Enantioselective synthesis of the lyngbouilloside macrolactone core

Article abstract of DOI:10.1055/s-0029-1217707

The macrocyclic core of the marine natural product lyngbouilloside has been prepared in a convergent and enantioselective manner. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217707

2320
LETTER
Enantioselective Synthesis of the Lyngbouilloside Macrolactone Core
Synthesis of the
L
y
a
ngbouillos
m
ide Macrolactone
C
i
ore en Webb, Alexandra van den Heuvel, Marion Kögl,† Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 29 May 2009
† Deceased
To date no total synthesis of lyngbouilloside has been re-
ported. Recently, however, Cossy disclosed the prepara-
tion of a linear and uncyclized C1–C13 fragment of
lyngbouilloside and this remains the only published ven-
ture towards the natural product.4 In light of this commu-
nication we wish to report our initial studies towards
lyngbouilloside that have resulted in an effective route to
the macrocyclic core of the natural product.
Abstract: The macrocyclic core of the marine natural product lyng-
bouilloside has been prepared in a convergent and enantioselective
manner.
Key words: lyngbouilloside, lactone, ring-closing metathesis,
dithiane
The cyanobacteria have been identified as a prolific
source from which to isolate bioactive natural products
that often possess unique molecular structures.1 Follow-
ing a collection of the ‘cobweb-like’ cyanobacterial spe-
cies Lyngbya bouillonii from the Northern Coast of Papua
New Guinea, the Gerwick group recently reported the iso-
lation and characterization of the novel and cytotoxic nat-
ural product lyngbouilloside (1, IC50 = 17 mM against
neuroblastoma cells).2 At the time of isolation, lyngbouil-
loside was only the second macrolide glycoside to be iso-
lated from a marine cyanobacterium.3a However, 1 bears
resemblance to a number of other secondary metabolites
that have been isolated from various marine sources sug-
gesting a common cyanobacterial origin.3
Our strategy to lyngbouilloside involves late-stage E,E-
diene installation and glycosylation5 of macrocycle 2
(Scheme 1). Preliminary studies indicated that macrolac-
tonization at the sterically encumbered C13 tertiary alco-
hol would prove highly challenging.6 To avoid this
difficult transformation we elected to disconnect macro-
cycle 2 at the C2–C3 and C8–C9 bonds. This retrosynthet-
ic simplification revealed fragments 3 and 4, which are of
similar complexity. It was anticipated that the C8–C9
bond would be established through ring-closing
metathesis7 whilst the C3 substituent of the pyran could be
installed through the addition of the enolate of ester 3 to
lactone fragment 4.
1
OMe
OH
O
OMe
OH
OMe
2
O
O
O
OPMB
3
O
O
13
O
O
8
13
BnO
H
9
OH
OTBS
lyngbouilloside (1)
2
Figure 1 Proposed structure of lyngbouilloside
2
O
The molecular structure of 1 was elucidated primarily by
NMR spectroscopic techniques and revealed a cyclic
trisubstituted six-membered hemiacetal embedded within
a 14-membered macrolactone (Figure 1). The macrocy-
clic ester linkage onto the fully substituted C13 stereo-
center is a particularly unusual and challenging motif for
synthesis.
O
OPMB
O
3
BnO
O
9
8
TBSO
3
4
Scheme 1 Retrosynthetic analysis of 1
The preparation of lactone 4 commenced from known
ynone 5, itself available in two steps from (S)-glycidol
(Scheme 2).8 Double conjugate addition of propane-1,3-
SYNLETT 2009, No. 14, pp 2320–2324
Advanced online publication: 31.07.2009
DOI: 10.1055/s-0029-1217707; Art ID: D14309ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

LETTER
Synthesis of the Lyngbouilloside Macrolactone Core
2321
dithiol, with concomitant in situ cyclization, proceeded group manipulations gave PMB ether 18 which could then
efficiently to provide lactone 6 in high yield and establish be oxidized to aldehyde 19. Exposure of 19 to Brown’s
the required latent oxygenation pattern.9 Reduction (+)-Ipc-derived crotylborane reagent (formed in situ) pro-
(DIBAL-H, CH2Cl2, –78 °C) and alkylation of the result- vided compound 20 with almost complete stereocontrol
ing mixture of lactol diastereomers (ca. 1.5:1 dr) afforded (>19:1 dr).16 The configuration of the C10 and C11 stereo-
nonfully anomerically stabilized acetal 7 in high yield and centers was confirmed by Mosher ester17 and coupling-
as a single C3 diastereomer.10 Installation of the terminal constant-based analysis18 of a derivative and is in accord
olefin occurred without incident to afford dithiane 9 that with previously reported additions employing the (+)-Ipc-
was oxidatively hydrolyzed using bis(trifluoroacet- derived crotylborane reagent. After silylation of crude 20
oxy)iodobenzene11 to yield crystalline ketone 10. Reduc- the now superfluous PMB ether was oxidatively cleaved
tion of 10 with sodium borohydride generated the desired (1.1 equiv DDQ then scavenging of the generated anis-
C5 alcohol 11 as a single diastereomer in essentially quan- aldehyde with polymer-supported benzylamine) to liber-
titative yield. X-ray crystallographic and NOE analysis ate the C13 tertiary alcohol. Finally, desired ester 3 was
confirmed the relative configuration of 11.12 Formation of obtained in good yield after prolonged exposure of 22 to
PMB ether 12 and a hydrolysis–oxidation sequence to re- isopropenyl acetate in the presence of a resin-bound tolu-
introduce the lactone motif (PPTS, H2O–MeOH, reflux, enesulfonic acid equivalent.19
then TPAP–NMO13) completed the synthesis of key frag-
ment 4.14
O
OH
13
a
b
O
S
S
O
OTBDPS
OH
OTBDPS
3
MeO
a
OTBS
O
13
14
5
OTBS
OR
OH
OH
6
BnO
e, f
RO
g
d
S
S
OTBDPS
MeO
MeO
X
h
e, f
b, c
3
17: R = H
15: R = H
5
c
O
18: R = PMB
16: R = Bn
O
OR
9: X = S(CH2)3S (X-ray)
10: X = O (X-ray)
7: R = TBS
8: R = H
g
d
OPMB
OPMB
CHO
BnO
BnO
j
h
11
10
O
OPMB
MeO
OR
OR
j, k
5
O
O
19
20: R = H
i
21: R = TBS
11: R = H (X-ray)
12: R = PMB
4
O
O
i
13 OH
TBSO
Scheme 2 Synthesis of lactone 4. Reagents and conditions: (a)
HS(CH2)3SH, NaOMe, THF, –78 °C to r.t., 87%; (b) DIBAL-H,
CH2Cl2, –78 °C, 99%, 1.5:1 dr; (c) KHMDS, 18-crown-6, MeI, THF,
–78 °C, 82%; (d) TBAF, THF, r.t., 99%; (e) SO3·py, i-Pr2NEt,
CH2Cl2, DMSO, 0 °C; (f) Ph3PCH3Br, KOt-Bu, THF, 0 °C to r.t.,
91% (2 steps); (g) BTI, MeCN–H2O (7:1), 0 °C to r.t., 95%; (h)
NaBH4, MeOH, –78 °C; (i) PMBBr, NaH, DMF, 0 °C, 61% (2 steps);
(j) PPTS, MeCN–H2O (3:1), reflux, ca. 2:1 dr; (k) TPAP, NMO, 4 Å
MS, CH2Cl2, 0 °C, 75% (2 steps).
BnO
BnO
k
TBSO
3
22
Scheme 3 Synthesis of ester 3. Reagents and conditions: (a) Allyl-
MgCl, THF, 0 °C to r.t.; (b) O3, CH2Cl2–MeOH (5:1), –78 °C, then
NaBH4, –78 °C to r.t.; (c) NaH, BnBr, THF, 0 °C to r.t.; (d) TBAF,
THF, r.t., 71% (4 steps); (e) 1-(dimethoxymethyl)-4-methoxyben-
zene, PPTS, CH2Cl2, r.t.; (f) DIBAL, CH2Cl2, –78 °C, 93% (2 steps);
(g) SO3·py, i-Pr2NEt, DMSO, CH2Cl2, 0 °C, 99%; (h) (E)-but-2-ene,
Our route to ester 3 began from enantiomerically enriched
epoxide 13 which was prepared using Jacobsen’s enantio-
selective ring-opening procedure in multigram quantities KOt-Bu, n-BuLi, THF–Et2O, –78 °C to –45 °C, (+)-(Ipc)2BOMe,
with >99:1 er (Scheme 3).15 Regioselective epoxide open-
ing of 13 with allyl magnesium chloride proceeded clean-
ly to generate 14 that was ozonolyzed with a reductive
workup (NaBH4) to afford primary alcohol 15. Protecting-
BF3·OEt2, then aldehyde 19, –78 °C, >19:1 dr; (i) TBSOTf, i-Pr2NEt,
CH2Cl2, –78 °C, 70% (2 steps); (j) DDQ, CH2Cl2, buffer pH 7, r.t.,
then Quadrapure BZATM, CH2Cl2, r.t., 94%; (k) isopropenyl acetate,
MP-TsOH, CH2Cl2, 4 Å MS, r.t., 77%.
Synlett 2009, No. 14, 2320–2324 © Thieme Stuttgart · New York

2322
D. Webb et al.
LETTER
With effective routes to fragments 3 and 4 in place, atten- Our initial attempts into completing the total synthesis of
tion was next turned to their successful union. Following lyngbouilloside have generated some interesting results
optimization we were pleased to find that the addition of (Scheme 5). Silyl group removal and alkene hydrogena-
lactone 4 to 2 equivalents of the lithium enolate of 3 fur- tion of 2 provides a compound whose exact spectroscopic
nished adduct 23 (n = 1705 cm–1) in essentially quantita- characterization is not possible as a consequence of con-
tive yield (Scheme 4). This key bond construction could siderable line broadening in the 1H NMR spectrum (the 1H
be performed on gram scale and excess 3 (required to ef- NMR spectrum of 26 did not exhibit line broadening24).
fect full conversion) could be recovered and recycled with This NMR phenomenon was unexpected as the fully re-
good efficiency. Lactol 23 was then converted into acetal solved 1H NMR spectrum of natural lyngbouilloside was
24 (n = 1727 cm–1) in preparation for the ensuing meta- obtained under identical experimental conditions.25 We
thetic macrocyclization.20 Spectroscopic analysis indicat- speculated that the presence of the methyl acetal in the
ed that trisubstituted tetrahydropyran 24 was the 2,4,6- macrocycle could be the cause of this unexpected spectro-
cis-configured isomer. Treatment of diene 24 with a scopic behavior. However, mild acid hydrolysis provided
variety of metathesis catalysts (Grubbs, Schrock, and 27, a compound that again failed to correlate with the 1H
Hoveyda types) failed to elicit detectable macrocycliza- NMR and 13C NMR spectra of the natural isolate. Al-
tion. However, following extensive model studies, we though far from definitive, these initial observations, in
found that ring-closing metathesis of diene 24 using conjunction with DFT-based NMR chemical shift calcu-
Grubbs–Hoveyda (G–H) catalyst 25 in the presence of lations we have conducted, serve as a warning that the
1,4-benzoquinone21 resulted in the formation of macrocy- proposed structure of lyngbouilloside may be incorrect. A
cle 2 (J = 16 Hz) in yields up to 80%.22 The stereocon- successful total synthesis of 1 is required to provide un-
trolled synthesis of macrolactone 2 represents the first ambiguous proof of its structure.
known preparation of a fully functionalized lyngbouillo-
side macrocycle and validates our strategy as a viable syn-
thetic approach for the total synthesis of lyngbouilloside.
It is interesting to note that recent reports on attempts to
engage vinyl groups on tetrahydropyran templates in
RCM-based macrocyclizations have met with consider-
able frustration.23
OMe
O
O
OPMB
a
O
BnO
H
OMe
O
OTBS
O
OPMB
2
O
O
BnO
O
OPMB
H
b, c
O
a
BnO
O
OH
26
TBSO
OH
O
OPMB
3
4
O
O
BnO
OR
O
O
OPMB
MesN NMes
Cl
O
Ru
Cl
OH
BnO
c
O
27
Scheme 5 Synthesis of lyngbouilloside core 27. Reagents and con-
ditions: (a) TBAF, THF, r.t., 58%; (b) H2, Pd/C, THF; (c) PPTS,
MeCN–H2O (3:1), r.t., quant.
TBSO
G–H II: 25
23: R = H
b
24: R = Me
OMe
O
O
OPMB
In conclusion, we have designed a highly convergent syn-
thesis of the macrocyclic core of lyngbouilloside. The for-
mation of macrocycle 2 by an enolate–lactone coupling
and ring-closing metathesis sequence provides a novel
and effective entry to the challenging macrolactone core
of the natural product. Particularly noteworthy is the com-
plexity of the fragments involved in the key coupling
event (3 + 4 → 23) and the requirement of 1,4-benzo-
quinone for an effective metathetic annulation. The elab-
oration of 2 to the proposed structure of lyngbouilloside is
ongoing in our laboratories and will be reported in due
course.
O
BnO
H
TBSO
2
Scheme 4 Synthesis of macrocycle 2. Reagents and conditions: (a)
3 (2 equiv), LDA, THF, –78 °C, then 4, 99%; (b) HC(OMe)3, PPTS,
MeOH, r.t., 98%; (c) G–H II (25), 1,4-benzoquinone, toluene, reflux.
80%.
Synlett 2009, No. 14, 2320–2324 © Thieme Stuttgart · New York

LETTER
Synthesis of the Lyngbouilloside Macrolactone Core
2323
285.1094. Anal. Calcd for C15H18O4: C, 68.68; H, 6.92.
Found: C, 68.64; H, 6.97.
(15) Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.
(16) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108,
5919.
(17) (a) Hub, L.; Mosher, H. S. J. Org. Chem. 1970, 35, 3691.
(b) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2,
2451.
(18) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J. Org. Chem. 1999, 64, 866.
Acknowledgment
The authors would like to thank the EPSRC and Pfizer for financial
support. We also wish to thank Dr. John E. Davies for X-ray diffrac-
tion analysis and Richard A. Booth for assistance in securing cry-
stals of compounds 10 and 11. Dr. Helen F. Sneddon, Dr. Marike
Herold-Dublin, and Patricia Vera-Luque are also acknowledged for
early studies on this project. We also appreciate the experimental
assistance of Dr. Colin M. Pearson and Dr. Peter Grice.
(19) Data for Compound 3
References and Notes
[a]D25 +26.5 (c 0.80, CHCl3). IR (neat): 2958, 2930, 2857,
1732, 1639, 1364, 1246, 1101, 1075, 1041 cm–1. 1H NMR
(600 MHz, CDCl3): d = 7.35–7.33 (4 H, m), 7.29–7.27 (1 H,
m), 5.74 (1 H, ddd, J = 17.3, 10.4, 6.8 Hz), 5.05–5.01 (2 H,
m), 4.49 (2 H, s), 3.89–3.87 (1 H, m), 3.46–3.42 (2 H, m),
2.42–2.40 (1 H, m), 2.08 (1 H, dd, J = 14.7, 3.7 Hz), 1.96–
1.93 (1 H, m), 1.95 (3 H, s), 1.87–1.84 (1 H, m), 1.63–1.56
(3 H, m), 1.45 (3 H, s), 1.00 (3 H, d, J = 6.9 Hz), 0.89 (9 H,
s), 0.08 (3 H, s), 0.07 (3 H, s). 13C NMR (150 MHz, CDCl3):
d = 170.2, 140.5, 138.5, 128.3, 127.7, 127.5, 114.9, 84.0,
73.0, 72.3, 70.6, 43.9, 41.0, 35.9, 26.0, 24.2, 24.2, 22.4, 18.1,
13.4, –4.0, –4.2. ESI-HRMS: m/z calcd for C26H44O4SiNa
[M + Na]+: 471.2907; found: 471.2907. Anal. Calcd for
C26H44O4Si: C, 65.59; H, 9.88. Found: C, 69.64; H, 9.85.
(20) Data for Compound 24
(1) For reviews, see: (a) Tan, L. T. Phytochemistry 2007, 68,
954. (b) Burja, A. M.; Banaigs, B.; Abou-Mansour, E.;
Burgess, J. G.; Wright, P. C. Tetrahedron 2001, 57, 9347.
(c) Gademann, K.; Portmann, C. Curr. Org. Chem. 2008, 12,
326.
(2) Tan, L. T.; Marquez, B. L.; Gerwick, W. H. J. Nat. Prod.
2002, 65, 925.
(3) (a) For the first lyngbyaloside, see: Klein, D.; Braekman,
J. C.; Daloze, D.; Hoffmann, L.; Demoulin, V. J. Nat. Prod.
1997, 60, 1057. (b) Callipeltosides: Zampella, A.; Dauria,
M. V.; Minale, L.; Debitus, C.; Roussakis, C. J. Am. Chem.
Soc. 1996, 118, 11085. (c) Aurisides: Sone, H.; Kigoshi, H.;
Yamada, K. J. Org. Chem. 1996, 61, 8956. (d) Dolastatin
19: Pettit, G. R.; Xu, J. P.; Doubek, D. L.; Chapuis, J. C.;
Schmidt, J. M. J. Nat. Prod. 2004, 67, 1252.
(4) Gebauer, J.; Arsenlyadis, S.; Cossy, J. Synlett 2008, 712.
(5) Nicolaou, K. C.; van Delft, F. L.; Conley, S. R.; Mitchell,
H. J.; Jin, Z.; Rodriguez, R. M. J. Am. Chem. Soc. 1997, 119,
9057.
(6) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5,
1147.
(7) For a review, see: Gradillas, A.; Perez-Castells, J. Angew.
Chem. Int. Ed. 2006, 45, 8086.
(8) Maguire, R. J.; Munt, S. P.; Thomas, E. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 2853.
(9) (a) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003,
5, 1147. (b) Gaunt, M. J.; Sneddon, H. F.; Hewitt, P. R.;
Orsini, P.; Hook, D. F.; Ley, S. V. Org. Biomol. Chem. 2003,
1, 15. (c) Sneddon, H. F.; van den Heuvel, A.; Hirsch, A. K.
H.; Booth, R. A.; Shaw, D. M.; Gaunt, M. J.; Ley, S. V.
J. Org. Chem. 2006, 71, 2715.
[a]D25 –31.80 (c 0.47, CHCl3). IR (neat): 2930, 2856, 1727,
1614, 1514, 1247, 1077, 1038 cm–1. 1H NMR (600 MHz,
CDCl3): d = 7.34–7.31 (4 H, m), 7.29–7.25 (1 H, m), 7.24 (2
H, d, J = 8.8 Hz), 6.85 (2 H, d, J = 8.8 Hz), 5.84 (1 H, ddd,
J = 16.9, 10.5, 6.1 Hz), 5.75 (1 H, ddd, J = 17.3, 10.8, 6.8
Hz), 5.26 (1 H, d, J = 16.9 Hz), 5.12 (1 H, d, J = 10.5 Hz),
5.05–5.00 (2 H, m), 4.49 (1 H, d, J = 11.3 Hz), 4.48 (2 H, s),
4.44 (1 H, d, J = 11.3 Hz), 4.01 (1 H, dd, J = 11.3, 5.4 Hz),
3.91–3.85 (2 H, m), 3.79 (3 H, s), 3.47–3.41 (2 H, m), 3.20
(3 H, s), 2.74 (1 H, d, J = 13.6 Hz), 2.51 (1 H, d, J = 13.6
Hz), 2.48 (1 H, dd, J = 13.0, 3.8 Hz), 2.45–2.40 (1 H, m),
2.10 (1 H, dd, J = 14.8, 3.3 Hz), 2.07 (1 H, d, J = 12.8 Hz),
1.95 (2 H, t, J = 7.9 Hz), 1.70–1.55 (4 H, m), 1.49 (3 H, s),
1,33 (1 H, q, J = 11.9 Hz), 1.00 (2 H, d, J = 6.9 Hz), 0.90 (9
H, s), 0.08 (3 H, s), 0.08 (3 H, s). 13C NMR (150 MHz,
CDCl3): d = 168.1, 159.1, 140.4, 138.6, 138.0, 130.8, 129.1,
128.3, 127.6, 127.5, 115.5, 114.9, 113.8, 99.7, 84.9, 72.9,
72.2, 71.2, 70.5, 70.1, 69.5, 55.3, 47.9, 43.9, 43.1, 41.0, 39.7,
37.2, 36.0, 26.0, 24.1 (2 × C), 18.1, 13.3, –3.9, –4.2. ESI-
HRMS: m/z calcd for C42H64O8NaSi [M + Na]+: 747.4268;
found: 747.4249. Anal. Calcd for C42H64O8Si: C, 69.58; H,
8.90. Found: C, 69.53; H, 9.07.
(10) (a) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Laine,
D. I. Angew. Chem. Int. Ed. 2003, 42, 4241.
(b) Richardson, R. D.; Hernandez-Juan, F. A.; Ward, J. W.;
Dixon, D. J. Chem. Eur. J. 2008, 14, 9607.
(11) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(12) X-ray crystallographic data for compounds 9–11 have been
deposited with the Cambridge Crystallographic Data Centre
as CCDC733929, CCDC733930 and CCDC733931,
respectively.
(21) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160.
(22) Data for Compound 2
[a]D25 –68.3 (c 0.925, C6H6). IR (neat): 2932, 2856, 1723,
1614, 1514, 1246, 1102, 1063 cm–1. 1H NMR (600 MHz,
CDCl3): d = 7.36–7.32 (4 H, m), 7.29–7.24 (3 H, m), 6.87 (2
H, d, J = 8.1 Hz), 5.92 (1 H, dd, J = 15.9, 2.7 Hz), 5.64 (1 H,
dd, J = 16.0, 9.6 Hz), 4.51–4.46 (3 H, br s), 4.45 (2 H, s),
3.95–3.90 (1 H, m), 3.80 (4 H, br s), 3.49–3.40 (2 H, m), 3.20
(3 H, s), 2.85 (1 H, br d, J = 16.5 Hz), 2.82 (1 H, d, J = 12.9
Hz), 2.42–2.37 (1 H, m), 2.31 (1 H, d, J = 12.9 Hz), 2.27–
2.18 (4 H, m), 1.75 (1 H, d, J = 16.1 Hz), 1.74–1.62 (2 H, m),
1.50–1.39 (2 H, m), 1.31 (3 H, s), 0.95 (2 H, d, J = 7.0 Hz),
0.86 (9 H, s), 0.03 (3 H, s), 0.01 (3 H, s). 13C NMR (150
MHz, CDCl3): d = 168.8, 159.1, 138.5, 136.3, 134.4, 130.8,
129.0, 128.4, 127.7, 127.5, 113.8, 98.1, 85.8, 73.7, 73.0,
70.5, 69.7, 69.7, 69.2, 55.3, 47.7, 45.5, 44.1, 41.0, 37.4, 35.8,
32.7, 25.9, 24.3, 23.5, 18.0, 11.7, –3.8, –4.8. ESI-HRMS:
(13) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
(14) Data for Compound 4: [a]D25 –10.6 (c 0.805, CHCl3). IR
(neat): 2932, 1734, 1612, 1513, 1355, 1302, 1245, 1172,
1075, 1031 cm–1. 1H NMR (600 MHz, CDCl3): d = 7.25 (2
H, d, J = 8.5 Hz), 6.89 (2 H, d, J = 8.6 Hz), 5.90 (1 H, ddd,
J = 17.2, 10.5, 6.0 Hz), 5.37 (1 H, d, J = 17.2 Hz), 5.26 (1 H,
d, J = 10.5 Hz), 4.66–4.63 (1 H, m, H7), 4.50 (2 H, s), 3.97–
3.93 (1 H, m), 3.81 (3 H, s), 2.90 (1 H, dd, J = 17.3, 6.0 Hz),
2.58 (1 H, dd, J = 17.3, 7.9 Hz), 2.35 (dt, 1 H, J = 13.8, 3.4
Hz), 1.72 (1 H, ddd, J = 13.8, 11.8, 9.4 Hz). 13C NMR (150
MHz, CDCl3): d = 169.8, 159.5, 135.3, 129.5, 129.3, 117.4,
114.0, 77.3, 70.1, 69.7, 55.3, 36.9, 35.3. ESI-HRMS: m/z
calcd for C15H18O4Na [M + Na]+: 285.1103; found:
Synlett 2009, No. 14, 2320–2324 © Thieme Stuttgart · New York

2324
D. Webb et al.
LETTER
m/z calcd for C40H60O8NaSi [M + Na]+: 719.3955; found:
719.3945.
(23) (a) Fürstner, A.; Fasching, B.; O’Neil, G. W.; Fenster, M.;
Godbout, C. D.; Ceccon, J. Chem. Commun. 2007, 3045.
(b) Ball, M.; Bradshaw, B. J.; Dumeunier, R.; Gregson, T. J.;
MacCormick, S.; Omori, H.; Thomas, E. J. Tetrahedron
Lett. 2006, 47, 2223.
(1 H, m), 3.35–3.27 (2 H, m), 3.29 (3 H, s), 3.02 (3 H, s), 2.88
(1 H, J = 12.2 Hz), 2.73 (1 H, br d, J = 16.1 Hz), 2.53 (1 H,
dd, J = 13.5, 9.1 Hz), 2.54–2.46 (1 H, m), 2.31 (1 H, dd,
J = 13.5, 7.1 Hz), 2.22–2.15 (1 H, m), 2.15 (1 H, d, J = 12.2
Hz), 2.14–2.08 (1 H, m), 1.75–1.66 (3 H, m), 1.63–1.54 (1
H, m), 1.47 (1 H, d, J = 16.1 Hz), 1.41 (3 H, s), 1.01 (3 H, d,
J = 6.8 Hz). 13C NMR (125 MHz, C6D6): d = 168.5, 159.7,
139.4, 136.9, 134.6, 131.4, 128.5, 128.3, 127.7, 127.5,
114.1, 98.9, 85.7, 73.0, 72.7, 70.7, 69.9, 69.9, 69.7, 54.7,
47.4, 45.0, 44.2, 39.8, 38.5, 36.1, 33.5, 24.8, 23.7, 11.9. ESI-
HRMS: m/z calcd for C34H46O8Na [M + Na]+: 605.3090;
found: 605.3078.
(24) Data for Compound 26
[a]D25 –61 (c 0.235, CHCl3). IR (neat): 3464, 2924, 2853,
1721, 1613, 1514, 1455, 1246, 1098, 1041 cm–1. 1H NMR
(500 MHz, C6D6): d = 7.33 (2 H, d, J = 7.8 Hz), 7.22 (2 H, d,
J = 8.6 Hz), 7.19 (2 H, d, J = 7.5 Hz), 7.12–7.07 (1 H, m),
6.80 (2 H, d, J = 8.6 Hz), 6.04 (1 H, dd, J = 15.9, 3.5 Hz),
5.97 (1 H, ddd, J = 15.9, 8.2, 1.1 Hz), 4.36 (1 H, d, J = 11.6
Hz), 4.34–4.31 (4 H, m, H7), 4.01–3.96 (1 H, m), 3.74–3.70
(25) We have conducted our own NMR analysis of a sample of
natural lyngbouilloside kindly donated to us by Professor
Gerwick.
Synlett 2009, No. 14, 2320–2324 © Thieme Stuttgart · New York