1 Hz, H12), 3.93 (dt,
1H, J = 5.7, 5.1 Hz, H6), 3.67 (ddd, 1H, J = 9.6, 6.3, 4.2 Hz, H7), 3.36 (dt, 1H, J = 7.2, 5.4 Hz, H13),
2.55-2.49 (m, 2H, H5), 2.19 (ddd, 1H, J = 14, 7.2, 6.3 Hz, H8), 2.01 (dd, 1H, J = 13, 5.1 Hz, H11), 1.93
(ddd, 1H, J = 14, 9.6, 3.9 Hz, H8), 1.69 (ddd, 1H, J = 13, 10, 5.1 Hz, H11), 1.48 (quint, 2H, J = 7.2 Hz,
H14), 0.99 (t, 3H, J = 7.2 Hz, H15), 0.90 (s, 9H, TBS), 0.19 (s, 9H, TMS), 0.09 (s, 3H, TBS), 0.08 (s, 3H,
TBS); 13C-NMR (75 MHz, CDCl3) δ 140.7, 111.2, 102.0, 99.3, 84.0, 83.8, 82.4, 80.5, 74.8, 71.8, 36.2, 35.7,
34.6, 27.2, 26.0, 18.3, 10.2, 0.14, −4.22, −4.26; FT-IR (film on ZnSe) 3483, 3025, 2956, 2929, 2897, 2858,
2150, 1472, 1463, 1436, 1389, 1361, 1251, 1189, 1081, 1005cm-1; HRMS (ESI-neg): m/z calcd for
C24H45O4Si2 [M + H]+ 453.2851, found 453.2846. Data for 13S-alcohol: colorless oil; 1H-NMR (300 MHz,
CDCl3) δ 5.99 (dt, 1H, J = 11, 7.7 Hz, H4), 5.55 (br d, 1H, J = 11 Hz, H3), 4.75 (br dt, 1H, J = 8.2, 4.4 Hz,
H9), 4.43 (br t, 1H, J = 4.8 Hz, H10), 4.07 (ddd, 1H, J = 10, 4.9, 3.0 Hz, H12), 3.97-3.91 (m, 1H, H6),
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3.81-3.76 (m, 1H, H13), 3.66 (ddd, 1H, J = 10, 6.0, 4.0 Hz, H7), 2.55-2.49 (m, 2H, H5), 2.21 (ddd, 1H, J =
13, 7.9, 6.0 Hz, H11), 1.96-1.77 (m, 3H, H8×2, H11), 1.44-1.36 (m, 2H, H14), 0.99 (t, 3H, J = 7.5 Hz, H15),
0.90 (s, 9H, TBS), 0.19 (s, 9H, TMS), 0.09 (s, 3H, TBS), 0.08 (s, 3H, TBS); FT-IR (film on ZnSe) 3470,
3026, 2957, 2929, 2896, 2857, 2149, 1728, 1472, 1463, 1435, 1407, 1389, 1361, 1251, 1076 cm-1; HRMS
(ESI-pos): m/z calcd for C24H45O4Si2 [M + H]+ 453.2851, found 453.2841.
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To a solution of 13R-alcohol (2.2 mg, 4.9 µmol) in CH2Cl2 (1 mL) were added DMAP (2.6 mg, 21 µmol),
Et3N (6.8 µL, 49 µmol) and (R)-(−)-MTPACl (1.8 µL, 9.7 µmol). The mixture was stirred for 21 h at room
temperature and quenched by the addition of 3-dimethylaminopropylamine (1.2 µL, 9.7 µmol). The
resulting mixture was stirred for 30 min before concentration. The residue was purified by flash
chromatography (n-hexane/EtOAc = 10 → 2) to give (S)-MTPA ester 17S (0.9 mg, 1.4 µmol, 27%) as a
colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.62-7.58 (m, 2H, Ph), 7.40-7.37 (m, 3H, Ph), 5.97 (dt, 1H, J =
11, 7.8 Hz, H4), 5.54 (br d, 1H, J = 11 Hz, H3), 5.02 (dt, 1H, J = 7.2, 5.7 Hz, H13), 4.61 (ddd, 1H, J = 7.8,
5.1, 3.9 Hz, H9), 4.25 (t, 1H, J = 5.1 Hz, H10), 4.17 (dt, 1H, J = 9.6, 5.7 Hz, H12), 3.89 (td, 1H, J = 5.4, 4.2
Hz, H6), 3.64 (ddd, 1H, J = 9.3, 6.6, 4.5 Hz, H7), 3.56 (br s, 3H, OMe), 2.53-2.46 (m, 2H, H5), 2.11 (ddd,
1H, J = 14, 7.2, 6.3 Hz, H8), 1.98 (dd, 1H, J = 14, 5.4 Hz, H11), 1,86 (ddd, 1H, J = 14, 9.3, 3.6 Hz, H8),
1.76-1.66 (m, 2H, H14), 1.49 (ddd, 1H, J = 14, 9.6, 5.4 Hz, H11), 0.97 (t, 3H, J = 7.4 Hz, H15), 0.86 (s, 9H,
TBS), 0.19 (s, 9H, TMS), 0.06 (s, 3H, TBS), 0.04 (s, 3H, TBS); FT-IR (film on ZnSe) 2954, 2929, 2885,
2858, 2149, 1750, 1472, 1463, 1452, 1388, 1361, 1252, 1171, 1124, 1081, 1020 cm-1; HRMS (ESI-pos):
m/z calcd for C34H55O6NF3Si2 [M + NH4]+ 686.3515, found 686.3502.
(R)-1-((2R,3aS,5S,6aS)-5-((R,Z)-1-((tert-Butyldimethylsilyl)oxy)-6-(trimethylsilyl)hex-3-en-5-yn-1-yl)hex
ahydrofuro[3,2-b]furan-2-yl)propyl (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (17R). To a solution
of 13R-alcohol (3.0 mg, 6.6 µmol) in CH2Cl2 (1 mL) were added DMAP (3.4 mg, 28 µmol), Et3N (9.2 µL,
66 µmol) and (S)-(+)-MTPACl (2.5 µL, 13 µmol). The mixture was stirred for 21 h at room temperature and
quenched by the addition of 3-dimethylaminopropylamine (1.7 µL, 13 µmol). The resulting mixture was
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stirred for 30 min before concentration. The residue was purified by flash chromatography
(n-hexane/EtOAc = 7 → 5 → 2) to give (R)-MTPA ester 17R (1.7 mg, 2.5 µmol, 38%) as a colorless oil.
1H-NMR (300 MHz, CDCl3) δ 7.68-7.64 (m, 2H, Ph), 7.40-7.35 (m, 3H, Ph), 5.97 (dt, 1H, J = 11, 7.5 Hz,
H4), 5.56 (br d, 1H, J = 11 Hz, H3), 5.07 (td, 1H, J = 8.1, 3.6 Hz, H13), 4.75 (dt, 1H, J = 8.4, 4.2 Hz, H9),
4.40 (t, 1H, J = 5.1 Hz, H10), 4.18 (ddd, 1H, J = 10, 6.9, 4.8 Hz, H12), 3.93 (ddd, 1H, J = 6.6, 5.7, 3.9 Hz,
H6), 3.67 (ddd, 1H, J = 9.6, 6.0, 3.9 Hz, H7), 3.59 (br s, 3H, OMe), 2.54-2.47 (m, 2H, H5), 2.19 (ddd, 1H, J
= 13, 7.5, 6.0 Hz, H8), 2.05 (dd, 1H, J = 13, 5.1 Hz, H11), 1.92 (ddd, 1H, J = 13, 9.6, 4.2 Hz, H8), 1.67-1.50
(m, 3H, H11, H14), 0.86 (s, 9H, TBS), 0.83 (t, 3H, J = 7.5 Hz, H15), 0.19 (s, 9H, TMS), 0.07 (s, 3H, TBS),
0.05 (s, 3H, TBS); FT-IR (film on ZnSe) 2955, 2929, 2898, 2857, 2150, 1751, 1471, 1464, 1452, 1389,
1361, 1251, 1185, 1169, 1126, 1081, 1021 cm-1; HRMS (ESI-pos): m/z calcd for C34H55O6NF3Si2 [M +
NH4]+ 686.3515, found 686.3503.
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Tetrahydro-2-furancarboxaldehyde (I).49 To a solution of (COCl)2 (2.58 mL, 30.1 mmol) in CH2Cl2 (15
mL) was added a solution of DMSO (4.25 mL, 49.9 mmol) in CH2Cl2 (68 mL) through a dropping funnel
over 40 min at −78 °C. After 20 min, a solution of tetrahydrofurfuryl alcohol (2.53 g, 24.8 mmol) in CH2Cl2
(50 mL) was added through a dropping funnel over 20 min. After 10 min at −78 °C, Et3N (17.8 mL, 128
mmol) was added and the reaction mixture was warmed to room temperature. The reaction mixture was
quenched by the addition of water and extracted with CH2Cl2 (3×). The combined organic layer was dried
over anhydrous MgSO4, filtered and concentrated. The residue was passed through a short plug of silica gel
and eluted with n-hexane/EtOAc (7:3). The fractions containing aldehyde was concentrated and the residue
was distilled with a Kugelrohr apparatus to give aldehyde I (1.52 g, 15.2 mmol, 61%, bp. 90 °C/2.7 kPa) as
a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 9.66 (d, 1H, J = 1.8 Hz, H6), 4.27 (ddd, 1H, J = 8.7, 6.0, 1.8
Hz, H7), 3.94 (t, 2H, J = 6.6 Hz, H10), 2.21-1.83 (m, 4H, H8, H9).
(Z)-1-(Tetrahydrofuran-2-yl)-6-(trimethylsilyl)hex-3-en-5-yn-1-ol (IV). To a mixture of Zn dust (1.54 g
mg, 23.6 mmol) and propargyl bromide (1.31 mL, 17.4 mmol) was added a solution of aldehyde I (590 mg,
29
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