Total synthesis and confirmation of the revised structures of azaspiracid-2 and azaspiracid-3

Article abstract of DOI:10.1002/anie.200600295

The 39 steps: The recently proposed revised structures of azaspiracid-2 and -3 (see picture), the two most potent members of the azaspiracid family, have been confirmed through the total syntheses of the two compounds. These 39-step syntheses represent a

Full text of DOI:10.1002/anie.200600295

Angewandte
Chemie
Natural Product Synthesis
DOI: 10.1002/anie.200600295
Total Synthesis and Confirmation of the Revised
Structures of Azaspiracid-2 and Azaspiracid-3**
K. C. Nicolaou,* Michael O. Frederick, Goran Petrovic,
Kevin P. Cole, and Eriketi Z. Loizidou
Dedicated to Professor Dieter Enders
on the occasion of his 60th birthday
The azaspiracids are a group of notorious marine neurotoxins
whose accumulation in mussels causes serious human poison-
ing known as azaspiracid poisoning syndrome (AZP) upon
their consumption.[1] In a series of papers,[2–4] we recently
reported the revision of the originally proposed structure, 1a,
and the total synthesis of the revised structure of azaspiracid-1
(1, Figure 1). Isolated from Mytilusedulis and first reported in
1998,[5] azaspiracid-1( 1) is the most abundant member of this
class of marine natural products. Herein, we report the total
synthesis of the revised structures of azaspiracid-2 (2) and -3
[*] Prof. Dr. K. C. Nicolaou, M. O. Frederick, Dr. G. Petrovic, K. P. Cole,
E. Z. Loizidou
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR
spectroscopic and mass spectrometric assistance, respectively.
Financial support for this work was provided by The Skaggs Institute
for Chemical Biology, the National Institutes of Health (USA), a
predoctoral fellowship from the National Science Foundation (to
M.O.F.), and grants from Amgen and Merck.
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(3, Figure 1), the two most potent members of the azaspiracid
family (azaspiracid-1: LD50(against mice) = 0.20 mgkgꢀ1
;
azaspiracid-2: LD50 = 0.11 mgkgꢀ1
; azaspiracid-3: LD50 =
0.14 mgkgꢀ1),[6,7] by a route that differs significantly from
that employed[2–4] to construct azaspiracid-1( 1). The reported
Figure 2. Retrosynthetic analysis of azaspiracid-2 (2) and -3 (3).
Piv=trimethylacetyl, PFP=pentafluorophenyl, Teoc=2-(trimethylsilyl)-
AHCTREeUGN thoxycarbonyl, TES=triethylsilyl.
yield (two steps from 9). Exposure of 11 to HgCl2 in the
presence of ethylene glycol resulted in the exchange of the
dithiane group with an ethylene ketal. Subsequent removal of
the silyl group (TBAF) from the newly generated compound
followed by exposure to Ph3P, I2, and imidazole furnished
iodide 12 in 41% overall yield for the three steps. Upon
iodine–lithium exchange (tBuLi), the resulting lithium deriv-
ative of 12 added smoothly to aldehyde 14, which was
generated from previously synthesized alcohol 13[11] by
1) selective removal of the TBS group with TMSOTf, 2) for-
Figure 1. Originally proposed (1a–3a) and revised (1–3) structures of
azaspiracid-1, -2, and -3.
total syntheses are shorter by eleven steps and deliver the
product in considerably higher overall yield. They also
confirm our recently proposed structures[4a] for the titled
compounds and, furthermore, should be applicable to the
synthesis of azaspiracid-1( 1).
mation of the bisCAHTRE(UNG TES) derivative with TESCl and imidazole,
and 3) selective oxidation of the primary TES ether[12] with
(COCl)2, DMSO, and Et3N. Oxidation of the resulting
secondary alcohol with DMP led to ketone 15 in 81% overall
yield from 12. The much anticipated cascade reaction of
precursor 15 with the D7,8 double bond in place proceeded
smoothly under the influence of TMSOTf[13] in CH2Cl2 at
ꢀ908C to afford the desired tetracyclic system 16 in 72%
yield, together with its chromatographically separable C10
diastereomer in a favorable 6:1ratio (Scheme 1). Indeed, the
presence of the C7–C8 double bond during the cyclization
allowed the shortening of the route by several steps and
improved the overall efficiency in the construction of the
ABCD ring system of the azaspiracids.
As in the case of azaspiracid-1, our devised synthetic
strategy for the total syntheses of azaspiracid-2 and -3 was
based on a retrosynthetic analysis that involved a dithiane
[9]
coupling[8] (C20–C21bond) and a Stille reaction (C27–C28
bond), and required the key building blocks, pentafluoro-
phenyl esters 4 and 5, dithianes 6 and 7, and stannane 8
(Figure 2).
It was in the construction of the ABCD ring systems 16
and 21 of azaspiracid-2 and -3 (2 and 3, Figure 1) that the new
total syntheses shined over the original synthesis of azaspir-
acid-1( 1) in terms of both brevity and efficiency. Owing to
their similarity, only the synthesis of azaspiracid-2 (2) will be
described in detail, while the route leading to azaspiracid-3
(3) is only summarized in the schemes. Starting from the
known alcohol 9 (Scheme 1),[10] the corresponding allylic
chloride was synthesized by the action of NCS and Me2S and
treated with the lithium derivative of dithiane 10 (nBuLi,
THF, ꢀ308C) to afford coupling product 11 in 70% overall
With multigram quantities of the ABCD tetracycle 16 in
hand, the extension of its side chain to afford the requisite
pentafluorophenyl ester 4 was accomplished as depicted in
Scheme 2. Thus, the hydroxy group at C5 of 16 was oxidized
under carefully controlled conditions (DMP, no buffer), and
the resulting, rather labile g,d-unsaturated aldehyde was
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treated immediately and without purifi-
cation with the ylide derived from
Ph3P+CH3Brꢀ and nBuLi to afford termi-
nal olefin 22 in 55% overall yield for the
two steps. Engagement of 22 with a three-
fold excess of pivaloate 24 in an olefin
metathesis reaction under the initiating
influence of Grubbsꢀ catalyst II (23)
afforded, after three reiterations, bis-
AHCTREUNG
D
which was removed by chromatography.
The functionality at C20 was then elabo-
rated through
a four-step sequence,
involving 1) TBAF-induced removal of
the TBDPS group, 2) Swern oxidation to
the aldehyde with (COCl)2, DMSO, and
Et3N, 3) oxidation with NaClO2 to the
carboxylic acid, and 4) DCC-mediated
coupling with pentafluorophenol, to
afford the coveted intermediate 4 in
72% overall yield (Scheme 2).
Scheme 1. Synthesis of ABCD precursors 16 and 21. Reagents and conditions: a) NCS
(1.3 equiv), Me2S (1.4 equiv), CH2Cl2, ꢀ40!08C, 1 h; b) 10 (1.4 equiv), nBuLi (1.3 equiv),
THF, ꢀ308C, 2 h; then chlorides from 9 or 17; then ꢀ30!08C, 1 h, 70% for 11 (from 9),
68% for 18 (from 17); c) HgCl2 (3.5 equiv), CaCO3 (10 equiv), (HOCH2)2/CH3CN (1:3), 08C,
30 min; d) TBAF(1.0 m in THF, 1.1 equiv), THF, 258C, 12 h; e) I2 (1.3 equiv), imid (1.5 equiv),
Ph3P (1.5 equiv), THF, 258C, 30 min, 41% over three steps for 12, 33% over three steps for
19; f) TMSOTf (3.0 equiv), CH2Cl2, ꢀ308C, 3 h, 75%; g) TESCl (3.0 equiv), imid (5.0 equiv),
CH2Cl2, 258C, 1 h, 100%; h) (COCl)2 (2.0 equiv), DMSO (4.0 equiv), CH2Cl2, ꢀ788C, 1 h; then
Et3N (8.0 equiv), ꢀ78!08C, 97%; i) tBuLi (2.0 equiv), 12 or 19 (1.0 equiv), Et2O, ꢀ788C, 1 h;
then 14, 30 min; j) DMP (1.2 equiv), NaHCO3 (10 equiv), CH2Cl2, 258C, 1 h, 81% over two
steps for 15, 74% over two steps for 20; k) TMSOTf (1.0m in CH2Cl2, 5.0 equiv), CH2Cl2,
ꢀ908C, 72% for 16, 65% for 21. NCS=N-chlorosuccinimide, TBDPS=tert-butyldiphenylsilyl,
TBAF=tetra-n-butylammonium fluoride, imid=imidazole, TBS=tert-butyldimethylsilyl,
TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl, DMSO=dimethyl sulfoxide, DMP=Dess–
Martin periodinane.
While the dithiane fragment required
for azaspiracid-2 (2) was the same as that
needed for azaspiracid-1, that is, 6 (Fig-
ure 2),[2a] the dithiane desired for incor-
poration into azaspiracid-3 (see 7,
Figure 2) required new chemistry for its
construction (Scheme 3). Thus, hydroxy
methyl ester 28 was converted into its
iodide 29 by known chemistry[14] and
treated with the anion derived from 1,3-
dithiane and nBuLi to afford dithiane
derivative 30 in 93% yield. Further elab-
oration of the latter compound (TBAF;
(COCl)2, DMSO, and Et3N) led to alde-
hyde 31, which was coupled with vinyl
iodide 32 under Nozaki–Hiyama–Kishi
conditions[15] (CrCl2/NiCl2) to afford
allylic alcohol 33 in 69% overall yield
from 30, in favor of the desired C25 dia-
stereomer (ca. 2:1ratio). Removal of the
TBS group (TBAF) followed by trans-
formation of the generated 1,3-diol
system to a cyclic silyl ether (tBu2Si-
AHCTRE(UGN OTf)2) furnished the desired intermedi-
ate 7 in 62% overall yield after chromato-
graphic separation from its undesired
C25 epimer (Scheme 3).
The advancement of pentafluoro-
phenyl ester 4 to allylic acetate 36, the
required Stille coupling partner, is shown
in Scheme 4. Note that the new Stille
partner differs from the one originally
used in the synthesis of azaspiracid-1
(1)[3b] in that the hydroxy group at C25
is now internally engaged in a six-mem-
bered lactol ring, a feature that allowed it
to perform in a superior manner in the
Scheme 2. Construction of pentafluorophenol esters 4 and 5. Reagents and conditions:
a) DMP (2.0 equiv), CH2Cl2, 258C, 1 h; b) Ph3PCH3+Brꢀ (5.0 equiv), nBuLi (1.6m in hexanes,
4.0 equiv), THF, 08C, 1 h; then ꢀ788C; then aldehyde from 16 or 21, ꢀ78!258C, 18 h, 55%
over two steps for 22, 49% over two steps for 26; c) 23 (0.1 equiv), 24 (3.0 equiv), CH2Cl2,
408C, 14 h, 60% for 25 with 35% recovered 22 (repeat two more times, 90% for the three
cycles), 60% for 27 with 35% recovered 26 (repeat two more times, 90% for the three
cycles); d) TBAF(1.0 m in THF, 2.0 equiv), THF, 258C, 14 h; e) (COCl)2 (5.0 equiv), DMSO
(10 equiv), CH2Cl2, ꢀ788C, 1 h; then Et3N (20 equiv), ꢀ78!08C; f) NaClO2 (10 equiv),
NaH2PO4 (10 equiv), 2-methyl-2-butene (excess), tBuOH/H2O (4:1), 258C, 1 h; g) DCC
(2.0 equiv), PFPOH (1.5 equiv), CH2Cl2, 258C, 2 h, 72% over four steps for 4, 75% over four
steps for 5. DCC=dicyclohexylcarbodiimide.
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with a related compound[3b,17] and was sub-
sequently confirmed by the arrival at the
final target, azaspiracid-2 (2, see below).
The primary hydroxy groups within 35 were
then selectively acetylated through reaction
with AcCl and 2,4,6-collidine[18] at ꢀ788C,
and the dithiane moiety was removed by
(OCOCF3)2,[19] which led to
exposure to PhIACHTREUNG
spontaneous collapse of the incipient hy-
droxy ketone to give lactol 36 in 80%
overall yield for the two steps. Compound
39 was similarly prepared as summarized in
Scheme 4.
Scheme 5 outlines the final stages of the
total synthesis of azaspiracid-2 (2) and -3 (3)
starting with the Stille coupling of allylic
acetate 36 with vinyl stannane 8.[4a] The
reaction was admirably catalyzed by [Pd2-
AHCTRE(NUG dba)3] in the presence of LiCl, AsPh3, and
iPr2NEt in DMF at ambient temperature,
leading to intermediate 40 in 80% yield (see
Scheme 3. Construction of dithiane fragment 7. Reagents and conditions: a) 1,3-dithiane
(2.0 equiv), nBuLi (1.6m in THF, 1.9 equiv), THF, ꢀ308C, 3 h; then 29, ꢀ308C, 20 min
93%; b) TBAF(1.0 m in THF, 1.2 equiv), THF, 258C, 7 h, 98%; c) (COCl)2 (1.2 equiv),
DMSO (2.4 equiv), CH2Cl2, ꢀ788C, 1 h; then Et3N (5.0 equiv), ꢀ78!08C; d) CrCl2
(4.0 equiv), NiCl2 (0.02 equiv), 32, DMF, 08C, 30 min, 71% over two steps, ca. 2:1 ratio;
e) TBAF(1.0 m in THF, 2.2 equiv), THF, 258C, 3 h, 99%; f) tBu2SiACHTRE(UNG OTf)2 (1.5 equiv), 2,6-
Table 1for characterization). It was pleas-
ing to note the improvement of this final
lutidine (4.0 equiv), CH2Cl2, ꢀ308C, 30 min, 62%. DMF=dimethylformamide.
coupling as a consequence of the reengin-
eering of the allylic acetate component
intended Stille coupling (see below) as compared to its TBS-
protected, open-chain counterpart.[3b] The organometallic
species derived from dithiane 6 and nBuLi/nBu2Mg[16] was
treated with 4 at ꢀ908C to afford ketone 34 in 65% yield.
Treatment of 34 with DIBAL-H at ꢀ908C led to reduction of
the carbonyl group at C20 and concomitantly cleaved the
pivaloate ester group to give a dihydroxy compound from
which the cyclic silyl ether was dismantled (TBAF) to afford
tetraol 35 (47% overall yield for the two steps). The assigned
stereochemistry at C20 was based on our previous findings
which relieved it from the steric hindrance of the original
partner that carried a protecting group at C25.[3b] Selective
removal of the TES group from compound 40 (TBAF)
followed by NIS-induced iodoetherification led to product 41
(48% yield for the two steps). Iodoether 41 was then exposed
to the action of TESCl and imidazole, leading to the bisACHTREUNG(TES)
ether (C20 and C25) of its open hydroxy-keto form which was
treated with nBu3SnH and Et3B to remove the now redundant
iodine residue to furnish the advanced intermediate 42 in
86% overall yield.
Scheme 4. Synthesis of allylic acetate Stille coupling partners 36 and 39. Reagents and conditions: a) 6 or 7 (6.0 equiv), nBuLi/nBu2Mg (1.1m in
hexanes, 5.3 equiv), THF, 258C, 1.5 h; then ꢀ908C; then 4 or 5, 30 min, 65% for 34, 74% for 37; b) DIBAL-H (1.0m in CH2Cl2, 10 equiv), CH2Cl2,
ꢀ908C, 30 min; c) TBAF(1.0 m in THF, 3.0 equiv), THF, 258C, 16 h, 47% over two steps for 35, 44% over two steps for 38; d) AcCl (20 equiv),
2,4,6-collidine (40 equiv), CH2Cl2, ꢀ788C, 6 h; e) PhI
ACHTRE(UNG OCOCF3)2 (0.01m in CH3CN, 1.2 equiv), CH3CN/pH 7 buffer (4:1), 08C, 15 min, 80% over
two steps for 36, 72% over two steps for 39. DIBAL-H=diisobutylaluminum hydride.
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Scheme 5. Completion of the total syntheses of azaspiracid-2 (2) and -3 (3). Reagents and conditions: a) 8 (2.0 equiv), [Pd2ACHTRE(UNG dba)3] (0.3 equiv),
AsPh3 (0.3 equiv), LiCl (6.0 equiv), iPr2NEt (10 equiv), DMF, 258C, 1 h, 80% for 40, 69% for 44; b) TBAF(1.0 m in THF, 1.5 equiv), THF, 08C,
30 min; c) NIS (2.0 equiv), NaHCO3 (10 equiv), THF, 08C, 12 h, 48% over two steps for 41, 51% over two steps for 45; d) TESCl (30 equiv), imid
(60 equiv), CH2Cl2, 258C, 16 h; e) Et3B (1.0m in hexanes, 0.2 equiv), nBu3SnH/toluene (1:2), 08C, 5 min, 86% over two steps for 42, 88% over
two steps for 46; f) K2CO3 (5.0 equiv), MeOH, 258C, 1 h; g) (COCl)2 (20 equiv), DMSO (40 equiv), CH2Cl2, ꢀ788C, 1 h; then Et3N (80 equiv),
ꢀ78!08C; h) NaClO2 (10 equiv), NaH2PO4 (10 equiv), 2-methyl-2-butene (excess), tBuOH/H2O (4:1), 258C, 1.5 h; i) TBAF(1.0 m in THF,
5.0 equiv), THF, 258C, 15 h, 26% over four steps for 2, 21% over four steps for 3. dba=dibenzylideneacetone, NIS=N-iodosuccinimide.
Compound 42 was tailored so as to allow its selective
conversion to carboxylic acid 43 by a three-step sequence
involving 1) deacetylation (K2CO3, MeOH), 2) Swern oxida-
tion to the aldehyde, and 3) further oxidation with NaClO2.
Finally, exposure of 43 to TBAF in THF led to the removal of
all three protecting groups and the spontaneous folding of the
molecule into its natural form (azaspiracid-2, 2). In a similar
way, azaspiracid-3 (3) was synthesized from key building
blocks 5, 7, and 8 as summarized in Schemes 1–5. The spectral
data for synthetic azaspiracid-2 (2) and -3 (3) were identical to
those reported[6] for the naturally occurring substances, thus
confirming their revised structures[4a] as 2 and 3.
applicable to the synthesis of azaspiracid-1( 1). As the
approach described herein is considerably shorter than our
previous route[4] to azaspiracid-1( 1; 39 linear steps versus 50)
and given the extreme natural scarcity of these long sought
after natural products, the present strategy also renders them
readily available for much needed biological investigations.[20]
Received: January 23, 2006
Published online: March 20, 2006
The described syntheses confirm the newly proposed[4a]
structures for azaspiracid-2 (2) and -3 (3) and should be
Keywords: azaspiracids · fused-ring systems · natural products ·
.
spiro compounds · total synthesis
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Table 1: Selected physical properties for compound 40, azaspiracid-2 (2), compound 44, and azaspiracid-3 (3).
40: Rf =0.59 (silica gel, EtOAc/hexanes 2:3); [a]D25 =7.9 (c=0.93, CH2Cl2); IR (film): nmax =3450, 2955, 2910, 2868, 1737, 1654, 1458 cmꢀ1; 1H NMR
(500 MHz, C6D6): d=5.67–5.56 (m, 2H), 5.43 (s, 1H), 5.24 (s, 1H), 5.09 (s, 1H), 5.00 (br s, 1H), 4.71–4.67 (m, 1H), 4.65 (d, J=4.0 Hz, 1H), 4.55 (q,
J=6.8 Hz, 1H), 4.38–4.35 (m, 1H), 4.30–4.26 (m, 2H), 4.22 (d, J=9.5 Hz, 1H), 4.00–3.96 (m, 1H), 3.90 (t, J=7.0 Hz, 2H), 3.81 (d, J=5.5 Hz, 1H),
3.74–3.73 (m, 1H), 3.68 (br s, 1H), 3.48 (dd, J=14.5, 6.0 Hz, 1H), 3.38 (t, J=12.5 Hz, 1H), 2.99 (d, J=16.0 Hz, 1H), 2.86 (d, J=16.0 Hz, 1H), 2.58
(dd, J=14.5, 6.5 Hz, 1H), 2.34–2.00 (m, 9H), 1.97–1.85 (m, 2H), 1.83–1.70 (m, 2H), 1.64 (s, 6H), 1.58 (s, 3H), 1.47–1.40 (m, 4H), 1.38–1.27 (m,
8H), 1.07 (d, J=7.0 Hz, 3H), 1.06 (d, J=7.0 Hz, 3H), 1.03 (t, J=8.0 Hz, 9H), 0.98 (d, J=7.0 Hz, 3H), 0.80 (d, J=7.0 Hz, 3H), 0.79 (d, J=7.0 Hz,
3H), 0.78 (d, J=7.0 Hz, 3H), 0.65 (q, J=8.0 Hz, 6 Hz), 0.06 ppm (s, 9H); 13C NMR (125 MHz, CDCl3): d=170.7, 156.9, 152.7, 146.2, 143.4, 133.7,
131.0, 130.0, 126.8, 123.3, 114.4, 111.0, 105.0, 104.9, 100.6, 99.1, 97.5, 87.8, 84.7, 80.5, 79.0, 77.2, 72.8, 72.2, 72.1, 71.9, 68.0, 63.7, 50.1, 47.2, 40.0,
39.1, 37.7, 37.5, 37.5, 35.7, 33.3, 32.3, 32.2, 30.8, 29.6, 29.5, 29.0, 27.9, 26.7, 26.0, 25.7, 24.2, 21.1, 19.5, 18.6, 17.6, 17.2, 7.8, 5.7, ꢀ0.9 ppm; HRMS
(ESI): calcd for C62H103NO14Si2Na+ [M+Na+]: 1164.6814; found 1164.6789.
2: Rf =0.48 (silica gel, CHCl3/MeOH/H2O 40:9:1); [a]2D5 =ꢀ11.9 (c=0.21, MeOH); IR (film): nmax =3450, 2955, 2910, 2868, 1737, 1654, 1458 cmꢀ1
;
1H NMR (600 MHz, CD3OD): d=5.70 (dt, J=13.2, 6.0 Hz, 1H), 5.41 (dd, J=13.2, 6.0 Hz, 1H), 5.35 (s, 2H), 5.17 (s, 1H), 4.99 (br s, 1H), 4.72 (br s,
1H), 4.61 (br s, 1H), 4.44–4.41 (m, 1H), 4.35 (br s, 1H), 4.20 (s, 1H), 4.04–4.00 (m, 1H), 3.98 (d, J=9.0 Hz, 1H), 3.92–3.86 (m, 2H), 2.88–2.85 (m,
1H), 2.82–2.78 (t, J=12.6 Hz, 1H), 2.61 (dd, J=14.4, 4.8 Hz, 1H), 2.44–2.41 (m, 3H), 2.36–2.29 (m, 5H), 2.27–2.20 (m, 2H), 2.18–2.15 (m, 1H),
2.07–1.93 (m, 8H), 1.85–1.80 (m, 3H), 1.76–1.72 (m, 1H), 1.68 (s, 3H), 1.68–1.62 (m, 4H), 1.53–1.48 (m, 1H), 1.45–1.27 (m, 5H), 0.97 (d, J=6.6 Hz,
3H), 0.95 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 6H), 0.91 (d, J=6.6 Hz, 3H), 0.84 ppm (d, J=6.0 Hz, 3H); 13C NMR (150 MHz, CD3OD): d=177.8,
149.1, 133.0, 132.95, 131.9, 123.8, 118.1, 112.1, 108.2, 101.0, 99.5, 97.5, 82.3, 80.4, 80.0, 79.0, 77.6, 75.6, 74.1, 73.6, 73.4, 50.1, 47.0, 44.9, 43.1, 42.5,
41.1, 39.0, 38.5, 38.2, 37.8, 37.5, 36.5, 36.1, 35.6, 34.0, 33.4, 31.7, 30.2, 29.6, 27.2, 24.3, 23.8, 19.3, 18.9, 17.4, 17.2, 16.2 ppm; HRMS (ESI): calcd for
C48H73NO12H+ [M+H+]: 856.5208; found 856.5208.
44: Rf =0.60 (silica gel, EtOAc/hexanes 2:3); [a]2D5 =ꢀ5.5 (c=1.1, CH2Cl2); IR (film): nmax =3447, 2954, 2907, 2861, 1735, 1700, 1654, 1458 cmꢀ1
;
1H NMR (500 MHz, C6D6): d=5.69–5.54 (m, 4H), 5.19 (s, 1H), 5.07 (s, 1H), 5.00 (br s, 1H), 4.67 (d, J=4.0 Hz, 1H), 4.63 (dt, J=9.5, 6.5 Hz, 1H),
4.57 (q, J=6.0 Hz, 1H), 4.43–4.39 (m, 1H), 4.34 (d, J=10.0 Hz, 1H), 4.32–4.26 (m, 2H), 4.16 (br s, 1H), 4.01–3.98 (m, 1H), 3.94 (t, J=7.0 Hz, 1H),
3.89 (t, J=6.5 Hz, 2H), 3.76–3.74 (m, 1H), 3.57 (d, J=6.5 Hz, 1H), 3.53 (dd, J=14.5, 5.5 Hz, 1H), 3.38 (t, J=12.0 Hz, 1H), 2.97 (d, J=15.5 Hz, 1H),
2.90 (d, J=15.5 Hz, 1H), 2.58 (dd, J=14.5, 6.0 Hz, 1H), 2.40–2.24 (m, 4H), 2.20–2.06 (m, 6H), 2.03–1.97 (m, 4H), 1.89–1.82 (m, 4H), 1.78–1.73 (m,
2H), 1.64 (s, 6H), 1.53–1.47 (m, 4H), 1.37–1.32 (m, 4H), 1.08 (d, J=7.0 Hz, 3H), 1.04 (t, J=8.0 Hz, 9H), 0.81 (d, J=6.5 Hz, 3H), 0.80 (d, J=6.5 Hz,
3H), 0.76 (d, J=6.5 Hz, 3H), 0.73 (d, J=7.5 Hz, 3H), 0.66 (q, J=8.0 Hz, 6H), 0.07 ppm (s, 9H); 13C NMR (125 MHz, C6D6): d=171.8, 156.3, 152.0,
145.4, 142.7, 131.1, 131.0, 130.2, 126.1, 122.7, 114.6, 110.3, 105.9, 104.3, 99.8, 97.4, 96.9, 83.9, 80.8, 79.3, 78.8, 77.2, 72.7, 72.1, 71.7, 71.2, 63.6, 63.0,
49.4, 38.8, 38.1, 37.9, 37.2, 37.1, 35.1, 33.0, 32.6, 31.7, 30.7, 30.2, 30.0, 28.9, 28.3, 27.8, 25.1, 23.2, 18.8, 18.1, 18.0, 17.0, 16.4, 7.2, 5.1, ꢀ1.5 ppm;
HRMS (ESI): calcd for C60H99NO14Si2Na+ [M+Na+]: 1136.6496; found 1136.6468.
3: Rf =0.48 (silica gel, CHCl3/MeOH/H2O 40:9:1); [a]2D5 =ꢀ25.0 (c=0.10, MeOH); IR (film): nmax =3450, 2955, 2910, 2868, 1737, 1654, 1458 cmꢀ1
;
1H NMR (600 MHz, CD3OD): d=5.75–5.72 (m, 2H), 5.64 (d, J=10.2 Hz, 1H), 5.46 (dd, J=15.0, 7.2 Hz, 1H), 5.34 (s, 1H), 5.18 (s, 1H), 5.00 (s, 1H),
4.81 (br s, 1H), 4.44–4.40 (m, 1H), 4.36 (s, 1H), 4.22 (s, 1H), 4.08–4.05 (m, 2H), 3.90 (s, 1H), 3.64–3.62 (m, 1H), 2.90–2.88 (m, 1H), 2.83 (t,
J=12.0 Hz, 1H), 2.64–2.61 (m, 1H), 2.54–2.41 (m, 3H), 2.39–2.22 (m, 7H), 2.16–2.04 (m, 5H), 2.00–1.89 (m, 5H), 1.87–1.83 (m, 2H), 1.77–1.74 (m,
1H), 1.70–1.60 (m, 4H), 1.56–1.53 (m, 2H), 1.39–1.26 (m, 3H), 1.02–0.95 (m, 12H), 0.87 ppm (d, J=6.6 Hz, 3H); 13C NMR (150 MHz, CD3OD):
d=177.8, 149.1, 133.0, 132.95, 131.9, 123.8, 118.1, 112.1, 108.2, 101.0, 99.5, 97.5, 82.3, 80.4, 80.0, 79.0, 77.6, 75.6, 74.1, 73.6, 73.4, 50.1, 47.0, 44.9,
43.1, 42.5, 41.1, 39.0, 38.5, 38.2, 37.8, 37.5, 36.5, 36.1, 35.6, 34.0, 33.4, 31.7, 30.2, 29.6, 27.2, 24.3, 23.8, 19.3, 18.9, 17.4, 17.2, 16.2 ppm; HRMS (ESI):
calcd for C46H69NO12H+ [M+H+]: 828.4892; found 828.4893.
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Angewandte
Chemie
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comparisons with those of its counterpart encountered en route
to azaspiracid-1[3b] and was finally proven by its conversion to
azaspiracid-3.
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