Total synthesis of ivorenolide a following a base-induced elimination protocol

Article abstract of DOI:10.1021/acs.orglett.5b00138

A concise and stereocontrolled first total synthesis of Ivorenolide A (1) is reported in 16 longest linear steps with a 13.4% overall yield starting from (+)-diethyl tartrate (DET). Key features are base-induced elimination protocol for the construction of chiral propargyl alcohols in both fragments, Pd-catalyzed cross-coupling of terminal acetylenes, and Shiina's 2-methyl-6-nitrobezoic anhydride (MNBA) mediated macrolactonization.

Full text of DOI:10.1021/acs.orglett.5b00138

Letter
pubs.acs.org/OrgLett
Total Synthesis of Ivorenolide A Following a Base-Induced
Elimination Protocol
Debendra K. Mohapatra,* Gonela Umamaheshwar, R. Nageshwar Rao, T. Srinivasa Rao,
Sudheer Kumar R, and Jhillu S. Yadav*
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
S
* Supporting Information
ABSTRACT: A concise and stereocontrolled first total synthesis of
Ivorenolide A (1) is reported in 16 longest linear steps with a 13.4%
overall yield starting from (+)-diethyl tartrate (DET). Key features are
base-induced elimination protocol for the construction of chiral propargyl
alcohols in both fragments, Pd-catalyzed cross-coupling of terminal
acetylenes, and Shiina’s 2-methyl-6-nitrobezoic anhydride (MNBA)
mediated macrolactonization.
acrolactones with polyacetylene moieties represent a
Munique family of natural products endowed with
impressive biological properties such as immunosuppressive
activities. Usually, immunosuppressive agents are used in the
treatment of organ grafts and also for autoimmune chronic
inflammatory disorders. In the past few decades, the discovery
of cyclosporin (CsA)1 and tacrolimus (FK506)2 enabled
Figure 1. Structures of Ivorenolide A (1) and B (2).
successful transplantation of the major organs in humans.
However, neither drug can be used for managing trans-
plantation tolerance for the long-term.3,4 Recently discovered
immunosuppressants such as tetranactin,5 didemnin B,6 and
discodermolide7 all seem to have related but unique modes of
action, suggesting that these compounds have discrete
intracellular target mechanisms. In addition, the search for
new immunosuppressants that possess better therapeutic effects
or those which can be combined with currently used drugs for
longer time maintenance and reduced side effects is of great
interest. Traditional Chinese medicines (TCM) have been used
for centuries in China to treat various immune-mediated
disorders.8 The search for immunosuppressants from TCM has
led to the isolation of many limonoids from an antirheumatic
Chinese herb Khaya ivorensis A. Chev. (Meliaceae), which has
shown cytotoxic, anti-inflammatory, and antimalarial activities.9
Very recently, Ivorenolide A (1) and B (2) were isolated by
Yue et al. from the stem bark of K. ivorensis.10 These natural
products contain conjugated acetylenic bonds including five
and four oxygenated centers embedded in 18- and 17-
membered macrolides, respectively (Figure 1). Ivorenolide A
has been reported to exhibit significant inhibition of ConA-
induced T-cell proliferation and LPS-induced B-cell prolifer-
ation. Owing to their interesting biological properties and
intriguing structural motifs, the Ivorenolides have attracted the
attention of synthetic chemists.
struct a diacetylenic moiety,12 and Shiina’s MNBA macro-
lactonization13 as a pivotal step.
The initial disconnection in the retrosynthesis involved
cleavage of the macrolactone linkage at C1 to provide a diyne
system (Scheme 1). This diyne could be accessible from an
alkyne and a bromoalkyne through a Sonogashira coupling
strategy. The alkyne and bromoalkyne fragments could be
easily accessible from (+)-DET and known aldehyde 816
respectively, by utilizing sequences which relied on the
implementation of a chiral propargyl alcohol construction
protocol.
The synthesis of alkyne fragment 5 is delineated in Scheme 2,
which was prepared in a stereoselective manner commenced
with the primary alcohol 7 which was in turn obtained from
(+)-DET.14 TBS protected primary alcohol 7 was oxidized with
Dess-Martin periodinane (DMP)15 and subjected to a Wittig
reaction with bromo(9-((4-methoxybenzyl)oxy)nonyl)-
triphenyl phosphorane in the presence of LHMDS to afford
olefin 9 as an exclusive Z-isomer in 78% yield. The TBS group
was deprotected using TBAF to afford 10 in 97% yield. The
primary alcohol was converted to chloride 11 using CCl4−Ph3P
under reflux conditions, which was subjected to our protocol11
of a base-induced elimination reaction to provide the chiral
acetylenic alcohol 12, with n-BuLi at −78 °C, in 87% yield. The
product was converted to its corresponding MOM ether 5
Herein, a full account of our work is presented which
culminated in the first total synthesis of Ivorenolide A, using
our own developed protocol for the construction of chiral
propargyl alcohols,11 metal-catalyzed cross-coupling to con-
Received: January 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00138
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Organic Letters
Letter
Scheme 1. Retrosynthetic Analysis
Scheme 3. Synthesis of Bromo Alkyne 6
(Pd(PPh3)2Cl2, CuI, i-Pr2NH, THF)12 gave the required cross-
coupling product 4 in 74% yield along with homocoupling of
excess bromoalkyne as the byproduct. Further investigation
gave an inferior result with (CuI, PPh3, K2CO3, EtOH) in 61%
yield (Table 1).19 The coupled product was subjected to
Scheme 2. Synthesis of Alkyne 5
Table 1. Cross-Coupling of Alkyne and Bromoalkyne
a
entry
reaction conditions
time
yield (%)
1
2
Pd(PPh3)2Cl2, CuI, i-Pr2NH, THF
1 h
6 h
74
61
CuI, PPh3, K2CO3, EtOH
a
Isolated yield.
deprotection of the TBS group with TBAF to afford 17 in 97%
yield. Treatment of compound 17 with DDQ in the presence of
pH 7 buffer in CH2Cl2 afforded diol 18 in 92% yield. Selective
oxidation of the primary alcohol with (diacetoxyiodo)benzene
(BAIB) in the presence of TEMPO and subsequent oxidation
of the aldehyde with NaClO2 in the presence of NaH2PO4 as
the buffer furnished 19 in 91% yield over two steps.
using MOM-Cl and DIPEA in the presence of a catalytic
amount of DMAP in 95% yield.
The focus was then shifted toward the synthesis of chiral
subunit 6, which was achieved in good yield and optical purity
when compared to the previous route.10a For this, the known
aldehyde 816 was transformed to unsaturated ester 13 through
two carbon homologation in 93% yield. Reduction of 13 with
DIBAL-H gave the allylic alcohol, which was subjected to the
Sharpless asymmetric epoxidation17 to obtain epoxy alcohol 14
as the sole product in 84% yield over two steps (Scheme 3).
This set the stage for the base-induced elimination protocol for
the second time. The epoxy alcohol 14 was converted to a
chloro product with CCl4−Ph3P under reflux conditions,
followed by base-induced elimination with n-BuLi at −78 °C
affording chiral propargylic alcohol 15 in 82% yield over two
steps. This secondary alcohol was protected as its MOM-ether
with MOM-Cl, in the presence of N,N-diisopropylethyl amine
(DIPEA) to afford compound 16 in 95% yield. The terminal
acetylene 16 on treatment with NBS and a catalytic amount of
With a seco acid in hand, the attention was turned toward
macrolactonization to complete the synthesis of Ivorenolide A.
Recently, in a related transformation,13b it was found that
Shiina’s lactonization protocol (MNBA, DMAP, PhMe)
appeared to be an excellent method for macrolactonization
owing to its remarkable efficiency and simple operation. On
treating with MNBA and DMAP in toluene at room
temperature, the seco acid smoothly provided the macrolide
20 in 84% yield (Scheme 4). Treatment of compound 20 with
3 N HCl in ethanol afforded 3 in 74% yield. Oxidation of 3 (Z-
form) with m-chloroperoxybenzoic acid (m-CPBA) afforded 1
as the sole product in 81% yield assuming that the m-CPBA
approached the double bond from the sterically less hindered
face of the molecule as reported earlier.10a The spectral and
18
23
AgNO3 furnished bromo alkyne 6 in 97% yield.
analytical data {[α]D27 = +49.6 (c 0.43, MeOH); lit.10a [α]D
=
With the requisite fragments in hand, the coupling reaction
between 5 and 6 was carried out next. However, an ensuing
investigation revealed that the modified Sonogashira conditions
−50.9 (c 0.157, MeOH)} for the synthetic molecule was in
good agreement with the data reported for the natural
product.10a
B
DOI: 10.1021/acs.orglett.5b00138
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Accomplishment of the First Total Synthesis of
Ivorenolide A (1)
REFERENCES
■
(1) For a comprehensive review, see: Ishizaka, K.; Lachmann, P. J.;
Kallos, P.; Waksman, B. H. In Progress in Allergy; Borel, J. F., Ed.;
Karger: Basel, Switzerland, 1986; Vol. 38.
(2) Kino, T.; Hatanake, H.; Miyata, S.; Inamura, N.; Nishiyama, M.;
Yajima, T.; Gotto, T.; Okuhara, M.; Kohsaka, M.; Aoki, H.; Ochai, T. J.
Antibiot. 1987, 40, 1356.
(3) Toungouz, M.; Donckier, V.; Goldman, M. Transplantation 2003,
75, 58S.
(4) Offermann, G. Drugs 2004, 64, 1325.
(5) (a) Tanouchi, Y.; Shichi, H. Immunology 1988, 63, 471.
(b) Callewaert, D. M.; Radcliff, G.; Tanouchi, Y.; Sichi, H.
Immunopharmacology 1988, 16, 25.
(6) (a) Montgomery, D. W.; Celniker, A.; Zukoski, C. F.
Transplantation 1987, 43, 133. (b) Montgomery, D. W.; Zukoski, C.
F. Transplantation 1985, 40, 49. (c) Longley, R. E.; Caddigan, D.;
Harmody, D.; Gunasekera, M.; Gunasekera, S. P. Transplantation
1991, 52, 650.
(7) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.;
Gunasekera, S. P. Transplantation 1991, 52, 650.
(8) Ramgolam, V.; Ang, S. G.; Lan, Y. H.; Loh, C. S.; Yah, H. K. Ann.
Acad. Med. Singapore 2000, 29, 11.
(9) Agbedahunsi, J. M.; Fakoya, F. A.; Adesanya, S. A. Phytomedicine
2004, 11, 504.
(10) (a) Zhang, B.; Wang, Y.; Yang, S. P.; Zhou, Y.; Wu, W. B.; Tang,
W.; Zuo, J. P.; Li, Y.; Yue, J. M. J. Am. Chem. Soc. 2012, 134, 20605.
(b) Wang, Y.; Liu, Q. F.; Xue, J. J.; Zhou, Y.; Yu, H. C.; Yang, S. P.;
Zhang, B.; Zuo, J. P.; Li, Y.; Yue, J. M. Org. Lett. 2014, 16, 2062.
(11) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron
1990, 46, 7033.
(12) (a) Sonogashira, K. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York,
2002; Vol. 1, p 493. The formation of homocoupling products during
the cross-coupling reaction has been observed earlier. For reviews, see:
(b) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979. (c) Siemsen,
P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39,
2632.
In summary, the investigation described above has resulted in
the first total synthesis of Ivorenolide A (1) in 16 longest linear
steps with a 13.4% overall yield. Highlights of the synthetic
sequence include a base-induced elimination protocol for the
construction of both fragments in a concise and stereoselective
manner and Pd-catalyzed cross-coupling to construct a diyne
system. For the macrocyclization, the MNBA-mediated
lactonization for its high efficiency and simple operation has
been demonstrated. Further studies toward the total synthesis
of Ivorenolide B (2) are currently underway in our laboratory
and will be reported in due course.
(13) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822. (b) Parenty, A.; Moreau, X.; Campagne, J. M.
Chem. Rev. 2006, 106, 911.
(14) Wood, J. L.; Jeong, S.; Salcedo, A.; Jenkins, J. J. Org. Chem.
1995, 60, 286 and references therein.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(16) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983,
48, 5180.
(17) Martin, V. S.; Woodward, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
(18) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett
1994, 485.
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AUTHOR INFORMATION
Corresponding Authors
■
(19) Wang, S.; Yu, L.; Li, P.; Meng, L.; Wang, L. Synthesis 2011,
1541.
*E-mail: mohapatra@iict.res.in.
*E-mail: yadavpub@iict.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Dr. A. V. Rama Rao, Former Director, CSIR-IICT
(Managing Director, AVRA Research Laboratories Pvt. Ltd.,
Hyderabad, India), on the occasion of his 80th birthday. The
authors thank the Council of Scientific and Industrial research
(CSIR), New Delhi, India, for financial support as part of the
XII Five Year plan programme under the title ORIGIN (CSC-
0108). G.U., R.N., T.S.R., and S.K.R thank UGC and CSIR,
New Delhi, India, for financial assistance in the form of
fellowships.
C
DOI: 10.1021/acs.orglett.5b00138
Org. Lett. XXXX, XXX, XXX−XXX