Facile synthesis of the C1-C13 fragment of lyngbouilloside

Article abstract of DOI:10.1055/s-2008-1042805

A highly efficient synthesis of the C1-C13 fragment of the marine macrolide lyngbouilloside is presented starting from commercial (S)-citramalic acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042805

712
LETTER
Facile Synthesis of the C1–C13 Fragment of Lyngbouilloside
Synthesis
u
of the
C
1–C1
l
3
F
rag
i
ment
o
a
f
Lyngboui
nlloside Gebauer, Stellios Arseniyadis,* Janine Cossy*
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr; E-mail: stellios.arseniyadis@espci.fr
Received 7 December 2007
Abstract: A highly efficient synthesis of the C1–C13 fragment of
the marine macrolide lyngbouilloside is presented starting from
commercial (S)-citramalic acid.
O
13
OPMB
OH OH
O
O
1
O
1
O
Key words: lyngbouilloside, cross-metathesis, crotyltitanation
2
CM
Marine cyanobacteria are an exceptionally rich source of
bioactive mainly nitrogenous secondary metabolites.1 Iso-
lated from the filamentous species Lyngbya bouillonii
(Oscillatoriaceae) collected off the coast of Papua New
Guinea, lyngbouilloside (1) represents one of the first gly-
cosidic macrolides of cyanobacterial origin and its struc-
ture was determined as a 14-membered lactone containing
a six-membered hemiacetal, a pendant dienyl side chain
and a rhamnose derivative attached at C5 (Figure 1).2
While 1 shares these structural features with the related
callipeltosides3a or the aurisides,3b the presence of an un-
usual tertiary methyl carbinol at C13 is in common only
with lyngbyaloside B, a brominated analogue from Lyng-
bya sp.4
O
13
OPMB
O
OH
O
O
9
O
+
1
O
8
3
4
OH
O
CO2H
HO2C
4-pentenal
(S)-citramalic acid
Scheme 1 Retrosynthetic analysis of the C1–C13 fragment 2
Despite its interesting cytotoxic activity against neuro-2a
tumor cells (IC50 = 17 mM) and its challenging chemical
structure no total synthesis of 1 has been reported to date.
In the course of our ongoing efforts towards a first total
synthesis of 1, we herein wish to present a rapid access to
the linear carbon backbone 2 containing the complete ste-
reochemical information of the macrocyclic core
(Scheme 1). As the key step in our convergent approach
we envisioned a selective cross-metathesis (CM) of the
fully functionalized C1–C8 and C9–C13 fragments 3 and
4 which are easily derived from commercial (S)-citramal-
ic acid and 4-pentenal, respectively. Subsequent protect-
ing-group manipulations in fragment 2 followed by
introduction of the side chain and thermal macrolacton-
ization via intramolecular ketene trapping5 should then
give rise to the aglycon of lyngbouilloside in a few steps.
While the C5 stereocenter in the eastern fragment 4 was
planned to be introduced via an asymmetric vinylogous
aldol reaction, the 1,2-anti relationship found in the west-
ern fragment 3 at C10 and C11 should be installed by an
enantioselective crotyltitanation of the corresponding al-
dehyde.
Thus, the synthesis of 3 began with an esterification of
(S)-citramalic acid using SOCl2 in MeOH followed by
LiAlH4 reduction of the resulting dimethyl citramalate
(Scheme 2). Selective 1,2-diol protection with acetone in
the presence of PTSA then gave the known acetal 5 in
76% overall yield (three steps).6 Treatment of the crude
aldehyde obtained upon PCC oxidation of 5 with the high-
ly face-selective crotyltitanium complex (S,S)-Ti7 pro-
duced the homoallylic alcohol 6 with excellent
diastereoselectivity (dr >95:5) in 72% overall yield. The
latter was then protected as a PMB ether (NaH, PMBBr,
DMF–THF) to efficiently afford the desired CM partner
3.8
OH
MeO
OMe
O
O
5
8
9
O
OH
lyngbouilloside (1)
1
O
O
13
OH
Figure 1 Proposed structure of lyngbouilloside
Whereas various examples for the asymmetric aldol reac-
tion of silyl dienol ethers of type 7 with aromatic or ole-
finic aldehydes are known, efficient and highly
enantioselective methods for the conversion of aliphatic
SYNLETT 2008, No. 5, pp 0712–0714
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1042805; Art ID: G40307ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

LETTER
Synthesis of the C1–C13 Fragment of Lyngbouilloside
713
1. SOCl2, MeOH, r.t.
2. LiAlH4, THF, 65 °C
1. PCC, CH2Cl2, r.t.
OH
O
OH
O
OR
2. (S,S)-Ti, Et2O, –78 °C
CO2H
O
O
HO2C
3. p-TsOH, acetone, r.t.
72%, dr > 95:5
(S)-citramalic acid
76%
6: R = H
5
NaH, PMBBr, DMF,
THF, 0 °C to r.t., 93%
Ph
O
3: R = PMB
Ph
O
Ti
O
O
Ph Ph
(S,S)-Ti
1. SeO2, t-BuOOH
CH2Cl2, 40 °C
1. 4-pentenal, TiCl4
CH2Cl2, –78 °C to r.t.
OH
O
O
O
OH
O
O
O
O
O
O
OTMS
2. chiral prep. HPLC
40%, > 99% ee
2. DDQ, THF, r.t.
42%
7
8
4
Scheme 2 Synthesis of the CM partners 3 and 4
aldehydes are rare and the availability of the required cat- enone gave rise to the entire carbon backbone of 1 in 79%
alyst systems is usually low.9 As initial attempts to control (Scheme 3).16 Finally 1,3-anti reduction of 9 with tetra-
the C5 stereocenter in 8 by reaction of 7 with 4-pentenal methylammonium triacetoxyborohydride (TABH)17 then
using conditions described by Sato10 and Denmark et al.11 afforded the C1–C13 fragment 2 as the only product (dr
were rather unsatisfying, we decided to separate the race- >95:5) in almost quantitative yield.18
mate of 8 by preparative chiral HPLC.12
In conclusion, we have described a facile stereoselective
Fortunately, the pure R-enantiomer 8 could be obtained in access to the fully functionalized C1–C13 fragment 2 of
40% overall yield from commercial 4-pentenal.13 In lyngbouilloside (1), which was obtained in nine steps and
course of the subsequent allylic oxidation we were 38% overall yield starting from commercially available
pleased to find that a sequential treatment of alkene 8 with (S)-citramalic acid. The completion of the total synthesis
SeO2 and t-BuOOH in refluxing CH2Cl2 and DDQ in THF of lyngbouilloside (1) will be reported in due course.
regioselectively furnished the desired enone 4 in an ac-
ceptable yield of 42% (two steps).14
Acknowledgement
With both fragments available, CM of 3 with a slight ex-
We would like to thank Johnson & Johnson Pharmaceutical Rese-
cess (1.2 equiv) of 4 in the presence of 20 mol% of the
arch & Development (division of Janssen-Cilag France), particular-
ly David Speybrouck and Jérome Guillemont, for the separation of
compound 8. J.G. thanks the CNRS for a grant.
Hoveyda–Grubbs catalyst Ru15 followed by direct cata-
lytic hydrogenation (1 atm H2, Pd/C, EtOAc) of the crude
References and Notes
4 (1.2 equiv)
3
+
(1) Tan, L. T. Phytochemistry 2007, 68, 954.
(2) Tan, L. T.; Márquez, B. L.; Gerwick, W. H. J. Nat. Prod.
2002, 65, 925.
1. Ru (20 mol%), CH2Cl2, 40 °C
2. H2, Pd/C, EtOAc, r.t.
79%
(3) (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.
Tetrahedron 1997, 53, 3243. (b) Sone, H.; Kigosi, H.;
Yamada, K. J. Org. Chem. 1996, 61, 8956.
(4) Luesch, H.; Yoshida, W. Y.; Harrigan, G. G.; Doom, J. P.;
Moore, R. E.; Paul, V. J. J. Nat. Prod. 2002, 65, 1945.
(5) Gebauer, J.; Blechert, S. J. Org. Chem. 2006, 71, 2021.
(6) Gill, M.; Smrdel, A. F. Tetrahedron: Asymmetry 1990, 1,
453.
O
13
OPMB
O
OH
O
O
O
1
O
9
MesN NMes
(7) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807.
(8) Compound 3: [a]D20 –26.2 (c 1.0, CHCl3). 1H NMR (C6D6):
d = 7.29 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 5.92–
5.83 (m, 1 H), 5.19–5.14 (m, 2 H), 4.47 (d, J = 11.0 Hz, 1 H),
4.25 (d, J = 11.0 Hz, 1 H), 3.96 (d, J = 8.5 Hz, 1 H), 3.77 (d,
J = 8.5 Hz, 1 H), 3.69 (m, 1 H), 3.41 (s, 3 H), 2.74 (m, 1 H),
1.92 (dd, J = 14.3, 3.0 Hz, 1 H), 1.85 (dd, J = 14.3, 9.3 Hz, 1
H), 1.54 (s, 3 H), 1.50 (s, 3 H), 1.40 (s, 3 H), 1.15 (d, J = 7.0
Hz, 3 H). 13C NMR (C6D6): d = 159.7 (Cq), 141.0 (CH),
131.2 (Cq), 129.5 (CH), 114.9 (CH2), 114.1 (CH), 108.6
(Cq), 80.8 (Cq), 79.3 (CH), 75.8 (CH2), 70.7 (CH2), 54.8
Cl
Cl
Ru
TABH, MeCN
AcOH, –40 °C
95%
O
Ru
O
13
OPMB
OH OH
O
O
O
1
O
2
Scheme 3 Synthesis of the C1–C13 fragment 2
Synlett 2008, No. 5, 712–714 © Thieme Stuttgart · New York

714
J. Gebauer et al.
LETTER
(CH3), 40.5 (CH2), 39.5 (CH), 27.6 (CH3), 27.4 (CH3), 25.0
(CH3), 12.8 (CH3). ESI-HRMS: m/z calcd for C20H30NaO4:
357.2036; found 357.2035.
H), 4.27 (m, 1 H), 3.97 (d, J = 8.5 Hz, 1 H), 3.70 (d, J = 8.5
Hz, 1 H), 3.65 (m, 1 H), 3.44 (s, 3 H), 3.17 (br s, 1 H), 2.26–
2.11 (m, 5 H), 2.03–1.94 (m, 3 H), 1.84 (m, 2 H), 1.66 (m, 1
H), 1.55 (s, 3 H), 1.52 (s, 3 H), 1.46 (s, 3 H), 1.45 (s, 3 H),
1.42 (s, 3 H), 0.98 (d, J = 6.7 Hz, 3 H). 13C NMR (C6D6):
d = 209.7 (Cq), 168.0 (Cq), 160.1 (Cq), 159.7 (Cq), 131.2
(Cq), 129.5 (CH), 114.1 (CH2), 108.6 (Cq), 106.3 (Cq), 96.1
(CH), 80.8 (Cq), 79.2 (CH), 75.9 (CH2), 70.6 (CH2), 64.9
(CH2), 54.8 (CH3), 48.4 (CH2), 41.5 (CH2), 40.7 (CH2), 40.2
(CH2), 34.1 (CH), 27.7 (CH3), 27.4 (CH3), 26.9 (CH2), 25.2
(CH3), 25.0 (CH3), 24.4 (CH3), 13.6 (CH3). ESI-HRMS: m/z
calcd for C30H44NaO9: 571.2878; found: 571.2870.
(9) Denmark, S. E.; Heemstra, J. R.; Beutner, G. L. Angew.
Chem. Int. Ed. 2005, 44, 4682.
(10) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles
1995, 41, 1435.
(11) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125,
7800.
(12) CHIRALPAK AD-H (SFC), MeOH/CO2 = 8:92.
(13) The absolute configuration of alcohol 8 was determined by
hydrogenation of the terminal double bond and comparison
of the optical rotation {[a]D20 –21.0 (c 1.0, CHCl3)} with the
literature {[a]D20 +19.8 (CHCl3) for the enantiomer}.10
(14) Compound 4: [a]D20 +19.0 (c 1.0, CHCl3). 1H NMR
(CDCl3): d = 6.30 (dd, J = 17.8, 10.3 Hz, 1 H), 6.19 (d,
J = 17.8 Hz, 1 H), 5.88 (d, J = 10.3 Hz, 1 H), 5.29 (s, 1 H),
4.34 (m, 1 H), 2.80–2.67 (m, 2 H), 2.44–2.29 (m, 2 H), 1.64
(s, 3 H), 1.63 (s, 3 H), 1.50 (br s, 1 H). 13C NMR (CDCl3):
d = 200.3 (Cq), 168.3 (Cq), 161.0 (Cq), 136.4 (CH), 129.8
(CH2), 106.7 (Cq), 95.5 (CH), 64.7 (CH), 45.1 (CH2), 40.5
(CH2), 25.5 (CH3), 24.6 (CH3). ESI-HRMS: m/z calcd for
C12H16NaO5: 263.0890; found 263.0885.
(17) Bode, S. E.; Wolberg, M.; Müller, M. Synthesis 2006, 4, 557.
(18) Compound 2: [a]D20 –21.8 (c 0.15, CHCl3). 1H NMR (C6D6):
d = 7.34 (d, J = 8.8, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 5.42 (s,
1 H), 4.52 (d, J = 11.0 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1 H),
4.28 (m, 1 H), 3.97 (d, J = 8.5 Hz, 1 H), 3.81 (d, J = 8.5 Hz,
1 H), 3.65 (m, 1 H), 3.44 (s, 3 H), 3.17 (br s, 1 H), 2.25–2.10
(m, 5 H), 2.03–1.90 (m, 3 H), 1.84 (m, 2 H), 1.67 (m, 1 H),
1.55 (s, 3 H), 1.52 (s, 3 H), 1.46 (s, 3 H), 1.45 (s, 3 H), 1.42
(s, 3 H), 0.98 (d, J = 6.7 Hz, 3 H). 13C NMR (C6D6):
d = 209.7 (Cq), 168.0 (Cq), 160.1 (Cq), 159.7 (Cq), 131.2
(Cq), 129.5 (CH), 114.1 (CH), 108.6 (Cq), 106.3 (Cq), 96.1
(CH), 80.8 (Cq), 79.2 (CH), 75.9 (CH2), 70.6 (CH2), 65.0
(CH), 54.8 (CH3), 48.4 (CH2), 41.5 (CH2), 40.7 (CH2), 40.2
(CH2), 34.1 (CH), 27.7 (CH3), 27.4 (CH3), 26.9 (CH2), 25.2
(CH3), 25.0 (CH3), 24.4 (CH3), 13.6 (CH3). ESI-HRMS: m/z
calcd for C30H46NaO9: 573.3034; found: 573.3024.
(15) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(16) Compound 9: [a]D20 –11.5 (c 1.0, CHCl3). 1H NMR (C6D6):
d = 7.34 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 5.42
(s, 1 H), 4.52 (d, J = 11.0 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1
Synlett 2008, No. 5, 712–714 © Thieme Stuttgart · New York

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