Stereoselective synthesis of the right-hand cores of 16-methylated oxazolomycins

Article abstract of DOI:10.1016/j.tet.2017.12.036

The right-hand heterocyclic cores of oxazolomycins having either 16R or 16S-methyl group configurations on the β-lactones were stereoselectively synthesized from the common intermediate utilized for our previous syntheses of neooxazolomycin and oxazolomycin A. In addition, the right-hand segment required for the synthesis of KSM-2690 and lajollamycin members was also synthesized in a stereoselective manner.

Full text of DOI:10.1016/j.tet.2017.12.036

Accepted Manuscript
Stereoselective synthesis of the right-hand cores of 16-methylated oxazolomycins
Kohei Eto, Jun Ishihara, Susumi Hatakeyama
PII:
S0040-4020(17)31304-2
10.1016/j.tet.2017.12.036
TET 29192
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 November 2017
Revised Date: 13 December 2017
Accepted Date: 16 December 2017
Please cite this article as: Eto K, Ishihara J, Hatakeyama S, Stereoselective synthesis of the right-hand
cores of 16-methylated oxazolomycins, Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.036.
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Stereoselective synthesis of the right-hand
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Kohei Eto, Jun Ishihara, Susumi Hatakeyama

1
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Tetrahedron
journal homepage: www.elsevier.com
Stereoselective synthesis of the right-hand cores of 16-methylated oxazolomycins
Kohei Etoa , Jun Ishiharaa and Susumi Hatakeyamab,
a Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
b Medical Innovation Center, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The right-hand heterocyclic cores of oxazolomycins having either 16R or 16S-methyl group
configurations on the β-lactones were stereoselectively synthesized from the common
intermediate utilized for our previous syntheses of neooxazolomycin and oxazolomycin A. In
addition, the right-hand segment required for the synthesis of KSM-2690 and lajollamycin
members was also synthesized in a stereoselective manner.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Oxazolomycins
Antibiotics
Stereoselective synthesis
———
Corresponding author. e-mail: susumi@nagasaaki-u.ac.jp

2
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1. Introduction
The oxazolomycin family of antibiotics identified to date
includes neooxazolomycin,1 oxazolomycins A-C,1,2 16-
methyloxazolomycin,3 curromycins A and B,4 KSM-2690 B and
C,5 lajollamycin,6 and lajollamycin B-D7 (Figure 1). These
oxazolomycins are of great interest8 due to the synthetically
challenging structures and wide-ranging biological activities such
as antibacterial, antiviral, and antitumor activities.9 The
characteristic β-lactone-γ-lactam motif draws much attention due
to the structural similarity with the pharmacophores of omuralide
and salinosporamide A, representative 20S proteasome
inhibitors.10 Therefore, a number of efforts have been dedicated
towards the synthesis of oxazolomycins.8,11,12 However, among
these twelve members, only neooxazolomycin13,14 and
oxazolomycin A15 have been successfully synthesized so far. In
this context, the development of a comprehensive synthetic
methodology applicable to most members of the oxazolomycin
family is in high demand.
Scheme 1. Right-hand cores and segment.
2. Results and discussion
We first examined the stereoselective introduction of a methyl
group at the C16 position of the neooxazolomycin core 1
(Scheme 2).
Fig. 1. Oxazolomycin family of antibiotics.
We utilized neooxazolomycin core
1 as a common
intermediate for the constructions of the key right-hand segments
2 and 3 in our convergent syntheses of neooxazolomycin and
oxazolomycin A13b,15 (Scheme 1). To further extend this
methodology to the synthesis of other oxazolomycins, we studied
the stereoselective constructions of the right-hand spiro-β-
lactone-γ-lactam cores 4 and 5 having either 16S or 16R-methyl
group configurations from 1, which are found in 16-methylated
members of the oxazolomycin family. Donohoe and co-workers
reported the synthesis of the right-hand core having a 16R-methyl
group, and this has been the only approach for 16-methylated
oxazolomycins.16 In addition, we studied the synthesis of the
right-hand segment 6 which are required for the syntheses of
KSM-2690 and lajollamycin members.
Scheme 2. Synthesis of the right-hand core 4 with a 16S-
methyl group.

3
Upon Dess-Martin oxidation followed by Grignard reaction
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using methylmagnesium bromide at –78 °C in THF, 1 was found
to afford 16S-isomer 7 and 16R-isomer 8 in a ratio of 3:1 in 65%
total yield. The reaction using methyllithium in Et2O at –40 °C
produced a 4:1 mixture of 7 and 8 in low yield (25%). In this
case, the lactone carbonyl also partially reacted with
methyllithium. The C16 configurations of both isomers were
unambiguously determined by the modified Mosher’s method.17
The preferential production of 7 over 8 in the Grignard reaction
can be explained by assuming chelated intermediate 918 where
the si face attack of MeMgBr is favored because the re face is
Thus, compound 1 was protected as its MOM ether to give 15
quantitatively. The lactone ring of 15 was reduced with NaBH4 to
give the corresponding triol, the primary alcohol of which was
protected as its TIPS ether to afford 16 in 94% yield. Methyl
etherification of 16 was undertaken in the same manner as
described for that of 11 to give 17 in 70% yield. ZrCl4-mediated
cleavage of the MOM protecting group of 17 occurred cleanly to
afford 18 in 86% yield. After Swern oxidation of 18, the
aldehyde was subjected to Grignard reaction using
methylmagnesium bromide at –78 °C in THF to give 19 as a 1:11
mixture of 16S and 16R-isomers in 69% yield. In this case, the
observed high diastereoselectivity can be understood by
assuming chelated intermediate 20 where the highly bulky
(TIPSoxy)methyl group hinders the si face attack of MeMgBr.
Without separation of the stereoisomers, 19 was desilylated with
TBAF to give triol 21 quantitatively, the primary alcohol of
which was selectively converted into a carboxylic acid by
TEMPO oxidation followed by Pinnick oxidation to afford
hydroxy acid 22. In the same manner described for the
condensation of 14, 20 was treated with HATU and Hünig’s base
in THF at room temperature to give 4 and 5 in 6% and 61%
yields in 3 steps, respectively, after chromatographic separation.
It is important to note that compound 4 showed an NOE between
16-Me and N-Me as observed for 16-methyloxazolomycin3a but
compound 5 did not; instead, it exhibited an NOE between 16-H
and N-Me as observed for lajollamycin6 (Fig. 2).
more
shielded
by
the
sterically
demanding
N-
methylpyrrolidinone moiety. The major isomer 7 was then
converted to MOM ether 10 which, upon NaBH4 reduction
followed by silylation, gave diol 11 in 64% yield. The
subsequent methyl etherification of 11 was achieved using
Meerwein’s reagent and a proton sponge19 to give methyl ether
12, desilylation of which afforded 13 in 67% yield. Upon Jones
oxidation followed by Pinnick oxidation and ZrCl4-mediated
cleavage of the MOM protecting group,20 13 afforded hydroxy
acid 14 in 61% yield. Treatment of 14 with 1-
[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-
b]pyridinium 3-oxide hexafluorophosphate (HATU)21 and N,N-
diisopropylethylamine (Hünig’s base) in THF at room
temperature allowed us to obtain the right-hand core 4 with a
methyl group of 16S configuration in 74% yield.
On the other hand, the right-hand core 5 with a methyl group
of 16R configuration was also prepared from the
neooxazolomycin core 1 stereoselectively (Scheme 3).
Fig. 2. Definitive NOEs.
With intention of synthesizing both KSM-2690 and
lajollamycin members, we then investigated the preparation of
the right-hand segment 6 following the methodology we have
developed in the synthesis of oxazolomycin A15 (Scheme 4).
Thus, crude hydroxy acid 22 obtained from triol 21 was
selectively
esterified
with
triisopropylsilyloxymethyl(dodecyl)sulfane22 in the presence of
CuBr2, tetra-n-butylammonium bromide, and triethylamine to
give 23 as an epimeric mixture in 68% yield from 21. After
protection of 23 as the dioxasilinane and hydrogenolytic
debenzylation of 24, the 16S/R-epimers became separable to
afford 25 and 26 in 8% and 91% yields, respectively. Dess-
Martin oxidation of 26 gave aldehyde 27 in 90% yield, which
was then subjected to Nozaki-Hiyama-Takai-Kishi reaction23,24
with dienyl iodide 28 to produce a 1:1 mixture of 6 and its 7S-
epimer. The epimeric mixture was then successively subjected to
Dess-Martin oxidation to give ketone 29, which, upon L-
selectride reduction, afforded a 16:1 mixture of 6 and the 7S-
epimer. Chromatographic separation of the epimeric mixture
allowed us to obtain the desired right-hand segment 6 in 31%
overall yield from 27.
Scheme 3. Synthesis of the right-hand core 5 with a 16R-
methyl group.

4
Tetrahedron
layer chromatography (TLC) was performed using precoated
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silica gel plates (0.2 or 0.5 mm thickness). Column
chromatography was performed using silica gel (particle size
100-210 µm (regular) or 40-50 µm (flash)). Optical rotations
were recorded on digital polarimeter at ambient temperature.
Infrared spectra (FTIR) were measured on a Fourier transform
1
infrared spectrometer. H NMR (400 MHz) and 13C NMR (100
MHz) spectra were measured using CDCl3 and as solvent, and
chemical shifts are reported as δ values in ppm based on internal
internal (CH3)4Si (0.00 ppm, 1H) or solvent peak CHCl3 (1H: 7.26
ppm; 13C: 77.0 ppm). Mass (MS) and high resolution mass
(HRMS) spectra were taken in EI (dual focusing sector field) or
FAB (dual focusing sector field) mode.
4.2. (3R,3aS,4S,6aR)-4-((R)-3-(Benzyloxy)-2-methylpropyl)-
dihydro-3a-hydroxy-6a-((S)-1-hydroxyethyl)-1,3-dimethyl-1H-
furo[3,4-b]pyrrole-2,6(3H,6aH)-dione (7) and (3R,3aS,4S,6aR)-
4-((R)-3-(benzyloxy)-2-methylpropyl)-dihydro-3a-hydroxy-6a-
((R)-1-hydroxyethyl)-1,3-dimethyl-1H-furo[3,4-b]pyrrole-
2,6(3H,6aH)-dione (8)
To a solution of 1 (133 mg, 0.35 mmol) in CH2Cl2 (3.5 mL)
were added Dess-Martin periodinane (373 mg, 0.88 mmol) and
NaHCO3 (74 mg, 0.88 mmol) at room temperature. After being
stirred at room temperature for 2.5 h, the reaction was quenched
with 10% Na2S2O3 (5.0 mL) at 0 °C. The mixture was extracted
with AcOEt and the extract was washed with saturated NaHCO3,
dried, and concentrated to give the corresponding aldehyde (138
mg) as a yellow oil.
The crude aldehyde (138 mg) was dissolved in THF (2.5 mL)
and the mixture was cooled to –78 °C. MeMgBr (3.0 M in Et20;
0.93 mL, 2.81 mmol) was then added and the mixture was stirred
at –78 °C for 16 h. The reaction was quenched by the addition of
saturated NH4Cl (3 mL) at –78 °C. The mixture was extracted
with AcOEt, washed with saturated NaHCO3, dried, and
concentrated to give a yellow oil (112 mg), the 1H NMR of which
showed the ratio of 16S- and 16R-epimers to be 1:3. Purification
of the crude product by flash column chromatography (SiO2 6.0
g, hexane:AcOEt = 2:1 to 1:2) gave 7 (64.7 mg, 47%) and 8 (25.4
mg, 18%) each as a yellow oil.
Scheme 4. Synthesis of the right-hand segment 6 for KSM-
2690 and lajollamycin members.
22
1
Compound 7: [α]D +34.5 (c 0.89, CHCl3); H NMR (400
MHz, CDCl3) δ 7.38-7.29 (m, 5H), 4.53 (s, 2H), 4.34 (brs, 1H),
4.28-4.22 (m, 2H), 3.43 (dd, J = 4.6, 8.8 Hz, 1H), 3.27 (t, J = 8.4
Hz, 1H), 2.94 (s, 3H), 2.81 (brs, 1H), 2.49 (q, J = 7.6 Hz, 1H),
2.03 (dt, J = 14.0, 5.2 Hz, 1H), 1.85-1.80 (m, 1H), 1.74 (dt, J =
14.0, 6.4 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 7.6 Hz,
3H), 1.01 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
175.5, 171.3, 137.3, 128.5, 128.0, 127.9, 86.7, 81.7, 75.2, 73.4,
67.1, 46.0, 32.3, 30.1, 27.0, 18.6, 18.3, 11.7; FTIR (neat) 3383,
2932, 1769, 1679, 1454, 1394, 1233, 1104, 1013, 916 cm–1; MS
(EI) m/z 91(100), 157, 289, 307, 392 [(M+1)+]; HRMS (EI) calcd
for C21H29NO6 [(M+1)+] 392.2073, found 392.2076.
3. Conclusion
The stereoselective routes to right-hand heterocyclic cores of
oxazolomycins having either 16S- or 16R-methyl group
configurations have been developed starting from the
neooxazolomycin core 1, which relied on a chelation-controlled
Grignard reaction in a pyrrolidinone aldol system. Furthermore,
the right-hand segment 6 required for the syntheses of KSM-
2690 and lajollamycin members has been synthesized in highly
stereoselective manner for the first time. The synthesis of
lajollamycin employing 6 is currently under investigation.
23
1
Compound 8: [α]D +43.6 (c 0.68, CHCl3); H NMR (400
MHz, CDCl3) δ 7.38-7.29 (m, 5H), 4.78 (s, 1H), 4.53 (s, 2H),
4.49 (q, J = 7.2 Hz, 1H), 4.25 (t, J = 7.0 Hz, 1H), 3.44 (dd, J =
4.6, 9.0 Hz, 1H), 3.29 (dd, J = 8.4, 9.0 Hz, 1H), 3.04 (d, J = 7.2
Hz, 1H), 2.83 (s, 3H), 2.52 (q, J = 7.6 Hz, 1H), 2.00 (ddd, J =
14.4, 7.2, 5.2 Hz, 1H), 1.86-1.79 (m, 1H), 1.72 (dt, J = 14.4, 6.8
Hz, 1H), 1.32 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 7.6 Hz, 3H), 1.01
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 172.3,
137.3, 128.5, 128.0, 127.9, 87.4, 81.4, 75.2, 73.4, 72.4, 67.0,
46.2, 32.5, 30.0, 26.1, 18.3, 17.6, 11.3; FTIR (neat) 3355, 2940,
2873, 1770, 1673, 1454, 1376, 1231, 1104, 1006 cm–1; MS (EI)
m/z 91, 136, 154(100), 307, 392 [(M+1)+]; HRMS (EI) calcd for
C21H29NO6 [(M+1)+] 392.2073, found 392.2085.
4. Experimental section
4.1. General
Where appropriate, reactions were performed in flame-dried
glassware under argon atmosphere. All extracts were dried over
MgSO4 and concentrated by rotary evaporation below 30 °C at
25 Torr. Commercial reagents and solvents were used as supplied
with
following
exceptions.
Acetonitrile
(MeCN),
dichloromethane (CH2Cl2), 1,2-dichloroethane (ClCH2CH2Cl),
and dimethyl sulfoxide (DMSO) were distilled from CaH2. Thin

5
4.3. (3R,3aS,4S,6aS)-4-((R)-3-(Benzyloxy)-2-methylpropyl)-
dihydro-3a-hydroxy-6a-((S)-1-(methoxymethoxy)ethyl)-1,3-
dimethyl-1H-furo[3,4-b]pyrrole-2,6(3H,6aH)-dione (10)
4.5. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3-
ACCEPTED MANUSCRIPT
methylbutyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy-
5-((S)-1-(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one
(12)
To an ice-cooled solution of 7 (60.6 mg, 0.15 mmol) in
ClCH2CH2Cl (1.5 mL) were added N,N-diisopropylethylamine
(0.22 mL, 1.84 mmol) and methoymethyl chloride (0.10 mL,
0.92 mmol). The mixture was heated under reflux for 9 h, and
saturated NaHCO3 (5.0 mL) was added with cooling in an ice
bath. The mixture was extracted with AcOEt, washed with brine,
dried, and concentrated. The residue was purified by column
chromatography (SiO2 5.0 g, hexane:AcOEt = 2:1 to 3:2) to give
10 (58.2 mg, 87%) as a yellow oil. [α] D 22 +48.9 (c 1.08, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 4.76 (d, J = 7.1
Hz, 1H), 4.53 (d, J = 7.1 Hz, 1H), 4.50 (s, 2H), 4.35-4.30 (m,
2H), 3.38 (dd, J = 5.2, 9.3 Hz, 1H), 3.32-3.28 (m, 1H), 3.31 (s,
3H), 2.96 (s, 1H), 2.90 (s, 3H), 2.44 (q, J = 7.6 Hz, 1H), 1.96 (m,
1H), 1.92 (dd, J = 14.4, 4.1 Hz, 1H), 1.74 (dd, J = 14.4, 5.6 Hz,
1H), 1.43 (d, J = 6.8 Hz, 3H), 1.27 (d, J = 7.6 Hz, 3H), 1.02 (d, J
= 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.7, 170.9,
138.2, 128.4, 127.6, 94.6, 87.3, 81.9, 74.8, 74.5, 73.1, 69.3, 56.3,
45.7, 31.7, 30.3, 25.3, 18.0, 15.4, 11.0; FTIR (neat) 3418, 2945,
1770, 1698, 1454, 1386, 1151, 1106, 1033, 918 cm–1; MS (EI)
m/z 136, 154 (100), 307, 404, 436 [(M+1)+]; HRMS (EI) calcd
for C23H33NO7 [(M+1)+] 436.2336, found 436.2371.
To a mixture of 11 (49 mg, 0.09 mmol) and molecular sieves
4 Å (200 mg, preactivated at 200 °C for 3 h in vacuo) in CH2Cl2
(1.5 mL) were added trimethyloxonium tetrafluoroborate (106
mg, 0.72 mmol) and proton sponge (163 mg, 0.76 mmol) at 0 °C,
and the mixture was stirred at 0 °C. After 8 h and 20 h,
trimethyloxonium tetrafluoroborate (106 mg, 0.72 mmol) and
proton sponge (163 mg, 0.76 mmol) were added each time, and
stirring was continued at 0 °C for additional 8 h. The mixture was
filtered through Celite and the filter pad was washed with AcOEt.
The filtrate and washings were washed with 1 M HCl, saturated
NaHCO3, and brine, dried, and concentrated. The residue was
purified by preparative TLC (hexane:AcOEt = 1:1) to give 12
22
(36.2 mg, 71%) as a colorless oil. [α]D +17.2 (c 0.95, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 5H), 4.66 (d, J = 6.8
Hz, 1H), 4.50 (d, J = 6.8 Hz, 1H), 4.48 (s, 2H), 4.31 (q, J = 6.4
Hz, 1H), 4.08 (d, J = 11.5 Hz, 1H), 3.81 (dd, J = 3.9. 5.9 Hz, 1H),
3.64 (d, J = 11.5 Hz, 1H), 3.41-3.36 (m, 1H), 3.39 (s, 3H), 3.37
(s, 3H), 3.26 (dd, J = 6.8. 8.9 Hz, 1H), 2.83 (s, 3H), 2.74 (s, 1H),
2.37 (q, J = 7.4 Hz, 1H), 2.02 (dt, J = 15.0, 5.9 Hz, 1H), 1.85-
1.80 (m, 1H), 1.32 (d, J = 6.4 Hz, 3H), 1.29-1.22 (m, 1H), 1.19
(d, J = 7.4 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H), 0.86 (s, 9H), 0.07
(s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.9,
138.4, 128.3, 127.4, 95.6, 81.6, 75.6, 75.5, 75.3, 73.0, 61.3, 55.9,
55.8, 43.2, 33.1, 31.8, 27.8, 25.8, 18.1, 17.9, 10.2, -5.4, -5.6;
FTIR (neat) 3450, 2951, 2892, 1690, 1466, 1255, 1091, 1029,
838, 420 cm–1; MS (EI) m/z 85, 91(100), 154, 298, 538, 568
[(M+1)+]; HRMS (EI) calcd for C30H53NO7Si [(M+1)+] 568.3669,
found 568.3699.
4.4. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-hydroxy-3-
methylbutyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy-
5-((S)-1-(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one
(11)
To an ice-cooled solution of 10 (52.9 mg, 0.12 mmol) in THF-
EtOH (1:1) (1.2 mL) was added NaBH4 (23 mg, 0.61 mmol), and
the mixture was stirred at room temperature for 3 h. NaBH4 (14
mg, 0.36 mmol) was added again and the mixture was stirred at
room temperature for 21 h. The mixture was cooled in an ice
bath, and saturated NH4Cl (5.0 mL) was added. The mixture was
extracted with AcOEt, washed with brine, dried, and
concentrated. The residue was dissolved in MeOH (20 mL) and
evaporated to dryness to remove the moisture content. As a
result, the corrsponding triol (48.1 mg) was obtained as a yellow
oil.
4.6. (3R,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3-
methylbutyl)-4-hydroxy-5-(hydroxymethyl)-5-((S)-1-
(methoxymethoxy)ethyl)-1,3-dimethylpyrrolidin-2-one (13)
To a solution of 12 (36 mg, 0.064 mmol) in THF (1.0 mL)
was added tetra-n-butylammonium fluoride (1.0 M in THF, 0.19
mL, 0.19 mmol), and the mixture was stirred at room temperature
for 2 h. The mixture was diluted with saturated NH4Cl (3.0 mL)
and extracted with AcOEt. The extract was washed with brine,
dried, and concentrated. The residue was purified by preparative
The crude triol (48.1 mg) was dissolved in CH2Cl2 (1.2 mL)
and cooled to –78 °C. Then, 2,6-lutidine (57 ꢀL, 0.49 mmol) and
tert-butyldimethylsilyl trifluoromrthanesulfonate (56 ꢀL, 0.24
mmol) were added, and the mixture was stirred at–78 °C for 22 h.
The reaction was quenched with saturated NaHCO3 (3.0 mL) and
the mixture was allowed to warm to room temperature. The
mixture was extracted with AcOEt, washed with 1 M HCl,
saturated NaHCO3, and brine, dried, and concentrated. The
residue was purified by flash column chromatography (SiO2 4.0
g, hexane:AcOEt = 1:1) to give 11 (49 mg, 74%, 2 steps) as a
23
TLC (AcOEt) to give 13 (25 mg, 94%) as a colorless oil. [α]D
1
+20.8 (c 0.70, CHCl3); H NMR (400 MHz, CDCl3) δ 7.35-7.27
(m, 5H), 4.67 (d, J = 7.0 Hz, 1H), 4.53 (d, J = 7.0 Hz, 1H), 4.48
(s, 2H), 4.20 (q, J = 6.3 Hz, 1H), 3.80 (d, J = 5.6 Hz, 1H), 3.74 (t,
J = 5.0 Hz, 1H), 3.44 (s, 3H), 3.41-3.34 (m, 2H), 3.36 (s, 3H),
3.16 (s, 1H), 2.88 (s, 3H), 2.55 (q, J = 7.6 Hz, 1H), 2.10-2.03 (m,
1H), 1.98-1.89 (m, 1H), 1.45-1.39 (m, 1H), 1.32 (d, J = 6.3 Hz,
3H), 1.12 (d, J = 7.6 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 176.6, 138.3, 128.3, 127.6, 127.5, 95.4,
82.5, 81.5, 75.9, 75.2, 75.0, 73.2, 60.7, 57.8, 56.0, 43.2, 35.0,
32.2, 27.3, 18.2, 17.6, 9.6; FTIR (neat) 3353, 2940, 1667, 1454,
1399, 1214, 1149, 1084, 1027, 976 cm–1; MS (EI) m/z 91, 136,
154(100), 307, 454 [(M+1)+]; HRMS (EI) calcd for C24H39NO7
[(M+1)+] 454.2805, found 454.2797.
24
1
colorless oil. [α]D +6.8 (c 0.64, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.36-7.29 (m, 5H), 4.64 (d, J = 6.8 Hz, 1H), 4.53 (d, J
= 12.0 Hz, 1H), 4.52 (d, J = 6.8 Hz, 1H), 4.49 (d, J = 12.0 Hz,
1H), 4.23 (q, J = 6.3 Hz, 1H), 4.17-4.13 (m, 1H), 3.95 (d, J =
11.0 Hz, 1H), 3.82 (d, J = 11.0 Hz, 1H), 3.60 (d, J = 5.4 Hz, 1H),
3.40 (m, 2H), 3.37 (s, 1H), 3.30 (s, 3H), 2.82 (s, 3H), 2.28 (q, J =
7.3 Hz, 1H), 2.13-2.07 (m, 1H), 1.71 (dt, J = 3.7, 11.0 Hz, 1H),
1.48-1.42 (m, 1H), 1.35 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 7.3 Hz,
3H), 1.00 (d, J = 7.0 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.02 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.9, 137.7, 128.4, 127.7,
127.5, 95.8, 80.8, 75.5, 75.2, 73.3, 71.2, 61.2, 55.8, 43.6, 36.8,
30.5, 27.2, 25.7, 18.0, 17.8, 10.6, -5.6, -5.7; FTIR (neat) 3452,
2944, 1654, 1462, 1396, 1255, 1095, 1032, 842, 777 cm–1; MS
(EI) m/z 91 (100), 154, 272, 360, 554 [(M+1)+]; HRMS (EI)
calcd for C29H51NO7Si [(M+1)+] 554.3513, found 554.3525.
4.7. (3S,4S,7R,8S)-8-((1S,3R)-4-(benzyloxy)-1-methoxy-3-
methylbutyl)-8-hydroxy-3,5,7-trimethyl-2-oxa-5-
azaspiro[3.4]octane-1,6-dione (4)
To a solution of 13 (26 mg, 0.057 mmol) in acetone (1.0 mL)
was added Jones’ reagent (2.67 M, 67 ꢀL, 0.18 mmol) at 0 °C.
After stirring at 0 °C for 30 min, the reaction was quenched with
i-PrOH (1.0 mL), and the mixture was filtered through Celite,
and extracted with AcOEt. The extract was washed with water

6
Tetrahedron
and brine, dried, and concentrated to give the corresponding
1386, 1234, 1112, 1043, 953 cm-1; MS (EI) m/z 91, 149, 189,
ACCEPTED MANUSCRIPT
aldehyde (26 mg).
238, 376, 421 (100) (M+); HRMS (EI) calcd for C22H31NO7 (M+)
421.2100, found 421.2094.
The crude aldehyde (26 mg) was dissolved in t-BuOH-H2O
(5:1) (1.2 mL) and then NaH2PO4·2H2O (28 mg, 0.18 mmol), 2-
methyl-2-butene (0.20 mL, 1.80 mmol), and NaClO2 (22 mg,
0.24 mmol) were added at 0 °C. After being stirred at room
temperature for 12 h, the mixture was diluted with brine (2.0
mL), and extracted with AcOEt. The extract was washed with
brine, dried, concentrated to give the corresponding carboxylic
acid (34 mg).
4.9. (3R,4S,5R)-4-((1S,3R)-4-(benzyloxy)-1-hydroxy-3-
methylbutyl)-4-hydroxy-5-((methoxymethoxy)methyl)-1,3-
dimethyl-5-(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (16)
To a solution of 15 (307 mg, 0.73 mmol) in THF-EtOH (1:1,
7.4 mL) was added NaBH4 (136 mg, 3.64 mmol) at 0 °C, and the
mixture was stirred at room temperature for 24 h. The mixture
was diluted with saturated NH4Cl (10 mL) at 0 oC, extracted with
AcOEt, washed with brine, dried, and concentrated to give the
corresponding triol (315 mg).
The crude carboxylic acid (34 mg) was dissolved in i-PrOH
(1.0 mL) and ZrCl4 (14 mg, 0.06 mmol) was added at room
temperature. The mixture was heated under reflux for 4 h, diluted
with water (2.0 mL), extracted with AcOEt. The extract was
dried, concentrated, and purified by reverse phase column
chromatography (Cosmosil 1.5 g, H2O:MeCN = 2:1) to give 14
(14.5 mg) as a colorless oil.
To a solution of the crude triol (315 mg) in CH2Cl2 (5.0 mL)
were added 2,6-lutidine (0.51 mL, 4.37 mmol) and
triisopropylsilyl trifluoromethanesulfonate (0.59 mL, 2.19 mmol)
at –78 °C, and the mixture was stirred at –78 °C for 21 h. The
mixture was diluted with AcOEt, washed with 1 M HCl and
saturated NaHCO3, dried, and concentrated. The residue was
purified by flash column chromatography (SiO2 12 g,
hexane:AcOEt = 1:2 to AcOEt then AcOEt:MeOH = 20:1) to
give 16 (398 mg, 94%, 2 steps) as a colorless oil. [α]D23 –11.0 (c
To a solution of 14 (14.5 mg) in THF (1.0 mL) were added
HATU (26.1 mg, 0.069 mmol) and N,N-diisopropylethylamine
(17 ꢀL, 0.14 mmol) at room temperature, and the mixture was
stirred at room temperature for 18 h. The mixture was diluted
with brine (1.0 mL) and extracted with AcOEt. The extract was
washed with brine, dried, and concentrated. The residue was
purified by preparative TLC (hexane:AcOEt = 2:3) to give 4
(10.3 mg, 45%; 4 steps) as a colorless oil. [α]D23 +9.1 (c 0.51,
1
0.55, CHCl2o:13); H NMR (400 MHz, CDCl3) δ 7.36-7.28 (m,
5H), 4.64 (d, J = 6.7 Hz, 1H), 4.60 (d, J = 6.7 Hz, 1H), 4.50 (d, J
= 12.1 Hz, 1H), 4.48 (d, J = 12.1 Hz, 1H), 4.13-4.08 (m, 1H),
3.98 (d, J = 12.8 Hz, 1H), 3.96 (d, J = 12.8 Hz, 1H), 3.87 (d, J
=10.5 Hz, 1H), 3.81 (d, J = 10.5 Hz, 1H), 3.60 (d, J = 5.6 Hz,
1H), 3.47 (s, 1H), 3.44 (dd, J = 6.1, 9.0 Hz, 1H), 3.38 (s, 3H),
3.36 (m, 1H), 2.86 (s, 3H), 2.43 (q, J = 7.3 Hz, 1H), 2.19-2.08
(m, 1H), 1.69 (dt, J = 4.1, 11.0 Hz, 1H), 1.52 (dt, J = 2.7, 11.0
Hz, 1H), 1.53-1.48 (m, 1H), 1.21 (d, J = 7.3 Hz, 3H), 1.12-1.01
(m, 24H); 13C NMR (100 MHz, CDCl3) δ 175.9, 138.1, 128.3,
127.6, 127.4, 96.9, 81.4, 77.2, 75.2, 73.1, 71.2, 70.8, 67.5, 62.4,
56.0, 43.1, 36.5, 30.3, 26.2, 18.4, 17.9, 11.8, 10.0; FTIR (neat)
3454, 2944, 2866, 1652, 1462, 1404, 1099, 1041, 882, 697 cm-1;
MS (FAB) m/z 91(100), 202, 307, 538, 582 [(M+1)+]; HRMS
(FAB) calcd for C31H56NO7Si [(M+1)+] 582.3818, found
582.3828.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.15
(q, J = 6.6 Hz, 1H), 4.49 (d, J = 11.9 Hz, 1H), 4.47 (d, J = 11.9
Hz, 1H), 3.78 (s, 1H), 3.46 (t, J = 4.3 Hz, 1H), 3.40 (dd, J = 4.2,
9.0 Hz, 1H), 3.34 (s, 3H), 3.29 (dd, J = 6.6, 9.0 Hz, 1H), 3.00 (s,
3H), 2.48 (q, J = 7.3 Hz, 1H), 1.96-1.89 (m, 2H), 1.49 (d, J = 6.6
Hz, 3H), 1.36-1.27 (m, 1H), 1.12 (d, J = 7.3 Hz, 3H), 0.98 (d, J =
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.3, 169.2, 138.1,
128.3, 127.6, 85.2, 81.2, 80.2, 77.2, 75.6, 73.2, 56.9, 41.6, 33.5,
31.7, 30.0, 18.4, 15.0, 11.7; FTIR (neat) 3396, 2927, 2860, 1817,
1695, 1454, 1378, 1287, 1089, 1024 cm-1; MS (FAB) m/z 91, 137
(100), 289, 307, 406 [(M+1)+]; HRMS (FAB) calcd for
C22H32NO6 [(M+1)+] 406.2229, found 406.2245.
4.8. (3R,3aS,4S,6aS)-4-((R)-3-(Benzyloxy)-2-methylpropyl)-
dihydro-3a-hydroxy-6a-((methoxymethoxy)methyl)-1,3-dimethyl-
1H-furo[3,4-b]pyrrole-2,6(3H,6aH)-dione (15)
4.10. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3-
methylbutyl)-4-hydroxy-5-((methoxymethoxy)methyl)-1,3-
dimethyl-5-(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (17)
To a solution of 1 (0.92 g, 2.44 mmol) in CH2Cl2 (24 mL)
were added methoxymethyl chloride (0.39 mL, 3.65 mmol) and
N,N-diisopropylethylamine (0.89 mL, 7.31 mmol) at 0 °C. After
stirring at room temperature for 9 h, methoxymethyl chloride
(0.39 mL, 3.65 mmol) and N,N-diisopropylethylamine (0.89 mL,
7.31 mmol) were added again, and the mixture was stirred at
room temperature for 17 h. Additional methoxymethyl chloride
(0.39 mL, 3.65 mmol) and N,N-diisopropylethylamine (0.89 mL,
7.31 mmol) were added, and stirring was continued at room
temperature for 19 h. The mixture was diluted with saturated
NaHCO3 (20 mL) at 0 °C, extracted with AcOEt. The extract was
washed with brine, dried, and concentrated. The residue was
purified by column chromatography (SiO2 30 g, hexane:AcOEt =
To a mixture of 16 (1.65 g, 2.83 mmol) and molecular sieves 4
Å (5 g, preactivated at 200 °C for 3 h in vacuo) in CH2Cl2 (6.0
mL) were added trimethyloxonium tetrafluoroborate (3.13 g, 21.2
mmol) and proton sponge (4.87 g, 22.7 mmol) at 0 °C, and the
mixture was stirred at 0 °C. After 6 h, trimethyloxonium
tetrafluoroborate (3.13 g, 21.2 mmol) and proton sponge (4.87 g,
22.7 mmol) were added again, and stirring was continued at 0 °C
for additional 2 h. The mixture was filtered through Celite and
the filter pad was washed with AcOEt. The filtrate and washings
were washed with 1 M HCl, saturated NaHCO3, and brine, dried,
and concentrated. The residue was purified by flash column
chromatography (SiO2 50 g, hexane:AcOEt = 3:1 to 1:1) to give
23
17 (1.18 g, 70%) as a colorless oil. [α]D –0.85 (c 0.97, CHCl3);
20
1H NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 4.64 (d, J = 6.6
Hz, 1H), 4.58 (d, J = 6.6 Hz, 1H), 4.49 (s, 2H), 4.01 (d, J = 10.7
Hz, 1H), 3.98 (d, J = 10.7 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H),
3.79 (d, J = 11.2 Hz, 1H), 3.69 (t, J = 5.2 Hz, 1H), 3.57 (s, 1H),
3.40 (s, 3H), 3.37 (s, 3H), 3.42-3.36 (m 1H), 3.31-3.25 (m, 1H),
2.91 (s, 3H), 2.57 (q, J = 7.1 Hz, 1H), 2.02-1.85 (m, 2H), 1.37
(dt, J = 14.4, 6.6 Hz, 1H), 1.19 (d, J = 7.1 Hz, 3H), 1.11-1.01 (m,
24H); 13C NMR (100 MHz, CDCl3) δ 175.6, 138.5, 128.3, 127.4,
96.8, 82.1, 81.1, 77.2, 75.5, 73.0, 70.6, 67.8, 63.1, 56.9, 55.8,
43.0, 33.6, 31.5, 26.6, 18.3, 18.0, 17.9, 11.8, 9.0; FTIR (neat)
1:2) to afford 15 (1.12 g, 100%) as a yellow oil. [α]D +44.3 (c
1
1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 5H),
4.66 (d, J = 6.4 Hz, 1H), 4.59 (d, J = 6.4 Hz, 1H), 4.51 (s, 2H),
4.34 (m, 1H), 3.92 (d, J = 11.0 Hz, 1H), 3.87 (d, J = 11.0 Hz,
1H), 3.58 (s, 1H), 3.41 (m, 1H), 3.34 (s, 3H), 3.29 (m. 1H), 2.87
(s, 3H), 2.47 (q, J = 7.6 Hz, 1H), 1.97-1.93 (m, 2H), 1.72 (m,
1H), 1.25 (d, J = 7.6 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 175.1, 170.7, 137.9, 128.4, 127.7, 96.7,
86.7, 80.3, 75.0, 73.2, 71.5, 62.2, 55.9, 44.9, 32.0, 30.2, 25.8,
18.1, 11.1. FTIR (neat) 3380, 2933, 2884, 1770, 1675, 1455,

7
3453, 2943, 2866, 1693, 1462, 1382, 1097, 1041, 882 cm-1; MS
(FAB) m/z 91 (100), 145, 207, 388, 596 [(M+1)+]; HRMS (FAB)
calcd for C32H58NO7Si [(M+1)+] 596.3981, found 596.3973.
4.13. (3R,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3-
methylbutyl)-4-hydroxy-5-((R)-1-hydroxyethyl)-5-
(hydroxymethyl)-1,3-dimethylpyrrolidin-2-one (21)
ACCEPTED MANUSCRIPT
4.11. (3R,4S,5R)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3-
methylbutyl)-4-hydroxy-5-(hydroxymethyl)-1,3-dimethyl-5-
(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (18)
To a solution of 19 (50 mg, 0.089 mmol) in THF (1.0 mL)
was added tetra-n-butylammonium fluoride (1.0 M in THF, 0.18
mL, 0.18 mmol), and the mixture was stirred at room temperature
for 2.5 h. The mixture was diluted with saturated NH4Cl (3.0 mL)
and extracted with AcOEt. The extract was washed with brine,
dried, and concentrated. The residue was purified by preparative
TLC (AcOEt) to give 21 (37 mg, 0.089 mol, 100%), a colorless
To a solution of 17 (1.20 g, 2.01 mmol) in i-PrOH (20 mL)
was added ZrCl4 (141 mg, 0.60 mmol) at room temperature, and
the mixture was heated under reflux for 3.5 h. The mixture was
diluted with water (10 mL) and extracted with AcOEt. The
extract was washed with brine, dried, and concentrated. The
residue was purified by flush column chromatography (SiO2 40
g, hexane:AcOEt = 2:1 to 1:2) to give 18 (0.96 g, 86%) as a
1
oil, as an epimeric mixture (16S:16R = 1:11). H NMR (400
MHz, CDCl3) δ 7.37-7.28 (m, 5H), 4.50 (d, J = 11.5 Hz, 1H),
4.46 (d, J = 11.5 Hz, 1H), 4.39 (q, J = 7.0 Hz, 1H), 3.98-3.89 (m,
1H), 3.80-3.78 (m, 1H), 3.67 (d, J = 12.7 Hz, 1H), 3.54-3.43 (m,
6H), 3.32 (dd, J = 9.0, 7.5 Hz, 1H),, 2.94 (s, 2.75H), 2.85 (s,
0.25H), 2.65-2.58 (m, 1H), 2.14-1.99 (m, 2H), 1.50-1.43 (m, 1H),
1.33 (d, J = 7.1 Hz, 3H), 1.02-0.98 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ (176.1), 175.8, 137.4, 128.5, 128.4, 128.0, (127.8),
(83.3), 83.1, (82.0), 81.7, (77.2), 76.3, 73.6, (72.7), 72.6, (69.5),
67.2, (60.5), (60.4), (59.7), 59.3, 59.1, (59.0), (42.8), 42.0, (37.4),
36.2, 32.4, (31.9), (29.6), 27.4, (26.1), (19.9), (18.9), 18.5, 18.4,
(8.7), 8.3, 7.8; FTIR (neat) 3360, 2940, 2877, 1665, 1458, 1387,
1090, 737 cm-1; MS (FAB) m/z 91, 154, 202, 410 (100)
[(M+1)+]; HRMS (FAB) calcd for C22H36NO6 [(M+1)+]
410.2543, found 410.2580. Note that 13C NMR peaks in the
parentheses belong to the minor epimer.
1
colorless oil. [α]D23 +11.2 (c 1.06, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.36-7.29 (m, 5H), 4.49 (s, 2H), 4.03 (d, J = 12.0 Hz,
1H), 3.77 (t, J = 4.7 Hz, 1H), 3.72 (s, 1H), 3.69-3.65 (m, 1H),
3.54-3.48 (m, 1H), 3.36 (s, 3H), 3.45 (m, 1H), 3.38 (d, J = 11.0
Hz, 1H), 3.32 (d, J = 11.0 Hz, 1H), 2.89 (s, 3H), 2.53 (q, J = 7.3
Hz, 1H), 2.06-1.90 (m, 2H), 1.39-1.33 (m, 1H), 1.16 (d, J = 7.3
Hz, 3H), 1.09-0.99 (m, 24H); 13C NMR (100 MHz, CDCl3) δ
175.4, 137.9, 128.4, 127.7, 127.6, 83.1, 81.0, 77.2, 75.8, 73.2,
71.9, 63.0, 61.7, 56.7, 42.6, 33.9, 31.7 , 26.4, 18.3, 18.0, 17.9,
11.8, 8.9; FTIR (neat) 3326, 2942, 2866, 1667, 1463, 1400, 1096,
1013, 883, 696 cm-1; MS (FAB) m/z 85, 91, 154, 344, 552 (100)
[(M+1)+]; HRMS (FAB) calcd for C30H54NO6Si [(M+1)+]
552.3721, found 552.3730.
4.14. (3R,4S,7R,8S)-8-((1S,3R)-4-(Benzyloxy)-1-methoxy-3-
methylbutyl)-8-hydroxy-3,5,7-trimethyl-2-oxa-5-
azaspiro[3.4]octane-1,6-dione (5)
4.12. (3S,4S,5S)-4-((1S,3R)-4-(Benzyloxy)-1-methoxy-3-
methylbutyl)-4-hydroxy-5-((R)-1-hydroxyethyl)-1,3-dimethyl-5-
(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one (19)
To a solution of 21 (52 mg, 0.13 mmol) in CH2Cl2 (1.3 mL)
were added (diacetoxyiodo)benzene (82 mg, 0.25 mmol) and
2,2,6,6-tetramethylpiperidine 1-oxyl (TEPMPO) (6.0 mg, 0.038
mmol) at 0 °C. After stirring at 0 °C for 24 h, the reaction was
quenched with saturated Na2S2O3 (5.0 mL), and the mixture was
extracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to give the corresponding aldehyde
(54 mg).
To a stirred solution of oxalyl chloride (34 ꢀL, 0.39 mmol) in
CH2Cl2 (0.5 mL) at –78 °C was added DMSO (41 ꢀL, 0.58
mmol). After stirring at –78 °C for 1 h, a solution of 18 (71 mg,
0.13 mmol) in CH2Cl2 (0.8 mL) was added. After stirring at –78
°C for 1 h, triethylamine (0.11 mL, 0.77 mmol) was added and
the mixture was stirred at room temperature for 30 min. The
mixture was neutralized with 1 M HCl and extracted with
AcOEt. The extract was washed with brine and saturated
NaHCO3, dried, and concentrated to give the corresponding
aldehyde (77 mg) as a yellow oil.
The crude aldehyde (54 mg) was dissolved in t-BuOH-H2O
(5:1) (1.5 mL) and NaH2PO4·2H2O (59 mg, 0.38 mmol), 2-
methyl-2-butene (0.44 mL, 3.80 mmol), and NaClO2 (46 mg,
0.51 mmol) were added at 0 °C. After being stirred at room
temperature for 24 h, the mixture was diluted with brine (2.0
mL), and extracted with AcOEt. The extract was washed with
brine, dried, concentrated to give hydroxy acid 22 (87 mg).
The crude aldehyde (77 mg) was dissolved in THF (1.5 mL)
and cooled to –78 °C. MeMgBr (0.99 M in Et2O; 0.65 mL, 0.64
mmol) was then added and the mixture was stirred at –78 °C for
15 h. The reaction was quenched by the addition of saturated
NH4Cl (3.0 mL) at –78 °C. The mixture was extracted with
AcOEt, washed with brine, dried, and concentrated. The residue
was purified by preparative TLC (hexane:AcOEt = 1:1) to give
19 (50 mg, 69%, 2 steps), a colorless oil, as an epimeric mixture
Crude 22 (87 mg) was dissolved in THF (1.5 mL) were added
HATU (96.2 mg, 0.25 mmol) and diisopropylethylamine (62 ꢀl,
0.51 mmol) at room temperature, and the mixture was stirred at
room temperature for 6 h. The mixture was diluted with brine
(3.0 mL) and extracted with AcOEt. The extract was washed with
brine, dried, and concentrated. The residue was purified by
preparative TLC (hexane:AcOEt = 4:5) to give 4 (3.2 mg, 6%, 3
1
(16S:16R = 1:11). H NMR (400 MHz, CDCl3) δ 7.37-7.28 (m,
5H), 4.55-4.45 (m, 0.1H), 4.49 (s, 2H), 4.36 (q, J = 6.8 Hz,
0.9H), 3.96-3.88 (m, 2H), 3.75-3.62 (m, 3H), 3.55 (s, 0.25H),
3.41 (s, 2.75H), 3.38-3.30 (m, 2H), 2.98 (s, 0.25H), 2.94 (s,
2.75H), 2.52 (q, J = 7.3 Hz, 1H), 2.00-1.90 (m, 2H), 1.38-1.29
(m, 1H), 1.26-0.96 (m, 30H); 13C NMR (100 MHz, CDCl3) δ
175.9, (175.1), 138.1, 128.3, 127.6, 127.5, (84.0), 83.1, 81.2,
(80.5), (77.2), (76.2), 75.7, 73.8, 73.2, (68.1), 66.8, (64.3), 61.6,
(60.0), 56.5, 42.9, (37.8), 33.7, 31.3, (31.0), (27.6), (27.4), (20.1),
(19.0), 18.5, 18.4, 18.0, (11.9), 11.8, 9.8, (8.6); FTIR (neat) 3337,
2943, 2866, 1669, 1461, 1391, 1090, 996, 882, 695 cm-1; MS
(FAB) m/z 91, 340, 358, 566 (100) [(M+1)+]; HRMS (FAB)
calcd for C31H56NO6Si [(M+1)+] 566.3877, found 566.3909.
Note that 13C NMR peaks in the parentheses belong to the minor
epimer.
23
steps) and 5 (31 mg, 61%, 3 steps) each as a colorless oil. [α]D
1
+44.7 (c 1.41, CHCl3); H NMR (400 MHz, CDCl3) δ 7.36-7.27
(m, 5H), 4.83 (q, J = 6.4 Hz, 1H), 4.51 (d, J = 12.2 Hz, 1H), 4.48
(d, J = 12.2 Hz, 1H), 3.70 (t, J = 4.6 Hz, 1H), 3.40-3.37 (m, 1H),
3.39 (s, 3H), 3.29 (dd, J = 7.0, 9.0 Hz, 1H), 3.18 (s, 1H), 2.91 (s,
3H), 2.44 (q, J = 7.6 Hz, 1H), 2.07-1.90 (m, 2H), 1.73 (d, J = 6.4
Hz, 3H), 1.36-1.27 (m, 1H), 1.20 (d, J = 7.6 Hz, 3H), 0.99 (d, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.9, 169.5, 138.0,
128.3, 127.6, 84.2, 81.2, 77.2, 75.8, 73.2, 57.3, 42.9, 34.2, 31.6,
26.5, 18.7, 16.6, 9.8; FTIR (neat) 3404, 2932, 1820, 1695, 1456,
1389, 1299, 1267, 1183, 1088, 1036 cm-1; MS (FAB) m/z 136,

8
Tetrahedron
ACCEPTED MANUSCRIPT
22
1
154 (100), 289, 307, 406 [(M+1)+]; HRMS (FAB) calcd for
Compound 25. [α]D –21.7 (c 0.81, CHCl3); H NMR (400
C22H32NO6 [(M+1)+] 406.2229, found 406.2246.
MHz, CDCl3) δ 5.48 (d, J = 3.0 Hz, 1H), 5.43 (d, J = 3.0 Hz,
1H), 4.88 (q, J = 6.7 Hz, 1H), 3.58-3.49 (m, 2H), 3.38 (s, 3H),
3.33 (dd, J = 10.7, 2.0 Hz, 1H), 2.94 (s, 3H), 2.75 (q, J = 7.1 Hz,
1H), 2.17 (dt, J = 4.0, 10.7 Hz, 1H), 1.84-1.75 (m, 1H), 1.70-1.60
(m, 1H), 1.51 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 7.1 Hz, 3H), 1.11-
0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) δ 176.4, 168.6,
86.0, 85.5, 77.1, 75.3, 68.7, 68.3, 61.0, 41.8, 36.6, 32.9, 29.2,
20.6, 17.6, 17.0, 16.7, 16.6, 14.0, 13.2, 11.8, 7.6; FTIR (neat)
3450, 2945, 2870, 1743, 1698, 1462, 1171, 1118, 999, 690 cm-1;
MS (FAB) m/z 85, 145 (100), 284, 558, 632 [(M+1)+]; HRMS
(FAB) calcd. for C31H62NO8Si2 [(M+1)+] 632.4014, found
632.4059.
4.15. (2S,3S,4R)-((Triisopropylsilyl)oxy)methyl 3-((1S,3R)-4-
(benzyloxy)-1-methoxy-3-methylbutyl)-3-hydroxy-2-((R)-1-
hydroxyethyl)-1,4-dimethyl-5-oxopyrrolidine-2-carboxylate (23)
To a mixture of crude 22 (366 mg), obtained from 21 (258
mg, 0.63 mmol) as described above, and molecular sieves 4 Å
(2.0 g, preactivated at 180 °C for 3 h in vacuo) in CH2Cl2 (8.3
mL) were added C12H25SCH2OTIPS (245 mg, 0.63 mmol), tetra-
n-butylammonium bromide (203 mg, 0.63 mmol), CuBr2 (140
mg, 0.63 mmol), and tiethylamine (0.18 mL, 1.26 mmol) in that
o
order at 0 C. The mixture was stirred in the dark at room
temperature for 1 h, and C12H25SCH2OTIPS (490 mg, 1.26
mmol), tetra-n-butylammonium bromide (406 mg, 1.26 mmol),
and CuBr2 (280 mg, 1.26 mmol) were again added at 0 °C. After
being stirred in the dark at room temperature for 1 h, the mixture
was filtered through Celite and the filter pad was washed with
AcOEt. The filtrate and washings were washed with saturated
NaHCO3 and brine, dried, and concentrated. The residue was
purified by flash column chromatography (SiO2 25 g,
hexane:AcOEt = 3:1 to 1:3) to give 23 (263 mg, 68% from 21), a
yellow oil, as an epimeric mixture. 1H NMR (400 MHz, CDCl3) δ
7.36-7.28 (m, 5H), 5.51 (d, J = 3.9 Hz, 1H), 5.47 (d, J = 3.9 Hz,
1H), 4.64 (q, J = 6.8 Hz, 1H), 4.49 (s, 2H), 3.98 (s, 1H), 3.60 (dd,
J = 3.0, 6.4 Hz, 1H), 3.40-3.30 (m, 2H), 3.35 (s, 3H), 2.87 (s,
3H), 2.49 (q, J = 7.2 Hz, 1H), 1.99-1.93 (m, 1H), 1.83-1.77 (m,
1H), 1.46-1.42 (m, 1H), 1.15-0.90 (m, 24H), 0.97 (d, J = 6.6 Hz,
3H).
23
1
Compound 26. [α]D +30.0 (c 0.61, CHCl3); H NMR (400
MHz, CDCl3) δ 5.46 (s, 2H), 4.98 (q, J = 6.6 Hz, 1H), 3.59 (dd, J
= 5.4, 10.5 Hz, 1H), 3.49 (dd, J = 6.3, 10.5 Hz, 1H), 3.40-3.32
(m, 1H), 3.35 (s, 3H), 2.94 (s, 3H), 2.69 (q, J = 7.1 Hz, 1H),
1.99-1.80 (m, 3H), 1.51 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 7.1 Hz,
3H), 1.11-0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) δ 176.5,
168.8, 86.0, 85.3, 82.3, 77.2, 75.6, 68.2, 67.6, 60.0, 41.9, 33.6,
32.8, 29.6, 29.3, 20.6, 18.0, 17.6, 17.0, 16.8, 14.0, 13.3, 11.8,
11.5, 7.7; FTIR (neat) 3450, 2944, 2869, 1742, 1698, 1462, 1170,
1125, 998, 886 cm-1; MS (FAB) m/z 87, 115, 145 (100), 284,
558, 632 [(M+1)+]; HRMS (FAB) calcd for C31H62NO8Si2
[(M+1)+] 632.4014, found 632.4031.
4.18. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 2,2-
diisopropyl-7a-((1S,3R)-1-methoxy-3-methyl-4-oxobutyl)-4,5,7-
trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-b]pyrrole-4a-
carboxylate (27)
4.16. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a-
((1S,3R)-4-benzyloxy-1-methoxy-3-methylbutyl)-2,2-diisopropyl-
4,5,7-trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-
b]pyrrole-4a-carboxylate (24)
To a solution of 26 (190 mg, 0.30 mmol) in CH2Cl2 (3.0 mL)
were added Dess-Martin periodinane (255 mg, 0.60 mmol) and
NaHCO3 (51 mg, 0.60 mmol), and the mixture was stirred at
room temperature for 2 h. The mixture was diluted with saturated
Na2S2O3 (5.0 mL) at 0 °C and extracted with AcOEt. The extract
was washed with saturated NaHCO3 and brine, dried,
concentrated. The residue was purified by flush column
chromatography (SiO2 10 g, hexane:AcOEt = 5:1) to give 27
(171 mg, 90%) as a colorless oil. [α]D22 +44.3 (c 1.68, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 9.62 (d, J = 2.0 Hz, 1H), 5.48 (d, J =
3.8 Hz, 1H), 5.40 (d, J = 3.8 Hz, 1H), 4.93 (q, J = 6.4 Hz, 1H),
3.30-3.20 (m, 1H), 3.24 (s, 3H), 2.95 (s, 3H), 2.69 (q, J = 7.2 Hz,
1H), 2.62 (brs, 1H), 2.40 (ddd, J = 14.0, 10.4, 3.6 Hz, 1H), 2.26
(dd, J = 14.0, 8.4, 2.4 Hz, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.16-
0.95 (m, 41H); 13C NMR (100 MHz, CDCl3) δ 204.0, 176.2,
168.6, 85.9, 85.6, 81.0, 77.2, 75.3, 60.3, 43.6, 41.8, 30.9, 29.2,
20.6, 17.6, 17.1, 17.0, 16.9, 16.7, 13.9, 13.2, 11.7, 7.6; FTIR
(neat) 2943, 2867, 1729, 1713, 1463, 1384, 1123, 1005, 883, 684
cm-1; MS (FAB) m/z 55, 145, 284, 440, 600, 630 (100) [(M+1)+];
HRMS (FAB) calcd. for C31H60NO8Si2 [(M+1)+] 630.3857,
found: 630.3870.
To a solution of 23 (263 mg, 0.43 mmol) in 1,2-
dichloroethane (4.3 mL) were added 2,6-lutidine (0.50 mL, 4.32
mmol) and diisopropyl bis(trifluoromethanesulfonate) (0.42 ml,
1.42 mmol) at room temperature, and the mixture was refluxed
for 1 h. The mixture was diluted with AcOEt, washed with 1 M
HCl, saturated NaHCO3, and brine, dried, and concentrated. The
residue was purified by column chromatography (SiO2 13 g,
hexane:AcOEt = 7:1) to give 24 (273 mg, 88%), a yellow oil, as
an epimeric mixture. 1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m,
5H), 5.45 (brs, 2H), 4.95 (q, J = 6.6 Hz, 0.9H), 4.90 (q, J = 6.6
Hz, 0.1H), 4.51 (d, J = 12.1 Hz, 1H), 4.47 (d, J = 12.1 Hz, 1H),
3.45-3.25 (m, 3H), 3.31 (s, 3H), 2.94 (s, 3H), 2.68 (q, J = 7.1 Hz,
1H), 2.00-1.80 (m, 3H), 1.51 (d, J = 6.6 Hz, 3H), 1.16-0.83 (m,
41H); 13C NMR (100 MHz, CDCl3) δ 176.6, 168.7, 138.5, 128.2,
127.5, 127.4, 86.0, 85.3, 77.2, 75.9, 75.6, 73.1, 68.2, 60.1, 41.9,
34.2, 31.5 , 29.2, 20.7, 19.1, 17.6, 17.0, 16.8, 13.9, 13.2, 11.8, 7.7
; FTIR (neat) 2943, 2866, 1738, 1710, 1463, 1381, 1164, 1109,
991, 883 cm-1; MS (FAB) m/z 91 (100), 157, 284, 648, 722
[(M+1)+]; HRMS (FAB) calcd for C38H68NO8Si2 [(M+1)+]
722.4483, found 722.4494.
4.19. Nozaki-Hiyama-Takai-Kishi (NHTK) reaction of 27 and 28
To a solution of NiCl2 (2.70 mg, 0.021 mmol) in degassed
THF-DMSO (3:1) (1.0 mL) was added CrCl2 (105 mg, 0.86
mmol) at 0 °C, and the mixture was stirred at room temperature
for 10 min. Then a solution of 27 (135 mg, 0.21 mmol) and 28
(184 mg, 0.43 mmol) in degassed THF-DMSO (3:1) (2.0 mL)
was added. After stirring at room temperature for 67 h in the
dark, the reaction was quenched with water (3.0 mL) at 0 °C, and
the mixture was filtered through Celite. The filtrate was extracted
with AcOEt, dried, concentrated, and purified by flash column
chromatography (SiO2 20 g, hexane:AcOEt = 4:1) to give a 1:1
mixture of 6 and its 7S-epimer (121 mg, 0.13 mmol, 61%) as a
4.17. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a-
((1S,3R)-4-hydroxy-1-methoxy-3-methylbutyl)-2,2-diisopropyl-
4,5,7-trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-
b]pyrrole-4a-carboxylate (26)
A mixture of 24 (260 mg, 0.36 mmol) and 20% Pd(OH)2 (150
mg) in AcOEt (3.6 mL) was stirred at room temperature under
hydrogen atmosphere. After being stirred at room temperature for
1 h, the mixture was filtered through Celite and the filtrate was
concentrated. The residue was purified by flash column
chromatography (SiO2 12 g, hexane:AcOEt = 4:1 to 1:1) to give
25 (18 mg, 8%) and 26 (208 mg, 91%) each as a yellow oil.

9
colorless oil. Compound 6 and its 7S-epimer were obtained in
pure forms by preparative TLC (toluene:AcOEt = 4:1).
307, 903, 933 [(M+1)+]; HRMS (FAB) calcd for
C51H77N2O10Si2 [(M+1)+] 933.5117, found 933.5137.
ACCEPTED MANUSCRIPT
28
1
4.21. L-Selectride reduction of 29 giving 6
Compound 6. [α]D +12.8 (c 0.45, CHCl3); H NMR (400
MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.6 Hz,
2H), 7.40 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 6.25-6.13
(m, 2H), 5.72-5.67 (m, 2H), 5.46 (d, J = 3.0 Hz, 1H), 5.45 (d, J =
3.0 Hz, 1H), 4.96 (q, J = 6.8 Hz, 1H), 4.89 (brs, 1H), 4.42 (d, J =
7.0 Hz, 2H), 4.22 (t, J = 7.0 Hz, 1H), 3.97 (t, J = 6.8 Hz, 1H),
3.86 (brs, 2H), 3.41 (dd, J = 2.4, 9.6 Hz, 1H), 3.37 (s, 3H), 2.94
(s, 3H), 2.69 (q, J = 7.2 Hz, 1H), 2.13-2.06 (m, 1H), 1.97-1.88
(m, 2H), 1.82-1.75 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H), 1.17 (d, J =
7.2 Hz, 3H), 1.14-0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) δ
176.5, 168.8, 156.1, 143.9, 141.3, 134.3, 131.2, 130.7, 129.6,
127.6, 127.0, 124.9, 119.9, 86.1, 85.3, 82.9, 77.1, 75.6, 68.3,
66.7, 60.1, 47.2, 42.6, 41.8, 37.4, 32.4, 29.6, 29.3, 20.6, 17.7,
17.1, 17.0, 16.8, 16.5, 14.1, 14.0, 13.3, 11.8, 7.7; FTIR (neat)
3414, 3333, 2943, 2866, 1729, 1710, 1694, 1463, 1245, 991 cm-1;
MS (FAB) m/z 69 (100), 145, 284, 549, 905, 935 [(M+1)+];
HRMS (FAB) calcd for C51H79N2O10Si2 [(M+1)+] 935.5273,
found 935.5250.
To a solution of 29 (16.6 mg, 0.0178 mmol) in THF (1.0 mL)
was added L-selectride (1.0 M in THF, 36 µL, 0.036 mmol) at –
78 °C, and the mixture was stirred at –78 °C for 30 min. The
reaction was quenched with saturated NH4Cl (3.0 mL), and the
mixture was extracted with AcOEt. The extract was dried, and
concentrated. The residue was purified by preparative TLC
(hexane:AcOEt = 2:1) to give a 16:1 mixture of 6 and its 7S-
epimer (12.1 mg, 73%). Pure 6 (10.0 mg, 60%) was obtained as a
colorless oil by further preparative TLC (toluene:AcOEt = 4:1).
Acknowledgments
This work was supported by JSPS KAKENHI Grant Numbers
JP25253002 and JP16H05074.
1
7S-Epimer of 6. [α]D25 +23.0 (c 1.70, CHCl3); H NMR (400
References and notes
MHz, CDCl3) δ 7.77 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 7.2 Hz,
2H), 7.40 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 6.27-6.15
(m, 2H), 5.75-5.66 (m, 2H), 5.46 (brs, 2H), 4.98 (q, J = 6.4 Hz,
1H), 4.84 (brs, 1H), 4.42 (d, J = 6.8 Hz, 2H), 4.22 (brs, 2H), 3.87
(brs, 2H), 3.40-3.30 (m, 1H), 3.86 (s, 3H), 2.95 (s, 3H), 2.67 (q, J
= 7.2 Hz, 1H), 2.19-2.11 (m, 1H), 1.85-1.74 (m, 2H), 1.51 (d, J =
6.4 Hz, 3H), 1.17 (d, J = 7.2 Hz, 3H), 1.15-0.95 (m, 38H); 13C
NMR (100 MHz, CDCl3) δ 176.5, 168.7, 156.1, 143.8, 141.3,
134.8, 131.2, 129.9, 129.4, 127.6, 127.0, 124.9, 119.9, 86.0, 85.3,
82.8, 77.2, 75.7, 68.2, 66.7, 60.0, 47.2, 42.6, 41.9, 36.0, 32.3,
29.3, 20.6, 17.6, 17.1, 16.8, 15.4, 13.9, 13.3, 11.8, 7.9; FT-IR
(neat) 3419, 3335, 2944, 2866, 1725, 1707, 1692, 1246, 1163,
991 cm-1; MS (FAB) m/z 145, 179 (100), 284, 666, 739, 935
(M++1); HRMS (FAB) calcd for C51H79N2O10Si2 (M++1)
935.5273, found: 935.5267.
1. (a) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.;
Katayama, C.; Iwadare, S.; Shizuri, Y.; Mitomo, R.; Nakano, F.;
Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1073. (b) Takahashi,
K.; Kawabata, M.; Uemura, D.; Iwadare, S.; Mitomo, R.; Nakano,
F.; Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1077.
2. Kanzaki, H.; Wada, K.; Nitoda, T.; Kawazu, K. Biosci.
Biotechnol. Biochem. 1998, 62, 438.
3. (a) Ryu, G.; Hwang, S.; Kim, S.-K. J. Antibiot. 1997, 50, 1064. (b)
Ryu, G.; Kim, S.-K. J. Antibiot. 1999, 52, 193.
4. Ogura, M.; Nakayama, H.; Furihata, K.; Shimazu, A.; Seto, H.;
Otake, N. J. Antibiot. 1985, 38, 669.
5. Otani, T.; Yoshida, K. I.; Kubota, H.; Kawai, S.; Ito, S.; Hori, H.;
Ishiyama, T.; Oki, T. J. Antibiot. 2000, 53, 1397.
6. Manam, R. R.; Teisan, S.; White, D. J.; Nicholson, B.; Grodberg,
J.; Neuteboom, S. T. C.; Lam. K. S.; Mosca, D. A.; Lloyd, G. K.;
Potts, B. C. M. J. Nat. Prod. 2005, 68, 240.
7. Ko, K.; Lee, S.-H.; Kim, E.-H.; Oh, K.-B.; Shin, J.; Oh, D.-C. J.
Nat. Prod. 2014, 77, 2099.
4.20. (4R,4aS,7R,7aS)-((Triisopropylsilyl)oxy)methyl 7a-
((1S,3R,5E,7E)-9-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-
1-methoxy-3-methyl-4-oxonona-5,7-dien-1-yl)-2,2-diisopropyl-
4,5,7-trimethyl-6-oxohexahydro-[1,3,2]dioxasilino[5,4-
b]pyrrole-4a-carboxylate (29)
8. For a review, see: Moloney, M. G.; Trippier, P. C.; Yaqoob,
Wang, Z. Curr. Drug Discovery Technol. 2004, 1, 181.
9. (a) Kawai, S.; Kawabata, G.; Kobayashi, A.; Kawazu, K. Agric.
Biol. Chem. 1989, 53, 1127. (b) Kawazu, K.; Kanzaki, H.;
Kawabata, G.; Kawai, S.; Kobayashi, A. Biosci. Biotechnol.
Biochem. 1992, 56, 1382.
10. For reviews, see: (a) Masse, C. E.; Morgan, A. J.; Adams, J.;
Panek, J. S.; Eur. J. Org. Chem. 2000, 2513. (b) Shibasaki, M.;
Kanai, M.; Fukuda, N. Chem. Asian J. 2007, 2, 20. (c) Potts, B.
C.; Lam, K. S. Mar. Drugs 2010, 8, 835.
11. Ishihara, J.; Hatakeyama, S. Chem. Rec. 2014, 14, 663 and
references therein.
12. (a) Hale, K. J.; Hatakeyama, S.; Urabe, F.; Ishihara, J.;
Manaviazar, S.; Grabski, M.; Maczka, M. Org. Lett. 2014, 16,
3536. (b) Athawale, P. R.; Kashinath, K.; Reddy, D. S.
ChemistrySelect 2016, 1, 495.
13. (a) Kende, A. S.; Kawamura, K.; DeVita, R. J. J. Am. Chem. Soc.
1990, 112, 4070. (b) Onyango, E. O.; Tsurumoto, J.; Imai, N.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem. Int. Ed.
2007, 46, 6703.
14. Bastin, R.; Dale, J. W.; Edwards, M. G.; Papillon, J. P. N.; Webb,
M. R.; Taylor, R. J. K. Tetrahedron 2011, 67, 10026.
15. Eto, K.; Yoshino, M.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Org. Lett. 2011, 13, 5398.
16. There has been only one report describing the synthesis of the
right-hand core having 16R-methyl group: Donohoe, T. J.; Chiu, J.
Y. K.; Thomas, R. E. Org. Lett. 2007, 9, 421.
17. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
18. For chelation-controlled Grignard reactions of aldols; see: (a)
Reetz, M. T. Angew. Chem. Int. Ed. 1984, 23, 556. (b) Iwasaki, J.;
Ito, H.; Nakamura, M.; Iguchi, K. Tetrahedron Lett. 2006, 47,
1483. (c) Moon, N. G.; Harned, A. M. Org. Lett. 2015, 17, 2218.
To a solution of the NHTK coupling product (21 mg, 0.023
mmol) in CH2Cl2 (1.0 mL) were added Dess-Martin periodinane
(19 mg, 0.045 mmol) and NaHCO3 (3.8 mg, 0.045 mmol), and
the mixture was stirred at room temperature for 1 h. The reaction
was quenched with saturated Na2S2O3 (3.0 mL) at 0 °C, and the
mixture was extracted with AcOEt. The extract was washed with
saturated NaHCO3 and brine, dried, and concentrated. The
residue was purified by preparative TLC (hexane-AcOEt = 2:1)
to give 29 (18 mg, 84%) as a colorless oil. [α]D28 +25.1 (c 0.83,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.2 Hz, 2H),
7.58 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.6
Hz, 2H), 7.22-7.19 (m, 1H), 6.31-6.23 (m, 2H), 6.14-6.10 (m,
1H), 5.49 (d, J = 3.8 Hz, 1H), 5.39 (d, J = 3.8 Hz, 1H), 4.95-4.87
(m, 2H), 4.45 (d, J = 6.8, 2H), 4.22 (t, J = 6.8 Hz, 1H), 3.94 (brs,
2H), 3.23 (s, 3H), 3.13 (dd, J = 1.8, 10.6 Hz, 1H), 3.02-2.96 (m,
1H), 2.94 (s, 3H), 2.67 (q, J = 6.8 Hz, 1H), 2.41-2.32 (m, 1H),
2.12-2.04 (m, 1H), 1.51 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.8 Hz,
3H),1.17-0.95 (m, 38H); 13C NMR (100 MHz, CDCl3) δ 202.8,
176.5, 168.5, 156.1, 143.7, 141.4, 139.4, 129.3, 128.1, 127.7,
124.9, 120.0, 86.0, 85.5, 77.2, 75.4, 68.3, 66.7, 60.9, 47.2, 42.5,
41.9, 41.7, 32.4, 29.2, 20.6, 18.8, 17.6, 17.1, 17.0, 16.8, 14.0,
13.3, 11.8, 7.7; FTIR (neat) 3325, 2943, 2867, 1725, 1705, 1692,
1463, 1245, 1123, 1001 cm-1; MS (FAB) m/z 136, 154 (100),

10
Tetrahedron
ACCEPTED MANUSCRIPT
19. Fortanet, J. C.; Debergh, J. R.; De Brabander, J. K. Org. Lett.
2005, 7, 685.
22. Yoshimura, H.; Eto, K.; Takahashi, K.; Ishihara, J.; Hatakeyama,
S. Chem. Pharm. Bull. 2012, 60, 1334.
20. Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R.
Tetrahedron Lett. 2004, 45, 9229.
23. Panek, J. S.; Liu. P. J. Am. Chem. Soc. 2000, 122, 11090.
24. Gil, A.; Albericio, F.; Álvarez, M. Chem. Rev. 2017, 117, 8420.
21. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.