Enantioselective synthesis of the C5-C23 segment of biselyngbyaside

Article abstract of DOI:10.1016/j.tetlet.2012.11.015

Stereo and enantioselective synthesis of C5-C23 fragment of cytotoxic marine natural product biselyngbyaside is achieved using E-selective methyl lithium addition onto enyne, Crimmin's acetate aldol reaction, Sharpless asymmetric epoxidation, and Julia-Kocienski olefination as the key steps.

Full text of DOI:10.1016/j.tetlet.2012.11.015

Tetrahedron Letters 54 (2013) 252–255
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Tetrahedron Letters
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Enantioselective synthesis of the C5–C23 segment of biselyngbyaside
⇑
Srivari Chandrasekhar , Gontla Rajesh, Tumma Naresh
Division of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereo and enantioselective synthesis of C5–C23 fragment of cytotoxic marine natural product bis-
elyngbyaside is achieved using E-selective methyl lithium addition onto enyne, Crimmin’s acetate aldol
reaction, Sharpless asymmetric epoxidation, and Julia–Kocienski olefination as the key steps.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 25 September 2012
Revised 31 October 2012
Accepted 2 November 2012
Available online 10 November 2012
Keywords:
Biselyngbyaside
Julia–Kocienski olefination
Crimmin’s acetate aldol reaction
The marine cyanobacteria (blue green algae) have provided very
potent metabolites with activities including antitumor,1 antiviral,2
anti-HIV,3 immunosuppressive,4 and antibiotic5 properties. Several
of marine natural products are either in clinics or in preclinical
studies.6 Very recently, Suenaga et al., based on fraction guided
activity studies, have discovered a new 18-membered macrolide
natural product from cyanobacterium Lyngbya species having anti-
tumor activity and named it as biselyngbyaside 1 (Fig. 1).7
Our point of departure for the synthesis of aldehyde 3 was the
alkynoate 7. Copper(I)-catalyzed regioselective coupling between
crotyl bromide and ethyl propiolate facilitates the desired alkyno-
ate 7 (80%) along with its minor isomer 7a (20%) as inseparable
mixture and the ratio was determined by HPLC.11,12 Michael addi-
tion of lithium dimethylcuprate (Me2CuLi) to the mixture of acety-
lenic ester furnished the expected enoate 8 with requisite olefin
geometry13 in 70% yield.14 Controlled reduction of ester functional-
ity in 8 to corresponding aldehyde 5 was achieved using DIBAL-H
in 65% yield (Scheme 2).
This compound has similar macrolide ring size as that of Ted-
anolide8 isolated from Tedania ignis. Biselyngbyaside 1 has shown
cytotoxicity against HeLaS3 cells (IC50 = 0.1
l
g/mL). This molecule
The desired chirality at C17 hydroxyl in biselyngbyaside was in-
stalled with an auxiliary based asymmetric acetate aldol reaction
via Crimmin’s et al.15 The titanium enolate was generated from
known chiral auxiliary (S)-1-(4-benzyl-2-thioxothiazolidin-3-
yl)ethanone 916 using titanium(IV) chloride and Hunig’s base,
which was rapidly treated with aldehyde 5 provided the mixture
of aldol adducts, 10 and 10a (65% >88:12 dr) along with unex-
pected product 11 and 1217 as shown in Scheme 3.
besides having an 18-membered macrocycle also encompasses
four asymmetric carbons, six geometrically defined olefin func-
tionalities, and an O-glycoside unit. Our focused interest in the syn-
thesis of bioactive secondary metabolites isolated from the sea,9
encouraged us to look at this rather complex marine natural prod-
uct. The synthesis of C5–C23 fragment 2 of biselyngbyaside is
achieved for the first time and being documented herein in this
Letter.10
As illustrated in Scheme 1, compound 1 is expected to achieve
from the union of C5–C23 fragment (2) with C1–C4 sugar linkage
fragment (2a) through Yamaguchi esterification followed by ring-
closing metathesis reactions. The C5–C23 fragment 2 could be
obtained via coupling of two fragments, aldehyde 3 and tetrazole
4, using Julia–Kocienski olefination. Aldehyde 3 was obtained from
aldehyde 5 by Crimmin’s acetate aldol and Wittig olefination. The
tetrazole 4 could in turn be prepared from 6 by deprotection of
silyl group followed by installation of sulfone ring (Scheme 1).
The mixture of diastereomeric products was easily separated by
silica gel column chromatography. The major diastereomer was
the more polar syn-aldol adduct 10 (53%). Unsurprisingly, the aldol
23
17
10
O
O
O
1
4
7
HO
HO
O
OMe
MeO
OH
1
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Figure 1. Structure of biselyngbyaside.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.015

S. Chandrasekhar et al. / Tetrahedron Letters 54 (2013) 252–255
253
Ph
N
O
S
O
N
N
N
CHO
1
OH
OTBS
OMe
3
4
OMe
2
TBDPSO
O
OH
OH
O
OH
2a
6
5
Scheme 1. Retrosynthetic analysis of biselyngbyaside.
corresponding a-b-unsaturated aldehyde 3 as exclusively E-isomer
in 90% yield (Scheme 3). Sub target 3 was thus available in seven
COOEt
COOEt
a
COOEt
Ethyl propiolate
b
steps and in 10% overall yield from ethylpropiolate.
As outlined in Scheme 4, our efforts to synthesize the tetrazole 4
commenced with known allyl alcohol 15,19 which was conve-
niently prepared in four steps from commercially available 1,3-
propane diol. Allyl alcohol 15 was subjected to Sharpless asymmet-
ric epoxidation20 with (ꢀ)-diethyl tartrate to afford the corre-
sponding epoxy alcohol 16 in 80% yield. The regioselective ring
opening of epoxide 16 was performed with Me3Al at 0 °C to pro-
duce 1,2-diol 17 as a sole product in 75% yield. The oxidative cleav-
age of diol 17 using NaIO4 in THF/H2O (1:1) provided the
corresponding aldehyde, which was subsequently subjected to
Wittig olefination with ethyl-2-(triphenyl phosphoranylidene)
7 (80%)
7a (20%)
c
OEt
O
O
8
5
Scheme 2. Reagents and conditions: (a) Crotyl bromide, CuI, K2CO3, DBU, DMF, 3 h,
85%; (b) MeLi, CuI, dry THF, ꢀ78 °C, 2 h, 70%; (c) DIBAL-H, CH2Cl2, ꢀ78 °C, 20 min,
65%.
propanoate to afford
a,b-unsaturated ester 18 in 82% yield.
adduct 10 would decompose within hours on the bench at room
temperature but, it could be stable under low temperatures in a
freezer. Secondary hydroxyl of the aldol adduct 10 was protected
as TBS ether 13 using TBSOTf and 2,6-lutidine in 80% yield. The
cleavage of chiral auxiliary was performed by controlled reduction
of 13 with DIBAL-H to provide the desired aldehyde 14 (65%),
which was immediately subjected to Wittig olefination with stable
ylide (triphenylphosphoranylidene) acetaldehyde18 to furnish the
Controlled reduction of ester functionality in 18 was achieved by
DIBAL-H in CH2Cl2 at ꢀ78 °C to give corresponding aldehyde,
which on subsequent treatment with allyl bromide in the presence
of zinc under Barbier allylation conditions furnished the mixture of
allyl alcohols 6 and 6a in 1.2:1, ratio respectively. The absolute
stereochemistry of the newly generated hydroxyl group during
the allylation was confirmed by modified Mosher’s analysis.21
S
S
O
O
OH
OH
S
N
N
S
Bn
Bn
S
O
syn -53%
a
10
S
N
S
S
O
O
Bn
S
NH
Bn
N
S
9
Bn
18%
11
S
O
OTBS
d
c
b
O
O
N
S
10
OTBS
OTBS
14
Bn
13
Scheme 3. Reagents and conditions: (a) TiCl4, DIPEA, CH2Cl2, 5, ꢀ78 °C, 1 h, 88:12 dr; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 15 min, 80%; (c) DIBAL-H, CH2Cl2, ꢀ78 °C,
5 min, 65%; (d) Ph3PCH@CHO, benzene, reflux, 2 h, 90%.

254
S. Chandrasekhar et al. / Tetrahedron Letters 54 (2013) 252–255
O
b
n-butylammonium fluoride in THF at 0 °C to provide the title com-
pound 2 in 86% yield as depicted in Scheme 5.
a
HO
OTBDPS
OTBDPS
HO
OTBDPS
OTBDPS
15
16
O
Conclusion
OH
d
g
c
HO
EtO
In conclusion, we have demonstrated a highly stereoselective
synthesis of C5–C23 segment of biselyngbyaside using Barbier ally-
lation, E-selective methylation, and Julia–Kocienski olefination as
key transformations.25 The desired chiral centers were successfully
installed through Crimmin’s acetate aldol reaction and Sharpless
asymmetric epoxidation. We believe that the approach described
herein is potentially useful in the total synthesis of biselyngbya-
side. Studies in this direction are underway.
18
17
TBDPSO
TBDPSO
TBDPSO
f
OH
6
OH
6a
OMe
19
Acknowledgments
e
Ph
G.R. thanks UGC, New Delhi and T.N. thanks CSIR, New Delhi for
research fellowships. The author acknowledges partial support by
the King Saud University, Global Research Network for Organic
Synthesis (GRNOS).
O
S
NO2
N
HO
N
h
N
N
O
PNBA =
COOH
OMe
20
OMe
Supplementary data
4
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.
015.
Scheme 4. Reagents and conditions: (a) (ꢀ)-DET, Ti(OiPr)4, TBHP, CH2Cl2, ꢀ30 °C,
8 h, 80%; (b) Me3Al, CH2Cl2, 0 °C, 2 h, 75%; (c) (i) NaIO4, THF:H2O (1:1), (ii)
Ph3P@C(Me)COOEt, C6H6, rt, 3 h, 82% for two steps; (d) (i) DIBAL-H, CH2Cl2, ꢀ78 °C,
2 h, (ii) allyl bromide, Zn, THF, rt, 2 h, 80% for two steps; (e) (i) TPP, DIAD, PNBA, dry
THF, 10 °C to rt, 16 h; (ii) K2CO3, MeOH, 30 min, 90% for two steps; (f) NaH, MeI, dry
THF, 0 °C to rt, 1 h, 90%; (g) NH4F, MeOH, rt, 12 h, 85%; (h) (i) TPP, DIAD, PTSH, dry
THF, 0 °C to rt, 3 h, (ii) Mo7O24(NH4)6ꢂ4H2O, H2O2, ethanol, rt, 24 h, 87% for two steps.
References and notes
1. (a) Jiang, T. L.; Liu, R. H.; Salmon, S. E. Cancer Chemother. Pharmacol. 1983, 11, 1–
4; (b) Moore, B. S.; Chen, J. L.; Patterson, G. M. L.; Moore, R. E.; Brinen, L. S.; Kato,
Y.; Clardy, J. J. Am. Chem. Soc. 1990, 112, 4061–4063.
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1999, 73, 4360–4371.
3. (a) Gustafson, K. R.; Cardellina, J. H., II; Fuller, R. W.; Weislow, O. S.; Kiser, R. F.;
Snader, K. M.; Patterson, G. M.; Boyd, M. R. J. Natl. Cancer Inst. 1989, 81, 1254–
1258; (b) Hayashi, K.; Hayashi, T.; Kojima, I. AIDS Res. Hum. Retroviruses 1996,
12, 1463–1471.
4. (a) Wu, X.; Stockdill, J. L.; Wang, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2010,
132, 4098–4100; (b) Andrus, M. B.; Li, W.; Keyes, R. F. J. Org. Chem. 1997, 62,
5542–5549.
a
b
3
4
OTBS
OH
5. (a) Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 6517–6522; (b) Hirata, K.;
Yoshitomi, S.; Dwi, S.; Iwabe, O.; Mahakhant, A.; Polchai, J.; Miyamoto, K. J.
Biosci. Bioeng. 2003, 95, 512–517.
6. Molinski, T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes, J. P. Nat. Rev. Drug Disc.
2009, 8, 69–85.
OMe
OMe
21
2
Scheme 5. Reagents and conditions: (a) KHMDS, dry THF, ꢀ78 °C, 1 h, 88%, 95:5
(E:Z) mixture; (b) TBAF, dry THF, 0 °C to rt, 3 h, 86%.
7. Teruya, T.; Sasaki, H.; Kitamura, K.; Nakayama, T.; Suenaga, K. Org. Lett. 2009,
11, 2421–2424.
8. (a) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J. J. Org. Chem. 1988, 53,
3644–3646; (b) Jefford, C. W.; Bernadinelli, G.; Tanaka, J.; Higa, T. Tetrahedron
Lett. 1996, 37, 159–162; (c) Mooberry, S. L.; Tien, G.; Hernandez, H. A.;
Plubrukarn, A.; Davidson, B. S. Cancer Res. 1999, 59, 653–660.
9. (a) Chandrasekhar, S.; Yaragorla, S. R.; Sreelakshmi, L.; Reddy, C. R. Tetrahedron
2008, 64, 5174–5183; (b) Chandrasekhar, S.; Vijeender, K.; Chandrashekar, G.;
Reddy, C. R. Tetrahedron: Asymmetry 2007, 18, 2473–2478; (c) Chandrasekhar,
S.; Sultana, S. S.; Kiranmai, N.; Narsihmulu, Ch. Tetrahedron Lett. 2007, 48,
2373–2375; (d) Chandrasekhar, S.; Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62,
12098–12107; (e) Chandrasekhar, S.; Narsihmulu, Ch.; Jagadeeshwar, V.;
Sultana, S. S. ARKIVOC 2005, 92–98.
The alcohol 6a was converted into desired allyl alcohol 6 under
Mitsunobu conditions and secondary hydroxyl group in 6 was pro-
tected as its methyl ether 19 using NaH and MeI in 90% yield.
TBDPS group in 19 was desilylated with NH4F in MeOH to afford
primary alcohol 20 (85%) which was converted into sulfone 4 by
a two-step process initially; to thioether by employing Mitsunobu
protocol22 using commercially available 1-phenyl-1H-tetrazole-5-
thiol (PTSH) in THF, followed by over oxidation into sulfone 4 using
hexaammonium heptamolybdate tetrahydrate23 and H2O2 in etha-
nol with 87% yield for two steps (Scheme 4). Fragment 4 was thus
obtained in nine steps and in 26% overall yield from alcohol 15.
With successful completion of the desired fragments 3 and 4,
we next turned our attention to construct C5–C23 segment by cou-
pling of the two partners under Julia–Kocienski olefination condi-
tions,24 which gave highly E-selective conjugate diene system
(C12–C15) in biselyngbyaside 1 (Scheme 5). The sulfone 4 was
deprotonated using potassium hexamethyldisilazane (KHMDS) un-
der anhydrous conditions in THF, followed by trapping of anion
10. For synthesis of the C1–C13 fragment of biselyngbyaside, see: Sawant, P.;
Martin, M. E. Synlett 2011, 3002–3004.
11. (a) Bieber, L. W.; Da Silva, M. F. Tetrahedron Lett. 2007, 48, 7088–7090; (b)
Boland, W.; Mertes, K. Synthesis 1985, 705–708.
12. HPLC column dC18, 150 ꢁ 4.6 mm, 5
l, Mobilephase: 70% ACN + 30% water
(1 mL/min), rt: 5.23 (93%) and 5.90 (7%).
13. Corey, E. J.; Katzenellenbogen, J. J. Am. Chem. Soc. 1969, 91, 1851–1852.
14. At this stage, we could able to isolate compound 8 (obtained from 7) in pure
form along with the inseparable mixture of unidentified compounds.
15. Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66,
894–902; (b) Hodge, M. B.; Olivo, H. F. Tetrahedron 2004, 60, 9397–9403.
16. (a) Yadav, J. S.; Kumar, V. N.; Rao, R. S.; Srihari, P. Synthesis 2008, 1938–1942;
(b) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775–777.
17. Yadav, J. S.; Rajendar, J. Eur. J. Org. Chem. 2011, 2011, 6781–6788.
18. Famer, J. L.; Marron, K. S.; Koch, S. S. C.; Hwang, C. K.; Kallel, E. A.; Zhi, L.;
Nadzan, A. M.; Robertson, D. W.; Bennani, Y. L. Bioorg. Med. Chem. Lett. 2006, 16,
2352.
with
a
,b-unsaturated aldehyde 3 at ꢀ78 °C for 1 h provided the
separable mixture of E-isomer as major along with Z-isomer
(95:5) in 88% yield. The TBS group in 21 was cleaved using tetra-

S. Chandrasekhar et al. / Tetrahedron Letters 54 (2013) 252–255
255
19. Allylic alcohol 15 was prepared by synthetic route as depicted below.
(m, 1H), 2.81–2.57 (m, 2H), 2.56–2.34 (m, 2H), 1.66 (d, J = 6.6 Hz, 3H), 1.59 (s,
3H), 0.85 (s, 9H), 0.01 (s, 3H), 0.0 (s, 3H). 13C NMR (75 MHz, CDCl3): d 193.9,
155.4, 134.5, 128.7, 128.3, 126.9, 126.5, 68.6, 42.5, 35.6, 25.7, 23.3, 18.0, 17.8,
ꢀ4.2, ꢀ4.9. MS (ESI): m/z 347 [M+K]+. Compound 4: Colourless gummy liquid.
1. PDC
TBDPSCl
Imidazole
CH2Cl2, rt, 4 h
½ ꢃ ꢀ6.9 (c 1.75, CHCl3). IR (KBr): mmax 2934, 1640, 1497, 1338, 1152, 1092,
a 3D0
HO
OH
HO
OTBDPS
CH2Cl2,rt
919, 763, 690, 543 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.70–7.66 (m, 2H), 7.62–
.
2. Ph3P = CHCOOEt
CH2Cl2, rt, 2 h
88% overall yield
1, 3 Propane diol
7.56 (m, 3H), 5.74–5.64 (m, 1H), 5.10 (d, J = 9.5 Hz, 1H), 5.04 (d, J = 17.0 Hz, 1H),
4.99 (d, J = 10.5 Hz, 1H), 3.70 (t, J = 7.6 Hz, 1H), 3.60 (dt, J = 4.7, 10.5 Hz, 1H),
3.52 (t, J = 7.6 Hz, 1H), 3.17 (s, 3H), 2.67–2.57 (m, 1H), 2.44–2.35 (m, 1H), 2.26–
2.18 (m, 1H), 2.06–1.94 (m, 1H), 1.8–1.7 (m, 1H), 1.54 (s, 3H), 1.05 (d, J = 6.6 Hz,
3H). 13C NMR (75 MHz, CDCl3): d 134.6, 132.5, 131.3, 129.6, 124.9, 116.8, 86.5,
57.4, 54.5, 38.0, 31.2, 29.0, 21.1, 12.7. MS (ESI): m/z 413(100) [M+Na]+. HRMS
(ESI): calcd for C19H26NaN4OS [M+Na]+: 413.2682, found: 413.2688. Compound
4 h, 90%
O
DIBAL-H, CH2Cl2
-78 °C - rt, 2 h, 88%
EtO
OTBDPS
HO
OTBDPS
2: Colourless liquid (0.13 g, 86% yield). ½a D28
ꢃ
+11.46 (c 1.0, CHCl3). IR (KBr): mmax
15
3436, 2956, 2925, 2851, 1642, 1437, 1218, 1092, 968, 910, 772 cmꢀ1
.
1H NMR
20. Sharpless, K. B.; Kolb, H. C.; Van Nieuwenhze, M. S. Chem. Rev. 1994, 94, 2483–
2547.
(500 MHz, CDCl3): d 6.10–5.91 (m, 2H), 5.74–5.63 (m, 1H), 5.56–5.46 (m, 2H),
5.46–5.30 (m, 2H), 5.21 (d, J = 8.0 Hz, 1H), 5.14 (d, J = 10 Hz, 1H), 5.04 (d,
J = 18 Hz, 1H), 4.99 (d, J = 10 Hz, 1H), 4.41–4.31 (m, 1H), 3.43 (t, J = 6.8 Hz, 1H),
3.14 (s, 3H), 2.78–2.58 (m, 2H), 2.52–240 (m,1H), 2.38–2.29 (m, 1H), 2.28–2.22
(m, 2H), 2.22–2.14 (m, 1H), 2.08-1.92 (m, 2H), 1.65–1.61 (m, 3H), 1.53 (s, 3H),
1.50 (s, 3H), 0.95 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 135.1, 133.6,
131.6, 131.3, 131.1, 129.1, 128.5, 128.1, 127.3, 126.8, 126.6116.1, 86.9, 68.1,
54.5, 42.6, 41.0, 38.2, 35.6, 29.6, 17.9, 17.8, 16.6, 10.7. MS (ESI): m/z 381 (100)
[M+Na]+. HRMS (ESI): cacld for C24H38NaO2 [M+Na]+: 381.2764, found:
381.2764
21. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519; (b) Sullivan, G.
R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143–2147; (c) Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
22. For review on Mitsunobu reaction see Mitsunobu, O. Synthesis 1981, 1.
23. Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963, 28, 1140–1142.
24. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
25. Spectral data for selective compounds: Compound 3: Pale yellow liquid. ½a D30
ꢃ
+10.0 (c 2.0, CHCl3). IR (KBr): mmax 2926, 2855, 1697, 1462, 1251, 1071, 967,
.
834, 775 cmꢀ1 1H NMR (300 MHz, CDCl3): d 9.48 (d, J = 7.9 Hz, 1H), 6.90–6.77
(m, 1H), 6.18–6.06 (m, 1H), 5.51–5.24 (m, 2H), 5.16 (d, J = 8.4 Hz, 1H) 4.57–4.44