Total synthesis of the aspercyclides

Article abstract of DOI:10.1002/chem.200802681

Two different approaches to the eleven-membered biaryl ether lactones of the aspercyclide family are disclosed. The core regions of these highly strained targets, which are able to interfere with the binding of immunoglobulinE to its high affinity receptor, can either be forged by ring-closing olefin metathesis (RCM) or by a highly diastereoselective chromium-mediated Nozaki-Hiyama-Kishi (NHK) reaction. Whereas the RCM approach turned out to be responsive to minor changes in the substitution pattern of the substrate, the NHK route is more generally applicable. The preparation of the required cyclization precursor 43 hinged on a palladium-catalyzed orthoiodination reaction of 2-methylbenzoic acid, an efficient copper-catalyzed Ullmann coupling, and a Takai-Utimoto olefination as the key steps. Moreover, the esterification of the 2,6-disubstituted benzoic acid 34 with the sterically hindered secondary alcohol 37 was far from trivial. However, this and related transformations were accomplished by recourse to the corresponding acid fluorides, which provided excellent yields in cases in which the more commonly used acid chlorides or mixed anhydrides failed to afford any of the desiredproducts.

Full text of DOI:10.1002/chem.200802681

DOI: 10.1002/chem.200802681
Total Synthesis of the Aspercyclides
Jirˇꢀ Pospꢀsˇil, Christoph Mꢁller, and Alois Fꢁrstner*[a]
Abstract: Two different approaches to
changes in the substitution pattern of
the substrate, the NHK route is more
generally applicable. The preparation
of the required cyclization precursor 43
hinged on a palladium-catalyzed ortho-
iodination reaction of 2-methylbenzoic
acid, an efficient copper-catalyzed Ull-
mann coupling, and a Takai–Utimoto
olefination as the key steps. Moreover,
the eleven-membered biaryl ether lac-
tones of the aspercyclide family are dis-
closed. The core regions of these highly
strained targets, which are able to in-
terfere with the binding of immunoglo-
bulin E to its high affinity receptor, can
either be forged by ring-closing olefin
metathesis (RCM) or by a highly dia-
the esterification of the 2,6-disubstitut-
ed benzoic acid 34 with the sterically
hindered secondary alcohol 37 was far
from trivial. However, this and related
transformations were accomplished by
recourse to the corresponding acid flu-
orides, which provided excellent yields
in cases in which the more commonly
used acid chlorides or mixed anhy-
drides failed to afford any of the de-
sired products.
stereoselective
chromium-mediated
Keywords: chromium · metathesis ·
natural products · total synthesis ·
Ullmann coupling
Nozaki–Hiyama–Kishi (NHK) reac-
tion. Whereas the RCM approach
turned out to be responsive to minor
Introduction
ꢀ200 mm),[1] it is remarkable that this rather small molecule
impedes docking of two very large proteins.[4] The aspercy-
clide family may therefore constitute an interesting starting
point for further investigations.
Bioassay-guided fractionation of the extracts of the fermen-
tation broth of an Aspergillus sp. collected in Olduvai
Gorge, Tanzania, led to the isolation of three closely related
eleven-membered biaryl ether lactones termed aspercyclides
A–C (1–3).[1] These structurally rather unique metabolites
were shown to interfere with the binding of immunoglobu-
lin E antibodies (IgEs) to the human high-affinity IgE re-
ceptor FceRI located in the membrane of mast cells and ba-
sofils. As this binding event constitutes a critical first step of
a complex cascade with immunological effector functions,
any compound capable of interfering with this interaction is
of potential interest for the development of novel therapeu-
tic agents for the treatment of allergic disorders, including
asthma.[2,3] Even though the reported efficacy of 1 in the
IgE receptor binding ELISA assay is moderate (IC50
ˇ
[a] Dr. J. Pospꢀsil, Dr. C. Mꢁller, Prof. A. Fꢁrstner
Max-Planck-Institut fꢁr Kohlenforschung
45470 Mꢁlheim/Ruhr (Germany)
Fax : (+49)208-306-2994
To this end, a productive and flexible synthesis route is
mandatory in order to allow for systematic editing of the
compounds. Despite their relatively moderate size and the
presence of only two chiral centers, any such approach must
cope with a highly strained molecular frame comprising no
less than seven sp2-hybridized carbon atoms within an 11-
E-mail: fuerstner@mpi-muelheim.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802681: The experimental
part for the synthesis of some of the metathesis precursors that have
already previously been communicated (7, 9, 10, 13) as well as for
compounds 22–24, 52, 54 and 55.
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FULL PAPER
membered ring flanked by a densely functionalized biaryl
ether moiety. The difficulties posed by this intricate array
transpire from the fact that the successful metathesis-based
approach to aspercyclide C previously communicated by this
laboratory[5,6] could not be extended to the preparation of
the seemingly closely related sister compounds aspercyclide
A and B. Rather, a significant change in strategy was neces-
sary before these congeners succumbed to total synthesis.
Outlined below is a full account of our work in this area,
summarizing the ultimately successful routes to these poten-
tial lead compounds and a small set of synthetic analogues.
Results and Discussion
Aspercyclide C: Our excellent experiences with the forma-
tion of cycloalkenes of various size and complexity by ring-
closing metathesis (RCM) suggested application of this pow-
erful transformation in the present context too.[7–9] Yet, a
careful review of the literature showed that only a rather
limited number of eleven-membered rings had previously
been formed by RCM.[10] Furthermore, RCM usually deliv-
ers E/Z mixtures whenever the incipient ring is large
enough to accommodate both geometric isomers. This is
likely the case for aspercyclide C (3), as semi-empirical cal-
culations of its dimethyl ether suggested that the required E
isomer is only about 1.8 kcalmolꢁ1 more stable than its Z-
configured counterpart.[5] At the outset of the project it was
therefore by no means obvious that metathesis would open
an efficient and selective approach to this natural product
and its relatives.
Despite these concerns, a synthetic blueprint was pursued
that hinges upon closure of the strained core of 3 by RCM.
The required cyclization precursor was readily obtained
starting from the commercial benzoic acid 4 (Scheme 1),
which was esterified prior to conversion into bromide 7 by
reduction of the nitro group followed by a Sandmeyer reac-
tion. Subsequent Ullmann coupling[11] with 8 in the presence
of CuO and K2CO3 in pyridine[12] gave biaryl ether 9 in 55%
yield, an outcome that was deemed acceptable in view of
the rather encumbered neighborhood of the newly formed
ether linkage.
After saponification with aqueous NaOH in methanol,
the resulting acid 10 was esterified with alcohol 13 (92% ee,
dr >95:5) which was prepared by a titanium-mediated anti-
oxyallylation of hexanal.[13] The seemingly routine esterifica-
tion of 10 and 13, however, turned out to be difficult.
Whereas some of the standard methods employing either
the acid chloride derived from 10, mixed anhydrides or acti-
vated esters thereof, as well as various dehydrating agents
failed to afford any of the desired product, application of N-
methyl-2-chloropyridinium iodide (Mukaiyamaꢃs reagent)[14]
furnished ester 14 in good yield.
Scheme 1. a) MeI, K2CO3, acetone, reflux, 98%; b) H2 (1 atm), Pd/C
(10% w/w), EtOH, quant.; c) NaNO2/HBr; then CuBr, HBr, 08C ! RT,
97%; d) CuO, K2CO3, pyridine, 1308C, 55%; e) aq. NaOH, MeOH, then
aq. HCl quant.; f) secBuLi, then complex 12, hexanal, THF/Et2O, ꢁ788C,
69%; g) N-methyl-2-chloropyridinium iodide, Et3N, MeCN, reflux, 82%;
h) complex 15 (20 mol% in portions), toluene, reflux, 69% (E:Z=5:1);
i) CAN, MeCN/H2O, 0 8C, 67%; j) BBr3, CH2Cl2, ꢁ788C ! 08C, 44%.
CAN=cerium ammonium nitrate; PMP=para-methoxyphenyl.
ensure an acceptable reaction rate. Since Grubbs-type com-
plexes in general, however, have short lifetimes at such ele-
vated temperatures,[17] a total of 20 mol% of the catalyst
was added in portions to the reaction mixture over the
course of 4 h.[18] Cycloalkene 16 was formed as a 5:1 mixture
of isomers; routine flash chromatography furnished the
major product in analytically pure form, the E configuration
of which was unambiguously established by crystal structure
analysis (Figure 1).[19] Cleavage of the -OPMP group with
cerium ammonium nitrate (CAN)[20] followed by demethyla-
tion with the aid of BBr3 led to aspercyclide C (3) in good
overall yield. The excellent match of the NMR data of the
synthetic material with those of the authentic natural prod-
uct confirmed its identity, even though the rotatory power
of our samples were significantly higher than those of 3 re-
ported in the literature (cf. Experimental Section).[1]
Exploration of a metathesis approach to aspercyclide A and
B: The fairly uneventful completion of the total synthesis of
aspercyclide C suggested that the same strategy should also
bring its sister compounds 1 and 2 into reach. To this end,
only phenol 8 needed to be replaced by compound 21 de-
Gratifyingly, this diene could be cyclized with the aid of
the second-generation ruthenium carbene complex 15,[15,16]
even though forcing conditions were necessary. Specifically,
the ring closure was best performed in refluxing toluene to
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5957

A. Fꢁrstner et al.
Figure 1. Structure of compound (E)-16 in the solid state (only one of the
two crystallographically independent molecules in the unit cell is depict-
ed). Anisotropic displacement parameters are drawn at the 50% proba-
bility level.
rived from commercial 2,5-dihydroxybenzaldehyde 18 in a
few straightforward steps (Scheme 2).
Even though this phenol underwent Ullmann cross cou-
pling with bromide 7, the yield was disappointingly low
under the previously used conditions (CuO, K2CO3, <30%).
Better but still not satisfactory results were obtained when a
mixture comprising CuCl (10 mol%), 2,2,6,6-tetramethyl-
heptane-3,5-dione (20 mol%) and Cs2CO3 in pyridine was
employed to promote this transformation.[21] The subsequent
esterification of 23 with 13 also turned out to be difficult,
and even the Mukaiyama protocol,[14] which had been suc-
cessful in the aspercyclide C case, gave only 49% of the de-
sired ester 24. However, we abstained from any further opti-
mization at this stage, since diene 24 failed to afford work-
Scheme 2. a) Br2, CHCl3, 95%; b) NaBH4, EtOH, 08C; c) pTsOH
(10 mol%), 2,2-dimethoxypropane/acetone 10:1 v/v, 80–97% (over two
steps); d) Bu3SnCH=CH2, [PdACHTNUTRGNEU(GN PPh3)4] (10 mol%), toluene, reflux, 88%;
e) 7, CuCl (10 mol%), Cs2CO3, 2,2,6,6-tetramethylheptane-3,5-dione
(20 mol%), pyridine, reflux, 51%; f) KOH, MeOH, reflux, 96%; g) 13,
N-methyl-2-chloropyridinium iodide, Et3N, MeCN, reflux, 49%; h) see
Table 1.
ACHTUNGTRENNUNGable amounts of the corresponding cycloalkene 25, inde-
pendent of whether catalyst 15[15,16] or 27[22] was used. In
either case compound 26 was formed as the major product
by stoichiometric metathesis of the less hindered alkene in
24 with the benzylidene unit of the ruthenium complex
(Table 1).
Table 1. Attempted RCM reactions of diene 24 with the aid of different
ruthenium carbene complexes in refluxing toluene.
Entry
Catalyst
25
26
In an attempt to disfavor this alkylidene transfer, the in-
denylidene complex 28 was used to promote the reac-
tion.[23,24] Even though this catalyst, which had previously
served the formation of medium and macrocyclic rings with
considerable success,[25] did afford the desired product, a
loading of up to one equivalent had to be used to ensure
complete consumption of the starting diene (Table 1); in
this case, however, the high ruthenium content of the result-
ing crude material rendered the isolation of analytically
pure cycloalkene 25 difficult. Since attempted cyclizations of
an assortment of related substrates (Scheme 3), differing
from 24 in the chosen protecting group and oxidation pat-
tern, led to a similarly disappointing outcome, the envisaged
synthesis of aspercyclide A and B via RCM was abandoned.
1
2
3
4
15 (20 mol%)
15 (100 mol%)
27 (100 mol%)
28 (100 mol%)
–
4%
14%
43%
traces
72%
33%
–
Nozaki–Hiyama–Kishi approach to aspercyclide A and B:
The failure of the metathesis-based approach led us consider
alternative strategies for the formation of the strained edi-
fice of the target compounds. Among the various possibili-
ties contemplated, we opted for an intramolecular Nozaki–
Hiyama–Kishi (NHK) reaction at the site of the allylic alco-
hol. NHK reactions do not only have a spectacular track
record in natural product total synthesis, but largely benefit
from the strength of the emerging O Cr bond formed
III
ꢁ
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Total Synthesis of the Aspercyclides
FULL PAPER
Scheme 3. Additional substrates that could not be effectively cyclized by
RCM with the aid of catalysts 15, 27 or 28.
upon addition of an organochromium reagent to an alde-
hyde partner.[26–28] This enthalpic gain might provide suffi-
cient driving force for the formation of the encumbered 11-
membered core of aspercyclide A and B. Although NHK re-
actions generally favor a non-chelation controlled pathway
in additions to aldehydes bearing heteroatoms at the a-posi-
tion, largely variable degrees of diastereoselectivities have
been reported in the literature.[27] Therefore it was uncertain
whether this venerable transformation would be suitable in
the present case, in which formation of an anti-configured
1,2-diol unit is mandatory.
Scheme 4. a) PdACTHUNRGTNEUNG(OAc)2 (10 mol%), N-iodosuccinimide (NIS), DMF,
The revised strategy must not only ensure an efficient clo-
sure of the medium-sized ring, but should also address the
other shortcomings of the exploratory studies, most notably
the rather low yields of the Ullmann coupling and the ester-
fication. To this end, it was envisaged to forge the critical
ester bond at an earlier stage and to replace the bromide
leaving group in 7 by an arguably more reactive iodide in
order to increase the efficiency of the aryl ether formation.
This plan was reduced to practice as shown in Scheme 4.
The required benzoic acid derivative 34 was conveniently
obtained on a multigram scale by a PdII-catalyzed ortho-io-
dination reaction of commercial 32, which is thought to pro-
ceed via directed ortho-palladation followed by metal–
iodine exchange with regeneration of the catalytically active
palladium species.[29]
1008C, 95–98%; b) ent-37, DEAD, PPh3, THF, 08C, 75%; c) 35, CH2Cl2,
pyridine, 08C; d) KHMDS, 37, THF, 08C, then 36, 93% (over both
steps); e) 21, CuCl (10 mol%), Cs2CO3, 2,2,6,6-tetramethylheptane-3,5-
dione (20 mol%), pyridine, reflux, 92%; f) O3, CH2Cl2/MeOH 1:1,
ꢁ788C, then Zn, HOAc, 78%; g) CHI3, CrCl ·
2 ACHTUNGTRENN(NUG THF)1.4, THF, 08C, 44%
(E-41), 8% (Z-41); h) HF·pyridine, THF, pyridine, 08C ! RT, 92 %; i)
Dess–Martin periodinane, CH2Cl2, 08C, then NaHCO3, 81%; j) CrCl2·-
AHCTNUGTERN(GNUN THF)1.8, NiCl2 (2–4 mol%), DMF, 79%; k) pTsOH (10 mol%), MeOH,
98%; l) TBDPSCl, imidazole, CH2Cl2, 96%; m) pTsOH (10 mol%),
MeOH, 61%; n) MnO2, CH2Cl2, 55%; o) HF·pyridine, THF (crude), cf.
main text; DEAD=diethyl azodicarboxylate; KHMDS=potassium
hexamethyldisilazide; TBS=tert-butyldimethylsilyl; TBDPS=tert-butyl-
diphenylsilyl.
prepared by copper-catalyzed epoxide opening of ent-48[31]
with BuMgBr (Scheme 5).[32]
As forecasted by the exploratory studies, the esterification
of 34 with the readily accessible but sterically hindered alco-
hol 37 (Scheme 5) turned out to be difficult, furnishing dis-
appointingly low yields under a variety of standard condi-
tions, independent of whether the corresponding acid chlo-
ride, various mixed anhydrides, dehydrating agents, or even
the Mukaiyama protocol were applied. However, activation
of the alcohol rather than the acid component, as is the case
under Mitsunobu conditions,[30] proved viable. As this
esterification proceeds with inversion of configuration, ent-
37 had to be used as the reaction partner, which was again
During the course of the project, however, an alternative
method for the esterification of sterically hindered benzoic
acid derivatives was found, which was inspired by the results
Scheme 5. a) TBSCl, imidazole, Et3N, CH2Cl2, 08C ! RT, quant.; b)
BuMgBr, CuI (20 mol%), THF, ꢁ208C, 95%.
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A. Fꢁrstner et al.
Yield [%]
Table 2. Esterification reactions of 2,6-disubstituted benzoic acid fluoride derivatives.[a]
Entry
Acid fluoride
Alcohol
Base
Product
1
2
3
LiHMDS
NaHMDS
KHMDS
65
89
94
4
KHMDS
97
5
6
KHMDS
KHMDS
93 (R=TBS)
91 (R=TBDPS)
7
KHMDS
89
8
NaHMDS
91[b]
[33]
[a] All reactions were preformed in THF at 08C unless stated otherwise; [b] ꢁ788C ! RT, cf. ref.
.
of another total synthesis pursued by our group.[33] We were
pleased to observe that the corresponding acid fluoride 36,
formed upon treatment of 34 with 2,4,6-trifluorotriazine (35,
cyanuric fluoride),[34] reacted smoothly with the alkali salt of
alcohol 37, furnishing ester 38 in remarkable 93% yield.
The best result was obtained with the potassium salt, al-
though the sodium and lithium salts also lead to respectable
outcomes (Table 2, entries 1–3). Even though this pro-
nounced influence of the counterion is suggestive, we have
to leave the question as to why the acid fluoride performs
so much better than its chloride counterpart open until
more detailed mechanistic studies have been completed. In
any case, the examples compiled in Table 2 indicate a con-
siderable scope of this methodology, allowing esterifications
of sterically hindered benzoic acid derivatives to be per-
formed with excellent yields under notably mild conditions,
which are difficult to accomplish otherwise.
Gratifyingly, the subsequent Ullmann coupling of 38 was
not only unaffected by the fairly bulky ester moiety of this
substrate, but was also much higher yielding than the corre-
sponding transformation of bromide 7 which had been a se-
rious bottleneck in the model studies (see Scheme 2). Prod-
uct 39 was obtained in 92% yield when the reaction was
promoted with CuCl (10 mol%) and 2,2,6,6-tetramethylhep-
tane-3,5-dione (20 mol%) as the ligand in the presence of
Cs2CO3 in hot pyridine.[21] Ozonolysis of the double bond in
39 furnished aldehyde 40 in good yield, provided that the
reaction was performed in CH2Cl2/MeOH at ꢁ788C and the
ozonide was reduced with Zn/HOAc at the same tempera-
ture. A subsequent Takai–Utimoto olefination in THF[27,35,36]
gave alkenyl iodide 41; as the crude E/Z mixture could be
separated by conventional flash chromatography, respecta-
ble amounts of (E)-41 were obtained in analytically pure
form. Cleavage of the TBS-ether with HF·pyridine[37] fol-
lowed by oxidation of the resulting primary alcohol 42 with
Dess–Martin periodinane[38] furnished aldehyde 43 and set
the stage for the envisaged intramolecular NHK reaction.[27]
We were pleased to find that this key transformation pro-
ceeded with good yield and excellent diastereoselectivity
(dr > 95:5) in favor of the required anti-configured alcohol
44 when performed with excess CrCl2 (doped with NiCl2) in
DMF (0.02m) solution. Control experiments suggested that
this highly selective Felkin–Anh pathway is enforced by the
crowded neighborhood which restricts the substrateꢃs con-
formational space (see below). The best chemical yield
(79%) was secured with Kishiꢃs optimized work up proce-
dure, using aq. sat. potassium serinate as metal scavenger
for the removal of the chromium salts.[39]
With alcohol 44 in hand, the completion of the total syn-
thesis of aspercyclide B (2) required only cleavage of the
cyclic acetal with catalytic pTsOH in MeOH. Overall, the
ultimately successful route comprises no more than 11 steps
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Total Synthesis of the Aspercyclides
FULL PAPER
in the longest linear sequence and furnishes this valuable
compound in ꢀ17% overall yield. The analytical and spec-
troscopic properties of synthetic 2 were in excellent accord
with the reported data of the natural product.[1] Interesting-
ly, however, we found that the chemical shift of the aromatic
protons, in particular H-5 and H-6, were strongly concentra-
tion dependent. An even more pronounced effect was ob-
served for the benzylic protons H-26, which show an AB
pattern at high concentration but collapse to a singlet upon
dilution (Figure 2). These striking spectral changes are at-
tributed to a hydrogen bonding event that locks the benzylic
alcohol and hence causes the observed diastereotopy of the
adjacent protons.
Investigations into the stereochemical course of the NHK-
cyclization reaction and preparation of aspercyclide ana-
logues: As mentioned above, the formation of the 11-mem-
bered core of aspercyclide B by an intramolecular Nozaki–
Hiyama–Kishi reaction was not only highly productive but
also surprisingly selective, furnishing the required anti-con-
figured product 44 almost exclusively (dr > 95:5). This ste-
reochemical outcome was unambiguously confirmed by
comparison of the synthetic samples with the natural prod-
uct.[1] It is best explained by a Felkin–Anh transition state,
which is known to be the preferred pathway in additions of
organochromium reagents to aldehydes bearing heteroatoms
in the a- or b-position,[27,40] but rarely populated with similar
levels of selectivity. Therefore we assumed that the confor-
mational preferences of compound 43 may also contribute
to the exceptional diastereocontrol (Scheme 6). Specifically,
its ester group is likely forced out of coplanarity with the
benzene ring by the ortho substituents on either side; this
effect restricts the available conformational space and helps
preorganize the substrate in a favorable conformation. The
same argument pertains to the equally ortho,ortho’-disubsti-
tuted alkenyl iodide moiety.
Scheme 6. Conformational bias synergizing with the preferred Felkin-
Anh addition pathway in the chromium-induced cyclization of compound
43.
Figure 2. Concentration dependent 1H NMR spectrum (600 MHz) of as-
percyclide B (2): bottom to top: 1.2 mg, 2.2 mg, 4.2 mg, 8.1 mg of the
compound in CDCl3 (600 mL); arbitrary numbering as shown in the
Insert.
To probe this aspect experimentally, the two truncated an-
alogues 51 and 54 (Scheme 7) were prepared by following
the synthesis blueprint outlined above and subjected to the
same cyclization conditions. In fact, compound 51 devoid of
the methyl branch delivered only a 3:1 diastereomeric ratio
when exposed to CrCl2 in DMF. Likewise, substrate 54 lack-
ing the acetal moiety adjacent to the alkenyl iodide reacted
less selectively (anti/syn 10:1) than the fully functionalized
parent compound 43. Hence, we conclude that the substitu-
ents ortho to the reacting sites in 43 exert a gearing effect
that locks the substrate in a conformation wherein the tor-
sional strain and the inherent preferences of organochromi-
um reagents synergize. In any case, these examples show
that the chosen NHK route to the targets is able to accom-
modate structural variations and should therefore qualify
for the preparation of designer analogues of the aspercy-
clides, as required for a systematic study of the structure/ac-
tivity relationships of these interesting lead compounds.
Attempts to obtain aspercyclide A (1) by selective oxida-
tion of the benzylic alcohol group of 2 were unsuccessful,
most likely because the allylic OH group and/or the elec-
tron-rich arene oxidize with similar rates. However, 1 could
be approached by temporary protection of 44 as TBDPS-
ether 45, removal of the acetal, MnO2-mediated oxidation
of the released primary alcohol in 46 and final cleavage of
the silyl ether of 47 with HF·pyridine. Surprisingly, however,
the resulting product turned out to be rather unstable. Al-
though the NMR of the crude product clearly showed the
formation of 1,[1] all attempts to obtain analytically pure
samples by flash chromatography or HPLC resulted in par-
tial decomposition. Since the isolation paper does not men-
tion any such instability, we are unable to explain these ob-
servations at this point.
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A. Fꢁrstner et al.
Experimental Section
General: All reactions were carried out under Ar in flame-dried glass-
ware. The solvents used were purified by distillation over the drying
agents indicated and transferred under Ar: THF, Et2O, 1,4-dioxane (Mg/
anthracene), CH2Cl2, Et3N, CH3CN, DMSO, (CaH2), hexane, toluene
(Na/K), DMF (Desmodur 15, dibutyl tin dilaurate), MeOH, EtOH (Mg).
Flash chromatography (FC): Merck silica gel 60 (230–400 mesh) or Com-
biFlash (Teledyne Isco). NMR: Spectra were recorded on Bruker DPX
300, AMX 300, AV 400, DPX 600 and AVIII 600 spectrometer in the sol-
vents indicated; chemical shifts (d) are given in ppm relative to TMS,
coupling constants (J) in Hz. The solvent signals were used as references
and the chemical shifts converted to the TMS scale (CDCl3: dC =
77.23 ppm; residual CHCl3 in CDCl3: dH =7.27 ppm; CD2Cl2: dC =
53.8 ppm; residual CHCl2: dH =5.32 ppm; CD3OD dC =49.0 ppm; residu-
al CHD2OD: dH =3.30 ppm; [D8]-acetone: dC =29.8 ppm; residual [D]7-
acetone: dH =2.05 ppm). IR: Magna IR750 (Nicolet) or Spectrum One
(Perkin-Elmer) spectrometer, wavenumbers (n˜) in cmꢁ1. MS (EI): Finni-
gan MAT 8200 (70 eV), ESI-MS: ESQ3000 (Bruker), accurate mass de-
terminations: Bruker APEX III FT-MS (7 T magnet) or Mat 95 (Finni-
gan). Melting points: Bꢁchi melting point apparatus B-540 (corrected).
Elemental analyses: H. Kolbe, Mꢁlheim/Ruhr. All commercially avail-
able compounds (Fluka, Lancaster, Aldrich) were used as received. The
Scheme 7. a) CrCl ·
3:1); b) PPTS (10 mol%), MeOH, 408C, 75%; c) CrCl ·
(2–4 mol%), DMF, 59% (anti/syn 10:1).
(THF)1.8, NiCl2 (2–4 mol%), DMF, 58% (anti/syn
CTHUNGTRENNUNG
CrCl2ACHTNUGRTNEUNG
(THF)1.4 adduct was formed according to a literature procedure.[41]
Compound 14: A mixture comprising acid 10 (150 mg, 0.53 mmol), alco-
hol 13 (70.0 mg, 0.79 mmol) and NEt3 (107 mg, 1.06 mmol) in MeCN
(2 mL) was added to a solution of 2-chloro-1-methylpyridinium iodide
(202 mg, 0.79 mmol) in MeCN (2 mL) and the resulting suspension
stirred at reflux temperature for 21 h. For work up, the mixture was dilut-
ed with water (5 mL) and acidified with HCl (3m) until a pH of ꢀ1 was
reached. The solution was extracted with tert-butyl methyl ether (3ꢄ
10 mL), the combined organic phases were washed with brine (10 mL),
dried over MgSO4 and evaporated. Purification of the residue by flash
chromatography (hexanes/tert-butyl methyl ether gradient) furnished the
title compound as a pale yellow oil (115 mg, 82%). [a]2D0 = ꢁ5.18 (c=1
in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.20–6.67 (m, 10H), 6.22 (d,
J=8.3 Hz, 1H), 5.96 (ddd, J=17.0, 10.6 Hz, 6.3 Hz, 1H), 5.73 (d, J=
17.7 Hz, 1H), 5.41 (dt, J=9.6, 3.6 Hz, 1H), 5.34 (d, J=17.4 Hz, 1H), 5.29
(d, J=10.6 Hz, 1H), 5.20 (d, J=11.2 Hz, 1H), 4.78 (dd, J=6.1, 4.0 Hz,
1H), 3.72 (s, 3H), 3.67 (s, 3H), 2.34 (s, 3H), 1.89–1.18 (m, 8H), 0.77 ppm
(t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=167.8, 155.3, 153.9,
152.7, 152.1, 140.3, 136.7, 134.3, 132.4, 130.5, 129.8, 125.6, 123.4, 123.1,
119.0, 117.7, 117.3, 115.9, 114.3, 112.0, 110.5, 81.0, 76.1, 56.0, 55.6, 31.7,
29.3, 25.1, 22.4, 19.4, 13.9 ppm; IR (film): n˜ =3069, 2955, 2931, 2860,
1828, 1585, 1506, 1462, 1273, 1227, 1072, 993, 916, 825, 766 cmꢁ1; MS
(EI): m/z (%): 530 (6) [M++Na], 407 (71), 267 (100), 123 (3); HRMS
(ESI): m/z: calcd for C33H38O6Na [M++Na]: 553.2558, found: 553.2561;
elemental analysis calcd (%) for C33H38O6: C 74.69, H 7.22; found: C
74.61, H 7.16.
Conclusion
Even though the biaryl-ether lactone derivatives of the as-
percyclide family antagonize binding of immunoglobuline E
to its high-affinity receptor only weakly,[1] it is striking that
these rather small compounds are capable of interfering
with the binding of two very large proteins. Therefore the
aspercyclides constitute potential lead compounds in the
quest for small molecules that may help alleviate the symp-
toms of allergic disorders, including asthma. Two different
approaches to these highly strained targets have been ex-
plored, which are either based on ring-closing metathesis
(RCM) or on an intramolecular Nozaki–Hiyama–Kishi
(NHK) reaction for the formation of the 11-membered core.
Although RCM paved the way to aspercyclide C, it was
found inappropriate for the preparation of the seemingly
closely related sister compounds. However, the latter could
be made available by intramolecular addition of an alkenyl-
chromium reagent onto an a-chiral aldehyde, which pro-
ceeded in high chemical yield and with remarkable diaste-
reoselectivity. Moreover, the driving force resulting from the
Compound 16: A solution of diene 14 (152 mg, 0.286 mmol) in toluene
(2 mL) was added to a solution of the ruthenium complex 15 (24 mg,
0.03 mmol) in toluene (50 mL) and the resulting mixture was refluxed for
2 h. After that time, the same amount of catalyst (24 mg, 0.03 mmol), dis-
solved in the minimum amount of toluene (ca. 0.5 mL), was introduced
via syringe and reflux was continued for another 2 h. For work up, the
solvent was evaporated and the residue purified by flash chromatography
to give product 16 as a mixture of isomers (99.3 mg, 69%, E/Z 5:1). (E)-
16 (> 95% pure, 65.1 mg, 45%) could be obtained by subjecting this
mixture to flash chromatography (Combiflash, hexanes/tert-butyl methyl
ether gradient), whereas preparative HPLC was required to obtain ana-
lytically pure samples of (Z)-16 (18.0 mg, 13%). (E)-16: White solid;
m.p. 48–498C; [a]2D0 =+75.88 (c=1 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.13–7.07 (m, 2H), 6.93–6.80 (m, 6H), 6.71 (d, J=8.4 Hz,
1H), 6.61 (d, J=8.4 Hz, 1H), 6.35 (d, J=16.1 Hz, 1H), 5.94 (dd, J=
16.1 Hz, J=9.6 Hz, 1H), 5.48 (dt, J=9.3 Hz, J=2.1 Hz, 1H), 4.41 (m,
1H), 3.89 (s, 3H), 3.76 (s, 3H), 2.38 (s, 3H), 2.12–1.19 (m, 8H), 0.92 ppm
(t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=167.5, 154.3, 154.0,
153.6, 152.1, 143.0, 135.9, 134.7, 133.5, 129.8, 129.5, 128.5, 126.5, 125.4,
III
ꢁ
emerging O Cr bond seems to accommodate structural
variations on the backbone of the substrate, thus rendering
the NHK-based approach potentially more general and ver-
satile.
The successful syntheses also take advantage of the effica-
cy of a copper-catalyzed Ullmann reaction for the formation
of the biaryl ether backbone. Moreover, a highly productive
method for the esterification of sterically hindered 2,6-di-
ACHTUNGTRENNUNGsubstituted benzoic acids was developed that relies on the
use of the corresponding acid fluorides as the acylating
agents. Since the latter are easy to obtain with the aid of
commercial cyanuric fluoride and turned out to be vastly su-
perior to the more commonly used acid chlorides, it is be-
lieved that this protocol may find widespread use in the con-
text of other syntheses as well.
5962
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5956 – 5968

Total Synthesis of the Aspercyclides
FULL PAPER
123.8, 121.5, 117.9, 117.9, 114.5, 114.5, 111.7, 83.6, 75.3, 56.0, 55.7, 32.1,
31.6, 25.3, 22.5, 19.3, 14.0 ppm; IR (film): n˜ =3067, 2955, 2930, 2858,
1739, 1584, 1506, 1459, 1225, 1072, 956, 825, 779, 762 cmꢁ1; MS (EI): m/z
(%): 502 (5) [M+], 402 (1), 379 (23), 241 (100), 225 (13), 139 (45);
HRMS (EI): m/z: calcd for C31H34O6 [M++Na]: 525.2253, found:
525.2248; elemental analysis calcd for C31H34O6: C 74.08, H 6.82; found:
C 73.89, H 6.74.
125.0, 121.4, 115.5, 114.7, 77.5, 77.0, 31.6, 31.6, 25.3, 22.5, 19.5, 14.0 ppm;
IR (film): n˜ =3248, 2957, 2924, 2859, 1709, 1588, 1458, 1267, 963,
763 cmꢁ1; MS (EI): m/z (%): 382 (1) [M+], 282 (50), 264 (29), 254 (22),
253 (100), 236 (30), 211 (10), 135 (19); HRMS (ESI): m/z: calcd for
C23H26O5Na [M++Na]: 405.1675, found: 405.1672; elemental analysis
calcd (%) for C23H26O5: C 72.23, H 6.85; found: C 72.18, H 6.73.
2-Bromo-3,6-dihydroxybenzaldehyde (19):[42] A solution of Br2 (1.94 mL,
37.7 mmol) in CHCl3 (120 mL) was added over a period of 1.5 h to a so-
lution of 2,5-dihydroxybenzaldehyde (18, 5.00 g, 36.2 mmol) in CHCl3
(170 mL) and the resulting mixture was stirred for 2 h once the addition
was complete. For work up, the solution was repeatedly washed with aq.
sat. Na2S2O3 (6ꢄ100 mL) before the organic layer was dried over MgSO4
and evaporated. Purification of the residue by flash chromatography
(hexanes/EtOAc 3:2) furnished the title compound as a yellow solid
(7.45 g, 95%). M.p. 130–1318C; 1H NMR (400 MHz, CDCl3): d=11.6 (s,
1H), 10.3 (s, 1H), 7.24 (d, J=9.1 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H),
5.36 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=196.9, 158.3, 145.6,
125.4, 118.6, 116.5, 118.9 ppm; IR (film): n˜ =3277, 1633, 1610, 1459, 1289,
1172, 834, 785, 672 cmꢁ1; MS (EI): m/z (%): 216 (100) [M+], 198 (9), 188
(5), 170 (8), 159 (3), 133 (3), 119 (10), 108 (22), 91 (2), 81 (17), 63 (10),
53 (33); HRMS (EI): m/z: calcd for C7H5BrO3: 215.9422, found:
215.9424.
(Z)-16: Colorless oil; [a]2D0 =ꢁ77.08
(c=1.1
in
CHCl3);
1H NMR
(400 MHz, CDCl3): d=7.20–7.15 (m,
2H), 6.97 (d, J=8.1 Hz, 1H), 6.92 (d,
J=7.5 Hz, 1H), 6.75 (d, J=8.3 Hz,
1H), 6.70–6.66 (m, 3H), 6.62–6.60 (m,
2H), 6.42 (d, J=11.8 Hz, 1H), 5.67
(dd, J=11.7 Hz, J=9.8 Hz, 1H), 5.23
(t, J=7.4 Hz, 1H), 4.83 (t, J=8.5 Hz,
1H), 3.88 (s, 3H), 3.73 (s, 3H), 2.46 (s,
3H), 1.99–1.28 (m, 8H), 0.87 ppm (t,
J=6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=168.1, 156.4, 154.1, 153.1,
151.6, 142.7, 139.7, 132.9, 131.3, 131.0, 129.1, 125.4, 125.4, 123.8, 122.0,
117.1, 117.1, 116.4, 114.4, 114.4, 112.1, 77.8, 77.2, 55.9, 55.7, 31.6, 30.4,
25.2, 22.6, 20.3, 14.0 ppm; IR (film): n˜ =3066, 2955, 2929, 2858, 1717,
1597, 1506, 1465, 1274, 1227, 1077, 826, 791, 762, 712 cmꢁ1; MS (EI): m/z
(%): 502 (7) [M+], 379 (32), 241 (100), 225 (23), 139 (63); HRMS (EI)
m/z: calcd for C31H34O6 [M++Na]: 525.2253, found: 525.2248.
5-Bromo-2,2-dimethyl-4H-benzo[d]ACHTNUTRGNENUG[1,3]dioxin-6-ol (20): NaBH4 (0.531 g,
14.03 mmol) was added portionwise to a solution of aldehyde 19 (1.45 g,
6.68 mmol) in EtOH (33 mL) at 08C and the resulting mixture stirred at
this temperature for 30 min. The pH of the solution was adjusted to pH 4
by careful addition of aq. HCl (3.0m). The resulting suspension was fil-
tered through Celite, the filter cake was washed with tert-butyl methyl
ether (2ꢄ20 mL) and the combined filtrates were evaporated.
Compound 17: A solution of CAN (78.0 mg, 0.143 mmol) in MeCN/water
(4:1, 8 mL) was added to a solution of (E)-16 (51.2 mg, 0.102 mmol) in
MeCN/water (4:1, 2 mL) at 08C and the resulting mixture was stirred at
that temperature for 60 min. The suspension was filtered through a plug
of silica, the filtrate was extracted with tert-butyl methyl ether (3ꢄ5 mL),
the combined organic layers were washed with brine (10 mL) and dried
over MgSO4. Evaporation of the solvent followed by purification of the
residue by flash chromatography (hexanes/EtOAc 1:0 ! 7:3) furnished
the title compound as a colorless solid (27 mg, 67%). M.p. 223–2248C;
[a]2D0 =+ 43.08 (c=1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.12 (t,
J=7.9 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.84 (d,
J=7.6 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 6.29 (d,
J=15.9 Hz, 1H), 6.00 (dd, J=15.9, 9.2 Hz, 1H), 5.22 (dt, J=9.2, 2.4 Hz,
1H), 4.06 (t, J=9.3 Hz, 1H), 3.90 (s, 3H), 2.35 (s, 3H), 2.11–2.05 (m,
1H), 1.83 (bs, 1H), 1.74–1.33 (m, 7H), 0.92 ppm (t, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=167.8, 154.0, 153.7, 143.0, 137.6, 134.7,
133.5, 129.7, 128.0, 126.6, 125.5, 123.8, 121.5, 114.4, 111.6, 77.1, 77.0, 56.0,
31.8, 31.6, 25.3, 22.5, 19.3, 14.0 ppm; IR (film):n˜ =3505, 2954, 2924, 1720,
1584, 1458, 1272, 1083, 968, 783, 767 cmꢁ1; MS (EI): m/z (%): 396 (1)
[M+], 296 (24), 267 (100), 250 (7), 182 (2), 161 (7), 135 (6); HRMS
(ESI): m/z: calcd for C24H28O5Na [M++Na]: 419.1828, found: 419.1829;
elemental analysis calcd (%) for C24H28O5: C 72.70, H 7.12; found: C
72.58, H 7.04.
A
solution of the resulting crude alcohol (1.46 g, 6.68 mmol) and
pTsOH·H2O (0.127 g, 0.668 mmol) in 2,2-dimethoxypropane (30.4 mL)
and acetone (3.04 mL) was stirred for 4 h. The reaction was quenched
with water (20 mL), the aqueous layer was extracted with tert-butyl
methyl ether (3ꢄ50 mL), and the combined organic phases were washed
with brine (10 mL), dried over MgSO4 and evaporated. Purification of
the residue by flash chromatography (hexanes/Et2O, 4:1) gave product 20
as a colorless oil (1.73 g, quant.). 1H NMR (300 MHz, CDCl3): d=6.89
(d, J=8.9 Hz, 1H), 6.74 (d, J=8.9 Hz, 1H), 5.22 (brs, 1H), 4.72 (s, 2H),
1.52 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=146.0, 145.6, 119.1,
117.2, 115.0, 107.1, 99.3, 61.9, 24.4 ppm; IR (film): n˜ =3340, 2993, 1588,
1481, 1437, 1258, 1205, 1144, 1073, 963 cmꢁ1; MS (EI): m/z (%): 258 (15)
[M+], 202 (98), 200 (100), 172 (25), 143 (2), 121 (22), 93 (9), 59 (24);
HRMS (EI): m/z: calcd for C10H11O3Br: 257.9892, found 257.9890; ele-
mental analysis calcd (%) for C10H11O3Br: C 46.36, H 4.28; found: C
46.16, H 4.18.
2,2-Dimethyl-5-vinyl-4H-benzo[d]
(2.60 mL, 8.90 mmol) was added to a solution of bromide 20 (1.92 g,
7.41 mmol) and [Pd(PPh3)4] (0.857 g, 0.741 mmol) in toluene (50 mL) and
ACHTUNGTRENUN[NG 1,3]dioxin-6-ol (21): Tributylvinyltin
AHCTUNGTRENNUNG
the resulting mixture was refluxed for 3 d. The reaction was quenched
with H2O (30 mL), the aqueous layer was extracted with EtOAc (3ꢄ
40 mL), the combined organic phases were washed with brine (15 mL),
dried over MgSO4 and evaporated. The residue was purified by flash
chromatography (hexanes/EtOAc 1:0 ! 5:1) to yield product 21 as a
pale yellow oil (1.35 g, 88%). 1H NMR (400 MHz, CDCl3): d=6.76 (d,
J=8.8 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 6.51 (dd, J=18.0, 11.6 Hz, 1H),
5.68 (dd, J=11.6, 1.6 Hz, 1H), 5.62 (dd, J=18.0, 1.6 Hz, 1H), 5.25 (br s,
1H), 4.77 (s, 2H), 1.52 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
146.4; 144.7, 129.7, 121.5, 120.4, 117.7, 117.2, 115.2, 98.6, 60.1, 24.5 ppm;
IR (film): n˜ =3396, 2991, 2940, 1630, 1472, 1374, 1258, 1204, 1146,
1063 cmꢁ1; MS (EI): m/z (%): 206 (27) [M+], 148 (100), 131 (6), 120 (37),
105 (10), 91 (53), 82 (14), 65 (18), 55 (11); HRMS (EI): m/z: calcd for
C12H14O3: 206.0943; found 206.0946; EA for C12H14O3: calcd C 69.88, H
6.84; found: C 69.80, H 6.78.
Aspercyclide C (3): A solution of compound 17 (12.1 mg, 0.03 mmol) in
CH2Cl2 (1 mL) was added to a solution of BBr3 (1m in CH2Cl2, 0.46 mL,
0.46 mmol) at ꢁ788C and the resulting mixture was stirred at that tem-
perature for 30 min and for 9 h at 08C. Prior to work up, the solution was
cooled to ꢁ788C before aq. sat. NaHCO3 (2 mL) was introduced. The
mixture was allowed to reach ambient temperature before the aqueous
phase was extracted with tert-butyl methyl ether (3ꢄ5 mL). The com-
bined organic layers were washed with brine (10 mL) and dried over
MgSO4. All volatile materials were evaporated and the residue was puri-
fied by flash chromatography (hexanes/EtOAc 10:1 ! 7:3) to give com-
pound 3 as a colorless solid (5.1 mg, 44%). M.p. 89–908C; [a]2D0 =+229.78
(c=0.4 in MeOH), ref.:[1] [a]2D0 =+122.5 (c=0.39 in MeOH); 1H NMR
(400 MHz, CDCl3): d=7.13 (t, J=8.0 Hz, 1H), 7.07 (t, J=7.9 Hz, 1H),
6.98 (dd, J=8.1, 1.6 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.68 (bd, J=
7.6 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.27 (d, J=15.9 Hz, 1H), 5.99 (dd,
J=15.9, 9.5 Hz, 1H), 5.22 (dt, J=9.3, 2.0 Hz, 1H), 4.04 (t, J=9.3 Hz,
1H), 2.37 (s, 3H), 2.07 (m, 1H), 1.72–1.65 (m, 3H), 1.55 (m, 2H), 1.37
(m, 4H), 0.93 ppm (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
167.8, 153.7, 150.0, 141.9, 137.5, 135.4, 132.5, 130.3, 128.1, 126.7, 126.0,
2-Iodo-6-methylbenzoic acid (34): PdACHTNUTRGNEUNG(OAc)2 (0.628 g, 2.80 mmol) was
added to the solution of 2-methylbenzoic acid 32 (3.81 g, 28.0 mmol) and
N-iodosuccinimide (6.93 g, 30.8 mmol) in DMF (140 mL) and the result-
ing solution was stirred at 1008C for 16 h. After reaching ambient tem-
perature, water (50 mL) was added and the mixture was extracted with
Chem. Eur. J. 2009, 15, 5956 – 5968
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5963

A. Fꢁrstner et al.
EtOAc (3ꢄ100 mL). The combined organic layers were washed with
brine (50 mL), dried over MgSO4 and evaporated. Residual DMF was
evaporated under high vacuum (708C for 4 h) to give acid 34 as pale
yellow crystals (7.30 g, 98%). 1H NMR (400 MHz, CDCl3): d=9.32 (brs,
1H), 7.70 (d, J=7.8 Hz, 1H), 7.21 (dd, J=7.7, 0.5 Hz, 1H), 7.03 (t, J=
7.8 Hz, 1H), 2.45 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=172.7,
141.6, 133.2, 132.1, 131.8, 128.5, 126.1, 22.3 ppm; MS (EI): m/z (%): 263
(9) [M++1], 262 (100) [M+], 245 (38), 244 (30), 217 (9), 216 (8), 90 (18),
89 (17), 77 (14), 63 (11); the data are in agreement with those reported
in the literature.[43]
(S)-1-(tert-Butyldimethylsilyloxy)heptan-2-yl
(38)
2-iodo-6-methylbenzoate
Method A: A solution of acid 34 (500 mg, 2.02 mmol), alcohol ent-37
(0.380 mL, 2.22 mmol) and PPh3 (582 mg, 2.22 mmol) in THF (20 mL)
was cooled to 08C before DEAD (0.351 mL, 2.22 mmol) was added drop-
wise. The resulting mixture was stirred at ambient temperature for 12 h
before the solvents were evaporated. Purification of the residue by flash
chromatography (hexanes/Et2O 20:1) furnished ester 38 as a pale yellow
oil (722 mg, 75%).
Method B: Prepared according to the representative procedure from acid
fluoride 36 and alcohol 37 as a colorless oil (711 mg, 93%). [a]2D0 =ꢁ10.2
(c=1.1 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.65 (d, J=7.9 Hz,
1H), 7.17 (d, J=7.6 Hz, 1H), 6.98 (t, J=7.8 Hz, 1H), 5.17 (quint., J=
5.7 Hz, 1H), 3.85 (dd, J=10.8, 5.2 Hz, 1H), 3.80 (d, J=10.9, 4.8 Hz, 1H),
2.37 (s, 3H), 1.80–1.75 (m, 2H), 1.56–1.28 (m, 6H), 0.91 (s, 9H), 0.90 (t,
J=6.9 Hz, 3H), 0.08 (s, 3H), 0.07 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=169.0, 140.7, 136.6, 130.6, 129.9, 91.9, 76.8, 64.1, 32.0, 30.7,
26.1, 25.2, 22.8, 21.3, 18.5, 14.3, ꢁ5.1 ppm; IR (film): n˜ =2954, 2929, 2857,
1-(tert-Butyl-dimethylsilyloxy)heptan-2(S)-ol (37): A pre-cooled (ꢁ208C)
solution of BuMgBr (1m in THF, 122 mL, 122 mmol) was added to a so-
lution of epoxide 49 (11.5 g, 61.1 mmol)[31] and CuI (2.33 g, 12.21 mmol)
in THF (300 mL) at ꢁ208C and the resulting mixture was stirred at this
temperature for 3 h. The reaction was quenched with aq. sat. NH4Cl
(250 mL), the aqueous layer was extracted with tert-butyl methyl ether
(3ꢄ80 mL), the combined extracts were dried over MgSO4 and evaporat-
ed, and the residue was purified by flash chromatography (hexanes/
EtOAc 20:1) to give the title compound as a colorless oil (14.3 g, 95%).
1H NMR (400 MHz, CDCl3): d=3.58 (d, J=7.2 Hz, 2H), 3.34 (t, J=
7.2 Hz, 1H), 1.45–1.17 (m, 8H), 0.88 (s, 9H), 0.81 (t, J=6.5 Hz, 3H),
0.05 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=71.5, 66.9, 32.4, 31.6,
25.3, 24.9, 22.2, 17.9, 13.6, ꢁ5.7 ppm; the spectroscopic data correspond
to those reported in the literature.[44]
1728, 1588, 1560, 1462, 1445, 1362, 1267, 1096, 1065, 1005, 833, 769 cmꢁ1
;
MS (EI): m/z (%): 433 (9), 320 (16), 319 (100), 245 (83); HRMS (ESI):
m/z: calcd for C21H35O3ISiNa: 513.1292, found 513.1292.
Compound 39:
A flask containing a mixture of phenol 21 (1.00 g,
4.85 mmol), iodide 38 (1.19 g, 2.42 mmol), 2,2,6,6-tetramethylheptane-3,5-
dione (100 mL, 0.49 mmol), CuCl (24 mg, 0.24 mmol) and Cs2CO3 (1.66 g,
326 mmol) in pyridine (12 mL) was immersed into a pre-heated oil bath
(1208C) and the mixture was stirred at that temperature for 24 h before
it was allowed to reach ambient temperature. Quenching of the reaction
with H2O (10 mL) followed by a standard extractive work up and purifi-
cation of the crude material by flash chromatography (hexanes/Et2O
10:1, then hexanes/EtOAc 4:1) furnished product 39 as a colorless syrup
(1.27 g, 92%). 1H NMR (400 MHz, CDCl3): d=7.07 (t, J=7.8 Hz, 1H),
6.82 (d, J=7.6 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H),
6.50 (dd, J=11.8, 18.1 Hz, 1H), 6.42 (d, J=8.3 Hz, 1H), 5.54 (dd, J=2.0,
18.7 Hz, 1H), 5.42 (dd, J=2.0, 11.4 Hz, 1H), 4.87 (s, 2H), 5.12 (m, 1H),
3.66 (dAB, J=5.1, 10.6 Hz, 2H), 2.35 (s, 3H), 1.52 (s, 6H), 1.67–1.15 (m,
8H), 0.84 (s, 9H), 0.77 (t, J=6.5 Hz, 3H), 0.02 (s, 3H), ꢁ0.01 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=168.3, 154.7, 147.5, 136.5, 129.6,
128.2, 126.5, 125.1, 123.5, 120.7, 120.4, 117.8, 116.7, 113.0, 98.4, 75.4, 63.9,
60.1, 31.4, 30.3, 25.5, 24.4, 24.3, 24.2, 22.2, 22.1, 19.0, 13.6, ꢁ5.8 ppm;
HRMS (EI): m/z: calcd for C33H48O6Si: 568.3220, found 568.3223.
Representative procedure for the preparation of acid fluorides: 2-Bromo-
6-methyl-benzoyl fluoride: Cyanuric fluoride (295 mL, 4.95 mmol) was
added dropwise to a solution of 2-bromo-6-methylbenzoic acid (710 mg,
3.30 mmol) and pyridine (800 mL, 9.90 mmol) in CH2Cl2 (33 mL) at 08C.
After stirring for 45 min at this temperature, the mixture was diluted
with water (20 mL), the aqueous layer was extracted with CH2Cl2 (3ꢄ
20 mL), the combined organic phases were dried over MgSO4 and evapo-
rated, and the residue was purified by flash chromatography (hexanes/
EtOAc 5:1) to give the title compound as a colorless oil (456 mg, 64%).
1H NMR (400 MHz, CDCl3): d=7.50 (d, J=7.6 Hz, 1H), 7.30–7.23 (m,
2H), 2.38 ppm (d, J=1.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
156.9 (d, JCF =356 Hz), 139.1, 132.5, 131.0 (d, JCF =123 Hz), 130.9, 129.7
(d, JCF =1.6 Hz), 120.1, 20.5 ppm; IR (film): n˜ =2925, 1808, 1750, 1448,
1203, 967, 770 cmꢁ1; MS (EI): m/z (%): 218 (98) [M++1], 216 (100), 199
(12), 198 (54), 197 (13), 196 (54), 171 (11), 170 (21), 169 (12), 168 (20),
137 (13), 109 (46), 108 (30), 107 (20), 90 (16), 89 (34), 83 (19), 63 (26), 62
(13), 39 (12); HRMS (EI): m/z: calcd for C8H6OBrF: 215.9586, found
215.9588.
Compound 40: Ozone was bubbled through a solution of compound 39
(650 mg, 1.143 mmol) in CH2Cl2 (5.7 mL) and MeOH (5.7 mL) at ꢁ788C
for 30 min. The mixture was then purged with Ar for 15 min before Zn
dust (149 mg, 2.29 mmol) and acetic acid (262 mL, 4.57 mmol) were intro-
duced. Stirring was continued for 30 min at ꢁ788C and for 2 h at ambient
temperature before all volatile materials were evaporated and the resi-
due was purified by flash chromatography (hexanes/Et2O 20:1) to give al-
dehyde 40 as a colorless oil (508 mg, 78%). [a]2D0 =ꢁ4.2 (c=0.92 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=10.48 (s, 1H), 7.23 (t, J=
8.0 Hz, 1H), 7.02 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 6.87 (d, J=
9.0 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H), 5.19 (s, 2H), 5.15 (ddd, J=10.3, 8.1,
5.1 Hz, 1H), 3.71 (dd, J=10.8, 5.6 Hz, 1H), 3.65 (dd, J=10.8, 4.8 Hz,
1H), 2.42 (s, 3H), 1.70–1.49 (m, 2H), 1.55 (s, 6H), 1.36–1.13 (m, 6H),
0.86 (s, 9H), 0.82 (t, J=7.0 Hz, 3H), 0.03 (s, 3H), 0.02 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=191.5, 167.2, 154.6, 154.5, 147.9, 137.9,
130.6, 126.8, 125.8, 124.7, 123.5, 121.8, 119.9, 115.5, 99.3, 85.6, 76.3, 64.5,
61.6, 31.9, 30.8, 26.0, 25.1, 24.8, 24.7, 22.7, 19.7, 18.5, 14.2, ꢁ5.2 ppm; IR
(film): n˜ =2994, 2955, 2929, 2858, 1729, 1683, 1608, 1593, 1581, 1460,
1402, 1385, 1375, 1273, 1255, 1242, 1146, 1106, 1034, 983, 873, 837, 778,
689 cmꢁ1; MS (EI): m/z (%): 570 (1) [M+], 514 (10), 513 (28), 455 (15),
313 (10), 297 (25), 282 (10), 281 (48), 267 (9), 266 (6), 240 (18), 239 (100),
223 (25), 208 (16), 207 (95), 73 (16); HRMS (ESI): m/z: calcd for
C32H46O7SiNa: 593.2905, found 593.2909.
ACHTUNGTRENNUNG(3R,4S)-3-(4-Methoxyphenoxy)non-1-en-4-yl 2-bromo-6-methylbenzoate
(Table 2, entry 4): KHMDS (0.5m in toluene, 2.19 mL, 1.09 mmol) was
added dropwise to a solution of alcohol 13 (263 mg, 1.0 mmol) in THF
(10 mL) at 08C and the resulting mixture was stirred for 10 min before a
solution of 2-bromo-6-methyl-benzoyl fluoride (324 mg, 1.492 mmol) in
THF (0.5 mL) was introduced. After additional 30 min at 08C, the mix-
ture was allowed to warm to ambient temperature and stirring was con-
tinued for 2 h. The reaction was quenched with sat. aq. NH4Cl (5 mL),
the aqueous layer extracted with tert-butyl methyl ether (3ꢄ25 mL), the
combined organic phases were washed with brine (10 mL), dried over
MgSO4 and evaporated, and the residue was purified by flash chromato-
ACHTUNGTRENNUNGgraphy (hexanes/Et2O, 10:1) to give the title compound as a colorless oil
(444 mg, 97%). [a]2D0 =+1.2 (c=0.92 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.39–7.36 (m, 1H), 7.24–7.12 (m, 2H), 6.86 (d, J=9.2 Hz,
2H), 6.79 (d, J=9.2 Hz, 2H), 3.77 (s, 3H), 5.98–5.89 (m, 1H), 5.43–5.35
(m, 3H), 4.88–4.85 (m, 1H), 2.29 (s, 3H), 2.05–1.91 (m, 1H), 1.78–1.71
(m, 1H), 1.61–1.30 (m, 6H), 0.91 ppm (t, J=7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=168.0, 154.3, 152.2, 137.1, 136.4, 134.2, 130.5,
130.1, 129.1, 119.6, 119.1, 117.4, 114.7, 80.6, 77.4, 55.9, 31.8, 28.8, 25.5,
22.7, 19.9, 14.2 ppm; IR (film): n˜ =2955, 1644, 1500, 1465, 1272, 1227,
1039, 932, 824, 774 cmꢁ1; MS (EI): m/z (%): 462 (2), 460 (2), 339 (44),
337 (44), 255 (5), 199 (97), 197 (100), 124 (10), 123 (8), 119 (6), 90 (6), 81
(6); HRMS (ESI): m/z: calcd for C24H29O4BrNa: 483.1142, found
483.1136; elemental analysis (%) calcd for C24H29O4Br: C 62.48, H 6.34;
found: C 62.32, H 6.30.
Compound 41: A solution of CHI3 (724 mg, 1.840 mmol) and aldehyde
40 (500 mg, 0.876 mmol) in THF (2.0 mL) was added dropwise to a cold
(08C) suspension of CrCl2ACTHNUTRGNEUNG
(THF)1.4 (1.76 g, 7.01 mmol)[41] in THF
(2.3 mL). The resulting mixture was stirred at 08C for 2 h before the re-
action was quenched with water (10 mL). The aqueous layer was extract-
5964
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5956 – 5968

Total Synthesis of the Aspercyclides
FULL PAPER
ed with tert-butyl methyl ether (3ꢄ30 mL), the combined organic phases
were dried over MgSO4 and evaporated, and the residue purified by flash
chromatography (hexanes/Et2O 40:1 ! 4:1) to give (E)-41 (268 mg,
44%) and (Z)-41 (50 mg, 8% yield) as colorless oils each; E/Z 5:1
(1H NMR of the crude product).
arated. The aqueous phase was extracted with EtOAc (3ꢄ15 mL), the
combined organic layers were dried over MgSO4 and evaporated, and the
residue was purified by flash chromatography (hexanes/EtOAc 10:1) to
give aldehyde 43 as a pale yellow oil (81 mg, 81%). [a]2D0 =ꢁ10.3 (c=2 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=9.60 (d, J=0.7 Hz, 1H), 7.24
(d, J=15.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.03 (d, J=15.0 Hz, 1H),
6.97 (d, J=7.6 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 6.74 (d, J=8.9 Hz, 1H),
6.55 (d, J=8.1 Hz, 1H), 5.24 (dd, J=8.6, 4.5 Hz, 1H), 4.86 (s, 2H), 2.46
(s, 3H), 1.92–1.70 (m, 2H), 1.55 (s, 6H), 1.45–1.18 (m, 6H), 0.84 ppm (t,
J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=198.6, 167.4, 154.9,
148.0, 147.2, 138.1, 136.2, 131.1, 125.9, 125.0, 120.5, 118.1, 117.9, 114.4,
99.2, 85.1, 79.4, 60.3, 31.6, 29.1, 24.83, 24.77, 24.74, 22.6, 19.7, 14.1 ppm;
IR (film): n˜ =3071, 2988, 2954, 2929, 2868, 1731, 1604, 1580, 1457, 1384,
(E)-41: [a]2D0 =+0.9 (c=2.1 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.23 (d, J=14.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 7.10 (d, J=14.9 Hz,
1H), 6.92 (d, J=8.3 Hz, 1H), 6.78 (d, J=8.9 Hz, 1H), 6.73 (d, J=8.9 Hz,
1H), 6.50 (d, J=8.3 Hz, 1H), 5.17 (dq, J=7.9, 5.2 Hz, 1H), 4.86 (s, 2H),
3.75 (dd, J=10.7, 5.7 Hz, 1H), 3.67 (dd, J=10.7, 5.0 Hz, 1H), 2.40 (s,
3H), 1.72–1.61 (m, 2H), 1.55 (s, 6H), 1.40–1.17 (m, 6H), 0.87 (s, 9H),
0.83 (t, J=7.2 Hz, 3H), 0.04 (s, 3H), 0.03 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=167.5, 154.4, 147.8, 147.5, 137.4, 136.1, 130.4,
126.1, 125.7, 124.8, 120.6, 118.0, 117.6, 114.3, 99.1, 85.6, 76.1, 64.5, 60.4,
31.9, 30.9, 26.1, 25.1, 24.8, 24.7, 22.7, 19.6, 18.5, 14.2, ꢁ5.2ppm; IR (film):
n˜ =2990, 2954, 2928, 2857, 1728, 1603, 1581, 1459, 1384, 1374, 1360, 1253,
1204, 1145, 1106, 1074, 1030, 973, 945, 874, 836, 777 cmꢁ1; MS (EI): m/z
(%): 695 (4) [M++1], 694 (9) [M+], 637 (10), 580 (14), 579 (40), 523
(12), 452 (14), 391 (12), 340 (10), 339 (34), 338 (100), 265 (19), 264 (54),
236 (13), 229 (22), 173 (8), 169 (16), 155 (33), 135 (52), 75 (11), 73 (30);
HRMS (ESI): m/z: calcd for C33H47O6SiINa: 717.2079, found 717.2085.
(Z)-41: [a]2D0 =ꢁ8.1 (c=1.8 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.19 (d, J=8.2 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H),
6.85 (d, J=8.6 Hz, 1H), 6.81 (d, J=8.9 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H),
6.60 (d, J=8.3 Hz, 1H), 5.14 (dq, J=7.6, 5.1 Hz, 1H), 4.77 (d, J=2.0 Hz,
2H), 3.75 (dd, J=10.7, 5.4 Hz, 1H), 3.68 (dd, J=10.8, 5.0 Hz, 1H), 2.37
(s, 3H), 1.73–1.60 (m, 2H), 1.58 (s, 6H), 1.44–1.20 (m, 6H), 0.88 (s, 9H),
0.83 (t, J=7.1 Hz, 3H), 0.05 (s, 3H), 0.04 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=167.6, 155.2, 148.1, 146.4, 136.9, 135.0, 130.2,
128.2, 125.8, 124.2, 120.5, 118.4, 118.0, 114.4, 99.6, 89.4, 75.9, 64.4, 60.8,
32.0, 30.9, 26.1, 25.02, 24.98, 24.8, 22.7, 19.5, 18.5, 14.2, ꢁ5.1 ppm; IR
(film): n˜ =2995, 2954, 2929, 2857, 1727, 1605, 1581, 1459, 1385, 1375,
1253, 1203, 1140, 1105, 1074, 1029, 975, 872, 836, 777, 689 cmꢁ1; MS (EI):
m/z (%): 695 (9) [M++1], 694 (23) [M+], 637 (13), 636 (10), 581 (9), 580
(30), 579 (81), 523 (24), 487 (13), 467 (19), 466 (18), 465 (63), 452 (20),
449 (20), 391 (45), 339 (31), 338 (100), 294 (10), 265 (25), 264 (89), 236
(14), 236 (23), 235 (17), 229 (24), 204 (16), 169 (28), 155 (54), 135 (78),
118 (12), 75 (16), 73 (44), 55 (10); HRMS (ESI): m/z: calcd for
C33H47O6SiINa: 717.2079, found 717.2081.
1375, 1252, 1204, 1143, 1110, 1074, 1029, 974, 947, 872, 828, 781, 740 cmꢁ1
;
MS (EI): m/z (%): 579 (2) [M++1], 578 (5) [M+], 520 (18), 266 (18), 265
(100), 264 (12), 263 (23), 236 (9), 235 (12), 135 (30), 118 (20), 95 (6), 43
(5); HRMS (ESI): m/z: calcd for C27H31O6INa: 601.1058, found 601.1059.
Compound 44: A solution of compound 43 (30 mg, 0.052 mmol) in fresh-
ly distilled, amine free DMF (5.2 mL) was added dropwise to a mixture
of CrCl2ACHTUNGTRNEUNG
(THF)1.4 (142 mg, 0.519 mmol)[41] and NiCl2 (0.067 mg,
0.519 mmol) and the resulting suspension was stirred for 2 h. The reaction
was quenched by addition of aq. potassium serinate solution (5 mL, pre-
pared by dissolving of 0.84 g of serine and 0.6 g of KHCO3 in 7 mL of
water), the mixture was extracted with EtOAc (3ꢄ20 mL), the combined
organic layers were washed with brine (2ꢄ10 mL), dried over MgSO4
and evaporated, and the residue was purified by flash chromatography
(hexanes/EtOAc 10:1 ! 4:1) to give product 44 as a colorless oil
(18.6 mg, 79%, anti/syn
>
95:1). [a]2D0 =+82.2 (c=0.34 in CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.23 (d, J=8.7 Hz, 1H), 7.11 (t, J=
8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.78 (d, J=
8.3 Hz, 1H), 6.03–6.01 (m, 2H), 5.24 (td, J=9.5, 2.3 Hz, 1H), 4.69 (d, J=
15.7 Hz, 1H), 4.64 (d, J=15.7 Hz, 1H), 4.09 (ddd, J=8.8, 5.7, 2.9 Hz,
1H), 2.36 (s, 3H), 2.09 (ddt, J=13.5, 9.1, 2.3 Hz, 1H), 1.70 (tdd, J=17.4,
10.9, 6.5 Hz, 1H), 1.53 (s, 6H), 1.49–1.22 (m, 6H), 0.93 ppm (t, J=6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=168.2, 154.8, 148.3, 146.3, 139.0,
135.4, 129.9, 128.4, 126.8, 124.5, 124.3, 124.1, 119.4, 116.4, 113.3, 99.4,
77.4, 77.3, 60.0, 32.0, 31.8, 25.5, 25.2, 24.6, 22.7, 19.5, 14.2 ppm; IR (film):
n˜ =3439, 2993, 2952, 2924, 2860, 1717, 1598, 1589, 1580, 1460, 1385, 1374,
1252, 1206, 1140, 1078, 970, 869, 828, 671 cmꢁ1; MS (EI): m/z (%): 453
(4) [M++1], 452 (13) [M+], 395 (10), 394 (39), 295 (15), 294 (73), 293
(20), 279 (14), 277 (18), 276 (10), 267 (10), 266 (52), 265 (100), 251 (11),
249 (16), 237 (6), 200 (7), 161 (9), 160 (77), 135 (33); HRMS (ESI): m/z:
calcd for C27H32O6Na: 475.2091, found 475.2094.
Compound 42: Pyridine (349 mL, 4.32 mmol) was added to a cold (08C)
solution of compound 41 (150 mg, 0.216 mmol) in THF (2.2 mL) and the
resulting mixture was stirred for 5 min before HF·pyridine (372 mL,
2.159 mmol) was introduced. Stirring was continued for 15 min at 08C
and for 3 h at room temperature before the reaction was quenched at
08C with sat. aq. NaHCO3 (10 mL). The aqueous layer was extracted
with EtOAc (3ꢄ50 mL), the combined extracts were washed with brine
(10 mL), dried over MgSO4 and evaporated, and the residue was purified
by flash chromatography (hexanes/EtOAc 4:1) to furnish alcohol 42 as a
colorless oil (115 mg, 92%). [a]2D0 =ꢁ10.2 (c=1.8 in CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=7.24 (d, J=15.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H),
7.00 (d, J=15.0 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.9 Hz,
1H), 6.75 (d, J=8.9 Hz, 1H), 6.50 (d, J=8.3 Hz, 1H), 5.25 (dddd, J=
11.0, 8.4, 4.4, 2.2 Hz, 1H), 4.85 (s, 2H), 3.77 (dd, J=11.8, 2.6 Hz, 1H),
3.68 (dd, J=12.2, 6.7 Hz, 1H), 2.42 (s, 3H), 1.74–1.61 (m, 2H), 1.55 (s,
6H), 1.41–1.27 (m, 6H), 0.86 ppm (t, J=7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=167.8, 154.7, 148.2, 146.7, 137.7, 136.1, 130.6,
126.2, 124.9, 120.8, 118.2, 118.0, 114.0, 99.3, 85.1, 76.9, 65.0, 60.3, 31.1,
30.7, 25.2, 24.9, 24.6, 22.7, 19.6, 14.2 ppm; IR (film): n˜ =3488, 2957, 2929,
2850, 1727, 1600, 1582, 1459, 1385, 1375, 1269, 1253, 1202, 1146, 1116,
1076, 1029, 975, 947, 871, 829 cmꢁ1; MS (EI): m/z (%): 581 (1) [M++1],
580 (4) [M+], 523 (4), 522 (15), 391 (2), 281 (22), 265 (12), 263 (9), 237
(13), 136 (9), 135 (100), 118 (12); HRMS (ESI): m/z: calcd for
C27H33O6INa: 603.1214, found 603.1220.
Aspercyclide B (2): A solution of compound 44 (10.0 mg, 0.022 mmol)
and pTsOH (ca. 1 mg) in MeOH (1.0 mL) was stirred for 12 h before a
solution of sat. aq. NaHCO3 (2 mL) was added. The mixture was extract-
ed with EtOAc (3ꢄ5 mL), the combined organic layers were dried over
MgSO4, the solvents were evaporated and the residue was purified by
flash chromatography (hexanes/EtOAc 1:1) to give the title compound as
a colorless solid (8.91 mg, 98%). [a]2D0 =+209.8 (c=0.84 in MeOH),
ref.:[1] [a]2D0 =+210 (c=0.6 in MeOH); IR (film): n˜ =3349, 2956, 2827,
2855, 1714, 1603, 1586, 1455, 1337, 1252, 1235, 1114, 1075, 1024, 1075,
1024, 968, 830, 782, 728 cmꢁ1; MS (ESI): m/z (%): 435 [M++Na], 389;
HRMS (ESI): m/z: calcd for C24H28O6Na: 435.1778, found 435.1773. For
a compilation of the NMR data, see Tables 3 and 4.
4-Desmethylaspercyclide B (53): Prepared analogously using pyridinium
p-toluenesulfonate as catalyst; colorless solid (5 mg, 78%, d.r. 3:1).
[a]2D0 =+167.4 (c=0.35 in CH2Cl2); 1H NMR (400 MHz, CDCl3, resolved
signals of the minor isomer are marked *): d=7.74* (brs, 1H), 7.71 (brs,
1H), 7.34–7.23 (m, 6H), 7.05 (t, J=7.5 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H),
6.85 (d, J=8.7 Hz, 2H), 6.11 (d, J=15.9 Hz, 2H), 5.85 (dd, J=15.7,
8.3 Hz, 2H), 5.38* (m, 1H), 5.16 (td, J=9.2, 2.3 Hz, 1H), 5.17 (brs, 4H),
4.08 (t, J=8.6 Hz), 3.66* (t, J=6.8 Hz), 2.45 (brs, 2H), 2.34 (br s, 2H),
2.09–2.01 (m, 1H), 1.99–1.90* (m, 1H), 1.89–1.81* (m, 1H), 1.74–1.67 (m,
1H), 1.58–1.27 (m, 12H), 0.94 (t, J=6.9 Hz, 3H), 0.92* ppm (t, J=
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=168.2, 156.2, 154.6, 143.2,
138.2, 137.8, 131.1, 130.5, 128.2, 125.7, 124.8, 122.7, 119.9, 116.3, 113.6,
77.6, 73.6, 63.6, 31.9, 31.8, 25.3, 22.8, 14.3 ppm; IR (film): n˜ =3327, 2967,
Compound 43: Dess–Martin periodinane (110 mg, 0.258 mmol) was
added to
a solution of alcohol 42 (100 mg, 0.172 mmol) in CH2Cl2
(2.3 mL) at 08C and the resulting mixture was stirred at ambient temper-
ature for 1 h. Sat. aq. NaHCO3 (5 mL) was introduced and the resulting
mixture vigorously stirred for 30 min before the resulting layers were sep-
Chem. Eur. J. 2009, 15, 5956 – 5968
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5965

A. Fꢁrstner et al.
Table 3. Comparison of the 1H NMR data (CDCl3) of synthetic aspercyclide B (2), recorded at two different concentrations, with the reported data of
the natural product; for the concentration dependence of the spectrum, see also Figure 2.
Position
Ref.[1] (300 MHz)
Recorded Data (400 MHz)
22 mg in 600 mL
8.1 mg in 600 mL
5
6
7
11
12
16
17
18
19
20
6.85 (d, J=8.0 Hz)
7.18 (t, J=8.0 Hz)
6.75 (d, J=8.0 Hz)
7.19 (d, J=8.8 Hz)
6.84 (d, J=8.8 Hz)
6.13 (d, J=16.0 Hz)
5.81 (dd, J=16.0, 9.2 Hz)
4.08 (t, J=9.2 Hz)
5.20 (td, J=9.2, 2.0 Hz)
2.08 (m)
6.83 (d, J=7.6 Hz)
7.08 (t, J=8.0 Hz)
6.71 (d, J=8.4 Hz)
7.06 (d, J=8.7 Hz)
6.76 (d, J=8.7 Hz)
6.03 (d, J=15.9 Hz)
5.71 (dd, J=15.9, 9.3 Hz)
4.01 (t, J=9.2 Hz)
5.17 (td, J=9.4, 1.6 Hz)
2.07
6.85 (d, J=7.9 Hz)
7.15 (t, J=8.1 Hz)
6.74 (d, J=8.0 Hz)
7.16 (d, J=8.8 Hz)
6.83 (d, J=8.8 Hz)
6.11 (d, J=16.0 Hz)
5.78 (dd, J=16.0, 9.2 Hz)
4.06 (t, J=9.2 Hz)
5.19 (td, J=9.2, 2.0 Hz)
2.08 (m)
1.71 (m)
1.68
1.70 (m)
21
1.65 (m)
1.53
1.63 (m)
22
1.55 (m)
1.43
1.54 (m)
23
1.44 (m)
1.36
1.42 (m)
24
25
0.94 (t, J=6.8 Hz)
2.37 (s)
0.92 (t, J=7.0 Hz)
2.34 (s)
0.93 (t, J=6.8 Hz)
2.36 (s)
26
OH-13
OH-18
4.82 (AB, J=12.0 Hz)
7.76 (brs)
not observed
4.70 (AB, J=13.2 Hz)
7.37
2.49
4.81 (AB, J=12.0 Hz)
7.72 (brs)
not observed
2941, 2881, 1714, 1584, 1469, 1456, 1373, 1223, 1208 cmꢁ1; MS (EI): m/z
(%): 399 (2) [M++1], 398 (12) [M+], 298 (3), 280 (19), 269 (13), 267
(16), 254 (27), 252 (24), 251 (100), 177 (9), 160 (12), 121 (16); HRMS
(ESI): m/z: calcd for C23H26O6Na: 421.1622, found 421.1625.
Table 4. Comparison of the 13C NMR (CDCl3) data of synthetic aspercy-
clide B (2), recorded at two different concentrations, with the reported
data of the natural product; arbitrary numbering Scheme as shown in the
insert.
Compound 45: A solution of alcohol 44 (90 mg, 0.20 mmol), TBDPSCl
(61.3 mg, 0.24 mmol) and imidazole (27 mg, 0.4 mmol) in CH2Cl2 (2 mL)
was stirred at ambient temperature for 11 h before the reaction was
quenched with aq. sat. NaHCO3 (5 mL). A standard extractive work up
followed by flash chromatography (hexanes/Et2O 20:1) gave compound
45 as a colorless oil (132 mg, 96%). [a]2D0 =+90.1 (c=2.0 in CH2Cl2);
1H NMR (400 MHz, CDCl3): d=7.64 (d, J=6.8 Hz, 2H), 7.54 (d, J=
6.8 Hz, 2H), 7.34–7.19 (m, 6H), 7.08 (d, J=10.2 Hz, 1H), 6.97 (t, J=
6.8 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.63 (t, J=10.2 Hz, 2H), 10.3 Hz,
1H), 5.94 (dd, J=16.2, 5.40 (d, J=16.2 Hz, 1H), 5.28 (m, 1H), 4.15 (d,
J=16 Hz, 1H), 3.86 (t, J=9.4 Hz, 1H), 3.67 (d, J=16 Hz, 1H), 2.22 (s,
3H), 1.42 (s, 3H), 1.31 (s, 3H), 1.50–1.02 (m, 5H), 0.98 (s, 9H), 0.88–
0.73 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=168.2, 154.8, 148.2,
146.2, 139.6, 136.5, 136.4, 135.4, 135.2, 133.8, 133.4, 130.4, 130.1, 129.4,
128.6, 128.2, 128.1, 127.7, 126.9, 124.3, 124.0, 119.7, 116.3, 113.2, 99.4,
78.1, 77.0, 59.7, 32.0, 31.7, 27.3, 26.3, 25.4, 23.9, 22.9, 19.6, 14.4 ppm; MS
(EI): m/z (%): 690 (6) [M+], 632 (12), 576 (19), 575 (43), 532 (16), 475
(100), 445 (12), 397 (48), 355 (11), 337 (12), 199 (33), 135 (22); HRMS
(ESI): m/z: calcd for C43H50O6Si [M++Na]: 713.3272, found: 713.3269.
Position Ref.[1]
(75 MHz)
Recorded data (100 MHz)
8.1 mg in
600 mL
dD
22 mg in
dD
600 mL
2
168.1
168.7
125.8
130.9
124.9
126.6
113.3
153.5
145.8
124.5
116.1
154.7
130.1
135.4
124.1
138.4
77.4
77.1
31.8
25.5
22.8
31.9
14.2
19.5
60.9
0.6
168.3
0.2
0.1
0.2
0.1
0.2
0.3
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0.3
0.2
0.3
0.2
0.2
0.3
0.2
0.2
0.2
0.2
0.2
3
4
5
6
7
8
127.2
135.2
125.6
129.7
112.8
153.5
145.6
124.9
116.0
154.4
130.3
136.5
123.8
138.4
78.0
77.3
31.6
25.2
22.5
31.7
14.0
19.3
61.4
ꢁ1.4 127.3
ꢁ4.3 135.4
ꢁ0.8 125.7
ꢁ3.1 129.9
Compound 46: p-Toluenesulfonic acid (2.7 mg, 0.016 mmol) was added to
a solution of compound 45 (110 mg, 0.159 mmol) in MeOH (1.6 mL) and
the resulting solution was stirred for 11 h before the reaction was
quenched with aq. sat. NaHCO3 (5 mL). Extraction of the aqueous layer
with EtOAc (3ꢄ10 mL), drying of the combined organic phases over
MgSO4, evaporation of all volatile materials, and flash chromatography
of the crude product (hexanes/EtOAc 4:1) furnished compound 46 as a
colorless syrup (63 mg, 61%). [a]2D0 =+76 (c=1.1 in CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=7.68–7.57 (m, 5H), 7.38–7.25 (m, 6H), 7.08 (d, J=
8.1 Hz, 1H), 6.96 (t, J=8.0 Hz, 1H), 6.71 (m, 2H), 6.59 (d, J=8.1 Hz,
1H), 5.84 (dd, J=11.5, 18 Hz, 1H), 5.50 (d, J=18.5 Hz, 1H), 5.24 (m,
1H), 4.22 (d, J=16.2 Hz, 1H), 3.95–3.87 (m, 2H), 2.22 (s, 3H), 1.53–1.13
(m, 9H), 0.97 (s, 9H),0.83 ppm (t, J=6.5 Hz, 3H); HRMS (ESI): m/z:
calcd for C40H46O6Si [M++Na]: 673.2959, found: 673.2956.
0.5
0.0
0.2
113.1
153.7
145.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
ꢁ0.4 125.1
0.1
0.3
116.2
154.6
ꢁ0.2 130.5
ꢁ1.1 136.7
0.3
0.0
124.1
138.6
ꢁ0.6 78.3
ꢁ0.2 77.5
0.2
0.3
0.3
0.2
0.2
0.2
31.8
25.5
22.7
31.9
14.2
19.5
Compound 47: MnO2 (80 mg, 0.92 mmol) was added to a solution of
compound 46 (30 mg, 0.046 mmol) in CH2Cl2 (1 mL) and the resulting
suspension was stirred for 1 h, before it was filtered through a pad of
Celite, which was carefully rinsed with EtOAc (5 mL). The combined fil-
trates were evaporated and the residue purified by flash chromatography
ꢁ0.5 61.6
5966
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5956 – 5968

Total Synthesis of the Aspercyclides
FULL PAPER
(hexanes/EtOAc 4:1) to give aldehyde 47 as a colorless syrup (15.9 mg,
55%). [a]2D0 =+88.9 (c=0.75 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d=11.45 (s, 1H), 8.97 (s, 1H), 7.62–7.22 (m, 11H), 7.00 (t, J=8.1 Hz,
1H), 6.82 (d, J=8.9 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.52 (d, J=8.5 Hz,
1H), 5.96 (dd, J=9.6, 16.8 Hz, 1H), 5.83 (d, J=16.8 Hz, 1H), 5.27 (br t,
J=10.6 Hz, 1H), 4.07 (m, 1H), 2.24 (s, 3H), 1.50–1.15 (m, 5H), 0.98 (s,
9H), 0.88–0.80 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=196.0,
141.6, 136.3, 136.2, 135.8, 133.8, 130.4, 130.3, 130.0, 128.2, 127.9, 124.6,
122.8, 117.6, 113.0, 53.8, 32.0, 31.8, 27.2, 25.3, 22.8, 19.7, 19.6, 14.3 ppm;
IR (film): n˜ =3068, 29602929, 2861, 1740, 1654, 1455, 1253, 1114, 1092,
1077, 700 cmꢁ1; HRMS (ESI): m/z: calcd for C40H44O6SiNa [M++Na]:
671.2793, found: 671.2799.
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h) A. Fꢁrstner, A. Korte, Chem. Asian J. 2008, 3, 310–318.
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X-ray crystal structure analysis of compound (E)-16: C31H34O6, Mr =
502.58 gmolꢁ1, colorless block, crystal size 0.09ꢄ0.08ꢄ0.08 mm, mono-
clinic, space group P21, a=8.2766(3), b=38.0828(13), c=8.3107(3) ꢅ, b=
90.227(2)8, V=2619.48(16) ꢅ3, T=100 K, Z=4, 1calcd =1.274 gcm3, l=
0.71073 ꢅ,
mACHTUNGTRENNUNG , Multi-Scan absorption correction
(MoKa)=0.087 mmꢁ1
(Tmin =0.92, Tmax =0.96), Nonius KappaCCD diffractometer, 3.25 < q <
31.07, 35388 measured reflections, 13334 independent reflections, 11557
reflections with I > 2s(I), Structure solved by direct methods and re-
fined by full-matrix least-squares against F2 to R1 =0.043 [I > 2s(I)],
wR2 =0.105, absolute structure parameter=ꢁ0.4(6), 676 parameters, H
´
rier, F. Teply, C. Aꢇssa, E. Moulin, O. Mꢁller, J. Am. Chem. Soc.
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M. D. B. Fenster, C. Godbout, J. Ceccon, Chem. Commun. 2007,
3045–3047.
atoms riding, S=1.012, residual electron density +0.2/ꢁ0.2 e ꢅꢁ3
.
CCDC 705570 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Generous financial support by the MPG and the Fonds der Chemischen
Industrie (Kekulꢆ stipend to C.M.) is gratefully acknowledged. We thank
Dr. C. W. Lehmann for solving the X-ray structure.
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Received: December 19, 2008
Revised: February 18, 2009
Published online: May 5, 2009
5968
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Chem. Eur. J. 2009, 15, 5956 – 5968