Total synthesis of 13-demethyllyngbyaloside B

Article abstract of DOI:10.1021/ol400408w

Total synthesis of 13-demethyllyngbyaloside B, an unnatural analogue of a marine macrolide glycoside lyngbyaloside B, has been achieved. The 14-membered macrocyclic backbone was constructed in a convergent manner via esterification and ring-closing metathesis. The bromodiene side chain was introduced by means of a Stille-type reaction and a subsequent bromodesilylation. Finally, the rhamnopyranose unit was stereoselectively introduced by glycosylation under Schmidt conditions.

Full text of DOI:10.1021/ol400408w

ORGANIC
LETTERS
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Vol. XX, No. XX
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Total Synthesis of
13-Demethyllyngbyaloside B
Haruhiko Fuwa,* Naoya Yamagata, Asami Saito, and Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku,
Sendai 980-8577, Japan
hfuwa@m.tohoku.ac.jp
Received February 12, 2013
ABSTRACT
Total synthesis of 13-demethyllyngbyaloside B, an unnatural analogue of a marine macrolide glycoside lyngbyaloside B, has been achieved. The
14-membered macrocyclic backbone was constructed in a convergent manner via esterification and ring-closing metathesis. The bromodiene
side chain was introduced by means of a Stille-type reaction and a subsequent bromodesilylation. Finally, the rhamnopyranose unit was
stereoselectively introduced by glycosylation under Schmidt conditions.
There is an emerging interest in the secondary metabo-
lites of marine cyanobacteria as a source of novel biologi-
cally active compounds with therapeutic potential.1
Lyngbyaloside B (1, Figure 1) was isolated from the
marine cyanobacterium Lyngbya sp. collected at the
Ulong Channel, Palau, by Moore and co-workers.2
The gross structure and relative stereochemistry of 1 were
proposed on the basis of extensive NMR analyses; how-
ever, the absolute configuration of 1 remains to be
established because of a lack of the authentic sample.
Moore et al. reported that 1 exhibited moderate cytotoxi-
city against KB cells (IC50 = 4.3 μM) and LoVo cells
(IC50 ≈ 15 μM). A structurally related macrolide
glycoside, lyngbouilloside (2), was identified from the
marine cyanobacterium Lyngbya bouillonii by the Ger-
wick group.3 Recently, Luesch et al. reported the isola-
tion of natural congeners of 1 from L. bouilloni.4 These
macrolide glycosides also displayed moderate cytotoxic
activity against human cancer cell lines. The intriguing
structural aspects of 1 and related natural products have
attracted the interest of the synthetic community.5À8
Herein we report a total synthesis of 13-demethyllyng-
byaloside B (3), an unnatural analogue of 1.
ꢀ
(3) Tan, L. T.; Marquez, B. L.; Gerwick, W. H. J. Nat. Prod. 2002, 65,
925–928.
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H. J. Nat. Prod. 2010, 73, 1544–1552.
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W. H. Curr. Opin. Biotechnol. 2010, 21, 787–793. (b) Williams, P. G.
Trends Biotechnol. 2009, 27, 45–52. (c) Tan, L. T. Phytochemistry 2007,
68, 954–979. See also: (d) Gerwick, W. H.; Moore, B. S. Chem. Biol.
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r
10.1021/ol400408w
XXXX American Chemical Society

Hoye,5 Ley6 and Cossy7 have independently reported
the synthesis of the 14-membered macrolactone of 1 and 2,
which contains an acylated tertiary alcohol along the
backbone. Meanwhile, we chose 3 as an initial target
in our ongoing studies toward the total synthesis of
1 and related macrolide glycosides. Our synthesis plan
toward 3 is summarized in Scheme 1. We envisioned that
the rhamnopyranose unit could be attached to the aglycon
4 by glycosylation9 with trichloroacetimidate 5. We
planned to construct the bromodiene side chain via a
Stille-type reaction10 using the vinyl stannane 6. Finally,
we considered that the macrolactone domain of 4 would
be available from the alcohol 7 and the carboxylic acid 8a
or 8b. Thus, esterification of 7 and 8a,b followed by ring-
closing metathesis (RCM)11 would forge the macrocyclic
framework of 4.12
Scheme 1. Synthesis Plan toward 3
an approximately 1:1 mixture of diastereomers; hence, the
homoallylic alcohol 9 was used as the starting material.
Silylation of 12 followed by removal of the MPM group
gave the alcohol 13. Mitsunobu reaction17 of 13 and
subsequent reduction of the derived p-nitrobenzoate af-
forded the alcohol 7.
Figure 1. Structures of lyngbyaloside B (1), lyngbouilloside (2),
and 13-demethyllyngbyaloside B (3).
Scheme 2. Synthesis of Alcohol 7
The synthesis of the alcohol 7 started with protection of
the known homoallylic alcohol 913 as its p-methoxyphe-
nylmethyl (MPM) ether,14 followed by oxidative cleavage
of the double bond, to give the aldehyde 10 (Scheme 2).
Roushcrotylation15 of 10withthe crotylboronate11under
˚
standard conditions (4 A molecular sieves (MS), toluene,
À78 °C) provided the alcohol 12 in 84% yield with 10:1
diastereoselectivity.16 By contrast, asymmetric crotylation
of ent-10 (not shown) using 11 was mismatched and gave
(9) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19,
731–732.
(10) (a) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
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2748–2749. For a review, see: (b) Prokopcova, H.; Kappe, C. O. Angew.
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Chem., Int. Ed. 2006, 45, 6086–6101. (c) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527.
(12) For a related strategy in the total synthesis of a 14-membered
macrolide neopeltolide, see: Fuwa, H.; Saito, A.; Sasaki, M. Angew.
Chem., Int. Ed. 2010, 49, 3041–3044.
(13) Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1
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Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339–6348.
(16) See the Supporting Information for the stereochemical
assignment.
The synthesis of the carboxylic acids 8a,b is illustrated in
Scheme 3. The known alcohol 14,18 readily prepared by
B
Org. Lett., Vol. XX, No. XX, XXXX

Evans anti-aldol reaction18 of trans-cinnamaldehyde, was
silylated to give the silyl ether 15, which was reduced with
DIBAL-H to provide the aldehyde 16. Vinylogous
Mukaiyama aldol reaction19 of 16 with the dienol silyl ether
1720 afforded the β-hydroxy ketone 18 in 95% yield with
10:1 diastereoselectivity. Exposure of 18 to pyridinium
p-toluenesulfonate (PPTS) in MeOH delivered the methyl
acetal 19.16 At this stage, the minor diastereomer at C5 was
removed by flash column chromatography using silica gel.
After protection of the C5 hydroxy group as its MPM ether
20, the ester group was hydrolyzed to afford the carboxylic
acid 8a. Meanwhile, oxidative cleavage of the double bond
of 20, Takai olefination21 of the derived aldehyde, and
subsequent hydrolysis provided the carboxylic acid 8b.
With the requisite fragments 7 and 8a,b available, we
focused our attentiononthe assemblyofthe fragmentsand
subsequent RCM (Scheme 4). Esterification of 8 and 9a,b
under Yamaguchi conditions22 proceededcleanly to afford
the dienes 21a,b. We first examined the RCM of 21a using
the second-generation Grubbs (G-II)23 or HoveydaÀ
Grubbs (HG-II)24 precatalyst under various conditions.
However, only traces of the macrolactone 22 were ob-
tained, and the partial degradation of 21a was observed.
We thought that the low reactivity of 21a toward the RCM
could be ascribed to the styryl group. Accordingly, we next
investigated the RCM of 21b and eventually found that 22
could be isolated in 81% yield upon exposure of 21b to
HG-II (11 mol %) and 1,4-benzoquinone (1.5 equiv)25 in
toluene (3 mM) at 140 °C. The stereochemistry of the
newly generated double bond was determined to be E by a
Scheme 3. Synthesis of Carboxylic Acids 8a,b
3
large coupling constant, JH‑8,H‑9 = 15.5 Hz.26 At this
point, the minor diastereomer resulting from the Roush
crotylation of 10 was removed by flash column chromato-
graphy using silica gel.
Scheme 4. Construction of the Macrocyclic Backbone
Completion of the total synthesis is depicted in Scheme 5.
Hydrogenation of 22 followed by selective removal of the
TBDPS group27 gave the alcohol 23. Oxidation of 23 and
Takai olefination28 of the resultant aldehyde provided,
(19) (a) Mukaiyama, T.; Ishida, A. Chem. Lett. 1975, 319–322. For a
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Chem. Soc. 2005, 127, 17160–17161.
(26) The stereoselectivity observed for RCM of 21b was opposite to
that observed in our previous syntheses of structurally related
14-membered macrolides. See: Fuwa, H.; Yamaguchi, H.; Sasaki, M.
Tetrahedron 2010, 66, 7492–7503and ref 12. It appears that the C10 and
C11 substituents affected the stereochemical outcome.
(27) Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.;
Nakata, M. Synlett 2000, 1306–1308.
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C

Coupling of 4 with the vinyl stannane 629 was best per-
formed by using copper(I) thiophen-2-carboxylate (CuTC)10
to afford the vinyl silane 24. The bromodesilylation30 of
24 led to the aglycon 25.31 The stereoselective introduc-
tion of the rhamnopyranoside unit to 25 was exten-
sively investigated, and it was eventually found that the
glycosylation of 25 with the trichloroacetimidate 532
Scheme 5. Completion of the Total Synthesis of 3
˚
(TMSOTf, 4 A MS, CH2Cl2, À78 to À40 °C) proceeded
cleanly to furnish the R-glycoside 26 in 86% yield
(dr >20:1).16 Removal of the benzoyl group with NaOMe,
followed by cleavage of the silyl ether and methyl acetal,
furnished 13-demethyllyngbyaloside B (3). The anti-
proliferative activity of 3 against KB cells was moderate
(IC50 = 36 μM) according to the WST-8 colorimetric
assay.33
In conclusion, we completed a total synthesis of
13-demethyllyngbyaloside B (3) in 20 steps (longest linear
sequence) with an overall yield of 7% from the known
homoallylic alcohol 9. The salient features of our synth-
esis include (1) a convergent synthesis of the 14-membered
macrocyclic framework by exploiting an esterification/
RCM strategy; (2) a stereoselective construction of the
bromodiene side chain via a CuTC-catalyzed Stille-type
reaction; and (3) a highly stereoselective glycosylation to
attach the rhamnopyranose unit to the aglycon. Further
investigations toward the total synthesis of lyngbyaloside
B (1) and related compounds are currently underway in
our laboratory.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Young Scientists (A) (No. 23681045)
from JSPS and by a Grant-in-Aid for Scientific Research
on Priority Areas “Chemical Biologyof Natural Products”
(Nos. 23192916, 24102507) from MEXT, Japan.
Supporting Information Available. Detailed experimen-
1
tal procedure, spectroscopic data, and copies of H and
13C NMR spectra for all new compounds, and stereo-
chemical confirmation of compounds 12, 19, and 26. This
material is available free of charge via the Internet at
http://pubs.acs.org.
after removal of the MPM group, the (E)-vinyl iodide 4
(E/Z = 13:1). The Z-isomer was removed by flash
column chromatography using silica gel.
(29) Cunico, R. F.; Clayton, F. J. J. Org. Chem. 1976, 41, 1480–1482.
(30) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996,
37, 8647–8650.
(31) Compound 25 was contaminated with minor impurities ascrib-
able to partial isomerization of the stereochemistry of the diene
moiety.30 The impurities could not be removed until HPLC purification
of 3.
(32) See the Supporting Information for the preparation of 5.
(33) Tominaga, H.;Ishiyama, M.; Ohseto, F.;Sasamoto, K.;Hamamoto,
T.; Suzuki, K.; Watanabe, M. Anal. Commun. 1999, 36, 47–50.
The authors declare no competing financial interest.
D
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