Total synthesis of (?)-orthodiffenes A and C

Article abstract of DOI:10.1021/jo301829p

The efficient and concise synthesis of (?)-orthodiffenes A and C has been accomplished for the first time in eight steps from readily available chiral synthons, d-mannose and d-ethyl lactate. Our work confirmed the complete structure of orthodiffenes A and C, including their absolute stereochemistry. The key steps of our total synthesis involved cis-fused tetrahydrofuran cyclization, one-pot deprotection-lactonization, and intramolecular benzoyl migration according to a biosynthetic hypothesis of orthodiffenes.

Full text of DOI:10.1021/jo301829p

Article
pubs.acs.org/joc
Total Synthesis of (−)-Orthodiffenes A and C
Jun Liu,*,†,‡ Yi Liu,†,§ Xing Zhang,†,§ Chaoli Zhang,†,§ Yangguang Gao,†,§ LinLin Wang,†,§
and Yuguo Du*,†,§
†State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-Environmental Sciences, Chinese
Academy of Sciences, Beijing 100085, China
‡State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China
§School of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: The efficient and concise synthesis of (−)-or-
thodiffenes A and C has been accomplished for the first time in
eight steps from readily available chiral synthons, D-mannose
and D-ethyl lactate. Our work confirmed the complete
structure of orthodiffenes A and C, including their absolute
stereochemistry. The key steps of our total synthesis involved
cis-fused tetrahydrofuran cyclization, one-pot deprotection−
lactonization, and intramolecular benzoyl migration according
to a biosynthetic hypothesis of orthodiffenes.
diffenes A−D are composed of a similar unusual furanopyrone
skeleton with an extra olefinic side chain connecting at C8−C9.
Furthermore, the four consecutive stereogenic centers (C5−
C8) on tetrahydrofuran framework were determined to be cis
to each other from the coupling relationship. These all-syn
tetrasubstituted furanopyrans are relatively rare in nature.
Despite the promising biological activity of orthodiffenes, the
mode of action in terms of pharmacology remains unknown.
To the best of our knowledge, the total synthesis of
orthodiffenes has not been reported yet. The impressive
biological activity, novel structural features, and the lack of
structure−activity relationship (SAR) studies on orthodiffenes
encouraged us to undertake a total synthesis of these novel
natural products. Owing to the intriguing structural features of
the unusual furanopyrone and consecutive all-syn tetrasub-
stituted tetrahydrofuran structural framework, the total syn-
thesis of these compounds represents a challenge.
Orthodiffenes A and C have the same carbon backbone and
stereochemistry, except for the benzoyl ester on the side chain
which attaches to C-11 and C-12, respectively. This
phenomenon is usually ascribed to the esterase involved in
the natural biosynthetic process, suggesting that orthodiffenes A
and C could be isomerized through an intramolecular ester
migration at C-11 and C-12 via orthoester intermediates with
retention of chirality.4 Accordingly, we expected that
orthodiffenes A and C could be prepared from the same
INTRODUCTION
■
Bioactive natural products have long been recognized as the
major source of drugs and lead structures in the field of
anticancer drug discovery.1 About 75% of anticancer agents
under clinical trials are either natural products or derived from
natural products.2 Very recently, Das and co-workers reported
the isolation and structure elucidation of four novel
furanopyrans, named as orthodiffenes A−D (Figure 1), from
Figure 1. Structures of orthodiffenes A−D.
the Indian herb Orthosiphon diffuses.3 The orthodiffenes A−C
exhibit high cytotoxic activities against various tumor cell lines
in vitro, and orthodiffene A (1) and orthodiffene B (2) were
found to possess activity comparable to camptothecin against
HL-60 and Jurkat cells, respectively. The structures of these
compounds were established based on extensive spectroscopic
analysis including 2D NMR experiments. In addition, the
relative stereochemistry of orthodiffene A (Figure 1) was
determined by using X-ray crystallographic diffraction analysis,
whereas the absolute configuration is still unknown. Ortho-
Received: August 27, 2012
Published: October 11, 2012
© 2012 American Chemical Society
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precursor and transformed to each other under a controlled
benzoyl migration condition.
elaborated from well functionalized (Z)-α,β-unsaturated ethyl
ester 5 by one-pot acetonide deprotection/lactonization
accompanied by benzoyl migration (Scheme 1). The trans-
olefin moiety at C9/C10 could be installed by coupling of β-D-
C-furanoside subunit 6 with the olefinic side chain 7 involving
an olefin cross-metathesis strategy. The β-D-C-furanoside
subunit 6, in which all four cis stereocenters are in place,
could be readily accessible from the natural carbohydrate
2,3:5,6-di-O-isopropylidene-α-D-mannofuranose (8). The Bz
and TBS group protected allylic alchol 7 can be easily prepared
from D-ethyl lactate through reduction and Grignard addition
by a one-pot sequence in three steps. Details of the studies thus
undertaken are described below.
Our synthesis commenced with transformation of D-mannose
to the diol 9 in two steps according to a modified procedure
from Singh (Scheme 2).5 The known 2,3:5,6-di-O-isopropyli-
dene-α-D- mannofuranose (8), easily obtained from D-mannose
in 90% yield using iodine as catalyst in dry acetone,6 was
treated with 5.0 equiv of vinylmagnesium bromide, leading to a
known compound 9 as a separable 5.3:1 mixture of
diastereoisomers in almost quantitative yield (98%). Attempts
to improve the diastereoselectivity of this reaction by changing
solvents or running at lower temperature (−20 °C to −80 °C)
were fruitless. Chemoselective tosylation of diol 9, with 1.1
equiv of p-toluenesulfonyl chloride (TsCl) in pyridine at 65
°C,7 initiated a favorable regioselective intramolecular SN2
substitution at the allylic position to form the configuration-
inversed and cis-fused cyclization compound 6 in 84% yield.
Other methods using triflic anhydride,8 FeCl3,9 SOCl2,10 and
Mitsunobu reaction11 did not show an acceptable yield
improvement. It is noteworthy that cis-fused tetrahydrofuran
6 was obtained as a single diastereomer, and the other isomers
were not observed even when adding excessive TsCl (up to 2.2
equiv). The stereochemistry of the resulting β-C-glycosides was
confirmed by NOE experiments and derivatization of 6 to the
known compound 1012 in two steps (oxidative cleavage of
olefins with osmium tetraoxide−sodium periodate13 followed
by sodium borohydride reduction).
Due to the structural similarities between L-mannofuranoside
and the desired furanopyrone skeleton (C3−C10) of
orthodiffenes (Figure 1), we initially imagined that the natural
orthodiffenes could be derived from unnatural L-mannose.
Given the prohibitive cost of L-mannose and the unknown
absolute configurations of the orthodiffenes, we were interested
in synthesizing both the natural (1−4) and unnatural
enantiomer (1′−4′) for structural determination and further
biological studies. Consequently, our synthetic blueprint
required swift access to either enantiomer of the orthodiffenes,
based on the readily available natural carbohydrate D-mannose.
Herein, we report the first total synthesis of (−)-orthodiffenes
A and C by a short and efficient route.
RESULTS AND DISCUSSION
The retrosynthetic analysis of orthodiffenes A and C is outlined
in Scheme 1. We envisaged that orthodiffenes A and C could be
■
Scheme 1. Retrosynthetic Analysis of Orthodiffenes A and C
With the completion of the β-C-furanoside subunit, our
attention was then focused on the synthesis of the olefinic side
chain 7 as shown in Scheme 3. The protected allylic alchol 7
was prepared from D-ethyl lactate via the known TBS-protected
ethyl lactate 11.14 Reduction of 11 with DIBAL-H to the
corresponding lactaldehyde and subsequent treatment with
vinylmagnesium chloride delivered the required (R,S)-12 as a
Scheme 2. Synthesis of β-C-Glycosides 6
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(ethoxycarbonylmethylene)triphenylphosphorane, afforded
predominantly (Z)-α,β-unsaturated ester 5 in 80% yield with
cis:trans > 13:1.17
Scheme 3. Synthesis of 7
After screening several conditions, we achieved one-pot
acetonide deprotection/lactonization by treatment of 5 with a
catalytic amount of p-toluenesulfonic acid (PTSA) in methanol,
or 50% trifluoroacetic acid (TFA) aqueous solution in THF;18
both approaches furnished a mixture of orthodiffenes A (1′)
and C (3′) which were readily separated by column
chromatography (Scheme 4). Interestingly, treatment of either
pure orthodiffene A (1′) or orthodiffene C (3′) with a catalytic
amount of PTSA in methanol at room temperature for 72 h
afforded a mixture of orthodiffenes A (1′) and C (3′) in a
balanced ratio from 1:1.3 to 1:1.7 (Scheme 4). We assumed
that such an acidolysis equilibrium between orthodiffene A (1′)
and orthodiffene C (3′) probably resulted from a process of
intramolecular transesterification via dioxolane intermediate.4c
The spectroscopic data (1H, 13C NMR, IR, and HRMS) of both
synthetic orthodiffene A (1′) and orthodiffene C (3′) were in
good agreement with those of the natural products (see the
Supporting Information). However, the optical rotation
obtained for synthetic samples are opposite in sign to the
value reported for the natural products, which shows that our
synthetic (−)-orthodiffene A (1′) and C (3′) are the
enantiomers of the natural products.19
7.8:1 mixture of diastereoisomers in a one-pot process.15
Blocking of the corresponding allylic alcohol as a benzoyl ester
provided 7. This approach afforded the desired protected allylic
alchol 7 in a yield of 74% over three steps from D-ethyl lactate
(Scheme 3).
With both key fragments in hand, we then investigate the
olefin cross metathesis of β-C-furanoside 6 with 7 (Scheme 4).
This reaction carried out smoothly using an excess of 7 (4.8
equiv) and a catalytic amount of Grubbs-II in DCM at room
temperature for 12 h generated the desired olefin 13 in a yield
of 67% with excellent E:Z selectivity (>15:1).16 Selective
hydrolysis of the 1,2-acetonide and TBS protecting group with
Amberlite IR-120 (H+) ion-exchange resin in methanol
afforded 14 in 89% yield. Oxidative cleavage of the diol in 14
with NaIO4, followed by immediate Wittig olefination with
Scheme 4. Total Synthesis of Orthodiffenes A and C
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80.8, 81.6, 82.5, 83.2, 108.9, 112.5, 119.2, 132.1; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C14H22O5Na 293.1365; Found 293.1376.
Synthesis of ((3aR,4S,6R,6aS)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-
yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol
(10).12 To a mixture of compound 6 (108 mg, 0.4 mmol), 2,6-lutidine
(0.1 mL, 0.79 mmol), and solid NaIO4 (129 mg, 0.6 mmol) in dioxane
(8 mL) and deionized H2O (2 mL) was added a solution of OsO4 (5
mg) in tBuOH and stirred at rt for 12 h. After completion, the reaction
was quenched by the addition of saturated aq NH4Cl (10 mL). The
reaction mixture was extracted with DCM (3 × 10 mL). The
combined organic phase was washed with brine, dried over Na2SO4,
and concentrated under vacuum. The crude aldehyde was used for the
next step without further purification. To a solution of crude aldehyde
(ca. 0.4 mmol) in MeOH (5 mL) was added solid NaBH4 (31 mg, 0.8
mmol) in two portions at 0 °C. After 5 min, the solution was warmed
to rt and stirred for a further 15 min. The mixture was concentrated
under vacuum. The residue was added into saturated aqueous NaCl
(10 mL) and extracted with DCM (3 × 50 mL). The combined
organic phase was dried over Na2SO4 and concentrated under vacuum.
The crude material was purified by flash column chromatography
(hexanes/EtOAc 1:1) to give compound 10 as a colorless oil (88 mg,
80% for two steps). Data are consistent with a previously characterized
compound.12
CONCLUSION
■
We have completed the first total synthesis of compounds 1′
and 3′, the enantiomers of natural orthodiffenes A and C,
respectively, in eight steps from readily available D-mannose
and D-ethyl lactate. The key transformations involved in this
work are the tosylation-mediated, one-pot, cis-fused tetrahy-
drofuran cyclization, olefin cross metathesis, and one-pot
tandem deprotection/lactonization. In addition, we observed
intramolecular benzoyl migration between orthodiffene C11 and
C12 under acidic conditions in methanol, supporting a possible
biotransformation of orthodiffenes through esterase-promoted
ester migration. The current method offers an opportunity to
prepare orthodiffenes A and C with the same process at the
same time. We believe our strategy also provides a short and
efficient approach for the syntheses of other orthodiffene-like
natural products.
EXPERIMENTAL SECTION
■
1. General Experimental. Unless noted otherwise, commercially
available materials were used without further purification. All solvents
were dried according to the established procedures ahead of use. All
reagents were purchased from commercial corporations. Flash
chromatography (FC) was performed using silica gel (200−300
mesh) according to the standard protocol. All reactions under standard
conditions were monitored by thin-layer chromatography (TLC) on
gel F254 plates. Optical rotations were measured using a polarimeter
with a thermally jacketed 5 cm cell at approximately 25 °C. Infrared
spectra were recorded as KBr discs using a FT-IR spectrophotometer
with wave numbers expressed in cm−1. High-resolution mass
spectrometry data (HRMS) were acquired using a Q-TOF analyzer
in acetone as solvent. 1H NMR and 13C NMR were measured on 400
or 100 MHz spectrometers (in CDCl3 with TMS as an internal
standard). Chemical shifts (δ) are given in ppm relative to residual
Synthesis of (3S,4R)-4-(tert-Butyldimethylsilyloxy)pent-1-en-3-yl
Benzoate (7). To a solution of TBS-protected lactate 11 (2.33 g, 10
mmol) in dry ether (50 mL) was added DIBAL-H (11.7 mL, 14
mmol) via syringe in three portions at −98 °C under N2 atmosphere.
After 15 min, vinylmagnesium chloride (28.6 mL, 20 mmol) was
added into the mixture via syringe. The solution was then warmed to
room temperature and stirred overnight. The reaction was quenched
by the slow addition of a saturated solution of K/Na tartrate. (80 mL,
Caution!). The aqueous layer was extracted with ether (3 × 80 mL).
The combined organic phase was washed with brine, dried over
Na2SO4, and concentrated under vacuum. The crude allylic alcohol 12
was used for next step without further purification. To a solution of
crude allylic alcohol (ca. 10 mmol) in dry pyridine (25 mL) was added
BzCl (1.74 mL, 15 mmol) by two portions at 0 °C. After 15 min, the
solution was warmed to rt and stirred for a further 15 min. The
reaction was quenched by the addition of MeOH (10 mL) and
concentrated with toluene. The residue was poured into saturated
aqueous CuSO4 (50 mL) and extracted with DCM (3 × 50 mL). The
combined organic phase was washed with brine, dried over Na2SO4,
and concentrated under vacuum. The crude was purified by flash
column chromatography (hexanes/EtOAc 30:1) to give compound 7
1
solvent (usually chloroform; δ 7.26 for H NMR or 77.0 for proton-
decoupled 13C NMR), and coupling constants (J) in hertz. Multiplicity
is tabulated as s for singlet, d for doublet, t for triplet, q for quadruplet,
m for multiplet, and br when the signal in question is broadened.
2. Experimental Procedures. Synthesis of (3aS,4R,6S,6aR)-4-
((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-
vinyltetrahydrofuro[3,4-d][1,3]dioxole (6). To a solution of 2,3:5,6-
di-O-isopropylidene-α-D-mannofuranose (6.9 g, 26.54 mmol) in dry
THF (60 mL) was added vinylmagnesium bromide (133 mmol) via
syringe in three portions at −20 °C under N2 protection. After 90 min,
the solution was warmed to room temperature and stirred for another
20 h. The reaction was quenched by the slow addition of aq NH4Cl
(50 mL, Caution!). The aqueous layer was extracted with ether (3 ×
100 mL). The combined organic phase was washed with brine, dried
over Na2SO4, and concentrated under vacuum. The crude diol could
be used for the next step without further purification. To a solution of
crude diol (ca. 26.54 mmol) in dry pyridine (60 mL) was added TsCl
(11.2 g, 58.4 mmol) in three portions at rt under N2 protection. After
10 min, the solution was warmed to 65 °C and stirred for a further 8−
10 h. The reaction was quenched at rt by the addition of MeOH (20
mL). The solution was concentrated with toluene and poured into
saturated aqueous CuSO4 (100 mL) and then extracted with DCM (3
× 120 mL). The combined organic phase was washed with brine, dried
over Na2SO4, and concentrated under vacuum. The crude was purified
by flash column chromatography (hexanes/EtOAc 7:1) to give
25
as a colorless oil (2.36 g, 74% for two steps). [α]D −24.8 (c 1.7,
CHCl3); 1H NMR (400 MHz): δ 0.04 (s, 6H), 0.89 (s, 9H), 1.20 (d, J
= 6.4 Hz, 3H), 4.02−4.09 (m, 1H), 5.26−5.45 (m, 3H), 5.96−6.05
(ddd, J = 17.2 Hz, J = 10.4 Hz, J = 6.8 Hz, 1H); 7.44 (t, J = 7.6 Hz,
2H), 7.56 (t, J = 7.6 Hz, 1H), 8.07 (d, J = 7.6 Hz, 2H); 13C NMR (100
MHz) δ −4.8, −4.5, 18.0, 19.8, 25.7, 69.7, 79.4, 118.7, 128.3, 129.7,
130.6, 132.9, 133.1, 165.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C18H28O3SiNa 343.1705; Found 343.1708.
Synthesis of (3S,4R,E)-4-(tert-Butyldimethylsilyloxy)-1-((3aR,4S,6-
R , 6a S) -6 -(( R)-2 , 2-di methy l-1, 3 -d io xo la n-4 - yl) - 2, 2 -
dimethyltetrahydrofuro[3, 4-d][1,3]dioxol-4-yl)pent-1-en-3-yl Ben-
zoate (13). Grubbs second catalyst (15 mg, 0.018 mmol) was added to
a mixture of 7 (1.38 g, 4.3 mmol) and 6 (243 mg, 0.9 mmol) in dry
DCM (75 mL). The reaction was stirred for 12 h at rt. The solution
was concentrated and purified by flash column chromatography
(hexanes/EtOAc 6:1) to give compound 13 as a colorless oil (339 mg,
67%) and 6 (34 mg, 14%). [α]D25 13.8 (c 2.1, CHCl3); 1H NMR (400
MHz): δ 0.02 (s, 3H), 0.03 (s, 3H), 0.88 (s, 9H), 1.19 (d, J = 6.0 Hz,
3H), 1.29 (s, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 1.44 (s, 3H), 3.52 (dd, J
= 7.6 Hz, J = 3.6 Hz, 1H), 4.01 (dd, J = 6.4 Hz, J = 3.6 Hz, 1H), 4.03−
4.10 (m, 3H), 4.38−4.42 (m, 1H), 4.65 (dd, J = 6.0 Hz, J = 3.6 Hz,
1H), 4.76 (dd, J = 6.0 Hz, J = 3.6 Hz, 1H), 5.41 (dd, J = 6.4 Hz, J = 4.0
Hz, 1H), 5.90 (dd, J = 16.0 Hz, J = 6.4 Hz, 1H), 5.97 (dd, J = 16.0 Hz,
J = 6.4 Hz, 1H), 7.41−7.45 (m, 2H), 7.54 (dt, J = 7.6 Hz, J = 1.2 Hz,
1H), 8.05−8.07 (m, 2H); 13C NMR (100 MHz) δ −4.8, −4.5, 18.0,
19.9, 24.7, 25.3, 25.7, 25.8, 26.9, 67.0, 69.7, 73.1, 78.4, 80.9, 81.7, 82.2,
25
compound 6 as a yellow oil (5.01 g, 70% for two steps). [α]D
−16.1 (c 3.2, CHCl3); H NMR (400 MHz): δ 1.31 (s, 3H), 1.36 (s,
1
3H), 1.43 (s, 3H), 1.47 (s, 3H), 3.52 (dd, J = 7.6 Hz, J = 3.6 Hz, 1H),
3.97 (dd, J = 7.2 Hz, J = 3.6 Hz, 1H), 4.04−4.11 (m, 2H), 4.38−4.43
(m, 1H), 4.65 (dd, J = 6.0 Hz, J = 3.6 Hz, 1H), 4.76 (dd, J = 6.0 Hz, J
= 3.6 Hz, 1H), 5.29 (dd, J = 10.4 Hz, J = 0.8 Hz, 1H), 5.35 (dd, J =
17.2 Hz, J = 0.8 Hz, 1H), 5.95 (ddd, J = 17.2 Hz, J = 10.4 Hz, J = 7.2
Hz, 1H); 13C NMR (100 MHz) δ 24.5, 25.2, 25.7, 26.9, 66.9, 73.0,
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82.5, 109.0, 112.6, 128.2, 128.5, 129.3, 129.7, 130.6, 132.8, 165.6;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C30H46O8SiNa
585.2860; Found 585.2863.
132.8, 133.1, 141.9, 161.3, 166.2; IR (film): 3418, 2925, 2853, 1713,
1632, 1451, 1262, 1110, 802 cm−1; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C19H20O7Na 383.1107; Found 383.1089;
Synthesis of (3S,4R,E)-1-((3aR,4S,6R,6aS)-6-((Z)-3-Ethoxy-3-oxo-
prop-1-enyl)-2, 2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-
hydroxypent-1-en-3-yl Benzoate (5). Amberlite IR-120 acidic resin
(25 mg) was added to the solution of 13 (175 mg, 0.31 mmol) in
MeOH (15 mL). The reaction was stirred for 24 h at rt. The solid
resin was filtered with cotton wool. The solution was concentrated
under vacuum to afford 14 as a colorless oil. The crude triol 14 could
be used for the next step without any purification. A small sample was
ASSOCIATED CONTENT
* Supporting Information
Spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: junliu@rcees.ac.cn; duyuguo@rcees.ac.cn.
Notes
■
25
purified on a silica gel column to get the physical data of 14: [α]D
31.0 (c 1.0, CHCl3); 1H NMR (400 MHz): δ 1.25 (d, J = 6.4 Hz, 3H),
1.30 (s, 3H), 1.40 (s, 3H), 2.56 (br s, 3H), 3.56 (dd, J = 8.0 Hz, J = 3.6
Hz, 1H), 3.74 (dd, J = 11.6 Hz, J = 5.6 Hz, 1H), 3.85 (dd, J = 11.6 Hz,
J = 3.2 Hz, 1H), 4.00−4.09 (m, 3H), 4.66 (dd, J = 6.0 Hz, J = 3.6 Hz,
1H), 4.83 (dd, J = 6.0 Hz, J = 4.0 Hz, 1H), 5.48 (dd, J = 4.8 Hz, J = 0.4
Hz, 1H), 5.92 (dd, J = 16.0 Hz, J = 5.6 Hz, 1H), 6.00 (dd, J = 16.0 Hz,
J = 5.6 Hz, 1H), 7.42−7.46 (m, 2H), 7.58 (dt, J = 7.2 Hz, J = 1.2 Hz,
1H), 8.05−8.07 (m, 2H); 13C NMR (100 MHz) δ 18.5, 24.8, 25.8,
64.5, 69.0, 70.1, 77.9, 80.9, 81.3, 81.6, 82.2, 112.8, 127.8, 128.4, 129.1,
129.7, 130.1, 133.1, 165.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C21H28O8Na 431.1682; Found 431.1671. To a solution of triol 14
(102 mg, 0.25 mmol) in MeOH (20 mL) was added solid NaIO4 (80
mg, 0.375 mmol) at rt. The mixture was stirred for 30 min and filtered
with Celite. To the resulting solution was added
(ethoxycarbonylmethylene)triphenylphosphorane (174 mg, 0.5
mmol) at 0 °C. After being stirred at 0 °C for 60 min, the reaction
was concentrated under vacuum. The crude material was purified by
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the MOST of China
(2012ZX09502001-001), NNSF of China (projects
2012CB822101, 21072217, and 21202193). We gratefully
acknowledge financial support from the State Key Laboratory
of Natural and Biomimetic Drugs of Peking University
(K20110101). We also thank Professor Chu-Yi Yu of CAS
Key Laboratory of Molecular Recognition and Function
(Institute of Chemistry, Chinese Academy of Sciences) for
kindly measuring the optical rotation of orthodiffene A (1′) and
orthodiffene C (3′).
flash column chromatography (hexanes/EtOAc 2:1) to give
25
compound 5 as a colorless oil (89 mg, 80%). [α]
−41.4 (c 3.5,
D
REFERENCES
1
■
CHCl3); H NMR (400 MHz): δ 1.25 (s, 3H), 1.26 (t, J = 6.8 Hz,
3H), 1.27 (d, J = 6.0 Hz, 3H), 1.40 (s, 3H), 2.42 (br s, 1H), 4.00−4.08
(m, 1H), 4.10 (dd, J = 5.6 Hz, J = 4.0 Hz, 1H), 4.16 (q, J = 6.8 Hz,
2H), 4.68 (dd, J = 5.6 Hz, J = 4.0 Hz, 1H), 5.03 (dd, J = 6.0 Hz, J = 3.6
Hz, 1H), 5.05−5.08 (m, 1H), 5.51 (dd, J = 6.0 Hz, J = 4.0 Hz, 1H),
5.94−6.01 (m, 2H), 6.05 (dd, J = 16.0 Hz, J = 5.6 Hz, 1H), 6.35 (dd, J
= 12.0 Hz, J = 6.4 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.54−7.58 (m,
1H), 8.05−8.07 (m, 2H); 13C NMR (100 MHz) δ 14.1, 18.5, 24.8,
25.8, 60.4, 69.0, 78.0, 78.6, 81.5, 82.4, 82.9, 112.5, 120.9, 127.8, 128.3,
129.4, 129.7, 130.1, 133.1, 144.8, 165.7; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C24H30O8Na 469.1838; Found 469.1810.
(1) (a) Danishefsky, S. Nat. Prod. Rep. 2010, 27, 1114−1116.
(b) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311−335.
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the intramolecular transesterification reaction, see: (a) Thuggacins
A−C: Steinmetz, H.; Irschik, H.; Kunze, B.; Reichenbach, H.; Hofle,
G.; Jansen, R. Chem.Eur. J. 2007, 13, 5822−5832. (b)
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Synthesis of Orthodiffene A (1′) and Orthodiffene C (3′). To a
solution of ester 5 (42 mg, 0.094 mmol) in MeOH (5 mL) was added
PTSA·H2O (3.6 mg, 0.019 mmol) at rt. The mixture was stirred for 48
and concentrated under vacuum. The crude was purified by flash
column chromatography (hexanes/EtOAc 1:3) to give orthodiffene A
(1′) (11.5 mg, 34%) and orthodiffene C (3′) (14.9 mg, 44%).
(5) van Boggelen, M. P.; van Dommelen, B. F. G. A.; Jiang, S.; Singh,
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25
1
(6) Schmidt, O. T. Methods in Carbohydrate Chemistry; Whistler, R.
L., Wolfrom, M. L., Eds.; Academic Press Inc.: New York, 1963; Vol. 2,
pp 318−319.
Orthodiffene A (1′): white solid, [α]D −35.2 (c 0.8, CHCl3); H
NMR (400 MHz): δ 1.25 (d, J = 6.8 Hz, 3H), 3.05 (br s, 2H), 4.04
(dq, J = 6.8 Hz, J = 2.0 Hz, 1H), 4.47 (t, J = 4.8 Hz, 1H), 4.55 (dd, J =
4.8 Hz, J = 4.0 Hz, 1H), 4.61 (ddd, J = 6.8 Hz, J = 4.0 Hz, J = 1.2 Hz,
1H), 5.06 (dd, J = 6.8 Hz, J = 4.8 Hz, 1H), 5.39−5.42 (m, 1H), 5.90
(dd, J = 15.6 Hz, J = 4.4 Hz, 1H), 5.93 (dd, J = 15.6 Hz, J = 4.4 Hz,
1H), 6.08 (dd, J = 10.0 Hz, J = 1.2 Hz, 1H), 6.79 (dd, J = 10.0 Hz, J =
4.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.56−7.59 (m, 1H), 8.04−8.06
(m, 2H); 13C NMR (100 MHz) δ 18.7, 67.1, 69.0, 73.6, 78.1, 79.1,
79.3, 121.9, 128.4, 128.6, 129.5, 129.7, 130.0, 133.3, 141.6, 161.1,
165.8; IR (film): 3410, 2923, 2852, 1713, 1633, 1452, 1261, 1106,
1025, 802 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C19H20O7Na 383.1107; Found 383.1093. Orthodiffene C (3′): white
solid, [α]D25 −33.7 (c 0.6, CHCl3); 1H NMR (400 MHz): δ 1.36 (d, J
= 6.8 Hz, 3H), 2.48 (br s, 2H), 4.36 (t, J = 4.4 Hz, 1H), 4.38−4.41(m,
1H), 4.48 (dd, J = 4.8 Hz, J = 4.0 Hz, 1H), 4.60 (ddd, J = 6.0 Hz, J =
4.0 Hz, J = 0.8 Hz, 1H), 5.04 (dd, J = 6.0 Hz, J = 4.8 Hz, 1H), 5.18
(dq, J = 6.8 Hz, J = 4.4 Hz, 1H), 5.87 (dd, J = 15.6 Hz, J = 4.8 Hz,
1H), 5.92 (dd, J = 15.6 Hz, J = 4.8 Hz, 1H), 6.06 (dd, J = 10.0 Hz, J =
0.8 Hz, 1H), 6.74 (dd, J = 10.0 Hz, J = 4.0 Hz, 1H), 7.43 (t, J = 8.0 Hz,
2H), 7.53−7.58 (m, 1H), 8.02−8.04 (m, 2H); 13C NMR (100 MHz) δ
15.1, 66.9, 73.5, 73.6, 74.1, 79.0, 79.4, 121.6, 127.5, 128.4, 129.6, 130.2,
(7) Buchanan, J. G.; Dunn, A. D.; Edgar, A. R. J. Chem. Soc., Perkin
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Chem. 2005, 3, 4432−4443.
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Toyoshima, H.; Shimizu, M.; Togo, H. J. Chem. Soc., Perkin Trans. 1
1997, 29.
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Gadikota, R. R.; Maju, J.; Arora, S. K.; Dastida, S. G.; Agarwal, S.
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The Journal of Organic Chemistry
Article
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(17) The Wittig reaction of stabilized ylides with α-alkoxy or β-alkoxy
aldehydes can stereoselectively form (Z)-α,β-unsaturated ester in
alcoholic solvents, and the correlation between the structure of the
starting carbonyl compound and the stereoselectivity of the reaction
was also well established; For preliminary communications, see:
(a) Tronchet, J. M. J.; Gentile, B. Helv. Chim. Acta 1979, 62, 2091−
2098. (b) Minari, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
1109−1111. (c) Valverde, S.; Martin-Lomas, M.; Herradon, B.; Garcia-
Ochoa, S. Tetrahedron 1987, 43, 1895−1901. (d) Sanchez-Sancho, F.;
Valverde, S.; Herradon, B. Tetrahedron: Asymmetry 1996, 7, 3209−
3246. For a comprehensive review, see: (e) Maryanoff, B. E.; Reitz, A.
B. Chem. Rev. 1989, 89, 863−927. For a recent synthesis of natural
products involving the reactions, see: (f) Baird, L. J.; Timmer, M. S.
M.; Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem. 2009, 74, 2271−
2277. (g) Barros, M. T.; Charmier, M. A. J.; Maycock, C. D.; Michaud,
T. Tetrahedron 2009, 65, 396−399. (h) Du, Y. G.; Liu, J.; Linhardt, R.
J. J. Org. Chem. 2007, 72, 3952−3954. (i) Sabitha, G.; Swapna, R.;
Babu, R. S.; Yadav, J. S. Tetrahedron Lett. 2005, 46, 6145−6148.
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(18) (a) Meira, P. R. R.; Moro, A. V.; Correia, C. R. D. Synthesis
2007, 2279−2286. (b) Dowex 50WX8 and HCl/MeOH were also
employed for the one-pot acidolysis. However, the desired product
was obtained in a low yield (5−10%).
(19) Synthetic orthodiffene A and orthodiffene C exhibit physical
properties (1H, 13C NMR, IR, and HRMS) that are in good agreement
with those of natural orthodiffene A and orthodiffene C. See
1
Supporting Information for detailed comparative H and 13C NMR
of synthetic (−)-orthodiffenes A (1′) and C (3′) and natural
orthodiffenes A and C. However, the measured optical rotation for
the synthetic (−)-orthodiffenes A (1′) and C (3′) material does not
compare well to the reported value for the natural orthodiffene A and
25
orthodiffene C { (−)-orthodiffene A (1′): [α]D −35.2 (c 0.8,
CHCl3); [α]D +84.1 (c 0.5, CHCl3) lit.;3 (−)-orthodiffene C (3′):
25
3
25
25
[α]D −33.7 (c 0.6, CHCl3); [α]D +139.6 (c 1.0, CHCl3) lit. }. We
are currently working to understand this discrepancy.
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