An asymmetric formal synthesis of fasicularin

Article abstract of DOI:10.1002/chem.200400749

An asymmetric formal synthesis of fasicularin (1) is described. This natural product, isolated from the extracts of the marine invertebrate Nephteis fasicularis, has shown modest cytotoxicity towards Vero cells. Fasicularin is among only two members of th

Full text of DOI:10.1002/chem.200400749

FULL PAPER
An Asymmetric Formal Synthesis of Fasicularin
Michaꢀl D. B. Fenster[b] and Gregory R. Dake*[a]
Abstract: An asymmetric formal syn-
thesis of fasicularin (1) is described.
This natural product, isolated from the
extracts of the marine invertebrate
Nephteis fasicularis, has shown modest
cytotoxicity towards Vero cells. Fasicu-
larin is among only two members of
the cylindricine family of natural prod-
ucts, along with lepadiformine (2), to
possess a trans A–B ring junction. Key
steps of this approach to 1 involve a
siloxy-epoxide semipinacol rearrange-
ment of 5 to 6, a B-alkyl Suzuki–
Miyaura coupling reaction by using
enol trifluoromethanesulfonate 19 and
a substrate-directed hydrogenation re-
action of 24. This formal synthesis also
highlights the difficulty in the incorpo-
ration of the thiocyanate functionality
present in 1.
Keywords:
alkaloids
·
cross-coupling
· semipinacol
rearrangement · spirocycle
Introduction
Bioassay-guided screening of an extract of the marine inver-
tebrate Nephteis fasicularis led to the isolation of fasicularin
(1) in 1997 by Patil and co-workers (Figure 1).[1] Ultimately,
1 demonstrated selective activity in a yeast strain in which
the RAD 52 gene, implicated in the recombination and
repair of DNA double strand breaks, was deleted.[2] Modest
cytotoxicity (IC50 =14 mgmLꢀ1) of 1 towards Vero cells was
subsequently uncovered. Its intriguing tricyclic structure
proved to be similar to that of a small family of recently iso-
lated marine-derived natural products, lepidiformine (2) and
the cylindricines.[3] Unlike the other members of the cylin-
dricine family, 1 lacks oxygenation at its C4 position and is
epimeric at C10, the spiro-ring junction adjacent to a nitro-
gen atom, thus resulting in a trans-1-azadecalin A–B ring
system.
Figure 1.
stereochemical assignment of 2.[7] In considering a synthetic
approach towards 1, we were intrigued by the 1-azaspirobi-
cyclic structure embedded within its tricyclic framework.
The use of semipinacol rearrangement reactions in the
context of total synthesis has become increasingly more im-
portant, perhaps because of the wider accessibility of enan-
tiomerically and diastereomerically enriched starting materi-
als for this process.[8] Our interest in 1 stemmed from the
possibility of using a semipinacol rearrangement in order to
construct the 1-azaspirobicyclic framework and set the ster-
eochemical identity at C10 in a single operation. During the
course of our investigations, two total syntheses that pro-
duce 1 in racemic form were disclosed.[4a,b] Each of these ap-
proaches established the spirocyclic center in 1 by using ele-
gant cycloaddition strategies. An N-acylnitroso Diels–Alder
The tricyclic structure and potential pharmacological
properties of 1 and its relatives in the cylindricine family
have made them attractive targets for the synthetic organic
chemistry community.[4–6] Interestingly, total synthesis
proved to be vitally important in the ultimate structural and
[a] Prof. Dr. G. R. Dake
Department of Chemistry, 2036 Main Mall
University of British Columbia, Vancouver, BC V6T 1Z1 (Canada)
Fax : (+1)604-822-2847
E-mail: gdake@chem.ubc.ca
[b] Dr. M. D. B. Fenster
Present address: Max-Planck-Institut fꢀr Kohlenforschung 45470
Mꢀlheim an der Ruhr (Germany)
Chem. Eur. J. 2005, 11, 639 – 649
DOI: 10.1002/chem.200400749
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
639

reaction was utilized in the Kibayashi approach,[4a] and a 2-
amidoacrolein Diels–Alder cycloadduct formed the precur-
sor to the spirocyclic ring system in the method of Funk and
Maeng.[4b]
Our analysis is presented in Scheme 1. We considered that
late stage annulation of the A-ring onto the 1-azaspirobicy-
clic system a might be possible. An intramolecular SN2 reac-
was established using X-ray crystallography.[15] With the key
1-spirobicyclic ketone 6 in hand, efforts for its elaboration
to 1 began in earnest.
As some standard methods to generate a xanthate ester
from the alcohol function at C11 in 6 (NaH, CS2, MeI or
ꢀ
tion would be used to form the N1 C2 bond. The advantage
of this approach—the ability to efficiently control the ster-
ꢀ
eochemical outcome during the formation of the N1 C2
bond—outweighed its major drawback that the “annulation”
fragment would have to be prepared in enantiomerically en-
riched form. At the outset, we believed a metal-catalyzed
ꢀ
cross-coupling reaction could effectively form the C4 C5
bond. Simplification of a led to 1-azaspirocyclic ketone b,
the key intermediate that we believed would be accessible
through a semipinacol reaction on enesulfonamide c. The
full details of the conversion of a 1-azaspirobicyclic com-
pound similar to b to 1 (ultimately in a formal sense) is the
subject of this report.
Scheme 2. a) DMDO, K2CO3, acetone, RT. b) TMSOTf (1.7 equiv), 2,6-
lutidine (2.6 equiv), THF, RT, 15 min (83% over both steps). c) TiCl4
(1.1 equiv), CH2Cl2, ꢀ788C, 30 min, 96%. d) TiCl4 (1.1 equiv), CH2Cl2,
ꢀ788C, 30 min, 55%.
KHMDS, CS2, MeI or C6F5OCSCl, 4-DMAP) were unsuc-
cessful,[16] an elimination–hydrogenation sequence was
adopted for its removal (Scheme 3). Conversion of 6 to its
methanesulfonate derivative 8 occurred uneventfully. We
took advantage of the pseuodoaxial orientation of this mesy-
late functional group, as the elimination using 27 equivalents
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) proceeded
smoothly to give alkene 9 in 91% yield. Attempts to
remove the p-toluenesulfonyl group proved more difficult.
Methods employing either sodium amalgam[17] or photo-
chemical conditions[18] yielded complex mixtures. Dissolved
metal reduction conditions[19] by using lithium metal in am-
monia provided sufficient quantities of the desired amine
10, although the reaction was capricious, perhaps due to the
presence of the ketone functional group (see below). Work
to optimize this deprotection process was not undertaken as
our attempts to carry out the subsequent step in our pro-
posed construction—the re-protection of the amine function
in 10 by using a carbamate protecting group uncovered the
first insurmountable obstacle.
Scheme 1.
Results and Discussion
Formation and elaboration of 1-azaspirobicyclic ring system:
As elaborated in detail elsewhere,[9] 5S-hydroxy-2-piperi-
done[10] could be elaborated to cyclopentanol 3 in five steps
(Scheme 2). Attempts to coerce 3 to ring expand using
Brønsted acids or N-bromosuccinimide were unsuccessful.[9a]
Thus, a siloxy-epoxide semipinacol rearrangement was en-
visoned to install the critical stereogenic center adjacent to
the nitrogen atom.[9,11–15] In the event, after efficient epoxi-
dation and trimethylsilylation, the submission of trimethyl-
silyl ether 5 to the action of 1.1 equivalents of titanium tet-
rachloride in dichloromethane at ꢀ788C resulted in the for-
mation of 1-azaspirobicyclic ketone 6 in 96% yield. A
number of features of this reaction are noteworthy: a) the
overall efficiency of the ring expansion reaction, especially
the clean stereochemical outcome in the formation of the
tertiary carbon (the spiro-ring junction) dictated by the ep-
oxide; and b) the requirement of a trimethylsilyl ether for
an effective process. Subjection of cyclopentanol 4 to identi-
cal conditions as that used for 5 resulted in a messy reaction
from which 6 and ketone 7 could be recovered in a 1.4:1
ratio in 55% overall yield. The relative stereochemistry of 6
Amine 10 was subjected to 2.1 equivalents of di-tert-butyl-
carbonate and 4-DMAP in dichloromethane at room tem-
perature to yield an unexpected product 11 in 93% yield.
1
While inspection of the H NMR spectrum of the product of
this reaction clearly revealed a signal attributable to the tert-
butyl group of the carbamate, attempts to engage the “car-
bonyl group” in further reactions were not successful. Anal-
ysis of the 13C NMR spectrum of this compound suggested
that the initially producted tert-butyl carbamate cyclized
640
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 639 – 649

Fasicularin
FULL PAPER
Construction of annulation fragments: Known methods to
generate chiral enantiomerically enriched propargyl alcohols
were selected to install the needed chirality center within
the annulation fragment. Our first experiments used N-
methylephedrine mediated addition of alkynylzinc triflates
to aldehydes as introduced by the Carriera group.[20] Al-
though the addition of trimethylsilylacetylene to heptanal
by using this protocol proceeded with acceptable enantiose-
lectivity (~90% ee), in our hands the efficiency of the reac-
tion was variable. Yields for this process ranged from 0–
60%. Unsatisfied with the fickle nature of this reaction, at-
tention was turned to the use of the Noyori transfer hydro-
genation protocol that had been demonstrated to provide
propargyl alcohols from ynones in high ee.[21]
In the event, the reaction of 1-trimethylsilyl-1-nonyn-3-
one and isopropanol in the presence of 12 mol% of Noyoriꢂs
ruthenium(ii) transfer hydrogenation catalyst 13 generated
propargylic alcohol 14 in 94% yield with 99% ee (estab-
lished using gas chromatography on a chiral column) (Sche-
me 4).[4c] This process was highly reproducible. Removal of
the trimethylsilyl group from 14 to generate terminal alkyne
Scheme 3. a) MsCl (2.4 equiv), 4-DMAP (4.0 equiv), CH2Cl2, RT, 30 min,
87%. b) DBU (27 equiv), toluene, reflux, 36 h, 91%. c) Li (72 equiv),
NH3/THF, ꢀ788C, 5 min, 65% (79% brsm). d) (Boc)2O (2.1 equiv), 4-
DMAP (3.1 equiv), CH2Cl2, RT, 30 min, 93%. e) Nitrobenzene, reflux,
97%.
into the adjacent ketone func-
tional group. The alkoxide
anion produced from this cycli-
zation then reacted with
a
second equivalent of di-tert-bu-
tylcarbonate to give functional-
ized oxazolidinone 11. Heating
11 in nitrobenzene converted it
back to 10 (97% yield), sup-
porting the structural assign-
ment. Use of one equivalent of
di-tert-butylcarbonate led only
to the formation of 11 in 37%
yield with 50% of recovered
Scheme 4. a) 13 (12 mol%), 2-propanol, RT, 103 h, 94%, (>99% ee). b) K2CO3 (3.0 equiv), MeOH, RT, 5 h,
94%. c) LiAlH4 (5.1 equiv), Et2O, RT, 10 d, 97 %. d) p-methoxybenzyl trichloroacetimidate, PPTs (31 mol%),
CH2Cl2, RT, 46 h, 73% (97% brsm). e) TBAF (1.1 equiv), THF, RT, 15 min, 95%. f) H2 (1 atm), Pd/CaCO3
(Pb poisoned) (11 mol%), EtOH, ꢀ68C, 1.75 h, 93%.
10. Other acylating agents such as trichloroethyloxycarbonyl
chloride gave similar results. Although the p-toluenesulfonyl
protecting group in 9 had been shown to be somewhat diffi-
cult to remove cleanly, this complication in the reprotection
of 10 forced us to modify the protecting group strategy.
Having decided to delay the removal of the p-toluenesul-
fonyl group in 9 until later in the synthesis, the ketone func-
tion in 9 was smoothly converted to enol trifluoromethane-
sulfonate 12 by using 2.1 equivalents of potassium hexame-
thyldisilazide and 2.3 equivalents of N-phenyltrifluorome-
thanesulfonimide in 96% yield [Eq. (1)]. Use of one equiva-
lent of base and triflating reagent lowered the yield of 12 to
81%. The next task was the enantioselective preparation of
a suitably functionalized annulation fragment.
15 occurred smoothly using potassium carbonate in metha-
nol (94%). The triple bond in 15 could be reduced smoothly
to allyl alcohol 16 by using conventional conditions (LiAlH4,
Et2O, 97%). Protection of the alcohol function in 14 as a
PMB ether was best undertaken using acidic conditions
(PPTs) with para-methoxybenzyl trichloroacetamidate,[22] as
anionic conditions (base and para-methoxybenzyl chloride)
appeared to give a product resulting from a Brook rear-
rangement.[23] Removal of the trimethylsilyl group in 17
(TBAF, THF, 95%) followed by hydrogenation over Lin-
dlarꢂs catalyst at temperatures below ꢀ68C gave alkene 19
in 94% yield. Overreduction of alkyne 18 was observed if
the reaction temperature for the hydrogenation warmed
above the specified temperature. With potential annulation
fragments 15, 16, 18 and 19 in hand, attention was turned on
ꢀ
the crucial carbon carbon bond forming reaction.
Cross-coupling experiments: The enol triflate function
within 12 is relatively hindered, and we were concerned that
it would not react efficiently with an appropriate organome-
Chem. Eur. J. 2005, 11, 639 – 649
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
641

G. R. Dake and M. D. B. Fenster
tallic reagent under standard cross coupling conditions. To
test this notion with a small organometallic reagent, a Sono-
gashira-type coupling of alkyne 15 or 18 was initially at-
tempted in order to probe the sensitivity of the triflate to
cross-coupling conditions.[24] The results are summarized in
Equation (2) and Table 1.
pared with (1,1’-diphenylphosphineferrocene)palladium di-
chloride. The catalyst loadings could be reduced to 10 or
5 mol% without a substantial decrease in the effectiveness
of the process. Our concerns regarding the efficiency of the
cross-coupling with this hindered enol triflate appeared to
be warranted as no reaction was observed for this process
until the reaction was warmed to 608C, even when using the
Johnson–Braun conditions.
ꢀ
Setting the C5 stereochemistry: With the critical C4 C5
bond formed, the p-toluenesulfonyl and p-methoxybenzyl
groups in 22b were simultaneously cleaved by using lithium
metal in liquid ammonia to produce amine 24 in 83% yield
[Eq. (4)]. This deprotection sequence was reproducible and
occurred without complications,
in sharp contrast to the experi-
ence with ketone 9. Cyclodehy-
Table 1. Sonogashira coupling of 12 with Alkynes 15 or 18.
Entry Alkyne
NR3
Additive T [8C] Solvent atm Yield [%] 20[a] Yield [%] 12[a] Yield [%] 21[a]
dration occurred uneventfully
by using triphenylphosphine
and diethylazodicarboxylate to
generate tricycle 25 in 92%
yield.[29]
1
2
3
4
18
18
18
15
PrNH2
NEt3
NEt3
NEt3
none
TBAI
TBAI
TBAI
25
50
60
60
PhH
DMF
DMF
DMF
N2
N2
Ar
Ar
0
3
51
60
97
82
42
30
35
30
23
nd[b]
[a] Isolated yield. [b] nd=not determined.
Adjustment of reaction parameters such as solvent and
the inert atmosphere were crucial to obtain the desired
cross-coupling product 20. The isolated yields of the enyne
products were moderate even under optimized conditions.
A major difficulty was the dimerization of the terminal
alkyne under these conditions.[25] Although stringent precau-
tions were undertaken to exclude trace amounts of oxygen
from the reaction conditions, this side reaction could not be
avoided. The moderate yields of this cross-coupling process
combined with the requirement to reduce the alkyne func-
tionality at a later stage suggested that we attempt a more
direct approach. We were pleased to find that the enol tri-
flate function within 12 could be engaged in a cross-coupling
event, and thus we turned to a B-alkyl Suzuki-Miyaura
cross-coupling reaction as a suitable alternative.[26]
Allyl alcohol 16 was therefore hydroborated by using the
9-BBN dimer under the conditions defined by Shibasaki,[27]
and then the resulting organoborane was treated with 12
under cross-coupling conditions described by Johnson and
Braun using a catalytic amount of either tetrakis(triphenyl-
phosphine)palladium(0) or (1,1’-diphenylphosphineferroce-
ne)palladium dichloride [Eq. (3), Table 2, entries 1 and 2].[28]
The Johnson–Braun reaction conditions have been reported
to significantly accelerate Suzuki cross-coupling reactions,
allowing them to take place at room temperature. In these
reactions absolutely no cross-coupling product 22a was ob-
served-only alkene 23 was formed, presumably via a path in-
volving a b-hydride elimination reaction of an organopalla-
dium intermediate. Fortunately, repeating the above se-
quence with the PMB ether 19 as the alkene starting materi-
al resulted in the formation of the desired cross-coupling
product 22b in good yields (entries 3–7). Tetrakis(triphenyl-
phosphine) palladium(0) was an inferior precatalyst com-
Table 2. B-Alkyl Suzuki–Miyaura coupling of 12.
Entry
Substrate
Pd
Loading
[mol%]
Yield [%]
Yield [%]
source[a]
22[b]
23[b]
1
2
3
4
5
6
7
16
16
19
19
19
19
19
A
B
A
B
A
B
B
20
20
20
20
5
0
0
74
60
16
14
20
13
8
61
82
48
75
84
5
10
[a] A=Tetrakis(triphenylphosphine)palladium(0), B=(1,1’-diphenylphos-
phineferrocene)palladium dichloride. [b] Isolated yield.
In the Kibayashi approach, the reductive amination of 26
was initially used to form the tricyclic system of 1 (Sche-
me 5).[4a] These experiments resulted in the slight preferen-
tial formation of the undesired isomer 27. Considering this
result, we expected that hydrogenation of the alkenes within
642
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 639 – 649

Fasicularin
FULL PAPER
25 might also occur from the “bottom” face, thus setting the
trans-junction in the azadecalin system of 1. Unfortunately,
in the event, hydrogenation of 25 over palladium on carbon
generated a mixture of epimers (favoring the undesired
isomer). Similar results were obtained by using an analogue
in which the tert-butyldimethylsilyl ether was removed.
tivity, resulting in a 10.5:1 ratio of diastereomers favoring 29
in 76% isolated yield (entry 8). Hydrogenations with this
catalyst system in methanol and ethyl acetate were also at-
tempted, but these reactions generated significant amounts
of unknown by-products. The diastereoselectivity of those
reactions could not be determined as signals resulting from
1
these by-products complicated the H NMR spectrum of the
crude reaction mixtures.
Table 3. Hydrogenations of 24.
Entry
Catalyst
Loading
[mol%]
p
Solvent
Ratio
Yield
[%]
Scheme 5.
[atm]
29:30[a]
1
2
3
4
5
6
7
8
[(PPh3)3RhCl]
Crabtreeꢂs
RuO2
20
22
26
120
21
21
21
20
27
1
1
1
1
1
41
1
CH2Cl2
CH2Cl2
EtOH
EtOH
EtOH
c-C6H12
EtOH
EtOH
n/a[b]
n/a[b]
n/a[b]
2.3:1
4.7:1
n/a[b]
4.8:1
no rxn
no rxn
no rxn
nd[c]
Consideration of (Dreiding) molecular models suggested
an option (Figure 2). Although both faces of tricycle 25 may
be sterically encumbered, resulting in low diastereoselectivi-
ty in the hydrogenation reaction, a bicyclic system similar to
24 could occur preferentially from the “bottom” face. Spe-
cifically, the hexyl side that is projected below the plane of
the A–B decalin ring in 25 is not present in bicycle 24, open-
ing up its “bottom” face. In addition, a directing effect of
the amine nitrogen group could also result in preferred hy-
drogenation from the bottom face of the bicyclic ring system
in 24.[30]
PtO2
Pd/C
Pd/C
Pd/C
nd[c]
no rxn
nd[c]
Rh/C
10.5:1[d] 76%[e]
[a] Based on 1H NMR. [b] n/a=not applicable. [c] nd=not determined.
[d] Based on isolated yield. [e] Isolated yield.
Completion of the formal synthesis: With the stereochemis-
try at C-5 established, the cyclization of the A-ring was per-
formed as previously described (PPh3, DEAD) to obtain
31.[29] The removal of the tert-butyldimethylsilyl group re-
quired the use of TBAF in the presence of 4 ꢃ molecular
sieves, yielding 32 in 80% yield.[31] The sieves were a crucial
additive, as their omission led to the formation of a number
of uncharacterizable by-products. Attempts to invert the
stereochemistry of the secondary alcohol function within 32
using a Mitsunobu procedure was unsuccessful as a mixture
of inversion and retention products were obtained.[32] Thus,
oxidation using TPAP-NMO[33] followed by reduction using
lithium tri(sec-butyl)borohydride generated alcohol 33
(Scheme 6), a late stage intermediate in both the Kibayashi
and the Funk constructions of 1.[4a,b] Transformation of the
hydroxyl functional group to a thiocyanate moiety remained
to be done.[34]
This reaction sequence, as performed by Kibayashi and
Funk, produces 1 in a small amount (~20%) as the minor
component in a mixture of at least three compounds. An
elimination product and the isothiocyanate corresponding to
1 are also produced during this reaction sequence. In addi-
tion, this reaction sequence has been reported to be capri-
cious. Neither the Funk team nor our group could effective-
ly reproduce the conditions reported by Kibayashi (HSCN,
PPh3, DEAD, benzene) to convert 33 to 1. Funk had conse-
quently developed an alternate set of conditions to carry out
Figure 2.
A summary of hydrogenation screening experiments on
24 is presented in Equation (5) and Table 3. Somewhat sur-
prisingly, hydrogenations over Wilkinsonꢂs catalyst, Crab-
treeꢂs catalyst or ruthenium dioxide gave no reaction (en-
tries 1–3), possibly because of the ability of the amine in 24
to ligate and inactivate the metal catalyst. Hydrogenation
over platinum oxide (used in a stoichiometric amount) did
yield the desired diastereomer 29 in a modest ratio (2.3:1)
(entry 4). A catalytic reaction was possible by using palladi-
um-on-carbon in ethanol, although this reaction failed when
using cyclohexane as solvent (entries 5 and 6). The diaster-
eoselectivity of this process was slightly better (4.7:1), and
performing the reaction under higher pressures of hydrogen
did not improve matters significantly (entry 7). Fortunately,
the use of rhodium-on-carbon in ethanol gave the best selec-
Chem. Eur. J. 2005, 11, 639 – 649
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
643

G. R. Dake and M. D. B. Fenster
Experimental Section
General methods: All reactions were performed under a nitrogen atmos-
phere in flame-dried glassware. The glass syringes, Teflon cannulae and
stainless steel needles used for handling anhydrous solvents and reagents
were oven dried, cooled in a desiccator, and flushed with dry nitrogen
prior to use. Plastic syringes were flushed with dry nitrogen before use.
Thin-layer chromatography (TLC) was performed on DC-Fertigplatten
SIL G-25 UV254 pre-coated TLC plates. Melting points were performed
using a Mel-Temp II apparatus (Lab devices USA) and are uncorrected.
Optical rotations of samples were measured using either a Perkin–Elmer
model MC-241 or a Jasco model P1010 polarimeter. Infrared (IR) spectra
were obtained using a Perkin-Elmer 1710 FT-IR spectrometer. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded in deutero-
chloroform using either a Bruker WH-400, Bruker AV-400, or a Bruker
AV-300 spectrometer. Carbon nuclear magnetic resonance (13C NMR)
spectra were recorded in deuterochloroform using a Bruker AV-400 or a
Bruker AV-300 spectrometer. Chemical shifts are reported in parts per
million (ppm) and are referenced to the centerline of deuterochloroform
Scheme 6. a) PPh3 (3.3 equiv), CBr4 (3.3 equiv), NEt3 (3.3 equiv), CH2Cl2,
08C!RT, 5 h, 84%. b) TBAF (3.1 equiv), 4 ꢃ molecular sieves, CH2Cl2,
RT, 30 min, 82%. c) TPAP (11 mol%), NMO (1.4 equiv), 4 ꢃ molecular
sieves, CH2Cl2, RT, 2 h, 79%. d) LiHB(sBu)3 (1.7 equiv), THF, ꢀ788C,
1 h, 67%. e) MsCl (1.9 equiv), NEt3 (2.1 equiv), 4-DMAP (0.64 equiv),
CH2Cl2, 08C, 3.5 h, 84%.
1
(d 7.24 ppm H NMR; 77.0 ppm 13C NMR). Coupling constants (J values)
are given in Hertz (Hz). The carbon–fluoride coupling constants are rep-
resented as follows: JC,F. Low resolution mass spectra (LRMS) and high
resolution mass spectra (HRMS) were recorded on either a Kratos-AEI
model MS 50 spectrometer (for EI), a Kratos MS 80 spectrometer (for
CI or DCI), a Micromass LCT (for ESI), or a Bruker Esquire~LC (for
ESI). Microanalyses were performed by the Microanalytical Laboratory
at the University of British Columbia on a Carlo Erba Elemental Ana-
lyzer Model 1106 or a Fisions CHN-O Elemental Analyzer Model 1108.
All solvents and reagents were purified and dried using established pro-
cedures. Tetrahydrofuran and diethyl ether were distilled from sodium
and benzophenone. Dichloromethane, toluene, triethylamine, 2,6-lutidine,
trimethylsilyl trifluoromethanesulfonate were distilled from calcium hy-
dride under an atmosphere of dry nitrogen. N,N-Dimethylformamide
(DMF) was purified by drying over 4 ꢃ molecular sieves. Solutions of
methyllithium in diethyl ether, n-butyllithium in hexanes were obtained
from the Aldrich Chemical Co. and were standardized using the proce-
dure of Kofron and Baclawski.[36] All other reagents were commercially
available and were used without further purification.
this procedure. Following their method, alcohol 33 was con-
verted to mesylate 34. Although the reaction of 34 with tet-
rabutylammonium thiocyanate was attempted several times,
only minute amounts of 1 could be observed in the crude re-
action mixture. Despite our efforts using column chromatog-
raphy or high pressure liquid chromatography, we were
unable to obtain an analytically pure sample of 1. A useful
solution to this problem remains as a challenge to the syn-
thetic organic chemistry community.
Unlike the previous approaches, our approach, if complet-
ed, would have stood as the first asymmetric synthesis of 1.
Unfortunately, as original samples of 1 from the isolate are
no longer available and because optical rotation data of 1
was not acquired due to a lack of sample,[35] no data is avail-
able for comparison to synthetic material. For this reason,
we did not pursue other approaches to install the thiocya-
nate moiety in 1.
Epoxide 5: Excess dimethyldioxirane solution in acetone was added to
alcohol 3 (1.08 g, 2.39 mmol, 1.0 equiv) and potassium carbonate (3.40 g,
24.6 mmol, 10 equiv) until the reaction was complete by TLC. The mix-
ture was poured into a saturated solution of aqueous ammonium chlo-
ride, extracted with dichloromethane, and the combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was dissolved in THF (60 mL) and a solution of fresh-
ly distilled trimethylsilyl trifluoromethanesulfonate (720 mL, 3.97 mmol,
1.7 equiv) and 2,6-lutidine (720 mL, 6.22 mmol, 2.6 equiv) in THF
(60 mL) were added. The mixture was stirred at RT for 15 min. The or-
ganic layer was washed sequentially with a saturated solution of aqueous
sodium bicarbonate and a saturated solution of aqueous sodium chloride.
The organic layer was dried over magnesium sulfate, filtered and evapo-
rated in vacuo. Purification by column chromatography (ethyl acetate/
hexanes 1:15; 1% triethylamine) on silica gel afforded a white solid
(1.07 g, 83%). M.p. 94–958C (methanol/hexanes); [a]2D6 =ꢀ12.3 (c = 0.23
in CHCl3); 1H NMR (300 MHz, CDCl3): d = 7.90 (d, J=8.3 Hz, 2H),
7.28 (d, J=8.3 Hz, 2H), 3.39–3.19 (m, 1H), 3.29 (d, J=3.1 Hz, 2H), 2.70
(dd, J=13.4, 9.9 Hz, 1H), 2.40 (s, 3H), 2.25 (dd, J=15.6, 6.4 Hz, 1H),
2.16–2.00 (m, 1H), 1.97–1.83 (m, 2H), 1.81–1.68 (m, 3H), 1.67–1.53 (m,
3H), 0.75 (s, 9H), 0.16 (s, 9H), ꢀ0.20 (s, 6H); 13C NMR (75 MHz,
CDCl3): d = 143.8, 137.4, 129.6, 128.5, 86.0, 72.4, 63.0, 55.6, 51.1, 40.0,
35.9, 33.0, 25.6, 23.5, 21.8, 21.5, 17.8, 2.0, ꢀ5.0; IR (KBr): n˜ =2954, 2859,
Conclusion
The details of our synthetic approach towards 1 have been
presented. This approach differs markedly from earlier strat-
egies as a cycloaddition reaction was not used to install the
critical spirocyclic ring system. Key transformations in this
approach are a siloxy-epoxide semipinacol rearrangement, a
B-alkyl Suzuki–Miyaura reaction in a complex molecular
setting, and a substrate-directed hydrogenation reaction to
install the stereochemistry at C-5. The stereogenic centres in
our route (except for C-2) were established by stereochemi-
cal relay of the C-13 stereogenic center, which was derived
from the inexpensive chiral pool reagent, l-glutamic acid.
Approaches to other members of the cylindricine family
using this synthetic strategy are currently ongoing in our
laboratories.
1353, 1250, 1164, 839 cmꢀ1
;
elemental analysis calcd (%) for
C26H45NO5SSi2 (539.9): C 57.84, H 8.40, N 2.59; found: C 57.96, H 8.51, N
2.68.
Ketone 6: A 1.0m dichloromethane solution of titanium tetrachloride
(180 mL, 0.18 mmol, 1.1 equiv) was added at ꢀ788C to a solution of epox-
ide 5 (89 mg, 0.17 mmol, 1.0 equiv) in dichloromethane (8.0 mL). The
mixture was stirred at ꢀ788C for 0.5 h and then warmed to RT and
644
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 639 – 649

Fasicularin
FULL PAPER
poured into a saturated solution of sodium chloride. The two layers were
separated and the aqueous layer was extracted with dichloromethane.
The combined organic layers were dried over magnesium sulfate, filtered,
and concentrated by evaporation in vacuo. Purification by column chro-
matography (ethyl acetate/hexanes 1:3) on silica gel yielded a white solid
(10) as a white solid (8.8 mg, 65%). M.p. 56–578C (methanol); [a]2D5 =+
136 (c = 0.20 in CHCl3); H NMR (400 MHz, CDCl3): d = 5.95 (dd, J=
1
10.4, 1.5 Hz, 1H), 5.86 (dd, J=10.4, 2.9 Hz, 1H), 3.96–3.90 (m, 1H), 2.96
(dd, J=13.4, 4.6 Hz, 1H), 2.69 (dd, J=13.6, 6.3 Hz, 1H), 2.65–2.59 (m,
1H), 2.48–2.38 (m, 1H), 2.16–2.06 (m, 2H), 1.99–1.61 (m, 5H), 0.86 (s,
9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3): d = 210.8, 132.9, 130.4,
64.3, 64.0, 47.3, 40.9, 38.4, 27.8, 25.9, 21.4, 18.2, ꢀ4.6; IR (KBr): n˜ =3320,
(75 mg, 96%). M.p. 137–1388C (methanol); [a]2D6 =ꢀ8.6 (c
= 0.25 in
CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.83 (d, J=8.4 Hz, 2H), 7.30
(d, J=8.0 Hz, 2H), 4.13–4.00 (m, 1H), 4.04 (d, J=2.4 Hz, 1H), 3.58 (s,
1H), 3.32 (dd, J=12.0, 8.0 Hz, 1H), 3.06–2.86 (m, 2H), 2.64–2.53 (m,
1H), 2.52–2.44 (m, 1H), 2.41 (s, 3H), 2.10–1.97 (m, 2H), 1.88–1.54 (m,
5H), 0.81 (s, 9H), ꢀ0.04 (s, 3H), ꢀ0.06 (s, 3H); 13C NMR (75 MHz,
CDCl3): d = 209.9, 143.6, 137.6, 129.6, 127.7, 69.9, 69.5, 62.0, 47.7, 40.9,
35.1, 33.7, 26.9, 25.7, 21.5, 20.2, 17.9, ꢀ4.9; IR (KBr): n˜ =3505, 2941,
2929, 1708, 1454 cmꢀ1
; HRMS (CI, ammonia/methane): calcd for
C16H30NO2Si: 296.2046; found: 296.2046 [M+H]+.
Carbamate 11: 4-Dimethylaminopyridine (79.6 mg, 0.651 mmol,
3.1 equiv) was added in one portion followed by the addition of a so-
lution of di-tert-butylcarbonate (93.8 mg, 0.430 mmol, 2.1 equiv) in di-
chloromethane (5.0 mL) to
1.0 equiv) in dichloromethane (5.0 mL). The mixture was stirred at RT
for 0.5 h. saturated solution of aqueous sodium bicarbonate was
a solution of 10 (61.9 mg, 0.209 mmol,
2858, 1718, 1329, 1149 cmꢀ1
; elemental analysis calcd (%) for for
C23H37NO5SSi (467.7): C 59.07, H 7.97, N 2.99; found: C 59.29, H 8.09, N
3.09.
A
added. The two layers were separated and the aqueous layer was extract-
ed with dichloromethane. The combined organic layers were dried over
magnesium sulfate, filtered, and the solvent was evaporated in vacuo. Pu-
rification by column chromatography (ethyl acetate/hexanes 1:5) on silica
gel yielded a clear oil (85.1 mg, 93%). 1H NMR (400 MHz, CDCl3): d =
5.77 (d, J=10.7 Hz, 1H), 5.65 (dd, J=10.5, 2.3 Hz, 1H), 4.41–4.33 (m,
1H), 4.08 (ddd, J=13.1, 6.7, 0.9 Hz, 1H), 2.75 (dd, J=13.1, 9.5 Hz, 1H),
2.27 (ddd, J=14.5, 5.5, 3.4 Hz, 1H), 2.01–1.89 (m, 1H), 1.81–1.57 (m,
4H), 1.55–1.45 (m, 2H), 1.41 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s,
3H); 13C NMR (75 MHz, CDCl3): d = 154.8, 150.1, 134.1, 124.8, 106.7,
82.8, 62.8, 62.6, 43.3, 31.6, 27.5, 25.7, 18.0, 16.8, 15.4, ꢀ4.7, ꢀ4.8; IR
(NaCl): n˜ =2956, 1786, 1760 cmꢀ1; HRMS (CI, ammonia/methane): m/z:
calcd for C22H41N2O6Si: 457.2734; found: 457.2733 [M+H2O]+.
Methanesulfonic ester 8: Methanesulfonyl chloride (190 mL, 2.45 mmol,
2.4 equiv) was added to a solution of 6 (475 mg, 1.01 mmol, 1.0 equiv)
and 4-dimethylaminopyridine (499 mg, 4.08 mmol, 4.0 equiv) in dichloro-
methane (35 mL). The mixture was stirred at RT for 0.5 h and poured
into a saturated solution of sodium chloride. The two layers were separat-
ed and the aqueous layer was extracted with dichloromethane. The com-
bined organic layers were dried over magnesium sulfate, filtered, and
concentrated by evaporation in vacuo. Purification by column chromatog-
raphy (diethyl ether/petroleum ether 8:5) on silica gel yielded a foam
(527 mg, 87%). [a]2D5 =ꢀ19.7 (c = 0.19 in CHCl3); 1H NMR (400 MHz,
CDCl3): d = 7.85 (d, J=8.2 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 5.14–5.09
(m, 1H), 4.19–4.08 (m, 1H), 3.41 (dd, J=14.3, 5.2 Hz, 1H), 3.09 (s, 3H),
3.06 (dd, J=14.3, 9.5 Hz, 1H), 3.00–2.88 (m, 1H), 2.70–2.59 (m, 1H),
2.53–2.30 (m, 2H), 2.42 (s, 3H), 2.06–1.95 (m, 1H), 1.87–1.59 (m, 5H),
0.81 (s, 9H), ꢀ0.02 (s, 3H), ꢀ0.04 (s, 3H); 13C NMR (75 MHz, CDCl3): d
= 203.9, 143.7, 137.7, 129.7, 127.5, 69.9, 62.2, 48.0, 40.8, 39.1, 27.6, 25.6,
Enol trifluoromethanesulfonate 12: A 0.52m toluene solution of potassi-
um bis(trimethylsilyl)amide (265 mL, 0.138 mmol, 2.1 equiv) was added to
a cold (ꢀ788C) solution of 9 (29.3 mg, 0.0652 mmol, 1.0 equiv) in THF
(1.6 mL). The mixture was stirred at ꢀ788C for 0.75 h. A solution of N-
phenylbis(trifluoromethanesulfonimide) (52.5 mg, 0.147 mmol, 2.3 equiv)
in THF (1.6 mL) was added and the mixture was stirred at ꢀ788C for
1 h. The mixture was warmed to RT and poured into a saturated solution
of aqueous ammonium chloride. The two layers were separated and the
aqueous layer was extracted with diethyl ether. The combined organic
layers were dried over magnesium sulfate, filtered, and the solvent was
evaporated in vacuo. Purification by column chromatography (ethyl ace-
tate/hexanes 1:12; 1% triethylamine) on silica gel yielded a clear oil
21.4, 20.6, 17.8, ꢀ5.0; IR (KBr): n˜ =2955, 2859, 1720, 1338, 1178 cmꢀ1
;
HRMS (DCI+, ammonia/isobutane): m/z: calcd for C24H40NO7S2Si:
546.2015; found: 546.2017 [M+H]+.
Alkene 9: A solution of 8 (590 mg, 0.980 mmol, 1.0 equiv) and 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (4.0 mL, 26 mmol, 27 equiv) in toluene (40 mL)
was heated to reflux and stirred for 36 h. The mixture was cooled to RT
and poured into water. The two layers were separated and the aqueous
layer was extracted with diethyl ether. The combined organic layers were
dried over magnesium sulfate, filtered, and concentrated by evaporation
in vacuo. Purification by column chromatography (ethyl acetate/hexanes
1:5) on silica gel yielded a white solid (402 mg, 91%). M.p. 102–1038C
(36.4 mg, 96%). [a]2D2:6 =+99.6 (c
=
0.261 in CHCl3); 1H NMR
(400 MHz, CDCl3): d = 7.83 (d, J=8.5 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H),
5.91–5.88 (m, 1H), 5.86 (d, J=10.1 Hz, 1H), 5.63 (d, J=10.1, 2.0 Hz,
1H), 3.96–3.89 (m, 1H), 3.27 (ddd, J=12.2, 5.2, 1.2 Hz, 1H), 2.82 (dd,
J=12.2, 9.5 Hz, 1H), 2.63 (td, J=12.8, 3.7 Hz, 1H), 2.48–2.37 (m, 2H),
2.40 (s, 3H), 2.34–2.21 (m, 2H), 1.95–1.85 (m, 1H), 1.81–1.65 (m, 1H),
0.74 (s, 9H), ꢀ0.16 (s, 3H), ꢀ0.18 (s, 3H); 13C NMR (75 MHz, CDCl3): d
(ethyl acetate/hexanes); [a]2D4 =+65.4 (c
=
0.20 in CHCl3); 1H NMR
(400 MHz, CDCl3): d = 8.00 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H),
5.82 (dd, J=10.4, 1.8 Hz, 1H), 5.74 (d, J=10.5 Hz, 1H), 4.05–3.95 (m,
1H), 3.31 (ddd, J=12.2, 6.8, 1.0 Hz, 1H), 2.87 (dd, J=12.1, 8.8 Hz, 1H),
2.80–2.59 (m, 2H), 2.51–2.28 (m, 2H), 2.40 (s, 3H), 2.04–1.86 (m, 2H),
1.81–1.61 (m, 2H), 0.75 (s, 9H), ꢀ0.13 (s, 3H), ꢀ0.15 (s, 3H); 13C NMR
(75 MHz, CDCl3): d = 205.6, 143.6, 137.2, 132.5, 129.4, 128.3, 126.0, 68.8,
64.7, 46.8, 39.8, 37.0, 25.6, 23.6, 22.3, 21.5, 18.0, ꢀ5.1, ꢀ5.2; IR (KBr): n˜ =
2933, 1725, 1597, 1331, 1159 cmꢀ1; elemental analysis calcd (%) for
C23H35NO4SSi (449.7): C 61.33, H 7.84, N 3.11; found: C 61.47, H 7.84, N
3.29.
= 147.2, 144.0, 136.8, 134.4, 129.4, 128.7, 127.9, 120.6, 118.4 (q, JC,F
=
317 Hz), 64.4, 61.8, 47.2, 34.8, 25.6, 24.0, 21.5, 19.5, 18.0, ꢀ5.3; IR (CCl4):
n˜ =2931, 2859, 1416, 1337, 1164 cmꢀ1; elemental analysis calcd (%) for
C24H34F3NO6S2Si (581.7): C 49.55, H 5.89, N 2.41; found: C 49.89, H 6.18,
N 2.27.
(ꢀ)-(3S)-1-Trimethylsilylnon-1-yn-3-ol (14): To a solution of 1-trimethyl-
silylnon-1-yn-3-one (1.21 g, 5.75 mmol, 1.0 equiv) in isopropanol (55 mL)
was added (h6-p-cymene)[(1S,2S)-N-p-toluenesulfonyl 1,2-diphenylethey-
lenediamine]ruthenium(ii) (13) (64.1 mg, 0.107 mmol, 0.019 equiv) in one
portion and the mixture was stirred at RT for 9.5 h. Subsequently addi-
tional amounts of 13 were added, each in one portion and the mixture
was stirred for the respective period: Compound 13 (57.6 mg,
0.0960 mmol, 0.017 equiv) for 22.5 h; compound 13 (75.4 mg, 0.126 mmol,
0.022 equiv) for 25 h; compound 13 (57.4 mg, 0.0957 mmol, 0.017 equiv)
for 45.5 h; compound 13 (78.0 mg, 0.130 mmol, 0.023 equiv) for 55 h;
compound 13 (84.1 mg, 0.0140 mmol, 0.024 equiv) stirred for another
48 h. The solvent was removed by evaporation in vacuo. Purification by
column chromatography (diethyl ether/petroleum ether 1:12) on silica gel
gave a pale yellow oil (1.15 g, 94%). [a]1D9:9 =ꢀ0.19 (c = 1.28 in CHCl3);
1H NMR (400 MHz, CDCl3): d = 4.31 (dd, J=12.2, 6.7 Hz, 1H), 1.95 (d,
J=5.8 Hz, 1H), 1.73–1.57 (m, 2H), 1.47–1.35 (m, 2H), 1.34–1.20 (m,
Amine 10: Lithium (23 mg, 3.3 mmol, 72 equiv) was washed three times
with HPLC grade pentane and dissolved in ammonia (8.0 mL) at ꢀ788C.
A solution of 9 (20.8 mg, 0.046 mmol, 1.0 equiv) in THF (8.0 mL) was
added. The mixture was stirred at ꢀ788C for 5 min and quenched by the
cautious dropwise addition of ethanol. A saturated solution of aqueous
ammonia chloride was added and the mixture was allowed to warm to
RT while open to the atmosphere to allow the ammonia to evaporate.
The two layers were separated and the aqueous layer was extracted with
diethyl ether. The combined organic layers were dried over magnesium
sulfate, filtered, and the solvent was evaporated in vacuo. Purification by
column chromatography (ethyl acetate/hexanes 1:5) on silica gel yielded
(+)-(3S,6R)-3-(tert-butyldimethylsilyloxy)-1-(toluene-4-sulfonyl)-1-aza-
spiro[5.5]undec-4-en-7-one (9) as
a white solid (3.7 mg, 18%) and
(+)-(3S,6R)-3-(tert-butyldimethylsilyloxy)-1-azaspiro[5.5]undec-4-en-7-one
Chem. Eur. J. 2005, 11, 639 – 649
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
645

G. R. Dake and M. D. B. Fenster
6H), 0.85 (t, J=6.7 Hz, 3H), 0.13 (s, 9H); 13C NMR (75 MHz, CDCl3):
d = 107.0, 89.2, 62.9, 62.8, 37.7, 31.7, 28.8, 25.0, 22.5, 14.0, 0.20, ꢀ0.17,
ꢀ0.51; IR (NaCl): n˜ =3338, 2932, 2860, 2173 cmꢀ1; elemental analysis
calcd (%) for C12H24OSi (212.4): C 67.86, H 11.39; found: C 67.56, H
11.66.
55.1, 35.6, 31.7, 28.9, 28.9, 25.1, 22.5, 14.0; IR (NaCl): n˜ =3293, 2931,
2859, 1613, 1515, 1249 cmꢀ1; elemental analysis calcd (%) for C17H24O2
(260.4): C 78.42, H 9.29; found: C 78.29, H 9.63.
(ꢀ)-(1S)-1-Methoxy-4-(1-vinylheptyloxymethyl)-benzene (19): (ꢀ)-(1S)-
1-(1-Ethynylheptyloxymethyl)-4-methoxybenzene
(18)
(229 mg,
(3S)-Non-1-yn-3-ol (15): A solution of (ꢀ)-(3S)-1-trimethylsilylnon-1-yn-
3-ol (14) (419 mg, 1.97 mmol, 1.0 equiv) and potassium carbonate
(823 mg, 5.95 mmol, 3.0 equiv) in methanol (40 mL) was stirred at RT for
5 h and then poured into a saturated solution of aqueous sodium chloride
and extracted with diethyl ether. The combined organic layers were dried
over magnesium sulfate, filtered, and the solvent was evaporated in
vacuo. Purification by column chromatography (diethyl ether/petroleum
ether 2:11) on silica gel afforded a pale yellow oil (261 mg, 94%).
1H NMR (400 MHz, CDCl3): d = 4.34 (t, J=6.2 Hz, 1H), 2.43 (d, J=
2.1 Hz, 1H), 1.89 (brs, 1H), 1.73–1.64 (m, 2H), 1.48–1.38 (m, 2H), 1.35–
1.22 (m, 6H), 0.86 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d =
85.0, 72.8, 62.3, 37.6, 31.7, 28.9, 24.9, 22.5, 14.0; IR (KBr): n˜ =3379, 3311,
0.879 mmol, 1.0 equiv) and Pd/C 5 wt% on calcium carbonate (209 mg,
0.0982 mmol, 0.11 equiv) were dissolved in ethanol (40 mL). Quinoline
(810 mL, 6.84 mmol, 7.8 equiv) was added and the mixture was cooled to
ꢀ68C. One atmosphere of hydrogen was introduced and the mixture was
stirred at ꢀ68C for 1.75 h. The suspension was filtered through Celite
and the solvent was removed by evaporation in vacuo. Purification by
column chromatography (ethyl acetate/hexanes 1:20) on silica gel yielded
a pale yellow oil (214 mg, 93%). [a]2D2:0 =ꢀ36.08 (c = 0.203 in CHCl3);
1H NMR (400 MHz, CDCl3): d = 7.25 (d, J=8.7 Hz, 2H), 6.87 (d, J=
8.7 Hz, 2H), 5.73 (ddd, J=17.1, 10.7, 7.6 Hz, 1H), 5.21 (d, J=2.4 Hz,
1H), 5.18 (dd, J=10.7, 1.1 Hz, 1H), 4.52 (d, J=11.6 Hz, 1H), 4.28 (d, J=
11.6 Hz, 1H), 3.79 (s, 3H), 3.73–3.66 (m, 1H), 1.69–1.58 (m, 1H), 1.53–
1.20 (m, 9H), 0.88 (t, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d =
159.0, 139.4, 131.0, 129.2, 116.7, 113.7, 80.2, 69.6, 55.2, 35.5, 31.8, 29.2,
25.3, 22.6, 14.0; IR (NaCl): n˜ =3076, 2932, 2859, 1615, 1466, 1041,
927 cmꢀ1. HRMS (EI): calcd for C17H26O2: 262.1933; found: 262.1938.
2929, 2859 cmꢀ1
.
(3S)-Non-1-en-3-ol (16): Lithium aluminum hydride (550 mg, 14.5 mmol,
5.1 equiv) was added in three portions with 10 min intervals to a cold
(08C) solution of (3S)-non-1-yn-3-ol (15) (400 mg, 2.85 mmol, 1.0 equiv)
in diethyl ether (40 mL). The mixture was warmed to RT and allowed to
stir for 10 d. The mixture was cooled to 08C and quenched by cautious
addition of water (2.2 mL). Magnesium sulfate was added and the mix-
ture was stirred at RT for 1 h. The mixture was filtered and the solvent
was evaporated in vacuo to afford a clear oil (393 mg, 97%). 1H NMR
(400 MHz, CDCl3): d = 5.85 (ddd, J=17, 11, 6.0 Hz, 1H), 5.19 (d, J=
17 Hz, 1H), 5.07 (d, J=11 Hz, 1H), 4.19–3.95 (m, 1H), 1.78–0.99 (m,
11H), 0.85 (t, J=7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 141.4,
114.4, 73.2, 37.0, 31.7, 29.2, 25.2, 22.5, 14.0; IR (NaCl): n˜ =3352, 2929,
Alkene 22b: DMF and water were degassed for 15 min prior to use by
sparging with nitrogen gas. To a solution of (ꢀ)-(1S)-1-methoxy-4-(1-vi-
nylheptyloxymethyl)-benzene (19) (706 mg, 2.69 mmol, 1.3 equiv) in THF
(18 mL) was added 9-borabicyclo[3.3.1]nonane dimer (2.07 g, 8.48 mmol,
4.1 equiv) and the mixture was stirred at RT for 1 h. Water (665 mL,
36.8 mmol, 17.7 equiv) was added and the mixture was stirred at RT for
1 h. To a round bottom containing dichloro[1,1’-bis(diphenylphosphino)-
ferrocene]palladium(ii) dichloromethane adduct (170 mg, 0.208 mmol,
0.10 equiv), triphenylarsine (66.5 mg, 0.217 mmol, 0.10 equiv), potassium
bromide (293 mg, 2.46 mmol, 1.2 equiv), and cesium carbonate (1.37 mg,
4.20 mmol, 2.0 equiv) was added a solution of 12 (1.21 g, 2.08 mmol,
1.0 equiv) in DMF (18 mL).
1644 cmꢀ1
(ꢀ)-(3S)-[3-(4-Methoxybenzyloxy)-non-1-ynyl]-trimethylsilane (17):
.
A
solution of 4-methoxybenzyl trichloroacetimidate (764 mg, 2.70 mmol,
1.6 equiv) in dichloromethane (25 mL) was added to a solution of (ꢀ)-
(3S)-1-trimethylsilylnon-1-yn-3-ol (14) (353 mg, 1.66 mmol, 1.0 equiv) in
dichloromethane (50 mL). Pyridium p-toluenesulfonate (130 mg,
0.517 mmol, 0.31 equiv) was added in one portion and the mixture was
stirred at RT for 46 h. The mixture was poured into a saturated solution
of aqueous sodium bicarbonate. The two layers were separated and the
aqueous layer was extracted with dichloromethane. The combined organ-
ic layers were dried over magnesium sulfate, filtered, and concentrated
by evaporation in vacuo. Purification by column chromatography (diethyl
ether/petroleum ether 1:12) on silica gel yielded the starting material as a
To this mixture was added the borane solution. The resulting dark red so-
lution was stirred at 608C for 14 h. The mixture was cooled to RT and
poured into a solution of diethyl ether. The organic layer was washed se-
quentially with water and a saturated solution of aqueous sodium chlo-
ride. The organic layer was dried over magnesium sulfate, filtered, and
the solvent was evaporated in vacuo. Purification by column chromatog-
raphy (ethyl acetate/hexanes 1:15) afforded a clear oil (1.22 g, 84%).
[a]2D0:5 =+100.7 (c = 0.212 in CHCl3); 1H NMR (400 MHz, CDCl3): d =
7.78 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.9 Hz, 2H),
6.84–6.78 (m, 2H), 5.64–5.56 (m, 2H), 5.53 (dd, J=10.2, 1.7 Hz, 1H),
4.42 (dd, J=18.3, 11.3 Hz, 2H), 4.11–4.04 (m, 1H), 3.76 (s, 3H), 3.46–
3.34 (m, 2H), 2.81 (dd, J=11.9, 9.2 Hz, 1H), 2.49–1.96 (m, 6H), 2.36 (s,
3H), 1.91–1.20 (m, 14H), 0.86 (t, J=6.7 Hz, 3H), 0.78 (s, 9H), ꢀ0.10 (s,
3H), ꢀ0.11 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 159.0, 143.2, 140.0,
137.8, 134.0, 131.4, 129.4, 129.2, 127.7, 122.8, 113.7, 78.8, 70.2, 65.3, 64.2,
55.2, 48.1, 34.0, 33.3, 32.6, 31.9, 29.6, 26.3, 25.7, 25.5, 24.9, 22.7, 21.4, 20.0,
18.1, 14.1, ꢀ4.9, ꢀ5.0; IR (CCl4): n˜ =2931, 2859, 1332, 1162 cmꢀ1; LRMS
(CI, ammonia): m/z (%): 696 (8) [M+H]+.
pale yellow oil (88.8 mg, 25%) and a clear oil (405 mg, 73%). [a]D19:9
=
ꢀ118.07 (c = 2.48 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.27 (d,
J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 4.70 (d, J=11.6 Hz, 1H), 4.43
(d, J=11.6 Hz, 1H), 4.02 (t, J=6.6 Hz, 1H), 3.79 (s, 3H), 1.78–1.61 (m,
2H), 1.48–1.36 (m, 2H), 1.30–1.21 (m, 6H), 0.86 (t, J=6.7 Hz, 3H), 0.19
(s, 9H); 13C NMR (75 MHz, CDCl3): d
= 159.2, 130.2, 129.6, 113.7,
105.2, 90.3, 70.0, 68.7, 55.1, 35.6, 31.7, 28.9, 25.2, 22.5, 14.0, 0.0; IR
(NaCl): n˜ =2956, 2859, 2168, 1613, 1515, 1250 cmꢀ1; elemental analysis
calcd (%) for C20H32O2Si (332.6): C 72.23, H 9.70; found: C 72.27, H
9.94.
Alkene 23: DMF and water were degassed for 15 min prior to use by
sparging with nitrogen gas. To (3S)-non-1-en-3-ol (16) (11.5 mg,
0.0866 mmol, 1.9 equiv) in THF (0.6 mL) was added 9-borabicyclo[3.3.1]-
nonane dimer (62.7 mg, 0.257 mmol, 6.2 equiv) and the mixture was stir-
red at RT for 1 h. Water (15 mL, 0.830 mmol, 20 equiv) was added via sy-
ringe and the mixture was stirred for 1 h. To a round bottom containing
dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium(ii) dichlorome-
thane adduct (6.8 mg, 0.0083 mmol, 0.20 equiv), triphenylarsine (2.5 mg,
0.0082 mmol, 0.20 equiv), potassium bromide (6.4 mg, 0.0538 mmol,
1.3 equiv), and cesium carbonate (28.2 mg, 0.0866 mmol, 2.1 equiv) was
added a solution of 12 (1.21 g, 2.08 mmol, 1.0 equiv) in DMF (0.3 mL).
(ꢀ)-(1S)-1-(1-Ethynylheptyloxymethyl)-4-methoxybenzene (18): Tetrabu-
tylammonium fluoride (1.40 mL, 1.40 mmol, 1.1 equiv) was added to a so-
lution of (ꢀ)-(3S)-[3-(4-methoxybenzyloxy)-non-1-ynyl]-trimethylsilane
(17) (405 mg, 1.22 mmol, 1.0 equiv) in THF (50 mL). The mixture was
stirred at RT for 15 min and then poured into water. The two layers were
separated and the aqueous layer was extracted with diethyl ether. The
combined organic layers were dried over magnesium sulfate, filtered, and
concentrated by evaporation in vacuo. Purification by column chromatog-
raphy (diethyl ether/petroleum ether 1:30) on silica gel yielded a clear oil
(301 mg, 95%). [a]2D2:4 =ꢀ110.22 (c
=
0.230 in CHCl3); 1H NMR
To this mixture was added the borane solution. The resulting dark red so-
lution was stirred at 608C for 16 h. The mixture was cooled to RT and
poured into a solution of diethyl ether. The organic layer was washed se-
quentially with water and a saturated solution of aqueous sodium chlo-
ride. The organic layer was dried over magnesium sulfate, filtered, and
the solvent was evaporated in vacuo. Purification by column chromatog-
(400 MHz, CDCl3): d = 7.27 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H),
4.71 (d, J=11.3 Hz, 1H), 4.42 (d, J=11.3 Hz, 1H), 4.02 (td, J=6.6,
2.1 Hz, 1H), 3.78 (s, 3H), 2.43 (d, J=2.1 Hz, 1H), 1.80–1.63 (m, 2H),
1.47–1.37 (m, 2H), 1.33–1.21 (m, 6H), 0.85 (t, J=6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d = 159.2, 129.9, 129.5, 113.7, 83.1, 73.6, 70.0, 68.0,
646
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 639 – 649

Fasicularin
FULL PAPER
raphy (ethyl acetate/hexanes 1:15) afforded a clear oil (10.8 mg, 60%).
[a]2D6:5 =+66.9 (c = 0.187 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
7.71 (d, J=8.2 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 5.79–5.73 (m, 1H), 5.57–
5.50 (m, 3H), 4.09 (dd, J=9.2, 5.5 Hz, 1H), 3.82 (dd, J=12.8, 5.5 Hz,
1H), 2.93 (dd, J=12.8, 9.2 Hz, 1H), 2.39 (s, 3H), 2.21 (ddd, J=12.8, 11.9,
3.7 Hz, 1H), 2.12–2.01 (m, 1H), 2.00–1.88 (m, 2H), 1.78–1.68 (m, 1H),
1.67–1.53 (m, 1H); 13C NMR (75 MHz, CDCl3): d = 142.9, 139.6, 133.7,
130.3, 129.3, 128.8, 128.1, 127.4, 65.1, 60.4, 47.6, 32.6, 25.7, 24.1, 21.4, 19.7,
18.1, ꢀ4.8, ꢀ4.9; IR (KBr): n˜ =2931, 2859, 1340, 1163 cmꢀ1; LRMS (CI,
ammonia): m/z (%): 434 (49) [M+H]+.
Compound 30: [a]2D0:4 =ꢀ22.37 (c
=
0.152 in CHCl3); 1H NMR
(400 MHz, CDCl3): d
= 3.57–3.47 (m, 2H), 2.77 (ddd, J=12.2, 4.6,
1.2 Hz, 1H), 2.55 (dd, J=12.2, 8.9 Hz, 1H), 2.09–1.99 (m, 1H), 1.82–1.65
(m, 3H), 1.63–1.15 (m, 20H), 1.06–0.96 (m, 3H), 0.87–0.83 (m, 12H),
0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 72.6, 69.3,
52.6, 47.6, 44.3, 37.5, 36.8, 32.5, 31.8, 30.6, 29.7, 29.4, 26.8, 25.9, 25.6, 24.3,
22.6, 21.2, 18.1, 14.1, ꢀ4.6; IR (CCl4): n˜ =3628, 3368, 2859 cmꢀ1; HRMS
(EI): m/z: calcd for C25H51NO2Si: 425.3689; found: 425.3697.
Amine 31: To a cold (08C) solution of (+)-(3S)-1-[(3S,6R,7R)-3-(tert-bu-
tyldimethylsilyloxy)-1-azaspiro[5.5]undec-7-yl]-nonan-3-ol (29) (36.7 mg,
0.0862 mmol, 1.0 equiv) and triphenylphosphine (74.6 mg, 0.284 mmol,
3.3 equiv) in dichloromethane (2.5 mL) was added carbon tetrabromide
(94.3 mg, 0.284 mmol, 3.3 equiv) followed by the addition of triethyl-
amine (40 mL, 0.287 mmol, 3.3 equiv). The pale yellow solution was al-
lowed to warm to RT and stirred for 5 h. The solvent was removed by
evaporation in vacuo. Purification by column chromatography (diethyl
ether/petroleum ether 1:4; 2% ammonium hydroxide) on silica gel af-
forded a clear oil (29.6 mg, 84%). [a]2D0:8 =+4.51 (c = 0.265 in CHCl3);
1H NMR (400 MHz, CDCl3): d=3.95–3.86 (m, 1H), 2.97–2.82 (m, 3H),
2.63 (d, J=13.1 Hz, 1H), 1.84–1.47 (m, 1H), 1.40–1.10 (m, 17H), 1.03–
0.93 (m, 1H), 0.86 (s, 12H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3):
d=62.5, 56.6, 53.5, 47.3, 45.9, 34.5, 34.2, 32.6, 31.8, 30.0, 29.9, 29.8, 27.2,
26.2, 25.9, 25.4, 22.8, 22.6, 18.2, 17.5, 14.1, ꢀ4.6; IR (CCl4): n˜ =2929, 2860,
1464, 1092 cmꢀ1; HRMS (EI): m/z: calcd for C25H49NOSi: 407.3583;
found: 407.3579.
Amine 24: Lithium (12.9 mg, 1.86 mmol, 29 equiv) was washed three
times with HPLC grade pentane and dissolved in ammonia (10 mL) at
ꢀ788C. A solution of 22b (44.4 mg, 0.0638 mmol, 1.0 equiv) in THF
(3.0 mL) was added. The mixture was stirred for 10 min at ꢀ788C and
quenched by the dropwise addition of methanol. A saturated solution of
aqueous ammonia chloride was added and the mixture was allowed to
warm to RT while open to the atmosphere to allow the ammonia to evap-
orate. The two layers were separated and the aqueous layer was extract-
ed with diethyl ether. The combined organic layers were dried over mag-
nesium sulfate, filtered, and the solvent was evaporated in vacuo. Purifi-
cation by column chromatography (diethyl ether/petroleum ether 1:2) on
silica gel yielded a clear oil (22.4 mg, 83%). [a]1D9:8 =+72.3 (c = 0.213 in
CHCl3); 1H NMR (400 MHz, CDCl3): d
= 5.67 (d, J=10.4 Hz, 1H),
5.60–5.55 (m, 1H), 5.25 (dd, J=10.4, 2.1 Hz, 1H), 4.33–4.26 (m, 1H),
3.52–3.42 (m, 1H), 2.99 (ddd, J=10.7, 5.8, 1.2 Hz, 1H), 2.66 (dd, J=10.7,
9.2 Hz, 1H), 2.14–1.87 (m, 6H), 1.69–1.61 (m, 1H), 1.60–1.49 (m, 1H),
1.47–1.18 (m, 12H), 0.86–0.81 (m, 3H), 0.84 (s, 9H), 0.04 (s, 3H), 0.03 (s,
3H); 13C NMR (75 MHz, CDCl3): d = 139.5, 134.0, 131.9, 125.3, 67.2,
65.8, 55.9, 46.3, 37.2, 36.6, 31.8, 31.8, 29.5, 26.0, 25.8, 25.4, 25.1, 22.6, 18.9,
18.0, 14.0, ꢀ4.6, ꢀ4.7; IR (CCl4): n˜ =3284, 2930, 2858, 1109 cmꢀ1; LRMS
(CI, ammonia): m/z (%): 422 (100) [M+H]+, 421 (8) [M]+.
Alcohol 32: A solution of silyl ether 31 (40.0 mg, 0.0981 mmol, 1.0 equiv)
in THF (5.0 mL) was added to a round bottom containing powdered acti-
vated 4 ꢃ molecular sieves (500 mg). Tetrabutylammonium fluoride, pre-
treated with 4 ꢃ molecular sieves, (300 mL, 0.300 mmol, 3.1 equiv) was
added and the mixture was stirred at RT for 0.5 h. The reaction was fil-
tered and the solvent removed by evaporation in vacuo. Purification by
gradient column chromatography (diethyl ether!diethyl ether/methanol
19:1; 2% ammonium hydroxide) afforded a white solid (23.7 mg, 82%).
Tricyclic amine 25: To a cold (08C) solution 24 (129 mg, 0.306 mmol,
1.0 equiv) and triphenylphosphine (160 mg, 0.612 mmol, 2.0 equiv) in di-
chloromethane (6.0 mL) was added carbon tetrabromide (203 mg,
0.612 mmol, 2.0 equiv) followed by the addition of triethylamine (85 mL,
0.610 mmol, 2.0 equiv). The pale yellow solution turned red as it was al-
lowed to warm to RT and stirred for 0.5 h. The solvent was removed by
evaporation in vacuo. Purification by column chromatography (diethyl
ether/petroleum ether 1:11) on silica gel afforded a pale yellow oil
M.p. 69–718C (ethyl acetate/hexanes); [a]2D0:3 =+4.2 (c
= 0.259 in
CHCl3); 1H NMR (400 MHz, CDCl3):d = 3.99–3.87 (m, 1H), 3.07 (ddd,
J=14.4, 4.6, 1.8 Hz, 1H), 2.90–2.80 (m, 2H), 2.57 (d, J=13.1 Hz, 1H),
1.95–1.47 (m, 8H), 1.41–0.96 (m, 18H), 0.85 (t, J=6.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d = 61.8, 56.7, 53.5, 47.1, 45.8, 34.5, 34.0, 32.5, 31.9,
29.9, 29.7, 27.1, 26.1, 25.5, 22.7, 22.6, 17.4, 14.1; IR (CCl4): n˜ =3084, 2925,
2860, 1469, 1083 cmꢀ1
.
(113 mg, 92%). [a]2D1:7 =+120.2 (c
=
0.205 in CHCl3); 1H NMR
Alcohol 33: A solution of alcohol 32 (22.9 mg, 0.0780 mmol, 1.0 equiv) in
dichloromethane (2.5 mL) was added to a round bottom containing pow-
dered activated 4 ꢃ molecular sieves (83 mg). Tetrapropylammonium
perruthenate (3.1 mg, 0.0088 mmol, 0.11 equiv) was added in one portion.
The mixture was cooled to 08C and 4-methylmorpholine N-oxide
(12.9 mg, 0.110 mmol, 1.4 equiv) was added in one portion. The mixture
was warmed to RT, stirred for 2 h, filtered through Celite, and the solvent
was removed by evaporation in vacuo. Purification by column chroma-
tography (diethyl ether/hexanes 1:1) on silica gel afforded a clear oil
(400 MHz, CDCl3): d 5.77 (dd, J=10.4, 1.5 Hz, 1H), 5.68 (d, J=
=
10.4 Hz, 1H), 5.43–5.39 (m, 1H), 4.40–4.32 (m, 1H), 3.18 (ddd, J=14.4,
6.2, 1.0 Hz, 1H), 3.10 (dd, J=14.4, 9.9 Hz, 1H), 2.74–2.66 (m, 1H), 2.38–
2.30 (m, 1H), 2.06–1.88 (m, 4H), 1.77–1.58 (m, 5H), 1.54–1.08 (m, 10H),
0.90–0.84 (m, 12H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR
(75 MHz, CDCl3): d = 139.2, 16.5, 129.6, 122.1, 60.7, 57.9, 55.5, 47.7,
39.9, 34.3, 32.4, 32.1, 31.8, 29.9, 26.0, 25.3, 25.2, 22.6, 20.2, 18.3, 14.1, ꢀ4.5,
ꢀ4.6; IR (CCl4): n˜ =3084, 2931, 2859, 1519, 1250 cmꢀ1; LRMS (CI, am-
monia): m/z (%): 404 (100) [M+H]+, 403 (5) [M]+.
(18.0 mg, 79%). [a]2D1:2 =+102.6 (c
=
0.178 in CHCl3); 1H NMR
Alcohol 29: Alkene 24 (143.9 mg, 0.341 mmol, 1.0 equiv) and Rh/C 5
wt% on carbon (141 mg, 0.0684 mmol, 0.20 equiv) were dissolved in eth-
anol (17 mL). The mixture was stirred under 1 atm H2 at RT for 24 h.
The mixture was filtered through Celite and the solvent was removed by
evaporation in vacuo. Purification by gradient column chromatography
(ethyl acetate/hexanes 1:2 ! ethyl acetate) on silica gel afforded (ꢀ)-
(3S)-1-[(3S,6R,7S)-3-(tert-butyldimethylsilyloxy)-1-azaspiro[5.5]undec-7-
(400 MHz, CDCl3): d=3.95–3.86 (m, 1H), 2.97–2.82 (m, 3H), 2.63 (d, J=
13.1 Hz, 1H), 1.84–1.47 (m, 1H), 1.40–1.10 (m, 17H), 1.03–0.93 (m, 1H),
0.86 (s, 12H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3): d=213.3, 56.5,
54.8, 53.6, 45.1, 35.8, 34.1, 33.8, 32.2, 31.8, 29.7, 26.8, 25.9, 24.7, 23.2, 22.6,
20.1, 14.0; IR (CCl4): n˜ =2931, 2861, 1719 cmꢀ1
To
.
a
cold (ꢀ788C) solution of (+)-(1R,7R,10R)-7-hexyl-6-azatricy-
clo[8.4.0.01,6]tetradecan-4-one (11.2 mg, 0.0384 mmol, 1.0 equiv) in THF
(1.9 mL) was added l-Selectride (25 mL, 0.0250 mmol, 1.7 equiv) and the
mixture was stirred at ꢀ788C for 1 h. 3n Sodium hydroxide (0.48 mL)
was added followed by the addition of 30% hydrogen peroxide
(0.42 mL). The mixture was warmed to RT and poured into a saturated
solution of aqueous potassium sodium tartrate. The two layers were sepa-
rated and the aqueous layer was extracted with dichloromethane. The
combined organic layers were dried over magnesium sulfate, filtered, and
the solvent was evaporated in vacuo. Purification by gradient column
chromatography (diethyl ether/methanol 19:1! diethyl ether/methanol
9:1; 1% ammonium hydroxide) on silica gel yielded a clear oil (7.5 mg,
67%). 1H NMR (400 MHz, CDCl3): d=3.77 (s, 1H), 3.43–3.33 (m, 1H),
yl]-nonan-3-ol (30) as
a clear oil (9.6 mg, 6.6%) and (+)-(3S)-1-
[(3S,6R,7R)-3-(tert-butyldimethylsilyloxy)-1-azaspiro[5.5]undec-7-yl]-
nonan-3-ol (29) as a clear oil (99.7 mg, 69%).
Compound 29: [a]2D0:7 =+31.60 (c
=
0.201 in CHCl3); 1H NMR
(400 MHz, CDCl3): d 3.59–3.44 (m, 2H), 2.80 (ddd, J=11.6, 5.5,
=
4.9 Hz, 1H), 2.69 (dd, J=11.6, 10.1 Hz, 1H), 2.28–2.19 (m, 1H), 1.78–
1.51 (m, 6H), 1.48–0.82 (m, 32H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR
(75 MHz, CDCl3): d = 70.3, 69.9, 53.3, 48.0, 46.1, 37.6, 35.9, 32.6, 31.8,
29.8, 29.4, 28.3, 25.8, 25.3, 25.1, 24.6, 22.6, 18.1, 14.1, ꢀ4.6; IR (CCl4): n˜ =
3255, 3148, 2929, 2857, 1456, 1361, 1110 cmꢀ1; HRMS (EI): m/z: calcd for
C25H51NO2Si: 425.3689; found: 425.3691.
Chem. Eur. J. 2005, 11, 639 – 649
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
647

G. R. Dake and M. D. B. Fenster
3.19 (d, J=16.2 Hz, 1H), 3.09 (dd, J=16.2, 2.4 Hz, 1H), 2.39 (d, J=
11.9 Hz, 1H), 2.05 (dt, J=13.7, 3.9 Hz, 1H), 1.87 (tt, J=14.0, 3.9 Hz,
1H), 1.82–1.54 (m, 5H), 1.45–0.93 (m, 19H), 0.85 (t, J=6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=67.4, 57.0, 55.5, 46.6, 45.1, 34.9, 33.8,
32.7, 31.9, 30.3, 30.0, 29.4, 27.7, 27.2, 26.2, 25.2, 22.7, 14.1, 13.0.
b) H. Abe, S. Aoyagi, C. Kibayashi, Angew. Chem. 2002, 114, 3143–
3146; H. Abe, S. Aoyagi, C. Kibayashi, Angew. Chem. 2002, 114,
3143–3146; Angew. Chem. Int. Ed. 2002, 41, 3017–3020; c) P. Sun,
C. Sun, S. M. Weinreb, J. Org. Chem. 2002, 67, 4337–4345; d) P.
Sun, C. Sun, S. M. Weinreb, Org. Lett. 2001, 3, 3507–3510; e) T. J.
Greshock, R. L. Funk, Org. Lett. 2001, 3, 3511–3514; f) H. Abe, S.
Aoyogi, C. Kibayashi, Tetrahedron Lett. 2000, 41, 1205–1208;
g) K. M. Werner, J. M. De los Santos, S. M. Weinreb, M. Shang, J.
Org. Chem. 1999, 64, 4865–4873; h) W. H. Pearson, Y. Ren, J. Org.
Chem. 1999, 64, 688–689; i) K. M. Werner, J. M. De los Santos,
S. M. Weinreb, M. Shang, J. Org. Chem. 1999, 64, 686–687; j) W. H.
Pearson, N. S. Barta, J. W. Kampf, Tetrahedron Lett. 1997, 38, 3369–
3372; k) R. Hunter, P. Richards, Synlett 2003, 271–273; l) S. Canesi,
P. Belmont, D. Bouchu, L. Rousset, M. A. Ciufolini, Tetrahedron
Lett. 2002, 43, 5193–5195.
Mesylate 34: Triethylamine (10 mL, 0.0717 mmol, 2.1 equiv), 4-dimethyl-
aminopyridine (2.7 mg, 0.022 mmol, 0.64 equiv) were added in one por-
tion and methanesulfonyl chloride (5.0 mL, 0.065 mmol, 1.9 equiv) to a
cold (08C) solution of alcohol 33 (10.2 mg, 0.0348 mmol, 1.0 equiv) in di-
chloromethane (1.0 mL). The mixture was stirred at 08C for 3.5 h and
then poured into a saturated solution of aqueous sodium bicarbonate.
The two layers were separated and the aqueous layer was extracted with
dichloromethane. The combined organic layers were dried over magnesi-
um sulfate, filtered, and the solvent was evaporated in vacuo. Purification
by column chromatography (ethyl acetate/methanol 9:1) on silica gel
gave a pale yellow oil (10.8 mg, 84%). [a]1D9:4 =ꢀ13.0 (c
= 0.108 in
[8] For examples, see: a) T. Saito, T. Suzuki, M. Morimoto, C. Akiyama,
T. Ochiai, K. Takeuchi, T. Matsumoto, K. Suzuki, J. Am. Chem. Soc.
1998, 120, 11633–11644; b) J. Li, S. Jeong, L. Esser, P. G. Harran,
Angew. Chem. 2001, 113, 4901–4906; J. Li, S. Jeong, L. Esser, P. G.
Harran, Angew. Chem. 2001, 113, 4901–4906; Angew. Chem. Int.
Ed. 2001, 40, 4765–4769; c) K. D. Eom, J. V. Raman, H. Kim, J. K.
Cha, J. Am. Chem. Soc. 2003, 125, 5415–5421; d) Y. Kita, S. Kitaga-
ki, Y. Yoshida, S. Mihara, D.-F. Fang, M. Kondo, S. Okamoto, R.
Imai, S. Akai, H. Fujioka, J. Org. Chem. 1997, 62, 4991–4997.
[9] a) G. R. Dake, M. D. B. Fenster, P. B. Hurley, B. O. Patrick, J. Org.
Chem. 2004, 69, 5668–5675; b) G. R. Dake, M. D. B. Fenster, M.
Fleury, B. O. Patrick, J. Org. Chem. 2004, 69, 5676–5683.
CHCl3); 1H NMR (400 MHz, CDCl3): d=4.70 (s, 1H), 3.40 (d, J=
17.1 Hz, 1H), 3.23 (dd, J=16.8, 2.3 Hz, 1H), 3.20–3.12 (m, 1H), 2.97 (s,
3H), 2.32 (d, J=12.5 Hz, 1H), 2.10–1.93 (m, 3H), 1.80–1.55 (m, 4H),
1.48–0.95 (m, 19H), 0.85 (t, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=78.4, 56.6, 54.8, 46.4, 43.7, 38.4, 34.2, 33.7, 32.3, 32.0, 30.0, 29.2, 27.0,
26.1, 25.6, 24.9, 22.7, 14.1, 13.1; IR (CCl4): n˜ =2931, 2861, 1462,
1342 cmꢀ1
.
[10] C. Herdeis, Synthesis 1986, 232–233.
Acknowledgement
[11] a) K. Maruoka, M. Hasegawa, H. Yamamoto, K. Suzuki, M. Shima-
zaki, G.-i. Tsuchihashi, J. Am. Chem. Soc. 1986, 108, 3827–3829;
b) K. Suzuki, M. Shimazaki, G.-i. Tsuchihashi, Tetrahedron Lett.
1986, 27, 6237–6240; c) K. Suzuki, T. Matsumoto, K. Tomooka, K.
Matsumoto, G.-i. Tsuchihashi, Chem. Lett. 1987, 113–116; d) K.
Suzuki, M. Miyazawa, G.-i. Tsuchihashi, Tetrahedron Lett. 1987, 28,
3515–3518; e) M. Shimazaki, H. Hara, K. Suzuki, G.-i. Tsuchihashi,
Tetrahedron Lett. 1987, 28, 5891–5894; f) K. Suzuki, M. Miyazawa,
M. Shimasaki, G.-i. Tsuchihashi, Tetrahedron 1988, 44, 4061–4072;
g) M. Shimazaki, H. Hara, K. Suzuki, Tetrahedron Lett. 1989, 30,
5443–5446; h) M. Shimazaki, M. Morimoto, K. Suzuki, Tetrahedron
Lett. 1990, 31, 3335–3338; i) T. Nagasawa, K. Taya, M. Kitamura, K.
Suzuki, J. Am. Chem. Soc. 1996, 118, 8949–8950; see also: j) C. J.
Cheer, C. R. Johnson, J. Am. Chem. Soc. 1968, 90, 178–183.
[12] a) K. Maruoka, T. Ooi, H. Yamamoto, J. Am. Chem. Soc. 1989, 111,
6431–6432; b) K. Maruoka, S. Nagahara, T. Ooi, H. Yamamoto, Tet-
rahedron Lett. 1989, 30, 5607–5610; c) K. Maruoka, R. Bureau, H.
Yamamoto, Synlett 1991, 363–364; d) K. Maruoka, T. Ooi, S. Naga-
hara, H. Yamamoto, Tetrahedron 1991, 47, 6983–6998; e) K. Maruo-
ka, J. Sato, H. Yamamoto, J. Am. Chem. Soc. 1991, 113, 5449–5450;
f) K. Maruoka, T. Ooi, H. Yamamoto, Tetrahedron 1992, 48, 3303–
3312; g) K. Maruoka, J. Sato, H. Yamamoto, Tetrahedron 1992, 48,
3749–3762; h) T. Ooi, K. Maruoka, H. Yamamoto, Org. Synth. 1995,
72, 95–103; i) H. Nemoto, H. Ishibashi, M. Nagamochi, K. Fukumo-
to, J. Org. Chem. 1992, 57, 1707–1712; j) H. Nemoto, M. Nagamo-
chi, H. Ishibashi, K. Fukumoto, J. Org. Chem. 1994, 59, 74–79.
[13] a) M. E. Jung, D. C. DꢂAmico, J. Am. Chem. Soc. 1993, 115, 12208–
12209; b) M. E. Jung, D. C. D’Amico, J. Am. Chem. Soc. 1995, 117,
7379–7388; c) M. E. Jung, D. C. DꢂAmico, J. Am. Chem. Soc. 1997,
119, 12150–12158; d) M. E. Jung, R. Marquez, Org. Lett. 2000, 2,
1669–1672; e) M. E. Jung, W. S. Lee, D. Sun, Org. Lett. 1999, 1,
307–310; f) M. E. Jung, B. Hoffmann, B. Rausch, J.-M. Contreras,
Org. Lett. 2003, 5, 3159–3161; g) M. E. Jung, A. van den Heuvel,
Org. Lett. 2003, 5, 4705–4707; h) M. E. Jung, A. van den Heuvel,
A. G. Leach, K. N. Houk, Org. Lett. 2003, 5, 3375–3378.
The authors thank the University of British Columbia and the Natural
Science and Engineering Research Council (NSERC) of Canada for the
financial support of our programs. M.D.B. F. thanks the Gladys Estella
Laird Foundation for a Laird Fellowship and UBC for a McDowell
Award.
[1] A. D. Patil, A. J. Freyer, R. Reichwein, B. Carte, L. B. Killmer, L.
Faucette, R. K. Johnson, D. J. Faulkner, Tetrahedron Lett. 1997, 38,
363–364.
[2] W. K. Eng, L. Faucette, R. K. Johnson, R. Sternglanz, Mol. Pharma-
col. 1988, 34, 755–760.
[3] a) Lepadiformine: J. F. Biard, S. Goyut, C. Roussakis, J. F. Verbist, J.
Vercauteren, J. F. Weber, K. Boukef, Tetrahedron Lett. 1994, 35,
2691–2694; b) M. Juge, N. Grimaud, J. F. Biard, M. P. Sauviat, M.
Nabil, J. F. Verbist, J. Y. Petit, Toxicon 2001, 39, 1231–1237; c) cylin-
dricines A and B: A. J. Blackman, C. Li, D. C. R. Hockless, B. W.
Skelton, A. H. White, Tetrahedron 1993, 49, 8645–8656; d) cylindri-
cines C–G: C. Li, A. J. Blackman, Aust. J. Chem. 1994, 47, 1355–
1361; e) cylindricines H–K: C. Li, A. J. Blackman, Aust. J. Chem.
1995, 48, 955–965.
[4] Total and formal syntheses of 1, see: a) H. Abe, S. Aoyagi, C. Ki-
bayashi, J. Am. Chem. Soc. 2000, 122, 4583–4592; b) J.-H. Maeng,
R. L. Funk, Org. Lett. 2002, 4, 331–333; c) M. D. B. Fenster, G. R.
Dake, Org. Lett. 2003, 5, 4313–4316.
[5] For other synthetic approaches to 1, see: a) D. J. Wardrop, W. M.
Zhang, C. L. Landrie, Tetrahedron Lett. 2004, 45, 4229–4231; b) D. J.
Wardrop, M. S. Burge, W. Zhang, J. A. Ortiz, Tetrahedron Lett. 2003,
44, 2587–2591.
[6] For synthetic work on the cylindricines, see: a) J. F. Liu, C. H.
Heathcock, J. Org. Chem. 1999, 64, 8263–8266; b) G. A. Molander,
M. Rçnn, J. Org. Chem. 1999, 64, 5183–5187; c) B. B. Snider, T. Liu,
J. Org. Chem. 1997, 62, 5630–5633; d) B. M. Trost, M. T. Rudd, Org.
Lett. 2003, 5, 4599–4602; e) W. Oppolzer, C. G. Bochet, Tetrahe-
dron: Asymmetry 2000, 11, 4761–4770; f) S. Canesi, D. Bouchu,
M. A. Ciufolini, Angew. Chem. 2004, 116, 4436–4438; S. Canesi, D.
Bouchu, M. A. Ciufolini, Angew. Chem. 2004, 116, 4436–4438;
Angew. Chem. Int. Ed. 2004, 43, 4336–4338.
[14] a) C. M. Marson, A. J. Walker, J. Pickering, A. D. Hobson, R. Wrig-
glesworth, S. J. Edge, J. Org. Chem. 1993, 58, 5944–5951; b) C. M.
Marson, S. Harper, A. J. Walker, J. Pickering, J. Campbell, R. Wrig-
glesworth, S. J. Edge, Tetrahedron 1993, 49, 10339–10354; c) Y. Q.
Tu, L. D. Sun, P. Z. Wang, J. Org. Chem. 1999, 64, 629–633; d) C.-A.
Fan, B.-M. Wang, Y. Q. Tu, Z.-L. Song, Angew. Chem. 2001, 113,
[7] a) The synthetic work on lepadiformine has been nicely summar-
ized: S. M. Weinreb, Acc. Chem. Res. 2003, 36, 59–65; see also:
648
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 639 – 649

Fasicularin
FULL PAPER
3995–3998; C.-A. Fan, B.-M. Wang, Y. Q. Tu, Z.-L. Song, Angew.
641–643; e) R. ter Halle, A. Brꢇhꢇret, E. Schulz, C. Pinel, M. Lem-
aire, Tetrahedron: Asymmetry 1997, 8, 2101–2108; f) L. F. Tietze, Y.
Zhou, E. Tçpken, Eur. J. Org. Chem. 2000, 2247–2252.
[22] N. Nakajima, K. Horita, R. Abe, O. Yonemitsu, Tetrahedron Lett.
1988, 29, 4139–4142.
[23] a) A. G. Brook, J. Am. Chem. Soc. 1958, 80, 1886–1889; b) A. G.
Brook, C. M. Warner, M. E. McGriskin, J. Am. Chem. Soc. 1959, 81,
981–983; c) A. G. Brook, Acc. Chem. Res. 1974, 7, 77–84.
[24] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16,
4467–4470.
[25] C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422–424; for a recent
review: b) P. Siemsen, R. C. Livingston, F. Diederich, Angew. Chem.
2000, 112, 2740–2767; P. Siemsen, R. C. Livingston, F. Diederich,
Angew. Chem. 2000, 112, 2740–2767; Angew. Chem. Int. Ed. 2000,
39, 2632–2657.
[26] a) N. Miyaura, T. Ishiyama, M. Ishikawa, A. Suzuki, Tetrahedron
Lett. 1986, 27, 6369–6372; b) M. Miyaura, T. Ishiyama, H. Sasaki,
M. Ishikawa, M. Satoh, A. Suzuki, J. Am. Chem. Soc. 1989, 111,
314–321; c) T. Oh-e, N. Miyaura, A. Suzuki, J. Org. Chem. 1993, 58,
2201–2208; d) M. Sato, N. Miyaura, A. Suzuki, Chem. Lett. 1989,
1405–1408; For a recent review, see: e) S. R. Chemler, D. Trauner,
S. J. Danishefsky, Angew. Chem. 2001, 113, 4676–4701; S. R. Chem-
ler, D. Trauner, S. J. Danishefsky, Angew. Chem. 2001, 113, 4676–
4701; Angew. Chem. Int. Ed. 2001, 40, 4544–4568.
Chem. 2001, 113, 3995–3998; Angew. Chem. Int. Ed. 2001, 40, 3877–
3880; e) S. W. Baldwin, P. Chen, N. Nikolic, D. C. Westheimer, Org.
Lett. 2000, 2, 1193–1196; f) Y. Q. Tu, C. A. Fan, S. K. Ren, A. S. C.
Chan, J. Chem. Soc. Perkin Trans. 1 2000, 3791–3794; g) L. Petters-
son, T. Frejd, J. Chem. Soc. Perkin Trans. 1 2001, 789–800; h) J. F.
Bickley, B. Hauer, P. C. A. Pena, S. M. Roberts, J. Skidmore, J.
Chem. Soc. Perkin Trans. 1 2001, 1253–1255; i) F. Wang, Y. Q. Tu,
C. A. Fan, S. H. Wang, F. M. Zhang, Tetrahedron: Asymmetry 2002,
13, 395–398; j) C. M. Marson, A. Khan, R. A. Porter, A. J. A. Cobb,
Tetrahedron Lett. 2002, 43, 6637–6640; k) B. Hauer, J. F. Bickley, J.
Massue, P. C. A. Pena, S. M. Roberts, J. Skidmore, Can. J. Chem.
2002, 80, 546–550; l) C. M. Marson, C. A. Oare, J. McGregor, T.
Walsgrove, T. J. Grinter, H. Adams, Tetrahedron Lett. 2003, 44, 141–
143; m) C. A. Fan, X. D. Hu, Y. Q. Tu, B. M. Wang, Z. L. Song,
Chem. Eur. J. 2003, 9, 4301–4310; n) X. D. Hu, C. A. Fan, F. M.
Zhang, Y. Q. Tu, Angew. Chem. 2004, 116, 1734–1737; X. D. Hu,
C. A. Fan, F. M. Zhang, Y. Q. Tu, Angew. Chem. 2004, 116, 1734–
1737; Angew. Chem. Int. Ed. 2004, 43, 1702–1705; for reviews of a-
hydroxy epoxide reactions, see: o) G. Magnusson, Org. Prep.
Proced. 1990, 22, 547–574; p) B. Rickborn, in Comprehensive Or-
ganic Synthesis, Vol. 3 (Eds.: B. M. Trost, I. Fleming), Pergamon,
Oxford, 1991, pp. 733–775.
[15] M. D. B. Fenster, B. O. Patrick, G. R. Dake, Org. Lett. 2001, 3,
2109–2112.
[16] a) D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans. 1
1975, 1574–1585; b) M. J. Robins, J. S. Wilson, F. Hansske, J. Am.
Chem. Soc. 1983, 105, 4059–4065; c) D. H. R. Barton, J. C. Jaszbere-
nyi, Tetrahedron Lett. 1989, 30, 2619–2622.
[27] a) K. Kondo, M. Sodeoka, M. Shibasaki, Tetrahedron: Asymmetry
1995, 6, 2453–2464; b) K. Kondo, M. Sodeoka, M. Shibasaki, J. Org.
Chem. 1995, 60, 4322–4323.
[28] C. R. Johnson, M. P. Braun, J. Am. Chem. Soc. 1993, 115, 11014–
11015.
[17] a) T. N. Birkinshaw, A. B. Holmes, Tetrahedron Lett. 1987, 28, 813–
816; b) F. Chavez, A. D. Sherry, J. Org. Chem. 1989, 54, 2990–2992.
[18] a) A. Abad, D. Mellier, J. P. Pꢄte, C. Portella, Tetrahedron Lett.
1971, 12, 4555–4558; b) W. Yuan, K. Fearson, M. H. Gelb, J. Org.
Chem. 1989, 54, 906–910.
[29] a) Y. Shishido, C. Kibayashi, J. Org. Chem. 1992, 57, 2876–2883;
b) D. F. Taber, P. B. Deker, L. J. Silverberg, J. Org. Chem. 1992, 57,
5990–5994.
[30] A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307–
1370.
[19] C. H. Heathcock, K. M. Smith, T. A. Blumenkopf, J. Am. Chem.
Soc. 1986, 108, 5022–5024.
[31] H. C. Kolb, S. V. Ley, A. M. Z. Slawin, D. J. Williams, J. Chem. Soc.
Perkin Trans. 1 1992, 2735–2762.
[20] a) D. Boyall, F. Lꢅpez, H. Sasaki, D. Frantz, E. M. Carreira, Org.
Lett. 2000, 2, 4233–4236; b) D. E. Frantz, R. Fꢆssler, C. S. Tomooka,
E. M. Carreira, Acc. Chem. Res. 2000, 33, 373–381; c) D. E. Frantz,
R. Fꢆssler, E. M. Carreira, J. Am. Chem. Soc. 2000, 122, 1806–1807;
d) N. K. Anand, E. M. Carreira, J. Am. Chem. Soc. 2001, 123, 9687–
9688; e) H. Sasaki, D. Boyall, E. M. Carreira, Helv. Chim. Acta
2001, 84, 964–971; f) D. Boyall, D. E. Frantz, E. M. Carreira, Org.
Lett. 2002, 4, 2605–2606.
[21] a) K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori,
Angew. Chem. 1997, 109, 297–300; K.-J. Haack, S. Hashiguchi, A.
Fujii, T. Ikariya, R. Noyori, Angew. Chem. 1997, 109, 297–300;
Angew. Chem. Int. Ed. Engl. 1997, 36, 285–288; b) K. Matsumura,
S. Hashigushi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1997, 119,
8738–8739; for the preparation of the catalyst, see: c) M. A. Ben-
nett, T.-N. Huang, T. W. Matheson, A. K. Smith, Inorg. Synth. 1982,
21, 74–78; d) T. Oda, R. Irie, T. Katsuki, H. Okawa, Synlett 1992,
[32] C. Ahn, R. Correia, P. DeShong, J. Org. Chem. 2002, 67, 1751–1753.
[33] a) W. P. Griffith, S. V. Ley, G. P. Whitcombe, A. D. White, J. Chem.
Soc. Chem. Commun. 1987, 1625–1627; b) S. V. Ley, J. Norman,
W. P. Griffith, S. P. Marsden, Synthesis 1994, 639–666
[34] a) A. W. Erian, S. M. Sherif, Tetrahedron 1999, 55, 7957–8024;
b) L. A. Spurlock, G. W. Cox, J. Am. Chem. Soc. 1971, 93, 146–151;
c) Y. Tamura, T. Kawasaki, M. Adachi, M. Tanio, Y. Kita, Tetrahe-
dron Lett. 1977, 18, 4417–4420; d) J. Burski, J. Kieszkowski, J. Mi-
chalski, M. Pakulski, A. Skowronska, Tetrahedron 1983, 39, 4175–
4181; e) H.-R. Sliwka, S. Liaaen-Jensen, Tetrahedron: Asymmetry
1993, 4, 361–368.
[35] Personal communication with Drs. Patil and Freyer.
[36] W. G. Kofron, L. M Baclawski, J. Org. Chem. 1976, 41, 1879–1880.
Received: July 20, 2004
Published online: November 25, 2004
Chem. Eur. J. 2005, 11, 639 – 649
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
649