Total synthesis of biselyngbyolide A

Article abstract of DOI:10.1021/ol500996n

Biselyngbyolide A is an 18-membered macrolide that exhibits significant biological activities such as growth-inhibitory activity and apoptosis inducing activity against cancer cells. In this study, the first total synthesis of biselyngbyolide A by using a

Full text of DOI:10.1021/ol500996n

Letter
pubs.acs.org/OrgLett
Total Synthesis of Biselyngbyolide A
Yurika Tanabe, Eisuke Sato, Naoya Nakajima, Akifumi Ohkubo, Osamu Ohno, and Kiyotake Suenaga*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522,
Japan
S
* Supporting Information
ABSTRACT: Biselyngbyolide A is an 18-membered macrolide that exhibits significant biological
activities such as growth-inhibitory activity and apoptosis inducing activity against cancer cells. In this
study, the first total synthesis of biselyngbyolide A by using an intramolecular Stille coupling reaction
as a key step is achieved.
n 2009, we elucidated the structure of biselyngbyaside (1)
isolated from the marine cyanobacterium Lyngbya sp.
Scheme 1. Retrosynthetic Analysis of Biselyngbyolide A
I
collected at Okinawa (Figure 1).1 Biselyngbyaside (1) exhibited
Figure 1. Structures of biselyngbyaside and biselyngbyolide A.
growth-inhibitory activity against cancer cells with IC50 values
of 2.5 μM (HeLa S3) and 0.31 μM (HL60). In addition, 1 was
shown to inhibit osteoclastogenesis and induce the apoptosis of
osteoclasts, and thus may be useful for the prevention of bone
lytic diseases.2 We recently found five biselyngbyaside
congeners including biselyngbyolide A.3−5 Biselyngbyasides
also induced apoptosis of cancer cells and increased the
cytosolic Ca2+ concentration in HeLa S3 cells.4 Biselyngbyolide
A, an aglycone of biselyngbyaside B, showed much more potent
activity against cancer cells with IC50 values of 0.039 μM (HeLa
S3) and 0.012 μM (HL60) than biselyngbyaside.
These biological activities and its novel 18-membered
macrolide structure prompted us to synthesize biselyngbyolide
A (2). Synthetic studies of biselyngbyaside have been reported
by Maier6 and Chandrasekhar.7 We describe here the first total
synthesis of biselyngbyolide A (2).
Scheme 1 outlines our strategy for synthesizing biselyngbyo-
lide A (2). We planned to construct its 18-membered cyclic
structure by an intramolecular Stille coupling reaction8 of ester
3, which could be synthesized by condensation between alcohol
4 and carboxylic acid 5. Carboxylic acid 5 might be obtained
from the Nozaki−Hiyama−Kishi (NHK) reaction9 between
vinyl iodide 6 and aldehyde 7. Initially, we planned to construct
the macrolide ring by macrolactonization of hydroxyl carboxylic
acid 9. However, we could not obtain 9 from alcohol 8 in good
yield, because the conjugated diene moiety in 8 was unstable
under the oxidation reaction conditions. Therefore, we decided
to construct the conjugated diene in the last stage of the
synthesis.
The synthesis of alcohol 4 began with the ring-opening
reaction of trityl glycidyl ether (10) with lithium acetylide.
Protection of the resultant hydroxyl group with TBDPS
(Scheme 2, 99% in two steps) followed by removal of the
trityl protecting group led to alcohol 11 (85%). Oxidation of
alcohol 11 with Dess-Martin periodinane gave aldehyde (96%),
Received: April 4, 2014
© XXXX American Chemical Society
A
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Scheme 2. Synthesis of Alcohol 4
Scheme 3. Synthesis of Carboxylic Acid 5
the Horner−Wadsworth−Emmons reaction of which with
Ando’s reagent10 afforded conjugated ester 12 (93%).
Reduction of 12 provided the corresponding allylic alcohol
(89%), which was converted into allylic bromide 13 (quant).
The Suzuki−Miyaura coupling reaction11 of 13 with trans-1-
propen-1-yl-boronic acid gave diene 14 (52%) as an inseparable
ca. 2:1 mixture of 18Z and 18E isomers.12 We tried various
conditions for Suzuki−Miyaura coupling, boronate esters, a
variety of bases, and Pd catalysts such as Pd(PPh3)4, Pd(OAc)2,
Pd(MeCN)2Cl2, and Pd(dppf)Cl2, but the yield and Z/E
selectivity were not improved. The 18E isomer could be
separated at a later stage in the synthesis, i.e., after
macrocyclization of ester 3. Diene 14 was transformed into
vinylstannane 15 with tributylstannane and AIBN (72%).
Removal of the TBDPS group in 15 gave alcohol 4 as a mixture
with TBDPS fluoride.
Two small segments, vinyl iodide 6 and aldehyde 7, were
prepared as follows (Scheme 3). Vinyl iodide 6 was prepared
from known aldehyde 16.13 Aldehyde 16 was converted into
the corresponding dibromoolefin (97%), which was treated
with a base followed by methylation providing alkyne 17
(96%). Hydrozirconation of 17 followed by iodination gave
vinyl iodide 6 (90%). Aldehyde 7 was synthesized from known
alcohol 18,14 with subsequent protection of the hydroxyl group
(74%) followed by oxidative cleavage of the olefin providing
aldehyde 19 (78%). Stereoselective allylation with (+)-iso-
pinocampheylborane15 delivered alcohol 20 (89%). The
stereochemistry of the C5 hydroxyl group was determined on
the basis of NOE experiments for the derived cyclic PMP acetal
(see the Supporting Information). Treatment of 20 with DDQ
(83%) followed by oxidative cleavage of the olefin afforded
aldehyde 7 (96%).
The NHK coupling reaction between vinyl iodide 6 and
aldehyde 7 provided diastereomeric alcohols 21 and epi-21
(82%), which could be separated by chromatography. The
B
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stereochemistry of each was determined by a modified Mosher
method16 (see the Supporting Information). Undesired epi-21
was transformed into alcohol 21 by oxidation (quant) followed
by stereoselective reduction with Corey−Bakshi−Shibata
(CBS) reagent (R)-22 (80%);17 desired alcohol 21 was
obtained from aldehyde 7 in 76% yield, including the
conversion of epi-21 into 21. The secondary hydroxyl group
of 21 was methylated (84%), and the benzyl group was
selectively removed in the presence of the PMP acetal with
lithium di-tert-butylbiphenylide (LiDBB) (81%).18 Oxidation of
the resulting primary alcohol (quant) followed by the Takai
olefination reaction19 gave vinyl iodide 23 (58%). Removal of
the TBDPS group in 23 (85%) followed by catalytic TEMPO
oxidation afforded the corresponding aldehyde (87%), which
was further oxidized with sodium chlorite to carboxylic acid 5
(92%).
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic data, and H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: suenaga@chem.keio.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research (B) (No. 24310160) from the Japan Society for the
Promotion of Science and the MEXT-Supported Program for
the Strategic Research Foundation at Private Universities, 2009-
2013 from the Ministry of Education, Culture, Sports, Science
and Technology, Japan. We thank Sanyo Fine Co., Ltd. for
their gift of chiral trityl glycidyl ether.
The stage was set for the task of connecting alcohol 4 and
carboxylic acid 5 (Scheme 4). Esterification between 4 and 5
Scheme 4. Synthesis of Biselyngbyolide A
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D
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