Total synthesis of (-)-isatisine A via a biomimetic benzilic acid rearrangement

Article abstract of DOI:10.1016/j.tet.2014.09.028

The biomimetic total synthesis of potential anti-HIV (-)-isatisine A, a novel alkaloid with an unprecedented fused tetracyclic skeleton, was accomplished in eight steps from indole and known 4,6-O-isopropylidene-protected glucal. The synthetic strategy was inspired primarily by the proposed biogenetic hypothesis that indole C-furanoside would be derived from indole C-glucoside via a ring contractive benzilic acid rearrangement. The biogenetic hypothesis was enabled by model studies: the O-glucoside was converted to O-furanoside via a benzilic acid rearrangement.

Full text of DOI:10.1016/j.tet.2014.09.028

Tetrahedron xxx (2014) 1e10
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Tetrahedron
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Total synthesis of (ꢀ)-isatisine A via a biomimetic benzilic acid
rearrangement
*
Mingxing Xiao, Wei Wu, Lin Wei, Xiaojie Jin, Xiaojun Yao, Zhixiang Xie
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, 222 Tianshui South Road,
Lanzhou, Gansu 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2014
Received in revised form 2 September 2014
Accepted 9 September 2014
Available online xxx
The biomimetic total synthesis of potential anti-HIV (ꢀ)-isatisine A, a novel alkaloid with an un-
precedented fused tetracyclic skeleton, was accomplished in eight steps from indole and known 4,6-O-
isopropylidene-protected glucal. The synthetic strategy was inspired primarily by the proposed bio-
genetic hypothesis that indole C-furanoside would be derived from indole C-glucoside via a ring con-
tractive benzilic acid rearrangement. The biogenetic hypothesis was enabled by model studies: the O-
glucoside was converted to O-furanoside via a benzilic acid rearrangement.
Keywords:
Biomimetic synthesis
Isatisine A
Ó 2014 Published by Elsevier Ltd.
Benzilic acid rearrangement
Anti-HIV
1. Introduction
The structure and relative configuration of 1was elucidated by
1D and 2D NMR experiments and finally determined by single-
As a fundamental traditional Chinese medicine, Isatis indigotica
Fort. (Cruciferae) has been used for the treatment of viral diseases
for hundreds of years in China.1 Chemical investigation of its root
and leave, respectively named ‘Ban-Lan-Gen’ and ‘Da-Qing-Ye’ in
Chinese, has led to the isolation of diverse structures and significant
biological activities compounds.2 In 2007 Chen and co-workers
have reinvestigated and isolated isatisine A acetionide (1) from
the leaves (Da-Qing-Ye) (Fig. 1).3 This compound showed moderate
crystal X-ray diffraction. The unique bisindole alkaloid possessed
an unprecedented fused pentacyclic framework containing
a densely substituted furan subunit and five contiguous stereo-
centers. Furthermore, an isopropylidenyl group was embedded in
the core. Natural compounds containing the isopropylidenyl group
have often been reported, however, the use of acetone as a solvent
in their purification process made Chen and co-workers doubt
whether the acetonide derivative 1 was an artifact. They did further
investigations and confirmed that isatisine A (2) was a genuine
natural product in the leaves of Isatis indigotica.3 Unfortunately, the
bioactivity of natural isatisine A (2) was not reported in the paper
that described its isolation due to the scarcity of the isolated
material.
anti-HIV-1 activity with EC50¼37.8
7.98. Furthermore, isatisine A acetionide (1) exerted cytotoxicity
against C8166 with CC50¼302 M.
mM and selectivity index (SI)¼
m
Its uncharacterized bioactivity and intrigued molecular archi-
tecture has drawn the attention of organic chemists to make this
compound as an unusually appealing synthetic target.4 In 2010,
Kerr reported the first total synthesis of (þ)-isatisine A (2), and
revised the absolute configuration of the natural alkaloids as
(ꢀ)-isatisine A (3) (Scheme 2).4aeb Their strategy involved the use
of a Lewis acid-catalyzed cyclization of homochiral (S)-vinyl-
cycopropane diester (4) and N-tosylindole-2-carboxaldehyde (5) to
construct the tetrahydrofuran ring and an indole oxidation, fol-
lowed by an electrophilic aromatic substitution to install the sec-
ond indole moiety. Following this, Panek4c and Liang4d reported the
total synthesis of (þ)-isatisine A (2) and (ꢀ)-isatisine A (3), re-
spectively. A key feature of Panek’s synthesis was the application of
Fig. 1. Original proposed structure of isatisine A (2) and its acetionide (1) and revised
structure of isatisine A (3).
* Corresponding author. E-mail addresses: xiezx@lzu.edu.cn, xiezxg@qq.com
(Z. Xie).
http://dx.doi.org/10.1016/j.tet.2014.09.028
0040-4020/Ó 2014 Published by Elsevier Ltd.
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2
M. Xiao et al. / Tetrahedron xxx (2014) 1e10
a silyl-directed Mukaiyama-type [3þ2]-annulation for the prepa-
ration of a fully substituted furan core and a nucleophilic addition
of indole to an intermediate N-acyliminium ion to form the qua-
ternary center. Liang’s synthesis featured an aldol reaction of ace-
tylindole (12) and
D
-ribose derivative ketone (13), an
unprecedented intramolecular C glycosylation of an indole, and
a subsequent oxidative ring contraction. In 2012, Ramana4f re-
ported their employment of late-stage four consecutive metal-
mediated transformations to achieve (ꢀ)-isatisine A. All these el-
egant strategies had a common feature that a late-stage nucleo-
philic addition of indole was adopted to install the second indole
moiety (Scheme 1).
Scheme 2. Proposed biogenetic pathway of isatisine A.
an intermediate that would undergo a benzilic acid rearrange-
ment,8 dehydration, to afford isatisine A.
Our retrosynthetic analysis of isatisine A is outlined in Scheme 3.
To support this biogenetic pathway, the benzilic acid rearrange-
ment was devised as a key biomimetic reaction for the synthesis of
(ꢀ)-isatisine A. We envisioned that isatisine A would be afforded
via selective oxidation of the a-hydroxy of 24 and the immediate
benzilic acid rearrangement of the corresponding 1,2-diketone.
Bisindole-glycoside 25 would be derived from the addition of
D
-
glucal derivative 27 to 2-indolyl-3-one-3H-indole 26 and the ste-
reochemistry of the newly formed aza-quaternary center would be
induced by the stereostructure of 27. Known 2-Indolyl-3-one-3H-
indole 26 and
D-glucal derivative 27 could be obtained from com-
mercial available indole 28 and triacetyl-
D
-glucal 29, respectively.
Scheme 1. Total synthesis of (þ)- and (ꢀ)-isatisine A.
Fascinated by the unprecedented molecular structures of isati-
sine A, and the interesting hypothesis regarding their origins, we
contemplated its biomimetic synthesis. We felt an endeavor that
could lead to new synthetic strategies toward the indole C-glyco-
side species. For this novel alkaloid possessing an unprecedented
fused tetracyclic skeleton, Chen did not give explanation of the
source from the biogenetic view.3 Studies suggest that the poly-
hydroxy core of some natural products is likely to arise in nature
from glycosides.5 We envisioned that indican (19), isolated from the
same species, could be the precursor of isatisine A (3). After further
survey, indican (19) was found in higher concentration in the young
leaves than the old leaves of I. indigotica and as an important pre-
cursor for other compounds.6 Thus, a plausible biogenetic pathway
for (ꢀ)-isatisine A (3) was proposed by us, as shown in Scheme 2.
Indican (19) may be first subjected to a rearrangement and sub-
sequent oxidation to afford iminium 20, which is immediately
converted to bisindole C-glucoside 21 via a nucleophilic addition of
indole.7 Selective oxidation of 21 would provide 1, 2-diketone 22,
Scheme 3. Retrosynthetic analysis of isatisine A.
In previous communication,4e our group disclosed the bio-
mimetic total synthesis of (ꢀ)-isatisine A (3), in which a convergent
nucleophilic addition for installation of the indole moiety and an
unprecedented benzilic acid rearrangement for construction of the
densely substituted furan subunit were applied. In this article, we
provided a full account of our investigation that led to the bio-
mimetic total synthesis of (ꢀ)-isatisine A.
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M. Xiao et al. / Tetrahedron xxx (2014) 1e10
3
2. Results and discussion
between iminium 26 and aldehyde or ketone (Scheme 6), we
doubted that whether -glucal derivative 47 was suitable for it.
D
Benzilic acid rearrangement8 (BAR) was discovered by Liebig in
1883 and since then a number of theoretical studies were pro-
ceeded, however, few applications was found in synthesis of nat-
ural product. In 1996, Stoltz and Wood8e reported the unexpected
employment of an efficient, highly stereoselective benzilic acid
rearrangement on the pyranosylated indolocarbazole 30 to give the
According to reported methods,11,12 2-indolyl-3-one-3H-indole 26
could be obtained from indole in three steps. Meanwhile, the
cleavage of the acetyl group of commercial triacetyl- -glucal 43,
D
followed by selective TBS-protection of the primary hydroxyl, gave
44 in 89% overall yield. The ketone 47 was obtained via MOM group
protection of
the remaining dihydroxy,
regioselective
K252a tetrahydrofuran moiety 31 via a putative
a
-diketone in-
hydroboration-oxidation, and DesseMartin oxidation (Schemes 7
termediate using methanolic CuCl (Scheme 4). More early, one
example of tetrahydropyran ring contracting to tetrahydrofuran
and 8).
ring was reported by Hanessian via an
a-ketol rearrangement in the
total synthesis of spectinoic acid.9
Scheme 6. Asymmetric Mannich reaction between 2-Indolyl-3-one-3H-indole 26 and
cyclohexanone 39.
Scheme 4. Application of BER by Stoltz and Wood.
Scheme 7. Synthesis of compound 26.
Scheme 8. Synthesis of compound 47.
Scheme 5. Model studies of benzilic acid rearrangement.
After a number of surveys, the addition of 47 to the 2-indolyl-3-
one-3H-indole 26 in the presence of L
-proline11 or chiral phos-
phoric acid failed (Scheme 9). The different electron and steric ef-
fects might account for this. At this point, another addition method
should be adopted. We envisioned that the enolate of ketone 47
would be an active intermediate that could be added to the car-
bonyl or the iminium carbon of 26. According to McWhorter’s re-
port,13 the product from addition to the carbonyl carbon could be in
turn rearranged to yield the product from addition to the iminium
carbon under acid conditions (Scheme 10 and 11).
Thus, we initially conducted the model studies. The known
benzylidene-protected glucose derivative 3210 underwent Swern
oxidation to afford
a-hydroxy ketone 33. Under Stoltz and Wood’s
conditions,8e
a
-Hydroxy ketone 33 was refluxed in DCM/MeOH
(1:1) in the presence of excess CuCl to obtain the deprotection
product, and further heating led to the decomposition. The addi-
tional six-membered ring in 33 would presumably prevent the
rearrangement due to restrict in the respect of stereo-chemical
configuration. Therefore, the benzyl group was chose to selec-
tively protect the dihydroxy. Benzyl-protection of 34, followed
cleavage of the isopropylidene group, gave diol 36 in 69% yield.
Swern oxidation of 36 afforded a-hydroxy ketone 37 in 52% yield.
The benzilic acid rearrangement of 37 in DCM/MeOH (1:1) in the
presence of CuCl successfully gave the desired product 38 as a sin-
gle isomer. The configuration of 38 was determined by 1H NOE
spectroscopy. The successful ring contractive rearrangement of O-
glucoside to O-furanoside increased our confidence in the bio-
mimetic synthesis of isatisine A.
Scheme 9. Mannich reaction of 47 and 26.
In our previous studies,11 we reported a Mannich reaction of 2-
aryl-3H-indol-3-ones with aldehydes or ketones in the presence of
To our delight, the enolate of 47, in situ formed by LDA, was
L-proline as a catalyst, giving the corresponding aza-quaternary
added to the iminium carbon rather than the carbonyl carbon to
carbon addition product in good yield with excellent regio- and
enantioselectivity. Although the Mannich reaction proceeded well
afford 52 in 61% yield as a sole diastereoisomer. Although the
hydroxy was eliminated, the hydroxyl could be reintroduced via
b-
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M. Xiao et al. / Tetrahedron xxx (2014) 1e10
Scheme 10. The rearrangement of 50 to 51.
Scheme 11. Synthesis of compound 55.
Fig. 2. The CD and ECD spectra of 56.
dihydroxylation to furnish 53. Treatment of 53 with CuCl in CH2Cl2/
MeOH (1:1)8e uneventfully gave ring contraction product,
a, b-
successfully tested and biomimetic benzilic acid rearrangement
was realized in the synthesis. Those studies lay a solid foundation to
achieve the biomimetic synthesis of isatisine A.
dihydroxy ester 54, in 91% yield. The stereochemistry of C10 and
C13 were established by NOE experiment. Obviously, the stereo-
structure of C10 was inconsistent with that of isatisine A. We sur-
mised that the negative result could be attributed to the E1cb
elimination of OMOM group before addition. The elimination
would result in the configuration change of lithium enolate to favor
attack to iminium carbon of 26 from more sterically accessible
According to Kerr’s report,4aeb the C2-epimer could be iso-
merized to the desired stereochemistry under acid conditions.
Thus, controlling the stereochemistry of C10 was the key step to
synthesize isatisine A and the stereochemistry of C9 was expected
to be induced by the correct 2H-pyran-3-one configuration. We
enolate a-face. Unfortunately, endeavors toward the epimerization
of 52 were unfruitful, due to the unstable nature of 52.
In order to explore the last reaction conditions and synthesize
the isomer of isatisine A, we conducted the subsequent experiment.
Attempts (Mg/MeOH, Na/aphthalene, SmI2, and TBAF)14 to cleave
the Tos group of 54 were unfruitful. The acid 55 was obtained in
82% yield via deprotected the Tos group and hydrolysis of the
methyl ester in the presence of K2CO3/MeOH.14h We tried a number
of condensation conditions (DIC/NHS, BOP/Et3N, EDC, EDCI, DEPBT,
and Mukaiyama reagent), but did not obtain the desired lactam 56.
We wondered whether the lactamization could realize before the
deprotection of the Tos group. Gratifyingly, treatment of 54 with
PTSA in refluxing toluene gave compound 57 in 64% yield, accom-
panying the cleavage of TBS group. On the base of previous surveys,
photo-assisted cleavage of Tos group15 afforded lactam 56 in 27%
yield. We have synthesized the p-bromobenzoyl derivative of 56,
but the single crystal of which could not be obtained after many
trials.
Scheme 12. Attempts to the synthesis of lactam 56.
In order to elucidate the stereochemistry of C2 and C9 in 56, the
electronic circular dichroisms (ECD) of four possible candidate ste-
reoisomers of 56 were performed (Fig. 2) (See Supplementary data).
The experimental spectra match those calculated for structure 56a
and 56b as can be seen from the comparison of positive CEs at 230.
Therefore, compound 56 is more likely to be the structure of 56a or
56b. Given the model study of benzilic acid rearrangement shown in
Scheme 5, the hydroxyl group at C3 in compound 38 is R configu-
ration, conforming to that of the hydroxyl group at C9 in compound
56a. Thus, the structure of 56 was proposed to be 56a. The config-
uration of C9 in 56a was also in consistency with the experimental
result that the lactamization of 55 to form the trans-fused five
member ring was difficult (Scheme 12) because such a process in the
present case would experience high strain.
Scheme 13. Synthesis of lactam 56.
Although the correct stereostructure of isatisine A was not
achieved, the enolate addition to the iminium carbon was
Scheme 14. Synthesis of 2H-pyran-3-one 61.
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M. Xiao et al. / Tetrahedron xxx (2014) 1e10
5
63b was chose to explore the subsequent route. The BOM group
of 63b was removed under hydrogenation in the presence of
Pd(OH)2/C to give the corresponding triol, which was treated with
CuCl in refluxing MeOH/CH2Cl2 (1:1)8e to furnish the desired
b-
hydroxy ester 64b in overall 62% yield. It is worth to note that the
precursor, which was only removed the BOM group with iso-
propylidene group retained could not be rearranged under the
same condition. We envisioned that the stereochemistry of newly
formed C9 stereocenter via benzilic acid rearrangement would be
closely related to the stereostructure of 2H-pyran-3-one ring.
According to the previous study, deprotection of the Tos group prior
to lactamization was better. Finally, cleavage of the Tos group,
subsequent lactamization by treatment with CSA for 48 h, gave
(ꢀ)-isatisine A in 29% yield from 64b. As Kerr’s report,4aeb the in-
appropriate configuration of C2 was epimerized under acid condi-
tions. The spectral data of the synthetic 3 were in accord with those
reported for the natural (ꢀ)-isatisine A.3
Scheme 15. Synthesis of 63a and 63b.
In addition, 63a was converted to (ꢀ)-isatisine A in overall 16%
yield from 63a under a same protocol (Schemes 13e17).
3. Summary
In conclusion, the biomimetic total synthesis of (ꢀ)-isatisine A
has been achieved in eight steps from known 58. A convergent
nucleophilic addition of 2-indolyl-3-one-3H-indole 26 with lithium
enolate of D-glucal derivative was developed and applied to as-
semble the biindole-glucal structure, and a biomimetic benzilic
acid rearrangement was used to construct the densely substituted
4H-furan subunit. The stereochemistry of all newly formed ster-
eocenters in the two reactions was found to be controlled by the
stereostructure of pyranone ring. Our synthetic efforts have
established an efficient route towards indole C-glycoside and con-
spicuously demonstrated the utility of benzilic acid rearrangement
for diastereoselective preparation of densely substituted furan
subunit from glucal derivative.
Scheme 16. Total synthesis of (ꢀ)-isatisine A from 63b.
4. Experimental section
4.1. General
Scheme 17. Total synthesis of (ꢀ)-isatisine A from 63a.
All moisture-sensitive reactions were performed under an at-
mosphere of Ar. Glassware was flame dried prior to use. THF was
dried by distillation over Na/K. CH2Cl2 was dried by distillation over
CaH2. Unless otherwise stated, solvents and reagents were used as
received. Column chromatography was generally performed on
silica gel (200e300 mesh) and TLC inspections were on silica gel
GF254 plates. 1H NMR spectra were recorded at 400 MHz spec-
envisioned that the configuration of C10 would be desired, if the
E1cb elimination was avoided. Therefore, the isopropylidene group
was chose to protect the diol at C13 and C14. It is believed that the
newly installed six-membered ring would make the group at C13
hard to leave.
trometers. Chemical shifts (
downfield from Si(CH3)4 with the partially deuterated solvent as
the internal standard (CDCl3 7.26). Data are reported as follows:
d) are reported in parts per million
The known isopropylidene protected
D
-glucal 58 was obtained
from triacetyl-
D
-glucal 43 according to the literature.16 The screen
d
of protecting group of the remaining hydroxyl expended a lot of
time. BOM was found to be the best protecting group. For others,
such as SEM, MOM and TBS, confronted the failure of addition to
the iminium or the decomposition of the starting material in the
deprotection procedure. Regioselective hydroboration-oxidation of
60, followed by DesseMartin oxidation, afforded the 2H-pyran-3-
one 61 in 83% yield of two steps.
The lithium enolate of 61 was added to iminium carbon of 26 to
give a 1.9:1 mixture of 62 in 75% yield. To the best of our knowledge,
this reaction represents the first addition of a glucoside derivative to
the iminium carbon of indolone. After cleavage of the isopropylidene
group, 63a and 63b were isolated, and the stereochemistry of the
newly formed C10 stereocenter was identified by NOE experiment
and the configuration at C2 was distributed by experimental and
computational optical rotation data.17 As we expected, the configu-
ration of C10 was consistent with that of isatisine A.
chemical shift, multiplicity (s¼singlet, d¼doublet, t¼triplet,
dd¼doublet of doublet, b¼broad, q¼quartet, m¼multiplet). 13C
NMR spectra were recorded at 100 MHz spectrometers. Chemical
shifts are reported in ppm from tetramethylsilane with the solvent
as the internal standard (CDCl3 d 77.0, CD3OD d 49). IR spectra were
recorded on a Nicolet 670 FTIR spectrophotometer and reported in
wave numbers (cmꢀ1). HRMS data were determined on a Bruker
Daltonics APEXII 47e FT-ICR spectrometer. Optical rotation calcu-
lations were performed using Gaussian 09 package.
4.2. Experimental procedures and data of synthetic
intermediates
4 . 2 .1. ( 2 R , 4 a R , 6 S , 8 S , 8 a S ) - 6 - ( A l l yl o x y ) - 8 - hy d ro x y- 2 -
phenyltetrahydropyrano[3,2-d][1,3]dioxin-7(6H)-one (33). To a solu-
tion of DMSO (97 mL, 1.4 mmol) in DCM (5 mL), was slowly added
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6
M. Xiao et al. / Tetrahedron xxx (2014) 1e10
(COCl)2 (55
m
L, 0.65 mmol) at ꢀ78 ꢁC, and the mixture was stirred at
823.7, 738.6, 703.7. HRMS (ESI): calcd for C25H32O8Na [MþNa]þ:
this temperature for 15 min, then a solution of 32(168 mg,
0.54 mmol) in DCM (3 mL) was added dropwise. After 1 h at ꢀ78 ꢁC,
Et3N (0.38 mL, 2.7 mmol) was added and the reaction was warmed
to rt over 30 min, then saturated aq NH4Cl was added. The mixture
was extracted by EtOAc. The organic layer was washed with H2O
and brine, dried over Na2SO4, filtered, concentrated in vacuo. Pu-
rification by flash column chromatography (petroleum ether/ethyl
483.1989; found 483.1982.
4.2.4. (2S,3R,4R,5S,6R)-2-(Allyloxy)-5-(benzyloxy)-6-((benzyloxy)
methyl)tetrahydro-2H-pyran-3,4-diol (36). To
a solution of 35
(677 mg, 1.5 mmol) in DMF (10 mL) was added NaH (110 mg, 80%,
3.7 mmol), and after 10 min, BnBr (0.42 mL, 3.5 mmol) was added.
The reaction was stirred for 4 h at rt, then it was quenched by water,
followed by extraction with EtOAc. The organic layer was washed
with H2O and brine, dried over Na2SO4, filtered, concentrated in
vacuo. Purification by flash column chromatography (petroleum
acetate 3:1 to 2:1) yielded alcohol 33 (50 mg, 30%) as a white
þ159.0 (c 1.00, CHCl3). 1H
26.3
flocculent solid. mp 180e182 ꢁC. [
a
]
D
NMR (400 MHz, DMSO-d6): d 7.43e7.45 (m, 2H), 7.39e7.40 (m, 3H),
5.86e5.94 (m, 1H), 5.67 (s, 1H), 5.50 (d, J¼8.0 Hz, 1H), 5.34 (dq,
J¼1.6, 17.2 Hz 1H), 5.23 (d, J¼4.4 Hz, 1H), 5.18 (dd, J¼2.0, 10.4 Hz,
1H), 4.60 (dd, J¼1.6, 9.6 Hz, 1H), 4.44e4.48 (m, 1H), 4.32 (dd, J¼4.4,
9.6 Hz,1H), 4.16e4.21 (m, 1H), 4.00e4.06 (m,1H), 3.92 (t, J¼10.0 Hz,
ether/ethyl acetate 6:1) yielded Bn-protected product 350 (840 mg,
26.2
89%) as a colorless oil. [
(400 MHz, CDCl3):
a
]
D
þ21.0 (c 1.00, CHCl3). 1H NMR
d
7.31e7.40 (m, 12H), 7.22e7.30 (m, 2H), 6.92 (d,
J¼8.4 Hz, 4H), 5.96e6.06 (m, 1H), 5.38 (d, J¼17.2 Hz, 1H), 5.27 (d,
J¼10.4 Hz, 1H), 4.99 (d, J¼10.4 Hz, 1H), 4.92 (d, J¼10.8 Hz, 1H),
4.77e4.87 (m, 3H), 4.67 (d, J¼11.6 Hz, 2H), 4.51e4.56 (m, 2H), 4.23
(dd, J¼5.2, 12.8 Hz, 1H), 4.05e4.11 (m, 2H), 3.83e3.89 (m, 1H), 3.81
(d, J¼3.6 Hz, 6H), 3.78 (d, J¼3.6 Hz,1H), 3.68e3.72 (m, 2H), 3.62 (dd,
1H), 3.81e3.87 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 200.0, 137.6,
134.5, 129.5, 128.6, 126.8, 117.8, 102.4, 101.0, 81.4, 75.1, 68.9, 68.6,
66.0. IR (thin film, cmꢀ1
)
nmax: 3407.9, 3076.1, 2958.0, 2921.6,
2866.2, 1744.7, 1643.3, 1549.0, 1498.3, 1452.3, 1213.2, 1077.1, 1041.7,
996.7, 755.1, 697.4. HRMS (ESI): calcd for C16H22NO6 [MþNH4]þ:
324.1442; found 324.1439.
J¼3.6, 9.6 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 159.19, 158.99,
138.20, 137.81, 133.68, 130.94, 130.19, 129.47, 129.40, 128.14, 127.65,
127.61, 127.44, 127.43, 117.87, 113.64, 113.60, 95.62, 81.66, 79.44,
77.55, 75.18, 74.79, 73.22, 72.62, 70.08, 68.37, 67.99, 55.01. IR (thin
4.2.2. (2R,4aR,6S,7R,8S,8aR)-6-(Allyloxy)-7,8-bis((4-methoxy benzyl)
oxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine (34). The diol 33
(1.4 g, 4.6 mmol) dissolved in DMF (6 mL) and THF (4 mL) was
added dropwise at 0 ꢁC (ice bath) to a suspension of NaH (392 mg,
70%, 11.4 mmol) in DMF (6 mL) and THF (4 mL), followed by addi-
tion of PMBCl (1.4 mL, 10.1 mmol) and TBAI (338 mg, 0.92 mmol).
The mixture was stirred at 0 ꢁC for 10 min, and then at rt overnight
(12 h). The reaction was quenched by water, then extracted by
EtOAc. The organic layer was washed with H2O and brine, dried
over Na2SO4, filtered, concentrated in vacuo. Purification by flash
film, cmꢀ1
) nmax: 3054.9, 2924.2, 2858.7, 1655.1, 1611.5, 1545.8,
1513.3, 1458.8, 1264.8, 1094.7, 1067.7, 1034.9, 739.3, 703.6. HRMS
(ESI): calcd for C39H44O8Na [MþNa]þ: 663.2928; found 663.2913.
To a solution of Bn-protected product 350 (651 mg, 1.0 mmol) in
DCM (8 mL) and buffer solution (3 mL, 0.4 M Na2HPO4/0.4M
NaH2PO4, 2:1), was added DDQ (578 mg, 2.5 mmol). The reaction
was stirred at rt for 18 h, and then quenched by saturated aq NH4Cl,
followed by extraction by EtOAc. The organic layer was washed
with H2O and brine, dried over Na2SO4, filtered, concentrated in
vacuo. Purification by flash column chromatography (petroleum
ether/ethyl acetate 6:1) yielded 36 (313 mg, 77%) as a colorless oil.
column chromatography (petroleum ether/ethyl acetate 4:1) yiel-
26.5
ded alcohol 34 (1.1 g, 45%) as a colorless oil. [
a]
ꢀ10.0 (c 1.00,
D
CHCl3). 1H NMR (400 MHz, CDCl3):
d
7.49 (d, J¼6.4 Hz, 2H),
[
a
]
26.7 þ117.0 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3):
d 7.21e7.30
D
7.26e7.37 (m, 7H), 6.84 (t, J¼8.4 Hz, 4H), 5.88e5.98 (m, 1H), 5.53 (s,
1H), 5.32 (d, J¼17.2 Hz, 1H), 5.22 (d, J¼10.0 Hz, 1H), 4.74e4.85 (m,
4H), 4.60 (d, J¼11.6 Hz, 1H), 4.14e4.26 (m, 2H), 4.00e4.06 (m, 2H),
3.84e3.90 (m, 1H), 3.76 (d, J¼4.4 Hz, 6H), 3.67 (t, J¼10.4 Hz, 1H),
(m, 10H), 5.83e5.93 (m, 1H), 5.27 (dd, J¼1.6, 17.2 Hz, 1H), 5.16 (dd,
J¼1.2, 10.4 Hz, 1H), 4.92 (d, J¼3.6 Hz, 1H), 4.82 (d, J¼11.2 Hz, 1H),
4.62 (d, J¼12 Hz, 1H), 4.48e4.55 (m, 2H), 4.18 (dd, J¼5.2, 12.8 Hz,
1H), 4.00 (dd, J¼6.4, 12.8 Hz, 1H), 3.87 (t, J¼9.2 Hz, 1H), 3.71e3.79
(m, 2H), 3.64e3.68 (m, 1H), 3.50e3.57 (m, 2H), 3.19 (s, 1H), 2.65 (d,
3.51e3.59 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 159.23, 159.03,
137.35, 133.56, 130.88, 130.18, 129.49, 129.47, 128.72, 128.04, 125.89,
118.09,113.65,113.55,101.05, 96.70, 82.03, 78.73, 78.17, 74.86, 73.04,
J¼9.2 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 138.24, 137.85, 133.51,
128.30, 128.27, 127.83, 127.79, 127.64, 127.60, 117.72, 97.25, 77.36,
68.86, 68.30, 62.41, 55.07. IR (thin film, cmꢀ1
)
nmax: 3053.5, 2926.3,
75.05, 74.56, 73.39, 72.45, 70.30, 68.48, 68.37. IR (thin film, cmꢀ1
)
2866.4, 1686.7, 1612.4, 1586.1, 1513.4, 1461.9, 1265.0, 1248.6, 1087.0,
1035.0, 1001.5, 738.3, 701.1. HRMS (ESI): calcd for C32H36O8Na
[MþNa]þ: 571.2302; found 571.2296.
nmax: 3413.1, 3056.2, 2923.0, 2865.4, 1637.7, 1597.8, 1545.5, 1496.2,
1454.1, 1265.5, 1149.1, 1118.4, 1048.2, 738.7, 702.4. HRMS (ESI): calcd
for C23H28O6Na [MþNa]þ: 423.1778; found 423.1772.
4.2.3. (2R,3R,4S,5R,6S)-6-(Allyloxy)-2-(hydroxymethyl)-4,5-bis((4-
methoxybenzyl)oxy)tetrahydro-2H-pyran-3-ol (35). To a solution of
34(1.1 g, 2.0 mmol) in MeOH (10 mL) was added p-TsOH$H2O
(190 mg, 1.0 mmol), and the mixture was stirred at rt for 4 h. The
reaction was quenched by Et3N, and the solvent was removed un-
der reduced pressure. The residue was purified by column chro-
4.2.5. (2S,4S,5S,6R)-2-(Allyloxy)-5-(benzyloxy)-6-((benzyloxy)
methyl)-4-hydroxydihydro-2H-pyran-3(4H)-one (37). To a solution
of DMSO (73 mL,1.0 mmol) in DCM (5 mL), was slowly added (COCl)2
(43
m
L, 0.51 mmol) at ꢀ78 ꢁC, and the mixture was stirred at this
temperature for 15 min, then a solution of 36 (136 mg, 0.34 mmol)
in DCM (2 mL) was added dropwise. After 1 h at ꢀ78 ꢁC, Et3N () was
added and the reaction was warmed to rt over 30 min, then satu-
rated aq NH4Cl was added. The mixture was extracted by EtOAc.
The organic layer was washed with H2O and brine, dried over
Na2SO4, filtered, concentrated in vacuo. Purification by flash col-
umn chromatography (petroleum ether/ethyl acetate) yielded al-
matography (petroleum ether/ethyl acetate 1:1 to 1:2) to afford
26.8
alcohol 35 (762 mg, 80%) as a colorless oil. [
a]
þ24.0 (c 1.00,
D
CHCl3). 1H NMR (400 MHz, CDCl3):
d
7.26 (d, J¼8.4 Hz, 4H), 6.85 (d,
J¼8.0 Hz, 4H), 5.87e5.96 (m, 1H), 5.31 (dd, J¼1.6, 17.2 Hz, 1H),
5.19e5.22 (m, 1H), 4.90 (d, J¼10.8 Hz, 1H), 4.75 (d, J¼3.6 Hz, 1H),
4.65 (dd, J¼1.6, 11.2 Hz, 2H), 4.55 (d, J¼11.6 Hz, 1H), 4.14 (dd, J¼5.2,
13.2 Hz, 1H), 3.98 (dd, J¼6.4, 12.8 Hz, 1H), 3.72e3.80 (m, 7H),
3.60e3.64 (m, 2H), 3.50 (t, J¼9.2 Hz, 1H), 3.45 (dd, J¼3.6, 9.6 Hz,
cohol 37 (70 mg, 52%) as colorless oil. [
a
]
27.0 þ132.7 (c 0.52, CHCl3).
D
1H NMR (400 MHz, CDCl3):
d
7.33e7.37 (m, 5H), 7.28e7.32 (m, 5H),
5.79e5.89 (m, 1H), 5.25e5.30 (m, 2H), 5.19 (dd, J¼1.2, 10.4 Hz, 1H),
4.88 (d, J¼11.2 Hz, 1H), 4.63 (d, J¼12.4 Hz, 1H), 4.52 (d, J¼12.0 Hz,
1H), 4.44 (d, J¼11.2 Hz, 1H), 4.37 (dq, J¼1.2, 4.4 Hz, 1H), 4.32 (dd,
J¼1.2, 9.6 Hz, 1H), 4.14e4.19 (m, 1H), 3.98e4.06 (m, 2H), 3.72e3.81
2H), 2.93 (s, 1H), 2.49 (s, 1H). 13C NMR (100 MHz, CDCl3):
d 159.23,
159.13, 133.65, 130.84, 130.10, 129.46, 129.41, 117.95, 113.78, 113.70,
95.62, 80.89, 79.33, 74.82, 72.42, 70.93, 70.13, 68.09, 61.97, 55.09,
55.08. IR (thin film, cmꢀ1
)
nmax: 3431.9, 3054.5, 2924.3, 2838.5,
(m, 2H), 3.31 (d, J¼8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 204.6,
1612.5, 1586.0, 1513.6, 1463.1, 1265.3, 1249.0, 1094.9, 1057.6, 1035.2,
137.8, 137.1, 132.9, 128.4, 128.3, 128.1, 127.9, 127.8, 118.1, 100.2, 78.1,
Please cite this article in press as: Xiao, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.028

M. Xiao et al. / Tetrahedron xxx (2014) 1e10
7
77.2, 75.0, 73.6, 73.3, 68.8, 68.1 IR (thin film, cmꢀ1
)
nmax: 3447.7,
779.3. HRMS (ESI): calcd for C16H32O7NaSi [MþNa]þ: 387.1810;
3061.1, 3032.0, 2924.7, 2854.6, 1739.1, 1612.9, 1546.2, 1496.4,1454.8,
1264.8, 1074.7, 1049.2, 1027.8, 739.1, 700.4. HRMS (ESI): calcd for
found 387.1811.
C
23H26O6Na [MþNa]þ: 421.1622; found 421.1617.
4.2.9. 2-((2R,6S)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(methox-
ymethoxy)-3-oxo-3,6-dihydro-2H-pyran-2-yl)-2-(1-tosyl-1H-indol-3-
yl)indolin-3-one (52). To a solution of compound 47 (137 mg,
0.38 mmol) in anhydrous THF (3 mL) at ꢀ78 ꢁC was added a THF
solution of LDA (0.5 M,1.1 mL). The mixture was stirred for 30 min at
ꢀ78 ꢁC. A solution of compound 26 (94 mg, 0.24 mmol) in THF (1 mL)
was added dropwise. The resulting solution was warmed to ꢀ30 ꢁC
over 30 min, and then stirred for 4.5 h at rt, and then quenched with
water. The resulting mixture was transferred to a separatory funnel
and the phases were allowed to separate. The aqueous layer was
extracted with EtOAc (3ꢂ20 mL). The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and evaporated un-
der reduced pressure. The crude product was purified by silica gel
flash column chromatography (ethyl acetate/petroleum ether¼1:2)
4.2.6. (2S,4R,5R)-Methyl 2-(allyloxy)-4-(benzyloxy)-5-((benzyl oxy)
methyl)-3-hydroxytetrahydrofuran-3-carboxylate (38). To a solu-
tion of 37 (22 mg, 0.055 mmol) in MeOH (2 mL) and DCM (2 mL),
was added CuCl (109 mg, 1.11 mmol). The reaction was refluxed at
50 ꢁC for 6 h under air. The solid was filtered over a short silica
column chromatography with DCM. The organic solvent was
concentrated in vacuo, and the residue was purified by flash col-
umn chromatography (petroleum ether/ethyl acetate) to afford
27.2
alcohol 38 (11 mg, 47%) as a colorless oil. [
a
]
þ120.0 (c 0.10,
D
CHCl3). 1H NMR (400 MHz, CDCl3):
d
7.26e7.30 (m, 10H),
5.84e5.94 (m, 1H), 5.29 (dd, J¼1.2, 17.2 Hz, 1H), 5.18e5.21 (m, 2H),
4.70 (d, J¼12.0 Hz, 1H), 4.46e4.57 (m, 3H), 4.29e4.34 (m, 1H),
4.20e4.24 (m, 1H), 4.09e4.14 (m, 2H), 3.74 (s, 3H), 3.63e3.66 (m,
2H), 3.55 (dd, J¼5.2, 10.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
to afford 101 mg (61%) of 52. [
a
]
17.8 ꢀ24.9 (c 0.82, CH3OH). 1H NMR
D
(400 MHz, CDCl3):
d
7.88 (d, J¼8.4 Hz, 1H),7.61e7.74 (m, 5H), 7.41 (t,
d
172.2, 138.0, 137.3, 133.5, 128.4, 128.3, 128.1, 128.0, 127.7, 127.6,
J¼0.8 Hz, 1H),7.43 (s, 2H), 7.39e7.43 (m, 4H), 6.83 (t, J¼8.0 Hz, 2H),
6.25 (d, J¼4.4 Hz, 1H), 5.70 (s, 1H), 5.50 (s, 1H), 4.99 (d, J¼6.8 Hz, 1H),
4.94 (d, J¼6.8 Hz, 1H),4.54e4.56 (m, 1H), 3.87e3.91 (m, 1H),
3.67e3.71 (m, 1H), 3.37 (s, 3H), 2.29 (s, 3H), 0.83 (s, 9H), 0.01 (s, 3H),
117.9, 102.4, 80.8, 80.0, 79.7, 73.4, 73.0, 69.1, 69.0, 52.8. IR (thin
film, cmꢀ1
)
nmax: 3297.2, 3059.2, 3032.0, 2918.4, 2850.3, 1741.2,
1658.6, 1597.0, 1544.2, 1511.7, 1454.4, 1265.6, 1106.7, 1072.5,
1043.3, 738.6, 701.0. HRMS (ESI): calcd for C24H28O7Na [MþNa]þ:
451.1727; found 451.1719.
0.05 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 196.8, 187.6, 159.5, 147.3,
144.9,136.7,135.5,134.9,129.8,128.3,126.8,125.2,125.0,124.6,123.3,
121.7, 121.0, 120.1, 119.5, 118.7, 113.5, 111.8, 94.3, 82.4, 73.5, 70.3, 65.1,
4.2.7. (4R,5R,6R)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-4,5-
bis(methoxymethoxy)tetrahydro-2H-pyran-3-ol (46). To a stirred so-
lution of compound 45(800 mg, 2.3 mmol) in THF (20 mL) cooled in
an ice bath, was added an excess of BH3$SMe2 complex (0.81 mL, 2 M
in THF, 1.6 mmol). After stirring for 12 h at rt, excess borane was
destroyed by careful addition of water (1.1 mL). Sodium hydroxide
solution (3 M, 4.6 mL) was then added all at once, followed by
dropwise addition of aq hydrogen peroxide (30%, 11.5 mL). After 1 h,
the solution was diluted with ethyl acetate. The organic layer was
washed with H2O and brine, dried over Na2SO4, filtered, concentrated
in vacuo. Purification by flash column chromatography (petroleum
ether/ethyl acetate 4:1) yielded alcohol 46 (766 mg, 91%) as a color-
56.2, 25.6, 21.5, 18.0, ꢀ5.75, ꢀ5.80. IR (thin film, cmꢀ1
) nmax: 3399.8,
2954.1, 2929.1, 2856.7, 1700.6, 1618.9, 1486.5, 1469.2, 1371.2, 1320.7,
1173.4, 1147.7, 967.6, 838.2, 750.5, 537.2. HRMS (ESI): calcd for
C
37H42N2NaO8SSi [MþNa]þ: 725.2323; found 725.2314.
4.2.10. 2-((2R,5R,6R)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-4,4,5-
trihydroxy-3-oxotetrahydro-2H-pyran-2-yl)-2-(1-tosyl-1H-indol-3-
yl)indolin-3-one (53). To a solution of 52 (225 mg, 0.32 mmol) in
THF/H2O (3:1, 8 mL) was added NMO (150 mg, 50%), MeSO2NH2
(36 mg, 0.38 mmol), catalytic amount of OsO4 successively, and the
mixture was stirred at room temperature for 2 h. Then aq NaHSO3
was added, and the resulting mixture was extracted with EtOAc.
The combined organic fractions were dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by column chroma-
tography (petroleum ether/ethyl acetate, 4:1) to provide 53
(122 mg) in 55% yield. The product was unstable and the next step
was undergone immediately.
less oil. 1H NMR (400 MHz, CDCl3):
d
4.77e4.80 (m, 1H), 4.73 (d, J¼2.8
Hz, 3H), 4.34 (s, 1H), 4.00e4.04 (m, 1H), 3.86 (d, J¼11.6 Hz, 1H),
3.73e3.77 (m, 1H), 3.50e3.55 (m, 2H), 3.45 (s, 3H), 3.37 (d, J¼2.8 Hz,
3H), 3.25e3.29 (m, 1H), 3.10e3.16 (m, 2H), 0.87 (s, 9H), 0.06 (s, 6H).
13C NMR (100 MHz, CDCl3):
d 98.4, 97.9, 90.4, 80.3, 74.3, 69.1, 62.5,
56.0, 55.8, 25.8, 18.3, ꢀ5.2, ꢀ5.5. IR (thin film, cmꢀ1
) nmax: 3439.1,
2930.8, 2855.9, 1467.5, 1385.9, 1253.1, 1150.4, 1102.0, 1027.9, 835.9,
778.7. HRMS (ESI): calcd for C16H34O7NaSi [MþNa]þ: 389.1966; found
389.1962.
4.2.11. (2R,4R,5R)-Methyl 5-(((tert-butyldimethylsilyl)oxy) methyl)-
3,4-dihydroxy-2-(3-oxo-2-(1-tosyl-1H-indol-3-yl)indolin-2-yl)tetra-
hydrofuran-3-carboxylate (54). To
a solution of 53 (122 mg,
0.18 mmol) in MeOH/CH2Cl2 (1:1, 6 mL) was added CuCl (454 mg,
4.6 mmol), and the mixture was refluxed for 2 h. Then, the reaction
mixture was filtered over a short silica gel column using CH2Cl2. The
filtrate was concentrated in vacuo and the residue was purified by
4.2.8. (4S,5R,6R)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-4,5-
bis(methoxymethoxy)dihydro-2H-pyran-3(4H)-one (47). To a solu-
tion of Dess-Martin periodinane (1.36 g, 3.2 mmol) in CH2Cl2
(20 mL) at rt was added NaHCO3 (897 mg, 10.7 mmol) and alcohol
46 (782 mg, 2.1 mmol). The reaction was stirred for 2 h at rt, at,
which point it was quenched with water. The mixture was
extracted with CH2Cl2 for three times and the combined organic
fractions were dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography (petroleum ether/
ethyl acetate, 4:1) to provide 47 (707 mg, 91%) as a colorless oil.
column chromatography (petroleum ether/ethyl acetate, 2:1) to
17.8
provide 54 (113 mg, 91%). [
a
]
ꢀ1.5 (c 1.07, CH3OH). 1H NMR
D
(400 MHz, CDCl3):
d
7.87 (d, J¼8.4 Hz, 1H), 7.78 (s, 1H), 7.73e7.75
(m, 3H), 7.56 (d, J¼7.6 Hz, 1H), 7.47e7.51 (m, 5H), 6.94 (d, J¼8.0 Hz,
1H), 6.86 (t, J¼7.2 Hz, 1H), 5.56 (s, 1H), 5.27 (s, 1H), 4.60e4.65 (m,
1H), 4.27 (s,1H), 3.69e3.84 (m, 3H), 3.66 (s, 3H), 2.55 (d, J¼11.2,1H),
2.31 (s, 3H), 0.77 (s, 9H), ꢀ0.12 (s, 3H), ꢀ0.23 (s, 3H). 13C NMR
Rf¼0.20 (silica gel, petroleum ether/ethyl acetate 4:1) [
a
]
17.9 þ0.3 (c
(100 MHz, CDCl3): d 199.6, 172.1, 161.5, 144.9, 137.8, 135.6, 135.1,
D
0.94, CHCl3). 1H NMR (400 MHz, CDCl3):
d
4.80e4.85 (m, 2H),
129.8, 128.0, 1227.0, 125.1, 124.9, 124.6, 123.2, 121.7, 121.0, 119.9,
119.7, 113.5, 113.4, 83.7, 83.6, 81.2, 69.9, 62.4, 53.4, 25.6, 21.5, 18.1,
4.72e4.77 (m, 2H), 4.36 (d, J¼9.2 Hz, 1H), 4.15 (d, J¼15.2 Hz, 1H),
3.95e3.99 (m, 2H), 3.88e3.93 (m, 2H), 3.82e3.86 (m, 1H), 3.43 (s,
3H), 3.39 (s, 3H), 0.68 (s, 9H), 0.04 (s, 6H). 13C NMR (100 MHz,
ꢀ5.8, ꢀ5.8. HRMS (ESI): calcd for
C
36H43N2O9SSi [MþH]þ:
707.2453; found 707.2443.
CDCl3): d 203.3, 97.8, 96.8, 81.8, 80.4, 76.6, 72.6, 62.8, 56.3, 56.1, 25.8,
18.2, ꢀ5.4, ꢀ5.5. IR (thin film, cmꢀ1
)
nmax: 2954.3, 2931.3, 2895.0,
4.2.12. (2R,3R,10bR)-3,3a-Dihydroxy-2-(hydroxymethyl)-10a-(1-
tosyl-1H-indol-3-yl)-3,3a-dihydro-2H-furo[20,30:3,4]pyrrolo [1,2-a]
2857.0, 1743.8, 1468.5, 1361.8, 1254.1, 1151.2, 1106.5, 1025.6, 837.2,
Please cite this article in press as: Xiao, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.028

8
M. Xiao et al. / Tetrahedron xxx (2014) 1e10
indole-4,10(10aH,10bH)-dione (57). To a solution of 54 (125 mg,
0.18 mmol) in toluene (6 mL) was added p-TsOH$H2O (84 mg,
0.44 mmol) and the solution was refluxed for 2.5 h aq NaHCO3 was
poured into the flask and the mixture was extracted by EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and evaporated under reduced pressure. The res-
idue was purified by column chromatography (petroleum ether/
3.16e3.29 (m, 2H), 1.49 (s, 3H), 1.40 (s, 3H); 13C NMR (100 MHz,
CDCl3): 136.9, 128.5, 128.0, 127.9, 99.4, 95.9, 84.6, 72.5, 72.4, 70.2,
d
70.1, 69.8, 62.2, 29.0, 19.0; IR (thin film, cmꢀ1
) nmax: 3435.3, 2881.8,
1376.9, 1103.4, 1032.4; HRMS (ESI): calcd for C17H24NO6 [MþNH4]þ:
342.1911; found 342.1903.
4 . 2 .16 . ( 4 a R , 8 S , 8 a R ) - 8 - ( ( B e n z y l o x y ) m e t h o x y ) - 2 , 2 -
dimethyltetrahydropyrano[3,2-d][1,3]dioxin-7(6H)-one
(61). According to the similar procedure for 47, 61 (2.14 g) was
afforded as a colorless oil by flash column chromatography (pe-
ethyl acetate, 1:2) to provide 57 (63 mg) in 64% yield. [
a
]
17.8 ꢀ5.8 (c
D
1.06, CH3OH). 1H NMR (400 MHz, CDCl3):
d
7.91 (d, J¼8.4 Hz, 1H),
7.76 (s, 1H), 7.72 (d, J¼8.4 Hz, 2H), 7.66 (t, J¼8.8 Hz, 2H), 7.52e7.56
(m, 1H), 7.29 (t, J¼8.0 Hz, 1H) 7.17e7.20 (m, 3H), 7.12 (d, J¼8.4 Hz,
1H), 7.06 (t, J¼7.6 Hz, 1H), 6.17 (brs, 1H), 5.14 (s, 1H), 4.47 (s, 1H),
4.36 (d, J¼12.4 Hz, 1H), 4.25e4.28 (m, 1H), 2.31 (s, 3H). 13C NMR
troleum ether/ethyl acetate 10:1 to 4:1) in 95% yield. [
a
]
27.9 ꢀ31.5 (c
D
0.54, CHCl3). 1H NMR (400 MHz, CDCl3):
d
7.26e7.39 (m, 5H), 4.96
(dd, J¼6.8, 10.8 Hz, 2H), 4.80 (d, J¼11.2 Hz, 1H), 4.63 (d, J¼11.2 Hz,
1H), 4.41 (d, J¼10.4 Hz, 1H), 4.19 (d, J¼15.2 Hz, 1H), 4.00e4.04 (m,
2H), 3.95 (t, J¼9.6 Hz,1H), 3.80 (t, J¼10.0 Hz,1H), 3.58e3.64 (m,1H),
3.16e3.29 (m, 2H), 1.53 (s, 3H), 1.43 (s, 3H). 13C NMR (100 MHz,
(100 MHz, CDCl3):
d 197.8, 173.0, 158.4, 145.4, 136.9, 135.5, 134.7,
130.0,127.8,127.0,125.2,125.1,124.8,123.9,123.6,122.6,121.6,117.9,
115.0, 113.8, 86.5, 80.3, 79.6, 74.0, 71.3, 70.6, 21.5. IR (thin film,
cmꢀ1
)
nmax: 3644.7, 3297.7, 3150.6, 2920.7, 1752.4, 1703.4, 1614.6,
CDCl3):
d
202.3, 137.5, 128.4, 128.3, 127.8, 99.5, 94.4, 74.7, 74.2, 71.9,
nmax: 2922.7, 1737.0,
1470.5, 1370.2, 1172.1, 1090.4, 930.9, 754.5, 575.3. HRMS (ESI): calcd
69.5, 62.1, 29.0, 19.0; IR (thin film, cmꢀ1
)
for C29H25N2O6S [MþH]þ: 561.1326; found 561.1319.
1380.4, 1113.4, 1040.3, 699.5; HRMS (ESI): calcd for C17H26NO6
[MþNH4]þ: 340.1755; found 340.1762.
4.2.13. (2R,3R,10bR)-3,3a-Dihydroxy-2-(hydroxymethyl)-10a-(1H-
indol-3-yl)-3,3a-dihydro-2H-furo[20,30:3,4]pyrrolo[1,2-a]indole-
4,10(10aH,10bH)-dione (56). The compound 57 (20 mg,
0.036 mmol) in CH3OH/PhH (1:9, 10 mL) was carefully sealed and
irradiated using a UV lamp for 2.5 h. The resulting mixture was
concentrated in vacuo and then purified by flash column chroma-
4.2.17. 2-((4aR,6S,8S,8aR)-8-((Benzyloxy)methoxy)-2,2-dimethyl-7-
oxohexahydropyrano[3,2-d][1,3]dioxin-6-yl)-2-(1-tosyl-1H-indol-3-
yl)indolin-3-one (62). According to the similar procedure for 52, 62
(117 mg) was afforded as a colorless oil by flash column chroma-
tography (petroleum ether/ethyl acetate 9:2) in 75% yield. The
product is unstable, so 1H NMR and 13C NMR of pure 62 could not
be obtained, Rf¼0.38 (silica gel, petroleum ether: ethyl acetate 2:1).
tography (silica gel, CH2Cl2/MeOH 50:1) to give compound 56
17.8
(4 mg) in 27% yield. [
a
]
ꢀ12.4 (c 0.42, CH3OH). 1H NMR
D
(400 MHz, CD3OD):
d
7.51e7.57 (m, 3H), 7.45 (s, 1H), 7.31 (d, J¼8.0
Hz, 1H), 7.15 (d, J¼8.4 Hz, 1H), 7.04 (t, J¼7.6 Hz, 1H), 6.97 (t, J¼7.6 Hz,
1H), 6.89 (t, J¼8.0 Hz, 1H), 5.30 (s, 1H), 4.44 (s, 1H), 4.33 (s, 2H), 4.08
4.2.18. (S)-2-((2S,4S,5R,6R)-4-((Benzyloxy)methoxy)-5-hydroxy-6-
(hydroxymethyl)-3-oxotetrahydro-2H-pyran-2-yl)-2-(1-tosyl-1H-in-
dol-3-yl)indolin-3-one (63a) and (R)-2-((2S,4S,5R,6R)-4-((benzyloxy)
methoxy)-5-hydroxy-6-(hydroxymethyl)-3-oxotetrahydro-2H-pyran-
2-yl)-2-(1-tosyl-1H-indol-3-yl)indolin-3-one (63b). To a solution of
compound 62 (147 mg, 0.204 mmol) in MeOH (5 mL) at rt was
added HCl (2 N, 0.5 mL). The mixture was stirred for 2 h at, which
point the solvent was removed. The remaining yellow-orange res-
idue was preadsorbed onto silica and purified by flash column
chromatography (ethyl acetate/petroleum¼1.5:1) to yield com-
pound 63a (39.7 mg) and 63b (75.3 mg) as a light yellow solid,
Rf¼0.20 (silica gel, petroleum ether: ethyl acetate 1; 2).
(s, 1H). 13C NMR (100 MHz, CD3OD):
d 202.6, 175.3, 162.0, 139.0,
137.6, 126.4, 125.6, 125.4, 125.3, 122.7, 122.1, 121.9, 120.3, 115.9,
112.9, 112.7, 88.0, 82.4, 81.4, 75.2, 72.9, 72.8. IR (thin film, cmꢀ1
)
nmax: 3429.6, 2924.0, 2855.0, 1744.4, 1705.7, 1617.1, 1466.9, 1321.7,
1289.5, 1171.5, 1094.7, 749.8. HRMS (ESI): calcd for C22H19N2NaO6
[MþH]þ: 407.1238; found 407.1240.
4.2.14. (4aR,8R,8aS)-8-((Benzyloxy)methoxy)-2,2-dimethyl-
4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxine (59). To a solution of
compound 58 (1.55 g, 8.33 mmol) in CH2Cl2 (15 mL) was added
DIPEA (3.59 mL, 20.82 mmol), BOMCl (2.31 mL, 16.66 mmol) and
TBAI (306.27 mg, 0.83 mmol) at 0 ꢁC. The resulting mixture was
stirred under rt for 10 h. The reaction mixture was quenched with
saturated aqueous NH4Cl solution, and extracted with ethyl acetate.
The organic layer was washed with H2O and brine, dried over
Na2SO4, filtered, concentrated in vacuo. Purification by flash col-
Both of the absolute configurations of C11 in six-member ring of
63a and 63b were determined by its NOE experiments. Meanwhile,
the absolute configuration of C2 in 63a and 63b were determined
by the experimental and computational optical rotation data (the
B3LYP/6-31G method). Giving 63a as our desired configuration and
63b as its diastereomer, the sum of optical rotation data for can-
didate 63a is ꢀ274.44 and 63b is 233.78. The optical rotation of
minor and major product was measured to be ꢀ92.0 and 90.0, re-
spectively. The desired 63a was matched with the experimental
minor product, which suggested the configuration of minor prod-
uct. Thus, the minor S7 and major product was elucidated as 63a
and 63b, respectively. (Optical rotation calculations were per-
formed using PCM method of salvation and the methanol was
umn chromatography (petroleum ether/ethyl acetate 25:1) yielded
27.9
compound 59 (2.37 g, 93%) as a colorless oil. [
a
]
D
þ19.6 (c 0.51,
CHCl3) 1H NMR (400 MHz, CDCl3):
d
7.25e7.38 (m, 5H), 6.31 (dd,
J¼1.6, 6.4 Hz, 1H), 4.93 (d, J¼6.8 Hz, 1H), 4.84 (d, J¼7.2 Hz, 1H), 4.76
(dd, J¼2.0, 6.0 Hz, 1H), 4.61e4.68 (m, 2H), 4.39e4.42 (m, 1H),
3.86e4.00 (m, 2H), 3.72e3.83 (m, 2H), 1.51 (s, 3H), 1.40 (s, 3H); 13
C
NMR (100 MHz, CDCl3):
d 144.4, 137.8, 128.3, 127.9, 127.6, 102.4,
99.6, 93.6, 71.9, 71.7, 69.7, 69.3, 61.6, 29.0, 19.0; IR (thin film, cmꢀ1
)
specified as the solvent, which was in agreement with the experi-
ꢀ92.0 (c 0.10, CH3OH); 1H
19.3
nmax: 2887.8, 1639.5, 1382.9, 1268.1, 1091.0, 1043.5; HRMS (ESI):
ment condition). Compound 63a [
a
]
D
calcd for C17H26NO5 [MþNH4]þ: 324.1805; found 324.1813.
NMR (400 MHz, CDCl3):
d
7.89 (d, J¼8.4 Hz, 1H), 7.84 (d, J¼8 Hz, 1H),
7.28 (s, 1H), 7.68 (d, J¼8.4 Hz, 2H), 7.48 (d, J¼7.6 Hz, 1H), 7.39e7.43
(m, 3H), 7.15e7.28 (m, 4H), 7.10 (d, J¼8.4 Hz, 2H), 6.82 (d, J¼8.4 Hz,
1H), 6.76 (t, J¼7.2 Hz, 1H), 5.78 (s, 1H), 5.02 (s, 1H), 4.92 (d, J¼7.2 Hz,
1H), 4.69e4.72 (m, 2H), 4.55 (d, J¼11.6 Hz, 1H), 4.33 (d, J¼8.8 Hz,
1H), 3.97 (b,1H), 3.75e3.91 (m, 3H), 3.62e3.66 (m,1H), 2.23 (s, 3H);
4 . 2 .15 . ( 4 a R , 8 R , 8 a R ) - 8 - ( ( B e n z y l o x y ) m e t h o x y ) - 2 , 2 -
dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (60). According to
the similar procedure for 46, 60 (2.27 g) was afforded as a colorless
oil by flash column chromatography (petroleum ether/ethyl acetate
4:1) in 87% yield. 1H NMR (400 MHz, CDCl3):
d
7.26e7.36 (m, 5H),
13C NMR (100 MHz, CDCl3):
d 199.1, 198.4, 161.0, 145.0, 137.9, 136.6,
4.99 (d, J¼6.8 Hz, 1H), 4.87 (d, J¼7.2 Hz, 1H), 4.78 (d, J¼11.6 Hz, 1H),
4.62 (d, J¼11.6 Hz, 1H), 4.01e4.06 (m, 1H), 3.88e3.93 (m, 2H),
3.64e3.70 (m, 2H), 3.57 (t, J¼9.2 Hz, 1H), 3.44 (t, J¼8.8 Hz, 1H),
135.5, 134.7, 129.9, 128.6, 128.2, 127.7, 126.8, 125.0, 124.8, 124.6,
123.5, 121.8, 119.2, 119.1, 117.9, 113.8, 111.8, 95.0, 85.7, 82.0, 80.1, 74.1,
70.6, 69.1, 61.9, 21.5; IR (thin film, cmꢀ1
) nmax: 3516.2, 3411.9, 1712.7,
Please cite this article in press as: Xiao, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.028

M. Xiao et al. / Tetrahedron xxx (2014) 1e10
9
1621.9, 1423.5, 1362.7,1223.3, 1092.5756.4; HRMS (ESI): calcd for
d
7.92 (d, J¼8.0 Hz, 1H), 7.86 (d, J¼8.0 Hz, 1H), 7.68e7.73 (m, 1H),
C
63b [
37H34N2NaO9S [MþNa]þ: 705.1877; found 705.1872. Compound
7.57 (d, J¼7.6 Hz, 1H), 7.23e7.28 (m, 2H), 7.22 (s, 1H), 7.05 (td, J¼0.8,
7.2 Hz,1H), 6.98 (td, J¼0.8, 7.2 Hz,1H), 4.82 (s,1H), 3.98 (d, J¼4.0 Hz,
1H), 3.78 (dd, J¼4.8, 6.0 Hz, 1H), 3.27e3.33 (m, 2H); 13C NMR
a]
19.3 þ90.0 (c 0.10, CH3OH); 1H NMR (400 MHz, CDCl3):
d 7.91
D
(d, J¼8.4 Hz, 1H), 7.75 (s, 1H), 7.67e7.72 (m, 3H), 7.60 (d, J¼7.6 Hz,
1H), 7.35e7.39 (m, 1H), 7.22e7.31 (m, 5H), 7.11e7.16 (m, 3H), 6.81 (t,
J¼7.6 Hz,1H), 6.75 (d, J¼8.4 Hz,1H), 5.90 (s,1H), 4.86 (s,1H), 4.86 (d,
J¼6.8 Hz, 1H), 4.73 (d, J¼7.2 Hz, 1H), 4.67 (d, J¼11.6 Hz, 1H), 4.54 (d,
J¼11.6 Hz, 1H), 4.22 (d, J¼9.6 Hz, 1H), 3.93 (t, J¼9.2 Hz, 2H), 3.72 (s,
2H), 3.63e3.66 (b, 1H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3):
(100 MHz, CD3OD):
d 196.7, 174.6, 151.8, 139.0, 137.8, 127.3, 126.8,
126.1, 126.0, 124.5, 123.0, 121.4, 120.5, 117.7, 112.8, 110.5, 89.8, 88.9,
84.6, 76.7, 74.2, 63.1; IR (thin film, cmꢀ1
)
nmax: 3392.4, 2923.4,
1716.3, 1602.3, 1468.6, 1374.4, 1073.7, 747.5; HRMS (ESI): calcd for
C
22H22N3O6 [MþNH4]þ: 424.1503; found 425.1568.
d
198.4, 160.1, 145.2, 137.2, 136.8, 135.5, 134.5, 129.9, 128.44, 128.10,
128.07, 127.93, 126.7, 125.3, 124.8, 123.4, 121.6, 120.6, 119.1, 118.7,
Acknowledgements
113.7, 112.0, 95.3, 84.6, 79.7, 71.5, 70.3, 68.7, 61.4, 21.4; IR (thin film,
cmꢀ1
) nmax: 3392.6, 1698.6, 1619.6, 1447.5, 1370.0, 1174.1, 1094.2,
We gratefully acknowledge financial support from the NSFC
(Grant Nos. 21072083 and 21272104), 973 Program (Grant
2010CB833203), the program for Changjiang Scholars and In-
novative Research Team in University (PCSIRT: IRT1138), the fund
for the Doctoral Program of Higher Education of China (No.
20110211110009) and the Fundamental Research Funds for the
Central Universities (Nos. lzujbky-2012-56, lzujbky-2013-ct02).
749.0, 575.9; HRMS (ESI): calcd for C37H34N2NaO9S [MþNa]þ:
705.1877; found 705.1869.
4.2.19. (2S,3R,4R,5R)-Methyl 3,4-dihydroxy-5-(hydroxymethyl) -2-
((R)-3-oxo-2-(1-tosyl-1H-indol-3-yl)indolin-2-yl)tetrahydro-furan-
3-carboxylate (64b). To a solution of 63b (64 mg, 0.094 mmol) in
methanol (5 mL) was added 20w% Pd(OH)2/C (13 mg). After stirring
for 4 h under hydrogen atmosphere at room temperature, the re-
action mixture was filtrated. The filtrate was concentrated under
reduced pressure, then copper(I) chloride (279.2 mg, 2.82 mmol)
was added to a solution of the residue in 1:1 MeOH/CH2Cl2 (6 mL),
and the mixture was warmed to reflux for 6 h. The resulting mix-
ture was then directly subjected to flash column chromatography
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.09.028.
References and notes
(silica gel, CH2Cl2/MeOH 30:1) to give the desired 64b (34 mg) in
19.2
1. Zheng, H. Z.; Dong, Z. H.; Yu, Q. Modern Study of Traditional Chinese Medicine;
Xueyuan: Beijing, 1997, Vol. 1, pp 328e334.
62% yield, Rf¼0.59 (silica gel, CH2Cl2/MeOH 10:1) [
a
]
þ60.0 (c
D
0.10, CH3OH). 1H NMR (400 MHz, CDCl3):
d
7.93 (d, J¼8.0 Hz, 1H),
2. (a) Huang, Q. S.; Yoshihira, K.; Natori, S. Planta Med. 1981, 42, 308e310; (b) Wu,
X. Y.; Liu, Y. H.; Sheng, W. Y.; Sun, J.; Qin, G. W. Planta Med. 1997, 63, 55e57; (c)
Wu, X. Y.; Qin, G. W. Tetrahedron 1997, 53, 13323e13328; (d) Mak, N. K.; Leung,
C. Y.; Wei, X. Y.; Shen, X. L.; Wong, R. N.; Leung, K. N.; Fung, M. C. Biochem.
Pharmacol. 2004, 67, 167e174; (e) Peng, S. P.; Gu, Z. L. Chin. Wild Plant Resour.
2005, 24, 4e7; (f) Shi, X.; Ni, Y.; Liu, Y. H. Chin. Hosp. Pharm. J. 2006, 26,
1397e1399.
7.87 (d, J¼8.4 Hz, 1H), 7.72 (s, 1H), 7.65 (d, J¼8.0 Hz, 2H), 7.53 (d,
J¼7.6 Hz, 1H), 7.44 (t, J¼7.2 Hz, 1H), 7.24 (t, J¼8.0 Hz, 1H), 7.17 (t,
J¼7.6 Hz, 1H), 7.11 (d, J¼8.0 Hz, 2H), 6.93 (d, J¼8.4 Hz, 1H), 6.81 (t,
J¼7.6 Hz, 1H), 6.26 (s, 1H), 4.88 (s, 1H), 4.53 (b, 1H), 4.15 (b, 1H),
3.81e3.87 (b, 3H), 3.11 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz,
3. Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.; Zhang, X.-M.; Ma, Y.-B.
Org. Lett. 2007, 9, 4127e4129.
CDCl3):
126.8, 125.4, 124.8, 124.7, 123.5, 122.1, 119.7, 119.6, 119.64, 113.7,
112.2, 87.9, 83.8, 79.9, 73.6, 69.9, 61.4, 52.6, 21.5; IR (thin film, cmꢀ1
d 197.3, 172.0, 160.0, 145.1, 137.7, 135.7, 134.7, 129.9, 128.1,
4. (a) Karadeolian, A.; Kerr, M. A. Angew. Chem. Int. Ed. 2010, 49, 1133e1135; (b)
Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2010, 75, 6830e6841; (c) Lee, J.; Panek,
J. S. Org. Lett. 2011, 13, 502e505; (d) Zhang, X.; Mu, T.; Zhan, F. X.; Ma, L. J.;
Liang, G. X. Angew. Chem. Int. Ed. 2011, 50, 6164e6166; (e) Wu, W.; Xiao, M.;
Wang, J.; Li, Y.; Xie, Z. Org. Lett. 2012, 14, 1624e1627; (f) Pater, P.; Ramana, C. V. J.
Org. Chem. 2012, 77, 10509e10515.
)
nmax: 3394.1, 2922.8, 1726.3, 1619.0, 1446.5, 1370.1, 1174.4, 748.7;
HRMS (ESI): calcd for C30H28N2NaO9S [MþNa]þ: 615.1408; found
615.1398.
5. Watanabe, H.; Nakada, M. J. Am. Chem. Soc. 2008, 130, 1150e1151.
6. (a) Kokubun, T.; Edmonds, J.; John, P. Phytochemistry 1998, 49, 79e87; (b)
Maugarda, T.; Enauda, E.; Choisyb, P.; Legoya, M. D. Phytochemistry 2001, 58,
897e904.
4.2.20. (2S,3R,4R,5R)-Methyl 2-((R)-2-(1H-indol-3-yl)-3-oxoindolin-
2-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-3-
carboxylate (65b). The compound 64b (62 mg, 0.105 mmol) in
CH3OH/PhH (44 mL, 1:10) was carefully sealed and irradiated using
a UV lamp for 2.5 h. The resulting mixture was then directly sub-
jected to flash column chromatography (silica gel, CH2Cl2/MeOH
7. (a) Young, T. E.; Auld, D. S. J. Org. Chem. 1963, 28, 418e421; (b) Chien, C. S.;
Takanami, T.; Kawasaki, T.; Sakamoto, M. Chem. Pharm. Bull. 1985, 33,
1843e1848; (c) Ling, K. Q. Synth. Commun. 1996, 26, 149e152; (d) Clawson, R.
€
W., Jr.; Dacko, C. A.; Deavers, R. E., III; Akhmedov, N. G.; Soderberg, B. C. G.
Tetrahedron 2009, 65, 8786e8793; (e) Higuchi, K.; Sato, Y.; Kojima, S.; Tsuchi-
mochi, M.; Sugiura, K.; Hatori, M.; Kawasaki, T. Tetrahedron 2010, 66,
18:1) to give compound 65b (32.5 mg) in 46% yield, Rf¼0.29 (silica
ꢀ~
1236e1243; (f) Rueping, M.; Raja, S.; Nunez, A. Adv. Synth. Catal. 2011, 353,
20.9
gel, CH2Cl2/MeOH 10:1). [
a
]
350.5 (c 0.39, CH3OH); 1H NMR
D
563e568.
(400 MHz, CD3OD):
d
7.89 (d, J¼7.6 Hz, 1H), 7.43e7.48 (m, 2H), 7.29
8. For reviews, see: (a) Selman, S.; Easthan, J. F. Quart. Rev. Chem. Soc. 1960, 14,
221e235; (b) Rubin, M. B. Chem. Rev. 1975, 75, 177e202; (c) Burke, A. J.; Mar-
ques, C. S. Mini Rev. Org. Chem. 2007, 4, 310e316 For examples: (d) Rajyaguru, I.;
Rzepa, H. S. J. Chem. Soc., Perkin Trans. 2 1987, 1819e1827; (e) Stoltz, B. M.;
Wood, J. L. Tetrahedron Lett. 1996, 37, 3929e3930; (f) Hotchkiss, D. J.; Jenkinson,
S. F.; Storer, R.; Heinzc, T.; Fleet, G. W. J. Tetrahedron Lett. 2006, 47, 315e318; (g)
Marques, C. S.; Moura, N.; Burke, A. J. Tetrahedron Lett. 2006, 47, 6049e6052; (h)
Yamabe, S.; Tsuchida, N.; Yamazaki, S. J. Org. Chem. 2006, 71, 1777e1783; (i)
Umland, K. D.; Palisse, A.; Haug, T. T.; Kirsch, S. F. Angew. Chem. Int. Ed. 2011, 50,
9965e9968.
(d, J¼8.8 Hz,1H), 7.25 (s, 1H), 7.05 (t, J¼7.6 Hz, 1H), 6.86 (d, J¼8.0 Hz,
2H), 6.74 (t, J¼7.2 Hz, 1H), 5.04 (s, 1H), 4.44 (d, J¼7.2 Hz, 1H),
3.73e3.84 (m, 3H), 3.14 (s, 3H), 2.37 (s, 1H); 13C NMR (100 MHz,
CD3OD):
122.5, 122.1, 121.0, 120.0, 119.1, 113.0, 112.6, 90.4, 84.2, 81.7, 75.3,
72.2, 62.6, 52.4; IR (thin film, cmꢀ1
nmax: 3356.2, 2922.8, 1695.7,
d 200.7, 173.2, 162.5, 138.9, 138.3, 130.9, 128.3, 125.9, 124.5,
)
1616.6, 1326.0, 1248.1,1084.6; HRMS (ESI): calcd for C23H23N3O7
9. Hanessian, S.; Roy, R. Can. J. Chem. 1985, 63, 163e172.
10. Izumi, M.; Fukase, K.; Kusumoto, S. Biosci. Biotechnol. Biochem. 2002, 66,
[MþH]þ: 439.1500; found 439.1497.
211e214.
11. Li, L.; Han, M.; Xiao, M.; Xie, Z. Synlett 2011, 1727e1730.
12. (a) Astolfi, P.; Panagiotaki, M.; Rizzoli, C.; Greci, L. Org. Biomol. Chem. 2006, 4,
3283e3290; (b) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54,
13915e13928.
13. Liu, Y. H.; McWhorter, W. W. J. Org. Chem. 2003, 68, 2618e2622.
14. Mg/MeOH: (a) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997,
1017e1018; (b) Mandal, D.; Yamaguchi, A. D.; Yamaguchi, J.; Itami, K. J. Am.
Chem. Soc. 2011, 133, 19660e19663 Na/aphthalene: (c) Bergmeier, S. C.; Seth, P.
P. J. Org. Chem. 1999, 64, 3237e3243 SmI2: (d) Vedejs, E.; Lin, S. J. Org. Chem.
4.2.21. (ꢀ)-Isatisine A (3). To a solution of compound 65b (11 mg,
0.025 mmol) in CH2Cl2 (8 mL) CSA (17.5 mg, 0.075 mmol) was
added. The solution was stirred at room temperature for 48 h. The
resulting mixture was then directly subjected to flash column
chromatography (silica gel, CH2Cl2/MeOH 20:1) to give the desired
isatisine A (6.4 mg) in 63% yield. Rf¼0.48 (silica gel, CH2Cl2/MeOH
19.2
10:1) [
a
]
ꢀ235.0 (c 0.50, CH3OH). 1H NMR (400 MHz, CD3OD):
D
Please cite this article in press as: Xiao, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.028

10
M. Xiao et al. / Tetrahedron xxx (2014) 1e10
1994, 59, 1602e1603; (e) Hill, D. C.; Flugge, L. A.; Petillo, P. A. J. Org. Chem. 1997,
15. (a) Li, Y. Z.; Zou, H. X.; Gong, J. X.; Xiang, J.; Luo, T. P.; Quan, J. M.; Wang, G. X.;
Yang, Z. Org. Lett. 2007, 9, 4057e4060; (b) Reed, D. D.; Bergmeier, S. C. J. Org.
Chem. 2007, 72, 1024e1026.
16. Dotz, K. H.; Otto, F.; Nieger, M. J. Organomet. Chem. 2001, 621, 77.
17. See Experimental section.
62, 4864e4866; (f) Gritsch, P. J.; Stempel, E.; Gaich, T. Org. Lett. 2013, 15,
5472e5475 TBAF: (g) Jackson, S. K.; Kerr, M. A. J. Org. Chem. 2007, 72, 1405e1411
K2CO3/MeOH: (h) Bassoli, A.; Borgonovo, G.; Busnelli, G.; Morini, G.; Merlini, L.
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€
Please cite this article in press as: Xiao, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.028