Formal total synthesis of cyanolide a

Article abstract of DOI:10.1021/jo102401v

Formal total synthesis of cyanolide A, aglycosidic dimeric macrolide is accomplished. The key reactions involved are asymmetric acetate aldol reaction, CBS reduction, and Shiina's lactonization.

Full text of DOI:10.1021/jo102401v

NOTE
pubs.acs.org/joc
Formal Total Synthesis of Cyanolide A
Srihari Pabbaraja,* K. Satyanarayana, B. Ganganna, and J. S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, CSIR, Hyderabad -500607, India
S Supporting Information
b
ABSTRACT: Formal total synthesis of cyanolide A, aglycosidic dimeric macrolide
is accomplished. The key reactions involved are asymmetric acetate aldol reaction,
CBS reduction, and Shiina’s lactonization.
Scheme 1. Retrosynthesis
t is estimated that around 207 million people are infected
worldwide with schistosomiasis and over 779 million people
I
are at risk of infection.1 The pathology of schistomiasis includes a
complex immune response to schistosome eggs which get
trapped in tissues and result in causing hepatomegaly, spleno-
megaly, bladder cancer, or kidney malfunction and ultimately
lead to death.2 As helminthes require both aquatic snail host and
mammalian host to complete their reproductive cycle, simple
eradication of the disease in the mammalian host does not
protect against the possibility of reinfection if exposed to water
containing snail vectors. One fair way would also be to com-
pletely eradicate the snail vectors. Cyanolide A, a recently
isolated dimeric glycosidic macrolide obtained from extracts of
the Papua New Guinea collection of Lyngbya bouillonii,3 was
found to be highly toxic against Biomphalaria glabrata (LC50
=
1.2 μM), which makes it an efficient molluscidal agent. More
importantly, this dimeric macrolide was found to be noncyto-
toxic when tested against H-460 human lung adenocarcinoma
and Neuro-2a mouse neuroblastoma cell lines (maximum test
concentration of 35 μM).
Owing to the low availability of this natural material for further
screening and its utilization, we became interested in taking up
the total synthesis of this molecule. The inaugural synthesis4 has
been from Jiyong Hong's group wherein two complementary
routes for the total synthesis of cyanolide A have been developed
involving tandem allylic oxidation/oxa-Michael reaction and
MNBA-mediated dimerization. In the present context, we report
a linear and concise approach toward the formal total synthesis of
cyanolide A.
Wittig reaction with 1-(triphenylphosphoranylidene)-2-buta-
none ylide. Asymmetric reduction of the ketone with CBS
catalyst provides the chiral secondary alcohol 3. Hydroboration
and selective oxidation of the vinylic side chain of 3 provides the
acid that upon dimerization through Shiina’s lactonization (see
Scheme 1) can result in the formation of key dimeric macrolide 2.
The synthesis starts from the readily available chiral raw
material R-(-)-pantolactone, which was protected as the corre-
sponding benzyl ether by using benzyl imidate catalyzed by
BF3 Et2O (Scheme 2).5 The lactone 5 was reduced to lactal with
3
DIBAL-H and then subjected to one-carbon Wittig homologa-
tion reaction to yield alcohol 6. Oxidation of alcohol 6 with PCC
afforded aldehyde 7, which was subjected to Crimmin’s acetate
aldol reaction with (R)-1-(4-benzyl-2-thioxothiazolidin-3-
yl)ethanone 8 to yield an inseparable diastereomeric mixture of
Our approach relies on ring expansion of readily available
R-(-)-pantolactone to six membered lactone 4 achieved
through ring-opening, oxidation of free alcohol to aldehyde,
asymmetric acetate aldol reaction, and lactonization. Extension
of the side chain from the lactone moiety could be achieved by a
Received: December 4, 2010
Published: January 31, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 2. Synthesis of Lactone 4
Scheme 3. Synthesis of 3
syn and anti alcohols 9 and 9a in 9:1 ratio.6 With the required
geometry set for the secondary alcohol, the next step was to
deprotect the benzyl ether and cyclize with auxiliary cleavage
through basic hydrolysis. Toward this end, the substrate 9 was
converted to ester 9b with imidazole and MeOH. An attempt to
cleave the benzyl ether with lithium naphthalenide at this stage in
the presence of ester moiety was not successful and resulted in
decomposition of starting material.7 Hence, compound 9 was
directly converted into amide 10 by treating with Weinreb’s salt
and imidazole. The reaction of amide 10 with lithium naphtha-
lenide proceeded with debenzylation and also cleavage of the
N-O bond to provide amide 11. Treatment of 11 with Ba-
reaction (Scheme 3).9 The compounds 12 and 12a were
protected as their corresponding silyl ethers 13 and 13a with
TBSCl and 2,6-lutidine. The compounds 13 and 13a were easily
separable by column chromatography. The 2D NOESY spectra
for compound 13 in CD3OD10 revealed the protons geometry to
be in cis relation at C2, C4, and C6 positions by the presence of
strong NOE correlations (see the SI). The keto functionality in
13 was reduced to alcohol by using a catalytic amount of Corey’s
chiral borane, S-CBS catalyst11 14 in presence of BH3 DMS to
3
yield an easily separable mixture of products 3 and 3a (dr =
8:2).12
The terminal olefin 3 was subjected to hydroboration upon
(OH)2 8H2O provided lactone 4 in good yields.8
treatment with BH3 DMS to yield primary alcohol 15. Selective
3
3
With the six-membered lactone in hand, the remaining goal
was to build up the side chains at both ends on C2 and C6
carbons and proceed toward the total synthesis. Accordingly, the
lactone 4 was reduced with DIBAL-H to yield the corresponding
lactal, which was treated with 1-(triphenylphosphoranylidene)-
2-butanone to yield a mixture of inseparable diastereomers 12
and 12a in 7:2 ratio following a one-pot Wittig and oxa-Michael
oxidation of primary alcohol with TEMPO and BAIB afforded an
acid13 that was directly utilized for dimerization. Thus, the
monomeric unit comprised of acid and alcohol functionality
was subjected to Shiina’s lactonization14 protocol employing
2-methyl-6-nitrobenzoic anhydride (MNBA) and DMAP to
provide dimeric macrolide 16 as previously done by Hong's
group.4 Finally, TBS deprotection with HF-pyridine afforded the
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The Journal of Organic Chemistry
NOTE
Scheme 4. Formal Total Synthesis of Cyanolide A Aglycone
known intermediate cyanolide A aglycone 2. The spectroscopic
data of the synthesized compound, i.e., 1H NMR, 13C NMR, and
optical rotation, were compared with those of the earlier known
synthesized intermediate4a and found to be identical. As this
intermediate was already utilized for the total synthesis, we claim
a formal total synthesis of cyanolide A (Scheme 4).
In conclusion, a linear approach for the synthesis of cyanolide
A aglycone has been described starting from readily available
R-(-)-pantolactone in 16 steps with an overall yield of 6.6% for
the intermediate 2. The strategy is also being investigated for
other analogue synthesis toward the availability of the synthetic
material for further biological evaluation. The concise approach
with good yields merits its further exploitation toward gram scale
synthesis.
two-necked, round-bottomed flask charged with a magnetic stir
bar was added 0.029 mL of a 1 M solution of (S)-CBS 14 in toluene
(0.029 mmol). The toluene was then removed by placing the flask on a
high-vacuum pump for approximately 1 h. The flask was then placed
under argon atmosphere and THF (4 mL) was added. The reaction
mixture was cooled to -30 °C and 0.45 mL of a 1 M solution of
BH3 S(CH3)2 in THF (0.45 mmol) was added. To this reaction
3
mixture was added dropwise a solution of ketone 13 (100 mg, 0.294
mmol) dissolved in THF (1 mL). The reaction was stirred for 12 h
at -30 °C before MeOH (∼3 mL) was carefully added to destroy
excess BH3. The reaction was diluted with saturated aqueous NH4Cl
(∼2 mL) and extracted with EtOAc (3 ꢀ 5 mL). The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated. The crude oil was purified by flash
chromatography with hexane/EtOAc (22:1), giving dr = 8:2 (70.8 mg
with 71% major isomer 3, 17.7 mg with 17% minor isomer 3a as a
’ EXPERIMENTAL SECTION
colorless oil). Rf 0.4 (hexane/EtOAc, 9:1). Major isomer 3: [R]23
D
þ7.30 (c 0.92, CHCl3); IR (neat) 3445, 2925, 2853, 1252, 1095, 835
(3S,5S)-1-((R)-4-Benzyl-2-thioxothiazolidin-3-yl)-5-(benzyloxy)-
3-hydroxy-4,4-dimethylhept-6-en-1-one (9). To a dry round-
bottomed flask under argon atmosphere was added (R)-1-(4-benzyl-
2-thioxothiazolidin-3-yl)ethanone (8) (2.3 g, 9.16 mmol) dissolved in
CH2Cl2 (30 mL). The solution was cooled to 0 °C and titanium
tetrachloride (1.2 mL, 10.99 mmol) was added dropwise. The thick
suspension was stirred for 10 min upon which diisopropylethylamine
(1.89 mL, 10.99 mmol) was added dropwise at 0 °C and stirring was
continued. After 10 min the reaction mixture was cooled to -78 °C and
to this was added freshly prepared aldehyde 7 (1.6 g, 7.33 mmol)
dissolved in CH2Cl2 (8 mL). After 10 min the reaction mixture was
quenched with aq saturated ammonium chloride solution (10 mL) and
warmed to room temperature. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 ꢀ 30 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was purified by
flash column chromatography with hexane/EtOAc (12:1) to provide a
mixture of diasteriomeric (dr = 9:1) product 9 (3.65 g, 85%) as a yellow
oil; Rf 0.4 (hexane/EtOAc, 4:1); [R]23 -141.2 (c 0.54, CHCl3); IR
(neat) 3468, 2922, 1692, 1260, 772 cm-1D; 1H NMR (300 MHz, CDCl3)
δ 7.39-7.17 (m, 10H), 5.96-5.74 (m, 1H), 5.47-5.22 (m, 3H), 4.59
(d, J = 11.5 Hz, 1H), 4.29 (d, J = 11.5 Hz, 1H), 4.23 (d, J = 10.6 Hz, 1H),
3.75 (d, J = 8.1 Hz, 1H), 3.45-3.16 (m, 5H), 3.10-2.96 (m, 1H), 2.86
(d, J = 11.5 Hz, 1H), 0.93 (s, 3H), 0.90 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 201.2, 173.0, 137.6, 136.4, 134.2, 129.3, 128.7, 128.3, 127.8,
127.6, 127.0, 120.1, 87.7, 73.2, 70.5, 68.7, 41.4, 40.4, 36.5, 32.0, 20.9,
20.6; MS (ESI) m/z 470 (M þ H)þ; HRMS (ESI) calcd for
C26H32NO3S2 (M þ H)þ 470.1823, found 470.1802.
cm-1 1H NMR (300 MHz, CDCl3) δ 5.88-5.70 (m, 1H), 5.20
;
(s, 1H), 5.16 (d, J = 4.5 Hz, 1H), 3.77-3.57(m, 3H), 3.50 (d, J = 6.4 Hz,
1H), 3.44-3.35 (m, 1H), 1.71-1.31 (m, 6H), 0.98-0.87 (m, 12H),
0.84 (s, 3H), 0.81 (s, 3H), 0.05 (d, J = 2.8 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 134.1, 117.3, 85.1, 75.6, 73.5, 41.8, 39.2, 38.1, 30.3, 25.8, 23.1,
18.0, 14.1, 12.7, 9.8, -3.9, -4.9; MS (ESI) m/z 343 (M þ H)þ; HRMS
(ESI) calcd for C19H38O3NaSi (M þ Na)þ 365.2487, found 365.2479.
Minor isomer 3a: [R]23D þ78.30 (c 0.2, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 5.84-5.72 (m, 1H), 5.24-5.10 (m, 2H), 3.85-3.76 (m, 1H),
3.74-3.65 (m, 1H), 3.46-3.39 (m, 2H), 1.70-1.57 (m, 3H), 1.52-1.39
(m, 3H), 0.98 (t, J = 7.3 Hz, 3H), 0.90 (s, 9H), 0.85 (s, 3H), 0.80 (s, 3H),
0.05 (d, J = 2.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 134.5, 117.1, 85.2,
76.3, 73.6, 69.8, 41.8, 39.4, 37.5, 30.5, 26.1, 23.3, 18.2, 13.2, 10.3, -3.6, -4.6.
Diolide 16. To a vigorously stirred solution of alcohol 15 (40 mg,
0.11 mmol) in CH2Cl2 (2 mL) and H2O (1 mL) was added TEMPO
(6.9 mg, 0.04 mmol) and BAIB (178 mg, 0.55 mmol). Stirring was
continued until TLC indicated complete conversion of the starting
material. The reaction mixture was quenched by the addition of
saturated Na2S2O3 solution (5 mL). The mixture was then extracted
with CH2Cl2 (3 ꢀ 10 mL) and the combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was employed in the next step without
further purification. To a solution of 2-methyl-6-nitrobenzoic anhydride
(MNBA, 114.5 mg, 0.33 mmol) and DMAP (270 mg, 2.22 mmol) in
toluene (50 mL) was slowly added the above acid in toluene (15 mL) by
a syringe pump at 90 °C for 12 h. The reaction mixture was concentrated
under vacuum. The residue was purified by column chromatography
with hexane/EtOAc (10:1) to afford 16 as a colorless oil (21.3 mg, 54%).
Rf 0.7 (hexane/EtOAc, 9:1); [R]25D -1.5 (c 0.79, CHCl3); IR (neat)
(R)-1-((2R,4S,6S)-4-(tert-Butyldimethylsilyloxy)-5,5-dimethyl-
6-vinyltetrahydro- 2H-pyran-2-yl)butan-2-ol (3). To a 25 mL,
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NOTE
1
1718, 1463, 1206, 1092, 1023 cm-1; H NMR (300 MHz, CDCl3) δ
(10) As the protons were merged in CDCl3, the NOESY spectrum
was not supportive for all syn geometry (for C2, C4, and C6 protons).
However, In CD3OD, the NOESY was clear to support the syn geometry
for all three protons.
(11) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551–5553. (b) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990,
31, 611–614. (c) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986–2012.
4.90 (dd, J = 7.6, 6.8 Hz, 2H), 3.47-3.35 (m, 6H), 2.45-2.20 (m, 4H),
1.91-1.76 (m, 2H), 1.72-1.48 (m, 8H), 1.34 (q, J = 12.8, 11.3 Hz, 2H),
0.89 (s, 18H), 0.87-0.78 (m, 18H), 0.06 (d, J = 3.8 Hz, 12H); 13C NMR
(75 MHz, CDCl3) δ 172.0, 80.4, 75.7, 74.9, 73.6, 40.9, 39.0, 37.9, 35.4,
28.2, 25.8, 22.8, 18.0, 12.8, 9.5, -3.9, -4.9; MS (ESI) m/z 713 (M þ
H)þ; HRMS (ESI) calcd for C38H72O8NaSi2 (M þ Na)þ 735.4663,
found 735.4644.
(12) The ratio was based on the yield of the isolated products after
column chromatography.
(13) A similar procedure was adapted as given in: Yadav, J. S.; Suresh
Reddy, Ch. Org. Lett. 2009, 8, 1705–1708.
(14) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822–1830. (b) Shiina, I.; Fukui, S.; Sasaki, A. Nat.
Protoc. 2007, 2, 2312–2317.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization data, and 1H NMR and 13C NMR spectra of all the
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ NOTE ADDED AFTER ASAP PUBLICATION
’ AUTHOR INFORMATION
This paper was published on the Web on Jan 31, 2011, with
errors in Scheme 1 and the Supporting Information. The
corrected version was reposted on Feb 23, 2011.
Corresponding Author
srihari@iict.res.in
’ ACKNOWLEDGMENT
K.S. thanks UGC, New Delhi and B.G. thanks CSIR,
New Delhi for the award of fellowships toward financial assis-
tance. P.S. acknowledges research grant (P 81-113) from Human
Resources Research Group-New Delhi through the Council of
Scientific & Industrial Research (CSIR) Young Scientist Award
Scheme.
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