Cross-Metathesis Approach to the Tricyclic Marine Alkaloids (-)-Fasicularin and (-)-Lepadiformine A

Article abstract of DOI:10.1021/acs.joc.7b01135

A cross-metathesis protocol has been developed to provide facile access to highly hindered trisubstituted α-branched olefins, which when coupled with a cationic azaspirocyclization reaction, generates the marine alkaloids (-)-fasicularin 2 and a pro-forma synthesis of (-)-lepadiformine A 1.

Full text of DOI:10.1021/acs.joc.7b01135

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Article
A cross-metathesis approach to the tricyclic marine
alkaloids (-)-fasicularin and (-)-lepadiformine A
James Burnley, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01135 • Publication Date (Web): 11 Jul 2017
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A cross-metathesis approach to the tricyclic marine
alkaloids (-)-fasicularin and (-)-lepadiformine A
James Burnley,‡ Zhen J. Wang,‡ W. Roy Jackson, and Andrea J. Robinson*
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School of Chemistry, Monash University, Clayton, 3800, Victoria, Australia
Andrea.Robinson@monash.edu
Supporting Information Placeholder
A cross-metathesis protocol has been developed to provide facile access to highly hindered tri-substituted α-branched olefins,
which when coupled with a cationic aza-spirocyclisation reaction generates the marine alkaloids (-)-fasicularin 2 and a pro-forma
synthesis
of
(-)-lepadiformine
A
1.
often thwarted by unwanted homocoupled by-product
formation which is circumvented only by the use of
large excesses of reagents or by careful electronic or
steric tuning which may not always be applicable during
the course of a natural product synthesis.3 Some of these
issues have been addressed by employing our recently
disclosed CM protocol for sterically demanding olefins,
which gives rapid access to complex constructs bearing
an α-substituted methylene cyclohexane core.5 This,
coupled with acid promoted aza-spirocyclisation,6 deliv-
ers core architectures that are displayed by many alka-
INTRODUCTION
Olefin metathesis has featured as a key transformation in
natural product synthesis especially since its modern
inception in the early 1990s.1 Largely it appears in the
ring-closing metathesis guise (RCM),2 often utilized in
the late stage construction of large unsaturated macrocy-
cles. This is testament to the mild reaction conditions
employed, wide substrate tolerance and low by-product
formation when suitable conditions are applied.3 Cross-
metathesis (CM) however, is less utilised in the con-
struction of advanced intermediates4 even though a pri-
ori it is a highly attractive transformation that efficiently
couples two components and rapidly generates syntheti-
cally useful olefinic products. The application of CM is
loids
(-)-lepadiformine A 1, (-)-fasicularin 2, (+)-cyclindricine
and (-)-cephalotaxine (Figure 1A).
including
A
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Figure 1: (A) Selected examples of natural products with an aza-spirocyclic core, (B) accessible using the cross-metathesis/cationic cy-
clisation
methodology.
(-)-Lepadiformine A 1 and (-)-fasicularin 2 are spirocy-
clic marine alkaloids that have a rich history and their
highly appealing structures have attracted the interest of
the synthetic community for over two decades;7 as such
there are now many innovative and successful routes for
their synthesis.8,9,10 The key challenges facing our new
synthetic approach were i) development of a highly effi-
cient CM strategy with practical reagent stoichiometry,
and ii) the development of chemo- and diastereoselec-
tive conditions for the acid-mediated cyclisation (Figure
1). Subsequent elaboration of the appropriately func-
tionalised 1-azaspirocyclic core to (-)-lepadiformine A 1
involves deprotection, cyclodehydration and hydrogen-
olysis. To access (-)-fasicularin 2, a diastereomeric series
was required, in addition to [4.5]- to [5.5]-ring expan-
sion, to generate the spiropiperidine core.
ing the alcohol 10 in a concise number of chemical
transformations (Scheme 1).14 The intermediate 10
served as a point of divergence in this synthesis and
could be readily protected using benzoyl chloride under
basic conditions to give 11, or epimerized under
Mitsunobu’s conditions to give the diastereomeric ben-
zoyl ester 12, both in good yield (Scheme 1).15
Our previous studies had shown that CM of α-branched
1,1-disubstituted olefins are problematic due to for-
mation of nonproductive 1,3-metallocyclobutane inter-
mediates and homocoupled by-products.5 To overcome
this, we developed a steric reversal strategy, employing
prenylated cross-partners rather than allylated cross-
partners, to facilitate formation of the productive 1,2-
metallocyclobutane during the CM reaction. The result
was a significant increase in yield of the desired cross-
product. Therefore, we decided to adopt a similar strate-
gy in our synthesis of spirocyclic marine alkaloids 1 and
2 by using the prenylated cross-partner 15 (Scheme 2).
Synthesis of 15 began from the commercially available
(S)-allylglycine derivative 13. Suitable protection of the
primary alcohol and amine functionalities delivered the
tosylamide 14 in good yield. Prenylation to give 15 was
affected using isobutylene and Hoveyda-Grubbs second
generation catalyst.16
RESULTS AND DISCUSSION
Synthesis commenced with the construction of suitably
functionalised metathesis partners. The readily available
homochiral iodoalcohol 511 underwent smooth TBS pro-
tection under basic conditions with TBSOTf to give the
alkyl iodide 6 in excellent yield (Scheme 1). Next, reac-
tion of the protected iodide 6 with commercially availa-
ble allyl 2-oxocyclohexane-1-carboxylate 7 in DMF at
50 °C using Cs2CO3 gave the β-keto ester 8 in good
yield as an inconsequential mixture of diastereoiso-
mers.12 The resulting β-keto ester 8 was subjected to the
stereoselective, decarboxylative protonation protocol
developed by Stoltz et al..13 The β-keto ester 8 gave the
α-substituted ketone 9 in good yield, reasonable dia-
stereoselectivity (8:1), and was routinely prepared on a
gram scale. Wittig methenylation was effected using
Scheme 2: Synthesis of the chiral prenyl amine 15
methyltriphenylphosphonium
bromide
and
n-
butyllithium which proceeded in excellent yield, and
was followed by TBS deprotection with TBAF deliver-
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With both cross-partners in hand, we next explored the
tities of 16. Extending the reaction time to 3 days led to
key CM reaction. The conditions reported in our previ-
ous work required a large excess (30 equiv.) of the α-
branched cross-partner. Using these conditions, we were
able to deliver an excellent yield of tri-substituted olefin
16 (Table 1, entry 1). Although the cross-partner 11
could be recovered and recycled, it was considered to be
a major drawback to our methodology and we saw an
opportunity to seek conditions which required fewer
equivalents of 11.17 Unfortunately, halving the number of
equivalents of 11 led to a significant decrease in yield of
olefin 16 (Table 1, entry 2) and reducing the equivalents
to five (Table 1, entry 3) only provided negligible quan-
a 61% yield of olefin 16 (Table 1, entry 4) but this was
still considered to be unacceptable in terms of practicali-
ty. Eventually it was found that use of a higher catalyst
loading and intermediate reaction time led to syntheti-
cally useful yields of 16 with only two equivalents of 11
(Table 1, entries 5 and 6). These reaction conditions
were implemented at a 1 mmol scale (Table 1, entry 7)
which could also be applied to the S-epimer 17 (Table 1,
entry 8). Although the catalyst loading was high, it facil-
itated rapid, modular construction of the advanced target
intermediates 16 and 17 under relatively mild condi-
tions.
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Scheme 1. Construction of the methylene cyclohexane cross partners 11 and 12
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Table 1: Optimisation of key cross-metathesis reaction
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Entry
Metathesis
conditions5
Product
16
Yield
89
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After examining several conditions, selective deprotec-
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8
30 equiv. 11,
5 mol% HGII, 16 h5
15 equiv. 11,
tion of the tosylamide and benzoyl ester of 18 and 19
was effected with Na/Hg (10%) in methanol to give
amino alcohols 20 and 21 respectively in good yield
(Scheme 4). Annulation of the amino alcohol 20 was
effected using the Zhao modification8l,9o of the
Kibayashi8c cyclodehydration protocol to give the pro-
tected tricycle 22. Final hydrogenation of the benzyl
ether 22 and ring expansion of alcohol 23 under the
Mitsunobu protocol delivered (-)-fasicularin 2 in re-
spectable yield in 13 steps from readily available starting
materials. Difficulties were encountered obtaining inter-
pretable NMR spectra due to peak broadening of tricy-
cles 22 and 23 even when rigorous deacidification of
deuterated chloroform was carried out. However, clear
1H and 13C spectra for 2 were obtained in 5% KOH/d4-
methanol or d5-pyridine. The spectra of 18-22 showed
peaks at the same frequencies as those reported by
Kibayashi9c but clear resolution of multiplets varied with
solvent. The spectra of (-)-fasicularin in d5-pyridine was
identical in all aspects to those in the literature.10
45
16
5 mol% HGII, 16 h
5 equiv. 11,
15
16
5 mol% HGII, 16 h
5 equiv. 11,
61
16
5 mol% HGII, 72 h
2 equiv. 11,
73
16
25 mol% HGII, 48 h
2 equiv. 12,
67
17
25 mol% HGII, 48 h
Entry 5
70
16
1.64 mmol scale
Entry 6
74
17
1 mmol scale
The cyclisation conditions reported by us6 and Knight18
were examined using a catalytic quantity of triflic acid
(20 mol%) in both toluene and chloroform at room tem-
perature. This approach was only moderately successful
because the high reactivity of triflic acid resulted in de-
composition. After extensive optimisation it was found
that a 1:1 mixture of dry TFA and chloroform provided
the target spirocycles 18 and 19 in good yield (Scheme
3). The observed high diastereoselectivity presumably
arises from the pendent α-substituent directing facial-
selection during the carbocationic cyclisation, resulting
in a trans-relationship between the amide and the α-
substituent. This cationic 5-endo-trig cyclisation is rare-
ly applied to such complex systems19 and could lend
itself to more widespread use in the synthesis of spiro-
cyclic alkaloids.
Scheme 4: Synthesis of (-)-fasicularin 2
The epimeric alcohol 21 was also subjected to the same
cyclodehydration protocol to give the tricyclic benzyl
ether 24 which was followed by hydrogenolysis to give
(-)-lepadiformine A 1 in 12 steps from readily available
starting materials (Scheme 5).8c,8l Again problems were
encountered in obtaining clear spectra for 1 which was
in stark contrast to the behavior of its precursor 24
which generated a well resolved spectrum in 5%
KOH/d4-methanol. Because of the difficulties in obtain-
ing a pure sample we can only claim a formal synthesis
Scheme 3. Cationic cyclisation of tri-substituted olefins 16
and 17 leading to spirocycles 18 and 19.
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of (-)-lepadiformine A from the unambiguously charac-
terized precursor 24.
used as specified. Multiplicities are denoted as singlet
(s), doublet (d), triplet (t), quartet (q), apparent quintet,
multiplet (m) or prefixed broad (b), or a combination
where necessary.
Scheme 5. Formal synthesis of (-)-lepadiformine A 1
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Carbon-13 nuclear magnetic resonance (13C-NMR)
spectra were recorded on Bruker DPX300, AV400 or
AV600 spectrometers operating at 75, 100 or 125 MHz
respectively, as solutions in deuterated solvents as speci-
fied. Chemical shifts (δ), measured in parts per million
(ppm), are reported relative to the residual proton peak
in the deuterated solvent (as specified).
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Low resolution electrospray ionisation (ESI) mass spec-
tra were recorded on a Micromass Platform Electrospray
mass spectrometer (QMS-quadrupole mass spectrome-
try) as solutions in specified solvents. Spectra were rec-
orded in positive and negative modes (ESI+ and ESI-) as
specified. High resolution electrospray mass spectra
(HRMS) were recorded on a Bruker BioApex 47e Fouri-
er Transform mass spectrometer (4.7 Tesla magnet) fit-
ted with an analytical electrospray source. The mass
spectrometer was calibrated with an internal standard
solution of sodium iodide in CH3OH.
CONCLUSION
This chemistry demonstrates the power of our cross-
metathesis/aza-spirocyclisation methodology through
the total synthesis of two spirocyclic marine alkaloid
natural products, (-)-fasicularin 2 and (-)-lepadiformine
A 1. The tandem methodology allows for rapid construc-
tion of advanced intermediates in good chemical yield
and diastereoselectivity from comparatively simple
components thus facilitating the short asymmetric syn-
thesis of two complex molecular architectures. The
methodology could also be applied to the synthesis of
other spirocyclic systems such as cephalotaxine 4.
Solvents and Reagents
Dichloromethane (DCM) was supplied by Merck and
distilled over CaH2 prior to use. Diethyl ether (Et2O),
tetrahydrofuran (THF) and toluene (C6H5CH3) were
supplied by Merck and distilled over potassium prior to
use. Ethyl acetate (EtOAc), hexane, methanol (CH3OH)
and triethylamine (Et3N) were used as supplied by
Merck. All reagents were purchased from Sigma-Aldrich
and used as received, unless otherwise stated.
EXPERIMENTAL SECTION
General Experimental Information
Instrumentation
Melting points (m.p.) were determined using a Reichert
hot-stage melting point apparatus and are uncorrected.
((2R,3R)-3-Hexyloxiran-2-yl)methanol (S1). Com-
pound S1 was prepared following a modified procedure
developed by Sharpless and coworkers.22 DCM (600
mL) was added to 4 Å molecular sieves (7.00 g) and the
Infrared spectra (IR) were recorded on a Perkin-Elmer
1600 series Fourier Transform infrared spectrophotome-
ter as thin films between sodium chloride plates. IR ab-
sorptions (νmax) are reported in wavenumbers (cm-1) with
the relative intensities expressed as s (strong), m (medi-
um) or prefixed b (broad).
o
mixture was cooled to -20 C. (-)-DIPT (2.96 g, 12.7
mmol), Ti(OiPr)4 (3.00 g, 10.5 mmol) and (E)-non-2-en-
1-ol (15.0 g, 105 mmol) were added sequentially and the
t
resulting mixture was stirred for 0.5 h. BuOOH (38.3
mL, 5.50 M in heptane, 211 mmol) was added using a
syringe pump over 20 min, the internal temperature nev-
er reaching greater than -15 oC. Stirring was continued
Proton nuclear magnetic resonance (1H-NMR) spectra
were recorded on Bruker DPX300, AV400 or AV600
spectrometers operating at 300, 400 or 600 MHz respec-
tively, as solutions in deuterated solvents as specified.
Each resonance was assigned according to the following
convention: chemical shift; multiplicity; observed cou-
pling constants (J Hz); number of protons. Chemical
shifts (δ), measured in parts per million (ppm), are re-
ported relative to the residual proton peak in the solvent
o
for 4 h, at ≤-4 C, at which point the reaction mixture
was poured onto an aqueous solution (200 mL) of FeSO4
(33.0 g) and citric acid (11.0 g), and the biphasic mixture
was stirred for 2 h. The mixture was separated and the
aqueous phase extracted with ether (3x100 mL). The
combined organic extract was then stirred with aqueous
sodium hydroxide (2 M, 300 mL) at room temperature
for 2 h. The phases were again separated and the aque-
ous phase further extracted with ether (2x100 mL). The
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combined organic phase was dried (Na2SO4), filtered
and concentrated under reduced pressure. The crude res-
idue was recrystallized from hexane to yield S1 (6.50 g).
Two further crops could be obtained through concentra-
tion and crystallization (4.50 g) and (3.00 g). Total yield
of S1 as a colorless semi-solid (14.0 g, 84%). [ꢀ]ꢁꢂꢂ
assessed by integration of H NMR signals (d.r. =
22:1), and verified by synthesis of compound S4, vide
infra.
(3-Hexyloxiran-2-yl)methyl
(2S)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate (S4). Synthesised ac-
cording to the procedure for S3 from S2. H-NMR (400
1
1
+26.0 (c 0.94, CHCl3). IR νmax 3279b cm-1. H-NMR
MHz, CDCl3): δ 7.55-7.52 (m, 2H), 7.43-7.40 (m, 3H),
4.59-4.51 (m, 1H), 4.25-4.20 (m, 1H), 3.57-3.60 (m,
3H), 3.02-2.97 (m, 1H), 2.86-2.81 (m, 1H), 1.57-1.52
(m, 2H), 1.43-1.38 (m, 2H), 1.35-1.25 (m, 6H), 0.89 (t, J
= 6.8 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 166.5,
132.2, 129.9, 128.6, 127.4, 121.9 (qC-F, J = 290 Hz),
84.7 (qC-F, J = 30 Hz), 66.4, 56.9, 56.7, 54.7, 31.8, 31.6,
29.1, 25.9, 22.7, 14.2. Enantiomeric excess = 0%, as-
sessed by chiral HPLC, Daicel AS column, 10 ꢀL injec-
tion, 100% hexane → 1.5% IPA: hexane. tR = 10.22 min,
tR = 6.68 min.
(400 MHz, CDCl3): δ 3.90 (ddd, J = 16.8, 8.8, 3.6 Hz,
1H), 3.61 (ddd, J = 16.8, 8.8, 6.0 Hz, 1H), 2.97-2.90 (m,
2H), 1.83 (dd, J = 9.6, 2.0 Hz, 1H), 1.60-1.53 (m, 2H),
1.46-1.25 (m, 8H), 0.88 (t, J = 9.2 Hz, 3H) 13C-NMR
(100 MHz, CDCl3): δ 61.9, 58.6, 56.2, 31.9, 31.7, 29.2,
26.0, 22.7, 14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
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+
for C9H19O2 159.1380; Found 159.1389.
(3-Hexyloxiran-2-yl)methanol (S2). mCPBA (485 mg,
2.81 mmol) was added to a solution of (E)-non-2-en-1-ol
(200 mg, 1.41 mmol) in DCM (5 mL). After stirring for
3 h, the reaction was quenched with saturated aqueous
sodium thiosulfate (5 mL). The product was extracted
with Et2O (2x5 mL) and the combined organic extract
was washed with aqueous sodium hydroxide (2 M, 3x5
mL), dried (Na2SO4), filtered and concentrated under
reduced pressure. The crude material was purified by
column chromatography (1:1, EtOAc:hexane) to afford
S2 (80 mg, 36%) as a colorless solid. All relevant data
matches that reported for compound S1.
(R)-Nonane-1,3-diol (S5). Compound S5 was prepared
following a modified procedure developed by Sharpless
and coworkers.23 Red-Al® (7.13 mL, 22.9 mmol, 65%
w/w in toluene) in THF (50 mL) was added dropwise
(over 15 min) to a cooled (0 oC) and magnetically stirred
solution of epoxide S1 (3.30 g, 20.8 mmol) in THF (100
mL). The mixture was allowed to warm to room temper-
ature and then stirred for 16 h. The reaction was
quenched with by careful addition of MeOH (5 mL) at 0
oC. Saturated aqueous Rochelle’s salt (200 mL) and
DCM (100 mL) were added and the biphasic mixture
stirred until a clear solution was obtained (5 h). The
product was extracted with DCM (3x50 mL) and the
combined organic extract dried (Na2SO4), filtered and
concentrated under reduced pressure. The crude material
was purified by column chromatography (EtOAc) to
afford S5 (3.15 g, 95%) as a colorless oil. Contains ~2%
1,2-diol judged by integration of 13C NMR signals (ob-
servable peaks denoted by *). IR νmax 3331b cm-1.
1H-NMR (400 MHz, CDCl3): δ 3.82-3.70 (m, 4H), 3.50
(br s, 1H), 1.70-1.54 (m, 2H), 1.45-1.30 (m, 3H), 1.26-
1.21 (m, 7H), 0.84 (t, J = 7.2 Hz, 3H). 13C-NMR (100
MHz, CDCl3): δ 72.3*, 71.7, 66.7*, 61.3, 38.4, 37.8,
33.1*, 31.9, 29.4, 29.3*, 25.6*, 25.6, 22.7, 14.1. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C9H21O2+ 161.1536;
Found 161.1540.
((2R,3R)-3-Hexyloxiran-2-yl)methyl
trifluoro-2-methoxy-2-phenylpropanoate
(S)-3,3,3-
(S3).
(S)-Mosher’s acid (157 mg, 0.66 mmol), EDCI.HCl (127
mg, 0.66 mmol), and DMAP (7 mg, 0.06 mmol) were
added to DCM (2 mL) at room temperature. The epoxide
S1 (100 mg, 0.63 mmol) and triethylamine (0.25 mL,
1.89 mmol) were then added and the mixture stirred for
6 h. The reaction was quenched with aqueous HCl (1 M,
5 mL). The product was extracted with DCM (2x5 mL)
and the combined organic extract was washed with
aqueous sodium hydroxide (2 M, 3x5 mL), dried
(Na2SO4), filtered and concentrated under reduced pres-
sure. The crude material was purified by column chro-
matography (1:5 → 1:1, EtOAc : hexane) to afford S3
(89 mg, 38%) as a colorless oil. IR νmax 1755s, 1770s
cm-1. 1H-NMR (400 MHz, CDCl3): δ 7.55-7.52 (m, 2H),
7.43-7.40 (m, 3H), 4.53 (dd, J = 12.0, 3.6, 1H), 4.23 (dd,
J = 12.0, 6.4 Hz, 1H), 3.57 (q, J = 1.2 Hz, 3H), 3.00-
2.97 (m, 1H), 2.83 (td, J = 5.6, 2.0 Hz, 1H) 1.57-1.52
(m, 2H), 1.43-1.38 (m, 2H), 1.35-1.25 (m, 6H), 0.89 (t, J
= 6.8 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 166.5,
132.2, 129.9, 128.6, 127.4, 121.9 (qC-F, J = 290 Hz),
84.7 (qC-F, J = 30 Hz) 66.4, 56.9, 56.7, 54.7, 31.8, 31.6,
(R)-1-Iodononan-3-ol (5). Iodine (1.50 g, 5.93 mmol) in
MeCN:Et2O (1:2, 100 mL) was added dropwise over 3 h
to a solution of diol S5 (1.00 g, 6.24 mmol), imidazole
(467 mg, 6.86 mmol) and triphenylphosphine (2.46 g,
o
9.36 mmol) in MeCN:Et2O (1:2, 100 mL) at 0 C. The
reaction was warmed to room temperature and stirred for
16 h. The mixture was concentrated under reduced pres-
sure and Et2O (100 mL) was added. The precipitate was
filtered and washed with Et2O (2x100 mL). The com-
bined organic extract was dried (Na2SO4), filtered and
concentrated under reduced pressure. The crude material
was purified by column chromatography (50:1 → 20:1,
EtOAc : hexane) to afford 5 (1.31 g, 78%) as a colorless
19
29.1, 25.9, 22.7, 14.2. F-NMR (100 MHz, CDCl3): δ -
71.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
+
C19H26F3O4 375.1778; Found 375.1779. Enantiomeric
excess = >95%, assessed by chiral HPLC, Daicel AS
column, 10 ꢀL injection, 100% hexane → 1.5% IPA:
hexane. tR major = 9.69 min. Optical purity was also
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8
1
oil. IR νmax 3353b cm-1. H-NMR (400 MHz, CDCl3): δ
3.71 (br s, 1H), 3.33-3.28 (m, 2H), 1.99-1.83 (m, 2H),
1.45-1.41 (m, 4H), 1.38-1.26 (m, 7H), 0.88 (t, J = 7.6
Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 71.9, 40.9,
37.4, 31.9, 29.4, 25.6, 22.7, 14.2, 3.3. HRMS (ESI-TOF)
m/z: [M + H - OH2]+ Calcd for C9H18I+ 253.0448; Found
253.0448.
2-((R)-3-((tert-
Butyldimethylsilyl)oxy)nonyl)cyclohexan-1-one (S6).
Pd2(dba)3 (22 mg, 0.024 mmol) and dppf (16 mg, 0.029
mmol) in 1,4-dioxane (3 mL) were heated at 60 C for
o
0.5 h. The resulting bright orange homogenous solution
was then cooled to 13 oC and a solution of β-keto ester 8
(100 mg, 0.235 mmol) and Meldrum’s acid (85 mg,
0.589 mmol) in 1,4-dioxane (3 mL) was added via a
cannula over 2 min. The mixture was stirred at 13 oC for
2 h. The reaction was quenched by addition of hexane
(10 mL) and the resulting suspension filtered through a
short pad of silica and washed with hexane (2x10 mL).
The combined organic extract was dried (Na2SO4), fil-
tered and concentrated under reduced pressure. The
crude material was purified by column chromatography
(1:20, EtOAc: hexane) to afford S6 (62 mg, 74%) as a
colorless oil. R,R-Diastereoisomer denoted in 13C NMR
spectrum by *. 1H-NMR (400 MHz, CDCl3): δ 3.63 (ap-
parent quintet, J = 6.0 Hz, 1H), 2.40-2.35 (m, 1H), 2.30-
2.23 (m, 2H), 2.08-2.00 (m, 2H), 1.78-1.60 (m, 4H),
1.42-1.22 (m, 14H), 0.90-0.83 (m, 12H), 0.04 (s, 6H).
13C-NMR (100 MHz, CDCl3): δ 213.5, 72.7, 72.5*,
51.1, 51.0*, 42.1, 42.0*, 37.3, 37.0*, 34.7, 34.6*, 34.1,
34.0*, 32.0, 29.7, 29.7*, 28.2, 28.2*, 26.1, 26.1*, 25.6,
25.4, 25.4*, 25.1, 25.0, 24.9*, 22.8, 18.3, 14.2, -4.3.
9
(R)-tert-Butyl((1-iodononan-3-yl)oxy)dimethylsilane
(6). A solution of iodide 5 (1.25 g, 4.63 mmol) in DCM
(20 mL) was added to a magnetically stirred and cooled
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
(0 C) mixture of TBSOTf (1.16 mL, 5.09 mmol) and
Hünig’s base (1.01 mL, 5.78 mmol). The mixture was
allowed to warm to room temperature and then stirred
for 1 h. The reaction was quenched by addition of satu-
rated aqueous sodium bicarbonate (20 mL). The product
was extracted with DCM (3x50 mL) and the combined
organic extract was dried (Na2SO4), filtered and concen-
trated under reduced pressure. The crude material was
purified by column chromatography (hexane) to afford 6
(1.61 g, 91%) as a colorless oil. IR νmax 2928s, 2856m,
1462m, 1254m, 1065m, 833s cm-1. 1H-NMR (400 MHz,
CDCl3): δ 3.73-3.68 (m, 1H), 3.26-3.15 (m, 2H), 1.99-
1.92 (m, 2H), 1.44-1.41 (m, 2H), 1.32-1.22 (m, 8H),
0.92-0.82 (m, 12H), 0.10 (s, 3H), 0.09 (s, 3H). 13C-NMR
(100 MHz, CDCl3): δ 72.4, 41.1, 37.1, 32.0, 29.6, 26.0,
25.0, 22.7, 18.2, 14.2, 3.6, -4.1, -4.2. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C15H34IOSi+ 385.1418; Found
385.1413.
(S)-2-((R)-3-((tert-
Butyldimethylsilyl)oxy)nonyl)cyclohexan-1-one (9).
Compound 9 was prepared following a modified proce-
dure developed by Stoltz and coworkers.13 The reaction
was carried out in triplicate, d.r. 8:1, judged by integra-
tion of 13C NMR signals, verified by synthesis of com-
pound S6, vide infra. Pd2(dba)3 (104 mg, 0.140 mmol)
and (S)-tBuPHOX (110 mg, 0.284 mmol) in 1,4-dioxane
(30 mL) were heated at 60 C for 0.5 h. The resulting
bright orange homogenous solution was then cooled to
13 C and a solution of β-keto ester 8 (1.00 g, 2.28
mmol) and Meldrum’s acid (821 mg, 5.70 mmol) in 1,4-
Allyl 1-((R)-3-((tert-butyldimethylsilyl)oxy)nonyl)-2-
oxocyclohexane-1-carboxylate (8). To a magnetically
stirred solution of iodide 6 (8.70 g, 22.6 mmol) and allyl
2-oxocyclohexane-1-carboxylate 720 (3.91, 21.5 mmol)
in DMF (50 mL) was added Cs2CO3 (14.7 g, 45.2
o
o
mmol). The resulting suspension was warmed to 50 C
and then stirred for 16 h. The yellow reaction mixture
was quenched by addition of water (100 mL). The prod-
uct was extracted with Et2O (3x50 mL) and the com-
bined organic extract was dried (Na2SO4), filtered and
concentrated under reduced pressure. The crude material
was purified by column chromatography (hexane →
1:20, EtOAc: hexane) to afford 8 (7.34 g, 78%) as a col-
orless oil. The β-ketoester 8 was obtained as an inconse-
quential 1:1 mixture of diastereoisomers, split peaks in
the 13C NMR spectrum are arbitrarily assigned with *.
IR νmax 1734m, 1717m cm-1. 1H-NMR (400 MHz,
CDCl3): δ 5.94-5.84 (m, 1H), 5.32 (dt, J = 17.2, 1.2 Hz,
1H), 5.24 (dq, J = 10.4, 1.2 Hz, 1H), 4.61-4.58 (m, 2H),
3.61-3.57 (m, 1H), 2.50-2.39 (m, 3H), 1.98-1.91 (m,
2H), 1.63-1.43 (m, 4H), 1.34-1.31 (m, 4H), 1.29-1.21
(m, 8H), 0.90-0.81 (m, 12H), 0.05-0.00 (m, 6H).
13C-NMR (100 MHz, CDCl3): δ 207.8, 207.7*, 171.8,
171.8*, 131.7, 119.1, 72.4, 72.3*, 65.7, 60.8, 60.8*,
41.2, 41.1*, 37.1, 36.9*, 36.1, 36.0*, 32.0, 31.4, 31.4*,
30.6, 29.6, 26.0, 25.9*, 25.4, 25.3*, 22.7, 22.6, 18.2,
14.2, 1.1, -4.3, -4.3. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C25H46NaO4Si+ 461.3063; Found 461.3054.
o
dioxane (30 mL) was added via cannula over 2 min. The
mixture was stirred at 13 C for 2 h. The reaction was
o
quenched by addition of hexane (100 mL) and the result-
ing suspension filtered through a short pad of silica and
washed with hexane (2x100 mL). The combined organic
extract was dried (Na2SO4), filtered and concentrated
under reduced pressure. The crude material was purified
by column chromatography (1:20, EtOAc: hexane) to
afford 9 (663 mg, 82%) as a colorless oil. Minor R,R-
diastereoisomer denoted in the 13C NMR spectrum by
*.IR νmax 1711s cm-1. H-NMR (400 MHz, CDCl3): δ
1
3.63 (apparent quintet, J = 6.0 Hz, 1H), 2.40-2.35 (m,
1H), 2.30-2.23 (m, 2H), 2.08-2.00 (m, 2H), 1.78-1.60
(m, 4H), 1.42-1.22 (m, 14H), 0.90-0.83 (m, 12H), 0.04
(s, 6H). 13C-NMR (100 MHz, CDCl3): δ 213.5, 72.7,
72.5*, 51.2, 51.1*, 42.1, 42.0*, 37.3, 37.0*, 34.6*, 34.1,
34.0*, 32.0, 31.7*, 27.9, 28.2, 26.1, 25.8, 25.6, 25.4,
22.8, 18.3, 14.2, 14.3, -4.3, -4.3. HRMS (ESI-TOF) m/z:
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[M + H]+ Calcd for C21H43O2Si+ 355.3027; Found
with DCM (3x50 mL) and the combined organic ex-
355.3027.
tert-Butyldimethyl(((R)-1-((S)-2-
methylenecyclohexyl)nonan-3-yl)oxy)silane (S7). Bu-
tract was dried (Na2SO4), filtered and concentrated un-
der reduced pressure. The crude material was purified by
column chromatography (1:100, EtOAc: hexane) to af-
ford 11 (540 mg, 94%) as a colorless oil. IR νmax 1715s
cm-1. 1H-NMR (400 MHz, CDCl3): δ 8.06-8.03 (m, 2H),
7.47-7.41 (m, 1H), 7.44-7.41 (m, 2H), 5.13 (apparent
quintet, J = 8.4 Hz, 1H), 4.65 (br s, 1H), 4.56 (br s, 1H),
2.20-2.16 (m, 1H), 2.02-1.97 (m, 2H), 1.76-160 (m, 7H),
1.43-1.21 (m, 13H), 0.86 (t, J = 7.6 Hz, 3H). 13C-NMR
(100 MHz, CDCl3): δ 166.5, 152.7, 132.8, 131.1, 129.7,
128.4, 106.0, 75.6, 43.3, 34.8, 34.4, 34.0, 32.4, 31.9,
29.4, 28.9, 27.8, 25.5, 24.3, 22.7, 14.2. HRMS (ESI-
n
tyllithium (4.40 mL, 7.04 mmol, 1.60 M hexane) was
o
added to a stirred and cooled (0 C) solution of methyl-
triphenylphosphonium bromide (4.20 g, 11.7 mmol) in
Et2O (60 mL). After 0.5 h, the resulting yellow solution
was cooled to -25 oC and a solution of ketone 9 (2.00 g,
5.64 mmol) in Et2O (10 mL) was added over 2 min. The
mixture was then warmed to room temperature and left
to stir for 16 h. The reaction mixture was filtered
through a short pad of celite® and the filter cake washed
with Et2O (2x100 mL). The combined organic extract
was dried (Na2SO4), filtered and concentrated under re-
duced pressure. The crude material was purified by col-
umn chromatography (1:100, EtOAc: hexane) to afford
S7 (1.71 g, 86%) as a colorless oil. IR νmax 833s, 772m
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TOF) m/z: [M + H]+ Calcd for C23H35O2 343.2632;
+
Found 343.2635.
(S)-1-((S)-2-Methylenecyclohexyl)nonan-3-yl
benzoate 12 ((-)-lepadiformine A precursor). Diethyl
azodicarboxylate (0.751 mL, 4.79 mmol) was added to a
solution of PPh3 (1.26 g, 4.79 mmol) in THF (30 mL) at
1
cm-1. H-NMR (400 MHz, CDCl3): δ 4.65 (br s, 1H),
o
4.56 (br s, 1H), 3.63 (apparent quintet, J = 7.2 Hz, 1H),
2.23-2.17 (m, 1H), 2.03-1.96 (m, 2H), 1.66-1.51 (m,
3H), 1.47-1.35 (m, 5H), 1.31-1.01 (m, 12H), 0.97-0.83
0 C. The reaction was stirred for 0.5 h before (R)-1-
((S)-2-Methylenecyclohexyl)nonan-3-ol 10 (760 mg,
3.19 mmol) was added by syringe. After stirring for a
further 0.5 h, benzoic acid (585 mg, 4.79 mmol) was
added. The mixture was warmed to room temperature
and stirred for 4 h. The reaction was quenched with H2O
(50 mL) and extracted with Et2O (3 x 50 mL). The com-
bined organic extracts was washed with brine, dried
(MgSO4), filtered and concentrated under reduced pres-
sure. Diastereoselectivity of the crude product was as-
sessed by integration of the 13C signal at 75.4 ppm as
5:1; only the major signals are described below. The
crude residue was purified by column chromatography
(1:100, EtOAc:hexane) to afford S,S-12 (830 mg, 88%)
13
(m, 12H), 0.01 (s, 6H). C-NMR (100 MHz, CDCl3): δ
153.3, 105.6, 72.8, 43.6, 37.4, 35.1, 35.0, 34.1, 32.1,
29.7, 29.0, 28.0, 26.1, 25.5, 24.5, 22.8, 18.3, 14.2, 1.2, -
4.2, -4.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H45OSi+ 353.3234; Found 353.3223.
(R)-1-((S)-2-Methylenecyclohexyl)nonan-3-ol
(10).
TBAF (10.0 mL, 10.0 mmol, 1.0 M THF) was added to
a stirred and cooled (0 oC) solution of olefin S7 (1.70 g,
4.83 mmol) in THF (2 mL). After 0.5 h, the resulting
yellow solution was warmed to room temperature and
stirred for 16 h. The reaction mixture was quenched by
addition of saturated aqueous ammonium chloride (50
mL). The product was extracted with DCM (3x50 mL),
the combined organic extract was dried (Na2SO4), fil-
tered and concentrated under reduced pressure. The
crude material was purified by column chromatography
(1:50, EtOAc: hexane) to afford R,S-10 (800 mg, 78%)
as a colorless oil. IR νmax 1714s cm-1. H-NMR (400
1
MHz, CDCl3): δ 8.01-7.98 (m, 2H), 7.49-7.45 (m, 1H),
7.39-7.26 (m, 2H), 5.10 (apparent quintet, J = 8.4 Hz,
1H), 4.60 (br s, 1H), 4.52 (br s, 1H), 2.27-2.11 (m, 1H),
1.98-1.94 (m, 2H), 1.71-.41 (m, 7H), 1.41-1.21 (m,
13H), 0.80 (t, J = 7.6 Hz, 3H). 13C-NMR (100 MHz,
CDCl3): δ 166.4, 152.4, 132.7, 131.0, 129.6, 128.4,
106.0, 75.4, 43.2, 34.7, 34.4, 34.1, 32.2, 31.8, 29.3, 28.9,
27.7, 25.4, 24.2, 22.7, 14.1. HRMS (ESI-TOF) m/z: [M
1
as a colorless oil. IR νmax 2927s cm-1. H-NMR (400
MHz, CDCl3): δ 4.66 (br s, 1H), 4.57 (br s, 1H), 3.61-
3.57 (m, 1H), 2.25-2.18 (m, 1H), 2.03-1.96 (m, 2H),
1.66-1.38 (m, 10H), 1.30-1.21 (m, 11H), 0.86 (t, J = 8.0
Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 153.0, 105.8,
72.5, 43.5, 37.7, 35.6, 34.8, 34.0, 32.0, 29.5, 29.0, 28.2,
25.8, 24.3, 22.8, 14.2. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C16H31O+ 239.2369; Found 239.2370.
+
+ H]+ Calcd for C23H35O2 343.2632; Found 343.2639.
Synthesis of prenyl cross-partner (15)
Methyl
(S)-2-((tert-butoxycarbonyl)amino)pent-4-
enoate (S8). Potassium carbonate (4.81 g, 34.9 mmol)
was added to a stirred solution of N-Boc-allylglycine
(2.50 g, 11.6 mmol) in DMF (50 mL) at room tempera-
ture. Iodomethane (2.17 mL, 34.9 mmol) was then added
to the resulting suspension and the reaction mixture was
stirred for 16 h at room temperature. The reaction mix-
ture was diluted with Et2O (50 mL) and washed with
water (2 x 50 mL), 10% aqueous CuSO4 (50 mL) and
brine (50 mL). The organic layer was then dried
(MgSO4), filtered and concentrated under reduced pres-
sure. The residue was further purified by silica column
(R)-1-((S)-2-Methylenecyclohexyl)nonan-3-yl
benzoate ((-)-fasicularin precursor) (11). Benzoyl
chloride (0.21 mL, 1.84 mmol) was added dropwise to a
stirred and cooled (0 oC) solution of alcohol 10 (400 mg,
1.68 mmol) and pyridine (0.20 mL, 2.51 mmol) in DCM
(2.5 mL). After 0.5 h, the resulting solution was warmed
to room temperature and stirred for 16 h. The reaction
mixture was quenched by addition of saturated aqueous
ammonium chloride (50 mL). The product was extracted
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chromatography (EtOAc: hexane, 1:4) to give S8 as a
HRMS (ESI-TOF) m/z: [[M - Boc + H]+ Calcd for
colourless oil (2.55 g, 96%).24 IR νmax 3369w, 2979w,
C12H18NO+ 192.1383; Found 192.1378.
(S)-N-(1-(Benzyloxy)pent-4-en-2-yl)-4-
1
1701s cm-1. H-NMR (400 MHz, CDCl3): δ 5.73-5.63
(m, 1H), 5.14-5.10 (m, 2H), 5.03 (d, J = 6.0 Hz, 1H),
4.36 (dt, J = 6.4, 6.0 Hz, 1H), 3.72 (s, 3H), 2.55-2.42 (m,
2H), 1.42 (s, 9H). 13C-NMR (100 MHz, CDCl3): δ
172.5, 155.2, 132.4, 118.9, 79.7, 52.9, 52.1, 36.7, 28.2.
methylbenzenesulfonamide (14). Trifluoroacetic acid
(5.0 mL) was added to a solution of ether S9 (1.00 g,
3.43 mmol) in DCM (5.0 mL). The resulting mixture
was stirred for 2 h at room temperature. The solution
was then concentrated under reduced pressure. Residual
TFA was co-evaporated with several portions of DCM.
The residue was then dissolved in fresh DCM (50 mL)
and cooled to 0 oC. Triethylamine (1.20 mL, 8.58 mmol)
and p-TsCl (719 mg, 3.77 mmol) were then added to the
solution and the mixture was warmed to room tempera-
ture and stirred for 4 h. The reaction mixture was
washed with water (2 x 50 mL), 10% aqueous CuSO4
(50 mL) and brine (50 mL), dried (MgSO4), filtered and
concentrated under reduced pressure. The residue was
purified by silica column chromatography (EtOAc: hex-
ane, 1:3) to give 14 as a colourless solid (900 mg, 76%),
9
tert-Butyl
(S)-(1-hydroxypent-4-en-2-yl)carbamate
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(13). A solution of ester S8 (2.00 g, 8.73 mmol) in THF
(90 mL) was added to a two-neck RBF equipped with a
stir-bar and an efficient reflux condenser. Sodium boro-
hydride (663 mg, 17.5 mmol) was added to the stirred
solution at room temperature and the resulting suspen-
o
sion was heated to 70 C. Methanol (10 mL) was added
dropwise to the heated suspension via a syringe and the
resulting mixture was heated to reflux for 3 h. The reac-
tion mixture was then cooled to room temperature and
concentrated under reduced pressure. Diethyl ether was
added to the residue and the resulting suspension was
filtered. The filtrate was concentrated under reduced
pressure and the residue purified by silica column chro-
matography (EtOAc: hexane, 1:1) to afford 13 as a col-
ourless oil (1.44 g, 82%). IR νmax 3355m, 2979m,
m.p. 50.7-51.3 C. IR νmax 3307m cm-1. H-NMR (600
MHz, CDCl3): δ 7.75 (d, J = 7.8 Hz, 2H), 7.34-7.29 (m,
3H), 7.24 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 6.6 Hz, 2H),
5.62-5.55 (m, 1H), 5.05 (d, J = 7.8 Hz, 1H), 5.02-4.99
(m, 2H), 4.37 (s, 2H), 3.44-3.39 (m, 2H), 3.29-3.26 (m,
1H), 2.40 (s, 3H), 2.33-2.26 (m, 2H). 13C-NMR (150
MHz, CDCl3): δ 143.2, 137.9, 137.8, 133.6, 129.6,
128.4, 127.8, 127.6, 127.1, 118.5, 73.1, 70.7, 53.0, 36.7,
21.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H24NO3S+ 346.1471; Found 346.1470.
o
1
1
2933m, 1683s cm-1. H-NMR (400 MHz, CDCl3): δ
5.81-5.70 (m, 1H), 5.11-5.05 (m, 2H), 4.85 (br s, 1H),
3.65-3.53 (m, 3H), 3.15 (br s, 1H), 2.32-2.17 (m, 2H),
1.41 (9H). 13C-NMR (100 MHz, CDCl3): δ 156.4, 134.4,
117.8, 79.6, 64.6, 52.1, 36.0, 28.4. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C5H12NO+ 102.0913; Found
102.0907.
(S)-N-(1-(Benzyloxy)-5-methylhex-4-en-2-yl)-4-
methylbenzenesulfonamide (15). A solution of tosylate
14 (900 mg, 2.61 mmol) in DCM (10 mL) was added to
a flame-dried pressure tube under a nitrogen atmosphere.
The solution was frozen with liquid nitrogen and HGII
(81.7 mg, 0.130 mmol) was added under a flow of nitro-
gen. Isobutylene (5 mL) was condensed into the reaction
mixture and the vessel was sealed, warmed to room
temperature and then lowered into an oil bath preheated
to 40 C. The reaction was stirred for 16 h at 40 C,
cooled to room temperature and the excess isobutylene
carefully vented from the vessel. The remaining solution
was quenched with ethyl vinyl ether (1 mL) and concen-
trated under reduced pressure. The residue was purified
by silica column chromatography (EtOAc: hexane, 3:1)
to afford 15 (810 g, 83%) as a viscous oil which solidi-
fied on standing, m.p. 56.8-58.1 oC. IR νmax 3311m cm-1.
1H-NMR (600 MHz, CDCl3): δ 7.75 (dt, J = 7.8, 1.2 Hz,
2H), 7.32 (tt, J = 7.2, 1.2 Hz, 2H), 7.30-7.27 (m, 1H),
7.24 (dd, J = 7.2, 1.2 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H),
5.06 (d, J = 7.8 Hz, 1H), 4.88 (tt, J = 7.2, 1.2 Hz, 1H),
4.38 (s, 2H), 3.41 (ABX, J = 9.0, 4.2 Hz, 1H), 3.37-3.32
(m, 1H), 3.29 (ABX, J = 9.0, 4.8 Hz, 1H), 2.39 (s, 3H),
2.29-2.17 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H). 13C-NMR
(150 MHz, CDCl3): δ 143.1, 137.9, 137.9, 135.1, 129.5,
128.3, 127.6, 127.6, 127.1, 119.2, 73.1, 70.9, 53.6, 30.8,
tert-Butyl
(S)-(1-(benzyloxy)pent-4-en-2-
yl)carbamate (S9). A solution of alcohol 13 (1.40 g,
6.96 mmol) in DMF (100 mL) was added to a flame-
dried Schlenk flask equipped with an efficient stir-bar.
The solution was cooled to -20 oC in an ice bath contain-
ing 50% CaCl2. Sodium hydride (351 mg, 14.6 mmol)
was added in small portions to the solution and the mix-
ture was stirred for 1 h at -20 oC. Benzyl bromide (0.827
mL, 6.96 mmol) was then added dropwise via syringe
and the resulting mixture was allowed to warm to room
temperature. After complete consumption of the alcohol,
the reaction was quenched with saturated aqueous
NH4Cl solution (50 mL) and extracted with Et2O (3 x 50
mL). The combined organic extract was washed with
water (2 x 50 mL), 10% aqueous CuSO4 (50 mL) and
brine (50 mL), dried (MgSO4), filtered and concentrated
under reduced pressure. The residue was purified by
silica column chromatography (EtOAc: hexane, 1:3) to
give S9 as a colourless oil (1.52 g, 75%). IR νmax 1696s
cm-1. 1H-NMR (400 MHz, CDCl3): δ 7.37-7.27 (m, 5H),
5.82-5.72 (m, 1H), 5.11-5.04 (m, 2H), 4.75 (br s, 1H),
4.53 (ABq, J = 16.8, 12.0 Hz, 2H), 3.82 (br m, 1H),
o
o
13
3.55-3.45 (m, 2H), 2.44-2.28 (m, 2H), 1.46 (s, 9H). C-
NMR (100 MHz, CDCl3): δ 155.6, 138.3, 134.7, 128.5,
127.8, 127.7, 117.8, 79.4, 73.4, 71.3, 50.1, 36.6, 28.6.
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25.7, 21.5, 17.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
139.5, 138.4, 132.8, 131.2, 129.7, 129.5, 128.52,
for C21H28NO3S+ 374.1784; Found 374.1782.
128.50, 128.4, 127.9, 127.7, 75.9, 75.6, 73.4, 71.8, 59.9,
45.1, 34.6, 34.3, 32.8, 31.9, 30.1, 29.5, 26.5, 25.7, 25.6,
25.5, 25.4, 25.0, 22.8, 21.6, 14.2. HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C40H53NNaO5S+ 682.3537;
Found 682.3532.
General Procedure for Sterically Hindered Cross-
Metathesis. Prenyl substrate (1.00 equiv.) and meth-
ylene substrate (2.00 equiv.) were dried by co-
evaporation with toluene (3x2 mL) in a pressure tube.
HGII (25 mol%) was added, followed by toluene (0.50
M) and the mixture placed under partial vacuum. The
(R)-1-((2S,5S,6S)-2-((Benzyloxy)methyl)-1-
azaspiro[4.5]decan-6-yl)nonan-3-ol (20). Sodium
amalgam (104 mg, 4.55 mmol, 10% w/w) added to the
spirocycle 18 (300 mg, 0.455 mmol) in methanol (10
mL). After heating at reflux for 16 h, the mixture was
cooled and filtered and washed (2x10 mL) through glass
filter paper. The methanol was removed under reduced
pressure and the residue was purified by column chro-
matography (CHCl3 → 200:9:1, CHCl3:MeOH:NH3) to
afford 20 (150 mg, 82%) as a colorless oil. [ꢀ]ꢂꢁꢂ -37.3
(c 1.20, CHCl3, lit.9k [ꢀ]ꢁꢂꢃ-38.4o, CHCl3). IR νmax 3385b,
9
o
resulting green mixture was heated at 120 C for 48 h.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
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32
33
34
35
36
37
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39
40
41
42
43
44
45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
After cooling, the solvents were removed under reduced
pressure, ethyl vinyl ether (1 x reaction volume) and
EtOAc (1 x reaction volume) were added and the mix-
ture was stirred at room temperature for 1 h. The sol-
vents were then removed under reduced pressure and the
residue purified by column chromatography (1:20 →
1:10 → 1:5, EtOAc: hexane).
Total Synthesis of (-)-Fasicularin (2).
2925s, 2855m cm-1. H-NMR (400 MHz, CDCl3): δ
1
(R)-1-((S,E)-2-((S)-4-(Benzyloxy)-3-((4-
7.30-1.20 (m, 5H), 4.49 (ABq, J = 12.0 Hz, 1H), 4.41
(ABq, J = 12.0 Hz, 1H), 4.25-3.80 (br s, 2H), 3.67-3.65
(m, 1H), 3.51 (ABX, J = 9.2, 4.0 Hz, 1H), 3.42-3.37 (m,
1H), 3.37-3.42 (m, 1H), 1.78-1.74 (m, 1H), 1.70-1.54
(m, 8H), 1.44-1.15 (m, 16H), 1.02-0.91 (m, 2H), 0.82 (t,
methylphenyl)sulfonamido)butylidene)cyclohexyl)no
nan-3-yl benzoate (16). Synthesised according to gen-
eral procedure for sterically hindered cross-metathesis:
Table 1, Entry 7: Prenyl substrate 15 = 1.64 mmol, yield
of 16 (756 mg, 70%), pale yellow oil. IR νmax 3284b,
13
1
1711s cm-1. H-NMR (400 MHz, CDCl3): δ 8.04-8.02
J = 6.4 Hz, 3H). C-NMR (100 MHz, CDCl3): δ 138.4,
128.4, 127.6, 127.6, 73.1, 71.5, 68.6, 67.0, 59.3, 45.1,
40.1, 37.8, 34.8, 32.0, 30.9, 29.7, 29.2, 28.7, 26.2, 26.1,
25.7, 24.6, 22.7, 14.2. HRMS (ESI-TOF) m/z: [M + H]+
(m, 2H), 7.71-7.69 (m, 2H), 7.56-7.52 (m, 1H), 7.45-
7.41 (m, 2H), 7.34-7.28 (m, 3H), 7.24-7.19 (m, 5H),
5.12-5.04 (m, 1H), 4.84 (t, J = 7.2 Hz, 1H), 4.726 (d, J =
7.2 Hz, 1H), 4.32 (br s, 2H), 3.37-3.34 (m, 1H), 3.33-
3.26 (m, 1H), 3.26-3.22 (m, 1H), 2.40 (s, 3H), 2.25-2.22
(m, 2H), 2.00-1.95 (m, 2H), 1.94-1.87 (m, 1H), 1.62-
1.44 (m, 7H), 1.31-1.14 (m, 12H), 0.86 (t, J = 6.8 Hz,
3H). 13C-NMR (100 MHz, CDCl3): δ 166.5, 145.6,
143.2, 138.1, 137.9, 132.8, 130.9, 129.7, 129.6, 128.5,
128.4, 127.8, 127.7, 127.2, 115.7, 75.3, 73.3, 70.6, 53.9,
44.7, 34.3, 33.6, 32.5, 31.8, 30.1, 29.4, 28.2, 27.5, 26.4,
25.5, 23.4, 22.7, 21.6, 14.2. HRMS (ESI-TOF) m/z: [M
+ Na]+ Calcd for C40H53NNaO5S+ 682.3537; Found
682.3540.
+
Calcd for C26H44NO2 402.3367; Found 402.3365.
(3S,5,7aS,11aS)-3-((Benzyloxy)methyl)-5-
hexyldecahydro-1H-pyrrolo[2,1-j]quinoline
(22).
Compound 22 was prepared following a modified pro-
cedure developed by the Kibayashi/Zhao group and
coworkers.9k,9i The amino alcohol 20 (20 mg, 0.05
mmol), PPh3 (40 mg, 0.15 mmol), DMAP (2.0 mg, 0.02
mol) and NEt3 (0.02 mL, 0.15 mmol) were dissolved in
o
DCM (2 mL) at 0 C. CBr4 (50 mg, 0.15 mmol) was
added in one portion and the solution was warmed to
room temperature and stirred for 16 h. The reaction mix-
ture was quenched by addition of saturated aqueous so-
dium bicarbonate (5 mL). The product was then extract-
ed with DCM (3x5 mL). The combined organic extract
was dried (K2CO3), filtered and concentrated under re-
duced pressure. The crude material was purified by col-
(R)-1-((2S,5S,6S)-2-((Benzyloxy)methyl)-1-tosyl-1-
azaspiro[4.5]decan-6-yl)nonan-3-yl benzoate (18).
Freshly distilled TFA (2.0 mL) was added to a solution
of olefin 16 (400 mg, 0.607 mmol) in CDCl3 (2.0 mL).
The reaction vessel was sealed and the mixture stirred at
room temperature for 48 h. The solution was then con-
centrated under reduced pressure and the residue puri-
fied by silica column chromatography (EtOAc: hexane,
1:4) to give 18 as a colourless oil (268 mg, 67%). IR
νmax 3255w, 1714s cm-1. 1H-NMR (300 MHz, CDCl3): δ
8.07 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.54
(t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 7.35-7.26
(m, 7H), 7.21 (d, J = 8.0 Hz, 2H), 5.13 (apparent quintet,
J = 6.0 Hz, 1H), 4.43 (ABq, J = 24.4 & 6.0 Hz, 2H),
3.91-3.86 (m, 1H), 3.69-3.66 (m, 1H), 3.32 (t, J = 9.6
Hz, 1H), 2.39 (s, 3H), 2.28 (t, J = 9.6 Hz, 1H), 2.11 (t, J
= 9.6 Hz, 1H), 1.86-1.26 (m, 23H), 0.86 (t, J = 6.4 Hz,
3H). 13C-NMR (150 MHz, CDCl3): δ 166.5, 142.8,
umn
chromatography
(CHCl3
→
200:9:1,
CHCl3:MeOH:NH3) to afford 22 (16 mg, 84%) as a col-
orless oil. IR νmax 2925s, 2857m cm-1. H-NMR (400
1
MHz, 5% KOH d4-MeOD): δ 7.35-7.25 (m, 5H), 4.53
(ABq, J = 14.8, 12.4 Hz, 1H), 4.49 (ABq, J = 14.8, 12.4
Hz, 1H), 3.61 (dd, J = 9.2, 6.4 Hz, 1H), 3.38 (dd, J =
9.2, 7.6 Hz, 1H), 3.14 (apparent quintet, J = 8.0 Hz, 1H),
2.12-2.16 (m, 1H), 2.13-2.09 (m, 1H), 1.89-1.83 (m,
1H), 1.83-1.78 (m, 1H), 1.74-1.64 (m, 4H), 1.62-1.54
(m, 3H), 1.48-1.37 (m, 2H), 1.34-1.09 (m, 17H), 0.89 (t,
J = 4.0 Hz, 3H). 13C-NMR (100 MHz, 5% KOH d4-
MeOD): δ 139.9, 129.3, 128.7, 128.6, 78.0, 74.0, 69.7,
66.5, 64.4, 45.2, 38.6, 37.5, 33.0, 32.8, 32.5, 30.7, 27.8,
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27.7, 27.4, 25.2, 24.5, 23.7, 22.7, 14.5. HRMS (ESI-
24.0, 22.9, 22.7, 19.3, 14.2. HRMS (ESI-TOF) m/z:
TOF) m/z: [M + H]+ Calcd for C26H42NO+ 384.3266;
[M + H]+ Calcd for C20H35N2S+ 335.2515; Found
335.2514.
Found 384.3265.
Total Synthesis of (-)-lepadiformine A (1)
5
6
7
8
9
((3S,5S,7aS,11aS)-5-Hexyldecahydro-1H-pyrrolo[2,1-
j]quinolin-3-yl)methanol (23). Compound 23 was pre-
pared following a modified procedure developed by
Kibayashi group and coworkers.9k Tricyclic amine 22
(10 mg, 26.1 ꢀmol) and Pd(OH)2 (10 mg, 1:1 w/w) were
added to MeOH (5 mL) at room temperature. Hydrogen
was introduced through three purge/refill cycles using a
three way stopcock, partial vacuum and a balloon. The
reaction mixture was stirred at room temperature for 16
h, at which point the mixture was filtered and washed
(2x2 mL) through glass filter paper with methanol. The
solvent was removed under reduced pressure to afford
23 (6.0 mg, 80%) as a colorless oil that required no fur-
(S)-1-((S,E)-2-((S)-4-(Benzyloxy)-3-((4-
methylphenyl)sulfonamido)butylidene)cyclohexyl)no
nan-3-yl benzoate (17). Synthesised according to gen-
eral procedure for sterically hindered cross-metathesis:
Table 1, Entry 6: Prenyl substrate 15 = 0.58 mmol, yield
of 17 = 67% (255 mg), pale yellow oil as a mixture of
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15
16
17
18
19
20
21
22
23
24
25
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28
29
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31
32
33
34
35
36
37
38
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41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
E/Z isomers. IR νmax 3284b, 1713s cm-1. H-NMR (400
MHz, CDCl3): δ 8.06-7.02 (m, 2H), 7.73-7.71 (m, 2H),
7.55-7.52 (m, 1H), 7.45-7.41 (m, 2H), 7.30-7.29 (m,
3H), 7.26-7.219 (m, 5H), 5.10-5.08 (m, 1H), 4.93-4.84
(m, 2H), 4.39-4.32 (m, 2H), 3.37-3.32 (m, H3), 2.40 (br
s, 3H), 2.27-2.10 (m, 2H), 2.00-1.92 (m, 3H), 1.67-1.48
(m, 9H), 1.33-1.27 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H).
13C-NMR (100 MHz, CDCl3): δ 166.7, 145.9, 145.8*,
143.5, 143.4*, 138.4, 138.3*, 138.2, 138.1*, 133.0,
131.1, 129.9, 128.7, 128.7, 127.0, 127.9, 127.9, 127.4,
119.5, 115.8, 115.7*, 75.5, 73.5, 70.8, 70.8*, 54.1,
53.9*, 44.8, 44.8*, 34.5, 34.4*, 34.2, 33.9*, 32.1, 31.2,
30.3, 30.1*, 29.6, 28.5, 28.5*, 26.1, 25.7, 23.7, 23.6*,
22.9, 21.8, 14.4. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C40H53NNaO5S+ 682.3537; Found 682.3538.
1
ther purification. IR νmax 3396b cm-1. H-NMR (400
MHz, 5% KOH d4-MeOD): δ 3.67 (dd, J = 10.4, 6.0 Hz,
1H), 3.42 (dd, J = 10.4, 8.8 Hz, 1H), 3.06-3.03 (m, 1H),
2.21-2.20 (m, 1H,), 2.10 (dt, J = 12.4, 8.4 Hz, 1H), 1.89
(ABX, 12.0, 3.2 Hz, 1H), 1.83 (ABX, 12.0, 7.6 Hz, 1H),
1.72-1.66 (m, 4H), 1.62-1.55 (m 3H), 1.50-1.43 (m, 2H),
1.34-1.12 (m, 16H), 0.90 (t, J = 6.4 Hz, 3H). 13C-NMR
(100 MHz, 5% KOH d4-MeOD): δ 69.4, 69.1, 68.5,
64.1, 45.2, 38.9, 37.6, 33.1, 32.5, 32.4, 30.7, 27.9, 27.4,
27.2, 27.2, 25.4, 24.5, 23.7, 14.4. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C19H36NO+ 294.2791; Found
294.2788.
(S)-1-((2S,5S,6S)-2-((Benzyloxy)methyl)-1-tosyl-1-
azaspiro[4.5]decan-6-yl)nonan-3-yl benzoate (19).
Freshly distilled TFA (2.5 mL) was added to a solution
of olefin 17 (255 mg, 0.607 mmol) in CDCl3 (2.5 mL).
The reaction vessel was sealed and the mixture stirred at
room temperature for 16 h. The solution was then con-
centrated under reduced pressure and the residue puri-
fied by silica column chromatography (EtOAc: hexane,
1:4) to give 19 as a colourless oil (181 mg, 71%). IR
νmax 3308w, 1632s cm-1. 1H-NMR (400 MHz, CDCl3): δ
8.06-7.98 (m, 2H), 7.75-7.70 (m, 2H), 7.57-7.53 (m,
1H), 7.45-7.42 (m, 2H), 7.32-7.26 (m, 6H), 7.21 (br d, J
= 8.0 Hz, 2H), 4.88 (apparent quintet, J = 6.4 Hz, 1H),
4.14 (br s, 2H), 3.85-3.82 (m, 1H), 3.64 (dd, J = 9.6, 3.2
Hz, 1H), 3.35 (t, J = 9.6 Hz, 1H), 2.50 (dt, J = 12.0, 2.8
Hz, 1H), 2.37 (s, 3H), 2.28 (br t, J = 12.0 Hz, 1H), 2.06
(app quartet, J = 7.6 Hz, 1H), 1.91-1.88 (m, 1H), 1.84-
1.78 (m, 1H), 1.72-1.61 (m, 7H), 1.40-1.16 (m, 14H),
0.86 (t, J = 6.8 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ
166.5, 142.9, 139.9, 138.5, 132.8, 131.1, 129.7, 128.82,
128.82, 128.7, 128.5, 127.6, 127.3, 75.6, 75.5, 73.3,
71.8, 60.8, 42.6, 42.5, 33.9, 32.4, 31.9, 31.7, 30.2, 29.4,
27.6, 26.9, 25.6, 25.2, 24.9, 22.7, 21.6, 14.2. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C40H53NNaO5S+
682.3537; Found 682.3534.
(-)-Fasicularin (2). Compound 2 was prepared follow-
ing a modified procedure developed by Kibayashi and
coworkers.9k DEAD (16.0 ꢀL, 0.102 mmol), tri-
phenylphosphine (18.0 mg, 0.102 mmol) and ammoni-
um thiocyanate (10.0 mg, 0.128 mmol) were added to
DCM (1 mL) and stirred at room temperature for 0.5 h.
Tricyclic amino alcohol 23 (15.0 mg, 0.05 mmol) in
DCM (1 mL) was added and the solution stirred at room
temperature for 16 h. The reaction mixture was
quenched by addition of saturated aqueous sodium bi-
carbonate (2 mL). The product was then extracted with
DCM (3x2 mL). The combined organic extract was
dried (K2CO3), filtered and concentrated under reduced
pressure. The crude material was purified by column
chromatography (20:1, hexane: EtOAc) to afford 2 (7.0
mg, 41%) as a colorless oil. [ꢀ]ꢂꢁꢂ -4.0 (c 0.10, MeOH,
lit9k [ꢀ]ꢁꢂꢄ -4.4o (c 0.47, MeOH). IR νmax 2924s, 2857m,
1
2361m, 2156m, 1464m cm-1. H-NMR (400 MHz, d5-
pyridine): δ 3.58-3.52 (m, 1H), 3.38 (dd, J = 14.4, 12.0
Hz, 1H), 3.28 (ddd, J = 14.4, 4.4, 2.0 Hz, 1H), 2.91 (ddt,
J = 12.0, 6.0, 3.1 Hz, 1H), 2.52 (d, J = 12.0 Hz, 1H),
1.97-1.91 (m, 1H), 1.86 (dd, J = 12.0, 4.4 Hz, 1H), 1.83-
1.74 (m, 1H), 1.89-1.83 (m, 1H), 1.83-1.78 (m, 1H),
1.58-0.96 (m, 21H), 0.84 (t, J = 6.8 Hz, 3H). 13C-NMR
(100 MHz, d5-pyridine): δ 111.6, 56.3, 52.3, 46.5, 46.1,
40.2, 34.3, 34.1, 32.3, 32.1, 30.2, 29.5, 27.7, 27.2, 26.3,
(S)-1-((2S,5S,6S)-2-((Benzyloxy)methyl)-1-
azaspiro[4.5]decan-6-yl)nonan-3-ol (21). Sodium
amalgam (126 mg, 5.49 mmol, 10% w/w) added to the
spirocycle 19 (181 mg, 0.274 mmol) in methanol (10
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mL). After heating at reflux for 4 h, the mixture was
tial vacuum and a balloon. The reaction mixture was
cooled and filtered and washed (2x10 mL) through glass
filter paper. The methanol was removed under reduced
pressure and the residue was purified by column chro-
matography (CHCl3 → 200:9:1, CHCl3:MeOH:NH3) to
afford 21 (85 mg, 77%) as a colorless oil. [ꢀ]ꢂꢁꢂ -30.2 (c
0.96, MeOH, lit.9k [ꢀ]ꢁꢂꢅ -33.2o (c 0.98, MeOH)). IR νmax
stirred at room temperature for 16 h, at which point the
mixture was filtered and washed with MeOH (2x2 mL)
through glass filter paper. The solvent was removed un-
der reduced pressure and the residue was purified by
column chromatography (CHCl3
CHCl3:MeOH:NH3) to afford crude 1 (1.8 mg, 24%) as
a colorless oil.21 [ꢀ]ꢁꢂꢂ -5.2 (c 0.08, MeOH, lit.9k [ꢀ]ꢁꢂꢇ
15.0 (c 0.37, MeOH)). IR νmax 3676b, 2459b, 2211m,
1465m, 1120s, 973
→
200:9:1,
1
3402b, 2924m cm-1. H-NMR (400 MHz, CDCl3): δ
-
9
7.35-7.26 (m, 5H), 4.54 (ABq, J = 12.0 Hz, 1H), 4.48
(ABq, J = 12.0 Hz, 1H), 3.62-3.58 (m, 1H), 3.56 (ABX,
J = 12.0, 4.8 Hz, 1H), 3.46 (ABX, J = 12.0, 4.6 Hz, 1H),
3.46-3.18 (m, 1H), 2.82 (br s, 2H), 1.87-1.81 (m, 1H),
1.72-1.57 (m, 8H), 1.51-1.37 (m, 5H), 1.32-1.83 (m,
11H), 1.10-1.01 (m, 1H), 099-0.81 (m 1H), 0.87 (t, J =
6.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 138.4,
128.5, 128.1, 127.7, 73.7, 73.3, 71.9, 67.2, 59.6, 48.1,
40.0, 37.0, 36.2, 32.0, 30.5, 29.9, 29.8, 29.5, 28.7, 27.8,
25.9, 25.3, 22.8, 14.2. HRMS (ESI-TOF) m/z: [M + H]+
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
s
cm-1. H-NMR (400 MHz, 5% KOH d4-MeOD): δ 2.19
(app triplet, J = 7.6 Hz, 2H), 2.04 (br q, J = 4.8 Hz, 3H),
1.62-1.46 (m, 8H), 1.60-1.24 (m, 18H), 1.09 (dq, J =
12.5, 3.2 Hz, 1H), 0.90 (t, J = 6.4 Hz, 3H). 13C-NMR
(100 MHz, 5% KOH d4-MeOD): δ 69.2, 67.6, 60.5,
55.2, 41.7, 38.8, 39.1, 34.9, 33.2, 31.5, 30.1, 30.4, 29.2,
27.1, 26.7, 25.0, 24.6, 23.0, 14.0. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C19H36NO+ 294.2791; Found
294.2796.
1
+
Calcd for C26H44NO2 402.3367; Found 402.3361.
(3S,5R,7aS,11aS)-3-((Benzyloxy)methyl)-5-
hexyldecahydro-1H-pyrrolo[2,1-j]quinoline
(24).
ASSOCIATED CONTENT
Supporting Information
Compound 24 was prepared following a modified pro-
cedure developed by Kibayashi/Zhao group and
coworkers.9k,9i The amino alcohol 21 (20 mg, 0.05
mmol), PPh3 (65 mg, 0.25 mmol), DMAP (2.0 mg, 0.02
mol) and NEt3 (70.0 ꢀL, 0.500 mmol) were dissolved in
1H and 13C{1H} NMR spectra of compounds S1, S3-9, 1, 2, 5, 6,
8-24. This material is available free of charge on the ACS Publi-
cations website.
o
DCM (2 mL) at 0 C. CBr4 (83 mg, 0.25 mmol) was
AUTHOR INFORMATION
Corresponding Author
added in one portion and the solution was warmed to
room temperature and stirred for 16 h. The reaction mix-
ture was quenched by addition of saturated aqueous so-
dium bicarbonate (5 mL). The product was then extract-
ed with DCM (3x5 mL). The combined organic extract
was dried (K2CO3), filtered and concentrated under re-
duced pressure. The crude material was purified by col-
* School of Chemistry, Monash University, Clayton, 3800, Victo-
ria, Australia
Andrea.Robinson@monash.edu. Fax: 61 03 9905 4597; Tel: 61
03 9905 4553
umn
chromatography
(CHCl3
→
200:9:1,
Author Contributions
CHCl3:MeOH:NH3) to afford 24 (15 mg, 78%) as a col-
orless oil. [ꢀ]ꢂꢁꢆ -22.3 (c 0.81, MeOH, lit.9k -22.0 (c 0.71,
MeOH)). IR νmax 2927s, 2859m, 1467m, 1116m cm-1.
1H-NMR (400 MHz, 5% KOH d4-MeOD): δ 7.32-7.24
(m, 5H), 4.52 (ABq, J = 24.4, 12.4 Hz, 1H), 4.45 (ABq,
J = 24.4, 12.4 Hz, 1H), 3.51 (dd, J = 8.8, 4.0 Hz, 1H),
3.28-3.25 (m, 1H), 3.11 (app triplet, J = 8.8 Hz, 1H),
3.00 (br t, J = 7.6 Hz, 1H), 2.03-2.00 (m, 1H), 1.72-1.66
(m, 6H), 1.59-1.41 (m, 6H), 1.28-1.16 (m, 14H), 1.10-
1.02 (m, 2H), 0.87 (t, J = 6.8 Hz, 3H). 13C-NMR (100
MHz, 5% KOH d4-MeOD): δ 139.5, 129.0, 128.4,
128.2, 77.7, 73.6, 68.9, 58.4, 54.9, 41.3, 38.6, 34.7, 32.6,
31.7, 30.3, 29.7, 28.5, 28.3, 27.1, 25.0, 24.7, 22.3, 22.8,
14.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C26H42NO+ 384.3266; Found 384.3264.
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script. ‡These authors contributed equally.
ACKNOWLEDGMENT
The authors wish to acknowledge the financial support of the
Australian Research Council (DP120104169) and the award of a
postgraduate research award to Z.J.W.
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19
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10
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11
Made in three steps from commercially available trans-2-nonen-
1-ol.
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