First total syntheses of oresbiusins A and B, their antipodes, and racemates: Configuration revision and anti-HIV activity

Article abstract of DOI:10.1002/ejoc.201200689

The first total syntheses of oresbiusin A in the (+)-, (-)-, and (±)-forms were accomplished in five steps with overall yields of ca. 70 %. The key intermediates with optical activity were generated through a Sharpless asymmetric dihydroxylation reaction. These efforts allowed us to establish the absolute configuration of this natural product with dextrorotary and a 2S configuration. In addition, the total syntheses of both enantiomers of oresbiusin B along with its racemate were accomplished in six steps with overall yields of 58 %. Among these compounds, the unnatural oresbiusin A with a levorotary rotation was found to possess dose dependent anti-HIV-1 activity in H9 cells, whereas the other compounds were inactive. Copyright

Full text of DOI:10.1002/ejoc.201200689

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200689
First Total Syntheses of Oresbiusins A and B, Their Antipodes, and
Racemates: Configuration Revision and Anti-HIV Activity
Jih Ru Hwu,*[a,b] Tirumala G. Varadaraju,[a] Ibrahim S. Abd-Elazem,[c] and
Ru Chih C. Huang*[c]
Keywords: Chirality / Biological activity / Configuration determination / Natural products / Total synthesis
The first total syntheses of oresbiusin A in the (+)-, (–)-, and
(Ϯ)-forms were accomplished in five steps with overall yields
of ca. 70%. The key intermediates with optical activity were
generated through a Sharpless asymmetric dihydroxylation
reaction. These efforts allowed us to establish the absolute
configuration of this natural product with dextrorotary and
a 2S configuration. In addition, the total syntheses of both
enantiomers of oresbiusin B along with its racemate were ac-
complished in six steps with overall yields of 58%. Among
these compounds, the unnatural oresbiusin A with a levorot-
ary rotation was found to possess dose dependent anti-HIV-
1 activity in H9 cells, whereas the other compounds were
inactive.
We noticed that several optically pure caffeic acid
derivatives isolated from the aqueous extracts of Salvia
miltiorrhiza (Dan-shen) possess an α-hydroxy or α-acetoxy
moiety as those in oresbiusins A (1) and B (2).[5,6] These
caffeic acids exhibit various biological activities of impor-
tance, including anti-ischemia reperfusion, antithrombosis,
antihypertension, antioxidation, antitumor,[6] and antihu-
man immunodeficiency virus (HIV).[7] On the other hand,
α-hydroxy acids and esters are frequently encountered as
parts of biologically active compounds, such as methyl 4-
hydroxyphenyl lactate, ragaglitazar, tesaglitazar, and their
analogues.[8,9] In these compounds, the stereochemistry of
the hydroxy functional group is essential to the anticancer
and antidiabetic activities.[8,9]
Introduction
Found in open dry rocky areas of Sichuan and Yunnan,
China, the dried plant of Isodom oresbius has been used in
traditional Chinese folk medicine for years. It is often used
in the treatment of blood clots in internal organs of the
body.[1] In 1996, Huang and co-workers[2] reported the iso-
lation of oresbiusins A (1a) and B (2a) from the same re-
source. By possessing a common α-hydroxy ester moiety,
their absolute configuration was unfortunately not as-
signed. In 2010, Zhu and co-workers[3] disclosed that ores-
biusin A (1b) isolated from the Ranunculus chinensis was a
light yellow gum with [α]2D2 = +7.9 (c = 0.410, MeOH). It
was assigned as the (2R) enantiomer. In 2009, Synder and
Kontes[4] published their synthesis of enantiomerically en-
riched (R)-oresbiusin B derivatives from naturally occurring
(R)-rosmarinic acid. They also utilized its benzylated spe-
cies in the total syntheses of polyhydroxylated complex nat-
ural products.
[a] Department of Chemistry and Frontier Research Center on
Fundamental and Applied Sciences of Matters
National Tsing Hua University
Hsinchu, Taiwan, 30013 Republic of China
Fax: +886-3-572-1594
E-mail: jrhwu@mx.nthu.edu.tw
Homepage:
33468.php
http://chem-en.web.nthu.edu.tw/files/13-1117-
[b] Department of Chemistry
National Central University
Jhongli City, Taiwan 32001 Republic of China
[c] Department of Biology
The Johns Hopkins University
We have been working on a project devoted to the devel-
opment of natural products and their derivatives with ac-
tivity against HIV. We have found that the activity can be
improved significantly by converting the naturally occurring
nordihydroguaiaretic acid (i.e., NDGA) into its tetrameth-
ylated derivative.[10,11] Furthermore, several heterocycle-
3400 North Charles Street, Baltimore, MD 21218, USA
Fax: +1-410-516-5213
E-mail: rhuang@jhu.edu
Homepage: http://www.bio.jhu.edu/Faculty/Huang/
Default.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200689.
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J. R. Hwu, T. G. Varadaraju, I. S. Abd-Elazem, R. C. C. Huang
SHORT COMMUNICATION
containing NDGA derivatives with good aqueous solubility
and stability have been synthesized that exhibit appealing
anti-HIV activity.[12] Recently, we have also developed per-
glycosylated NDGA as anticancer agents.[13]
Scheme 1. Initial attempts at the asymmetric synthesis of acetylated
lactate 5.
40 °C) for 24 h, the starting material decomposed. Chang-
ing the solvent to acetone or water along with increasing
the amount of AD-mix-α also met with failure.
The components in the reagent AD-mix-α include potas-
sium osmate [K2OsO2(OH)4], (DHQ)2-PHAL, K3Fe(CN)6,
and K2CO3.[14] Serving as a nonvolatile Os source, potas-
sium osmate reacts with an inorganic co-oxidant K3Fe-
(CN)6 to generate OsO4 in situ.[18] Because OsO4 is electro-
philic,[19] the rate of its osmylation of electron-deficient ole-
fins (e.g., RRЈC=C–CO2RЈЈ) could be very low. However,
some unsaturated esters still give satisfactory reaction rates
at room temperature under the standard asymmetric dihy-
droxylation conditions. We believe that difficulties in the
reaction of AD-mix-α with substrate 3 came from the ad-
ditional two acetyl groups attached to the styrene moiety.
With its electron-withdrawing nature,[20] the acetyl groups
decreased the electron density of the C=C bond in α,β-un-
saturated ester 3 and, thus, impeded its reaction with OsO4.
To circumvent the problem of osmylation, we considered
optically active silylated lactate 8 as an ideal common inter-
mediate in the asymmetric total syntheses of oresbiusins A
and B (Scheme 2). The tert-butyldimethylsiloxyl [i.e., –OSi-
Me2(tBu)] moiety therein possesses electron-donating capa-
bility. Therefore, it could serve our purpose of introducing
chirality onto α,β-unsaturated ester 6b by using AD-mix-α
or AD-mix-β. AD-mix-α differs from AD-mix-β by con-
Our long-term interests in the development of new anti-
HIV agents promoted us to investigate the syntheses of
compounds in the family of oresbiusins. To the best of our
knowledge, no total syntheses of oresbiusins A and B have
been reported to date. Here we describe our success on the
first total syntheses of all optical isomers of oresbiusins A
(1b and 1c) and B (2b and 2c) in highly enantiomeric excess
(Ͼ 99%ee) as well as their racemates (i.e., 1a and 2a). We
also discovered that the absolute stereochemistry of the nat-
ural oresbiusin A should be revised from the (2R)- to the
(2S)-configuration (i.e., 1c). Among the newly synthesized
six oresbiusins A and B, the oresbiusin A (1b) was found to
exhibit the biological activity against HIV-1 replication.
Results and Discussion
For the total syntheses of optically active oresbiusins A taining the chiral ligand (DHQD)2-PHAL instead of
and B, our first stage was to obtain a common asymmetric (DHQ)2-PHAL (DHQD: dihydroquinine; DHQ: dihy-
lactate intermediate, such as compound 5 (Scheme 1). We droquinidine; PHAL: phthalazine).
envisioned that Sharpless asymmetric dihydroxylation[14] of
Our synthesis commenced with caffeic acid (6a), which
α,β-unsaturated ester 3 would fulfil our need of introducing can be converted into 3,4-bis(tert-butyldimethylsiloxy)-
the stereogenic centers. Subsequently, selective dehydroxyl- cinnamate (6b)[21] in two steps by Duynstee’s procedure
ation at the benzylic position of 1,2-diol 4 would afford α- (Scheme 2). Asymmetric dihydroxylation of cinnamate
hydroxy ester 5. We selected the acetyl protecting group in 6b[21] with AD-mix-α[14] (1.40 g/1.00 mmol) in the presence
phenol derivative 3 because (1) it can be easily removed in of methanesulfonamide (1.0 equiv.) afforded diol (2R,3S)-7
the final step to complete the total synthesis, (2) acetylated in 85% yield with 99%ee and [α]2D6 = –2.2. The stereogenic
analogues could serve as candidates for the identification of centers were assigned on the basis of establish methods re-
an inhibitor-binding site of HIV-1 integrase through affinity ported by various research groups.[18,22] Moreover,
acetylation,[15] and (3) several acetylated Dan-shen deriva- Sharpless asymmetric dihydroxylation[14] of diversely sub-
tives with closely related moieties in our target molecules stituted cinnamates in the presence of AD-mix-α has been
show antimyocardial ischemia activity.[16]
reported to proceed smoothly to afford a diol with the abso-
We applied AD-mix-α[14] to the asymmetric dihydrox- lute configuration as 2R,3S at the two newly generated
ylation of (3,4-diacetoxy)cinnamate (3)[17] in the presence of stereogenic centers.[18,22] Then, we dehydroxylated optically
methanesulfonamide at 0 °C. After a reaction time of 24 h active diol 7 by using Et3SiH[23] (1.1 equiv.) in the presence
and longer, only the starting material was recovered. When of CF3COOH at different temperatures. The optimal yield
this reaction was performed at elevated temperatures (e.g., we obtained was only 20% (Table 1, entries 1–3). Replace-
2
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First Total Syntheses of Oresbiusins A and B
(1c)[25] in 95% yield with [α]2D1 = +9.1, of which the spectro-
scopic data were fully consistent with those of 1a and 1b.
Both compounds 1b[3] and 1c are pale yellow gums that
turned to foam under low pressure. Accordingly, we were
unable to obtain the crystal structures of 1b and 1c to estab-
lish their absolute configuration. Nevertheless, the absolute
configuration of 1b was confirmed by comparison of the
specific rotation of synthetic 9 with the data reported by
Dong et al.[16]
Zou and co-workers[3] assigned isolated oresbiusin A
with dextrorotary as the (2R)-enantiomer (i.e., 1b). We
adopted the well-established Sharpless asymmetric dihy-
droxylation method with the reagent AD-mix-β to generate
the compound of the same skeleton with dextrorotary as
well. Nevertheless, many reports unanimously indicate that
asymmetric dihydroxylation on α,β-unsaturated esters with
AD-mix-β affords the products with 2S configuration. Ac-
cordingly, we believe that the configuration at C2 should be
revised from R to S for naturally occurring oresbiusin A.
In addition to (+)- and (–)-oresbiusin A, we prepared
(Ϯ)-oresbiusin A for anti-HIV assay. All of the synthetic
steps were the same as those described in Scheme 2 except
that AD-mix-α was replaced by osmium tetroxide[26] and
N-methylmorpholine N-oxide (NMO).
Scheme 2. Asymmetric total synthesis of (R)-oresbiusin A (1).
[24]
ment of CF3COOH with BF3·OEt2
allowed us to im-
prove the yield to 90% by performing the dehydroxylation
reaction at –78 °C over 2.0 h (Table 1, entry 5). White solids
of desired product 8 (m.p. 46–47 °C) displayed positive spe-
cific rotation with [α]2D6 = +7.0 and its enantiomeric excess
was determined to be Ͼ99% by HPLC analysis with a Chi-
ralcel OD column. Finally, treatment of (+)-8 with HF–
Et3N in pyridine[21] at room temperature gave target 1b in
Our second objective was to perform an asymmetric total
synthesis of oresbiusin B (2). To the best of our knowledge,
its absolute configuration has never been given. Therefore,
we decided to obtain molecules of its skeleton with dextro-
rotary and levorotary specific rotations as well as the race-
mic form. As shown in Scheme 3, our synthesis started with
ferulic acid (10), which can be converted into silylated inter-
mediate 11 by following the Snyder’s method.[4] Esterifica-
tion of cinnamic acid 11 with (+)-(R)-methyl lactate 8 in
the presence of 4-dimethylaminopyridine (DMAP), 1-ethyl-
3-(3Ј-dimethylaminopropyl)carbodiimide (EDCI), and 1-
hydroxybenzotriazole (HOBt) provided trisilylated interme-
diate (+)-(R)-12 as a yellow gum in 80% yield with Ͼ99%ee
and [α]1D9 = +43.0. This compound exhibited two singlets
1
90% yield as a pale yellow gum. Its H NMR spectrum,
13C NMR spectrum, and HRMS were in full agreement
with those of the naturally isolated oresbiusin A (1a).[2]
Table 1. Reductive dehydroxylation of optically pure diol 7.
Entry
Acid (equiv.)
Et3SiH
[equiv.]
T
[°C]
t
[h]
Yield
[%]
1
2
3
4
5
CF3COOH (5.0)
CF3COOH (5.0)
CF3COOH (5.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
1.1
1.1
1.1
2.0
2.0
r.t.
0
–78
0
–78
12
0
0
20
45
90
4.0
2.0
5.0
2.0
1
between 3.70 and 3.81 ppm in its H NMR spectrum for
the six protons resulting from the methoxy and methyl ester
To our surprise, synthetic target 1b displayed a levorotary groups. In its 13C NMR spectrum, resonance occurred at
specific rotation with [α]2D0 = –7.8 (c = 0.600, MeOH), which 166.39 and 170.40 ppm for the α-carboxy and the α,β-un-
did not match that of isolated natural 1c with [α]2D2 = +7.9 saturated ester sp2 carbon atoms, respectively. Moreover, its
(c = 0.410, MeOH).[25] Recently, Dong et al.[16] reported exact mass was detected as 730.3742, which well agreed to
triacetylate 9 with [α]2D0 = +3.6 (c = 1.0, CHCl3). Therefore, the theoretical value of 730.3752 for C38H74O8Si3. Finally,
we acetylated triol 1b with acetic anhydride in pyridine to treatment of (+)-(R)-12 with HF–Et3N in pyridine[21] gave
produce 9 (95% yield) for comparison, and we found that (+)-(R)-oresbiusin B (2b) in 98% yield as a yellow gum with
[α]2D1 = +4.8 (c = 1.0, CHCl3), which is consistent with that [α]1D9 = +21.0. Its H NMR, 13C NMR, and HRMS data
1
reported by Dong et al. To this stage, we are certain about are consistent with those of the naturally isolated oresbiu-
the 2R configuration of triol 1b.
sin B (2) reported by Huang and co-workers.[2]
Furthermore, we decided to synthesize the antipode of
Furthermore, the enantiomer of (+)-(R)-2b was synthe-
1b to reconfirm the optical rotation of oresbiusin A. We sized through the same steps shown in Scheme 3 except that
repeated the aforementioned synthetic strategy for the total (–)-(S)-methyl lactate 8 was used to replace its antipode (+)-
synthesis of (2S)-oresbiusin A (1c) except that AD-mix-β[14] (R)-8. As the result, a yellow gum of (–)-(S)-oresbiusin B
was replaced by AD-mix-α. Accordingly, enantiomerically (2c) with [α]2D1 = –29.3 was generated with success. More-
enriched diol (+)-(2S,3R)-7 and dehydroxylated (–)-(2S)- over, we utilized the aforementioned synthetic strategy and
methyl lactate (8) were generated with Ͼ99%ee. Finally, de- intermediate (Ϯ)-methyl lactate 8 to accomplish a total syn-
silylation of lactate 8 produced (+)-(2S)-oresbiusin A thesis of (Ϯ)-oresbiusin B (2a).
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J. R. Hwu, T. G. Varadaraju, I. S. Abd-Elazem, R. C. C. Huang
SHORT COMMUNICATION
acid, the total syntheses included six steps with ca. 58%
overall yields. Among the six compounds in the family of
oresbiusins, unnatural (–)-(R)-1b exhibited activity against
HIV-1 replication.
Supporting Information (see footnote on the first page of this arti-
1
cle): Synthetic procedures, H NMR and 13C NMR spectroscopic
data, HPLC chromatograms, and biological data for new com-
pounds.
Acknowledgments
Scheme 3. Asymmetric total synthesis of (+)-(R)-oresbiusin B (2).
We thank the National Science Council (Grant No. 99-2113M-007-
008-MY3) and Ministry of Education, Republic of China (Grant
No. 100N2017E1), as well as the Dorthy Yien Trust (Grant No.
P690-C25-2407) for support of this research.
Investigation on the activities of the newly synthesized
six oresbiusins A and B against HIV-1RTMF infection was
performed in H9 cells. We measured their viral replication
in the absence and presence of compounds 1a–c and 2a–c [1] H. Hao, S. Handong, Z. Shouxun, Phytochemistry 1996, 42,
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[2] H. Huang, H. D. Sun, M. S. Wang, S. X. Zhao, J. Nat. Prod.
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at concentrations of 0, 1.25, 2.5, 5.0, 10, 20, 40, and 80 μm
by using the HIV-1 p24 antigen ELISA after 8 d as de-
scribed by Huang et al.[7] The optically active isomers of
oresbiusin A (1b and 1c) showed striking differences in their
anti-HIV activities. Only (R)-1b showed dose-dependent
anti-HIV activity, whereas both (S)-1c and racemate 1a
were inactive (Figure 1). Meanwhile, 2a–c were found to be
inactive.
2010, 46, 19–21.
[4] S. A. Snyder, F. Kontes, J. Am. Chem. Soc. 2009, 131, 1745–
1752.
[5] R. S. Xu, Dan-Shen (Salvia miltiorrhiza) – Its Biology and Ap-
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[6] For biological activities, see: a) R. W. Jiang, K. M. Lau, P. M.
Hon, T. C. W. Mak, K. S. Woo, K. P. Fung, Curr. Med. Chem.
2005, 12, 237–246; b) A. Watzke, S. J. O’Malley, R. G.
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[8] N. J. Lawrence, S. Brown, Tetrahedron 2002, 58, 613–619 and
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[9] E. J. Hicken, Ph. D. Thesis, Brigham Young University, 2005.
[10] J. R. Hwu, W. N. Tseng, J. Gnabre, P. Giza, R. C. Huang, J.
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[11] H. Chen, L. Teng, J. N. Li, R. Park, D. E. Mold, J. Gnabre,
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Figure 1. Effect of compounds 1a–c on HIV-1 replication in H9
cells. HIV-1RTMF (AZT-resistant virus) was treated with increasing
concentrations (0, 1.25, 2.5, 5.0, 10, 20, 40, and 80 μm) of 1a–c
compounds. Viral replication in the absence and presence of 1a–
c was measured by using HIV-1 p24 antigen ELISA after 8 d of
infection.
[13] J. R. Hwu, C.-I. Hsu, M. H. Hsu, Y. C. Liang, R. C. Huang,
Y. C . L e e, Bioorg. Med. Chem. Lett. 2011, 21, 380–382.
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of oresbiusin A (i.e., 1b and 1c) as well as racemate 1a were [18] H. C. Kolb, M. S. Vannieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483–2547.
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dihydroxylation was utilized to the construct the stereogenic
607.
centers with excellent enantioselectivity (Ͼ99%e). The out-
come allowed us to establish the absolute stereoconfigura-
tion of oresbiusin A: this natural product was dextrorotary
and should be the (2S) enantiomer. In addition, an efficient,
convergent route was developed for the total syntheses of
(+)-, (–)-, and (Ϯ)-oresbiusin B. By starting with caffeic
[20] J. March, Advanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 4th ed., Wiley, New York, 1992, ch. 9, pp. 273–
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[21] H. I. Duynstee, M. C. de Koning, H. Ovaa, G. A. van der Ma-
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[22] For representative works, see: a) Z. M. Wang, H. C. Kolb,
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4
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First Total Syntheses of Oresbiusins A and B
Das, G. Panda, Tetrahedron 2008, 64, 4162–4173; c) C. Xiong,
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[25] The specific rotation for naturally occurring oresbiusin A was
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Received: May 22, 2012
Published Online: ᭿
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J. R. Hwu, T. G. Varadaraju, I. S. Abd-Elazem, R. C. C. Huang
SHORT COMMUNICATION
Total Synthesis
J. R. Hwu,* T. G. Varadaraju,
I. S. Abd-Elazem,
R. C. C. Huang* ............................... 1–6
First Total Syntheses of Oresbiusins A and
B, Their Antipodes, and Racemates: Con-
figuration Revision and Anti-HIV Activity
The first total synthesis of oresbiusin A
was accomplished, and the key intermedi-
ate with optical activity was generated
through a Sharpless asymmetric dihydrox-
ylation reaction. The absolute configur-
ation of this natural product was deter-
mined. The total syntheses of oresbiusin B
and its racemate were also accomplished,
and their anti-HIV-1 activities were investi-
gated.
Keywords: Chirality / Biological activity /
Configuration determination
products / Total synthesis
/ Natural
6
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