Total Syntheses of C60- And C100-Dolichols

Article abstract of DOI:10.1021/acs.joc.0c01327

C60- and C100-dolichols were synthesized. A Z-selective Wittig reaction was achieved with high selectivity in a microflow system to realize the scalable supply of the Z-isoprene unit. An isoprene chain was efficiently elongated by an SN2-type coupling between allyl sulfone and allyl chloride using t-BuOK. These key reactions enabled the efficient syntheses of dolichols. This study will pave the way for the functional studies of dolichols.

Full text of DOI:10.1021/acs.joc.0c01327

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Total Syntheses of C60- and C100-Dolichols
Kohtaro Hirao, Risako Ono, Yoshiyuki Manabe, Seiji Masui, Haruyuki Atomi, and Koichi Fukase
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01327 • Publication Date (Web): 30 Jul 2020
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The Journal of Organic Chemistry
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Total Syntheses of C60- and C100-Dolichols
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Kohtaro Hirao,1 Risako Ono,1 Yoshiyuki Manabe,*1, 2 Seiji Masui,1 Haruyuki Atomi,3 and
Koichi Fukase*1, 2
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1 Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka,
Osaka 560-0043, Japan
2 Core for Medicine and Science Collaborative Research and Education, Project Research Center for Fundamental
Sciences, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan
3 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University,
Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
Supporting Information Placeholder
KEYWORDS: total synthesis, dolichol, flow chemistry, isoprenoid
ABSTRACT: C60- and C100-dolichols were synthesized. Z-Selective Wittig reaction was achieved with high selectivity in a
microflow system to realize the scalable supply of Z-isoprene unit. Isoprene chain was efficiently elongated by an SN2-type
coupling between allyl sulfone and allyl chloride using t-BuOK. These key reactions enabled the efficient syntheses of
dolichols. This study will pave the way for the functional studies of dolichols.
Polyisoprenes such as dolichols and polyprenols are long-
chain lipids composed of repeating isoprene units. Among
their various biological functions, the most fundamental
function of these polyisoprenes is their role as glycan
carriers in the biosynthetic glycosylation process.1-4 Glycans
on polyisoprenes are transferred to proteins by
glycosyltransferases. Despite their universal role as glycan
carriers, the structure, including their chain length, E/Z
isomeric pattern, and unsaturation pattern, varies
depending on the organism (Figure 1a).1-3 Among
eukaryotes, mammals use C90-C105 dolichols as N-glycan
carriers, while plant have higher diversity of dolichols or
polyprenols. Archaea use shorter dolichols (C30-C70) with
several saturated isoprene units.5, 6 Bacteria employ Lipid II,
composed of a glycopeptide and undecaprenol (C55), as a
precursor substrate for the biosynthesis of cell wall. Since
polyisoprenes are involved in the key steps of the
glycoconjugate
biosynthesis,
a
comprehensive
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understanding of these steps requires a functional study of synthesized
Page 2 of 17
The
all-trans-C100-polyprenol.36
1
polyisoprenes as well as the analysis of the glycan moiety.
Structure–activity relationship studies revealed the
importance of polyisoprene structure in glycosyltransferase
recognition.7-18 However, the significance of polyisoprenes
in the biosynthesis of glycoconjugates has been barely
elucidated at a molecular level.3 Studies on the molecular
recognition of polyisoprenes by glycosyltransferases are
still very limited. Although the flipping of polyisoprene-
semisyntheses of dolichols from isolated polyprenols have
been also reported.37-42 Hydrogenation of allylic alcohol in
polyprenols gave dolichols.37, 39, 40, 42 Coupling between the
polyprenyl unit derivatized from isolated polyprenol and
the reduced isoprene unit gave C95-dolichol.38, 41 Despite
the above mentioned reports about the syntheses of
dolichols, it remains difficult to synthesize sufficient
amounts of dolichols, thereby, dolichols have been mainly
supplied by the isolation from natural sources. However,
chemical syntheses of dolichols are indispensable for
elucidating the molecular basis of dolichol function. Thus,
reliable and versatile methods for the syntheses of dolichols
are required.
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linked oligosaccharides is
a
crucial step in the
glycoconjugate biosynthesis, the eukaryotic and archaeal
flippases have not been identified. In addition, the unique
structure-based physiological properties of polyisoprenes
are poorly elucidated. These aspects can be addressed using
chemical biology approaches, including co-crystallization,
structure–activity relationship studies, and conformational
and dynamics analyses using labeled compounds, and thus,
we were motivated to investigate the chemical syntheses of
polyisoprenes to obtain sufficient supplies of various
polyisoprenes and their derivatives.
Several groups have reported the syntheses of
polyisoprenes.19-36 The key steps in the syntheses of
polyisoprenes involve the 1) preparation of Z-isoprene units,
and 2) coupling of isoprene units (Figure 1b). Sato et al.
reported the preparation of Z-isoprene units via kinetically
controlled Wittig reaction using the unstable ylide25 and
finally synthesized short-chain prenols.26 Isoprene chain
elongation, which is an essential step in the synthesis of
polyisoprenes, is generally achieved by an SN2-type
coupling at the allylic position.19 Several polyprenols and
dolichols, including long lipid chains, were synthesized
using these fundamental synthetic methods. Sato et al.
synthesized C100-dolichol29 while Shinada et al.
Figure 1. a) Structure of polyisoprenes. b) Key reactions in
the syntheses of polyisoprenes.
Scheme 1. Retrosynthetic analysis of dolichol 1a, 1b
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synthesis, and hence, the use of an expensive phosphazene
1
2
3
base (Aldrich: 16300 yen/1 mL) is not desirable. We
therefore reinvestigated the Wittig reaction using n-BuLi as
the base. We conducted the Wittig reaction in a microflow
system (entry 5) as it allows efficient removal of reaction
heat, resulting in a precise control of the reaction
temperature.45-48 Ylide, generated from 9, and ketone 10
were injected with syringe pumps and mixed using Comet-
X01 micromixer at −78 °C. The results of the microflow
Wittig reaction were comparable to the best results under
batch conditions (microflow: 73% yield, Z:E = 13:1 batch:
68% to 81% yield, Z:E = 6.8:1 to 13:1). Furthermore, a
reproducible gram-scale synthesis of 6 was achieved using
a continuous flow system with small optimization for large-
scale (The flow rate was increased to ten times faster);
reaction between 1.80 g of 9 and 0.497 g of 10 gave 0.716 g
of 6 in 67% yield with high Z-selectivity (Z:E = 11:1). This is
the first report of a kinetically controlled Wittig reaction in
a microflow system.
In this study, we achieved the total syntheses of
archaeal dolichol 1a and eukaryotic dolichol 1b via an
efficient and versatile synthetic route. We first
reinvestigated the two key reactions shown in Figure 1b. Z-
Selective Wittig reaction was conducted in a microflow
system to enhance the selectivity and reproducibility.
Isoprene units were efficiently coupled by treating a
mixture of allyl phenyl sulfone (SO2Ph) and allyl chloride
with t-BuOK. In the previous study, the anions generated
from allyl SO2Ph were pooled prior to coupling with the
allyl chloride. However, in this study, the anions were
generated in the presence of allyl chloride to avoid the
handling of the unstable anion. Improvements of the above
mentioned two key reactions led to an efficient and reliable
synthesis of dolichols. Dolichols 1a and 1b were synthesized
via convergent routes (Scheme 1). Dolichols 1a and 1b were
synthesized from 3 units, namely, Z/E isoprene unit 2, Z-
repeating isoprene unit 3a (or 3b), and 4 containing
saturated isoprene unit. These isoprene units were coupled
via the SN2 reaction of allyl SO2Ph and allyl chlorides.
Isoprene units 2, 3a (or 3b), and 4 were synthesized from
geraniol (5), 6, and 7, respectively. Since dolichols contain
repeating Z-isoprene units, the large-scale synthesis of 6 is
essential. Scalable synthesis of key intermediate 6 was
achieved via Z-selective Wittig reaction conducted in a
microflow reactor. Saturated unit 7 was obtained via the
asymmetric reduction of geraniol (5).
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Table 1. Investigation of Z-selective Wittig reaction.
The Wittig reaction of phosphonium salt 9 and ketone 10
was investigated (Table 1). THP protected ketone 10 was
reported to show high Z-selectivity.43 The reactions under
batch conditions did not afford reproducible results (entry
1). Considering that both yield and Z-selectivity decreased
at room temperature (entry 2), it was inferred that the
increase in reaction temperature due to the reaction heat
reduced the reproducibility under the conditions listed in
entry 1. We first investigated base (entries 3, 4). Screening
of several bases suggested that the Z-selectivity improved
upon decreasing the coordination property of the counter
cation of the ylide.44 Especially, phosphazene base, a strong
organic base, gave 6 with complete Z-selectivity (entry 4).
However, a large amount of 6 will be required for dolichol
entry
1
base
method temp
(ºC)
yield (Z/E)
n-BuLi
batch
−78
68-83%
(6.8:1 - 13:1)
41% (3:1)
9% (8:1)
55% (Z only)
2
3
4
n-BuLi
t-BuOK
P4-
phosphazen
n-BuLi
batch
batch
batch
rt
rt
−78
5
flow
−78
73% (13:1)1
67% (11:1)2
1 228 mg of 9 and 63 g of 10 was used to give 112 mg of 6.
2 1.80 g of 9 and 0.497 g of 10 was used to give 0.716 g of 6.
We next investigated SN2 coupling between allyl
SO2Ph 2 and allyl chloride 3a after synthesizing them from
6 according to a previous protocol (Table 2).15 The reported
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coupling condition involving the use of n-BuLi gave 11. phosphonium salt 16, Wittig reaction with ketone 10
1
However, the reproducibility was low, probably due to the
difficulty in handling the unstable anion generated from 2
(entry 1). To overcome these technical shortcomings, we
generated the anion in the presence of 3a for trapping it
smoothly, referring to Shinada’s report.36 t-BuOK, a bulky
base, was added to the mixture of 2 and 3a. This method
gave 11 in good yields, with high reproducibility (entry2). As
described in the syntheses of dolichols 1a and 1b, these
coupling conditions were applicable to the coupling of
various other isoprene units having different lengths, even
in large scale. Thus, we established an operationally easy
and reliable coupling method for preparing a wide range of
polyisoprenes.
yielded 7 with high Z-selectivity even under batch
conditions (E/Z = 1/20). Deprotection of 7 followed by
chlorination yielded 17. Coupling between 17 and 1815
proceeded smoothly using the method described above to
give 19 in high yield. For further coupling, 19 was converted
to allyl chloride 4.
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Table 3. Stereoselective reduction of geraniol (5)
entry conc.
results
60% (80%ee)
70% (96%ee)
1
0.1 M
2
0.01 M
Table 2. Investigation of SN2-coupling conditions.
Scheme 2. Synthesis of saturated isoprene unit 4.
entry
1
2
method base
temp (ºC) yield
A
B
n-BuLi
t-BuOK
−78
−50
0–80%
87%
Saturated isoprene unit 4 was prepared via
asymmetric reduction of geraniol (5) (Table 3, Scheme 2). A
minor optimization of the asymmetric reduction of
geraniol (5) reported by Wo et al.49 gave 13 in high
enantiomeric excess: high dilution conditions improved the
stereoselectivity (Table 3). Protection of the hydroxy group
of 13 with TBDPS, bromohydrin formation followed by
epoxide formation, and oxidative cleavage by sodium
periodate afforded aldehyde 14. Reduction of 14 and the
introduction of a tosyl group gave 15. After derivatization to
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Total syntheses of dolichols 1a and 1b were
polyisoprenes. Our versatile synthesis scheme also enables
the preparation of polyisoprene derivatives having different
chain lengths, E/Z patterns, and saturation patterns,
allowing precise structure–activity relationship studies.
Isotope-labeled polyisoprenes can also be prepared.
Chemical biology study using these polyisoprene probes for
revealing the molecular basis of dolichols in the
biosynthetic glycosylation process are under way. Therefore,
this study paves the way for the functional studies of
polyisoprenes.
achieved (Scheme 3). Coupling between allyl SO2Ph 3a and
allyl chloride 4 gave 20 in 89% yield. Removal of TBDPS
group followed by the reduction of SO2Ph afforded dolichol
1a. Dolichol 1b was synthesized similarly. Compound 21,15
synthesized from 6, was converted to 22. Allyl SO2Ph 22 was
coupled with 3a to give 23. After conversion to allyl chloride
3b, coupling with 12, containing Z/E isoprene units,
afforded 24. Introduction of SO2Ph generated 25, which was
coupled with 4, containing saturated isoprene unit, to give
26. Removal of TBDPS group and subsequent reduction of
SO2Ph led to the total synthesis of C100-dolichol 1b.
Remarkably, all of the SN2-coupling of isoprene units
performed here produced the desired compounds in high
yields, with high reproducibilities, under almost the same
conditions, even when long-chain isoprene units were used.
This excellent versatility of the reaction allowed the
efficient total syntheses of dolichols 1a and 1b.
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EXPERIMENTAL SECTION
General procedure. H- and 13C{1H} NMR spectra were
1
measured in indicated solvents with a JEOL ECA500,
ECS400, or Bruker AVANCE700 spectrometers. The
chemical shifts in CDCl3 are given in δ values from
tetramethylsilane (TMS, δ = 0) or residual solvent peak
(CDCl3, 1H: δ = 7.26, C: δ = 77.0) as an internal standard.
13
In summary, we achieved the total syntheses of
Multiplicities are reported using the following
abbreviations: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad. High-resolution mass
spectra were obtained on an ESI-LTQ-Orbitrap XL(FTMS)
mass spectrometer. Unless otherwise noted, reactions in
anhydrous solvent were carried out under Ar atmosphere.
Optical rotations were measured with PERKIN-ELMER
241Polarimeter.
C60- dolichol 1a and C100-dolichol 1b by convergent
synthetic routes. Wittig reaction in a microflow system
allowed the scalable supply of Z-isoprene unit. Isoprene
units were efficiently coupled using an optimized protocol
involving t-BuOK. The wide applicability of our synthetic
method is evident from the total syntheses of 1a and 1b.
Our synthetic method realizes a reliable supply of
Scheme 3. Syntheses of dolichol 1a, 1b
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Wittig reaction between 9 and 10
mL, 1.88 mmol) in THF (24.4 mL, 0.1 M) was stirred for 1 h
1
Preparation of 9 and 10: Compound 9 was prepared
according to Davis’s report.15 Compound 10 was prepared
according to Eisenreich’s report.50 1H NMR of 9 and 10 was
identical to the previous reports.15, 50
at rt, the solution was filled in the syringe. A solution of
ketone 10 (497 mg, 3.14 mol) in THF (4.83 mL, 0.65 M) was
filled in the other syringe. The syringes were pumped at a
flow rate of 1.0 mL/min (solution of 9), and 0.2 mL/min
(solution of 10), respectively (precooling time: 10 min,
residence time = 5 min). After passing through, the
solution was quenched with H2O. After extraction with
AcOEt/hexane = 1/1, the organic layer was dried over
Na2SO4. After concentration in vacuo, the residue was
purified by silica gel column chromatography
(hexane/AcOEt = 97/3 to 95/5 to 90/10) to afford 6 (0.741 g,
2
3
4
5
6
7
8
9
<Batch>
To a solution of 9 (1.71 g, 2.31 mmol) in THF (21 mL) was
added dropwise n-BuLi (1.37 M solution in hexane, 1.96 mL,
2.68 mmol) at rt. After being stirred for 1 h at rt, the
mixture was cooled to -78 ˚C. After being stirred for 1 h at
-78 ˚C, to the mixture was added dropwise a solution of 10
(639 mg, 4.02 mmol) in THF (6.18 mL). After being stirred
for 3 h, the solution was diluted with AcOEt/hexane = 1/1
and quenched with H2O. After extraction, the organic layer
was dried over Na2SO4. After concentration in vacuo, the
residue was purified by silica gel column chromatography
(hexane/AcOEt = 97/3 to 95/5 to 90/10) to afford 6 (948 mg,
83%, E/Z = 11/1) as a colorless oil. 1H NMR was identical to
the previous report.15
10
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67%, Z/E = 11/1) as a colorless oil. H NMR NMR was
identical to the previous report.15
Compound 11
<Method A>
To a solution of 2 (79.6 mg, 0.146 mmol) and 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMTP, 0.146 mL)
in THF (1.46 mL) was added dropwise n-BuLi (1.22 M
solution in hexane, 0.180 mL, 0.219mmol) at -78 ˚C. After
the mixture was warmed to -10 ˚C and stirred for 20 min,
the mixture was cooled to -78 ˚C. To the mixture was added
dropwise a solution of 3a (82.2 mg, 0.117 mmol). After being
stirred for 4 h at -78 ˚C, the mixture was diluted with
hexane/AcOEt = 1/1 and quenched with NH4Cl aq. After
extraction, the organic layer was dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 85/15 to
75/25 to 65/35) to afford 11 (115mg, 80%) as a colorless oil.
<Method B>
<Microflow (Figure S1 and S2)>
Small-scale: A flow reactor system consisting of syringe
pump, Comet X-01 micromixer (Techno Applications Co.,
Ltd.) was used. After a solution of phosphonium salt 9 (228
mg, 0.308 mmol) and n-BuLi (1.32 M solution in hexane,
0.181 mL, 0.271 mmol) in THF (0.308 mL, 0.1 M) was stirred
for 1 h at rt, the solution was filled in the syringe. A solution
of ketone 10 (63.1 mg, 0.400 mol) in THF (0.617 mL, 0.65
M) was filled in the other syringe. The syringes were
pumped at a flow rate of 0.1 mL/min (solution of 9), and
0.02 mL/min (solution of 10), respectively (precooling
time: 10 min, residence time = 5 min). After passing
through, the solution was quenched with H2O. After
extraction with AcOEt/hexane = 1/1, the organic layer was
dried over Na2SO4. After concentration in vacuo, the
residue was purified by silica gel column chromatography
(hexane/AcOEt = 97/3 to 95/5 to 90/10) to afford 6 (112 mg,
73%, Z/E = 13/1) as a colorless oil. 1H NMR was identical to
the previous report.15
To a solution of 2 (31.3. mg, 0.564 mmol) and 3a (33.7 mg,
0.0479 mmol) in DMF (0.36 mL) was added dropwise t-
BuOK (6.64 mg, 0.0592 mmol) solution in DMF (0.197mL)
at -50 ˚C. After being stirred for 20 min at -50 ˚C, the
mixture was diluted with hexane/AcOEt = 1/1 and
quenched with NH4Cl aq. After extraction, the organic
layer was dried over Na2SO4. After concentration in vacuo,
the residue was purified by silica gel column
chromatography (hexane/AcOEt = 85/15 to 75/25 to 65/35)
Large-scale: A flow reactor system consisting of syringe
pump, Comet X-01 micromixer (Techno Applications Co.,
Ltd.) was used. After a solution of phosphonium salt 9 (1.80
g, 2.43 mmol) and n-BuLi (1.50 M solution in hexane, 0.181
1
to afford 11 (50.8 mg, 87%) as a colorless oil. H NMR and
13C{1H} NMR were identical to the previous report.15
Compound 12
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After cleavage of TBDPS group from 11 using TBAF,15 to a
concentrated in vacuo. The residue was purified by silica
1
2
3
4
5
6
7
8
solution of the obtained alcohol (206 mg, 0.210 mmol), LiCl
(29.8 mg, 0.703 mmol) and 2,4,6-collidine (110 L, 0.832
mmol) in DMF (4.2 mL) was added methanesulfonyl
chloride (50 L, 0.64 mmol) at 0 ˚C. After being stirred for
2 h at rt, the mixture was diluted with hexane/AcOEt = 1/1
and quenched with saturated NaHCO3 aq. After extraction,
the organic layer was washed with saturated NH4Cl aq. and
brine, and dried over Na2SO4. After concentration in vacuo,
the crude was obtained as a yellow oil. To a solution of the
crude in DMF (2.1 mL) was added NaSO2Ph (55.5 mg, 0.335
mmol) at rt. After being stirred for 18 h, the mixture was
diluted with hexane/AcOEt = 1/1 and quenched with 1 M
HCl aq. After extraction, the organic layer was washed with
saturated NaHCO3 aq. and dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 90/10 to
80/20 to 70/30) to give 12 as white powder (120 mg, 51%).
1H NMR (396 MHz, CDCl3) δ 7.87-7.79 (m, 8H), 7.65-7.57
(m, 4H), 7.55-7.47 (m, 8H), 5.17 (t, J = 7.8 Hz, 1H), 5.11-4.84
(m, 7H), 3.85-3.74 (m, 5H), 2.83 (d, J = 13.4 Hz, 1H), 2.68-
2.59 (m, 2H), 2.44-2.33 (m, 2H), 2.24-2.18 (m, 1H), 1.89-1.83
(m, 6H), 1.79-1.45 (m, 8H), 1.69 (s, 3H), 1.66 (s, 3H), 1.61 (s,
3H), 1.57 (s, 9H), 1.53 (s, 3H), 1.42 (s, 3H), 1.38-1.24 (m, 2H),
1.11 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.6, 144.9,
144.71, 144.70, 144.63, 138.9, 137.9, 137.8, 137.7, 133.6, 133.5,
133.4, 131.9, 130.74, 130.72, 130.70, 130.5, 130.3, 129.18, 129.14,
129.10, 129.0, 128.8, 128.73, 128.72, 128.66, 128.4, 127.9, 127.8,
127.71, 127.65, 127.25, 127.23, 123.4, 117.78, 117.76, 117.72, 117.69,
117.3, 110.1, 63.4, 63.3, 63.12, 63.09, 63.03, 63.01, 62.9, 55.8,
39.6, 37.23, 37.19, 31.80, 31.76, 31.66, 31.52, 31.50, 30.1, 30.03,
29.97, 29.93, 29.89, 26.2, 25.93, 25.91, 25.88, 25.70, 25.65,
23.49, 23.46, 23.43, 23.33, 23.28, 23.24, 23.21, 17.6, 16.2, 15.8;
HRMS (ESI-LTQ-Orbitrap) m/z [M+Na]+ calculated for
C64H82NaO8S4, 1129.4785, found 1129.4778.
gel column chromatography (hexane/AcOEt = 90/10) to
afford 13 (31 mg, 70%) as a colorless oil.
<Evaluation of optical purity>48
Mosher esterification of 13 to determine of enantiomeric
excess.
To a solution of 13 (10.6 mg, 77.4 mol) and pyridine (6.84
L) in DCM (0.522 mL) was added (R)-(-)--methoxy--
(trifluoromethyl)phenylacetyl chloride (25 L, 0.13 mmol)
at rt. After being stirred for 3 h, to the mixture was added
(R)-(-)--methoxy--(trifluoromethyl)phenylacetyl
chloride (15 L, 0.078 mmol) at rt. After being stirred for 2
h, to the mixture was added (R)-(-)--methoxy--
(trifluoromethyl)phenylacetyl chloride (25 L, 0.13 mmol)
at rt. After being stirred for 2 h, to the mixture was added
(R)-(-)--Methoxy--(trifluoromethyl)phenylacetyl
chloride (19 L, 0.099 mmol) at rt. After being stirred for 2
h, the mixture was quenched with water. After extraction,
the organic layer was washed with brine and dried over
Na2SO4. After concentration in vacuo, the residue was
purified by silica gel column chromatography
(hexane/AcOEt = 95/5) to give the Mosher ester as
colorless oil (26.6 mg, quant).The obtained Mosher ester
was analyzed by HPLC with Chiralcel OJ-H column (Daicel,
250 mm, =4.6 mm), hexane/i-PrOH = 98/2, 1 mL/min, and
optical purity was evaluated based on the integration of the
respective peak.
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Compound 14
To a solution of 13 (260 mg, 1.66 mmol) and imidazole (123
mg, 1.86 mmol) in DMF (0.50 mL) was added TBDPSCl
(0.450 ml, 1.76 mmol) at rt. After being stirred for 1.5 h at
rt, the mixture was diluted with hexane/AcOEt = 1/1 and
quenched with 1 M HCl aq. After extraction, the organic
layer was washed with saturated NaHCO3 aq. and dried
over Na2SO4. After concentration in vacuo, the crude was
obtained as a yellow oil. To a solution of the crude in
THF/H2O (3.45 mL/1.15 mL) was added N-
bromosuccinimide (328 mg, 1.85 mmol) at 0 ˚C. The
mixture was stirred for 3.5 h at 0 ˚C. After concentration in
vacuo, the residue was dissolved to hexane/AcOEt = 1/1.
After extraction, the organic layer was washed with
saturated NaHCO3 aq. and dried over Na2SO4. After
Compound 13
To a solution of geraniol (5) (43.7 mg, 0.283 mmol) in i-
PrOH (30 mL) were added [(R)-tol-binap]RuCl2(p-
cymene) (8.4 mg, 8.5 mol), KOH (31.8 mg, 0.566 mmol).
After freeze (liquid N2)–pump–thaw cycles were
performed three times, the mixture was warmed to reflux
and stirred for 2 h. After being cooled to rt, the mixture was
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concentration in vacuo, the crude was obtained as a yellow
Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 144.6, 135.5, 134.0,
1
oil. To a solution of the crude in methanol (3.5 mL) was
added Potassium carbonate (443 mg, 3.21 mmol) at 0 ˚C.
After being stirred for 1.5 h at rt, the mixture was filtered.
After concentration in vacuo, the residue was dissolved in
hexane/AcOEt = 1/1. The organic layer was washed with
H2O, and dried over Na2SO4. After concentration in vacuo,
the crude was obtained as a colorless oil. To a solution of
the crude in dioxane/H2O (1.0 mL/0.50 mL) was added
H5IO6 (453 mg, 2.00 mmol) at 0 ˚C. After being stirred for
6.5 h at 0 ˚C, the mixture was filtered through celite,
extracted with hexane/AcOEt = 1/1. The organic layer was
washed with saturated NaHCO3 aq. and dried over Na2SO4.
After concentration in vacuo, the residue was purified by
silica gel column chromatography (hexane/AcOEt = 97/3
to 95/5 to 93/7) to afford 14 (312 mg, 51%) as a colorless oil.
1H NMR was identical to the previous report.51
133.2, 129.8, 129.5, 127.8, 127.6, 70.9, 61.8, 39.2, 32.5, 28.9,
26.8, 26.4, 21.6, 19.4, 19.1; []D27 -3 (c = 0.10, CHCl3); HRMS
(ESI-LTQ-Orbitrap) m/z [M+Na]+ calculated for
C30H40O4NaSSi, 547.2309, found 547.2308.
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3
4
5
6
7
8
9
Compound 16
To a solution of 15 (851 mg, 1.62 mmol) in acetone (2.4 mL)
was added NaI (605 mg, 4.04 mmol) at rt. The mixture was
heated to reflux and stirred for 1.5 h. After being cooled to
rt, the mixture was quenched with 10% Na2S2O3 aq. After
extraction with hexane, the organic layer was dried over
Na2SO4. After concentration in vacuo, the crude was
obtained as a colorless oil. To a solution of the crude (1.2 g,
1.62 mmol) in toluene (3.24 mL) was added PPh3 (560 mg,
2.14 mmol) at rt. The mixture was heated to reflux and
stirred for 3 h. After being cooled to rt, the mixture was
concentrated in vacuo. The residue was purified by silica
gel column chromatography (CHCl3/MeOH = 10/1) to
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Compound 15
1
To a solution of the aldehyde 14 (0.984 g, 2.67 mmol) in
EtOH (4.45 mL) was added NaBH4 (0.192 g, 5.07 mmol) at
0 ˚C. After being stirred for 2.5 h at 0 ˚C, the mixture was
quenched with 1 M HCl aq. The mixture was filtered
through celite. After concentration in vacuo, the residue
was dissolved in hexane/AcOEt = 1/1. The organic layer was
washed with brine and dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 93/7 to
85/15 to 78/22) to afford the alcohol (0.856 g, 86%) as a
colorless oil. 1H NMR was identical to the previous report.52
To a solution of the obtained alcohol (391 mg, 1.06 mmol)
in pyridine (0.80 mL) was added TsCl (244 mg, 1.28 mmol)
at rt. After being stirred for 3 h at rt, the mixture was
concentrated in vacuo, and the residue was dissolved in
hexane. After filtered to remove the insoluble pyridinium
salt, the organic layer was concentrated in vacuo. The
residue was purified by silica gel column chromatography
(hexane/AcOEt = 93/7 to 85/15 to 75/25) to afford 15 (387
afford 16 (1.12 g, 93%) as a yellow oil. H NMR (500 MHz,
CDCl3) δ 7.80-7.76 (m, 9H), 7.70-7.66 (m, 6H), 7.60-7.58 (m,
4H), 7.38-7.29 (m, 6H), 3.66-3.50 (m, 4H), 1.71-1.46 (m, 6H),
1.27-1.20 (m, 1H), 0.99 (m, 9H), 0.73 (d, J = 6.1 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 135.41, 135.40, 135.08,
135.06, 133.94, 133.88, 133.65, 133.56, 130.56, 130.46, 129.4,
127.5, 118.4, 117.7, 61.8, 38.9, 37.7, 37.6, 29.1, 26.8, 23.4, 23.0,
20.15, 20.11, 19.3, 19.1; []D27 +3 (c = 0.10, CHCl3); HRMS (ESI-
LTQ-Orbitrap) m/z [M+Na]+ calculated for C41H48NaOPSi,
615.3207, found 615.3211.
Compound 7
To a solution of 16 (252 mg, 0.340 mmol) in THF (3.4 mL)
was added n-BuLi (1.30 M solution in hexane, 0.30 mL, 0.39
mmol) at rt. After being stirred for 1h, the mixture was
cooled to -78 ˚C and a solution of 10 (70 mg, 0.44 mmol) in
THF (0.68 mL) was added dropwise. After being stirred for
2 h at -78 ˚C, the mixture was diluted with hexane/AcOEt
= 1/1 and quenched with H2O. After extraction, the organic
layer was dried over Na2SO4. After concentration in vacuo,
the residue was purified by silica gel column
chromatography (hexane/AcOEt = 95/5 to 90/10) to afford
7 as a colorless oil (103 mg, 65%, E/Z = 20/1, after isolation
1
mg, 70%) as a colorless oil. H NMR (500 MHz, CDCl3) δ
7.80 (dd, J = 8.1 Hz, 1.6Hz, 2H), 7.68-7.66 (m, 4H), 7.45-7.37
(m, 6H), 7.33 (d, J = 8.1 Hz, 2H), 4.00 (t, J = 5.7 Hz, 2H), 3.71-
3.63 (m, 2H), 2.44 (s, 3H), 1.69-1.53 (m, 4H), 1.37-1.23 (m,
2H), 1.14-1.09 (m, 1H), 1.05 (s, 9H), 0.80 (dd, J = 6.2 Hz, 2.0
1
of Z: 62%, Z only). H NMR (396 MHz, CDCl3) δ 7.69-7.67
(m, 4H), 7.45-7.36 (m, 6H), 5.35 (t, J = 7.2 Hz, 1H), 4.59 (t, J
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The Journal of Organic Chemistry
= 3.5 Hz, 1H), 4.13 (d, J = 11.3, 1H), 4.08 (d, J = 11.3 Hz, 1H), 5.34 (td, J = 7.4 Hz, 1.4 Hz, 1H), 4.04 (s, 2H), 3.73-3.65 (m,
1
3.92-3.87 (m, 1H), 3.75-3.65 (m, 2H), 3.54-3.49 (m, 1H), 2.12-
2.00 (m, 2H), 1.90-1.81 (m, 1H), 1.77 (d, J = 2.3 Hz, 3H), 1.76-
1.69 (m, 1H), 1.68-1.48 (m, 6H), 1.41-1.27 (m, 2H), 1.21-1.08
(m, 1H), 1.06 (s, 9H), 0.84 (d, J = 6.5 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 135.5, 134.1, 131.5, 131.5, 129.87, 129.85,
129.5, 127.6, 97.5, 95.49, 65.408, 65.401, 62.2, 62.14, 62.1,
39.59, 39.57, 37.4, 37.3, 30.7, 29.1, 29.0, 26.8, 25.5, 25.1, 25.0,
21.74, 21.67, 19.55, 19.54, 19.49, 19.47, 19.2; HRMS (ESI-LTQ-
Orbitrap) m/z [M+Na]+ calculated for C31H46NaO3Si,
517.3108, found 517.3111.
2H), 2.11-1.98 (m, 2H), 1.80 (d, J = 1.4 Hz, 3H), 1.68-1.56 (m,
2H), 1.40-1.31 (m, 2H), 1.20-1.15 (m, 1H), 1.05 (s, 9H), 0.84 (d,
J = 6.6 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 135.6, 134.1,
131.5, 131.0, 129.5, 127.6, 62.0, 43.7, 39.5, 36.9, 29.0, 26.7, 25.3,
21.5, 19.5, 19.2; []D27 +3 (c = 0.10, CHCl3); HRMS (ESI-LTQ-
Orbitrap) m/z [M+Na]+ calculated for C26H37ClNaOSi,
451.2194, found 451.2198.
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Compound 19
To a solution of 17 (32.9 mg, 0.0767 mmol) and 18 (30.1 mg,
0.0797 mmol) in DMF (0.767 mL) was added dropwise t-
BuOK (9.1 mg, 0.0811 mmol) solution in DMF (0.270 mL) at
-50 ˚C. After being stirring for 15 min at -50 ˚C, the mixture
was diluted with hexane/AcOEt = 1/1 and quenched with
saturated NH4Cl aq. After extraction, the organic layer was
dried over Na2SO4. After concentration in vacuo, the
residue was purified by silica gel column chromatography
(hexane/AcOEt = 85/15 to 80/20 to 75/25) to afford 19 as a
Compound 17
To a solution of 7 (71.8 mg, 0.145 mmol) in i-PrOH/Et2O
(0.358 mL/0.179 mL) was added p-toluene sulfonic acid
monohydrate (3.0 mg, 0.16 mmol) at rt. After being stirred
for 4 days, the mixture was diluted with hexane/AcOEt =
1/1 and quenched with saturated NaHCO3 aq. After
extraction, the organic layer was dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 93/7 to
85/15 to 79/21) to afford the alcohol as a colorless oil (50.6
mg, 85%). 1H NMR (500 MHz, CDCl3) δ 7.69-7.67 (m, 4H),
7.44-7.37 (m, 6H), 5.28 (t, J = 7.3 Hz, 1H), 4.13 (t, J = 12.4 Hz,
2H), 3.74-3.66 (m, 2H), 2.11-1.97 (m, 2H), 1.80 (s, 3H), 1.67-
1.59 (m, 2H), 1.39-1.29 (m, 2H), 1.20-1.11 (m, 2H), 1.06 (s, 9H),
1
colorless oil (52.6 mg, 89%). H NMR (500 MHz, CDCl3) δ
7.85-7.84 (m, 2H) 7.68-7.66 (m, 4H), 7.60-7.57 (m, 1H) 7.51-
7.48 (m, 2H), 7.43-7.36 (m, 6H), 5.17 (t, J = 7.2 Hz, 1H), 5.13
(t, J = 6.8 Hz, 1H), 4.98 (d, J = 10.5 Hz, 1H), 4.54 (t, J = 3.2
Hz, 1H), 4.05-4.02 (m, 1H), 3.98-3.95 (m, 1H), 3.89-3.84 (m,
2H), 3.72-3.64 (m, 2H), 3.53-3.48 (m, 1H), 2.71-2.67 (m, 1H),
2.53-2.46 (m, 1H), 1.96-1.73 (m, 6H), 1.72 (s, 3H), 1.70-1.67
(m, 1H), 1.64 (s, 3H), 1.61 (s, 3H), 1.59-1.40 (m, 7H), 1.38-1.19
(m, 2H), 1.10-1.00 (m, 1H), 1.05 (s, 9H), 0.81 (d, J = 5.4 Hz,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 144.71, 144.68, 144.66,
138.04, 138.02, 135.5, 134.1, 133.4, 132.56, 132.53, 129.49, 129.41,
129.40, 129.36, 129.32, 129.17, 129.16, 128.68, 128.66, 128.12,
128.09, 127.6, 117.91, 117.90, 117.86, 117.85, 97.41, 97.38, 65.19,
65.17, 63.34, 63.28, 62.115, 62.108, 62.07, 62.06, 39.67, 39.60,
37.23, 37.20, 32.1, 30.6 30.12, 30.08, 29.15, 29.10, 26.9, 25.54,
25.53, 25.51, 25.49, 25.44, 23.65, 23.64, 23.60, 23.59, 23.25,
21.6, 19.46, 19.43, 19.2; HRMS (ESI-LTQ-Orbitrap) m/z
[M+Na]+ calculated for C47H66NaO5SSi, 793.4292, found
793.4315.
13
0.84 (d, J = 6.3 Hz, 3H); C{1H} NMR (126 MHz, CDCl3) δ
135.58, 135.57, 134.1, 134.0, 129.5, 128.8, 127.6, 62.1, 61.6, 39.5,
27
37.4, 28.9, 26.9, 25.0, 21.2, 19.5, 19.2; []D +15 (c = 0.10,
CHCl3); HRMS (ESI-LTQ-Orbitrap) m/z [M+Na]+
calculated for C26H38NaO2Si, 433.2533, found 433.2532.
To a solution of the obtain alcohol (50.6 mg, 0.123 mmol),
LiCl (17.0 mg, 0.401 mmol) and 2,4,6-collidine (65.1 mL,
0.493 mmol) in DMF (0.51 mL) was added methanesulfonyl
chloride (28.6 L, 0.370 mmol) at 0 ˚C. After being stirred
for 2.5 h at rt, the mixture was diluted with hexane/AcOEt
= 1/1 and quenched with saturated NaHCO3 aq. After
extraction, the organic layer was washed with saturated
NH4Cl aq. and brine, and dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 97/3 to
93/7) to afford 17 as a colorless oil (43.3 mg, 82%). 1H NMR
(500 MHz, CDCl3) δ 7.68-7.65 (m, 4H), 7.43-7.36 (m, 6H),
Compound 4
To a solution of 19 (47.6 mg, 0.0617 mmol) in i-PrOH /Et2O
(0.686/0.343 mL) was added p-toluene sulfonic acid
monohydrate (1.13 mg, 5.94 mol). After being stirred for 5
days at rt, the mixture was diluted with hexane/AcOEt = 1/1
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and quenched with saturated NaHCO3 aq. After extraction, NMR (126 MHz, CDCl3) δ 144.42, 144.39, 138.0, 135.6, 134.1,
1
the organic layer was dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 85/15 to
80/20) to afford the alcohol as a colorless oil (38.4 mg, 91%).
1H NMR (500 MHz, CDCl3) δ 7.85-7.84 (m, 2H) 7.68-7.66
(m, 4H), 7.61-7.58 (m, 1H) 7.52-7.49 (m, 2H), 7.44-7.36 (m,
6H), 5.16 (t, J = 7.2 Hz, 1H), 5.10 (t, J = 7.2 Hz, 1H), 4.97 (d, J
= 10.6 Hz, 1H), 4.07 (d, J = 11.8 Hz, 1H), 4.01 (d, J = 11.8 Hz,
1H), 3.89-3.84 (m, 1H), 3.72-3.63 (m, 2H), 2.67-2.62 (m, 1H),
2.48-2.41 (m, 1H), 1.93-1.73 (m, 5H), 1.76 (s, 3H), 1.66 (t, J =
1.5 Hz, 3H), 1.63-1.53 (m, 3H), 1.59 (s, 3H), 1.39 (s, 1H), 1.35-
1.29 (m, 1H), 1.26-1.22 (m, 1H),1.08-1.01 (m, 1H), 1.05 (s, 9H),
0.79 (dd, J = 6.5 Hz, 1.1Hz, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 144.90, 144.87, 137.9, 135.5, 135.1, 134.1, 133.4, 129.50,
129.49, 129.41, 129.34, 129.30, 129.1, 128.7, 127.6, 127.1, 117.71,
117.66, 63.4, 62.1, 61.4, 39.65, 39.58, 37.18, 37.16, 32.4, 30.5,
29.11, 29.07, 26.9, 25.6, 25.5, 25.4, 23.66, 23.62, 23.36, 23.35,
21.3, 19.45, 19.43, 19.2; HRMS (ESI-LTQ-Orbitrap) m/z
[M+Na]+ calculated for C42H58NaO4SSi, 709.3717, found
709.3698.
133.4, 132.1, 129.9, 129.54, 129.50, 129.46, 129.38, 129.34, 129.17,
128.8, 127.6, 118.1, 118.0, 63.4, 62.1, 43.4, 39.7, 39.6, 37.19, 37.17,
31.9, 29.13, 29.10, 26.9, 25.9 , 25.5, 25.4, 23.73, 23.70 23.3, 21.5,
19.46, 19.44, 19.2; HRMS (ESI-LTQ-Orbitrap) m/z [M+Na]+
calculated for C42H57ClNaO3Si, 727.3378, found 727.3388.
Compound 20
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4
5
6
7
8
9
To a solution of 12 (30.1 mg, 0.0797 mmol) and 4 (32.9 mg,
0.0767 mmol) in DMF (0.767 mL) was added dropwise t-
BuOK (9.1 mg, 0.0811 mmol) solution in DMF (0.270 mL) at
-50 ˚C. After being stirring for 15 min at -50 ˚C, the mixture
was diluted with hexane/AcOEt = 1/1 and quenched with
saturated NH4Cl aq. After extraction, the organic layer was
dried over Na2SO4. After concentration in vacuo, the
residue was purified by silica gel column chromatography
(hexane/AcOEt = 93/7 to 85/15 to 78/22) to afford 20 as a
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14
15
16
17
18
19
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60
1
colorless oil (52.6 mg, 89%). H NMR (500 MHz, CDCl3) δ
7.83-7.78 (m, 10H), 7.67-7.65 (m, 4H), 7.63-7.56 (m, 5H),
7.52-7.48 (m, 10H), 7.42-7.35 (m, 6H), 5.18-4.84 (m, 11H),
3.88-3.76 (m, 5H), 3.70-3.63 (m, 2H), 2.83 (d, J = 13.1 Hz, 1H),
2.66-2.59 (m, 4H), 2.52-2.33 (m, 4H), 2.21 (t, J = 11.5 Hz, 1H),
1.89-1.81 (m, 6H), 1.80-1.02 (m, 21H), 1.66 (s, 3H), 1.62 (s, 3H),
1.60 (s, 6H), 1.58 (s, 3H), 1.56 (s, 6H), 1.55 (s, 6H), 1.53 (s, 3H),
1.42 (s, 3H), 1.10 (s, 3H), 1.04 (s, 9H), 0.80 (d, J = 6.25. Hz,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 144.9, 144.71, 144.68,
144.61, 144.5, 137.89, 137.87, 137.82, 137.81, 135.5, 134.1, 133.60,
133.57, 133.48, 133.42, 133.39, 132.0, 130.77, 130.75, 130.54,
130.39, 130.38, 130.36, , 130.24, 129.5, 129.41, 129.37, 129.30,
129.28, 129.20, 129.14, 129.07, 128.8, 128.76, 128.74, 128.69,
127.9, 127.8, 127.6, 127.24, 127.21, 123.5, 117.8, 117.3, 63.37,
63.36, 63.2, 63.0, 62.92, 62.85, 62.1, 39.66, 39.62, 39.5, 37.25,
37.22, 31.92, 31.88, 31.86, 31.84, 31.78, 31.56, 31.53, 31.52, 31.50,
30.19, 30.16, 30.15, 30.11, 30.07, 30.05, 30.02, 30.00, 29.97,
29.92, 29.15, 29.12, 29.09, 29.08, 26.9, 26.27, 26.25, 25.96,
25.94, 25.91, 25.90, 25.84, 25.78, 25.76, 25.70, 25.67, 25.54,
25.51, 25.4, 23.57, 23.55, 23.54, 23.50, 23.48, 23.43, 23.36, 23.33,
23.25, 23.21, 23.17, 19.5, 19.4, 19.2, 17.7, 16.22, 16.21, 15.83;
HRMS (ESI-LTQ-Orbitrap) m/z [M+Na]+ calculated for
C106H138NaO11S5Si, 1797.8504, found 1797.8487.
To a solution of the obtained alcohol (35 mg, 0.051 mmol),
LiCl (6.6 mg, 0.16 mmol) and 2,4,6-collidine (27 L,
0.20mmol) in DMF (0.85 mL) was added methanesulfonyl
chloride (12 L, 0.16 mmol) at 0 ˚C. After being stirred for
2.5 h at rt, to the mixture were added LiCl (7.0 mg, 0.17
mmol), 2,4,6-collidine (27 L, 0.20mmol) and
methanesulfonyl chloride (12 L, 0.16 mmol) at 0 ˚C. After
being stirred for 2 h at rt, the mixture was diluted with
hexane/AcOEt = 1/1 and quenched with saturated NaHCO3
aq. After extraction, the organic layer was washed with
saturated NH4Cl aq. brine and dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 93/7 to
85/15) to afford 4 as a colorless oil (29.1 mg, 81%). 1H NMR
(500 MHz, CDCl3) δ 7.87-7.85 (m, 2H) 7.68-7.66 (m, 4H),
7.62-7.58 (m, 1H) 7.52-7.49 (m, 2H), 7.44-7.35 (m, 6H), 5.20-
5.15 (m, 2H), 5.02 (d, J = 10.5 Hz, 1H), 3.99-3.94 (m, 2H),
3.88-3.83 (m, 1H), 3.72-3.64 (m, 2H), 2.69-2.64 (m, 1H) ,
2.50-2.43 (m, 1H), 1.90-1.72 (m, 5H), 1.77 (s, 3H), 1.67 (t, J =
1.5 Hz, 3H), 1.65-1.53 (m, 3H), 1.60 (s, 3H), 1.36-1.17 (m, 2H),
1.11-0.99 (m, 1H), 1.05 (s, 9H), 0.80 (d, J = 5.9 Hz, 3H); 13C{1H}
Compound 1a
To a solution of 20 (36.4 mg, 0.0205 mmol) in THF (2.0 mL)
was added TBAF (1 M in THF, 21 L, 0.021 mmol) at 0 ˚C.
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The Journal of Organic Chemistry
After being stirring for 2 h at rt, the mixture was diluted MHz, CDCl3) δ 135.4, 135.23, 135.19, 135.0, 134.95, 134.90, 131.2,
1
with hexane/AcOEt = 1/1 and added brine. After extraction,
the organic layer was dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 2/1 to 1/1 to
1/2) to afford the alcohol as a colorless oil (28.0 mg, 89%).
1H NMR (500 MHz, CDCl3) δ 7.86-7.80 (m, 10H), 7.66-7.58
(m, 5H), 7.56-7.49 (m, 10H), 5.23-4.85 (m, 11H), 3.86-3.76
(m, 5H), 3.71-3.62 (m, 2H), 2.84 (d, J = 8.4 Hz, 1H), 2.72 (d,
J = 12.4 Hz, 1H), 2.67-2.60 (m, 3H), 2.48-2.34 (m, 4H), 2.22
(t, J = 12.3 Hz, 1H), 1.98-1.90 (m, 6H), 1.78-1.24 (m, 30H), 1.67
(s, 3H), 1.65 (s, 3H), 1.60 (s, 9H), 1.58 (s, 6H), 1.43 (s, 3H),
1.12 (s, 3H), 1.18-1.06 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 144.87, 144.85, 144.70, 144.68,
144.67, 144.65, 144.63, 144.61, 144.52, 144.51, 137.87, 137.85,
137.82, 137.809, 137.797, 137.78, 133.61, 133.59, 133.52, 133.49,
133.45, 133.39, 132.0, 130.8, 130.7, 130.55, 130.53, 130.4, 130.38,
130.36, 130.29, 129.7, 129.19, 129.13, 129.1, 128.78, 128.75,
128.68, 127.89, 127.85, 127.81, 127.23, 127.20, 123.5, 117.85,
117.83, 117.77, 117.75, 117.68, 117.65, 117.29, 117.27, 63.37, 63.35,
63.02, 63.00, 62.93, 62.91, 62.90, 62.86, 60.96, 60.93, 39.9,
39.75, 39.65, 37.23, 37.20, 37.11, 37.09, 31.85, 31.81, 31.7, 31.51,
31.49, 30.14, 30.09, 29.98, 29.95, 29.89, 29.16, 29.11, 29.10,
26.26, 26.24, 26.0, 25.97, 25.89, 25.85, 25.80, 25.77, 25.66,
25.51, 25.48, 25.37, 23.73, 23.72, 23.70, 23.35, 23.32, 23.28,
23.24, 23.20, 19.54, 19.50, 17.6, 16.2, 15.8; HRMS (ESI-LTQ-
Orbitrap) m/z [M+Na]+ calculated for C90H120NaO11S5,
1559.7326, found 1559.7317.
125.4, 125.08, 125.05, 124.96, 124.4, 124.25, 124.18, 61.2, 40.0,
39.8, 39.7, 37.5, 32.25, 32.22, 32.0, 29.3, 26.8, 26.66, 26.65,
26.4, 25.7, 25.3, 23.46, 23.44, 19.5, 17.7, 16.0; []D27 -2 (c = 0.10,
CHCl3); HRMS (ESI-LTQ-Orbitrap) m/z [M+Na]+
calculated for C60H100ONa, 859.7666, found 859.7668.
Compound 22
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9
To a solution of 21 (223 mg, 0.309 mmol) in THF (3.1 mL)
was added TBAF (1 M in THF, 619 L, 0.619 mmol) at 0 ˚C.
After being stirred for 5 h at rt, the mixture was diluted
with hexane/AcOEt = 1/1 and added brine. After extraction,
the organic layer was dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 85/15 to
75/25 to 65/35) to afford the alcohol as a colorless oil (141
mg, 86%). 1H NMR (500 MHz, CDCl3) δ 7.85-7.83 (m, 2H),
7.63-7.60 (m, 1H), 7.54-7.50 (m, 2H), 5.45 (td, J = 7.1, 1.3 Hz,
1H), 5.23-5.06 (m, 2H), 4.98 (d, J = 10.6 Hz, 1H), 4.55-4.53
(m, 1H), 4.08 (d, J = 7.2 Hz, 2H), 4.03 (dd, J = 11.4, 4.4 Hz
1H), 3.96 (dd, J = 11.4, 3.7 Hz 1H), 3.87-3.83 (m, 2H), 3.58-
3.46 (m, 1H), 2.77 (d, J = 13.1 Hz, 1H), 2.46 (ddd, J = 13.1, 11.2,
6.9 Hz, 1H), 2.14-2.00 (m, 1H), 1.95-1.37 (m, 26H); 13C{1H}
NMR (126 MHz, CDCl3) δ 144.9, 144.8, 139.2, 137.7, 133.4,
132.5, 130.7, 129.2, 128.69, 128.67, 128.14, 128.09, 128.05, 124.7,
117.8, 97.4, 65.1, 63.4, 63.3, 62.1, 62.0, 58.8, 32.1, 31.9, 30.6,
29.92, 29.88, 26.6, 25.4, 23.7, 23.6, 23.5, 23.2, 21.6, 19.40,
19.35; HRMS (ESI-LTQ-Orbitrap) m/z [M+Na]+ calculated
for C31H46NaO5S, 553.2958, found 553.2957.
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To a solution of the obtained alcohol (25.5 mg, 0.0166
mmol) and (dppp)2PdCl2 (7.8 mg, 0.132 mmol) in THF (1.66
mL) was added super hydride (1 M in THF, 0.17 mL, 0.17
mmol) at 0 ˚C. After being stirring for 2.5 h at rt, the
mixture was diluted with hexane/AcOEt = 1/1 and
quenched with saturated NH4Cl aq. After extraction, the
organic layer was washed with and dried over Na2SO4.
After concentration in vacuo, the residue was purified by
silica gel column chromatography (hexane/AcOEt = 95/5
to 90/10 to 85/15) to afford 1a as a colorless oil (11.6 mg,
83%). 1H NMR (500 MHz, CDCl3) δ5.14-5.08 (m, 11H), 3.72-
3.63 (m, 2H), 2.08-1.96 (m, 42H), 1.68 (s, 27H), 1.62-1.55 (m,
2H) 1.609 (d, J = 1.0 Hz, 3H), 1.60 (s, 6H), 1.42-1.31 (m, 2H),
1.21-1.13 (m, 2H), 0.91 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (126
To a solution of the obtained alcohol (141 mg, 0.265 mmol),
LiCl (33.7 mg, 0.795 mol) and 2,4,6-collidine (140 L, 1.06
mmol) in DMF (5.76 mL) was added methanesulfonyl
chloride (61.5 L, 0.795 mmol) at 0 ˚C. After being stirred
for 3 h at rt, to the mixture were added 2,4,6-collidine (140
L, 1.06 mmol) and methanesulfonyl chloride (61.5 L,
0.795 mmol) at 0 ˚C. After being stirred for 1 h at rt, the
mixture was diluted with hexane/AcOEt = 1/1 and
quenched with saturated NaHCO3 aq. After extraction, the
organic layer was washed with saturated NH4Cl aq. and
water, and dried over Na2SO4. After concentration in vacuo,
the crude was obtained as a yellow oil. To a solution of the
crude in DMF (1.15 mL) was added NaSO2Ph (72.0 mg,
0.439 mmol) at 0 ˚C. After being stirred for 2 h at rt, to the
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mixture was added NaSO2Ph (60.0 mg, 0.365 mmol) at 0 Hz, 1H), 3.89-3.79 (m, 4H), 3.54-3.48 (m, 1H), 2.71-2.57 (m,
1
˚C. After being stirred for 1 h at rt, the mixture was diluted
with hexane/AcOEt = 1/1 and quenched with 1 M HCl aq.
After extraction, the organic layer was washed with
saturated NaHCO3 aq. and dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 90/10 to
80/20 to 70/30) to give 22 as white powder (157 mg, 90%).
1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 7.9, 2H), 7.81 (d, J
= 7.8 Hz, 2H), 7.64-7.57 (m, 2H), 7.55-7.47 (m, 4H), 5.17 (t,
J = 7.9 Hz, 1H), 5.09-5.02 (m, 2H), 4.92 (d, J = 10.6 Hz, 1H),
4.53-4.50 (m, 1H), 4.00 (dd, J = 11.4, 5.8 Hz, 1H), 3.93 (dd, J
= 11.5, 4.3 Hz 1H), 3.87-3.79 (m, 2H), 3.76 (d, J = 7.9 Hz, 2H),
3.52-3.46 (m, 1H) 2.68 (d, J = 13.2 Hz, 1H), 2.39 (ddd, J = 13.2,
11.0, 5.9 Hz, 1H), 1.96-1.32 (m, 26H); 13C{1H} NMR (126 MHz,
CDCl3) δ; 145.6, 144.81, 144.77, 138.8, 137.8, 133.6, 133.5, 132.65,
132.62, 130.87, 130.85, 129.2, 129.0, 128.73, 127.81, 128.4, 128.02,
127.98, 127.6, 117.9, 111.1, 97.43, 97.39, 65.1, 63.2, 63.1, 62.1,
55.8, 32.1, 31.7, 30.6, 29.93, 29.90, 25.9, 25.49, 25.45, 25.4,
23.5, 23.3, 21.6, 19.4; HRMS (ESI-LTQ-Orbitrap) m/z
[M+Na]+ calculated for C37H50NaO6S2, 677.2941, found
677.2941.
3H), 2.48-2.34 (m, 3H), 1.93-1.31 (m, 46H), 1.04 (s, 9H);
13C{1H} NMR (126 MHz, CDCl3) δ 144.74, 144.66, 144.6, 137.8,
134.0, 133.6, 133.53, 133.49, 133.45, 132.7, 132.6, 130.4, 130.3,
130.0, 129.5, 128.82, 128.78, 128.77, 128.74, 128.70, 128.4, 128.3,
128.0, 127.9, 127.8, 127.74, 127.73, 127.6, 125.3, 117.92, 117.86,
117.83, 117.81, 117.79, 117.67, 117.65, 65.11, 65.09, 63.13, 63.05,
63.0, 62.9, 62.1, 60.7, 32.1, 32.04, 32.00, 31.96, 31.91, 31.87,
31.84, 31.79, 31.76, 30.6, 30.2, 30.1, 26.8, 26.4, 26.3, 25.9, 25.7,
25.5, 25.40, 25.35, 23.43, 23.41, 23.39, 23.37, 23.33, 23.31, 23.28,
23.26, 23.23, 23.20, 21.6, 19.43, 19.40, 19.1; HRMS (ESI-LTQ-
Orbitrap) m/z [M+Na]+ calculated for C79H104NaO9S3Si,
1343.6504, found 1343.6498.
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Compound 3b
To a solution of 23 (150 mg, 0.113 mmol) in i-PrOH/Et2O
(1.51/0.75 mL) was added p-toluene sulfonic acid
monohydrate (1.34 mg, 8.04 µmol) at rt. After being stirring
for 3 days, to the mixture was added p-toluene sulfonic acid
monohydrate (0.30 mg, 1.8 µmol) at rt. After being stirring
for 1 days, to the mixture was added p-toluene sulfonic acid
monohydrate (0.49 mg, 2.9 µmol) at rt. After being stirring
for 1 days, the mixture was diluted with hexane/AcOEt = 1/1
and quenched with saturated NaHCO3 aq. After extraction,
the organic layer was dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 90/10 to
80/20 to 70/30 to 60/40) to afford the alcohol as a colorless
oil (113 mg, 81%). 1H NMR (500 MHz, CDCl3) δ 7.79-7.73 (m,
6H), 7.61 (d, J = 7.1 Hz, 4H) 7.59-7.49 (m, 3H), 7.49-7.38 (m,
6H), 7.38-7.28 (m, 6H), 5.31 (t, J = 6.4 Hz, 1H), 5.01-4.78 (m,
7H), 4.08 (d, J = 6.3 Hz, 2H), 3.99-3.89 (m, 2H), 3.80-3.72
(m, 3H), 2.63-2.49 (m, 3H), 2.37-2.22 (m, 3H), 1.86-1.28 (m,
40H), 0.97 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 144.9,
144.8, 144.7, 137.8, 136.8, 135.6, 135.2, 134.0, 133.6, 133.52,
133.46, 130.7, 130.6, 130.53, 130.48, 130.3, 130.0, 129.5, 129.2,
128.8, 128.4, 128.3, 127.92, 127.89, 127.84, 127.82, 127.7, 127.6,
126.9, 125.3, 117.8, 117.7, 117.6, 63.22, 63.15, 63.1, 61.3, 60.7, 32.3,
32.0, 31.89, 31.86, 31.8, 30.27, 30.25, 30.21, 30.19, 30.1, 26.8,
26.4, 26.3, 25.90, 25.85, 25.83, 25.81, 25.71, 25.66, 25.5, 23.6,
23.42, 23.39, 23.3, 23.30, 23.27, 21.3, 19.1; HRMS (ESI-LTQ-
Orbitrap) m/z [M+Na]+ calculated for C74H96NaO8S3Si,
1259.5929, found 1259.5987.
Compound 23
To a solution of 22 (137 mg, 0.209 mmol) and 3a (125 mg,
0.177 mmol) in DMF (1.36 mL) was added dropwise t-BuOK
(24.9 mg, 0.222 mmol) solution in DMF (0.74 mL) at -50 ˚C.
After being stirred for 50 min at -50 ˚C, to the mixture was
added dropwise t-BuOK (13.5 mg, 0.120 mmol) solution in
DMF (0.40 mL) at -50 ˚C. After being stirring for 1 h at -50
˚C, to the mixture was added dropwise t-BuOK (10.1 mg,
0.0900 mmol) solution in DMF (0.30 mL). After being
stirring for 2 h at -50 ˚C, the mixture was diluted with
hexane/AcOEt = 1/1 and quenched with saturated NH4Cl
aq. After extraction, the organic layer was and dried over
Na2SO4. After concentration in vacuo, the residue was
purified by silica gel column chromatography
(Toluene/AcOEt = 97/3 to 95/5 to 93/7 to 90/10 to 85/15) to
afford 23 as a colorless oil (168 mg, 72%). 1H NMR (500 MHz,
CDCl3) δ 7.83 (d, J = 6.4 Hz, 6H), 7.68 (d, J = 6.9 Hz, 4H),
7.66-7.57 (m, 3H), 7.55-7.47 (m, 6H), 7.41-7.35 (m, 6H), 5.38
(t, J = 6.3 Hz, 1H), 5.10-4.86 (m, 7H), 4.53 (s , 1H), 4.16 (d, J
= 6.3 Hz, 2H), 4.02 (dd, J = 11.3, 5.0 Hz 1H), 3.94 (d, J = 11.5
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1
To a solution of the obtained alcohol (106 mg, 0.0854
to 85/15) to afford 24 as a colorless oil (149 mg, 96%). H
NMR (500 MHz, CDCl3) δ 7.78 - 7.72 (m, 14H), 7.61 (d, J =
7.4, 4H), 7.59-7.51 (m, 7H), 7.49-7.40 (m, 14H), 7.36-7.28 (m,
6H), 5.31 (t, J = 6.2, 1H), 5.01-4.76 (m, 15H), 4.09 (d, J = 6.5,
2H), 3.82-3.68 (m, 7H), 2.77 (d, J = 13.8 Hz, 1H), 2.62-2.50
(m, 6H), 2.42-2.22 (m, 6H), 2.16 (t, J = 12.2, 1H), 1.89-1.16 (m,
1
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6
7
8
mmol), LiCl (12.4 mg, 0.289 mmol) and 2,4,6-collidine (45
L, 0.342 mmol) in DMF (1.71 mL) was added
methanesulfonyl chloride (20 L, 0.256 mmol) at 0 ˚C.
After being stirring for 3.5 h at rt, to the mixture were
added 2,4,6-collidine (90 L, 0.684 mmol) and
methanesulfonyl chloride (40 L, 0.512 mmol) at 0 ˚C. After
being stirred for 1 h at rt, the mixture was diluted with
hexane/AcOEt = 1/1 and quenched with saturated NaHCO3
aq. After extraction, the organic layer was washed with
saturated NH4Cl aq. water and brine, and dried over
Na2SO4. After concentration in vacuo, the residue was
purified by silica gel column chromatography
(hexane/AcOEt = 95/5 to 85/15 to 75/25) to afford 3b as a
83H), 0.97 (s, 9H); C{1H} (126 MHz, CDCl3) δ144.9, 144.8,
13
9
144.70, 144.69, 144.63, 144.61, 144.5, 137.8, 136.8, 135.6, 134.0,
133.62, 133.58, 133.52, 133.45, 133.4, 132.0, 130.6, 130.4, 130.0,
129.5, 129.22, 129.15, 129.1, 129.0, 128.82, 128.77, 128.7, 128.4,
128.3, 128.2, 127.93, 127.87, 127.8, 127.2, 125.3, 123.5, 117.82,
117.77, 117.7, 117.6, 117.3, 63.4, 63.13, 63.05, 63.0, 62.88, 62.85,
60.7, 39.7, 37.3, 32.0, 31.92, 31.86, 31.83, 31.79, 31.5, 30.1, 30.0,
29.9, 26.8, 26.4, 26.3, 25.9, 25.71, 25.68, 23.41, 23.38, 23.34,
23.29, 23.2, 21.4, 19.1, 17.7, 16.2, 15.8; HRMS (ESI-LTQ-
Orbitrap) m/z [M+Na]+ calculated for C138H176NaO15S7Si,
2348.0716, found 2348.0667.
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1
colorless oil (92.8 mg, 87%). H NMR (500 MHz, CDCl3) δ
7.81 (t, J = 8.4 Hz, 6H), 7.66 (d, J = 6.8 Hz, 4H), 7.64-7.55
(m, 3H), 7.53-7.46 (m, 6H), 7.42-7.32 (m, 6H), 5.36 (t, J =
6.4 Hz, 1H), 5.12 (t, J = 7.1 Hz, 1H), 5.07-4.85 (m, 6H), 4.13
(d, J = 6.3Hz, 2H), 3.92 (s, 2H), 3.86-3.76 (m, 3H), 2.67-2.54
(m, 3H), 2.44-2.31 (m, 3H), 1.92-1.32 (m, 40H), 1.02 (s, 9H);
13C{1H} NMR (126 MHz, CDCl3) 144.74, 144.66, 144.6, 144.3,
137.8, 136.8, 135.6, 134.0, 133.53, 133.47, 133.4, 132.20, 132.18,
130.7, 130.5, 130.3, 130.0, 129.8, 129.5, 129.2, 128.8, 128.4, 128.3,
127.91, 127.85, 127.8, 127.7, 127.6, 125.3, 118.14, 118.07, 117.9,
117.8, 117.7, 63.20, 63.15, 63.0, 60.7, 43.3, 32.0, 31.9, 31.8, 31.77,
31.7, 30.22, 30.19, 30.1, 30.0, 26.8, 26.3, 25.8, 25.71, 25.68, 25.6,
23.5, 23.42, 23.37, 23.33, 23.31, 23.28, 21.6, 19.1; HRMS (ESI-
Compound 25
To a solution of 24 (30.8 mg, 0.0132 mmol) in THF (1.07 mL)
was added TBAF (1 M in THF, 32.2 L, 0.0322 mmol) at 0
˚C. After being stirred for 6.5 h at rt, the mixture was
diluted with hexane/AcOEt = 1/1 and added brine. After
extraction, the organic layer was dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 100/0 to
90/10 to 80/20 to 70/30 to 60/40) to afford the alcohol as a
1
colorless oil (24.1 mg, 87%). H NMR (500 MHz, CDCl3) δ
LTQ-Orbitrap)
m/z
[M+Na]+
calculated
for
7.88-7.79 (m, 14H), 7.69-7.58 (m, 7H), 7.56-7.48 (m, 14H),
5.44 (td, J = 7.1, 1.5 Hz 1H), 5.22 (d, J = 8 Hz, 1H), 5.07-4.95
(m, 7H), 4.94-4.82 (m, 7H), 4.11-4.07 (m, 2H), 3.92-3.74 (m,
7H), 2.85 (d, J = 13.4 Hz, 1H), 2.75 (d, J = 9.3Hz, 1H), 2.71-
2.57 (m, 5H), 2.50-2.31 (m, 6H), 2.22 (t, J = 12.3 Hz, 1H), 1.95-
1.29 (m, 80H), 1.12 (s, 3H); 13C{1H} (126 MHz, CDCl3) δ 144.9,
144.8, 144.73, 144.71, 144.66, 144.6, 144.5, 139.3, 137.92, 137.90,
137.88, 137.84, 137.78, 133.7, 133.6, 133.5, 133.4, 132.0, 130.9,
130.84, 130.78, 130.76, 130.64, 130.61, 130.5, 130.4, 129.24,
129.21, 129.17, 129.1, 129.0, 128.9, 128.8, 128.7, 128.3, 128.2,
127.93, 127.89, 127.86, 127.2, 125.3, 124.8, 123.5, 117.84, 117.78,
117.4, 117.3, 63.41, 63.39, 63.36, 63.11, 63.06, 63.0, 62.9, 58.9,
39.7, 37.3, 37.2, 32.0, 31.9, 31.8, 31.6, 31.54, 31.51, 30.4, 30.1,
30.05, 30.0, 29.91, 29.86, 29.8, 28.9, 26.69, 26.67, 26.3, 26.0,
25.9, 25.8, 25.73, 25.72, 23.8, 23.71, 23.67, 23.6, 23.42, 23.37,
C74H95ClNaO7S3Si, 1277.5590, found 1277.5583.
Compound 24
To a solution of 12 (88.0 mg, 0.0795 mmol) and 3b (83.5 mg,
0.0665 mmol) in DMF (0.517 mL) was added dropwise t-
BuOK (9.37 mg, 0.0834 mmol) solution in DMF (0.278 mL)
at -50 ˚C. After being stirred for 50 min at -50 ˚C, to the
mixture was added dropwise t-BuOK (10.1 mg, 0.0900
mmol) solution in DMF (0.30 mL) at -50 ˚C. After being
stirred for 1.5 h at -50 ˚C, the mixture was diluted with
hexane/AcOEt = 1/1 and quenched with saturated NH4Cl
aq. After extraction, the organic layer was washed with
water and dried over Na2SO4. After concentration in vacuo,
the residue was purified by silica gel column
chromatography (toluene/AcOEt = 100/0 to 95/5 to 90/10
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23.34, 23.29, 23.27, 23.24, 23.21, 23.0, 17.7, 16.2, 15.9; HRMS BuOK (3.40 mg, 0.0303 mmol) solution in DMF (0.101 mL)
1
2
3
4
5
6
7
8
(ESI-LTQ-Orbitrap) m/z [M+Na]+ calculated for
C122H158NaO15S7, 2109.9538, found 2109.9509.
at -50 ˚C. After being stirred for 1 h at -50 ˚C, to the mixture
was added dropwise t-BuOK (2.70 mg, 0.0241 mmol)
solution in DMF (0.080 mL) at -50 ˚C. After being stirred
for 1.5 h at -50 ˚C, the mixture was diluted with
hexane/AcOEt = 1/1 and quenched with saturated NH4Cl
aq. After extraction, the organic layer was dried over
Na2SO4. After concentration in vacuo, the residue was
purified by silica gel column chromatography
(toluene/AcOEt = 100/0 to 90/10 to 85/15 to 80/20 to 75/25
To a solution of the obtained alcohol (70.4 mg, 0.0337
mmol), LiCl (8.6 mg, 0.202 mol) and 2,4,6-collidine (35.7
L, 0.270 mmol) in DMF (0.67 mL) was added
methanesulfonyl chloride (15.6 L, 0.202 mmol) at 0 ˚C.
After being stirred for 3 h at rt, to the mixture were added
2,4,6-collidine (35.7 L, 0.270 mmol) and methanesulfonyl
chloride (15.6 L, 0.202 mmol) at 0 ˚C. After being stirred
for 1.5 h at rt, the mixture was diluted with hexane/AcOEt
= 1/1 and quenched with saturated NaHCO3 aq. After
extraction, the organic layer was washed with saturated
NH4Cl aq. and water, and dried over Na2SO4. After
concentration in vacuo, the crude was obtained as a yellow
solid. To a solution of the crude in DMF (0.537 mL) was
added NaSO2Ph (10.7 mg, 0.0652 mmol) at 0 ˚C. After being
stirred for 1.5 h at rt, to the mixture was added NaSO2Ph
(10.9 mg, 0.0664 mmol) at 0 ˚C. After being stirred for 6 h
at rt, the mixture was diluted with hexane/AcOEt = 1/1 and
quenched with 1 M HCl aq. After extraction, the organic
layer was washed with saturated NaHCO3 aq. and water,
and dried over Na2SO4. After concentration in vacuo, the
residue was purified by silica gel column chromatography
(Toluene/AcOEt = 100/0 to 90/10 to 85/15 to 80/20 to 75/25
9
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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54
55
56
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58
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60
1
to 60/40) to afford 26 as a colorless oil (30.0 mg, 57%). H
NMR (500 MHz, CDCl3) δ 7.89-7.79 (m, 18H), 7.72-7.58 (m,
14H), 7.56-7.46 (m, 17H), 7.45-7.34 (m, 6H), 5.22-4.82 (m,
19H), 3.96-3.75 (m, 9H), 3.73-3.61 (m, 2H), 2.84 (d, J = 14.5
Hz, 1H), 2.73-2.60 (m, 8H), 2.55-2.31 (m, 8H), 2.22 (t, J = 12.2
Hz, 1H), 1.97-1.30 (m, 100H), 1.12 (s, 3H), 1.05 (s, 9H), 0.78
(d, J = 6.2 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 144.9,
144.72, 144.69, 144.6, 144.5, 138.0, 137.9, 135.6, 134.2, 133.7,
133.5, 133.4, 132.0, 130.9, 130.7, 130.5, 130.3, 129.54, 129.45,
129.4, 129.3, 129.2, 128.9, 128.8, 128.7, 128.0, 127.9, 127.6, 127.3,
123.5, 117.90, 117.86, 117.4, 63.5, 63.3, 63.1, 63.0, 62.9, 62.2,
39.7, 39.6, 37.33, 37.29, 32.0, 31.9, 31.8, 31.6, 30.24, 30.22,
30.03, 29.99, 29.95, 29.70, 29.66, 29.22, 29.18, 26.9, 26.3,
26.0, 25.9, 25.8, 25.7, 23.59, 23.55, 23.42, 23.36, 23.3, 23.24,
23.22, 19.52, 19.49, 19.2, 17.7, 16.3, 15.9; HRMS (ESI-LTQ-
Orbitrap) m/z [M+Na]+ calculated for C170H218NaO19S9Si,
2902.3240, found 2902.3191.
1
to 60/40) to give 25 as white powder (50.5 mg, 68%). H
NMR (500 MHz, CDCl3) δ 7.90-7.79 (m, 16H), 7.68-7.58 (m,
8H), 7.57-7.47 (m, 16H), 5.19 (t, J =7.8 Hz, 1H), 5.09 (q, J =
8.3 Hz, 1H) 5.04-4.83 (m, 14H), 3.89-3.75 (m, 9H), 2.85 (d, J
= 13.0 Hz, 1H), 2.72-2.58 (m, 6H), 2.49-2.32 (m, 6H), 2.23 (t,
J = 12.3 Hz, 1H), 1.94-1.29 (m, 80H), 1.11 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 144.9, 144.8, 144.7, 144.6, 138.9, 137.9,
133.7, 133.6, 133.5, 133.4, 130.8, 130.7, 130.5, 129.3, 129.2, 129.0,
128.9, 128.8, 128.7, 128.5, 128.2, 127.9, 125.3, 123.5, 117.9, 117.8,
117.4, 111.2, 63.5, 63.1, 62.9, 55.9, 39.7, 31.9, 31.83, 31.76, 30.03,
29.98, 29.95, 26.3, 26.0, 25.8, 25.7, 23.6, 23.5, 23.43, 23.38,
23.33, 23.25, 17.7, 16.3, 15.9; HRMS (ESI-LTQ-Orbitrap) m/z
[M+Na]+ calculated for C128H162NaO16S8, 2233.9521, found
2233.9473.
Compound 1b
To a solution of 26 (24.6 mg, 8.62 mol) in THF (0.862 mL)
was added TBAF (1 M in THF, 22.6 L, 0.0226 mmol) at 0
˚C. After being stirring for 1 day at rt, the mixture was
diluted with hexane/AcOEt = 1/1 and quenched with brine.
After extraction, the organic layer was dried over Na2SO4.
After concentration in vacuo, the residue was purified by
silica gel column chromatography (Toluene/AcOEt = 90/10
to 80/20 to 75/25 to 70/30) to afford the alcohol as a
1
colorless oil (18.3 mg, 80%). H NMR (500 MHz, CDCl3) δ
7.86-7.80 (m, 18H), 7.66-7.60 (m, 9H), 7.55-7.48 (m, 18H),
5.21 (d, J = 8.5 Hz, 1H), 5.05-4.84 (m, 18H), 3.91-3.74 (m, 9H),
3.72-3.61 (m, 2H), 2.85 (d, J = 14.1 Hz, 1H), 2.75-2.59 (m, 8H),
2.49-2.32 (m, 8H), 2.22 (t, J = 12.3 Hz, 1H), 1.95-1.86 (m, 4H),
1.77-1.24 (m, 96H), 1.12 (s, 3H), 0.89 (d, J = 6.3 Hz, 3H);
Compound 26
To a solution of 25 (44.8 mg, 0.0202 mmol) and 4 (12.8 mg,
0.0182 mmol) in DMF (0.0990 mL) was added dropwise t-
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13C{1H} NMR (126 MHz, CDCl3) δ 144.9, 144.73, 144.70,
The Supporting Information is available free of charge at
http://pubs.acs.org.
1
2
144.66, 144.62, 144.60, 144.57, 144.54, 144.51, 138.03, 138.01,
137.93, 137.87, 133.7, 133.6, 133.5, 133.4, 130.89, 130.87, 130.7,
130.5, 129.83, 129.79, 129.3, 129.2, 128.9, 128.8, 128.7, 127.9,
123.5, 117.9, 117.8, 117.42, 117.40, 63.5, 63.1, 62.9, 61.1, 61.0, 40.0,
39.8, 39.7, 37.34, 37.30, 37.18, 37.16, 31.9, 31.8, 30.0, 29.9, 29.3,
29.21, 29.20, 26.34, 26.32, 26.0, 25.9, 25.8, 25.7, 25.57, 25.55,
25.4, 23.9, 23.43, 23.37, 23.3, 23.2, 19.62, 19.58, 17.7, 16.28,
16.27, 15.9; HRMS (ESI-LTQ-Orbitrap) m/z [M+Na]+
calculated for C154H200NaO19S9, 2664.2062, found 2664.1992.
To a solution of the obtained alcohol (12.8 mg, 4.84 mol)
and (dppp)2PdCl2 (2.90 mg, 0.00492 mmol) in THF (0.50
mL) was added super hydride (1 M in THF, 0.090 mL, 0.090
mmol) at 0 ˚C. After being stirred for 1.5 h at 0 ˚C, to the
mixture was added super hydride (1 M in THF, 0.090 mL,
0.090 mmol) at 0 ˚C. After being stirred for 3 h at 0 ˚C, to
the mixture was added super hydride (1 M in THF, 0.090
mL, 0.090 mmol) at 0 ˚C. After being stirring for 2.5 h at 0
˚C, to the mixture was added super hydride (1 M in THF,
0.100 mL, 0.100 mmol) at 0 ˚C. After being stirring for 2.5 h
at 0 ˚C, to the mixture was added super hydride (1 M in
THF, 0.150 mL, 0.150 mmol) at 0 ˚C. After being stirring for
11 h at 0 ˚C, the mixture was diluted with hexane/AcOEt =
1/1 and quenched with saturated NH4Cl aq. After extraction,
the organic layer was dried over Na2SO4. After
concentration in vacuo, the residue was purified by silica
gel column chromatography (hexane/AcOEt = 100/0 to
95/5) to afford 1b as a colorless oil (5.5 mg, 82%). 1H NMR
(500 MHz, CDCl3) δ 5.28 (t, J = 6.2 Hz, 1H), 5.14-5.08 (m,
18H), 3.71-3.63 (m, 2H), 2.01-1.96 (m, 74H), 1.71-1.60 (m,
60H), 1.42-1.31 (m, 3H), 1.21-1.14 (m, 2H), 0.90 (d, J = 6.5 Hz,
3
4
5
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7
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Copies of NMR spectra for all products and
supporting tables (Table S1 and S2)
AUTHOR INFORMATION
Corresponding Authors
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Yoshiyuki Manabe - Department of Chemistry, Graduate
School of Science, Osaka University, 1-1 Machikaneyama-cho,
Toyonaka, Osaka 560-0043, Japan; Core for Medicine and
Science Collaborative Research and Education, Project
Research Center for Fundamental Sciences, Osaka University,
1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan;
orcid.org/0000-0002-5515-3923;
Email:
manabey12@chem.sci.osaka-u.ac.jp
Koichi Fukase - Department of Chemistry, Graduate School
of Science, Osaka University, 1-1 Machikaneyama-cho,
Toyonaka, Osaka 560-0043, Japan; Core for Medicine and
Science Collaborative Research and Education, Project
Research Center for Fundamental Sciences, Osaka University,
1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan;
orcid.org/0000-0001-8844-0710;
koichi@chem.sci.osaka-u.ac.jp
Email:
Authors
Kohtaro Hirao - Department of Chemistry, Graduate School
of Science, Osaka University, 1-1 Machikaneyama-cho,
Toyonaka, Osaka 560-0043, Japan
Risako Ono - Department of Chemistry, Graduate School of
Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka,
Osaka 560-0043, Japan
13
3H); C{1H} NMR (175 MHz, CDCl3) δ 137.33, 137.29, 135.4,
Seiji Masui - Department of Chemistry, Graduate School of
Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka,
Osaka 560-0043, Japan
135.2, 135.1, 135.01, 134.95, 134.9, 134.2, 131.3, 125.8, 125.5, 125.4,
125.1, 125.04, 124.95, 124.4, 124.24, 124.16, 61.2, 40.0, 39.8, 39.7,
37.6, 37.5, 36.4, 35.2, 32.2, 32.0, 31.9, 29.72, 29.67, 29.4, 29.2,
26.8, 26.7, 26.4, 25.7, 25.3, 23.5, 23.4, 19.5, 17.7, 16.0, 14.1;
[]D27 -2 (c = 0.10, CHCl3); HRMS (ESI-LTQ-Orbitrap) m/z
[M+Na]+ calculated for C100H164NaO, 1404.2674, found
1404.2673.
Haruyuki Atomi - Department of Synthetic Chemistry and
Biological Chemistry, Graduate School of Engineering, Kyoto
University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
ASSOCIATED CONTENT
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Page 16 of 17
15. Liu, F.; Vijayakrishnan, B.; Faridmoayer, A.; Taylor, T. A.;
Notes
Parsons, T. B.; Bernardes, G. J. L.; Kowarik, M.; Davis, B. G.,
Rationally Designed Short Polyisoprenol-Linked PglB
Substrates for Engineered Polypeptide and Protein N-
Glycosylation. J. Am. Chem. Soc. 2014, 136 (2), 566-569.
16. Massarweh, A.; Bosco, M.; Iatmanen-Harbi, S.; Tessier, C.;
Auberger, N.; Busca, P.; Chantret, I.; Gravier-Pelletier, C.;
Moore, S. E. H., Demonstration of an oligosaccharide-
diphosphodolichol diphosphatase activity whose subcellular
localization is different than those of dolichyl-phosphate-
dependent enzymes of the dolichol cycle. J. Lipid Res. 2016,
57 (6), 1029-1042.
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported in part by JSPS KAKENHI
Grant Number 15H05836 in Middle Molecular Strategy, JSPS
KAKENHI Grant Number 16H01885, JSPS KAKENHI Grant
Number 16H05924, JSPS KAKENHI Grant Number 18H03934,
JSPS KAKENHI Grant Number 19KK0145, JSPS KAKENHI
Grant Number 20H00404, JSPS KAKENHI Grant Number
20K05727, and JSPS KAKENHI Grant Number 20H04709.
9
17. Napiórkowska, M.; Boilevin, J.; Sovdat, T.; Darbre, T.;
Reymond, J.-L.; Aebi, M.; Locher, K. P., Molecular basis of
lipid-linked oligosaccharide recognition and processing by
bacterial oligosaccharyltransferase. Nat. Struct. Mol. Biol.
2017, 24 (12), 1100-1106.
18. Ramírez, A. S.; Boilevin, J.; Lin, C.-W.; Ha Gan, B.; Janser, D.;
Aebi, M.; Darbre, T.; Reymond, J.-L.; Locher, K. P., Chemo-
enzymatic synthesis of lipid-linked GlcNAc2Man5
oligosaccharides using recombinant Alg1, Alg2 and Alg11
proteins. Glycobiology 2017, 27 (8), 726-733.
19. Biellmann, J. F.; Ducep, J. B., Synthese du squalene par
couplage queue a queue. Tetrahedron Lett. 1969, 10 (42),
3707-3710.
20. Altman, L. J.; Ash, L.; Kowerski, R. C.; Epstein, W. W.; Larsen,
B. R.; Rilling, H. C.; Muscio, F.; Gregonis, D. E., Prephytoene
pyrophosphate. New intermediate in the biosynthesis of
carotenoids. J. Am. Chem. Soc. 1972, 94 (9), 3257-3259.
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