A carbohydrate based chiron approach to the lactone intermediate employed in the synthesis of BC-ring fragment of (+)-spirastrellolide A This paper is dedicated to Professor Teruaki Mukaiyama on the very special occasion of celebrating the 40th Anniversar

Article abstract of DOI:10.1016/j.tet.2013.07.009

A concise and stereoselective synthesis of the key intermediate used for constructing the BC-ring fragment of (+)-spirastrellolide A is described. The synthetic sequence represents a chiron approach that employs readily available and inexpensive l-arabino

Full text of DOI:10.1016/j.tet.2013.07.009

Accepted Manuscript
A Carbohydrate Based Chiron Approach to the Lactone Intermediate Employed in the
Synthesis of BC-Ring Fragment of (+)-Spirastrellolide A
Chao-Chao Wang, Yu Tang, Ka Yang, Xiao-Yu Li, Yi-Biao Wu, Richard P. Hsung
PII:
S0040-4020(13)01090-9
10.1016/j.tet.2013.07.009
TET 24590
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 May 2013
Revised Date: 29 June 2013
Accepted Date: 2 July 2013
Please cite this article as: Wang C-C, Tang Y, Yang K, Li X-Y, Wu Y-B, Hsung RP, A Carbohydrate
Based Chiron Approach to the Lactone Intermediate Employed in the Synthesis of BC-Ring Fragment of
(+)-Spirastrellolide A, Tetrahedron (2013), doi: 10.1016/j.tet.2013.07.009.
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A Carbohydrate Based Chiron Approach to
the Lactone Intermediate Employed in the
Synthesis of BC-Ring Fragment of (+)-
Spirastrellolide A.
Chao-Chao Wang,a Yu Tang,*a Ka Yang,a Xiao-Yu Li,a Yi-Biao Wu,a and Richard P. Hsung*b
aSchool of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery and High-Efficiency, Tianjin University,
b
Tianjin, 300072 P. R. China; Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, WI
53705 USA

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Tetrahedron
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TETRAHEDRON
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Pergamon
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A Carbohydrate Based Chiron Approach to the Lactone
Intermediate Employed in the Synthesis of BC-Ring Fragment of
(+)-Spirastrellolide A.†
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Chao-Chao Wang,a Yu Tang,*a Ka Yang,a Xiao-Yu Li,a Yi-Biao Wu,a and Richard P. Hsung*b
aSchool of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery and High-Efficiency,
Tianjin University, Tianjin, 300072 P. R. China
bDivision of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, WI 53705 USA
yutang@tju.edu.cn, rhsung@wisc.edu
Abstract—A concise and stereoselective synthesis of the key intermediate used for constructing the BC-ring fragment of (+)-
spirastrellolide A is described. The synthetic sequence represents a chiron approach that employs readily available and inexpensive L-
arabinose and sets up the stereochemical triad at C20-C22 all from the sugar. This lactone can be used to assemble the spiroketal in the
Southern Half through a cyclic acetal–tethered ring-closing metathesis strategy, and is poised for connecting with the Northern Half at C24-
C25.
Key Word: Spirastrellolide A, spiroketal containing marine natural product, cyclic acetal-tethered RCM, chiron approach, and carbohydrate.
©2013 Elsevier Science. All rights reserved.
regulating cellular signal transductions and should not be
ignored.
1. Introduction
(+)-Spirastrellolide A, a marine macrolide isolated from the
Caribbean sponge Spirastrella coccinea off the coast of
Dominica displays rather profound antimitotic properties
(Scheme 1). Its isolation was first documented by Roberge
and Andersen et al.1a Initially, relative stereochemistry was
sketchy at multiple stereogenic centers. Subsequently in
2004, all relative stereochemistry of (+)-spirastrellolide A
sans C46 and complete structural assignment were
reported.1b Ultimately in 2007, the isolation of (+)-
spirastrellolide B allowed for concise assignment of the
absolute configuration of the macrocyclic core through X-
ray crystallography.1c In the same year, isolations of (+)-
spirastrellolide C-G from the same marine sponge
Spirastrellolide coccinea were also reported.1d
C40-41:
Julia-Kocienski
Fragment 3: The Northern Half
CO2H
46
40
P1O
OMe
O
OH
D
O
37
O
Cl
macrolactonization
40
E
OMe
Cl
O
O
41
O
F
D
H
O
25
OH
O
24
37
1
A
anti-aldol
1
O
O
O
O
25
A
10
O
G
O
O
O
HO
23
11
HO
24
H
O
23
11
H
22 OH
aldol
O
10
OH
O
O
B
17
OMe
1: C1-C10
B
C
HO
OMe
2: C11-C23
(+)-spirastrellolide A
cyclic acetal
tethered RCM
OTBDPS
23
40
PMBO
P1O
OMe
Cl
11
O
H
O
D
O
The methyl esters of these macrolides exhibit potent
inhibitory activity against protein PP2A [IC50 ca. 1 nm]
with an excellent selectivity for PP2A over PP1, and those
do not inhibit PP2C.2 Its biological activities, therefore,
resemble other known Ser/Thr phosphatase inhibitors
fostriecin and okadaic acid.3 Development of protein
phosphatase inhibitors has lagged behind the interest in
kinase inhibitors because of the perceived notion that
kinases are more highly regulated and specific.4 However,
there has been a renewed interest in recent years because
reversible protein phosphorylation is critical "as the other
half" of checkpoints in cell cycles, and protein
phosphatases assume an equally important role in
22 OPiv
OMe
37
O
O
B
17
P2O
25
alkylation
I
Fragment 3'
4
O
O
O
P3O
OH
OH
24
11
17
O
H
S
S
22 OH
O
O
17
HO
B
OMe
24
OH
OMe OPiv
2': C11-C24
5: C17-C24 lactone
6: L-(+)-arabinose
Scheme 1. Strategies for A Totasl Synthesis (+)-Spirastrellolide A.
Those remarkable biological activities for the key
regulatory enzyme suggest that the spirastrellolides might

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represent promising lead compounds for the therapeutic
reagents for treatment of cancer. To date, there have been
many papers describing elegant synthetic efforts towards
these natural products4 in addition to two completed total
syntheses by Paterson5 and Fürstner.6 We became interested
in this natural product when we developed a new
methodology for constructing spiroketals.7 This strategy
features a cyclic acetal–tethered8a-c ring-closing metathesis
RCM,8d-g,9 and we were able to complete a synthesis of
C11-C23 fragment to showcase our method.10a-c
O
17
OEt
O
O
24
19 O
17
O
O
O
S
S
20
22
MeO
O
21
21
OMe
24
O
OMe OPiv
5
OMe OH
MeO
7
8
24
23
22
AcO
O
O
OH
O
19
20
O
23 OH
23
19
20
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21
21
MeO
O
MeO
20
OMe
HO
OH
OMe
O
MeO
9
O
OH
Our synthetic strategy is outlined in Scheme 1. The side
chain at C40-C41 will be connected by using Julia-
Kocienski olefination,4v The central macrolide core can be
divided into three major fragments: 1 [C1-C10],10d 2 [C11-
MeO
10
6: L-(+)-arabinose
Scheme 2. Retrosynthetic Analysis for Lactone 5.
C23],10-a-c and
3
[C24-C40], and penultimate
MeO
MeO
OMe
OMe
and CH(OMe)3
macrolactonization5a,5b would involve C1-COOH and C37-
OH to close the macrolide. A methyl ketone enolate 1,3-
anti-aldol empolying the Mukaiyama aldol reaction
conditions11 would connect fragments 1 and 2 at C10 and
C11, and we have already demonstrated such feasibility
previously.10b-d,12 The original plan was also to pursue an
anti-aldol linking together fragments 2 and 3 at C24 and
C23 and a reductive removal of the C25-oxo group. Our
revised approach would involve the connection of two new
fragments 2’ and 3’ at C24 and C25 via an enolate
alkylation. While neither fragment has been reported in our
previous synthetic efforts, synthesis of the new BC-ring
fragment 2’ will again adopt our cyclic acetal tethered
RCM strategy. Consequently, the new lactone intermediate
5 would be required for such effort, and we envision its
synthesis commencing from sugar L-(+)-arabinose 6. We
report here details of a carbohydrate-based chiron approach
for synthesizing this lactone intermediate that contains the
C17-24 subunit of (+)-spirastrellolide A.
23
23
O
O
OH
OH
OBn
OH
19
12
BnOH, AcCl
rt, 5 d
21
HO
HO
(+)-CSA, MeOH, reflux, 12 h
OH
OH
11: 80%
6: L-(+)-arabinose
23
23
O
OBn
O
OBn
O
NaH, MeI, DMF
0 oC to rt, 18 h
Pd/C, H2
HO
O
MeO
21
OMe
OMe
MeOH, 24 h
O
O
MeO
MeO
14: 85%
13: 70%
23
HO HO
O
OH
23
21
EtMgBr, THF
MeO
O
MeO
O
OMe
OMe
–40 oC to rt, 3 h
O
O
MeO
MeO
10: 95%
15: 95%
Scheme 3. Synthesis of Diol 15.
Our synthesis commenced with benzylation of L-(+)-
arabinose at C23-OH using BnOH and AcCl (Scheme 3).
The resulting benzyl ether 11 was protected bis-acetal 13
by treatment with 2,2,3,3-tetramethoxybutane 12.15 Bis-
acetal 13 was subsequently methylated with MeI to give
methyl ether 14 in 85% yield. With methyl ether 14 in hand,
hydrogenation with Pd-C gave the tri-protected L-(+)-
arabinose 10 in 98% yield. Reaction of 10 with excess of
2. Results and Discussions.
To access lactone 5, we designed a carbohydrate based
chiron approach that can provide a concise and high-
yielding synthetic process in comparison with our previous
effort. Our retrosynthetic strategy is shown in Scheme 2.
We envisioned reaching lactone 5 via keto-lactone 7 after
protections of C22-OH and C23-ketone. Keto-lactone 7
could be derived from the α,β-unsaturated ester 8 through a
sequence of hydrogenation, deprotection and lactonization.
Ester 8 could be obtained via selected Horner-Emmons-
Wadsworth olefination of dicarbonyl compound generated
from ketone 9, which could be synthesized from the tri-
o
EtMgBr in THF at -40 C to rt afforded diol 15 as a nearly
1:1 mixture of diastereomers in 95% isolated yield.
O
HO HO
O
O
19
23
Ph3P
19
[O]
OEt
MeO
O
MeO
O
OMe
OMe
CH2Cl2, rt
O
O
MeO
MeO
15
OEt
16
O
O
O
HO
O
19
O
protected
L-(+)-arabinose
10
through
standard
23
19
23
23
19
transformations including a Grignard addition to introduce
C24. It is noteworthy that we are adopting here Ley’s
protecting strategy to assemble 10.13,14
MeO
O
MeO
O
MeO
O
OMe
OMe
OMe
O
O
O
MeO
MeO
17
MeO
8: 10-30%
18: 30-55%
Scheme 4. Synthesis of Ester 8 via Bis-Oxidation and Wittig Reaction.

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For constructing the α,β-unsaturated ester 8, we initially
envisioned an oxidation of the diol to afford the dicarbonyl
compound 16, and then, pursuing a subsequent Wittig
olefination of 16 (Scheme 4). However, after screening a
number of conditions for example Swern oxidation, IBX,
Dess-Martin periodinane oxidation [DMP], PCC, Ley
oxidation, the desired α,β-unsaturated ester 8 was obtained
in poor yields (10-30%). The byproduct was found to be
lactone 18, which is likely formed from oxidation of the
hemi-acetal intermediate 17.
that neither Lewis acids nor Brønsted acids could produce
the desired ketal 23. The crude NMR spectra revealed that
the moiety of lactone was unstable to acidic conditions.
Ultimately, treatment of pivalate 22 with 1,2-ethanedithiol
.
was catalyzed by BF3 Et2O to afford the lactone
intermediate 5 with the dithiane protecting unit in 67%
yield.18
O
OEt
O
OEt
17
10
11
12
13
14
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16
17
18
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24
O
O
Pd/C, H2
FeCl3, H2O
23
19
MeO
O
MeO
O
EtOAc, rt, 1 h
AcOH, rt, 10 h
OMe
OMe
SH
O
O
AcO
O
HO HO
MeO
23
23
19
MeO
MeO
1) Ac2O, pyridine, 0 oC, 24 h
MeO
O
O
8
21: 95%
OMe
OMe
2) Dess-Martin periodinane [O]
CH2Cl2, rt, 3 h
O
O
O
O
O
O
MeO
MeO
PivCl, Et3N
DMAP
HS
O
O
O
O
17
S
S
15
19: 46% overall
OEt
BF3.Et2O
23
OMe OPiv 24
O
OH
OMe OPiv
OMe OH
O
1) DMP, CH2Cl2
K2CO3, rt
19
O
23
7: 60%
22: 95%
5: 67%
K2CO3, MeOH
rt, 1 h
23
19
MeO
O
OMe
O
MeO
O
O
O
2)
O
OMe
Ph3P
O
conditions
OEt
MeO
17
O
O
O
O
O
MeO
8: 85% overall
CH2Cl2, rt
20: 95%
23
24
HO(CH2)2OH, TsOH
Or: CH(OMe)3, CSA
Or: TMSO(CH2)2OTMS, TMSOTf
OMe OPiv
OMe OPiv
22
23
Scheme 5. A Successful Homologation.
Scheme 6. Completing the Synthesis of Lactone 5.
Recognizing that we might have asked too much in an
attempt to shorten the synthesis, we elected an alternative
route. The primary alcohol at C19 was first protected with
It is noteworthy that this new synthetic route to the
orthogonally protected lactone is comparable in
5
o
Ac2O in anhydrous pyridine at 0 C, and subsequently, a
efficiency to our earlier approach, as it took an overall 14
steps from L-(+)-arabinose. Our earlier synthesis of a
related lactone that contains the C17-C23 subunit started
from tartrate.10a-c Although it only took 12 steps, the
resulting lactone is two-carbon less than that of 5. More
importantly, the current lactone 5 containing the C17-24
subunit should prove to be much more versatile for
synthesizing the C11-C24 BC-ring fragment 2’ through the
cyclic acetal-tethered RCM strategy developed by our
group,10a-c, and ultimately for assembling the entire
Southern Half as well as connecting with the Northern Half
of (+)-spirastrellolide A now through the new strategy of
DMP oxidation of the secondary alcohol at C23 afforded
ester ketone 19 (Scheme 5). Methanolysis of 19 occurred
smoothly using K2CO3 in MeOH at room temperature to
give hemi-acetal 20 in 95% yield. Oxidation of the hemi-
acetal 20 using Dess-Martin periodinane protocol occurred
without incident, and the crude aldehyde reacted with ethyl
(triphenylphosphoranylidene) acetate to give the desired
α,β-unsaturated ester 8 in 85% yield over two steps.
Hydrogenation of sester 8 with Pd/C gave ester 21 in
almost quantitative yield (Scheme 6). A variety of acids
were screened to deketalization, upon which it was found
that most acid conditions [for example TFA, H2SO4] could
not afford the desired products. Ley’s deprotecting protocol
C24–C25 bond formation.
Consequently, success in
achieving route well worthy of effort because this should
provide an overall more efficient approach to (+)-
spirastrellolide A.
16
using FeCl3 was identified as the most superior for
deketalization, and the ensuing facile lactonization gave
keto-lactone 7 in 60% yield. The free alcohol in keto-
lactone 7 was protected as pivalate 22 in 97% yield.
3. Conclusion.
We recognized that there were two carbonyl groups in
pivalate 22, one being a ketone at C23, and the other at C17.
Thus, they may pose problems for our cyclic acetal-tethered
RCM given that they may possess similar reactivity toward
nucleophile including simple reduction using NaBH4.17 We
then decided to investigate the protection of C23-ketone
(Scheme 6). Initially, we had hoped to selectively protect
the C23 ketone as a ketal. However, after a number of acids
were screened to effect this transformation, it was found
In summary, we have developed here a concise and
stereoselective synthesis of the key lactone intermediate
used for constructing the BC-ring fragment of (+)-
spirastrellolide A. This chiron approach employs readily
available and inexpensive L-(+)-arabinose, and sets up the
stereochemical triad at C20-C22 all from the sugar, leading
the orthogonally protected lactone intermediate in 14 steps.
This lactone fragment can be utilized for assembling the

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Southern Half through the cyclic acetal tethered RCM
approach, as well as for connecting with the Northern Half
of (+)-spirastrellolide A through the C24–C25 bond
formation. These efforts are currently underway.
4H), 4.45 (d, 1H, J = 12.4 Hz), 4.58 (s, 2H), 4.66 (d, 1H, J
= 12.4 Hz), 4.75 (s, 1H), 7.26-7.39 (m, 5H); 13C NMR (100
MHz, DMSO-d6) δ 63.8, 68.8, 68.9, 69.1, 69.5, 99.4, 127.8,
127.9, 128.6, 138.7; IR (KBr) cm-1 3254brs, 2936m, 2856w,
1449m, 1337m, 1259m, 1135s, 1090s, 1070s, 1050s; mass
spectrum (ESI): m/e (% relative intensity) 279.0 (100) [M +
K]+; m/e calcd for C12H16O5Na+ (M + Na)+ 263.0890, found
263.0913.
4. Experimental Section.
All reactions were carried out without precaution of air and
stirred magnetically. 1H and 13C NMR spectra were
recorded on a 400 MHz BRUKER AVANCE and 600 MHz
BRUKER AVANCE spectrometer at 25 oC. Chemical
shifts values are given in ppm and referred as the internal
standard to TMS: 0.00 ppm. The peak patterns are indicated
as follows: s, singlet; d, doublet; t, triplet; q, quartet; qui,
quintet; m, multiplet; dd, doublet of doublets; dt, doublet of
triplets and dq, doublet of quartets; The coupling constants
J, are reported in Hertz (Hz). Optical rotations were
measured on an Anton Paar MLP 200 modular circular
digital polarimeter by using a 2-mL cell with a path length
of 1 dm. IR was recorded on a Bio Rad FTS-185 Fourier
Transform Infrared Spectrometer. Mass spectrum was
obtained on Agilent 6310 Ion Trap mass spectrometer.
High-resolution mass spectrometry (HRMS) was obtained
on a Q-TOF micro (BRUKER) spectrometer. Melting
points were determined with a national Micro Melting point
apparatus without corrections. Organic solutions were
concentrated by rotary evaporation below 40 °C in vacuum.
TLC plates were visualized by exposure to ultraviolet light.
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4.2 Bis-Acetal 13. To a suspension of benzyl ether 11 (24.0
g, 100.0 mmol) in CH3OH (500 mL) were added 2,2,3,3-
tetramethoxybutane13c (21.4 g, 120.0 mmol), trimethyl
orthoformate (43.8 mL) and camphorsulfonic acid (CSA)
(230.0 mg). The resulting mixture was heated under reflux
for 12 h before it was cooled to rt and treated with
powdered NaHCO3 (ca. 20.0 g). The resulting mixture was
filtered through CeliteTM, and the filtrate was concentrated
under reduced pressure. The crude residue was purified
through silica gel flash column chromatograph (Isocratic
eluent: 30% EtOAc in Petroleum Ether) to afford bis-acetal
13 as a white solid (24.8 g, 70%). Recrystallization from
Petroleum Ether/EtOAc gave 13 as white prisms.
13: Rf = 0.45 [50% EtOAc in Petroleum Ether]; mp 140-
141oC; [α]D20 = +18.0 (c 1.00, MeOH); 1H NMR (400 MHz,
CDCl3) δ 1.31 (s, 3H), 1.33 (s, 3H), 2.21 (brs, 1H), 3.22 (s,
3H), 3.27 (s, 3H), 3.70 (dd, 1H, J = 1.8, 12.6 Hz), 3.81 (dd,
1H, J = 1.2, 12.6 Hz), 3.92 (s, 1H), 4.14 (dd, 1H, J = 3.0,
10.8 Hz), 4.18 (dd, 1H, J = 3.0, 10.8 Hz), 4.70 (q, 2H, J =
12.6 Hz), 4.95 (d, 1H, J = 3.0 Hz), 7.42-7.28 (m, 5H); 13C
NMR (150 MHz, CDCl3) δ 17.8, 47.8, 47.9, 63.0, 65.2,
65.8, 68.1, 69.3, 96.9, 100.1, 100.2, 127.5, 127.9, 128.2,
137.7; IR (KBr) cm-1 3462brs, 2994m, 2932s, 2838w,
1459w, 1357w, 1126m, 1045s, 1001s; mass spectrum
(ESI): m/e (% relative intensity) 393.3 (100) [M + K]+; m/e
calcd for C18H26O7Na+ (M + Na)+ 377.1571, found
377.1571.
Tetrahydrofuran (THF) was freshly distilled under N2 from
sodium-benzophenone immediately prior to use. Dichloro-
methane (CH2Cl2) and triethylamine (Et3N) were distilled
under N2 from calcium hydride (CaH2). Methanol (MeOH)
was dried over magnesium (Mg) under N2 prior to use. All
reactions were performed in standard glassware, heated at
o
70 C for 3 h before use. Flash column chromatography
was performed over silica gel 100-200 m and the eluent
was a mixture of ethyl acetate (EtOAc) and petroleum ether
either in gradient or isocratic manner.
4.3. 2R,3R,4aR,8S,8aS-5-(Benzyloxy)-2,3,8-trimethoxy-
2,3-dimethyl-hexahydro-2H-pyrano[3,4-b][1,4]dioxine
(14). To a solution of bis-acetal 13 (3.00 g, 8.50 mmol) in
freshly distilled THF (120 mL) was added NaH (0.80 g,
21.2 mmol) in portion-wise under N2 atmosphere and at 0
oC with stirring. After addition, the mixture was stirred for
4.1. Benzyl Ether 11. Acetyl chloride (6.30 mL, 88.0
mmol) was added dropwise to BnOH (108.0 mL, 1.00 mol),
which was cooled to 0 oC in an ice-water bath with stirring.
o
To this solution at 0 C was added L-(+)-arabinose (20.0 g,
o
133.3 mmol), and after the addition, the resulting reaction
mixture was warmed to rt. The resulting mixture was
vigorously stirred at rt for 5 d. Petroleum Ether (400 mL)
was then added to precipitate the product, and the mixture
was filtered and the crude white solid was washed with
Petroleum Ether (200 mL). Recrystallization of the crude
solid from EtOH (1 L) gave benzyl ether 11 (25.6 g, 80%)
as white crystals.
an additional 15 min at 0 C. Subsequently, MeI (1.10 mL,
16.9 mmol) was introduced and the resulting mixture was
stirred for 8 h before being warmed up to rt. The reaction
mixture was then quenched using sat aq NH4Cl and
extracted with EtOAc (100 mL × 2). Combined organic
layers were washed with sat aq NaCl, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The
crude residue was purified through silica gel flash column
chromatograph (Isocratic eluent: 20% EtOAc in Petroleum
Ether) to afford methyl ether 14 (2.65 g, 85%) as a white
solid.
o
11: Rf = 0.66 [16% CHCl3 in MeOH]; mp 177-178 C;
20
1
[α]D = +201.0 (c 1.00, MeOH); H NMR (400 MHz,
DMSO-d6) δ 3.46 (dd, 1 H, J = 2.4, 11.4 Hz), 3.64-3.73 (m,

ACCEPTED MANUSCRIPT
Tetrahedron
5
1
2
3
4
5
6
7
8
9
14: Rf = 0.60 [50% EtOAc in Petroleum Ether]; mp 96-97
15 [A mixture of two diastereomers]: Rf = 0.30 [60%
EtOAc in Petroleum Ether]; H NMR (600 MHz, CDCl3)
oC; [α]D = +22.0 (c 0.50, MeOH); H NMR (600 MHz,
CDCl3) δ 1.33 (s, 6H), 3.23 (s, 3H), 3.27 (s, 3H), 3.46 (s,
3H), 3.49 (s, 1H), 3.67 (d, 1H, J = 12.6 Hz), 3.75 (d, 1H, J
= 12.6 Hz), 4.15-4.20 (m, 2H), 4.71 (q, 2H, J = 12.6 Hz),
4.95 (d, 1H, J = 2.4 Hz), 7.42-7.26 (m, 5H); 13C NMR (150
MHz, CDCl3) δ 17.8, 17.9, 47.8, 47.9, 57.7, 60.3, 65.5, 66.2,
69.3, 76.9, 96.9, 99.7, 99.9, 127.4, 127.9, 128.2, 137.9; IR
(KBr) cm-1 2995m, 2934s, 2839m, 1459w, 1357w, 1131m,
1125m, 1044s, 1003s; mass spectrum (ESI): m/e (%
relative intensity) 407.9 (100) [M + K]+; m/e calcd for
C19H28O7Na+ (M + Na)+ 391.1727, found 391.1721.
20
1
1
diastereomer-I: δ 0.99 (t, 3H, J = 11.0 Hz), 1.27 (s, 6H),
1.50-1.61 (m, 1H), 1.68-1.79 (m, 1H), 2.37 (brs, 2H), 3.24
(s, 3H), 3.27 (s, 3H), 3.31-3.33 (m, 1H), 3.43 (s, 3H), 3.55-
3.58 (m, 1H), 3.73-3.90 (m, 3H), 4.41-4.48 (m, 1H);
diastereomer-II: δ 1.01 (t, 3H, J = 10.3 Hz), 1.28 (s, 6H),
1.50-1.61 (m, 1H), 1.68-1.79 (m, 1H), 2.37 (brs, 2H), 3.25
(s, 3H), 3.28 (s, 3H), 3.31-3.33 (m, 1H), 3.41 (s, 3H), 3.55-
3.58 (m, 1H), 3.73-3.90 (m, 3H), 4.09-4.15 (m, 1H,
overlapped by EtOAc); 13C NMR (150 MHz, CDCl3)
diastereomer-I: δ 10.6, 17.4, 26.3, 47.9, 57.3, 60.4, 67.8,
71.4, 71.6, 80.7, 98.5, 98.7; diastereomer-II: δ 10.2, 17.5,
24.9, 48.1, 56.9, 59.7, 69.1, 72.7, 73.4, 80.7 (overlap), 98.5,
98.6; IR (KBr) cm-1 3508brs, 2951s, 2833s, 1458m, 1376m,
1237s, 1201m, 1132s, 1042s; mass spectrum (ESI): m/e (%
relative intensity) 331.1 [M + Na]+; m/e calcd for
C14H28O7Na+ (M + Na)+ 331.1727, found 331.1745.
10
11
12
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
53
54
55
56
57
58
59
60
61
62
63
64
65
4.4. 2R,3R,4aR,8S,8aS-2,3,8-Trimethoxy-2,3-dimethyl-
hexahydro-2H-pyrano[3,4-b][1,4]dioxin-5-ol (10). To a
solution of methyl ether 14 (1.80 g, 4.90 mmol) in MeOH
(60 mL) was added 5% Pd/C (300.0 mg, 5% mol) and the
o
mixture was stirred at 25 C under an atmosphere of H2.
After being stirred at rt under H2 for 12 h, the mixture was
filtered through CeliteTM and the filtrate was concentrated
under reduced pressure to give the tri-protected L-(+)-
arabinose 10 (1.30 g, 95%) as a white solid.
4.6.
2R,3R,4aS,8R,8aR-5-ethyl-2,3,8-trimethoxy-2,3-
dimethyl-tetrahydro-2H-pyrano[3,4-b][1,4]dioxin-
7(3H)-one (18). To a solution of diol 15 (100.0 mg, 0.32
mmol) in CH2Cl2 (3 mL) was added Dess-Martin
periodinane (285.0 mg, 0.67 mmol) portion-wise. The
solution was stirred at rt for 4 h when the TLC plate
showed complete consumption of the starting material 15.
Ethyl (triphenylphosphoranylidene)acetate (133.8 mg, 0.38
mmol) was then added to the solution, and the resulting
mixture was stirred for an additional 4 h. The mixture was
filtered with CeliteTM and the filtrate was concentrated
under reduced pressure. The crude residue was purified
through silica gel flash column chromatography (Gradient
eluent: 5% to 10% EtOAc in Petroleum Ether) to afford the
desired α,β-unsaturated ester 8 (35.9 mg, 30%) as colorless
oil (see information for 8), along with the undesired lactone
18 (53.5 mg, 55%) as a white solid.
10 [A mixture of two diastereomers]: Rf = 0.20 [50%
1
EtOAc in Petroleum Ether]; H NMR (600 MHz, CDCl3)
diastereomer-I: δ 1.31 (s, 3H), 1.33 (s, 3H), 3.26 (s, 3H),
3.27 (s, 3H), 3.48 (s, 3H), 3.53 (s, 1H), 3.86 (d, 1H, J =
12.0 Hz), 3.96 (d, 1H, J = 12.0 Hz), 4.12-4.14 (m, 1H),
4.19 (dd, 1H, J = 3.0, 10.6 Hz), 5.27 (d, 1H, J = 3.0 Hz);
diastereomer-II: δ 1.32 (s, 3H), 1.35 (s, 3H), 3.27 (s, 3H),
3.30 (s, 3H), 3.47 (s, 3H), 3.48 (s, 1H), 3.77 (dd, 1H, J =
3.0, 10.6 Hz), 3.84-3.87 (m, 2H), 4.12-4.14 (m, 1H), 4.67
(d, 1H, J = 7.6 Hz); 13C NMR (150 MHz, CDCl3)
diastereomer-I: δ 14.1, 17.7, 47.8, 47.9, 60.3, 65.6, 65.7,
76.8 (overlapped by CDCl3), 91.9, 99.92, 100.0, 171.1;
diastereomer-II: δ 17.8, 21.0, 57.5, 57.6, 64.1, 68.8, 69.9,
76.1, 95.8, 99.6, 99.96, 171.1 (overlap); IR (KBr) cm-1
3475brs, 2950s, 2904s, 2844m, 1459m, 1382m, 1329m,
1129s, 1071s, 1037s; mass spectrum (ESI): m/e (% relative
intensity) 301.1 [M + Na]+; m/e calcd for C12H22O7Na+ (M
+ Na)+ 301.1258, found 301.1259.
18: Rf = 0.30 [20% EtOAc in Petroleum Ether]; mp 54-56
oC; 1H NMR (600 MHz, CDCl3) δ 0.97 (t, 3H, J = 7.4 Hz),
1.26 (s, 3H), 1.27 (s, 3H), 1.54-1.60 (m, 1H), 1.67-1.74 (m,
1H), 3.22 (s, 3H), 3.26 (s, 3H), 3.48 (s, 3H), 3.63-3.65 (m,
1H), 3.85 (dd, 1H, J = 1.2, 9.8 Hz), 3.93 (d, 1H, J = 2.8 Hz),
4.31 (dd, 1H, J = 2.8, 9.8 Hz); 13C NMR (150 MHz,
CDCl3) δ 10.3, 17.43, 17.45, 26.3, 47.9, 58.8, 69.1, 69.7,
71.5, 80.7, 98.9, 99.2, 171.5; IR (KBr) cm-1 3453s, 2959s,
1733s, 1462w, 1380m, 1303m, 1129s, 1037s; mass
spectrum (ESI): m/e (% relative intensity) 327.1 [M + Na]+;
m/e calcd for C14H24O7Na+ (M + Na)+ 327.1414, found
327.1413.
4.5.1-((2S,3S,5R,6R)-3-((S)-2-Hydroxy-1-methoxyethyl)-
5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl)-propan-1-
ol (15). To a solution of 10 (2.00 g, 7.20 mmol) in THF at -
o
40 C was added EtMgBr (32.3 mL, 32.3 mmol, 1 M in
THF) dropwise via a syringe. The solution was then
allowed to warm up to rt over 2 h. The reaction was diluted
with sat aq NH4Cl and extracted with EtOAc (100 mL × 2).
The combined organic solutions were washed with sat aq
NaCl, dried over Na2SO4, filtered, and then concentrated in
vacuo. The residue was purified through silica gel flash
column chromatography (Isocratic eluent: 40% EtOAc in
Petroleum Ether) to afford diol 15 (2.20 g, 95%) as
colorless oil.
4.7.
S-2-(2S,3R,5R,6R-5,6-Dimethoxy-5,6-dimethyl-3-
propiony-l-1,4-dioxan-2-yl)-2-methoxy-ethyl acetate (19).
To a solution of diol 15 (200.0 mg, 0.65 mmol) in pyridine
(7.0 mL) was added Ac2O (0.067 mL, 0.71 mmol). The
solution was stirred at rt for 10 h until the TLC plate
showed complete consumption of the starting material. The

ACCEPTED MANUSCRIPT
6
Tetrahedron
1
2
3
4
5
6
7
8
9
solution was concentrated under reduced pressure and the
residue was purified through silica gel flash column
chromatography (Gradient eluent: 5% to 30% EtOAc in
Petroleum Ether) to afford the desired acetate (0.15 g, 65%)
as yellow oil.
mmol). The solution was stirred at room temperature for 1
h. The mixture was filtered through CeliteTM and the filtrate
was concentrated under reduced pressure to get hemi-acetal
20 (0.35 g, 95%) as a white solid.
20: Rf = 0.30 [50% EtOAc in Petroleum Ether]; mp 104-
o
20
1
The Acetate Intermediate [A mixture of two diastereomers]:
108 C; [α]D = -82.8 (c 0.70, MeOH); H NMR (600
MHz, CDCl3) δ 0.98 (t, 3H, J = 7.8 Hz), 1.29 (s, 3H), 1.32
(s, 3H), 1.69-1.75 (m, 1H), 1.79-1.86 (m, 1H), 2.43 (brs,
1H), 3.25 (s, 3H), 3,26 (s, 3H), 3.46 (s, 3H), 3.48-3,49 (m,
1H), 3.87 (m, 2H), 4.00 (d, 1H, J = 10.3 Hz), 4.08-4.11 (dd,
1H, J = 3.0, 10.3 Hz); 13C NMR (150 MHz, CDCl3) δ 6.4,
17.8, 17.9, 30.6, 47.8, 57.6, 61.1, 67.2, 67.5, 76.8, 97.7,
99.8, 100.1; IR (KBr) cm-1 3477brs, 2983s, 2943s, 1460m,
1370m, 1189s, 1117s, 1076s, 1038s; mass spectrum (ESI):
m/e (% relative intensity) 329.0 (100) [M + Na]+; m/e calcd
for C14H26O7Na+ (M + Na)+ 329.1571, found 329.1575.
1
Rf = 0.45 [40% EtOAc in Petroleum Ether]; H NMR (600
MHz, CDCl3) diastereomer-I: δ 0.99 (t, 3H, J = 7.2 Hz),
1.25 (s, 3H), 1.28 (s, 3H), 1.53-1.60 (m, 1H), 1.69-1.77 (m,
1H), 2.06 (s, 3H), 2.32 (brs, 1H), 3.23 (s, 3H), 3.25(s, 3H),
3.42 (s, 3H), 3.43-3.45 (m, 1H), 3.57-3.59 (m, 1H), 3.62-
3.64 (m, 1H), 4.12 (dd, 1H, J = 5.4, 9.6 Hz), 4.17-4.21 (m,
1H), 4.55 (dd, 1H, J = 3.0 , 12.0 Hz); diastereomer-II: δ
1.00 (t, 3H, J = 7.2 Hz), 1.26 (s, 3H), 1.27 (s, 3H),1.44-1.50
(m, 1H), 1.69-1.77 (m, 1H), 2.06 (s, 3H), 2.32 (brs, 1H),
3.27 (s, 3H), 3.28 (s, 3H), 3.40 (s, 3H), 3.53-3.55 (m, 1H),
3.53-3.59 (m, 1H), 3.72 (dd, 1H, J = 4.8, 9.6 Hz), 3.83 (dd,
1H, J = 7.2, 9.6 Hz), 4.17-4.21 (m, 1H), 4.60 (dd, 1H, J =
2.4, 12.0 Hz); 13C NMR (150 MHz, CDCl3) diastereomer-I:
δ 10.6, 17.40, 20.9, 26.2, 47.9, 57.6, 62.1, 66.9, 71.8, 72.6,
79.4, 98.48, 98.57, 170.9; diastereomer-II: δ 10.2, 17.45,
17.47, 20.9 (overlap), 24.9, 47.8, 57.3, 61.3, 68.2, 71.6,
73.7, 79.4 (overlap), 98.63, 98.8, 170.9 (overlap); IR (KBr)
cm-1 3510brs, 2950s, 2834s, 1740s, 1457m, 1376m, 1238s,
1132s, 1043s; mass spectrum (ESI): m/e (% relative
10
11
12
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
53
54
55
56
57
58
59
60
61
62
63
64
65
4.9.
(E)-ethyl
4-(2S,3R,5R,6R)-5,6-Dimethoxy-5,6-
dimethyl-3-propionyl-1,4-dioxan-2-yl)-4-methoxy-but-2-
enoate (8). To a solution of hemi-acetal 20 (0.31 g, 1.01
mmol) in CH2Cl2 was added Dess-Martin periodinane (0.64
g, 1.50 mmol) portion-wise, followed by addition of K2CO3
(14.0 mg, 0.10 mmol). The solution was stirred at rt for 4 h
when TLC showed complete consumption of the starting
material 20. Ethyl (triphenylphosphoranylidene) acetate
(0.52 g, 1.50 mmol) was added to this solution, and stirred
for another 4 h. The mixture was filtered through CeliteTM
and the filtrate was concentrated under reduced pressure.
The residue was purified through silica gel flash column
chromatography (Gradient eluent: 2% to 10% EtOAc in
Petroleum Ether) to afford α,β-unsaturated ester 8 (0.32 g,
85%) as colorless oil.
intensity) 373.0 (100) [M
+
Na]+; m/e calcd for
C16H30O8Na+ (M + Na)+ 373.1833, found 373.1832.
To a solution of the above acetate (0.63 g, 1.80 mmol) in
CH2Cl2 (15 mL) was added Dess-Martin periodinane (1.14
g, 2.70 mmol) portion-wise. The solution was stirred rt for
4 h and TLC showed complete consumption of the starting
material. The mixture was filtered through CeliteTM and the
filtrate was concentrated under reduced pressure. The
residue was purified through silica gel flash column
chromatography (Isocratic eluent: 30% EtOAc in
Petroleum Ether) to afford ester ketone 19 (0.44 g, 70%) as
colorless oil.
20
8: Rf = 0.55 [20% EtOAc in Petroleum Ether]; [α]D = -
85.0 (c 1.00, MeOH); 1H NMR (600 MHz, CDCl3) δ 1.04 (t,
3 H, J = 10.6 Hz), 1.27-1.31 (m, 9H), 2.58-2.66 (m, 2H),
3.18 (s, 3H), 3.20 (s, 3H), 3.25 (s, 3H), 3.80-3.90 (m, 2H),
4.04 (d, 1H, J = 14.0 Hz), 4.20 (q, 2H, J = 10.6 Hz), 6.05 (d,
1H, J = 24.0 Hz), 6.93 (dd, 1H, J = 9.0, 24.0 Hz); 13C NMR
(150 MHz, CDCl3) δ 7.0, 14.2, 17.3, 17.4, 32.2, 48.0, 48.1,
57.1, 60.4, 70.5, 76.8, 79.7, 98.8, 98.9, 123.6, 144.1, 165.9,
206.5; IR (KBr) cm-1 2984m, 2942m, 2835m, 1722s,
1699w, 1458m, 1372m, 1270m, 1269s, 1129s, 1040s; mass
spectrum (ESI): m/e (% relative intensity) 397.5 (100) [M +
Na]+; m/e calcd for C18H30O8Na+ (M + Na)+ 397.1833,
found 397.1837.
1
19: Rf = 0.60 [30% EtOAc in Petroleum Ether]; H NMR
(600 MHz, CDCl3) δ 1.03 (t, 3H, J = 7.2 Hz), 1.27 (s, 3H),
1.30 (s, 3H), 2.06 (s, 3H), 2.56-2.68 (m, 2H), 3.24 (s, 3H),
3.25 (s, 3H), 3.28 (s, 3H), 3.40-3.41 (m, 1H), 4.00-4.11 (m,
3H), 4.54 (d, 1H, J = 12.0 Hz); 13C NMR (150 MHz,
CDCl3) δ 6.9, 17.3, 17.4, 20.8, 31.9, 47.9, 48.0, 57.4, 61.4,
67.2, 77.0, 78.6, 98.7, 98.9, 170.7, 206.1; IR (KBr) cm-1
2946s, 1739s, 1457m, 1375m, 1238s, 1131s, 1042s; mass
spectrum (ESI): m/e (% relative intensity) 371.2 (100) [M +
Na]+; m/e calcd for C16H28O8Na+ (M + Na)+ 371.1676,
found 371.1675.
4.10.
S-Ehyl
4-((2S,3R,5R,6R)-5,6-Dimethoxy-5,6-
dimethyl-3-propionyl-1,4-dioxan-2-yl)-4-methoxy-
butanoate (21). To a solution of α,β-unsaturated ester 8
(1.40 g, 3.74 mmol) in EtOAc (40 mL) was added 5% Pd/C
o
4.8. 1-(2R,3S,5R,6R)-3-(S)-2-Hydroxy-1-methoxy-ethyl)-
5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl)-propan-1-
one (20). To a solution of ester ketone 19 (0.42 g, 1.20
mmol) in MeOH (2 mL) was added K2CO3 (165.5 mg, 0.12
(400.0 mg, 5% mol) and the mixture was stirred at 25 C
under an atmosphere of H2. After stirring at rt under H2 for
2 h, the mixture was filtered through CeliteTM and the

ACCEPTED MANUSCRIPT
Tetrahedron
7
1
2
filtrate was concentrated under reduced pressure to give
ester 21 (1.40 g, 95%) as colorless oil.
Petroleum Ether) to afford pivalate 22 (134.7 mg, 95%) as
a white solid.
3
4
5
6
7
8
9
20
21: Rf = 0.45 [20% EtOAc in Petroleum Ether]; [α]D = -
22: Rf = 0.50 [40% EtOAc in Petroleum Ether]; mp 51-
1
20
1
102.9 (c 1.40, MeOH); H NMR (600 MHz, CDCl3) δ 1.03
53oC; [α]D = +50.0 (c 0.20, MeOH); H NMR (600 MHz,
CDCl3) δ 1.06 (t, 3H, J = 7.2 Hz), 1.31 (s, 9H), 1.88-1.94
(m, 1H), 2.11-2.16 (m, 1H), 2.39 (dq, 1H, J = 7.0, 18.8 Hz),
2.47 (ddd, 1H, J = 6.0, 7.6, 14.0 Hz), 2.61 (dq, 1H, J = 7.0,
18.8 Hz), 2.71 (ddd, 1H, J = 6.0, 7.6, 14.0 Hz), 3.34 (s, 3H),
3.42 (td, 1H, J = 5.2, 7.6 Hz), 4.71 (dd, 1H, J = 2.2, 7.6 Hz),
5.34 (d, 1H, J = 2.2 Hz); 13C NMR (150 MHz, CDCl3) δ
6.8, 23.3, 27.0, 27.2, 32.6, 39.1, 56.9, 72.4, 76.3, 80.4,
169.6, 177.5, 206.4; IR (KBr) cm-1 2975s, 2890m, 1744s,
1466w, 1361m, 1294m, 1202s, 1140s, 1109s, 1044m; mass
spectrum (ESI): m/e (% relative intensity) 301.0 (100) [M +
(t, 3H, J = 7.2 Hz), 1.25 (t, 3H, J = 7.2 Hz), 1.28 (s, 3H),
1.30 (s, 3H), 1.91-1.96 (m, 1H), 1.97-2.02 (m, 1H), 2.39-
2.42 (m, 2H), 2.60-2.64 (m, 2H), 3.21 (s, 3H), 3.26 (s, 3H),
3.29 (s, 3H), 3.30-3.32 (m, 1H), 3.95 (dd, 1H, J = 6.4, 10.0
Hz), 4.02 (d, 1H, J = 10.0 Hz), 4.20 (q, 2H, J = 10.6 Hz);
13C NMR (150 MHz, CDCl3) δ 7.0, 14.2, 17.4, 17.5, 24.6,
29.6, 32.3, 48.1, 48.2, 57.3, 60.3, 68.3, 76.1, 79.3, 98.72,
98.75, 173.6, 206.5; IR (KBr) cm-1 2983s, 2943s, 2834s,
1731s, 1456m, 1376s, 1256m, 1139m, 1131s, 1041s; mass
spectrum (ESI): m/e (% relative intensity) 399.0 (100) [M +
Na]+; m/e calcd for C18H32O8Na+ (M + Na)+ 399.1989,
found 399.2038.
10
11
12
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
53
54
55
56
57
58
59
60
61
62
63
64
65
+
H]+; m/e calcd for C15H25O6 (M + H)+ 301.1646, found
301.1648.
4.11. (5S,6R)-6-(R-1-Hydroxy-2-oxobutyl)-5-methoxy-
tetrahydro-2H-pyran-2-one (7). To a solution of 21 (0.67
g, 1.78 mmol) and anhyd FeCl3 (14.4 mg, 0.089 mmol) in
glacial acetic acid (7.5 mL) was added a solution of H2O in
AcOH (5% v/v, 0.37 mL) at rt. The reaction mixture was
stirred at rt for ~ 12 h when TLC analysis indicated
complete consumption of the starting material. The
volatiles were removed under reduced pressure. The
residue was purified through silica gel flash column
chromatography (Gradient eluent: 10% to 50% EtOAc in
Petroleum Ether) to give keto-lactone 7 (0.23 g, 60%) as
colorless oil.
4.13. R-2-Ethyl-1,3-dithiolan-2-yl-(2S,3S)-3-methoxy-6-
oxotetra-hydro-2H-pyran-2-yl)-methyl pivalate (5). To a
solution of ketone 22 (140.0 mg, 0.47 mmol) in CH2Cl2 (3
mL) were added 1,2-ethanedithiol (66.3 mg, 0.70 mmol)
of) and BF3-OEt2 (0.10 mL) in this order. The resulting
mixture was stirred at rt overnight (~12 h) and 5% NaOH
(1 mL) was added. The organic layer was separated,
washed with H2O, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was
purified through silica gel flash column chromatography
(Gradient eluent: 5% to 20% EtOAc in Petroleum Ether) to
afford lactone 5 (176.7 mg, 67%) as a white solid.
20
7: Rf = 0.30 [40% EtOAc in Petroleum Ether]; [α]D
=
5: Rf = 0.30 [30% EtOAc in Petroleum Ether]; mp 73-74 oC;
+37.0 (c 1.00, MeOH); 1H NMR (600 MHz, CDCl3) δ 1.16
(t, 3H, J = 7.0 Hz), 1.86-1.92 (m, 1H), 2.24-2.29 (m, 1H),
2.46-2.58 (m, 2H), 2.60-2.69 (m, 2H), 3.45 (s, 3H), 3.80 (td,
1H, J = 4.6, 7.0 Hz), 4.36 (s, 1H), 4.58 (dd, 1H, J = 1.6, 7.0
Hz); 13C NMR (150 MHz, CDCl3) δ 7.4, 23.2, 27.0, 31.1,
56.9, 72.8, 75.6, 81.4, 169.7, 208.1; IR (KBr) cm-1 2985s,
2970m, 1741s, 1468w, 1365m, 1289s, 1244s, 1107m,
1041m; mass spectrum (ESI): m/e (% relative intensity)
[α]D = +40.0 (c 1.00, MeOH); 1H NMR (600 MHz,
20
CDCl3) δ 1.18 (t, 3H, J = 7.2 Hz), 1.25 (s, 9H), 1.87-1.93
(m, 1H), 1.95-2.01 (m, 1H), 2.08-2.14 (m, 1H), 2.17-2.23
(m, 1H), 2.35 (dt, 1H, J = 6.2, 17.6 Hz), 2.67 (ddd, 1H, J =
6.4, 9.0, 15.4 Hz), 3.23-3.26 (m, 2H), 3.31-3.36 (m, 3H),
3.43 (s, 3H), 4.82 (d, 1H, J = 6.3 Hz), 5.31 (d, 1H, J = 1.0
Hz); 13C NMR (150 MHz, CDCl3) δ 10.6, 22.5, 26.6, 27.2,
29.5, 39.3, 39.3, 40.2, 56.8, 74.3, 75.6, 75.9, 79.5, 169.9,
177.9; IR (KBr) cm-1 2973s, 2932m, 1735s, 1453w, 1383m,
1207s, 1166s, 1136s, 1038m; mass spectrum (ESI): m/e (%
relative intensity) 399.0 (100) [M + Na]+; m/e calcd for
C17H28O5S2Na+ (M + Na)+ 399.1270, found 399.1278.
239.0 (100) [M + Na]+; m/e calcd for C10H17O5 (M + H)+
+
217.1071, found 217.1075.
4.12. R-1-2S,3S-3-Methoxy-6-oxo-tetrahydro-2H-pyran-
2-yl)-2-oxobutyl pivalate (22). To a solution of the
unprotected keto-lactone 7 (100.0 mg, 0.46 mmol) and
Et3N (0.60 mL, 4.60 mmol) in CH2Cl2 (5 mL) were added
PivCl (0.20 mL, 1.39 mmol) and DMAP (11.3 mg, 0.10
mmol). The solution was stirred at rt overnight (~12 h) and
quenched with H2O. The organic phase was separated and
the aqueous fraction was extracted with CH2Cl2 (30 mL× 3).
The combined organic phase was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The
crude residue was purified through silica gel flash column
chromatography (Isocratic eluent: 20% EtOAc in
Acknowledgments
RPS thanks the NSF [CHE1012198] for financial support.
YT thanks National Natural Science Foundation of China
for generous founding [21172169, 21172168].

ACCEPTED MANUSCRIPT
8
Tetrahedron
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†
This paper is dedicated to Professor Teruaki Mukaiyama on
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C